WO2006104141A1

WO2006104141A1 - 3-propenylcephem derivative

Info

Publication number: WO2006104141A1
Application number: PCT/JP2006/306280
Authority: WO
Inventors: Koji Ishikura; Kenji Yamawaki; Katsuki Yokoo; Shuji Yonezawa; Makoto Kii
Original assignee: Shionogi & Co., Ltd.
Priority date: 2005-03-29
Filing date: 2006-03-28
Publication date: 2006-10-05
Also published as: TW200637559A; JP3928086B2; JPWO2006104141A1

Abstract

A compound represented by the formula: (I) wherein Acyl represents an acyl group which can be used in the field of β-lactams; T represents S, SO or O; the group represented by the formula: (Q) represents a heterocyclic group which may be substituted by a substituent other than '-Y1-Ar1-Y2-R1' and has a cationic N atom in the ring; Y1 and Y2 independently represent 1) a single bond, 2) a heteroatom-containing group selected from the group consisting of -NR2, -CO-, -NR2CO-, -CONR2-, -NR2CONR3-, -NR2SO2-, -SO2NR2-, -NR2SO2NR3- (where R2 and R3 independently represent a hydrogen or a lower alkly), -O-, -S-, -SO- and -SO2-, or 3) a lower alkylene or lower alkenylene group which may be bound through a heteroatom-containing group as listed in the item 2); Ar1 represents a single bond, a carbocyclic group which may be substituted or a haterocyclic group which may be substituted; R1 represents -CONHCN, -C(OH)=NCN or -COOH or a biologically equivalent acidic group thereof; and the wavy line means a cis, trans or a mixture thereof.

Description

Specification

3-Propenyl cefene derivatives

Technical field

[0001] The present invention relates to a broad-spectrum compound exhibiting a broad antibacterial spectrum against various pathogenic bacteria and a pharmaceutical composition containing the same.

Background art

[0002] In recent years, compounds having a quaternary ammonium group on the 3rd side chain of the Cefme skeleton have attracted attention as a broad-spectrum cephem compound for injection having strong antibacterial activity against Gram-positive and Gram-negative bacteria Has been. Among them, cefmes having 3-propenyl type side chains are known (eg, patent documents:! To 8).

Patent document 1 discloses the following compounds.

[Chemical 1]

[Chemical 2]

Is the fourth grade Ammonio group (Example:

Etc.) Patent Document 2 discloses the following compounds.

R1-R3: Lower alkyl

R4: Re, R, 5-membered heterocyclic lower alkyl having substituent

(Concrete example)

[Chemical 5]

Patent Document 3 discloses the following compounds.

[Chemical 6]

A: Cyclic or acyclic ammonio group

Examples of cyclic ammonio groups:

[Chemical 7]

Patent Document 4 discloses the following compounds.

[Chemical 8]

R1: amino group or acylamino group; R2, R3: lower alkyl; R4: strong rumoyl lower alkyl group

Patent document 5 discloses the following compounds.

[Chemical 9]

or acetyl Patent Document 6 discloses the following compounds.

[Chemical 10]

R3: acetyl group, having an appropriate substituent, may be, an amino group, an optionally substituted rubamoyl group, ureido, having an appropriate substituent Good heterocyclic group etc.

(Concrete example)

[Chemical 11]

Patent document 7 discloses the following compounds.

[Chemical 12]

R3: hydrogen, lower alkyl, (protected) carboxy; R4: hydrogen, lower alkyl A: Methylene, propenylene

(Concrete example)

[Chemical 13]

Patent document 8 discloses the following compounds.

[Chemical 14]

A: Quaternary nitrogen atom and the like.

In Patent Document 8, “quaternary nitrogen atom” means _c

[Chemical 15]

(Wherein R2, R3 and R4 together with the N atom contain an additional 5- or 6-membered aromatic heteroatom selected from oxygen, sulfur and nitrogen. (Represents a heterocycle that is condensed in some cases)

Cefmium compounds having a CONHCN group at the end of the 3-position side chain are known in the art. It is a len type (see: Patent Document 9).

[Chemical 16]

(Wherein Het contains one or more of the same or different atoms selected from N, 0 and S, monocyclic or polycyclic heterocycles; R1 is hydrogen, optionally substituted lower alkyl, or Substituted, ret or alk represents lower alkenyl, A is substituted, ret, may ele, lower alkylene, substituted les, pos, lower alkenylene or single bond; B is substituted Represents an imino or single bond, D is a single bond or

[Chemical 17]

Represents

Further, ceftriaxone sodium (trade name: Rocephine) is known as a continuous injection cefme for once or twice daily administration.

Patent Document 1: JP-A 59-172493

Patent Document 2: JP-A 62-195386

Patent Document 3: JP-A-1-156984

Patent Document 4: JP-A-5-339274

Patent Document 5: JP-A-5-59065

Patent Document 6: JP-A-7-41484

Patent Document 7: JP-A-9-110877

Patent Document 8: WO 99/67255

Patent Document 9: WO 97/37996

Disclosure of the invention Problems to be solved by the invention

[0003] Compared to conventional cephem compounds, there has been a demand for the development of a novel broad spectrum cephem compound that exhibits a stronger antibacterial activity or a different antibacterial pattern. In particular, the development of antibacterial agents that are effective against resistant bacteria such as pneumococci and Haemophilus influenzae, where drug resistance and nosocomial infections are problematic, is desired. More preferably, the development of a long-lasting antibacterial agent with good pharmacokinetics is desired.

Means for solving the problem

[0004] As a result of intensive studies, the present inventors have adopted a 3-propenyl-type side chain having a cyclic quaternary ammonium group such as a pyridine ring at the 3-position of cefme, and 3 We found that the introduction of an acidic group (eg, _C〇NHCN, _CO〇H) as a substituent at the end of the side chain yields a cephem compound that exhibits excellent antibacterial activity and good pharmacokinetics. The present invention has been completed. Furthermore, the present invention also provides an intermediate crystal of the cephem compound.

[0005] Equation (1):

[Chemical 18]

(Where

Acyl is an amino group that can be used in the field of β-ratata;

Τ is S, SO or O;

Formula:

A group represented by is a heterocyclic group optionally having a thione N atom in the ring, which may be substituted with a substituent other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ”;

Y ¹ and Y ² are each independently 1) a single bond, 2) — NR ² , —CO −, — NR ² C〇—, one CONR ² —, one NR ² CONR ³ —, one NR ² S〇 One, one SO NR ² —, one NR ² S〇 NR ^3-

2 2 2

, (R ² and R ³ are each independently hydrogen or lower alkyl), = N-, _N =, -O_, _S-, -SO-, and a heteroatom selected from the group consisting of 1 SO- Contains

2

A group, or 3) a heteroatom-containing group of 2) may be interposed, lower alkylene or lower alkenylene;

Ar ¹ represents a single bond or an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;

R ¹ is _CONHCN, _C (〇H) = NCN, or _C〇OH or a biologically equivalent acidic group thereof;

Wavy line means cis, trans or a mixture thereof;

However,

1) When the heterocyclic group having a cationic N atom in the ring is a pyridinium group and Ar ¹ is a single bond, R ¹ shall be CONHCN or one C (OH) = NCN;

2) A heterocyclic group having a cationic N atom in the ring is a bicyclic heterocyclic group, Ar ¹ is a single bond, and R ¹ is —CONHCN or —C (OH) ═NCN If either not name, "a ^{^{^{Y 1 - Ar 1 - Y 2}}} - R 1" group represented by the have a bond to cephem 3-position side chain moiety in said bicyclic heterocyclic group Or a pharmaceutically acceptable salt or solvate thereof.

[0006] (2) The compound according to (1) above, wherein T is S, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0007] (3) Acyl is the formula:

[Chemical 20]

(Where

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group) or = NOR ° (R ° is Hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, substituted les, may les, cycloalkyl, substituted les, may les, aryls or substituted Good heterocyclic group)

Or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(4) The compound according to (3) above, wherein X is CH and / or I ^ = NOR ° (R ° is hydrogen or optionally substituted lower alkyl).

Equation (5):

[Chemical 21]

Groups represented in the "A ^{^{Y 1 - Ar 1 - Y-}} R 1" may be substituted with other substituents, a bicyclic heterocyclic group having a pin Rijiniumu group or a cation, The compound according to (1) above, a pharmaceutically acceptable salt thereof or a solvate thereof.

(6) The compound according to (1), a pharmaceutically acceptable salt or a solvate thereof, wherein Y ¹ and / or Y ² is a single bond.

(7) Ar ¹ tt, a single bond, an optionally substituted aryl, or an optionally substituted heteroaryl, the compound according to (1) above, a pharmaceutically acceptable salt thereof, or a solvate thereof object.

(8) The compound according to (1), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein 1 ^ is CONHCN C (◯ H) = NCN or COOH.

(9) is the compound according to the above (1), pharmaceutically acceptable salt or solvate thereof, wherein —CONHCN or —C (OH) ═NCN. (10) R ¹ is COOH or a biologically equivalent acidic group thereof, and the acidic group is CONHR ⁴ -SO H -SO NHR ⁵ (R ⁴ and R ⁵ are each independently an amino residue)

3 2

-PO H OH COCH = C (〇H) CF NHSO CF CONHSO CF

3 2 3 2 3 2 £

-NHSO Me, -CONHSO Me _NHC〇Me _C〇NHCOMe -COCH

, 2 2 2

COMe, or a compound as described in the above (1), which is a 5- to 6-membered heterocyclic group which may be substituted and has NH_ and other heterocyclic atoms as a ring-constituting atom, its pharmaceutically acceptable Salts or solvates thereof.

Equation (11):

[Chemical 22]

Groups represented in the "A Y ^¹ - Ar ¹ - Y one R ^1" may be substituted with other substituents, Pi Rijiniumu group; Y ¹ and Y ² is a single bond; Ar ¹ represents a substituted Optionally substituted aryl, or optionally substituted heteroaryl; R ¹ is one CONHCN or one C (0H) = NCN, the compound according to the above (1), or a pharmaceutically acceptable salt thereof Or a solvate thereof. Equation (12):

[Chemical 23]

(Where

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group) or = NOR ° (R. Hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, Substituted, may, cycloalkyl, substituted, may, aryl, or an optionally substituted heterocyclic group)

A group represented by:

Y ¹ and Y ² are each independently 1) a single bond, 2)

-CO-, _NR ² C〇_, one CONR ² —, one NR ² CONR ³ —, one NR ² S〇 one, one SO NR ² —, one NR ² S〇 NR ^3-

2 2 2

, (R ² and R ³ are each independently hydrogen or lower alkyl), = N-, _N =, -O_, _S-, -SO-, and a hetero selected from the group consisting of 1 SO- Containing atoms

2

Wavy line means cis, trans or a mixture thereof;

However, when Ar ¹ is a single bond, R ¹ shall be-CONHCN or-C (OH) = NCN. )

Or a pharmaceutically acceptable salt or solvate thereof.

(13) The compound according to (12), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein 1 ^ is —CONHCN or C (OH) ═NCN.

(14) Y ¹ is a single bond; Ar ¹ is an optionally substituted aryl or an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is CONHCN or one C (〇H) = NCN The compound according to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(15) Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is —CONHCN or —C (OH) ═NCN, according to (12) above Compound, its pharmaceutically acceptable salt or solvate thereof.

(16) X is CH; R is = CHZ (Z is substituted, optionally, lower alkyl) or = NO R ° (R. is hydrogen, substituted, optionally, lower, lower) Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is , —CONHCN or —C (OH) ═NCN, the compound according to (12) above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(17) X is CH; Rtt = NOR ° (R ° is hydrogen, substituted, optionally, lower alkyl or optionally substituted aryl); Y ¹ is a single bond; Ar ¹ is substituted Yes, 5 or 6 membered heteroarynoles containing 1 to 4 heteroatoms identical or different selected from the group consisting of S and N; Y ² is a single bond; R ¹ is a compound according to the above (12), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein 1 CONHCN or 1 C (OH) = NCN.

(18) X is CH; R is = N ° R ° (R ° is lower alkyl or substituted or aryl); Y ¹ is a single bond; Ar ¹ consists of 〇, S and N 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms identical or different selected from the group; Y ² is a single bond; R ¹ is —CO NHCN or _C (〇H) = NCN, The compound according to (12) above, a pharmaceutically acceptable salt thereof or a solvate thereof.

Equation (19):

[Chemical 24]

(In the formula

[Chemical 25]

The group represented by is a bicyclic heterocyclic group having a cationic N atom;

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, optionally substituted lower alkyl, optionally substituted Cycloalkyl or an optionally substituted heterocyclic group) or = NOR ° (R. is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, A group represented by (moly), cycloalkyl, substituted les, moth may, aryl, or heterocyclic groups;

Y ¹ and Y ² are each independently 1) a single bond, 2)

2 2 2

(Wherein R ² and R ³ are each independently hydrogen or lower alkyl), a heteroatom-containing group selected from the group consisting of _〇_, —S—, —S 〇_, and —S〇—, or 3) 2)

2

A hetero atom-containing group may be present, lower alkylene or lower alkenylene; Ar ¹ is a single bond, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group ;

Wavy line means cis, trans or a mixture thereof;

However, when Ar ¹ is a single bond and R ¹ is neither CONHCN nor —C (OH) = NCN, the group represented by “Y ¹ — Ar ¹ — Y ² — R ¹ ” is In the bicyclic heterocyclic group, it should be present on the ring that does not have a bond with the side chain moiety of the caffeine 3-position)

Or a pharmaceutically acceptable salt or solvate thereof.

(20) The compound according to (19), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein 1 ^ is —CONHCN or C (OH) ═NCN.

(21) Y ¹ is a single bond; Ar ¹ is a single bond; Y ² is a single bond; R ¹ is —CONHCN or _ C (OH) = NCN, the compound according to (19) above, its pharmaceutically acceptable Salts or solvates thereof.

(22) X is CH; R is = CHZ (Z is an optionally substituted lower alkyl) or = N OR ° (R. is hydrogen, substituted, optionally, lower alkyl or substituted Y ¹ is a single bond; Ar ¹ is a single bond; Y ² is a single bond; R ¹ is —CONHCN or —C (OH) = NCN, (19 ) Or a pharmaceutically acceptable salt thereof Their solvates.

(23) The compound according to any one of the above (19) to (22), a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the bicyclic heterocyclic group is any of the following: object.

[Chemical 26]

(24) A pharmaceutical composition comprising the compound according to (1) to (23) above, any one of the above, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(25) A compound in which the amino and Z or carboxy moieties at the 7-position side chain end of the compound described in (1) to (23) above are protected, a pharmaceutically acceptable salt thereof, or a compound thereof Solvent.

Equation (26):

[Chemical 27]

(Where

Y ¹ and Y ² are each independently 1) a single bond, 2) _NR ² , -CO-, _NR ² C〇_, one CONR ^2- , one NR ² CONR ^3- , one NR ² S〇 one, 1 SO NR ² —, 1 NR ² S〇 NR ³ _ (R and R are each independently hydrogen or lower alkyl), = N— — N = — containing a heteroatom selected from the group consisting of OS SO— and SO—

2

A lower alkylene or a lower alkenylene, optionally intervened by a group, or 3) a heteroatom-containing group of 2);

R ¹ is one CONHCN or one C (OH) = NCN;

Provided that Y ¹ and Y ² are a single bond and Ar ¹ is pyrrolyl, pyrazolyl, or chenyl), a pharmaceutically acceptable salt thereof, or a solvate thereof.

(27) Y ¹ and Y ² are a single bond; R ¹ is —CONHCN or —〇 (〇Η) = Ν〇Ν; Α is a group derived from any of the following heterocycles (26) Or a pharmaceutically acceptable salt or solvate thereof.

[Chemical 28]

Equation (28):

[Chemical 29]

(Where formula:

[Chemical Formula 30]) The ring represented by (Q) is a bicyclic pyridine ring optionally substituted with a substituent other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ”; Y ¹ and Y ² are each independently 1) single bond, 2) — NR ² —CO −, — NR ² C〇—CONR ² NR ² CONR ³ NR ² S〇 1, SO NR ² NR ² S〇 NR ³ —

2 2 2

(Wherein R ² and R ³ are each independently hydrogen or lower alkyl), a heteroatom-containing group selected from the group consisting of O—, —S—, —S 0 —, and —S 0 —, or 3 2)

2

R ¹ is one CONHCN or _C (OH) = NCN)

Or a pharmaceutically acceptable salt or solvate thereof.

(29) Ar ¹ and Υ ² are a single bond; R ¹ is —CONHCN or —C (OH) ═NCN, the compound according to (28) above, a pharmaceutically acceptable salt thereof, or a solvate thereof .

(30) Y ¹ is a single bond; Ar ¹ is substituted, may, allyl or substituted, may be heteroaryl; R ¹ is COOH, described in (12) above Or a pharmaceutically acceptable salt or solvate thereof.

(31) Y ¹ is a single bond; Ar ¹ is optionally substituted heteroaryl; Y ² is a single bond; R ¹ is a biologically equivalent acidic group of COOH, (12) Or a pharmaceutically acceptable salt or solvate thereof.

(32) Y ¹ is a single bond; Ar ¹ is a substituted, substituted, aryl, or substituted heteroaryl; R ¹ is —COOH biologically equivalent The compound according to (12) above, which is an acidic group, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(33) Υ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond;

The compound according to (12) above, which is a biologically equivalent acidic group of COOH, a pharmaceutically acceptable salt thereof, or a solvate thereof.

(S ^ Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is an optionally substituted ring atom _NH_ and other heteroatoms The compound according to (12), a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a 56-membered heterocyclic group having

Equation (35): [Chemical 273]

Or a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by (12) above, wherein the moiety represented by:

[Chemical 274]

(36) Any of the following compounds, pharmaceutically acceptable salts or solvates thereof:

[Chemical 275]

In the Toryechiruamin salt of compound represented by the crystal _c

Equation (38):

[Chemical 277]

(G-2)

A crystal of hydrochloride of the compound represented by

Equation (39):

[Chemical 278]

(Where BH is Benshydryl)

Of the hydrochloride salt of the compound represented by

Formula (40):

[Chemical 279]

(Where BH is Benshydryl)

A crystal of hydrochloride of the compound represented by

The invention's effect

This compound exhibits a strong antibacterial action against various bacteria. Preferred compounds are particularly effective against gram-positive bacteria such as staphylococci and pneumococci and gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Haemophilus influenzae. More preferably, pneumococcal or influenza-resistant [Ιϋί 十生菌, 特 ((penicillin-resistant Streptococcus pneu moniae: PRSP) or / 3--lactamase non-producing ampicillin-resistant Haemophilus influenzae (Beta-1 actamase-negative, ampicillin-resistant Haemophilus influenzae: BLNAR), and the more preferred compound is the blood concentration-time curve bottom area (AUC), which is highly soluble in water, Because it has good pharmacokinetics such as clearance and half-life, it is suitable as a sustained injection.

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, unless otherwise specified, each term has the following meanings either independently or in combination.

Acyl means an asinole group that can be used in the field of β-ratata. For example, the amino group at position 6 of a penicillin derivative that has been conventionally known is substituted with an amino group at the 6-position of the penicillin derivative. Substituting with the 7-position amino group in means a ruyl group. Examples of such acyl groups include organic carboxylic acid-derived acyl groups such as formyl groups, alkylcarbonyl groups (alkanoyl groups), preferably (C1-C6) alkyl-carbonyl groups (eg, acetylenoles). ), Propionyl, butyrinole, isobutyryl, valerinole, isovaleryl, pivalolyl, hexanol, etc.), C3-5 alkenoyl group (eg, attalyloinole, crotonoinole, maleoyl etc.), c 3-10 cycloalkyl-carbonyl group (eg, cyclopropylcarbonyl) ), Cyclopentino carbonyl, cyclopentyl carbonyl, cyclohexyl carbonyl, cycloheptyl carbonyl, adamantyl carbonyl, etc.), C5-6 cycloalkenyl-carbonyl groups (eg, cyclopentenino decano levonole, cyclopenta genino decano levonole) , Shik Lohexenylcarbonyl, cyclohexaenylcarbonyl, etc.), allylcarbonyl group (alloy group), preferably (C6-C14) allyl carbonyl group (eg, benzoyl, 1 or 2 naphthoyl etc.), arral A kill carbonyl group, preferably a (C7-C19) aralkyl carbonyl group (eg phenylacetyl, phenylpropionyl, α, α, α triphenylacetyl, 2-phenethylcarbonyl, 1- or 2-naphthylmethyl) Carbonyl, benzhydrylcarbonyl, etc.), 5- to 6-membered aromatic heterocyclic carbonyl group (eg, 2 or 3 tenol, 2 or 3 furoyl, nicotinol, isonicotinoyl, 4 or 5 thiazolylcarbonyl, 1, 2,4 thiadiazole-3 Or -5-ylcarbonyl, etc.), 5- to 6-membered aromatic heterocyclic acetyl group (eg, 2_ or 3_ cherylacetyl, 2_ or 3_furylacetyl, 4_thiazolinolacetyl, 1, 2, 4_thiadiazonole 1-inoreacetinole, 1,3_thiazole_4-ylarcetyl, 1-tetrazolylacetyl, etc.), alkoxycarbonyl group, preferably (C1-C6) alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxy canolebonanol, propoxycanoleboninole, isopropoxycanoleboninole, butoxycanoleboninole, isobutoxycarbonyl, tertiary butoxycarbonyl, etc.), aryloxy A carbonyl group, preferably a (C6-C14) aryloxy-carbonyl group (eg, phenoxycarbonyl) , 11 or 2-naphthoxycarbonyl, etc.), aralkyloxycarbonyl group, preferably (C7-C19) aralkyloxycarbonyl group (eg, benzyloxycarbonyl etc.), aminoalkylcarbonyl group (eg, glycinole, Arranyl, valyl, leucyl, isoquinol, serinole, threonyl, cystinyl, cistur, methionyl, asparagyl, glutamyl, lizinole, arginyl, phenyldaricyl, vinylaranyl, tyrosyl, histidyl, tryptophaninole, aminocarbonyl, prolyl, 2_ Amino C1-6 alkyl-carbonyl group such as 3-aminopropylcarbonyl), monoalkylaminoalkylcarbonyl group (eg, monoaminoaminocarbonyl such as methylaminomethylcarbonyl, 2-ethylaminoethylcarbonyl, etc.) 6 alkylamine C1-6 alkyl-carbonyl group, etc.), dialkylaminoalkylcarbonyl groups (eg, dimethylaminomethylcarbonyl, diethylaminomethylcarbonyl, etc.) Monocarbonyl group, etc.).

These asinole groups include amino-containing nitros, halogens (eg, fluorine, chlorine, bromine, etc.), hydroxynoles, oxo, rubamoyl, (C1-C4) alkyl (eg, methinole, ethyl, propyl, isopropyl, butyl, etc.), (C1-C4) substituted with alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), optionally esterified carboxyl (eg, C16 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, etc.), carboxyl or halogen, etc. (C1-C4) alkoxyimino (eg, methoxyimino, ethoxyimino, carboxymethoxyimino, 1-carboxy 1-methylethoxyimino, fluoromethoxyimino, fluoroethoxyimino, etc.) , Hydroxyimino, 4-ethylil 2,3 dioxopiperazinoca norebonylamino, postscript R (= CHZ (Z is hydrogen, optionally substituted lower alkyl, substituted les, optionally les, cycloalkyl, substituted les, optionally les, aryls, or optionally substituted complex Cyclic group), or = N 0 R ° (where R ° is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted cycloalkyl, optionally substituted). 1 to 3 arbitrary positions may be substituted with a good aryl or heterocyclic group)) or the like.

Said Acyl is preferably of the formula:

[Chemical 31] (Acyl-1)

Is an acyl group represented by

X is N or CY (Y is hydrogen or halogen), preferably CY (Y is hydrogen or halogen), more preferably CH.

R is = CHZ (Z is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, substituted les, mayeles, aryl, or substituted les. , A heterocyclic group (preferably a 5- to 6-membered ring)), or = N ° R ° (R. is hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, substituted Optionally substituted cycloalkyl, substituted, optionally, aryl, or a heterocyclic group (preferably a 5-6 membered ring)).

R is preferably = CHZ (Z is an optionally substituted lower alkyl (eg ethyl)) or = N0R. And more preferably = N0R. It is. R. Is preferably hydrogen, substituted les, mayore, lower alkyl or substituted les, mayele, allyl, more preferably substituted les, mayele, lower alkyl (substituted) Examples of groups: halogen, substituted rhe or hetoleo bicyclic group (preferably 5 to 6 membered ring), or substituted rhe, het ole or aryl (eg, substituted with hydroxy, etc.) Particularly preferably lower alkyl (eg, ethyl, propinole (preferably isopropyl)) or substituted les, may, aralkyl (eg, benzyl). It is. Also = CHZ or = NOR. Z or OR of the part. The configuration is preferably a thin body.

The lower alkyl group is a linear or branched alkyl group having preferably 1 to 6 carbon atoms and the like, such as methinole, ethyl, n-propyl, isopropinole, n-butyl, isobutyl, sec-butyl, tert —Butyl, n_pentyl, n_hexyl and the like.

The lower alkenyl group is a straight chain or branched, preferably an alkenyl group having 2 to 6 carbon atoms, and examples thereof include aryl, propenyl, butyr, and pentul.

Cycloalkyl is an alkyl group having 3 to 6 carbon atoms, etc. Examples include til, cyclopentyl, cyclohexyl and the like.

The above substituted les, may les, lower alkyls, substituted les, may les, lower alkenyls, optionally substituted cycloalkyls, optionally substituted aryls or substituted Suitable substituents for the heterocyclic group include a carboxyl group, a lower alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl), a strong rubamoyl group, a lower alkylthio (eg, methylthio, ethylthio), a sulfamoyl group, an amino group, Examples include a hydroxyl group, a cyano group, a strong ruberamoyloxy group, a halogen (eg, F, C1), an optionally substituted heterocyclic group (preferably a 5- to 6-membered ring, eg: thiazolyl, chenyl), lower alkyl, etc. The Preferred is halogen (eg, F, C1) or hydroxyl group.

Heterocyclic group means “heterocycloalkyl” or “heteroaryl”. “Heterocycloalkyl” is a non-aromatic heterocyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring and having a bond at any substitutable position (preferably Is a 5- to 7-membered ring), for example, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolininole, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolinyl, 2-imidazolininole, 4-imidazolinyl , 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidininole, 1- virazolinyl, 3- virazolinyl, 4- virazolinyl, 1- virazolidinyl, 3-virazolidinyl, 4- virazolidinyl, piperidino, 2-piperidyl, 4-piperidyl, 4 -Piperidyl, 1-piperazinyl, 2-piperazinyl, 2-monoreforinole, 3-monoreforinole, morpholino, tetrahydropyrani Etc. The. The “non-aromatic heterocyclic group” may be saturated or unsaturated as long as it is non-aromatic.

“Heteroaryl” means monocyclic aromatic heterocyclic groups and fused aromatic heterocyclic groups.

A monocyclic aromatic heterocyclic group may contain 1 to 4 oxygen atoms, sulfur atoms, and Z or nitrogen atoms in the ring, any substitutable atom derived from a 5 to 8 membered aromatic ring. It means a group that has a bond at the position.

The fused aromatic heterocyclic group may contain 1 to 4 oxygen atoms, sulfur atoms, and Z or nitrogen atoms in the ring 5 to 8 membered aromatic ring force S,:! To 4 5 Bonded to any substitutable position fused to an 8-membered aromatic carbocycle or other 5- to 8-membered aromatic heterocycle. It means a group that has a joint and is a group.

Examples of “heteroaryl” include furyl (eg, 2-furyl, 3-furyl), cheryl (eg, 2-chenyl, 3-phenyl), pyrrolyl (eg, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (eg, 1_imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (eg, 1-pyrazolyl, 3-pyrazolyl, 4_pyrazolyl), triazolyl (eg, 1, 2, 4 -Triazolol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (eg 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl) ), Oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (eg 3-isoxazolyl, 4_isoxazolyl, 5_isoxazolyl), thiazolyl (eg 2_thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl, isothiazolyl (eg 3_isothiazolyl, 4-isothiazolyl, 5_isothiazolyl), pyridyl (eg 2_pyridyl, 3_pyridyl, 4 -Pyridyl), pyridazinyl (eg, 3-pyridazinyl, 4_pyridazinyl), pyrimidinyl (eg, 2-pyrimigenenole, 4-pyrimimigenole, 5-pyrimimigel), furazanyl (eg, 3-flazadinyl), birazinyl (eg, 2-pyrazinyl), oxadiazolyl (eg, 1, 3, 4-oxadiazol-2-yl), benzofuryl (eg, 2-benzo [b] furyl, 3-benzo [b] furyl, 4-benzo [b ] Furyl, 5-benzo [b] furyl, 6-benzo [b] furyl, 7_benzo [b] furyl), benzocenyl (eg 2-benzo [b] chenyl, 3-benzo [b] cheni , 4-Benzo [b] Cenyl, 5-Benzo [b] Chenyl, 6-Benzo [b] Chenyl, 7-Benzo [b] Chenyl), Benzimidazolyl (eg, 1-Benzimidazolyl, 2-Benzimidazolyl, 4- Benzoimidazolinol, 5-benzoimidazolinole), dibenzofurinole, benzoxazolinole, quinoxalyl (eg, 2-quinoxalinyl, 5-quinoxalinyl, 6-quinoxalinyl), cinnolinyl (eg, 3-cinnolinyl, 4_ Cinnolinyl, 5_cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), quinazolyl (eg, 2-quinazolinyl, 4-quinazolinyl, 5-quinazolinolinole, 6-quinazolinyl, 7-quinazolinyl, 8- Quinazolinyl), quinolyl (eg 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6_quinolyl, 7_quinolyl, 8 _Quinolyl), phthalazinyl (eg, 1_phthaladyl, 5-phthaladuryl, 6_phthaladul), isoquinolyl (eg, 1-isoquinolyl, 3_isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6_isoquinolyl, 7-isoquinolyl) 8_isoquinolyl), prill, pteridinyl (eg 2-pteridinyl, 4-peptidyl) Lysininore, 6-Pteridinyl, 7-Pteridinyl), Canolebasolinole, Phenanthridinyl, Atalidinyl (eg, 1-Ataridinyl, 2-Ataridinyl, 3-Ataridinyl, 4-Ataridinyl, 9-Ataridinyl), Indolyl (eg, 1- Indolyl, 2-indolyl, 3-indolyl, 4-indolinole, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl, guanazinyl (eg 1-phenazinyl, 2_phenazinyl) or phenothiazinyl (eg 1 -Phenothiazinyl, 2-phenothiazinyl, 3-phenothiazinyl, 4-phenothiazinyl) and the like.

T is S, S 0 or O, preferably S.

Formula:

[Chemical 32]

The group represented by is a heterocyclic group having a force thionic N atom (N ⁺ ) in the ring, which may be substituted with a substituent other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ”. It is. The heterocyclic group means the above-mentioned heterocyclic group containing at least one N atom, for example:! -4, and represents a monocyclic or condensed polycyclic group. means. Although the cationic N atom may be present at any position on the ring, it is preferably present at the position where the cenyl 3-position side chain is bonded to propenyl and is represented by the following formula. It is.

[Chemical 33]

The cation is preferably a counter ion of the 4-position carboxion. The heterocyclic group having a cationic N atom in the ring is preferably a pyridinium group or a bicyclic heterocyclic group having a cation. The bicyclic heterocyclic group having a cation is preferably a group represented by the following formula.

[Chemical 34]

(In the formula, each of A ring and B ring independently represents a saturated or unsaturated 5- to 7-membered ring which may be substituted, and includes 1 to 3 heteroatoms as ring-constituting atoms. It's okay.)

The bicyclic heterocyclic group is more preferably a bicyclic pyridine cyclic group in which either the ring A or B is a pyridine ring, and particularly preferably, the A ring is a pyridine ring, Ring B is a benzene ring, cyclopentene, cyclohexene, or the aforementioned 5- to 6-membered heterocyclic ring (eg, thiophene, pyrrole, imidazole, oxazole, thiazole).

Examples of the heterocyclic group having the cationic N atom represented by (Q) in the ring are shown below.

[Chemical 35]

[Chemical 36]

(Group B)

[Chemical 37]

(Group C) A heterocyclic group having a cationic N atom represented by (Q) in the ring is more preferable. Is selected from group c above.

Substituents other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ” are the same or different 1 to 4 and preferably 1 to 2 substituents selected from the following substituent group D: Exemplary force S, preferably lower alkyl. These substituents are preferably present on the ring (eg, ring A) bonded to the side chain moiety of the cepheme when the heterocyclic group is a condensed bicyclic group. The

(Substituent group D)

Lower alkyl, lower alkenyl, C3 to C7 cycloalkyl, optionally substituted lower alkyl (substituent: Ami lower alkylamino (eg, —NHCH), optionally substituted

Three

Good lower alkylamino (eg 1 NHCH CHOH), hydroxy, carboxy, halogen

twenty two

), Rubamoyl, lower alkyl rubamoyl, halogen, hydroxy, carboxy, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkylcarbonyl, lower alkylcarbonylamino optionally substituted amino (substituted) Group: lower alkyl, amino lower alkyl), lower alkylthio, sheared heterocyclic group, oxo.

The group represented by “one Y ¹ —Ar ¹ —Y ² —R ¹ ” may be present at any position of the heterocyclic group having a cationic N atom represented by (Q) in the ring, In the case of a bicyclic heterocyclic ring, it is preferably present on the ring that is not bonded to the propenyl moiety of the cefme 3-position side chain (eg, ring B above).

Y ¹ and Y ² are each independently 1) single bond, 2) —NR ² , —CO—, —NR ² CO CONR ² NR ² CONR ³ NR ² S〇 1, SO NR ² NR ² S〇 NR ³ —

2 2 2

, (R ² and R ³ are each independently hydrogen or lower alkyl), = N—, _N =, _O —, _S—, _SO _, and S1 Terror atom-containing groups,

2

Or 3) lower alkylene or lower anolenylene which may be intervened with the heteroatom-containing group of 2).

Lower alkyl includes linear or branched C1-C6 alkyl, and examples thereof include methyl, ethyl, n-propyl, i-propyl, t-butyl, n-pentyl, and n-hexyl. Lower alkylene means a divalent group derived from lower alkyl, preferably one (CH 3) m

2

-(m is:!-6, preferably an integer of 1 3).

Lower alkenylene means a straight or branched lower alkenylene group having 26 carbon atoms and having one or more double bonds in the lower alkylene, and examples thereof include vinylene, propenylene. Or butenylene is mentioned. Preferred is a straight chain lower alkenylene having 23 carbon atoms, and examples thereof include vinylene and propenylene. The term “intervening” in “optionally containing a heteroatom-containing group” means that the heteroatom-containing group is present between 1) a carbon atom constituting a lower alkylene or a lower alkenylene, or 2) a lower group. It means a case where it exists between the carbon atom constituting alkylene or lower alkenylene and the adjacent N atom-containing heterocyclic group and Z or Ar ¹ . The heteroatom-containing group (M) may be the same or different and one or more groups. For example, when a hetero atom group is present in lower alkylene, -M -CH -CH -M-CH -CH- M CH- M- M- CH-

2 2 2 2 2 2 Illustrated.

Y ¹ and Y ² are each independently, preferably a single bond, NR 0—, —CONR ² —, —NR 0 NR ³ — (R ² and R ³ are each independently preferably hydrogen), NH Or it is a lower alkylene, More preferably, it is a single bond.

Ar ¹ is a single bond or an optionally substituted carbocyclic group or an optionally substituted heterocyclic group. These may be either saturated or unsaturated.

When the N atom-containing heterocyclic group represented by (Q) to which “one Y ¹ —Ar ¹ —Y ² —R ¹ ” is bonded is a monocyclic group (eg, pyridine) (eg, compound) (I a)), Ar ¹ is preferably a substituted, may, carbocyclic group or a substituted, may,, heterocyclic group. More preferred is an unsaturated ring.

The N atom-containing heterocyclic group represented by (Q) to which “one Y ¹ —Ar ¹ —Y ² —R ¹ ” is bonded is a polycyclic group (eg, bicyclic group such as condensed pyridine) (Example: Compound (I_b)), Ar ¹ is preferably a single bond.

The saturated or unsaturated carbocyclic group in Ar ¹ is preferably a 3- to 10-membered ring and is a C3 C7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cycloto Xyl, cycloheptyl), C5-C7 cycloalkenyl (eg, cyclopentenyl, cyclohexenyl) and aryl (eg, phenyl, naphthyl).

The saturated or unsaturated heterocyclic group in Ar ¹ means the aforementioned heterocycloalkyl or heteroaryl, preferably heteroaryl. More preferably, it is a monocyclic aromatic heterocyclic group. Specifically, it contains an oxygen atom, a sulfur atom, and a Z or nitrogen atom in the ring:! To 4 5 to 8 member, preferably 5 to 6 member cyclic More preferred are furyl, phenyl, pyrrolyl, pyrazolyl, imidazolinole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinole, pyridazinyl, pyrimidinole, pyrajur, triazolyl and the like. Particularly preferred are pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. For example, when Ar ¹ is thiazolyl, 1 Y ² —! ^ Is preferably bonded to the 2-position of the thiazole ring.

The substituent in “optionally substituted” of Ar ¹ is selected from the substituent group D, and is preferably OH, halogen, or lower alkyl (eg, methyl).

R ¹ represents CONHCN C (〇H) = NCN, or 1 COOH or a biologically equivalent acidic group thereof. R ¹ is preferably CONHCN or C (OH) = NCN, and both are in an isomer relationship. R ¹ is important for the compounds of the present invention to exhibit high water solubility and excellent pharmacokinetics (eg, AUC, half-life) in addition to strong antibacterial activity. For example, when the compound of the present invention is used as an injection, it can be easily dissolved in water as an alkali metal salt (eg, Na salt).

The biologically equivalent acidic group of “COOH” generally means a so-called bioisosteric group that one skilled in the art can substitute in the hope of bioequivalence instead of “COOH”. Specifically, the chemical structure is relatively similar to “_COOH”, and it is expected to have the same tendency as “one COOH” in terms of physical properties such as acidity, water solubility, and Z or pharmacokinetics. And a group having an acidic proton, wherein the acidic proton moiety may form a salt (eg, alkali metal salt (eg, Na salt)), for example, J. Med. em. 1992, 35, 1176-1183, J Med. Chem. 1993, 36, 2485-2493, J Med. Chem. 1992,

35, 3691-3698, J Med. Chem. 1995, 38, 617-628, Med. Res. Rev. 1983, 3, 91-118, J Med. Chem. 2001, 44, 1560—1563, Bioorganic & Medicinal Chemistry Letters, V ol. 4, No. 1, 41-44, 1994, etc. Preferably, CONHR ⁴ SO H

Three

-SO NHR ⁵ (R ⁴ and R ⁵ are each independently an amino residue (eg hydrogen, OH, lower

2

Norequinole, substituted sulfonyl (eg, lower alkylsulfonyl, aminosulfonyl, halogenated lower alkylsulfonyl), aryl or heteroaryl)), -PO H, -〇H,

3 2 One C〇CH = C (〇H) CF, -NHSO CF, One C〇NHS〇 CF One NHS〇 Me, One

3 2 3 2 3, 2

C〇NHC〇Me, -CONHSO Me, one NHC〇Me, one C〇CH C〇Me, or

twenty two

May be substituted (examples of substituents; electron-withdrawing groups such as = 〇, = S, _〇H, lower alkyl (eg methyl)), as ring-constituting atoms—NH_ and other heteroatoms (Example: N, NR ′ (R ^a = hydrogen, lower alkyl, etc.), ○, S) The above-mentioned heterocyclic group, more preferably a 5- to 6-membered heterocyclic group. Specifically, the structure adjacent to —NH— has a structure such as C = N, N = N, = 0, and = S. The heterocyclic group is tetrazole, a derivative group thereof, or other heterocyclic group, and is exemplified below. These isomers are also within the scope of the present invention.

[Chemical 38]

When R ¹ represents a biologically equivalent acidic group of COOH, the following structure is preferably exemplified as the 3-position pyridine side chain moiety. The moiety may be isomerized, and may form a salt within or between molecules.

[Chemical 179]

The present invention also provides the intermediate of the above-mentioned 3-position pyridine side chain. These intermediates include, for example, the pyridine ring — Ar ¹ — Y ^ Ar ¹ : heterocyclic group; Y ³ = — CN, — CONHNH, — C (NH

2

) = NOH etc.) is synthesized by subjecting the Y ³ part of the compound represented by a ring formation reaction.

2 In compound (I), the wavy line is a force that means cis, trans or a mixture thereof, preferably trans.

The production method of compound (I) is exemplified below. Compound (I) is basically composed of a 7-amino-3-propenyl-type cephem compound as a raw material. 1) Asinoleation reaction at the 7-position, 2) At least “1 Υ ¹ — Ar ¹ — It can be synthesized by appropriately combining the reaction of forming the 3-position side chain by nucleophilic reaction of the cyclic amine having the Υ ² — R ¹ ″ group and 3) the desired deprotection reaction. Preferably, the cyclic amine is reacted at the 3-position of 7-acylamino-1-propenyl-type cefme and then deprotected if desired. Further, as exemplified in Example 68 and the like, the 7-position asylation reaction may be carried out after forming the 3-position side chain. Is shown by (Acyl_ l) The case will be described below as an example.

The compound (II) can be synthesized according to the method described in JP-A-59-172493, JP-A-1-156984, JP-A-5-339274, JP-A-7-41484, W099 / 67255, and the like. Compound (III) in which R ¹ is —C 4 NHCN or 1 C (OH) ═NCN can be synthesized according to the method described in W097 / 37996.

[Chemical 39]

(Wherein R ⁶ is a hydrogen or amino protecting group; R ⁷ is a hydrogen or carboxy protecting group; Y is a leaving group (eg, hydroxy, halogen (Cl, Br, I, etc.), force ruberamoyloxy, substitution force ruberamoyloxy, (Siloxy, methanesulfonyloxy, toluenesulfonyloxy, etc.)) (1) Method for producing compound (IV)

Compound (IV) is obtained by reacting compound (IV) with compound (III) or a salt thereof (eg, alkali metal salt). In this case, preferably R ⁶ is an amino protecting group; R ⁷ is a carboxy protecting group.

The amount of compound (ΠΙ) to be used is generally about:! -10 mol, preferably about:!-2 monolayer, per 1 mol of compound (11).

Examples of the reaction solvent include ethers (eg, dioxane, tetrahydrofuran, jetyl). Ethers, tert-butyl methyl ether, diisopropyl ether), esters (eg ethyl formate, ethyl acetate, n-butyl acetate), halogenated hydrocarbons (eg dichloromethane, chlorophenol, carbon tetrachloride), hydrocarbons (Example: n-hexane, benzene, toluene), alcohols (eg, methanol, ethanol, isopropanol), amides (example: formamide, N, N_dimethylformamide, Ν, Ν-dimethylacetamide, Ν -Methylpyrrolidone), ketones (eg, acetone, methyl ethyl ketone), nitriles (eg, MeCN, propionitrile), dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more.

The reaction temperature is usually about _20-100 ° C, preferably about 0-50 ° C.

The reaction time is several hours to several tens of hours.

Nal, NaBr, KI, etc. may be used as a reaction accelerator.

(2) Compound (I) can be obtained by deprotecting compound (IV) by a method well known to those skilled in the art, if desired.

Examples of the reaction solvent include ethers (eg, anisole, dioxane, tetrahydrofuran, jetyl ether, tert-butyl methyl ether, diisopropyl ether), esters (eg, ethyl formate, ethyl acetate, n-butyl acetate), Halogenated hydrocarbons (eg, dichloromethane, chlorophenol, carbon tetrachloride), hydrocarbons (eg, n-hexane, benzene, toluene), amides (eg, formamide, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, Ν-methylpyrrolidone), ketones (eg acetone, methyl ethyl ketone), nitriles (eg MeCN, propionitrile), nitros (eg nitromethane, nitrogen, nitrobenzene) , Dimethyl sulfoxide, water and the like. These solvents may be used alone or in combination of two or more.

The reaction temperature is usually about −70 to 50 ° C., preferably about −50 to 0 ° C.

Catalysts include Lewis acids (eg: 8 SnCl, TiCl), proton acids (eg: HC1, H 2 SO, HC10

3, 4 4 2 4

, HCOOH, phenol) and the like, and if desired, anisole is used in combination.

Four

The obtained compound (I) can be further chemically modified to synthesize another compound (I), a pharmaceutically acceptable salt thereof, or a solvate thereof.

Pharmaceutically acceptable salts include inorganic bases, ammonia, organic bases, inorganic acids, organic acids And salts formed by basic amino acids, halogen ions, etc., or inner salts. Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Mg, etc.), and examples of the organic base include pro-power-in, 2-phenylethylbenzylamine, dibenzylethylenediamine. , Ethanolamine, diethanolamine, trishydroxymethylaminomethane, polyhydroxyalkylamine, N-methyldarcosamine and the like. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Examples of the organic acid include p_toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, maleic acid and the like. Examples of basic amino acids include lysine, arginine, ornithine, histidine and the like. Examples of the solvate solvent include water and alcohol.

The present invention further provides compound (I) as an intermediate for the production of compound (I), a compound in which the amino and Z or carboxy moieties at the 7-position side chain end of compound (I) are protected, and a pharmaceutically acceptable salt thereof. Alternatively, solvates are also provided.

The compound in which the amino group at the 7-position side chain end is protected means, for example, the compound (IV) in which R ^{6 is} an amino protecting group. Examples of the amino protecting group include lower alkoxycarbonyl (eg, t-butoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl), (substituted) aralkanol (eg, p-nitrobenzoyl), and acyl (eg: Examples include formyl, chloroacetyl), (substituted) aralkyl (eg, trityl), and the like.

The compound in which the carboxy moiety is protected means a compound in which the compound (IV) is protected when R ⁷ is a carboxy protecting group and / or R ¹ is carboxy. Examples of the carboxy protecting group include lower alkyl (eg, methyl, ethyl, t-butyl), lower alkenyl (eg, allyl, prenyl), (substituted) aralkyl (eg, benzyl, benzhydryl, p methoxybenzyl, p nitro). Benzyl), a silinore protecting group (t-butyldimethylsilyl, diphenyl t-butylsilyl) and the like. In addition, when R ⁷ is a carboxy protecting group in the compound (IV), the heterocyclic group represented by (Q) in the 3-position side chain has a counter ion (eg, halogen). ,.

The present invention further provides the compound (ΠΙ), particularly the compounds (前記 -1) and (ΠΙ-2) as production intermediates of the compound (I).

The present invention further provides the following production intermediate of compound (II) and crystals thereof: [Chemical 280]

(1) Crystal of compound (G-1)

[Chemical 281]

Compound (G-1) is preferably crystallized as an amine salt, more preferably a trialkylamine salt, and even more preferably a triethylamine salt. The ammine salt may contain a solvent (eg, water, alcohol). The crystal of tolylamine salt preferably shows typical peaks at least in the following positions in the powder X-ray diffraction pattern (X-ray measurement conditions: tube CuKa line, tube voltage 40 kV, tube current 50 mA). .

2 Θ = 8.9, 12.2, 15.6, 16.5, 18.3, 19.4, 20.2, 24.1, 24.7, 25.2, 2

6.4 (unit: degree) The triethylamine salt is preferably prepared by dissolving compound (G-1) in a soluble solvent (eg, dimethylacetamide) and then adding triethylamine preferably at 10 to 30 ° C. Drops over time (Reference: Reference Example 10).

(2) Crystal of compound (G-2)

[Chemical 282]

Compound (G-2) is preferably crystallized as an inorganic acid salt, more preferably as a hydrochloride. The hydrochloride may contain a solvent (eg, water, alcohol). The hydrochloride crystal preferably has typical peaks at least at the following positions in the powder X-ray diffraction pattern (X-ray measurement conditions: tube CuK a line, tube voltage 40 kV, tube current 50 mA, and so on). Show. 2 Θ = 5.9, 9.9, 11.6, 13.9, 23.4, 23.9, 27.5, 27.8 (unit: degree) The hydrochloride is preferably the compound (G -1) is reacted with oxalyl chloride in an organic solvent (eg, dimethylformamide, methylene chloride or a mixture thereof) for several hours under ice-cooling at -40 ° C (Reference: Reference) Example 2).

(3) Crystal of compound (G-3)

[Chemical 283]

(Where BH is Benshydryl)

Compound (G-3) is preferably crystallized as an inorganic acid salt, more preferably as a hydrochloride. The hydrochloride may contain a solvent (eg, water, alcohol). In the powder X-ray diffraction pattern (X-ray measurement conditions: tube CuK strand, tube voltage 40 kV, tube current 50 mA, the same applies below), the hydrochloride crystals preferably have representative peaks at least at the positions shown below. Show.

2 Θ = 4.0, 16.1, 19.1, 20.2, 21.2 (Unit: degree)

The hydrochloride is preferably prepared by reacting compound (G-3) with hydrochloric acid in an organic solvent (eg, ethyl acetate), concentrating and stirring for several tens of minutes under ice cooling ( Reference: Reference Example 1 (4) Crystal of compound (G-4)

[Chemical 284]

(Where BH is Benshydryl)

Compound (G-4) is preferably crystallized as an inorganic acid salt, more preferably as a hydrochloride. The hydrochloride may contain a solvent (eg, water, alcohol). The hydrochloride crystal preferably has typical peaks at least at the following positions in the powder X-ray diffraction pattern (X-ray measurement conditions: tube CuK a line, tube voltage 40 kV, tube current 50 mA, and so on). Show.

2 Θ = 6.8, 8. 3, 11. 0, 15. 7, 18. 3, 21. 6, 23.5, 23.7 (unit: degree) The hydrochloride is preferably compound (G- It is prepared by reacting 4) with hydrochloric acid in an organic solvent (eg, ethyl acetate, methanol) and then concentrating (Reference: Reference Example 2).

Each of the above crystals has advantages such as being stable with few impurities and having good Z or handleability. Therefore, it is useful as a synthetic intermediate for the cephem compound of the present invention.

The production intermediate of the present invention contributes to the excellent antibacterial action and Z or pharmacokinetics of Compound (I).

The compound of the present invention has a broad antibacterial activity of Specetanol, and various diseases caused by pathogenic bacteria in various mammals including humans such as respiratory tract infections, urinary tract infections, respiratory infections, sepsis , Nephritis, cholecystitis, oral infection, endocarditis, pneumonia, osteomyelitis, otitis media, enteritis, pus, wound infection, opportunistic infection, etc. The compounds of the present invention are particularly effective against gram-positive bacteria such as staphylococci and pneumococci and gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa and Haemophilus influenzae. More preferably, resistant strains of pneumococci and Haemophilus influenzae, particularly penicillin-resis tant Streptococcus pneumoniae (PRSP) and non-lactamase non-producing ampicillin resistant It is also effective against Infnorensa (beta_lactamase_negative, ampicillin-resistant Haemophilus influenzae: BLNAR). In addition, preferred compounds are suitable as long-lasting injections because they have good water solubility and good pharmacokinetics such as the area under the blood concentration one hour curve (AUC) and clearance.

The compound of the present invention can be administered parenterally or orally as an injection, capsule, tablet or granule, but is preferably administered as an injection. The dosage is usually about 0.1 to: OOmg / day, preferably about 0.5 to 50mg / day per kg of patient or animal body weight, divided into 2 to 4 times a day as desired. What is necessary is just to administer. When used as an injection, the carrier is, for example, distilled water, physiological saline or the like, and a base for adjusting pH may be used. Carriers when used as capsules, granules, and tablets are known excipients (eg, starch, lactose, sucrose, calcium carbonate, calcium phosphate, etc.), binders (eg, starch, gum arabic, carboxymethyl cell) Mouth, hydroxypropyl cell, crystal cell, etc.), lubricants (eg, magnesium stearate, talc, etc.).

[0018] Examples are shown below.

(Abbreviation)

Me: Methyl; Et: Ethyl; iPr: Isopropyl; Bu: t-Butinole; Ac: Acetyl; DMF: Dimethylformamide; THF: Tetrahydrofuran; Bo t-Butoxycarbonyl; PMB: p_Methoxybenzyl;

Reference example 1

[0019] [Chemical 40]

(1) a → b → c

Compound a (266.5 g, 0.5 mol) was dissolved in tetrahydrofuran (1.51), and NaI (225 g, 1.5 mol) was added. The reaction solution was stirred at room temperature for 30 minutes and poured into ethyl acetate (1.51) and water (1.51). The organic layer was separated and washed with 5% Na 2 S 0 aqueous solution and brine in this order. It was dried over MgSO and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and PPh (157 g, 0.6 mol) was added under ice cooling. The mixture was stirred at room temperature for 1 hour and 40 minutes, cooled on ice, and further stirred for 20 minutes. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain compound c. Pale yellow powder. Yield 440g (99%)

(2) c → d

Compound c (440 g, 0.496 mol) was dissolved in methylene chloride (2.51), and 2N-NaOH (298 ml, 0.595 mol) was obtained by cooling with ice. The reaction solution was stirred at room temperature for 35 minutes, and the methylene chloride layer was separated and washed with brine. MgSO was dried and concentrated under reduced pressure. The residue was dissolved in methylene chloride (375 ml), ethyl acetate (750 ml) was added, and the mixture was stirred with ice cooling for 30 minutes. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain compound d. Brown powder. Yield 314 g (83%)

(3) d → e

Compound d (156 g, 206 mmol) was suspended in tetrahydrofuran (1.41) and dimethyl sulfoxide (160 ml), and 19.6% -ClCH2CHO / CHC13 (247 g, 616 mmol) was added to BSA (25.46 ml, 103 mmol). The reaction solution was stirred at room temperature for 2 hours and 30 minutes, and then ethyl acetate (1.51) and water (1.51) were added. added. The organic layer was separated and washed with water and then brine. MgSO 4 was dried and concentrated under reduced pressure. Isopropanol (1.01) was added to the residue, and the mixture was stirred at room temperature for 20 minutes. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain compound e. Pale yellow powder. Yield 103.9g (90%)

(4) e → f

Compound e (103.8 g, 186 mmol) was dissolved in methylene chloride (690 ml), and 4-chlorothiophenol (9.4 g, 65 mmol) was added followed by AVN * (16.1 g, 65 mmol). The reaction solution was stirred for 3 hours and 45 minutes under reflux, and then isopropanol (250 ml) was concentrated to half the volume. Further, isopropanol (350 ml) was added, and the deposited precipitate was collected by filtration and dried under reduced pressure to obtain compound f¾r. Pale yellow powder. Yield 74.09g (72%)

(5) f → g

PCI (55.2 g, 265 mmol) was suspended in methylene chloride (670 ml) and pyridine (23.6 ml, 29

2 mmol) was added dropwise over 5 minutes. Compound i (74.08 g, 133 mmol) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes, and then lowered to _40 ° C. and methanol (265 ml) was added. The reaction mixture was stirred for 15 minutes under ice cooling, and water (690 ml) was added. The methylene chloride layer was separated and washed with water, aqueous NaHCO 3 solution (23.5 g / 294 ml) and brine in this order. The solution was dried over MgSO, 4N-HCl / EtOAc (66.3 ml, 26

5 mmol) and ethyl acetate (330 ml) were added and concentrated. The solution was concentrated to a volume of 400 ml and stirred for 30 minutes under ice cooling. The precipitated crystals were collected by filtration and dried under reduced pressure to obtain compound g. White crystals. Yield 54.2 g (86%)

'H-NMR (d-DMSO): 3.76,3.98 (2H, Abq, J = 17.1Hz), 4.24 (2H, d, J = 6.3Hz), 5.23

(1H, q, J = 4.8Hz), 5.31 (1H, d, J = 5.1Hz), 5.38 (1H, m), 6.90 (1H, d, J = 15.6Hz), 6.99 (1H, s) , 7.28—7.50 (10H, m), 9.22 (3H, br-s).

Fig. 3 shows the powder X-ray diffraction pattern of compound g (hydrochloride crystals).

(6) g + h → 8

Compound g (17.36 g, 36.4 mmol) and compound h (12.62 g, 40 mmol) were suspended in ethyl acetate (200 ml), and PhOP (0) Cl (4.31 ml, 47.3 mmol) was added. The mixture was cooled to −30 ° C., and N-Metylylholine (18 ml, 164 mmol) was added dropwise over 15 minutes. The reaction solution was stirred for 10 minutes, diluted hydrochloric acid was added, and the organic layer was separated. The organic layer was washed with 5% NaHC03, water and brine in that order and dried over MgS04. Concentration under reduced pressure gave compound 8. Yield 17.52 g (102%) Ή-NMR (CDC1): 1.35 (3H, t, J = 6.9Hz), 1.52 (9H, s), 3.55, 3.63 (2H, Abq, J = 17.7

Three

Hz), 4.00 (2H, d, J = 6.6Hz), 4.36 (2H, q, J = 6.9Hz), 5.12 (1H, d, J = 5.1Hz), 5.99 (1 H, m), 6.02 (1H , dd, J = 4.8, 9.0Hz), 6.93 (1H, d, J = 15.9Hz), 7.00 (1H, s), 7.26-7.4 6 (12H, m).

Reference example 2

[Chemical 41]

(1) 1 → 2 → 3

Compound 1 (25 (¾, 1.2511101) was suspended in methylene chloride (2.51), and Boc20 (381.5 g, 1.75 mol) was added to DABCO (0.14 g, 1.25 mmol) .The mixture was stirred at room temperature for 3 days. The residue was dissolved in ethanol (190 ml) and added to ice-cooled NaOH (200 g, 5.0 mol) in water (1.1 31) and the mixture was stirred for 50 minutes before adding water ( 2N-hydrochloric acid (2.61) was added, and the precipitated crystals were collected by filtration to give compound 3. Yield 343.2 g (100%) NMR-NMR (d-DMSO): 1.48 (9H, s), 7.90 (1H, s).

(2) 3 → 4

Compound 3 (100.5 g, 369 mmol) was dissolved in methanol (300 ml), and a solution of NH2OEt′HCl (40 g, 406 mmol) and Et3N (56.6 ml, 406 mmol) in methanol (600 ml) was added. The mixture was stirred at room temperature for 2 hours and 30 minutes, and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl acetate. The organic layer was dried under MgS04 and concentrated under reduced pressure. Compound 4 was obtained by adding ethyl acetate and ethyl ether to the crystalline residue and filtering. Yield 99.7 g (86%). In the NMR analysis of this product, the anti-isomer of the talented oxime site was unacceptable.

'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9Hz), 1.47 (9H, s), 4.11 (2H, q, J = 6.9Hz), 7

• 34 (1H, s).

(3) 4 → 5

Trifluoroacetic acid (3 ml) was cooled on ice, and compound 4 (946 mg, 3 mmol) was added. The mixture was stirred at room temperature for 2 hours and 10 minutes, and then added to a solution of 4N HCl / EtOAc (0.9 ml, 3.6 mmol) in ethyl acetate (10 ml) that had been ice-cooled in advance. The mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration to obtain Compound 5. Yield 706 mg (94%). In the NMR analysis of this product, no anti-isomer at the oxime site was found.

'H-NMR (d-DMSO): 1.25 (3H, t, J = 7.2Hz), 4.19 (2H, q, J = 7.2Hz), 7.00 (1H, s).

(4) 6 → 7

Compound 6 (108 g, 0.5 mol) was suspended in dimethylformamide (375 ml), and Etl (60 ml, 0.75 mol) and then DBU (112 ml, 0.75 mmol) were added under ice cooling. The mixture was stirred for 30 minutes under ice cooling, warmed to room temperature, and further stirred for 1 hour and 30 minutes. Ice water (21) was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes, and the precipitated precipitate was collected by filtration. The precipitate was suspended in ethanol (400 ml) and 4N_NaOH (400 ml, 1.6 mol) was added. The mixture was stirred at 40 ° C for 2 hours, and then 6N-HCl (270 ml, 1.6 mol) was added under ice cooling. The mixture was stirred for 2 hours under ice cooling and the precipitated crystals were collected by filtration to obtain Compound 7. Yield 43.6 g (4 1%). In the NMR analysis of this product, no anti-isomer at the oxime site was observed. 'H-NMR (d-DMSO): 1.20 (3H, t, J = 6.9Hz), 4.11 (2H, q, J = 7.2Hz), 6.84 (1H, s), 7

• 23 (2H, s).

(5) 7 → 5 Compound 7 (19.4 g, 83 mmol) was suspended in acetic acid (100 ml), heated to 90 ° C. and completely dissolved. The mixture was gradually cooled to room temperature, and the precipitated crystals were collected by filtration. The crystals were suspended in ethyl acetate and 4N-HCl / EtOAc (27 ml, 108 mmol) was added. The precipitated oily precipitate was crystallized and collected by filtration to obtain Compound 5. Yield 18.5 g (89%). NMR analysis of this product showed the same spectral pattern as in (3) above. Also, no anti-isomer at the oxime site was observed.

(6) 5 → 8

Ogitalyl chloride (4.8 ml, 55 mmol) was added dropwise to a mixture of ice-cooled dimethylformamide (4.64 ml, 60 mmol) and methylene chloride (250 ml), and the mixture was stirred for 20 minutes under ice cooling. After cooling to _40 ° C, compound 5 (12.6g, 50mmol) was added and stirred at -30 ° C for 4 hours. Further, a methylene chloride solution of Vilsmeier reagent prepared from dimethylformamide (0.85 ml) and oxalyl chloride (0.87 ml) was added. The reaction solution was further stirred at _30 ° C for 1 hour and 20 minutes, and the precipitated crystals were collected by filtration to obtain Compound 8. Yield 11.2 g (83%). In the NMR analysis of this product, no anti-isomer at the oxime site was found.

'H-NMR (CD OD): 1.34 (3H, t, J = 7.2Hz), 4.33 (2H, q, J = 7.2Hz), 7.14 (1H, s).

Three

CD ester]

Three

Fig. 2 shows the powder X-ray diffraction pattern of Compound 8 (hydrochloride crystals).

(7) 8 + 9 → 10

Compound 9 (2.39 g, 5 mmol) was suspended in ethyl acetate (50 ml), N-methylmorpholine (2.20 ml, 20 mmol) was added at _30 ° C, and then Compound 8 (1.55 g, 5.74 mmol) was added to -30 ° The mixture was stirred at C for 1 hour. After dilute hydrochloric acid was added to the reaction solution for neutralization, the organic layer was separated and washed with water, an aqueous NaHC03 solution, and then brine. After drying with MgSO, 3.4N_HCl / MeOH (2.21 ml, 7.5 mmol) was added.

Four

Concentration under reduced pressure gave compound 10 as crystals. Yield 3.36 g (100%)

'H-NMR (d-DMSO): 1.27 (3H, t, J = 6.9Hz), 3.66, 3.91 (2H, ABq, J = 17.9 Hz), 4.

6

11-4.22 (4H, m), 5.29 (1H, d, J = 4.8Hz), 5.91 (1H, dd. J = 5.1, 8.1Hz), 6.27 (1H, m), 6.73 (1H, d, J = 15.3Hz), 6.88 (1H, s), 6.98 (1H, s), 7 · 29_7 · 51 (10mm, m), 9.80 (1H, d, J = 8.4Hz).

Fig. 4 shows the powder X-ray diffraction pattern of Compound 10 (hydrochloride crystals). Reference example 3

[Chemical 42]

ι- '

(1) 1-1 → 1-2

Compound l_l (173 mg, 0.31 mmol) is dissolved in dichloromethane (1.6 ml), and pyridine (45/11, 0.5611111101) and phosphorus pentachloride (116 mg, 0.56 mmol) are added under ice-cooling and stirring. After stirring for 30 minutes, methanol (2.4 ml) that had been ice-cooled in advance was stirred for 30 minutes. The reaction mixture was poured into water, extracted with dichloromethane, washed with aqueous sodium bicarbonate and brine, dried and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1.5 ml), and 4N-hydrochloric acid ethyl acetate solution (77 / i 1) was added dropwise with ice-cooling and stirring. Subsequently, the residue was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (2 ml), and ethyl ether (2 ml) was gradually added. The precipitated crystals were collected by filtration and dried to obtain compound l_2 (80 mg: yield; 54%).

'H-NMR (CDC1): 3.50— 4 · 10 (4Η, m), 5.00 (1H, d, J = 4.7Hz), 5.17 (1H, d, J = 4.7Hz

Three

), 5.76 (1H, m), 6.48 (0.9H, d, J = 11.3Hz), 6.92 and 6.98 (1H, s), 7.18 (0.1 H, d, J = 16.1Hz), 7.21-7.50 ( 10H, m)

(2) l-2 → l-4

Compound 1-2 (1.56 g, 3.3 mmol) and Compound l_3 (1.43 g, 4.25 mmol) were suspended in tetrahydrofuran (33 ml), cooled to _30 ° C, and N-methylmorpholine (l.lml, 9.8 mmol) was added. Then diphenyl neil phosphate dichloride (685 μl, 4.58 mmol) was added. The reaction solution was stirred for 1 hour and 10 minutes, acidified with 2N-hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to obtain compound 4 (2.0 g: yield; 81%). In the NMR analysis of this product, the double bond site of the propenyl group at position 3 of cefme was E: Z = 16: 84.

'H-NMR (DMSO-d6): 1.47 (9H, s), 3.40—4.00 (4H, m), 3.92 (3H, s), 5.25 (0.16H, d, J = 4.9Hz), 5.30 (0.84H , d, J = 4.9Hz), 5.56 (1H, m), 5.94 (1H, m), 6.28 (0.84H, d, J = 11.0Hz), 6.70 (0.16H, d, J = 15.5Hz), 6.88 And 6.99 (1H, s in total), 7.20-7.60 (10 H, m), 9.72 (1H, d, J = 8.5 Hz), 12.09 (1H, brs).

MS (ESI): 758 ⁺ (M + H) ⁺

Reference example 4

[Chemical 43]

(1) l-2 → l-6

Compound l-2 (1.95 g, 4.1 mmol) and compound l-5 (1.68 g, 5.3 mmol) were suspended in tetrahydrofuran (41 ml), cooled to -40 ° C, and N-methylmorpholine (1.34 ml, 12.2 mmol). Then, diphenyl phosphoric acid dichloride (854 μl, 5.71 mmol) was added and stirred for 1 hour. Further, N-methylmorpholine (0.45011, 4.11! 111101) was added, diphenyl phosphate dichloride (305 1,211111101) was added, and the mixture was stirred for 40 minutes. The reaction solution was acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate-n hexane) to obtain Compound l_6 (2.7 g: yield; 88%).

In the NMR analysis of this product, the double bond site of the propenyl group at position 3 of cefme was E: Z = 17: 83.

'H-NMR (DMSO-d6): 1.27 (3H, t, J = 7.1Hz), 1.51 (9H, s), 3.41-4.10 (4H, m), 4.22 (2H, q, J = 7.1Hz), 5.27 (0.17H, d, J = 5.0 Hz), 5.33 (0.83H, d, J = 5.0 Hz), 5.58 (1H, m), 5.98 (1H, m), 6.27 (0.83H, d, J = 10.2 Hz), 6.70 (0.17H, d, J = 15.5 Hz), 6.88 and 6 .99 (1H, s), 7.20-7.50 (10H, m), 9.70 (1H, d, J = 8.7Hz), 12.60 (1H, brs). MS (ESI): 739 ⁺ (M + H) ⁺

Reference Example 5

[Chemical 44]

(1) l-2 → l-8

Compound l_2 (1.64 g, 3.4 mmol) and compound l_7 (1.41 g, 4.5 mmol) are suspended in tetrahydrofuran (34 ml), cooled to -30 ° C and N-methylmorpholine (1.13 ml, 12.2 mmol) Then, diphenyl diphosphoric dichloride (721 xl, 4.82 mmol) was added and stirred for 1 hour and 40 minutes. The reaction mixture was acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate_n hexane) to obtain Compound 8 (2.19 g, yield; 86%).

In the NMR analysis of this product, the double bond site of the propenyl group at position 3 of cefme was E: Z = 16: 84.

'H-NMR (CDC1): 1.37 (3H, t, J = 7.1Hz), 1.54 (9H, s), 3.30—3 · 90 (4Η, m), 4.38 (2H,

Three

q, J = 7.1Hz), 5.12 (0.16H, d, J = 4.9 Hz), 5.16 (0.84H, d, J = 4.9Hz), 5.64 (1H, m), 6.06 (1H, m), 6.23 ( 0.84H, d, J = 11.4Hz), 6.93 and 6.99 (1H, s in total), 7.00 (0.16 H, d, J = 15.0Hz), 7.20—7.50 (11H, m)

Reference Example 6

[Chemical 45]

1-9

(1) 1-9 → 1-11 Compound l-10 (1.64 g, 5.5 mmol) is suspended in ethyl acetate (40 ml), cooled to _20 ° C and added with triethylenamine (0.98 ml, 7 mmol) and methanesulfonyl chloride (503 β1, 5.1311111101). The mixture was stirred at _20 ° 〇 to -10 ° C for 1 hour. Next, under cooling at −20 ° C., N-methylmorpholine (1.37 ml, 12.5 mmol) and compound l-9 (2.39 g, 5 mmol) were sequentially added and stirred for 15 minutes. The reaction solution was acidified with dilute hydrochloric acid, washed with brine, dried and concentrated under reduced pressure. The residue was subjected to silica gel chromatography (ethyl acetate-toluene) to obtain compound l_ll (3.49 g: yield; 97%).

'H-NMR (CDC1): 1.13 (3H, t, J = 7.5Hz), 1.46 (9H, s), 2.57 (2H, m), 3.14, 3.33 (2H,

Abq, J = 16.5Hz), 3.97-4.08 (2H, m), 5.02 (1H, d, J = 4.8Hz), 5.72 (1H, m), 5.87 (1H, m), 6.44 (3H, t, J = 7.5Hz), 6.76 (1H, s), 6.85 (1H, s), 6.99 (1H, d, J = 15.9Hz), 7.13- 7.41 (10H, m), 7.95 (1H, d, J = 8.1Hz ).

Reference Example 7

[0025] [Chemical 46]

1-9 1-13

(1) 1-9 → 1-13

Compound 1-9 (1.91 g, 4 mmol) and compound l_12 (1.25 g, 4 mmol) were suspended in ethyl acetate (20 ml), cooled to -50 ° C and diphenyl phosphate dichloride (717 μl, 4.8 mmol) Then, Ν-methylmorpholine (1.76 ml, 16 mmol) was added and stirred for 30 minutes. The reaction mixture was acidified with 2N-hydrochloric acid, extracted with ethyl acetate, washed successively with water, aqueous sodium hydrogen carbonate, and brine, dried and concentrated under reduced pressure to give compound l_13 (3.06 g).

'H-NMR (CDC1): 0.99 (3H, t, J = 7.2Hz), 1.53 (9H, s), 1.50- 1 · 58 (2Η, m), 2.56 (2H, m), 3.17, 3.35 (2H , Abq, J = 17.4Hz), 3.99—4.06 (2H, m), 5.03 (1H, d, J = 4.5Hz), 5.74 (1H, m), 5.87 (1H, m), 6.47 (3H, t, J = 7.5Hz), 6.77 (1H, s), 6.90 (1H, s), 6.99 (1H, d, J = 15.9Hz), 7.25-7.44 (10H, m), 7.90 (1H, d, J = 8.1 Hz).

Reference Example 8

[0026] [Chemical 47]

1-9 1-15

(1) 1-9 → 1-15

Compound l-15 (2.5 g) was obtained from compound l-9 (1.43 g, 3 mmol) and compound l_14 (988 mg, 3 mmol) in the same manner as in Reference Example 7.

'H-NMR (CDC1): 1.36 (6H, m), 1.53 (9H, s), 3.55, 3.64 (2H, Abq, J = 17.9Hz), 4.01 (

Three

2H, d, J = 6.9Hz), 4.66 (1H, m), 5.11 (1H, d, J = 4.8Hz), 5.94_6.04 (2Η, m), 6.93 (1H, d, J = 15.9Hz) , 7.02 (1H, s), 7.26_7.46 (11H, m), 7.56 (1H, d, J = 9.3Hz).

Reference Example 9

[Chemical 48]

1-9 1-17

(1) 1-9 → 1-17

Compound l-17 (2.3 g) was obtained from compound 1-9 (1.38 g, 2.9 mmol) and compound l_16 (965 mg, 2.9 mmol) in the same manner as in Reference Example 7.

'H-NMR (CDC1): 1.52 (9H, s), 3 · 53,3 · 60 (2Η, Abq, J = 17.7Hz), 4.01 (2H, d, J = 7.2

Three

Hz), 4.46-4.78 (4H, m), 5.12 (1H, d, J = 4.8Hz), 5.94-6.04 (2H, m), 6.96 (1H, d, J = 1 6.8Hz), 6.99 (1H, s), 7.26- 7.47 (11H, m), 7.52 (1H, d, J = 8.7Hz).

Reference Example 10

[Chemical 176] , s, (C ₂ H ₅ ) ₃ N _S-

H ₂ N, TEA H ₂ N,

N C0 ₂ H Ν ', C0 ₂ H

N DMA

'., OEt ■ OEt

Compound 1 (9 g, 41.8 mmol) was dissolved in 45 mL of dimethylenoacetamide, and triethinoreamin (6.4 mL, 45.98 mL) was added dropwise at 10 to 30 ° C. and reacted for 2 hours. The obtained crystals were filtered and washed with 27 mL of acetyl acetate to give compound 2 (triethylamine salt crystals). Yield 6.85 g (90.0%).

The powder X-ray diffraction pattern of Compound 2 is shown in FIG.

Reference Example 11

[Chemical 177]

, S, TEA

H ₂ NH

4 (EIA-TEA)

(1) Phosphorus pentachloride (2.8 g, 13.415 mmol) was dissolved in 15 mL of dichloromethane, cooled to 5 ° C., and pyridine (1.25 mL, 15. 203 mmol) was added dropwise. To this solution, a solution of compound 1 (5.00 g, 8.943 mmol) dissolved in 45 mL of dichloromethane was added dropwise at 15 ° C., and then reacted at −5 ° C. for 1.5 hours. This reaction solution was dropped into a mixed solution of methanol (5.45 mL) and dichloromethane (20 mL) cooled to -15 ° C, and reacted at -15 to 15 ° C for 1 hour. Thereafter, the reaction solution was poured into 25 mL of cold water, followed by liquid separation, and the organic layer was washed with 20% NaCl aqueous solution and tetra-n-butylammonium bromide.

(2) Compound 4 (2.83 g, 8.943 mmol) was dissolved in 8 mL of dimethinoreacetamide, -15 to 10. Cooled to C. Mesyl chloride (0.76 mL, 9.837 mmol) was added dropwise thereto, and the mixture was reacted at −15 to −10 ° C. for 2 hours. (3) — 15 to — The reaction solution of (2) is poured into the solution of (1) containing Compound 2 that has been cooled to 10 ° C., and N-methylolmonoreforin (0.998 mL, 8. 943 mmol) was added dropwise, followed by reaction at 15 to 15 ° C. for 1.5 hours. The reaction solution was poured into 25 mL of 0.5N aqueous hydrochloric acid, and the organic layer was concentrated, concentrated by adding 50 mL of ethyl acetate, and concentrated again by adding 50 mL of ethyl acetate. To this concentrated solution was added 10 mL of ethyl acetate, and the organic layer was concentrated again after washing 4 times with 25 mL of 5% NaCl aqueous solution. Ethanol (2.5 mL) was added to this concentrate at 20 to 25 ° C, seed crystals were added, and the mixture was cooled to 0 to 5 ° C. 4N Etyl acetate monoacetate was allowed to stand at 2 mL and 5 ° C for 15 hours. Compound 3 was obtained as white crystals. Yield 4.12g.

Example 1

[Chemical 49]

2

(1) 2 → 3

Silver nitrate (13.8 g, 81.2 mmol) was dissolved in water (50 ml), and sodium hydroxide (6.48 g, 162 mmol) was added. 2 (5.73 g, 30 mmol) was added to the obtained suspension under ice cooling, and the mixture was stirred for 1 hour 20 minutes under ice cooling. The insoluble material was filtered through a celite pad and washed with water. When concentrated hydrochloric acid was added to the filtrate, crystals were precipitated, which were collected by filtration and washed with water. The crystals were dried under reduced pressure to obtain Compound 3. Yield 5.71 g (92%) NMR-NMR (CDC13): 7.54 (1H, d, J = 1.5 Hz), 7.78 (1H, d, J = 1.5 Hz)

(2) 3 → 4

Compound 3 (5.64 g, 27.2 mmol) was dissolved in methanol (50 ml), and thionyl chloride (3.97 ml, 54.4 mmol) was added dropwise under ice cooling. The mixture was stirred at room temperature for 25 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed sequentially with aqueous NaHCO solution, water, and brine. No solution

Three

It was dried over water MgSO and concentrated under reduced pressure to give compound 4 as crystals. Yield 5.23g (87%)

Four

'H-NMR (CDC13): 3.93 (3H, s), 7.44 (1H, d, J = 1.5 Hz), 7.69 (1H, d, J = 1.5 Hz).

(3) 5 + 4 → 6

Compound 4 (l.llg, 5 mmol) and compound 5 (738 mg, 6 mmol) were suspended in a mixed solvent of dioxane (25 ml) and water (5 ml), and then 5N NaCO aqueous solution was added. Tetrakistri in the mixture

twenty three

After phenylphosphine palladium (289 mg, 0.25 mmol) was added, 100 under nitrogen flow. The mixture was stirred at C for 1 hour and 30 minutes. The reaction solution was diluted with ethyl acetate and washed twice with water and then with brine. The solution was dried over anhydrous MgSO and concentrated under reduced pressure. Ethyl acetate was added to the resulting solid residue.

Four

, And an aqueous NaHCO solution were added, and the deposited precipitate was removed by filtration. The filtrate is 2N-salt

Three

Acid was added to adjust the pH to 2 or less, and the aqueous layer was separated. Add NaHCO to pH 7 or higher.

Three

And then extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO and concentrated under reduced pressure.

Four

Compound 6 was obtained as colorless crystals. Yield 551mg (50%)

'H-NMR (CDC13): 3 · 90 (3Η, s), 7.49 (2H, dd, J = 1.5 Hz, 4.5Hz), 7.85 (1H, d, J = 1.8 Hz), 8.12 (1H, d , J = 1.8Hz), 8.65 (2H, d, J = 6Hz).

(4) 6 → 7

Compound 6 (532 mg, 2.43 mmol) was dissolved in methanol (10 ml), and cyanamide (102 mg, 2.43 mmol) and 1.02N_MeONa / MeOH (2.38 ml, 2.43 mmol) were added. After stirring at 50 ° C for 20 hours, cyanamide (204 mg, 4.85 mmol) and 1.02N_MeONa / MeOH (4.76 ml, 4.86 mmol) were added, and the mixture was further stirred at 50 ° C for 15 hours. The reaction solution was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 6.0 with 2N-HC1 to precipitate. The precipitate was collected by filtration and suspended in methanol. To this suspension, lN_Me 0 Na / Me 0 H was added to adjust the pH to 7.3 and dissolved, and then the solution was concentrated under reduced pressure to obtain Compound 7 as a light brown powder. Yield 333 mg (55%)

'H-NMR (d-DMSO): 7.71 (2H, d, J = 6.3Hz), 7.90 (1H, d, J = 1.5 Hz), 8.12 (1H, d,

6 J = 1.8Hz), 8.55 (2H, d, J = 6.0Hz).

(5) 8 + 7 → 9

Compound 8 (738 mg, lmmol) and compound 7 (25 lmg, lmmol) were suspended in dimethylformamide (2 ml), and sodium bromide (309 mg, 3 mmol) was stirred at room temperature for 4 hours and 20 minutes. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was suspended in water and lyophilized to obtain Compound 9 as an amorphous powder. Yield 851 mg (102%)

'H-NMR (d-DMSO): 1.24 (3H, t, J = 7.2Hz), 1.47 (9H, s), 3.66, 3.90 (2H, ABq, J =

17.7 Hz), 4.14 (2H, q, J = 7.2Hz), 5.21 (2H, d, J = 6.3Hz), 5.30 (1H, d, J = 5.1Hz), 5.95 (1H, dd.J = 4.8, 8.4Hz), 6.42 (1H, m), 6.87 (1H, d, J = 15.9Hz), 6.91 (1H, s), 7.27 -7.50 (11H, m), 8.20 (1H, d, J = 1.5 Hz), 8.48 (2H, d, J = 6.9Hz), 8.67 (1H, d, J = 1.5Hz), 8.87 (2H, d, J = 9.0Hz), 9.73 (1H, d, J = 7.2Hz ), 11.80 (1H, s)

(6) 9 → 1

Compound 9 (845 mg, lmmol) was dissolved in methylene chloride (5 ml) and anisole (lml), and 2M / l-TiCl2 / CHCI (3 ml, 6 mmol) was added at _30 ° C. After stirring the mixture at -30 ° C for 1 hour 30 minutes,

The mixture was poured into 0.3N-hydrochloric acid (30 ml) and isopropyl ether (30 ml) with stirring under ice cooling. The precipitated precipitate was collected by filtration and dissolved in a mixed solvent of dilute hydrochloric acid and acetonitrile. HP-20SS was added to the solution, concentrated, subjected to HP-20SS column chromatography, and dissolved with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the resulting residue (266 mg) was suspended in water (7 ml) and dissolved by adding NaHCO 3 (34 mg, 0.40 mmol). The solution was lyophilized to give Compound 1 as a powder. Yield 272mg (35%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.43, 3.49 (2H, ABq, J = 17.1 Hz), 4.

09 (2H, q, J = 7.2Hz), 5.05 (1H, d, J = 4.8Hz), 5.21 (2H, d, J = 7.2Hz), 5.60 (1H, dd. J = 4.8, 8.1Hz), 5.87 (1H, m), 6.72 (1H, s), 7.22 (2H, s), 7.29 (1H, d, J = 15.9Hz), 8.1 7 (1H, d, J = 1.8Hz), 8.48 (2H, d, J = 6.9Hz), 8.65 (1H, d, J = 1.5Hz), 8.93 (2H, d, J = 7.2Hz), 9.54 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3417, 2982, 2177, 1762, 1634, 1602, 1538, 1470, 1434, 1382, 1353, 1251, 1204.

MS (ESI): 709 ⁺ (M + H) ⁺ Elemental analysis CHNOS Na-4.5 HO-0.2NaHCO

30 25 8 6 2 2 3

Calculated values: C, 46.59; H, 4.43; N, 14.39; S, 8.24; Na, 3.54 (%)

Experimental value: C, 46.60; Η, 4.43; Ν, 14.63; SJ.45; Na, 3.48 (%)

Example 2

[Chemical 50]

(1) 11 → 12

Compound l l (4.02 g, 20 mmol) was dissolved in tetrahydrofuran (30 ml), and a solution of diphenyldiazomethane (3.88 g, 54.4 mmol) in tetrahydrofuran (30 ml) was added dropwise. The mixture was stirred at room temperature for 27 hours and concentrated under reduced pressure. Hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain Compound 12. Yield 7.07g (96%)

'H-NMR (CDC13): 7.09 (1H, s), 7.25-7.43 (10H, m), 7.59 (2H, d, J = 9.0Hz), 7.99 (2H, d, J = 8.7Hz)

(2) 12 + 13 → 14

Compound 12 (2.94 g, 8 mmol) and compound 13 (1.64 g, 8 mmol) were dissolved in dioxane (70 ml), and then K 3 PO 4 (8.49 g, 40 mmol) was added. Tetrakistriphenylphosphine in the mixture

3 4

Palladium (462 mg, 0.4 mmol) was added, and the mixture was stirred at 100 ° C for 4 hours under a nitrogen stream. Reaction liquid The filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, added anhydrous MgSO and filtered again. The filtrate was concentrated under reduced pressure to give compound 14. Yield 1.74 g (60%)

'H-NMR (CDC13): 7.15 (1H, s), 7.26- 7.47 (10H, m), 7.54 (2H, d, J = 5.4Hz), 7.72 (2H, d, J = 8.1Hz), 8.25 (2H, d, J = 6.9Hz), 8.71 (2H, d, J = 4.5Hz).

(3) 14 → 15

Compound 14 (1. lg, 3 mmol) was dissolved in tetrahydrofuran (5 ml) and methanol (10 ml), and 2N_Na 0 H (4.5 ml, 9 mmol) was added. The reaction solution is 60. The mixture was stirred at C for 30 minutes, and 2N_HCl was added to adjust the pH to 3.5 to precipitate crystals. The suspension was concentrated under reduced pressure, water and ethyl acetate were added, and the crystals were collected by filtration to give compound 15. Yield 502mg (84%)

'H-NMR (d-DMSO): 7.78 (2H, d, J = 6.0Hz), 7.87 (2H, d, J = 8.7Hz), 8.07 (2H, d, J

= 8.7Hz), 8.69 (2H, d, J = 6.3Hz).

(4) 15 → 16

Compound 15 (489 mg, 2.45 mmol) was suspended in dimethylformamide (5 ml) and Im CO (753 mg, 3.

92 mmol) was added. After stirring at 50 ° C for 30 minutes, NaNHCN (314 mg, 4.9 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water, and the pH was adjusted to slightly acidic with 2N-HC1 to precipitate the precipitate. The precipitate was collected by filtration and suspended in methanol. This suspension was dissolved by adding lN_MeONa / MeOH to pH 7.5, and then concentrated under reduced pressure to obtain Compound 16 as a white powder. Yield 654mg (108%)

'H-NMR (d-DMSO): 7.73 (2H, d, J = 6.6 Hz), 7.76 (2H, d, J = 8.7 Hz), 8.03 (1H, d,

J = 8.1Hz), 8.63 (2H, d, J = 6.3Hz).

(5) 8 + 16 → 17 → 10

Compound 8 (738 mg, 1 mmol) and Compound 16 (245 mg, 1 mmol) were used in the same manner as in Example 1 (5) to obtain Compound 17 as an amorphous powder. Yield 843 mg (91%). Compound 10 was obtained as a powder in the same manner as in Example 1, (6) using Compound 17 (828 mg, 0 • 90 mmol) in 2M / 卜 TiCl 2 / CH 2 CI (2.7 ml, 5.4 mmol). Yield 326mg (47%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.44, 3.50 (2H, ABq, J = 16.2 Hz), 4.

09 (2H, q, J = 7.2Hz), 5.05 (1H, d, J = 4.8Hz), 5.29 (2H, d, J = 6.6Hz), 5.60 (1H, dd. J = 4.5, 8.1Hz), 5.88 (1H, m), 6.72 (1H, s), 7.22 (2H, s), 7.32 (1H, d, J = 15.9Hz), 8.0 2 (2H, d, J = 8.4Hz), 8.11 (2H, d, J = 9.0Hz), 8.51 (2H, d, J = 6.6Hz), 8.93 (2H, d, J = 6.6Hz), 9.53 ( (1H, d, J = 8.1Hz).

IR (KBr) cm— 3409, 2983, 2151, 1763, 1634, 1599, 1563, 1531, 1462, 1364, 1306, 1200.

MS (FAB +): 681+ (M + H) +

Elemental analysis c H N O S Na-4.1 H O-0.17 NaHCO

28 23 8 6 3 2 3

Calculated values: C, 43.67; H, 4.08; N, 14.46; S, 12.42; Na, 3.47 (%)

Experimental value: C, 43.59; H, 4.10; N, 14.50; S, 12.11; Na, 3.47 (%)

Example 3

[Chemical 51]

19

(1) 17 → 18

Compound 17 (563 mg, 2.74 mmol) was suspended in dimethylformamide (10 ml) and Im CO (631 mg,

2

3.28 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, 4-methoxybenzyl alcohol (0.51 3 ml, 4.11 ml) was dissolved in dimethylformamide (5 ml), NaH (164 mg, 4. Immol) was added, and the mixture was stirred for 15 minutes. This solution was poured into the reaction solution and stirred at room temperature for 1 hour. The residue was diluted with ethyl acetate and washed twice with water. The organic layer was dried over anhydrous MgSO and then reduced pressure

Four

Concentrated with. The residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate (2: 1). The eluent was concentrated under reduced pressure to obtain Compound 18 as white crystals. Yield 882mg (92%) Ή-NMR (CDC13): 3 · 82 (3Η, s), 5 · 30 (2Η, s), 6.92 (2Η, d, J = 8.7Hz), 7.39 (2H, d, J = 8.7Hz), 7.47 (2H, d, J = 6.3Hz), 7.84 (1H, d, J = 1.5Hz), 8.10 (1H, d, J = 1.8Hz), 8.6 3 (2H, d, J = 6.0Hz)

(2) 8 + 18 → 19 → 16

Compound 8 (738 mg, 1 mmol) and Compound 18 (325 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 19 as an amorphous powder. Yield 985 mg (89%). Compound 16 was obtained as a powder in the same manner as in Example 6, (6), using Compound 19 (973 mg, 0.88 mmol) in 2M / 卜 TiCl 2 / CH 2 CI (4.4 ml, 8.8 mmol). Yield lllmg (15%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.42, 3.48 (2H, ABq, J = 17.1 Hz), 4.

09 (2H, q, J = 7.2Hz), 5.04 (1H, d, J = 4.8Hz), 5.20 (2H, d, J = 6.3Hz), 5.59 (1H, dd. J = 4.8, 8.4Hz), 5.85 (1H, m), 6.71 (1H, s), 7.22 (2H, s), 7.27 (1H, d, J = 15.9Hz), 7.9 0 (1H, d, J = 1.5Hz), 8.42 (2H, d, J = 6.9Hz), 8.53 (1H, d, J = 1.5Hz), 8.88 (2H, d, J = 6.9Hz), 9.52 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3409, 2982, 1763, 1634, 1598, 1536, 1470, 1434, 1362, 1203.

MS (ESI): 641 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-6.0H O-1.0 NaHCO

Calculated values: C, 39.34; H, 4.25; N, 9.83; S, 11.25; Na, 5.38 (%)

Experimental values: C, 39.34; H, 4.22; N, 10.09; S, 11.77; Na, 5.31 (%)

Example 4

[Chemical 52]

(1) 2 1 + 18 → 22 → 20 Using Compound 21 (721 mg, 1 mmol) and Compound 18 (325 mg, 1 mmol), Compound 22 was obtained as an amorphous powder in the same manner as in Example 1, (5). Yield 999 mg (88%). Using this compound 22 (983 mg, 0.86 mmol) in 2 M / ヽ TiCl 2 / CH CI (4.3 ml, 8.6 mmol), the same method as in Example 1, (6)

4 2 2

Compound 20 was obtained as a powder. Yield 98 mg (12%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.18 (2H, m), 3.44, 3.50 (2H, ABq, J =

16.4 Hz), 5.05 (1H, d, J = 4.8Hz), 5.20 (2H, d, J = 5.7Hz), 5.59 (1H, dd.J = 5.1, 8.1 Hz), 5.84 (1H, m), 6.20 (1H, s), 6.22 (1H, t, J = 8.1Hz), 7.00 (2H, s), 7.28 (1H, d, J = 15.9Hz), 7.90 (1H, s), 8.4 2 (2H, d , J = 6.6Hz), 8.53 (1H, s), 8.88 (2H, d, J = 6.6Hz), 9.22 (1H, d, J = 7.8Hz).

IR (KBr) cm ^_1 : 3409, 2969, 1761, 1633, 1602, 1536, 1470, 1435, 1362, 1252, 1223. MS (ESI): 624 ⁺ (M + H) ⁺

Elemental analysis c H N O S Na-6.0H O-0.7NaHCO

28 24 5 6 3 2 3

Calculated value: C, 42.51; Η, 4.35; Ν, 8.64; S, 11.86; Na, 4.82 (%)

Experimental value: C, 42.38; Η, 4.59; Ν, 8.75; S, 11.73; Na, 4.76 (%)

Example 5

[Chemical 53]

(1) 21 + 24 → 25 → 23

Using compound 21 (721 mg, lmmol) and compound 24 (236 mg, lmmol), compound 25 was obtained as an amorphous powder in the same manner as in Example 1, (5). Yield 919 mg (102%). This compound 25 (907 mg, l.Olmmol) was used in the same manner as (6) of Example 1 using 2 M / 卜 TiCl 2 / CH CI (3.0 ml, 6.0 mmol).

4 2 2

To obtain Compound 23 as a powder. Yield 246 mg (32%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.5Hz), 2.16 (2H, m), 3.43, 3.49 (2H, ABq, J = 16.8 Hz), 5.04 (1H, d, J = 4.8Hz), 5.31 (2H, d, J = 6.9Hz), 5.59 (1H, dd.J = 4.5, 7.8 Hz), 5.85 (1H, m), 6.19 (1H, s), 6.21 (1H, t, J = 7.8Hz), 6.98 (2H, s), 7.30 (1H, d, J = 15.9Hz), 7.69 (1H, s), 8.61 (2H, d, J = 7.2Hz), 9.15 (2H, d, J = 7.2Hz), 9.20 (1H, d, J = 7.8Hz).

IR (KBr) cm "': 3420, 2969, 2171, 1761, 1610, 1530, 1475, 1437, 1359, 1256.

MS (FAB): 655+ (M + H) +

Elemental analysis c H N O S Na-4.3H O-0.25 NaHCO

28 23 8 6 2 2 3

Calculated values: C, 45.05; H, 4.26; N, 14.88; S, 8.52; Na, 3.82 (%)

Experimental value: C44.38; H, 4.23; N, 15.19; S, 8.39; Na, 3.85 (%)

Example 6

[Chemical 54]

32

(1) 27

Compound 27 was synthesized by the method described in the literature (J. Heterocycl. Chem. L971, 8, 571-580).

(2) 27 → 28

Compound 27 (3.03 g, 30 mmol) and POBr (8.60 g, 33 mmol) were stirred at 100 ° C. for 1 hour. At room temperature

Three

After cooling, the pH was adjusted to 7 or higher after adding ice carbonate and sodium carbonate. Methyl chloride in the mixture And activated carbon treatment. The methylene chloride layer was separated from the filtrate, dried over MgS04, and concentrated under reduced pressure (300 mmHg, 40 ° C.) to obtain Compound 28 as a yellow oil. Yield 3.4 g (69%)

'H-NMR (CDC13): 7.19 (1H, d, J = 5.4Hz), 8.58 (1H, d, J = 5.1Hz)

(3) 28 + 13 → 29

Compound 29 (1.64 g, 10 mmol) and Compound 13 (2.05 g, 10 mmol) were used in the same manner as in Example 2, (2) to give compound 29. Yellow crystals. Yield 1.20 g (74%)

'H-NMR (CDC13): 7.71 (1H, d, J = 4.8Hz), 7.88 (2Η, d, J = 6.0Hz), 8.73 (2H, d, J = 5.7Hz), 8.80 (1H, d, J = 4.8Hz).

(4) 29 → 30

i-Pr NH (1.40 ml, 10 mmol) was dissolved in tetrahydrofuran (10 ml), and n-butyllithium hexane solution (6 M / L, 6.24 ml) was stirred with ice-cooling for 30 minutes under ice-cooling. The solution was cooled to −78 ° C., and a solution of Compound 29 (1.08 g, 6.66 mmol) in tetrahydrofuran (10 ml) was prepared. After stirring for 15 minutes, C1C OOMe (1.03 ml, 13.3 mmol) was added, and the mixture was further stirred for 20 minutes. 2N-HC1 was added to the mixture and the mixture was returned to room temperature, and then Na2C03 was added to adjust the pH to 7 or higher. Extraction was performed with ethyl acetate, and the organic layer was washed with water and brine in this order. The organic layer was dried over MgS04 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate (3: 1). The eluent was concentrated under reduced pressure to obtain Compound 30 as white crystals. Yield 450mg (31%)

'H-NMR (CDC13): 3 · 99 (3Η, s), 7.88 (2H, d, J = 6.3Hz), 8.02 (1H, s), 8.76 (2H, d, J = 6.0Hz).

(5) 30 → 31

Compound 30 (437 mg, 1.98 mmol) was dissolved in methanol (8 ml) and NaNHCN (139 mg, 2.17 mmol) was added. After stirring at room temperature for 1 hour and 30 minutes, NaNHCN (127 mg, 1.98 mmol) was added, and the mixture was further stirred at room temperature for 40 minutes. The reaction solution was concentrated under reduced pressure, diluted with water, and the pH was adjusted to 2.0 with 2N-HC1 to precipitate a precipitate. The precipitate was collected by filtration and suspended in methanol. This suspension was added with lN_Me 0 Na / Me 0 H to adjust the pH to 7.7 and dissolved, and then the solution was concentrated under reduced pressure to obtain Compound 31 as a light brown powder. Yield 501mg (100%)

'H-NMR (d-DMSO): 7.97 (2H, d, J = 6.3Hz), 8.17 (1H, s), 8.65 (2H, d, J = 6.3Hz).

(6) 8 + 31 → 32 → 26 Using Compound 8 (738 mg, Immol) and Compound 31 (252 mg, Immol), Compound 32 was obtained as an amorphous powder in the same manner as in Example 1, (5). Yield 871 mg (93%). This compound 32 (854 mg, 0.92 mmol) was used in the same manner as (6) of Example 1 using 2 M / 卜 TiCl 2 / CH 2 CI (2.8, 5.6 mmol).

4 2 2

Compound 26 was obtained as a powder. Yield 304 mg (41%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.44, 3.49 (2H, ABq, J = 16.8 Hz), 4.

6

09 (2H, q, J = 7.2Hz), 5.05 (1H, d, J = 4.8Hz), 5.30 (2H, d, J = 6.9Hz), 5.60 (1H, dd. J = 4.8, 8.4Hz), 5.87 (1H, m), 6.72 (1H, s), 7.22 (2H, s), 7.31 (1H, d, J = 15.6Hz), 8.5 3 (1H, s), 8.72 (2H, d, J = 6.9 Hz), 9.09 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.1Hz). IR (KBr) cm ^_1 : 3430, 2981, 2930, 2174, 1762, 1635, 1606, 1531, 1467, 1401, 1341, 1202.

MS (FAB): 688+ (M + H) +

Elemental analysis c H N O S Na-4.7H O-0.35NaHCO

27 22 9 6 3 2 3

Calculated value: C, 40.97; Η, 3.99; Ν, 15.72; S, 12.00; Na, 3.87 (%)

Experimental value: C, 40.96; H, 3.73; N, 15.90; S, 11.99; Na, 3.91 (%)

Example 7

[Chemical 55]

(1) 34 → 35

Compound 34 (1.49 g, 6 mmol) was suspended in 2N-NaOH (4.8 ml, 9.6 mmol) and stirred for 45 minutes at room temperature. Stir. Crystals of 2N-HCl (4.8 ml, 9.6 mmol) were precipitated in the reaction solution. The crystals were collected by filtration to give compound 35. White crystals. Yield 1.24 g (98%)

'H-NMR (d-DMSO): 8.11 (2H, d, J = 5.4Hz), 8.76 (2H, d, J = 5.4Hz), 8.92 (1H, s).

(2) 35 → 36

Compound 35 (1.24 g, 6.0 mmol) was suspended in dimethylformamide (10 ml), and Im CO (1.39 g, 7.2 mmol) was added. After stirring at room temperature for 2 hours, t_BuOH (2.87 ml, 30 mmol) and t-BuOK (67 mg, 0.6 mmol) were added and stirred at 50 ° C. for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO and concentrated under reduced pressure. The residue was crystallized from hexane and collected by filtration to give compound 36. Pale yellow crystals. Yield 1.04 mg (66%) H-NMR (CDC1): 1.66 (9H, s), 7.88 (2H, d, J = 6.3 Hz), 7.95 (1H, s), 8.70 (2H, br-s).

(3) 21 + 36 → 37

Compound 21 (721 mg, 1 mmol) and compound 36 (262 mg, 1 mmol) were dissolved in dimethylformamide (2m 1), and sodium bromide (309 mg, 3 mmol) was stirred at room temperature for 4 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO, and concentrated under reduced pressure to give compound 37. Yield 899mg (87%)

'H-NMR (d-DMSO): 1.03 (3Η, t, J = 7.2Hz), 1.48 (9H, s), 1.61 (9H, s), 2.23 (2H, m)

, 3.68, 3.93 (2H, ABq, J = 17.4 Hz), 5.33 (3H, m), 5.90 (1H, dd. J = 4.8, 7.8Hz), 6.36 (1H, t, J = 8.1Hz), 6.42 ( 1H, m), 6.78 (1H, s), 6.92 (1H, d, J = 15.6Hz), 6.92 (1H, s), 7.27-7.51 (10H, m), 8.64 (2H, d, J = 6.9Hz ), 8.82 (1H, s), 9.05 (2H, d, J = 6.9Hz), 9.4 1 (1H, d, J = 7.8Hz), 11.54 (1H, s)

(4) 37 → 33

Compound 37 (879 mg, 0.86 mmol) was dissolved in methylene chloride (10 ml) and anisole (0.86 ml), −30. In C, 1 / CH NO (8.6 ml, 8.6 mmol) was added to 1M / 卜 A. The mixture was stirred at _30 ° C for 30 minutes, and then poured into 0.3N-hydrochloric acid (70 ml) and acetonitrile (70 ml) with stirring under ice cooling. Isopropyl ether (50 ml) and hexane (25 ml) were added to the solution, and the aqueous layer (lower layer) was separated. HP-20SS was added to the aqueous layer, concentrated, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. Fractions containing the desired compound were collected and 2N-NaOH was carefully added while stirring, and when the pH exceeded 10, dry ice was added to bring the pH to 5 or less. Reduce solution Concentration under pressure and lyophilization gave compound 33 as a powder. Yield 85 mg (13%)

'H-NMR (D O): 1.05 (3Η, t, J = 7.5Hz), 2.22 (2H, m), 3.66 (2H, s), 5.27 (3H, m), 5.8

0 (1H, d, J = 4.8Hz), 6.12 (1H, m), 6.32 (1H, t, J = 7.8Hz), 6.46 (1H, s), 6.96 (1H, d, J = 15.6Hz), 8.47 (2H, d, J = 6.9Hz), 8.64 (1H, s), 8.81 (2H, d, J = 6.9Hz).

IR (KBr) cm ^_1 : 3409, 2967, 2872, 1762, 1634, 1529, 1489, 1457, 1368, 1286, 1212. MS (ESI): 625+ (M + H) +

Elemental analysis c H N O S Na-4.2 H O-0.45 NaHCO

Calculated values: C, 43.37; H, 4.22; N, 11.06; S, 12.66; Na, 4.39 (%)

Experimental value: C, 43.67; H, 4.11; N, 10.76; S, 11.83; Na, 4.42 (%)

Example 8

[Chemical 56]

39 40 41 42

(1) 39 + 40 → 41

Compound 39 (1.48 g, 10 mmol) and compound 40 (2.39 g, 15 mmol) were dissolved in acetic acid (20 ml), and Zn powder (2.45 g, 38 mmol) was prepared. The reaction solution was stirred at room temperature for 2 hours, stirred at reflux for 1 hour and 40 minutes, and concentrated under reduced pressure. Suspend the residue in ethyl acetate and water until the pH is 8 or higher. The CO was collected and filtered through a celite pad. The organic layer was separated from the filtrate, washed with brine and dried over MgSO. The solution was concentrated under reduced pressure, crystallized from the residue with ethyl ether, and collected by filtration to give compound 41. Pale yellow crystals. Yield 1.19 g (52%)

'H-NMR (CDC13): 1.40 (3H, t, J = 7.2Hz), 2.52 (3H, s), 4.37 (2H, q, J = 7.2Hz), 7.1

4 (1H, d, J = 3.0Hz), 7.38 (2H, d, J = 6.9Hz), 8.59 (2H, d, J = 6.9Hz).

(2) 41 → 42

Compound 41 (1.38 g, 6 mmol) was dissolved in methanol (200 ml), and 2N-NaOH (15 ml, 30 mmol) was added. The reaction solution was stirred under reflux for 2 hours, and after concentrating methanol under reduced pressure, 2N-HCK (15 ml, 30 mmol) was precipitated as a crystal. The crystals were collected by filtration to give compound 42. White crystals. Yield 1.19 g (98%)

'H-NMR (d-DMSO): 2.47 (3H, s), 7.44 (1H, s), 7.56 (2H, d, J = 6.3Hz), 8.55 (2H, d,

J = 6.3Hz).

(3) 42 → 43

Compound 42 (880 mg, 4.4 mmol) was suspended in dimethylformamide (10 ml), and Im CO (l. Lg, 5.72 mmol) was added. After stirring at room temperature for 2 hours and 30 minutes, t-BuOK (2.97 g, 26 mmol) was added, and the mixture was stirred at 60 ° C for 5 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether and collected by filtration to give compound 43. Pale yellow crystals. Yield 364 mg (32%)

'H-NMR (CDC13): 1 · 60 (9Η, s), 2.47 (3H, s), 7.07 (1H, d, J = 3.3Hz), 7.33 (2H, d, J = 6.3Hz), 8.58 ( (2H, d, J = 6.3Hz).

(4) 21 + 43 → 44 → 38

Compound 21 (721 mg, 1 mmol) and Compound 43 (258 mg, 1 mmol) were used in the same manner as in Example 7, (3) to obtain Compound 44 as an amorphous powder. Yield 962 mg (94%). Using Compound 44 (947 mg, 0 • 92 mmol) in 1 M / 卜 A and 1 / CH NO (9.2 ml, 9.2 mmol) in the same manner as in Example 7, (4), Compound 38 was obtained as a powder. . Yield 282 mg (42%)

'H-NMR (d-DMSO + D〇): 1 · 00 (3Η, t, J = 7.5Hz), 2.18 (2H, m), 3.46, 3.53 (2H, AB q, J = 16.8 Hz), 5.05 (1H, d, J = 5.1Hz), 5.09 (2H, d, J = 6.6Hz), 5.62 (1H, d. J = 4.8 Hz), 5.84 (1H, m), 6.22 (1H, s), 6.24 (1H, t, J = 7.8Hz), 7.23 (1H, d, J = 16.2Hz), 7.61 (1H, s), 8.04 (2H, d, J = 7.2Hz), 8.63 (2H, d, J = 6.9Hz).

IR (KBr) cm— 3407, 2966, 1761, 1633, 1565, 1533, 1472, 1442, 1402, 1334, 1216. MS (ESI): 621+ (M + H) +

Elemental analysis c H N O S Na-4.5H O-0.1NaHCO

29 27 6 6 2 2 3

Calculated value: C, 47.74; H, 4.97; N, 11.48; S, 8.76; Na, 3.45 (%)

Experimental value: C47.56; H, 4.75; N, 11.62; S, 8.73; Na, 3.43 (%)

Example 9

[Chemical 57]

(1) 46 → 47

i-Pr NH (1.21 ml, 8.63 mmol) was dissolved in tetrahydrofuran (10 ml), and n-butyllithiate was cooled with ice.

2

The hexane solution (2.7M / L, 3.19ml) was stirred with vigorous ice cooling for 30 minutes. The solution was cooled to −78 ° C., and a solution of compound 46 (1.08 g, 6.66 mmol) in tetrahydrofuran (10 ml) was added. After stirring for 15 minutes, dry ice powder was added and the mixture was further stirred at room temperature for 1 hour and 20 minutes. Ethyl acetate and water were added, NaHC03 was added, and the pH was adjusted to 7 or higher. The aqueous layer was separated, and 2N hydrochloric acid was added to adjust the pH to 2.1 to precipitate crystals. Filtration gave compound 47 as white crystals. Yield 812 mg (68%)

'H-NMR (d-DMSO): 8.06 (2Η, d, J = 6.0Hz), 8.58 (1H, s), 8.73 (2H, d, J = 6.0Hz).

6 (2) 47 → 48

Using Compound 47 (412 mg, 2 mmol), Compound 48 was obtained as a white crystal in the same manner as in Example 7, (2). Yield 313 mg (60%)

'H-NMR (CDC13): 1.62 (9H, s), 7.85 (2H, d, J = 6.3Hz), 8.10 (1H, s), 8.74 (2H, d, J = 6.0Hz)

(3) 21 + 48 → 49 → 45

Compound 21 (721 mg, 1 mmol) and Compound 48 (262 mg, 1 mmol) were used in the same manner as in Example 7, (3) to obtain Compound 49 as an amorphous powder. Yield 998 mg (97%). This compound 49 (980 mg, 0.95 mmol) 1M / l-AlCl 3 / CH 2 NO (9.5 ml, 9.5 mmol) was used, and compound 45 was obtained as a powder in the same manner as in Example 7, (4). Yield 152 mg (21%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.17 (2H, m), 3.47, 3.54 (2H, ABq, J =

17.4 Hz), 5.08 (1H, d, J = 5.1 Hz), 5.30 (2H, d, J = 6.6 Hz), 5.62 (1H, dd. J = 4.8, 7.8 Hz), 5.91 (1H, m), 6.21 (1H, s), 6.23 (1H, t, J = 7.8Hz), 7.00 (2H, s), 7.29 (1H, d, J = 16.2Hz), 8.25 (1H, s), 8.67 (2H, d, J = 6.3Hz), 9,07 (2H, d, J = 6.3Hz), 9.23 (2H, d, J

= 8.1Hz).

IR (KBr) cm ^_1 : 3409, 2968, 1763, 1605, 1526, 1467, 1397, 1344, 1217.

MS (ESI): 625 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.4H O-0.25 NaHCO

Calculated value: C, 43.82; Η, 4.33; Ν, 11.25; S, 12.88; Na, 3.85 (%)

Experimental value: C, 43.56; Η, 3.94; Ν, 11.63; S, 12.69; Na, 3.92 (%)

Example 10

[Chemical 58]

(1) 51 → 52

Compound 51 (497 mg, 2.61 mmol) was used in the same manner as in Example 7, (2) to give compound 52 as white crystals. Yield 161 mg (25%)

'H-NMR (CDC13): 1.64 (9H, s), 7.21 (1H, s), 7.76 (2H, d, J = 4.8Hz), 8.77 (2H, d, J = 6.3Hz)

(2) 21 + 52 → 53 → 50

Using Compound 21 (426 mg, 0.59 mmol) and Compound 52 (146 mg, 0.59 mmol), Compound 53 was obtained as an amorphous powder in the same manner as in Example 7, (3). Yield 564 mg (94%). From this compound 53 (545 mg, 0.54 mmol), 1 M / 卜 A 1 / CH NO (5.4 ml, 5.4 mmol) was used, the same as in Example 7 (4).

3 3 2

Compound 50 was obtained as a powder in the same manner. Yield 41 mg (10%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.2Hz), 2.18 (2H, m), 3.44, 3.49 (2H, ABq, J =

6

16.6 Hz), 5.05 (1H, d, J = 4.2 Hz), 5.32 (2H, d, J = 6.9 Hz), 5.60 (1H, dd. J = 5.1, 7.5 Hz), 5.84 (1H, m), 6.21 (1H, s), 6.22 (1H, t, J = 8.1Hz), 7.05 (2H, s), 7.32 (1H, d, J = 15.9Hz), 7.38 (1H, s), 8.60 (2H, d, J = 6.3Hz), 9.13 (2H, d, J = 6.6Hz), 9.22 (2H, d, J = 7.8Hz).

IR (KBr) cm— 3419, 2967, 1762, 1634, 1527, 1474, 1431, 1359, 1249.

MS (ESI): 609+ (M + H) +

Elemental analysis c HNOS Na- 3.6HO-0.7NaHCO Calculated value: C44. Ll; Η, 4 · 13; Ν, 11.14; S, 8.50; Na, 5.18 (%)

Experimental value: C, 43.81; Η, 4.01; Ν, 11.47; S, 8.41; Na, 5.24 (%)

Example 11

[Chemical 59]

60

(1) 55 → 56

Compound 55 (6.31 g, 50 mmol) was dissolved in acetic acid (50 ml), and a solution of Br (3.07 ml, 60 mmol) in acetic acid (25 ml) was added. The reaction was stirred at room temperature for 75 hours and concentrated under reduced pressure. Water was added to the residue and extracted with ethyl ether. The organic layer was washed with an aqueous NaHC03 solution and brine in that order, dried over MgS 04, and concentrated under reduced pressure. Hexane was added to the crystalline residue and collected by filtration to obtain Compound 56 as white crystals. Yield 5.86 g (57%)

'H-NMR (CDC13): 2.49 (3H, s), 7.59 (1H, s), 9.78 (1H, s).

(2) 56 → 57

Compound 56 (5.13 g, 25 mmol) was used as a white crystal in the same manner as in Example 1, (1). Yield 3.13 g (57%)

'H-NMR (CDC13): 2.46 (3H, s), 7.69 (1H, s).

(3) 57 → 58 Compound 57 (3.07 g, 13.9 mmol) was dissolved in methylene chloride (30 ml), and a solution of diphenyldiazomethane (3.51 g, 18.1 mmol) in methylene chloride (20 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. Hexane was added to the residue, and the precipitated crystals were collected by filtration to obtain Compound 58. Yield 4.14 g (77%)

'H-NMR (CDC13): 2.44 (3H, s), 7.02 (1H, s), 7 · 25_7 · 67 (10Η, m), 7.68 (1H, s).

(4) 13 + 58 → 59

Compound 59 was obtained in the same manner as in Example 2, (2) using Compound 13 (2.05 g, 10 mmol) and Compound 58 (3.87 g, 10 mmol). Colorless oil. Yield 3.57g (92%)

'H-NMR (CDC13): 2.59 (3H, s); 7.07 (1H, s); 7.25-7.43 (12H, m), 7.84 (1H, s), 7.67 (2H, d, J = 5.4Hz).

(5) 21 + 59 → 60 → 54

Compound 21 (721 mg, 1 mmol) and Compound 59 (385 mg, 1 mmol) were used in the same manner as in Example 7, (3) to obtain Compound 60 as an amorphous powder. Yield 1.10 g (96%). Using this compound 60 (1.09 g, 0.9 5 mmol) from 1 M / 卜 A 1 / CH NO (9.5 ml, 9.5 mmol), the same method as in Example 7, (4)

3 3 2

To obtain Compound 54 as a powder. Yield 91 mg (17%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.8Hz), 2.18 (2H, m), 3.45, 3.51 (2H, ABq, J =

6

16.8 Hz), 5.06 (1H, d, J = 4.8Hz), 5.25 (2H, d, J = 6.9Hz), 5.60 (1H, dd. J = 5.1, 8.1 Hz), 5.86 (1H, m), 6.21 (1H, s), 6.22 (1H, t, J = 7.8Hz), 7.00 (2H, s), 7.30 (1H, d, J = 15.9Hz), 7.49 (1H, s), 8.19 (2H, d, J = 6.9Hz), 8.92 (2H, d, J = 6.9Hz), 9.21 (2H, d, J = 7.5Hz).

IR (KBr) cm— 3409, 2966, 1762, 1633, 1599, 1535, 1456, 1437, 1386, 1355, 1295. MS (ESI): 638+ (M + H) +

Elemental analysis c H N O S Na- 5.1H O-0.1NaHCO

29 26 5 6 3 2 3

Calculated value: C, 45.99; H, 4.81; N, 9.22; S, 12.66; Na, 3.33 (%)

Experimental value: C, 45.94; H, 4.50; N, 9.31; S, 12.62; Na, 3.44 (%)

Example 12

[Chemical 60]

67

(1) 62 → 63,13 + 63 → 64

Compound 62 (2.46 g, 10 mmol) was dissolved in dimethylformamide (20 ml), and NaH in MineraloiK 480 mg, 12 mmol) was added. After stirring at room temperature for 30 minutes, POM_I (1.94 ml, 12 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO, and concentrated under reduced pressure. Residue (63) and compound 13 (2.05 g, 10

Four

Compound 64 was obtained in the same manner as in Example 2, (2). Yield 1.60g (45%) 'H-NMR (CDC13): 1 · 20 (9Η, s), 1 · 38 (3Η, t, J = 7.2Hz), 2.28 (6H, s), 4.35 (2H, q , J = 7.2Hz), 6.28 (2H, s), 7.21 (2H, d, J = 6.3Hz), 8.64 (2H, d, J = 6.0Hz).

(2) 64 → 65

Using compound 64 (1.59 g, 4.44 mmol), compound 65 was obtained as brownish brown crystals in the same manner as in Example 8, (2). Yield 643 mg (67%)

'H-NMR (d-DMSO): 2.24 (3H, s), 2.27 (3H, s), 7.28 (2H, d, J = 6.0Hz), 8.55 (2H, d,

6

J = 6.3Hz), 11.55 (1H, s), 12.2 (1H, br_s).

(3) 65 → 66

Compound 65 (640 mg, 2.96 mmol) was used in the same manner as in Example 8, (3) to give compound 66 as white crystals. Yield 242mg (30%) Ή-NMR (CDC13): 1 · 59 (9Η, s), 2.32 (6Η, s), 7.25 (2Η, d, J = 6.3Hz), 8.62 (2H, d, J = 6.0Hz), 8.86 (1H , br- s).

(4) 21 + 66 → 67 → 61

Compound 21 (620 mg, 0.86 mmol) and Compound 66 (234 mg, 0.86 mmol) were used in the same manner as in Example 7, (3) to obtain Compound 67 as an amorphous powder. Yield 824 mg (92%). From this compound 67 (8 07 mg, 0.78 mmol), 1 M / 卜 A 1 / CH NO (7.8 ml, 7.8 mmol) was used, and compound 61 was obtained as a powder in the same manner as in Example 7, (4). . Yield 244 mg (41%)

'H-NMR (DO): 1.03 (3H, t, J = 7.5Hz), 2.20 (2H, m), 2.38 (6H, s), 3.64 (2H, s), 5.17

(2H, d, J = 6.6Hz), 5.24 (1H, d, J = 4.8Hz), 5.78 (1H, d. J = 4.5Hz), 6.08 (1H, m), 6.31 (1H, t, J = 8.1Hz), 6.44 (1H, s), 6.93 (1H, d, J = 15.6Hz), 7.82 (2H, d, J = 6.6Hz), 8.58 (2H, d, J = 6.9Hz).

IR (KBr) cm ^_1 : 3399, 2966, 1761, 1632, 1577, 1528, 1498, 1468, 1418, 1366, 1330, 1214.

MS (ESI): 635 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.7H O-0.2NaHCO

Calculated value: C, 47.84; Η, 5 · 13; Ν, 11.08; S, 8.46; Na, 3.64 (%)

Experimental value: C, 47.80; H, 4.92; N, 11.15; S, 8.39; Na, 3.58 (%)

Example 13

[Chemical 61]

(1) 69 → 70

Compound 69 (4.27 g, 30 mmol) was dissolved in dimethylformamide (30 ml) and K 2 CO 3 (5.38 g, 39 m

2 3 mol) followed by Etl (4.80 ml, 60 mmol). The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with diethyl ether. The organic layer was washed with water and brine, dried over MgSO,

Four

Concentrated under. The residue was dissolved in acetic acid (20 ml) and AcONa (6.40 g, 78 mmol) was added. The mixture was heated to 60 ° C and Br (3.84 ml, 75 mmol) was added, followed by stirring at 85 ° C for 6 hours. 50 reaction solutions

2

The temperature was lowered to ° C, Zn powder (3.92 g, 60 mmol) was added, and the mixture was further stirred at 85 ° C for 50 minutes. The insoluble material was filtered through a celite pad, water was added to the filtrate, and the mixture was extracted with hexane. The organic layer was washed with water and a NaH C03 aqueous solution in this order, and concentrated under reduced pressure to obtain Compound 70. Yield 5.65g (76%) 'H-NMR (CDC13): 1.38 (3H, t, J = 7.2Hz), 2.55 (3H, s), 4.35 (2H, q, J = 7.2Hz), 7.4 2 (1H , S).

(2) 13 + 70 → 71

Compound 71 was obtained in the same manner as in Example 2, (2) using Compound 13 (2.05 g, 10 mmol) and Compound 70 (2.49 g, 10 mmol). White crystals. Yield 2.08 g (84%)

'H-NMR (CDC13): 1.40 (3H, t, J = 6.9Hz), 2.55 (3H, s), 4.38 (2H, q, J = 7.2Hz), 7.3 1 (2H, d, J = 6.0Hz ), 7.47 (1H, s), 8.68 (2H, d, J = 6.3Hz).

(3) 71 → 72 Compound 71 (2.04 g, 8.25 mmol) was dissolved in MeOH (20 ml) and 2N-NaOH (12.4 ml, 24.8 mmol) was added. After stirring at room temperature for 2 hours and 40 minutes and concentrating under reduced pressure, 2N-HCl (12.4 ml, 24.8 mmol) was added to precipitate crystals. The crystals were collected by filtration to give compound 72. White crystals. Yield 1.71 g (95%)

'H-NMR (d-DMSO): 2.49 (3H, s), 7.45 (2H, d, J = 6.0Hz), 7.96 (1H, s), 8.64 (2H, d,

J = 6.0Hz).

(4) 72 → 73

Compound 72 (822 mg, 3.75 mmol) was used in the same manner as in Example 7, (2) to give compound 73 as white crystals. Yield 1.04 g (100%)

'H-NMR (CDC13): 1.60 (9H, s), 2.52 (3H, s), 7.29 (2H, d, J = 6.3Hz), 7.42 (1H, s), 8.6 6 (2H, d, J = (6.3Hz)

(5) 21 + 73 → 74 → 68

Compound 74 was obtained as an amorphous powder in the same manner as in Example 7, (3) using Compound 21 (721 mg, 1 mmol) and Compound 73 (275 mg, 1 mmol). Yield 980 mg (94%). From this compound 74 (960 mg, 0.92 mmol), 1 M / 卜 A 1 / CH NO (9.2 ml, 9.2 mmol) was used, and compound 68 was obtained as a powder in the same manner as in Example 7, (4). . Yield 293 mg (42%)

'H-NMR (D O): 1 · 03 (3Η, t, J = 7.5Hz), 2.21 (2H, m), 2.51 (3H, s), 3.65 (2H, s), 5.25

(1H, d, J = 4.8Hz), 5.27 (2H, d, J = 6.9Hz), 5.78 (1H, d. J = 4.8Hz), 6.11 (1H, m), 6. 31 (1H, t, J = 8.1Hz), 6.45 (1H, s), 6.96 (1H, d, J = 15.9Hz), 7.91 (1H, s), 8.05 (2H, d, J = 6.9Hz), 8.77 (2H, d, J = 6.6Hz).

IR (KBr) cm— 3409, 2965, 1762, 1633, 1528, 1462, 1378, 1351, 1218.

MS (ESI): 638+ (M + H) +

Elemental analysis c H N O S Na-4.2H O-0.2NaHCO

Calculated values: C, 46.63; H, 4.64; N, 9.31; S, 12.79; Na, 3.67 (%)

Experimental value: C46.48; H, 4.56; N, 9.52; S, 12.70; Na, 3.61 (%)

Example 14

[Chemical 62]

(1) 76 + 59 → 77 → 75

Compound 77 was obtained as an amorphous powder in the same manner as in Example 7, (3) using Compound 76 (640 mg, 0.87 mmol) and Compound 59 (335 mg, 0.87 mmol). Yield 953 mg (94%). From this compound 77 (9 36 mg, 0.80 mmol), 1 M / 卜 A 1 / CH NO (8.0 ml, 8.0 mmol) was used, as in Example 7, (4).

3 3 2

Compound 75 was obtained as a powder in the same manner. Yield 115 mg (18%)

'H-NMR (D O): 0 · 89 (3Η, t, J = 7.5Hz), 1.45 (2H, m), 2.18 (2H, m), 2.63 (3H, s), 3.6

2

5 (2H, s), 5.25 (3H, m), 5.77 (1H, d. J = 4.5Hz), 6.10 (1H, m), 6.31 (1H, t, J = 8.1Hz), 6.43 (1H, s ), 6.96 (1H, d, J = 15.6Hz), 7.68 (1H, s), 8.03 (2H, d, J = 6.6Hz), 8.73 (2H, d, J = 6.0Hz).

IR (KBr) cm— 3409, 2968, 2929, 2870, 1762, 1632, 1600, 1535, 1456, 1437, 1385, 1357, 1294, 1224.

MS (ESI): 652+ (M + H) +

Elemental analysis c H N O S Na- 3.7H O-0.5NaHCO

30 28 5 6 3 2 3

Calculated values: C, 46.82; H, 4.63; N, 8.95; S, 12.30; Na, 4.41 (%)

Experimental value: C, 46.65; H, 4.43; N, 9.20; S, 11.64; Na, 4.22 (%)

Example 15

[Chemical 63]

(1) 76 + 48 → 79 → 78

Compound 76 (735 mg, 1 mmol) and compound 48 (262 mg, 1 mmol) were used in the same manner as in Example 7, (3), and compound 79 was obtained as an amorphous powder. Yield 985 mg (95%). From this compound 79 (968 mg, 0 • 93 mmol), 1 M / 卜 A 1 / CH NO (9.3 ml, 9.30 mmol) was used, as in Example 7 (4).

3 3 2

Compound 78 was obtained as a powder. Yield 151 mg (22%)

'H-NMR (D 2 O): 0.89 (3H, t, J = 7.5Hz), 1.45 (2H, m), 2.17 (2H, m), 3.65 (2H, s), 5.2

2

5 (1H, d, J = 4.5Hz), 5.31 (1H, d, J = 6.6Hz), 5.77 (1H, d.J = 4.5Hz), 6.11 (1H, m), 6.28 (1H, t , J = 7.5Hz), 6.41 (1H, s), 6.99 (1H, d, J = 15.6Hz), 8.17 (1H, s), 8.49 (2H, d, J = 6.3Hz), 8.89 (2H, d , J = 6.3Hz).

IR (KBr) cm " ¹ : 3410, 2958, 2930, 2870, 1763, 1608, 1527, 1466, 1396, 1344, 1293, 1217.

MS (ESI): 639 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na- 3.2H O-0.2NaHCO

28 25 6 6 3 2 3

Calculated value: C, 46.07; Η, 4.33; Ν, 11.43; S, 13.09; Na, 3.75 (%)

Experimental value: C, 46.19; H, 4.49; N, 11.17; S, 12.04; Na, 3.79 (%)

Example 16

[Chemical 64]

(1) 76 + 36 → 81 → 80

Compound 81 was obtained as an amorphous powder in the same manner as in Example 7, (3) using Compound 76 (735 mg, 1 mmol) and Compound 36 (262 mg, 1 mmol). Yield 954 mg (92%). Using this compound 81 (937 mg, 0 • 90 mmol) and 1 M / 卜 A1C1 / CH NO (9.0 ml, 9.0 mmol), the same method as in Example 7, (4)

3 3 2

Method gave compound 80 as a powder. Yield 177 mg (26%)

'H-NMR (D O): 0 · 90 (3Η, t, J = 7.2Hz), 1.46 (2H, m), 2.19 (2H, m), 3.65 (2H, s), 5.2

2

6 (3H, m,), 5.78 (1H, d. J = 4.8Hz), 6.11 (1H, m), 6.31 (1H, t, J = 7.5Hz), 6.44 (1H, s), 6.96 (1H, d, J = 15.9Hz), 8.46 (2H, d, J = 6.6Hz), 8.62 (1H, s), 8.80 (2H, d, J = 6.6H z).

IR (KBr) cm " ¹ : 3418, 2958, 2930, 2870, 1763, 1635, 1530, 1489, 1458, 1367, 1288, 1216.

MS (ESI): 639+ (M + H) +

Elemental analysis c H N O S Na-4.1H O-0.2NaHCO

28 25 6 6 3 2 3

Calculated values: C, 45.08; H, 4.48; N, 11.19; S, 12.80; Na, 3.67 (%)

Experimental value: C, 45.10; H, 4.18; N, 11.04; S, 11.84; Na, 3.67 (%)

Example 17

[Chemical 65]

(1) 83 + 36 → 84 → 82

Compound 83 (752 mg, 1 mmol) and Compound 36 (262 mg, 1 mmol) were used in the same manner as in Example 7, (3) to obtain Compound 84 as an amorphous powder. Yield 990 mg (93%). From this compound 84 (974 mg, 0.92 mmol), 1 M / 卜 A 1 / CH NO (9.2 ml, 9.2 mmol) was used, and compound 82 was obtained as a powder in the same manner as in Example 7, (4). . Yield 139 mg (19%)

'H-NMR (D 2 O): 1.29 (6H, m), 3.66 (2H, s), 4.48 (1H, m), 5.26 (3H, m), 5.80 (1H, d. J

= 4.5Hz), 6.12 (1H, m), 6.92 (1H, s), 6.97 (1H, d, J = 15.3Hz), 8.45 (2H, d, J = 6.6Hz), 8.62 (1H, s), 8.80 (2H, d, J = 6.6Hz).

IR (KBr) cm— 3410, 2977, 1764, 1635, 1532, 1488, 1456, 1368, 1292, 1210.

MS (ESI): 656 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.5H O-0.25NaHCO

Calculated values: C, 41.97; H, 4.30; N, 12.57; S, 12.34; Na, 3.69 (%)

Experimental value: C41.97; H, 4.25; N, 12.64; S, 11.80; Na, 3.76 (%)

Example 18

[Chemical 66]

87

(1) 41 → 86

Compound 41 (1.16 g, 5.74 mmol) was suspended in dimethylformamide (10 ml), and Im CO (753 mg, 3.

92 mmol) was added. After stirring at room temperature for 40 minutes, NaNHCN (845 mg, 13.1 mmol) was prepared and stirred at room temperature for 1 hour. The reaction solution was diluted with water and the pH was adjusted to 6.1 with 2N-HC1 to precipitate the precipitate. The precipitate was collected by filtration and suspended in methanol. This suspension was prepared by dissolving lN-MeONa / MeO H by adjusting the pH to 8.6 and then concentrating under reduced pressure to obtain Compound 86 as a white powder. Yield 1.33g (93%)

'H-NMR (d-DMSO): 7.73 (2H, d, J = 6.6Hz), 7.76 (2H, d, J = 8.7 Hz), 8.03 (1H, d,

J = 8.1Hz), 8.63 (2H, d, J = 6.3Hz).

(2) 21 + 86 → 87 → 85

Compound 87 was obtained as an amorphous powder in the same manner as in Example 1, (5) using Compound 21 (721 mg, 1 mmol) and Compound 86 (248 mg, 1 mmol). Yield 810 mg (89%). From this compound 87 (800 mg, 0.88 mmol), 1 M / 卜 A 1 / CH NO (8.8 ml, 8.8 mmol) was used, and compound 85 was obtained as a powder in the same manner as in Example 7, (4). It was. Yield 214 mg (32%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.2Hz), 2.18 (2H, m), 2.63 (3H, s), 3.44, 3.50 (

2H, ABq, J = 17.0 Hz), 5.06 (1H, d, J = 4.8 Hz), 5.12 (2H, d, J = 6.6 Hz), 5.60 (1H, d d. J = 5.1, 7.8 Hz), 5.82 (1H, m), 6.21 (1H, s), 6.23 (1H, t, J = 7.5Hz), 7.00 (2H, s), 7.27 (1H, d, J = 15.9Hz), 7.64 (1H, s), 8.08 (2H, d, J = 6.3Hz), 8.65 (2H, d, J = 5.4Hz), 9.22 (2H, d, J = 7.8Hz), 11.75 (1H, br-s).

IR (KBr) cm— 3397, 2967, 2153, 1761, 1633, 1565, 1535, 1442, 1393, 1329, 1220. MS (FAB): 689 ⁺ (M + H) ⁺

Elemental analysis c H N O S Na-4.3H O-0.15 NaHCO

Calculated value: C, 47.85; H, 4.76; N, 14.81; S, 8.47; Na, 3.49 (%)

Experimental value: C47.70; H, 4.66; N, 14.87; S, 8.66; Na, 3.44 (%)

Example 19

[Chemical 67]

(1) 89

Compound 89 was synthesized by the method described in the literature (J. Org. Chem. L996, 61, 9068 to 9069).

(2) 89 → 90

Compound 89 (4.38 g, 28.6 mmol) was dissolved in black mouth form (50 ml) to give NBS (5.09 g, 28.6 mmol). After stirring at room temperature for 90 minutes, an aqueous solution of Na SO and then 4N-NaOH (10 ml) were added. The organic layer was separated, dried over MgSO, and concentrated under reduced pressure to give compound 90 as white crystals. Yield 6.53g (98%)

'H-NMR (CDCl): 1.35 (3H, t, J = 7.2 Hz), 2.28 (3H, s), 4.30 (2H, q, J = 7.2 Hz), 6.8

3 (1H, d, J = 2.7Hz), 9.12 (1H, br-s). (3) 90 → 91,13 + 91 → 92 → 93

Compound 90 (2.32 g, 10 mmol) was dissolved in dimethylformamide (20 ml), and NaH in MineraloiK 440 mg, l mmol) was added. After stirring at room temperature for 15 minutes, POM-Cl (1.59 ml, 11 mmol) was added, and the mixture was stirred at room temperature for 30 hours. NaH in Mineraloil (0.12 g, 3 mmol) and POM_Cl (0.43 ml, 3 mmol) were added to the reaction solution, and the mixture was further stirred for 17 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over MgSO and concentrated under reduced pressure. Using the residue (91) and compound 13 (2.05 g, 10 mmol), the yield of compound 92 was 2.41 g (70%) in the same manner as (2) of Example 2. Using this compound 92 (2.4 g, 6.97 mmol), compound 93 was obtained as pale yellow crystals in the same manner as (2) of Example 8. Yield 1.33g (94%)

'H-NMR (d-DMSO): 2.45 (3H, s), 7.09 (1H, d, J = 2.7Hz), 7.46 (2H, d, J = 6.0Hz),

8.49 (2H, d, J = 6.3Hz), 11.93 (1H, s), 12.33 (1H, br-s).

(4) 93 → 94

Using compound 93 (809 mg, 4 mmol), compound 94 was obtained as pale yellow crystals in the same manner as in Example 18, (1). Yield 812 mg (82%)

'H-NMR (d-DMSO): 2.40 (3H, s), 6.72 (1H, d, J = 2.7Hz), 7.37 (2H, d, J = 6.3Hz),

8.42 (2H, d, J = 6.3Hz), 11.20 (1H, s).

(5) 21 + 94 → 95 → 88

Compound 95 was obtained as an amorphous powder in the same manner as in (5) of Example 1 using Compound 21 (721 mg, 1 mmol) and Compound 94 (248 mg, 1 mmol). Yield 811 mg (89%). From this compound 95 (800 mg, 0.88 mmol), 1M / 卜 A 1 / CH NO (8.8 ml, 8.8 mmol) was used, and compound 88 was obtained as a powder in the same manner as in Example 7, (4). It was. Yield 244 mg (37%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.17 (2H, m), 2.51 (3H, s), 3.44, 3.50 (

2H, ABq, J = 16.6 Hz), 5.05 (1H, d, J = 4.8 Hz), 5.10 (2H, d, J = 6.6 Hz), 5.59 (1H, d d. J = 4.8, 7.8 Hz), 5.81 (1H, m), 6.20 (1H, s), 6.22 (1H, t, J = 7.8Hz), 7.00 (2H, s), 7.06 (lH, s), 7.26 (1H, d, J = 15.9 Hz), 8.00 (2H, d, J = 7.2Hz), 8.62 (2H, d, J = 7.2Hz), 9 • 21 (2H, d, J = 8.1Hz), 11.82 (1H, s).

IR (KBr) cm ^_1 : 3399, 2967, 2152, 1761, 1633, 1578, 1525, 1497, 1464, 1365, 1319, 1222. MS (FAB): 667 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.7H O-0.05NaHCO

Calculated value: C, 47.77; Η, 4.86; Ν, 14.83; S, 8.49; Na, 3.20 (%)

Experimental value: C, 47.74; H, 4.61; N, 14.79; S, 8.92; Na, 3.17 (%)

Example 20

[Chemical 68]

104

(1) 97 → 98

Compound 97 (24.2g, 0.2mol) and cetyl oxalate (27.2ml, 0.2mol) were dissolved in tetrahydrofuran (200ml) and cooled to -78 ° C, then LiN (TMS) / THF (1M / L, 200ml) ) Was added dropwise over 30 minutes. The reaction solution was stirred at _78 ° C for 10 minutes, and then stirred for 1 hour and 30 minutes while gradually warming to room temperature. After the reaction, the mixture was cooled to _78 ° C., 6N-HCl (60 ml) was added, and the mixture was stirred while raising the temperature to room temperature. Concentration under reduced pressure gave a precipitate in which lN-NaOH (120 ml), ethyl acetate, and jetyl ether were precipitated and collected by filtration. The precipitate was washed with ice water and air-dried to obtain Compound 98. Pale yellow powder. Yield 47.01g with water (106%)

'H-NMR (CDC1): 1.26 (3H, t, J = 6.9Ηζ), 4 · 16 (2Η, q, J = 7.2 Hz), 6.41 (1H, s), 7.6

9 (2H, br-d, J = 4.2Hz), 8.65 (1H, br_d, J = 4.2Hz). (2) 98 → 99

Compound 98 (23.5 g, equivalent to O. lmol) obtained in Example 20 (1) and hydrazine monohydrate (4.4 ml, 90 mmol) were added to 4N-HCl (36 ml) previously cooled to -30 ° C. The mixture was stirred at 80 ° C for 1 hour. The reaction mixture was ice-cooled and lN-NaOH (65 ml) was added. The deposited precipitate was collected by filtration to obtain Compound 99. Pale yellow crystals. Yield 16.89 g (78%).

'H-NMR (d-DMSO): 1.33 (3H, m), 4.35 (2H, m), 7.47 + 7.53 (lH, s + s), 7.84 (2H, m),

8.64 (2H, m).

(3) 99 → 100 → 101

Compound 99 (4.34 g, 20 mmol) was suspended in ethanol (80 ml), and lN-NaOH (100 ml, 100 mmo 1) was added. The reaction solution was stirred at 60 ° C. for 2 hours, and ethanol was concentrated and removed under reduced pressure. Then, 2N-HCl (50 ml, 100 mmol) was added under ice cooling to precipitate crystals. The crystals were collected by filtration to give compound 100. Yield 3.90 g (103%). This compound 100 (946 mg, 5 mmol) was suspended in dimethylformamide (6 ml), and Im CO (973 mg, 6 mmol) was calored. After stirring at room temperature for 1 hour and 45 minutes, ethyl acetate (15 ml) was added to precipitate crystals. The crystals were collected by filtration to obtain Compound 101. Yield 1.05g (88%)

'H-NMR (d-DMSO): 7.17 (1H, s), 7.82 (1H, s), 7.93 (2H, d, J = 6.3Hz), 8.04 (1H, s),

8.70 (2H, d, J = 6.0Hz), 8.83 (1H, s).

(4) 101 → 102

NaNHCN (141 mg, 2.2 mmol) was suspended in dimethylformamide (lml) and 101 (239 mg, lmmol) was added. The reaction solution was stirred at room temperature for 1 hour and 10 minutes, diluted with water (4 ml), and adjusted to pH 3 with 2N-HC1 to precipitate crystals. The crystals were collected by filtration to obtain Compound 102. Yield 165 mg (77%)

'H-NMR (d-DMSO): 7.49 (1H, s), 8.19 (2H, br-s), 8.79 (2H, d, J = 6.6Hz).

(5) 102 → 103

Compound 102 (2.2 g, 10.3 mmol) was suspended in methanol (20 ml), and lN_MeoNa / Me0H (10 ml) was obtained under ice cooling. The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. Compound 103 was obtained by filtering the precipitate in which isopropanol was precipitated in the residue. Yield 2.40 g (102%) 'H-NMR (d-DMSO): 7.08 (1H, s), 7.79 (2H, d, J = 6.0 Hz), 8.56 (1H, d, J = 6.3 Hz). (6) 21 + 103 → 104 → 96

Using compound 21 (721 mg, 1 mmol) and compound 103 (235 mg, 1 mmol), compound 104 was obtained as an amorphous powder in the same manner as in Example 1, (5). Yield 782 mg (87%). From this compound 104 (770 mg, 0.86 mmol), 1M / 卜 A 1 / CH NO (8.6 ml, 8.6 mmol) was used, and compound 96 was obtained as a powder in the same manner as in Example 7, (4). Yield 208 mg (32%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.17 (2H, m), 3.45, 3.52 (2H, ABq, J =

17.1 Hz), 5.06 (1H, d, J = 5.1 Hz), 5.22 (2H, d, J = 6.9 Hz), 5.61 (1H, dd. J = 4.8, 7.8 Hz), 5.86 (1H, m), 6.20 (1H, s), 6.22 (1H, t, J = 7.5Hz), 7.00 (2H, s), 7.28 (1H, d, J = 15.9Hz), 7.44 (1H, s), 8.45 (2H, d, J = 6.9Hz), 8.91 (2H, d, J = 6.9Hz), 9.22 (2H, d, J = 8.1Hz), 14.04 (1H, br-s).

IR (KBr) cm ^_1 : 3409, 2967, 2165, 1762, 1636, 1604, 1530, 1473, 1437, 1398, 1347, 1214.

MS (ESI): 632 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.8H O-O. lNaHCO

Calculated value: C, 45.09; H, 4.54; N, 16.84; S, 8.57; Na, 3.38 (%)

Experimental value: C, 45.26; Η, 4.39; Ν, 15.71; S, 8.57; Na, 3.36 (%)

Example 21

[Chem 69]

108 (1) 59 → 106

Compound 59 (2.17 g, 5.64 mmol) was dissolved in tetrahydrofuran (10 ml) and methanol (20 ml), and 2 N-NaOH (8.5 ml, 17 mmol) was added. The reaction solution was stirred at room temperature for 2 hours and 20 minutes, and then 2N_HCl (8.5 ml, 17 mmol) was added to ethyl ether, and the pH was adjusted to 7 to precipitate crystals. The crystals were collected by filtration to obtain Compound 106. White crystals. Yield 1.16 g (94%)

'H-NMR (d-DMSO): 2.58 (3H, s), 7.52 (2H, d, J = 6.3Hz), 7.81 (1H, s), 8.63 (2H, d,

6

J = 6.0Hz).

(2) 106 → 107

Compound 106 (1.14 g, 5.2 mmol) was used in the same manner as in Example 18, (1) to give Compound 107 as white crystals. Yield 1.38 g (100%)

'H-NMR (d-DMSO): 2.49 (3H, s), 7.46 (2H, d, J = 6.0Hz), 7.46 (1H, s), 8.59 (2H, d, J

6

= 6.0Hz).

(3) 21 + 107 → 108 → 105

Compound 108 was obtained as an amorphous powder in the same manner as in Example 1, (5) using Compound 21 (721 mg, 1 mmol) and Compound 107 (265 mg, 1 mmol). Yield 805 mg (87%). From this compound 108 (791 mg, 0.85 mmol), 1 M / 卜 A 1 / CH NO (8.5 ml, 8.5 mmol) was used, as in Example 7 (4).

3 3 2

Thus, compound 105 was obtained as a powder. Yield 225 mg (34%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.5Hz), 2.17 (2H, m), 2.63 (3H, s), 3.45, 3.51 (

6

2H, ABq, J = 17.0 Hz), 5.06 (1H, d, J = 4.8 Hz), 5.26 (2H, d, J = 6.6 Hz), 5.60 (1H, d d. J = 5.1, 7.8 Hz), 5.86 (1H, m), 6.20 (1H, s), 6.22 (1H, t, J = 7.8Hz), 7.00 (2H, s), 7.30 (1H, d, J = 15.9Hz), 7.73 (1H, s), 8.24 (2H, d, J = 6.9Hz), 8.94 (2H, d, J = 6.9Hz), 9.22 (2H, d, J = 7.8Hz).

IR (KBr) cm ^_1 : 3408, 2966, 2168, 2144, 1761, 1633, 1541, 1456, 1437, 1388, 1348, 1246.

MS (ESI): 662+ (M + H) +

Elemental analysis c H N O S Na-4.6H O-O .2NaHCO

30 26 7 5 3 2 3

Calculated value: C, 46.30; H, 4.55; N, 12.52; S, 12.28; Na, 3.52 (%)

Experimental value: C, 46.27; H, 4.44; N, 12.61; S, 12.22; Na, 3.50 (%) Example 22

[0049] [Chemical 70]

(1) 21 + 7 → 110 → 109

Compound 21 (721 mg, 1 mmol) and Compound 7 (251 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 110 as an amorphous powder. Yield 783 mg (86%). This compound 110 (773 mg, 0.85 mmol) force 1M-A 1 / CH NO (8.5 ml, 8.5 mmol) was used, the same as in Example 7 (4).

3 3 2

The compound 109 was obtained as a powder by the method. Yield 261 mg (39%)

17.0 Hz), 5.05 (1H, d, J = 4.8Hz), 5.21 (2H, d, J = 7.2Hz), 5.60 (1H, dd.J = 5.1, 7.8 Hz), 5.85 (1H, m), 6.20 (1H, s), 6.22 (1H, t, J = 8.1Hz), 7.00 (2H, s), 7.28 (1H, d, J = 15.6Hz), 8.17 (1H, d, J = 1.5Hz), 8.48 (2H, d, J = 6.9Hz), 8.64 (1H, d, J = 1.5Hz), 8.92 (2H, d, J = 6.6Hz), 9.22 (2H, d, J = 7.8Hz).

IR (KBr) cm ^_1 : 3408, 2967, 2172, 1761, 1634, 1539, 1469, 1435, 1351, 1250, 1223. MS (ESI): 648 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-4.0H O-O. lNaHCO

29 24 7 5 3 2 3

Calculated value: C, 46.59; Η, 4.31; Ν, 13.07; S, 12.82; Na, 3.37 (%)

Experimental value: C, 46.55; Η, 4.15; Ν, 13.28; S, 12.59; Na, 3.40 (%)

Example 23

[0050] [Chemical 71]

(1) 21 + 112 → 113 → 111

Compound 21 (721 mg, 1 mmol) and Compound 112 (345 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 113 as an amorphous powder. Yield 778 mg (85%). From this compound 113 (759 mg, 0.83 mmol), 1 M / 卜 A 1 / CH NO (8.3 ml, 8.3 mmol) was used, as in Example 7, (4).

3 3 2

Thus, compound 111 was obtained as a powder. Yield 191 mg (30%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.18 (2H, m), 3.43, 3.51 (2H, ABq, J =

13.4 Hz), 5.07 (1H, d, J = 5.1 Hz), 5.31 (2H, d, J = 6.0 Hz), 5.61 (1H, dd. J = 4.8, 8.1 Hz), 5.86 (1H, m), 6.21 (1H, s), 6.22 (1H, t, J = 7.8Hz), 7.01 (2H, s), 7.32 (1H, d, J = 15.6Hz), 8.46 (1H, s), 8.59 (2H, d, J = 5.7Hz), 9.07 (2H, d, J = 6.3Hz), 9.23 (2H, d, J = 7.8Hz).

IR (KBr) cm " ¹ : 3416, 2966, 2159, 1761, 1634, 1604, 1523, 1468, 1354, 1299, 1215. MS (FAB): 671+ (M + H) +

Elemental analysis C H N O S Na-4.2H O-0.25 NaHCO

28 23 8 5 3 2 3

Calculated value: C, 44.22; Η, 4.16; Ν, 14.60; S, 12.54; Na, 3.75 (%)

Experimental value: C, 44.26; Η, 4.11; Ν, 14.56; S, 12.51; Na, 3.71 (%)

Example 24

[Chemical 72]

116

(1) 21 + 115 → 116 → 114

Compound 21 (721 mg, 1 mmol) and Compound 115 (252 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 116 as an amorphous powder. Yield 829 mg (91%). From this compound 116 (817 mg, 0.89 mmol), 1 M / 卜 A 1 / CH NO (8.9 ml, 8.9 mmol) was used, as in Example 7 (4).

3 3 2

Thus, compound 114 was obtained as a powder. Yield 171 mg (25%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.2Hz), 2.18 (2H, m), 3.45, 3.51 (2H, ABq, J =

6

16.7 Hz), 5.06 (1H, d, J = 5.1 Hz), 5.27 (2H, d, J = 6.9 Hz), 5.60 (1H, dd.J = 4.8, 7.8 Hz), 5.86 (1H, m), 6.21 (1H, s), 6.23 (1H, t, J = 7.5Hz), 7.00 (2H, s), 7.31 (1H, d, J = 15.9Hz), 8.59 (2H, d, J = 6.9Hz), 8.97 (1H, s), 9.02 (2H, d, J = 6.3Hz), 9.22 (2H, d, J = 7.8Hz).

IR (KBr) cm— 3419, 2966, 2179, 2153, 1762, 1635, 1605, 1530, 1492, 1458, 1361, 1216.

MS (FAB): 671+ (M + H) +

Elemental analysis c H N O S Na-4.1H O-0.4NaHCO

28 23 8 5 3 2 3

Calculated values: C, 43.83; H, 4.09; N, 14.40; S, 12.36; Na, 4.14 (%)

Experimental value: C, 43.69; H, 4.07; N, 14.64; S, 12.49; Na, 4.12 (%)

Example 25

[Chemical 73]

(1) 21 + 31 → 118 → 117

Compound 118 was obtained as an amorphous powder in the same manner as (5) of Example 1 using Compound 21 (635 mg, 0.88 mmol) and Compound 31 (224 mg, 0.88 mmol). Yield 687 mg (85%). From this compound 118 (6777 mg, 0.74 mmol), 1M / to A 1 / CH 2 NO (7.4 ml, 7.4 mmol) was used, and compound 117 was obtained as a powder in the same manner as in Example 7, (4). Yield 88 mg (16%)

'H-NMR (d-DMSO): 1.00 (3H, t, J = 7.5Hz), 2.17 (2H, m), 3.45, 3.51 (2H, ABq, J =

17.4 Hz), 5.06 (1H, d, J = 4.8Hz), 5.30 (2H, d, J = 6.9Hz), 5.61 (1H, dd. J = 4.8, 7.8 Hz), 5.87 (1H, m), 6.21 (1H, s), 6.22 (1H, t, J = 7.5Hz), 7.01 (2H, s), 7.31 (1H, d, J = 16.5Hz), 8.53 (1H, s), 8.72 (2H, d, J = 6.9Hz), 9.09 (2H, d, J = 7.2Hz), 9.23 (2H, d, J = 7.8Hz).

IR (KBr) cm " ¹ : 3417, 2966, 2172, 1761, 1635, 1604, 1527, 1466, 1400, 1337

MS (FAB): 671+ (M + H) +

Elemental analysis C H N O S Na- 3.5H O

Calculated values: C, 45.83; H, 4.12; N, 15.27; S, 13.11; Na, 3.13 (%)

Experimental value: C, 45.64; Η, 4 · 13; Ν, 15.39; S, 12.91; Na, 3.12 (%)

Example 26

[Chemical 74]

121

(1) 120 + 103 → 121 → 119

Compound 120 (700 mg, 0.92 mmol) and compound 103 (239 mg, 1.01 mmol) were suspended in dimethylacetamide (1.8 ml), and sodium bromide (949 mg, 9.2 mmol) was obtained under ice cooling. The reaction solution was ice-cooled and stirred for 4 hours and 20 minutes, and then poured into water (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was washed with ethyl ether and dried under reduced pressure to obtain Compound 121 as an amorphous powder. Yield 798 mg (92%). This compound 121 (798 mg, 0.85 mmol) is dissolved in methylene chloride (10 ml) and anisol (0.58 ml), and 2M / to 8 / CH NO (2.56 ml, 5.12 mmol) is added at -20 ° C. It was. The mixture was stirred at _20 ° C for 20 minutes, and then poured into 0.3N hydrochloric acid (25 ml) and acetonitrile (30 ml) with stirring under ice-cooling. Further, ethyl ether (25 ml) was separated from the aqueous layer. To the aqueous layer, 0.3N-hydrochloric acid (25 ml) and acetonitrile (25 ml) were added and completely dissolved. HP-20SS was concentrated, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the deposited precipitate was collected by filtration. This precipitate (184 mg) was suspended in water (5 ml) and acetonitrile (2.51111), and ^^^ 0 (23 mg, 0.28 mmol) was added and dissolved. The solution was concentrated and lyophilized to give Compound 119 as a powder. Yield 185 mg (25%). In the NMR analysis of this product, the double bond site of the propenyl group at position 3 of cefme was E: Z = 55: 45.

'H-NMR (DO): 3.39-3.74 (2H, m), 3.97 and 4.00 (3 ^ s in total), 5.1 to 5 · 38 (3Η, m ), 5.80 and 5.84 (total 1H, d, J = 4.8Hz), 5.89 and 6.13 (total 1 ^ m), 6.53 (0.45H, d, J = 11.4Hz), 7.00 (0.55 H, d, J = 16.2Hz), 7.22 and 7.25 (total 1 ^ s), 8.25 (2H, m), 8.71 and 8.76 (1H, d, J = 6.9Hz in total).

IR (KBr) cm ^_1 : 3410, 2165, 1762, 1637, 1605, 1538, 1472, 1437, 1399, 1349, 1216. MS (ESI): 669 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S ClNa- 5.1H O-O. lNaHCO

Calculated values: C, 39.61; H, 3.86; N, 17.70; S, 8.10; Cl, 4.48; Na, 3.20 (%)

Experimental value: C39.69; H, 3.72; N, 17.47; S, 8.62; Cl; 4.66; Na, 3.22 (%)

Example 27

[Chemical 75]

(1) 123 + 103 → 124 → 122

Compound 122 was obtained as a powder in the same manner as in Example 7, (4) using Compound 123 (690 mg, 0.93 mmol) and Compound 103 (241 mg, 1.03 mmol). Yield 184 mg (24%). In the NMR analysis of this product, the double bond site of the propenyl group at the 3-position of cefm was E: Z = 35: 65.

'H-NMR (D 2 O): 1.17 (3H, m), 3.26_3 · 56 (2Η, m), 4.20 (2H, m), 4.97-5.17 (3H, m), 5.

69 and 5.73 (total 1H, d, J = 4.5Hz), 5.76 and 6.02 (total 1 ^ m), 6.39 (0.65H, d, J = 11.1Hz), 6.85 (0.35H, d, J = 15.6Hz), 7.11 and 7.15 (1 s combined), 8.13 (2 H, m), 8.57 and 8.63 (1d combined, J = 6.3Hz).

IR (KBr) cm— 3417, 2983, 2165, 1762, 1637, 1602, 1533, 1473, 1401, 1351, 1216.

MS (ESI): 650 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S ClNa-4.7H O

26 22 11 6 2 2

Calculated values: C, 41.29; H, 4.18; N, 20.37; S, 8.48; Na, 3.04 (%)

Experimental value: C, 41.12; H, 4.07; N, 20.13; S, 8.37; Na, 3.31 (%)

Example 28

[Chemical 76]

1 27

(1) 126 + 103 → 127 → 125

Compound 126 (700 mg, 0.95 mmol) and Compound 103 (245 mg, 1.04 mmol) were used in the same manner as in Example 7, (4) to obtain Compound 125 as a powder. Yield 225 mg (27%). In the NMR analysis of this product, the double bond site of the propenyl group at the 3-position of Cephem was E: Z = 36: 64.

-NMR (D 0): 1 · 18 (3Η, m), 3.28-3 · 61 (2Η, m), 4.14 (2H, m), 4.96-5.19 (3H, m), 5.68

2

And 5.72 (total 1H, d, J = 4.5Hz), 5.79 and 6.04 (total 1H, m), 6.41 (0.64H, d, J = 10.8Hz), 6.82 and 6.83 (total 1H, s) 6.92 (0.36H, d, J = 17.7Hz), 7.07 and 7.10 (1H, s combined), 8.13 (2H, m), 8.57 and 8.63 (1H, d, J = 6.6Hz combined).

IR (KBr) cm " ¹ : 3418, 2979, 2164, 1763, 1637, 1603, 1532, 1473, 1439, 1396, 1348, 1207.

MS (FAB): 649+ (M_Na + 2H) +

Elemental analysis C H N O S ClNa- 3.9H O

26 22 11 6 2 2

Calculated values: C, 43.77; H, 4.19; N, 18.90; S, 8.66; Na, 3.10 (%)

Experimental value: C43.73; H, 3.95; N, 29.18; S, 8.43; Na, 3.36 (%))

Example 29

(1) 125 → 128

[Chemical 77]

Compound 125 (E: Z = 36: 64) was subjected to HP-20SS column chromatography in the form of Na salt and eluted with water-acetonitrile. Fractions containing only Z form were collected, concentrated under reduced pressure, and lyophilized to obtain Compound 128 as a powder. Yield 39 mg (3%)

H-NMR (d-DMSO): 1.30 (3H, t, J = 7.2Hz), 3.43, 3.67 (2H, ABq, J = 17.7 Hz), 4.2

6

6 (2H, q, J = 7.5Hz), 5.06- 5.29 (2mm, m), 5.30 (1H, d, J = 2.7Hz), 5.83 (1H, m), 5.90 (1 H, m), 5.51 (1H, d, J = l l. LHz), 6.98 (1H, s), 7.32 (1H, s), 8.29 (2H, m), 8.69 (2H, d, J = 5.7Hz).

IR (KBr) cm— 3421, 2980, 2550, 2165, 1925, 1763, 1667, 1636, 1534, 1473, 1398, 1352, 1210.

MS (FAB): 649+ (M-Na + 2H) +

Elemental analysis C H N 0 S Na-4.5H 0 + 1.8NaHCO + 0.3CitricacidNaSalt

28 23 8 5 3 2 3

Calculated values: C, 37.49; H, 3.63; N, 14.29; S, 6.54; Na, 8.68 (%)

Experimental value: C37.10; H, 3.55; N, 14.69; S, 6.44; Na, 8.88 (%)

(2) 127 → 190

[Chemical 78]

Using compound 127 (4.6 g, 5 mmol) force 2M / TiCl 2 / CH CI (15 ml, 30 mmol) and Example 1 (6)

4 2 2

In a similar manner, Compound 190 was obtained as a powder. Yield 0.61 g (19%)

6

IR (KBr) cm— 3419, 2967, 1762, 1634, 1527, 1474, 1431, 1359, 1249.

MS (ESI): 609 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 3.6H O -0.7NaHCO

27 2 3 6 7 2 2 3

Calculated values: C, 44.11; H, 4.13; N, 11.14; S, 8.50; Na, 5.18 (%)

Experimental value: C, 43.81; Η, 4.01; Ν, 11.47; S, 8.41; Na, 5.24 (%)

Example 30

[Chemical 79]

(1) 8 + 130 → 131 → 129 Compound 131 was obtained as an amorphous powder in the same manner as in Example 5, (5), using Compound 8 (738 mg, 1 mmol) and Compound 130 (234 mg, 1 mmol). Yield 795 mg (87%). Compound 129 was obtained as a powder in the same manner as in Example 6, (6), using Compound 131 (790 mg, 0.86 mmol), 2 M / 卜 TiCl 2 / CH 2 CI (2.5 ml, 5 mmol). Yield 210mg (29%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3.49 (2H, ABq, J = 16.5 Hz), 4.

09 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.8Hz), 5.08 (2H, d, J = 6.9Hz), 5.59 (1H, dd, J = 4.8, 8.1Hz), 5.83 (1H, m), 6.72 (1H, s), 7.17 (1H, s), 7.23-7.26 (3H, m), 7.86 (1H, s), 8.18 (2H, d, J = 7.2Hz), 8.64 (2H, d, J = 6.9Hz), 9.54 (1H, d, J = 8.1Hz), 12.03 (1H, s).

IR (KBr) cm ^_1 : 3398, 2984, 2154, 1761, 1635, 1572, 1530, 1475, 1393, 1335, 1296, 1219.

MS (FAB): 648+ (M- Na + 2H) ⁺

Elemental analysis C H N O S Na-6.5 H O

Calculated value: C, 42.74; H, 4.74; N, 16.02; S, 8.15; Na, 2.92 (%)

Experimental value: C, 43.00; H, 4.24; N, 15.90; S, 8.10; Na, 2.94 (%)

Example 31

[Chemical 80]

86 133

(1) 8 + 86 → 133 → 132

Compound 133 was obtained as an amorphous powder in the same manner as in Example 1, (5), using Compound 8 (738 mg, 1 mmol) and Compound 86 (248 mg, 1 mmol). Yield 847 mg (91%). This compound 133 (840 mg, 0.91 mmol) force 2 M / 卜 TiCl 2 / CH CI (2.5 ml, 5 mmol) was used in the same manner as in Example 1, (6). Compound 132 was obtained as a powder. Yield 284 mg (36%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 2.62 (3H, s), 3.42, 3.49 (2H, ABq, J =

17.1 Hz), 4.09 (2H, q, J = 6.9 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.12 (2H, d, J = 7.2 Hz), 5 • 60 (1H, dd, J = 4.5, 8.1Hz), 5.83 (1H, m), 6.72 (1H, s), 723_7 · 28 (3Η, m), 7.65 (1H, s), 8.08 (2H, d, J = 7.2Hz), 8.66 (2H, d, J = 7.2Hz), 9.54 (1H, d, J = 8.1Hz), 11.76 (1H, s).

IR (KBr) cm ^_1 : 3398, 2154, 1762, 1633, 1604, 1565, 1537, 1487, 1471, 1442, 1392,

1329, 1220.

MS (FAB): 684 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-6.0 H O

Calculated values: C, 43.99; H, 4.84; N, 15.92; S, 8.10; Na, 2.90 (%)

Experimental value: C, 44.12; H, 4.42; N, 15.85; S, 8.07; Na, 2.82 (%)

Example 32

[Chemical 81]

136

(1) 8 + 135 → 136 → 134

Compound 8 (738 mg, 1 mmol) and compound 135 (188 mg, 1 mmol) were used in the same manner as in Example 1, (5), and compound 136 was obtained as an amorphous powder. Yield 796 mg (82%). Using this compound 136 (790 mg, 0.82 mmol), 1M / NO 2 (2.5 ml, 5 mmol) for 2 M / ton A, compound 134 as a powder in the same manner as in Example 7, (4) Obtained. Yield 242mg (38%)

'H-NMR (D 2 O): 1.30 (3H, t, J = 7.2Hz), 3.65 (2H, s), 4.25 (2H, q, J = 6.9Hz), 5.17 (2

H, d, J = 6.0Hz), 5.26 (1H, d, J = 5.1Hz), 5.82 (1H, d, J = 4.8Hz), 6.10 (1H, m), 6.64 (1H, s), 6.93 (1H, d, J = 15.6Hz), 6.97 (1H, s), 7.01 (1H, s), 8.20 (2H, d, J = 7.2Hz), 8.54 (2H, d, J = 6.9Hz).

IR (KBr) cm— 3407, 2981, 1762, 1633, 1592, 1537, 1518, 1468, 1409, 1352, 1298, 1217.

MS (FAB): 646 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na- 6.5 H O

Calculated values: C, 42.52; H, 4.89; N, 12.85; S, 8.41; Na, 3.01 (%)

Experimental value: C, 42.82; H, 4.68; N, 12.90; S, 8.17; Na, 3.20 (%)

Example 33

[Chemical 82]

139

(1) 8 + 138 → 139 → 137

Compound 8 (370 mg, 0.5 mmol) and compound 138 (177 mg, 0.5 mmol) were used in the same manner as in Example 1, (5) to obtain compound 139 as an amorphous powder. Yield 509 mg (89%). From this compound 139 (500 mg, 0.44 mmol), 2M / 卜 A 1 / CH NO (2.0 ml, 4 mmol) was used, and compound 137 was obtained as a powder in the same manner as in Example 7, (4). Yield 185mg (67%)

'H-NMR (DO): 1.28 (3H, t, J = 7.2Hz), 3.63, 3,67 (2H, Abq, J = 17.6Hz), 4.22 (2H, q, J = 7.2Hz), 5.05 ( 2H, d, J = 6.9Hz), 5.24 (1H, d, J = 4.8Hz), 5.79 (1H, d, J = 4.8Hz), 6.06 (1H, m), 6.90_6.95 (3H, m ), 7.08 (1H, s), 7.66 (1H, s), 7.88 (2H, d, J = 6.3Hz), 8.41 (2H, d, J = 6.9Hz).

IR (KBr) cm ^_1 : 3398, 2984, 1762, 1634, 1569, 1533, 1476, 1398, 1341, 1296, 1217. MS (FAB): 624+ (M_Na + 2H) + Elemental analysis CHNOS Na- 7.0 HO

Calculated value: C, 42.02; Η, 4.96; Ν, 12.70; S, 8.31; Na, 2.98 (%)

Experimental value: C, 42.05; H, 4.74; N, 12.71; S, 8.36; Na, 3.35 (%)

Example 34

[Chemical 83]

(1) 141 → 142

Compound 141 (2.58, 12.911111101) and dimethylformamide dimethylacetal (1.7 (¾, 14.2111 mol) were dissolved in dimethylformamide (20 ml), stirred at 90 ° C for 3 hours, and concentrated under reduced pressure. Dissolved in toluene (20 ml) and stirred for 2 hours at 100 ° C. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with toluene-ethyl acetate. Yield 2.25 g (70%)

'H-NMR (CDCl): 0.87 (3H, t, J = 7.2Hz), 2.86 (3H, br—s), 3.28 (3H, br-s), 3.93 (2H, q, J = 7.2Hz), 7.50 (2H, br—d, J = 4.2Hz), 7.75 (1H, s), 8.68 (2H, d, J = 5.7Hz).

(2) 142 → 143

Compound 142 (2.24 g, 9.0 mmol) and H 2 NNH · Η0 (474 mg, 9.47 mmol) were dissolved in ethanol (10 ml), 2N-HCl (0.45 ml) was added, and the mixture was stirred at 80 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, and the precipitated crystals were collected by filtration and washed with water to give compound 143. Yield 1.71 g (87%) Ή-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 4.19 (2H, q, J = 6.9Hz), 7.74 (2H, d, J

= 6.0Hz), 8.35 (1H, s), 8.62 (2H, d, J = 5.7Hz).

(3) 143 → 144

Compound 143 (888 mg, 4.1 mmol) was dissolved in 4N-NaOH (10 ml, 40 mmol) and stirred under reflux for 3 hours. After returning to room temperature, 2N-HC1 was added to adjust the pH to 3.5, and the precipitated crystals were collected by filtration to obtain Compound 144. Yield 366 mg (47%)

'H-NMR (d-D MSO): 7.79 (2H, br-d, J = 4.5Hz), 8.38 (1H, br-s), 8.62 (2H, br_d, J

= 3.9Hz).

(4) 144 → 145

Compound 144 (366 mg, 1.93 mmol) was used in the same manner as in Example 18, (1) to obtain Compound 145. Yield 402 mg (89%)

'H-NMR (d-DMSO): 7.95 (2H, d, J = 4.2Hz), 8.01 (1H, s), 8.51 (2H, d, J = 4.8Hz).

(5) 8 + 145 → 146

Using Compound 8 (672 mg, 0.77 mmol) and Compound 145 (180 mg, 0.77 mmol), Compound 146 was obtained as an amorphous powder in the same manner as in Example 1, (5). Yield 714mg (101%)

(6) 146 → 147

Compound 146 (714 mg, 0.78 mmol) was dissolved in methylene chloride (10 ml) and anisole (0.8 ml), and 2 M / 卜 TiCl 2 / CH 2 CI (2.4 ml, 4.8 mmol) was added at −20 ° C. The mixture was stirred at −20 ° C. for 30 minutes, and then poured into 0.3N hydrochloric acid (30 ml) and isopropyl ether (30 ml) with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved in a mixed solvent of dilute hydrochloric acid and acetonitrile. HP-20SS was added to the solution, concentrated, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure to give compound 147. Yield 72 mg (14%)

(7) 147 → 140

Compound 147 (51.8 mg, 0.08 mmol) was suspended in water (10 ml) and acetonitrile (10 ml), and NaHCO 3 (6.7 mg, 0.08 mmol) was added. After complete dissolution, concentration under reduced pressure, and lyophilization, Compound 140 was obtained. Yield 53 mg (86%)

'H-NMR (d-DMSO): 1.21 (3H, t, J = 7.2Hz), 3.42, 3,48 (2H, Abq, J = 16.7Hz), 4.0 7 (2H, q, J = 7.2Hz), 5.02 (1H, d, J = 4.8Hz), 5.22 (2H, d, J = 6.9Hz), 5.56 (1H, dd, J = 5.1, 8.4 Hz), 5.84 (1H, m), 6.70 (1H, s), 7.19 (2H, s), 7.28 (1H, s, J = 15.9Hz), 8.13 (1H, s), 8.84 (2H, d, J = 7.2Hz ), 8.89 (2H, d, J = 7.2Hz), 9.51 (1H, d, J = 8.1Hz). IR (KBr) cm ^_1 : 3410, 2981, 2225, 2160, 1764, 1659, 1636, 1600, 1532 , 1464, 1369, 1297, 1238.

MS (ESI): 649 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5.0 H O-0.1 NaHCO

Calculated values: C, 42.32; H, 4.34; N, 18.21; S, 8.34; Na, 3.29 (%)

Experimental value: C41.89; H, 4.23; N, 17.88; S, 8.18; Na, 3.58 (%)

Example 35

[Chemical 84]

(1) 149 → 150

Compound 149 (5.0 g, 36.2 mmol) was suspended in methanol (40 ml), and thiollucide (8.61 g, 72.4 mmol) was added dropwise. The mixture was stirred at room temperature for 3 days, and further stirred under reflux for 3 hours. Toluene was concentrated in the mixed solution under reduced pressure. Dissolve the residue in water and neutralize with NaHCO

The precipitated crystals were collected by filtration to obtain Compound 150. Yield 4.58 g (83%)

'H-NMR (d-DMSO): 3.74 (3H, s), 6.43 (1H, d, J = 8.7Hz), 6.80 (2H, s), 7.80 (1H, dd

, J = 2.4, 8.7Hz), 8.48 (1H, d, J = 2.1Hz). (2) 150 → 151

BrCH CH (OMe) (10.65 g, 63 mmol) was dissolved in dilute hydrochloric acid (concentrated hydrochloric acid 1.5 ml and water 70 ml).

The mixture was stirred at ° C for 1 hour and 30 minutes. The mixture was returned to room temperature, and then Compound 150 (3.3 g, 21.7 mmol) and NaHCO 3 (5 g, 60 mmol) were added. After stirring at 60 ° C for 30 minutes, the pH was adjusted to 10 with K 2 CO and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO and concentrated under reduced pressure. The residue was dissolved in ethanol (40 ml) and concentrated sulfuric acid (1.2 ml) was added. The precipitated crystals were collected by filtration to give compound 151. Yield 3.3g (55%)

'H-NMR (d-DMSO): 3.97 (3H, s), 8.07 (1H, d, J = 9.3Hz), 8.27 (1H, dd, J = 1.8, 9.6

Hz), 8.28 (1H, d, J = 2.4Hz), 8.47 (1H, d, J = 2.1Hz), 9.64 (1H, m).

(3) 151 → 152

Compound 151 (3.27 g, 11.9 mmol) was suspended in a mixed solvent of methanol (50 ml) and tetrahydrofuran (50 ml) to obtain 4N—NaOH (12 ml, 48 mmol). The mixture was stirred for 2 hours under reflux, returned to room temperature, and then 2N-HC1) was added to adjust the pH to 3.5. The precipitated crystals were collected by filtration to obtain Compound 152. Yield 1.61 g (83%)

'H-NMR (d-DMSO): 7.59 (2H, m), 7.65 (1H, m), 8.08 (1H, s), 9.26 (1H, m).

(4) 152 → 153

Compound 153 was obtained in the same manner as in Example 18, (1), using Compound 152 (1.61 g, 9.93 mmol). Yield 525mg (25%)

'H-NMR (d-DMSO): 7.42 (1H, d, J = 9.3Hz), 7.54 (1H, d, J = 1.2Hz), 7.69 (1H, dd,

J = 1.5, 9.3Hz), 8.00 (1H, d, J = 1.2Hz), 9.04 (1H, m).

(5) 8 + 153 → 154 → 155 → 148

Compound 8 (738 mg, 1 mmol) and Compound 153 (208 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 154 as an amorphous powder. Yield 791 mg (97%). Using this compound 154 (791 mg, 0.97 mmol) strength, et al. 2 M / l-TiCl / CH CI (3.0 ml, 6 mmol), compound 155 was obtained as a powder in the same manner as in Example 34, (6). It was. Yield 92 mg (15%). Further, Compound 148 was obtained as a powder from Compound 155 (90.1 mg, 0.145 mmol) in the same manner as in Example 34 (7). Yield 95 mg (8 6%)

'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9Hz), 3.38, 3,45 (2H, Abq, J = 17.4Hz), 4.0 8 (2H, q, J = 6.6Hz), 5.01 (1H, d, J = 4.8Hz), 5.12 (2H, d, J = 6.3Hz), 5.57 (1H, m), 5.75 (1H, m ), 6.71 (1H, s), 7.18— 7.22 (3H, m), 8.12 (1H, d, J = 9.3Hz), 8.21 (1H, d, J = 2.1Hz), 8.37 (1H, d, J = 8.1Hz), 8.41 (1H, s), 9.41 (1H, s), 9.52 (1H, d, J = 7.5Hz). IR (KBr) cm— 3419, 2983, 2157, 1761, 1649, 1601, 1530, 1445, 1385, 1294, 1237. MS (FAB): 622 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 6.0 H O-0.1 NaHCO

Calculated values: C, 41.24; H, 4.52; N, 16.58; S, 8.44; Na, 3.33 (%)

Experimental value: C, 41.26; H, 4.10; N, 16.49; S, 8.55; Na, 3.73 (%)

Example 36

[Chemical 85]

(1) 157 → 158

Compound 157 (2.07 g, 14.61 mmol) with methyl thioglycolate (1.55 g, 14.61 mmol) and K

CO (2.42 g, 17.53 mmol) is added to dimethylformamide (15 ml) and 50. Stir at C for 3 hours. The reaction solution was returned to room temperature, insolubles were removed by filtration, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine in that order, dried over MgSO, and concentrated under reduced pressure. Hexane-ethyl acetate (4: 1) was added to the residue for crystallization, and the residue was collected by filtration to give Compound 158. Yield 842mg (30%)

'H-NMR (CDCl): 3.98 (3H, s), 7.37 (1H, m), 8.02 (1H, s), 8.17 (1H, m), 8.69 (1H, m). (2) 158 → 159

Compound 158 (842 mg, 4.36 mmol) and NaNHCN (279 mg, 4.36 mmol) were suspended in methanol (10 ml) and stirred at room temperature for 3 days. Isopropanol was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain Compound 159. Yield 597 mg (61%)

'H-NMR (d-DMSO): 7.23 (1H, dd, J = 4.8, 8.1Hz), 7.55 (1H, s), 8.07 (1H, dd, J = 1.

6

5, 8.1Hz), 8.38 (1H, dd, J = 1.5, 4.5Hz).

(3) 8 + 159 → 160 → 161 → 156

Compound 8 (738 mg, 1 mmol) and Compound 159 (225 mg, 1 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 160 as an amorphous powder. Yield 87 8 mg (97%). Using this compound 160 (878 mg, 0.97 mmol) force 2M / 卜 TiCl 2 / CH CI (2.9 ml, 5.8 mmol), the same as in Example 34 (6)

4 2 2

The compound 161 was obtained as a powder. Yield 72 mg (12%). Further, Compound 156 was obtained as a powder from Compound 161 (50.9 mg, 0.079 mmol) in the same manner as in Example 34, (7). Yield 52 mg (86%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3,49 (2H, Abq, J = 17.1Hz), 4.0

6

9 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 4.8Hz), 5.48 (2H, d, J = 7.2Hz), 5.58 (1H, dd, J = 4.2, 8.1Hz), 5.85 (1H, m), 6.72 (1H, s), 7.20 (2H, s), 7.37 (1H, d, J = 15.6Hz), 8.04 -8.09 (2H, m), 8.98 (1H, d, J = 8.1Hz), 9.15 (1H, d, J = 6.3Hz), 9.52 (1H, d, J = 8.4Hz).

IR (KBr) cm " ¹ : 3418, 2983, 2173, 1764, 1602, 1536, 1472, 1363, 1200.

MS (FAB): 639+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.0 H O-0.2 NaHCO

26 21 8 6 3 2 3

Calculated values: C, 41.00; H, 4.10; N, 14.60; S, 12.53; Na, 3.59 (%)

Experimental values: C, 41.26; H, 4.05; N, 15.11; S, 11.86; Na, 3.89 (%)

Example 37

[Chemical 86]

(1) 163 → 164

Compound 163 (3.15 g, 20 mmol) and Et N (2.02 g, 20 mmol) were dissolved in tetrahydrofuran (35 ml).

Three

C: OOEt (2.39 g, 22 mmol) was added at -15 ° C, and the mixture was stirred for 15 minutes. This solution was cooled to _15 ° C., a solution of NaBH (2.01 g, 53 mmol) in water (18 ml) was added, and the mixture was further stirred for 30 minutes. Reaction liquid

Four

Extracted water with ketyl acetate. The organic layer is washed with brine and then dried over MgSO.

Four

Concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane-ethyl acetate. The eluent was concentrated under reduced pressure to give Compound 164. Yield 2.32 g (81%) 'H-NMR (CDCl): 4.80 (2H, s), 7.29 (1H, m), 7.92 (1H, m), 8.30 (1H, m).

Three

(2) 164 → 157

C: ○ COCl (4.10 g, 32.2 mmol) was dissolved in methylene chloride (50 ml), dimethyl sulfoxide (2.74 ml, 38.6 mmol) in methylene chloride (30 ml) was added at _78 ° C, and the mixture was stirred at the same temperature for 15 min. Stir. Compound 164 (2.32 g, 16.1 mmol) and Et N (8.91 ml, 64.4 mmol) in methylene chloride (

Three

30 ml) solution was poured into the above reaction mixture. The reaction mixture was heated to _15 ° C and stirred for 20 minutes, and then a saturated NH 4 C1 aqueous solution was added. Separate the organic layer, wash with brine, and dry over MgSO

4 4 and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane-ethyl acetate. The eluent was concentrated under reduced pressure to give Compound 157. Yield 2.07g (91%) Ή-NMR (CDC1): 7.43 (1H, dd, J = 4.8, 7.8Hz), 8.24 (1H, dd, J = 2.1, 7.8Hz), 8.62 (

1H, dd, J = 2.1, 4.5Hz), 10.46 (1H, m).

(3) 157 → 165

Compound 157 (1.26 g, 8.93 mmol) was dissolved in tetrahydrofuran (20 ml), 3 mol / L_MeMgCl / THF was added at _40 ° C, and the mixture was stirred for 5 minutes. 2N-hydrochloric acid was added to the reaction mixture, and the mixture was neutralized with 5% aqueous NaHC0 and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane-ethyl acetate. The eluent was concentrated under reduced pressure to give Compound 165. Yield 1.33g (95%)

'H-NMR (CDCl): 1 · 52 (3Η, d, J = 6.3Hz), 5.24 (2H, q, J = 6.3Hz), 7.29 (1H, m), 7.9

7 (1H, m), 8.29 (1H, m).

(4) 165 → 166

C: ○ COCl (2.15 g, 16.9 mmol) was dissolved in methylene chloride (25 ml), dimethyl sulfoxide (1.44 ml, 20.3 mmol) was added at _78 ° C, and the mixture was stirred at _78 ° C for 15 minutes. Next, a solution of compound 165 (1.33 g, 8.46 mmol) and Et N (4.7 ml, 33.8 mmol) in methylene chloride (15 ml) was added to the above reaction solution. The reaction solution was heated to −15 ° C. and stirred for 30 minutes, and then a saturated NH 4 C1 aqueous solution was prepared. The organic layer was separated, washed successively with water and brine, dried over MgSO and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluting with hexane-ethyl acetate. The eluent was concentrated under reduced pressure to give Compound 166. Yield 1.17 g (89%)

'H-NMR (CDCl): 2.71 (3H, s), 7.35 (1H, dd, J = 4.5, 7.5Hz), 7.92 (1H, dd, J = 1.8,

7.5Hz), 8.50 (1H, dd, J = 1.8, 4.5Hz).

(5) 166 → 167

Compound 167 was obtained from compound 166 (707 mg, 4.54 mmol) in the same manner as in Example 36, (1). Yield 850 mg (90%)

'H-NMR (CDCl): 2.77 (3H, s), 3.95 (3H, s), 7.38 (1H, dd, J = 4.5, 8.1Hz), 8.12 (1H, m), 8.70 (1H, d, J = 4.2Hz).

(6) 167 → 168

Compound 168 was obtained from compound 167 (850 mg, 4.1 mmol) in the same manner as in Example 35, (3). . Yield 699mg (88%)

'H-NMR (d-DMSO): 2.72 (3H, s), 7.54 (1H, m), 8.38 (1H, m), 8.71 (1H, m).

(7) 168 → 169

Compound 168 (493 mg, 2.55 mmol) was suspended in dimethylformamide (5 ml), and carbonyldiimidazole (828 mg, 5.1 mmol) was added. After stirring at room temperature for 1 hour, NaNHCN (392 mg, 6.1 mmol) was added, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was diluted with water, and the pH was adjusted to 6.1 with 2N-HC1 to precipitate the precipitate. The precipitate was collected by filtration and dried under reduced pressure to obtain Compound 169. Yield 399mg (72%)

'H-NMR (d-DMSO): 2.67 (3H, s), 7.49 (1H, m), 8.29 (1H, m), 8.65 (1H, m).

(8) 169 → 170,8 + 170 → 171 → 172 → 162

Compound 169 (483 mg, 2.22 mmol) was suspended in methanol (5 ml) and lN_MeONa / MeOH (2.0 ml, 2 mmol) was added. The mixture was concentrated under reduced pressure to give compound 170. Yield 477 mg (100%). Compound 170 (468 mg, 1.96 mmol) and Compound 8 (1.45 g, 1.96 mmol) were used in the same manner as in Example 1, (5) to obtain Compound 171 as an amorphous powder. Yield 1.67 g (85%). Compound 172 was obtained as a powder in the same manner as in Example 34, (6), using this compound 17 l (1.67 g, 1.67 mmol) and 2 M / t TiCl 2 / CH 2 CI (5.0 ml, 10 mmol). Yield 233 mg (21%). Further, Compound 162 was obtained as a powder from Compound 172 (2 33 mg, 0.356 mmol) in the same manner as in Example 34, (7). Yield 245 mg (90%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 2.79 (3H, s), 3.42, 3,50 (2H, Abq, J =

17.0Hz), 4.09 (2H, q, J = 7.2Hz), 5.06 (1H, d, J = 4.8Hz), 5.46 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 4.8, 8.4Hz), 5.88 (1H, m), 6.71 (1H, s), 7.32 (2H, s), 7.37 (1H, d, J = 1 5.9Hz), 8.06 (1H, dd, J = 6.0, 8.1Hz), 8.94 (1H, dd, J = 1.2, 8.1Hz), 9.15 (1H, d, J = 6.0Hz), 9.52 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3420, 2983, 2166, 1764, 1664, 1601, 1534, 1383, 1331, 1200.

MS (FAB): 675+ (M + H) +

Elemental analysis C H N O S Na- 5.0 H O

Calculated value: C, 42.40; H, 4.35; N, 14.65; S, 12.58; Na, 3.01 (%)

Experimental value: C, 42.40; H, 4.29; N, 14.72; S, 12.44; Na, 3.37 (%) Example 38

[Chemical 87]

(1) 174 → 175

KHCO3 (2.0 g, 20 mmol) was dissolved in water, and compound 174 (1.26 g, 8.93 mmol) was added under ice cooling. Extracted with methylene chloride and the organic layer was dried over MgSO and concentrated under reduced pressure. The residue

Four

It was dissolved in tetrahydrofuran (10 ml) and added to a solution of LDA (i-Pr2NH3.5 ml, 25 mmol + 2.6 MnBuLi 9.2 ml, 24 mmol) in tetrahydrofuran (12 ml) cooled to _78 ° C. The reaction was stirred for 1 hour and dimethylformamide (2.5 ml, 32 mmol) was added. The reaction mixture was stirred while warming to room temperature, and water was added. After concentrating the low-boiling solvent under reduced pressure, it was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over MgS04, and concentrated under reduced pressure.

The residue was suspended in dimethylformamide together with methyl thioglycolate (1.94 g, 18.3 mmol) and K2C03 (2.75 g, 19.9 mmol), and stirred at 60 ° C for 3 hours. The reaction solution was cooled to room temperature, water was added, and the deposited precipitate was collected by filtration to obtain Compound 175. Yield 725mg (19%) 'H-NMR (CDCl): 3.98 (3H, s), 7.81 (1H, m), 8.16 (1H, s), 8.55 (1H, d, J = 5.7Hz), 9.

Three

19 (1H, s).

(2) 175 → 176

Compound 176 was obtained from compound 175 (730 mg, 3.8 mmol) in the same manner as in Example 35, (3). Yield 498mg (68%) Ή-NMR (d-DMSO): 7.89 (1H, m), 8.02 (1H, s), 8.29 (1H, d, J = 5.7Hz), 9.03 (1H, s)

(3) 176 → 177

Compound 177 was obtained from compound 176 (498 mg, 2.78 mmol) in the same manner as in Example 37, (7). Yield 560 mg (99%)

'H-NMR (d-DMSO): 7.97 (1H, s), 8.45 (2H, s), 9.30 (1H, s).

(4) 177 → 178,8 + 178 → 179 → 180 → 173

Compound 177 (560 mg, 2.75 mmol) was suspended in methanol (10 ml), and ΙΝ-MeONa / MeOH (2.48 ml, 2.48 mmol) was added. The mixture was dried under reduced pressure to give compound 178. Yield 602 mg (97%). Compound 179 was obtained as an amorphous powder in the same manner as in Example 5, (5) using Compound 178 (602 mg, 2.68 mmol) and Compound 8 (1.97 g, 2.68 mmol). Yield 2.44 g (92%). Next, from this compound 179 (2.43 g, 2.46 mol), 2M / 卜 TiCl 2 / CH CI (7.4 ml, 14.8 mmol) was used, and compound 180 was obtained as a powder in the same manner as in Example 34 (6). It was. Yield 713 mg (45%). Further, Compound 180 (720 mg, 1.13 mmol) force Compound 173 was obtained as a powder in the same manner as in Example 34 (7). Yield 741 mg (87%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.43, 3,49 (2H, Abq, J = 16.8Hz), 4.0

9 (2H, q, J = 6.6Hz), 5.04 (1H, d, J = 4.5Hz), 5.34 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 4.8, 8.4Hz), 5.88 (1H, m), 6.71 (1H, s), 7.22 (2H, s), 7.33 (1H, d, J = 15.6Hz), 8.13 (lH, s), 8.71 (2H, s), 9.53 (1H , d, J = 8.1Hz), 9.63 (1H, s).

IR (KBr) cm— 3425, 2173, 1761, 1604, 1531, 1483, 1457, 1360, 1199.

MS (FAB): 639+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.0 H O

Calculated values: C, 41.60; H, 4.16; N, 14.93; S, 12.81; Na, 3.06 (%)

Experimental value: C, 41.75; H, 4.22; N, 15.01; S, 12.25; Na, 3.43 (%)

Example 39

[Chemical 88] Body)

(1) 8 + 182 → 183 → 184 → 181

Compound 8 (738 mg, lmmol) and Compound 182 (202 mg, lmmol) were suspended in dimethylformamide (5 ml) and dimethylsulfoxide (5 ml), sodium bromide (309 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 4 hours. . The reaction solution was poured into 5% brine (30 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to give Compound 183 as an amorphous powder. Yield 952 mg (97%). Using this compound 183 (952 mg, 0.97 mol), 2M / ton TiCl 2 / CH 2 CI (2.9 ml, 5.8 mmol), compound 184 was obtained as a powder in the same manner as in (34) of Example 34. Yield 63 mg (10%). Further, this compound 184 (59 mg, 0.092 mmol) force Compound 181 was obtained as a powder in the same manner as in Example 34, (7). Yield 62 mg (88%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.42, 3,47 (2H, Abq, J = 16.5Hz), 3.8

9 (3H, s), 4.09 (2H, q, J = 6.9Hz), 5.03 (1H, d, J = 5.1Hz), 5.05 (2H, d, J = 6.6Hz), 5.58 (1H, dd , J = 4.8, 8.4Hz), 5.80 (1H, m), 6.71 (1H, s), 7.02 (1H, d, J = 2.1Hz), 7.21- 7.25 (3H, m), 7.78 (1H, d, J = 2.1Hz), 8.03 (1H, d, J = 6.9Hz), 8.59 (1H, d, J = 7.2Hz), 9.52 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3420, 2984, 1763, 1634, 1604, 1561, 1499, 1472, 1405, 1336, 1298, 1221.

MS (FAB): 638+ (M- Na + 2H) +

Elemental analysis C H N O S Na-6.0 H O

Calculated values: C, 43.80; H, 4.99; N, 12.77; S, 8.35; Na, 2.99 (%)

Experimental value: C, 43.41; H, 4.82; N, 12.64; S, 8.23; Na, 3.04 (%)

Example 40 [Chemical 89]

(1) 182 → 186 → 187

Compound 186 was obtained from compound 182 (408 mg, 2.02 mmol) in the same manner as in Example 37, (7). Yield 323 mg (71%). This compound 186 (323 mg, 1.43 mmol) was suspended in methanol (5 ml), and ΙΝ-MeONa / MeOH (1.35 ml, 1.35 mmol) was added. The mixture was dried under reduced pressure to give Compound 187. Yield 342 mg (96%)

'H-NMR (d-DMSO): 4.88 (1H, s), 6.99 (1H, d, J = 2.1Hz), 7.46 (3H, m), 8.40 (2H, d,

J = 6.0Hz).

(2) 8 + 187 → 188 → 189 → 185

Compound 188 was obtained as an amorphous powder in the same manner as in (5) of Example 1 using Compound 8 (1.0111¾, 1.3711111101) and Compound 187 (34111¾, 1.3711111101). Yield 1.04 g (75%). Using this compound 188 (1.04 g, 1.03 mmol) and 2M / 卜 TiCl 2 / CH CI (3.1 ml, 6.2 mmol), compound 189 was obtained as a powder in the same manner as in Example 34 (6). Yield 26 mg (4%). Further, Compound 185 was obtained as a powder from Compound 189 (25 mg, 0.038 mmol) in the same manner as in Example 34, (7). Yield 27 mg (91%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.3Hz), 3.35—3.48 (2H, m), 3.92 (3H, s), 4.09 (

2H, q, J = 6.3Hz), 5.03 (1H, d, J = 4.8Hz), 5.07 (2H, m), 5.58 (1H, m), 5.81 (1H, m), 6.72 (1H, s), 7.21-7.28 (4H, m), 7.92 (1H, m), 8.11 (1H, d, J = 6.6Hz), 8.66 (1H, d, J = 7.5Hz), 9.53 (1H, d, J = 8.4Hz).

IR (KBr) cm— 3420, 2983, 2181, 2146, 1763, 1634, 1604, 1561, 1496, 1469, 1433,

1402, 1334, 1220.

MS (FAB): 662+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.0 H O-0.1 NaHCO

Calculated value: C, 44.68; H, 4.65; N, 16.12; S, 8.20; Na, 3.23 (%)

Experimental value: C, 44.74; H, 4.67; N, 15.85; S, 8.15; Na, 3.50 (%)

Example 41

[Chemical 90]

(1) 2 + 3 → 4

Compound 2 (83911¾, 1.5011111101) and compound 3 (33111¾, 1.5011111101) were suspended in dimethylformamide (2.5 ml), sodium bromide (463 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 5% brine (75 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 4 as an amorphous powder. Yield 1.047g (98%)

'H-NMR (d-DMSO): 3.49, 3.55 (2H, ABq, J = 14.1 Hz), 3.60, 3.88 (2H, ABq, J = 1 8.2 Hz), 5.18 (1Η, d, J = 4.8Hz), 5.30 (2H, d, J = 6.2Hz), 5.76 (1H, dd.J = 8.3, 4.8Hz), 6.40 (1H, dt , J = 15.9, 6.2Hz), 6.79 (1H, d, J = 15.9Hz), 6.91 (1H, s), 7.20-7.50 (16H, m), 7.65 (1H, dd, J = 8.1, 6.0Hz ), 8.42 (1H, d, J = 8.1Hz), 8.66 (1H, d, J = 6.0Hz), 9.17 (1H, d, J = 8.3Hz), 13.1 (1H, brs)

(2) 4 → 1

Compound 4 (68½¾, 0.9651! 111101) was dissolved in methylene chloride (4.11111) and anisole (0.681111), cooled to 0 ° C., and 2.0 ml of TFA (trifluoroacetic acid) was obtained. The mixture was stirred at 0 ° C for 35 minutes, and then poured into 40 ml of IPA with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved in saturated NaHC water. The solution is subjected to HP-20SS column chromatography and water-acetononitrile is added.

Three

Elution. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 1 as a powder. Yield 342 mg (56%)

'H-NMR (D20): 3.50, 3.58 (2H, ABq, J = 17.4 Hz), 3.61, 3.67 (2H, ABq, J = 15.2 Hz), 5.05 (1H, d, J = 4.5 Hz), 5.41 (2H, d, J = 6.6Hz), 5.59 (1H, d. J = 4.5Hz), 6.12 (1H, dt, J = 15.9, 6.6Hz), 6.85 (1H, d, J = 15.9Hz), 7.19 (1H, s), 7.26-7.40 (5H, m), 7.70 (1H, dd, J = 8.1, 6.0Hz), 8.47 (1H, d, J = 8.1Hz), 8.59 (1H, d, J = 6.0 Hz).

IR (KBr) cm ^_1 : 3427, 2165, 1761, 1658, 1594, 1540, 1399, 1337, 1200, 766.

MS (FAB): 565 ⁺ (M + H) ⁺

Elemental analysis C H N O SNa- 3.9 H O

27 21 6 5 2

Calculated value: C, 51.08; H, 4.57; N, 13.24; S, 5.05; Na, 3.62 (%)

Experimental value: C, 51.07; H, 4.44; N, 13.23; S, 5.06; Na, 3.78 (%)

Example 42

[Chemical 91]

(1) 2 + 6 → 7

Compound 2 (839 mg, 1.50 mmol) and Compound 6 (339 mg, 1.50 mmol) were suspended in dimethyl sulfoxide (2.5 ml), sodium bromide (463 mg, 4.50 mmol) was added, and Example 41 (1) In the same manner as above, Compound 7 was obtained as an amorphous powder. Yield 1.123 g (103%)

'H-NMR (d-DMSO): 3.50, 3.57 (2H, ABq, J = 14.0 Hz), 3.63, 3.88 (2H, ABq, J = 1

7.7 Hz), 5.20 (1H, d, J = 4.8 Hz), 5.39 (2H, d, J = 6.3 Hz), 5.78 (1H, dd. J = 8.0, 4.8 Hz), 6.43 (1H, dt, J = 15.6, 6.3Hz), 6.93 (1H, d, J = 15.6Hz), 6.93 (1H, s), 7.15-7.52 (1 5H, m), 8.78 (1H, d, J = 6.9Hz), 8.82 ( 1H, d, J = 6.9Hz), 9.18 (1H, d, J = 8.0Hz), 9.9 5 (1H, s).

(2) 7 → 5

Compound 7 (1.114 g, 1.532 mmol) was dissolved in methylene chloride (7 ml) and anisole (1.1 ml), cooled to 0 ° C., 3.3 ml of TFA was added, and the same procedure as in (2) of Example 41 was performed. Thus, Compound 5 was obtained as a powder. Yield 482mg (48%)

'H-NMR (d-DMSO): 3.41, 3.50 (2H, ABq, J = 16.8 Hz), 3.49, 3.57 (2H, ABq, J = 1

1.1 Hz), 4.96 (1H, d, J = 4.8 Hz), 5.42 (2H, d, J = 6.9 Hz), 5.47 (1H, dd. J = 8.1, 4.8 Hz), 5.91 (1H, dt, J = 15.8, 6.9Hz), 7.15- 7.30 (6H, m), 7.34 (1H, d, J = 15.8Hz), 8.83 (1 H, d, J = 6.6Hz), 8.87 (1H, dd, J = 6.6 , 1.2Hz), 9.05 (1H, d, J = 8.1Hz), 9.99 (1H, d, J = 1.2Hz).

IR (KBr) cm— 3433, 2178, 1760, 1606, 1542, 1512, 1362, 1123, 856. MS (ESI): 561 (M-Na + 2H)

Elemental analysis C H N O S Na- 3.8 H O

Calculated value: C, 47.97; H, 4.12; N, 12.91; S, 9, 85; Na, 3.53 (%)

Experimental value: C48.01; H, 4.19; N, 12.71; S, 9,80; Na, 3.73 (%)

Example 43

[Chem 92]

10 11 12

(1) 10 → 11

Compound 10 (3.04 g, 16.0 mmol) was suspended in 28% aqueous ammonia (40 ml) and stirred at 60 ° C. for 7 hours. Water was added, and the precipitate was filtered and dried to obtain Compound 11 as brown crystals. Yield 1.60 g (62%)

'H-NMR (d-DMSO): 7.18 (1H, dd, J = 8.9, 4.5Hz), 7.26 (1H, s), 7.54 (1H, s), 7.77 (1

H, d, J = 8.9Hz), 8.11 (1H, s), 8.38 (1H, d, 4.5Hz), 11.74 (1H, s).

(2) 11 → 12

Compound 11 (1.58 g, 9.80 mmol) was dissolved in pyridine (19 ml), methanesulfur chloride (4.5 5 ml, 58.8 mmol) was added, and the mixture was stirred at 60 ° C. for 2 hours and 20 minutes. Pyridine was distilled off under reduced pressure, extracted by adding water and ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were dissolved in methanol (16 ml). Was added and stirred for 1 hour and 45 minutes. 2N hydrochloric acid was added to adjust the pH to 6, and the precipitate was filtered to obtain Compound 12 as a brown powder. Yield 281mg (20%)

'H-NMR (d-DMSO): 7.36 (1H, dd, J = 8.4, 4.5Hz), 7.52 (1H, s), 7.93 (1H, d, J = 8.4

6

Hz), 8.54 (1H, d, 4.5Hz), 12.69 (1H, s).

(3) 12 → 13

Compound 12 (27 4 mg, 1.91 mmol), sodium azide (137 mg, 2.10 mmol), ammonium chloride (112 mg, 2. lOmmol) were suspended in dimethylformamide (3 ml) at 115 ° C for 3 hours 45 Stir for minutes. Water was added to the reaction solution after cooling, and the precipitate was filtered to obtain Compound 13 as light brown crystals. Yield 225 mg (63%)

(Insoluble in DMSO, no NMR data)

(4) 13 → 14

Compound 13 (216 mg, 1.16 mmol) was dissolved in dimethylformamide (3 ml), and sodium hydride (46 mg, 1.16 mmol) and triphenylmethyl chloride (323 mg, 1.16 mmol) were sequentially added under ice cooling. Stir at room temperature for 2 hours. Water and ethyl acetate were added, insolubles were removed by filtration, and the filtrate was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. After the solvent was distilled off, silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1), compound 14 was obtained as colorless crystals. Yield 101mg (20%)

'H-NMR (d-DMSO): 7.10-7.24 (m, 8H), 7.40-7.48 (m, 9H), 7.82 (1H, d, J = 8.1Hz),

6

8.40 (1H, dd, 8.1, 1.1Hz), 12.23 (1H, s).

(5) 14 → 8

Compound 9 (153 mg, 0.221 mmol) was suspended in dichloromethane (4 ml), an aqueous sodium hydrogen carbonate solution (28 mg, 0.332 mmol dissolved in 4 ml of water) was added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After the solvent was distilled off, compound 14 (95 mg, 0.221 mmol) was quickly added and dissolved in dimethylformamide (1.8 ml), sodium bromide (68 mg, 0.664 mmol) was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 5% brine (20 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain a quaternary salt as an amorphous powder. This is dissolved in methylene chloride (l.lml) and anisole (0.19ml), cooled to 0 ° C, 0.56ml of TFA is added, and compound 8 is powdered in the same manner as in Example 41 (2). Got as. Yield 13 mg (7%) NMR-NMR (D20): 1.28 (3H, t, J = 6.9Hz), 3.59, 3.66 (2H, ABq, J = 17.3 Hz), 4.23 (2H, q, J = 6.9 Hz), 5.22 (1H, d , J = 4.8Hz), 5.42 (2H, d, J = 6.0Hz), 5.80 (1H, d. J = 4.8 Hz), 6.17 (1H, dt, J = 15.8, 6.0Hz), 6.84 (1H, d , J = 15.8Hz), 6.97 (1H, s), 7.32 (2H, s), 7.57 (1H, dd, J = 8.4, 6.0Hz), 8.43 (1H, d, J = 8.4Hz), 8.44 (1H , d, J = 6.0Hz). IR (KBr) cm— 3419, 1760, 1616, 1532, 1384, 1358, 1202, 1037.

MS (FAB): 644 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na- 5.3 H 0-1.9 NaHCO

25 11 11 5 2 2 3

Calculated value: C, 35.95; H, 3.87; N, 17.14 (%)

Experimental value: C, 36.25; H, 4.15; N, 16.76 (%)

Example 45

[Chemical 93]

19

(1) 20 → 19

Compound 20 (156 mg, 1.50 mmol), sodium azide (107 mg, 1.65 mmol), ammonium chloride (88 mg, 1.65 mmol) were suspended in dimethylformamide (1.5 ml) and stirred at 115 ° C for 2 hours. did. The inorganic salt was filtered and washed with dimethylformamide (1.5 ml) to obtain a dimethylformamide solution of compound 21. Compound 9 (1.038 g, 1.50 mmol) was suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (189 mg, 2.25 mmol dissolved in 10 ml of water) was added under ice-cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After distilling off the solvent, it was immediately dissolved in dimethylformamide (3 ml), mixed with a dimethylformamide solution of compound 21, sodium bromide (463 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 5 hours. 5% sodium chloride solution Water (50 ml) was added while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain a quaternary salt as an amorphous powder. This was dissolved in methylene chloride (5.6 ml) and anisole (0.939 ml), cooled to 0 ° C., 2.8 ml of TFA was added, and compound 19 was powdered in the same manner as (2) of Example 41. Obtained. Yield 45 mg (4%)

'H-NMR (D20): 1.29 (3H, t, J = 7.1Hz), 3.66 (2Η, s), 4.25 (2H, q, J = 7.1 Hz), 5.27 (1H, d, J = 4.5 Hz), 5.31 (2H, d, J = 6.9Hz), 5.82 (1H, d, J = 4.5Hz), 6.12 (1H, dt, J = 15.9, 6.9Hz), 6.97 (1H, s), 6.98 ( 1H, d, J = 15.9Hz), 8.51 (2H, d, J = 7.1Hz), 8.88 (2H, d, J = 7.1Hz).

IR (KBr) cm ^_1 : 3419, 1761, 1637, 1611, 1536, 1389, 1038.

MS (FAB): 605+ (M + H) +

Elemental analysis C H N O S Na- 6.0 H O-1.0 NaHCO

23 21 10 5 2 2 3

Calculated values: C, 36.18; H, 4.30; N, 17.58; S, 8.05; Na, 5.77 (%)

Experimental values: C, 36.10; H, 4.37; N, 17.58; S, 8.63; Na, 5.60 (%)

Example 46

[Chemical 94]

23 24 25

(1) 23 → 24

Compound 23 (318 mg, 1.50 mmol) was dissolved in tetrahydrofuran (3 ml), and methanesulfonamide (143 mg, 1.50 mmol) and then DBU (0.224 ml, 1.50 mmol) were added at room temperature. After stirring two hours at room temperature, concentrated under reduced pressure, water was set to _P H = 4 with 2N hydrochloric acid. Further, the precipitate formed by concentration under reduced pressure was filtered and washed with water to obtain Compound 24 as light brown crystals. Yield 311mg (87%) 'H-NMR (d-DMSO): 3.33 (3H, s), 7.36 (1H, dd, J = 8.4, 4.8Hz), 7.52 (1H, s), 7.97 (1

6

H, d, J = 8.4Hz), 8.51 (1H, dd, J = 4.8, 1.4Hz), 12.27 (1H, brs).

(2) 24 → 25

Compound 24 (286 mg, 1.20 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 7.3, and the resulting solution was concentrated under reduced pressure to obtain compound 25 as a brown powder. Yield 323 mg (103%).

'H-NMR (d-DMSO): 2.92 (3H, s), 6.82 (1H, s), 7.09 (1H, dd, J = 8.3, 4.5Hz), 7.73 (1

6

H, d, J = 8.3Hz), 8.30 (1H, dd, J = 4.5, 1.5Hz), 11.33 (1H, brs).

(3) 25 → 26

Compound 9 (809 mg, 1.20 mmol) is suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (151 mg, 0.332 mmol is dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. did. After distilling off the solvent, immediately dissolve in dimethylformamide (2.4 ml), mix with compound 25 (312 mg, 1.20 mmol), add sodium bromide (370 mg, 3.60 mmol), and stir at room temperature for 2 hours 30 minutes. did. The reaction solution was poured into 5% brine (30 ml) with stirring, and the precipitated precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 26 as an amorphous powder. Yield 857mg (85%)

'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9Hz), 2.94 (3H, s), 3.61, 3.89 (2H, ABq, J =

6

17.7 Hz), 4.09 (2H, q, J = 6.9 Hz), 5.26 (1H, d, J = 5.0 Hz), 5.46 (2H, d, J = 5.7 Hz), 5.89 (1H, dd, J = 8.3, 5.0Hz), 6.43 (1H, dt, J = 16.2, 5.7Hz), 6.74 (1H, s), 6.76 (1H, d, J = 16.2Hz), 6.91 (1H, s), 7.20_7.53 (m , 13H), 7.65 (1H, dd, J = 8.1, 5.9Hz), 8.43 (1 H, d, J = 8.1Hz), 8.66 (1H, d, J = 5.9Hz), 9.64 (1H, d, J = 8.3Hz), 13.0 (1H, brs).

(4) 26 → 22

Compound 26 (844 mg, 1.00 mmol) was dissolved in methylene chloride (5 ml) and anisole (0.84 ml), and 0 ° C After cooling to 2.5 mL of TFA, Compound 22 was obtained as a powder in the same manner as in Example 41 (2). Yield 479mg (59%)

17.7 Hz), 4.08 (2H, q, J = 6.9 Hz), 5.02 (1H, d, J = 5.0 Hz), 5.43 (2H, d, J = 7.2 Hz), 5.57 (1H, dd, J = 8.0, 5.0Hz), 5.87 (1H, dt, J = 15.6, 7.2Hz), 6.71 (1H, s), 7.21 (2H, s), 7.27 (1H, d, J = 15.6Hz), 7.30 (1H, s) , 7.70 (1H, dd, J = 8.1, 6.0Hz), 8.42 (1H, d, J = 8.1Hz), 8.73 (1H, d, J = 6.0Hz), 9.51 (1H, d, J = 8.0Hz) .

IR (KBr) cm ^_1 : 3417, 1764, 1666, 1594, 1533, 1389, 1362, 1300, 1115.

MS (FAB): 697+ (M + H) +

Elemental analysis c H N O S Na- 5.4 H O-0.1 NaHCO

Calculated values: C, 39.07; H, 4.51; N, 13.96; S, 11.99; Na 3.27 (%)

Experimental value: C, 39.02; H, 4.22; N, 13.94; S, 12.09; Na 3.22 (%)

Example 47

[Chemical 95]

(1) 23 → 28

Compound 23 (340 mg, 1.60 mmol) was dissolved in tetrahydrofuran (4 ml), and Boc_sulfamide (315 mg, 1.60 mmol) and then DBU (0.240 ml, 1.60 mmol) were added at room temperature. The mixture was stirred at room temperature for 1 hour and 30 minutes and at 50 ° C for 15 hours, then concentrated under reduced pressure, and adjusted to pH = 4 with water and 2N hydrochloric acid. The solution was subjected to HP-20SS column chromatography, and the desired fraction was concentrated under reduced pressure and then lyophilized to obtain Compound 28 as a colorless powder. Yield 106 mg (20%)

(2) 28 → 29

Compound 28 (101 mg, 0.296 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 7.7, and the resulting solution was concentrated under reduced pressure to obtain 28 sodium salt. Suspend compound 9 (199 mg, 0.296 mmol) in dichloromethane (6 ml), add aqueous sodium hydrogen carbonate solution (37.3 mg, 0.443 mmol dissolved in 6 ml of water) under ice-cooling, extract with dichloromethane, and dry over magnesium sulfate. did. After distilling off the solvent, immediately dissolve in dimethylformamide (lml), mix with 28 sodium salt, add sodium bromide (208mg, 0.887mmol), Stir at temperature for 2 hours 35 minutes. The reaction solution was poured into 5% brine (15 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 29 as an amorphous powder. Yield 208 mg (75%)

'H-NMR (d-DMSO): 1.21 (3H, t, J = 7.1Hz), 1.34 (9H, s), 3.61, 3.88 (2H, ABq, J =

17.3 Hz), 4.08 (2H, q, J = 7.1 Hz), 5.25 (1H, d, J = 4.8 Hz), 5.45 (2H, d, J = 6.0 Hz), 5.87 (1H, dd, J = 8.1, 4.8Hz), 6.42 (1H, dt, J = 15.9, 6.0Hz), 6.73 (1H, s), 6.75 (1H, d, J = 15.9Hz), 6.90 (1H, s), 7.15_7.53 (m , 13H), 7.66 (1H, dd, J = 8.3, 5.7Hz), 8.44 (1 H, d, J = 8.3Hz), 8.66 (1H, d, J = 5.7Hz), 9.61 (1H, d, J = 8.1Hz), 9.66 (1H, s). (3) 29 → 27

Compound 29 (201 mg, 0.214 mmol) was dissolved in methylene chloride (1.2 ml) and anisole (0.20 ml), cooled to −30 ° C., and 0.5 ml of 2M aluminum chloride nitromethane solution was added. The mixture was stirred at _30 ° C for 45 minutes and then poured into 10 ml of diisopropyl ether / 10 ml of 0.2N hydrochloric acid while stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with aqueous NaHCO. HP-20S solution

S column chromatography and elution with water-acetonitrile. The aqueous layer of the filtrate was purified in the same manner. Both were dissolved in NaHCO aqueous solution, subjected to HP-20SS column chromatography again and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 27 as a powder. Yield 30 mg (17%) 'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9 Hz), 3.43, 3.49 (2H, ABq, J = 16.5 Hz), 4.

08 (2H, q, J = 6.9 Hz), 5.01 (1H, d, J = 4.8Hz), 5.36 (2H, d, J = 6.0Hz), 5.57 (1H, dd, J = 8.1, 4.8Hz), 5.77 (2H, s), 5.86 (1H, dt, J = 16.1, 6.0Hz), 6.70 (1H, s), 7.21 (2H, s), 7.26 (1H, d, J = 16.1Hz), 7.52 (1H , brs), 8.34 (1H, d, J = 7.2Hz), 8.59 (1H, brs), 9.5 2 (1H, d, J = 8.1Hz).

IR (KBr) cm— 3418, 1761, 1595, 1533, 1388, 1305, 1300, 1127, 1036, 770.

MS (FAB): 698+ (M + H) +

Elemental analysis c H N O S Na- 5.0 H O-0.6 NaHCO

Calculated values: C, 36.68; H, 4.16; N, 15.04; S, 11.48; Na 4.39 (%)

Experimental values: C, 36.67; H, 4.04; N, 15.15; S, 11.56; Na 4.22 (%)

Example 49 [Chemical 96]

Na ⁺

41

(1) 31 → 38

Compound 31 (1.28 g, 5.46 mmol) was suspended in ethanol (10 ml), and 2N aqueous sodium hydroxide solution (13.7 ml, 27.4 mmol) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour and 20 minutes, and concentrated hydrochloric acid was added to adjust to pH = 3.5. The precipitate was collected by filtration and dried under reduced pressure to obtain compound 38 as light brown crystals. Yield 986 mg (88%)

'H-NMR (d-DMSO): 7.96 (2H, d, J = 5.6 Hz), 8.68 (2H, d, J = 5.6 Hz), 8.79 (1H, s).

(2) 38 → 39

Compound 38 (975 mg, 4.73 mmol) was suspended in dimethylformamide (10 ml), and force sulfonyldiimidazole (l. L lg, 5.23 mmol) was added at room temperature. The mixture was stirred at room temperature for 3 hours, and the reaction solution was poured into ethyl acetate (30 ml). The mixture was stirred under ice cooling, and the resulting precipitate was collected by filtration and dried under reduced pressure to obtain Compound 39 as light brown crystals. Yield 937 mg (77%) Ή-NMR (d-DMSO): 7.23 (1H, s), 8.06 (2H, d, J = 6.0 Hz), 8.19 (1H, s), 8.74 (2H, d,

6

J = 6.0 Hz), 9.08 (1H, s), 9.11 (1H, s).

(3) 39 → 40

Compound 39 (30611¾, 1.2011111101) was obtained as pale brown crystals by the same method as in Example 46 (1). Yield 282 mg (83%)

'H-NMR (d-DMSO): 3.37 (3H, s), 8.37 (2Η, d, J = 5.6 Hz), 8.83 (2H, d, J = 5.6 Hz)

6

, 8.79 (1H, s).

(4) 40 → 41

Compound 40 (276 mg, 0.976 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 7.5, and the resulting solution was concentrated under reduced pressure to obtain 40 sodium salt. Compound 9 (658 mg, 0.976 mmol) was suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (123 mg, 1.46 mmol dissolved in 10 ml of water) was added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After distilling off the solvent, it was quickly dissolved in dimethylformamide (2 ml), mixed with 40 sodium salt, sodium bromide (301 mg, 2.92 mmol) was added, and the mixture was stirred at room temperature for 2 hours and 10 minutes. The reaction mixture was poured into 5% brine (30 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 41 as an amorphous powder. Yield 783 mg (91%)

'H-NMR (d-DMSO): 1.21 (3H, t, J = 7.2Hz), 2.89 (3H, s), 3.63, 3.89 (2H, ABq, J =

6

17.9 Hz), 4.08 (2H, q, J = 7.2 Hz), 5.25 (2H, d, J = 6.9 Hz), 5.27 (1H, d, J = 5.1 Hz), 5.90 (1H, dd, J = 8.4, 5.1Hz), 6.41 (1H, dt, J = 15.8, 6.9Hz), 6.73 (1H, s), 6.86 (1H, d, J = 15.8Hz), 6.90 (1H, s), 7.21 (2H, s) , 7.23- 7.50 (m, 10H), 8.57 (2H, d, J = 7.1Hz), 8.95 (2H, d, J = 7.1Hz), 9.00 (1H, s), 9.62 (1H, d, J = 8.4 Hz).

(5) 41 → 37

Compound 41 (773 mg, 0.873 mmol) was dissolved in methylene chloride (4.6 ml) and anisole (0.77 ml), cooled to 0 ° C., and 2.3 ml of TFA was added, as in (2) of Example 41. By the procedure, compound 37 was obtained as a powder. Yield 387mg (54%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 2.90 (3H, s), 3.43, 3.51 (2H, ABq, J =

6

16.4 Hz), 4.09 (2H, q, J = 7.1 Hz), 5.05 (1H, d, J = 4.8 Hz), 5.26 (2H, d, J = 6.9 Hz), 5.60 (1H, dd, J = 8.4, 4.8Hz), 5.87 (1H, dt, J = 16.1, 6.9Hz), 6.72 (1H, s), 7.21 (2H, s), 7.30 (1H, d, J = 16.1 Hz), 8.58 (2H, d, J = 7.2 Hz), 8.98 (1H, s), 9.02 (2H, d, J = 7.2 Hz), 9.53 (1H, d, J = 8.4 Hz).

IR (KBr) cm ^_1 : 3410, 1765, 1636, 1601, 1531, 1387, 1345, 1257, 1125, 1034, 969.

MS (ESI): 719 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.4 H O

Calculated values: C, 39.54; H, 4.15; N, 13.66; S, 15.64; Na 2.80 (%)

Experimental value: C39.54; Η, 3.99; N, 13.79; S, 15.52; Na 3.01 (%)

Example 50

[Chemical 97]

(1) 43 → 44

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After distilling off the solvent, quickly dissolve in dimethylformamide (2 ml), mix with compound 43 (455 mg, l.OOmmol), add sodium bromide (309 mg, 3.00 mmol), and at room temperature for 5 hours 30 minutes. Stir. The reaction solution was poured into 5% brine (40 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 44 as an amorphous powder. Yield 9 61mg (84%)

'H-NMR (d-DMSO): 1.23 (3H, t, J = 6.9Hz), 3.64, 3.90 (2H, ABq, J = 17.1 Hz), 3.

74 (3H, s), 3.76 (3H, s), 4.10 (2H, q, J = 6.9Hz), 5.18-5.30 (7H, m), 5.91 (1H, dd, J = 8.3, 4.8Hz), 6.42 (1H, dt, J = 16.2, 7.2Hz), 6.74 (1H, s), 6.86_6.94 (7Η, m), 7.20-7.5 4 (16H, m), 8.28 (1H, dd, J = 8.9 , 2.3Hz), 8.33 (1H, d, J = 2.3H z), 8.49 (2H, d, J = 7.2 Hz), 8.92 (2H, d, J = 7.2Hz), 9.64 (1H, d, J = 8.3Hz).

(2) 44 → 42

Compound 44 (945 mg, 0.831 mmol) was dissolved in methylene chloride (10 ml) and anisole (0.945 ml), cooled to −30 ° C., and 4.2 ml of 2M aluminum chloride nitromethane solution was added. The mixture was stirred at _30 ° C for 45 minutes and then poured into 50 ml of diisopropyl ether / 50 ml of 0.2N hydrochloric acid while stirring under ice cooling. The deposited precipitate and the aqueous layer of the filtrate were mixed, and acetonitrile was dissolved to dissolve. HP-20SS was added and the mixture was concentrated under reduced pressure, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. Concentrate the desired fraction under reduced pressure and pH = 7 with aqueous NaHCO solution.

Dissolved as .8. This solution was again subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 42 as a powder. Yield 274 mg (43%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3.49 (2H, ABq, J = 17.1Hz), 4.1

9 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.8Hz), 5.16 (2H, d, J = 7.1Hz), 5.59 (1H, dd, J = 8.0, 4.8Hz), 5.83 (1H, dt, J = 15.9, 7.1Hz), 6.71 (1H, s), 6.78 (1H, d, J = 8.7Hz), 7.21 (2H, s), 7.27 (1H, d, J = 15.9Hz), 7.95 (1H, dd, J = 8.7, 2.7Hz), 8.30 (2H, d, J = 7.2Hz), 8.38 (1H, d, J = 2.7Hz), 8.74 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.0Hz).

IR (KBr) cm— 3421, 1764, 1627, 1601, 1533, 1488, 1387, 1300, 1159, 1036, 829. MS (FAB): 673+ (M- Na + 2H) +

Elemental analysis c H N O S Na-4.7 H O-0.2NaHCO

Calculated value: C, 39.47; H, 4.16; N, 15.22; S, 13.06; Na 3.75 (%)

Experimental value: C39.44; H, 4.01; N, 15.17; S, 13.00; Na 3.78 (%)

Example 52

[Chemical 98]

(1) 43 → 51

Compound 50 (765 mg, 1.06 mmol) and compound 43 (483 mg, 1.06 mmol) were suspended in a mixed solution of dimethylformamide (2.3 ml) and dimethyl sulfoxide (2.3 ml), and sodium bromide (328 mg, 3.18 mmol) was suspended. added. After stirring at room temperature for 5 hours and 40 minutes, the reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 51 as an amorphous powder. Yield 1.22g (94%)

'H-NMR (d-DMSO): 1.03 (3H, t, J 2 7.2Hz), 1.47 (9H, s), 2.22 (2H, sept, J = 7.2Hz

6

), 3.66, 3.91 (2H, ABq, J = 17.4 Hz), 3.75 (3H, s), 3.76 (3H, s), 5.15_5.30 (7H, m), 5.88 (1H, dd, J = 7.2, 5.4Hz), 6.30-6.45 (1H, m), 6.36 (1H, t, J = 7.2Hz), 6.77 (1H, s), 6.86-6.94 (7H, m), 7.20-7. 58 (14H , m), 8.28 (1H, dd, J = 9.0, 2.4Hz), 8.34 (1H, d, J = 2.4Hz), 8.49 (2H, d, J = 7.2Hz), 8.93 (2H, d, J = 7.2Hz), 9.39 (1H, d, J = 7.2Hz), 1 1.5 (1H, brs).

(2) 51 → 49

Compound 51 (1.21 g, 0.994 mmol) was dissolved in methylene chloride (12 ml) and anisole (1.2 ml), cooled to −30 ° C., 5.4 ml of 2M aluminum chloride nitromethane solution was added, and (2) of Example 50 ) To give Compound 49 as an amorphous powder. Yield 197 mg (26%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.6Hz), 2.18 (2H, sept, J = 7.6Hz), 3.43, 3.50 (

6

2H, ABq, J = 16.8Hz), 5.05 (1H, d, J = 4.8Hz), 5.16 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.0, 4.8Hz), 5.82 ( 1H, dt, J = 15.6, 7.2Hz), 6.21 (1H, s), 6.22 (1H, t, 7.6Hz), 6.7 8 (2H, d, J = 8.4Hz), 6.98 (2H, s), 7.28 (1H, d, J = 15.6Hz), 7.94 (1H, dd, J = 8.4, 2.8 Hz), 8.30 (2H, d , J = 7.2Hz), 8.39 (1H, d, J = 2.8Hz), 8.74 (2H, d, J = 7.2Hz), 9.20 (1 H, d, J = 8.0Hz).

IR (KBr) cm ^_1 : 3399, 1763, 1600, 1526, 1488, 1470, 1388, 1300, 1157, 829.

MS (FAB): 656+ (M + H) +

Elemental analysis c H N O S Na-4.4 H O-0.2NaHCO

30 26 5 7 2 2 3

Calculated values: C, 48.25; H, 4.69; N, 9.32; S, 8.53; Na 3.67 (%)

Experimental value: C48.17; H, 4.58; N, 9.73; S, 8.72; Na 3.73 (%)

Example 53

[Chemical 99]

Na ⁺

33 53

(1) 33 → 53

Compound 33 (562 mg, 3.00 mmol), sodium azide (215 mg, 3.30 mmol) and ammonium chloride (177 mg, 3.30 mmol) were suspended in dimethylformamide (6 ml) and stirred at 115 ° C for 2 hours and 25 minutes. did. After cooling to room temperature, water and then 2N-HC1 were added to adjust pH = 4, and the precipitate was collected by filtration to obtain Compound 53 as colorless crystals. Yield 764mg (lll%)

'H-NMR (d-DMSO): 8 · 13 (2Η, d, J = 6.0Hz), 8.78 (2H, d, J = 6.0Hz), 8.83 (1H, s).

6

(2) 53 → 52

Compound 9 (1.349 g, 2.00 mmol) is suspended in dichloromethane (15 ml), aqueous sodium hydrogen carbonate solution (252 mg, 3.00 mmol dissolved in 15 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After removing the solvent, quickly dissolve in dimethylformamide (4 ml). The mixture was mixed with Compound 53 (461 mg, 2.00 mmol), dimethylsulfoxide (12 ml) and sodium bromide (617 mg, 6.OOmmol) were added, and the mixture was stirred at room temperature for 7 hours. The reaction solution was poured into 5% brine (80 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain a quaternary salt as an amorphous powder. This was dissolved in methylene chloride (16 ml) and anisole (1.6 ml), cooled to _30 ° C, 4.8 ml of 2M aluminum chloride nitromethane solution was added, and compound 52 was prepared in the same manner as in Example 50 (2). Obtained as a powder. Yield 122 mg (8%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.8Hz), 3.46, 3.54 (2H, ABq, J = 17.0Hz), 4.0

6

8 (2H, q, J = 6.8 Hz), 5.08 (1H, d, J = 4.6 Hz), 5.29 (2H, d, J = 6.8 Hz), 5.63 (1H, dd, J = 7.6, 4.6 Hz), 5.93 (1H, dt, J = 16.0, 6.8Hz), 6.72 (1H, s), 7.25 (2H, s), 7.34 (1H, d, J = 16.0Hz), 8.62 (2H, d, J = 6.2Hz ), 8.97 (1H, s), 9.05 (2H, d, J = 6.2Hz), 9.56 (1H, d, J = 7.6Hz).

IR (KBr) cm ^_1 : 3398, 1762, 1635, 1530, 1388, 1300, 1155, 1036, 990.

MS (ESI): 666 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 4.6 H O-0.2 NaHCO

26 22 11 5 3 2 3

Calculated: C, 39.97; H, 4.02; N, 19.57; S, 12.22; Na 3.50 (%)

Experimental value: C, 40.08; H, 3.94; N, 19.36; S, 12.04; Na 3.59 (%)

Example 54

[Chemical 100]

56

(1) 55 → 56

Compound 50 (659 mg, 0.913 mmol) and compound 55 (350 mg, 0.913 mmol) were converted to dimethylformamide. (3 ml) and sodium bromide (282 mg, 2.74 mmol) was added. After stirring at room temperature for 7 hours, the reaction solution was poured into 5% brine (40 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 56 as an amorphous powder. Yield 936 mg (89%)

'H-NMR (d-DMSO): 1.03 (3H, t, J = 7.7Hz), 1.47 (9H, s), 2.23 (2H, sept, J = 7.7Hz

), 3.67, 3.91 (2H, ABq, J = 17.8 Hz), 5.32 (1H, d, J = 4.8 Hz), 5.35 (2H, d, J = 6.2 Hz), 5.89 (1H, dd, J = 7.6, 4.8Hz), 6.36 (1H, t, J = 7.7Hz), 6.45 (1H, dt, J = 15.8, 6.2Hz), 6.77 (1H, s), 6.92 (1H, s), 6.97 (1H, d, J = 15.8Hz), 7.28—7.58 (20H, m), 7.80-8.28 (3H, m), 8.62 (1H, d, J = 6.6Hz), 9.12 (2H, d, J = 6.6Hz), 9.39 (1H, d, J = 7.6Hz).

(2) 56 → 54

Compound 56 (933 mg, 0.812 mmol) was dissolved in methylene chloride (9 ml) and anisole (0.933 ml). After cooling to C, 4 ml of a 2M salt / aluminum nitromethane solution was added, and Compound 54 was obtained as an amorphous powder in the same manner as in Example 50 (2). Yield 199mg (33%)

'H-NMR (d-DMSO): 0.99 (3H, t, J = 7.6Hz), 2.17 (2H, sept, J = 7.6Hz), 3.44, 3.51 (

2H, ABq, J = 17.8Hz), 5.06 (1H, d, J = 4.8Hz), 5.29 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 7.4, 4.8Hz), 5.87 ( 1H, dt, J = 16.0, 7.2Hz), 6.20 (1H, s), 6.22 (1H, t, J = 7.6Hz), 7.00 (2H, s), 7.32 (1H, d, J = 16.0Hz), 7.64 (1H, t, J = 7.2Hz), 7.76 (1H, d, J = 7.2Hz), 7.79 (1H, d, J = 12.0Hz), 8.48 (1H, d, J = 6.4H z), 9.03 (2H, d, J = 6.4Hz), 9.21 (1 H, d, J = 7.4Hz).

IR (KBr) cm ^_1 : 3408, 1763, 1603, 1526, 1406, 1371, 1155.

MS (FAB): 636+ (M_Na + 2H) +

Elemental analysis C H FN O S Na-4.0 H O-O. lNaHCO

Calculated values: C, 48.98; H, 4.52; F, 2.57; N, 9.49; S, 8.69; Na 3.43 (%)

Experimental value: C48.83; H, 4.36; F, 2.52; N, 9.67; S, 8.77; Na 3.60 (%)

Example 55

[Chemical 101]

(1) 58 → 59

Compound 58 (2.130 g, 6.862 mmol) was dissolved in methanol (21 ml), and a methanol solution (16 ml) of silver perchlorate (1.56 g, 7.55 mmol) was added dropwise at room temperature. After stirring for 50 minutes, the precipitate was collected by filtration to obtain Compound 59 as pale yellow orange crystals. Yield 2.112 g (104%)

(2) 59 → 60

4-Bromopyridine hydrochloride (1.334 g, 6.862 mmol) was dissolved in jetyl ether / 2N NaOH and extracted with jetyl ether. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Dimethylformamide (13 ml) was added, and the ethyl ether was distilled off under reduced pressure. Compound 59 (2.112 g, 6.862 mmol) was added, and the mixture was stirred at 70 ° C. for 1 hour. Ethyl acetate was added, and the insoluble material was filtered through a Celite pad. The filtrate was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with hexane: ethyl acetate = 1: 3. The desired fraction was concentrated to give compound 60 as an oily substance. Yield 812 mg (44%)

'H-NMR (d-DMSO): 1.34 (3H, t, J = 7.2Hz), 4.43 (2H, t, J = 7.2Hz), 7.65 (2H, d, J

= 4.8Hz), 8.65 (2H, d, J = 4.8Hz).

(3) 60 → 61 Compound 60 (298 mg, 1.21 mmol) was suspended in methanol (3 ml), and cyanamide sodium salt (81 mg, 1.27 mmol) was added and stirred for 50 minutes. The solution was concentrated half way, and the resulting precipitate was removed and the resulting precipitate was filtered and dried under reduced pressure to obtain Compound 61 as colorless crystals. Yield 25 6mg (65%)

'H-NMR (d-DMSO): 7.54 (2H, d, J = 4.6Hz), 8.60 (2H, d, J = 4.6Hz).

(4) 61 → 62

Compound 9 (522 mg, 0.773 mmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (97 mg, 1.16 mmol dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. did. After the solvent was distilled off, it was quickly dissolved in dimethylformamide (2 ml), mixed with compound 61 (254 mg, 0.773 mmol), sodium bromide (239 mg, 2.32 mmol) was added, and the mixture was stirred at room temperature for 5 hours. The reaction solution was poured into 5% brine (25 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 62 as an amorphous powder. Yield 553 mg (83%)

^J H-NMR (d-DMSO): 1.23 (3H, t, J = 7.0Hz), 3.63, 3.86 (2H, ABq, J = 17.6Hz), 4.0

9 (2H, q, J = 7.0 Hz), 5.20 (2H, d, J = 6.0 Hz), 5.29 (1H, d, J = 4.8 Hz), 5.92 (1H, dd, J = 7.0, 4.8 Hz), 6.35 (1H, dt, J = 16.0, 6.0Hz), 6.76 (1H, s), 6.90 (1H, d, J = 16.0Hz), 6.94 (1H, s), 7.26-7.43 (m, 12H), 8.02 (2H, d, J = 5.8Hz), 8.77 (2H, d, J = 5.8Hz), 9.

65 (1H, d, J = 7.0Hz).

(5) 62 → 57

Compound 62 (539 mg, 1.04 mmol) was dissolved in methylene chloride (3.2 ml), cooled to 0 ° C., 1.6 ml of TFA was added, and compound 57 was prepared in the same manner as in Example 41 (2). Obtained as a powder. Yield 195 mg (39%)

'H-NMR (DMSO): 1.22 (3H, t, J = 6.9Hz), 3.40, 3.47 (2H, ABq, J = 16.8Hz), 4.09 (2H, q, J = 6.9Hz), 5.04 (1H , d, J = 4.8Hz), 5.19 (2H, d, J = 6.6Hz), 5.59 (1H, dd, J = 8 • 4, 4.8Hz), 5.78 (1H, dt, J = 16.2, 6.6Hz) , 6.72 (1H, s), 7.23 (2H, s), 7.26 (1H, d, J = 16.2Hz), 8.02 (2H, d, J = 7.2Hz), 8.81 (2H, d, J = 7.2Hz) , 9.54 (1H, d, J = 8.4Hz). IR (KBr) cm ^_1 : 3417, 2179, 2158, 1763, 1624, 1531, 1356, 1036.

MS (ESI): 699 ⁺ (M-Na + 2H) ⁺ Elemental analysis CHNOS Na- 3.1HO-0.2NaHCO

26 21 10 6 4 2 3

Calculated: C, 39.66; H, 3.48; N, 17.65; S, 16.17; Na, 3.48 (%)

Experimental values: C, 39.62; H, 3.47; N, 17.64; S, 16.13; Na, 3.59 (%)

Example 56

[Chemical 102]

(1) 64 → 65

Compound 64 (33011¾, 1.5011111101) was suspended in tetrahydrofuran (3.31111), diphenyldiazomethane (320 mg, 1.65 mmol) was added, and the mixture was stirred under reflux for 2 hours. Ethyl acetate and water were added and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with hexane: ethyl acetate = 1: 4. The desired fraction was concentrated under reduced pressure to give Compound 65 as a pale orange foam. Yield 348mg (60%)

'H-NMR (d-DMSO): 2.60 (3H, s), 7.12 (1H, s), 7.30—7.53 (10H, m), 7.64 (2H, d, J =

6

6.0Hz), 8.72 (2H, d, J = 6.0Hz).

(2) 65 → 66

Compound 50 (614 mg, 0.851 mmol) and compound 65 (329 mg, 0.851 mmol) were converted to dimethylformamide. (2.4 ml) and sodium bromide (263 mg, 2.55 mmol) was added. After stirring at room temperature for 7 hours, the reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 66 as an amorphous powder. Yield 883 mg (90%)

'H-NMR (d-DMSO): 1.03 (3H, t, J = 7.6Hz), 1.47 (9H, s), 2.24 (2H, sept, J = 7.6Hz

), 2.71 (3H, s), 3.68, 3.91 (2H, ABq, J = 17.6 Hz), 5.33 (1H, d, J = 4.8Hz), 5.39 (2H, d, J = 6.6Hz), 5.89 (1H , Dd, J = 7.6, 4.8Hz), 6.37 (1H, t, J = 7.6Hz), 6.48 (1H, dt, J = 15.2, 6.2Hz), 6.78 (1H, s), 6.93 (1H, s) 6.94 (1H, d, J = 15.2Hz), 7.12 (1H, s), 7.25-7.54 (20H, m), 8.39 (1H, d, J = 6.2Hz), 9.11 (2H, d, J = 6.2 Hz), 9.40 (1H, d, J = 7.6Hz), 11.5 (1H, brs).

(3) 66 → 63

Compound 66 (872 mg, 0.756 mmol) was dissolved in methylene chloride (4.4 ml) and anisole (0.872 ml), cooled to 0 ° C., and 4.4 ml of TFA was added, the same as in Example 41 (2). By the method, Compound 63 was obtained as a powder. Yield 146 mg (26%)

'H-NMR (d-DMSO): 1 · 00 (3Η, t, J = 7.5Hz), 2.17 (2H, sept, J = 7.5Hz), 3.43, 3.51 (

2H, ABq, J = 17.1Hz), 5.06 (1H, d, J = 4.8Hz), 5.27 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.0, 4.8Hz), 5.84 ( 1H, dt, J = 15.9, 6.9Hz), 6.20 (1H, s), 6.22 (1H, t, 7.5Hz), 7.0 1 (2H, s), 7.30 (1H, d, J = 15.9Hz), 8.20 (1H, d, J = 7.2Hz), 8.95 (2H, d, J = 7.2Hz), 9.23 (1H, d, J = 8.0Hz).

IR (KBr) cm ^_1 : 3408, 1763, 1631, 1526, 1360, 1158.

MS (ESI): 639+ (M-Na + 2H) +

Elemental analysis C H N O S Na- 3.4 H O-0.2 NaHCO

Calculated values: C, 44.76; H, 4.53; Ν, Ι Ι.10; S, 12.71; Na 3.65 (%)

Experimental value: C, 44.78; H, 4.41; N, 11.02; S, 12.76; Na 3.72 (%)

Example 57

[Chemical 103]

67

~ 67

(1) 40 → 68

Compound 40 (308 mg, 1.08 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 7.5, and the resulting solution was concentrated under reduced pressure to obtain 40 sodium salt. To this was added compound 50 (782 mg, 1.08 mmol), dissolved in dimethylformamide (3 ml), then sodium bromide (335 mg, 3.25 mmol) was added and stirred at room temperature for 5 hours. The reaction mixture was poured into 5% brine (30 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 68 as an amorphous powder. Yield 949 mg (90%)

'H-NMR (d-DMSO): 1.03 (3H, t, J = 7.2Hz), 1.48 (9H, s), 2.23 (2H, sept, J = 7.2Hz

), 2.89 (3H, s), 3.67, 3.91 (2H, ABq, J = 17.6 Hz), 5.27 (2H, d, J = 6.8Hz), 5.32 (1H, d, J = 5.2Hz), 5.89 (1H , dd, J = 8.0, 5.2Hz), 6.36 (1H, t, J = 7.2Hz), 6.43 (1H, dt, J = 16.4, 6.8Hz), 6.77 (1H, s), 6.91 (1H, d, J = 16.4Hz), 7.10—7.52 (m, 10H), 8.58 (2H, d, J = 6.0Hz), 8.96 (2H, d, J = 6.0Hz), 9.00 (1H, s), 9.38 (1H, d, J = 8.0Hz), 11.5 (1H, brs).

(2) 68 → 67

Compound 68 (949 mg, 0.980 mmol) was dissolved in methylene chloride (4.7 ml) and anisole (0.949 ml), cooled to 0 ° C., and 4.7 ml of TFA was added, as in (2) of Example 41. By the method, Compound 67 was obtained as a powder. Yield 239 mg (30%)

'H-NMR (d-DMSO): 1.00 (3H, t, 7.5Hz), 2.17 (2H, sept, 7.5Hz), 3.43, 3.51 (2H, A Bq, J = 17.1Hz), 5.06 (1H, d, J = 4.8Hz), 5.27 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.0, 4.8Hz), 5.84 ( 1H, dt, J = 15.9, 6.9Hz), 6.20 (1H, s), 6.22 (1H, t, 7.5Hz), 7.01 (2H, s), 7.30 (1H, d, J = 15.9Hz), 8.20 ( 1H, d, J = 7.2Hz), 8.95 (2H, d, J = 7.2Hz), 9.23 (1 H, d, J = 8.0Hz).

IR (KBr) cm ^_1 : 3408, 1763, 1631, 1526, 1360, 1158.

MS (ESI): 639 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 3.4 H O-0.2 NaHCO

Calculated values: C, 44.76; H, 4.53; Ν, Ι Ι.10; S, 12.71; Na 3.65 (%)

Experimental value: C, 44.78; H, 4.41; N, 11.02; S, 12.76; Na 3.72 (%)

Example 58

[Chemical 104]

(1) 70 → 71

Compound 71 was obtained as colorless crystals from Compound 70 (496 mg, 3.00 mmol) in the same manner as in Example 55, (3). Yield 398 mg (72%)

'H-NMR (d-DMSO): 3.28 (2H, s), 7.21 (2H, d, J = 4.4Hz), 8.41 (2H, d, J = 4.4Hz).

(2) 71 → 69

Compound 71 (183 mg, 1.00 mmol) was suspended in dimethylformamide (2 ml), and chlorotrimethylsilane (0.133 ml, 1.05 mmol) was added dropwise at room temperature. On the other hand, Compound 9 (674 mg, l.OOmmol) was suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol) was dissolved in 10 ml of water under ice-cooling, and extracted with dichloromethane. Dried over magnesium sulfate. After distilling off the solvent, immediately mix with the previous suspension (wash with 2 ml of dimethylformamide), Sodium bromide (309 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 3 hr 20 min. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder containing a quaternary salt. This was dissolved in salt methylene (3.6 ml) and anisole (0.605 ml), cooled to 0 ° C., 1.8 ml of TFA was added, and compound 69 was prepared in the same manner as in Example 41 (2). Obtained as a powder. Yield 44 mg (6%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 3.34 (2H, s), 3.41, 3.49 (2H, ABq, J =

15.9Hz), 4.09 (2H, q, J = 7.1 Hz), 5.03 (1H, d, J = 4.7Hz), 5.22 (2H, d, J = 7.7Hz), 5.59 (1H, dd, J = 8.1, 4.7Hz), 5.83 (1H, dt, J = 15.8, 7.7Hz), 6.72 (1H, s), 7.22 (2H, s), 7.27 (1H, d, J = 15.8Hz), 7.95 (2H, d, J = 6.9Hz), 8.83 (2H, d, J = 6.9Hz), 9.53 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3418, 2162, 1762, 1604, 1533, 1364, 1291, 1036.

MS (ESI): 597 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 3.5 H O-0.4NaHCO

Calculated: C, 42.65; H, 4.28; N, 15.67; S, 8.97; Na 4.50 (%)

Experimental values: C, 42.67; H, 4.45; N, 15.59; S, 9.13; Na 4.58 (%)

Example 59

[Chemical 105]

74

(1) 73 → 74

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol is dissolved in 10 ml of water) is added under ice cooling, followed by extraction with dichloromethane and sulfurization. Dried with magnesium acid. After distilling off the solvent, quickly dissolve in dimethylformamide (3 ml), mix with compound 73 (365 mg, 1.00 mmol), add sodium bromide (309 mg, 3.00 mmol), and stir at room temperature for 4 hours and 20 minutes. did. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 74 as an amorphous powder. Yield 954 mg (91%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.65, 3.90 (2H, ABq, J = 17.9Hz), 4.1

6

0 (2H, q, J = 7.2 Hz), 5.29 (1H, d, J = 4.8Hz), 5.33 (2H, d, J = 6.6Hz), 5.93 (1H, dd, J = 8.4, 4.8Hz), 6.44 (1H, dt, J = 15.8, 6.6Hz), 6.75 (1H, s), 6.93 (1H, s), 6.94 (1H, d, J = 15.8Hz), 7.11 (1H, s), 7.20—7.60 (m, 22H), 8.22 (2H, d, J = 8.7Hz), 8.34 (2H, d, J = 8.7Hz), 8.58 (2H, d, J = 6.9Hz), 9.07 (2H, d, J = 6.9Hz), 9.66 (1H, d, J = 8.4Hz). (2) 74 → 72

Compound 74 (94611¾, 0.90311111101) was dissolved in methylene chloride (5.71111) and anisole (0.9461111), cooled to 0 ° C., and 2.9 ml of TFA was added. Compound 72 was obtained as a powder. Yield 243 mg (36%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3.50 (2H, ABq, J = 16.8Hz), 4.0

6

9 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.9Hz), 5.28 (2H, d, J = 7.8Hz), 5.59 (1H, dd, J = 8.0, 4.9Hz), 5.87 (1H, dt, J = 15.8, 7.8Hz), 6.72 (1H, s), 7.24 (2H, s), 7.30 (1H, d, J

= 15.8Hz), 7.97 (2H, d, J = 8.3Hz), 8.02 (2H, d, J = 8.3Hz), 8.50 (2H, d, J = 6.8Hz),

9.01 (2H, d, J = 6.8Hz), 9.54 (1H, d, J = 8.0Hz).

IR (KBr) cm— 3408, 1763, 1631, 1526, 1360, 1158.

MS (ESI): 639 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 3.4 H O-0.2 NaHCO

28 25 6 6 3 2 3

Calculated values: C, 44.76; H, 4.53; Ν, Ι Ι.10; S, 12.71; Na 3.65 (%)

Experimental value: C, 44.78; H, 4.41; N, 11.02; S, 12.76; Na 3.72 (%)

Example 60

[Chem 106]

81

(1) 76 + 77 → 78

4-Bromopyridine hydrochloride 76 (1.95 g, 10.0 mmol) was dissolved in jetyl ether / 2N NaOH and extracted with jetyl ether. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Dimethylformamide (14 ml) was added and the diethyl ether was distilled off under reduced pressure. Under ice-cooling, Compound 77 (1.66 g, 10.0 mmol) and LiBHEt 1M tetrahydrofuran solution (11. Oml) were added, and the mixture was heated at 80 ° C. Stir for hours. The reaction mixture was poured into ethyl acetate and water, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, and eluted with hexane: ethyl acetate = 1: 3. The desired fraction was concentrated to give compound 78 as an oily substance. Yield 2.00 g (82%)

'H-NMR (d-DMSO): 1.33 (3H, t, J = 7.2Hz), 4.33 (2H, q, J = 7.2 Hz), 7.07 (2H, d, J

= 5.3Hz), 7.30 (2H, d, J = 8.7Hz), 8.06 (2H, d, J = 8.7Hz), 8.54 (2H, d, J = 5.3Hz).

(2) 78 → 79

Compound 79 was purified from Compound 78 (817 mg, 3.36 mmol) in the same manner as in Example 49, (1). Obtained as crystals. Yield 523mg (72%)

'H-NMR (d-DMSO): 7.24 (2H, d, J = 5.6Hz), 7.38 (2H, d, J = 8.4Hz), 8.07 (2H, d, J

= 8.4Hz), 8.65 (2H, d, J = 5.6Hz).

(3) 79 → 80

Compound 80 was obtained as colorless crystals from Compound 79 (323 mg, 1.50 mmol) in the same manner as in Example 56, (1). Yield 436 mg (76%)

'H-NMR (d-DMSO): 7.06 (2H, d, J = 6.0Hz), 7.07 (1H, s), 7.28—7.42 (8H, m), 7.53 (d, 4H, J = 7.2Hz), 8.21 (2H, d, J = 8.8Hz), 8.53 (2H, d, J = 6.0Hz).

(4) 80 → 81

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (3 ml), mixed with compound 80 (381 mg, 1.00 mmol), sodium bromide (309 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 81 as an amorphous powder. Yield 919mg (86%)

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.62, 3.88 (2H, ABq, J = 17.0Hz), 4.1

0 (2H, q, J = 7.2 Hz), 5.20 (2H, d, J = 6.9Hz), 5.29 (1H, d, J = 5.1Hz), 5.92 (1H, dd, J = 8.3, 5.1Hz), 6.37 (1H, dt, J = 15.9, 6.9Hz), 6.75 (1H, s), 6.87 (1H, d, J = 15.9Hz), 6.93 (1H, s), 7.09 (1H, s), 7.20-7.85 (m, 26H), 8.32 (2H, d, J = 8.7Hz), 8.84 (2H, d, J = 7.5Hz), 9.65 (1H, d, J = 8.3Hz).

(5) 81 → 75

Compound 81 (91111¾, 0.85611111101) was dissolved in methylene chloride (5.51111) and anisole (0.9111111), cooled to 0 ° C, TFA 2.7 ml was added, and the same procedure as (2) of Example 41 was used. Compound 75 was obtained as a powder. Yield 252 mg (39%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.39, 3.46 (2H, ABq, J = 18.0Hz), 4.0

9 (2H, q, J = 6.9Hz), 5.03 (1H, d, J = 5.0Hz), 5.17 (2H, d, J = 7.2Hz), 5.59 (1H, dd, J = 8.0, 5.0Hz), 5.79 (1H, dt, J = 15.6, 7.2Hz), 6.72 (1H, s), 7.18 (2H, d, J = 8.7Hz), 7. 22 (1H, d, J = 15.6Hz), 7.24 (2H, s), 7.53 (2H, d, J = 7.5Hz), 8.00 (2H, d, J = 8.7Hz) 8.85 (2H, d, J = 7.5Hz), 9.53 (1H, d, J = 8.0Hz).

IR (KBr) cm— 3398, 1765, 1639, 1604, 1560, 1534, 1511, 1383, 1292, 1200, 1159, 1035.

MS (ESI): 651 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.4 H O

Calculated values: C, 46.32; H, 4.53; N, 11.18; S, 8.53; Na 3.06 (%)

Experimental value: C46.27; H, 4.43; N, 11.33; S, 8.66; Na 3.31 (%)

Example 61

[Chemical 107]

84

(1) 43 → 84

Compound 83 (736 mg, 1.00 mmol) and compound 43 (483 mg, 1.06 mmol) were suspended in dimethylformamide (4.5 ml), and sodium bromide (309 mg, 3.00 mmol) was obtained. After stirring at room temperature for 4 hours and 35 minutes, the reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was reduced pressure dried to obtain Compound 84 as an amorphous powder. Yield 1.322 g (94%)

'H-NMR (d-DMSO): 0.90 (3H, t, J = 7.5Hz), 1.44 (2H, sext, J = 7.5Hz), 1.47 (9H, s), 2.20 (2H, q, J = 7.2 Hz), 3.66, 3.92 (2H, ABq, J = 18.0Hz), 3.75 (3H, s), 3.76 (3H, s), 5.12—5.30 (6H, m), 5.32 (1H, d, J = 4.8Hz ), 5.88 (1H, dd, J = 7.8, 4.8Hz), 6.38 (1H , t, J = 7.5Hz), 6.40-6.60 (1H, m), 6.77 (1H, s), 6.86_6.95 (7H, m), 7.15- 7 · 60 (14mm, m), 8.28 (1H, dd, J = 8.7, 2.4Hz), 8.34 (1H, d, J = 2.4Hz), 8.49 (2H, d, J = 7.2Hz), 8.93 (2H, d, J = 7.2Hz), 9.39 (1H, d, J = 7.8Hz), 11.5 (1H, brs).

(2) 84 → 82

Compound 84 (1.31 g, 0.987 mmol) was dissolved in methylene chloride (13 ml) and anisole (1.31 ml), cooled to −30 ° C., and 5.0 ml of 2M salt-aluminum nitromethane solution was added. Compound 82 was obtained as an amorphous powder by the same method as in (2). Yield 98 mg (12%)

'H-NMR (d-DMSO): 0.87 (3H, t, J = 7.5Hz), 1.40 (2H, sept, J = 7.5Hz), 3.41, 3.49 (

2H, ABq, J = 17.4Hz), 5.04 (1H, d, J = 5.0Hz), 5.14 (2H, d, J = 6.9Hz), 5.58 (1H, dd, J = 7.7, 5.0Hz), 5.81 ( 1H, dt, J = 15.3, 6.9Hz), 6.18 (1H, s), 6.23 (1H, t, 7.5Hz), 6.7 6 (2H, d, J = 8.9Hz), 6.9 8 (2H, s), 7.26 (1H, d, J = 15.3Hz), 7.93 (1H, dd, J = 8.9, 2.7 Hz), 8.28 (2H, d, J = 6.9Hz), 8.37 (1H, d, J = 2.7Hz), 8.72 (2H, d, J = 6.9Hz), 9.18 (1 H, d, J = 7.7Hz).

IR (KBr) cm ^_1 : 3408, 1762, 1626, 1601, 1527, 1489, 1389, 1301, 1158.

MS (ESI): 648+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5 H O-0.6 NaHCO

Calculated value: C, 47.37; H, 4.73; N, 8.74; S, 8.00; Na 4.59 (%)

Experimental value: C, 47.22; H, 4.64; N, 8.99; S, 8.41; Na 4.74 (%)

Example 62

[Chemical 108]

85

86 87 88

90

89

(1) 86 → 87

Compound 86 (1.54 g, 10.0 mmol) was suspended in ethanol (15 ml), concentrated sulfuric acid (0.15 ml) was added, and the mixture was stirred under reflux for 22 hours. Ethanol was distilled off under reduced pressure, water and ethyl acetate were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure and subjected to silica gel chromatography. Elution was performed with hexane: ethyl acetate = 1: 1, and the desired fraction was concentrated to obtain Compound 87 as an oily substance. Yield 1.72 g (94%)

'H-NMR (d-DMSO): 1.3K3H, t, J = 7.2Hz), 4.29 (2H, q, J = 7.2 Hz), 6.05 (1H, s),

6

7.43 (2H, d, J = 8.2Hz), 7.81 (2H, d, J = 8.2Hz).

(2) 76 + 87 → 88

4-Bromopyridine hydrochloride 76 (2.21 g, 11.4 mmol) was dissolved in jetyl ether / 2N NaOH and extracted with jetyl ether. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Dimethylformamide (15 ml) was added and the diethyl ether was distilled off under reduced pressure.Compound 87 (2.07 g, 11.4 mmol) and LiBHEt 1M tetrahydrofuran solution (12.6 ml) were added under ice cooling. In addition, the mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into ethyl acetate and water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with hexane: ethyl acetate = 1: 1. The desired fraction was concentrated to give compound 88 as an oil. Yield 2.00 g (82%) 'H-NMR (d-DMSO): 1.42 (3H, t, J = 7.2 Hz), 4.41 (2H, q, J = 7.2 Hz), 7.05 (2H, d, J

= 6.3Hz), 7.58 (2H, d, J = 8.7Hz), 8.09 (2H, d, J = 8.7Hz), 8.42 (2H, d, J = 6.3Hz).

(3) 88 → 89

Compound 89 was obtained as a colorless crystal from Compound 88 (1.06 g, 4.10 mmol) in the same manner as in Example 49, (1). Yield 717 mg (76%)

'H-NMR (d-DMSO): 7.17 (2H, d, J = 6.0Hz), 7.64 (2H, d, J = 8.4Hz), 8.02 (2H, d, J

= 8.4Hz), 8.44 (2H, d, J = 6.0Hz), 13.0 (1H, brs).

(4) 89 → 90

Compound 90 was obtained as pale brown crystals from Compound 89 (578 mg, 2.50 mmol) in the same manner as in Example 56, (1). Yield 892 mg (90%)

'H-NMR (d-DMSO): 6 · 99 (1Η, s), 7.20 (2Η, d, J = 6 · 2Ηζ), 7.29_7 · 56 (10Η, m), 7.69

(d, 2H, J = 8.4Hz), 8.18 (2H, d, J = 8.4Hz), 8.45 (2H, d, J = 6.2Hz).

(5) 90 → 91

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) is added under ice-cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After distilling off the solvent, quickly dissolve in dimethylformamide (3 ml), mix with compound 90 (398 mg, 1.00 mmol), add sodium bromide (309 mg, 3.00 mmol), and stir at room temperature for 8 hours 30 minutes. did. The reaction solution was poured into 5% brine (30 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 91 as an amorphous powder. Yield 970 mg (90%)

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.61, 3.85 (2H, ABq, J = 17.6Hz), 4.1

0 (2H, q, J = 7.2 Hz), 5.14 (2H, d, J = 6.9Hz), 5.28 (1H, d, J = 5.1Hz), 5.92 (1H, dd, J = 8.1, 5.1Hz), 6.32 (1H, dt, J = 15.9, 6.9Hz), 6.75 (1H, s), 6.86 (1H, d, J = 15.9Hz), 6.92 (1H, s), 7.11 (1H, s), 7.24—7.58 (m, 22H), 7.70 (2H, d, J = 7.4Hz), 7.87 (2H, d, J = 8.7Hz), 8.31 (2H, d, J = 8.7Hz), 8.61 (2H, d, J = 7.4Hz), 9.65 (1H, d, J = 8.1Hz).

(6) 91 → 85

Compound 91 (958 mg, 0.888 mmol) was dissolved in methylene chloride (5.8 ml) and anisole (0.958 ml), cooled to 0 ° C, TFA 2.9 ml was added, and the same as in Example 41 (2) By the method, Compound 85 was obtained as a powder. Yield 228 mg (33%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.0Hz), 3.37, 3.45 (2H, ABq, J = 17.1Hz), 4.0

6

9 (2H, q, J = 7.0Hz), 5.01 (1H, d, J = 4.8Hz), 5.17 (2H, d, J = 6.9Hz), 5.58 (1H, dd, J

= 8.1, 4.8Hz), 5.75 (1H, dt, J = 15.9, 6.9Hz), 6.71 (1H, s), 7.21 (1H, d, J = 15.9Hz),

7.22 (2H, s), 7.56 (2H, d, J = 8.4Hz), 7.58 (2H, d, J = 7.2Hz), 8.03 (2H, d, J = 8.4Hz)

8.64 (2H, d, J = 7.2Hz), 9.51 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3398, 1764, 1625, 1594, 1560, 1538, 1384, 1105, 1036.

MS (ESI): 667 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.5 H O-O. lNaHCO

29 25 6 7 3 2 3

Calculated value: C, 44.91; H, 4.42; N, 10.80; S, 12.36; Na 3.25 (%)

Experimental value: C, 44.95; H, 4.38; N, 10.95; S, 12.19; Na 3.25 (%)

Example 63

[Chemical 109]

la +

94 (1) 39 → 93

Compound 93 was obtained as colorless crystals from Compound 39 (308 mg, 1.20 mmol) and ethanesulfonamide (131 mg, 1.20 mmol) in the same manner as in Example 46, (1). Yield 282 mg (83%)

'H-NMR (d-DMSO): 1.28 (3H, d, J = 7.2Hz), 3.47 (2H, q, J = 7.2Hz), 8.22 (2H, d, J

6

= 5.6 Hz), 8.76 (2H, d, J = 5.6 Hz), 8.91 (1H, s).

(2) 93 → 94

Compound 93 (333 mg, 1.12 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 8.9, and the resulting solution was concentrated under reduced pressure to obtain 93 sodium salt. Compound 9 (756 mg, 1.12 mmol) was suspended in dichloromethane (10 ml), an aqueous sodium hydrogen carbonate solution (141 mg, 1.68 mmol dissolved in 10 ml of water) was added under ice-cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After distilling off the solvent, it was immediately dissolved in dimethylformamide (4 ml), mixed with 93 sodium salt, sodium bromide (346 mg, 3.36 mmol) was added, and the mixture was stirred at room temperature for 4 hours and 15 minutes. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 94 as an amorphous powder. Yield 836 mg (83%)

'H-NMR (d-DMSO): 1 · 13 (3Η, t, J = 7.4Hz), 1.22 (3H, t, J = 7.2Hz), 3.10 (2H, q, J

6

= 7.4 Hz), 3.65, 3.91 (2H, ABq, J = 17.6Hz), 4.10 (2H, q, J = 7.2Hz), 5.27 (2H, d, J = 6.6Hz), 5.29 (1H, d, J = 4.8Hz), 5.92 (1H, dd, J = 8.3, 4.8Hz), 6.43 (1H, dt, J = 15.8, 6.6Hz), 6.75 (1H, s), 6.87 (1H, d, J = 15.8Hz ), 6.92 (1H, s), 7.24 (2H, s), 7.24—7.52 (m, 10H), 8.59 (2H, d, J = 6.9Hz), 8.97 (2H, d, J = 6.9Hz), 9.01 (1H, s), 9.65 (1H, d, J = 8.3Hz).

(3) 94 → 92

Compound 94 (829 mg, 0.873 mmol) was dissolved in methylene chloride (5 ml) and anisole (0.83 ml), cooled to 0 ° C, 2.5 ml of TFA was added, and the same procedure as in Example 41 (2) was performed. Compound 92 was obtained as a powder. Yield 386 mg (50%)

'H-NMR (d-DMSO): 1.13 (3H, t, J = 7.5Hz), 1.22 (3H, t, J = 6.9Hz), 3.09 (2H, q, J

6

= 7.5Hz), 3.43, 3.51 (2H, ABq, J = 16.5Hz), 4.09 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 5.0Hz), 5.27 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.1, 5.0Hz), 5.87 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.22 (2H, s), 7.30 (1H, d, J = 15.9Hz), 8.59 (2H, d, J = 7.1Hz), 9.02 (2H, d, J = 7.1Hz), 8.98 (1H, s), 9.54 (1H, d, J = 8.1Hz).

I R (KBr) cm— 3422, 1764, 1636, 1600, 1531, 1388, 1341, 1255, 1218, 1113, 1035 827.

MS (ESI): 733 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 3.8 H O-0.1 NaHCO

Calculated values: C, 40.58; H, 4.21; N, 13.47; S, 15.42; Na, 3.04 (%)

Experimental values: C, 40.71; H, 4.15; N, 13.60; S, 15.15; Na, 3.08 (%)

Example 64

[Chem 110]

Na ⁺

97

(1) 39 → 96

Compound 96 was obtained as colorless crystals from Compound 39 (308 mg, 1.20 mmol) and trifluoromethanesulfonamide (179 mg, 1.20 mmol) in the same manner as in Example 46, (1). Yield 282 mg (90%) 'H-NMR (d-DMSO): 8 · 55 (2Η, d, J = 6 · 4Ηζ), 8.97 (2H, d, J = 6.4Hz), 9.02 (1H, s).

(2) 96 → 97

Compound 96 (358 mg, 1.06 mmol) was suspended in methanol, sodium methoxide methanol solution was added dropwise until pH = 8.2, and the resulting solution was concentrated under reduced pressure to give 96 sodium salt. Obtained. Compound 9 (715 mg, 1.06 mmol) was suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (134 mg, 1.59 mmol dissolved in 10 ml of water) was added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After distilling off the solvent, it was immediately dissolved in dimethylformamide (4 ml), mixed with 96 sodium salt, sodium bromide (327 mg, 3.18 mmol) was added, and the mixture was stirred at room temperature for 4 hours and 35 minutes. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 97 as an amorphous powder. Yield 943 mg (95%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.0Hz), 3.65, 3.90 (2H, ABq, J = 17.6Hz), 4.1

0 (2H, q, J = 7.0Hz), 5.28 (2H, d, J = 6.9Hz), 5.29 (1H, d, J = 4.7Hz), 5.92 (1H, dd, J = 8.3, 4.7Hz), 6.42 (1H, dt, J = 16.1, 6.9Hz), 6.75 (1H, s), 6.87 (1H, d, J = 16.1Hz), 6.92 (1H, s), 7.24 (2H, s), 7.24—7.53 (m, 10H), 8.60 (2H, d, J = 7.1Hz), 8.98 (2H, d, J = 7.1Hz), 9.10 (1H, s), 9.65 (1H, d, J = 8.3Hz) .

(3) 97 → 95

Compound 97 (933 mg, 0.994 mmol) was dissolved in methylene chloride (5.6 ml) and anisole (0.93 ml), cooled to 0 ° C., and 2.8 ml of TFA was added, as in Example 41 (2). By the method, Compound 95 was obtained as a powder. Yield 270 mg (31%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.43, 3.51 (2H, ABq, J = 16.5Hz), 4.0

9 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 4.8Hz), 5.28 (2H, d, J = 7.0Hz), 5.60 (1H, dd, J = 8.3, 4.8Hz), 5.86 (1H, dt, J = 15.8, 7.0Hz), 6.72 (1H, s), 7.22 (2H, s), 7.31 (1H, d, J = 15.8Hz), 8.61 (2H, d, J = 6.9Hz ), 9.04 (2H, d, J = 6.9Hz), 9.08 (1H, s), 9.54 (1H, d, J = 8.3Hz).

IR (KBr) cm— 3422, 1764, 1636, 1600, 1531, 1388, 1341, 1255, 1218, 1113, 1035, 827.

MS (ESI): 773 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H F N O S Na- 3.8 H O-0.3 NaHCO

Calculated values: C, 37.52; H, 3.26; F, 6.52; N, 12.82; S, 14.67; Na, 3.42 (%)

Experimental values: C, 37.71; H, 3.37; F, 6.14; N, 13.02; S, 14.79; Na, 3.29 (%)

Example 65 [Chem 111]

9

^ · ► 98

(1) 34 → 99

Compound 34 (1.758 g, 7.98 mmol) was suspended in dimethylformamide (18 ml), 1,1′-thiocarbonyldiimidazole (1.56 g, 8.78 mmol) was added, and the mixture was stirred for 1 hour and 20 minutes. Water was added, and the deposited precipitate was filtered and dried under reduced pressure to obtain Compound 99 as light brown crystals. Yield 2.44 g (93%)

'H-NMR (d-DMSO): 7.13 (1H, dd, J = 1.7, 1.2Hz), 7.84 (2H, s), 8.05 (1H, t, J = 1.7

6

Hz), 8.08 (2H, d, J = 6.3Hz), 8.67-8.74 (4H, m).

(2) 99 → 100

Compound 99 (2.428 g, 7.349 mmol) was suspended in tetrahydrofuran (24 ml), boron trifluoride jetyl ether complex salt (4.62 ml, 36.7 mmol) was added dropwise at room temperature, and 1 hour 45 minutes at room temperature. Stir at ° C for 1 hour. Concentrate in vacuo to half volume, add water, then saturated aqueous NaHCO

3 In addition, pH = 3.5. The resulting precipitate was filtered and dried under reduced pressure to obtain Compound 100 as pale yellow crystals. Yield 2.07 g (107%)

'H-NMR (d-DMSO): 8.34 (2H, d, J = 5.6Hz), 8.88 (2H, d, J = 5.6Hz), 8.97 (1H, s).

6

(3) 100 → 98

Compound 100 (394 mg, 1.50 mmol) was suspended in methanol, adjusted to pH = 8.3 with sodium methoxide methanol solution, and the resulting solution was concentrated under reduced pressure to obtain 100 sodium salt. Conversion Compound 9 (1.012 mg, 1.50 mmol) was suspended in dichloromethane (15 ml), and an aqueous sodium hydrogen carbonate solution (189 mg, 1.80 mmol dissolved in 15 ml of water) was added under ice cooling, followed by extraction with dichloromethane, magnesium sulfate. And dried. After distilling off the solvent, it was immediately dissolved in dimethylformamide (5 ml), mixed with 100 sodium salt, sodium bromide (463 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 3 hours and 20 minutes. The reaction solution was poured into 5% brine (45 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder containing a quaternary salt. This was dissolved in methylene chloride (7.2 ml) and anisole (1.20 ml), cooled to 0 ° C, 3.6 ml of TFA was added, and compound 98 was powdered in the same manner as in (2) of Example 41. Got as. Yield 46 mg (4%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.42, 3.50 (2H, ABq, J = 16.8Hz), 4.0

9 (2H, q, J = 7.2Hz), 5.04 (1H, d, J = 4.8Hz), 5.27 (2H, d, J = 6.3Hz), 5.59 (1H, dd, J = 8.4, 4.8Hz), 5.86 (1H, dt, J = 15.6, 6.3Hz), 6.72 (1H, s), 7.22 (2H, s), 7.30 (1H, d, J = 15.6Hz), 8.60 (2H, d, J = 6.9Hz ), 9.04 (2H, d, J = 6.9Hz), 9.54 (1H, d, J = 8.4Hz). IR (KBr) cm " ¹ : 3419, 1762, 1633, 1604, 1532, 1387, 1158, 1036.

MS (ESI): 698+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.2 H O-0.4 NaHCO

Calculated: C, 38.85; H, 3.90; N, 14.88; S, 15.14; Na, 3.80 (%)

Experimental value: C, 39.06; H, 3.95; N, 14.73; S, 14.64; Na, 3.81 (%)

Example 66

[Chem 112]

106

(1) 102 → 103

Compound 102 (789 mg, 3, 35 mmol) is dissolved in dimethylformamide (8 ml), and potassium carbonate (509 mg, 3.69 mmol) is added followed by p-methoxybenzyl bromide (741 mg, 3.69 mmol of dimethylformamide (2 ml) solution). And stirred at room temperature for 1 hour. The reaction mixture was poured into water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 103 as a liquid substance. Yield 1.18 g (9 9%)

'H-NMR (CDCl): 3.82 (3H, s), 5.30 (2H, s), 6.91 (2H, d, J = 8.7Hz), 7.38 (2H, d, J =

8.7Hz), 7.42 (1H, dd, J = 8.4, 2.1Hz), 7.63 (1H, d, J = 2.1Hz), 7.71 (1H, d, J = 8.4H z).

(2) 103 → 105

Compound 103 (1.154 g, 3,439 mmol), compound 104 (917 mg, 4.47 mmol) and potassium phosphate (2.19 g, 10.3 mmol) were suspended in dioxane (12 ml), and tetrakistriphenylphosphine paradium (199 mg, 0.172 mmol) was suspended. mmol) and microwave irradiation (120 ° Cxl for 5 minutes). The reaction solution was poured into water and ethyl acetate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with hexane: ethyl acetate = 1: 3. Concentrate the desired fraction and combine Compound 105 was obtained as colorless crystals. Yield 787mg (65%)

'H-NMR (CDCl 3): 3.83 (3H, s), 5.34 (2H, s), 6.93 (2H, d, J = 8.7Hz), 7.42 (2H, d, J =

8.7 Hz), 7.48 (2H, d, J = 6.2 Hz), 7.54 (1H, dd, J = 8.3, 1.8 Hz), 7.71 (1H, d, J = 1.8 Hz), 7.95 (1H, d, J = 8.3Hz), 8.71 (2H, d, J = 6.2 Hz).

(3) 105 → 106

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After distilling off the solvent, quickly dissolve in dimethylformamide (4 ml), mix with compound 105 (354 mg, 1.00 mmol), add sodium bromide (309 mg, 3.00 mmol), and stir at room temperature for 2 hours and 20 minutes. did. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 106 as an amorphous powder. Yield 874 mg (84%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.64, 3.90 (2H, ABq, J = 17.4Hz), 3.7

7 (3H, s), 4.10 (2H, q, J = 6.9 Hz), 5.29 (1H, d, J = 5.1 Hz), 5.32 (2H, d, J = 6.6 Hz), 5.34 (2H, s ), 5.92 (1H, dd, J = 8.1, 5.1Hz), 6.43 (1H, dt, J = 15.9, 6.6Hz), 6.75 (1H, s), 6.92 (1H, d, J = 15.9Hz), 6.92 (1H, s), 6.98 (2H, d, J = 8.7Hz), 7.21-7.58 (15H, m), 8.12 (1H, dd, J = 8.4, 1.8Hz), 8.31 (1H, d, J = 1.8Hz), 8.61 (2H, d, J = 7.1Hz), 9.09 (2H, d, J = 7.1Hz), 9.65 (1H, d, J = 8.1Hz).

(4) 106 → 101

Compound 106 (868 mg, 0.837 mmol) was dissolved in methylene chloride (5.2 ml) and anisole (0.87 ml), cooled to 0 ° C., and 2.6 ml of TFA was added, and the same as in Example 41 (2). By the procedure, compound 101 was obtained as a powder. Yield 167 mg (26%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 3.41, 3.49 (2H, ABq, J = 17.1Hz), 4.0

9 (2H, q, 7.1Hz), 5.04 (1H, d, J = 5.1Hz), 5.27 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.3, 5.1Hz), 5.86 (1H, dt, J = 16.1, 7.2Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 6.1 Hz), 7.44 (1H, d, J = 8.1 Hz), 7.88 (1H, dd, J = 8.1, 1.7Hz), 8.00 (1H, d, J = 1.7Hz), 8.10 (2H, d, J = 6.8Hz), 9.01 (2H, d, J = 6.8 Hz), 9.54 (1H, d, J = 8.3 Hz).

IR (KBr) cm ^_1 : 3418, 1764, 1634, 1598, 1531, 1386, 1298, 1158, 1035. MS (ESI): 669 (M-Na + 2H)

Elemental analysis C H C1N O S Na-4.8 H O

29 24 6 7 2 2

Calculated: C, 44.79; H, 4.36; N, 10.81; S, 8.25; Na, 2.96 (%)

Experimental values: C, 44.83; H, 4.24; N, 10.90; S, 8.27; Na, 3.21 (%)

Example 67

[Chem 113]

(1) 108 → 109

Compound 109 was obtained as a liquid substance from Compound 108 (645 mg, 3.00 mmol) in the same manner as in Example 66, (1). Yield 923mg (92%)

'H-NMR (CDCl): 2.57 (3H, s), 3.82 (3H, s), 5.26 (2H, s), 6.91 (2H, d, J = 8.7Hz), 7.

Three

33-7.4K4H, m), 7.78 (1H, d, J = 8.4Hz).

(2) 109 → 110

Compound 110 was obtained as colorless crystals from Compound 109 (874 mg, 2.60 mmol) in the same manner as in Example 66, (2). Yield 721mg (83%)

'H-NMR (CDCl): 2.68 (3H, s), 3 · 83 (3Η, s), 5 · 33 (2Η, s), 6 · 93 (2Η, d, J = 8.9Hz), 7.

Three

41 (2H, d, J = 8.9Hz), 7.45—7.53 (4H, m), 7.94 (1H, d, J = 8.7Hz), 8.68 (2H, d, J = 6.0 Hz). (3) 110 → 111

Compound 9 (675 mg, l.OOmmol) is suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After the solvent was distilled off, it was quickly dissolved in dimethylformamide (4 ml), mixed with compound 110 (333 mg, 1.00 mmol), sodium bromide (309 mg, 3.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 111 as an amorphous powder. Yield 877 mg (86%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 2.63 (3H, s), 3.64, 3.90 (2H, ABq, J =

18.2Hz), 3.77 (3H, s), 4.10 (2H, q, J = 7.1Hz), 5.27— 5.37 (5H, m), 5.92 (1H, dd, J = 8.3, 4.8Hz), 6.44 ( 1H, dt, J = 15.3, 6.6Hz), 6.75 (1H, s), 6.92 (1H, d, J = 15.3Hz), 6.92 (1H, s), 6.98 (2H, d, J = 8.7Hz), 7.22-7.57 (15H, m), 7.95-8.07 (2H, m), 8.56 (2H, d, J = 7.1Hz), 9.05 (2H, d, J = 7.1Hz), 9.65 (1H, d, J = (8.3Hz).

(4) 111 → 107

Compound lll (868 mg, 0.855 mmol) was dissolved in methylene chloride (5.2 ml) and anisole (0.87 ml), cooled to 0 ° C., and 2.6 ml of TFA was added, the same as in Example 41 (2). By the method, Compound 107 was obtained as a powder. Yield 248mg (38%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 2.52 (3H, s), 3.41, 3.49 (2H, ABq, J =

17.1Hz), 4.09 (2H, q, J = 7.1Hz), 5.04 (1H, d, J = 5.0Hz), 5.26 (2H, d, J = 6.8Hz), 5.59 (1H, dd, J = 8.0, 5.0Hz), 5.86 (1H, dt, J = 15.6, 6.8Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 15.6Hz), 7.53 (1H, d, J = 7.8Hz), 7.72-7.78 (2H, m), 8.45 (2H, d, J = 7.2Hz), 8.96 (2H, d, J = 7.2Hz), 9.54 (1H, d, J = 8.0 Hz).

IR (KBr) cm ^_1 : 3408, 1765, 1633, 1586, 1531, 1385, 1159, 1035.

MS (ESI): 649 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.7 H O

Calculated values: C, 47.70; H, 4.86; N, 11.13; S, 8.49; Na, 3.04 (%)

Experimental values: C, 47.66; H, 4.63; N, 11.36; S, 8.28; Na, 2.85 (%)

Example 68

Compound 5 (13011¾, valence 0.19511111101) was dissolved in water (5.21111) and adjusted to pH = 7.2 with 5% aqueous NaHCO 3 solution. Penicillin Gamidase (carrier fixed, 146U) (44.5 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours while adjusting the pH to 7-8 with 5% aqueous NaHCO 3 solution. Amidase was separated by filtration, washed with water (3 ml), 0.2N HC1 to ρΗ = 6.5, and acetonitrile (4 ml) was added. To this, Compound 11 3 (79.0 mg, 0.293 mmol) was added in 5 portions, 15.8 mg every 10 minutes. The acetonitrile was distilled off under reduced pressure, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 114 as a powder. Yield 104mg (apparent 81%)

Example 69

[Chemical 115]

(1) 1 → 2

Hydroxylamine hydrochloride (17.9 g) was added to a solution of 1 (27.6 g) in methanol (500 mL) with stirring in an ice bath. The mixture was naturally warmed to room temperature and further stirred at room temperature for 2 hours. After standing overnight, the methanol was distilled off under reduced pressure, Et 0 (400 mL) was added, and the crystalline precipitate was collected by suction filtration. After drying under reduced pressure, Compound 2 (39.6 g, yield 100%) was obtained as pale pink crystals.

'H-NMR (DMSO) δ: 8.11 (2Η, d, J = 6.9 Hz), 8.41 (2H, s), 8.87 (2H, q, J = 6.9 Hz), 12.7 (1H, brs).

(2) 2 → 3

N_chlorosuccinimide (33.4 g) was added to a solution of 2 (39.8 g) in DMF (500 mL) at room temperature. After stirring at room temperature for 3 hours, the mixture was allowed to stand at _20 ° C overnight. DMF was distilled off under reduced pressure, water (500 mL) was added, and the mixture was cooled in an ice bath. The pH was adjusted to around 3.5, and the precipitate was collected by suction filtration. After drying under reduced pressure, compound 3 (30.9 g, yield 79%) was obtained as a pale yellow powder.

'H-NMR (d-DMSO) δ: 7.77 (2Η, d, J = 5.1 Hz), 8.71 (2H, brs), 13.0 (1H, s).

(3) 3 → 4

3 (34.91 g) in THF (400 mL) was stirred with an ice bath to stir propylate ethyl (45.2 mL), and then triethylamine (37.3 mL) in THF (300 mL) was added dropwise over 5 hours. After stirring on ice for 1 hour, saturated ammonium chloride water (100 mL), water (200 mL), ethyl acetate (500 mL) The organic layer was concentrated to about 300 mL (as an organic layer) under reduced pressure. Ethyl acetate (300 mL) was added for liquid separation, and the organic layer was washed with saturated brine. This organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) .Compound 4 (28.0 g, yield 57%) was pale brown Obtained as crystals.

'H-NMR (CDC1) δ 1.45 (3H, t, J = 7.2 Hz), 4.48 (2H, q, J = 7.2 Hz), 7.31 (1H, s)

7.73 (2H, d, J = 6.0 Hz), 8.77 (2H, d, J = 6.0 Hz).

(4) 4 → 5

Cyanamide monosodium salt (9.8 4 g) was added to a solution of 4 (27.96 g) in methanol (300 mL) with stirring in an ice bath. After stirring at room temperature for 1.5 hours, methanol was concentrated under reduced pressure to about 50 mL. Isopropanol (300 mL) was added and the precipitate was collected by suction filtration. After drying under reduced pressure, compound 5 (31.5 g, yield 82%) was obtained as a light brown powder.

'H-NMR (d-DMSO) δ: 7.43 (1Η, s), 7.89 (2Η, d, J = 6.0 Hz), 8.73 (2H, d, J = 6.0

Hz).

(5) 6 → 7 → 8

Under a nitrogen atmosphere, sodium bromide (2.57 g, 25 mmol) was added to a solution of compound 6 (4.36 g, 5.0 mmol) in dimethylformamide (15 mL), and the mixture was stirred at room temperature for 6 hours. Compound 5 (984 mg, 4.17 mmol) was added to the reaction solution, and the mixture was further stirred for 6 hours. Dimethylformamide (10 mL) was added for dilution, and the mixture was poured into 5% brine (180 mL) with stirring and cooled in an ice bath. After stirring at the same temperature for 20 minutes, the precipitate was collected by suction filtration and dried using phosphorus pentoxide under reduced pressure to obtain a crude product 7 (4.57 g) as an ocher powder. This crude product was dissolved in methylene chloride (60 mL), and anisole (3.26 mL, 30 mmol) was added under a nitrogen atmosphere, followed by cooling to −40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 15 mL, 30 mmol) was added dropwise at _40 ° C, and the mixture was stirred at -20 ° C for 1 hour. The reaction mixture was poured into water (200 mL) under ice bath stirring, and diisopropyl ether (150 mL) was added. The precipitate obtained by suction filtration was dissolved in sodium bicarbonate water, and the fraction (water mononitrile) collected by HP20ss column chromatography was concentrated under reduced pressure, and further purified and concentrated by ODS column chromatography. Lyophilized. Compound 8 (52 mg, yield 14%) was obtained as a powder.

'H-NMR (DO) δ: 1.27 (3H, t, J = 7.1), 3.67 (2H, s), 4.22 (2H, q, J = 7.1), 5.26 (1 H, d, J = 4.5 Hz), 5.37 (1H, d, J = 6.9 Hz), 5.80 (1H, d, J = 4.5 Hz), 6.12 (1H, dt, J = 6.9, 15.6 Hz), 6.92 ( 1H, s), 7.02 (1H, d, J = 15.6 Hz), 7.47 (1H, s), 8.47 (2H, d, J = 6.6 Hz), 8.99 (2H, d, J = 6.6).

IR (KBr) cm— ¹ : 3411, 2982, 2171, 1763, 1607, 1561, 1532, 1475, 1439, 1389, 1357,

1299, 1201, 1150, 1091, 1034, 1000.

MS (ESI): 650+ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.9 H O

27 22 9 7 2 2

Calculated value: C, 42.67; H, 4.22; N, 16.59; S, 8.44; Na, 3.03 (%)

Experimental value: C42.60; H, 4.03; N, 16.41; S, 9.04; Na, 3.46 (%)

Example 70

[Chem 116]

10 11

13

(1) 9 → 10

Hydroxylamine hydrochloride (97%) (9.96 g, 134.7 mmol) was added to a methanol (180 mL) solution of compound 9 (14.9 g, 67.4 mmol), and the mixture was stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure, and then 2N sodium hydroxide was added to adjust the pH to around 3. Extract twice with ethyl acetate The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Compound 10 (13.68 g, 86% yield) was obtained as an orange oil.

'H-NMR (CDC1) δ 1.37 (3Η, t, J = 6.9 Hz), 3.24 and 3.54 (2H, ABq, J = 18.3 Hz

), 4.36 (2H, q, J = 6.9 Hz), 7.48 (2H, d, J = 4.8 Hz), 8.45 (2H, d, J = 4.8 Hz).

(2) 10 → 11

4N HC 卜 AcOEt (14 mL, 56.1 mmol) was added to a solution of compound 10 (13.9 g, 56.1 mmol) in ethyl acetate (100 mL). Ethyl acetate was distilled off under reduced pressure, and dimethylacetamide (150 mL) was stirred at 150 ° C. for 3 hours. After cooling to room temperature, it was allowed to stand overnight. Dimethylacetamide was distilled off under reduced pressure and extracted with ethyl acetate-saturated aqueous sodium bicarbonate. The organic layer was washed twice with water and once with saturated Japanese salt water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexyl monoacetate) to obtain Compound 11 (6.33 g, yield 52%) as colorless crystals.

'H-NMR (CDC1) δ 1.46 (3Η, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 7.13 (1H, s)

7.69 (2H, d, J = 6.0 Hz), 8.80 (2H, d, J = 6.0 Hz).

(3) 11 → 12

Cyanamide (1.28 g, 30.5 mmol) was added to a solution of compound 11 (6.33 g, 29 mmol) in methanol (45 mL), and 1.0N NaOMe / MaOH (30.5 mL, 30.5 mmol) was added to the room temperature in an ice bath. After heating, the mixture was stirred at the same temperature for 1 hour. Methanol was distilled off under reduced pressure, water (80 mL) was added, and the pH was adjusted to around 3 with IN HC1. The precipitate was collected by suction filtration and dried under reduced pressure to obtain a light ocher powder (4.32 g). IN NaOMe / MeOH (29 mL) was added to the suspension obtained by adding methanol (70 mL) to this powder while carefully checking the pH. Methanol was concentrated under reduced pressure, Et 0 was added, and the precipitate was collected by suction filtration to obtain Compound 12 (6.55 g, yield 96%) as a colorless amorphous powder.

'H-NMR (d-DMSO) δ: 7.43 (1Η, s), 7.89 (2Η, d, J = 6.3 Hz), 8.72 (2H, d, J = 6.3

Hz).

(4) 6 → 13

Compound 6 (4.3 mg) and 12 (708 mg, 3.0 mmol) were used in the same manner as in Example 69, (5) to give compound 13 (405 mg, yield 18%).

'H-NMR (DO) δ: 1.27 (3H, t, J = 7.1 Hz), 3.67 (2H, s), 4.22 (2H, q, J = 7.1 Hz), 5 .26 (1H, d, J = 4.5 Hz), 5.35 (1H, d, J = 6.6 Hz), 5.80 (1H, d, J = 4.5 Hz), 6.11 (1H, dt, J = 6.6, 15.6 Hz) , 6.93 (1H, s), 7.00 (1H, d, J = 15.6 Hz), 7.51 (1H, s), 8.42 (2H, d, J = 6.9 Hz), 8.97 (2H, d, J = 6.9 Hz) .

IR (KBr) cm— ¹ : 3424, 2980, 2171, 1763, 1606, 1532, 1468, 1387, 1338, 1200, 1150, 1091, 1035.

MS (ESI): 650+ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.9 H O

Calculated values: C, 43.71; H, 4.05; N, 16.99; S, 8.64; Na, 3.10 (%)

Experimental value: C43.64; H, 3.93; N, 16.87; S, 8.79; Na, 3.35 (%)

Example 71

[Chemical 117]

Compound 14 (1.26 g) and 5 (354 mg) were used in the same manner as in Example 69, (5) to give compound 15 (152 mg, yield 14%).

'H-NMR (D O) δ: 3.67 (2Η, s), 3.95 (3H, s), 5.26 (1H, d, J = 4.8 Hz), 5.37 (1H, d,

J = 6.6 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.13 (1H, dt, J = 6.6, 15.9 Hz), 6.95 (1H, s), 7.01 (1H, d, J = 15.9 Hz) , 7.48 (1H, s), 8.48 (2H, d, J = 6.9 Hz), 9.00 (2H, d, J = 6 • 9 Hz).

IR (KBr) cm " ¹ : 3481, 2940, 2170, 1763, 1608, 1561, 1532, 1474, 1439 1356, 1212, 1175, 1149, 1036, 1001.

MS (ESI): 636 ⁺ (M-Na + 2H) ⁺ Elemental analysis CHN NaO S -4.4 HO

Calculated values: C, 42.38; H, 3.94; N, 17.11; S, 8.70; Na, 3.12 (%)

Experimental value: C, 42.30; H, 3.91; N, 17.04; S, 8.92; Na, 3.48 (%)

Example 72

[0096] [Chemical 118]

Compound 14 (118 mg, yield 11%) was obtained in the same manner as in Example 69, (5), using Compound 14 (1.26 g) and Compound 12 (354 mg).

H-NMR (D O) δ: 3.67 (2Η, s), 3.95 (3H, s), 5.25 (1H, d, J = 4.8 Hz), 5.35 (1H, d,

J = 6.6 Hz), 5.79 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 6.6, 15.6 Hz), 6.95 (1H, s), 7.00 (1H, d, J = 15.6 Hz) , 7.52 (1H, s), 8.42 (2H, d, J = 6.9 Hz), 8.97 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3422, 2940, 2171, 1763, 1606, 1532, 1467, 1389, 1338, 1214, 1179,

1149, 1036, 1000.

MS (ESI): 636+ (M-Na + 2H) ⁺

Elemental analysis C H N NaO S3.2 H O

Calculated values: C, 43.66; H, 3.72; N, 17.62; S, 8.97; Na, 3.21 (%)

Experimental value: C43.72; H, 4.02; N, 17.62; S, 9.24; Na, 3.32 (%)

Example 73

[0097] [Chemical 119]

19

(1) 17 → 18

Compound 18 (2.47 g, yield 84%) was obtained from 17 (2.70 g) synthesized according to the method of Heterocycles 1998, 48, 1237 in the same manner as in Example 69 (4).

'H-NMR (d -DMSO) δ: 1.97 (2Η, m), 2.86 (2H, t, J = 7.5 Hz), 3.14-3.19 (4H, m)

6

7.41 (1H, d, J = 5.1 Hz), 8.22 (1H, d, J = 5.1 Hz).

(2) 6 + 18 → 19

Compound 19 (122 mg, 11 mg) was prepared in the same manner as in Example 69 (5) using 6 (1.31 g) and 18 (313 mg).

%).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 2.30 (2H, m), 3.30-3.40 (4H, m), 3.6

2

2 (2H, s), 4.25 (2H, q, J = 6.9), 5.21 (1H, d, J = 6.3 Hz), 5.25 (1H, d, J = 4.8 Hz), 5.81 (1H, d, J = 4.8 Hz), 6.00 (1H, dt, J = 6.3, 15.9 Hz), 6.98 (1H, s), 7.93 (1H, d, J = 6.3 Hz), 8.54 (1H, d, J = 6.3 Hz) .

IR (KBr) cm— ¹ : 3424, 2976, 2164, 1763, 1607, 1568, 1532, 1444, 1374, 1297, 1198,

1165, 1090, 1035.

MS (ESI): 645+ (M-Na + 2H) +

Elemental analysis C H N NaO S-3.7 H O

27 25 8 6 2 2

Calculated values: C, 45.59; H, 4.59; N, 15.75; S, 9.02; Na, 3.23 (%) Experimental value: C, 45.54; Η, 4.58; Ν, 15.65; S, 9.20; Na, 3.46 (%)

Example 74

[Chemical 120]

(1) 19 → 20

To a solution of compound 19 (2.0 g, 10.5 mmol) in EtOH (30 mL) was added 2N aqueous sodium hydroxide solution (26.3 mL), and the mixture was stirred at room temperature for 2 hr. After adding 5N hydrochloric acid aqueous solution (10.5 mL), EtOH was distilled off under reduced pressure. Water (30 mL) was added to the residue, ice-cooled, and 1N hydrochloric acid aqueous solution was added to adjust the pH to about 3. The precipitate was collected by suction filtration and dried under reduced pressure to obtain 20 (1.76 g, yield 100%) as a light brown powder.

'H-NMR (d -DMSO) δ: 7.15 (1Η, s), 7.26 (1Η, dd, J = 4.5, 8.4 Hz), 7.80-7.84 (1

6

H, m), 8.44 (1H, brs), 12.0 (1H, brs).

(2) 20 → 21

Carbonyldiimidazole (1.94 g, 11.9 mmol) was added to a DMF (20 mL) solution of compound 20 (1.76 g, 10.9 mmol), and the mixture was stirred at room temperature for 1 hour and then ice-cooled. To a solution of cyanamide (958 mg, 22.8 mmol) in DMF (10 mL) under ice-cooling, sodium hydride (60% w / w, 912 mg, 22.8 mmol) was added and stirred at the same temperature for 20 minutes. Added to. After stirring at room temperature for 1 hour, 2N hydrochloric acid (11.4 mL) was added, and DMF was distilled off under reduced pressure. Water (60 mL) was added to the residue and stirred under ice cooling. IN aqueous hydrochloric acid was added to adjust the pH to around 3. The deposited precipitate was collected by suction filtration and dried under reduced pressure to obtain 21 (1.18 g, 58%).

'H-NMR (d-DMSO) δ: 7.01 (1Η, s), 7.63 (1Η, dd, J = 5.7, 8.1 Hz), 8.40 (1H, d, J

= 8.1 Hz), 8.65 (1H, d, J = 5.7 Hz), 12.8 (1H, brs).

(3) 21 → 22

To a solution of compound 21 (1.18 g) in methanol (7 mL) was added 1.0N NaOMe / MeOH (4.5 mL), and the mixture was concentrated to dryness. The obtained light pink powder 22 was used in the next reaction.

(4) 6 + 22 → 23

Compound 23 (87 mg, yield 12%) was obtained in the same manner as in Example 69, (5), using Compound 6 (872 mg) and 22 (208 mg).

'H-NMR (D O) δ: 1.27 (3H, t, J = 6.9 Hz), 3.62 (2H, s), 4.22 (2H, q, J = 6.9 Hz), 5

.22 (1H, d, J = 4.8 Hz), 5.43 (2H, d, J = 6.3 Hz), 5.79 (1H, d, J = 4.8 Hz), 6.15 (1H

, dt, J = 6.3, 15.9 Hz), 6.87 (1H, d, J = 15.9 Hz), 6.93 (1H, s), 7.23 (1H, s), 7.69 (1

H, dd, J = 6.0, 8.5 Hz), 8.48 (1H, d, J = 8.5 Hz), 8.59 (1H, d, J = 6.0 Hz).

IR (KBr) cm " ¹ : 3409, 2984, 2164, 1762, 1664, 1592, 1532, 1460, 1335, 1201, 1160,

1122, 1091, 1036.

MS (ESI): 644 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.3 H O-0.2 NaHCO

Calculated value: C, 42.65; H, 4.21; N, 17.08; S, 8.69; Na, 3.74 (%)

Experimental value: C, 42.66; Η, 4.13; Ν, 16.87; S, 9.18; Na, 3.77 (%)

Example 75

[Chemical 121]

24 25 26 27

(1) 24 → 25

To a solution of compound 24 (2.57 g, 20 mmol) in THF (40 mL) was added triethylamine (2.79 mL, 20 mmo 1), and the mixture was cooled in an ice bath and stirred. To this solution, a solution of ethyl chloroglyoxynolate (2.23 mL, 20 mmol) in THF (20 mL) was added dropwise over 10 minutes. The mixture was warmed to room temperature, further stirred at the same temperature for 30 minutes, and extracted with ethyl acetate water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and dried under reduced pressure. Compound 25 (4.62 g, yield 100%) was obtained as pale ocher crystals.

'H-NMR (CDC1) δ 1.46 (3Η, t, J = 7.2 Hz), 4.46 (2H, q, J = 7.2 Hz), 7.41 (1H, d

, J = 5.4 Hz), 8.37 (1H, d, J = 5.4 Hz), 9.34 (1H, brs), 9.64 (1H, s).

(2) 25 → 26

Lawesson's reagent (2.43 g, 6.0 mmol) was added to a solution of compound 25 (1.14 g, 5.0 mmol) in toluene (10 mL), and the mixture was refluxed for 1 hour. After cooling to room temperature, the mixture was extracted with ethyl acetate-sodium bicarbonate water, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain Compound 26 (534 mg, yield 51%) as ocher crystals.

H-NMR (d -DMSO) δ 1.39 (3Η, t, J = 6.9). 4.46 (2H, q, J = 6.9 Hz), 8.32 (1H, dd

, J = 0.9, 5.7 Hz), 8.67 (1H, d, J = 5.7 Hz), 9.51 (1H, d, J = 0.9 Hz).

(3) 26 → 27

NaNHCN (5.89 g, 90.2 mmol) was added to a solution of compound 26 (18.25 g, 87.6 mmol) in methanol (300 mL) with stirring in an ice bath, and the mixture was stirred at room temperature for 2 hr. The precipitate was filtered off with suction and washed with a mixture of isopropanol and ethanol. The filtered product was dried under reduced pressure to give compound 27 (9.75 g, yield 4 9%) was obtained.

H-NMR (d-DMSO) δ 8.13 (1H, dd, J = 0.9, 5.4 Hz), 8.52 (1H, d, J = 5.4 Hz), 9.2

9 (1H, d, J = 0.9 Hz).

(4) 6 + 27 → 28

6 (689 mg) and 27 (149 mg) were used to obtain compound 28 (35 mg, yield 7%) in the same manner as in Example 69, (5).

'H-NMR (D O) δ: 1.28 (3H, t, J = 7.2 Hz), 3.67 (2H, s), 4.22 (2H, q, J = 7.2 Hz), 5

.26 (1H, d, J = 4.5 Hz), 5.47 (1H, d, J = 6.6 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.17 (1H, dt, J = 6.6, 15.6 Hz) , 6.93 (1H, s), 7.03 (1H, d, J = 15.6 Hz), 8.67 (1H, d, J = 6.6 Hz), 8.74 (1H, d, J = 6.6 Hz), 9.72 (1H, s) .

IR (KBr) cm " ¹ : 3425, 2180, 1762, 1606, 1532, 1363, 1304, 1200, 1166, 1123, 1084, 1036.

MS (ESI): 662 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-3.9 H O

Calculated value: C, 41.02; Η, 3.83; Ν, 17.22; S, 13.14; Na, 3.14 (%)

Experimental value: C, 40.98; H, 3.72; N, 17.21; S, 13.11; Na, 3.47 (%)

Example 76

[Chemical 122]

(1) 29 → 30, 31

A mixed solution of concentrated hydrochloric acid (2 mL) and water (4 mL) was cooled to −30 ° C., and compound 29 (2.21 g, 10 mmol) and methylhydrazine (0.51 mL, 9.5 mmol) were sequentially added. The mixture was warmed to room temperature and stirred at 80 ° C for 1 hour. The solution was cooled in an ice bath and the pH was adjusted to around 5 using IN NaOH aqueous solution. Ethyl acetate (100 mL) and black mouth form (50 mL) were added for extraction. The aqueous layer was extracted again with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 30 (509 mg, yield 22%) and compound 31 (591 mg, yield 26%) as colorless crystals.

30: 'H-NMR (CDC1) δ: 1.42 (3H, t, J = 7.2 Hz), 4.25 (3H, s), 4.39 (2H, q, J = 7.2

Hz), 7.21 (1H, s), 7.68 (2H, dd, J = 1.8, 4.8 Hz), 8.63 (2H, dd, J = 1.8, 4.8 Hz). 31: ^J H-NMR (CDC1) δ: 1.42 (3H, t, J = 7.2 Hz), 4.03 (3H, s), 4.45 (2H, q, J = 7.2

Hz), 6.97 (1H, s), 7.37 (2H, dd, J = 1.5, 4.5 Hz), 8.74 (2H, dd, J = 1.5, 4.5 Hz).

(2) 30 → 32

Cyanamide (96 mg, 2.19 mmol) and 1.0N NaOMe / MeOH were sequentially added to a methanol (4 mL) solution of compound 30 (505 mg, 2.18 mmol) while stirring in an ice bath, and the mixture was warmed to room temperature. The mixture was stirred at room temperature for 3 hours, then stirred at 50 ° C for 6 hours, and allowed to stand overnight at room temperature. Cyanamide (96 mg, 2.19 mmol) and 1.0N NaOMe / MeOH were added, and the mixture was stirred at 50 ° C. for 8 hours. After standing overnight at room temperature, methanol was evaporated under reduced pressure, water (5 mL) was added, and the mixture was cooled with ice and stirred. The pH was adjusted to around 3 with 2N HC1, and the precipitate was collected by suction filtration. The filtered product was dried under reduced pressure to obtain Compound 32 (369 mg, yield 74%).

'H-NMR (d-DMSO) δ: 4.20 (3Η, s), 7.50 (1Η, s), 8.29 (2H, brs), 8.81 (2H, brs).

(3) 32 → 33

1.0N NaOMe / MeOH (1.6 2 mL) is added to a suspension of compound 32 (369 mg, 1.62 mmol) in methanol (3 mL) to make a solution, and then concentrated to dryness to obtain compound 33 (455 mg) as a white powder. It was.

(4) 6 + 33 → 34

Compound 34 (120 mg, 15% yield) was obtained in the same manner as in Example 69, (5), using Compound 6 (1.08 g) and Compound 33 (258 mg).

'H-NMR (DO) δ: 1.28 (3H, t, J = 7.2 Hz), 3.64 (1H, d, J = 17.7 Hz), 3.71 (1H, d, J = 17.7 Hz), 4.11 (3H, s), 4.22 (2H, q, J = 7.2 Hz), 5.25-5.26 (2H, m), 5.80 (1H d, J = 4.5 Hz), 6.12 (1H, dt , J = 6.9, 15.6 Hz), 6.91 (1H, s), 6.99 (1H, d, J = 15.6

Hz), 7.23 (1H, s), 8.22 (2H, d, J = 7.2 Hz), 8.97 (2H, d, J = 7.2 Hz).

IR (KBr) cm— ¹ : 3419, 2980, 2186, 2151, 1764, 1636, 1604, 1522, 1475, 1437, 1388

1347, 1301, 1201, 1155, 1035, 1001.

MS (ESI): 663+ (M-Na + 2H) +

Elemental analysis C H N NaO S-4.6 H O

Calculated values: C, 43.81; H, 4.49; N, 18.25; S, 8.36; Na, 3.00 (%)

Experimental value: C, 43.81; H, 4.28; N, 18.15; S, 8.24; Na, 3.26 (%)

Example 77

[Chemical 123]

38-2

(1) 35 → 36

Bromopyruvate ethyl ester (90% w / w, 12.1 mL, 86.8 mmol) was added to a solution of compound 35 (10.0 g, 72.4 mmol) in ethanol (145 mL), and the mixture was stirred for 1.5 hours under reflux. Ethanol was distilled off by a half amount under reduced pressure, and the deposited precipitate was collected by suction filtration. The powder was extracted by adding ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate (200 mL). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitate was collected by suction filtration to give compound 36 (8.45 g, yield 50%) as pink crystals. NMR-NMR (CDC1) δ: 1.45 (3H, t, J = 6.9 Hz), 4.47 (2H, q, J = 6.9 Hz), 7.89 (2H, dd, J = 1.5, 4.5 Hz), 8.28 (1H, s), 8.75 (2H, d, J = 5.4 Hz).

(2) 36 → 37-l → 37-2

Compound 36 (8.44 g, 36 mmol) was suspended in methanol (100 mL), and NaNHCN (3.53 g, 54 mmol) was added. The mixture was stirred at 50 ° C for 30 minutes, and methanol was distilled off under reduced pressure. Ethanol was added and the insoluble material was collected by filtration to obtain Compound 37-l (7.82 g, yield 86%) as a light ocher powder.

H-NMR (d-DMSO) δ 7.89 (2Η, dd, J = 1.8, 4.5 Hz), 8.18 (1H, s), 8.70 (2H, dd, J

= 1.8, 4.5 Hz).

Compound 37-1 (1.26 g, 5 mmol) was dissolved in 15 ml of water and neutralized with 2N HCl (2.5 mL). The precipitate was collected by filtration and dried to obtain 1.2 g of powder. 0.6 g of this was suspended in methanol (10 mL), and a methanol solution of 1M tetramethyldanidine was added to adjust to pH 5.7. The reaction solution was concentrated and crystallized from isopropyl ether to obtain Compound 37_2 (698 mg).

H-NMR (d-DMSO) δ 2.89 (12H, s), 7.78 (1H, s), 7.88 (2H, dd, J = 1.5, 4.5 Hz),

8.70 (2H, dd, J = 1.5, 4.5 Hz).

(3) 6 + 37-l → 38-l

Compound 38-l (41 mg, 7% yield) was obtained in the same manner as in Example 69, (5), using Compound 6 (806 mg) and Compound 37-1 (202 mg).

'H-NMR (D O) δ: 1.28 (3H, t, J = 7.2 Hz), 3.65 (1H, d, J = 17.4 Hz), 3.71 (1H, d,

J = 17.4 Hz), 4.22 (2H, q, J = 7.2 Hz), 5.26 (1H, d, J = 4.5 Hz), 5.33 (1H, d, J = 6.9

Hz), 5.80 (1H, d, J = 4.5 Hz), 6.14 (1H, dt, J = 6.9, 15.3 Hz), 6.93 (1H, s), 7.01 (1

H, d, J = 15.3 Hz), 8.40 (1H, s), 8.47 (2H, d, J = 6.9 Hz), 8.91 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3846, 3418, 3055, 2984, 2162, 1762, 1635, 1598, 1532, 1469, 1440,

1357, 1300, 1203, 1156, 1124, 1091, 1037, 1002.

MS (ESI): 688+ (M + H) +

Elemental analysis C H N NaO S-5.3 H O

Calculated values: C, 41.41; H, 4.20; N, 16.10; S, 12.28; Na, 2.94 (%)

Experimental value: C, 41.31; H, 4.20; N, 16.08; S, 12.36; Na, 3.24 (%)

(4) 6- 2 + 37- 2 → 38- 2 Compound 6_2 (674 mg, l.OOmmol) was suspended in dichloromethane (10 ml), aqueous sodium hydrogen carbonate solution (126 mg, 1.50 mmol dissolved in 10 ml of water) was added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. . After distilling off the solvent, quickly dissolve in dimethylformamide (2 ml), mix with compound 37-2 (345 mg, 1.00 mmol), add sodium iodide (450 mg, 3.00 mmol), and at room temperature for 2 hours 30 minutes. Stir. The reaction mixture was poured into 5% brine (30 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain amorphous powder (874 mg). Dissolve this amorphous powder (874 mg) in methylene chloride (5 ml) and anisole (0.97 ml), cool to 0 ° C, add 5 ml of TFA (trifluoroacetic acid), stir for 45 minutes, and concentrate. did. The residue was washed with isopropyl ether, dissolved in a mixture of water and acetonitrile, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure to give compound 38-2 as a powder. Yield 286 mg (41%)

'H-NMR (d-DMSO) δ: 1.22 (3H, t, J = 6.9 Hz), 3.65,3.71 (2H, ABq, J = 17.6 Hz)

, 4.10 (2H, q, J = 6.9 Hz), 5.22 (1H, d, J = 5.1 Hz), 5.4 (1H, m), 5.81 (1H, dd, J = 5.1 Hz, 8.1 Hz), 6.33 (1H, m), 6.74 (1H, s), 6.97 (1H, d, J = 15.3 Hz), 7.22 (2H, s), 8. 48 (1H, s), 8.61 (2H, d, J = 6.9 Hz), 8.91 (2H, d, J = 6.9 Hz), 9.60 (1H, d, J = 8.1 Hz).

Elemental analysis C H N O S-3.8 H O

Calculated values: C, 44.17; H, 4.20; N, 17.17; S, 13.10 (%)

Experimental value: C, 44.24; H, 4.32; N, 17.10; S, 13.26 (%)

Example 78

[Chemical 124]

43 (1) 39 → 40

Acetylviridine 39 (22.1 g, 200 mmol) was dissolved in 30% HBr-AcOH (225 mL) and cooled in an ice bath. Bromine (11.3 mL, 220 mmol) was added dropwise, and the mixture was warmed to room temperature and stirred at the same temperature for 2 hr. The mixture was further heated to 60 ° C and stirred for 1 hour. After cooling to room temperature, the reaction solution was poured into jetyl ether (1 L) under ice-cooling and stirring. The deposited precipitate was collected by filtration and washed with jetyl ether and acetone. The obtained powder was dried under reduced pressure to obtain Compound 40 (53.8 g, 96%) as a pale yellow powder.

H-NMR (d -DMSO) δ 5.04 (2Η, s), 8.06 (2H, dd, J = 1.5, 4.8 Hz), 8.95 (2H, dd, J

= 1.5, 4.8 Hz).

(2) 40 → 41

Compound 40 (53.8 g, 192 mmol) was suspended in ethanol (500 mL), ethyl thioozamate (26.8 g, 201 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. The reaction solution was stirred for 30 minutes under ice cooling, and the precipitate was collected by filtration. The obtained powder was stirred and dissolved with ethyl acetate (500 mL) and NaHCO 3 (19.3 g) / H 0 (500 mL), and the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The crystals obtained after concentration under reduced pressure were washed with diisopropyl ether and dried under reduced pressure to give compound 41 (30.7 g, yield 68%) as brown crystals.

'H-NMR (CDC1) δ 1.48 (3Η, t, J = 7.2 Hz), 4.53 (2H, q, J = 7.2 Hz), 7.93 (2H, dd, J = 1.5, 4.5), 7.99 (1H, s ), 8.70 (2H, d, J = 6.0 Hz).

(3) 4 1 → 42

NaNHCN (650 mg, 10.2 mmol) was added to a solution of compound 41 (2.38 g, 10.2 mmol) in methanol (30 mL), and the mixture was stirred at room temperature for 1 hour. NaNHCN (195 mg) was added, and the mixture was stirred at 40 ° C for 1 hr. The reaction solution was ice-cooled, and the deposited precipitate was collected by filtration and dried under reduced pressure to obtain Compound 42 (1.30 g, yield 51%) as a colorless powder.

H-NMR (d -DMSO) δ 7.91 (2Η, dd, J = 1.5, 4.5 Hz), 8.43 (1H, s), 8.63 (2H, dd, J

= 1.5, 4.5 Hz).

(4) 6 + 42 → 43

Compound 43 (31 mg, 4% yield) was obtained in the same manner as in Example 69, (5), using Compound 6 (1.05 g) and Compound 42 (252 mg). Ή-NMR (DO) δ: 1.27 (3H, t, J = 6.9 Hz), 3.65 (1H, d, J = 17.4 Hz), 3.72 (1H, d,

2

J = 17.4 Hz), 4.22 (2H, q, J = 6.9 Hz), 5.25-5.30 (2H, m), 5.80 (1H, d, J = 4.8 Hz), 6.14 (1H, dt, J = 7.2, 15.3 Hz), 6.92 (1H, s), 7.00 (1H, d, J = 15.3 Hz), 8.39 (1H, d, J = 6.9 Hz), 8.56 (1H, s), 8.81 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3419, 2983, 2183, 2154, 1763, 1636, 1602, 1532, 1491, 1461, 1364, 1291, 1203, 1155, 1090, 1036, 1001.

MS (ESI): 688+ (M + H) +

Elemental analysis c H N NaO S -4.9 H O-0.1 NaHCO

27 22 9 6 3 2 3

Calculated values: C, 41.50; H, 4.10; N, 16.07; S, 12.26; Na, 3.22 (%)

Experimental value: C, 41.40; H, 3.96; N, 16.22; S, 12.31; Na, 3.42 (%)

Example 79

[Chemical 125]

(1) 31 → 45

Compound 31 (586 mg) compound 44 (503 mg) was obtained in the same manner as in Example 76, (2). H-NMR (d-DMSO) δ 4.04 (3Η, s), 7.23 (1H, brs), 7.67 (2H, brs), 8.75 (2H, brs).

6

(2) 44 → 45

Compound 45 (568 mg) was obtained from compound 44 (500 mg) in the same manner as in Example 76, (3). (3) 45 + 46 → 47 → 48

46 (664 mg, 0.90 mmol) and sodium bromide (278 mg, 2.7 mmol) were added to a DMF (3.0 mL) solution of compound 45 (180 mg, 0.722 mmol), and the mixture was stirred at room temperature for 6 hours. DMF (3 mL) was added for dilution, and the mixture was poured into 5% brine (80 mL) under ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried using phosphorus pentoxide under reduced pressure. Ocherous powdery crude product 47 (777 mg) was obtained. This crude product was dissolved in methylene chloride (15 mL), and anisole (0.4 7 mL, 4.32 mmol) was added under a nitrogen atmosphere, followed by cooling to -40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 2.16 mL, 4.32 mmol) was added dropwise at _40 ° C, and the mixture was stirred at -20 ° C for 1 hour. The reaction solution was poured into water (40 mL) with stirring in an ice bath, and diisopropyl ether (80 mL) was added. The precipitate obtained by suction filtration was dissolved in sodium bicarbonate water, and the fraction (water-acetonitrile) collected by ODS column chromatography was concentrated under reduced pressure and lyophilized. Compound 48 (62 mg, yield 10%) was obtained as a powder.

'H-NMR (DO) δ: 1.28 (3H, t, J = 7.2 Hz), 3.67 (2H, brs), 4.08 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 5.26 (1H , d, J = 4.5 Hz), 5.33 (1H, d, J = 6.9 Hz), 5.80 (1H, d, J = 4

.5 Hz), 6.12 (1H, dt, J = 6.9, 15.6 Hz), 6.94 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 7.1

4 (1H, s), 8.19 (2 H, d, J = 6.9 Hz), 8.89 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3427, 2168, 1762, 1636, 1606, 1536, 1475, 1388, 1368, 1338, 1294,

1201, 1157, 1090, 1038.

MS (ESI): 707 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-6.0 H O -0.4 NaHCO

Calculated value: C, 41.28; Η, 4.56; Ν, 16.95; SJ.76; Na, 3.89 (%)

Experimental value: C41.14; H, 4.26; N, 17.13; SJ.90; Na, 3.98 (%)

Example 80

[Chemical 126]

52

(1) 48 → 49

A solution of compound 48 (1.48 g, 4.90 mmol) in methanol (20 mL) was cooled in an ice bath, and 5N aqueous sodium hydroxide solution (3.9 mL) was added. After stirring at room temperature for 1 hour, 5N aqueous sodium hydroxide solution (0.98 mL) was added, and the mixture was further stirred for 1.5 hours. The mixture was ice-cooled again, 5N aqueous hydrochloric acid solution (4.8 mL) was added, and methanol was evaporated under reduced pressure. The pH of the residue was adjusted to around 3.5, and the precipitate was collected by filtration and dried under reduced pressure to obtain Compound 49 (580 mg, 66% yield) as an ocher powder.

H-NMR (d-DMSO) δ 7.42 (1H, s), 7.65 (1H, d, J = 6.0 Hz), 8.38 (1H, d, J = 6.0

Hz), 9.20 (1H, brs), 12.8 (1H, brs).

(2) 49 → 50

In the same manner as in Example 74 (2), compound 50 (578 mg, yield 87%) was obtained from compound 49 (580 mg).

H-NMR (d-DMSO) δ 7.24 (1H, s), 7.79 (1H, d, J = 6.9 Hz), 8.37 (1H, d, J = 6.9

Hz), 9.25 (1H, s), 12.9 (1H, brs).

(3) 50 → 51

Compound 51 was obtained as a light ocher powder by the same method as in Example 74, (3), and used as such in the next reaction.

(4) 46 + 51 → 52

Compound 52 (69 mg, 9% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (738 mg) and Compound 51 (208 mg).

H-NMR (DO) δ: 1.28 (3H, t, J = 6.9 Hz), 3.65 (2H, ABq, J = 17.8 Hz), 4.22 (2H, q, J = 6.9 Hz), 5.24 (3H, d, J = 4.8 Hz), 5.79 (1H, d, J = 6.6 Hz), 6.13 (1H, dt, J = 6.9, 15.9 Hz), 6.89-6.94 (2H, m), 7.27 (1H, s), 7.82 ( 1H, d, J = 7.2 Hz), 8.29 (1H, d, J = 7.2 Hz).

IR (KBr) cm— ¹ : 3425, 2160, 1762, 1598, 1535, 1372, 1333, 1202, 1165, 1120, 1092 1036, 1003.

MS (ESI): 644 ⁺ (M + H) +

Elemental analysis c H N NaO S-5.3 H O-0.2 NaHCO

26 22 9 6 2 2 3

Calculated values: C, 41.63; H, 4.37; N, 16.68; S, 8.48; Na, 3.65 (%)

Experimental value: C41.76; H, 4.33; N, 16.16; S, 8.88; Na, 3.85 (%)

Example 81

[Chemical 127]

55

(1) 53 → 54

Compound 54 (1.04 g, yield 61%) was obtained from compound 53 (1.37 g) in the same manner as in Example 75, (3).

H-NMR (d -DMSO) δ 7.30-7.34 (1H, m), 8.14-8.18 (1H, m), 8.52-54 (1H, m

6

), 9.00 (1H, m).

(2) 46 + 54 → 55

Compound 55 (236 mg, 18%) was obtained in the same manner as in Example 79, (3), using Compound 46 (1.86 g) and Compound 54 (338 mg).

'H-NMR (D O) δ: 1.30 (3H, t, J = 7.2 Hz), 3.65 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 5

2

.26 (1H, d, J = 4.8 Hz), 5.36 (2H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 6.9, 13.5 Hz) , 6.96 (1H, d, J = 13.5 Hz), 6.99 (1H, s), 8.10 (1H, t, J = 7.2 Hz), 8.51-8.94 (2H, m), 9.29 (1H, s). IR (KBr) cm: 3418, 2984, 2168, 1763, 1636, 1601, 1533, 1380, 1304, 1203, 1166

1136, 1037, 1002.

MS (ESI): 605+ (M + H) +

Elemental analysis C H N NaO S-3.7 H O

24 21 8 6 2 2

Calculated value: C, 42.94; H, 4.26; N, 16.69; S, 9.55; Na, 3.42 (%)

Experimental value: C42.99; H, 4.14; N, 16.61; S, 9.36; Na, 3.49 (%)

Example 82

[Chemical 128]

(1) 56 → 57

Compound 57 (939 mg, yield 56%) was obtained from compound 56 (1.51 g) in the same manner as in Example 75, (3).

H-NMR (d -DMSO) δ 7.74 (2Η, dd, J = 1.5, 4.5 Hz), 8.55 (2H, dd, J = 1.5, 4.5 H

6

z).

(2) 4 6 + 57 → 58

'H-NMR (DO) δ: 1.30 (3H, t, J = 7.2 Hz) obtained from compound 58 (253 mg, yield 19%) using compound 46 (1.86 g) and compound 57 (338 mg) , 3.64 (2H, s), 4.25 (2H, q, J = 7.2 Hz), 5

2

.26 (1H, d, J = 4.8 Hz), 5.34 (2H, d, J = 7.2 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.09 (1H, dt, J = 7.2, 15.6 Hz) , 6.97 (1H, d, J = 15.6 Hz), 6.98 (1H, s), 8.37 (2H, d, J = 6.9 Hz), 8.91 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3420, 3055, 2982, 2160, 1762, 1605, 1561, 1533, 1457, 1367, 1301, 1200, 1150, 1122, 1036, 1001.

MS (ESI): 605+ (M + H) +

Elemental analysis C H N NaO S-3.6 H O

Calculated values: C, 43.06; H, 4.25; N, 16.74; S, 9.58; Na, 3.43 (%)

Experimental value: C, 43.09; H, 4.22; N, 16.73; S, 9.48; Na, 3.64 (%)

Example 84

[Chemical 129]

(1) 20 → 63

Diphenyldiazomethane (2.14 g, 11 mmol) was refluxed for 3 hours in a suspension of compound 20 (1.62, 10 mmol) in tetrahydrofuran (20 mL). After cooling to room temperature, tetrahydrofuran was distilled off under reduced pressure. To the residue was added jetyl ether and hexane, and the precipitate was collected by filtration and dried under reduced pressure. Compound 63 (2.70 g, yield 82%) was obtained.

'H-NMR (CDC1) δ 7.14 (1H, s), 7.27-7.46 (11H, m), 7.55 (1H, s), 7.76 (1H, d,

J = 8.4 Hz), 8.58 (1H, brs), 9.11 (1H, brs).

(2) 46 + 63 → 64

Using Compound 46 (1.24 g) and Compound 63 (493 mg), Compound 64 (487 mg, Yield 46%) was obtained in the same manner as in Example 79, (3).

'H-NMR (D O) δ: 1.29 (3H, t, J = 7.2 Hz), 3.62 (2H, s), 4.24 (2H, q, J = 7.2 Hz),

5.23 (1H, d, J = 4.8 Hz), 5.45 (2H, d, J = 6.6 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.15 (1 H, dt, J = 6.6, 15.9 Hz) , 6.83 (1H, d, J = 15.9 Hz), 6.96 (1H, s), 7.23 (1H, brs), 7.6 8 (1H, dd, J = 5.7, 8.4 Hz), 8.50 (1H, d, J = 8.4 Hz), 8.58 (1H, d, J = 5.7). IR (KBr) cm: 3407, 1763, 1604, 1532, 1460, 1390, 1336, 1201, 1161, 1123, 1035.

MS (ESI): 620+ (M + H) +

Elemental analysis C H N NaO S -4.8 H O

Calculated value: C, 42.53; H, 4.51; N, 13.89; S, 9.08; Na, 3.26 (%)

Experimental value: C, 42.49; H, 4.25; N, 14.01; S, 8.80; Na, 3.29 (%)

Example 85

[Chem 130]

(1) 65 → 66

To a solution of compound 65 (832 mg, 4.0 mmol) in DMF (10 mL), add methanol (2 mL), palladium acetate (11), dppp (412 mg, 1.0 mmol), and triethylamine (5.6 mL, 40 mmol). The mixture was stirred at 80 ° C for 14 hours under a carbon oxide atmosphere. The reaction mixture was cooled to room temperature, extracted with ethyl acetate (100 mL) and water (20 mL), and the organic layer was washed three times with water and once with saturated brine. The extract was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography. Compound 66 (621 mg, yield 83%) was obtained as crystals. dppp: l, 3-Bis (diphenyl phospino) propane

^J H-NMR (CDC1) δ 4.03 (3H, s), 7.66 (1H, dd, J = 7.5, 8.4 Hz), 8.18 (1H, m), 8.4

6 (1H, dd, J = 1.5, 7.5 Hz), 8.65 (1H, d, J = 6.3 Hz), 8.78 (1H, m), 9.302 (1H, s).

(2) 66 → 67

Compound 67 (544 mg, 75%) was obtained as a powder from compound 66 (620 mg) in the same manner as in Example 75, (3).

(3) 46 + 67 → 68 Compound 68 (49 mg, 6% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (830 mg) and Compound 67 (219 mg).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 3.67 (2H, s), 4.24 (2H, q, J = 6.9 Hz),

5.27 (1H, d, J = 4.8 Hz), 5.44 (2H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.17 (1 H, dt, J = 6.9, 15.6 Hz) , 6.96 (1H, s), 7.04 (1H, d, J = 15.6 Hz), 8.01 (1H, t, J = 7.8 Hz), 8.45-8.48 (2H, m), 8.54 (1H, d, J = 7.2 Hz), 8.95 (1H, d, J = 7.2 Hz), 9.73 (1H, s).

IR (KBr) cm— ¹ : 3418, 2984, 2162, 1763, 1607, 1535, 1474, 1456, 1390, 1365, 1293, 1243, 1202, 1168, 1133, 1090, 1037, 1001.

MS (ESI): 655+ (M + H) +

Elemental analysis c H N NaO S-2.8 H O-0.6 NaHCO

Calculated values: C, 45.47; H, 3.90; N, 14.83; S, 8.49; Na, 4.87 (%)

Experimental value: C, 45.36; Η, 4.11; Ν, 15.01; S, 8.91; Na, 4.73 (%)

Example 86

[Chemical 131]

(1) 69 → 71 Compound 70 (2.0 g, 11.1 mmo) was added to a solution of aminoviridine 69 (1.15 g, 12.2 mmol) in acetic acid (11 mL).

1) was added and refluxed for 3 hours. The reaction mixture was cooled to room temperature, acetic acid was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 71 (964 mg, yield 46%) as pale yellow crystals.

'H-NMR (CDC1) δ 6.88 (1H, m), 7.24 (1H, m), 7.38 (2H, dd, J = 1.8, 4.8 Hz), 7.

Three

82 (1H, m), 8.72 (2H, dd, J = 1.8, 4.8 Hz), 9.90 (1H, s).

(2) 71 → 72

NaCIO (1.39 g, 12.3 mmol) and NH 2 SO H (1.19 g, 12.3 mmol) are melted into water (13 mL) and ice bathed.

2 2 3

The solution of compound 71 (960 mg, 5.58 mmol) in methanol (13 mL) was added dropwise with stirring and cooling. After stirring in an ice bath for 1.5 hours, add NaCIO (315 mg) and NH 2 SO H (271 mg).

2 2 3

The mixture was further stirred for 1 hour. Na2S203'5H20 (4.15 g) was added, and the mixture was further stirred for 20 minutes. Methanol was distilled off under reduced pressure, and 1N hydrochloric acid was added to adjust the pH to around 3. The precipitate was collected by filtration and dried under reduced pressure to obtain Compound 72 (1.07 g, yield 100%) as a pale yellow powder.

H-NMR (d-DMSO) δ 6.67 (1H, m), 7.71 (1H, m), 7.82 (2H, d, J = 6.3 Hz), 8.22 (

6

1H, m), 8.64 (1H, d, J = 6.3 Hz).

(3) 72 → 73

In the same manner as in Example 74 (2), compound 72 (1.06 g) was obtained as compound 73 (1.20 g, yield 100%) as a white powder.

H-NMR (d -DMSO) δ 6.84 (1H, m), 7.74-7.78 (3H, m), 8.38 (1H, m), 8.67 (2H,

6

d, J = 6.3 Hz).

(4) 73 → 74 → 75

N, O-pistrimethylsilylacetamide (0.49 mL, 2.0 mL) was added to a suspension of compound 73 (212 mg, 1.0 mmol) in DMF (3.0 mL), and the mixture was vigorously stirred to obtain a solution. Compound 46 (8 30 mg, 1.0 mmol, f = 0.89) and sodium bromide (309 mg, 3.0 mmol) were added to this solution, and the mixture was stirred at room temperature for 8 hours. DMF (3 mL) was added for dilution, and the mixture was poured into 5% brine (80 mL) with ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried using phosphorus pentoxide under reduced pressure to obtain an ocherous powdery crude product 74 (996 mg). This crude product was dissolved in methylene chloride (15 mL) Under an atmosphere of nitrogen, anisole (0.65 mL, 6.0 mmol) was added and cooled to -40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 3.0 mL, 6.0 mmol) was added dropwise at _40 ° C, followed by stirring at -20 ° C for 1 hour. The reaction mixture was poured into water (50 mL) under ice bath stirring, and diisopropyl ether (60 mL) was added. The precipitate obtained by suction filtration was dissolved in aqueous sodium bicarbonate, and the fraction (water-acetonitrile) collected by DS column chromatography was concentrated under reduced pressure and freeze-dried. Compound 75 (263 mg, yield 34%) was obtained as a powder.

'H-NMR (D O) δ: 1.28 (3H, t, J = 6.9 Hz), 3.65 and 3.73 (2H, ABq, J = 17.4 Hz),

4.22 (2H, q, J = 6.9 Hz), 5.21 (2H, d, J = 7.2 Hz), 5.26 (1H, d, J = 4.8 Hz), 5.80 (1 H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 7.2, 15.9 Hz), 6.60 (1H, m), 6.93 (1H, s), 6.97 (1H, d, J = 15.9 Hz), 7.42 (1H, m), 7.97 (2H, d, J = 7.2 Hz), 8.73 (2H, d, J = 7.2 Hz)

IR (KBr) cm " ¹ : 3418, 2983, 2154, 1762, 1639, 1587, 1558, 1529, 1496, 1389, 1333,

1254, 1215, 1160, 1089, 1037, 1002.

MS (ESI): 670 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-5.3 H O

Calculated value: C, 43.95; Η, 4.56; Ν, 16.48; S, 8.38; Na, 3.00 (%)

Experimental value: C, 44.00; Η, 4.60; Ν, 16.57; S, 8.27; Na, 3.10 (%)

Example 87

[Chemical 132]

(1) 76 → 77

Compound 77 (8 · 15 g) was obtained from 76 (4.74 mL) in the same manner as in Example 91, (1).

'H-NMR (CDC1) δ: 5.24 (2Η, s), 7.29 (1H, dd, J = 1.2, 4.8 Hz), 7.33 (1H, dd, J =

Three

1.2, 4.8 Hz), 7.42-7.44 (1H, m), 7.72-7.76 (2H, m), 7.78-7.82 (2H, m).

(2) 77 → 79

Compound 79 (14.3 g) was obtained from Compound 77 (11.2 g) and Compound 78 (12.7 g) in the same manner as in Example 91 (2).

'H-NMR (CDC1) δ: 1.54 (9H, s), 5.26 (2H, s), 7.09 (1H, dd, J = 1.2, 4.8 Hz), 7.22

Three

7.25 (1H, m), 7.29-7.33 (2H, m).

(3) 79 → 81

Compound 81 (5.71 g) was obtained from Compound 79 (3.07 g) and Compound 80 (3.82 g) in the same manner as in Example 91, (3).

'H-NMR (CDC1) δ 1.53 (9H, s), 3.45 (2H, s), 4.01 (2H, d, J = 6.9 Hz), 5.06 (1H,

Three

d, J = 5.1 Hz), 5.32 (2H, t-like), 5.91-6.01 (2H, m), 6.93 (1H, d, J = 15.9 Hz), 7.0 0 (1H, s), 7.13 (1H, d, J = 5.1 Hz), 7.22-7.45 (13H, m). (4) 81 + 57 → 82

Compound 82 (212 mg) was obtained in the same manner as in Example 79, (3), using Compound 81 (888 mg) and Compound 57 (169 mg).

'H-NMR (D O) δ: 3.50 and 3.57 (2H, ABq, J = 17.4 Hz), 5.18 (1H, d, J = 4.8 Hz),

5.30 (2H, d, J = 6.9 Hz), 5.37 (2H, s), 5.73 (1H, d, J = 4.8 Hz), 6.02 (1H, dt, J = 6.9, 15.9 Hz), 6.94-7.04 (3H, m), 7.19 (1H, d, J = 2.4 Hz), 7.43 (1H, d, J = 5.1 Hz): 8.32 (2H, d, J = 6.9 Hz), 8.86 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3418, 2159, 1764, 1667, 1604, 1561, 1533, 1457, 1368, 1302, 1198,

1148, 1060, 1047.

MS (ESI): 673+ (M + H) +

Elemental analysis C H N NaO S-3.5 H O

Calculated value: C, 44.08; H, 3.84; N, 15.23; S, 13.07; Na, 3.12 (%)

Experimental value: C, 43.98; Η, 3.69; Ν, 15.49; S, 12.81; Na, 3.18 (%)

Example 88

[Chemical 133]

Compound 83 (253 mg) was obtained in the same manner as in Example 79, (3), using Compound 81 (888 mg) and Compound 5 (236 mg).

'H-NMR (D O) δ: 3.50 and 3.58 (2H, ABq, J = 17.1 Hz), 5.16 (1H, d, J = 4.8 Hz),

5.31 (3H, m), 5.70 (1H, d, J = 4.8 Hz), 6.00 (1H, dt, J = 7.2, 15.6 Hz), 6.85 (1H, s), 7.15 (1H, m), 7.38-7.42 (2H, m), 8.67 (2H, d, J = 6.9 Hz), 8.89 (2H, d, J = 6.9 H z).

IR (KBr) cm— ¹ : 3420, 2170, 1764, 1608, 1561, 1532, 1474, 1438, 1357, 1300, 1257, 1199, 1149, 1059.

MS (ESI): 740 ⁺ (M + H) + Elemental analysis CHN NaO S -4.1 HO

Calculated values: C, 44.29; H, 3.74; N, 15.49; S, 11.82; Na, 2.83 (%)

Experimental value: C, 44.16; Η, 3.68; Ν, 15.49; S, 12.18; Na, 2.83 (%)

Example 89

[Chemical 134]

(1) 26 → 84

A solution of compound 26 (2.0 g, 9.6 mmol) in THF (15 mL) was stirred with 5N NaOH aqueous solution (3.9 mL, 19.5 mmol) at room temperature. After 1 hour, 5N NaOH7] solution (8.0 mL) was added, and the mixture was further stirred at room temperature for 2 hours. THF was distilled off under reduced pressure, and 5N hydrochloric acid was added to adjust the pH to 1.5. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain Compound 84 (1.60 g, yield 92%).

(2) 84 → 85

Diphenyldiazomethane (1.62 g, 8.32 mmol), methanol (5 mL) and THF (15 mL) were added to a solution of compound 84 (1.47 g, 8.17 mmol) in methylene chloride (15 mL) at 70 ° C. Stir for 1 hour. Diphenyl diazomethane (1.08 g) was added, and the mixture was further stirred at 70 ° C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give compound 85 (2.75 g, yield 97%).

(3) 81 + 85 → 86

Compound 86 (265 mg) was obtained in the same manner as in Example 79, (3), using Compound 81 (888 mg) and Compound 85 (346 mg).

'H-NMR (D O) δ: 3.52 and 3.60 (2H, ABq, J = 17.7 Hz), 5.18 (1H, d, J = 4.8 Hz),

5.35 (2H, s), 5.43 (2H, d, J = 6.9 Hz), 5.72 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6. 9, 15.6 Hz), 6.89 (IH, s), 7.00-7.05 (2H, m), 7.18 (IH, m), 7.42 (IH, m), 8.60 (1 H, d, J = 6.9 Hz), 8.63 (1H, d, J = 6.9 Hz), 9.66 (1H, s).

IR (KBr) cm— ¹ : 3417, 1764, 1637, 1532, 1506, 1465, 1362, 1303, 1197, 1118, 1058.

MS (ESI): 684+ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.4 H O

Calculated values: C, 41.31; H, 3.70; N, 12.49; S, 16.34; Na, 2.93 (%)

Experimental value: C41.23; H, 3.64; N, 12.56; S, 16.45; Na, 3.13 (%)

Example 90

[0113] [Chemical 135]

Compound 87 (171 mg) was obtained in the same manner as in Example 79, (3), using Compound 81 (888 mg) and Compound 27 (226 mg).

'H-NMR (D O) δ: 3.51 and 3.58 (2H, ABq, J = 17.4 Hz), 5.15 (IH, d, J = 4.5 Hz),

5.29 (2H, s), 5.42 (2H, d, J = 6.9 Hz), 5.69 (1H, d, J = 4.5 Hz), 6.07 (1H, dt, J = 6.9, 15.6 Hz), 6.82 (IH , s), 6.96-6.99 (IH, m), 7.06 (IH, d, J = 15.6 Hz), 7.14 (IH, m), 7.36-7.38 (1H, m), 8.57 (IH, d, J = 6.6 Hz), 8.63 (IH, d, J = 6.6 Hz), 9.66 (1 H, s).

IR (KBr) cm " ¹ : 3420, 3111, 2178, 1763, 1606, 1532, 1465, 1363, 1196, 1171, 1123,

1082, 1062.

MS (ESI): 730 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.1 H O

Calculated value: C, 41.85; Η, 3 · 54; Ν, 15.69; S, 15.96; Na, 2.86 (%)

Experimental value: C, 41.80; Η, 3.40; Ν, 15.76; S, 15.79; Na, 2.41 (%)

Example 91

[0114] [Chemical 136]

(1) 88 → 89

N_hydroxyphthalimide (3.26 g, 20 mmol) and triphenylphosphine (5.25 g) were added to a solution of compound 88 (2.36 g, 20 mmol) in THF (35 mL), and the mixture was cooled and stirred in an ice bath. To this solution was added DEAD in toluene (11.1 mL) dropwise, and the mixture was warmed to room temperature and stirred at the same temperature for 3 hours. THF was distilled off under reduced pressure, toluene was added and insolubles were removed by filtration. Toluene was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain Compound 89 (4.42 g, yield 84%) as crystals.

'H-NMR (CDCl) δ 2.04-2.15 (2Η, m), 2.23-2.32 (2H, m), 2.52-2.61 (2H, m)

Three

, 2.96-3.03 (2H, m), 4.22-4.28 (1H, m), 7.74-7.79 (2H, m), 7.81-7.86 (2H, m)

(2) 78 → 90

A solution of compound 89 (4.42 g, 16.8 mmol) in methylene chloride (30 mL) was ice-cooled to obtain methyl hydrazine (0.89 mL, 16.8 mmol). The mixture was stirred at the same temperature for 1.5 hours, and the deposited precipitate was removed by filtration. Methylene chloride was distilled off under reduced pressure to about 20 mL, methanol was added and the mixture was ice-cooled. Compound 78 (4.57 g, 16.8 mmol) was added to this solution, and the mixture was warmed to room temperature and stirred for 2 hours. Methanol was distilled off under reduced pressure, ethyl acetate (120 mL) was added, and the mixture was washed with 0.2N hydrochloric acid, water, and saturated brine in this order. anhydrous It was dried over magnesium sulfate and concentrated. The precipitate formed by collecting the jetyl ether and hexane was collected by filtration and dried under reduced pressure to obtain Compound 90 (4.95 g, yield 76%).

'H-NMR (CDC1) δ 1.98-2.09 (2Η, m), 2.16-2.25 (2H, m), 2.46-2.54 (2H, m)

, 2.77-2.86 (2H, m), 4.37 (1H, m), 7.33 (1H, s).

(3) 90 → 91

A solution of compound 90 (2.32 g, 6.0 mmol) in methylene chloride (30 mL) was cooled to _30 ° C and compound 80 (2.86 g, 6.0 mmol), phenylphosphoric dichloride (1.08 mL, 7.2 mmol), N_methylmorpholine (1.98 mL) was added in order, and the mixture was stirred at −20 ° C. for 2 hours. A 10% aqueous citrate solution (30 mL) was added and the mixture was warmed to room temperature, and then concentrated to about 20 mL of sodium chloride. Ethyl acetate (100 mL) was added for extraction, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and then dried over anhydrous magnesium sulfate. The residue obtained by concentration was purified by silica gel column chromatography to obtain Compound 91 (2.88 g, yield 56%) as a light brown foam.

'H-NMR (CDC1) δ 1.54 (9Η, s), 1.92-2.05 (2H, m), 2.26-2.34 (2H, m), 2.56-

2.65 (2H, m), 2.78-2.88 (2H, m), 3.56 and 3.68 (2H, ABq, J = 17.8 Hz), 4.00 (2H, d, J = 7.3 Hz), 4.36 (1H, m), 5.12 (1H, d, J = 4.8 Hz), 5.96-6.06 (2H, m), 6.91 (1H, d, J = 15.9 Hz), 7.02 (1H, s), 7.13 (1H, d, J = 8.7 Hz) , 7.29-7.45 (11H, m).

(4) 91 → 92

Compound 92 (382 mg, 47% yield) was obtained in the same manner as in Example 79, (3), using Compound 91 (863 mg) and Compound 27 (226 mg).

'H-NMR (D O) 5: 1.91-1.97 (2Η, m), 2.11-2.21 (2H, m), 2.53-2.60 (2H, m), 2

.78-2.84 (2H, m), 3.64 and 3.72 (2H, ABq, J = 17.7 Hz), 4.29 (1H, m), 5.27 (1H, d, J = 4.8 Hz), 5.47 (2H, d, J = 6.9 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.17 (1H, dt, J = 6.9, 15.6 Hz), 6.89 (1H, s), 7.05 (1H, d, J = 15.6 Hz), 8.66 (1H, d, J = 6.9 Hz), 8.7 4 (1H, d, J = 6.9 Hz), 9.71 (1H, s).

IR (KBr) cm— ¹ : 3410, 2940, 2178, 1764, 1604, 1531, 1362, 1190, 1122, 1081, 1061, 1022.

MS (ESI): 712+ (M-Na + 2H) +

Elemental analysis CHN NaO S -4.7 HO Calculated value: C, 41.09; Η, 4.11; Ν, 15.40; S, 15.67; Na, 2.81 (%)

Experimental value: C, 40.91; Η, 3.98; Ν, 15.34; S, 15.77; Na, 3.11 (%)

Example 92

[0115] [Chemical 137]

(1) 91 → 93

Compound 93 (259 mg, 32% yield) was obtained in the same manner as in Example 79, (3), using Compound 91 (863 mg) and Compound 85 (341 mg).

'H-NMR (D O) δ: 1.95-2.04 (2Η, m), 2.12-2.22 (2H, m), 2.53-2.62 (2H, m), 2

.80-2.88 (2H, m), 3.64 and 3.71 (2H, ABq, J = 17.7 Hz), 4.29-4.35 (1H, m), 5.2 8 (1H, d, J = 4.8 Hz), 5.46 (2H, d, J = 6.9 Hz), 5.83 (1H, d, J = 4.8 Hz), 6.16 (1H, dt, J = 6.9, 15.6 Hz), 6.94 (1H, s), 7.02 (1H, d, J = 15.6 Hz), 8.66 (1H, d, J = 6.9 Hz), 8.71 (1H, d, J = 6.9 Hz), 9.69 (1H, s).

IR (KBr) cm " ¹ : 3399, 2938, 1765, 1636, 1531, 1362, 1191, 1118, 1058, 1022.

MS (ESI): 688 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N NaO S -4.1 H O-0.3 NaHCO

Calculated value: C, 40.54; Η, 4.05; Ν, 12.12; S, 15.86; Na, 3.70 (%)

Experimental value: C, 40.52; Η, 4.03; Ν, 11.99; S, 15.90; Na, 3.66 (%)

Example 93

[0116] [Chemical 138]

Compound 94 (272 mg, 36% yield) was obtained in the same manner as in Example 79, (3), using Compound 91 (863 mg) and Compound 57 (169 mg).

'H-NMR (D O) 5: 1.94-2.05 (2Η, m), 2.13-2.23 (2H, m), 2.54-2.62 (2H, m), 2

2

• 80-2.87 (2H, m), 3.62 and 3.69 (2H, ABq, J = 17.4 Hz), 4.30-4.37 (1H, m), 5.2 7 (1H, d, J = 4.5 Hz), 5.33 (2H, d, J = 6.9 Hz), 5.83 (1H, d, J = 4.5 Hz), 6.09 (1H, dt, J = 6.9, 15.9 Hz), 6.95-6.99 (2H, m), 8.36 (2H, d, J = 6.9 Hz), 8.91 (1H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3410, 3055, 2940, 2159, 1764, 1667, 1604, 1561, 1532, 1455, 1365, 1240, 1196, 1146, 1060, 1022.

MS (ESI): 677 ⁺ (M + H) +

Elemental analysis c H N NaO S -4.0 H O-0.1 NaHCO

27 25 8 6 3 2 3

Calculated values: C, 42.99; H, 4.41; N, 14.80; S, 12.70; Na, 3.34 (%)

Experimental value: C, 42.74; H, 4.26; N, 14.79; S, 12.98; Na, 3.47 (%)

Example 94

[Chem 139]

(1) 41 → 95

Compound 41 (2.34 g) force Compound 95 (1.92 g, yield 93%) was obtained in the same manner as in Example 74, (1).

H-NMR (d-DMSO) δ 7.96 (2Η, dd, J = 1.8, 4.8 Hz), 8.68 (2H, d, J = 6.0 Hz), 8.7

6

8 (1H, s).

(2) 95 → 96

Compound 96 (3.08 g, yield 88%) was converted from compound 95 (1.92 g) in the same manner as in Example 84, (1). Obtained.

'H-NMR (CDCl) δ 7.20 (1H, s), 7.31-7.49 (10H, m), 7.92 (2H, d, J = 6.0 Hz), 8

.02 (1H, s), 8.72 (2H, d, J = 4.8 Hz).

(3) 81 + 96 → 97

Compound 97 (145 mg, yield 18%) was obtained in the same manner as in Example 79, (3), using Compound 81 (888 mg) and Compound 96 (372 mg).

'H-NMR (DO) δ: 3.46 and 3.57 (2H, ABq, J = 17.1 Hz), 5.15-5.20 (3H, m), 5.33 and 5.38 (2H, ABq, J = 13.2 Hz), 5.69 (1H, d, J = 4.5 Hz), 5.95 (1H, dt, J = 6.9, 1 5.6 Hz), 6.81 (1H, s), 6.97-7.02 (2H, m), 7.13 (2H, d, J = 2.7 Hz) , 7.39 (1H, dd, J = 1.2, 5.1 Hz), 8.33 (2H, d, J = 6.6 Hz), 8.54 (1H, s), 8.67 (2H, d, J = 6.6 Hz). IR (KBr) cm " ¹ : 3408, 1763, 1635, 1532, 1487, 1458, 1367, 1292, 1200, 1156, 1109, 1064.

MS (ESI): 710 ⁺ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.4 H O

Calculated value: C, 42.95; Η, 3.83; Ν, 12.09; S, 15.81; Na, 2.83 (%)

Experimental value: C, 42.74; Η, 3.65; Ν, 11.80; S, 15.72; Na, 2.74 (%)

Example 95

[Chemical 140]

(1) 98 → 99

Compound 99 (2.06 g, yield 57%) was obtained from compound 98 (2.28 g) in the same manner as in Example 91, (1).

'H-NMR (CDC1) δ 5.24 (2Η, s), 7.29 (1H, dd, J = 1.2, 4.8 Hz), 7.33 (1H, dd, J =

1.2, 4.8 Hz), 7.42-7.44 (1H, m), 7.72-7.76 (2H, m), 7.78-7.82 (2H, m).

(2) 78 → 100

Compound 100 (4.33 g, yield 99%) was obtained from compound 93 (2.95 g) and compound 78 (3.25 g) in the same manner as in Example 91, (2).

'H-NMR (CDC1) δ: 1.54 (9H, s), 5.26 (2H, s), 7.09 (1H, dd, J = 1.2, 4.8 Hz), 7.2

2-7.25 (1H, m), 7.29-7.33 (2H, m).

(3) 100 → 101

Compound 101 (7.92 g, yield 81%) was obtained from compound 100 (4.33 g) and compound 80 (5.39 g) in the same manner as in Example 91, (3).

'H-NMR (CDC1) δ 1.53 (9H, s), 3.45 (2H, s), 4.01 (2H, d, J = 6.9 Hz), 5.06 (1H, d, J = 5.1 Hz), 5.32 (2H, t-like), 5.91-6.01 (2H, m), 6.93 (1H, d, J = 15.9 Hz), 7.0 0 (1H, s), 7.13 (1H, d, J = 5.1 Hz), 7.22-7.45 ( 13H, m). (4) 101 + 96 → 102

Compound 102 (315 mg, yield 39%) was obtained in the same manner as in Example 79, (3), using Compound 101 (860 mg) and Compound 96 (372 mg).

'Η-NMR (D O) δ: 3.46 and 3.55 (2H, ABq, J = 17.4 Hz), 5.15 (1H, d, J = 9.5 Hz),

2

5.17 (2H, s), 5.22 (2H, d, J = 6.9 Hz), 5.70 (1H, d, J = 4.5 Hz), 5.99 (1H, dt, J = 6.9, 15.6 Hz), 6.82 (1H , s), 6.99 (1H, d, J = 15.6 Hz), 7.16 (1H, m), 7.37 (1H, m), 7.4 4 (1H, m), 8.36 (2H, d, J = 6.9 Hz), 8.55 (1H, s), 8.70 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3399, 1764, 1635, 1531, 1487, 1458, 1365, 1199, 1155, 1109, 1063, 1001.

MS (ESI): 710+ (M -Na + 2H) +

Elemental analysis C H N NaO S -4.5 H O

29 22 7 7 4 2

Calculated values: C, 42.85; H, 3.84; N, 12.06; S, 15.78; Na, 2.83 (%)

Experimental value: C, 42.69; Η, 3.49; Ν, 12.24; S, 15.79; Na, 2.95 (%)

Example 96

[Chem 141]

[Chemical 1 4 2

(1) 36 → 103

Compound 103 (4.47 g, yield 97%) was converted from compound 36 (5.21 g) in the same manner as in Example 74 (1). Obtained.

H-NMR (d -DMSO) δ 7.76 (2H, dd, J = 1.5, 4.8 Hz), 8.46 (1H, s), 8.57 (2H, d, J

= 1.5, 4.8 Hz).

(2) 103 → 104

Compound 104 (3.49 g, yield 94%) was obtained from compound 103 (2.06 g) in the same manner as in Example 84, (1).

'H-NMR (CDC1) δ 7.18 (1H, s), 7.25-7.47 (10H, m), 7.94 (2H, dd, J = 1.8, 4.5

Hz), 8.37 (1H, s), 8.75 (2H, dd, J = 1.8, 4.5 Hz).

(3) 101 + 104 → 105

Compound 105 (329 mg, yield 40%) was obtained in the same manner as in Example 79, (3), using Compound 101 (860 mg) and Compound 104 (372 mg).

'H-NMR (D O) δ: 3.49 and 3.57 (2H, ABq, J = 17.1 Hz), 5.17 (1H, d, J = 4.8 Hz),

5.20 (2H, s), 5.28 (2H, d, J = 6.9 Hz), 5.72 (1H, d, J = 4.8 Hz), 6.02 (1H, dt, J = 6.9, 15.6 Hz), 6.87 (1H , s), 7.00 (1H, d, J = 15.6 Hz), 7.19 (1H, dd, J = 1.2, 5.1 Hz), 7.40 (1H, dd, J = 3.0, 5.1 Hz), 7.46 (1H, m) 8.37 (1H, s), 8.45 (2H, d, J = 6.9 Hz), 8.82 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3399, 1763, 1634, 1599, 1531, 1466, 1437, 1357, 1294, 1199, 1155, 1060, 1011.

MS (ESI): 710 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.3 H O-0.2 NaHCO

Calculated values: C, 42.46; H, 3.76; N, 11.87; S, 15.53; Na, 3.34 (%)

Experimental value: C, 42.42; H, 3.72; N, 11.68; S, 15.60; Na, 3.34 (%)

Example 97

[Chemical 142]

[Chemical 1 4 2

Compound 106 (230 mg, 23% yield) was obtained in the same manner as in Example 79, (3), using Compound 81 (1.05 g) and Compound 104 (440 mg).

'H-NMR (D O) δ: 3.51 and 3.59 (2H, ABq, J = 17.4 Hz), 5.18 (1H, d, J = 4.8 Hz),

2

5.27 (2H, d, J = 6.9 Hz), 5.34 (2H, s), 5.72 (1H, d, J = 4.8 Hz), 6.02 (1H, dt, J = 6.9, 15.6 Hz), 6.89 (1H , s), 6.98-7.04 (2H, m), 7.18 (2H, d, J = 3.0), 7.43 (1H, dd, J = 1.2, 5.1 Hz), 8.38 (1H, s), 8.44 (2H, d , J = 6.9 Hz), 8.81 (2H, d, J = 6.9 Hz). IR (KBr) cm " ¹ : 3408, 1763, 1633, 1602, 1531, 1467, 1436, 1358, 1295, 1200, 1156, 1061 , 1010.

MS (ESI): 710 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N NaO S-5.2 H O-0.1 NaHCO

29 22 7 7 4 2 3

Calculated values: C, 41.91; H, 3.93; N, 11.76; S, 15.38; Na, 3.03 (%)

Experimental value: C41.86; H, 3.70; N, 11.94; S, 15.38; Na, 3.12 (%)

Example 99

[Chemical 144]

(1) 110 → 111

NaB H4 (92% w / w, 1.41 g, 34.2 mmol) was added to an ethanol (40 mL) solution of the aldehyde 110 (3.87 g, 34.2 mmol) with stirring under ice cooling, and the temperature was raised to room temperature. After stirring at the same temperature for 1 hour, water (50 mL) was added and the mixture was extracted four times with Kuroguchi Form. Compound 111 (2.96 g, 99% yield) was obtained as an oily substance.

'H-NMR (CDC1) δ: 4.98 (2Η, s), 7.34 (1H, d, J = 3.3 Hz), 7.76 (1H, d, J = 3.3 Hz)

)

(2) 111 → 112

Compound 112 (6.98 g, yield 79%) was obtained from compound lll (3.90 g) in the same manner as in Example 91, (1).

'H-NMR (CDC1) δ 5.49 (2H, s), 7.49 (1H, d, J = 3.3 Hz), 7.73-7.83 (5H, m).

(3) 112 → 113

Compound 113 (5.24 g, yield 99%) was obtained from Compound 112 (3.12 g) and Compound 78 (3.43 g) in the same manner as in Example 91, (2). ^J H-NMR (CDC1) δ 1.53 (9H, s), 5.62 (2H, s), 7.36 (1H, d, J = 3.3 Hz), 7.40 (1H,

Three

s), 7.76 (1H, d, J = 3.3 Hz).

[0123] (4) 113 → 114

Compound 114 (7.94 g, yield 78%) was obtained from compound 113 (5.24 g) and compound 80 (5.69 g) in the same manner as in Example 91, (3).

'H-NMR (CDC1) δ 1.52 (9H, s), 3.50 and 3.58 (2H, ABq, J = 17.6 Hz), 4.00 (2H,

Three

d, J = 6.9 Hz), 5.13 (1H, d, J = 4.9 Hz), 5.64 and 5.71 (2H, ABq, J = 15.3 Hz), 5.9 2-6.02 (2H, m), 6.88 (1H, d, J = 15.6 Hz), 7.01 (1H, s), 7.25-7.46 (12H, m), 7.6 9 (1H, d, J = 3.4 Hz), 9.59 (1H, d, J = 8.1 Hz).

[0124] (5) 114 + 96 → 115

Compound 115 (408 mg, yield 50%) was obtained in the same manner as in Example 79, (3), using Compound 114 (857 mg) and Compound 96 (372 mg).

'H-NMR (D O) δ: 3.57 (2H, brs), 5.20 (1H, d, J = 4.8 Hz), 5.25 (2H, d, J = 6.6 Hz

2

), 5.47 (2H, s), 5.76 (1H, d, J = 4.8 Hz), 6.06 (1H, dt, J = 6.6, 15.6 Hz), 6.95 (1H, s), 6.98 (1H, d, J = 15.6 Hz), 7.57 (1H, d, J = 3.3 Hz), 7.75 (1H, d, J = 3.3 Hz), 8.4

2 (2H, d, J = 7.2 Hz), 8.59 (1H, s), 8.77 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3408, 1764, 1635, 1533, 1488, 1458, 1366, 1293, 1200, 1153, 1110,

1064, 1023, 1001.

MS (ESI): 711 ⁺ (M -Na + 2H) ⁺

Elemental analysis C H N NaO S-5.0 H O

28 21 8 7 4 2

Calculated value: C, 40.87; Η, 3.80; Ν, 13.62; S, 15.59; Na, 2.79 (%)

Experimental value: C40.79; H, 3.64; N, 13.71; S, 15.59; Na, 2.94 (%)

Example 101

[0125] [Chemical 146]

(1) Compound 118 (127 mg, 18% yield) was obtained in the same manner as in Example 79, (3), using Compound 117 (721 mg) and Compound 57 (169 mg).

'H-NMR (D O) δ: 1.05 (3H, t, J = 7.5 Hz), 2.23 (2H, m), 3.64 (2H, s), 5.26 (1H, d

, J = 4.8 Hz), 5.34 (2H, d, J = 7.2 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.09 (1H, dt, J = 7.2, 15.9 Hz), 6.35 (1H , d, J = 8.1 Hz), 6.48 (1H, s), 6.96 (1H, d, J = 15.9 Hz), 8.37 (2H, d, J = 6.9 Hz), 8.91 (2H, d, J = 6.9 Hz) ).

IR (KBr) cm " ¹ : 3418, 3056, 2967, 2160, 1761, 1607, 1562, 1528, 1456, 1368, 1145, 1063, 1003.

MS (ESI): 588 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-3.7 H O-0.4 NaHCO

Calculated values: C, 44.35; H, 4.37; N, 14.25; S, 9.32; Na, 4.68 (%)

Experimental value: C, 44.35; Η, 4.16; Ν, 14.08; S, 9.53; Na, 5.01 (%)

Example 103

[Chemical 148]

(1) 125 → 126

Cyanamide (126 mg, 3.0 mmol) was added to a methanol (3.0 mL) solution of compound 125 (589 mg, 3.0 mmol), and the mixture was ice-cooled, and IN NaOMe (3.0 mL) was added dropwise. After raising the temperature to room temperature, the mixture was stirred at the same temperature for 2 hours, and methanol was distilled off under reduced pressure. Water (6 mL) was added and ice-cooled, and the pH was adjusted to around 3.5 using 5N hydrochloric acid and 1N hydrochloric acid. The deposited precipitate was collected by filtration and dried under reduced pressure using phosphorus pentoxide to obtain Compound 126 (535 mg, yield 93%) as a pale yellow solid.

H-NMR (d-DMSO) δ 7.76 (1H, s), 8.08 (1H, s), 9.74 (1H, s).

(2) 46 → 127

Compound 127 (195 mg, 33% yield) was obtained in the same manner as in Example 86, (4), using Compound 46 (803 mg) and Compound 126 (192 mg).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 3.66 (2H, s), 4.25 (2H, q, J = 6.9 Hz),

5.11 (2H, d, J = 6.6 Hz), 5.40 (1H, d, J = 4.5 Hz), 5.81 (1H, d, J = 4.5 Hz), 6.09 (1 H, dt, J = 6.6, 15.9 Hz) , 6.88 (1H, d, J = 15.9 Hz), 6.97 (1H, s), 7.72 (1H, d, J = 1.5 Hz), 8.12 (1H, s), 9.69 (1H, d, J = 1.5 Hz).

IR (KBr) cm— ¹ : 3426, 2980, 2167, 1763, 1606, 1576, 1534, 1369, 1311, 1237, 1163,

1111, 1092, 1036.

MS (ESI): 628+ (M + H) +

Elemental analysis C H N NaO S -4.8 H O

Calculated values: C, 39.16; H, 4.05; N, 17.12; S, 13.07; Na, 3.12 (%)

Experimental value: C39.08; H, 3.55; N, 17.21; S, 12.88; Na, 3.30 (%)

Example 104 [Chemical 149]

(1) 128 → 130

A solution of compound 128 (19.9 g, 133 mmol) in DMF (40 mL) was ice-cooled, and sodium hydride (60% w / w, 5.3 g, 132 mmol) was added. On the other hand, a DMF (30 mL) solution of Compound 129 (6.2 g, 44.2 mmol) was ice-cooled, sodium hydride (60% w / w, 1.77 g, 44.2 mmol) was added, and the mixture was stirred with ice-cooling for 30 minutes. Later added to the previous solution. The reaction solution was heated to 130 ° C and stirred for 8 hours. After cooling to room temperature, DMF was distilled off under reduced pressure, and water was collected and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain compound 130 (1.34 g, yield 14%) as pale yellow crystals. 'H-NMR (CDC1) δ 1.44 (3H, t, J = 7.2 Hz), 4.46 (2H, q, J = 7.2 Hz), 7.05 (1H, d

, J = 2.7 Hz), 7.76 (2H, dd, J = 1.5, 4.5 Hz), 8.72 (2H, d, J = 2.7 Hz), 8.72 (1H, d, J = 5.4 Hz).

(2) 130 → 131

Compound 131 (1.36 g, yield 99%) was obtained from compound 130 (1.34 g) in the same manner as in Example 74, (1).

H-NMR (d-DMSO) δ 7.03 (1H, d, J = 2.7 Hz), 7.94 (2H, dd, J = 1.8, 4.8 Hz), 8.7

6 (2H, dd, J = 1.8, 4.8 Hz), 8.81 (1H, d, J = 2.7 Hz).

(3) 131 → 132

In the same manner as in Example 74, (2), compound 131 (1.36 g) to compound 132 (1.50 g, yield) Rate 98%).

H-NMR (d-DMSO) δ 7.17 (1Η, d, J = 2.7 Hz), 8.05 (2H, dd, J = 1.5, 4.8 Hz), 8.7

6

8 (2H, dd, J = 1.8, 4.8 Hz), 8.90 (1H, d, J = 2.7 Hz).

(4) 46 → 133

Compound 133 (215 mg, 27% yield) was obtained in the same manner as in Example 86, (4), using Compound 46 (803 mg) and Compound 132 (213 mg).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 3.67 (2H, s), 4.23 (2H, q, J = 6.9 Hz),

2

5.26-5.28 (3H, m), 5.81 (1H, d, J = 4.5 Hz), 6.07-6.17 (1H, m), 6.95-6.99 (3H, m), 8.31 (2H, d, J = 7.2 Hz) , 8.49 (1H, d, J = 2.7 Hz), 8.85 (2H, d, J = 7.2 Hz). IR (KBr) cm— ¹ : 3420, 2981, 2162, 1764, 1638, 1599, 1536, 1475, 1446 , 1384, 1332, 1203, 1158, 1036.

MS (ESI): 649 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N NaO S-6.5 H O

27 23 10 6 3 2

Calculated value: C, 41.17; Η, 4.61; Ν, 17.78; S, 8.14; Na, 2.92 (%)

Experimental value: C, 41.04; Η, 4.09; Ν, 17.77; S, 8.31; Na, 3.06 (%)

Example 105

[Chemical 150]

(1) 134 → 137

A solution of compound 134 (1.46 g, 10 mmol) in THF (50 mL) -70. After cooling to C, n_butyl (1.58 M hexane solution, 6.96 mL, 11 mmol) was added dropwise. After stirring at the same temperature for 1 hour, ethyl cyanoformate (0.87 mL, 11 mmol) was added dropwise, and the mixture was stirred at -70 ° C for 1 hour and then warmed to room temperature. . Saturated aqueous ammonium chloride solution (20 mL) was added to the mixture, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and dried under reduced pressure to obtain a mixture (1.94 g) of Compound 135 and Compound 134. This residue was used as such for the next reaction.

This mixture was dissolved in methanol (20 mL), and 2N NaOH aqueous solution (9.5 mL) was added under ice-cooling and stirred for 1.5 hours. 5N hydrochloric acid was added to neutralize. Methanol was distilled off under reduced pressure, and the pH was adjusted to around 3.5 with 1N hydrochloric acid under ice cooling. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain a mixture (1.25 g) of Compound 136 and Compound 134.

Carbonyldiimidazole (1.59 g, 9.86 mmol) was added to a DMF (15 mL) suspension of this mixture, and the mixture was stirred overnight. Sodium hydride (60% w / w, 526 mg, 13.1 mmol) was added to a DMF (10 mL) solution of cyanamide (690 mg, 16.4 mmol) under ice-cooling and stirring, and the mixture was stirred at the same temperature for 30 min. This solution was added to the previous reaction solution under ice cooling, and the mixture was warmed to room temperature and stirred for 2 hours. DMF was distilled off under reduced pressure, water (20 mL) was added, and the pH was adjusted to around 3.5 using 1N hydrochloric acid. The deposited precipitate was collected by filtration and dried under reduced pressure using phosphorous pentoxide to obtain a compound 137 (1.19 g, yield 56% from 134) as an ocher powder.

H-NMR (d-DMSO) δ 8.04 (2Η, d, J = 6.6 Hz), 8.27 (1H, s), 8.83 (2H, d, J = 6.6

Hz).

(2) 137 → 138

Compound 138 (246 mg, yield 31%) was obtained in the same manner as in Example 86, (4), using Compound 46 (803 mg) and Compound 137 (214 mg).

H-NMR (D O) δ: 1.28 (3H, t, J = 7.2 Hz), 3.66 (2H, s), 4.22 (1H, d, J = 7.2 Hz),

5.26 (1H, d, J = 4.8 Hz), 5.29 (2H, d, J = 6.9 Hz), 5.79 (1H, d, J = 4.8 Hz), 6.10 (1 H, dt, J = 6.9, 15.6 Hz) , 6.92 (1H, s), 6.98 (1H, d, J = 15.6 Hz), 8.17 (1H, s), 8.29 (2H, d, J = 6.9 Hz), 8.85 (2H, d, J = 6.9 Hz) .

IR (KBr) cm— ¹ : 3424, 2981, 2169, 1764, 1637, 1607, 1531, 1496, 1463, 1382, 1334,

1291, 1201, 1146, 1035,.

MS (ESI): 650+ (M-Na + 2H) +

Elemental analysis CHN NaO S-6.1 HO Calculated value: C, 41.49; Η, 4.41; Ν, 16.13; S, 8.21; Na, 2.94 (%)

Experimental value: C, 41.38; Η, 4.86; Ν, 16.35; S, 8.21; Na, 3.08 (%)

Example 107

[0130] [Chemical 152]

(1) 144 → 146

Compound 146 (172 mg, 19% yield) was obtained in the same manner as in Example 79, (3), using Compound 144 (986 mg) and Compound 104 (372 mg).

'H-NMR (D 2 O) δ: 3.59 and 3.66 (2H, ABq, J = 17.7 Hz), 5.10 (2H, s), 5.21 (1H, d,

2

J = 4.8 Hz), 5.31 (2H, d, J = 6.6 Hz), 5.78 (1H, d, J = 4.8 Hz), 5.82 (1H, s), 6.13 (1H, dt, J = 6.6, 15.9 Hz) , 6.97 (1H, d, J = 15.9 Hz), 7.01 (1H, s), 8.39 (1H, s), 8.52 (2H, d, J = 6.9 Hz), 8.89 (2H, d, J = 6.9 Hz) .

IR (KBr) cm— ¹ : 3419, 1762, 1631, 1522, 1468, 1359, 1295, 1200, 1156, 1062, 1011. MS (ESI): 711 ⁺ (M + H) ⁺

Elemental analysis c H N Na O S-5.8 H O-0.3 NaHCO

28 20 8 2 9 3 2 3

Calculated value: C, 38.43; Η, 3.64; Ν, 12.67; S, 10.88; Na, 5.98 (%)

Experimental value: C, 38.61; Η, 3 · 51; Ν, 12.85; S, 10.58; Na, 6.19 (%)

Example 108

[0131] [Chemical 153]

147

(1) 144 → 147 Compound 147 (394 mg, yield 43%) was obtained in the same manner as in Example 79, (3), using Compound 144 (986 mg) and Compound 27 (226 mg).

'H-NMR (D O) δ: 3.59 and 3.66 (2H, ABq, J = 17.4 Hz), 5.09 (2H, s), 5.20 (1H, d,

2

J = 4.8 Hz), 5.47 (2H, d, J = 6.6 Hz), 5.78 (1H, d, J = 4.8 Hz), 5.81 (1H, s), 6.18 (1H, dt, J = 6.6, 15.9 Hz) , 6.98-7.03 (2H, m), 8.67 (1H, d, J = 6.6 Hz), 8.72 (1H, d, J = 6.6 Hz), 9.72 (1H, s).

IR (KBr) cm— ¹ : 3419, 2182, 1763, 1610, 1510, 1363, 1120, 1028, 1001.

MS (ESI): 709 ⁺ (M + H) +

Elemental analysis C H N Na O S-9.0 H O-0.1 NaHCO

27 18 10 2 8 3 2 3

Calculated values: C, 35.26; H, 3.94; N, 15.17; S, 10.42; Na, 5.23 (%)

Experimental values: C, 34.99; H, 3.13; N, 15.08; S, 10.17; Na, 5.38 (%)

Example 109

[Chemical 154]

(1) 148 → 149

Diphenyldiazomethane (2.33 g, 12 mmol) was added to a THF (20 mL) solution of compound 148 (2.07 g, 10 mmol), and the mixture was stirred at room temperature for 30 minutes. Diphenyl diazomethane (388 mg) was added, and the mixture was further stirred for 1 hr. THF was distilled off under reduced pressure, hexane was added, and the precipitate was collected by filtration and dried under reduced pressure to obtain Compound 149 (790 mg, yield 21%). The filtrate was further concentrated, and the residue was purified by silica gel column chromatography to obtain compound 149 (total 2.95 g, yield 79%).

'H-NMR (CDC1) δ: 7.03 (1H, s), 7.09 (1H, d, J = 3.9 Hz), 7.29-7.41 (10H, m),

Three

7.62 (1H, d, J = 3.9 Hz).

(2) 149 → 150 To a solution of compound 149 (1.87 g, 5.0 mmol) in toluene (50 mL), 4_aminoviridine (565 mg, 6.0 mmol), BINAP (311 mg, 0.5 mmol), cesium carbonate (2.28 g, 7.0 mmol) Was added. After deaeration and substitution with nitrogen, palladium acetate (IIX112 mg, 0.5 mmol) was added and the mixture was stirred at 110 ° C for 15 hours. After cooling to room temperature, the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography. Compound 150 (291 mg, yield 15%) was given.

'H-NMR (CDC1) δ 7.03-7.46 (15H, m), 7.62 (1H, d, J = 4.2 Hz).

Three

(3) 150 → 151

Compound 151 (350 mg, 62% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (605 mg) and Compound 150 (291 mg).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 3.63 (2H, s), 4.25 (2H, q, J = 6.9 Hz),

2

4.91 (2H, d, J = 6.3 Hz), 5.24 (1H, d, J = 4.8 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.03 (1 H, dt, J = 6.9, 15.9 Hz) , 6.79 (1H, d, J = 15.9 Hz), 6.97 (1H, m), 7.18 (2H, d, J = 7.2 Hz), 7.45 (1H, d, J = 3.9 Hz), 8.15 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3409, 2978, 1763, 1645, 1602, 1528, 1461, 1361, 1209, 1167, 1034"

MS (ESI): 656+ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.1 H O

27 24 7 7 3 2

Calculated values: C, 43.15; H, 4.32; N, 13.05; S, 12.80; Na, 3.06 (%)

Experimental value: C, 43.16; H, 4.25; N, 13.11; S, 12.71; Na, 3.21 (%)

Example 110

[Chemical 155]

(1) 152 → 153 Bromopyruvate ethyl ester (90% w / w, 2.92 mL, 16.5 mmol) was added to a solution of thiourea 152 (2.30 g, 15 mmol) in ethanol (30 mL) and refluxed for 1.5 hours. Ethanol was distilled off under reduced pressure, and the resulting precipitate was collected by filtration and collected by filtration and dried under reduced pressure to obtain Compound 153 (3.83 g, yield 77%).

H-NMR (d -DMSO) δ 1.30 (3Η, t, J = 7.2 Hz), 4.32 (2H, q, J = 7.2 Hz), 8.05 (2H

, Brs), 8.18 (1H, s), 8.66 (2H, d, J = 7.2 Hz), 12.1 (1H, brs).

(2) 153 → 154

In the same manner as in Example 74, (1), compound 153 (3.83 g) to compound 154 (2.58 g, yield 100)

%).

H-NMR (d-DMSO) δ 7.62 (2Η, dd, J = 1.5, 4.8 Hz), 8.40 (2H, dd, J = 1.5, 4.8 H z).

(3) 154 → 155

Carbonyldiimidazole (973 mg, 6.0 mmol) was added to a DMF (10 mL) solution of compound 154 (1.11 g, 5.0 mmol), and the mixture was stirred at room temperature for 2 hours. Carbonyldiimidazole (639 mg) was added, and the mixture was further stirred for 1 hr. t-Butanol (2.4 mL) and KOBu (56 mg) were added, and the mixture was stirred at room temperature for 1 hour, and further ΚΟΒι (560 mg) was added. After stirring for 30 minutes, saturated ammonium chloride was extracted with ketyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the resulting precipitate was collected by filtration using hexane and ethyl acetate. After drying under reduced pressure, Compound 155 (258 mg, yield 19%) was obtained.

H-NMR (CDC1) δ 1.60 (9Η, s), 7.49 (2H, d, J = 6.6 Hz), 7.60 (1H, s), 8.42 (1H, d, J = 6.6 Hz).

(4) 46 → 156

Compound 156 (101 mg, 13% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (746 mg) and Compound 155 (258 mg).

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9 Hz), 3.65 (2H, brs), 4.24 (2H, q, J = 6.9 Hz)

, 5.02 (2H, d, J = 6.9 Hz), 5.25 (1H, d, J = 4.5 Hz), 5.81 (1H, d, J = 4.5 Hz), 6.07 (1H, dt, J = 6.9, 15.9 Hz) , 6.84 (1H, d, J = 15.9 Hz), 6.97 (1H, s), 7.70 (1H, s), 7.97 (2H, brs), 8.37 (2H, d, J = 7.8 Hz). IR (KBr) cm: 3417, 2979, 1763, 1642, 1604, 1517, 1440, 1385, 1281, 1177, 1118 1037,.

MS (ESI): 657 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N NaO S-7.0 H O

Calculated value: C, 38.80; Η, 4.63; Ν, 13.92; S, 11.95; Na, 2.86 (%)

Experimental value: C38.68; Η, 3.94; Ν, 13.85; S, 12.03; Na, 2.95 (%)

Example 111

[Chemical 156]

, NH ₂ OH

HO H

NH ₂ 0-, f N

157 158 159 160

(1) 157 → 159

Diaminopyridine 157 (20.23 g, 185 mmol) and glycolic acid (31 g, 407 mmol) were mixed and stirred at 150 ° C. for 64 hours. After cooling to room temperature, the aqueous layer washed with a mixture of sodium bicarbonate and CHC1-MeOH-THF (10: l: 2) was concentrated to dryness under reduced pressure. Was collected by filtration and dried under reduced pressure to obtain Compound 159 (19.2 g, yield 70%).

H-NMR (d-DMSO) δ 4.71 (2Η, s), 7.17 (1H, dd, J = 4.2, 7.2 Hz), 7.88 (1H, dd, J

= 1.5, 7.2 Hz), 8.27 (1H, dd, J = 1.5, 4.2 Hz).

(2) 159 → 160

A solution of potassium permanganate (9 g) in water (190 mL) was boiled, and a solution of compound 159 (5 g) and sodium carbonate (3.8 g) in boiling water (120 mL) was added to this solution. After refluxing for 5 hours, the mixture was cooled to 60 ° C and filtered through celite. Concentrated hydrochloric acid is added to the filtrate to pH 2. The precipitate is collected by filtration and dried under reduced pressure. Drying gave compound 160 (3.49 g, yield 64%).

H-NMR (d-DMSO) δ 7.37 (1H, dd, J = 4.8, 8.1 Hz), 8.10 (1H, d, J = 8.1 Hz), 8.5

6

2 (1H, d, J = 4.8 Hz).

(3) 160 → 161

In the same manner as in (1) of Example 74, Compound 160 (1.63 g) strength Compound 161 (2.03 g, yield 100%) was obtained.

H-NMR (d-DMSO) δ 7.57 (1H, dd, J = 4.8, 8.1 Hz), 8.17 (1H, d, J = 8.1 Hz), 8.6

6

4 (1H, d, J = 4.8 Hz).

(4) 161 → 162

1.0 M NaOMe / MeOH (11 mL) was added dropwise to a methanol (100 mL) suspension of compound 161 (2.18 g, 11.6 mmol) at room temperature, and methanol was concentrated under reduced pressure. Compound 162 (2.2 g, yield 95%) was obtained. H-NMR (d-DMSO) δ 7.21 (1H, dd, J = 4.5, 7.8 Hz), 7.89 (1H, brs Hz), 8.35 (1H

6

, d, J = 4.5Hz).

(5) 162 → 163

Compound 163 (229 mg, yield 10%) was obtained in the same manner as in Example 79, (3), using Compound 46 (2.28 g) and Compound 162 (627 mg).

'H-NMR (d-DMSO) δ: 1.21 (3Η, t, J = 6.9), 3.37 and 3.48 (2H, ABq, J = 16.8 Hz)

6

, 4.07 (2H, q, J = 6.9 Hz), 5.01 (1H, d, J = 5.1 Hz), 5.28 (1H, dd, J = 6.6, 14.7 Hz), 5.49-5.61 (2H, m), 5.85 ( 1H, m), 6.70 (1H, s), 7.25-7.35 (4H, m), 8.29 (1H, d, J = 7.2 Hz), 9.51 (1H, d, J = 8.5 Hz) ,.

IR (KBr) cm— ¹ : 3418, 2981, 2341, 2260, 2168, 1762, 1585, 1532, 1482, 1440, 1370,

1300, 1201, 1162, 1121, 1090, 1036.

MS (ESI): 667+ (M + H) +

Elemental analysis C H N Na O S-6.7 H O

25 20 10 2 6 2 2

Calculated values: C, 38.14; H, 4.28; N, 17.79; S, 8.15; Na, 5.84 (%)

Experimental value: C38.10; H, 3.94; N, 17.75; S, 8.34; Na, 5.98 (%)

Example 112

[Chemical 157] -OH 0 'OO Na ⁺

EtO, one

OEt ^ — C0 ₂ Et

NH ₂ EtO "

OEt, N

164a 173 164 165

(1) 164a → 164

Compound 164a (3.0 g, 27.2 mmol) and compound 173 (24 g, 109 mmol) were mixed and stirred at 100 ° C for 30 hours. After cooling to room temperature, ethyl acetate was added and insolubles were removed by filtration. The filtrate was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 164 (748 mg, yield 14%).

'H-NMR (CDC1) δ 1.52 (3Η, t, J = 6.9 Hz), 4.59 (2H, d, J = 6.9 Hz), 7.66 (1H, dd

, J = 1.2, 5.7 Hz), 8.74 (1H, d, J = 5.7 Hz), 9.26 (1H, d, J = 1.2 Hz).

(2) 164 → 165

Compound 165 (385 mg) was obtained from compound 164 (430 mg) in the same manner as in Example 75, (3). H-NMR (d-DMSO) δ 7.85 (1H, dd, J = 1.2, 5.7), 8.60 (1H, d, J = 5.7 Hz), 9.09 (

(1H, d, J = 1.2 Hz).

(3) 165 → 166

Compound 166 (89 mg, 26% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (1.35 g) and Compound 165 (385 mg).

'H-NMR (d-DMSO) δ: 1.22 (3Η, t, J = 6.9 Hz), 3.42 and 3.49 (2H, ABq, J = 17.4

Hz), 4.09 (2H, q, J = 6.9 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.40 (2H, d, J = 6.9 Hz), 5. 60 (1H, dd, J = 5.1 , 8.4 Hz), 5.91 (1H, m), 6.71 (1H, s), 7.21 (2H, brs), 7.30 (1H, d, J = 15.9 Hz), 8.58 (1H, d, J = 6.9 Hz), 9.05 (1H, dd, J = 1.2, 6.9 Hz), 9.52 (1H, d, J = 8.1 Hz), 9.88 (1H, brs).

IR (KBr) cm— ¹ : 3426, 2174, 1762, 1615, 1532, 1474, 1442, 1369, 1286, 1255, 1187, 1151, 1118, 1092, 1036, 1002.

MS (ESI): 624 ⁺ (M-Na + 2H) ⁺ Elemental analysis CHN NaO S 5.8 HO

:

Calculated value: C, 40.03; H, 4.25 N, 16.81; S, 8.55 Na, 3.06 (%)

Experimental value: C, 39.90 H, 3.86 N, 16.61; S, 8.26 Na, 3.00 (%)

Example 113

[0136] [Chemical 158]

(1) 85 → 167

Compound 167 (281 mg, 14% yield) was obtained in the same manner as in Example 79, (3), using Compound 46 (599 mg) and Compound 85 (281 mg).

'H-NMR (d-DMSO) δ: 1.22 (3Η, t, J = 6.9 Hz), 3.42 and 3.50 (2H, ABq, J = 16.8

Hz), 4.09 (2H, q, J = 6.9), 5.02-5.05 (IH, m), 5.40 (2H, d, J = 6.3 Hz), 5.57-5.6 2 (IH, m), 5.87-5.96 (1H , M), 6.72 (IH, s), 7.21 (2H, brs), 7.32 (IH, d, J = 15.9 Hz), 8.76-8.82 (2H, m), 9.53 (IH, d, J = 8.1 Hz) , 9.88 (IH, s).

IR (KBr) cm— ¹ : 3418, 2158, 1763, 1638, 1533, 1506, 1363, 1303, 1200, 1166, 1119, 1036, 1002.

MS (ESI): 616+ (M-Na + 2H) +

Elemental analysis C H N NaO S -4.7 H O

Calculated values: C, 39.91; H, 4.10; N, 13.57; S, 13.32; Na, 3.18 (%)

Experimental value: C39.87; H, 3.99; N, 13.69; S, 13.13; Na, 3.29 (%)

Example 114

[0137] [Chemical 159]

(1) 168 → 169

In the same manner as in Example 74, (1), Gyre, Compound 168 (942 mg, 5.77 mmol), et al. Compound 16 9 (1.02 g, yield 95%) was obtained.

H-NMR (d-DMSO) δ 7.90 (1H, d, J = 6.3 Hz), 8.51 (1H, d, J = 6.3 Hz), 9.34 (1H

, Brs).

(2) 169 → 170

IN NaOMe / MeOH (5.5 mL) was added to a suspension of compound 169 (1.02 g, 5.46 mmol) in methanol (50 mL), concentrated to dryness, isopropanol and ethanol were added, and the insoluble precipitate was collected by filtration and dried under reduced pressure. . Compound 170 (1.08 g, yield 87%) was obtained.

H-NMR (d-DMSO) δ: 7.39 (1H, d, J = 5.4 Hz), 8.08 (1H, d, J = 5.4 Hz), 8.79 (1

H, brs).

(3) 170 → 171

Compound 171 (70 mg, yield 4%) was obtained in the same manner as in Example 79, (3), using Compound 46 (2.21 mg) and Compound 170 (679 mg).

'H-NMR (d-DMSO) δ: 1.21 (3Η, t, J = 7.2 Hz), 3.42 and 3.49 (2H, ABq, J = 17.4

Hz), 4.08 (2H, q, J = 7.2 Hz), 5.03 (1H, d, J = 5.1 Hz), 5.23 (2H, d, J = 6.3 Hz), 5.59 (1H, dd, J = 4.8 , 8.4 Hz), 5.89 (1H, m), 6.71 (1H, s), 7.20-7.25 (3H, m), 7.86 (1H, d, J = 6.6 Hz), 8.27 (1H, d, J = 6.6 Hz ), 9.17 (1H, s), 9.52 (1H, d, J = 8.1 Hz). IR (KBr) cm— ¹ : 3433, 2170, 1761, 1617, 1532, 1473, 1364, 1313, 1243, 1201, 1160 , 1120, 1035.

MS (ESI): 645+ (M + H) +

Elemental analysis Q.6 (CHN NaO S)-0.4 (CHN NaO S)-6.0 HO Calculated value: C, 39.43; H, 4.32; N, 18.39; S, 8.42; Na, 4.23 (%)

Experimental value: C, 39.34; Η, 3.94; Ν, 18.20; S, 8.48; Na, 4.53 (%)

Example 115

[Chemical 160]

(1) 172 → 174

Compound 173 (41.63 g, 189 mmol) was added to compound 172 (7.76 g, 63 mmol) and heated at 100 ° C. for 7 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and the concentrated residue was purified by silica gel column chromatography. Compound 1 74 (900 mg, yield 7%) was obtained.

'H-NMR (CDC1) δ 1.51 (3H, t, J = 6.9 Hz), 3.70 (3H, s), 4.59 (2H, q, J = 6.9 Hz),

7.15 (1H, d, J = 5.7 Hz), 8.52 (1H, d, J = 5.7 Hz), 8.85 (1H, s).

(2) 174 → 175

NaNHCN (296 mg, 4.53 mmol) was added to a solution of compound 174 (884 mg, 4.3 mmol) in methanol (8 mL), and the mixture was stirred at 50 ° C. for 14 hours. After cooling to room temperature, the precipitate was collected by filtration. The obtained solid was suspended in water and the pH was adjusted to around 2 with 6N hydrochloric acid. The deposited precipitate was collected by filtration and dried under reduced pressure to obtain Compound 175 (539 mg, yield 62%).

H-NMR (d-DMSO) δ 3.53 (3Η, s), 7.48 (1H, d, J = 5.7 Hz), 8.38 (1H, d, J = 5.7

Hz), 8.59 (1H, brs).

(3) 175 → 176

Compound 176 (370 mg, 25% yield) was obtained in the same manner as in Example 86, (4), using Compound 46 (738 mg) and Compound 175 (201 mg). NMR-NMR (d-DMSO) δ: 1.22 (3H, t, J = 6.9 Hz), 3.40 and 3.48 (2H, ABq, J = 17.1

6

Hz), 3.55 (3H, s), 4.09 (2H, q, J = 6.9), 5.04 (1H, d, J = 4.8 Hz), 5.14 (1H, d, J = 6.6 Hz), 5.58 (1H , Dd, J = 4.5, 8.1 Hz), 5.82-5.92 (1H, m), 6.71 (1H, s), 7.21 (2H, b rs), 7.25 (1H, d, J = 16.5 Hz), 7.69 (1H , D, J = 6.6 Hz), 8.34 (1H, d, J = 6.6 Hz), 8. 71 (1H, brs), 9.52 (1H, d, J = 8.1 Hz).

IR (KBr) cm— ¹ : 3417, 2983, 2151, 1763, 1683, 1626, 1570, 1517, 1485, 1394, 1291,

1185, 1143, 1084, 1034, 1002.

MS (ESI): 659+ (M + H) +

Elemental analysis C H N NaO S-4.5 H O

26 23 10 6 2 2

Calculated value: C, 42.22; H, 4.36; N, 18.94; S, 8.67; Na, 3.11 (%)

Experimental value: C42.25; H, 4.40; N, 18.98; S, 8.83; Na, 3.13 (%)

Example 116

[Chemical 161]

(1) 177 → 178

To a solution of compound 177 (2.50 g, 21.2 mmol) in methylene chloride (40 mL) was added benzyltriethyl ammonium chloride (0.13 g, 0.55 mmol) and cooled in an ice bath. To this solution were added NaOH (powder, 2.54 g) and benzenesulfuryl chloride (3.4 mL), and the mixture was stirred in an ice bath for 15 minutes, and further stirred at room temperature for 2.5 hours. Insoluble matter in the reaction solution was filtered off through celite. The filtrate was concentrated, and the precipitated crystals were collected by filtration using hexane-ethyl acetate. Vacuum drying Drying gave compound 178 (4.58 g, 84% yield).

'H-NMR (CDC1) δ 6.59 (1H, d, J = 3.9 Hz), 7.17 (1H, dd, J = 4.8, 7.8 Hz), 7.44

-7.59 (3H, m), 7.72 (1H, d, J = 3.9 Hz), 7.84 (1H, dd, J = 1.2, 7.8 Hz), 8.17-8.20 (2H, m), 8.42 (1H, dd, J = 1.2, 4.8).

(2) 178 → 179

A solution of diisopropylamine (4.9 mL) in THF (10 mL) is ice-cooled, and n_butyllithium (1.6 M hexane solution, 19.8 mL) is added dropwise over 15 minutes under a nitrogen atmosphere, followed by stirring at the same temperature for 40 minutes. did. This solution was added dropwise to a THF (35 mL) solution of compound 178 (4.55 g) that had been cooled to _70 ° C. in a nitrogen atmosphere. After stirring at _70 ° C for 1.5 hours, CO gas was generated from dry ice and blown into the reaction solution for 10 minutes. After raising the temperature to -5 ° C, 2N HC1 (9 mL) was added. THF was removed under reduced pressure, and 2N hydrochloric acid was added to the residue to adjust the pH to around 4. Ethyl acetate was added for extraction, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The crystalline solid obtained by concentration was washed by adding jetyl ether and collected by filtration to obtain Compound 179 (4.19 g, yield 79%).

'H-NMR (CDC1) δ 7.11 (1H, s), 7.25 (1H, dd, J = 4.8, 7.8 Hz), 7.51-7.64 (3H, m), 7.92 (1H, dd, J = 1.8, 7.8 Hz ), 8.40-8.43 (2H, m), 8.55 (1H, dd, J = 1.8, 4.8 H z).

(3) 179 → 180

In the same manner as in Example 74, (1), Compound 180 (1.44 g, yield 88%) was obtained from Compound 179 (1.56 g, 5.0 mmol).

H-NMR (CDC1) δ: 7.08 (1H, s), 7.21 (1H, dd, J = 4.2, 7.8 Hz), 7.45-7.57 (3H, m), 7.85 (1H, d, J = 7.8 Hz), 8.24 (2H, d, J = 7.5 Hz), 8.52 (1H, d, J = 4.2 Hz).

(4) 180 → 181

To a solution of compound 180 (1.41 g) in ethanol (14 mL) was added 2N (^ aqueous solution (10.8 mL) and stirred at room temperature for 4 hours. Cooled in an ice bath, and 2N hydrochloric acid (14 mL) was added to precipitate. The resulting precipitate was collected by filtration and dried under reduced pressure to give compound 181 (567 mg, yield 70%).

H-NMR (d-DMSO) δ 7.20 (1H, dd, J = 4.5, 7.8 Hz), 7.33 (1H, s), 8.20 (1H, dd,

J = 1.8, 7.8 Hz), 8.44 (1H, brd, J = 4.5 Hz). (5) 181 → 182

IN NaOMe / MeOH (2.4 mL) was added to a suspension of compound 1 81 (448 mg) in methanol (9 mL) and concentrated to dryness to give compound 182 (552 mg).

H-NMR (d-DMSO) δ 6.76 (1H, s), 7.03 (1H, dd, J = 4.5, 7.8 Hz), 7.94 (1H, d, J

6

= 7.8 Hz), 8.22 (1H, d, J = 4.5 Hz), 11.6 (1H, brs).

(6) 182 → 183

Compound 183 (120 mg, yield 7%) was obtained in the same manner as in Example 79, (3), using Compound 46 (1.52 g) and Compound 182 (460 mg).

'H-NMR (d-DMSO) δ: 1.21 (3Η, t, J = 6.9 Hz), 4.08 (2H, q, J = 6.9 Hz), 5.01 (1

6

H, d, J = 5.1 Hz), 5.24 (1H, dd, J = 6.3, 14.4 Hz), 5.52-5.62 (2H, m), 5.90 (1H, m

), 6.71 (1H, s), 7.02-7.07 (2H, m), 7.21 (2H, brs), 7.31 (1H, d, J = 15.6 Hz), 8.18

(1H, d, J = 6.3 Hz), 8.28 (1H, d, J = 7.8 Hz), 9.53 (1H, d, J = 7.8 Hz).

IR (KBr) cm " ¹ : 3409, 2981, 2286, 2153, 1762, 1611, 1533, 1475, 1456, 1394, 1365,

1301, 1259, 1200, 1163, 1122, 1089, 1037.

MS (ESI): 622 ⁺ (M-2Na + 3H) +

Elemental analysis C H N Na O S-4.7 H O

26 21 9 2 6 2 2

Calculated value: C, 41.62; Η, 4.08; Ν, 16.08; S, 8.55; Na, 6.13 (%)

Experimental value: C, 41.47; H, 3.75; N, 16.86; S, 8.52; Na, 6.18 (%)

Example 117

[Chemical 162]

(1) 184 → 185

Compound 185 (7.45 g, yield 84%) was obtained from compound 184 (4.06 g) in the same manner as in Example 78, (1).

H-NMR (d-DMSO) δ: 1.86 (3H, d, J = 6.3 Hz), 5.92 (2H, q, J = 5.9 Hz), 8.26 (2

6

H, d, J = 6.3 Hz), 9.06 (2H, brs).

(2) 185 → 186

Compound 185 (6.78 g) force Compound 186 (4.41 g, yield 77%) was obtained in the same manner as in Example 78, (2).

H-NMR (CDC1) δ: 1.45 (3Η, t, J = 7.2 Hz), 2.70 (3H, s), 4.49 (2H, q, J = 7.2 Hz),

Three

7.64 (2H, dd, J = 1.5, 4.8 Hz), 8.72 (2H, brs).

(3) 186 → 187a

In the same manner as in Example 78, (3), compound 186 (2.20 g) to compound 187a (703 mg, yield 30)

%).

H-NMR (d-DMSO) δ 2.61 (3Η, s), 7.69 (2H, dd, J = 1.5, 4.2 Hz), 8.64 (2H, dd, J

6

= 1.5, 4.2 Hz). (4) 187a → 187b

Dissolve compound 187a (455 mg, 1.71 mmol) in 6 ml of water and add 0.86 ml (1.71 mmol) with 2N hydrochloric acid. The precipitated crystals are collected by filtration and dried. The crystals obtained are suspended in 7 ml of methanol. A methanol solution of 1M-tetramethyldanidine was added to adjust the pH to 6.2. The reaction solution was sufficiently dried under reduced pressure to obtain compound 187b (681 mg), which was directly used in the next reaction.

(5) 187b → 189 (ATZ amine free, TFA deprotection method)

Compound 188 (1.15 g, lJlmmol) is suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (216 mg, 2.57 mmol is dissolved in 10 ml of water) is added under ice cooling, extracted with dichloromethane, and dried over magnesium sulfate. did. After the solvent was distilled off, compound 187b (663 mg, 1.71 mmol) was quickly added and dissolved in dimethyl sulfoxide (5 ml). Sodium iodide (769 mg, 5.13 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into 5% brine (80 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain a quaternary salt as an amorphous powder. This was dissolved in methylene chloride (10 ml) and anisole (1.6 ml), cooled to 0 ° C., and 5 ml of TFA was added. The mixture was stirred at 0 ° C for 1 hour and then poured into 50 ml of IPA with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with saturated aqueous NaHCO 3 solution. The solution was subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 189 as a powder. Yield 145 mg (9%) 'H-NMR (D20): 1.27 (3H, t, J = 6.8 Hz), 2.70 (3H, s), 3.73, 3.99 (2H, ABq, J = 17.3 Hz), 4.21 (2H, q, J = 6.8 Hz), 5.26 (1H, d, J = 4.8 Hz), 5.27-5.30 (2H, m), 5.79 (1H, d, J = 4.8 Hz), 6.14 (1H, dt, J = 15.5, 7.2 Hz), 6.89 (1H, s), 7.04 (1H, d, J = 15.5 Hz), 8.25 (2H, d, J = 6.8 Hz), 8.80 (2H, d, J = 6.8 Hz).

IR (KBr) cm— ¹ : 3408, 2981, 2153, 1763, 1635, 1598, 1530, 1463, 1366, 1295, 1200,

1148, 1090, 1035, 1002.

MS (ESI): 702 ⁺ (M + H) +

Elemental analysis C H N NaO S-5.2 H O

Calculated values: C, 42.28; H, 4.36; N, 15.85; S, 12.09; Na, 2.89 (%)

Experimental value: C, 42.17; H, 4.17; N, 15.85; S, 12.07; Na, 3.24 (%)

Example 118 [Chemical 163]

(1) 186 → 190

Compound 190 (661 mg, yield 100%) was obtained from compound 186 (825 mg) in the same manner as in Example 74, (1).

H-NMR (D 0-DC1) δ: 2.88 (3Η, s), 8.39 (2H, dd, J = 1.2, 5.4 Hz), 8.87 (2H, d, J

= 1.2, 5.4 Hz).

(2) 19 0 → 191

To a solution of compound 190 (230 mg) in methanol (2 mL) was added 1.0M NaOMe / MeOH (1.0 mL), and the mixture was stirred at room temperature and concentrated to dryness to give compound 191 (250 mg).

(3) 191 → 192 (ATZ amine free, TFA deprotection law)

Using compound 188 (702 mg) and compound 191 (250 mg), compound 192 (114 mg, 13% yield) was obtained in the same manner as in Example 117, (5).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9 Hz), 2.73 (3H, s), 3.45—3.53 (2H, m), 4.0

9 (2H, q, J = 6.9 Hz), 5.05 (1H, d, J = 5.1 Hz), 5.29 (2H, d, J = 6.6 Hz), 5.60 (1H, dd, J = 5.1, 8.4 Hz), 5.87 (1H, dt, J = 15.6, 6.6 Hz), 6.72 (1H, s), 7.23 (2H, s), 7.29 (1H, d, J = 15.6 Hz), 8.38 (2H, d, J = 6.9 Hz ), 8.99 (2H, d, J = 6.9 Hz), 9.55 (1H, d, J = 8.4 Hz).

IR (KBr) cm— ¹ : 3410, 2982, 1763, 1635, 1531, 1458, 1371, 1298, 1200, 1152, 1115, 1037.

MS (ESI): 700 ⁺ (M + Na) +

Elemental analysis c HN NaO S-6.6 HO-0.4 NaHCO Calculated value: C, 39.64; Η, 4.56; Ν, 11.81; S, 11.59; Na, 3.88 (%)

Experimental value: C, 39.33; Η, 4.18; Ν, 12.05; S, 11.98; Na, 4.08 (%)

Example 119

[Chemical 164]

193 194 195 196

(1) 193, 194 → 195

Bromoacetone 193 (4.25 mL, 50.5 mmol) was added to a solution of compound 194 (6.66 g, 50 mmol) in ethanol (50 mL) with ice cooling and stirring, and the mixture was heated to 50 ° C. and stirred for 1 hr. Bromoacetone (0.85 mL) was added, and the mixture was further stirred for 1 hour, and then cooled to room temperature. The reaction solution was poured into a 10% aqueous sodium carbonate solution (100 mL), ethanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. Compound 195 (8.60 g, yield 100%) was obtained by drying under reduced pressure.

H-NMR (CDC1) δ: 1.44 (3Η, t, J = 6.9 Hz), 2.55 (3H, s), 4.48 (2H, q, J = 6.9 Hz)

Three

7.19 (1H, s).

(2) 195 → 19 6

Compound 195 (8.60 g, 50 mmol) in carbon tetrachloride (80 mL) was added to iron powder (279 mg, 5.0 mmol), Bromine (6.41 mL, 125 mmol) was added and stirred at room temperature for 21 hours under a nitrogen atmosphere. The reaction solution was added to 1M Na 2 S 0 aqueous solution (500 mL) and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated Japanese brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain compound 196 (4.07 g, yield 33%).

H-NMR (CDC1) δ: 1.44 (3Η, t, J = 7.2 Hz), 2.50 (3H, s), 4.47 (2H, q, J = 7.2 Hz).

(3) 196 → 198

Compound 197 (2.29 g, 9.47 mmol) and tetrakistriphenylphosphine palladium (913 mg, 0.79 mmol) were added to a solution of compound 196 (1.97 g, 7.89 mmol) in toluene (70 mL) and stirred at 120 ° C for 24 hours. did. After cooling to room temperature, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography to obtain Compound 198 (2.17 g).

H-N MR (CDC1) δ 1.35 (3Η, t, J = 7.2 Hz), 2.58 (3H, s), 4.40 (2H, q, J = 7.2 Hz)

7.62 (2H, dd, J =), 8.71 (2H, dd, J = 1.8, 4.8 Hz).

(4) 198 → 199

Compound 199 (757 mg) was obtained from compound 198 (825 mg) in the same manner as in Example 74 (1). H-NMR (D 0-DC1) δ: 8.25 (2Η, d, J = 6.9 Hz), 8.87 (2H, d, J = 6.9 Hz).

(5) 199 → 200

To a solution of compound 199 (379 mg) in methanol (3 mL) was added 1.0M NaOMe / MeOH (1.5 mL), and the mixture was stirred at room temperature and concentrated to dryness to give compound 200 (364 mg).

(6) 200 → 201

Compound 201 (77 mg, yield 6%) was obtained in the same manner as in Example 117, (5), using Compound 188 (1.01 g) and Compound 200 (364 mg).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9 Hz), 2.62 (3H, s), 3.42-3.47 (2H, m), 4

• 09 (2H, q, J = 6.9 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.27 (2H, d, J = 6.6 Hz), 5.60 (1H, dd, J = 5.1, 8.4 Hz) , 5.86 (1H, dt, J = 15.9, 6.6 Hz), 6.71 (1H, s), 7.22 (2H, s), 7.30 (1H, d, 15.9 Hz), 8.19 (2H, d, J = 6.6 Hz), 8.95 (2H, d, J = 6.6Hz), 9.55 (1H, d, J = 8.4 Hz).

IR (KBr) cm— ¹ : 3409, 2982, 1762, 1632, 1531, 1434, 1361, 1298, 1200, 1160, 1120, 1037. MS (ESI): 656+ (M-Na + 2H) +

Elemental analysis C H N NaO S -8.0 H O-O. lNaHCO

Calculated values: C, 39.20; H, 4.87; N, 11.81; S, 11.59; Na, 3.05 (%)

Experimental value: C38.94; H, 5.55; N, 12.18; S, 11.65; Na, 3.02 (%)

Example 120

[Chemical 165]

206

(1) 202 → 203

Compound 202 (3.40 g, 15.5 mmol) in dioxane (100 mL) was added to compound 197 (3.18 g, 15.5 mmol), K Ρ〇 (16.5 g, 77.5 mmol), tetrakistriphenylphosphine palladium (896 mg, 0.775 mmol) was added, and the mixture was stirred at 100 ° C for 1 hour under a nitrogen atmosphere. The reaction mixture was added to a 5% aqueous citrate solution (200 mL) with stirring on ice, and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography to obtain Compound 203 (3.43 g, yield 96%). H-NMR (d -DMSO) δ 3.90 (3Η, s), 7.80-7.91 (4H, m), 8.03 (1H, t, J = 8.1 Hz),

8.71 (2H, dd, J = 1.8, 4.8 Hz).

(2) 203 → 204

Compound 204 (938 mg) was obtained from Compound 203 (1.39 g) in the same manner as in Example 74, (1). H-NMR (d -DMSO) δ 7.74-7.91 (4H, m), 7.84 (1H, m), 7.98 (1H, t, J = 7.8 Hz), 8.70 (2H, brs).

(3) 204 → 205

Compound 204 (938 mg) compound 205 (1.45 g, yield 88%) in the same manner as in Example 84 (1)

)

H-NMR (d -DMSO) δ 7.09 (1H, s), 7.29-7.34 (2H, m), 7.40 (1H, t, J = 7.5 Hz),

7.54 (4H, d, J = 7.5 Hz), 7.83 (2H, dd, J = 2.1, 3.6 Hz), 7.92 (1H, d, J = 12.6 Hz), 8.15 (1H, t, J = 8.1 Hz), 8.72 (2H, dd, J = 2.1, 3.6 Hz).

(4) 205 → 206

Compound 206 (724 mg, 33% yield) was obtained in the same manner as in Example 117, (5), using Compound 188 (1.88 g) and Compound 205 (1.07 g).

'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9Hz), 3.46 (2H, Abq, J = 16.5 Hz), 4.09 (2

H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.8Hz), 5.28 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 4.8, 7.8Hz), 5.88 ( 1H, dt, J = 15.9, 6.9 Hz), 6.71 (1H, s), 7.24 (2H, s), 7.30 (1H, d, 15.9 Hz), 7.61-7.83 (3H, m) 8.50 (2H, d, J = 6.9Hz), 9.03 (2H, d, J = 6.9 Hz), 9.5 4 (1H, d, J = 7.8Hz).

IR (KBr) cm " ¹ : 3399, 2982, 1763, 1601, 1530, 1463, 1376, 1306, 1200, 1157, 1110, 1036.

MS (ESI): 653+ (M-Na + 2H) +

Elemental analysis C H FN NaO S -4.7 H O-0.2NaHCO

Calculated value: C, 45.19; Η, 4.36; Ν, 10.83; S, 8.26; F, 2.45; Na, 3.55 (%)

Experimental value: C, 44.96; Η, 4.06; Ν, 10.96; S, 8.55; F, 2.27; Na, 3.77 (%)

Example 121

[Chemical 166]

209

(1) 198 → 207

In the same manner as in Example 78, (3), compound 198 (877 mg) to compound 207 (458 mg, yield 49)

%).

H-NMR (d-DMSO) δ 2.50 (3Η, s), 7.53 (2H, dd, J = 1.5, 4.5 Hz), 8.64 (2H, dd, J

6

= 1.5, 4.5 Hz).

(2) 207 → 208

A precipitate in which 2N hydrochloric acid (0.86 m, 1.71 mmol) was precipitated in a suspension of compound 207 (455 mg, 1.71 mmol) in water (6 mL) was collected by filtration. Methanol (7 mL) was added to the solid, and 1M tetramethylguanidine in methanol (1.71 mL) was added. The reaction solution was concentrated to obtain Compound 208 (681 mg).

H-NMR (d-DMSO) δ 2.51 (3Η, s), 2.89 (12H, s), 3.37 (3H, s), 7.54 (2H, brs), 7.

6

79 (2H, brs), 8.66 (2H, brs).

(3) 208 → 209

Compound 209 (145 mg, 9% yield) was obtained in the same manner as in Example 117, (5), using Compound 188 (1.15 g) and Compound 208 (663 mg).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2 Hz), 2.63 (3H, s), 3.46 (2H, ABq, J = 16.

6

5 Hz), 4.09 (2H, q, J = 7.2 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.28 (2H, d, J = 6.9 Hz), 5.60 (1H, dd, J = 5.1, 8.1 Hz), 5.86 (1H, dt, J = 16.2, 6.9 Hz), 6.72 (1H, s), 7.22 (2H, s), 7.30 (1H, d, J = 16.2 Hz), 8.25 (2H, d, J = 6.6 Hz), 8.98 (2H, d, J = 6.6 Hz), 9.54 (1H, d, J = 8.1 Hz).

IR (KBr) cm " ¹ : 3425, 2982, 2163, 1763, 1632, 1530, 1442, 1358, 1200, 1160, 1090, 1036, 1001.

MS (ESI): 680+ (M-Na + 2H) +

Elemental analysis C H N NaO S-6.0 H O-1.0 NaHCO

28 24 9 6 3 2 3

Calculated values: C, 38.97; H, 4.17; N, 14.10; S, 10.76; Na, 5.15 (%)

Experimental value: C, 38.87; H, 3.82; N, 14.11; S, 10.92; Na, 4.94 (%)

Example 122

[Chemical 167]

(1) 3 → 4

Compound 3 (2.17 g, 10.0 mmol) was suspended in 28% aqueous ammonia (25 ml), heated to 60 ° C., and stirred for 8 hours. The solid was collected by filtration to give 4 as a solid. Yield 1.41 g (75%).

'H-NMR (d-DMSO): 7.36 (1H, s), 7.50 (lH, bs), 7,73 (2H, d, J = 4.5Hz), 7.87 (lH, bs),

6

8.63 (2H, d, J = 4.5Hz).

(2) 4 → 5

Compound 4 (188 mg, 1 mmol) was suspended in 5 ml of tetrahydrofuran, trifluoroacetic anhydride (141 μL, 1 mmol) and pyridine (81 a L, 1 mmol) were added dropwise, and the mixture was stirred overnight and evaporated under reduced pressure. Purified water In addition, neutralization with sodium bicarbonate gave 5 as a solid. Yield 170mg

'H-NMR (d-DMSO): 7.70 (1H, s), 7.80 (2H, d, J = 5.4Hz), 8.71 (2H, d, J = 5.4Hz).

(3) 5 → 6

Compound 5 (492 mg, 2.89 mmol), sodium azide (207 mg, 3.18 mmol) and ammonium chloride (170 mg, 3.18 mmol) were suspended in dimethylformamide (5 ml) and stirred at 115 ° C for 1 hour and 35 minutes. . Water was added after cooling to room temperature, pH was adjusted to 3.5 with 2N HC1, and the precipitate was filtered to obtain Compound 6 as colorless crystals. Yield 553 mg (90%).

'H-NMR (d-DMSO): 7.59 (1H, s), 7.89 (2H, d, J = 4.4Hz), 8.71 (2H, d, J = 4.4Hz), l

4.4 (1H, br s).

(4) 6 → 7

Compound 2 (1.387 g, 2.06 mmol) is suspended in dichloromethane (20 ml), an aqueous sodium hydrogen carbonate solution (259 mg, 3.08 mmol dissolved in 20 ml of water) is added under ice cooling, extracted with dichloromethane, and magnesium sulfate is added. Dried. After distilling off the solvent, quickly dissolve in dimethylformamide (4 ml), mix with compound 6 (438 mg, 1.20 mmol), add dimethyl sulfoxide (3 ml) and then sodium bromide (635 mg, 6.17 mmol). And stirred at room temperature for 5 hours. The reaction solution was poured into 5% saline (60 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 7 as an amorphous powder. Yield 1.799 g (107%).

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.1Hz), 3.66, 3.91 (2H, ABq, J = 18.2Hz), 4.1

0 (2H, q, J = 7.1Hz), 5.28 (2H, d, J = 7.7Hz), 5.29 (1H, d, J = 4.8Hz), 5.93 (1H, dd, J = 8.1, 4.8Hz), 6.44 (1H, dt, J = 15.3, 7.7Hz), 6.75 (1H, s), 6.91 (1H, d, J = 15.3Hz), 6.93 (1H, s), 7.20-7.55 (m, 12H), 8 00 (1H, br s), 8.60 (2H, m), 9.02 (2H, m), 9.66 (1H, d, J = 7.7Hz).

(5) 7 → 1

Compound 7 (1.782 g, 2.19 mmol) was dissolved in methylene chloride (11 ml) and anisole (1.78 ml), cooled to 0 ° C., and 5.3 ml of trifluoroacetic anhydride was added. The mixture was stirred at 0 ° C for 55 minutes, and then poured into 80 ml of isopropanol with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with saturated aqueous NaHCO. The solution was subjected to HP-20SS column chromatography and eluted with water-acetonitrile. Concentrate the fraction containing the desired compound under reduced pressure and concentrate Was lyophilized to obtain Compound 1 as a powder. Yield 133 mg (8%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 3.43, 3.51 (2H, ABq, J = 16.8Hz), 4.0

9 (2H, q, J = 7.1 Hz), 5.05 (1H, d, J = 5.0Hz), 5.24 (2H, d, J = 6.8Hz), 5.60 (1H, dd, J = 8.0, 5.0Hz), 5.86 (1H, dt, J = 16.1, 6.8Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 16.1Hz), 7.51 (1H, s), 8.52 (2H , D, J = 7.1Hz), 8.93 (2H, d, J = 7.1Hz), 9.54 (1H, d, J = 8.0Hz), 14.2 (1H, br s).

IR (KBr) cm ^_1 : 3408, 1763, 1636, 1535, 13899, 1369, 1036, 970.

MS (ESI): 649 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5.2H O -O.lNaHCO

Calculated value: C, 40.57; H, 4.37; N, 21.75; S, 8.30; Na, 3.27 (%)

Experimental value: C40.60; H, 4.34; N, 21.50; S, 8.45; Na, 3.26 (%)

Example 123

[Chemical 168]

Ten

(1) 9 → 10

Compound 9 (4.69 g, 20.0 mmol) was suspended in 28% aqueous ammonia (71 ml), heated to 60 ° C., and stirred for 1 hour 30 minutes. The solid was collected by filtration to give 10 as a solid. Yield 3.1 g (76%).

'H-NMR (d-DMSO): 7.74 (1H, br), 8.01 (3H, dd, J = 1.8, 4.8Hz), 8.45 (1H, s), 8.75 (

(2H, dd, J = 1.8, 4.8Hz). (2) 10 → 11

Compound 10 (3.0 g, 14.6 mmol) was dissolved in pyridine (36.5 mL), and trifluoroacetic anhydride (6.7 5 g, 32.1 mmol) was added dropwise. After stirring at 60 ° C for 2 hours, toluene (35 ml) was added and pyridine was distilled off under reduced pressure. Purified water was added and extracted with black mouth form. The organic layer was washed with purified water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the crude product was washed with diisopropyl ether to obtain 11 as a brown solid. Yield 2.50 g (92%)

'H-NMR (d-DMSO): 7.96 (2H, dd, J = 1.5, 4.5Hz), 8.77 (2H, dd, J = 1.5, 4.5Hz), 9.

07 (1H, s).

(3) 11 → 12

Compound ll (562 mg, 3.00 mmol), sodium azide (215 mg, 3.30 mmol) and ammonium chloride (177 mg, 3.30 mmol) were dissolved in dimethylformamide (6.00 mL) and stirred at 110 ° C. for 2 hours. After cooling to 0 ° C, purified water (10 ml) was added, and the pH was adjusted to 3.5 with 2M hydrochloric acid. The precipitated solid was collected by filtration to obtain 12 as a pale yellow solid. Yield 669 mg (97%)

'H-NMR (d-DMSO): 8.02 (2H, dd, J = 1.8, 4.5Hz), 8.74 (1H, s), 8.81 (2H, dd, J = 1

.8, 4.5Hz), 9.07 (1H, s).

(4) 12 → 8

Compound 2 of Example 122 (1.68 g, 2.50 mmol) was suspended in dichloromethane (20 ml), and an aqueous sodium hydrogen carbonate solution (315 mg, 3.75 mmol was dissolved in 20 ml of water) was added under ice cooling, followed by extraction with dichloromethane and sulfuric acid. Dried with magnesium. After distilling off the solvent, quickly dissolve in dimethyl sulfoxide (10 ml), mix with compound 12 (576 mg, 2.50 mmol), add sodium iodide (1.10 g, 7.50 mmol), and at room temperature for 4 hours. Half stirred. The reaction mixture was poured into 5% brine (100 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder (2.48 g). Amorphous powder (2.48 g) was dissolved in dichloromethane (25.0 ml), and anisole (2.50 ml) was added and cooled to -30 ° C. 2M titanium tetrachloride (dichloromethane solution 5.24 ml) was added dropwise, and the mixture was stirred at _20 ° C for 2 hours and 15 minutes. The mixture was poured into water (120 ml) with stirring under ice-cooling, 120 ml of diisopropyl ether was added, and the deposited precipitate was filtered. The filtered product was suspended in water, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 7.5, and acetonitrile was further added to remove insolubles. HP-20SS was added to the obtained filtrate and concentrated under reduced pressure. The sample was eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 8 as a powder. Yield 103mg (4.9% in 2 steps)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.43, 3.51 (2H, ABq, J = 17.1Hz), 4.0

6

9 (2H, q, 6.9Hz), 5.06 (1H, d, J = 4.8Hz), 5.33 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.7, 4.8Hz), 5.86 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.23 (2H, s), 7.27 (1H, d, J = 1 5.9Hz), 7.44 (1H, d, J = 8.1 Hz), 8.37 (1H, s), 8.63 (2H, d, J = 6.9Hz), 9.09 (2H, d, J = 6.9Hz), 9.55 (1H, d, J = 8.7Hz).

IR (KBr) cm ^_1 : 3408, 1761, 1634, 1532

MS (ESI): 667 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5.7 H O-0.5 (NaHCO)

26 22 11 5 3 2 3

Calculated values: C, 38.24; H, 4.10; N, 18.51; S, 11.56; Na, 4.14 (%)

Experimental values: C, 38.27; H, 4.13; N, 18.36; S, 11.50; Na, 4.27 (%)

Example 124

[Chemical 169]

(1) 14 → 15

Compound 14 (562 mg, 3.00 mmol) was suspended in pyridine (6.8 ml), trifluoroacetic anhydride (0.847 ml, 6.00 mmol) was added, and the mixture was stirred at 60 ° C. for 4 hours. Toluene was added and the mixture was concentrated under reduced pressure, water and ethyl acetate were added, and extraction was performed with ethyl acetate. The aqueous layer was made alkaline with 2N NaOH and extracted with ethyl acetate. All organic layers were combined, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diisopropyl ether to obtain Compound 15 as light brown crystals. Yield 264 mg (52%).

'H-NMR (d-DMSO): 7.56 (1H, t, J = 1.8Hz), 7.62 (2H, d, J = 6.3Hz), 7.91 (1H, dd,

J = 3.0, 1.8Hz), 8.50 (2H, d, J = 6.3Hz), 12.4 (1H, br s).

(2) 15 → 16

Compound 16 was obtained as colorless crystals from compound 15 (346 mg, 2.05 mmol), sodium azide (146 mg, 2.25 mmol), and ammonium chloride (120 mg, 2.25 mmol) in the same manner as in Example 122 (3). It was. Yield 346 mg (80%).

'H-NMR (d-DMSO): 7.47 (1H, t, J = 1.8Hz), 7.93 (2H, d, J = 6.6Hz), 8.06 (1H, dd, J = 3.0, 1.8Hz), 8.63 (2H, d, J = 6.6Hz), 12.8 (1H, br s).

(3) 16 + 2 → 17

Compound 2 of Example 122 (1.082 g, 1.60 mmol) was suspended in dichloromethane (15 ml), and an aqueous sodium hydrogen carbonate solution (202 mg, 2.41 mmol dissolved in 15 ml of water) was added under ice cooling, followed by extraction with dichloromethane. And dried over magnesium sulfate. After distilling off the solvent, quickly dissolve in dimethyl sulfoxide (6 ml), mix with compound 16 (340 mg, 1.60 mmol), then add sodium iodide (720 mg, 4.81 mmol) and stir at room temperature for 4 hours. did. The reaction solution was poured into 5% brine (50 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 17 as an amorphous powder. Yield 1.544g.

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.65, 3.91 (2H, ABq, J = 18.0Hz), 4.1

1 (2H, q, J = 7.2Hz), 5.16 (2H, d, J = 6.0Hz), 5.29 (1H, d, J = 4.8Hz), 5.92 (1H, dd, J = 8.4, 4.8Hz), 6.41 (1H, dt, J = 15.5, 6.0Hz), 6.75 (1H, s), 6.86 (1H, d, J = 15.5Hz), 6.92 (1H, s), 7.25-7.60 (m, 12H), 8.21 (1H, m), 8.25 (2H, d, J = 6.9Hz), 8.32 (1H, m), 8.74 (2H, d, J = 6.9Hz), 9.76 (1H, d, J = 8.4Hz), 13.1 (1H, brs).

(4) 17 → 13

Compound 17 (1.532 g, 1.882 mmol) was dissolved in methylene chloride (15 ml) and anisole (1.53 ml), cooled to −30 ° C., and 7.5 ml of 2M tetrasalt titanium titanium dichloromethane solution was added. The mixture was stirred at −30 ° C. for 15 minutes, nitromethane (6 ml) was added, and the mixture was further stirred for 45 minutes, and then poured into water (40 ml) with stirring under ice cooling. 40 ml of diisopropyl ether was added, and the deposited precipitate was filtered. The filtered product was suspended in water, saturated aqueous sodium hydrogen carbonate was added to adjust the pH to 7.5, and acetonitrile was further added to filter insoluble matters. HP-20SS was added to the obtained filtrate, and the filtrate was concentrated under reduced pressure, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 13 as a powder. Yield 308mg (25% from 2)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 3.42, 3.56 (2H, ABq, J = 16.8Hz), 4.0

9 (2H, q, J = 7.1 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.09 (2H, d, J = 7.5 Hz), 5.59 (1H, dd, J = 8.1, 5.1 Hz), 5.83 (1H, dt, J = 15.6, 7.5Hz), 6.72 (1H, s), 7.11 (1H, d, J = 1.8Hz), 7 • 23 (2H, s), 7.25 (1H, d, J = 15.6Hz), 7.95 (1H, d, J = 1.8Hz), 8.20 (2H, d, J = 6.9Hz), 8.63 (2H, d, J = 6.9Hz), 9.54 (1H, d, J = 8.1Hz), 12.3 (1H, br s).

1R (KBr) cm— 3398, 1762, 1634, 1612, 1549, 1385, 1357, 1166, 1143, 1035.

MS (ESI): 648+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.0H O-0.2NaHCO

27 24 11 5 2 2 3

Calculated value: C, 42.07; H, 4.44; N, 19.84; S, 8.24; Na, 3.55 (%)

Experimental value: C42.08; H, 4.46; N, 19.64; S, 8.44; Na, 3.61 (%)

Example 125

[Chemical 170]

twenty three

(1) 5 → 20

Hydroxyammonium chloride (2.78 g, 40.0 mmol) was dissolved in dimethyl sulfoxide (8 ml), and triethylamine (4.04 g, 40.0 mmol) was added. The insoluble material was removed by filtration, compound 5 was added, and the mixture was stirred at 75 ° C overnight. Purified water was added to adjust the pH to 5.1, and the precipitate was collected by filtration to obtain 20 as a brown powder. Yield (1.20g, 68%)

(2) 20 → 21

Compound 20 (610 mg, 3.OOmmol) was suspended in dimethylformamide (6ml), thiocarbodiimidazole (588mg, 3.30mmol) was added, stirred for 1.5 hours, and purified water (10mL) was added. The precipitated solid was collected by filtration to obtain 21. Yield (723mg, 77%) (3) 21 → 22

Compound 21 (723 mg, 2.3111111101) was suspended in dimethylformamide (7.51111), and a fluorine trifluoride ether complex (1.64 g, 11.2 mmol) was added dropwise thereto, followed by stirring at room temperature for 6 hours, and then at 60 ° C. Stir for 1 hour. Purified water (7.5 ml) was added to the reaction solution to adjust the pH to 3.5, and the precipitated solid was collected by filtration to obtain 22. Yield (353mg, 62%)

(4) 22 + 19 → 23

Compound 19 (1.24 g, 1.31 mmol) and Compound 22 (328 mg, 1.34 mmol) are dissolved in dimethyl sulfoxides 2.6 ml), sodium iodide (601 mg, 4.01 mmol) is added, and the mixture is stirred at room temperature for 6 hours and a half for 6 hours. did. The reaction mixture was poured into 5% brine (30 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain 23 as an amorphous powder (1.27 g).

'H-NMR (d-DMSO): 1.25 (3H, t, J = 7.2Hz), 1.45 (9H, s), 3.66, 3.91 (2H, ABq, J =

18.0Hz), 4.14 (2H, q, J = 7.2Hz), 5.26_5.31 (3H, m), 5.95 (1H, dd, J = 8.1, 4.8Hz), 6. 42 (1H, dt, J = 15.1, 6.6Hz), 6.92 (1H, s), 7.29-7.50 (13H, m) .7.86 (lH, s), 8.46 (1H, br), 9.05 (2H, d, J = 7.1Hz), 9.73 ( (1H, d, J = 8.1Hz).

(5) 23 → 18

Amorphous powder 23 (1.24 g) was dissolved in dichloromethane (12.5 ml), anisole (1.25 ml) was added, and the mixture was cooled to -30 ° C. 2M Tetrachloride-titanium (dichloromethane solution) was added dropwise (5.24 ml), and Compound 18 was obtained as a powder in the same manner as in Example 1 23 (3). Yield 273 mg (25% in 2 steps)

JH-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.44, 3.51 (2H, ABq, J = 17.1Hz), 4.0

9 (2H, q, J = 7.2Hz), 5.05 (1H, d, J = 4.8Hz), 5.23 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.1, 4.8Hz), 5.86 (1H, dt, J = 15.6, 7.2Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 15.6Hz), 7.48 (1H, s), 8.48 (2H , d, J = 6.6Hz), 8.92 (2H, d, J = 6.6Hz), 9.54 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3397, 1761, 1636, 1603, 1535, 1391

MS (ESI): 681 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.4 H O -0.5 (NaHCO)

Calculated values: C, 40.08; H, 3.95; N, 17.00; S, 11.67; Na, 4.19 (%)

Experimental values: C, 40.09; H, 4.10; N, 17.17; S, 11.52; Na, 4.26 (%) Example 126

[Chemical 171]

2S

(1) 25 → 26

Compound 25 (1.17 g, 5.0 mmol) was suspended in ethanol (12 ml), hydrazine monohydrate (1.30 g, 25.0 mmol) was added, and the mixture was stirred for 1 hour. The precipitate was collected by filtration to obtain 26 as a solid. Yield 890 mg (81%).

^J H-NMR (d-DMSO): 8.04 (2Η, d, J = 6.0 6ζ), 8.69 (2Η, d, J = 6.0Hz), 8.72 (1H, s).

6

(2) 26 → 27

Compound 26 (853 mg, 3.89 mmol) was suspended in tetrahydrofuran (100 ml), triethylamine (433 mg, 4.28 mmol) was added, and the mixture was cooled to 0 ° C. To the reaction solution, carbonyldiimidazole (883 mg, 5.44 mmol) was stirred at room temperature for 4 and a half hours. 90 ml of tetrahydrofuran was distilled off, purified water was added to adjust the pH to 3.5, and the precipitated solid was collected by filtration to obtain 27. Yield 901 mg (94%).

'H-NMR (d-DMSO): 7.97 (2H, d, J = 4.5Hz), 8.70 (2H, d, J = 4.5Hz), 8.77 (1H, s).

6

(3) 27 → 28

Compound 2 of Example 122 (1.01 g, 1.50 mmol) was suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (189 mg, 3.75 mmol was dissolved in 10 ml of water) was added under ice cooling, followed by extraction with dichloromethane and sulfuric acid. Dried with magnesium. Immediately after distilling off the solvent, dimethylsulfoxide It was dissolved in side (6 ml), mixed with compound 27 (369 mg, 1.50 mmol), sodium iodide (675 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 5 and a half hours. The reaction solution was poured into 5% brine (45 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain 28 (1.21 g) as an amorphous powder.

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.65, 3.90 (2H, ABq, J = 17.7Hz), 4.1

0 (2H, q, J = 7.2Hz), 5.29 (1H, d, J = 5.1), 5 · 839_5 · 941 (1Η, m), 6.43 (1H, m), 6.75-7.50 (14H, m ), 7.97 (1H, d, J = 6.0Hz), 8.70 (1H, d, J = 6.0Hz), 8.76 (1H, s), 9.63 (1H, d, J = 8.1Hz).

(4) 28 → 24

Compound 28 (1.21 g) was dissolved in dichloromethane (7.20 ml), anisole (1.21 ml) was added, and the mixture was cooled to -30 ° C. Trifluoroacetic acid (3.6 ml) was added dropwise to give Compound 24 as a powder in the same manner as in Example 123 (3). Yield 184mg (15.0% in 2steps)

^J H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.43, 3.51 (2H, ABq, J = 16.5Hz), 4.0

9 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 5.1Hz), 5.27 (2H, d, J = 6.0Hz), 5.59 (1H, dd, J = 8.4, 5.1Hz), 5.87 (1H, dt, J = 16.2, 6.9Hz), 6.72 (1H, s), 7.27 (2H, s), 7.30 (1H, d, J = 16.2Hz), 8.58 (2H, d, J = 6.0Hz ), 8.92 (1H, s), 9.03 (2H, d, J = 6.0Hz), 9.54 (1H, d, J = 8.4Hz).

IR (KBr) cm " ¹ : 3419, 1762, 1667, 1634, 1531, 1387

MS (ESI): 682 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.8 H O-0.3 (NaHCO)

Calculated values: C, 40.21; H, 3.94; N, 15.46; S, 11.80; Na, 3.67 (%)

Experimental values: C, 40.40; H, 3.99; N, 15.39; S, 11.50; Na, 3.61 (%)

Example 127

[Chemical 172]

31

(1) 6 + 30 → 31

Compound 30 (802 mg, 1.07 mmol) and compound 6 (227 mg, 1.07 mmol) are dissolved in dimethyl sulfoxide (1 • 5 ml) and dimethylformamide (2. Oml), sodium bromide (269 mg, 3.20 mmol) is added, Stir at room temperature overnight. While cooling, the reaction solution was poured into 5% brine (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain 31 as an amorphous powder (959 mg).

^J H-NMR (d-DMSO): 1.24 (6H, m), 3.66, 3.92 (2H, ABq, J = 18.0Hz), 4.35 (2H, m, J

= 6.3Hz), 5.23 (1H, d, J = 6.3Hz), 5.31 (2H, d, J = 5.1Hz), 5.95 (1H, dd, J = 8.4, 5.1 Hz), 6.43 (1H, m), 6.93 (2H, s), 7.28-7.48 (14H, m), 8.52 (2H, d, 6.9Hz), 8.89 (2H, d, J = 6.9Hz), 9.69 (1H, d, J = 8.4Hz), 11.81 (1H, s).

(2) 31 → 29

Compound 31 (959 mg) was dissolved in dichloromethane (10.0 ml), anisole (1.00 ml) was added, and the mixture was cooled to -30 ° C. Tetrachloride-titanium (2M dichloromethane solution, 4.1 ml) was added to obtain compound 29 as a powder in the same manner as in Example 123 (3). Yield (248mg, 29.0% in 2 steps)

'Η-NMR (d-DMSO): 1.20 (6H, m), 3.43, 3.51 (2H, ABq, J = 16.8Hz), 4.30 (1H, m,

J = 6.3Hz), 5.05 (1H, d, J = 5.1Hz), 5.23 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.1, 6.3Hz), 5.89 (1H, dt , J = 15.9, 5.1Hz), 6.70 (1H, s), 7.22 (2H, s), 7.30 (1H, d, J = 15.9Hz), 8.50 (2H, d, J = 6.9Hz), 8.92 ( 2H, d, J = 6.9Hz), 9.47 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3408, 1761, 1636, 1535, 1371

MS (ESI): 663 ⁺ (M-Na + 2H) ⁺ Elemental analysis CHNOS Na- 5.2 HO-0.3 (NaHCO)

Calculated: C, 40.80; H, 4.48; N, 20.92; S, 7.98; Na, 3.72 (%)

Experimental values: C, 40.89; H, 4.55; N, 20.65; S, 8.21; Na, 3.78 (%)

Example 128

[Chemical 173]

38

35

(1) 3 → 36

Compound 3 (869 mg, 4.00 mmol) was suspended in ethanol (9 ml), and hydrazine monohydrate (0.62 3 ml, 20.0 mmol) was added and stirred at room temperature for 5 hours, then at 70 ° C for 17 hours and 40 minutes. did. The mixture was cooled on ice, and the precipitate was filtered to obtain Compound 36 as a colorless powder. Yield 715 mg (88%).

'H-NMR (d-DMSO): 4.51 (2H, br s), 7.34 (s, 1H), 7.72 (2H, d, J = 6.0Hz), 8.63 (2H, d, J = 6.0Hz), 9.73 (1H, br s), 13.9 (1H, br s).

(2) 36 → 37

Compound 36 (699 mg, 3.44 mmol) was suspended in tetrahydrofuran (7 ml) and triethylamine (0. 671 ml, 4.82 mmol), 1,1, -carbonyldiimidazole (803 mg, 3.78 mmol) were added. The mixture was stirred at room temperature for 2 hours and 50 minutes, and at 60 ° C for 15 minutes. After cooling to room temperature, water was added and the pH was adjusted to 3.5 with 2N HC1. The precipitate was filtered to obtain Compound 37 as light brown crystals. Yield 739 mg (93%). 'H-NMR (d-DMSO): 7.50 (1H, s), 7.89 (2H, m), 8.69 (2H, d, J = 6.3Hz), 12.6 (1H, b

6

r s), 14.4 (1H, br s).

(3) 37 + 20 → 38

Compound 20 (1.698 g, 2.00 mmol) and compound 37 (458 mg, 2.00 mmol) were dissolved in dimethylformamide (6 ml), sodium bromide (617 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 4 hours and 35 minutes. . The reaction solution was poured into 5% brine (60 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 38 as an amorphous powder. Yield 2.107g.

'H-NMR (d-DMSO): 1.24 (3H, t, J = 7.2Hz), 3.66, 3.79 (2H, ABq, J = 17.6Hz), 4.1

6

7 (2H, q, J = 7.2Hz), 5.28 (2H, d, J = 8.1Hz), 5.31 (1H, d, J = 5.0Hz), 5.95 (1H, dd, J = 8.1, 5.0Hz), 6.43 (1H, dt, J = 16.5, 8.1Hz), 6.90 (1H, d, J = 16.5Hz), 6.92 (1H, s), 7.28—7.54 (m, 10H), 7.29 (s, 1H), 8.58 (2H, m), 8.97 (2H, m), 9.75 (1H, d, J = 8.1Hz), 11.8 (1H, br s).

(4) 38 → 35

Compound 38 (2.098 g, 2.253 mmol) was dissolved in methylene chloride (21 ml) and anisole (2.10 ml), cooled to −30 ° C., and 11.3 ml of a 2M tetrasalt titanium titanium dichloromethane solution was added. The mixture was stirred at −30 ° C. for 45 minutes and then poured into 80 ml of water under ice cooling to obtain Compound 35 as a powder in the same manner as in Example 123 (3). Yield 129 mg (7% from 20).

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.43, 3.51 (2H, ABq, J = 16.8Hz), 4.0

6

9 (2H, q, J = 7.2 Hz), 5.04 (1H, d, J = 5.1 Hz), 5.08 (2H, d, J = 7.5 Hz), 5.60 (1H, dd, J = 8.3, 5.1 Hz), 5.84 (1H, dt, J = 15.6, 7.5Hz), 6.72 (1H, s), 7.18 (1H, s), 7.22 (2H, s), 7.27 (1H, d, J = 15.6Hz), 8.24 (2H , d, J = 6.8Hz), 8.60 (2H, d, J = 6.8Hz), 9.54 (1H, d, J = 8.3Hz).

IR (KBr) cm ^_1 : 3418, 1762, 1633, 1535, 1389, 1164, 1037.

MS (ESI): 665 ⁺ (M-Na + 2H) ⁺

Elemental analysis CHNOS Na- 6.2HO -0.9NaHCO Calculated value: C, 38.34; H, 4.19; N, 16.03; S, 7.34; Na, 5.00 (%)

Experimental value: C, 38.27; H, 4.34; N, 15.85; S, 7.89; Na, 4.93 (%)

Example 129

[Chemical 174]

(1) 9 → 40

Compound 9 (937 mg, 4.00 mmol) was suspended in ethanol (9 ml), hydrazine monohydrate (0.62 3 ml, 20.0 mmol) was added, and the mixture was stirred at room temperature for 2 hours and then at 70 ° C. for 2 hours. The mixture was cooled on ice, and the precipitate was collected by filtration to obtain Compound 40 as a colorless powder. Yield 7 98 mg (91%).

'H-NMR (d-DMSO): 4.61 (2H, brs), 8 · 02 (2Η, d, J = 6.2Hz), 8.44 (s, 1H), 8.75 (2H,

6

d, J = 6.2Hz), 9.88 (1H, brs).

(2) 40 → 41

Compound 40 (786 mg, 3.57 mmol) was suspended in tetrahydrofuran (8 ml), and triethylamine (0.700 ml, 4.99 mmol) and 1, -carbonyldiimidazole (833 mg, 3.92 mmol) were obtained under ice cooling. The mixture was stirred at room temperature for 2 hours and 45 minutes, water was added under ice cooling, and the pH was adjusted to 3.5 with 2N HC1. The precipitate was filtered to obtain compound 41 as light brown crystals. Yield 739 mg (93%). NMR-NMR (d-DMSO): 7.95 (2H, d, J = 6.0Hz), 8.56 (1H, s), 8.77 (2H, d, J = 6.0Hz),

6

12.8 (1H, brs).

(3) 41 + 19 → 42

Compound 19 (1.698 g, 2.00 mmol), Compound 41 (492 mg, 2.00 mmol) was dissolved in dimethylformamide (6.8 ml), sodium bromide (617 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 9 hours. Stir for 35 minutes. The reaction solution was poured into 5% brine (50 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was reduced-pressure dried to obtain Compound 42 as an amorphous powder. Yield 2.078g.

'H-NMR (d-DMSO): 1.24 (3H, t, J = 7.0Hz), 3.66, 3.91 (2H, ABq, J = 17.7Hz), 4.1

6

4 (2H, q, J = 7.0Hz), 5.31 (1H, d, J = 4.8Hz), 5.37 (2H, d, J = 8.4Hz), 5.95 (1H, dd, J = 8.1, 4.8Hz), 6.44 (1H, dt, J = 16.1, 8.4Hz), 6.92 (1H, d, J = 16.1Hz), 6.92 (1H, s), 7.27-7.52 (m, 10H), 8.68 (2H, d, J = 7.1Hz), 8.84 (s, 1H), 9.ll (2H, d, J = 7.1Hz), 9.74 (1H, d, J = 8.1Hz), 11.9 (1H, brs), 12.9 (1H, brs).

(4) 42 → 39

Compound 42 (2.066 g, 2.179 mmol) was dissolved in methylene chloride (20 ml) and anisole (2.07 ml), cooled to −30 ° C., and 11.3 ml of 2M tetrasalt-titanium dichloromethane solution was added. The mixture was stirred at −30 ° C. for 45 minutes, then poured into 80 ml of water under ice cooling, and compound 39 was obtained as a powder in the same manner as in Example 123 (3). Yield 509 mg (31% from 19).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.42, 3.50 (2H, ABq, J = 16.2Hz), 4.0

6

9 (2H, q, J = 7.2 Hz), 5.05 (1H, d, J = 5.0 Hz), 5.33 (2H, d, J = 6.9 Hz), 5.60 (1H, dd, J = 8.1, 5.0 Hz), 5.87 (1H, dt, J = 15.9, 7.5Hz), 6.72 (1H, s), 7.22 (2H, s), 7.32 (1H, d, J = 15.9Hz), 8.25 (1H, s), 8.61 (2H , d, J = 6.9Hz), 9.09 (2H, d, J = 6.9Hz), 9.54 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3410, 1764, 1664, 1634, 1531, 1389, 1363, 1037.

MS (ESI): 682 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 5.3H O-0.2NaHCO

27 22 9 7 3 2 3

Calculated value: C, 40.04; H, 4.05; N, 15.45; S, 11.79; Na, 3.38 (%)

Experimental value: C, 40.04; H, 4.10; N, 15.47; S, 11.86; Na, 3.29 (%)

Example 130 [Chemical 175]

43

(1) 44 → 45

Compound 44 (1.00 g, 4.27 mmol) was suspended in 28% aqueous ammonia (15 ml), and compound 45 was obtained as pale orange crystals in the same manner as in Example 122 (2). Yield 715 mg (82%).

'H-NMR (d-DMSO): 8 · 00 (1Η, s), 8 · 03 (2Η, d, J = 6.0Hz), 8.34 (1H, s), 8.69 (2H, d,

J = 6.0 Hz), 8.73 (1H, s).

(2) 45 → 46

Compound 45 (715 mg, 3.48 mmol) was suspended in pyridine (8.5 ml), trifluoroacetic anhydride (0.984 ml, 6.91 mmol) was added, and the mixture was stirred at 60 ° C. for 5 hours. Toluene was added and the mixture was concentrated under reduced pressure. Water and ethyl acetate were collected and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude crystals were washed with diisopropyl ether to obtain Compound 46 as tan crystals. Yield 583 mg (89%).

'H-NMR (d-DMSO): 7.98 (2H, d, J = 6.3Hz), 8.71 (2H, d, J = 6.3 Hz), 8.99 (1H, s).

(3) 46 → 47

Hydroxylamine hydrochloride (1.42 g, 20.4 mmol) was dissolved in dimethyl sulfoxide (5 ml), and triethylamine (2.85 ml, 20.4 mmol) was added dropwise at room temperature. The resulting precipitate was filtered and washed with tetrahydrofuran, and then the tetrahydrofuran in the filtrate was concentrated under reduced pressure. Convert to the resulting solution Compound 46 (765 mg, 4.09 mmol) was added, and the mixture was stirred at 75 ° C. for 13 hours and 30 minutes. After cooling to room temperature, water was added and the precipitate was collected by filtration and then dried under reduced pressure to give Compound 47 as colorless crystals. Obtained. Yield 78 7 mg (87%).

'H-NMR (d-DMSO): 6.14 (2H, s), 8.01 (2H, d, J = 6.3Hz), 8.44 (1H, s), 8.66 (2H, d,

J = 6.3 Hz), 10.24 (1H, s).

(4) 47 → 48

Compound 47 (768 mg, 3.45 mmol) was dissolved in dimethylformamide (6 ml), and pyridine (0.31 ml, 3.8 mmol) and 2-ethylhexyl chloroformate (0.75 ml, 3.8 mmol) were added under ice cooling. The mixture was stirred for 1 hour. Ethyl acetate and water were added, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, dissolved in xylene (8 ml), and stirred at 150 ° C. for 2 hours. After cooling to room temperature, the precipitate was collected by filtration and washed with diisopropyl ether to obtain Compound 48 as a light brown powder. Yield 717 mg (84%).

'H-NMR (d-DMSO): 8.02 (2H, d, J = 6.2 Hz), 8.72 (2H, d, J = 6.2 Hz), 8.82 (1H, s).

(5) 48 + 2 → 49 → 43

Compound 48 (369 mg, 1.50 mmol) was suspended in methanol, a sodium methoxide methanol solution was added dropwise until pH = 7.8, and the resulting solution was concentrated under reduced pressure to obtain 48 sodium salts. Compound 2 of Example 122 (1.012 g, 1.50 mmol) was suspended in dichloromethane (12 ml), and an aqueous sodium hydrogen carbonate solution (189 mg, 2.25 mmol dissolved in 12 ml of water) was added under ice-cooling and extracted with dichloromethane. And dried over magnesium sulfate. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (3 ml), mixed with 48 sodium salt, sodium bromide (463 mg, 4.50 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 5% brine (40 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder of Compound 49. This was dissolved in methylene chloride (6.6 ml) and anisole (1.1 ml), cooled to 0 ° C., and 3.3 ml of trifluoroacetic acid was added. The mixture was stirred at 0 ° C for 45 minutes and then poured into 60 ml of isopropanol while stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with saturated aqueous NaHCO. HP solution

-20SS column chromatography eluting with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 43 as a powder. Yield 184 mg (17%). Ή-NMR (d-DMSO): 1.22 (3H, t, J = 7.1Hz), 3.43, 3.51 (2H, ABq, J = 16.5 Hz), 4.

09 (2H, q, J = 7.1 Hz), 5.05 (1H, d, J = 5.0 Hz), 5.28 (2H, d, J = 6.9 Hz), 5.60 (1H, dd, J = 8.1, 5.0 Hz), 5.87 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d J = 15.9Hz), 8.60 (2H, d, J = 6.9Hz) , 9.05 (2H, d, J = 6.9Hz), 9.05 (1H, s), 9.54 (1H, d, J = 8.1Hz).

IR (KBr) cm— 3418, 1763, 1672, 1635, 1529, 1387, 1364, 1036.

MS (FAB): 704 ⁺ (M + H) ⁺

Elemental analysis c H N O S Na-4.8 H O-0.3NaHCO

Calculated values: C, 40.21; H, 3.94; N, 15.46; S, 11.80; Na 3.67 (%)

Experimental value: C40.21; H, 3.87; N, 15.40; S, 11.75; Na 3.93 (%)

Example 131

[Chemical 178]

(1) 3 → 4

Compound 3 (5.19 g, 30 mmol) was dissolved in dimethylformamide (30 ml), potassium carbonate (4.97 g, 36 mmol) and para-methoxybenzyl bromide (4.76 ml, 3.3 mmol.) Were added, and the mixture was stirred overnight at room temperature. . Water was extracted from the reaction solution with ketyl ether, washed with water, dried and concentrated to give 4 as crystals. Yield 6.47 g (74%).

'H-NMR (CDC13): 3 · 82 (3Η, s), 5 · 31 (2Η, s), 6.92 (2Η, d, J = 8.7Hz), 7.37 (2H, d, J = 8.7Hz), 7.68 (1H, d, J = 5.1Hz), 7.85 (1H, d, J = 5.1Hz). (2) 4 → 5

Compound 4 (6.42 g, 22 mmol) was dissolved in 200 ml of EtOH, and an aqueous solution (10 ml) of ammonium chloride (3.5 g, 66 mmol) was added and refluxed. Next, iron powder (l lg, 198 mmol) was added in small portions and refluxed for 4.5 hours. The insoluble material was filtered off and concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate, washed with water and dried to obtain 4NHC1 in ethyl acetate (6.7 ml) and concentrated to give 5 as crystals. Yield 4.04 g (62%).

'H-NMR (d-DMSO): 3.75 (3H, s), 5.11 (2H, s), 5.89 (1H, d, J = 3.9Hz), 6.93 (2H, d,

J = 8.7Hz), 7.33 (2H, d, J = 9.0Hz), 7.35 (1H, d, J = 4.2Hz).

(3) 5 + 6 → 7

Compound 5 (1.80 g, 6 mmol) was dissolved in dimethylformamide (5 ml), triethylamine (0.9 lml, 6.5 mmol) and compound 6 (601 mg, 5 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was extracted with ethyl acetate and water, washed with water, dried and concentrated to give 7 as crystals. Yield 965 mg (50%

).

'H-NMR (d-DMSO): 3.76 (3H, s), 5.20 (2H, s), 6.66 (1H, d, J = 4.2Hz), 6.96 (2H, d,

J = 8.7Hz), 7.37 (2H, d, J = 8.7Hz), 7.46 (2H, d, J = 6.3Hz), 7.59 (1H, d, J = 4.2Hz), 8.39 (2H, d, J = 6.3Hz), 9.45 (1H, bs), 10.51 (1H, bs).

(4) 7 + 2 → 8

Compound 7 (383 mg, 1 mmol) and Compound 2 (738 mg, 1 mmol) were dissolved in dimethylformamide (2 ml). Then NaBr (309 mg, 3 mmol) was added and stirred at room temperature for 6 hours. The reaction solution was poured into a mixed solution of ethyl acetate and water. The organic layer was washed with water, dried and concentrated to give Compound 8 (969 mg) as a powder.

(5) 8 → 1

Compound 8 (957 mg) was dissolved in methylene chloride (10 ml) and anisole (0.82 ml) and cooled to -30 ° C. A nitromethane solution (8.2 ml) of 1MA1C1 was stirred for 40 minutes. The reaction solution was poured into a dilute hydrochloric acid-acetonitrile mixture with stirring under ice cooling. The aqueous layer was washed with an isopropyl ether-hexane mixture, then subjected to HP-20SS column chromatography and eluted with dilute NaHC 0 water-acetonitrile. Concentrate the fraction containing the desired compound under reduced pressure, 2 The mixture was neutralized with NHC1 and the precipitate was collected by filtration. The precipitate was dissolved in a dilute aqueous NaOH solution and freeze-dried to obtain Compound 1 as a powder. Yield 367 mg (48%)

'H-NMR (D 2 O): 1.25 (3H, t, J = 7.2Hz), 3.61, 3.68 (2H, ABq, J = 17.8Hz), 4.19 (2H,

2

q, J = 7.2 Hz), 4.91 (2H, m), 5.23 (1H, d, J = 4.8Hz), 5.78 (1H, d J = 5.1Hz), 6.01 (1 H, m), 6.45 (1H, m), 6.81 (1H, d, J = 15.6Hz), 6.91 (1H, s), 7.16 (1H, m), 7.65 (2H, d J = 5.1Hz), 8.20 (2H, d, J = 7.2Hz ).

IR (KBr) cm— ¹ : 3407, 2981, 1763, 1715, 1609, 1531, 1459, 1374, 1304.

MS (ESI): 699+ (M + H) +

Elemental analysis c H N O S Na- l. LNaCl-0.4NaHCO -6H O

28 25 8 8 3 3 2

Calculated values: C, 36.81; H, 4.07; N, 12.09; S, 10.38; Cl, 4.21; Na, 6.20 (%)

Experimental value: C, 36.83; H, 4.08; N, 12.32; S, 10.63; Cl, 4.25; Na, 6.11 (%)

Example 132

[Chemical 179]

(6) 10 → 11

Compound 10 (5.73 g, 30 mmol) was dissolved in toluene (50 ml), ethylene glycol (10 ml) and p-toluenesulfonic acid (571 mg, 3 mmol) were added, and the mixture was refluxed for 6.5 hours. The reaction solution was washed with water, dried and concentrated to obtain 11. Yield 7.08g. ^J H-NMR (CDC1): 3.97—4 · 13 (4Η, m), 6.02 (1H, s), 6.90 (1H, d, J = 4.5Hz), 6.93 (1H, d, J = 3.6Hz).

(7) 11 + 12 → 13

Compound l l (3.53 g, 15 mmol) is dissolved in tetrahydrofuran (30 ml). _78. Add 2.7Nn_butyllithium-hexane solution (5.8ml) in C and stir for 30 minutes, then precooled to _78 ° C in solution of Compound 12 (1.86ml, 19.5mmol) in tetrahydrofuran (30ml) Added to the inside. After stirring at the same temperature for 45 minutes, the solution was extracted by adding an aqueous salt ammonium solution and then ethyl acetate. The organic layer was washed with water, dried and concentrated to give 13 as crystals. Yield 1.79 g (45%)

'H-NMR (CDCl): 3.97-4.13 (4H, m), 6 · 01 (1Η, s), 6 · 03 (1Η, s), 6.85 (1H, d, J = 4.2

Hz), 7.02 (1H, d, J = 4.2Hz), 7.41 (2H, d, J = 6.9Hz), 8.54 (1H, d, J = 6.0Hz).

(8) 13 → 14

Compound 13 (1.77 g, 6.7 mmol) was suspended in black mouth form (30 ml), manganese dioxide (5.84 g, 67 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. The insoluble material in the reaction solution was removed by filtration and concentrated to obtain Compound 14 (1.74 g) as crystals.

'H-NMR (CDCl): 4.04-4.18 (4H, m), 6.16 (1H, s), 7.22 (1H, d, J = 4.5Hz), 7.54 (1H, d, J = 3.9Hz), 7.66 ( 2H, d, J = 6.0Hz), 8.82 (2H, d, J = 6.0Hz).

(9) 14 → 15

To compound 14 (1.66 g, 6.4 mmol) was added 2NHCl (9.5 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was neutralized with NaHCO and extracted with ethyl acetate to obtain Compound 15 as crystals. Yield 1.33 g (96%)

'H-NMR (CDCl): 7.69 (2H, d, J = 6.0Hz), 7.72 (1H, d, J = 3.9Hz), 7.82 (1H, d, J =

3.9Hz), 8.87 (2H, d, J = 6.0Hz), 10.04 (1H, s).

(10) 15 → 16

Silver nitrate (2.93 g) was dissolved in water (6 ml), and 8N NaOH (3.5 ml) was added and stirred. The reaction mixture was ice-cooled, compound 15 (1.22 g, 5.6 mmol) was added, and the mixture was stirred for 2 hr. The insoluble material was removed by filtration, neutralized with 6NHC1, and the precipitate was collected by filtration and dried to give compound 16. Yield 265mg (20%)

'H-NMR (d-DMSO): 7.76-7.82 (4H, m), 8.86 (2H, d, J = 7.5Hz).

(12) 16 → 17 Compound 16 (265 mg, l.lmmol.) Was dissolved in dimethylformamide (2 ml), carbonyldiimidazole (370 mg, 2.2 mmol.) Was added, and the mixture was stirred for 30 minutes. Subsequently, t-butanol (0.55 ml) and t-butoxypotassium (265 mg, 0.1 mmol.) Were added, and the mixture was stirred at 50 ° C. for 30 minutes. The reaction solution was cooled and extracted by adding ammonium chloride aqueous solution and then ethyl acetate. The organic layer was washed with water, dried and concentrated to give 17 as crystals. Yield 201 mg (63%)

'H-NMR (CDCl): 1 · 60 (9Η, s), 7.58 (1H, d, J = 3.9Hz), 7.69 (2H, d, J = 6.0Hz), 7.7

3 (1H, d, J = 3.9Hz), 8.85 (2H, d, J = 5.7Hz).

(13) 17 + 2 → 18

Compound 18 (663 mg) was obtained as a powder from Compound 17 (199 mg, 0.69 mmol) and Compound 2 (509 mg, 0.69 mmol) in the same manner as (4).

(14) 18 → 9

Compound 9 was obtained as a powder in the same manner as Compound (5) from Compound 18 (957 mg). Yield 247 mg (52%) 'H-NMR (DO): 1.29 (3H, t, J = 7.2 Hz), 3.67 (2H, bs), 4.25 (2H, q, J = 7.2 Hz), 5.2

7 (1H, d, J = 4.5Hz), 5.43 (2H, d, J = 7.2Hz), 5.82 (1H, d J = 4.8Hz), 6.14 (1H, dt, J = 15.6, 7.2Hz), 6.97 (1H, s), 7.02 (1H, d, J = 15.6Hz), 7.58 (1H, d, J = 3.9Hz), 7.67 (2H, d, J = 4.2Hz), 8.39 (2H, d, J = 6.6Hz), 9.10 (2H, d, J = 6.6Hz).

IR (KBr) cm " ¹ : 3410, 2982, 1765, 1603, 1532, 1454, 1365, 1333.

MS: 669 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-0.3NaHCO -4H O

Calculated value: C, 43.14; H, 4.00; N, 10.67; S, 12.21; Na, 3.79 (%)

Experimental value: C, 43.42; H, 3.95; N, 10.32; S, 12.39; Na, 3.81 (%)

Example 133

[Chemical 180]

twenty four

(15) 20 → 21

Compound 20 (5.35 g, 29 mmol) was dissolved in methylene chloride (50 ml), diphenyldiazomethane was added, and the mixture was stirred at room temperature. The reaction mixture was concentrated to give 21. Yield 10.5g

'H-NMR (CDCl): 7.16 (1H, s), 7.29-7 · 47 (11Η, m), 8.39-8 · 44 (1Η, m), 8.88-8.91 (1

Three

H, m).

(16) 21 → 22

Compound 21 (10.5 g, 29 mmol) was obtained in the same manner as (2) to obtain 22 as crystals. Yield 6.28 g (68%). 'H-NMR (CDCl): 6.95-7.09 (2H, m), 7 · 08 (1Η, s), 7.23-7.45 (10H, m), 7.52-7.55 (1

Three

H, m).

(17) 22 + 6 → 23

Compound 22 (1.93 g, 6 mmol) was obtained in the same manner as (3) to give 23. Yield 1.66 g (75%)

'H-NMR (CDCl): 7.01-7.07 (2H, m), 7 · 18_7 · 43 (10Η, m), 7.50 (2H, d, J = 6.6Hz), 7

Three

• 70 (1H, m), 7.91 (1H, m), 8.20 (2H, d, J = 6.3Hz), 8.58 (1H, bs), 9.20 (1H, bs).

(18) 23 + 2 → 24

Compound 24 (1.18 g) was obtained as a powder in the same manner as Compound 23 (383 mg, Immol) and Compound 2 (738 mg, Immol) force, et al. (4).

(19) 24 → 19

Compound 19 was obtained as a powder in the same manner as Compound (5) from Compound 24 (1.16 g). Yield 530mg (56%) 'H-NMR (DO): 1.27 (3H, t, J = 7.2Hz), 3.63 (2H, m), 4.22 (2H, q, J = 6.9Hz), 5.02 ( 2H, d, J = 6.6Hz), 5.25 (1H, d, J = 4.5Hz), 5.80 (1H, d J = 4.8Hz), 6.03 (1H, dt, J = 16.2, 6.6Hz), 6.83 ( 1H, d, J = 15.3Hz), 6.94 (1H, s), 7.10 (1H, m), 7.44-7.53 (2H, m), 7.79 (2H, d, J = 6.6Hz), 8.37 (2H , d, J = 6.9Hz).

IR (KBr) cm— ¹ : 3407, 2980, 1764, 1725, 1609, 1530, 1490, 1374, 1313.

MS: 711 ⁺ (M + H) ⁺

Elemental analysis c H F N O S Na- 2.6NaCl-6H O

30 26 1 8 8 2 2

Calculated values: C, 36.30; Η, 3.86; Ν, 11.29; S, 6.46; F, 1.91; Cl, 9.29; Na, 8.34 (%)

Experimental values: C, 36.31; H, 3.69; N, 11.33; S, 6.49; F, 1.80; Cl, 9.15; Na, 8.64 (%)

Example 134

[Chem 181]

(20) 26 → 27

Compound 26 (6.31 g, 50 mmol) was dissolved in acetic acid (50 ml) and a solution of bromine (3.07 ml) in acetic acid (25 ml) was added dropwise.

And stirred overnight. The reaction mixture was concentrated to obtain ethyl ether and water, and the organic layer was washed with water, dried and concentrated to obtain compound 27 as crystals. Yield 5.86 g (57%).

'H-NMR (CDCl 3): 2.49 (3H, s), 7.59 (1H, s), 9.77 (1H, s).

Three

(21) 27 → 28

Silver nitrate (11.47 g) was dissolved in water and NaOH (5.4 g) was added and stirred. The reaction mixture was ice-cooled, compound 27 (5.13 g, 25 mmol.) Was added, and the mixture was stirred for 3 hr. Insoluble material is filtered off and neutralized with HC1 The precipitate was collected by filtration and dried to obtain Compound 28. Yield 265mg (57%)

'H-NMR (CDCl): 2.46 (3H, s), 7.69 (1H, s).

Three

(22) 28 → 29

Compound 28 (3.07 g, 13.9 mmol.) Was obtained in the same manner as (15) to give compound 29 as crystals. Yield 4.14 g (77%)

'H-NMR (CDCl): 2.44 (3H, s), 7.02 (1H, s), 7.25-7.41 (10H, m), 7.68 (1H, s).

Three

(23) 29 + 30 → 31

Compound 29 (3.87 g, 10 mmol.) And compound 30 (2.05 g, 10 mmol.) Are dissolved in dioxane (80 ml). Add K 3 PO 4 (10.61 g, 50 mmol.) And Pd (PPh 3) and stir at 100 ° C for 5 hours. The reaction solution is cold

3 4 3 4

On the contrary, the insoluble material is removed by filtration and then concentrated. The residue was purified by column chromatography to give compound 31. Yield 3.57g (85%)

'H-NMR (CDCl): 2.59 (3H, s), 7.07 (1H, s), 7.16-7.43 (12H, m), 7.84 (1H, s), 8.67 (2

Three

(H, d, J = 5.4Hz).

(24) 31 + 33 → 32

Compound 32 (1.0 g) was obtained as a powder from compound 31 (340 mg, 0.88 mmol) and compound 33 (662 mg, 0.88 mmol) in the same manner as (4).

(25) 32 → 25

Compound 25 was obtained as a powder from Compound 32 (957 mg) in the same manner as in (5). Yield 334 mg (48%) 'H-NMR (D 2 O): 1.28 (6H, bd, J = 6.0 Hz), 2.63 (3H, s), 3.67 (2H, m), 4.47 (1H, m), 5.

2

21-5.27 (3H, m), 5.79 (1H, d J = 4.5Hz), 6.11 (1H, m), 6.90 (1H, s), 6.98 (1H, d, J = 1 5.6Hz), 7.66 (1H , s), 8.02 (2H, bd, J = 5.1Hz), 8.73 (2H, bd, J = 5.7Hz).

IR (KBr) cm— ¹ : 3399, 2976, 1762, 1634, 1596, 1537, 1437, 1386, 1356.

MS: 669+ (M + H) +

Elemental analysis c H N O S Na-0.5NaHCO -4.7H O

29 27 6 7 3 3 2

Calculated values: C, 43.36; H, 4.51; N, 10.29; S, 11.77; Na, 4.22 (%)

Experimental value: C43.53; H, 4.54; Ν, ΙΟ.01; S, 11.17; Na, 4.39 (%)

Example 135

[Chemical 182]

(26) 35 → 36

Compound 35 (946 mg, 5 mmol) was dissolved in dimethylformamide (10 ml), p-methoxybenzyl alcohol (0.62 ml, 5 mmol) was added, and then ethyldimethylaminopropylcarbodiimide hydrochloride (1.15 g, 6 mmol) and 4-dimethylaminopyridine (183 mg, 0.15 mmol) were added, and the mixture was stirred at room temperature at 50 ° C for 3.5 hours. Ethyl acetate-water was added to the reaction solution, and the organic layer was washed with water, dried and concentrated to obtain 36 as crystals. Yield 878 mg (57%).

'H-NMR (CDCl): 3 · 82 (3Η, s), 5.33 (2H, s), 6.92 (2H, d, J = 8.7Hz), 7.25 (1H, s), 7.

39 (2H, d, J = 8.7Hz), 7.75 (2H, d, J = 6.0Hz), 8.70 (2H, d, J = 6.3Hz).

(27) 36 + 33 → 37

Compound 37 (1.0 g) was obtained as a powder in the same manner as Compound (4) from Compound 36 (309 mg, Immol) and Compound 33 (752 mg, Immol).

(28) 37 → 34

Compound 34 was obtained as a powder in the same manner as Compound (5) from Compound 37 (1.0 g). Yield 374mg (54%) 'H-NMR (DO): 1.28 (6H, d, J = 6.0Hz), 3.65, 3.68 (2H, ABq, J = 17.3Hz), 4.47 (1H, m), 5.26 (3H , m), 5.80 (1H, d J = 4.5Hz), 6.11 (1H, dt, J = 7.2, 15.6Hz), 6.90 (1H, s), 6.98 (1H, d, J = 15.9Hz), 7.28 ( 1H, s), 8.28 (2H, d, J = 6.0Hz), 8.75 (2H, d, J = 5.7H z).

IR (KBr) cm " ¹ : 3409, 2977, 1763, 1635, 1604, 1532, 1472, 1438, 1398, 1347, 1301. MS: 639 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na- 0.3NaHCO -4.7H O

Calculated value: C, 42.56; H, 4.54; N, 14.54; S, 8.32; Na, 3.88 (%) Experimental value: C, 42.53; H, 4.67; N, 14.56; S, 8.30; Na, 3.70 (%)

Example 136

[Chemical 183]

(29) 39 → 40

Compound 39 (1.37 g, 10 mmol) was dissolved in tetrahydrofuran (30 ml) and triethylamine (1.67 ml, 12 mmol) was added. : θ. ΟΟΒι (1.8 ^, 11πΐΓηο1) was added and refluxed for 5 hours. Ethyl acetate-water was added to the reaction solution, and the organic layer was washed with water, dried and concentrated. The precipitated crystals were washed with a mixture of isopropyl ether and hexane to obtain 40 as crystals. Yield 1.54 g (62%).

'H-NMR (CDCl): 1 · 69 (9Η, s), 8.05 (2H, d, J = 5.7Hz), 8.82 (2H, d, J = 6.0Hz).

Three

(30) 40 + 33 → 41

Compound 41 (0 · 91 g) was obtained as a powder from Compound 40 (247 mg, Immol) and Compound 33 (752 mg, Immol) in the same manner as (4).

(31) 41 → 38

Compound 38 was obtained as a powder in the same manner as Compound (5) from Compound 41 (0.91 g). Yield 189 mg (28%) 'H-NMR (D 2 O): 1.28 (6H, d, J = 6.0Hz), 3.67 (2H, m), 4.48 (1H, m), 5.27 (1H, d, J =

2

4.5Hz), 5.40 (2H, d, J = 6.3Hz), 5.81 (1H, d J = 4.8Hz), 6.13 (1H, dt, J = 6.9, 15.6Hz), 6.93 (1H, s), 7.02 ( 1H, d, J = 15.3Hz), 8.65 (2H, d, J = 6.9Hz), 9.06 (2H, d, J = 6.6 Hz).

IR (KBr) cm— ¹ : 3410, 2978, 2935, 2170, 1764, 1669, 1610, 1533, 1456, 1384, 1347. MS: 641 ⁺ (M + H) ⁺

Elemental analysis c HNOS Na-0.3NaHCO -4.3HO Calculated values: C, 41.20; H, 4.20; N, 14.64; S, 8.38; Na, 3.91 (%)

Experimental value: C, 41.26; H, 4.29; N, 14.78; S, 8.57; Na, 3.84 (%)

Example 137

[Chemical 184]

(32) 43 + 45 → 44

Compound 44 was obtained as a powder from Compound 43 (291 mg, 0.78 mmol) and Compound 45 (618 mg, 0.78 mmol) in the same manner as (4).

(33) 44 → 42

Compound 42 was obtained as a powder from Compound 44 in the same manner as (5). Yield 204 mg (31%)

'H-NMR (D O): 3.66 (2Η, m), 4.64-4.72 (1Η, m), 5.26 (3Η, m), 5.79 (1Η, d J = 3.9Hz

2

), 6.11 (1H, dt, J = 8.1, 15.0Hz), 7.00 (1H, d, J = 15.6Hz), 7.02 (1H, s), 8.43 (2H, d, J = 6.3Hz), 8.60 (1H , s), 8.79 (2H, d, J = 5.7Hz).

IR (KBr) cm " ¹ : 3408, 1764, 1636, 1533, 1488, 1458, 1368, 1301.

MS: 696+ (M + H) +

Elemental analysis C H F N O S Na- 0.2NaHCO-5.5H O

26 19 3 7 7 3 3 2

Calculated value: C, 37.75; Η, 3.65; Ν, 11.76; S, 11.54; F, 6.84; Na, 3.31 (%)

Experimental value: C, 37.71; H, 3.23; N, 11.50; S, 11.16; F, 6.46; Na, 3.23 (%)

Example 138

[Chemical 185]

(34) 47 → 48

Compound 47 (8.24 g, 50 mmol) was dissolved in dimethylformamide (50 ml), triphenylphosphine (13.2 g, 50 mmol) was added, and the mixture was stirred at 80 ° C. for 1 hour. Ethyl acetate was added to the reaction mixture, and the precipitated crystals were collected by filtration to give 48. Yield 14.9 g (69%).

'H-NMR (d-DMSO): 5 · 69 (2Η, d, J = 17.1Hz), 7.47 (2H, d, J = 6.6Hz), 7.76-7.97 (15

H, m), 8.70 (2H, d, J = 6.3Hz).

(35) 48 + 49 → 50

Compound 48 (1. lg, 2.6 mmol) and compound 49 (647 mg, 2 mmol) are dissolved in dimethylformamide (10 ml). DBU (0.9 ml, 6 mmol) was added and stirred at room temperature for 1 hour. The reaction solution was washed with water, dried, concentrated, and purified by column chromatography to obtain 50 (E / Z mixture). Yield 402 mg (48%) _o

(36) 50 → 51

Compound 50 (391 mg, 0.94 mmol) is dissolved in methylene chloride (5 ml). 2,2′-Azobis (2,4-dimethylvaleronitrile) (117 mg, 0.47 mmol) and 4_chlorothiophenol (68 mg, 0.47 mmol) were added and refluxed for 5 hours. A small amount of activated carbon was added to the reaction solution and filtered. The filtrate was concentrated and purified by column chromatography to give compound 51. Yield 156 mg (40%)

'H-NMR (CDCl 3): 7.17-7.57 (16H, m), 8 · 59 (2Η, d, J = 5.1 Hz).

(37) 51 + 2 → 52

Compound 51 (156 mg, 0.38 mmol) and compound 2 (281 mg, 0.38 mmol) to compound similar to (4) 52 was obtained as a powder.

(38) 52 → 46

The compound 46 was obtained as a powder in the same manner as the compound 52 to (5). Yield 127 mg (41%)

'H-NMR (D 2 O): 1.27 (3H, t, J = 7.2Hz), 3.66 (2H, m), 4.22 (2H, q, J = 7.2Hz), 5.19 (

2H, d, J = 6.6Hz), 5.26 (1H, d, J = 5.1Hz), 5.80 (1H, d J = 5.1Hz), 6.07 (1H, dt, J = 7 • 5, 15.6Hz), 6.94 (1H, s), 6.95 (1H, d, J = 15.9Hz), 7.41 (1H, d, J = 16.2Hz), 7.69 (1 H, d, J = 15.9Hz), 7.89 (lH, s), 8.00 (2H, d, J = 6.3Hz), 8.61 (2H, d, J = 6.3Hz).

IR (KBr) cm— ¹ : 3408, 2981, 1763, 1621, 1532, 1470, 1367.

MS: 668+ (M + H) +

Elemental analysis C H N O S Na-0.2NaHCO -6H

Calculated value: C, 41.58; H, 4.48; N, 12.04; S, 11.81; Na, 3.39 (%)

Experimental value: C41.18; H, 4.38; N, 11.96; S, 11.82; Na, 3.33 (%)

Example 139

[Chemical 186]

(39) 54 + 55 → 56

Compound 54 (1.78 g, 10 mmol) was dissolved in methylene chloride (20 ml) to remove compound 55 (1.29 ml, 10 mmol), pyridine (1.71111, 2111111101) was added, and the mixture was stirred under ice-cooling for 1 hour. After further stirring at room temperature for 1 hour, utyl acetate was added to the reaction solution, washed with water, dried and concentrated. The precipitated crystals were collected by filtration while washing with isopropyl ether to obtain 56. Yield 2.07 g (81%).

'H-NMR (CDCl): 3.99 (3Η, s), 7.19 (1H, m), 7.64 (1H, m), 7.92 (2H, d, J = 6.9Hz), 8. 12 (1H, m), 8.85 (2H, d, J = 6.0Hz), 8.90 (1H, d, J = 8.4Hz).

(40) 56 → 57 → 58

Compound 56 (1.99 g, 7.8 mmol) was dissolved in methanol (10 ml), 2NNaOH (8.5 ml) was added, and the mixture was stirred at room temperature for 45 minutes. The reaction solution was neutralized with 2N HCl (8.5 ml), and the precipitated crystals were collected by filtration to obtain 57.

Subsequently, it was dissolved in black mouth form (30 ml), and diphenyldiazomethane was added to obtain Compound 58 as crystals. Yield 3.08 g (97%).

'H-NMR (CDCl): 7.18— 7.46 (12H, m), 7.66 (1Η, m), 7.86 (2H, d, J = 6.0 Hz), 8.32 (1

H, m), 8.82 (2H, d, J = 6.3Hz), 8.90 (1H, d, J = 8.7Hz).

(41) 58 + 2 → 59

Compound 59 was obtained as a powder from Compound 58 (613 mg, 1.5 mmol) and Compound 2 (l.llg, 1.5 mmol) in the same manner as (4).

(42) 59 → 53

Compound 53 was obtained as a powder in the same manner as in Compound 59 to (5). Yield 127 mg (41%)

'H-NMR (D 2 O): 1.29 (3H, t, J = 7.2Hz), 3.68 (2H, m), 4.24 (2H, q, J = 7.2Hz), 5.28 (

1H, d, J = 4.8Hz), 5.35 (2H, d, J = 6.3Hz), 5.83 (1H, d, J = 4.8Hz), 6.10 (1H, dt, J = 6.9, 15.9Hz), 6.96 ( 1H, s), 7.04 (1H, d, J = 15.6Hz), 7.22 (1H, m), 7.50 (1H, m), 7.92 (1H, m), 8.31 (2H, d, J = 6.9Hz), 8.33 (1H, m), 8.98 (2H, d, J = 6.9Hz).

IR (KBr) cm " ¹ : 3408, 3055, 2981, 1765, 1668, 1586, 1505, 1439, 1371, 1307.

MS: 678+ (M + H) +

Elemental analysis C H N O S Na-0.6NaHCO -2H O

Calculated value: C, 46.75; Η, 3.92; N, 12.47; S, 8.16; Na, 4.68 (%)

Experimental value: C47.86; H, 4.31; N, 11.86; S, 5.93; Na, 4.56 (%)

Example 140

[Chemical 187]

(43) 61 → 62

Compound 61 (1.83 g, 10 mmol) was dissolved in dimethylformamide (30 ml), potassium carbonate (3.45 g, 25 mmol) and P-methoxybenzyl bromide (3.03 ml, 21 mmol) were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated to obtain 62 as crystals. Yield 1.58 g (37%).

'H-NMR (d-DMSO): 3.75 (3H, s), 3.77 (3H, s), 5.24 (2H, s), 5.27 (2H, s), 6.89 (2H, d

, J = 8.7Hz), 6.93 (2H, d, J = 9.0Hz), 7.31 (2H, d, J = 8.7Hz), 7.37 (2H, d, J = 8.7H z), 7.49 (1H, d, J = 9.6Hz), 8.41 (1H, dd, J = 3.0, 9.3Hz), 8.47 (1H, d, J = 2.7Hz).

(44) 62 → 63

Compound 62 (1.56 g, 3.68 mmol) was obtained in the same manner as (2) to give 63 as crystals. Yield 1.50g 'H-NMR (CDCl): 3.80 (6Η, s), 4.97 (2H, s), 5.25 (2H, s), 6.77 (1H, dd, J = 2.4, 8.4H z), 6.85 (5H, m), 7.16 (1H, d, J = 2.7Hz), 7.31 (4H, m).

(45) 54 + 63 → 64

Compound 54 (765 mg, 10 mmol) and compound 63 (1.46 g, 3.6 mmol) were obtained in the same manner as (39) to give 64. Yield 1.57g (88%).

'H-NMR (CDCl): 3.80 (3H, s), 3.81 (3H, s), 5.08 (2H, s), 5.25 (2H, s), 6.83-6.88 (4H

, M), 7.04 (1H, d, J = 9.0Hz), 7.29-7.35 (4H, m), 7.69 (2H, d, J = 5.7Hz), 7.83 (1H, d, J = 3.0Hz), 7.97 (2H, m), 8.77 (2H, d, J = 5.7Hz).

(46) 64 + 2 → 65 Compound 65 was obtained as a powder in the same manner as (4) from compound 64 (748 mg, 1.5 mmol) and compound 2 (l. L lg, 1.5 mmol).

(47) 65 → 60

Compound 60 was obtained as a powder in the same manner as Compound (5) from Compound 65. Yield 618mg (50%)

'H-NMR (DO): 1.29 (3H, t, J = 7.2Hz), 3.66 (2H, m), 4.24 (2H, q, J = 7.2Hz), 5.26 (

2

1H, d, J = 4.5Hz), 5.38 (2H, d, J = 6.9Hz), 5.82 (1H, d, J = 4.5Hz), 6.11 (1H, dt, J = 6.9, 15.6Hz), 6.90 ( 1H, d, J = 9.0Hz), 6.97 (1H, s), 7.00 (1H, d, J = 15.3Hz), 7.60 (1H, dd, J = 2.7, 8.7Hz), 7.87 (1H, d, J = 2.7Hz), 8.33 (2H, d, J = 6.6Hz), 8.99 (2H, d, J = 6.9Hz).

IR (KBr) cm— ¹ : 3420, 3056, 2982, 1764, 1633, 1538, 1492, 1436, 1377, 1316.

MS: 694 ⁺ (M + H) ⁺

Elemental analysis c H N O S Na- 0.3NaHCO-5H O

30 26 7 9 2 3 2

Calculated value: C, 43.88; H, 4.41; N, 11.82; S, 7.73; Na, 3.60 (%)

Experimental value: C, 43.98; H, 4.33; N, 11.60; S, 7.15; Na, 3.59 (%)

Example 141

[Chemicalization 188]

(48) 67 → 68

Compound 67 (2.21 g, 10 mmol) was dissolved in tetrahydrofuran (50 ml), diphenyldiazomethane was added and stirred, and then concentrated to obtain 68 as crystals. Yield 3.99g Ή-NMR (CDC1): 7.15 (1H, s), 7.31—7.44 (10Η, m), 8.13 (2H d, J = 8.7Hz), 8.36 (2H, d, J = 9.0Hz).

(49) 68 → 69

4-Aminopyridine (1.24 g, 13.2 mmol) was dissolved in pyridine, compound 68 (3.41 g, 8.8 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate, washed with water, dried and concentrated. The residue was purified by column chromatography to obtain 69 as crystals. Yield 645 mg (16%).

'H-NMR (d-DMSO): 6.93 (2H, d, J = 7.2Hz), 7.05 (1H, s), 7.27-7.53 (10H, m), 7.95

(4H, m), 8.20 (2H, d, J = 8.4Hz).

(50) 69 + 2 → 70

Compound 70 was obtained as a powder from Compound 69 (595 mg, 0.98 mmol) and Compound 2 (724 mg, 0.98 mmol) in the same manner as (4).

(51) 70 → 66

Compound 66 was obtained as a powder in the same manner as Compound (7) from Compound 70. Yield 171 mg (20%)

'H-NMR (D 2 O): 1.29 (3H, t, J = 7.2Hz), 3.60 (2H, m), 4.26 (2H, q, J = 7.2Hz), 4.82 (

2H, d, J = 6.6Hz), 5.24 (1H, d, J = 4.2Hz), 5.82 (1H, d, J = 5.4Hz), 5.95 (1H, dt, J = 6.9, 16.5Hz), 6.80 ( 1H, d, J = 16.2Hz), 6.99 (1H, s), 7.05 (2H, d, J = 6.3Hz), 7.94 (4H, s), 8.00 (2H, d, J = 6.6Hz).

IR (ATR) cm— ¹ : 3333, 2324, 2050, 1759, 1635, 1596, 1531, 2504, 1380, 1353.

MS: 714 ⁺ (M + H) ⁺

Elemental analysis C H N O S Na-7H O

Calculated value: C, 39.37; H, 4.57; N, 11.08; S, 10.87; Na, 5.20 (%)

Experimental value: C, 49.19; H, 4.31; N, 11.21; S, 10.71; Na, 5.21 (%)

Example 142

[Chemical 189]

(1) 3 → 4

Dissolve compound 3 (886 mg, 5 mmol) in dimethylformamide (10 ml) and add mono-1-butylmalonate (927 mg, 5.5 mmol) and ethyldimethylaminopropylcarbodiimide hydrochloride (1.15 g, 6 mmol). And stirred at room temperature overnight. The reaction solution was poured into 5% brine, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 4 as a powder. Yield 1.37 g (86%) 'H-NMR (CDCl): 1.54 (9H, s), 3.52 (2H, s), 7.43 (1H, s), 7.79 (2H, dd, J = 1.8, 4.8

Three

Hz), 8.65 (2H, dd, J = 1.8, 4.8 Hz), 11.0 (1H, s).

(2) 4 + 2 → 5

Compound 4 (479 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml). Compound 2 (1.20 g, 1.5 mmol) and NaBr (463 mg, 4.5 mmol) were then added and stirred overnight at room temperature. The reaction solution was poured under stirring with 5% saline, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 5 (1.60 g) as a powder.

(3) 5 → 1

Compound 5 (1.60 g) was dissolved in methylene chloride (20 ml) and anisole (0.98 ml) and cooled to _40 ° C. After 2 MTiCl in methylene chloride (4.5 ml) was added, the mixture was stirred for 45 minutes under ice cooling. Reaction

Four

2NHC1 (5 ml) -isopropyl ether (60 ml) was added to the solution and stirred. After allowing the reaction solution to stand, the supernatant was decanted and the precipitate was further washed with isopropyl ether. The precipitate was dissolved in 0.5NHC1-acetonitrile, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The eluent was further neutralized with 0.2N NaOH and concentrated, then subjected to 0 DS column chromatography and eluted with water-acetonitrile. Fluxi containing the desired compound Yon was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 1 as a powder. Yield 515mg (41%)

'H-NMR (D O) δ: 1.26 (3Η, t, J = 7.2 Hz), 3.50 (2H, brs), 3.66 (2H, brs), 4.20 (2

2

H, q, J = 7.2 Hz), 5.22-5.26 (3H, m), 5.78 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6. 9, 15.6 Hz), 6.90 (1H , s), 6.97 (1H, d, J = 15.6 Hz), 8.13 (1H, s), 8.32 (2H, d, J = 6 • 9 Hz), 8.73 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3309, 2324, 1756, 1634, 1593, 1538, 1458, 1371, 1216, 1154, 1034. MS (ESI): 699+ (M + H) +

Elemental analysis c H N NaO S -6.9 H O-0.1 NaHCO

28 25 8 8 3 2 3

Calculated values: C, 39.55; H, 4.59; N, 13.13; S, 11.27; Na, 2.96 (%)

Experimental value: C39.54; H, 4.23; N, 13.23; S, 10.96; Na, 3.09 (%)

Example 143

[Chemical 190]

(4) 7 → 8

Compound 7 (1.03 g, 5 mmol) was dissolved in dimethylformamide (10 ml), and glycine-1-butynole ester (923 mg, 5.5 mmol), ethyldimethylaminopropyl carbodiimide hydrochloride (1.15 g, 6 mmol) and triethylamine were dissolved. Min (0.77 ml, 5.5 mmol) was added and stirred overnight at 0 ° C. to room temperature. The reaction solution was extracted by adding water-ethyl acetate. The organic layer was washed with water, dried and concentrated, and purified by column chromatography to obtain 8. Yield 548 mg (34%)

'H-NMR (CDCl): 1.53 (9H, s), 4.19 (2H, d, J = 5.4 Hz), 7.79 (1H, brs), 7.86 (2H, d , J = 6.3 Hz), 7.97 (lH, s), 8.71 (2H, d, J = 6.3 Hz).

(5) 8 + 2 → 9

Compound 2 (1.20 g, 1.5 mmol) and compound 8 (479 mg, 1.5 mmol) were also obtained in the same manner as (2). Yield 1.70g

(6) 9 → 6

Compound 9 (1.70 g) was dissolved in methylene chloride (20 ml) and anisole (0.98 ml) and cooled to _40 ° C. After 2 MTiCl in methylene chloride (4.5 ml) was added, the mixture was stirred for 45 minutes under ice cooling. 2NHCl (5 ml) -isopropyl ether (60 ml) was added to the reaction solution and stirred. After allowing the reaction solution to stand, the supernatant was decanted and the precipitate was further washed with isopropyl ether. The precipitate was dissolved in 0.5NHC1-acetonitrile, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain compound 6 as a powder. Yield 739mg (60%)

'H-NMR (D O) δ: 1.27 (3Η, t, J = 6.9 Hz), 3.67 (2H, brs), 4.01 (2H, brs), 4.22 (2

H, q, J = 6.9 Hz), 5.25-5.30 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6. 9, 15.9 Hz), 6.91 (1H , s), 6.98 (1H, d, J = 15.9 Hz), 8.50 (2H, d, J = 6.9 Hz), 8.76 (1H, s), 8.83 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3362, 29970, 1751, 1634, 1593, 1531, 1456, 1377, 1216, 1156, 1034 MS (ESI): 699+ (M + H) ⁺

Elemental analysis C H N NaO S-5.4 H O-0.1 NaHCO

Calculated value: C, 40.84; Η, 4.38; Ν, 13.56; S, 11.64; Na, 3.06 (%)

Experimental value: C40.85; H, 4.33; N, 13.67; S, 11.36; Na, 3.23 (%)

Example 144

[Chemical 191]

(7) 7 → 11

To compound 7 (1.03 g, 5 mmol) was added thionyl chloride (12 ml), and the mixture was heated to reflux for 1 hour. Ethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration. Methylene chloride (15 ml) was added to the precipitated crystals, and alanine mono-t_butyl ester hydrochloride (999 mg, 5.5 mmol) and pyridine (1.5 ml, 15.5 mmol) were added and stirred at 0 ° C. Ethyl acetate and water were added to the reaction solution, and the organic layer was washed with water, dried and concentrated to obtain a crystalline residue. The residue was filtered with isopropyl ether and hexane to obtain 11. Yield 1.06 g (64%)

'H-NMR (CDCl): 1.52 (9H, s), 1.56 (3H, d, J = 6.9 Hz), 4.68 (1H, m), 7.89 (2H, d

, J = 6.3 Hz), 7.98 (lH, s), 8.71 (2H, d, J = 6.3 Hz).

(8) 11 + 2 → 12

Compound 12 (1.20 g, 1.5 mmol) and Compound ll (500 mg, 1.5 mmol) were used to obtain 12 in the same manner as (2). Yield 1.67g

(9) 12 → 10

Compound 10 (1.67 g) was also obtained in the same manner as in (6). Yield 719mg (58%) 'H-NMR (D O) δ: 1.28 (3Η, t, J = 6.9 Hz), 1.51 (3H, d, J = 7.2 Hz), 3.67 (2H, brs)

, 4.22 (2H, q, J = 6.9 Hz), 5.25-5.30 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.6, 15.6 Hz), 6.92 ( 1H, s), 6.98 (1H, d, J = 15.6 Hz), 8.51 (2H, d, J = 6.9 Hz), 8.76 (1H, s), 8.83 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3360, 2970, 1750, 1635, 1590, 1531, 1456, 1365, 1217, 1158, 1034. MS (ESI): 713+ (M + H) + Elemental analysis CHN NaO S-5.0 HO-0.1 NaHCO

Calculated values: C, 41.95; H, 4.49; N, 13.45; S, 11.54; Na, 3.04 (%)

Experimental value: C, 41.96; H, 4.54; N, 13.51; S, 11.52; Na, 3.05 (%)

Example 145

[Chemical 192]

(10) 14 → 15

15 was obtained as crystals from compound 14 (2.16 g, 5 mmol) in the same manner as in (4). Yield 1.77 g (65%) 'H-NMR (CDCl): 1.45 (9H, s), 3.39 (2H, d, J = 4.8 Hz), 5.77 (1H, t, J = 4.8 Hz),

6.97 (1H, s), 7.16-7.33 (15H, m), 7.59 (2H, dd, J = 1.5, 4.5 Hz), 8.57 (2H, dd, J = 1.5, 4.5 Hz).

(11) 15 + 2 → 16

16 was obtained from Compound 2 (1.20 g, 1.5 mmol) and Compound 15 (817 mg, 1.5 mmol) in the same manner as (2). Yield 1.91g

(12) 16 → 13

Compound 16 (931 mg, 5 mmol), 13 was obtained as a powder in the same manner as in (6). Yield 512mg (41%) 'H-NMR (DO) δ: 1.28 (3Η, t, J = 7.2 Hz), 3.66 (2H, brs), 3.96 (2H, s), 4.23 (2H, q, J = 7.2 Hz), 5.23-5.26 (3H, m), 5.80 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6.6, 15.6 Hz), 6.93 (1H, s), 6.96 (1H, d , J = 15.6 Hz), 7.47 (1H, s), 8.28 (2H, d, J = 6.9 Hz), 8.73 (2H, d, J = 6.9 Hz). IR (KBr) cm: 3323, 1755, 1634, 1587, 1532, 1474, 1385, 1295, 1216, 1154, 1034. MS (ESI): 682+ (M + H) +

Elemental analysis C H N NaO S -4.8 H O-0.4 NaHCO

Calculated: C41.41; H, 4.40; N, 15.30; SJ.79; Na, 3.91 (%)

Experimental value: C41.20; H, 4.59; N, 15.34; SJ.79; Na, 4.21 (%)

Example 146

[Chemical 193]

(13) 18 → 19

Compound 19 was obtained in the same manner as Compound 18 (579 mg, 2.1 mmol) and mono-1-butylmalonic ester (368 mg, 2.3 mmol), et al. (1). Yield 612mg (72%)

'H-NMR (CDCl): 1.51 (9H, s), 3.37 (2H, s), 3.78 (3H, s), 5.33 (2H, s), 6.85 (2H, dd, J = 2.1, 6.6 Hz), 6.97 (1H, s), 7.24 (2H, dd, J = 2.1, 6.6 Hz), 7.81 (2H, dd, J = 1.5, 4.8 Hz), 8.60 (2H, dd, J = 1.5, 4.8 Hz), 9.94 (1H, brs).

(14) 19 + 2 → 20

Compound 20 (1.20 g, 1.5 mmol) and Compound 19 (612 mg, 1.5 mmol) 20 were obtained in the same manner as (2). Yield 1.70g

(15) 20 → 17

In the same manner as in (6), 17 was obtained as a powder from compound 20 (1.70 g). Yield 271 mg (23%).

'H-NMR (DO) 5: 1.27 (3Η, t, J = 6.9 Hz), 3.40 (2H, s), 3.66 (2H, s), 4.22 (2H, q, J = 6.9 Hz), 5.23-5.28 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.09 (1H, dt, J = 6.9, 15.6 Hz), 6.92 (1H, s), 6.96 (1H, d, J = 15.6 Hz), 8.22 (2H, d, J = 6.9 Hz), 8.75 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3291, 1752, 1636, 1586, 1533, 1475, 1373, 1216, 1155, 1034.

MS (ESI): 682+ (M + H) +

Elemental analysis c H N NaO S -4.6 H O-0.1 NaHCO

Calculated values: C, 42.46; H, 4.48; N, 15.86; S, 8.07; Na, 3.18 (%)

Experimental value: C42.48; H, 4.55; N, 15.69; SJ.96; Na, 3.43 (%)

Example 147

[Chemical 194]

(16) 22 → 23

Compound 22 (1.21 g, 3 mmol) was dissolved in methylene chloride (12 ml), and pyridine (0.26 ml, 3.15 mmol) and t_butyl succinate chloride (518 mg, 3.15 mmol) were added under ice-cooling for 1 hour. Stir. Ethyl acetate and water were added to the reaction solution, and the organic layer was washed with water, dried and concentrated to obtain a crystalline residue. Isopropyl ether was added to the residue and collected by filtration to obtain 23 as a powder. Yield 1.37g (86%) 'H-NMR (d-DMSO): 1.29 (9H, s), 7.13-7.16 (6H, m), 7.23 (1H, s), 7.36-7.44 (

9H, m), 7.54 (2H, d, J = 5.7 Hz), 8.26 (1H, brs), 8.58 (2H, d, J = 5.7 Hz).

(17) 23 + 2 → 24

24 was obtained from Compound 2 (1.20 g, 1.5 mmol) and Compound 23 (796 mg, 1.5 mmol) in the same manner as (2). Yield 1.86g (18) 24 → 21

Compound 24 (1.86 g) was also obtained as a powder in the same manner as (6). Yield 291 mg (16%).

'H-NMR (D O) δ: 1.28 (3Η, t, J = 6.9 Hz), 3.66 (2H, brs), 4.22 (2H, q, J = 6.9 Hz)

, 5.25 (3H, m), 5.80 (1H, d, J = 4.5 Hz), 6.10 (1H, dt, J = 6.6, 15.9 Hz), 6.93 (1H, s), 6.96 (1H, d, J = 15.9 Hz), 8.24 (2H, d, J = 6.9 Hz), 8.77 (2H, d, J = 6.9 Hz). IR (KBr) cm— ¹ : 3284, 1753, 1636, 1595, 1531, 1366, 1205, 1154 , 1033.

MS (ESI): 668+ (M + H) +

Elemental analysis C H N NaO S -6.8 H O

Calculated values: C, 39.93; H, 4.67; N, 15.52; SJ.90; Na, 2.83 (%)

Experimental value: C39.95; H, 4.38; N, 15.39; SJ.83; Na, 3.12 (%)

Example 148

[Chem 195]

(19) 26 + 2 → 27

27 was obtained from Compound 2 (1.20 g, 1.5 mmol) and Compound 26 (463 mg, 1.5 mmol) in the same manner as (2). Yield 1.70g

(20) 27 → 25

Compound 27 (1.70 g) force was also obtained in the same manner as (6) to obtain 25 as a powder. Yield 250 mg (34%).

'H-NMR (D O) δ: 1.29 (3Η, t, J = 6.9 Hz), 3.67 (2H, brs), 4.24 (2H, q, J = 6.9 Hz)

, 5.26 (1H, d, J = 4.5 Hz), 5.32 (2H, d, J = 7.2 Hz), 5.81 (1H, d, J = 4.5 Hz), 6.12 (1H, dt, J = 7.2, 15.9 Hz) , 6.95 (1H, s), 6.99 (1H, d, J = 15.9 Hz), 8.38 (1H, s), 8.52 (2H, d, J = 6.9 Hz), 8.75 (2H, d, J = 6.9 Hz) . IR (KBr) cm: 3309, 1752, 1590, 1523, 1466, 1352, 1216, 1156,

MS (ESI): 642+ (M + H) +

Elemental analysis C H N NaO S -4.1 H O-O. l NaHCO

Calculated value: C, 42.02; H, 4.09; N, 13.14; S, 12.90; Na, 3.39 (%)

Experimental value: C41.95; H, 4.15; N, 13.18; S, 12.97; Na, 3.72 (%)

Example 149

[Chem 196]

(37) 48 + 49 → 50

Compound 48 (6.59 g, 70 mmol) and compound 49 (16.6 g, 77 mmol) were mixed and stirred while heating at 110 ° C. for 3 hours. The ethanol produced was distilled off, and the residue was purified by column chromatography to obtain 50 as crystals. Yield 17.9g (97%)

'H-NMR (CDCl): 1.32-1.41 (6H, m), 4.24-4.36 (4H, m), 7.02 (2H, dd, J = 1.5,

4.5 Hz), 8.49-8.54 (3H, m), 10.9 (1H, d, J = 13.2 Hz).

(38) 50 → 51

Compound 50 (5.29 g, 20 mmol) was stirred with diphenyl ether (20 ml) at 240 ° C. for 20 minutes with heating. Isopropyl ether was added to the reaction solution to obtain 51 as a precipitate. Yield 990 mg

1H-NMR (CDCl): 1.28 (3H, t, J = 7.2 Hz), 4.22 (2H, q, J = 7.2 Hz), 7.51 (2H, d, J

= 5.4 Hz), 8.63-8.65 (2H, m), 9.24 (1H, s).

(39) 51 → 52 Compound 51 (1.0 g, 4.5 mmol) was dissolved in ethanol (10 ml), 2N NaOH (6.5 ml) was added, and the mixture was stirred at 70 ° C. for 1.5 hours. The reaction solution was neutralized with 6NHC1, and ethanol was distilled off. The residue of the aqueous solution was adjusted to PH 2.6, and the precipitate was collected by filtration and dried to obtain Compound 52. Yield 544 mg (64%)

'H-NMR (d-DMSO): 7.72 (1H, d, J = 6.0 Hz), 8.84 (1H, d, J = 6.0 Hz), 9.01 (1H, s), 9.46 (1H, s), 13.5 ( 1H, brs), 14.7 (1H, brs).

(40) 52 → 53

Compound 52 (544 mg, 2.9 mmol) was dissolved in tetrahydrofuran (10 ml), and diphenyldiazomethane (1.95 g) was added thereto and stirred at reflux. The reaction mixture was concentrated, isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration and dried to give compound 53. Yield 654mg (64%)

'H-NMR (d-DMSO): 7.00 (1H, s), 7.24-7.60 (11H, m), 7.19 (1H, d, J = 6.0 Hz),

8.74 (1H, s), 9.32 (1H, s).

(41) 53 + 2 → 54

54 was obtained in the same manner as (2) from Compound 2 (1.20 g, 1.5 mmol) and Compound 54 (535 mg, 1.5 mmol). Yield 1.67g

(42) 54 → 47

Compound 54 (1.67 g) force was also obtained as 47 in the same manner as (6). Yield 241 mg (21%).

'H-NMR (D O) δ: 1.30 (3Η, t, J = 7.8 Hz), 3.66 (2H, brs), 4.25 (2H, q, J = 7.8 Hz)

, 5.23-5.27 (3H, m), 5.82 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.9, 13.8 Hz), 6.9 6 (1H, d, J = 13.8 Hz), 6.99 (1H, s), 7.83 (1H, d, J = 7.2 Hz), 8.33 (1H, dd, J = 1.5, 7.2 Hz), 8.70 (1H, s), 9.39 (1H, d, J = 1.5 Hz) .

IR (KBr) cm— ¹ : 3315, 1750, 1650, 1587, 1536, 1474, 1366, 1314, 1201, 1173, 1114, 1034.

MS (ESI): 626+ (M + H) +

Elemental analysis c H N Na O S-4.5 H O-0.1 NaHCO

Calculated values: C, 41.30; H, 4.00; N, 12.92; S, 8.45; Na, 6.36 (%)

Experimental value: C41.33; H, 3.91; N, 12.76; S, 8.40; Na, 6.52 (%)

Example 150 [Chemical 197]

(1) 3 + 4 → 5

Compound 4 (1.63 g, 10.8 mmol) was dissolved in dimethylformamide (9 ml), and compound 3 (1.08 g, 9 mmol) was collected and stirred at room temperature for 1 hour, and then left overnight. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried and purified by silica gel chromatography to obtain 5 as crystals. Yield 1.8g (74%).

'H-NMR (d-DMSO): 3.69 (3H, s), 7.25—7.31 (2H, m), 7.4_7.5 (2H, m), 8.03 (lH, m),

8.18-8.21 (2H, m), 8.99 (lH, bs).

(2) 5 → 6

Compound 5 (1.76 g, 6.5 mmol) was suspended in EtOHlOml, and 7 ml of 2N NaOH was added dropwise and stirred for 4.5 hours. The reaction solution was neutralized with 7 ml of 2N HC1, and then 40 ml of water was added. The precipitate was collected by filtration and dried to obtain 6 as a solid. Yield (1.75g)

(3) 6 → 7

After dissolving dimethylformamide (10 ml) in compound 6 (1.75 g, 6.5 mmol), carbonyldiimidazole (2.1 g, 13 mmol) was added and stirred at 40 ° C. for 30 minutes. Next, 6.7 ml of prenyl alcohol and 5 mg of 4-dimethylaminopyridine were added and stirred at 60 ° C. for 3.5 hours. The reaction mixture was cooled, and extracted by adding ethyl acetate and water. The organic layer was washed with an aqueous sodium bicarbonate solution and water, then dried and concentrated. The residue obtained was purified by silica gel chromatography to obtain 7. yield l. lg (52%).

'H-NMR (d-DMSO): 1.75 (6H, m), 4.79 (2H, d, J = 7.2Hz), 5.44 (1H, m), 7.4-7.47 (2H, m), 7.6-7.7.7 (2H, m), 8.15 (H, m), 8.36-7 · 38 (2Η, m) 9.19 (1H, bs).

(4) 7 + 2 → 8

Compound 2 (674 mg, lmmol) was suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (126 mg, 1.5 mmol dissolved in 10 ml of water) was added under ice cooling, extracted with dichloromethane, and dried over sodium sulfate. . After distilling off the solvent, quickly dissolved in dimethylformamide (2 ml), mixed with compound 7 (325 mg, l.Ommol), added sodium bromide (309 mg, 3 mmol), and stirred at room temperature for 4 hours. . The reaction solution was poured under stirring with 5% brine (40 ml), and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 8 (896 mg) as a powder.

(5) 8 → 1

Compound 8 (896 mg) was dissolved in methylene chloride (5 ml) and anisole (0.8 ml), cooled to 0 ° C., and 2.4 ml of TFA was added. The mixture was stirred at 0 ° C for 2 hours and then poured into 50 ml of isopropyl ether with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with saturated NaHCO 3 aqueous solution. The solution was subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 1 as a powder. Yield 361 mg (45%)

'H-NMR (D O): 1 · 16 (3Η, t, J = 7.2Hz), 3.52 (2H, ABq, J = 18.3Hz), 4.11 (2H, q, J =

7.2 Hz), 4.89 (2H, d, J = 6.6Hz), 5.13 (1H, d, J = 4.8Hz), 5.69 (1H, d J = 4.8Hz), 5.9

1 (1H, dt, J = 15.9, 6.6Hz), 6.70 (1H, d, J = 15.9Hz) 6.84 (1H, s), 7.29 (1H, m), 7.4-7.

5 (2H, m), 7.64 (lH, m), 7.68 (2H, d, J = 7.2Hz), 8.24 (2H, d, J = 7.2Hz).

IR (KBr) cm— ¹ : 1766, 1725, 1614, 1522.

MS: 693+ (M-Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated value: C, 45.28; H, 4.56; N, 14.08; S, 8.06; Na, 2.87 (%)

Experimental value: C, 45.43; H, 4.46; N, 14.04; S, 8.15; Na, 3.28 (%)

Example 151

[Chemical 198]

14

(6) 3 + 10 → l l

11 was obtained as crystals from compound 10 (1.63 g, 10.8 mmol) and compound 3 (1.08 g, 9 mmol) in the same manner as (1). Yield 1.76 g (72%).

'H-NMR (d-DMSO): 3.38 (3H, s), 7.42-7.44 (2H, m), 7, 58 (2H, d, J = 9Hz), 7, 89 (2H,

6

d, J = 9Hz) 8.35-8.37 (2H, m), 9.25 (1H, bs), 9.29 (1H, bs).

(7) 11 → 12

In the same manner as in (2), 12 was obtained as a solid from compound l 1 (1.48 g, 5.5 mmol). Yield (1.30g)

(8) 12 → 13

Compound 12 (1.2 g, 4.6 mmol) was obtained in the same manner as (3) to give 13. Yield 1.18 g (72%).

'H-NMR (d-DMSO): 1.74 (6H, m), 4.75 (2H, d, J = 7.2Hz), 5.43 (1H, m), 7.44-7.46 (2H,

6

m), 7.59 (2H, J = 8.7Hz), 7.89 (2H, J = 8.7Hz), 8.36-7.38 (2mm, m) 9.27 (2H, bs).

(9) 13 + 2 → 14

Compound 14 (914 mg) was obtained from Compound 2 (674 mg, lmmol) and Compound 13 (325 mg, l.Ommol) in the same manner as (4).

(10) 14 → 9

Compound 14 (914 mg) was obtained in the same manner as (5) to give Compound 9 as a powder. Yield 410 mg (51%) 'H-NMR (D 2 O): 1.27 (3H, t, J = 6.9 Hz), 3.65 (2H, bs), 4.21 (2H, q, J = 6.9 Hz), 5.00

2

(2H, d, J = 6.9Hz), 5.25 (1H, d, J = 4.2Hz), 5.81 (1H, d J = 4.8Hz), 6.05 (1H, dt, J = 1 6.2, 6.9Ηζ), 6.80 (1H, d, J = 16.2Hz) 6.95 (1H, s), 7.41 (1H, bd, J = 8.1Hz), 7.78 (4H, b d + bd, J = 6.9Hz , 8.1Hz), 8.35 (2H, d, J = 6.9Hz).

IR (KBr) cm— ¹ : 1765, 1601, 1518.

MS: 693 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.6H O

Calculated values: C, 45.18; H, 4.57; N, 14.05; S, 8.04; Na, 2.88 (%)

Experimental value: C, 44.94; H, 4.38; N, 14.14; SJ.98; Na, 3.19 (%)

Example 152

[Chemical 199]

(11) 16 + 4 → 17

Compound 16 (1.23 g, l mmol) is suspended in dimethylformamide (10 ml), carbonyldiimidazole (1.62 g, 10 mmol) is added and stirred. Compound 4 (1.69 g, llmmol) was then added and stirred at room temperature for 1 hour. Ethyl acetate-water-sodium bicarbonate was added to the reaction solution and stirred. The precipitate was collected by filtration and dried to obtain 17. Yield 0.70 g (27%).

'H-NMR (d-DMSO): 3.88 (3H, s), 7.54 (lH, t), 7.74 (lH, d), 7.89 (2H, m), 8.07 (1H, m)

, 8.46 (1H, m), 8.8l (2H, m).

(12) 17 → 18

Compound 18 (927 mg, 3.62 mmol) was also obtained in the same manner as (2). Yield 813 mg (93%). (13) 18 → 19

Compound 18 (813 mg, 3.36 mmol) was obtained in the same manner as (3) to give 19. Yield 926 mg (90%).

'H-NMR (d-DMSO): 1.76 (6H, m), 4.81 (2H, d, J = 7.2Hz), 5.45 (1H, m), 7.53 (lH, m)

7.72 (1H, m), 7.89 (2H, m), 8.09 (1H, m), 8.40 (1H, m) 8.80 (2H, m).

(14) 19 + 2 → 20

Compound 20 (918 mg) was obtained as a powder from Compound 2 (674 mg, lmmol) and Compound 19 (310 mg, l.Ommol) in the same manner as in (4).

(15) 20 → 15

Compound 15 (918 mg) was obtained in the same manner as (5) to give compound 15 as a powder. Yield 175 mg (20%) 'H-NMR (D 2 O): 1.18 (3H, t, J = 7.2Hz), 3.54 (2H, bs), 4.13 (2H, q, J = 7.2 Hz), 5.15 (

1H, d, J = 4.8Hz), 5.28 (2H, d, J = 6.6Hz), 5.70 (1H, d J = 4.8Hz), 6.00 (1H, dt, J = 1

5.6, 6.6Hz), 6.85 (1H, d, J = 15.6Hz) 6.86 (1H, s), 7.41 (1H, m), 7.62-7.68 (4H, m), 8.

32 (2H, d, J = 6.9Hz), 8.93 (2H, d, J = 6.9Hz).

IR (KBr) cm " ¹ : 1765, 1667, 1608, 1557.

MS: 678+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated values: C, 46.15; H, 4.52; N, 12.56; S, 8.21; Na, 2.94 (%)

Experimental value: C, 45.94; H, 4.24; N, 12.58; S, 8.04; Na, 3.48 (%)

Example 153

[Chemical 200]

(16) 22 + 4 → 23

In a nitrogen atmosphere, Pd (dba) 169 mg, l, 3-Bis (2,6-diisopripylphenyl) imi dazolium chloride 126 mg, potassium t-butoxide 166 mg, cesium carbonate 9.64 g were added to 45 ml of dioxane, and then compound 22 (1.68 g , 14.8 mmol) and compound 4 (2.68 g, 17.7 mmol) were added, and the mixture was stirred at 100 ° C for 8 hours. The reaction solution was cooled, and extracted by adding 30 ml of 1NHC1, water and ethyl acetate. The organic layer was washed with water, dried and concentrated, and the resulting residue was purified by silica gel chromatography to give 23 as crystals. Yield 1.04 g (31%).

'H-NMR (d-DMSO): 3.86 (3H, s), 6.93 (2H, m), 7.48 (2H, m), 7.59 (lH, m), 7.75 (1H, m), 8.23 (2H, m ), 9.01 (lH, s).

(17) 23 → 24

24 was obtained from Compound 23 (1.04 g, 4.5 mmol) in the same manner as in (2). Yield 949 mg (98%).

(18) 24 → 25

Compound 24 (914 mg, 4.3 mmol) was obtained in the same manner as (3) to give 25. Yield 803 mg (67%).

'H-NMR (d-DMSO): 1.73 (6H, m), 4.77 (2H, d, J = 7.2Hz), 5.42 (1H, m), 6.91 (2H, m),

7.46 (2H, m), 7.56 (lH, m), 7.71 (1H, m), 8.21 (2H, m), 8.99 (lH, s).

(19) 25 + 2 → 26

Compound 26 (873 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 25 (282 mg, l.Ommol) in the same manner as (4).

(20) 26 → 21

Compound 26 (873 mg) was obtained in the same manner as (5) to give compound 21 as a powder. Yield 307mg (32%) 'H-NMR (D O): 1 · 18 (3Η, t, J = 6 · 9Ηζ), 3.51 (2H, ABq, J = 18.5Hz), 4.13 (2H, q, J =

6.9Hz), 4.75 (2H, d, J = 6.3Hz), 5.12 (1H, d, J = 4.8Hz), 5.69 (1H, d J = 4.8Hz), 5.90 (

1H, m), 6.65 (1H, d, J = 15.6Hz), 6.86 (1H, s), 6.97 (2H, J = 7.5Hz), 7.33 (1H, m), 7.4

0 (lH, m), 7.65 (2H, m), 7.95 (2H, d, J = 7.5Hz).

IR (KBr) cm— ¹ : 1763, 1647, 1606, 1541.

MS: 650+ (M-Na + 2H) +

Elemental analysis C H N O S Na-4H O

Calculated value: C, 46.83; H, 4.61; N, 13.18; S, 8.62; Na, 3.09 (%) Experimental value: C, 46.81; H, 4.54; N, 13.31; S, 8.80; Na, 3.35 (%)

Example 154

[Chemical 201]

32

(21) 3 + 28 → 29

29 was obtained as a crystal from compound 28 (1.78 g, 10.8 mmol) and compound 3 (1.08 g, 9 mmol) in the same manner as in (1). Yield 565 mg (81%).

'H-NMR (d-DMSO): 2.35 (3H, s), 3.82 (3H, s), 7.27 (lH, m), 7.42 (2H, m), 7.46 (lH, m)

7.84 (1H, m), 8.30 (lH, bs), 8.34 (2H, m), 9.43 (lH, bs).

(22) 29 → 30

Compound 29 (2.07 g, 7.3 mmol) force 30 was obtained in the same manner as (2). Yield 1.79 g (91%).

(23) 30 → 31

Compound 30 (1.79 g, 6.6 mmol) was obtained in the same manner as (3) to give 31. Yield 1.88 g (84%).

'H-NMR (CDCl 3): 1.76 (6H, m), 2.41 (1H, s), 4.77 (2H, d, J = 6.9Hz), 5.43 (1H, m),

7.23 (lH, m), 7.43 (2H, m), 7.47 (lH, bs), 7.63 (lH, m), 7.72 (lH, m), 8.33 (2H, m), 8.77 (lH, s).

(24) 31 + 2 → 32

Compound 3 2 (936 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 31 (339 mg, l.Ommol) in the same manner as (4). (25) 32 → 27

Compound 32 (936 mg) was obtained in the same manner as (5) to give compound 27 as a powder. Yield 437mg (51%) H-NMR (D 0): 1 · 30 (3Η, t, J = 7.2Hz), 2.26 (3H, s), 3.64 (2H, bs), 4.25 (2H, q, J = 7.2

Hz), 5.06 (2H, d, J = 6.6Hz), 5.25 (1H, d, J = 4.8Hz), 5.81 (1H, d J = 4.8Hz), 6.06 (1H: m), 6.83 (1H, d , J = 15.6Hz), 6.99 (1H, s), 7.25—7.38 (3H, m), 7.88 (2H, d, J = 7.2Hz), 8.44 (2H, d, J = 7.2Hz).

IR (KBr) cm— ¹ : 1765, 1723, 1604, 1519.

MS: 707 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4H O

Calculated values: C, 46.50; H, 4.66; N, 13.99; S, 8.01; Na, 2.87 (%)

Experimental value: C46.47; H, 4.56; N, 13.97; SJ.71; Na, 3.24 (%)

Example 155

[Chemical 202]

(26) 22 + 10 → 34

34 was obtained as a crystal from compound 22 (897 mg, 7.9 mmol) and compound 10 (1.43 g, 9.5 mmol) in the same manner as in (16). Yield 1.06 g (59%).

'H-NMR (d-DMSO): 3.82 (3H, s), 7.06 (2H, m), 7.27 (2H, d, J = 8.7Hz), 7.90 (2H, d, J

= 8.7Hz), 8.30 (2H, m), 9.25 (1H, bs), 9.27 (1H, bs).

(27) 34 → 35 Compound 34 (1.05 g, 4.6 mmol) force 35 was obtained in the same manner as (2). Yield 824 mg (84%).

(28) 35 → 36

Compound 35 (817 mg, 3.8 mmol) was obtained in the same manner as (3) to give 36. Yield 772 mg (72%).

'H-NMR (d-DMSO): 1.74 (6H, m), 4.75 (2H, d, J = 6.9Hz), 5.43 (1H, m), 7.06 (2H, m),

7.27 (2H, J = 9Hz), 7.89 (2H, J = 9Hz), 8.30 (2H, m) 9.27 (1H, bs).

(29) 36 + 2 → 37

Compound 37 (859 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 36 (282 mg, 1.0 mmol) in the same manner as in (4).

(30) 37 → 33

Compound 37 (859 mg) was obtained in the same manner as (5) to give compound 33 as a powder. Yield 351 mg (43%) 'H-NMR (D 2 O): 1.29 (3H, t, J = 6.9 Hz), 3.64 (2H, bs), 4.25 (2H, q, J = 6.9 Hz), 4.88

(2H, dJ = 6Hz), 5.24 (lH, d, J = 4.8Hz), 5.80 (1H, d, J = 4.8Hz), 6.03 (1H, m,), 6.77 (1H

, D, J = 15.6Hz), 6.97 (1H, s), 7.16 (2H, d, J = 6Hz), 7.36 (2H, d, J = 8.4Hz), 7.92 (2H, d

, J = 8.4Hz), 8.09 (1H, d, J = 7Hz).

IR (KBr) cm " ¹ : 1762, 1648, 1602, 1536.

MS: 650+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated: C, 46.27; H, 4.69; N, 13.03; S, 8.52; Na, 3.05 (%)

Experimental value: C, 46.14; H, 4.58; N, 13.08; S, 8.60; Na, 3.06 (%)

Example 156

[Chemical 203]

(31) 4 + 39 → 40

Compound 4 (1.51 g, 10 mmol) was suspended in ethyl acetate (30 ml), 3. lml of triethylamine was added, then compound 39 (1.78 g, 10 mmol) was added, and the mixture was stirred at room temperature. After standing overnight, the reaction mixture was further added with ethyl acetate and washed with water-sodium bicarbonate. The organic layer was dried and concentrated, and the resulting residue was purified by silica gel chromatography to obtain 40 as crystals. Yield 1.05 g (41%). 'H-NMR (d-DMSO): 3.88 (3H, s), 7.54 (lH, m), 7.59 (lH, m), 7.72 (lH, m), 8.07 (lH, m)

, 8.32 (1H, m), 8.47 (lH, m), 8.78 (lH, m), 9.14 (lH, m), 10.66 (lH, bs).

(32) 40 → 41

Compound 40 (1.05 g, 4.1 mmol) was obtained in the same manner as (2) to obtain 41. Yield 898 mg (91%).

(33) 41 → 42

Compound 41 (898 mg, 3.7 mmol) was obtained in the same manner as (3) to give 42. Yield 1.13 g (93%).

'H-NMR (d-CDC1): 1.78 (6H, m), 4.82 (2H, d, J = 6.6Hz), 5.47 (1H, m), 7.47 (1H, m),

7.51 (1H, m), 7.86 (lH, m), 8.10 (lH, m), 8.16 (lH, m), 8.30 (lH, m), 8.33 (lH, bs), 8.79 (lH, m), 9.21 (lH, bs).

(34) 42 + 2 → 43

Compound 43 (882 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 42 (310 mg, l.Ommol) in the same manner as (4).

(35) 43 → 38 Compound 43 (882 mg) was obtained in the same manner as (5) to give Compound 38 as a powder. Yield 292mg (36%) 'H-NMR (DO): 1.29 (3H, t, J = 6.9Hz), 3.66 (2Η, bs), 4.24 (2H, q, J = 6.9Hz), 5.26 (

1H, d, J = 4.5Hz), 5.42 (2H, d, J = 6.6Hz), 5.81 (1H, d, J = 4.5Hz), 6.14 (lH, m), 6.99

(1H, s), 6.98 (1H, d, J = 15.9Hz), 7.52 (1H, m), 7.7—7.8 (2H, m), 7.96 (lH, m), 8.21 (1H, m), 8.97- 9.04 (2H, m), 9.39 (1H, bs).

IR (KBr) cm— ¹ : 1765, 1670, 1609, 1559.

MS: 678 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.5H O

Calculated value: C, 46.15; H, 4.52; N, 12.56; S, 8.21; Na, 2.94 (%)

Experimental value: C46.29; H, 4.37; N, 12.73; S, 8.21; Na, 3.29 (%)

Example 157

[Chemical 204]

(36) 45 + 4 → 46

Compound 45 (0.96 ml, 10 mmol) and compound 4 (1.81 g, 12 mmol) were obtained in the same manner as (16) as 46. Yield 375 mg (16%).

'H-NMR (d-DMSO): 3.84 (3H, s), 7.27-7.53 (4H, m), 7.65 (lH, m), 8.10 (lH, m), 8.38 (1

H, m), 8.62 (1H, s).

(37) 46 → 47

Compound 46 (372 mg, 1.6 mmol) 47 was obtained in the same manner as the force (2). Yield 338 mg (97%). (38) 47 → 48

Compound 47 (338 mg, 1.6 mmol) was obtained in the same manner as (3) to give 48. Yield 406 mg (91%).

'H-NMR (d -CDC1): 1 · 79 (6Η, m), 4.81 (2H, d, J = 7.2Hz), 5.46 (1H, m), 6.01 (lH, bs),

7.20-7.48 (3H, m), 7.66 (lH, m), 7.74 (lH, m), 8.20 (lH, m), 8.42 (lH, m).

(39) 48 + 2 → 49

Compound 49 (878 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 48 (282 mg, l.Ommol) in the same manner as (4).

(40) 49 → 44

Compound 49 (878 mg) was obtained in the same manner as (5) to give Compound 44 as a powder. Yield 352 mg (44%) 'H-NMR (D 2 O): 1.30 (3H, t, J = 7.2Hz), 3.63 (2H, bs), 4.25 (2H, q, J = 7.2Hz), 5.14 (

2H, d, J = 7.2Hz), 5.26 (lH, d, J = 4.8Hz), 5.82 (1H, d, J = 4.8Hz), 6.07 (lH, m), 6.86 (1H

, D, J = 15.9Hz), 6.99 (1H, s), 7.38 (lH, m), 7.48 (lH, m), 7.64-7.75 (2H, m), 7.96 (1H, m),

8.11 (lH, m), 8.30 (lH, bs).

IR (KBr) cm " ¹ : 1764, 1565, 1509.

MS: 650+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4H O

Calculated values: C, 46.83; H, 4.61; N, 13.18; S, 8.62; Na, 3.09 (%)

Experimental value: C, 46.78; H, 4,46; N, 13.31; S, 8.79; Na, 3.31 (%)

Example 158

[Chemical 205]

(41) 10 + 39 → 51

Compound 10 (1.51 g, 10 mmol) and compound 39 (1.78 g, 10 mmol) were obtained in the same manner as (31) to give 51. Yield 885 mg (35%).

'H-NMR (d-DMSO): 3.85 (3H, s), 7.59 (lH, m), 7.96 (2H, m), 8.31 (lH, m), 8.79 (lH, m),

9.12 (1H, m).

(42) 51 → 52

Compound 51 (881 mg, 3.4 mmol) was obtained in the same manner as (2) to give 52. Yield 777 mg (93%).

(43) 52 → 53

Compound 52 (777 mg, 3.2 mmol) was obtained in the same manner as (3) to give 53. Yield 675 g (63%).

'H-NMR (d-DMSO): 1.74 (6H, m), 4.78 (2H, d, J = 7.2Hz), 5.44 (1H, m), 7.59 (lH, m),

7.95 (4H, m), 8.31 (lH, m), 8.78 (lH, m), 9.12 (lH, m).

(44) 53 + 2 → 54

Compound 54 (896 mg) was obtained as a powder in the same manner as Compound 2 (675 mg, lmmol) and Compound 53 (310 mg, l.Ommol) force (4).

(45) 54 → 50

Compound 54 (896 mg) was obtained in the same manner as (5) to give compound 50 as a powder. Yield 316mg (40%) 'H-NMR (D 2 O): 1.28 (3H, t, J = 6.9Hz), 3.66 (2H, ABq, J = 19.4, 17.6Hz), 4.22 (2H, q,

J = 6.9Hz), 5.26 (1H, d, J = 4.8Hz), 5.41 (2H, dJ = 6.6Hz), 5.81 (1H, d, J = 4.8Hz), 6.1 4 (1H, m), 6.96 ( 1H, s), 6.99 (lH, d, J = 12.9Hz), 7.64 (2H, d, J = 8.1Hz), 7.87 (2H, d, J = 8.1) Hz), 8.19 (lH, m), 8.94 (1H, d, J = 8.1Hz), 9.03 (lH, d, J = 6Hz), 9.36 (lH, bs).

IR (KBr) cm— ¹ : 1765, 1669, 1603, 1532.

MS: 678+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5.5H O

Calculated values: C, 45.11; H, 4.67; N, 12.27; S, 8.03; Na, 2.88 (%)

Experimental value: C, 45.15; H, 4.44; N, 12.44; S, 8.28; Na, 3.34 (%)

Example 159

[Chemical 206]

(46) 56 → 57

After dissolving dimethylformamide (15 ml) in compound 56 (1.38 g, 10 mmol), carbonyldiimidazole (1.95 g, 12 mmol) was added, and the mixture was stirred at 55 ° C. for 30 minutes. Next, 10 ml of prenyl alcohol was added and stirred at 55 ° C. for 8 hours. After cooling the reaction solution, extraction was performed with cetyl acetate and water. The organic layer was washed with an aqueous sodium bicarbonate solution and water, then dried and concentrated. The residue obtained was purified by silica gel chromatography to obtain 57. Yield 1.48 g (72%).

'H-NMR (CDCl): 1.79 (6H, m), 4.78 (2H, d, J = 7.8Hz), 5.45 (1H, m), 6.48 (lH, d, J

= 8.4Hz), 8.03 (1H, dd, J = 2.4, 8.4Hz), 8.72 (lH, d, J = 2.4Hz).

(47) 3 + 57 → 58

58 was crystallized from Compound 57 (1.24 g, 6 mmol) and Compound 3 (720 mg, 6 mmol) in the same manner as (1). Yield 620 mg (32%). NMR-NMR (d-DMSO): 1.74 (6H, m), 4.79 (2H, d, J = 7.2Hz), 5.44 (1H, m), 7.53 (2H, m),

7.73 (1H, d, J = 8.7Hz), 8.24 (1H, dd, J = 2.4, 8.7Hz), 8.41 (2H, m), 8.84 (lH, dd, J = 0.6, 2.4Hz).

(48) 58 + 2 → 59

Compound 59 (94 4 mg) was obtained from Compound 2 (674 mg, lmmol) and Compound 58 (326 mg, lmmol) in the same manner as in (4).

(49) 59 → 55

Compound 59 (944 mg) was obtained in the same manner as (5) to give compound 55 as a powder. Yield 290 mg (36%) 'H-NMR (D 2 O): 1.27 (3H, t, J = 7.2 Hz), 3.66 (2H, bs), 4.21 (2H, q, J = 7.2 Hz), 5.08

(2H, d, J = 6.9Hz), 5.25 (lH, d, J = 4.5Hz), 5.81 (1H, d, J = 4.5Hz), 6.07 (1H, m), 6.8

8 (1H, d, J = 15.6Hz), 6.94 (1H, s), 7.30 (1H, d, J = 9.3Hz), 7.93 (2H, d, J = 7Hz), 8.12 (

1H, d, J = 8.7Hz), 8.47 (2H, d, J = 7Hz), 8.67 (1H, br s).

IR (KBr) cm " ¹ : 1766, 1590, 1516.

MS: 694+ (M_Na + 2H) +

Elemental analysis C H N O S Na- 5H O

Calculated values: C, 43.23; H, 4.50; N, 15.64; S, 7.96; Na, 2.85 (%)

Experimental value: C, 43.35; H, 4.40; N, 15.75; S, 8.12; Na, 3.49 (%)

Example 160

[Chemical 207]

(50) 56-1 + 57- 1 → 58- 1

Compound 57-l (1.8 g, 10 mmol) is suspended in dimethylformamide (15 ml), carbodiimidazole (1.63 g, 10 mmol) is added and stirred. Next, Compound 56-l (940 mg, 10 mmol) was added and stirred at 100 ° C. for 9 hours. Ethyl acetate-water was added to the reaction solution. The organic layer was washed with water, dried and concentrated to give 58-1. Yield 1.21 g (47%).

'H-NMR (d-DMSO): 3.91 (3H, s), 7.42 (lH, m), 8.11 (4H, m), 8.20 (lH, m), 8.34 (lH, dd,

), 8.93 (1H, d, J = 2.4Hz).

(51) 58-1 → 59-1

Compound 58-1 (1.21 g, 4.7 mmol) force 59_1 was obtained in the same manner as in (2). Yield 1.08 g (95%).

(52) 59-1 → 60-1

Compound 59-1 (1.08 g, 4.5 mmol) was obtained in the same manner as (3) to give 60-1. Yield 1.23 g (84%).

'H-NMR (d-DMSO): 1.76 (6H, m), 4.80 (2H, d), 5.46 (1H, m), 7.42 (lH, m), 8.09 (4H, m

), 8.19 (1H, m), 8.33 (lH, dd), 8.92 (lH, dd,).

(53) 60-1 + 2 → 61-1

Compound 61-l (916 mg) was obtained as a powder in the same manner as Compound 2 (675 mg, lmmol) and Compound 60_l (310 mg, l.Ommol) force (4).

(54) 61- 1 → 55_1

Compound 61-l (916 mg) was obtained in the same manner as (5) to give compound 55_1 as a powder. Yield 346 mg (44 %)

'H-NMR (DO): 1.27 (3H, t, J = 7.2Hz), 3.67 (2H, ABq, J = 17.4, 20.4Hz), 4.21 (2H, q, J = 7.2 Hz), 5.26 (1H, d, J = 4.5Hz), 5.32 (2H, d, J = 6.9Hz), 5.80 (1H, d, J = 4.5H z), 6.13 (1H, m), 6.95 (1H, s), 7.99 (1H , dd), 8.55 (1H, d), 8.60 (1H, d), 9.35 (lH, s). IR (KBr) cm— ¹ : 1765, 1669, 1594, 1552, 1506.

MS: 678+ (M-Na + 2H) + elemental analysis C H N O S Na-5 H O

Calculated value: C, 45.62; H, 4.59; N, 12.41; S, 8.12; Na, 2.91 (%)

Experimental value: C45.59; H, 4, 53; N, 12.55; S, 8.26; Na, 3.27 (%)

Example 161

[Chemical 208]

(55) 22 + 61 → 62

62 was obtained as a crystal from Compound 22 (947 mg, 8.3 mmol) and Compound 61 (1.58 g, 9.6 mmol) in the same manner as in (16). Yield 1.33 g (66%).

'H-NMR (d-DMSO): 2.28 (3H, s), 3.83 (3H, s), 6.90 (2H, m), 7.40 (lH, d, J = 8.4Hz), 7.77 (l

H, dd, J = 2.1, 8.4Hz), 7.86 (lH, d, J = 1.5Hz), 8.23 (2H, m), 8.41 (lH, s).

(56) 62 → 63

Compound 62 (1.32 g, 5.5 mmol) force 63 was obtained in the same manner as (2). Yield 1.19 g (96%).

(57) 63 → 64 Compound 35 (1.19 g, 5.2 mmol) was obtained in the same manner as (3) to give 64. Yield 1.3 g (84%).

'H-NMR (CDCl): 1.79 (6H, m), 2.31 (3H, s), 4.81 (2H, dJ = 7.2Hz), 5.47 (1H, m),

6.12 (lH, bs), 6.83 (2H, m), 7.37 (lH, d, J = 8.4Hz), 7.89 (lH, m), 7.94 (lH, bs) 8.32 (2H, m).

(58) 64 + 2 → 65

Compound 65 (827 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 64 (310 mg, 1.0 mmol) in the same manner as in (4).

(59) 65 → 60

Compound 65 (827 mg) was obtained in the same manner as (5) to give Compound 60 as a powder. Yield 339 mg (44%) 'H-NMR (DO): 1.29 (3H, t, J = 6.9Hz), 3.63 (2H, bs), 4.26 (2H, q, J = 6.9 Hz), 4.9 (

2H, d, J = 6Hz), 5.26 (lH, d, J = 4.2Hz), 5.80 (1H, d, J = 4.2Hz), 6.02 (1H, m,), 6.77 (1H, d, J = 15.6 Hz), 6.92 (2H, bd), 6.99 (1H, s), 7.35 (lH, d, J = 8.1Hz), 7.76 (1H, d, J = 8.1 Hz), 7.85 (lH, bs) 8.06 (lH , d, J = 6.6Hz).

IR (KBr) cm " ¹ : 1765, 1647, 1536.

MS: 664+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated value: C, 46.99; H, 4.86; N, 12.79; S, 8.36; Na, 3.00 (%)

Experimental value: C, 46.77; H, 4.81; N, 12.84; S, 8.21; Na, 3.27 (%)

Example 162

[Chemical 209]

(60) 67 → 68

Compound 67 (7.55 g, 50 mmol) was obtained in the same manner as in (3) to give 68. Yield 9.4g (88%).

'H-NMR (CDCl): 1.78 (6H, m), 2.19 (3H, s), 4.76 (2H, d, J = 7.2Hz), 5.45 (1H, m), 6.6

5 (1H, d, J = 8.4Hz), 7.75 (1H, dd, J = 2.1, 8.4Hz), 7.76 (lH, bs).

(61) 16 + 68 → 69

Suspend compound 16 (369 mg, 3 mmol) in dimethylformamide (3 ml), add carbonyldiimidazole (486 mg, 3 mmol) and stir. Next, compound 68 (788 mg, 3.6 mmol) was added and heated and stirred at 120 ° C. Ethyl acetate was added to the reaction solution, which was washed with water, dried, concentrated, and purified by silica gel chromatography to obtain 69. Yield 348 mg (36%).

'H-NMR (d-DMSO): 1.75 (6H, m), 2.33 (3H, s) 4.79 (2H, d, J = 6.9Hz), 5.45 (1H, m)

, 7.61 (1H, d, J = 8.4Hz), 7.83 (1H, dd, J = 1.8, 8.4Hz), 7.88 (lH, bs). 7.88 (2H, m), 8.8 0 (2H, m).

(62) 69 + 2 → 70

Compound 70 (922 mg) was obtained as a powder from Compound 2 (675 mg, 1 mmol) and Compound 69 (324 mg, 1.0 mmol) in the same manner as in (4).

(63) 70 → 66

Compound 70 (827 mg) was obtained in the same manner as (5) to give Compound 66 as a powder. Yield 272mg (33%) H-NMR (DO): 1.30 (3H, t, J = 7.1Hz), 2.33 (3H, s), 3.43, 3.66 (2H, bs), 4.25 (2H, q,

J = 7.1 Hz), 5.27 (1H, d, J = 5.1Hz), 5.42 (2H, d, J = 6.3Hz), 5.83 (1H, d, J = 5.1Hz), 6.13 (1H, m), 6.98 (lH, d, J = 15.3Hz), 6.99 (1H, s), 7.42 (1H, d, J = 8.1Hz), 7.75 (lH, dd J = 1.2,8.1Hz), 7.82 (lH, bs), 8.48 (2H, m), 8.99 (2H, m).

IR (KBr) cm ^_1 : 1765, 1666, 1594, 1532.

MS: 692+ (M-Na + 2H) +

Elemental analysis C H N O S Na- 5.5H O

Calculated value: C, 45.81; H, 4.84; N, 12.06; SJ.89; Na, 2.83 (%)

Experimental value: C, 45.52; H, 4.71; N, 12.20; S, 8.25; Na, 3.48 (%)

Example 163

[Chemical 210]

(64) 22 + 72 → 73

73 was obtained from Compound 22 (908 mg, 8 mmol) and Compound 72 (1.78 g, 9.6 mmol) in the same manner as (16). Yield 357 mg (17%).

'H-NMR (d-DMSO): 3.85 (3H, s), 7.06 (2H, m), 7.56 (lH, d, J = 8.7Hz), 7.86 (2H, dd, J =

2.1,8.4Hz), 8.00 (1H, d, J = 2.1Hz), 8.31 (2H, m), 8.78 (lH, bs).

(65) 73 → 74

Compound 73 (349 mg, 1.3 mmol) force 74 was obtained in the same manner as (2). Yield 257 mg (78%). (66) 74 → 75

Compound 74 (257 mg, 1.0 mmol) was obtained in the same manner as (3) to give 75. Yield 257 mg (79%).

'H-NMR (d-DMSO): 1.75 (6H, m), 4.78 (2H, d, J = 7.2Hz), 5.43 (1H, m),

7.05 (2H, m), 7.56 (lH, d, J = 8.7Hz), 7.84 (2H, dd, J = 2.1, 8.7Hz), 7.98 (lH, d, J = 2.1Hz), 8.30 (2H, m ), 8.78 (lH, bs).

(67) 75 + 2 → 76

Compound 76 (718 mg) was obtained as a powder from Compound 2 (540 mg, 0.8 mmol) and Compound 75 (257 mg, 0.8 mmol) in the same manner as (4).

(68) 76 → 71

Compound 76 (827 mg) was obtained in the same manner as (5) to give Compound 71 as a powder. Yield 239 mg (38%) 'H-NMR (D 2 O): 1.29 (3H, t, J = 7.2 Hz), 3.64 (2H, bs), 4.25 (2H, q, J = 7.2 Hz), 4.91

(2H, d, J = 6.6Hz), 5.24 (1H, d, J = 5.4Hz), 5.81 (1H, d, J = 5.4Hz), 5.03 (1H, m), 6.7

8 (1H, d, J = 15.3Hz), 6.99 (lH, bs), 7.06 (2H, d, J = 7.2Hz), 7.53 (1H, d, J = 8.1Hz), 7.

85 (1H, d, J = 8.1Hz), 8.02 (lH, bs), 7.86 (2H, d, J = 7.2Hz).

IR (KBr) cm " ¹ : 1764, 1647, 1597, 1534.

MS: 684+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated: C, 44.25; H, 4.35; N, 12.46; Cl, 4.50 S, 8.15; Na, 3.27 (%)

Experimental value: C, 44.11; H, 4.31; N, 12.46; Cl, 4.44 S, 8.24; Na, 2.92 (%)

Example 164

[Chemical 211]

(69) 16 + 57 → 78

78 was obtained from Compound 16 (492 mg, 4 mmol) and Compound 57 (824 mg, 4 mmol) in the same manner as (61). Yield 772 mg (62%).

'H-NMR (CDCl 3): 1.79 (6H, m), 4.85 (2H, d, J = 7.2Hz), 5.48 (lH, m), 7.79 (2H, m), 8.38-8.

47 (2H, m), 8.86 (2H, m), 8.95 (lH, m).

(70) 78 + 2 → 79

Compound 79 (887 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 78 (311 mg, 1.0 mmol) in the same manner as in (4).

(71) 79 → 77

Compound 77 (887 mg) was obtained in the same manner as (5) to give Compound 77 as a powder. Yield 119 mg (15%) 'H-NMR (D 2 O): 1.28 (3H, t, J = 7.2 Hz), 3.65 (2H, bs), 4.22 (2H, q, J = 7.2 Hz), 5.26

(1H, d, J = 4.5Hz), 5.42 (2H, d, J = 6.6Hz), 5.51 (1H, d, J = 4.5Hz), 6.12 (1H, m), 6.95 (lH, bs) , 6.99 (lH, d, J = 15.9Hz), 8.00 (1H, d, J = 8.4Hz), 8.31 (1H, d, J = 8.4Hz), 8.47 (2H, d, J = 6.3Hz), 8.79 (lH, bs), 9.08 (2H, d, J = 6.3Hz).

IR (KBr) cm " ¹ : 1765, 1670, 1607, 1532.

MS: 679+ (M_Na + 2H) + Elemental analysis CHNOS Na- 5H O

Calculated: C, 44.05; H, 4.46; N, 14.17; S, 8.11; Na, 3.29 (%)

Experimental value: C, 44.26; H, 4.36; N, 14.24; S, 8.07; Na, 3.48 (%)

Example 165

[Chemical 212]

(72) 56-l + 81 → 82

Compound 81 (1.58 g, 8.1 mmol) was suspended in dimethylformamide (8 ml), and 56_l (762 mg, 8.1 mmol) was added. Next, ethyldimethylaminopropylcarbodiimide hydrochloride (1.56 g, 8.1 mmol) was added and stirred for 5 hours. Ethyl acetate-water was added to the reaction solution, and the organic layer was washed with water, dried and concentrated to obtain 82. Yield 1.87 g (85%).

'H-NMR (d-DMSO): 1.37 (3H, t, J = 6.9Hz), 4.41 (2H, qJ = 6.9Hz), 7.40-7.44 (lH, m),

8.29-8.36 (3H, m), 8.55 (2H, dd, J = 2.1,8.1Ηζ), 9.08 (1Η, m), 9.19 (lH, m).

(73) 82 → 83

Compound 82 (1.87 g, 6.9 mmol) force 83 was obtained in the same manner as (2). Yield 1.55 g (93%).

(74) 83 → 84

Compound 83 (1.55 g, 6.4 mmol) was dissolved in dimethylformamide (10 ml), and 1 ml of prenyl alcohol was added. Next, ethyldimethylaminopropylcarbodiimide hydrochloride (1.46 g, 7.6 mmol) and 233 mg of 4-dimethylaminopyridine were added, and the mixture was stirred at room temperature for 5.5 hours. reaction The solution was extracted with ethyl acetate and water. The organic layer was washed with water, dried and concentrated. The residue obtained was purified by silica gel chromatography to obtain 84. Yield 1.55 g (73%).

'H-NMR (CDCl 3): 1.81 (6H, m), 4.90 (2H, d, J = 7.2Hz), 5.49 (lH, m), 7.38 (lH, dd, J = 5.1,8.

4Hz), 8.35-8.55 (3H, m), 8.86 (1H, m), 9.22 (lH, m).

(75) 84 + 2 → 85

Compound 85 (894 mg) was obtained as a powder from Compound 2 (675 mg, lmmol) and Compound 84 (311 mg, l.Ommol) in the same manner as (4).

(76) 85 → 80

Compound 85 (916 mg) was obtained in the same manner as (5) to give Compound 80 as a powder. Yield 162 mg (21%) 'H-NMR (D 2 O): 1.24 (3H, t, J = 7.2Hz), 3.68 (2H, bs), 3.98 (2H, q, J = 7.2 Hz), 5.26 (

1H, d, J = 4.8Hz), 5.35 (2H, d, J = 6.3Hz), 5.80 (1H, d, J = 4.8Hz), 6.34 (1H, m), 6.8

9 (1H, s), 7.02 (lH, d, J = 15.3Hz), 8.02 (1H, dd,), 8.13 (1H, d, J = 8.4Hz), 8.32 (2H, d,

J = 8.1Hz), 8.63 (2H, m), 9.00 (lH, bs), 9.49 (lH, bs).

IR (KBr) cm " ¹ : 1765, 1668, 1604, 1532.

MS: 679+ (M_Na + 2H) +

Elemental analysis C H N O S Na-4.5H O

Calculated: C, 44.56; H, 4.38; N, 14.33; S, 8.20; Na, 2.94 (%)

Experimental value: C, 44.44; H, 4,17; N, 14.36; S, 8.45; Na, 3.31 (%)

Example 166

[Chemical 213]

(1) 3 → 4

Compound 3 (4.7 g, 20 mmol) is dissolved in dimethylformamide (30 ml), sodium carbonate (3.04 g, 22 mmol) is added and stirred, and para-methoxybenzenole bromide is added and stirred at room temperature for 1.5 hours. did. Water was added to the reaction solution, extracted with ethyl acetate, washed with water and dried to obtain 4. Yield 8.4g

'H-NMR (d-DMSO): 3.77 (3H, s), 5.34 (2H, s), 6.95_6 · 98 (2Η, m), 7.40-7.43 (2H, m

), 8.12 (1H, d, J = 8.4 Hz), 8.54 (1H, d, J = 2.4 Hz), 8.61 (1H, dd, J = 8.4, 2.4 Hz).

(2) 4 → 5

Compound 4 (8.4 g, 20 mmol) was dissolved in 160 ml of ethanol to prepare an aqueous solution (14 ml) of ammonium chloride (3.2 g, 60 mmo 1). Next, iron powder (10.1 g, 180 mmol) was added and refluxed for 1.5 hours. The insoluble material was filtered off and concentrated. Water was extracted from the residue with ketyl acetate, washed with water and dried to obtain 5. Yield 7.3g.

'H-NMR (d-DMSO): 3.76 (3H, s), 5 · 17 (2Η, s), 6.32 (2H, s), 6.76 (2H, dd, J = 8.7, 2.1

Hz), 6.92-6.97 (2H, m), 6.99 (1H, d, J = 2.1 Hz), 7.34-7.39 (2H, m), 7.68 (1H, d, J = 8.7 Hz).

(3) 5 + 6 → 7

Compound 5 (1.83 g, 5 mmol) was dissolved in methylene chloride (15 ml), and then compound 6 (1.18 g, 6.6 mmol 1) and pyridine (1.05 ml, 13 mmol) were added and stirred at 0 ° C. for 2 hours. The reaction mixture was concentrated, extracted with ethyl acetate and water, washed with water, and dried to give 7. Yield 2.25g. Ή-NMR (d-DMSO): 3.77 (3H, s), 5.28 (2H, s), 6.97 (2H, d, J = 8.4 Hz), 7.41 (2H, d,

6

J = 8.4 Hz), 7.88-7.90 (2H, m), 7.95 (1H, d, J = 8.7 Hz), 8.20 (1H, dd, J = 8.7, 1.5 Hz), 8. 36 (1H, d, J = 1.5 Hz), 8.82-8.84 (2H, m), 11.00 (1H, s).

(4) 7 + 2 → 8

Compound 7 (646 mg, 1.5 mmol) was dissolved in dimethylformamide (5 ml). Compound 2 (1.28 g, 1.5 mmol) and NaBr (463 mg, 4.5 mmol) were then added and stirred at room temperature for 18 hours. The reaction solution was poured under stirring with 5% brine, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 8 (1.91 g) as a powder.

(5) 8 → 1

Compound 8 (1.88g) was dissolved in methylene chloride (19ml), nitromethane (9ml) and anisole (1.88ml) and cooled to -30 ° C. A salt solution of 2MTiCl in methylene chloride (6 ml) was stirred for 1 hour. Reaction

Four

The solution was poured into water (40 ml) -isopropyl ether (50 ml) with stirring under ice cooling. The precipitated precipitate is collected by filtration, dissolved in NaHCO aqueous solution, and subjected to HP-20SS column chromatography.

Three

And eluted with water-acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 1 as a powder. Yield 490 mg (37%)

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2 Hz), 3.50 (2H, m), 4.10 (2H, q, J = 7.2 Hz), 5.

6

05 (1H, d, J = 5.1Hz), 5.38 (2H, d, J = 8.7 Hz), 5.63 (1H, dd, J = 8.1, 5.1 Hz), 5.92 (1H, dt, J = 15.9, 8.7 Hz ), 6.72 (1H, s), 7.23 (1H, s), 7.29 (1H, d, J = 15.9 Hz), 7.45_7.50 (1H, m), 7.89-7.9K1H, m), 8.18 (1H, m), 8.63 (2H, d, J = 6.3 Hz), 9.21 (2H, d, J = 6.3 Hz), 9.56 (1H, d, J = 8.1 Hz), 10.87 (1H, s).

IR (KBr) cm— ¹ : 3298, 1761, 1588, 1534, 1381, 1320, 1118, 1035.

MS: 746 ⁺ (M + H) ⁺

Elemental analysis c H F N O S Na- 5.4H O-0.3NaHCO

31 25 3 7 8 2 2 3

Calculated value: C, 42.23; H, 4.09; F, 6.40; Ν, ΙΙ.01; SJ.20; Na, 3.36 (%)

Experimental value: C, 42.02; H, 4.00; F, 6.15; N, 11.31; SJ.48; Na, 3.33 (%)

Example 167

[Chemical 214]

(6) 5 → 10

Dissolve CuBr (1.34 g, 6 mmol) in acetonitrile (7 ml), add t_butyl nitrite (891 μ 1,7.5 mmol) and compound 5 (1.83 g, 5 mmol), and stir at 0 ° C for 2 hours. did. The reaction solution was added to ice water and extracted with ethyl acetate. Washed with water, dried and concentrated to give 10. Yield 1.94g.

'H-NMR (d-DMSO): 3.77 (3H, s), 5.28 (2H, s), 6.94_6.98 (2H, m), 7.37-7.42 (2H, m

), 7.78 (1H, d, J = 8.1 Hz), 8.03 (1H, dd, J = 8.1, 2.1 Hz), 8.07 (1H, d, J = 2.1 Hz).

(7) 10 + 11 → 12

Compound 10 (1.91 g, 4.9 mmol) and Compound l l (1.31 g, 6.38 mmol) are dissolved in dioxane (20 ml). K PO (3.12 g, 14.7 mmol) and Pd (PPh) (289 mg, 0.25 mmol) were added and after 1 hour at room temperature, 1

The mixture was stirred at 10 ° C for 3 hours. Further, Pd (PPh 3) (289 mg, 0.25 mmol) was added and stirred at 120 ° C. for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried and concentrated, and purified by column chromatography. Yield 1.43g (75%)

'H-NMR (d-DMSO): 3.77 (3H, s), 5.32 (2H, s), 6.96_6 · 99 (2Η, m), 7.41-7.44 (2H, m

), 7.84-7.86 (2H, m), 7.98 (1H, d, J = 8.7 Hz), 8.20-8.23 (2H, m), 8.71-8.73 (2H, m).

(8) 12 + 13 → 14

Compound 13 (1.01 g, 1.5 mmol) was suspended in ethyl acetate (9 ml), aqueous sodium hydrogen carbonate solution (252 mg, 3 mmol dissolved in 16 ml of water) was added, extracted with ethyl acetate, and dried over sodium sulfate. . After distilling off the solvent, it was immediately dissolved in dimethylformamide (2 ml) to give compound 12 (581 mg, 1.5 mmol), sodium bromide (309 mg, 3 mmol) was added, and the mixture was stirred at room temperature for 7 hours. The reaction solution was poured under stirring with 5% brine (70 ml), and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 14 (1.43 g) as a powder.

(9) 14 → 9

Compound 14 (1.42 g) was obtained in the same manner as (5) to give Compound 9 as a powder. Yield 301 mg (25%) 'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9 Hz), 3.33, 3.35 (2H, ABq, J = 16.8 Hz), 4.09 (

6

2H, q, J = 6.9 Hz), 5.05 (1H, d, J = 4.8 Hz), 5.30 (2H, m), 5.60 (1H, dd, J = 8.1, 4.8 Hz), 5.88 (1H, dt, J = 15.6, 7.2 Hz), 6.71 (1H, s), 7.23 (1H, s), 7.32 (1H, d, 15.6 Hz), 7.54 (1 H, d, J = 8.4 Hz), 8.15-8.17 (2H, m), 8.55 (2H, d, J = 6.9 Hz), 9.04 (2H, d, J = 6.9 Hz), 9.53 (1H, d, J = 8.1 Hz).

IR (KBr) cm " ¹ : 3330, 1758, 1592, 1529, 1379, 1331, 1261, 1128, 1038.

MS: 703 ⁺ (M + H) ⁺

Elemental analysis C H F N O S Na- 4.5H O

30 24 3 6 7 2 2

Calculated: C, 44.72; H, 4.13; F, 7.07; N, 10.43; SJ.96; Na, 2.85 (%)

Experimental value: C, 44.93; H, 4.16; F, 6.78; N, 10.67; S, 8.12; Na, 3.12 (%)

Example 168

[Chemical 215]

(10) 16 → 17 Compound 16 (9.55 g, 50 mmol) and hydroxylamine hydrochloride (6.25 g, 90 mmol) are dissolved in N-methylpyrrolidine (70 ml). The mixture was stirred at 110 ° C for 7 hours. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried, concentrated, and purified by column chromatography to obtain 17. Yield 7.75 g (82%) 'H-NMR (d-DMSO): 8.09-8.10 (1H, m), 8.18-8.19 (1H, m).

(11) 17 + 11 → 18

Compound 17 (1.88 g, 10 mmol) and compound l l (2.67 g, 13 mmol) are dissolved in dioxane (30 ml). K 3 PO 4 (6.37 g, 30 mmol) and Pd (PPh 3) (578 mg, 0.5 mmol) were added and stirred at room temperature for 30 minutes, and then stirred at 120 ° C. for 30 minutes. The reaction solution was poured into water, extracted with ethyl acetate, washed with water, dried, concentrated, and purified by column chromatography to obtain 18. Yield 1.91g

'H-NMR (d-DMSO): 7.77-7.79 (2H, m), 8.60—8.61 (2H, m), 8.64—8.68 (2H, m).

(12) 18 → 19

Compound 18 (93 lmg, 5 mmol) was dissolved in dimethylformamide (7 ml), NaN (488 mg, 7.5 mmol) and ammonium chloride (401 mg, 7.5 mmol) were added, and the mixture was stirred at 115 ° C for 2 hours. After cooling the reaction solution, water (10 ml) was added, then neutralized with 2NHC1, and the precipitate was collected by filtration and dried to obtain 19. Yield 923 mg (81%).

'H-NMR (d-DMSO): 7.80-7.82 (2H, m), 8.31 (1H, d, J = 1.8 Hz), 8.52 (1H, d, J = 1.8

Hz), 8.66-8.68 (2H, m).

(13) 19 + 13 → 20

20 was obtained in the same manner as (8) from Compound 13 (1.01 g, 1.5 mmol) and Compound 19 (344 mg, 1.5 mmol). Yield 1.45g

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2 Hz), 3.66, 3.91 (2H, ABq, J = 18.0 Hz), 4.10 (

2H, q, J = 7.2 Hz), 5.27_5.30 (3 mm, m), 5.92 (2H, dd, J = 8.4, 4.8 Hz), 6.45 (1H, dt, J = 16 • 5, 6.6 Hz) , 6.75 (1H, s), 6.89 (1H, d, J = 16.5 Hz), 6.92 (1H, s), 7 · 29_7 · 50 (10Η, m), 8. 49-8.53 (2H, m), 8.74 (1H, m), 9.00—9.02 (3H, m), 9.65 (1H, d, J = 8.4 Hz).

(14) 20 → 15

Compound 20 (1.45 g) was dissolved in trifluoroacetic acid (7.3 ml) and anisole (1.5 ml) and stirred at 0 ° C. for 1 hour. The reaction solution was poured into 30 ml of isopropyl ether with stirring under ice cooling. The deposited precipitate was collected by filtration and dissolved with saturated aqueous NaHCO. HP-20SS column chromatography Subjected to matography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 15 as a powder. Yield 321 mg (27%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2 Hz), 3.43, 3.52 (2H, ABq, J = 17.1 Hz), 4.09 (

6

2H, q, J = 7.2 Hz), 5.05 (lH, d, J = 4.8 Hz), 5.23 (2H, d, J = 6.9 Hz), 5.60 (2H, dd, J = 8.1, 4.8 Hz), 5.88 ( 1H, dt, J = 15.3, 6.9 Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 15.3 Ηζ), 8.15 (1 Η, m), 8.52 (2H , d, J = 7.2 Hz), 8.61 (1H, m), 8.95 (2H, d, J = 7.2 Hz), 9.54 (1H, d, J = 8.1 Hz).

IR (KBr) cm— ¹ : 3326, 1759, 1633, 1599, 1530, 1386, 1297, 1157, 1034.

MS: 665+ (M + H) +

Elemental analysis C H N O S Na- 6.2H O-O. lNaHCO

27 23 10 5 3 2 3

Calculated values: C, 40.34; H, 4.43; N, 17.36; S, 11.92; Na, 3.13 (%)

Experimental value: C, 40.32; H, 4.45; N, 17.33; S, 12.07; Na, 3.23 (%)

Example 169

[Chemical 216]

(15) 22 → 23

Compound 23 (4.78 g, 25 mmol) was obtained in the same manner as (10). Yield 3.79 g (81%)

H-NMR (d-DMSO): 7.46 (1H, d, J = 4.2 Hz), 7.85 (1H, d, J = 4.2 Hz).

6 (16) 23 + 11 → 24

Compound 23 (1.88 g, 10 mmol) was obtained in the same manner as (11). Yield 1.69 g (91%)

H-NMR (d-DMSO): 7.75_7.77 (2H, m), 7.97 (1H, d, J = 3.9 Hz), 8.09 (1H, d, J = 3.9

Hz), 8.67-8.69 (2H, m).

(17) 24 → 25

Compound 24 (931 mg, 5 mmol) force 25 was obtained in the same manner as in (12). Yield l. Llg (97%).

'H-NMR (d-DMSO): 7.78-7.80 (2H, m), 7.86 (1H, d, J = 3.9 Hz), 7.98 (1H, d, J = 3.9

Hz), 8.65-8.67 (2H, m).

(18) 25 → 26

Compound 25 (688 mg, 3 mmol) is dissolved in dimethylformamide (10 ml). Under ice-cooling, sodium hydride (203 mg, 5 mmol) was added and stirred. Next, benzyloxymethyl chloride (B 0 M-Cl) (0.42 ml, 3 mmol) was added and stirred at room temperature for 1.5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and concentrated to give 26. Yield 424 mg (40%)

'H-NMR (d-DMSO): 4.72 (2H, s), 6 · 16 (2Η, s), 7.30-7.36 (5H, m), 7.75-7.77 (2H, m

), 7.91 (1H, d, J = 3.9 Hz), 7.95 (1H, d, J = 3.9 Hz), 8.63_8 · 65 (2 mm, m).

(19) 26 + 13 → 27

In the same manner as in (8), 27 was obtained from compound 13 (810 mg, 1.2 mmol) and compound 26 (420 mg, 1.2 mmol). Yield 1.45g

'H-NMR (d-DMSO): 1.23 (3H, t, J = 6.9 Hz), 3.65, 3.91 (2H, ABq, J = 17.7 Hz), 4.11 (

2H, q, J = 6.9 Hz), 4.73 (2H, s), 5.27- 5.31 (3H, m), 5.93 (2H, dd, J = 8.4, 4.8 Hz), 6.20 (2H, s), 6.44 (1H , dt, ”= 15.9, 6.3 Hz), 6.81 (1H, s), 6.90 (1H, d, J = 15.9 Hz), 6.93 (1H, s), 7.28-7.5K15H, m), 8.09 (1H, d , J = 3.9 Hz), 8.41 (1H, d, J = 3.9 Hz), 8.51 (2H, d, J = 7.2 Hz), 8.97 (2H, d, J = 7.2 Hz), 9.66 (1H, d, J = 8.4Hz).

(20) 27 → 21

Compound 27 (1.13 g) was obtained in the same manner as (5) to give compound 21 as a powder. Yield 268mg (28%) 'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9 Hz), 3.44, 3.51 (2H, ABq, J = 16.8 Hz), 4.09 (

2H, q, J = 6.9 Hz), 5.05 (lH, d, J = 4.8 Hz), 5.18 (2H, d, J = 6.9 Hz), 5.60 (2H, dd, J = 8.1, 4.8 Hz), 5.86 ( 1H, dt, J = 15.9, 6.9 Hz), 6.72 (1H, s), 7.21 (2H, s), 7.29 (1H, d, J = 15.9 Hz), 7.62 (lH, d, J = 3.9 Hz), 8.21 (1H, d, J = 3.9 Hz), 8.31 (2H, d, J = 6.9 Hz), 8.83 (2H d, J = 6.9 Hz), 9.53 (1H, d, J = 8.1Hz).

IR (KBr) cm— ¹ : 3312, 1754, 1632, 1523, 1381, 1226, 1160, 1034.

MS: 665+ (M + H) +

Elemental analysis C H N O S Na- 5.2H O-0.3NaHCO

27 23 10 5 3 2 3

Calculated value: C, 40.70; H, 4.22; N, 17.39; S, 11.94; Na, 3.71 (%)

Experimental value: C, 40.63; H, 4.29; N, 17.38; S, 12.21; Na, 3.74 (%)

Example 170

[Chemical 217]

(1) 1 → 3

A solution of compound 1 (890 mg) in DMF (10 mL) was ice-cooled, and after compound 2 (1.50 g) and triethylamine (2.30 mL) were collected, the mixture was stirred at room temperature for 5 hours. The reaction solution was extracted with ethyl acetate and water, and the resulting organic layer was dried over anhydrous magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography to obtain 3 (191 mg) as light brown crystals.

H-NMR (CDC13) δ 3.82 (3Η, s), 5.27 (2H, s), 6.78 (1H, d, J = 4.2 Hz), 6.91 (2H, d, J = 2.1, 8.7 Hz), 7.37 (2H , dd, J = 2.1, 8.7 Hz), 7.67 (1H, d, J = 4.2 Hz), 7.73 (2 H, d, J = 6.0 Hz), 8.77 (1H, brs), 8.84 (2H, d, J = 6.0 Hz).

(2) 4 → 5

Add 4 (414 mg) and sodium bromide (159 mg) to a solution of compound 3 (190 mg) in DMF (1.2 mL). Stir at room temperature for 12 hours. DMF (3 mL) was added for dilution, and the mixture was poured into 5% brine (80 mL) under ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried under reduced pressure. The obtained crude product (594 mg) was dissolved in methylene chloride (8 mL), and anisole (0.34 mL) was added under a nitrogen atmosphere, followed by cooling to -40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 1.56 mL) was added dropwise at _40 ° C, followed by stirring with ice cooling for 1 hour. The reaction mixture was poured into water (40 mL) with stirring in an ice bath, and diisopropyl ether (60 mL) was added. Fractions collected by suction filtration of the precipitate were dissolved in aqueous sodium bicarbonate, and fractions collected by HP20ss column chromatography were concentrated under reduced pressure, and fractions collected by ODS column chromatography were collected again. Concentrated in vacuo and lyophilized. Compound 5 (154 mg) was obtained as a powder.

'H-NMR (D O) δ: 1.29 (3H, t, J = 6.9), 3.62 and 3.68 (2H, ABq, J = 6.9 Hz), 4.25

(2H, q, J = 6.9), 5.26 (1H, d, J = 4.8 Hz), 5.32 (2H, d, J = 6.6 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6.6, 15.6 Hz), 6.90 (1H, d, J = 4.2 Hz), 6.97 (1H, s), 7.43

(1H, d, J = 4.2 Hz), 8.39 (2H, d, J = 6.9 Hz), 8.89 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3398, 1762, 1631, 1536, 1454, 1432, 1374, 1330, 1200, 1158, 1118,

1036, 1002.

MS (ESI): 684 ⁺ (M + H) ⁺

Elemental analysis C H N Na O S-6.2 H O

Calculated values: C, 40.06; H, 4.25; N, 11.68; S, 11.46; Na, 5.48 (%)

Experimental value: C, 40.02; H, 4.02; N, 11.68; S, 11.61; Na, 4.69 (%)

Example 171

[Chemical 218]

(3) 6 → 8

A suspension of Compound 6 (1.78 g) in THF (20 mL) was ice-cooled, and after compound 7 (2.53 g) and triethylenoamine (8.35 mL) were prepared, the mixture was heated under reflux. Stir for 14 hours. The organic layer obtained by extracting the reaction solution with ethyl acetate and water was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain Compound 8 (2.79 g) as a light brown solid.

H-NMR (CDC13) δ 1.35 (3Η, t, J = 6.9 Hz), 4.29 (2H, d, J = 6.9 Hz), 7.88 (2H, d, J = 6.0 Hz), 7.91 (1H, s), 8.89 (2H, d, J = 6.0 Hz).

(4) 8 → 9

A solution of Compound 8 (2.79 g) in ethanol (30 mL) was ice-cooled, 2N sodium hydroxide (10 mL) was added, and the mixture was stirred at the same temperature for 1 hr and then at room temperature for 1 hr. 2N sodium hydroxide (5 mL) was added, and the mixture was allowed to stand at room temperature. The mixture was neutralized with 5N hydrochloric acid, and ethanol was distilled off under reduced pressure. Under ice-cooling, the pH was adjusted to pH 3.0 with dilute hydrochloric acid, and the deposited precipitate was collected by suction filtration. The obtained solid was suspended in a mixed solution of isopropanol and jetyl ether (1: 1), collected by suction filtration and dried under reduced pressure. Compound 9 (2.60 g) was obtained as a pale yellow solid.

H-NMR (d6-DMSO) δ: 8.06 (2H, d, J = 5.4 Hz), 8.11 (1H, s), 8.85 (2H, brs), 13.4 (1H, brs).

(5) 9 → 10 P-Methoxybenzyl alcohol (0.37 mL), W SCD (690 mg) and dimethylaminopyridine (110 mg) were added to a suspension of compound 9 (748 mg) in DMF (6 mL), and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into water (50 mL), and the deposited precipitate was collected by suction filtration. Drying under reduced pressure gave Compound 10 (907 mg) as pale pink crystals.

H-NMR (d6-DMSO) δ: 3.76 (3H, s), 5.23 (2H, s), 6.94-6.99 (2H, m), 7.38-7.4 2 (2H, m), 7.99 (2H, d, J = 6.0 Hz), 8.19 (1H, s), 8.81 (2H, d, J = 6.0 Hz), 13.3 (1H, brs).

(6) 4 + 10 → l l

4 (802 mg) and sodium bromide (309 mg) were added to a solution of compound 10 (369 mg) in DMF (3.0 mL), and the mixture was stirred at room temperature for 14 hours. DMF (3 mL) was added and diluted, and poured into 5% brine (80 mL) under ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried under reduced pressure. The obtained crude product (1.12 g) was dissolved in methylene chloride (15 mL), and anisole (0.65 mL) was added under a nitrogen atmosphere, followed by cooling to -40 ° C. Titanium (IV) chloride (2.0 M methylene chloride solution, 3.0 mL) was added dropwise at −40 ° C., and the mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water (40 mL) with stirring in an ice bath, and diisopropyl ether (60 mL) was added. The deposited precipitate was collected by suction filtration, dissolved in 1N hydrochloric acid and acetonitrile, added with HP20ss, concentrated, and 0.2N sodium hydroxide was added dropwise with stirring to the fraction collected by HP20ss column chromatography. When pH 9 was exceeded, a small amount of dry ice was added. Concentration and lyophilization gave Compound 11 (227 mg) as a powder.

1H-NMR (D O) δ: 1.29 (3Η, t, J = 6.9 Hz), 3.65 (2H, brs), 4.25 (2H, q, J = 6.9 Hz

2

), 5.02 (1H, d, J = 4.8 Hz), 5.32 (1H, d, J = 6.9 Hz), 5.83 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6.9, 15.6 Hz) ), 6.98 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 7.66 (1H, s), 8.49 (2H, d, J = 6.6 Hz), 8.88 (2H, d, J = 6.6 Hz) ).

IR (KBr) cm— ¹ : 3398, 1763, 1586, 1538, 1454, 1382, 1290, 1197, 1157, 1123, 1036, 1001.

MS (ESI): 685+ (M + H) +

Elemental analysis c H N Na O S -4.4 H O -0.1 (NaHCO)

27 22 8 2 8 3 2 3

Calculated values: C, 39.87; H, 3.82; N, 13.73; S, 11.78; Na, 5.91 (%) Experimental value: C, 39.95; Η, 3.89; Ν, 13.61; S, 11.64; Na, 6.11 (%)

Example 172

[Chemical 219]

(7) 13 → 14

A solution of Compound 12 (1.88 g) in DMF (40 mL) was ice-cooled, Compound 13 (4.56 g) and WSCD (4.60 g) were added, and the mixture was stirred at room temperature for 6 hr. DMF was distilled off under reduced pressure and extracted with ethyl acetate and water. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The precipitated solid was washed with a mixed solution of ethyl acetate-jetyl ether and dried under reduced pressure to obtain Compound 14 (5.09 g) as light brown crystals.

H-NMR (d6-DMSO) δ: 7.41 (1H, d, J = 4.2 Hz), 7.74 (2H, dd, J = 1.5, 4.5 Hz), 7. 91 (1H, d, J = 4.2 Hz), 8.48 (2H, dd, J = 1.5, 4.5 Hz), 10.6 (1H, brs).

(8) 14 → 15

P-Methoxybenzyl alcohol (1.25 mL), Pd (OAc) (225 mg), dppp (412 mg), and triethylamine (5.58 mL) were added to a solution of compound 14 (1.42 g) in DMF (10 mL). The mixture was stirred at 80 ° C for 7 hours under a carbon atmosphere. The reaction solution was extracted with ethyl acetate and water, and the organic layer was washed with water and saturated brine. The crude product obtained by drying over anhydrous magnesium sulfate and concentrating under reduced pressure was purified by silica gel column chromatography to obtain Compound 15 (631 mg) as milky white crystals. H-NMR (d6-DMSO) δ: 3.77 (3Η, s), 5.29 (2H, s), 6.97 (2H, d, J = 9.0 Hz), 7.42 (2 H, d, J = 9.0), 7.72 (2H, d, J = 6.3 Hz), 7.90 (1H, d, J = 3.9 Hz), 8.08 (1H, d, J = 3.9 Hz), 8.49 (2H , D, J = 6.3 Hz), 10.8 (1H, brs).

(9) 4 + 15 → 16

Sodium bromide (309 mg) was added to a DMF (3.0 mL) solution of compound 15 (368 mg) and compound 4 (802 mg), and the mixture was stirred at room temperature for 12 hours. DMF (3 mL) was added for dilution, and the mixture was poured into 5% brine (80 mL) under ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried under reduced pressure. The obtained crude product (1.16 g) was dissolved in methylene chloride (15 mL), and anisole (0.65 mL) was added under a nitrogen atmosphere and cooled to -40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 3.0 mL) was added dropwise at _40 ° C, and the mixture was stirred for 1 hour in an ice bath. The reaction mixture was poured into water (40 mL) with stirring in an ice bath, and diisopropyl ether (80 mL) was added. 1N Hydrochloric acid (50 mL) —acetononitrile (50 mL) was added and separated, and the organic layer was extracted with 1N hydrochloric acid and acetonitrile (1: 1). The combined aqueous layer was subjected to HP20ss column chromatography, and the fraction collected by dissolution with water-acetonitrile-NaHCO was concentrated. The concentrated solution was subjected to ODS column chromatography and eluted with water-acetonitrile. The fraction collected was concentrated and lyophilized. Compound 16 (492 mg) was obtained as a powder.

'H-NMR (D O) δ: 1.26 (3H, t, J = 6.3 Hz), 3.62 and 3.69 (2H, ABq, J = 17.4 Hz),

4.20 (2H, q, J = 6.3 Hz), 5.13 (2H, d, J = 6.9 Hz), 5.25 (1H, d, J = 4.5 Hz), 5.79 (1 H, d, J = 4.5 Hz), 6.08 (1H, dt, J = 6.9, 15.6 Hz), 6.90 (1H, d, J = 15.6 Hz), 6.92 (1 H, s), 7.44 (1H, d, J = 4.2 Hz), 7.83 (1H, d , J = 4.2 Hz), 8.18 (2H, d, J = 7.2 Hz), 8.55 (2H, d, J = 7.2 Hz).

IR (KBr) cm— ¹ : 3398, 1764, 1674, 1596, 1515, 1463, 1365, 1324, 1261, 1204, 1161, 1112, 1034.

MS (ESI): 684+ (M + H) +

Elemental analysis C H N NaO S-5.7 H O

Calculated values: C, 41.60; H, 4.41; N, 12.13; S, 11.90; Na, 2.84 (%)

Experimental value: C, 41.62; H, 4.11; N, 12.20; S, 11.78; Na, 2.87 (%)

Example 173

[Chemical 220]

(10) 12 → 19

Compound 17 (2.97 g) and WSCD (3.45 g) were added to a solution of compound 12 (1.41 g) in DMF (30 mL), and the mixture was stirred at room temperature for 12 hours. The reaction solution was poured into water (160 mL), and the deposited precipitate was collected by suction filtration and washed with water and ether to obtain 18. Suspend this crude 18 in ethanol (40 mL), add 2N aqueous sodium hydroxide solution (22.5 mL) under ice-cooling and stir at room temperature for 2 hours, then add 2N sodium hydroxide (20 mL). The mixture was stirred for 6 hours at room temperature. The pH was adjusted to 3 with 5N hydrochloric acid, and the precipitate was collected by suction filtration. After drying under reduced pressure, compound 19 (3.1 g) was obtained as a colorless solid.

H-NMR (d6-DMSO) δ: 7.79 (2Η, d, J = 6.0 Hz), 8.05 (2H, d, J = 8.4 Hz), 8.10 (2 H, d, J = 8.4 Hz), 8.50 (2H , d, J = 6.0 Hz), 10.8 (1H, brs).

(11) 19 → 20

P-Methoxybenzyl alcohol (1.60 mL), WSCD (2.94 g), and dimethylaminopyridine (469 mg) were stirred in a DMF (25 mL) suspension of Compound 19 (3.10 g) at room temperature for 14 hours. . The reaction solution was extracted with ethyl acetate-water, and the organic layer was washed with water and brine. The solid obtained by drying over anhydrous magnesium sulfate and concentration under reduced pressure was washed with ether-ethyl acetate and collected by filtration. After reduced pressure drying, compound 20 (3.17 g) was obtained as a colorless solid. H-NMR (CDC) δ: 3.82 (3H, s), 5.33 (2H, s), 6.93 (2H, d, J = 8.7 Hz), 7.40 (2H, d, J = 8.7 Hz), 7.69 (2H, d, J = 5.4 Hz), 7.94 (2H, d, J = 8.1 Hz), 8.16 (2H, d, J = 8.1 Hz), 8.25 (1H, brs), 8.55 (2H, d, J = 5.4 Hz).

(12) 4 + 20 → 21

Compound 21 (445 mg) was obtained from Compound 4 (802 mg) and Compound 20 (362 mg) in the same manner as Compound 5.

1H-NMR (D O) δ: 1.29 (3Η, t, J = 6.9 Hz), 3.65 (2H, brs), 4.23 (2H, q, J = 6.9 Hz)

), 5.16 (2H, d, J = 6.9 Hz), 5.25 (1H, d, J = 4.8 Hz), 5.81 (1H, d, J = 4.8 Hz), 6.08 (1H, dt, J = 6.9, 15.6 Hz) ), 6.88 (1H, d, J = 15.6 Hz), 6.96 (1H, s), 7.95 (4H, s), 8.20 (2H, d, J = 7.2 Hz), 8.61 (2H, d, J = 7.2 Hz) ).

IR (KBr) cm " ¹ : 3410, 1765, 1596, 1518, 1459, 1384, 1325, 1256, 1204, 1160, 1089. MS (ESI): 678 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-5.8 H O-0.2 (NaHCO)

Calculated value: C, 44.18; Η, 4.64; Ν, 11.94; SJ.81; Na, 3.36 (%)

Experimental value: C, 44.06; H, 4.47; N, 12.05; SJ.98; Na, 3.40 (%)

Example 174

[Chem 221]

(1 3) 22 → 24

Compound 23 (1.99 g), K ΡΟ (10.6 g) in a solution of compound 22 (2.05 g) in 1,4-dioxane (80 mL)

After degassing by adding 34, Pd (PPh 3) (578 mg) was added and stirred for 6 hours. Bring the reaction solution to room temperature

3 4

After cooling, the mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product obtained was subjected to silica gel column chromatography, and eluted with ethyl acetate to obtain Compound 24 (2.03 g) as a colorless crystal. .

H-NMR (CDC13) δ: 2.66 (3Η, s), 7.62 (2H, dd, J = 1.5, 4.8 Hz), 7.75 (2H, dd, J = 1.5, 6.0 Hz), 8.09 (2H, dd, J = 1.5, 6.0 Hz), 8.73 (2H, dd, J = 1.5, 4.8 Hz).

(14) 24 → 25

A solution of compound 24 (1.02 g) in THF (20 mL) was cooled to _70 ° C, and lithium hexamethyldisilazide (1.0 M in THFX5.2 mL) was added dropwise. After stirring at the same temperature for 30 minutes, trifluoroethyl acetate (0.68 mL) was added, and the mixture was stirred at −50 ° C. for 3 hours. 1N Hydrochloric acid (5.2 mL) was added, and THF was evaporated under reduced pressure. After adjusting the pH to 3 with 1N hydrochloric acid, ether was added and the precipitated precipitate was collected by suction filtration. Drying under reduced pressure gave Compound 25 (1.13 g) as a yellow powder. H-NMR (DMSO) δ: 7.02 (1H, brs), 7.85 (2H, d, J = 5.4 Hz), 8.02 (2H, d, J = 8.7 Hz), 8.25 (2H, d, J = 8.4 Hz) , 8.72 (2H, d, J = 5.4 Hz). (15) 4 + 25 → 26

To a suspension of compound 25 (293 mg) in DMF (2 mL) was added N, 0_bistrimethylsilylacetamide (0.4 9 mL), and the mixture was stirred at room temperature for 15 minutes. Compound 4 (802 mg), DMF (1 mL), and sodium bromide (309 mg) were added to the reaction mixture and stirred for 6 hours, and then diluted with DMF (3 mL). It was poured into% brine (80 mL). After stirring at the same temperature for 20 minutes, the solution was collected by suction filtration and dried under reduced pressure to obtain a light brown solid (1.07 g). This solid was dissolved in methylene chloride (15 mL), added with anisole (0.65 mL) under a nitrogen atmosphere, and cooled to _40 ° C. Titanium chloride (IV) (2.0M methylene chloride solution, 3.0 mL) was added dropwise at _40 ° C, and the mixture was stirred for 1 hour in an ice bath. The reaction mixture was poured into water (50 mL) with stirring in an ice bath, and diisopropyl ether (60 mL) was added. The precipitate was collected by suction filtration, dissolved in aqueous sodium hydrogen carbonate, and fractions collected by ODS column chromatography (water-acetonitrile) were concentrated under reduced pressure and lyophilized. Compound 26 (445 mg) was obtained as a powder.

'H-NMR (D O) δ: 1.28 (3H, t, J = 6.9 Hz), 3.65 (2H, brs), 4.22 (2H, q, J = 6.9 Hz)

, 5.24-5.28 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.05-6.15 (2H, m), 6.93 (1H, s), 6.97 (1H, d, J = 15.6 Hz ), 7.88 (4H, s), 8.26 (2H, d, J = 6.6 Hz), 8.78 (2H, d, J = 6.6 Hz).

IR (KBr) cm " ¹ : 3418, 2982, 1766, 1632, 1576, 1554, 1237, 1175, 1122, 1035, 1011. MS (ESI): 729 ⁺ (M + H) ⁺

Elemental analysis C H F N NaO S-4.5 H O-0.2 (NaHCO)

Calculated value: C, 45.58; Η, 4.18; F, 6.72; N, 9.90; SJ.56; Na, 3.25 (%)

Experimental value: C, 45.29; Η, 3.89; F, 6.44; N, 9.98; SJ.65; Na, 3.33 (%)

Example 175

[Chemical 222]

(16) 27 → 28

To a suspension of compound 27 (1.95 g) in DMF (30 mL) was added triethylamine (1.58 mL), N_methoxy_N_methylamine hydrochloride (1.11 g), and WSCD (2.18 g) was added under ice cooling, followed by stirring at room temperature for 16 hours. did. DMF was distilled off under reduced pressure and extracted with ethyl acetate-water, and the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. Diisopropyl ether was added to the solid obtained after filtration and concentration, and the insoluble material was collected by filtration and dried under reduced pressure. Compound 28 (1.03 g) was obtained as light brown crystals.

H-NMR (CDC13) δ: 3.95 (3Η, s), 7.87 (2H, d, J = 5.4 Hz), 8.00 (1H, s), 8.70 (2H, brs).

(17) 28 → 29

To a suspension of compound 28 (1.90 g) in THF (25 mL) under stirring with ice cooling, methylmagnesium chloride (3

.0 M in THFX3.3 mL) was added, and the mixture was stirred at the same temperature for 45 minutes. The mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate-water. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained solid was collected by suction filtration using hexane-diisopropyl ether and dried under reduced pressure to obtain Compound 29 (1.48 g) as light brown crystals.

H-NMR (CDC13) δ 2.81 (3Η, s), 7.88 (2H, d, J = 6.0 Hz), 8.06 (1H, s), 8.74 (2H, brs).

(18) 29 → 30

A solution of compound 29 (1.48 g) in THF (20 mL) was cooled to -50 ° C and lithium hexamethyldisiyl Zido (8.0 mL) was added dropwise. After stirring at −50 ° C. for 30 minutes, trifluoroethyl acetate (2.13 mL) was stirred with ice-cooling for 1 hour. After neutralizing with 1N hydrochloric acid, THF was distilled off under reduced pressure, and the pH was adjusted to 3 with 1N hydrochloric acid. The precipitate formed by adding ether was collected by filtration and dried under reduced pressure to obtain Compound 30 (1.62 g) as a pale yellow solid.

H-NMR (d6-DMSO) δ: 6.33 (1H, brs), 8.36 (2H, d, J = 5.7 Hz), 8.85 (2H, d, J = 5 • 7 Hz), 9.06 (1H, brs).

(19) 4 + 30 → 31

Compound 4 (802 mg), Compound 30 (300 mg) to Compound 31 (162 mg) in the same manner as Compound 26

)

'H-NMR (D O) δ: 1.27 (3H, t, J = 7.2 Hz), 3.64 and 3.71 (2H, ABq, J = 17.4 Hz),

2

4.22 (2H, q, J = 7.2 Hz), 5.24-5.27 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 6.9, 15.6 Hz), 6.43 (1H , S), 6.91 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 8.38 (1H, d, J = 6.9 Hz), 8.60 (1H, s), 8.78 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3480, 2982, 1633, 1516, 1388, 1392, 1206, 1180, 1131, 1036.

MS (ESI): 758 ⁺ (M + Na + H) +

Elemental analysis C H F N NaO S-6.1 H O-0.2 (NaHCO)

29 23 3 7 7 2 2 3

Calculated value: C, 39.65; Η, 4.03; F, 6.44; N, 11.09; S, 10.88; Na, 3.12 (%)

Experimental value: C, 39.62; Η, 3.40; F, 6.20; N, 11.16; S, 10.86; Na, 3.29 (%)

Example 176

[Chem. 223]

(20) 20 + 32 → 33 Compound 33 (319 mg) was obtained from Compound 32 (752 mg) and Compound 20 (362 mg) in the same manner as Compound 5.

'H-NMR (D O) δ: 1.26-1.29 (6Η, m), 3.62 and 3.68 (2H, ABq, J = 17.7 Hz), 4.47

(1H, m), 5.15 (2H, d, J = 7.2 Hz), 5.25 (1H, d, J = 4.5 Hz), 5.80 (1H, d, J = 4.5 Hz), 6.08 (1H, dt, J = 7.2, 15.6 Hz), 6.89 (1H, d, J = 15.6 Hz), 6.94 (1H, s), 7.94 (4H, s), 8.18 (2H, d, J = 7.2 Hz), 8.60 (2H, d , J = 7.2 Hz).

IR (KBr) cm— ¹ : 3417, 2976, 1765, 1596, 1518, 1459, 1383, 1325, 1255, 1204, 1160, 1117, 1090, 1042, 1014.

MS (ESI): 692+ (M + H) +

Elemental analysis C H N NaO S -4.5 H O

Calculated values: C, 46.85; H, 4.69; N, 12.34; S, 8.07; Na, 2.89 (%)

Experimental value: C, 46.64; H, 4.39; N, 12.43; SJ.94; Na, 3.13 (%)

Example 177

[Chemical 224]

34

(21) 10 + 32 → 34

Compound 34 (192 mg) was obtained from Compound 32 (752 mg) and Compound 10 (369 mg) in the same manner as Compound 11.

'H-NMR (D O) δ: 1.27-1.31 (6Η, m), 3.54 (2H, brs), 4.37 (1H, m), 5.27 (1H, d, J

= 6.9 Hz), 5.33 (2H, d, J = 4.8 Hz), 5.83 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 6.9, 15.6 Hz), 6.97 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 7.66 (1H, s), 8.49 (2H, d, J = 6.3 Hz), 8.89 (2H, d, J = 6.3 Hz).

IR (KBr) cm— ¹ : 3399, 2978, 1763, 1631, 1586, 1540, 1454, 1381, 1290, 1197, 1157, 1119, 1062, 1043.

MS (ESI): 699+ (M + H) +

Elemental analysis C H N Na O S-3.3 H O-0.2 (NaHCO)

Calculated values: C, 41.36; H, 3.79; N, 13.68; S, 11.75; Na, 6.18 (%)

Experimental values: C, 41.56; H, 4.12; N, 13.75; S, 11.24; Na, 6.25 (%)

Example 178

[Chemical 225]

32 + 35 → 36

Compound 36 (260 mg) was obtained from Compound 32 (752 mg) and Compound 35 (310 mg) in the same manner as Compound 11.

'H-NMR (D O) δ: 1.27-1.30 (6Η, m), 3.62 and 3.69 (2H, ABq, J = 17.7 Hz), 4.49

(1H, m), 5.27 (1H, d, J = 4.8 Hz), 5.40 (1H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.9, 15.6 Hz), 6.96 (1H, s), 6.97 (1H, d, J = 15.6 Hz), 7.67 (2H, d, J = 8.7 Hz), 8.43 (2H, d, J = 6.9 Hz), 9.05 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3418, 3055, 2976, 1765, 1668, 1604, 1532, 1455, 1381, 1326, 1201,

1175, 1117, 1041.

MS (ESI): 692+ (M + H) +

Elemental analysis c H N NaO S-5.1 H O-0.2 NaHCO

Calculated value: C, 45.57; H, 4.71; N, 11.92; SJ.80; Na, 3.35 (%)

Experimental value: C45.52; H, 4.73; N, 12.05; SJ.81; Na, 3.31 (%)

Example 179 [Chem 226]

(23) 32 + 37 → 38

Compound 38 (275 mg) was obtained from Compound 32 (752 mg) and Compound 37 (310 mg) in the same manner as Compound 11.

'H-NMR (D 2 O) δ: 1.27-1.31 (6Η, m), 3.66 (2H, brs), 4.49 (1H, m), 5.27 (1H, d,

J = 4.8 Hz), 5.40 (1H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.9, 15.6 Hz), 6.96 (1H, s) , 6.98 (1H, d, J = 15.6 Hz), 7.53 (1H, t, J = 7.8 Hz), 7.74-7.98 (2H, m), 7.97 (1H, t, J = 1.8 Hz), 8.44 (2H, d, J = 7.2 Hz), 9.05 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3409, 3057, 2977, 1765, 1669, 1610, 1559, 1455, 1431, 1382, 1300, 1201, 1162, 1118, 1041.

MS (ESI): 692+ (M + H) +

Elemental analysis C H N NaO S -4.3 H O-0.2 NaHCO

Calculated value: C, 46.38; H, 4.59; N, 12.13; SJ.94; Na, 3.41 (%)

Experimental value: C, 46.37; H, 4.35; N, 12.02; SJ.74; Na, 3.44 (%)

Example 180

[Chemical 227]

(24) 39 → 40

A solution of diphenyldiazomethane (11.6 g) in THF (50 mL) was added dropwise over 30 minutes to a THF (50 mL) solution of the compound 39 (10 g). The reaction solution was stirred at room temperature for 30 minutes, concentrated under reduced pressure, and dried to obtain Compound 40 (20 g) as a yellow oily substance.

H-NMR (CDC13) δ: 4.33 (2Η, s), 6.99 (1H, s), 7.30-7.41 (10H, m).

(25) 40 → 42

Compound 41 (95% w / w) (1.40 g) was added to a solution of compound 40 (3.33 g) in THF (20 mL), and the mixture was stirred for 6 hours while heating under reflux. After cooling to room temperature, extraction was performed with cetyl acetate and sodium bicarbonate water, and the organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate, the collected organic layer was dried over anhydrous magnesium sulfate, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain Compound 42 (1.67 g ) Was obtained as cream crystals.

H-NMR (CDC13) δ 1.45 (3Η, t, J = 7.2 Hz), 4.49 (2H, q, J = 7.2 Hz), 7.17 (1H, s), 7.26-7.45 (10H, m), 8.45 (1H , s).

(26) 42 → 43

Anisole (2.87 mL) and trifluoroacetic acid (20 mL) were added to compound 42 (4.85 g), and the mixture was stirred at room temperature for 45 minutes. Jetyl ether was added to the reaction solution, and the deposited precipitate was collected by filtration and dried under reduced pressure to obtain Compound 43 (1.73 g) as colorless crystals. H-NMR (CDC) δ 1.46 (3H, t, J = 7.2 Hz), 4.52 (2H, q, J = 7.2 Hz), 8.53 (1H, s)

(27) 43 → 44

Compound 43 (1.73 g) was added to a solution of 4-aminopyridine (809 mg) in DMF (17 mL), and the mixture was ice-cooled. After adding WSCD (1.98 g), the mixture was warmed to room temperature and stirred for 12 hours. Ethyl acetate and water were added, insoluble matter was collected by filtration, and dried under reduced pressure to obtain Compound 44 (1.08 g) as a colorless powder. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting solid residue was washed with ether-ethyl acetate, filtered and dried under reduced pressure to give compound 44. (340 mg) was obtained as colorless crystals.

H-NMR (CDC13) δ 1.49 (3Η, t, J = 7.2 Hz), 4.54 (2H, q, J = 7.2 Hz), 7.79 (2H, d, J = 6.6 Hz), 8.53 (1H, s), 8.58 (2H, d, J = 6.6 Hz), 9.48 (1H, brs).

(28) 44 → 45

A solution of compound 44 (1.42 g) in ethanol (10 mL) was ice-cooled, 2N sodium hydroxide (5.1 mL) was added, and the mixture was stirred at the same temperature for 1.5 hr. 2N Hydrochloric acid (5.1 mL) was added for neutralization, ethanol was evaporated under reduced pressure, and the deposited precipitate was collected by filtration and dried under reduced pressure to give compound 45 (1.29 g) as a colorless solid.

H-NMR (d -DMSO) δ 7.91 (2Η, d, J = 5.4 Hz), 8.50 (2H, brs), 8.77 (1H, s), 10.7

6

(1H, brs).

(29) 45 → 46

To a suspension of compound 45 (1.29 g) in DMF (10 mL), p-methoxybenzyl alcohol (0.70 mL), WSCD (1.18 g), N, N-dimethylaminopyridine (188 mg) were sequentially added, and DMF was added. (10 mL) was added, followed by stirring at room temperature for 16 hours. The reaction mixture was added to water (150 mL) with ice-cooling and stirred for 20 minutes, and the precipitated insoluble material was collected by filtration and dried under reduced pressure to give compound 46 (738 mg) as a pale brown solid.

H-NMR (d6-DMSO) δ: 3.75 (3H, s), 5.38 (2H, 2), 6.96 (2H, d, J = 8.7 Hz), 7.44 (2H, d, J = 8.7 Hz), 7.83 ( 2H, d, J = 6.6 Hz), 8.46 (2H, d, J = 6.6 Hz), 8.83 (1H, s).

(30) 4 + 46 → 47

Compound 4 (820 mg) and Compound 46 (369 mg) to Compound 47 (388 mg) in the same manner as Compound 5 Got.

NMR-NMR (D O) δ: 1.16 (3H, t, J = 6.9 Hz), 3.54 (2H, brs), 4.11 (2H, q, J = 6.9 Hz)

, 5.04 (2H, d, J = 7.2 Hz) 5.14 (1H, d, J = 4.5 Hz), 5.69 (1H, d, J = 4.5 Hz), 5.97 (1 H, dt, J = 7.2, 15.9 Hz) , 6.80 (1H, d, J = 15.9 Hz), 6.83 (1H, s), 8.12 (2H, d, J = 7.5 Hz), 8.46 (1H, s), 8.50 (2H, d, J = 7.5 Hz).

IR (KBr) cm— ¹ : 3412, 2979, 1765, 1631, 1521, 1461, 1363, 1328, 1120, 1161, 1111, 1035.

MS (ESI): 685+ (M + H) +

Elemental analysis c H N NaO S-5.6 H O-0.1 NaHCO

Calculated values: C, 39.89; H, 4.24; N, 13.73; S, 11.79; Na, 3.10 (%)

Experimental value: C39.86; H, 4.04; N, 13.71; S, 11.66; Na, 3.20 (%)

Example 181

[Chemical 228]

(31) 48 → 51

Compound 48 (11.1 g) was added to a solution of compound 49 (19.8 g) in ethanol (80 mL), and the mixture was stirred with heating under reflux for 10 hours. Ethanol was distilled off under reduced pressure and ethyl acetate was added to precipitate, and the deposited precipitate was collected by filtration and dried to obtain crude 50. Ethanol (80 mL) was added to the obtained 50 and cooled with ice. A sodium hydroxide aqueous solution (40 mL) was stirred at room temperature for 2 hours, 2N aqueous sodium hydroxide solution (20 mL) was added, and the mixture was stirred at 45 ° C for 2 hours. The reaction mixture was neutralized with 5N hydrochloric acid under ice-cooling, ethanol was distilled off under reduced pressure, pH was adjusted to 2 with dilute hydrochloric acid, and the deposited precipitate was collected by filtration and dried under reduced pressure. Compound 51 (8.67 g) was obtained as a cream solid.

H-NMR (d6-DMSO) δ: 2.71 (3H, s), 7.92 (2H, dd, J = 1.8, 4.8 Hz), 8.74 (2H, dd, J = 1.8, 4.8).

(32) 51 → 52

Diphenyldiazomethane (2.33 g) was added to a suspension of compound 51 (2.20 g) in THF (30 mL), and the mixture was heated and refluxed for 4 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and recrystallization from diisopropyl ether-hexane gave Compound 52 (3.48 g).

H-NMR (CDC13) δ 2.82 (3Η, s), 7.08 (1H, s), 7.29-7.44 (10H, m), 7.86 (2H, d, J = 6.0 Hz), 8.74 (2H, d, J = 6.0 Hz).

(33) 4 + 52 → 53

To a solution of compound 52 (386 mg) and compound 4 (820 mg) in DMF (3.0 mL) was added sodium bromide (309 mg), and the mixture was stirred at room temperature for 7 hours. DMF (3 mL) was added for dilution, and the mixture was poured into 5% brine (80 mL) with ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried under reduced pressure. The resulting crude product (1.24 g) was dissolved in methylene chloride (15 mL), and anisole (0.65 mL) was added under a nitrogen atmosphere, followed by cooling to -40 ° C. Titanium (IV) chloride (2.0M methylene chloride solution, 3.0 mL) was added dropwise at -40 ° C, and the mixture was stirred in an ice bath for 1 hour. The reaction mixture was poured into water (40 mL) under ice-cooling and stirring, and diisopropyl ether (80 mL) was added. 1N Hydrochloric acid (50 mL) and acetonitryl (50 mL) were added for liquid separation, and the organic layer was extracted with 1N hydrochloric acid-acetonitrile (1: 1). The combined aqueous layer was subjected to HP20ss column chromatography, 0.2N aqueous sodium hydroxide solution was carefully added to the fraction collected by elution with water-acetonitrile, dry ice was added when the pH was reached, and the sample was frozen after concentration. Dried. Compound 53 (256 mg) was obtained as a powder

1H-NMR (DO) δ: 1.28 (3Η, t, J = 6.9 Hz), 2.69 (3H, s), 3.67 (2H, brs), 4.22 (2H, q, J = 6.9 Hz), 5.26 (1H, d, J = 4.8 Hz) 5.31 (2H, d, J = 6.6 Hz), 5.77 (1H, d, J = 4 • 8 Hz), 6.10 (1H, dt, J = 6.6, 15.6 Hz), 6.91 (1H , s), 7.00 (1H, d, J = 15.6 Hz), 8.3 9 (2H, d, J = 7.2 Hz), 8.88 (2H, d, J = 7.2 Hz).

IR (KBr) cm— ¹ : 3426, 1765, 1632, 1602, 1530, 1465, 1360, 1297, 1208, 1156, 1033.

MS (ESI): 656+ (M + H) +

Elemental analysis C H N NaO S -4.7 H O

27 24 7 7 3 2

Calculated value: C, 42.54; H, 4.42; N, 12.86; S, 12.62; Na, 3.02 (%)

Experimental value: C, 42.55; H, 4.35; N, 12.94; S, 12.59; Na, 3.27 (%)

Example 182

[Chemical 229]

(34) 54 → 56

Compound 54 (6.91 g) was added to a solution of compound 55 (13.4 g) in ethanol (50 mL), and the mixture was stirred at 80 ° C. for 6 hours. After cooling to room temperature, ethanol was distilled off under reduced pressure and extracted with ethyl acetate-sodium bicarbonate water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain compound 56 as light brown crystals.

H-NMR (CDC13) δ: 1.30 (3Η, t, J = 7.2 Hz), 2.46 (3H, s), 3.82 (2H, s), 4.22 (2H, q, J = 7.2 Hz), 7.77 (2H, dd, J = 1.8, 4.8 Hz), 8.67 (2H, dd, J = 1.8, 4.8 Hz).

(35) 56 → 57

Add 2N aqueous sodium hydroxide solution (5 mL) to compound 56 (1.31 g) and stir at room temperature for 2 hours. It was. The mixture was neutralized with 2N hydrochloric acid and adjusted to pH 2.7. After stirring in an ice bath for 20 minutes, the insoluble material was collected by filtration and dried under reduced pressure to obtain Compound 57 (1.09 g) as a colorless solid.

H-NMR (d6-DMSO) δ: 2.37 (3Η, s), 3.91 (2H, s), 7.81 (2H, dd, J = 1.5, 4.2 Hz), 8 • 67 (2H, dd, J = 1.5, 4.2).

(36) 57 → 58

Diphenyldiazomethane (1.08 g) was added to a suspension of compound 57 (1.09 g) in THF (14 mL), and the mixture was heated and refluxed for 2.5 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, and the residue was recrystallized from diisopropyl ether-hexane to obtain Compound 58 (1.78 g) as light brown crystals.

H-NMR (CDC13) d: 2.42 (3H, s), 3.93 (2H, s), 6.92 (1H, s), 7.27-7.37 (10H, m), 7.75 (2H, dd, J = 1.8, 4.5 Hz), 8.67 (2H, dd, J = 1.8, 4.5 Hz).

(37) 32 + 58 → 59

Compound 59 (330 mg) was obtained from Compound 32 (855 mg) and Compound 58 (369 mg) in the same manner as Compound 53.

'H-NMR (D O) 5: 1.27-1.30 (6Η, m), 2.43 (3H, s), 3.66 (2H, brs), 3.80 (2H, brs)

, 4.48 (1H, m), 5.25-5.29 (3H, m) 5.80 (1H, d, J = 4.5 Hz), 6.10 (1H, dt, J = 6.9, 16.2 Hz), 6.92 (1H, s), 6.98 (1H, d, J = 16.2 Hz), 8.34 (2H, d, J = 6.9 Hz), 8.81 (2 H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3409, 2976, 2932, 1766, 1632, 1599, 1531, 1467, 1371, 1275, 1206, 1152, 1119, 1030.

MS (ESI): 684+ (M + H) +

Elemental analysis C H N NaO S-3.8 H O-0.3 NaHCO

Calculated value: C, 44.02; H, 4.53; N, 12.26; S, 12.03; Na, 3.74 (%)

Experimental value: C, 43.76; H, 4.60; N, 12.29; S, 12.10; Na, 4.04 (%)

Example 183

[Chemical 230]

(38) 4 + 58 → 60

In the same manner as in Compound 53, Compound 60 (317 mg) was obtained from Compound 4 (869 mg) and Compound 58 (400 mg).

1H-NMR (D O) δ: 1.28 (3Η, t, J = 6.9 Hz), 2.43 (3H, s), 3.66 (2H, brs), 3.80 (2H,

2

s), 4.23 (2H, q, J = 6.9 Hz), 5.25-5.28 (3H, m) 5.80 (1H, d, J = 4.5 Hz), 6.10 (1H, dt, J = 6.9, 15.3 Hz), 6.92 (1H, s), 6.98 (1H, dt, J = 15.3 Hz), 8.34 (2H, d, J = 7.2 Hz), 8.80 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3419, 2980, 1765, 1632, 1599, 1532, 1467, 1373, 1276, 1205, 1156, 1090, 1032, 1000.

MS (ESI): 670 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.5 H O-0.1 NaHCO

28 26 7 7 3 2 3

Calculated value: C, 43.20; Η, 4 · 53; Ν, 12.55; S, 12.31; Na, 3.24 (%)

Experimental value: C, 43.23; Η, 4.51; Ν, 12.63; S, 12.04; Na, 3.26 (%)

Example 184

[Chemical 231]

(39) 32 + 52 → 61

Compound 61 (330 mg) was obtained from Compound 32 (855 mg) and Compound 52 (309 mg) in the same manner as Compound 53.

'H-NMR (D O) δ: 1.26-1.30 (6Η, m), 2.69 (3H, s), 3.63 and 3.70 (2H, ABq, J =

17.1 Hz), 4.47 (1H, m), 5.23 (1H, d, J = 4.8 Hz) 5.31 (2H, d, J = 7.2 Hz), 5.80 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 7.2, 15.6 Hz), 6.91 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 8.39 (2H, d, J = 7.2 Hz), 8.88 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3410, 2976, 1765, 1632, 1600, 1529, 1465, 1360, 1296, 1208, 1150, 1119, 1061, 1031.

MS (ESI): 670 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.7 H O-0.1 NaHCO

Calculated value: C, 43.00; Η, 4.56; Ν, 12.49; S, 12.26; Na, 3.22 (%)

Experimental value: C, 42.92; Η, 4.41; Ν, 12.41; S, 12.46; Na, 3.38 (%)

Example 185

[Chemical 232]

62

(40) 32 + 3 → 62

Compound 62 (148 mg) was obtained from Compound 32 (855 mg) and Compound 3 (368 mg) in the same manner as Compound 11.

'H-NMR (D O) δ: 1.27-1.30 (6Η, m), 3.62 and 3.69 (2H, ABq, J = 17.4 Hz), 4.49

(1H, m), 5.26 (1H, d, J = 4.8 Hz) 5.32 (2H, d, J = 7.2 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 7.2 , 15.6 Hz), 6.90 (1H, d, J = 4.2 Hz), 6.96 (1H, s), 6.97 (1H, d, 15.6 Hz), 7.41 (1H, d, J = 4.2 Hz), 8.38 (2H, d, J = 6.9 Hz), 8.89 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3398, 2977, 1763, 1631, 1536, 1454, 1433, 1373, 1330, 1201, 1156, 1117, 1038.

MS (ESI): 698+ (M + H) ⁺

Elemental analysis C H N Na O S-5.4 H O

Calculated value: C, 41.51; Η, 4.30; Ν, 11.69; S, 11.47; Na, 5.48 (%)

Experimental value: C, 41.57; H, 4.24; N, 11.52; S, 11.50; Na, 5.14 (%)

Example 186

[Chemical 233]

(41) 63 → 64

Diphenyldiazomethane (4.27 g) was carefully added to a solution of compound 63 (3.14 g) in THF (40 mL), and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with hexane-diisopropyl ether and dried under reduced pressure to obtain Compound 64 (7.12 g).

H-NMR (CDC13) d: 7.12 (1H, s), 7.33-7.40 (10H, m), 7.50 (1H, s), 11.5 (1H, brs).

(42) 64 → 65

To a solution of compound 64 (7.12 g) in ethanol (210 mL) was added NH4CK3.21 g) in water (12 mL) and iron powder (10.1 g), and the mixture was stirred with heating under reflux for 5 hours. The mixture was cooled to room temperature and filtered through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate-water was added for extraction, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Ethyl acetate was added to the residue, 4N hydrochloric acid-ethyl acetate (6 mL) was added, and the deposited precipitate was collected by filtration and dried under reduced pressure. Compound 65 (5.40 g) was obtained as a colorless powder.

H-NMR (d6-DMSO) d: 6.56 (1H, s), 7.03 (1H, s), 7.27-7.41 (6H, m), 7.51-7.53 (4H, m).

(43) 65 → 66

A suspension of compound 6 (890 mg) in salt methylene chloride (10 mL) was ice-cooled, and with stirring, compound 65 (1.65 g) and triethylamine (2.23 mL) were collected and the temperature was raised to room temperature. The mixture was stirred at room temperature for 3 hours, extracted with ethyl acetate-water, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. Filter and concentrate under reduced pressure. Methylene chloride (20 mL) was added to the residue, 40% methylamine-methanol solution (0.255 mL) was added with stirring under ice cooling, and the mixture was stirred at the same temperature for 10 min.Compound 6 (354 mg), pyridine (0.49 mL) I got The mixture was stirred in an ice bath for 2 hours, extracted with ethyl acetate-water, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crystalline residue was washed with diisopropyl ether and dried under reduced pressure to obtain Compound 66 (1.23 g) as pale yellow crystals.

H-NMR (d6-DMSO) d: 7.06 (1H, s), 7.28-7.53 (6H, m), 7.53-7.55 (4H, m), 7.91 (2H, dd, J = 1.5, 4.2 Hz), 8.78 (2H, dd, J = 1.5, 4.2 Hz), 11.5 (1H, brs), 13.9 (1H, brs).

(44) 4 + 66 → 67

Compound 67 (201 mg) was obtained from Compound 4 (869 mg) and Compound 66 (398 mg) in the same manner as Compound 11.

'H-NMR (D O) δ: 1.29 (3H, t, J = 7.2 Hz), 3.65 (2H, brs), 4.25 (2H, q, J = 7.2 Hz)

, 5.27 (1H, d, J = 4.8 Hz), 5.38 (2H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.9, 15.9 Hz) , 6.82 (1H, brs), 6.97 (1H, dt, J = 15.9 Hz), 6.99 (lH, s), 8. 43 (2H, d, J = 6.6 H z), 9.01 (2H, d, J = (6.6 Hz).

IR (KBr) cm " ¹ : 3410, 1764, 1669, 1599, 1534, 1455, 1362, 1342, 1302, 1200, 1164, 1132, 1035.

MS (ESI): 668 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S -4.2 H O-0.8 NaHCO

Calculated value: C40. Ll; H, 4.02; N, 15.14; SJ.70; Na, 4.97 (%)

Experimental value: C, 40.01; H, 4.16; N, 15.38; SJ.72; Na, 5.09 (%)

Example 187

[Chemical 234]

(45) 32 + 66 → 68

Compound 68 (216 mg) was obtained from Compound 32 (855 mg) and Compound 66 (398 mg) in the same manner as Compound 11.

1H-NMR (D 2 O) δ: 1.27-1.30 (6Η, m), 3.62 and 3.69 (2H, ABq, J = 17.4 Hz), 4.4

9 (IH, m), 5.27 (1H, d, J = 4.8 Hz), 5.39 (2H, d, J = 6.9 Hz), 5.82 (1H, d, J = 4.8 Hz), 6.12 (1H, dt, J = 6.9, 15.6 Hz), 6.83 (1H, brs), 6.96 (IH, s), 6.98 (1H, d, J = 15.6 Hz), 8.43 (2H, d, J = 6.9 Hz), 9.02 ( 2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3408, 2978, 1766, 1596, 1533, 1456, 1397, 1342, 1304, 1200, 1119, 1041.

MS (ESI): 682+ (M + H) +

Elemental analysis C H N NaO S -4.5 H O-0.8 NaHCO

Calculated value: C, 40.60; H, 4.24; N, 14.80; SJ.53; Na, 4.86 (%)

Experimental value: C, 40.46; H, 4.31; N, 14.79; SJ.82; Na, 4.85 (%)

Example 188

[Chemical 235]

(46) 69 → 71

To a solution of compound 69 (301 mg) in methylene chloride (3 mL) is added pyridine (0.144 mL) and compound 70 (294 mg) in salted methylene chloride (2 mL) with ice-cooling and stirring at the same temperature for 3 hours. Stir. The mixture was extracted with ethyl acetate-water, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crystalline residue was washed with diisopropyl ether and dried under reduced pressure to obtain Compound 71 (470 mg) as a cream powder.

H-NMR (CDC13) d: 1.63 (9H, s), 7.53 (1H, s), 7.79 (2H, d, J = 6.0 Hz), 8.68 (1H, br s), 10.3 (1H, brs).

(47) 4 + 71 → 72

4 (1.23 g) and sodium bromide (463 mg) were added to a solution of compound 71 (458 mg) in DMF (4.5 mL), and the mixture was stirred at room temperature for 8.5 hours. DMF (4 mL) was added for dilution, and the mixture was poured into 5% brine (100 mL) with ice-cooling and stirring. After stirring at the same temperature for 20 minutes, the precipitate was collected by filtration and dried under reduced pressure. The obtained crude product (1.62 g) was dissolved in methylene chloride (20 mL), and anisole (0.98 mL) was added under a nitrogen atmosphere, followed by cooling to -40 ° C. Titanium chloride (IV) (2.0M methylene chloride solution, 4.5 mL) was added dropwise at _40 ° C, followed by stirring in an ice bath for 1 hour. To this reaction solution were added 2N hydrochloric acid (5 mL) and di-sip pill ether (40 mL), and the mixture was stirred for 10 minutes, and then the organic layer was removed by decantation. The residue was washed 3 times by decantation with diisopropyl ether (20 mL). Dissolve the residue in 1N hydrochloric acid and acetonitrile, cover and concentrate HP20ss, and then use HP20ss column chromatography. 0.2N sodium hydroxide was added dropwise to the fraction collected by matography with stirring, and a small amount of dry ice was added when pH 9 was exceeded. Concentration and lyophilization gave Compound 72 (453 mg) as a powder.

'H-NMR (D O) δ: 1.26 (3H, t, J = 7.2 Hz), 3.63 and 3.70 (2H, ABq, J = 17.7 Hz),

4.19 (2H, q, J = 7.2 Hz), 5.22-5.26 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.11 (1H, dt, J = 6.9, 15.3 Hz), 6.89 (1H , S), 6.98 (1H, d, J = 15.3 Hz), 8.16 (1H, s), 8.31 (2H, d, J = 6.9 Hz), 8.73 (2H, d, J = 6.9 Hz).

IR (KBr) cm— ¹ : 3421, 1762, 1663, 1634, 1451, 1458, 1380, 1274, 1206, 1155, 1035, 1001.

MS (ESI): 685+ (M + H) +

Elemental analysis C H N NaO S -4.9 H O-0.2 NaHCO

Calculated values: C, 40.24; H, 4.10; N, 13.80; S, 11.85; Na, 3.40 (%)

Experimental value: C, 40.28; Η, 4 · 10; Ν, 13.81; S, 11.64; Na, 3.44 (%)

Example 189

[Chemical 236]

(48) 48 → 74, 75

To a solution of compound 48 (6.91 g) in ethanol (70 mL), a solution of compound 73 (11.6 g) in ethanol (30 mL) was stirred with heating under reflux for 2 hours. After cooling to room temperature, ethanol was distilled off under reduced pressure, and extraction was performed by adding ethyl acetate-aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The insoluble matter was removed by filtration, and the residue obtained by concentration again was purified by silica gel column chromatography to obtain Compound 74 (2.54 g) and Compound 75 (4.17 g) as pale brown Obtained as crystals.

74: H-NMR (CDC13) δ: 1.47 (3Η, t, J = 7.2 Hz), 2.68 (3H, s), 4.52 (2H, q, J = 7.2 Hz), 7.89 (2H, d, J = 6.0 Hz), 8.79 (2H, d, J = 6.0 Hz).

75: H-NMR (CDC13) δ: 1.46 (3H, t, J = 7.2 Hz), 2.88 (3H, s), 4.46 (2H, q, J = 7.2 Hz), 7.97 (2H, d, J = 4.8 Hz), 8.78 (2H, d, J = 4.8 Hz).

(49) 74 → 77

Similar to the method for obtaining Compound 58 from Compound 56, Compound 74 (2.54 g) to Compound 77 (2.15 g) Got.

76: H-NMR (d6-DMSO) δ: 2.63 (3Η, s), 7.96 (2H, dd, J = 1.8, 4.5 Hz), 8.78 (2H, dd, J = 1.8, 4.5 Hz).

77: H-NMR (CDC13) δ: 2.45 (3H, s), 7.20 (1H, s), 7.30-7.49 (10H, m), 7.91 (2 H, d, J = 5.7 Hz), 8.80 (2H, brs).

(50) 4 + 77 → 78

Compound 78 (546 mg) was obtained from Compound 4 (1.22 g) and Compound 77 (623 mg) in the same manner as Compound 71.

'H-NMR (DO) δ: 1.29 (3H, t, J = 7.2 Hz), 2.70 (3H, s), 3.66 (2H, brs), 4.24 (2H, q, J = 7.2 Hz), 5.27 (1H , d, J = 4.8 Hz), 5.34 (1H, d, J = 7.2 Hz), 5.81 (1H, d, J = 4 • 8 Hz), 6.12 (1H, dt, J = 7.2, 15.6 Hz), 6.96 (1H, s), 6.99 (1H, d, J = 15.6 Hz), 8.54 (2H, d, J = 7.2 Hz), 8.96 (2H, d, J = 7.2 Hz).

IR (KBr) cm " ¹ : 3410, 1763, 1633, 1530, 1463, 1359, 1289, 1210, 1153, 1032, 1000. MS (ESI): 684 ⁺ (M + H) ⁺

Elemental analysis C H N NaO S-3.1 H O-0.1 NaHCO

Calculated values: C, 43.83; H, 3.97; N, 12.73; S, 12.49; Na, 3.28 (%)

Experimental value: C, 43.79; H, 4.22; N, 12.87; S, 12.56; Na, 3.30 (%)

Example 190

[Chemical 237]

(51) 75 → 80

Analogously to the method for obtaining compound 58 from compound 56, compound 80 (4.42 g) was obtained from compound 75 (4.17 g).

79: H-NMR (d6-DMSO) δ: 2.73 (3Η, s), 7.97 (2H, d, J = 6.0 Hz), 8.74 (2H, d, J = 6.0 Hz).

80: H-NMR (CDC13) δ: 2.84 (3H, s), 7.04 (1H, s), 7.30-7.47 (10H, m), 7.92 (2H, dd, J = 1.5, 4.8 Hz), 8.76 (2H , dd, J = J = 1.5, 4.8 Hz).

(52) 4 + 80 → 81

Compound 81 (133 mg) was obtained from Compound 4 (1.22 g) and Compound 80 (623 mg) in the same manner as Compound 71.

'H-NMR (DO) δ: 1.27 (3H, t, J = 7.2 Hz), 2.76 (3H, s), 3.67 (2H, brs), 4.21 (2H, q, J = 7.2 Hz), 5.25 (1H , d, J = 4.8 Hz), 5.34 (1H, d, J = 7.2 Hz), 5.78 (1H, d, J = 4 • 8 Hz), 6.11 (1H, dt, J = 7.2, 16.2 Hz), 6.89 (1H, s), 7.01 (1H, d, J = 16.2 Hz), 8.50 (2H, d, J = 6.9 Hz), 8.94 (2H, d, J = 6.9 Hz).

IR (KBr) cm " ¹ : 3419, 2982, 1763, 1633, 1531, 1481, 1381, 1325, 1209, 1155, 1034. MS (ESI): 684 ⁺ (M + H) ⁺

Elemental analysis CHN NaO S -4.9 HO-0.3 NaHCO Calculated values: C, 41.49; H, 4.20; N, 11.97; S, 11.74; Na, 3.65 (%)

Experimental value: C, 41.37; H, 4.20; N, 12.23; S, 11.79; Na, 3.77 (%)

Example 191

[Chemical 238]

(53) 82 → 89

Compound 89 was synthesized in the same manner as that for obtaining Compound 46.

83: H-NMR (CDC13) δ: 1.81 (3Η, d, J = 6.9 Hz) 5.16 (2H, d, J = 6.9 Hz), 6.99 (1 H, s), 7.26-7.48 (10H, m).

84: H-NMR (CDC13) δ: 1.43 (3H, t, J = 7.2 Hz), 2.82 (3H, s), 4.46 (2H, q, J = 7.2 Hz), 7.14 (1H, s), 7.27- 7.47 (10H, m).

85: H-NMR (CDC13) δ: 1.44 (3H, t, J = 6.9 Hz), 2.89 (3H, s), 4.48 (2H, q, J = 6.9 Hz).

87: H-NMR (CDC13) δ: 1.36 (3H, t, J = 6.9 Hz), 2.84 (3H, s), 4.42 (2H, q, J = 6.9 Hz), 7.84 (2H, dd, J = 1.5 , 4.8 Hz), 8.47 (2H, dd, J = 1.5, 4.8 Hz), 10.6 (1H, brs).

88: H-NMR (d6-DMS0) δ: 2.87 (3H, s), 8.47 (2H, d, J = 7.2 Hz), 8.79 (2H, d, J = 7.2 Hz) 11.7 (1H, brs). 89: H-NMR (d6-DMSO) δ: 2.80 (3H, s), 3.75 (3H, s), 5.35 (2H, s), 6.96 (2H, dd, J = 2.1, 6.6 Hz), 7.41 (2H , dd, J = 2.1, 6.6 Hz), 7.80 (2H, dd, J = 1.5, 4.8 Hz), 8.44 (2H, dd, J = 1.5, 4.8 Hz), 10.6 (1H, brs).

(54) 4 + 89 → 90

Compound 90 (335 mg) was obtained from Compound 4 (1.27 g) and Compound 89 (575 mg) in the same manner as Compound 5.

1H-NMR (D O) δ: 1.27 (3Η, t, J = 7.2 Hz), 2.77 (3H, s), 3.64 and 3.71 (2H, ABq,

J = 17.4 Hz), 4.21 (2H, q, J = 7.2 Hz), 5.14 (2H, d, J = 6.6 Hz), 5.26 (1H, d, J = 4.8 Hz), 5.81 (1H, d, J = 4.8 Hz), 6.10 (1H, dt, J = 6.6, 15.6 Hz), 6.91-6.96 (2H, m), 8.13 (2H, d, J = 7.5 Hz), 8.57 (2H, d, J = 7.5 Hz) .

IR (KBr) cm " ¹ : 3418, 2981, 1764, 1616, 1519, 1458, 1369, 1328, 1196, 1165, 1108, 1038.

MS (ESI): 699+ (M + H) ⁺

Elemental analysis C H N NaO S-5.2 H O

Calculated value: C, 41.29; Η, 4.38; Ν, 13.76; S, 11.81; Na, 2.82 (%)

Experimental value: C, 41.10; H, 4.47; N, 13.69; S, 12.11; Na, 2.56 (%)

Example 192

[Chemical 239]

(55) 91 + 92 → 93

Compound 92 (1.11 g) and potassium tert-butoxide (617 mg) were added to a solution of compound 91 (881 mg) in THF (15 mL), and the mixture was stirred at room temperature for 1.5 hours. Compound 92 (405 mg) and potassium tert-butoxide (224 mg) were added, and the mixture was further stirred for 30 minutes, and then THF was distilled off under reduced pressure. 2N Hydrochloric acid was added to adjust to pH 3.0, diisopropyl ether was added and the mixture was stirred in an ice bath for 15 minutes. The insoluble material was collected by filtration and dried under reduced pressure. Compound 93 (1.53 g) was obtained as a light brown solid.

H-NMR (d6-DMSO) δ: 1.54 (9H, s), 6.80 (1H, s), 7.92 (2H, dd, J = 1.8, 4.5 Hz), 8.47 (1H, brs), 8.64 (2H , dd, J = 1.8, 4.5 Hz).

(56) 4 + 93 → 94

N, 0_bistrimethylsilylacetamide (0.3 7 mL) was added to a suspension of compound 93 (457 mg) in DMF (4 mL), and the mixture was stirred at room temperature for 15 min. Compound 4 (1..22 g), DMF (0.5 mL), and sodium bromide (463 mg) were added to the reaction mixture and stirred at room temperature overnight, then diluted with DMF (4 mL) and ice-cooled. The mixture was poured into 5% brine (80 mL) with stirring. After stirring at the same temperature for 20 minutes, the solution was collected by suction filtration and dried under reduced pressure to obtain a light brown solid (1.69 g). This solid was dissolved in methylene chloride (3 mL), anisole (0.98 mL) was added under a nitrogen atmosphere, and the mixture was ice-cooled. Trifluoroacetic acid (7.5 mL) was added, and the mixture was stirred at the same temperature for 2 hr. After additional TFA (5 mL) was stirred and further stirred at room temperature for 2.5 hours, the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, and the deposited precipitate was collected by filtration. This solid was dissolved in acetonitrile, water, and hydrochloric acid, concentrated by adding HP20ss, and then subjected to HP20ss column chromatography, and the collected fractions were concentrated. The concentrated solution was adjusted to pH 8, and fractions collected by ODS column chromatography were concentrated and lyophilized. Compound 94 (208 mg) was obtained as a powder.

'H-NMR (D O) δ: 1.24-1.29 (3Η, m), 3.65-3.67 (2H, m), 4.17-4.25 (2H, m), 5

.24-5.26 (3H, m), 5.79 (1H, d, J = 4.8 Hz), 6.07-6.14 (1H, m), 6.89-7.02 (2H, m), 8.21-8.49 (3H, m), 8.71 -8.77 (2H, m).

IR (KBr) cm— ¹ : 3408, 1763, 1634, 1605, 1532, 1457, 1389, 1207, 1156, 1090, 1036.

MS (ESI): 684+ (M + H) +

Elemental analysis C H N NaO S -4.9 H O

Calculated values: C, 42.36; H, 4.29; N, 12.35; S, 12.12; Na, 2.90 (%) Experimental value: C, 42.26; Η, 4.33; Ν, 12.32; S, 12.33; Na, 3.15 (%)

Example 193

[Chemical 240]

(5) 9 → 1 0

Compound 9 (946 mg, 5 mmol) was dissolved in dimethylformamide (8 ml), carbonyldiimidazole (1.06 g, 6.5 mmol) was added, and the mixture was stirred for 3 hours. Next, trifluoromethanesulfamide (745 mg, 5 mmol) and DBU (0.75 ml, 5 mmol) were added and stirred at 60 ° C. for 2 hours. The reaction solution was ice-cooled and neutralized with 6N HC1, and the precipitate was collected by filtration and dried to obtain Compound 10. Yield 1.33g (67%) 'H-NMR (d-DMSO): 7.53 (1H, s), 8.44 (2H, d, J = 6.6Hz), 8.86 (2H, d, J = 6.6Hz).

(6) 10 → 11

Compound 10 (0.79 g, 2 mmol) was suspended in 8 ml of methanol, and 1.8 ml of 1M sodium methylate was added. The reaction solution was concentrated to obtain 11, which was used in the next reaction as it was. Yield 0.88g.

(7) 11 + 8 → 12

Compound 8 (1.7 g, 2 mmol) is dissolved in dimethylformamide (6.5 ml), mixed with compound 11 (0.88 g, 2 mmol), sodium bromide (617 mg, 6 mmol) is added and stirred at room temperature for 6 hours. did. The reaction mixture was poured into 5% brine (60 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 12 (2.32 g) as a powder.

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 1.48 (9H, s), 3.67, 3.92 (2H, ABq, J = 18.0Hz), 4.15 (2Η, q, J = 7.2Hz), 5.26 (2H, d, J = 6.4Hz), 5.31 (1H, d, J = 5.2Hz), 5.95 (1 H, dd, J = 8.0, 5.2Hz), 6.44 (1H, dt, J = 15.6, 6.4Hz), 6.89 (1H, d, J = 15.6Hz), 6.93 (1H, s), 7.27-7.52 (11H, m), 7.96 (1H, s), 8.51 (2H, d, J = 6.4Hz), 8.91 (2H, d, J = 6.4Hz), 9 • 74 (1H, d, J = 8.0Hz).

(8) 12 → 7

Compound 12 (2.31 g) was dissolved in methylene chloride (23 ml) and anisole (2.3 ml) and cooled to -30 ° C. A solution of 2MTiCl in methylene chloride (11 ml) was stirred for 1 hour. The reaction mixture was poured into water-isopropyl ether with stirring under ice cooling. The deposited precipitate was collected by filtration, dissolved in NaHC 0 water, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. Fractions containing the desired compound were concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain compound 7 as a powder. Yield 0.94g (48%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3.50 (2H, ABq, J = 16.5Hz), 4.0

9 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.8Hz), 5.22 (2H, d, J = 6.8Hz), 5.59 (1H, dd, J = 8.1, 4.8Hz ), 5.84 (1H, dt, J = 15.9, 6.8Hz), 6.72 (1H, s), 7.22 (2H, s), 7.29 (1H, d, J = 15.9 Hz), 7.52 (1H, s), 8.49 (2H, d, J = 6.8Hz), 8.91 (2H, d, J = 6.8Hz), 9.53 (1H, d, J = 8.1Hz)

IR (KBr) cm " ¹ : 3420, 1763, 1636, 1533, 1394, 1299, 1203, 1119, 1035, 963, 819, 60 8.

MS (ESI): 756 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H F N O S Na'4.5H O 'O. lNaHCO

Calculated: C, 37.53; H, 3.73; N, 14.54; F, 6.57; S, 11.09; Na, 2.92 (%)

Experimental value: C37.45; H, 3.84; N, 14.56; F, 6.40; S, 11.36; Na, 3.11 (%)

Example 194

[Chemical 241]

(14) 21 → 22

Compound 21 (3.04 g, 15 mmol) was suspended in dimethylformamide (30 ml), carbonyldiimidazole (3.51 g, 21.7 mmol) was added, and the mixture was stirred for 2 hours. The reaction mixture was poured into ethyl acetate under ice-cooling, insoluble material was removed by filtration, and 28% aqueous ammonia (15 ml) was added. Ethyl acetate was added to the reaction solution, washed with water, dried and concentrated to obtain 22 as crystals. Yield 2.14 g (70%)

'H-NMR (d-DMSO): 2.43 (3H, s), 7.06 (2H, brs), 7.30 (1H, s), 7.41 (2H, d, J = 6.0Hz)

8.50 (2H, d, J = 6.0Hz), 11.5 (1H, brs).

(15) 22 → 23

Compound 22 (1.12 g, 5.6 mmol) was dissolved in pyridine (13 ml), trifluoroacetic anhydride (0.91 ml, 6.7 mmol) was added, and the mixture was stirred for 1.5 hours. After concentrating the reaction solution, a mixed solution of ethyl acetate and water was added, insoluble materials were filtered off, and the mother liquor was washed with water, dried and concentrated to obtain 23 as crystals. Yield 0.46g (45%)

'H-NMR (d-DMSO): 2.35 (3H, s), 7.06 (2H, brs), 7.48 (2H, d, J = 6.2Hz), 7.63 (1H, s)

, 8.54 (2H, d, J = 6.2Hz), 12.4 (1H, brs).

(16) 23 → 24

Compound 23 (971 mg, 5.3 mmol) was dissolved in dimethylformamide (10 ml) to give NaN (379 mg, 5.8

3 mmol) and ammonium chloride (312 mg, 5.83 mmol), and after 4 hours, further NaN (379 mg, 5.

83 mmol) and ammonium chloride (312 mg, 5.83 mmol) were added and stirred overnight at 115 ° C. The reaction solution was cooled and neutralized with 2N HC1, and the precipitate was collected by filtration and dried to obtain 24 as crystals. Yield 8 70 mg (73%).

'H-NMR (d-DMSO): 2.48 (3H, s), 7.50—7.56 (2H, m), 8.54 (2H, d, J = 6.3Hz), 11.9 (1

6

H, brs).

(17) 24 + 8 → 25

Compound 8 (1.527 g, 1.8 mmol) and compound 24 (407 mg, 1.8 mmol) were dissolved in dimethyl sulfoxide (9 ml), sodium iodide (809 mg, 5.4 mmol) was added, and the mixture was stirred for 5 hours. The reaction solution was poured under stirring with 5% brine (50 ml), and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 25 (2.23 g) as a powder.

'H-NMR (d-DMSO): 1.24 (3H, t, J = 6.9Hz), 1.47 (9H, s), 2.54 (3H, s), 3.66, 3.92 (2

6

H, ABq, J = 17.3Hz), 4.14 (2H, q, J = 6.9Hz), 5.18 (2H, d, J = 6.6Hz), 5.30 (1H, d, J = 4.8Hz), 5.95 (1H , dd, J = 8.3, 4,8Hz), 6.43 (1H, dt, J = 15.6, 6.9Hz), 6.87 (1H, d, J = 15.6 Hz), 6.92 (1H, s), 7.25-7.54 (l lH, m), 8.06 (1H, s), 8.18 (2H, d, J = 7.1Hz), 8.71 (2H, d, J = 7.1Hz), 9.74 (1H, d, J = 8.3Hz), 11.80 ( 1H, s), 12.6 (1H, brs).

(18) 25 → 20

Compound 25 (2.22 g) was obtained in the same manner as (8) to give Compound 20 as a powder. Yield 464 mg (28%) 'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 2.69 (3H, s), 3.42, 3.51 (2H, ABq, J =

6

16.5Hz), 4.09 (2H, q, J = 7.2Hz), 5.04 (1H, d, J = 5.1Hz), 5.11 (2H, d, J = 6.9Hz), 5.60 (1 H, dd, J = 8.1 , 5.1Hz), 5.84 (1H, dt, J = 16.1, 6.9Hz), 6.72 (1H, s), 7.23 (2H, s), 7.27 (1 H, d, J = 16.1Hz), 7.80 (1H, s), 8.13 (2H, d, J = 7.2Hz), 8.64 (2H, d, J = 7.2Hz), 9.54 (1H, d, J = 8.1Hz), 12.K1H, brs).

IR (ATR) cm— ¹ : 3308, 1758, 1633, 1602, 1537, 1385, 1150, 1033.

MS (ESI): 662 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5.0H O -O.lNaHCO

28 26 11 5 2 2 3

Calculated value: C, 43.15; H, 4.65; N, 19.70; S, 8.20; Na, 3.23 (%)

Experimental value: C, 43.15; H, 4.71; N, 19.73; S, 8.22; Na, 3.28 (%)

Example 195

[Chemical 242]

(19) 27 → 28

Compound 27 (10.37 g, 71 mmol) is dissolved in acetic acid (12.4 ml), and an aqueous solution of sodium nitrite (5.6 3 g, 82 mmol) (68 ml) is added dropwise under ice cooling. After stirring for 1 hour, add ethyl ether to the reaction mixture, wash with water, dry and concentrate. The residue was crystallized from hexane to give 28. Yield 6.72 g (54%)

'H-NMR (CDCl): 3.48 (3H, s), 3.92 (3H, s), 4.55 (2H, s), 9.97 (1H, brs).

(20) 28 + 29 → 30

Compound 28 (5.5, 31.511111101) and compound 29 (3.1, 2111111101) are dissolved in acetic acid (441111) to obtain zinc powder (3.1 g, 47 mmol). After stirring for 2 hours, ethyl acetate and aqueous sodium carbonate solution were added to the reaction solution. The insoluble material is removed by filtration, and the organic layer is washed with water, dried and concentrated. The residue was purified by column chromatography to obtain 30 as crystals. Yield 1.83 g (35%)

'H-NMR (CDCl): 3.47 (3H, s), 3.93 (3H, s), 4.68 (2H, s), 7.20 (1H, d, J = 3.3Hz), 7.53

(2H, d, J = 6.2Hz), 8.60 (2H, d, J = 6.2Hz), 9.52 (1H, brs).

(21) 30 → 31

Compound 30 (1.78 g, 7.23 mmol) is dissolved in ethanol (14 ml), 2NNaOH (18 ml) is added, and the mixture is stirred at 70 ° C. for 1.5 hours. Concentrate the reaction, add water, cool, and neutralize with dilute HC1. The precipitated crystals were collected by filtration and dried to obtain 31. Yield 1.21 g (72%)

'H-NMR (d-DMSO): 3 · 30 (3Η, s), 4 · 72 (2Η, s), 7.67 (1Η, d, J = 3.3Hz), 7.81 (2H, d, J

= 6.0Hz), 8.54-8.75 (2H, m), 12.3 (1H, brs). (22) 31 + 8 → 32

Compound 31 (348 mg, 1.5 mmol) is dissolved in dimethylformamide (5 ml), bis-trimethylsilyltrifluoroacetamide (0.4 ml, 1.5 mmol) is added and stirred for 1 hour. Then, compound 8 (1.18 g, 1.5 mmol) and sodium bromide (463 mg, 4.5 mmol) were added and stirred for 6 hours. The reaction solution was poured into 5% brine (50 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 32 (1.36 g) as a powder, which was directly used in the next reaction.

(23) 32 → 26

Compound 32 (2.22 g) was obtained in the same manner as (8) to give Compound 26 as a powder. Yield 149mg (13%) 'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.27 (3H, s), 3.41, 3.50 (2H, ABq, J =

16.8Hz), 4.09 (2H, q, J = 6.9Hz), 5.03 (2H, s), 5.04 (1H, d, J = 5.1Hz), 5.08 (2H, d, J = 6.9Hz), 5.59 ( 1H, dd, J = 8.1, 5.1Hz), 5.82 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.23 (2H, s), 7.25 (1H, d, J = 15.9 Hz), 7.67 (1H, s), 8.12 (2H, d, J = 7.2Hz), 8.65 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.1Hz).

IR (ATR) cm— ¹ : 3300, 1760, 1633, 1581, 1537, 1393, 1335, 1152, 1034.

MS (ESI): 667 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5H O -O.lNa HPO

Calculated value: C, 43.87; H, 4.84; N, 12.35; S, 8.08; Na, 3.47 (%)

Experimental value: C, 43.78; H, 4.71; N, 12.43; S, 8.14; Na, 3.42 (%)

Example 196

[Chemical 243]

(24) 33 → 34

34 was obtained as crystals from compound 33 (14.42 g, 100 mmol) in the same manner as (19). Yield 10.19 g (59%)

H-NMR (CDCl): 1.13 (3H, t, J = 7.2Hz), 1.36 (3H, t, J = 7.2Hz), 2.82 (2H, q, J = 7.2Hz

), 4.39 (2H, q, J = 7.2Hz), 9.09 (1H, brs).

(25) 34 + 29 → 35

35 was obtained as a crystal from compound 34 (6.49 g, 37.5 mmol) and compound 29 (4.14 g, 25 mmol) in the same manner as (20). Yield 1.35 g (22%)

'H-NMR (CDCl): 1 · 23 (3Η, t, J = 7.5Hz), 1.40 (3H, t, J = 7.4Hz), 2.93 (2H, q, J = 7.5Hz

), 4.38 (2H, q, J = 7.4Hz), 7.09 (1H, d, J = 3.0Hz), 7.35 (2H, d, J = 6.2Hz), 8.59 (2H, d, J = 6.2Hz), 9.44 (1H, brs).

(26) 35 → 36

36 was obtained as a crystal from compound 35 (1.30 g, 5.32 mmol) in the same manner as (21). Yield 0.84 g (73

%)

'H-NMR (d-DMSO): 1 · 13 (3Η, t, J = 7.5Hz), 2.92 (2H, q, J = 7.5Hz), 7.36 (1H, d, J = 3.

3Hz), 7.49 (2H, d, J = 6.2Hz), 8.54 (2H, d, J = 6.2Hz), 11.9 (1H, brs), 12.4 (1H, brs).

(27) 36 → 37 Compound 36 (0.83 g, 15 mmol) force 37 was obtained as crystals in the same manner as in (14). Yield 0.66g (80%)

'H-NMR (d-DMSO): 1.10 (3H, t, J = 7.5Hz), 2.91 (2H, q, J = 7.5Hz), 7.05 (2H, s), 7.2

5 (1H, s), 7.38 (2H, d, J = 6.2Hz), 8.50 (2H, d, J = 6.2Hz), 11.4 (1H, brs).

(28) 37 → 38

Compound 37 (652 mg, 3 mmol) was obtained in the same manner as in (15), 38 as crystals. Yield 529 mg (89%)

'H-NMR (d-DMSO): 1.13 (3H, t, J = 7.5Hz), 2.77 (2H, q, J = 7.5Hz), 7.45 (2H, d, J = 5.

9Hz), 7.55 (1H, d, J = 3.3Hz), 8.55 (2H, d, J = 5.9Hz), 12.5 (1H, brs).

(29) 38 → 39

Compound 38 (463 mg, 2.3 mmol) was dissolved in dimethylformamide (5 ml), NaN (764 mg, 11.8 mmol) and triethylamine hydrochloride (1.62 g, 11.8 mmol) were added, and the mixture was stirred at 115 ° C for 6 hours. . The reaction solution was cooled, neutralized with 2N HC1, and the precipitate was collected by filtration and dried to obtain 39 as crystals. Yield 506 mg (90%).

'H-NMR (d-DMSO): 1.11 (3H, t, J = 7.5Hz), 2.98 (2H, q, J = 7.5Hz), 7.47 (1H, d, J = 3.

OHz), 7.50 (2H, d, J = 6.3Hz), 8.54 (2H, d, J = 6.3Hz), 11.9 (1H, brs).

(30) 39 + 2 → 40

Compound 2 (1.214 g, 1.8 mmol) was suspended in ethyl acetate (20 ml), aqueous sodium hydrogen carbonate solution (227 mg, 2.7 mmol dissolved in 20 ml of water) was added, extracted with ethyl acetate and dried. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (5 ml), mixed with compound 39 (432 mg, 1.8 mmol), sodium bromide (556 mg, 5.4 mmol) was added, and the mixture was stirred at room temperature for 7.5 hours. The reaction solution was poured into 5% brine (50 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 40 (1.492 g) as a powder.

'H-NMR (d-DMSO): 1.17 (3H, t, J = 7.2Hz), 1.23 (3Η, t, J = 7.2Hz), 3.14 (2H, q, J = 7.

2Hz), 3.65, 3.92 (2H, ABq, J = 17.7Hz), 4.10 (2H, q, J = 7.2Hz), 5.18 (2H, d, J = 6.6Hz), 5.29 (1H, d, J = 4.8 Hz), 5.92 (1H, dd, J = 8.3, 4,8Hz), 6.43 (1H, dt, J = 16.5, 6.6Hz), 6.75 (1H, s), 6.88 (1H, d, J = 16.5 Hz), 6.92 (1H, s), 7.20—7.55 (12H, m), 8.06 (1H, d, J = 3.3Hz), 8.15 (2H, d, J = 6.6Hz), 8.73 (2H, d, J = 6.6Hz), 9.65 (1H, d, J = 8.3Hz), 12.7 (1H, brs).

(31) 40 → 32-1

Compound 40-1 (1.48 g) was obtained in the same manner as (8) to give compound 32-1 as a powder. Yield 460mg (34%) 'H-NMR (d-DMSO): 1.15 (3H, t, J = 7.5Hz), 1.22 (3H, t, J = 7.2Hz), 3.24 (2H, q, J =

6

7.5Hz), 3.43, 3.51 (2H, ABq, J = 17.0Hz), 4.09 (2H, q, J = 7.2Hz), 5.04 (1H, d, J = 5.1

Hz), 5.11 (1H, d, J = 5.1Hz), 5.11 (2H, d, J = 7.2Hz), 5.59 (1H, dd, J = 8.1, 5.1Hz), 5.84 (

1H, dt, J = 15.9, 7.2Hz), 6.72 (1H, s), 7.22 (2H, s), 7.27 (1H, d, J = 15.9Hz), 7.76 (1H, s

), 8.08 (2H, d, J = 7.2Hz), 8.64 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.1Hz), 12.0 (1H, brs).

IR (ATR) cm— ¹ : 3299, 1758, 1632, 1599, 1533, 1354, 1149, 1033.

MS (ESI): 675 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 0.1NaCl -4.2H O

29 26 11 5 2 2

Calculated value: C, 44.70; H, 4.71; N, 19.77; S, 8.23; Na, 3.25 Cl, 0.45 (%)

Experimental value: C, 44.75; H, 4.61; N, 19.70; S, 8.23; Na, 3.24 Cl, 0.63 (%)

Example 197

[Chemical 244]

(32) 42 → 43

Compound 42 (4.32 g, 20 mmol) was dissolved in tetrahydrofuran (34 ml), diphenyldiazomethane was added, and the mixture was heated and stirred. Ethyl acetate is added to the reaction solution, washed with water, dried and concentrated. The residue was purified by column chromatography to give 43. Yield 6.25 g (82%)

H-NMR (CDCl): 5.7 (2H, brs), 6 · 56 (1Η, d, J = 6.0Hz), 7.05 (1H, s), 7.25- 7.45 (11H, m), 8/12 (1Η, d, J = 2.4Hz).

(33) 43 → 44

Compound 43 (1.5 g, 3.9 mmol) was dissolved in methylene chloride (12 ml), pyridine (1.65 ml) and methanesulfur chloride (1.59 ml) were added in portions, and the mixture was stirred under reflux. After adding ethyl acetate and 2N HC1 to the reaction solution, neutralize with sodium bicarbonate water, wash with water, dry and concentrate. The crystalline residue was washed with hexane-ethyl acetate to give 44 as crystals. Yield 1.56g (86%)

'H-NMR (CDCl): 3 · 00 (3Η, s), 7.09 (1H, s), 7.05 (1H, s), 7.30-7.46 (10H, m), 7.62-

7.70 (2H, m), 8.29-8.33 (1H, m), 10.31 (1H, s).

(34) 44 + 45 → 46

Compound 44 (1.40 g, 3 mmol) and compound 45 (811 mg, 4 mmol) are dissolved in dioxane (14 ml). Add K 3 PO 4 (1.93 g, 9 mmol) and Pd (PPh 3) (176 mg, 0.15 mmol) and reflux for 5 hours. Add ethyl acetate to the reaction mixture, wash with water, dry and concentrate. The residue was purified by column chromatography to obtain Compound 46 as crystals. Yield 688mg (49%)

'H-NMR (CDCl): 3.07 (3H, s), 7.15 (1H, s), 7.30-7.46 (10H, m), 7.49 (2H, d, J = 6, 0Hz), 7.81-7.9K2H, m), 8.48 (1H, d, J = 1.8Hz), 8.70 (2H, d, J = 6,0Hz), 10.51 (lH, s).

(35) 46 + 2 → 47

Compound 47 (1.492 g) was obtained as a powder from Compound 2 (919 mg, 1.4 mmol) and Compound 46 (625 mg, 1.4 mmol) in the same manner as (30).

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.32 (3H, s), 3.65, 3.91 (2H, ABq, J = 17.

6Hz), 4.10 (2H, q, J = 7.2Hz), 5.30 (1H, d, J = 4.8Hz), 5.32 (2H, d, J = 6.9Hz), 5.93 (1H, dd, J = 8.4, 4.8 Hz), 6.45 (1H, dt, J = 15.5, 6.9Hz), 6.75 (1H, s), 6.92 (1H, s), 6.92 (1H, d, J = 15.5Hz), 7.12 (1H, s), 7.23— 7.66 (22H, m), 7.85 (1H, d, J = 9.0Hz), 8.35 (1H, dd, J = 9.0, 2.6Hz), 8.56 (2H, d, J = 6.9Hz), 8.70 (1H , d, J = 2.6Hz), 9.01 (2H, d, J = 6.9Hz), 9.65 (1H, d, J = 8.4Hz), 10.4 (1H, s) ·

(36) 47 → 41

Compound 47 (1.5 g) was dissolved in methylene chloride (8 ml) and anisole (1.5 ml), cooled to 0 ° C., and 7.5 ml of TFA was added. The mixture was stirred at 0 ° C., and then poured into a mixture of 40 ml of isopropyl alcohol with stirring under ice cooling. The deposited precipitate was collected by filtration and saturated NaHCO 3 aqueous solution. Dissolved. The solution was subjected to HP-20SS column chromatography and dissolved with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 41 as a powder. Yield 497mg (46%)

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 2.97 (3H, s), 3.42, 3.50 (2H, ABq, J = 16.

6

8Hz), 4.09 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 5.0Hz), 5.22 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.4, 5.0 Hz), 5.85 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.22 (2H, s), 7.29 (1H, d, J = 15.9Hz), 7.57 (1H, d, J = 9.0Hz), 8.07 (1H, dd, J = 9.0, 2.6Hz), 8.40 (2H, d, J = 7.2Hz), 8.59 (1H, d, J = 2.6Hz), 8.87 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.4Hz).

IR (ATR) cm— ¹ : 3315, 1760, 1615, 1531, 1487, 1354, 1298, 1144, 1034, 969.

MS (ESI): 727 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na-O. LNaHCO -0. LNaCl- 3.6H O

30 28 7 9 3 3 2

Calculated values: C, 43.62; H, 4.29; N, 11.83; S, 11.61; Na, 3.33 Cl, 0.43 (%)

Experimental value: C, 43.39; H, 4.35; N, 11.93; S, 12.24; Na, 3.16 Cl, 0.54 (%)

Example 198

[Chemical 245]

(37) 43 → 49

Compound 43 (1.58 g, 4.1 mmol) was dissolved in methylene chloride (13 ml), pyridine (0.5 ml, 6.2 mmol) and acetyl chloride (0.44 ml, 6.2 mmol) were added and stirred. After adding ethyl acetate and water to the reaction solution, neutralize, wash with water, dry and concentrate. Wash the crystalline residue with hexane to remove 49 Obtained as crystals. Yield 1.56g (89%)

'H-NMR (CDCl 3): 2.19 (3H, s), 7.08 (1H, s), 7.28-7.45 (10H, m), 7.64 (1H, dd, J = 9.3,

2.4Hz), 8.29 (lH, d, J = 2.4Hz), 8.65 (1H, d, J = 9.3Hz), 10.90 (1H, s).

(38) 49 + 45 → 50

Compound 50 was obtained as crystals from compound 49 (1.27 g, 3 mmol) and compound 45 (801 mg, 4 mmol) in the same manner as in (34). Yield 589mg (46%)

'H-NMR (CDCl): 2.23 (3H, s), 7.14 (1H, s), 7.30—7.47 (10H, m), 7.50 (2H, d, J = 6.3H z), 7.84 (1H, dd, J = 8.9, 2.3Hz), 8.48 (1H, d, J = 2.3Hz), 8.68 (2H, d, J = 6.3Hz), 8.87 (1 H, d, J = 8.9Hz), 11.04 (1H, s ).

(39) 50 + 2 → 51

Compound 51 (1.723 g) was obtained as a powder in the same manner as Compound 2 (857 mg, 1.3 mmol) and Compound 50 (537 mg, 1.3 mmol) (30), and used as it was in the next reaction.

(40) 51 → 48

Compound 51 (1.72 g) was obtained in the same manner as (36) to give Compound 48 as a powder. Yield 419mg (33%) 'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 2.11 (3H, s), 3.42, 3.50 (2H, ABq, J = 16.

5Hz), 4.09 (2H, q, J = 6.9Hz), 5.05 (1H, d, J = 5.1Hz), 5.24 (2H, d, J = 6.8Hz), 5.59 (1H, dd, J = 8.0, 5.1 Hz), 5.86 (1H, dt, J = 16.1, 6.8Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 16.1Hz), 8.07 (1H, dd, J = 8.6, 2.7Hz), 8.42 (2H, d, J = 7.2Hz), 8.64 (1H, d, J = 8.6H z), 8.65 (1H, d, J = 2.7Hz), 8.91 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.0Hz),.

IR (ATR) cm— ¹ : 3313, 1763, 1584, 1499, 1370, 1288, 1161, 1035, 829.

MS (ESI): 691 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na-0.2NaHCO -4.2H O

Calculated value: C, 46.48; H, 4.58; N, 12.16; SJ.95; Na, 3.42 (%)

Experimental value: C46.48; H, 4.68; N, 12.36; S, 8.00; Na, 3.35 (%)

Example 199

[Chemical 246]

(1) 3 → 4

4-Bromophthalic acid 3 (735mg, 3.OOmmol) is dissolved in dimethylformamide (7.50ml), and potassium carbonate (912mg, 6.60mmol) and paramethoxybenzyl bromide (1.33g, 6.60mmol) are added and stirred for 3 hours. did. Purified water (7.50 ml) was added, and the organic layer was extracted with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, subjected to zirica gel chromatography, and eluted with hexane-ethyl acetate system to obtain compound 4. 775 mg (53%).

'H-NMR (CDCl): 3.80 (6H, s), 5.15 (2H, s), 5.16 (2H, s), 6.89 (4H, m), 7.29 (4H, m

), 7.61 (2H, m), 7.78 (1H, m).

(2) 4 → 5

Compound 4 was dissolved in 1,4-dioxane, tripotassium phosphate (987 mg, 4.65 mmol), 4_pyridylboronic acid pinacol ester (414 mg, 2.02 mmol) and tetrakistriphenylphosphine palladium (89 mg, 0.0775 mmol). In addition, the mixture was stirred at 120 ° C for 35 minutes under microwave irradiation. Purified water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and then dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the residue was subjected to silica gel chromatography, eluting with a hexane-ethyl acetate system to obtain Compound 5. 501 mg (67%).

'H-NMR (CDCl): 3.80 (6H, s), 5.20 (4H, s), 6.89 (4H, m), 7.30 (4H, m), 7.29 (4H, m), 7.55 (2H, d, J = 5.1Hz), 7.76 (1H, dd, J = 8.1, 1.5Hz), 7.86 (1H, d, J = 8.1Hz), 7.95 (1H, d, J = 1.5Hz).

(3) 5 + 2 → 6 → l

Compound 2 (1.38 g, 2.04 mmol) is suspended in dichloromethane (10 ml), and an aqueous sodium hydrogen carbonate solution (257 mg, 3.06 mmol is dissolved in 10 ml of water) is added under ice-cooling, followed by extraction with dichloromethane and saturated brine. And dried over magnesium sulfate. After distilling off the solvent, it was immediately dissolved in dimethylformamide (6 ml), mixed with compound 5 (465 mg, 0.9634 mmol), sodium bromide (29 7 mg, 2.89 mmol) was added, and the mixture was stirred at room temperature for 4 hours. . While cooling, the reaction solution was poured into 5% saline (30 ml) while stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain amorphous powder compound 6 (1.10 g). Compound 6 (1.10 g) was dissolved in dichloromethane (6.0 ml), and anisole (1.00 ml) was added and cooled to -30 ° C. Trifluoroacetic acid (3 ml) was added dropwise, and the mixture was stirred for 1 hour and 15 minutes. The reaction solution was poured into a mixed solvent of diisopropyl ether / 2-propanol (1/1, 40 ml), and the precipitated solid was collected by filtration. This solid was suspended in purified water (40 ml), and the pH was adjusted to 7.2 with a saturated aqueous solution of sodium hydrogen carbonate. This solution was filtered, subjected to HP-20SS column chromatography and ODS chromatography, and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 1 as a powder. Yield 273 mg (34%).

^J H-NMR (DO): 1 · 17 (3Η, t, J = 6.9Hz), 3.54 (2H, s), 4.13 (2H, q, J = 6.9Hz), 5.15 (

2

1H, d, J = 4.5Hz), 5.16 (2H, d, J = 6.9Hz), 5.70 (1H, d, J = 4.5Hz), 6.00 (1H, dt, J = 17.1, 6.9Hz), 6.84 ( 1H, s), 6.86 (1H, d, J = 17.1Hz), 7.50 (1H, d, J = 6.0Hz), 7.80 (1H, d, J = 6.0Hz), 7.89 (1H, s), 8.18 ( 2H, d, J = 7.2Hz), 8.68 (2H, d, J = 7.2Hz).

IR (KBr) cm— 3407, 2324, 1762, 1636, 1609, 1584, 1532, 1463, 1396, 1300.

MS (ESI): 679 ⁺ (M-2Na + 4H) ⁺

Elemental analysis c H N O S Na-5.3H O -0.3 (NaHCO)

30 24 6 9 2 2 2 3

Calculated values: C, 43.15; H, 4.17; N, 9.97; S, 7.60; Na, 6.27 (%)

Experimental values: C, 43.02; H, 4.35; N, 10.43; S, 7.75; Na, 5.92 (%)

Example 200

[Chemical 247]

(4) 9 → 10

Compound 9 (4.24 g, 19.5 mmol) was dissolved in dimethylformamide (42.0 ml), potassium carbonate (5.9 4 g, 43.0 mmol) and paramethoxybenzyl bromide (8.65 g, 643.0 mmol) were added, and the mixture was stirred overnight. Purified water was added and extracted from the aqueous layer with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, the residue was subjected to zirica gel chromatography and eluted with a hexane-ethyl acetate system to obtain Compound 10. 1.22g (53%).

'H-NMR (CDCl): 3.81 (3H, s), 3.82 (3H, s), 5.05 (2H, s), 5.24 (2H, s), 6.82-6.90 (4

H, m), 7.11 (1H, dd, J = 1.8, 8.1Hz), 7.18 (1H, d, J = 1.8Hz), 7.25-7.34 (4H, m), 7.6 9 (1H, d, J = 8.1 Hz).

(5) 10 → 11

Compound 10 (1.22 g, 2.67 mmol) was dissolved in 1,4-dioxane (12.0 ml), tripotassium phosphate (987 mg, 4.65 mmol), 4-pyridylboronic acid pinacol ester (1.22 g, 2.67 mmol), and Tetrakistriphenylphosphine palladium (154 mg, 0.134 mmol) was added and heated to reflux for 2 hours. Purified water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and then dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, the residue was subjected to silica gel chromatography and eluted with a hexane-ethyl acetate system to obtain Compound 11. 651 mg (54%). Ή-NMR (CDC1): 3.81 (3H, s), 3.82 (3H, s), 5.17 (2H, s), 5.29 (2H, s), 6.86 (2H, d, J

Three

= 9.0Hz), 6.80 (2H, d, J = 9.0Hz), 7.24-7.27 (2H, m), 7.32 (2H, d, J = 9.0Hz), 7.36 (2H, d, J = 9.0Hz), 7.62 (2H, d, J = 6.3Hz), 7.94 (1H, d, J = 8.4Hz), 8.71 (2H, d, J = 6 • 3Hz).

(6) 11 + 8 → 12 → 7

Compound 8 (1.06 g, 1.43 mmol) and Compound l l (652 mg, 1.43 mmol) were dissolved in dimethylformamide (4.5 ml), sodium bromide (442 mg 4.29 mmol) was added, and the mixture was stirred for 6 hours. The reaction solution was cooled and poured into 5% brine (45 ml) with stirring, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 12 (1.80 g) as an amorphous powder. Compound 12 (1.80 g) was dissolved in dichloromethane (18.0 ml), and anisole (1.80 ml) was added and cooled to -30 ° C. 2M titanium tetrachloride (dichloromethane solution) was added dropwise (5.70 ml), and the mixture was stirred for 50 minutes. The reaction solution was poured into purified water (50 ml), and a solid precipitated with diisopropyl ether (50 ml) was collected by filtration. This solid was suspended in purified water (50 ml), adjusted to pH 7.3 with saturated aqueous sodium hydrogen carbonate solution, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 7 as a powder. Yield 284 mg (26%).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.42, 3.50 (2H, ABq, J = 16.8Hz), 4.0

6

9 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 4.8Hz), 5.27 (2H, d, J = 6.9Hz), 5.59 (1H, dd, J = 4.8, 8.1Hz), 5.86 (1H, dt, J = 15.3, 4.8Hz), 6.72 (1H, s), 7.21 (2H, s), 7.25 (1H, dd, J = 1.8, 7.8Hz), 7.31 (1H, d, J = 15.3Hz), 7.32 (1H, d, 1.8Hz), 7.84 (1H, d, J = 8.1Hz), 8.46 (2H, d, J = 6.9Hz), 8.97 (2H, d, J = 6.9Hz) , 9.52 (1H, d, J = 8.1Hz).

IR (KBr) cm— 3418, 2324, 1762, 1634, 1525, 1425, 1376.

MS (ESI): 651 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na-4.3 H O-0.2 (NaHCO)

29 25 6 8 3 2 3

Calculated values: C, 45.73; H, 4.44; N, 10.96; S, 8.36; Na, 3.60 (%)

Experimental values: C, 45.64; H, 4.42; N, 11.08; S, 8.64; Na, 3.53 (%)

Example 201

[Chemical 248]

(7) 14 → 15

Compound 14 (2.37 g, lO.Ommol) is dissolved in dimethylformamide (25.0 ml), potassium carbonate (1.52 g, l l.Ommol) is added, and paramethoxybenzyl bromide (2.21 g, ll.Ommol) is added. And stirred for 2 hours. Purified water (25 ml) was added and extracted from the aqueous layer with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the resulting solid was washed with diisopropyl ether to obtain Compound 15 as a white solid. 2.51 g (70%).

'H-NMR (CDCl): 3.82 (3H, s), 5.32 (2H, s), 6.91 (1H, d, J = 8.7Hz), 7.14 (1H, d, J

Three

= 7.2Hz), 7.37 (1H, d, J = 8.7Hz).

(8) 15 → 16

Compound 15 (2.42 g, 6.77 mmol) was dissolved in 1,4-dioxane (25. Oml), tripotassium phosphate (4.31 g, 20.4 mmol), 4-pyridylboronic acid pinacol ester (1.80 g, 8.80 mmol) Tetrakistriphenylphosphine palladium (391 mg, 0.339 mmol) was added, and the mixture was heated to reflux for 3 hours. Purified water (25 ml) was added and extracted from the aqueous layer with ethyl acetate, and the organic layer was washed with purified water and saturated Japanese saline, and then dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the residue was subjected to silica gel chromatography, eluting with hexane-ethyl acetate system to obtain Compound 16 as a pale yellow gum. 2.35g (98%).

'H-NMR (CDCl): 3.82 (3H, s), 5.36 (2H, s), 6.92 (2H, d, J = 8.7Hz), 7.12 (2H, d, J = 8.4Hz), 7.40 (2H, d, J = 8.7Hz), 7.45 (2H, dd, J = 1.8, 4.5Hz), 8.72 (2H, dd, J = 1.8, 4.5Hz).

(9) 16 + 8 → 17 → 13

Compound 8 (1.48 g, 2.00 mmol) and compound 16 (711 mg, 2.00 mmol) were dissolved in dimethylformamide (6.0 ml), sodium bromide (617 mg, 6.00 mmol) was added, and the mixture was stirred for 5 hours. The reaction mixture was poured into 5% brine (80 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 17 (2.19 g) as an amorphous powder. Compound 17 (2.19 g) was dissolved in dichloromethane (22.0 ml), anisole (2.20 ml) was added, and the mixture was cooled to -30 ° C. A 2M titanium tetrachloride solution in dichloromethane (8.00 ml) was added dropwise and stirred for 75 minutes. The reaction solution was poured into purified water (80 ml), diisopropyl ether (80 ml) was added, and the precipitated solid was collected by filtration. This solid was suspended in purified water (20 ml), adjusted to pH 7.3 with saturated aqueous sodium hydrogen carbonate solution, subjected to HP-20SS column chromatography, and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 13 as a powder. Yield 274 mg (17%).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.41, 3.49 (2H, ABq, J = 16.8Hz), 4.0

9 (2H, q, J = 6.9Hz), 5.04 (1H, d, J = 5.1Hz), 5.27 (2H, d, J = 6.9Hz), 5.59 (1H, dd, J = 5.1, 8.1Hz), 5.86 (1H, dt, J = 15.9, 4.8Hz), 6.72 (1H, s), 7.22 (2H, s), 7.30 (1H, d, J = 15.9Hz), 8.53 (2H, d, J = 7.2Hz ), 9.05 (2H, d, J = 7.2Hz), 9.53 (1H, d, J = 8.1Hz). IR (KBr) cm ^_1 : 3408, 1763, 1611, 1531, 1411, 1375, 1032.

MS (ESI): 671 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H F N O S Na '5.2H O' 0.1 (NaHCO)

Calculated values: C, 43.98; H, 4.25; N, 10.57; S, 8.07; Na, 3.18; F, 4.78 (%)

Experimental values: C, 43.83; H, 4.23; N, 10.57; S, 8.37; Na, 3.32; F, 4.71 (%)

Example 202

[Chemical 249]

(10) 18 → 19

Compound 18 (4.98 g, 30. Ommol) was dissolved in dimethylformamide (50. Oml), potassium carbonate (9.12 g, 66.0 mmol) and paramethoxybenzyl bromide (13.3 g, 66.0 mmol) were added, and the mixture was stirred overnight. . Purified water (50.0 ml) was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the resulting solid was washed with diisopropyl ether to obtain Compound 19 as a white solid. Yield 3.22 g (91%).

'H-NMR (d -DMSO): 3.78 (6H, s), 5.23 (4H, s), 6.88 (2H, d, J = 8.7Hz), 6.92 (2H, d, J = 8.7Hz), 7.31 ( 2H, d, J = 8.7Hz), 7.36 (2H, d, J = 8.7Hz), 7.46 (1H, d, J = 8.7Hz), 8.07 (1H, dd, J = 2.1, 8.7Hz), 8.19 ( 1H, d, J = 2.1Hz), 9.90 (1H, s).

(11) 19 → 20

Compound 19 (7.84 g, 19.3 mmol) was suspended in 2-methyl-2-propanol (60.0 ml), and 2_methyl-2-butene (20.0 ml) and purified water (25 ml) were added. The reaction solution was cooled to 0 ° C., and sodium chlorite was added dropwise over 5 minutes, followed by stirring for 24 hours. A 1M aqueous sodium thiosulfate solution (190 ml, 190 mmol) and ethyl acetate were stirred. The precipitated solid was collected by filtration to obtain Compound 20 as a white solid. Yield 5.83 g (13.8 mmol).

'H-NMR (d-DMSO): 3.76 (6H, s), 5.18 (2H, s), 5.21 (2H, s), 6.89 (2H, d, J = 8.7H z), 6.92 (2H, d, J = 8.7Hz), 7.31 (2H, d, J = 8.7Hz), 7.35 (1H, d, J = 9.0Hz), 7.36 (2 H, d, J = 8.7Hz), 7.46 (1H, d, J = 8.7Hz), 8.06 (1H, dd, J = 2.4, 9.0Hz), 8.21 (1H, d, J = 2.4Hz).

(12) 20 → 21

Compound 20 (5.83 g, 13.8 mmol), 4-aminopyridine (1.30 g, 13.8 mmol), and 4-dimethylaminopyridine (193 mg, 15.2 mmol) were suspended in dichloromethane (60. Oml). 1_Ethyl _3_ (dimethylaminopropyl) -carpositimide hydrochloride (2.91 g, 15.2 mmol) was added and stirred for 2 days. Purified water (60 ml) was added, dichloromethane was distilled off, and the precipitated solid was collected by filtration to obtain Compound 21 as a white solid. Yield (6.51g, 95%).

'H-NMR (d -DMSO): 3.76 (6H, s), 5.20 (2H, s), 5.23 (2H, s), 6.88 (2H, d, J = 8.7Hz

), 6.91 (2H, d, J = 8.7Hz), 7.31 (2H, d, J = 8.7Hz), 7.36 (1H, d, J = 8.7Hz), 7.41 (1H, d, J = 9.0Hz), 7.76 (2H, d, J = 6.3Hz), 8.17 (1H, dd, J = 9.0, 2.1), 8.28 (1H, d, J = 2 • lHz), 8.45 (2H, d, J = 6.3Hz).

(13) 21 + 2 → 22 → 17-1

Compound 2 (2.02 g, 3.00 mmol) was suspended in ethyl acetate (21 ml), and an aqueous sodium hydrogen carbonate solution (378 mg, 4.50 mmol dissolved in 21 ml of water) was added under ice cooling, followed by extraction with ethyl acetate and saturated food. After dehydrating with brine, it was dried over magnesium sulfate. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (9 ml), mixed with compound 21 (1.45 g, 3.00 mmol), sodium bromide (926 mg, 9.00 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 5% brine (100 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 22 (3.38 g) as an amorphous powder. Compound 22 (3.38 g) was charged with anisole (3.30 ml) and cooled to 0 ° C. Trifluoroacetic acid (16.5 ml) was added dropwise and stirred for 2 hours. The reaction mixture was poured into a mixed solvent of 2-propanol / diisopropyl ether (1/1, 90 ml), and the precipitated solid was collected by filtration. This solid was suspended in purified water (20 ml), and the pH was adjusted to 7.3 with a saturated aqueous solution of sodium bicarbonate. The solution was filtered, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 17-1 as a powder. Yield 1.10 g (46% in 2steps) ₀

'H-NMR (d-DMSO): 1.23 (3H, t, J = 7.2Hz), 3.42, 3.51 (2H, ABq, J = 16.8Hz), 4.1

5 (2H, q, J = 7.2Hz), 5.03 (1H, d, J = 4.8Hz), 5.10 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 4.8, 7.8Hz), 5.81 (1H, dt, J = 15.0, 4.8Hz), 6.716 (1H, d, J = 8.7Hz), 6.721 (1H, s), 7.22 (2H, s), 7.25 (1H, d, J = 15.0Hz), 7.89 (1H, dd, J = 8.7, 2.7Hz), 8.31 (2H, d, J = 6.6Hz), 8.50 (1H, d , J = 2.7Hz), 8.72 (2H, d, J = 6.6Hz), 9.54 (1H, d, J = 7.8Hz), 11.52 (1H, br).

IR (ATR) cm— 3566, 1749, 1594, 1514, 1375, 1203.

MS (ESI): 694 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 3.8 H O-0.1 (NaHCO)

30 26 7 9 2 2 3

Calculated values: C, 45.62; H, 4.29; N, 12.37; S, 8.09; Na, 3.19 (%)

Experimental values: C, 45.63; H, 4.34; N, 12.53; S, 8.11; Na, 3.14 (%)

Example 203

[Chemical 250]

(14) 23 → 24

Compound 23 (4.74 g, 20.0 mmol) is dissolved in dimethylformamide (47.0 ml), potassium carbonate (3.04 g, 22.0 mmol) is added, paramethoxybenzyl bromide (4.42 g, 22.0 mmol) is added, and the mixture is stirred for 2 hours. did. Purified water (50.0 ml) was added, and the aqueous layer was extracted with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered and the solvent was distilled off to obtain Compound 24 as a green oily substance. Yield 7.54 g (quant.). 'H-NMR (CDCl): 3.82 (3H, s), 3.88 (3H, s), 5.14 (2H, s), 6.91 (2H, dd, J = 2.1, 6.

Three

6Hz), 7.39 (1H, s), 7.45 (2H, dd, J = 2.1, 6.6Hz). (15) 24 → 25

Compound 24 (7.54 g, 21.1 mmol) was dissolved in methanol (75. Oml) and tetrahydrofuran (25.0 ml), 2N aqueous sodium hydroxide solution (53 ml, 105.5 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Methanol and tetrahydrofuran were distilled off, and the aqueous layer was washed with ethyl acetate. The aqueous layer was adjusted to pH 1, extracted from the aqueous layer with ethyl acetate, washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the precipitated solid was washed with hexane to obtain Compound 25 as a yellow solid. Yield 6.20 g (86%).

'H-NMR (CDCl): 3.82 (3H, s), 5.24 (2H, s), 6.91 (2H, d, J = 8.7Hz), 7.41 (2H, d, J

= 8.7Hz), 7.52 (1H, s).

(16) 25 → 26

Compound 25 (6.20 g, 18.2 mmol) is dissolved in dimethylformamide (60.0 ml), potassium carbonate (2 • 76 g, 20.0 mmol) is added, paramethoxybenzyl bromide (4.02 g, 20.0 mmol) is added, and 3 hours. Stir. Purified water (60.0 ml) was added, and the aqueous layer was extracted with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the precipitated solid was washed with diisopropyl ether to obtain Compound 26 as a brown solid. Yield 4.87 g (58%).

'H-NMR (d-DMSO): 3.75 (3H, s), 3.77 (3H, s), 5.02 (2H, s), 5.26 (2H, s), 6.87 (2H, d, J = 8.7Hz), 6.96 (2H, d, J = 8.7Hz), 7.24 (2H, d, J = 8.7Hz), 7.40 (1H, d, J = 8.7Hz), 8.04 (1H, s).

(17) 26 → 27

Compound 26 (2.32 g, 5.00 mmol) and trimethyl (4-pyridyl) tin (1.45 g, 6.00 mmol) were suspended in toluene (23.0 ml), tetrakistriphenylphosphine palladium (578 mg, 0.50 mmol) was added, and 5 Heated to reflux for hours. The solvent was distilled off, and the residue was subjected to silica gel chromatography to obtain Compound 27 as a yellow oily substance. Yield 1.57 g (68%).

'H-NMR (d-DMSO): 3.72 (3H, s), 3.77 (3H, s), 4.91 (2H, s), 5.28 (2H, s), 6.78 (2H, d, J = 8.7Hz), 6.97 (2H, d, J = 8.7Hz), 7.05 (2H, d, J = 8.7Hz), 7.55 (2H, dd, J = 1.8, 4.5Hz), 8.24 (1H, s), 8.56 (2H , dd, J = 1.8, 4.5Hz).

(18) 27 + 2 → 28 → 22-l Compound 2 (1.35 g, 2.00 mmol) was suspended in ethyl acetate (15 ml), and an aqueous sodium hydrogen carbonate solution (252 mg, 3.00 mmol dissolved in 15 ml of water) was added under ice-cooling, followed by extraction with ethyl acetate and saturated food. After dehydrating with brine, it was dried over magnesium sulfate. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (6 ml), mixed with compound 27 (923 mg, 2.00 mmol), sodium bromide (617 mg, 6.00 mmol) was added, and the mixture was stirred at room temperature for 6 hours. . The reaction solution was poured into 5% brine (60 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 28 (2.05 g) as an amorphous powder. Anisole (2.00 ml) was added to compound 28 (1.91 g) and cooled to 0 ° C. Trifluoroacetic acid (10.0 ml) was added dropwise and stirred for 1 hour. The reaction solution was poured into a mixed solvent (1/1, 90 ml) of 2_propanol / diisopropyl ether, and the precipitated solid was collected by filtration. This solid was suspended in purified water (60 ml), and the pH was adjusted to 7.3 with a saturated aqueous solution of sodium bicarbonate. The solution was filtered, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was lyophilized to obtain Compound 22-1 as a powder. Yield 510 mg (32%).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.42, 3.50 (2H, ABq, J = 16.8Hz), 4.0

9 (2H, q, J = 7.2Hz), 5.04 (1H, d, J = 4.8Hz), 5.16 (2H, d, J = 6.6Hz), 5.59 (1H, dd, J = 4.8, 8.1Hz), 5.81 (1H, dt, J = 15.9, 6.6Hz), 6.71 (1H, s), 7.21 (2H, s), 7.26 (1H, d, J

= 15.9Hz), 8.60 (1H, s), 8.75 (2H, d, J = 6.9Hz), 8.84 (2H, d, J = 6.9Hz), 9.52 (1H, d,

J = 8.1Hz).

IR (ATR) cm ^_1 : 3324, 1759, 1633, 1599, 1566, 1538, 1384.

MS (ESI): 656+ (M-Na + 2H) +

Elemental analysis C H N O S Na- 5.7 H O-0.11 (NaHCO)

Calculated values: C, 41.18; H, 4.40; N, 10.63; S, 12.17; Na, 3.23 (%)

Experimental values: C, 40.91; H, 4.47; N, 10.89; S, 12.45; Na, 3.51 (%)

Example 204

[Chemical 251]

(19) 30 → 31

Compound 30 (6.52 _8, 30.011111101) was suspended in dimethylformamide § bromide (65.01111), t-Butokishikari © beam (4.04 g, 36.0 mmol) was added and stirred for 25 minutes. Next, methyl iodide (3.69 g, 1.62 ml) was added and stirred for 1 hour. Purified water (65.0 ml) was added to the reaction solution, and the organic layer was extracted with ethyl acetate. The extracted organic layer was washed with purified water and saturated brine, and dehydrated with sodium sulfate. Sodium sulfate was filtered off, the solvent was distilled off, and the residue was washed with jetyl ether to obtain 31 as a white solid. Yield 4.13g (60%).

'H-NMR (CDCl) 4.39 (2H, q, J = 7.2Hz), 7.265 (1H, s), 7.74 (2H, dd, J = 1.8, 4.8H

Three

z) ,: 8.64 (2H, dd, J = 1.8, 4.8Hz).

(20) 31 → 32

Compound 31 (3.50 g, 15.1 mmol) is dissolved in tetrahydrofuran (16.5 ml) and methanol (16.5 ml), aqueous sodium hydroxide solution (2N, 23.0 ml) is added, and the mixture is stirred at room temperature for 30 minutes and further heated. Refluxed. The reaction solution was cooled to pH 5.0 and tetrahydrofuran and methanol were distilled off. The precipitated solid was collected by filtration to obtain 32 as a white solid. Yield 2.62 g (85%).

'H-NMR (d-DMSO): 4.16 (3H, s), 7 · 50 (1Η, s), 7.74 (2H, dd, J = 1.8, 4.8Hz), 8.60

6

(2H, dd, J = 1.8, 4.8Hz). (21) 32 → 33

Compound 32 (2.36 g, 11.6 mmol) was suspended in dimethylformamide (25.0 ml), carboninodiimidazole (2.10 g, 12.8 mmol was added and stirred for 70 minutes at room temperature, then 28% aqueous NH (15.0 ml) ) And stirred, and purified water (25 ml) was added, and the precipitated solid was collected by filtration to give 33 as a white solid, yield (2.0 g, 86%).

'H-NMR (d-DMSO): 4.13 (3H, s), 7.43 (1H, s), 7.65 (1H, br), 7.69 (2H, dd, J = 1.5

, 4.5Hz), 8.05 (1H, br), 8.61 (2H, dd, J = 1.5, 4.5Hz).

(22) 33 → 34

Compound 33 (1.93 g, 9.54 mmol) was suspended in tetrahydrofuran (20.0 ml), pyridine (2.23 g, 2 8.6 mmol) and trifluoroacetic anhydride (2.60 g, 12.4 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. . Purified water (20.0 ml) was added and extracted from the aqueous layer with ethyl acetate. The organic layer was washed with purified water and saturated brine, and then dehydrated with magnesium sulfate. Magnesium sulfate was filtered, and the organic layer was concentrated to obtain 34. Yield (1.72g, 98%)

'H-NMR (d-DMSO): 4.10 (3H, s), 7.78 (2H, dd, J = 1.5, 4.8Hz), 7.84 (1H, s), 8.64

(2H, dd, J = 1.5, 4.8Hz).

(23) 34 → 35

Compound 34 (1.70 g, 9.22 mmol), ammonium chloride (543 mg, lO. Lmmol) and sodium azide (660 mg, 10.1 mmol) were suspended in dimethylformamime (17 ml) and stirred at 110 ° C for 3 and a half hours. . 20 ml of purified water was added to adjust the pH to 4.3. The precipitated solid was collected by filtration to obtain Compound 35. Yield 2.15 g (quant.).

'H-NMR (d-DMSO): 4.28 (3H, s), 7.54 (1H, s), 7.95 (2H, d, J = 6.0Hz), 8.68 (2H, d, J = 6.0Hz).

(24) 35 → 36

Compound 35 (905 mg, 4.00 mmol) was dissolved in dimethylformamide (10 ml), sodium hydride (106 mg, 4.40 mmol) was added, and the mixture was stirred at 0 ° C. Subsequently, benzyl chloromethyl ether (689 mg, 4.40 mmol) was added and stirred for 3 hours. Further, sodium hydride (192 mg, 8.00 mmol) and benzyl chloromethyl ether (1.25 g, 8.00 mmol) were added and stirred for 1.5 hours. Purified water (10.0 ml) was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. Saturate organic layer with purified water The extract was washed with brine and dehydrated with sodium sulfate. Sodium sulfate was filtered and ethyl acetate was distilled off. The obtained gum-like substance was washed with hexane to obtain Compound 36. Yield 763 mg (5 5%).

'H-NMR (d-DMSO)

6

Major isomer: 4.27 (3H, s), 4.74 (2H, s), 6.21 (2H, s), 7.30-7.38 (5H, m), 7.66 (IH, s), 7.89 (2H, dd, J = 6.0Hz ), 8.63 (2H, dd, J = 1.2, 6.3Hz).

Minor isomer: 4.15 (3H, s), 4.69 (2H, s), 6.05 (2H, s), 7.30-7.38 (5H, m), 7.56 (IH, s), 7.79 (2H, d, J = 4.8Hz ), 8.65 (2H, d, J = 4.8Hz).

(25) 36 + 2 → 37 → 29

Compound 2 (1.38 g, 2.04 mmol) is suspended in ethyl acetate (10 ml), aqueous sodium hydrogen carbonate solution (257 mg, 3.06 mmol dissolved in 10 ml of water) is added under ice-cooling, and the mixture is extracted with ethyl acetate. After dehydrating with brine, it was dried over magnesium sulfate. After the solvent was distilled off, it was immediately dissolved in dimethylformamide (6 ml), mixed with compound 36 (709 mg, 2.04 mmol), sodium bromide (630 mg, 6.12 mmol) was added, and the mixture was stirred at room temperature for 2.5 hours. . The reaction mixture was poured into 5% brine (100 ml) with stirring under cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain Compound 37 (1.89 g) as an amorphous powder. Compound 37 (1.88 g) was dissolved in dichloromethane (20.0 ml), anisole (2.00 ml) was added, and the mixture was cooled to -30 ° C. 2M Titanium tetrachloride in dichloromethane (8.00 ml) was added dropwise and stirred for 1 hour and 15 minutes. The reaction solution was poured into purified water (60 ml), and the precipitated solid was collected by filtration. This solid was suspended in purified water (6 ml), and the pH was adjusted to 7.3 with a saturated aqueous solution of sodium bicarbonate. The solution was filtered, subjected to HP-20SS column chromatography and eluted with water-acetonitrile. The fraction containing the desired compound was concentrated under reduced pressure, and the concentrated solution was freeze-dried to obtain Compound 29 as a powder. Yield 239 mg (15%).

'H-NMR (d-DMSO): 1.21 (3H, t, J = 6.9Hz), 3.41, 3.50 (2H, ABq, J = 16.8Hz), 4.1

6

7 (2H, q, J = 6.9Hz), 4.32 (3H, s), 5.03 (1H, d, J = 5.1Hz), 5.22 (2H, d, J = 6.6Hz), 5.57 (1H, dd , J = 7.8, 5.1Hz), 5.85 (1H, dt, J = 15.9, 5.1Hz), 6.71 (1H, s), 7.21 (2H, s), 7.28 (1H, d, J = 15.9Hz), 7.57 (1H, s), 8.48 (2H, d, J = 6.0Hz), 8.92 (2H, d, J = 6.0Hz), 9.47 (1H, d, J = 7.8Hz).

IR (ATR) cm ^_1 : 3334, 2324, 1757, 1634, 1602, 1537, 1478, 1362. MS (ESI): 662 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 6.6 H O -0.1 (NaHCO)

Calculated values: C, 40.09; H, 4.75; N, 20.70; S, 7.90; Na, 3.11 (%)

Experimental values: C, 40.16; H, 4.60; N, 20.46; S, 8.14; Na, 3.28 (%)

Example 205

[Chemical 252]

(26) 39 → 40

Compound 39 (4.69 g, 20 mmol) was suspended in 28% aqueous ammonia (70 ml), and heated and stirred at 60 ° C. for 1.5 hours. The precipitate was collected by filtration, washed with water and dried to obtain 40. Yield 3.1 g (76%).

2H, dd, J = 1.8, 4.8Hz).

(27) 40-41

Compound 40 (3.0 g, 14.6 mmol) was dissolved in pyridine (36.5 ml), and trifluoroacetic anhydride (4.54 ml, 32.1 mmol) was added dropwise. The reaction solution was stirred at 60 ° C. for 2 hours and then concentrated. The reaction mixture was extracted with chloroform and water. The organic layer was washed with water, dried and concentrated to give a residue. Washing with isopropanol and filtration of the solid gave 41. Yield 2.50 g (92%).

'H-N R (d -DMSO): 7.96 (2H, dd, J = 1.5, 4.5Hz), 8.77 (2H, dd, J = 1.5, 4.5Hz), 9.

07 (1H, s).

(28) 41 → 42 42 was obtained from Compound 41 (562 mg, 3 mmol) in the same manner as (23). Yield (669mg, 97%) 'H-NMR (d-DMSO): 8.02 (2H, dd, J = 1.8, 4.5Hz), 8.74 (1H, s), 8.81 (2H, dd, J = 1

6

.8, 4.5Hz), 9.07 (1H, s).

(29) 42 + 2 → 43 → 38

Compound 2 (1.68 g, 2.5 mmol) and Compound 42 (576 mg, 2.5 mmol)

43 (2.48 g) was obtained, and then compound 38 was obtained as a powder. Yield 103 mg (5%).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 6.9Hz), 3.43, 3.51 (2H, ABq, J = 17.1Hz), 4.0

6

9 (2H, q, 6.9Hz), 5.06 (1H, d, J = 4.8Hz), 5.33 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.7, 4.8Hz), 5.86 (1H, dt, J = 15.9, 6.9Hz), 6.72 (1H, s), 7.23 (2H, s), 7.27 (1H, d, J = 1 5.9Hz), 7.44 (1H, d, J = 8 .1Hz), 8.37 (1H, s), 8.63 (2H, d, J = 6.9Hz), 9.09 (2H, d, J = 6.9Hz), 9.55 (1H, d, J = 8.7Hz).

IR (KBr) 001 ^_1 : 3408, 1761, 1634, 1532

MS (ESI): 667 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na- 5.7 H O-0.5 (NaHCO)

26 22 11 5 3 2 3

Calculated values: C, 38.24; H, 4.10; N, 18.51; S, 11.56; Na, 4.14 (%)

Experimental values: C, 38.27; H, 4.13; N, 18.36; S, 11.50; Na, 4.27 (%)

Example 206

[Chemical 253]

(30) 45 → 46

Compound 45 (5.65 g, 30 mmol) was dissolved in pyridine (60 ml), and methanesulfonyl chloride (13.9 ml, 180 mmol) was added dropwise under ice cooling. The reaction solution was stirred at 60 ° C. for 2 hours and then concentrated. The reaction solution was extracted by adding ethyl acetate and water. The organic layer was washed with water, dried and concentrated to give a residue. Washing with hexane-ethyl ether and filtration of the solid gave 46. Yield 3.38 g (66%). 'H-NMR (d-DMSO): 7.70 (1H, s), 7.79 (2H, dd, J = 1.8, 4.8Hz), 8.71 (2H, dd, J = 1.

8, 4.8Hz), 14.8 (1H, br).

(31) 46 → 47

Hydroxylamine hydrochloride (2.78 g, 40 mmol) was dissolved in dimethyl sulfoxide (8 ml), and tritylamine (5.57 ml, 40 mmol) was added and stirred. Compound 46 (1.36 g, 8 mmol) was added to the mother liquor from which insolubles had been filtered off, and the mixture was heated and stirred at 75 ° C. Water was added to the reaction solution for neutralization, and the precipitate was collected by filtration and dried to obtain 47. Yield 1.2g (68%).

'H-NMR (d -DMSO) peak is very broad and unreadable

(32) 47 → 48

Compound 47 (610 mg, 3 mmol) was dissolved in dimethylformamide (6 ml), and thiocarbodiimidazole (588 mg, 3.3 mmol) was added thereto and stirred at room temperature for 1 hour. Water was added to the reaction solution, and the precipitate was collected by filtration and dried to obtain 48. Yield 773 mg (77%).

'H-NMR (d -DMSO) peak is very broad and unreadable

(33) 48 → 49

Compound 48 (723 mg, 2.3 mmol) was dissolved in tetrahydrofuran (7.5 ml), and BF · Εΐ 0 (1.45 ml, 1

1.5 mmol) was added and stirred at room temperature to 60 ° C for 7 hours. Water was added to the reaction solution, and the precipitate was collected by filtration and dried to obtain 49. Yield 353 mg (62%).

'H-NMR (d -DMSO) peak is very broad and unreadable

(34) 49 + 8 → 50 → 44

Compound 8 (987 mg, 1.3 mmol) and compound 49 (328 mg, 1.3 mmol) to compound (9) in the same manner

50 (1.27 g) was obtained and then compound 44 was obtained as a powder. Yield 273 mg (25%).

'H-NMR (d-DMSO): 1.22 (3H, t, J = 7.2Hz), 3.44, 3.51 (2H, ABq, J = 17.1Hz), 4.0

9 (2H, q, J = 7.2Hz), 5.05 (1H, d, J = 4.8Hz), 5.23 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 8.1, 4 · 8Ηζ), 5.86 (1H, dt, J = 15.6, 7.2Hz), 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 15.6Hz), 7.48 ( 1H, s), 8.48 (2H, d, J = 6.6Hz), 8.92 (2H, d, J = 6.6Hz), 9.54 (1H, d, J = 8.1Hz).

IR (KBr) cm ^_1 : 3397, 1761, 1636, 1603, 1535, 1391

MS (ESI): 681 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.4 H O -0.5 (NaHCO)

Calculated values: C, 40.08; H, 3.95; N, 17.00; S, 11.67; Na, 4.19 (%)

Experimental values: C, 40.09; H, 4.10; N, 17.17; S, 11.52; Na, 4.26 (%)

Example 207

[Chemical 254]

(42) 64 → 65

Compound 64 (615 mg, 3 mmol) is suspended in dimethylformamide (6 ml), carbonyldiimidazole (535 mg, 3.3 mmol) is added, sodium cyanamide (21 lmg, 3.3 mmol) is added, and the mixture is stirred at room temperature for 6.5 hours. did. Water was added to the reaction solution and neutralized with dilute hydrochloric acid. The precipitate was collected by filtration and dried to obtain 65. Yield 529 mg (77%).

'H-NMR (d DMSO)-7.25 (1H, dd, J = 5.1, 3.7 Hz), 7.75 (1H, dd, J = 5.1, 1.2 Hz),

7.79 (1H, dd, J = 3.7, 1.2 Hz), 8.52 (1H, t, J = 2.1 Hz), 8.95 (1H, d, J = 2.0 Hz), 9. 16 (1H, d, J = 2.1 Hz) ).

(43) 65 + 2 → 66 → 63

Compound 66 (1.32 g) was obtained in the same manner as (25) from Compound 2 (1.35 g, 2 mmol) and Compound 65 (459 mg, 2 mmol), and then Compound 63 was obtained as a powder. Yield 322 mg (21%). Ή-NMR (d DMSO)-1.22 (3H, t, J = 7.0 Hz), 3.44 (2H, ABq, J = 17.4 Hz), 4.08 (2

H, q, J = 7.0 Hz), 5.04 (1H, d, J = 5.0 Hz), 5.38 (2H, d, J = 6.6 Hz), 5.58 (IH, dd, J = 8.1, 5.0 Hz), 5.90 ( IH, dt, J = 15.6, 6.6 Hz), 6.71 (IH, s), 7.20 (2H, s), 7.29 (IH, dd, J = 3.7, 5.0 Hz), 7.31 (IH, d, J = 15.6 Hz ), 7.89 (1H, dd, J = 5.0, 1.0 Hz), 7.9 7 (IH, dd, J = 3.7, 1.0 Hz), 8.91 (1H, s), 9.24 (IH, s), 9.43 (IH, s ), 9.52 (1H, d, J = 8.1 Hz).

IR (ATR) cm ^_1 : 3325, 2164, 1751, 1582, 1530, 1373.

MS (ESI): 664 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-4.4 H O

Calculated values: C, 43.90; H, 4.18; N, 14.63; S, 12.56; Na, 3.00 (%)

Experimental values: C, 43.92; H, 3.95; N, 14.66; S, 12.40; Na, 3.07 (%)

Example 208

[Chemical 255]

(44) 68 → 69

Compound 69 was obtained in the same manner as Compound 68 (621 mg, 3 mmol) force (42). Yield 608mg (96%) 'H-NMR (d DMSO)-6.37 (2H, t, J = 2.2 Hz), 7.56 (2H, t, J = 2.2 Hz), 8.44 (IH, dd, J = 2.6, 1.9 Hz), 8.88 (1H, d, J = 1.9 Hz), 9.14 (1H, d, J = 2.6 Hz).

(45) 69 + 2 → 70 → 67

Compound 70 (1.68 g) was obtained in the same manner as (25) from compound 2 (1.35 g, 2 mmol) and compound 69 (424 mg, 2 mmol), and then compound 67 was obtained as a powder. Yield 343 mg (23%). H-NMR (d DMSO) -1.21 (3H, t, J = 7.0 Hz), 3.44 (2H, ABq, J = 16.8 Hz), 4.08 (2

H, q, J = 7.0 Hz), 5.04 (1H, d, J = 4.9 Hz), 5.35-5.37 (2H, m), 5.58 (1H, dd, J = 8.

0, 4.9 Hz), 5.91 (1H, dt, J = 15.9, 7.0 Hz), 6.43 (2H, t, J = 2.1 Hz), 6.71 (1H, s), 7.

20 (2H, s), 7.32 (1H, d, J = 15.9 Hz), 7.71 (2H, t, J = 2.1 Hz), 8.93 (1H, s), 9.21 (1

H, s), 9.46 (1H, s), 9.52 (1H, d, J = 8.0 Hz).

IR (ATR) cm ^_1 : 3336, 2167, 1754, 1584, 1530, 1505, 1375.

MS (ESI): 648 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na-4.60 H O-O.l (NaCl)

28 24 9 6 2 2

Calculated values: C, 44.34; H, 4.41; N, 16.62; S, 8.46; Na, 3.33 (%)

Experimental values: C, 44.36; H, 4.31; N, 16.39; S, 8.64; Na, 3.60 (%)

Example 209

[Chemical 256]

(1) 2 + 3 → l

Compound 2 (802 mg, l.OOmmol) and compound 3 (339 mg, l.OOmmol) were dissolved in dimethylformamide (2.0 ml), sodium bromide (309 mg, 3.00 mmol) was added, and the mixture was stirred for 3 hours. The reaction mixture was poured into 5% brine (30 ml) with stirring while cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder (1.1 lg). Amorphous powder (1.10 g) was dissolved in dichloromethane (8.0 ml), and anisole (1.00 ml) was added and cooled to -15 ° C. 2M titanium tetrachloride (dichloromethane solution, 4.90 ml) was added and stirred for 1.5 hours. While cooling the reaction mixture, Et O (30 ml) and 0.3 N-

2

The mixture was added dropwise to a mixture of HCl (30 ml), and the precipitated solid was collected by filtration. Add water, acetonitrile, and 2N-HC1 to this solid and dissolve, add HP-20SS to concentrate, and then HP-20SS column chromatograph. The sample was eluted with water-acetonitrile. Fractions containing the desired compound were collected and 2N NaOH was carefully added with stirring. When the pH exceeded 10, dry ice was added to bring the pH to 5 or less. The solution was concentrated under reduced pressure and lyophilized to obtain Compound 1 as a powder. Yield 138 mg (19%).

'H-NMR (DO): 1.29 (3H, t, J = 6.6Hz), 2.28 (3H, s), 3.44, 3.53 (2H, ABq, J = 17.7Hz), 4.25 (2H, q, J = 6.6Hz), 5.03 (2H, d, J = 6.6Hz), 5.25 (1H, d, J = 4.5Hz), 5.81 (1H, d, J = 4.5Hz), 6.04 (1H, dt, J = 14.1, 6.6Hz), 6.84 (1H, d, J = 14.1Hz), 6.98 (1H, s),

7.33 (1H, d, J = 7.5Hz), 7.66 (1H, d, J = 7.5Hz), 7.81 (2H, d, J = 6.6Hz), 7.84 (1H, s), 8.38 (2H, d, J = 6.6Hz).

IR (KBr) cm ^_1 : 3387, 1764, 1611, 1530, 1382.

MS (FAB): 729 ⁺ (M + Na + H) ⁺

Elemental analysis c H N O S Na- 5.5H O-0.8NaHCO -0.3NaCl.

Calculated value: C, 41.85; H, 4.51; N, 12.28; S, 7.03; Na, 5.29; Cl, 1.17 (%)

Experimental value: C, 41.76; H, 4.43; N, 12.30; S, 7.07; Na, 5.40; Cl, 1.18 (%)

Example 210

[Chemical 257]

(2) 2 + 5 → 4

Compound 4 was obtained as a powder from Compound 2 (802 mg, l.OOmmol) and Compound 5 (310 mg, l.OOmmol) in the same manner as (1). Yield 170mg (24%, 2steps) ₀ Ή-NMR (DO): 1.29 (3H, t, J = 7.2Hz), 3.65 (2H, s), 4.24 (2H, q, J = 7.2Hz), 5.26 (1

H, d, J = 4.5Hz), 5.40 (2H, d, J = 6.9Hz), 5.82 (1H, d, J = 4.5Hz), 6.12 (1H, d, J = 15.0, 6.9Hz), 6.97 (1H, s), 6.97 (1H, d, J = 15.0Hz), 7.66 (2H, d, J = 8.1Hz), 7.90 (2H, d, J = 8.1Hz), 8.42 (2H, d, J = 5.4Hz), 9.04 (2H, d, J = 5.4Hz).

IR (KBr) cm ^_1 : 3408, 1764, 1668, 1604, 1532, 1382.

MS (FAB): 722 ⁺ (M + 2Na) ⁺

Elemental analysis c H N O S Na-4.9H O-0.1NaHCO -O.lNaCl.

Calculated value: C, 45.07; H, 4.51; N, 12.22; SJ.99; Na, 3.44; Cl, 0.44 (%)

Experimental value: C, 45.15; H, 4.45; N, 12.28; SJ.64; Na, 3.49; Cl, 0.51 (%)

Example 211

[Chemical 258]

(3) 2 + 7 → 6

Compound 6 was obtained as a powder from Compound 2 (802 mg, l.OOmmol) and Compound 7 (360 mg, l.OOmmol) in the same manner as (1). Yield 459mg (61%, 2steps) ₀

^J H-NMR (DO): 1.28 (3H, t, J = 7.2Hz), 3.62, 3.66 (2H, ABq, J = 16.8Hz), 4.23 (2H, q, J = 7.2Hz), 4.96 (2H, d, J = 6.9Hz), 5.24 (1H, d, J = 4.8Hz), 5.80 (1H, d, J = 4.8Hz), 6.02 (1H, dt, J = 15.0, 6.9Hz), 6.87 (1H , d, J = 15.0Hz), 6.96 (1H, s), 7.39 (1H, d, J = 8.1Hz), 7.53 (1H, d, J = 8.1Hz), 7.66 (2H, d, J = 6.6Hz ), 8.20 (1H, s), 8.27 (2H, d,

J = 6.6Hz). IR (KBr) cm: 3412, 1765, 1609, 1570, 1520, 1379, 1195, 1165.

MS (FAB): 749+ (M + Na + H) +

Elemental analysis C H C1N O S Na-4.2H O-0.3NaHCO.

Calculated values: C, 42.81; H, 4.11; N, 13.18; SJ.54; Na, 3.52; Cl, 4.17 (%)

Experimental value: C, 42.86; H, 4.12; N, 13.25; SJ.45; Na, 3.54; Cl, 4.02 (%)

Example 212

[Chemical 259]

(4) 9 → 10

Compound 9 (1.21 g, lO.Ommol) was dissolved by adding 30% HBr-AcOH (l lml), and bromine (564 μl, ll.Ommol) was added dropwise under cooling. The mixture was warmed to room temperature and stirred for 1 hour. The suspension was poured into precooled Et 2 O (60 ml) and the solid was collected by filtration. Drying under reduced pressure gave compound 10.

. Yield 2.90 g (quant).

'H-NMR (DMSO): 5.05 (2H, s), 7.82 (1H, dd, J = 7.8, 5.1Hz), 8.58 (1H, d, J = 7.8Hz), 8.94 (1H, d, J = 5.1 Hz), 9.28 (1H, s)

(5) 10 → 11

Compound 10 (2.80 g, lO.Ommol) and ethylthioxamate (1.40 g, lO.Ommol) were suspended in EtOH (45 ml) and stirred at 95 ° C for 1 hour, and then concentrated under reduced pressure. Saturated aqueous NaHCO 3 was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and anhydrous sulfuric acid Dry with magnesium. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with ethyl acetate to obtain Compound 11. Yield 2.06g (88%)

'H-NMR (CDCl): 1.48 (3H, t, J = 7.2Hz), 4.53 (2H, q, J = 7.2Hz), 7.42 (1H, dd, J =

Three

7.9, 5.0Hz), 7.87 (1H, s), 8.33 (1H, dd, J = 7.9, 2.1Hz), 8.63 (1H, dd, J = 5.0, 2.1Hz), 9.16 (1H, d, J = 2.1 Hz).

(6) 11 → 12

Compound 11 (1.95 g, 8.32 mmol) was dissolved in ethanol (40 ml), 2N_NaOH (8.3 ml) was added, and the mixture was stirred at 65 ° C. for 30 minutes. After distilling off ethanol, 2N_HCl (8.3 ml) was added, and the precipitated one was collected by filtration and dried under reduced pressure to obtain Compound 12. Yield 1.69 g (99%)

'H-NMR (DMSO): 7 · 53 (1Η, m), 8.36 (1H, ddd, J = 8.1, 2.4, 1.8Hz). 8.60 (1H, dd, J = 4.8, 1.8Hz), 8.64 (1H , s), 9.21 (1H, dd, J = 2.4, 0.9Hz)

(7) 12 → 13

Compound 12 (1.69 g, 8.20 mmol) was dissolved in dimethylformamide (12 ml), paramethoxybenzyl alcohol (1.02 ml, 8.20 mmol), WSCD (1.89 g, 9.84 mmol), 4_dimethylaminopyridine (301 mg, 2.46 mmol) was added and the mixture was stirred at room temperature for 29 hours. Purified water was added and extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with ethyl acetate-hexane system to obtain Compound 13. Yield 1.59 g (59%)

'H-NMR (CDCl): 3.82 (3H, s), 5.42 (2H, s), 6.93 (2H, d, J = 6.6Hz), 7.41-7.47 (1H,

Three

m), 7.44 (2H, d, J = 6.6Hz), 7.87 (1H, s), 8.35 (1H, d, J = 6.3Hz), 8.62 (1H, d, J = 4.8 Hz), 9.16 (1H, s).

(8) 2 + 13 → 8

Compound 8 was obtained as a powder from Compound 2 (722 mg, 0.90 mmol) and Compound 13 (294 mg, 0.90 mmol) in the same manner as (1). Yield 202 mg (34%).

'H-NMR (DMSO): 1.21 (3H, t, J = 7.2Hz), 3.42, 3.52 (2H, ABq, J = 17.4Hz), 4.08 (2H, q, J = 7.2Hz), 5.04 (1H , d, J = 4.8Hz), 5.41 (2H, d, J = 6.0Hz), 5.61 (1H, dd, J = 8 • 1, 4.8Hz), 5.98 (1H, J = 15.3, 6.0Hz), 6.71 (1H, s), 7.24 (2H, s), 7.36 (1H, d, J = 15.3 Hz), 8.19 (1H, dd, J = 7.8, 5.4 Hz), 8.53 (1H, s), 8.98 (1H, d, J = 5.4Hz), 9.03 (1H, d, J = 7.8Hz), 9.54 (1H, d, J = 8.1Hz), 9.66 (1H, s).

IR (KBr) cm ^_1 : 3407, 1764, 1614, 1531, 1367.

MS (FAB): 664 ⁺ (M + Na + H) ⁺

Elemental analysis c H N O S Na-4.2H O-0.06 NaHCO.

26 22 7 7 3 2 3

Calculated value: C, 42.05; H, 4.12; N, 13.17; S, 12.92; Na, 3.27 (%)

Experimental value: C, 42.05; H, 4.10; N, 13.38; S, 12.87; Na, 3.27 (%)

Example 213

[Chemical 260]

(9) 15 → 16

Diisopropylamine (631 μΐ, 4.50 mmol) was added to THF (6 ml) and 0. In C, n_BuLi (2.7 M hexane solution, 1.70 ml, 4.50 mmol) was added dropwise and stirred for 40 minutes. −78 ° C., and a solution of compound 15 (485 mg, 3.00 mmol) in THF (6 ml) was added to the reaction solution. After stirring at -78 degrees for 20 minutes, the dry ice powder was heated to 0 ° C and stirred for 1 hour. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, and the aqueous layer was separated. After 2N-HC1 was adjusted to pH 2 in the aqueous layer, it was concentrated under reduced pressure until precipitation. The compound 16 was obtained by filtering and drying under reduced pressure. Yield 490 mg (79%)

'H-NMR (DMSO): 7.54 (1H, dd, J = 7.8, 5.0Hz), 8.46 (1H, dd, J = 7.8, 1.8Hz), 8.54 (1H, s), 8.66 (1H, dd, J = 5.0, 1.8Hz), 9.28 (1H, d, J = 1.8Hz).

(10) 16 → 17

Compound 16 (480 mg, 2.33 mmol) was dissolved in DMF (5 ml) and paramethoxybenzyl alcohol was dissolved. Nore (291 μ1, 2.33 mmol), WSCD (536 mg, 2.80 mmol), 4_dimethylaminopyridine (85 mg, 0.70 mmol) were added, and the mixture was stirred at room temperature for 23 hours. Purified water was added and extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with an ethyl acetate-toluene system to obtain Compound 17. Yield 598mg (59%)

'H-NMR (CDCl): 3 · 83 (3Η, s), 5.34 (2H, s), 6.94 (2H, d, J = 8.7Hz), 7.40 (1H, d, J =

8.7Hz), 7.44 (1H, ddd, J = 8.1, 4.8, 0.9Hz), 8.30 (1H, ddd, J = 8.1, 2.1, 2.1Hz), 8.6 7 (1H, dd, J = 4.8, 2.1Hz) , 9.17 (1H, dd, J = 2.1, 0.9Hz).

(11) 2 + 17 → 14

Compound 14 was obtained as a powder from Compound 2 (722 mg, 0.90 mmol) and Compound 17 (294 mg, 0.90 mmol) in the same manner as (1). Yield 350 mg (59%, 2st mark s).

^J H-NMR (DMSO): 1.22 (3H, t, J = 7.2Hz), 3.43, 3.49 (2H, ABq, J = 16.5Hz), 4.09 (2H, q, J = 7.2Hz), 5.04 (1H , d, J = 4.8Hz), 5.38 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.1, 4.8Hz), 5.93 (1H, dt, J = 15.6, 6.9Hz) , 6.71 (1H, s), 7.23 (2H, s), 7.33 (1H, d, J = 15.6Hz), 8.14 (1H, s), 8.20 (1H, dd, J = 8.1, 6.0Hz), 9.02 ( 1H, d, J = 6.0Hz), 9.11 (1H, d, J = 8.1Hz), 9.54 (1H, d, J = 8.1Hz), 9.71 (1H, s)

IR (KBr) cm ^_1 : 3398, 1763, 1603, 1531, 1398, 1346.

MS (FAB): 686 ⁺ (M + 2Na) ⁺

Elemental analysis C H N O S Na- 3.7H O-0.21

Calculated values: C, 42.09; H, 3.99; N, 13.11; S, 12.86; Na, 3.72 (%)

Experimental value: C, 42.00; H, 4.05; N, 13.39; S, 12.94; Na, 3.73 (%)

Example 214

[Chemical 261]

23 24

(12) 20 + 21 → 22

Compound 20 (4.10 g, 20. Ommol), Compound 21 (3.28 g, 20. Ommol) were added with dioxane (200 ml), and potassium phosphate (21.2 g, lOOmmol), Pd (PPh) (1.15 g, l.OOmmol) And stirred at 100 for 2.5 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (70 ml), anhydrous magnesium sulfate was added and filtered again. The filtrate was concentrated, subjected to silica gel chromatography and eluted with an ethyl acetate-toluene system to give compound 22. Yield 2.17 g (6 7%)

'H-NMR (DMSO): 7.82 (2H, d, J = 4.5Hz), 7.94 (1H, d, J = 4.8Hz), 8.54 (2H, d, J = 4.5Hz), 9.08 (1H, d, J = 4.8Hz).

(13) 22 → 23

Compound 23 was obtained in the same manner as (9) from THF (25 ml) of Compound 22 (2.16 g, 13.3 mmol). Yield 2.29 g (83%)

'H-NMR (DMSO): 8.08 (2H, d, J = 4.5Hz), 8.60 (1H, s), 8.74 (2H, d, J = 4.5Hz).

(14) 23 → 24

Compound 23 (2.28 g, ll.lmmol) Compound (24) was obtained in the same manner as in (10). Yield 2.64g (73%)

'H-NMR (CDCl): 3.83 (3H, s), 5.34 (2H, s), 6.93 (2H, d, J = 8.9Hz), 7.40 (2H, d, J =

8.9Hz), 7.82 (2H, d, J = 6.0Hz), 8.17 (1H, s), 8.73 (2H, d, J = 6.0Hz). (15) 19 + 24 → 18

Compound 18 was obtained as a powder from Compound 19 (738 mg, l.OOmmol) and Compound 24 (326 mg, l.OOmmol) in the same manner as in (1). Yield 265mg (39%, 2steps) ₀

'H-NMR (DMSO): 1.21 (3H, d, J = 5 · 7Ηζ), 1.23 (3Η, d, J = 5.7Hz), 3.43, 3.50 (2H, A Bq, J = 16.2Hz), 4.30 ( lH, m), 5.05 (1H, d, J = 4.8Hz), 5.29 (2H, d, J = 6.9Hz), 5.61 (1 H, dd, J = 8.1, 4.8Hz), 5.88 (1H, dt, J = 15.0, 6.9Hz), 6.70 (1H, s), 7.24 (2H, s), 7.30 (1H, d, J = 15.0Hz), 8.25 (1H, s), 8.67 (2H, d, J = 6.6 Hz), 9.06 (2H, d, J = 6.6Hz), 9. 49 (1H, d, J = 8.1H z).

IR (KBr) cm ^_1 : 3418, 1760, 1607, 1530, 1396, 1344.

MS (FAB): 700 ⁺ (M + 2Na) ⁺

Elemental analysis c H N O S Na-4.4H O-0.2NaHCO -0.4NaCl.

26 22 7 7 3 2 3

Calculated value: C, 40.18; Η, 3.99; N, 12.52; S, 12.28; Na, 4.70; Cl, 1.81 (%)

Experimental value: C, 40.49; H, 4.26; N, 12.13; S, 11.77; Na, 4.62; Cl, 1.80 (%)

Example 215

[Chemical 262]

(16) 2 + 24 → 25

Compound 25 was obtained as a powder from Compound 2 (738 mg, l.OOmmol) and Compound 24 (294 mg, 0.90 mmol) in the same manner as (1). Yield 121 mg (20%, 2st mark s).

^J H-NMR (DMSO): 1.22 (3H, t, J = 7.2Hz), 3.43, 3.49 (2H, ABq, J = 17.0Hz), 4.09 (2H, q, J = 7.2Hz), 5.05 (1H , d, J = 4.8Hz), 5.29 (2H, d, J = 6.9Hz), 5.60 (1H, dd, J = 8.1, 4.8Hz), 5.87 (1H, dt, J = 15.6, 6.9Hz) , 6.72 (1H, s), 7.23 (2H, s), 7.30 (1H, d, J = 15.6Hz), 8.25 (1H, s), 8.67 (2H, d, J = 6.9Hz), 9.06 (2H, d, J = 6.9Hz), 9.54 (1H, d, J = 8.1Hz)

IR (KBr) cm— 3398, 1763, 1605, 1530, 1395, 1343.

MS (FAB): 686 ⁺ (M + 2Na) ⁺

Elemental analysis c H N O S Na-4.5H O-0.55NaHCO -0.15NaCl.

Calculated value: C, 39.87; Η, 3.98; Ν, 12.26; S, 12.03; Na, 4.89; Cl, 0.66 (%)

Experimental value: C39.78; Η, 3.90; Ν, 12.36; S, 12.05; Na, 4.92; Cl, 0.78 (%)

Example 216

[Chemical 263]

(17) 28 → 29

2N_NaOH (2.5 ml) was added to compound 28 (1.04 g, 3.30 mmol), and the mixture was stirred at room temperature for 1 hour. 2N_HCl (2.5 ml) was added, and the precipitated solid was collected by filtration. Drying under reduced pressure gave Compound 29. Yield 6 65mg (97%)

'H-NMR (CDCl): 8.27 (2H, d, J = 6.0Hz), 8.85 (2H, d, J = 6.0Hz), 9.04 (1H, s).

(18) 29 → 30

Compound 30 (650 mg, 3.20 mmol) Compound 30 was obtained in the same manner as (10). Yield 585 mg (57

%)

'H-NMR (CDCl): 3 · 82 (3Η, s), 5.42 (2H, s), 6.93 (2H, d, J = 8.7Hz), 7.43 (2H, d, J =

8.7Hz), 7.98 (1H, s), 8.70 (2H, d, J = 6.0Hz), 7.88 (2H, d, J = 6.0Hz).

(19) 27 + 30 → 26

Compound 26 was obtained as a powder from Compound 27 (677 mg, 0.90 mmol) and Compound 30 (294 mg, 0.90 mmol) in the same manner as (1) .Yield 101 mg (17%).

'H-NMR (DMSO): 0.88 (3H, t, J = 7.5Hz), 1.63 (2H, qt, J = 7.5, 6.6Hz), 3.43, 3.49 ( 2H, ABq, J = 17.1Hz), 3.99 (2H, t, J = 6.6Hz), 5.05 (1H, d, J = 4.8Hz), 5.25 (2H, d, J = 7.2Hz), 5.60 (1H, dd, J = 7.8, 4.8Hz), 5.88 (1H, dt, J = 15.9, 7.2Hz), 6.70 (1H, s),

7.23 (2H, s), 7.29 (1H, d, J = 15.9Hz), 8.56 (2H, d, J = 6.6Hz), 8.90 (1H, s), 9.01 (2H, d, J = 6.6Hz), 9.54 (1H, d, J = 7.8Hz).

IR (KBr) cm ^_1 : 3407, 1764, 1635, 1532, 1367.

MS (FAB): 678 ⁺ (M + Na + H) ⁺

Elemental analysis c H N O S Na-4.8H O-0.35 NaHCO -0.25NaCl.

27 24 7 7 3 2 3

Calculated values: C, 40.65; H, 4.23; N, 12.13; S, 11.90; Na, 4.55; Cl, 1.10 (%)

Experimental value: C, 40.72; H, 4.16; N, 12.23; S, 11.70; Na, 4.60; Cl, 1.02 (%)

Example 217

[Chemical 264]

(20) 27 + 24 → 31

Compound 31 was obtained as a powder from Compound 27 (677 mg, 0.90 mmol) and Compound 24 (294 mg, 0.90 mmol) in the same manner as in (1). Yield 228 mg (37%, 2st mark s).

'H-NMR (DMSO): 0 · 89 (3Η, t, J = 7.5Hz), 1 · 63 (2Η, qt, J = 7.5, 6.6Hz), 3.43, 3.49 (2H, ABq, J = 17.1Hz ), 3.99 (2H, t, J = 6.6Hz), 5.05 (1H, d, J = 5.4Hz), 5.29 (2H, d, J

= 7.5Hz), 5.60 (1H, dd, J = 7.8, 5.4Hz), 5.88 (1H, dt, J = 15.9, 7.5Hz), 6.71 (1H, s), 7.24 (2H, s), 7.30 (1H , d, J = 15.9Hz), 8.26 (1H, s), 8.68 (2H, d, J = 6.3Hz), 9.06 (2H, d, J = 6.3Hz), 9.54 (1H, d, J = 7.8Hz ).

IR (KBr) cm ^_1 : 3409, 1763, 1605, 1530, 1395, 1343.

MS (FAB): 678 ⁺ (M + Na + H) ⁺ Elemental analysis CHNOS Na-4.7HO-O. lNaHCO -0.15NaCl.

Calculated value: C, 41.75; H, 4.33; N, 12.58; S, 12.34; Na, 3.69; Cl, 0.68 (%)

Experimental value: C, 41.76; H, 4.10; N, 12.78; S, 12.18; Na, 3.60; Cl, 0.72 (%)

Example 218

[Chemical 265]

(21) 33 → 34

Toluene (50 ml), ethylene glycol (4.0 ml) and TsOH (57 lmg, 3.00 mmol) were added to compound 33 (5.73 g, 30.0 mmol), and the mixture was heated to reflux for 2 hours. Ethylene glycol (2.0 ml) was added, and the mixture was further heated under reflux for 2 hours. A 2% aqueous sodium carbonate solution (50 ml) was added and extracted with jetyl ether.

The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 34. Yield 7.68g (quant)

'H-NMR (CDCl): 4.00-4.16 (4H, m), 6.02 (1H, s), 6.91 (1H, d, J = 3.6Hz), 6.94 (1H, d, J = 3.6Hz).

(22) 34 + 35 → 36

Compound 34 (3.53 g, 15.0 mmol) was dissolved in THF (30 ml) at -78 ° C and n-BuLi (1.54 M hexane Solution, 10.20 ml, 15.8 mmol) was added dropwise and stirred for 30 minutes. Subsequently, a THF (lOml) solution of compound 35 (1.93 g, 18.0 mmol) was added to the reaction solution. The mixture was stirred at _78 ° C for 1 hour, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound 36. Yield 2.60 g (66%)

'H-NMR (CDCl): 3.97-4.13 (4H, m), 6.01 (1Η, s), 6 · 03 (1Η, s), 6.85 (1H, d, J = 3.6

Hz), 7.01 (1H, d, J = 3.6Hz), 7.39 (2H, d, J = 6.0Hz), 8.54 (2H, d, J = 6.0Hz).

(23) 36 → 37

Compound 36 (2.60 g, 9.87 mmol) was dissolved in black mouth form (45 ml), manganese dioxide (12.87 g, 148.1 mmol) was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated to obtain Compound 37. 2.60g (quant)

(24) 37 → 38

2N-HCl (14.7 ml) was added to Compound 37 (2.60 g, 9.87 mol), and the mixture was stirred at room temperature for 2 hours. Sodium bicarbonate was added to pH> 7 and extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with an ethyl acetate-toluene system to obtain Compound 38. Yield 2.09 g (98%)

'H-NMR (CDCl): 7.68-7.73 (3H, m), 7.82 (1H, d, J = 3.6Hz), 8.87 (2H, d, J = 5.7Hz

), 10.05 (1H, s).

(25) 38 → 39

Purified water (50 ml) was added to NaCIO (2.39 g, 21.1 mmol) and NH 2 SO 4 (2.05 g, 21.1 mmol), and the mixture was cooled and stirred. Compound 38 was added and stirred for 1 hour. An aqueous solution (25 ml) of Na 2 SO 4 (5.32 g, 42.2 mmol) was added to the reaction solution and stirred for another 30 minutes. The compound 39 was obtained by filtering and drying under reduced pressure. Yield 1.40 g (63%)

'H-NMR (DMSO): 7.75-7.8K4H, m), 8.85 (2H, d, J = 6.0Hz).

(26) 39 → 40

Compound 39 (1.38 g, 5.92 mmol) was dissolved in dimethylformamide (10 ml), paramethoxybenzenoleanolone (736 μΐ, 5.92 mmol), WSCD (1.36 g, 7.08 mmol), 4-dimethylaminobiphenyl. Lysine (216 mg, 1.77 mmol) was added, and the mixture was stirred at room temperature for 3.5 hours. Purified water was added and extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, subjected to silica gel chromatography, and eluted with ethyl acetate-toluene system to obtain Compound 40. Yield 1.40 g (67%)

'H-NMR (CDCl): 3 · 82 (3Η, s), 5.31 (2H, s), 6.92 (2H, d, J = 8.7Hz), 7.38 (2H, d, J =

8.7Hz), 7.59 (1H, d, J = 3.9Hz), 7.65 (2H, d, J = 5.7Hz), 7.81 (1H, d, J = 3.9Hz), 8.8 4 (2H, d, J = 5.7 Hz).

(27) 19 + 40 → 32

Compound 19 (855 mg, l.OOmmol) and compound 40 (353 mg, l.OOmmol) were dissolved in dimethylformamide (2. Oml), sodium bromide (309 mg, 3.00 mmol) was added, and the mixture was stirred for 5 hours. The reaction mixture was poured into 5% brine (30 ml) with stirring while cooling, and the deposited precipitate was collected by filtration. The precipitate was dried under reduced pressure to obtain an amorphous powder (1.23 g). Amorphous powder (1.22 g) was dissolved in dichloromethane (12.0 ml), anisole (1.0 ml) was added, and the mixture was cooled to -30 ° C. 1M-aluminum chloride (nitromethane solution, 10 ml) was added, and the mixture was stirred for 1 hour while raising the temperature to _10 ° C. The reaction solution was added dropwise to a solution of MeCN (50 ml) and 0.3N_HCl (50 ml) with stirring under ice cooling. Et 0 was added and the aqueous layer was separated. HP-20SS was added and concentrated, subjected to HP-20SS column chromatography and eluted with water-nitrile. Fractions containing the desired compound were collected and 2N_NaOH was carefully added with stirring, and when the pH exceeded 10, dry ice was added to bring the pH to 5 or less. Concentration under reduced pressure and lyophilization gave Compound 32 as a powder. Yield _{284mg (40%, 2steps) 0} 'H-NMR (DO): 1.28 (3H, d, J = 3.3Hz), 1.30 (3H, d, J = 3.3Hz), 3.66, 3.66 (2H, AB q, J = 19.5Hz), 4.49 (1H, m), 5.27 (1H, d, J = 4.5Hz), 5.44 (2H, d, J = 6.9Hz), 5.81 (1 H, d, J = 4.5Hz), 6.13 (1H, dt, J = 15.3, 6.9Hz), 6.94 (1H, s), 7.03 (1H, d, J = 15.3Hz), 7.58 (1H, d, J = 3.3Hz), 7.66 (1H, d , J = 3.3Hz), 8.38 (2H, d, J = 5.4Hz), 9.10 (2H, d, J = 5.4Hz).

IR (KBr) cm ^_1 : 3417, 1765, 1604, 1521, 1366, 1321, 1297.

MS (FAB): 705 ⁺ (M + Na + H) ⁺

Elemental analysis c H N O S Na-4.4H O-0.2NaHCO.

Calculated value: C, 43.80; H, 4.28; N, 10.49; S, 12.01; Na, 3.45 (%) Experimental value: C43.96; H, 4.13; N, 10.42; S, 11.64; Na, 3.47 (%)

Example 219

[Chemical 266]

(28) 34 + 42 → 43 → 44 → 45

In the same manner as (22), (23) and (24), compound 45 was obtained from compound 34 (3.53 g, 15.0 mmol 42 (1.84 ml, 19.5 mmol) via compound 43 and compound 44. Yield 1.44 g ( 44% from34) 'H-NMR (CDCl): 7.50— 7 · 54 (1Η, m), 7.73 (1H, d, J = 3.9Hz), 7.83 (1H, d, J = 3.9Hz

), 8.20 (1H, ddd, J = 8.1, 2.1, 1.8Hz), 8.83 (1H, br s), 9.12 (1H, br s), 10.04 (1H, s).

(29) 45 → 46

Compound 45 (1.43 g, 6.58 mmol) was obtained in the same manner as (25) to give compound 46. Yield 1.15 g (75%). 'H-NMR (CDCl): 7 · 63 (1Η, dd, J = 7.8, 5.0Hz), 7.78 (1H, d, J = 3.9Hz), 7.81 (1H, d

, J = 3.9Hz), 8.25 (1H, ddd, J = 7.8, 1.8, 2.1Hz), 8.86 (1H, dd, J = 5.1, 1.8Hz), 9.01 (1 H, d, J = 2.1Hz).

(30) 46 → 47

Compound 47 (1.15g, 4.93mmol) Compound 47 was obtained in the same manner as in (26). Yield 1.14g (66%)

'H-NMR (CDCl 3): 3.83 (3H, s), 5.32 (2H, s), 6.92 (2H, d, J = 9.0Hz), 7.39 (2H, d, J =

9.0Hz), 7.49 (1H, dd, J = 7.8, 4.8Hz), 7.61 (1H, d, J = 3.9Hz), 7.82 (1H, d, J = 3.9H z), 8.17 (1H, ddd, J = 7.8, 1.5, 1.2Hz), 8.85 (1H, dd, J = 4.8, 1.2Hz), 9.09 (1H, d, J = 1.5Hz).

(31) 2 + 47 → 41

Compound 41 was obtained as a powder in the same manner as Compound 2 (812 mg, l.lOmmol) and Compound 47 (353 mg, l.OOmmol) force (27). Yield 307 mg (44%, 2st mark s).

'H-NMR (D 2 O): 1.29 (3H, t, J = 7.2Hz), 3.65, 3.65 (2H, ABq, J = 18.3Hz), 4.21 (2H

, q, J = 7.2Hz), 5.26 (1H, d, J = 4.8Hz), 5.44 (2H, d, J = 7.2Hz), 5.80 (1H, d, J = 4.8

Hz), 6.14 (1H, dt, J = 15.0, 7.2Hz), 6.96 (1H, s), 7.00 (1H, d, J = 15.0Hz), 7.58 (1H, d

, J = 4.2Hz), 7.70 (1H, d, J = 4.2Hz), 8.26 (1H, dd, J = 6.9, 5.7Hz), 8.95 (1H, d, J = 6

• 9Hz), 9.10 (1H, d, J = 5.7Hz), 9.34 (1H, s).

IR (KBr) cm— 3397, 1764, 1601, 1519, 1362, 1316.

MS (FAB): 713 ⁺ (M + 2Na) ⁺

Elemental analysis c H N O S Na- 3.4 H O-0.2 NaHCO.

Calculated value: C, 44.06; Η, 3.93; N, 10.93; S, 12.51; Na, 3.59 (%)

Experimental value: C44.27; H, 3.90; N, 10.71; S, 12.08; Na, 3.65 (%)

Example 220

[Chemical 267]

(32) 49 + 35 → 50 → 51

Compound 49 (3.44 g, 15.0 mmol) was mixed with THF (30 ml) and Compound 35 (1.93 g, 18.0 mmol) force (22). In this way compound 50 was obtained (4.69 g).

Compound 51 (4.69 g) was obtained in the same manner as (23) to give compound 51. Yield 2.24g (59%, 2steps) 'H-NMR (CDCl): 4.03—4 · 17 (4Η, m), 5.86 (1Η, s), 7.55 (1Η, dd, J = 7.8, 7.8Hz), 7.6

0 (2H, d, J = 6.0Hz), 7.77 (1H, d, J = 7.8Hz), 7.82 (1H, d, J = 7.8Hz), 7.93 (1H, br s), 8.82 (2H, d, J = 6.0Hz).

(33) 51 → 52

Compound 52 (2.23 g, 8.74 mmol) was obtained in the same manner as (24) to give compound 52. Yield 1.72g (93%) 'H-NMR (CDCl): 7 · 61 (2Η, d, J = 5.7Hz), 7.73 (1H, dd, J = 7.8, 7.8 Hz), 8.11 (1H, d, J = 7.8Hz), 8.18 (1H, d, J = 7.8Hz), 8.30 (1H, s), 8.86 (2H, d, J = 5.7Hz), 10.11 (1H, s).

(34) 52 → 53

Compound 53 (1.72 g, 8.14 mmol) was obtained in the same manner as (25) to give compound 53. Yield 1.73 g (93%). 'H-NMR (DMSO): 7.66 (2H, d, J = 5.7Hz), 7.74 (1H, d, J = 7.8Hz), 8.04 (1H, d, J = 4.8Hz), 8.25-8.28 (2H, m), 8.84 (2H, d, J = 5.7Hz).

(35) 53 → 54

Compound 54 (1.72 g, 7.57 mmol) was obtained in the same manner as (26) to give compound 54. Yield 1.25g (48%) 'H-NMR (CDCl): 3.82 (3H, s), 5.33 (2H, s), 6.91 (2H, d, J = 6.6Hz), 7.38 (2H, d, J =

6.6Hz), 7.58-7.63 (3H, m), 8.01 (1H, d, J = 8.1Hz), 8.31 (1H, d, J = 7.8Hz), 8.45 (1H, s), 8.84 (2H, d, J = 6.6Hz).

(36) 2 + 54 → 48

Compound 48 was obtained as a powder from Compound 2 (886 mg, 1.20 mmol) and Compound 54 (347 mg, l.OOmmol) in the same manner as in (27). Yield 309 mg (45%, 2st mark s).

'H-NMR (D O): 1.30 (3H, t, J = 6.9Hz), 3.67 (2H, s), 4.25 (2H, q, J = 6.9Hz), 5.27 (1

H, d, J = 4.5Hz), 5.44 (2H, d, J = 7.2Hz), 5.83 (1H, d, J = 4.5Hz), 6.15 (1H, dt, J = 1 5.3, 7.2Hz), 6.98 (1H, s), 7.03 (1H, d, J = 15.3Hz), 7.67 (1H, dd, J = 8.1, 7.8Hz), 7.9 9 (1H, d, J = 8.1Hz), 8.22 (1H, d , J = 7.8Hz), 8.23 (lH, s), 8.33 (2H, d, J = 5.1Hz), 9.0 9 (2H, d, J = 5.1Hz).

IR (KBr) cm ^_1 : 3399, 1765, 1668, 1605, 1564, 1533, 1383. MS (FAB): 685 (M + Na + H)

Elemental analysis C H N O S Na- 5.3H O-O.lNaHCO.

30 25 6 8 2 2 3

Calculated: C, 45.85; H, 4.56; N, 10.66; S, 8.13; Na, 3.21 (%)

Experimental value: C45.86; H, 4.37; N, 10.78; SJ.97; Na, 3.14 (%)

Example 221

[Chemical 268]

(37) 56 + 57 → 58

Acetic acid (15 ml) was added to compound 56 (1. llg, 7.49 mmol) and compound 57 (1.79 g, 11.24 mmol). Zinc (1.84 g, 28.1 mmol) was slowly added under bath cooling, and the mixture was stirred at room temperature for 30 minutes and then heated to reflux for 45 minutes. After the solvent was distilled off, purified water and ethyl acetate were added, and sodium carbonate was added until pH> 7. The solid was removed by filtration and the filtrate was extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, Et 0 was added to the residue and filtered to obtain Compound 58. Yield 1.00g (58%)

2

'H-NMR (CDCl): 1 · 39 (3Η, t, J = 7.0Hz), 2.51 (3H, s), 4.37 (2H, q, J = 7.0Hz), 7.12

Three

(1H, d, J = 3.3Hz), 7.35 (2H, d, J = 6.0Hz), 8.60 (2H, d, J = 6.0Hz), 9.32 (1H, br s).

(38) 58 → 59

Compound 58 (1.00 g, 4.34 mmol) was dissolved in ethanol (15 ml), 2N_NaOH (10.9 ml) was added, and the mixture was stirred at 70 ° C. for 2 hours. After distilling off ethanol, 2N-HCl (10.9 ml) was added, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain Compound 59. Yield 630 mg (72%) Ή-NMR (CDC1): 2.46 (3H, s), 7.35 (1H, d, J = 3.3Hz), 7.45 (2H, d, J = 6.0Hz), 8.51

Three

(2H, br s).

(39) 19 + 59 → 55

Compound 55 was obtained as a powder from Compound 19 (855 mg, l.OOmmol) and Compound 59 (202 mg, l.OOmmol) in the same manner as in (27). Yield 328mg (49%, 2steps) ₀

'H-NMR (D 2 O): 1.28 (6H, d, J = 3.3Hz), 2.52 (3H, s), 3.65, 3.65 (2H, ABq, J = 19.5

2

Hz), 4.47 (1H, m), 5.13 (2H, m), 5.25 (1H, m), 5.79 (lH, m), 6.08 (1H, m), 6.90 (1H, s), 6.92 (1H, d , J = 15.3Hz), 7.55 (1H, s), 7.93 (2H, br s), 8.47 (2H, br s).

IR (KBr) cm ^_1 : 3388, 1763, 1633, 1566, 1534, 1403, 1334.

MS (FAB): 674 ⁺ (M + Na + H) ⁺

Elemental analysis c H N O S Na- 5.1H O-0.17 NaHCO.

29 28 7 7 2 2 3

Calculated value: C, 44.93; H, 4.96; N, 12.57; S, 8.22; Na, 3.45 (%)

Experimental value: C, 44.89; H, 4.82; N, 12.52; S, 8.17; Na, 3.41 (%)

Example 222

[Chemical 269]

(40) 61 + 57 → 62

Compound 62 was obtained from Compound 61 (5.28 g, 30.0 mmol) and Compound 57 (7.17 g, 45.0 mmol) in the same manner as in (37). Yield 920mg (12%)

'H-NMR (CDCl): 1.40 (3H, t, J = 7.2Hz), 2.67 (3H, s), 4.39 (2H, q, J = 7.2Hz), 7.19 (1H, d, J = 3.6Hz), 7.56 (2H, d, J = 5.7Hz), 8.77 (2H, d, J = 5.7Hz).

(41) 62 → 63

Compound 62 (910 mg, 3.50 mmol) was obtained in the same manner as (38) to give compound 63. Yield 426mg (53%) 'H-NMR (DMSO): 2.57 (3H, s), 7 · 25 (1Η, d, J = 3.6Hz), 7.58 (2H, d, J = 4.5Hz), 8.7 5 ( 2H, br s).

(42) 19 + 63 → 60

Compound 60 was obtained as a powder from Compound 19 (940 mg, l.lOmmol) and Compound 63 (230 mg, l.OOmmol) in the same manner as in (27). Yield 424 mg (60%, 2st mark s).

'H-NMR (D 2 O): 1.29 (6H, d, J = 2.1Hz), 2.57 (3H, s), 3.66, 3.66 (2H, ABq, J = 18.3

Hz), 4.50 (1H, m), 5.26 (1H, d, J = 4.2Hz), 5.40 (2H, d, J = 7.2Hz), 5.81 (1H, d, J = 4.2Hz), 6.12 (1H , dt, J = 14.7, 7.2Hz), 6.95 (1H, s), 6.98 (1H, d, J = 14.7Hz), 7.26 (1H, s), 8.68 (2H, d, J = 3.9Hz), 9.01 (2H, d, J = 3.9Hz).

IR (KBr) cm ^_1 : 3398, 1765, 1629, 1532, 1403, 1321.

MS (ESI): 680 ⁺ (M-Na + 2H) ⁺

Elemental analysis C H N O S Na-6.1H O-O.lNaHCO.

Calculated: C, 44.09; H, 4.95; N, 11.96; S, 7.82; Na, 3.08 (%)

Experimental value: C, 44.00 H, 4.60; N, 12.04; S, 7.91; Na, 3.09 (%)

Example 223

[Chemical 270]

(43) 65 + 66 → 67

To a solution of compound 65 (5.00 g, 15.0 mmol) and compound 66 (1.35 g, 15.0 mmol) in THF (60 ml) was added dipropylethylamine (2.60 ml, 15.0 mmol) and stirred at room temperature for 1.5 hours. . Solvent After distilling off under reduced pressure, Et 0 and purified water were added to the residue and suspended, and then the precipitate was collected by filtration to obtain a coupled product (3.06 g). This coupled product (2.88 g, 8.40 mmol) was dissolved in THF (30 ml), Ts OH-HO (160 mg, 0.84 mmol) was added, and the mixture was stirred with heating at 60 ° C for 2 hr. After concentration under reduced pressure, Et 0 was added and collected by filtration to obtain Compound 67. Yield 2.64 g (96%)

'H-NMR (CDCl): 2.97 (3H, d, J = 3.0Hz), 6.98 (1H, br s), 7.01 (1H, s), 7.25-7.48 (1

OH, m).

(44) 67 → 68

To a solution of compound 67 (2.74 g, 8.45 mmol) and isonicotinic acid chloride hydrochloride (1.50 g, 8.45 mmol) in dichloromethane (20 ml) was added Et N (3.53 ml, 25.4 mmol) and stirred at room temperature for 2 hours. did. Further, the mixture was stirred at 40 degrees for 3 hours. Purified water was added and extracted with ethyl acetate. The organic layer was washed with purified water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography and eluted with ethyl acetate-toluene system to obtain Compound 68. Yield 2.9 2g (80%)

'H-NMR (CDCl): 3.70 (3H, s), 7.14 (1H, s), 7.26-7.46 (12H, m), 8.06 (1H, s), 8.81 (2

(H, d, J = 6.0Hz).

(45) 2 + 68 → 64

Compound 64 was obtained as a powder from Compound 2 (886 mg, 1.20 mmol) and Compound 68 (429 mg, l.OOmmol) in the same manner as in (27). Yield 334 mg (46%, 2steps) ₀

^J H-NMR (DO): 1 · 30 (3Η, t, J = 7.2Hz), 3.62 (3H, s), 3.66 (2H, m), 4.26 (2H, q, J = 7

.2Hz), 5.27 (1H, d, J = 4.8Hz), 5.42 (2H, br s), 5.83 (1H, d, J = 4.8Hz), 6.12 (1H, m),

6.99 (1H, s), 7.01 (1H, d, J = 14.7Hz), 7.89 (1H, s), 8.30 (2H, br s), 9.10 (2H, br s).

IR (KBr) cm ^_1 : 3408, 1765, 1637, 1599, 1377, 1290.

MS (FAB): 721 ⁺ (M + Na + H) ⁺

Elemental analysis C H N O S Na- 5.7H O.

Calculated values: C, 40.84; H, 4.46; N, 13.61; S, 11.68; Na, 2.79 (%)

Experimental value: C, 40.84; H, 4.32; N, 13.57; S, 11.53; Na, 2.72 (%)

Example 224

[Chemical 271]

(50) 76 → 77

To a THF solution (15 ml) of compound 76 (1.31 g, 5.00 mmol) and methyl carbamate (1.13 g, 15.0 mmol) was added pyridine (890 μl, l l.O mmol) and heated to reflux for 4 hours. After the solvent was distilled off, purified water, 2 N-HC1, and acetonitrile were added, and the precipitate was collected by filtration to obtain Compound 77. Yield 270 mg (40%) 'H-NMR (DMSO): 3.80 (3H, s), 8.72 (2H, d, J = 6.6Hz), 9.01 (2H, d, J = 6.6Hz), 9.2 7 (1H, s), 11.44 (1H, s).

(51) (77 → 78) + 2 → 75

1M tetramethyldanidine was added to a methanol solution of compound 77 (300 mg, l.OOmmol) until the pH force was exceeded (methanol solution), then the pH was adjusted to 6.3 with 1N-HC1, and the solvent was distilled off under reduced pressure. Compound 78 was obtained. Compound 75 was obtained as a powder from Compound 2 (811 mg, l.OOmmol) and Compound 78 (total amount, l.OOmmol) in the same manner as (27). Yield 260mg (37%, 3steps) ₀

'H-NMR (DMSO): 1.22 (3H, t, J = 6.9Hz), 3.45, 3.52 (2H, ABq, J = 17.2Hz), 3.80 (3 H, s), 4.09 (2H, q, J = 6.9Hz), 5.06 (1H, d, J = 5.1Hz), 5.31 (2H, d, J = 6.0Hz), 5.61 (1H, dd, J = 7.8, 5.1Hz), 5.94 (1H, dt, J = 14.5, 6.0Hz), 6.72 (1H, s), 7.22 (3H, m), 8. 87 (2H, d, J = 6.6Hz), 9.16 (2H, d, J = 6.6Hz), 9.34 (1H, s), 9.54 (1H, d, J = 7.8Hz) IR (KBr) cm ^_1 : 3389, 1770, 1636, 1605, 1530, 1385, 1304, 1202.

MS (ESI): 699+ (M + H) +

Elemental analysis C H N O S -4.1H O.

Calculated value: C, 43.53; H, 4.46; N, 14.50; S, 12.45 (%)

Experimental value: C, 43.50; H, 4.41; N, 14.54; S, 12.46 (%)

Example 225 [Chemical 272]

(52) 2 + 59 → 79

Compound 79 was obtained as a powder in the same manner as Compound 2 (849 mg, l.OOmmol) and Compound 59 (202 mg, l.OOmmol) force (27). Yield 396mg (60%, 2steps) ₀

^J H-NMR (DO): 1.28 (3H, t, J = 6.9Hz), 2.50 (3H, s), 3.65, 3.65 (2H, ABq, J = 18.5H z), 4.22 (2H, q, J = 6.9Hz), 5.11 (2H, d, J = 5.4Hz), 5.24 (1H, d, J = 4.5Hz), 5.78 (1H, d, J = 4.5H), 6.07 (1H, dt, J = 16.5, 5.4Hz), 6.90 (1H, s), 6.93 (1H, d, J = 16.5Hz), 7.52 (1H, s), 7.90 (2H, d, J = 5.4Hz), 8.45 (2H, d, J = 5.4Hz).

IR (ATR) cm— 3309, 1758, 1632, 1561, 1531, 1397, 1332.

MS (ESI): 638 ⁺ (M-Na + 2H) ⁺

Elemental analysis c H N O S Na- 5.0 H O-0.2 NaHCO.

Calculated value: C, 44.19; H, 4.76; N, 12.79; S, 8.37; Na, 3.60 (%)

Experimental value: C44.14; H, 4.78; N, 12.86; S, 8.55; Na, 3.65 (%)

Test example 1

The antibacterial activity of compound (I) was investigated.

(Test method)

The minimum growth inhibitory concentration (MIC: μg / ml) was measured according to the standard method of the Japanese Society of Chemotherapy, the inoculum was 1000 cfu / spot, the test medium was a sensitive disk medium, and the agar plate dilution method was used. . As a control, the compound described in Example 9 described in W097Z37996 (Compound A) was used. As pharmacokinetics (ADME), AUC and the like were examined by intravenously administering the test compound to monkeys at lmg / kg.

urn Z90C / 900Zdf / X3d IQ £ 0Ϊ / 900Ζ OAV

Z90C / 900Zdf / X3d 68S 0Ϊ / 900Ζ OAV

The compound of the present invention exhibits strong antibacterial activity against gram-positive and gram-negative bacteria. Special t-Henicillin [Penicillin-resistant Streptococcus pneumoniae (PRSP), β-lactamase-negative, ampiciliin-resistant Haemophilus influenzae: BLNAR, etc. Even if this size is reduced, it is effective. The pharmacokinetics was also significantly improved. As a comparison, a compound in which the substituent corresponding to R ¹ of the compound (I) is -COCH, _S0 i _Pr, etc. was examined in the same manner.

3 2

Pharmacokinetics etc. were not preferable.

Brief Description of Drawings

[FIG. 1] FIG. 1 shows a powder X-ray diffraction pattern of a triethylamine salt crystal of compound (G-1).

FIG. 2 shows a powder X-ray diffraction pattern of hydrochloride crystals of compound (G-2).

FIG. 3 shows a powder X-ray diffraction pattern of hydrochloride crystals of compound (G-3).

FIG. 4 shows a powder X-ray diffraction pattern of hydrochloride crystals of compound (G-4).

Claims

The scope of the claims

[Chemical 1]

(Where

Acyl is an acylol group that can be used in the field of β-latata;

Τ is S SO or O;

Formula:

[Chemical 2]

The group represented by \ no is a heterocyclic group having a force thionic N atom in the ring, which may be substituted with a substituent other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ”;

Y ¹ and Y ² are each independently 1) a single bond, 2) — NR ² , —CO −, — NR ² C〇—, CONR ² NR ² CONR ³ NR ² S〇 1, SO NR ² NR ² S〇 NR ³ —

2 2 2 (R ² and R ³ are each independently hydrogen or lower alkyl), = N— — N = — OS SO—, and a heteroatom selected from the group consisting of SO—

2

R ¹ is _CONHCN _C (〇H) = NCN, or _C〇OH or a biologically equivalent acidic group thereof;

Wavy line means cis, trans or a mixture thereof; However,

2) A heterocyclic group having a cationic N atom in the ring is a bicyclic heterocyclic group, Ar ¹ is a single bond, and R ¹ is either CONHCN or _C (OH) = NCN Otherwise, the group represented by “one Y ¹ — Ar ¹ — Y ² — R ¹ ” does not have a bond with the side chain moiety of the caffeine 3-position in the bicyclic heterocyclic group. Or a pharmaceutically acceptable salt or solvate thereof.

[2] The compound according to claim 1, wherein T is S, a pharmaceutically acceptable salt thereof, or a solvent thereof.

[3] Acyl is the formula:

[Chemical 3]

(Where

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group) or = NOR ° (R. Hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, substituted les, may les, cycloalkyl, substituted les, may les, aryls or substituted Good heterocyclic group)

2. The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a group represented by:

[4] The compound according to claim 3, wherein X is CH and / or I ^ S = NOR ° (R. is hydrogen or lower alkyl which may be substituted).

[5] Formula:

[Chemical 4] A group represented by (Q) is "A ^{^{^{Y 1 - Ar 1 - Y 2}}} - R 1" in a non-substituent may be substituted, Pi Rijiniumu group or bicyclic heterocyclic having cation, The compound according to claim 1, which is a group, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[6] The compound according to claim ^1, wherein Y ¹ and / or Y ² is a single bond, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[7] The compound according to claim 1, Ar ¹ , a pharmaceutically acceptable salt thereof, or a solvent thereof, wherein Ar ¹ is a single bond, an optionally substituted aryl, or an optionally substituted heteroaryl. Japanese products.

[8] The compound, pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R ¹ is CONHCN, —C (OH) ═NCN or COOH.

[9] The compound, pharmaceutically acceptable salt or solvate thereof according to claim 1, wherein R ¹ is CONHCN or —C (OH) ═NCN.

[10] R ¹ is COOH or a biologically equivalent acidic group thereof, wherein the acidic group is -CON

HR ⁴ , -SO H, -SO NHR ⁵ , (R ⁴ and R ⁵ are each independently an amino residue), —P

3 2

O H, One OH, -COCH = C (OH) CF, -NHSO CF, -CONHSO CF One N

3 2 3 2 3 2 3,

HSO Me, -CONHSO Me, _NHC〇Me, _C〇NHCOMe, -COCH CO

2 2 2

The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is Me or a 5- to 6-membered heterocyclic group which may be substituted and has NH_ and other hetero atoms as a ring-constituting atom. Or a solvate thereof.

[11] Formula:

[Chemical 5]

The group represented by can be substituted with a substituent other than “one Y ¹ — Ar ¹ — Y ² — R ¹ ”, A lysine group; Y ¹ and Y ² are a single bond; Ar ¹ is an optionally substituted aryl, or an optionally substituted heteroaryl; R ¹ is CONHCN or one C (〇H) = NCN The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. formula:

[Chemical 6]

(Where

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group), or = NOR ° (R ° is Hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, substituted les, may les, cycloalkyl, substituted les, may les, aryls or substituted May be a heterocyclic group)

A group represented by:

Y ¹ and Y ² are each independently 1) single bond, 2) — NR ² —CO −, — NR ² C〇—CONR ² NR ² CONR ³ NR ² S〇 1, SO NR ² NR ² S〇 NR ³ —

2

R ¹ is -CONHCN, _C (〇H) = NCN, or _C〇OH or a biologically equivalent acidic group thereof;

Wavy line means cis, trans or a mixture thereof; However, when Ar ¹ is a single bond, R ¹ is CONHCN or —C (〇H) = NCN. )

Or a pharmaceutically acceptable salt or solvate thereof.

[13] The compound according to claim 12, wherein R ¹ is —CONHCN or —C (OH) ═NCN, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[14] Y ¹ is a single bond; Ar ¹ is substituted, may, Les, aryl, or substituted, may, heteroaryl; Y ² is a single bond; R ¹ is one CONHCN Or the compound according to claim 12, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein C (OH) = NCN.

[15] The method according to claim 12, wherein Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is —CO NHCN or _C (〇H) ═NCN Compound, its pharmaceutically acceptable salt or solvate thereof.

[16] is ○ 1 ^; 1 is = 〇112 is optionally substituted lower alkyl) or = N〇R ° (R ° is hydrogen, optionally substituted lower alkyl or optionally substituted) 13. Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is —CO NHCN or —C (OH) ═NCN. Or a pharmaceutically acceptable salt or solvate thereof.

[17] X is CH; = NOR ° (R. is hydrogen, optionally substituted lower alkyl or optionally substituted aryl); Y ¹ is a single bond; Ar ¹ is optionally substituted Yes, 5 and 6-membered heteroarynoles containing 1 to 4 heteroatoms identical or different selected from the group of S and N force; Y ² is a single bond; R ¹ is CONHCN or one C 13. The compound according to claim 12, a pharmaceutically acceptable salt thereof or a solvate thereof, wherein (OH) = NCN.

[18] X is CH; I ^ i = NOR ° (R. is lower alkyl or optionally substituted aryl); Y ¹ is a single bond; Ar ¹ is selected from the group consisting of 〇, S and N The 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms which are the same or different; Y ² is a single bond; R ¹ is —CONHC N or —C (〇H) ═NCN Compound, its pharmaceutically acceptable salt or solvate thereof.

[19] Formula:

[Chemical 7]

(Where

Formula:

[Chemical 8]

X is N or CY (Y is hydrogen or halogen);

R is = CHZ (Z is hydrogen, an optionally substituted lower alkyl, an optionally substituted cycloalkyl or an optionally substituted heterocyclic group) or = NOR ° (R. Hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, substituted les, may les, cycloalkyl, substituted les, may les, aryls or heterocyclic groups) A group represented by:

2 2 2

, (R ² and R ³ are each independently hydrogen or lower alkyl), a heteroatom-containing group selected from the group consisting of O—, —S—, —SO—, and SO—, or 3) 2) of

2

Wavy line means cis, trans or a mixture thereof;

However, Ar ¹ is a single bond, and R ¹ is CONHCN or —C (OH) = NCN If not a shift, "A ^{^{^{Y 1 - Ar 1 - Y 2}}} - R 1" groups represented by have no bond to Sefuwemu 3-position side chain moiety in said bicyclic heterocyclic group On the other ring)

Or a pharmaceutically acceptable salt or solvate thereof.

[20] The compound according to claim 19, wherein R ¹ is —CONHCN or —C (OH) ═NCN, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[21] Y ¹ is a single bond; Ar ¹ is a single bond; Y ² is a single bond; R ¹ is —CONHCN or _C (OH) = N

20. A compound according to claim 19, which is CN, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[22] X is CH; R is = CHZ (Z is an optionally substituted lower alkyl) or = N ° R ° (R ° is hydrogen, substituted or less, lower alkyl or 21. Y ¹ is a single bond; Ar ¹ is a single bond; Y ² is a single bond; R ¹ is —CONHCN or —C (OH) = NCN Or a pharmaceutically acceptable salt or solvate thereof.

[23] The compound according to any one of claims 19 to 22, the pharmaceutically acceptable salt or solvate thereof, wherein the bicyclic heterocyclic group is any of the following:

[Chemical 9]

[24] A pharmaceutical composition comprising the compound according to any one of claims 1 to 23, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[25] Claim: A compound wherein the amino and / or carboxyl moiety at the 7-position side chain end of the compound according to any one of! To 23 is protected, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[26] Formula:

[Chemical 10]

(Where

2 2 2

2

R ¹ is one CONHCN or one C (OH) = NCN;

[27] The compound according to claim 26, wherein Y ¹ and Y ² are a single bond; R ¹ is CONHCN or one C (〇H) = NCN; Ar ¹ is a group derived from any of the following heterocycles: , A pharmaceutically acceptable salt thereof, or a solvate thereof.

[Chemical 11]

[28] Formula:

[Chemical 12]

(Where formula:

[Chemical 13]

The ring represented by is a bicyclic pyridine ring optionally substituted with a substituent other than “one Y ¹ —Ar ¹ —Y ² —R ¹ ”;

2 2 2 (R ² and R ³ are each independently hydrogen or lower alkyl), a heteroatom-containing group selected from the group consisting of O——S——S 〇_, and —S〇—, or 3 2)

2

R ¹ is one CONHCN or _C (OH) = NCN)

Or a pharmaceutically acceptable salt or solvate thereof.

[29] Y ¹ Ar ¹ and Y ² are a single bond; R ¹ is one CONHCN or one C (〇H) ═NCN, The compound according to claim 28, a pharmaceutically acceptable salt thereof, or a solvent thereof Japanese products.

[30] Y ¹ is a single bond; Ar ¹ is an optionally substituted aryl or an optionally substituted heteroaryl; R ¹ is COOH, The pharmaceutically acceptable compound thereof Is Salts or solvates thereof.

[31] Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is — C

13. The compound, its pharmaceutically acceptable salt or solvate thereof according to claim 12, which is a biologically equivalent acidic group of OOH.

[32] Y ¹ is a single bond; Ar ¹ is an optionally substituted aryl or an optionally substituted heteroaryl; R ¹ is a biologically equivalent acidic group of _COOH. 13. The compound according to claim 12, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[33] Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is —C

[34] Y ¹ is a single bond; Ar ¹ is an optionally substituted heteroaryl; Y ² is a single bond; R ¹ is an optionally substituted ring atom — NH_ and other hetero Having an atom 5

13. The compound according to claim 12, which is a ˜6-membered heterocyclic group, a pharmaceutically acceptable salt thereof, or a solvate thereof.

[Chemical 14]

13. The compound according to claim 12, a pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the moiety represented by is a structure of any of the following:

[Chemical 15]

[36] Any of the following compounds, pharmaceutically acceptable salts or solvates thereof:

[Chemical 16]

Formula of the hydrochloride salt of the compound represented by:

[Chemical 19]

(Wherein BH is Benzhydryl) Hydrochloride crystals of the compound represented by

[40] Formula:

[Chemical 20]