JPS6110552A - Azetidinone compound - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is (substituted) amino, substituted hydroxy, azido, or halogen; R<2> is hydroxymethyl, aryl, aralkenyl, formyl, carboxy, etc.; R<3> is group shown by the formula II (R<4> is aryl, aralkyl, arylthioalkyl, etc.; R<5> is carboxy or its derivative), or group shown by the formula III (R<6> is alkyl, haloalkyl, arylthio, etc.; R<7> is H, haloalkyl, or heterocyclic thioalkyl)]. EXAMPLE:2-(2-Oxo-3-phthalimido-1-azetidinyl)-2-(2-thienyl)acetic acid methyl ester. USE:Having antimicrobial activity, useful as a drug, also useful as an intermediate for synthesizing other antimicrobial substances. PREPARATION:For example, a 2-substituted acetic acid shown by the formula IV(R<1>' is R<1> except unsubstituted amino) is reacted with a compound shown by the formula V (R<2> is aryl, aralkenyl, or nucleophilic compound residue; Ra<3> is group shown by the formula II wherein R<4> is aryl), to give a corresponding compound shown by the formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel azetidinone compounds with antibacterial activity.

More specifically, the present invention provides novel azetidinone compounds, particularly compounds having various substituted carboxyalkyl groups at the 1-position of the azetidine nucleus and compounds having various substituents at the 4-position of the azetidine nucleus.

Conventionally, the following compounds are known as azetidinone compounds, but these compounds have almost no antibacterial activity or have a certain level of antibacterial activity.
It has antibacterial activity only against negative bacteria, such as Pseudomonas aeruginosa.

As a result of intensive research, the inventors succeeded in synthesizing an azetidinone compound that has antibacterial activity against not only GRA-negative bacteria but also GRA-positive bacteria, and completed this invention.

0OH (US Patent No. 3925.977) The azetidinone compound of this invention is represented by the following general formula +1+.

[In the formula, R1 is amino, substituted amino, substituted hydroxy,
azide or a halogen atom, R is a hydrogen atom, hydroxymethyl, aralkoxyiminomethyl, aryl, afulkenyl, formyl, carboxy or a residue of a nucleophilic compound, and R3 is a group -CB-R' (in the group 1R4 represents an aryl, aralkyl, arylthioalkyl or heterocyclic group, and R represents a carboxyne group or a derivative thereof) or a group -C=C(R)(R) in which
R6 means alkyl, haloalkyl, heterocyclic thioalkyl or arylthio, and R7 means hydrogen atom, haloalkyl or heterocyclic thio, respectively, and R1 has an acyl ρ moiety derived from amino or an organic carboxylic acid or an organic sulfonic acid. When it is an acylamino group and R is a hydrogen atom, R5 is a group -CH-R' (in the group, R4 is phenyl, naphthyl, having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy, means an aralkyl, arylthioalkyl, or heterocyclic group, and R has the same meaning as above), a group -C=C(R)(R) (
In the group, R means alkyl, haloalkyl or heterocyclic thioalkyl, R means haloalkyl or heterocyclic thioalkyl, and R5 has the same meaning as above) or the group -C=CH-R8 (in the group, R means arylthio and R has the same meaning as above), respectively;
Further, when R1 is amino, substituted amino or azide, and R2 is aryl, halogen or the residue of a sulfur-nucleophilic compound, R3 is a group -CH-R' (wherein R4 is aryl, aralkyl , arylthioalkyl or heterocyclic group (R5 has the same meaning as above), group -C=C(R6) (
R') (in the group, R6 means alkyl or heterocyclic thioalkyl, and R7 means heterocyclic thioalkyl,
The alkane, arene and heterocycle in each group defined in the formula in which R has the same meaning as above may have one or more suitable substituents at any position thereof] Azetidinone compound of the present invention (1)) In this case, due to the presence of asymmetric carbon and/or double bonds in the molecule, one or more optical and/or
May have geometric isomers.

The azetidinone compound (Il) of the present invention can be produced by various methods V shown in the following formulas. Among these methods, Processes 1 to 10 and Process 21 are basic methods for synthesizing the azetidinone compound.

(1) Process 1: R''-Cl2COOH+CCH2=N-R').

(n) (I [I) [wherein R represents a substituted amino, substituted hydroxy, azide or halogen atom, and n means an integer of 1 to 3, R3 has the same meaning as above, R1' is an acylamino group having an acyl moiety derived from an organic carboxylic acid or an organic nulphonic acid, R3 is a group -C8-
R' (in the group, R4 is phenyl, naphthyl, aralkyl, arylthioalkyl having N-substituted or unsubstituted alkannulfonamide or aroyl alkoxy,
or a heterocyclic group, R5 has the same meaning as above), a group -C==OCR)(R), in which R6 is alkyl, haloalkyl or heterocyclic thioalkyl, and R is haloalkyl or heterocyclic group. (R has the same meaning as above) or a group -C=CH-
(2) Process 2: +n) (in which R is the residue of an ary-11 aralkenyl or a nucleophilic compound, and R is a group -C8-Ra (in the group R4
means aryl, R5 has the same meaning as above, and R1' has the same meaning as above] (6) Process 3: (Vl (I") methyl, aryl, aralkenyl or the residue of a nucleophilic compound, R1) is a group -C)l
-R (in the group, Ra means alkyl having rupoxy or its derivatives or carboxy or its derivatives, and R4 has the same meaning as above) or the group -C-C
(R6) R5 (R') (in the group, R5, R6 and R7 have the same meanings as above)] (4) Process 4: (1') [In the formula, Rλ is a protected amino acid. , and the scolding is the group -CB -R' (
(in the group, R4 and R5 have the same meanings as above), a group -C=C
(RJ(R') (in the group, a a R6 means alkyl, haloalkyl or heterocyclic thioalkyl, and R means haloalkyl or heterocyclic thioalkyl, R has the same meaning as above) or the group -C
=CH-R8 (in the group, R5 and R have the same meaning as above)
and when R2 is a hydrogen atom, R3 is a group -CH-R' (in the group, R4 is phenyl, naphthyl, aralkyl with N-substituted or unsubstituted alkannulfonamide or alloy alkoxy) , arylthioalkyl, or a heterocyclic group, R has the same meaning as above), and R7 has the same meaning as above)
(or groups with the same meaning)] (5) Process 5: [In the formula, R means acylamino, R6 and.

and R have the same meanings as above, and when R5 is a hydrogen atom, R3 is a group -CI-R' (in the group, R4 is an N-substituted or unsubstituted alkannulfonamide or aroylpurkoxy) (6) Process 6: (In the formula, R means dialkylamino-substituted methylene amino or aralkylidene amino, and R9 means sialkylamino or aryl, and R3 has the same meaning as above.) (7) Process 7: [In the formula, Rd is acylamino or azide, and R
o means the group -CH=CH-R (in the group, R means aryl), R5 has the same meaning as above] (8) Process 8: [In the formula, R11 is aralkyl, and R2d is the group -C
H=N-OR (in the group, R means the same meaning as above), R1) and R2 have the same meaning as above] (9) Process 9: (wherein R5 has the same meaning as above) (In the formula, J and R3 have the same meanings as above) (In the formula, R:
means an aralkylamino, azide or halogen atom, and R3 has the same meaning as above) (1~ Process 12: (XrV) (112) (in the formula,
The town is an acylamino group having at least one group selected from protected amino, protected hydroxy, and protected carboxy, and R is at least one group selected from amino, hydroxy, and carboxy). (In the group, R6 means a phenylene, naphthyl, aralkyl, arylthioalkyl, or heterocyclic group having N-substituted or unsubstituted alkanesulfonamide or aroyl alkoxy, and R5 has the same meaning) or group -c: means CH-R8 (in the group, R5 and R8 have the same meanings as above)] [In the formula, RL is the group -CH-R'C, and the leaves are (where R has the same meaning as above), a group -C=C(Ra)(Ryu)RL (in which Rb1Ra and 7 have the same meanings as above), or a group -c = cH-R (in the group, Rb and R8 have the same meanings as above, and Rr means an organic cation and R4 has the same meaning as above), group -
c=c(R:)(R:) (base middle, 00M M, Ryu and R, L have the same meanings as above) or the same meaning) respectively, and R1 and Rko have the same meanings as above. , RL, is a hydrogen atom, or means a phenyl, naphthyl, aralkyl, arylthioalkyl, or heterocyclic group having an unsubstituted alkanesulfonamide or aroylalkoxy,
(Rb has the same meaning as above), (In the group, R-1R8 has the same meaning as above, and R3 is a group -CH-'R'
(In the group, R4 is phenyl, naphthyl, aralkyl, having N-substituted 000M or unsubstituted alkanesulfonamide or aroyl alkoxy,
means ary-lithioargyl or a heterocyclic group, M
has the same meaning as above), 1&-C=C'CR: )
(RL) in the C group, R:, RL and M have the same meanings as above)] Aralkyl having at least one group selected from protected amino, protected hydroxy and protected carboxy , R5 means the same as above (in the group, R6 means an aralkyl having at least one group selected from amino, hydroxy and carboxy, R5 has the same meaning as above), R has the same meaning as above] (1L) Process 15: (wherein Rj is the residue of a nucleophilic compound selected from alkylthio, aralkylthio, arylthio and heterocyclicthio, and Ro is / (16) Process 16: (wherein, R means a residue of a nucleophilic compound excluding halogen, and R, R, and Ra have the same meanings as above) (same meaning as above) 67) Process 17: R12 and R16 each mean alkyl, R5
has the same meaning as above), Rj is a group or haloalkyl, and Rb is heteroalkyl, R
(1B) Process 18; Rg is alkyl or heterocyclic thioalkyl, and R is
means a heterocyclic thioalkyl, R has the same meaning as above, R and R have the same meaning as above] [wherein Rj is a group -c! +cH2-R” (in the group, R5
(20) Process 20: (bean) (120) (wherein, the width is means a halogen atom, and Rj has the same meaning as above) (21) Process 21: [In the formula, R is a group R" -C0CONH- (in the group, R1
4 means substituted or unsubstituted aryl), 1 means the same meaning as above), and R and R6
has the same meaning as above, and when Ra is a hydrogen atom, R5 is a group -CH-R' (in the group, R4 is a phenyl, naphthyl, aralkyl group having N-substituted or unsubstituted alkannurphonamidroyl alkoxy) , means an arylthioalkyl formula group, R5 has the same meaning as above), (in the group, R and R8 have the same meaning as above)] In the above Procenes 1 to 21, in the formula (A), the group R and R1
It is assumed that R and R, Rb and Rb1, R6 and R7, and R12 and R16 are bonded to the same carbon atom. (b) The alkane, arene, and heterocyclic moieties in the group defined in the formula may be substituted with one or more suitable substituents, and examples of such substituents include those described below for the acyl moiety of acylamino. The exemplified substituents can be listed as they are. (c) The carboxy group defined by R5 in the above formula may be introduced into a salt thereof, and examples of such salts include alkali metal salts such as sodium salts and potassium salts, calcium salts, magnesium salts, etc. Inorganic or organic bases such as alkaline earth metal salts, ammonium salts, methylamine salts, triethylamine salts, triethylamine salts, dicyclohexylamine salts, hyridine salts, ethanolamine salts, jetanolamine salts, N,N-dimethylaniline salts, etc. Salt can be given.

In addition, the amino group which is a substituent of each group defined in the formula may be introduced into a salt with an acid, and examples of such salt include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; Examples thereof include salts with inorganic or organic acids such as dilic acid, acetic acid, maleic acid, fumaric acid/K acid, l'ff1 taric acid, methanemelonic acid, p, ), and reninsulfonic acid.

It includes fulkylamino, dialkylaminoamino, and aralkylideneamino, and specific examples of such groups will be described in detail below.

a) Acylamino group; Here, the acylamino group is aliphatic acylamino, aromatic acylamino, aromatic substituted aliphatic acylamino, heterocyclic acylamino group, heterocyclic substituted aliphatic or aryl methylene, and X is μbonyl or imino. and Z means oxo or aryl or heterocyclic substituted methylene, respectively).

The acyl moiety in the above acylamino is an acyl moiety derived from an organic acid, an organic sulfonic acid, and an organic phosphoric acid.
Examples of such acyl include aliphatic acyl, aromatic acyl, aromatic substituted aliphatic acyl, heterocyclic acyl, and heterocyclic substituted aliphatic acyl.More detailed examples are as follows.

Examples of the fat IM7vt include alkenoyl groups such as formyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, valmitoylmethacryloyl, crotonoyl, isocrotonoyl, methyloxalyl, dichloromethane, propylleoxalyl, Alkyloxalyl μ such as inpropyl oxalyl, alkanes such as ethane 7, lephonyl, propanesulfonyl 7/L/honyl, alkenes μ such as ethylenenulfonyl, propanesulfonyl, etc., methoxy Carbonylcarbonylμ, propoxycarbonyl, impropoxycarbonyl, butoxycarbonyl, 6th-butoxycarbonyl, pentyloxycarbonyl, etc. (1) “fμ Coki V
Examples thereof include carbonyl group, dialkyp-honuphoryl group such as dimethylhonuphoryl, 'diethylhonuphoryl, and diisopropylhonuphoryl.

Examples of the aromatic acyl include aroyl groups such as benzoyl, toluoyl, xyloyl, naphthoyl, fucroyl, phenyloxalyl, tolyloxalyl, naphthyl, etc.
Alkyloxalyl groups such as leoxalyl, 7-lane sulfonyl groups such as benzenesulfonyl and xylene sulfonyl tv, and diary groups such as diphenylphosphoryl! Examples include lehonuphoryl group.

Examples of the aromatic substituted aliphatic acyl include phenylacetyl, naphthylacetyl, biphenylylacetyl, phenylpropionyl, tolylpropionyl, naphthylpropionyl, 2-methyl/l/-3-phenylpropionylp12-methfJv-2+ Fenino V propionyl, 2.
Methyl/I/-3-naphthylglobioni μ.

phenylbutyryl Valery A/, tolylvaleryl, naphthylbutyryl p.

Diphenylacetyl, diphenylpropioni/L' fathom 1-ralkanoyl group, aralkyloxalyltolylmesylnulfonyl such as benzyloxalylnetyloxalyl, 7-ralkanesulfonyl group such as naphthylethanesulfonylpropane-nulfonyl, phenylbutane-nulfonyl, etc. , phenylethylene 7/L/
+1 to 2/L/,) lyleethylenesulfonyl, naphthylethylenesulfonylnylbutenesulfonyl, etc. Examples include araρoxycarbonyl A4 such as levonyl, phenethyloxycarbonyl, phenylpropoxycarbonyl, diphenylmethoxycarbonyl, and diafulkyl to phosphoryl groups such as dibenzylphosphoryl. Examples of the heterocyclic ring p include a 3- to 6- (preferably 5)-membered monocyclic or fused polycyclic heterocyclic force p containing at least one hetero atom selected from nitrogen atoms, oxygen atoms, and sulfur atoms. Examples of such heterocyclic carbonyl groups include aziridine carbonyl, azetidine carbonyl, pyrrole force l reponi/l/, 2H-pyro p carbonyl group, etc.
Bonyl, imidazole carbonyl, piwosol carbonyl, pyridine carbonyl, hirashinkaflebonyl, hyperizinka! levonyl, bipetuzine carbonyl p1 pyrimidine carbonyl, viridazine force tv,) rear sea p
Carbonyl, thiazoline carbonyl, triazine carbonyl, pyrrolidine carbonyl μ, imidazolysine carbonyl, oxyγ rank carbonyl p1 furoyl, biocarbonyl p1, thenoyl, heppholine carbonyl, furazine carbonyl, oxazo-ρ carbonylxazole carbonyl , thiazo-p carbonyl, thiadiazole-μ carbonyl, oxadiazole kallidine carbonyl, IH-indazole carbonyl, purine carbonyl, benzimidazo-ρ carbonyl, benzothiazole carbonyl, quinoline carbonyl lysine carbonyl, quinoxaline carbonyl nazoline carbonyl chromene carbonyl, iso Examples of the heterocyclic oxalyl group include benzofurancarbonylcarbonyl diisoxazolecarbonylcarbonyl, and examples of the heterocyclic oxalyl group include thhenyloxalyltetrazolyloxalyl, and examples of the heterocyclic aliphatic a, sil group such as thenyl acetyl, (pyridy- 1-oxide) acetyl, hyloryl acetyl, imidazolylacetylμ, bifuzolylρacetyl/
I/, ) lyazolyl acetyl, tetrasilyl rarecetyl p1 oxacylylacetyl, oxazizoazolyl acetyl, thiazolyl acetyl linyl acetyl, thiasia silylacetyl, 7p phorinyl acetyl, vilani-heptyl, pyrrolinyl acetyl, pyrrolinylacetyl, chenylpropionyl, ferpropionyl, pyridylpropionyllylpropionyl, oxadiazolylpropionyl,
Thiazolylpropioniμ, thiadiazolylpropionyl, penzocheniμ acetyl, benzoxacyacylylacetyl, benzothiazolylacetyl, benxoxacylyμ acetyl, benzisooxacylylacetyl, benzotriazolylacetylpurinylpropionyl, Heterocyclic-substituted alkanoyl p groups such as indolylpropionyl, Teniμoxalyl, Furfur! Oxari p1 Piriji! Examples include heterocyclic-substituted apkyloxalyl μ groups such as lemethyloxalyl, tetofuzolyl, methyloxalyl azolyl, and methyl leoxalyl.

The aliphatic hydrogen ash moieties (e.g. alkane or alkene moieties), aromatic hydrogen hydride moieties (e.g. arene moieties) and heterocyclic moieties in the above-mentioned acyls may have one or more suitable substituents. Commonly such substituents include, for example, methyl, ethyl, propyl, inpropyl, butyl, isobutyl, 6-butyl, pentyl,
Alkyl groups such as isopentyl and neopentyl, alkenyl groups such as vinyl, propenyl, impropenyl, butenyl, aryl groups such as phenyl, tolyl, xylyl, mesityl, naphthyl, methylnaphthyl, methylamino, ethylamino, isopropylamino, Mono or shea p such as butylamino, dimethylamino, diethylamino, etc.
Kylamino group, arylamino group such as anilino, phtoluidino, xylidino, nagtylamino, aralkylamino group such as benzylamino, phenethylamino, diphenylmethylamino, tritylamino, methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy V , isopentyloxy,
Alkoxy groups such as neobenzifuroxy, phenoxy,
Aryloxy groups such as tolyloxy, xylyloxy, naphthoxy, aralkoxy groups such as benzyloxy, phenethyloxy, phenyl-lepropoxy, phenylbutoxy, diphenylmethoxy, methylthio, ethylthio, proylthio, isopropylthio, butylthio, isobutylthio, pentylthio, isopentylthio , alkylthio groups such as neopentylthio, arylthio groups such as phenylthio, tolylthio, xylylthio, naphthylthio,
7 such as benzifrethio, phenethylthio, phenylprohylthio, phenylbutylthio, diphenylmethylthio, etc.
Ralkylthio Y, alkannurphonamides such as propanesulfonamides, pionamides, butyramides, isobutyramides, etc. 7
N-alkylcarbamoyl groups such as μcanamide group, carbamoyltylcarbamoyl, N-methylcarbamoyl, N-propylcarbazoylpamoyl, N-butylcarbamoy/7,N-isobutyμcarbamoyl, carbazole, N-methylcarbazoyl, N - N-alkylcarbazoyl groups such as ethylcarbazoyl, N-propylcarbazoyl, and N-isoproylcarbazoyl ρ, 7-rukoxyimino groups such as methoxyimino, ethoxyimino, and propoxyimino, hydroxy groups, hydroxyimino groups,
Examples include a carboxy group, a nitro group, a halogen, a 7-)v group, a cyano group, a mercapto group, an amino group, an imino group, or a group formed by combining these substituents. The arene moiety may be substituted with a suitable substituent (such substituents include, for example, amino, retamono- or dialkylaminodroxy, carboxy, nitro, halogen, sulfo, cyano, etc. as exemplified above). Among such substituents, amino, imino, hydroxy (including hydroxy added to hydroxy and imino) mercapto and carboxy groups may be protected with suitable protecting groups, such as the following. Amino and imino protecting groups include, for example, substituted or unsubstituted alkoxycarbonylthyloxy such as methoxycarbonylponipropoxycarbonylμ, butoxycarbonylcarbonylcarbonyl, bromoethoxycarbonylbromoethoxycarbonylcarbonyl, etc. Carbonylnylmobenzyloxycarbonyl, methoxypenzyloxycarbonyl, dinitrobenzyloxycarbonylyl-substituted alkanoyl ρ group, benzylmethyl, trityl, bromobenzyl, substituted or unsubstituted araμkyl group such as nitrobenzyl, phenylthio, nitro Substituted or unsubstituted arylthio groups such as phenylthio and dinitrophenylthio, ethylidene, impropylidene, 2
-Methoxyfulponide μm1-methylethyldene (or its tautomer 2-methoxyfulponylidene μm1-
Specific examples thereof include substituted or unsubstituted alkylidene groups such as methvinyl), substituted or unsubstituted aralkylidene groups such as benzylidene and salicylidene, and examples of hydroxyl groups and mercapto protecting groups include the amino and imino protecting groups mentioned above. Substituted or unsubstituted acetyl, colopionyl, butyryl, isobutyryl, valeryl, bromoacetyl, dichloroacetyl, trifluoroacetyl-benzoyl, toluoylnitrobenzoyl, bromobenzoyl, salicylyl, etc. Substituted aroyl group, aroylmethyl such as phenacyl. Examples of carboxy-protecting groups include ester μ containing a silyl ester heterocycle;
As a specific example, examples of esters in derivatives of carboxine groups can be cited.

Typical examples of the acyl defined above include bromoacetyl, dichloroacetyl, cricoloyl, glycyl-1pheniρ-glycoloyl, phenylglycy, 2-hydroxyimino-2-phenylacetyl,
2-hydroxyimino-2-(4-hydroxyimino/
L/) acetyl, 4-hydroxyphenylcrisi&,N-・(2,2.2-
trichloroethoxycarbonyl)-2-phenylglycy A/, N-penzyloxycarbony/l/-2-bira, nylglycy ρ, 3+5-dinitrobenzoyl, azidoacetyl, 6-amino-6-phenylpropionyl, 2
-bromo2...phenylacetyl, amethoxyacetyl #, -2 - (2-・〃minor2-poxyethoxy)acetyl, methylthioacetyl,
2-(2-amino-2-carboxyethylthio)acetyl, phenoxyacetyl, naphthoxyacetyl, phenylthioacetyl, methoxybenzoyl, 4-methoxyphenylglyoxyloyl-hydroxyphenylglyoxyloyl, 5+methipisooxazo-p carlebonyl, 2-hydroxyimino-2-(4,,methoxyphenyl)acetylv, 2-Cb-mesylaminophenyl/I/)crisyl, cyanoacetyy12-(2-amino-4-thiazolyl)acetyρ, 2... (2-Imino・
-4-thiazoline-4...i/V) acetyl, 2-hydroxyimino 2-(, +-(3-tertiary-butoxycarbonylamino-phenylthioacetyl, 2-hydroxyimino-2...
:4-(5.phthalimido-6-medoxycarponylpropoxy...tertiary-butoxycarbonylamino-6-methoxycarbonylproboxy)phenylglyoxyloyl, 4-
(3-7thalimido-6-methoxycarbonylfurboxy) phenylglyoxyloyl, 2-benzoyloxyimino-2-(4-(6-tert-butoxycarbonylamino 3-methoxycarpo diμpropoxy) phenyl/l
') 7 ceti/l', 4-(3-(4-methoxybenzyloxycarbonyfv)・3-S-class poxycarponylaminoproboxy] phenylglyoxyloyl, 2-(
3-(6-amino-5-carboxypropoxy)pheniμ]-2-hydroxyiminoacetyl/l/, 3-(3
-amino-6-carpoxyproboxy)phenylglyoxyloyl and the like.

A more preferred example of the acyl defined above is phthalimide or an acyl represented by the following formula.

a (wherein, Ra is a hydrogen atom or an alkoxy which may be substituted with an amino group and/or a carboxy group)
is a hydrogen atom or an amino group, Ro is a hydrogen atom, or R and Ro together represent oxo or hydroxyimino, R is aryloxydialkyl, heterocyclic substituted 7ρyl, substituted or unsubstituted aryl, aralkoxy and Re respectively mean alkyl ρ, and amino, hydroxyimino and ρ boxy may be protected with a suitable protecting group, such as the above-mentioned amino, hydroxy and carboxy protecting groups. Here, examples of alkoxy in Ra include methoxy, ethoxy, propoxy, impropoxy, butoxy, isobutoxy, secondary butoxy, pentyloxy,
The aryloxyalkyl in R is, for example, phenoxymethyl, phenoxyethyl, and the heterocyclic alkyl substituted in tolyloxymethyl, such as isopentyloxy, and the heterocyclic group in the heterocyclic substituted aliphatic acyl is Examples of the alkyl moiety include methyl, ethyl, propyl, isopropyl, butyl, pentyl, and hexyl. Further, as the alkyl in Re, examples of the alkyl moiety of the aryloxyalkyl in R 1 above can be cited as they are.

The alkanes, plains, and heterocycles in the preferred acyl represented by the above formula may have a suitable substituent at any position, and such substituents include the specific substituents mentioned for the acyl above. I can just give you an example.

b) Aralkylamino group; Specific examples of aralkylamino include benzyl, diphenylmethy! ,
Trityl, phenethyl, phenylproyl, phenylbutylmethybenzyl, 4-methylphenethyl, naphthylmethyl may have one or more suitable substituents, such as the above-mentioned acylamino Specific examples of the substituents exemplified for the acyl group can be listed as they are.

C) dialkylamino-substituted methyleneamino group; Specific examples of the dialkylamino moiety in the dialkylamino-substituted methyleneamino group include dimethylamino,
NIN-dialkylamino groups such as diethylamino, dipropylamino, diisopropylamino, digtylamino, cyhexylamino, N-ethyl...1-methylamino, ethyleneamino, trimethyleneamino, tetramethyleneamino, pentamethyleneamino, hexamethylene Examples include polymethylene amino groups such as amino, heptamethylene amino, and octamethylene amino.

d) Aralkylidene amino group; Examples of the aralkylidene moiety in the aralkylidene amino group include benzylidene, tolylmethylene, xylylmethylene, naphthylmethylene, etc., and one such group may be present at any position thereof. It may have the above-mentioned suitable substituents, and examples of such substituents include the specific examples of the substituents exemplified for the acylamino acyl.

2, 7 syl amino group c, 1, R2, bow and RQ]
Concerning: As specific examples of the acyl moiety in the acylamino group, the examples of the acyl moiety in the acylamino group mentioned in Section 1 a) above can be cited as they are.

6. Regarding substituted hydroxy groups [R1 and R1']:
Each of these groups will be explained in detail below.

a) Alkoxy group Examples of the alkyl moiety in the alkoxy group include methyl, ethyl, propyl, isopropyl, butyρ,
Butyl, isobutyl μ, secondary butyl/L/, hentyl,
Examples include inpentyl, neopentyl, and hexyl.

b) Aralkoxy Group Specific examples of the aralkyl moiety in the aralkoxy group include the examples of the aryl moiety of the awalkylamino group described in item 1 b) above.

G) Aryloxy group Specific examples of the aryl moiety in the aryloxy group include phenyl, tolyl, xylyl, naphthyl, etc. These groups have one or more suitable substituents at any position. Examples of such substituents include the specific examples of the substituents exemplified for the acyl moiety of the acylamino group described in Section 1 &) above.

d) Acyloxy group As specific examples of the acyl moiety in the acyloxy group, examples of the acyl moiety in the acylamino group mentioned in section 1 &) above can be cited as they are.

4, halogen (RI R”, R-containing, R2 and R,
): Here, specific examples of halogen include fluor, chlor-1-brome, and iodine.

5. Regarding the protected amino group [RI￥]: Preferred examples of the amino protecting group in the protected amino group include, for example, alkoxycarbonyl, cyanopropylene,
1 aflukoxycarponyl, dialkylphosphoryl,
Aroyl, aralkylamino, etc., and specific examples of such groups include the specific examples of the acyl moiety of the acylamino group exemplified in Section 1 a) Ic above, where x3 has the same meaning as above, and Such groups include 2,4,5-)lioxooxazolidin-3-yl and 6,5-dioxo-1,2,4-oxadiazo.

(In the group, R has the same meaning as above).

6 dialkylamino-substituted methyleneamino group [Sia l in the dialkylamino-substituted methyleneamino group with respect to R′3
As a specific example of the rekylamino moiety, for example, the specific example of the sialylekylamino moiety of the dialkylamino-substituted methylene amino group mentioned in Section 1 C) above can be cited as is.

2 Regarding the aralkylideneamino group (R); Specific examples of the aralkylidene 917 moiety in the aralkylideneamino group include, for example, the specific examples in the aralkylidene moiety of the aralkylideneamino group described in Section 1 d) above. can be given as is.

8, aralkylamino group [R1], afurkoxyiminomethymo group [R2] and aralkyymuthio group (:R21
Afuruki p moiety in, as well as Aral 4 4'
4 4 11 Kyl group (R,
Regarding Rb, Ro, R4 and R]; Specific examples of the aryl moiety and afpkyl group in the above groups include, for example, the aralkyl p-amino group described in item 1 b) above. A specific example in the Rekiru section can be given as is.

9 Protected amino group, protected hydroxy group and protected carboxy m(R: and R4) Respective V and force in protected amino group, protected hydroxy group and protected p boxy group ! Specific examples of protecting groups for levoxy can be listed directly.

10, Aryl group [R% RIL% Rb''% R11
% 8% R and R] and arylthio group (Re
1R and R] and the aryl moiety in the arylthioalkyl group [R and R6]; Specific examples of the av-/l/ group and the aryl moiety in the above groups include, for example, Feniμ, tolyl.

Examples include xylyl, mesiti, naphthyl, etc., and such groups may have one or more suitable substituents at any position thereof. Examples of such substituents include the above-mentioned Specific examples of the substituents in the ash moiety mentioned in Section 1 &) can be given as they are, and furthermore, N-phenypglyoxyloylmethylamino, N-phenylglyoxy
N-arylglyoxyloyl amide, N-tolylglyoxyloyl propane sulfonamide, roy l remedy p amino, etc.! Lecanulphonamide 1 &, '・-(henmeamide acetate/I/) medi/I/7 mino, N-(phthalimide acetyl acetyl) etanne l lefonamide, N-(phthalimide acetyl) Provence/lefonamide, N −()
N- such as ptreimidopropioni/l/) mesylamino
(Alloy p-aminoacanoyl/I/) alkanesulfonamide middle ethoxy, pencypropoxy, and N-substituted alkanesulfonamides.

11, 7ralkenyl: Here, specific examples of the aralkeniμ group include styryl, cinnamyl, tolylvinyl, xylylvinyl, naphthylvinylμ, etc., and the arene moiety of such a group has 1 at any position. It may have one or more suitable substituents, and examples of such substituents include the first
Specific examples of the substituents in the aVlv moiety described in section &) can be listed as they are.

12. Regarding the residues of nucleophilic compounds (R, , R,, Rb and R2): The residues of the above nucleophilic compounds are halogen, disubstituted amino,
Residues of nitrogen-nucleophilic compounds such as azide, residues of oxygen-nucleophilic compounds such as 7μ koxy, aryloxy, aralkoxy, alkylthio, arylthio, aralkylthio,
Examples include residues of sulfur-nucleophilic compounds such as heterocyclic thio, and the ary-ρ and heterocyclic groups of such groups have one or more suitable substituents at any position thereof. Examples of such substituents include the above-mentioned item 1 &)
Specific examples of the substituents in the acyl moiety mentioned above can be listed as they are.

Here, the above-mentioned di-substituted amino group includes, for example, dimethylamino, N-ethyl-N-methylamino, N-methifle-N-propylamino, dipropylamino, N-ethyl-N-propylamino, diisopropylamino, dipropylamino. cyalyl-reamino group such as amino, N-methylanilino, N-ethyl-leanilino, N-propylanilino, N-impropylanilino, N-methyltoluidinolydino, N-propyltoluidinooxylidino , N-ethylxylidino, N-methifurene N-naphthylamino, N-ethyl-N-naphthylamino, N-propyl-N-naphthylamino, etc.; ethylamino, N-benzyl-N-10 bireamino, N
-diphenylmethyl- N-diphenylmethy/l/-N-ethyl p-amino, etc.
Afurkyl-N-alkyl-reamino groups, etc. are included.

Further, as specific examples of the halogen in the above group, the specific examples of the halogen described in the above section 4 can be cited as they are.

Further, as specific examples of the alkyl moiety in 7ruk≠#d and 7/L/kylthio, the specific examples of the alkyl moiety of the alkoxy group described in Section 6 a) above can be cited as they are.

Further, as specific examples of the aralkyl moiety of aralkoxy and aralkylthio, the specific examples of the aralkylamino moiety described in item 1 b) above can be cited as they are.

Further, as specific examples of the 7lyl moiety of aryloxy and arylthio, the specific examples of the aryl moiety in the aryloxy group mentioned in Section 6) above can be cited as they are.

As the heterocycle of the heterocycle thio group, for example, the above-mentioned item 1 a)
Specific examples of the heterocycle in the heterocyclic acyl mentioned above can be given as they are.

13, heterocyclic group (R4 and heart) and heterocyclic thio group CRe':J and heterocyclic thioalkyl group CR6
, R6, R6, R7, R7 and R]: Specific examples of the heterocycle in the above group include, for example, the specific examples of the heterocycle in the heterocyclic acyl described in item 1 a) above. I can give it to you.

14, alkyl group (Rb1R, R11L, Rb, R
,, R and R13) and alkylthio group [R],
Regarding alkyl moieties in aarylthioalkyl [R and Rb] and heterocyclic tyro 677 oa to kyl groups [R, R, R, R, R and R7]: Specific examples of fulky μ in the above groups include, for example: Methyl, ethyl, propylene), isopropyl, butyl,
Isobutyl, secondary butyl, pentyl, isopentyl,
Neopentyl, hexyl v'4, etc. may be mentioned, and such groups may have one or more suitable substituents at any position thereof, such substituents include, for example, the first
Specific examples of the substituents in the acyl moiety mentioned in section a) can be listed as they are.

1s, N-(i2-substituted or unsubstituted alkanesulfonamide-bearing phenyl (R4 and toge))
Regarding substituted or unsubstituted alkanesulfonamide moieties: N-substituted alkanes in the above groups 7. Specific examples of sulfonamides include those of the to-substituted alkanes p-phonamides in the substituent of the 7-aryl group in Item 10 above, and specific examples of unsubstituted alkanes p-phonamides include, for example, the above-mentioned The specific examples of the american sulfonamide exemplified as the substituent in the acyl described in Section 1 a) can be cited as they are.

16, phenyl with 70yl alkoxy, (R4
Regarding the aroyl alkoxy moiety in Rb:I: Specific examples of the aroyl alkoxy in the above group include the specific examples of the aroyl alkoxy in the aryl substituent described in Section 10 above. .

17 Regarding carboxyl group derivatives (R5 and R5): Examples of carboxyl group derivatives include acid amides, esters, nitriles, etc. Specific examples of these derivatives include the following. It will be done.

a) Acid amide: N-unsubstituted amide, N-methyl amide,
N-alkylamides such as N-ethylamide, N,N-dimethylamide, N,N-diethylamide, N-ethyl-
N,N-dialkylamides such as N-methylamide, N-
In addition to acid amides such as phenylamide, acid amides with pyrazole, imidazole, 4-flukylimidazole, etc. can be mentioned.

b) Esters: Examples of esters include silyl esters, aliphatic esters, esters containing aromatic rings or heterocycles, and esters with N-hydroxy compounds. Examples of the silyl ester include trimethylsilyl and triethylsilyl.

Aliphatic esters include saturated or unsaturated, cyclic or acyclic (including linear and branched) aliphatic esters, typical examples of which include methyl ester, aryl ester, propyl ester, and isopropyl. Ester, butyl ester, +m alkyl ester such as butyl ester, octyl ester, nonyl ester, undecyl ester, vinyl ester, 1
- Alkenyl esters such as propenyl ester, allyl ester, and 6-butenyl ester; alkynyl esters such as 6-butenyl ester and 4-pentynyl ester;
Examples include nocycloalkyl esters such as cyclopentyl ester, cyclohexyl ester, and cyclopeptyl ester.

Examples of esters containing an aromatic ring include aryl esters such as phenyl ester, tolyl ester, xylyl ester, naphthyl ester, indanyl ester, and dihydroanthryl ester, heptadralyl esters such as pendyl ester and phenethyl ester, and phenoxymethyl ester. , phenoxyethyl ester, phenoxypropyl) aryloxyalkyl ester such as V ester,
Arylthioalkyl esters such as phenylthiomethyl ester, phenylthioethyl ester, phenylthiopropyl ester, aroylalkyl esters such as benzenesulfinylmethyl ester, benzenesulfinyl ethyl ester, alkyl ester, phenacyl ester, toluoyl ethyl ester, etc. can give.

Examples of esters containing heterocycles include saturated or unsaturated, monocyclic or condensed, 6- to 10-membered heterocycles containing 1 to 4 heteroatoms such as oxygen, sulfur, and nitrogen atoms. Examples of such esters include pyridyl esters, piperidyl esters, and piperidyl esters.
) V esters, 2-pyridon-1-yl esters, tetrahydropyranyl esters, quinolyl esters, pyrazolyl esters and other heterocyclic esters, and heterocyclic alkyl substituted with the above-mentioned heterocycles (e.g. methyl,
ethyl, propyl, etc.) esters.

Examples of the N-hydroxy compound in the ester with the N-hydroxy compound include N,N-dimethylhydroxylamine, N,N-diethylhydroxylamine,
N,N-dialkylhydroxylamines such as N,N-dialkylhydroxylamines, propanal oxime,
Examples include aldoximes or ketoximes such as putanam oxime and acetone oxime, and N-hydroquinimide compounds such as N-hydroxyphthalimide and N-hydroxyphthalimide.

Ester moieties such as silyl esters, aliphatic esters, esters containing aromatic rings or heterocycles, and esters with N-hydroxy compounds may have one or more suitable substituents at any position. Examples of such substituents include methyl, ethyl, propyl, isopropyl, butyl, alkyl such as 5M butyl, cycloalkyl such as cycloproyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 5M butoxy, etc.
alkoxy such as acetoxy, propionyloxy, pivaloyloxy, alkylthio such as methylthio, ethylthio, propylthio, alkanesulfinyl such as methanesulfinyl, ethannurfinyl, propanenulfinyl, alkanoyl phosphor such as mesyl, ethannulfonyl, etc. nil, phenylazo,
Examples include halogens such as chloro, bromine, and iodo, and substituents such as cyano and nitro.

Specific examples of esters having the above substituents include chloromethyl ester, bromoethyl ester, dichloromethyl ester, 2. 2-1-
Mono such as trifluoroethyl ester, cyanoalkyl ester such as trihaloalkyl ester, cyanomethyl ester, cyanoethyl ester, 4-chlorophenyl ester, 6,5-dibromophenyl ester, 2.

4, 5-)lichlorophenylester)v, 2,
4. Mono, di, tri, and tetra such as 6-trichlorophenyl ester and pentachlorophenyl ester; Schiff also refers to cycloalkyl-substituted purkyl esters such as pentaherophenyl ester and 1-cyclopropylethyl ester.
etc. can be mentioned.

18 Regarding the ester in the esterified carboxy group [Rb,]t: Examples of the ester in the above group include the 17th
Specific examples of esters in the carboxy group derivatives mentioned above can be cited.

19. Regarding haloalkyl groups (R6, 吋, R 已, R7, R and Rb): Here, specific examples of haloalkyl groups include chloromethyl, bromomethyl, iodomethyl, 1-bromoethyl, 1-bromopropyl, 1- Examples include chlorogutyl, 1-iodoethyl, 1-bromohexyl, and the like.

20 Inorganic or organic cation C M ]f? :PA
LX: Specific examples of inorganic or organic cations include metal cations (e.g., alkali metal cations such as sodium cations and potassium cations, alkaline earth metal cations such as calcium cations and magnesium cations, etc.), and inorganic cations such as ammonium ions. , methylammonium ion, trimethylammonium ion, trimethylammonium ion, dicyclohexylammonium ion, hyridinium ion, 2-hydroxyethylammonium ion, bis(2-hydroxyethyl)ammonium ion, N,N-dimethyl-N-
Examples include organic cations such as phenylammonium ion.

21 Regarding the dialkylamino group (R) 2 As specific examples of the above-mentioned dialkylamino group, specific examples of the dialkylamino moiety in the dialkylamino-substituted methyleneamino group described in Section 6 above can be cited as they are.

22.7 Regarding the aryl group [R9]: Specific examples of the aryl group mentioned above include the specific examples of the aryl group in the aralkylidene amino group t described in the above section 7.

23. Regarding the residue (R) of the sulfur-nucleophilic compound: Specific examples of the residue of the sulfur-nucleophilic compound include - Specific examples of residues of nucleophilic compounds can be listed.

The starting materials of this invention include known and novel compounds, and these compounds can be produced, for example, by the following methods.

(a) Manufacturing method of starting material @) in process 1:
It can be produced by reacting formaldehyde with the amino acid represented by

R-NH2+HCHO-+CCH2=N-R)n (in the formula, R and n have the same meanings as above) The raw material amino acid (R-Nl2) contains a new compound, and the new compound can be prepared by, for example, a conventional method. It can be produced by amino acid synthesis method. The amino acid represented by the formula R-Nl2 can be used in the form of a salt with an acid or a base, and examples of the salt with an acid include inorganic acids such as hydrochloride and hydrobromide. Examples include salts with organic acids such as salts of salts, p-toluenesulfonates, p-toluenesulfonates, etc. Salts with bases include sodium salts, potassium salts, calcium salts, magnesium salts, etc. Examples include salts with inorganic bases, salts with organic bases such as trimethylamine salts, dicyclohexylamine salts, pyridine salts, picoline salts, lutidine salts, ethanolamine salts, and morpholine salts. This reaction is usually carried out in a solvent, and water, methanol, ethanol, diethyl ether, etc. are frequently used, but other general organic solvents that do not have an adverse effect on this reaction can also be used.

Further, the reaction temperature is not particularly limited, but it is usually carried out under cooling or heating conditions in many cases.

(b) Method for producing the starting material in process 2:
An example of the production of this starting material acquisition) is as follows.

C6H3CHCOOH N= CH-3CH5 (C1 Manufacturing method of starting material (XI[I) in Process 11: Of this starting material (X[[l), compound (XIIIA
) and (x[l]B) are shown below.

(XI[lA) (XIIIB) (d) The following is an example of the production of the starting material in process 17 (Mayo production method: this starting material 0).

Publication) Next, each process of the method for producing the azetidinone compound of the present invention described above will be described in detail.

(1'') This process is carried out by treating the compound (011) with a 2-substituted acetic acid (Ill or a reactive derivative thereof) in the presence of a mono-Lewis acid and a base.

The 2-substituted acetic acid (Il) used in this process
Typical examples of reactive derivatives of l include acid anhydrides,
Examples include esters, acid halides, acid amides, azides, etc., and specific examples thereof are shown below.

■ Acid anhydrides Nidialkyl phosphoric acid, monoaryl or diaryl phosphoric acid, dialkyl phosphoric acid, halophosphoric acid, dialkyl phosphorous acid, sulfuric acid, alkyl subacid, aliphatic carboxylic acid,
Mixed acid anhydrides or symmetrical acid anhydrides with aromatic carboxylic acids, etc. are mentioned, and preferable examples of these acid anhydrides include diethyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, ethyl subacid, 5th-class acid anhydrides, etc. Examples include mixed acid anhydrides with buty-IV hypoacid, trichloroethyl/I/hypoacid, pivalic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, and the like.

■ Esthetics: Usually active amides are used as esters.
Such active esters include, for example, cyanomethyl esters, methoxymethyl esters, etc., allyl esters having substituents, allyl esters, and other fulkenyl esters, and propalyl esters. alkynylester such as 4-nitrophenyl ester, 2,4-cynitrophenyl ester, pentachlorophenyl ester, trimethyl silyl ester, dimethyl-methoxysilyl ester, etc. In addition to silyl ester p such as ν, acetoxime, N-hydroxyphthalimide, N-hydroxyphthalimide, 1-hydroxy-6-riol IH
Examples include combinations with N-hydroxy compounds such as -benzotriacyl and the like.

(2) Acid amide: Active amides are commonly used as acid amides, and examples of such active amides include amides with pyrazole, imidazole, 4-methylreimidazole, and the like.

■ Acid halide: Examples include acid chloride and acid bromide.

Lewis acids used in this process include metal halides or nonmetals, and preferred examples of such Lewis acids include boron trifluoride, boron trichloride, and tribromine. Trihalogenated boron such as halogen, trihalogenated boron and ether/L/ (e.g., diethyl ether, etc.), after-recording/L/ (e.g., methanol-p, etc.), carboxylic acid (e.g., Coordination compounds with solvents such as acetic acid, etc., aluminum halides such as aluminum chloride and aluminum bromide, zinc halides such as zinc chloride, tin halides such as tin chloride, and L halides such as iron chloride. Examples include titanium halides such as titanium, silicon tetrahalides such as silicon tetrachloride, and antimony halides such as antimony chloride.Among these Lewis acids, boron trifluoride diethyl etherate is effective in this reaction. It is most suitable for

In addition, examples of the base used in this reaction include trialkylamine (e.g., trimethifleamine, triethylamine, tributifleamine, etc.), NlN-sial
lekylaniline (e.g., N,N-dimethylaniline,
N,N-diethylaniline, etc.), N,N-dialkylbendi p-amines (e.g. L"+N-dimethylbendi-Ileamine, etc.), N-substituted or unsubstituted heterocyclic compounds (e.g. ILlN-methylmorpholine, N-methyl piperidine,
Pyridine, dimethylaminopyridine, picoline, lutidine, quinoline, 1,5-diazabicyclo(4,3,0)
-5-nonene, 1,4-diazavinchlo[:2,2.2
) octane, 1,8-diazabicyclo (5,4,0:1
Examples include organic bases such as -8-undecene.

This reaction is usually carried out under mild conditions such as cooling or room temperature. In addition, this reaction is usually carried out in a solvent, and dichloromethane, chloroform, carbon tetrachloride, diethyl ether, dioxane, pyridine, dimethylformamide, or a mixed solvent thereof is often used, but other solvents that do not adversely affect this reaction General organic solvents can also be used, and if the Lewis acid and base are liquids, they can also be used as a solvent.

In this reaction, during the reaction or during the post-treatment of the reaction, for example, (1) if the carboxy group in compound (1') or 0II) is converted to its derivative, and if the derivative of the force I levoxy group is converted to the free force I levoxy group; In the case, the amino group, monosubstituted amino group, alkane I lephonamide group, mercapto group and hydroxy group in R of @compound@) are acylated by compound (Ill),
When converting to the corresponding acyfuramino group, N-[substituted acylleaamino group, N-azila Ilecannulphonamido group, acylthio group, and acylfleoxy group, the amino group in R3' tr- of compound @) is hydrochloric acid, When forming a salt with an inorganic acid such as hydrobromic acid, or an organic acid such as dilic acid, acetic acid, thuma/cyanoic acid, maleic acid, or P-toluene-nulphonic acid, ■ R1 of compound (III) or CI'') The protecting groups on the amino, imino, hydroxy, mercapto, and carboxy groups in ' and R5 are removed, resulting in free amino, imino, hydroxy, hydroxyimino,
Side reactions such as conversion to mercapto and levoxy groups may occur, but such cases are also included within the scope of this process.

The compound (1'') produced by this process may be produced as a mixture of two stereoisomers due to the asymmetric carbon at the 6-position of the azetidine nucleus. Each can be divided.

(2) Process 2e: This process is carried out by reacting compound EV) with 2-substituted acetic acid ω) or a reactive derivative thereof.

As a representative example of the reactive derivative on the 2-substituted acetic acid side used in this process, the same examples as those of the 2-substituted acetic acid described in Process 1 can be cited.

This reaction is carried out in a conventional manner, for example, the reaction conditions are cooling to room temperature, and the solvent is usually ethyl acetate, dichloromethane, chloroform,
Carbon tetrachloride, benzene, dimethylformamide, water and the like are often used, but other common organic solvents that do not adversely affect this reaction can also be used. Further, this reaction is usually preferably carried out in the presence of a base, and such a base includes, for example, the above-mentioned process.

Specific examples of the bases mentioned in 1 are listed, but further examples include inorganic bases such as sodium carbonate, potassium carbonate, magnesium carbonate, carbonate/recium, calcium hydrogen carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. .

This reaction may be carried out in the presence of a Lewis acid, and examples of such a leimeic acid include the specific examples of the Lewis acid described in Process 1 above.

(5) Regarding process B: (Vl (1') This process is carried out by reducing the and group of compound (V).

The starting material (V) in this process can be produced, for example, by a process such as process 1.27 above.

The reduction method in this process is, for example, a conventional method such as chemical reduction or catalytic reduction.

Examples of reducing agents used in the chemical reduction include metals such as tin, zinc, and iron, or metal compounds such as chromium chloride and chromium acetate, and hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid, propionic acid, and trifluorochloride. Examples include combinations with inorganic or organic acids such as acetic acid, P-)/renine sulfonic acid, and the like. In addition, examples of catalysts used for catalytic reduction include:
Platinum plate, platinum sponge, platinum black, platinum colloid, platinum oxide, platinum catalyst such as platinum wire, palladium sponge, palladium black, palladium oxide,
Palladium catalysts such as palladium on carbon, palladium colloid, palladium barium sulfate, palladium barium carbonate, reduced nickel, nickel oxide, Raney nickel, etc. (7
) = Sokel contact L Cobalt catalysts such as reduced cobalt and Raney cobalt, iron catalysts such as reduced iron and Raney iron, and copper catalysts such as reduced copper and Ullmann copper.

Chemical reduction is usually carried out in a solvent, such as water, methanol, ethanol, probanol, or a mixed solvent of these solvents and other general organic solvents. In some cases, it can also be used as a solvent. Catalytic reduction is also usually carried out in a solvent, and specific examples include diethyl ether, dioxane, tetofhydrofuran, and mixed solvents thereof in addition to the solvents mentioned in the above chemical reduction.

This reaction is usually carried out under mild conditions such as cooling or heating.

In this process, a protected amino, protected hydroxy, protected carboxy or ester/carboxylated carboxyl group in the compound tel is converted into the corresponding free amine, hydroquine or It may be converted to carboxy, and such cases are also included in this process.

The target substance of this process, 6-aminoazetidinone compound (I6), includes new and known compounds, and contains various antibacterial compounds, such as 2-[:, S-[2-(4-
(3-amino-6-carboxypropoxy)phenyl)
-2-Hydroxyiminoacetamide]-2-oxo-
1-azetidinyl]-2~(4-hydroxyphenyl)
acetic acid or 2-(3-(2-(4-(3-amino-6-
carboxypropoquine) phenyl)-2-hydroxyiminoacetamide]-2-oxo-1-azetidinyl)
It is useful as a synthetic intermediate for producing -2-(2-f-enyl)acetic acid and the like.

This process is carried out by subjecting the compound to an elimination reaction of its amino protecting group.

Methods for removing the amino protecting group used in this process include hydrolysis, reduction, and the use of an iminohalogenating agent and then an iminoetherifying agent, followed by hydrolysis if necessary. This will be explained in detail next.

(1) Hydrolysis: Here, hydrolysis refers to solvolysis such as hydrolysis, acidolysis, alunyl decomposition, amine decomposition, and hydrazine decomposition.

Hydrolysis is usually carried out in the presence of an acid or base,
Examples of such acids include inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid; organic acids such as sulfuric acid, acetic acid, trifluoroμ acetic acid, propionic acid, benzene sulfonic acid, and P-)/renin sulfonic acid; Acidic ion exchange resins can also be used. Examples of bases include alkali metal or alkaline earth metal hydroxides, carbonates, or hydrogen carbonates (e.g., sodium hydroxide, potassium carbonate, sodium hydrogen carbonate, calcium hydroxide, magnenium hydroxide, etc.), hydroxide Inorganic bases such as ammonium, afrecoxides or phenoxides of alkali metals or alkaline earth metals (e.g. sodium methoxide, sodium ethoxide, lithium phenoxide, etc.) mono-, di- or trialkylamines methylamine, ethylamine, propylamine , isopropylamine, butylamine, N,N-dimethyl-1.
3-propanediamine, triethylamine, triethylamine, etc.), unsubstituted or mono (or di) substituted arylamines (e.g., aniline, N-methylaniline, N,N-dimethylaniline, etc.), heterocyclic compounds (e.g., Examples include organic salts such as pyrrolidine, morpholine, N-methylmorpholine, N,N-dimethylpiperazine, pyridine, etc.) hydrazines (eg, hydrazine, methylpiperidine, ethylhydrazine, etc.), as well as basic ion exchange resins.

The reaction temperature for this hydrolysis is usually carried out under mild conditions such as cooling or heating. This reaction is usually carried out in a solvent such as water, methanol, ethanol,
Propertool, dimethylformamide, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc. are often used, but when the acid or base exemplified above is liquid, it can also be used as a solvent.

@Reduction: Here, the reduction reaction is carried out by conventional methods such as chemical ring reduction and catalytic reduction. The reaction conditions can also be listed as they are.

In this method, when the amino protecting group in R of the compound (■) is an organic carboxamide, the carboxamide bond is is more easily cleaved and removal of the amino protecting group is more likely to occur.

The first step (iminohalogenation) and the second step (iminoetherification) of this process are carried out at relatively low temperatures in an anhydrous solvent, for example, an aprotic solvent such as dichloromethane, chloroform, diethyl ether, dioxane, etc. solvents are often used.

It is preferred that the reactions of the first, second and fifth stages (hydrolysis) of this process are carried out in one system without isolation.

Examples of iminohalogenating agents in this method include:
Examples include phosphorus compounds such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, and phosphorus oxychloride, thionyl chloride, and honugen.

Examples of the iminoether I converting agent in this method include alkanols such as methanol, ethanol, fupanol, isopropanol, butanol, and tertiary butanol, alkoxy-substituted alkanols such as methoxyethanol and ethoxyethanol, methanethiol, and ethane. Examples include alkanethiols such as thiols, and alkali or alkaline earth metal salts of the above-mentioned alkals and alkanethiols (eg, sodium methoxide, potassium ethoxide, magnesium ethoxide, lithium methoxide, potassium methanethiolate, etc.).

Compounds obtained by the action of iminohalogenating agents and iminoetherifying agents are hydrolyzed by conventional methods as necessary, but the hydrolysis is usually carried out under cooling or at room temperature; Alternatively, the reaction proceeds simply by adding a mixture of water and a hydrophilic solvent such as methanol or ethanol, but an acid or base as described in 0 above may be added as necessary.

In this method, when the amino protecting group in H of the compound (W) is a group such as phthalimide, the protection/elimination of the group does not proceed completely and a phthalamic acid or phthalamide type intermediate may be produced. However, in such cases, compound CI) can be obtained by further reaction.

Also, during the reaction or post-treatment of the reaction, certain substituents on R of the compound (V or IcI) (e.g.
N-substituted or unsubstituted alkanemephonamide, p-pamoyl, protected hydroxy, protected p-boxy, protected amino, etc.) respectively correspond to the corresponding alkanemelphonamide, amino, hydroxy or force! It may be converted to levoxy, etc., and such cases are also included in this process.

(5) Regarding Process 5: This process is carried out by allowing the compound (■) to act with an acylating agent.

In this reaction, 3-amino-2 used as a starting material
- The amino group in the azetidinone compound (■) may be activated, and examples of such activated amino groups include incyanate, inthiocyanate,
Schiff's base, salts with acids such as hydrochloric acid, hydrobromic acid, etc., silyl compounds such as trimethylsilyl chloride, phosphorus compounds such as phosphorus oxychloride, and groups formed by the reaction of amino groups with conventional amino groups, etc. Reactive derivatives can be mentioned.

The acylating agent used in this reaction is an organic acid such as organic carboxylic acid, organic carbonic acid, organic carbamic acid, organic sulfonic acid, or organic phosphoric acid, and the acyl moiety of the organic acid is The acyl moieties mentioned in paragraph 1 a) may be mentioned as such, and such acyl moieties may consist of aliphatic, aromatic, aromatic-substituted aliphatic, heterocyclic and heterocyclic-substituted aliphatic acyls. be.

Organic acids as acylating agents as mentioned above are usually converted into their reactive derivatives, such as 2-substituted acetic acid (as described in Process 1 above).
Specific examples of the reactive derivatives in step n) can be cited as they are; in such cases, it is usually preferable to carry out the reaction in the presence of a base, and such bases include the bases mentioned in Process 1 and Process 2 above. I can give you a concrete example.

When a free organic acid is used as an acylating agent, it is preferable to carry out the reaction in the presence of a condensing agent, such as N,N'-dicyclohexylcarbodiimide, N-cyclohexylcarbodiimide, and N-cyclohexylcarbodiimide. N'-Phorphorinoethylcarbodiimide, N-cyclohequine N'-(
4-diethylaminocyclohexyl)carbodiimide,
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3-
dimethylaminopropyl) carbodiimide, N, N
'-Carbonylbis(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylene #17 f 7-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, poly Ethyl phosphate, impropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(3-sulfonate) phenyl)inoxacillium hydroxide, (chloromethylene)
Dimethylammonium chloride, 2,2,4,4,6.
6-hexachloro-1,3,5,2,4,6-) riazatriphosphine, triphenylphosphine and carbon tetrahalides such as carbon tetrachloride and carbon tetrabromide, or halogens such as chlorine, bromine, and iodine. Examples include condensing agents in combination with

This reaction is usually carried out in a solvent, and water, acetone, dichloromethane, chloroform, methylpolamide, etc. are often used, but other general organic solvents that do not have a negative effect on this reaction can also be used, and in addition, as mentioned above, Liquid bases and condensing agents can also be used as solvents.

During the reaction or post-treatment of the reaction in this process,
For example, cases in which the amine, monosubstituted amino, hydroxy, and mercapto groups in compound (■) are acylated with an acylating agent are also included in this process.

(6) Regarding process 6: (V+u) (
This process gives the compound (■) the formula R'-CHO(
In the formula, RQ has the same meaning as above) or a reactive derivative thereof.

Herein, R15 and RI6 in the formyl group of the formyl compound each mean an alkyl group). (eg, dichloride, dibromide, etc.).

This reaction is preferably carried out in a conventional manner, for example, in the presence of a condensing agent as mentioned in Process 5 above, as well as a Lewis acid such as phosgene, thionyl chloride, phosphorus oxychloride, or phosphorous bromide.

(7) Regarding process 7I: This process is carried out by subjecting compound (IX) to an oxidative cleavage reaction of the carbon-carbon double bond of the aralkenyl group substituted at the 4-position.

This oxidation reaction is carried out by a conventional method, for example, using a permanganate such as potassium permanganate, a metal oxide such as chromium dioxide or osmium tetroxide, or an oxidizing agent such as dinitrogen dioxide, hydrogen peroxide, or K-syn. It can be done in the presence of

(X,) ” (do) This process consists of compound (X) + ζ formula R”0-Nu, (,
This is carried out by reacting a compound having an amino group represented by (in E, R11 has the same meaning as above) by a conventional method.

A compound having the above amino group (the amino group in R0-NHρ is, for example, an inorganic acid such as hydrochloric acid or sulfuric acid, an acidic acid, acetic acid,
It may be converted into a salt with an organic acid such as P-toluenesulfonic acid, and when such a compound is used,
Alkaline It is preferable to carry out the reaction under the following conditions.

(9) Regarding process 9: This process is carried out by subjecting the compound (x1) having a formyl group to a reduction reaction of the formyl group by a conventional method.

Examples of the reducing agent used in this reduction reaction include metal borohydrides such as sodium borohydride and lithium borohydride.

(10) Regarding Process 10: (Xll) (1-0) This process is carried out by subjecting the formyl group-containing compound ω) to an oxidation reaction of the formyl group to a carboxy group using conventional method I.

Examples of oxidizing agents used in this oxidation reaction include:
Permanganates such as potassium permanganate, chromium dioxide, nitric acid, hydrogen peroxide, organic peracids, or their salts (
Examples include perbenzoic acid, m-chloroperbenzoic acid, peracetic acid, or their sodium or potassium salts, and metal oxides such as silver oxide.

(11) Regarding Process 11: (Xll+) (L'') This process is carried out by subjecting the compound (x1) or a reactive derivative of the compound at the carboxy group to an intramolecular ring-closing reaction by a conventional method.

The reactive derivative at the carboxy group of compound (xi) is the 2-substituted acetic acid (n
) can be directly cited as examples of variants of reactive derivatives.

This reaction is preferably carried out in the presence of a condensing agent and a base, and examples of such condensing agents and bases include the bases mentioned in Processes 1 and 2 above and the condensation agents mentioned in Process 5 above. Specific examples of the agent can be cited as they are, and further include acetic anhydride, Grignard reagents such as ethylmagnesium bromide and phenylmagnesium bromide, and trialkyl metals such as triisobutylaluminum.

(12) Problem with process 121: (XIV) ””) This process is a process that allows amino acids in compound (XIV) to be
This is carried out by subjecting it to an elimination reaction of hydroxy and carboxy protecting groups.

This protective group is removed by conventional methods such as hydrolysis, reduction, and methods using metal salts such as metal halides, metal mercaptides, metal cyanides, and metal thiocyanates. , reaction conditions (e.g., reaction solvent, reaction temperature, etc.) can be the same as those described for each of the corresponding methods described in Processes 3 and 4 above.

Through this reaction, the protected amino group, protected hydroxy group, and protected carboxy group in the acylamino group represented by R1 of compound □□□) are converted to -
ζ Converts to the corresponding free amino group or hydroxyl group.

(13) Regarding process 13: This process is carried out by subjecting compound (XV) to an elimination reaction of the carboxy-retaining group.

In this process, the method for eliminating carboxy-retained wiii& is carried out by conventional methods such as hydrolysis, reduction, and methods using metal salts such as metal halides, metal mercaptides, metal cyanides, and metal thiocyanates. The reaction reagents, reaction conditions (for example, reaction solvent, reaction temperature, etc.) in lζ can be the same as those described in the corresponding methods described in Menu Processes 3 and 4.

(14) Regarding process 14: This process is carried out by subjecting compound (xvl) to one elimination reaction of amino, hydroxy and carboxy protecting groups.

The method for removing the retention group in this process 1 is carried out, for example, by conventional methods such as hydrolysis and reduction, and the reaction reagents, reaction conditions P+ (e.g. reaction solvent, reaction temperature, etc.) in such methods are , the corresponding methods mentioned above in Processes 3 and 4'1g - the explanations in which can be cited directly, and in such a method, the protected amino group on the aralkyl in .R: of compound (XVI), The protective groups on the protected hydroxy group and the protected carboxy group are removed and converted into the corresponding free amino group, hydroxy group, and carboxy group.

(15) Regarding Process 15: (XVII) (115) This process is carried out by halogenating the compound (candle) by a conventional method.

Examples of the halogenating agent used here include halogens such as chloro, bromine, and iodo; inorganic halogen compounds such as phosphorus pentachloride, thionyl chloride, and cupric chloride;
Haloamide (e.g., N-bromoacetamide, N-iodoacetamide, etc.), N-haloimide (e.g., N-
chlorohydantoin, N--j romosuccinimide, N
-chlorophthalimide, etc.), organic halogen compounds such as pyridinium promide/perpromide, dioxane/promide, hypohalous acid or its alkyl ester such as hypochlorous acid, tertiary butyl hypochlorous acid ester, benzenesulfenyl Examples include sulfenyl halides such as chloride and quinoline-2-sulfenyl chloride.

(16) Regarding process 16: (11 (,T j6) The process of B always adds a nucleophilic compound represented by -H (in the formula, the same meaning as above) to the compound (■"). According to the method, the reaction is carried out in one step.

The nucleophilic compound represented by the formula R-H is a nitrogen-nucleophilic compound such as hydronitridic acid, an amine, an aliphatic or aromatic substituted aliphatic or aromatic hydroxy compound (e.g., an alkanol, an alkanol, a phenol, etc.). ), aliphatic, aromatic substituted aliphatic, aromatic or heterocyclic thiol compounds (e.g. alkanethiols,
arenethiol, aralkanethiol, heterocyclic thiol, etc.); Examples of compounds include:

The above-mentioned nucleophilic compounds may be used in the form of salts of metals such as alkali metals and alkaline earth metals, and examples of such alkali metals and alkaline earth metals include sodium, Examples include potassium, magnesium, and calcium. Further, hydronitride acid is often used in the form of a salt with an alkali metal such as sodium.

(17) Regarding process 171ζ: This process is carried out by halogenating compound (XW) by a conventional method.

Examples of the halogenating agent used here include halogens such as ha, chloro, bromo, and iodo; N-haloacetamides (e.g., N-bromoacetamide, etc.);
- haloimide (e.g. N-chlorohydantoin, N-
promosuccinimide, N-bromophthalimide, etc.),
Examples include N-heroamides such as N-halohydantoin (eg, N-chlorohydantoin, N-bromohydantoin, etc.).

This halogenation reaction is carried out by a conventional method, preferably under ultraviolet irradiation or in the presence of a catalytic amount of a radical reaction initiator.

Examples of the radical reaction initiator include peroxides such as benzyl peroxide, m-chloroperbenzoic acid, and tertiary butyl hydroperoxide, azobis(imbutyronitrile), α,α′-azoinbutane, etc. An acid methyl ester type azo compound or the above peroxide (e.g. tertiary
Examples include combinations of cobalt or copper salts of organic carboxylic acids (butyl hydroperoxide) and organic carboxylic acids.

(18) Regarding process 18: (11're
(Step 1) This process is carried out by allowing a polycyclic thiol to act on the halogenated compound (117).

The heterocyclic thiol used herein is represented by the formula R''-8H (wherein R17 means a heterocyclic group), and the heterocyclic group defined by RI7 is the first
Specific examples of the heterocyclic group in the heterocyclic acyl mentioned in the acyl moiety in item a) can be cited as they are.

This process is a reaction in which the haloalkyl group defined by Rg and/or R of the starting material (I'') reacts with the above-mentioned heterocyclic thiol to form a heterocyclic thioalkyl.

This reaction is carried out by a conventional method, and for example, it is preferable to carry out this reaction in the presence of a base. Examples of such a base include the specific examples of the bases mentioned in Processes 1 and 2 above. can.

(19) Regarding process 19: This process is carried out by halogenating compound (XIX) and subsequently subjecting it to a dehydrohalogenation reaction.

In this process, the compound (XIX) is first halogenated to obtain a compound represented by the primary formula 1.

(QC)H (wherein, R1 and R8 have the same meanings as above, and X4
(means a halogen base such as chlor or brome) Examples of the halogenating agent used in the halogenation reaction include halogens such as chlor and brome, sulfuryl halides such as sulfuryl chloride, and N-bromoacetamide. N/% loimides such as N-haloamide, N-promosuccinimide, N-bromophthalimide, N-chloro-
IH-benzotriazole, 1.3.5-)lichloro2.4.6-)lioxoperhydrotriazine, etc.
-Hao heterocyclic compounds, complex compounds of halo compounds and halogens such as tuunily iodochloride and pyridinium iodopromide, and metal halides such as second chloride,
Other conventional halogenating agents capable of halogenating the carbon atom adjacent to the sulfur atom can be used.

The target compound (I) is obtained by dehydrohalogenating the compound thus produced, but this dehydrohalogenation reaction is carried out by a conventional method. For example, good results are usually obtained when carried out in the presence of a base. There are many things. Here, as specific examples of the base, for example, the specific examples of the base in the hydrolysis described in Process 4 can be cited as they are.

(20) About Process 20: This process is a process that uses 3-halo 2-azetidinone compounds (X
X) This can be carried out by the action of hydronitridic acid or its salts.

The hydronitridic acid salts used in this process include:
Examples include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, and the like.

(21) Regarding process 21: This process is carried out by reacting compound (XXI) with hydroxylamine or a salt thereof.

The salts of hydroxylamine used in this process include, for example, salts with inorganic acids such as hydrochloric acid and sulfuric acid, and salts with organic acids such as acetic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.

This reaction is usually carried out in the presence of a base, and specific examples of such bases include those mentioned in Processes 1 and 2 above.

This reaction is usually carried out in a solvent, and water, methanol, ethanol, propatool, dimethylformamide, or a mixed solvent thereof is often used, but other general organic solvents that do not adversely affect this reaction can also be used.

This reaction is often carried out under mild conditions ranging from room temperature to elevated temperatures.

The desired target products obtained in the above processes 1 to 21 are isolated and purified by conventional methods, and the compounds obtained in each process can also be used as they are as starting materials for the next process without being isolated and purified.

The azetidinone compound (I) of the present invention has antibacterial activity and is useful as a medicine, and is also useful as a synthetic intermediate for producing other antibacterial substances. That is, among azetidinone compounds (I), for example, 3-acylamino-2-azetidinone compounds exhibit antibacterial activity as shown in the following table and are useful as pharmaceuticals. The -2-azetidinone compound is useful as a synthetic intermediate for producing the above-mentioned 3-acylamino-2-azetidinone compound.

Here, the antibacterial activity (minimum inhibitory concentration) of representative examples of the azetidinone compound (1) of the present invention is shown below.

Test method: One platinum loopful of the slant of the test bacteria is inoculated into a medium-sized test tube containing 5-bouillon, and cultured overnight at 30°C. The cultured bacteria 196 were grown on Mueller-Hinton medium (agar 1
In addition to 96), dispense into 10 8a diameter petri dishes. 10 u/m of the target substance obtained by this invention shown below
Dissolve in water, 2% sodium bicarbonate aqueous solution, or methanol to compensate. This was tested by applying it to pulp with an order of 8 major diameters, and it was determined that the minimum concentration indicating inhibition was obtained.
, 1. C.

(minimum inhibitory concentration).

M, 1. C.

Compound of Example 91: 0.0 against Escherichia coli.
25r, 4r against Pseudomonas aeruginosa
t Compound of Example 108: 0 against Escherichia coli
．． 5 r.

Compound of implementation flJ 114: 3.75 against Staphylococcus aureus? , 15r against Pseudomonas aeruginosa, 15r against Escherichia coli, 15r against Bacillus zupulitis.

Compound of Example 115: 60r against Staphylococcus aureus.

Next, the present invention will be explained with reference to examples.

Preparation of a new raw material: Production Example 1 1,8.5-)Lis(1)-1-methoxycarbonyl-1-(2-chenyl)methylsieperhydro-1,8
, 5-triazine H-forming diD-2-(2-fenyl)glycine methyl ester hydrochloride 25. Og was dissolved in 130 ml of water, and 250 ml of benzene was added dropwise to the water bath liquid. To this mixed solution, 120ml of a normal hydroxide bath solution was added dropwise under ice-cooling, and then 91nl of a 37% thiformaldehyde aqueous solution was added dropwise. added. The mixture was then stirred for 2 hours at the same temperature. The benzene layer was separated from the reaction solution, and the remaining nine aqueous layer was extracted with ethyl acetate. This extract was combined with the previously separated Be/Zenli#, washed with water, and dried over magnesium sulfate. The fibrillation was removed under reduced pressure, and the residue was crystallized with diisopropyl ether to give 1°8.5-tris(D-1-methoxycarbonyl-1-(2-chenyl)methylsieperhydro-1,8).
16.5 g of 5-triazine was obtained.

Infrared absorption spectrum (hereinafter referred to as engineering R) νam
(Nushor) N MRt & yield spectrum (hereinafter referred to as MMR) (internal standard: tetramethylsilane, hereinafter referred to as TMS) δypm (oDo13) 8b9C9H%B), 8.78 (6H, B) April 9 (3
H, a), 6mepe, 43 (9n, m) The following compound was produced by reacting the corresponding amine derivative with formaldehyde in substantially the same manner as in Production Example 1.

Production Example 2 1.8.5-tris(D-a-methoxycarbonyl-3
-Mesylaminobenzyl)-perhydro-1゜8.5-
triazine.

Engineering R νcm (film) 3550 (broad), 3240.173ONMR (T
MS, ) 4, t) H24(2H1m) 4, Li
2 (l H* d s J==2 Hz)5.18
(l H-s ) 4.56 (I
H* d* J=2 Hz)'1. J O (5B #
8) 5-' 4 (111*a
)7.30(5H,θ) Example 33 2-[3-amino-4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-1-7zetidinyl]-2 -Methyl phenylacetate [mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νam' (Film) 32B0,1770.1640 Example 34 2-[3-amino-4-(5-methy?l, 8.4-thiadiazol-2-ylthio)-2-oxo-1-azetidinylcou2 -Methyl phenylacetate [a mixture of two cis isomers at the 3rd and 4th positions of the azetidine ring].

Engineering R νam' (film) 3350.1765.1740 Actual htB example 35 2-(3-amino-4-methylthio-2-ox7-1-
benzyl azetidinyl)-2-phenylacetate [a mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νam' (film) 340ON3300, 1770.174o, 16sO Example 36゛2-(3-a-deno-2-oxo-1-azetidinyl)-
2-(2-chenyl)acetic acid.

Engineering R νam' (nujol) 2750-2250.1760 (waste), 1745.1h
20 Example 37 2-(3-amino-2-oxo-1-azetidinyl)-
2-(2-furyl)acetic acid.

Engineering R δppm (CD013) 8.08 (3H, a), 8fll (5H, broad e)
14j3 (IH, a).

? -0-17.6(4H-m)S7.71(lHe Broad 8) Production Example 3 1.8.5-) Lis(af-1-methoxycarbonyl-
1-(1-naphthyl]methyl]-noζ-hydro-1,8
, 5-1 riazine, now 14J4~151”c.

Production Example 4 1.8.5-)lis(af-1-methoxycarbonyl-
2-phenylthioethyl)-no-hydro-1,8゜5
-Triazine O NMR (7M8) δppm (cna13) LL()-an(15H,m), &68(9H*a),
7.1”'7.5 (15H*m) Production Example 5 1.8.5-tris(4-benzyloxy-a-methoxycarbonylphenethyl)-perhydro-1°8,5-
Triazine, 106-109°C.

Production Example 6 1.8.5-tris(af-erythro α-methoxycarbonyl-β-methoxyphenethyl-perhydro-1
,8,5-triazi/.

Production Example 7 1,8.5-tris(af-1-(2-furyl)-1-
Medo dicarbonylmethyl]-perhydro-1゜8.5
−) riazine.

wytx (7M8) δppm (aDex,) 8shi18B (12Ht m) e 4. ? 4 (
3H*s) *628 (6H*m) S7
．． 32(3H,m) Production Example 8 t,a,s-tris(methoxycarbonylmethyl)-perhydro-1,8,5-triazine.

R νam (film) 174 t1755 NMR (7M8) δTlT1! +1 (0DO13) 8.48 (6H, s), 8.73 (15H, sr) Production Example 9 1.8.5-1Js(ethoxycarbonylmethyl)-perhydro-1,8,5-1 riazine.

Engineering R νam' (Film) 173 To175 O NMR (TMS) δ'p'pm (CD015) 1 no 5 (9HttsJ=6Hz) S8.45 (6H+5
)S873(6H+a)+4.17(6H,q,J=f
iHz) Production Example 10 1.8.5-1 Lis(benzyloxycarbonylmethyl)-perhydro-1,8,5-triazine.

Engineering R νam (Film) 74O NMR (TMS) δT)T)m (OD 013) 8.44 (6H, s) S81 (6Hss) s5JO (6
H,s) +7.40 (15Hes) Production Example 11 1.8.5-Tris(D-a-methoxycarbonylbenzyl)-perhydro-1,8,5-)riazine, 1
48-155°C.

Engineering R νcm' (Nujol) 7JO NMR (TMEI) δppm (CD015) 149 (9H, a), 8.51 (fiHI8), 4,5
0(lH,5)S7.42 information 0 (15Hs m) Production example 12 1,8.5-tris(D-4-benzyloxy-α-methoxycarbonylbenzyl)-perhydro-1,8,5
-) Riazine, i.e. 141N 145°C.

Engineering R νam' (nujol) NMR (TME3) δppm (0DO15) 3.58j15H1s)v4jO(3'H*θ), 6ρ
4(6a,e), sat.

(6H, a, J=9Hz), 7.29 (6a, a, J=
9az), 7.4((15a,s) Production Example 13 1.8.5-)Lis(D-4-benzyl-o-dicarbonyloxy-a-methoxycarbonylbenzyl)-barhydro 1.8.5-1 riazine .

Engineering R νcm' (film) 174f), 171O NMR (Tus) δppm (aDe13) 850 (15H, θ), 4.42 (3H, B), 523
(6H, s), 6ri9 (6H, a, J=9az), 7.
:<3(6a,a,J=9az),7.27(11,s
), Production Example 14 1.8.5-) Lis(dJ-2-methoxycarbonyl-
1-Phenylethyl)-Bircht rcoi, a, s
- Triazine, mp 91-96°C.

Engineering R νCm (Nushor) 7J5 Production Example 15 1.8.5- ) IJs(4-methoxycarbonylphenyl)-barbitro-1,8,5-1 riazine, m'
p208-209.5°C (decomposed).

Production Example 16 1.3.5-Us(D-α-benzyloxybenzylbenzyl)-perhydro-1,8,5-) IJ azine, mpH 8-19°C.

Engineering R νcm (Nushor) 1730.1740 (Shoulder) NMR (TMS) δppm (CDCj15) 8EI7 (6H, +3), 4A2 (3Hes), 4ri!
) (June, θ), 6.95-7.45 (301!, m) a pickling example 17 1.8.5-11Js (D-α-methoxycarbonyl-
3-nitrobenzyl)-perhydro-1,B,5-triazine.

Engineering R νam' (liquid film) 74O NMR (TMEI) δppm (a:ocx3) 8B5 (15H,) b-dos), 4fi5 (3H, a)
, 7.4 sea 82 (12H+m).

Production Example 18 1,(,5-tris(D-α-benzyloxycarbonyl-4-benzyloxybenzyl)-perhydro-1
,8,5-t'/7di/, mp108~110°C.

Engineering R νam' (nujol) 1745.1735.172O NMR (TM13) δppm (cDc13) 155 (6a, s), 4.47 (3a, a) 4ri2 (1
2H, s) 6.76 (6H, d,, r=8Hz), 7.
0pe44 (36H, m) Production Example 19 1.8.5-tris(4-zenatyloxy-α-zenatyloxycarbonylbenzyl)-perhydro-1,
8,5-) Production of riazine: N-tertiary butoxycarbonyl-2-(4-hydroxyphenyl)glycine 9.1
A solution of 8 g of phenacylbromide, 6.86 g of phenacylbromide, and 137 g of sodium hydroxide dissolved in 100 d of N,N-dimethylformamide was stirred at room temperature for 4 hours. Pour the reaction mixture into 500 ml of water and add 50 ml each of ethyl acetate.
1? Extracted three times using i-. Combine the extracts and wash with water.
Dry with magnesium sulfate. Evaporate the solvent under reduced pressure;
Oily N-14 tertiary butoxycarbonyl-2-(4-hydroxyphenyl)glycine zenatyl ester18.
19g was obtained.

Process R 1'Cm' (film) 3400 (protono, 1750.171t), 1690 obtained above (8.56g of compound, 1.84g of fenatelbromide)
and 1.28 g of potassium carbonate each in dry acetone 71 g.
The bath solution dissolved in m/m was heated to reflux for 7 hours. Filtering off insoluble materials from the reaction mixture, 1. Solution M was evaporated to dryness under reduced pressure, and the resulting residue was dissolved in chloroform. The chloroform solution was washed with water and dried over magnesium sulfate. Chloroform was distilled off under reduced pressure to obtain a residue. Diinpropyl ether was added to the residue to obtain 4.12 g of crystals of N-13fi butoxycarbonyl-2-(4-zenatyloxyphenyl) chrysine fecatyl ester. When crystal is recrystallized with ethanol, mp l 25-126℃
A pure product was obtained.

Compound 1gf obtained above: dissolved in ethyl acetate,
2 ml of a mixture of hydrobromic acid and acetic acid (4:1 by volume) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Precipitated crystal t? When washed with ethyl acetate, 830 ml of 2-(4-7 enathyloxyphenyl)glycine zenatyl ester hydrobromide was recovered. When crystals are recrystallized from a mixture of ethanol, methanol and diethyl ether, country 17
When 0.55 g of a pure product with a temperature of 6 to 177°C was obtained, 9.5 g of the thus obtained chemical &wJ was reacted with 6 Tnl of a 37-ton formaldehyde water bath solution in substantially the same manner as in Production Example 1, resulting in 1 , 8.5-1 lis(4-7 enathyloxy-α-7 enathyloxycarponylbenzyl)-perhydro-1,8,5-) riazine 7,25
G was asked. Immediately 80-90℃.

NMR (TMS) 6ppm (cDa13) 870 (6Hs s ) *4β5(3H,8),
5” 9 (6H, 8).

5.23 (6H, a), 6f16-8ρ4 (42H+m
).

Production Example 120 Production of D-2-(4-benzyloxyphenyl)-N-methylthiomethylene glycine benzyl ester; 8.9 g of triethylamine was dissolved in 10 dK of dry chloroform.
The dissolved solution was added to a solution of 20 g of D-2-(4-benzyloxyphenyl)glycine benzyl ester CD+p-toluenesulfone in 400 d of dry chloroform.
The mixture was added dropwise while stirring under water cooling.

mfli, in which 5.21 g of thioacid 〇-ethyl ester was introduced and dissolved in ψ chloroform solution d, was added dropwise to the mixture at the same temperature. The reaction mixture was then stirred at room temperature overnight, poured into 400ml of ice water, and insoluble materials were removed. The organic bath solution l- was washed with an aqueous phosphoric acid bath solution and water, and then dried over magnesium sulfate, and then the solvent was evaporated to dryness under reduced pressure. 1 g of the residue 1a-1 was developed on a chromatograph using 100 g of silica gel and eluted with benzene. When the fraction containing the target substance is sweetened and the solvent is completely distilled off under reduced pressure,
8.66 g of crystals of D-2-(4-benzyloxyphenyl)-N-thioformylglycine benzyl ester were obtained. When the crystal was recrystallized with benzene and n-hex 7f#la, a pure product with a mp l of 24 to 126°C was obtained.

D-2-(4-Benzyloxyphenyl)-N-thioformylglycine benzyl ester 8.56 g 1 A mixture of 0.63 g of potassium carbonate and 8.89 g of methyl iodide in 35 mf of dry acetone was mixed at room temperature for 23 hours. Stirred. The solid was removed and the electrolyte was evaporated to dryness under reduced pressure. The residue was dissolved in chloroform, washed with water, dried over magnesium sulfate, and further evaporated to dryness under reduced pressure to obtain a crystalline substance.

When diisopropyl ether is added to the crystal, crushed and separated, D-2-(4-benzyloxyphenyl)-N-1
8 g of methylthiomethyleneglycine benzylic ester 8D was obtained. Recrystallization with ethanol gave a pure product with a temperature of 78-80°C.

Engineering R νam' (Nujol) 1730.161O NMR (TMS) δ'p'pm (ODO'15) 236 (3H, 8) 15. UO(2H, θ), 5D8(
IH, θ), 5.10(2H, s'), 6.
The following compounds (Production Examples 21 and 22) were produced by substantially the same method as in Production Example 20.

Production Example 21 D-2-(4-be/zyloxyphenyl)-N-methylthiomethyleneglycine methyl ester.

NMR (TMS) δppm (ODOI,) 2.41J (FH, s), 8J55 (3H, s) *5.
L)l(lH,s), 5D6(IH,s), 6J3-7
．． 53 (9HIm), 828 (lH, s) Production Example 22 D-N-methylthiomethylene-2-phenylglycine methyl ester.

NMR (7M8) δppm (0DO15) 236 (3Hte), 8i (3H, 8), 5.03 (I
H, 8) 7.25 (5Hss) s820 (1 also 8) Production example 23 Production of D-N-benzylidene-2-(4-hydroxyphenyl)glycine methyl ester: D-2-(4-hydroxyphenyl)glycine 16.8g of methyl ester and 6g of benzaldehyde in 2501nI of methanol!
The solution was heated under reflux for 1 hour. Methanol was distilled off under reduced pressure, and the residue was dissolved in benzene at 200 sdK.

When the precipitated crystals are collected and recrystallized with benzene, mp
l 21.0 g of DN-benzylidene-2-(4-hydroxyphenyl)glycine methyl ester at 28°C was added.

The following compounds (Production Examples 24 and 25) were produced by substantially the same method as Production Example 23.

Production example available - N-bendi IJ f no 2-phenylglycine methyl ester.

R SicI! l-1 (Nujol) 1740.1635 Production Example 25 D-N-cinnamylidene-2-phenylglycine methyl ester.

Engineering R νcm= (Film) 1740.1635 NMR (7M8) δ'p'pm (OD(13) 8ft6 (3H, a), 5n5 (IH, a), 6J3-
I, 08 (l H* m) s 7-I N, b O
(10Hs m ) * 8D5 (l H+ q ) Production of targeted proboscis: Example 1 480 mg of pyridine was dissolved in 2 me of dichloromethane, and 1.34 g'i of 2-phthalimide chloride was dissolved in 20 me of dichloromethane. , -35 to -30
The dropwise addition took 15 minutes at a temperature of °C.

On the other hand, 1,8.5-tris(D-1-(2-chenyl)-
1-Me)quincarbonylmethylcooperhydro-1,3
,5-) 550 tng of riazine and 430 my of a diethyl ether complex compound of borohydride trifluoride were added to 10 m of dichloromethane.
1', and this bath liquid was added dropwise to the previously obtained solution at a temperature of -60°C over a period of 15 minutes. The reaction mixture was stirred at the same temperature for 2 hours, and further stirred for 30 minutes under water cooling. The reaction mixture was evaporated to dryness under reduced pressure, and 30 me of ethyl acetate and 30 me of water were poured into the residue to remove insoluble materials. The ethyl acetate layer was separated from the σζ solution, and the remaining aqueous layer was extracted with ethyl acetate. The ethyl acetate layers were combined, washed three times with dilute hydrochloric acid, three times with aqueous sodium bicarbonate solution, and once with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was developed on a column chromatograph using 20 g of silica gel. Elution was performed with chloroform, and fractions containing the target substance were collected. Chloroform was distilled off from this concentrated solution under total reduced pressure, resulting in an oily D-2-(2
-oxo-3-phthalimido-1-acetidinyl)-2
720 ml of methyl -(2-f enyl)acetate were obtained (the crystal is a mixture of the two isomers at the 3-position of the azetidine ring).

When the compound thus obtained is recrystallized from ethanol,
One of the isomers of the compound was obtained in crystalline form (300
■). Cape 167-170°C0 In substantially the same manner as in Example 1, the following compound (Example 2 -15) were produced.

Example 2 Methyl D-2-(3-azido-2-oxo-1-azetidinyl)-2-phenylacetate [mixture of the isomer at the 3-position of the azetidine ring (al and (b) (mixture ratio 3:l) '
)).

Engineering R νam' (film) 2080, 1760, 1730° NMR (TMS) δppm (CDC13) Isomer (a); Isomer (b); 2.
93 (LH, q, J=2Hz, 6Hz) 326=8
76 (2H, m) 3.73 (3H, s )
8J30 (3H, s) 3.86 (LH, t, J=6
Hz) 4.50 (LH, q, J=2Hz, 5H
z) 4.63 (IH, q, J=2Hz, 6H2) 5
．． 60 (lH, 5) 556 (LH, s)
7.33 (5H, s) 7.28 (5H, θ) Example 3 dl-2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthiopropionic acid/thyl ester [azetidine Isomers (a) and f at the 3rd position of the ring
Mixture of b) (mixing ratio approx. 342): l.

Engineering R νam' (Nujol) 1785.1770, 1735.1715NMR (TM
S) δppm (CD'C13) Isomer (a): Isomer (b): 81
~B! 1 (4a+m) a,
x ~a9(4a+m)8.76(3H,a)
8.76 (3H, El) 4.64 (lH, d, d
, J=85,5Hz) 4.64(IH, d, d, J=
8s, 5Hz) 25JO (IH, d, d,, T=6.3
Hz) 5.40 (la, t, J=6az) 7, 30
(5H, m) 7.30 (5H+m) 7.7
0(4H+m) 7.70(4H,m) Example 4 dj'-2-(1-naphthyl)-2-(2-okino 3
-phthalimido-1-azetidinyl)methyl acetate, mp
200.5-201.5°C.

Engineering R νcm' (Nujol) 1724.1740, 1750.1782NMR (TM
S) δppm (CDC!13) 8U6 (la, a, a, J=6,3az), IBO (3
a, e), 8J39 (lH, t, J=6H2), 5.5
0(IH, cl, d, J=6,3Hz)16.45 (
IH,,8), 7.3-83 ('7H,m) Example 5 dl-erythro 3-methoxy-3-phenyl-2-(
Methyl 2-oquino-3-phthalimido-1-azetidinyl)propionate [mixture of two isomers (al and (b) (mixture ratio approximately 3:2)).

Isomers (a).

m9150~155℃ R νcm (Nushor) 1785 (Shoulder), 1760.1735j1715N
MR (TMS) δppm (cD(,13) 8.24(3H,s), 1j36(3H,e), 4.5
6 (iH, a, J=8az).

4.84 (IH, d, J=8H2), 5138 (IH,
d, d, J=d, f+H2).

7.37 (5HIs) + 7-b~7.8 (4
H1m) Isomer (b): NMR (TMS) δp, pm (CDO13') 3.36 (3H, s), 3.68 (3H, s), 4.7
[LH, d, J”6Hz).

4.95 (lH, d1J=6 Hz), 53
B (l H, d, d, J=6T4 Hz) +
7.40 (5H, s), 7.6~7.9<4H
, m) Example 6 Methyl dl-3-(4-benzyloxyphenyl)-2-oxo-3-phthalimido-1-azetidinyl)pro2ionate (mixture of two stereoisomers).

Engineering R νcm' (Nujol) 1780.1?60,1738.1705 Example 7 D-2-(3-azido-2-oxo-1-7zetidinyl)-2-(2-chenyl)acef-) ( Isomers at the 3-position of the azetidine ring (mixture of al and (bl (mixture ratio approximately 1:1)).

NMR (TMS) δppm (CDC13) Isomer (a); Isomer (b); 3"
7 (IH, d, d,, T=2.5.6Hz) 3.60
(2H,m)8flO(3H,s) 3
B2(3H,-8)C95(IH,t,J=6H2)
4.53 (LH, d, d, J=2.5.6H2)
4.70 (IH2d, d, J-25, 6H2) 5B7 (
IHLs)5B8(LH,s)
7.05 (2H, m) 7.05 (2H, m)
7.26 (LH, m) Fruit 2ii8i Shiori 8 D-2-(2-oxo-3-(2-oxo-4゜5-diphenyl-4-oxazolin-3-i/l/-1-7zetidinyl) -2-(2-chenyl)methyl acetate [mixture of isomer (a) and (bl) at the 3-position of the azetidine ring (
Mixing ratio 2:1)).

NMR (TMS) δppm (CDCl2) Isomer (al/ Isomer (b): 3.6
7 (la, d, a, y = 2.5.6Hz) 3.60 (
lH,t,y=6Hz)3.76(3H,S)
3BO(3H,s)3.84(IH,t,J=
6H2) 4.08 (LH, d, d, J=2
．． 5,6H2)4.92(lH,a,a,J=2.5,
6az) 4.80 (LH, a, a, J=2.5.6H
z)5g2(LH,s) 5.78(I
H, s) 6.88-7.62 (13H, m)
6.88-7.62 (13H, m) Example 9 D-2-(2-oxo-3-7thalimido-1-azetidinyl)-2-(4-7 enathyloxy/phenyl)zenatyl acetate [3 of the azetidine ring Isomer at position (a)
and (b) mixture wJ (mixing ratio 2:l)].

Engineering R νcm' (film) 1780 (shoulder), 1760.1720, 1700.1
680 (Shoulder) NMR (TMS) δppm (cDc13): Isomer (a); Isomer (b); 3
．． 43 (lH, d, d, J=3Hz, 5H2) 3.
55 (4H, t, J = 5Hz) 182 (IH, t, J =
5Hz) 4.06 (LH, d, d, J=3H
z, 51 (z) 5.30-5.54 (5H, m)
530-634 (5a, m) Example 1O dl-2-(2-furyl)-2-(2-oxo-3-phthalimido-1-azetidinyl) methyl acetate [two isomers (a) and (b) ) mixture (mixture ratio 41)], i.e. 1
76-178°C0 Engineering R νcm (nuzoyol) 1770, (shoulder), 1760.1730.1710 Example 11, -2-(3-azido-2-oxo-1-azetidinyl)-2-(4-benzyloxy phenyl) megahapendyl [isomers at the 3-position of the azetidine ring (al and (bl
mixture].

Engineering R νcm (Film) 2 1 00.1765.1735 NMR (TMS) δppm CODO13): Isomer (a); Isomer (b); 2
．． 94 (LH, d, d,, T = 2Hz, 5Hz)
3.35 (LH, t, J=5Hz) 37U (LH, t,
J=5Hz) , 3.56(IH, d, d, ,
T = 2Hz, -5Hz) 4.62 (LH, d, d, J =
2Hz, 5Hz) 4.46 (LH, d, d,, T=
2Hz, 5Hz) 5.03 (2H-s)
5.03 (2H, s) 5.18 (2n, s)
5 Yu 8 (2H, s) 5.61
(LH, s) 558 (LH, s)7.
09 (4H, AB-(1, J=8Hz) 7.09
(4H, AB-q, J=8H2) 7.127.56
(10H1m)' 7.127.56 (
10H+ m) Example 12 dl-2-(3-benzyloxy-2-oxo-1-fuzetidinyl)-2-benzyl phenylacetate [Mixture of two isomers (a) and (bl) (mixture ratio 5. 2)].

Engineering R νcm (Film) 1760.174O NMR (TMS) δppm ((!DC15): Isomer (a); Isomer (b); 3
．． 18 (L H+ d, a, J-4HZ, 5
Hz) 8.52 (L H, a, d+ X-4
Hz + 5 Hz) 4.02 (LH, a, a, J=
5Hz, 6Hz) 3.78 (lH, d, d, J=2
Hz, 4Hz) 5.17 (4H, s)
5''2 (LH,, d, d, J=2Hz, 6Hz)5.
27 (IH, d, d, J = 2Hz, 5Hz) 5 near (4a, s) 5.75 (IH, s)
5.72 (IH, 5) 6f! r-7,4(15H,m
) 6.8=7.4(15H+m) Example 13 D-2-(3-7dinoxy2-oxo-1=azetidinyl)-2-phenylacetate methyl [isomer (a) at the 3-position of the azetidine ring and (b) (mixing ratio of about 1:
1)).

Engineering R νcm' (Film) 1790.174O NMR (TMS) δppm (CDC13) Isomer (a); Isomer (b); 3
．． 15 (LH, d, d, J=2H2, 6Hz) 8.
52(lHld,d,,T=5H2゜3.70(3H,
s) 'B, 70C3H, 5)
528 (IH, d, d, J=2Hz, 5Hz) 5.
06(IH,4,d,',r=2Hz.

5.67 (IH, θ) 5.
63 (l H, '6'') 6.8~7.4 (IOH, m
) 6ru ~ 7.4 (10Hr m
) Example 14 Methyl D-2-(3-chloro-2-oxo-1-azetidinyl)-2-phenylacetate [Mixture of isomer (a) and (bl) at the 3-position of the azetidine ring [Mixing ratio approximately 1: '1
)].

Engineering R νcm (film) 1770 (broad), 174O NMR (Tns) δppm (CDC13) Isomer (a); Isomer (b); 3
U4 (lH, d, d, J=2H2, 6Hz) 3.
60 (IH, t, J=6Hz) 8.75 (3H, s)
8.78 (3H, s) 4.81 (IH
, d, d, J=2Hz, 5Hz) 4.77 (IH,
d, d,, T=2Hz, 6Hz5.64 (IH, s)
' 5.61 (LH, s) 6 Hz)
7.27.5 (5H+m) 7
．． 2-7.5 (5H+ m ) Example 15 Methyl ochine-1-azetidinyl)-2-phenylacetate [mixture of two isomers at position 3 of the azetidine ring].

R νcrn (film) 3450.1750, 1710.1270 Example 16 1.3.5-to1)(D-α-methoxycarbonyl-
3-Mesylaminobenzyl)-perhydro-1゜3.5
-) 2.53 g of riazine were reacted with 8.38 g of 2-7 thalimidoacetic acid chloride in substantially the same manner as in Example 1, and D-2-(3-(N-mesyl- 2-(phthalimido)acetamido)phenyl,)
= 2.2 g of methyl 2-(2-oxo-3-phthalimido-1-azetidinyl) acetate was administered.

Engineering R cm-1 (nujol) 1780 (shoulder), 1770, 1730.172ON
MR (TMS) δppm (CDCl2) 3.57 (3H, 8), 3.74 (IH, m), l, 8
5 (3H, 8) 14.03 (LH, t, y = 6Hz),
422 (2u, s).

5.54 (LH, a, d, J = 6Hz, 3Hz).

5! 33 (lH, e), 7.60 (12 Jm) Actual power top side 17 D-2-(4-benzyloxyphenyl)-N-methylthiomethyllene benzyl ester 2.67 g1
Soluble in methylene chloride. On the other hand, add 1.47 g of phthalimidoacetic acid chloride to 10 ml of methylene chloride.
This solution was added to the previously obtained bath solution at 0 to 5°C for 10 minutes with stirring. It took a while to drip. After stirring for an additional 15 minutes at the same temperature, a solution of 0.67 g' of triethylamine and lOme of methylene chloride was added dropwise to the mixture at room temperature, and stirring was continued for 40 minutes. the reaction mixture with water,
The mixture was washed with dilute hydrochloric acid, a sodium bicarbonate aqueous solution, and water in this order, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. 3.69 g of the residue was applied to a chromatograph using 110 g of 7-liquid gel and eluted with chloroform.

The eluted fractions were combined and evaporated to dryness to form an oily D-2-(4-
3.15ge of benzyloxyphenyl)-2-(4-,'tilthio-2-oxo-3-7thalimido-1-azetidinyl)acetate was obtained. The crystal is two 3.4-)
It was identified as an approximately 1:1.7 mixture of lance isomers (a) and (b).

Engineering R νcm (Film) 1780.1770, 1740.172°NMR (7M
8) δppm (ano13) isomer (a); isomer (day・210(
3H*s) 4.69 (l H* d-; f=23 Hz)
1J13 (3He s ) 6.01 (2H, s)
53)2(2H,5)5JO(IH,
d,,T=2.5Hz) 5j9(2H,5)5j
117(IH,s) 5AOCIH,
s) b-69-/1.52 (14H*m)
6# needle 4.52 (14Hs m) 7.5fy4
．． 94 (4H, m) 7.56-7.94 (4
H, m) The following compounds (Examples 18 to 29) were prepared by reacting the corresponding glycine derivative with 2-IJjt-converted acetic acid chloride in substantially the same manner as in Example 17.
t-manufactured.

Example 18 D-2-(4-benzyloxyphenyl)-2-(4-
Methylthio-2-oxo 3-7thalimido l-azetigel) acetic acid chloride [mixture of two trans isomers (al and (b) in the 3- and 4-positions of the azetidine ring (mixture ratio 2:l):).

Engineering R νam (Film) 1780.1770,174 (1,172ONMR(7
M8) δppm (0DO1,) Isomer (a); Isomer (b); 2.
14 (3Hsa) 187 (JHss) 1
79 (3H*s) August 1 (31i, 5)
t71(ia*a,>2jxg) 5ρ5(2Hs
s)5i)4 (2Hs s) 5:4
0 (2H+s)5-33(lHecLJ=15H
g) 6-86", 54 (9Hsm) 5.54 (
l Hs s ) 7.5 Toy, 96
(4H-m) 6J 4.54 (9H*m) 7.5 96 (4H*m) Example 19 2-(3-azido-4-methylthio-2-oxo-l-
azetidinyl)-2-yenyl methyl acetate [a mixture of two trans isomers (al and (b) at positions 3 and 4 of the azetidine ring)]. ' (7M8) δppm (oDo13) Isomer (-; Isomer +tl!; 1.7J
(JH, s) 14) 8 (JHss) 8.7
4 (3H9s) 8.74 (3B, s) 4.
54 (IH, d,, T = 2Hg) 4.38 (IH
ld, J=2Hg) 4.82 (IH@dwJ=2Hg)
4.5+(la, a, J=2Hz)5.40 (
l H* s ) 528 (l Ill
*s) 7.40 (5H*s) 7. JH
(5H*a) Example 20 2-(3-azido-4-methylthio-2-oxo-1-
7zetidinyl) -2-phenylacetate benzyl [two trans isomers at positions 3 and 4 of the azetidine ring (a
) and (b)].

Engineering R νam (Film) 2110.1780.174O NMR (7M8) δppm (ODOI, 5) Isomer (aJ; Isomer (4; 1.6)
7 (3B, a) 1riJ (31 (os) 4
．． 45 (l H-ds J=2 Htx)
4 no 3 (lHed+J=2Hg) 4J O(l H*
d e J engineering 2Hg) 4.48 (IH, d, J=
2ch) 526 (2H*s) 526 (2H
9s) 5.43(lH*s) 530(l
H,s) 7.30 (5H*ts) 7
-27 (b Hs s ) 7.35 (5! Ies) 7
．． 32(5H,s) Practice 91121 2-(3-azido-4-methylthio-2-ox, /-1
-azetidinyl)-2-(4-benzyloxyphenyl)acetidine methyl [a mixture of two trans isomers (a) and (bl) at the 3- and 4-positions of the azetidine ring].

Engineering R νam (Film) 2120.1775.1745 NMR (7M8) δppm C0D013 ”) Isomer (-; Isomer (Odor; 1.74 (3
Hss) 21)0(3H,s)8.76(
JH+s) 8.76 (3H*s) 4.49
(I Hs d * 2 Hz) 4; 3 b
(l H* d t to 2 H2)4J O(l H
*d, J=2 Hz) 4.49 (l He
d e I=lHts )5β4 (l H,s )
5JJ4 (2H,s)'524(lH,
s') 524 (IH, a) 6.9292-
156 (9Hs 6J〆-56 (9Hsm) Example 22 Methyl 2-(3-azido-2-oxo-4-phenyl-1-azetidinyl)-2-phenylacetate [mixture of stereoisomers].

Engineering R νcm' (film) 2100.177tl, 1740 Example 23 2-(3-benzyloxycargenylamino-2-J-
Methyl quin-4-phenyl-1-7zeticinyl)-2-phenylacetate [mixture of stereoisomers].

Engineering R νam' (film) ・332σ, '17? '0m1740,1720wM
R (TMS) δppm (OD013) 836.8.70 (3L each s), 4B6 (2aes) t
5.0 Nb 2 (2E[s m ), 652 (
l H* s ) *6.68-7.50 (15H, m
) Implementation 91124 2-(2-oxo-3-) King Tsukishi 4-Feni-1
-7zefdinyl)-2-phenylacetate methyl (mixture of stereoisomers).

Engineering R νam' (film) 1770.1740 Example 25 D-2-(3-azido-2-oxo-4-fuzeticinyl)-2-(4-human E12-1' diphenyl) methyl acetate [3 of azetidine ring A mixture of two cis isomers (a) and (4) in position and 4.

Isomer (-; m1) 138=142℃.

Engineering R νam' (onol,) 33L10.2120.17 (i5,1745NMR(
TMEI) 6719m (0DC13) +367 (3H, s), 494 (lH, dl, r=5H
z).

6.015(lHsd+, T=5Hz)s5J8(lH
ss) s6.56 (21Ld*P8Hz) s61 (
2H, a, J==8Hz)s7.12(5H,m) Isomer (cut; mp 67-71℃ Engineering R νam (01013) 3300.212υ, 1765.175ONMR(TM
8) dppm (ODO15) 3j30 (J Hs s) s 4.82 (I
H* d e I=b11z ) s4.90 (IH,
d#J=51g) $512 (lHss) e6.72 (2
a, 4. J=8Hz), 7.08(2H,d, J=8H
g) 17.36 (5H, a) Example 26 D-2-(4-) lance-styryl-2-okino 3-
Methyl phthalide l-azetidinyl]-2-phenylacetate [mixture of two cis isomers at the 3- and 4-positions of the azetidine ring], 144-145'Q R νam (nujol) 1770.174 (1 ( N), 1720 Confirmation Example 27 D-2-(3-azido-4-trans-styryl-2-
Methyl oxo-1-7zetidinyl]-2-phenylacetate [a mixture of two cis isomers at positions 3 and 4 VC of the azetidine ring].

Engineering R sham'''-1 (film) 2120.1780.1770,175υNMR (TM
, S) δppm (C!DO13) 8ji8. d, 75 (JH + each s) *4.12-4.9
4 (2H*m).

5.48.5730 (IH, 8 each) 16.1-6j52
(2H, m) 17.36 (5Hss) Example 28 In substantially the same manner as Example 17, diethyl ether of boron trifluoride K in the presence of the compound φ.

When the reaction is carried out, 2-(3-azido-2-oxo-4-
Methyl phenyl-1-7zeticinyl)-2-phenylacetate (10,000 of the two trans isomers) was obtained.

Engineering R νam' (Film) 2120.1770.174O NMR (TMS) δppm (ODO13) 8i (3a, s), 4.30 (IH, a,, r=2.5
nzL4.35 (IH, a,, r=2,5az), 52
2 (in, a)? 6.8 do, 55 (IOH, m) Example 29 2-[3-azido-4-(5-methyl-1,8,4°-
Methyl thiadiazol-2-ylthio)-2-oxo-1-azetidinyl)-2-phenylacetate (31 g of the azetidine ring and a mixture of the two trans isomers at position 2 at position 4), mp 81-84°C.

Example 30 8.4 g of D-2-(3-azido-2-oquino-1-azetidinyl)-2-,(2-chenyl)methyl acetate was added to dioxane 3411II! 1 palladium-carbon was added as a catalyst to this solution. The reaction mixture was subjected to a reduction reaction at room temperature for 3 hours under water and a stream of hydrogen gas using several pressures of the solvent. was removed, and the mother liquor was evaporated to dryness under reduced pressure to obtain 2.98 g of an oily residue.This was applied to a column chromatograph using 50 g of 7 L gel and eluted with chloroform.

The fractions containing the target substance were combined and the solvent was distilled off under reduced pressure, resulting in methyl D-2-(3-amino-2-oxo-1-fuzetidinyl')-2-(2-chenyl)acetate [azetidine mixture of two isomers at the 3-position of the ring) 2.60
g was obtained.

Engineering R νam (Film) 3390.1765.1740 When the corresponding compound* containing an azide group is reduced in substantially the same manner as in Example 30, the following compounds (Examples 31 to
45) was obtained.

Example 31 2-(3-amino-4-methylthio-2-oxo-1-
azetidinyl)-2-(4-pencilio#'/7:t,
methyl acetate [°mixture of the two trans isomers (a) and (b) at positions 3 and 4 of the azetidine ring].

Engineering R νam (film) 3400.1770.174O NMR (TMI δppm (cDc13) Isomer (a); Isomer (cut; 1.71 (
2H, s) 1.72 (3H, s) 2.01
(3H9s) 1flO(2H*a)
8.78 (3Hs e ) 8.78
(JHes) 4.03-4.28 (2H, m)
4.15 (IH, d, J = 2H2) 5.07 (
2H,s) 4.63(iH,a,J=
2Hz) 5:2J(lHI8) 6i)7
(2Hss)6.8 ()-7,b O(9H+ m
) 5J 7 (l He s ) 6.8()
-7,60(9H,m) Example 32 2-(3-amino-4-methylthio-2-oxo-1-
Methyl azetidinyl)-2-phenylacetate [a mixture of the two trans isomers (a) and fb) at positions 3 and 4 of the azetidine ring].

Engineering R νcm' (film) 3380.1770.174O NMR (TMS) δppm (0DO13) Isomer (a); Isomer (b); IJ5
(2H, s) 1.70 (3H, a) IJ8
(3Hes) 1Δ0(2H,θ)-8,7
0(3Hms)' 8.74(J
Ht s ) Simi m-1 (Nujol) 1725.1640 Example 38 2-(3-amino-2-oxo-1-azetidinyl-1
-(1-naphthyl)methyl acetate.

Engineering R νcm' (film) 3aso, 3ooo, (shoulder), 1740 ()゛load) Example 39 2-(3-amino-2-oxo-1-azetidinyl)-
Methyl 2-(a-mesylaminophenyl)acetate.

Engineering R νcm (Film) 3350 () pl ) *: < 15or (Broad), 1730 (Broad) Example 40 Erythro 2-(3-amino-2-oxo-1-acetidinyl)-3-methoxy-3- Methyl phenylpropionate.

Engineering R νcm (film) 3380.1750 Example 41 2-(3-amino-2-oquino-1-azetidinyl)-
3-7 Methyl dindylthiobrobionic acid.

Engineering R νcm' (film) 3380.33υ0 (shoulder), 1740 ()゛load)
Example 142 2-(3-amino-2-oxo-1-azetidinyl)-
Methyl 3-(phenylthio)acrylate.

Engineering R ShiC Go 1 (Film) 3: (80,3320 (shoulder), 1760.174t),
1720° implementation 43 2-(3-amino-2-oxo-1-azetidinyl)-
Methyl 3-(4-hydroxyphenyl)furopionate.

Engineering R Example 44 2-(3-amino-2-oxo-1-azetidinyl)-
Methyl 3-(4-benzyloxyphenyl)furopionate.

Engineering R νcm　’　　　(Nujol) 3300.1750, 1740, 172Ll.

Example 45 Methyl 2-(3-amino-4-trans-styryl-2-oxo-1-azetidinyl)-2-phenylacetate [mixture of two cis isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm' (film) 3350.177tl, 1740,1h60 Example 46 2-(2-oxo-3-phthalimido-1-azetidinyl)-2-(2-chenyl)acetic acid 2.22gfr, methanol 30me and chloroform 18meK In addition, N,N-dimethyl-1,3-propanediamine 13 was added to this mixture.
2 g was added and the mixture was then stirred at room temperature overnight. After the reaction, the reaction mixture '112I was dried to dryness under reduced pressure, and the residue was dissolved in ethyl acetate. Add this solution to 1N hydrochloric acid 6.4
Extract three times with an aqueous solution consisting of 1R1, and water 10-. The combined extracts were adjusted to pH 8 with sodium bicarbonate and saturated with sodium chloride. This solution was extracted with ethethyl, and the extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. This bath liquid was evaporated to dryness under reduced pressure,
1.57 g of the residue/li was developed on a column chromatograph using 25 g of silica gel. Elution is performed with chloroform, the fractions containing the target substance are combined, and the solvent is distilled off under reduced pressure to obtain 2-
(3-amino-2-oxo-1-azetidinyl-2-(
0.96 g of 2-chenyl)acetic acid CQ methyl was obtained.

Engineering R νcm (Film) 3390.1765.174O NMR, CTwa) Jppm (aD○13) 2.00. 2.09 (2H, each a), 2Je8,8,
1 (5 (iH, each d, dl, T = 1516Hg) @8j
53,8f16(IH, each tsJ=6nz)s&73(
3H, s) 4.05,512 (111!, each a, a,,
T==2,5 *6Hz).

5B3CIH, s), 6.75-7.55 (3H, m)
When N,N-dimethyl-1,3-propanediamine is reacted with the corresponding compound containing a 7-talimide group in substantially the same manner as Example 46, the following compounds (Examples 47-63) are obtained. It was done.

Example 47 2-(3-amino-2-oxo-1-azetidinyl)-
2-(2-chenyl)acetic acid.

Engineering R νam (nujol) 275 to 2250.1760 (shoulder), 1745, 16
20゜MMR [Internal standard: Sodium 2,2,8.3-tetradeuterium-3-(trimethylsilyl)teropionate, hereinafter simply T
MSF] δppm (D20) Li2,8.45 (IIl, each q t :r”2Hz
@5 Htl) *8j4,8H2(la, each t
, J=5H2) *4.21,4.31(lH*each q
@J==2HZ 65 HM) e5.54.5
．． 56 (IH, each a) 4.10 (2H, m) s7.46
(lH*m) Example 2-(3-amino-2-oxo-1-azetidinyl)-
2-(2-furyl)acetic acid.

Engineering R νam' (Nujol) 1725.164O NMR (7M8P) δppm (:o2o) 836 (IH4'1', 114; 1'; 2Hz, 6k
), 8jl[) (IH, 6, d, J=6Hvs
'I, 5Hz).

5A 1(l I(*s) + 6.49 (2H
em ) 7.37 (IH, m) Example 49 2-(3-amino-2-oquino-1-azetidinyl)
-2-(1-naphthyl)notyl acetate.

Engineering R νam (film) 8380.3000 (shoulder), 1740 (broad).

Nll (TMS) δppm (cno13) 1.70 (2II, a) t2.48,8,37 (IH,
each d* 6 s, r=3ngt6Eg)*8D2,8A
4 (IB, each (1, d.

J=3Hgs6Hr), J1191,4.21(iH,
Each (L, d.

1=3HMe6M5.8:14,8.75C3H, each s
).

6.43.6.44 CIH, each a) s u ~ μ (7
H*, m) Example 50 2-(3-amino-2-oxo-1-acetidinyl)-
Methyl 2-(3-mesylaminophenyl)acetate.

Engineering R νam' (film) 3350 (shoulder), 3150 (puto), x7; (o(
broad).

Example 51 Methyl erythro 2-(3-amino-2-oquino-1-azetidinyl)-3-methoxy-3-phenylpropionate.

R νam (film) 3380.1750°MMR (TM8) δppm (0DO15) 137 (2Ni + s) -823-8:32
(J H-each s), 8.71, 8.78 (3H9 each 8)
e4.65 (lLtLIJ=5HgL4months (l H
t a eJ=5Hz ) * 7.3 b (5Ht
s).

Example 52 2-(3-amino-2-oxo-1-azetidinyl)-
3-Phenylthiopropion m1fk.

Engineering R νcm= (film) 3380.3300 (scrap), 1740 (broad).

NMR (TMI δ1) 1) m (opol,) 298S43,16 (4H* m) e 8B8
(J R-s) -4J) 4t 4-15(IH
, each 6*t1. I-x61ha, 3Hvs>9454(
IH,6@d,,T==10Hi*5Hg)*77.
5(5H,m) Example 53 2-(3-amino-2-oxo-1-azetidinyl)-
Methyl 3-phenylthioacrylate.

Engineering R νarn (film) 3380, 33213 (scrap), 1760, 1740.
1720°NMR (TM8) 8911m (0DO14) lJ4 (2a, 5) e8j5 (la, a*a,, r=6
ag, 3ag).

8.76 (3H9B), 855 (lHIt, J=(iH
2) e4.33 (IH*tl*69: f=6Hz, 3H
z).

To 7.2 4.6 (6E s m ) Example 54 2-(3-Amino-2-okino-1'-azetidinyl)
-3-Methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)methyl acrylate [mixture of cis isomer firefly and trans isomer**].

Engineering R νam (film) 178 tl, 1760.1720° are on opposite @ of the double bond, and in the cis isomer they are on the same side of the 2@ bond.

The above-mentioned relationship between the trans isomer and the cis isomer in the Hinoki cypress compound also applies to the following Examples.

Example 55 2-(3-'7 minnow 2-oxo 1-azetidinyl)
Methyl -8,3-bis(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)acrylate.

Engineering R νam (Film) 3400.1780, 1760.1?213゜Real'JJ
IJi Example 56 2-(3-amino-2-oquinol-7zetidinyl)-
Methyl 3-(4-hydroxyphenyl)propionate.

Engineering R νcm (film) 3200.1750, 1720° Example 57 2-(3-amino-2-oxo-1-azetidinyl)-
: Methyl 1-(4-benzyloxyphenyl)furopionate.

Engineering R νam　’　　　(Nujol) 3300.1750, 1740, 172L).

Implementation 1+! l 58 2-(3-7ono4-methylthio-2-oxo-1-
azetidinyl)-2-(4-benzyloxyphenyl)
Methyl acetate [a mixture of two trans isomers at the 3 and 4 positions of the azetidine ring].

Engineering R stain m-1 (film) 3400.177 (j, 1740° Actual example 59 2-(3-amino-4-methylthio-°2-oxo 1
-Azetidinyl)-2-methyl phenylacetate [mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

R νam' (film) 3380.1770, 1740° Example 60 2-[3-Aquinol-4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-1-azetidin 2-phenylacetate-methyl acetate [mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm’ (film) 3280, 1770, 1640.

Example 6 2-[3-Amino-4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxicui-azetidinyl)-2-,yenylmethyl acetate [azetidine ring mixture of two cis isomers at the 3 and 4 positions].

Engineering R νam' (Filmun 3350.1765, 1740゜Real #1 Example 62 2-(3-amino-4-methylthio-2-oxo-1-
benzyl azetidinyl)-2-phenylacetate [a mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νam' (film) 340ON3300.177fJ, 1740,168(
J.

Example 63 2-(3-amino-2-oxo-1-azetidinyl)-
:3-(2-be/dithiazolylthiomethyl)-3-methyl acrylate [mixture of cis and trans isomers].

Process R νcm' (film) 1790.1770.1730.1710゜Example 64 2-(4-trans-styryl-2-ox2:E7thalimide 1
By reacting methyl -azetidinyl)-2-phenylacetate with hydrazide l-hydrate as the amine, 2-(3-amino-4-trans-styryl-2-oxo-1'-azenacinyl)-2 -Methyl phenyl vinegar rice (0).

Engineering R νcrn (film) 335tJ, 177υ, 1740, 166u.

NMR (TMS) δppm (0DO13) 1.78 (2H,)゛Loadll), 8B8.8.74
(3H,!s).

4.13, 4.78 (IHsmSqsJ=5H2,6H
2) 1433+4.46 (LH, each a, J=5Hz)*
51+5150(lHt each s)+L24-6.54(2
H, m) 17.02 to 4,56 (IUH, m).

Example 65 3-Methyl-3-(5-methyl-1,8,4,-thiadiazol-2-ylthiomethyl)-2-(2-oxo-
Mixture of cis and trans isomers of 3-phthalimido-1-azetidinyl) methyl acrylate 0.300
g to ethanol 1511d! Dissolved in methylamine 3
omg<0.1- of solution M in ethanol was added to the bath solution. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in ethyl acetate, washed with water, and dried over magnesium sulfate.

The bath liquid was evaporated under reduced pressure to leave an oily residue, which was developed on a column chromatograph using 5 g of silica gel. Elution with chloroform yields 2-[3-(2-(N-methylcarbamoyl)benzamido)-2-oxo-1-azetidinyl-3-methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl ) The trans isomer of methyl acrylate was first bathed out, and then the cis isomer 70~ of the target substance was bathed out. The yield of the trans isomer was 95q and the yield of the cis isomer was 70~.

Trans isomer engineering R νam (film) 178 (1,1760,1730,1660°NMR(
TMS) δpDm (OD30D) 2.29 (3H, s), 2.70 (3H, e) *2] 8
(3H,p)+111.82(3H,5)18.84-
4.00 (2H, m).

424.450 (2H, hB-q, J=14Hz),
-5,08,5J2(IH,d,d,,T=4H
z).

7.5υ~7.72 (4H, a).

cis)゛(German body; Engineering R νam' (film) 1970.1770,1730,1660゜NMR(T
MS) δppm (0D50D) 2.18 (3H, 8), 2.74 (3H, a), 2.9
0 (3H, 5) 181 (3a, s), 8.72~8f1
8(2I(,m).

4.52 (2H, 8) + 51) 6,6 u 0 (la*at
a,, r=5az).

7.60 (4H+s) Implemented? +! 166 3-Methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-(2-oxo-3
-Phthalimido-1-azetidinyl) Dissolve 0.470 g of a mixture of cis and trans isomers of methyl acrylate in methanol, and add 0.1 N aqueous sodium hydroxide solution at 0 to 5°C. was added at a temperature of The reaction mixture was then stirred at the same temperature for 10 minutes, and after the reaction was complete, methanol was distilled off under reduced pressure and the aqueous solution was purified with dilute hydrochloric acid.
Adjusted to H2-3. The aqueous solution was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure, and the residue was developed on a silica gel 10g column chromatograph. When bathed in a mixture of chloroform and methanol (volume ratio 100:2), 2-(3-(2-carboxybenzamide)-2-oxo-1-azetidinyl]-3-methyl-3-(5-methyl- The trans isomer of methyl 1,8,4-thiadiazol-2-ylthiomethyl)acrylate 1054 elutes first, and then the mixture of the trans and cis isomers of the target substance '?I140
PIg was washed out and finally the cis isomer 971n9 was washed out.

trans isomer Engineering R νcm’ (film) 1780.1?60,1720,166tl.

NMR (TMS) δ17I1m (OD, 0D) 2,:30 (:IH9θ)+2.72(JHls)s
8B2 (dHss).

184-4.00 (2H, m), 424-4.48 (
2H, AB-qS: r-x 2Hz ) + 5.07
+ 5.12 (IE, a + a + J=5az
) +7.5L) -8,08 (4H, m).

cis isomer Engineering R νam (film) 1780.1?60,171t1. ]66U.

NMR (TMS) δppm (CD60D) 2.17 (3H, s), 2.71 (3H, s), 8.7
8 (3H, s) + 8 B 8 (2H + d * J =
4 Hz) s 4.48 (l Ht s ).

6β3 (lH, t), 7.46-8.06 (4H, m)
.

Implementation 1fBl 67 2-(3-amino-2-oxo-yo-7zetidinyl)-
380 g of 2-(2-chenyl)acetic acid was suspended in 15 ml of dichloromethane with VCM, and to this suspension was added 0.60 g of bis(trimethylsilyl)acetamide and N.

Add 0.25 m of N-dimethylformamide. This mixture was stirred at violet temperature for 6 minutes to remove insoluble matter. 1li
T&ni bis(trimethylsilyl)acetamide 0.20g
was added, and the mixture was stirred for 30 minutes to prepare a dichloromethane solution. On the other hand, 0.440 g of 4-(3-31I&butoxycarbonylamino-3-methoxycarbonylpropoxy)phenylglyoxyl was added to 10 m of dichloromethane.
K suspension, to which 10.120 g of triethylamine and NI
B-dimethylbenzylamine 2#i was added. This mixture was mixed for a while to form a solution, and 0.0% of ethyl chlorate was prepared.
A bath solution of 5 m/dichloromethane containing 125 g was heated to -60
It was added dropwise to the above bath solution over a period of 3 minutes at a temperature of .degree.

This mixture was stirred for 00 minutes at the same temperature, and then further stirred for -20 to -
Stirring was continued for 20 minutes at 15°C to dissolve. The previously submerged dichloromethane solution was added dropwise to this 2-year-old solution at -60°C over a period of 20 minutes. The mixture was then stirred at the same temperature for 30 minutes and then at -15°C for another 30 minutes. 1 more at 0℃
Stirring was continued for an additional 1.5 hours at 20-25°C. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was diluted with hydrogen carbonate. I understand. The obtained solution was washed with diethyl ethyl and adjusted to pH 5.51c using diluted salt.
After mashing, evaporate to dryness under vinegar pressure to obtain 2-1:3-(4-
0.100 g of (3-strand tertiary butoxycarbonylannor-3-methoxycarbonylpropoxy)phenylgliosiloylamino)-2-oquine-l-azetigel]-2-(2-chenyl)acetic acid was obtained.

Engineering R νam (film) 345 to 3; 130, 1760, 1730, 1710.
168ON1660°NMR (7M8) δppm (cDo13) 1.41 (9H, a), 2.12"'2.34 (2H,
mL&3(h-4,1d(4H,m),87W(3Hs
s) *4J6"-4jl(1'H, m).

5B6 (lH, broad 8), 7.92 (lH, d,,
T-"8Hg) 16J O-0-828 (7Hs.

In substantially the same manner as in Example 67, the following compounds (Examples 68 to 77) were obtained by reacting the corresponding compound having an amino group with the corresponding acylating agent.

Example 68 2-[3-(4-(tert-butoxycarbonylamino-
Methyl 3-(4-methoxybenzyloxycarbonyl)carboxy)phenylglyoxytetraylamino]-2-oxo-1-azetidinyl]-2-(2-chenyl)acetate.

Engineering R νam (film) 345ON3350, 1760.174Ll, 1711
7,1690,166Ll.

HMR(7M8) δ1)I)! II CaDaz5) 1.40 (9g, s), Us←4J8 (2H-m) *8
J 4A(20(4i,m), 8.78.8flO(3
g, s), 4.4N, 60 (l H * m ) * 5
”2 (l Ht m ) * 5jIFr'5.43
(l H-m) ・194(IH,5)e71,8j
)3(lHsd, J=8HzL6.78-8.40(l
la, m).

Example 69 2-(L-3-(D-N-benzylox7carbonyl-2-phenylchrysinamide)-2-oxo-1-azetidinyl)-2-(2-thenyl)acetic acid [2 digits at the 2-position of acetic acid] mixture of L-form and D-form].

Develop this chemical & substance on a column chromatograph, L-form and D-form.
The body was separated.

L body; Engineering R νcm' (film) 3300.2550, 1740, 1715.167ON
MR (TMS) d1'Pm (0D30D) 8.48 (2H, m), 4,92 (IHId, d, J=
2.5) IZI5H2).

5.04 (2H, G), 127 (IH, a), 5J31
(IH, 5) s6n toy, 56 (l J H-m
3 m9 body; mp 159=163℃ Engineering R νam' (Nujol) 3320.3250, 26uO, 1740, 1705,
1685°NMR (7M8) δT)pm (OD30D) 8''4 (lHtd, d, t7 = 21g, 5Hg) 18.
75 (IH, t, J = 5Hsg), 4JO (lH, 4,
a.

J=2.5! Iz*5Hz), 5Jj2(2H,s),
528 (IH, e) 180 (lH, a), 6J4-7.
56(13H,m) Example 70 3.3-bis(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-1:2-oxo-3-
Methyl (2-phenoxyacetamide)-1-azetidinylcoacrylate.

Engineering R νam' (Film) 3350.1770.172 (J, 1670°NMR (
7M8) δppm (aDo13) 2.60 (3H, a), 2.70 (3111ts) *8
J'l0(3H,s)+1364.8fi6(lH,4
, d, J=2Hg, 5Hss)8]6(lH,t,J=
5Hz)*434(2H,s), 4.3U, 4.66(
2HsAB q, IF8Hz) *5j4~ also, 42(I
H*m)*7, :IH4,82(5Ht m), 7
．． 9 j (I He 6 e J=8 Hz) Example 71 8.3-piece (5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-(2-o-so-3-
(2-(2-chenyl)acetamide)-1-7zetedinyl]acrylic acid - methyl.

Engineering R νcm' (nujol) 3400,176υ,
1720,168ONMR (7M8) δp:pm (apel,) 8.73 (6HI 8 ), 8BS (31,8)s 8
23-<jJO(2H,m) 14.62(2H,5)
14.27, 4.73 (21, Mushi 1.J=14Hj!
+).

113-5.40 (IH, m), 6J3-JL33 (3
H, m) I7.85 (lLd, J=8H2).

Example 72 Methyl 2-[4-methylthio-2-oxo-3-(2-phenylacetamide)-1-(azetidinyl]-2-(4-benzyloxyphenyl)acetate [azetidine ring, 0
a mixture of two trans isomers at the 3- and 4-positions].

Engineering R νcm (Fill A) 3300, 1?70, 1750, 1670°NMR (7
M8) δppm (ODOl3) IJ32, 2D5C3B, each 5L8BO (2H, s) I
8.78 (JH, a).

4.4 t4j1) 8 (2H, m) 9512 (2H, a)
, 5,3015; (5(IH, each a) I6,50(lH
*d*J=8Bg) *6B toy, I2 (14nym)
.

Example 73 2-(4-methylthio-2-oxo-3-(2-(2-
Methyl (chenyl)acetamide)-1-7zetidinyl)-2-phenylacetate [a mixture of two trans isomers (a) and (4) at positions 3 and 4 of the azetidine ring].

R νcm (nujol) 3250.1770,1750,1660゜MMR(7
M8) δ1) pm (ODOl, 5) Isomer (a); Isomer (b)
;2.04(3H,s) 1.78(
3H, Iri 8.76 (5H, s) 8
．． 76 (5H, s) 4.44 (1'H-d t J=
2Hz) 4B 3-484 (j H* m
)4.87 (IH*deJ=2Hz*7
Hz) 5j5(lH*8)5.30(lH,
a) 6.63 (IH, d,, r=7
Hz) 6.63 (IH, d, J=7Hz) 6
JO” 4.69 (8Hv m) 6A Toy, 69
(8H, m) Real bj! Example 74 2-1: 4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oquine-3-(2-(2-chenyl)acetamide)-1-azetidinylcou-2-phenylacetic acid Methyl [2 at positions 3 and 4 of the azetidine ring
mixture of two cis isomers].

Engineering R νcm (Film) 3300.1780, 1745, 1680°NMR (7
M8) δppm (0D015) 2.60, 2.63 (3HI 5 each) t8B5 (2H-s
) J372 (3H-o) I51) 5~stone, 90 (3H,
m), 6.40-J! , 75 (9H, m).

Saishi M75 2-(4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-3-(i-(2-chenyl)acetamide)-1-azetidinyl)-2- Methyl phenylacetate [a mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm= (Film) 1785.1750.1670°NMR (7M8) δT)))m (ODOl, 5) 2.65 (3H, s), 8.74 (3Hts), 87M
(2H,a)I4.6 N72 (2H-m) -5
J 4 m 554 (l B-5 each) I6.64P-
Jl, 40 (8Hs m) Example 76 2-C4-Methylthio-2-oxo-3-(2-phenylacetamide')-1-7zetidinyl]-ER Simi m-1 (Nujol) 329 (1 , 1785, 1770 (shoulder), 176υ, 1
665°NMR (TMS) δ1) pm (C! DOI6) Isomer (-; Isomer (Koji; 1
．． 93(,3r+,θ) 1.76(3
H, θ) a, 50 (2H, s) 851
(2H,a)8.71 (JH=s)
8.71 (JHs s ) 4.46 (IH, d
*=2Hz) 4.7N, 8) 1(2H, m
) 4.90 (IH, q, J = 2Hz, 6Hz) 5-3
9 (lass) 5.33 (LH, a)
690 (IH, cl, J=6Hz) 6.90 (IH, d
, J=6Hz) 7.04-7.50(lOHI
m) 7.04-7.5 I) (l OH, m) Real M
Example 77 2-[4-Methylthio-2-oxo-J-(2-phenylacetamide)-1-azetidinyl-2-phenylacetate w benzyl [two trans isomers at positions 3 and 4 of the azetidine ring (al mixture of (b)].

(Film) 330υ, 1770.1740.1671) NMR (T
MS) 61m (ODo:L,') Isomer (a); Isomer (4; 1
．． 72 (3Hss) Ii3 (3H
*5) 8J3 (2H, s) 830 (
2H, θ) 4.42 (l H* d s , y=-z
Hz) 4.41 (l H+ tl * 1
=2Hz)482(IH,d,J=2H2)
4.85 (IH, d, J = 2H2) 5 u 6 (2H, s
) 518 (2H+s)
5;3:((IH,8) 6.23
(IH, 8) 7.2J”7.33 (15H*m)
Ii 3S/? , JJ (15H1m) Example 78 In substantially the same manner as Example 67, methyl 2-(3-amino-2-oxo-1-azetidinyl)-2-(3-mesylaminophenyl)acetate and phenylglyo By reacting medium siloyl chloride, 2-(3-(N
-Methyl-N-phenylglyoxyroylamino)phenyl)-2-(2-oxo-3-phenylglyoxyroylamino-1-azetidinyl)methyl acetate was obtained. R νcm (film) 3380.1750,1670゜NM, R (TMS) δppm (0DO13) 834.8.40 (3a, 8g), 8.71.8.75
(3H9 each s).

822-81 (3H, zn), 5U7 (IH, m), 5
j55゜5.75 (l H+ s) + 7.3~
8;3 (9H#m).

Practical example 79 2- (2,2-cycloacetoxy</), -2-
Phenyl vinegar e660 instant gold dichloromethane 51rd! 950q of phosphorus pentachloride was added to this IvlI'fA solution and left at room temperature for 40 minutes. The reaction mixture was evaporated to dryness under reduced pressure and benzene was added to the residue. Then, benzene was distilled off under reduced pressure to obtain the above chloride, which was dissolved in dichloromethane. On the other hand, 450 tFq of methyl 2-(3-amino-2-oxo-1-azetidinyl)-3-(phenylthio)propionate! Tobis(trimethylsilyl)acetamide was dissolved in 3.25 g't dichloromethane lO-, and the above solution t'' was added to this bath solution for 55 minutes at -27 to -20°C with stirring.Then, -38 to -
Stirring was continued for an additional 50 minutes at 25°C.

50 dt of water was poured into the reaction mixture, and the resulting mixture was adjusted to 1)E[)1 with a saturated sodium bicarbonate water bath.

The dichloromethane layer was added to the IJ! , & was washed 4 times with dilute hydrochloric acid, then with an aqueous solution of sodium bicarbonate, and then with water, and then dried over magnesium sulfate. The bath medium was distilled off under reduced pressure, and the residue was developed on a column chromatograph using 15 g of silica gel. For fermentation, mix chloroform, methanol and chloroform (volume ratio 1:100) (3-(
2-Hydroxyξ〕-2-phenylacetamide)・−
230 g of methyl 2-oxo-1-azetidinyl) -:(-(phenylthio)propionate was obtained.

νam' (nujol) 3480.1?60.1730,1670°NMR(T
MS) δppm((CD3)2Co) a J36-a-q o C4a 1m)+ az;
b CJ H * s ) +4.50 (lH, m),
5” 2 (LH, m).

7.2'1.7 (l OH, m).

By reacting the corresponding compound with an amino group with 2-(2,2-dichloroacetoxyimino)-2-phenyl acetate t=chloride in a manner virtually identical to Example N'79, the following compound was prepared: (Examples 80 to 89) were obtained.

Example 80 2-(3-(2-hydroxyimino-2-phenylacetamido-2-oxo-1-azetidinyl)-3-(:y
(enylthio) methyl acrylate.

Engineering R νam (Nushor) 1750.1710, 1660°NMR (TMS) δppm ((cn3)2oo) 8.76 (3H, s), 8J-43 (2H, mt5.4
0(LH, mt7.3(, 7(IOH, m).

8.49 (lH, d,, T = 8 Hz) Example 81 Erythro 2-(3-(2-hydroxyimino-2-phenylacetamido)-2-oxo-1-azetidinylcy 3-methoxy-3-phenylpropyl Methyl onate, m
p l 73-176°C.

Engineering R νam' (Nujol) 3300.1725,1665°NMR (7M8) δppm 1. '(CD3) 2C! O) 8.27 (3
H,5)t8.73(:(H,a),8ha?(lH,
m).

4.09 (IH, t, J=6H2) 14.61 (IH,
d,,T=5H2).

April 9 (lHed, J=5Hz) + 524 (IH, d,
d, ci, J = 3Hz.

6Hz, 7Hz), 7.2~4.7 (12H
Im), &25(lH, cL.

J=7H2), 10.73(IH,s).

Example 82 2-L: 3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl) -2-
(2-chenyl)methyl acetate, mp174-178℃ (
Disassembly).

Engineering R νam' (Nujol) 3300.1755,1730,1665°NMR(T
MS) δTIT) mt, (CD, 5) 200) 8.48 (lH
, a, a, J=2,5Hz, 6Hz).

3.98 (IH, t, J = 6H2) t5u2 (lH, m
).

5B8 (l Hls ) + 6.9 J to q, 8
J (8H9m).

Example 83 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl, l-2-(
1-naphthyl) methyl acetate.

Engineering R νcrn (film) 3250.1740,166υ.

Mass spectrometry m/e 431 (M10) Example 84 2-(3-(2-human xymin-2-phenylacetamide)-2-oxo-1-azetidinyl-3-methyl-3-(5-methyl- 1,8,4-thiadiazole-
2-ylthiomethyl acrylic version of methyl [mixture of trans and cis isomers].

This compound was developed on a Wt-column chromatograph to separate cis isomer and trans isomer.

Trans isomer; Engineering R νcm' (film) 3300.1760,1730,1670°NMR (7
M8) δppm (aDe15) 2.22 (JHe s ) * 2,52 (JH *
s ) * 8.70 (JH * e ) −8,6
2-85) ic2H, m), 4.08-4.40C2H
, m).

4.08-4.40 (2HIAB-q, T=14Hz
) J2 (ln, m) to 15u5, 1.5 to 7.0'4
6 (5H, m), 8J) 4 (IHrtLe, T = 8Hz
).

Cis isomer; Engineering R νom = (film) 33LIO, 177υ, 1730.1670°NMR (
TMS) δppm (oDox3) 2.08 (3H, s), 2.66 (3H, a), 3.7
0(3H,5)s872-8B2(2H*m)*4:3
6 (2H * 11) * 4J2-5JJ6 (lH, m), 7
．． 24S! L52 (5n, m1s7.82 (la, a,
y=aug).

Example 85 3-(2-benzothiazolylthiomethyl)-2-(3-
(2-hydroxyimino-2-phenylacetamide)-
Methyl 2-oxo-1-azetidinyl-3-methylacrylate [while mixing trans and cis isomers].

Engineering R νcm= (Film) 3250.1760,1720,1670°NMR(T
M8) δppm (ODO], 3) 2, lO, 224C3H, each s), 8B6.8B8 (3
H, each 8).

5D4-520.4jj訃-54) 8 (IH, each m).

7.22-? , 80 (94m).

Example 86 2-(3-(2-hydroxyimino-2-phenylacetoxide)-2-oxo-1-7zetidinyl)-2-(2
-7lyl) acetic acid.

Engineering R νam' (nujol) 3300.1755, 1735, 1710, 1660°NMR (TM8) δppm C (OD3) 200) 8.41 (lH, 1, 1,, T = 3Hffi, 6Hg)
, 839 (IH.

t*, y=sHts) @ 5j 5 (l H
g m ) 65.71 (l Hg s ) t6.4
6 (IH, m), 6.58 (IBIdlJ=3Hg).

7.3-7.7 (6H, m), J320 (la, m).

Example 87 2-(3-(2-Hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl:)-2-phenylacetate Nikami methyl.

Engineering R νcn+1 (nujol): (230,1750,1725,1642゜Example part D-2-(4-) lance-styryl-3-(2-hydroxyamino-2-phenylacetamide)-2-oxo −
Methyl 1-azetidinyl)-2-7 enylacetate [mixture of two cis isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm (Film) 3350.177ON1740.1670゜Example 89 D-2-(3-(2-hydroxyimino-2-phenylacetamide)-4-hydroxymethyl-2-oxo-1
-azetidinyl)-2-phenylacetate methyl (mixture of two cis isomers at positions 3 and 4 of the azetidine ring)
.

This compound was developed on a sword ram chromatograph and the isomer (a
) and (bl) were separated.

Isomer (a); mp　179-1815℃.

Isomer (season; mp19t198℃.

Example 90 3-Methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-(2-oxo-3
-Phthalimide-1-azetidinyl) acrylic 0.350 g of a mixture of cis and trans isomers of methyl was dissolved in 20 tne of ethanol, and 0.050 g of hydrazine monohydrate was added to this solution, followed by 19 hours at room temperature. Stirred. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in dilute hydrochloric acid. The water bath solution was washed with ethyl acetate, and sodium hydrogen carbonate was added to adjust the concentration to 11H8.5. This was extracted with ethyl acetate, washed with water, and then dried over magnesium formic acid. This solution was evaporated to dryness under reduced pressure and the residue was dissolved in dichloromethane lOd.
ni fI! I understand. To this solution, a solution of 5 d of dichloromethane containing 01,612 g of 2-phenoxyacetic acid chloride was added dropwise at -5 to -1θ°C, and the mixture was stirred at the same temperature for 2 hours. Mix the reaction mixture with dilute hydrochloric acid, water, and 5% hydrogen carbonate) I
It was washed with a Jumium aqueous solution and then with water, and dried with magnesium sulfate. This solution was evaporated to dryness under reduced pressure, and the resulting oily residue Bk (0.120 g) was developed on a column chromatograph using 4 g of silica gel.

It was eluted with chloroform and the fraction containing the target substance was collected. 3-Methyl-3-(5-methyl-1,8,4thiadiazol-2-ylthiomethyl)-2-(2-oxo-
The first fraction containing the trans isomer of methyl 3-(2-]dinoΦcyacetamide)-i-azetidinylcoacrylate was evaporated to dryness under reduced pressure to yield 0.023 g of the above material. In the same manner, 0.020 g of a mixture of cis and trans isomers of the above substance and 0.027 g of cis isomer Q were obtained.

Trans isomer engineering R cm-1 (CHC15) 3450.1760,1730,1685゜11MR(
TM8) δppm (OD(31!1) 227C3H,a), 2.63C3H18), 8 near 6
(3H9B)*8I34,8fi8(lH*dtdsJ
-2Hg', 5ug) *8J6(lHtts, T=
5Hz), 4.06, 4.44 (2H.

AB-qlJ=14Hg), 4.56(2H,a), 5
22-538 (lHIm) 16.86S/1.40 (5
H, m)t7.86 (l Hs de J=8 Hz
) Cis isomer; Engineering R νcm (OHC113) 3450,1765
, 1725, 1690°NMR (TMS) δppm (onox3) 2.06 (3F1s a ) * 2-62 (J H
s s ) s 8711 (3H-s ) -8S9,
8.73CIH96*a*: J=2HM, 5Hz)t8
90 (IH9t, J=5Hz) *4J2 (2Hes)1
4, aa(2a*5)s5ρ or 41)8 (l Hs
m) *6J14-J1.48 (51, m).

Example 91 2-(3-(4-(3-amino-3-carboxypropoxy)phenylglyoxychloroylamino)-2-oxo-1-7zetidinyl)-2-(2-chenyl)ff[4
00 my and hydroxyimino 130 rng in water 7 dK
M? j3 L, pH 7.0KFA with sodium bicarbonate
This was then dissolved. This mixture was heated at 35-38°C for 1
．． Stir for 5 hours and treat with charcoal. The I)H of the solution was adjusted to 8.2 to 8.0 with dilute hydrochloric acid, heated to 35 to 38°C under reduced pressure, and concentrated to 15.

The concentrated solution was developed on a column chromatograph using N absorbent fat Amberly) XAD-4 (trademark: manufactured by Rohm E & Ken Haas Company) 80-. Elution was performed with water and then methanol, and the fractions containing the desired quality were combined. The solvent was distilled off under reduced pressure, and the residue was ground with acetonitrile to give 2-(3-
(2-(4-(3-amino-3-carboxypropoxy)7enyl)-2-hydroxyiminoacetamide]-2
-oxo-1-azetidinyl)-2-(2-chenyl)
230~ of acetic acid was obtained.

Engineering R νcm' (nujol) 3400 (broad), 1740, 166 to 1640,
1610゜iMR (TM81)) δppm (D20) 238-(!, 4 g (2III * m) *
8J 6P-4MO(3H-m).

4.0FM28 (2H, m), 5DO-510 (I
III, m).

5B0.5bBCIH, 8), 6JJM, 59 (7M,
m) The following compounds (Examples 92-102) were obtained by reacting the corresponding compounds containing phenylglyoxyloyl groups with hydroxylamine hydrochloride in substantially the same manner as in Example 91.

Example 92 Methyl 2-(3-(2-hydroxyimino-2-phenylacetamido)-2-oxo-1-azetidinyl)-3-(phenylthio)propionate.

Engineering R νcm' (nujol) 3480.1760.1730,1670゜Example 93 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-7zetidinyl) -:i
-(phenylthio)methyl acrylate.

Engineering R νcm' (Nujol) 1750.1710,1660゜Example 94 Erythro 2-(3-(2-hydroxyi mino-2-
Methyl phenylacetamide)-2-oxo-1-azetidinyl]-3-methoxy-3-phenylpropionate.

Engineering R νcm　’　　　(Nujol) 3300.1725,1665.

Example 95 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl, l-2-(
2-chenyl) [2-methyl.

Engineering R νcm' (Nujol) 3300.1755.1730,1665゜Example 96 2-(3-(2-hydroxyzumino-2-phenylacetamide)-2-oxo-1-azetidinyl)-2-( 1
-su7tyl) methyl acetate.

Engineering R νcm (Film) 3250.1740, 1fi60° Example 97 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oquin-l-azetidinyl]-3-methyl-3-(5 -Methyl-1,8,4-thiadiazole-
2-ylthiomethyl) methyl acrylate [mixture of trans and cis isomers].

This compound was developed on a column chromatograph to separate trans and cis isomers.

Engineering R νcm (film) Trans isomer; Cis isomer; Example 98 3-(2-benzoteazolylthiomethyl)-2-(3-
(2-hydroxyimino-2-phenylacetamide)-
2-oxo-1-7zetidinyl]-3-(2-hydroxyimino-2-phenylacetamide-2-oxo-1-
Methyl azetidinylcy-3-methylacrylate [mixture of trans isomer and cis 14-isomer].

1 νam' (film) 3250.1760,1720,1670゜Example 99 2-(:3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl)-2-(
2-7lyl) acetic acid.

Engineering R νam' (nujol) 3300.1755.1?35,1710,1660゜Example 100 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl)- 3-(4
-hydroxyphenyl) methyl furopionate.

Engineering R νcm' (nujol) 3230.1750, 1725, 1642° Example 10
1 D-2-(4-trans-styryl-3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-
1-7zefdinyl)-2-methyl phenylacetate [mixture of two cis isomers at the 3- and 4-positions of the azetidine ring@-
thing〕.

Engineering R νam' (film) 3350.177 1740,1670゜Example 102 D-2-(3-(2-hydroxyimino-2-phenylacetamide)-4-hydroxymethyl-2-oxo-1
-Azetidinyl-methyl 2-phenylacetate [g@- product of two cis isomers at positions 3 and 4 of the azetidine ring].

This compound was developed using chromatography to separate each cis isomer.

One isomer: mp 17ih 1813°C Other isomer: mp 196-198°C Example 103 0.39 g of triphenylphosphine is bath dissolved in 10 d of anhydrous acetonitrile, and to this bath solution 51 nI of anhydrous acetonitrile containing 024 g of bromine! was added dropwise over a period of 5 minutes at 5° C., and the mixture was then stirred at the same temperature for 25 minutes. On the other hand, 0.32 g of 2-azido-3-(α-methoxycarbonylbenzylamino)propionic acid chloride and 041 g of triethylamine'f: anhydrous acetonitrile 5
This solution was added dropwise to the above mixture after 15 minutes of incubation at 5°C. The mixture was stirred at the same temperature for 30 minutes and continued stirring at room temperature for an additional 4 hours. Acetonitrile was distilled off under reduced pressure, and ether was added to the residue. Insoluble matter was removed and the solvent was distilled off under reduced pressure. The residue was applied to a column chromatograph using 20 g of silica gel and eluted with chloroform. The fractions containing the target product were combined and the solvent was distilled off under reduced pressure, resulting in 1-(3-azido-2-o).
A mixture 9 (1) of two isomers (al and (b) of methyl azetidinyl)-2-phenylacetate was obtained.

Engineering R νcm (Film) 2080.1760, 1730°NMR (TM8) δppm (oDalB) Isomer (a); 2J3 (IH, q, , r=2Hz, , T=6Hz)8.
73 (JHsa) 816 (LH, t, J=6Hz) 4-63 (l H* q * to lHz s to 6 H
z ) 5:l6 (lHts) 7.28 (5Hws) Isomer (season; 826-8.76 (2H, m) August 0 (J Hls ) 4.50 (l H+ (1s I”l Hz * J
=5HZ ) 5.60 (l H* s ) 7.33 (5Hs s ) Performed in substantially the same manner as Example 103 by using the following condensing agents or bases (a) to (b). The same target substance as in Example 103 was obtained.

(a) N,N'-dicyclohexycarbodiimide (b)
N, N'-diisopropylcarbodiimide fc)
N l 'N'N dithylaniline, [2-azido-
3-(α-Methoxycarbonylbenzylamic acid) Proviola (using loride hydrochloride as the raw material).

((1) Ethylmagnesium bromide [2-azido-
Methyl 3-(a-methoxycarbonylbenzylaminocopropionate was used as the raw material).

In the same manner as in Example 103, the corresponding 2 and 3
-N as an anti-inflammatory agent in disubstituted propionic acid.

By reacting N'-cyfuclohexycarbodiimide, the following compounds (Examples 104 to 106) τ were obtained.

Real 1M Example 104 D-2-(3-azido-2-oxo-1-azetidinyl)-2-phenylacetic acid [2 at position 3 of azetidine ring
mixture of two isomers].

Engineering R νcm (Film) 2100.1750 (Broad) NMR (TM8) δppm (ODOI3) 82-8B (2H, m), 4.48 (lH, m) 5.5
4 (IH, Broad 8), 7.35 (5H, 8) Example 105 D-2-(3-bromo-2-oxyso-1-azetidinyl)-2-phenylacetic acid [two isomers at the 3-position of the azetidinyl ring body (at and (b) o mixture)].

This compound was separated into its respective isomers (a) and (b) by column chromatography.

NMR (TMS) δppm (ODO13) Isomer (a); 8.20 (IH, tl, d, J = 2Bg, 6Hff) 4
”7 (IH, d, d, J=5Hg, J=6Hri4J 3
(l H* (1t (L e J==2HM*
J==OHEM)5B8(lH9B) 7.2P-4,76(IH*m) Isomer (b); August 8 (2H,nx) )5fI(IH
,s) 7.17-'1.45 (5H,m) Example 106 2-(4-hydroxyphenyl)-2-(2-oxo-
3-Tritylamino-1-azetidinyl)acetic acid, Moan 13
5-139°C (decomposition).

Engineering R νam' (nujol) 3320.1740.17
20゜NMIt (7M8) δppm ((CD3)280) 168(la,m)8160(IH,t,,7==6H
z) 1892 (l H* m ) * 524 (l
He tr ) *6.6()4.72(i9Hwm
) Example 107 2-(3-(4-(3-83-class poxycarbonyl-]-3-methoxycarbonylpropoxy)phenylglyoxyroylamino)-2-oxo-1-7zetidinyl)-2-( 2-chenyl) vinegar was dissolved in 3-methanol, and to this solution was added 2 ml of a constant aqueous sodium hydroxide solution while cooling with water. The mixture was stirred at the same temperature for 7 hours, during which time the pH was adjusted to 9.0 with IJum.
Adjusted to #4 at ~9.5.

After the reaction was completed, the pH of the reaction solution was adjusted to 7.0 with dilute hydrochloric acid, and the mixture was evaporated to dryness under reduced pressure on a water bath. Dissolve the residue in a small amount of water and add dilute hydrochloric acid to this water bath solution to make it pm5.5Ki.
After J-adjustment, the mixture was extracted with ethyl acetate.

Add dilute hydrochloric acid to the aqueous solution to pH 4.0-4. At -5, extract again with ethyl acetate. The extracted liquid was dried under reduced pressure, and 2-(
3-(4-(3-filled tertiary butoxycarbonylamino-3
-carboxypropoxy)phenylglyoxy70ylamino)-2-oxo-1-azetidinyl)-2-(2-
chenyl) acetic acid 03508-)! ? Ta.

Engineering R νcm (film) 340t; 3300, 1750, 1730, 1710.
168()-1660゜Example 1 (18 2-[;E(4-(3-Tertiary-butoxycarbonylamino-3-carboxypropoxy)-phenylglyoxyroylamino)-2-oxo-1-azetidinyl)-
2-(2-chenyl) vinegar 20°830g'i benzene 4
In addition to the mixed solution of Mt and 7 nisole l-, 1112 mf of 2,2.2-11 fluoroacetic acid was added to this mixture under water cooling.

The resulting mixture was stirred at the same temperature for 2.5 hours, and 50 dt of diethyl ether was added. Thereafter, the mixture was stirred for an additional 30 minutes under water cooling, and the insoluble materials were collected by filtration and suspended in 30 mK of ethyl acetate. ,2-(,j-(
0.49 g of 4-(3-72-no-3-carboxypropoxy)phenylglyoxyroylamino)-2-oxo-1-azetidinyl)-2-(2-chenyl)acetic acid was added.

Engineering R νcm (Nujol) 3450-3300.1740, 1680, 166U,
1600°NMR (TMS) δppm (D20+)flLHOO3)22)1-
-2,54 (2H* m) -8J 2-4Jυ(
3H, m).

41 oS-4,38(2Pi*m)s 5D
Needle bar 12 (2H-ra) -5,61,5fi7(l
a * each s ) e 7. Oo~a, o 8 (7H*
m) Example 109 2-(3-(N-benzyloxycarbonyl-2-phenylglycinamide)-2-oxo-1-azetidinyl)=2-(2-thenyl]acetic acid 0°19gt-Dissolved in methanol 201nt Then, 15 gtl of 10% palladium-charcoal After that, the catalyst was removed, and the oil solution was dried under reduced pressure to obtain an oily substance.This was solidified with ethyl acetate, and 0.09 g of the obtained powder was added to a mixture of acetonilyl and water (volume ratio 20). :l), 2-C3-(2
0.02 g of -phenylglycinamide)-2-oxo-1-7zetidinyl)-2-(2-chenyl)acetic acid was obtained. mpl 99-215°C (min y4).

Engineering R νam' (nujol) 3300.1730, 1690°NMR (TMS) δppm (aD5oD) 8u0 (lH+d*dj=2.5H2s5H2)sMarch 6 (lH, t, J=5Hz), 4.90( lHva,a
s; r=25Hz * 5Ez'), 556 (11 (*
s) t4.92 (LH, s), 6J4-7.60
81
0tng was dissolved in acetone 4#1/, and 8.81d of a 0.1N aqueous sodium hydroxide solution was added to this IW solution under stirring while cooling with water.
was next to it. After stirring was continued for an additional 5 minutes at the same temperature, acetone was distilled off under reduced pressure.

5 d of water was added to the remaining aqueous solution, and after washing with ethyl acetate, the pH was adjusted to 2 with 3N hydrochloric acid. This bath M was mixed with 10% ethyl acetate.
The extract was extracted twice each with m/, and the extract was washed with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. When the solvent was distilled off under reduced pressure, 2-(3-(2-hydroxyiξ)
-2-phenylacetamide)-2-oxo-1-azetidinylcy 3-methoxy-3-phenylpropion@6
5~ were obtained. mi'! 81-85°C (decomposition).

Engineering R νon (film) 3300 (broad), 1750 (scrap), 1720 (broad).

1650°NMR (7M8) δppm ((OD5) fJo) 8.27 (3H, s), 8.70 (IH, m), 4.1
0(IH,t.

, T=6Hz), 4.56(lH,d,,T=5Hg)
, 4J3 (IE, d.

J==5HZ) + 520 (lH+m)
+ 7.2-7.8 (m) *8.18 (l H
+ rr, ) The corresponding compound having a methyl ester bond was hydrolyzed in substantially the same manner as in Example 110 to obtain the following compound (Example 111N126).

Example 111 2-[;go(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinylcou-3-phenylthiopropionic acid.

Engineering R νam' (film) 3250 ()゛load), 290α 2700,173
0 (broad).

1670 (Broad).

NMR (TMS) δppm ((OD3)200) 824-8U2 (4H, m), 453 (IH, m).

E), 14 (in, m), 7.1 cm, 80 (10H
+m).

8.39 (LH, m) Example 112 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl:]-2-(
2-chenyl)acetic acid.

Engineering R νam' (nuji, yawl) 3350.1755,17υ0,1650゜IJMR(
7M8) δppm (OD30D) 8.43 (la+asa, r=2sHgs6Hz),
81 (In, t.

J=(i Hz) e 5.08 (l H* m
) s 5J(4(l H* s ) * 6jJ o
-7,7; ((8Hsm) Example 113 2-(3-[4-(3-tertiary-butoxycarbonylamino-3-(4-methoxybenzyloxycarbonyl)propoxy)phenylglyoxyroylamino]-2 -oxo-1-azetidinyl]-2-(2-chenyl)acetic acid.

Engineering R νon' (film) 345 to 3300, 1760.1730.1710゜1
680-166 (1゜Example 114 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-7zetidinyl,: l-2-
(1-naphthyl)acetic acid. □Work R νcm' (film) 3250 ()゛load), 2900~2700.173
0 (broad).

1670 (Broad).

Practice 911115 2-(3-(2-Hydroxyimino-2-phenylacetamide)-2-oquin-l-7zetidinyl)-3-phe, nylacryl ff, 78-83<0>C (decomposition).

Engineering R νcm' (nujol) 1740.1710,168υ()゛load)NMR(
TM11) δppm C(CD3)2ao) 8B(MJ(2H,m), 5.40(la,m).

7.2-7.8 (IIH, m), 8.53 (IH, d,
, T=8Hz) Example 116 3-Methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-(2-oxo-3
-(2-phenoxyacetamide)-1-azetidinylcoacrylic acid.

Engineering R νcm' (Nujol) 3250.174U, 1720,1650°NMR (7
M8) δppm (OD, 011) 2.28 (3u, a), 2.68 (1, a), 8.72
,8.76(IH+ d@ d@ , T==2Hz I
5Hz) g 8jlN) (IH, t * J=
5H2)+4.16,4.46(2HIA?q, J=1
4Hg), 4j56(2H,a)? 5.08,5yu2a
H, a, a,, r=2Hg, 5az), 5g6N6. +
9 (5azm).

Example 117 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-azetidinyl-3-methyl-3-(5-methyl-1,a, 4-thiadiazole-2- ylthiomethyl)acrylic acid.

Engineering R νcm (Nushor) 330t), 1740, 1720, 166L).

Example 118 3-(2-benzothiazolylthiomethyl)-2-(3-
(2-hydroxyimino-2-phenylacetamide)-
2-oxo-1-azetidinyl]-:(-methylacrylic "5-n.

Engineering R νcm (Snoyol) 325 (J, 17・↓U, 1721, 1660゜Example 119 3.3-bis(5-methyl-1,a, 4-thiadiazol-2-ylthiomethyl)-2-C2- Oxo-3-
(2-(2-chenyl)acetamide)-i-azetidinylcyacrylic acid dicyclohexylamine salt.

Engineering R νcm (Nushor) 3300.1760.1675,164 NMR (7M8) δppm (CD30D) 1.28 to 2.18 (IUH, m) + 2.68 (6H,
s), 8.08-828 (21(, m), 81.8,5
6 (lH, d, d, J = 2H2゜5Hz), +75 (l
a, t, J = sazLa, 76 (2a, s) + 4.34
(2H=s)*436(2Hte)+4.98s5D2
(l Ht a * a + J-=4 a Z )
e 6.92 ha, 26 (3H, m).

Example 120 2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oquinol-l-azetidinyl)-3-(4
-hydroxyphenyl)propionic acid.

Engineering R νam' (film) 3400.1735, 1720, 1660° Example 12
1 2-(4-benzyloxif;nyl)-2-C4-methylthio-2-oxo-3-(2-phenylacetamide)
-1-Azetidinyl]acetic acid [a mixture of two trans isomers at the 3 and 4 positions of the azetidine ring].

R νcm' (Film) 3300.1760,1740,1670°NMR(T
MS) clppm C(aD3)2co) 1.22, 1.89 (3L each 8), 857C2T19
B)+4.51~5. IJ3(2I(Im), 515(
2H@S), 5; (0(lHI8)6.9toy, 61J
(14H+ m) + 810 (l H* d
e to 8 HZ) Example 122 2-1:4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-3-(2-(2-chenyl)acetamide)-1 -Azetidinyl c-2-phenylacetic acid [mixture of two cis isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm (Nuzoyol) 1775.1740,166 (1° NMR (TMS) δppm (aD6oD) 2.60 (3H, a), 8.72 (2H, 5) 15.4
8 (LH, Be5.66 (lH, d, J = 4Hg), 6
．． 14 (IH, 4, J = 4HK) 16.68-J? ,
60 (8H, m) Example 123 2-(4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-3-(2-(2-chenyl)acetamide)-1 - Azenacinylcy 2-phenylacetate [mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm' (nujol) 1775.1750, 1640°NMR (TMS) δT'pm (CI), 0D) 2.60 (3H*s), 8.72 (2H, s), 510
(JH, d, J=2Hz)+5.42(11(1B)1
5B6 (IH, d, J = 2Hg), 6.6 () - 7,3
6(8Hs m ) Example 124 2-[4-methylthio-2-oxo-3-(2-(2-
chenyl)acetamide)-1-acetidinylcy2-phenylacetic acid [a mixture of two trans isomers at positions 3 and 4 of the azetidine ring].

Engineering R νcm (Film) 3300.1770, 1750, 1670°NMR (T
MS) δppm (ODOI3) January 2, 2J) 5 (3H, each BLabo (2Hts)
18.78 (JHIθ).

4.4()-4,98(2H, m), 5.12(2H,
s), 5; 30,535 (1a e each 8) *6.
50 (I H* d * J”8 Hg) +bH
s~7. b 2 (14Ht m ) Example 125 2-(4-) lance-styryl-3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-1-
azetidinyl]-2-phenyl vinegar n〆.

Engineering R νam' (nujol) 3250.260()"2500,1760,1740
,16! JO Example 126 2-(3-(2-hydroxyimino-2-phenylacetamide)-4-hydroxymethyl-2-oxo-1-azetidinyl-2-phenylacetamide) 1 set.

Engineering R νam' (nujol) 3380.3200, 1750, 1720.1700 (
Shoulder), 1650 Example 127 3.0 g of methyl 2-(2-oquino-3-phthalimido-1-azetidinyl)-2-(2-chenyl)acetate and 8.4 g of lithium iodide were added to 40 me of dry pyridine, and the mixture was The mixture was heated under reflux for 2 hours. After the reaction, the mixture was poured into ice water at 250 ml.
Pour into a mixture of 300ml of me and ethyl acetate and cool with water.
The pH was adjusted to 2 with O% sananic acid. When the precipitated crystals were collected, 0.20 g of 2-(2-oxo-3-phthalene-l-azetidinyl)-2-(2-chenyl)acetic acid was collected.

The ethyl acetate layer was separated, and the water layer was further extracted with ethyl acetate.
& JAel magnesium. When the solvent was distilled off under reduced pressure, 2.26 g of the same substance as above was obtained. 0.17 g of the same substance was also obtained from the motherboard. total acid fi
t 2.64 gt mp l 9 '9 - 201℃ Engineering R νam' (Nujol) 275t 2500.17?0,1740.172ONM
R(TMSF) δppm (D20+1iaHOO3)836(lHI
qeJ=3Hffi, 5H2) S8#1(lHIt, J
=5H2) 15J 8 (I H+ q * to J H
z * 5 Hz ) * 574 (l Hs 8)
*7, t) M, 80 (7H, m) In substantially the same manner as in Example 127, the following compound ( Example 1
2s, l 29c were obtained.

Example 128 2-(3-azido-2-oxo-1-azetidinyl)-
2-Phenylacetic acid [a mixture of two 14-mers (a) and (b) at the 3-position of the azetidine ring].

Engineering R νam (Film) 2570.2100,1740,17201iMR(T
MS) δppm (on3on) Isomer K (a); Isomer (b); 19
5 (lH, q, , T = 2Hg, 5Hg) 839 (IH
, t, J=5H2) 8-90 (l H* t @ P
5Hg) 856 (l Hsq + J:
=:2Hz I 5Hz )4-77('HtqsJ=
2H, 5Hffi) 4.59 (lH, q, J=2H
z, 5Hz) 556 (lH, s)
554 (IH, s) 7.36 (5H, s)
7.36 (5H,s) Example 129 D-2-(2-phenoxy l-azetidinyl)-2-phenylacetic acid [two isomers (a) at the 3-position of the azetidine ring and ( mixture of b)].

1 cm7' (film) 1740 (broad) NMR (TM&) δppm ((op5)2co) isomer (cry; isomer (b);8.
18 (LIE, d, d,, r=2Hz, 6Hg) 8.
56 (LH, m) 4.02 (IH, t, , T = 6HH)
8.77 (IH, m) 527 (l H=
m ) 5J 3 (l Hs m )
5.72(lH,s) 5B9(IH@
a) 6 to 7.5 < IOH, m) 6 to, 5
(lOH,m) Example 130 D-2-(3-
benzyloxy-2-oxo-1-azetidinyl)-2
- By reacting benzyl phenylacetate with anhydrous lithium iodide in pyridine, D-2-(3-benzyloxy-2-oxo-1-azetidinyl)-2-phenylacetic acid [two at the 3-position of the azetidine ring] Isomer (a)
and (b)] was obtained.

Engineering R νam (Film) 1730 (Broad) NMR (TMS) δppm CCaD5')po] Isomer (aJ; Isomer (b); 8
．． 14(IH, d, d,, T=3Hz, 8jy"-
'8E(lH,m)6HM) 5JO
(IH, d, d, J = 3H2゜4.00 (LH, t, J
=6Hi) 6HB)5.41(lH*6*eL,
J=3HH,5β3(laws)6Hg)
6J+SJ1.5 (l OH, m)
5455 (11,B) 6to7.5 (10H, m) Example 131 2-(3-amino-2-oxo-1-azetidinyl)-
3-Methyl-3-(5-methyl-1,8,4-thiadiazol-2-ylthiomethyl)acrylic methyl 656
Fv1 was dissolved in 15me of acetone, and further diluted with water cooling and stirring for 0.000 min.
20° of a 1N aqueous sodium hydroxide solution was added. The mixture was stirred at 10-15° C. for 5 hours, and 2 ml of hydrogen carbonate was added.

To this mixture, N-(2,2,2-)lichloroethoxycarbonyl)-2-phenylcrisyl chloride 83
A bath solution of acetone 5-containing Qrng was added dropwise to the mixture at 0 to 5° C. while stirring, and the mixture was further stirred for two periods at the same temperature. Acetone was distilled off under reduced pressure, and the aqueous layer was extracted with ethyl acetate. The extract was washed successively with dilute hydrochloric acid, water, and a 5% sodium bicarbonate aqueous solution, and dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure to obtain an oily residue, which was developed on a column chromatogram using 12 g of silica gel. Elution was performed with chloroform, the target product and the fractions containing it were combined, and the chloroform was distilled off under reduced pressure to yield 2-(3-(N-(2,2,2-1lichloroethoxy7carbonyl)-2-yenylglycine). amido)-2-oxo-1-azetidinyl-3-methyl-3-(5-methyl-1,8,4-thiadiazole-2
-ylthiomethyl)acrylic acid 13Qtnq was obtained.

Engineering R νcm' (Film) 3250.1760, 1720, 1700.167ON
MR (TMS) δppm (cDo15) 2 no 4 (3H, s), 2.66 (3H, s), l, 56
,8fiO(IH,d,d.

, T=2Hz, 5Hg), 8B4(lHIt), 8jJ
8.4,52 (2H.

AB-q, J=14Hg), 4.71(2H,a),
4J'+8.4.92 (Dr.

d, d,, T=g2Hg, 5Hg), 7.2 & 4.48
(5H, m) Example 132 1.5 g of methyl 3-(4-benzyloxyphenyl)-2-(2-oxo-3-7thalimido l-azetidinyl)propionate? 20 parts of ethanol and 1 part of ethyl acetate
After dissolving the cedar in a mixture of Wt, 1.5 liters of typalladium-carbon
g was added. The reduction reaction was carried out in a hydrogen stream at room temperature for 3 days using a pressurizing device, and the calculated amount of hydrogen was absorbed into the reaction mixture. After the reaction, the catalyst was plotted as a line. The 4 liquids were evaporated to dryness under reduced pressure, and 1.01 g of the residue was crystallized from a mixture of diethyl ether and ethyl acetate to give 3-(4-hydroxyphenyl)-
0.33 g of methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)propionate was obtained. The same substance was also recovered from the mother and father fluids, and the total yield was 0.388.

Engineering R νcm (Nujol) 3250.1780, 1762, 1735.1690 Real MIN1a3 2-(3-azido-4-methylthio-2-okino 1-
Methyl azenacinyl)-2-phenylacetate (mixture of two trans isomers) 0.60 g was dissolved in methylene chloride 110 #A element 7 7 tngk methylene chloride 5d
The solution was added dropwise over a period of 10 minutes at -65 to -70°C. The mixture was stirred at the same temperature for 1 hour, washed with sodium thiosulfate solution and water, and dried over magnesium sulfate. The bath medium was distilled off under reduced pressure, and the remaining fA (0.64 g) was developed on a column chromatograph using 15 g of silica gel. It was washed out with chloroform, and all fractions containing the target product 'fi were collected. When the solvent was distilled off under reduced pressure, 2-(3-azido-4-
0.44 g of an oily mixture of four isomers (two trans and two cis isomers) of methyl chloro-2-oxo-1-azetidinyl)-2-phenylacetate was served.

Engineering R Mixture of two cis isomers stain m-1 (liquid film) 2120, 1780.1745 '6#. of two trans isomers. 2120, 1790, 175L1 NMR of two cis isomers (TMS) δppm (liquid film)
ODC! 15) One of the cis isomers The other of the cis isomers8,76
(3H.11) 8.76 (3H, l1l
)4,74(lH+deJ=5Hz) 4.86(
lH. (1.J=5H2)5,34(lH.s)
5.48 (IH, 5) 5h 8 (l H *
d * J: 5Hz) 6.0 7 (l
H * d * J-5 Hz) 7, 4 0 (5
H, s) 7-4 0 L 5 H
s s ) Example 134 In substantially the same manner as Example 133, 2-[3-azido-4-(5-methyl-1.8.4-thiadiazol-2-ylthio)-2-oxo-1 -7 zetidinyl]
- A mixture of two trans isomers of methyl 2-phenylacetate gIJO. 3 7 g'ft:tM'jKiθ.
l), 2-(3-azido-4
-Chloro-2-oxo-1-azetidinyl)-2-phenyl pickled methyl [2 at positions 3 and 4 of the azetidine ring
Mixture of one trans isomer and two cis isomers J2
Attended 40 Takumi.

Mixture of two trans isomers νcm' (film) 2120.1790.1750 # of two cis isomers, fixture cm (film) 2120.1785,1745 Working sample l: 35 2-(3-azido-4 4.0 g of a mixture of the two trans and two cis isomers of methyl -chloro-2-oxo-1-azetidinyl)-2-phenylacetate are dissolved in 50 rnl of dry methylene chloride, and 1 liter of anhydrous calcium carbonate is added to this solution. .13g and 5-methyl-1,B,4-
Thiadiazole-2-thiol2. 1 Og was added. The mixture was stirred in an oven for 81 minutes, poured into ice water, and extracted with ether.

The extract was washed with a 1% potassium carbonate water bath and then with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the remaining tit (4.05 g) was developed on a chromatograph using 160 g of silica gel. The fractions containing the target substance were eluted with chloroform and the solvent was distilled off under reduced pressure to obtain 2-[3
-azido-4-(5-methyl-1,8,4-thiadiazol-2-ylthio)-2-oxo-1-azetidinyl)-2-7 methyl acetate (two trans and tos isomers each) 2.81 g of the mixture was obtained.

Two trans isomers m981-84℃ EngR νcm' (Nujol) 2131J, 1790.178 (J (shoulder), 1745
Two cis isomer engineering R νcm' (film) 212d, 178tJ, 1745 Example 136 8.3-Dimethyl-2-(2-oxo-J-phthalimido-1-azetidinyl) methyl acrylate Q, 3: (
4g, IJ-bromosuccinimide 0.360g and benzoic acid peroxide 0.020ge4m reconstituted element 30
ml and then heated under R flow for 1 hour. After the reaction,
The precipitated substance was determined, and the saliva was iced and dried under reduced pressure to obtain an oily substance. When this is crushed by adding carbon tetrachloride, crystalline 8,3-bis(bromomethyl)-2-(
Methyl 2-oxo-3-phthalimido-1-azetidinyl)acrylate, mpl 27.5-l 31'c was obtained.

Engineering Rνcm>) 17s 0,1770,1730.17
2ONMR (TMS) 61m ((aD-3)2co) 8.75 (3H,s), 4. (7(zH,d,,T=
5Hz) 4j5, 4.75 (2H+AB-q +J-1
tlHz), 4.60.April 7 (2H, AB-Q +
:J-I UHz) *5. b5(lH+, t
+J=5Hz) s7.93 (4H,s) Example 137 3.3-dimethyl-2-(2-oxo-3-7thalimido-l-azetidinyl)acrylic in substantially the same manner as ν11136 When 0.344 g of methyl acid was reacted with 0.178 g of N-bromosuccinimide, the cis A mixture of 331.5*1 isomers and trans isomers was obtained.

Engineering R νam' (film) 1780.1765.171O NMR (TMS) δ1>I)m (ODO13) 2.31.2; 37C3H, ta), 8B4.8H8C
3H,B), 8APr-4,12(2H,m), 412
, 4.76.43814.70 (2H, each AB-q,
J=10Hz ) * 5j '5B 4 (I L
m ) * 7.7 Toy, 96 (4Ht m ) Example 138 3-Bromomethyl-3-methyl-2-(2-oxo-3
-Phthalimido-1-azetidinyl) acrylic methyl 107q was dissolved in N,N-dimethylformamide 21R1, and 5-methyl-1,8,4-thiadiazole-
411rlgi of 2-thiol was added. To this bath liquid, triethylamine Jl~ was added dropwise while stirring while cooling with water, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice diluted hydrochloric acid and extracted with ethyl acetate.

The extract was washed with dilute hydrochloric acid, water, an aqueous sodium bicarbonate solution, and water in this order, and dried over magnesium sulfate. The solution was evaporated to dryness under reduced pressure, and the residue was developed on a column chromatograph using 4 g of silica gel.

It was eluted with chloroform, and the fractions containing the target substance were combined.

3-methyl-3-(5-methyl-1゜8.4-
The eluate containing the trans isomer of methyl thiadiazol-2-ylthiomethyl)-2-(2-oxo-3-phthalimido-1-azetidinyl)acrylate was evaporated to dryness under reduced pressure to yield the same substance 18■. . Similar treatment of the eluate containing a mixture of cis and trans isomers of the compound yielded 30 fng of a mixture of cis and trans isomers of the compound. Further, 28 fng of the cis isomer was obtained in the same manner.

Trans isomer technology R νcm (film) 1790.1770, 1730.172ONMR (TM
8) δppm (ono15) 2.38 (3H, s) #2.73 (3Hee), 8B5
(3H,s), 4.1O (2H@d@, T=5Hm)1
4,2814.78 (2HtAB-qlJ=10Hz)
*5fi4(la, t, J=5ag), 8.0()-7
,76(4a,m)cis isomer νcm' (Nujol) 1780.1760,1730.172ONMR(TM
S) δppm (ODOI3) 2.33 (3Hsg) *2.74 (3H1s), 8B6
(3Ht8)*8.92-4.08 (2H, m)14.
85, 4.72 (2H, AB-qsJ=lOH2)15
,56. a60(lHIdld,,T=5H2).

7.7i', 98 (4] II * m) Example 1
39 In substantially the same manner as in Example 138, 8,3-bis(
Methyl bromomethyl)-2-(2-oxo-3-phthalimito l-azetidinyl)acrylate 500~ and 5-
Methyl-1,8,4-thiadiazole-2-fol 3
By reacting 10 zrq, 8.3-bis(5
-Methyl-1,8,4-thiadiazol-2-ylthiomethyl)-2-(2-oxo-3-7thalimido 1-
590 μm of methyl 7-acrylate (azetidinyl), 7-acrylate were obtained.

Engineering R νcm' (Film) 1790.1770, 1730.172ONMR (TM
S) δppm (ODO]4) 2.75 (3H, G), 2.77 (3H, s), 8j9
0 (3H, 8), 4.13 (2H, cl, J=4H2)
, 4.47,430 (2H, AB-q, J=-14Hz
), 4.77 (2H, 5L5B2 (la, t, J=4a
zL7.40-7.90 (4a, m) Example 140 In substantially the same manner as Example 138, 3-bromomethyl-3-methyl-2-(2-oxo-3-phthalimido-1-azetidinyl) Mixture of methyl acrylate and methyl 8.3-bis(bromomethyl)-2-(2-oxo-3-phthalimido-1-azetidinyl)acrylate2.
54g to 0.870g benzothiazole-2-thiol
3-(2-benzothiazolylthiomethyl)-3-methyl-2-(2-oxo-3-7
Thalimidol-l-azetidinyl) methyl acrylate,!
-8,3-bis(2-benzoteazolylthiomethyl)-
2.53 g of a mixture of methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)acrylate was obtained.

Engineering R νcm (film) 1780.1760.1720 Example 141 2-(3-amino-2-oxo-1-azetidinyl)-
120.236 g of 2-(4-hy)roxyphenyl was suspended in dry chloroform and 0.406 g of bis(trimethylsilyl)acetamide was added. Thereafter, the mixture was stirred overnight at room temperature, 0.200 g of 1-(1,1-dimethoxymethyl)perhydroazepine was added to the mixture, and the mixture was stirred for an additional 2 hours while observing the temperature. Water 3- was added to the reaction mixture and stirring was continued gradually. The mixture was evaporated to dryness under reduced pressure and the residue was suspended in a small amount of acetone. The suspension was stirred at room temperature for 20 minutes and the powder was collected by t-slope method. Repeat this operation 3 times and collect the resulting powder.)
When washed with water, 2-(4-hydroxy7enyl)-2-
0.330 g of (2-oxo-3-(perhydro-1-azevinylmethylene akinol-azetidinyl)acetic acid was obtained.

Engineering R νcm' (Nujol) 350 3400, 1740, 1690.1600 Example 142 5.1 g of methyl 2-(2-oxo-3-phthalimido-1-azetidinyl)-3-phenylthiopropionate and 4.0 g of pyridine was dissolved in dichloromethane It)OdKm, and a solution of 20 tnt of dichloromethane containing 2.0 g of sulfuryl chloride was added dropwise to this solution at 35 to 40°C with stirring at 70 fi, and stirring was continued for one hour at the same temperature. . After the reaction was completed, it was evaporated to dryness under reduced pressure and 10% of ethyl acetate was added.
0Wf! And water 50me+! I - Added and stirred gradually. The ethyl acetate layer was separated, and the remaining aqueous layer was extracted with ethyl acetate. This extract was combined with the ethyl acetate layer and diluted with dilute hydrochloric acid for 3 minutes.
degree, sodium bicarbonate saturated water #! ! 3 times with liquid, 2 times with water
After washing each time, it was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the oily residue was developed on a column chromatograph using 30 g of silica gel. It was eluted with chloroform, and the fractions containing the target substance were combined. The solvent was distilled off under reduced pressure to obtain 4.23 g of methyl 2-(2-oxo-3-7talindole-l-azetidinyl)-3-phenylthioacetate (mixture of trans and cis isomers). This compound l11! ! 1 was crushed and recrystallized with ethanol to obtain 0.84 g of one of the cis and trans isomers. m
l) 170-171°C.

Engineering R νam' (nujol) 1780.1760.1720 (shoulder) 1710.16
1ONMR(TMS) δpl)m (ODO13) 8j(0(31(,5)041(lH,t,,7=6H
g) 14.29 (lH, dsa, J=6H2,3gg)
, 5β3(lLdldl, 7'=6Hffi, 31(g
)e7J-8,0(10a,m) Example 143 D-2-(3-promo-2-oxo-1-1zetidinyl)-2-phenylacetic acid 120■ and sodium azide l
l 44 to N, 11-dimethylformamide 1.2 r
The mixture was stirred at -70°C for 3 hours. After evaporating the solvent under reduced pressure, the residue was added to ethyl acetate and washed with 3% hydrochloric acid and water. The ethyl acetate layer was extracted twice with charcoal, water, sodium saturated water and S solution each. Combine the water layers and
After adjusting the N to pa2 with % hydrochloric acid, the extract was extracted 3 times with ethyl acetate, dried over magnesium sulfate, and then evaporated to dryness under reduced pressure. The oily residue was first passed through a thin layer of silica gel chromium togelaf and developed with a mixture of benzene, ethyl acetate and arsenic acid (volume ratio 6:22 L), and the desired fractions were collected, resulting in D-2-(3 -azido-2-osol
-azetidinyl)-2-phenylacetic acid was obtained. The crystal was identified by the specimen prepared in Example 103 and by R.

Example 144 2-(4-)lans-styryl-2-oxo-3-phthalimido-1-azetidinyl)-2-7ethyl acetic acid (mixture of two cis isomers at positions 3 and 4 of the azetidine ring) ) 18.0g was poured into dichloromethane 300dJ/C#. This l? ! Absorb and explode ozone gas in liquid, -78℃
Absorption continued until the color of ozone appeared (45 minutes). Next, nitrogen gas was blown in at the same temperature for 30 minutes.
6.4 d of dimethyl sulfide was added and left to stand for a while. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was dissolved in dichloromethane. This solution was washed twice with 100% water and an aqueous sodium chloride solution, and dried over magnesium sulfate.

The solution was dried with S under reduced pressure, and the residue was developed on a column chromatograph using 200 g of alumina. Elution was performed with benzene and then chloroform, and the fractions containing the target substance were combined, and the solvent was distilled off under reduced pressure to obtain 2-(4-formyl-2-oquino-3-phthalimido-l-azetidinyl) -2
9.14 g of methyl -phenylacetate (mixture of the two cis isomers at positions 3 and 4 of the azetidine ring) were obtained.

Engineering R νam (film) 1785.17 season Q),, 1730.1710 (shoulder) N
MR (7M8) 'PPm C0DO15) 8EOC3H, B) 9427.4.78CLH, 6 each.
eL, :f=4HI5°6Hz) @5,51,5.79
(IH, each d, T = 6Eg) *6J8゜5J3 (IH,
Each aL7.4a (sHssLtsdo, 94 (4H, m)
e8.79, 9.98 (lH*each A*y=-4Hz
) Example 145 2-(4-formyl-2-oxo-3-phthalimide-
1-azetidinyl)-2-phenyl acetic acid e methyl 390■
and o-benzylhydroxylamine (7170 mg) were dissolved in dry benzene 10-, and the solution was stirred at room temperature for 4 hours and then heated at 50-60°C for 1°C. The reaction mixture was washed with 1 ml of hydrochloric acid, water and an aqueous sodium chloride solution, and dried over magnesium sulfate. This solution was evaporated to dryness under reduced pressure, and the resulting residue was developed on a column chromatograph using 560 to 15 g of t-silica gel. It was eluted with chloroform, and the fractions containing the target substance were combined. When the solvent was distilled off under reduced pressure, 2-(4-benzyloxyimino-
2-oxo-3-phthalimido-1-azetidinyl)-
530~ of 2-phenylacetic acid was obtained.

R νam' (film) 1790.1780.1750 (shoulder), 1730 Example 146 2-(3-azido-4-hol is 2-oxo-1-7
2.30 g of zetidinyl)-2-phenylacetic acid, hydrogenated #
A mixture consisting of 310 fl#g of sodium boronate, 40 d of ethanol, and 51 R1 of water was stirred at 10 to 0°C for 1 hour. Add 10% hydrochloric acid to the reaction mixture at 11fl temperature to give XlH4~5 [! [did. The ethanol was then distilled off and sodium chloride was added to the aqueous residue. Obtained water S
The liquid was extracted twice with chloroform, and the extract was washed with an aqueous sodium chloride solution.

After drying with magnesium sulfate, it was evaporated to dryness under reduced pressure, and the residue was developed on a column chromatograph using 2.02 g of alumina and 20 g of alumina. It was eluted with chloroform, and the fractions containing the target substance were combined. The solvent was distilled off under reduced pressure to obtain 0.95 g of methyl 2-(3-azido-4-hydroxymethyl-2-oxo-1-7zetidinyl)-2-phenylacetate.

Engineering R νam (film) 3450.2130.1780 (/#), 1770.1
740 Example 147 2-(4-formyl-2-oxo-3-phthalimide-
Methyl 1-azetidinyl)-2-phenylacetate 0.38
A mixture of 0.92 g of silver oxide, 9 me of tetrahydrofuran, and 1 ml of water was stirred in a separate chamber for 400 hours. Insoluble matter was filtered off, and tetrahydrofuran was distilled off under reduced pressure.

Water was added to the residue, the pH was adjusted to 2 with 10 g of hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with a 1% aqueous sodium bicarbonate solution, and adjusted to pH 2 with washing solution t-10'16 hydrochloric acid.

This aqueous solution was extracted with ethyl acetate, and this extract and the previous extract were combined, washed with water, and dried over magnesium chloride. When the solvent was distilled off under reduced pressure, 2-(4-carboxy-2-oxo-3-phthalimido-1-azetidi-2)-2
-7x methyl nylacetate (mixture of two cis isomers at positions 3 and 4 of the azetidine ring (aJ and (b)) 200
~was gotten.

Engineering R νam (film) 260 to 2500, 1770, 1760, 174 to 17
2t) NMR (7M8) δppm ((ODD)200) Isomer (a); Isomer (b); 8-
66 (3Hls) 8f39 (J
Hs s ) 4.89 (Ig, a, J = 5ag)
4.78 (IHtd, y=5Hz) 559 (lHss)
556 (IFI+s) 5.89 (IH,
do, T=5Hz) 6.79 (IH, d, J=5
Hz) 7.28-7.70 (5H, m) 7.2
4.70 (5H, m) 7Jl flj4 (4H, m)
7.8()=&54(4)f,m) Example 30
The following compound (Example 14) was prepared by substantially the same method as
8-150) were obtained.

Fruit 2 @ Example 148 D-2-(3-amino-2-oxo-4-pheni-1
-7zetidinyl)-2-(4-hydroxyphenyl)methyl acetate [3-α-4-α-coordination of azetidine ring].

Engineering R νam (Nushor) 3250.1745, 1735 (scrap) NMR (TMS) δppm (aDe16) 8.73 (3a, s), 4.52 (lH, a,, y=6
az), 5J3CIH, d, ; J=6Hz>, 537
(lH,B), 6.47-4.34 (9HI m ) Example 149 D-2-(3-amino-2-oxo-4-phenyl-1
-azetidinyl)-2-(4-hydroxyphenyl)methyl acetate [3-β-4-β-coordination of azetidine ring].

Engineering R νam' (Film) 33L) 0.1750.173O NMR (TMS) δppm (CD015) 8.48C2HI Broad 5) s8j58 (JH9s)
e4.21 (IH, 1, J = 6gZ), 4.78 (IH
, d, J=6Hz) 15.2' (l HI 8 )
16.70 (2a*a*J=lOHg)
*7.16-4.52 (5Hzm)* 7.08 (2
]1! sd*J=10Hg) Example 150 Methyl D-2-(3-amino-4-hydroxymethyl-2-oxo-1-7zetidinyl)-2-phenylacetate [
A mixture of cis isomers of 2') at the 3- and 4-positions of the azetidine ring].

R νam' (film) 3400.1760.1740 3-amino-2-azetidinone compound and 2-(2;2-cy/CIroacetoΦ
The following compounds (Examples 150 and 152) were obtained by reacting ξ)-2-phenylacetic acid.

Example 151 D-2-(3-(2-hydroxyimino-2-phenylacetamide)-2-ogiso-4-phenyl-1-azetidinyl)-2-(4-hydroxyphenyl)methyl acetate [3 of azetidine ring −α−4α −self position )om
p209-211''C.

Engineering R νam' (nujol) 32711.1765,17: (5,1645 Example 1
52 D-2-(3-(2-hydroxyimino-2-phenylacetamide)-2-oxo-4-pheny/l/-1-azetidinyl, :l-2-(4-hydroxyphenylacetate methyl 3-β-4-β-coordination of azetidine ring:) o
mpl 91-l 92-5°C.

Engineering R νam' (nujol) 335 (J, 3280.174υ, 1710.1670
IJMR(TMEI) δIl'19m ((ODS)280]856C3H+
s), 4.95 (iHId, J=6Hg), 528 (l
) (, a) t518 (IH, d, d, J=6.8Hz)
, 6.484.56 (14H, m).

9.40CIH, d, J=8Hz), 9.54CIH,
e) The following compound (actual mga 153) was obtained by hydrolysis to the corresponding compound alIJ' having a methyl ester base in substantially the same manner as in Example 110.

Example 153 2-(3-(2-hydroxyimino-2-phenylacetamido)-2-oxo-4-phenyl]-2-(4-hydroxyphenyl)acetic acid C at the 3rd and 4th positions of the azetidine ring 2 cis isomers].

Engineering R νam'(nujol); (260,1735 (waste →, 1710.1650 Example 154 2-(3-azido-2-oxo-1-azetidinyl)-
After 0.529 F of 2-phenylacetic acid and 0.18 F of sodium bicarbonate were dissolved in 3 ml of water and 5 rnl of methanol, 0.26 F of 1096 palladium on carbon was added and catalytic reduction was carried out at room temperature in a hydrogen stream. After absorbing the calculated amount of hydrogen gas for about 2 hours, the catalyst was removed. Methanol is distilled off from the liquid under reduced pressure, and the remaining aqueous solution is washed with ethyl acetate.

When this aqueous solution is freeze-dried, the sodium salt of 2-(3-amino-2-oxo-1-azetidinyl)-2-phenylacetic acid [two isomers at the 3-position of the azetidinone ring (
A mixture of a) and (bl), 10.41 g was obtained.

R νas' (film) 1740, 160O NMR (TMSP) δppm (D20) Isomer (a): 2.91 (IH, d, d, J=2.5Hz, 5
Hz) 3.78 (IH, t, J=5Hz) 472
(IH, d, d, J=2.6Hz, 5Hz)5.
32 (IH, 8) 7.40 (5H, m) Isomer (b): 404 (IH, t, J=5Hz) 420 (IH, d, d, J=2.5Hz, 5H
z) 472 (IH, d, d, J=2.5Hz,
5Hz) 5.30 (IH, r,) 7.40 (5H, m) Example 155 3-(3-azido-2-oxo-1-azetidinyl)-
3-Phenylpropionic acid was fused and reduced in substantially the same manner as in Example 154 to obtain 3-(3-amino-2-oxo-1-azetidinyl)-3-phenylpropionic acid methyl ester.

νcm’ (film)

Claims (1)

[Claims] General formula ▲ Numerical formula, chemical formula, table, etc. iminomethyl, aryl, aralkenyl, formyl, carboxy or a residue of a nucleophilic compound, and R^3 is a group ▲ has a mathematical formula, chemical formula, table, etc. (wherein R^4 is aryl, aralkyl, arylthio (wherein R^6 is alkyl, haloalkyl, heterocyclic thioalkyl or and R^7 means a hydrogen atom, haloalkyl or heterocyclic thioalkyl, and R^5 has the same meaning as above), R^1 is amino, substituted amino or azide, and When R^2 is an aryl, halogen, or sulfur residue of a nucleophilic compound, R^3 is a group ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in the group,
R^4 and R^5 have the same meanings as above), groups ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (in the groups, R^6 is alkyl or heterocyclic thioalkyl,
and R^7 means heterocyclic thioalkyl, R^5 has the same meaning as above) or a group ▲ has a mathematical formula, chemical formula, table, etc. ▼ (in the group, R^5 and R^8 have the same meaning as above) The alkanes, arenes and heterocycles in each group defined in the above formula may have one or more suitable substituents at any position.]
Azetidinone compound represented by