JPS6230743A - Novel compound, manufacture and medicinal composition - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION OBJECTS OF THE INVENTION Industrial Application The present invention relates to a group of β-lactam derivatives having antibacterial activity and having value in the treatment of infections in animals, including mammals and especially humans. Regarding. In particular, the present invention relates to a group of β-lactam derivatives having an acyl group in the side chain derived from vinylglycine or a substituted derivative thereof. The invention also relates to processes for the preparation of such compounds, and to pharmaceutical compositions containing them.

[Structure of the invention]

Means for Solving the Problems The present invention is based on the formula (1) %formula% (wherein R1 is a group [wherein R''rR3 and R4 are the same or different, each is hydrogen;), rogene; substituted Cl may be
-a alkyl, optionally substituted C3-7 cycloalkyl; optionally substituted C2-6 fulkenyl; optionally substituted C2-6 alkynyl; amido; cyano; carboxy; formyl + C1-6 alkoxycarbonyl ; mono- or di(Cl-a)alkylamide + C1-6 alkylcarbonyl; aryl group; heterocyclyl group, or R3 and R4 are bonded together to give a total of 3 to 7 carbon atoms on the ring; or R3 and R4 are joined together to form a carbon residue with R3
and R4 together form -(CH2)mX (CHg
) n - (wherein X represents oxygen, sulfur or the group NR5, where R5 is hydrogen, acyl, an amino protecting group or CL
6 alkyl, m is 1-3, and n is 1-3
3), and Y is [wherein R1γ is hydrogen or C1-6 alkyl;
Rts and Rle may be the same or different, each being C2-6 alkyl and di; p is an integer having the value 0.1 or 2, and Yl is oxygen, sulfur, 5O9SO
x t or -CHz-; and Z is hydrogen, ) rogen or C1-4 alkoxy, -CHzQ or -
CH=CH-Q (wherein Q is hydrogen,)-logen, hydroxy, mercapto, cyano, carboxy, carbamoyloxy, carboxyl ester, Cl-4 alkyloxy, acyloxy, aryl, heterocyclyl group bonded via carbon , a heterocyclylthio group or a nitrogen-containing heterocyclic group bonded via nitrogen], where Y is -S -C(CH3)
2- and R2 is methyl, R3 is R4
cannot be hydrogen when is phenyl, and R3 is R4
is hydrogen, it cannot be phenyl), or a pharmaceutically suitable salt or in vivo hydrolyzable derivative thereof.

Preferably, Y is -8-C(CF(3)z-, -8-C
Hz-.

-S -CH2-C(CH2Q) =: or -
O-CH2-C(CH2Q)=.

Preferred values for Y in the compound represented by formula (1) are -8-C(CHxh- and -S-CH2-C(CH2Q)=, that is, the compound represented by formula (1) is It is a derivative of phosphorus.

A particularly preferable value for Y is -3-C(CH3)2-0.The 114 groups present on these groups R2, R3 and R4, which have the same meaning as above and may be substituted, include halogen, Carboxy, C1-s alkoxycarbonyl, carbamoyl, aryl, heterocyclyl, hydroxy, CI-a alkazyloxy, cyano, amino, CI-6 flukanoylamino, mono- or di(
CI-s) alkylamino, aryl (CI-s)
Alkylthio, CI-. Includes alkoxy or C3-7 cycloalkyl.

As used herein, the term "aryl" includes five
fluorine, chlorine, C]-6 alkyl, C,-, flukoxy, 7-alkyl, hydroxy, amino, carboxy, C troalkoxycarbonyl or C8-6 alkoxycarbonyl (CI-a) g) Includes phenyl and naphthyl which may be monosubstituted with an alkyl group.

The term "heterocyclyl" herein refers to a single or fused aromatic or non-aromatic heterocyclyl linked via a carbon atom to the rest of the molecule, which contains oxygen, nitrogen and Containing up to 4 heteroatoms selected from sulfur and up to 3 nohalogens, Cl-6 alkyl, CI. Alkoxy, halo (C>-a)-alkyl, hydroxy, amine, carboxy, C1-5 alkoxycarbonyl, CI-a alkoxycarbonyl (C
l-6) May be substituted with furkyl, 71J-l or oxo group. Preferably the heterocycle contains 4 to 7 ring atoms, preferably 5 or 7 atoms. Depending on the nature of the heterocyclyl group, certain compounds encompassed by formula (1) may appear in two or more tautomeric forms, which are encompassed within the scope of the present invention.

The term halogen means fluorine, chlorine, bromine and iodine.

Honmei? #i As used herein, the term "acyl" means Cl-6 alkylcarbonyl, arylcarbonyl or arylC1-6 alkylcarbonyl.

As used herein, the term "amine protecting group" refers to an "amine protecting group" that is easily cleaved to release a free amino group (-NH2 or -
means a group bonded to nitrogen that can give NH-).

Such groups and the conditions for their cleavage are well known in the art [e.g.
protective Groupsin Organi
cSynthesis) J + T meeting WsGrec
John Wile 7 and 5ons, 1
981)]. Examples of amino-protecting groups include those substituted on the phenyl group by one or two substituents selected from 01-4 alkyl, Cl-4 alkoxy, trifluoromethyl, 1-10 gene or nitro. Cl-4 alkoxy, optionally substituted on the alkyl group by up to 3 substituents selected from Cl-4 alkoxy, halo or nitro; Carbonyl, sidelight Id 2
,2,2-IJ chloroethoxycarbonyl or 1-chloroethoxycarbonyl.

As used herein, the term carboxylic acid ester includes Ct-6 alkyl, C2-6 alkenyl and aryl C1-6 alkyl esters, and easily cleavable esters such as and other ester groups described herein below as being removable under normal conditions.

The marked carbon atom in formula (1) is asymmetric and the compound has the D-1L- or DL-configuration I at that position.
7'o can be derived from a side chain with tk. All forms represented by formula (1) are included in the present invention. Preferably the crossed carbon atom is derived from the D-configuration and compounds with that configuration are referred to herein as D-stereoisomers.

The term “in vivo hydrolysable derivative” includes the formula (
In vivo hydrolyzable esters and other pro-drugs of compounds represented by 1) are included.

Ester group adhesives that can be hydrolyzed in vivo and are suitable as pharmaceuticals include those that easily decompose in the human body and leave the original acid or its salt. A suitable ester group of this type has subformula (1) below.

(11) and (i*i) can be determined.

Ha-CO2CH-0. CO,R(1) -CO2Rc -N (i+) ■ e -C02CH20Rf(!If) In the formula, Ha is hydrogen, methyl or phenyl,
Rb is Cl-6alkyl RC represents C1-6 alkylene which may be substituted with a methyl or ethyl group, Rd and R8 independently represent C3-6 alkyl; Rf represents Cl-6 alkyl. Examples of suitable in vivo hydrolyzable ester groups include acyloxyalkyl groups such as acetoxymethyl, piparoyloxymethyl, α-acetoxyethyl and α-piparoyloxyethyl groups; ethoxycarbonyloxymethyl and α- Alkoxycarbonyloxyalkyl groups such as ethoxycarbonyloxyethyl; dialkylaminoalkyl, especially di-lower alkylaminoalkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; lactones such as thallidyl and dimethoxyphthalidyl Included are groups of the formula: where R6 is hydrogen, Cl-6 alkyl or phenyl; groups attached to a second β-lactam antibiotic or to a β-lactapase inhibitor.

As can be easily understood by those skilled in the art, the compound of the present invention represented by formula (+) has an amine group and C0N in the side chain.
It contains a H moiety and therefore forms cyclic derivatives when reacted with aldehydes (eg formaldehyde) or ketones (eg acetone). Such cyclic derivatives are also additional examples of in vivo hydrolyzable derivatives or premedicines of compounds of formula (1).

Thus, according to another aspect of the invention, the formula (wherein R''
1" and Y have the same meanings as in formula (1) above, and R7 and R8 are the same or different, each being hydrogen or C1-6 alkyl) A pre-medicinal compound or a pharmaceutically suitable salt or in vivo hydrolyzable ester thereof is provided.

Preferred compounds encompassed by formula (1a) include R7 and R
Included are those in which all 8 are hydrogen or all methyl.

The compounds of the invention contain both amino and carboxyl groups and therefore can exist as counterions or form salts with suitable acids or bases.

Suitable pharmaceutical salts of compounds of formula (1) or (1a) include metal salts, such as aluminum salts,
alkali metal salts such as sodium or potassium;
alkaline earth metal salts such as calcium or magnesium, and ammonia or U-substituted ammonium salts, e.g. lower alkylamines such as triethylamine, 2-hydroxyethylamine, bis-(2-hydroxyethyl)-amine or tri(2-hydroxyethyl)-amine; -hydroxy-lower alkylamines such as -hydroxyethyl)-amines, with cycloalkylamines such as bicyclohexylamine, procaine, dibenzylpiperidine,
Included are N-benzyl-β-phenethylamine, dehydroabiethylamine, N-N'-pisdehydroabiethylamine, ethylenediamine, or with pyridine type bases such as pyridine, collidine or quinoline.

Suitable acid addition salts of compounds of formula (1) or (1a) include pharmaceutically suitable inorganic salts such as sulfates, nitrates, phosphates, borates, hydrochlorides and hydrobromides; and acetates, tartarates, maleates, citrates, succinates, benzoates, ascorbates, methanesulfonates, α-ketogeltanates, α-glycerophosphates and glucose-1-phosphates. Included are organic acid addition salts suitable as pharmaceutical agents. Preferably, the acid addition salt is hemisuccinate, hydrochloride, α-ketoglutarate, α-glycerophosphate or glucose-1-phosphate, especially the hydrochloride.

Salts encompassed by formula (+) or (1a) can be prepared by salt exchange using conventional methods. For example, an aqueous solution of a lithium salt can be prepared from an ion-exchange resin bed in the sodium form (e.g., A
mberlite IR120; sodium salt of sulfonated polystyrene divinylbenzene copolymer) in approximately a 10-fold excess until elution is complete. The resulting sodium salt can be obtained by freeze-drying or the like.

Similarly, sodium salts can be converted to lithium salts and sodium salts can be converted to sodium salts in a similar manner. (Note: Amber
lite is a trade name) C1-6 alkyl groups suitable as R3 and R4 may be straight chain or branched silver, methyl, ethyl,
Included are n- or iso-propyl, n-1see-, iso- or tert-butyl. In these cases where the Cl-11 alkyl group has a substituent, Hs.

Preferred groups for R3 and R4 include methyl, ethyl and n-propyl.

Suitable C3-1 cycloalkyl groups for R2, R3 and R4 include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Suitable C2-7 alkenyl groups for R"#R" and R4 include KH ethynyl, propenyl and butenyl.

Suitable C2-6 alkynyl groups for R2, R3 and R4 include ethynyl, propynyl and butynyl.

Preferably, when R3 and R4 are joined together to form a carbocycle, the carbocycle contains a total of 3,4.5 or Fi6 carbon atoms in the ring. The carbocycle may be fully saturated or contain up to two conjugated or non-conjugated double bonds.

Preferably, one of the integers n and m has a value of 2 when R'' and R4 are joined together to form a heterocase.

Preferably, n and m are both 2.

Suitable aryl groups as R2, Rs and R4 include phenyl, Cl-6 alkyl, hydroxy, C1-
It may be mono- or di-substituted by 6-alkoxy, trifluoromethyl, chlorine or fluorine.

Suitable heterocyclyl groups K as R2, R3 and R4
Included are 12-chenyl, 3-chenyl, 2-71J/I/, and 3-furyl.

More preferably R2 is hydrogen, methyl, ethyl, hydroxymethyl, methoxymethyl, phenyl or 2-chenyl.

More preferably R3 is hydrogen, methyl, acetoxymethyl,
Ethyl, hinyl, cyclohexyl, 4-cyclophenyl, phenylmata are chlortheal.

More preferably R4 is hydrogen, methyl or chloro.

One group of preferred sub-concepts encompassed by the present invention is the formula ([1
) (wherein R'', R3r R' and 窀 have the same meanings as above) or a pharmaceutically suitable salt or ester thereof which can be hydrolyzed in vivo.

Preferred groups for R2 include hydrogen, phenyl, methyl and ethyl.

Preferred groups for R3 and R4 include hydrogen, ethyl and chlorine.

In one preferred aspect of the invention, R21R3 and R4 are all hydrogen.

In a particularly preferred aspect of the invention R2 is hydrogen and R3 and R4 are both chlorine.

In another particularly preferred aspect of the invention R3 is ethyl and R2 and R4 are both hydrogen.

Furthermore, in another particularly preferred aspect of the invention, R2 is hydrogen and R3 and R4- together form a carbocycle having a total of 6 carbon atoms.

Since the β-lactam antibiotic compounds of the present invention are intended for use in pharmaceutical compositions, they are each in substantially pure form, e.g., at least 50% pure, more preferably at least 75% pure. and preferably at least 9
It will be readily understood that 5% pure 1% is provided on a weight/quantity basis. Impure formulations of compounds can be used to prepare purer forms for use in pharmaceutical compositions. Although the purity of the intermediate compounds of the present invention is less important, it will be readily appreciated that substantially pure forms are preferred for β-lactam antibiotic compounds. Preferably, whenever possible, the compounds of the invention are obtained in crystalline form.

Certain compounds of the invention can be crystallized or recrystallized from aqueous solvents. In such cases, water of hydration may be formed. The present invention also includes within its scope stoichiometric hydrates as well as compounds containing varying amounts of water that can be produced by treatments such as lyophilization.

Suitable values for Q in the compound represented by formula (1) or (1a) include acetoxy, a heterocyclylthio group, and a nitrogen-containing heterocyclic group bonded via nitrogen.

When the group 2 having the same meaning as above is -CH=CHQ, preferred values of Q include 4-methyl-1,3-thiazol-5-yl. The heterocyclylthio group is preferably of the formula % % (wherein, Het is unsubstituted or C1-6 alkyl, C1
-6 alkoxy, aminoalkyl, hydroxyalkyl, C+-a fulkenyl, alkoxyalkyl, carboxyalkyl, sulfonylalkyl, carbamoylalkyl, trifluoromethyl, hydroxy, halogen, oxo, mono- and di(C+-a) alkylaminoalkyl and 1 or 2 selected from carboxyalkyl
is a 5- or 6-membered heterocycle containing 1 to 4 atoms substituted with 2 groups, or the 2 substituents can be joined to form a heterosalt or a carbocyclic residue.

Examples of groups r Het J include unsubstituted or substituted imidazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxasilyl, triazinyl and oxadiazolyl.0 Suitable groups r Het J include 1,2.3-) riazolyl, 1.2.4-) riazolyl, tetrazolyl, oxacylyl, thiazolyl, 1,3.4-oxadiazolyl, 1.3.4-thiadiazolyl or 1,2.4-thiadiazolyl. Thus, a heterocyclylthio group can be, for example, 1-methyl-IH-tetrazol-5-ylthio, 2-methyl-1,3,4-thiadiazol-5-ylthio, 1-rupoxymethyl-IH-tetrazol-5-ylthio.
It may be ylthio or 6-hydroxy-2-methyl-5-oxy-2H-1,2,4-triazin-3-ylthio.

When the group Z having the same meaning as above is CH, Q, a preferable heterocyclylthio group has the following structure 1
, 2.3-triazol-4-ylthio.

The nitrogen-containing heterocyclic group bonded via nitrogen is preferably an optionally substituted pyridinium group, preferably the pyridinium group is Cl-a alkyl 1C 1-6 alkoxy, hydroxyalkyl% Cl-6 fluorenyl, Substituted with one or two groups selected from alkoxyalkyl, carboxyalkyl, sulfonylalkyl, carbamoylmethyl, carbamoyl, trifluoromethyl, hydroxy, halogen, oxo and aminoalkyl.

More preferably, the nitrogen-containing heterocyclic group bonded via nitrogen is an optionally f-substituted tetrazolyl group, particularly 5-methyltetrazolyl-2-yl having the following structure.

Specific compounds encompassed by the present invention include the following or their pharmaceutically suitable salts or in vivo hydrolysable esters:

6β-(D-2-aminopt-3-enamido)penicillanic acid, 6β-(D-2-amino-3-phenylpt-3-enamido)penicillanic acid, 6β-(D-2-amino-4,4-dichlorpt) -3-
7β-(D-2-amino-3-methylpt-3-enamido)cephalosporanic acid, 7β-[0 -2-amino-3-methylpt-3-ninamide]-3-desacetoxyhsialosborin, 6β-(D-2-amino-3-ethylpt-3-enamide)penicillanic acid, 6β-(D -2-amino-3-methylpent-3(E)
-enamido)penicillanic acid 6β-(D-2-amino-pent-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-3-methylhex-3(E)
, 5-dienamido)penicillanic acid, 6β-(D-2-
Aminohex-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-4-cyclohexylpto-3
(E)-enamido)penicillanic acid, 6β-(D-2-
Amino-4-phenylpt-3-(E)-enamido)penicillanic acid, 6β-[D,L-2-amido-4-
(4-Chlorphenyl)put-3(E)-enamido]penicillanic acid, 6β-(D-2-amino-3-trifluoromethylput-3-enamido)penicillanic acid, 6β-(D-2-amino- 3-thien-2-ylpt-3-enamido)penicillanic acid, 6β-(D,L-2-amino-4-chloro-3-thien-2-ylpt-3(Z)-enamido)penicillanic acid, 6β- (D,L-2-amino-4-chloro-3-thien-2-ylft-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-4-chloro-3-methylbut-3(E) )-enamide) penicillanic acid, 6β-(D,
L-2-amino-4-chloro-3-methylbut-3(
Z)-enamido)penicillanic acid, 6β-[5-acetoxy-D-2aminopent-3(E)-enamido]henicillanic acid, 6β-(D-2-amino-3-cyclohexylidenepropanamide)penicillanic acid, 6β-(I), L-2-amino-4-methoxy-3-
methyleneputanamide) penicillanic acid, 6β-(D-2
-Amino-4-methylpent-3-enamido)penicillanic acid, the compound represented by formula (1) has the formula (Ill)H (wherein, even if the amine group is replaced by a group capable of causing acylation) and RX is hydrogen or a carboxyl blocking group), a compound of the formula (
IV) R1-CH,C02H Nl2 (IV) (wherein R1
and (1) have the same meaning as in the above formula (1), and any reactive group may be protected). and then, if necessary, the following step (+) removing any carboxyl blocking group Rx (11) removing any protecting group elsewhere in the molecule, (Di > converting the product to its salt or It can be produced by performing one or more of the following steps: hydrolysis in the body and conversion into vine derivatives.

The in vivo hydrolyzable derivative (pre-medicinal) represented by formula (Ia) can be obtained by a conventional method, that is, the compound represented by formula (1) or its pharmaceutically suitable salt or in vivo hydrolyzable ester. An aldehyde represented by the formula (wherein R7 and R8 have the same meanings as above) can be produced by reacting with a ketone.

Formula (1)″ or (1
The compound represented by a) can be separated according to conventional methods from a mixture of diastereomers represented by formula (1) or (1a), or can be prepared from an amino acid represented by formula (IV) having the D configuration.

The amino group in the α-amino acid of formula (V) is usually seeded with a blocking group that can be removed before the reactive N-acylating derivative is formed. Alternatively, amino acids (
The amine group in IV) can be protected by prior formation of an acid addition salt, for example a hydrochloride.

Suitable groups capable of undergoing acylation and which may be present on the amino group of the starting material of formula (ill) include N-silyl, N-stannyl and N-phosphorus groups, such as trimethylsilyl. trialkylsilyl group, trialkyltin group such as tri-n-butyl, formula -P,R
'R10 (wherein Rs is alkyl, haloalkyl, aryl, aralkyl A alkoxy, haloalkoxy,
preferred such The phosphorus group is -P(
OCzH++)x, -P(C2E(5)2゜Formula (IV
Suitable amine blocking groups that can be used to block the amino groups in ) are those amino protecting groups that are well known in the art and are removed under normal conditions without destroying the remainder of the molecule.

Particularly preferred examples of amino-protecting groups that can be used in derivatives with protected amine groups include 2.2.2-) IJ dichlorothyloxycarbonyl and 3-methoxycarbonylpro-7''-2-enyl-yl. .

Carboxy-blocking derivatives suitable as the group -COzRx in formula (Ill) K include salts and esters of carboxylic acids. The derivative is preferably one that can be easily cleaved at a later stage of the reaction. Suitable salts include metal salts, such as those with sodium, potassium and lithium, and tertiary amine salts, such as tri-lower alkylamines, N-ethylpiperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine, dimethyl Includes those with piperazine.

A preferred salt is with triethylamine.

Suitable ester-forming carboxy blocking groups are those that can be removed under normal conditions. Such groups as RIC include benzyl, p-methoxybenzyl, 2.4.6-
Trimethylbenzyl, 3,5-di-t-7'f-4-
Hydroxy-benzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2.2.2-) lipromuethyl, 2.2.2-) lipromuethyl, t-butyl, t-amyl, diphenylmethyl, triphenylmethyl, Adamantyl, 2-benzyloxyphenyl, 4-
Methylthiophenyl, tetrahydrofuran-2-yl,
Tetrahydropyran-2-yl, pentachlorfe
p-) Luenesulfonylethyl, methoxymethyl;
Silyl, stannyl or phosphorus-containing groups, such as those mentioned above, of the formula -N=CHR11, where R11 is an aryl or a heterocycle, or an in vivo hydrolyzable ester radical with the same meaning as above. It includes the oxime radical represented by

Carboxyl groups can be hydrogenated by conventional methods appropriate to the particular RX group, such as by acid- and base-catalyzed hydrolysis, or by enzyme-catalyzed hydrolysis, or under conditions that leave the rest of the molecule unaffected. can be regenerated from any of the above esters.

Reactive N- of salts or N-protected derivatives of amino acids (IV)
Acylating derivatives are used in the above method.

The choice of reactive derivative can of course be influenced by the chemical nature of the acid substituents.

Suitable N-acylating derivatives of the salts or N-protected derivatives of the acid of formula (fV) include acid rides, preferably acid chlorides or bromides.

Acylation with acid halides involves acid binders, such as tertiary amines (e.g. triethylamine or dimethylaniline), which bind the nine hydrogen halides liberated in the acylation reaction;
This can be accomplished in the presence of an inorganic base (eg calcium carbonate or sodium bicarbonate) or an oxirane. The oxirane is preferably a (C1-5)-1,2-alkylene oxide, such as ethylene oxide or propylene oxide. Acylation reaction Fi using acid halide
-s.

℃ to +50℃, preferably -20℃ to +20℃
acetone aqueous solution, tetrahydrofuran aqueous solution, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1.
The 2-cyclolethanemata is carried out in an aqueous or non-aqueous medium such as a mixture thereof. Alternatively, the reaction may be carried out in a water-immiscible solvent, especially an unstable emulsion of an aliphatic ester or ketone such as methyl isobutyl ketone or butyl acetate. Derivatives can be prepared by reacting the derivatives with halogenating (e.g. chloride or bromide) agents such as phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Alternatively, the N-acylating derivative of the salt or N-protected derivative of amino acid (IV) may be a symmetrical or mixed anhydride. Suitable mixed anhydrides are alkoxyformic anhydrides or, for example, carbonic monoesters, trimethylacetic acid, thioacetic acid, diphenylacetic acid, benzoic acid, phosphorous acids (for example phosphoric acid or phosphorous acid) or aliphatic or aromatic sulfonic acids (
For example, p-toluenesulfonic acid). The reaction is carried out in the presence of an organic base such as triethylamine.

Further N-acylating derivatives of the salts or N-protected derivatives of acid (IV) are acid azides; or 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2,4-
Dinitrophenol, thiophenol, halophenols (including pentachlorophenol), monomethoxyphenol, N-/hydroxysuccinimide, N-
Activated esters such as esters with hydroxybenzotriazole or 8-hydroxyquinoline; or amides such as N-acylsaccharin or N-acylphthalimide; or alkylideneiminos prepared by reaction of acid (IV) with oxime. It's ester.

Salts of acids (IV) or other reactive N- derivatives of N-
The acylated derivative is a condensing agent, such as a carbodiimide,
For example N,N'-diethyl-, di-n-propyl- or diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, or N-ethyl-N'
-3-dimethylaminopropylcarbodiimide; suitable carbonyl compounds such as N,N'-carbonyldiimidazole or N,N'-carbonylditriazole:
Isoxazolinium salts, such as N-ethyl-5-phenyl isoxazolinium-3-sulfonate or N
-t-butyl-5-methylisoxazolinium perchlor; til″l″N-alkoxycarbonyl 2
-alkoxy-1,2-dihydroquinoline, e.g. N-
Includes a reactive intermediate generated in situ by reaction with ethoxycarbonyl 2-ethoxy-1,Z-dihydroquinoline. Other condensing agents include Lewis acids; or phosphoric acid condensing agents such as diethylphosphoryl cyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example dichloromethane, dimethylformamide, acetonitrile, alcohol, benzene, dioxane or tetrahydrofuran.

The compound represented by formula (IV) is represented by formula (IVA)R''
CC02H j (wherein R1 has the same meaning as above, and R is hydrogen, Cl-6 alkyl, C2-6 alkenyl, C3-7
cycloalkyl or aryl C1-6 alkyl) or a salt or ester thereof with a reducing agent that does not substantially affect the rest of the molecule, and then, if necessary, convert the product to the free acid. It can be manufactured by conversion.

Suitable reducing agents include, for example, zinc in the presence of formic acid, and other reagents known in the art to be able to convert hyoximes and oximinoethers to amines.

The compounds of formula (IVA) are new and form another aspect of the invention.

The compound represented by formula (IVA) is 5yn- or an
It will be understood that ti - may have either stereochemistry. Both the qyn- and anti-stereoisomers and mixtures of these two stereoisomers in any proportion are within the scope of this invention.

Preferably, the group R in the compound of formula (IVA) is methyl.

According to the present invention, there is also provided a method for producing a compound represented by formula (IV) from a compound represented by formula (IVA) by the above-mentioned method.

The compound represented by formula (IVA) can also be represented by formula (fVB) (
In the formula, R, R2, R3 and R4 have the same meanings as above).

The compound represented by formula (IVB) can be prepared by various methods.
For example, it can be produced by the Wlttig or modified Wittig reaction shown in the schematic diagram below. In addition, R in the diagram
, R2, R3 and R4 have the same meaning as above, and RX
is a readily removable carboxylic acid blocking group that can be removed at the end of the synthesis, Ar is an aryl group with the same meaning as above, and R2O is Cl-6 alkyl.

Details of the conditions and reagents used to achieve the transformations shown in the above formulas are found in the Examples below.

Preferably the group Ar is phenyl, di, and R” Fi
C1-4 alkyl, especially methyl.

The compound represented by formula (IV) can also be produced by deprotecting the N-protected derivative of the compound represented by formula (IV).

Useful intermediates of this type have the formula (IVC), where R''
sR3, R' and RX have the same meaning as above)
These can be converted into compounds of formula (IV) by treatment with an aqueous mineral acid solution, for example 5N hydrochloric acid, and then, if necessary, removing the group RX.

The compound represented by formula (iVc) is F', He1nze
r andD, Be1luspHelv, Chem, A
cta, + 1981, 64 m 2279 by reacting 2-oxazoline, appropriately placed in a suitable solvent such as ditetrahydrofuran, with activated zinc powder. .

Formula (V) (wherein Yl, r Het J , R" and R
A subgroup of compounds represented by the formula (Vl) RH (wherein Y"sR"*Rx and bone have the same meanings as above, and where any The reactive group may also be protected and is suitably prepared by reacting a compound of the formula (RH is a leaving group) with a thiol of the formula.

Suitable leaving groups R12 include halogens such as iodine or bromide ions, acyloxy groups such as the acetoxy group, or aryl- or C1 such as p-toluenesulfokyloxy or methanesulfonyloxy.
-6 alkylsulfonyloxy group is included.

The thiol HetSH can be reacted as a free compound or as a salt with an alkali metal such as sodium or potassium. This reaction is preferably carried out in a solvent. For example, water or an organic solvent inert towards the starting compounds,
For example, dimethylformamide, dimethylacetamide,
It is possible to use dioxane, acetone, alcohol, 1,2-dichloroethane, acetonitrile, dimethylsulfoxide or tetrahydrofuran or mixtures thereof.

The reaction mixture and time will vary depending on the starting compound and solvent used, among other factors, but generally the reaction will be between 0 and 1
The temperature is maintained at a selected temperature within the range of 0.000 C for a selected period of time ranging from several hours to several days.

The reaction is preferably carried out at a pH of 3 to 7.

In order to prevent oxidation of the thio compound, the -reaction is preferably carried out in an inert gaseous atmosphere, for example ♀ elementary gas.

A group of sub-concepts encompassed by the present invention and represented by the formula (■) (wherein RITY"lRX and Tatami have the same meanings as above, and R13 is an optionally substituted pyridinium group) The compound can be produced by reacting a compound represented by the formula (-■) having the same meaning as above with an appropriately substituted pyridine.

Suitably, the reaction with pyridine is carried out in a polar solvent such as water.
It is carried out in the presence of a catalyst such as an alkali metal thiocyanate or an alkali metal halide such as sodium iodide.

The antibiotic compounds according to the invention can be formulated for use in medicine or veterinary medicine in a manner analogous to other antibiotics and for administration in any convenient manner, and the invention therefore includes within its scope the compounds represented by formula (1). or a pharmaceutically suitable salt or in vivo hydrolyzable derivative thereof together with a pharmaceutically suitable carrier or excipient.

The compositions may take the form of any route, eg oral, topical or lozenges, creams or liquid preparations, eg oral or sterile parenteral solutions or suspensions.

Tablets and capsules for administration may be in unit dosage form and may contain the usual excipients such as syrup, acacia, gelatin, sorbitol) binders such as tragacanth or polyvinylpyrrolidone; lactose, sucrose, corn. fillers such as starch, calcium phosphate, sorbitol or glycine; tableting lubricants such as magnesium stearate, Merck, polyethylene glycol or silica; disintegrants such as Vallesia starch; or suitable agents such as sodium lauryl sulfate. It can contain a wetting agent. Tablets may be coated by methods well known in normal pharmaceutical practice. Oral liquid preparations may take the form of elixirs, e.g., aqueous or oily suspensions, solution emulsions, syrups, or elixirs, or may be dried for reconstitution with water or other suitable vehicle before use. Can be provided as a product. Such liquid preparations contain the usual additives: e.g. sorbitol, methylcellulose,
suspending agents such as glucose syrup, gelatin, hydroxyethylcellulose, carboxydimethylcellulose, stearic aluminum gel or hydrogenated edible lubricants; emulsifiers such as lecithin, sorbitan monooleate or gum arabic; almond oil, A non-aqueous medium such as an oily ester (e.g. glycerin), polyethylene glycol or ethyl alcohol (which may contain an edible oil); a preservative such as methyl or propyl p-hydroxybenzoate or sorbic acid; and, if desired It can contain gold as usual flavoring or coloring agents.

Suppositories contain conventional bases such as cocoa butter or other glycerides.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile vehicle, preferably water. The compound, depending on the vehicle and grading used, can be either suspended or dissolved in the vehicle. In preparing the solution,
The compound can be dissolved in an injectable solution, filter sterilized, and then filled into a suitable vial or ampoule and sealed. Advantageously, agents such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle. To increase stability, the water can be removed under vacuum after the composition is filled into the vial.

The dry lyophilized powder is then enclosed in a vial, which may be accompanied by an attached vial of water for injection to reconstitute the solution before use. Parenteral III! Suspensions can be prepared in substantially the same manner except that the compound is suspended instead of being dissolved in the vehicle and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide and then suspended in a sterile medium. Advantageously, a surfactant or wetting agent is included in the composition to promote uniform distribution of the compound.

The compositions may contain from 0.1 to 99.5% by weight of active substance, preferably from 10 to 60 fft, depending on the method of administration. When the composition is in dosage units, each unit preferably contains from 50 to 500 active ingredients. The dose f used in the treatment of adults is preferably 1001 M1 for an average adult patient (70 kg) depending on the route and frequency of administration.
~209, for example, the daily allowance would be v1500 ~. Such dosages range from about 1.5 to 285 per day.
Corresponds to mf / kg. Preferably the dosage is 9 per day.
It is 0.259-69.

8 doses are preferably provided by administering the compound of the invention several times over a 24 hour period. Typically, 25
Although 04P is administered three times per 92" per day, in practice the most suitable dose and frequency of dosing for an individual patient will vary depending on the patient's age, weight and response, and the physician may recommend a higher or There may be opportunities to choose lower dosages and different dosing frequencies.Such dosage guidance is within the scope of the invention. No toxic effects are shown when the in vivo hydrolyzable derivatives are administered in the above dosage range.

The compound of formula (1) or its pharmaceutically suitable salt or in vivo hydrolysable derivative may be the only therapeutic agent in the composition of the invention or may be combined with other antibiotics or with other antibiotics. Combinations with β-lac2--ase inhibitors can also be used.

Advantageously, the composition also has the formula (■) [wherein A is hydroxyl, substituted hydroxyl: f au A/;
-II alkyl); a substituted thiol; an amino; a mono- or di-hydrocarpyl-substituted amino; a mono- or di-acylamino; a thiazolyl group optionally substituted with 1; or European Patent Publication No. 005389
3) or a pharmaceutically suitable salt or ester thereof. Preferred substituents A in formula (vlA) include hydroxyl, tetrazol-1-
yl and tetrazol-2-yl.

Another advantageous composition is a compound of formula (1) containing a pharmaceutically suitable salt or an in vivo hydrolysable derivative of formula (IX), wherein B is hydrogen, halogen or (wherein Rls and R16 are the same or different and each is hydrogen, Cl-1 alkoxycarbonyl, or carboxy or a pharmaceutically suitable salt thereof)] or a pharmaceutical thereof; Contains an appropriate salt or ester that can be hydrolyzed in vivo.

Another suitable β-lactamase inhibitor is European Patent Application No. 81301683.9 (Publication No. 004]768).
6-alkylidenepenams such as those described therein are included.

Other suitable β-lactamase inhibitors include 6β-brompenicillanic acid and its salts and in vivo hydrolysable esters and β-iodopenicillanic acid and its salts and in vivo hydrolysable esters.

Compositions of the invention containing β-lactamase inhibitors are formulated in a conventional manner.

The present invention also provides a complete method of treating bacterial infections in animals, particularly humans or domestic mammals, comprising administering the compositions of the present invention. A preferred method of administration is by the oral route.

The antibiotic compounds of the present invention can be used against a wide range of Durum-positive bacteria, such as S. subtilis eM (B, 5ubtilis); S. aureus W4 (S, aureus)%, e.g.
d; B, catarrhalis; S, faeca
lis I: Streptococcus pyogenes (S, I) 70g6ns
) CNIO; H, 1nfluenxa; Escherichia coli (g,
coli) ; and P, mi rab i 1 is
It is active against.

A special feature of the compounds of the invention of formula (1) and their pharmaceutically suitable salts and in vivo hydrolysable derivatives is their excellent absorption after oral administration, as shown in animal species.

The excellent absorption properties of these compounds also contribute to their absorption indices [i.e. oral (p,o) and subcutaneous (s,c) in animal species.
), which is generally comparable to, and in some cases significantly superior to, that of well-known antibacterial agents such as amoxicillin.

The following examples illustrate the preparation and biological activity of the compounds of this invention.

The following abbreviations were used.

Abbreviation Official name DMF' Dimethylformamide 6-APA
6β-Aminopenicillanic acid THF Tetrahydrone 7-ACA 7β-Aminocephalosporanic acid 7-
ADCA 7β-Amino-3-desacetoxycephalosporanic acid NOE Nuclear Augerhauser Effect Example 1 0,87 M solution of potassium hydroxide in methanol (6,
Methyl acetoacetate (0,61q+e, 5.6 mmol) and D-2-aminobut-3-enoic acid (0,515
9.5°1 mmol) was heated under reflux for 40 minutes and evaporated to dryness under vacuum. Toluene (10d) and ethanol (5ml)'l! added to the residue and then reevaporated,
The title compound (
1,14051°86%) was obtained.

νmax (KBr) 1645, 1610, 1565,
1500.1436°1369.1269,1159.
925 and 784ctn-'; δH(250ME(z
.

4.8-5. '0 (2H, m), 5.95-6.15 (
IH, m), and 9.10 (IHld, JNH, H26
, 6Hz).

Potassium D-2-(3-methoxycarbonylprop-2-en-2-ylamino)put-3-enoate (0,4749, 2 mmol) in acetone (8-) was cooled to -20 °C and then treated with N - Methylmorpholine (2 μe) and ethyl chloroformate (192 μg) were added to the mixture t-4.
A solution of 06β-aminopenicillanic acid (0,481?, 2.2 nmol) and triethylamine (320 μe) in acetone (8 ml) and water (16d) stirred at −20 ± 5 °C for 0 min was added and the solution was 1 without cooling
Stir for hours. The acetone was removed under vacuum and the aqueous residue was kept at 1 pl (1 pl) with 5N hydrochloric acid for 20 min and treated with ether (2X
The cells were washed with 25 m), inoculated into 1i14 cells in 4.7 paddy fields, and freeze-dried (1.249 p.m.).

Chromatography eluting with HP20SS tap water gave the title compound (0,1049,17%).

νmax(KBr) 1767, 1695, . 15
91, 1534, 1393.

1388.1255 and 1122c1n-1; δH(2
50MHz, D20) 1.53 (3H, s), 1.
64 (3H, s), 4.26 (IH, s), 4.69 (
IH, d, J 7.5Hz), 5.54 (IH, d,
J 3.8Hz), 5.58 (IH, d, J 3.
8Hz), 5.6-5.7 (2H, m) and 5.9-6
．． 1 ((IH, m), [Mass spectrometry: +ve ion (glycerin/H, 0)M (300)).

Example 2 Chlorformic acid 2.2.2-trichloroA/ethyl (0,'56m, 4.1 mmol) in acetone (10*)?
: D-2-aminopt-3-enoic acid (0,3734i', 3.7 mm) in water (20 m) and acetone (10 <) maintained at pH 9,8 ± 0.2 with 2.5 N NaOH.
ol). The solution was then stirred for 30 min, concentrated under vacuum, washed with ether (2X30d) and
Acidify to pH2 and m
I put it out. The extract was washed with water (2XBOd), dried and recrystallized from ethyl acetate-chlorohexane to give the title compound as a crystalline solid (0.7419.73
%) 0 melting point 141-142℃; [α]20D-3.16
° (c 1., EtOH); δH (60 MMZ.

(CD3)2CO)4.72(2H,s), 4.7-5
．． 1 (IH, m), 5.1-5.5 (2H2m), 5
．． 7-6.3 (IHlm), 7.05 (IHld,
JNHlH-37Hz)- and 9.41(IH,b,r
s) A suspension in D-2-(2,2,2-)dichloroethoxycarbonylamino)put-3-dyne [(0,6399°2,5 mmol) was dissolved in oxalyl chloride (0
, 5 ml) and DMF' (5 μe) and stirred for approximately 1 h until a clear solution was obtained. The solvent was removed under vacuum and the acid chloride, umax (CHzCgz) 1
800.1750 and 1502 sub-1 acetone (10
d) The solution in water (20,d) and acetone (10d)
The solution was added to 6-APA (0,648Q, 3 mmol) and triethylamine (850 μe) in the solution. 1 solution
After stirring for an hour, it was concentrated under vacuum and ether (2
X25d), acidified to pH 2.51 and extracted with chloroform (4X25d). Wash the extract with water 2
X50d), drying and evaporation gave a foam (1,0994?) t-. This material in ether (20m) was dissolved in 4-methylpentan-2-one (1,16d
) with 2N sodium 2-ethylhexanoate,
It was diluted to a gas oil boiling point of 60-80°C (20d), and the precipitated sodium salt was collected and evaporated under vacuum (0.9969°C).
．． 80%).

Freshly activated zinc powder (1,59) was dissolved in 0.25 M potassium dihydrogen phosphate (16d) and T7' (4m).
β-(D-2-(2,2,2-trichloroethoxycarbonylamino)put-3-enamide] was added to sodium penicillanate (0,776 g) and the mixture was reduced to 40%
It was held at p)C5 with orthophosphoric acid.

After 10 minutes, further activated zinc powder (1,59) was added,
Stirring was continued for 10 minutes, after which time the reverse phase HPLC showed no remaining starting material. Zinc t-F was removed, F solution was washed with ether (2x25d), square wired under vacuum, and HP
Chromatographed on 2O8S eluting with water. The product-containing fractions were combined and concentrated to about 24 n-
It was diluted with propatool (4d) and crystallized by standing at 0°C. The crystalline dihydrate was collected and dried under vacuum (0.1
719.33%), (Elemental analysis: Experimental value: C, 43,
22; H, 6, 02; N, 12.44; S, 9
．． 86%o C+zH+yN304S, 2H2017
) Theoretical value: C942,97; H, 6,31; N, 12
．． 53; S, 9.56%): IR and base spectra are identical to those in Example 1b. Example 3 D-2-aminopt-3-diphosphate hydrochloride ( 0,1389+ 1mm
Hydrogen chloride gas was blown into the tank for 30 minutes. The mixture was cooled in a water bath and freshly sublimed pentachloride fTt (0
, 21C1, 1,005 mmol)'e in dichloromethane (3d) was added. After 30 minutes, the suspension was evaporated to dryness and toluene (5at) was added.
It was re-evaporated and the residue was triturated with anhydrous ether. The acid chloride hydrochloride was suspended in dichloromethane (5-), cooled to -30°C, and N in dichloromethane (10 m)
O-bistrimethylsilyl 6-APA (6-APA
0.2169, 1 mmol). The mixture was stirred for 2 hours without cooling, then water (2X10.+
! /) was extracted. Adjust the aqueous extract to pH 4.8,
Lyophilized (0.60'Og).

Chromatography on HP 20 SS followed by preparative reverse phase HPLC gave the same material as described in Example 1b.

Reference Example I N-benzyloxycarbonyl-D-glutaric 5-methyl ester (3,65'j, 12.4 mmol
) and copper(1) acetate hydrate (0,62&, 3.1
mmol) in total toluene (75d) under an argon atmosphere at 20° C. for 1 hour. Acetic acid-free tetraacetic acid feed ((1
1,059.24.8 mmol) was added and the mixture was stirred and heated at 100° C. for 3 hours. The cooled solution was diluted with ethyl acetate (75, d), filtered through Celite, and diluted with water (75, d).
An oil (3,17419) was obtained by washing with 2×50 ml) and saturated sodium bicarbonate solution (2×50.d), drying and evaporation. Flash chromatography with 10 ethyl acetate in hexane yielded the title compound (0,974?, 3
2%).

δH (60MHz, CD (Js) 3.65 (3H1
8), 4.7-5.05 (IH.

m), 5.08(2H,s), 5.1-5.
5 (2H, m), 5.5-5.7 (IH1mL5.6
-6.2 (3H1mL and 7.27 (5H,s)
.

b D-2-aminopt-3-enohydrochloride 6N salt #
! Methyl D-2-(benzyloxycarbonylamino)put-3-nidioate (2,30F) in (45d) was heated under reflux for 1 hour, cooled, washed with chloroform (2X25d), and evaporated to dryness. . The title compound (1,0581?,
83%).

Melting point 168-170℃: min 4; (αl” D-6
3,640 (c 1.9 + HzO): δH (25
0MHz, DzO) 4.60 (IH, d, J7
Hz), 5.5-5.65 (2H, m), and 5.9-
6.1 (IH, m).

Propylene oxide (1,35 m/) was added to a stirred solution of the above hydrochloride (o, 92c+y) in methanol (4d). After 2 hours, more methanol (4d) was added and the solid was Washed with methanol (2-) and dried under vacuum (0.5659.82 inches) mp 218-2
22°C (decomposition).

(α]20D −79, (150(Q 1 , H2O)
; (Experimental value; C, 47, 32; H, 6, 84; N,
13.64, theoretical value of C<HrNO2: C, 47
, 52, IL6.98; N, 13.85 chi.

Example 4 Monoenoic acid, L-2-amino-3-phenylbut-3-dyne H
(0,514gm 2.9mmol +F, He1nz
er and (converted to the title compound as described in 912a (0.650 g, section 63). Melting point 103
-105℃. (From ethyl acetate-cyclohexane; (Experimental value: C244,27; H-3,38:N, 4.02
;Ce, 30.14%.

C13H12C/1sNch O theoretical value: C, 44,
28; , H, 3, 43; N, 3.97: Ce, 30.
16%) 0δH (60MHz, (CDri2CO)4.7
3 (2H, s), 5.32 (IH.

d, J 8Hz), 5.42 and 5.52 (2H, 2
s) t6.60 (IH.

br a), 6.73 (LH, d, J 8Hz),
and 7.0-7.6 (5H.

m).

rum Prepared as described in Example 2b (78 pieces).

6β-[D,L-3-phenyl-2-(2,2,2-
Deprotection of sodium trichloroethoxycarbonylamino)put-3-enamide]penicillanate (0,439) was performed as described in Example 2c. 96β-(L
-2-amino-3-phenylpt-3-enamido)penicillanic acid (50d, 17%) was obtained.

νmax (KBr) 1769, 1676.1602, 1
512.1397 and] 318cWI-”;JH(
250MHz, D20) 1.45 (3H, s).

1.46 (3H, s), 4.17 (IH, s), 4.9
3 (IH, s), 5.40 (IH, d, J4Hz), 5
．． 53 (IH, d, J4Hz), 5.54 and 5.65
(2H,2s), 7.43(5H,s); Then, D-, L-solid compound 1t1: mixture of bodies (73ml
.

25% concentration was obtained, followed by 6β-(D-2-amino-
3-phenylpt-3-enamido)penicillane d(3
5 m, 12%) was obtained.

νmax (KBr) 1767.1675, 1603.1
511.1398 and 1318cW1-'; JH(2
50 MI (Z, D20) 1.42 (3H, s
).

1.51 (3H, s), 4.14 (LH, s), 4.7
2 (LH, s), 5.3-5.4 (2H, m), 5.4
6 and 5.55 (2H, 2!l), and 7.41 (5)
I.

8).

[Mass spectrum: +ve ion (thioglycero-/
k) MFr (376), Boa” (398)).

Example 5 a ILL-C4-dichloro-2-(21712-)
Chloroformic acid 2.2.2-
Trichloroethyl (1,5rd * llmmol)
Treatment with -9,25±0.25 gave the title compound (1,6239,47%). Melting point 155-15
6°C (from ethyl acetate-cyclohexane).

JH (60MHz, (CD3)2CO) 4.81
(2H,s), 5.16(H(.

dd, JH-2, H-39Hz*JH-2, N-H8H
z), 6.22 (1H” IJH-3, H-29Hz
), 7.16 (IH, d-JNH', H-28Hz)
, and 9.65 (11,br s).

Rum produced using the method described in Example 2b (52%
)0 JH (60MHz, (CDs)2co)1.53(3H
, s), 1.63 (3H.

s), 4.27 (IH, +), 4.67 (2H, s),
4.7-5.2 (IH, m).

5.2-5.5 (2H, m), 6.00 (IH, d, J
9Hz), 7.0-7.7 (2H, m) and 8.8
5 (IH, br s).

6β-(D,L-4,4-dichloro-2-(2,2,
2-Trichloroethoxylponylamino)but-3-
Enamide] sodium penicillanate (0,7259)
was deprotected as described in Example 2c and HP 2
6β-(L-2-7/-4,4-diclupto-3-enamido)penicillanic acid (55 μm) was obtained by chromatography on OS 8, eluting with 1% aqueous THF and then 2% aqueous THF.

11%).

νrnax (KBr) 1766.1675, 1608,
1507.1397 and 1320cm-”, :JH(
250MHz, DzO) 1.50 (3H,s),
1.61 (3H, s), 4.24 (IH, s), 4.
44 (IH, d, J 9Hz).

5.43 (IH, d, J 4Hz), 5.57 (IH
, d, J 4Hz), and 6.07 (IH, d, J
9 Hz); then a mixture of D- and L-stereoisomers (51~, 1
1 H) is obtained, and then 6β-(D-2-amino-4
,4-dichloropt-3-enamido)penicillanic acid (
45w9.9%) was obtained.

νmax (KBr) 1770, 1690, 1615, 1
520.1396 and 1320cm-”; JH (25
0MHz, DzO) 1.50 (3H,s),
1.60 (3H, s), 4.27 (IH, s), 4.9
8 (IH, d, J 10Hz).

5.46 (IH, d, J 4Hz), 5.56 (IH
, d, J 4Hz), and 6.22 (IH, d, , J
10Hz).

[Mass spectrum: +ve ion (thioglycerol) (368), MNa'' (390)].

Example 6! D-2-Amino-3-methylput-3-enoic acid (2,6
309e 17.3mmol +J, E, Baldwi
n+S,B.

Haber+C, Ho5kins and L, 1. K
It was converted to the title compound (3,4529,69%) by ruse+J, Org, Chem, e method. Melting point 95-9
9℃ (from cyclohexane) 0δH (60MHz,
(CD3)2CO)1.87(3H,d, Jl-2H
z).

4.82 (2H, s), 4.8-5.3 (3H, m),
7.0 (LH, br s).

and 10.5(LH,s).

Prepared as described in Example 2b (88%).

6, β-[D-3-Methyl-2-(2,2,2-trichloroethoxycarbonyl 2-aminopt-3-enamide] sodium penicillanate deprotection af carried out as described in Example 2c. Chromatography of the crude product on HP20SS eluting with 0.66-1.25 THF aqueous solution gave the title compound (50%).

umax(KBr)2971,1771.1686,1
599,1520°1389 and 1315cy++-'
; δH (250MHz, DzO) 1.48 (3H.

s), 1. f30 (3H, s), 1.80 (3H, s)
, 4.22(LH,s).

4.64 (IH, s), 5.33 and 5.34 (2H,
2s), 5.51 (IH.

d, J 4Hz), and 5.54 (IH, d, J
4 [(z).

[Mass spectrum; +ve ion (thioglycerol) MH+ (314), zM+H+ (627)).

Protrusion 1 [7 Kudo As described in Example 2b, however, 7-ACA was used instead of 6-APA (37CH) 7,β
Deprotection of sodium -[D-3-methy/'-2-(2,2,2-)lychloroethoxycarbonylamino)put-3-enamide]cephalosporanate was performed as described in Example 2c. Ta. crude organisms) (P 20 S
The title compound (33) was obtained by chromatography on S, eluting with 1→2% THF water bath.

umax(KBr)1770.1693,1602.1
387.1340 and 1234cn1-arch δH (250
MHz, D20) 1.81 (3H,s) 13
．． 35 and 3.63 (2H, 2d, J 18Hz),
4.64 (IH, s), 4.65-4.86 (2H, 2
d, under HOD), 5.15 (IH, d, J 4.7H
z).

5.35(2H,m)l and 5.73(LH,d,J
4.7Hz).

[Mass spectrum: →-ve ion (thioglycerol) MH+-AcOH (3i 0 ), I Tsukuda + (37
0), 2M+H” (739)).

Example 8 7,β prepared as described in Example 2b, but using 7-ADcA instead of 6-APAO (47CH)
-[D-3-methyl-2-(2,2,2-trichloroethoxycarbonylamino)put-3-enamide]-3
Deprotection of sodium -desacetoxycephalosporanate was performed as described in run f112c. Chromatography of the crude product on HP2O8S with 1+-2% aqueous solution gave the title compound (50).

umax (KBr) 3403, 2976, 175
7, 1688, 1584 and 1359m-1; δH
(250MHz, IhO) 1.80 (3H,s
) -1,87(3H,s), 3.18 and 3.56(
2H, 2d, J 18Hz) - 4,57 (IH, s)
, 5.08 (LH, d, J 4.5Hz) t5.30 (
2H.

brsL and 5.62 (IH, d, J 4.5Hz)
.

[Mass spectrum: 10ve ion (thioglycerol) MH+ (312), 2M10H+ (623), 3M
+H+ (936)) Example 9 N-2-amino-3-ethylbut-3-enoic acid hydrochloride (260Tlqm 1.57mmol +F', H
elnzerand D, Be1lus+He1v, C
him+Acta, #1981a64t2279)
was converted to the title compound as described in Example 2a (320-, 67%).

δH(60MHz, (CDRI2CO)1.09(3
H,t, J7Hz) -2,25(21-1,
q, J 7Hz), 4.80 (2H,s)
, 4.85-5.3 (3H.

Sodium 6β-[D,L-3-ethyl-2-(2,2,2-trichloroethoxycarbonylamino)put-3-enamide]penicillanate, prepared as described in Example 2b. Deprotection of (417111F) was performed as described in Example 2c. Crude product β-To chromatographed on HP20SS, eluting with 75-1% aqueous THF solution 6
．． β-(L-2-amino-3-ethylpt-3-enamido)penicillane fi (954°36%) was obtained.

νmax (KBr) 2968, 1771, 1686
, 1600, . 1516°1394 and 1316ty
n-”δH (250MHz, 020), 1.06 (3
H.

t, J 7.3Hz), 1.50 (3H, s), 1.5
7 (3H, s), 2.08 (2H, m), 4.25 (I
H,a), 4.68(IH,s), 5.37(L
H.

s), 5.40 (IH, s), 5.46 (LH, d, J
4.0Hz), and 5.58 (IH, d, J 4.
0Hz).

[Mass spectrum: +ve ion (thioglycerol)
MH” (328)) A mixture of D- and L-stereoisomers is then obtained followed by 6.β-(D-2-amino-3-ethylpt-3-enamido)penicillane!!1! .6%) was obtained.

umax(KBr)2968,1767.1688,1
597,1395° and 1320cm-”; δH(2
50MHz, D20) 1.07 (3H, t, J7.3M
Hz), 1.48 (3H, s), 1.60 (3H, s)
, 2.06 (2H.

m), 4.21 (IH, s), 4.64 (IT (, s)
, 5.35 (IH, s).

5.37 (IH, s), and 5.52 (2H, m).

[Mass spectrum: + ■ ion (Thio! IJ SeI:
MH'' (328), MH''+ thioglycerol (436), 2M+H+ (655)].

Example 10 D,L -2-amino-3-methylpent-3(E)-
Enohydrochloride (1,369, 8,2 mmol) (F, He1zer and D, Be1l for production)
ussHelv.

Chim, Acta, 1981, 64. '279] was converted to the title compound as described in Example 2a (1.629,65'%). Melting point 133-137℃
(chloroform-cyclohexane).

(Actual isthmus value: C, 35,90; H, 4,09; N, 4
．． 61; (J, 34.70%C HnC1sNO
Theoretical value of 4: C, 35,49; H, 3,97; N,
4.60CL34.92chi); δH(250MHz, (CDs)tcO)1.64(3
H, d, J 6.8Hz).

1.71 (3H, s), 4.73 (IH, d, J 7.
9Hz), 4.79 (2H.

s), 5.68 (IH, q, J 6.5Hz), 7.1
2(IH,br d), and 11.1(1)(+br
s).

Some two isomers of the title compound were also present in an E:z ratio of 8:1. δH especially 5.32 (d, J 7.8H
z).

[Mass spectrum: 10ve ion (ammonia) MH
” (304), Station H+4 (321)).

Prepared as described in Example 2b, but without conversion to the sodium salt. (79%) 6β-(D,L-
Deprotection of 3-methyl-2-(2,2,2-trichloroethoxycarbonylamino)bent-3(E)-enamido]penicillane 11 (1,58!9) was performed as described in Example 2c. Ta.

The crude product was purified with 0.5-0.8% TH on HP20SS.
6β-(L-2-amino-3-methylpent-3-
(E)-enamido)penicillanic acid (17!1JHi.

17%).

νmax(KBr)2969,1771.1688,1
602, 1515° 1388 and l 315c! n-1
; δH (250MHz, D20) 1.49 (3H.

s), 1.55(3H,s), 1.64(3f(,s
), 1.69 (3H, d, δ6.6Hz), 4.25 (
II, s), 4.62 (LH, s), 5.44 (IH,
d.

J 3.9Hz), 5.59 (IH, d, J 3.
9Hz), and 5.95 (LH.

brq, J 6.6Hz).

[Mass spectrum: +ve ion (thioglycerol) MH (328)].

Then the D- and L-stereoisomers (354q.

34%) was obtained, followed by 6β-(D-2-amino-3
-methyl pen) -3(E)-enamide) penicillane [(111■, 11%) was obtained at 0 νmax (KB
r) 2970, 1767.1684, 1599, 152
2゜1390, and 1318 cm-'; δH(250
MHz, D20) 1.49 (3Hs),
1.59 (3H, s), 1.65 (3H, s),
1.69 (3H, d, δ6.9Hz), 4.2
2(IH,s), 4.56(IH,s), 5.5
0(IH, d.

J 3.9Hz), 5.54 (IH, d, J 3.
9Hz) and 5.91 (IH.

brq).

[Mass spectrum: 10ve ion (thioglycerol)
MH+ (328)).

Example 11 D,L -2-amino-pent-3(E)-enoic hydrochloride (1,979, crude) (W, J for preparation.

Greenlee+J +Org, Chem, e 1
984*49.26323 was converted to the example title compound (0,5349) as described in Example 2a. Melting point 139-140°C.

(Experimental value: C, 33, 33;) (, 3, 38; N,
4.86; CJ, 36.17%C5HraCe3N
Theoretical value of 04: C', 33.07; H, 3,47; N
, 4.82CL36.61%); δH (250, MHz
, (CD!)zco) 1.72 (3H.

m), 4.77 (IH, m), 4.81 (2H, ABq
, J 12. IHz).

5.65 (IH, m), 5.91 (IH, m), and 7
．． 19 (IH, d, J7Hz); When irradiated at δ1.7, the signal at δ5.65 is a double doublet)' (J 15.3 and 6.9Hz)
The signal at δ5.91 collapsed into a doublet (δ15.3 and 0.9Hz), thus confirming the E configuration.

(Quantitative) 06β-[D,L
-2-(2,2,2-trichloroethoxycarbonylamino)bento-3(E)-enamide]penicillane t'
Deprotection of R (690m!, 1.7mmol) was carried out as described in Example 2c.

Crude product I (0.5-1% T on P20SS)
6β-(L-2-amino-pent-3(E
)-enamide) penicillanic acid (1051Ni, 20%
) obtained O νmax(KBr)2971,1766.1683,1
596.1520°1395 and 1317cfn-'
; δH (250MHz, 020 ) 1.54 (3H.

s), 1.63 (3H, s), 1.80 (3H, d, J
6.3Hz), 4.29(IH,s), 4.63(I
H, d, J 8.3Hz), 5.5-5.7 (3H,
m) and 6.19 (IH, m).

[Mass spectrum: +'ie ion (thioc IJ cerol) MH (314)], then a mixture of D- and L-stereoisomers (106, 20) was obtained, then 6
β-(D-2aminopent-3(E)-enamido)penicillanic acid (129μ, 24%) was obtained.

νmax (KBr) 3411, 2969, 1764, 1
683,1602゜1394 and 131 Bon-'
; δH (250MHz, D20) 1.54 (3H.

s), 1.64 (3H, s), 1.81 (3H, dd,
J 6.4 and 1.4Hz) 4.27 (IH, s),
4.63 (IH, d, J 8.5Hz), 5.5-5.
7 (3H, m), and 6.18 (IH, m).

Example 12 Allyltriphenylphosphonium bromide (9,582
g, 25 mmol)'e dry ether (150 g)
n-butyllithium (1,6M,
15.6m, 25mmol). The mixture was stirred at room temperature for 2.5 hours, then stirred in dry ether (1
Ethyl 2-methoxyimino-3-oxobutanoate <4.3259.25 mmol) in 00,d) was added slowly and the mixture was heated for 3 hours. After filtration, the solution was mixed with saturated ammonium chloride (100 ml) and brine (100 In
Washing with t), drying and evaporation gave an oily solid (3,489). Flash chromatography on silica gel using 0-5 ethyl thiacetate in 7-chlorohexane as eluent gave a colorless oil (1,249,25%).

δK (60MHz, CDCh) 1.32 (3H,
t, J 7Hz), 1.96 (3H, s),
3.92 (3H, s), 4.38 (2H, q, J 7H
z), and 5.2-5.6 and 6.0-7.2 (4t(
, 2m).

Ethanol (30d), water (15d) and formic acid (30m
) in 2-methoxyimino-3-methyllihexy-3 (
E), ethyl 5-dienoate (1,231it, 6.
2 mmol) f: Cool to about 5°C, add zinc powder (2 mmol)
, 859, 44 mmol) in several batches.

The mixture was then stirred for 1 hour at room temperature, filtered and evaporated. The residue was dissolved in water, washed with ether (2X30-), adjusted to p) (7) and extracted with ethyl acetate (3X40d). The combined extracts were washed with brine, dried and evaporated. The title compound was converted into an orange oil (0,54
59.52%).

δH (60MHz, CDCgs) 1.22 (3H, t,
J 7Hz), 1.80 (3H, s), 2.80 (2H
,s) *3.9-4.5 (3H, m+q, J 7Hz)
and 5.0-5.5 and 6.0-7.0 (4I(,2m
).

Ethyl 2-amino-3-methyl-hex-3(E),5-dienoate (0,545F3.2) maintained at pH 7.5.
2 mmo 1 ) of TFnl' (25d) and water (
25d) in a stirred solution of 2,2.2-)lichloroethyl chloroformic acid (0.54 ml, 3.9 mmol)
t was added slowly.

The mixture was stirred for 1.5 hours, then ethyl acetate (3X2
5d). The combined extracts were washed with brine, dried and evaporated to give the crude product as a red oil. The title compound was purified by flash chromatography on silica gel using 0-10% ethyl acetate in hexane as eluent as a yellow oil (0%
, 745g.

67%).

δH (250MHz, CD (Js) 1.29 (3H, t
, J 7.1. Hz), 1.80 (3H, sL4.24
(2H, m), 4.73 (2H, s), 4.78 (IH
.

d, J 7.4Hz), 5.20(1) I, d, J 1
0.2Hz), 5.29 (IH.

d=J 16.8Hz)*5.91(IH-br d)
, 6.18 (IH-d-Jl 0.8I(z) , and 6.54 (IH, ddd, J 16.8, 10.8
．． 10.2Hz)-3-methyl-2-(2,2,
2-) +J Chlorethoxycarbonylamino)hexy-3(E), ethyl 5-dienoate (0,73!92.
12 mmol 1 ) in an aqueous sodium hydroxide solution (IM).

2,3 d, 2.3 mmol) for 1 hour. Dilute the solution with water and ether (2x20rIt)
Washed with water, acidified and extracted with ethyl acetate (3X30@t).

The combined extracts were washed with brine, dried and evaporated to give the title compound as a pale yellow oil (0.5309
,79%) ,! = 1. Get f(.

δ) ((60MHz, (CDs)zco) 1.9(3H
, s), 4.8 (2H, s).

4.85 (LH, d), 5.1-5.5 (2H,
m), 6.1-. 7.1 (3H, m).

and 9.25 (IH, s).

! Prepared as described in Example 2b, but without conversion to the sodium salt (71%).

6β-(D,L-3-methyl-2-(2,2,2-trichloroethoxycarbonylamino)hexy-3(E)
, 5-dienamide] penicillanic acid (0,585 g
+ 1.14 mmol) was carried out as described in Example 2C. 6β-(L-2-amino-
3-Methylhexy-3(E),5-dienamido)penicillanic acid (70μ, 18%) was obtained.

νmax (KBr) 2970, 1771.1688.1
598.1515°1393 and 1314cf++-”
: δH (250MHz, DzO) 1.48 (3H2s
), 1.52 (3H, s), 1.78 (3H, s), 4
．． 24 (LH, s).

4.68(IH,s), 5.37(IH,d,
J 10.3Hz), 5.44 (IH.

d, J 4Hz), 5.45 (LH, d, J 16.8
Hz), 5.59 (IH.

d, J 4f(z), 6.40(IH, d, J 1
0.8Hz), and 6.64 (IH, ddd, J 16
．． 8, 10.8, 10.3Hz).

[Mass spectrum: +ve ion (thioglycerol)
MH(340)1 then a mixture of D- and L-stereoisomers C1ooq, 26%) was obtained, followed by 6β-(D-
2-Amino-3-methylhex-3(E),5-dienamido)benicilla:'l1N (581n915th) was obtained.

νmax (KBr) 3401.2972, 1766.1
683,1595°1395 and 1318z-'; δ
H (250MHz, 020) 1.46 (3H.

s), 1.55 (3H, s), 1.81 (3H, d, J
0.6Hz), 4.21(IH,s), 4.63(I
H, s), 5.36 (IH, d, J -10,2Hz
).

5.40-5.48 (2H, m), 5.54 (IH, d
, J 3.8Hz), 6.36(LH,d, J 1
0.9Hz), and 6.65(LH, ddd, J 1
6.8°10.9, 10.2Hz).

[Mass spectrum: +Ve ion (thioglycerol) MH+ (340)) Example 13 a Ethyl 3-bromo-2-methoxyiminopropanoate bromopyruvate (12.6d, 0.1 mol)
) and methoxyamine hydrochloride (8,3519,0,1m
ol) was dissolved in ethanol (120d) and stirred at room temperature for 2 hours. After evaporation, the residue was taken up in ethyl acetate, washed with water and brine, dried and evaporated. The title compound was purified by flash chromatography on silica gel using 0-12% ethyl acetate in hexane as eluent as a pale yellow oil (C21, 49, 96%).
obtained as.

(Experimental values: M++ 222, 9843, CsH
+Theoretical value M of oBrNOs, 222.9845); νmaxc thin film) 1720, 1370, 1330, 1
200, 1180° 1050 and 1020cm-”;
δH (250MHz, CDC65) 1.38 (3Ht,
J7. IHz), 4.18 and 4.21 (combined 3H22s+E and 2 isomers), 4.17 and 4.
36 (combined 2H92a-E and 2 isomers), and 4.
38 (2H, q, J 7.IHz).

Triphenylphosphine (34,109, 0,13mo
l) and ethyl 3-bromo-2-methoxyiminopropanoate (3009, 0.13 mol) t THF (
2204) and refluxed for 5 hours. After cooling, the product was filtered, washed with ether, and dried to yield a white solid (46,519,74%).

Melting point 137-139℃ νmax (KBr) 1715, 1434, 1108, 1
040,742°691 and 510cm-”: δH(
250MHz, CDCgs) 1.15 (3H.

t, J 7.1Hz), 3.80 (3H, s), 4.1
2 (2H, q, J 7.IHz), 5.25 (2H, d
, J 16.3Hz), and 7.66-7.90(1
5H, m).

A second crop of the title compound was obtained by refluxing for an additional 30 minutes as a pale yellow powder C9,77'j, 15%). Melting point 123-130°C.

Ethyl 2-iL)oxycarbonyl-2-methoxyiminoethyltriphenylphosphonium proside (109+ 20m
mol) eN+N'-dimethylpropylene urea (D
MPU ) (4,+d) and THF (20,d
), cooled to about 5°C, and dissolved in n-butyllithium (1
,6M.

12,8 d, 20 mmol). The mixture was then stirred for 1.5 hours,
Cool and add propanal (2*t*28mmol
) in TIP (10 ba) was then added. Stirring was continued overnight, the mixture was evaporated and the residue was dissolved in water.
Extracted with ether (2×60d). The combined extracts were washed with brine, dried and evaporated. 0- in hexane
The title compound was purified as a yellow oil by flash chromatography using 5% ethyl acetate as eluent (1,8
5150%).

(Experimental value: M+185.1052.CsH+5NOs
Theoretical value of: M+185.1052); umax (thin film) 2970, 2930, 1730, 1
260, 1160°1120 and l Q 5 QcIn
-'; δ) ((250MHz, cDc6g) 1.07
(3T (t, J 7.4Hz), 1.37 (3H, t
, J 7.1Hz), 2.24 (2H.

m), 4.05 (3H, a), 4.34 (2H, q, J
7. IHz), 6.50 (IM, dt, J 16
．． 3,1.5Hz), and 6.77(1)i,dt,J
1 6.3, 6.4 Hz) ; Another signal for the 2-olefin was present in the spectrum, and integration revealed that the product was a 9:IE:Z mixture.

d Ethyl 2-aminohexy-3(E)-enoate Prepared as described in Example 12b (84 t); umax (thin film) 2960, 2930, 1730.1
180, 1020° and 970 儒凰; δH (60MH
z, CDC/(s) 1.0 (3H, t, J7.8Hz
), 1.25 (3H1t, J 7.2) (z)
*2.05 (2H1m) -2,55 (2H,s),
4.0-4.5 (3H, m+q, J 7.2Hz),
and 5.35-6.2 (2H, m).

Prepared as described in Example 12c (77ch); δH (60MHz, CDCJs) 1.0 (3H, t
, J7.5Hz), 1.3(3Ht, J7
．． 2Hz), 2.1 (2H, m), 4.25 (2H, q
, J 7.2Hz) 4.75(2H,s), 4.95(
IH,m) and 5.3-6.25(3)i,m).

Prepared as described in Example 12d but using only 1 equivalent of base (68%). Melting point 120-121
°C (ethyl acetate/cyclohexane) (experimental value: M+-
HtOa 284, 9733 m C*H+n,'N
Theoretical value of 0sCls: M, 284,9726; Experimental value: M"-C02H+257, 9863, C5H
uNOzCes O theoretical value: M”, 257.9855)
umax(KBr)3307.1736.1710.1
696.1534°1249, and 7213-'; δ
H (250MHz, (CD3)2CO) 0.99 (3H
, t, J 7.5Hz), 2.1 (2H, m), 4.7
5-4.87 (3H.

m), 5.64 (IH, ddt, J 15.4.6.6
．． 1.5Hz), 5.95 (IHdtd, J 15.
4-6.3+1.2Hz), and 7.21(IH, br
d).

(Also contained traces of 2-olefin).

g 6β-(D,L-2=<2.2.2-trichloroethoxycarbonylamino)-hex-3(E) prepared as described in Example 2b, but not converted to the sodium salt. &(911)6β-(D,L-2-(
2,2,2-Trichloroethoxycarbonylamino)hex-3(E)-enamide] penicillanic acid (0,89
Debinding of 9,1,8 mmol) was carried out as described in Example '2c.

The crude product was chromatographed on HP20SS eluting with an aqueous solution of 6β-(
L-2-amino-hex-3(E)-enamido)penicillanic acid (125μ, 21'%) was obtained.

umax(KBr)2967.1771,1686.1
602, 1515° 1393 and 1317m-"; δ
H (250MHz, DzO) 0.98 (3H.

t, J 7.5Hz), 1.50 (3H, s), 1.5
9 (3H, s), 2.13 (2H, m), 4.25 (l
H, s), 4.61 (IH, d, J 8.4Hz) = 5
．． 48 (IH, d, J 4.IHz), 5.59 (IH
, d, J 4. IHz).

5.50-5.61 (IH, m) and 6.21 (IH,
dt, J 15.4, 6.3 Hz) Then a mixture of D- and L-stereoisomers (63 capes, 11%) was obtained,
Thereafter, 6β-(D-2-aminohex-3(E)-enamido)penicillanic acid (80Hy, 13tllI) was obtained.

umax (KBr) 2967, 1771, 1687.
1603.1520°1393 and 131851-'
; δH (250MHz, D20) 1.00 (3H1t
, J 7.5Hz), 1.49 (3H,s), 1.59
(3H, s), 2.13 (2H, m), 4.23 (IH
, s), 4.60 (IH, d, J 8.6 Hz).

5.49 (IH, d, J 3.9Hz) C5-55 (I
Hld, J 3.9Hz).

5.52-5.60 (IH, m), and 6.2 (IH,
dtd, J 15.2°6.3, 0.5Hz)
.

[Mass spectrum: +ve ion (thioglycero-Jv
) MH(328), -ve ion M"-H(32
6)).

Example 14 As described in Example 13c, except that 1 equivalent (20 m
The title compound (2,60 L; I, 54%) was obtained after chromatography by preparation using cyclohexanecarboxaldevide (2,60 L; I, 54%).

(Experimental value: M+, 239,1523.Cl5H21N
Theoretical value of O32M1239.1521); δH(250
MHz, CDCll3) 1.07-1.3 and 1.6
-1.85 (1074, 2m), 1.36 (3H, t,
J7. IHz).

2.10 (IH, m), 4.04 (3H, s), 4.3
4 (2H, q, J 7.1Hz), 6.47 (IH,
dd, J 16.4.1.0Hz), and 6.65(
IH.

dd, J 16.4, 6.8Hz).

(Less than 5% of other isomers were present).

(44ch) δH(60MHz, CDCll3) 1.0-2.2(
14H, m+t, J 7Hz).

2.6 (2H, s), 4.05・-4,5 (3H, m+
d, J 7Hz), and 5.35-6.1 (2H,
, m).

Prepared as described in Example 12c (42 pieces).

δH (60MHz, CDCh) 1.0-2.3 (14H
, m+t, J 7Hz).

4.25 (2H, q, J 7Hz), 4.75-5.0
5 (3H, rn+s), and 5.25-6.15 (3H
, m).

Prepared as described in Example 12d, but using 1 equivalent of base. (70%). Melting point 168-170℃ (
? Thf! ethyl/cyclohexane).

δH (250MHz, (CD3)2CO)1.0-1
．． 4 and 1.6-1.8 (10I (2m) + 2
．． 01 (m+Ds-in acetone), 4.74-4
．． 86 (3H, m) 5.61 (IH, ddd, J 1
5.6, 6.6, 1.1Hz), 5.87 (IH.

ddd, J 15.6.6.611.1Hz) l
and 7.21 (IH, br d.

J7.9Hz).

[Mass spectrum: +ve ion ('/-nitrobenzyl alcohol) (3-NOBA/Na), sodium salt MNa (402)].

88%]06β-[D,L-
4-Cyclohexyl-2-(2゜2.2-trichloroethoxycarbonylamino)put-3(E)-enamido]penicillanic acid (0,6289+ 1.1 mmol
) was carried out as described in Example 2c. 6β by chromatography of the crude product on HP2O8S eluting with 7-25% aqueous THF.
-(L-2-amino-4-cyclohexypt-3 (
EE)-enamide) penicillanic acid (50+I!Ii,
12%).

νmax (KBr) 2923, 2851, 1759, 1
688.1609°1511.1389 and 1319!
-1; δH (250MHz, D20) 1°O-1,8
(16H, 2m+2s), 2.06 (IH, m), 4.
25 (IHls), 4.28 (IH+d, J 7.5H
z), 5.43J'-5,60 (3H.

m+2d, J 4.0Hz), and 5.96 (1tL
dd, J 16.0°6.6Hz); then a mixture of D- and L-stereoisomers (231N!.

5) was obtained, followed by 6β-(D-2-amino-4-
Cyclohexyrpto-3(E)-enamide) Benicilla 7f%2 (80rNi, 1c+%) was obtained.

νmax (KBr) 2924, 2850.1771.1
683.1599°1515.1393 and 1315m
-1: δH (250MHz, D20) 1.0-1.8
(16H, 2m+2s), 2.05 (IH, m), 4.
22 (IH.

s), 4.46 (IH, d, J 8.2I(z), 5.
43-5.61 (3H, m+2dJ 3.9Hz),
and 6.05 (LH, dd, J 15.6, 6.5H
z).

[Mass spectrum: +ve ion (thioglycerol)
MW+(382)).

Example 15 Prepared as described in Example 13c, but using 1 equivalent of benzaldehyde to give the title compound after chromatography (77%).

(Experimental value: M+, 233.1044.C+3H+5N
The theoretical value of Os is 2M, 233.1052); δH (400MHz, CDCll3) 1.40 (3H
, t , J 7. IHz), 4.13 (3H,
s), 4.40 (2H, d, J 7.IHz), 7.2
2 (LH, d, J16.7t(z), 7.30-7.3
9 (3H, m), 7.51-7.53 (2H, m) and 7.59 (IH, d, J 16.7Hz) (single isomer).

Ethyl 2-methoxyimino-4-phenylbut-3(E)-enoate ((2,91 L) in ethanol (60 m)
j, 12.5 mmol) with an aqueous sodium hydroxide solution (IM, 37a/e 37 mmol) at room temperature.
Time processed. The solution ft# was concentrated, diluted with water and washed with ether (2X50d). Then the aqueous phase'tpH2
and extracted with ethyl acetate (3X60st/). The combined extracts were washed with brine, dried and evaporated to give a white solid (2,4:l) which was recrystallized from ethyl acetate/cyclohexane to give colorless needles (2,115 !9°82cm) was obtained. Melting point 1
10-111℃.

(Experimental values: C, 64,67; H, 5,36; N, 6.
68chi, theoretical value of CoHoNOs: C,64,38;
H, 5,40; N, 6.83%).

δH (60MHz, (CD3)2CO)4.1(3H1
s) 17.25 (IHld.

J 17Hz), 7.35-7.70 (5H, m), 7
．． 85 (IIH, d, Jl 7Hz), and 10.
3 (IH, bra).

c 2-Amino-4-phenylput-3(E)-enoic acid 2-methoxyimino-4-phenylput-3(E) -
-! -ionic acid (0,595'j, 2.9 mmol) in ethane'' (15 sf), water (7.5 ml) and ant ff (
15d), cooled to about 0.5°C, and dissolved in zinc powder (
1,011e (15 mmol) was added little by little. 5
After minutes, the mixture was filtered and concentrated. Count the solid precipitate,
Washing with acetone then ether and drying under vacuum gave the title compound as a white crystalline solid (0.4509
, 88%). Melting point 197-199°C.

umax (KBr) 2946, 1646, 158
5, 1396, 1354゜1331.962 and 7
34crn-'; δH(250MHz -LJ20/
DCl ) 4.53 (IH, dd, J 8.5, 0.
4Hz), 6.00 (IH, dd, Jl5.9.8.4
Hz), 6.65 (IH, dd, J 15.9.0.
4Hz), and 7.05-7.23 (5H, m).

[Mass spectrum: +ve ion (ammonia) Mu
” (178)].

The title compound (37, 7) was obtained by P20SS chromatography (from aqueous solution).

2-Amino-4-phenylpt-3(E)-enoic acid (0
, 46 g, 2.5 mmol) in water (15*) and T
Suspended in HF (15at), 2.2.
2-Trichloroethyl (0.5ml e 3.6mmo
I) was treated by dropping a bath in THF (5 d) while I) was maintained at 7.7±0.2. The mixture was stirred for 1 hour, concentrated and diluted with ether (2X30.d
), acidified and extracted with ethyl acetate (3×30d). The combined extracts were washed with brine, dried and evaporated. Recrystallization from ethyl acetate/cyclohexane gave the title compound as a pale yellow powder (2 flF!, 40
%) Yo, a, eh. Melting point. . 5-207℃.

δH (250MHz, (CDs)2CO) 4.
85 and 4.88 (2H, ABq.

J 12.2Hz), 5.03 (IH, m), 6.46
(IH, dd, J 16.0°6.7Hz), 6.84
(IH, d, J 16.0Hz), and 7.25-7
．． 50(6Hem)- [Mass spectrum 2 'L+(351'), M+-
Cow (306)] prepared as described in Example 2b but not converted to sodium salt (82%)
.

6β-[D,L-4-phenyl-2-(2,2,2-
trichloroethoxycarbonylamino)put-3(E)
-enamide]penicillanic acid (1,417,2,5mm
Deprotection of ol) was performed as described in Example 2c. The crude product was transferred to HP 20SS for 5-25 hours.
6β-(L-2-amino-4-phenylbut-3) by chromatography eluting with aqueous F'
(E)-enamide) penicillane [(46■, 5%)
I got it.

νmax(KBr)2970.1773.1690,1
602, 1517° 1395 and 1315Crn-1,
δH (250MHz, D20N, 45(6H.

s), 4.22 (IH, s), 4.8 (LH, obscured by HOD).

5.49 (IH, d, J 4.0Hz), 5.60 (
LH, d, J 4.0Hz).

6.31 (LH, dd, J 15.9, 8.5Hz)
, 7.01 (IH, d, Jl 5.9H2) , and 7
．． 36-7.58(5)i,m): then a mixture of D and L stereoisomers (106+N?.

11) was obtained, and then 6β-(D-2-amino-4
-Phenylzo)-3(E)-enamido)penicillanic acid (80++v, 9th) was obtained.

νmax (KBr) 2971, 1772, 1689, 1
599,1517°1395 and 1317crn-1;
δH (250MHz, D20) 1.40 (6H.

s), 4.19 (1 to 1.s), 4.8 (LH, HOD
(obscured by)

5.45 (LH, d, J 3.7Hz), 5.55 (I
H, d, J 3. '7Hz).

6.29 (IH, dd, J 15.9.8.6Hz),
7.0 (IH, d, J 15.9Hz), and 7.40
-7.57 (5H, m).

[Mass spectrum: +ve ion (thioglycerol)
MH+(376)).

Example 16 As shown in Example 13c, however, 0.97 t
(29 mmol) (7) Prepared using 4-chlorobenzaldehyde and after chromatography, the title compound (3,31 L?, 43%) was obtained in total.

δH (60MHz, CDCe3) 1.4 (3H, t, J
7Hz), 4.1 (3H.

s), 4.4 (2H, q, J 7Hz), 7.1 (]H
, d, J 17Hz).

7.1-7.4(4H,m)- and 7.6(IH,d,
J 17Hz).

[Mass spectrum: M+(269)].

Prepared as described in Example 15b (1.735
9.78), melting point 73-80°C (cyclohexane); , δH (60MHz, (CDs)2co) 4.1 (3
H,s), 7.1(IH,d.

J 17Hz), 7.5 (4H, m), 7.8 (IH
, d, J 17Hz), and 10.7 (IH, br
s).

Prepared as described in Example 15c (1.213
9.80%); νmax (KBr) 2950, 1643, 1586.1
490, 1392°964 and 817cm-”: δH
(250MHz, D20 + DCI) 4.3
8 (LH, dd, J 8.4.0.6Hz), 5.8
2 (IH, dd, J 15.8° 8.4Hz), 6.
45 (IH, d, J 15.8Hz), and 6.87
-7.00 (4H, m).

Prepared as described in Example 15d (0.784
9.36%) Melting point 188-193°C (ethyl acetate/cyclohexane); νmax (KBr) 1728.1510.1491,1
406,1246°1093 and 809crn-'; δ
H (250MHz, (CD3)2CO).

483 and 4.86 (2H, ABq, J 12.2H
z), 5.03 (LH+m).

6.49 (IH, dd, J 16.0, 6.6Hz),
6.84 (LH, dd, Jl 6.0, 0.91 (z
), and 7.36-7.54 (5H, m).

[Mass spectrum: M+(385) + M+-C0
2H (340)).

amine)put-3(E)-enamido]penicillanic acid 6β-[D,L-4-( 4-chlorophenyl)-2-
(2,2,2-toIJchloroethoxycarbonylamino)put-3(E)-enamido]penicillanic acid (0,8
Deprotection of 9 g, 1.5 mmol) was performed as described in Example 2c. Chromatography of the crude product over I(P2O8S) eluting with 10-35% THF in water gave the title compound (158
7%).

νmax (KBr) 1773, 1688.1594, 1
513,1491°1392 and 1317cm-”;
δH (250MHz, D20) 1.37 (3H.

1.43 (3H, S), 4.17 and 420 (LH, 2s in total).

4.8 (obscured by IH, HOD), 5.42 and 5.47 (combined IH, 2d, J 3.7, 4.1
Hz), 5.53 and 5.58 (total IH.

2d, J 3.7.4.1Hz), 6.2-6.35
(In total IH, 2dd, Jl 5.9, 8.6Hz
), 6.94 and 6.96 (total IH, 2cl,
J 15.9Hz), and 7.36-7.50 (4H
, m).

[Mass spectrum: +ve ion (thioglycerol)
M)(+(410)] Example 17 Methyltriphenylphosphonium bromide (7,145
9,20mmol)'kT)IF (100d)
suspended in n-butyllithium (1,5M, 13.3d, 20mrnol) and cooled to about -25°C.
) was added slowly. The mixture was stirred at -20 °C for 1.5 h, cooled to about -70 °C, and TI(F' (20 d
) in which 2-methoxyimino-3-okine-4.4.4-
Ethyl trifluorobutanoate (4,5431?, 2
0mmol) [C, 5colast for manufacturing
ico et al., 5ynth-esis, 198
5.850] was added slowly. The mixture was then stirred while slowly returning to room temperature and stirred overnight at room temperature. The mixture was then evaporated and the residue dissolved in ethyl acetate, washed with water and brine, dried and evaporated.

Crude product all on silica gel, 0- in hexane as a bathing agent
Purification by flash chromatography using ethyl 5-thiacetate afforded the title compound as a volatile colorless oil (1°139, 25%).

δH (60MHz, CDCe5) 1.35 (3H, t
, J7Hz), 4.05 (3Hes), 4.4
(2H9q, J 7Hz), and 5.85 and 6.2
5 (2H, 2m).

Prepared as described in Example 12b (0.7(1
, 71ch).

δH (60MHz, CDCJ!s) 1.25 (3H, t
, J 7Hz), 2.0 (2H*br s)*4.2
5 (3H1m+q*J 7Hz)+ and 5.85 and 6.0 (2H, 2m).

Prepared as described in Example 12c (1.3'l
l, galvanostatic) 0 δH (60MHz, CDCJs) 1.3 (3H, t, J
7Hz), 4.35 (2H, Q, J 7Hz),
4.8 (2H, s), 5.25 (IH, d.

J 8Hz), 5.95 and 6.15 (2H, 2m)
, and 6.35 (IH.

br d, J 8Hz).

[Mass spectrum: M+ (371)] 3-enoic acid prepared as described in Example 12d (0.96
59.80%).

δH (60MHz, (CD3)2CO)4.85(2H
1B)-5,15 (IH, d, J 8Hz), 6. −
6.3 (2H, m) and 7.4 (IH.

br d, J 8Hz).

Acid prepared as described in Example 2b but not converted to sodium salt (1.321?, 87%)f
6. β-(amino-3-trifluoromethylproβ-
D,L -2-(2,2,2,-)lychloroethoxycarbonylamino)-3-trifluoromethylbut-3-
enamide] penicillanic acid (1,329+ 2.4mm
Deprotection of ol) was performed as described in Example 2C. Crude product on HP20SS 0.5-3%
You should apply chromatography using an aqueous THF solution! 116β-(L-2-amino-3-trifluoromethylput-3-enamido)penicillanic acid (80
1r9.9%) was obtained.

umax(KBr)1774.1694.1607.1
516.13141174 and 1130cm-"; δ
H (250MHz, Ih0) 1.50 (3Hs), 1
．． 59 (3H, s), 4.25 (IH, s), 4.99
(IH, s) 5.50 (IH, d, J4.0f(z),
5.59 (IH, d, J4.0 Hz) and 6.19 and 6.41 (2He2br s)+; then a mixture of D- and L-stereoisomers (72k, 8th) is obtained, then 6. β-(D-2-amino-3-trifluoromethylpt-3-enamido)penicillanic acid (601Ni,
7%) was obtained 0νmax (KBr) 1772,16
94.1520.1318°1246.1176 and 1
129m-”; δH (250MHz, D20)1
．． 49 (3H, s), 1.60 (3H, s), 4.22
(IH, s).

4.96 (IH, s), 5.55 (LH, d, J3.9
Hz), 5.58 (LH, d, J3.9Hz), and 6.21 and 6.42 (2H, 2br s) [Mass spectrum: +ve ion (thioglycerol) MH
(368)) Example 18 Copper oxide (1) (0,059) was dissolved in 2-chloroacetylthiophene (1,61!9°10m) in toluene (25g).
mol) and methyl isocyanoacetate (0.91d10m
mol) and then the mixture was stirred and heated at 70° C. for 5 hours. The reaction mixture was concentrated in vacuo and the residue was flash chromatographed on silica gel to give the title compound (1,49,9.57%).

(Experimental value: M+, 259, 0067, C+o
Theoretical value of H+oCeNOsS: M, 259.0069
); δH(60MHz, CD(J!a)3.33(3H,s
), 4.00 (2H.

s ), 5.02 (LH, d , J2Hz ), and 6
．． 8-7.4 (4H, m).

Activated zinc powder (2,39) was converted into Tl(F' (25d
5-chloromethyl-5-cheso-2-yl-3- in )
Oxazolin-4-ylcarbonyl methyl (4,595
1) in an argon atmosphere and heated under reflux for 2 hours. Ethyl acetate (50y) and 0.5N hydrochloric acid (50d)
F was added and the mixture was filtered and extracted twice more with ethyl acetate. The extract was washed with brine (3×50 ml), dried, the solvent was evaporated and the residue was flash chromatographed on silica gel to give the title compound (3,019, 61%).

(Experimental value: M, -, 225, 0460r Cl0H
Theoretical value M of IINO3S, 225.0460); δH(60MHz, CD(,13)3.78(3H
, 3), 5.28 (IH.

s), 5.62 (IH, s), 5.65 (IH, d, J
8Hz), 6.74 (IH, br d, J8Hz, D
20), 6.9-7.3 (3H.

m), and 8.25 (IH, s).

Methyl 2-formamido-3-thien-3-ynoate (1
, 049) to give a homogeneous bath solution which, after stirring overnight, was evaporated under vacuum to give the title compound as a crude foam (0.99t, 92t).

δH (60MHz, CD30D) 3.83 (3H,
s), 5.23 (IH.

s), 5.55 (LH, s), 5.83 (LH, s),
and 6°9-7.5 (3H, m).

Methyl 2-amino-3-thien-2-ylbuenoic acid diphosphate hydrochloride (0,99
Q, 4.2 mmol) e2.5N sodium hydroxide to maintain the pH at 7 ± 0.5, while adding chloroformic acid 2,
2.2-Trichloroethyl (0,725Rt.

5.25 mmol) was added dropwise. Solution tpH7±0.
5 for an additional 0.5 h, then chloroform (3x
25d). The extracts were washed with water (2 x 50.d), dried, the solvent was evaporated under vacuum and the residue was flash chromatographed on silica gel to yield the title compound (0,959).

61%).

(Actually, '141ffL: M+, 370.9557
．． C++*H+z(43NO4S (D theoretical value: M, 3
70.9553); δH (60MHz, CDCgs) 3.77 (3H,s
), 4.73 (2H,s).

5.28 (IH, s), 5.33 (IH, d, J 8
Hz), 5.63 (IH, s), 6.18 (IH, br
d, J8Hz, replace D20) and 6.85-7.
3 (3H, 1Tl).

-enoic acid N Methyl 3-thien-2-yl-2-(2,2°2-trichloroethoxycarbonylamino)but-3-enoate (1,2) in sodium hydroxide (5d) and methanol (5i) 54'j*4.1 mmol) was stirred for 2 hours. The solution was washed with chloroform (2x1oy) and P
Acidified with H2,5 and extracted with chloroform (3X15d). Wash the extract with water 2! M) Table tl compound m (1,04Q,
70%) t-obtained.

δH (60MHz, (CDri2CO)4.83(2
H,s), 5.37 (IH,d, J8Hz), 5
．． 38 (IH, s), 5.65 (IH, s).

6.9-7.5 (4H, m), and 8.47 (LH+b
r 31D20).

Prepared as described in Example 2b, but the Omotama compound was isolated as crude free a-acid (82-thi).

6β-(D,L-3-thien-2-yl-2-(2,
2,2-Trichloroethoxycarbonylamino)but-
3-enamido]penicillanic acid (1,14&) was deprotected as described in Example 2c. HP2 crude product
6β-(L-2-amino-3-cheso-2-ylpt-3-enamido)pe-silane acid (15
J') was obtained.

umax(KBr)3349.1766.1669.
1601 and 1515m-'; δH (250MHz
, DzO) 1.42 (3H,s).

1.46 (3H, s), 4.19 (LH, s), 5.0
9 (IH, s).

5.46 (H (, d, J4.1Hz), 5.52 (IH
, s), 5.58 (IHd, J4.1Hz), 5.
87 (IH,s), and 7.0-7.5 (3H.

m); a mixture of D- and L-stereoisomers (15J) is then obtained, followed by 6β-(D-2-amino-3-cheso-2-ylpt-3-enamido)pe-silane acid (16J);
)was gotten.

umsx(KBr)3373.1766.1675.
1599 and 1516 cm-'; δH (250MHX
, D20) 1.44 (3H, 8).

1.52 (3H, s), 4.17 (IH, s), 4.9
7 (IH, s).

5.47 (IH, d, J3.9Hz), 5.48 (
IH,s), 5.53 (IHd, J3.9Hz), 5
．． 82 (IH, s), and 7.05-7.45 (3H.

m) [Mass spectrum: +ve ion (thioglycerol) MH+ (382), MNa+ (404)) Example 19 Sul7lyl chloride (21st) 'k, carbon tetrachloride (50, d) cooling in a water bath It was added dropwise to 2-acetylthiophene (16, 2d) in the solution. The mixture was stirred for 1.5 hours and then distilled to give the title compound (1,9,
199) was obtained. Boiling point 144-148℃/12h; δH (60MHz, CDCh) 6.50 (IH, s
), and 7.1-8.1 (3H, rn); about 30% 2-
Contains (Gl-acetyl)thiophene, δH (among others) 4.60 (2H, s).

Chil 2-(dichloroacetyl)thiophene (6,779+
34.5mmol + 2- (ChloA/acetyl)
isocyanoacetate (mixed with 72.37 g of thiophthi) in toluene (30 g) cooled in a water bath.
3d, 30mrnol) and triethylamine (
4,3yd, 30mmol). The reaction was stirred at room temperature for 24 hours, then acetic acid (1,8d)t'
and more ethyl acetate (100d). The mixture was washed with water (2X50d) and brine (50d),
The title compound (7,309
, 83%).

(Experimental value a M” + 292.9668 + Cl0
Theoretical value of H9Ce 2NO3S: M, 292.968
0); δH (250MHz, CDC63) 3.43 (3H,
s) -5, 13 and 5.26 (total IH+2d+J
2Hzt isomer ratio 1:4), 6.00 and 6
．． 46 (combined I H+ 2 s + ratio 4:1), and 7.0-7.4 (4H.

m).

c 4-chloro-2-formamido-3-thien-2
Methyl -ylpt-3-enoate 5-dichloromethyl-5-4-2-2-1-2-oxazolin-4-ylcarboxylate was treated with activated zinc powder in THF as described in Example 18b.
Chromatography of the crude product on silica gel gave the E isomer (9%) of the title compound. A sample was recrystallized from ethyl acetate/hexane. Melting point 92-93
℃.

(Experimental value: C, 46,29; H, 389; N, 5.
43; cg, 13.71.

S, 12.18%, C+oH+oCeNO3
Theoretical value of S: C, 46,25; H, 3,88; N,
5.39; C6,13,65; S, 12.35%)
; δH (60MHz, CDCl!3), 3.80 (3H
, s), 6.11 (LH.

d, J8Hz), 6.62 (LH, s), 6.87 (I
H, br d, J8 Hz + D 20 exchange),
6.9-7.4 (3H, m), and 8.23 (IH, s
).

Furthermore, the column was separated from the bath, and ethyl acetate-hexane was used for crystallization to obtain two isomers (42 in number) of the surface compound. Melting point 117-119°C (experimental value: C,46,3
5; H, 3,87; N, 5.36; (J, 13
．． 47; S, 12.41%, C+oH+o
Theoretical value of CeNO3S: C, 46,25; H, 3,88
;N, 5.39;cg, 13.65;S,
12.35ch); δH (250MHz, CDCe5
), 3.79(3H,s), 5.59(IH,
d, J7.7Hz), 6.56(LH,br d,J
7.7Hz).

6.61(IH,s), 7.05-7.45(3J(,
m), and 823 (IH, s).

Confirmed as Z isomer by N, O, and E.

Methyl 4-chloro-2-formamido-3-thien-2-ylbut-3(Z)-enoate (0,97!9) was hydrolyzed as described in Example 18c.

The nominal compound was obtained as a crystalline solid by powdering the crude product in a needle, with a (0.80?) melting point of 1.
90-1°C; (actual value: C, 40,03; H, 4,14; N, 5.
25;S, 12.21 polyC9'HII (JzNOzS
theory (ii: C, 40, 31; HI3.13; N
15.22; S, 11.96ch): δH(60
MF (z, CD30D) 3.90 (3H2s)
, 5.33 (1f(.

s ), 7.07 (IH, s ), and 7.1-7.8
(3H,m).

2-amino-4-chloro-3-thien-2-ylbut-
3(Z)-Methyl enoate hydrochloride (1,229) was prepared as described in Example 18d from Chlor ant #1.2°2.2-
Acylation was performed with trichloroethyl (0,665, g). The title compound was crystallized from hexane (mp 1.42
9.77%).

Melting a66-7℃ (Experiment+Hi: C, 35,55; H, 2,66; N
, 3.39:Ce+34.79';3S,
7.82 % OCI 2 mountains + Theoretical value of Ce 4NO4S: C, 35, 4Qlij) (, 2, 72; N, 3.4
4; Ce, 34.83; S, 7.88%); δH(
60MHz, CDCe3) 3.77 (3H, s)
, 4.73 (2H.

s)+5.25(LH+d+J8Hz)+6.07(1
) (replaced with tbr d+J8 Hz r D20-)
, 6.58 (LH,s ), and 6.95-7.5 (3
1(,m).

4-chloro-3-thien-2-yl-2-(2°2.2
- trichloroethoxycarbonylamino)put-3(
z)-Methyl enoate (1°429) Hydrolyzed as described in all Example 18c. The title metal was crystallized from ethyl acetate/hexane ((0,51!?, 37%), melting point 112-3°C; (experimental value: M+, 390,9009, CuHe(J
! 3W theoretical value of 4No4S, 390.9007); δH (60MHz, (CD3)2CO), 4.
77 (3H, s), 5.38 (IH, d, J8H
z), 6.70 (IH, s), 6.9-7.5 (4H.

m), and 9.80 (I H+ b r se
(Replace D20).

Prepared as described in Example 2b, but the title compound was isolated as the crude free acid (77%).

6β-[D,L-4-chloro-3-thien-2-yl-2-(2,2,2-trichloroethoxycarbonylamino)put-3(Z)-enamide]benicillanic acid as described in Example 2c I removed the protection as I did.

Chromatography on HP20SS (7%) gave the title compound as a white lyophilized solid.

νmax (KBr) 3379, 1771, 1688.1
601,1515° and 7 Q gcrn-”, δH(
250MH2, D20) 1.45.1.47 and 1.5
6 (total 6H, 3s), 4.20 and 4.22 (total IH, 2s) 5.18 and 5.20 (total IH,
2s), 5.45/ and 5.54 (total IH, 2d
, J4Hz), 5.59 and 5.60 (total LH, 2
d, J4Hz), 7.00 and 702 (total II (1
28) l and 7.1-7.2 (3H, m).

[Mass spectrum: +ve ion (glycerol/DM
SO) MH+ (416), 2M+H+ (831))
.

Example 20 Methyl 4-chloro-2-form7mido-3-theen-2-ylbut-3(E)-enoate (0,50?.

from Example 19c) was hydrolyzed as described in Example 18c. The surface compound is a coarse foamy substance (0.50g,
Section 96) was obtained.

δH (60MHz, CD5OD) 3.85 (3H,
s), 5.57 (IH.

s ), 6.97(iH,s )+ and 7.0-7.6
(3H, m).

2-amino-4-chloro-3-thien-2-ylbut-
Methyl 3(E)-enoate hydrochloride (0.50 g) was acylated as described in Example 18d.

The title compound was crystallized from hexane (0.63184
h), melting point 67-9°C; (experimental values: C, 35,64; H, 2,62; N, 3.
28; C'g, 34.86; S, 7.93%, Crt
Ho C1l 4NO4S (7) Theoretical value: C, 3
5,40; H, 2,72; N, 3.44; cg,
34.83; S, 7.88%); δH (60M
Hz, CDCJs) 3.78 (3H,s),
4.73 (2H.

s), 5.83 (IH, d, J8Hz), 6.15 (I
H, d, J8Hz) 6.60 (LH, s), and 6.8
5-7.3 (3H, m).

2-amino-3-thien-2-yl-2-(2°2.2
-trichloroethoxycarbonylamino)put-3 (
E)
[Compound m1all-like material <0.459.86%].

δH (60MHz, (CD3), 2CO>4.77(
2H, s), 5.88 (IH, d, J7Hz), 6.7
8 (HLs), 6.9-7.5 (4H-m), and 9.
20 (IH, br s+D20tl-exchange).

The title compound was obtained as the free acid by preparation as described in Example 2b (quantitative).

6β-[D,L-4-chloro-3-thien-2-yl-2-(2,2,2-)IJ dichlorotoxycarbonylamino)put-3(E)enamide]penicillanic acid (0
, 67g) was deprotected as described in Example 2c. The title compound was obtained by chromatography on HP20SS as a white lyophilized solid (25W9.5T).

νmax (KBr) 3339, 1774.1688.1
599゜1511 and 709G single layer δH (250MH2
, D20) 1.43, 1.46 and 1.55 (total 6
H, 3g), 4.18 and 4.21 (combined IH.

2s), 5.43 and 5.47 (total IH, 2d, J
4Hz), 5.55-5.7 (2H, m), and 7.
0-7.5 (4H, m) - [Mass Spect A/ Knee 1
-76 ion (3-N0BA/Na+) MNa (4
38), MNa" (Na salt) (460)] Example 21 1.1-Dichloroacetone (9,6d) and methyl isocyanoacetate (6,9m) were prepared using triethylamine using the method described in Example 19b. The title compound (17,14g, 84g) was obtained by reaction in the presence of (12,9d).
h) was obtained.

δH (60MHz, CDCd3) 1.52 (3H, s
), 3.67 (3H.

s), 4.72 (IH, d, J2Hz), 5.53 (L
H,s), and 6.72 (IH,d, J2Hz).

[Mass spectrum: +ve (Amemonia) MW+
(226)] 5-dichloromethyl-5-methyl-2-oxazoline-
Methyl 4-ylcarboxylate was treated with activated zinc powder as described in Example 1Sb.

Chromatography of the crude product on silica gave two isomers of the title compound as a colorless oil (3 strips).

(Experimental value, 8f, 190°0265, CrHq
Theoretical value of C13N03 2M, 190.0271); δH (60MHz, CDC63) 1.78 (3H, br
s), 3.82 (3H, s), 5.75 (LH, d
, J7Hz), 6.12 (LH.

br s), 6.87 (IH, br s, replaced DzO) and 8.27 (IH, s).

Elution on column 4 gave the E isomer of the title compound, which was crystallized from ethyl acetate-hexane (13%). Melting point 103-105°C.

(Experimental values: C, 44,00; H, 5,30; N, 7
．． 25; (J!, 18.88chiCtH+oC11
Theoretical value of N03: C, 43,88; H, 5,26; N,
731; CJ, 18.50%); δH (250MHz, CDC/s) 1.76 (3H,
d, J3Hz).

3.80 (3H, s), 5.19 (IH, d, J7.4
Hz), 6.32 (IHm), 6.61 (IH+ b
r s +DzOe exchange), and 8.23 (IH.

Confirmed to be E isomer by s), N, O, and E.

4-chloro-2-formami)'-3-mefluputo3
Methyl (E)-enoate (1,569) was hydrolyzed as described in Example 18c. The crude product was triturated with ether to give a di-crystalline solid (x, 429.88%
) to obtain the title compound.

Melting point 169-71°C (dec): δF((60MHz CD30D) 1.82(3
H,s), 3.83 (3H.

3) 14.92 (IH13) l and 6.68 (LH, b
rs).

d 4-chloro-3-methyl-2-(2,2,2-)2
-Amino-4-chloro-3-methylput-3(E)-enoic acid methyl hydrochloride (1,001) was acylated as described in Example 18d. The title compound was crystallized from hexane (1.06 g, 63%) mp 79-82°C; (experimental values: C, 31,67; H, 3,19; N, 4.
18; (J, 41.41%C9E(oCe4NO4
]t'JL logical value: C, 31, 89; H, 3, 27; N,
4.13; Ce2.41.83%); δH (60MHz, CDC11!3) 1.78 (3H,
br s), 3.80 (3H, s), 4.72 (2H
, s), 4.87 (LH, d, J8Hz).

6.07 (IH, br d, J8Hz, DzO exchange), and 6.32 (IH, br s).

Methyl 4-chloro-2-methyl-2-(2,2,2-trichloroethoxycarbonylamino)but-3(E)-enoate (0,519)t-hydrolyzed as described in Example 18e. By doing so, a gummy substance (0.41g,
The title compound was obtained as (84%).

(Experiment (fi: M+-Cg, 287', 95
99, C, H9C1l! 3NO40 theoretical value: M, 2
77.9309); δH (60 MHz, CDCe3) 1.87 (3H, br
s), 4.80 (2H, s), 4.93 (IH, d
, J8Hz), 6.48(LH,brs)+7.31(
IH+br d+J8Hz+D20 replacement), and 7
．． 82 (L Hr b r s * Replacement of DzO).

The title compound was obtained as the free acid (88%) by preparation as described in Example 2b.

6β-[D,L-4-chloro-3-methyl-2-(2
,2,2-trichloroethoxycarbonylamino)put-3(E)-enamide]penicillanic acid (0,589
) was deharvested as described in Example 2C.

The crude product was purified by chromatography on P20SS (52~, 1
4 yen).

umax 3368.1766.1683.1602 and 1511t1n1; δH (250MHz, D20
)1.50(3H,s), 1.58(3H,s
) 1.80 (3H, d, Jl, 5Hz), 4.25 (I
H, s), 4.65 (IHs), 5.45 (LH, d,
J4Hz), 5.58 (IH, d, J4H2) and 6.
59 (IH, br s); then a mixture of D- and L-stereoisomers (26■, 7
%) was obtained, and the D-stereoisomer (5%) of the photographic compound was obtained.
9■, 15%) was obtained.

umax(KBr)3382, 1767.1685
．． 1602 and 1521crn-"; δH (250M
Hz, D20) 1.49 (3H,s).

1.59 (3H, s), 1.82 (3H, d, Jl, 3
Hz), 4.22 (IHs), 4.70 (LH,s)
, 5.47 (IH, d, J3.8Hz), 5.55 (L
H,d, J3.8Hz), and 6.60(LH,b
r s); [Mass spectrum: +ve ion (thioglycerol) MH+ (348)) Example 22 a 2-amino-4-chloro-3-methylput-4-chloro-2-formamide-3-methylput-3 (z )−
Hydrolysis of ethyl enoate (0,78+?, from Example 21b) as described in Example 18c gave the title compound as a foam (0,689,84%).

δH (60MHz-, CD5OD) 1.88 (3H, b
r s), 3.90 (3H2s), 5.30 (lH+
s) * and 6.58 (IH, br s).

2-amino-4-chloro-3-methylbut-3<E)-
Methyl enoate hydrochloride (0.68 g) was acylated as described in Example 18d. The title compound was crystallized from hexane (0.66g, 58%).

Melting point 110-3°C; δH (60MHz, CDCJs) 1.82 (3H, br
s), 3.86 (3H, s), 4.80 (2H, s
), 5.62 (LH, d, J8Hz).

6.18 (IH, br s), and 6.30 (IH,
br d, J8Hz) Replace D20).

(278)] Ethyl 4-chloro-3-methyl-2-(2,2,2-trichloroethoxycarbonylamino)put-3(z)-enoate (0,41,9)? : Hydrolyzed as described in Example 18c. The title compound was crystallized from ethyl acetate-hexane (0.21 g).

53chi).

Fusion 132-4℃; δH (60MHz, CDCJs) 1.83 (3H
, d, JIHz).

4.75 (2H1s), 5.56 (IHld,
J7Hz), 6.23 (IHsq, JIHz), 6
．． 98 (IH, br d, J7Hz), and 8.07
(IH, br s).

Mino)put-3(Z)-enamido]penicillanic acid The title compound was obtained by preparation as described in Example 2b and isolated as the free acid (52%) lanic acid 6β-(D,L- 4-chloro-3-methyl-2-(2
,2,2-)lychloroethoxycarbonylamino)put-3(z)-enamido]penicillanic acid (0,54g)
Deprotection as described in Example 2c gave the title compound, which was isolated by chromatography on HP20SS as a white lyophilized solid (0.109.2
8%).

umax(KBr)3344.1771, 1688
．． 1602゜1514 and tN1313z-1; δH(2
50MHz, D20) 1.49.

1.50, 1.57 and 1.60 (6H, 4s in total)
), 1.79 and 1.80 (total 3H, 2d, Jl
, 6Hz), 4.24 and 4.25 (total IH.

2s), 5.20 and 5.21 (total LH, 2s),
5.47 and 5.52 (combined), H, 2d, J4H
z ), 5.56 and 5.60 (together IH.

2d, J4Hz) and 6.45(1,H,br
s).

[Mass spectrum: +ve ion (thioglycerol > MH+ (348)) Example 23 T of pl-18±1) Performing D-2 aminopent-4-enoic hydrochloride (2,339') in IF water bath solution Acylation with 2,2.2-)dichloroethyl chloroformate (2,5,d) using the method described in Example 2a. Flash chromatography gave the title compound as a colorless oil (2,9Sl, 55%).

δH (60MHz, (CD3)2CO)2.4-2
．． 8 (2H, rn), 4.2-4.6 (IH, m)
, 4.80(2H,s), 5.0-5.4(
2H, m).

5.6-6.3(IH,m), 7.75(H(,d+J
8Hz), and 8.99 (IH, !3).

Diphenyldiazomethane (1,639) in drill dichloromethane (20-f)
It was added dropwise over 2,2-trichloroethoxycarbonylamine. At the end of the dripping, all the pink color had disappeared, so I added diphenylazomethane (0.
1951), a permanent pink color was again obtained. After 1 hour, the V solution was decolorized by adding glacial acetic acid. The mixture was then condensed under vacuum to give an oil which solidified by standing overnight to give the title compound from hexane (3.871.91
%).

Melting point 8 4-8 7. 5°C; νmax (KBr) 3357, 1743, 1725, 1
534.

1270, 1238.1220.1107 and 70
2cm-”; δH (60MHz, (CDshC
O) 2.4-2.9 (2H, m), 4.3-4,
8 (IH, m) 4.82 (2H, s), 4.
9-5.4 (2H.m).

5, 6-6, 3 (IH.m), 6.98 (IH.s),
and 7.44 (101-i.

s).

C3-hydroxy-D-2-(2.2.2
- A 70% aqueous solution (1.85, d) of t-butyl hydroperoxide in tricdichloroethane (ca. 40 d) was dried over M9SO4 and filtered. Add this solution to 2
- (2,2.2-trichloroethoxycarbonylamino)benzhydrylbent-4-enoic acid (3.3
09) and selenium dioxide (0.369).

The mixture was heated to reflux at 71° C. for 3.5 hours, then stirred at room temperature over the weekend. The liquid was removed by decantation, partially evaporated and then after flash chromatography on silica gel the title compound (0.949.28%)'f
f: Got it. Unreacted starting material (2.109.64%) was collected and treated as above to yield the title compound (0
．． 909.40%). The total yield after two passes is 54
%Met.

δ(((60MHz, (CD3)2CO)4.7(2H
, s), 4.4-5.5 (4H, m), 5.5-6.
3 (LH, m), 6.7 (IH, d.shi9Hz) 6
, 87 (IH,s), and 7.4. (1 0H,
s).

d 3-acetoxy-D-2-(2.2-tricacetic anhydride (0.069) in pyridine (5d)
-Hydroxy-D-2-(2.2.2-trichloroethoxycarbonylamino)benzhydrylbent-4-enoic acid (0.29 g) and 4-dimethylaminopyridine (ln) were added. The reaction mixture was placed in an argon atmosphere. Stirred at room temperature for 6 hours. The mixture was diluted with water, acidified and extracted with ethyl acetate (2X30d). The combined organic extracts were washed with water (2X30d) and brine, dried and extracted under vacuum. After flash chromatography on silica, the title compound was obtained as a mixture of D- and E-0-acetyl isomers (0.219.67%).

δH (60MHz, CDCis) 1.7
6 and 1.93 (3H, 2s in total) 4, 76 (2H
．． s), 4.6-4.9 (IF(, m), 5.1-6.
2 (5H.

m) + 6.95 (IHe s ) + and 7.36 (1
0H. s).

[Mass spectrum/l/: +76 ions (3-
NOBA.

Na+)MNa+(536)) 3-acetoxy-D-2-(2,2°2-trichloroethoxycarbonylamino)bento-4 in dry THF
-Benzhydryl enoate (1.35 g) and bischloride (
Acetonitrile) Palladium(I) (651r1g)
The mixture was left exposed to the atmosphere and then boiled at room temperature for 24 hours. The mixture was concentrated under vacuum to give the title compound (0,859,63%) after flash chromatography on silica.

δH (60MHz, CD (11!s) 1.97 (
3H,s), 4.45-4.65(2H,m),
4.72 (2H, s), 5.1 (IH, br d),
5.8-6.0 (2H, m), 6.1 (IH, d, J8
Hz), 6.97 (IH.

s), and 7.33 (IOF(,s).

-enoic acid trifluoroacetic acid (,4,5d) and anisole (Q,
63m) and 5-acetoxy-D-2-(2,2
,2-)lychlorethoxylponylamino)bento-
Added to benzhydryl 3-enoate (0,709).

The mixture was stirred for 6 minutes at room temperature, then diluted with toluene and concentrated under vacuum, which was repeated twice. After flash chromatography, the title compound (0,33F, 69%) was obtained by trituration from hexane. Melting point 9
4.5-97°C.

νmax (KBr) 3413.3000 (br), 29
95.1734゜1694.1533.1403.13
28,1227.1196°1101.823,711
．． and 570 cm-”; δH (60 MHz.

CDCh) 2.09 (3H, s), 4.6-5.
0 (5H, m), 5.75-6.0 (3H, m), and 8.5 (IH, br s).

Oxalyl chloride (0,07 g) was dissolved in DMF (0,04
J? ) was added. The mixture was stirred in a water bath for 15 minutes,
It was then cooled to -20°C. 5-acetoxy-D-2-(2,2,2-trichloroethoxycarbonylamino)bent-3-enoic acid (0,
209) was added. The mixture was stirred in a water bath for 15 minutes and then cooled to -15°C. Dichloromethane (3-
) in 6-amitubenicilane ester triethylammonium salt (0.21!?) and triethylamine (0.07 g
) was added and the mixture was stirred at room temperature for 1.1 hours. Mixed @
Concentrate the material under vacuum, add water (15d) and ethyl acetate (
15d) Partitioned, acidified and separated for minutes. The aqueous phase was re-extracted with ethyl acetate (15d).

The combined organic extracts were diluted with water (15 dX2) and brine (15
The crude title compound (0,339, quantitative) was obtained by washing with
I got it.

The title compound was prepared from 6β-[5-acetoxy-D-2(2,2,2-
) to dichloroethoxycarbonylamino)/)-3(F
l:)-enamide] obtained from penicillanic acid (0.11
19.52%).

11max (KBr) 3389, 2969, 17
71, 1688, 1602°1386.1316 and 12423-1; δH (250MHz, D20)
1.49 (3H, s), 1.60 (3H, s), 2.1
2 (3H, s).

4.23(IH,s)e 4.58-4.69(3)
(, m), 5.48 (IH.

d, J3.8Hz), 5.55 (IH, d, J3.8H
z), 5.81-5.91 (IH, m)l and 6.14
−6.24 (IH, m).

[Mass spectrum: +ve ion (thioglycerol)
MW+(372) ].

Example 24 Methylbromopyruvate (43,66F, 0.24
1 mol) and methoxyamine hydrochloride (20,15!9
゜0.241 mol) to methanol/' (220 m
1) and stirred at room temperature for 4 hours. After evaporation, the residue was washed with <*V in ethyl acetate, water and brine, dried and evaporated to give a yellow oil (45,09.
90%). After flash chromatography,
A pure sample was obtained.

δH (60MHz, CD (J!s) 3.9 (3H, s)
, 4.17 (3H,s) and 4.21 and 4.38 (2
H, 2s).

Methyl 3-bromo-2-methoxyiminopronoate (
20,00Q, 95 mmol) and trimethyl phosphite (40d) were refluxed for 1 hour. After pre-distillation of dimethyl methanephosphonate by removing excess trimethyl phosphite under vacuum and distilling the residue, νmax (thin 111%
) 1720, 1270, 1210, 1170.1040
゜850 and 780m-1; δH (250MHz,
CDClls) 3.34 (2H, d, J23.5H
z), 3.75 (6H, d, Jll, 2Hz).

3.89(3H,s), and 4.13(3H,s
)t (single isomer) 3- in THF (20at)
Methyl dimethylphosphonyl-2-methoxyiminopropanoate C7, 17 g 30 mmol) was dissolved in sodium hydride (50% solution in oil, 1,44'i, 30 mmol).
) was added dropwise to a stirred solution of THF (100 m/) in THF (15, d
) in cyclohexano7 (3,11,m130mmo
l) was added dropwise. The mixture was stirred overnight, then diluted with ammonium chloride solution (150 Pnt) and extracted with ethyl acetate (3×50.+d). The combined extracts were washed with brine, dried and evaporated.

The title compound was purified as a colorless oil by flash chromatography on silica gel using 0-5% ethyl acetate in hexane as eluent (2,319,36
%).

νmax (thin film) 2930, 1730. ], 430,1
200, 1150°1050 and 760 cm-”;
δH (250MHz, CDCIJ3], 5.-2.
4 (IOH, m), 3.85 (3H, s), 4.05 (
3H,s), and 5.77(IH,s), (single isomer).

Prepared as described in Example 12b (49%
).

νmax(thin[)2930.2850.1735.14
40.

1430.1200 and 1170 cm-'; δH(6
0MHz, CDCe5) 1.4-2.4(12H, m
), 3.7 (3H, s), 4.3 (LH, d, J9Hz
), and 5.1 (LH,d, J9Hz).

Methyl acid Prepared as described in Example 12c (quantitative).

δH (60MHz, CD(J?s) 1.4-1.8(6
H, rn), 2.0-2.5 (4H, m), 3.7
5 (3H,s), 4.75 (2H,s), 5.
0-5.3 (2H1m) + and 5.93 (IH, br
).

Acid was prepared as described in Example 12d, but using only 1 equivalent of base (56%).

Melting point 139-140℃ (ethyl acetate/cyclohexane)
.

νmax (KBr) 3334, 2937, 1706, 1
526°1292.1240.1052 and 723cr
n-1; δH(250ME(z.

(CDs)2cO) 1.58(6H,m), 2.14(
2H, m), 2.33 (2H, m), 4.77 and 4.
82 (2H, ABq, J12.2Hz) +5.03
(IH, dd, J9.1, 7.6Hz), 5.23 (L
H, d, J9, IHz), and 7.14 (IH, br
d, DzOe exchange).

Prepared as described in Example 2b, but without conversion to the sodium salt. (92chi)6β-[D,L-
Deprotection of 3-cyclohexylidene-2-(2,2,2-trichloroethoxycarbonylamino)propanamide]penicillanic acid (1.6 g, 2.9 mmol) was performed as described in Example 2C. Crude product t-HP
Chromatography on 20SS eluting with 6-7% THF* solution gave 6β-(L-2-amino-3-cyclohexylidenepropanamide)henisilanic acid (105μ, 10%).

νmax(KBr)2929, 2855, 175
7, 1710.

1606.1511 and 1322crn-"; δH(
250MHz, D20) 1.5-1.7(12H, m
), 2.1-2.45 (4H, m), 4.61 (IHs
), 4.96 (IH, d, Jlo, 0Hz), 5.23
(IH, d, Jlo, 0Hz), 5.51 (IH, d,
J4. IHz), and 5.69 (IH.

d, J4. IHz); then the mixture of D- and L-stereoisomers (163~,
15%) was obtained, followed by 6β-(D-2-amino-3
-cyclohexylidenepropanamide) penicillanic acid (
90■, 8%) was obtained.

νmax (KBr) 2926, 1766.1701.1
608°1512.1396 and 1325m-'; δ
H (250MHz, DzO) 1.45-1.7(1
2H, m), 2.15-2.4 (4H, m), 4.5
6 (LH, s), 4.90 (IH, d, Jlo, 0Hz
), 5.19 (IH.

d, Jlo, 0Hz), 5.52 (IH, d, J4.0
Hz), and 5.62(LH,d, J4.01(z
).

Example 25 Methyl xobutanoate A solution of methyl 4-methoxyacetoacetate (21,9 g) in glacial acetic acid (30 d), cooled to 20° C. in a water bath, was added with an aqueous solution of sodium nitrite (11,6,9) (45 d). 0.
It took 5 hours to drip. The mixture was stirred for an additional 0.25 hours and then the cooling was removed.

After a further 0.25 hours, the mixture was diluted with water and extracted with ethyl acetate (4 x 50m). The combined organic extracts were diluted with water (2
x 50 ml), I M NaHCO3 solution (3
x50-) and brine (2 x 50g).

The aqueous phase was back extracted with ethyl acetate. The organic phase' was dried, concentrated and crystallized from ethyl acetate/hexane (19
．． 79.75%).

Melting point 109-112°C; (Experimental values: C, 41,30; H, 4,99; N, 7.
95%, theoretical value of C-p H9Nos: C,41,
15; H, 5, 18; N, 8.00%); νrnax (
KBr) 3213, 1755, 1704, 1384゜1
030 and 10073-''; δH (60 MHz, (
CDs)2CO)3.38(3H,s;, 3.84(3
H,s), 4.54(2H,s), and 11.81(I
H,s).

Methyl 2-hydroxyimino-4-methoxy-3-oxobutanoate (19,279) and potassium carbonate (15,293) and acetone (80, g 0.2 of a bath solution of dimethyl sulfate (10d) in acetone (20d)
The dropwise cooling was removed after 5 hours and the mixture was stirred at room temperature for 4.5 hours. Vinegar 11! Ethyl (100d) and water (100d) were added to the partially concentrated above solution. The aqueous phase was extracted again with ethyl acetate. The combined organic extracts were washed with water and brine, dried and concentrated under vacuum.

The title compound (10,6fi
9.51%).

νmax (*film) 1752.1715.1439,13
09°1221 and 1049m-"; δH (60MH
z, CDCl! ! 3) 3.44 (3H, s), 3.8
7(3H,s)+4.10(3H,s), and 4.54
(2H, s).

Methyl potassium renbutanoate t-butoxide (4,451?) in THF (5
To a suspension in THF (35 m) was added methyltriphenylphosphonium bromide (14,16 g) in portions at room temperature under an argon atmosphere. Methyl methoxy-2-methoxyimino-3-oxobutanoate (35d) a: Added. The mixture was heated to 60° C. for 5 minutes and then cooled. Water (50m) and ethyl acetate (50,+d) were added and the aqueous phase was extracted again with ethyl acetate (50m). The combined organic extracts were dissolved in water (2 x 50 m) and saline (2 x so*
), dried with W and concentrated under vacuum. The title compound C2,359,47 was obtained by flash chromatography eluting with 10 ethyl thiacetate/hexane.
h) was obtained.

νmax (thin film) 1747, 1343.1243.10
88 and l Q 41z-1; δH (60MHz, C
DCh) 3.35 (3H, s).

3.80 (3H,s), 3.87 (3H,s)
, 4.0-4.2 (2H, m) 5.2-5.3 (1)
t, m), and 5.6-5.7 (IH, m).

Methyl 2-amino-4-methoxy-3-methylenebutanoate Prepared as described in Example 12b (70%) νmax ($1419) 2900 (br), 17
50, 1580 (br).

1240 and 1100 crn-1; δH (60 MHz
, CDCes) 3.30 (3H,s), 3.78
(3H, s), 4.05 (2H, s), 4.59 (IH
,s), 5.3-5.6(2H,m), and 8.6-
9.0 (2H.

br).

4-Methoxy-3-methylene-2-(2,2,2-trichloroethoxycarbonylamino)butane-methyl prepared as described in Example 12c (81%).

Melting point 50-52°C. (hexane) max (KBr)3
407,1735.1501,1322゜1203 and 1089crn-"; δH (60MHz, CDC
113) 3.32 (3H, s), 3.77 (3H, s
), 4.01 (2H,s), 4.76 (2H+s), 4
．． 97 (IHld, J6.7Hz), 5.36 (2H.

sL and 6.1 (LH, br).

4-Methoxy-3-methylene-2-(2,2,2-trichloroethoxycarbonylamino)butane! Prepared as described in Example 12d (35 pieces).

1'max (KBr) 3390, 1744, 1,
714, 1699, 1514 and 1223crn-
1; δH (60MHz, (CD3)2CO)3.29
(3Hs), 4.05([(,s), 4.79(2H,
s), 4.91 (IH, d.

J8.7Hz), 5.2-5.5 (2H, m), 7.
0(LH,br), and 8.45(LH,br).

Prepared as described in Example 2b, but without conversion to the sodium salt (88%).

6β-[D,L -4-methoxy-3-methylene-2-
Debinding of (2,2,2-to-1,1 chloroethoxycarbonylamide)butanamide]penicillane d(0,71+?), 4, was carried out as described in Example 2c to give the title compound, HP20SS Obtained as a white frozen solid (0,11,9,23%) after chromatography.

umax (KBr) 3220, 1775, 168
9, 1610.

1524.1391.1316 and 1095cyy+-
” +δH (250MHzD20) 1.54 and 1
．． 55 (3H, 2g in total), 1.63 and 1.64
(3H, 2s in total), 3.397' and 3.40 (3H128 in total) 14.1g 4.14 (2H in total)
, 2s), 4.27 and 4.28 (total IH2s)
, 4.78 and 4.79 (total I H+ 2 g)
* and 5.5-5.7 (4H, m).

Example 26 Prepared as described in Example 24c but with excess acetone and chromatographed to give the title compound (24%) (Experimental: M+, 1
71.0893, CsH+3NO3 (D theory i:M,
171.0895); νmaxc thin film) 1730, 1440, 1300, 12
00°1150.1060 and 1040cm-'; δ
H (60MHz, CDCe5) 1.62 (3H, s)
, 1.9 (3H, s), 3.84 (3H, s), 4.0
2(3HIS)e and 5.9(IH,m).

methyl Manufactured as described in Example 12b.

δH(60MHz, CI)Ce3) 1.75 (
6H,s), 2.1 (2H.

s), 3.72 (3H, s), 4.3 (IH, d, J9
Hz), and 5.2 (IH, m).

methyl Prepared as described in Example 12c (quantitative).

δH(60M)Iz, CDC6:s) 1.75(3H
,s), 1.80 (3H.

s)+3.7(3H+s)+4.7(2H,s)+5.
0(2HIm)* and 6.0(IH,br).

Prepared as described in Example 12d, but using only one base (34% di over 3 steps). Melting point 1
99-200℃ (ethyl acetate/cyclohexane) νmax (KBr) 3297, 1733, 170
1, 1541.

1288.1250 and 72] c11t-'; δH(2
50MHz, (CD3)2CO)1.77(3H,d
, Jl, IHz), 1.82 (3H, d, Jl. IHz
).

4.78 and 4.82 (2H, ABq, Jl2.2H
z), 4.97 (IH.

dd, J9.1, 7.7Hz), 5.28 (IH, dt
, J9.1.1.1Hz) and 7.15(iF(,br
d).

Prepared as described in Example 2b, but without conversion to the sodium salt (87%).

6β-[D,L-4-methyl-2-(2,2,2-trichloroethoxycarbonylamino)bent-3-enamide]penicillanic acid C1,709,3,4 mmol
) was performed as described in Example 2C. By chromatography of the crude product on HP20SS eluting with 2*THF aqueous solution! l16β
-(L-2-amino-4-methylpent-3-enamido)penicillanic acid (38Tli, 3.4%)'jfr:
Obtained.

umax(KBr)2972.1774.1689.
1607.

1517.1389 and 1315w-1; δH(250
MHz, D20) 1.56 (3H, s), 1.62
(3H, s), 1.89 (6H, s).

4.31 (IH, s), 4.90 (IH, d, Jlo,
0Hz), 5.30 (IH, m), 5.49 (IH, d
, J4.0f(z)l and 5.65(LH.

d, J4. OHz); then a mixture of D- and L-stereoisomers (276 cape,
25 yen) was obtained, and then 6β-CD-2-amino4
-methylpent-3-enamido)penicillane fR(7
7.17%) was obtained.

νmax(KBr)2970.1774,1690,1
604°1517.1390 and 1316cm-”;
δH (2'50MHz, D20) 1.55 (3H
, s), 1.63 (3H, a), 1.88 (6H, d,
Jl, 0Hz), 4.29 (IH, s), 4.90 (I
H, d, Jlo, 0Hz) 5.30 (IH, m), 5.
52 (IH, d, J3.9Hz) = and 5.60 (II
(,d,J3.9Hz).

Example 27 The table below shows the absorption index [i.e., oral (pro) and subcutaneous (s, c)] after administration of the compound of the present invention at a dose of 't-50η/yu to 72 animals (5 animals in each group). Ratio of urine recovered from administration] All shown. Comparative figures for amoxicillin are also shown.

Example 1 Absorption index (average) recovery rate (chi) in mice (p, o/s, c) (1) 79 98
0.8 (4) CD-Bunsou Kusara (゛生40 21
86 0.3(5) (D-stereoisomer)
37 87 0.4(6) +-
' 44 103 0.4 (9)
(D-Tachi Ireto 4-1 8゛2L Noi L)
34 116 0.3(11) (D-stereoisomer) 48 63 0.76(1
3) (D-stereoisomer) 45 61
0.74(14) (D-stereoisomer) 11 1
8 0.6 Amoxicillin 23
56 0.4 Example 28 The table below shows the average squirrel monkey (5zurr-ee M
onks)') Serum concentrations are expressed in units of tdi/-.

Comparative figures for amoxicillin given at the same dose are also shown.

Actual example 29 In the table below, Streptococcus pyogenes (S + P)'ogene
s) CNIO and Escherichia coli (E, colt) N
The minimum inhibitory concentrations (MIC'I) of some of the compounds of the present invention against CT C10418 are shown. E. coli was cultured in tryptic soy broth and S.
es were cultured in Todd Hewitt broth. The microorganisms were incubated for 24 hours and then 1 μg of sample was inoculated onto agar plates (containing 5% v/v live horse blood agar) supplemented with compounds of the invention in two-fold serial dilutions. After a further 24 hours, r) MIC([ was determined by visual inspection.

Table 3 MIC data (1)
0.03
8(4) (D-stereoisomer) <0.03
8(5) (Kano stereoisomer)〈0.03
2(6) <0.0
3 2 (7)
0.25 32(9)(D-
stereoisomer) (0,032(10)(D-stereoisomer)<0.06 2(11)(D
-stereoisomer) <0.06
8(12) (D-stereoisomer) 0.06
2(13)CD-stereoisomer) (
0,064(14) (D-stereoisomer) <0.0
6 1605) (D-stereoisomer)
<0.06 16 (16)
<0.06 16
(17) (D-stereoisomer) (0,064(18
) (D-stereoisomer) 0.06
16(19) <0.03
16 (20)
0.06 32 (21) (D-
stereoisomer) 0.06 4
(22) 0.12
8 (23) 0
．． 12 32 Example 30 The table below shows the CD obtained after infecting groups of mice with lethal inoculum of various bacteria and then treating the mice with the cited compounds.
5o (i!E), where the CD5o value indicates the f of the compound required to protect the animal.

Table 4 CD5o data total CD relationship (
η/9) S, aureus Sm1th p, o,
0.05 o,ogS,c,
0.08 0.15p, o,
0.25 0.115s, c,
0.09 0. IS(MIC(μVat)
)0.06 0.1λS, agalactia
e n, o, 0.6 3.8279
8 s, c, 0.12 1
．． 1p, o, 0.9 3.6
s, c, 0.5 1.
5(MIC(μVat) 0.06
0.25) E, colt 96 R-p, o,
40 32s, C1
22 6p, o, 40
40s, C1 40
28 (MIC (μsec-) 2 4) Agent Patent attorney Masamitsu Akisawa and 1 other person

Claims (15)

[Claims] (1) Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) {In the formula, R^1 is a group ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2, R^3 and R^4 are the same or different, and each is hydrogen; halogen; optionally substituted C_1_-_6 alkyl; optionally substituted C_3
____7 cycloalkyl; optionally substituted C_2
____6 alkenyl; optionally substituted C_2_-
_6 alkynyl; amido; cyano; carboxy; formyl; C_1_-_6 alkoxycarbonyl; mono- or di-(C_1_-_6) alkylamide; C_1_-
_6 alkylcarbonyl; an aryl group; a heterocyclyl group, or R^3 and R^4 are joined together to form a carbocyclic residue having a total of 3 to 7 carbon atoms on the ring; or R^3 and R^4 are joined together to form R^
3 and R^4 together form the formula -(CH_2)mX(C
H_2) n^- (wherein, X is oxygen, sulfur, or a group NR^
5, in which R^5 is hydrogen, acyl, amino protecting group or C_1_-_6 alkyl, m is 1-3, and n is 1-3) ], and Y has ▲mathematical formulas, chemical formulas, tables, etc.▼ ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼ ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1^7 is hydrogen or C_1_-_6 alkyl; R^1^8 and R^1^9 may be the same or different, each being C_2_-_6 alkyl; p is an integer having the value 0, 1 or 2; Y^1
are oxygen, sulfur, SO. SO_2 or -CH_2-; and Z is hydrogen, halogen or C_1_-_4 alkoxy, -CH_2Q or -CH=CH-Q, where Q is hydrogen, halogen, hydroxy, mercapto, cyano, carboxy, carbamoyloxy, carboxyl ester, C_1_-_4 alkyloxy, acyloxy, aryl, heterocyclyl group bonded via carbon, heterocyclylthio group or nitrogen-containing heterocyclic group bonded via nitrogen)] Yes, but when Y is -S-C(CH_3)_2- and R^2 is methyl, R^3 cannot be hydrogen when R^4 is phenyl, and R^3 is R When ^4 is hydrogen, it cannot be phenyl} or a pharmaceutically suitable salt or in vivo hydrolyzable derivative thereof. (2) Y is -S-C(CH_3)_2- or -S-C
The compound according to claim (1), wherein H_2-CZ=. (3) The compound according to claim (1) or (2), wherein Y is -S-C(CH_3)_2-. (4) R^2 is hydrogen or C_1_-_6 alkyl, and R^3 and R^4 are the same or different, and each is halogen, C_1_-_6 alkyl,
or compounds according to any one of claims (1) to (3) which together form a carbocycle containing 5 or 6 carbon atoms. (5) R^2 is hydrogen, and R^3 and R^4 are the same or different, each being a halogen or C_1
The compound according to claim (3), which is ____6 alkyl. (6) R^2 is hydrogen and R^3 and R^4 together form a carbocycle containing 5 or 6 carbon atoms; Compound. (7) 6β-(D-2-aminopt-3-enamide)
Penicillanic acid, 6β-(D-2-amino-3-phenylpt-3-enamido)penicillanic acid, 6β-(D-2-amino-4,4-dichloropt-3-
enamido)penicillanic acid, 6β-(D-2-amino-3-methylpt-3-enamido)penicillanic acid, 7β-(D-2-amino-3-methylpt-3-enamido)cephalosporanic acid, 7β-[D- 2-Amino-3-methylpt-3-enamido]-3-desacetoxy-cephalosporanic acid, 6β-(D-2-amino-3-ethylpt-3-enamido)penicillanic acid, 6β-(D-2-amino- 3-methylpent-3(E)
-enamido)penicillanic acid, 6β-(D-2-amino-pent-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-3-methylhex-3(E)
, 5-dienamido)penicillanic acid, 6β-(D-2-
Aminohex-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-4-cyclohexylpto-3
(E)-enamido)penicillanic acid, 6β-(D-2-
Amino-4-phenylput-3(E)-enamido)penicillanic acid, 6β-[D,L-2-amino-4-(4-chlorophenyl)put-3(E)enamido]penicillanic acid, 6,β- (D-2-amino-3-trifluoromethylput-3-enamide)penicillanic acid, 6β-(D-2-
amino-3-thien-2-ylpt-3-enamide)
Penicillanic acid, 6β-(D,L-2-amino-4-chloro-3-thien-2-ylpt-3(Z)-enamido)penicillanic acid, 6β-(D,L-2-amino-4-chlor -3-thien-2-ylpto-3(E)-enamido)penicillanic acid, 6β-(D-2-amino-4-chloro-3-methylpto-3(E)-enamido)-penicillanic acid, 6β-( D
, L-2-amino-4-chloro-3-methylput-3(
Z)-enamido)penicillanic acid, 6β-[5-acetoxy-D-2aminopent-3(E
)-enamide] penicillanic acid, 6β-(D-2-amino-3-cyclohexylidenepropanamide) penicillanic acid, 6β-(D,L-2-amino-4-methoxy-3-methyleneputanamide) penicillanic acid , 6β-(D-2-amino-4-methylpent-3-enamido)penicillanic acid, or the compound according to any one of claims (1) to (6). Pharmaceutically suitable salts or esters that can be hydrolyzed in vivo. (8) A pharmaceutical composition comprising a compound according to any one of claims (1) to (7) together with a pharmaceutically suitable carrier or excipient. (9) The pharmaceutical composition according to claim (8), further comprising a β-lactamase inhibitor. (10) Formula (III) ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, the amino group may be substituted with a group capable of causing acylation, and R^X is hydrogen or carboxyl blocking group) is represented by the formula,
(IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, R^1 and * have the same meaning as in formula (I) described in claim (1), and an N-acylating compound formed from a salt or N-protected derivative of an amino acid represented by also removing the group R^X; (ii) removing any other protecting groups elsewhere in the molecule; and (iii) converting the product into its salt or in vivo hydrolysable derivative. A method for producing the compound according to claim (1), characterized in that: (11) The compound has the formula (I a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( I a) (wherein, R^1, * and Y are the formula ( I ), and R^7 and R^8 are the same or different, and each is hydrogen or C_1_-_6 alkyl) or a pharmaceutical thereof that can be hydrolyzed in the living body The compound according to claim (1), which is a suitable salt or an ester that can be hydrolyzed in vivo. (12) Formula (IVA) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IVA) (In the formula, R^1 is the formula described in claim (1))
has the same meaning as in I), and R is hydrogen,
C_1_-_6 alkyl, C_2_-_6 alkenyl,
C_3_-_7 cycloalkyl or aryl C_1_
−_6 alkyl). (13) Formula (IVA) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IVA) (In the formula, R^1 is the formula described in claim (1))
has the same meaning as in I), and R is hydrogen,
C_1_-_6 alkyl, C_2_-_6 alkenyl,
C_3_-_7 cycloalkyl or aryl C_1_
A reducing agent that can convert a compound represented by -__6alkyl) into a group ▲a mathematical formula, chemical formula, table, etc.▼ without changing the rest of the molecule. Formula (IV) ▲ Formula, which is characterized by processing with
There are chemical formulas, tables, etc. ▼(IV) (In the formula, R^1 has the same meaning as above) Manufacturing method of the compound. (14) a) Formula ▲ Numerical formula, chemical formula, table, etc. ▼ (In the formula, Ar is aryl, R^2 has the same meaning as in claim (1), and R The compound represented by the formula ▲ has the same meaning as in claim (12), and R ^3 and R^4 have the same meaning as in claim (1)), or b) formula ▲ has a numerical formula, chemical formula, table, etc. ▼ (in the formula, R, R^2 and R^X have the same meanings as above, and R^2^0 is C_1_-_6 alkyl) The compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. (wherein R^3 and R^4 have the same meaning as in claim (1)), or c) formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, Ar, R^3 and R^4 have the same meanings as above) A compound represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (In the formula, R, R^2 and R^ X has the same meaning as above); and if necessary, after any of the above steps a), b) or c), the following step i) carboxyl protecting group R^X (IVB) ▲Mathematical formulas, chemical formulas, tables, etc.▼(IVB) A method for producing a compound represented by: or a salt thereof or a derivative capable of being hydrolyzed in vivo. (15) Use of the compound represented by formula (1) according to claim (1), or a pharmaceutically suitable salt thereof or a derivative capable of being hydrolyzed in vivo, for producing a pharmaceutical for therapeutic purposes.