CS253572B2 - Process for preparing 1-sulfo-2-oxoazetidine - Google Patents

Abstract

1-sulfo-2-oxoazetidine of the general formula X R is prepared by reacting a compound of the general formula X with a compound of the general formula R°COOH. The prepared compound has excellent antimicrobial activity and beta-lactamase inhibition ability.

Description

The invention relates to novel 1-sulfo-2-oxoazetidine derivatives having excellent antimicrobial activity and beta-lactamase inhibitory ability and a process for their preparation.

Various 2-oxoazetidine derivatives have been synthesized and described in the prior art, see for example Tetrahedron 34, 1731-1767 (1978), Chemical Reviews 76, 11b-346 (1976), Synthesis 1973, 327-346. However, it is not known that any of these described 2-oxoazetidines has a sulfo group in the 1-position and a substituent in the 4-position.

The invention of formula I relates to a process for the preparation of novel 1-sulfo-2-oxoazetidine derivatives of the general formula

(I) where means a group of the general formula

R ² c I 3 < ^CH 2>n

SO ₃ H where n is an integer from 0 to 3,

3

R and R which are the same or different, a hydrogen atom, an alkyl group, a cycloalkyl group optionally substituted, an optionally substituted aryl or aralkyl group, an optionally substituted heterocyclic group, an alkoxycarbonyl group or an acyl group, or together represent an oxo group, r4 a hydrogen atom, an alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a halogen atom, a cyano group, a hydroxyl group, an alkoxy group, an optionally substituted aryloxy group, an aralkyloxy group with an optionally substituted alkyl moiety, an acyloxy group, a carbamoyloxy group, a hydroxysulfonyloxy group, an alkylsulfonyloxy group, an arylsulfonyloxy group with an optionally substituted aryl moiety, a sulfooxy group, a nitro group, an amino group, an azido group, a carboxyl group, alkoxycarbonyl group, alkoxycarbonylalkyloxy group, aminocarbonyl group, alkylthiocarbonyl group, acyl group, mercapto group, alkylthio group, aminoalkylthio group, acylaminoalkylthio group, aralkylthio group with an optionally substituted alkyl moiety, arylthio group with an optionally substituted aryl moiety, optionally substituted heterocyclic thio group or optionally substituted quaternary ammonium group, or means a cycloalkyl group, alkenyl group, alkynyl group, cycloalkenyl group, aryl or heterocyclic group, which are optionally substituted by one or more substituents, wherein the substituents of the optionally substituted alkenyl and alkynyl groups are selected from the group comprising an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, alkoxycarbonyl group, acyl group, oxo group, halogen atom, cyano group, hydroxyl group, alkoxy group, aryloxy group with optionally substituted aryl moiety, acyloxy group, carbamoyloxy group, hydroxysulfonyloxy group, alkylsulfonyloxy group, arylsulfonyloxy group with optionally substituted aryl moiety, nitro group, amino group, carboxyl group, aminocarbonyl group, alkylthiocarbonyl group, mercapto group, alkylthio group, aminoalkylthio group, acylaminoalkylthio group, aralkylthio group with optionally substituted alkyl moiety, arylthio group with optionally substituted aryl moiety, heterocyclic thio group with optionally substituted heterocyclic moiety and optionally substituted quaternary ammonium group, wherein the above-mentioned optionally substituted groups contain at least one substituent, the same or different and optionally the substituents of the substituted cycloalkyl group, cycloalkenyl group, aryl group, aralkyl group, heterocyclic group and quaternary ammonium group are selected from the group comprising an alkyl group, an alkoxy group, an alkenyl group, an aryl group, an aralkyl group, mercapto group, an alkylthio group, an arylthio group, an aralkylthio group, an alkylsulfonyl group, an arylsulfonyl group, an aralkylsulfonyl group, a trihaloalkyl group, a hydroxy group, an oxo group, a thioxo group, a halogen atom, a nitro group, an amino group, a cyano group, a carbamoyl group, a carboxyl group, an acyl group, an acyloxy group, an acylamino group, a hydroxyalkyl group, a carboxyalkyl group, a haloalkyl group and a monoalkylaminoalkyl group and a dialkylaminoalkyl group, wherein the above-mentioned amino group, carboxyl group and hydroxyl group may be protected, wherein the above-mentioned alkyl group and alkoxy group each contain 1 up to 6 carbon atoms, alkenyl and alkynyl groups of 2 to 6 carbon atoms, cycloalkyl and cycloalkenyl groups of 3 to 8 carbon atoms, the amino group may be substituted by an acyl group, an alkyl group, a hydroxyalkyl group, an aralkyl group with an optionally substituted alkyl moiety, an optionally substituted aryl group, an optionally substituted heterocyclic group, a sulfo group, an alkylsulfonyl group, an aralkylsulfonyl group with an optionally substituted alkyl moiety, an arylsulfonyl group with an optionally substituted aryl moiety, an alkoxycarbonyl group, an aralkyloxycarbonyl group with an optionally substituted alkyl moiety, an acyloxycarbonyl group with an optionally substituted aryl moiety and an aminocarbonyl group, with the optional substituents being defined above, an aralkyl group always meaning a benzyl group, phenethyl, phenylpropyl or naphthylmethyl, an aryl group means a phenyl, alpha-naphthyl, beta-naphthyl, biphenyl or anthryl group, a heterocyclic group means a five- to eight-membered heterocyclic radical with one to four heteroatoms from the group comprising a nitrogen atom, including N-oxide, oxygen and sulphur, an acyl group always means a formyl group, an alkylcarbonyl group with 1 to 6 carbon atoms, a benzoyl group optionally substituted by a hydroxyl group or an alkyl group with 1 to 6 carbon atoms, an aralkylcarbonyl group with 7 to 9 carbon atoms optionally substituted by a hydroxyl group or an alkyl group with 1 to 6 carbon atoms or a five-membered heterocyclic carbonyl or acetyl group containing at least one oxygen, nitrogen and sulphur atom, optionally substituted by an amino group,

R·*· an amino group or an acylated amino group, the acyl moiety having the general formula

WHAT WHERE DOES IT MEAN?

R' is an alkyl or optionally substituted heterocyclic group or the general formula

R - NH - CH - CO '7 where R represents a hydrogen atom, a glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl, methionyl, alpha-spartyl or beta-aspartyl group, alpha-glutamyl or gamma-glutamyl group, a lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl or prolyl group or an amino protecting group or a group of the general formula

R ⁸ -< ^CH 2) _n - CO g where R represents an optionally substituted heterocyclic group and n^ is an integer from 0 to 2, an alkyl group, an optionally substituted phenyl group, a heterocyclic carbonylamino group with an optionally substituted heterocyclic moiety or an optionally substituted heterocyclic group.

or the acyl moiety has the general formula

R ⁹ - R ¹⁰ where R* represents a group of the general formula

R ¹¹ - C

Sr ¹² where ,11 represents an optionally substituted alkyl group, an optionally substituted heterocyclic or phenyl group and a hydrogen atom, an alkyl group or a group of the general formula

-R ¹³ -R ¹⁴ where means

R is an alkylene group or an alkenylene group and

R ¹⁴ optionally substituted phenyl group, carboxyl group or its alkyl ester or monoalkylamino group or dialkylamino group, "12

R ¹⁰ a direct bond or a group of the general formula

- CO - NH

CH 115 R ° where means

R ¹⁵ is an alkyl group, an optionally substituted phenyl group or an optionally substituted thiazolyl group or the acyl moiety has the general formula

where represents a hydroxy group, a hydroxysulfonyloxy group, a carboxy group, an optionally substituted ureido group, an optionally substituted sulfamoyl group, a sulfo group, an optionally substituted phenoxycarbonyl group or a formyloxy group and

R is a hydrogen atom, an alkyl group, an alkoxy group, a halogen atom, a nitro group or a hydroxy group or has an acyl moiety of the general formula where

R is a cyano group, an optionally substituted phenyl group, an optionally substituted phenoxy group, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted heterocyclic group and

R is a direct bond or a sulfur atom, wherein

19 in the case of the meanings of the symbols R to R, a heterocyclic group always means a five- to eight-membered heterocyclic ring with 1 to 4 heteroatoms selected from the group comprising a nitrogen atom (including N-oxide), oxygen and sulfur, a pyrido-£2,3-d]pyrimidyl group, a benzopyranyl group, a 1,8-naphthyridyl group, a 1,5-naphthyridyl group, a 1,6-naphthyridyl group, a 1,7-naphthyridyl group, a 2,7-naphthyridyl group, a 2,6-naphthyridyl group, a quinolyl group or a thienof2,3-6_/pyridyl group, optionally substituted by a heterocyclic group, a phenyl group, a thiazolyl group, a phenoxycarbonyl group and a phenoxy group always mean groups substituted by one to two groups selected from the group comprising an alkyl group, an alkoxy group, alkenyl group, aryl group, aralkyl group, mercapto group, alkylthio group, arylthio group, aralkylthio group, alkylsulfonyl group, arylsulfonyl group, aralkylsulfonyl group, trihaloalkyl group, hydroxy group, oxo group, thioxo group, halogen atom, nitro group, amino group, cyano group, carbamoyl group, carboxy group, acyl group, acyloxy group, acylamino group, hydroxylalkyl group, carboxyalkyl group, haloalkyl group, monoalkylaminoalkyl or dialkylaminoalkyl group, wherein the acyl group has the above-mentioned meaning, the alkyl and alkoxy part each has 1 to 6 carbon atoms, the alkenyl group each has 2 to 6 carbon atoms and the aralkyl and aryl part have the above-mentioned meaning,

2535Ί2 in the case of a substituted alkyl group, the substituents are selected from the group comprising a halogen atom, a hydroxy group, a cyano group and a trifluoromethyl group, in the case of a substituted ureido group, the substituents are selected from the group comprising a sulfo group in the form of a cation, a carbamoyl group, a sulfamoyl group, an amidino group or an alkyl group with 1 to 6 carbon atoms, optionally the substituted sulfamoyl group has as substituents an alkyl group with 1 to 6 carbon atoms or an amino group, the amino group, the carboxyl group and/or the hydroxyl group may be protected, the amino group may be substituted as mentioned above in the case of the symbol R, or represents an amino group protected by a phthaloyl group, a p-nitrobenzoyl group, a p-tert-butylbenzoyl group, a p-tert-butylbenzenesulfoyl group, further by a benzenesulfonyl, toluenesulfonyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, maleyl, succinyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, beta,beta,beta-trichloroethoxycarbonyl, beta-trimethylsilylethoxycarbonyl, beta-methylsulfonylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl, p-nitrobenzyl or a proton, wherein the alkyl moiety, alkoxy moiety, the alkenyl moiety, the alkynyl moiety, the cycloalkyl moiety, the cycloalkenyl moiety, the aralkyl moiety and the aryl moiety always have the meaning as given in the case of the symbol R,

X is a hydrogen atom or a methoxy group, or their salts or their esters, by reacting a compound of general formula III (III)

_H2N

0 ^; so ₃ h where the individual symbols have the above meaning, or a salt thereof or an ester thereof, with a compound of general formula II

R°COOH (II) where R°CO represents an acyl group as defined above as an acylated portion of an amino group as defined by the symbol R°, or a reactive derivative thereof at the carboxyl group and optionally the protecting group is cleaved.

The compound of general formula I has excellent antimicrobial properties and efficacy manifested by beta-lactamase inhibition.

In the above formulas I and XII, the symbol R represents an organic group attached to the 2-oxoazetidine nucleus at the 4-position carbon atom of the above organic group, that is, a group derived from an organic compound by removing one hydrogen atom from the corresponding carbon atom. Such organic groups include, for example, alkyl, cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl, heterocyclic and the like, which may optionally be substituted with one or more substituents.

Any group that may optionally be substituted is hereinafter referred to as a superscript +. For example, an alkyl group that may be optionally substituted will be referred to as an alkyl ⁺ group. In such cases, the number of substituents is not limited to a single substituent. Some substituted groups may have two or more substituents, either the same or different.

Alkyl group preferably means a lower alkyl group having 1 to 6 carbon atoms with a straight or branched chain, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like. Cycloalkyl group preferably means a cycloalkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc.

Alkenyl group preferably means a lower alkenyl group having 2 to 6 carbon atoms with a straight or branched chain, such as vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-butenyl and the like. Alkynyl group preferably means a lower alkynyl group having 2 to 6 carbon atoms with a straight or branched chain, such as ethynyl, 1-propynyl, 2-propynyl or the like.

Cycloalkenyl groups include, for example, cycloalkenyl groups with 3 to 8 carbon atoms, such as 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,

1- cycloheptenyl, 1,4-cyclohexadienyl group, etc.

A preferred cycloalkenyl group is a cycloalkenyl group having 4 to 6 carbon atoms. Aryl groups include, for example, phenyl, alpha-naphthyl, beta-naphthyl, biphenyl, anthryl and the like. Of these groups, phenyl and naphthyl are usually preferred. Heterocyclic groups include, for example, five- to eight-membered heterocyclic rings having one to several heteroatoms, such as nitrogen (including N-oxide), oxygen and sulfur.

Also included are corresponding fused rings that have an available binding site on a carbon atom. Examples of such a heterocyclic group that is usually preferred include

2- or 3-propyl, 2- or 3-furyl, 2- or 3-thienyl, 2- or 3-pyrrolidinyl,

2-, 3- or 4-pyridyl, N-oxido-2-, N-oxido-3- or N-oxido-4-pyridyl, 2-, 3- or 4-piperadinyl, 2-, 3- or 4-pyranyl, 2-, 3- or 4-thiopyranyl, pyrazinyl,

2-, 4- or 5-thiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isothiazolyl, 3-,

4- or 5-isoxazolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazolyl, 3- or 4-pyridazinyl, N-oxido-3- or N-oxido-4-pyridazinyl, 2-, 4- or 5-pyrimidinyl, N-oxido-2-, N-oxido-4- or N-oxido-5-pyrimidinyl, piperazinyl, 4- or 5-(1,2,3-thiadiazolyl), 3- or 5-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 4- or 5-(1,2,3-oxadiazolyl), 3- or 5-(1,2,4-oxadiazolyl) 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, pyrido[2,3-d]pyrimidyl, benzopyranyl, 1,8-, 1,5-, 1,6-, 1,7-, 2,7-, or 2,6-naphthhydridyl, quinol, thieno[2,3-b]pyridyl and similar groups.

Preferred groups include, but are not limited to, five- or six-membered heterocyclic rings with one to four heteroatoms, which may be nitrogen or sulfur, such as thienyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl or similar groups.

Of these groups, the alkyl, alkenyl and alkynyl group may be substituted with one to three substituents, such as cycloalkyl ⁺ , cycloalkenyl , aryl ⁺ , heterocyclic ⁺ , alkoxycarbonyl and acyl group, oxo group, halogen atom, cyano group, hydroxyl and alkoxy group, aryl ⁺ -oxy group, acyloxy group, carbamoyloxy group, hydroxysulfonyloxy group, alkylsulfonyloxy group and aryl ⁺ -sulfonyloxy group, nitro group, amino group, carboxy group, aminocarbonyl and alkylthiocarbonyl group, mercapto group, alkylthio group, aminoalkylthio group, acylaminoalkylthio group, aralkyl -thio group, aryl ⁺ -thio group, heterocyclo ⁺ -thio group, quaternary ammonium group or the like. The substituted alkyl groups include, for example, the group of the general formula A ^x '2 í

C Ø ³ < ^CH 2>n (A), where n is a number from 0 to 3,

3 +

R and R can independently represent a hydrogen atom, an alkyl, cycloalkyl, aralkyl ⁺ , aryl ⁺ , heterocyclic ⁺ , alkoxycarbonyl or aoyl group or

3

R and R together represent an oxo group and

R^ represents a hydrogen atom, an alkyl, cycloalkyl ⁺ , aryl ⁺ , heterocyclic ⁺ group, a halogen atom, a cyano group, a hydroxyl group, an alkoxy group, an aryl -oxy group, an aralkyl -oxy group, an aroyloxy group, a carbamoyloxy group, a hydroxysulfonyloxy group, an alkylsulfonyloxy group, an aryl -sulfonyloxy group, a sulfoxy group, a nitro group, an amino and azide group, a carboxy group, an alkoxycarbonyl group, an alkoxycarbonylalkyloxy group, an aminocarbonyl, an alkylthiocarbonyl and an aroyl group, a mercapto group, an alkylthio group, an aminoalkylthio group, an acylaminoalkylthio group, an aralkyl -thio group, an aryl -thio group, a heterooxy -thio group or a quaternary ammonium group,

In the substituent on the alkyl, alkenyl and alkynyl group and the group of the general formula R, ^R or R, the alkoxy group preferably means a lower alkoxy group with a straight or branched chain of 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec.butoxy, tert.butoxy, pentyloxy, isopentyloxy, hexyloxy, isohexyloxy or the like.

Aralkyl groups include, for example, benzyl, phenethyl, phenylpropyl, naphthylmethyl, etc. Halogen atoms include fluorine, chlorine, bromine and iodine. Quaternary ammonium groups include, for example, the group of the general formula

wherein W represents a hydrogen atom, an alkyl, carbamoyl and carboxyl group, a sulfo group or an alkoxy group, which may be derived from pyridine derivatives, such as pyridine, carbamoyl-substituted pyridine (e.g. nicotinamide, isonicotinamide, etc.), carboxyl-substituted pyridine (e.g. nicotinic acid, isonicotinic acid, etc.), sulfo-substituted pyridine (e.g. pyridine-sulfonic acid, etc.), cholinium, etc.

These quaternary ammonium groups can form internal salts with a sulfo group at the 1/2-oxoazetidine nucleus. Acyl groups include, for example, formyl, alkylcarbonyl, aryl ⁺ -carbonyl, aralkyl ⁺ -carbonyl, heterocyclo ⁺ -acetyl, etc., as well as the acyl groups mentioned above for R ³ . Of these groups, for example, an alkylcarbonyl group having 1 to 6 carbon atoms (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, etc.), a benzoyl group which may be substituted (e.g., benzoyl, 4-hydroxybenzoyl, 4-methoxybenzoyl, etc.), an aralkylcarbonyl group having 7 to 9 carbon atoms which may be substituted (e.g., phenylacetyl, 4-hydroxyphenylacetyl,

4-methoxyphenylacetyl group, etc.), a five-membered heterocyclocarbonyl or -acetyl group with at least one oxygen, nitrogen and/or sulfur atom, which may be substituted (e.g. 2-thienylcarbonyl, 2-furylcarbonyl, 2-, 4- or 5-thiazolylacetyl, 2- or 3-thienylacetyl, 2- or 3-furylacetyl, 2-amino-4- or 2-amino-5-thiazolylacetyl, etc.).

The alkyl group in the alkylsulfonyloxy group, the alkylthiocarbonyl group, the alkylthio group, the aminoalkylthio group, the acylaminoalkylthio group and the alkoxycarbonylalkyloxy group, the alkoxy group in the alkoxycarbonyl group and the alkoxycarbonylalkyloxy group and the acyl group in the acyloxy group and the acylaminoalkylthio group have the same meanings as above.

Substituents that may be present in a cycloalkyl, cycloalkenyl, aralkyl, aryl, heterocyclic and quaternary ammonium group include, for example, alkyl, alkoxy, alkenyl, aryl and aralkyl groups, mercapto groups; alkylthio, arylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, trihaloalkyl and hydroxyl groups, oxo, thioxo, halogen, nitro, amine, cyano, carbamoyl, carboxyl and acyl groups, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, haloalkyl, mono- or di-alkylaminoalkyl and the like (wherein alkyl, alkoxy, alkenyl, aryl, aralkyl and acyl groups and halogen are as defined above).

If the organic group R, which is connected to the azetidine ring through a carbon atom, contains an amino group, the above-mentioned amino group may be substituted or protected; if it contains any carboxyl and hydroxyl groups, such groups may also be protected. Optional substituents of the amino group include the acyl group mentioned above for R ¹ and also alkyl, alkoxy, hydroxyalkyl, aralkyl ⁺ , aryl ⁺ , heterocyclic ⁺ + + + sulfo-, alkylsulfonyl, aralkyl , aralkyl -sulfonyl, aryl -sulfonyl, alkoxycarbonyl, aralkyl ⁺ -oxycarbonyl, aryl ⁺ -oxycarbonyl and the like (wherein alkyl, + + + alkoxy, aralkyl , aryl and heterocyclic groups are as defined above).

Optionally, the amino group may be taken together with such a substituent to form a cyclic amino group, such as a pyrrolidine, piperidine, morpholine, piperazine or the like. Amino protecting groups include, for example, those groups listed below as amino protecting groups. The carboxyl protecting group may be any carboxyl protecting group conventionally used in the field of beta-lactams and other organic chemistry, such as an ester residue (e.g. methyl, ethyl, propyl, isopropyl, tert-butyl, tert-amyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, beta-methylsulfonylethyl, beta-trimethylsilylethyl, methylthiomethyl, trityl, beta,beta,beta-trichloroethyl, beta-iodoethyl, trimethylsilyl, dimethylsilyl, acetylmethyl, p-nitrobenzoylmethyl; phthalimidomethyl, propionyloxymethyl, 1,1-dimethylpropyl, 3-methyl-3-butenyl, succinimidomethyl, 3,5-di-tert.butyl-4-hydroxybenzyl, mesylmethyl, benzenesulfonylmethyl, phenylthiomethyl, dimethylaminoethyl, pyridine-1-oxido-2-methyl, methylsulfinylmethyl, bis(p-methoxyphenyl)methyl, 2-cyano-1,1-dimethylethyl group, etc.), silyl and similar groups.

The hydroxyl protecting group may be any hydroxyl protecting group conventionally used in the field of beta-lactams and other organic chemistry, such as ester residues, e.g. acetyl group, chloroacetyl group, etc., esterified carboxyl groups, e.g. beta,beta,beta-trichloroethoxycarbonyl, beta-trimethylsilylethoxycarbonyl group, etc., ether residues, e.g. tert-butyl, benzyl p-nitrobenzyl, trityl, methylthiomethyl, beta-methoxyethoxymethyl group, etc., silyl ether residues, e.g. trimethylsilyl, tert-butyldimethylsilyl group, etc., acetal residues, e.g. 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl group, etc. and similar groups.

The choice of the above-mentioned hydroxyl protecting group is not critical to the present invention, nor is the choice of the above-mentioned amino and carboxyl protecting groups.

Preferred examples of organic groups R are groups of the general formula A, with the proviso that if 2-3 of 4 both R and R represent a hydrogen atom, then R does not represent a hydrogen atom or an alkyl group (especially a straight-chain alkyl group) or if one of the groups R or R represents a hydrogen atom and the other represents an alkyl group (especially a straight-chain alkyl group) and n represents the number zero, then R does not represent a hydrogen atom.

Of the groups of general formula A, group of general formula B is usually used

R ² ' c ~

Ø ³ ' (CH ₂ ) _n - R (Β) , in which n is as above,

2*3' 2'

R and R independently represent a hydrogen atom or an alkyl group or R and '

R together represent an oxo group and +

R represents a hydrogen atom, an alkyl group, an aryl group, a halogen atom, a cyano group, a hydroxyl and alkoxy group, an aralkyl-oxy group, an acyloxy group, a carbamoyloxy group, an alkylsulfonyloxy group, a sulfo-oxy group, an amino group, an azide, carboxyl and alkoxycarbonyl group, an alkoxycarbonylalkyloxy group, an alkylthio group, a heterocyclo ⁺ -thio group or a quaternary ammonium ⁺ group.

Of these groups, the amino group is optionally substituted or protected and the carboxyl group is optionally protected as described above for R 1 , R 2 and R 3 .

Of the groups of general formulas A and B, the more advantageous are

3 2 ' 3 ”

1. those groups of general formula A and B in which R and R , respectively R and R together represent an oxo group and R , respectively R represents an amino group which may be substituted or protected, i.e. a group of general formula C

CON (C) , in which Q ³ and Q ⁴ can independently represent a hydrogen atom, an alkyl ⁺ , alkoxyl, aralkyl ⁺ , aryl ⁺ and heterocyclic ⁺ group, a sulfo group, aralkyl ⁺ -sulfonyl, alkylsulfonyl, amino, aryl ⁺ -sulfonyl, alkoxycarbonyl, aralkyl -oxycarbonyl and aryl ⁺ -oxycarbonyl group, an acyl group or a protecting group listed below for the symbol R ¹ , preferably a group of the general formula

CON ^X Q ⁴ ' in which Q ³ and Q ⁴ can independently represent a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkoxy group with one to 6 carbon atoms, an amino group, a carboxyalkyl group, where the alkyl group is a group with 1 to 6 carbon atoms, an alkyl(with 1 to 6 carbon atoms) carbonyl group which may be substituted by a halogen atom, a sulfo group, a phenyl group, a benzoyl group, a carbamoyl-£alkyl(with 1 to 6 carbon atoms)J11 group, a p-nitrobenzyloxycarbonyl group or a beta-alkyl(with 1 to 6 carbon atoms)sulfonyl-alkoxy fwith 1 to 6 carbon atomsj carbonyl group and in particular a carbamoyl group, a mono- or di-alkyl(with 1 to 6 carbon atoms)carbamoyl group, phenylcarbamoyl group, sulfocarbamoyl group, alkoxy(1 to 6 carbon atoms)carbamoyl group, carboxy-alkyl(1 to 6 carbon atoms)carbamoyl group, etc.,

3 9 * 3'

2. those groups of general formula A and B in which R and R respectively Rr and R together represent an oxo group and R and R respectively represent a hydroxyl group, an alkoxy group, an aryl ⁺ -oxy group, an aralkyl ⁺ -oxy group or an alkoxycarbonylalkyloxy group, i.e. a group of general formula D

- COQ ⁵ (D), in which Q ⁵ represents a hydroxyl group which may be protected, an alkoxy group, an aryloxy group which may be substituted, an aralkyloxy group which may be substituted or an alkoxycarbonylalkyloxy group, preferably a group of the general formula

-COQ ⁵ in which Q ⁵ represents an alkoxy group with 1 to 6 carbon atoms, a p-nitrobenzyloxy group or an alkoxy(1 to 6 carbon atoms)carbonyl-alkyl(1 to 6 carbon atoms)oxy group,

3 2* 3

3. those groups of general formula A and B in which R, R, R and R represent hydrogen atoms, for example the group of general formula E

- (CH ₂ ) _m - X ¹ - Q ⁶ (E), in which m is a number from 1 to 4, and

X represents a group -NH-, a sulfur atom or an oxygen atom or a bond and

Q ⁶ represents a hydrogen atom, a carbamoyl group, an acyl group which may be substituted, an alkyl group, a heterocyclic group which may be substituted, or a carboxyl group which may be protected, preferably a group of the general formula

- < ^CH 2>m - ^χ1 ' in which ma and X^ have the same meanings as above and

Q ⁶ represents an alkyl(1 to 6 carbon atoms)carbonyl group which may be substituted by a halogen atom, an alkyl group having 1 to 6 carbon atoms, a benzoyl group,

A 5- or 6-membered heterocyclic group containing a nitrogen atom (e.g., pyrrolyl, thiazolyl, thiadiazolyl, diazolyl, oxazolyl, oxadiazolyl, triazolyl, and tetrazolyl groups, etc.) which may be substituted with an alkyl group having 1 to 6 carbon atoms or a 5- or 6-membered heterocyclothioacetyl group containing a nitrogen atom, the heterocyclic ring of which may be substituted with an alkyl group having 1 to 6 carbon atoms.

Specific examples of the group of general formula C include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, N,N-dimethylcarbamoyl, N,N-dimethylcarbamoyl, N-sulfocarbamoyl, N-methoxycarbamoyl, N-ethoxycarbamoyl, N-propoxycarbamoyl, N-isopropoxycarbamoyl, N-hydroxycarbamoyl, N-aminocarbamoyl, fl-(L)-benzyloxycarbonylethylaminocarbonyl, f1-(L)-carboxyethylaminocarbonyl, N-phenylcarbamoyl, N,N-diphenylcarbamoyl, N-(p-chlorophenyl)carbamoyl, N-benzylcarbamoyl, N,N-dibenzylcarbamoyl, N-hydroxymethylcarbamoyl, N-hydroxyethylcarbamoyl, N-chloromethylcarbamoyl, N-acetylcarbamoyl, N-propionylcarbamoyl, N-carboxycarbamoyl, N-methoxycarbonylcarbamoyl, N-ethoxycarbonylcarbamoyl, N-phenoxycarbonylcarbamoyl and similar groups. Specific examples of the group of general formula D include carboxyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentoxycarbonyl, benzyloxycarbonyl, phenethyloxycarbonyl, methoxycarbonylmethyloxycarbonyl, ethoxycarbonylmethyloxycarbonyl, phenyloxycarbonyl, p-chlorophenyloxycarbonyl, hydroxymethyloxycarbonyl, sulfomethyloxycarbonyl and the like.

Specific examples of the group of general formula E include acylaminoalkyl (e.g. acetylaminomethyl, propionylaminomethyl, butyrylaminomethyl, isobutyrylaminomethyl, acetylaminoethyl, propionylaminoethyl, acetylaminopropyl, acetylaminobutyl, benzoylaminoethyl, benzoylaminomethyl, benzoylaminopropyl, formylaminomethyl, phenylacetylaminomethyl, 4-hydroxyphenylacetylaminomethyl, 2-thienylcarbonylaminomethyl, 2-furylcarbonylaminomethyl, thienylacetylaminomethyl, 2-amino-4-thiazolylacetylaminomethyl, etc.), carbamoylaminoalkyl (e.g. carbamoylaminomethyl, carbamoylaminoethyl, carbamoylaminopropyl, etc.), acyloxyalkyl (e.g. acetoxymethyl, propionyloxymethyl, isopropionyloxymethyl, acetoxyethyl, 2-(2-chloro acetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl, 2-(2-aminoO'-4-thiazolyl)-(Z)—2— -methoxyiminoacetoxymethyl, 2-thienylacetoxymethyl, 2-furylacetoxymethyl, thiazolylacetoxymethyl, 2-amino-4-thiazolylacetoxymethyl, benzoyloxymethyl, benzoyloxyethyl, 4-hydroxybenzoyloxymethyl, 4-methoxybenzoyloxymethyl, monochloroacetoxymethyl, trichloroethoxycarbonyloxymethyl, acetoacetoxyethyl, (1-methyl-1H-tetrazol-5-yl)thioacetoxymethyl, (1-N,N-dimethylaminoethyl-1H-tetrazol-5-yl)thioacetoxymethyl, (2-methylthiadiazol-5-yl)thioacetoxymethyl, (2-methyloxadiazol-5-yl)thioacetoxymethyl, (1-methyl-1H-triazol-5-yl)thioacetoxymethyl group, etc.), carbamoyloxyalkyl group (e.g. carbamoyloxymethyl, carbamoyloxyethyl, carbamoyloxypropyl, carbamoyloxyisopropyl group, etc.), heterocyclothioalkyl group /e.g. thienylthiomethyl, thienylthioethyl, thienylthiopropyl, furylthiomethyl, furylthioethyl, thiazolylthiomethyl, thiazolylthioethyl, 2-aminothiazolylthiomethyl, 2-aminothiazolylthioethyl, 2-aminothiazolylthioisopropyl, (2-methyl-thiadiazol-5-yl)thiomethyl, (2-methyloxadiazol-5-yl)thimethyl, oxazolylthiomethyl, (1-methyl-1H-triazol-5-yl)thiomethyl, (1-methyl-1H-tetrazol-5-yl)thiomethyl, (1-N,N-dimethylaminoethyl-1H-tetrazol-5-yl)thiomethyl, (1-carboxymethyl-1H-tetrazol-5-yl)thiomethyl, (1-methyl-1H-tetrazol-5-yl)thioethyl, (1-methyl-1H-tetrazol-5-yl)thiopropyl group etc./, alkylthioalkyl group (e.g. methylthiomethyl, methylthioethyl, methylthiopropyl, methylthioisopropyl, ethylthiomethyl, ethylthioethyl, propylthiomethyl, propylthioethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, sec.butylthiomethyl group, etc.), carboxyalkyl or esterified carboxyalkyl group (e.g. carboxymethyl, carboxy ethyl, carboxypropyl, carboxyisopropyl, carboxybutyl, carboxyisobutyl, carboxy sec.butyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, phenoxycarbonylmethyl, phenoxycarbonylethyl, benzyloxycarbonylmethyl, benzyloxycarbonylethyl, p-hydroxybenzyloxycarbonylmethyl, p-methoxybenzyloxycarbonylmethyl, carboxymethyloxycarbonylmethyl, etc.), and the like groups.

In the above general formula I, ΙJ represents an acylated amino group. The acyl groups of the acylated amino group include any conventional acyl group of the 6- or 7-amino groups of known penicillin or cephalosporin derivatives, respectively. Examples of the acyl group are:

i) group of general formula F

R ⁵ - CO (F) , in which R represents a lower alkyl or heterocyclic group, il) a group of the general formula G

R ⁶ - NH - CH - 'CO - (G) ,

Á ⁷ in which R ⁸ represents a hydrogen atom, an amino acid residue, an amino protecting group or a group of the general formula R ⁸ -(CH,) -CO-, in which R ⁸ represents a heterocyclic* group sn, ⁿ i ♦ + * represents a number from 0 to 2, and R represents a lower alkyl, phenyl, heterocyclocarbonylamino or heterocyclic group, iii) a group of the general formula H

R ⁹ - R ³⁰ - CO 9 13

In which R represents a group of general formula R in ntel

N

In 12 oir ⁴ + + + 12 R represents an alkyl, heterocyclic or phenyl group and R represents a hydrogen atom, a lower alkyl and lower alkenyl group or a group of the general formula -R ³³ -R ³⁴ , in which R ³³ represents a lower alkylene or lower alkenylene group and R ³⁴ represents a phenyl* group, a carboxyl group, an ester of a carboxyl group or a mono- or di-(lower alkyl)amino group and

R ³⁸ represents a bond or a group of the general formula -CO-NH-CH-, in which R ³⁵ represents a lower alkyl, phenyl*, or thiazolyl* group, iv) a group ^of the general formula I

(I), in which R ³⁸ represents a hydroxyl group, a hydroxysulfonyloxy group, a carboxy group, a ureido* group, a sulfamoyl* group, a sulfo group, a phenoxy*-carbonyl or a formyloxy group and R ³⁷ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a nitro group or a hydroxyl group,

v) group of general formula J

R ³⁸ - R ¹⁹ - CH ₂ - CO (J), wherein R ³⁸ represents a cyano group, a phenyl* group, a phenoxy* group, a lower alkyl* group, an alkenylene or heterocyclic group and R represents a bond or a group -S-, and the like.

Alkyl group, heterocyclic group, alkoxy group and halogen atom in symbols 5 19

R to R represent the respective groups mentioned above for the symbol R. Amino acid residues include, for example, glycyl, alanyl, valyl, laucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl, methionyl, alpha- or beta-asparagyl, alpha- or gamma-glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl, prolyl and the like.

The protecting groups of the amino group include those groups listed below as the protecting group of the amino group. The alkylene group preferably means a lower alkylene group β of 1 to 3 carbon atoms with a straight or branched chain, for example, methylene, ethylene, propylene, isopropylene and the like.

Alkenylene group preferably means a lower alkenylene group having 2 to 4 carbon atoms with a straight or branched chain, such as vinylene, propenylene or the like. Carboxylic acid esters include lower alkyl esters having 1 to 6 carbon atoms in the above alkyl residue, such as methyl ester, ethyl ester, propyl ester, butyl ester, isobutyl ester, tert-butyl ester, etc.

The substituents on the heterocyclic ⁺ , phenyl ⁺ , thiazolyl ⁺ , phenoxy ⁺ -carbonyl and phenoxy*- group mean those substituents on the heterocyclic ⁺ and aryl ⁺ groups which are described above for the symbol R. In addition, the substituent on the thiazolyl ⁺ group may be, for example, an acylamino group having 2 to 4 carbon atoms substituted by an alkyl group, an alkoxy group, a halogen atom, a hydroxyl group, an amino group or the like.

The substituent on the heterocyclic* group may be, for example, a phenyl group substituted with an alkyl group, an alkoxy group, a halogen atom, a nitro group, an amino group, etc.

Substituents on the ureido ⁺ group include, for example, a sulfo group in the form of a salt with a suitable cation such as a sodium or potassium cation, a carbamoyl group, a sulfamoyl group, an amidine group, an alkyl group having 1 to 3 carbon atoms, and the like.

The substituent on the sulfamoyl* group means, for example, a lower alkyl group having one to three carbon atoms, an amidine group and the like. The substituent on the lower alkyl* group means, for example, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group and the like. The substituent on the alkenylene* group means, for example, a carboxyl group, a cyano group and the like.

The general formula R ^x -Cj- for R means either the syn isomer

11 of the formula R ^A -C- or the anti isomer of the formula R -C- or a mixture thereof.

fi <

N N

R ¹² -0^ ^X 0-R ¹²

A preferred group of the groups of general formula G is the group of general formula

R - NH - CH - CO R ⁷ ' * 8 in which R ⁶ represents an amino protecting group or a group of the general formula R -(CH2)n^-CO-, in which R ⁸ represents a heterocyclic* group and ηχ represents a number from 0 to 2, and ar' represents a phenyl or heterocyclic group.

A preferred group of the groups of general formula H is the group of general formula

R ¹¹ - C - CO II N

- R ¹² ' in which

R ¹¹ represents a heterocyclic* or phenyl* group and

R ¹² 'represents a hydrogen atom, a lower alkyl group or a group of the general formula -R -R , in which R ¹³ is as defined above and R ¹⁴ is a carboxyl or esterified carboxyl group.

The highest group from the groups of the general formula J ιφ» the group of the general formula

R ¹⁸ - R ¹⁹ - CHj- CO - , in which ? ⁸ ' „19 represents a heterocyclic ⁺ group and is as defined above, etc.

As an acyl residue of an acylated amine group for R, especially from the point of view of antibiotic activity, a group of the general formula in which is more useful is

Vl

-c-what—

II

N \j—Q ⁸ represents an amino group or a protected amino group and

Q ⁸ represents a lower alkyl group, a lower alkenyl group, a group of the general formula -CH,COOQ or CH, zfj Q

- C - COOQ, ch ₃

Q where COOQ represents a free or esterified carboxyl group.

Examples of the above-mentioned acyl groups of the general formula R -CO- include 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-ylcarbonyl, 4-ethyl-2,3-dioxo-1-piperazinocarbonyl and the like.

Examples of the above-mentioned acyl groups of the general formula R®-NH-CH-CO- include

P

D-alanyl, benzyl-N ^a -carbobenzoxy-gamma-D-glutamyl-D-alanyl, D-phenylglycyl-D-alanyl, N-carbobenzoxy-D-alanyl, N-carbobenzoxy»D-phenylglycyl, D-alanyl-D-phenylglycyl, gamma-D-glutamyl-D-alanyl, 2-(4-ethyl-2,3-dioxo-1-piperazino-carboxamido)-2-phenylacetyl,

2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-eulfoxyphenyl)acetyl, N-(4-ethyl-2,3-dioxo-1-piperazinocarboriyl)-D-alanyl, N-(4-ethyl-2,3-dithioxo-1-piperazinocarbonyl)-D-phenylglycyl, 2,2-bis -(4-ethyl-2,3-dioxo-3 -piperazinocarboxamido)acetyl, 2-(2^amino-4-thiazolyl)-2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)acetyl, 2-(4-hydroxy-6-methyl-nicotinamido)-2-phenylacetyl, 2-(4-hydroxy-6-methyl-nicotinamido)-2-(4-hydroxyphenyl)acetyl, 2-[5,8-dihydro-2-(4-formyl-1-piperazinyl)-5-oxopyridof2,3-d]pyrimidine-6-carboxamido-2-phenylacetyl, 2-(3,5-dioxo-1,2,4-triazine-6-carboxamido)-2-(4-hydroxyphenyl)acetyl, 2-(3-furfuridenamino-2-oxoimidazolidin-1-carboxamido)-2-phenylacetyl, 2-(coumarin-3-carboxamido)-2-phenylaoethyl, 2-<4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamido)-2-phenylacetyl, 2-<4- ⁱ hydroxy-7-trifluoromethylquinoline-3-carboxamido)-2-phenylacetyl, N-[2-(2-amino-4-thiazol-D-acetyl]-D-phenylglycylS, 2-(6-bromo-1-ethyl-1,4-dihydro-4-oxotriphenyl)2,3-b-pyridine-3-carboxamido)-2-phenylacetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 2-(4-pentyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 2-(4-octyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 2-(4-cyclohexyl-2,3-dioxo-1-piperazinocarboxamido)-2-thienylacetyl, 2-(4-phenylethyl)-2,3-dioxo-1-piperazinocarboxamido7-2-thienylacetyl, 2-(3-methylsulfonyl-2-oxoimidazolidine-1-carboxamido)-2-phenylacetyl,

2-(3-furfuridenamino-2-oxoimidazolidine-1-carboxamido)-2-(4-hydroxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-benzyloxyphenyl)acetyl, 2-(4-ethyl-2,3-dioxo-1-piperazinocarboxamido)-2-(4-methoxyphenyl)acetyl, 2-(8-hydroxy-1,5-naphthylidine-7-carboxamido)-2-phenylacetyl, 2-(2-amino-4-thiazolyl)-2-formamidoacetyl, 2-(2-amino-4-thiazolyl)-2-acetamidoacetyl and similar groups.

10

Examples of the above-mentioned acyl groups of the general formula R -R -CO- include N-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl]-D-alanyl, N-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetyl]-D-phenylglycyl, 2-(2-amino-4-thiazolyl)-2-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]acetyl, 2-(2-chloro-acetamido-4-thiazolyl)-2-methoxyiminoacetyl,

2-(2-amino-4-thiazolylJ*2-inethoxyiminoacetyl, 2-(2-amino-4-thiazolyl)+2-ethoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-propoxyiminoacetyl, 2-r2-araino-4-thiazolylJ-2-butoxyiminoacetyl, 2-(2-Amino-4-thiazolyl)-2-benzyloxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-allyethoxyiminoacetyl, 2-(2-amino-4-thiazolyl)t2-f(1-methyl-1-carboxyethyl)oxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2- [(1-methyl-1-methoxycarbonylethyloxyiminoacetyl,

2-(2-Amino-4-thiazolyl)-2-carboxymethyloxyiminoethyl, 2-(2-amino-4-thiazolyl)-2-carboxyvinyloxyiminoacetyl, 2-(2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-5-bromo-4-thiazolyl)-2-methoxyiminoacetyl, 2-(2-amino-4-thiazolyl)-2-oxyiminoacetyl,

2-(2-Amino-4-thiazolyl)-2-carboxyethyloxyiminoethyl, 2-(2-amino-4-thiazolyl)-2-methoxycarbonylethyloxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2-(1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetyl, 2-(1,2,4-thiadiazol-5-yl)-2-methoxyiminoacetyl, 2-(1,3,4-thiadiazolyl)-2-methoxyiminoacetyl, 2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-oxyiminoacetyl, 2-[4-(gamma-D-glutamyloxy)phenyl]-2-oxyiminoacetyl, 2-[4-(3-amino-4-carboxypropoxy)phenyl]-2-oxyiminoacetyl and similar groups.

Among the examples of the above-mentioned acyl groups; of the general formula

include alpha-sulfophenylacetyl, alpha-hydroxyphenylacetyl, alpha-ureidophenylacetyl, alpha-sulfoureidophenylacetyl, alpha-sulfamoylphenylacetyl, alpha-phenoxycarbonylphenylacetyl, alpha(p-tolyloxycarbonyl)phenylacetyl, alpha-formyloxyphenylacetyl and similar groups.

19

Examples of the above-mentioned acyl groups of the general formula R -R -CHj-CO- include cyanoacetyl, phenylacetyl, phenoxyacetyl, trifluoromethylthioacetyl, cyanomethylthioacetyl, 1H-tetrazolyl-1-acetyl, thienylacetyl, 2-(2-amino-4-thiazolyl)acetyl, 4-pyridylthioacetyl, 2-thienylthioacetyl, 3,5-dichloro-1,4-dihydro-4-oxopyridine-1-ylethyl, beta-carboxyvinylthioacetyl, 2-(2-aminomethylphenyl)acetyl and the like.

The amino, carboxyl and/or hydroxyl groups in the above examples of acyl groups may be protected by a protecting group. The protecting groups of the amino groups are those protecting groups described below as "amino group protecting groups".

/

The protecting groups of the carboxyl and hydroxyl groups are those described above for the symbol R.

Suitable amino protecting groups include any amino protecting groups used for this purpose in the field of beta-lactams or in peptide synthesis. Examples of such amino protecting groups include aromatic acyl groups such as phthaloyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzoyl, butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, etc., aliphatic acyl groups such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, maleinyl, succinyl, etc., esterified carboxyl groups such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, 2-cyanoethoxycarbonyl, beta,beta,beta-trichloroethoxycarbonyl, beta-trimethylsilylethoxycarbonyl, beta-methylsulfonylethoxycarbonyl, benzyloxycarbonyl, p-nitroben2yloxycarbonyl, p-methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl etc., non-acyl protecting groups of amino groups such as trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl and p-nitrobenzyl groups, proton etc.

The choice of protecting group for the amino group is not critical to the present invention.

The symbol R and/or R^ in the compound of general formula I according to the present invention may contain a 1-sulfo group or a carboxyl group or carboxyl groups in the free state. Such groups or groups may also exist as a salt with a non-toxic cation, for example sodium, potassium, etc., a basic amino acid, for example arginine, ornithine, lysine, histidine, etc., a polyhydroxyalkylamine, for example N-methylglucosamine, diethanolamine, triethanolamine, trishydroxymethylaminomethane, etc., or the like.

If R and/or contains a basic group, then the compound of general formula I may exist as a salt with an organic acid, for example with acetic acid, tartaric acid, methanesulfonic acid, etc., with an inorganic acid, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc., with an acidic amino acid, for example aspartic acid, glutamic acid, etc., or the like.

If R and/or R 1 contains a carboxyl group, then the compound of general formula I can be converted into the corresponding biologically active ester derivative, which contributes to an increase in blood concentration and a prolongation of in vivo efficacy. Ester groups that are effective in this manner include, for example, alpha-alkoxy-alpha-substituted methyl groups (e.g., alkoxymethyl or (alpha-alkoxy)ethyl groups such as methoxymethyl, ethoxymethyl, isopropoxymethyl, alpha-methoxyethyl, alpha-ethoxyethyl, etc.), alkylthiomethyl groups such as methylthiomethyl, ethylthiomethyl, isopropylthiomethyl, etc., acyloxymethyl or alpha-acyloxy-alpha-substituted methyl groups such as pivaloyloxymethyl, alpha-acetoxybutyl, etc., alpha-alkoxycarbonyloxy-alpha-substituted methyl groups such as ethoxycarbonyloxymethyl, alpha-ethoxycarbonyloxyethyl, etc., and the like.

The compound of formula I according to the present invention may exist as various steric isomers (e.g. cis-trans, syn, anti and optically active compounds). It is to be understood that the present invention covers both individual isomers and mixtures thereof. These isomers can be used as medicaments either alone or as mixtures.

The spherical isomer of the compound of general formula I according to the present invention can be described, for example, by the general formula

so ₃ h wherein R, (beta-configuration) and X (alpha-configuration) are as defined above and the wavy line indicates the trans or cis configuration of the R group to the R group at position 3.

The compounds of general formula I according to the present invention include compounds Nos. 1 to 57 listed below:

R ¹ /* /

SOqH

Compound cich ₂ conh^ _with .CONH-COOCH,

OCH,

och ₃ ^H 2 ^N ^S _x

1, H CONH— u

N ^OCHj —ch ₂ oconh-

CH-.O

-COOCH,

N— N

CHoS —II ² N—N

AND

CH,

-COOCH,

-COOCH,

II

N ./ —ch ₂ conh—ch ₂ conhC>He-N~AcONHCHCONHH ioo

-COOCH,

-COOCH, table continued

Compound

c ₂ h ₅ -n nconhchconh-cooch ₃

-COOCHj

-cooch ₃

-oh ₃ -cooch ₃

H -COOCjHg

-COOC ₄ Hg(n) o· & r ii c ₂ h ₅ -n nconhchconh-COOH o· or II /—\ c ₂ h ₅ -n nconhchconhn ó

-y ch ₃

H _S N

CONHOC ₂ H ₅

-COOCHj

I continuation of the table

h ₂ nh ₂ n

-COOCH,

-cooc ₂ h ₅ h ₂ n

_H2N ,

CONH-COOC ₄ H ₉ (n)

OCH,

N—N

N—U. /CONH-CH ₂ 8—Q

CH, ,s

OCH,

-COOCH, ch ₂ conh(1_1^ ^CONH 'CH'

NHCONH, /

CH ílH ₂

CONH-COOCH,

-COOCH,

table continued Compound ^R 1 X R 28 ^H2N Vs N—!1 ^CONH- ^OCH, H 29 ^CONH- H H -COOCH^ N ^OCHj 30 ^H2 \ ^S > ÍJ_Jl >CONH- H -CONH— II N ^x och ₃ 31 n^s /CONH- c Λ ^x och ₃ H -CH ₃ 32 _Z o _N „- ^och ₃ H -Ό 33 ^H2N v ^s > (i!_íl CONH- Λ ^X OCH ₃ H Λ3

•22 table continuation

Compound ^H 2 ^N \ c

CONH —

-ch ₂ ch ₂ -£^ ^H2N ^s 'OCH,

CONH-COCH, ^h 2M^ _s 'OCHj ^CONH'OCH, c

N \

.CONH—

-COOH

OCH, ^H 2 ^N \.S.

,CONHH -CH ₂ NH ₂ 'OCH, h ₂ n /CONH. 1

in.

OCH, table continued

Compound ^HzN in ^s >

CONH —

OCH,

-CONH.,

H,N

H,N.

N—LL

CONH

OCH ₂ COOH /CONHŇ <T ^H 3 ^X OC-COOH

AND

CH,

ΎΛ /CONH—

C

N ^X OC-COOH

I ch ₃

-OCH,

H,N

Y|]

N—LL /CONH-C CH,

II I ³ N—OC-COOH

I ch ₃

-COOCH,

-CONH _n

-CONH, < <5

^Ύs il

N-—!L

CONHN <f ^H 3 \oC-COOH

AND

CH, continuation tables

Compound

___________ll________________ ^H!N in ^s i, /CONH- N—LI— |Š CH, ^OC-COOH 1 ch ₃ ir |1 CONH- N_!_ -C Λ \)-C-COOH 1 ch ₃ Tl_ ^CONH- ~C II N \och ₂ cooh

h ₂ n

CONH/ ch ₃ o I ^{3 X} C-COOH

I ch ₃ h ₂ ki

CONH-ch ₂ (ch ₂ ) ₃ oconh ₂

-ch ₂ oh

-CH(CH ₃ ) ₂

-CH^OCOCH-j

V Grill ^x o _K I ³

C~CGGK ch ₃

-ch ₂ nhcoch ₃

_{-CH2CONHCH3 ​}

-cooch ₃

25357 table continuation

Compound

Ίύ_<

CONH-cooch ₃ c-cooc ₂ h ₅

CH.

' ² \jl _c z ^{co h} i

NHCOCH3

-CONH2

H ₉ N tL h ₂ n

C—CONH—

-conh ₂

C-CONHθ”3 O-C-COOH I

CH,

_{-CH2CONH2 ​}

Among others, a preferred compound of the compounds of general formula I according to the present invention may be a compound of general formula

CONH II N ^X 0-Q ^{8 0}

in which

Q ³ , Q ^{4 * *} , Q ⁷ , Q ⁸ and the tilde are as defined above, or a salt or ester thereof. If Q ⁷ in the above general formula represents an amino group, then this compound may form an internal salt between the amino group Q· and the sulfo group at position 1.

The compound of the general formula I according to the invention and its salts or esters are valuable antibiotics effective against various gram-positive and gram-negative bacteria. They are used in the form of medicines in humans or domestic animals as safe antimicrobial agents in the treatment of infections caused by gram-positive or gram-negative bacteria. Furthermore, the antimicrobial agents according to the invention are used to be added to the daily rations of animals as agents that disinfect and protect food.

Antibiotics can also be used in the form of aqueous compositions at a concentration of 0.1 to 100 ppm (i.e. 0.1 to 100 parts of antibiotic per million parts of solution) as antimicrobial agents that kill harmful bacteria or prevent their growth, for example on medical or dental equipment or in industrial aqueous environments, e.g. in aqueous paints or in white water passed through a paper mill.

The compounds of general formula I and their salts or esters can be used alone or in combination with one or more other active ingredients in various pharmaceutical compositions, such as capsules, tablets, powders, solutions, suspensions and elixirs (medicinal drinks).

These agents can be administered orally, intravenously, or intramuscularly.

Tablets for oral administration may contain conventional excipients such as binding agents, e.g. syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers, e.g. lactose and other sugars, corn starch, calcium phosphate, sorbitol or glycine, lubricants, e.g. magnesium stearate, talc, polyethylene glycol or silicon dioxide, disintegrating agents, e.g. potato starch, or available wetting agents, e.g. sodium lauryl sulphate.

The tablets may be coated in a manner well known to those skilled in the art. Liquid preparations intended for oral administration may be in dosage forms such as aqueous or oily suspensions, solutions, emulsions, syrups, elixirs, etc., or as lyophilisates for eventual dissolution in water or a suitable solvent. These liquid preparations may contain suspending agents, e.g. sorbitol syrup, methylcellulose, glucose syrup (sugar), gelatin, hydroxyethylcellulose, carboxymethylcellulose, or aluminum stearate gel, hydrogenated edible oil, e.g. almond oil, coconut oil fractions, oily esters, propylene glycol or ethyl alcohol, or preservatives, e.g. methyl or propyl ester of p-hydroxybenzoic acid or sorbic acid.

Suppositories may contain a conventional suppository base, for example cocoa butter or other glycerides.

Injectable compositions may be presented in ampoules or other containers containing a unit dose, with the addition of preservatives. These compositions may be in such dosage forms as, for example, suspensions, solutions or emulsions in oily or aqueous vehicles and may contain a suitable adjuvant or adjuvants, such as, for example, suspending agents, stabilizing and/or dispersing agents.

The active ingredient may also exist in the form of powders which may be reconstituted with a suitable solvent or sterile, pyrogen-free water before use.

The active ingredient can also be formulated in suitable dosage forms absorbable through the nasal and throat mucosa or bronchial tissues, e.g., as powders, liquid sprays or inhalants, lozenges, throat swabs, etc.

For ophthalmic or otological application, they can be administered as liquids or semi-solids or as drops for instillation. In addition, they can be formulated with hydrophobic or hydrophilic pharmaceutical bases in such dosage forms as ointments, creams, lotions (washes), swabs, powders, etc., which are pharmaceutical compositions for external application.

In addition to carriers, these compositions may contain other ingredients such as stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, rheological agents, or agents that provide a uniform consistency. In addition, another active ingredient or ingredients may be included in the composition to provide a broader antimicrobial spectrum.

For administration to domestic animals, the active ingredient of the present invention can be formulated with an agent that causes the active ingredient to be released slowly. This results in slow-release compositions (i.e. compositions that release the active ingredient slowly).

The compounds of general formula I according to the present invention can be applied to mammals as ^therapeutic agents useful against microbial infection in the treatment of, for example, respiratory tract infections, urinary tract infections, purulent diseases, bile duct infections, intestinal infections, gynecological infections, surgical infections, etc.

The daily dose depends on the condition of the patient being treated, on his weight, on the method (route) and frequency of administration and in particular on whether it is a parenteral route of administration, which is generally suitable for infections, or an oral route of administration, which is used for intestinal infections.

The oral daily dose is generally an amount of about 15 to 600 mg of active ingredient per kg of body weight of the patient administered in one or more doses. A suitable daily dose for non-oral administration to adult patients is about 10 to about 200 mg of active ingredient per kg of body weight; this amount can be advantageously administered in 2 to 4 doses of about 2.5 to 100 mg/kg.

A pharmaceutical composition comprising a compound of formula I may be administered, for example, in various solid or liquid orally administered unit dosage forms. The liquid or solid composition may contain from 0.5 to 99% of the active ingredient. A preferred concentration of the active ingredient is from about 10 to about 60%. The composition will typically contain from about 15 to 1500 mg of the active ingredient in each individual dosage form. It is typically preferred to use unit dosage forms containing from about 250 to 1000 mg of the active ingredient.

In addition to the above uses, the compounds of the general formula I according to the present invention, their salts and esters can be used in combination with beta-lactam antibiotics because they have the activity of inhibiting beta-lactamase. Examples of beta-lactam antibiotics include penicillin antibiotics such as benzylpenicillin, phenoxymethylpenicillin, carbenicillin, ampicillin, amoxicillin, sulbenicillin, etc., cephalosporin antibiotics such as cephaloridine, cephalothin, cephalozin, cephalexin, cefositine, cefacetril, cefamandole, cefmenoxin, cefsulodin, cefotiam, cefotaxime, cefapirin, ceftizoxime, cephradine, cephaloglycine, etc., and the like.

1-Sulfo-2-oxoazetidine derivatives of general formula I, which are compounds of the present invention, can be prepared by acylation of a compound of general formula XII

_θ /~%ο ₃ Η in which R and X have the same meanings as above.

The acylation according to this procedure is carried out by treating 1 mole of the compound of general formula III (its various salts, esters or silyl derivatives) with at least one mole, preferably 1.2 to 4 moles, of an acylating agent.

As salts and esters of the compound of general formula III, those salts and esters whose examples are given above for the compounds of general formula I, etc. are used. The compound of general formula III can also be silylated with a silylating agent.

The silylating agent may be a compound of the general formula

3

P^P^Si.Hal ,

2 3 in nemz Ρ , P and P represent a hydrocarbon group such as a lower alkyl group having 1 to 4 carbon atoms (for example, methyl, ethyl, propyl, isopropyl, butyl, etc.), an aryl group (for example, phenyl, tolyl, etc.) or similar groups and

Hal represents a halogen atom, preferably a chlorine or bromine atom, and one or more of the substituents P, P and P may represent a halogen atom, preferably a chlorine or bromine atom, and one of the substituents P, P and P may represent a hydrogen atom. As a silylating agent, hexa-alkyl(with 1 to 4 carbon atoms) cyclotrisilazane, octaalkyl(with 1 to 4 carbon atoms)cyclotetrasilazane, trialkyl(with 1 to 4 carbon atoms)silylacetamide and bid-tri-alkyl(with 1 to 4 carbon atoms)silylacetamide can be used.

A preferred silylating agent is a compound of the general formula

Y ¹ γ - si - y ³ , in which

Y represents a reactive group that is released from the silyl compound,

2

Y or Y represents a lower alkyl group with 1 to 4 carbon atoms, a phenyl, benzyl or lower alkoxy group with 1 to 4 carbon atoms and

Y represents a tert-butyl or isopropyl group.

2

The lower alkyl group Y and Y may be methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like. Examples of the lower alkoxy group Y and Y include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy and the like.

Examples of a reactive group that is released from a silyl compound include a halogen atom (e.g., chlorine, bromine), N-(trialkylsilyl)trifluoroacetamidoyloxy,

N-(trialkylsilyl)acetimidoyloxy, an acylamino group, such as a formylamino, acetylamino, propionylamino, butylamino or trifluoroacetylamino group, a (trialkylsilyl)amino group, such as a (tri-tert-butyldimethylsilyl)amino group, an isopropyldimethylsilylamino or (chloromethyldimethylsilyl)amino group, an amine group, an alkylamino group, such as a methylamino, ethylamino or propylamino group, an N,N-dialkylamino group, such as a N,N-dimethylamino, N-chloromethyl-N-methylamino, N,N-diethylamino, N,N-dipropylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino or N-ethyl-N-propylamino, or a heterocyclic group, such as an imidazolyl group.

The alkyl group in the above reactive group preferably means an alkyl group having 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and tert-butyl groups. Specific examples of the above-described silyl compounds are N,O-bis(tert-butyldimethylsilyl)trifluoroacetamide, N,O-bis(isopropyldimethylsilyl)acetamide, bis(dimethylisopropylsilyl)acetamide, isopropyldimethylsilylacetamide, bis(dimethyl-tert-butylsilyl)acetamide, N-methyl-N-tert-butyldimethylsilylacetamide, N-methyl-N-isopropyldimethylsilyltrifluoroacetamide, N-tert-butyldimethylsilyldiethylamine, 1,3-bis(chloromethyl)-1,1,3?3-tetra-tert-butyldimethyldisilazane, N-isopropyldimethylsilylimidazole, tert-butyldiphenylchlorosilane, isopropyldiethylchlorosilane, isopropylmethyldichlorosilane, tert-butyldimethylchlorosilane, isopropyldimethylchlorosilane, isopropyldimethylchlorosilane, or tert-butyldiethylchlorosilane.

Preferred of the above compounds is tert-butyldimethylchlorosilane or isopropyldimethylchlorosilane; The silylation reaction is carried out in a conventional manner. The reaction temperature of the silylation is about 0 to 50°C, preferably not higher than 38°C, usually room temperature (about 20°C). The reaction time is from a few minutes (about 10 minutes) to about 24 hours.

The treatment is preferably carried out, for example, in ethyl acetate, dioxane, tetrahydrofuran, N,N-dimethylacetamide, N,N-dimethylformamide, dichloromethane, chloroform, benzene, toluene, acetone, methyl ethyl ketone or acetonitrile, in any mixture thereof or in any solvent which is inert to this treatment.

The treatment can also be carried out in the presence of inorganic bases such as sodium hydroxide or potassium carbonate, trialkylamines such as triethylamine or tributylamine, triarylalkylamines such as tribenzylamine, an organic tertiary amine such as N-methylmorpholine, N-methylpiperidine, N,N-dialkylaniline, N,N-dialkylbenzylamine, pyridine, picoline or lutidine, or organic bases such as 1,5-diazabicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4,4]undecene-7. If the base is a liquid, it can also be used as a solvent.

The silyl derivative of the compound of general formula III thus produced can be used as a starting material in acylation, either as a reaction mixture or after isolation or purification by the conventional method described below.

The acylating agent used in this reaction can be either an organic carboxylic acid containing an acyl group at R ¹ [R°COOH, where R°CO represents the acyl group mentioned above as the acyl group of the acylated amine group at R ¹ ], or a reactive derivative thereof at the carboxyl group.

Reactive derivatives of organic carboxylic acids include, for example, acid anhydrides, active amides, active esters, etc. Examples of these reactive derivatives are given below:

1. Acid anhydrides:

Acid anhydrides include, for example, mixed acid anhydrides with a hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid, etc.), with a monoalkylcarboxylic acid, an aliphatic carboxylic acid (e.g., acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), with an aromatic carboxylic acid (e.g., benzoic acid, etc.), and also symmetrical acid anhydrides.

2. Active amides: ^Z

Active amides include, for example, amides with pyrazole, imidazole, 4-substituted imidazole, dimethylpyrazole, benzotriazole, etc.

3. Active esters:

Active esters include, for example, such esters as methyl, ethyl, methoxymethyl, propargyl, 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters, as well as esters of the abovementioned carboxylic acids with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide and N-hydroxyphthalimide or similar esters.

The choice of reactive organic carboxylic acid derivative depends on the acid used. If the acylating agent used is a free carboxylic acid, then the treatment is preferably carried out in the presence of a condensing agent. Examples of such condensing agents are N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide and the like.

The acylation is usually carried out in a solvent. The solvent may be water, acetone, dioxane, acetonitrile, methylene chloride, chloroform, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, pyridine or other suitable organic solvents that do not affect the reaction. Of these solvents, hydrophilic solvents can be used in combination with water.

Acylations can also be carried out in the presence of a base, such as an alkali metal carbonate, a trialkylamine (e.g. trimethylamine, triethylamine, tributylamine, N-methylmorpholine, N-methylpiperidine, etc.), N,N-dialkylaniline, N,N-dialkylbenzylamine, pyridine, picoline, lutidine,

1,5-diazabicyclo[4,3], Oj nonan-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,8-diazabicyclo[5,4,4_jundecene-7-, etc.

Liquid bases and liquid condensation agents mentioned above can also serve as solvents. The reaction temperature is not critical. The work-up is carried out while cooling to room temperature. The reaction is completed within a few minutes to a few tens of hours. The resulting compound of general formula I can be isolated and purified by known methods, such as concentration, alkalization of an acidic liquid medium or vice versa, by changing the solvent, extraction with a solvent, crystallization, recrystallization, fractional distillation, chromatography and the like.

If the starting compound of general formula III or its salt and/or the acylating agent used in the acylation contains an asymmetric carbon in the molecule, then either the individual stereoisomers or a mixture thereof can be used.

If two or more stereoisomeric products are formed upon acylation, then the individual isomers can be isolated, if necessary, by conventional means such as column chromatography, recrystallization, or the like.

The R group of a compound of formula I according to the invention can be converted to a south group, while the compound of formula I retains the 1-sulfo group. This leads to the production of another compound of the invention. For example, if R is an acetoxymethyl, methanesulfonyloxymethyl, iodomethyl or the like, it can be converted to another desired group by reaction with a nucleophilic reagent.

Examples of nucleophilic reagents include alkyl ⁺ -thiols, aryl*-thiols, heterocyclo*-thiols, pyridines* and similar reagents. Compounds of general formula I according to the invention are thus obtained, in which R represents a substituted thiomethyl, quaternary ammonium*-methyl or similar group.

Alkyl*, aryl*, heterocyclic* and quaternary ammonium* groups in these nucleophilic reagents are as defined above. The treatment is preferably carried out in an aqueous solution, or in a water-miscible solvent, such as acetone, acetonitrile, N,N-dimethylformamide or similar solvents, or in a mixture of water and a water-miscible solvent. In some cases, it is beneficial to add a base, such as an alkali metal carbonate, an alkali metal phosphate or the like.

The work-up is usually carried out at temperatures in the range of 20 to 100° C. The resulting compound of formula I can be isolated and purified in a known manner, as in the case of compounds prepared by sulfonation or acetylation.

If the compound of formula I according to the invention thus produced carries a protecting group; then, if desired, this group can be removed. Such a protecting group can be removed by conventional methods such as, for example, a method using an acid, a base and hydrazine, reduction, a method using an iminohalogenating agent, then an iminoetherifying agent and, if necessary, followed by hydrolysis.

Whether one or the other method is used depends on the type of protecting group to be removed. If the protecting group is removed by the action of an acid, then inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc., organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc., and also acidic ion exchangers are used as acids.

The choice of acid depends on the type of protecting group and other conditions. If the protecting group is removed by the action of a base, then inorganic bases such as alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., calcium, magnesium, etc.), hydroxides, carbonates, etc., and organic bases such as metal alkoxide, organic amine, quaternary ammonium salt, etc., and basic ion exchangers are used as the base. The choice of base depends on the type of protecting group and other conditions.

If the protecting group is removed by the action of an acid or base in a solvent, then the solvent used is usually a hydrophilic organic solvent, water or a mixture of solvents.

When the protecting group is removed by reduction, for example, reduction with metals such as tin and zinc, or metal compounds such as chromium chloride or chromium acetate, and an organic or inorganic acid such as acetic acid, propionic acid or hydrochloric acid, catalytic reduction in the presence of metal hydrogenation catalysts or the like is used, depending on the type of protecting group and other conditions.

Catalysts used in catalytic reduction include, for example, platinum catalysts such as platinum wire, sponge platinum, platinum black, platinum dioxide, colloidal platinum, etc., palladium catalysts such as sponge palladium, palladium black, palladium oxide, palladium on barium sulfate, palladium on barium carbonate, palladium on carbon, palladium on silica gel, colloidal palladium, etc., nickel catalysts such as reduced nickel, nickel oxide, Raney nickel, Urushihara nickel, etc., and the like.

In the metal-acid reduction, metals such as iron, chromium, or the like, and inorganic acids such as hydrochloric acid, or organic acids such as formic acid, acetic acid, or propionic acid are used as metal compounds.

Removal of the protecting group by reduction is usually carried out in a solvent. Solvents commonly used in catalytic reduction include, for example, alcohols such as methanol, ethanol, isopropanol, propanol, etc., ethyl acetate and the like.

The reduction with metal and acid is preferably carried out in water, acetone or a similar medium, if the acid is liquid, then it can itself serve as a solvent.

According to any of the methods in which acid, base or reduction is used, the treatment is usually carried out with cooling to heating.

If the protecting group is removed by treatment with an iminohalogenating agent, then with an iminoetherifying agent, and, if necessary, subsequent hydrolysis, then the iminohalogenating agents used may be, for example, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus oxychloride, thionyl chloride, phosgene, etc.

The reaction temperature is not critical; the reaction is usually carried out at temperatures ranging from room temperature to temperatures achieved by cooling. The resulting reaction product is then treated with an iminoetherifying agent, alcohols and metal alkoxides. Alcohols include alkanols such as methynol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, tert-butyl alcohol, etc., as well as those compounds in which the alkyl group of the above alcohols is substituted by an alkoxy group such as methoxyl, ethoxyl, propoxyl, isopropoxyl, butoxyl or the like.

Metal alkoxides include alkali metal alkoxides such as sodium alkoxide, potassium alkoxide, etc., and alkaline earth metal alkoxides such as calcium alkoxide, barium alkoxide, etc., which are derived from the above-mentioned alcohols.

If the protecting group is an organic acid residue and if a free amino group, hydroxyl group, mercapto group, carboxyl group or sulfo group is attached to the carbon adjacent to the carbonyl group of the carboxyl residue, then it is advantageous to carry out a preliminary treatment, which results in the fact that the reactivity of the carbonyl group is increased by the influence of the substituent on the carbon atom adjacent to the carbonyl of the carboxyl before the reaction in which the protecting group is removed is carried out.

This will be illustrated, for example, by the case where the substituent on the carbon atom adjacent to the carboxyl group is a free amino group. In such a case, the protecting group can be removed by converting the amino group to a thioureido group followed by deacylation, or any known method of peptide chain cleavage can be used.

The temperature at which the treatment is carried out is not critical. The appropriate temperature is selected according to the type of protecting group and the method by which the protecting group is removed. The treatment is preferably carried out under mild conditions, such as cooling or even heating.

If R and/or R ³ in the above reactions represent a group containing a carboxyl group, then the derivative at the carboxyl group can be converted into the corresponding free carboxyl compound. Such a case is naturally included in the present invention.

The free compound of formula I thus produced can be converted into the desired salt by the conventional method described above.

A compound of formula I which contains a sulfo group is usually treated with a base to form salts. A compound of formula I may therefore be prepared in the form of a salt. The salt so prepared may be further converted to the free compound or to another salt. A compound of formula X which is prepared as a free compound may be converted to a salt.

A compound of the general formula I which exists in the form of a salt can, for example, be converted into the free compound of the general formula I by the action of acids. Depending on the type of salt and other conditions, the acid used is preferably an inorganic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or an organic acid, such as formic acid, acetic acid or p-toluenesulfonic acid.

An acidic ion exchanger or the like can also be used. As the solvent, a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane or similar solvents, water or a mixture of solvents is usually used.

The treatment is usually carried out at room temperature, cooling or heating may be used. The reaction time depends on the acid used, the solvent and the temperature. It is usually advantageous if the treatment is completed within a short time. The resulting compound of general formula I in the free state can be isolated by the above-mentioned known method.

The starting compound of general formula III used in the present invention can be produced, for example, by the following or similar procedures.

Procedure 1

OCH ₃

ARCHIOLOGY

oh ₃ k ₂ s ₂ o ₈

H H

ArCHjOCONH = =^ ^CO 2 ^CH 3 sulfonation

(VI)

H,

Pd-C

H H

_H2N = _{= CO2CH3}

0' S° ₃ ^h (Vlil)

OCH,

_NaBH4

ArCHjOCONH 5 = CH ₂ 0H

O' ^CHj —(/ \ ^0X1 OCH,

oh ₃ ch ₃ coci

^N 2 ^S 2°8

ArCH ₂ OCONH 8 8 CH ₂ OCOCH ₃

(XI) sulfonation.

ArCH ₂ OCONH 8 ^CH ₂ OCOCH ₃

About ^SO.H (XII)

H,

H,N 8 ; ch,ococh.

Pd-C

(XIII)

Procedure 3

O

OCH ₃

NaBH. - >» ^K 2 ^S 2°8

->

R ¹ ' BB CHjOSO ₂ CH ₃ (XVIII)

Procedure 4

N, b H _Ar \ž IZ ^h 2

Pd-C =>

introduction of protecting groups

X (XXIII)

Ar(XXI)(XXII) removal of the protecting group

M W ^H H .

² VJ/

X.

Procedure 5

H ₂

Pd-C och ₃

introduction of a protecting group

(XXVI) ch ₂ ch(och ₃ ) ₂ ^K 2 ^S 2®8 ->

oh ₃

,. Η H r ¹ ^J = ch ₂ ch(och ₃ ) _{2 acqh} ,, Η H

D* “ (XXVII)

R' = = _CH2CHO

X (XXVIII)

Jones oxidation -

(XXIX) ch ₂ co ₂ h sulfonation deprotection

Procedure 6

H H

ArOCH,CONH = = Ar (XXXII)

H ₂ , Pd-C sulfonation

Procedure 7

co ₂ ch ₃ (XXXIII) sulfonation ____ removal of the protecting group (Vlil)

Procedure 8

1’ H H ,ch ₂ nhcoch ₃ H,N ² .CH.NHCOCH ιχ sulfonation removal _/ ² r ^H (XXIX) protecting groups C< ^sat ₃ h

Procedure 9

introduction of a protecting group

^N 2 ^S 2°8

sulfonation removal of the protecting group

Procedure 10

ch ₃ sulfonation deprotection

_H2N

COjCHg so ₃ h

A ¹ '5 (XLVI)

O

och ₃ (XVI)

_{NH2NH2H2 °}

oh ₃

Procedure 12

H ₂ , Pd-C sulfonation

Procedure 13

(LVII) introduction of a protecting group

CO ₂ Et (LVIII)

Procedure 14 sulfonation removal ** protecting group ^h 2N : COjEt

KH = = .CO ₂ CH ₃

SE

JX to ₂ what ₃

ArCH ₂ OCONH ti ti CO.H (CH ₃ ) ₂ NH

X.S

O

1) CHqNHNH, Η Η u M

-- -- >ArCH ₂ OCONH ; = .CHjCHjAr sulfonation ^h 2 ⁿ .= ? CH ₂ CH ₂ Ar

2) ARCHjOCOCI 'Š-removed -3<

* I I protecting groups l |

3) K ₂ S ₂ O ₈ -Nh (LXVII)

O .'SOiH (LXVIH) ³

Procedure 16

ArCH ₂ OCONH 9 = CO ₂ CH ₃

_NH4OH

ArCH ₂ OCONH z = CONH ₂ (VI) ./ ^NH (lxix)

H ₂ , Pd-C h ₂ nyy conh ₂ sulfonation

X, (LXX)

Procedure 17 “J-C?

1) LiN(isoPr),

2) ^CH 3—so ₂ n ₃ (LXXI) trans isomer (LXXII)

1) Jones oxidation

2) CH ₂ N ₂ ch ₂ co ₂ ch ₃

N _H

trans isomer (LXXIII)

H ₂ /Pd-C ^ch ₂ co ₂ ch ₃ sulfonation

trans isomer (lxxiv)

In the above formulas

Ac

Et

Me isoPr

R·

1'

DBU

DCC means acetyl group, means ethyl group, means methyl group, means isopropyl group, means aryl group, means protected amine group, means 1,3-diaza-bicyclo[5.4.0]-7-undecene and means dicyclohexylcarbodiimide.

The starting materials used in the above processes 1 to 17 are, for example, cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester (IV) described in J. Amer. Chem. Soc. 99, 2352 (1977), cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester (XIV) described in Japanese Patent Laid-Open No. 136 694/1976, cis-3-azido-4-phenyl-2-oxoazetidine (XXI) described in J. Org. Chem. 34, 1477 (1969), cis-3-azido-1-(2,4-dimethoxybenzyl)-4-(2,2-dimethoxyethyl)-2-oxoazetidine (XXIV) described in J. Amer. Chem. Soc. 101, 4730 (1979), cis-1-(3,4-dimethoxybenzyl) ^-1-3 -phenoxyacetamido-4-phenyl-2-oxoazetidine (XXXI) described in Synthesis 1979, 543 and 2,2-dimethyl-1-aza-3-oxabicyclo[4.2.0]octan-8-one (LXXI), which is described in J. Amer. Chem. Soc. 100,

313 (1978).

These examples are not intended to limit the starting materials. Any compound suitable for the purpose of the present invention may be used as the starting compound. Examples of such starting materials will be given in the following reference examples.

Sulfonation with the above process is a treatment in which a sulfo group is introduced into the 1-position of the compound to be sulfonated. Sulfonation is carried out by treating the compound to be sulfonated, for example, with sulfur trioxide or a reactive derivative thereof.

Reactive derivatives of sulfur trioxide include, for example, its adducts, such as the sulfur trioxide-base adduct (e.g., sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, sulfur trioxide-picoline, sulfur trioxide-lutidine, etc.), sulfur trioxide-N,N-dimethylformamide, sulfur trioxide-dioxane, sulfur trioxide-chlorosulfonic acid, and the like.

This reaction uses about 1 to 10 moles, preferably about 1 to 5 moles of sulfur trioxide or its reactive derivative per mole of the compound to be sulfonated. The reaction temperature is in the range of -78 to 80°C, preferably about -20 to 60°C. The reaction can be carried out in the presence of a solvent.

In such a case, conventional organic solvents including water, ethers such as dioxane, tetrahydrofuran, diethyl ether, etc., esters such as ethyl acetate, ethyl formate, etc., halogenated hydrocarbons such as chloroform, dichloromethane, etc., hydrocarbons such as benzene, toluene, hexane, etc., amides such as N,N-dimethylformamide, N,N-dimethylacetamide, etc., and the like may be used either alone or as a mixture. The treatment is usually completed within a few minutes to hours, depending on the type of starting compound to be sulfonated, the sulfonating agent, the reaction temperature and the solvent used; however, in some cases, days are required to complete the reaction. After the treatment is completed, the reaction mixture is subjected to suitable purification and separation methods which are generally known, such as solvent extraction, recrystallization, chromatography or the like. The desired compound is produced in any purity.

The present invention is illustrated in further detail below by way of examples and reference examples. It should be understood, however, that the examples are given for the purpose of illustration only and are not intended to limit the invention. Many variations are possible without departing from the spirit and scope of the invention.

In the following reference examples and examples, the column chromatography elution procedure is checked by thin layer chromatography (TLC). Merck 60 ^F 25 ₄ TLC plates are used for TLC. The plates are eluted with the same solvent as the column chromatography elution. An ultraviolet detector is used for detection. Fractions containing the desired compound are isolated, the spot of which is colored red-purple by the action of ninhydrin, spraying with 48% hydrobromic acid and heating to cause hydrolysis.

If two types of solvents are used for elution, the first solvent described is used to elute the column and remove the by-product. The second solvent is used to elute the desired product, except where specifically described otherwise.

The compound is dried over anhydrous sodium sulfate unless otherwise specified. Unless otherwise specified in the Examples and Reference Examples, for purification by chromatography on an Amberlite or Sephadex column, water is used first, then an aqueous ethanol solution with a gradient increasing ethanol concentration is used for elution.

Amberlite resin is a product manufactured by Rohn and Haas Co., USA. Dowex is a product of Dow Chemical Co., Sephadex is a product of Pharmacia Fine Chemicals. All temperatures are uncorrected. All percentages are weight percentages except for percentages used for solvents.

Solvents are always given in volume percentages. The NMR spectra reported were measured on a Varian Model EM 390 (90 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as internal and external standards.

All values (delta) are given in ppm. The symbol s means singlet, the symbol d means doublet, q means quartet, ABq means AB-type quartet, t, means triplet, dd means doublet of a doublet, m means multiplet, sh means shoulder, br means broad (for example, brs means broad singlet) and J means interaction constant. The symbols in the examples and reference examples have the following meanings:

mg « milligram g = gram ml = milliliter = liter >

decomp. - by decomposition ppm - part per million mmol = millimol

M - molar (concentration)

HZ = Herz ph - phenyl group

Me = methyl group

Et = ethyl group °C = degrees Celsius = maximum max

NMR = nuclear magnetic resonance absorption

IR = infrared absorption

DMSO = dimethyl sulfoxide

D^O = heavy water.

Try

The table below shows the minimum inhibitory concentrations (MIC) of some typical compounds of formula I according to the invention prepared in the examples.

Method

The minimum inhibitory concentrations of the test compounds were determined by the agar dilution method. Specifically, 1.0 ml of the aqueous solution of the test compounds diluted by serial dilutions is poured into a test Petri dish. Then 9.0 ml of Trypticase Soy Agar is added to the dish and mixed.

O

One loop of suspension (about 10 CFU/ml) of the test microorganism is spread on a plate with stirred agar. Incubate overnight at 37 °C. The minimum inhibitory concentration is the lowest concentration of test compounds that causes a clear inhibition (complete) of the growth of the test microorganism.

Tested microorganism:

(1) Enterobacter cloacae IFO 12,937 (2) Klebsiella penumoniae TN 1,711

Result:

(g/ml) Compound Microorganism ” (1) (2) example no; 39 (3) 6.25 0.2 example no. 1 (5) 3.13 0.78 example no. 40 (2) 1.56 - example no. 65 (3) 1.56 0.39 example no. 66 (2) - 1.56 example no. 67 (2) - 6.25 example no. 69 (2) 6.25 3.13 example no. 70 (3) 3.13 0.39 example no. 74 (2) 3.13 6.25

Example 1 (1) To a solution of 278 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 2.8 ml of N,N-dimethylformamide was added 320 mg of pyridine-sulfur trioxide complex.

The mixture is stirred for 2 days at room temperature. Another 120 mg of pyridine-sulfur trioxide complex is added to the reaction mixture. The mixture is stirred for another day.

50 ml of ether is added to the reaction mixture. The resulting powdery precipitate is filtered off and washed with ether. The powdery product is dissolved in 5 ml of water. The solution is passed through a column of Dowex 50W (Na-form). The lyophilisate of the eluent is dissolved in a small amount of water and purified by chromatography on an Amberlite XAD-II column.

The lyophilisate of the product thus purified provides the sodium salt of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid. IR spectrum (V cm ^- ^) 5 3 300 and 1 750. NMR spectrum (DMSO-dg, ppm): 3.56 (3H, s CHj) , 4.43 (1H, d, J = 5 Hz, C ₄ ~H), 7.36 (5H, s, phenyl protons), 8.13 (1H, d, J = 9 Hz, NH) . For ^c i3 ^H i3 ^N 2 ^NaO 8 ^S ' ^H 2° calculated:

39.19% C, 3.79% H, 7.03% N, found: 39.04% C, 3.99% H, 7.26% N.

(2) To a solution of 190 mg of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid ^sodium salt monohydrate in 10 ml of water, 190 mg of 10% palladium on carbon was added. Then, the mixture was catalytically reduced for one hour at room temperature and normal pressure. The reaction mixture was passed through a layer of celite to filter out the catalyst.

The filtrate is lyophilized. The sodium salt of cis-3-amino-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid is produced. IR spectrum (V ' ^{om ! 3} 450, 1 770, 1 740 and 1 060. NMR spectrum (DMSO-d ₆ , ppm): 2.7 to 3.5 (2H, broad singlet, NH ₂ >, 3.67 (3H, s, CH ₃ ), 4.33 (2H, s, C ₃ ~H and C^-H). For CgH ₂ N ₂ NaOgS.1 1/2 HjO calculated: 21.98% C, 3.68% H, 10.35% N, found:

22.10% C, 3.69% H, 10.48% N.

(3) In a mixture of 20 ml of water and 20 ml of tetrahydrofuran, 950 mg of cis-3-benzyloxy]carboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt prepared in Example 1 was dissolved. To the solution, 950 mg of 10% palladium on carbon was added.

The mixture was stirred for one hour at room temperature under a hydrogen atmosphere. The catalyst was then filtered off and washed with a 1:1 mixture of water and tetrahydrofuran (40 ml). The filtrate was combined with the washed liquid. Under ^ice -cooling and stirring, 504 mg of sodium hydrogen carbonate and 1.55 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p·^-nitrobenzyloxycarbonyl)ethyloxyimino]acetyl chloride hydrochloride were added thereto. The mixture was stirred for 40 minutes under ice-cooling.

Then it is concentrated under reduced pressure. The residue is chromatographed on an Amberlite XAD-II column. The eluate is lyophilized. The sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-]-1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino-acetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced as a colorless powder.

IR spectrum (V

KBr

-1, cm ) :

775, 1,740, 1,680, 1,550, 1,525, 1,280 and 1,055. NMR spectrum

4.33 (2H, s, C1CH ₂ (1H, d, J = 6 Hz, C ₄ -H)í» 5.31 (2H, s, COOCH ₂ ) , 5.52 (1H, dd, J == 6 Hz, J = 9 Hz, C 7.25 (1H, s, S _V H), 7.62 d 8.07 (2 x 2H, 2 xd, aromatic protons).

(DMSO-dg, ppm): 1.50 (6H, s, 2 Hz,

CH,

4.51 (H) ,

For C ₂₃ H ₂₂ ClNgNaO ₁₃ S ₂ .3H ₂ O calculated: 36.01% C, 3.68% H, 10.96% N, found:

36.09% C, 3.36% H, 11.06% N.

(4): Dissolve 1.158 g of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethoxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) in 30 ml of water. Add 241 mg of monomethyldithiocarbamic acid sodium salt to this solution under ice-cooling and stirring. Then add 241 mg of monomethyldithiocarbamic acid sodium salt.

The mixture was stirred for an additional hour. The reaction mixture was then washed with ether and concentrated under reduced pressure. The concentrate was chromatographed on an Amberlite XAD-II column. The eluate was lyophilized. The sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was produced as a colorless powder.

IR spectrum (V cm ^-1 ): 1,775, 1,740, 1,680, 1,615, 1,520, 1,280 and 1,055. NMR spectrum

ΠΙαΧ (DMSO-dg, ppm): 1.48 (6H, s, 2 x CH ₃ ), 3.63 (3H, s, COOCH ₃ ), 4.50 (1H, d, J = 6 Hz, C ₄ ~H),

5.33 (2H, s, COOCH ₂ ), 5.47 (1H, dd, J -- 6 Hz, J = 9 Hz, Cj-H) , 6.59 (1H, s, SH) , 7.24 (2H, br s, NH ₂ ) , 7.65 and 8.14 (2 x two protons, 2 x d, aromatic protons), 'K 9.18 (1H, d, J = 9 Hz, C ₃ -NH).

For C ₂₁ H ₂₁ N ₆ NaO ₁₂ S ₂ .2 1/2 H ₂ 0 calculated: 37.01% C, 3.84% H, 12.33% N, found:

36.99% C, 3.87% H, 12.34% N.

(5) In a mixture of 25 ml of water and 25 ml of tetrahydrofuran, 500 mg of sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is dissolved.

To the solution was added 500 mg of 10% palladium on carbon. The mixture was stirred for one hour under a hydrogen atmosphere at room temperature. 25 ml of aqueous sodium bicarbonate solution (62 mg) was added. The catalyst was filtered off. The filtrate was washed with ethyl acetate and concentrated under reduced pressure.

The residue is chromatographed on an Amberlite XAD-II column. The eluate is lyophilized. The disodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido] isomer is produced.

580, 1280 and 1055. NMR spectrum (s, COOCH-j) , 4.53 (1H, d, J =

-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn

IR spectrum (in ^x'^{cr<1 ! 1} 740, 1 660, 1 630, (DMSO-dg, ppm): 1.36 (3H, s, CHj), 1.45 (3H, s, CH ₃ ), 3.61 = 6 Hz, C ₄ -H), 6.60 (1H , s, Sy H), 7.13 (2H, br s, NHj).

For C ₁₄ H ₁₅ N ₅ Na ₂ O ₁₀ S ₂ .4H ₂ O calculated: 28.24% C, 3.89% 3.68% H, 11.62% N.

(6) Dissolve 85 mg of disodium salt in 4 ml of cold water

H, 11.76% N, found: 28.26% C, s'' . cis-3-[]2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer). The solution is chromatographed on a Dowex 50W column (1^forma) (10 ml), eluting with water. The fractions that absorb in the UV region are combined and concentrated under reduced pressure.

The concentrate is chromatographed on a Sephadex LH-20 column. The eluate is lyophilized.

Cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced as a colorless powder.

IR spectrum (V cm ^-1 ): 1775, 1730, 1670, 1630, 1280 and 1050. NMR spectrum (DMSO-dg, ppm): 1.50 <6H, s, 2 x CH ₃ >, 3.63 (3H, s, COOCH ₃ ), 4.53 (1H, d, J = 6 Hz, C ₄ ~H),

5.45 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H), 6.87 (1H, s, S _in H), 9.29 (1H, d, J = 9 Hz, C ₃ ~NH).

For C ₁₄ H ₁₇ N ₅ O ₁₀ S ₂ .2.3H ₂ O calculated: 32.28% C, 4.18% H 4.11% H, 13.20% N.

13.45% N, found: 32.38% C,

Example 2 (1) By the same procedure as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxozaethidine-1-sulfonic acid sodium salt (syn-isomer) was prepared.

IR spectrum (in cm : 3 (DMSO-dg, ppm): 3.6 (s, COOCH ₃ ), C ₄ -H), 5.38 (dd, J = 6 Hz, J = 8

400, 3,222, 1,780, 3.84 (s, =N-OCH ₂ ), Hz, C ₃ ~H), 7.23 (s.

735, 1 4.29 (s,

670 and 1,055. NMR spectrum

C1-CH ₂ -), 4.45 (d, 9.41 (d, J = 8 Hz,

(2) To 2 ml of an aqueous solution containing 85 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was added 23.85 mg of monomethyldithiocarbamic acid sodium salt under ice-cooling and stirring. Stirring was continued for 40 minutes at room temperature. Another 7 mg of monomethyldithiocarbamic acid sodium salt was added.

Stirring was continued for another 30 minutes. The reaction mixture was then filtered. The filtrate was washed with ether. The aqueous layer was purified by column chromatography on Amberlite XAD-II and then lyophilized. The sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was produced.

^{cm max!} 3350, 1775, 1055. NMR spectrum (DMSO-dg, ppm): 3.61 (s, , =N-OCH ₃ ), 4.45 (d, J = 6 Hz, C ₄ -H), 5.35 (dd, J = 6 Hz, H = 8 Hz, C ₃ ~H), 7.1 (br s,, -NH ₂ ), 9.33 (d, J = 8 Hz, NH 1-.).

IR spectrum COOCH ₃ ), 3.81 (s 6.56 (s, S,yH),

AND

O (3) Dissolve 300 mg of the lyophilized sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) prepared in paragraph 2 in 3 ml of water. The mixture is stirred for a while. The solution first becomes cloudy, then crystals develop.

The mixture was allowed to stand overnight under cooling. Then, 10 ml of ethanol was added and the mixture was cooled for another 3 hours. The resulting crystalline precipitate was filtered off and dried. This gave the monohydrate of the above compound as colorless crystals (241 mg), mp 235-245 °C (dec.).

IC spectrum < ^v ^ _ax » cm L: 1,785, 1,750 and 1,690. For ₃ H _3n N,.NaOgS ₂ ·H ₂ O calculated:

29.53% C, 3.15% H, 15.66% N, found: 29.48% C, 3.13% H, 15.54% N.

Example 3 (1) In the same manner as in Example 1 (1) and (3), cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

in π.- — 1

IR spectrum (V _max » ^cm ) ppm): 1.95 (s, -OCOCHj), 3.83 5.15 (dd, J = 4 Hz, J = 8 Hz,

400, 3.250, 1760, 1665 and 1045. NMR spectrum (DMSO-dg, (s, =N-OCH ₃ ), 3.8 to 4.4 (m, C ₄ ~H and -CH ₂ OCO), 4.3 (s, C1CH ₂ C ₃ -H), 7.3

9.3 (d, J = 8 Hz, NH

(2) Under ice-cooling and stirring, 41 mg of monomethyldithiocarbamic acid sodium salt is added to 4 ml of an aqueous solution containing 150 mg of cis-4-acetoxymethyl-3-[2-(2-chloroacetaAido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer).

The mixture is stirred for 30 minutes at room temperature. Another 10 mg of sodium salt of monos· methyldithiocarbamic acid is added. Stirring is continued for another 30 minutes. The reaction mixture is filtered. The filtrate is then washed with ether, the aqueous layer is purified by column chromatography on Amberlite XAD-II. After lyophilization, the sodium salt of cis-4-acetoxymethyl-3-[]2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced.

IR spectrum (in

KBr max'

425, 3300, 1760, 1660 and 1050. NMR spectrum (DMSO-dg, =N-OCH ₃ ), 3.9 to 4.4 (m, C ₄ ~H and -CH ₂ OCO), 5.15 (dd, J = ppm): 1.94 (s, -OCOCHj), 3.78 (a = 4.5 Hz, J = 8 Hz, C ₃ -H), 6.66 (s, S^. H), 7.1 (br s, -NH ₂ ), 9.2 (d,

J = 8 Hz, -NH

).

-1.

Example 4

Acylation according to Example 1 (3) produces the sodium salt of cis-3-benzyloxycarboxamido-4-(1-methyl-5VT3y> _1

-tetrazolylthiomethyl)-2-oxoazetidine-1-sulfonic acid. IR spectrum (in ^ΛβΑ / cm ): 3,300, max

775, 1690 and 1055. NMR spectrum (DMSO-dg, ppm): 8.87 (s, -NCHj), 3.8 to 4.3 (m, C^-H and CH ₂ S-), 4.96 (dd, J = 5 Hz, J = 10 Hz, C^-H), 5.1 (s, -CH ₂ O-), 7.35 (s, -CgHg), 8.16 (d, J = 10 Hz, -NH).

Example 5

In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (anti isomer) was prepared.

KRr — 1

IR spectrum (V ^cm ) with 1,760, 1,670 and 1,040. NMR spectrum (DMSO-dg, ppm): 3.69 (s, -COOCH ₃ ), 3.98 (s, N0CH ₃ ), 4.35 (s, C1-CH ₂ ~), 4.49 (d, J = 6 Hz, C ₄ ~H), 5.41 (dd, J = = 6 Hz, J = 9 Hz, C ₃ -H), 7.99 (s, S-^H) ' ^{9.14 (d} ' ^J = ⁸ Hz, ^NH —-1 )· y—n O (2) To 2 ml of aqueous solution containing 85 mg of sodium salt cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (anti isomer), 21 mg of sodium salt of monomethyldithiocarbamic acid is added under ice-cooling and stirring. The mixture is stirred for one hour at room temperature.

Another 7 mg of monomethyldithiocarbamic acid sodium salt was added. Stirring was continued for another hour. The reaction mixture was filtered. The filtrate was washed with ether. The aqueous layer was purified by column chromatography on Amberlite XAD-II and lyophilization. The sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (anti-isomer) was produced.

VJJy — 1

IR spectrum (V , cm ): 1,760, 1,050. NMR spectrum (DMSO-d _c , ppm); 3.68 (s, -COOCH-), max o J

3.92 (s, =NOCH ₃ ), 4.46 (d, J = 6 Hz, C ₄ »H), 5.36 (dd, J = phi Hz, J = 8 Hz, C ₃ ~H), 7.03 (broad singlet, “ ^N H ₂ ),

7.38 (s, S _V H), 9.04 (d, J = 8 Hz, NH

Example 6

In the same manner as in Example 1 (1) and (3), the sodium salt of cis-4-methoxycarbonyl-3-phenylacetamido-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (in cm h: 1,770,

740, 1650, 1255 and 1055. NMR spectrum (DMSO-dg, ppm): 3.46 (CH ₂ CO and OCH ₃ ), 4.39 (d,

J = 6 Hz), 5.25 (dd, J = 6 Hz, J = 8 Hz), 7.24 (s, phenyl protons), 8.82 (d, CONH).

Example 7

In the same manner as in Example 1 (1) and (3), sodium salt of cis-4-acetamidomethyl-3-phenyl-acetamido-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (V cm S: 3,400 (broad band), 1,760, 1,640, 1,515, 1,255 and 1,050. NMR spectrum (D^O.-ppm): 1.91 (s, COCHj), 3.52 (d, J = 6 Hz, CH ₂ N), 3.68 (s, CH ₂ CO), 4.37 (dd, J = 5.5 Hz, J = 6 Hz, Cj-H), 5.19 (d, J = = 5.5 Hz, C ₃ -H), 7.38 (m, CgHg).

Example 8 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum (in cm ^-1 ): 3,600 to 3,200, 1,790 to 1,750, 1,700 to 1,670 and 1,055.

NMR spectrum (DMSO-dg, ppm): 1.23 (3H, t, J = 6 Hz, CH ₂ CH ₃ ), 3.62 (3H, s, CHOOOCHj), 4.12 (2H, q, J = 6 Hz, CH^Hj), 4.34 (2H, s, CICHj), 4.49 (1H, d, J = 6 Hz, C ₄ ~H) , 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 7.29 (1H, s, S·^, H) , 9.40 (1H, d, J = 9 Hz, C ₃ -NH), 12.92 (1H, broad singlet, CICI^CONH). AND.

(2) To a solution of 110 mg of sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) in 8 ml of water, 30 mg of sodium salt of monomethyldithiocarbamic acid is added under ice-cooling.

The mixture was stirred for one hour at room temperature. Then, another 10 mg of monomethyldithiocarbamic acid sodium salt was added to the reaction mixture. The reaction mixture was stirred for another hour. The resulting reaction mixture was filtered and the filtrate was washed with ether. The aqueous layer was purified by column chromatography on Amberlite XAD-II and then lyophilized.

The sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced. IR spectrum (1/ cm ^-1 ): 3,500 to

300, 1,790 to 1,750, 1,680, 1,625 and 1,055. NMR spectrum (DMSO-d6, ppm): 1.21 (3H, t,

J = 7 Hz, CH ₂ CH ₃ ), 3.61 (3H, s, COOCHj), 4.07 (2H, q, J = 7 Hz, CH ₂ CH ₃ >, 4.47 (1H, d, '

J = 6 Hz, C ₄ -H) , 5.39 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H) , 6.56 (1H, s, S ^1K br s, NH ₂ ), 9.30 (1H, d, J = 9 Hz, Cj-NH).

For ^c i ₂ ^H 14 ^N 5 ^NaO 8 ^S 2' ^2H 2° calculated: 30.06% C, 3.78% H, 14.61% N, found: 30.33% C,

3.53% H, 14.76% N.

Example 9 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-propoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum (V , cm ^-1 ):-3 250, 2 970, 1 780, 1 750, 1 680 and 1 055. NMR spectrum (DMSO-dg, ppm): 0.89 (3H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 1.65 (2H, sextet, J = 7 Hz, C^CHjCHj).

3.60 (3H, s, COOCH ₃ ), 4.01 (2H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 4.32 (2Η, s, CICH^, 4.48 (1H, d, J = 6 Hz, C ₄ -H) ), 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H) , 7.25 (1H, s, S-^,Η) , 9.4 (1H, s, J = 9 Hz, C ₃ -NH), 12.9 (1H, br s, CICHjCONH).

(2) In the same manner as in Example 8 (2), sodium salt of cis-3-[2-(2-amino-4-thiazolyl)+2-(propoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (V _cn ,-1) . _{3 425} , χ 780, 1 750, 1 680, 1 620 and 1 055.

NMR spectrum (DMSO-dg, ppm): 0.88 (3H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 1.62 (2H, sextet, J = 7 Hz,

CH ₂ CH^CH ₃ ), 3.61 (3H, s, COOCHj), 3.98 (2H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 4.48 (1H, d, J = 6 Hz,

C ₄ -H) , 5.4 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) , 6.52 (1H, s, SyH), 7.14 (2H, br s, NH ₂ ) ,

9.31 (1H, d, J = 9 Hz, C 1 -NH). -AND

For Cl ₃ NlgN ₅ NaOgS ₂ .2H ₂ O calculated: 31.64% C, 4.09% H? 14.19% N, found: 31.70% C, 3.81% H, 14.43% N.

Example 10 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-isopropoxyiminoacetamido]-4-methoxycarbonyl-2-oxozaethidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum ( _in ^KBr , cm ^-1 ): 3,600 to 3,300, 1,780 to 1,750, 1,700 to 1,670, 1,055. max

NMR spectrum (DMSO-dg, ppm): 1.23 (6H, d, J = 6 Hz, CH(CH ₃ > ₂ ), 3.62 (3H, s, COOCHp, 4.31 (1H, m, CH(CH ₃ ) ₂ ), 4.33 (2H, s, C1CH ₂ >, 4.50 (1H, d, J = 6 Hz, C ₄ ~H), 5.45 (1H, ad, J = = 6 Hz, J = 9 Hz, C ₃ -H), 7.24 (1H, s, Sy Η), 9.32 (1H, d, J = 9 Hz, C ₃ ~NH), 12.90 (1H, broad singlet, CICHjCONH). X (2) In the same way as in example 8 (2) the sodium salt is prepared cis-3-[2-(2-amino-4-thiazolyl)-2-isopropoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

iC spectrum (V cm ^{2 3} ΠΧα,Χ

NMR spectrum (DMSO-d _g , ppm): (1H, septet, CH(CH ₃ ) ₂ ), 4.47 C ₃ -H) , 6.53 (1H, s, Η) , ): 3600 to 3200, 1780 to 1750, 1680, 1620 and 1055.

1.20 (6H, d, J = 6 Hz, CH(CH ₃ ) ₂ ), 3.62 (3H, s, COOCH ₃ >, 4.27 (1H, d, J = 6 Hz, C ₄ -H), 5.41 (1H, dd, J = 6 Hz, J = 9 Hz,

7.12 (2H, br s, NH ₂ ), 9.18 (1H, d, J = 9 Hz, Cj-NH).

For C ₁₃ H _lg N ₅ NaOgS ₂ .2H ₂ O calculated: 31.64% C, 3.85% H, 14.37% N.

4.09% H? 14.19% N, found: 31.92% C,

Example 11 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(butoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IC spectrum (V

KBr max' ): 2,960, 1,780, 1,750, 1,680 and 1,055.

NMR spectrum (DMSO-d _g , ppm): 0.89 (3H, t, J = 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.1 to 1.8 (4H, m, CH ₂ -CH ₂ CH ₂ CH ₃ ), 3.60 (3H, s, COOCH ₃ ), 4.04 (2H, t, J = 6 Hz, CH ₂ CH ₂ CH 2 CH ₃ ). ₃ ), 4.30 (2H, s, C1CH ₂ ), 4.49 (1H, d, J = 6 Hz, Cjj-H) , 5.42 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H) , 7.20 (1H, s, ^S ^jj--H) , 9.37 (1H, d, J = 9 Hz, C 1 -NH).

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-(butoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum (V ^cm L ^: 3,450 to 3,350, 1,790 to 1,750, 1,680, 1,620,

050. NMR spectrum (DMSO-d _g , ppm): 0.89 (tj 3H, J = 6 Hz, CH^CH ₂ CH ₂ Cg ₃ ), 1.1 to 1.8 (4H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 3.61 (3H, s, COOCH ₃ ), 4.01 (2H, t, J = 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.47 (1H, d, J = 6 Hz, C ₄ -H) , 5.39 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H) , 6.54 (1H, s, S^-H) , 7.13 (2H, br s, NH ₂ ), 9.3 (1H, d, J = 9 Hz, Cj-NH). X

For C ₃₄ H _lg N _g NaOgS ₂ .2H ₂ O calculated: 33.13 i C, 4.37% H, 13.80% N, found: 33.01% C, 4.10% H, 13.85% N.

Example 12 (1) In the same manner as in Example 1 (1) and (3), cis-3-[]2-(2-chloroacetamido-4-thiazolyl)-2-benzyloxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^-1 ): 3,550 to 3,250, 1,780, 1,750, 1,680 and 1,055.

(DMSO-dg, ppm): 3.52 (3H, s, COOCHp, 4.33 (2H, s, CICH^ , 4.51 (1H, d, J = 5.16 (2H, s, phenyl-CH ₂ ), 5.49 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H)), '7.27 (1H, 7.38 (5H, s, phenyl protons, 9.59 (1H, d, J = 9 Hz, Cj-NH), 12.9 (1H, br cich ₂ conh).

NMR spectrum

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-benzyloxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn-isomer) was prepared. IR spectrum (V^^, cm ³ ): 3450 to 3325, 1780, 1750, 1675, 1620 and 1055. NMR spectrum (DMSO-d _g , ppm): 3.54 (3H, s, COOCHj), 4.49 (1H, d, J = 6 Hz, C ₄ ~H), 5.12 (2H, s, phenyl-CH ₂ ), 5.42 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H) , 6.57 (1H, s, S^H) , 7.16 (2H, br s, NH ₂ ) , 7.37 (5H, s, phenyl protons), 9.48 (1H, d, J = 9 Hz, C 1 -NH).

and

For ^c 17 ^H 16 ^N 5 ^NaO g ^s 2·2H ₂ O calculated: 37.70 8 C, 3.72 % H. 1.93 8 N, found: 37.26 8 C,

3.37% H, 12.93% N.

Example 13 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(5-chloro-2-chloroacetamido-4-thiazolyl)-2-(methoxyiminoacetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum (γ^Br, _cm - ¹ ): 1790, 1740, 1680, 1550 and 1060. NMR spectrum (DMSO-dg, ppm): 3.63 (3H, s, COOCHj ), 3.89 (3H, s, NOCHj ), 4.37 (2H, s, CICHj ), 4.46 (1H, d, J = = 6 Hz, C ₄ -H), 5.40 (1H, dd, J = 6 Hz, Cj-H), 9.48 (1H, d, J = 9 Hz, Cj-NH), 13.1 (1H, br s, CICHjCONH).

(2) In the same manner as in Example 8 (2), cis-3-[2] (2-amino-5-chloro-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in _cn) -lj . _{3 400} , j ₇₈₀ , j ₇₅₀ , j ₆₈₀ , j _620< ] _{540 and} j ₀₆₀ . NMR spectrum (DMSO-dg, ppm): 3.64 (3H, s, COOCHj), 3.83 (3H, s, NOCHj), 4.44 (1H, d, J = 6 Hz, C ₄ -H),

5.36 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 7.30 (2H, s, NH ₂ ), 9.32 (1H, d, J = 9 Hz, Cj-NH).

For C ₁₁ H ₁₁ ClN ₅ NaO _g S ₂ .2H ₂ O calculated: 26.43 8 C, 3.02 8 H, 14.01 8 N, found: 26.11 8 C, 3.15 8 H, 14.13 8 N.

Example 14 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(butoxycarbonyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

KRr — 1

IR spectrum (in _max > cm ) ^! 3250, 1780, 1740, 1680 and 1060. NMR spectrum (DMSO-dg, ppm): 0.73 to 1.73 (7H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 3.86 (3H, s, NOCHj ), 4.43 (2H, s, CICH^ , 4.46 (1H, d, J = 5 Hz, C ₄ -H), 5.40 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), 7.30 (1H, s, S^H),

9.41 (III, d, J = 9 Hz, C ₃ -NH), 11.93 (1H, br s, C1CH ₂ CONH). A (2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(butoxycarbonyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum (V ^ax' ^{cm :} 3450, 3220, 1790, 1750, 1670 and 1050. NMR spectrum (DMSO-dg, ppm): 0.7 to 1.76 (7H, CH ₂ CH ₂ CH ₂ CH ₃ ), 3.80 (3H, s, NOCH ₃ ), 4.00 (2H, t, CH ₂ CH ₂ ~ CH ₂ CH ₃ ) , 4.43 (1H, d, J = 5 Hz, C ₄ ~H) , 5.33 (1H, dd, J = 5 Hz, J = 9 Hz, CjH) , 6.56 (1H, s, ΰ-,ΙΙ), 7.13 (2H, br s, NH ₂ ) , 9.41 (1H, d, J = 9 Hz, (C2-NH) .

For C ₁₄ H ₁₈ NgNaOgS^.H ₂ O calculated: 34.35% C, 4.11 8 H, 14.30% N, found: 34.51 8 C, 4.07 8 H, 14.42% N.

Example 15 (1) In the same manner as in Example 1 (1) and (3), trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (v _max , s, COOCH^), 3.9 (3H, s, dd, J = 2 Hz, J = 9 Hz, cm ^-3 !: 1,780, 1,670 and 1,550. NMR spectrum (DMSO-dg, ppm): NOCH ₃ ), 4.1 (1H, d, J = 2 Hz, C ₄ ~H), 4.35 (2H, s, C1CH ₂ ), C 1 -H), 7.4 (IR, s, S - 2 H), 9.6 (1H, d, J = 9 Hz, C 1 -NH).

X

3.7 (3H,

4.8 (1H, (2) In 2 ml of water, 50 mg of trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) prepared in Example 1 was dissolved. 15 mg of monomethyldithiocarbamic acid sodium salt was added to the suspension while cooling with an ice-water mixture and stirring. The mixture was stirred at room temperature for 30 minutes.

Another 15 mg of monomethyldithiocarbamic acid sodium salt was added and the mixture was stirred for 30 minutes. The reaction mixture was filtered. The filtrate was washed with ether. The aqueous layer was chromatographed on an Amberlite XAD-II column. The eluate was lyophilized. The sodium salt of trans-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was produced.

IC spectrum (' ^U max' cm : 3400 and 1780. NMR spectrum (DMSO-d^, ppm): 3.70 (3K, s, COOCH ₃ ), 3.85 (3H, s, NOCH ₃ ), 4.10 (1H, s, d, J = 2 Hz, C^-H), 4.77 (1H, dd, J = 2 Hz,

J = 9 Hz, C-.-H) , 6.70 (1H, s, S ^H), 7.20 (2H, br s, NH _? ) , 9.47 (1H, d, J = 9 Hz, C--NH) , λ

Example 16 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared.

IR spectrum cm ^-1 ): 3,600 to 3,200, 1,790 to 1,760, 1,680, 1,060. NMR spectrum (DMSO-d _g ppm): 3.26 (2H, s, S

Xc ), 3.56 (3H, s, COOCH ₃ ), 4.32 (2H, s, C1CH ₂ ), 4.43 (1H, d,

J = 6 Hz, Cjj-H) , 5.29 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H) , 6.92 (1H, s, S _v/ H), 8.70 (1H, d, J = 9 Hz, C ₃ -NH), 12.56 (1H, br s, C1CH ₂ CONH) .

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR spectrum ^cm_1 ): 3330, 1790 to 1750, 1680, 1625 and 1060. NMR spectrum (DMSO-d _g , ppm): 3.32 (2H, s, CH ₂ ), 3.59 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 6 Hz, C ₄ ~H), 5.29 (1H, dd, J = 6 Hz, J = = 9 Hz, C,-H), 6.28 (1H, s, S ,H), 7.20 (2H, br s, NH„), 8.59 (1H, d, J = 9 Hz, C,-NH).

X

For C ₁₀ H _1:l N ₄ NaO ₇ S ₂ .H ₂ O calculated: 29.70% C, 3.24% H, 13.85% N, found: 29.98% C, 3.49% H, 13.53% N.

Example 17

In the same manner as in Example 1 (1) and (3), cis-3-[D-2-[4-(butyl)-2,3-dioxo-1-piperazinecarboxamido]-2-phenylacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared.

Ich spectrum (in ^KBr , cm ¹ ): 1,775, 1,720 and 1,685. ^r max

Example 18

In the same manner as in Example 1 (1) and (3), sodium salt of cls-3-[D-2-[4-(butyl)-2,3-dioxo-1-piperazinecarboxamido]-2-(2-thienyl)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared.

IC spectrum ( , ^KBr , cm ^-1 ): 3,300, 1,775, 1,710 and 1,675. ^c ' max

Example 19

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[D-2-[4-(octyl)-2,3-dioxo-1-piperazinecarboxamido]-2-(2-thienyl)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. X-ray spectrum (λmax' ^{cm 3} 400, λ 760 and 1 670.

Example

In the same manner as in Example 1 (1) and (3), trans-3-D-2-[4-(octyl)-2,3-dioxo-1-piperazinecarboxamido]-2-(2-thienyl)-acetamido'-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR spectrum (V j^ax' ^{crn :} * ⁿ 680.

Example 21 (1) By following the same procedure as in Example 1 (1) and (3), sodium salt of cis-4-acetamidomethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonic acid (syn-isomer) was produced.

IC spectrum (in cm ^-1 ): 3,340, 1,770, 1,660, 1,650, 1,275 and 1,050. NMR spectrum (DMSO-d 6 , ppm): 1.84 (3H, s, COCH 3 ), 3.1 to 3.4 (2H, m, CH ₂ NH ), 3.84 (311, s, NOCH ₃ > , 3.9 to

4.2 (1H, m, C ₄ ~H) , 4.40 (2H, s, C1CH ₂ ), 5.19 (1H, ad, J = 5 Hz, J = 9 Hz, CjH) , 7.51 (1H, s, H), 9.40 (1H, d, J = 9 Hz, C ₃ -NH), 12.65 (3H, broad singlet, ClCHjCONH).

(2) In the same manner as in Example 8 (2), sodium salt of cis-4-acetamidomethyl-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidomethyl]-2-oxoazetidine-1-sulfonic acid (syn-isomer) was prepared. IR spectrum (V _CJT , λ . 3400, 1765, 1660, 1540, 1280, 1250 and 1050.

NMR spectrum (DMSO-d2 ppm): 1.77 (3H, s, COCH2), 3.20 to 3.60 (2H, m, C12NH),

3.86 (3H,

NOCH ₃ ), 3.8 to 4.1 (1H, m, C ₄ ~H), 5.12 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 6.81 (1H,

H), 7.15 (2H, br s, NH _? ), 9.33 (1H, d, J

For C._N,

15 6

4.12% H, 17.34% N.

Example 22 (1) In the same manner as in Example 1 (1) and (3), cis-4-benzamidomethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in λx' cm^): 1,770, 1,645, 1,550, 1,280 and 1,050. NMR spectrum (DMSO-dg, ppm): 3.3 to 3.6 (2H, m, CH^NH), 3.92 (3H, s, NOCH^, 4.0 to 4.3 (1H, m, C ₄ “H), 4.45 (2H, s, C1CH ₂ ), 5.28 (1H, dd, J = 5 Hz, J = 8 Hz, C ₃ “H), 7.54 (1H, s, S. ,H), 7.4 to 7.9 (5H, m, phenyl protons), 9.49 (1H, d, J ~ 9 Hz, C ₃ ~NH). Á, (2) In the same way as in Example 8 (2) the sodium salt is prepared cis-3-[_2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-benzamidomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (V cm^): 1,765, 1,645, 1,280 and 1,050. NMR spectrum (DMSO-d6, ppm):

3.3 to 3.7 (2H, m, CH ₂ NH), 3.86 (3H, s, NOCH ₃ ), 3.9 to 4.3 (1H, m, C ₄ “H), 5.23 (1H, dd,

J = 5 Hz, J - 9 Hz, C ₃ -H) , 6.82 (1H, s, S^H), 7.17 (2H, br s, NH ₂ ) , 7.4 to 7.9 (5H, m, phenyl protons), 9.36 (1H, d, J = 9 Hz, C^-NH).

For C^^H^^NgNaO^S ₂ .2H ₂ O calculated: 37.78% C, 3.92% H, 15.55% N, found: 37.51% C, 3.73% H, 15.67% N.

Example 23 (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetamido)-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine-1-sulfonic acid was prepared.

IR spectrum (V_i, cm 11aX (DMSO-d 6 , ppm): 3.83 to 3.89

4.4 (2H, m, CH _n OC-), 4.80 to ² II

O

7.19 to 7.53 (2 χ 1H, 2 xs, : 1770, 1765, 1670, 1560, 1275 and 1050. NMR spectrum (2 χ 3H, 2 xs, 2 x NOCH ₃ ), 4.31 (4H, s, 2 x CICHp , 4.1 to 5.10 (1H, m, C/H), 5.31 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), x S, , H) , 9.34 (1H, s,

X

J = 9 Hz, C3- _NH ).

For C2QH^^Cl2NgNaO^^S ₃ .4^0 calculated: 29.67% C, 3.36% H, 29.53% C, 3.11% H, 13.83% N.

13.84% N, found:

(2) To a solution of 221 mg of sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetamido]-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine-1-sulfonic acid in 10 ml of water, .85 mg of sodium salt of monomethyldithiocarbamic acid was added with stirring under ice-cooling. The mixture was stirred for one hour at room temperature, then 40 mg of sodium salt of monomethyldithiocarbamic acid was added, and the reaction mixture was stirred for another one hour at room temperature.

The reaction mixture was washed with ethyl acetate and ether in that order. Then, the reaction mixture was concentrated under reduced pressure. The concentrate was purified by column chromatography on Amberlite XAD-II. After subsequent lyophilization, cis-3-[2-(2-amino-4-thiazolyl)-(Z)-2-methoxyiminoacetamido]-4-[2-(2-amino-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine-1-sulfonic acid sodium salt was obtained.

IR spectrum (V cm ^): 1760, 1670, 1540, 1275 and 1050. NMR spectrum (DMSO-dg, ppm): 3.80 and 3.86 (2 χ 3H, 2 xs, 2 x NOCH~), 4.1 to 4.4 (2H, m, CH _? OC+), 4.8 to 5.05 (1H,

O m, C^-H), 5.25 (1H, dd, J = 5 Hz, J = 9 Hz, C^-H), 6.63 to 6.94 (2 χ 1H, 2 xs, 2 x group S^H), 7.10 (2H, br s, NH _O ), 9.22 (1H, d, J = 9 Hz, C--NH).

^X3

For C ₁₆ H ₁₇ N ₈ NaO _g S ₃ .3H ₂ O calculated: 30.09% C, 3.63 i H, 17.55% N, found: 30.18% C, 3.51% H, 17.68% N.

Example 24 (1) In 20 ml of methylene chloride, 708 mg of 1-methyl-1H-tetrazol-5-yl-thioacetic acid, which was prepared according to Reference Example 184, was dissolved. 806 mg of thionyl chloride was added under ice-cooling, and the mixture was refluxed for one hour. The reaction mixture was then evaporated under reduced pressure. The residue was dissolved in 10 ml of methylene chloride.

In a mixture of 50 ml of tetrahydrofuran, 50 ml of methylene chloride and 0.5 ml of pyridine, 1 g of cis-3-(p-nitrobenzyloxycarboxamido)-4-hydroxymethyl-2-oxoazetidine, which was prepared according to Reference Example 182, was dissolved. The acyl chloride solution prepared above was added dropwise at room temperature.

The mixture was stirred for 4 hours at room temperature. The product was extracted with a mixture of ethyl acetate and tetrahydrofuran (3:1). The extract was washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate solution, brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by column chromatography on silica gel (140 g, eluting with ethyl acetate:methanol 8:1 to 4:1, starting with pure ethyl acetate). 1.52 g of cis-3-(p-nitrobenzyloxycarboxamido)-4-(1-methyl-1H-tetrazol-5-yl)thioacetoxymethyl-2-oxoazetidine was obtained.

This product was sulfonated in the same manner as in Example 1 (1) above. The sodium salt of cis-3-(p-nitrobenzyloxycarboxamido)-4-(1-methyl-1H-tetrazol-5-yl)thioacetoxymethyl-2-oxoazetidine-1-sulfonic acid was produced.

iC spectrum ('. ^ΧΒι , cm ^): 3 400 , 3 320, 1 760, 1 730 and 1 685. NMR spectrum (DMSO-d,, nuix o ppm): 3.98 (3H, s, N-CIlj) , 4.90 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) . For ^c i6 ^H 16 ^N 7 ^NaO 10 ^S 2' ^H 2° calculated: 33.63 % C, 3.17 * H, 17.16 % N, found: 33.42 % C, 3.06 % H, 17.17 % N.

(2) In a mixture of 20 ml of tetrahydrofuran and 20 ml of water, 1.02 g of sodium salt of cis-3-(p-nitrobenzyloxycarboxamido)-4-(1-methyl-1H-tetrazol-5-yl)thioacetoxymethyl-2-oxoazetidine-1-sulfonic acid is dissolved.

To the solution was added 1 g of 10% palladium on carbon. The mixture was stirred under a hydrogen atmosphere for 5 hours. The catalyst was filtered off. The filtrate was neutralized with aqueous sodium bicarbonate and washed twice with ethyl acetate. The aqueous layer was mixed with 30 ml of tetrahydrofuran. Under ice-cooling, 356 mg of sodium bicarbonate was added to this solution, followed by 1.16 g of 2-(2-chloroacetamido-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetyl chloride hydrochloride.

The mixture was stirred under ice-cooling for one hour. 476 mg of monomethyldithiocarbamic acid sodium salt was added. The mixture was stirred for one hour at room temperature. The reaction mixture was washed twice with ether and evaporated. The residue was purified by chromatography on an Amberlite XAD-II column (elution: water, 20% ethanol and then 30% ethanol).

The eluate is lyophilized. The sodium salt of cls-3-[2-(2^amino-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetamido]-4-(1-methyl-1H-tetrazol-5-yl)thioazoethoxyKBx* -1 methyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced. IR spectrum (V _max < cm ): 3,420,

760, 1,740 and 1,670.

545 mg of the above product was suspended in 2.5 ml of anisole. 12 ml of trifluoroacetic acid was added while cooling to -12°C. The mixture was stirred for 30 minutes at -10 to -13°C. 40 ml of ether and 20 ml of hexane were then added. The resulting solid precipitate was washed three times with 60 ml of ether and then dissolved in 40 ml of water.

Sodium bicarbonate is added and the mixture is filtered. The filtrate is concentrated and purified by column chromatography on Amberlite XAD-II (elution with water). The eluate is lyophilized. The disodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido-1-4-(1-methyl-1H-tetrazol-5-yl)thioacetoxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced.

τλ i,. , KBr -1

IC spectrum (V _max i cm

CH, ): 3400, 3.97 (3H,

760, 1680. NMR spectrum (DMSO-d _g , ppm): 1.38 (3H, s, N-CH ₃ ), 5.27 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H),

6.77 (1H, y ¹ ·

Example 25 (1) By the method of Example 24, the sodium salt of η·8-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-thienylacetoxymethyl)-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (v ^ _ax ' cm ^): 3410, 1765, 1670, 1550, 1270 and 1050. NMR spectrum (DMSO-dg, ppm): 3.72 (2H, br s, Π Π ), 3.95 to 4.52 (1H, m, C ₄ ~H), 4.30 (2H, s, • ^s ch ₂

CÍCH,), 5.25 (1H, dd, J = 6 Hz, J = 9 Hz, C,-H) , 7.41 (1H, s, S...H) ’

X (2) In the same manner as in Example 8 (2), cis-3-[-2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido3-4-(2-thienylacetoxymethyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum (in cm ^-1 ): 3,400, 1,770, 1,740, 1,670, 1,615, 1,535, 1,270, 1,250 and

050. NMR spectrum <DMSO-d _g , ppm): 3.75 (3H, s, NOCH ₃ ), 5.20 (1H, dd, J = 6 Hz, J = 9 Hz, C«-H), 6.71 (1H, s, S-,Η), 7.14 (2H, br s, NH„), 9.22 (1H, d, C,-NH).

X

Example 26 (1) By following the procedure of Example 24, cis-3-[2-(2-Chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazolyl(-5)-thiomethyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^-1 ): 3420, 1765, 1660, 1560 and 1050. NMR spectrum (DMSO-dg, ppm): 3.91 (3H, s, NCH ₃ >, 3.94 (3H, s, OCH ₃ ), 4.34 (2H, s, CICHj), 5.29 (1H, dd, J = 6Hz,

J = 9 Hz, C 1 -H), 7.48 (1H, s, S UI), 9.46 (1H, d, J = 9 Hz, C 1 -NH).

λ (2) In the same manner as in Example 8 (2), cis-3-[_2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido-4-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR (DMSO-d c ₃ -h), , Z KBr -1 spectrum (v _max z cm θ, ppm): 3.88 (3Η, s, 6.75 (1Η, s, Η),

X ): 3,410, 1,770, 1,660, 1

NCH ₃ ), 3.92 (3H, s, OCH ₃ )

7.13 (2H, br s, NH ₂ ), 9.31

610, 1535, 1280 and 1050. NMR spectrum , 5.22 (1H, dd, J = 6 Hz, J = 9 Hz, (1H, d, J = 9 Hz, C ₃ -NH).

For C ₁₂ H ₁₄ N ₉ NaOgS ₃ .2 1/2H ₂ O calculated: 26.46% C, 3.52 i H? 22.70 i N, found: 26.46% C, 3.59 4 H, 22.70% N.

Example

IR spectrum (DMSO-dg, ppm): (2H, s, _C1CH2 ), (2) (1) By the same method as in Example 24, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylthiomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

(V max' ^cm 3 420, 1 760, 1 660, 1 550, 1 270, 1 240 and 1 050. NMR spectrum 2.08 (3H, s, SCH ₃ ), 2.68 to 3.06 (2H, m, CH ₂ S), 3.89 (3H, s, NOCH ₃ ), 4.32 7.42 (1H, s, S^zH) .

By the method as in Example 8 (2), the sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylthiomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum cm ^-1 ): 3,400, 1,760, 1,660, 1,605, 1,535, 1,380, 1,245 and 1,050.

NMR spectrum (DMSO-dg, ppm): 2.08 (s, 3H, SCHj), 2.70 to 3.12 (2H, m, CH ₂ S), 3.71 <3H, s, NOCH ₃ ), 6.74 (1H, s, SyH), 7.14 (2H, broad singlet, NH^ ).

Example 28 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum ( ⁱⁿ _λ in cm ^-1 ): 3420, 1760, 1670, 1560, 1275 and 1055.

NMR spectrum (DMSO-dg, ppm): 1.26 (3H, d, J = 6 Hz, C ₄ -CH ₃ >, 3.98 (3H, s, NOCH ₃ >, 4.32 (2H, s, C1CH ₂ ), 5.10 (1H, dd, J = 6 Hz, J = 9 Hz, C1-H), 7.38 (1H, s, S. . Η), 9.33 (1H, d, J = 9 Hz, C ₃ -NH). X (2) In the same manner as in Example 8 (2), the sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (in cm ¹ ): 3,410, 1,760, 1,660, 1,535, 1,245 and 1,060. NMR spectrum (DMSO-d g , ppm): 1.22 (3H, d, C ₄ -CH ₃ ), 3.82 (3H, s, NOCH 3 ), 5.08 (1H, dd, J = 6 Hz, J = 9 Hz, C 3 -H),

6.72 (1H, s, S. Η), 7.16 (2H, broad singlet, NH.,), 9.24 (1H, d, J = 9 Hz, C ₃ -NH).

Example 29 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-chlorophenyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (DMSO-dg, ppm): 5.32 (1H, dd, J (V

KBr max 3.73 (3H = 5 Hz, / s, J = ) : 3,450, 1,760, 1,665

NOCH ₃ ), 4.30 (2H, s,

Hz, C ₃ -H), 5.75 (1H, , 1 550, CÍCH.,) , ·' Ύ

270 and 1,045. NMR spectrum 5.11 (1H, d, J ~ 5 Hz, C ₄ -H),

H) , 9.23 (1H, <3, J = 8 Hz, C-j-NH) .

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-chlorophenyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum (V^, cm ^-1 ): 3420, 1758, 1660, 1525, 1270 and 1050. NMR spectrum (DMSO-dg + D ₂ O; ppm): 3.88 (3H, s, NOCH ₃ >, 5.11 (1H, s, S^H), 5.33 (1H, d, J = 5 Hz,

C ₄ -H), 5.45 (1H, d, J = 5 Hz, C 1 -H). JL

For C ₃₅ H ₁₃ ClNgNaOgS ₂ .3H ₂ O calculated: 33.61% C, 3.57% H7 13.07% N, found: 33.61% C 3.28% H, 12.77% N.

Example 30 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(N,N-dimethylcarbamoyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

1C spectrum (in _cm 1). j 770, 1,660 and 1,550. NMR spectrum (DMSO-d 6 , ppm): 2.8 a

3.0 (2 χ 3H, 2 xs, N(CH ₃ ) ₂ ),3.86 (3H, s, NOCHj), 4.2 (2H, s, CICHj), 5.0 (1H, d, J = = 6 Hz, C ₄ -H), 5.53 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ “H).

(2) In the same manner as in Example - ___ -- ______ __________ _____ _____ _ _t _______ ____ zolyl)-2-methoxyiminoacetamido]-4-(Ν,Ν-dimethylcarbamoyl)-2-oxoazetidine-1-sulfonic acid;

. KBr -1................... . . ______ .

(2) sodium sul cis (syn isomer) is produced. IR spectrum (in cm ^- '*'):

350, 1780 and 1660. NMR spectrum (DMSO-dg, ppm):

^JL max b

2.8 and 3.0 (2 χ 3H, 2 xs, N(CH ₃ ) ₂ >, 3.83 (3H, s, NOCH ₃ ), 4.93 (1H, d, J = 6 Hz, C ₄ ~H),

5.3 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 6.6 (1H, s, S^-H), 8.96 (1H, d, J = 9 Hz, Cj-NH).

Example

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-(2-thienylacetKBr — 1 amido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (V _max < cm ):

350, 1770, 1680, 1540, 1440, 1260 and 1060. NMR spectrum (DMSO-dg, ppm): 3.53 (3H, s, CH ₃ ), 3.68 (2H, s, CH ₂ ), 4.43 (1H, d, J = 6 Hz, C ₄ ~H), 5.26 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 8.85 (1H, d, J = 9 Hz, NH).

Example 32

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-(1H-tetrazol-1-yl-acetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (V _max >

cm ^-1 ): 3400, 1770, 1700, 1630, 1550, 1440, 1280, 1260, 1180, 1100 and 1060.

NMR spectrum (DMSO-dg, ppm): 3.68 (3H, s, CHj), 4.48 (1H, d, J = 6 Hz, C ₄ -H), 5.26 (2H, s, CH,), 5.29 (1H, dd, J = 6 Hz, J = 9 Hz, C,-H), 9.30 (1H, s, N=N. ), 9.31 (1H, ^{z J} I N_ d, J = 9 Hz, NH). I /

N=C

H

For CgHgNgNaO^S. 1 1/2II ₂ O calculated: 26.01% C, 3.28% H, 22.76% N, found: 25.98% C, 3.25 « H, 22.72% N.

Example 33

In the same manner as in Example 1 (1) and (3), the sodium salt of cis-3-(1*-ethyl-1,4-dihydro-7-methyl-4-oxo-),8-naphthylidin-3-ylcarbonylamino)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared, except that the reaction time was shortened to one hour. , max' 3,450, 1,770, 1,660, 1,615, 1,540, 1,500, 1,450, 1,370, spectrum (DMSO-dg, ppm): 1.40 (3H, t, J = 7 Hz, CH ₂ CH ₃ >, 2.63 (3H, s, COOCH ₃ ), 4.57 (1H, d, J = 6 Hz, C ₄ ~H), 4.58 (2H, quartet, J =

IR spectrum (at 1260 and 1060. NMR

= 7 Hz, CH ₂ CH ₃ ), 5.68 (1H, dd, J = 6 Hz, J = 9 Hz, CjH), 7.49 and 8.58 (2 x 1H, 2 xd, J » J = 9 Hz, NH).

Et

Example 34

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-(2-hydroxy-2-phenylacetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared as a mixture of diastereoisomers. IR spectrum (V cm ¹ ): 3,400, 1,770, 1,680, 1,520, 1,445, 1,380, 1,260, 1,100 and 1,060. NMR spectrum (DMSO-d g , ppm): 3.44 and 3.56 (3H, 2 xs, COOCH ₃ ), 4.43 and 4.44 (1H, xd, J = 6 Hz, C ₄ -H), 4.98 and 5.01 (1H, 2 xs, phenyl-CH), 5.31 (1H, dd, J = 6 Hz, J = = 9 Hz, Cj-H), 7.32 (5H, s, phenyl protons), 8.00 and 8.33 (1H, 2 xd, NH).

Example 35

In the same manner as in Example 1 (1) and (3), the disodium salt of cis-3-(D-2-sulfo-2-phenylacetamido)-4-methoxycarbonyl-1-sulfo-2-oxoazetidine was prepared as a mixture of diastereoisomers.

IR spectrum (V cm ^-1 ): 3,450, 1,770, 1,680, 1,535, 1,440, 1,290, 1,250, 1,100 and 1,055.

NMR spectrum (DMSO-dg, ppm): 3.42 and 3.66 (3H, 2 xs, COOCHj), 4.39 and 4.42 (1H, 2 xd, J = = 6 Hz, C ₄ -H), 4.50 and 4.54 (1H, 2 xs, phenyl-CH), 5.2 to 5.5 (1H, m, C ₃ -H), 7.1 to 7.6 (5H, m, phenyl protons), 8.87 and 8.96 (1H, 2 xd, J = 9 Hz, NH).

Example 36 (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-(2-benzyloxycarbonyl-2-phenylacetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared as a mixture of diastereoisomers.

IR spectrum (in cm^): 3400, 1780, 1750, 1535, 1450, 1260 and 1060. NMR spectrum (DMSO-dg, ppm): 3.02 and 3.42 (3H, 2xs, COOCH-j), 4.36 and 4.45 (1H, 2xd, J = 6 Hz, C ₄ ~H) ,

4.86 and 4.89 (1H, 2 xs, phenyl-CH), 5.12 and 5.15 (2H, 2 xs, phenyl-CH,,) , 5.1 to 5.4 (1H, m, C ₃ ~H), 7.34 (10H, s, 2 x phenyl group), 9.11 (1H, d, J = 9 Hz, NH).

For ^C 21 ^H 19 ^N 2 ^NaO 9 ^S ' ^H 2° calculated: 48.84% C, 4.10% H, 5.42% N, found: 48.60% C,

4.25% H, 5.63% N.

(2) To 6 ml of 80% ethanol, 106 mg of cis-3-(2-benzyloxycarbonyl-2-phenylacetamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt, 106 mg of 5% palladium on carbon and 16.8 mg of sodium bicarbonate were added. The mixture was vigorously stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 3.5 hours.

The reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The concentrate is purified by column chromatography on Amberlite XAD-II. After lyophilization, the disodium salt of cis-3-(2-carboxy-2-phenylacetamido)-4-methoxycarbonyl-1-sulfo-2-oxoazetidine is obtained as a mixture of diastereoisomers.

ΚΒι* — 1

IR spectrum cm ): 3,420, 1,770, 1,670, 1,620, 1,530, 1,380, 1,290, 1,250 and 1,060. NMR spectrum (DMSO-d 6 , ppm): 3.45 and 3.46 (3H, 2 xs, COOCH ₃ ), 4.40 and 4.48 (1H, xd, J = 6 Hz, C ₄ -H), 5.1 to 5.4 (1H, m, C 1 H), 5.59 and 5.62 (1H, 2 xs, phenyl-CH), 7.23 (5H, s, phenyl protons), 8.83 (1H, d, J = 9 Hz, NH).

For C ₁₄ H ₁₂ N ₂ Na ₂ O _g S.3 1/2H ₂ O calculated: 34.08% C, 3.88% H, 5.68% N, found:

34.40% C, 4.13% H, 5.97% N.

Example 37

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-cyanomethylcarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (in ^KBr , cm ^-1 ):

250, 1780, í 740, 1675, 1570, 1048. NMR spectrum (DMSO-dg, ppm): 3.64 (2H, s, CH ₂ ), 3.67 (3H, s, CH ₃ ), 4.48 (1H, d, J = 6 Hz, C ₄ -H), 5.27 (1H, J = 6 Hz, 6 Hz, J = 9 Hz, dd, CjH) , 9.12 (1H, d, J = 9 Hz, NH).

Example 38 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxycarbonylmethyloxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V^, cm ¹ ): 1790 to 1730, 1680, 1550 and 1055. NMR spectrum (DMSO-dg, ppm): 3.6 (3H, s, COOCH-j) , 3.7 (3H, s, COOCH ₃ ), 4.4 (2H, s, C1CH ₂ >, 4.5 (1H, d, J = 6 Hz, C ₄ -H), 4.68 (2H, s, NOCH ₂ ), 5.45 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H), 7.3 (1H, s, S,/H),

9.37 (1H, d, J = 9 Hz, C 1 -NH).

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxycarbonylmethyloxyiminoacetamide]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ¹ ): 3,300, 1,790 to 1,730, 1,670, 1,610, 1,530 and 1,055. NMR spectrum (DMSO-dg, ppm): 3.60 (3H, s, COOCHj), 3.69 (3H, s, COOCH ₃ ), 4.49 (1H, d, J = 6 Hz, C ₄ -H), 4.64 (2H, s, NOCH ₂ ), 5.41 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) , 6.64 (1H, s, S^xH) , 7.18 (2H, br s, NHj), 9.29 (1H, d, J = 9 Hz, C ₃ ~NH). Λ

For C ₃₃ H ₃₄ NgNaO ₃ gS ₂ .2H ₂ O calculated: 29.83% C, 3.47% H, 13.38% N, found: 30.14% C, 3.52% H, 13.48% N.

Example 39 (1) In the same manner as in Example 1 (1) and (3), cis-3-p-(2-chloroacetamido-4-thiazolyl)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)-acetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V , cm ): 3250, 1790 to 1730, 1670, 1520 and 1050. NMR spectrum J = 6 Hz, C ₃ -H), = 9 Hz, C ₃ -H), 7.36 (DMSO-dg, ppm): 3.61 (3H, s, COOCH ₃ >, 4.36 (2H, s, _C1CH2 ), 4.53 (1H, d.

4.82 (2H, s (1H, s,

NIGHT,

5.37 (2H, s, COOCH ₂ ), 5.48 (1H, dd, J = 6 Hz,

S^-H), 9.49 (1H, d, J = 9 Hz, Cj-NH), 12.95 (1H, singlet and broad singlet, _C1CH2CONH

XH (2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in ^KBr , cm ¹ ): 3,450, 3,330, 1,790 to 1,730, 1,680, 1,610 and 1,050.

^Fmax

NMR spectrum (DMSO-dg, ppm): 3.6 (3H, s, COOCH ₃ ), 4.5 (1H, d, J = 6 Hz, C ₄ -H), 4.77 (2H, s, NOCH ₂ ), 5.35 (2H, s, COOCHp , 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H), 6.66 (1H, s, SyH) 7.2 (2H, br s, NH ₂ ), 9.39 (1H, d, J = 9 Hz, Cj-NH).

For ^c 19H ₁₇ NgNaO ₁₂ S ₂ .2 H ₂ 0 calculated: 35.40% C, 3.28% H, 13.04 ϊ N, found:

35.45% C, 3.22% H, 12.83% N.

(3) In a mixture of 25 ml of water and 25 ml of tetrahydrofuran, 500 mg of sodium salt of cis-3-p-(2-amino-4-thiazolyl)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is dissolved.

To the solution was added 500 mg of 10% palladium on carbon. The mixture was stirred for one hour under a hydrogen atmosphere. 25 ml of aqueous sodium bicarbonate solution (66 mg) was added. The catalyst was filtered off. The filtrate was washed with 30 ml of ethyl acetate and concentrated to 10 ml under reduced pressure. The concentrate was chromatographed on an Amberlite XAD-II column, eluting with water.

The first 130 ml fraction is discarded. The immediately following fractions (40 ml) are lyophilized. This produces the disodium salt of cis-3-p-(2-amino-4-thiazolyl)-2-carboxylmethyloxyiminoacetamic acid.

KBr iodo]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer). iC spectrum (\/ _max cm ¹ ): 3,350, 1,780, 1,750, 1,670, 1,600 and 1,055. NMR spectrum (DMSO-dg, ppm): 3.58 (3H, s, COOCH ₃ ), 4.27 (2H, s, NOCH ₂ ), 4.5 (1H, d, J = 6 Hz, C ₄ ~H), 5.37 (1H, dd, J = 6 Hz,' J = = 9 Hz, C ₃ -H) , 6.72 (1H, s, S^/H), ^{7.11 (2H} ' ^{br s} ' ^NH 2 ^! ' ^{11(3 (1} H, d, J = 9 Hz, C ₃ ~NH) ).

For ^c i2 ^H ll ^N 5 ^NaO 2°10 ^S 2' ² 1/2H ₂ O calculated: 26.67% C, 2.98% H, 12.96% N, found:

26.63% C, 3.02% H, 12.93% N.

Example 40 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-allyloxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^_1 ): 3250, 1780, 1750, 1680 and 1055. NMR spectrum (DMSO-dg, ppm): 3.60 (3H, s, COOCH ₃ >, 4.32 (2H, s, C1CH ₂ ), 4.49 (1H, d, J = 6 Hz, C ₄ -H), 7.27 (1H, s, SH), 9.49 (1H, d, J = 9 Hz, C, -NH).

X (2) In the same manner as in Example 8 (2), cis-[2-(2-amino-4-thiazolyl)-2-allyloxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum (V ^cm: 3,325, 1,790 to 1,740, 1,670 and 1,050. NMR spectrum (DMSO-dg, ppm): 3.60 (3H, s, COOCH-j), 4.4 to 4.7 (3H, m, CH ₂ CH=CH ₂ and C ₄ ~H), 5.0 to 5.5 (3H, m, CH ₂ CH=CH ₂ and CjH), 5.7 to 6.2 (1H, m, CH ₂ CH=CH ₂ > , 6.56 (1H, s, S y H), 7.12 (2H, br s, NH ₂ ), 9.39 (1H, d, J = 9 Hz, Cj-NH). *·

For C. _O H.,N _c Na0 _o S _n .l 1/2H.0 calculated: 32.36% C, 3.55% H, 14.52% N, found:

0 0 6 6

32.47% C, 3.75% H, 14.46% N.

Example 41 (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloromethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum cm ): 1,770, 1,670, 1,550, 1,270 and 1,055.

NMR spectrum (DMSO-dg, ppm): 3.89 (3H, s, NOCH ₃ >,.4.34 (2H, s, C1CH ₂ ), 5.28 (1H, dd, J =' 6 Hz, J = 9 HZ, C ₃ -H), 7.38 (1H, s, S_, H), 9.37 (1H, d, J = 9 Hz, Cj-NH), 1.90 (1H, br s, C1CH ₂ CONH ₂ ). Λ (2) In the same manner as in Example 8 (2), the sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloromethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (V^, cm ^-1 ): 1,770.1 660, 1610, 1530, 1270 and 1050.

For C ₁₀ H _1:1 ClN ₅ NaOgS ₂ .2H ₂ O calculated: 26.35% C, 3.32% H, 15.36% N, found: 26.31% C, 3.18% H, 15.33% N.

Example 42 (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-S-[2-(2-chloroacetamido-4-thiazolyl)-2-methyloxyiminoacetamido]-4-methylsulfonyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was obtained.

IR spectrum (v™^, ^cro_1 ): 1770, 1670, 1560, 1350, 1275, 1175 and 1050. NMR spectrum (DMSO-dg, ppm): 3.10 (3H, s, SOOCHj ), 3.90 (3H, s, NOCH-j ), 4.35 (2H, s, C1CH ₂ ) , 5.33 (1H, dd, J = 5 Hz, J = 9 Hz, C _? -H) , 7.41 (1H, s, SH) , 9.42 (1H,'d, J = 9 Hz, Cj-NH) , 12.91 (1H, br s, C1CH ₂ CONH). X (2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylsulfonyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in ^KBr , cm^): 1,770, ^c max

NMR spectrum (DMSO-dg, ppm): 3.10 (3H, = 5 Hz, J = 9 Hz, C ₃ -H), 6.74 (1H, s,

670, 1620, 1535, 1s, SO ₂ CH ₃ ), 3.86 (3H,

S .,H), 9.30 (1H, d, J

350, 1280, 1175 and 1055. s, NOCH ₃ ), 5.28 (1H, dd, J = = 9 Hz, C ₃ -NH).

For C ₃₃ H ₃₄ NgNaOgS ₃ .2H ₂ O calculated: 25.63% C, 3.52% H, 13.59% N, found: 25.64% C, 3.41% H, 13.56% N.

Example 43 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido-4-benzoyloxymethyl]-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V ^ ^Br , _C m S: 3250, 1770, 1720 to 1660, 1545 and 1050. NMR spectrum max (DMSO-dg, ppm): 3.69 (3H, s, NOCHg), 4.35 (2H, s, C1CH ₂ ), 5.32 (1H, dd; J = 6 Hz, J = 9 Hz, C1-H) , 7.35 (1H, s, S . , H).

A (2) In the same manner as in Example 3 (2), sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyaminoacetamido]-4-benzoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (γ cm h ^{1 8} 300, 1 770, 1 710, 1 665 and 1 050. NMR spectrum (DMSO-dg ppm): 3.67 (3H, s, NOCH ₃ ), 5.28 (1H, dd, J = 6 Hz, J = 9' HZ, Cj-H), 6.62 (1H, s, S^H),

7.12 (2H, br s, NH^, 9.38 (1H, d, J = 9 Hz, Cj-NH). A

For C ₁₇ H ₃ gNgNaOgS ₂ .1 1/2H ₂ O calculated: 38.34% C, 3.60% H, 13.15% N, found:

38.23% C, 3.53% H, 13.15% N.

Example 44 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-acetyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V^x' ^{cm :} 3420, 1760, 1 ppm): 2.30 (3H, s, COCH^, 3.85 (3H, s, NOCHj), C ₄ -H), 5.18 (1H, dd, J = 10 Hz, J = 5 Hz, C ₃ ~H)

650, 1,540 and 1,265. NMR spectrum (DMSO-dg 31CH ₂ ),

7.40 (1H, s, S _{K X} H).

4.34 (2H, s, C1CH ₂ ), 4.40 (1H, d, J = 5 Hz, (2) In the same manner as in Example 8 (2), the sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-acetyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

KBr max'

IR spectrum (V ppm): 2.30 (3H, s, t, C ₃ -H), 6.64 (1H, cr/b:

400, 1760, 1660, 1535, 1260 and 1050. NMR spectrum (DMSO-dg, 4.40 (1H, d, J = 5 Hz, C ₄ -H), 5.26 (1H,

COCH ₃ ), 3.81 (3H, S,~NOCH ₃ 'X

H) .

Example

In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-sulfonatooxymethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer) was prepared.

IR spectrum , .KBr -1, (V , cm , ' max' 1:1,765, _year 1,665, 1 545, 1,275, 1,240, 1,055 and 1,030. NMR spectrum (DMSO-dg, ppm): 3.90 (3H, s, NOCHj), 4.35 (2H, s, _C1CH2 ), 5.34 (1H, dd, J = 4.5 Hz, J = = 9 Hz, C ₃ -NH), 7.66 (1H, s, S H) , X 9.38 (1H, d, J = 9 Hz, c ₃ -nh).

Example 46

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum ( ⁱⁿ _λmax ' cm): 1,770, 1,690,

550, 1275 and 1050. NMR spectrum (DMSO-dg, = 6 Hz, CH ₂ SO ₂ ), 3.93 (3H, s (1H, dd, J = 6 Bz, J = 9 Hz, C ppm): 3.97 (3H,

_SOOCH3 ), 3.44 (2H, t, J

NOCH ₃ ), 4.34 (2H, t, J - 6 Hz, COOCH,,), 4.37 (2H, s, C1CH ₂ ),

-H), 7.51 (1H, •X

H) , 9.48 (1H, d, J = 9 Hz, c ₃ -nh).

Example 47 (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-trifluoroacetylaminomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (in ^KB f, cm L: 1,770, 1,710, 1,670, 1,550, max

270 and 1050. NMR spectrum (DMSO-dg, ppm): 3.91 (3H, s, NOCH ₃ >, 4.36 (2H, s, CICH.,), 5.28 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 7.49 (1H, s, S^x H), 9.46 (1H, d, J = 9 Hz, C ₃ ~NH).

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-trifluoroacetylaminomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum ( _λmax , cm L: 1,770, 1,720, 1,670, 1,530 and 1,050. NMR spectrum δ, S _V H), 7.12 (2H, br s, NH ₂ ), 9.35 (1H, d, J = 9 Hz, C^-NH).

(DMSO-dg, ppm): 3.85 (3H, s, NOCHp, 5.17 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H) , 6.80 (1H, ¹

X

For C^2^i2 ^F 3^6 ^Na °7^2'^^2° ⁱⁿ YP°^ ^teno: 26.19% C, 3.30% H, 15.27% N, found: 26.30% C, 3.07% H, 15.05% N.

Example 48

In the same manner as in Example 1 (1) and (3), the beta and alpha isomers of the sodium salt of cis-3-[d-2·-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid were prepared.

IR spectrum (nm, cm ^-1 ): 1,770, 1,710, 1,675 and 1,510.

Example 49

In the same manner as in Example 1 (1) and (3), the beta and alpha isomers of sodium salt of cis-3-[[[2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid were obtained.

IR spectrum ^cm 1,770, 1,705 and 1,665.

max

Example 50

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[D-2-[3-(furan-2-aldimino)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum cm: 1,770 and 1,725,

Example 51

In the same manner as in Example 1 (1) and (3), the beta and alpha isomers of the sodium salt of cis-3-[D-2-[3-(thiophene-2-aldimino)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid were prepared.

Beta-isomer: IR spectrum cm 1 770, 1 735, 1 660, 1 530, 1 405, 1 270 and

235. NMR spectrum (DMSO-dg, ppm): 3.11 (3H, s, COOCHj), 3.80 (4H, s, NCH ₂ CH ₂ N), 4.33 (IH, d, J = 6 Hz, C ₄ -H), 5.30 (IH, dd, J = 6 Hz, J = 9 Hz) (CjtH), 5.55 (IH, d, J = 7 Hz, C 4 -H). phenyl-CH), 8.11 (IH, s, N=CH), 9.07 (IH, d, J = 7 Hz, phenyl-CHNH), 9.22 (IH, d, J = 9 Hz, c ₃ -nh).

Alpha-isomer: IR spectrum (ν^χ, ^{cm 1} ) : 1765, 1740, 1680, 1535, 1405, 1270 and 1240. NMR spectrum (DMSO-dg, ppm): 3.62 (3H, s, COOCHj), 3.80 (4H, s, NCH ₂ CH ₂ N) . 4.45 (IH, d, J = 6 Hz, C ₄ -H), 5.11 (IH, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 5.47 (IH, d, J = 7 Hz, phenyl-CH), 8.10 (IH, s, N=CH).

Example 52

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-methyl-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (cm b): 3,425, 1,770, 1,750, 1,275 and 1,050. NMR spectrum (D ₂ O, ppm): 2.72 (3H, s, CH ₃ x^ S), 3.81 (3H, s, COOCH-j), 4.05 (3H, s, NOCHj), 5.04 (1H, d,

NJ = 6 Hz, C.-H), 5.75 (IH, d, J = 6 Hz, C,-H), 7.68 (IH, s, S</H).

Example (1) In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-diethylphosphonoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum cm ^-1 ): 3,450, 1,770, 1,750, 1,670, 1,540, 1,260, 1,230 and

050.

(2) In the same manner as in Example 8 (2), sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-diethylphosphonoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared.

IC spectrum (V £Br, _cm l,. _{3 40} 0, _{χ 775( χ 750(} χ ₆₇₀₍ χ _510j χ ₂ 70, 1 230 and 1 045.

For C ₁₄ H ₂₀ N ₄ NaO ₁₀ PS ₂ .2H ₂ O calculated: 30.11% C, 4.33% H, 10.03% N, found: 30.39% C, 4.14% H, 10.20% N.

Example 54

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-(2-triethylsilylethylcarboxamido)-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (ν, cm ^-1 ): 3,450, 1,775, 1,745, 1,660, 1,540, 1,260, 1,250 and 1,055. NMR spectrum (DMSO-dg, ppm): 3.61 (3H, s, COOCHj), 4.41 (1H, d, J = 6 Hz, C ₄ ~H), 5.24 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 8.59 (1H, d, J = 9 Hz, Cj-NH).

Example 55 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamino-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-phenylethyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IC spectrum cm ^-1 ): 3,450, 1,750, 1,660, 1,540, 1,260 and 1,045. NMR spectrum (DMSO-dg,+:D ₂ O( ppm): 3.82 (IH, s, NOCH ₃ ), 4.38 (2H, s, C1CH ₂ >, 5.32 (IH, d, J = 6 Hz, (DMSO-dg + D ₂ O, ppm): 3.82 (1H, s, NOCHg), 4.38 (2H Cg-H), 7.34 (5H, s, phenyl protons), 7.42 (1H, s, ^s x

_C1CH2 ), H).

5.32 (1H d, J = 6 Hz, (2) In the same manner as in Example 8 (2), cis-3-^2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamidoJ-4-(2-phenylethyl)-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (DMSO-dg, ppm): S H), 7.10

KRr —1 * (V cm ) : 3,425, 1,750, 1,660, 1,610, 1,520 3.64 (3H, s, NOCHg), 5.15 (1H, dd, J - 6 Hz, J = (2H, br s, NH ₂ ), 9.34 (1H, d, J = 9 Hz, C ₃ -NH).

240 and 1050. NMR spectrum 9 Hz, C ₃ -H), 6.66 (1H,

For ^c 32H^gNgNaOgS ₂ .2 1/2H ₂ O calculated: 39.55% C, 4.21% H, 13.47% N.

39.22% C,

4.45% H? 13.46% N found:

Example

In the same manner as in Example 1 (1) and (3), the sodium salt of cis-3-[2-(2-hydroxy-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared:

IR spectrum (V cm ^-1 ): 3,450, 1,770, 1,750, 1,660, 1,530, 1,440, 1,250 and 1,050.

NMR spectrum (DMSO-d _g , ppm): 3.61 (3H, s, COOCHg), 3.87 (3H, s, NOCHg), 4.50 (1H, d, C ₄ ~H), 5.38 (1H, Cg-H), 6.33 (1H, s, S·^H), 9.60 (1H, Cj-NH).

Example 57 (1) In the same manner as in Example 1 (1) and (3), the following compounds were prepared: syn and anti isomers of sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-[[methoxyiminoacetamide]-4-ethoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

Syn-isomer: IC spectrum cm : 3350, 1770, 1670, 1610 and 1050. NMR spectrum max (DMSO-dg, ppm): 1.19 (3H, t, J = 7 Hz, CHgCHg), 3.86 (3H, s, NOCHg), 4.07 (2H, quartet,

J = 7 Hz, CH ₂ CH ₃ ), 4.36 (2H, s, C1CH ₂ ), 4.46 (1H, d, J = 5 Hz, C ₄ -H), 5.40 (1H, dd, J = = 5 Hz, J = 9 Hz, C-,-ΙΙ) , 7.28 (1H, s, S^zH), 9.44 (1H, d, J = 9 Hz, C, -NH).

X

Anti-isomer: IR spectrum (V cm ¹ ): 3300, 1760, 1660 and 1050. NMR spectrum (DMSO-dg ppm): 1.20 (3H, t, J = 7 Hz, CHgCHg), 3.96 (3H, s, NOCHg), 4.16 (2H, quartet, J = 7 Hz,

CH ₂ CH ₃ ), 4.33 (2H, s, C1CH ₂ ), 4.47 (1H, d, J = 5 Hz, C ₄ ~H), 5.42 (1H, dd, J = 5 Hz, J = = 9 Hz, Cg-H), 8.00 (1H, s, SyH), 9.12 (1H, d, J = 9 Hz, Cg-NH).

(2) In the same manner as in Example 8 (2), the following compounds were prepared: syn and anti isomers of cis-3-[]2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-ethoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt.

syn-isomer: IR spectrum cm ¹ ): 3,450, 3,250, 1,780, 1,730, 1,670. NMR spectrum (DMSO-dg, ppm): 1.18 (3H, t, J = 7 Hz, CH^CHg), 3.80 (3H, s, NOCHg), 4.04 (2H, quartet,

J = 7 Hz, CHgCHg), 4.43 (1H, d, J = 5 Hz, C ₄ ~H), 5.36 (1H, dd, J = 5 Hz, J = 9 Hz, Cg-H), 6.57 (1H, s, Sx/H), 7.12 (2H, br s, NH,), 9.32 (1H, d, J = 9 Hz, C„-NH).

X

For ^c i2 ^H l4 ^N 5 ^NaO 8 ^S 2' ² 1/2 HgO calculated: 29.50% C, 3.92% H, 14.33% N, found:

29.39% C, 3.71% H, 14.09% N.

KBr ¹ -1 anti-isomer: IR spectrum <V _max , cm ): 3,300, 1,770, 1,720 and 1,660. NMR spectrum (DMSO-dg ppm): 1.18 (3H, t, J = 7 Hz, CH ₂ CH ₃ ), 3.90 (3H, s, NOCHj), 4.15 (2H, quartet, J = 7 Hz, CH ₂ CH ₃ ), 4.43 (1H, d, J = 5 Hz, C ₄ -H), 5.36 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), 7.06 (2H, br s, NH„), 7.36 (1H, s, S _x/ H), 9.02 (1H, d, J = 9 Hz, C--NH) .

X

For C^2 ^H i4 ^N 5^ ^aO 8^2*calculated: 29.50% C, 3.92% H, 14.33% N, found:

29.84% C, 3.88% H, 14.17% N.

Example 58 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-phenylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum ( cm ^-1 ): 3450, 3250, 1770, 1680, 1050. NMR spectrum (DMSO-dg, ppm): 3.67 (3H, s, NOCHj), 4.30 (2H, s, CICHp, 4.60 (1H, d, J = 5 Hz, C ₄ ~H), 5.4 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ ~H).

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-phenylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (y

3.66

6.64 (3H, s, (1H, s,

KBr max

9.95 (1H, ^with x

H), 4.55 (1H, , 6.9 to 7.7

300 d, J (5H, = 5 m,

770, 1680 and 1050. NMR spectrum (DMSO-dg, ppm):

Hz, C ₄ -H), 5.36 (1H, dd, J = 5 Hz, J = 9 Hz, C 1 H), phenyl protons), 9.23 (1H, d, J = 9 Hz, C 1 -NH), br s, CONH-phenyl).

Example (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-ethoxycarbonylmethyloxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^-1 ): 1780, 1765, 1740, 1670, 1550, 1280 and 1055. NMR spectrum (DMSO-dg, ppm): 1.19 (3H, t, J = 7 Hz, CH^CH ₃ >, 3.85 (3H, s, NOCHj), 4.11 (2H, q, J = 7 Hz, CH ₂ CH ₃ ), 4.36 (2H, s, CICH^), 4.63 (1H, d, J = 6 Hz, C ₄ ~H), 4.64 (2H, q, J = 15 Hz, OCH ₂ CO), 5.52 (1H, dd, J = 6 Hz, J = 9 Hz, C 4 ~H), 7.31 (1H, s, J = 9 Hz, C 4 ~H). (Sx, H), 9.23 (1H, d, J = 9 Hz, C1-NH).

X (2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido3-4-ethoxycarbonylmethyloxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in cm ^-1 ): 1,770, 1,750, 1,670, 1,535, 1,285 and 1,055. NMR spectrum (DMSO-dg, ppm): 1.20 (3H, t, J = 7 Hz, CH ₂ CH ₃ ), 3.80 (3H, s, NOCHj), 4.12 (2H, q, J = 7 Hz, CH ₂ CH ₃ ), 4.60 (1H, d, J = 6 Hz, C ₄ ~H), 4.64 (2H, q, J = 15 Hz, OCH ₂ CO), 5.48 (1H, dd, J = = 6 Hz, J = 9 Hz, C^-H) , 6.59 (1H, s, δ^,Η), 7.12 (2H, br s, NH ₂ ).

zX

For C ₁₄ H ₁₆ N ₅ NaO ₁₍₎ S ₂ • ^2H 2° calculated: 31.29% C, 3.75% H, 13.03% N, found: 31.38% C, 3.65% H, 12.95% N.

Example (1) In the same manner as in Example 1 (1) and (3), trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum < V™ _x , cm ^-1 ): 3450, 1765, 1730, 1640, 1540, 1250 and 1040. NMR spectrum (DMSO-dg, ppm): 2.04 (3H, s, COCH ₃ >, 3.90 (3H, s, NOCH ₃ ), 4.35 (2H, s, _C1CH2 >, 4.77 (1H, dd, J “ 3 Hz, J = 8 Hz, C ₃ -H) , 7.39 (1H, s, S^ · H) , 9.45 (1H, d, J - 8 Hz, C ₃ -NH) .

(2) In the same manner as in Example 8 (2), trans-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in

KBr max' cm ¹ ) :

420, 1765, 1730, 1660, (DMSO-dg, ppm): 2.01 (3H, s, COCHj), 3.83 (3H, s, NOCH ₃ ), C/H) , 6.70 (1H, s, S^, H) , 7.16 (1H, br s, NH ₂ )J, 9.30 (1H

530, 1245 and 1050. NMR spectrum 4.76' (1H,,dd, J = 3 Hz, J = 8 Hz, , d, J = 8 Hz, C/NH).

^{For ^} 2^14^^8^- ¹ 3.65% H, 14.95% N.

1/2H ₂ O calculated:

30.64:% C,

3.64% H, 14.89% N, found: 30.66% C

Example 61 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum cm ¹ ): 3,250, 1,770, 1,650 and 1,050. NMR spectrum (DMSO-d 6 , ppm):

2.68 (3H, d, J = 5 Hz, NHCHj ), 3.85 (3H, s, NOCHj ), 5.3S (1H, dd, J = 5 Hz, J = 9 Hz, C/H), 7.50 (1H, s, Sv/H).

(2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4′-thiazolyl)-2-methoxyiminoacetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^-1 ) 3350, 1770, 1670, and 1050. NMR spectrum (DMSO-d,-, ppm):

max about

2.60 (3H, d, J = 5 Hz, NHCHj) , 3.80 (3H, s, NOCH ₃ ) , 4.35 (1H, d, J = 5 Hz, C/H) , 5.28 (1H, dd, J = 5 Hz, J = 9 Hz, C/H), 6.86 (1H, s, SyH), 7.13 (2H, br s, NH ₂ ) , 7.65 (1H, d, J = 5 Hz, NHCH ₃ ), 9.01 (1H, d, J = 9 Hz, χ

C/NH) .

Example 62 (1) In the same manner as in Example 1 (1) and (3), trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxylcarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared.

IR spectrum (V _cm ^-1 ) _; 3,400 to 3,200, 2,980, 1,780, 1,740, 1,680 and 1,050.

(2) In the same manner as in Example 1 (4), trans-3-[2-(2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (ω £Br, cm' ¹ ): 3 325, 1 780, 1 740, 1 670, 1 600, 1 520 and 1 050. NMR spectrum (DMSO-dg, ppm): 1.5 (6H, s, 2 x CHj) , 3.69 (3H, s, COOCHj) , 4.15 (1H, d, J = 3 Hz, C/H) , 4.82 (1H, dd, J = 3 Hz, J = 9 Hz, C/H) , 5.33 (2H, s, COOCHp , 6.7 (1H, s, S _V .HI , 7.25 (2H, br s, NH ₂ ) , 7.65 and 8.15 (2 χ 2H, 2 xd, aromatic protons), ' X

9.37 (1H, d, J = 9 Hz, C/NH). For ^c 21 ^H 2i ^N 6 ^NaO i2 ^S 2 . 2 1/2 H ₂ 0 calculated: 37.01% C, 3.84% H, 12.33 i N, found: 36.90% C, 3.78% H, 12.30% N.

(3) In the same manner as in Example 1 (5), trans-3-[2-(2-amino-4-thiazolyl)-2-(1-carboxy-1-methylethoxyimino)acetamide]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer) was prepared. IR spectrum cm ¹ : 3,375, 1,780, 1,745, 1,580 and 1,050.

NMR spectrum (DMSO-dg, ppm): 1.40 and 1.43 (2x 3H, two s, 2x CHp, 3.7 (3H, s, COOCH ₃ ), 4.17 (1H, d, J = 3 Hz, C/H) ), 4.85 (1H, dd, J = 3 Hz, J = 9 Hz, C/H) , 6.73 (1H, s, SyH) , 7.12 (2H, NH ₂ ), 11.7 (1H, J = 9 Hz, C/NH ₎ . For C ₁₄ H ₁₅ N ₅ Na ₂ O _1Q S ₂ .

calculated: 27.41 Ϊ C, 4.11 % Η, 11.42 % N, found: 27.10 % C, 3.90 i H, 11.46 % N.

Example 63 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(1-methoxycarbonyl-1-methylethoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in cm ^-1 ): 3,250, 2,950, 1,780, 1,740 and 1,680. NMR spectrum (DMSO-d g , ppm): 1.46 (6H, s, NOCMe^, 3.63 and 3.66 (1 χ 3H, two singlets, twice COOCH ₃ ), 4.33 (2H, s, C1CH ₂ ), 4.15 (1H, d, J = 6 Hz, C ₄ H) , 5.49 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) , 7.27 (1H, s, S. .H), 9.22 (1H, d, J = 9 Hz, C,-NH), 12.93 (1H, br s, CÍCH,CONH).

X (2) In the same manner as in Example 8 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methoxycarbonyl-1-methylethoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ^-1 ): 3,400, 1,780, 1,735 and 1,670. NMR spectrum (DMSO-d g , ppm):

1.43 (6H, s, NOCMe ₂ ), 3.62 and 3.64 (2 χ 3H, two singlets, 2 x COOCH-j) , 4.48 (1H, d, J = = 6 Hz, C ₄ -H) , 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) , 6.58 (1H, s, J = = 9 Hz, CjH) SyH), 7.2 C2H, s, NH ₂ ), 9.05 (1H, d, J = 9 Hz, Cj-NH). AND

For C ₁₅ H _lg N ₅ NaO ₁₀ S ₂ .2H ₂ O calculated: 32.67 t C, 4.02 % H, 12.70 % N, found: 32.63 % C

3.96% H, 12.43% N.

Example 64 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cn b: 3,400, 1,775 and 1,740, NMR spectrum (DMSO-dg, ppm): 0.92 (2H, CHjSi), 1.45 (6H, s, NOCMe ₂ ), 3.64 (3H, s, COOCH ₃ >, 4.16 (2H, COOCH ₂ ), 4.35 (2H, s, C1CH ₂ ), 4.50 (1H, d, J = 6 Hz,'C ₄ -H), 5.50 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-NH) , 7.24 (1H, s, ^S J^H), 9- ¹¹ d, J = 9 Hz, C ₃ -NH) , 12.89 (1H, br s, C1CH ₂ CONH) .

(2) In the same manner as in Example 8 (2), sodium salt of cis-3-[2-(2-amino-4-thiolyl)-2-(1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (λ max' ^{cm !} 2410, 1780, 1740 and 1675. NMR spectrum (DMSO-d 6 , ppm):

0.95 (2H, _CH2Si ) , 1.48 (6H, s, , NOCMe ₂ ), 3.66 (3H, With, COOCH2), 4.18 (2H, COOCH2 ₎ ), 4.50 (1H, d, J - 6 Hz, C ₄ " H), 5.47 (1H, dd, J = 6 Hz, J = 9 HZ , C ₃ -H), 6.60 (1H, s, S, H), 7.19 (2H, br s, NH ₂ ), 8.98 (1H, d. J = 9 Hz, C3- _NH ). A Example 65 (1) By the same in a way like in example 1 (1) and (3) the cis-3 sodium salt is produced -[2- (2-chloro·

acetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum ^ax' ^cm_1 >'· ^{3 420} ' ^{1 770} ' ^{1 73} °- ^{1 69} °, ¹ 520, ^{1 350, 1} 280 and 1 055.

NMR spectrum (DMSO-dg, ppm): 1.50 (6H, s, 2 x CH ₃ ), 4.34 (2H, s, C1CH ₂ ), 4.38 (1H, d, J = = 6 Hz, C ₄ -H), 5.31 (2H, s, COOCH ₂ ), 5.34 (1H, dd, J = = 6 Hz, CjH) , 7.54 (1H, s, S-. .H), 7.62 and 8.07 (2 X 2H, 2 xd, aromatic protons).

X (2) In 20 ml of water, dissolve 280 ml of sodium salt of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer), which was prepared according to ad (1).

Under ice cooling and stirring, 104 mg of sodium salt of monomethyldithiocarbamic acid is added. The mixture is stirred for 1.5 hours at room temperature. The reaction mixture is washed twice with ether and then purified by chromatography on a column of Amberlite XAD-II (40 g), eluting with water, later with 20% ethanol.

The fractions containing the desired product were combined and lyophilized to give cis-3-[]2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer).

IR spectrum (V cm" ¹ ): 3,410, 1,770, 1,730, NMR spectrum (DMSO-dg, ppm): 1.48 (6H, s, 2 x CH^), (2H, s, COOCH,), 6.92 (1H, s, S _V H), 7.12 (2H, br

AND

685, 1525, 1350, 1280 and 1055 4.37 (1H, d, J = 6 Hz, C ₄ -H), 5.33 , NH ₂ ), 7.40 (2H, br s, NH ₂ ), 7.68 and 8.16 (2 x 2H, d, J = 9 Hz, aromatic protons), 8.82 (1H, d, J ~ 9 Hz, C 2 -NH).

(3) In 10 ml of water, dissolve 200 mg of sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-[]1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer), which was prepared according to paragraph (2).

To the solution was added 200 mg of 10% palladium on carbon. The mixture was stirred for one hour under a hydrogen atmosphere at room temperature. The catalyst was filtered off. Under ice-cooling, 27 mg of sodium bicarbonate was added.

The mixture was stirred for 5 minutes, washed with ethyl acetate, 30 ml of Dowex 50W (H form) was added to the aqueous layer and the mixture was stirred for 1.5 hours. The resin was filtered off. The filtrate was then concentrated under reduced pressure to about half its original volume.

The residue is chromatographed on a column of Amberlite XAD-II (40 g), eluting with water, then 15% ethanol. The fractions containing the desired product are combined and lyophilized. This produces cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

KBr-1,

IR spectrum (V _max , (DMSO-d

J = 9 Hz, C ₃ -H), 7.18 (1H, s, S ): 3,250, 1,770, 1,690, 1,625, 1,280, 1,230 and 1,045. NMR spectrum g, ppm): 1.51 (6H, s, 2 x CHj), 4.36 (1H, d, J = 6 Hz, C ₄ ~H), 5.33 (1H, dd, J = 6 Hz,

H), 9.18 (1H, d, J = 9 Hz, C 1 -NH).

For ^c i3 ^H i6 ^N 6°9 ^S 2·1 i/ ^2H 2° calculated: 31.77% C, 3.90% H, 17.10% N, found: 31.69% C, 3.90% H, 17.00% N.

(4) The eluate fractions (10 to 20% ethanol) obtained by chromatography on an Amberlite XAD-II column in (1) were lyophilized. 174 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[]1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]]-4-sulfoaminocarbonyl-2)-oxoazetidine-1-sulfonic acid disodium salt (syn isomer) were obtained as a colorless powder.

The protecting group(s) of the amine group and the protecting group of the carboxyl group are removed from this product in the same manner as in paragraph (2) and paragraph (3), respectively. The trisodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-sulfoaminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced.

IR spectrum (V ^KBr , cm ¹ ): 3,400, 1,770 and 1,630. NMR spectrum (DMSO-d, + :D,0; ppm):

IdclX in Z

1.34 (3H, s, CH ₃ ), 1.50 (3H, s, CH ₃ > , 4.49 (1H, d, J = 6 Hz, C ₄ ~H), 5.45 (1H, d, J = 6 Hz, C,-H) , 6.77 (1H, s, S _in H) .

³ times

Example 66 (1) In the same manner as in Example 1 (1), (3) and (4), sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-p.-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (V cm ^-1 ): 3,400, 1,770, 1,740 and 1,670. NMR spectrum (DMSO-d g , ppm):

1.47 (6H, s, 2 X CH ₃ ), 1.95 (3H, s, COCH ₃ ), 6.66 (1H, s, S^H), 7.13 (2H, br s, NH ₂ ).

(2) In the same manner as in Example 1 (5), the disodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-acetoxymethyl-2-oxoazetidine-1-

-sulfonic acids (syn isomer) IR spectrum (V cm ¹ ): 3 350, 1,760 and 1,650. NMR spectrum (DMSO- dg , ppm): 1.36 (3H, s, _CH3 ), 1.43 (3H, with, ch ₃ ), 1.93 (3H, with, coch ₃ ) , 5.25 (1H, dd, J = 5 Hz, J = 9 Hz C3 _- H), 6.70 (1H, s, Sy (Ή), 7.10 <2H, br s, nh ₂ ).

Λ

Example 67 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V^/ cm ¹ ): 1770, 1700, 1690 and 1650. NMR spectrum (DMSO-dg, ppm): 3.87 (3H, s, NOCH ₃ ), 4.33 (2H, s, CICHj), 5.27 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ ~H), 6.38 (2H, br s, NH ₂ ), 7.39 (1H, s, S 2 , H) , 9.16 (1H, d, J = 9 Hz, C 1 -NH) .

(2) In the same manner as in Example 2 (2), cis-3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in ^ ^Br , cm ¹ ): 3,400, 1,780, 1,690 and 1,645. NMR spectrum (DMSO-d 1 , ppm):

max □

3.83 (3H, s, NOCH ₃ ), 5.24 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), 6.36 (2H, br s, NH ₂ > , 6.70 (1H, s, S\^H), 7.10 (2H, br s, NH ₂ ), 9.10 (1H, d, J = 9 Hz, C 1 -NH).

For C ₃₃ H ₃₃ NgO _g S ₂ Na.3H ₂ O calculated: 26.50% C, 3.84% H, 16.86 i N, found: 26.51% C, 3.49% H, 16.42% N.

Example 68

In the same manner as in Example 1 (1) and (3), sodium salt of cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine-1-sulfonic acid was prepared.

IR spectrum (λ, cm ^-1 ): 3,410, 3,250, 1,780 and 1,680. NMR spectrum (DMSO-d 6 , ppm):

4.26 (1H, d, J - 6 Hz, C ₄ ~H), 4.98 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 5.02 (2H, s, CgHgCHp, 7.23 (5H, s, CgHg), 7.67 (1H, d, J = 9 Hz, C ₃ NH).

In the same manner as above, trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. This product was a hygroscopic powder.

Example 69 (1) In the same manner as in Example 1 (1), (3) and (4), trans-3-[2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V ^x' ^{cm !} 3,400, 1,765, 1,730, 1,690 and 1,670. NMR spectrum (DMSO-d 6 , ppm): 1.50 (6H, s, 2 x CH 2 ), 5.32 (2H, s, COOCH 2 , 6.85 (1H, s, S^> H) (2) In the same manner as in Example 1 (5), trans-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum 1.61 (6H, s, two C ₃ -H), 7.11 (1H, ^(V max' ^{3 280} ' ^{1 760} ' ^{1 66} °- ^NMR spectrum (DMSO-d g + methyl groups), 4.17 (1H, d, J - 3 Hz, C^-H), 4.84 (1H, s

H).

D ₂ O, ppm): d, J - 3 Hz,

Example 70 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]-acetamido]-4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (in ): 3350, 1780-1730, 1690-1630. NMR spectrum (DMSO-d ppm): 1.52 (6H, s, 2 x CH ₃ >, 1.81 (3H,

J = 9 Hz, C ₃ -H), 5.31 (2H, s, COOCH ₂ ), 7.37 (1H,

6'

COCH ₃ ), 4.35 (2H, s, C1CH ₂ ), 5.2 (1H, dd, J = 6 Hz,

H) .

(2) In the same manner as in Example 1 (4), cis-3-[2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

KBr

IR spectrum (V ppm): 1.5 (6H,

5.31 (2H, s, COOCH

-1, cm ) :

x _CH3 ), 1.74,), 6.27

350, 1780 to 1730 (3H, (1H, s, S.

COCH ₃ ), , 1680 to 1600. NMR spectrum (DMSO-d,, O

5.13 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H) (1H, d, J = 9 Hz, C ₃ -NH).

For C ₂₂ H ₂₄ N ₇ 0 ₁₁ S ₂ .3H ₂ 0 calculated: 37.55% C, 4.29% H, 13.94% N, found: 37.56% C, 4.12% H, 14.03% N.

(3) In the same manner as in Example 1 (5), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (in cm ^{2 3} ): 3,325, 1,770, 1,720, 1,670 and 1,635. NMR spectrum (DMSO-dg, ppm): 1.49 (3H, s, CH ₃ ), 1.51 (3H, s, CH ₃ ), 1.8 (3H, s, COCH ₃ >, 5.17 (1H, dd, J = 6 Hz,

J = 9 Hz, C ₃ -H), 7.0 (1H, s, S^H), 9.35 (1H, d, J = 9 Hz) (C 1 -NH).

For C^gH ₂ gNgOgS ₂ .2 1/2H ₂ O calculated: 33.51% C, 4.69% H, 15.64% N, found: 33.70% C 4.75% H, 15.33% N.

Example 71 (1) In the same manner as in Example 1 (1) and (3), cis-3-[]2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-isopropyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (v max' ^c ™ ^{: 3 3 33} θ' ³ ?30, 1680 and 1050. NMR spectrum (DMSO-dg, ppm): 0.92 (3H, d, J = 6 Hz, CHj), 1.04 (3H, d, J = 6 Hz, CH ₃ >, 1.49 (3H, s,

CH ₃ ), 1.52 (3H, s, CH ₃ ), 3.73 (1H, dd, J = 6 Hz, J = 7 Hz, C ₄ ~H), 4.33 (2H, s, C1CH ₂ ),

5.15 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 7.32 (1H, s, Sx>H).

(2) In the same manner as in Example 1 (4), cis-3-[]2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-isopropyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum 0.89 (3H, d, CH ₃ ) COOCH ₂ ), 6.64 (1H (V cm

KBr max'

): 3 300 d, CH ₃ ),

770 to 1730 and 1670 1.49 (3H, s, CH ₃ ), 1.52

NMR spectrum (DMSO-dg, ppm): (3H, s, CH ₃ ), 5.31 (2H, s,

For C ₂₂ H ₂ gNgNaO ₃ gS ₂ .2H ₂ O calculated: 40.24% C, 4.45% H, 4.22% H, 12.69% N.

12.80% N, found

40.10% C, (3) In the same manner as in Example 1 (5), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-isopropyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

NMR spectrum (DMSO-dg, ppm): 3.71 (1H, dd, J = 6 Hz, J = 9 Hz, C ₄ -H), 5.13 (1H, dd,

J = 6 Hz, J = 9 Hz, C ₃ -H), 6.90 (1H, s, S^ Η), 9.27 (1H, d, J = 9 Hz, C 8 -NH).

For ^c i5 ^H 21 ^N 5°8 ^S 2' ^3H 2° calculated: 34.81% C, 5.26% H, 12.53% N, found: 34.51% C,

4.96% H, 13.25% N.

Example 72 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[]1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR (6H, s, = 5 Hz, spectrum (in _ma *, cm 2 x CHg), 2.63 (3H, C ₄ -H), 5.33 (2H, s, ): 3,350, 1,780 and 1,670. NMR spectrum (DMSO-dg, ppm): 1.52 d, J = 5 Hz, NHCHg), 4.33 (2H, s, C1CH ₂ ), 4.43 (1H, d, J = COOCH ₂ ), 7.53 (1H, s, S _{x /} II).

'X (2) In the same manner as in Example 1 (4), cis-3-[2-(2-amino-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR spectrum (V cm ¹ ): 3,330.1 (6H, s, 2 x CHg), 2.60 (3H, d, J = 4 Hz,

with.

Η), 7.21 (2H, br s, NH ₂ ).

770 and 1 nhch ₃ ),

760. NMR spectrum (DMSO-dg, ppm): 1.49 4.38 (1H, d, J = 5 Hz, C ₄ ~H), 6.86 (1H,

For C ₂₄ H ₂₂ N ₂ NaO ₄₄ S ₂ .2H ₂ O calculated: 37.55% C, 3.90 8 H, 14.59 8 N, found: 37.54 8 C, 3.80 8 H, 14.63 8 N.

(3) In the same manner as in Example 1 (5), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

IR spectrum (V^ _ax , 2 x CH ₃ ), 2.62 (3H, d, J = 5 Hz, J = 9 Hz, Cg-H),

-1» ·, cm ) : 1

800 and 1650. NMR spectrum (DMSO-dg, ppm):

= 4 Hz, NHCH ₃ ), 4.40 (1H, d, J = 5 Hz, C ₄ ~H), 5.33 7.16 (1H, s, Sγ Η), 7.83 (1H, q, J = 4 Hz, NHCHg).

1.50 (6H, s, (1H, dd, J =

For C ₁₄ H ₁₈ N ₆ O ₉ S ₂ .2 1/2H ₂ O calculated: 32.11% C, 4.42 8 H, 16.05 8 N, found: 32.39 8 C 4.30 8 H, 15.87 8 N.

Example 73

In the same manner as in Example 1 (1) and (3), 3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared.

VRy* — 1 acid (syn isomer). IR spectrum (^ _max í cm ) : 3,455, 1,760, 1,730 and 1,660.

•The above product was treated in the same manner as described in Example 8 (2) above. This removed the protecting group of the amino group. Thus, 3-[2-(2-amino-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was produced.

IR spectrum: 30.06% C, λ (v _max , cm ): 3,400, 1,762, 1,730 and 1,665. For C ₁₂ H ₁₄ N ₅ NaO ₈ S ₂ .2H ₂ O calcd. 3.78% H, 14.61% N, found: 30.13% C, 3.71% H, 14.43% N.

Example 74 (1) According to the procedure of Example 1 (1), trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine, which was prepared according to Reference Example 108, was sulfonated. Thus, trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid sodium salt was obtained.

IR spectrum (λ< cm ^-1 ): 3,425, 2,125, 1,762 and 1,730.

(2) 268 mg of trans-3-azido-4-methoxycarbonylmethyl-2-oxo-azetidine-1-sulfonic acid sodium salt was dissolved in 5 ml of N,N-dimethylformamide. 150 mg of 10% palladium on carbon was added to the solution. The mixture was stirred for 45 minutes under a hydrogen atmosphere at room temperature.

The catalyst is then filtered off and washed with 5 ml of N,N-dimethylformamide. The filtrate and the washed N,N-dimethylformamide solution are combined. To the mixture are added 284 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-(1-methyl-1-(tert-butoxycarbonyl)ethyloxyiminoacetic acid, 110 mg of N-hydroxybenzotriazole monohydrate and 150 mg of dicyclohexylcarbodiimide.

The mixture was stirred for 4 hours at room temperature and then allowed to stand overnight at 5°C. 20 ml of water was added to the mixture. Insoluble materials were filtered off and washed with 5 ml of water. The filtrate and the washed solution were combined. Sodium monomethyldithiocarbamic acid was added thereto.

The mixture was treated in the same manner as described above in Example 8 (2). Trans-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-(tert-butoxycarbonyl)ethyloxyimino)acetamido]-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was produced.

IR spectrum (V cm b: 3,425, 1,760, 1,725 and 1,660.

IPAX

Under ice-cooling and stirring, 84 mg of the above product was added to 2 ml of trifluoroacetic acid. The mixture was stirred for three hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue was dissolved in 5 ml of water and purified by chromatography on an Amberlite XAD-II column (eluent: water, later 10% ethanol) and then on a Sephadex LH-20 column (eluent: water).

The eluate is lyophilized. The lyophilizate is dissolved in 5 ml of water and the solution is stirred for 10 minutes with 2 g of Dowex 500W (H-form). The resin is filtered off. The filtrate is lyophilized. Trans-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) is produced.

and 1725. NMR spectrum (DjO, ppm): 1.72 (6H, s, COOCHj), 4.60 (1H, m, C ₄ ~H), 5.08 (1H, ): 3375, 1760

IC spectrum (V _max < cm s, 2 x CH ₃ ), 3.24 (2H, m, C ₄ -CH ₂ ), 3.86 (3H, d, J = 2 Hz, Cj-H), 7.30 (1H, s, S^B).

Example 75 (1) In the same manner as in Example 1 (1), sodium salt of cis-3-benzyloxycarboxKBr —1 amido-4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (V _max , cm ) 3,270, 1,760 and 1,680. For ^c 13 ^H i4 ^N 3 ^NaO g ^s · ¹ 1/2H ₂ O calculated: 36.97% C, 4.06% H, 9.95% N, found: 36.99% C, 4.06% H, 9.97% N.

s, OCH ₃ ), 4.33 (1H, d, J = 6 Hz, C ₄ ~H), 5.36 (2H, s, COOCH ₂ ), 6.83 (1H, (2) In the same way as in Example 1 (3) and (4), the sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2- Γΐ-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxyKBr —1 aminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (V _max / cm ):

400, 1775, 1730 and 1680. NMR spectrum (DMSO- dg , ppm): 1.51 (6H, s, 2 x CH 1 ), 3.57 (3H, _{S 1} H ).

(3) In the same manner as in Example 65 (3), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR spectrum (in cm ^-1 ): 3,280, 1,770, 1,730 and 1,670. NMR spectrum (DMSO-dg, ppm): 1.52 (611, s, 2 x CHj), 3.60 (3H, s, OCH-j), 4.34 (1H, d, J = 6 Hz, C ₄ -H), 5.38 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 7.14 (1H, s, S y H), 9.02 (1H, d, J = 9 Hz, c ₃ -nh). X

For C ₁₄ H ₁₇ NgO _1Q S ₂ .2 1/2H ₂ O calculated: 31.23% C, 4.12% H, 15.61% N, found: 31.06% C,

3.96% H, 15.40% N.

Example 76 (1) In the same manner as in Example 1 (1) and (3), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared. IR spectrum (V max' ^cn|- ^) ^!

400, 1,750 and 1,720.

(2) In the same manner as in Example 1 (4), sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetamido]-4-carbamoyloxymethylKBr was prepared.

-2-oxoazetidine-1-sulfonic acid (syn isomer). IR spectrum (V _max , cm ): 1,760, 1,720 and 1,670.

(3) To 1 ml of anisole, add 250 mg of sodium salt of cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-benzhydryloxycarbonylethyloxyimino)acetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer). While stirring, add 5 ml of trifluoroacetic acid dropwise at -20 °C.

The mixture is stirred for 30 minutes at -15° C. Then 10 ml of ether and 10 ml of petroleum ether are added.

The resulting powder is isolated by centrifugation, dissolved in water and Dowex 50W (in H-form) is added to the solution. The mixture is then stirred. The resin is filtered off. The filtrate is evaporated and the residue is purified by chromatography on an Amberlite XAD-II column (elution: successively 100 ml of water, 100 ml of 10% ethanol, 100 ml of 30% ethanol and finally 50 ml of 40% ethanol).

The fractions obtained by eluting with 30% and 40% ethanol are lyophilized to yield cis-3-p-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

cm ^-1 ): 1,760,

1H, s, S..H) , 9.23 (1H, d, J = 9 Hz,

IR spectrum (\) (6H, s, 2 x CH ₃ ), 7.01 (

710 and 1630. NMR spectrum (DMSO-dg, ppm): 1.51 C ₃ -NH).

In the same manner as in the above examples, the following compounds can be prepared: , cis-3-[2-(2-amino-4-thiazolyl)-2-carboxymethyloxyiminoacetamido]-4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer), cis-3-p-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer), cis-3-[2-(2-amino-4-thiazolyl)-2-carboxymethyloxyiminoacetamido]-4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-isopropyl-2-oxoazetidine-1-sulfonic acid (syn isomer), cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer) and cis-3-[2-(2-amino-4-thiazolyl)-2-(1-methyl-1-carboxyethyloxyimino)acetamido]-4-methylcarbamoyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer).

Reference example 1

Under ice cooling and stirring, 6.7 ml of propylene oxide and 3.24 g of carbobenzoxy chloride are added to a solution of 2.94 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 12 ml of methylene chloride. The reaction mixture is stirred for 30 minutes at room temperature.

The solvent is distilled off in vacuo. Ether is added to the residue. The separated crystals are filtered off with suction. Cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester is produced, mp 115-116 °C.

For ^22 ^Η 24 ^Ν 2°7 ⁱⁿ yp°^ ^predicted: 61/67% C, 5.65% H, 6.54% Ò, found: 61.64% C, 5.67% H, 6.49% N.

Reference example 2

A solution of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester (2.7 g) in 150 ml of acetonitrile is heated under a stream of nitrogen and with stirring to a temperature of 90-95 ° C. To this solution is added dropwise 55 ml of an aqueous solution containing 2.73 g of potassium persulfate and 1.65 g of potassium hydrogen phosphate.

After the dropwise addition is complete, the mixture is stirred for 3 hours at the same temperature. The reaction mixture is cooled. The pH of the reaction mixture is adjusted to 6 to 7 by adding potassium hydrogen phosphate.

Acetonitrile and water are distilled off in vacuo. The residue is dissolved in chloroform.

The solution was washed with water and brine. The chloroform solution was dried over anhydrous sodium sulfate. The solvent was then distilled off in vacuo. The residue was chromatographed on a silica gel column.

Elution with ethyl acetate produces cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, mp 127-128 °C. For ^ι^Η-^Ν^Οι- ⁱⁿ YP°c ^tenos 56.11 0 C, 5.07% H, 10.07% N, found: 56.03% C, 5.01% H, 9. _ř 99% N.

Reference example 3

To a suspension of 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 20 ml of ethanol is added 0.8 g of 5% palladium on carbon. Catalytic hydrogenation is carried out at atmospheric pressure with stirring. When the consumption of hydrogen stops, the catalyst is filtered off. The filtrate is concentrated in vacuo. The remaining oil is left to stand under cooling to crystallize.

The precipitated crystals are filtered off with suction. 0.38 g of methyl ester (92%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid is produced, mp 59-61 °C. For C ₅ H _g N ₂ O ₃ calculated: 41.66% C,

5.59% H, 19.44% N, found: 41.54% C, 5.59% H, 19.67% N.

Reference example 4

Under ice cooling and stirring, 6 ml of an aqueous solution containing 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 561 mg of sodium bicarbonate is added to a suspension of 1.18 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn isomer) in 10 ml of tetrahydrofuran.

The mixture is stirred for two hours at room temperature. The solvent is distilled off in vacuo.

The remaining residue solidifies. Water is added to the solidified residue, the mixture is filtered and the crystals obtained are washed first with water and then with ethanol. Cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido^-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) is produced, mp 270-275 °C (dec.).

For C ₁₃ H ₁₄ ClN ₅ 0gS calculated: 38.66% C, 3.49% H, 17.35% N, found: 38.50 í C,

3.78% H, 17.25% N.

Reference example 5

Under ice cooling and stirring, 250 ml of an aqueous solution containing 2.65 g of sodium borohydride is added to a solution of 12 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 500 ml of tetrahydrofuran. The reaction mixture is stirred for five hours at room temperature.

Tetrahydrofuran is distilled off in vacuo. Water is added to the reaction mixture. The precipitated crystals are filtered off. After drying, 9.8 g (87%) of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine are obtained, mp 129-131 °C.

For ^C 2i ^H 24 ^N 2°6 ⁱⁿ yP°^ ^tenO! 62.99% C, 6.04 i H, 7.00% N, found: 62.78% C, 5.91% H, 7.05% N.

Reference example 6

To a solution of 5.1 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine in 50 ml of methylene chloride, 3.8 ml of pyridine and then 2.04 ml of acetyl chloride are added dropwise at 0 °C with stirring. The reaction mixture is stirred for 30 minutes. The solvent is distilled off in vacuo.

The residue is chromatographed on a silica gel column, eluting with ethyl acetate. 5.45 g (96%) of cis-4-acetoxymethyl-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are produced, mp 110-111 °C. For ^C 23 ^H 26 ^N 2°7 ⁱⁿ yP°^ ^found: 62.63% C, 5.92% H, 6.33% N, found:

62.26% C, 5.68% H, 6.07% N.

Reference example 7

A solution of 4.862 g of cis-3-acetoxymethyl-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine in 275 ml of acetonitrile is heated to 80-83°C in a stream of nitrogen with stirring.

To this solution is added 110 ml of an aqueous solution containing 4.752 g of potassium persulfate and 2.871 g of potassium hydrogen phosphate.

After addition of the ingredients, the mixture is stirred for a further 2.5 hours at 90°C. While cooling, the pH is adjusted to 6-7 by adding potassium hydrogen phosphate. Acetonitrile and water are distilled off in vacuo. Chloroform is added to the residue. Insoluble materials are filtered off, washed with water and chloroform and dried. *

Cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine is produced, m.p. 137-138 °C. Calcd.: 57.53% C, 5.52% H, 9.59% N, found: 57.38% C, 5.43% H,

9.59% N.

Reference example 8

To a suspension of 1.46 g of cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine in 50 ml of ethanol is added 1.5 g of 5% palladium on carbon. The mixture is catalytically reduced with stirring at atmospheric pressure. The reaction is complete within 30 minutes. The catalyst is filtered off. The filtrate is evaporated to dryness in vacuo.

750 mg (95%) of cis-4-acetoxymethyl-3-amino-2-oxoazetidine (colorless oil) is produced.

IR spectrum (\ cm: 3300, 1770-1710. NMR spectrum (CDCl^r ppm): 1.83 (br s,

-NH^), 2.1 (s, -CH^), 3.6 to 4.1 (m, 4.1 to 4.8 (m, C^-H and C^-H), 6.0 to 6.3 (br s,

NH) .

Reference example 9

To a suspension of 2.36 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn isomer) in 20 ml of tetrahydrofuran is added 12 ml of an aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium bicarbonate. The mixture is stirred for two hours at room temperature. The solvent is then distilled off in vacuo. The remaining residue solidifies. Water is added to the solidified residue and the mixture is filtered.

The crystals are washed successively with aqueous sodium bicarbonate, water, ether and dried. This gives cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn isomer), mp 180-190 °C (dec.).

For C^^H^^ClN^OgS calculated: 40.24% C, 3.86% H, 16.76% N, found: 39.89% C,

3.67% H, 16.60% N.

Reference example 10

While stirring and cooling with ice, 1.94 g of methanesulfonyl chloride is added to a solution of 4.5 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine in 30 ml of pyridine. The mixture is stirred for 30 minutes at room temperature.

100 ml of ethyl acetate and 50 ml of water are added to the reaction mixture. The reaction mixture is then acidified with dilute hydrochloric acid. The precipitated crystals are separated. The filtrate is divided into an aqueous and organic layer. The organic layer is distilled to dryness in vacuo.

Water is added to the residue, and the resulting crystals are filtered off and combined with the crystals obtained above. The combined crystal portions are washed successively with aqueous sodium bicarbonate solution, water, ether and dried.

5.0 g (93%) of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methanesulfonyloxymethyl-2-oxoazetidine are produced, mp 140-141 °C.

For C _n <N,O _n S calculated: 55.22% C, 5.48% H, 5.85% N, found: 55.16% C, 5.40% H, 22 26 2 o

5.61% N.

Reference example 11

A solution of 3.83 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methanesulfonyloxymethyl-2-oxoazetidine in 200 ml of acetonitrile is heated to 80-83 °C with stirring in a stream of nitrogen. To the solution is added dropwise 80 ml of an aqueous solution containing 3.46 g of potassium persulfate and 2.09 g of potassium hydrogen phosphate.

After the addition was complete, the mixture was stirred for 3 hours at 85-90°C. The solvent was then distilled off in vacuo. 200 ml of water was added to the residue and the resulting crystals were filtered off.

The crystals obtained are washed with water, then with ether and dried. This gives cis-3-benzyloxycarboxamido KBr -1-do-4-methanesulfonyloxymethyl-2-oxoazetidine, mp 132-133 C. IR spectrum (V _max ' cm ) ^!

325, 1,770 and 1,690.

Reference example 12

To 55 ml of methyl ethyl ketone were added 1.4 g of cis-3-benzyloxycarboxamido-4-methanesulfonyloxymethyl-2-oxoazetidine and 4.2 g of sodium iodide. The mixture was stirred for 2 hours at 90 °C and then for 12 hours at 60 °C. The solvent was distilled off in vacuo. The residue was shaken thoroughly with 100 ml of water and 50 ml of chloroform. Insoluble materials were filtered off, washed with water and chloroform.

After drying, cis-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine is obtained, mp 160-162°C.

For ^c i2 ^H 13 ^IN 2°3 calculated: 40.02% C, 3.64 i H, 7.78% N, found: 40.26 i C,

3.64% H, 7.93% N.

Reference example 13

To a solution of 103.5 mg of sodium dissolved in 9 ml of methanol is added 522 mg of 1-methyl-5-tetrazolyl mercaptan. The mixture is stirred for 15 minutes at room temperature. The methanol is distilled off in vacuo. The residue is dissolved in 12 ml of N,N-dimethylformamide.

To the resulting solution was added 900 mg of cis-3-benzyloxycarboxamido-4-iodomethyl-2-oxoazetidine and the mixture was stirred for 19 hours at room temperature. 100 ml of water was added to the reaction mixture. The precipitated crystals were filtered off with suction and washed successively with water and ether.

The crystals are then dissolved in ethyl acetate. The solution is passed through a small silica gel column. The solvent is distilled off from the eluate in vacuo. 780 mg (90 fc) of cis-3-benzyloxycarboxamido-4-(1-methyl-5-tetrazolyl-thiomethyl)-2-oxoa^ethidine are produced as colorless crystals, m.p. 151-152 °C. For calculated: 48.26% C., 4.63 i H, 24.13% N, found:

48.38% C, 4.65% H, 23.89% N.

Reference example 14

Under ice cooling and stirring, an aqueous solution (6 ml) containing 288 mg of cis-3-amino-2-oxoazetine-4-carboxylic acid methyl ester and 560 mg of sodium bicarbonate is added to a suspension of 1.18 g of 2-(2-chloroacetoamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (anti isomer) in 10 ml of tetrahydrofuran.

The mixture was stirred for two hours at room temperature. The solvent was distilled off in vacuo.

The remaining residue solidified. Water was added to the solidified residue and the mixture was filtered. The filtrate was neutralized with aqueous sodium bicarbonate solution and the product was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate.

The solvent is distilled off in vacuo to give cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (anti isomer), mp 119-129 °C.

For CjjH^^ClNjOgS calculated: 38.66% C, 3.49% II, 17.34% N, found: 38.56% C,

3.60% H, 17.05% N.

Reference example 15

Under ice cooling and stirring, 2.10 ml of triethylamine is added to a solution of 2.94 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of methylene chloride. Then 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride is added dropwise over one hour.

The reaction mixture was stirred for another hour under ice cooling. Then it was washed successively with dilute hydrochloric acid, 5% aqueous sodium bicarbonate, aqueous sodium chloride solution, dried over magnesium sulfate and the solvent was distilled off in vacuo.

Ether is added to the residue. The precipitated crystals are filtered off. Cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester is produced, m.p.

124 to 126°C.

π

For ^C 22 ^H 24 ^N 2°6 ⁱⁿ yP° ^ethene: 64.07% C, 5.86% H, 6.79% N, found: 63.98% C, 5.98% H, 6.70% N.

Reference example 16

A mixture of 412 mg of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester, 810 mg of potassium persulfate and 261 mg of potassium hydrogen phosphate in 20 ml of acetonitrile and 20 ml of water is refluxed for one hour.

The reaction mixture is evaporated to dryness in vacuo. The residue is dissolved in ethyl acetate, washed successively with aqueous 5% sodium bicarbonate solution, aqueous sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue.

The precipitated crystals are filtered off. Cis-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester is produced, mp 176 to 180 °C. XC spectrum (γ max' ^cm_1 ) ^: 1,790, 1,740 and 1,655. NMR spectrum (DMSO-dg, ppm): 3.47 (s, CH ₂ CO and OCH ₃ >, 4.20 (d, J = 6 Hz, C^-H),

5.35 (dd, J = 6 Hz, J = 8 Hz, Cj-H), 7.32 (s, CgHg), 8.44 (s, NH), 8.62 (d, J = 8 Hz, CONH).

Reference example 17

Under ice-cooling and stirring, 12 ml of an aqueous solution containing 570 mg of sodium borohydride is added to a solution of 2.06 g of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester in 24 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes under ice-cooling and 1.5 hours at room temperature.

Tetrahydrofuran was distilled off in vacuo. An aqueous sodium chloride solution and ethyl acetate were added to the residue. The resulting ethyl acetate layer was separated and washed successively with aqueous sodium bicarbonate and aqueous sodium chloride, dried over magnesium sulfate, and the solvent was distilled off in vacuo.

Ether is added to the residue. The separated crystals are filtered off with suction. 1.75 g (91%) of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine are produced, mp 152 to 154 °C. For ^C 2i ^i! 24 ^N 2°5 ^ν ΥΡ ^θ ^'* ^: θηο: 65.61 % C, 6.29 i H, 7.29 % N, found: 65.37 % C, 6.47 % H,

7.55% N.

Reference example 18

To a solution of 1.12 g of p-toluenesulfonyl chloride in 6 ml of pyridine was added 1.73 g of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine with stirring at 0° C. The reaction mixture was stirred for 2 hours and then left to stand overnight in a refrigerator.

0.68 ml of lactic acid was added to the reaction mixture and the mixture was stirred for one hour. The reaction mixture was then diluted with 45 ml of ethyl acetate and 15 ml of tetrahydrofuran, washed successively with hydrochloric acid, aqueous sodium chloride solution, aqueous sodium bicarbonate solution and aqueous sodium chloride solution.

The organic phase is dried over magnesium sulfate and the solvent is distilled off in vacuo. A mixture of ether and ethyl acetate (5:1) is added to the residue. The resulting crystals are filtered off. 2.21 g (91%) of cis-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymethyl)-2-oxoazetidine are thus produced, melting point 109-110 °C.

For C ₂ gH ₃ gN ₂ O ₇ S calculated: 62.43% C, 5.63% H, 5.20% N, found: 62.18 i C, 5.72% H 5.07% N.

25357?

Reference example 19

To 70 ml of acetone are added 2.27 g of cls-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-4-(p-toluenesulfonyloxymelliyl)-2-oxoazetidine and 4.95 g of sodium iodide. The mixture is refluxed with stirring for six hours. The reaction mixture is evaporated in vacuo. To the residue are added methylene chloride and water.

After the residue was dissolved, the methylene chloride layer was separated and washed with aqueous sodium thiosulfate and aqueous sodium chloride. The methylene chloride layer was then dried over magnesium sulfate and the solvent was distilled off in vacuo. Ethyl acetate was added to the residue.

The precipitated crystals are filtered off. Cis-1-(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine is produced, mp 181-182 °C. For ^C 2i ^H 23 ³ ' ^N 2 ^O 4 calculated: 51.03% C,

4.69 i H, 5.67% N, found: 51.14% C, 4.64% H, 5.81% N.

Reference example 20

To 6 ml of N,N-dimethylformamide are added 740 mg of cis-1-(2,4-dimethoxybenzyl)-4-iodomethyl-3-phenylacetamido-2-oxoazetidine and 146 mg of sodium azide. The mixture is stirred for 4 days at room temperature. The solvent is distilled off in vacuo. Ethyl acetate and water are added to the residue.

The ethyl acetate layer was separated, washed with brine and dried over magnesium sulfate. The solvent was distilled off in vacuo. Ether was added to the residue. The precipitated crystals were filtered off.

Cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine is produced, mp 110-111 °C. IR spectrum (in cm^): 3,270, 2,210, 1,755 and 1,650. NMR spectrum (CDCl^, ppm): 3.32 (m, -CH^) ) 3.63 (s, CH ₂ CO) , 3.83 (s, 2 x OCH-j), 4.36 (dd, J = 14 Hz, CH ₂ Ar) , 5.28 (q, J = 5 Hz, C ₃ -H) , 6.40-6.80 (m, ArII and CONH) , 7.16 (m, ArH) , 7.15 (s, _W .

Reference example 21

To a solution of 449 mg of cis-4-azidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine in 80 ml of diethanol was added 200 mg of 10% palladium on carbon. The mixture was hydrogenated for 1.5 hours at room temperature and atmospheric pressure.

The catalyst is filtered off. The filtrate is distilled to dryness in vacuo. The residue is dissolved in 30 ml of methylene chloride. 0.20 ml of triethylamine is added to the methylene chloride solution with stirring at 0 °C.

To this solution was added dropwise 0.10 ml of acetyl chloride in methylene chloride over 10 minutes. The reaction mixture was stirred for 40 minutes. The reaction mixture was then washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution, aqueous sodium chloride solution, dried over magnesium sulfate, and the solvent was distilled off in vacuo.

Ethyl acetate is added to the residue. The resulting crystals are filtered off. Cis-4-acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine is produced, mp 105-207°C.

IR spectrum (V cm ^-1 ): 3,270, 1,750 and 1,640.

Reference example 22

A mixture of 298 mg of cis-4-acetamidomethyl-1-(2,4-dimethoxybenzyl)-3-phenylacetamido-2-oxoazetidine, 576 mg of potassium persulfate and 183 mg of potassium hydrogen phosphate in 15 ml of water and 15 ml of acetonitrile is refluxed for 1.5 hours.

25357?

The reaction mixture is concentrated in vacuo. The concentrate is dissolved in ethyl acetate. The solution is washed successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The ethyl acetate solution is dried over magnesium sulfate and the solvent is distilled off in vacuo. Ethyl acetate is added to the residue.

The precipitated crystals are filtered off. Cis-4-acetamidomethyl-3-phenylacetamide-2-oxoazetidine is produced, mp 200-202 °C. IR spectrum (V ^cm_1 ): 3250, 1750, 1640 and 1520.

NMR spectrum (DMSO-dg, ppm): 1.77 (s, COCH-j), 3.11 (m, CH,N), 3.69 (dt, J = 5 Hz, J - 6 Hz, C^-H), 5.00 {dd, J = 5 Hz, J = 8 Hz), 7.26 (s, CgH^), 7.59 {m, NH), 8.20 (broad band

8.75 (d, CONH, J = 8 Hz).

Reference example 23

To 200 ml of benzene are added 8.5 g of cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester and 3.1 g of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture is refluxed for 72 hours. 100 ml of ethyl acetate is added to the reaction mixture while cooling.

The solution is washed successively with 100 ml and 50 ml of 1N hydrochloric acid and 100 ml of water.

To the resulting mixture was added 100 ml of chloroform and the solution was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. To the residue was added 50 ml of ethyl acetate. The resulting insoluble material was filtered off and washed with 30 ml of ethyl acetate.

6.4 g of crude product are obtained, which, upon crystallization from 220 ml of ethyl acetate, gives trans-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester, mp 186-188°C.

For ^C 22 ^ði 20 ^N 2°7 ⁱⁿ yP°^ ^calculated: 62.26% C, 4.75% H, 6.60% N, found: 62.13% C, 4.64% H, 6.43% N.

Reference example 24

To 83 ml of methylene chloride were added 8.3 g of 2,4-dimethoxybenzylamine and 6.0 g of anhydrous magnesium sulfate. A solution of 6.5 g of glyoxylic acid butyl ester in 65 ml of methylene chloride was added dropwise to the mixture under ice-cooling and stirring. The mixture was stirred for another two hours.

The reaction mixture is filtered. To the filtrate are added 5 g of triethylamine and a solution of 11 g of phthalimidoacetyl chloride in 110 ml of methylene chloride. The mixture is stirred overnight. Then it is washed successively with dilute hydrochloric acid, aqueous sodium chloride solution, aqueous sodium bicarbonate solution, aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The mixture was filtered and the filtrate was concentrated. Ether was added to the concentrate. Insoluble material was filtered off. The filtrate was evaporated under reduced pressure. 20.1 g (86%) of cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid butyl ester (orange-colored oily product) was produced.

A portion of the product is purified by column chromatography on silica gel. The product is obtained as a colorless foam. However, the above product is used in the crude state for the following work-up.

IR spectrum (V™ ¹⁰¹ , cm ^-1 ): 1,770 and 1,720. NMR spectrum (CDCl ₃ , ppm): 4.26 (1H, d,

J = 5 Hz, C ₄ -H), 5.63 (1H, d, J = 5 Hz, C 1 -H).

Reference example 25

To a solution of 19 g of cis-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine-4-carboxylic acid butyl ester in 190 ml of methylene chloride is added 3.7 g of methylhydrazine. The mixture is stirred overnight at room temperature. The reaction mixture is filtered. The filtrate is distilled off under reduced pressure.

Ethyl acetate is added to the residue. Insoluble material is removed by filtration. The filtrate is extracted with two 100 ml portions of 1N hydrochloric acid. The extracts are neutralized with sodium bicarbonate. The resulting solution is extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure.

12 g (87.5%) of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid butyl ester (oil) are produced. IR spectrum (V ^cm_1 ) ^{: 3 48} θ ^{and 1} 750. ^NMR spectrum (CDCl ₃ , ppm): 3.83 and 3.93 (2 X 3H, 2 xs, 2 x OCHj).

In a similar manner, the following was prepared: trans-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester (oil). IR spectrum (V ^{cm 1} ): 3,400, 3,330 and 1,760.

NMR spectrum (CDClj, ppm): 3.70 (1H, d, J = 2 Hz, C ₃ “H), 3.79, 3.80 and 3.81 (3 x 3H, 3 xs, x CH ₃ ), 4.21 (1H, d, J = 2 Hz, C ₄ -H), 4.95 (2H, q, J = 14 Hz, CH ₂ ).

Reference example 26

To a solution of 10 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid butyl ester in 40 ml of methylene chloride, first 1.8 g of propylene oxide and then 5.5 g of carbobenzoxy chloride are added under ice cooling and stirring.

The mixture is warmed to room temperature. Stirring is carried out at this temperature for one hour. The solvent is evaporated off under reduced pressure. Isopropyl ether is added to the residue. The resulting crystals are filtered off. 11.7 g (83.5%) of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid butyl ester are thus produced as colorless crystals, mp 97-98 °C. For C ₂₅ H ₃₀ N ₂ O ₇ calculated: 63.81% C, 6.42% H, 5.95% N, found: 63.51% C, 6.26% H, 6.09% N.

Similarly, trans-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester was prepared. Since this product did not crystallize under the same treatment as above, it was purified by chromatography on a silica gel column (elution with hexane/ethyl acetate 1:1).

clean -1

A colorless oily product is produced. Yield 89 i, IR spectrum (in _max z cm ): 3,340,

770, 1740 and 1720. NMR spectrum (CDCl ₃ , ppm): 3.93 (1H, d, J = 3 Hz, C ₄ ~H), 5.07 (2H, s, CH ₂ -phenyl).

Reference example 27

To a mixture of 60 ml of acetonitrile and 60 ml of water are added 2.35 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid butyl ester, 4.05 g of potassium persulfate and 1.75 g of potassium hydrogen phosphate. The resulting mixture is refluxed for one hour under an argon atmosphere.

Acetonitrile was evaporated under reduced pressure. Ethyl acetate and water were added to the residue and the resulting mixture was shaken. The ethyl acetate layer was separated, washed with aqueous sodium bicarbonate solution, aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The solvent is distilled off under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a mixture of ethyl acetate and hexane in a ratio of 1:1. Crystals of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid butyl ester are produced, mp 112-113 °C.

For ^C 16 ^H 2O ^N 2°5 ⁱⁿ YP° ^ethene! 59.98 * ^c , 6.29% H, 8.74% N, found: 60.25% C, 6.33% H, 8.53% N.

In a similar manner, trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester is prepared, mp 139-140°C.

Reference example 28

To a suspension of 640 mg of cis-3-benzylcarboxamido-2-oxoazetidine-4-carboxylic acid butyl ester in 23 ml of ethanol is added 640 mg of 10% palladium on carbon. The mixture is catalytically hydrogenated with stirring at normal pressure. When the consumption of hydrogen is complete, the catalyst is filtered off from the reaction mixture.

The filtrate was concentrated under reduced pressure. The residue was crystallized. 330 mg (87.1%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid butyl ester was thus produced. A portion of the product was recrystallized from ethyl acetate and hexane.

Orange-colored flaky crystals are produced, m.p. 87 to 89°C. Calcd.: 51.60% C>, 7.57% H, 15.04% N, found: 51.35% C, 7.58% H, 14.80% N.

In a similar manner, trans-3-amino-2-oxoazetine-4-carboxylic acid methyl ester is prepared, mp 135-136°C.

Reference example 29

To a solution of 13.6 g of 2-hydroxyiminoacetoacetic acid methyl ester in 70 ml of acetone, 20.8 g of potassium carbonate are added under ice-cooling. 17.0 g of propyl iodide are added dropwise to the mixture over a period of thirty minutes. After the dropwise addition, the mixture is stirred for 2 hours at room temperature. The acetone is evaporated under reduced pressure.

250 ml of water is added to the residue. The mixture is extracted with methylene chloride. The extract is washed twice with water, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. 2-(propoxyimino)acetoacetic acid methyl ester is produced as a light yellow oily product.

iC spectrum (V cm ^-1 ): 2,975, 1,750, 1,695 and 1,600. NMR spectrum (CDCl,, ppm):

max j

0.95 (3H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 1.75 (2H, sextet, J 7 Hz, CH ₂ CH ₂ CH ₃ ), 2.38 <3H, s,

CH ₃ CO), 3.86 (3H, s, COOCH-j).

The following compounds are produced in a similar manner:

2-(butoxyimino)acetoacetic acid methyl ester, light yellow oily product, purity 80%. IR spectrum (V

975, 1,755, 1,700 and 1,600. NMR spectrum (CDCl ₃ , ppm): 0.94 (3H, t, J = 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 1.2 to 2.0 (4H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 2.36 (3H, s, CH 2 CO), 3.85 (3H, s, COOCH 2 ), 4.29 (2H, t, J = 6 Hz, CH ₂ CH _{2 CH 3} ) and methyl ester of 2-benzyloxyiminoacetoacetic xylene, light yellow oily product, yield 98%. IR spectrum (V pure, _cm 1 ). i 750 and 1690. NMR spectrum (CDC1 _Q , ppm): 2.36 (3H, max □ s, CH ₃ CO), 3.84 (3H, s, COOCH ₃ ), 5.28 (2H, s, CH ₂ ), 7.27 (5H, s, phenyl protons).

Reference example 30

To a solution of 7.4 g of methyl 2-(propoxyimino)acetoacetic acid ester in 7.4 ml of acetic acid 253572 linseed oil was added 5/5 g of sulfuryl chloride. The mixture was stirred for 10 minutes at 40 °C and then for 6 hours at room temperature. The reaction mixture was poured into 100 ml of ice-water. The product was extracted twice with chloroform. The extract was washed with aqueous sodium chloride solution, aqueous sodium bicarbonate solution, water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.

8.2 g (94%) of 4-chloro-2-(propoxyimino)acetoacetic acid methyl ester (light yellow oily product) are produced. IC spectrum (in max^' cm ^): 2980, 1750, 1720 and 1595.

NMR spectrum (CDCl-j, ppm): 0.97 (3H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 1.77 (2H, sextet, J = 7 Hz,

CH ₂ CH ₂ CH ₃ ), 3.89 (3H, s, COOCHp

4.30 (2H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ )

4.56 (2H, s, _ClCH2 ).

The following compounds are prepared in a similar manner:

4-chloro-2i-(butoxyimino) acetoacetic acid methyl ester, light yellow oily product, yield 92%. IR spectrum (in "ax^' ^ ¹ ) ^{! 2 975} ' ^{1 750} < ^{1 720 and 1 595} · ^NMR spectrum (CDCl ₃ , ppm): 0.97 (3H, t, J = 6 Hz, CHjCH^CHjCHj), 1.2 to 2.0 (4H, m, CH ₂ CH ₂ CH ₂ CH ₃ ), 3.88 (3H, s, COOCH ₃ ), 4.33 (2H, t, J =» 6 Hz, CH ₂ CH ₂ CH ₂ CH ₃ ), 4.56 (2H, s, ClCH ₂ ) and methyl ester of 4-chloro-2-benzyloxyiminoacetoacetic acid, light yellow oily product, yield 97%. IR spectrum (In ^cm 5 : 1 755 and 1 720. NMR spectrum (CDCl ₃ , ppm): 3.87 (3Η, s, COOCH ₃ ), 4.50 (2H, s, plCH ₂ ), 5.29 (2H, s, CH ₂ -phenyl), 7.28 (5Η, s, phenyl protons).

Reference example 31

To a mixture of 20 ml of water and 25 ml of ethanol were added 7/0 g of methyl 4-chloro-2-(propoxyimino) acetoacetic acid, 2.4 g of thiourea and 4.3 g of sodium acetate trihydrate. The mixture was stirred for one hour at 40°C. After cooling, the pH of the reaction mixture was adjusted to 6.5 by adding saturated aqueous potassium carbonate solution. The reaction mixture was then stirred for 30 minutes. The resulting crystals were filtered off, washed with water, isopropyl ether and dried. Thus, crystals of methyl 2-(2-amino-4-thiazyl)-(Z)-2-(propoxyimino)acetic acid were produced, m.p. 115-116°C.

For C _g H ₁₃ N ₃ O ₃ S calculated: 44.43% C, 5.39% H, 17.27% N, found: 44.20% C, 5.38% H, 17.11% N.

In a similar manner, 2-(2-amino-4-thiazolyl)-(Z)-(butoxyimino)acetic acid methyl ester, m.p. 118°C, and 2-(2-amino-4-thiazolyl)-(Z)-2-benzyloxyiminoacetic acid, m.p. 148-149°C, are prepared.

Reference example 32

To a solution of 5.0 g of methyl 2-(2-amino-4-thiazolyl)-(Z)-2-(propoxyimino)acetic acid ester in 35 ml of N,N-dimethylacetamide, 3.25 g of chloroacetyl chloride are added dropwise over a period of ten minutes under ice-cooling and stirring. The mixture is stirred for one hour at room temperature, then poured into 200 ml of ice-water.

An oily product is separated. This product is allowed to stand to crystallize. The crystals are filtered off, washed with water and dried. 6.35 g (96.7%) of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(propoxyimino)acetic acid methyl ester are produced, m.p. 100°C.

For jHj^CINjO^S calculated: 41.35% C, 4.41% H, 13.14% N, found: 41.35% C,

4.34% H, 13.14% N.

In a similar manner, 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(butoxyimino)acetic acid methyl ester, mp 86-87 °C, yield 85%, and 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(benzyloxyimino)acetic acid methyl ester, mp 110-115 °C, yield 96% were prepared.

Reference example 33

A solution of 2.23 g of potassium hydroxide (85%) in 20 ml of water was added to a solution of 3.2 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(propoxyimino)acetic acid methyl ester in 50 ml of ethanol under ice-cooling and stirring. The mixture was stirred for 5 hours at room temperature.

The reaction mixture is then concentrated under reduced pressure. The concentrate is dissolved in 30 ml of water. The solution is washed twice with 30 ml portions of ethyl acetate, after which activated carbon is added to the solution. The carbon is filtered off, the pH is adjusted to 2 by adding 1N hydrochloric acid, the resulting crystals are filtered off, washed with water, hexane and ether and dried.

2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(propoxyimino)acetic acid is produced, m.p.

170-171 °C (dec.). Calcd. for C^gH^jClN^O^S: 39.28% C, 3.96% H, 13.74% N, found: 39.34% C, 3.84% H, 13.41% N.

In a similar manner, 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-butoxyiminoacetic acid, mp 167-168 °C (dec.) and 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-benzyloxyiminoacetic acid, mp 160-161 °C (dec.) are prepared.

Reference example 34

To a suspension of 583 mg. 2—(2'-chloroacetamido-4-thiazolyl) - (Z)-2-methoxyiminoacetic acid in 5 ml of methylene chloride is added 243 mg of triethylamine under ice cooling. To the mixture is added 416.5 mg of phosphorus pentachloride. The mixture is stirred for 30 minutes at room temperature. Methylene chloride is distilled off under reduced pressure.

The residue is washed three times with hexane and suspended in 7 ml of tetrahydrofuran. A solution of 216 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester and 308 mg of sodium bicarbonate in 4.2 ml of water is added dropwise to the suspension. The mixture is stirred for two hours at room temperature.

The solvent is evaporated. 20 ml of water is added to the residue. The solution is made slightly alkaline by adding sodium bicarbonate. The undissolved material is filtered off, washed successively with aqueous sodium bicarbonate, water, hexane and ether and dried.

This produces cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-ethoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), mp 270 to 280 °C (dec.). For C16H18ClN2OgS calcd.: 40.24% C, 3.86% H, 16.76% N, found: 39.98% C, 3.80% H,

16.91% N.

The following compounds are produced in a similar manner:

cis-3-[j2-(2-chloroacetamido-4-thiazolyl)-2-(propoxyimino)acetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 260 to 270 °C (dec.), cis-3-^2-(2-chloroacetamido-4-thiazolyl)-2-isopropoxyiminoaoetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 215 to 225 °C (dec.), cis-3-Q2-(2-chloroacetamido-4-thiazolyl)-2-(propoxyimino)acetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 275 to 280 °C (dec.), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-benzyloxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 275 to 285 °C (dec.), cis-3-[2-(5-chloro-2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 215 to 220 °C (dec.), cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid butyl ester (syn isomer), m.p. 235-239 °C (dec.) and methyl ester of trans-3-| 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamidoJ-2-oxoazetidine-4-carboxylic acid (syn isomer), mp 137-139 °C, for Cj^H^ClNgOgS.CE^OH calcd: 38.57 t C, 4.16 % H, 16.07 % N, found: 38.39 % C, 4.15 % H, 16.04 % N.

Reference example 35

To a solution of 9.3 g of ethyl 2-amino-4-thiazolyl acetate in 50 ml of N,N-dimethylacetamide was added 7.91 g of chloroacetyl chloride under ice-cooling and stirring. The mixture was stirred for one hour at room temperature. 300 ml of water was added to the reaction mixture. The resulting crystals were filtered off.

The crystals are washed with water, ether, dried over phosphorus pentoxide and weighed. This gives 12.1 g (92%) of ethyl 2-chloroacetamido-4-thiazolyl+acetic acid ester, mp 145-146 °C. For C _g H ₁₁ ClN ₂ O ₃ S calculated: 41.14% C, 4.22% H, 10.66% N, found: 41.16% C,

4.14% H, 10.86% N.

Reference example 36

To a solution of 2.5% potassium hydroxide in 10 ml of water and 100 ml of ethanol was added 3.0 g of ethyl 2-chloroacetamido-4-thiazolylacetic acid ester. The mixture was stirred for one hour at room temperature. The solvent was distilled off under reduced pressure.

10 ml of water is added to the residue. The resulting aqueous solution is washed with ethyl acetate. The pH of the solution is adjusted to 2 by adding 10% hydrochloric acid. Crystals begin to fall out of the solution. The crystals are filtered off, washed with water and dried.

2.2 g (84%) of 2-chloroacetamido-4-thiazolyl-acetic acid are produced, mp 193 to 195 °C. For C ₂ H ₂ C1N ₂ O ₃ S calculated: 35.83% C, 3.01% H, 11.94% N, found: 36.00% C,

3.15% H, 12.24% N.

Reference example 37

To a suspension of 1.41 g of 2-chloroacetamido-4-thiazolyl-acetic acid in 30 ml of methylene chloride is added 1.5 g of phosphorus pentachloride with ice-cooling and stirring. The mixture is stirred for 40 minutes at room temperature. After filtration, 1.7 g (98%) of the corresponding acid chloride hydrochloride (colorless crystals), mp 123-125 °C (dec.), is obtained. IR spectrum τ^max' cm ¹ ): 1,780 and 1,712.

To a solution of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in a mixture of 4 ml of water and 4 ml of tetrahydrofuran, 840 mg of sodium bicarbonate and then 864 mg of the above-mentioned acid chloride hydrochloride are added under ice-cooling and stirring.

The mixture was stirred for two hours at room temperature and then evaporated to dryness under reduced pressure. 5 ml of water was added to the residue. The insoluble material was filtered off, washed successively with aqueous sodium bicarbonate, water, hexane and ether and dried. This gave cis-3-[2-(2-chloroacetamido-4-thiazolyl)acetamido]-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 120-122 °C.

For ^c x2 ^H 13 ^C1N 4°5 ^S '1/2H ₂ O calculated: 38.97% C, 3.82% H, 15.15% N, found:

39.01% C, 4.23% H, 15.40% N.

Reference example 38

To a solution of 1 g of 1-butyl-2,3-dioxopiperazine in 10 ml of dry methylene chloride was added 0.766 g of trimethylchlorosilane. To the mixture was added 0.712 g of triethylamine under a stream of nitrogen at room temperature. The mixture was then stirred for one hour.

The reaction mixture is cooled to -30°C. 0.39 ml of trichloromethyl chloroformate is added dropwise to the cooled reaction mixture. The temperature of the mixture is gradually increased. The mixture is stirred for 30 minutes at room temperature. It is then evaporated to dryness under reduced pressure.

To a suspension of 0.924 g of D-(2-thienyl)glycine in 20 ml of dry methylene chloride was added 1.28 g of trimethylchlorosilane, then 1.19 g of triethylamine. The mixture was stirred for one hour at room temperature. The reaction mixture was cooled to 0°C. The solid material obtained by the above evaporation was added to the reaction mixture. The mixture was stirred for two hours at room temperature, dissolved in ethyl acetate, the solution was washed with water and brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. D-2-[4-butyl-2,3-dioxo-1-piperazinecarboxamido]-2-(2-thienyl)acetic acid was produced as a solid compound in quantitative yield.

IR spectrum (γ cm 5 : 1715, 1510 and 1180. NMR spectrum (CDCl1, ppm): 5.72 (1H, d, J = 6 Hz, CHCOOH), 9.70 (1H, d, NH).

The following two compounds are prepared in a similar manner: D-2-(4-octyl-2,3-dioxo-1-piperazinecarboxamido)-2-(2-thienyl)acetic acid, IR spectrum (in cm ^-1 ): 3,250 and 1,720.

NMR spectrum (CDCl , ppm): 5.72 (1H, d, J = 6 Hz CHCOOH), 9.75 (1H, d, J = 6 Hz, NH) and

TCRt*

D-2-(4-butyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetic acid, IR spectrum (in cm ^-1 ): 1,715, NMR spectrum (CDCl 2 , ppm): 5.40 (1H, d, J = 7 Hz, CHCOOH), 7.22 (5H, s, phenyl protons), 9.73 (1H, d, NH).

Reference example 39

To a solution of 362 mg of D-2-[4-butyl-2,3-dioxo-1-piperazinecarboxamido]-2-phenylacetic acid and 150 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 3 ml of dry N,N-dimethylformamide was added 236 mg of dicyclohexylcarbodiimide under ice-cooling. The mixture was stirred under a nitrogen stream at room temperature for 5 hours. Tetrahydrofuran was added to the reaction mixture and the insoluble material was filtered off. The filtrate was distilled off under reduced pressure.

The residue was purified by column chromatography on silica gel (200 g, eluting with a 1:1 mixture of ethyl acetate and chloroform and then with a 15:15:1 mixture of ethyl acetate, chloroform and methanol).

Cis-3-[D-2-(4-butyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester is produced as a mixture of diastereoisomers. Tentatively, the first eluted compound in the above column chromatography is called the beta-isomer, the second eluted compound is called the alpha-isomer. '

Beta-isomer: IR spectrum (in cm^): 3280, 1780, 1715 and 1680. NMR spectrum (CDCl^, ppm): 3.12 (3H, s, COOCH^), 7.24 (5H, br s, phenyl protons).

Alpha-isomer: X-ray spectrum (λ cm 2 ): 3295, 1780, 1720 and 1680. NMR spectrum (CDCl ₃ , ppm): 3.44 (br s, COOCH ₃ ), 7.27 (5H, broad singlet, phenyl protons).

The following pairs of isomers were produced in a similar manner:

cis-3-[d-2-<4-Butyl-2,3-dioxo-1-piperazinecarboxamido)-2-(2-thienyl)acetamido]-2-oxoazetidine-4-carboxylic acid methyl ester:

Beta-isomer: IR spectrum (V cm“ ¹ ): 3,300, 1,775, 1,710 and 1,675. NMR spectrum

CDCl ₃ , ppm): 3.30 (3H, s, COOCH 2 ).

Alpha-isomer: IR spectrum (γ cm- ¹ ): 3300, 1780, 1720 and 1680.

cis-[D-2-(4-octyl-2,3-dioxo-1-piperazinecarboxamido)-2-(2-thienyl)acetamido]-2-oxoazetidine-4-carboxylic acid methyl ester:

Beta-isomer: NMR spectrum (CDCl 2 , ppm): 3.31 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 5 Hz, c ₄ -h).

Alpha-isomer: NMR spectrum {CDCl 2 , ppm): 3.45 (3H, s, COOCH 3 ), 4.40 (1H, d, J = 5 Hz, c ₄ -h).

Trans-3-[D-2-(4-octyl-2,3-dioxo-1-piperazinecarboxamido)-2-(2-thienylacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester;

Beta-isomer: IR spectrum (in cm^): 3,280, 2,920, 1,780, 1,710 and 1,670. NMR spectrum (CDC1 ₃ , ppm): 3.68 (3H, s, COOCH ₃ ), 4.14 (1H, d, J = 2 Hz, C ₄ -H).

Alpha-isomer: IR spectrum and NMR spectrum are identical to the IR and NMR spectrum of the beta-isomer.

Reference example 40

To a solution of 1.18 g of cis-3-amino-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester in 5 ml of methylene chloride is added 2.7 ml of propylene oxide under ice-cooling and stirring. Then, a solution of 0.83 ml of 2,2,2-trichloroethyl chloroformate in 1 ml of methylene chloride is added dropwise over 10 minutes. The mixture is stirred for 30 minutes at room temperature. The solvent is distilled off under reduced pressure, and the residue crystallizes. The crystals are washed with ether and dried. 1.67 g (89%) of cis-1-(2,4-dimethoxybenzyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester is produced, m.p. 135-136 °C. For C^yH-^Cl^yO calculated:

43.51% C, 4.34% H, 6.34% N, found: 43.64% C, 4.42% H, 6.16% N.

Reference example 41

A solution of 228 mg of sodium borohydride in 10 ml of water was added to a solution of 939 mg of cis-1-(2,4-dimethoxybenzyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester in 10 ml of tetrahydrofuran under ice-cooling and stirring. The mixture was stirred for 10 minutes under ice-cooling and then for 4.5 hours at room temperature. The excess sodium borohydride was decomposed by adding acetic acid under ice-cooling.

The solvent was distilled off under reduced pressure. A saturated aqueous sodium chloride solution was added to the residue, and the mixture was then extracted with ethyl acetate. The extract was washed successively with 5% aqueous sodium hydrogen carbonate solution, saturated aqueous sodium chloride solution, dilute hydrochloric acid, saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a silica gel column (30 g, elution with a mixture of ethyl acetate and chloroform in a ratio of 2:1). The solvent of the eluate is distilled off. Ether is added to the residue. The resulting crystals are filtered off. The product is

with cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-?'-oxoazetidine, mp 112-114 °C. For ^c ig ^H i9 ^C l3 ^N 2°6 ⁱⁿ YP°^ ^held: 43.51% C, 4.34% H, 6.44% N, found: 43.64% C, 4.42% H, 6.16% N.

Reference example 42

To a solution of 340 mg of cis-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in 3 ml of pyridine was added 132 mg of methanesulfonyl chloride under ice-cooling and stirring. The mixture was stirred for 50 minutes at room temperature. Water and ethyl acetate were added to the mixture, and the pH was adjusted to 2 by adding dilute hydrochloric acid. The ethyl acetate layer was separated and washed successively with aqueous sodium chloride solution (saturated solution), aqueous sodium bicarbonate solution, aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

The residue crystallizes out. Ether is added to the crystals and the crystals are filtered off. 375 mg (94%) of colorless crystals of cis-1-(2,4-dimethoxybenzyl)-4-methanesulfonyloxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine are produced, m.p. · 139 to 140 °C. For C^I^Cl^^OgS calculated: 39.28% C, 4.07% H, 5.39% N, found: 39.21% C, 4.16% H, 5.48% N.

Reference example 43

A solution of 7.79 g of potassium persulfate and 4.70 g of potassium hydrogen phosphate in 180 ml of water was added dropwise to a solution of 8.32 g of cis-1-(2,4-dimethoxybenzyl)-4-methanesulfonyloxymethyl-3-(2,2,2-trichloromethoxycarboxamido)-2-oxoazetidine in 450 ml of acetonitrile while stirring for 20 minutes under a nitrogen stream at 85 °C to 90 °C. The mixture was stirred for a further 2.5 hours at the same temperature. After cooling, the pH of the solution was adjusted to 6 to 7 by adding potassium hydrogen phosphate. The product was concentrated under reduced pressure.

The concentrate is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a silica gel column (270 g, elution with ethyl acetate and hexane in a ratio of 2:1, later with pure ethyl acetate). Colorless crystals of cis-4-methanesulfonyloxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine are produced, mp 85 to 86 °C. For C _g H _1:L Cl ₃ N ₂ O ₆ S calculated: 26.00% C, 3.00% H, 7.58% N, found: 26.15% C, 3.04% H,

7.62% N.

Reference example 44

To 130 ml of methyl ethyl ketone were added 3.7 g of cis-4-methanesulfonyloxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine and 8.85 g of sodium iodide. The mixture was refluxed for three hours under a nitrogen stream. The solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed successively with aqueous sodium sulfite solution, aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

When the solvent is evaporated under reduced pressure, the residue crystallizes. Ether is added to the crystals. The crystals are filtered off. 3.56 g (88.6%) of colorless crystals of cis-3-(2,2,2-trichloroethoxycarboxamido)-4-iodomethyl-2-oxoazetidine are produced, mp 152 to 154 °C. For C ₇ HgCl ₃ IN ₂ C ₃ calculated: 20.95% C, 2.01% H, 6.98% N, found: 21.19% C, 2.06% H, 7.21% N.

Reference example 45

To a solution of 3.21 g of cis-3-(2,2,2-trichloroethoxycarboxamido)-4-iodomethyl-2-oxoazetidine in 40 ml of N,N-dimethylformamide was added 0.78 g of sodium azide. The mixture was stirred for 43 hours at room temperature, after which another 260 mg of sodium azide was added. The mixture was stirred for another 12 hours at 35 °C. Dimethylformamide was distilled off under reduced pressure. Water and ethyl acetate were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (150 g, elution with ethyl acetate and hexane in a ratio of 1:1). Colorless crystals of cis-4-azidomethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine are produced, m.p.

up to 95 °C.

Reference example 46

To a solution of 1.12 g of cis-4-azidomethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in 35 ml of ethanol is added 560 mg of 5% palladium on carbon. The mixture is stirred in a stream of hydrogen at room temperature for two hours. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of 10 ml of methylene chloride and 10 ml of N,N-dimethylacetamide. To the solution is added successively 2.45 ml of propylene oxide and 0.50 ml of acetyl chloride while cooling with ice and stirring. The mixture is stirred for 2 hours at room temperature.

The solvent was distilled off under reduced pressure. 50 ml of saturated aqueous sodium chloride solution was added to the residue. The reaction mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran (4:1). The extract was washed successively with dilute hydrochloric acid, saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. The extract was then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. 40 ml of hexane was added to the residue.

The mixture is left to stand overnight under cooling. The resulting crystals are filtered off and washed with ether. This gives cis-4-acetamidomethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine, m.p. 178-180 °C. For CgH^^CljNjO^ calcd.: 32.50% C, 3.64% H, 12.63% N, found:

32.83% C, 3.60% H, 12.79% N.

Reference example 47

To a solution of 372 mg of cis-4-acetamidomethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in 30 ml of tetrahydrofuran is added 3.0 g of activated zinc. To the mixture is added 6 ml of an aqueous solution of a mixture of phosphoric acid - potassium dihydrogen phosphate (of 1 molar concentration). The mixture is stirred for 8 hours at room temperature. To the reaction mixture is added 30 ml of tetrahydrofuran. The zinc is filtered off. The filtrate is evaporated under reduced pressure. To the residue are added 15 ml of water and 20 ml of ethyl acetate and the mixture is shaken.

The aqueous layer was separated and concentrated under reduced pressure to a volume of 11 ml. 11 ml of tetrahydrofuran was added to the concentrate. 282 mg of sodium bicarbonate and 559 mg of 2-(2-chloroacetamido-1-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride were added to the mixture under ice-cooling, while the reaction mixture was stirred. The mixture was stirred under ice-cooling for one hour. Then, 2 g of sodium bicarbonate and a saturated aqueous sodium chloride solution were added. The mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran.

The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to crystallize the residue. The crystals are mixed with ethyl acetate and ether and the mixture is filtered. Colorless crystals of cis-4-acetamidomethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn isomer) are obtained, which do not show any specific melting point, gradually decomposing with coloration at temperatures between 140 and 165 °C.

1.73 (1H,

IR spectrum (V * _ax , cm (3H, s, COCH ₃ ), 3.6 to quartet, J = 5 Hz, J = ): 3,380, 3,250, 1,760 and 1,600. NMR spectrum (DMSO-d _g , ppm):

4.0 (1H, m, C.-H), 3.90 (3H,

OCH,), 4.33 (2H, s, C1CH,), 5.16

Hz, C ₃ -H), 7.46 (1H, s, H).

Reference example 48

In 20 ml of tetrahydrofuran, 1.0 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine, 787 mg of triphenylphosphine and 441 mg of phthalimide are dissolved. 0.471 ml of diethyl azodicarboxylic acid ester is added to the solution. The mixture is stirred for one hour at room temperature. The solvent is distilled off under reduced pressure. The residue crystallizes.

To the solid crystallized residue was added 30 ml of ethyl acetate. The insoluble material was filtered off and washed with ethyl acetate to obtain 882 mg of colorless crystals of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-phthalimidomethyl-2-oxoazetidine.

The mother liquors and washings were combined and purified by silica gel column chromatography to give an additional 280 mg of colorless crystals. The total yield was 1.16 g (87.8%), m.p.

182 to 184 °C. For ^C 29 ^H 27 ^N 3°7 ⁱⁿ YP°^ ^teno: 65.11% C, 5.20% H, 7.85% N, found: 65.05% C, 5.17% H, 7.80% N.

Reference example 49

To a suspension of 1.059 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-phthalimidomethyl-2-oxoazetidine in 80 ml of ethanol is added 0.39 ml of hydrazine hydrate. The mixture is refluxed for 3.5 hours. The reaction mixture is cooled. The precipitated crystals are filtered off. The filtrate is concentrated under reduced pressure. 30 ml of methylene chloride is added to the residue. Insoluble material is filtered off. The filtrate is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 10 ml of methylene chloride and 5 ml of N,N-dimethylacetamide.

To the solution, under ice-cooling, 1.4 ml of propylene oxide and then 0.28 ml of acetyl chloride are added first. The mixture is stirred for 1 hour at room temperature. To the mixture, 10 ml of methylene chloride and 50 ml of aqueous sodium bicarbonate solution are added. The mixture is shaken. The methylene chloride layer is separated, washed successively with water, diluted hydrochloric acid, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure.

The residue is purified by chromatography on a silica gel column (100 g, elution with a mixture of chloroform and acetonitrile in the ratio 4:1, later 3:2). The solvents are distilled off from the eluate under reduced pressure. A mixture of ethyl acetate and ether (1:3) is added to the residue. The precipitated crystals are filtered off with suction.

This gives cis-4-acetamidomethyl-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, mp 195-196 °C. For ^C 23 ^H 27 ^N 3 ^O g calculated: 62.57% C, 6.16% H, 9.52% N, found: 62.20% C, 6.08% H, 9.41% N.

In a similar manner, cis-3-benzyloxycarboxamido-4-benzamidomethyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, mp 112-115°C, is prepared.

Reference example 50

To a suspension of 1.104 g of cis-4-acetamidomethyl-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine in 65 ml of acetonitrile, a solution of potassium persulfate (1.080 g) and potassium hydrogen phosphate (653 mg) in 25 ml of water was added dropwise over 15 minutes under a stream of nitrogen, while the reaction mixture was refluxed. The reaction mixture was refluxed for 1.5 hours. It was then neutralized with aqueous sodium bicarbonate and concentrated under reduced pressure.

The residue is extracted with a mixture of ethyl acetate and tetrahydrofuran (1:1). The extract is washed with an aqueous solution of sodium bicarbonate, saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off. Ethyl acetate is added to the residue. The precipitated crystals are filtered off. Cis-4-acetamidomethyl-3-benzyloxycarboxamido-2-oxoazetidine is produced, m.p. 226-228 °C.

In a similar manner, cis-3-benzyloxycarboxamido-4-benzamidomethyl-2-oxoazetidine is prepared, mp 209-211°C.

Reference example 51

To a suspension of 364 my cn s-X-aceterriciomethyl 1-3-benzyloxycarboxamido-2-oxoazetidine in a mixture of 80 ml of ethanol and 20 ml of methanol is added 364 mg of 5% palladium on carbon. The mixture is catalytically reduced with stirring, room temperature and normal pressure. The catalyst is filtered off. The solvent is distilled off from the filtrate under reduced pressure. The residue is dissolved in a mixture of 12 ml of tetrahydrofuran and 12 ml of water. To the mixture is added first 315 mg of sodium bicarbonate and then 624 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride with stirring and ice cooling.

The mixture was then stirred for one hour under ice-cooling. Then, the reaction mixture was shaken successively with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and ethyl acetate-tetrahydrofuran mixture (2:1). The organic layer was separated. The aqueous layer was extracted four times with ethyl acetate-tetrahydrofuran mixture (2:1). The organic layers were combined, washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue crystallized.

A mixture of ethyl acetate and ether (1:2) is added to the crystalline residue. The crystals are filtered off. Colorless crystals of cis-4-acetamidomethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn isomer) are produced, which have no distinct melting point, but gradually decompose with coloration in the temperature range from 140 to 165 °C. The IR and NMR spectra of this product are identical to the IR and NMR spectra of the product prepared in Reference Example 47.

In a similar manner, cis-4-benzamidomethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2- * -methoxyiminoacetamido]-2-oxoazetidine (syn isomer) is prepared. This product has no specific melting point, but gradually decomposes with coloration at temperatures in the range of 130 to 150 °C.

IC spectrum (V cm ^-1 ): 3,420, 3,260, 1,755 and 1,660. For ^C 19 ^H 19 ^C1N 6°5 ^S calculated: 47.65% C,

4.00% H, 17.55% N, found: 47.48% C, 3.86% H, 17.26% N.

Reference example 52

To a solution of 557 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in 2.6 ml of tetrahydrofuran, 1.3 ml of an aqueous solution of 189 mg of sodium borohydride was added while stirring and cooling the mixture with ice. The mixture was stirred for 80 minutes while cooling with ice. The excess sodium borohydride was then decomposed with acetic acid. The tetrahydrofuran was distilled off under reduced pressure. A saturated aqueous solution of sodium chloride was added to the residue and the mixture was extracted with ethyl acetate.

The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (30 g, eluting with ethyl acetate:acetonitrile 4:1). Colorless crystals of cis-3-benzyloxycarboxamido-4-hydroxymethyl-2-oxoazetidine were produced, m.p.

103 to 104 °C. For ^C 12 ^H 14 ^N 2°4 ⁱⁿ yP ^calculated: 57/59% C, 5.64% H, 11.19% N, found: 57.32% C, 5.41% H, 11.12% N.

Reference example 53

To a solution of 250 mg of cis-3-benzyloxycarboxamido-4-hydroxymethyl-2-oxoazetidine in 5 ml of ethanol is added 250 ml of 5% palladium on carbon. The mixture is catalytically reduced at room temperature and normal pressure with stirring. The catalyst is filtered off. The filtrate is concentrated under reduced pressure and allowed to stand while cooling. The residue crystallizes. The crystals are filtered off. 108 mg (93%) of cis-3-amino-4-hydroxymethyl-2-oxoazetidine are produced, mp 105 to 107 °C.

For C ₄ H _g N ₂ O ₂ calculated: 41.37% C, 6.94% H, 24.12% N, found: 41.40% C, 6.84% H, 23.85% N.

Reference example 54

To a solution of 58 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine in a mixture of 5 ml of methylene chloride and 1 ml of N,N-dimethylacetamide is added 0.4 ml of triethylamine under ice-cooling and stirring. Then 498 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride is added to the mixture. The mixture is stirred under ice-cooling for one hour. Then 20 ml of water is added to the mixture and the pH is adjusted to 7 to 8 with sodium bicarbonate. The reaction mixture is concentrated under reduced pressure.

The residue is extracted with a mixture of ethyl acetate and tetrahydrofuran (2:1). The extract is washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue crystallizes. A mixture of ethyl acetate and ether (1:2) is added to the crystallized residue. The crystals are filtered off. Yellow crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetamido-4-[2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetoxymethyl]-2-oxoazetidine are produced. mp 157-159 °C.

For ^C 2O ^H 2od2 ^N 8°8 ^B 2 calculated: 37.80% C, 3.17% H, 17.63% N, found: 37.85% C,

3.27% H, 17.22% N.

Reference example 55

To a solution of cis-1-(2,4-dimethoxybenzyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester in 20 ml of acetonitrile, 716 mg of crystalline sodium hydrogen phosphate and 1.08 g of potassium persulfate in 20 ml of water are added dropwise over 10 minutes while the reaction mixture is refluxed. The reaction mixture is refluxed for a further 30 minutes. After cooling the reaction mixture, the acetonitrile is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The solution obtained is washed with 5% aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a silica gel column (20 g, elution with a mixture of chloroform and ethyl acetate in a ratio of 1:2). Cis-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester is produced (colorless crystals), mp 140-141 °C. For CgH^Cl ₂ K _? O _f . calculated: 30.07% C, 2.84% H,

8.77% N, found: 30.30% C, 2.82% H, 8.87% N.

Reference example 56

To a solution of 1.41 g of cis-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester in 40 ml of tetrahydrofuran, a solution of 417 mg of sodium borohydride in 20 ml of water is added under ice-cooling and stirring. The mixture is stirred for 30 minutes under ice-cooling and one hour at room temperature. The tetrahydrofuran is distilled off under reduced pressure. The residue is dissolved in ethyl acetate. The solution is washed twice with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

The solvent is distilled off. The residue crystallizes. Ether is added to the crystallized residue. The crystals are filtered off. Cis-4-hydroxymethyl-4-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine is produced, m.p. 162 to 164 °C. IR spectrum (in max): 3,450, 3,300, 1,720 and 1,700.

cm

Reference example 57

To a solution of 468 mg of 2-thienylacetic acid in 7 ml of dry methylene chloride is added 424 mg of thionyl chloride. The mixture is refluxed for two hours. The reaction mixture is evaporated under reduced pressure. The residue is dissolved in 5 ml of dry methylene chloride.

In addition, 416 mg of triethylamine was added to a solution of cis-4-hydroxymethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in 30 ml of dry methylene chloride. To this mixture, while stirring and cooling with ice, a methylene chloride solution of the 2-thienylacetyl chloride prepared above was added dropwise. The resulting mixture was stirred for 20 minutes under ice cooling and then stirred overnight at room temperature. Ethyl acetate was added to the reaction mixture. The mixture was washed successively with 3N hydrochloric acid, aqueous sodium bicarbonate solution, aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated.

The residue is purified by chromatography on a silica gel column (60 g, elution with hexane/ethyl acetate (1:1 and 2:3). Cis-4-(2-thienylacetoxymethyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine is produced. NMR spectrum (CDCl 3 , ppm): 3.92 (2H, s

OCCH„),

I ²

O

4.71 (2H,

CClgCHg), 5.14 (1H, dd,

J = 5 Hz, J = 9 Hz, C„-H), 6.10 (1H, d, J

Hz, OCNH). II O

Reference example 58

To a solution of 600 mg of cis-4-(2-thienylacetoxymethyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in a mixture of 25 ml of tetrahydrofuran and 5 ml of IN aqueous ammonium acetate solution is added 2.16 g of activated zinc. The mixture is stirred for 5 hours at room temperature. The mixture is filtered through celite. Methylene chloride is added to the filtrate. The solution is dried over anhydrous magnesium sulfate. The filtrate is evaporated under reduced pressure. The residue is dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water. 850 g of sodium bicarbonate is added to the solution under ice cooling. 720 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride is added to the mixture.

The reaction mixture is stirred vigorously for 15 minutes under ice cooling. After stirring vigorously for one hour at room temperature, the solvent is distilled off under reduced pressure. Water is added to the residue. The separated crystals are filtered off and washed successively with water, aqueous sodium bicarbonate solution, ether and hexane. This gives cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-thienylacetoxymethyl)-2-oxoazetidine (syn isomer), mp 201 and 204 °C (dec.).

IR spectrum (in cm^): 3,280, 1,760 and 1,660. NMR spectrum (DMSO-dg, ppm): 3.86 (3H, s, OCH ₃ ), 3.90 (2H, s, OCCH ₂ ), 4.32 (2H, s, ClCH ₂ ), 7.48 (1H, s, SH).

About X

Reference example 59

To a solution of 314 mg of 1-methyl-1H-tetrazol-5-yl-mercaptan in 2 ml of dry N,N-dimethylformamide, 65 mg of sodium hydride was added under ice-cooling. The mixture was stirred for 10 minutes under ice-cooling and 10 minutes at room temperature. To the mixture was added a solution of 724 mg of cis-3-(2,2,2-trichloroethoxycarboxamido)-4-iodomethyl-2-oxoazetidine in 3 ml of N,N-dimethylformamide. The reaction mixture was stirred for two days at room temperature. The reaction mixture was dissolved in ethyl acetate, the solution was washed five times with water, then with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (60 g, elution with a mixture of hexane and ethyl acetate in a ratio of 1:2 and 1:4).

610 mg (86.8%) of crystals of cis-4-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine are produced, mp 67-69 °C. IR spectrum (in ™ ^:

300 and 1,740.

Reference example 60

To 10 ml of tetrahydrofuran is added 1.49 ml of a solution of methyl mercaptan in 4N tetrahydrofuran. A solution (1.37 ml) of butyl lithium in (1.6N) hexane is then added dropwise to this solution under ice cooling. The mixture is stirred for 10 minutes under a stream of nitrogen under ice cooling. The mixture is then cooled to -45 °C. To the thus cooled mixture is added a solution of 800 mg of cis-3-(2,2,2-trichloroethoxycarboxamido)-4-iodomethyl-2-oxoazetidine in 5 ml of tetrahydrofuran. The temperature of the reaction mixture is gradually increased to -20 to -30 °C.

At this temperature, the reaction mixture was stirred for 4 hours. Then, the reaction mixture was dissolved in ethyl acetate, saturated aqueous ammonium chloride solution was added, and the mixture was stirred. The organic layer was separated, washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100 g, elution with hexane/ethyl acetate in a ratio of 2:1 and 1:1), to give crystals of cis-4-methylthiomethyl-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine, m.p. 114 to 115 °C.

IC spectrum (in ^KBr , cm ¹ ): 3,350, 1,780 and 1,715. ^ť max '

Reference example 61

To a solution of 674 μl of cis-4-(1-methyl-1H-tetrazol-5-yl-thiomethyl)-3-(2,2,2-trichloroethoxycarboxamido)-2-oxoazetidine in 10 ml of tetrahydrofuran is added 2 ml of 1N aqueous ammonium acetate solution. To the mixture is added 1 g of activated zinc. The mixture is stirred for 3 hours at room temperature. The reaction mixture is filtered. To the filtrate is added methylene chloride. The solution is dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 3 ml of tetrahydrofuran and 3 ml of water. To the solution is added 1.02 g of sodium bicarbonate under ice-cooling. To the mixture is added 863 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride.

The mixture was then stirred under ice-cooling for 15 minutes and 1 hour at room temperature. The solvent was distilled off under reduced pressure. Water was added to the residue. The separated crystals were filtered off with suction, washed successively with water, aqueous sodium bicarbonate solution, ether and hexane and dried. Crystals of cis-3-[2-(2-chloroactamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(1-methyl-1H-tetrazol-5-ylthiomethyl)-2-oxoazetidine (syn isomer) were produced, mp 195-198°C (dec). IR spectrum ( ^λ

In a similar manner, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylthiomethyl-2-oxoazetidine (syn isomer), mp 172-176°C (dec.), is prepared.

Reference example 62

To a suspension of 1.0 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methanesulfonyloxymethyl-2-oxoazetidine in 50 ml of methyl ethyl ketone was added 1.88 g of sodium iodide. The mixture was stirred for 6 hours at 90 °C. The solvent was distilled off under reduced pressure. 150 ml of ethyl acetate and 100 ml of water were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate.

The solvent is distilled off under reduced pressure. The resulting solid residue is recrystallized from 50 ml of a mixture of hexane and ethyl acetate (1:1). 850 mg (80%) of colorless needles of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-iodomethyl-2-oxoazetidine are produced, mp 165-166 °C. For ^C 2i ^H 23 ^IN 2°5 ⁱⁿ YP° read: 49.43 % C, 4.54 % H, 5.49 % N, found: 49.55 % C, 4.56 % H,

5.67% N.

Reference example 63

To a solution of 3.29 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-iodomethyl-2-oxoazetidine in 10 ml of hexamethylphosphoramide is added 1.62 g of sodium cyanoborate. The mixture is stirred for 5 hours under a stream of nitrogen at 90 to 100 °C. The reaction mixture is added to 250 ml of ether, washed with six 20 ml portions of water, once with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure.

Ether and hexane were added to the resulting solid residue. The mixture was filtered. 2.15 g (86.7%) of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methyl-2-oxoazetidine were thus produced, mp 130-132 °C. For ^C 2i ^H 24 ^N 2°5 ⁱⁿ YP°^ ^, 65.61% C, 6.29% H, 7.29% N, found:

65.23% C, 6.49% H, 7.53% N.

Reference, example 64

To an aqueous solution of potassium carbonate is added 5.10 g of 2,4-dimethoxybenzyl amine hydrochloride. The resulting oily product is extracted with 120 ml of benzene. The extract is washed with water and dried over anhydrous sodium sulfate. To the extract is added 3.50 g of p-chlorobenzaldehyde. The mixture is refluxed for one hour with a device that removes moisture from the reaction mixture (water separator).

After evaporation of the solvent, the residue crystallizes. The crystals are dissolved in 68 ml of methylene chloride. A solution of 3.8 ml of triethylamine in 20 ml of methylene chloride is added to the resulting solution while stirring at a temperature of -5 °C to -10 °C. A solution of 6.15 g of phthalimidoacetyl chloride in 25 ml of methylene chloride is added dropwise to the mixture. After 20 minutes, a solution of 1.9 ml of triethylamine in 10 ml of methylene chloride and a solution of 3.1 g of phthalimidoacetyl chloride in 13 ml of methylene chloride are added. The resulting mixture is stirred for 7 hours under ice cooling and then left to stand overnight under cooling.

The mixture is washed successively with water, aqueous sodium bicarbonate solution, 5¾ hydrochloric acid, water, dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure.

The residue is purified by chromatography on silica gel (60 g, elution with a mixture of chloroform and methanol in a ratio of 20 μl). 9.4 g (84%) of colorless crystals of cis-4-(4-chlorophenyl)-1-(2,4-dimethyoxybenzyl)-3-phthalimido-2-oxoazetidine are produced. Recrystallization from a mixture of acetone and hexane produces colorless prisms, mp 178 to 180 °C. For ^26 ^Η 21^1 ^Ν 2θ5 ⁱⁿ YP°^ ^observed: 65.46 % C, 4.44 % H, 5.87 % N, found: 65.42 % C, 4.42 % H, 5.90 % N.

Reference example 65

To a solution of 4 g of cis-4-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-phthalimido-2-oxoazetidine in 50 ml of methylene chloride was added 0.89 ml of methylhydrazine. The mixture was stirred for 17 hours at 35-40°C, then filtered and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue. The resulting insoluble material was filtered off. The filtrate (about 100 ml) was extracted with a mixture of water (30 ml) and 10% hydrochloric acid (10 ml). The extract was neutralized with aqueous sodium bicarbonate, extracted twice with methylene chloride and saturated aqueous sodium chloride.

The washed extract was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue (2.6 g) was dissolved in 30 ml of methylene chloride. 5.5 ml of propylene oxide was added to the solution with stirring and ice-cooling. Then 2.3 g of carbobenzoxy chloride was added dropwise. The mixture was stirred for 2 hours at room temperature. The solvent was distilled off under reduced pressure.

Hexane was added to the residue. The resulting crystals were filtered off and washed with isopropyl ether. 3.31 g (81%) of cis-3-benzyloxycarboxamido-4-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-2-osphe- ‘ azetidine were produced. *

IR spectrum (in ^KBr , cm ^-1 ): 3,325, 1,759 and 1,688. NMR spectrum (CDC1,, ppm): 3.59 and 3.77 max -j (2 χ 3H, 2 xs, 2 x OCH-,) , 4.70 (1H, d, J = 5 Hz, C ₄ -H), 5.20 (Ih, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 5.82 (1H, d, J = 9 Hz, NH).

Reference example 66

To a solution of 2.15 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methyl-2-oxoazetidine in 150 ml of acetonitrile, a solution of 2.42 g of potassium persulfate and 1.46 g of potassium hydrogen phosphate in 75 ml of water was added dropwise at a temperature ranging from 90 to 100 °C. The mixture was heated at the same temperature under reflux for 1.5 hours. The acetonitrile was evaporated under reduced pressure. Ethyl acetate and water were added to the residue and the mixture was shaken. The ethyl acetate layer was separated, washed with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (200 g, elution with a hexane-ethyl acetate mixture in a ratio of 1:2).

Crystals of cis-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine are produced, mp 168-169°C. For ^c i2 ^H 14 ^N 2°3 ⁱⁿ yP ^calculated: 61.53% C, 6.02% H, 11.96% N, found: 61.36% C, 6.05% H, 11.65% N.

In a similar manner, cis-3-benzyloxycarboxamido-4-(4-chlorophenyl)-2-oxoazetidine is prepared.

IR spectrum (λ ^cm 310, 3225, 1772, 1722 and 1684. NMR spectrum (DMSO-d 6 , ppm):

4.85 (2H, s, CH ₉ ), 7.74 (IH, d, J = 9 Hz, OCNH), 8.55 (IH, broad singlet, Ν _Ί -Η), 6.90 to — I ·*

7.50 (9H, aromatic protons). O

Reference example 67

To a suspension of 210 mg of cis-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine in 10 ml of ethanol was added 210 mg of 5% palladium on carbon. The mixture was stirred for one hour under a stream of hydrogen. The mixture was filtered and the solvent was distilled off from the filtrate. The residue crystallized (m.p. 111-112 °C).

1 ml of water and 1 ml of tetrahydrofuran were added to the crystals. 382 mg of sodium bicarbonate were added to the solution under ice-cooling. 453 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride were added to the mixture under vigorous stirring. The resulting mixture was stirred under ice-cooling for 15 minutes and one hour at room temperature.

Then, the solvent was distilled off under reduced pressure. Water was added to the residue. The insoluble material was filtered off, washed with water, aqueous sodium hydrogen carbonate solution, ether and hexane in order. 276 mg (84%) of crystals of cis-3-p-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido-4-methyl-2-oxoazetidine (syn isomer) were obtained, mp 212-215°C (dec.).

and,

IR spectrum (in _ma ^, ^cm J = 6 Hz, C ₄ -CH ₃ ), 3.90 Hz, C ₃ -H), 7.40 (IH, p.

- ¹ ): 3260, 1755 and 1670. NMR spectrum (DMSO-dg, ppm): 1.16 (3H, (3H, s, OCH ₃ ), 4.36 (2H, s, C1CH ₂ ), 5.15 (IH, dd, J = 5 Hz, J =

In a similar manner, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(4-chlorophenyl)-2-oxoazetidine (syn isomer) was prepared. IR spectrum (V cm ¹ ): 3,250, 1,740 and 1,652. NMR spectrum (DMSO-dg, ppm): 3.66 (3H, s, OCH ₃ ), 4.30 (2H, s, C1CH ₂ ), 4.96 (1H, d, J = 5 Hz, C ₄ -H) , 5.39 (1H, dd, J = 5 Hz, J = 9 Hz), 5.82 (1H, s, SyH), 9.24 (1H, d,

J = 9 Hz, C ₃ -NH). A

Reference example 68

To a solution of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid 1,4 methyl ester in 14 ml of methanol, a solution of 0.9 g of potassium carbonate in 9 ml of water was added dropwise under ice-cooling. The mixture was stirred for one hour at room temperature. The methanol was distilled off. The remaining aqueous solution was washed with ethyl acetate and neutralized with dilute hydrochloric acid. The neutralized solution was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.

The residue crystallizes. Ethyl acetate is added to the crystals and the mixture is filtered. 1.1 g (84.6%) of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid is thus produced. Recrystallization from acetonitrile gives crystals with mp 156-157 °C. For ^c y2 ^H 12 ^N 2 ^O 5 ⁱⁿ yP°^ ^teno!

54.54% C, 4.57% H, 10.60% N, found: 54.55% C, 4.45% H, 10.77% N.

Reference example 69

To a solution of 1.32 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid in dry tetrahydrofuran was added 4 g of dicyclohexylcarbodiimide. After ten minutes, 0.5 ml of a 40% aqueous solution of dimethylamine was added to the mixture. The mixture was stirred for two hours at room temperature.

The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. To the residue were added ethyl acetate and an aqueous sodium bicarbonate solution. The mixture was shaken. The ethyl acetate layer was separated, washed with an aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. Crystal salts of cis-3-benzyloxycarboxamido-4-(Ν,Ν-dimethylcarbamoyl)-2-oxoazetidine were produced.

IR spectrum (in ^χθ ¹ ' cm ^-1 ): 3,280, 1,785, 1,770, 1,730, 1,690 and 1,640. NMR spectrum (DMSO-dg, ppm): 2.77 and 2.80 (2 x 3H, 2 xs, 2 x CH.j), 4.53 (1H, d, J = 5 Hz, C ₄ ~H) , 5.36 (1H, dd, J = 5 Hz, J = 9 Hz) (CjH) .

Reference example 70

To a solution of 291 mg of cis-3-benzyloxycarboxamido-4-(Ν,Ν-dimethylcarbamoyl)-2-oxoazetidine in 10 ml of methanol was added 291 mg of 5% palladium on carbon. The mixture was catalytically reduced at room temperature and normal pressure. After two hours, the reaction mixture was filtered and the solvent was evaporated from the filtrate. 141 mg (90%) of colorless crystals of cis-3-amino-4-(Ν,Ν-dimethylcarbamoyl)-2-oxoazetidine were produced. This product was treated with 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride in the same manner as in Reference Example 34. Crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(N,N-dimethylcarbamoyl)-2-oxoazetidine are produced, mp 160-165 °C. IR spectrum CV ^ax^' ^cm ^) ^{! 3} 200,

760 and 1,640.

Reference example 71

To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 10 ml of tetrahydrofuran and 5 ml of 1N sodium bicarbonate, which is stirred under ice-cooling, a solution of 0.32 ml of 2-thienyl-acetyl chloride in 10 ml of tetrahydrofuran is added dropwise. After stirring for 10 minutes, 100 ml of ethyl acetate and 20 ml of saturated aqueous sodium chloride solution are added to the mixture. The mixture is then further stirred. The organic layer is separated. The aqueous layer is extracted with 30 ml of ethyl acetate. The extract is combined with the organic layer. The combined organic layers are washed with 3 x 20 ml of saturated aqueous sodium chloride solution, dried and the solvent is distilled off under reduced pressure.

4 ml of a solvent mixture (ethyl acetate and hexane in a ratio of 1:2) are added to the residue. The separated crystals are filtered off and dried. 430 mg (80%) of cis-3-(2-thienylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester are obtained, mp 133 to 136 °C. For CjjHijNjOjS calculated 49.43% C, 4.15% H, 10.48% N, found: 49.00% C, 4.37% H, 10.20% N.

Reference example 72

To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 4 ml of propylene oxide and 3 ml of N,N-dimethylacetamide, which is stirred under ice cooling, is added dropwise

400 mg of ΙΗ-tetrazol-1-yl-acetyl chloride. The reaction mixture is stirred for thirty minutes. ♦ 50 ml of ethyl ether is added to the mixture. Stirring is continued while cooling to -30 C. The upper layer is removed by decantation. The lower layer is treated (twice) as above. 10 ml of acetone is added to the mixture. The resulting solution is purified by chromatography on a silica gel column (40 g, x 10 cm), eluting with a mixture of acetone - methylene chloride (1:1).

After drying, 403 mg (84%) of cis-3-(1H-tetrazol-1-yl-acteamido)-2-oxoazetidine-4-carboxylic acid methyl ester was obtained. For CgH^gNgO^;2/3CH ₃ COCHg calculated: 41.00% C, 4.82% H,

28.69% N, found: 41.16% C, 5.08% H, 28.65% N.

Reference example 73

To a mixture of 697.6 mg of nalidixic acid and 10 ml of methylene chloride, which is stirred at room temperature, 2 ml of thionyl chloride are added and stirring is continued for two hours. The reaction mixture is evaporated to dryness under reduced pressure. The residue is dissolved in 5 ml of N,N-dimethylacetamide.

In addition, a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 6 ml of propylene oxide and 3 ml of N,N-dimethylacetamide was stirred under ice-cooling. To this solution was added 5 ml of the N,N-dimethylacetamide solution prepared above. The mixture was stirred at room temperature for two hours. Insoluble materials were filtered off. The filtrate was shaken with a mixture of 100 ml of ethyl acetate and 200 ml of water. The organic layer was separated, washed with saturated aqueous sodium chloride solution (3 x 50 ml), dried and distilled to dryness under reduced pressure. The residue was purified by silica gel column chromatography. Cis-3-(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-ylcarbonylamino)-2-oxoazetidine-4-carboxylic acid methyl ester is prepared,

mp 223 to 224 °C. 1C spectrum (in cm ^-1 ): 3,400, 1,780, 1,765 and 1,745.

max

Reference example 74

To a solution of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester in 2 ml of N,N-dimethylacetamide, which is stirred under ice-cooling, is added 534 mg of mixed mandelic and carbonic anhydride. The mixture is stirred for 30 minutes at room temperature. Then the mixture is stirred under ice-cooling: 1.05 ml of chloroacetyl chloride is added dropwise to the thus stirred mixture and stirring is continued for 3 hours at room temperature. The reaction mixture is shaken with 100 ml of ethyl acetate and 20 ml of IN hydrochloric acid. The organic layer is then separated. The organic layer is washed successively with saturated aqueous sodium chloride solution (3 x 30 ml), 20 ml of IN aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution (3 x 30 ml), dried and the solvent is distilled off under reduced pressure.

The residue was purified by silica gel column chromatography to give cis-3-(2-chloroacetyloxy-2-phenylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester. IR spectrum (cm ^-1 ): 3300, 1760, 1695, 1530, 1220, 1160, 740 and 700.

Reference example 75

To a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 1 ml of tetrahydrofuran, 2 ml of water and 15 ml of 1N aqueous sodium bicarbonate solution, which is stirred under ice-cooling, 469 mg of D-alpha-sulfophenylacetyl chloride is added dropwise. The mixture is stirred for 10 minutes under ice-cooling and then for one hour at room temperature. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in 5 ml of water. The aqueous solution is chromatographed on an Amberlite XAD-II column and then on a Sephadex LH-20 column.

The eluate is lyophilized. The sodium salt of cis-3-(D-2-sulfo-2-phenylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester is produced. For C^H^N^NaO^S. 3/2^0 calculated: 39.90% C, 4.12% H 7.16% N, found: 39.78% C, 4.48% H, 7.29% N.

Reference example 76

A mixture of 2.7 g of phenylmalonic acid monobenzyl ester and 5 ml of thionyl chloride is stirred for 16 hours at room temperature. The mixture is concentrated under reduced pressure. To the residue is added enough methylene chloride to make the total volume 10 ml.

In addition, a mixture of 288 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, 0.42 ml of triethylamine and 10 ml of methylene chloride is prepared and stirred under ice-cooling.

To this mixture, 3 ml of the methylene chloride mixture prepared above was added dropwise. The reaction mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure. 200 ml of ethyl acetate and 30 ml of water were added to the residue and the mixture was shaken. The organic layer was separated, washed with saturated aqueous sodium chloride solution (3 x 30 ml), 20 ml of 1N hydrochloric acid, saturated aqueous sodium chloride solution (2 x 20 ml), dried and the solvent was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column with a mixture of ethyl acetate and methylene chloride (1:1). Cis-3-(2-benzyloxycarbonyl-2-phenylacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester is produced, IR spectrum cm ^-1 ): 3,300, 1,780, 1,740, 1,690, 1,530, 1,270, 1,210 and 1,160.

Reference example 77

The 3-amino compound, which was prepared from 400 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in a similar manner to Reference Example 3, was dissolved in 151 ml of tetrahydrofuran. To the solution was added 120 mg of cyanoacetic acid, and the mixture was stirred under ice-cooling. To the mixture was added 290 mg of dicyclohexylcarbodiimide, and the mixture was stirred for two hours. The reaction mixture was filtered, and the filtrate was concentrated. To the residue was added 30 ml of ethyl acetate, the solution was filtered again, and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (20 g, elution with ethyl acetate).

Cis-3-(2-cyanoacetamido)-2-oxoazetidine-4-carboxylic acid methyl ester is produced.

IR spectrum (V cm ¹ ): 3,300, 2,250, 1,758 and 1,680. NMR spectrum (DMSO-dg, ppm): 3.60 (2H, s, CH ₂ ), 3.67 (3H, s, CHj), 4.39 (1H, d, J= 6 Hz, C ₄ -H), 5.28 (1H, dd, J = 6 Hz, J = = 9 Hz, C ₃ -H).

Reference example 78

A solution of 552 mg of potassium carbonate in 12 ml of water was added dropwise to a suspension of 808 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) in 40 ml of methanol under ice-cooling. The mixture was stirred for one hour at room temperature. 6 ml of 1N hydrochloric acid was added to the reaction mixture. The methanol was distilled off. The remaining aqueous solution was washed with ethyl acetate. The pH was adjusted to 2 by adding dilute hydrochloric acid.

The product is extracted with a mixture of ethyl acetate and tetrahydrofuran (1:2). The extract is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The residue is suspended in a mixture of 40 ml of methylene chloride and 10 ml of tetrahydrofuran. 1.0 ml of pyridine is added to the suspension while stirring at room temperature. Then, a solution of 864 mg of p-nitrobenzyl chloroformate in 4 ml of methylene chloride is added dropwise over 30 minutes, the mixture is stirred for 30 minutes at room temperature, washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and aqueous ammonium chloride solution.

After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (100 g, elution with ethyl acetate). Crystals of p-nitrobenzyl ester of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid (syn isomer) are produced, mp 231 to 236 °C (dec.) IR spectrum (V cm ^-1 ): 3,250, 1,760, 1,750, 1,670, 1,550 and 1,510. NMR spectrum (DMSO-dg, ppm): 3.83 (3H, s, NOCHj), 4.33 (2H, s, ClCH ₂ ), 4.58 (1H, d, J = 6 Hz, C^-B), 5.25 (2h, s, OCH ₂ Ar), 5.48 (1H, dd, J = 6

ArH), 8.17 (2H, d, J » 9 Hz,

12.87 (1H, br s, _C1CH2CONH ).

Reference example 79

ArH), 8.77 (1H, br s, Nj-H), 9.56 (1H, d, J = 9 Hz, C ₃ -NH),

In a mixture of 510 ml of dioxane and 42.6 ml of acetic acid, 53.2 g of ethyl 2-chloroacetamido-4-thiazolyl acetic acid ester are dissolved. 28.3 g of selenium dioxide are added to the mixture. The mixture is stirred for 4 hours at 110-115 °C. After cooling, the resulting black precipitate is removed. The solution obtained is concentrated under reduced pressure. The residue is dissolved in 3 liters of ethyl acetate. The solution is washed twice with aqueous sodium bicarbonate and then twice with water, dried over anhydrous sodium sulfate and concentrated to a volume of 1 liter.

The concentrate is refluxed until the precipitate dissolves. 800 ml of hexane is added and the solution is cooled. Fine needles of ethyl 2-chloroacetamido-4-thiazolylglyoxylic acid are produced, which melt at 178-180 °C after recrystallization from a mixture of ethyl acetate and hexane. IR spectrum (V, cm b): 3220, 3000, 1740, 1710, 1680 and 1550. NMR spectrum (DMSO-dg, ppm): 1.31 (3H, t, CH ₂ CH ₃ ), 4.55 (2H, q, Cl^ClI-*), 4.40 (2H, s, C1CH ₂ ), 8.49 (1H, s,

S. /H) .

For Cg118Cl12O2S calculated: 39.07% C, 3.28% H, 10.12% N, found: 39.16% C, 3.21% H, 10.13% N.

Reference example 80

35 g of ethyl 2-chloroacetamido-4-thiazolyl-glyoxylic acid ester are suspended in 646 ml of ethanol. 1N aqueous potassium hydroxide solution (250 ml) is added dropwise to the suspension while cooling with ice and stirring. The mixture is stirred for one hour at room temperature. It is then concentrated under reduced pressure to a volume of 200 ml. Water (200 ml) is added and the mixture is washed with 400 ml of ethyl acetate. After decolorization with activated carbon, the pH of the solution is adjusted to 1.5 by adding 10% hydrochloric acid, whereby light yellow crystals are separated.

The crystals are filtered off, washed first with water, then with hexane and dried. 2-chloroacetamido-4-thiazolylglyoxylic acid is produced. Recrystallization from a mixture of ethyl acetate and hexane gives light yellow prisms, mp 205-210 ^° C (dec.). IR spectrum (V cm b: 3,450,

200, 1,730 to 1,690, 1,680 and 1,560. NMR spectrum (DMSO-d6, ppm): 4.29 (2H, s, ClCH3)', and 8.30 (1H, s, S^. H). For C^H^ _C1N2O ^S calculated: 33.81% C, 2.03% H, 11.27% N, found:

33.94% C, 2.04% H, 11.23% N.

Reference example 81

To 50 ml of dry N,N-dimethylformamide are added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate. Then 8.5 g of potassium carbonate are added. The mixture is stirred for 2 days at room temperature, after which it is poured into 400 ml of water. The resulting crystalline precipitate is filtered off, washed with water, then with hexane and finally with ether. Colorless needles of N-methoxy-carbonyl-methyloxyphthalimide are produced. mp 137-142 °C. IR spectrum cmb: 1,790, 1,760 and 1,730. NMR spectrum (DMSO-dg, ppm): 3.71 (3H, s, COOCH ₃ ), 4.8 (2H, s, NOCH ₂ ), 7.77 (4H, s, aromatic protons).

In the same manner as above, the following compound is prepared: N-(-nitrobenzyl-.

n KBr oxycarbonylmethyloxy)phthalimide, mp 158 to 160 C. IR spectrum ( ⁱⁿ ma^/cm ): 1785, 1760 and 1730. NMR spectrum (DMSO-dg, ppm): 4.94 (2H, s, NOCHp, 5.32 (2H, s, COOCH ₂ ).

For ^C 17 ^H 12 ^N 2°7 calculated: 57.31% C, 3.40% H, 7.86% N, found: 57.22% C, 3.32% H, 7.93% N.

Reference example 82

3.5 g of N-methoxycarbonylmethyloxyphthalimide was dissolved in 60 ml of methylene chloride, and 745 mg of hydrazine hydrate was added under ice cooling and stirring. The mixture was stirred for 2 hours at room temperature. Then, another 149 mg of hydrazine hydrate was added. The mixture was stirred for 2 hours. The resulting crystalline precipitate was filtered off. The filtrate was washed with 15 ml of dilute aqueous ammonia and then 15 ml of water. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off.

10 ml of ether was added to the residue and the insoluble material was filtered off. Concentration of the filtrate produced a light yellow oil of O-methoxycarbonylmethylhydroxylamine.

IR spectrum (V cmb: 3,320, 2,950 and 1,740. NMR spectrum (CDC1 _Q + DMSO-d,, ppm):

max o o

3.73 (3H, s, CH ₃ ), 4.2 (2H, s, CH ₂ ), and 6.07 (2H, br s, NH ₂ ).

100

In the same manner as above, the following compound was prepared: O-(p-nitrobenzyloxycarbonylmethyl)-hydroxylamine. IR spectrum ( ^{in cm} 5 : 3325, 1760, 1720 and 1600.

NMR spectrum (CDCl 3 , ppm): 4.33 (2H, s, NOCH 3 ).

Reference example 83

In a mixture of 20 ml of water and 12 ml of tetrahydrofuran, 1.0 g of 2-chloroacetamido-4-thiazolylglyoxylic acid, prepared according to Example 80, was dissolved. 465 mg of O-methoxycarbonylmethylhydroxylamine was added under ice cooling. The pH of the mixture was adjusted to 5 by adding 1N aqueous sodium hydroxide solution. The mixture was stirred for 20 hours at room temperature. The pH was adjusted to 7 by adding aqueous sodium bicarbonate. The solution was washed with two (15 ml) portions of ethyl acetate.

The aqueous layer was separated and the pH was adjusted to 2 by adding 2N hydrochloric acid. The precipitated crystals were filtered off and washed successively with water, hexane and ether to give colorless crystals of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetic acid, mp 177-179 °C (dec.).

IR spectrum (V cm ¹ ): 3,200, 1,750, 1,725 and 1,690. NMR spectrum (DMSO-d 6 , ppm):

3.69 (3H, s, COOCH ₃ ), 4.39 (2H, s, CICHJ, 4.71 (2H, s, NOCHj ), 7.41 (1H, s, SH), 12.7 (1H, br s, NH). A

In the same manner as above, the following compound was prepared: 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)acetic acid, m.p.

168 to 170 °C (decomposition). IR spectrum (ν™ _χ , cm ^-1 ): 3,200, 1,760, 1,710 to 1,680, 1,520.

NMR spectrum (DMSO-dg, ppm): 4.34 (2H, s, CICHj), 4.84 (2H, s, NOCHp, 5.33 (2H, s, COOCH ₂ ) ,

For C^gH^jClN^OgS calculated: 42.06% C, 2.87% H, 12.27% N, found: 41.95% C,

2.86 i H, 12.30% N.

Reference example 84

810 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetic acid was suspended in 20 ml of methylene chloride. 602 mg of phosphorus pentachloride was added under ice-cooling and stirring. The mixture was stirred under ice-cooling for one hour and at room temperature for 30 minutes. 30 ml of hexane was added under ice-cooling. The resulting crystals were filtered off and washed with hexane, yielding 910 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetyl chloride hydrochloride, m.p. 77-80 °C.

IR spectrum (V ^χ' ^cm_1 ) ^: 3,000, ^1,775 ' ^{1,740 and} 1,695. ^For C ₁₍₎ H ₉ C1 ₂ N ₃ O ₅ S.HC1 calculated: 30.74 i C, 2.58 % H, 10.76 % N, found: 30.69 % C, 3.46 % H, 10.89 i N.

In the same manner as above, the following compound is prepared: 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)acetyl chloride hydrochloride, mp 158 to 161 °C. IR spectrum <V max' c®” ¹ ) ^{! 2 940} < ^{1 7θθ} ' ^{1 740 and 1} 680. ^{For C} 16 ^H 12 ^C1 2 ^N 4°7 ^S · .HC1 calculated: 37.55% C, 2.56% H, 10.59% N, found: 37.61% C, 2.65% H, 10.87% N.

Reference example 85

280 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester is dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of water. 773 mg of sodium bicarbonate is added to the solution.

Under ice cooling and stirring, 910 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxycarbonylmethyloxyiminoacetyl chloride hydrochloride is added. The mixture is stirred for two hours at room temperature. Water is added to the reaction mixture. The resulting crystals are filtered off and washed successively with water, hexane and ether. Cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxycarbonylmethyloxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) is produced,

m.p. 260 to 265 °C (dec.).

i101

IR spectrum (V cm ^X ) : 3,290, 2,950, 1,780 to 1,730, 1,685 and 1,660. For ^c 15 ^H 16ClN ₅ O _g S calculated: 39.01% C, 3.49% H, 15.17 » N, found: 39.00 » C, 3.58% H, 15.06% N.

In the same manner as above, the following compound was prepared: cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-(p-nitrobenzyloxycarbonylmethyloxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer), mp 270-275°C (dec.).

IR spectrum (y cm 5 : 3 250, 1 760, 1 700 and 1 675. For ^C 2i ^H i9 ^C1N 6°10 ^S calculated:

43.27% C, 3.38% H, 14.42% N, found: 42.85% C, 3.38% H, 14.27% N.

Reference example 86

15.3 g of p-nitrobenzyl alcohol are dissolved in 250 ml of dry ether. 8.90 ml of pyridine are added to the solution under ice-cooling and stirring. 25.3 g of alpha-bromoisobutyl bromide are then added dropwise over 50 minutes. The mixture is stirred for 5 hours at room temperature. The resulting crystalline precipitate is filtered off and washed with ether: the filtrate with the washed ether portions are combined and 150 ml of ethyl acetate is added to this solution. The mixture is washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate, aqueous sodium chloride and dried over anhydrous magnesium sulfate.

The solvent is then distilled off under reduced pressure. The residue is chromatographed on silica gel (600 g silica gel on a column, column elution with a mixture of chloroform and hexane in a ratio of 1:1). 29.6 g of a yellow oil of p-nitrobenzyl ester of alpha-bromoisobutyric acid are thus produced. This product solidifies over time on standing under cooling. IR spectrum (V ^{cm !} 735, 1,520,

345 and 1150. NMR spectrum (CDCl ₃ , ppm): 1.96 (6H, s, 2 x methyl group), 5.27 (2H, s, COOCH 3 ), 7.49 and 8.13 (2 x 2H, 2 xd, aromatic protons).

Reference example 87

In 75 ml of dry N,N-dimethylformamide, 14.7 g of N-hydroxyphthalimide and 27.2 g of alpha-bromoisobutyric acid p-nitrobenzyl ester are dissolved. 12.4 g of potassium carbonate are added to the solution. The mixture is stirred for one hour at room temperature. Since stirring becomes increasingly difficult due to the precipitation of an orange-colored solid, 75 ml of N,N-dimethylformamide are added to the mixture. The mixture is stirred for 24 hours at room temperature. The volume of the reaction mixture is reduced to about one half of the original volume by distilling off the solvents and the concentrate is poured into 700 ml of water under ice cooling and stirring. The mixture is stirred for 30 minutes. The resulting crystalline precipitate is filtered off and washed with water.

The crystals were dissolved in 500 ml of methylene chloride. The solution was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The solid residue was washed with a 1:1 mixture of ether and petroleum ether with a small amount of ether. Colorless crystals of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide (27.0 g) were obtained, m.p. 145-146 °C.

IR spectrum (in _ma ^z cni ): 1,790, 1,740, 1,735, 1,520 and 1,345. NMR spectrum (DMSO-dg, ppm): 1.61 (6H, s, 2 x CH ₃ ), 5.28 (2H, s, NOCH ₂ ), 7.59 á 8.10 (2 x 2H, two doublets,

NO ₂ ), 7.75 (4H, s, (^J

For C _lg H ₁₆ N ₂ O ₇ calculated: 5í.38% C, 4.20% H? 7.29% N, found: 59.14% C, 4.27% N, 7.26% N.

102

Reference Example 88 7.68 g of N-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxy]phthalimide were dissolved in 80 ml of methyl chloride. Under ice cooling and stirring, 0.97 ml of hydrazine hydrate was added. The mixture was stirred for two hours at room temperature. Then, another 0.97 ml of hydrazine hydrate was added. The mixture was stirred for three hours, and the resulting crystalline precipitate was filtered off and washed with methylene chloride. The filtrate was combined with the washed methylene chloride portions. The combined solutions were further washed with dilute aqueous ammonia, water and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (300 g, eluting with a 1:1 mixture of ethyl acetate and hexane). 4.58 g of yellow oil of O-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyl]hydroxylamine were obtained. This product solidified upon cooling.

IR spectrum (V cm ^-1 ): 3,310, 3,250, 2,980, 2,930, 1,740, 1,535 and 1,350. NMR spectrum (CDCl ₃ , ppm): 1.46 (6H, s, 2 x CH 2 ), 5.26 (2H, s, COOCH ₂ ), 5.33 (2H, br S, NH ₂ ), 7.48 and 8.17 (2 x 2H, 2 xd, aromatic protons).

Reference example 89

In a mixture of 30 ml of water and 18 ml of tetrahydrofuran, 1.49 g of 2-chloroacetamido-4-thiazoleglyoxylic acid is dissolved. Under ice-cooling and stirring, 1.83 g of O-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyl) hydroxylamine is added. The pH of the mixture is adjusted to 5.0 by adding aqueous 1N sodium hydroxide. The mixture is stirred for 12 hours at room temperature. The pH is then adjusted to 7 with aqueous sodium bicarbonate. Tetrahydrofuran is distilled off under reduced pressure. The remaining aqueous solution is washed with ether, the pH is adjusted to 2 with dilute hydrochloric acid, and the product is extracted with ethyl acetate. The extract is washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure.

The residue is dissolved in ether and poured into twice the volume of petroleum ether. The resulting powdery precipitate is filtered off. 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methylKBxr —1

-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetic acid. IR spectrum (in _ma ]]r cm ): 1,740,

695, 1540, 1520 and 1345. NMR spectrum (CDCl-j, ppm): 1.61 <6H, s, 2 x CHj) , 4.29 (2H, s, C1CH ₂ ), 5.23 (2H, s, NOCHJ , 7.26 (1H, s, S ^H) , 7.43 and 8.05 (2 x 2H) (2 xd, aromatic protons) .

Reference example 90

In 15 ml of methylene chloride, 1.445 g of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetic acid is dissolved. 686 mg of phosphorus pentachloride is added under ice-cooling and stirring. The mixture is stirred for thirty minutes under ice-cooling. Then, 4.5 ml of hexane is added to the mixture. The resulting crystalline precipitate is filtered off and washed with hexane. 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetyl chloride hydrochloride is produced, m.p. 79-82 °C.

IR spectrum (in cm ^-1 ): 2,998, 1,775, 1,735, 1,715, 1,565, 1,520, 1,340 and 1,140.

For C ₁₈ H ₁₇ C1 ₃ N ₄ O ₇ S calculated: 40.04% C, 3.16% H, 10.38% N, found: 39.80% C, 3.31% H, 10.30% N.

Reference example 91

In 20 ml of ethanol, 417 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 2 and 200 mg of 5% palladium on carbon were suspended. The mixture was stirred under a hydrogen atmosphere for thirty minutes. Then, the catalyst was filtered off. The filtrate was concentrated under reduced pressure. The residue was dissolved in 15 ml of water and 15 ml of tetrahydrofuran. Then, 336 mg of sodium bicarbonate was added under ice-cooling and stirring.

103 and 972 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino] acetyl chloride hydrochloride. After stirring for 30 minutes, the reaction mixture is extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract is washed successively with aqueous sodium bicarbonate, aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. The solid residue is washed first with a mixture of ether and ethyl acetate (5:1), then with ether. This produces colorless crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer), mp 198-202 °C (dec.).

IR spectrum (in cm ¹ ): 3,360, 1,770, 1,745, 1,690, 1,525 and 1,350. NMR spectrum (DMSO-dgpppm): 1.52 (6H, s, 2 x CH^ , 3.63 (3H, s, COOCH ₃ > ), 4.34 (2H, s, C1CH ₂ ), 4.47 (1H, d,

J = 6 Hz, C^-H) , 5.29 (2H, s, COOCII ₂ ) , 5.48 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ ~H); 7.23 <1H,

Reference example 92

19 g of 2-hydroxyiminoacetoacetic acid methyl ester are dissolved in 50 ml of methylene chloride. 19.6 g of sulfuryl chloride are added dropwise while cooling with ice and stirring. The mixture is stirred for 3 days at room temperature. The methylene chloride is then distilled off under reduced pressure. The residue is dissolved in 200 ml of ether and washed seven times with 100 ml portions of water. The ether layer is dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. 20.2 g of light yellow oil of 4-chloro-2-hydroxyiminoacetoacetic acid methyl ester were produced. NMR spectrum (CDCl ₃ , ppm): 2.65 (1H, br s, N-OH), 3.90 (3H, s, COOCH 2 , 4.57 (2H, s, ClCH ₂ ).

This product is dissolved in 200 ml of a mixture of water and tetrahydrofuran (1:1). To this solution, 16.96 g of thiourea and 49.27 g of sodium acetate trihydrate are added under ice cooling.

The mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 7.0 by addition of sodium bicarbonate.

The solution was saturated with sodium chloride, and the organic layer was separated. The aqueous layer was extracted with tetrahydrofuran. The tetrahydrofuran solution and the above organic layer were combined, the combined solution was washed twice with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was then distilled off. The oily residue was crystallized from 100 ml of ether. The solution with the crystals was allowed to stand overnight, the crystals were filtered off and washed well with water.

The resulting crystals are dissolved in a mixture of ethyl acetate and methanol (in a ratio of 5:1). The product is concentrated until crystals begin to fall out of the solution. The concentrate is left to stand overnight. The resulting crystalline precipitate is filtered off and dried. Light yellow granules of 2-(2-amino-4-thiazolyl)-(Z)-2-hydroxyiminoacetic acid methyl ester are produced, mp 191-192 °C (dec.). IR spectrum (V cm ^-1 ): 3,420, 3,300, 3,220, 3,130, 1,730 and 1,620.

NMR spectrum (DMSO-d _g , ppm): 3.80 (3H, s, COOCH ₃ ), 6.87 (1H, s, SH), 7.17 (2H, br s, NH ₂ ), 11.67 (1H, s, N-OH). *

For CgH ₇ N ₃ O ₃ S calculated: 35.81% C, 3.51% H, 20.89% N? found: 36.05% C, 3.52% H, 20.96% N.

Reference example 93

4.62 g of 2-(2-amino-4-thiazolyl)-(Z)-2-hydroxyiminoacetic acid methyl ester are dissolved in 10 ml of N,N-dimethylformamide. 3 ml of triethylamine are added to the solution. Then 6.42 g of trityl chloride are added over one hour with stirring at -30 °C. The mixture is further stirred at this temperature for one hour and then for another two hours at 15 °C.

AND

104

200 ml of water was added to the reaction mixture and the mixture was extracted with 200 ml of ethyl acetate. The ethyl acetate extract was washed with two 200 ml portions of water and dried over anhydrous sodium sulfate. The solvent was then distilled off. The residue was purified by chromatography on silica gel (100 g, eluting with a 1:1 mixture of hexane and ethyl acetate).

The resulting crystals were recrystallized from ethyl acetate to give colorless granules of 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetic acid methyl ester, mp 204-205°C.

IR spectrum (in cm ^-1 ): 3,375 and 1,740. NMR spectrum (DMSO-d 2 , ppm): 3.45 (3H, s, COOCH 2 ),

IuaX about □

6.70 (1H, s, SH), 7.18 (15H, s, 3 phenyl groups), 8.47 (1H, br s, NH), 11.27 (1H, s,

N-OH).

For C ₂₅ H ₂₁ N ₃ O ₃ S calculated: 67.70% C, 4.77% H, 9.48% N, found: 67.55% C, 4.67% H, 9.14% N.

Reference example 94

To 70.5 ml of N,N-dimethylformamide were added 7.05 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-hydroxyiminoacetic acid ester and 3.3 g of potassium carbonate. Then, 2.12 g of allyl bromide were added dropwise over a period of five minutes under ice-cooling and stirring. The mixture was further stirred under ice-cooling for four hours. To this reaction mixture were added 1.65 g of potassium carbonate and 1.06 g of allyl bromide. The mixture was stirred for another four hours. The reaction mixture was diluted with 150 ml of water and extracted with three (100 ml) portions of ether. The ether extract was washed with two (100 ml) portions of aqueous sodium chloride and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The residue is purified by column chromatography on silica gel (300 g, elution with a 1:1 mixture of hexane and ethyl acetate). The product is crystallized from a mixture of ether and hexane. 7.0 g of methyl 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid ester are produced, mp 115-116 °C. IR spectrum (in cm 5 : 3360 and 1740. NMR spectrum (CDCl 2 , ppm): 3.88 (3H, s, COOCH ₃ > , 6.52 (1H, s, S/H), 6.93 (1H, br s, NH) , 7.30 (15H, s, three phenyl groups)!

For C ₂ 8 ^H 25 ^N 3°3 ^S calculated: 69.54% C, 5.21% H, 8.69% N, found: 69.57% C, 5.18% H, 8.51 i N.

Reference example 95

6.45 g of 2-(2-tritylamino-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid methyl ester were dissolved in 32 ml of tetrahydrofuran. 32 ml of 50% formic acid was added to the solution. The mixture was stirred for 40 minutes at 60 °C. The reaction mixture was distilled off under reduced pressure. The solid residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column (150 g, elution with a 1:1 mixture of hexane and ethyl acetate).

The solvent is distilled off. The solid residue is washed first with hexane, then with a small amount of ether and dried. This gives 2-(2-amino-4-thiazolyl)-Z)-2-allyloxyiminoacetic acid methyl ester, mp 133-134 °C. IR spectrum: 3,420, 3,230, 1,720, 1,610 and 1,540.

NMR spectrum (CDCl 1 , ppm): 3.90 (3H, s, COOCH 2 ), 5.98 (2H, broad isnglet, NH ₂ ), 6.67 (1H, s, S^xH).

Reference example 96

In the same manner as in Reference Example 32, 2-(2-chloroacetamide)methyl ester was prepared.

-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid, mp 114-115 C. IR spectrum (V, cm ^-1 ): 3,150, 3,060, 2,950, 1,740, 1,710, 1,680 and 1,565. NMR spectrum (CDCl 3 , ppm): 3.93 (3H, s, COOCH ₃ ), 4.28 (2H, s, CÍCH.,) , 7.25 (1H, s, S-/H), 10.12 (1H, br s, CONH).

105

Reference example 97

In the same manner as in Reference Example 33, 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid was prepared, mp 162 °C (dec.). IR spectrum (V ^KBr cm ^-1 ):

max

180, 2950, 1715-1680. NMR spectrum (DMSO-d6, ppm): 4.33 (2H, s, _C1CH2 ), 7.42 (1H, s, S.

X

For C ₁₀ H ₁₀ ClN ₃ O ₄ S calculated: 39.54% C, 3.32% H, 13.84% N, found: 39.41% C,

3.55% H, 13.71% N.

Reference example 98

610 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-allyloxyiminoacetic acid was suspended in 13 ml of methylene chloride. To this solution was added 502.4 mg of phosphorus pentachloride while cooling with ice and stirring. The mixture was stirred for thirty minutes at room temperature. Then, 100 ml of hexane was added to the reaction mixture. The precipitated crystals were filtered off and washed with hexane. 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-allyloxyiminoacetethyl chloride hydrochloride was obtained, m.p.

up to 70 °C. For C-^HgClN^S.HCl calculated: 33.49% C, 2.81% H, 11.72% N, found:

33.87% C, 2.76% H, 11.79% N.

Reference example 99

185.5 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester is dissolved in 2 ml of tetrahydrofuran and 2 ml of water. To the solution, under ice-cooling and stirring, 469.6 mg of sodium bicarbonate and then 600 mg of 2-(.-chloroacetamido-4-thiazolyl)-(Z)-allyloxyiminoacetyl chloride hydrochloride are added first. The mixture is stirred for two hours at room temperature. The solvent is distilled off under reduced pressure.

20 ml of water was added to the residue. The insoluble material was filtered off, washed successively with aqueous sodium bicarbonate, water, hexane and ether and dried. Light yellow granules of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-allyloxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) were produced, mp 270-280 °C (dec.).

720 and 1680. NMR spectrum (DMSO-dg, (1H, d, J = 6 Hz, C ₄ -H), 7.29 (1H,

IC spectrum (V ) : 3,260, 1,770, 1,745, 1 ppm): 3.60 (3H, s, COOCHp, 4.33 (2H, s, H 1 , 9.49 (1H, d, J

For C^gli^gClNgOgS calculated: 41.91% C, 3.75% H, 3.5% H, 16.37% N.

16.29% N, found: 41.83% C,

Reference example 100

In 7.8 ml of N,N-dimethylformamide, 657 mg of cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine, which was prepared according to Reference Example 11, was dissolved. This solution was poured into a solution of 861 mg of lithium chloride in 7.8 ml of argon at a temperature of 73. °C. The reaction mixture was cooled, poured into 60 ml of aqueous sodium chloride solution and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column, eluting with a 1:2 mixture of hexane and ethyl acetate (the column contained 50 g of silica gel).

The crystals obtained are washed with ether. This gives cis-3-benzyloxycarboxamido-4-chloromethyl-2-oxoazetidine, mp 147-149 °C. For ^c i2 ^H 13 ^C ' ^í ' ^N 2 ^O 3 calculated: 53.64% C, 4.88% H, 10.43% N, found: 53.49% C, 4.81% H, 10.35% N.

AND

106 tidmu (syn isomer), mp 212 to 217 C (dec.). IC spectrum (v , cm ):

max

755, 1660 and 1560. NMR spectrum (DMSO-dg, ppm): 3.90 (3H, s, NOCH, ), 5.28 = 5 Hz, J = 9 Hz, C,-H), 4.34 (2H, s, CICH.), 7.46 (1H, s, S ... II), 8.72 (1H,

Reference example 101

376 mg of cis-3-benzyloxycarboxamido-4-chloromethyl~2-oxoazetidine are suspended in 20 ml of methanol. 376 mg of 5% palladium on carbon are added to the suspension. The mixture is stirred for 20 minutes at room temperature under a hydrogen atmosphere. The catalyst is then filtered off and the filtrate is evaporated. The solid residue is dissolved in 28 ml of a mixture of tetrahydrofuran and water (1:1). 470 mg of sodium bicarbonate are added with ice cooling and stirring. 698 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride (syn-isomer)1 are then added. The mixture is stirred for 30 minutes under ice cooling. The reaction mixture is then extracted with ethyl acetate. The aqueous layer is extracted again with a mixture of ethyl acetate and tetrahydrofuran. The extracts were combined, the resulting solution was washed successively with aqueous sodium bicarbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The solid residue was washed with a mixture of ethyl acetate and ether (1:3). Colorless crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloromethyl-2-oxoaze3 420, 3 260, (1H, dd, J = br s, N^-H), were produced.

9.33 (1H, d, J = 9 Hz, Cj-NH), 12.57 (1H, br s, _C1CH2 COONH).

Reference example 102

According to Reference Example 11, cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine is prepared, which is further processed in the same manner as mentioned above in Reference Example 88. Thus, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylsulfonyloxymethyl-2-oxoazetidine (syn isomer) is prepared, mp 186-189 °C (dec.). For C^^H^gClN^O^Sg calculated: 34.40% C, 3.55% H, 15.43% N, found: 34.27% C, 3.63% H, 15.28% N.

Reference example 103

3.28 g of cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine, which is prepared according to the above-mentioned Reference Example 11, is suspended in 100 ml of ethanol.

3.28 g of 5% palladium on carbon are added to the suspension. The mixture is stirred under a hydrogen atmosphere for fifty minutes at room temperature. The catalyst is then filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in a mixture of 100 ml of methylene chloride and 15 ml of N,N-dimethylacetamide. Under ice cooling and stirring, 6.99 ml of propylene oxide are added first and then a solution of 2.79 g of 2-methylsulfonyl-ethyl chloroformate in 25 ml of methylene chloride. The mixture is stirred for two hours at room temperature.

Methylene chloride is distilled off. Water and a mixture of ethyl acetate and tetrahydrofuran (1:1) are added to the residue. The mixture is shaken well. The organic layer is separated. The aqueous layer is evaporated to dryness under reduced pressure. The residue is dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate and combined with the above-mentioned organic layer. The combined mixture is dried again over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is purified by chromatography on a silica gel column (150 g, eluted with ethyl acetate, later with a mixture of ethyl acetate and ethanol in a ratio of 9:1). The resulting crystals are washed with a mixture of ethyl acetate and ether (1:1).

Colorless crystals of cis-3-(2-methylsulfonylethoxycarbaboxamido)-4-methylsulfonyloxymethyl-2-oxoazetidine are produced, mp 141-142 °C. For ^C 9 ^H xg ^N 2°8 ^S 2 calculated: 31.39% C,

3.68% H, 8.14% N, found: 31.34% C, 4.76% H, 8.34% N.

107

Reference example 104

In 75 ml of methyl ethyl ketone, 1.894 g of cis-3-(2-methylsulfonylethoxycarboxamido)-4-methylsulfonyloxymethyl-2-oxoazetidine and 4.864 g of sodium iodide are suspended. The suspension is refluxed for three hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure. Water, ethyl acetate and aqueous sodium thiosulfate are added to the concentrate. The resulting crystalline precipitate is filtered off and washed successively with water, ethyl acetate and ether. 382 mg of colorless crystals of cis-3-(2-methylsulfonylethoxycarboxamido)-4-iodomethyl-2-oxoazetidine are produced. The filtrate is combined with the washings. The organic layer is separated. The aqueous layer is saturated with sodium chloride and extracted with a mixture of tetrahydrofuran and ethyl acetate (4:1).

This extract was combined with the organic layer and the combined phase was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crystalline residue was washed with ethyl acetate. 1.367 g of the above 4-iodomethyl compound was produced. m.p.

186 to 190 °C (decomposition).

For CgH^ ₃ IN ₂ 0gS calculated: 25.54% C, 3.48% H, 7.45% N, found: 25.64% C, 3.53% H, 7.34% N.

Reference example 105

To 20 ml of N,N-dimethylformamide are added 1.504 g of cis-3-(2-methylsulfonylethoxycarboxamido)-4-iodomethyl-2-oxoazetidine and 390 mg of sodium azide. The mixture is stirred for 66 hours at room temperature and then for 24 hours at 40 °C. The solvent is distilled off from the reaction mixture under reduced pressure. The residue is purified by chromatography on a silica gel column (100 g, elution with ethyl acetate, later with a mixture of ethyl acetate and ethanol in a ratio of 9:1). The solvent is then distilled off. The residue is recrystallized from ethyl acetate. The crystals are filtered off. Colorless crystals of cis-3-(2-methylsulfonylethoxycarboxamido)-4-azidoethyl-2-oxoazetidine are produced, mp 158-160 °C. IR spectrum (V^, cm ^-1 ): 3,200, 2,110, 1,780, 1,700 and 1,550.

Reference example 106

To a mixture of 60 ml of ethanol and 6 ml of N,N-dimethylformamide was added 757 mg of cis-3-(2-methylsulfonylethoxycarboxamido)-4-azidomethyl-2-oxoazetidine. Under ice-cooling and stirring, 11.4 ml of 0.5N ethanolic sodium hydroxide was added. After forty minutes, 5.7 ml of 1N hydrochloric acid was added and the mixture was concentrated under reduced pressure. To the concentrate, 15 ml of water and 15 ml of tetrahydrofuran were added. Under ice-cooling and stirring, 874 mg of sodium bicarbonate was added. Then, 1.297 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride (syn isomer) was added and the mixture was stirred for forty minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water, brine and dried over anhydrous magnesium sulfate.

The solvent is distilled off under reduced pressure. The crystalline product is washed first with ethyl acetate, then with ether and finally dried. This gives colorless crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-azidemethyl-2-oxoazetidine (syn isomer), mp 223 to 230 °C (dec.). IR spectrum (in cm ¹ ): 3,420, 3,250, 2,110,

760, 1660 and 1550. NMR spectrum (DMSO-dg, ppm): 3.4 to 3.6 (2H, m, CHgNg), 3.90 (3H, s, NOCHg), 4.34 (2H, s, CICHg), 5.22 (1H, dd, J = 5 Hz, J = 9 Hz, Cg-H), 7.37 (1H, s, Cg-H). SH), 8.49 (1H, br s, Ν _χ -Η), 9.20 (1H, d, J = 9 Hz, Cg-NH). AND

Reference example 107

In 50 ml of methylene chloride, 5.0 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine, which is prepared according to Reference Example 5, is dissolved.

To the solution was added 3.75 ml of pyridine at 0°C with stirring. To the mixture was added dropwise 3.94 g of benzoyl chloride and the mixture was stirred for 1.5 hours at room temperature. To the reaction mixture was added 100 ml of ice water.

108

The organic layer is separated, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue is purified by column chromatography on silica gel (325 g, elution with a mixture of hexane and ethyl acetate in a ratio of 1:2). The solvent is distilled off. Hexane is added and the crystalline product is filtered off. Colorless crystals of cis-3-benzyloxycarboxamido-4-benzoyloxymethyl-1-(2,4-dimethoxybenzyl) -2-oxoazetidine are thus obtained, mp 133-134 °C. For ^C 28 ^H 28 ^N 2°7 calculated: 66.65% C, 5.59% H, 5.55% N found: 66.48% C, 5.49% H, 5.36% N.

Reference example 108

In the same manner as in Reference Example 7, cis-3-benzyloxycarboxamido KRr -· 1 was prepared.

-4-benzoyloxymethyl-2-oxoazetidine, mp 188 to 189 C. IR spectrum (V _max i cm ): 3,300,

770, 1,725 and 1,690. For ^c i9 ^H ig ^N 2°5 calculated: 64.40% C, 5.12% H, 7.91% N, found: 64.42% C, 4.96% H, 7.86% N.

Reference example 109

550 mg of cis-3-benzyloxycarboxamido-4-benzoyloxymethyl-2-oxoazetidine are suspended in 20 ml of ethanol. 550 mg of 5% palladium on carbon are then added to the suspension. The suspension is stirred for two and a half hours in a hydrogen atmosphere. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. Colorless crystals of cis-3-amino-4-benzoyloxymethyl-2-oxoazetidine are thus obtained, m.p. 150 to 151 °C. IR spectrum (in cm S : 3,200, 1,735 and 1,710. Calcd.: 59.99 « C, 5.49 % H, 12.72 % N, found: 60.06 « C, 5.66 % H, 12.84 % N.

Reference example 110

In the same manner as in Reference Example 9, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-benzoyloxymethyl-2-oxoazetidine (syn isomer) was obtained, m.p.

210 to 220 °C (decomposition). IR spectrum cm ^-1 ): 3,250, 1,760, 1,715 and 1,660.

For C ₁₉ H ₁ a ClN ₅ 0gS calculated: 47.55% C, 3.78% H, 14.59% N, found: 47.06% C,

3.63% H, 14.53% N.

Reference example 111

To 250 ml of benzene, 35 g of alpha-methylcinnamylaldehyde and 29.5 g of p-anisidine are added.

The mixture is refluxed for one hour, while water is azeotropically distilled off. The solvent is then distilled off under reduced pressure. The residue is dissolved in one liter of methylene chloride. 29 g of triethylamine are added dropwise with ice cooling and stirring, followed by a solution of 53.5 g of phthalimidoacetoethyl chloride in 250 ml of methylene chloride. The mixture is stirred for 24 hours at room temperature, washed with water, dried over anhydrous magnesium sulfate, and the solvent is distilled off. The solid residue is recrystallized from a mixture of ethyl acetate and hexane.

Cis-3-phthalimido-4-(alpha-methylstyryl)-1-(4-methoxyphenyl)-2-oxoazetidine is produced, mp 105-107°C. IR spectrum (V cm ^-1 ): 1,760, 1,725, 1,515, 1,385 and 1,250. NMR spectrum (CDC1 ₃ , ppm): 1.70 (3H, br s, =C-CH ₃ ), 3.74 (3H, s, NOCH ₃ '), 4.77 (1H, d, J = 6 Hz, C ₄ -H), 5.52 (1H, d, J = 6 HZ, Cj-H), 6.50 (1H, br s, =CH-phenyl).

Reference example 112

28 g of cis-3-phthalimido-4-(alpha-methylstyryl)-1-(4-methoxyphenyl)-2-oxoazetidine are dissolved in 200 ml of dimethoxyethane. 10.2 g of methylhydrazine are added to the solution. The mixture is stirred for 12 hours at room temperature. The resulting crystalline precipitate is filtered off. The filtrate is concentrated. The concentrate is dissolved in 200 ml of methylene chloride. 14.8 g of propylene oxide and 10.62 g of carbobenzoxychloride are added successively. The mixture is then stirred for one hour, after which it is concentrated under reduced pressure.

109

The residue is purified by chromatography on a silica gel column (300 g, elution first with a mixture of hexane and ethyl acetate in a ratio of 1:1, later with the same mixture in a ratio of 1:2). Cis-3-benzyloxycarboxamido-4-(alpha-methylstyryl)-1-(4-methoxyphenyl)-2-oxoazetidine is produced, IR spectrum (V cm ¹ ): 1,750, 1,720 and 1,680. NMR spectrum (CDCl ,, ppm): 1.85 (3H, br s, =C- _CHO ) ,' max jj

3.75 (3H, s, OCH ₃ ), 5.08 (2H, s, phenyl-CI^), 5.50 (IH, dd, J = 6 Hz, J = 9 Hz, CjH) , 6.43 (IH, br s, =CH-phenyl), 7.84 (IH, d, J = 9 Hz, C ₃ ~NH).

Reference example 113

In 750 ml of methylene chloride, 75 g of cis-3-benzyloxycarboxamido-4-(alpha-methylstyryl)-1-(4-methoxyphenyl)-2-oxoazetidine are dissolved. Excess ozone is passed through the solution at a temperature of -78 °C. Then, the excess ozone is flushed with nitrogen and 11.6 g of dimethyl sulfide are added to the solution. The mixture is stirred for 30 minutes at room temperature. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on a silica gel column (400 g, elution with a mixture of hexane and ethyl acetate in a ratio of 1:2, later 1:4). Cis-3-benzyloxycarboxamido-4-acetyl-1-(4-methoxyphenyl)-2-oxoazetidine is produced, m.p. 188 to 191 °C.

KBr — 1

IR spectrum (V _raax , cm ): 1,760, 1,720, 1,700 and 1,655. NMR spectrum (DMSO-dg, ppm): 2.20 (3H, s, COCH ₃ ), 3.74 (3H, s, OCH ₃ ), 5.15 (2H, s, phenyl-CH ₂ ), 5.20 (IH, d, J = 6 Hz, C ₄ -H), 5.64 (IH, dd, J = 6 Hz, J = 9 Hz, C ₃ »H), 9.48 (IH, d, J = 9 Hz, C ₃ -NH).

Reference example 114

In a mixture of 50 ml of acetonitrile and 25 ml of water, 1 g of cis-3-benzyloxycarboxamido-4-acetyl-1-(4-methoxyphenyl)-2-oxoazetidine is dissolved. The solution is cooled to -15 °C. At this temperature, ammonium cerium nitrate (3 g) is added and the mixture is stirred for ten minutes. The reaction is terminated by adding saturated aqueous sodium sulfite solution. The pH of the solution is adjusted to 5-6 by adding sodium bicarbonate.

Acetonitrile was distilled off under reduced pressure. The residue was acidified with 3N hydrochloric acid and extracted with chloroform. The aqueous layer was extracted with a mixture of chloroform and ethanol (4:1) (twice). The extracts were combined, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (80 g), eluting with a mixture of hexane and ethyl acetate (1:2), ethyl acetate and finally with a mixture of ethyl acetate and methanol (9 ml). Cis-3-benzyloxycarboxaracido-4-acetyl-2-oxoazetidine was produced.

IR spectrum (in cm ^-1 ): 3,240, 1,770, 1,705, 1,635, 1,540, 1,450, 1,380, 1,305 and 1,180. NMR spectrum (CDC1 ₃ , ppm): 2.20 (3H, s, COCH ₃ ), 4.58 (IH, d, J = 6 Hz, C ₄ ~H),

5.20 (2H, s, phenyl-CH ₂ ), 8.18 (1H, d, J = 9 Hz, C 1 -NH).

Reference example 115

In the same manner as in Reference Example 67, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetainido]-4-acetyl-2-oxoazetidine (syn isomer) was prepared. IR spectrum (V cm- ¹ ): 3350, 1760, 1650 and 1545. NMR spectrum (DMSO-dg, ppm): 2.12 (3H, s, COCH-j), 3.73 (3H, br s, NOCH ₉ ), 4.35 (2H, s, C1CH _? ), 7.90 (1H, s, S_H).

X

Reference example 116

In a mixture of 2 ml of tetrahydrofuran and 2 ml of water, 75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine, which was prepared according to the above-mentioned Reference Example 53, was dissolved.

Under ice-cooling and stirring, 168 mg of sodium bicarbonate was added, followed by 332 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-methoxyiminoacetyl chloride hydrochloride. The mixture was stirred under ice-cooling for one hour. The reaction mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate-tetrahydrofuran (2:1).

110

The extract was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. A mixture of ethyl acetate and ether (1:2) was added. The crystalline product was filtered off. Colorless crystals of cis-3-[2-(2-chloroactamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn isomer) were produced, mp 238-241 °C (dec.). IR spectrum max' ^{cm 3 400} (broad band), 1 750, 1 660 and 1 045. NMR spectrum (DMSO-dg, ppm): 2.07 (1H, s, OH), 3.89 (3H, s, NOCH ₃ >, 4.34 (2H, s, C1CH ₂ ), 5.20 (1H, dd, J = 5 Hz, J = 9 Hz, Cg-Η), 7.50 (1H, s, S^H), 9.15 (1H, d, J = 9 Hz, Cg-NH).

Reference example 117

In a mixture of 17 ml of methylene chloride and 6 ml of N,N-dimethylformamide, 172 mg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-hydroxymethyl-2-oxoazetidine (syn isomer) is dissolved. 0.2 ml of pyridine is added to the solution. While cooling with ice with sodium chloride and stirring, 0.12 ml of chloroacetyl chloride is added dropwise to the mixture. The mixture is stirred for 30 minutes under cooling. The solvent is distilled off. An aqueous solution of sodium chloride and ethyl acetate are added to the residue and the mixture is shaken well. The organic layer is separated, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The residue is recrystallized from ether. Recrystallization from a chloroform-methanol mixture gives colorless crystals of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-chloroacetoxymethyl-2-oxoazetidine (syn isomer), mp 225 to 227 °C (dec.). For C ₁₄ H ₁₅ Cl ₂ N ₅ O _g S calculated: 37.17% C, 3.34% H, 15.48% N, found: 36.69% C, 3.37% H, 15.44% N.

Reference example 118

4.45 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-phthalimidomethyl-2-oxoazetidine, which is prepared according to Reference Example 48, is suspended in 320 ml of ethanol.

2.03 ml of hydrazine hydrate are added to the mixture. The mixture is refluxed for two hours.

After cooling, the reaction mixture is filtered. The filtrate is concentrated under reduced pressure. 200 ml of methylene chloride is added to the concentrate. The material that remains undissolved is filtered off. The filtrate is washed with water, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in a mixture of 85 ml of methylene chloride and 11 ml of N,N-dimethylacetamide. Under ice-cooling and stirring, first 5.88 ml of propylene oxide are added and then a solution of 2.35 g of beta-methylsulfonylethyl chloroformate in 20 ml of methylene chloride is added dropwise.

The mixture was stirred for one hour at room temperature, washed successively with water, aqueous sodium bicarbonate, water, dilute hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and ^the solvent was distilled off under reduced pressure. The crystalline residue was washed with ethyl acetate.

2.94% of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine is produced, mp 172-174°C. IR spectrum t^^ax' ^cm:

400, 1755, 1690, 1610, 1535 and 1125. NMR spectrum (DMSO-dg, ppm): 2.97 (3H, s, SO ₂ CH ₃ >, 3.38 (2H, t, J = 6 Hz, CH ₂ SO ₂ ), 3.75 and 3.77 (2X CH ₃ , 2X s, 2 x OCHj), 4.24 (2H, quartet,

J = 15 Hz, N ₁ -CH ₂ ), 4.28 (2H, t, J = 6 Hz, COOCHj), 4.82 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), 5.05 (2H, s, phenyl-CH ₂ ), 7.37 (5H, s, phenyl group), 8.05 (1H, d, J = 9 Hz, Cj-NH).

Reference example 119

In the same manner as in Reference Example 50, cis-3-benzyloxycarboxamido-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine was prepared, mp 149-150°C. For ^16 ^H 21 ^N 3°7® calculated: 48.11% C, 5.30% H, 10.52% N, found: 47.99% C, 5.22% H,

10.37% N.

111

Reference example 120

In the same manner as in Reference Example 51, cis-3-(2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine (syn isomer) was prepared. This product gradually decolorized at 150 to 170°C and decomposed at 195 to 199°C.

IR spectrum (in cm ^-1 ): 3,250, 1,760, 1,690, 1,650 and 1,550. For C^H^ClNgOgS calculated: 36.61 8 C, 4.03 8 H, 16.01 8 N, found: 36.48 8 C, 4.08 8 H, 15.02 8 N.

Reference example 121

In 3 ml of N,N-dimethylformamide, 1.197 g of cis-3-benzyloxycarboxamido-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine, which was prepared according to Reference Example 119, was dissolved. 475 mg of dimethyl-tert-butylsilyl chloride was added to the solution, and 0.46 ml of triethylamine was added dropwise while cooling to 0°C. The mixture was stirred for 30 minutes under ice-cooling. Ethyl acetate and water were added. The ethyl acetate layer was separated, washed with dilute hydrochloric acid, aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue was chromatographed on a silica gel column (100 g, elution with hexane/ethyl acetate 1:2, later 1:3). Cis-3-benzyloxycarboxamido-4-(2-methylsulfonylethoxycarbonylaminomethyl)-1-dimethyl-tert-butylsilyl-2-oxoazetidine was obtained as a foam.

IR spectrum cm^): 3,330, 1,750, 1,720 and 1,695. NMR spectrum (CDCl^, ppm):

0.26 (3H, s, SiCH^ ), 0.28 (3H, s, SiCH^ ), 0.96 (9H, s, tert.butyl ''group), 2.93 (3H, s, SO ₂ CH ₃ ), 3.28 (2H, t, J = 6 Hz, CH ₂ SO ₂ ), 4.50 (2H, t, J = 6 Hz, COOCH ₂ ), 5.03 (1H, dd,

J = 5 Hz, J = 9 Hz, C ₃ -H) , 5.15 (2H, s, phenyl-CHp, 6.18 (1H, d, J = 9 Hz, C ₃ ~NH) ), 7.38 (5H, s, phenyl protons).

Reference example 122

514 mg of cis-3-benzyloxycarboxamido-4-(2-methylsulfonylethoxycarbonylaminomethyl)-1-dimethyl-tert-butylsilyl-2-oxoazetidine are dissolved in 20 ml of ethanol. 4.4 ml of ethanolic sodium hydroxide (0.5N) are added under ice cooling and stirring. The mixture is stirred for 15 minutes under ice cooling. 2.2 ml of 1N hydrochloric acid are added to the reaction mixture. The solvent is distilled off under reduced pressure. The residue is extracted with a mixture of methylene chloride and tetrahydrofuran. The extract is washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure.

Under ice-cooling, 4 ml of dry trifluoroacetic acid and 2 ml of trifluoroacetic acid are added. The mixture is stirred for 30 minutes. The solvent is distilled off under reduced pressure. The residue is purified by chromatography on a silica gel column (40 g, elution with a mixture of hexane and ethyl acetate in a ratio of 1:1, later 1:2). This produces cis-3-benzyloxycarboxamido-4-trifluoroacetylaminomethyl-2-oxoazetidine, mp 197 to 201 °C. IR spectrum (in ^χ' cm ¹ ) : 3,280, 1,760, 1,705 and 1,690. For calculated: 48.70% C, 4.09% H, 12.17% N, found: 48.31% C,

4.00% H, 12.01% N.

The above reaction also produces yellow crystals of the by-product cis-3-benzyloxycarboxamido-4-trifluoroacetylaminomethyl-1-dimethyl-tert-butylsilyl-2-oxoazetidine, m.p.

130 to 135 °C. IR spectrum (V cm ^-1 ): 3,300, 1,765, 1,700 and 1,685.

Reference example 123

In the same manner as in Reference Example 67, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-trifluoroacetylarainomethyl-2-oxoazetidine (syn isomer, m.p. 220-225°C (dec.)) was prepared.

112 νη γ» — 1

IR spectrum IV _max ' ^cnl ): 3270, 1760, 1705 and 1660. NMR spectrum. (DMSO-dg, ppm): 3.89 (3H, s, NOCH ₃ ), 4.31 (2H, s, ClCHj ), 5.22 (1H, dd, J = 5 Hz, J = 9 Hz, Cj-H), 7.43

Reference example 124

In a mixture of 25 ml of ethanol and 5 ml of N,N-diethylfomaroid, 525 µg of cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetomido]-4-(2-methylsulfonylethoxycarbonylaminomethyl)-2-oxoazetidine (syn isomer), which is prepared according to Reference Example 119, is suspended.

5 ml of ethanolic sodium hydroxide (0.5N) is added to the suspension. The mixture is stirred for 20 minutes at room temperature. Then 2.5 ml of 1N hydrochloric acid is added. The ethanol is distilled off under reduced pressure. The residue is dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran.

Under ice cooling and stirring, 185 mg of sodium bicarbonate is added, then a solution of 432 mg of chloroformic acid p-nitrobenzyl ester in 10 ml of tetrahydrofuran is added dropwise over 50 minutes.

The mixture was stirred for 20 minutes under ice-cooling. 10 ml of water and 20 ml of ethyl acetate were added to the reaction mixture. The mixture was shaken well. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. This ethyl acetate extract and the above organic layer were combined. The combined portions were washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure; The residue was recrystallized from ethyl acetate. The crystals were filtered off.

Cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(p-nitrobenzyloxycarbonylaminomethyl)-2-oxoazetidine (syn isomer) is produced, mp 235-245 °C (dec.).

IR spectrum (λ, cm ^-1 ): 3,380, 3,230, 1,760, 1,690, 1,660, 1,550 and 1,520.

Reference example 125

In the same manner as in Reference Example 39, the following compounds are prepared:

cis-3-[]D-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester:

beta-isomer: IR spectrum (λ cm ¹ ) : 1 770, 1 740, 1 710, 1 675, NMR spectrum (DMSO 4 10

-dg) ppm): 1.11 (3H, t, J = 7 Hz, N-CHjCHj) , 3.08 (3H, s, COOCH-j) , 4.30 (1H, d, J = 6 Hz, C ₄ -H) , 5.38 (1H, dd, J = 6 Hz, J = 9 Hz, C 3 -H) , 5.52 (1H, d, J = 6 Hz, C ₃ -H) = 7 Hz, phenyl-CH-), 8.6'8 (1H, s, N ₁ -H), 9.26 (1H, d, J = 9 Hz, C ₃ -NH), 9.86 (1H, d, J = 7 Hz, phenyl-CH-NH).

alpha-isomer: IR spectrum (in ^βχ' ^{cnl ! 1} 770, 1 740, 1 710 and 3 670. NMR spectrum (DMSO-dg, ppm): 1.10 (3H, t, J = 7 Hz, N-CH ₂ CH ₃ ), 3.55 (3H, s, COOCH ₃ ), 4.40 (1H, d, J = = 6 Hz, C ₄ -H) , 5.20 (1H, dd, J = 6 Hz, J = 9 Hz, CjH) , 5.47 (1H, d, J = 7 Hz, phenyl-CH), 8.70 (1H, s, N ₁ ~H), 9.25 (1H, d, J = 9 Hz, Cj-NH), 9.80 (1H, d, J = 7 Hz, Cj-NH) phenyl-CH-NH).

cis-3-[]D—2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-4-methyl-2-oxoazetidine:

beta-isomer: IR spectrum (V _cm -1). | 750, 1710 and 1670. NMR spectrum ( _CDCl3 , ppm): 1.15 (3H, d, J=4 Hz, C4 _{- CH3} ).

cis-3-[D-2-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-2-phenylacetamido]-4-acetoxymethyl-2-oxoazetidine:

vtjv· _ 1 beta-isomer: IR spectrum (in _max and cm 1:1 770, 1 710 and 1 670. NMR spectrum (CDClj, ppm): 1.85 (3H, s, OCOCHp.

113

25357 alpha-isoiner: IR spectrum < ^V max' ^cm_1 ) ^{! 1770} , ^{1720 and} 1670. ^NMR spectrum (CDCl ₃ , ppm): 1.90 (3H, s', OCOCH 2 ).

Reference example 126

By the method of Reference Example 39, 300 mg of D-2-[3-(furan-2-aldimino)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetic acid was treated with 110 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester. Cis-3-[D-2-3-(furan-2-aldimino)-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido-2-oxoazetidine-4-carboxylic acid methyl ester was prepared.

beta-isomer: IR spectrum (V max' ^cm 5 : 1 760, 1 720 and 1 660. alpha-isomer: IR spectrum (V ™χ' ^cn, 5 : 1 770, I 720 and 1 660 .

In the same manner as described above, the following compound was prepared: cis-[]D-2-J]3-(thiophene-2-aldimino-2-oxo-1-imidazolidinecarboxamido]-2-phenylacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester.

beta-isomer: IR spectrum (in ^X5r , _c[n lj _; 765, 1,725 and 1,660.

ΪΏ3.Χ

ZPr — 1 alpha-isomer: IR spectrum (in _max > cm ): 1,770, 1,720 and 1,660.

Reference example 127

The 3-amino compound (which is prepared from 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in the same manner as in Reference Example 3) was dissolved in 10 ml of tetrahydrofuran. Under ice-cooling and stirring, 1.2 ml of trimethylamine was added. To the solution was added dropwise a solution of 1.2 g of 2-(2-chloroacetamido-4-thiazolyl)-2-diethylphosphonoacetyl chloride in 10 ml of tetrahydrofuran. The mixture was stirred for 2 and a half hours at room temperature. Tetrahydrofuran was distilled off. Ethyl acetate and water were added to the residue and the mixture was shaken well. The organic layer was separated, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The residue is purified by chromatography on a silica gel column (elution with a mixture of chloroform and methanol in a ratio of 95:5). Cis-3-[2-(2-chlorobractamido-4-thiazolyl)-2-diethylphosphonoacetamido]-2-oxoazetidine-4-carboxylic acid methyl ester is produced. IR spectrum (V cm- ¹ ): 3,250, 1,770, 1,750, 1,685, 1,540, 1,230, 1,050 and 1,025.

Reference example 128

The 3-amino compound (which is prepared from 0.8 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester in the same manner as above in Reference Example 3) is dissolved in 20 ml of tetrahydrofuran. 0.42 ml of triethylamine and 0.56 g of 3-triethylsilylpropionyl chloride are successively added under ice-cooling and stirring. The mixture is stirred at room temperature for 3 hours. Tetrahydrofuran is distilled off. Water and ethyl acetate are added to the residue. The phases are separated. The organic layer is washed with water, saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue is recrystallized from a mixture of chloroform and ether. The crystals are filtered off.

This produces cis-3·; (2-triethylsilylethylcarboxamido)-2-oxoazetidine-4-carboxylic acid methyl ester, mp: 143 to 145 °C. IR spectrum (V ^cm 5 3 260, 1 790, 1 750, 1 640 and 1 540. For C^H^N^O^Si calculated: 53.47 % C, 8.33 % H, 8.91 % N, found: 53.54 % C,

8.40% H, 8.73% N.

3,572

114 .Reference pi O Jed 129

5.01 g of 2,4-dimethoxybenzylamine are dissolved in 100 ml of methylene chloride. 4.2 g of trans-cinnamyl aldehyde and 30 g of anhydrous magnesium sulfate are added to the solution. The mixture is stirred for three and a half hours at room temperature. The reaction mixture is then filtered. 8.4 ml of triethylamine are added to the filtrate under ice-cooling and stirring. A solution of 7.0 g of phthalimidoacetyl chloride in 50 ml of methylene chloride is added dropwise over 30 minutes.

The mixture is stirred for two and a half hours at room temperature, washed with water, dried over anhydrous sodium sulfate and the mixture is concentrated under reduced pressure. 50 ml of chloroform is added to the concentrate. The precipitate is filtered off. The filtrate is evaporated and the residue is passed through a column of silica gel (30 g). The eluate is evaporated and the solid residue is recrystallized from ethyl acetate. This gives cis-3-phthalimido-4-(E)-styryl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, m.p. 173-177 °C.

IR spectrum (V ^KBr , cm ^): 1,750, 1,720 and 1,390. For calculated·: 71.78% C, ma xz□ zq z ó

5.16% H, 5.98% N, found: 72.14% C, 5.01% H, 5.85% N.

Reference example 130

5 g of cis-3-phthalimido-4-(E)-styryl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are dissolved in 150 ml of tetrahydrofuran. 2.5 g of 10% palladium on carbon are added to the solution. The mixture is stirred for 30 minutes under a hydrogen atmosphere. The catalyst is filtered off. The filtrate is concentrated under reduced pressure. The concentrate is crystallized from ether. The crystals are filtered off. 4.8 g of cis-3-phthalimido-4-(2-phenylethyl)-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are produced, m.p. 148-150 °C.

IR spectrum (\) ^KBr , cm b : 1 750 , 1 720 and 1 390. For C ₉₀ Ei _9ř -N„0 _r calculated: 71.47 % C, r max zo zoz _)

5.57% H, 5.96% N, found: 71.55% C, 5.45% H, 5.75% N.

Reference example 131

4.1 g of cis-3-phthalimido-4-(2-phenylethyl)-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are suspended in 35 ml of dimethoxyethane. 1.4 ml of methylhydrazine are added to the suspension. The mixture is left to stand for three days at room temperature. The resulting precipitate is filtered off. The filtrate is evaporated. The residue is dissolved in ethyl acetate and the solution is extracted three times with dilute hydrochloric acid. The pH of the solution is adjusted to 7-8 by adding sodium bicarbonate.

The solution was extracted three times with chloroform. This extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure.

The residue is dissolved in 50 ml of methylene chloride. 20 ml of propylene oxide is added to the solution and then 3 ml of carbobenzoxy chloride are added dropwise. The mixture is stirred for 2 hours at room temperature. The reaction mixture is evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a mixture of chloroform and ethyl acetate (1:1). The solvent is then distilled off and the residue is crystallized from ether. The crystals are filtered off. Cis-3-benzyloxycarboxamido-4-(2-phenylethyl)-1-(2,4-dimethoxybenzyl)-2-oxoazetidine is produced, m.p. 150-152 °C.

IR spectrum (V cm“ ¹ ): 3 300, 1 760, 1 680, 1 535 and 1 265. For C ₂ gH ₃₍₎ N ₂ O ₅ calculated:

70.86% C, 6.37% H, 5.90% N, found: 70.68% C, 6.44% H, 6.09% N.

Reference example 132

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-4-(2-phenylethyl)-2-oxoazetidine was prepared, mp 173-175°C. IR spectrum (V cm ¹ ): 3,300,

770, 1,685, 1,540 and 1,260. For ^c 19 ^H 20 ^N 2°3 ⁱⁿ yP° ^etheneO! 70.35% C, 6.22% H, 8.64% N, Found: 70.13% C, 6.05% H, 8.48% N.

115

Reference example 133

In the same manner as in Reference Example 67, cis-3-[2-(2-chloroacetaniido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(2-phenylethyl)-2-oxoazetidine (syn isomer) was prepared. IR spectrum (V ^KBr , cm- ¹ ): 3260, 1740, 1700, 1650 and 1540.

Reference example 134

9.6 g of 2-methoxyiminoacetoacetic acid methyl ester are dissolved in 40 ml of chloroform.

While stirring at 40°C, a solution of 9.1 g of bromine in 10 ml of chloroform is added dropwise. The mixture is stirred for 20 minutes. Then it is poured into a mixture of ice and water. The organic layer is separated, washed successively with saturated aqueous sodium bicarbonate, water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure.

13.12 g of 4-bromo-2-methoxyiminoacetoacetic acid methyl ester oil are produced. 10.74 g of this oil and 4.4 g of thiocarbamic acid methyl ester are added to 40 ml of ethanol. The mixture is refluxed for one and a half hours. The ethanol is distilled off. The residue is dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure. Crystals of 2-(2-hydroxy-4-thiazolyl)-(Z)-2-methoxyiminoacetic acid methyl ester are produced, m.p. 97-98 °C.

IR spectrum (\) ^ax' ^{cm : 1} 1 670, 1 440, 1 260, 1 150 and 1 040. NMR spectrum (CDCl ₃ , ppm): 3.93 and 4.03 (2 χ 3H, 2 xs, COOCH ₃ and NOCH ₃ ), 6.35 (1H, s, S^H).

Reference example 135

1.0 g of methyl 2-(2-hydroxy-4-thiazolyl)-(Z)-2-methoxyiminoacetic acid ester is dissolved in 3 ml of ethanol. 5 ml of aqueous potassium hydroxide solution (1.3 g) is added dropwise under ice-cooling. The mixture is left to stand for 4 hours, the pH is adjusted to 2-3 with 1N hydrochloric acid and the solution is extracted three times with butanol. The extracts are combined, dried over anhydrous sodium sulfate and the solvent is distilled off under reduced pressure. This procedure produces a light brown powder of 2-(2-hydroxy-4-thiazolyl)-(Z)-2-methoxyiminoacetic acid, m.p. 143-145 °C (dec.).

IR spectrum (V cm *): 1740, 1490, 1620, 1450, 1170 and 1040. NMR spectrum (DMSO-dg, ppm): 4.02 (3H, s, NOCH ₃ ), 6.79 (1H, s, S^H), 11.76 {1H, s, COOH).

Reference example 136

In the same manner as in Reference Example 34, cis-3-[2-(2-hydroxy-4-thiazolyl)-2-methoxyiminoacetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer) was prepared, mp 202-204°C (dec.). IR spectrum (in cm ^-1 ): 3260, 1775, 1735, 1685, 1660, 1520, .

440, 1220 and 1040. NMR spectrum (DMSO-dg, ppm): 3.50 (3H, s, COOCH ₃ ), 3.86 (3H, s, NOCHj), 4.33 (1H, d, J = 5 Hz, C/H), 5.25 (1H, dd, J = 5 Hz, J = 8 Hz), 6.23 (1H, d, J = 5 Hz, J = 8 Hz). s, S^H), 8.35 (1H, broad singlet, N/H), 9.33 (1H, d, J = 8 Hz, C/NH).

Reference example 137

In 150 ml of methanol, 2.14 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 1, was dissolved. Under ice-cooling and stirring, 25 ml of an aqueous solution of potassium carbonate (0.83 g) was added. The mixture was stirred for six and a half hours at room temperature. The methanol was distilled off under reduced pressure. Water was added to the residue, the mixture was washed with a mixture of ethyl acetate and ether, and the solution was acidified with 1N hydrochloric acid. The resulting precipitate was filtered off, washed with water and dried. 1.95 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoO KRr —1 azetidine-4-carboxylic acid are produced, mp 189-191 C. IR spectrum (V _max < cm ): 3,300,

760, 1,705 and 1,690.

116

Reference example 138

4.1 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid are dissolved in 80 ml of dry tetrahydrofuran. 4 ml of oxalic acid chloride are added to the solution. The mixture is refluxed for 30 minutes. The solvent is distilled off. The residue is washed with hexane and dissolved in 80 ml of methylene chloride. While cooling with ice water, 4 ml of ethanol are added and the mixture is stirred for 20 minutes. The solvent is distilled off. The residue is recrystallized from ether. The crystals are filtered off. Colorless crystals of ethyl ester of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid are produced, which melt at 117 to 118 °C after recrystallization from ethanol.

TfRy· _ 1

IR spectrum (V ~. cm ): 3,250, 1,770, 1,735 and 1,680. For C„,H_,N„O^ calculated:

ΙΠαΧ aj 2b z Z

62.43% C, 5.92% H, 6.33% N, found: 62.43% C, 5.91% H, 6.05% N.

Reference example 139

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid ethyl ester was prepared, mp 134-135 °C. IR spectrum (in cm ^-1 ): 3,300, 1,800, 1,740 and 1,720. For ^C 14 ^H 16 ^N 2 ^O 5 calculated: 57.52% .C, 5.51% H, 9.58% N, found: 57.58% C, 5.44% H, 9.60% N.

Reference example 140

In the same manner as in Reference Example 3, cis-3-amino-2-oxoazetidine-4-carboxylic acid ethyl ester was obtained, mp 105-106°C (dec.). IR spectrum (in max^' ^{om :}

400, 3,200, 1,745, 1,720 and 1,700. For C _g H ₁₀ N ₂ O ₃ calculated: 45.56% C, 6.37% H, 17.71% N, found: 45.66% C, 6.20% H, 17.70% N.

Reference example 141

In the same manner as in Reference Example 4, the following compounds were prepared:

cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine-4-carboxylic acid ethyl ester:

syn-isomer: mp 280-283 °C (dec.) '30 and 1670. NMR spectrum (DMSO-dg, ppm):

-- 5 Hz, J = 9 Hz, C ₃ -H) , 7.42 (1H, s, S^, . IR spectrum (in JJax°^' ^{cm 8} 1.20 (3H, t, J = 7 Hz, CHjCHj) H) .

230, 1,750, 5.73 (1H, dd, anti-isomer: mp 108 to 110 °C. IR spectrum (V om ¹ ): 3,250, 1,760, 1,720

IuaX and 1650. NMR spectrum (DMSO-dg, ppm): 1.20 (3H, t, J = 7 Hz, CH ₂ CH ₃ ), 5.50 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H) , 8.00 (1H, s, S^H) .

Reference example 142

In 60 ml of dry tetrahydrofuran, 2 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-2-oxoazetidine-4-carboxylic acid, which was prepared according to Reference Example 137, was dissolved. 2 ml of ethanoic acid chloride was added to the solution. The mixture was refluxed for 30 minutes. The solvent was then distilled off. The residue was washed with hexane and dissolved in 40 ml of dry tetrahydrofuran. Aniline (1 ml) was added to the mixture under ice-water cooling, and the mixture was stirred for 30 minutes. The resulting crystalline precipitate was filtered off and washed first with ether and then with methanol. Cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-phenylcarbamoyl-2-oxoazetidine is produced, which melts at 255-257 °C after recrystallization from a chloroform-methanol mixture.

117

IR spectrum (in \ δ: 3250, 1760, 1690 and 1670. For C^yH^yN^Og calculated:

66.24% C, 5.55% H, 8.50$, N, found: 65.80% C, 5.34% H, 8.34% N.

Reference example 143

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido~4O KRv —1 was prepared.

-phenylcarbamoyl-2-oxoazetidine, mp 235 to 238 C (dec.). IR spectrum (V _max » cm }:

270, 1760, 1690 and 1670. NMR spectrum (DMSO-dg, ppm): 4.4 (1H, d, J - 5 Hz, C^-H),

5.0 .(2H, s, phenyl-CH ₀ ), 5.15 (1H, dd, J = 5 Hz, J - 9 Hz, C 2 -H).

Reference example 144

In the same manner as in Reference Example 3, cis-3-amino-4-phenylcarbamoyl-2-oxoazetidine was prepared _{, mp} 152-154°C (dec.). IR spectrum (in cm 2 : 3,300, 1,740 and 1,690.

Reference example 145

In the same manner as in Reference Example 4, cis-3-[2-(2-chloroacetamido-4thiazolyl)-2-methoxyiminoacetamido]-4-phenylcarbamoyl-2-oxoazetidine (syn isomer) was prepared. NMR spectrum (DMSO-dg, ppm): 3.53 (3H, s, NOCH ₃ ), 4.3 (2H, S, C1CH ₂ ), 4.48 (1H, d, J = 5 Hz, C^-H),

5.57 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ ~H).

Reference example 146

In 160 ml of methanol, 2.502 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 2, was dissolved. 50 ml of an aqueous solution of potassium carbonate (1.242 g) was added under ice-cooling and stirring. The mixture was stirred for 70 minutes at room temperature. 9 ml of 1N hydrochloric acid was added under ice-cooling and stirring. The methanol was distilled off under reduced pressure. The remaining aqueous solution was washed with ethyl acetate and the solvent was distilled off under reduced pressure. The residue was chromatographed on an Amberlite XAD-II column. The eluate was lyophilized. A colorless powder of potassium cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate was produced.

IR spectrum ( _in cm ¹ ): 1,770, 1,755, 1,705, 1,675, 1,590, 1,410 and 1,320.

NMR spectrum (DMSO-dg, ppm): 3.82 (1H, d, J - 5 Hz, C^-H), 4.78 (lH, dd, J = 5 Hz, J = 9 Hz, C ₃ ~H), 5.01 (2H, s, CH^), 7.29 (5H, s, phenyl protons), 7.31 (1H, d, J - 9 Hz, C ₃ -NH), 8.26 (1H, broad singlet, N^-H).

Reference example 147

In 5 ml of N,N-dimethylformamide, 717 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid (as potassium salt) is dissolved. While cooling with ice and stirring, 0.25 ml of ethyl bromoacetate is added thereto. The mixture is stirred for one hour at room temperature. 50 ml of water is added and the solution is extracted with ethyl acetate. The extract is washed with aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure. Ether is added to the solid residue. By filtration, colorless crystals of cis-3-benzyloxycarboxamido-4-ethoxycarbonylmethyloxycarbonyl-2-oxoazetidine are obtained, m.p. 109 to 111 °C. ' ®

IR spectrum (V cm“ ¹ ); 3 350, 3 260, 1 775, 1 710 and 1 675. For C _lg H _lg N ₂ O ₇ calculated:

54.86 i C, 5.18% H, 8.00 i N, found: 54.90% C, 5.24% H, 7.79% N.

Reference example 148

In the same manner as in Reference Example 67, cis-3-£2-(2-chloroacetamido-

-4-thiazolyl)-2-methoxyiminoacetamidoJ -4-ethoxycarbonylmethyloxycarbonyl-2-Oxoazetidine

118 (syn isomer), mp 226-231 °C (dec.). X-ray spectrum (in ^cm 5 ^: 3270, 1765, 1750,

690 and 1 670. For ^c ig ^H jg ^C1N 5°8 ^S calculated: 40.38% C, 3.81% H, 14.72 i N, found:

40.08% C, 3.97% H, 14.51% N.

Reference example 149

Ether was added to trans-3-benzyloxycarboxamido-1-(2,4-dimethyloxybenzyl)-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 26.

The mixture is allowed to cool. Crystals are separated by standing, which are filtered off with suction and washed with water. Colorless crystals are produced, mp 65 to 68 °C. For ^C 22 ^B 24 ^ÍÍ 2°7 ⁱⁿ YP°^ ^tello! 61.67% c, 5.65% H,

6.54% N, found: 61.84% C, 5.48% H, 6.36% N.

The above product was reduced with sodium borohydride in the same manner as in Reference Example 5. The product was purified by silica gel column chromatography (elution with hexane/ethyl acetate 1:4). Trans-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine was obtained as a colorless oil. IR spectrum (V _a ® ^t , cm ^-1 ): 3,400, 3,325, 1,740 (broad band) and 1,030.

Reference example 150

5.8 g of trans-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine are dissolved in 50 ml of methylene chloride. To this solution, under ice-cooling and stirring, 2.29 g of pyridine and then 1.54 ml of acetyl chloride are added first. The mixture is stirred at room temperature for one hour. The solvent is distilled off under reduced pressure. The residue is dissolved in ethyl acetate, washed successively with 3N hydrochloric acid, aqueous sodium bicarbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is dissolved in 300 ml of acetonitrile. The mixture is refluxed. An aqueous solution containing 5.87 g of potassium persulfate and 3.78 g of potassium hydrogen phosphate is added dropwise.

After the dropwise addition, the mixture was refluxed for one hour. Acetonitrile was distilled off under reduced pressure. The remaining aqueous solution was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate and then with aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (140 g, elution with hexane/ethyl acetate 1:2). Trans-3-benzyloxycarboxamido-4-acetoxymethyl-2-oxoazetidine was produced, m.p. 119 to

121°C. IR spectrum (in ^KBr , cm ^-1 ): 3,245, 1,750, 1,725, 1,705, 1,550, 1,270, 1,250 and max

035.

Reference example 151

In the same manner as in Reference Example 67, trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-acetoxymethyl-2-oxoazetidine (syn isomer), m.p.

177 to 190 °C (dec.). IR spectrum (in ??*, cm ^-1 ): 3,180, 1,760, 1,735, 1,710, 1,640, max

565 and 1,040.

Reference example 152

18.3 g of trans-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine were dissolved in 50 ml of pyridine. 5.76 g of methanesulfonyl chloride were added under ice cooling. The mixture was stirred for one hour at room temperature. The reaction mixture was added to ethyl acetate and the mixture was washed with 6N hydrochloric acid, then with aqueous sodium bicarbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. This residue was dissolved in 400 ml of methyl ethyl ketone. 34.25 g of sodium iodide was added to the solution. The mixture was heated to reflux for two and a half hours. Then the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate.

119

The solution is washed with saturated aqueous sodium sulfite, aqueous sodium chloride, dried over anhydrous magnesium sulfate and the solvent is distilled off under reduced pressure. This procedure produces an oil of trans-3-benzyloxycarboxamido-4-iodomethyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, IR spectrum (in cm ^-1 ): 3,300, 1,760, 1,710, 1,605, 1,510, 1,285, 1

260 and 1,210. NMR spectrum (CDCl ₃ , ppm): 3.78 (6H, s, 2 x OCH ₃ ), 5.00 (2H, s, phenyl-CH ₂ ), 7.28 (5H, s, phenyl protons).

Reference example 153

In the same manner as in Reference Example 63, trans-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-methyl-2-oxoazetidine was prepared. This compound did not crystallize. It was therefore purified by chromatography on a silica gel column (350 g, elution with hexane-ethyl acetate in a ratio of 2:1, later 1:2). IR spectrum (V ^part Ý, cm ^-1 ): 3,280, 2,950, 1,750, 1,710, 1,605, max

505, 1260 and 1210. NMR spectrum (CDClg, ppm): 1.20 (3H, d, J = 6 Hz, C ₄ -CH ₃ ), 3.75 (6H, s, 2 x OCH ₃ ), 5.02 (2H, s, phenyl-CH ₂ ), 5.55 (1H, dd, J = 6 Hz, J = 8 Hz, C 2 -H), 7.21 (5H, s, phenyl protons).

Reference example 154

In the same manner as in Reference Example 66, trans-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine was prepared, mp 109-111°C. IR spectrum (V cm^): 3,320, 3,220, 1,780,

690, 1535, 1450, 1265, 1045 and 730.

Reference example 155

In the same manner as in Reference Example 67, trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido2-4-methyl-2-oxoazetidine (syn isomer) was prepared, mp 240-248°C (dec.). IR spectrum cm ^-1 ): 3,330, 1,740, 1,680, 1,665, 1,575, 1,540, 1,355, and 1,045.

Reference example 156

140 mg of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine are dissolved in 1.4 ml of dry tetrahydrofuran. 0.1 ml of a 40% methylamine solution and one drop of acetic acid are added to the solution. The mixture is left to stand in the cold (5 °C) for four hours. The resulting crystalline precipitate is filtered off and washed with ether. Cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine is produced, which melts at 207-208 °C after recrystallization from a mixture of ethyl acetate and methanol. IR spectrum (in cm ¹ ): 3 270, 1 770, 1 700 and 1 660. NMR spectrum (DMSO-dg, ppm): 2.56 (3H, d, J = 5 Hz, NHCl), 4.13 (1H, d, J = 5 Hz, C ₄ ~H), 7.33 (5H, s, phenyl protons), 8.33 (1h, d, J = 5 Hz, NHCHj), For ^χ ₃ ®χ5 ^Ν 3θ4 calculated: 56.30 % C, 5.45 % H, 15.15 % N, found: 56.17 % C, 5.31 % H, 15.23 % N.

Reference example 157

In a mixture of 50 ml of tetrahydrofuran and 50 ml of methanol, 831 mg of cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine is dissolved. 830 mg of 5% palladium on carbon is added to the solution. The mixture is stirred for one hour under a hydrogen atmosphere. The catalyst is filtered off. The filtrate is evaporated under reduced pressure. 410 mg of colorless powder of cis-3-amino-4-methylcarbamoyl-2-oxoazetidine is produced. IR spectrum (V ” _and ^1Ol ( cm ¹ ): 3,300, 1,750 and 1,650. NMR spectrum (DMSO-dg, ppm): 2.70 (3H, d, J = 5 Hz, NHCH ₃ ), 3.96 and 4.23 (2 X 1H, 2 xd, J = 5 Hz, C ₃ ~H and C ₄ ~H).

This product (320 mg) was dissolved in a mixture of 6 ml of water and 6 ml of tetrahydrofuran. To this solution was added 500 mg of sodium bicarbonate. Under ice-cooling and stirring, 960 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-(Z)-methoxyiminoacetyl chloride hydrochloride was added.

The mixture was stirred for one hour. The tetrahydrofuran was distilled off. The remaining mixture was filtered. The resulting powder was washed successively with aqueous sodium bicarbonate, water, ethanol and ether.

120

Produces εο cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-methylcarbamoyl-2-oxoazetidine (syn isomer). IR spectrum cm b : 3 220, 1 750, 1 700 and 1 660. NMR spectrum (DMSO-dg, ppm): 2.50 (3H, d, J = 5 HZ, NHCHj), 3.76 (3H, s, NOCHj),

5.3 (1H, dd, J = 5 Hz, J = 9 Hz, C. ₃ -H) , 7.28 (1H, s, SyH), .7.8 (1H, d, J = 5 Hz, NHCHj),

8.3 (1H, br s, N _x -H).

Reference example 158

The procedure of Reference Example 91 was repeated, using trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester instead of the corresponding cis compound. Crystals of trans-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer) were thus obtained, mp 110-120°C (dec.).

IR spectrum (V cm ^-1 ): 3,280, 2,980, 1,790 to 1,740, 1,680 and 1,525. For ^C 23 ^íi 23 ^C1N 6°10 ^S calculated: 45.21% C, 3.79% H, 13.76% N, found: 45.60% C, 4.14% H, 13.14% N.

Reference example 159

In the same manner as in Reference Example 81, the following compounds were prepared:

N-(1-methoxycarbonyl-1-methylethoxy)phthalimide, mp 106 to 107 °C IR spectrum (V cm ^-1 ): 2,990, 2,960, 1,790 and 1,740. For ε _χ3 Η _χ3 ΝΟ ₅ calculated: 59.31% C, 4.98% H, 5.32% N, found: 59.60% C, 4.98% H, 5.22% N. \

N-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyphthalimide. IR spectrum cm ^-1 ): 2,940, 1,790 and 1,735. NMR spectrum (CDCl ₃ , ppm): 0.10 (9H, s, SiMe ₃ >, 0.92 (2H, t, J = 9 Hz, CH ₂ Si), 1.62 (6H, s, NOCMe ₂ ), 4.31 (2H, t, J = 9 Hz, COOCH 2 ), 7.73 (4H, s, aromatic protons).

Reference example 160

In the same manner as in Reference Example 82, the following compounds were prepared:

clean -1

O-(1-methoxycarbonyl-1-methylethyl)hydroxylamine. IR spectrum < ^v _max , om ): 3 325,

980, 2950, 1735. NMR spectrum (CDCl1, ppm): 1.43 (6H, s, CMe ₂ ), 3.75 (3H, s, COOCH ₃ >, 5.33 (2H, br s, NH ₂ ).

O-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethyl] hydroxylamine. IR spectrum (VA cm ^-1 ): 3,320, 2,950 and 1,730. NMR spectrum (CDCl-j, ppm): 0.10 (9H, s, SiMe ₃ ), 1.12 (2H, t, CH ₂ Si), 1.45 (6H, s, NOCMe ₂ ), 4.25 (2H, t, J » 9 Hz, COOCHj), 5.12 (to 5.43 (2H, broad band, NH ₂ ).

Reference example 161

In the same manner as in Reference Example 83, the following compounds were prepared:

2-(2-chloroacetamido-4-thiazolyl)-2-(1-methoxycarbonyl-1-methylethoxyimino)acetic acid. IR spectrum ( _λmax < cm ^-1 ): 3,200, 2,980, 1,750 and 1,680. NMR spectrum (CDCl 2 , ppm):

1.58 (6H, s, CMe ₂ ), 3.72 (3H, s, COOCH-j ), 4.3 (2H, s, ClCH ₂ ), 7.33 (1H, s, thiazole 5-H).

AND

2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetic acid. IR spectrum (V cm 2 ): 3,420, 3,200, 2,960, 1,740 and 1,730.

121

Reference example 162

In the same manner as in Reference Example 84, 2-(2-chloroacetamido-4-thiazolyl)-2-(1-methoxycarbonyl-1-methylethoxyimino)acetyl chloride hydrochloride was prepared, mp 105 to 115 °C. IR spectrum (V cm ^-1 ): 2,980, 1,790, 1,745 and 1,700. For C ₁₂ H ₁₃ Cl ₂ N ₃ C> ₅ S.HCl calculated: 34.42% C, 3.37% H, 10.03% N, found: 34.94% C, 3.46% H, 10.21% N.

Reference example 163

In the same manner as in Reference Example 85, cis-3-β2-(2-chloroacetamido-4-thiazolyl)-2-(1-methoxycarbonyl-1-methylethoxyimino)acetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer) was prepared, mp 212-214°C (dec.). IC spectrum (V cm ^- ' ¹ '); 3,300, 3,080,

975, 1780 to 1750, 1720 and 1660. Calcd for C^yí^gClNgOgS: 41.68% C, 4.12% H,

14.30% N, found: 41.47% C, 4.14% H, 14.06% N.

Reference example 164

820 mg of 2-(2-chloroacetamido-4-thiazolyl)-2-[Ί-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyiminoacetic acid was dissolved in 25 ml of methylene chloride. To this solution, 221 mg of triethylamine and 380 mg of phosphorus pentachloride were added under ice-cooling. The mixture was stirred for 15 minutes under ice-cooling and two hours at room temperature. The reaction mixture was concentrated under reduced pressure.

The residue is dissolved in 5 ml of tetrahydrofuran to obtain a solution containing the acid chloride.

In addition, 219 mg of cis-3-amino-4-methoxycarbonyl-2-oxoazetidine was dissolved in a mixture of 5 ml of tetrahydrofuran and 10 ml of water. To this solution was added 638 mg of sodium bicarbonate under ice-cooling. To this solution was added dropwise the above acid chloride solution under stirring. The mixture was stirred for 15 minutes under ice-cooling and then for one hour at room temperature. The solution was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off.

cis-3-[2-(2-chloroacetamido-4-thiazolyl)~2-[1-methyl-1-(2-trimethylsilylethoxycarbonyl)ethoxyimino]acetamido]-4-methoxycarbonyl-2-oxoazetidine (syn isomer) is produced.

IR spectrum (in ^KBr , cm ^-1 ): 3,280, 2,950, 1,760, 1,730 and 1,685. NMR spectrum (CDC1, + DMSO-d,, max oo ppm): 1.18 (2H, CH ₂ Si), 1.81 (6H, NOCMe ₂ ), 4.40 (2H, COOCHJ, 4.44 (2H, s, _C1CH2 ), 4.67 (1H, d, J = 6 Hz, C ₄ -H), 5.88 (1H, dd, J = 6 Hz, J = 9 Hz, Cj-H), 7.57 (1H, s, S^, Η) ,

8.03 (1H, br s, N ₂ ~H) , 8.29 (1H, d, J = 9 Hz, C 1 -NH) . Ά

Reference example 165

In 20 ml of tetrahydrofuran, 1.5 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 2, was dissolved. 10 ml of 1M aqueous ammonium chloride was added to the solution. While stirring at room temperature, 0.5 ml of aqueous ammonia (25 to 28%) was added and the mixture was stirred for three hours. Then, another 2 ml of aqueous ammonia was added. The mixture was stirred for 16 hours. Tetrahydrofuran was distilled off under reduced pressure. The resulting crystalline precipitate was filtered off, washed first with water, then with ether and dried. Thus, cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine was prepared, m.p. 236 to 237 °C (dec.).

IR spectrum (in cm ^-1 ): 3 400, 3 300, 3 200, 1 760 and 1 670. NMR spectrum (DMSO-d _g , ppm): 4.14 (1H, d, J = 6 Hz, C ₄ ~H), 5.05 (2H, s, phenyl-CH ₂ ), 5>08 (1H, dd, J = 6 Hz, J = = 10 Hz, C ₃ ~H), 7.36 (5H, s, aromatic protons). For ^ε χ2 ^Η 13 ^Ν 3°4 ⁱⁿ yP°° ^{it was found:} 54.57 % C,

4.98% H, 15.96% N, found: 54.93% C, 4.90% H, 15.65% N.

122

The corresponding trans compound is prepared in the same manner as above.

Reference example 166

304 mg of cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine was suspended in 15 ml of ethanol. 304 mg of 5% palladium on carbon was added to the suspension. The mixture was stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of 6 ml of tetrahydrofuran and 6 ml of water. 534 mg of sodium bicarbonate was added under ice-cooling. To this solution was added 686 mg of 2-(2-chloroacetamido-4-thiazolyl)-(Z)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetyl chloride hydrochloride, which was prepared according to the above-mentioned Reference Example 90.

The mixture was stirred for 15 minutes under ice-cooling and one hour at room temperature. Then, 200 ml of ethyl acetate was added, which was used to extract the solution. The organic layer was washed twice with 0.1N aqueous sodium hydroxide solution, once with aqueous sodium chloride, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Thus, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-Q1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-carbamoyl-2-oxoazetidine (syn isomer) was produced as a foam, mp 144-147 °C.

IR spectrum (in cm^): 3,380, 1,760, 1,750 and 1,680. NMR spectrum (DMSO-dg, ppm):

1.52 (6H, s, 2 x CH ₃ ), 4.27 (1H, d, J = 6 Hz, C ₄ ~H), 4.34 (2H, s, C1CH ₂ >, 5.32 (2H, s, COOCH ₂ ), 5.46 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 7.41 (1H, s, S^/H).

The corresponding trans compound is prepared in the same manner as above.

Reference example 167

In 80 ml of methylene chloride, 4 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxoazetidine, which is prepared according to Reference Example 5, is dissolved.

While cooling with ice-water, 0.9 ml of chlorosulfonyl isocyanate was added to the solution and the mixture was stirred for another 10 minutes. The reaction mixture was added dropwise to 60 ml of aqueous sodium sulfite solution (2.8 g) while cooling with ice-water and stirring. The mixture was stirred for one hour at room temperature, during which crystals precipitated.

The crystals are dissolved by adding methylene chloride. The methylene chloride layer is separated, washed with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off. Ether is added to the residue. The resulting crystals are filtered off. Thus,

3.3 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-carbamoyloxymethyl-2-oxoazetidine. IR spectrum _C m ^-1 ): 3,400, 3,300, 3,200, 1,760 and 1,690.

The above product was added to a mixture of 75 ml of acetonitrile and 37.5 ml of water. To the mixture were added 6.5 g of potassium persulfate and 3.9 g of potassium hydrogen phosphate. The mixture was stirred under argon for one hour while heating to 95°C. After cooling, ethyl acetate was added. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off. Ether was added to the residue. Insoluble materials were filtered off and purified by column chromatography on silica gel (90 g, elution with chloroform/methanol/ethyl acetate 85:10:5). Colorless crystals of cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-oxoazetidine were produced, melting at 205-207°C.

IR spectrum (in ^cm ^) ^! 430, 3300, 1760 and 1700. NMR spectrum (DMSO-d6, ppm):

6.33 (2H, br s, NH ₂ ), 7.30 (5H, s, C _g H ₅ ), 7.8 (1H, d, J = 9 Hz, C ₃ ~NH), 8.16 (1H, br s,

N ₂ ~H). For C^ ₃ H^ ₅ N ₃ O ₅ calculated: 53.23% C, 5.15% H, 14.32% N, found: 53.33% C,

4.90% H, 14.09% N.

123

Reference example 168

In a mixture of 30 ml of tetrahydrofuran and 30 ml of water, 3 g of trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 27, were dissolved. To this solution, under ice-cooling, 6 ml (1M) of aqueous ammonium chloride solution were first added, followed by 4' ml of 25-28% aqueous ammonia. The mixture was stirred for 3 hours at room temperature. Tetrahydrofuran was distilled off under reduced pressure. Sodium chloride was added to the remaining aqueous solution, and the solution was extracted twice with a mixture of chloroform and ethanol (in a ratio of 3:1). The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by chromatography on silica gel (180 g, elution with ethyl acetate, then with a mixture of ethyl acetate and methanol in a ratio of 8:1). Trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine is produced, mp 179-184°C.

IR spectrum (V max' ^crn: 280, 1,760, 1,695 and 1,660. NMR spectrum (DMSO-dg, ppm):

3.90 (1H, d, J = 3 Hz, C ₄ ~H), 4.42 (1H, dd, J = 3 Hz, J = 9 Hz, C^-H), 8.04 (1H, d, J = “ 9 Hz, C ₃ -NH).

Reference example 169

Dissolve 31.0 g of freshly distilled methacrolein in 300 ml of methylene chloride.

36.9 g of 2,4-dimethoxybenzylamine are added to the solution. 100 g of anhydrous sodium sulfate and 440 mg of p-toluenesulfonic acid monohydrate are added to this solution. The mixture is stirred for 3 hours at room temperature. The reaction mixture is filtered. The filtrate is concentrated under reduced pressure. The residue is dissolved in 300 ml of methylene chloride. A solution of 24.5 g of triethylamine in 100 ml of methylene chloride is added dropwise with ice cooling and stirring. Then a solution of 49.4 g of phthalimidoacetyl chloride in 300 ml of methylene chloride is added dropwise over about one hour. The mixture is stirred overnight at room temperature.

This reaction mixture was filtered. The insoluble materials were washed with methylene chloride. The filtrate was combined with the washed dichloromethane solution and the combined fractions were concentrated under reduced pressure to a volume of 0.5 liter. The concentrate was washed successively with 200 ml of 1N hydrochloric acid, 200 ml of water, 300 ml of 2% aqueous sodium bicarbonate (twice) and 200 ml of water and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was chromatographed on a silica gel column (400 g, eluting with hexane/ethyl acetate 1:1).

Thus, 55.8 g of crude product cis~3~phthalimido-4-isopropenyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are produced. This product is dissolved in 500 ml of methanol and the solution is mixed with 25 g of 5% palladium on carbon. The solution is stirred for 7 hours under a hydrogen atmosphere, while 870 ml of hydrogen is absorbed, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate, washed first three times (100 ml) with 1N hydrochloric acid and then once with aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure.

47 g of residue are obtained. This residue is dissolved in 700 ml of ethanol. 47 g of 5% palladium on carbon are added to the solution. The mixture is stirred for 24 hours under a hydrogen atmosphere, while 1,900 ml of hydrogen is absorbed. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by column chromatography on silica gel (400 g, elution with a 1:1 mixture of hexane and ethyl acetate). The solvent is distilled off and ethanol is added to the residue. The resulting crystalline precipitate is filtered off. 8.6 g of cis-3-phthalimido-4-isopropyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are obtained. The mother liquor is concentrated and the residue is dissolved in 450 ml of ethanol. The product is catalytically reduced using 5% palladium on carbon (15 g).

700 ml of hydrogen are absorbed. The catalyst is filtered off and the filtrate is concentrated. A crystalline precipitate is obtained. This crystalline precipitate is filtered off, washed with ethanol and dried. This produces another portion (5.3 g) of the above 4-isopropyl derivative. Recrystallization from ethanol gives colorless crystals melting at 151-152°C.

124

Mass spectrum: m/z 408 (M ⁺ ). IR spectrum ( _in ^ _ax ^O1 i cm ^-1 ): 1,760 and 1,715.

For C ₂₃ H, ₄ N ₂ O ₅ calculated: 67.63 i C, 5.92 % II, 6.86 % N, found: 67.53 % C, 5.89 % H,

6.79% N.

Reference example 170

8.5 g of cis-3-phthalimido-4-isopropyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are dissolved in 170 ml of dimethoxyethane. 2.1 ml of methylhydrazine are added dropwise while cooling with ice and stirring. The mixture is stirred for 4 hours at room temperature and then for 2 hours at a temperature of 35 to 40 °C. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The previously filtered crystals are added to the residue, 120 ml of dichloromethane are added and the mixture is stirred for 3 hours at a temperature of 60 to 70 °C. After cooling, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate. The solution is extracted first with 50 ml, then with 20 ml of 1N hydrochloric acid and the extract is washed with ether. After addition of 8.4 g of sodium bicarbonate, an oil separated. This oil was extracted with chloroform, washed with brine and dried over anhydrous sodium sulfate.

The solvent is then distilled off under reduced pressure. The residue is dissolved in 10 ml of methylene chloride. 30 ml of propylene oxide is added to the solution. Under ice-cooling and stirring, a solution of 3.55 g of carbobenzoxy chloride in 10 ml of methylene chloride is then added dropwise, whereby crystals precipitate. 70 ml of propylene oxide and 30 ml of methylene chloride are added, and the mixture is stirred at room temperature.

The above crystals gradually dissolved into a clear solution (over 4 hours). The solvent was then distilled off. The residue was purified by column chromatography on silica gel (250 g, elution with hexane/ethyl acetate 1:1). Crystallization from ether gave 4.7 g of cis-3-benzyloxycarboxamido-4-isopropyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, melting at 123-125°C.

IR spectrum (ν2ϊ^ ^θ1 > cm ¹ ): 3 300, 1 760 and 1 690. For C„,H. _Q N ₉ 0 _K calculated: 66.97 i C, max 22 2o 2

6.84% H, 6.79% N, found: 66.96% C, 6.83% H, 6.81% N.

Reference example 171

To a mixture of 50 ml of acetonitrile and 25 ml of water are added 2.06 g of cis-3-benzyloxycarboxamido-4-isopropyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine, 1.89 g of potassium persulfate and 1.13 g of potassium hydrogen phosphate. The mixture is heated to 95 °C with stirring for 2 hours under reflux. After ^cooling , the acetonitrile is distilled off under reduced pressure. 50 ml of water is added. The resulting solution is extracted with 200 ml of ethyl acetate. The extract is washed with two 100 ml portions of 2% aqueous sodium bicarbonate and once with aqueous sodium chloride. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. The residue is heated slightly with 50 ml of benzene and allowed to cool. Insoluble materials are filtered off and washed first with benzene, then with a small amount of ether.

1.1 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine is produced, melting at 184-185 °C. IR spectrum (V cm: 3340, 1760, 1690, For ^C ^4 ^H ^8 ^N 2°3 ⁱⁿ YP ^o read:

64.10% C, 6.92% H, 10.68% N, found: 63.58% C, 6.75% H, 10.47% N.

Reference example 172

1.0 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine was suspended in 30 ml of ethanol. 1.0 g of 5% palladium on carbon was added to the suspension. The suspension was stirred for 30 minutes under a hydrogen atmosphere. The catalyst was then filtered off. The filtrate was evaporated to dryness under reduced pressure. 430 mg of crystals of cis-3-araino-4-isopropyl-2-oxoazetidine were thus produced, melting at 91-93 °C.

KRr — 1

IR spectrum (ν' _max < cm ): 3,350 to 3,150, 1,735. NMR spectrum (CDC1 ₃ , ppm): 0.95 (6H, d, J = 6 Hz, 2 x CH ₃ ), 1.59 (2H, br s, NH ₂ >, 3.2(1H, dd, J = 5 Hz, J = 9 Hz, C ₄ ~H), 4.17 (1H, d, J = 5 Hz, C ₃ -H).

125

For C ₆ H ₁₂ N ₂ O calculated: 56.22% C, 9.44% H, 21.86% N, found: 56.35% C, 9.45% H, 21.38% N.

Reference example 173

3.7 g of p-anisidine are dissolved in 100 ml of methylene chloride. 4.2 g of trans-cinnamaldehyde and 30 mg of anhydrous magnesium sulfate are added to the solution. The mixture is stirred for two hours at room temperature. The reaction mixture is filtered and the filtered material is washed with 60 ml of dichloromethane. The filtrate and the washed dichloromethane portion are combined. Under ice cooling and stirring, first 8.4 ml of triethylamine are added and then a solution of 7 g of phthalimidoacetyl chloride* in 50 ml of methylene chloride is added dropwise. The mixture is stirred for one and a half hours at room temperature. The reaction mixture is washed with water and aqueous sodium chloride. The methylene chloride is distilled off under reduced pressure.

50 ml of chloroform is added to the residue. Insoluble materials are filtered off. The filtrate is concentrated under reduced pressure. The residue is crystallized from 25 ml of ethyl acetate. The crystals are filtered off. Thus, cis-3-phthalimido-4-(E)-styryl-1-(p-methoxyphenyl)-2-oxozaethidine is produced, melting at 202 to 203 °C. IR spectrum (V cm ¹ ): 1740 and 1720. NMr spectrum (CDC1 ₃ , ppm): 3.74 (3H, s, OCHj), 5.00 (1H, dd, J = 5 Hz, J = 7 Hz, C/H), 5.65 (1H, d, J = 5 Hz, C,-II), 6.24 (1H, dd, J = 7 Hz, J = 16 Hz, H ), 6.78 (1H, d, J = 16 Hz, _-phenyl.

For ^C 16 ^H 2O ^N 2°4 ⁱⁿ yP°^ ^tenO! 73.57% C, 4.75% H, 6.60% N, found: 73.56% C, 4.58% H, 6.87% N.

Reference example 174

In 25 ml of tetrahydrofuran, 1 g of cis-3-phthalimido-4-(E)-styryl-1-(p-methoxyphenyl)-2-oxoazetidine is dissolved. To this solution, while stirring at a temperature of -5 °C to -10 °C, a solution of cerium ammonium nitrate (3 g) in 10 ml of water is added dropwise over five minutes. The mixture is stirred for twenty minutes at -5 °C to 0 °C. Tetrahydrofuran is distilled off under reduced pressure and the residue is shaken with ethyl acetate and water. The ethyl acetate layer is separated, washed with aqueous sodium sulfite, then with aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is distilled off. The residue is purified by chromatography on a silica gel column (elution with a mixture of chloroform and ethyl acetate in a ratio of 7:3). The product is crystallized from a mixture of ethyl acetate and ether.

Cis-3-phthalimido-4-(E)-styryl-2-oxoazetidine is produced, melting at 168-170°C.

IR spectrum (V cm ¹ ): 3,250, 1,750 and 1,720. NMR spectrum (CDCl 3 , ppm): 4.68 (1H, dd,

J = 5 Hz, J = 8 Hz, C/H), 5.57 (1H, d, J = 5 Hz, C/H), 6.66 (1H, s, N/H). For C ₁₉ H ₂₄ N ₂ O ₃ calculated: 71.69% C, 4.43% H, 8.80% N, found: 71.61% C, 4.37% H, 8.55% N.

Reference example 175

547 g of cis-3-phthalimido-4-(E)-styryl-2-oxoazetidine are dissolved in 6 ml of N,N-dimethylformamide. 0.36 ml of triethylamine and 323 mg of tert-butyldimethylsilyl chloride are added under ice cooling and stirring. The mixture is stirred for 30 minutes and then for 4 hours at room temperature. The reaction mixture is then shaken with ethyl acetate and water. The ethyl acetate layer is separated, washed twice with water, once with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. It is concentrated under reduced pressure and the residue is chromatographed on a silica gel column (elution with chloroform). The product is recrystallized from ether.

Cis-3-phthalimido-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine is produced, melting at 167 to 168 °C. IR spectrum (in _cm 1). χ 759 _and χ 715. NMR spectrum (CDCl^, ppm): 4.58 (1H, m, C/H), 5.62 (1H, d, J = 6 Hz, C/H). For ^C 25 ^H 28 ^N 2°3 ^S1 calculated: 6Í.41% C 6.52% H, 6.48% N, found: 69.22% C, 6.46% H, 6.48% N.

126

Reference example 176

440 mg of cis-3-phthalimido-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine are suspended in 5 ml of dimethoxyethylene. 0.26 ml of methylhydrazine is added to the suspension and the mixture is stirred for 30 minutes at room temperature. The solvent is then distilled off under reduced pressure. The residue is dissolved in 5 ml of methylene chloride and the solution is left to stand overnight. The precipitate is filtered off. The filtrate is concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (elution with a mixture of chloroform and ethyl acetate in a ratio of 6:4). An oil of cis-3-amino-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine is produced. This oil is dissolved in 10 ml of tetrahydrofuran. With cooling and stirring, 0.2 ml of triethylamine and then 0.212 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride are added. The mixture is stirred under ice-cooling for 10 minutes, then for 30 minutes at room temperature, after which the mixture is shaken with ethyl acetate and water.

The ethyl acetate layer was separated, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (elution with chloroform:ethyl acetate 7:3). The product was recrystallized from ether. j

Cis [-2-(2-Chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido']-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine (syn isomer) is produced, melting at 228-231 °C / (dec.). IC spectrum ^Cm'1 ): 1,725 and 1,670. NMR spectrum (CDCl2, ppm): 3.15 (3H, s, OCH2), 4.20 (2H, s, _C1CH2 ), 4.63 (1H, m, _C4 -H), 5.50 (1H, dd, J = 6 Hz, J = 6 Bzr, Cj-H), 7.20 (1H, s, S\^,H), 8.50 (1H, d, J = 6 HZ, Cg-NH).

Reference example 177

While stirring and under a stream of nitrogen, 50 ml of dry tetrahydrofuran are cooled to -78°C.

Then 20 ml of a 15% solution of butyllithium in hexane are added thereto. 3.66 ml of diisopropylamine are added dropwise and the mixture is stirred for 15 minutes at a temperature of -78 °C. A solution of 3.1 g of 2,2-dimethyl-1-aza-3-oxabicyclo [4.2.0] octan-8-one in 15 ml of dry tetrahydrofuran is added dropwise to the mixture. The mixture is stirred for one hour at a temperature of -78 °C. Then a solution of 4.34 g of p-toluenesulfonyl azide in 15 ml of dry tetrahydrofuran is added dropwise. The mixture is stirred for one and a half hours at a temperature in the range of -50 to -60 °C. 5.1 ml of trimethylsilyl chloride are added dropwise to this mixture and the reaction mixture is refluxed for five hours. After cooling, insoluble materials are filtered off.

The filtrate was concentrated under reduced pressure. The residue was shaken with water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The solvent was distilled off. The residue was purified by silica gel column chromatography.

2,2-Dimethyl-7-a2ido-1-aza-3-hexabiocyclo[4.2.0]-octan-8-one is produced as a mixture of cisKBf —1 and trans isomers (in the ratio 1:4). IC spectrum (V _max » ^cm )« ² 100 and 1 750. NMR spectrum (CDCl 2 , ppm): 4.20 (d, J “ 1.5 Hz, trans-Cj-H), 4.68 (d, J “ 5 Hz, cis-Cj-H).

Crystallization of the above mixture from diisopropyl ether selectively crystallizes the trans-compound, which melts at 78-80°C.

Reference example 178

330 mg of trans-2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4.2.0]-octan-8-one was dissolved in 30 ml of acetone. 3.3 ml (8N solution) of Jones reagent was added under ice-cooling and stirring. The mixture was stirred for two and a half hours. Then 5 ml of isopropyl alcohol was added and the mixture was stirred for another 10 minutes. The materials that remained undissolved were filtered off through celite. The filtrate was concentrated under reduced pressure. The residue was shaken with tetrahydrofuran and a little

127 with a saturated aqueous sodium chloride solution. The tetrahydrofuran layer was separated and extracted three times with tetrahydrofuran. The tetrahydrofuran layers were combined and dried over anhydrous sodium sulfate. A solution of diazomethane in ether was added to the solution. The mixture was allowed to stand. The solvent was then distilled off and the residue was shaken with water and ethyl acetate. The ethyl acetate layer was separated, washed successively with aqueous sodium bicarbonate, water and dried over anhydrous sodium sulfate.

The ethyl acetate solution was concentrated under reduced pressure. The residue was chromatographed on a silica gel column. Trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine was produced. NMR spectrum (CDCl ₃ , ppm): 12.76 (2H, d, J = 6 Hz, C ₄ ~CH ₂ ), 3.70 (3H, s, COOCH ₃ ), 3.82 (1H, m, C ₄ H),

4.36 (1H, C ₃ -H), 6.75 (1H, s, N^H).

If the same procedure is followed but starting from a mixture of cis- and trans-isomers (in a ratio of 1:4), then the 2-oxoazetidine compound is produced in the form of cis- and trans-isomers as a mixture (in a ratio of 1:4). NMR spectrum (CDCl ₃ , ppm): 4.83 (cis-C ₃ ~H).

Reference example 179

In a mixture of 20 ml of tetrahydrofuran and 10 ml of water, 800 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid, which was prepared according to Reference Example 68, was dissolved. 280 mg of sodium bicarbonate was added under ice-cooling. 303 mg of o-methylhydroxylamine hydrochloride and 638 mg of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride were added to the mixture. The mixture was stirred at room temperature. After three hours, sodium chloride was added to the mixture, and the reaction mixture was extracted with ethyl acetate-ethanol (10:1). The extract was washed with 3N hydrochloric acid, saturated aqueous sodium bicarbonate, aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. This produces cis-3-benzyloxycarboxamido-4-methoxyaminocarbonyl-2-oxoazetidine, melting at 212-216 °C (decomposition). IR spectrum (in cm ¹ ): 3 290, 1 760 and 1 680.

Reference example 180

To 8 ml of dry dimethyl sulfoxide was added 5.1 g of cis-3-benzyloxycarboxamido-1-(2,4-dimethoxybenzyl)-4-iodomethyl-2-oxoazetidine, which was prepared according to Reference Example 62. To this solution were added 2.6 g of potassium cyanide and 50 mg of 18-crown-6.

The mixture is stirred for two days at room temperature, for 3 hours at 50 °C, then poured into 250 ml of ethyl acetate. The reaction mixture is washed first three times with water, once with sodium chloride (solution in water), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica gel column (400 g, elution with a mixture of ethyl acetate and hexane in a ratio of 1:2, later 2:1).

Cis-3-benzyloxycarboxamido-4-cyanomethyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine is produced. IR spectrum (λ cm ¹ ): 3290, 2920, 1770, 2240 and 1690. NMR spectrum (CDCl 2 , ppm):

2.48 (2H, d, J = 6 Hz, CH ₂ CN), 3.78 (3H, s, OCH ₃ ), 3.80 (3H, s„ OCILj), 4.82 (1H, dd, J = = 5 Hz, J = 8 Hz, C ₃ -H).

Reference example 181

In a mixture of 210 ml of acetonitrile and 70 ml of water, 1.7 g of cis-3-benzyloxycarboxamido-4-cyanomethyl-1-(2,4-dimethoxybenzyl)-2-oxoazetidine are dissolved. 1.68 g of potassium persulfate and 1.085 g of potassium hydrogen phosphate are added to the solution. The mixture is heated for two and a half hours at a temperature of 85 to 90 °C under reflux. The acetonitrile is distilled off under reduced pressure. The residue is extracted with ethyl acetate. The extract is washed successively with saturated aqueous sodium bicarbonate, aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a silica gel column (140 g, elution with a mixture of ethyl acetate and hexane in a ratio of 1:2, then 1:1/3). Cis-3-benzyloxycarboxamido-4-cyanomethyl-2-oxoazetidine is produced, melting at 113 to 115 °C. IR spectrum cm“ ¹ ): 3 300, 2 250, 1 760 and 1 685.

128

Reference example 182

In the same manner as in Reference Example 166, cis-3-[2-(2-chloroacetamido-4-thiazolyl)-2-[1-methyl-1-(p-nitrobenzyloxycarbonyl)ethyloxyimino]acetamido]-4-cyanomethyl-2-oxoazetidine (syn isomer) was prepared. IR spectrum (V cm ¹ ) i 3360, 2980, 2250, 1740, 1680,

600, 1,520, 1,345 and 1,140.

Reference example 183

In a mixture of 100 ml of tetrahydrofuran and 100 ml of water, 4 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, which was prepared according to Reference Example 2, was dissolved. 1.359 g of sodium hydrogen diborate was added under ice-cooling. The mixture was stirred for one hour under ice-cooling and then for two hours at room temperature. Tetrahydrofuran was distilled off under reduced pressure. The residue was extracted three times with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

The residue is dissolved in 30 ml of ethanol. 1 g of 5% palladium on carbon is added and the mixture is stirred for four hours under a hydrogen atmosphere. The catalyst is then filtered off and the filtrate is concentrated. The residue is dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran. 3.62 g of sodium bicarbonate is added under ice-cooling. Then 3.41 g of p-nitrobenzyloxycarbonyl chloride is added and the mixture is stirred for two hours at room temperature. This reaction mixture is extracted three times with chloroform. The extract is dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure. The residue is chromatographed on a silica gel column (160 g, elution with a 4:1 mixture of ethyl acetate and methanol) when pure ethyl acetate is used as the eluent initially).

Cis-3-(p-nitrobenzyloxycarboxamido-4-hydroxymethyl-2-oxoazetidine) is produced, melting at 166 to 167 °C. IR spectrum (V Cm ¹ ): 3,280, 1,770 and 1,700. For C|2 ^H 13 ^N 3°6 ^V ^~ calculated: 48.82% C, 4.44% H, 14.23% N, found: 48.58% C, 4.53% H, 13)87% N.

Reference example 184

2.28 g of sodium hydride are suspended in 40 ml of dry tetrahydrofuran. A solution of 3 g of 1-methyl-1H-tetrazol-5-yl-thiol in 40 ml of tetrahydrofuran is added under ice-cooling. A solution of 3.59 g of bromoacetic acid in 80 ml of dry ethanol is then added. The mixture is stirred for 30 minutes under ice-cooling and then for one hour at room temperature. It is concentrated under reduced pressure and the residue is shaken with 100 ml of water and 100 ml of ether. The aqueous layer is separated, acidified with 3N hydrochloric acid and extracted twice with a mixture of chloroform and ethanol (3:1). The extract is dried over anhydrous magnesium sulfate. The solvent is distilled off.

KBx “1

1-Methyl-1H-tetrazol-5-yl-thioacetic acid is produced. IR spectrum (V , cm ):

990 and 1700. NMR Spectrum (CDC1 ₃ + DMSO-d _g , ppm): 3.82 (3H, s, CH-j) , 3.98 (2H, s, CH ₂ ) ,

4.10 (1H, s, CO2H).

Claims (44)

A process for the preparation of a 1-sulfo-2-carboxylic acid of the formula I R ¹ (I) Where SO is H; - < ^CH 2> n ^-R R ^J where n is an integer from 0 to 3, 2 3 R and R which are the same alkyl group or different, a hydrogen atom, an alkyl group, a optionally substituted, optionally substituted aryl or aralkyl group, an optionally substituted heterocyclic group, an alkoxycarbonyl group or an acyl group, or together together represent oxo, hydrogen, alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, halogen, cyano, hydroxyl, alkoxy with optionally substituted alkyl, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy, arylsulfonyloxy, arylsulfonyloxy, , alkoxycarbonyl, alkoxycarbonylalkyloxy, aminocarbonyl, alkylthiocarbonyl, acyl, acylaminoalkylthio, aral an optionally substituted alkylthio group, an optionally substituted arylthio group, an optionally substituted heterocyclic thio group, or an optionally substituted quaternary ammonium group, or is a cycloalkyl, alkenyl, alkynyl, cycloalkenyl, aryl or heterocyclic group optionally substituted by one or a plurality of substituents, wherein the substituents of the optionally substituted alkenyl and alkynyl groups are selected from the group consisting of optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heterocyclic, alkoxycarbonyl, acyl, oxo, halogen, cyano, hydroxyl an alkoxy group, an aryloxy group with an optionally substituted aryl moiety, an acyloxy group upine, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, arylsulfonyloxy with optionally substituted aryl, nitro, amino, carboxyl, aminocarbonyl, alkylthiocarbonyl, mercapto, alkylthio253572 130, aminoalkylthio, acylaminoalkylthio, aralkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, heterocyclic thio with optionally substituted heterocyclic, and optionally substituted quaternary ammonium, wherein at least one of the aforementioned optionally substituted groups or the various and optional substituents of substituted cycloalkyl, cycloalkenyl, aryl, aralkyl, heterocyclic and quaternary ammonium groups are selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, alkylthio, arthio, arthio , alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, trihaloalkyl hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxyl, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, haloalkyl and monoalkylamino , the carboxyl and hydroxyl groups may be protected, each of the above alkyl and alkoxy groups having 1 to 6 carbon atoms, alkenyl and alkynyl groups having 2 to 6 carbon atoms, cycloalkyl and cycloalkenyl groups having 3 to 8 carbon atoms, the amino group being substituted by an acyl group , alkyl, hydroxyalkyl, aralkyl with optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclic, sulfo, alkylsulfonyl, an aralkylsulfonyl group with an optionally substituted alkyl group, an arylsulfonyl group with an optionally substituted aryl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group with an optionally substituted alkyl group, an aryloxycarbonyl group with an optionally substituted aryl group, and an aminocarbonyl group, wherein any substituents are as defined above, aralkyl benzyl, phenethyl, phenylpropyl or naphthylmethyl, aryl means phenyl, alpha-naphthyl, beta-naphthyl, biphenyl or anthryl, heterocyclic means a 5- to 8-membered heterocyclic radical having from one to four heteroatoms from the group consisting of nitrogen, including N-oxide, oxygen and sulfur, acyl group means in each case formyl group, alkylcarbonyl group having 1 to 6 carbon atoms, benzoyl group substi optionally substituted with a hydroxyl or C 1 -C 6 alkyl group, a C 7 -C 9 aralkylcarbonyl group optionally substituted by a hydroxyl or C 1 -C 6 alkyl group or a five-membered heterocyclic carbonyl or acetyl group containing at least one oxygen, nitrogen and sulfur, optionally substituted with amino, R &lt; 1 &gt; amino or an acylated amino group, wherein the acyl group has the formula R ⁵ -COC wherein R is alkyl or optionally substituted heterocyclic group, 131 or the general formula -NH-CH-COWhere R ⁸ is hydrogen, glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl, methionyl, alpha-aspartyl or beta-aspartyl, alpha-glutamyl or gamma-glutamyl, lysyl , arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophanyl or propyl, or an amino protecting group or a group of the formula R ⁸ - (CH ₂ ) _n -CO-- wherein R ⁸ represents an optionally substituted heterocyclic group and an integer of 0 to 2 alkyl, an optionally substituted phenyl group, a heterocyclic carbonylamino group with an optionally substituted heterocyclic moiety or an optionally substituted heterocyclic group, or an acyl moiety general formula R ⁹ -R ¹⁰ -COwhere R ³ represents a group of the general formula R ¹¹ -CII Where R ^{11 represents an} optionally substituted alkyl group, an optionally substituted heterocyclic or phenyl group, and a hydrogen atom, an alkyl group or a group of the formula -r ¹⁴ -r ¹⁴ R ¹⁰ wherein R is an alkylene or alkenylene group; and R ¹⁴ optionally substituted phenyl, carboxyl or alkyl ester thereof or monoalkylamino or dialkylamino, a direct bond or a group of the formula -CO-NH-CH ¹⁵ where R ^{18 is} an alkyl group, an optionally substituted phenyl group or an optionally substituted thiazolyl group. 132 or an acyl moiety having the general formula Where R ¹⁷ is R ^{16 is} hydroxy, hydroxy sulfonyloxy, carboxy, optionally substituted ureido, optionally substituted sulfamoyl, sulfo, optionally substituted phenoxycarbonyl or formyloxy, and R is hydrogen, alkyl, alkoxy, halogen, nitro or hydroxy or has an acyl moiety of the formula R is cyano, optionally substituted phenyl, optionally substituted phenoxy, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted heterocyclic, and R is a direct bond or a sulfur atom, wherein For the meaning of R and R, a heterocyclic group is taken to mean a 5- to 8-membered heterocyclic ring having from 1 to 4 heteroatoms selected from the group consisting of nitrogen (including N-oxide), oxygen and sulfur, pyrido [2,3-d] pyrimidyl a group, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl or thieno [2,3-6] pyridyl, optionally substituted with heterocyclic, phenyl, thiazolyl, phenoxycarbonyl, and phenoxy, in each case refers to groups substituted with one to two groups selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl , mercapto, alkylthio, arylthio, aralkylthio, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl trihaloalkyl, hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxy, acyl, acyloxy, acylamino, hydroxyalkyl, hydroxyalkyl or haloalkylalkyl, carboxyalkyl or haloalkyl; is as defined above, the alkyl and alkoxy moieties are each of 1 to 6 carbon atoms, the alkenyl group is always 2 to 6 carbon atoms, and the aralkyl and aryl moieties are as defined above; in the case of a substituted alkyl group the substituents are selected from halogen, hydroxy , cyano and trifluoromethyl, in the case of a substituted ureido group, the substituents are selected from the group consisting of a sulfo group in the form of a cation, a carbamoyl group, a sulfamoyl group, an amidino group or an alkyl group having 1 to 6 atoms. hlíku, The optionally substituted sulfamoyl group has as C1 -C6 alkyl or amino as substituents, the amino, carboxyl and / or hydroxyl group may be protected, the amino group may be substituted as described above for R, or R &lt; 6 &gt; amino protected with phthaloyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, trifluoromethyl, methanesulfonyl, ethanesulfonyl, ethanesulfonyl, ethanesulfonyl, ethanesulfonyl, ethanesulfonyl ethoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, 2-cyanethoxycarbonyl, beta, beta, beta-trichloroethoxycarbonyl, beta-trimethylsilylthoxycarbonyl, beta-methylsulfonylethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzobenzyl, p-nitrobenzoyl yloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidyl, alkenyl, the moiety, the aralkyl and the aryl moieties are in each case as defined for R, X is hydrogen or methoxy or a salt or ester thereof, characterized in that a compound of the formula III is reacted with a compound as defined above, or a salt or ester thereof, with a compound of the formula II R ° COOH (II) wherein R ° CO is an acyl group as defined above as an acyl moiety of the amino group as meaning R ¹ , or a reactive derivative thereof on the carboxyl group and optionally a protecting group is cleaved. 2. Process according to claim 1, characterized in that the corresponding starting materials are used Compounds of formula (II) and (III) to form a compound of formula (I) wherein R and R 4 are each hydrogen and R is not hydrogen or a straight chain alkyl group, the other symbols being as defined in point 1. 3. A process according to claim 1 wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein one of R1 and R2 is hydrogen and the other is a straight-chain alkyl group. the chain of n and zero and R ^ do not represent a hydrogen atom, the other symbols having the meaning given in point 1. 4. A process according to claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein R is not a straight chain alkyl group and the other symbols are as defined in point 1. 134 5. A process as claimed in any one of claims 1 to 4, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein the carboxy-protected protecting group is an ester radical or a C1 -C6 trialkylsilyl. in the alkyl moiety and the individual symbols have the meanings given in 1-4. 6. A process according to any one of claims 1 to 4, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein the hydroxy-protected group is an ether, silyl ether, acetal, ester or an esterified carboxyl group and the individual symbols are as defined in 1 to 4 above. 7. A process according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to give a compound of the formula I wherein R is optionally substituted alkenyl, optionally substituted aryl or a group of formula - V ^<CH 2> n Where n is an integer from 0 to 2 3 ' 3, R and R, which are the same or different, in each case a hydrogen atom or an alkyl group or R ² and R ³ together represent an oxo group and R 1 represents a hydrogen atom, an alkyl group, an optionally substituted aryl group, halogen atom, cyano group, hydroxyl group , alkoxy, optionally substituted aralkyloxy, acyloxy, carbamoyloxy, alkylsulfonyloxy, sulfooxy, amino, azido, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyloxy, optionally substituted alkylthio, alkylthio, optionally substituted alkylthio, alkylthio, alkylthio , optionally substituted aryl, optionally substituted aralkyl, acyl, optionally substituted aralkyl, acyl, optionally substituted heterocyclic and, alkyl and alkoxy are specified in more detail in item 1. 2 '3 * 4' 8. A process as claimed in claim 7, wherein R, R and R are subject to the proviso that in the case of a '3' 4 'case, where R and R are each hydrogen, R is not a hydrogen atom or an alkyl 2' 3 'group. with a straight chain or when one of R and R is hydrogen, A 4 * second straight chain alkyl group with n zero, does not represent a hydrogen atom. 9. The process of claim 7, wherein the alkenyl group having 2 to 6 carbon atoms is an optionally substituted alkenyl group optionally substituted with a phenyl group. 10. The process of claim 7 wherein the optionally substituted aryl group is a phenyl group optionally substituted with a halogen atom. 11. The method of claim 7, wherein the optionally substituted aralkyloxy group is a benzyloxy group optionally substituted by a nitro group. 12. A process according to claim 7, wherein the acyl moiety of the aoyloxy group is an alkylcarbonyl group, a haloalkylcarbonyl group, an arylcarbonyl group, or a group of the formula: - CO - X - Q ¹ wherein X represents a group -CH ₃ -f -CH ₂ S- ^{not 4} ° 135 -Οι ο wherein the five membered heterocyclic ring is 1 to 4 heteroatoms selected from the group consisting of nitrogen or sulfur, wherein the heterocyclic ring is optionally substituted with an amino group or an alkyl group and Q is an alkoxy group wherein the alkyl group and the alkoxy group have 1 to 6 carbon atoms and the aryl group is further specified in point 1. 13. The method of claim 7, wherein the optionally substituted heterocyclic thio group is a tetrazolyl group which may be substituted with an alkyl group of 1 to 6 carbon atoms. 14. The process of claim 7 wherein the quaternary ammonium group is a pyridinium group. 15. The method of claim 7, wherein the substituent or protecting group substituted or protected amino group is one or two of C1 -C4 alkylcarbonyl, arylcarbonyl, C1 -C4 alkyl. , (C1 -C4) alkylsulfonylalkyloxycarbonyl, (C1 -C4) haloalkylcarbonyl, esterified carboxyl, sulfo, (C1 -C4) alkoxy and (C1 -C4) carboxyalkyl; alkyl moiety, wherein the aryl group or moiety is as defined in point 1. 16. The process of claim 7 wherein the protecting group of the protected carboxyl group is an alkyl group having 1 to 6 carbon atoms. 2 '3 17. A process according to claim 7, wherein R and R are each hydrogen or 2 '3' R and R are C 1 -C 4 alkoxy, C 1 -C 4 alkylcarbonyloxy, five- or six-membered nitrogen-containing heterocyclic group having one to four heteroatoms selected from oxygen and / or sulfur in addition to> nitrogen and optionally substituted with C 1 -C 4 alkyl or amino optionally protected with an aliphatic acyl group. 18. The method of claim 1 wherein R represents a group of the formula wherein Q ³ and Q ⁴ are the same or different and represent hydrogen, optionally substituted alkyl, alkoxy, amino, optionally substituted aralkyl, optionally substituted aryl an optionally substituted heterocyclic group, a sulfo group, an alkylsulfonyl group, an optionally substituted aralkyl group, an optionally substituted arylsulfonyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group an optionally substituted, optionally substituted aryloxycarbonyl group, a group of the formula CO R - NH - CH - CO R ⁹ - R ¹⁰ WHAT 136 or R ¹⁸ - R ¹⁹ - CH ₂ - CO 5 to 18 wherein Ra to Rc are as defined in claim 1 and the optional substituents are alkyl and alkoxy group, which are specified in point 1. 19. The process of claim 18 wherein Q and Q are the same or different, hydrogen, C1-C6 alkyl, C1-C6 alkoxy, amino, C1-C6 carboxyalkyl (C 1 -C 6) alkyl, (C 1 -C 6) carbamoylalkyl, (C 1 -C 6) alkylcarbonyl optionally substituted by halogen, sulfo, phenyl, benzoyl, p-nitrobenzyloxycarbonyl or a beta-alkylsulfonylalkoxycarbonyl group having 1 to 6 carbon atoms in the alkyl moiety and having 1 to 6 carbon atoms in the alkoxyl moiety. 20. The method of claim 18, wherein aq is the same or different is hydrogen, (C1-C6) alkyl, (C1-C6) alkoxy, phenyl, sulfo, or (C1-C6) carboxyalkyl. 6 carbon atoms in the alkyl moiety. 21. The process of claim 1 wherein R is a group of formula -COQ ⁵ wherein Q represents a hydroxyl group which is optionally protected, an alkoxy group having 1 to 6 carbon atoms, an aryloxy group optionally substituted, an aralkyloxy group optionally substituted or an alkoxycarbonylalkyloxy group having 1 to 6 carbon atoms in the alkoxy group and having 1 to 6 carbon atoms in the alkyl moiety the aryl and aralkyl groups are always defined in point 1. 22. A process according to claim 21, which is C1 -C6 alkoxy, p-nitrobenzyloxycarbonyl or C1 -C6 alkoxycarbonylalkyloxy. C 6 -C 6 alkoxy and C 1 -C 6 alkyl. 23. The process of claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein R is a group of formula - (CH ₂ ) _m - X ¹ - Q ⁶ where m is an integer from 1 to 4, X ¹ is -NH-, sulfur, oxygen or direct bond and Οθ hydrogen, carbamoyl, optionally substituted acyl, alkyl (C 1 -C 6) group, optionally substituted heterocyclic group, or optionally protected carboxyl group, the acyl group and the heterocyclic group and their substituents being further defined in (1) in connection with the definition of R. 24. The method of claim 23 wherein m is an integer from 2 to 4. 25. The process of claim 23 wherein the alkylcarbonyl group having 1 to 6 carbon atoms in the alkyl moiety optionally substituted by a halogen atom is an alkylcarbonyl group. 137 is a C 1-6 alkyl group, a benzoyl group, a five or six membered nitrogen-containing heterocyclic group, an optionally substituted C 1-6 alkyl group, or a five or six membered nitrogen-containing heterocyclothioacetyl group, the heterocyclic ring of which is optionally substituted with C 1-6 alkyl; carbon atoms, the nitrogen containing heterocyclic group being further defined in point 17. 26. The method of claim 1, wherein the starting materials used are compounds of formula II and III to form a compound of formula I, wherein the acyl group an acylated amino group has the formula wherein R ⁶ is amino protecting group or a group of formula " R ⁸ - _{<CH2) n} - CO g wherein R is an optionally substituted heterocyclic group and n, an integer of 0 to 2 7 ^"χ and R is an optionally substituted phenyl or optionally substituted heterocyclic group, where the optionally substituted groups are further defined in point 1 . 27. A process according to claim 1, wherein the compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I), wherein the acylated moiety of the acylated amino group is R ¹¹ -C-CO 11 N wherein R is an optionally substituted heterocyclic group or an optionally substituted phenyl group, R is a hydrogen atom, a C 1 -C 6 alkyl group or a group of the formula wherein R ¹ is a C 1 -C 6 alkylene group or an alkenylene group of 1 to 6 carbon atoms and R is a carboxyl or esterified carboxyl group, wherein the wavy line in the formula indicates that the group has a syn or anti-configuration and the optionally substituted groups are as defined in 1 above. 28. A process according to claim 1, wherein the compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein the acyl moiety of the acylated amino group is R ¹⁸ - R ¹⁹ - CH ₂ - CO of 1 '29 wherein R represents an optionally substituted heterocyclic group, and R a direct bond or a sulfur atom, where the optionally substituted groups are further defined in point 1. 29. A process according to claim 1, wherein the compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I), wherein the acyl moiety of the acylated amino group is 138 Wherein Q represents an amino or protected amino group and Q represents an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 1 to 6 carbon atoms, a group of the formula A -CII ^ COOQ group of formula o and a COOQ carboxyl or esterified carboxyl group. 30. A process according to any one of claims 1 to 29, wherein the starting materials are compounds of formula II and III to form a compound of formula I, wherein the pl group has a beta configuration and the X group has an alpha configuration with respect to azetidine ring. 31. A method according to claim 30, wherein the starting materials are compounds of formula II and III to form a compound of formula I, wherein the R group has a trans configuration with respect to the R group. 32. A process according to claim 30, wherein the compounds of formula (II) and (III) are used as starting materials to form a compound of formula (I) wherein the R group has a cis configuration with respect to the R group. 33. The process of claim 1 wherein the starting materials are those compounds of formula (I) wherein X is hydrogen and the other symbols are as defined in point 1. 34. A process according to claim 30, wherein the compounds of formula (II) and (III) are used as starting materials to form compounds of formula (I) wherein R1 is a group of formula C — CONH— Wherein q 'is an amino or protected amino group and a C 1 -C 6 alkyl group, a C 2 -C 6 alkenyl group, a group of the formula -ch ₂ cooq or a group of formula 139 or a group of formula CH _O and JCI CH ~ COOQ ⁹ q and COOQ represents a carboxyl group or an esterified carboxyl group, and R represents a group of the formula wherein Q ^3a , which have the same or different meanings, are hydrogen or C 1 -C 6 alkyl. 3 * 4 ' 35. The method according to claim 34, wherein Q and Q are each hydrogen and Q ^R is amino. 36. The method of claim 34, wherein the R group has a trans configuration with respect to the R ¹ group. 37. The method of claim 34, wherein the R group has a cis configuration with respect to the R ¹ group. 38. A process according to any one of claims 34 to 37, wherein the compound of formula I is prepared in racemic form. 39. The method of Claim 35, wherein the starting materials used are compounds of formula II and III to form a compound of formula I in the form of inner salts of formula ⁸ where Q is as defined in point 34. 40. The process of claim 1, wherein the compounds of formula II and III are used as starting materials to provide trans-3-L2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino). (acetamino) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomerd), cis-3-j] 2- (2-amino-4-thiazolyl) -2-allyloxyiminoacetamido] -4-methoxycarbonyl-1- oxoazetidine-1-sulfonic acid (syn-isomer), cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonyl-1-oxoazetidine-1-sulfonic acid (syn-isomer cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn-isoemer), cis-3-Q2- (2) amino-4-thiazolyl) -2- (1-methyl-1-carboxyethylimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn-isomer), cis-3- [2- (2- amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer), trans-3 - [] 2- (2- amino-4-thiazolyl) -2- (1-methyl); -1-carboxyethyloxyimino) acetamido] -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn-isomer), cis-3 - [] 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4 -carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer), cis-3-Q2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-acetamido -methyl-2-oxoazetidine-1-sulfonic acid (syn-isomer) or cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- carbamoyl oxymethyl-2-oxoazetidine-1-sulfonic acid (syn-isomer). 140 41. The method according to claim 7, characterized in that as the starting compounds those of formula II and III to form a compound of formula I wherein R ⁴ represents a carbamoyloxy radical. 42. A process according to claim 7 or 41, wherein the corresponding compounds of the formulas II and III are used as starting materials to form a compound of the formula I, Wherein R and R have the same or different meanings and represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms. 43. The process of claim 7, wherein the corresponding ₂ ' 3 ' compounds of the formulas II and III are used as starting materials to form a compound of the formula I wherein R @ 1 and R @ 2 are each hydrogen; carbamoyloxy. 44. A process according to claim 7 or claim 43, wherein the corresponding compounds of the formulas II and III are used as starting materials to give a compound of the formula I wherein n is zero.