CS253572B2 - Method of 1-sulpho-2-oxoazetidine preparation - Google Patents

Abstract

1-Sulfo-2-oxoazetidine is prepared general formula X R by reacting a compound of the formula X with a compound of formula R ° COOH. The compound prepared has excellent antimicrobial properties potency and ability to inhibit beta-lactamases.

Description

The present invention relates to novel 1-sulfo-2-oxoazetidine derivatives having excellent properties. antimicrobial activity and ability to inhibit beta-lactamase and methods 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, lib-346 (1976), Synthesis 1973, 327-346. However, it is not known that one of these 2-oxoazetidines described had a sulfo group at the 1-position and a substituent at the 4-position.

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

(I) wherein is a group of the general formula

R ² C 3 ^<CH2> n

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

3

R and R, which are the same or different, are hydrogen, alkyl, cycloalkyl optionally substituted, optionally substituted aryl or aralkyl, optionally substituted heterocyclic, alkoxycarbonyl or acyl, or together are oxo, R4 is hydrogen, alkyl optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic, halogen, cyano, hydroxyl, alkoxy, optionally substituted aryloxy, aralkyloxy with optionally substituted alkyl, acyloxy, carbamoyloxyalkyl, hydroxy, sulfonyloxy, hydroxy, moieties, sulfooxy, nitro, amino, azido, carboxyl, alkoxycarbonyl, alkoxycarbonylalkyloxy alkyl, thiocarbonyl, acyl, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, optionally substituted heterocyclic thio, or optionally substituted alkyl; alkenyl, alkynyl, cycloalkenyl, aryl or heterocyclic, optionally substituted with one or more substituents, wherein the substituents of optionally substituted alkenyl and alkynyl groups are selected from optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl , optionally substituted heterocyclic, alkoxycarbonyl acyl, oxo, halogen, cyano, hydroxyl, alkoxy, aryloxy, optionally substituted aryl, acyloxy, carbamoyloxy, hydroxysulfonyloxy, alkylsulfonyloxy, arylcarbonyloxy, arylsulfonyloxy, mercapto, alkylthio, aminoalkylthio, acylaminoalkylthio, aralkylthio with optionally substituted alkyl, arylthio with optionally substituted aryl, heterocyclic thio with optionally substituted heterocyclic, and optionally substituted quaternary ammonium, wherein the above-mentioned optionally substituted or containing the same various and optional substituents of the substituted cycloalkyl group, cycloalkenyl, aryl, aralkyl, heterocyclic, and quaternary ammonium groups are selected from the group consisting of alkyl, alkoxy, alkenyl, aryl, aralkyl, mercapto, alkylthio, arylthio, aralkylthio, aralkylsulfonyl, aralkylsulfonyl, arylsulfonyl, and arylsulfonyl; , trihaloalkyl, hydroxy, oxo, thioxo, halogen, nitro, amino, cyano, carbamoyl, carboxyl, acyl, acyloxy, acylamino, hydroxyalkyl, carboxyalkyl, dialkyl and monoalkyl and the above alkyl, haloalkyl and the above amino, carboxyl and hydroxyl groups may be protected, each of the above alkyl and alkoxy groups having 1 to 6 carbon atoms, alkenyl and alkynyl 2 to 6 carbon atoms, cycloalkyl and cycloalkenyl of 3 to 8 carbon atoms, the amino group may be substituted by acyl, alkyl, hydroxyalkyl, aralkyl with optionally substituted alkyl, optionally substituted aryl, optionally substituted heterocyclic, sulfo, alkylsulfonyl, aralkylsulfonyl with optionally substituted alkyl, arylsulfonyl with optionally substituted aryl, alkoxycarbonyl, aralkyloxycarbonyl with optionally substituted alkyl, alkoxycarbonyl with optionally substituted aryl and aminocarbonyl, wherein the optional aralkyl groups are as defined above, is always benzyl, phenethyl, phenylpropyl or naphthylmethyl, aryl means a phenyl, alpha-naphthyl, beta-naphthyl, biphenyl or anthryl group, a heterocyclic group means a 5- to 8-membered heterocyclic radical having one to four heteroatoms selected from the group consisting of nitrogen, including N-oxide, oxygen and sulfur, formyl, C 1 -C 6 alkylcarbonyl, benzoyl optionally substituted by hydroxyl or C 1 -C 6 alkyl, C 7 -C 9 aralkylcarbonyl optionally substituted by hydroxyl or C 1 -C 6 alkyl, or a five membered heterocyclic carbonyl or acetyl group containing at least one oxygen, nitrogen and sulfur atom, optionally substituted by an amino group,

R 6 is an amino or acylated amino group, the acyl moiety having the general formula

WHAT MEANS

R 1 is an alkyl or optionally substituted heterocyclic group or a general formula

R - NH - CH - CO '7 wherein is hydrogen, glycyl, alanyl, valyl, leucyl, isoleucyl, seryl, threonyl, cysteinyl, cystyl, methionyl, alpha-spartyl or beta-aspartyl, alpha-glutamyl or gamma- glutamyl, lysyl, arginyl, phenylalanyl, phenylglycyl, tyrosyl, histidyl, tryptophananyl or prolyl or amino protecting group or formula

R ⁸ - ^<CH2) _n - CO g wherein R is an optionally substituted heterocyclic group, an-integer from 0 to 2, alkyl, optionally substituted phenyl, a heterocyclic carbonylamino group optionally substituted with a heterocyclic whom share or an optionally substituted heterocyclic group.

or the acyl moiety has the general formula

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

R ¹¹ - C

Sr ¹² wherein 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 formula

-R ¹³ -R ¹⁴ where is

R is an alkylene or alkenylene group; and

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

R ^{10 is a} direct bond or a group of formula

- CO - NH

CH 115 R ° where denotes

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

wherein 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

19 in the case of the meanings of the symbols R to R, a heterocyclic group always means 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-2,3,3-pyrimidyl , benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl or thienof2 3-6-pyridyl optionally substituted by heterocyclic, phenyl, thiazolyl, phenoxycarbonyl and phenoxy are each 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, acylalkyl, aminoalkyl, aminoalkyl the radical is as defined above, the alkyl and alkoxy radicals each have from 1 to 6 carbon atoms, the alkenyl radical always has from 2 to 6 carbon atoms and the aralkyl and aryl radicals are as defined above,

In the case of a substituted alkyl group, the substituents are selected from the group consisting of halogen, hydroxy, cyano and trifluoromethyl; in the case of a substituted ureido group, the substituents are selected from the group consisting of a cation, sulfamoyl, sulfamoyl, amidino or 1-alkyl group. optionally substituted sulfamoyl has 1-6 alkyl or amino as substituents, amino, carboxyl and / or hydroxyl can be protected, amino can be substituted as described above for R , or is phthaloyl-protected amino, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfoyl, benzenesulfonyl, toluenesulfonyl, formyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethansuflonylovou, trifluoroacetyl, maleyl, succinyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, 2-kyanethoxykarbonylovou, beta, beta, beta-trichloroethoxycarbonyl, beta-trimethylsilylethoxycarbonyl, beta-methylsulfonylethoxykarbonylovou, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p - methoxybenzyloxycarbonyl, diphenylmethyloxycarbonyl, methoxymethyloxycarbonyl, acetylmethyloxycarbonyl, isobornyloxycarbonyl, phenyloxycarbonyl, trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidyl, cycloalkyl, cycloacenyl, aralkyl and aryl are each as defined for R,

X is a hydrogen or methoxy group, or a salt or ester thereof, by reacting a compound of formula III (III)

H ₂ N

0 ^; _SO3 H wherein the symbols have the above meanings, or a salt or ester thereof, with a compound of formula II

R ° COOH (II) wherein R ° CO is an acyl group as defined above as an acylated moiety of the group R 1, or a reactive derivative thereof on a carboxyl group and optionally a protecting group is cleaved.

The compound of formula (I) has excellent antimicrobial properties and potency in inhibiting beta-lactamase.

In the above formulas I and XII, R represents an organic group attached to the 2-oxoazetidine nucleus at the 4-position by a carbon atom of the above-mentioned 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 be optionally substituted is designated by a cross + in the superscript hereinafter. 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.

An alkyl group is preferably a straight or branched chain lower alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and similar groups. Cycloalkyl is preferably C3-C8-cycloalkyl, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, etc.

Alkenyl is preferably a straight or branched chain C 2 -C 6 alkenyl group such as vinyl, allyl, isopropenyl, 2-methallyl, 2-butenyl, 3-butenyl and the like. An alkynyl group is preferably a straight or branched chain C 2 -C 6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl or the like.

Cycloalkenyl groups include, for example, C 3 -C 8 cycloalkenyl groups such as 1-cyclopropenyl, 1-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl,

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

A preferred cycloalkenyl group is a C 4 -C 6 cycloalkenyl group. Aryl groups include, for example, phenyl, alpha-naphthyl, beta-naphthyl, biphenyl, anthryl, and the like. Of these, phenyl and naphthyl are usually preferred. Heterocyclic groups include, for example, 5- to 8-membered heterooyl rings with one to several heteroatoms, such as nitrogen (including N-oxide), oxygen and sulfur.

Also included are the corresponding fused rings having an available binding site on the carbon atom. Examples of such a heterocyclic group, which 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-naphthyridyl, quinol, thienof2,3-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 the like.

Of these, alkyl, alkenyl and alkynyl may be substituted with one to three substituents such as cycloalkyl ⁺ , cycloalkenyl, aryl ⁺ , heterooyl ⁺ , alkoxycarbonyl and acyl, oxo, halogen, cyano, hydroxy and alkoxy, aryl ⁺ -oxyskupina, acyloxy, carbamoyloxy, hydroxysuflonyloxyskupina, an alkylsulfonyloxy group and an ^{aryl-sulfonyloxy,} nitro, amino, carboxy, aminocarbonyl, and alkylthiocarbonyl, mercapto, alkylthio, aminoalkylthioskupina, acylaminoalkylthioskupina, aralkyl thio group, aryl thio group ^{+, heterocyclo-thio} group, quaternary ammonium or the like. Substituted alkyl groups include, for example, the group of formula A ^x '2'

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

3 +

R @ 1 and R @ 2 may each independently be hydrogen, alkyl, cycloalkyl, aralkyl ⁺ , aryl ⁺ , heterooyl ⁺ , alkoxycarbonyl or aoyl or

3

R and R taken together are oxo and

R 6 represents hydrogen, alkyl, cycloalkyl ⁺ , aryl ⁺ , heterocyclic ⁺ , halogen, cyano, hydroxyl, alkoxy, aryl-oxy, aralkyl-oxy, aoyloxy, carbamoyloxy, hydroxy-sulfonyloxy, alkylsulfonyloxy, sulfonyl, sulfonyloxy, nitro, amino and azide, carboxy, alkoxycarbonyl, alkoxycarbonylalkyloxy, aminocarbonyl, alkylthiocarbonyl and aoyl, mercapto, alkylthio, + + aminoalkylthio, acylaminoalkylthio, heteroalkyl-thio, aralkyl-thio, aralkyl-thio, aralkyl-thio, aralkyl-thio, aralkyl-thio,

In a substituent on an alkyl, alkenynyl and alkynyl group and a group of formula R, R ³ or R 6, the alkoxy group preferably represents a straight or branched lower alkoxy group having 1 to 6 carbon atoms such as, for example, 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. Halogens include fluorine, chlorine, bromine and iodine. Mezi kvartem! ammonium groups include, for example, a group of the 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 (eg nicotinamide, isonicotinamide, etc.), carboxyl substituted pyridine (eg, nicotinic acid, isonicotinic acid, etc.), sulfo-substituted pyridine (eg, pyridine-sulfonic acid, etc.), cholinium, etc.

These quaternary ammonium groups may form internal salts with a sulfo group at the 1/2-oxoazetidine core position. Acyl groups include, for example, formyl, alkylcarbonyl, aryl ⁺ -carbonyl, aralkyl ⁺ -carbonyl, heterocyclo ⁺ -acetyl, etc., as well as the acyl groups listed above for R ³ . Among these groups, for example, a C 1 -C 6 alkylcarbonyl group (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, etc.), a benzoyl group which may be substituted (e.g., benzoyl, 4-hydroxybenzoyl, -methoxybenzoyl, etc.), C7 -C9 aralkylcarbonyl which may be substituted (e.g., phenylacetyl, 4-hydroxyphenylacetyl,

4-methoxyphenylacetyl, etc.), a five-membered heterocyclo-carbonyl or -acetyl group with at least one oxygen, nitrogen and / or sulfur atom which may be substituted (eg, 2-thienylcarbonyl, 2-furylcarbonyl, 2-, 4- or 5 -thiazolylacetyl, 2- and 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 alkylthipas 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 as defined above for the acyloxy group.

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

If the organic group R, which is attached to the azetidine ring by a carbon atom, contains an amino group, the above-mentioned amino group may be substituted or protected; if it contains a carboxyl and hydroxyl group, such a group may also be protected. Optional amino group substituents include the acyl group listed 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 together with such a substituent may form a cyclic amino group such as pyrrolidine, piperidine, morpholine, piperazine or the like. Amine protecting groups include, for example, those listed below as amino protecting groups. The carboxyl protecting group may be any carboxyl protecting group conventionally used in the beta-lactams and other organic chemistry such as the ester moiety (e.g., methyl, ethyl, propyl, isopropyl, tert-butyl, tert-butyl, benzyl, p-nitrobenzyl, p-methoxybenzyl, benzhydryl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaloyloxymethyl, beta-methylsulfonylethyl, beta-trimethylsilylethyl, methylthiomethyl, beta, trityl, beta, trityl, beta, trityl, beta, trityl, beta, beta-iodoethyl, trimethylsillyl, 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, pyr idine-1-oxido-2-methyl, methylsulfinylmethyl, bis (p-methoxyphenyl) methyl, 2-cyano-1,1-dimethylethyl, etc.), silyl and the like.

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

The choice of the aforementioned hydroxyl protecting group is not critical in the present invention, as is the choice of the above amino and carboxyl protecting groups.

Preferred examples of organic R groups are those of formula A, provided that if 2 of 4 both R and R are both hydrogen, then R is not a hydrogen atom or an alkyl group of 3 (especially a straight chain alkyl group) or 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 a number zero, then R 6 does not represent a hydrogen atom.

Of the groups of formula (A), a group of formula (B) is usually used

R ² 'c ~

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

2 * 3 '2'

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

R together taken together represent oxo and +

R is hydrogen, alkyl, aryl, halogen, cyano, hydroxyl and alkoxy, aralkyl-oxy, acyloxy, carbamoyloxy, alkylsulfonyloxy, sulfoxy, amino, azide, carboxyl and alkoxycarbonyl, heterocyclo ⁺ -thio or quaternary ammonium ⁺ .

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

Of the groups of formulas A and B, they are more preferred

3 2 '3 ”

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

CON (C) wherein Q ³ and Q ⁴ can each independently be hydrogen, alkyl ⁺ , alkoxy, aralkyl ⁺ , aryl ⁺ and heterocyclic ⁺ , sulfo, aralkyl ⁺ -sulfonyl, alkylsulfonyl, amino, aryl ⁺ -sulfonyl , alkoxycarbonyl, aralkyl-oxycarbonyl and aryl ⁺ -oxycarbonyl, acyl or protecting group R @ ^{1 below} , preferably - a group of the formula

CON ^X Q ⁴ 'wherein Q ³ and Q ^{4 may} independently of one another represent hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, carboxyalkyl, wherein the alkyl group is (C 1 -C 6) -alkyl, (C 1 -C 6) -alkyl, a carbonyl group which may be substituted by a halogen atom, a sulfo group, a phenyl group, a benzoyl group, a carbamoyl-C 1-6 alkyl group (C 1-6), p-nitrobenzyloxycarbonyl or beta-alkyl (1 to 6 carbon atoms) sulfonyl-alkoxy of 1 to 6 carbon atoms and in particular carbamoyl, mono- or di-alkyl (1 to 6 carbon atoms) carbamoyl, phenylcarbamoyl a group, a sulfocarbamoyl group, an alkoxy (C 1 -C 6) carbamoyl group, a carboxyalkyl (C 1 -C 6) carbamoyl group, etc.,

3 9 * 3 '

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

- COQ ⁵ (D) wherein 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 formula

-COQ ⁵ wherein Q ⁵ is a C 1 -C 6 alkoxy, p-nitrobenzyloxy or C 1 -C 6 alkoxy carbonyl (C 1 -C 6) oxy group,

3 2 * 3

3. those groups of formula A and B in which R, R, R and R are hydrogen, for example a group of formula E

- (CH ₂ ) _m - X ¹ - Q ⁶ (E), wherein m represents the number 1 to 4, i

X represents an -NH- group, 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 formula

- < ^CH 2> m - ^χ 1 'in which m and X are as defined above and

Q ⁶ represents an alkyl (C 1 -C 6) 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 that contains a nitrogen atom (eg, pyrrolyl, thiazolyl, thiadiazolyl, diazolyl, oxazolyl, oxadiazolyl, triazolyl and tetrazolyl, etc.), which may be substituted by a C1-C6 alkyl group or a 5- or 6-membered alkyl a nitrogen-containing heterocyclo-thioacetyl group, the heterocyclic ring of which may be substituted by an alkyl group having 1 to 6 carbon atoms.

Specific examples of the group of formula C include carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, Ν, Ν-dimethylcarbamoyl, Ν, Ν-dimethylcarbamoyl, N-sulfocarbamoyl, N-methocarbamoyl, -ethoxycarbamoyl, N-propoxycarbamoyl, N-isopropoxycarbamoyl, N-hydroxycarbamoyl, N-aminocarbamoyl, N - (L) -benzyloxycarbonylethyljaminocarbonyl, N - (L) -carboxyethyljaminocarbonyl, N-phenylcarbamoyl, N-phenylcarbamoyl, N-phenylcarbamoyl, chlorophenyl) carbamoyl, N-benzylcarbamoyl, Ν, Ν-dibenzylcarbamoyl, N-hydroxymethylcarbamoyl, N-hydroxyethylcarbamoyl, N-chloromethylcarbamoyl, N-acetylcarbamoyl, N-propionylcarbamoyl, N-carboxycarbamoyl, N-carboxycarbamoyl, N-carboxycarbamoyl, phenoxy-253572 carbonylcarbamoyl and the like. Specific examples of groups of formula D are carboxyl, methoxycarbonyl, ethoxycarbonyl, prbpoxykarbonylová, isopropoxycarbonyl, butyloxycarbonyl, isobutyloxycarbonyl, sek.butyloxykarbonylová, pentoxycarbonyl, benzyloxycarbonyl, fenethyloxykarbonylová, methoxykarbonylmethyloxykarbonylová, ethoxykarbonylmethyloxykarbonylová, phenyloxycarbonyl, p-chlorfenyloxykarbonylová, hydroxymethyloxykarbonylová, sulfomethyloxýkarbonylová and the like.

Specific examples of groups of formula E include acylaminoalkyl (e.g. acetylaminomethyl, propionylaminomethylová, butyryl aminomethyl, isobutyrylaminomethylová, acetylaminoethyl, propionylaminoethylová, acetylaminopropylová, acetylaminobutyl, benzoylaminoethylová, benzoylaminomethylová, benzoylaminopropylová, formyláminomethylová, fenylacetylaminomethylová 4-hydroxyfenylacetylaminomethylová 2-thienylkarbonylaminomethylová 2 furylkarbonylaminomethylová , thienylacetylaminomethyl, 2-amino-4-thiazolylacetylaminomethyl, etc.), carbamoylaminoalkyl (e.g., carbamoylaminomethyl, carbamoylaminoethyl, carbamoylaminopropyl, etc.), acyloxyalkyl (e.g., acetoxymethyl, propionyloxymethyl, 2-propionyloxymethyl, isopropoxyloxymethyl, isopropoxyloxymethyl) -4-thiazolyl) - (Z) -2-methoxyiminoacetoxymethyl, 2- (2-amino-4-thiazolyl) - (Z) -2-methoxyiminoacetoxymethyl, 2-thienylation Toxymethyl, 2-furylacetoxymethyl, thiazolylacetoxymethyl, 2-amino-4-thiazolylacetoxymethyl, benzoyloxymethyl, benzoyloxyethyl, 4-hydroxybenzoyloxymethyl, 4-methoxybenzoyloxymethyl, monochloroacetoxymethyl, trichloroethoxycarbonyloxymethyl, theto-acetoacetoethoxymethyl, acetoaceto-acetoacetetoethoxy, acetoaceto-acetoacetetoethoxy, 1N, 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, etc.), heterooyl-thioalkyl group (e.g. thienylthiomethyl, thienylthioethyl, thienylthiopropyl, furylthiomethyl, furylthioethyl, thiazolylthiomethyl, thiazolylthioethyl, 2-aminothiazolylthiomethyl, 2-aminothiazolylthioethyl, 2-aminothiazolylthioethyl 2-aminothiazolylthioethyl oxazolylthiomethyl, (1-methyl-1H-triazol-5-yl) thiomethyl, (1-methyl-1H-tetrazol-5-yl) thiomethyl, (1N, 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-butyl-thiomethyl or the like, etc.) a modified carboxyalkyl group (e.g. carboxymethyl, carboxy ethyl, carboxypropyl, karboxyisopropylová, carboxybutyl, karboxyisobutylová, carboxy-sec-butyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, propoxykarbonylmethylová, isopropoxykarbonylmethylová fenoxykarbonylmethylová, fenoxykarbonýlethylová, benzyloxycarbonylmethyl, benzyloxykarbonylethylová, hýdroxybenzyloxykarbonylmethylová p, p-methoxybenzyloxykarbonylmethylová, karboxymethyloxykarbonylmethylová group etc.). and similar groups.

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

i) a group of formula F

R ⁵ -CO (F), wherein R represents a lower alkyl or heterocyclic group, il) a group of formula G

R ⁶ -NH-CH-CO (G),

^{7 7} wherein R ⁸ is a hydrogen atom, an amino acid residue, an amino protecting group or a group of the formula R ⁸ - (CH 2) -CO-, wherein R ⁸ is a heterocyclic group with n, ⁿ i ♦ + * is 0 to 2, and R is a lower alkyl, phenyl, heterocyclo-carbonylamino or heterocyclic group, iii) a group of the formula H

R ⁹ - R ³⁰ - CO 9 13

Wherein R is a group of formula R in ntel

N

In the OIR 12 ⁴ + + 12 R is alkyl, heterocyclic or phenyl group and R is hydrogen, alkyl, and below a lower alkenyl group or a group of formula -R ³³ -R ³⁴ wherein R ³³ is 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 formula -CO-NH-CH- in which R ³⁵ represents a lower R ³⁵ alkyl, phenyl * or thiazolyl * group; iv) a group of the formula I

(I) wherein R ³⁸ is hydroxyl, hydroxysulfonyloxy, carboxy, ureido *, sulfamoyl *, sulfo, phenoxy * carbonyl or formyloxy, and R ³⁷ is hydrogen, lower alkyl, lower alkoxy, halogen, nitro or hydroxyl,

(v) a group of formula J

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

Alkyl, hetericyclic, alkoxy, and halogen in the 5 &apos;

R @ 1 to R @ 2 denote the respective R groups above. The 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 groups.

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

Alkenylene is preferably a straight or branched chain C 2 -C 4 alkenylene group such as vinylene, propenylene or the like. Carboxylic acid esters include lower alkyl esters of 1 to 6 carbon atoms in the above alkyl moiety, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl and the like.

The substituents on the heterocyclic ⁺ , phenyl ⁺ , thiazolyl ⁺ , phenoxy ⁺ -carbonyl, and phenoxy * groups are those substituents on the heterocyclic ⁺ and aryl ⁺ groups as described above for R. In addition, the substituent on the thiazolyl ⁺ group may, for example, be C 2 -C 4 acylamino substituted with alkyl, alkoxy, halogen, hydroxyl, amino 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, and the like.

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

A substituent on a sulfamoyl group is, for example, a lower alkyl group having 1 to 3 carbon atoms, an amidino group and the like. A substituent on a lower alkyl group is, for example, a halogen atom, a hydroxyl group, a cyano group, a trifluoromethyl group and the like. A substituent on an alkenylene group is, for example, carboxyl, cyano and the like.

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

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

fí <

N N

R ¹² -O- ^X 0-R ¹²

A preferred group of G is a group of formula

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

A preferred group of H is a group of the 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 formula -R-R wherein R ¹³ is as defined above and R ¹⁴ is a carboxyl or esterified carboxyl group.

The preferred group from the groups of formula J is a group of formula

R ¹⁸ - R ¹⁹ - CH ³ - CO - in which? ⁸ '19 is a heterocyclic ⁺ group and is as defined above, and the like.

As the acyl residue of the acylated amine group for R, particularly from the standpoint of antibiotic activity, a group of the general formula wherein EMI2.0 is more useful

Vl

-c-co—

II

N ⁸ -Q ⁸ represents an amine group or a protected amine group α

Q ⁸ represents a lower alkyl group, a lower alkenyl group, a group of the general formula -CH, COOQ or CH, z Q 1

- C - COOQ, ch ₃

Q wherein COOQ represents a free or esterified carboxyl group.

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

P

D-alanyl, benzyl-N ^and -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-piperazinecarboxamido) -2-phenylacetyl,

2- (4-ethyl-2,3-dioxo-1-piperazinocarboxamido) -2- (4-sulfonophenyl) 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-oxoimidazolidine-1-carboxamido) -2-phenylacetyl, 2- (coumarin-3-carboxamido) -2-phenylaethyl, 2- <4-hydroxy-7-methyl-1,8-naphthyridine-3-carboxamido) -2-phenylacetyl, 2- <4- ^and hydroxy-7-trifluoromethylquinoline-3-carboxamido) -2-phenylacetyl, N- £ 2- (2-amino-4-thiazolyDacetylJ fenylglycýlovS-D-2- (6-thunder-l-ethyl-l, 4-dihydro- -4-oxotb Phenof2,3-bpyridine-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-piperazinecarboxamido) - 2-thienylacetyl, 2Tf4- (2-phenylethyl) -2,3-dioxo-1-piperazinocarboxamido7-2-thienylacetyl, 2r (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-naphthytidine-7-carboxamido) -2- phenylacetyl, 2- (2-amino-4-thiazolyl) -2-formamidoacetyl, 2- (2-amino-4-thiazolyl) -2-acetamidoacetyl and the like.

10

Examples of the above-mentioned acyl groups of the formula R-R-CO- include N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl] -D-alanyl, N- [2- (2-amino-4-thiazolyl)] 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-thiazolyl) 2-inethoxyiminoacetyl, 2- (2-amino-4-thiazolyl) + 2-ethoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-propoxyiminoacetyl, 2 2- (2-Amino-4-thiazolyl) -2-butoxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-benzyloxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2-allyitoxyiminoacetyl, 2- (2- amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyl) oxyiminoacetyl, 2- (2-amino-4-thiazolyl) -2 - [(1-methyl-1-methoxycarbonylethylloxyimino) acetyl,

2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoaoethyl, 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-carboxyethyloxyiminoaoethyl, 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 the like.

Examples of the above 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 the like.

19 Dec

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

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

/

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

As amino protecting groups, any of the amino protecting groups used for this purpose in the beta-lactams or peptide synthesis may be suitably used. Examples of such amino protecting groups include, for example, aromatic acyl groups such as phthaloyl, p-nitrobenzoyl, p-tert-butylbenzoyl, p-tert. butylbenzenesulfonyl, benzenesulfonyl, toluenesulfonyl, etc., aliphatic acyl groups such as formyl, acetyl, propionyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, methanesulfonyl, ethanesulfonyl, trifluoroacetyl, maleinylcarbonyl, ethoxycarbonyl, ethoxy, succinyl, succinyl, etc. , tert-butoxycarbonyl, isopropoxycarbonyl, 2-kyanoethoxykarbonylová, beta, beta, beta-trichloroethoxycarbonyl, beta-trimethylsilylethoxycarbonyl, beta-methylsulfonylethoxykarbonylová, benzyloxycarbonyl, p-nitroben2yloxykarbonylová, p-methoxy benzyloxycarbonyl, difenylmethyloxykarbonylová, methoxymethyloxykarbonylová, acetylmethyloxykarbonylová, isobornyloxycarbonyl, phenyloxycarbonyl etc. , non-acyl amino protecting groups such as trityl, 2-nitrophenylthio, benzylidene, 4-nitrobenzylidene, trialkylsilyl, benzyl and p-nitrobenzyl groups, proton etc.

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

In the compound of formula (I) of this invention, R and / or R1 may contain a 1-sulfo group or a carboxyl group and / or carboxyl groups in the free state. Such groups or groups may also exist as a salt with a non-toxic cation such as sodium, potassium, etc., a basic amino acid such as arginine, ornithine, lysine, histidine etc., polyhydroxyalkylamine such as N-methylglucosamine, diethanolamine, triethanolamine, trishydroxymethylaminomethanamine. or below.

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

When R and / or R 6 contains a carboxyl group, the compound of formula I can be converted to the corresponding biologically active ester derivative, which contributes to increasing blood concentration and prolonging in vivo efficacy. Ester groups which are effective in this way include, for example, alpha-alkoxy-alpha-substituted methyl groups (e.g., alkoxymethyl) or (alpha-alkoxy) ethyl, 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-alkoxycarbonyl, etc. -alpha -substituted methyl groups such as ethoxycarbonyloxymethyl, alpha-ethoxycarbonyloxyethyl etc., and the like.

The compound of formula (I) of the present invention may be present as various steric isomers (eg, 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.

For example, the spherical isomer of a compound of formula (I) of the present invention may be described by the formula

to ₃ h where R (beta-configuration) and X (a-configuration) are as defined above and the wavy line represents cis or trans configuration of R to R in position 3rd

Compounds of Formula I of this invention include Compounds No. 1 to 57 below:

R ¹ / * /

SOqH

Compound cich ₂ conh ^ _s. CONH-COOCH,

OCH,

and ₃ ^H 2 ^{N 4} 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, continued table

Compound

c ₂ h ₅ -n nconhchconh-cooch ₂

-COOCHj

-cooch ₃

-och ₃ -cooch ₃

H -COOClHg

-COOC ₄ Hg (n) o · rr 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 continue the table

h ₂ nh ₂ n

-COOCH,

-cooc ₂ h ₅ h ₂ n

H ₂ N,

CONH-COOC ₄ H ₉

OCH,

N — N

N — U. / CH ₂ CONH-Q-8

CH,, p

OCH,

-COOCH, ch ₂ conh (1_1 ^ ^ CONH 'CH')

NHCONH, /

CH ₂ H ₂

CONH-COOCH

-COOCH,

continued table Compound ^R 1 X R 28 ^H2N Vs N - 11 ^ CONH - OCH, H 29 ^ CONH- H H -COOCH2 N ^ OCHj 30 ^H2 \ ^S >CON_-> CONH- H -CONH— II N ^x och ₃ 31 n ^ s / CONH- c Λ ^x och ₃ H -CH ₃ 32 _Z o _N '- ^ and ₃ H -Ό 33 ^H2N in ^s> (i! _Íl CONH- Λ ^X _OCH3 H Λ3

• 22 continued table

Compound ^H 2 ^N c

CONH -

-CH ₂ CH ₂ - £ ^ ^H2N ^ s' OCH

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

N \

.CONH—

-COOH

OCH, ^H 2 ^N \ .S.

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

in.

OCH, continuation of the table

Compound ^{H 2 N} v ^s >

CONH -

OCH,

-CONH.,

H, N

H, N.

N — LL

CONH

OCH ₂ COOH / CONH <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

Il ^s il

N -—! L

CONHN < 3 ^H 3 C-COOH

AND

CH, continued tables

Compound

___________ll________________ ^{H! N} in ^s i, / CONH- N — LI— CH 2 O 2 OC-COOH 1 CH ₃ ir | 1 CONH- N _! _ -C (C) - C-COOH 1 CH ₃ Tl_ ^ CONH- ~ C II N and ₂ cooh

h ₂ n

CONH / CH ₃ O ^{3 X} C-COOH

I ch ₃ h ₂ ki

CONH-ch ₂ (ch ₂ ) ₃ oc ₂

-ch ₂ oh

-CH (CH _{3) 2}

-CH2OCOCH-j

V Grill ^x o _K I ³

C ~ CGGK ch ₃

-ch ₂ nhcoch ₃

-CH ₂ CONHCH ₃

-cooch ₃

25357 continued table

Compound

Ίύ_ <

CONH coo ₃ c coo ₂ h ₅

CH.

' ² \ jl _c of ^{what h} i

NHCOCH3

-CONH2

H ₉ N tL h ₂ n

C — CONH—

-conh ₂

C-CONHθ 3 O-C-COOH I

CH,

-CH ₂ CONH ₂

Among other things, a preferred compound of the compounds of formula (I) of this invention may be a compound of formula (I)

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

in which

Q ³ , Q ^{4 * *} , Q ⁷ , Q ⁸ and the wavy line are as defined above, or a salt or ester thereof. ⁷ When Q in the above formula is an amino group, then the compound may form an inner salt between the amino group and Q · sulfo position first

The compound of the formula I according to the invention and its salts or esters are valuable antibiotics effective for various Gram-positive and Gram-negative bacteria. They are used in the form of medicaments in humans or pets as safe antimicrobial agents in the treatment of infections caused by Gram-positive or Gram-negative bacteria. Further, the antimicrobial agents of the invention are used to add 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 0.1-100 ppm (i.e., 0.1-100 parts antibiotic per million parts solution) as antimicrobial agents that kill or prevent the growth of harmful bacteria, for example on medical or dental devices or in industrial aquatic environments such as aqueous paint or white water passed through a paper mill.

The compounds of formula (I) and salts or esters thereof may be used alone or in combination with one or more other active ingredients in various pharmaceutical formulations such as capsules, tablets, powders, solutions, suspensions and elixirs (medicated drinks).

These compositions may be administered orally, intravenously or intramuscularly.

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

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

The suppositories may contain a conventional suppository base such as cocoa butter or other glycerides.

Formulations for injection may be prepared in ampoules or other containers containing a unit dose, with the addition of preservatives. Such compositions may exist 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 a suspending agent, a stabilizer and / or a dispersing agent.

The active ingredient may also be in powder form, which may be formulated with a suitable solvent or sterile pyrogen-free water prior to use.

The active ingredient may also be formulated in suitable dosage forms absorbable by the mucous membranes of the nose and throat or bronchial tissues, e.g., as powders, liquid nebulizers or inhalants, lozenges, compositions which are used to wipe the throat mucosa, etc.

For ophthalmological or otological application, they can be administered as liquids or semisolids or as drops for dripping. In addition, they may be formulated together with hydrophobic or hydrophilic pharmaceutical bases in such dosage forms as ointments, lotions, lotions, lotions, 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 delivery agents. In addition, another active ingredient or other active ingredients may be included in the composition to provide a broader antimicrobial spectrum.

For administration to domestic animals, the active ingredient of the invention may be formulated with an agent that causes slow release of the active ingredient. This provides slow release agents (i.e., agents that slowly release the active ingredient).

The formula I compounds of this invention can be applied to mammals as a therapeu- tic ^r useful agents against microbial infection in the treatment of e.g. respiratory tract infections, urinary tract infections, suppurative diseases, bile duct infections, intestinal infections, gynecological infections, surgical infections, etc.

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

The oral daily dose is generally an amount of about 15 to 600 mg of active ingredient per kg body weight of the patient administered in one or more doses. A suitable daily dose for neoral administration to adult patients is about 10 to about 200 mg of active ingredient per kg body weight? this amount is preferably 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 doses. The liquid or solid composition may contain 0.5 to 99% of the active ingredient. A preferred concentration of active ingredient is about 10 to about 60%. The composition will usually contain about 15 to 1500 mg of active ingredient in each unit dose. It is generally preferred to use unit doses containing about 250 to 1000 mg of the active ingredient.

In addition to the above uses, the compounds of formula (I) of the present invention, their salts and esters can be used in combination with beta-lactam antibiotics because of their activity in inhibiting beta-lactamase. Examples of beta-lactam antibiotics include penicillin antibiotics such as benzylpenicillin, phenoxymethylpenicillin, carbenicillin, ampicillin, amoxicillin, sulbenicillin etc., cephalosporin antibiotics such as cefaloridine, cephalothine, cephalosine, cefalexin, cefetrin, cefetrin, cefetrin, cefetrin cefotiam, cefotaxime, cefapirin, ceftizoxime, cefradine, cephaloglycine, etc., and the like.

The 1-sulfo-2-oxoazetidine derivatives of formula I, which are compounds of this invention, can be produced by acylating a compound of formula XII

_θ / ~% ο ₃ Η in which R and X are as defined above.

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

As salts and esters of the compound of formula (III), those salts and esters are exemplified above for the compounds of formula (I), etc. The compound of formula (III) may also be silylated with a silylating agent.

The silylating agent may be a compound of formula

3

P ^ P ^ Si.Hal,

In 3, β, 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, wherein one or more of the substituents Ρ, P and P may be halogen, preferably a chlorine or bromine atom, and one of the substituents Ρ, P and P may be a halogen atom. hydrogen atom. As the silylating agent, hexa-alkyl (C 1 -C 4) cyclotrisilazane, C 1 -C 4 octaalkyl) cyclotetrasilazane, trialkyl (C 1 -C 4) silylacetamide and bid-tri-alkyl (C 1 -C 4) can be used silylacetamide.

A preferred silylating agent is a compound of formula

Y ¹ γ - si - y ³ , in which

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

2

Y and Y respectively represent a lower alkyl group having 1 to 4 carbon atoms, a phenyl, benzyl or lower alkoxy group having 1 to 4 carbon atoms, and

Y represents a tert-butyl or isopropyl group.

2

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

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

N- (trialkylsilyl) acetimidoyloxy, acylamino, such as formylamino, acetylamino, propionylamino, butylamino or trifluoroacetylamino, (trialkylsilyl) amino, such as (tri-tert-butyldimethylsilyl) amino, isopropyldimethylsilyl or (propyldimethylsilyl) , an amino group, an alkylamine group such as methylamine, ethylamine or propylamine group, a Ν, Ν-dialkylamine group such as Ν, Ν-dimethylamine, N-chloromethyl-N-methylamine, N, N-diethylamine, N, N a dipropylamine, N-methyl-N-ethylamine, N-methyl-N-propylamine or N-ethyl-N-propylamine group, or a heterocyclic group such as an imidazolyl group.

The alkyl group in the above-mentioned reactive group is preferably an alkyl group having 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Specific examples of the above-described silyl compounds are Ν, Ο-bis (tert-butyldimethylsilyl) trifluoroacetamide, Ν, Ο-bis (isopropyldimethylsilyl) acetamide, bis (dimethylisopropylsilyl) acetamide, isopropyldimethylsilylacetamide, bis (dimethyl-tert-butylsilyl) acetamide, N 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, or t-butyldiethylchlorosilane.

A preferred such compound is tert-butyl dimethylchlorosilane or isopropyldimethyllohlorosilane; 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, Ν, Ν-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, triarylakylamines such as tribenzylamine, an organic tertiary amine such as N-methylmorpholine, N-methylpiperidine, Ν, Ν-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] iundecene-7. If the base is a liquid, it can also be used as a solvent.

The thus prepared silyl derivative of the compound of formula (III) may be used as the starting material in the acylation, either as a reaction mixture or after isolation or purification in a conventional manner as follows.

The acylating agent used in this reaction may be either an organic carboxylic acid that contains an acyl group in R ¹ -R ° COOH, where R ° CO is the acyl group mentioned above as the acyl group of the acylated amine group in 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 such reactive derivatives are given below:

1. Acid anhydrides:

Acid anhydrides include, for example, mixed acid anhydrides with hydrohalic acid (e.g., hydrochloric acid, hydrobromic acid, etc.), monoalkylcarboxylic acid, aliphatic carboxylic acid (e.g., acetic acid, pivalic acid, valeric acid, isovaleric acid, trichloroacetic acid, etc.), aromatic carboxylic acid (e.g. benzoic acid, etc.) as well as 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, esters such as methyl, ethyl, methoxymethyl, propargyl, 4-nitrophenyl, 2,4-dinitrophenyl, trichlorophenyl, pentachlorophenyl and mesylphenyl esters, as well as esters of the above carboxylic acids with 1-hydroxy-1H-2-pyridone, N-hydroxysuccinimide and N-hydroxyphthalimide or the like esters.

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

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, Ν, dim-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.

The acylation may 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.), Ν, Ν-dialkylaniline, Ν, Ν-dialkylbenzylamine, pyridine. , picolin, lutidine,

1,5-diazabicyclo [4,3.3] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.4] -undecen-7- and the like.

The liquid bases and liquid condensation agents mentioned above may also serve as solvents. The reaction temperature is not critical. The work-up is carried out with cooling to room temperature. Within a few minutes to several tens of hours the reaction is complete. The resulting compound of formula (I) can be isolated and purified by known methods such as, for example, concentration, basification of an acidic liquid medium, or vice versa, solvent change, solvent extraction, crystallization, recrystallization, fractional distillation, chromatography and the like.

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

If two or more stereoisomeric products are formed in the acyl group, then the individual isomers may be isolated, if necessary, by conventional means such as column chromatography, recrystallization or the like.

The R group of the compound of formula (I) of the present invention can be converted to the southern group, wherein the compound of formula (I) retains the 1-sulfo group. This leads to the production of another compound of the invention. For example, when R is acetoxymethyl, methanesulfonyloxymethyl, iodomethyl, or the like, it can be converted by reaction with a nucleophilic reagent to another desired group.

As the nucleophilic reagent, for example, alkyl ⁺ -thiols, aryl * -thiols, heterocyclo * -thiols, pyridines * and the like. There is thus obtained a compound of the formula I according to the invention in which R represents a substituted thiomethyl, quaternary ammonium * -methyl or the like.

The 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 a water-miscible solvent, such as acetone, acetonitrile, N, N-dimethylformamide or the like, 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 treatment is usually carried out at temperatures ranging from 20 to 100 ° C. The resulting compound of formula (I) can be isolated and purified in a manner known per se, as in the case of compounds produced by sulfonation or acetylation.

When the compound of formula (I) thus produced carries a protecting group; then, if desired, this group can be removed. Such a protecting group may be removed by conventional methods such as using acid, base and hydrazine, reduction, iminohalogenating agent, iminoetherifying agent and, if necessary, hydrolysis.

Whether or not this method is used depends on the type of protecting group to be removed. When the protecting group is removed by acid treatment, inorganic acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, and the like, such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, benzenesulfonic acid, benzenesulfonic acid, are used as acids. p-toluenesulfonic, etc., as well as acidic ion exchangers.

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

When the protecting group is removed by treatment with an acid or a base in a solvent, the hydrophilic organic solvent, water or solvent mixture is usually used as the solvent.

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

Catalysts used in the catalytic reduction include, for example, platinum catalysts such as platinum wire, sponge platinum, plain black, platinum oxide, 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, Urushihar nickel, etc., and the like.

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

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 the like, if the acid is liquid, it can itself serve as a solvent.

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

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

The reaction temperature is not critical? the reaction is usually carried out at temperatures ranging from room temperature to temperatures obtained 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 wherein the alkyl group of the above alcohols is substituted with an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or the like.

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

If the protecting group is an organic acid residue and if the free amino, hydroxyl, mercapto, carboxyl or sulfo group is attached to the carbon adjacent to the carbonyl group of the carboxyl radical, it is preferable to carry out a pretreatment which results in a substituent on the carbon atom adjacent to the carbonyl of the carboxyl, the reactivity of the carbonyl group is increased before the deprotection reaction is carried out.

This will be illustrated, for example, in 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 may be removed by converting the amino group into a thioureido group followed by deacylation, or any known method of cleaving the peptide chain may be used.

The processing temperature is not critical. The appropriate temperature is selected according to the type of protecting group and the manner in which the protecting group is removed. The treatment is preferably carried out under mild conditions, such as, for example, under cooling, optionally under heating.

When R and / or R ³ in the above reactions is a group containing a carboxy group may then be a derivative of the carboxyl group converted into the corresponding free carboxyl compounds. Such a case is naturally included in the present invention.

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

The compound of formula I which contains a sulfo group is usually treated with a base to form salts. Thus, the compound of formula (I) may be prepared in the form of a salt. The salt thus produced can be further converted to the free compound or another salt. The compound of formula X, which is produced as the free compound, can be converted to a salt.

A compound of the formula I which exists in the form of a salt can be converted, for example by treatment with acids, into the free compound of the formula I. Depending on the type of salt and other conditions, the acid 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. The solvent is generally a hydrophilic organic solvent such as acetone, tetrahydrofuran, methanol, ethanol, dioxane or the like, water or a solvent mixture.

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 preferred that the processing is completed within a short time. The resulting compound of formula (I) in the free state can be isolated by the known method described above.

The starting compound of formula (III) used in the present invention can be prepared, for example, by the following or similar processes.

Procedure 1

OCH ₃

ArCHjOCOCI

och ₃ to ₂ with ₂ o ₈

Η H

ArCHjOCONH = ^ ^CO 2 ^CH 3 sulfonation

(VI)

H,

Pd-C

Η H

H ₂ N = CO ₂ CH ₃

0 'N ₃ ^h (Vlil)

OCH,

NaBH ₄

ArCHjOCONH 5 = CH ₂ 0H

O '^ ^CHj - (/ / ^0X1 OCH)

and ₃ ch ₃ coci

^K 2 ^N 2 ° 8

ArCH ₂ OCONH 8 8 CH ₂ OCOCH ₃

(XI) sulfonation.

ArCH ₂ OCONH 8 ^ CH ₂ OCOCH ₃

O ^ SO.H

H,

H, N8; ch, eyes.

Pd-C

(XIII)

Procedure 3

O

OCH ₃

NaBH. ^K 2 ^N 2 ° 8 °

->

R ¹ 'BB CHOSOSO ₂ CH ₃ (XVIII)

Procedure 4

N, b H _Ar \ ž IZ ^h 2

Pd-C = &gt;

introducing a protecting group

X (XXIII)

Ar (XXI) (XXII) deprotection

Μ W ^H H.

² VJ /

X.

Procedure 5

H ₂

Pd-C and ₃

the introduction of a protecting group

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

och ₃

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

D * '(XXVII)

R '= CH ₂ CHO

X (XXVIII)

Jones oxidation -

(XXIX) CH ₂ CO ₂ H sulfonation deprotection

Procedure 6

Η H

ArOCH, CONH = Ar (XXXII)

H ₂ , Pd-C sulfonation

Procedure 7

co ₂ ch ₃ (XXXIII) sulfonation ____ deprotection (Vlil)

Procedure 8

1 'H , ch ₂ nhcoch ₄ H, N ² .CH.NHCOCH ιχ sulfonation removal _ / ² r ^H (XXIX) protecting groups C < ^ so ₃ h

Procedure 9

the introduction of a protecting group

^K 2 ^N 2 ° 8

sulfonation deprotection

Procedure 10

CH ₃ sulfonation deprotection

H ₂ N

CO ₃ CH ₃ with ₃ h

A ¹ '5 (XLVI)

O

₃ (XVI)

NH ₂ NH ₂ H ₂ °

och ₃

Procedure 12

H ₂ , Pd-C sulfonation

Procedure 13

(LVII) introduction of a protecting group

CO ₂ Et (LVIII)

Procedure 14 sulfonation deprotection ** protecting group ^h 2N: CO 3 Et

KH = CO ₂ CH ₃

SE

JX k ₂ co ₃

_ArCH2 OCONH ti ti Co.Hi _{(CH3) 2} NH

X.S

O

1) CHqNHNH, Η Η u Μ

-> ArCH ₂ OCONH; Sulfonation ^h 2 ⁿ . CH ₂ CH ₂ Ar

2) ArCH3OCOC1S-removal -3 <

* I I protecting groups 1 |

3) K ₂ S ₂ O ₈ -Nh (LXVII)

O, SOiH (LXVIH) ³

Procedure 16

ArCH ₂ OCONH 9 = CO ₂ CH ₃

NH ₄ OH

_ArCH2 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 —s ₂ n ₃ (LXXI) trans isomer (LXXII)

1) Jones oxidation

2) CH ₂ N ₂ ch _{2 and} co ₂ ch ₃

Ň _H

trans isomer (LXXIII)

H ₂ / Pd-C 2 CH ₂ CO ₂ CH ₃ sulfonation

trans isomer (lxxiv)

In the above formulas

Ac

Et

Me isoPr

R ·

1 '

DBU

DCC stands for acetyl, stands for ethyl, stands for methyl, stands for isopropyl, stands for aryl, stands for protected amino, stands for 1,3-diaza-bicyclo [5,4,0] -7-undecene and stands for dicyclohexylcarbodiimide.

The starting materials used in the above procedures 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) disclosed in Japanese Patent Laid-open Publication 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-l- 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 mentioned herein as limiting the starting materials. Any compound that satisfies the purpose of the invention may be used as the starting compound. Examples of such starting materials will be given in the following Reference Examples.

Sulfonation according to the above process is a treatment in which a sulfo group is introduced into position 1 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 sulfur trioxide derivatives are, for example, adducts thereof, such as sulfur trioxide-base adduct (e.g. sulfur trioxide-pyridine, sulfur trioxide-trimethylamine, sulfur trioxide-picoline, sulfur trioxide-rlutidine, etc.), sulfur trioxide-N, N-dimethylformamide , sulfur trioxide-dioxane, sulfur trioxide-chlorosulfonic acid and the like.

In this reaction, about 1 to 10 moles, preferably about 1 to 5 moles of sulfur trioxide or a reactive derivative thereof is used for each 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 may be carried out in the presence of a solvent.

In this case, conventional organic solvents including water, ethers such as dioxane, tetrahdrofuran, diethyl ether etc., esters such as ethyl acetate, ethyl formate etc., halogenated hydrocarbons such as chloroform, dichloromethane etc., hydrocarbons such as is, for example, benzene, toluene, hexane, etc., amides such as Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide, etc., and similar solvents, either alone or as mixtures. The work-up is usually complete in a few minutes to hours, depending on the type of starting compound to be sulfonated, the sulfo-257272 reagent, the reaction temperature and the solvent; however, in some cases days are required to complete the reaction. After completion of the work-up, 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 invention is illustrated below in further detail by way of examples and reference examples. However, it is to be understood that the examples are given for illustration only and not to limit the invention. There are many variations that do not depart from the spirit and scope of the invention.

In the following Reference Examples and Examples, the procedure for eluting column chromatography is controlled by thin layer chromatography (TLC). Merck 60 ^F 25 TLC plates are used in the TLC. _{4 The} elution of the plates is performed with the same solvent as the elution of the chromatography by column chromatography. An ultraviolet detector is used for detection. Fractions with the desired compound are isolated, stained with ninhydride, sprayed with 48% hydrobromic acid, and heated to hydrolyze, reddish-purple.

If two kinds of solvents are used for elution, the by-product is eluted from the column with the first solvent described. The second solvent elutes the desired product, except where specifically described otherwise.

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

Amberlit 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 percent by weight except for percentages used with solvents.

Solvents are always used in percent by volume. The NMR spectra were measured on a Varian Model EM 390 (90 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as internal and external standard.

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

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

rozkl. - decomposition ppm - part per million mmol = millimol

M - molar (concentration)

HZ = Herz ph - phenyl

Me = methyl

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

NMR = nuclear magnetic resonance absorption

IR = infrared absorption

DMSO = dimethylsulfoxide

D ^ O = heavy water.

Try

The table below shows the minimum inhibitory concentrations (MICs) of some typical compounds of Formula I of the present invention produced in the Examples.

Method

Minimum inhibitory concentrations of test compounds were determined by the agar dilution method. Specifically, 1.0 ml of an aqueous solution of test compounds diluted with 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 applied to the agar plate. Incubate overnight at 37 ° C. The minimum inhibitory concentration is the lowest concentration of test compounds that causes marked inhibition of (complete) 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 Ν, Ν-dimethylformamide was added 320 mg of pyridine-sulfur trioxide complex.

The mixture was stirred at room temperature for 2 days. An additional 120 mg of pyridine-sulfur trioxide complex was added to the reaction mixture. The mixture was stirred for an additional day.

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

The lyophilisate of the product thus purified provides the sodium salt of cis-3-benzyloxycarboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid. IR spectrum (cm ^- ^) 5 3300 750. 1 H NMR (DMSO-d₆, ppm): 3.56 (3H, s CH₃), 4.43 (1H, d, J = 5 Hz, _C4 HH), 7.36 (5H, s, phenyl protons), 8.13 (1H, d, J = 9 Hz, NH). For ^{c 13 H 13 N} 2 ^NaO 8 ^S 1 ^H 2 ° calculated:

H, 3.79; N, 7.03. Found: C, 39.04; H, 3.99; N, 7.26.

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

The filtrate was lyophilized. The sodium salt of cis-3-amino-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR (V ^{'om! 3450,} 1770, 1740 and 060. 1 H NMR (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 1 H) For C ₉ H ₂ N ₂ NaO ₅ S 1 1/2 H 2 O calculated C, 21.98%, 68% H, 10.35% N, found:

H, 3.69; N, 10.48.

(3) 950 mg of cis-3-benzyloxy-carboxamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt produced in Example 1 are dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran. 950 mg of 10% palladium are added to the solution. on coal.

The mixture was stirred at room temperature under hydrogen atmosphere for one hour. 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. ¹ while cooling with ice and stirring, is added thereto 504 mg of sodium hdyrogenuhličitanu and 1.55 g of 2- (2-chloroacetamide-4-thiazolyl) - (Z) -2- £ l-methyl-l- (p ^ · (nitrobenzyloxycarbonyl) ethyloxyimino] acetyl chloride. The mixture was stirred for 40 minutes under ice-cooling.

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

IR spectrum (V

KBr

-1, cm):

775, 1740, 1680, 1550, 1525, 1280 and 1055. NMR Spectrum

4.33 (2H, s, CCH ₂ (1H, d, J = 6 Hz, C ₄ -H) δ 5.31 (2H, s, COOCH ₂ ), 5.52 (1H, dd, J == 6 Hz, J = 9 Hz; 7.25 (1H, s, _s H), 7.62 d 8.07 (2 x 2H, 2 xd, aromatic protons).

(DMSO-d6, ppm): 1.50 (6H, s, 2 Hz,

CH,

4.51 • H),

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

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

(4): Dissolve 1,158 g of cis-3- [2- (2-chloroetamido-4-thiazolyl) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethoxyimino] acetamido] sodium salt in 30 ml of water - 4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer). To this solution was added 241 mg of monomethyldithiocarbamic acid sodium salt with ice-cooling and stirring. 241 mg of sodium monomethyldithiocarbamic acid are then added.

The mixture was stirred for an additional hour. The reaction mixture was then washed with ether and concentrated under reduced pressure. The concentrate is 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- is prepared. sulfonic acids (syn isomer) as a colorless powder.

IR (cm ^-1 ): 1775, 1740, 1680, 1615, 1520, 1280 and 1055. NMR Spectrum

ΠΙαΧ (DMSO-d6, 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, C 1 H), 6.59 (1H, s, SH), 7.24 (2H, br s, NH ₂ ), 7.65 and 8.14 (2 x two protons, 2 xd, 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:

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

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

To the solution was added 500 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen at room temperature for one hour. Add 25 mL of aqueous sodium bicarbonate solution (62 mg). 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 was lyophilized. The cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] isomer disodium salt was prepared.

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

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

Ir (? X ^{'cr <1! 1740,} 1660, 1630, (DMSO-d₆, ppm): 1.36 (3H, s, CH₃), 1.45 (3H, s, _CH3) 3.61 = 6 Hz, C ₄ -H), 6.60 (1H, s, Sy H), 7.13 (2H, br s, NH 3).

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, N, 11.76. Found: C, 28.26; 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 (1m form) column (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 was lyophilized.

Cis-3-Q2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared as colorless powder.

IR (cm ^-1): 1775, 1730, 1670, 1630, 1280 and 050. 1 H NMR (DMSO-d₆, ppm): 1.50 <6H, s, 2 x CH _3> 3.63 (3H, s, COOCH ₃ ), 4.53 (1H, d, J = 6Hz, C ₄ -H),

5.45 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 6.87 (1H, s, _S H), 9.29 (1H, d, J = 9Hz, (NH ₃ ).

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.

N, 13.45. Found: C, 32.38.

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- oxozaetidine-1-sulfonic acid (syn-isomer).

IR spectrum (cm 3 (DMSO-d₆, ppm): 3.6 (s, COOCH _3), C ₄ -H), 5.38 (dd, J = 6 Hz, J = 8

400, 3222, 1780, 3.84 (s, = N-OCH ₂ ), Hz, C ₃ -H), 7.23 (s.

735, 1.29 (s,

670 and 1055. NMR Spectrum

_C1-CH2 -), 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), 23.85 mg of monomethyldithiocarbamic acid sodium salt are added under ice-cooling and stirring. Stirring was continued for 40 minutes at room temperature. An additional 7 mg of sodium monomethyldithiocarbamic acid 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 Amberlite XAD-II column chromatography 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 prepared.

max ' ^cm! 3350, 1775, 055. 1 H NMR (DMSO-d₆, ppm): 3.61 (s, = _N-OCH3), 4.45 (d, J = 6Hz, C ₄ -H) 5.35 (dd, J = 6 Hz, H = 8Hz, _C3-H), 7.1 (br s ,, _NH2), 9.33 (d, J = 8Hz, NH 1. ).

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

AND

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

The mixture was allowed to stand overnight with cooling. Ethanol (10 ml) was added and the mixture was cooled for an additional 3 hours. The resulting crystalline precipitate was filtered off and dried. The monohydrate of the above compound was thus obtained as colorless crystals (241 mg), m.p. 235 DEG-245 DEG C. (dec.).

IR ^<v ^ _x »L cm: 1785, 1750 and 1 690. For N ₃ H _{3 N,} .NaOgS ₂ · H ₂ O Calculated:

Found:% C, 29.48;% H, 3.13;% N, 15.54.

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- was prepared. oxoazetidine-1-sulfonic acid (syn isomer).

v π.- - 1

IR spectrum (ν _max » ^cm ) ppm): 1.95 (s, -OCOCH3), 3.83 5.15 (dd, J = 4 Hz, J = 8 Hz,

400, third 250, 1760, 1665 and 045. 1 H NMR (DMSO-d, (s, = _N-OCH3), 3.8 to 4.4 (m, _C4-H and -CH ₂ OCO), 4.3 (s, C ₁ CH ₂ C ₃ -H), 7.3

9.3 (d, J = 8Hz, 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-chloroacetamide-4-thiazolyl) - 2-methoxyiminoacetamido] -2-oxoazetidine-1-sulfonic acid (syn isomer).

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

IR spectrum (in

KBr max '

425, 3300, 1760, 1660 and 050. 1 H NMR (DMSO-d, = _N-OCH3), 3.9 to 4.4 (m, _C4-H and CH ₂ OCO), 5 15 (dd, J = ppm): 1.94 (s, -OCOCH 3), 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 = 8Hz, -NH

).

-1.

Example 4

Acylation according to Example 1 (3) produces the sodium salt of cis-3-benzyloxycarboxamido-4- (1-methyl-5VT 3y).

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

775, 1690 and 1055. NMR Spectrum (DMSO-d 6, ppm): 8.87 (s, -NCH 3), 3.8-4.3 (m, C 1 H and CH ₂ S-), 4 96 (dd, J = 5 Hz, J = 10 Hz, C H -H), 5.1 (s, -CH ₂ O-), 7.35 (s, -C 8 H 8), 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 was prepared. acid (anti isomer).

KRr - 1

IR spectrum ^(cm) 1760, 1670 and 040. 1 H NMR (DMSO-d₆, ppm): 3.69 (s, -COOCH _3), 3.98 (s, N0CH _3), 4.35 (s, _C1-CH2), 4.49 (d, J = 6Hz, C ₄ -H), 5.41 (dd, J = 6 Hz, J = 9 Hz, _C3 -H) 7.99 (s, S, 1H) ^{9.14 (d, J} = ⁸ Hz, ^NH- 1) y-n O (2) To 2 ml of an aqueous solution containing 85 mg of cis sodium -3- [2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (anti isomer) is added with ice-cooling and stirring with 21 mg of sodium salt monomethyldithiocarbamic acids. The mixture was stirred at room temperature for one hour.

An additional 7 mg of sodium monomethyldithiocarbamic acid was added. Stirring was continued for an additional hour. The reaction mixture was filtered. The filtrate was washed with ether. The aqueous layer was purified by Amberlite XAD-II column chromatography 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 prepared.

VJJy - 1

IR spectrum (in cm): 1760, 1 050. NMR (DMSO-d _c, ppm); 3.68 (s, -COOCH-), max

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 H), 9.04 (d, J = 8Hz, NH

Example 6

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

740, 1650, 1255 and 055. 1 H NMR (DMSO-d₆, ppm): 3.46 (CH ₂ CO and the 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), cis-4-acetamidomethyl-3-phenyl-acetamido-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR spectrum (V cm S: 3400 (broad band), 1760, 1640, 1515, 1255 and 1050). NMR spectrum (D 16 O-ppm): 1.91 (s, COCH 3), 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, C 1 H), 5 19 (d, J = 5.5 Hz, C ₃ -H), 7.38 (m, C ₈ H 8).

Example 8 (1) In the same manner as in Examples 1 (1) and (3), cis-3- [2- (2-chloro-acetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -4-methoxycarbonyl- 2-oxoazetidine-1-sulfonic acid (syn isomer).

IC spectrum (cm ^-1 ): 3600 to 3200, 1790 to 1750, 1700 to 1670 and 1055.

NMR (DMSO-d₆, ppm): 1.23 (3H, t, J = 6Hz, CH ₂ CH _3), 3.62 (3H, s, ČOOCHj), 4.12 (2H, q, J = 6 Hz, CH 2 H 3), 4.34 (2H, s, CH 3), 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 · 4, H), 9.40 (1H, d, J = 9 Hz, C ₃ -NH), 12.92 ( 1H, broad singlet, (ClCl (CONH)). AND.

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

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

The sodium salt of cis-3-Q2- (2-amino-4-thiazolyl) -2-ethoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. IR (l / cm ^{@ -1} ): 3500-

300, 1790-750, 1680, 1625 and 1055. NMR Spectrum (DMSO-d6, ppm): 1.21 (3H, t,

J = 7 Hz, CH ₂ CH ₃ ), 3.61 (3H, s, COOCH 3), 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, C 1 H), 6.56 (1H, s, S ^1K br s, NH ₂ ) , 9.30 (1H, d, J = 9Hz, Cl-NH).

For ^C 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,

H, 3.53; N, 14.76.

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

IC spectrum (ν, cm ^-1 ): -350, 2970, 1780, 1750, 1680 and 1055. NMR spectrum (DMSO-d6, ppm): 0.89 (3H, t, J = 7) Hz, CH ₂ CH ₂ CH ₃ ), 1.65 (2H, sextet, J = 7 Hz, CH ₂ CH ₃ CH ₃ ),

3.60 (3H, s, COOCH ₃ ), 4.01 (2H, t, J = 7 Hz, CH ₂ CH ₂ CH ₃ ), 4.32 (2Η, s, CCH 3), 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, CH 3 CONH).

(2) In the same manner as in Example 8 (2), cis-3- [2- (2-amino-4-thiazolyl) + 2- (propoxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine-1 sodium salt is prepared. -sulfonic acids (syn isomer). IR spectrum (V _max , -1). _3,425 , 780, 1,750, 1,680, 1,620, and 1,055.

NMR (DMSO-d₆, ppm): 0.88 (3H, t, J = 7Hz, CH ₂ CH ₂ CH _3), 1.62 (2H, sextet, J = 7 Hz,

CH ₂ CH 2 CH ₃ ), 3.61 (3H, s, COOCH 3), 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 = 6Hz, J = 9Hz, C ₁ H), 6.52 (1H, s, SyH), 7.14 (2H, br s, NH ₂ ) ,

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

CL ₃ NlgN ₅ NaOgS ₂ .2H ₂ O Calculated: 31.64% C, 4.09% H? N, 14.19. Found: C, 31.70; H, 3.81; N, 14.43.

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 is prepared. -oxozaetidine-1-sulfonic acid (syn isomer).

IR spectrum ( _in ^KBr , cm ^-1 ): 3600 to 3300, 1780 to 1750, 1700 to 1670, 1055 max

NMR Spectrum (DMSO-d6, ppm): 1.23 (6H, d, J = 6Hz, CH (CH3 > ₂ )), 3.62 (3H, s, COOCHp, 4.31 (1H, m, CH) _{(CH3) 2),} 4.33 (2H, s, C1CH _2>, 4.50 (1H, d, J = 6Hz, C ₄ -H), 5.45 (1H, ad, J = 6 Hz, J = 9Hz, _C3 -H), 7.24 (1H, s, Sy Η), 9.32 (1H, d, J = 9Hz, _C3-NH), 12.90 (1H, X (2) In the same manner as in Example 8 (2), cis-3- [2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamido] -4-methoxycarbonyl-2-sodium is prepared. -oxoazetidine-1-sulfonic acid (syn isomer).

iC spectrum (V cm2 ³ ΠΧα, Χ

NMR _(DMSO-dg, ppm) (1H, septet, CH _{(CH3) 2),} 4.47 C ₃ -H), 6.53 (1H, s, Η)) 3 600-3 200, 1780 to 1750, 1680, 1620 and 1055.

1.20 (6H, d, J = 6Hz, CH _{(CH3) 2),} 3.62 (3H, s, COOCH _3>, 4.27 (1H, d, J = 6Hz, C ₄ -H 5.41 (1H, dd, J = 6Hz, J = 9Hz,

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

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

4.09% H? N, 14.19. Found: C, 31.92;

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

(KBr max): 2960, 1780, 1750, 1680 and 1055.

NMR _(DMSO-dg, ppm): 0.89 (3H, t, J = 6Hz, 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 ), 4.30 (2H, s, ClCH ₂ ), 4.49 (1H, d, J = 6Hz, C ₁ H -H), 5.42 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H), 7.20 (1H 1H, s, ^S (J = H), 9.37 (1H, d, J = 9 Hz, C-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 sodium salt is prepared. -sulfonic acids (syn isomer). IR spectrum ( ^{cm -1} L ^: 3450 to 3450, 1790 to 1750, 1680, 1620,

050. NMR _(DMSO-dg, ppm): 0.89 (i.e., 3H, J = 6 Hz, CH = CH ₂ CH ₂ -C _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 4 -H), 7 13 (2H, br s, NH ₂ ), 9.3 (1H, d, J = 9Hz, C 1 -NH). X

For C ₃₄ H N _{g g} NaOgS ₂ .2H ₂ O Calculated: C, 33.13 and, 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 is prepared. -oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm ^-1 ): 3500 to 3250, 1780, 1750, 1680 and 1055.

(DMSO-d6, ppm): 3.52 (3H, s, COOCH3, 4.33 (2H, s, CCH3), 4.51 (1H, d, J = 5.16 (2H, s, phenyl-CH) _2), 5.49 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), '7.27 (1H, 7.38 (5H, s, phenyl-H, 9.59 (1 H , d, J = 9 Hz, C 1 -NH), 12.9 (1H, br ₂ ch).

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 is prepared. (syn-isomer). IR (^^ V cm ^3): 3 450-3 325, 1780, 1750, 1675, 1620 and 055. 1 H NMR _(DMSO-dg, ppm): 3.54 (3H, s , COOCHj), 4.49 (1H, d, J = 6Hz, C ₄ -H), 5.12 (2H, s, _Ph-CH2), 5.42 (1H, dd, J = 6Hz, 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 = 9Hz, C 1 -NH).

and

For ^c 17 ^H 16 ^N 5 ^NaO 2 ^S · 2H ₂ O calculated: 37.70 8 C, 3.72% H, 93.8 N, found: 37.26 8 C,

H, 3.37; N, 12.93.

Example 13 (1) The sodium salt of cis-3- [2- (5-chloro-2-chloroacetamido-4-thiazolyl) -2- (methoxyiminoacetamido) -4- methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IC spectrum (γ Br, _cm ^-1 ): 1790, 1740, 1680, 1550 and 1060. NMR Spectrum (DMSO-d6, ppm): 3.63 (3H, s, COOCH3), 3, 89 (3H, s, NOCH 3), 4.37 (2H, s, CH 3), 4.46 (1H, d, J = 6 Hz, C ₄ -H), 5.40 (1H, dd, J = 6 Hz, C 1 H, 9.48 (1H, d, J = 9 Hz, C 1 -NH), 13.1 (1H, br s, C H 2 CONH).

(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 (syn isomer).

IR ( _vn) -1. ₃₄₀₀ , j ₇₈₀ , j ₇₅₀ , j ₆₈₀ , j _{620 &lt}; _{540 and} j ₀₆₀ . NMR (DMSO-d₆, ppm): 3.64 (3H, s, COOCHj), 3.83 (3H, s, NOCHj), 4.44 (1H, d, J = 6Hz, C ₄ -H) ,

5.36 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 7.30 (2H, s, _NH2), 9.32 (1H, d, J = 9Hz, Cj- NH).

For C ₁₁ H ₁₁ ClN ₅ NaO ₂ 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 (syn isomer).

KRr - 1

IR spectrum (v _max > cm) ^! 3250, 1780, 1740, 1680 and 060. 1 H NMR (DMSO-d₆, 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, ClCH ^, 4.46 (1H, d, J = 5 Hz, C ₄ -H), 5.40 (1H, dd, J = 5 Hz J = 9 Hz, C--H), 7.30 (1H, s, S ^H),

9.41 (III, d, J = 9Hz, _C3 -NH), 11.93 (1H, br s, CONH ₂ C1CH). 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 sodium salt is prepared. -sulfonic acids (syn isomer). IR spectrum (ν max) ^cm: 3450, 3220, 1790, 1750, 1670 and 1050. NMR Spectrum (DMSO-d6, 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 = 5Hz, J = 9Hz, C ₃ H), 6.56 (1H, s, ΰ-, ΙΙ), 7.13 (2H, br s , NH ₂ ), 9.41 (1H, d, J = 9 Hz, C 1 -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 8 H 4.07, N 14.42% .

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- is prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR (v _max , s, COOCH3), 3.9 (3H, s, dd, J = 2 Hz, J = 9 Hz, cm @ ³ : 1780, 1670 and 1550). NMR spectrum (DMSO) (dd, ppm): NOCH ₃ ), 4.1 (1H, d, J = 2 Hz, C ₄ -H), 4.35 (2H, s, C ₁ CH ₂ ), C, -H), 7.4 (IR, s, S-H), 9.6 (1H, d, J = 9 Hz, C, -NH).

X

3.7

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

An additional 15 mg of sodium monomethyldithiocarbamic acid 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. Trans-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer) was prepared.

IR ( ^"U max" cm: 3400 and 1 780. NMR (DMSO-d ^, ppm): 3.70 (3H, s, _COOCH3), 3.85 (3H, s, NOCH ₃₎ 4.10 (1H, s, d, J = 2Hz, C-H), 4.77 (1H, dd, J = 2Hz,

J = 9 Hz, C--H), 6.70 (1H, s, S HH), 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 sodium salt was prepared. -sulfonic acids.

IR cm ^-1): 3600 and 3 200, 1 790 to 1 760 1 680, 1 060. NMR (DMSO-d _g ppm): 3.26 (2H, s, S

Xc), 3.56 (3H, s, _COOCH3), 4.32 (2H, s, C1CH _2), 4.43 (1H, d,

J = 6 Hz, Cj-H), 5.29 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 6.92 (1H, s, S _{v /} H), 8.70 (1H, d, J = 9Hz, _C3 -NH), 12.56 (1H, br s, CONH ₂ C1CH).

(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 cm ^_1): 3330, 1 790 to 1 750 and 1 680, 1 625 and 1 060. NMR _(DMSO-dg, ppm): 3.32 (2H, s, _CH2), 3.59 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 6Hz, C ₄ -H), 5.29 (1H, dd, J = 6Hz, J = 9Hz, C- H), 6.28 (1H, s, S, H), 7.20 (2H, br s, NH +), 8.59 (1H, d, J = 9Hz, 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-sodium salt was prepared. -methoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

IR spectrum (V ^KBr , cm ^-1 ): 1775, 1720 and 1685. ^r max

Example 18

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

IC spectrum ( ^KBr , cm ^-1 ): 3300, 1775, 1710 and 1675. ^c 'max

Example 19

In the same manner as in Example 1 (1) and (3), cis-3- [D-2- [4- (octyl) -2,3-dioxo-1-piperazinecarboxamido] -2- (2-thienyl) sodium salt was prepared. (Acetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid. Λ spectrum (λ max ^{cm 3} 400, λ 760 and 1670).

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) sodium salt was prepared. acetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid. IR (.nu.max) ^{: n =} 680.

Example 21 (1) Following the same procedure as in Example 1 (1) and (3), cis-4-acetamidomethyl-1-3-1- (2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido) sodium salt was prepared. -2-oxoazetidine-1-sulfonic acid (syn-isomer).

IC spectrum (cm ^-1 ): 3340, 1770, 1660, 1650, 1275 and 1050. NMR Spectrum (DMSO-d6, ppm1: 1.84 (3H, s, COCH3), 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, C ₁ CH ₂ ), 5.19 (1H, d, J = 5 Hz, J = 9 Hz, C 1 H), 7.51 (1H, s, H), 9.40 (1H, d, J = 9Hz, _C3 -NH), 12.65 (3H, bs, ClCHjCONH).

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

Nuclear Magnetic Resonance Spectrum (DMSO-d 2 ppm): 1.77 (3H, s, COCH 3), 3.20-3.60 (2H, m, C 1 H 4 NH),

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

H, 4.12; N, 17.34.

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- was prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR (vmax x cm @ -1): 1770, 1645, 1550, 1280 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.3-3.6 (2H, m, CH3); NH), 3.92 (3H, s, NOCH ^, 4.0 to 4.3 (1H, m, _C4 '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), 7.4-7.9 (5H, m, phenyl protons), 9, 49 (lH, d, J ~ 9Hz, _C3-NH)., and (2) in the same manner as in Example 8 (2) Preparation of the sodium salt of cis-3 - [_ 2- (2-amino-4-thiazolyl -2-methoxyiminoacetamido] -4-benzamidomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm -1): 1765, 1645, 1280 and 1050. 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, _C4 'H), 5.23 (1 H, dd,

J = 5 Hz, J - 9Hz, _C3 -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 1 -NH).

For C ^^ H ^^ NGNA ^ 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), cis-3- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetamido) -4- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonic acid.

IR spectrum (broad spectrum, cm &lt; 1 &gt; and [delta] (DMSO-d6, ppm): 3.83 to 3.89

4.4 (2H, m, CH? C- _N), 4.80 ² II

O

7.19 to 7.53 (2 χ 1H, 2 xs, 1,770, 1,765, 1,670, 1,560, 1,275 and 1,050). NMR spectrum (2 χ 3H, 2 xs, 2 x NOCH ₃ ), 4.31 (4H, s, 2.times.CCH3, 4.1-5.10 (1H, m, C / H), 5.31 (1H, dd, J = 5Hz, J = 9Hz, C-H) 1 H, s), 9.34 (1H, s,

X

J = 9 Hz, C ₃ -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 sodium; cis-3- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetamido] -4- [2- (2-chloroacetamido-4-thiazolyl)] - (Z) -2-methoxyiminoacetoxymethyl] -2 To oxoazetidine-1-sulfonic acid in 10 ml of water was added 85 mg of monomethyldithiocarbamic acid sodium salt with stirring under ice-cooling. The mixture was stirred at room temperature for one hour, then 40 mg of monomethyldithiocarbamic acid sodium salt was added and the reaction mixture was stirred for another hour at room temperature.

The reaction mixture was washed with ethyl acetate and ether, respectively. The reaction mixture was then concentrated under reduced pressure. The concentrate was purified by Amberlite XAD-II column chromatography. Following lyophilization, cis-3- [2- (2-amino-4-thiazolyl) - (Z) -2-methoxyiminoacetamido] -4- [2- (2-amino-4-thiazolyl) - (Z) -] is obtained. 2-methoxyiminoacetoxymethyl] -2-oxoazetidine-1-sulfonic acid.

IR spectrum (cm -1): 1760, 1670, 1440, 1275 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.80 and 3.86 (2 × 3H, 2 xs, 2 x) NOCH ~), 4.1 to 4.4 (2H, m, _CH? + OC), 4.8 to 5.05 (1H,

O m, C 1-4 -H), 5.25 (1H, dd, J = 5 Hz, J = 9 Hz, C 1-4 -H), 6.63-6.94 (2 χ 1H, 2 xs, 2 x S (4 H), 7.10 (2H, br s, NH ₀ ), 9.22 (1H, d, J = 9 Hz, C-NH).

X ³

For C ₁₆ H ₁₇ N ₈ NaO _g S ₃ .3H ₂ O Calculated: 30.09% C, 3.63 H, 17.55% N Found: 30.18% C, 3.51% H, 17 , 68% N.

Example 24 (1) 708 mg of 1-methyl-1H-tetrazol-5-yl-thioacetic acid prepared according to Reference Example 184 are dissolved in 20 ml of methylene chloride. 806 mg of thionyl chloride are added under ice-cooling and the mixture is boiled under reflux condenser. The reaction mixture was then evaporated under reduced pressure. The residue is dissolved in 10 ml of methylene chloride.

1 g of cis-3- (p-nitrobenzyloxycarboxamido) -4-hydroxymethyl-2-oxoazetidine, prepared according to Reference Example 182., is dissolved in a mixture of 50 ml of tetrahydrofuran, 50 ml of methylene chloride and 0.5 ml of pyridine. acyl chloride solution prepared above.

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

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

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 prepared.

@ 1 C spectrum (.delta., cm @ -1): 3400, ³³²⁰ , ¹⁷⁶⁰ , ¹⁷³⁰ and 1685. NMR (DMSO-d6, nuix ppm): 3.98 (3H, s, N-Cl) 4.90 (1H, dd, J = 6Hz, J = 9Hz, C1H). For ^C i6 ^H 16 ^N 10 ^NaO 7 ^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) 1.02 g of cis-3- (p-nitrobenzyloxycarboxamido) -4- (1-methyl-1H-tetrazol-5-yl) thioacetoxymethyl-2-oxoazetidine sodium salt is dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of water. -1-sulfonic acids.

1 g of 10% palladium on carbon was added to the solution. 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 the 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 sodium monomethyldithiocarbamic acid are added. The mixture was stirred at room temperature for one hour. The reaction mixture was washed twice with ether and evaporated. The residue is purified by chromatography on an Amberlite XAD-II column (elution: water, 20% ethanol and then 30% ethanol).

The eluate was lyophilized. The salt of cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-benzhydryloxycarbonylethyloxyimino) acetamido] -4- (1-methyl-1H-tetrazol-5-yl) was prepared. thioaoethoxyKBx * -1 methyl-2-oxoazetidine-1-sulfonic acid (syn isomer). IR spectrum (V _max <cm): 3420,

760, 1740 and 1670.

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

Sodium bicarbonate was added and the mixture was filtered. The filtrate was concentrated and purified by Amberlite XAD-II column chromatography (eluting with water). The eluate was lyophilized. Cis-3- [2- (2-Amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4- (1-methyl-1H-tetrazol-5-yl) disodium salt was prepared. ) thioacetoxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

τλ i ,. , KBr -1

IC spectrum (V _max i cm)

CH3): 3400, 3.97 (3H,

760, 680. 1 H NMR _(DMSO-dg, ppm): 1.38 (3H, s, N-CH _3), 5.27 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 ~ H),

6.77 (1H, y1 ⁾

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

IR ( _νmax cm -1): 3410, 1765, 1670, 1550, 1270 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.72 (2H, br s, Π Π) 3.95-4.52 (1H, m, C ₄ -H), 4.30 (2H, s, ^s ch ₂₎

CEL,), 5.25 (1H, dd, J = 6Hz, J = 9Hz, 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-methoxyiminoacetamido-4- (2-thienylacetoxymethyl) -2-oxoazetidine- 1-sulfonic acid (syn isomer).

IC spectrum (cm ^-1 ): 3400, 1770, 1740, 1670, 1615, 1535, 1270, 1250 and

050. NMR _<g d-DMSO, 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) Following the procedure of Example 24, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (1-methyl-1H-tetrazolyl) sodium salt was prepared ( (5) -thiomethyl) -2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm ^-1 ): 3420, 1765, 1660, 1560 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.91 (3H, s, NCH3 ₎ , 3.94 ( 3H, s, OCH ₃ ), 4.34 (2H, s, CH 3), 5.29 (1H, dd, J = 6 Hz,

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

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

IR (DMSO-d c ₃ -h), δ KBr -1 spectrum (ν _max z cm cm, 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, 1 535, 1 280 and 1 050. NMR, 5.22 (1H, dd, J = 6 Hz, J = 9 Hz, (1H, d, J = 9Hz, _C3 -NH).

For C ₁₂ H ₁₄ N ₉ NaO ₃ S ₃ .2 1 / 2H ₂ O Calculated: C, 26.46; H, 3.52; N, 22.70. Found: C, 26.46; C, 3.59; N, 22.70.

Example

IR spectrum (DMSO-d₆, ppm): (2H, s, C1CH ₂₎ (2) In the same (1) of Example 24 was prepared the sodium salt of cis-3- [2- (2-chloroacetamide-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylthiomethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

(Ν max ^cm 3 420, 1760, 1660, 1550, 1270, 1240 and 1050). NMR spectrum 2.08 (3H, s, SCH ₃ ), 2.68-3.06 (2H, m, CH ₂ S), 3.89 (3H, s, NOCH ₃ ), 4.32 7.42 (1H, s, S 2 H 2 H).

X was prepared as in Example 8 (2) to produce cis-3- [2- (2-amino-4-thiazolyl-2-methoxyiminoacetamido) -4-methylthiomethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer).

IR (cm ^-1 ): 3400, 1760, 1660, 1 605, 1 535, 1 380, 1 245 and 1 050.

NMR (DMSO-d₆, ppm): 2.08 (s, 3H, SCHj), 2.70 to 3.12 (2H, m, _CH2 S), 3.71 <3H, s, NOCH ₃₎ 6.74 (1H, s, SyH), 7.14 (2H, broad singlet, NH4).

Example 28 (1) In the same manner as in Examples 1 (1) and (3), cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methyl-2-oxoazetidine sodium salt was prepared. -1-sulfonic acid (syn isomer). IR spectrum ^(? _Max from cm ^-1): 3420, 1760, 1670, 1560, 1275 and 1 055th

NMR (DMSO-d₆, ppm): 1.26 (3H, d, J = 6Hz, C ₄ -CH _3>, 3.98 (3H, s, NOCH _3>, 4.32 (2H, s, ClCH ₂ ), 5.10 (1H, dd, J = 6Hz, J = 9Hz, C 1 H), 7.38 (1H, s, S.I.), 9.33 (1H, d, J = 9Hz, _C3 -NH). X (2) in the same manner as in Example 8 (2) Preparation of the sodium salt of cis-3- £ 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoJ-4- methyl 2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm ^-1): 3410, 1760, 1660, 1535, 1245 and 060. 1 H NMR (DMSO-d₆, ppm): 1.22 (3H, d, C ₄ -CH ₃₎ 3.82 (3H, s, NOCH3), 5.08 (1H, dd, J = 6Hz, J = 9Hz, C1-H),

6.72 (1H, s, S. Η), 7.16 (2H, broad singlet, NH.,), 9.24 (1H, d, J = 9Hz, _C3 -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) sodium salt was prepared. -2-oxoazetidine-1-sulfonic acid (syn isomer).

IR (DMSO-d6, ppm): 5.32 (1H, dd, J)

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

NOCH ₃ ), 4.30 (2H, s,

Hz, C ₃ -H), 5.75 (1H, 1.550, C H ₂ O),

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

H), 9.23 (1H, <3, J = 8 Hz, C-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 sodium salt was prepared. 1-sulfonic acid (syn isomer).

IR (W₁, cm ^-1): 3420, 1758, 1660, 1525, 1270 and 050. 1 H NMR (DMSO-d₆ + 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- (Ν, Ν) sodium salt was prepared. (dimethylcarbamoyl) -2-oxoazetidine-1-sulfonic acid (syn isomer).

iC spectrum (in _cm -1). J 770, 1660 and 1550. NMR Spectrum (DMSO-d6, ppm): 2.8 a

3.0 (2 × 3H, 2 xs, N (CH ₃ ) ₂ ), 3.86 (3H, s, NOCH 3), 4.2 (2H, s, CH 3), 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 thiazolyl) -2-methoxyiminoacetamido] -4- (Ν, Ν-dimethylcarbamoyl) -2-oxo-azetidine-l-sulfonic acids;

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

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

350, 1780 and 1660. NMR Spectrum (DMSO-d6, 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, _C3-H), 6.6 (1H, s, S-H), 8.96 (1H, d, J = 9Hz (C1-NH).

Example

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

350, 1770, 1680, 1540, 1440, 1260 and 060. 1 H NMR (DMSO-d₆, ppm): 3.53 (3H, s, _CH3), 3.68 (2H, s, CH ₂ ), 4.43 (1H, d, J = 6Hz, C ₄ -H), 5.26 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H), 8.85 (1H, d, J = 9Hz, NH).

Example 32

In the same manner as in Example 1 (1) and (3), cis-3- (1H-tetrazol-1-yl-acetamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR ( _Vmax &gt;)

cm ^-1 ): 3 400, 1 770, 1 700, 1 630, 1 550, 1 440, 1 280, 1 260, 1 180, 1 100 and 1 060.

NMR (DMSO-d₆, ppm): 3.68 (3H, s, CH₃), 4.48 (1H, d, J = 6Hz, C ₄ -H), 5.26 (2H, s, CH ), 5.29 (1H, dd, J = 6Hz, J = 9Hz, C, -H), 9.30 (1H, s, N = N), 9.31 (1H, ^{of J 1} N_) d, J = 9 Hz, NH 3). I /

N = C

H

For C 8 H 9 N 6 NaO 2 S. 1 1/2 II 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 way as in the example! (1) and (3) produce the sodium salt of cis-3- (1'-ethyl-1,4-dihydro-7-methyl-4-oxo-8,8-naphthidin-3-ylcarbonylamino) -4- methoxycarbonyl-2-oxoazetidine-1-sulfonic acid, the reaction time being reduced to one hour. max. 3,450, 1,770, 1,660, 1,615, 1,540, 1,500, 1,450, 1,370, spectrum (DMSO-d6, ppm): 1.40 (3H, t, J = 7 Hz, CH ₂ CH ₃ >, 2.63 (3H, s, (3H, s, COOCH ₃ ), 4.57 (1H, d, J = 6Hz, C ₄ -H), 4.58 (2H, quartet, J =

IR (v 1260 and 1060) NMR

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

Et

Example 34

In the same manner as in Example 1 (1) and (3), cis-3- (2-hydroxy-2) -phenylacetamido-4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared as a mixture of diastereoisomers. ¹ ): 3,400, 1,770, 1,680, 1,520, 1,445, 1,380, 1,260, 1,100 and 1,060. NMR Spectrum (DMSO-d6, 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 = 6Hz, J = 9Hz, C1-H), 7.32 (5H, s, phenyl protons), 8.00 and 8.33 (1H, 2xd, NH).

Example 35

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

IR (cm ^-1 ): 3450, 1770, 1680, 1535, 1440, 1290, 1250, 1 100 and 1 055.

NMR (DMSO-d₆, ppm): 3.42 and 3.66 (3H, 2 xs, COOCHj), 4.39 and 4.42 (1H, 2 xd, J = 6Hz, C ₄ -H) , 4.50 and 4.54 (1H, 2 x s, Ph-CH), 5.2 to 5.5 (1H, m, C ₃ -H), 7.1 to 7.6 (5H, m, Ph- protons), 8.87 and 8.96 (1H, 2xd, J = 9 Hz, NH).

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

IR spectrum (cm @ -1): 3400, 1780, 1750, 1535, 1450, 1260, and 1060. NMR Spectrum (DMSO-d6, ppm): 3.02 and 3.42 (3H, 2 H); xs, COOCH-j), 4.36 and 4.45 (1H, 2 xd, 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-CH3), 5.1-5.4 (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 1 ^H 2 ° calculated: 48.84% C, 4.10% H, 5.42% N, found: 48.60% C,

H, 4.25; N, 5.63.

(2) To 6 ml of 80% ethanol was added 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. The mixture was stirred vigorously under a hydrogen atmosphere at room temperature and atmospheric pressure for 3.5 hours.

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

*Ι * - 1

IR spectrum (cm): 3420, 1770, 1670, 1620, 1430, 1380, 1290, 1250 and 1060. NMR Spectrum (DMSO-d6, 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 ₃ 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:

H, 4.13; N, 5.97.

Example 37

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

250, 1780, i 740, 1675, 1570, 048. 1 H NMR (DMSO-d₆, ppm): 3.64 (2H, s, _CH2), 3.67 (3H, s, _CH3) 4.48 (1H, d, J = 6Hz, C ₄ -H), 5.27 (1H, J = 6Hz, J = 9Hz, dd, C ₃ H), 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 sodium salt was prepared. -1-sulfonic acid (syn isomer).

IR (.delta., Cm @ ^-1 ): 1790-730, 1680, 1550 and 1055. NMR spectrum (DMSO-d6, ppm): 3.6 (3H, s, COOCH3), 3, 7 (3H, s, _COOCH3), 4.4 (2H, s, C1CH _2>, 4.5 (1H, d, J = 6Hz, C ₄ -H), 4.68 (2H, s, N0CH _2), 5.45 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 7.3 (1H, s, s / H)

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

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

IR spectrum (cm ^-1 ): 3,300, 1,790 to 1,730, 1,670, 1,610, 1,530 and 1,055. NMR Spectrum (DMSO-d6, ppm): 3.60 (3H, s, COOCH3), 3.69 (3H, s, COOCH ₃ ), 4.49 (1H, d, J = 6Hz, C ₄ -H), 4.64 (2H, s, NOCH ₂ ), 5.41 (1H, dd) J = 6 Hz, J = 9 Hz, C 1 H), 6.64 (1H, s, S + H), 7.18 (2H, br s, NH 3), 9.29 (1H, d, J = 9) Hz, _C3 -NH). Λ

For C ₃₃ H _{34 3} g NGNA 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-chloroetamido-4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetamido -4- sodium salt was prepared. Methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (ν, cm): 3,250, 1,790 to 1,730, 1,670, 1,520 and 1,050. NMR Spectrum J = 6 Hz, C ₃ H), = 9 Hz, C ₃ H, 7 36 (DMSO-d₆, ppm): 3.61 (3H, s, COOCH _3>, 4.36 (2H, s, C1CH _2), 4.53 (1H, d.

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

NOCH,

5.37 (2H, s, COOCH _2), 5.48 (1H, dd, J = 6Hz,

S ^ -H), 9.49 (1H, d, J = 9 Hz, C-NH), 12.95 (1H, singlet and broad singlet, ₂ CONH C1CH

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- is prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR (in ^KBr , cm &^lt; ^{-1 &gt};): 3450, 3330, 1790-730, 1680, 1610 and 1050.

^F max

NMR (DMSO-d₆, ppm): 3.6 (3H, s, _COOCH3), 4.5 (1H, d, J = 6Hz, C ₄ -H), 4.77 (2H, s, NOCH _2), 5.35 (2H, s, COOCHp, 5.43 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H), 6.66 (1H, s, SyH) 7.2 (2H, br s, NH ₂ ), 9.39 (1H, d, J = 9Hz, C 1 -NH).

For ^C 19 H _{17 12} S NGNA ₂ .2 H ₂ 0: calculated: 35.40% C, 3.28% H, 13.04 ϊ N Found:

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

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

To the solution was added 500 mg of 10% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for one hour. Add 25 mL of aqueous sodium bicarbonate solution (66 mg). The catalyst was filtered off. The filtrate is 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 fractions were discarded. The immediately following fractions (40 mL) were lyophilized. This produces cis-3-β- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetamic disodium salt.

KBr jido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer). IR (\ / _max cm ^-1): 3350, 1780, 1750, 1670, 1600 and 055. 1 H NMR (DMSO-d₆, ppm): 3.58 (3H, s, COOCH ₃₎ 4.27 (2H, s, NOCH ₂ ), 4.5 (1H, d, J = 6Hz, C ₄ -H), 5.37 (1H, dd, J = 6Hz, J = 9Hz , C ₃ -H), 6.72 (1H, s, ^ s / H), ^{7.11 (2H 'bs' NH2!' 11 (3 (1} H, d, J = 9 Hz, _C3 NH).

For ^{C 12 H} 11 ^N 5 ^NaO 2 ° 10 ^S 2 ' ² 1 / 2H ₂ O calculated: 26.67% C, 2.98% H, 12.96% N, found:

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

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- is prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR (cm ^_1): 3250, 1780, 1750, 1680 and 055. 1 H NMR (DMSO-d₆, ppm): 3.60 (3H, s, COOCH _3>, 4.32 (2H with, C1CH _2), 4.49 (1H, d, J = 6Hz, C ₄ -H), 7.27 (1H, s, SH), 9.49 (1H, d, J = 9Hz, 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 is produced ( son isomer). IR spectrum (V ^cm: 3 325, 1790 to 1740, 1670 and 1050). NMR spectrum (DMSO-d6, ppm): 3.60 (3H, s, COOCH-j), 4.4-4. 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 C ₁ H), 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, CI · NH).

For C _O H N _C S to 0 _{by n} 1 .L / 2H.0 calculated: 32.36% C, 3.55% H, 14.52% N Found:

0 0 6 7

H, 3.75; N, 14.46.

Example 41 (1) In the same manner as in Example 1 (1) and (3), cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloromethyl-2- oxoazetidine-1-sulfonic acid (syn isomer). IR (cm -1): 1770, 1670, 1550, 1270 and 1055.

NMR (DMSO-d₆, ppm): 3.89 (3H, s, NOCH _3> ,. 4.34 (2H, s, C1CH _2), 5.28 (1H, dd, J = 6, J = 9 Hz, C ₃ -H), 7.38 (1H, s, S_, H), 9.37 (1H, d, J = 9 Hz, C 1 -NH), δ, 90 (1H, br s, C1CH ₂ CONH _2). Λ (2) in the same manner as in Example 8 (2) Preparation of the sodium salt of cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-chlormethy1-2 -oxoazetidine-1-sulfonic acid (syn isomer) IR spectrum (ν max, cm ^-1 ): 1770, 1660, 1610, 1530, 1270 and 1050.

For C ₁₀ H _{1: l} 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), cis-Sf 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylsulfonate is obtained. 1-oxoazetidine-1-sulfonic acid loxymethy (syn isomer).

Ir (™ ^ CRO ^_1): 1770, 1670, 1560, 1350, 1275, 1175 and 050. 1 H NMR (DMSO-d₆, 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, 1H, J = 9 Hz, C 1 -NH), 12.91 (1H, br s, C ₁ CH 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 is prepared. acid (syn isomer).

IR ( ^KBr , cm cm): 1770, ^c max

NMR (DMSO-d₆, ppm): 3.10 (3H, = 5 Hz, J = 9 Hz, _C3 -H), 6.74 (1H, s,

670, 1620, 1535, 1 s, 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 sodium salt was prepared. 1-sulfonic acid (syn isomer).

IR spectrum (Vmr ^Br , _C m S: 3250, 1770, 1720 to 1660, 1545 and 1050). NMR spectrum max (DMSO-d6, ppm): 3.69 (3H, s, NOCHg) , 4.35 (2H, s, C1CH _2), 5.32 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 7.35 (1H, br, s., H) .

A (2) In the same manner as in Example 3 (2), cis-3- [2- (2-amino-4-thiazolyl) -2-methoxyaminoacetamido] -4-benzoyloxymethyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. acid (syn isomer). IR (cm h y ^{1 8300,} 1770, 1710, 1665 and 050. 1 H NMR (DMSO-d ppm): 3.67 (3H, s, NOCH _3), 5.28 (1H, dd J = 6 Hz, J = 9 (2H, Cj-H), 6.62 (1H, s, S ^H),

7.12 (2H, br s, NH4), 9.38 (1H, d, J = 9Hz, Cl-NH).

For C ₁₇ H ₃ gNgNaOgS 1 ₂ .1 / 2H ₂ O Calculated: 38.34% C 3.60% H 13.15% N Found:

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

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

IR (V ^ x ^{'cm: 3420,} 1760, 1 ppm): 2.30 (3H, s, CO ^, 3.85 (3H, s, NOCHj), C ₄ -H), 5.18 (1H, dd, J = 10 Hz, J = 5 Hz, _C3-H)

650, 1540 and 265. 1 H NMR (DMSO-d 31CH ₂₎

7.40 (1H, s, H S _KX).

4.34 (2H, s, C1CH _2), 4.40 (1H, d, J = 5Hz, (2) In the same manner as in Example 8 (2) Preparation of the sodium salt of cis-3- [2- (2 (amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

KBr max '

IR spectrum (in ppm): 2.30 (3H, s, t, C ₃ -H), 6.64 (1H, Cr / B:

400, 1760, 1660, 1535, 1260 and 050. 1 H NMR (DMSO-d₆, 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 was prepared. (son isomer).

IR spectrum , .KBr -1, (H, cm, 'max' 1: 1,765, _r 1 665, 1 545, 1275, 1240, 1055 and 1030. NMR Spectrum (DMSO-d6, ppm): 3.90 (3H, s, NOCHj), 4.35 (2H, s, C ₁ CH ₂ ), 5.34 (1H, dd, J = 4.5 Hz, J = = 9 Hz, C ₃ -NH) 7.66 (1 H, s, S H), X 9.38 (1 H, d, J = 9 Hz, c ₃ -nh).

Example 46

In the same manner as in Example 1 (1) and (3), cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacteamido] -4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine sodium salt was prepared. -1-sulfonic acid (syn isomer). IR spectrum ^(? _Max 'cm): 1770, 1690,

550, 1275 and 050. 1 H NMR (DMSO-d = 6Hz, CH ₂ SO _2), 3.93 (3H, s (1H, dd, J = 6 Bz, J = 9 Hz, C ppm) : 3.97 (3H,

Soocha _3), 3.44 (2H, t, J

NOCH _3), 4.34 (2H, t, J - 6Hz, COOCH ,,), 4.37 (2H, s, ₂ C1CH)

-H), 7.51 (1H, X)

H), 9.48 (1H, d, J = 9Hz, c ₃ -nh).

Example 47 (1) The sodium salt of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-trifluoroacetylaminomethyl-2-oxoazetidine was prepared in the same manner as in Example 1 (1) and (3). -1-sulfonic acid (syn isomer). IR spectrum (in ^KB f, cm L: 1770, 1710, 1670, 1550, max

270 and 1050. NMR Spectrum (DMSO-d6, ppm): 3.91 (3H, s, NOCH3 ₎ , 4.36 (2H, s, CH2Cl2), 5.28 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H), 7.49 (1H, s, 5 H 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 is prepared. (son isomer). IR spectrum (? _Max, cm L: 1770, 1720, 1670, 1530 and 050. 1 H NMR spectrum, _S H), 7.12 (2H, br s, NH _2), 9.35 (1 H, d, J = 9 Hz, C 1 -NH).

(DMSO-d6, ppm): 3.85 (3H, s, NOCHp, 5.17 (1H, dd, J = 6Hz, J = 9Hz, C1-H)), 6.80 (1H, 1H) ^;

X

For C ^ 2 ^ 3 ^ i2 ^F 6 ° 7 ^Na 2 ^ '^^ 2 ° ° ^{in YP-theory:} 26.19% C, 3.30% H, 15.27% N Found: 26.30% H, 3.07; N, 15.05.

Example 48

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

IR (vmax, cm ^-1 ): 1770, 1710, 1675 and 1510.

Example 49

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

IR spectrum ^cm 1770, 1,705 and 1,665.

max

Example 50

In the same manner as in Example 1 (1) and (3), cis-3- [D-2- [3- (furan-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamido] -4- -methoxycarbonyl-2-oxoazetidine-1-sulfonic acid. IR spectrum cm: 1770 and 1725,

Example 51

The beta and alpha isomers of the cis-3- [D-2- [3- (thiophen-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] sodium salt was prepared in the same manner as in Example 1 (1) and (3) - 2-Phenylacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

Beta-Isomer: IR spectrum cm 1770, 1735, 1660, 1530, 1440, 1270 and

235. NMR (DMSO-d₆, ppm): 3.11 (3H, s, COOCHj), 3.80 (4H, s, _{NCH2 CH2} N), 4.33 (IH, d, J = 6Hz , C ₄ -H), 5.30 (1H, dd, J = 6Hz, J = 9Hz) (C ₁ H), 5.55 (IH, d,> J = 7Hz, phenyl-CH), 8, 11 (1H, s, N = CH), 9.07 (1H, d, J = 7Hz, phenyl-CHNH), 9.22 (1H, d, J = 9Hz, c ₃ -nh).

Alpha-Isomer: IR spectrum ( ^{cm -1} , ^{cm -1} ): 1765, 1740, 1680, 1535, 1440, 1270 and 1240. NMR Spectrum (DMSO-d6, ppm): 3.62 ( 3H, s, COOCH 3), 3.80 (4H, s, NCH ₂ CH ₂ N), 4.45 (1H, d, J = 6Hz, C ₄ -H), 5.11 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H), 5.47 (IH, d, J = 7 Hz, Ph-CH), 8.10 (IH, s, N-CH).

Example 52

In the same manner as in Examples 1 (1) and (3), cis-3- [2- (2-methyl-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. acid (syn isomer). 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 6 S), 3.81 ( 3H, s, COOCH-j), 4.05 (3H, s, NOCH 3), 5.04 (1H, d,

NJ = 6 Hz, C.-H), 5.75 (1H, d, J = 6Hz, C, -H), 7.68 (1H, s, S < / H).

Example (1) The sodium salt of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-diethylphosphonoacetamido] -4-methoxycarbonyl-2-oxoazetidine was prepared in the same manner as in Example 1 (1) and (3). -1-sulfonic acids. IR (cm ^-1 ): 3450, 1770, 1750, 1670, 1440, 1260, 1230 and

050.

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

Ir (£ Br, l ,. _{cm 3 40} 0 _{775 χ (χ 750 (670} χ _(χ χ _{510j 2} 70 1 230 1 045th

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 µ H, 10 , 20% N.

Example 54

In the same manner as in Example 1 (1) and (3), cis-3- (2-triethylsilylethylcarboxamido) -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. IR (.delta., Cm @ ^-1 ): 3450, 1775, 1745, 1660, 1440, 1260, 1250 and 1055. NMR Spectrum (DMSO-d6, ppm): 3.61 (3H) with, COOCHj), 4.41 (IH, d, J = 6Hz, C ₄ -H), 5.24 (IH, dd, J = 6 Hz, J = 9 Hz, C-H), 8, 59 (1H, d, J = 9Hz, C 1 -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) sodium salt was prepared. -2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum cm ^-1): 3450, 1750, 1660, 1540, 1260 and 045. 1 H NMR (DMSO-d + D ₂ O (ppm): 3.82 (IH, s, NOCH ₃ ), 4.38 (2H, s, C1CH _2>, 5.32 (IH, d, J = 6 Hz, (DMSO-d + d ₂ O, ppm): 3.82 (1H, s, NOCHg) 4.38 (2H of C8-H), 7.34 (5H, s, phenyl protons), 7.42 (1H, s, ^s x

(CH ₂ ), H).

5.32 (1H d, J = 6 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 is prepared. - (2-phenylethyl) -2-oxoazetidine-1-sulfonic acid (syn isomer).

IR (DMSO-d6, ppm): [delta] H), 7.10

KRr -1 (V cm): 3,425, 1,750, 1660, 1610, 1520 3.64 (3H, s, NOCHg), 5.15 (1H, dd, J = 6 Hz, J = ( 2H, br s, NH _2), 9.34 (1H, d, J = 9Hz, _C3 -NH).

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

For ^C 32 ^ .2 gNgNaOgS 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), cis-3- [2- (2-hydroxy-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid sodium salt was prepared. Acids (syn isomer):

IR spectrum (cm ^-1 ): 3450, 1770, 1750, 1660, 1530, 1440, 1250 and 1050.

NMR _(DMSO-dg, ppm): 3.61 (3H, s, COOCHg), 3.87 (3H, s, NOCHg), 4.50 (1H, d, C ₄ -H), 5.38 (1H, C8-H), 6.33 (1H, s, S, 1H), 9.60 (1H, C1-NH).

EXAMPLE 57 (1) The following compounds were prepared in the same manner as in Example 1 (1) and (3): syn and anti-isomers of cis-3-Q2- (2-chloroacetamido-4-thiazolyl) - N -methoxyiminoacetamide sodium salt] -4-ethoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

Syn-isomer: IC spectrum cm: 3550, 1770, 1670, 1610 and 1050. NMR Spectrum max (DMSO-d6, ppm): 1.19 (3H, t, J = 7 Hz, CHgCHg), 3.86 (3H, s, NOCHg), 4.07 (2H, quartet,

J = 7Hz, 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 -, -), 7.28 (1H, s, S S zH), 9.44 (1H, d, J = 9Hz, C, ,H).

X

Anti-isomer: IR spectrum (cm ^-1 ): 3,300, 1,760, 1,660, and 1,050. 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 = 5Hz, _C4-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) The following compounds were prepared in the same manner as in Example 8 (2): syn and anti-isomers of the sodium salt of cis-3 - [] 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonyl -2-oxoazetidine-1-sulfonic acid.

syn-isomer: IR spectrum cm ^-1 ): 3450, 3250, 1780, 1730, 1670. NMR Spectrum (DMSO-d6, ppm): 1.18 (3H, t, J = 7 Hz, CH3). CH3), 3.80 (3H, s, NOCHg), 4.04 (2H, quartet,

J = 7 Hz, CH 3 CH 3), 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 3), 9.32 (1H, d, J = 9 Hz, C 1 -NH).

X

For ^{C 12 H} 14 ^N 5 ^NaO 8 ^S 2 ' ² 1/2 ^H 6 O calculated: 29.50% C, 3.92% H, 14.33% N, found:

H, 3.71; N, 14.09.

KBr -1 ¹ anti-isomer: IR <V _max, cm): 3300, 1770, 1720 and 660. 1 H NMR (DMSO-d ppm): 1.18 (3H, t, J = 7 Hz CH ₂ CH ₃ ), 3.90 (3H, s, NOCH 3), 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 = 5Hz, J = 9Hz, C 1 H), 7.06 (2H, br s, NH 4), 7.36 (1H, s, _{Sx /} H), 9.02 (1H, d, J = 9Hz, C-NH).

X

For C ^ 2H ^H NN ^{N % aO} ^ ^ ^ ^: C, 29.50; H, 3.92; N, 14.33. Found:

H, 3.88; N, 14.17.

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 sodium salt was prepared. 1-sulfonic acid (syn isomer).

IR (cm ^-1 ): 3450, 3250, 1770, 1680, 1050. NMR Spectrum (DMSO-d6, ppm): 3.67 (3H, s, NOCH3), 4.30 (2H, s, CICH p, 4.60 (1H, d, J = 5Hz, C ₄ -H), 5.4 (1H, dd, J = 5Hz, J = 9Hz, 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 is produced ( son isomer).

IR spectrum (s)

3.66

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

KBr max

9.95 (1H, ^s x)

H, 4.55 (1H, 6.9-7.7)

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

770, 1680 and 1050. NMR Spectrum (DMSO-d6, 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), the sodium salt of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-ethoxycarbonylmethyloxycarbonyl-2- is prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm ^-1 ): 1780, 1765, 1740, 1670, 1550, 1280 and 1055. NMR spectrum (DMSO-d6, ppm): 1.19 (3H, t, J = 7 Hz, CH 2 CH ₃ >, 3.85 (3H, s, NOCH 3), 4.11 (2H, q, J = 7 Hz, CH ₂ CH ₃ ), 4.36 (2H, s, C ₁ H ₃ ) 4.63 (1H, d, J = 6Hz, C ₄ -H), 4.64 (2H, q, J = 15Hz, OCH ₂ CO), 5.52 (1H, dd, J = 6Hz) J = 9 Hz, C, -H), 7.31 (1H, s, Sx, H), 9.23 (1H, d, J = 9Hz, C, -NH).

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

IR spectrum (cm ^-1 ): 1770, 1750, 1670, 1535, 1285 and 1055. NMR Spectrum (DMSO-d6, ppm): 1.20 (3H, t, J = 7 Hz, CH ₂ CH ₃ ), 3.80 (3H, s, NOCH 3), 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 1 H), 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-Q2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-acetoxymethyl-2-oxoazetidine sodium salt was prepared. 1-sulfonic acid (syn isomer).

IR _<x V ™, cm ^-1): 3450, 1765, 1730, 1640, 1540, 1250 and 040. 1 H NMR (DMSO-d₆, ppm): 2.04 (3H, s , COCH ₃ >, 3.90 (3H, s, NOCH ₃ ), 4.35 (2H, s, C ₁ CH ₂ >, 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, _C3 -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 is produced ( son isomer).

IR spectrum (in

KBr max cm ¹ ):

420, 1765, 1730, 1660, (DMSO-d₆, ppm): 2.01 (3H, s, COCH), 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).

^To ^ 2 ^^ 14 ^ 8 ^ - ¹ 3.65% H, 14.95% N.

1 / 2H ₂ O calculated:

30.64:% C,

H, 3.64; N, 14.89. Found: C, 30.66

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

IR (cm ^-1 ): 3250, 1770, 1650 and 1050. NMR Spectrum (DMSO-d6, ppm):

2.68 (3H, d, J = 5Hz, NHCH3), 3.85 (3H, s, NOCH3), 5.3S (1H, dd, J = 5Hz, J = 9Hz, 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 was prepared. acid (syn isomer).

IR spectrum (V cm &^lt; -1 ^&gt; )! 3,350, 1,770, 1,670, a'1050. NMR Spectrum (DMSO-d 6 ppm):

max o

2.60 (3H, d, J = 5 Hz, NHCHj), 3.80 (3H, s, NOCH _3), 4.35 (1H, d, J = 5Hz, 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 = 5Hz, NHCH _3), 9.01 (1H, d, J = 9Hz, χ

(NH 3).

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- (nitrobenzyloxy) grbonyl) ethyloxyimino] acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid.

IR spectrum (V _cm ^-1 ) _; 3,400-3,200, 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) sodium salt was prepared. Ethyloxyimino] acetamido] -4-methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR (.delta. Br, cm @ ^-1 ): 3,325, 1,780, 1,740, 1,670, 1,600, 1,520, and 1,050. NMR Spectrum (DMSO-d6, ppm): 1.5 (6H, s) 2.times.CH3), 3.69 (3H, s, COOCH3), 4.15 (1H, d, J = 3Hz, C / H), 4.82 (1H, dd, J = 3Hz, J = 9 Hz, C / H), 5.33 (2H, s, COOCHp, 6.7 (1H, s, _s .HI, 7.25 (2H, br s, _NH2), 7.65 and 8 15 (2 χ 2H, 2 xd, aromatic protons), X

9.37 (1H, d, J = 9Hz, C / NH). Pro ^c 21 ^H 2 ^N 6 ^NaO i 2 ^S 2. 2 2.1 H ₂ 0: calculated: 37.01% C, 3.84% H, 12.33 and N Found: 36.90% C, 3.78% H, 12.30% N.

(3) In the same manner as in Example 1 (5), trans-3-β] 2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoxyimino) acetamide η 4 -4-methoxycarbonyl disodium salt was prepared. -2-oxoazetidine-1-sulfonic acid (syn isomer). IR (cm ^-1 ): 3375, 1780, 1745, 1580 and 1050.

NMR (DMSO-d₆, ppm): 1.40 and 1.43 (2x 3H, two s, 2 x CHP, 3.7 (3H, s, _COOCH3), 4.17 (1H, d, J = 3 Hz, C / H), 4.85 (1H, dd, J = 3Hz, J = 9Hz, C / H), 6.73 (1H, s, SyH), 7.12 (2H, s, NH _2), 11.7 (1H, d, J = 9 Hz, C / NH). For C ₁₄ H ₁₅ N ₅ O ₂ S _{1Q 5.2} H ₂ O X.

calculated: 27.41 ° C, 4.11%:, 11.42% N, found: 27.10% C, 3.90% 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) sodium salt was prepared. [alpha] -4-Methoxycarbonyl-2-oxoazetidine-1-sulfonic acid acetamide (syn isomer),

IR (cm ^-1 ): 3250, 2950, 1780, 1740 and 1680. NMR Spectrum (DMSO-d6, ppm): 1.46 (6H, s, NOCMe4, 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 δ d, J = 6 Hz, J = 9 Hz, C 1 H), 7.27 (1H, s, S.H), 9.22 (1H, d, J = 9 Hz, C, -NH), 12 93 (1H, br s, CH 2, 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- is prepared. -methoxycarbonyl-2-oxoazetidine-1-sulfonic acid (syn isomer),

IR spectrum (cm ^-1 ): 3400, 1780, 1735 and 1670. NMR spectrum (DMSO-d6, 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, SyH), 7.2 C2H, s, NH _2), 9.05 (1H, d, J = 9Hz, C 1 -NH). AND

For C ₁₅ H N _{g 5} NaO ₁₀ S ₂ .2H ₂ O Calculated: C 32.67 tons, 4.02% H, 12.70% N Found: 32.63% C,

H, 3.96; N, 12.43.

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

Ir (b cn: 3400, 1775 and 1740; NMR spectrum (DMSO-d₆, ppm): 0.92 (2H, CHjSi), 1.45 (6H, s, ₂ NOCMe), 3.64 (3H, s, COOCH ₃ >, 4.16 (2H, COOCH ₂ ), 4.35 (2H, s, C ₁ CH ₂ ), 4.50 (1H, d, J = 6 Hz, C ₄ -H) , 5.50 (1H, dd, J = 6 Hz, J = 9 Hz, C-NH), 7.24 (1H, s, ^s ^ J H) 9 ¹¹ d, J = 9 Hz, _C3 -NH), 12.89 (1H, br s, C ₁ CH ₂ CONH).

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

IR spectrum (ν max ^{cm -1} 2400, 1780, 1740 and 1675). NMR spectrum (DMSO-d6, ppm):

0.95 (2H, CH ₂ Si) 1.48 (6H, s, , NOCMe ₂ ), 3.66 (3H, WITH, 4.18 (2H, COOCH2 ₎ 4.50 (1H, d, J - 6 Hz, C ₄ “ H), 5.47 (1H, dd, J = 6Hz, J = 9 HZ C ₃ -H), 6.60 (1H, s, S, H, 7.19 (2H, br s, NH ₂ ) 8.98 (1 H, d). J = 9 Hz, C ₃ -NH). AND Example 65 (1) Same in a way like in Example 1 (1) a (3) cis-3 sodium salt was prepared - [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 λmax ^cm -1> ^{3 420} ' ¹⁷⁷⁰ ' ^{1 73} ° ^-169 °, ¹ 520, ¹ 350, 1 280 and 1 055.

NMR (DMSO-d₆, ppm): 1.50 (6H, s, 2 x _CH3), 4.34 (2H, s, C1CH _2), 4.38 (1H, d, J = 6Hz, C ₄ -H), 5.31 (2H, s, COOCH ₂ ), 5.34 (1H, dd, J = 6 Hz, J = 9 Hz, C 1 H), 7.54 (1H, s, S-). H, 7.62 and 8.07 (2 X 2H, 2 xd, aromatic protons).

X (2) 280 ml 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 produced according to ad (1).

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

Fractions containing the desired product are combined and lyophilized. The sodium salt of cis-3 - [] 2- (2-amino-4-thiazolyl) -2-? 1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] -4-carbamoyl-2-oxoazetidine-1 was prepared. -sulfonic acids (syn isomer).

IR spectrum (cm ^-1 ): 3410, 1770, 1730, NMR spectrum (DMSO-d6, ppm): 1.48 (6H, s, 2 x CH3), (2H, s, COOCH3) , 6.92 (1H, s, _s H), 7.12 (2H, br

AND

685, 1525, 1350, 1280 and 1 055 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 × 2H, d, J = 9 Hz, aromatic protons), 8.82 (1H, d, J = 9 Hz, C 1 -NH).

(3) 200 mg of cis-3- [2- (2-amino-4-thiazolyl) -2 - [] 1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] - are dissolved in 10 ml of water. 4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer), which was produced according to (2).

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

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 is then concentrated to about half its original volume under reduced pressure.

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

KBr -1,

IR spectrum (V _max , (DMSO-d6)

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 CH₃), 4.36 (1H, d, J = 6Hz, C ₄ -H), 5.33 (1H, dd, J = 6Hz,

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

For ^{C 13 H} 16 ^N 6 ° 9 ^S 2 · 1 / ^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 Amberlite XAD-II column chromatography in (1) are lyophilized. 174 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2 - [] 1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] -4-sulfoaminocarbonyl-2) are obtained. -oxoazetidine-1-sulfonic acid (syn isomer) as a colorless powder.

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

IR spectrum ( ^KBr , cm ^-1 ): 3400, 1770 and 1630. NMR spectrum (DMSO-d6, +: 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 X

EXAMPLE 66 (1) In the same manner as in Example 1 (1), (3) and (4), the salt of cls-3- [2- (2-amino-4-thiazole; Lyl) -2-p. methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] -4-acetoxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (cm ^-1 ): 3400, 1770, 1740 and 1670. NMR spectrum (DMSO-d6, ppm):

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

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

-sulfonic acids (syn isomer) IR spectrum (V cm ¹ ): 3 350, 1 760 and 1,650. NMR Spectrum (DMSO-d6, ppm): 1.36 (3H, s, CH ₃ ), 1.43 (3H, s, ch ₃ ) 1.93 (3H, s, coch ₃ ) 5.25 (1H, dd, J = 5Hz, J = 9Hz) C ₃ -H), 6.70 (1H, s, Sy ,10), 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- (sodium) salt was prepared. oxoazetidine-1-sulfonic acid (syn isomer).

IR (V? / Cm ^-1): 1770, 1700, 1690 and 650. 1 H NMR (DMSO-d₆, ppm): 3.87 (3H, s, NOCH _3), 4.33 (2H, s, CCH 3), 5.27 (1H, dd, J = 5Hz, J = 9Hz, C ₃ -H), 6.38 (2H, br s, NH ₂ ), 7.39 (1H, s, S, 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 is produced ( son isomer).

IR (vmr ^Br , cm ^-1 ): 3400, 1780, 1690 and 1645. NMR Spectrum (DMSO-d 6 ppm):

max □

3.83 (3H, s, NOCH ₃ ), 5.24 (1H, dd, J = 5 Hz, J = 9 Hz, C 1 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-NH).

For C ₃₃ H ₃₃ S _{2 g} Ngo Na.3H ₂ O: calculated: 26.50% C, 3.84% H, 16.86 and N Found: 26.51% C, 3.49% H, 16 42% N.

Example 68

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

IR (.delta., Cm @ ^-1 ): 3410, 3250, 1780 and 1680. NMR spectrum (DMSO-d6, ppm):

4.26 (1H, d, J - 6Hz, C ₄ -H), 4.98 (1H, dd, J = 6 Hz, J = 9 Hz, C-H), 5.02 (2H, s, C ₈ H ₈ CH ₃ , 7.23 (5H, s, C 8 H 8), 7.67 (1H, d, J = 9 Hz, C ₃ NH).

The sodium salt of trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine-1-sulfonic acid was prepared in the same manner as above. This product is 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] sodium salt was prepared. -1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (νmax ^{cm -1} 3400, 1765, 1730, 1690 and 1670). NMR spectrum (DMSO-d6, ppm): 1.50 (6H, s, 2 x CH3), 5.32 (2H, s, COOCHp, 6.85 (1H, s, S &gt; H) (2) In the same manner as in Example 1 (5), trans-3- [2- (2-amino-4-thiazolyl) was prepared. -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR 1.61 (6H, s, C ₃ -H two), 7.11 (1H, ^(V max ^{'3280' 1760 '1 66} ° - ^NMR (DMSO-d₆ + methyl group), 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 (syn isomer).

IR spectrum (v): 3,350, 1,780 to 1,730, 1,690 to 1,630. NMR Spectrum (DMSO-d ppm): 1.52 (6H, s, 2.times.CH3 ₎ , 1.81 (3H,

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

6 '

_COCH3), 4.35 (2H, s, C1CH _2), 5.2 (1H, dd, J = 6Hz,

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 (syn isomer).

KBr

IR (ppm): 1.5 (6H,

5.31 (2H, s, COOCH)

-1, cm):

x CH ₃ ), 1.74, 6.27

350, 1780-730 (3H, (1H, s, S.).

COCH _3), 1 680-1 600. NMR (DMSO-d ,, O

5.13 (1H, dd, J = 6 Hz, J = 9 Hz, _C3-H) (1H, d, J = 9Hz, _C3 -NH).

For C ₂₂ H ₂₄ N ₇ O ₁₁ S ₂ .3H ₂ O Calculated: C 37.55, H 4.29, N 13.94. Found: C 37.56, H 4.12. , 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 was prepared. -oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (in cm ² ): 3225, 1770, 1720, 1670 and 1635. NMR Spectrum (DMSO-d 6, ppm): 1.49 (3H, s, CH ₃ ), 1.51 ( 3H, s, _CH3), 1.8 (3H, s, COCH _3>, 5.17 (1H, dd, J = 6Hz,

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 gNgOgS ₂ .2 ₂ 1 / 2H ₂ O Calculated: 33.51% C, 4.69 tons 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 (syn isomer).

IR spectrum (v max ^'c ™ ^{3 3 33} θ' ^3? 30, 1 680 and 1 050. NMR (DMSO-d₆, ppm): 0.92 (3H, d, J = 6 Hz, CH₃), 1.04 (3H, d, J = 6Hz, CH3 & gt _; ), 1.49 (3H, s,

_CH3), 1.52 (3H, s, _CH3), 3.73 (1H, dd, J = 6 Hz, J = 7 Hz, C ₄ -H), 4.33 (2H, s, ₂ C1CH )

5.15 (1H, dd, J = 6Hz, J = 9Hz, C1-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] sodium is produced. acetamido] -4-isopropyl-2-oxoazetidine-1-sulfonic acid (syn isomer).

IR 0.89 (3H, d, CH ₃₎ COOCH _2), 6.64 (1H (in cm

KBr max '

): 3 300 d, CH ₃

770 to 1 730 and 1 670 1.49 (3H, s, _CH3), 1.52

Nuclear Magnetic Resonance Spectrum (DMSO-d6, 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

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

NMR (DMSO-d₆, 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 2 H), 9.27 (1H, d, J = 9 Hz, C 8 -NH).

I5 for ^C 21 ^H 8 ^N ° 5 ^S 2 ^'3H 2 ° Calculated: 34.81% C 5.26% H 12.53% N Found: 34.51% C,

H, 4.96; N, 13.25.

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 (syn isomer).

IR (6H, s, = 5 Hz, spectrum (in _ma *, cm 2 x CH 3)), 2.63 (3H, C ₄ -H), 5.33 (2H, s,): 3 350, 1780 and 1 670. NMR (DMSO-d₆, 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).

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

IR spectrum (V cm &^lt; -1 ^&gt; ): 3,330.1 (6H, s, 2 * CH3), 2.60 (3H, d, J = 4 Hz,

with.

Η), 7.21 (2H, br s, NH ₂ ).

770 and 1 nhch ₃ ),

760. NMR (DMSO-d₆, ppm): 1.49 4.38 (1H, d, J = 5Hz, _C4-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 63 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 was prepared. -oxoazetidine-1-sulfonic acid (syn isomer).

IR spectrum (? _Max, 2 x _CH3), 2.62 (3H, d, J = 5 Hz, J = 9 Hz, Cg-H)

-1 (· cm): 1

800 and 1650. NMR Spectrum (DMSO-d6, ppm):

= 4 Hz, NHCH ₃ ), 4.40 (1H, d, J = 5Hz, C ₄ -H), 5.33 7.16 (1H, s, Sγ Η), 7.83 (1H, q, J = 4 Hz, NHCH3).

1.50 (6H, s, (1 H, 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 (.delta. _Max 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 removes the amino protecting group. There was thus obtained 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid sodium salt (syn isomer).

IR spectrum teno; 30.06% C, vo-1 (in _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 requires 3.7% H, N, 14.61. Found: C, 30.13; H, 3.71; N, 14.43.

Example 74 (1) Following the procedure of Example 1 (1), trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine, which is produced according to Reference Example 108, is sulfonated to give trans-3-azido-4 sodium salt. -methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid.

IR (νmax cm ^-1 ): 3425, 2125, 1762 and 1730.

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

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

The mixture was stirred at room temperature for 4 hours and then allowed to stand overnight at 5 ° C. 20 ml of water are 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 sodium salt was added thereto.

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

IR (V cm &lt; 3 &gt;: 3,425, 1,760, 1,725 and 1,660).

ΙΠαΧ

Under ice-cooling and stirring, 84 mg of the above product is 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 is dissolved in 5 ml of water and purified by chromatography on an Amberlite XAD-II column (eluent: water, then 10% ethanol) and then on a Sephadex LH-20 column (eluent: water).

The eluate was lyophilized. The lyophilisate 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 was filtered off. The filtrate was lyophilized. Trans-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared. .

and 1,725. NMR Spectrum (D 2 O, ppm): 1.72 (6H, s, COOCH 3), 4.60 (1H, m, C ₄ -H), 5.08 (1H,): 3,375, 1,760

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, C 1 H), 7, 30 (1H, s, S-B).

EXAMPLE 75 (1) In the same manner as in Example 1 (1), the sodium salt of cis-3-benzyloxycarboxKBr-1-amido-4-methoxyaminocarbonyl-2-oxoazetidine-1-sulfonic acid was prepared. IR spectrum (v _max, cm) 3270, 1760 and 1 680. for ^C 13 ^H i4 ^N 3 ^{NaO G 1} · 1 / 2H ₂ O Calculated: 36.97% C, 4.06% H, 9, Found: C, 36.99; H, 4.06; N, 9.97.

s, OCH ₃ ), 4.33 (1H, d, J = 6Hz, C ₄ -H), 5.36 (2H, s, COOCH ₂ ), 6.83 (1H, (2) In the same manner as in Example 1 (3) and (4) produce ois-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) IR spectrum (V _max / cm):

400, 1775, 1730 and 680. 1 H NMR (DMSO-d₆, ppm): 1.51 (6H, s, 2 x CH₃), 3.57 (3 H, _S 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 was prepared. -oxoazetidine-1-sulfonic acid (syn isomer). IR spectrum (cm ^-1 ): 3280, 1770, 1730 and 1670. NMR Spectrum (DMSO-d6, ppm): 1.52 (611, s, 2xCH3), 3.60 (3H, s, OCH-j), 4.34 (1 H, d, J = 6 Hz, C ₄ -H), 5.38 (1 H, dd, J = 6 Hz, J = 9 Hz, C 1 H), 7 14 (1H, s, 5yH), 9.02 (1H, d, J = 9Hz, c ₃ -nh). X

For C ₁₄ H ₁₇ S ₂ Ngo _1Q .2 1 / 2H ₂ O Calculated: 31.23% C 4.12% H 15.61% N Found: 31.06% C,

H, 3.96; N, 15.40.

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) sodium salt was prepared. acetamido] -4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer). IR spectrum (V max ^{'cn | - ^)!}

400, 1750 and 1720.

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

-2-oxoazetidine-1-sulfonic acid (syn isomer). IR (V _max , cm): 1760, 1720 and 1670.

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

The mixture was stirred at -15 ° C for 30 minutes. Then 10 ml ether and 10 ml petroleum ether were added.

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

Fractions obtained by elution with 30% and 40% ethanol are lyophilized. Cis-3-β- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-carbamoyloxymethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) was prepared.

cm ^-1 ): 1,760

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

IR (\) (6H, s, 2 x _CH3), 7.01 (

710 and 630. 1 H NMR (DMSO-d₆, ppm): 1.51 C ₃ -NH).

The following compounds can be prepared in the same manner as in the above examples: cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetamido] -4-acetoxymethyl-2-oxoazetidine-1 disodium salt sulfonic acids (syn isomer), cis -3- [beta] - (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-acetamidomethyl-2-oxoazetidine-1- sulfonic acid (syn isomer), cis-3- [2- (2-amino-4-thiazolyl) -2-carboxymethyloxyiminoacetamido] -4-acetamidomethyl-2-oxoazetidine-1-sulfonic acid disodium salt (syn isomer), disodium salt cis -3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-isopropyl-2-oxoazetidine-1-sulfonic acid (syn isomer), disodium salt cis-3-L2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methoxycarbonylmethyl-2-oxoazetidine-1-sulfonic acid (syn isomer) and disodium salt cis-3- [2- (2-amino-4-thiazolyl) -2- (1-methyl-1-carboxyethyloxyimino) acetamido] -4-methylcarbamoyl-2-oxo azetidine-1-sulfonic acid (syn isomer).

Reference Example 1

Under ice-cooling and stirring, 6.7 ml of propylene oxide and 3 ml of methylene 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. , 24 g of carbobenzoxy chloride. The reaction mixture was stirred at room temperature for 30 minutes.

The solvent was distilled off in vacuo. Ether was added to the residue. The precipitated crystals are aspirated. Cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 115-116 ° C.

For ^ 22 ^Η 24 ^Ν 2 ° 7 ⁱⁿ % C ^: 61 ^/ 67% C, 5.65% H, 6.54% H, 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 was heated to 90-95 with stirring under nitrogen flow. 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 completion of the dropwise addition, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled. The pH of the reaction mixture was adjusted to 6-7 by the addition of potassium hydrogen phosphate.

Acetonitrile and water were distilled off in vacuo. The residue was dissolved in chloroform.

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

Elution with ethyl acetate gave cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, mp 127-128 ° C. For ^ ι ^ ^ Ν ^ Η- Οι- ⁱⁿ YP ^Tenos 56.11 ° C 0 C 5.07% H 10.07% N Found: 56.03% C, 5.01% H, 9th _ø 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 was added 0.8 g of 5% palladium on carbon. The catalytic hydrogenation is carried out at atmospheric pressure with stirring. When the uptake of hydrogen ceased, the catalyst was filtered off. The filtrate was concentrated in vacuo. The residual oil was allowed to stand while cooling to crystallize.

The precipitated crystals are aspirated. 0.38 g of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester (92%) is obtained, mp 59-61 ° C. For C ₅ H _G N ₂ O ₃ Calculated: C 41.66%,

H, 5.59; N, 19.44. Found: C, 41.54; H, 5.59; N, 19.67.

Reference Example 4

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

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

The remaining residue solidified. Water is added to the solidified residue, the mixture is filtered and the crystals obtained are washed first with water, then with ethanol. Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-4-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) was prepared, m.p. 270 DEG-275 DEG C. (dec.).

For C ₁₃ H ₁₄ ClN ₅ O ₈ S: calculated: 38.66% C, 3.49% H, 17.35% N, found: 38.50 ° C,

H, 3.78; N, 17.25.

Reference Example 5

Under ice-cooling and stirring, 250 ml of an aqueous solution containing 2 ml of 2-oxoazetidine-4-carboxylic acid methyl ester of 12-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid are added to a solution of 12 g of methyl ester. 65 g of sodium borohydride. The reaction mixture was stirred at room temperature for five hours.

Tetrahydrofuran was distilled off in vacuo. Water was 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, m.p. Mp 129-131 ° C.

For ^C 21 ^H 24 ^N 2 ^O 6 ^{in P} 2 ^{O 4;} Found:% C, 62.78;% H, 5.91;% N, 7.05.

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 is added dropwise at 0 ° C, at first dropwise, 3.8 ml of pyridine and then 2.04 ml of acetyl chloride. The reaction mixture was stirred for 30 minutes. The solvent was 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 obtained, m.p. 110-111 ° C. For ^C 23 ^H 26 ^N 2 ° ^to 7 ° ^ yP ^theory: 62.63% C 5.92% H 6.33% N Found:

% C, 62.26;% H, 5.68;

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 was heated to 80-83 ° C under a stream of nitrogen with stirring.

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

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

Cis-4-acetoxymethyl-3-benzyloxycarboxamido-2-oxoazetidine, m.p. Mp 137-138 ° C. H, 5.52; N, 9.59. Found: C, 57.38; H, 5.43.

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 was added 1.5 g of 5% palladium on carbon. The mixture is catalytically reduced under stirring at atmospheric pressure. The reaction is complete in 30 minutes. The catalyst was filtered off. The filtrate was evaporated to dryness in vacuo.

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

IR spectrum (cm @ -1: 3,300, 1,770-1,710). NMR spectrum (CDCl3 ppm): 1.83 (br s,

-NH 4), 2.1 (s, -CH 4), 3.6 to 4.1 (m, 4.1 to 4.8 (m, C 1 H-and C 1 H), 6.0 up 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 was 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 was stirred at room temperature for two hours. The solvent was then distilled off in vacuo. The remaining residue solidified. Water was added to the solidified residue and the mixture was filtered.

The crystals were washed successively with aqueous sodium bicarbonate solution, water, ether and dried. Cis-4-acetoxymethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine (syn isomer) was prepared, m.p. Mp 180-190 ° C (dec.).

H, 3.86; N, 16.76. Found: C, 39.89;

H, 3.67; N, 16.60.

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 was stirred at room temperature for 30 minutes.

To the reaction mixture were added 100 mL of ethyl acetate and 50 mL of water. The reaction mixture was then acidified with dilute hydrochloric acid. The precipitated crystals are separated. The filtrate was separated into aqueous and organic layers. The organic layer was distilled to dryness in vacuo.

Water was added to the residue and the resulting crystals were filtered off and combined with the crystals obtained above. The combined crystals were 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 obtained, m.p. 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 2 O 22 26

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 was heated to 80-83 ° C with stirring under a stream of nitrogen. 80 ml of an aqueous solution containing 3.46 g of potassium persulfate and 2.09 g of potassium hydrogen phosphate are added dropwise to the solution.

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

The crystals obtained are washed with water, then with ether and dried. Cis-3-benzyloxycarboxamio KBr-1 to 4-methanesulfonyloxymethyl-2-oxoazetidine, mp 132-133 ° C, was prepared. IR spectrum (ν _max cm) ^!

325, 1,770 and 1,690.

Reference Example 12

To 55 ml of methyl ethyl ketone was added 1.4 g of cis-3-benzyloxycarboxamido-4-methanesulfonyloxymethyl-2-oxoazetidine and 4.2 g of sodium iodide. The mixture was stirred at 90 ° C for 2 hours and then at 60 ° C for 12 hours. The solvent was distilled off in vacuo. Shake the residue 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, m.p. Mp 160-162 ° C.

For ^C 13 ^H I2 ^IN 2 ° 3: calculated: 40.02% C, 3.64 H and 7.78% N Found: 40.26 C i,

H, 3.64; N, 7.93.

Reference Example 13

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

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

The crystals were then dissolved in ethyl acetate. Pass the solution through a small column of silica gel. The solvent was distilled off from the eluate in vacuo. 780 mg (90%) of cis-3-benzyloxycarboxamido-4- (1-methyl-5-tetrazolyl-thiomethyl) -2-oxo-etidine are obtained as colorless crystals, m.p. Mp 151-152 ° C. H, 4.63; N, 24.13. Found:

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

Reference Example 14

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

The mixture was stirred at room temperature for two hours. 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 and the product was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate.

The solvent was distilled off in vacuo. Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (anti isomer) was prepared, m.p. Mp 119-129 ° C.

For CjjH ^^ ClNNOOS requires: C, 38.66; C, 3.49; N, 17.34. Found: C, 38.56;

H, 3.60; N, 17.05.

Reference Example 15

With ice-cooling and stirring, 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 is added 2.10 ml of triethylamine. 2.31 g of phenylacetyl chloride in 15 ml of methylene chloride are then added dropwise over one hour.

The reaction mixture was stirred for an additional hour with ice cooling. It is then washed successively with dilute hydrochloric acid, 5% aqueous sodium bicarbonate, aqueous sodium chloride solution, dried over magnesium sulfate and the solvent is distilled off in vacuo.

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

Mp 124-126 ° C.

π

For ^C 22 ^H 24 ^N 2 ° 6 ⁱⁿ php ^: 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 boiled for one hour under reflux.

The reaction mixture was evaporated to dryness in vacuo. The residue was dissolved in ethyl acetate, washed successively with aqueous 5% sodium hydrogen carbonate solution, aqueous sodium chloride solution, 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-3-Phenylacetamido-2-oxoazetine-4-carboxylic acid methyl ester, mp 176-180 ° C, was prepared. XC spectrum (Y max ^{'cm -1): 1790,} 1740 and 655. 1 H NMR (DMSO-d₆, ppm): 3.47 (s, CH ₂ CO and the OCH _3>, 4.20 (d, J = 6 Hz, C (-H),

5.35 (dd, J = 6 Hz, J = 8 Hz, C 1 H), 7.32 (s, C 8 H 8), 8.44 (s, NH), 8.62 (d, J = 8 Hz, CONH).

Reference Example 17

Under ice-cooling and stirring, 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 is added 12 ml of an aqueous solution containing 570 mg of sodium borohydride. The reaction mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1.5 hours.

Tetrahydrofuran was distilled off in vacuo. 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 brine, dried over magnesium sulfate, and the solvent was distilled off in vacuo.

Ether was added to the residue. The precipitated crystals are aspirated. 1.75 g (91%) of cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3-phenylacetamido-2-oxoazetidine are obtained, mp 152-154 ° C. For ^C 2i ^i! 24 ^N ° 5 2 ^{ν ΥΡ θ} ^ ^'*: θηο: 65.61% C, 6.29 H and 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 under stirring at 0 ° C. The reaction mixture was stirred for 2 hours and then left to stand overnight in the refrigerator.

Lactic acid (0.68 ml) 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 sulphate and the solvent is distilled off in vacuo. A mixture of ether and ethyl acetate (5: 1) was added to the residue. The resulting crystals were filtered off. Thus, 2.21 g (91%) of cis-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-4- (p-toluenesulfonyloxymethyl) -2-oxoazetidine are obtained, m.p. 109-110 ° C.

For C ₂ gH, gN _{3 2} O ₇ S Calculated: 62.43% C 5.63% H 5.20% N Found: 62.18 and C 5.72% H 5.07% N

25357?

Reference Example 19

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

After dissolving the residue, the methylene chloride layer was separated and washed with aqueous sodium thiosulfate solution and aqueous sodium chloride solution. 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, mp 181-182 ° C, was prepared. For ^C 21 ^H 23 ³ ' ^N 2 ^O 4 calculated: 51.03% C,

H, 4.69; N, 5.67. Found: C, 51.14; H, 4.64; N, 5.81.

Reference Example 20

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

Cis-4-azidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine, mp 110-111 ° C, was prepared. IR (cm ^): 3270, 2210, 1755 and 650. 1 H NMR (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, _CH2 Ar), 5.28 (q, J = 5Hz, _C3 -H), 6.40 6.80 (m, ArH 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 at room temperature and atmospheric pressure for 1.5 hours.

The catalyst was filtered off. The filtrate was distilled to dryness in vacuo. The residue is dissolved in 30 ml of methylene chloride. To the methylene chloride solution was added 0.20 ml of triethylamine under 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 was added to the residue. The resulting crystals were filtered off. Cis-4-acetamidomethyl-1- (2,4-dimethoxybenzyl) -3-phenylacetamido-2-oxoazetidine, m.p. 105-207 ° C.

IR (V cm ^-1 ): 3270, 1750 and 1640.

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 hosphate in 15 ml of water and 15 ml of acetonitrile is boiled for 1.5 hours under reflux.

25357?

The reaction mixture was concentrated in vacuo. The concentrate was dissolved in ethyl acetate. The solution was washed successively with aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The ethyl acetate solution was 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-4-acetamidomethyl-3-phenylacetawido-2-oxoazetidine, mp 200-202 ° C, was prepared. IR (cm ^_1): 3250, 1750, 1640 and 1 520th

Nuclear Magnetic Resonance Spectrum (DMSO-d6, ppm): 1.77 (s, COCH-j), 3.11 (m, CH, N), 3.69 (dt, J = 5 Hz, J = 6 Hz, C, 6) -H), 5.00 (dd, J = 5 Hz, J = 8 Hz), 7.26 (s, C 8 H 4), 7.59 (m, NH), 8.20 (broad band)

8.75 (d, CONH, J = 8Hz).

Reference Example 23

To 200 ml of benzene was 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, O] -7-undecene. The mixture was refluxed for 72 hours. Ethyl acetate (100 ml) was added to the reaction mixture with 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. Ethyl acetate (50 ml) was added to the residue. The resulting insoluble material was filtered off and washed with 30 mL of ethyl acetate.

6.4 g of crude product are obtained, which is crystallized from 220 ml of ethyl acetate to give trans-1- (2,4-dimethoxybenzyl) -3-phthalimido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 186-188 ° C.

For ^{C22 of manufacture} 20 ^N 2 ° ^to 7 ° ^ yP ^theory: 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 was 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 is added dropwise with ice-cooling and stirring. The mixture was stirred for an additional two hours.

The reaction mixture was filtered. To the filtrate was added 5 g of triethylamine and a solution of 11 g of phthalimidoacetyl chloride in 110 ml of methylene chloride. The mixture was 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. The 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) are obtained.

A portion of the product was purified by silica gel column chromatography. The product is obtained in the form of a colorless foam. However, the above-mentioned crude product is used for the following processing.

IR spectrum (V ™ ¹⁰¹ , cm ^-1 ): 1770 and 1720. NMR spectrum (CDCl ₃ , ppm): 4.26 (1H, d,

J = 5 Hz, C ₄ -H), 5.63 (1H, d, J = 5 Hz, C-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 was added 3.7 g of methylhydrazine. The mixture was stirred overnight at room temperature. The reaction mixture was filtered. The filtrate was distilled off under reduced pressure.

Ethyl acetate was added to the residue. Insoluble material was removed by filtration. The filtrate was extracted in two portions of 100 ml of 1N hydrochloric acid. The extracts were neutralized with sodium bicarbonate. The resulting solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was 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) were prepared. IR spectrum ^{(cm -1): 3 48} θ ^{1 and} 750. ^NMR (CDC1 _3, ppm): 3.83 and 3.93 (2 x 3H, 2 x s, 2 x OCH).

In a similar manner, trans: 3-amino-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester (oil) was prepared. IR (V ^{cm @ -1} ): 3400, 3330 and 1760.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 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 = 2Hz, C ₄ -H), 4.95 (2H, q, J = 14 Hz, _CH2).

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 is added first with 1.8 g of propylene oxide and then with stirring. 5 g of carbobenzoxy chloride.

The mixture was warmed to room temperature. Stir at this temperature for one hour. The solvent was evaporated under reduced pressure. Isopropyl ether was added to the residue. The resulting crystals were filtered off. This gave 11.7 g (83.5%) of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid butyl ester 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 prepared: trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester. Since this product does not crystallize in the same treatment as above, it was purified by silica gel column chromatography (eluting with hexane / ethyl acetate 1: 1).

net -1

A colorless oil is produced. Yield 89%, IR (in _max cm): 3,340,

770, 1740 and 720. 1 H NMR (CDC1 _3, ppm) 3.93 (1H, d, J = 3 Hz, _C4-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 was refluxed under argon for one hour.

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 bicarbonate solution, aqueous sodium chloride solution and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a 1: 1 mixture of ethyl acetate and hexane. Crystals of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid butyl ester, m.p. Mp 112-113 ° C.

For ^C 16 ^H 20 ^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.

Similarly prepared trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. 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 was added 640 mg of 10% palladium on carbon. The mixture is catalytically hydrogenated under stirring at normal pressure. When hydrogen uptake is complete, the catalyst is filtered off from the reaction mixture.

The filtrate was concentrated under reduced pressure. The residue crystallized. This gives 330 mg (87.1%) of cis-3-amino-2-oxoazetidine-4-carboxylic acid butyl ester. A portion of the product was recrystallized from ethyl acetate and hexane.

Orange colored flaky crystals, m.p. Mp 87-89 ° C. H, 7.57; N, 15.04. Found: C, 51.35; H, 7.58; N, 14.80.

In a similar manner, trans-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 135-136 ° C.

Reference Example 29

To a solution of 2-hydroxyiminoacetacetic acid methyl ester (13.6 g) in acetone (70 ml) was added potassium carbonate (20.8 g) under ice-cooling. 17.0 g of propyl iodide are added dropwise over 30 minutes. After the dropwise addition, the mixture was stirred at room temperature for 2 hours. Acetone was evaporated under reduced pressure.

250 ml of water are added to the residue. The mixture was extracted with methylene chloride. The extract was washed twice with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. 2- (Propoxyimino) acetic acid methyl ester was prepared as a pale yellow oily product.

IR spectrum (cm ^-1 ): 2 975, 1 750, 1 695 and 1 600. NMR spectrum (CDCl 3, ppm):

max j

0.95 (3H, t, J = 7Hz, CH ₂ CH ₂ CH _3), 1.75 (2H, sextet, J 7Hz, CH ₂ CH ₂ CH _3), 2.38 <3H, s,

CH ₃ CO ₃ , 3.86 (3H, s, COOCH-j).

The following compounds were prepared in a similar manner:

2- (butoxyimino) acetacetic acid methyl ester, pale yellow oily product, 80% pure. IR spectrum (V

975, 1755, 1700 and 600. 1 H NMR (CDC1 _3, ppm): 0.94 (3H, t, J = 6Hz, CH ₂ CH ₂ CH ₂ CH _3), 1.2 to 2.0 4 4H, m, CH ₂ CH ₂ CH ₂ CH ₃ , 2.36 (3H, s, CH ₃ CO), 3.85 HH, s, COOCH,, 4.29 (2H, t, J = 6 Hz, CH ₂₎ CH ₂ CH ₂ CH ₃ ) and methyl 2-benzyloxyiminoacetate acid, light yellow oily product, 98% yield. IR spectrum (neat, _{cm -1} ). and 750 and 690. 1 H NMR (CDC1 _Q, ppm): 2.36 (3H, max □ s, CH ₃ CO), 3.84 (3H, s, _COOCH3), 5.28 (2H, s, CH ₂ ), 7.27 (5H, s, phenyl protons).

Reference Example 30

To a solution of 7.4 g of 2- (propoxyimino) acetacetic acid methyl ester in 7.4 ml of acetic acid is added 5/5 g of sulfuryl chloride. The mixture was stirred at 40 ° C for 10 minutes and then at room temperature for 6 hours. 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) acetacetic acid methyl ester (pale yellow oily product) were obtained. IC spectrum (ν max cm -1): 2980, 1750, 1720 and 1595.

Nuclear Magnetic Resonance Spectrum (CDCl 3, 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 = 7Hz, CH ₂ CH ₂ CH ₃₎

4.56 (2H, s, ClCH ₂ ).

In a similar manner, the following compounds were produced:

4-Chloro-2- (butoxyimino) acetic acid methyl ester, pale yellow oily product, 92% yield. IR (vmax): &^lt; ¹ & gt ^{; 2975 '1 750 <1 720 and 1 595} · ^NMR (CDC1 _3, ppm): 0.97 (3H, t, J = 6Hz, 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 4-chloro-2-benzyloxyiminoacetoctové acid, pale yellow oily product, yield 97%. IR spectrum (V ^cm 5: 1755 and 1720). NMR spectrum (CDCl ₃ , ppm): 3.87 (3Η, s, COOCH ₃ ), 4.50 (2H, s, p1CH ₂ ), 5.29 ( 2H, s, _CH2 phenyl), 7.28 (5Η, s, Ph).

Reference Example 31

To a mixture of 20 ml of water and 25 ml of ethanol is added 7/0 g of 4-chloro-2- (propoxyimino) acetic acid methyl ester, 2.4 g of thiourea and 4.3 g of sodium acetate trihydrate. The mixture was stirred at 40 ° C for one hour. From cooling, the pH of the reaction mixture was adjusted to 6.5 by addition of saturated aqueous potassium carbonate solution. The reaction mixture was then stirred for 30 minutes. The resulting crystals were filtered, washed with water, isopropyl ether and dried. Crystals of 2- (2-amino-4-thiazollyl) - (Z) -2- (propoxyimino) acetic acid methyl ester, m.p. Mp 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 were prepared: 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. M.p. 148-149 ° C.

Reference Example 32

To a solution of 5.0 g of 2- (2-amino-4-thiazolyl) - (Z) -2- (propoxyimino) acetic acid methyl ester in 35 ml of Ν, Ν-dimethylacetamide was added dropwise over 10 minutes while cooling with ice and stirring. 25 g of chloroacetyl chloride. The mixture was stirred at room temperature for one hour, then poured into 200 ml of ice-water.

The 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, m.p. Mp 100 ° C.

H, 4.41; N, 13.14. Found: C, 41.35;

H, 4.34; N, 13.14.

In a similar way, make! 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (butoxyimino) acetic acid methyl ester, m.p. 86-87 ° C, yield 85%; 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (benzyloxyimino) acetic acid methyl ester, m.p. Mp 110-115 ° C, yield 96%.

Reference Example 33

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 is added a solution of 2.23 g of potassium hydroxide (ice) with stirring. 85%) in 20 ml of water. The mixture was stirred at room temperature for 5 hours.

The reaction mixture was then concentrated under reduced pressure. The concentrate was dissolved in 30 ml of water. The solution was washed twice with 30 ml portions of ethyl acetate, then activated carbon was added to the solution. The charcoal is filtered off, the pH is adjusted to 2 by addition of 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 was obtained, m.p.

170-171 ° C (dec.). H, 3.96; N, 13.74. Found: C, 39.34; H, 3.84; N, 13.41.

Similarly prepared 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-butoxyiminoacetic acid, m.p. 167-168 ° C (dec.) And 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-benzyloxyiminoacetic acid, m.p. 160-161 ° C (dec.).

Reference Example 34

To a suspension of 583 mg. 243 mg of triethylamine were added under 2- (2'-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid in 5 ml of methylene chloride under ice-cooling. 416.5 mg of phosphorus pentachloride were added to the mixture. The mixture was stirred at room temperature for 30 minutes. The methylene chloride was 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 was stirred at room temperature for two hours.

The solvent was evaporated. Water (20 ml) was added to the residue. The solution was made slightly alkaline by addition of sodium bicarbonate. The undissolved material was filtered off, washed successively with aqueous sodium bicarbonate solution, water, hexane and ether and dried.

There was thus obtained cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-ethoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 270 DEG-280 DEG C. (dec.). H, 3.86; N, 16.76. Found: C, 39.98; H, 3.80;

16.91% N.

The following compounds were prepared in a similar manner:

cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2- (propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 260 DEG -270 DEG C. (dec.), Cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-isopropoxyiminoaoetamido] -2-oxo-azetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 215 DEG-225 DEG C. (dec.), Cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2- (propoxyimino) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 275 DEG-280 DEG C. (dec.), Cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-benzyloxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer), m.p. 275-285 ° 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 DEG-220 DEG C. (dec.), Cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid butyl ester (syn isomer), m.p. 235 DEG-239 DEG C. (dec.) And trans-3- methyl ester 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-2-oxoazetidine-4-carboxylic acid (syn isomer), m.p. 137-139 [deg.] C., for C ^ ^H H ClNNOCESSCECEOH requires: C, 38.57; H, 4.16; N, 16.07. Found: C, 38.39; H, 4.15; 16.04% N.

Reference Example 35

To a solution of 9.3 g of 2-amino-4-thiazolylacetic acid ethyl ester in 50 ml of N, N-dimethylacteamide was added, with ice-cooling and stirring, 7.91 g of chloroacetyl chloride. The mixture was stirred at room temperature for one hour. Water (300 ml) was added to the reaction mixture. The resulting crystals were filtered off.

The crystals were washed with water, ether, dried over phosphorus pentachloride and weighed. There was thus obtained 2-chloroacetamido-4-thiazolyl + acetic acid ethyl ester (12.1 g, 92%), 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,

H, 4.14; N, 10.86.

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 2-chloroacetamido-4-thiazolylacetic acid ethyl ester. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure.

Water (10 ml) was added to the residue. The resulting aqueous solution was washed with ethyl acetate. The pH of the solution was adjusted to 2 by the addition of 10% hydrochloric acid. The crystals are filtered off, washed with water and dried.

2.2 g (84%) of 2-chloroacetamido-4-thiazolyl-acetic acid are obtained, mp 193-195 ° C. For C ₂ H ₂ ClN ₂ O ₃ S calculated: 35.83% C, 3.01% H, 11.94% N, found: 36.00% C,

H, 3.15; N, 12.24.

Reference Example 37

To a suspension of 1.41 g of 2-chloroacetamido-4-thiazolyl-acetic acid in 30 ml of methylene chloride, 1.5 g of phosphorus pentachloride are added under stirring with ice. The mixture was stirred at room temperature for 40 minutes. Filtration gave 1.7 g (98%) of the corresponding acid chloride hydrochloride (colorless crystals), mp 123-125 ° C (dec.). IR spectrum? Max t 'cm ^-1): 1780 and 1 712th

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 was added 840 mg of sodium bicarbonate followed by 864 mg of the above acid chloride hydrochloride under ice cooling.

The mixture was stirred at room temperature for two hours and then evaporated to dryness under reduced pressure. Water (5 ml) was added to the residue. The insoluble material was filtered off, washed successively with aqueous sodium bicarbonate solution, water, hexane and ether and dried. Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) acetamido] -2-oxoazetidine-4-carboxylic acid methyl ester, m.p. Mp 120-122 ° C.

For ^{C x} 2 ^H 13 ^ClN 4 ° 5 ^S 1 / 2H ₂ O calculated: 38.97% C, 3.82% H, 15.15% N, found:

H, 4.23; N, 15.40.

Reference Example 38

To a solution of 1 g of 1-butyl-2,3-dioxopiperazine in 10 ml of dry methylene chloride is added 0.766 g of trimethylchlorosilane. 0.712 g of triethylamine are added to the mixture in a stream of nitrogen at room temperature. The mixture was then stirred for one hour.

The reaction mixture was cooled to -30 ° C. 0.39 ml of trichloromethylchloroformate was added dropwise to the cooled reaction mixture. The temperature of the mixture gradually increases. The mixture was stirred at room temperature for 30 minutes. 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, followed by 1.19 g of triethylamine. The mixture was stirred at room temperature for one hour. The reaction mixture was cooled to 0 ° C. The solid material obtained by evaporation was added to the reaction mixture. The mixture was stirred at room temperature for two hours, dissolved in ethyl acetate, 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 prepared as a solid in quantitative yield.

IR spectrum (γ cm 5: 1715, 1510 and 1180). NMR spectrum (CDCl 3, ppm): 5.72 (1H, d, J = 6Hz, CHCOOH), 9.70 (1H, d, NH) .

In a similar way, the following two compounds were prepared: D-2- (4-octyl-2,3-dioxo-1-piperazinecarboxamido) -2- (2-thienyl) acetic acid, IR spectrum (cm ^-1 ): 3250 and 1 720.

NMR spectrum (CDCl3, ppm): 5.72 (1H, d, J = 6Hz, CHCOOH), 9.75 (1H, d, J = 6Hz, NH) and

TCRt *

D-2- (4-butyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetic acid, IR (cm ^-1 ): 1715, NMR (CDCl3, 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 with 3 ml of dry Ν 236 mg of dicyclohexylcarbodiimide was added with Ν-dimethylformamide. The mixture was stirred under a stream of nitrogen 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 silica gel column chromatography (200 g, eluting with a 1: 1 mixture of ethyl acetate and chloroform and then a 15: 15: 1 mixture of ethyl acetate with chloroform and methanol).

Cis-3- [D-2- (4-Butyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester was prepared as a mixture of diastereoisomers. Experimentally, the first eluted compound in the above column chromatography is called the beta-isomer, the second eluted compound is the alpha-isomer. '

Beta-isomer: IR spectrum (cm -1): 3280, 1780, 1715 and 1680. NMR spectrum (CDCl3, ppm): 3.12 (3H, s, COOCH2), 7.24 (5H). , br s, phenyl protons).

Alpha-isomer: 1 H NMR (CDCl ₃ ): 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 (cm ^-1 ): 3,300, 1,775, 1,710 and 1,675. NMR Spectrum

CDCl ₃ , ppm): 3.30 (3H, s, COOCH 3).

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 3, ppm): 3.31 (3H, s, COOCH ₃ ), 4.42 (1H, d, J = 5 Hz, c ₄ -h).

Alpha-Isomer: NMR Spectrum (CDCl 3, 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 (cm ^): 3280, 2920, 1780, 1710 and 670. 1 H NMR (CDC1 _3, ppm): 3.68 (3H, s, COOCH _3), 4, 14 (1H, d, J = 2Hz, C ₄ -H).

Alpha-Isomer: IR and NMR spectra are identical to those 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 was added 2.7 ml of propylene oxide while cooling with ice and stirring. A solution of 0.83 ml of 2,2,2-trichloroethyl chloroformate in 1 ml of methylene chloride was then added dropwise over 10 minutes. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue crystallized. The crystals were 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, m.p. Mp 135-136 ° C. For C: yHH ^Cl ^ yOO calculated:

H, 4.34; N, 6.34. Found: C, 43.64; H, 4.42; N, 6.16.

Reference Example 41

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 was added a solution with ice cooling and stirring. 228 mg of sodium borohydride in 10 ml of water. The mixture was stirred under ice-cooling for 10 minutes and then at room temperature for 4.5 hours. Excess sodium borohydride was quenched by the addition of 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 bicarbonate solution, saturated aqueous sodium chloride solution, dilute hydrochloric acid, 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 a 2: 1 mixture of ethyl acetate and chloroform). The eluate solvent was distilled off. Ether was added to the residue. The resulting crystals were filtered off. Produces i

cis-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-3- (2,2,2-trichloroethoxycarboxamido) -? - oxoazetidine, mp 112-114 ° C. For Ig ^{C H C} l3 i9 ^N 2 ° ^to 6 ° ^YP-theory: 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 at room temperature for 50 minutes. Water and ethyl acetate were added to the mixture and the pH was adjusted to 2 by addition of 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. Ether was added to the crystals and the crystals were filtered off. 375 mg (94%) of colorless crystals of cis-1- (2,4-dimethoxybenzyl) -4-methanesulfonyloxymethyl-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. 139-140 ° C. H, 4.07; N, 5.39. Found: C, 39.21; H, 4.16; N, 5.48.

Reference Example 43

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 was stirred under nitrogen flow for 20 minutes under stirring. a solution of 7.79 g of potassium persulfate and 4.70 g of potassium hydrogen phosphate in 180 ml of water is added dropwise at 85-90 ° C. The mixture was stirred for another 2.5 hours at the same temperature. After cooling, the pH of the solution was adjusted to 6-7 by the addition of potassium hydrogen phosphate. The product was concentrated under reduced pressure.

The concentrate was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (270 g, eluting with ethyl acetate / hexane 2: 1, then pure ethyl acetate). Colorless crystals of cis-4-methanesulfonyloxymethyl-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, mp 85-86 ° C, were prepared. For C _{1 g of H: 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 was 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 under nitrogen flow for three hours. 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.

Upon evaporation of the solvent under reduced pressure, the residue crystallized. Ether was added to the crystals. The crystals were filtered off. 3.56 g (88.6%) of colorless crystals of cis-3- (2,2,2-trichloroethoxycarboxamido) -4-iodomethyl-2-oxoazetidine are obtained, mp 152-154 ° 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 Ν, Ν-dimethylformamide was added 0.78 g of sodium azide. The mixture was stirred at room temperature for 43 hours and an additional 260 mg of sodium azide was added. The mixture was stirred for an additional 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 brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150 g, eluting with a 1: 1 mixture of ethyl acetate and hexane). Colorless crystals of cis-4-azidomethyl-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p.

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 was added 560 mg of 5% palladium on carbon. The mixture was stirred in a stream of hydrogen at room temperature for two hours. The catalyst was filtered off. The filtrate was evaporated under reduced pressure. The residue is dissolved in a mixture of 10 ml of methylene chloride and 10 ml of Ν, Ν-dimethylacetamide. 2.45 ml of propylene oxide and 0.50 ml of acetyl chloride are added successively to the solution under ice-cooling and stirring. The mixture was stirred at room temperature for 2 hours.

The solvent was distilled off under reduced pressure. To the residue was added 50 ml of saturated aqueous sodium chloride solution. The reaction mixture was extracted with ethyl acetate / tetrahydrofuran (4: 1). The extract was washed sequentially 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 are added to the residue.

The mixture was allowed to stand overnight with cooling. The resulting crystals were filtered off and washed with ether. Cis-4-acetamidomethyl-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. 178 DEG-180 DEG. H, 3.64; N, 12.63. Found:

% C, 32.83;% H, 3.60;% N, 12.79.

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 was added 3.0 g of activated zinc. 6 ml of an aqueous solution of phosphoric acid-potassium dihydrogen phosphate (1 molar concentration) was added to the mixture. Stir for 8 hours at room temperature. To the reaction mixture was added 30 mL of tetrahydrofuran. The zinc was filtered off. The filtrate was evaporated under reduced pressure. Water (15 ml) and ethyl acetate (20 ml) were added to the residue and the mixture was shaken.

The aqueous layer was separated and concentrated to a volume of 11 ml under reduced pressure. To the concentrate was added 11 mL of tetrahydrofuran. 282 mg of sodium bicarbonate and 559 mg of 2- (2-chloroacetamido-1,4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride were added to the mixture with ice-cooling, with stirring. The mixture was stirred under ice-cooling for one hour. Then, 2 g of sodium bicarbonate and saturated aqueous sodium chloride solution are added. The mixture was extracted with ethyl acetate-tetrahydrofuran.

The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, a residue crystallized. The crystals were mixed with ethyl acetate and ether, and the mixture was filtered. Colorless crystals of cis-4-acetamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine (syn isomer) are obtained which show no specific tt, decomposing gradually as coloring at temperatures between 140 and 165 ° C.

1.73 (1 H,

IR (V * _ax cm (3H, s, COCH _3), 3.6 to quartet, J = 5 Hz, J): 3380, 3250, 1760 and 600. 1 H NMR (DMSO-d _g , ppm):

4.0 (1H, m, C.-H), 3.90 (3H,

OCH3, 4.33 (2H, s, CH2), 5.16

Hz, C ₃ -H), 7.46 (1H, s, H).

Reference Example 48

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 in 20 ml of tetrahydrofuran. 0.471 ml of azodicarboxylic acid diethyl ester are added to the solution. acid. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure. The residue crystallizes.

Ethyl acetate (30 ml) was added to the solid crystallized residue. The insoluble material was filtered off, washed with ethyl acetate to give 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. This gave an additional 280 mg of colorless crystals. The overall yield is 1.16 g (87.8%), m.p.

Mp 182-184 ° C. For ^C 29 ^H 27 ^N 3 ° 7 ⁱⁿ YP ° C ^: 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 was refluxed for 3.5 hours. The reaction mixture was cooled. The precipitated crystals are filtered off. The filtrate was concentrated under reduced pressure. To the residue is added 30 ml of methylene chloride. The insoluble material was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate. The solvent was 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.

1.4 ml of propylene oxide and then 0.28 ml of acetyl chloride are added to the solution under ice-cooling. The mixture was stirred at room temperature for 1 hour. To the mixture was added 10 mL of methylene chloride and 50 mL of aqueous sodium bicarbonate solution. Shake the mixture. The methylene chloride layer was separated, washed sequentially with water, dilute hydrochloric acid, a 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 (100 g, eluting with chloroform / acetonitrile 4: 1, then 3: 2). The solvents were distilled off from the eluate under reduced pressure. Ethyl acetate / ether (1: 3) was added to the residue. The precipitated crystals are aspirated.

There was thus obtained 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.

Similarly prepared cis-3-benzyloxycarboxamido-4-benzamidomethyl-1- (2,4-dimethoxy benzyl) -2-oxoazetidine, m.p. Mp 112-115 ° C.

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 was added dropwise a solution of potassium persulfate (1.080 g) and potassium hydrogen phosphate (653 mg) in 25 ml. of water for 15 minutes under a stream of nitrogen while refluxing the reaction mixture. The reaction mixture was refluxed for 1.5 hours. It is then neutralized with aqueous sodium bicarbonate solution and concentrated under reduced pressure.

The residue was extracted with ethyl acetate / tetrahydrofuran (1: 1). The extract was washed with aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off. Ethyl acetate was added to the residue. The precipitated crystals are filtered off. Cis-4-acetamidomethyl-3-benzyloxycarboxamido-2-oxoazetidine, m.p. Mp 226-228 ° C.

Similarly prepared cis-3-benzyloxycarboxamido-4-benzamidomethyl-2-oxoazetidine, m.p. Mp 209-211 ° C.

Reference Example 51

To a suspension of 364 my cis-X-aceterriiciomethyl-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 under stirring, room temperature and normal pressure. The catalyst was filtered off. The solvent was 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. 315 mg of sodium bicarbonate and then 624 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride were added to the mixture with stirring and ice-cooling.

The mixture was then stirred under ice-cooling for one hour. The reaction mixture was then shaken successively with saturated aqueous sodium chloride solution, aqueous sodium bicarbonate solution and ethyl acetate / tetrahydrofuran (2: 1). The organic layer was separated. The aqueous layer was extracted four times with a 2: 1 mixture of ethyl acetate and tetrahydrofuran. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue crystallized.

Ethyl acetate / ether (1: 2) was 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 obtained which do not have a distinct melting point but gradually they decompose at temperatures ranging from 140 to 165 ° C. The @ 1 C and NMR spectra of this product are identical to the IR and NMR spectra of the product produced in Reference Example 47.

Similarly, cis-4-benzamidomethyl-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxymethoxyacetamido] -2-oxoazetidine (syn isomer) was prepared. This product does not have a specific melting point, but decomposes gradually with coloration at temperatures in the range of from 130 to 150 ° C.

IR (cm ^-1): 3420, 3260, 1755 and 1 660. For ^C 19 ^H 19 ^C1N 5 ^S 6 ° Calculated: 47.65% C,

H, 4.00; N, 17.55. Found: C, 47.48; H, 3.86; N, 17.26.

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 was added, with stirring and ice-cooling, 1.3 mL of an aqueous solution of 189 mg of sodium borohydride. The mixture was stirred under ice-cooling for 80 minutes. The excess sodium borohydride is then decomposed with acetic acid. Tetrahydrofuran was distilled off under reduced pressure. A saturated aqueous sodium chloride solution was added to the residue, and the mixture was extracted with ethyl acetate.

The extract was washed with a 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 a 4: 1 mixture of ethyl acetate and acetonitrile). Colorless crystals of cis-3-benzyloxycarboxamido-4-hydroxymethyl-2-oxoazetidine, m.p.

Mp 103-104 ° C. For ^C 12 ^H 14 ^N 2 ° ⁴ yP ^octene: 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 was filtered off. The filtrate was concentrated under reduced pressure and allowed to stand with cooling. The residue crystallizes. The crystals were filtered off. 108 mg (93%) of cis-3-amino-4-hydroxymethyl-2-oxoazetidine are obtained, m.p. 105-107 ° 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 was added 0.4 ml of triethylamine under ice-cooling and stirring. 2- (2-chloroacteamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride. The mixture was stirred under ice-cooling for one hour. 20 ml of water are then added and the pH is adjusted to 7-8 with sodium bicarbonate. The reaction mixture was concentrated under reduced pressure.

The residue was extracted with ethyl acetate / tetrahydrofuran (2: 1). The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue crystallizes. Ethyl acetate / ether (1: 2) was added to the crystallized residue. The crystals were filtered off. Yellow crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetamido-4- [2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-] were prepared. methoxyiminoacetoxymethyl-2-oxoazetidine. m.p. 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,

H, 3.27; N, 17.22.

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 was added dropwise to the reaction mixture at reflux for 10 minutes. 716 mg of crystalline sodium phosphate dibasic and 1.08 g of potassium persulfate in 20 ml of water, the reaction mixture is refluxed for a further 30 minutes, after cooling of the reaction mixture, acetonitrile is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. aqueous sodium bicarbonate solution, 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 (20 g, eluting with 1: 2 chloroform: ethyl acetate). Cis-3- (2,2,2-Trichloroethoxycarboxamido) -2-oxoazetidine-4-carboxylic acid methyl ester (colorless crystals), mp 140-141 ° C, was prepared. For C 8 H 11 Cl ₂ K _? O _f . calculated: 30.07% C, 2.84% H,

N, 8.77. Found: C, 30.30; H, 2.82; N, 8.87.

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 was added a solution of 417 mg of sodium borohydride in 20 ml of water under cooling with ice. . The mixture was stirred under ice-cooling for 30 minutes and at room temperature for one hour. Tetrahydrofuran was distilled off under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed twice with aqueous sodium chloride solution and dried over anhydrous magnesium sulfate.

The solvent was distilled off. The residue crystallizes. Ether was added to the crystallized residue. The crystals were filtered off. Cis-4-hydroxymethyl-4- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. Mp 162-164 ° C. IR (vmax): 3450, 3300, 1720 and 1700.

cm

Reference Example 57

To a solution of 468 mg of 2-thienylacetic acid in 7 mL of dry methylene chloride was added 424 mg of thionyl chloride. The mixture was refluxed for two hours. The reaction mixture was evaporated under reduced pressure. The residue is dissolved in 5 ml of dry methylene chloride.

In addition, to a solution of cis-4-hydroxymethyl-3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 30 mL of dry methylene chloride was added 416 mg of triethylamine. Methylene chloride solution of the above-prepared 2-thienylacetyl chloride was added dropwise to this mixture with stirring and ice-cooling. the resulting mixture was stirred under ice-cooling for 20 minutes and then stirred at room temperature overnight. 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 was purified by silica gel column chromatography (60 g, eluting with hexane / ethyl acetate (1: 1 and 2: 3)) to give cis-4- (2-thienylacetoxymethyl) -3- (2,2,2-trichloroethoxycarboxamido). ) -2-oxoazetidine NMR Spectrum (CDCl3, ppm): 3.92 (2H, s

OCCH "),

I ²

O

4.71 (2H,

CClgCHg), 5.14 (1H, dd,

J = 5 Hz, J = 9 Hz, Cn-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 1N aqueous ammonium acetate solution is added 2.16 g of activated zinc . The mixture was stirred at room temperature for 5 hours. The mixture was filtered through celite. Methylene chloride was added to the filtrate. The solution was dried over anhydrous magnesium sulfate. The filtrate was 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 are added to the solution under ice-cooling. 720 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride was added.

The reaction mixture was stirred vigorously for 15 minutes under ice-cooling. After stirring vigorously at room temperature for 1 hour, the solvent was distilled off under reduced pressure. Water was added to the residue. The precipitated crystals were filtered off and washed successively with water, aqueous sodium bicarbonate solution, ether and hexane. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-thienylacetoxymethyl) -2-oxoazetidine (syn isomer), m.p. 201 and 204 ° C (dec.).

IR (cm ^): 3280, 1760 and 660. 1 H NMR (DMSO-d₆, ppm): 3.86 (3H, s, _OCH3), 3.90 (2H, s, ₂ occhi) , 4.32 (2H, s, ClCH _2), 7.48 (1H, s, SH).

O X

Reference Example 59

To a solution of 314 mg of 1-methyl-1H-tetrazol-5-yl-mercaptan in 2 ml of dry Ν, Ν-dimethylformamide was added 65 mg of sodium hydride under ice-cooling. The mixture was stirred under ice-cooling for 10 minutes and at room temperature for 10 minutes. A solution of 724 mg of cis-3- (2,2,2-trichloroethoxycarboxamido) -4-iodomethyl-2-oxoazetidine in 3 ml of Ν, Ν-dimethylformamide was added to the mixture. The reaction mixture was stirred at room temperature for two days. The reaction mixture was dissolved in ethyl acetate, washed five times with water, then brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (60 g, eluting with 1: 2 and 1: 4 hexane: ethyl acetate).

610 mg (86.8%) of crystals of cis-4- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine, m.p. 68 ° C. IR spectrum (in ™ ^:

300 and 1 740.

Reference Example 60

To 10 ml of tetrahydrofuran was added 1.49 ml of a solution of methyl mercaptan in 4N tetrahydrofuran. Under ice-cooling, a solution (1.37 ml) of butyllithium in (1.6N) hexane was then added dropwise. The mixture was stirred for 10 minutes under a stream of nitrogen while cooling with ice. The mixture was then cooled to -45 ° C. To the cooled mixture was 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 gradually increases to -20 to -30 ° C.

At this temperature, the reaction mixture was stirred for 4 hours. 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, eluting with 2: 1 and 1: 1 hexane: ethyl acetate) to give cis-4-methylthiomethyl-3- (2,2,2-trichloroethoxycarboxamido) -2 crystals. -oxoazetidine, mp Mp 114-115 ° C

IR ^(KBr, cm ^-1): 3350, 1780 and 1 715. ^Tmax '

Reference Example 61

To a solution of 674 my cis-4- (1-methyl-1H-tetrazol-5-yl-thiomethyl) -3- (2,2,2-trichloroethoxycarboxamido) -2-oxoazetidine in 10 mL tetrahydrofuran was added 2 mL IN aqueous solution ammonium acetate. To the mixture was added 1 g of activated zinc. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. Methylene chloride was added to the filtrate. The solution was dried over anhydrous magnesium sulfate and the solvent was 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 was added 1.02 g of sodium bicarbonate under ice-cooling. 863 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride was added.

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 precipitated crystals are suction filtered, 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-yl-thiomethyl) -2-oxoazetidine (syn isomer) were prepared. mp 195-198 ° C (dec). IR ( ^vmax): 270, 1760 and 1660.

Similarly prepared cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-methylthiomethyl-2-oxoazetidine (syn isomer), m.p. M.p. 172-176 ° C (dec.).

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 at 90 ° C for 6 hours. The solvent was distilled off under reduced pressure. 150 ml of ethyl acetate and 100 ml of water are added to the residue and the mixture is shaken. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. The resulting solid residue was recrystallized from 50 mL of 1: 1 hexane-ethyl acetate. 850 mg (80%) of colorless needles of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-iodomethyl-2-oxoazetidine are obtained, mp 165-166 ° C. For ^C 21 ^H 23 ^IN 2 ° 5 ⁱⁿ YP ° read: C 49.43, H 4.54, N 5.49, found: C 49.55, H 4.56,

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 was added 1.62 g of sodium cyanoborohydride. The mixture was stirred at 90-100 ° C for 5 hours under a stream of nitrogen. The reaction mixture was added to 250 ml of ether, washed with six 20 ml portions of water, once with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

Ether and hexane were added to the resulting solid residue. The mixture was filtered. There was thus obtained cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-methyl-2-oxoazetidine (2.15 g, 86.7%), mp 130-132 ° C. For ^C 21 ^H 24 ^N 2 ° 5 ⁱⁿ YP ° C ^: 65.61% C, 6.29% H, 7.29% N, found:

H, 6.49; N, 7.53.

Reference, example 64

To the aqueous potassium carbonate solution was added 5.10 g of 2,4-dimethoxybenzyl amine hydrochloride. The resulting oily product is extracted with 120 ml of benzene. The extract was washed with water and dried over anhydrous sodium sulfate. 3.50 g of p-chlorobenzaldehyde are added to the extract. 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 crystallized. The crystals were dissolved in 68 ml of methylene chloride. A solution of 3.8 mL of triethylamine in 20 mL of methylene chloride was added to the resulting solution with stirring at -5 ° C to -10 ° C. A solution of 6.15 g of phthalimidoacetyl chloride in 25 ml of methylene chloride was added dropwise. 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 were added. The resulting mixture was stirred under ice-cooling for 7 hours and then allowed to stand overnight with cooling.

The mixture was washed successively with water, aqueous sodium bicarbonate solution, 5¾ hydrochloric acid, water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.

The residue was purified by silica gel chromatography (60 g, eluting with chloroform / methanol (20 µl)). 9.4 g (84%) of colorless crystals of cis-4- (4-chlorophenyl) -1- (2,4-dimethyoxybenzyl) -3-phthalimido-2-oxoazetidine are obtained. Recrystallization from acetone-hexane gave colorless prisms, mp 178-180 ° C. For ^ 26 ^Η 21 ^ 1 ^Ν 2θ5 ⁱⁿ YP ° ^: % C, 65.46;% H, 4.44;% N, 5.87. Found:% C, 65.42;% H, 4.42; % 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 is added 0.89 ml of methylhydrazine. The mixture was stirred at 35-40 ° C for 17 hours, 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 solution, extracted twice with methylene chloride and saturated aqueous sodium chloride solution.

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 were added to the solution with stirring and ice-cooling. 2.3 g of carbobenzoxy chloride are then added dropwise. The mixture was stirred at room temperature for 2 hours. 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-sulfazetidine are obtained. *

IR spectrum (in ^KBr , cm ^-1 ): 3225, 1759 and 1688. NMR spectrum (CDCl3, 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, _C3 -H), 5.82 (1H, d, J = 9Hz, 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 is added dropwise a solution of 2.42 g of potassium persulfate and 1.46 g of potassium hydrogen phosphate in 75 ml of water 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 brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (200 g, eluting with hexane / ethyl acetate 1: 2).

Crystals of cis-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine, mp 168-169 ° C, were prepared. For ^C i2 ^H 14 ^N 2 ° ³ yP ^octene: 61.53% C 6.02% H 11.96% N Found: 61.36% C, 6.05% H, 11.65% N .

Similarly prepared cis-3-benzyloxycarboxamido-4- (4-chlorophenyl) -2-oxoazetidine.

IR ( ^{cm -1,} 310, 3225, 1772, 1722 and 1684). NMR spectrum (DMSO-d6, ppm):

4.85 (2H, s, CH ₉ ), 7.74 (1H, d, J = 9Hz, OCNH), 8.55 (1H, broad singlet, Ν _Ί -Η), 6.90 to - · *

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 under a stream of hydrogen for one hour. 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 are added to the crystals. 382 mg of sodium hydrogencarbonate were added to the solution under ice-cooling. 453 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride were added with 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 is filtered off, washed with water, aqueous sodium bicarbonate solution, ether and hexane, respectively. There were obtained 276 mg (84%) of crystals of cis-3-β- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido-4-methyl-2-oxoazetidine (syn isomer), m.p. Mp 212-215 ° C (dec.).

and,

IR spectrum (in ^_mA-cm J = 6Hz, C ₄ -CH _3), 3.90 Hz, C ₃ -H), 7.40 (IH, s.

- ^1): 3260, 1755 and 670. 1 H NMR (DMSO-d₆, ppm): 1.16 (3H, (3H, s, _OCH3), 4.36 (2H, s, ₂ C1CH) 5.15 (1H, dd, J = 5Hz, J =

Similarly prepared cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (4-chlorophenyl) -2-oxoazetidine (syn isomer). IR spectrum (cm ^-1): 3250, 1740 and 652. 1 H NMR (DMSO-d₆, ppm): 3.66 (3H, s, _OCH3), 4.30 (2H, s, ₂ C1CH) , 4.96 (IH, d, J = 5 Hz, C ₄ -H), 5.39 (IH, dd, J = 5 Hz, J = 9 Hz), 5.82 (IH, s, SyH) 9.24 (1H, d,

J = 9 Hz, C ₃ -NH). AND

Reference Example 68

To a solution of 1.4 methyl cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid in 14 ml methanol was added dropwise a solution of 0.9 g potassium carbonate in 9 ml water under ice-cooling. The mixture was stirred at room temperature for one hour. The methanol is 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 was added to the crystals and the mixture was filtered. Thus 1.1 g (84.6%) of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid are obtained. Recrystallization from acetonitrile gave crystals of mp 156-157 ° C. For ^C y2 ^H 12 ^N 2 ^O 5 ⁱⁿ yP ° ^{Teno ^!}

% C, 54.54;% H, 4.57;% N, 10.60. Found:% C, 54.55;% H, 4.45;

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 10 minutes, 0.5 mL of a 40% aqueous dimethylamine solution was added to the mixture. The mixture was stirred at room temperature for two hours.

The insoluble material was filtered off and the filtrate was concentrated under reduced pressure. Ethyl acetate and aqueous sodium bicarbonate solution were added to the residue. Shake the mixture. The ethyl acetate layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography. Crystals of cis-3-benzyloxycarboxamido-4- (Ν, Ν-dimethylcarbamoyl) -2-oxoazetidine were prepared.

Ir (^ χθ ¹ 'cm ^-1): 3280, 1785, 1770, 1730, 1690 and 640. 1 H NMR (DMSO-d₆, ppm): 2.77 and 2.80 (2 x 3H, 2 xs, 2 x CH 3), 4.53 (1H, d, J = 5Hz, C ₄ -H), 5.36 (1H, dd, J = 5Hz, J = 9Hz) (C 1 H).

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 is 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 are obtained. 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, mp 160-165 ° C, were prepared. IR spectrum? Max CV ^ '^ ^{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. After stirring for 10 minutes, 100 mL of ethyl acetate and 20 mL of saturated aqueous sodium chloride solution were added to the mixture. The mixture is then further stirred. The organic layer was separated. The aqueous layer was extracted with 30 mL of ethyl acetate. The extract was combined with the organic layer. The combined organic layers were washed with brine (3 x 20 mL), dried, and the solvent was distilled off under reduced pressure.

4 ml of a 1: 2 mixture of solvents (ethyl acetate and hexane) were added to the residue. The precipitated crystals are filtered off and dried. 430 mg (80%) of cis-3- (2-thienylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester are obtained, m.p. Mp 133-136 ° C. For C 10jH, 10N,00OjS: C, 49.43; H, 4.15; N, 10.48. Found: C, 49.00; H, 4.37;

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 Ν, Ν-dimethylacetamide, which is stirred under ice-cooling, is added dropwise.

400 mg of ΙΗ-tetrazol-1-yl-acetyl chloride. The reaction mixture was stirred for thirty minutes. 50 ml of ethyl ether were added to the mixture. Stirring was continued with cooling to -30 C. The upper layer was removed by decantation. The backsheet was treated (twice) as described above. To the mixture was added 10 mL of acetone. The resulting solution was purified by silica gel column chromatography (40 g, x 10 cm), eluting with acetone-methylene chloride (1: 1).

After drying, cis-3- (1H-tetrazol-1-yl-acteamido) -2-oxoazetidine-4-carboxylic acid methyl ester (403 mg, 84%) was obtained. For CGH gNgO ^ ^; 2/3 CH ₃ COCHg calculated: 41.00% C, 4.82% H,

N, 28.69. Found: C, 41.16; H, 5.08; N, 28.65.

Reference Example 73

To a mixture of 697.6 mg of nalidixic acid and 10 ml of methylene chloride, which was stirred at room temperature, 2 ml of thionyl chloride were added and stirring was continued for two hours. The reaction mixture was evaporated to dryness under reduced pressure. The residue is dissolved in 5 ml of Ν, Ν-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 Ν, Ν-dimethylacetamide was stirred under ice-cooling. To this solution is added 5 ml of the above prepared Ν, Ν-dimethylacetamide solution. The mixture was stirred at room temperature for two hours. Insoluble materials are 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 a saturated aqueous sodium chloride solution (3 x 50 mL), dried and distilled to dryness under reduced pressure. The residue is 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,

mp 223-224 ° C. IR spectrum (cm ^-1 ): 3400, 1780, 1765 and 1745.

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 Ν, Ν-dimethylacetamide, which was stirred under ice-cooling, 534 mg of mixed mandelic anhydride and carbonic anhydride was added. The mixture was stirred at room temperature for 30 minutes. Then the mixture was stirred under ice-cooling: To this stirred mixture was added dropwise 1.05 ml of chloroacetyl chloride and stirring was continued for 3 hours at room temperature. The reaction mixture was shaken with 100 ml of ethyl acetate and 20 ml of 1N hydrochloric acid. The organic layer was then separated. The organic layer was washed successively with saturated aqueous sodium chloride solution (3 x 30 mL), 20 mL of 1 N aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution (3 x 30 mL), dried and the solvent was distilled off under reduced pressure.

The residue is purified by silica gel column chromatography. Cis-3- (2-chloroacetyloxy-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester was prepared. IR (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, is added dropwise. -sulfophenylacetyl chloride. The mixture was stirred under ice-cooling for 10 minutes and then at room temperature for one hour. The reaction mixture was 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 was lyophilized. The sodium salt of cis-3- (D-2-sulfo-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester was prepared. For C ^ HH ^N ^NOO ^S. H, 4.12; N, 7.16. Found: C, 39.78; H, 4.48; N, 7.29.

Reference Example 76

A mixture of phenylmalonic acid monobenzyl ester (2.7 g) and thionyl chloride (5 ml) was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. Methylene chloride was added to the residue to give a total volume of 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, which is stirred under ice-cooling.

To this mixture was added dropwise 3 ml of the above-prepared methylene chloride mixture. 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. silica gel column with ethyl acetate / methylene chloride (1: 1). Cis-3- (2-Benzyloxycarbonyl-2-phenylacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester, IR spectrum cm ^-1 ) was ^prepared : 3300, 1780, 1740, 1690, 1530, 1270 , 1 210 and 1 160.

Reference Example

The 3-amino compound, which is prepared from 400 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, in a similar manner to Reference Example 3, is dissolved in 15% of methanol. ml of tetrahydrofuran. 120 mg of cyanoacetic acid was added to the solution, and the mixture was stirred under ice-cooling. 290 mg of dicyclohexylcarbodiimide was added and the mixture was stirred for two hours. The reaction mixture was filtered and the filtrate was concentrated. 30 ml of ethyl acetate were added to the residue, the solution was filtered again and the filtrate was concentrated. The concentrate was purified by silica gel column chromatography (20 g, eluting with ethyl acetate).

Cis-3- (2-Cyanoacetamido) -2-oxoazetidine-4-carboxylic acid methyl ester was prepared.

IR spectrum (cm ^-1): 3300, 2250, 1758 and 680. 1 H NMR (DMSO-d₆, ppm): 3.60 (2H, s, _CH2), 3.67 (3H, s, CH), 4.39 (1H, d, J = 6Hz, C ₄ -H), 5.28 (1H, dd, J = 6 Hz, J = 9 Hz, _C3 -H).

Reference Example

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 was added dropwise a solution 552 with ice-cooling. mg of potassium carbonate in 12 ml of water. The mixture was stirred at room temperature for one hour. 6 ml of 1N hydrochloric acid were added to the reaction mixture. The methanol is distilled off. The remaining aqueous solution was washed with ethyl acetate. The pH is adjusted to 2 by addition of dilute hydrochloric acid.

The product was extracted with ethyl acetate / tetrahydrofuran (1: 2). The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue is suspended in a mixture of 40 ml of methylene chloride and 10 ml of tetrahydrofuran. Pyridine (1.0 mL) was added to the suspension with stirring at room temperature. A solution of 864 mg of p-nitrobenzyl chloroformate in 4 ml of methylene chloride was then added dropwise over 30 minutes, the mixture was stirred at room temperature for 30 minutes, washed successively with water, dilute hydrochloric acid, water, aqueous sodium bicarbonate and aqueous ammonium chloride.

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, eluting with ethyl acetate). Crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid p-nitrobenzyl ester (syn isomer), mp 231-236 ° C (dec. ) IR (cm ^-1): 3250, 1760, 1750, 1670, 1550 and 510. 1 H NMR (DMSO-d₆, 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, _OCH2 Ar), 5.48 (1H, dd , J = 6

ArH), 8.17 (2H, d, J &gt; 9 Hz,

12.87 (1H, br s, C ₁ CH ₂ CONH).

Reference Example

ArH), 8.77 (1H, br s, Nj-H), 9.56 (1H, d, J = 9Hz, C ₃ -NH),

53.2 g of 2-chloroacetamido-4-thiazolylacetic acid ethyl ester are dissolved in a mixture of 510 ml of dioxane and 42.6 ml of acetic acid. 28.3 g of selenium dioxide are added to the mixture. The mixture was stirred at 110-115 ° C for 4 hours. After cooling, the resulting black precipitate was removed. The solution is concentrated under reduced pressure. The residue was dissolved in 3 L of ethyl acetate. The solution was 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 was refluxed to dissolve the precipitate. Hexane (800 ml) was added and the solution was cooled. Two needles of 2-chloroacetamido-4-thiazolylglyoxylic acid ethyl ester, which, after recrystallization from ethyl acetate-hexane, melted at 178-180 ° C, were prepared. IR spectrum (cm-B: 3220, 3000, 1740, 1710, 1680 and 550. 1 H NMR (DMSO-d₆, ppm): 1.31 (3IJ, t, CH ₂ CH _3), 4.55 (2H, q, Cl 2 Cl 2 -), 4.40 (2H, s, C ₁ CH ₂ ), 8.49 (1H, s,

S. / H).

H, 3.28; N, 10.12. Found: C, 39.16; H, 3.21; N, 10.13.

Reference Example 80

35 g of 2-chloroacetamido-4-thiazolyl-glyoxylic acid ethyl ester are suspended in 646 ml of ethanol. 1N aqueous potassium hydroxide solution (250 ml) was added dropwise to the suspension under ice-cooling and stirring. The mixture was stirred at room temperature for one hour. It is then concentrated under reduced pressure to a volume of 200 ml. Water (200 mL) was added and the mixture was washed with 400 mL of ethyl acetate. After decolourising with charcoal, the pH of the solution was adjusted to 1.5 with 10% hydrochloric acid, giving off light yellow crystals.

The crystals are filtered off, washed first with water, then with hexane and dried. 2-Chloroacetamido-4-thiazolylglyoxylic acid was prepared. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 205-210 ^U C (dec.). IR spectrum (cm @ 3: 3,450,

200, 1730-1679, 1680 and 1560. NMR Spectrum (DMSO-d6, ppm): 4.29 (2H, s, CCH3), and 8.30 (1H, s, S3). ). For C ^ H ^ O ^ C1N ₂ S: calculated: 33.81% C, 2.03% H, 11.27% N Found:

% H, 2.04;% N, 11.23.

Reference Example 81

To 50 ml of dry Ν, Ν-dimethylformamide was added 10 g of N-hydroxyphthalimide and 9.38 g of methyl bromoacetate. Then 8.5 g of potassium carbonate are added. The mixture was stirred at room temperature for 2 days and then poured into 400 ml of water. The resulting crystalline precipitate was filtered off, washed with water, then hexane and finally ether. Colorless needles of N-methoxycarbonylmethyloxyphthalimide were prepared. mp 137-142 ° C. CMB IR: 1790, 1760 and 730. 1 H NMR (DMSO-d₆, ppm): 3.71 (3H, s, _COOCH3), 4.8 (2H, s, NOCH _2), 7.77 (4H, s, aromatic protons).

The following compound was prepared in the same manner as above: N - (- nitrobenzyl-).

(KBr oxycarbonylmethyloxy) phthalimide, mp 158-160 C. IR spectrum ( ⁱⁿ m / cm): 1785, 1760 and 1730. NMR spectrum (DMSO-d6, ppm): 4.94 (2H, s, NOCH3). 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 are dissolved in 60 ml of methylene chloride and 745 mg of hydrazine hydrate are added under stirring with ice and stirring. The mixture was stirred at room temperature for 2 hours. Then an additional 149 mg of hydrazine hydrate was added. The mixture was stirred for 2 hours. The resulting crystalline precipitate is filtered off. The filtrate is washed with 15 ml of dilute aqueous ammonia and then with 15 ml of water. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off.

Ether (10 ml) was added to the residue and the insoluble material was filtered off. Concentration of the filtrate gave a light yellow oil of O-methoxycarbonylmethylhydroxylamine.

IR (V CMB: 3320, 2950 and 740. 1 H NMR (CDC1 _Q + DMSO-d ,, ppm):

max o o

3.73 (3H, s, _CH3), 4.2 (2H, s, _CH2) and 6.07 (2H, br s, NH _2).

100 ALIGN!

The following compound was prepared in the same manner as above: O- (p-nitrobenzyloxycarbonylmethyl) -hydroxylamine. IR spectrum ⁽ '5 ^cm: 3325, 1760, 1720 and 1 600th

NMR Spectrum (CDCl3, ppm): 4.33 (2H, s, NOCH3).

Reference Example 83

1.0 g of 2-chloroacetamido-4-thiazolylglyoxylic acid, prepared according to Example 80, are dissolved in a mixture of 20 ml of water and 12 ml of tetrahdyrofuran. 7a Ice-cooling add 465 mg of O-methoxycarbonylmethylhydroxylamine. The pH of the mixture was adjusted to 5 by the addition of 1N aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 20 hours. The pH was adjusted to 7 by the addition of 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 addition of 2N hydrochloric acid. The precipitated crystals are filtered off and washed successively with water, hexane and ether. Colorless crystals of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxycarbonylmethyloxyiminoacetic acid, m.p. Mp 177-179 ° C (dec.).

IR spectrum (cm ^-1 ): 3200, 1750, 1725 and 1690. NMR spectrum (DMSO-d6, ppm):

3.69 (3H, s, COOCH ₃ ), 4.39 (2H, s, CICHJ), 4.71 (2H, s, NOCH 3), 7.41 (1H, s, SH), 12.7 (1H, s, br s, NH)

The following compound was prepared in the same manner as above: 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetic acid, m.p.

Mp 168-170 ° C (dec.). IR ( _CDCl3 , cm ^-1 ): 3200, 1760, 1710 - 1680, 1520.

Nuclear Magnetic Resonance Spectrum (DMSO-d6, ppm): 4.34 (2H, s, CCH 3), 4.84 (2H, s, NOCH 3, 5.33 (2H, s, COOCH ₂ ),

For C 2,8 gHH jClClN OOS S: C, 42.06; H, 2.87; N, 12.27. Found: C, 41.95;

2.86 and H, 12.30% N.

Reference Example 84

810 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxycarbonylmethyloxyiminoacetic acid are suspended in 20 ml of methylene chloride. 602 mg of phosphorus pentachloride are 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 are added under ice-cooling. The resulting crystals were filtered and washed with hexane to give 910 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxycarbonylmethyloxyiminoacetyl chloride hydrochloride, m.p. 77-80 ° C.

Ir (χ ^ ^{'cm -1): 3000, 1775' and 1740 to 1} 695 C _{1 ()} H ₉ C1 ₃ N ₂ O ₅ S.HC1 Calculated: C 30.74 and 2.58% N, 10.76. Found: C, 30.69; H, 3.46; N, 10.89.

The following compound was prepared in the same manner as above: 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetyl chloride hydrochloride, mp 158-161 ° C. IR spectrum <V max 'c® ” ¹ ) ^{! 2940 <1 7θθ '1740 and 1} 680. ^{For C} 16 ^H 12 ^C1 2 ^N 4 ^S · 7 ° .HC1 calculated: 37.55% C 2.56% H 10.59% N Found: 37 % H, 2.65;% N, 10.87.

Reference Example 85

280 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester are dissolved in a mixture of 5 ml of tetrahydrofuran and 5 ml of water. 773 mg of sodium bicarbonate was added to the solution.

910 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxycarbonylmethyloxyiminoacetyl chloride hydrochloride are added under ice-cooling and stirring. The mixture was stirred at room temperature for two hours. Water was added to the reaction mixture. The resulting crystals were 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) was prepared.

m.p. 260 DEG-265 DEG C. (dec.).

i101

IR spectrum (cm ^X): 3290, 2950, 1 780 to 1 730, 1 685 and 1 660 for ^C 15 ^H ₅ O 16ClN _g S: calculated: 39.01% C, 3.49% H, 15 N, Found: 39.00; C, 3.58%, N, 15.06%.

The following compound was prepared in the same manner as above: cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2- (p-nitrobenzyloxycarbonylmethyloxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine (syn isomer), m.p. 270 DEG-275 DEG C. (dec.).

IR spectrum (γ cm 5: 3,250, 1,760, 1,700, and 1,675) For ^C 21 ^{H 19 ClN} 6 ° 10 ^S calculated:

Found:% C, 42.85;% H, 3.38;% N, 14.27.

Reference Example 86

15.3 g of p-nitrobenzyl alcohol are dissolved in 250 ml of dry ether. Pyridine (8.90 ml) was 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 was stirred at room temperature for 5 hours. The resulting crystalline precipitate was filtered off and washed with ether: the filtrate with washed ether was combined and 150 ml of ethyl acetate were added to this solution. The mixture was washed successively with dilute hydrochloric acid, water, aqueous sodium bicarbonate, brine and dried over anhydrous magnesium sulfate.

The solvent was then distilled off under reduced pressure. The residue is chromatographed on silica gel (600 g silica gel column, eluting with 1: 1 chloroform: hexane). This gives 29.6 g of a yellow oil of alpha-bromoisobutyric acid p-nitrobenzyl ester. This product solidifies over time on cooling. IR spectrum ( ^{cm -1} 735, 1520,

345 and 150. 1 H NMR (CDCl _g, ppm): 1.96 (6H, s, 2 x methyl), 5.27 (2H, s, COOCH ^), 7.49 and 8.13 (2 x 2H, 2 xd, aromatic protons).

Reference Example 87

14.7 g of N-hydroxyphthalimide and 27.2 g of alpha-bromoisobutyric acid p-nitrobenzyl ester are dissolved in 75 ml of dry Ν, Ν-dimethylformamide. To the solution was added 12.4 g of potassium carbonate. The mixture was stirred at room temperature for one hour. As stirring becomes increasingly difficult due to the drop of an orange-colored solid, 75 ml of Ν, Ν-dimethylformamide are added to the mixture. The mixture was stirred at room temperature for 24 hours. The volume of the reaction mixture was reduced to about half the original volume by distilling off the solvents, and the concentrate was poured into 700 ml of water under ice-cooling and stirring. The mixture was stirred for 30 minutes. The resulting crystalline precipitate was 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 prepared, m.p. Mp 145-146 ° C.

IR spectrum _(m ^ from CNI): 1790, 1740, 1735, 1520 and 345. 1 H NMR (DMSO-d₆, ppm): 1.61 (6H, s, 2 x CH _3), 5 , 28 (2H, s, NOCH ₂ ), 7.59 and 8.10 (2 x 2H, two doublets,

NO ₂ ), 7.75 (4H, s, (

For _Ig C H ₁₆ N ₂ O ₇ vypčoteno: 5R, 38% C, 4.20% H? N, 7.29. Found: C, 59.14; N, 4.27. N, 7.26.

102

Reference Example 88 was dissolved in 80 ml of methyl chloride. 7.68 g of N- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxy] phthalimide was dissolved. 0.97 ml of hydrazine hydrate are added under ice-cooling and stirring. The mixture was stirred for two. hours of room temperature. An additional 0.97 ml of hydrazine hydrate was then 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 1: 1 ethyl acetate: hexane). 4.58 g of a yellow oil of O- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl] hydroxylamine are obtained. This product solidifies upon cooling.

IR spectrum (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 3) ), 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

1.49 g of 2-chloroacetamido-4-thiazolglyoxylic acid are dissolved in a mixture of 30 ml of water and 18 ml of tetrahydrofuran. While cooling with ice and stirring, 1.83 g of O- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyl) hydroxylamine are added. The pH of the mixture was adjusted to 5.0 by addition of aqueous 1N sodium hydroxide. The mixture was stirred at room temperature for 12 hours. The aqueous sodium bicarbonate is then adjusted to pH 7. Tetrahydrofuran is distilled off under reduced pressure. The remaining aqueous solution was washed with ether, the pH was adjusted to 2 with dilute hydrochloric acid and the product was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

The residue was dissolved in ether and poured into twice the volume of petroleum ether. The resulting powdery precipitate was filtered off. 2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2- [1-methylKBxr-1] was prepared.

-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetic acid. IR spectrum (in _mA]] r cm): 1740,

695, 1540, 1520 and 345. 1 H NMR (CDCl-j, ppm): 1.61 <6H, s, 2 x CH₃), 4.29 (2H, s, C1CH _2), 5.23 ( 2H, s, NOCH3, 7.26 (1H, s, S, H), 7.43 and 8.05 (2 * 2H) (2 * d, aromatic protons).

Reference Example 90

1,445 g of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetic acid are dissolved in 15 ml of methylene chloride. 686 mg of phosphorus pentachloride are added under ice-cooling and stirring. The mixture was stirred for thirty minutes under ice-cooling. 4.5 ml of hexane are then added to the mixture. The resulting crystalline precipitate was filtered off and washed with hexane. 2- (2-Chloroetamido-4-thiazolyl) - (Z) -2- [1-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetyl chloride hydrochloride was prepared, m.p. Mp 79-82 ° C.

IR spectrum (cm ^-1 ): 2,998, 1,775, 1,735, 1,715, 1,565, 1,520, 1,340 and 1,140.

For C ₁₈ H ₁₇ Cl 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

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 are suspended in 20 ml of ethanol. The mixture was stirred under a hydrogen atmosphere for thirty minutes. The catalyst is then filtered off. The filtrate was concentrated under reduced pressure. The residue is dissolved in 15 ml of water and 15 ml of tetrahydrofuran. 336 mg of sodium bicarbonate are then 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 was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed successively with aqueous sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The solid residue was washed first with ether: ethyl acetate (5: 1) then ether. This gives colorless crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-fl-methyl-1- (p-nitrobenzyloxycarbonyl) ethyloxyimino] acetamido] -4-methoxycarbonyl-2-oxoazetidine (syn isomer) ), tt Mp 198-202 ° C (dec.).

IR spectrum (cm ^-1 ): 3,360, 1,770, 1,745, 1,690, 1,525, and 1,350. NMR Spectrum (DMSO-d6pppm): 1.52 <6H, s, 2 x CH3, 3.63 (3H, s, COOCH _3>, 4.34 (2H, s, C1CH _2), 4.47 (1H, d,

J = 6 Hz, C 1 H, 5.29 (2H, s, COOCl ₂ ), 5.48 (1H, dd, J = 6 Hz, J = 9 Hz, C ₃ -H); 7.23 <1H,

Reference Example 92

19 g of 2-hydroxyiminoacetacetic acid methyl ester are dissolved in 50 ml of methylene chloride. While cooling with ice and stirring, 19.6 g of sulfuryl chloride are added dropwise. The mixture was stirred at room temperature for 3 days. The methylene chloride was then distilled off under reduced pressure. The residue was dissolved in 200 ml of ether and washed seven times with 100 ml portions of water. The ether layer was dried over anhydrous sodium sulfate.

The solvent was distilled off under reduced pressure. 20.2 g of a pale yellow oil of 4-chloro-2-hydroxyimino-acetic acid methyl ester are obtained. NMR (CDC1 _3, ppm) 2.65 (1H, br s, N-OH), 3.90 (3H, s, COOCHp, 4.57 (2H, s, ClCH _2).

This product was dissolved in 200 mL of water / tetrahydrofuran (1: 1). Under ice-cooling, 16.96 g of thiourea and 49.27 g of sodium acetate trihydrate are added to this solution.

The mixture was stirred overnight at room temperature. The pH of the reaction mixture was adjusted to 7.0 by the addition of sodium bicarbonate.

The solution was saturated with sodium chloride ‘while separating the organic layer. The aqueous layer was extracted with tetrahydrofuran. The tetrahydrofuran solution and the above organic layer were combined, washed twice with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent is then distilled off. The oily residue was crystallized from 100 ml of ether. The crystal solution is allowed to stand overnight, the crystals are filtered off and washed well with water.

The resulting crystals were dissolved in a mixture of ethyl acetate and methanol (5: 1). The product is concentrated until crystals precipitate out of solution. The concentrate was allowed to stand overnight. The resulting crystalline precipitate was filtered off and dried. Light yellow granules of 2- (2-amino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester, mp 191-192 ° C (dec.), Were prepared. IR spectrum (cm ^-1 ): 3420, 3300, 3220, 3130, 1730 and 1620.

NMR _(DMSO-dg, ppm): 3.80 (3H, s, _COOCH3), 6.87 (1H, s, SH), 7.17 (2H, br s, NH _2), 11.67 (1 H, s, N-OH). *

For C ₈ H ₇ N ₃ O ₃ S calculated: 35.81% C, 3.51% H, 20.89% N? Found: C, 36.05; H, 3.52; N, 20.96.

Reference Example 93

4.62 g of 2- (2-amino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester are dissolved in 10 ml of Ν, Ν-dimethylformamide. 3 ml of triethylamine are added to the solution. 6.42 g of trityl chloride are then added with stirring at -30 ° C over one hour. The mixture was further stirred at this temperature for one hour and then at 15 ° C for a further two hours.

AND

104

Water (200 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 ml). The ethyl acetate extract was washed with two 200 ml portions of water and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue was purified by silica gel chromatography (100 g, eluting with hexane / ethyl acetate 1: 1).

The resulting crystals were recrystallized from ethyl acetate. Colorless granules of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester, m.p. Mp 204-205 ° C.

IR spectrum (cm ^-1 ): 3,375 and 1,740. NMR spectrum (DMSO-d 6 ppm): 3.45 (3H, s, COOCH 3),

IuaX o □

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

To 70.5 ml of Ν, Ν-dimethylformamide was added 7.05 g of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-hydroxyiminoacetic acid methyl ester and 3.3 g of potassium carbonate. 2.12 g of allyl bromide are then added dropwise with ice-cooling and stirring over five minutes. The mixture was further stirred under ice-cooling for four hours. To this reaction mixture was added 1.65 g of potassium carbonate and 1.06 g of allyl bromide. The mixture was stirred for an additional 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 brine and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The residue was purified by silica gel column chromatography (300 g, eluting with hexane / ethyl acetate 1: 1). The product was crystallized from ether / hexane. 7.0 g of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-allyloxyiminoacetic acid methyl ester are obtained, m.p. 115-116 ° C. IR spectrum (cm 5: 3,360 and 1,740). NMR (CDCl3, ppm): 3.88 (3H, s, COOCH3 ₎ , 6.52 (1H, s, S / H), 6.93 ( 1H, br s, NH), 7.30 (15H, s, three phenyl groups)!

For C 8 ^H 25 ₂ 3 ^N ° 3 ^S calculated: 69.54% C 5.21% H 8.69% N Found: 69.57% C, 5.18% H, 8.51 and N .

Reference Example

6.45 g of 2- (2-tritylamino-4-thiazolyl) - (Z) -2-allyloxyiminoootic acid methyl ester are dissolved in 32 ml of tetrahydrofuran. To the solution was added 32 ml of 50% formic acid. The mixture was stirred at 60 ° C for 40 minutes. The reaction mixture was distilled off under reduced pressure. The solid residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150 g, eluting with hexane / ethyl acetate 1: 1).

The solvent was distilled off. The solid residue was washed first with hexane, then with a small amount of ether and dried. 2- (2-Amino-4-thiazolyl) -2-allyloxyiminoacetic acid methyl ester, m.p. Mp 133-134 ° C. IR: 3420, 3230, 1720, 1610 and 1540.

NMR (CDCl, ppm): 3.90 (3H, s, COOCHj), 5.98 (2H, br isnglet, _NH2), 6.67 (1H, s, S ^ XH).

Reference Example 96

In the same manner as in Reference Example 32, methyl 2- (2-chloroacteamide) of ΚΒΐ * was prepared.

(4-thiazolyl) - (Z) -2-allyloxyiminoacetic acid, mp 114-115 C. IR (V, cm ^-1 ): 3150, 3060, 2950, 1740, 1710, 1680 and 1680. 565. NMR (CDCl, ppm): 3.93 (3H, s, _COOCH3), 4.28 (2H, s, smell.,), 7.25 (1H, s, s / H) 10 12 (1H, br s, CONH).

105

Reference Example 97

2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2-allyloxyiminoacetic acid, mp 162 ° C (dec.), Was prepared in the same manner as in Reference Example 33. IR spectrum ( ^KBr cm ^-1 ):

max

180 2950 1 715 to 1 680. NMR (DMSO-d₆, ppm): 4.33 (2H, s, C1CH _2), 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,

H, 3.55; N, 13.71.

Reference Example 98

610 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-allyloxyiminoacetic acid are suspended in 13 ml of methylene chloride. To this solution was added 502.4 mg of phosphorus pentachloride under ice-cooling and stirring. The mixture was stirred at room temperature for thirty minutes. 100 ml of hexane are then added to the reaction mixture. The precipitated crystals are filtered off and washed with hexane. 2- (2-Chloroacetamido-4-thiazolyl) - (Z) -2-allyloxyimino-acetyl chloride hydrochloride is obtained, m.p.

to 70 ° C. For C 2,8 ^HgClN ^ S. S.HCl calculated: 33.49% C, 2.81% H, 11.72% N, found:

% H, 2.77;% N, 11.79.

Reference Example 99

185.5 mg of cis-3-amino-2-oxoazetidine-4-carboxylic acid methyl ester are dissolved in 2 ml of tetrahydrofuran and 2 ml of water. 469.6 mg of sodium bicarbonate and then 600 mg of 2- (N-chloroacetamido-4-thiazolyl) - (Z) -allyloxyiminoacetyl chloride hydrochloride were added to the solution under ice-cooling and stirring. The mixture was stirred at room temperature for two hours. The solvent was distilled off under reduced pressure.

Water (20 ml) was added to the residue. The insoluble material was filtered off, washed successively with aqueous sodium bicarbonate, water, hexane and ether and dried. Cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-allyloxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester (syn isomer) was prepared, m.p. 270 DEG-280 DEG C. (dec.).

720 and 680. 1 H NMR (DMSO-d, (1H, d, J = 6Hz, C ₄ -H), 7.29 (1H,

IC spectrum (V): 3260, 1770, 1745, 1 ppm): 3.60 (3H, s, COOCHp, 4.33 (2H, s, H1, 9.49 (1H, d, J))

H, 3.75; H, 3.75; and 5%, H, 16.37.

N, 16.29. Found: C, 41.83;

Reference Example 100

657 mg of cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine, prepared according to Reference Example 11, are dissolved in 7.8 ml of N, N-dimethylformamide. This solution is poured into a solution of 861 mg of lithium chloride in 7.8 ml of argon at 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 brine and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue is purified by silica gel column chromatography, eluting with a 1: 2 mixture of hexane and ethyl acetate (the column contains 50 g of silica gel).

The obtained crystals were washed with ether. There was thus obtained cis-3-benzyloxycarboxamido-4-chloromethyl-2-oxoazetidine, m.p. 147-149 ° C. For ^C 13 ^H I2 ^{C 'i' 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 thym (syn isomer), m.p. 212 DEG-217 DEG C. (dec.). IC spectrum (H, cm):

max

755, 1660 and 1560. NMR Spectrum (DMSO-d6, ppm): 3.90 (3H, s, NOCH3), 5.28 = 5 Hz, J = 9 Hz, C, -H), 34 (2H, s, CH 2), 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. To the suspension was added 376 mg of 5% palladium on carbon. The mixture was stirred at room temperature under hydrogen atmosphere for 20 minutes. The catalyst was then filtered off and the filtrate was evaporated. The solid residue was dissolved in 28 mL of a 1: 1 mixture of tetrahydrofuran and water. 470 mg of sodium bicarbonate are added under ice-cooling and stirring. 698 mg of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride hydrochloride (syn-isomer) was then added. The mixture was stirred under ice-cooling for 30 minutes. The reaction mixture was then extracted with ethyl acetate. The aqueous layer was extracted again with a mixture of ethyl acetate and tetrahydrofuran. The extracts were combined, washed successively with aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.

The solid residue was washed with ethyl acetate / ether (1: 3). Colorless crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloromethyl-2-oxoase were prepared. 420, 3260, (1H, dd, J = br s, N @ +). -H),

9.33 (1H, d, J = 9 Hz, C 1 -NH), 12.57 (1H, br s, C ₁ CH ₂ COONH).

Reference Example 102

Reference Example 11 produced cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine, which was further processed in the same manner as described in Reference Example 88 above to produce cis-3- [2- (2-chloroacetamido). -4-thiazolyl) -2-methoxyiminoacetamido] -4-methylsulfonyloxymethyl-2-oxoazetidine (syn isomer), m.p. Mp 186-189 ° C (dec.). H, 3.55; N, 15.43. Found: C, 34.27; H, 3.63; N, 15.28. .

Reference Example 103

3.28 g of cis-3-benzyloxycarboxamido-4-methylsulfonyloxymethyl-2-oxoazetidine, prepared according to Reference Example 11 above, are suspended in 100 ml of ethanol.

To the suspension was added 3.28 g of 5% palladium on carbon. The mixture was stirred under a hydrogen atmosphere for fifty minutes at room temperature. The catalyst is then filtered off. The filtrate was concentrated under reduced pressure. The concentrate was dissolved in a mixture of 100 ml of methylene chloride and 15 ml of Ν, Ν-dimethylacetamide. While cooling with ice and stirring, first add 6.99 ml of propylene oxide and then a solution of 2.79 g of 2-methylsulfonyl-ethyl chloroformate in 25 ml of methylene chloride. The mixture was stirred at room temperature for two hours.

The methylene chloride was distilled off. Water and ethyl acetate / tetrahydrofuran (1: 1) were added to the residue. Shake the mixture well. The organic layer was separated. The aqueous layer was evaporated to dryness under reduced pressure. The residue was dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate, and combined with the above organic layer. The combined mixture was dried again over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (150 g, eluted with ethyl acetate, then a 9: 1 mixture of ethyl acetate and ethanol). The resulting crystals were washed with a 1: 1 mixture of ethyl acetate and ether.

Colorless crystals of cis-3- (2-methylsulfonylethoxycarboxamido) -4-methylsulfonyloxymethyl-2-oxoazetidine, mp 141-142 ° C, were prepared. For ^C 9 ^H x ^N 2 ° 8 ^S 2 calculated: 31.39% C,

H, 3.68; N, 8.14. Found: C, 31.34; H, 4.76; N, 8.34.

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 was refluxed under nitrogen for three hours. The reaction mixture was concentrated under reduced pressure. Water, ethyl acetate and aqueous sodium thiosulfate were added to the concentrate. The resulting crystalline precipitate was 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 obtained. The filtrate was combined with the washings. The organic layer was separated. The aqueous layer was saturated with sodium chloride and extracted with tetrahydrofuran / 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 are obtained. m.p.

Mp 186-190 ° C (dec.).

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

1.504 g of cis-3- (2-methylsulfonylethoxycarboxamido) -4-iodomethyl-2-oxoazetidine and 390 mg of sodium azide are added to 20 ml of id, Ν-dimethylformamide. The mixture was stirred at room temperature for 66 hours and then at 40 ° C for 24 hours. The solvent was distilled off from the reaction mixture under reduced pressure. The residue was purified by silica gel column chromatography (100 g, eluting with ethyl acetate, then with a 9: 1 mixture of ethyl acetate and ethanol). The solvent is then distilled off. The residue was recrystallized from ethyl acetate. The crystals were filtered off. Colorless crystals of cis-3- (2-methylsulfonylethoxycarboxamido) -4-azidoroethyl-2-oxoazetidine, mp 158-160 ° C, were prepared. IR (.delta., Cm @ ^-1 ): 3200, 2110, 1780, 1700 and 1550.

Reference Example 106

To a mixture of 60 mL of ethanol and 6 mL of Ν, Ν-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 are added. After forty minutes 5.7 ml of 1N hydrochloric acid are added and the mixture is concentrated under reduced pressure. 15 ml of water and 15 ml of tetrahydrofuran are added to the concentrate. 874 mg of sodium bicarbonate are added under ice-cooling and stirring. 1.297 g of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride (syn isomer) hydrochloride are then added and the mixture is stirred for 40 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 was distilled off under reduced pressure. The crystalline product is washed first with ethyl acetate, then with ether and finally dried. Colorless crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-azidimethyl-2-oxoazetidine (syn isomer), m.p. 223-230 ° C (dec.), Are thus obtained. IR (cm ^-1 ): 3420, 3250, 2110,

760, 1660 and 1550. NMR Spectrum (DMSO-d6, ppm): 3.4 to 3.6 (2H, m, CHgNg), 3.90 (3H, s, NOCHg), 4.34 (2H, s, CICH g), 5.22 (1H, dd, J = 5Hz, J = 9Hz, Cg-H), 7.37 (1H, s, SH), 8.49 (1H, br s, Ν _χ) Δ), 9.20 (1H, d, J = 9Hz, C 8 -NH). AND

Reference Example 107

5.0 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine, prepared according to Reference Example 5, are dissolved in 50 ml of methylene chloride.

To the solution was added 3.75 mL of pyridine at 0 ° C with stirring. 3.94 g of benzoyl chloride was added dropwise and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 100 mL of ice water.

108

The organic layer was separated and washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The solvent is then distilled off. The residue was purified by silica gel column chromatography (325 g, eluting with hexane / ethyl acetate 1: 2). The solvent was distilled off. Hexane was added and the crystalline product was filtered off. This gives colorless crystals of cis-3-benzyloxycarboxamido-4-benzoyloxymethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine, 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-benzyloxycarboxamidoo KRr-1 is produced.

-4-benzoyloxymethyl-2-oxoazetidine, mp 188-189 ° C. IR spectrum (ν _max. Cm): 3 300,

770, 1725 and 1 690. For i9 ^{C H} 2 Ig ^N ° 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 was stirred under an atmosphere of hydrogen for two and a half hours. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. Colorless crystals of cis-3-amino-4-benzoyloxymethyl-2-oxoazetidine are obtained, m.p. Mp 150-151 ° C. IR (cm &lt; 3 &gt; S: 3200, 1735 and 1710). Calculated: C, 59.99; H, 5.49; N, 12.72. Found: C, 60.06; H, 5.66. , 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.

Mp 210-220 ° C (dec.). IR (cm ^-1 ): 3250, 1760, 1715 and 1660.

For C ₁₉ H ₅ ClN _la 0gS calculated: 47.55% C 3.78% H 14.59% N Found: 47.06% C,

H, 3.63; N, 14.53.

Reference Example 111

To 250 ml of benzene was added 35 g of alpha-methylcinnamylaldehyde and 29.5 g of p-anisidine.

The mixture was refluxed for one hour while water was azeotropically distilled off. The solvent was then distilled off under reduced pressure. The residue was dissolved in one liter of methylene chloride. While cooling with ice and stirring, 29 g of triethylamine and then a solution of 53.5 g of phthalimidoaoethyl chloride in 250 ml of methylene chloride are added dropwise. The mixture was stirred at room temperature for 24 hours, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The solid residue was recrystallized from ethyl acetate-hexane.

Cis-3-phthalimido-4- (alpha-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine, mp 105-107 ° C, was prepared. IR (cm ^-1): 1760, 1725, 1515, 1385 and 250. 1 H NMR (CDC1 _3, ppm): 1.70 (3H, br s, = C-CH ₃₎ 3 74 (3H, s, NOCH ₃ '), 4.77 (1H, d, J = 6Hz, C ₄ -H), 5.52 (1H, d, J = 6 Hz, C 1 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 was stirred at room temperature for 12 hours. The resulting crystalline precipitate was filtered off. The filtrate is concentrated. The concentrate was dissolved in 200 ml of methylene chloride. 14.8 g of propylene oxide and 10.62 g of carbobenzoxy chloride are added successively. The mixture was then stirred for one hour and then concentrated under reduced pressure.

109

The residue was purified by silica gel column chromatography (300 g, eluting first with 1: 1 hexane: ethyl acetate, then 1: 2 with the same mixture). Cis-3-benzyloxycarboxamido-4- (alpha-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine was prepared, IR spectrum (cm &^lt; -1 ^&gt; ): 1,750, 1,720 and 1,680. , ppm): 1.85 (3H, br s, C = _CH-O) 'max jj

3.75 (3H, s, OCH ₃ ), 5.08 (2H, s, phenyl-CH 2), 5.50 (1H, dd, J = 6 Hz, J = 9 Hz, C 1 H), 6.43 (IH, br s, = CH-phenyl), 7.84 (IH, d, J = 9Hz, _C3-NH).

Reference Example 113

75 g of cis-3-benzyloxycarboxamido-4- (alpha-methylstyryl) -1- (4-methoxyphenyl) -2-oxoazetidine are dissolved in 750 ml of methylene chloride. Excess ozone was passed through the solution at -78 ° C. The excess ozone was then purged with nitrogen and 11.6 g of dimethylsulfide was added to the solution. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (400 g, eluting with hexane / ethyl acetate 1: 2, then 1: 4). Cis-3-Benzyloxycarboxamido-4-acetyl-1- (4-methoxyphenyl) -2-oxoazetidine, m.p. Mp 188-191 ° C.

KBr-1

Ir _(raax, cm): 1760, 1720, 1700 and 655. 1 H NMR (DMSO-d₆, ppm): 2.20 (3H, s, _COCH3), 3.74 (3H, s OCH ₃ ), 5.15 (2H, s, phenyl-CH ₂ ), 5.20 (1H, d, J = 6Hz, C ₄ -H), 5.64 (1H, dd, J = 6Hz) J = 9 Hz, C ₃ H), 9.48 (1H, d, J = 9 Hz, C ₃ -NH).

Reference Example 114

1 g of cis-3-benzyloxycarboxamido-4-acetyl-1- (4-methoxyphenyl) -2-oxoazetidine is dissolved in a mixture of 50 ml of acetonitrile and 25 ml of water. The solution was cooled to -15 ° C. Ammonium cerium nitrate (3 g) was added at this temperature and the mixture was stirred for 10 minutes. The reaction was quenched by the addition of a saturated aqueous sodium sulfite solution. The pH of the solution was adjusted to 5-6 by the addition of 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 chloroform / 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 hexane / ethyl acetate (1: 2), ethyl acetate, and finally ethyl acetate / methanol (9 µl). Cis-3-Benzyloxycarboxarcido-4-acetyl-2-oxoazetidine was prepared.

IR (cm ^-1): 3240, 1770, 1705, 1635, 1540, 1450, 1380, 1305 and 180. 1 H NMR (CDC1 _3, ppm): 2.20 (3H , s, COCH ₃ ), 4.58 (1H, d, J = 6Hz, C ₄ -H),

5.20 (2H, s, _Ph-CH2), 8.18 (IH, d, J = 9 Hz, C-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 (in cm &^lt; -1 & gt ^; ): 3,350, 1,760, 1,650 and 1,545. NMR (DMSO-d6, ppm): 2.12 (3H, s, COCH-1), 3.73 (3H, br s, N0CH _9), 4.35 (2H, s, _C1CH?), 7.90 (IH, s, S_H).

X

Reference Example 116

75 mg of cis-3-amino-4-hydroxymethyl-2-oxoazetidine, prepared according to Reference Example 53 above, are dissolved in a mixture of 2 ml of tetrahydrofuran and 2 ml of water.

168 mg of sodium bicarbonate and then 332 mg of 2- (2-chloroacetamido-4-thiazolyl) - (Z) -2-methoxyiminoacetyl chloride hydrochloride were added under ice-cooling and stirring. 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. Ethyl acetate / ether (1: 2) was added. The crystalline product is filtered off. Colorless crystals of cis-3- [2- (2-chloroactamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-hydroxymethyl-2-oxoazetidine (syn isomer) were prepared, mp 238-241 ° C (dec.). IR spectrum max ' ^{cm 3400} (broad band), 1750, 1660 and 1045. NMR spectrum (DMSO-d6, 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, H-s 9.15 (1H, d, J = 9Hz, Cg-NH).

Reference Example 117

172 mg of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-hydroxymethyl-2-oxoazetidine (syn isomer) are dissolved in a mixture of 17 ml of methylene chloride and 6 ml of Ν, Ν-dimethylformamide. . 0.2 ml of pyridine was added to the solution. With ice-cooling with sodium chloride and stirring, 0.12 ml of chloroacetyl chloride is added dropwise to the mixture. The mixture was stirred under cooling for 30 minutes. The solvent was distilled off. Aqueous sodium chloride solution and ethyl acetate were added to the residue and the mixture was shaken well. The organic layer was separated, washed with brine and dried over anhydrous sodium sulfate.

The solvent is then distilled off. The residue was recrystallized from ether. Recrystallization from chloroform-methanol gave colorless crystals of cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-chloroacetoxymethyl-2-oxoazetidine (syn isomer), mp 225-227 ° 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, prepared according to Reference Example 48, are suspended in 320 ml of ethanol.

2.03 ml of hydrazine hydrate was added to the mixture. The mixture was refluxed for two hours.

After cooling, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. To the concentrate was added 200 ml of methylene chloride. The material that remains undissolved is filtered off. The filtrate was washed with water, dried over anhydrous magnesium sulfate, and the solvent was 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, 5.88 ml of propylene oxide are added first 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 # brine, dried over anhydrous magnesium sulfate and the solvent is ^one distillation under reduced pressure. The crystalline residue was washed with ethyl acetate.

2.94% cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine, m.p. 172-174 ° C, was prepared. IR spectrum .nu.max ^{: cm} @ ^-1:

400, 1755, 1690, 1610, 1535 and 1125. NMR Spectrum (DMSO-d6, 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 (2 X CH ₃ , 2 X s, 2 x OCH 3), 4.24 (2H, quartet,

J = 15 Hz, N ₁ -CH ₂ ), 4.28 (2H, t, J = 6 Hz, COOCH 3), 4.82 (1H, dd, J = 5 Hz, J = 9 Hz, C 1 H) , 5.05 (2H, s, _Ph-CH2), 7.37 (5H, s, phenyl), 8.05 (1H, d, J = 9 Hz, C-NH).

Reference Example 119

In the same manner as in Reference Example 50 cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine, mp 149-150 ° C, was prepared. 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. decolorizes at 150-170 ° C and decomposes at 195-199 ° C.

IR (cm ^-1 ): 3250, 1760, 1690, 1650, and 1550. Calc'd: C, 36.61; H, 4.03; H, 16.01. found: 36.48 8 C, 4.08 8 H, 15.02 8 N.

Reference Example 121

1.197 g of cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -2-oxoazetidine, prepared according to Reference Example 119, are dissolved in 3 ml of Ν, Ν-dimethylformamide. of chloride and, while cooling to 0 ° C, 0.46 ml of triethylamine is added dropwise. The mixture was stirred under ice-cooling for 30 minutes. Ethyl acetate and water were added. The ethyl acetate layer was separated, washed with dilute hydrochloric acid, brine, and dried over anhydrous magnesium sulfate.

The solvent was distilled off under reduced pressure. The residue is chromatographed on a silica gel column (100 g, eluting with hexane / ethyl acetate 1: 2, then 1: 3). Cis-3-benzyloxycarboxamido-4- (2-methylsulfonylethoxycarbonylaminomethyl) -1-dimethyl-tert-butylsilyl-2-oxoazetidine is obtained as a foam.

IR (cm -1): 3330, 1750, 1720 and 1695. NMR spectrum (CDCl 3, ppm):

0.26 (3H, s, SiCH2), 0.28 (3H, s, SiCH2), 0.96 (9H, s, t-butyl group), 2.93 (3H, s, SO2 ₎ CH ₃ ), 3.28 (2H, t, J = 6Hz, CH ₂ SO ₂ ), 4.50 (2H, t, J = 6Hz, COOCH ₂ ), 5.03 (1H, dd,

J = 5 Hz, J = 9 Hz, _C3 -H), 5.15 (2H, s, Ph-CHP, 6.18 (1H, d, J = 9Hz, _C3-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 was stirred under ice-cooling for 15 minutes. 2.2 ml of 1N hydrochloric acid were added to the reaction mixture. The solvent was distilled off under reduced pressure. The residue is extracted with a mixture of methylene chloride and tetrahydrofuran. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure.

4 ml of dry trifluoroacetic acid and 2 ml of trifluoroacetic acid are added under ice-cooling. The mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (40 g, eluting with hexane / ethyl acetate 1: 1, then 1: 2). Thus cis-3-benzyloxycarboxamido-4-trifluoroacetylaminomethyl-2-oxoazetidine, mp 197-201 ° C, is prepared. IR ([nu] cm & lt ^; -1 &gt; cm & lt ^; -1 ^&gt; ): 3280, 1760, 1 705 and 1690. Calcd: 48.70% C, 4.09% H, 12.17% N, found: 48.31% C,

H, 4.00; N, 12.01.

Yellow crystals of the by-product cis-3-benzyloxycarboxamido-4-trifluoroacetylaminomethyl-1-dimethyl-tert-butylsilyl-2-oxoazetidine, m.p.

Mp 130-135 ° C. IR (cm ^-1 ): 3300, 1765, 1700 and 1685.

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, mp 220-225 ° C) was prepared. (dec.).

112 points »- 1

IR spectrum ( _max ( ^cm @ ^-1 )): ^{3270, 1760, 1725} and 1660. NMR Spectrum. (DMSO-d₆, ppm): 3.89 (3H, s, NOCH _3), 4.31 (2H, s, ClCHj), 5.22 (1H, dd, J = 5 Hz, J = 9 Hz, C -H), 7.43

Reference Example 124

In a mixture of 25 ml of ethanol and 5 ml of Ν, Ν-diroethylfomaroid, 525 µg of cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiniinoacetomido] -4- (2-methylsulfonylethoxycarbonylaminomethyl) -2 is suspended. oxoazetidine (syn isomer), which was produced according to Reference Example 119.

To the suspension was added 5 mL of ethanolic sodium hydroxide (0.5 N). The mixture was stirred at room temperature for 20 minutes. Then 2.5 roles of 1N hydrochloric acid are added. Ethanol was distilled off under reduced pressure. The residue was dissolved in a mixture of 8 ml of water and 10 ml of tetrahydrofuran.

Under ice-cooling and stirring, 185 mg of sodium bicarbonate are added, then a solution of 432 mg of p-nitrobenzyl chloroformate in 10 ml of tetrahydrofuran is added dropwise over 50 minutes.

The mixture was stirred under ice-cooling for 20 minutes. Water (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture. Shake the mixture well. The organic layer was separated. The aqueous layer was extracted with ethyl acetate. The ethyl acetate extract and the above organic layer were combined. The combined portions were washed with brine 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), m.p. 235 DEG-245 DEG C. (dec.).

IR (.delta. ( ^{Cm @ -1} , cm ^{@ -1} )): 3,380, 3,230, 1,760, 1,690, 1,660, 1,550 and 1,520.

Reference Example 125

The following compounds were produced in the same manner as in Reference Example 39:

cis-3 - [] D-2- (4-ethyl-2,3-dioxo-1-piperazinecarboxamido) -2-phenylecetamido] -2-oxoazetidine-4-carboxylic acid methyl ester:

beta-isomer: IR spectrum (νmax cm ^-1 ): 1770, 1740, 1710, 1675, NMR (DMSO-d6)

(dg) ppm): 1.11 (3H, t, J = 7Hz, N-CH3CH3), 3.08 (3H, s, COOCH-j), 4.30 (1H, d, J = 6Hz, C ₄ -H), 5.38 (1H, dd, J = 6Hz, J = 9Hz, C ₃ -H), 5.52 (1H, d, J = 7Hz, phenyl-CH-), 8 6.68 (1H, s, N ₁ -H), 9.26 (1H, d, J = 9Hz, C ₃ -NH), 9.86 (1H, d, J = 7Hz, phenyl-CH -NH).

alpha-isomer: IR spectrum ( ^vmax) 1770, 1740, 1710 and 3670. NMR Spectrum (DMSO-d6, ppm): 1.10 (3H, t, J = 7 Hz, N- CH ₂ CH ₃ ), 3.55 (3H, s, COOCH ₃ ), 4.40 (1H, d, J = 6Hz, C ₄ -H), 5.20 (1H, dd, J = 6Hz J = 9 Hz, C 1 H), 5.47 (1H, d, J = 7Hz, phenyl-CH), 8.70 (1H, s, N ₁ -H), 9.25 (1H, d, J = 9 Hz, Cl-NH), 9.80 (1H, d, J = 7 Hz, 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, 1 710 and 1 670. NMR (CDC1 _3, 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:

t R-1 beta-isomer: IR spectrum (ν _max cm -1: 1,770, 1,710 and 1,670). NMR spectrum (CDCl 3, ppm): 1.85 (3H, s, OCOCH 3).

113

25357 alpha-isoiner: IR spectrum < ^V max ' ^cm-1 ) ^{! 1770 '1 720 and 1} 670. ^NMR (CDC1 _3, ppm): 1.90 (3H, s', OCOCHj).

Reference Example 126

The procedure of Reference Example 39 treats 300 mg of D-2- [3- (furan-2-aldimino) -2-oxo-1-imidazolidinecarboxamido] -2-phenylacetate with 110 mg of cis-3-amino-2-oxoazetidine methyl ester -4-carboxylic acids. 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 (ν max) ^cm 5: 1760, 1720 and 1660. alpha-isomer: IR spectrum (νmax ^, 5: 1770, 1720 and 1660).

The following compound was prepared in the same manner as described above: cis - [] D-2-J] 3- (thiophen-2-aldino-2-oxo-1-imidazolidinecarboxamido] -2-phenylacetamido] -2-oxoazetidine methyl ester 4-carboxylic acid.

beta-isomer: IR spectrum (in ^X5r , _{c [} ^delta _{] ;} 765, ¹⁷²⁵ and 1660).

ΪΏ3.Χ

ZPr - 1 alpha isomer: IR spectrum (v _max > cm): 1770, 1720 and 1660.

Reference Example 127

The 3-amino compound (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. 1.2 ml trimethylamine are added under ice-cooling and stirring. A solution of 1.2 g of 2- (2-chloroacetamido-4-thiazolyl) -2-diethylphosphonoacetyl chloride in 10 ml of tetrahydrofuran was added dropwise. The mixture was stirred at room temperature for 2.5 hours. 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 was purified by silica gel column chromatography (95: 5 chloroform-methanol). Cis-3- [2- (2-Chloroactamido-4-thiazolyl) -2-diethylphosphonoacetamido] -2-oxoazetidine-4-carboxylic acid methyl ester was prepared. IR (in cm &^lt; -1 & gt ^; ): 3,250, 1,770, 1,750, 1,685, 1,540, 1,230, 1,050, and 1,025.

Reference Example 128

The 3-amino compound (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) was dissolved in 20 ml of tetrahydrofuran. ml of triethylamine and 0.56 g of 3-triethylsilylpropionyl chloride under ice-cooling and stirring, stirred for 3 hours at room temperature, the tetrahydrofuran was distilled off, water and ethyl acetate were added to the residue, the phases were separated. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-ether and the crystals were filtered off.

This affords cis-3-methyl ester; (2-triethylsilylethylcarboxamido) -2-oxoazetidin-4-carboxylic acid, mp: 143-145 ° C. IR ( ^cm &^lt; 3 &gt; 3,260, 1,790, 1,750, 1,640 and 1,540) Calc'd for C C ^H ^ NN ^O ^Si: C, 53.47; H, 8.33; N, 8.91. found: 53.54% C,

8.40% H, 8.73% ’N.

3 572

114 .Reference Pi O Poison 129

5.01 g of 2,4-dimethoxybenzylamine are not 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 was stirred at room temperature for three and a half hours. 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 was added dropwise over 30 minutes.

The mixture was stirred for two and a half hours from room temperature, washed with water, dried over anhydrous sodium sulfate, and the mixture was concentrated under reduced pressure. To the concentrate was added 50 ml of chloroform. The precipitate was filtered off. The filtrate was evaporated and the residue was passed through a silica gel column (30 g). The eluate was evaporated and the solid residue was recrystallized from ethyl acetate. Cis-3-phthalimido-4- (E) -styryl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. Mp 173-177 ° C.

IR ( ^KBr , cm ^): 1750, 1720 and 1390. Calculated: C, 71.78;

H, 5.16; N, 5.98. Found: C, 72.14; H, 5.01; N, 5.85.

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. To the solution was added 2.5 g of 10% palladium on carbon. The mixture was stirred under a hydrogen atmosphere for 30 minutes. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. The concentrate was crystallized from ether. The crystals were filtered off. 4.8 g of cis-3-phthalimido-4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine are obtained, m.p. M.p. 148-150 ° C.

IR (\), ^KBr, cm-B: 1750, 1720 and 1 390. For C ₉₀ E _{9 R} -N _"r 0 Calculated: C 71.47%, R max of ZOZ _)

H, 5.57; N, 5.96. Found: C, 71.55; H, 5.45; N, 5.75.

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 was allowed to stand at room temperature for three days. The resulting precipitate was filtered off. The filtrate was evaporated. The residue was dissolved in ethyl acetate and the solution was extracted three times with dilute hydrochloric acid. The pH of the solution was adjusted to 7-8 by addition of sodium bicarbonate.

The solution was extracted three times with chloroform. The 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. Propylene oxide (20 ml) was added to the solution and carbobenzoxy chloride (3 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure. The residue is chromatographed on a silica gel column, eluting with a 1: 1 mixture of chloroform and ethyl acetate. The solvent was then distilled off and the residue was crystallized from ether. The crystals were filtered off. Cis-3-benzyloxycarboxamido-4- (2-phenylethyl) -1- (2,4-dimethoxybenzyl) -2-oxoazetidine, m.p. Mp 150-152 ° C.

IR (cm ^"1): 3300, 1760, 1680, 1535 and 1 265. For gH ₃ C _{2 ()} N ₂ O ₅ Calculated:

C, 70.86; H, 6.37; N, 5.90. Found: C, 70.68; H, 6.44; N, 6.09.

Reference Example 132

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-4- (2-phenylethyl) -2-oxoazetidine, mp 173-175 ° C, was prepared. IR spectrum (cm ^-1 ): 3 300,

770, 1 685, 1 540 and 1 260. For ^c 19 ^H 20 ^N 2 ° 3 ⁱⁿ yP ° ^ethene! % C, 70.35;% H, 6.22;% N, 8.64. Found:% C, 70.13;% H; 6.05;

115

Reference Example 133

In the same manner as in Reference Example 67, re-produced cis-3- [2- (2-chloroeetaniido-4-thiazolyl) -2-methoxyiminoacetamido] -4- (2-phenylethyl) -2-oxoazetidine (syn isomer). IR ( ^KBr , cm “ ¹ ): 3260, 1740, 1700, 1650 and 1540.

Reference Example 134

9.6 g of 2-methoxyiminoacetacetic 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 was added dropwise. The mixture was stirred for 20 minutes. It is then poured into ice-water. The organic layer was separated, washed successively with saturated aqueous sodium bicarbonate, water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure.

13.12 g of an oil of 4-bromo-2-methoxyimino-acetic acid methyl ester are obtained. To 40 ml of ethanol was added 10.74 g of this oil and 4.4 g of thiocarbamic acid methyl ester. The mixture was refluxed for one and a half hours. Ethanol was distilled off. The residue was dissolved in chloroform, washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Crystals of 2- (2-hydroxy-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid methyl ester, m.p. Mp 97-98 ° C.

IR (\) ^ x ^{'cm 1} 1670, 1440, 1260, 1150 and 040. 1 H NMR _(CDCl3, ppm): 3.93 and 4.03 (2 χ 3H, 2 x s, COOCH ₃ and NOCH ₃ ), 6.35 (1H, s, 5H).

Reference Example 135

1.0 g of 2- (2-hydroxy-4-thiazolyl) - (Z) -2-methoxy-iminoacetic acid methyl ester is dissolved in 3 ml of ethanol. 5 ml of aqueous potassium hydroxide solution (1.3 g) are added dropwise under ice-cooling. The mixture was allowed to stand for 4 hours, adjusted to pH 2-3 with 1N hydrochloric acid, and extracted three times with butanol. The extracts were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This gives a light brown powder of 2- (2-hydroxy-4-thiazolyl) - (Z) -2-methoxyiminoacetic acid, m.p. 143-145 ° C (dec.).

IR spectrum (cm⁻¹): 1740, 1490, 1620, 1450, 1170 and 040. 1 H NMR (DMSO-d₆, ppm): 4.02 (3H, s, NOCH _3), 6, 79 (1H, s, 5H), 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 (cm ^-1 ): 3260, 1775, 1735, 1685, 1660, 1520,.

440, 1 220 and 1 040. NMR (DMSO-d₆, ppm): 3.50 (3H, s, _COOCH3), 3.86 (3H, s, NOCHj), 4.33 (1H, d, J = 5 Hz, C / H), 5.25 (1H, dd, J = 5Hz, J = 8Hz), 6.23 (1H, s, S1H), 8.35 (1H, broad singlet, N / H), 9.33 (1H, d, J = 8Hz, C / NH).

Reference Example 137

2.14 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid methyl ester, prepared according to Reference Example 1, are dissolved in 150 ml of methanol under ice-cooling and stirring. 25 mL of aqueous potassium carbonate solution (0.83 g) was added. The mixture was stirred at room temperature for six and a half hours. The methanol was distilled off under reduced pressure. Water was added to the residue, the mixture was washed with ethyl acetate-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-oxo-O-Kr-1-azetidine-4-carboxylic acid, m.p. 189-191 C, were prepared. 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 was refluxed for 30 minutes. The solvent was distilled off. The residue was 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 was distilled off. The residue was recrystallized from ether. The crystals were filtered off. Colorless crystals of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid ethyl ester, which melted at 117-118 ° C after recrystallization from ethanol, were prepared.

TfRy · _ 1

IR spectrum (H-cm): 3250, 1770, 1735 and 1680. Calcd for C17 H17 N3 O:

2ΠαΧ May 2b of Z

% C, 62.43;% H, 5.92;% N, 6.33. Found:% C, 62.43;% H, 5.91;% N, 6.05.

Reference Example 139

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid ethyl ester, mp 134-135 ° C, was prepared. IR (cm ^-1 ): 3,300, 1,800, 1,740, and 1,720. ^C 14 ^H 16 ^N 2 ^O 5 calculated: 57.52% C, 5.51% H, 9.58% N Found:% C, 57.58;% H, 5.44;% N, 9.60.

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 (max. Max.) ^:

400, 3200, 1745, 1720 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, H, 6.20; N, 17.70.

Reference Example 141

The following compounds were produced in the same manner as in Reference Example 4:

Cis-3- [2- (2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -2-oxoazetidine-4-carboxylic acid ethyl ester:

syn-isomer: m.p. 280-283 ° C (dec.) 30 and 1670. NMR Spectrum (DMSO-d6, ppm):

- 5 Hz, J = 9 Hz, C ₃ -H), 7.42 (1H, s, S H), IR spectrum (ν max) ^{cm -1} 1.20 (3H, t, J = 7 Hz (CH 2 CH 3 H).

230, 1750, 5.73 (1H, dd, anti-isomer: mp 108-110 ° C. IR spectrum (νm ¹ ): 3250, 1760, 1720

IuaX 1 and 650. NMR (DMSO-d₆, ppm): 1.20 (3H, t, J = 7Hz, CH ₂ CH _3), 5.50 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -H), 8.00 (1H, s, S 1 H).

Reference Example 142

2 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -2-oxoazetidine-4-carboxylic acid, prepared according to Reference Example 137, are dissolved in 60 ml of dry tetrahdyrofuran and 2 ml of acid chloride are added to the solution. ětavelové. The mixture was refluxed for 30 minutes. The solvent is then distilled off. The residue is 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 chloroform-methanol.

117

IR (.delta.): 3,250, 1,760, 1,690, and 1,670.

Found:% C, 65.80;% H, 5.34;% N, 8.34.

Reference Example 143

In the same manner as in Reference Example 2, cis-3-benzyloxycarboxamido-40 KRv -1 was prepared.

-phenylcarbamoyl-2-oxoazetidine, mp 235-238 ° C (dec.). IR spectrum (V _max »cm}:

270, 1760, 1690 and 1670. NMR Spectrum (DMSO-d6, ppm): 4.4 (1H, d, J = 5 Hz, C-H),

5.0. (2H, s, _Ph-CH-0), 5.15 (1H, dd, J = 5Hz, J - 9 Hz, C-H).

Reference Example 144

In the same manner as in Reference Example 3 was prepared cis-3-amino-4-phenylcarbamoyl-2-oxoazetidine _of mp 152-154 ° C (dec.). IR spectrum (cm &lt; -1 &gt; 300, 1740 and 1690).

Reference Example 145

In the same manner as in Reference Example 4, cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-phenylcarbamoyl-2-oxoazetidine (syn isomer) was prepared. NMR (DMSO-d₆, ppm): 3.53 (3H, s, NOCH _3), 4.3 (2H, S, C1CH _2), 4.48 (1H, d, J = 5Hz, C ^ - H),

5.57 (1H, dd, J = 5 Hz, J = 9 Hz, _C3 -H).

Reference Example 146

2.502 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, prepared according to Reference Example 2, are dissolved in 160 ml of methanol. 50 ml of aqueous potassium carbonate solution (1.242 g) are added under ice-cooling and stirring. . The mixture was stirred at room temperature for 70 minutes. 9 ml of 1N hydrochloric acid are 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 is chromatographed on an Amberlite XAD-II column. The eluate was lyophilized. A colorless potassium cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylate powder was prepared.

IR spectrum _(cm ^-1): 1770, 1755, 1705, 1675, 1590, 1410 and 1 320th

Nuclear Magnetic Resonance Spectrum (DMSO-d6, ppm): 3.82 (1H, d, J = 5 Hz, C (-H), 4.78 (1H, dd, J = 5 Hz, J = 9 Hz, C ₃ -) H), 5.01 (2H, s, CH 2), 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

717 mg of cis-3-benzyloxycarboxamido-2-oxoazetine-4-carboxylic acid (as potassium salt) are dissolved in 5 ml of Ν, Ν-dimethylformamide. 0.25 ml ethyl bromoacetate was added under ice-cooling and stirring. The mixture was stirred at room temperature for one hour. Add 50 ml. water and the solution was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. Ether was added to the solid residue. Filtration gave colorless crystals of cis-3-benzyloxycarboxamido-4-ethoxycarbonylmethyloxycarbonyl-2-oxoazetidine, m.p. Mp 109-111 ° C. '®

IR spectrum (V cm ^-1 ); 3350, 3260, 1775, 1710 and 1 675. For C _g H _g N ₂ O ₇ Calculated:

C, 54.86; H, 5.18; N, 8.00. Found: C, 54.90; H, 5.24; N, 7.79.

Reference Example 148

Cis-3- [2- (2-chloroacetamido)] was prepared in the same manner as in Reference Example 67

-4-thiazolyl) -2-methoxyiminoacetamido-4-ethoxycarbonylmethyloxycarbonyl-2Oxoazetidine

118 (syn isomer), mp 226-231 ° C (dec.). XC spectrum (in ^cell 5 ^: 3,270, 1,765, 1,750,

690 and 670. 1 ^H for ^C ig jg ^C1N 5 ° 8 ^S: calculated: 40.38% C, 3.81% H, 14.72 and N Found:

% C, 40.08;% H, 3.97;% N, 14.51.

Reference Example 149

Ether was added to the trans-3-benzyloxycarboxamido-1- (2,4-dimethoxy-benzyl) -2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 26.

The mixture was allowed to cool. On standing, crystals precipitate which are suctioned off and washed with water. Colorless crystals are obtained, mp 65-68 ° C. For ^C 22 ^B 24 ^II 2 ° ^to 7 ° ≤ YP ^Tello! 61.67% c, 5.65% H,

N, 6.54. Found: C, 61.84; H, 5.48; N, 6.36.

The above product was reduced by treatment with sodium borohydride in the same manner as in Reference Example 5. The product was purified by silica gel column chromatography (1: 4 hexane / ethyl acetate). A colorless oil of trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine was prepared. IR (V ^ ® _and ^th, cm ^-1): 3400, 3325, 1740 (br), and 1 030th

Reference Example 150

5.8 g of trans-3-benzyloxycarboxamido-1- (2,4-dimethoxy benzyl) -4-hydroxymethyl-2-oxoazetidine are dissolved in 50 ml of methylene chloride. To this solution was first added 2.29 g of pyridine and then 1.54 ml of acetyl chloride under ice-cooling and stirring. The mixture was stirred at room temperature for one hour. The solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with 3N hydrochloric acid, aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was 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 brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (140 g, eluting with hexane / ethyl acetate 1: 2). Trans-3-benzyloxycarboxamido-4-acetoxymethyl-2-oxoazetidine, m.p. 119 to

121 ° C. IR ( ^KBr , cm ^-1 ): 3245, 1750, 1725, 1725, 1550, 1270, 1250 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) was prepared, m.p.

Mp 177-190 ° C (dec.). IR (vmax, cm ^-1 ): 3,180, 1,760, 1,735, 1,710, 1,640, max

565 and 1040.

Reference Example 152

18.3 g of trans-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine are dissolved in 50 ml of pyridine. 5.76 g of methanesulfonyl chloride are added under ice-cooling. The mixture was stirred at room temperature for one hour. The reaction mixture was added to ethyl acetate and washed with 6N hydrochloric acid, then aqueous sodium bicarbonate and brine, 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 are added to the solution. The mixture was heated at 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 was washed with saturated aqueous sodium sulfite, brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. By this procedure, trans-3-benzyloxycarboxamido-4-iodomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine oil is obtained, IR spectrum (cm ^-1 ): 3 300, 1760, 1710, 1 605, 1 510, 1 285, 1

260 and 1 210. The nmr spectrum (CDC1 _3, ppm): 3.78 (6H ,, s, 2 x _OCH3), 5.00 (2H, s, _Ph-CH2), 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 does not crystallize. It was therefore purified by silica gel column chromatography (350 g, eluting with hexane / ethyl acetate 2: 1, then 1: 2). IR spectrum ( ^{ν max} , cm ^-1 ): 3 280, 2 950, 1 750, 1 710, 1 605, max

505, 1260 and 210. 1 H NMR (CDCl, ppm): 1.20 (3H, d, J = 6Hz, C ₄ -CH _3), 3.75 (6H, s, 2 x _OCH3); 5.02 (2H, s, _Ph-CH2), 5.55 (1H, dd, J = 6 Hz, J = 8 Hz, C-H), 7.21 (5H, s, Ph).

Reference Example 154

In the same manner as in Reference Example 66, trans-3-benzyloxycarboxamido-4-methyl-2-oxoazetidine, m.p. Mp 109-111 ° C. IR spectrum (cm -1): 3220, 3220, 1780,

690, 1 535, 1 450, 1 265, 1 045 and 730.

Reference Example 155

In the same manner as in Reference Example 67, trans-3- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -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. To the solution was added 0.1 mL of a 40% methylamine solution and one drop of acetic acid. The mixture was allowed to stand in the cold (5 ° C) for four hours. The resulting crystalline precipitate was filtered off and washed with ether. Cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine was prepared, which melted at 207-208 ° C after recrystallization from ethyl acetate-methanol. IR spectrum (cm ^-1 ): 3270, 1770, 1700 and 1660. NMR Spectrum (DMSO-d6, ppm): 2.56 (3H, d, J = 5 Hz, NHCl 3), 4.13 ( 1Η, d, J = 5Hz, C ₄ -H), 7.33 (5H, s, phenyl protons), 8.33 (1h, d, J = 5Hz, NHCH 3), Pro ^ χ ₃ χ ₅ ^Ν H, 5.45; N, 15.15. Found: C, 56.17; H, 5.31; N, 15.23.

Reference Example 157

831 mg of cis-3-benzyloxycarboxamido-4-methylcarbamoyl-2-oxoazetidine are dissolved in a mixture of 50 ml of tetrahdyrofuran and 50 ml of methanol. To the solution was added 830 mg of 5% palladium on carbon. The mixture was stirred under an atmosphere of hydrogen for one hour. The catalyst was filtered off. The filtrate was evaporated under reduced pressure. 410 mg of a colorless powder of cis-3-amino-4-methylcarbamoyl-2-oxoazetidine are prepared. IR (V ^_"1-ol (cm ^-1): 3300, 1750 and 650. 1 H NMR (DMSO-d₆, ppm): 2.70 (3H, d, J = 5Hz, NHCH ₃₎ 3, 96 and 4.23 (2 x 1H, 2 xd, J = 5 Hz, _C3-H and _C4-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. 960 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- (Z) -methoxyiminoacetyl chloride hydrochloride are added under ice-cooling and stirring.

The mixture was stirred for one hour. 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: 3220, 1750, 1700 and 1660. NMR spectrum (DMSO-d6, ppm): 2.50 (3H, d, J = 5 Hz, NHCH3), 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 = 5Hz, NHCHj) ,

8.3 (1 H, br s, _{χ χ} -Η).

Reference Example 158

The procedure of Reference Example 91 was repeated except that the trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester was used in place 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), m.p. Mp 110-120 ° C (dec.).

IR (cm ^-1): 3280, 2980, 1 790 to 1 740 1680 and 1 525. For ^C 23 ^Feb 23 ^C1N 6 ° 10 ^S: calculated: 45.21% C, 3.79% H N, 13.76. Found: C, 45.60; H, 14.14; N, 13.14.

Reference Example 159

The following compounds were prepared in the same manner as in Reference Example 81:

N- (1-methoxycarbonyl-1-methylethoxy) phthalimide, mp 106-107 ° C IR spectrum (cm ^-1 ): 2 990, 2 960, 1 790 and 1 740. For ε _χ3 Η _χ3 ΝΟ ₅ calculated: 59 Found:% C, 59.60;% H, 4.98;% N, 5.22.

N- [1-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyphthalimide. IR spectrum cm ^-1 : 2940, 1790 and 1735. 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 3), 7.73 (4H, s, aromatic protons).

Reference Example 160

The following compounds were prepared in the same manner as in Reference Example 82:

net -1

O- (1-methoxycarbonyl-1-methylethyl) hydroxylamine. IR ( ^v _max , [delta]): 3225,

980, 2950, 1 735. NMR (CDCl, 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] hydroxlamine. IR spectrum (VA cm ^-1 ): 3,320, 2950 and 1730. NMR spectrum (CDCl 3, 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, COOCH 3), 5.12 (up to 5.43 (2H, broad band, NH ₂ )).

Reference Example

The following compounds were prepared in the same manner as in Reference Example 83:

2- (2-chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetic acid. IR spectrum (? _Max <cm ^-1): 3200, 2980, 1750 and 680. 1 H NMR (CDCl, 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 (in cm &lt; -1 &gt;): 3420, 3200, 2960, 1740 and 1730.

121

Reference Example 162

2- (2-Chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetyl chloride, m.p. 105-115 ° C, was prepared in the same manner as in Reference Example 84. IR (cm ^-1): 2980, 1790, 1745 and 1 700. For C ₁₂ H ₁₃ C1 ₂ N ₃ C> ₅ S.HC1 calculated: 34.42% C, 3.37% H, N, 10.03. Found: C, 34.94; H, 3.46; N, 10.21.

Reference Example 163

In the same manner as in Reference Example 85, cis -3- [2- (2-chloroacetamido-4-thiazolyl) -2- (1-methoxycarbonyl-1-methylethoxyimino) acetamido] -4-methoxycarbonyl-2-oxoazetidine (syn isomer) was prepared. mp 212-214 ° C (dec.). IR (cm ^{- '1');} 3,300, 3,080,

975, 1780-750, 1720 and 1660. Calc'd for C ^ yN ^ gClClNNOgS: C, 41.68; H, 4.12;

N, 14.30. Found: C, 41.47; H, 4.14; N, 14.06.

Reference Example 164

820 mg of 2- (2-chloroacetamido-4-thiazolyl) -2- [Ί-methyl-1- (2-trimethylsilylethoxycarbonyl) ethoxyiminoacetic acid are dissolved in 25 ml of methylene chloride. To this solution were added 221 mg of triethylamine and 380 mg of phosphorus pentachloride under ice-cooling. The mixture was stirred under ice-cooling for 15 minutes and at room temperature for two hours. The reaction mixture was concentrated under reduced pressure.

The residue is dissolved in 5 ml of tetrahydrofuran. This gives a solution containing the acid chloride.

In addition, 219 mg of cis-3-amino-4-methoxycarbonyl-2-oxoazetidine are 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. The above acid chloride solution is added dropwise to this solution with stirring. The mixture was stirred under ice-cooling for 15 minutes and then at room temperature for one hour. 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) was prepared.

IR ( ^KBr , cm ^-1 ): 3280, 2950, 1760, 1730, and 1685. NMR Spectrum (CDCl3, + DMSO-d6 max, ppm): 1.18 (2H, CH2 ₎ Si), 1.81 (6H, NOCMe ₂ ), 4.40 (2H, COOCH 3, 4.44 (2H, s, C ₁ CH ₂ ), 4.67 (1H, d, J = 6 Hz, C ₄ -H) ), 5.88 (1H, dd, J = 6Hz, J = 9Hz, 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

1.5 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester prepared according to Reference Example 2 are dissolved in 20 ml of tetrahydrofuran and 10 ml of 1M aqueous ammonium chloride are added to the solution. With stirring at room temperature, 0.5 ml of aqueous ammonia (25-28%) was added and the mixture was stirred for three hours. A further 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 is filtered off, washed first with water, then with ether and dried. Cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine, m.p. Mp 236-237 ° C (dec.).

IR (cm ^-1): 3400, 3300, 3200, 1760 and 670. 1 H NMR _(DMSO-dg, ppm) 4.14 (1H, d, J = 6Hz, C ₄ ~ H), 5.05 (2H, s, Ph-CH ₂₎ 5> 08 (1H, dd, J = 6 Hz, J = 10 Hz, _C3-H), 7.36 (5H, s , aromatic protons). For ^ε χ2 ^Η 13 ^Ν 3 ° 4 ⁱⁿ yP °° ^teno: 54,57% C,

H, 4.98; N, 15.96. Found: C, 54.93; H, 4.90; N, 15.65.

122

The same trans compound was prepared in the same manner as above.

Reference Example 166

304 mg of cis-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine are suspended in 15 ml of ethanol. To the suspension was added 304 mg of 5% palladium on carbon. The mixture was stirred at room temperature under hydrogen atmosphere for 1.5 hours. The catalyst is filtered off and the filtrate is 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 are 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, prepared as described above. Reference Example 90.

The mixture was stirred under ice-cooling for 15 minutes and at room temperature for one hour. Ethyl acetate (200 ml) was added to extract the solution. The organic layer was washed twice with 0.1 N aqueous sodium hydroxide solution, once with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. There was thus obtained cis-3- [2- (2-chloroacetamido-4-thiazolyl) -2-Q1-methyl-1- (p-nitrobenzxyloxycarbonyl) ethyloxyimino] acetamido] -4-carbamoyl-2-oxoazetidine (syn isomer) as foam, m Mp 144-147 ° C.

IR spectrum (cm @ -1): 3380, 1760, 1750 and 1680. NMR spectrum (DMSO-d6, ppm):

1.52 (6H, s, 2 x _CH3), 4.27 (1H, d, J = 6Hz, 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, _C3 -H), 7.41 (1H, s, ^ s / H).

The same trans compound was prepared in the same manner as above.

Reference Example 167

4 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-hydroxymethyl-2-oxoazetidine, prepared according to Reference Example 5, are dissolved in 80 ml of methylene chloride.

While cooling with ice-water, 0.9 ml of chlorosulfonyl isocyanate was added to the solution, and the mixture was stirred for an additional 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 at room temperature for one hour while crystals were precipitated.

The crystals were dissolved by addition of methylene chloride. The methylene chloride layer was separated, washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off. Ether was added to the residue. The resulting crystals were filtered off. It will be produced

3.3 g of cis-3-benzyloxycarboxamido-1- (2,4-dimethoxybenzyl) -4-carbamoyloxymethyl-2-oxoazetidine. IR _Cm ^-1): 3400, 3300, 3200, 1760 and 1 690th

The above product was added to a mixture of 75 ml of acetonitrile and 37.5 ml of water. 6.5 g of potassium persulfate and 3.9 g of potassium hydrogen phosphate were added to the mixture. The mixture was stirred under a stream of argon for one hour with heating to 95 ° C. 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 silica gel column chromatography (90 g, eluting with a 85: 10: 5 mixture of chloroform and methanol and ethyl acetate). Colorless crystals of cis-3-benzyloxycarboxamido-4-carbamoyloxymethyl-2-oxoazetidine, melting at 205-207 ° C, were prepared.

IR (in ^cm @ -1) ^; 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 = 9Hz, _C3-NH), 8.16 ( 1H, br s,

N ₂ -H). For C ₃ H _{3 N-5} to _5: calculated: 53.23% C 5.15% H 14.32% N Found: 53.33% C,

H, 4.90; N, 14.09.

123

Reference Example 168

3 g of trans-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, prepared according to Reference Example 27, are dissolved in a mixture of 30 ml of tetrahydrofuran and 30 ml of water. % aqueous ammonium chloride solution and then 4 ml of 25-28% aqueous ammonia. The mixture was stirred at room temperature for 3 hours. Tetrahydrofuran was distilled off under reduced pressure. Sodium chloride was added to the remaining aqueous solution and extracted twice with a 3: 1 mixture of chloroform and ethanol. The extracts were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off in vacuo. The residue was purified by silica gel chromatography (180 g, eluting with ethyl acetate, then ethyl acetate-methanol 8: 1). Trans-3-benzyloxycarboxamido-4-carbamoyl-2-oxoazetidine, m.p. Mp 179-184 ° C.

IR spectrum ( ^ν max) ^: 280, 1760, 1695 and 1660. NMR Spectrum (DMSO-d6, ppm):

3.90 (1H, d, J = 3Hz, C ₄ -H), 4.42 (1H, dd, J = 3Hz, J = 9Hz, C 4 H), 8.04 (1H, d J = 9 Hz, C ₃ -NH).

Reference Example 169

31.0 g of freshly distilled methacrolein are dissolved in 300 ml of methylene chloride.

36.9 g of 2,4-dimethoxybenzylamine are added to the solution. To this solution was added 100 g of anhydrous sodium sulfate and 440 mg of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered. The filtrate was 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. A solution of 49.4 g of phthalimidoacetyl chloride in 300 ml of methylene chloride is then added dropwise over about one hour. The mixture was stirred overnight at room temperature.

The reaction mixture was filtered. Insoluble materials were washed with methylene chloride. The filtrate was combined with the washed dichloromethane solution and concentrated under reduced pressure to a volume of 0.5 L. The concentrate was washed sequentially 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 is chromatographed on a silica gel column (400 g, eluting with hexane / ethyl acetate 1: 1).

55.8 g of crude product cis-3-phthalimido-4-isopropenyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine are thus obtained. This product was dissolved in 500 ml of methanol and treated with 25 g of 5% palladium on carbon. The solution was stirred under an atmosphere of hydrogen for 7 hours while 870 ml of hydrogen were absorbed, the catalyst was filtered off and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, washed first with three times (100 ml) of 1N hydrochloric acid and then once with brine. After drying over anhydrous sodium sulfate, the solvent was 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 was stirred under a hydrogen atmosphere for 24 hours while absorbing 1900 ml of hydrogen. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (400 g, eluting with hexane-ethyl acetate 1: 1). The solvent was distilled off and ethanol was added to the residue. The resulting crystalline precipitate was 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 was 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. The crystalline precipitate was filtered off, washed with ethanol and dried. A further portion (5.3 g) of the above 4-isopropyl derivative was prepared. Recrystallization from ethanol gave colorless crystals which melted at 151-152 ° C.

124

Mass spectrum: m / z 408 (M ^& lt ^{; +} & gt ^; ). IR spectrum _{(? Max} cm ^Ol i ^-1): 1760 and 1 715th

For C ₂₃ H ₄ N ₂ O ₅ Calculated: C, 67.63 and 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. While cooling with ice and stirring, 2.1 ml of methylhydrazine is added dropwise. The mixture was stirred at room temperature for 4 hours and then at 35-40 ° C for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Pre-filtered crystals were added to the residue, 120 mL of dichloromethane was added, and the mixture was stirred at 60-70 ° C for 3 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was extracted first with 50 ml, then with a 20 ml portion of 1N hydrochloric acid, and the extract was washed with ether. After addition of 8.4 g of sodium bicarbonate, the oil is separated. This oil was extracted with chloroform, washed with brine and dried over anhydrous sodium sulfate.

The solvent was then distilled off under reduced pressure. The residue is dissolved in 10 ml of methylene chloride. To the solution was added 30 ml of propylene oxide. A solution of 3.55 g of carbobenzoxy chloride in 10 ml of methylene chloride is then added dropwise under ice-cooling and stirring, whereupon crystals are precipitated. 70 ml propylene oxide and 30 ml methylene chloride were added and the mixture was stirred at room temperature.

In doing so, the above crystals gradually dissolve to a clear solution (over 4 hours). The solvent is then distilled off. The residue was purified by silica gel column chromatography (250 g, eluting 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 (ν2ϊ ^ ^θ1> cm ^1): 3300, 1760 and 1 690. For the C "H. _Q N ₉ 0 _K calculated: 66.97 i C, max 22 2o 2

H, 6.84; N, 6.79. Found: C, 66.96; H, 6.83; N, 6.81.

Reference Example 171

To a mixture of 50 ml of acetonitrile and 25 ml of water is 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. Potassium hydrogen phosphate. The mixture was heated to 95 ° C with stirring for 2 hours under reflux. After cooling ^of the acetonitrile was removed under reduced pressure. 50 ml of water are added. The resulting solution was extracted with 200 mL of ethyl acetate. The extract was washed with two 100 ml portions of 2% aqueous sodium bicarbonate and once with brine. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue is heated a little with 50 ml of benzene and allowed to cool. Insoluble materials are filtered off and washed first with bezene, then with a small amount of ether.

1.1 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine are obtained, melting at 184-185 ° C. IR (cm⁻¹: 3340, 1760, 1690, for ^C 4 ^H 8 ^N ^ 2 ° 3 ⁱⁿ YP ^reading:

Found:% C, 63.58;% H, 6.75;% N, 10.47.

Reference Example 172

1.0 g of cis-3-benzyloxycarboxamido-4-isopropyl-2-oxoazetidine is suspended in 30 ml of ethanol. 1.0 g of 5% palladium on carbon was added to the suspension. The suspension was stirred under a hydrogen atmosphere for 30 minutes. The catalyst is then filtered off. The filtrate was evaporated to dryness under reduced pressure. This gives 430 mg of cis-3-araino-4-isopropyl-2-oxoazetidine crystals melting at 91-93 ° C.

KRr - 1

IR spectrum (ν ' _max <cm): 3350 to 3150, 1735. NMR spectrum (CDCl 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, _C4-H), 4.17 (1H, d, J = 5Hz, C ₃ - H).

125

For C ₆ H ₁₂ N ₂ O Calculated: C 56.22, H 9.44, N 21.86. Found: C 56.35, H 9.45, N 21.38.

Reference Example 173

3.7 g of p-anisidine are dissolved in 100 ml of methylene chloride. 4.2 g of trans-cinnamyl aldehyde and 30 mg of anhydrous magnesium sulfate are added to the solution. The mixture was stirred at room temperature for two hours. The reaction mixture was filtered and the filtered material was washed with 60 mL of dichloromethane. The filtrate and the washed dichloromethane fraction were combined. While cooling with ice and stirring, 8.4 ml of triethylamine are added first and then a solution of 7 g of phthalimidoacetyl chloride * in 50 ml of methylene chloride is added dropwise. The mixture was stirred at room temperature for one and a half hours. The reaction mixture was washed with water and brine. The methylene chloride was distilled off under reduced pressure.

To the residue was added 50 ml of chloroform. Insoluble materials are filtered off. The filtrate was concentrated under reduced pressure. The residue was crystallized from 25 ml of ethyl acetate. The crystals were filtered off. Thus cis-3-phthalimido-4- (E) -styryl-1- (p-methoxyphenyl) -2-oxozaetidine melts at 202-203 ° C. IR spectrum (cm ^-1): 1740 and 1 720. NMR (CDC1 _3, ppm): 3.74 (3H, s, OCH), 5.00 (1H, dd, J = 5 Hz, J = 7 Hz, C / H), 5.65 (1H, d, J = 5Hz, C, -II), 6.24 (1H, dd, J = 7Hz, J = 16Hz, H), 6.78 (1H, d, J = 16Hz, _-phenyl).

For ^C 16 ^H 20 ^N 2 O 4 ^{in ?} % C, 73.57;% H, 4.75;% N, 6.60. Found:% C, 73.56;% H; 4.58;

Reference Example 174

1 g of cis-3-phthalimido-4- (E) -styryl-1- (p-methoxyphenyl) -2-oxoazetidine is dissolved in 25 ml of tetrahydrofuran. To this solution is added dropwise a solution of cerium ammonium nitrate (3 g) in 10 ml of water dropwise at -5 ° C to -10 ° C over a period of five minutes. The mixture was stirred at -5 ° C to 0 ° C for twenty minutes. Tetrahydrofuran was distilled off under reduced pressure and the residue was shaken with ethyl acetate and water. The ethyl acetate layer was separated, washed with aqueous sodium sulfite, then brine, and dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by silica gel column chromatography (7: 3 chloroform: ethyl acetate). The product was crystallized from a mixture of ethyl acetate and ether.

Cis-3-phthalimido-4- (E) -styryl-2-oxoazetidine is produced, which melts at 168-170 ° C.

IR spectrum (cm ^-1 ): 3250, 1750 and 1720. NMR spectrum (CDCl3, ppm): 4.68 (1H, dd,

J = 5Hz, J = 8Hz, C / H), 5.57 (1H, d, J = 5Hz, 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 Ν, Ν-dimethylformamide. 0.36 ml of triethylamine and 323 mg of tert-butyldimethylsilyl chloride are added under ice-cooling and stirring. The mixture was stirred for 30 minutes and then at room temperature for 4 hours. The reaction mixture was then shaken with ethyl acetate and water. The ethyl acetate layer was 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 (eluted with chloroform). The product was recrystallized from ether.

Cis-3-phthalimido-4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine was prepared, melting at 167-168 ° C. IR spectrum ( _{cm @} -1). ν 759 _and χ 715. 1 H NMR spectrum (CDCl 3, 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: 6i, 41% C 6.52% H 6.48% N, nalzeno: 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 dimethoxyethane. To the suspension was added 0.26 ml of methyl hydrazine and the mixture was stirred at room temperature for 30 minutes. The solvent is then distilled off under reduced pressure. The residue was dissolved in 5 ml of methylene chloride and allowed to stand overnight. The precipitate was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (6: 4 chloroform: ethyl acetate). cis-3-amino-4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxoazetidine oil was prepared. This oil was dissolved in 10 mL of tetrahydrofuran. While cooling and stirring, 0.2 ml of triethylamine was added, followed by 0.212 of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl chloride hydrochloride. The mixture was stirred under ice-cooling for 10 minutes, then at room temperature for 30 minutes, then 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 (7: 3 chloroform: ethyl acetate). The product was recrystallized from ether. j

Cis [-2- (2-Chloroacetamido-4-thaisolyl) -2-methoxyiminoacetamido] -4- (E) -styryl-1- (tert-butyldimethylsilyl) -2-oxo-azetidine (syn isomer) is obtained, which melts at Mp 228-231 ° C / (dec.). IR cm ^<-1): 1 725 and 1 670. NMR (CDCl, ppm): 3.15 <3H, s, OCHjj), 4.20 (2H, s, C1CH _2), 4.63 (IH, m, C ₄ -H), 5.50 (1H, dd, J = 6 Hz, J = 6 Hz, C 1 H), 7.20 (1H, s, S 1 H, H), 8.50 ( 1H, d, J = 6 H2 (C8-NH3).

Reference Example 177

While stirring under a stream of nitrogen, 50 mL of dry tetrahydrofuran is cooled to -78 ° C.

20 ml of a 15% solution of butyllithium in hexane are then added thereto. 3.66 ml of diisopropylamine are added dropwise and the mixture is stirred at -78 ° C for 15 minutes. 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 was added dropwise. The mixture was stirred at -78 ° C for one hour. A solution of 4.34 g of p-toluenesulfonyl azide in 15 ml of dry tetrahydrofuran is then added dropwise. The mixture was stirred for one and a half hours at a temperature ranging from -50 to -60 ° C. To this was added dropwise 5.1 ml of trimethylsilyl chloride and the reaction mixture was 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 is purified by silica gel column chromatography.

2,2-Dimethyl-7-aido-1-aza-3-exabioyclo [4.2.0] octan-8-one was prepared as a mixture of cis-KBf-1 and trans-isomers (1: 4). IC spectrum (ν _max » ^cm ) ² 2,100 and 1,750. NMR spectrum (CDCl3, ppm): 4.20 (d, J 1.5 Hz, trans-C 1 H), 4.68 (d, J) 5 Hz, cis-C1-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 trana-2,2-dimethyl-7-azido-1-aza-3-oxabicyclo [4.2.0] octan-8-one are dissolved in 30 ml of acetone. 3.3 ml (8N solution) of Jones reagent are added under ice-cooling and stirring. The mixture was stirred for two and a half hours. 5 ml of isopropyl alcohol are then added and the mixture is stirred for a further 10 minutes. Materials that remain undissolved are filtered through celite. The filtrate was concentrated under reduced pressure. Shake the residue with tetrahdyrofuran and small

127 amounts of saturated aqueous sodium chloride. 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 is chromatographed on a silica gel column. Trans-3-azido-4-methoxycarbonylmethyl-2-oxoazetidine was prepared. Nuclear Magnetic Resonance 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 prepared as the cis and trans isomers as a mixture (in a ratio of 1: 4). ). NMR (CDC1 _3, ppm): 4.83 _(cis-3-C H).

Reference Example 179

800 mg of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid, prepared according to Reference Example 68, are dissolved in a mixture of 20 ml of tetrahydrofuran and 10 ml of water. 280 mg of sodium bicarbonate are added under ice-cooling. 303 mg o-methylhydroxylamine hydrochloride and 638 mg 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, brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Cis-3-benzyloxycarboxamido-4-methoxyaminocarbonyl-2-oxoazetidine was prepared, melting at 212-216 ° C (dec.). IR (cm &^lt; -1 ^&gt; ): 3290, 1760 and 1680.

Reference Example 180

To 8 ml of dry dimethylsulfoxide 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. 6 g of potassium cyanide and 50 mg of 18-crown-6.

The mixture was stirred at room temperature for 2 days, at 50 ° C for 3 hours, then poured into 250 mL of ethyl acetate. The reaction mixture is washed first with water three times, once with sodium chloride (solution in water), dried over magnesium sulphate and concentrated. The residue was purified by silica gel column chromatography (400 g, eluting with ethyl acetate / hexane 1: 2, then 2: 1).

Cis-3-Benzyloxycarboxamido-4-cyanomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine was prepared. IR (^, x 'cm ^-1): 3290, 2920, 1770, 2240 and 690. 1 H NMR (CDCl, ppm):

2.48 (2H, d, J = 6 Hz, CH ₂ CN), 3.78 (3H, s, OCH ₃ ), 3.80 (3H, s "OCl 11), 4.82 (1H, dd, J) = 5 Hz, J = 8 Hz, C ₃ -H).

Reference Example 181

1.7 g of cis-3-benzyloxycarboxamido-4-cyanomethyl-1- (2,4-dimethoxybenzyl) -2-oxoazetidine are dissolved in a mixture of 210 ml of acetonitrile and 70 ml of water. 1.68 g of potassium persulfate and 1.085 g of potassium hydrogen phosphate are added to the solution. The mixture was heated at 85-90 ° C under reflux for two and a half hours. The acetonitrile was distilled off under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (140 g, eluting with ethyl acetate / hexane 1: 2 then 1: 1/3). Cis-3-benzyloxycarboxamido-4-cyanomethyl-2-oxoazetidine was prepared, melting at 113-115 ° C. IR (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 was prepared. -oxoazetidine (syn isomer). IR spectrum (cm &^lt; -1 ^&gt; ) 1336, 2980, 2250, 1740, 1680,

600, 1,520, 1,345 and 1,140.

Reference Example 183

4 g of cis-3-benzyloxycarboxamido-2-oxoazetidine-4-carboxylic acid methyl ester, prepared according to Reference Example 2, are dissolved in a mixture of 100 ml of tetrahdyrofuran and 100 ml of water. 1.595 g of sodium hydrodiboronate are added under ice-cooling. The mixture was stirred under ice-cooling for one hour and then at room temperature for two hours. Tetrahydrofuran was distilled off under reduced pressure. The residue is 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 was added and the mixture was stirred under an atmosphere of hydrogen for four hours. The catalyst is then filtered off and the filtrate is concentrated. The residue was dissolved in a mixture of 20 ml of water and 20 ml of tetrahydrofuran. 3.62 g of sodium bicarbonate are added under ice-cooling. 3.41 g of p-nitrobenzyloxycarbonyl chloride was then added and the mixture was stirred at room temperature for two hours. This reaction mixture was extracted three times with chloroform. The extract was dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue is chromatographed on a silica gel column (160 g, eluting with a 4: 1 mixture of ethyl acetate and methanol) using initially pure ethyl acetate as the eluent).

Prepared cis-3- (p-nitrobenzyloxykarboxamido-4-hydroxymethyl-2-oxo-azetidine, which melts at 166-167 ° C. IR (cm ^-1): 3280, 1770 and 1 700. For C | 2 ^H 13 ^N ° 3 ⁶ ~ ^ reckoned: 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 was stirred under ice-cooling for 30 minutes and then at room temperature for one hour. It is concentrated under reduced pressure and the residue is shaken with 100 ml of water and 100 ml of ether. The aqueous layer was separated, acidified with 3N hydrochloric acid, and extracted twice with chloroform-ethanol (3: 1). The extract was dried over anhydrous magnesium sulfate. The solvent was distilled off.

KBx “1

1-Methyl-1H-tetrazol-5-yl-thioacetic acid was prepared. IR spectrum (H, cm):

990 and 700. 1 H NMR (CDC1 ₃ + _DMSO-dg, ppm): 3.82 (3H, s, CH-j), 3.98 (2H, s, _CH2),

4.10 (1H, s, CO 3 H).

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.