CS245753B2 - Production method of 7 beta-acylamido-3-cefem-4-carboxyle acids - Google Patents

Abstract

1399086 Cephalosporin compounds GLAXO LABORATORIES Ltd 12 May 1972 [14 May 1971 1 Oct 1971] 15082/71 and 45884/71 Heading C2C Novel 7 - acylamidoceph - 3 - em carboxylic acids and their salts, esters and 1-sulphoxides, wherein the acylamido group has the structure in which R is hydrogen or an organic group and R<SP>a</SP> is an etherifying monovalent organic group linked to the oxygen atom through a carbon atom, the said compounds having the syn isomeric form as regards the configuration of the group OR<SP>a</SP> with respect to the carboxamido group, or being a mixture of the syn and anti isomers containing at least 75% of the syn isomer, are prepared by acylating a 7-amino or 7-isocyanato-cephem carboxylic acid or its salt, ester or 1-oxide, with an acylating agent corresponding to the acid of formula and then recovering the desired acylamidocephem compound, if necessary after separation of the syn and anti isomers.

Description

(54) A method for producing 73-acylamine-3-cephem-4-carboxylic acids

The invention relates to a process for the production of a novel antibiotic of the cephalosporin series.

The nomenclature of the cephalosporin compounds as used in the specification is in agreement with J. Amer. Chem. Soc. 1962, 84 3 400. Thus, the term 'cefem' refers to a basic cepham structure with one double bond.

Cephalosporin autibiotics are known to be, for example, N-acylamido-cep-3-em-4-carboxylic acids and various non-toxic derivatives thereof, for example 9α, esters, lactones, if any, amides, hydrates and the corresponding sulfoxides. These antibiotics may carry various substituents, especially at the 3-position, including substituted or unsubstituted methyl groups, which may further carry various substituents as described in the literature.

The novel compounds of the invention have the property that the acylamide group of the cephalosporin antibiotic is a (α-etherified oximinojacylamide group), wherein the compounds may be syn-isomers or occur in mixtures where the syn-isomer form predominates.

According to one embodiment of the process according to the invention, a compound from the group of 7H-aminoamidoceph-3-em-4-carboxylic acids in which the acylamido group has the structure

R — C — CONH—

II

N \

ORa kde

R is hydrogen or an organic radical and

Ra represents an etherified monovalent organic group which is bonded to an oxygen atom by a carbon atom, the whole compound may be in the form of the syn-isomer or in a mixture containing at least 75% of the syn-isomer. It is preferred that the mixture of isomers comprises at least 90% of the syn-isomer and at most 10% of the anti-isomer®.

The compounds of the invention have the syn- (cis) isomeric form with respect to the configuration of the ORα group relative to the carboxamide group. The configuration is considered to be a syn-isomer

R — C — CO — NH—

II

N \

OR ^{and a} configuration is considered an anti-isomer These configurations are named after

Ahmad and Spencer (Can. J. Chem., 1961, 39, R-C-CO-NH-1340).

|| The compounds of the invention can be represented by the general formula I:

R ^and O

R С СО li

Z Í / J

COOtf /

where

^And R and R are as defined above,

В represents a sulfur atom or S → O and

Z represents a group in which 2 carbon atoms are bonded to the sulfur atom contained in the nucleus and a carbon atom which carries a carboxyl group and at the same time is Δ ³ unsaturated.

Accordingly, the present invention provides a process for the preparation of 7β-acylamido-3-cephem-4-carboxylic acids of formula I

(n

COOH where

R represents a hydrogen atom or a group R ', wherein

R ^u represents an aryl group having carbon ring having 6 to 12 carbon atoms, e.g. fenylovlou or naphthyl, five or six membered heterocyclic aryl containing at least one heteroatom loose from the group consisting of sulfur, nitrogen and oxygen, or a heterocyclic group fused with a benzene ring, for example, 2-thienyl, 3-thienyl, furyl, pyridyl, pyrrolyl, N-methylpyrrolyl, N-benzyloxymethylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-4 -isoxazolyl, benzothienyl, benzofuryl, indolyl, or sydnon, C 3 -C 7 cycloalkyl, for example cyclopentyl or cyclohexyl, any of the above being optionally substituted by halogen, hydroxy, C 1 -C 6 alkyl , nitro, amino, alkyl (C 1 -C 6) lamino, (C 1 -C 6) dialkylamino in each alkyl moiety, (C 1 -C 6) alkanoyl, (C 1 -C 6) alkyl amido, (C 1 -C 6) alkoxy, (C 1 -C 6) alkylthio carbon atoms in the alkyl moiety or cyclohexadienyl or R is a formula of the formula

R ^u (CH 2) _m Q _n (CH2) _p, wherein

R ^u is as defined above, m is 0 or an integer of 1-4, n is 0 or 1, p is an integer from 1 to 4 and

Q represents a sulfur atom, an oxygen atom or a group = NR ² where

R ² is hydrogen, or R represents a group of formula

Where n is an integer from 1 to 7, wherein these groups have a straight or branched chain and are optionally interrupted by an oxygen or sulfur atom or by a group = NR 2, where

R ² has the abovementioned meaning, or the group is optionally substituted by cyano, karboxyskuplnou, alkoxycarbonyl with 2-7 carbon atoms, hydroxy or a group of the formula carboxycarbonyl

HOOC-CO- or halogen, or R represents a group of formula

СпН ₂ п-Ь where J n is an integer q / 2 to 7, where this group is straight or branched, optionally interrupted by an oxygen or sulfur atom or by a group = NR 2, where

R ² is as defined above, or R represents a group of formula

СпНгп-з where n is an integer of 2 to 7 or a cyano, amido or alkoxycarbonyl group having 2 to 7 carbon atoms in the alkoxy moiety,

R ^a represents a C 1 -C 16 alkyl group, for example a methyl, ethyl, propyl, butyl / octyl or dodecyl group, a C 2 -C 16 alkenyl group, for example a vinyl, allyl, isopropenyl or dimethylallyl group, an alkynyl group having 2 to 16 carbon atoms C uhlíku-C,,, such as propargyl, C až-C cyk cyk cycloalkyl, for example cyclopropyl, cyclopentyl or cyclohexyl, C 4-C 7 cyk cycloalkenyl, for example cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, aryl ring with a carbon ring From 6 to 12 carbon atoms, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen or sulfur, optionally fused to a benzene ring or another such atom; a heterocyclic group such as a pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, thiadiazolyl, diazolyl, thiazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl or purinyl or C 1 -C 4 alkyl group having a carbon atom of 1 to 4 carbon atoms or a heterocyclic ring as defined above, for example, benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl, furylmethyl, pyridylmethyl or pyrrolylmethyl, each of which is optionally substituted with a halogen atom such as chlorine or bromine, hydroxy, C1-C6alkoxy , for example, methoxy, ethoxy or propoxy, aryloxy of 6 to 12 carbon atoms, for example phenoxy, phenylalkoxy of 1 to 4 carbon atoms in the alkyl moiety, for example benzyloxy, mercapto C1-6 alkylthio, e.g. methylthio or ethylthio, C6-12 arylthio, C1-4 alkylthio, C1-4 alkylthio, amino, C1-6 alkylamino, e.g., methylamino, dialkylamino or ethylamino; from 1 to 6 carbon atoms in each alkyl moiety, for example, dimethylamino, nitro, azido, carboxy, alkoxycarbonyl of 2 to 7 carbon atoms in the alkoxy moiety, for example methoxycarbonyl or ethoxycarbonyl, benzyloxycarbonyl, formyl, 1 to 10 acyl , for example, acetyl, propionyl or benzoyl, acyloxy of 1 to 10 carbon atoms, for example acetoxy, propionyloxy or pivaloyloxy, cyano, phthalimido, acylamido of 1 to 10 carbon atoms, for example aceta a mono or benzoxybenzyl group, and alkoxycarbony laminos C 2 -C 7 alkoxy groups, for example methoxycarbonylamino or C 2 -C 5 phenylalkoxycarbonylamino, for example benzyloxycarbonylamino

G represents a hydrogen atom or a methyl or ethyl group or a group of the formula

R ³ /

-CH = C \

r4 kde

R ³ and R ⁴ , which are the same or different, represent a hydrogen atom, a nitrile group, a C 2 -C 7 alkoxycarboxy group, a C 1 -C 6 alkyl group, a C 5 -C 7 cycloalkyl group, a C 1 -C 7 phenylalkyl group up to 4 carbon atoms in the alkyl moiety or an aromatic group having 6 to 12 carbon atoms, optionally substituted by a nitro group, for example a vinyl group or a group of the formula

CHžY kde

Y represents a pyridine, base, N-pyrimidine, N-purine, N-pyridazine, N-pyrazine, N-pyrazole, N-imidazole, N-triazole or N-thiazole cation radical optionally substituted by a 1-alkyl group C 1 -C 6 aryl, C 1 -C 4 aryl, C 1 -C 4 phenylalkyl, C 2 -C 7 alkoxymethyl, formyl, C 1 -C 8 acyloxy, C 2 -C 8 acyloxymethyl 9 carbon atoms in the acyl moiety, alkoxycarbonyl of 2 to 7 carbon atoms in the alkoxy moiety, benzyloxycarbonyl, alkoxy of 1 to 6 carbon atoms, aryloxy of 6 to 12 carbon atoms, phenylalkoxy of 1 to 4 carbon atoms in the alkoxy moiety, alkylthio (C 1 -C 6), (C 6 -C 12) arylthio, (C 1 -C 4) phenylalkylthio, cyano, hydroxy, carbamoyl, N-monoalkylcarbamoyl of 1-6 carbon atoms in the alkyl moiety, Ν, Ν-dialkylcarbamoyl of 1-6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl of 1-6 carbon atoms in the alkyl moiety, or carbamoylalkyl (C až-C části) alkyl moiety, (Cid-C az) azido, amino or acylamido group, derived from a derivative obtained by the reaction of a compound in which Y is an azido group with a dipolarophilic acetylene or ethylene or cyano group,

R 5 —C — CO — R ⁷

- S (O) _n R ⁸ where

R ⁸ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having a carbon ring having 6 to 12 carbon atoms, or a phenylalkyl group having 1 to carbon in the alkyl moiety, or above, m thiadiazolyl, vu, tetrazolyl, thiazolyl, zolyl, bemzimidazolyl, benzoxazolyl, zothiazolyl, triazolopyridinyl, purinyl, pyridyl or pyrimyl group or any of those substituted with both alkyl and carbon atoms, phenyl group if or nitro, n is 0, n, 0, n, further preferably Y represents a group of the formula irocyclic atoms, for example diazolyl, triazolylothiatriaoxazolyl, oxadiazylphlyl, benidyl group having from 1 to 6 ll of O, -OR 'where

R 'represents a hydrogen atom, an acetoxy group, a group of the formula —O — COR ⁹ wherein

R ⁵ and R ⁶ which are the same or different denote hydrogen, cyano, C 1 -C 6 alkyl, phenyl, halogenphenyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkoxyphenyl C 6 alkoxy, nitrophenyl, aminophenyl, C 1 -C 6 alkylaminophenyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 5 mono- or diphenylalkoxycarbonyl, alkylcarbonyl a (C 2 -C 7) alkyl group, a (C 1 -C 4) phenylalkyl group, or a (C 5 -C 6) cycloalkyl group; and

R ⁷ represents a hydrogen atom, a C 1-6 alkyl group, a phenyl group, a halophenyl group, an alkylphenyl group having 1 to 6 carbon atoms in the alkyl moiety, an alkoxyphenyl group having 1 to 6 carbon atoms in the alkoxy moiety, a nitrophenyl group, an aminophenyl group , (C 1 -C 6) alkylaminophenyl, (C 1 -C 4) phenylalkyl or C 5 or C 6 cycloalkyl;

R &lt; ^{9 &gt}; is an organic group having a weight of at least 16, which is selected from the group consisting of a pattern

3.

Where n represents an integer of 1 to 7 and a straight or branched chain, optionally interrupted by an oxygen or sulfur atom or an imino group or substituted by cyano, carboxy, alkoxycarbonyl of 2 and m and C in alkoxy, hydroxy, carboxycarbonyl halogen or aminoskupinod nu is full of formula wherein Y7 is atoэи, ATO., skupiCnHán-i wherein n is an integer of 2-7 and R is a straight or branched chain PC case interrupted by ^one oxygen atom, sulfur atom or imino group of the formula

Where ^R

R ^v represents a C 6 -C 12 carbon ring aryl group, for example a phenyl or naphthyl group of 6 or 6 membered heterocycles, a pentyl aryl group containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, or such a heterocyclic group fused with a benzene ring such as 2-thien, 3-thien, furyl, pyridyl, pyrrolyl-N-methylpyrrolyl, N-benzyloxymethylpyronlylvyl, isothiazolyl, thiadiazolyl, othiazolyl, 3- or 4-isoxazolyl, 3-phenyl- or 5-phenylphenyl -methyl-4-isoxazolyl, benzothienyl, benzofuryl, indolyl or cyan, cycloalkyl of 3 to 7 carbon atoms, e.g. cyclopentyto or -cyclohexyl, any of the above being optionally substituted by halogen, hydroxy, (C 1 -C 6) alkyl, nitro, amino u, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, in each alkyl moiety, (C 1 -C 6) alkanoyl, (C 1 -C 6) alkanoylamino, (C 1 -C 6) alkoxy, or an alkylthio group having 1 to 6 carbon atoms in the alkyl moiety or a cyclohexadienyl group, or a group of the formula

R ^v - (CH ₂ j _m where

R ^v is as defined above and m is an integer from 1 to 4, a group of the formula -O-CO-AR ^9a wherein

A represents an oxygen atom, a sulfur atom or a group = NH and

R9 ^and - represents a hydrogen atom, a methyl group or - a group R9 as defined above, a group of the formula —O — CO — NH (CH2) mD wherein:

D represents a halogen atom, for example a chlorine, bromine, iodine or fluorine atom, and m is an integer from 1 to 4, for example 2-chloroethylaminocarbonyloxy, or a chlorine, bromine or iodine atom, as well as non-toxic pharmaceutically acceptable salts and sulfoxides.

The term non-toxic means derivatives of the compounds of the invention which are physiologically acceptable at the dosages at which they are administered.

The salts that can be made from the compounds of the invention are, for example,

a] salts with an inorganic base such as an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium - and an organic base such as procaine, phenylethylbenzylamine and dibenzylethylenediamine, bj-acid addition salts such as hydrochloric acid, hydrobromic, sulfuric, nitric, phosphoric, -paratoluenesulfonic and methanesulfonic.

The salts may also be in the form of resins formed, for example, with a polystyrene resin containing amino groups, a quaternary ammonium group or a sulfonic acid residue, or with a resin containing carboxyl groups, for example polyacrylate. It is also possible to use a resin which contains cross bridges, for example a copolymer of styrene and divinylbenzene, which contains one of the groups mentioned above. In addition, the derivatives of the compounds of the invention may take the form of a chelate with a heavy metal, for example iron or copper.

The compounds of the present invention and their non-toxic derivatives have high antibacterial activity against a wide variety of gram-positive and gram-negative microorganisms, as well as very high stability with respect to the enzymes / Mactamases produced by various gram-negative microorganisms.

Stability with respect to β-lactamases is determined, for example, by comparison with cefatoridine, whose degradation rate is determined to be> one relative to the microorganism used.

The properties of the compounds of the invention allow the use of these compounds for the treatment of various diseases caused by pathogenic bacteria in humans and animals.

Preferred cephalosporin compounds of the invention can be represented by formula II

В

RC-CONH — r— (O ⁴ OR ^and OX> W ₍ | D where

R, Ra and B mean the same thing as above and

P is an organic radical or is a non-toxic derivative thereof. In formula II, B is preferably a divalent sulfur atom.

The invention also includes cephalosporin compounds that do not specifically fall within the scope of Formula II, for example 2-methylcephalosporin and 2-methylencephalosporin.

In the above formula, the group R &lt; a ^&gt; can be any group that contains a single free valence carbon atom, so that this group can form the desired ether group with the carbon atom. The Ra group contains no more than 16 carbon atoms.

Ra can be, for example, alkyl of 1 to 16 carbon atoms, in particular lower alkyl of 1 to 8 carbon atoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, octyl or dodecyl, alkenyl of 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, such as vinyl, allyl, isopropenyl or dimethylallyl, alkynyl of 2 to 16 carbon atoms, preferably 2 to 8 carbon atoms, for example propynyl or; propargyl, cycloalkyl of 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl or cyclohexyl, cycloalkenyl of 4 to 7 carbon atoms such as cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, aryl containing a carboxyl group such as phenyl or naphthyl, a heterocyclic group, in particular with a 5- or 6-membered ring containing at least one heteroatom, namely oxygen, nitrogen or sulfur, such as pyridyl, pyrimidyl, furyl, thienyl, thiazolyl, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl or benzoxazolyl or lower alkyl further substituted with aryl containing a carboxyl group or a heterocyclic radical, the alkyl portion of which contains 1 to 4 carbon atoms, for example benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl such as thien-2-ylmethyl, furylmethyl such as furfuryl , pyridylmethyl or pyrrolylmethyl.

The group R a may be unsubstituted or may carry 1 or more substituents, for example hydroxyl, alkoxy, such as methoxy, ethoxy, n-propoxyl or isopropoxyl, methoxymethyl or 1-ethoxyethyl, further aryloxy, for example phenoxyl, apylalkoxy, for example benzyloxy, mercapto an alkylthio group such as methylthio or ethylthio, arylthio, arylalkylthio, amino such as 2-aminoethyl, substituted amino such as methylamino or ethylamino or dimethylamino, a halogen atom such as chloro or bromo to form, for example, 2-bromoethyl, nitro, a carboxyl group, an esterified carboxyl group, for example a lower alkoxycarbonyl such as methoxycarbonyl or ethoxycarbonyl, benzyloxycarbonyl, formyl, acyl such as acetyl, propionyl or benzoyl, acyloxy such as acetoxy, propionyloxy or pivaloyloxy, phthalimido, cyano, a lamido group such as acetamido or benzamido, alkoxycarbonylamino such as methoxycarbonylamino or ethoxycarbonylamino, or arylalkoxycarbonylamino such as benzyloxycarbonylamino.

The group R in the above formula may have the following meanings, but is not intended to be limiting:

i) hydrogen, if any) ^with the group R, ⁱⁿ which R is aryl and · · with the carbon or heterocyclic ring, cycloalkyl, substituted aryl, substituted cycloalkyl Nu, cycloalkadienyl, or non-aromatic group or a group containing · zwitterion. Examples of these groups are phenyl, naphthyl, such as 1-naphthyl, phenyl or naphthyl further substituted with a halogen atom such as chlorine or bromine to form, for example, o-chlorophenyl, hydroxy, lower alkyl such as methyl, nitro, amino, lower alkylamino, for example methylamino, di (lower) alkylamino such as dimethylamino, lower alkanoyl, for example acetyl, lower alkanoylamido, lower. alkoxy, such as methoxy or ethoxy, lower alkylthio, such as methylthio. Ru may also be a 5 or 6 membered heterocyclic ring containing at least 1 heteroatom, namely sulfur, nitrogen or oxygen, for example thien-2-yl, thien-3-yl, furyl such as fur-2-yl, pyridyl such as pyrid-3 -yl, pyrrolyl, N-substituted pyrrolyl, such as N-methylpyrrolyl, isothiazolyl, thiadiazolyl, oxadiazole,

3- or 4-isoxazolyl, substituted with 3 or 4

4-isolxazolyl, such as 3- (4-methyl-5-methylisoxazole) -4-

-yl, wherein aryl is phenyl or halo-phenyl; fused heterocyclic groups containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, such as benzothienyl, for example benzothien-3-yl, benzofuryl, indolyl, cyclohexyl, cyclopentyl, sydnon, and cyclohexadienyl. (iii) R ^u (CH 2) _m Q, ₁ (CH 2) p, wherein R ^u is as defined above, m represents 0 or · an integer from 1 to 4, n represents 0 or · 1, p is an integer from 1 to 4 4 and Q represents a sulfur atom, an oxygen atom or an NR group wherein R represents a hydrogen atom or an organic group, for example an alkyl such as methyl or an aryl such as phenyl. · Examples of such groups are methyl, ethyl, or · butyl substituted ^with R groups as listed in Section II), e.g., benzyl, and appropriately substituted benzyl.

iv) C _n H _{2n + 1} , where n is an integer from 1 to 7. These groups may be straight or branched and optionally interrupted by an oxygen or sulfur atom or by an NR group where R is a hydrogen atom or an organic group, for example alkyl such as methyl or aryl such as phenyl; or it may be substituted by cyano, carboxyl, alkoxycarbonyl, hydroxycarbonyl or carbocarbonyl in the group -HOOC-CO- or halogen. Examples of such groups are hexyl, heptyl, butylthiomethyl, cyanomethyl or trihalomethyl.

v) CnH2n-i, where n is an integer from 2 to 7. This group may be straight or branched, optionally interrupted by an oxygen or sulfur atom or by a group NR, where R represents a hydrogen atom or an organic group, for example alkyl such as methyl or aryl such as phenyl. Examples of such groups are vinyl or propenyl.

24575 13 vi] C _n H _2n 3, where n is an integer from 2 to 7. An example of such groups is ethynyl.

vii] Various organic groups attached to a carbon atom, for example cyano, amido or lower carbonyl.

The substituent P at the 3-position of the above compounds of formula (II) may be any organic group since the essential group for the properties of the compounds of the invention is the 7-position. P may therefore be an saturated or unsaturated, substituted or unsubstituted organic group of 1 to 20 atoms. carbon. Of the saturated organic groups, methyl and ethyl are preferred, of the unsaturated organic groups, vinyl and substituted vinyl groups of the formula

R 3 / -CH-C 1 R 4 wherein

R 3 and R ^4, which may be the same or different, represent a hydrogen atom - or a substituted or unsubstituted aliphatic group (alkyl, preferably alkyl of 1 to 6 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, etc.), cycloaliphatic a C 5 -C 7 group, such as cyclopentyl or · cyclohexyl, an-C 7 -C 10 -arylaliphatic group, for example benzyl or phenylethyl, an aromatic group having 6 to 12 carbon atoms (for example phenyl or nitrophenyl), nitrile or lower alkoxycarbonyl .

When P is substituted methyl, this group can be represented by the formula —CH2 where

Y represents an atom or a group, for example a nucleophile residue or a substituted nucleophile residue.

Thus, Y may be derived from a wide variety of nucleophilic substances which are characterized in that they contain a nucleophilic nitrogen, carbon, sulfur or oxygen atom. These compounds have previously been extensively described in the patent literature and in the literature on cephalosporin chemistry. Examples of nucleophilic groups include:

Nitrogen-containing nucleophiles

Examples of such compounds are tertiary aliphatic, aromatic, araliphatic and cyclic amines such as trialkylamines, for example triethylamine, pyridine bases such as pyridine and alkylpyridines, heterocyclic amines with more than one heteroatom, at least one of which is a nitrogen atom such as pyrimidines, purines, pyrida3 zines, pyrazines, pyrazoles, imidazoles, triazoles and thiazoles.

A preferred group of nucleophiles containing a nitrogen atom are compounds of formula

N wherein n is 0 or an integer from 1 to -5 a

Rd which, when n is 2 to -5, may be the same or different, represents an aliphatic group, for example, lower alkyl such as methyl, ethyl, n-propyl, isopropyl etc., aryl, such as phenyl, arylaliphatic such as phenyl substituted by lower alkyl i.e. benzyl, phenylethyl and the like, alkoxymethyl such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl etc., acyloxymethyl such as alkanoyloxymethyl - for example acetoxymethyl, formyl, - carbamoyl, acyloxy such as alkanoyloxy such as acetoxyl, esterified carboxyl, alkoxy such as methoxy, ethoxy, n-propoxyl, isopropoxyl and the like, aryloxy such as phenoxy, arylalkoxy such as benzyloxy, alkylthio such as methylthio and ethylthio, arylthio, hydroxy, mono, arylalkylthio, arylalkylthio, N-methylcarbamoyl, N-ethylcarbamoyl and the like, N, N-di (lower alkylcarbamoyl, such as Ν, Ν-dimethylcarbamoyl, N, N-diethylcarbamoyl and the like, N- (h) hydroxy (lower alkyl)] carbamoyl, such as N- (hydroxymethyl) carbamoyl, N- (hydroxyethyl) carbamoyl and so on, carbamoyl (lower-alkyl) such as carbamoylmethyl, carbamoylethyl-etc.

Another preferred class of these are azides, for example with alkali metals such as sodium azide.

When Y is a derivative or a residue of a nucleophile, it may be -amino or acylamido. Compounds in which Y is amino can be derived by reduction of the corresponding azide, for example by catalytic hydrogenation of the azide, using a precious metal such as palladium or platinum as the catalyst.

The amino group can be subjected to acylation to form a compound containing an -acylaminomethyl group at the 3-position. These compounds can be formed by any method suitable for acylating an aminocephalosporin, for example by reacting a 3-aminomethyl compound with an acid chloride, acid anhydride, mixed anhydride or an acid whose acyl group is the desired group.

The 3-aminomethyl compounds can also be reacted with a substituted isocyanate to form urea or thiourea derivatives. Other compounds in which Y is a derivative or residue of a nucleophile can be obtained by coupling the 3-azidomethyl compound with a dipolarophilic group. A preferred class of dipolarophilic substances are acetylene, ethylene and cyano-containing compounds.

The acetylene-type dipolarophilic groups can be represented by the general formula

R1-C = C-R ² wherein

Rl and ^R2 which may be identical or different, represent the atoms or groups listed above.

It is preferred that R1 and preferably R2 are of an electronegative nature. Examples of such groups are cyano, CO ² R ³ , COR ³ (where R ³ is, for example, lower alkyl, aryl or lower arylalkyl), and trihalomethyl such as trifluoromethyl.

And preferably R ¹ and R 2 but can also be electropositive nature, can mean for example alkoxy or alkylamino.

^R1 and R2 may together form a ring, thus creating for instance arin.

In case that ^R1 and R2 are separated by atoms or groups which are the same, formed in the reaction with azidocefalosporinem compound which is a single type ·. When these symbols have different meanings, a mixture of positional isomers is usually obtained.

Dipolarophilic groups of the ethylene type can be represented by the general formula

R ^with R \ /

C == C / \

R®R® where

R ⁵ , R 6, R 7 and R ⁸ may be the same or different and represent the atoms or groups mentioned above.

Although R 5, R 7, R 7 and R 8 may all be hydrogen, ethylene alone, as well as acetylene, reacts slowly with azide groups. R 5 and R ⁷ together may form a ring, for example a carbon, in which two double bonds may be adjacent to each other. Examples of groups containing chained double bonds are norbornenes, trans-cycloalkenes and acenaphthalene.

Other dipolarophile compound of ethylenic type, which may be used include compounds of the type in itself R5r8-C = CR ⁷ R® wherein at least one of R5, R®, R ⁷ and R 8 is an electronegative group ·. R 5 and R 7 can be the same electronegative groups and R ® and R 8 can be other negative groups as desired. R 8 and R 8 may form a ring together. Examples of such groups are benzoquinone and nucleosubstituted benzoquinone, as well as maleic imide. All R 5, R 7, R 7 and R 8 groups may be the same electronegative groups. Groups which may be used include those already mentioned in the calculation of acetylene type dipolarophilic substances. Examples thereof are dicyanoethylene and lower mono- and dialkoxycarbonylethylenes.

One or more of R 5, R 8, R 7 and R 8 may be electropositive.

Cyano compounds, especially those activated by electronegative groups, may act as dipolarophilic substances containing cyano groups. Examples of such groups are cyanogen and lower alkoxycarbonyl cyanides.

Carbon nucleophiles

The term organic cyanides, pyrroles and substituted pyrroles, for example indoles and compounds which may be a source of fixed anions based on a carbon atom, for example acetylenes and compounds containing β-diketone groups such as acetic and esters of malonic acid , cyclohexane-1,3-diones, enamines, inamines or enols.

These groups can give rise to cephalosporin compounds having a substituent at the 3-position in which the carbonyl group is attached to the cephalosporin nucleus by two carbon atoms. These compounds therefore have a group of the general formula at the 3-position

R2

I —CH2 — C — CO — R ⁴

AND

R3 where

R 2 and R 3, which may be the same or different, are hydrogen, cyano, lower alkyl such as methyl or ethyl, phenyl substituted with halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino, lower alkoxycarbonyl, mono- or diaryl (lower alkoxy) carbonyl, lower alkylcarbonyl, aryl (lower alkyl) or cycloalkyl of 5 to 6 carbon atoms, and

R 4 is hydrogen, lower alkyl such as methyl or ethyl, phenyl, phenyl substituted with halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino, aryl (lower alkyl) or cycloalkyl of 5 to 6 carbon atoms.

Sulfur-containing nucleophiles

Examples of sulfur-containing nucleophilic groups are thiourea and thioureas substituted with aliphatic, aromatic, arylaliphatic, allylcyclic and heterocyclic dithlokarbamates, aromatic, aliphatic and cyclic thioamides,

24S753 for example thioacetamide thicsemicarbazide, thiosulfates, thiols, thiophenols, thioacids _; for example thiobenzoic acid or thiopicolinic acid and dithioacid.

Preferred are those which can be represented by the formula

R ¹ —S (O) _n H where

R 1 represents an aliphatic group, for example a lower alkyl group such as methyl, ethyl, n-propyl etc., an alicyclic group such as cyclohexyl, cyclopentyl and the like, an aromatic group such as phenyl, naphthyl and the like, an aryl aliphatic group such as benzyl or heterocyclic; an integer of 0, 1 or 2.

A particularly preferred class of these compounds are those which can be represented by the general formula

R ⁶ SH where

R ⁶ represents an aliphatic group, for example, methyl, ethyl, n-propyl and the like, an arylaliphatic group such as phenyl substituted by lower alkyl, i.e. benzyl, phenylethyl and the like, or substituted phenyl, further substituted by lower alkyl, alicyclic groups such as cyclopentyl or cyclohexyl aromatic groups such as phenyl or substituted phenyl · or a 5- to 6-membered heterocyclic ring containing at least one oxygen, nitrogen and sulfur atom, for example triadiazolyl groups, in particular 5-methyl-1,3,4-thiadiazol-2-yl Diazolyl, triazolyl. Tetrazo, lyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl and pyrimidyl, or a substituted heterocyclic group, including groups substituted by divalent groups, to form a fused nucleus, for example Benzimidazolyl, benzoxazolyl, triazolopyridyl and purinyl.

Oxygen-containing nucleophiles

Examples of such compounds are water, alcohols, for example alkanoyl such as methanol, ethanol, propanol and butanol, and acids derived from lower alkanes and alkenes.

Thus, the term "oxygen-containing nucleophiles" includes compounds of the general formula

ROH where

R 6 is lower alkyl such as methyl, ethyl, n-propyl, isopropyl. n-butyl, isobutyl etc., lower · alkenyl, for example allyl, lower alkynyl, for example propynyl etc., lower cycloalkyl, for example cyclopropyl, cyclopentyl, cyclohexyl, etc., (lower cyclOalkyl) - (lower alkyl) for example cyclopropylmethyl , cyclopentylmethyl ,. cyclohexylethyl and the like, aryl such as phenyl or naphthyl, aryl (lower alkyl) such as benzyl, heterocyclic group, lower alkyl substituted heterocyclic group such as furfuryl or any of these groups further substituted by, for example, one or more lower alkoxy groups such as methoxy, ethoxy and the like, lower alkylthio such as methylthio or ethylthio and the like, halogen, such as chlorine, bromine, iodine or fluorine, lower alkyl such as methyl, ethyl and the like, nitro, hydroxyl, acyloxy, carboxyl, carbalkoxy, lower alkylcarbornyl, alkylsulfonyl, lower alkoxysulfonyl, amino, lower alkylamino or acylamino.

When the nucleophilic oxygen-containing group is water, 3-hydroxymethylcephalosporin is obtained. These compounds can be represented by formula (A)

R-C-CONH ·!!

N. a. O ^0R СООЦ

where

R and Ra mean the same as above.

Compounds of formula (A) and non-toxic derivatives thereof have antibacterial activity and may in principle be metabolites of compounds of formula (II) in which B represents a sulfur atom and P represents acetoxymethyl. Compounds of formula (A) may be acylated to derivatives containing 3-CH2-O-CO-R9 or 3-CH2-O-CO-AR10 wherein A is O, S or R, R9 is methyl or organic an atomic mass group of at least 16 and R 10 represents a hydrogen atom or R 9.

The group R 9 CO - or R ^W ACO - may be any of a wide group of residues that have been described in the literature and contain up to 20 carbon atoms. Thus, R9 may be a hydrocarbon radical which may be optionally substituted by one or more atoms or by one or more groups. The groups R9 can be selected, for example, from the following groups:

(i) C _n H _? n + 1, where n is an integer from 1 to 7, for example from 2 to 4. The group may be straight or branched and, if desired, may be interrupted by an oxygen or sulfur atom or an imino group, or may be substituted by cyano, carboxyl , alkoxycarbonyl, hydroxyl, carboxycarbonyl, a halogen atom such as chlorine, bromine or iodine, or an amino group. Examples of these groups are ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and 2-chloroethyl.

(ii) Cr; H _2n. -i, where n is an integer from 2 to 7. The group may have a straight or branched chain.

If desired, it may be interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups are vinyl or proipenyl.

(iii) R ^v , wherein R ^v is aryl, with a carbon ring or a heterocyclic, cycloalkyl, substituted aryl or substituted cycloalkyl. Examples of such groups are phenyl, substituted phenyl such as hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl, as well as trien-2-yl and trien-3-yl, pyridyl, cyclohexyl, cyclopentyl, cyclopropyl, sydnon, naphthyl , substituted naphthyl such as 2-ethoxynaphthyl.

(iv) R ^v (CH 2) _m , wherein R ^v is as defined above and _m is an integer from 1 to 4. Examples of such groups may be methyl, ethyl or butyl substituted with various R ^v groups as described in (iii) for example benzyl and appropriately substituted benzyl groups.

An important group of cephalosporin compounds are those containing the 3-NgNa1 group, where Hal is a chlorine, bromine or iodine atom. These compounds are also very valuable intermediates in the production of active cephalosporin compounds.

An important group of antibiotics which can be produced by the method of the invention and which have a broad spectrum of antibiotic activity, including activity against different strains of Haemphilus influenzae together with stability to β-lactamase, which is produced by different gram-negative microorganisms

or they are nontoxic derivatives of these compounds. In formula В R ^among phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl and pyridyl, or any of these groups further substituted with halogen, namely chlorine, bromine, iodine or fluorine, hydroxy, lower alkyl, nitro-ou, amino, lower alkylamino, di (lower alkyl) amino, lower alkanoyl, lower alkanoylamido, lower alkoxy, lower alkylthio or carbamoyl, R ^b represents lower alkyl, cycloalkyl of 3 to 7 carbon atoms or aryl with a carbon or heterocyclic ring, lower alkyl or any of these groups further substituted by hydroxyl, carboxyl, esterified carboxyl, amido, cyano, alkanoyl, amino, amino substituted, halogen or lower alkoxy. The group Y is selected from the group consisting of (a) an acetoxy group, (b) a nitrogen-containing nucleophile residue of the general formula wherein

R ^d and n are as defined above, in which case the 4-position of the compound of formula (V) is -CO 2;

(c) a -SW group wherein W is thiadiazolyl, preferably 5-methyl-1,3,4-thiadiazol-2-yl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, triazolopyridyl, purinyl, pyridyl or ¹ pyrimidyl;

(d) lower alkylthio of 1 to 4 carbon atoms;

(e) -O-CO-R ⁹ wherein R ⁹ is alkyl of 2-4 carbon uhlíkp or alkenyl of 2-4 carbon atoms, (f) -O-CO-NH- (CHžjmD, wherein m is an 1 to 4 and D represents a chlorine, bromine, iodine or fluorine atom and (g) an azido group.

A particularly important group of compounds of formula (V) with respect to the aptlbiotic spectrum, including activity against various strains of Pseudomonas pyocyanea, are compounds of formula (C).

CO-NH

СООЦ (C) where

R ^x is phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl and

R ^c represents alkyl of 2 to 4 carbon atoms, benzyl, phenylethyl, thienylmethyl or furylmethyl, as well as non-toxic derivatives thereof.

Important compounds that fall under formula C are the following compounds in their syn-isomeric form:

3-Acetoxymethyl-7 / 3-

- (2-Ethoxyimino-2-phenyl-l- acetamide) ceph-3-em-4-carboxylic acid, 3-acetoxymethyl-7 _l 6-

- (2-t-butoxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl-7 ->

- [2- (2-Thienyl) methoxyimino-2-

- (2-Thienyl) acetamido] cef-3-em-4-

-carboxylic acid, 3-acetoxymethyl-7 -

- [2-t-butoxyimino-2- (2-furyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl-7 / 3-

- [2-benzyloxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, 3-acetoxymethyl-7H-

- [2- t -butoxyimino-2- (1-naphthyl) acetamido] cef-3-em-4-carboxylic acid and 3-acetoxymethyl-7 -

- [2-n-butoxyimino-2- (2-thienyl) acetamido] cef-3-em-4-carboxylic acid, especially in the form of its sodium or potassium salts.

An important group of compounds that fall under the general formula V due to their broad antibiotic spectrum together with high activity against various strains of Haemophilus influenzae are compounds of the general formula D

COOH _(D) where

R ^x and R ^b have the above meanings of a

T represents an acetoxy group, an azide group, a nitrogen-containing nucleophile residue of the formula

where

R ^d and n are as defined above, or -O-CO-R ⁹ , wherein R ⁹ is alkyl of 2 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or phenyl, as well as non-toxic derivatives thereof.

Another important group of compounds of formula VI with a large absorption coefficient for oral administration in animal experiments and with a broad spectrum of activity are compounds of formula E

where

R ^x and R ^b are as defined above,

V is lower alkylthio of 1 to 4 carbon atoms, alkanoyl of 2 to 4 carbon atoms or alkenoyl of 2 to 4 carbon atoms, as well as non-toxic derivatives of these compounds.

Another important group of compounds of formula (V) with a high degree of activity against various gram-positive and gram-negative microorganisms and with high stability to the action of β-lactamases produced by different microorganisms are compounds of formula F

COOH

CH 2 OCOCH 2 (F) wherein

R ^x is the same as above in formula C, as well as the non-toxic derivatives of these compounds.

A particularly preferred compound of formula F is 3-acetoxymethyl-7β- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of its syn isomer, particularly as the sodium or potassium salt.

The compounds of the invention can be prepared by any suitable method. In one embodiment of the process of the invention, compounds of formula (I) may be prepared

R = C-CO-NH

II

Z Í / J

COOH /

where

R * is the same as above in formula C as well as the non-toxic derivatives of these compounds.

A particularly preferred compound of formula F is 3-acetoxymethyl-73- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of its syn isomer, particularly as the sodium or potassium salt.

The compounds of the formula I as well as their non-toxic pharmaceutically acceptable salts and sulphoxides are prepared according to the invention by producing a compound of the formula III

(1Ш where

G is as defined above and

R ¹⁰ represents a hydrogen atom or a carboxy protecting group, or an N-silylated derivative thereof or an acid addition salt thereof, condensed with an acylating agent corresponding to the acid of formula IV

R = C-COOH

II

N \

ORa (IV) wherein

R and R a are as defined above, and then optionally removing the protecting groups R 10 on the carboxy group and isolating the resulting compound of formula I optionally after conversion to a non-toxic pharmaceutically acceptable salt or sulfoxide thereof, for example by treatment with a base such as sodium 2-ethylhexoate; % potassium isomeric mixtures of isomers having a content of at least 75 percent, preferably at least 90% or more of the syn-isomer or preferably in the form of a synisomer free of the corresponding anti-isomer.

It is generally preferred to condense the acylating agent corresponding to the acid of formula VII

R = C-COOH

II

N \

ORa (VII) wherein

^And R and R are as defined above, with an amino compound of formula III obecného-

where

Z and B are as defined above and

R 10 is a hydrogen atom or a carboxyl-protecting group, for example an ester-forming alcohol residue, aliphatic or -arylaliphatic, phenol, silanol, stannanol or acid, the condensation may be carried out in the presence of a condensing agent and followed by removal of the R 10 group .

In the case of producing preferred cephalosporin compounds of formula II, the amino compound of formula III may have the formula VIII

where

R ¹⁰ , V and P are as defined above. Derivatives of these amino compounds can also be used, for example their salts as tosylate.

Thus, the compounds of formula (I) may be prepared by using an acid halide, especially chloride or bromide, as the acylating agent. The acylation is carried out at temperatures of -50 to 4 ° C ^, preferably -2 to +30 degrees Celsius. The acylating agent can be prepared by reacting an acid of formula VII or a salt thereof with a halogenating agent, for example, phosphorus pentachloride, thionyl chloride or oxalyl chloride. The use of oxalyl chloride together with the sodium or potassium salt of the acid of formula (VII) is advantageous since isomerisation is minimal under these conditions. The acylation can be carried out in both aqueous and non-aqueous media such as a mixture of water and ketone, for example a mixture of water and acetone, an ester such as ethyl acetate, an amide such as dimethylacetamide, or a nitrile such as acetonitrile or mixtures of these solvents.

The acylation with the acid halide is preferably carried out in the presence of an acid binding agent, for example a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bicarbonate or oxirane, thereby binding the hydrogen halide liberated in the acylation reaction. The oxirane is preferably a lower 1,2-alkylene oxide, for example ethylene oxide or propylene oxide.

When the acids of formula (VII) are used in free form, suitable condensing agents for the preparation of the compounds of the invention are carbodiimides, such as ΐΨ, ΐΨ-methyl, dipropyl or diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide, or N-ethyl- N'-7-dimethylaminopropylcarbodiimide. Suitable carbonyl compounds, for example carbonyldiimidazole or isoxazoliniová salt, for example N-ethyl-5-fenylisoxazolinium ^{c-3-sulfonate} and N-tert-butyl-5-methylisoxazoliniumperchlorát. The condensation reaction is preferably carried out in an anhydrous reaction medium, for example methylene chloride, dimethylformamide or acetonitrile, since in this case the reaction conditions, such as temperature, are much better controlled.

Acylation can also be carried out using other acid derivatives capable of forming amides, such as symmetrical anhydride or mixed anhydride with, for example, pivalic acid or a haloformate, for example a lower alkyl haloformate. The mixed or symmetric anhydride may be formed in situ. For example, a mixed anhydride may be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed using phosphoric acids such as phosphoric acid or phosphorous acid, sulfuric acid or aliphatic and aromatic sulfonic acids such as toluenesulfonic acid. Another preferred acylating agent is an activated ester, for example a compound of formula IX

R = C-CO-L

N *

OR ^and (IX) wherein

L is, for example, azide, oxysuccinimide, oxybenztriazole, pentachlorophenoxy or p-nitrophenoxy.

Compounds of formula I may also be prepared from compounds of formula V

(In I where

B, Z and R ¹⁰ are as defined above, except that R ¹⁰ cannot be hydrogen by reacting the compound with an acid of formula (VII) or a precursor thereof, and then removing the group R ¹⁰ , as already mentioned, for example, in Belgian Patent No. 760,494.

The reaction of the compound of formula (III) or (V) can be carried out in one step, so that further reactions to be carried out are only deprotection and purification.

If desired, a compound of formula (X) may be prepared first

where

R, R ^10, В and Z are the same as above, followed by reaction of compound X with a compound of formula R ^a -O-NH ?, kcle ^and R is as defined above, and additionally if necessary, removing the group R ¹⁰ R. The reaction product can be isolated to give the desired syn-isomer before or after removal of the R ¹⁰ group.

A suitable precursor of the desired ^R C ^-O- II-2 OH group is the corresponding 2-hydroxyiminoacyl group of formula

R-C-COII N 1

OR since these groups can be easily converted to the desired group by etherification. Thus, compounds of formula I can be prepared by reacting a compound of formula XI

R-C-CO-NH2;

N

OH

Z®1 kz coor í xu where

R, R ^10, B and Z are as hereinbefore defined, with etheriflkačním agent serving to introduce the group R ^and, then, if necessary, carry out any of the reactions D (ii) to (viili) which have been previously described and the compound of formula I are separated after separation into isomers, if necessary.

The etherifying agent may be, for example, an organic halide or sulfate or sulfonate, such as tosylate. Other etherifying agents may be diazoalkanes such as diazomethane or palzomethane, alkyl fluorosulfonates such as methyl fluorosulfonate and alkyloxonium tetrafluoroborates such as triethyloxonium tetrafluoroborate and diphenyl oxonium bromide. Etherification using diazo compounds, fluorosulfonates or tetrafluoroborates may still require an auxiliary agent, such as Lewis acid, such as BF3.

Compounds of formula I wherein R is an activating group such as cyano or 2- or 4-pyridyl can be prepared by nitrosation and etherification of the resulting oxime. A compound containing an acylamide group may be nitrosated

L R = CH 2 CONH- or

R — CH — CO — NH—

AND

COOH, for example, using nitrous acid, which can be made directly in the reaction mixture by reaction from an alkali metal nitrite with a weak acid, for example acetic acid, a nitrosyl chloride or an organic nitrosating agent, for example an alkyl nitrite, cycloalkylditanate or arylalkylditanate. In the case of nitrosation of a compound containing a group

R — CH — CO — NH—

AND

COOH decarboxylation occurs. After nitrosation or etherification, the product can be separated into the syn-isomer and the anti-isomer, if necessary.

If desired, the P group can be replaced with another more preferred group after acylation of the 7-amino compound or the 7-isocyanate compound. Especially when P is a group

-CH2Y kdp

Y is as defined above, the group Y can be introduced as described in the literature. Compounds in which Y. is a halogen atom, an ether group, or a thioether group, can be prepared as described in Belgian Pat. 719 711, 719 710, 734 532 and 734 533. Compounds in which Y is a nucleophile residue can also be prepared by reacting 3-acetoxymethylcephalosporinic acid with a nucleophile, for example pyridine or another tertiary amine, as described in British Application No. 912 541 ; sulfur and nitrogen containing or inorganic nucleophiles as described in British Patent Nos. 1 059 562, 1 101 423 and 1 206 305 as well as British Patent Nos. 1 · 012 943; or a nitrogen-containing nucleophile as described in British Patent Nos. 1,030,630, 1,082,943, and 1,082,962.

Compounds in which Y is a derivative of a nucleophile residue, such as an amino or acylamide group, derived from an azido group may be prepared as described in British Patent Nos. 1,057,883 and 1211,694. These patents further describe the reaction of compounds in which Y is an azido group with a dipolarophilic compound. Compounds of the invention wherein Y is a nucleophile residue can also be prepared by reacting 3-halomethylcephalosporin with any of the aforementioned nucleophiles, for example as described in Belgian Patent No. 719,711. When Y is hydroxyl. group, the compounds can be produced by the method of British Patent No. 1,121,308.

Compounds containing a vinyl or substituted vinyl group at the 3-position can be prepared by the method of Belgian Patent No. 761,897.

In the case that Y is halogen, for example chlorine, bromine or iodine, can be prepared starting ceph-3-halogenation of compounds emove ester 1-oxide ester 7 _l tf-acylamido-3-methylceph-3-em-4-carboxylate with subsequent reduction of the 1'-oxido group as described in Belgian Patent No. 755,256.

The corresponding cef-2-em compounds can be prepared by the method of Dutch Patent Application Publication No. 6,902,013 by reacting a cef-2-em-3-methylated compound with N-bromosuccinimide to give the cef-2-em-3-bromomethylated compound.

When Y is hydrogen, these compounds can be prepared according to British Patent No. 957,569 or from penicillin as described in U.S. Patent Nos. 3,275,626 and Belgian Patent Nos. 747,119 and 747,120.

Cephalosporin compounds containing an acyloxymethyl group at the 3-position can be produced by any suitable method, for example, from a cephalosporin having a -CH 2 Y group in the 3-position in which Y = OH or a HY acid residue of pKa not higher than 4.0 and preferably lower than 3 , 5, in water at 25 degrees Celsius.

The group Y may be a chlorine, bromine or iodine atom, formyloxyl or acetoxyl containing at least one electron-bonding substituent on an α-carbon atom or a benzyloxy group substituted on the nucleus, the substituent on the nucleus again being a substituent that binds at least one electron, as described in British Patent No. 1,241,657, and the reaction that removes the nucleophilic moiety to introduce the desired substituent can be carried out by the method of the aforementioned British Patent Application No. 1,241,657.

In the case where Y is hydroxy, the desired 3-acyloxymethylcephosphorosporin can be prepared by acylation according to British Patent No. 1,141,293; the same specification also describes a process for producing A ³ -cephalosporin which also contains acyloxymethyl at the 3-position of the 3-hydroxymethyl analogue by attaching an arylalkyl group to the carboxy group at the 4-position, then acylating the 3-hydroxymethyl group of the compound so protected and finally removing the arylalkyl protecting group.

The acylation is carried out by any suitable method, for example an acid chloride, an acid anhydride or a mixed anhydride as the acylating agent, preferably in the presence of an acid binding agent, for example an organic base such as pyridine or a lower alkylene oxide such as ethylene oxide or propylene oxide. it is preferably carried out in an inert anhydrous solvent, for example methylene chloride. Acylation can also be carried out in a mixture of water, acetone and aqueous sodium bicarbonate. The preferred acylating agent is acid chloride.

The acylation reaction should be carried out as quickly as possible, otherwise conditions may occur under conditions suitable for both acylation and the formation of the A ² -derivative, especially when the aryloxy group is introduced into the methylene group at the 3-position which is not bound directly to the nucleus atom.

The compounds of formula (III) may be used in the form of an ester; the compounds of formula (V) already have an ester form. A free amino acid or a free amino acid addition salt or ester thereof can also be used. Among the salts which may be used, there are addition salts with hydrochloric, hydrobromic, sulfuric, and methanesulfonic acid.

Esters can be formed with an alcohol, phenol, silanol or stannanol of up to 20 carbon atoms, since these groups can be easily separated again at a later stage of the reaction.

The esterifying group to substitute the 4-carboxyl group in the compounds of formula III, V and X is preferably an alcohol, an aliphatic or arylaliphatic substituted phenol, silanol, stannanol or acid, as these groups can be readily separated in a later reaction step.

Thus, suitable esters are those which contain as the ester group a group selected from the following list of compounds, but other ester groups may also be used.

i) -COOCR ^f R ^g R ^h , wherein at least one of R ^f , R ^s and R ^b is an electron donor, for example p-methoxyphenyl, 2,4,6-trimethylphenyl, 9-anthryl, methoxy, acetoxyl or fur -2-yl. The remaining R ^f , R ^g and R ^h may be hydrogen or an organic group. Suitable ester groups of this type are p-methoxybenzyloxycarbonyl and 2,4,6-trimethylbenzyloxycarbonyl.

ii) a Group -COOCR ^f R ^g -R ^b, wherein at least one of R ^r, R ^g and R ^h is the electron acceptor, such as benzoyl, p-nitrophenyl,

4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl, cyanomethyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or cyano. The remaining symbols ^of R, R ^2, and R ^h can be hydrogen or an organic group. Suitable esters of this type are benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and 2,2,2-tribromethoxycarbonyl.

iii) a group - COOCR ^R R ^g R ^h, wherein at least two of the groups R ^f, R ^a and R ^b denote a hydrocarbon radical, for example methyl, ethyl or aryl such as phenyl and the remaining R ^f, R ^2, and R ^h can also mean a hydrocarbon residue or a hydrogen atom. Suitable esters of this type are tert-butyloxycarbonyl, tert-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl.

(ivj - COOR ^j group wherein R is adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl or tetrahydropyran-2-yl.

(v) Silyloxycarbonyl groups obtained by reacting a carboxyl group with a silanol derivative. The silanol derivative is preferably a halosilane or a silazane of the formula

R 3 ⁿ SiD; R2 ⁿ S1D2; R3IISINN2IN;

R3 ^{u u} SiNHSÍR3; R 3 ⁱⁿ SiNHCOR 1;

R 3 is -NR 2 ^u ; R3 ⁱⁿ Si-NH-SiR 3 ^{U; 11} S1 R3 ^{-NH-COR; 11} R 3 Si-NH-CO-NH-SiR 3 ^{U; U} R NH-CO-NR ^U -SÍR311 or RIIC (OSiR3 ^u j;

NSIR3II, where

D represents a halogen atom and the groups R 11, which may be the same or different, represent a hydrogen atom or an alkyl, for example methyl, ethyl, n-propyl, isopropyl, aryl such as phenyl, arylalkyl such as benzyl.

Preferred silanol derivatives are silyl chlorides, for example dlmethylchlorosilane and trimethylchlorosilane.

The carboxyl groups may be regenerated from the ester by any conventional means, for example by hydrolysis, catalyzed using an acid or base, or enzymatic hydrolysis. However, it may happen that aqueous solutions are poor solvents for these compounds and that is why isomerization, molecule rearrangements, side reactions and decomposition occur, so special methods need to be used.

A suitable method of de-esterification of the above compounds is

1) Reaction with Lewis acids

Suitable acids of this type are trifluoroacetic acid, formic acid, hydrochloric acid and acetic acid, zinc bromide in benzene and aqueous solutions, or suspensions of copper (III) compounds. The reaction with acids can be facilitated by the addition of a nucleophile, for example anisole.

2) Reduction

Suitable reduction systems include a mixture of zinc and acetic acid, zinc and formic acid, zinc and the lower alcohol, zinc and pyridine, palladium-hydrogen-activated charcoal, and a mixture of sodium and liquid ammonia.

3) Effect of nucleophiles

Suitable nucleophiles are those containing a nucleophilic oxygen or sulfur atom, for example alcohols, mercaptans and water.

4) Oxidation methods, for example those involving the use of hydrogen peroxide and acetic acid.

5) Irradiation

When the product of the reaction is a compound in which B is > S- > O and it is necessary to obtain a compound in which B is &gt; sulfide, for example by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, which is prepared directly in the reaction mixture by treatment with, for example, acetyl chloride when the acetoxysulfonium salt is to be prepared, for example with sodium dithionite or an iodide ion, for example with potassium iodide in a miscible solvent with water, for example acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of -20 to +50 degrees Celsius.

The reduction of the 1-sulfinyl group can also be carried out with phosphorus trichloride or bromide in a solvent such as methylene chloride, dimethylformamide or tetrahydrofuran, preferably at a temperature of -20 to +50 ° C.

When the resulting compound is cef-2-em-4-ester, the desired cef-3-em compound can be obtained by treatment with a base.

The acid of formula IV, which is an acylating agent, can be produced by reacting a glyoxylic acid of formula r-CO-COOH wherein:

R is as defined above, or an ester thereof with a compound of the type

R ^and O — NH2, wherein

Ra is as defined above.

The resulting acid or ester is then optionally resolved into individual isomers by crystallization, chromatography, or distillation followed by ester hydrolysis, if necessary.

Especially in the case of 2-alkoxyiminoarylacetic acid esters, i.e. those acid esters of formula IV, wherein R is an aryl group with a carbon or heterocyclic ring and Ra is alkyl, separation of the two isomers can be accomplished by selective ester hydrolysis since the anti-isomer can be saponified more rapidly better to remove in the form of the free acid, so that the synester remains in the mixture. The separated ester-ester syn-isomer can then be converted at any time to the corresponding acylating agent.

The acid of formula (IV) may also be prepared by O-alkylation or O-arylamino, the reaction being of the type where the compound of formula (I) is used.

R - С - СООН

For example, 2-hydroxyimino acids are preferred, but the ester is more preferred. The reaction may be carried out by treatment with an organic halide, sulphate or sulphonate, for example a compound of formula R ^and J, wherein R ^a is as defined above and J represents a halogen atom, a sulphate or sulphonate group such as a tosylate. The 2-hydroxyimino acid or ester thereof may also be reacted with a diazoalkane, for example, diazomethane, alkylfluorosulfonate, for example methylfluorosulfonate, alkyloxoniumtetrafluoroborate, for example, trialkyloxoniumtetrafluoroborate, such as .

These reactions with diazo compounds, fluorosulfonate or tetrafluoroborate may require an adjuvant such as Lewis acid BF3.

When converting an acid of formula IV to an acylating agent, it should be noted that any amino group present in the R or R substituent ^and should be protected to avoid unwanted side reactions, similar protection of the amino groups is desirable also when the acylating agent is mentioned. in reaction with compounds of formula III or V.

The syn-isomer and the anti-isomer may be distinguished from each other in a suitable manner, for example, by ultraviolet absorption spectrum, thin-layer or paper chromatography, or nuclear magnetic resonance. For example, the compound of formula I in dimethylsulfoxide-d6 solution has a doublet for the lower amide NH amide in the case of the syn-isomer or in the case of the anti-isomer. These factors can also be used for monitoring reactions.

The antibacterial compounds of the invention may be incorporated into the compositions for administration by any suitable route analogous to the routes of administration of other antibiotics, and the invention also encompasses pharmaceutical compositions having as active ingredient compounds of formula I or non-toxic derivatives thereof, e.g. These preparations are suitable for use in human and veterinary medicine. The active substances are usually employed in these preparations together with a pharmaceutical carrier.

The compounds of the invention may be incorporated into injectables into ampoules or larger containers with the addition of a preservative. These preparations may take the form of suspensions, solutions, emulsions in oily or aqueous liquids and may contain auxiliary substances, for example suspending aids, stabilizing agents and / or dispersing agents. The active ingredient may also be in powder form and mixed with a suitable liquid carrier, for example sterile pyrogen-free water, just prior to preparation.

The compositions may also be in a form suitable for absorption by the gastrointestinal tract. Tablets and capsules for oral administration may be presented in unit dosage form and may contain other excipients such as binding agents such as syrups, acacia, gelatin, sorbitol, gum tragacanth or polyvinylpyrrolidone, and may contain fillers such as lactose, sugars, corn starch, phosphate calcium, sorbitol or glycine, lubricants such as magnesium stearate, talc, polyethylene glycol, silica or potato starch, as well as acceptable wetting agents such as sodium laurine sulfate. The tablets may be coated in a known manner. Liquid preparations for oral administration may take the form of a suspension in water or in oil, solutions, emulsions, syrups, elixirs and the like, or may be presented as a powder for reconstitution in water or other liquid carrier just prior to use. These preparations may usually contain adjuvants such as suspending aids, for example sorbitol syrup, methylcellulose, syrup consisting of a mixture of glucose and cane sugar, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifying agents such as lecithin, monooleate sorbitan or acacia rubber. Non-aqueous liquids, for example, edible oils such as almond oil, coconut oil, oil esters, propylene glycol or ethyl alcohol, a preservative such as methyl or propyl p-hydroxybenzoate or sorbinic acid may also be used in the compositions. Suppositories consist of a conventional base such as cocoa butter or other triglycerides.

Preparations suitable for absorption through the mucous membrane of the nose, nasopharynx or bronchial mucosa may also be made; these preparations are in the form of a powder or aerosol and are used as inhalants, sprays, longets, and the like. If the preparation is to be used to treat ocular or ear diseases, the preparations may be in the form of capsules in liquid or semi-solid form or droplets. For application to the skin, the composition may take the form of an ointment, cream, powder, paste in a hydrophobic or hydrophilic base.

For use in veterinary medicine, preparations can be made, for example, as intramammary preparations, either with rapid or slow release of the active ingredient.

The compositions contain at least 0.1%, preferably 10 to 60%, of active compound, depending on the route of administration. In case that

The preparation is composed of individual doses, each dose preferably containing 50 to 500 milligrams of active ingredient. The dosage for adults ranges from 100 to 3000 milligrams, for example 1500 mg per day, depending on the route of administration and the frequency of administration.

The compounds of the invention may also be administered in conjunction with other therapeutic agents, for example antibiotics such as other cephalosporins, penicillins or tetracyclines.

The invention is illustrated by the following examples.

Preparation 1

2-Methoxyiminophenylacetic acids in the form of the syn-isomer and the anti-isomer

To a solution of 5 g of sodium in 100 ml of benzoic-methanol was added a solution of 15 g of O-methylhydroxylamine hydrochloride in 100 ml of anhydrous methanol until the solution was neutral with respect to phenolphthalein. The precipitated sodium chloride was removed by filtration and the filtrate was added to a solution of 25 g of phenylglyoxylic acid in 100 ml of anhydrous methanol. The solution was heated under reflux for 2 hours, then cooled and evaporated to an oily residue which was dissolved in 200 ml of ether, filtered again and evaporated to 32.9 g of an oily liquid which recrystallized from petroleum ether, b.p. 60-80 °. C yields 19.61 g of a white solid and 3.9 g of an oily liquid.

17.8 g of solid and 3.9 g of oily liquid were combined to 21.7 g of the resulting material and methylated with a solution of diazomethane in ether to give an oil of 24.2 g. Purification on 600 g of silica gel gave syn-methyl -2-methoxyiminophenylacetate in the form of an oily liquid, in an amount

13.6 g, in a yield of 55% Amax (ethanol, hereinafter EtOH) 259 nm (ε 10,400) and anti-methyl-2-methoxymethoxy-β-β-β-β-β-α-β-α ^ (^ <^ calculate, as the slower component in the form of '8.7 g solid in 35% yield, melting at 54 ° C, A _m ax (EtOH) 251 nm (ε 7260).

8.7 g of methyl 2-methoxyiminophenylacetate as an isomer is dissolved in 100 ml of methanol and 22 ml of 2 N sodium hydroxide solution are added. The solution was stirred at room temperature for 1 hour, the pH was adjusted to 7 with 2 N hydrochloric acid solution, the methanol was removed by evaporation, 150 ml of water was added and the solution was acidified to pH 1.5 with 2 N hydrochloric acid solution. The mixture was extracted with ethyl acetate (3.times.100 ml), the organic extracts were combined, freed from water and evaporated to give 6.74 g of a solid, recrystallized from petroleum ether, b.p. 60-80 DEG C. and benzene, 4.84 g. anti-2-methoxyiminophenylacetic acid, m.p. 103-104 ° C .lambda.max (EtOH) 248 nm (ε 7 010), τ (CDCl3) values show 2.64 (Ph), 5.92 (CH3).

13.6 g of methyl 2-methoxyiminophenyiacetate in the form of the syn-isomer is hydrolyzed in a similar manner, but the mixture to be hydrolyzed is stirred at room temperature for 40 hours. 11.13 g of a white solid are obtained, which is recrystallized from a mixture of petroleum ether, b.p. 60-80 DEG C. and benzene, to give 10.02 g of syn-2-methoxyiminophenylacetic acid as a white solid, m.p. 97 ° C, λ max (EtOH) 255 nm, (ε 13,200), τ (CDCl 3) values show 2.2 to 2.8 (Ph), 5.92 (CH 3).

Preparation 2

2-Methoxyimino- (thien-2-yl) acetic acid in the form of the syn- and anti-isomer

5.85 g of a solution of methoxyamine hydrochloride in 60 ml of anhydrous methanol are neutralized with a solution of methoxide in methanol, which is prepared by introducing 2.5 g of sodium into 50 ml of anhydrous methanol. Precipitated sodium chloride was removed by filtration and the filtrate was added to a solution of 10 g. Thien-2-yl-glyoxylic acid in 60 mL of anhydrous methanol. The resulting solution was heated at reflux for 1 hour, cooled and evaporated to an oily residue. Ether (100 ml) was added, the mixture was filtered and the filtrate was evaporated to an oil residue (13.06 g). 12.5 g of this residue were dissolved in 50 ml of ether and an ethereal solution of diazomethane was added until a stable yellow color was obtained. The excess diazomethane was removed by allowing the solution to stand in the sun for 1 hour. Evaporation of this solution yielded 13.2 g of an oily residue.

10.33 g of this residue are purified by preparative chromatography on silica plates (Kleselgel PF254 +3), developing as 75% petroleum ether (boiling point 60-80 ° C in benzene) three times to give the title compound.

(a) methyl 2-methoxyimino-2- (thienyl-2-yl) acetate in the form of the syn-isomer (3,44 g, 27%), Amax (EtOH) 290 nm (ε 11 250), Αω 271 nm · (Ε 5 400) vmax (0ΗΒγ3) 1,738 and 1230 cm ^-1 (CO ² Me). τ points to (CDCl3) ie 6.06 (s, CO2CH3), 5.78 (s, OCH3).

(b) Methyl-2-methoxyimmo-2- (thien-2-yl) acetate as an anti-isomer (1,21 g, 9,5%), Amax (EtOH) 221 and 288 nm- (ε 5 020; 11,000). ^p max (CHBrn) 1732 and 1212 cm ^-1 (CO ² Me), τ (CDCl 3) values show 6.06 (s, Co 2 Me), 6.00 (s, OCH 3) and other fractions that were a mixture of isomers.

8.27 ml of 2 N sodium hydroxide are added to a solution of 3.28 g of methyl 2-methoxyimmh-2- (thien-2-yl) acetate as the syn-isomer in 50 ml of methanol and the solution thus obtained is stirred at a temperature of room 18 hours. Water (20 ml) was added and the solution was evaporated to remove methanol and washed with ethyl acetate. The pH of the solution in 50 ml of ethyl acetate was reduced to 2 by treatment with 2N hydrochloric acid. The solution was divided into two layers which were separated and the aqueous layer was extracted with ethyl acetate. The organic extracts are combined and concentrated to 2.58 g of a white solid which was recrystallised from cyclohexane to give ¹

2.23 g of the syn-isomer of 2-methyl-imino- (thien-2-yl) -acetic acid in 73% yield, m.p. 105.5 ° C, λ max (EtOH) 289 nm (ε 10,100), A-nf 262 and 271 nm. (ε 7 750 and 8 150), τ (CDCl 3) values show 0.32 (OH) and 5.92 (OCHs).

Analogous hydrolysis of the α-methylethyl ether yielded the 2-methoxy-mino- (imen-2-yl) acetic acid ant-n-ysmse as an antis isomer (0.85 g), Amax (EtOH) 286-287 nm. (ε 10 200), τ (CHCH) values show 1.31 (OH) and 5.73 (OCHs).

Preparation 3

Syn-p-butoxyimmsthien-2-yl-acetic acid

A solution of 6.2 g of thisn-2-yl-glyoxylic acid and 3.36 g of sodium hydrogen carbonate in 100 ml of water is added dropwise with stirring to the solution of t-butyxsamine in the form of hydrosulfide in an amount of 5.65 g. 78 g of sodium hydrogen carbonate in 100 ml of water at 0-5 ° C and stirred at room temperature for 18 hours. The mixture was then acidified to pH 2.0 with 2 N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with water, dehydrated and concentrated to a residue

9.75 g of solid. Pg scrytals from a boiling point of 60-80 ° C gave 4.0 g of the title compound in a yield of 44%, melting point 106-107 ° C, λ max (EtOH) 290 nm (ε 11,600), τ (CDCl 3) values show 2 46, 2.66, 2.98 (d-doublets, thienyl protons), 8.60 [C (CH3) 5].

Preparation 4

2-Ethyloxyimino-phenylacetic acid in the form of the syn- and anti-isomer

4.0 g of ethoxamine hydrochloride and 6.0 g of fensyl glycolic acid are dissolved in 50 ml of water and the resulting solution is adjusted to pH 4.5 with base and stirred at this pH for 15 hours. The mixture was acidified and extracted with ethyl acetate and evaporated to give a mixture of syn- and anti-ethoxy-mins-phenylacetic acid (7.4 g, 94% yield). The mixture was recrystallized four times from cyclohexane, but no pure acid was obtained. However, evaporation of the mother liquor from the first crystallization and recrystallization of the cyclohexane residue gave 1.36 g (17% yield, 17%), mp 90.9-91.6 ° C, _λmax (ethane!) 249. nm (ε 7,600), τ (DMSO-d6) values show 2.52 (s, Ph) 5.74 (q, CH 2), 8.76 (t, - CH 3).

A solution of 4.0 g of a mixture of acids in 100 ml of ether was treated with an ethereal solution of diazomethane until a yellow color persisted. Acetic acid was added to remove excess diazsmsthay and the ethereal solution was washed with sodium bicarbonate. water, saturated sodium chloride solution and then evaporated. Evaporation of the ether gave 4.1 g of the methyl esters as an orange oil. The liquid was divided into five 40 x 20 cm plates, eluting with a 3: 1 mixture of petroleum (40-60 ° C) and ether. The slower component was washed with chloroform and removed of this solvent. gains

1.45 g of ant-methyl-2-soyoylimine oynylastic acid in the form of a pale yellow oily liquid, τ (CDCl3) values showing '2.58' (Ph, '5.66, qq, CH2), 6 12 (s, OCH 3), 8.72 (t, CH 3). Similar treatment of the slower band yields ssn-methyl-2-ethoxyiminophenylacetate (2.45 g) as a pale yellow oil, τ (CDCl 3) values of 2.3 to 2.7 (m, Ph), 5.72 ( q CH 2), 6.06 (s, OCH 3), 8.67 (t, CH 3).

A solution of 2.39 g of monoethyl ester in 60 ml of methanol was treated with 12 ml of 2N sodium hydroxide solution and stirred for 18 hours. The methanol was removed by evaporation and the aqueous mixture was extracted with ethyl acetate after acidification to pH 1.5. The washed and dehydrated extracts were evaporated to dryness and the residue was crystallized from cyclohexane to give 836 mg of syn-sthoxkimine-n-sulfanyl-acetic acid, m.p. 77.9-79.0 degrees Celsius, Amax (ethanol) 256.5 nm. (ε 12,800), τ (DMSO-de) values show 2.48 (m, Ph), 5.74 (q, CH 2), 8.71 (t, CH 3).

Preparations 5 to 23

2-Alkoxysiminoarylacetic acid

General procedure

A mixture of the substituted glysxylic acid and a 10-15% excess of alkoxyamrine in the form of a hydrosulfide is suspended in water or a mixture of water and ethanol, mixed and adjusted to pH 4 to 5 with sodium hydroxide solution (1 to 10). N). A clear solution of pH 4-5 is maintained at this value throughout the reaction by adding sodium hydroxide in ethanol, if necessary. The reaction mixture is maintained at room temperature until all of the acid has been consumed, but it is sometimes necessary to add an additional amount of more volatile alkoxyamine. Upon completion, the mixture was acidified, extracted with ethyl acetate, and the extract analyzed on thin layers of yilicags using a 18: 2: 1 mixture of chloroform, methanol and acetic acid as developing systems. The alkoxyimetic acid is less polar than the starting keto acid. The reaction time ranges from 2 hours to 2 days. Reactions which are carried out at pH 4-5 are included under

2457S3 by method (b), reactions carried out at pH 7.8 are included under method (a). After completion of the reaction, the pH is adjusted to 7-8 and any residual ethanol is removed by evaporation. The aqueous mixture is extracted with ether, the extract is discarded and the aqueous phase is acidified to pH &lt; 2 with dilute hydrochloric acid. The mixture is further extracted with ethyl acetate, the extract is dehydrated and evaporated to give a crude product which is further purified by one of these methods.

a) Crystallization and possible recrystallization from aqueous solvent,

b) The crude product is mixed after dissolution in ether with a small excess of a solution of diazomethane in ether. Excess reagent was removed from acetic acid and the solution was washed with sodium bicarbonate and evaporated to give a mixture of crude methyl esters. These esters are separated by preparative chromatography or silica gel column chromatography, followed by conventional alkaline hydrolysis to give pure syn-acid,

c) The methyl ester mixture is prepared as in b), but the individual isomers are separated by crystallization from a suitable solvent and then hydrolyzed in a similar manner.

These general methods have been used to produce the intermediates listed in Table 1 in the form of syn-isomers.

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Preparation 24

Methoxyiminoiminopyrid-S'-ylacetic acid in the form of syn. and an antidsomer

3.02 g of pyridine-3-yigiyoxyic acid and 2.09 g of methoxylamine hydrochloride are heated to reflux in 50 ml of ethanol, then mixed with a solution of sodium ethoxide in ethanol until the mixture is alkaline using phenolphthalate. As an indicator, the mixture was maintained at reflux for 1.5 hours, then an additional aliquot of 0.5 g of methoxylamine as hydrochloride and ethanolic sodium ethoxide solution was added, followed by heating at reflux for an additional hour. The resulting mixture was filtered through silica and evaporated to dryness. The residue was dissolved in a small amount of ethanol and the resulting fine suspension was made clear by further filtration. The filtrate was diluted with ethyl acetate to give a crystalline solid, which was washed with ethyl acetate and dried to give β-methoxyiminopyrid-3'-ylacetoacetic acid as a mixture of isomers in an amount of 2.72 g in 70% yield, A. _ni3x (pH 0). , buffer) 250 nm (ε 0 030), max (nujol) 1010 (GOr) and 1038 cm ^-1 (^ 0-0-), r (de DMSO) 1.21, 1.43, 2.02 2.00 (multiplet, aromatic protons), 0.20 (s, OCHs).

Preparation 25

a) Methyl- (i-ethoxy) ethoxyimino-2- (thien-2-yl) acetic acid in the form of the syn-isomer

To a mixture of 3.98 g of methyl 2-hydroxyimino-2- (thiopren-2-yl acetate) as the syn-isomer and

2.5 ml of ethyl vinyl ether in 25 ml of ethyl acetate were added with 2 drops of phosphorous oxychloride. After standing at 50 ec for 20 minutes, the ethyl acetate layer was washed with saturated sodium bicarbonate solution, dehydrated with sodium sulfate and evaporated to an oily liquid to give 5.7 g of methyl (1-ethoxy) ethoxyimino-2- (thien-2- yl acetate in the form of the syn-isomer at 100% yield, λ max (EtOH) 289 nm (ε 11,700), τ (CDCl 3, 00 MHz) 2.01 (multiplet, thienyl β),

2.82 to 2.97 (multiplet, thienyl H 3 and Ш), 4.04 (quartet, J5 Hz, -O-CH-), 0.00 (Singlet, Lm-COOCH3), 0.24 (quartet, J7 Hz OCH 2) 8.50 (doublet of J 5 Hz, CH-CH 3), 8.79 triplet, J 7 Hz, O-CH 2 CH 3).

b) 2 '- [1-ethoxy) ethoxyimino-2- (thien-2-yl) acetic acid sodium salt in the form of a syn-isomer equivalent to 1 N sodium hydroxide solution and enough methanol to form a homogeneous system is added to the solution 5.7 g of methyl (1-ethoxy) ethoxyimino-2- (thifn-2-yl) acetate as the syn-isomer. The mixture is held at 50 ° C for 4 hours, then the methanol is evaporated and the residue is mixed with a mixture of benzene and methanol and evaporated again to give 4.0 g of a white solid consisting essentially of sodium 2- (1- ethoxy) ethoxyimino-2- (thier-2-yl) in the form of the syn-isomer in a yield of 78.5%, A _m and _X (pH 0, buffer) 287.5 nm (ε 10 050), τ ( D) values of 2.42 (multiplet, thienyl Hs), 2.08 to 2.84 (multipeet-thienyl Нз and H1) - 4.033 (quartet, J5 Hz, —CH—) t 0.21 (quartet, J7 Hz) , i

CH 3 '- CH 2 - CH 3), - 8.57 (doublet, J 5' Hz, '- CH 3),

CHs

8.82 (tear-7 Hz-CH2-CH3).

Preparation 20

Synthien-2-yioxyimino (thien-2-yl) acetic acid

7.37 g of thin-2-yioxamine in. form, hydrochloride and 0.24 g of thien-2-ylglyoxic acid are dissolved in a mixture of 110 ml of ethanol and 20 ml of water. The pH of the solution was adjusted to 5.0 and the solution was stirred for 22 hours. The ethanol was evaporated and the aqueous mixture was neutralized, washed twice with ether and acidified. pH 1.5. The mixture is then extracted with ethyl acetate, the extracts are combined, washed, dehydrated and evaporated to dryness to give 9.2 g of a yellow oil in 80% yield, which is left to crystallize. It has been shown that the crystalline substance is a mixture of isomers. Recrystallization of this solid from cyclohexane does not separate the isomers. 5.0 g of this mixture were then esterified with diazomethane to give a mixture of methyl esters as a pale yellow oil.

To a solution of 2.14 g of a mixture of methyl esters in 50 ml of methanol is added 7.0 ml of 2 N sodium hydroxide solution. The mixture was stirred for 14 hours and then neutralized. The methanol is evaporated and the aqueous residue is extracted with ethyl acetate, the extracts are washed with water, dehydrated and evaporated to dryness to give 1.0 g of a yellow oily liquid which is dissolved in 25 ml of methanol and stirred with 5 ml of 2 N hydroxide for 18 hours. sodium. The methanol was evaporated and the aqueous residue was washed with ethyl acetate and acidified to pH 1.7 with ethyl acetate. The extracts were washed, dehydrated and evaporated to dryness to give 730 mg of solid which was recrystallized twice from cyclohexane to give 309 mg of syn-then-2-yloxyimino- (thien-2-yl) acetic acid at temperature m.p. 101-102 ° C, λ max (EtOH) 239, 289.5 nm (ε 11700, 12,300), τ (DMSO-do) values. They show 4.07 (s, CH 2).

Preparation 27

Syn-2-benzoyloxyiminobenzo [b] thien-3'-ylacetic acid

2.27 g of benzo [b] -thien-3-ylglyoxylacetic acid and 1.915 g of benzyloxyamine hydrochloride are dissolved in 70 ml of ethanol and 30 ml of water. The solution was adjusted to pH 4.5 with 40% sodium hydroxide solution and stirred at this pH for 2 hours, then allowed to stand overnight. The pH is then adjusted to pH 5. 9 and the mixture is washed with ether, the aqueous phase is acidified and the organic layer is washed with water, saturated sodium chloride solution and then water-free. Evaporation gave a mixture of both isomers as a crystalline solid in 3.4 g in 99% yield. The crude acid in the ether solution is contacted with an excess of the ether solution of diazomethane at 0-5 ° C. Excess diazomethane was removed with acetic acid, and the ethereal solution was washed with sodium bicarbonate solution, water and dried. Evaporation gave 3.34 g of a pale brown oil in 93% yield. 100 ml of the crude product in methanol are treated with 10 ml of N sodium hydroxide solution at room temperature and the mixture is allowed to stand for 1 hour. After hydrolysis, thin layer chromatography on silica gel is performed. 5 ml of a 2 N hydrochloric acid solution are added to stop the hydrolysis, after which the methanol is removed by evaporation. Ethyl acetate was added and the anti-2-benzyloxyiminobenzO [b] -thien-3‘-ylacetic acid was removed by washing with sodium bicarbonate. The ethyl acetate layer was washed with water, dehydrated and evaporated to give 1.99 g of a light orange oil in 56% yield. This liquid was mixed with 90 mL of methanol and 10 mL of 1 N sodium hydroxide solution. at room temperature and allowed to stand for 7 hours. An additional 5 mL of 1 N sodium hydroxide solution was added and the solution was allowed to stand for 2 days to complete the hydrolysis. The methanol was removed by evaporation and the residue was dissolved in a mixture of ethyl acetate and water. Mixture. The solution was adjusted to pH 1.5 and the ethyl acetate layer was washed with water, saturated sodium chloride solution. and then dried. Evaporation gave

1.82 g of yellow crystals in a yield of 50%. Crystallization from benzene / cyclohexane gave the title product as 1.29 grams of light orange crystals, yield 36%, mp 120.5-121 ° C _{m and} (EtOH) 232, 285.5, 296.5, 306.5 nm (ε 22 500, 11 800, 11 500, 10 400), r values (DMSO-de) show 1.90, 1.97, 2.3 to 2.7 (aromatic protons), 4.64 (CH 2 singlet) ).

Preparation 28

Syn-2-benzyloxyiminobenzo [b] thien-2‘-ylacetic acid

3.092 g of benzo [b] thien-2-ylglyoxyl acetic acid a. 2.72 g of benzyloxyamine hydrochloride in 170 ml of ethanol and 70 ml of water are treated with 40% sodium hydroxide solution to adjust the pH to 4.5. The solution was stirred at this pH and at room temperature for 6 hours. 500 mg of benzyloxyamine hydrochloride is added and the solution is allowed to stand overnight at the same temperature. The pH of the solution was adjusted to 8 and the mixture was washed with ether. The aqueous phase was acidified to pH 1.5, the ether layer was washed with water and then freed from water. Evaporation gave 4.28 g of a cream colored solid in a yield of 91 percent, this crude product with a mixture of isomers.

The mixture is mixed in an ethereal solution and an excess of an ethereal diazomethane solution at 0-5 ° C. Excess diazomethane was removed with acetic acid, and the ethereal solution was washed with sodium bicarbonate and water, then freed from water. Evaporation gave 4.45 g of an oily liquid in 91% yield. This liquid was dissolved in 140 mL of methanol and treated at room temperature with 14 mL of 1 N sodium hydroxide solution. The mixture is left to stand for 2¼ hours, 7 ml of 2 N hydrochloric acid solution are added and the alcohol is removed by evaporation. The aqueous phase is partitioned by shaking between sodium bicarbonate solution and ether. The ether layer was washed with water, drained and evaporated to give 2.16 g of an oily liquid in 44% yield. This liquid is directly hydrolyzed in 70 ml of methanol by heating with 7 ml of 1 N sodium hydroxide solution under reflux for 4 hours. The methanol was removed by evaporation and the residue thus obtained was partitioned between water and a small amount of ether. The aqueous layer was still acidified with ether to pH 1.5, whereupon the ether layer was washed with water, drained and evaporated to give 1.97. g of a light beige solid in a yield of 42%. Crystallization from benzene / cyclohexane gave 1.61 g of the title compound as a white crystalline solid, yield 35%, mp 141-143 ° C dec., Amax (EtOH) 230.5, 253, 297.5 nm ( ε 16,400, 7,400, 24100), τ (DMSO-d6) values show 2.00, 2.36, 2.55 (atomatic protons), 4.71 (CH2 singlet).

Preparation 29

(a) (2-tert-butoxycarboxamido) ethoxyimino-thien-2-yl-acetic acid in the form of the syn-isomer

1.12 g of N-carbo-tert-butoxy-2-bromoethylamine is added to a solution of 1.035 g of methyl syn-hydroxylminothien-4-yl acetate in 30 ml of 2: 1 benzene: dimethylformamide and the resulting mixture is stirred for 16 hours. . Ethyl acetate (50 ml) was added and the mixture was washed several times with water, then freed from water and evaporated to dryness to give 1.21 g of methyl-syn- (2-tert-butoxycarboxamidoethoxy) iminothien-2-yl acetate, m.p. (CDCl 3) values show 2.62 2.86, 2.99 (thienyl proton),

5.10 (NH), 6.06 (s, SD), 8.58 [s, SD (SD) з (.

1.1 g of the crude ester in 20 ml of methanol were mixed with 3.4 ml of 2 N sodium hydroxide solution and the mixture was allowed to stand for 16 hours. The methanol was evaporated and the aqueous residue acidified to pH 2.0 after washing with ether and extracted with ethyl acetate. The extracts were washed with water and saturated sodium chloride solution, freed from water and evaporated to dryness. Recrystallization of the residue from cyclohexah gave, in 90% yield, 951 mg of the final product, mp 112.8-114.4 ° C, λ _max (EtOH) 290.5 nm, (ε 11600), τ (DMSO-d6) 2.19, 2.6 to 2.9 (thienyl protons), 3.14 (NH), 8.52 [s, С (СНз) з].

The alkylating agent used in the above processes was prepared as follows:

b) N-carbo-tert-butoxy-2-bromoethylamine

A mixture of 15.81 g of tert-butylazidoformate and 30 ml of triethylamine is added dropwise with stirring to a suspension of 20.5 g of 2-bromomethylamine hydrobromide in 100 ml of methylene chloride. The mixture was stirred for 3 hours and then filtered. The filtrate was concentrated to a small volume and this residue was then partitioned between ether and water. The ether layer was dehydrated and then distilled under reduced pressure to collect a fraction having a boiling point of 92-94 ° C at 120 Pa to give 1.756 g of N-carb-tert-butoxy-2-bromoethylamine.

Preparation 30

Pyrid-2-ylmethoxyiminothien-2-yl) acetic acid in the form of the syn-isomer.

2.8 ml of 2-chloromethylpyridine as a 25% solution in toluene is added to a solution of 1 035 g of methyl syn-hydroxyiminothien-2-ylacetate in 30 ml of a 2: 1 by volume mixture of benzene and dimethylformamide. After 18 hours, 50 ml of ethyl acetate are added and the mixture is washed several times with water, dehydrated and evaporated to dryness to give 1.4 g of a dark green oily liquid. This liquid is chromatographed on two 40 X 20 cm chromatographic plates using chloroform as the developing system, then chloroform / ethanol (9: 1 by volume) to form the main strip from which the solvent is evaporated. 889 mg of methyl [pyrid-2-ylmethoxyimino (thien-2-yl) acetate] in 47% yield, which accounts for 75% of the syn-isomer and 25% of the anti-isomer. A solution of 828 mg of the crude ester in 20 ml of methanol and 3 ml of 2 N sodium hydroxide solution was allowed to stand for 16 hours.

After removal of methanol, the aqueous mixture was acidified to pH 2.0 in the presence of methylene chloride. The acidic mixture was then extracted with methylene chloride, and the extracts were washed with water and saturated sodium chloride solution, then freed from water and evaporated to dryness. The residue was triturated with ether to give the title compound (210 mg, 27%), mp 152.1-152.9 ° C; λt _α (EtOH) 260.5,266,289 nm (ε 12,300,12,000) , 11700), τ (DMSO-d 6) values show 4.66 (singlet, CH 2).

Preparation 31

N-Butoxyiminothien-2-ylacetic acid in the form of the syn-isomer

0.6 ml of 1-bromobutane was added to a solution of methyl syn-hydroxyiminothien-2-yl acetate, which was prepared by reacting methyl syn-hydroxyiminothien-2-ylacetate with 1 equivalent of sodium methoxide. A solution of 1.0 g of this compound in a 2: 1 mixture of 15 ml of benzene and dimethylformamide was stirred at room temperature for 17 hours, then poured into water. The aqueous solution was extracted with ethyl acetate, washed with water, dehydrated and evaporated to give 0.88 g of the syn-methyl ester as a pale yellow oil.

Add 4.0 ml of 2 N sodium hydroxide solution to a solution of 0.85 g of syn-methyl ester in 10 ml of methanol and allow the mixture to stand at room temperature for 18 hours. The methanol was removed by evaporation, the aqueous residue was diluted with water, washed with ether and acidified to pH 2.0 with 2 N hydrochloric acid. The mixture was extracted with ethyl acetate, the extracts were combined and washed with water, then freed from water and evaporated to give 0.74 g of the title product in 81% yield as a pale yellow oil. Rf values (DMSO-d6) showed 2.30, 2.7 to 3.0 (thien-2-yl protons), 5.84 (OCH 2),

9.10 (s).

Preparation 32

2-Methoxymethoxyimino (thien-2-yl) acetic acid in the form of the syn-isomer

A solution of approximately 0.2 M sodium methoxide in methanol is added to 0.5 g of methyl 2-hydroxyimino-2- (thien-2-yl) acetate as the syn-isomer, and the resulting solution is evaporated to a yellow oily liquid, which was subjected to azeotropic distillation with petroleum ether at a boiling point of 40-60 ° C to give 0.49 g of methyl 2-hydroxy imino-2- (thien-2-yl) acetate sodium salt in the form of syn- isomer. To a solution of 0.49 g of sodium salt was added 5 ml of a 2: 1 mixture of benzene and dimethylformamide with stirring, and 0.22 ml of chlorodimethyl ether. After 10 minutes, the reaction mixture was poured into saturated sodium bicarbonate solution and extracted with benzene. The extracts were dried

It is washed with water, dehydrated with sodium sulphate and evaporated to a yellow oil which is the syn-isomer of methyl 2-methoxymethoxyimino (thien-2-yl) acetate in an amount of 0.62 g in 100% yield. _Amax (EtOH) 288 nm (ε 10 300), vmax (CHBrs) 1730 (COOCH3), 1660 cm ⁴ (—C = N—), τ (CDCl3), values show 2.61 to 2.83 (multiplet, thien-2-yl) ), 4.83 (singlet, CH -), 6.06 (CO 2 CH 3) 6.56 (singlet, CH 2 OCH 3).

A solution of 4 ml of 2 N sodium hydroxide in methanol was added to 0.4 g of the methyl ester. After> 30 minutes, the reaction mixture was poured into water and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 2 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate was dehydrated and evaporated to a colorless oil which was azeotroped with petroleum ether at 40-60 ° C to afford 0.21 g of syn-2-methoxymethoxyimino acid as a white solid (55% yield). - (thien-2-yl) acetic acid, m.p. 61.2 ° C, λ max (EtOH) 286 nm (ε 10 400), λ max (nujol) 1732, 2600 cm 1 (CO 2 H), τ (DMSO-de) 2.26 (multiplet, thienyl H5), 2.7 to 2.9 (multiplet, thienyl H 3 and H a), 4.88 (singlet, O-CH 2 -), 6.6 (snglet, OCH 3).

Preparation · 33

2-tert-Butoxyiminobenzo- [b] thien-2‘-ylacetic acid in the form of the syn-isomer

3.09 g of benzo-4-thien-2-ylglyoxylic acid and 1.98 g of tert-butoxyaminohydrochloride are dissolved in 100 ml of 50% aqueous ethanol. The solution was adjusted to pH 4.5 with sodium hydroxide solution and maintained. . se, at this pH value 4 hours · at. room temperature. When chromatography on. It was found that the reaction was incomplete. 500 mg of tert-butoxyamine hydrochloride are added and the solution is allowed to stand overnight at room temperature. The alcohol is removed by evaporation, the pH of the aqueous phase is adjusted to 8 and the mixture is washed with ether. The aqueous phase is then acidified to pH 1.5 below. ether layer. Water was added to the ether layer, after which the solution was drained and evaporated to give 4.05 g of a beige solid. Fractionated crystallization from cyclohexane yielded the anti-isomer of the final product in an amount of 1.6 g. The mother liquors were combined and evaporated to give 2.11 g of a beige solid which was taken up in ether and excess diazomethane added at temperature 0-5 ° C. Excess reagent was removed with acetic acid and the ethereal solution was washed with sodium bicarbonate, water, then dehydrated and evaporated to give 1.75 g of an oily liquid which was dissolved in 70 ml of methanol and treated with 7 ml of 1 N hydroxide solution. sodium for 3 hours at room temperature. 3.5 ml of 2 N hydrochloric acid solution are then added to the solution and the methanol is removed by evaporation. The remaining aqueous solution was partitioned between ether and sodium bicarbonate solution. The ether layer was washed with water, dehydrated and evaporated to give 0.92 g of an oily liquid which was dissolved in 20 ml of methanol and mixed with 7 ml.

The mixture was then heated for 3 hours, at which time 5 ml of 1 N sodium hydroxide solution was added and the mixture was refluxed for 6 hours. Methanol is removed by evaporation. - and the remainder is partitioned between ether and water. The aqueous phase is acidified to pH 1.5 under ether layer. The ether layer was washed with water, dehydrated and evaporated to dryness to give 760 mg of a pale orange crystalline solid in 18% yield. Crystallization from a mixture of benzene and cyclohexane gave 430 mg of syn-tert-butoxyiminobenzo [b] thien-e-ylacetic acid, m.p. 108-109 ° C. Amax (EtOH) 231, 253, 297 nm (ε 1700, 7,240, 24,500).

Preparation 34

Benzo [b] -thien-2-ylglyoxylic acid and benzo (b) -thien-2-ylglyoxyacetic acid

11.0 g of a 2: 3 mixture of 2- and 3-acetylbenzolbiphthifene in 80 ml of pyridine are heated to 60 ° C with vigorous stirring, added in portions

9.92 g of selenium oxide. The mixture was heated to 110 ° C, causing an exothermic reaction and thus raising the temperature to 120 ° C. The reaction mixture was stirred at 90 ° C for 45 minutes and then allowed to cool. 80 ml of water are added and the mixture is filtered through a pad of silica gel. The pyridine was removed by evaporation and the aqueous portion was filtered again. The filtrate was acidified under a - ether layer to pH 2 with 40 ml of 40% orthophosphoric acid.

The aqueous phase was extracted with ether, the ether fractions were combined, washed with water, dehydrated and evaporated to dryness to give 11.0 g of an orange crystalline solid in 86% yield. Crystallization from 100 ml of benzene gave - clearly - yellow crystals of benzo (b) -thlen-e-ylglyoxylic acid in an amount of 2.3 g, yield 18%, mp 175.9 ° C, Amax (EtOH), 233,247, Aifni 308 nm. - (ε 11400, 7 200, 14 600), τ (DMSO-d6) values show

1.83 (C-4 and C-7 proton), 1.42 (C-3 potton),

2.40 (C-5 and C-6 proton).

The mother liquor was concentrated to an orange oil, from which 8 g of crystals precipitated on standing. Recrystallization from 20 ml of benzene gave 1.6 g of light yellow needle crystals of benzo- [b] -thien-3-ylglyoxylic acid in 12.5% yield, m.p. 92-93 ° C, τ (DMSO-de) values. show 0.83 (C-2 proton), 1.32 (C-4 proton), 1.79 (c-7 proton), 2.40 (c-5 and C-6 proton), Amax (EtOH) 235 310.5 nm (ε

II 200 and 7 400).

2-Alkoxyiminoarylcellchkindy

Preparation 35 syn-2-md: hnx (R) -imino (n-H) -methylcyclide

5.21 g of phosphorus pentachloride are added in portions, while stirring, to a mixture of 4.51 g of syn-2-methoxyiniinophenyl acetic acid in 2% anhydrous benzene. Thionyl chloride (0.3 ml) was added and the solution was heated under reflux for 30 minutes. Benzene was removed - by evaporation, the residue was distilled to give a mixture of chlorides -syn-acid and anti-acid in a ratio of approximately 1: 1 as a colorless oil in an amount of 3.08 g in a yield of 62 y / o, b.p. 74 ^'O C at 1.3 Pa. This reaction was repeated using 5.04 mmol at room temperature to also produce a mixture of isomers and acid chlorides.

The chloride mixture was separated and purified by preparative thin layer chromatography, whereby a 1: 1 column was developed three times with 60-80 ° C petroleum ether to give 1.43 g of the final product as a colorless oily liquid at 24% yield.

In another experiment, a 10 g mixture of syn- and anti-2-methoxyiminophenylacetic acid at a ratio of about 1: 1 was converted to a mixture of the acid chlorides similar to the above and chromatographed on 1'00 g silica gel (Hopkins and Williams, MFCJ using petroleum ether, b.p. 80 DEG-80 DEG C., 4.31 g of syn-2-methoxyimino-phenylacdyl chloride was obtained in a yield of 39%.

A general method for converting 1-alkoxyiminoarylacetic acids to the chlorides of these acids without isomerization

A solution of 1 equivalent pure acid _syn-1-t aCkoxy iminoaryCocCové in methanol in an amount of about 1 to -4 mL / mmol was treated with 1 equivalent of sodium methoKidu in methanol at 0 to 15 ° C and the mixture was evaporated to give a gain of sodium a salt which is dried by either azeotropic distillation with several portions of benzene and / or vacuum drying in the presence of phosphorus pentoxide.

the equivalent of the anhydrous sodium salt is suspended in 5 ml of anhydrous benzene per 1 mmol of salt, benzene containing a few drops of anhydrous dimethylformamide and mixed with 1 to 2.5 equivalents of freshly distilled oxalyl chloride. The mixture was stirred at room temperature for 1 hour, then the benzene was removed by evaporation. The resulting chlorides are dissolved in acetone - or methylene chloride and used directly to acylate - the corresponding cephalosporin nucleus. In this way, chlorides of the following acids can be obtained:

syn-2-eChnxyimmophenyNic acid _? acid syn-2-terc.butoxyiminofenyloctová acid, syn-2-be'nzylo.xyiminofenytoctová acid, ^{syn-2-then-2'-yloxximmofenyloctová} acid, syn-2-methoxyimino

- (thien-2-yl) acetic acid, syn-2-ethoxyimino- (thien-2-yl iodoic acid, syn-2-benzyloxyoxy- (fur-2-yl iodoic acid, syn-2-n-butoxyimino-thien) -2-yl Iodoic acid, syn-2-tert-butyl-4-yimino-4-

- (thien-2-yl iodoic acid-syn-2- (2-bromoethoxy) imino- (thien-2-yl) iodoic acid syn-2- (2-tert-butoxycarbonylaminoethoxy) imino- (thien-2-yl) Acetic acid syn-2-benzyloxyimino-thien-2-yl Acetic acid syn-2-then-2-yCoxyimino-

- [thien-2-yl iodoic acid, syn-2- (1-ethoxy) methoxyimino (-thien-2-yl iodic acid, syn-2- {pyrid-2-ylmethyl) Joxyimino- (thien-2-yl iodic acid) acid, syn-2-methnxyimmicnaf ¢ -Γ-yioctová acid, syn-2 -: - butoxyiminonaftcΓ-yCocCová acid, syn-Z-benzylOxyllmnona f i-1 ^4-ylacetic acid, syn-2-methoxyiminobenzo-

- [b] -thien-3'-yl-acetic acid, syn-1-tert-butoxyimino-benzo-b] -thien-3'-yl-hydroic acid, syn-2-benzyloxyiminobenzo-

- [b] -thien-3‘-ylacetic acid, syn-2-methoxyimino-benzo z-

- [b 1-thien-4-ylacetic acid, syn-2-tert-butoxyiminobenzo-

- [b] -Chien-2'-yCodyne _?

52 syn-2-benzyloxy-benzo [b] thien-2'-ylacetic acid, syn-2-methoxyimino (fur-2-yl) acetic acid, syn-2-tert-butoxyimino-

- (fur-2-yl) acetic acid, syn-2-benzyloxyimino-

- (fury-2-yl) acetic acid, syn-2-furfuryloxyimino- (fur-2-yl) acetic acid, syn-2-ethoxyimino- (fur-2-yl) acetic acid.

Preparation 40

2-Phenoxyimino-2-phenylacetic acid (syn-isomer)

A solution of syn-2-hydroxyimino-2-phenylacetic acid (33 g) in anhydrous methanol (500 ml) was treated with 1.105 N sodium methoxide solution (486 ml) and stirred for 15 minutes. Diphenyl iodonium bromide (90 g) was added to the solution and the resulting mixture was stirred under nitrogen for 18 hours. A small amount of solid was filtered off and the filtrate was evaporated to dryness. Water (600 mL) and ether (600 mL) were added to the residue, and the mixture was adjusted to pH 7.0 with concentrated hydrochloric acid. The aqueous layer was washed twice with ether and then acidified under ether to pH 1.8 with concentrated hydrochloric acid. The acidic mixture was extracted into ether and the combined extracts were washed (water, saturated sodium chloride solution), freed from water and evaporated to give a dark brown solid (35 g). This was triturated with ice-cold nitromethane. The solid was collected, washed with a little cold nitromethane and dried in vacuo to give pale brown crystals of 2-phenoxyimino-2-phenylacetic acid (24.41 g, 51%), mp 104.8-105.1 degrees Celsius Λ _max '(ethanol) 267.5 nm (ε 11,600; 10,100).

Similarly, the following were prepared:

Preparation 41

2-Phenoxyimino-2- (thien-2-yl) -acetic acid (syn-isomer) (52%), mp 98.3-99.5 ° C, λ _max (ethanol) 267.5; 303 nm (ε is 9,900 and 12,000).

Preparation 42

2-Phenoxyimino-2- (fur-2-yl) acetic acid (syn-isomer) (34%), mp 100.7-100.9 ° C, λ _max (ethanol) 270.5,292, 5 nm (ε = 14,300 and 15,700).

Preparation 43

2-Cyclopentyloxyimino-2- (fur-2-yl) acetic acid (syn-isomer)

Fur-2-ylglyoxalic acid (2.80 g) and cyclopentyloxamine hydrochloride (3.3 g) were dissolved in a mixture of water (100 ml) and ethanol (50 ml) and the pH of the solution was adjusted to 5.0. The solution was stirred for 19 hours, the alcohol was evaporated and the solution was acidified to pH 1.5 under ethyl acetate. The acidic mixture was extracted into ethyl acetate and the combined extracts were washed, dehydrated and evaporated to give the crude acid (4.38 grams). This acid was treated with a suspension of activated carbon in benzene for 15 minutes, filtered and the filtrate evaporated to a solid which was recrystallized twice from cyclohexane to give the resulting acid (2.28 g, 51%), mp 96.6-97, 7 ° C, λ _max (ethanol)

277.5 nm (ε = 15,600).

Preparations 44—50

2-Alkoxyimino-2-arylacetic acids

General procedures

The substituted glyoxylic acid mixture and excess (10-15%) alkoxyamine hydrochloride are suspended in water or a mixture of water and ethanol, stirred and the pH of the mixture is adjusted to 4 and 5 with sodium hydroxide solution (1N to 10N). The clear solution at pH 4-5 is maintained during the reaction by further addition of sodium hydroxide solution and ethanol as needed. The reaction mixture is maintained at room temperature until all the keto acid has been consumed (it may be necessary to add an additional amount of more volatile alkoxyamines). The progress of the reaction was monitored by acidifying an aliquot, extracting with ethyl acetate, and thin layer chromatography on silica gel plates (induced by a mixture of chloroform: methanol: acetic acid in a ratio of 18: 2: 1). Alkoxyiminoacetic acids are less polar than the starting keto acids. Reaction times range from 2 hours to 2 days. After completion of the reaction, the pH of the mixture was adjusted to 7-8 and the ethanol was removed by evaporation. The aqueous mixture is extracted with ether, the extract is discarded and the aqueous phase is acidified to pH <2 with dilute hydrochloric acid. The mixture is extracted with ethyl acetate or ether, the extract is dehydrated and evaporated to a crude product which is purified by one of the following methods:

(a) Crystallization and recrystallization (if necessary) from a suitable solvent.

(b) The crude product dissolved in ether is exposed to a small excess of a solution of palzomethane in ether. The excess was then removed with acetic acid and the solution was washed with sodium bicarbonate solution and evaporated to the crude methyl esters. The esters are separated by preparative thick layer silica gel chromatography or silica gel column chromatography and then hydrolyzed in the conventional manner with alkali to syn-acids which are purified by crystallization from a suitable solvent.

These methods are used to prepare the intermediates listed in Table 4 (syn-isomers).

0 ООО О O O О 0 ООО О O О О 05 / b Mi in CM O О Me O 00 in 00 CD WHAT τμ CM tH CM CM tH tH rH tH

10 it it 1—1 2 * CD b WHAT Me O) it 05 / 00 05 O 00 00 it 00 CM CM CM 00 CM CM CM CM

rt b co 0? Й 0 Я И O Xl ξ £

00 it to » WHAT Me 00 00 00 * Me <4 00 00 n I t— £ to CD 00 00 * 00 * to 0 WHAT* b * 00 *

in to Ml CO

0 2 cm cm co CO b CM CO 0to0 05 / 00 AND 1 1 0 t> C5 ^b CD £ MF CD CM * 1 to CM 00 * 2 2 * 00 00 00 CM * CM * b CM * CM * CM *

7? 00 2 00 2 gb ^ CDb ^ 2 * 2 * 2 * M ¹ *

R CO2H

Г — 1

A «3 H

CMto yHMi * bCM

00 00 00 1 WHAT* Me O) 00

Cl Honor C2 X X Φ φ Λ AND whose O O Φ pH N with ti b> r-s φ A O 03 ω 00 A *

tí

Φ

N t f_ φ Cti A

Й ΰ ti * X X Φ Φ AND Λ fi O 2 Φ 0 N 3 0 ^N b cr> »Φ A Q And drawbars * 4 «/ * —- * * —'' — _

CH2CO2But (a) 88.5 2.47 5.32 253 13 800 (tetrachloro methane 8.58

Preparation 51

2- (Thien-2-ylmethoxyimino) - (1-methylpyrrol-2-yl) acetic acid as syn-isomer

A solution of 4.6 g of 1-methylpyrrol-2-ylglyoxylic acid and 5.46 g of thien-2-ylmethoxamine hydrochloride in 100 ml of a 1: 1 mixture of water and ethanol is adjusted to pH

The mixture was stirred at room temperature for 24 hours at pH 4.8 with 10 N sodium hydroxide solution. An additional 0.5 g of thien-1'-ylmetholamine was added and the solution was maintained at pH 4.8 at room temperature for an additional two days. The pH was adjusted to 8 with potassium bicarbonate solution and ethanol was removed by evaporation. The aqueous solution was washed with ether and the aqueous phase was then acidified to pH 1.5 under a layer of ether with 2 N hydrochloric acid solution. The ether extracts were combined and washed with water, dehydrated and evaporated to an orange oil (8.8 g). The crude mixture of syn-isomer and anti-isomer was esterified with a small excess of diazomethane in ether.

To a solution of 7.7 g of the mixed methyl esters in 100 ml of methanol was added 28 ml of 1 N sodium hydroxide solution. The mixture is kept at room temperature for 3 days, then the sample is chromatographed to show only traces of residual ester in anti-isomeric form. After a further 30 minutes, 12 ml of 2 N hydrochloric acid solution are added and the methanol is removed by evaporation. The residue was partitioned between ether and excess sodium bicarbonate in water. The ether layer was separated, washed with water, dehydrated and dried to give 5.9 g of a light orange oil.

This liquid was treated with 4.5 ml of 10N sodium hydroxide solution in 100 ml of methanol and held at room temperature for 16 hours. An additional 4.5 ml of 10 N sodium hydroxide solution was added and after standing at room temperature for 24 hours, the mixture was heated to 60 ° C for 30 minutes. Methanol was removed by evaporation and the residue was partitioned between ether and sodium bicarbonate solution in water. The aqueous phase was acidified under a layer of ether with 2 N hydrochloric acid solution. The ether extracts are combined, washed with water and dehydrated. Evaporation of the ether yielded 4.8 g of a pale orange oil which was crystallized from carbon tetrachloride to pale brown crystals of the title compound (1.9 g), m.p. 70-71 ° C. A _ma x (EtOH) · = 235 and 287.5 nm (ε = 11600 and 17100). τ (DMSO-d 6) values including 4.70 (S, CH 2) and 6.18 (S, CH 3).

General method for converting 2-substituted oxyimino-2-arylacetic acid to acid chloride without isomerization

A solution of 1 equivalent of pure syn-2-substituted oxylminoarylacetic acid in methanol in an amount of 2-4 ml / mmol is mixed with 1 equivalent of sodium methoxide in methanol at 0-25 ° C and the mixture is evaporated to give the sodium salt which it can be dried by azeotropic distillation with several parts of benzene and / or by drying under reduced pressure over phosphorus pentoxide.

an equivalent of anhydrous sodium salt is suspended in anhydrous benzene at 5 ml / mmol with a few drops of anhydrous dimethylformamide and then mixed with 1 to 2.5 equivalents of freshly distilled oxalyl chloride. The mixture was stirred at room temperature for 0.5-1 hour and then the benzene was removed by evaporation. The resulting acid chlorides were not characterized but were immediately used to acylate the corresponding cephalosporin nucleus. ,

The acids described in Preparations 40-51 were also converted to their acid chlorides in the same manner.

Preparation 52

Cyclopentyloxamine hydrchloride

A mixture of 14.9 g of bromocyclopentane, 16.3 g of N-hydroxyphthalimide, 15 ml of triethylamine and 30 ml of dimethylformamide is stirred for 16 hours and then poured into 500 ml of water. The oily mixture is extracted with ethyl acetate, the extracts are combined, washed with water, dehydrated, the solvent is removed to give a white solid which is recrystallized from ethanol to give crystalline N-cyclopentyloxyphthalimide at 11.37 g 49% yield, m.p. 81.2 to 82.5 ° C, Amax (CHB ≠ j includes 1780, 1720 ^cm-1 \ Z (CO-N-CO), 970 cm ^"1 (N-O-CH) δ (DMSO-d 6) 2.08 (4 Ar-H), 5.12 · (cyclopentyl 1-H), δ 18 (4-CH 2).

A mixture of 11 g of N-cyclopentyloxyphthalimide, 2.6 g of 100% hydrazine hydrate and 30 ml of ethanol is heated under reflux for 5 minutes. Concentrated hydrochloric acid (6 ml) was added and the mixture was heated for a further 5 minutes. 20 ml of water are then added, the mixture is cooled to room temperature and filtered. The filtrate is evaporated to dryness, 50 ml of ethanol are added to the residue and a small portion of the insoluble material is collected by filtration. The filtrate was evaporated to dryness and the residue was recrystallized from ethanol / ether to give 6.28 g of 96% yield of cyclopentyloxamine hydride (m.p. 156.9 ° C).

Preparation 53 tert-Butoxycarbnylmethoxamine

Tertiary butyl chloroacetate (13.0 g, prepared according to Org. Synth., Coll. Vol. 4, 263) is added dropwise while stirring.

14.2 g of N-hydroxyphthalimide, 23.0 g of triethylamine and 30 ml of dimethylformamide were added and the resulting mixture was further stirred for 4 hours. The mixture was poured into 500 ml of water, the precipitated solid was collected, washed with water and dried. Recrystallization from ethanol gave 17.2 g of N-tert-butoxycarbonylmethoxyphthalimide, yield 72%, mp 145.6 ° C. Τ (DMSO-d 6) 2.09 (4 Ar-N), 5.28 (CH 2), 8.56 (Bu ‘).

A solution of 21 g of N-tert-butoxycarbonylmethoxyphthalimide in 250 ml of methylene chloride is treated with 7.6 ml of 100% hydrazine hydrate in 15 ml of methanol and stirred for 1.5 hours. To dissolve the resulting precipitate, a 5 N solution of ammonia is added. The organic layer was separated, the aqueous layer was further extracted with methylene chloride. The extracts are combined, washed with water, drained and evaporated to a pale yellow solid. To this was added ether, the mixture was filtered and the filtrate was evaporated to give 8.88 g of tert-butoxycarbonylmethoxamine as a pale yellow liquid, yield 80%. » _Ma x (Nujol) 3,330, 3,260 cm ¹ (NH 2), 1742 cm ¹ (—COOBu ¹ ), τ (DMSO-d ⁶ ) 3.75 (—NH 2), 5.96 (CH 2), 8, 55 (Bu &apos;).

Preparation 54

Methyl N-benzyloxymethylpyrrol-2-ylglyoxylate

306 mg of methylpyrrole glyoxylate in dlglyme was mixed with 63 mg of sodium hydroid and stirred at room temperature for 3 hours. Benzyloxymethyl chloride (376 mg) was then added and the mixture was stirred at room temperature for 3 hours. The suspension is filtered and the filtrate is evaporated to dryness. The residue was taken up in ether, washed with sodium bicarbonate solution, water, then freed from water and evaporated to give 530 mg of the crude product as a brown oil. Purification by preparative chromatography gave, in 46% yield, 250 mg of a colorless oil, (DMSO-d6) values being 6.10 (—CH3),

4.20 (.dbd.NJ - CH2 -), 5.47 (- OCH2 -), 2.70 (--Ph).

Preparation 55

N-benzyloxymethylpyrrol-2-ylglyoxylic acid

Crude methyl N-benzyloxymethylpyrrol-2-ylglyoxylate (10 mg) in 150 mL of methanol was treated with 40 mL of sodium hydroxide at 1 N at room temperature for 1 hour. Thin layer chromatography showed complete hydrolysis. 20 ml of a 2 N hydrochloric acid solution are added and the methanol is removed by evaporation. The residue was shaken with sodium bicarbonate solution and ether. The aqueous layer was acidified under an ether layer and the ether extract was washed with water, washed with water and evaporated to give 4.5 g of the title acid as an orange oil in 55% yield. This material is directly used to produce the syn-methoxime described in Preparation 49.

Example 1

3-Acetoxymethyl-7.S-

- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

To a solution of 1.15 g of dicyclohexylcarbodiimide and 1.83 g of tert-butyl 3-acetoxymethyl-7S-aminoceph-3-em-4-carboxylate in 30 ml of anhydrous methylene chloride is added a solution of 1 g of syn-2-methoxyiminophenylacetic acid in anhydrous methylene chloride (15 ml) and the resulting solution was stirred at room temperature for 1.5 hours. The mixture was filtered and the filtrate was washed with 2 N hydrochloric acid solution, water, saturated sodium bicarbonate solution, water and then freed from water, then evaporated to 2.60 g of orange grit. 0.21 g of this pulp is triturated with petroleum ether, b.p. 60-80 ° C, to give 0.15 g of syn-tert-butyl-3-acetoxymethyl-7- (2-methoxyimino-2-phenylacetamido). Cef-3-em-4-carboxylate as a solid, λ max (EtOH) 258 nm (ε 17,400), λ max (CHBr 3) 1784 cm -1 (η 3 -lactam), t (CDCl 3) 2.99 (doublet J) 9.0, NH), 2.2 to 2.7 (multiplet, Ph), 5.97 (singlet, OCH 3) 7.93 (singlet, acetate), 8.48 (singlet, t-butyl).

The residue (2.4 g) was shaken with 10 ml of trifluoroacetic acid at room temperature for 10 minutes, then evaporated to an oily liquid. About 80 mL of ether was added to give a solution in which 1.58 g of a precipitate consisting essentially of syn-acetoxymethyl-7 / S- (2-methoxyimino-2-phenylacetamido) cef on standing yielded 66% in yield. -3-em-4-carboxylic acid as a white solid, [.alpha.] D @ 20, + 55 DEG (c = 1.02 in dioxane), .lambda.max (pH 6 phosphate buffer) 258 nm (e1950), .lambda.max (nujol) ) 1782 cm ^-1 (β-actam), τ (DMSO-de) 0.21 (doublet, J 8.0 Hz, NH), 2.3 to 2.6 (multiplet, Ph), 6.08 (singlet, OCH3)

7.98 (singlet, acetate).

Example 2

3-Crotonoyloxymethyl-7 $ -

- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

A suspension of 1.0 g of p-toluenesulfonate salt of diphenylmethyl-Z-2-iminodotrotonyloxymethylcef-3-em-4-carboxylate in 20 ml of ethyl acetate was shaken with sodium bicarbonate solution. The ethyl acetate layer was washed with water and saturated sodium chloride solution, freed from water and evaporated under reduced pressure, the residue was dissolved in ml of methylene chloride and 0.324 g of dicyclohexylcarbodiimide was added. The resulting solution was treated with 0.281 g of 2-methoxyimino-2-phenylacetic acid as the syn-isomer. The mixture was allowed to stand for 1 hour, then filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was washed with 2 N hydrochloric acid solution, sodium bicarbonate solution, water and saturated sodium chloride solution, then freed from water and concentrated under reduced pressure. 1.0 g of a foam is obtained, which is dissolved in 2 ml of anisole and treated with 8 ml of trifluoroacetic acid. After standing at 20 ° C for 5 minutes, the solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the solution was quickly extracted with sodium bicarbonate solution. The extracts were combined, washed with ethyl acetate and acidified with 2 N hydrochloric acid solution, then extracted again with ethyl acetate. The extract was washed with water and saturated sodium chloride solution, freed from water, concentrated under reduced pressure, and then added under stirring to kerosene to precipitate the resulting methoxime in a yield of 67% a, 0.467 g [iw] n + 37, 3 ° (c equals 0.9 in DMSO Am max (pH 6 phosphate buffer) 258 nm (ε 17,800), in _{ra and} x (nujol) 1,782 (ε-actam), 1710 (CO 2 H), 1680 and 1,540 ' (CONH) and 1660 cm ^-1 (unsaturated ester), - τ (DMSO-d 6, 100 MHz) 0.19 (doublet, J 8 Hz), 0.30 (multiplet, CH = CH-CH 3), 6, 06 (singlet, NOCH3), 6.28 and 6.50 [2 doublets (quaternary portions), J 18 Hz, C-2 CH3], and

8.12 (double doublets - J 7 and 1.5 Hz, CH == = CH-CH 3).

Examples 3 to 11

General procedures for the preparation of acids

7β- (2-alkoxyimino-2-substituted-acetamido) -3- (substituted) methylcef-3-em-4-carboxylic acid using dicyclohexylcarbodiimide (i) Process for the preparation of the acid and its intermediate esters, reactions

Method A

To a solution of 1 equivalent of tert-butyl ester or diphenylmethyl ester of N, N-amino-3- (ss) -methylcef-3-em-4-carboxylic acid and 1 to 1.2 equivalents of dicyclohexylcarbodiimide in anhydrous methylene chloride (dimethylformamide is used as co-solvents) or dioxane), a solution of 1 equivalent of syn-2-alkoxyimino acid (substoacetic acid in anhydrous methylene chloride) is added at 0 to 20 ° C. The mixture is stirred at room temperature for 45 minutes to 3 hours, filtered and washed successively with 2N. hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, the organic phase is drained and evaporated to give the desired ester as an oil or gas.

Method B

The procedure is the same as in Method A, but instead of methylene chloride, dimethylethylene glycol is used.

Method C

The procedure is the same as that of Method A, except that the ester is further purified by silica gel chromatography.

Method D

The procedure is the same as in Method A, but the 7-p-toluenesulfonic acid salt ester is pre-regenerated by shaking with ethyl acetate and an excess of saturated sodium bicarbonate solution. After washing with water and saturated sodium chloride solution, the organic layer was evaporated to dryness and redissolved in methylene chloride.

(ii) Deprotection of esters which are intermediates in the process of the invention

Method E

The tert-butyl or diphenylmethyl ester is dissolved in 5 to 10 ml of trifluoroacetic acid per g of ester and the mixture is allowed to stand at room temperature for 5 to 10 minutes and then evaporated under reduced pressure. The crude product was taken up in ether or ethyl acetate, extracted with sodium bicarbonate solution and washed with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed, dehydrated and evaporated to dryness to give the desired syn-73- (2-alkoxyimino-2 [(subst.] Acetamido) -3- (sub-s)) methylcef-3-em-4-carboxylic acid. .

Method F

The ester is dissolved in anisole at a rate of 1 to 5 ml of anisole per g of ester and contacted with trifluoroacetic acid at a rate of 4 to 10 ml of acid per 1 g of ester and allowed to stand for 5 to 10 minutes at room temperature. is processed by method E.

(iii) A process for preparing a β 4 -isulfonic acid salt of diphenylmethyl-7 ₍ d-amino-3-cyclopropylpropylcarbonyloxymethylcef-3-em-4-carbsxylate) starting from Example 11 (a) Diphenylmethyl 3-cyclopropylcarbonyl oxymethyl-7 P - (thlen-2-yl) acetamido-3-em-4-carboxylate

To a solution of 8 g of diphenylmethyl-4-hydroxymethyl-73- (thien-2-yl) acetamidocapho-3-em-4-carboxylate in 20 ml of anhydrous tetrahydrofuran containing 6.7 ml of anhydrous pyridine is added a cyclopropane carbonyl chloride solution (made from acid). and 6.7 g of thionyl chloride at room temperature (reaction time 90 minutes) in anhydrous tetrahydrofuran in an amount of 10 ml over 10 minutes at room temperature. The mixture was stirred at the same temperature for 2 hours, then evaporated to near dryness and diluted with 100 ml of ethyl acetate. The mixture was washed successively with sodium bicarbonate solution, 2N hydrochloric acid solution and water. The organic layer was treated with activated carbon at room temperature for 1 hour, then filtered and the filtrate was evaporated to a foamy product which was triturated with petroleum ether, b.p. 60-80 ° C, yielding 87% yield.

7.8 g of the resulting ester, [a] _ _D + 28 ° (c = 0.83 in dioxane) Ainf (EtOH) 235, - 255 nm (ε 12800, 7700), in _Nia x (CHBr3) 1780 (04actam), 1728 cm (esters), τ (DMSO-d 5) hoid values show 0.8 (doublet of NH 3) 3.02 (CHPh 2),

8.4 (multiplet, -C [beta] 3), 9C3- [beta]), 2 (CH2 groups in the cyclopropane ring).

EXAMPLE 3 (a) tert-Butyl 3-methyl-7S- (2-methoxyimino-2-phenylacetamido) (β-3,4-carboxylate as syn-isomer) was obtained as a yellow solid, m.p. ° C (dec.), Λ max (EtOH) 255 nm (ε 16 350), λ max (CHBr 3) 1785 (δ-lactam),

1720 (t-buitylester), 1690, 1520 cm * ¹ (CONH), τ (CDCl3) 3.02 - (doublet J 8.0 Hz, NH) - 2.3 to 2.7 (multiplet, Ph ), 5.96 (singlet, OCH 3), 7.89 (singlet, - CH 3) 8.48, (singlet, t-butyl) by Method A. Removal of the protecting group E by Method E gives:

(b) 3-methyl-7H- (2-methoxyimino-2-phenylacetamido) c, N-carboxylic acid as the syn-isomer as a beige solid in 67% yield, mp 145 ° C ( decomposition), [α] D 7 + 100 ° (c = «= 1.32 in dioxane) Amax (pH 6.0, phosphate buffer) 258 - to 259 nm (ε 18 650), Vmax (nujol) 1760 (Β-actam), 1702 (CO 2 H), 1660, 1536 (CONH), τ (DMSO-d 6) 0.24 (doublet J 8.0 Hz, NH), 2.3 to 2.6 (multiplet, Ph ), 6.05 singlet, OCH 3), 7.94 (singlet, CH 3).

EXAMPLE 4 (a) tert-Butyl 3-acetoxymethyl 1-70- (2-benzyloxyimino-2-phenylacetamido) cis-.alpha.-carboxylate in the form of the syn-isomer, m.p. 123 DEG-125 DEG C., Amax (EtOH) 259 nm (TE 20- 500), the _m ax (CHBrs) 1796 (0-lactam),

1732 (acetate and ester), 1694 and 1522 cm -1, CONH), τ (CDCl 3) 3.00 (doublet J 9.0 Hz, NH) 2.38, 2.60 (multiplet, Ph), 2.60 (benzyl aromatic protons), 4.74 (singlet, methylene group on benzyl), 7.94 (singlet, acetate), 8.48 (singlet, t-butyl) were obtained by Method A. Removal of the protecting group by Method E gave:

(b) 3-acetoxymethyl-7.3- (2-benzyloxyimino-2-enylacetamido) -cyl-4'-carboxylic acid as the syn-isomer as a white solid in 58% yield, m.p. 167 DEG C. (dec.); e + 50.5 ° (c - 0.85 in dioxane), Amax (pH 6.0, - phosphate buffer) 259 nm (ε 20,700), in _milx (nujol) 1771 (O-lactam), 1735, 1 252 (acetate),

650 and 1530 cm (CONH), τ (DMSO-de), 0.14 (doublet J 8.0 Hz, NH), 2.3 to 2.7 (multiplet, atomatic protons), 4.79 (singlet, CH2) benzyl groups), 7.96 (singlet, acetate).

Example 5 (a) Dienylmethyl 73- (2-methoxyimino-2H-enylacetamido) -3-methylthiomethylceph-4-ε-carboxylate in the form of the syn-isomer Amax (EtOH) 259 nm (ε 18 550), γ _{m and} x - (CHBr 3) 1785 (3-actam), 1722 (benzhydryl ester), 1688 and 1518 cm (CONH), τ (CDCl 3) 3.01 (doublet 7 Hz, NH), 2.32, 2.64, 2 , 65 '. (aromatic protons) 5.97 (singlet, OCH 3), 8.16 (singlet, SCH 3) were produced by Method A. Removal of the protecting group by Method E gave:

(b) 3- nethylth ^ ^ i ^ c ^ u ^ E3Hy '- Z' _and 3- (2lmethoxyiminol2lfenylacetamido) ceph-3-em-4-carboxylic acid, syn isomer yield as a precipitate, and a yield of 51 -% - [°:] d ² 6 + + 51 ° (c = 0.98 in dioxane), Amax (pH-6.0 phosphate buffer) 259 nm, (ε 18 300), - umax - (nujol) 1781 ( 3-actam), 1770 (CO 2 H), 1670 and 1531 cm -1 (CONH), τ (DMSO-d 6) 0.22 - (doublet J 9 Hz, NH), 6.06 (singlet OCH 3), 8, 01 (singlet SCH3).

EXAMPLE 6 (a) Di-phenylmethyl-3-benzoyloxymethyl-7β- (2-methoxyiminol-12-phenylacetamido) -ceta-.alpha.-carboxylate in the form of the syn-isomer was prepared in crude form as an orange solid yield 80% by method A. Removal of the protecting group by method F gives:

(b) 3-benzoyloxymethyl-173- (2-methoxyimino-12-phenylacetamido) cis-4-carboxylic acid as the syn-isomer as a white powder in 48% yield, [α] _D + + 46.5 ° (c = 0) 9 in DMSO) Amax (pH 6, phosphate buffer) 232.5 (ε 22 400) and 258.5 nm (ε 21400) vmax (nujol) 1780 (3-actam), 1720 and 1 265 (benzoate), 1 705 (CO2H), 1675 and 1532 cm -1 (CONH) τ (DMSO-d6, 100 MHz) 0.16 (doublet, J 8 Hz, 4.06 (double doublet J 5 and 8 Hz, C- 7H), 4.70 (doublet, J 5 Hz, C-6 H),

6D

6.03 [singlet, NOCH 5], and 6.14 and 6.44 [doublets (quartet portions), J 18 Hz, C-2 CH 2].

Example 7 (a) Diphenylmethyl-3-isobutyryloxymethyl-7β- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylate in the form of the syn-isomer was obtained by Method A and deprotected by Method F, thereby is obtained:

(b) 3-isobutyryloxymethyl-7H- (2-methoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer in 73% yield, [α] _D + 48.5 ° (c = 1.0 in DMSO) λ max [pH 6 phosphate] 258 nm (ε 18,700), λ max (nujol) 1783 (/ / β-cam), 1725 (carboxylic acid ester and acid), 1670 and 1530 cm ^-1 (CONH), τ (DMSO-d 6, 100 MHz) 0.19 (doublet J 8 Hz, NH) 2.2 to 2.6 (multiplet, aromatic protons), 4.09 (double doublet, J 5 and 8 Hz, C-7H), 4.76 (doublet, J 5 Hz, C-7H), 4.94 and 5.26 [2 doublets (quartet portions), J 13 Hz, C-3 CH2], 6.04 (singlet, NOCH3), 6.28 + 6.50 [2 doublets (quartet portions), J 18 Hz, C-2 CH2], 7.40 (septet, J 7 Hz, CH (CH3) 2) and 8.80 (doublet), J 7 Hz, CH (CH 3) 2).

Example 8 (a) tert-Butyl 3-acetoxymethyl-7,3- [2-methoxyimino-2- (thien-2-yl) acetamido] - [eta] &lt; 3 &gt; -3-em-4-carboxylate in form. syn-isomer. is obtained as a solid in 85% yield, λ max (EtOH) 262 to 263 nm (ε 14 900), _{λ n} 280 nm (ε 13 280) λ max (CHBr 3) 3400 (NH), 1780 (iS-1-latam) ), 1738, 1120 · (CO 2 R) and 1684, 1514 cm -1 (CONH) τ (CDCl 3) 2.5 to 2.7, 2.95 (thienyl protons), 5.97, (OMe), 7, 93 (OAc), and 8.48 (tert-butyl), method A. Removal of the protecting group yields free:

(b) 3-acetoxymethyl-73- [2-methoxyimino-2- (thienyl-2-yl) acetamido] cef-3-em-4-carboxylic acid in the form of the syn-isomer in 56% yield, [a] _D ² 3 + 60 ° (c = 0.8 in dioxane) and _m x 262 nm (ε 15,700) and _INF 290 nm (ε 10700), vmax 3275 (NH), 1768 (? -lactam) 1728 (OAc), 1700, 2600 (CO 2 H), and 1648, 1520 cm ¹ (CONH), τ (DMSO-d 6) 2.2 to 2.9 (thienyl), 6.08 (OMe), 0, 13 (NH),

4.12, 4.76 (O-lactam), 6.28, 6.52 (J = 18 Hz, CH2 in the ring), 4.94, 5.27 (J = 13 Hz, CH2 OAC), and 7, 94 (OAc).

Example 9 (a) tert-Butyl-1-methoxymethyl-N - (2- t -butoxyimino-2-phenylacetamido) cef-3-em-4-carboxylate in the form of the syn-isomer was obtained by Method B and Purification by chromatography on silica gel, Method C, gives a pale yellow foam in 43% yield, which is recrystallized from isopropyl ether to give an ester, m.p. 150-153 ° C. τ (CDCl 3) 2.2-2.75 (multiplet, atomatic) protons), 2.83 (doublet, NH), 8.61 (t-butoximine), 8.46 (tert-butyl ester). Removal of the protecting group by method F yields:

(b) acid-3-aaetoxχmeteyl 7 _l /--(2-tera.butoximino-2-f phenylacetamido) ceph-3-em-4-karbooχlová syn isomer as a pale yellow foam, vmax (CHBr3) 1782 ' (β-actam) 1,685, 1,522 cm ^-1 (CONH), τ (DMSO-d 6) 2.2 to 2.75 (multiplet, aromatic protons), 0.4 (doublet, NH), 8 , 70 (t-butox).

Example 10 (a) tert-Butyl-3-acetoxymethyl-73- [2-methoxy-amino-2- (thien-2-yl) acetamido] cef-S-ε-carboxylate in the form of the syn-isomer, .lambda.max (EtOH) 260 nm (ε 12940), vmax (CHBrS) 1778 (.beta.-lactam), 1688 and 1510 ^cm-1 (CONH), τ (CDC13) 2.74 (d, NH)

4.76 (—OCH2OCH3), 6.49 (OCH2OCH3), 7.91 (OCOCH3), 8.44 (But), were prepared by Method A and then contacted with trifluoroacetic acid by Method E to afford :

(b) 3- (2-methoxy-imino-2- (thien-2-yl) acetamido) a-3-em-4-carboxylic acid, 3-kethoxy-methyl-7, 3- [2-methoxy-imino-4-carboxylic acid, [&lt;]&gt; ° (c - 0.8, DMSO), Amax (pH 6, phosphate buffer) 262.5 nm (ε 16 400), vmax (nujol) 1778 (0-lactam), 1670, 1530 cm ¹ (CONH), τ (DMSO-d 6) 0.11 (doublet, NH),

4.89 (OCH 2 OCH 3), 66: 2 (OCH 2 OCH 3), 7.96 (OCOCH 3).

EXAMPLE 11 (a) Diphenylmethyl 3-cyclopropylcarbone-oxymethyl 1-7 β- (2-ethoxy-imino-2-phenyl-acetamido) cef-3-em-4-carboxylate in the form of the syn-isomer Amax (EtOH) 256 , 5 nm '(ε 15 800) Wmax (CHBr 3) 1780 (/ S-ackam), 1680, 1510 (CONH), 1720 cm ^-1 (esters), τ (DMSO-d6) values including 0,19 (doublet, NH), 3.01 (CHPH 2], 5.76 (CH 2 CH 3), 8.68 (CH 3), 8.35 (multiplet) 9.2 (CH 2 groups in the cyclopropane ring) were prepared by Method C and deprotected by Method F to obtain:

(b) 3-cyclopropylcarbonyloxymethyl-73- (2-ethoxyimino-2-enylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer, [α] _D + 75 °, [c = 0.86 dioxane ), Amax (pH 6, phosphate buffer) 257 nm (ε 16 000), vmax (nujol) 1780 cm-1 (δ-aktam) τ (DMSO-de) values including 0,25 (doublet of NH), 5,80 (CH 2 CH 3), 8.73 (CH 3).

Example 12

3-Acetooylmeth-1-7 / 3- (2-methoximino-2-phenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

To 0.565 g of a solution of 3-kaethoxymethyl-7H-aminocephene-4-carboxylic acid in 10 ml of acetone and 10 ml of water containing 0.42 g of anhydrous sodium bicarbonate is added a solution of 0.495 g at 0-5 ° C. syn-2-methoxyiminophenylacetyl chloride in 5 ml acetone over 5 minutes. The solution was stirred at room temperature for 30 minutes and then evaporated to remove acetone. The residue is washed with 20 ml of ether and the aqueous phase is acidified under a 50 ml layer of ethyl acetate to pH 2 with 2 N hydrochloric acid solution. The mixture was filtered and the layers were separated. The aqueous phase was extracted with ethyl acetate. The organic extracts were combined, dehydrated and evaporated to give 0.48 g of a white solid which was triturated with ether to give 0.45 g of the title compound in 64% yield. [a] D ¹ 7 + 56 ° (1.04 dioxan'u), .lambda.max (pH 6 phosphate buffer) 259 nm (ε - 19,700), P _{m a} x (nujol) 1778 (/ ^ -! l ^ l δ t ^ <am), 1740, 1262 (OCOCH.3) 1712 (CO2H), 1660, 1534 cm @ ¹ (CONH), τ (DMSO-d6) values including 0.2 (doublet, J 8.0) Hz, NH), 2.3 to 2.6 (multiplet, Ph), 6.05 (singlet, OCH 3), 7.94 (singlet, acetate).

Example 13

3-Acetoxymethyl-7 / 3-

- (21ethoxyimin0121phenylacetamido) cef-S-em-1-carboxylic acid in the form of the syn-isomer

0.26 ml of -oxalyl chloride is added to a suspension of sodium syn-ethoxyiminophenylacetate [made from 300 mg of the corresponding acid and

3.62 ml of 0.43 N sodium methoxide] followed by drying over phosphorus pentoxide] in 20 ml of anhydrous benzene with 1 drop of dimethylformamide. The mixture was stirred for 1 hour, then evaporated to dryness. The residue is dissolved in 15 ml of acetone and this solution is added dropwise to an ice-cooled solution of N-aminocephaosporanic acid 424 mg in 20 ml of water containing 262 mg of sodium bicarbonate with stirring. The mixture was stirred for 2 hours, the acetone was evaporated and the aqueous solution was acidified to pH 1.5. This mixture was extracted with ethyl acetate, the extracts were combined, washed with water and saturated sodium chloride solution, then freed from water and evaporated to give the title product as a colorless foam [.alpha.] D -56 DEG (89% yield). c = 1.04 dioxane], a _m ax (pH 6 phosphate buffer), 257.5 nm (ε 20200), vmax (Nujol) 1772 (/ .beta.-lactam), 1656 and 1518 cm "1 (CONH), τ δ MSO-d 6 values including 0.23 (doublet, J 8 Hz, NH),

2.3 to 2.6 (multiplet, aromatic protons),

5.75 (quartet, CH 2 CH 3) 8.68 (triplet, CH 2 CH 3), 7.96 (OCOCH 3).

Example 14

3-Acetoxymethyl-7 (3-

- (2-tert-butoxyiminothien-2‘-yl-acetamido) cef-3-em-41-carboxylic acid in the form of the syn-isomer

7.5 ml of a -0.53 N solution of sodium methoxide in methanol are added dropwise with stirring to 0.9 g of syn-tert-butoxyimino-thifn-2-yloetic acid in solution in 10 ml of anhydrous methanol at 0-5. The mixture was evaporated to remove methanol and dehydrated by azeotropic distillation with anhydrous benzene. 0.63 ml, 0.95 g of oxalyl chloride and 40 ml of anhydrous benzene with 3 drops of dimethylformamide were added to the sodium salt suspension with stirring. The mixture was stirred at room temperature for 1 hour, then the benzene was evaporated. 10 ml of the acid chloride is stirred to a solution of 1.09 g of 7/3 aminocephalosporanic acid and 0.672 g of sodium bicarbonate in a mixture of 20 ml of acetone and 20 ml of water at 0-5 ° C and the mixture is further stirred at room temperature for 2 hours. The acetone was removed by evaporation and the mixture was washed with ethyl acetate. The aqueous solution was acidified in the presence of ethyl acetate

N hydrochloric acid solution to pH 1.5 and extracted with ethyl acetate. The extracts were combined, washed with water, dehydrated and evaporated to give the title product (61%) as a pale yellow foam [.alpha.] D @ ²³ - (~ 61 DEG (c = 1.0, dioxane)). .lambda.max (pH 6 phosphate buffer) 260 nm (ε 12,500), umax (nujol): 1780 (/ .beta.-lactam), 1666 and 1520 ^cm-1 (CONH) values τ (DMSO-d6) including 0.28 (d, J = 8 Hz, NH), 2.36 and 2.84 (2H) (thien-2-yl protons), 7.98 (OAc), 8.68 (But).

Example 15

3-Aethoxymethyl-731 acid

- (2-tert-butoxyiminobenzo [b] thien-3‘-yl-acetamido] cef-3-em-4-carboxylic acid in the form of the syn-isomer

0.976 g of syn-tert-butoxyiminobenzo [b] thien-3-ylacetic acid is reacted with 0.445 M of sodium methoxide solution in an amount of 6.1 ml at room temperature. Evaporation gave 1.05 g of the sodium salt as a white powder. This product is dried over phosphorus pentoxide overnight.

0.5 g of the sodium salt was suspended in 10 ml of anhydrous benzene with 1 drop of dimethylformamide and treated at room temperature with 0.4 ml of oxalyl chloride and allowed to stand at this temperature for 1 hour. The solvent was removed by evaporation and the residue in 20 ml of acetone was added dropwise to a solution of -0.49 g of 7H-aminocaphalosporanic acid and 0.378 g of sodium bicarbonate in 30 ml of water at 0-5 ° C. The resulting pale yellow suspension was stirred at the same temperature for 2.5 hours. The acetone was removed by evaporation and the aqueous phase was acidified to pH 2 in the presence of ether. The ether fraction was washed with water, dehydrated and evaporated to give a beige foam which was dissolved in methylene chloride and evaporated again to give 0% yield. , 85 g of the resulting substance o [«] _t)

61 ° (c = 1 dioxane), Aroax (pH 6, buffer) 230,

297, 304 inf. nm (ε 27 600, 11 500, 10 630), τ (DMSO-de) values including 0.29 (doublet, NH), 4.04 (double doublet, 7 protons), 4.73 (doublet, 6-proton) 8.59 (But).

Example 16

3-Acetoxymethyl-7 / 3-

- (2-tert-butoxyiminofur-2'-ylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

2.11 g of syn-tert-butoxyiminofur-2-ylacetic acid are mixed at room temperature with

19.1 ml, i.e. 0.525 mol of sodium methoxide. The methanol was evaporated and the resulting powder was dried over phosphorus pentoxide overnight. 933 mg of sodium salt in 10 ml of anhydrous benzene containing 1 drop of dimethylformamide was mixed with 0.8 ml of oxalyl chloride for 1 hour at room temperature. The solvent was removed by evaporation and the residue was dissolved in 30 ml of acetone, then added dropwise to a solution of 1.09 g of 7-aminoccephalosporanic acid and 672 mg of sodium bicarbonate in 50 ml of water at 0-5 ° C. The resulting solution was stirred at room temperature for 1.5 hours, then the acetone was removed by evaporation and the pH of the aqueous phase was adjusted to 8, then the aqueous phase was washed with a small amount of ether and acidified to pH 2.0 in the presence of ether. The organic layer was washed with water, dehydrated and evaporated to a pale yellow foam which was freed of water through a pad of silica gel and potassium hydroxide to give the title product (1.6 g, 86%) as a pale yellow foam with [a] _D + 62 ^(c = 1, dioxane). A _max (pH 6, phosphate buffer) 272 nm (ε 18 600), v _max (СНВгз) 1780 (β-lactam) 1674 and 1510 cm ^-1 (CONH), τ (DMSO-de) values including 0, 34 (doublet, NH), 2.17 and 3.34 (fur-2-yl), protons 8.71 (But).

Example 17

3-Azidomethyl-7 -

- (2-benzyloxyiminophenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

1.28 g of syn-benzyloxyiminophenyl acetic acid are mixed with 9.55 ml of a 0.525 molar solution of sodium methoxide in methanol at room temperature. Evaporation gave the sodium salt as a white powder.

The sodium salt was suspended in 15 ml of anhydrous benzene containing 2 drops of dimethylformamide, treated with 0.51 ml of oxalyl chloride and allowed to stand at room temperature for 1 hour. After filtration through a porcelain filter, the solution is evaporated and the residue is dissolved in 20 ml of anhydrous methylene chloride and added to a solution of 1.27 g of 7-amino-3-azidomethylceph-3-em-4-carboxylic acid and 2.07 ml of triethylamine. 50 ss milliliters of anhydrous methylene chloride at 0-5 ° C. The resulting pale orange solution was stirred at room temperature for 114 hours, then evaporated to a brown foam, which was dissolved in water, washed with a small amount of ether, and acidified to pH 1.8 in the presence of ethyl acetate. Evaporation of ethyl acetate gave the crude product in an amount

1.9 g in 77% yield as a yellow foam which is dissolved in 50 ml of sodium hydrogencarbonate solution and then 1.4 g of the title product precipitated with dilute acid in a yield of 56%, [α] _D + 49.5 ° ( c = 1, dioxane) λ _max (pH 6, phosphate buffer) 258.5 nm (ε 19 400) at _max (СНВгз) 1782 (0-lactam) 1684 and 1512 cm ¹ (CONH) τ values [DMSO-de] including 0.077 (doublet, J 8 Hz, NH), 2.58 (multiplet, aromatic protons), 4.76 (CH2PI1), 4.05 (double doublets of the C7 proton).

Example 18

3-Azldomethyl-7 / 3- (2-methoxyimino-

Sodium -2-phenylacetamido) cef-3-em-4-carboxylate in the form of the syn-isomer

To a solution of 4.6 g of 3-azidomethyl-7β-aminocef-3-em-4-carboxylic acid in 100 ml of acetone and 100 ml of water containing 3.66 g of sodium bicarbonate is added dropwise at 0 to 5 ° C. A solution of 4.32 g of syn-2-methoxyiminophenylacetyl chloride was added over 20 minutes and the resulting yellow solution was stirred at room temperature for 30 minutes. The acetone was removed by evaporation and the dark green solution was washed with ether, 100 ml of ethyl acetate were added and the pH was adjusted to 2 with 2 N hydrochloric acid solution. The two layers were separated and the aqueous phase was extracted with ethyl acetate. The organic extracts are combined, dehydrated and evaporated to 8.2 g of light brown pulp which is triturated with light petroleum at 60-80 ° C and decolourised with activated charcoal to give 7.67 g of the final product as a beige pulp. This product was dissolved in 30 mL of ethyl acetate and a 10% solution was added

Sodium 2-ethylhexanoate in n-butanol (34.8 ml) with stirring, dropwise, whereby the final product (4.05 g) is precipitated in 51% yield [.alpha.] @ ²³ +63.5 DEG (c - 1.0 in water), A _max (pH 6.0 phosphate buffer) 258 to 259 nm (ε 18 850), p _max (nujol) 2110 (N3), 1756 (0-lactam), 1596 (CO2) 1, 622 and 1528 cm ^-1 (CONH), r (DMSO-d 6) values including 0.22 (doublet J 8 Hz, NH), 2.3 to 2.6 (multiplet, Ph) and 6, 04 (singlet, ОСНз).

Examples 19 to 46

General procedure for the production of acids

3-Substituted-methyl-7 -

- (2-Suboxyoxy-2-aryl lacetamido) cef-3-em-4-carboxylic acid

Έ9

Method A

A solution of the appropriate syn-2-substoxyoxy-2-arylacetyl chloride (prepared from 1 equivalent of the corresponding sodium salt with oxalyl chloride) was dissolved in acetone and added dropwise with stirring at 0-5 ° C to the acid solution 7. 1-aminocephalosporanic acid or 1 equivalent of 3-azidomethyl-73-aminoceph-3-em-4-carboxylic acid in water containing 2 to 2

2.5 equivalents of sodium bicarbonate. The mixture was stirred for 30 minutes to 2.5 hours while allowing the temperature to reach room temperature. The acetone is evaporated under reduced pressure, the pH is adjusted to 1.5-2.0 and the resulting product is extracted with ethyl acetate or ether. The extracts were washed with water or saturated sodium chloride solution, freed from water and evaporated to a foamy or solid product.

Method B

The procedure is the same as in Method A, but the product is purified by dissolution in an aqueous solution of sodium bicarbonate and reprecipitated by acidification.

Method C

The procedure is the same as in Method A, but the sodium salt is extracted with ethyl acetate and the extract is washed successively with 2 N hydrochloric acid solution and water, after which it is freed from water and evaporated to a foamy product.

Method D equivalent to a solution of the appropriate acid chloride is dissolved in anhydrous methylene chloride at a ratio of approximately 5 ml / mmol and added to a suspension or solution of 1 equivalent of 7/3-amino-cepaiosporanic acid or 3-azidomethyl-7/3-aminocephene. 3-em-4-carboxylic acid and 3 equivalents of triethylamine in methylene chloride at 0-5 ° (1. The mixture is stirred for 1 to 1.5 hours at room temperature, then evaporated to dryness, the residue is dissolved in water, washed with ethyl acetate and aqueous. The layer was acidified to pH 1.5 in the presence of ethyl acetate The ethyl acetate extract was washed with water and saturated sodium chloride solution and then evaporated to a foamed or solid product.

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Example 47

Acid

-2‘-Ylacetamido) -3- (2-methyl-1,3,4-thiadiazole-5-piperidinyl) cef-3-em-4-carboxylic acid in the form of the syn-isomer

0.45 ml of oxalyl chloride is added with stirring to a suspension of 0.747 g of sodium syn-benzyloxyiminothien-2-ylacetate in 20 ml of anhydrous benzene containing 1 drop of dimethylformamide. The mixture was stirred for 1 hour and then evaporated to dryness. The residue is dissolved in 25 ml of ethyl acetate and this solution is added dropwise with stirring to a suspension of 1.35 g of diphenyimethyl-73-amino-3- (2-methyl-1,3,4-thiadiazol-5-ylthiomethyl) cef. Of 3-em-4-carboxylate in 20 ml of ethyl acetate with 1.0 ml of propylene oxide. The solid dissolved rapidly and the resulting solution was stirred for 16 hours. The solvent was evaporated and the residue was redissolved in 50 ml of ethyl acetate. This solution is washed sequentially with 3% sodium bicarbonate solution, 2 N hydrochloric acid solution, water and saturated sodium chloride solution, then drained and evaporated to dryness to give 2.01 g of the title product diphenylmethyl ester as a tan foam, τ value including (DMSO-d 6) 0.03 (doublet, NH), 4.79 (CH 2 P 1 H), 7.26 (CH 3).

1.67 g of this crude ester were mixed with 0.24 g of anisole and 10 ml of trifluoroacetic acid. The resulting solution was allowed to stand for 10 minutes at room temperature, then the trifluoroacetic acid was removed by evaporation and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was acidified to pH 1.7 and extracted three times with ethyl acetate. The extracts were combined, washed with water and saturated brine, dehydrated and evaporated to dryness to give 1.04 g of a red foam. The foam was dissolved in aqueous sodium bicarbonate and then precipitated again by the addition of 2N hydrochloric acid. This procedure was repeated once more to give 350 mg of the final product - o [a] D - 96 ^c - (c = 0.97 in dioxane), Amax (pH 6, buffer) 274 nm in 28% yield. ε 18 500), in _ma x (nujol) 1,784 (^ - aktam) τ values including (DMSO-ds) 0.07 (doublet, NH), 2.60 (Ph), 4.81 (CH2) and 7.32 (CH 3).

Example 48 (a) tert-Butyl 3-acetoxymethyl-73- (2-methoxyiminopyrid-3'-ylacetamido) -cef-3-em-4-carboxylate in the form of the syn-isomer

A suspension of 1.8 g of 2-methoxyiminopyrid-3‘-ylacetic acid in 50 ml of dichloromethane was cooled to -10 ° C and treated with 2.08 g of phosphorus pentachloride. The mixture was stirred at this temperature for 1.5 hours, after which time most of the solid dissolved. The cold mixture is treated with 3.0 g of tert-butyl-73-amino-3-aethoxymethyl-6-β-3-em-4-carboxylate and 2 ml of propylene oxide and stirred for a further 30 minutes. The solution was partitioned between ethyl acetate and saturated sodium chloride solution and then extracted with ethyl acetate. The organic extracts were combined, washed with water - and then extracted with 2 N hydrochloric acid. The unchanged amine is removed by adding excess sodium nitrite to the cooled acid extract, then the mixture is washed with ethyl acetate for about 5 minutes at 0 ° C. The resulting aqueous phase was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extract was washed with water, dehydrated with magnesium sulfate and evaporated to give 1.33 g of a mixture of the syn-isomer and anti-isomer of the title product as a foam.

Chromatography on silica gel using chloroform / methanol (99: 1) gave the anti-isomer 394 mg and then 683 mg of the syn-isomer as a foam. The syn-isomer is dissolved in ethyl acetate and precipitated by the addition of petroleum ether, b.p. 40-60 ° C. The amorphous solid was washed with petroleum ether and dried to give 484 mg of the desired ester in 10% yield, [ «] D ² ° + 49 ⁰ (c = 0.45, DMSO), _.lambda.max (EtOH) 255 nm (ε 16 10 °), w (CHBrs) 3,396 (NH), 1,786 (/ Maktam), 1,735 (OAc), 1,724 (CO2R), 1,682 and 1518 cm @ 1 (CONH), τ (c ^ 6 DMSO) 0.14 (d, J 8 Hz, NH), 1.26, 1.30, 2.03 and 2.48 (multlets, aromatic protons), 4.10 (q, J 5 and 8 Hz, C-7H) 4.74 (d, J 5 Hz), C-6H), 5.03 and 5.36 (2d, J 13 Hz, C-3 CH 2), 6.03 (s, OCH 3), 6.28 and 6.52 (2d, J 18 Hz, C-2 Hz), 7.97 (s, OCOCH 3), 8.52 (s, C (CH 3) 3).

(b) 3-Acetoxy-ethyl-73- (2-methoxyiminopyrid-3'-ylacetamido) cef-3-yl-4-carbonyloxy ^salt in the form of the syn-isomer

A solution of 440 mg of tert-butyl-B-acetoxymethyl-N- [3- (2-methoxyiminopyrid-3-ylacetamido) cef13-em-4-carboxylate as the syn-isomer in 7 ml of trifluoroacetic acid is allowed to stand at 20 ° C 15 min. The solvent was evaporated and the residue was dissolved three times in benzene, each benzene being evaporated to dryness. The resulting gummy product was dissolved in a small amount of acetone and slowly added to an excess of petroleum ether, boiling at 40-60 ° C with stirring. The solid was collected by filtration, washed with petroleum ether, and dried to give 561 mg of the title product as a pale yellow powder, (ajn® + -3 ° (c = 0.88, DMSO), Amax (pH 6 buffer) 254 nm (ε 14 30 °), vmax (nujol) 3 250 (NH), 2600 and 1720 (CO2H), 1782 (β-lactam), 1736 (OAc), 1670 (CF3CO22), 1670 and 1 550 cm- ¹ ( CONH), τ (de-DMSO) 0.08 (d, J 8 Hz, - NH), 1.16, 1.22,

1.90 and 2.36 (m, 5% of aromatic protons) · 4.06 (q, J 5 and 8 Hz, C-7H), 4.73 (d, J 5 Hz, 4.93 and 5.26 (2d, J 13 Hz, C-3 CH '),

5.98 (s, OD, · 6.66 and 6.49 (2d, J 18 Hz, C-2 H '), 7.94 (s, OCOCH3).'

Example 49

7β- (2-methcxyiminc-2-f enolkcetkxňdo) -3-pyridiniummethylcef-3-em-4-carboxylate syn-isomer to the acid 3 g aceCoxymethyl 7 _l-S- [2-methyl-2 · thdxoimmd-fenytacetkmldd) The cef-3-em-4-carboxylic acid syn-isomer in a solution of 30 ml of water, 30 ml of acetone and 2.8 ml of pyridine was heated at 50 ° C for 4 hours. Then 2.8 ml of pyridine was added and the solution was heated at 50 ° C for 16 hours. The dark brown solution was decanted from the rubber residue, evaporated to remove acetone and washed with methylene chloride. Excess solvent was removed by evaporation and the solution was passed through a column of a tont-exchange resin (Dowex-1 in an acetate cycle), eluting with water. The eluate was lyophilized and the resulting solid was triturated with acetone to give 0.84 g of the title product as a beige solid, [.alpha.] D @ ²³ = 6.4 DEG (c = 0.95 in water) .lambda.max (pH 6, 0 phosphate buffer) 257 nm (ε 19 900), u _m ax (nujol) 1770 (/ Maktam), 1 660, 1 540 (CONH) and 1604 cm ^-1 (CO 2 "j, τ [Džjj values including 1,03 ,

1.90 and 1.40 (α, β and γ- protons in the pyridinium ring), 2.2-2.6 (multiplet, Ph), 5.99 (singlet, OCH3), (DMSO-d6) values show 0 27 (doublet, J 8 Hz, NH), 6.10, (singlet, OCH 3).

Example 50

7β- (2-Methoxoimino-2- (6-mercaptimidamide) -3- (4-carbamylpyridiniummethyl) cef-O-4-carboxylate in the form of stn-1-formic acid 3-acetoxymethyl-7 ₍ S- (6-methoxyimine-2)) C 6 -3-em-4-carboxy-4-carboxylic acid syn-isomer and 4.2 g of isnicctinamide were added to a mixture of 150 ml of water and 30 ml of acetone and the suspension was heated at 50 ° C for 20 hours. filtered, evaporated to remove acetone, and the aqueous solution was passed through an ion exchange column (Dowex-1 3 x 16 cm in an acetate cycle), washed with water, and the resulting solid was mixed with 250 mL acetone for 30 minutes, suspension filtered to give 1.4 g of title product [0% ^23-50 ° (c = 1.06 in DMSO), and _m and _X (pH 6 buffer) 260 nm (ε 20900), vmax (Nujol) 1770 (, / Makkam), 1 675 and 1 560 (CONH) and 1605 cm ⁴ (CO "-], τ (DMSO-de) values show 0.33, 1.49 (α, α-β-protons in the poridinic ring) ), 1.19 and 1.74 (—CONH2): 2.4 to 2.6 (multiplet: Ph) · 0.26 (j, 8 Hz) , NH), 6.10 (singlet, OCH 3).

Example 51

3-Hydroxymethyl-7: ₁ d-

- ('-Methoxyimine-2-fluoroacetamido) cef-em-d-carboxylate sodium in the form of the sonomer

Dissolve 2.0 g of 3-acetomethoxy-7α- (--methoxyimindyl-6-oxo-6-acetamido) -ceta-3-em-4-carboxylic acid as syn-isomer in a minimum amount of saturated sodium bicarbonate solution and dilute with 160 ml water and heated to 37 degrees Celsius. 15 grams of defatted wheat bran are added and the mixture is stirred for 3.5 hours at pH 7.4. The mixture was poured into 200 mL of acetone and filtered through diatomaceous earth. The acetone is evaporated under reduced pressure at 30 ° C and the aqueous solution is covered with a layer of ethanol acetate, brought to pH 2.7 by addition of concentrated hydrochloric acid, the layers are separated and the aqueous layer is extracted again with 6-methyl acetate. The ethyl acetate extracts are combined, washed with water, then a large amount of water is added to the extract and the pH is brought to 7 by carefully adding 2 N sodium hydroxide solution. The organic layer was then further extracted with water and the combined aqueous solutions were washed with ethyl acetate and ether, degassed and filtered to give 1.52 g of the title methoxide as a brown solid at 82% + + 104 ° (82% yield). c = 1.1, DMSO) Amax (pH 6 phosphate)

258.5 nm (ε 14100), vmax (Nujol) 1730 (6-lactam), 1570 (COO ') 1640 and 1520 cm ^"1 (CONH), τ (D" O, 100 MHz)? 2.2 to 2.6 (multipleH, aromatic protons), 4.16 (doublet, J 4 Hz, C-7H), 4.79 (doublet, J 4 Hz, C-6H), 5.72 singlet, C -2 CH 3), 5.97 (singlet, NOCH 3), 6.32 and 6.59 [2 doublets (quaternary portions), J 18 Hz, C-3 CH ").

Example 52

S-Hydroxymethyl-4-acetic acid

- (2-benzoldxyimindthlene-2 (-tetlacetamido) cef-b-em-d-carboxyide in the form of son-isdmin)

To a suspension of 1.0 g of 3-acetylmethyl-N - (2-benzolyclohexylthiazol-2'-yiacetamido) (3-em-4-carbonyloxy) in 50 ml of water is added a sufficient amount of saturated solution of potassium carbonate. to dissolve the solid and bring the solution to pH 7.0. 8.0 g of defatted wheat germ are added and the mixture is stirred for 21 hours at pH 6.8 to 7.0. The pH is maintained by the addition of acetic acid. After 5 hours, the pH was no longer changed and the reaction (thin layer (CHCl3: CH3OH: CH3COOH = 18:: 2: 1)) showed that the reaction was nearly complete.

The mixture was filtered and the pH of the filtrate adjusted to 4.5. Filtration with masonic clay gave 75

The yellow solution was adjusted to pH 2.5 under ethyl acetate. The aqueous mixture was extracted with ethyl acetate, and the combined extracts were washed with water and saturated sodium chloride solution, freed from water and evaporated to dryness to a brown solid. Trituration with methylene chloride afforded 480 mg of a colorless solid, the nuclear magnetic resonance spectrum of which corresponds to the hydroxymethyl derivative.

366 mg of this solid are dissolved in 10 ml of 50% aqueous ethanol and the mixture is carefully neutralized with 3.02 ml of 0.1 N sodium hydroxide solution. The ethanol was evaporated and the aqueous mixture was extracted three times with ether. Evaporation of the aqueous solution yielded 132 mg of 3-hydroxymethyl-7- (2-benzyloxyiminothien-2'-ylacetamido) cef-3-em-4-carboxylic acid sodium salt as the dihydrate, [α] _D -H 88 ° (c) = 0.89, DMSO), 16100) p _max (nujol) 1744 (.beta.-lactam), 1650 and 1522 (CONH), 1580 (CO 2 ') ⁴ cm, τ (DMSO-d6) values show 0 13 (doublet, NH), 2.54 (Ph) 4.76 (CH 2 Ph), 4.26 (quartet, 7-proton).

Example 53

3- (2-Chloroethylcarbamoyloxymethyl) -7- (2-methoxyiminophenylacetamido) cef-3-em-4-carboxylic acid in the form of the syn-isomer

A solution of 0.35 g of 3-hydroxymethyl-7β- (2-methoxyiminophenylacetamido) cef-3-em-4-carboxylic acid as the syn-isomer, 0.097 g of 2-chloroethyl isocyanate and 1.79 g of triethylamine in 10 ml of dimethylformamide is stirred at at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution and the aqueous phase was washed with ethyl acetate, acidified and extracted with ethyl acetate. The extracts are decanted, dehydrated and concentrated to a volume of approximately 5 ml, then added dropwise to 250 ml of petholether with stirring. The resulting solid was filtered and dried to give the title acid in a yield of 35% of 0.157 g, λ _max (pH 6, buffer) 258 nm (ε 16,800), λ _max (nujol) 3,250 (NH), 2 600 and 1715 (CO2H), 1 700 and 1 530 (NHCO2R), 1660 and 1 540 cm ⁴ (CONH), τ (DMSO-de) values show 0.22 (doublet J 9 Hz, 7/5-NH), 2,3 to

2.6 (multiplet, aromatic protons), 6.05 (singlet, ОСНз), 6.40 multiplet, С-2 CH2 and —CH2Cl), 6.65 (multiplet, —NHCH2).

Example 54 (a) tert-butyl-3-acetoxymethyl-7 / l ·

- (pyrid-4-ylacetamido) cef-3-em-4-carboxylate

A suspension of 6.0 g of pyrid-4-ylacetyl chloride as the hydrochloride in 50 ml of ethyl acetate with 12 ml of propylene oxide was mixed, cooled in ice and added dropwise to a solution of 5.0 g of tert-butyl-3-acetoxymethyl-7 (1). The mixture was stirred at 20 ° C for 20 hours, then washed with saturated sodium bicarbonate solution and extracted with 2 N hydrochloric acid solution. The aqueous extract was washed with ethyl acetate, neutralized with saturated solution. The extract was washed with water, dehydrated with magnesium sulphate and evaporated to a small volume where crystallization occurred. The crystalline solid was washed well with petroleum ether, b.p. 40-60 ° C, and freed from water to give 5.4 g of the title compound as a powdery solid in 80% yield based on amine, 250 mg of this material was recrystallized from ethyl acetate to give 170 mg of white needles. J-94 ° (c - 0.9, DMSO), _{ma m} (EtOH)

256.5 nm (ε 9,900), v _max (СНВгз) 3,412 (NH), 1,784 (β-lactam), 1,736 (OAc), 1,722 (CO2R), 1,690 and 1512 cm ⁴ (CONH) , τ (de-DHSO) 0.81 (d, J 8 Hz, NH), 1.47 and 2.68 (2d, J 5 Hz, aromatic protons), 4.27 (q, J 8 and 5 Hz, C-7H), 4.85 (d, J 5 Hz, C-6H), 5.01 and 5.36 (2d, J 13 Hz, C-H 2 N 2), 6.38 (s, CH 2 CONH), 6, 39 (s, C-2H 2), 7.96 (s, 5%), and 8.50 (s, 3 (S)).

(b) tert-butyl 3-acetoxymethyl-7 H -3- (2-hydroxyiminopyrid-4'-ylacetamido) cef-3-em-4-carboxylate

3.0 g of tert-butyl 3-acetoxymethyl-7- (pyrid-4'-ylacetmido) cef-3-em-4-carboxylate in solution in 30 ml of acetic acid are cooled in an ice crush and the cooled solution is dissolved in a solution of 1.38 g of sodium nitrite in 10 ml of water is added dropwise over 3-4 minutes. The mixture was stirred at 20 ° C for 30 minutes, then diluted with water and extracted with ethyl acetate. The organic extract was washed with saturated sodium bicarbonate solution and water, and then freed from moisture with magnesium sulfate. Evaporation almost to dryness yielded a residue which was dissolved in as little acetone as possible and added dropwise to petroleum ether at boiling point 40-60 ° C with stirring. The resulting solid was washed with petroleum ether and dehydrated to give the title oxime as a white powder (91: 29%) as a white powder which was a 30: _f : 70 mixture as shown by nuclear magnetic resonance. .

2.5 g of the oxime mixture are chromatographed on silica gel with methanol / chloroform 1:49 to give the title compound as an anti-isomer.

Further elution with a 1:49 mixture of methanol and chloroform gave a material which was dissolved in acetone and added with stirring to petroleum ether at a boiling point of 40 ° C to yield 0.81 g of tert-butyl in 32% yield. _-3-divided aeetxxymethyl 7-3- (2-hydrQxyiminQpyгid-4'-ylacetamidt) ceph-3-em-4-carboxylate syn-isomer, [a] _D plus 57 ° (c = 1.11, DMSO) , A _max (EtOH)

253.5 nm (ε 17,600), λ _max (nujol) 3220 (NH), (β-lactam), 1744 (OAc), 1710 (CO 2 R), 1640 and 1526 nm '^; (CONH), τ (de-DMSO) -2.26 (s, NOH), 0.27 (d, J 8 Hz, NH), 1.33 and 2.47 (2d, aromatic protons), 4.04 (q, J 5 and 8 Hz, C-7H), 4.71 (d, J 5 Hz, C-6H), 4.98 and

5.33 (2d> J 13 Hz, C-3 CH 2), 6.20 and 6.53 (2d, J 18 Hz, C-2 H 2) 7.94 (s, OCOCH 3), 8.49 (s, C (CH 3) 3).

(c) tert-Butyl-3-acetxxymethyl-73-

- (2-Methoximino-pyrimidin-4-yl-acetamide) -isomer

A solution of 50 mg of tert -butyl-3-acethoxymethyl-7H-3- (2-hydroxyimino-pyridin-4'-ylacetamido) cis-η 4 -carboxylate as the syn-isomer in 10 ml of tetrahydrofuran was cooled to 0 ° C and treated with excess diazomethane solution. The mixture was stirred at 5 ° C for 45 minutes and then washed with water. The organic extract was dehydrated and evaporated to give 48 mg of the title ester as a yellow foam [ _.alpha. ] _D + 55.5 DEG (c = 0.88, DMSO), Amax (EtOH), 257, 93%; 5 nm (ε 16,580), in _ma x (CHBT3) 3,390 (NH) 1,784 (<3-lactam), 1,736 (OAc), 1,726 (CO2R), 1,684 and 1516 cm ^-1 (CONH) , τ (de-DMSO) 0.20 (d, J 8 Hz, NH), 1.33 and 2.48 (multiplet, aromatic protons), 4.09 (q, J 5 and 8 Hz, C-7H) 4.74 (d, J 5 Hz, C-6H), 5.01 and 5.35 (2d, J 13 Hz, C-3CH2), 5.99 (s, NOCH3), 6.38 (broad singlet) C-2H2), 7.96 (s, OCOCH3), 8.52 (s, C (CH3) 3).

(d) 3-Acetoxymethyl-7.8-

- (2-Methoxymethylpyrid-4-yl-acetamido) -. Alpha.-.Alpha.-.Alpha.-d-carboxylic acid with trifluoromethyl acid in the form of the syn-isomer

A solution of 0.35 g of tert-butyl-3-acethoxymethyl-7- [3- (2-methoxy-iminopyrid-4-ylacetoamido) -c-5-N-carboxylate in the form of the syn-isomer in 10 ml of trifluoroacetic acid is allowed to stand. at 20 ° C for 15 minutes. The solution was diluted with benzene and evaporated to dryness to give a gum which was triturated with ether to give 0.26 g of the title salt as a solid in 67% yield, [α] _D + + 42 ° (c = 0.45, DMSO), λmax (pH 6, buffer) 255 nm (ε 19,000), in _m x (nujol) 3,250 (NH), 2,600 and 1,720 (CO 2 H), 1,778 (β-lactam) ) 1,734 (OAc), 1,666 (CF 3 CO 2 -), 1,670 and 1,520 cm -1 (CONH), τ (DMSO-d 6) 0.10 (d, J 8 Hz, NH),

1.23 and 2.36 (multiplet aromatic protons),

4.11 (q, J 5 and 8 Hz, C-7H) 4.76 (d, J 5 Hz, C-6H), 4.98 and 5.29 (2d J 13 Hz, C-3 CH2), 5.97 (s, NOCH 3), 6.29 and 6.52 (2d, J 18 Hz, C-2Hz),

7.98 (s, OCOCH 3).

Example 55

3-Acethoxymethyl-7.3- [2-amintethoxyimino [(thien-4-yl) acetamido] trans] -3-amino-4-carboxylic acid salt with trifluoroacetic acid in the form of synoxide

A solution of syn- (2-tert-butyloxycarbtxamido) -thiiminobenzothien-2-ylacetyl chloride prepared from 314 mg of acid in 10 ml of acetone is added dropwise with ice-cooling and stirring, to a solution of 272 mg of 73- ^and aninoteralosporine in 20 ml of water containing 168 mg of sodium bicarbonate. The solution was stirred for 2 hours after which time the acetone was evaporated. The aqueous mixture was acidified to pH 2.0 in the presence of ethyl acetate and extracted with ethyl acetate. The ethyl acetate extracts are combined, washed with water and saturated sodium chloride solution, freed from water and evaporated to dryness to give 540 mg of 3- acetoxymethyl -7.Sl [21-tert-butoxycarbt) xamideteth) xyiminQ (thien) in 95% yield. R-DMSO-d6-values including 0.27 (d, NH), 7.96 (s, OCOCH3), 8.62 [s, C (CH3) 3).

500 mg of the crude acid is dissolved in 5 ml of trifluoroacetic acid and this solution is allowed to stand at room temperature for 5 minutes, then evaporated to dryness at the same temperature. Anhydrous benzene (25 ml) was added and the mixture was evaporated again to dryness. The oily residue was triturated with ether to give the title compound (64% yield) as a colorless solid of [.alpha.] + 39 DEG (= 0.97 in dioxane), Amax (pH 6, phosphate buffer), 283 nm. (ε 16 500), vmax (nujol) 1780 cm -1, τ (DMSO-d6) values including 0.31 (doublet, J 8 Hz, NH), 1.98 (+ NHs), 4.08 (C- 7 proton), 5.66 / (—OCH2), 6.8 (—CH2-N), 7.96 \

(OCOCH 3).

Example 56

73- [2-tert-Butoxyimino-2-benzo [b] thien-4-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylceph-3-yl-4'-carbonyloxy acid in the form of syn-isomer

A solution of 1.11 g of 2- (tert-butyloxy) -2- (bromo [b] thien-3-yl) acetic acid in 5 ml of methylene chloride and 1 ml of diethyl ether was added to a solution of 2.04 g of diphenylmethyl. N-amino-4- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3- (1,4-carbonyl) -oxide in ml of methylene chloride. A solution of 0.823 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride was added to the above solution at 20 ° C. The mixture is maintained at 5 ° C

80 hours and then filtered. The filtrate was washed with 2 N hydrochloric acid solution, dilute sodium bicarbonate solution, water and brine, freed from moisture with magnesium sulfate, and concentrated under reduced pressure to give 3.37 g of the crude diphenylmethyl ester of the title compound as an orange foam. The foam was dissolved in 6 ml of anisole and treated with 25 ml of trifluoroacetic acid. After standing at 20 ° C for 5 minutes, the solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate, and the solution was evaporated again. The residue is then divided between. ethyl acetate and dilute sodium bicarbonate solution. The ethyl acetate layer was extracted thoroughly with dilute sodium bicarbonate solution, the extracts were combined, washed with ethyl acetate and adjusted to pH 2 with concentrated hydrochloric acid under the ethyl acetate layer. The two layers were separated and the aqueous layer was extracted with ethyl acetate. Combine the ethyl acetate extracts, wash with water and brine, dehydrate and concentrate under reduced pressure to a small volume. The resulting solution was then added dropwise to 400 ml of petroleum ether, b.p. 40-60 ° C, with stirring, and the precipitate was washed with petroleum ether to give 1.0 g of the title acid as a solid in 41% yield. [α] D -87 ° (c = 1 in DMSO), λmax (pH 6, phosphate buffer) 277.5 nm (ε 16 850), in _ma x (nujol) including 1786 (β-lactam), 1672 and 1,520 cm ^-1 (CONH) τ values (DMSO-d6) including 0.27 (d, J 8 Hz, NH),

1.38 (m, H-4 benzo-t-thienyl) 1.86 (m, benzo [b] thienyl H-7), 2.15 (s, benzo [b] thienyl H 2) 2.4 (m, benzo- [h] -thienyl H-5 and H-6), 4.05 '(dd, J 8 and 5 Hz, H-7), 4.72 (d, J 5 Hz) H-6), 5.40 + 5.74 (2 d, J 13 Hz, C-3 CH2), 6.13 + 6.37 (2 d, J 18 Hz, C-2 CH2),

7.29 (s, 2H) and 8.57 (s, C (CH3) 3).

Example 57

7β-12-ethoxyimino-2-phenylacetamido] -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylcef-3-em-4-carboxylic acid as syn-isomer

Prepared essentially according to example 56. Yield: 61%. [α] _D - 86 ° (c = 1.1 in DMSO) Amax (pH 6, phosphate) 262.5 nm (ε 22 350) vmax (nujol) including 1780 (β'-lactam) and 1,664 and 1,520 cm (CONH), τ values (DMSO-d 6) 0.21 (d, J 8 Hz, NH), 2.46 (m, aromatic protons) 4.06 (dd, J 8 and 5 Hz, H-7) 4.73 (d, J 5 Hz, H-6), 540 + 5.72 (2 d, J 14 Hz, C-3 CH 2), 5.74 (q, J 7 Hz, CH 3 CH 2 O)

6.11 + 6.39 (12 d, J 118 Hz, C-2 CH2), 7.27 (s, CH3 in thiadiazole) 8.68 (t, J 7 Hz, CH3 CH2 O).

Example 58

7β- [2-tert-Butoxyimino-2- (thien-2-yl) acetamido] -3-

- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethylceph-3-em-4-carboxylic acid in the form of the syn-isomer

Prepared according to Example 56 to give the resulting acid in 58% yield. [α] D - 76 ° (c = 1, in DMSO) λ _max (pH 6, phosphate) 271 nm (ε 14,400), vmax (nujol) including 1780 ((S-aktam) and 1,670 and 1,530) cm (CONH), τ values (DMSO-d 6) including 0.26 (d, J 8 Hz, NH), 2.32 + 2.80 (ms, thienyl protons), 4.08 (dd, J 8 and 5) Hz, H-7) 4.73, (d, J 5 Hz, H-6) 5.38 + 5.73 (2 d, J 13 Hz, C-3 CH2),

6.10 + 6.36 (2 d, J 18 Hz, C-2 CH2), 7.27 (s, CH3) and 8.64 [s, C (CH3) 3].

Example 59

a) tert-butyl-3-acetoxymethyl-73l

- (2-ethoxy-aminopyrid-4-ylacetamido) cef-3-em-4-carboxylate in the form of the syn-isomer

A solution of 1.15 g of tert-butyl-3-acetoxymethyl-3- [2- (2-hydroxyimino) -pyridine-4-yl] -cetamido] cef-3-em-4-carboxylate as syn. The isomer in 20 ml of tetrahydrofuran was treated with an excess of diazoethane at 20 DEG C. for 40 minutes, diluted with ether, washed with water and extracted with 2N hydrochloric acid, the aqueous extract was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate. yields the resulting ester as a foam in an amount of 0.84 g and a yield of 69%, [α] D + 47 ° (c = 0.84, in DMSO), _TOTo (EtOH) 259 nm (ε 15 450), ν x (nujol) 3.300 (NH), 1788 ((Maktam), 1740 (OAc), 1724 (CO2R), 1678 and 1540 cm (CONH), τ (de-DMSO) values including 0.12 (d, J 8 Hz) (NH), 1.26 and

2.42 (multispets, aromatic protons), 2.69 (q, J 7 Hz, OCH 3 CH 2), 7.93 (s, OCOCH 3), 8.50 [s, (CH 3) 3], and 8.69 (t, J 7 Hz, OCH 2 CH 3).

(b) 3-Acetoxymethyl acid salt - 7.3-

- (2-ethoxyiminopyridl-4-ylacetamido) cef13-em-4-carboxylic acid with trifluoroacetic acid in the form of the syn-isomer

0.75 g of tert-butyl 3-acetoxymethyl-73- (2-ethoxyiminopyrid-4lylacetamido) cef-3-em-4-carboxylate is deprotected with 10 ml of trifluoroacetic acid in the usual manner to give the resulting salt as a powder in an amount of 0.61 g 73% yield, HJO + 30 ° (c = 0.4, in DMSO) and _m ax (pH 6 buffer) 257 nm (ε 12800), vmax (Nujol) 3300 (NH) 2 600 and 1720 (CO 2 H), 1782 (/ Mactam), 1740 (OAc), 1680 (CF 3 CO 2 -), 1670 and 1 552 cm ¹ , (CONH), τ (d6-DMSO) values including 0.06 (d, J 7 Hz, NH), 1.20 and 2.28 (multiplets, aromatic protons), 5.65 (q, J 7 Hz, OCH 2 CH 3), 7.92 (s, OCOCH 3) and 8.64 (t, J 7) Hz, OCH 2 CH 3).

Example 60

3-acetoxymethyl-7.0-

Sodium (2-phenoxyimino-2-phenylacetamido) cef-3-em-4-carboxylate in the form of the syn-isomer

A solution of 8.6 g of syn-2-phenoxyiminophenylacetic acid in 30 ml of anhydrous methanol is neutralized with a 1.105 N solution of sodium methoxide in 32.3 ml of methanol. The methanol is evaporated and the sodium salt obtained (dried under vacuum over phosphorus pentoxide for 48 hours) is suspended in 75 ml of anhydrous benzene containing 1 drop of Ν, Ν-dimethylformamide. This suspension was treated with 4.5 mL of oxalyl chloride, stirred for 1 hour, and then the solvent and excess reagent were evaporated. The residual acid chloride solution was added to the cooled solution of 9.71 ml of 7'-aminocephalosporanic acid in 500 ml of water and 250 ml of acetone containing over a period of 30 minutes with stirring.

6.5 g of sodium bicarbonate. After the addition was complete, the mixture was stirred for an additional 2 hours and then the acetone was evaporated under reduced pressure. The aqueous mixture was layered with ether (500 mL) and acidified to pH 1.8. The acidic layer was further extracted with ether. The ethereal extracts are combined, washed with water and saturated sodium chloride solution, drained and evaporated to dryness to give 15.06 g of syn-3-acetoxymethyl-7 ₍ [3- (2-phenoxyimino-2-phenylacetamido) cef- 3-em-4-carboxylic acid in the form of a pale yellow foam.

14.5 g of this acid are dissolved in 150 ml of acetone and added over 15 minutes to a solution of 5.5 g of sodium 2-ethylhexanoate in 50 ml of acetone. The precipitated solid was collected, washed with acetone, and dried in vacuo to give 12.92 g of the title compound;

[α] ²² -4 111 ° (c = 1.13, DMSO), in _max (pH 6 buffer) 260 nm (ε 19,400), 285 nm (ίε

000), _{ν max} (nujol) 3270 (NH), 1752 cm ^-1 (δ-lactam), r values (DMSO-d6) include —0.05 (d) (NH), 4.16 (dd) (7 - (H), 4.82 (d) (6-H), 7.97 (s) (-).

Examples 61—70

General procedure for the production of acids

3-acetoxymethyl-7- (2-substituted oxyimino-2-arylacetamido) cef-3-em-4-carboxylic acid

Method A

A solution of the appropriate syn- (2-substituted oxyimino) -2-arylacetyl chloride (prepared from 1 equivalent of the corresponding sodium salt with oxalyl chloride) was dissolved in acetone and this solution was added dropwise to a stirred, 0-5 ° warm solution to the equivalent of acid 7. -aminocephalosporan in water containing 2-2.5 equivalents of sodium bicarbonate. The mixture was stirred for 0.5 to 2.5 h while allowing the temperature to rise to room temperature. The acetone is removed by evaporation under reduced pressure, ethyl acetate is added, the pH is adjusted to 1.5-2.0 and the product is extracted with ethyl acetate. The extracts were washed with water and saturated sodium chloride solution, drained and evaporated to a foam or solid.

Way В

The procedure was the same as in Method A, but the product was extracted with ether.

The cephalosporin derivatives thus prepared are shown in Table 5.

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Example 71

3- (1-Methyltetrazol-5-ylthio methyl) -7β- [2-phenoxyimino-2-phenylacetamido] cef-3-em-4-carboxylic acid in the form of the syn-isomer

A suspension of 464 mg of 2-phenoxylmino-2-phenylacetic acid in 25 ml of anhydrous methylene dichloride was added over 5 minutes to a stirred solution of 989 mg of diphenylmethyl-7/3-amino-3- (1-methyltetrazol-4-ylthiomethyl) cef-3-em. Of 4-carboxylate and 454 mg of dicyclohexylcarbodiimide in 25 ml of methylene dichloride. After stirring for an additional 2 hours, the solvent was evaporated in vacuo. The residue is suspended in 60 ml of ethyl acetate, the insoluble material is collected by filtration, and the filtrate is washed with a 1: 1 mixture of saturated sodium chloride solution and water, then water and brine (30 ml each), freed from water and Evaporate to 1.56 g of a foamy product. A solution of this product in 10 ml of benzene was purified by chromatography on 60 g of silica gel using a 10: 1 mixture of benzene and ethyl acetate as eluent. The appropriate fractions were combined and evaporated to dryness in vacuo to give 1.16 g of diphenylmethyl-3- (1-methyltetrazo-5-ylthiomethyl) -7β- [2-phenoxyimino-2-phenylacetamido] cef-3-em. 4-carboxylate as the syn-isomer as an orange foam in 87% yield. A solution of this foam in a mixture of 4 ml of trifluoroacetic acid and 1 ml of anisole is maintained at 23 DEG C. for 5 minutes, then the solvent is evaporated off under vacuum at 50 mm Hg. The residue is dissolved in 80 ml of ether, 120 ml of sodium bicarbonate and water (1: 3) are added and the mixture is stirred until the solid is dissolved [about 10 minutes]. The aqueous phase is separated, overlaid with 150 ml of ethyl acetate and acidified to pH 2 with N hydrochloric acid solution. The organic phase is separated, washed with 50 ml of water and 50 ml of brine and the solvent is evaporated off under vacuum. The residue is dissolved in 50 ml of acetone, the solution is stirred for 5 minutes with 1 g of activated carbon, and then filtered through a pad of silica gel. The filtrate was dehydrated and evaporated to 780 mg of a foamy product which was dissolved in ethyl acetate and the solution was poured into petroleum ether to give 640 mg of the title acid as a colorless solid in 63.3% yield. [α _D 23 - 64 ° (c = 1.01, acetone), λ max [0.1 M - pH 6, phosphate buffer), 261 nm (ε 19,200), τ (DMSO-de) values include 00, 11 (NH, d J 8 Hz), 4.00 (7-H, dd, J 5 and 8 Hz), 4.70 (6-H, d, J 5 Hz) and 6.04 (CH 3 -).

Examples 72 to 87

General procedure for the preparation of β- (2-substituted oxyimino-2-arylacetamido) -3- (substituted) cef-3-em-4-carboxylic acid using dicyclohexylcarbodiimide (i) To a tertiary butyl ester solution (Example 87) or diphenylmethyl ester 7 3-Amino-3- (substituted) cef-3-em-4-carboxylic acid in an amount of 1 equivalent and 1 to 1.2 equivalents of dicyclohexylcarbodiimide in anhydrous methylene chloride is added at 0 to 20 ^° C a solution of 1 equivalent of syn-2 -alkoxy- or 2-aryloxyimino-2-arylacetic acid in anhydrous methylene chloride. The mixture was stirred at room temperature for 45 minutes to 3 hours, then filtered and the filtrate evaporated to dryness. The residue in ethyl acetate was washed successively with sodium bicarbonate solution; water and brine. The organic phase is dehydrated and evaporated to dryness to a foamy product or solid. This resulting ester was further purified by crystallization or silica gel chromatography and characterized by NMR spectrum and thin layer chromatography.

When the starting material β-amino compound is obtained in the form of a salt with p-toluenesuffonic acid (Example 86), the free base is liberated by shaking with ethyl acetate and an excess of saturated sodium bicarbonate solution.

After washing with water and brine, the organic layer is evaporated to dryness and the free amine is redissolved in methylene chloride.

(ii) The ester forms thus obtained are deprotected by dissolving in a mixture of 3 to 10 ml of trifluoroacetic acid per g of ester and 1 to 5 ml of anisole per g of ester, which solution is left at room temperature for 5 to 10 ml. minutes, after which time the solvent was removed by evaporation under reduced pressure. The crude acid was shaken with ether or ethyl acetate and an excess of aqueous sodium bicarbonate solution and the aqueous layer was washed with ethyl acetate. The aqueous phase was separated, overlaid with ethyl acetate and acidified to pH 1 with 2 N hydrochloric acid. The organic layer is washed, dehydrated and evaporated to give the desired syn-7H- (3-alkoxy- or 2-aryloxy-2-arylacetamido) -3- (substituted) cef-3-em-4-carboxylic acid. The compounds thus obtained are listed in Table 6.

(iii) Diphenylmethyl 7S-amino-3 - ((ethyl-tetramethyl) -4- (5-ylthio) methyl) -4- (4-carboxylate) -4- (4-carboxylate) used as starting material for Example 73.

(a) Diphenylmethyl 3- [1-ethyltetrazol-5-ylthiomethyl) -7 H -3- (2-thienylacetamido) cef-3-em-4-carboxylate.

A solution of 11.67 g of diphenylmethyl-3-bromomethyl 1-7 / 3- (2-thienylacetamido) cef-3-em-4-carboxylate and 2.6 g of 1-ethyltetrazoline-4-thione in anhydrous tetrahydrofuran (150 ml) was swollen. at 0 ° C, then a solution of 2.8 ml of triethylamine in 25 ml of tetrahydro furan is added dropwise with stirring over 5 minutes. The resulting suspension was stirred for an additional 25 minutes, during which time the temperature was allowed to rise to 20 degrees Celsius, to which 50 ml of a 2 N hydrochloric acid solution, 350 ml of water, 350 ml were added over 5 minutes with stirring. ml of saturated sodium chloride solution and 600 ml of ethyl acetate. The organic phase was separated and washed with 2 N hydrochloric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution and then evaporated to 11.71 g of a foamy product. A solution of this product in 26 ml of benzene was purified by chromatography on 200 g of silica gel using 5: 1 benzene / ethyl acetate as eluent. The appropriate fractions were combined and evaporated to dryness in vacuo. The residue was redissolved in methylene dichloride and the solution was poured into petroleum dichloride to give the title ester as a pale yellow solid (8.585 g, 68% yield). [α] D 23 - 131 ° (c = 0.97, CHCl 3) λ max (EtOH) 264 nm (ε 7,300), τ (CDClh) values include 4.12 (7-H, dd, J 5 and 9 Hz) 5.04 (6-H, d, J 5 Hz), 5.83 (CH 3 CH 2 -, q, J 7 Hz) and 8.57 (CH 3 CH 2 -, t, J 7 Hz).

(b) A solution of 2.13 ml of pyridine in 10 ml of anhydrous methylene dichloride was added over 5 minutes to a suspension of 5.47 g of phosphorus pentachloride in 20 ml of methylene dichloride with stirring. After 10 minutes, the suspension is cooled to 0 ° C and a solution of 8.3 g of diphenylmethyl-3- (1-ethyltetrazo) -5-ylthiomethyl) -7β- (2-tbienylacetamiilo) cef is added dropwise over 10 minutes. -3-em-4-carboxylate. The resulting mixture was stirred for an additional hour, during which time the temperature was allowed to rise to 23 ° C, after which the whole mixture was added to a warm mixture of 30 ml of methanol and 60 ml of methylene dichloride over 10 minutes. After 15 minutes, 50 ml of N hydrochloric acid solution were added and the mixture was further stirred for 10 minutes. The organic phase is separated, stirred for 30 minutes with 200 ml of saturated sodium bicarbonate solution, washed with saturated sodium carbonate solution and saturated sodium chloride solution and mixed with a small amount of activated carbon. The suspension is filtered through a pad of silica gel, the filtrate is dehydrated and evaporated to 7.47 g of an oily substance. This material was triturated with 15 mL of ethyl acetate to give the title amine as a pale yellow solid (3.854 g, 58% yield). [a] ^ ^3-213 ° (c = · = 1.14, CHC13) and _m ax (CHC13) 265 nm (ε 7,900), 268.5 nm (ε 7900] and 279.5 nm ( ε 7,800), τ (DMSO-ds) values include 4.92 (d, J 5 Hz) and 5.11 (d, J 5 Hz), (6-H and 7-H) and

5.72 (q, J 7 Hz) and 8.61 (t, J 7 Hz), (CH 3 CH 2 -).

(iv) Diphenylmethyl-7 H -ammo-3-

- (G-nitrobenzothiazol-4-ylthiomethyl) cef-3-em-4-carboxylate in the form of the hydrochloride used as starting material in Examples 75 and 79,

A solution of 10.068 g of diphenylmethyl-3-bromomethyl-7,3-formamidoceph-3-em-4-carboxylate-1,5-oxide and 4,244 g of 2-mercapto-6-nitrobenzothiazole in 125 ml of anhydrous N, N-dimethylformamide was treated with a solution of 3.2 ml of triethylamine in 25 ml of Ν, dimethyl-dimethylformamide is added dropwise over a period of 5 minutes, and the mixture is stirred for 2 hours while allowing the temperature to rise to 23 CC. The solvent is evaporated at 40 DEG C. under 1 mm Hg and the residue is partitioned between 300 ml of methylene dichloride and 300 ml of water, the organic phase is washed with 2 N hydrochloric acid solution, water and saturated sodium chloride solution and evaporated to 14.35 g of a foamy product. . A solution of this product in 200 mL of anhydrous methylene dichloride was stirred at -20 ° C, and a solution of 2.5 mL, i.e. 1.5 equivalents of phosphorus tribromide in 25 mL of methylene dichloride was added dropwise over 5 minutes, followed by stirring for 30 minutes. at -10 to -15 ° C. The resulting solution was stirred with 250 ml of saturated sodium bicarbonate solution for 30 minutes, the organic phase was separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and treated with a small amount of activated carbon. The suspension is filtered through a pad of silica gel, the filtrate is dehydrated and evaporated to 10.71 g of a foamy product. A suspension of this product in 200 ml of methanol is stirred at 0 ^DEG C., 3.66 ml, i.e. 2 equivalents of phosphorus oxychloride, is added over 2 minutes and the mixture is further stirred at 23 DEG C. during which time it is dissolved. any solid. The solvent is then evaporated, 100 ml of ethyl acetate are added and the resulting suspension is evaporated to dryness in vacuo. The resulting gum was dissolved in methylene dichloride (100 mL), stirred at 0 ° C, and ether (300 mL) was added over 5 minutes. The resulting precipitate was collected by filtration, washed with ether (100 ml) and dried in vacuo to give the title hydrochloride (9.744 g) as pale yellow flakes in 78% yield. [α] ²³ - - 94 ° (c = 1.0, DMSO), _λmax (EtOH) 328 nm (ε 13,400), τ · (DMSO-d6) values include

4.72 (6-H and 7-H], 5.10 and 5.57 (3-CH 2 · q · J Hz), and 6.10 (2 CH 2).

(v) Diphenyl-methyl-7β-amino-3-

- (6-nitrobenzothiazol-2-ylthirmethyl) cef-3-em-4-carboxylate

A solution of 910 mg of the above hydrochloride in 50 ml of methylene dichloride is stirred for 30 minutes with 50 ml of saturated sodium bicarbonate solution. The organic phase was separated, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution * and treated with a small amount of activated carbon. The suspension is filtered through a pad of silica gel and the filtrate is dehydrated and evaporated to 660 mg of a foamy product. This product was treated with 50 mL of methanol to give the title amine as a light yellow solid (432 mg, 50%). [A] η ^{20 to} 195 ° ^(c 1.01, CHC13)

Л _тах (CHCl 3) 251 nm (ε 14,500) and 334 nm (ε 16,800), r (CDCl 3) values include 5.04 and

5.22 (doublets, J 5 Hz, 6-H and 7-H) and 7.96 (NH 2).

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Example 88

Diethanolammonium-3-acetoxymethyl-7 / 3- (2-phenoxyimino-2-phenylacetamido) cef-3-em-4-carboxylate (syn-isomer)

To a solution of 5.94 g of crude syn-3-acetoxymethyl-7- (2-phenoxyimino-2-phenylacetamido) cef-3-em-4-carboxylic acid prepared as described in Example 60 in 30 ml of 2-propanol was added solution 3. , 8 ml of diethanolamine in 8 ml of 2-propanol. The precipitated solid was collected, washed with 2-propanol and then with ether and dried in vacuo to give 3.43 g of the title product, m.p. 139.5 ° C. Τ values (DMSO-d6) include -0.06 (d) , NH), 4.13 (dd, 7-H), 4.78 (d, 6-H), 6.96 and

7.96 (- CH ₂ -Cl _2-I -). '

Example 89

Then-2-yloxamine hydrochloride (starting material for Preparation 7) (a) N- (then-2-yloxy) phthalimide

11.04 g of anhydrous potassium carbonate are added, while stirring, with 17.12 g of N-hydroxyphthalimide in 200 ml of anhydrous dimethylsulfoxide. It develops a brown color, then 28.5 g of 2-chloromethylthiophene is added dropwise and the mixture is stirred for 16 hours. During this time, discoloration disappears, the suspension is poured into 8 ml of water and cooled to 5 degrees Celsius. The resulting white precipitate was filtered off and recrystallized in ethanol to give 23.4 g (83%) of colorless needle crystals of N- (then-2-yloxy) phthalimide, mp 129.7-130.9 ° C τ ( DMSO-d6) 4.58 (CH2) »

2.28, 2.68, 2.90 (thienylprotones) 2.08 (phthalimidoprotons).

(b) Then-2-yloxamine hydrochloride

A mixture of 22.4 g of N- (then-2-yloxy) phthalimide, 5 grams of 100% hydrazine hydrate and 600 ml of ethanol was heated to reflux for 2 hours, initially forming a yellow solution, starting to precipitate in a short while. The reaction mixture is acidified with 12 ml of concentrated hydrochloric acid and the precipitated phthalhydrazide is filtered off and washed with 3 X 50 ml of ethanol and 100 ml of water, the filtrates and washings are combined and evaporated to dryness and the residue is suspended in a cabinet. Sodium hydroxide solution ^1. The mixture was then extracted with ether, the extracts were combined, washed with water and saturated sodium chloride solution, freed from water and saturated with anhydrous hydrogen chloride, and the precipitated solid was collected and washed well with ether to give 87% yield. M.p. 157.1-157.5 DEG C. 12.45 g of then-2-yloxamine hydrochloride are recrystallized from ethanol / ether, m.p. i: 161.7 to 162.1 ^C , τ values (DMSO-d 6) including 4.69 (CH 2), 2.30, 2.72, 2.90 (thienyl protons).

Example 90

Furfuryloxamine hydrochloride (starting material for preparation 22) (a) N-furfuryloxyphthalimide

To a mixture of 41 g of N-hydroxyphthalimide, 26.4 g of anhydrous potassium carbonate and 400 ml of anhydrous dimethylsulfoxide is added, with stirring, 2-chloromethylfuran (freshly prepared but without distillation, using 46.2 g of furfuryl alcohol and according to WR Kirner (J. Am. Chem. Soc. 1928, 59, 1955) The mixture is stirred for 18 hours and then poured into 1.5 liters of water. The precipitated solid is collected by filtration, washed well with water and recrystallized from ethanol. 42.8 g of N-furfuryloxyphthalimide, m.p.

145.3 to 146.2 ° C τ (DMSO-do) 4.80 (CH 2), 2.22, 3.30, 3.50 (furyl protons) 2.08 (phthalimide protons).

b) Furfuryloxamine hydrochloride ml of 100% hydrazine hydrate was added with stirring to a solution of 42.0 g of N-furfuryloxyphthalimide in 600 ml of methylene chloride. A large precipitate was formed immediately and the mixture was further stirred for 45 minutes. 500 ml of 5 N ammonium hydroxide solution are added to dissolve the precipitate, the two layers are separated and the aqueous layer is washed twice with methylene chloride. The combined methylene chloride extracts were washed with saturated sodium chloride solution and dehydrated. The methylene chloride was evaporated and the remaining liquid was dissolved in 250 ml of ether. Anhydrous hydrogen chloride was passed through the solution for 1 hour. The precipitate formed is filtered off, washed with ether, freed from water and recrystallized from isopropanol to give 12.89 g of furfuryloxyamine hydrochloride in 50% yield, mp 135 DEG-136 DEG C., τ (DMSO-d6) including 4.87 (CH2), 2.20,

3.27, 3.44 (furyl protons).

Preparation 36 to 39

The general procedures described in Preparations 5 to 23 for the preparation of 2-alkoxyiminoarylacetic acids are used to produce the intermediates listed in the following table, which is essentially a continuation of Table 1.

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Example 40

2-AlSoxyimiooarylacetylcSlorides (continued)

The following acids were converted to chlorides in a general manner to convert 2-alkoxyiminoarylacetic acids to chlorides without isomerization, as described in Preparation 35:

acid ^syn-2-l butsxyiminsfenyloct their acid syn-2-isopropsxyiminofenyloctová acid 2-syn-syn-propюxyiminofenyloctová acid -propoxyimmo (thien-2-yl -acetic acid syn-2-ethsxyimlns (benzo [b] -f ur-2- yl Acetic acid thin-2-ethoxyimino (thien-3-yl) acetic acid.

Example 91

Tyn-isssprsρsxyimin acid ^| ofenyloctová

A mixture of 3.0 g of phenylglyoxylic acid, 2.5 g of its propoxyaminohydride, 100 ml of ethanol and 50 ml of water is mixed and the pH is adjusted to 4.5-5 with 2 N sodium hydroxide solution. The solution was further stirred for 5 hours while maintaining the pH at 4.5-5 with additional addition by pouring a sodium hydroxide solution. Ethanol was removed by evaporation and the aqueous layer was acidified, then the product was extracted with ethyl acetate. The ethyl acetate was evaporated to give 4.2 g of a brown oily liquid which was esterified in the usual manner with diazomethane to a mixture of the syn-methyl ester and the -imethyl ester of the title compound in a total amount of 4.04 g as an oily liquid.

4.0 g of the ester mixture in 60 ml of methanol were mixed with 19.0 ml of 2 N sodium hydroxide solution and the resulting mixture was kept at room temperature for 2 hours. The methanol was evaporated, the residue was diluted with water and extracted with ethyl acetate, freed from moisture with magnesium sulfate and evaporated to give 0.82 g of crude syn-methyl ester. -0.82 g of this ester in 20 ml of methanol are mixed with 3.6 ml of 2 N sodium hydroxide solution and kept at room temperature for 31 hours. Conventional isolation of the acidic fraction yielded 0.706 g of crude syn isomer, which was recrystallized from cyclohexane to give 0.358 g of the title compound, mp 59.5 Am, λ max (EtOH) 258 nm (ε 12,700), τ (DMSO-da) values (including 2.47 (phenyl), 5.53 (O-CH), 8.71 (CH3)).

Example 92

Syn-propsxyiminothien-2-ylacetic acid

A mixture of 3,12 g of thien-2-ylglyoxylic acid,

2.8 g of n-propsxyamine hydrochloride, 75 ml of ethanol and 75 ml of water are adjusted to pH 4.5-5 with 2 N sodium hydroxide solution, and the resulting mixture is stirred at room temperature while maintaining the pH at 4.5-5 with further addition of the mixture. and ethanol. After 4 hours, 1.4 g of n-propoxyamino-anhydride chloride was added and the mixture was stirred for an additional 3 hours at pH 4.5-5, then allowed to stand overnight. The ethanol was evaporated and the remaining solution was diluted with water, acidified and extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate and evaporated to yield

4.8 g of a mixture of the syn-isomer and the anti-isomer of the resulting acid as an oily liquid.

This mixture is esterified with diazomethane in a conventional manner to give 3.175 g of syn- and anti-methyl ester.

The mixture of esters in 50 ml of methanol was stirred with 14 ml of 2 N sodium hydroxide solution for 10 minutes at room temperature. The methanol was removed by rapid evaporation and the residue was diluted with water and extracted with ethyl acetate. The extract was dehydrated with magnesium sulfate and evaporated to give 0.416 g of the syn-methyl ester. The ester in 10 ml of methanol was mixed with

1.7 ml of 2N sodium hydroxide solution and allowed to stand at room temperature for 26 hours. Conventional acid isolation yielded 0.235 g of the title compound as an oily liquid τ (DMSO-d 6) value including 2.28, 2.7-2.9 (thienyl, 5.90 (O-CH 2)).

Examples 93 to 98

The general procedure for the preparation of the 3-substituted methyl-7H- [2-substituted-oxyimino-2-arylacetamido) cef-3-em-4-carboxylic acids described in Examples 19-46 is used to prepare the compounds listed in the following the table, which is essentially a continuation of Table 2.

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Example 99

3- (5-Methyl-1,3,4-Chiadiazol-2-yl) -thimethyl-7 H -3- [2- (then-2-yl) -oxyimino-2- (thien-2-yl) -acetamido C-3-em-4-carboxylic acid in the form of the syn-isomer

A solution of 715 mg syn-then-4- (2-yloxyiminoquinolin-2-yl ₎ acetic acid in 20 ml of methanol is neutralized with 8.7 ml of a 0.32 N sodium methoxide solution. The solvent was evaporated in vacuo and the sodium salt was dehydrated by azeotropic distillation with 2 X 20 ml benzene. To a suspension of this salt in 30 ml of benzene containing 1 drop of Ν, Ν-dimethylformamide was added 685 mg of oxalyl chloride. The resulting solution was stirred at 20 ° C for 1.5 hours, then evaporated to dryness in vacuo to give the acid chloride.

A solution of this chloride in 20 ml of acetone was added dropwise with stirring to 1.00 g of 7-Samino-3- acid hydrochloride.

- (5-η (R-methyl-1,3,4-thiadiazin-2-yl) trifluoromethylceph-3-em-4-carboxylic acid in 30 ml of water containing 660 mg of sodium bicarbonate at 0 ° C. hours and allowed to warm to room temperature. the acetone was evaporated in vacuo and acidified to pH 1.9. the solution was extracted with 6 x 70 ml of ethyl acetate, the extracts are combined and washed with water, anhydrified and evaporated to dryness ^one. The crude product was washed with 2 X 20 mL of 1: 1 benzene-cyclohexane, then washed with pure cyclohexane and dried to give 863 mg of the title compound, [α] _D -61 ° (c = 1.44 in DMSO), .lambda.max (pH 6 buffer) 239 nm [ε 17900], 273 nm (ε 19,150), V ^ x (Nujol] 1784 cm ^_1 ((lactam) τ (DMSO-d6) values including 0.09 (d, NH), 4.68 (s, CH 2 -thienyl), 7.31 (s, CH 3).

The sodium and potassium salts of the compounds exemplified are prepared in a conventional manner by reaction with sodium or potassium 2-ethylhexanoate. In order to elucidate the preparation of these salts in greater detail, we provide a process for the preparation of the 3-acetoxymethyl-7S- (2-methylimino-2-phenyl-acetamido) cef-3-em-4-carboxylate sodium salt as the syn-isomer.

10.84 g of syn-3-acetoxymethyl-7-

The (2-methooyiminine-2-ellylacetamido) cef-3-em-4-carboxylic acid was dissolved in 280 ml of ethyl acetate and 25 ml of a 1 M sodium ethylhexanoate solution was added dropwise with stirring. The solution was further stirred for 20 minutes after cooling to 0 ° C for a further 2 hours. The precipitated salt was removed by filtration and stirred for 2 hours with 100 ml of ethyl acetate, whereupon 9.6 g of the precipitated solid was filtered, washed with water and dehydrated. The resulting product was washed with 2 X 200 ml of ether over 30 minutes at room temperature in a yield of 78% gave 8.9 g of the title compound, [a ^ n + 60 ° (C - 1.06 in water) and _has x [pH 6 buffer] 258 to 259 nm (ε 19 150).

In the following examples, the processing of the active ingredients produced by the process according to the invention into pharmaceutical preparations is illustrated.

Example 100

Powdered preparation for solution for injection

The sterile sodium bis (2-phenylacetamido) cef-3-em-4-carboxylate sterile sodium meth-4-carboxylate is filled into vials such that one vial contains 500 mg or 1.0 g. antibiotics. The filling is performed aseptically under a nitrogen layer. The vials are closed with rubber stoppers which are held in position by aluminum sealing rings so that gas or microorganisms are not penetrated. The resulting product is intended to be diluted with water for injection or other suitable sterile solvent just prior to administration.

Example 101

Intramammary infusion for cattle

% Composition in% wt.

Sodium 3-acetoxymethyl-7β- (2-ethoxyimino-2-phenyl-aceto-tamoxyl) cef-3-em-4-carboxylate in the form of the syn-isomer10.00 Solvent to 100.00 solvent composition:

Tween 603,00 white beeswax6,00 peanut oil91,00

The solvent components were heated together at 150 ° C for 1 hour and then cooled to room temperature with stirring. A sterile -antibiotic powder is added to the mixture and the product is mixed thoroughly. Then the resulting mixture is aseptically filled into sterile aluminum tubes so that each lead contains 3.0 g of a formulation containing 300 mg of cephaleporin derivative.

Example 102

Mixture for the preparation of syrup for oral administration

3-Acetoxymethyl-73- (2-methoxy-quinino-2-thien-2'-ylacetamido) lef-3-em-4-carbooylate

in the form of the syn-isomer 5,00 g saccharin sodium 0,10 g sodium citrate (anhydrous) 1,00 g citric acid (anhydrous) 0,10 g flavor (Amaranth) 0.01 g dried raspberry essential oil spraying 1,00 g sucrose up to 75,00 §

The product is intended to be reconstituted with a sufficient quantity of purified water to a final volume of 100 ml to be consumed in a few days, each containing 5 milligrams of syrup containing 250 mg of ceralosporin derivative.

Amaranth is mixed with a portion of sodium citrate and ground. The sodium saccharin and citric acid are mixed, the rest of sodium citrate, the flavoring and the antibiotic are mixed, blended, mixed with sucrose and 75 g of the mixture is filled into 150 ml bottles, which are stoppered.

Example 103

Capsules for oral administration

Sodium 3-acetoxymethyl-4- (2-ethoxyimino-2-phenylacetamido) cef-3-em-4-carboxylate as syn-isomer is mixed with 1% magnesium stearate and filled into gelatin capsules of size 0 to 250 mg cephalosporin antibiotics. The capsules are filled into glass vials with plastic caps for protection against moisture.

Claims (15)

OBJECT OF INVENTION A process for the preparation of 7β-acylamido-3-cephem-4-carboxylic acids of the general formula I COOtf where R is hydrogen or a group R ⁱⁿ which R ^u represents an aryl group having carbon ring having 6 to 12 carbon atoms such as phenyl or naphthyl, five or six membered heterocyclic aryl containing at least one heteroatom loose from the group consisting of sulfur, nitrogen and oxygen, or a heterocyclic group condensed with a benzene ring, e.g. 2-thien, 3-thien, furyl, pyridyl, pyrrolyl, N-methylpyrrolyl, N-benzyloxymethylpyrrolyl, isothiazolyl, thiadiiazolyl, oxadiazolyl, 3- or 4-isoxaziolyl, 3-phenyl- or 3-halophenyl-5-methyl-4 isoxazolyl, benzothienyl, benzofuryl, indolyl or sydlonone, C 3 and C 7 cycloalkyl, for example cyclopentyl or cyclohexyl, each of which is optionally substituted with halogen, hydroxy, C 1 -C 6 alkyl, nitro, amino, alkylam C 1 -C 6 dialkylamino, C 1 -C 6 dialkylamino, C 1 -C 6 alkanoyl, C 1 -C 6 alkanoylamino, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio the carbon atoms in the alkyl moiety or the cyclohexadienyl group or R represents a group of formula \ R ^u (CH 2) _m Q _n (CH2) _p, wherein R ^u is as defined above, m is 0 or an integer of 1-4, n is 0 because, by 1, p is an integer from 1 to 4 and Q represents a sulfur atom, an oxygen atom or a group = NR ² where R ² represents a hydrogen atom or R represents a group of the formula C _n H _{2n +} 1 wherein n is an integer from 1 to 7, wherein the ¹ groups have a straight or branched chain and are optionally interrupted by an oxygen or sulfur atom or a group = NR ² , wherein R ² has the abovementioned meaning, or the group is optionally substituted by cyano, carboxy, alkoxycarbonyl with 2-7 carbon atoms, hydroxy, or carbonyl group of formula HOOC-CO- or halogen, or R represents a group of formula Where n is an integer of 2 to 7, wherein the group is straight or branched, optionally interrupted by an oxygen or sulfur atom or a group = NR ² , wherein R ² is as defined above, or R is a group of the formula ^U n ^H 2n -3 ^, wherein n is an integer of 2 to 7 or a cyano, amino or C 2 -C 7 alkoxycarbonyl group, R a represents a C 1 -C 16 alkyl group, for example a methyl, ethyl, propyl, butyl, octyl or dodecyl group, a C 2 -C 16 alkenyl group, for example a vinyl, allyl, isopropenyl or dimethylalkyl group, a C 2 -C 2 alkynyl group C uhlíku-C,, for example pnopargyl, Clo-C cyk cyk cycloalkyl, for example cyclopropyl, cyclopentyl or cyclohexyl, C 4-C 7 cyk cycloalkenyl, for example cyclopentenyl, cyclohexenyl, cyclopentadienyl or cyclohexadienyl, a carbon ring aryl group From 6 to 12 carbon atoms, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen or sulfur, optionally fused to a benzene ring, or ¹ other group a heterocyclic group, for example, pyridyl, pyrimidyl, furyl, thienyl, thienyl, thiadiazolyl, diazol, triazolyl, tetrazolyl, thlatriazlyl, oxazolyl, oxadiazollyl, benzimidazolyl, benzoxazolyl or puroxyl or puroxyl or benzoxazolyl or puroxyl groups; up to 4 carbon atoms which is substituted with an aryl with a carbon or heterocyclic ring as defined above, for example, a benzyl, phenylethyl, diphenylmethyl, triphenylmethyl, thienylmethyl, furylmethyl, pyridylmethyl or pyrrtlylmethyl group, each such group being optionally substituted with a halogen or halogen atom Bromine, hydroxy, C1 -C6 alkoxy, for example methoxy, ethoxy or propoxy, C6 -C12 aryloxy, for example phenoxy, C1 -C4 phenylalkoxy, for example benzyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylthio, for example methylthio or ethylthio, C 6 -C 12 arylthio, C 1 -C 4 phenylalkylthio, amino, C 1 -C 6 alkylamino, e.g. methyl · · oskupinιtu amine or ethylamintskupinou, dialkylami№skupintu having 1-6 carbon atoms in each alkyl part, for example dirnethylamintskupinou, nitro, azido, carboxy, alkoxyιkarbtnylovou group having 2-7 carbon atoms in the alkoxy part, or for example methloxykarbonylovou ^{ethoxykarbonylovn:} u, benzyloxykarbtnyltvou a formyl group, an acyl group having 1 to 10 carbon atoms, for example an acetyl, propityl or benzoyl group, an acyl group having 1 to 10 carbon atoms, for example an acetoxy, propynyloxy or pivaloyloxy group, cyano, phthalimido-1-phthalimido group for example an acetamido or benzamido group, an alkoxycarbonylamino group having 2 to 7 carbon atoms in the alkoxy moiety, for example a methoxycarbonylamino group, or a phenylalkoxycarbonynyl group having 2 to 5 carbon atoms in the alkoxy moiety, for example a benzyloxycarbonynylamino group G represents a hydrogen atom or a methyl or ethyl group or a group of the formula R ³ —CH — C \ R4 where _χ R ³ and R 4, which are the same or different, are hydrogen, niiril, C 2 -C 7 -alkoxy, C 1 -C 6 -alkyl, C 5 -C 7 -cycloalkyl, phenylalkyl; C 1 -C 4 alkyl or C 6 -C 12 aromatic, optionally substituted by nitro, for example vinyl, or -CH 2 Y, wherein: Y represents a pyridine base residue, N-pyrimidine, N-purine, N-pyridazine, N-pyrazine, N-pyrazole, N-imidazole, N-triazole or N-thiazole cation optionally substituted by an alkyl group of 1 to 6 C 6 -C 12 aryl, C 1 -C 4 phenylalkyl, alkoxymethyl C 2 -C 7, C 1 -C 8 acyloxy, C 1 -C 8 acyloxy, C 2 -C 9 acyloxymethyl, C 2 -C 7 alkoxycarbonyl, alkoxy, benzylthoxycarbonyl, alkoxy C 1 -C 6 aryl, C 6 -C 12 aryloxy, C 1 -C 4 phenylalkoxy, C 1 -C 6 alkylthio, C 6 -C 12 arylthio, C 1 -C 4 phenylalkylthio in the alkyl part, 100 cyano, hydroxy, carbamoyl, N-monoalkylcarbyoyl of 1 to 6 carbon atoms in the alkyl moiety, N, N-dialkylcarbyoyl, in the case of 1 to 6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl of 1 to 6 atoms the alkyl moiety is not a C 1 -C 6 carbamoylalkyl moiety, an azido, amino or C 1 -C 8 acylamido group derived from a derivative obtained from the reaction of a compound wherein Y is an azido group with a dipolarophilic acetylene or ethylene group or a cyano group , group R 5 —C — CO — R ⁷ AND R® where R ⁵ and R ® which are the same or different denote hydrogen atoms, cyano, C 1 -C 6 alkyl, phenyl, halophenyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkoxyphenyl C 6 alkoxy, nitrophenyl, aminophenyl, C 1 -C 6 alkylaminophenyl, C 2 -C 7 alkoxycarbonyl, C 2 -C 5 mono- or diphenylalkoxycarbonyl, alkylcarbonyl a C 2 -C 7 alkyl group, a C 1 -C 4 phenylalkyl group, or a C 5 or C 6 cycloalkyl group; and R 7 represents a hydrogen atom, a C 1-6 alkyl group, a phenyl group, a halophenyl group, an alkylphenyl group of 1-6 carbon atoms in the alkyl moiety, an alkoxyphenyl group of 1-6 carbon atoms in the alkoxy moiety, a nitrophenyl group, an aminophenyl group, (C 1 -C 6) alkylaminophenyl, (C 1 -C 4) phenylalkyl or C 5 or C 6 cycloalkyl; R ⁸ represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having a carbon ring having 6 to 12 carbon atoms, or a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety; a group as defined above, for example, thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridyl, or pyridyl or any pyridyl, An alkyl group having from 1 to 5 carbon atoms; N is 0, 1 or 2, preferably · 0, further Y is a group of the formula -OR 4, wherein: R1 represents a hydrogen atom, an acetoxy group, a group of the formula -O-COR9, wherein R 9 represents an organic group having an atomic mass of at least 16, which is selected from the group consisting of the formula CnH2n + 1, wherein n is an integer from 1 to 7 and the group has a straight or branched chain, optionally interrupted by an oxygen or sulfur atom or an imino group or substituted by cyano, carboxy, alkoxycarbonyl of 2 to 7 7 carbon atoms in the alkoxy moiety, a hydroxy group, a carboxycarbonyl group, a halogen atom or an amino group, a group of the formula C n H 2 n-i, where n is an integer from 2 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen atom, a sulfur atom or an imino group, a group of the formula Rv where Rv represents a (C 6 -C 12) carbon ring aryl group, for example a phenyl or naphthyl group, a 5- or 6-membered heterocyclic aryl group containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, or such a benzene ring fused heterocyclic group; for example 2-ienone, 3-thien, furyl, pyridyl, pyrrolylone, N-methylpyrrolidine, N-benzyloxymethylpyrrolyl, thiothlazolylone) thiazolyloloxadiazolylone. 101 102 3- or 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-.alpha.-isoxazolyl, benzothienyl, benzofuryl, indolyl or sydnon group, cycloalkyl or sydione group, cycloalkyloalkyl cyclopentyl or cyclohexyl group, any of the above said groups optionally substituted by halogen, hydroxy, C1-C6 alkyl, nitro, amino, C1-C6 alkylamino, C1-C6 dialkylamino, in each alkyl moiety, C1-C6 alkanoyl (C 1 -C 6) -alkynyl (C 1 -C 6) -alkoxy, (C 1 -C 6) -alkoxy, or (C 1 -C 6) alkylthio or C 1 -C 6 -alkylthio; R ^at - (CH 2) _m where Rv is as defined above and m is an integer from 1 to 4, a group of the formula -O-CO-AR ^9a , wherein A is O, S or NH R 9a represents a hydrogen atom, a methyl group or a group R ⁹ as defined above, a group of the formula -O-CO-NH 4 H 4 mD, wherein D represents a halogen atom, for example a chlorine, bromine, iodine or fluorine atom; and am is from 1 to 4, for example 2-chlorothylaminocarbonyl-10'X, or a chlorine, bromine or iodine atom, and non-toxic pharmaceutically acceptable salts and sulfoxides thereof; in that the compound of formula III COOR ^Zi> (II) where G is as defined above and R10 represents a hydrogen atom or a carbonyl protecting group, or an N-silylated derivative thereof or an acid addition salt thereof, condensed with an acylating agent corresponding to the acid of formula IV R = C-COOH N \ OR ^and (IV), where ^And R and R are as defined above, and then optionally deprotecting the protecting group at ^R10 karbfxχskupině and isolating the resulting compound of formula I, optionally after conversion of a non-toxic pharmaceutically acceptable salt thereof or a sulfoxide, for example by reaction with a base as-2- sodium or potassium ethoxidexanoate, in the form of a mixture of isomers containing at least 75%, preferably at least 90% or more of the syn-isomer or, preferably, in the form of a syn-isomer free of the corresponding anti-isomer. 2. The process according to item 1, for the preparation of compounds of the general formula Γ R‘ represents an aryl five or six membered heterocyclic group containing at least one sulfur, nitrogen or oxygen atom, R a 'represents a C 1 -C 4 alkyl group, a C 2 -C 5 alkenyl group, a propynyl group, a propargyl group, a C 3 -C 6 cyclohexyl group, a phenyl group, a C 1 -C 4 phenylalkyl group alkyl moieties, triphenylmethyl, thienylmethyl, or pyridylmethyl, these groups being optionally substituted with at least one substituent selected from the group consisting of hydroxyl, methoxy, ethoxy, bromo, nitro, amino, carboxy or benzyl and G 'represents a methyl or vinyl group or a group of the formula -CH 2 -Y ¹ , wherein Y ‘represents a pyridinium radical, a carbamaylopyridinium radical or a hetero radical 103 104 a cyclic amine containing more than one heteroatom, wherein at least one heteroatom is a nitrogen atom, an azido group, a group of the formula -S (O) _n R '' where R ⁸ 'is C 1 -C 4 alkyl or a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, and n is 0, 1 or 2, hydroxy, -O-CO-R ⁹ ', where R ⁹ 'represents an alkyl group having 1 to 4 carbon atoms, a vinyl, propenyl, phenyl or cycloalkyl group having 3 to 6 carbon atoms, a group of the formula -O-CO-NH (CH 2) _m D', wherein D‘ represents a hydrogen, fluorine, chlorine, bromine or iodine atom and m represents an integer from 1 to 4, or a carbamoyloxy or pyridylcarbamoyloxy group, acceptable salts and sulfoxides thereof, characterized in that the compound of formula III A COOk (IIA) where G ‘has the meaning given above and R ¹⁰ represents a hydrogen atom or a carboxy protecting group, or an N-silylated derivative thereof, as an acid addition salt thereof, condensed with an acylating agent corresponding to the acid of formula IVA R‘ — С — COOH II N \ OR ^a '(IVA) where R 'and R ^{and <are} as hereinbefore defined and thereafter optionally removing the protecting group on the carboxy group and isolating the resulting compound of formula I, optionally after conversion of a non-toxic pharmaceutically acceptable salt or a sulfoxide thereof, for example by reaction with a base such as 2-ethylhexanoate sodium or potassium in the form of a mixture of isomers containing at least 75%, preferably at least 90% or more of the syn-isomer, or preferably in the form of the syn-isomer, free of the corresponding anti-isomer. 3. The process of claim 1 wherein the acid chloride or bromide of the formula IV is used as the acylating agent. 4. A process according to claim 3, wherein the compound of formula III is condensed with an acid chloride or bromide in the presence of an acid-binding agent, for example a tertiary amine such as triethylamine or dimethylaniline, an inorganic base such as calcium carbonate or sodium bicarbonate; oxirane, preferably 1,2-alkylene oxide having 2 to 6 carbon atoms in the alkyl moiety such as ethylene oxide or propylene oxide, preferably in the presence of a solvent consisting of a mixture of water and ketone such as aqueous acetone, ester such as ethyl acetate, amide such as dimethylacetamide; or mixtures of two or more of such solvents at a temperature of -50 to -50 ° C, preferably -20 to +30 ° C. 5. A process according to claim 1, wherein the compound of formula III is condensed with an acid of formula IV in the presence of a condensing agent such as carbodiimide, a carbonyl compound such as carbonyldiimidazole or isoxazolinium salt, preferably in an anhydrous reaction medium such as methylene chloride. dimethylformamide or acetonitrile. 6. A process according to claim 1, wherein the compound of formula III is condensed with an amide-forming acid derivative of formula IV, for example an asymmetric or mixed anhydride or an activated ester, such as a compound of formula IX. R = C-CO-L N \ OR ^and (ix) where R and R ^and are as defined in point 1, L is azido and oxysuccinimido, oxybenztriazolo, pentachlorophenoxy or p-nitrophenoxy. 7. A process according to any one of Claims 1 to 6, characterized in that the compounds o 105 106 of formula III or IIIA will use compounds of formula VIII (VIIIa) wherein R10 is as defined in 1 a G 'represents a methyl or ethyl group or a group of the formula R ³ —CH — C \ R4 where R 3 and R ⁴ , which are the same or different, represent a hydrogen atom, a nitrile group, a C 2 -C 7 alkoxycarbonyl group, a C 1 -C 6 alkyl group, a C 5 -C 7 cycloalkyl group, a C 1 -C 7 phenylalkyl group 4 carbon atoms in the alkyl moiety or an aromatic group having 6 to 12 carbon atoms, optionally substituted by a nitro group, or G "denotes a group of the formula" CH 2 Y ", where Y 'represents a group of the formula wherein n is 0 or an integer from 1 to 5 and R ^d , which when n is an integer of 2 to 5 are the same or different and represents an alkyl group having 1 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety , (C 2 -C 7) alkoxymethyl, formyl, (C 1 -C 8) acyloxy, (C 2 -C 9) acyloxymethyl, (C 2 -C 7) alkoxycarbonyl, benzyloxycarbonyl , (C 1 -C 6) alkoxy, (C 6 -C 12) aryloxy, (C 1 -C 4) phenylalkoxy, (C 1 -C 6) alkylthio, (C 6 -C 12) arylthio, (C 1 -C 4) phenylalkylthio group carbon atoms in the alkyl moiety, cyano, hydroxy, carbamoyl, N-monoalkylcarbamoyl of 1 to B carbon atoms in the alkyl moiety N, N-dialkylcarbamoyl having 1 to 6 carbon atoms in each alkyl moiety, N-hydroxyalkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety, or carbamoylalkyl having 1 to 6 carbon atoms in the alkyl moiety, azido, amino or acylamido groups having 1 to 8 carbon atoms in the acyl moiety, a group derived from a derivative obtained by the reaction of a compound in which Y 'represents an azido group with a dipolarophilic acetylene or ethylene group or a cyano group, a group of the formula R @ 5 —C — CO — R @ 7 Ra kde R 5 and R ⁶ , which are the same or different, represent a hydrogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, a phenyl group, a halogenophenyl group, an alkylphenyl group having 1 to 6 carbon atoms in the alkyl moiety, an alkoxyphenyl group having 1 to 6 carbon atoms in the alkoxy part, nitrophenyl, aminophenyl or alkylaminophenyl having 1 to 6 carbon atoms in the alkyl part, alkoxycarbonyl having 2 to 7 carbon atoms, a mono- or diphenylalkoxycarbonyl group having 2 to 5 carbon atoms in the alkoxy part, an alkoxycarbonyl group having 2 to 7 carbon atoms in the alkoxy moiety, a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety or a cycloalkyl group having 5 or 6 carbon atoms, and R 7 is hydrogen, C 1 -C 6 alkyl, phenyl, halophenyl, C 1 -C 6 alkylphenyl, C 1 -C 6 alkoxyphenyl, triphenyl, aminophenyl, alkylaminophenyl. C 1 -C 6 alkyl, C 1 -C 4 phenylalkyl or C 5 -C 6 cycloalkyl Y is furthermore a group of formula -S ^ (O) "R" ‘where R 8 ‘represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having a carbon ring having 6 to 12 carbon atoms 107 Or a phenylalkyl group having 1 to 4 carbon atoms in the alkyl moiety, or a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur and optionally substituted alkyl of 1 to 6 carbon atoms, or a phenyl or nitro group and / or fused to a benzene ring or a further 5- or 6-membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, for example thiadiazolyl, especially 5-methyl-1,3,4-thiadiazole- 2-ylpyrrole, diazolyl, triazolyl, tetrazcyl, thiazolyl, thiatriazolyl, oxazolvyl, oxadiazolyl, benzimidazolyl, benzoxazrlyl, bezthiazollyl, triazrirpyridyl, purinyl, pyridyl or any of the pyridyl or pyridyl, or any of the pyridyl or pyridyl groups; nitrogroup another, n represents 0, 1 or 2, preferably 0, a group of the formula -OR ', where R 'represents a hydrogen atom, an acetroxy group, a group of the formula —O — COR ⁹ , wherein R 9 is an organic group having a total atomic mass of at least 16, selected from the group consisting of ^C n ^H 2n + 1 where n is an integer from 1 to 7 and the group has a straight or branched chain optionally interrupted by an oxygen atom; a sulfur atom or an imino group. or substituted by cyano, carbonyl, alkenylcarbnyl having 2 to 7 carbon atoms in the alkoxy moiety, hydroxy, carboxycarbnyl, halogen or amino, CnH2n ^- 1 & ^{apos ;} wherein n is an integer of 2 to 7 and the group has a direct or a branched chain optionally interrupted by an oxygen atom, a sulfur atom or an imino group; R ^at , where R ^v is an aryl group having a carbon ring of 6 to 12 carbon atoms, for example a phenyl or naphthyl group, a four or six membered aryl group containing at least one heteroatom selected from the group consisting of sulfur, nitrogen and oxygen, or such a heterocyclic group fused with benzene a ring, such as 2-thien, B-t-methylene, furyl, pyridyl, pyrrolyl, N-methylpyrrolyl, N-benzyloxymethylpyrrrlyl, isothiazolyl, thiadiazolyl, oxadiazolyl, 3- or A 4-isoxazolyl, 3-phenyl- or 3-halophenyl-5-methyl-4-isoxazolyl, benzothienyl, benzofuryl or sydnon group, a C 3 -C 7 cycloalkyl group, for example a cyclopentyl or cyclohexyl group, any of the above optionally substituted by halogen, hydroxy, C 1 -C 6 alkyl, nitro, amino, C 1 -C 6 alkylamino, C 1 -C 6 -alkylamino, C 1 -C 6 alkanoyl C 1 -C 6 alkanrylamino, C 1 -C 6 alkoxy or C 1 -C 6 alkylthio in the alkyl moiety or a group of the formula -O-CO-NH [CH 2] _m D, wherein D represents a halogen atom, for example a chlorine, bromine, iodine or fluorine atom, and m is an integer from 1 to 4, for example a 2-chloroethylaminocarbonyloxy group or a chlorine, bromine or iodine atom. 8. The method of claim 1 · characterized by condensing a compound of formula III with an acylating reagent that corresponds · · acid of general formula IV wherein R is hydrogen or a group selected from R _u wherein _Ua R represents phenyl, hydroxy-oxyfenylovou, chlrrfenylovru, fluorophenyl · Eva, tolyl, nitrrí'enylovru, aminophenyl, methrxyfenylrvru, methylthirfenylrvou, naphthyl or 2-ethoxynaftylovru group, five or six membered heterrcyklickou group containing at least one heteгratrm selected from the group consisting of oxygen, nitrogen and sulfur such as 2-thienyl, 3-thienyl, furyl, pyridyl, A 4-isoxazololyl, 3-phenyl- or 3-halophenyl-5-methyl-4-isrxazrlyl or sydnonvr, or a cyclopentyl or cyclohexyl group of the formula Ru ^a (CH 2) _m Q _n (CH 2) p) 109 ПО where R ^11a is as defined above, m is 0 or an integer from 1 to 4, n is 0 or 1, p is an integer from 1 to 4, and R ^v - (CH 2 J m where R ^v is as defined above and m is an integer from 1 to 4, a group of the formula -O-CO-AR ^9a , wherein A is O, S or NH R ^9a represents a hydrogen atom, a methyl group or R ⁹ , as defined above, a group of the formula Q represents a sulfur atom, an oxygen atom or a group = NH, or represents a group of the formula Wherein n is an integer from 1 to 7, wherein these groups are straight or branched chain and are optionally interrupted by an oxygen or sulfur atom, or optionally substituted by cyano, carboxy, hydroxy or carboxycarbonyl or halogen, or represents Cribun - b wherein n is an integer from 2 to 7, wherein the group is straight or branched, optionally interrupted by an oxygen or sulfur atom, or represents a group of the formula Where n is an integer from 2 to 7 and a cyano or amido group, R ^A is R ^aa, denoting alkyl of 1 to 8 carbon atoms, napřílkad methyl, ethyl, propyl or butyl, optionally substituted by hydroxy, carboxy, amido, cyano, acetyl or amino groups, or meaning benzyl, phenethyl, phenyl or naphthyl and the remaining substituent is as defined in item 1 when R ¹⁰ is required to be removed and a compound of formula I or a non-toxic pharmaceutically acceptable salt or sulfoxide thereof containing preferably at least 90% of the synisomer is isolated. 9. A process according to claim 8, wherein the compound of formula III is a compound of formula VIII as defined in item 7, wherein G 'is methyl, vinyl or formula -CH2Y kde “where Y '' represents hydroxy, ^1- acetoxy, methoxy, methylthio, azido, pyridinium or chlorine, bromine or iodine. 10. The method according to claim 8, characterized in that as compounds of formula III is the compound of formula VIII as defined in claim 7, wherein G 'represents a group -CH 2 COR ^9' wherein R ⁹ 'represents a group selected from the group consisting of the formula GnH2n + 1, wherein n is an integer from 2 to 7, wherein the group is straight or branched chain and is optionally interrupted by an oxygen, sulfur or imino group or is optionally substituted by cyano, carboxy, hydroxy or carboxycarbonyl or halogen , or a group of the formula С11Н2П - 1, where n is an integer from 2 to 7, where the group is straight or branched, optionally interrupted by an oxygen atom, a sulfur atom or an imino group, a group of the formula R ^va where R ^va means phenyl, naphthyl, thienyl, pyridyl, sydnon, cyclopentyl, cyclohexyl, hydroxyphenyl, chlorophenyl, fluorophenyl, tol 111 112 is a nitrile, nitrophenyl, aminophenyl, methoxyphenyl or methylthotenyl group of formula Rv ^and (CH2U where R a is as defined above ^{and m} represents an integer of 1 to 4 -a methyl substituted by at least one halogen atom, such as chlorine or bromine, or an amino group. 11. The process of item 7, for producing a compound of formula XX (XX) wherein R ^ub means - a group selected from the group consisting of phenyl, naphthyl, thienyl, furyl, benzothienyl, benzofuryl, pyridyl or one of these groups substituted by a halogen atom such as chlorine, bromine, iodine or fluorine, hydroxy, alkyl (C 1 -C 6), nitro, amino, (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino, (C 1 -C 6) alkanoyl, (C 1 -C 6) alkanoylamino, (C 1 -C 6) alkoxy (1-6C) alkyl, (1-6C) alkylthio or carbamoyl, R ^b is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl substituted with C 6 -C 12 aryl or 5- or 6-membered aryl. a group containing at least one heteroatom selected from oxygen, nitrogen and sulfur, or any of them substituted with hydroxy, carboxy, alkoxycarbonyl of 2 to 7 carbon atoms, benzyloxycarbonyl, amino, cyano, alkanoylamino of 1 to 6 carbon atoms, - (C 1 -C 6) alkylamino, (C 1 -C 6) dialkylamino in each alkyl moiety, halogen or C 1 -C 6 alkoxy, Y ^a represents an acetoxy group or a group of the formula wherein Rd is as defined in 7 and n is 0 or an integer from 1 to 5, a group of formula -SW, where W represents thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, triazolopyridyl, purinyl, pyridyl, pyrimidyl, or one of these groups; nitro full, for example 5-methylil, 3,4-thiadiazole · e-yl group, alkylthio of 1 - 4 carbon atoms, -O - CO-R ⁹ ', where R ⁹ 'represents an alkyl or alkenyl group having 2 to 4 carbon atoms or a phenyl group, a group of the formula -O-CO-NH- (CHe) mD, wherein m is an integer of 1 to 4, and D represents a chlorine, bromine, iodine or fluorine atom, or an azidoscupine, and the non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound of the general formula (VIII) mentioned in point 7, - G 'is -CH2 ^and wherein ^And Y is as defined above, 113 114, or an N-silylated derivative thereof, or an acid addition salt thereof, is coupled with an acylating Kδ corresponding to the acid of formula Rub — c — COOH N \ OR ^b where Rev and Rb are as defined above and, if desired, the R ¹⁰ protecting groups are removed and the compound of Formula I or a non-toxic pharmaceutically acceptable salt or sulfoxide thereof is isolated. 12. The process of item 11, for producing a compound of formula XXI O 0 OR N CHO-CO-Cu i COOH (XX H where Rx 'represents a phenyl, naphthyl, thienyl, furyl, benzothenyl or benzo group and R 0 represents a (C 2 -C 4) alkyl, benzyl, phenethyl, thienylmethyl or furylmethyl group, as well as the non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound of the formula (VIII) where G 'is an acetoxymethyl group, or an N-sylated derivative thereof, or an acid addition salt thereof, is condensed with an ocular agent corresponding to the acid of formula Rx = C = COOH N \ OR ° where R ^x and R 0 are as defined above. 13. The process of item 11, for producing a compound of formula XXII r-c-conh II b ^C OR ^b COOH (XXII) where R ^x is phenyl, naphthyl, thienyl, phenyl, benzsthienyl or benzofuryl, Rb is as defined in point 11a T represents an acetyloxy group, an azide group or a group of the formula wherein R ^d is as defined in point 7 and y is zero or an integer from 1 to 5 and a group of the formula —O — CO — R ⁹ “, where R ⁹ 'represents an alkyl or alkenyl group having 2 to 4 carbon atoms or a phenyl group, as well as non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound of formula VIII, wherein: G 'represents a group of the formula —CH2T, where T is as hereinbefore defined, or an N-substituted derivative thereof or an acid addition salt thereof is condensed with an acylating agent corresponding to an acid of the formula Rx = C = COOH II N \ ORb where Rx is as defined above and Rb is as defined in point 11. 14. The process of item 11, for producing a compound of formula XXIII 115 11В Rkde Rx is as defined above and Rb has the meaning given in point 11. 15. The process of item 11, for producing compounds of formula XXIV wherein R ^x represents a phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl group, R ^x is phenyl, naphthyl, thiV is C 1 -C 4 alkylthio or C 2 -C 4 alkanoyloxy or C 2 -C 4 alkenoyloxy, and their non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound is of formula VIII wherein G 'represents a group of formula —CH2 V, where V is as hereinbefore defined, or an N-silyl derivative thereof or an acid addition salt thereof is condensed with an acylating agent corresponding to the acid of the formula Rx — C — COOH II N OR ^b CH 2 OCOCH 3 PCX IV) where R @ ¹ represents a phenyl, naphthyl, thienyl, furyl, benzothienyl or benzofuryl group, as well as non-toxic pharmaceutically acceptable salts and sulfoxides thereof, characterized in that the compound of formula (VIII): G 'represents an acetoxymethyl group, condensed with an acylating agent corresponding to the acid of formula R ^{X =} C-COOH II N \ 0CH3 where Rx is as defined above.