CS216938B2 - Method of making the derivatives of the 7 beta-aminothiazolylycetamido-3-cefem-4-carboxyl acid - Google Patents

Abstract

1. A 7 beta-aminothiazolylacetamido-3-cephem-4-carboxylic acid compound of the formula see diagramm : EP0008343,P9,F1 wherein R1 is hydrogen or an amino protective group, A is methylene substituted by methoxyimino and R2 is pivaloyloxymethyl, or a salt of such a compound containing a salt-forming group.

Description

The invention relates to a process for the preparation of novel N-aminothiazolylacetamido-3-cephem-4-carboxylic acid derivatives which are not substituted in the 2-position and in the 2-position. 3 cefem circle. These compounds have valuable pharmacological properties and can be used as antibiotics.

More particularly, the present invention relates to a process for the preparation of 7/3 aminothiazolylacetaniido-3-cephem-4-carboxylic acid derivatives of the formula I,

or methoxyimino substituted methylene,

R3 is hydrogen, methoxy or methoxy-substituted with C1-6alkylthio, tolylthio or phenylthio; and

R2 is a C1 -C7 alkyl group esterifying an alkyl radical of 1 to 7 carbon atoms and

R 1 is hydrogen, C 1 -C 4 alkyl or C 1 -C 18 acyl or mono-, di- or triphenylmethyl,

A-methylene or amino, hydroxy, sulfo, oxo or optionally carboxylated hydroxyimino of up to 11 carbon atoms, a methyl group, a phenylmethyl group in which the phenyl is represented by one or two optionally alkyl of 1 to 4 carbon atoms, an alkoxy group of 1 to 4 atoms carbon, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen substituted benzoylmethyl radical, polyhalophenyl radical, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radicals, alkanoyloxymethyl radical having 1 C 1 -C 4 alkanoyl, C 1 -C 4 aminoalkanoyloxymethyl, C 1 -C 4 alkoxycarbonyloxymethyl, C 1 -C 4 alkoxycarbonyloxyethyl, alkanoyoyl C 1 -C 4 alkanoyl, thiomethyl C 1 -C 4 alkanoylaminomethyl C 1 -C 4 alkanoyl optionally substituted by halogen, benizoylaminomethyl radical, phthalidyl my carbon in alkoxy radical, 2-aminoalkyl radical having 1 to 4 carbon atoms in the alkyl part or a 2-aminocycloalkyl radical having 3 to 8 carbon atoms in the cycloalkyl moiety, the amino group being substituted by two alkyl radicals having 1 to 4 carbon atoms or an alkylene group having 2 to 8 carbon atoms or an alkylene group having 2 to 8 carbon atoms, which optionally contains an oxo group, and salts of such compounds with salt-forming groups.

The lower alkyl group R 1 is in particular a lower alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl or tert-butyl.

The functional groups present in the compounds of formula I, in particular the carboxyl and amino, hydroxy, hydroxyimino and sulfo groups, are optionally protected by protecting groups used in the chemistry of penicillins, cephalosporins and peptides.

Such protecting groups are readily cleavable, i.e., they are cleavable without undesirable side reactions, for example solvolytically, reductively, photolytically or else under physiological conditions.

Protective groups of this type and methods for their cleavage are described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London, New York, 1973, and in "The Peptides", Vol. I. Schroeder and Lubke, Academic Presss, London, New York, 1965.

The acyl group Ac is an acyl radical of an organic carboxylic acid having up to 18 carbon atoms, in particular optionally, for example halogen or aryl, substituted aliphatic carboxylic acids or optionally, for example halogen, lower alkoxy or nitro, substituted aromatic carboxylic acids or carbon tetrachloride. Such acyl groups are, for example, lower alkanoyl, such as formyl, acetyl, propionyl, halogen (lower jalkanoyl, such as 2-haloacetyl, especially 2-chloro, 2-bromo, 2-iodo, 2,2-dichloro - or 2,2,2-trichloroacetyl, phenylacetyl, phenoxyacetyl, thienylacetyl, benzoyl, 4-chloro-, 4-methoxy- or 4-nitrobenzoyl, lower alkoxycarbonyl, earth tertiary (lower) alkoxycarbonyl, for example tert-butoxycarbonyl, polycycloalkoxycarbonyl, for example adamantyloxycarbonyl, arylmethoxycarbonyl, in which aryl is preferably one or two optionally, for example lower alkyl, in particular target, lower alkyl, for example tert, butyl, lower alkoxy, such as methoxy, halogen, hydroxy, , for example, chloro and / or nitro, mono- or polysubstituted phenyl radicals, such as optionally substituted benzyloxycarbonyl, for example 4-nitrobenzyloxycarbonyl, or substituted diphenylmethoxycarbonyl, for example benzhydryloxycarbonyl or di [4-methoxyphenyl) methyl ^{l-ethoxycarbonyl,} or 2-halo (lower) alkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, especially aroylmethoxycarbonyl, in which the aroyl group is preferably optionally halogen, such as bromo, substituted with a benzoyl group, such as phenacyloxycarbonyl.

Preferred acyl groups R 1 are the acyl radicals of 2-haloacetic acid, in particular 2-chloroacetyl, as well as carbonic acid polosters, in particular tert-butoxycarbonyl, optionally, as mentioned above, substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halogen (lower) alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group, such as ^{2,2,2-trichlorethoxykarbo,} butoxycarbonyl, and trityl.

The amino group can also be protected in proton form. Suitable anions are, in particular, the anions of strong inorganic acids, such as hydrohalic acids, for example chloride or bromide, or sulfonyl acids, such as p-toluenesulfonic acids.

The carbamoylated hydroxyimino group in residue A is a group of the partial formula = N - O - C (= O) - NHR 6, wherein

R4 represents lower alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms, aryl (lower) alkyl of 7 to 10 carbon atoms or aryl of 6 to 10 carbon atoms.

The lower alkyl group R a is especially a lower alkyl group having 1 to 6 carbon atoms, such as a methyl, ethyl, propyl, butyl, pentyl or hexyl group, which groups may be straight or branched. Branched lower alkyl groups are, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl groups.

The cycloalkyl group Rd is a cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The aryl (lower) alkyl group R d is a group having from 7 to 10 carbon atoms and is, for example, benzyl, phenylethyl, phenylpropyl or phenylbutyl.

The aryl group R 1 has 6 to 10 carbon atoms and is, for example, phenyl or naphthyl.

A preferred radical R d is ethyl, n-propyl, isopropyl, butyl, isobutyl, cyclohexyl and especially methyl.

The group R 1 replaceable by methoxy is, for example, ethyl, propyl, butyl or, in particular, methylthio, or phenyl or p-toluylthio.

The residue R 2 esterifying the carboxy group is preferably readily cleavable under gentle conditions, including physiological. Such R 2 radicals are especially tert-butyl, adamantyl, phenylmethyl, in which phenyl is preferably one or two, optionally tert-butyl, methoxy, hydroxy, halogen, such as chlorine and / or nitro, mono- or polysubstituted phenyl. residues, such as optionally, for example, as mentioned above, substituted benzyl, for example 4-nitrobenzyl, or 4-methoxybenzyl, or, for example, as mentioned above, substituted diphenylmethyl, for example benzhydryl or di - (4-methoxyphenyl) methyl, or 2-halo (lower alkyl having 1 to 4 carbon atoms, for example a 2, 2 ', 2-trichloroethyl radical, in particular a benzoylmethyl radical in which the henzoyl group is preferably optionally, for example, halogen, such as bromine, substituted with benzoyl such as for example a phenacyl radical or a polyhalophenyl radical such as the pentachlorophenyl radical The radical R @ 2 is furthermore a silyl group, in particular an organic silyl group or a corresponding stannyl group. In these groups, the silicon atom or the tin atom as substituents preferably contains an alkyl group having 1 to 4 carbon atoms, such as a methyl group, furthermore a alkoxy group having 1 to 4 carbon atoms, for example methoxy, and / or a halogen such as chlorine. Suitable silyl or stannyl protecting groups are, in particular, a trialkylsilyl group having 1 to 4 carbon atoms in the alkyl group, in particular a tri methylsilyl group, further a dimethyl tert-butylsilyl group, a (lower) alkoxy (lower alkyl halogensilyl group having 1 to 4 carbon atoms) , for example, methoxymethylchlorosilyl, or di (lower) C 1 -C 4 alkylhalogensilyl, for example dimethylchlorosilyl, or correspondingly substituted stannyl groups, for example toi-n-butylstannyl.

Preferred protecting groups for R 2 are, in particular, the tert-butyl radical or, for example, as mentioned, a substituted benzyl radical, for example a 4-nitrobenzyl radical and a diphenylmethyl radical.

The R 2 residue cleavable under physiological conditions imparts improved oral carboxylic acid absorption and / or prolonged efficacy to its own effective carboxylic acids. Numerous such ester groups are known in the art of penicillins and cephalosporins. Examples include —G (= OJ — O — Rz, where ·

R2 represents a methyl group substituted by an acyl group, an acyloxy group, an etherified hydroxy group and optionally another organic radical, wherein the methyl group may also be bonded to the carbonyl of the acyl group via a carbon-containing bridge, or it represents a 2-aminoaliphatic group. In such groups, acyl is an organic carboxylic acid radical of up to about 18 carbon atoms and is, for example, optionally substituted alkanoyl, cycloalkanoyl, aroyl, heterocyclylcarbonyl, for example also heterocyclylcarbonyl of carboxylic acid of formula I, or biologically active foam. or a acyl radical of a carbonic acid semi-ester. The etherified hydroxy group in the methyl group is a hydroxy group etherified with a hydrocarbon radical, in particular a lower alkyl radical. The organic radical optionally substituted in addition to the methyl group contains up to 7 carbon atoms and is especially lower alkyl, such as methyl or aryl, such as phenyl. Said bridge contains 1 to 3 carbon atoms, in particular 2 carbon atoms, so that a lactone, especially ydactone, is present. The aliphatic group in said 2-aminoaliphatic group may be of an fphatic or cycloaliphatic nature and may be saturated or unsaturated. The amino group is preferably substituted by two lower alkyl groups or an alkylene group optionally containing an oxo group. In such physiologically cleavable ester groups

-0 == 0 J-O-R2 is

R 2 is, for example, lower C 1 -C 4 lower alkanoyloxymethyl, for example acetyloxymethyl or pivaloyloxymethyl, amine (lower) C 1 -C 4 lower alkanoyl, in particular α-amino (lower) alkanoyloxymethyl; C 1 -C 4 lower alkanoyl, for example glycyloxymethyl, L-valyloxymethyl, L-leucyloxymethyl, C 1 -C 4 lower alkoxycarbonyloxymethyl, or

1- (lower) C 1 -C 4 alkoxycarbonyloxyethyl, for example 1-ethyloxycarbonyloxyethyl, lower C 1 -C 4 lower alkanoyl, for example acetylthiomethyl or pivaloylthiomethyl, lower alkanoylaminomethyl C 1 -C 4 lower alkanoyl, in which the C 1 -C 4 lower alkanoyl group may be optionally substituted by halogen, such as chlorine, for example acetylaminomethyl or ^: 2,2-lichloroacetylaminomethyl, benzoylaminomethyl, or as an example for R 2 containing a lactone phthalidyl group, a lower alkoxymethyl group having 1 to 4 carbon atoms in the lower alkoxy group, in particular a methoxymethyl group, a 2-amino (lower) alkyl group having 1 to 4 carbon atoms, such as a 2-aminoethyl group wherein amino substit C 1 -C 4 alkyl or C1 -C4 lower alkyl radicals

2- to 8-carbon atoms optionally containing an oxo group such as 2-dimethylaminoethyl, 2-diethylamino-4-ethyl or 2- (1-morpholino) ethyl or 2-aminocycloalkyl of 3 to 8 carbon atoms, for example, a 2-dimethylaminocyclohexyl group. Particular emphasis should be placed on acetyloxymethyl, pivaloyloxymethyl, 1-ethyl-oxycarbonyloxyethyl and phthalidyl.

The compounds of formula I - with a basic group may form acid addition salts with, for example, inorganic acids, such as hydrochloric, sulfuric or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example with trifluoroacetic acid, as well as with amino acids, such as arginine and lysines. The compounds of the formula I with a free carboxyl group and a free amino group can also be present in the form of internal salts, i.e. in the form containing zwitterion.

The center of asymmetry optionally present in residue A, i.e. when A represents a hydroixymethylene, aminomethylene or sulfomethylene group, is present in the R, S- or preferably in the R-configuration. The optionally carbamoylated hydroxyimino- and methoxyiminomeithylene group A is preferably in the syn-form (Z-form).

Compounds of formula I wherein the carboxyl group is esterified in physiologically cleavable form and the functional groups in residue A are present in unprotected form, and their pharmaceutically usable, non-toxic salts are valuable, antibiotic active substances which can be used in particular as antibacterial antibiotics. For example, they are active in vitro against Gram-positive and Gram-negative bacteria such as Staphylococcus aureus, Streptococcus pyogenes, Streptococcus faecalis, Streptococcus pneumoniae, Neisseria gonorrhoeae and Neisseria meningitidis, at minimum concentrations of about -from -0.005 to 1 g / ml to 1 g / ml. bacteria such as Escherichia coli, Klebsiella pneumoniae, Serratia marcesceins, Entetrobacter sp., Proteus sp. indole + and indole -, Pseudomonas aeruginosa and Haemophilus influenzae, including against β-lactamase-producing strains, at minimum concentrations of <- 0.01 to 8 µg / ml. In vivo, by subcutaneous administration of mice, they are effective, for example, against enterobacteria as well as anti-other gram-negative and gram-positive microorganisms at minimum doses of ED50 <0.1 mg to 100 mg / kg. Accordingly, the novel compounds can be appropriately used, for example, in the form of antibiotic active agents for the treatment of infections caused by Gram-positive or in particular Gram-negative agents of infection, in particular infections caused by enterobacteria such as Escherichia coli, Klebsiella and Proteus (indole + and indole).

The compounds of formula I in which the functional groups are protected are used as starting materials for the production of antibiotic active compounds of formula I.

More particularly, the present invention relates to compounds of formula I wherein R1 is hydrogen, lower alkyl of 1 to 4 carbon atoms, lower alkanoyl of 1 to 4 carbon atoms, or 2-halogen (lower jalkanoyl of 1 to 4 carbon atoms) 4-carbon atoms, A represents methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene or methoxyiminomethylene, R 5 represents hydrogen or methoxy and R 2 is a leaving group cleavable under physiological conditions, and their pharmaceutically usable salts as well as the corresponding compounds thereof protected by functional groups.

Particular mention should be made of the compounds of formula (I) in which R1 is hydrogen as well as a 2-halo (lower) alkanoyl group having 1 to 4 carbon atoms in the lower alkanoyl moiety such as > 2-chloro [lower] alkanoyl A is hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene, R5 is hydrogen or methoxy

As described in the examples, their pharmaceutically usable salts, as well as the starting materials and intermediates described therein.

The compounds of the invention are prepared by methods known per se.

According to the invention, the compounds of formula (I) and their salts are prepared by forming a acetyloxymethyl group, a pivaloyloxymethyl group, a 1-ethyloxycarbonyloxyethylene group or a phthalidyl group, and a pharmaceutically usable group thereof in a compound of formula 1 ° and R 2 under physiological conditions. salts, as well as corresponding compounds with protected functional groups.

In particular, the invention relates to compounds of the formula

RjHN

in which

R1, A and R1 have the meanings given in Formula I or in its reactive functional. of a derivative, optionally in reactive form, the carboxyl group present in the 4-position of the cephem ring by esterification with an esterified carboxyl group —COOR2, wherein R2 is as defined above, whereupon optionally the R1, R2 or A residue is converted to another R1 , R2 or A, and / or the compound of formula I obtained is optionally converted into a salt or the obtained salt is converted into a free compound of formula I or another salt.

The esterification of the free carboxyl group or its reactive functional derivative at the 4-position of the cephem ring in the compound of formula 1 is carried out in a manner known per se, optionally with the protection of other functional groups.

Thus, esters are obtained, for example, by reacting the free carboxyl group -COOH with a suitable diazo derivative, such as a diazof lower alkane, for example diazomethane or diazobutane, or a phenyldiazoph lower alkane such as diphenyldiazomethane, optionally in the presence of a Lewis acid such as boron trifluoride by reaction with an alcohol of formula R2-OH suitable for esterification in the presence of an esterifying agent such as a carbodiimide, for example dicyclohexylcarbodiimide, carbonyldiimidazole and further with N, N ^t -di'substituovanou on an oxygen atom or sulfur atom substituted isourea or isothiourea, wherein the oxygen or sulfur atom is substituted, for example, by a lower alkyl radical, in particular a tert-butyl radical, a phenyl (lower) alkyl radical or a cycloalkyl radical and the substituents on the nitrogen atoms N or N 'are for example a lower alkyl radical, particularly isopropyl, cycloalkyl or any other known and suitable esterification procedures such as the reaction of an acid salt with a reactive alcohol ester of formula R2-OH and a strong inorganic acid or a strong organic sulfonic acid. Further, acid halides such as acid chlorides (produced, for example, by the action of oxalyl chloride), activated esters [e.g., with N-hydroxy derivative of nitrogen-containing compound, lacquer with N-hydroxysuccinimide] or mixed anhydrides (obtained e.g. with lower alkyl esters of haloformic acid) ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride), can be converted by reaction with alcohols of formula R2-OH, optionally in the presence of a base, such as pyridine, to the esterified carboxyl group -COOR2.

In the compound having an esterified group of the formula —COOR2, this group can be converted to another esterified carboxyl group of the formula, for example 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone to 2-iodoethoxycarbonyl.

Advantageously, physiologically cleavable ester groups -COOR 2 are formed by any of the above methods.

The carboxyl group protected by an organic silyl or stannyl group may be formed in a manner known per se, for example by reacting compounds of the formula němž in which R 2 is hydrogen or salts thereof, for example alkali metal salts such as sodium salts, with a suitable a silylating or stannylating agent (see, for example, British Patent Specification No. 1,073,530, and Dutch Unexamined Patent Publication No. 67/1717 / .0.7).

The esterification reactions may be carried out in the presence or absence of an inert solvent such as an optionally halogenated hydrocarbon such as methylene chloride, benzene, chlorobenzene, an amide such as dimethylsulfoxide, nitrile such as acetonitrile or similar solvents, or optionally in excess of alcohol depending on the method used. between about -5 ° C and 10 ° C.

Additional operations:

The compound of formula (I) obtained can be converted to another compound of formula (I) by converting the radicals R 1, R 2 or A as defined above into other radicals R 1, R 2 or A. This applies in particular to the cleavage of protecting groups R 1 and but also additional variations of the rest of A.

In the compounds of formula I obtained in which the functional groups are protected, these groups, for example protected carboxyl, amino, hydroxy, mercapto and / or sulfo groups, may be known in a manner known per se, such as by solvolysis, in particular by hydrolysis, alcoholysis or acidolysis or by reduction, in particular by hydrogenolysis or by chemical reduction, optionally simultaneously or gradually released.

Thus, for example, a tertiary (lower alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group) can be converted to the free carboxyl group by hydrogen, optionally with the addition of a nucleophilic compound in the presence of a hydrogen atom in the presence of a hydrogen atom in the presence of a hydrogen atom. a catalyst such as a palladium catalyst.

Further, certain substituted benzyloxycarbonyl groups, such as 4-nitrobenzyloxycarbonyl, can also be converted to the free carboxyl group by chemical reduction, for example by treatment with an alkali metal dithionite, for example sodium dithionite, or by a reducing active metal, for example zinc or a metal salt, as chromium salts, for example chromium chloride, usually in the presence of a hydrogen releasing agent, which together with the metal allows the production of a nascent hydrogen, such as an acid, in particular acetic acid, as well as formic acid, or an alcohol, preferably water. By the action of the reducing-active metal or metal salt as described above, the 2-halogen (lower) alkoxycarbonyl group (optionally after conversion of the 2-bromo (lower jalkoxycarbonyl group) to 2-iodo (lower alkoxycarbonyl) or acylmethoxycarbonyl group) the polyhalogenaryloxycarbonyl group, such as pentachlorophenyloxycarbonyl, is saponified under mild basic conditions, such as by dilute sodium hydroxide solution or organic bases in the presence of water, to the carboxylate under mild basic conditions in the presence of water group.

The carboxyl group protected, for example, by silylation or stannylation, can be released in a conventional manner, for example by treatment with water or an alcohol.

The protected amino group is liberated in a manner known per se and depending on the type of cover group differently, for example by solvolysis or reduction, 2-Halogen (lower) alkoxycarbonylamino (optionally after conversion of 2-bromo (lower) alkoxycarbonyl to 2-iodo (lower) alkoxycarbonyl acylmethoxycarbonylamino or 4Hnitrobenzyloxycarbonylamino can be carried out, for example, by treatment with a suitable chemical reducing agent, such as zinc in the presence of aqueous acetic acid, aroylmethoxycarbonylamino, also by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxide for example sodium dithionite, diphenylmethoxycarbonylamino, tert. (lower) alkoxycarbonylamino or polycycloalkoxycarbonylamino by treatment with, for example, formic or trifluoroacetic acid, optionally substituted hydroxy, for example by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst, such as a palladium, amine, triaryl, by hydrolysis or alcoholysis and thus released. A 2-haloacetyl group, such as a 2-chloroacetyl group, can be released from the resulting condensation product by treatment with thiourea in the presence of a base or with thioxide as the thiourea alkali metal thioxide, followed by solvolysis such as alcoholysis or hydrolysis.

The hydroxy group protected by an acyl, silyl or stannyl group or an optionally substituted α-phenyl (lower) alkyl group is released as a correspondingly protected amino group. The hydroxy group protected by the 2-oxa- or 2-thiaaliphatic or -cycloaliphatic hydrocarbon radical is released by acidolysis.

The protected sulfo group is released analogously to the protected carboxyl group.

The protecting groups may be chosen so that all of them can be simultaneously cleaved, for example acidolytically, such as with trifluoroacetic or formic acid, or reductively, such as with zinc and glacial acetic acid, or with hydrogen and hydroge216938 of a tannic catalyst, such as palladium on carbon. of the catalyst.

By selecting suitable reaction conditions, the capping groups can also be removed selectively. For example, a diphenylmethoxycarbonyl group can be converted to a free carboxyl group by treatment with trifluoroacetic acid at 0 ° C, while the present tert-butoxycarbonylamino group can be converted to a free amino group by the same reagent only at a higher temperature, e.g. .

The cleavage reactions described are otherwise carried out under known conditions, optionally with cooling or heating, in a closed vessel and / or in an inert gas atmosphere, for example under a nitrogen atmosphere.

In the compound of formula I obtained, the hydroxymethylene group A can be oxidized to an oxomethylene group. The oxidation can optionally be carried out with the protection of the free amino and carboxyl groups in a manner known per se, i.e. in a manner known for the oxidation of hydroxy groups to oxo groups. Suitable oxidizing agents are oxidizing oxides, such as manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium oxide, for example Jones reagent, or chromium oxide in the presence of acetic acid, sulfuric acid or pyridine, nitrogen dioxide, dimethylsulfoxide optionally in the presence of dicyclohexylcarbodiimide or oxygen, and peroxides, such as hydrogen peroxide, oxygen-containing acids, such as permanganic, chromic or chloric acid, or salts thereof, such as potassium permanganate, sodium or potassium dichromate or potassium hypochlorite. Hydroxymethylene group can be converted to a group also oxomethylenovou Oppenauer oxidation, i.e. with a salt of a sterically hindered alcohol, such as ^one or potassium tert-butoxide, aluminum isopropoxide or aluminum phenoxide or potassium · · in the presence of a ketone such as acetone, cyclohexanone or fluorfenonu. Another possibility of converting a hydroxymethylene group to an oxomethylene group is by dehydrogenation, for example with Raney nickel.

Depending on the oxidizing agent, the oxidation is carried out in water or in a solvent which optionally contains water at temperatures from about 0 ° C to about 100 ° C.

In the compound of formula (I) in which A is an oxomethylene group, this group can be converted, optionally with functional protection, by hydroxylamine, O-protected or O-carbamoylated hydroxylamine or O-methylhydroxylamine to a hydroxyliminomethylene group in which the hydroxy group is present in an optionally protected or carbamoylated form, optionally on a methoxyiminomethyl group.

The reaction of the oxomethylene group with the hydroxyamine derivative is carried out in a conventional manner, for example by reacting both reactants in a solvent such as water or in an organic solvent such as an alcohol such as methanol at a slightly elevated or reduced temperature, optionally an inert gas atmosphere, such as a nitrogen atmosphere. The hydroxylamine derivative may also be released in situ from one of its salts, for example a hydrohalide such as hydrochloride, by treatment with an inorganic base such as an alkali metal hydroxide such as sodium hydroxide or an organic base such as a tertiary amine such as tri (lower jalkylamine, such as triethylamine or ethyldiisopropylamine, or a heterocyclic tertiary base such as pyridine.

In the compound of formula I in which A represents a methylene group, the methylene group can be converted to a hydroxyimino group, for example, analogously to that described in Belgian Patent Specification No. 8,555,953, by nitrosation, the hydroxy group then, optionally, is protected, carbamoylated in a known manner or can be converted to the methoxy group by methylation. Furthermore, the methylene group A can be sulfonated to a sulfomethylene group, for example by treatment with a sulfur trioxide complex and dioxane, for example analogously to DOS No. 2-8,028.

Salts of the compounds of formula I can be prepared in a manner known per se. Thus, compounds of formula I with acidic groups can be converted into salts by treatment with metal compounds, such as metal salts of suitable carboxylic acids, for example sodium α-ethyl caproic acid or sodium bicarbonate, or with ammonia or a suitable inorganic amine, preferably a stoichiometric amount or only a small excess of the salt-forming agent. Acid addition salts of the compounds of formula I are obtained in a conventional manner, for example by reaction with an acid or with a suitable ion exchange resin. The internal salts of the compounds of formula I which contain a free carboxyl group can be formed, for example, by neutralizing salts, such as acid addition salts, to the isoelectric point, for example by treatment with weak bases, or by treatment with liquid ion exchangers.

These processes also include those embodiments in which they are used as. of the starting materials of the compounds obtained as intermediates and the missing process steps are carried out with these compounds or the process is interrupted at any stage. Furthermore, the starting materials can be used in the form of derivatives or can be formed in situ, optionally under reaction conditions.

The starting compounds of the formula 1 ° can be prepared, for example, by reacting

a) 7/3-amino group in the compound of formula (II);

R-HN— (|

dli

wherein the amino group is optionally substituted with an acylating group and a

R 2 and R 5 are as defined in formula I or 1 °, acylated by the action of an acylating agent, acyl radical of the carboxylic acid of formula III, ^R 1 ^NH -O-A-COOH (III) wherein:

R 1 and A are as defined in formula I and wherein the optionally present functional groups are present in protected form, or

(b) a compound of formula IV;

in which

X is halogen,

R 2, R 5 and A have the meanings given in formula I or 1 ° and in which the functional groups are optionally protected or the salt thereof condenses with the thiourea of the formula

Rt — NH — CS — NH2 wherein

R 1 is as defined in formula (I), or with a salt thereof, or (h) to produce a compound of formula (1 °) wherein R 3. represents a methoxy group, it is replaced in the compound of the formula · · in which

R 5 represents hydrogen or a group which is replaceable by methoxy,

R1, R2 and A have the meanings given in formula I or 1 °, and all functional groups are present in protected form, the residue Rs in the 7-position by methoxy, or

(i) for the preparation of a compound of the formula 1 ° in which A is a carbamoylated hydroxyiminomethylene or methoxy-aminomethylene group and in which R 1, R 5 and R 2 are as defined in formula 1 ° in a compound of formula I ",

in which

R 1, R 2 and R 5 are as defined in formula I or 1 °, carbamoylated or methylated hydroxyimino, or is used to produce a compound of Formula 1 where R 1 is hydrogen and wherein A, R 2 and R 5 are as defined under with the formula 1 °, cleaves from the compound of formula 1 °, wherein R 1 is an amino-capping group and A, R 2 and R 5 have the meanings given under formula 1 °, the amino-capping group R 1 and replaced with hydrogen;

1) for the preparation of a compound of formula 1 ° in which R 1, A and R 5 have the meanings below formula 1 ^o , in the obtained compound of formula 1 ° in which R 2 represents a carboxylic acid esterifying residue and R 1, A and R 5 are as defined above under the formula · 1 °, cleaves this residue Rž · and is replaced by hydrogen or a cation ·, whereas in the starting materials of formulas II, IV, 1 °, Γ and I ', the residue Rž does not need to be identical to the residue · R2 · The final product.

Procedure a)

Optionally present amino-substituting and acylating-permitting moieties in the starting material of formula II are, for example, organic silyl or stannyl groups, as well as yliene groups which together with the amino group form a Schiff base. Said organic silyl or stannyl groups are, for example, the same as those with

The 4-carboxy group on the cephem ring allows the formation of a protected carboxyl group. When silylating or stannylating a carboxy group in the starting material of formula II, an amino group can also be silylated or stannylated using an excess of a silylating or a stannizing agent.

Said ylidene groups are preferably arylmethylene groups in which the aryl is in particular a carbocyclic, in particular a monocyclic aryl radical, for example optionally substituted as a nitro or hydroxy substituted phenyl radical. Such arylmethylene groups are, for example, benzylidene, 2-hydroxybenzylidene or 4-nitrobenzylidene, further optionally, for example, carboxy substituted oxacycloalkyliidene, for example 3-carboxy-2-oxacyclohexylidene.

Acylating agents introducing an acyl residue of a carboxylic acid of formula (III) are, for example, the carboxylic acid itself or its reactive functional derivatives.

When the free acid of formula III is used as the acylating agent, in which all functional groups except the reacting carboxyl group are protected, suitable condensing agents such as carbodiimides, for example N, NMiethyl-, N, N'-dipropyl-, N, are usually used. , N'-diisopropyl-, N, N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole or isoxazolinium salts, for example N-ethyl-5-phenylisOxazolinium- 3'-sulfohate and N-tert-butyl-5-methylisoxazolinium perchlorate, or an acylamino derivative, for example 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.

The condensation reaction is preferably carried out in an anhydrous reaction medium, preferably in the presence of a solvent or diluent, for example methylene chloride, dimethylformamide, acetonitrile or tetrahydrofuran, optionally or, if necessary, with cooling or heating and / or an inert gas atmosphere.

The reactive, i.e., amide-forming or ether-forming functional derivative of the acid of formula III, in which all functional groups except the reacting acid moiety are protected or can be protected, is primarily the anhydride of such an acid, including and preferably mixed anhydride but also internal anhydride, i.e. the corresponding ketene. Mixed anhydrides are, for example, anhydrides with inorganic acids, such as hydrohalic acids, i.e. corresponding acid halogens, for example acid chlorides or bromides, further with hydrazoic acid, i.e. corresponding acid azides, with phosphorus-containing acids, e.g. with phosphorous acid, or with sulfur-containing acid, for example with sulfuric acid or with hydrocyanic acid. Further mixed anhydrides are, for example, anhydrides with organic carboxylic acids, such as optionally, for example halogen, such as fluorine or chlorine, substituted with lower alkanicarboxylic acids, for example with pivalic or trichloroacetic acid, or with semi-esters, in particular lower alkylpoloesters of carbonic acid; as with ethyl or ¹ with isobutylpolester of carbonic acid, or with organic, in particular aliphatic or aromatic sulfonic acids, for example with p-toluenesulfonic acid. From the acid of formula III, when A is a hydroxymethylene group, it is also possible to use a mixed internal anhydride with a semi-ester of carbonic acid of the α-hydroxy group.

Other reactive derivatives of the acid of formula III are activated esters, such as esters with vinyl alcohols (i.e. enols), such as vinyl lower alkenols, or arylesters, such as 4-nitrophenyl or 2,4-dintrophenyl esters, heteroaromatic esters such as benztriazole-, for example, 1-benztriazolesters, benztriazole-, for example, 1-benztriazolesters, or diacylamino ester, such as succinylimino or phthalyliminoesters.

The acylation with acid derivatives such as anhydride, especially acid halide is preferably carried out in the presence of an acid binding agent, for example an organic base such as an organic amine, for example a tertiary amine, such as tri (lower alkylamine, for example triethylamine, triethylamine or ethyldiisopropylamine, or N, N-di (lower) alkylaniline, for example Ν, Ν-dimethyhylamine, or a cyclic tertiary amine, such as * N- (lower) alkylated morpholine, such as N-methylmorpholine, or bases of the pyridine type such as pyridine, an inorganic base such as hydroxide, carbonate or bicarbonate · an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, potassium ,, calcium or · or ^one oxirane include low venule 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The abovementioned acylations are preferably carried out in an inert, preferably anhydrous solvent or in a solvent mixture, for example a carboxylic acid amide, such as a formamide, for example dimethyl, for example, a halogenated hydrocarbon, for example methylene chloride, carbon tetrachloride or chlor216938 benzene, ketone, e.g. acetone, in an ester, e.g. in ethyl acetate, or in a nitrile, e.g. in acetonitrile, or mixtures thereof, at room temperature, optionally at a reduced or elevated temperature, e.g. when, ^-4Ο: C to about 100 "C, preferably at -10 ° C - + 40 ° C and / or under inert gas, - for example in a nitrogen atmosphere.

In addition to the acid of the formula III or its acid derivative, which are intended for acylation, the protected amino group may also be present - in ionic form, i.e. the starting material of formula III - may be used in the form of an acid addition salt, preferably - a strong inorganic acid, such as a hydrohalic acid, for example hydrochloric acid, or sulfuric acid.

Furthermore, the acid derivative can, if desired, form an in situ. Thus, for example, a mixed anhydride is obtained by reacting an acid of formula II: i; or a suitably protected functional group or a suitable salt thereof, such as an ammonium salt, for example with an organic amine, such as 4-methylmorpholine, or a metal salt, for example an alkali metal salt, with a suitable derivative. acids, such as the corresponding halide acids, optionally substituted lower alkanecarboxylic acids, for example with trichloroacetyl chloride, or with a semiesterempolohalogenide, carbonic acid, for example with ethyl or isobutyl chloroformate, and the mixed anhydride thus obtained is used without insulation.

Procedure - b)

In the starting material IV, the radical X as halogen is in particular chlorine, but also bromine, iodine or fluorine. The thiourea is used in the form of a salt, in particular an alkali metal thioxide, such as lithium, sodium or potassium, or else in the form of an ammonium derivative thioxide, in an equivalent amount or in up to a six-fold excess. The compound of formula (IV) - which contains - acidic groups, for example R2 is hydrogen and when A is a sulfomethylene - group, can also be used in the form of a salt, for example in the form of a - alkali metal salt or - ammonium salts, for example in the form of lithium, sodium, potassium, tri (lower alkyl), such as tri-methyl or triethylammonium salts.

The reaction is generally carried out in a solvent such as water, or in an organic, non-reactive solvent, or ¹ - mixtures thereof. Suitable organic solvents are alcohols, such as methanol, ethanol, isopropanol, ketones such as acetone, ethers such as dioxan or tetrahydrofuran, nitriles such as acetonitrile, halogenated hydrocarbons such as meithylene chloride, chloroform or carbon tetrachloride, esters such as ethyl acetate, or amides, such as dimethylformamide or dimethylacetamide, and the like. The reaction may be carried out in the presence of a base, when the free compounds are used. Suitable bases are alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates such as sodium carbonate or potassium, or organic tertiary nitrogen bases such as tri (lower) alkylamines, for example trimethylamine, triethylamine, ethyldiisopropylamine, pyridine and the like. The reaction temperature is about room temperature, but may be higher or lower, preferably - between -10 ° C and + 10 ° C, especially between 0 and 40 ° C.

The reaction can also be carried out in a stepwise manner, by first forming the intermediate ring-opened intermediate of the formula:

R1-NH-C- (- = NH) -S-CH2-CO-A, which is then dehydrated in the second step.

Procedure (h)

The 7a-methoxy group Rs can be introduced in a manner known per se in a manner known per se into the compound of the formula I in which R 5 represents hydrogen or a group which is replaceable by methoxy and all functional groups are present in protected form.

For example, the compound in which R 5 is hydrogen can be treated sequentially with an anionic reagent, an N-halogenating agent and methanol to introduce a methoxy group.

A suitable anion-forming agent is in particular an organometallic base, in particular an organometallic base, in which the metal is an alkali metal and in particular lithium. Such compounds are in particular the corresponding alkoxides, such as suitable lower lithium alkoxides, in particular lithium methoxide, or the corresponding basic metal hydrocarbon compounds, such as lower alkanes and lithium and phenyllithium compounds. The reaction with the anion-forming orangocase is generally carried out with cooling, for example at about 0 ° C to about -80 degrees Celsius, and in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran, using lithium methoxide also in the presence. methanol, and optionally in a closed vessel and / or in an inert gas atmosphere, for example a nitrogen atmosphere.

As halogenating agents for nitrogen halogenation, sterically hindered organic hypohalites, in particular hypochlorite and in particular the corresponding aliphatic hypohalite, for example hypochlorite, such as hypohalite, (lower) alkyl, for example tert-butyl hypochlorite and non-isolated, are used. anion forming agent.

The intermediate halogenated on the nitrogen atom is converted to the reaction conditions and without isolation in the presence of an excess of anion-forming base, in particular lithium methoxide.

The 7-acyliminocephemerivative was converted to the 7α-methoxycephemerivative by addition of methanol. If necessary, residues of hydrohalic acid, especially hydrochloric acid, must be cleaved from the intermediate product which is halogenated at the nitrogen atom. This is done by adding a base leaving halogenovodfk as ^one suitable lower alkoxide, alkali metal ·, for example, lithium tert -butoxide, wherein the 'reaction is usually carried out under reaction conditions at which the forming anions and at which the formation of a compound halogenated at the nitrogen atom, working in the presence of methanol and instead of the acylimino derivative, the 7α-methoxycephemerivative can be obtained directly. Generally, starting from a compound of formula I wherein R 5 is hydrogen and the functional groups are present in protected form, this compound is reacted with an excess of anionic reagent, for example. with lithium methoxide or phenyllithium, in the presence of methanol, then treated with a nitrogen halogenating agent, for example tert-butyl hypochlorite, to directly obtain the desired compound of formula I wherein R 5 is methoxy and the functional groups are protected. Methane! You can also be added later, and it is possible dehydrohalogenation and the addition of methanol conducted at somewhat higher temperatures than reactions with anions and reactions in which form the compound halogenated at the nitrogen, for example at about 0 ° to about С --20 degrees Cei _S i _and and optionally in a closed vessel and / or in an inert gas atmosphere, for example a nitrogen atmosphere.

According to a further procedure, a methoxy group can be substituted for a compound of formula Γ in which R 5 is a methoxy-replaceable group.

Thus, the etherified mercapto group R5, in particular methylthio, can be replaced by a methoxy group in a manner known per se by the action of methanol in the presence of a mercuric, thallium, bismuth or leaded salt. Suitable salts are, for example, the corresponding acetates, trifluoroacetates, nitrates, fluorides, chlorides or bromides or also salts derived from other organic or inorganic acids. Mercury acetate and thallium nitrate are preferred. These salts are used in equimolar amounts, or in excess, up to about 10 times equimolar, based on the starting material of formula (I).

The reaction takes place in an excess of methanol, and other inert solvents such as tetrahydrofuran, methylene chloride or chloroform may also be added to improve dissolution. The reaction temperature is generally about 15-25 ° C, i.e. operating at room temperature, whereby cooling or heating can be performed to slow or accelerate the reaction.

Procedure i)

The carbamoylation or methylation of the hydroxyiminomethylene group A in the compound of formula I is carried out in a manner known per se by the action of a carbamoylating or methylating agent. In the starting material, in addition to the hydroxyimino group, any optional other functional groups are preferably protected.

Suitable carbamoylating agents are, for example, isocyanates of the formula Rd-NCO, wherein Rd is as defined above. Carbamoylation is carried out in the presence or absence of an inert solvent and optionally in the presence of a catalyst. Suitable inert solvents are, for example, ketones such as acetone, diethyl ketone or methyl ethyl ketone, nitriles, ethers such as diethyl ether, dioxane or tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide, esters such as ethyl acetate or halogenated hydrocarbons, such as benzene, toluene, chlorobenzene or methylene chloride, and similar inert solvents. Suitable catalysts are tertiary amines such as tri '(lower jalkylamines such as triethylamine, lower alkyl (lower cycloalkylamines such as N, N-dimethylcyclohexylamine, N, N-diethylcyclohexylamine, N-methyldicyclohexylamine, or cyclic amines such as N-methylmorpholine). ethylmorpholine, N-methylpiperidine or pyridine or tertiary diamines such as N, N, N ', N; -tetramethyl-1,3-propanediimine or N, N, N', N'-telramethyl-1,4- The carbamcylation reaction is carried out with cooling or heating at temperatures between about -30 ° C to about + 100 ° C, preferably about 10 to 50 ° C.

Suitable methylating agents are, for example, diazomethane, reactive methanol esters, such as methyl halides such as methyl iodide, sulfonic acid esters such as methanesulfonic acid methyl ester, trifluoromethanesulfonic acid, or p-toluenesulfonic acids, or sulfuric acid esters such as dimethyl sulfate, dimethylacetals such as 2.2 dimethoxypropane, orthoesters, for example, orthoformic acid trimethyl ester, trimethyloxonic acid salts, for example trimethyloxonium fluoroforonate, -hexachlorantimonate, · -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbonium magnesium salt, for example dimethoxorhexorphorium bromide, The methylation is carried out in a manner known per se, usually in an inert solvent, such as an ether, for example dioxane or tetrahydrofu. in the case of a halogenated hydrocarbon such as benzene, chlorobenzene, methylene chloride or similar solvents, optionally in the presence of suitable condensing agents such as bases or acids, with cooling or with heating, e.g. temperatures between about -20 ° C to about 100 ° C

Procedure j)

The cleavage of the amino-protecting group R 1 from the compound of formula I is carried out, if appropriate, selectively, in a manner known per se and depending on the type of the protecting group, by a different method, for example by solvolysis or reduction. The 2-halo (lower) alkoxycarbonyl group (optionally converting the 2-bromo (lower) alkoxycarbonyl group to the 2-iodo (lower) alkoxycarbonyl group), the acylmethoxycarbonyl group R 1 may be cleaved and replaced with hydrogen, for example by treatment with a suitable chemical reducing agent such as zinc in the presence of aqueous acetic acid, an aroylmethoxycarbonyl group can also be cleaved and replaced with hydrogen by treatment with a nucleophilic, preferably salt-forming agent such as sodium thiophenoxide, and a 4-nitrobenzyloxycarbonyl group can be cleaved and replaced with hydrogen with lower) an alkoxycarbonyl group or a polycycloalkoxycarbonyl group can be cleaved off and replaced with hydrogen by the action of formic or trifluoroacetic acid, or an optionally substituted benzyloxycarbonyl group can be cleaved and replaced hydrogen, for example by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst, a trialkylmethyl group can be cleaved and replaced with hydrogen by an aqueous mineral acid, and an organic silyl or stannyl group R 1 can be cleaved and replaced by hydrogen, for example by hydrolysis or alcoholysis. A 2-haloacetyl group, such as a 2-chloroacetyl group R 1, can be cleaved to form the condensation product by treatment with thiourea in the presence of a base or with a thioxide such as thiourea alkali metal thioxide and subsequent solvolysis such as alcoholysis or hydrolysis.

These solvolysis or reduction reactions are carried out optionally in the presence of a reaction solvent or an inert solvent under cooling or heating, for example at temperatures from -20 ° C to about 100 ° C.

Procedure 1)

Conversion of the esterified carboxyl group —COOR2, to cleave the esterifying moiety R @ 2, to the free or salt-present carboxyl group, i.e., wherein R @ 2 is hydrogen or a cation in the compound of formula Г, is carried out in a manner known per se, in particular by solvolysis , such as hydrolysis, alcoholysis or acidolysis, or reduction, such as hydrogenolysis or chemical reduction.

Thus, for example, a tertiary (lower) alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group may be converted to the free carboxyl group by treatment with a suitable acidic agent such as formic or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole. For example, an optionally substituted benzyloxycarbonyl group can be liberated by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst. Furthermore, certain substituted benzyloxycarbonyl groups such as 4-nitrobenzyloxycarbonyl can also be converted to the free carboxyl group by chemical reduction, for example by treatment with an alkali metal dithionite, for example sodium dithionite, or by a reducing active metal such as zinc or a metal salt such as chromium, chromium (III), usually in the presence of a hydrogen releasing agent, which together with the metal allows the production of a nascent hydrogen, such as an acid, in particular acetic acid, as well as formic acid, or an alcohol, preferably water. The 2-halogen (lower J-alkoxycarbonyl group (optionally after converting the 2-bromo (lower) alkoxycarbonyl group to 2-iodo (lower) alkoxycarbonyl)) or the acylmethoxycarbonyl group can also be converted by the action of the reducing metal or metal as described above. the aroylmethoxycarbonyl group can also be cleaved by treatment with a nucleophilic agent, preferably a salt forming agent such as sodium thiophenoxide or sodium iodide. in the presence of water, saponify to the free carboxyl group.

The carbonyl group protected, for example, by silylation or stannylation, can be released in a conventional manner, for example by treatment with water or alcohol.

In the case of hydrolysis under basic conditions or in the case of alcoholysis, a carboxylic acid salt can be obtained.

The reaction is carried out in the solvolysing agent itself, if it is a solvent, or optionally in an inert solvent or mixture thereof, depending on the method used, at a reduced or elevated temperature, for example at temperatures between about -50 ° C and 160 ° C.

The starting compounds of the formulas II and IV are known or can be prepared analogously to known processes.

Thus, the starting compounds of formula II in which R 3 is hydrogen are known from DOS 21 151 567. The starting compounds of formula II in which R 5 is methoxy or a convertible group can be prepared in a manner known per se, for example by introducing an etherified mercapto group into the compounds. of formula II, wherein R 3 is hydrogen, and by exchange of an etherified mercapto group for a methoxy group.

The starting compounds of the formula III are known, for example, from Belgian patents 8152 971 and 853 545, further from DOS 2 556 736 and 2 6318 626.

The starting compounds of formula IV can be prepared by acylating compounds of formula II with an acid of formula

X - CH 2 - CO - A - COOH or a reactive functional derivative thereof, for example analogously to process a).

The starting materials of formula I in which R 5 is a methoxy-replaceable group, in particular an etherified mercapto group, such as methylthio, required for process h) are conveniently prepared from the corresponding compounds of formula IV according to process b).

The pharmacologically usable compounds of the invention can be used, for example, for the manufacture of pharmaceutical compositions which contain an effective amount of the active ingredient together or in admixture with inorganic or organic, solid or liquid pharmaceutically acceptable carriers and which are suitable for enteral or parenteral administration.

For enteral administration, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricating agents, for example kieselguhr, talc, stearic acid or salts thereof, such as the magnesium or calcium salt of stearic acid, and / or polyethylene glycol. The tablets also contain binding agents, for example magnesium aluminum silicate, starches such as corn, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and optionally tablet disintegrating agents such as starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavors, and sweeteners. Suppositories are mainly emulsions or fat suspensions.

The pharmacologically active compounds according to the invention are preferably used in the form of injectables, for example intravenously or subcutaneously administered preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which compositions may be prepared prior to use, for example, from lyophilized preparations which contain the active ingredient alone or together with a carrier such as mannitol. The pharmaceutical preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. Pharmaceutical compositions which, if desired, may contain other pharmacologically valuable substances are prepared in a manner known per se, for example by conventional mixing dissolution or lyophilization processes, and contain about 0.1 to 100%, in particular about 1 to about 50% active ingredients, lyophilisates up to 100% of active ingredient. Depending on the type of infection, the condition of the infected organism, daily doses of about 0.5 g to about 5 g s.c. are used. to treat warm-blooded · weight of about 70 kg.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

R-values ⁽ for thin-layer chromatography:

DS: thin layer chromatography of finished silica gel plates SL 254 (manufactured by Antec, Birsfelden).

The solvent systems used have the following composition:

52A:

a mixture of n-butanol, glacial acetic acid and water (67: 10: 23),

67:

mixture of n-butanol, ethanol and water (40: 10: 50) (upper phase), 10 µl:

a mixture of n-butanol, pyridine, glacial acetic acid and water (38: 24: 8: 30),

1011 A:

a mixture of n-butanol, pyridine, glacial acetic acid and water (42: 24: 4: 30).

In aminothiazole-2-methoxyiminoacetic acid derivatives, the 2-methoxyimino group has a syn configuration.

Example 1

а) In solution, 1.14 g of 2- (2-chloroacetamido-4-thiazodyl) -2-methoxyiminoacetic acid in 15 ml of tetrahydrofuran is added at -10 ° C to 0.85 g of N, N'-dicyclohexylcarbodiimide and 0.56 g of 1-hydroxybenztriazole and at a temperature of about -5 to -10 ° C, the reaction mixture is stirred under a nitrogen atmosphere for 1 1/2 hours. After adding a solution of 1.0 g of 7/3 amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of tetrahydrofuran, the reaction mixture was first stirred at the same temperature for 1 hour and then stirred at room temperature for 4 hours. The reaction mixture was then filtered and the filtrate was evaporated in vacuo. The residue is taken up in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and then the filtrate is concentrated in vacuo. This residue is taken up in ethyl acetate and after stirring at room temperature. by filtration of the insoluble matter, the filtrate is again evaporated. Chromatography on silica gel using toluene with increasing proportions of ethyl acetate (up to 30 o / o) gives 7β- [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester .

DS: _Rf value ~ 0.57 (ethyl acetate)

IC spectrum (methylene chloride): absorption bands at

3350, 3-20Ό ^1, 178'2, 1770 (shoulder), 1724, 17015, 1684, 1540 cmi.

b) A mixture of 1.25 g of diphenylmethyl 7β- [2-] ester

(2-Chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, 12 mL of methylene chloride, 0.08 mL of anisole and 3.4 mL of trifluoroacetic acid was stirred for 30 minutes under ice-cooling. After the dropwise addition of 100 ml of diethyl ether, the reaction mixture was further stirred at the same temperature for 45 minutes. The precipitated N - [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetaimido] -3-cephem-4-carboxylic acid is filtered off, washed with diethyl ether and dried.

DS: _Rf value 0.37 (n-butanol: glacial acetic acid: water 67:10:23).

c) To a solution of 700 mg of N - [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in 17 ml of N, N'-dimethylacetamide is added 2) 60 mg of thiourea and the reaction mixture was stirred at room temperature for 19 hours. After addition of 2100 ml ^; of diethyl ether and decanting off the solvent, the precipitate obtained is washed with 100 ml of diethyl ether and dissolved in 25 ml of water. The cloudy solution was cooled with ice and the pH was adjusted to 7 by the addition of sodium bicarbonate. The precipitate was filtered off, washed with water and the filtrate and washings were transferred to a 180 ml column of Amberlite XAD-2 ^U. This column was washed with water and then with a 85: 15 mixture of water and isopropanol. Fractions containing 7 / 3- [2- (2-amino-4'-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt the acids are combined and evaporated. The sodium salt is then triturated with acetone, filtered off and dried.

DS: ~ R value _of 0.19 (n-butanol: glacial acetic acid: water 67 '10: 2i3).

UV spectrum (in ethanol):

Λmax = 21 »3 nm (ε = 15,500) and 200 nm (wide) (ε –5,500).

Example 2

(a) To a solution of 3,31 g of 2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 35 ml of tetrahydrofuran, add 1,50 g of 1-hydroxybenztriazole and 2,27 g of N, N '^; -dicyclohexylcarbodiimide and the reaction mixture was stirred at 0 ° C for 2 hours. A solution of 3.66 g of 7/3-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 45 ml of tetrahydrofuran was added to the reaction mixture, and the reaction mixture was further stirred at 0 ° C for 1 hour and at room temperature for 4 hours. The precipitated urea is filtered off, the filtrate is concentrated in vacuo and the residue is treated with ethyl acetate, citrate buffer, saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution. Drying of the organic phase with sodium sulfate, evaporation in vacuo, column chromatography of the crude product on silica gel using toluene / ethyl acetate (4: 1) as eluent, and crystallization of the purified product from methylene chloride / diethyl ether gave 7β- [2- (2) diphenylmethyl ester. tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, m.p. 154-157 ° C.

DS: _Rf value = 0,3i7 (toluene: ethyl acetate (1: 1).

UV spectrum (in ethanol)

Λ max = 2'34 nm (ε = 15,500), 295 nm (arm).

IC spectrum (in methylene chloride): absorption bands at

3400, 1792, 1775 (shoulder), 1728, 1680, 1640, 1545 cm ^-1 .

Example 3

To a solution of 840 mg of 2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 9 ml of methylene chloride and 0.26 ml of pyridine at -15 ° C is added 0.5 ml of diethylphosphorobromidate at -15 ° C and the reaction mixture was stirred at this temperature for 30 minutes. After addition of 1.00 g of N, N-amino-3-cephem-4-carboxylic acid diphenylmethyl ester at -15 ^° C, the reaction solution is stirred at room temperature for 2 hours, then diluted with chloroform, washed successively with dilute sulfuric acid, water, aqueous sodium bicarbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography using toluene / ethyl acetate (1: 1). The compound described in Example 2 was obtained.

Example 4

A solution of 15.0 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester in 75 ml of methylene chloride and 75 ml of trifluoroacetic acid is stirred 1 hour at room temperature, then cold toluene is added and the mixture is evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried. Obtained light beige, powdered 7β- [2- (2216938

(amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is suspended in 90 ml of water. The pH of the suspension was adjusted to 7.1 by the addition of 2N sodium hydroxide. The solution is filtered and the clear filtrate is chromatographed on 1200 ml of "Amberlite XAD-2". Elution with a mixture of water and 15% isopropanol and lyophilization of the combined fractions containing the desired product yields a slightly yellowish sodium salt of N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid. .

IC spectrum (in nujol):

characteristic absorbent bands at

3‘300i (wide), 1770, 167'0 '(wide), 1600, 1532, 1460 cm-1

A solution of 100 mg of the sodium salt obtained in 5 ml of water was adjusted to pH 3.5 by addition of 0.5 N hydrochloric acid. The precipitated N - [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed extensively with water and acetone and dried under vacuum.

Example 5

A solution of N - (2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido) -3-chloro-4-carboxylic acid diphenylmethyl ester (3.3 g) in methylene chloride (35 ml) was stirred with trifluoroacetic acid (15.4 ml). The reaction mixture was stirred at room temperature for 30 min at 0 ° C, cold toluene was added and the mixture was evaporated in vacuo, digested with diethyl ether, filtered and dried, the yellow powder obtained was dissolved in 10 mL of methanol, added with methanolic solution. sodium ethylhexanoate, and to complete the precipitation of diethyl ether and the mixture was stirred under ice-cooling for 1 1/2 hours, and the obtained N- (2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido) -3- The 4-carboxylic acid was filtered off, washed well with diethyl ether and dried.

DS: ~ R value _of 0.47 (n-butanol: acetic acid: water 67: 10 ': 23).

UV spectrum (in water):

Λ _max = 233 nm (ε = 15,500), 290 nm (arm).

To convert to the free acid, 1.5 g of the sodium salt obtained is suspended in ethyl acetate and this suspension is acidified with 2N hydrochloric acid. The organic phase was washed with water and brine, dried and evaporated in vacuo. The residue was chromatographed on silica gel (deactivated with 5% water) using methylene chloride, methylene chloride / ethyl acetate (increasing from 10 to 50%) and finally pure ethyl acetate. The obtained N- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyimino-acetamido] -3-cephem-4-carboxylic acid is recrystallized from a mixture of methanol, diethyl ether and hexane. Melting point about 21 ° C (decomposition).

DS: ~ R value _of 0.42 (using a solvent-dumping system 52A).

UV spectrum (in ethanol):

A _niax = 2i60nm (ε = 1688Ο),

232 nm (£ = 19,900)

224 nm (ε = 20 ° C).

IR (nujol): absorption bands at

3370, 3180, 1782, 1718, 1654 сиг ^first

Example 6

A mixture of 2.25 ml of chloromethyl pivalate and 9.0 g of sodium iodide in 30 ml of acetone was stirred at room temperature for 3 hours. A solution of 2.6 g of N - [2- (2-tert-butoxycarbonylamino-4-thiazolyl) - ^: 2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 50 ml of dimethylformamide is added to the mixture. After concentrating in vacuo, the residue was dissolved in ethyl acetate and the solution was washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the crude product obtained after evaporation in vacuo was chromatographed on silica gel. toluene, which contains 20-30% ethyl acetate, yields pivaloyloxymethyl ester of N- (2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid.

DS: R _f = C 16.6 (in ethyl acetate).

UV spectrum (in ethanol): λmax-23-4 nm (λ = 1600), 293 nm (shoulder).

IR spectrum (in methylene chloride): absorption bands at

3360, 1789, 1773 (shoulder), 1725, 1680, 16318, 1545 cm ^-1 .

Example 7

To a solution of N - [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carbonyl-pivaloyloxymethyl ester in 8.7 ml of methylene chloride was added. 8.7 ml of trifluoroacetic acid are added and the mixture is stirred at room temperature for 1 hour. After addition of cold toluene, the reaction mixture was evaporated in vacuo. The residue is stirred with a 1: 1 mixture of diethyl ether and hexane, filtered off and dried. The brown powder obtained is taken up in ethyl acetate, the ethyl acetate solution is washed with cold saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried in a high vacuum. vacuum. The obtained 7-3- [2- (2-amino-4-thiiazolyl) -2-methoxy-oxoacetoamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester decomposes from about 13 ° C.

DS: Rf ~ 0.28 (in ethyl acetate). UV spectrum (in ethyl acetate):

Λmax = 235 nm (ε = 16-32'0 ·), 295 nm (shoulder ·).

Spectrum (in methylene chloride): characteristic absorption bands at

3480, 33'90, 3330, 1782, 1753, 1680, 1620, 1530 cm @ -1.

Example 8

A mixture of 0.11 ml of chloromethyl pivalate and 0.45 g of sodium iodide in 1.5 ml of acetone was stirred at room temperature for 3 hours. To this suspension was then added 0.2Ci 2 g of 7H-2- (2-thiazol-4-thiazolyl) -2-methoxyethoxyimino [eta] < 3 &gt; -cyclohexyl] -3-cepham-4-carboxylic acid sodium salt in 3 ml of dimethylformamide and stirred for 3 hours at room temperature. The reaction was then diluted with ethyl acetate, shaken with aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel using a mixture of toluene and ethyl acetate (1 L = 1) and ethyl acetate as eluent to give -7- 2- (2-amloo-4-thlazolyl) -2-methoxyiminoacetamite to] -S- carboxylic acid.

Example 9

A capsule containing 0.230 g of 7 / 3- [2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cepentanecarboxylic acid pivaloyloxymethyl ester is prepared as follows:

Composition (for 100000capsules):

pivaloyloxymethyl ester N- [2- (2-amino-4-thiazolyl) t-2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid 25 000 g wheat starch 2Ό00'g magnesium stearate 1000 g

Plvaloyloxymethyl 7H-2 - [(4-amino-4-thiazolyl) -1-methoxyiminoacetamido] -3-trifluoromethyl-4-carboxylic acid, wheat starch and magnesium stearate are mixed well and filled into size # 1 capsules.

Example - 10

Capsules containing 7-p- [2-amino-4-hiazolyl) -2-methoxyiminoacetamido] -tetrafluoro-4-carboxylic acid pivaloyloxymethyl ester are prepared as follows:

Composition (for 2000 capsules): pivaloyloxymethyl ester 7 / 3- (2- (2-Amino-d-thiazolyl) -1-methoxyiminoacetic amido] -3-cephem-4-carboxylic acid polyvinylpyrrolidine corn starch magnesium stearate salt

The N- [2- (2-thiool-4'-thiazolyl) -2-methoxyminoacetamido] -3-methyl-4-carboxylic acid plvaloyloxymethyl ester is moistened with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol, sieved through a 3 mm sieve and dried under reduced pressure. at 40-50 ° C. - The granulate is then passed through a 0.8 mm sieve, maize starch and magnesium stearic acid salt are added, mixed - and the mixture is filled into - retractable capsules (size 0).

Claims (7)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of N-aminothiazolylactylether-dot-3-tert-4-carboxylic acid derivatives of the general formula I, wherein: R1 is hydrogen, (C1-C4) -alkyl or acyl of up to 18-carbon atoms or mono-, di- or triphenylmethyl, A methylene or amino, hydroxy, sulfo, oxo or, optionally, carboxymethyl of up to 11 carbon atoms or methoxymethyl substituted methylene, R 3 is hydrogen, methoxy, or an alkylthio-substituted alkylthio group having a methoxy group; (1-6C) atoms, tolylthio or phenylthio; and R 2 carboxyl group esterifying an alkyl moiety of from 1 to 7 carbon atoms, adaman (!) 216838 tulyl, phenylmethyl, wherein the phenyl is represented by one or two optionally C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen substituted benzoylmethyl radical, polyhalophenyl radical, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl. C1 -C4 alkanoyloxymethyl radical, C1 -C4 alkanoyloxymethyl radical; (C 1 -C 4) alkanoyl moiety, (C 1 -C 4) alkoxycarbonyloxymethyl, (C 1 -C 4) alkoxycarbonyloxyethyl, (C 1 -C 4) alkanoylthiomethyl radical, alkanoylaminomethyl radical (C 1 -C 4) alkanoyl optionally substituted by halogen, benzoylaminomethyl, phthalidyl, (C 1 -C 4) alkoxymethyl, A 2-aminoalkyl radical having 1 to 4 carbon atoms in the alkyl moiety or a 2-aminocycloalkyl radical having 3 to 8 carbon atoms in the cycloalkyl moiety wherein the amino group is substituted by two alkyl radicals having 1 to 4 carbon atoms or. an alkylene group having from 2 to 2 carbon atoms ^; 8 carbon atoms optionally containing an oxo group and salts of such compounds having salt-forming groups, characterized in that in the compound of the general formula Γ, a °} in which: R1, A and R5 have the meanings given in formula I, or, in the reactive functional derivative thereof, the optionally present reactive form will convert the carboxyl group present in the 4-position of the cephem ring by esterification to an esterified carboxyl group - C-OOR2; and optionally converting the radical R 1, R 2 or A into another radical R 1, R 2 or A in the compound of formula I obtained, and / or converting the compound of formula I optionally to a salt or converting the obtained salt into a free compound of formula I another salt. Ϊ. The method of item 1 for the preparation of compounds of formula I wherein R 3 is hydrogen or methoxy, R 2 is as defined in item 1, A is methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene or. methoxyiminomethylene and R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl or C 1 -C 4 haloalkanoyl, and salts thereof, characterized in that, in a compound of the formula: 1 ° or in a salt thereof, wherein R 1, A and R 3 are as defined above, will convert the optionally present 4-carboxy group in the form of a salt by treatment with an esterifying agent such as R 2 -diazoderivative, alcohol R 2 -OH or its active derivative; R2 is as defined above, to the esterified carboxy group -COOR2. where R? is as defined above, and in the compound of formula I obtained, undesired protecting groups are cleaved, and / or in the compound of formula I obtained, the esterified carboxy group is converted to the otherwise esterified carboxy group -COOR2 and / or the compound of formula I obtained. to a pharmaceutically acceptable salt. 3. A process according to claim 1 for the preparation of compounds of formula I wherein R3 is hydrogen or methoxy, R2 is a physiologically cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalidyl group and A is hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene R 1 represents hydrogen or a 2-haloalkanoyl group having 1 to 4 carbon atoms, as well as salts thereof, characterized in that it is a compound of general formula. of formula 1 °, wherein R 1, A and R 5 are as defined above, or a salt thereof, such as an alkali metal salt, for example a sodium salt, is treated with an esterifying agent, in particular an acid halide, and unwanted protecting groups are cleaved and / or recovered. the compound of formula I is converted to an otherwise esterified carboxy group -COOR2, and / or the compound of formula I obtained is converted to a pharmaceutically acceptable salt. 4. A process according to claim 1 for the preparation of N, N-aminothiazolylacetamido-3-cephem-4-carboxylic acid derivatives of the general formula I wherein R5 is hydrogen, R1 is hydrogen, C1-C4 alkyl, acyloalkyl. A is methylene or amino, hydroxy, sulfo, oxo, hydroxyimino or methoxyimino substituted methylene, and R2 is a carboxyl group esterifying an alkyl group having 1 to 7 carbon atoms, or a mono-, dine or triphenylmethyl group; carbon atoms, adamantyl radical, phenylmethyl radical in which the phenyl is represented by one or two optionally C1 -C4 alkyl, C1 -C4 alkoxy, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen substituted benzoylmethyl a polyhalogenphenyl radical, C1 -C4 alkoxy, alkyl (C1 -C4) and / or halogen substituted silyl or stannyl radical, (C1 -C4) alkanoyloxymethyl radical, (C1 -C4) alkanoyloxymethyl radical, (C1 -C4) alkanoyl radical, phthalidyl radical or 1-ethyloxycarbonyloxyethyl radical, and salts of such compounds having salt-forming groups, characterized in that the optionally present 4-carboxy group in the reactive functional derivative of this compound is converted into a compound of the formula 1 ° in which R 1, R 3 and A are as defined above with an esterifying agent on the esterified carboxyl group, whereupon optionally the residue R 1, R 2 is converted in the compound of formula I obtained; or A to another radical R 1, R 2 or A, or the poorly obtained compound of formula I is converted to a salt or the obtained salt is converted to a free compound of formula I or to another salt. 5. The process according to item 1 for the preparation of 7-aminothiazolylacetamido-3-cephem-4-carboxylic acid derivatives of the general formula I in which R5 represents hydrogen, R1 hydrogen, C1-C4 alkyl or acyl of up to 18 atoms. A is methylene or amino, hydroxy, sulfo, oxo, hydroxyimino or methoxyimino substituted methylene and R2 is a carboxyl group esterifying an alkyl radical of 1 to 7 carbon atoms, adamantyl a phenylmethyl radical in which the phenyl is represented by one or two optionally C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen-substituted benzoylmethyl radical, polyhalophenyl radical , (C 1 -C 4) -alkyl, and C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radicals, C 1 -C 4 alkanoyloxymethyl radicals, C 1 -C 4 aminoalkanoyloxymethyl radicals, C 1 -C 4 alkanoylcarbonyloxymethyl radicals alkanoyl moiety, C 1 -C 4 alkoxycarbonyloxyethyl, C 1 -C 4 alkanoylthiomethyl moiety, C 1 -C 4 alkanoylaminomethyl moiety, C 1 -C 4 alkanoyl moiety optionally substituted with halogen, benzoylaminomethyl, phthalidyl, C 1 -C 4 alkoxymethyl, C 1 -C 4 aminoalkyl or C 3 -C 8 2-aminocyctoalkyl radical; amino substituted with two lower alkyl radicals having 1 and or 4 to 8 carbon atoms or an alkylene radical having 2 to 8 carbon atoms, optionally containing an oxo group, and salts of such compounds having salt-forming groups, characterized in that in the compound of the formula 1 ° in which R 1, R 5 and A have the meanings indicated under the formula I, or in a reactive functional derivative thereof, optionally in reactive form, the carboxy group present in the 4-position of the cephem ring is converted by esterification to an esterified carboxyl group, whereupon optionally the R1, R2 or A residue R 1, R 2 or ¹ A and / or the compound of formula (I) obtained, respectively. converted to a salt; or * the salt obtained is converted to a free compound of formula I or ¹ to another salt. 6. The process of item 5 for the preparation of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester, characterized in that it is converted to the sodium salt. 7 / 3- (2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyimino acetamido) -3-cephem-4-carboxylic acid is treated with chloromethyl pivalate and sodium iodide. 7. A process according to claim 5 for the preparation of 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester, characterized in that 7 / 3- [2- (2-Amino-4-thiazolyl) -2-methyl-4-carboxylic acid-4-carboxylic acid sodium salt acts with chloromethyl pivalate and sodium iodide.