CS216937B2 - Method of making the derivatives of 7 beta-aminothiazolylacetamido-3-cefem-4-carboxyle 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

A methylene or amino, hydroxy, sulfo, oxo or optionally carbamoylated hydroxyimino having up to 11 carbon atoms or methoxyimino substituted methylene,

R @ 5 is hydrogen, methoxy or C1-C6-substituted alkylthio, tolylthio or phenylthio; and

R? hydrogen or a (C 1 -C 7) -alkyl-esterifying group, an adamantyl radical, a phenylmethyl radical in which 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 radicals, polyhaloigenphenyl radicals, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or / and halogen substituted silyl or non-stannyl radicals, C 1 -C 4 alkanoyl oxymethyl radicals C1 -C4 aminoalkanoyloxymethyl radical, C1 -C4 aminoalkanoyloxymethyl radical, C1 -C4 alkoxycarbonyloxymethyl radical, C1 -C4 alkoxycarbonyloxyethyl radical, C1 -C4 alkanoylthiomethyl radical in alkanoyl C 1 -C 4 alkanoylaminomethyl moiety in the alkanoyl group optionally substituted by halogen, benzoylaminomethyl radical, phthalidyl radical, alkoxymethyl radical of 1 to 4 carbon atoms in the alkoxy radical, 2-aminoalkyl radical 1-4 carbon atoms in the alkyl moiety or 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 x atoms; The carbon atoms optionally containing an oxo group and salts of such compounds having salt-forming groups.

The carbamoylated hydroxyiminoscuipine in residue A is a partial group of formula = N — O — C (= O) - NHRa in which:

Rd represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an arylalkyl group having 7 to 10 carbon atoms or an aryl group having 6 to 10 carbon atoms.

In particular, the alkyl group Rt is an alkyl group having 1 to 6 carbon atoms, such as a methyl, ethyl, propyl, butyl, pentyl or hexyl group. These groups may be straight or branched. Branched alkyl groups are, for example, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl or neopentyl groups.

The cycloalkyl group R 4 is a cycloalkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl.

The arylalkyl group R4 has 7 to 1 carbon atoms and is represented, for example, by benzyl-phenylethyl, phenylpropyl or phenylbutyl.

The aryl group R 4 has 6 to 10 carbon atoms and is, for example, phenyl or naphthyl.

The radical R1 is preferably ethyl, propyl, isopropyl, butyl, cyclohexyl and especially methyl.

The group R 5, which is replaceable by methoxy, is, for example, ethyl, propyl, butyl or, in particular, methylthio or also phenyl or p-tolylthio.

The radical R @ 2 esterifying the carboxyl group is preferably easily cleaved off. environmentally friendly, including physiological. Such radicals R2 are, for example, an alkyl radical having 1 to 4 carbon atoms, in particular a tert-butyl radical. An adiamamtyl radical, a phenylmethyl radical, in which the phenyl is preferably represented by one or two, optionally, for example tert-butyl, methoxy, hydroxy, halogen, for example chlorine ¹ , , Or or a nitro group, mononeb® · rivet residues. if any, for example, benzyl, such as 4-nitrobenzyl or 4-methoxybenzyls, or, for example, in the aforementioned manner, substituted as described above. substituted diphenylmethyl, for example, benzhyduyl, or di- (4-methoxyphenyl) methyl or 2'-haloalkyl-8-4-carbon atoms, for example 2 ', 2', 2-trichkioethyl], especially benzoylmethyl, wherein the benzoyl group preferably represents, optionally, for example, a halogen such as bromine, a substituted benzoyl group, for example phenacyl, or a polyhalophenyl such as pentachlorophenyl. In these groups, the silicon atom or the tin atom preferably contains, as substituents, an alkyl group having 1 to 4 carbon atoms, in particular a methyl group, furthermore an alk. C 1 -C 4 oxy, for example methoxy, and / or halogen, for example chlorine, suitable suitable protecting groups are, in particular, a trialkylsilyl group having 1 to 4 carbon atoms in the alkyl group, in particular. dimethyl-tert-alkyl-C1-4 alkoxyalkyl halogensilyl having 1 to 4 carbon atoms in the alkoxy and alkyl moieties, for example methoxymethylchlorosilyl, or dialkyl halogensyl having 1 to 4 carbon atoms in the alkyl, for example dimethyl chlorosilyl, e.g. or a correspondingly substituted stannyl group, for example tri-n-butyrstannyl.

Preferred protecting groups R @ 2 are, in particular, tert-butyl, optionally ¹ , for example as mentioned, substituted benzyl, for example 4-nitrobenzyl and diphenylmethyl.

The R 2 residue cleavable under physiological conditions imparts to the active carboixylic acids itself improved absorption upon araal administration and / or prolonged efficacy. Numerous such ester groups are known in the art of penicillins. And cephalosporins. Mention may be made, for example, of the groups C (= O-O-R2, where

R 2 represents a methyl group substituted with an acyl group, an acyloxy group, an acylthio group. An acylamino group with an etherified hydroxy group and optionally an additional organic moiety, wherein the methyl group may also be bonded to the carbonyl of the acyl group via a bridge containing atoms. Or i is 2-amino and phenyl. In such groups is the acyl radical of an organic carboxylic · 'about acids' up to 1'8 carbon atoms, and is constituted for example · optionally substituted by alkanoyl, cycloalkanoyl, aroyl, at heterocyklýíkτrbonyloVnu group, for example also heterOcyklylka · ^ι rbonylovnu carboxylic acid group ·. of formula I, or bioteoically. 'active. Penam-3- or cefern-4-carbonyl acids. The carbohydrate, or the acyl residues of the carbonic acid, and the ethyl ether of the hydroxy group in the methyl group, is a hydroxy group of ethyl ether. The alkyl moiety, in particular a lower alkyl moiety, is used. The organic radical optionally substituted with a methyl group contains up to 7 carbon atoms and is especially lower alkyl such as methyl or aryl such as phenyl. Said bridgehead carbon atoms contain 1 to 3, in particular 2, carbon atoms, so that a lactone, in particular γ-1-kton, is present. The aliphatic group in said 2-aminoaliphatic group may be aliphatic or cycloaliphatic in nature and may be saturated or unsaturated. The 2-amino group is preferably substituted by two lower alkyl groups or an alkylene group which optionally contains an oxo group. In such physiologically cleavable ester groups, -O (= O) -O-R 2 is

For example, a lower C 1 -C 4 alkanoyloxymethyl group such as an acetyloxymethyl or pivaloyloxymethyl group, an amino (lower C 1 -C 4 alkanoyloxy) group, in particular an α-amino (lower Jalkanoyloxymethyl) group. 1-4 carbon atoms in the alkanoyl moiety, for example, glycytoxymethyl, L-valyloxymethyl, L-leucyloixylmethyl, lower alkoxycarbonyloxymethyl of 1 to 4 carbon atoms in the alkoxy moiety or 1- (lower) alkoxycarbonyloxyethyl group containing 1 to 4 carbon atoms alkoxycarbonyl, for example 1-ethyloxykarbonylovou, lower alkanoylthiomethylovou · group having 1 to 4 carbon atoms in alkarioytové part, e.g. acetylthiOmethylovou or · · · plvkloylthio ^ι methyl group, a lower alka.noylaminomethylovou · group having 1 to 4 carbon atoms in the alkanoyl part in which he can C 1 -C 4 lower alkanoyl optionally substituted by halogen, such as chlorine, for example, acetylaminomethyl or 2,2-dichloroacetylaminomethyl, benzoylaminomethyl, or, for example, R 6 containing lactone phthalidyl, methoxymethyl, 2-aminoalkyl 1-4 carbon atoms, such as a 2-aminoethyl group, wherein the amino group is substituted by two lower alkyl groups having 1 to 4 carbon atoms or an alkylene group having 2 to 8 carbon atoms optionally containing an oxo group such as e.g. 2-dimethylaminoethyl, 2-diethylaminoethyl or 2- (1-morpholino) ethyl or 2-aminocycloalkyl of 3 to 8 carbon atoms, for example 2-dimethylaminocyclohexyl. Particular emphasis should be placed on acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl and phthalidyl.

Salts are in particular salts of compounds of the formula

Even with a free carboxyl group, in particular metal salts or ammonium or ammonium salts, such as alkali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or ammonium salts salts with suitable organic amines, the aliphatic, cycloaliphatic, cycloaliphaticaliphatic or araliphatic primary, secondary or tertiary mono-, di or polyamines as well as heterocyclic bases such as lower alkylamines, for example triethylamine, hydroxy ( lower Lalts of lamina, for example Zr-hydroxyethylamine, bis- (2-hydroxyethylthylamine or tris- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, for example 2-dlethylaminoethyl ester of 4-aminobenzoic acid, lower alkylenamines, for example cycloalkylamines, for example · dicyclohexylamine, or · benzylamines, for example N, N'-dibenzylethylenediam 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. acids such as trifluoroacetic acid as well as amino acids such as ¹ with arginine and lysine. The compounds of 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 of a zwitterionic ion.

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

Compounds of formula I in which the carboxy group is esterified optionally in physiologically cleavable form and the functional groups in residue A are present in an 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 effective against anti-gram positive. and Gram-negative bacteria such as Staphylαααccus aureus, Streptococcus pyogenes, Streptococcus faecalis, Streptococcuss pneumoniae, Neisseria gonorrhoeae and Neisseria · meningitidis, at minimum concentrations of about 0.005 · to 1 / 4g / ml, and against Gram negative; is Esoherichia coli, Klebsiella pneumoniae, Serratia marcescen, Enterobacter sp., Proteus sp. indole + and indole, Phoudomonas aeruginosa, and Haemophilus influenzae, including against lactamase-producing strains, at nin ^and other concentrations <0.011 to 8 µg / ml. In vivo, at subcutaneous administration to mice, they are effective, for example, against enterobacteria. as well as against other Gram-negative and Gram-positive microorganisms at minimum doses of ED 50 <0.1 mg to 100 mg / kg The novel compounds may therefore be used, for example, in the form of antibiotics, for the treatment of infections caused by Gram-positive or Gram-negative agents. , in particular infections caused by enterobacteria such as Escherichia coli, Klebsiella and Protnes (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.

In particular, the invention relates to compounds of formula I wherein A is methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene or methoxyiminomethylene, R 5 is hydrogen or methoxy and R 2 is hydrogen or a residue cleavable under physiological conditions, and their pharmaceutically acceptable useful salts, as well as corresponding compounds with protected functional groups.

Particular mention should be made of the compounds of formula (I) in which A is hydroxyimino-methylene, N-methylcarbamoyloxyiminomethylene or methoxyimino-methylene, R 5 hydrogen or methoxy and R 2 hydrogen or physiologically cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalicyl, as well as the corresponding compounds with protected functional groups.

In particular, the invention relates to the compounds of formula (I) described in the Examples, their pharmaceutically usable salts, as well as the starting materials and intermediates described therein.

Compounds of the invention are prepared by methods known per se ^one.

Thus, compounds of formula (I) are prepared by producing compounds of formula (1),

in which

R1 represents an acyl group of up to 18 carbon atoms, a mono-, di- or triphenylmethyl group or an organic silyl or stannyl group, and

A, R 2 and R 3 have the meanings given in formula I, cleaving the group: R 1 and replacing · with hydrogen, optionally converting the radical R 2 or A into ¹ other radical R 2 or A in the compound of formula I obtained; the compound of formula (I) is optionally converted into a salt or the resulting salt is converted into a free compound or another salt.

The amino protecting group R 1 is preferably an acyl group Ac, a mono-, di- or triphenylmethyl group, or a silyl group or a stannyl group.

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 acid, or semiester of carbonic acid. Such acyl groups are, for example, a lower alkanoyl group such as formyl, acetyl, propionyl, halogen (lower alkanoyl group, such as a 21-haloalkoacetyl group, especially 2-chloro, 2-bromo, 2-iodo). -, 2,2 - (-)

2, 2, 2-trichloroacetyl, phenylacetyl, phenoxyacetyl, thienylacetyl, benzoyl, 4-chloro, 4-methoxy or 4-nitrobenzciyl, lower alkoxycarbonyl, especially tertiary (lower) alkoxycarbonyl, for example tert-butyloxycarbonyl, polycycloalkoxycarbonyl, for example adamantyloxycarbonyl, arylmethoxycarbonyl in which aryl is represented by one or two, optionally, for example lower alkyl, in particular tert-lower alkyl, for example tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen such as chlorine and / or nitro, mono- or polysubstituted phenyl radicals ^{how! and} · a is optionally substituted benzyloxycarbonyl, for example 4 · nitrobenzyCoxykarbOnyl difenylmethoKykarbonyl or substituted, for example benzhydryloxycarbonyl or · di (4-methcxyfenyljmetoxxykarbonyl or 2-halogenjnižší) alУoχ · yУarbonyl, for example 2,2,2-ťrtchlorethoxyУarbon.yl, 2- chloroethoxycarbonyl, 2 _! 1- (10-o-methoxy) -carbonyl or 2-iodoethoxycarbonyl, or acylmethoxycarbonyl, in particular aroylmethoxycarbonyl, in which the aroyl group is preferably represented by, optionally, a.

for example, halogen, such as bromine, substituted with a benzoyl group, such as phenacyloxycarbonyl.

The silyl or stannyl group R 1 is preferably an organic silyl or stannyl group in which the silicon or tin atom is preferably substituted by a lower alkyl group, in particular a methyl group, further by a lower alkoxy group such as a methoxy group and / or a halogen such as chlorine. The corresponding silyl or stannyl groups are, in particular, a tri- (lower) alkylsilyl group, especially a trimethylsilyl group, furthermore dimethylteo-tert-butylsilyl, (lower) alkoxy (lower alkylhalo-silyl, for example methoxychlorosilyl, or di (lower) alkyl) halogensilyl, such as dimethylchlorosilyl, or a correspondingly substituted stannyl, such as tri-n-butylstannyl.

Preferred amino-protecting groups R @ 2 are acyl residues of 2-haloacetic acid, in particular 2-chloroacetyl, and semi-esters of carbonic acid, especially tert-lower alkoxycarbonyl, for example tert-butoxycarbonyl, optionally, for example, substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halo (lower C 1 -C 4 loweralkoxycarbonyl), such as 2,2'-trichloro-thiocarbonyl-1-carbonyl, as well as trityl.

The same amino protecting groups may be present in the protected amino group found in residue A.

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 cleavage of the amino protecting group R 1 from the compound of formula 1 ° is carried out, if appropriate, selectively, as is known per se, depending on the type of protecting group, by various methods, for example by solvolysis or reduction. 2-Haloalkoxy (lower) alkoxycarbonyl (optionally after conversion of 2-bromo (lower) alkoxycarbonyl to 2-iodo (lower jalkoxycarbonyl), acylmethoxycarbonyl or 4-nitrobenzyloxycarbonyl) The R 1 group can 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, and the aroylmothoxycarbonyl group can be cleaved and replaced with hydrogen also with a nucleophilic, preferably salt forming agent such as sodium thiophenoxide. and the 4-nitrobenzyl-oxycarbonyl group can be cleaved and replaced by hydrogen also by treatment with an alkali metal dithionite such as sodium dithionite, a diphonylmethoxycarbonyl group, a target (a lower jalkoxycarbonyl group or a polycycloalkoxycarbonyl group can be cleaved and replaced with a hydrogen) optionally substituted The benzyloxycarbonyl group can be cleaved and replaced with hydrogen, for example by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst, the trialkylmotyl group can be cleaved and replaced with hydrogen by the action of an aqueous mineral acid and an organic silyl or stannyl group R 1. cleavage and replace with hydrogen, eg by hydrolysis or alcoholysis. A--haloacetyl group, such as the 2i-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 thioid such as thiourea alkali metal thioxide and subsequent solvolysis such as alcoholysis or hydrolysis.

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

Additional operations:

The compound of formula I obtained can be converted to another compound of formula I by converting the radicals R @ 2 or A within the meaning defined above into other radicals R @ 2 or A. This applies in particular to the cleavage of the protecting groups R2 and the protecting groups in residue A, · 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, can be carried out in a manner known per se, such as solvolysis, in particular hydrolysis, alcoholysis or acidolysis. or by reduction, in particular hydrobromide or chemical reduction, optionally simultaneously or gradually released.

Thus, for example, a tertiary (lower) alkoxycarbonyl group, a polycycloalkoxycarbonyl group or a diphenylmothoxycarbonyl group can be converted to the free acid by treatment with a suitable acidic agent such as formic or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as o-phenol or anisole. carboxyl group. An optionally substituted benzyloxycarbonyl group can be liberated, for example, by hydrogenolysis with hydrogen in the presence of a hydrogenation catalyst such as a palladium catalyst. Furthermore, certain substituted benzyloxycarbonyl groups, such as a 4-mtrobonzyloxycarbonyl group, can also be converted to the free carboxyl group by chemical reduction, for example, by treatment with an alkali metal dithionite, for example sodium dithioate, or by reducing metal such as zinc. or a metal salt, such as chromium (III) salt, for example chloride, chromium, usually in the presence of a hydrogen releasing agent which, together with the metal, makes it possible to produce a nascent hydrogen such as acid, especially acetic acid and formic acid or alcohol preferably water is added. 2-h-allogen (lower Jalkoxycarbonyl) [optionally after conversion of the 2-bromo (lower Jalkoxycarbonyl group to 2-iodo (lower Jalkoxycarbonyl) group) by the action of the reducing metal or metal salt as described above or a acylmethoxycarbonyl group to be converted into: a free carboxylic acid group, wherein the aroyimethoxycarbonyl group is optionally cleaved by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophene oxide or sodium iodide. saponification to a free carboxyl group by treatment with a dilute sodium hydroxide solution or organic bases in the presence of water.

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. .

Protected amine (otaupinia) is released in a manner known per se and depending on the type of the protecting group differently, for example by solvolysis or reduction 2-Ha.logen (lower Jalkoxycarbonylamino group [optionally after conversion of 2-bnom (lower Jalkoxycarbonyl groups) 2-iodo (lower Jalkoxykarbonylovou group], a 'and c ^ ^ y ^ ' i ^ i ^ ⁱ ^ c Htoxxkart ^ r ^ y ^ divided ^ i ^ ii ^ <^ i ^ ^ l ^ i] · full or For example, the 4-nitrobenzyloxycarbonylamino group can also be treated by nucleophilic treatment with a suitable chemical reducing agent such as zinc in the presence of aqueous acetic acid, aroylmethylaminocarbonyl amino. , preferably salt-forming reagent, such as sodium thiophenolate, and ^{a-thread-robenzyloιxykarbonylam!} inoskupina treatment also dithionlčitanu sodium difenylmethoxykarbotnylaminoskupíina, tert. (lower] alkoxkkarbonylammoskupina or pxíycykIoalkox.ykarbrol.ylaminoskuplna působením- example formic or trifluoroacetic · · acidly optionally substituted benzyloxycarbonylamino, for example by hydrogenolysis with hydrogen in the presence of a hydrogenation agent ^; a catalyst such as a palladium catalyst, a triarylmethyl group, for example by treatment with an aqueous mineral acid, and an amino group protected with an organic silyl or stannyl group, for example, by hydrolysis or alcoholysis. 2í-HalxgeιnIace ^! The protected amino group can be liberated from the resulting condensation product by treatment with thiourea in the presence of a base or by treatment with thioxide. as an alkali metal thioxide of thiourea, followed by solvolysis, such as alcohol or hydrolysis.

The hydroxy group protected by an acyl, hyl or tert-naphthyl group or an optionally substituted α-phenynyl (lower) alkyl group is liberated as the correspondingly protected amino group, or a 2-oxa- or 2-thtaaliphatic or hydroxy-protected hydroxy group. The cycloialiphatic hydrocarbon residue is released by acidolysis.

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

The protecting groups may be chosen such that all of them can be cleaved simultaneously, for example by acidolysis, such as by treatment with trifluoroacetic or formic acid, or by reducing, such as by treatment with zinc and glacial acetic acid, or with hydrogen and a hydrogenation catalyst such as palladium-on-carbon catalyst.

By selecting suitable reaction conditions, the capping groups can also be removed selectively. For example, by dif · enylmethoιxykrrbonylovou group converted with trifluoroacetic acid at a temperature of ⁹ C, a free carboxyl group, while the coexistent terc.butoxkkaгbonklaminoskupina · · may be converted to the free · aminoiskupinu treatment with the same agent only at a higher temperature, for example room temperature, and optionally also for a longer reaction time.

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

The conversion of the free carboxyl group in the compound of formula (I) obtained into an esterified carboxyl group which is cleavable under physiological conditions is carried out by per se known esterification methods, for example by carrying out a compound of formula I in which other functional groups such as amino - ,. the hydroxy or silane groups are optionally present in a protected form or, as regards the carboxyl group to be esterified, a reactive functional derivative of the acid, or a salt thereof in reaction with the corresponding alcohol or a reactive functional derivative thereof, for example a halide, such as a chloride, and thereby esterified.

In the compound of formula I obtained, the hydroxymethylene group A can be oxidized to an oxomethyl group. The oxidation can be carried out, optionally, with the protection of the free amino group and the carboxy group, in a manner known per se, i.e. in a manner known per se, for the oxidation of the hydroxy groups to the oxo groups. Suitable oxidizing agents are oxidizing oxides, such as manganese, chromium, nitrogen or sulfur, such as manganese dioxide, chromium oxide, for example Joines' 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, acid-containing acids, such as permanganic, chromic or hypochlorous acid, or salts thereof, such as potassium permanganate, sodium or potassium dichromate or potassium hypochlorite. The hydroxymethylene group can also be converted to the oxomethylene group by Oppeinaueir oxidation, i.e. by treatment with a salt of a sterically hindered alcohol such as aluminum or potassium tert-butoxide, isopropoxide or aluminum or potassium phenoxide in the presence of a ketone such as acetone, cycloihexanone or fluoronone. 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 oxo-methylene group, this group can be converted into a hydroxylmiin-omiethylene- group in which it is optionally functionalized by treatment with hydroxyoxy, protected or O-carbamoylated hydroxylamine or O-methylhydroxylamine. the hydroxy group present in an optionally protected or carbamoylated form, optionally on a methoxyimino-methylene group.

The reaction of the oxomethylene group with the hydroxylamine 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 in an inert gas atmosphere such as a nitrogen atmosphere. The hydroxylaimine 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 teircamine such as tri [lower] an alkylamine such as triethylamine or ethyldiisopropylamine, or a heterocyclic tertiary base such as pyridine.

In the compound of formula (I) in which A is a methylene group, the tutomethylene group can be converted to a hydroxyimino group, for example analogously to Belgian patent specification 855 953, by nitrosation, whereby the hydroxy group is then optionally known per se by way of protection, carbamoylation or by methylation can be converted to methoxy. Furthermore, the methylene group A can be sulfonated to a sulfo-methylene group, for example by treatment with sulfur trioxide-dioxane complex, for example analogously to DOS 2,638,128.

Salts of the compounds of the 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, sodium, N-ethylcapro- bonic acid, or sodium bicarbonate, or with ammonia or a suitable organic amine. preferably a stoichiometric amount or only a small excess of the salt-forming agent is used. The 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 (amex). 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 with liquid ion exchangers.

These processes also include those starting with the compounds obtained as intermediates and carrying out the missing process steps with these compounds or interrupting the process 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 materials of the formula 1 ° can be prepared, for example, by reacting

a) 7-amino in the compound of formula II,

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

R2 and R5 are as defined in formula (I), acylated by the action of an acylating agent introducing an acyl carboxylic acid residue of formula (III),

A-COOH (III) wherein

R 1 and A are as defined in the formula

And wherein the optionally present functional groups are present in a protected form;

(b) a compound of formula IV;

? 3. x-CH ₂ CO-A-C ONH — 4-- 0> -γ COOR ₂

(IV) in which:

X is halogen,

R 2, R 5 and A have the meanings given below the formula. 1 °, and in which they are. the functional groups optionally protected, or the salt thereof is condensed with the thiourea of the general formula

R1 — NH — CS — NH2 in which

R 1 is as defined in Formula I, or with a salt of the compound, or with a salt thereof

(h) for the manufacture of a compound of formula (1) wherein:

Rs is methoxy, replacing the compound of formula 1 ° ^HN-CoNH4 JLa ^ ^ - ^ \

COOR _Z (1 °) in which

R 3 represents hydrogen or a group which is replaceable by methoxy,

R 1, R 2 and A have the meanings given in formula 1 ° above, in which all functional groups are present in protected form, the radical R 3 in the 7-position by methoxy, or

i) for the preparation of a compound of formula 1 ° wherein A is a carbamoylated hydroxyiminomethylene group or a methoxyethoxyiminomethylene group and in which R 1, R 2 and R 5 have the meanings given in formula I in compound ^{1 of the} general formula 1 °,

in which

R1, R2 and R3 have the meanings given above. under the formula 1 ° from above carbamoylated, optionally methylated, a hydroxyl amino group;

k] to produce a compound of formula Γ wherein Rž is a carboxyl esterifying moiety and R 1, A and R 3 have the meanings given by formula 1 °, · transforms into a compound of formula I wherein Rž is hydrogen, and · R 1, a and R have the meanings given under formula 1 ° above, the free carboxyl group at position 4 cefemovéího hu floe or a reactive functional derivative thereof, ^one mouth action of an esterification reagent to esterified carboxyl group, · or

1) to produce a compound of formula 1 ° in which R 2 is hydrogen and R 1, A and R 3 are as defined in formula 1 ° in a compound of formula 1 ° in which R 2 is a carboxylic acid esterifying moiety; A and R 5 are as defined in formula 1 °, cleave this residue R 2 and replace with hydrogen or a cation;

Procedure a)

Optionally present amino-substituting and acylating-permitting residues in the starting material of formula II are, for example, organic silyl or stannyl groups, as well as ylidene groups which together with the amino group form the S-chiff base. The organic silyl or stannyl groups mentioned are, for example, the same as those which, with the carboxy group on the cephem ring, allow the formation of a protected carboxyl group. When the carboxy group has the strength or the stinylation of the carboxy group in the starting compound of the formula II, it can also be silylated or stannily and measured by using an excess of a silylating or stannylating agent.

Said ylidene groups are, in particular, -arylmethylene groups in which the aryl is in particular a carbocyclic, in particular a mino-nocyclic aryl radical, for example optionally substituted by 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 oxacycloalkylidene, for example carboxy-2-oxacyclohexyl humans.

Acylating agents introducing an acyl radical 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, e.g.

N, N'-diethyl-, N, N'-dipropyl-, Ν, Ν, -diisopropyl-, N, N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropylcarbodiimide, suitable carbonyl compounds, e.g. carbonyldiimidazole or isoxazoline salts, for example

N-ethyl-5-phenylisoxazolium-3'-sulfononate and N-tert-butyl-5-methylisoxazolinium imperate, or as amine oderate, 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, or, if necessary, with cooling or heating and / or inert atmosphere. gas.

The reactive, i.e., amide-forming or ester-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 preferably mixed anhydride but also internal anhydride, i.e. the corresponding ketone. Mixed anhydrides are, for example, anhydrides with inorganic acids, such as hydrohalic acids, i.e. corresponding acid halides, for example acid chlorides or bromides, further with azidic acid, i.e. corresponding acid azides, with phosphorus-containing acids, for example phosphoric or phosphorous acid, or with a sulfur-containing acid such as sulfuric acid or hydrocyanic acid. Other mixed anhydrides are, for example, anhydrides with organic carboxylic acids, such as optionally, for example, halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, for example pivalic or trichloroacetic acid, or with semiconductors, especially lower alkylpoiloesters of carbonic acid, such as with ethyl or isobutylpolester of carbonic acid, or with organic, in particular aliphatic or aromatic sulfonic acids, for example with p-toduenesulfonic 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 .alpha.-hydroxy carbonic acid semi-ester.

Other reactive derivatives of the acid of formula III are activated esters, such as esters with vinyl alcohols (i.e. enoils), such as vinyl lower alkenols, or aryl esters, such as 4-nitrophenyl or 2,4-dmitrophenyl esters, heteroaromatic esters such as benztriazole, for example 1-benztriazolesters, benztriazole-, for example 1-benztriazolesters, or diacyliminoesters, such as tin (III) or phthalyliminoesters.

The acylation with an acid derivative, such as an anhydride, in particular an 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 trimethamine, triethylamine or ethyldiisopropylamine , or N, N-di (lower j-alkyl lamine, for example N, N-dimethylaniline, or a cyclic tertiary amine such as N- (lower J-alkylated morpholine such as * N-methylmorpholine) or a pyridine type base such as pyridine, an inorganic base such as an alkali or alkaline earth metal hydroxide, carbonate or acid carbonate such as sodium, potassium or calcium carbonate, carbonate or bicarbonate, or an oxirane such as lower 1,2-alkylene oxide such as ethylene oxide or propylene oxide.

The aforesaid compounds are preferably carried out in an inert, preferably anhydrous solvent or solvent mixture, for example a carboxylic acid amide, such as a formamide such as dimethylformamide, a halogenated hydrocarbon such as methylene chloride, carbon tetrachloride or chlorobenzene, a ketone such as acetone in an ester , for example in ethyl acetate, or in a nitrile, for example in acetonitrile, or; in mixtures thereof, at room temperature, optionally at a reduced or elevated temperature, for example at about -40 ° C to about 100% preferably at -10 ° C to + 40 ° C, and / or under an inert gas atmosphere, for example nitrogen atmosphere .

In the acid of formula III or its acid derivative to be acylated, 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; with a hydrohalic acid, for example hydrochloric acid, or sulfuric acid.

Further, the acid derivative, if desired, can be formed in situ. Thus, for example, a mixed anhydride is obtained by reacting an acid of formula III with appropriately protected functional groups, or a suitable salt thereof, such as an ammonium salt, for example an organic amine such as 4-methylmorpholine, or a metal salt, for example an alkali metal salt with a suitable acid derivative. as the corresponding acid halide of an optionally substituted lower alkanecarboxylic acid, for example trichloroacetyl chloride, or a semi-ester of a carbonic acid halide halide, for example ethyl ester or isobutyl ester of chloroformate, and the mixed anhydride thus obtained is used without isolation.

In the starting material of formula IV, the radical X as halogen is in particular chlorine, but also bromine, iodine or fluorine. The thiourea is used in the free form or in the form of a salt, in particular in the form of an alkali metal thioxide such as lithium, sodium or potassium, or also in the form of an ammonium derivative thioxide, in equivalent amounts or in up to six-fold excess. A compound of formula IV which contains acidic groups, for example when R 2 is hydrogen and when A is a sulfo-methylene group, can also be used in the form of a salt, for example an alkali metal salt or an ammonium salt, for example lithium, sodium. potassium, tri (lower alkyl, such as trimethyl or triethylammonium salts.

The reaction is generally carried out in a solvent such as water or an organic, non-reactive solvent or mixtures thereof. Suitable organic solvents are alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, ethers such as dioxane or tetrahydrofuran, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride, chloroform or tetra-chloromethane, esters such as ethyl acetate, or amides such as dimethylformamide or dimethylacetamide and the like. The reaction may, if the free compounds are used, be carried out in the presence of a base. Suitable bases are alkali metal hydroxides such as sodium or potassium hydroxide, alkali metal carbonates ₍ such as sodium or potassium carbonate, or organic tertiary nitrogen bases such as tri (lower) alkylamines, for example trimethylamine, triethylamine, ethyldiisopropylamine, pyridine and the like. the temperature is about room temperature, but may be higher or lower, preferably between -10 ° C to +100 ° C, especially between 0 ° C and 40 ° C.

The reaction may also be carried out stepwise, by first forming the ring-opened intermediate of the partial formula

R 1 - NH - C (= NH) - S - CH 2 - CO - A -, which is then dehydrated in the second step.

Procedure (h):

A compound of formula 1 ° wherein R 5 ° is hydrogen or a methoxy-replaceable group and where all the functional group is present in a protected form can be introduced in a manner known per se by a 7α-methoxy group R 5.

For example, the compound in which R 50 is hydrogen can be treated sequentially with an anionic reagent, an N-halogenating agent, and methanol to introduce a methoxy group.

A suitable anionic 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 organometallic base is generally carried out under cooling, for example at about 0 ° C to about -80 ° C, and in the presence of a suitable solvent or diluent, for example an ether such as tetrahydrofuran, using Tithium methoxide also in methanol. and optionally in a closed vessel and / or in an inert gas atmosphere, for example under a nitrogen atmosphere.

As ^one halogenating agents к halogenate nitrogen is used usually sterically hindered organic hypohalite, in particular hypochlorite, and especially the corresponding aliphatic, halo, e.g. hypochlorite as hypohalite tert. (Lower [-alkyl-, such as hypochlorite, tert. (Lower) -alkyl-. In particular, hypochlorite is used tert. The butyl and unisolated reaction product is reacted with an anionic reagent.

The intermediate halogenated at the atom du216937 in the excess of the base is formed by whose anions, in particular the methoxide / lithium reaction conditions, and the reaction conditions are transformed into isolation without isolation.

The 7-acyliminocephemerivative is converted to 11a and 7a-methoxycephemerivative by addition of methanol. If necessary, residues of hydrohalic acid, especially hydrochloric acid, must be removed from the intermediate which is halogenated at the nitrogen atom. This is accomplished by the addition of a hydrogen halide cleavage base as a suitable lower alkali metal alkoxide, such as lithium tert-butoxide, typically under anionic reaction conditions to form a halogenated compound on the nitrogen atom while operating in the presence of methanol, and instead of the acyliminoclerivative, the 7α-meithoxycephemerivative 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, the compound is reacted with an excess of anionic reagent, for example lithium methoxide or phenyllithium, in the presence of methanol, whereupon with a nitrogen-halogenating agent, for example tert-butyl hypochlorite, and in this way directly obtains the desired compound of formula I in which R 5 is methoxy and the functional groups are protected.

Methanol can also be added additionally; the dehydrohalogenation and methanol addition may be carried out at somewhat higher temperatures than the anionic reactions and reactions to form a halogenated compound on nitrogen, for example at about 0 ° C to about -20 ° C and optionally in a closed vessel and / or inert gas atmosphere , for example in a nitrogen atmosphere.

In another embodiment, in the compound of formula 1 °, where R 5 is a methoxy-replaceable group, the group may be replaced by an imethoxy group.

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

The reaction proceeds in an excess of methanol, and other inert solvents such as tetrahydroifuran, methylene chloride or chloroform may also be added to improve dissolution. The reaction temperature is generally about 15 to 2.5 ° C, i.e. operating at room temperature, allowing cooling or heating to slow or accelerate the reaction.

Procedure i]

The carbamoylation or hiethylation of the hydroxyiminomethylene group A in the compound of formula 1 is carried out in a manner known per se (by the action of a carbamioylating or methylating agent. In addition to the hydroxyimino group, any additional functional groups present are preferably protected.

Suitable carbamoylating agents are, for example, isocyanates of the formula R 4 -NCO, wherein R 4 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 such as acetonitrile, 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, chloirbenzene or methylene chloride, and similar inert solvents. Suitable catalysts are tertiary amines such as tri (lower N-amylamines such as triethylamine, lower alkyl (lower cycloalkylamines such as N, N-dimethylcyclohexylamine, N, N-diethylcyclohexylamine, N-methyldicyclohexylamine, or cyclic amines such as N-methylmorpholine, N-ethylmorpholine, N-methylpiperidine or pyridine, or tertiary diamines, Jato N, N, N ', ^{N'-tetramethyl-t,} 3-propanediamine or- N, N, N', N'-te: tiramethyl-l, 4 butanediamine and the like. The carbamoylation reaction is carried out with cooling or heating at temperatures between about -30 to about + 100 ° C, preferably about 10 to 50 ° C.

Suitable methylating agents are, for example, diazomethane, reactive methanol esters such as methyl halide such as methyl iodide, sulfonic acid esters such as methanesulfonic acid methyl ester, trifluoromethanesulfonic acid or p-toluenesulfonic acid esters, or sulfuric acid esters such as dimethyl sulphate, dimethylaicethoxy such as 2,2-diethanol. propane, orthoesters, for example trimethyl formic acid ester, trimethyloxonium salts, for example trimethyloxoniumfluorantimonate, -hexachlorantimonate, -hexafluorophosphate or -tetrafluoroborate, dimethoxycarbonium salts, for example dimethoxycarboniumhexafluoroborate, or 3-p-tosyl-1-methylphenylene. The methylation is carried out in a manner known per se, usually in an inert solvent such as an ether such as dioxane or tetrahydrofuran, or in an optionally halogenated hydrocarbon such as benzene, chlorobenzyl, methylene chloride, or similar solvents, optionally in the presence of suitable condensing agents, as a base or an acid, with cooling or heating, for example at temperatures between about -2 ° C to about 100 ° C.

Procedure k); 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 - optionally - to protect other functional groups; in a known manner.

Thus, esters are obtained, for example, by reaction of the free carboxyl group -COOR2- with a suitable diazoderivative; as - with - di-lower alkane, for example - diazomethane - or - diazobutane; i or with phenyldiazole ^{: the} lowest-alkane; for example with diphenyldiazomethane, optionally in the presence of a Lewis acid, such as boron trifluoride, or also by reaction with an alcohol of formula R 2 -CH, an appropriate k-els - caking in: - the presence of an ester-ificating agent such as carbodiimide; - for example - dicyclohexyl-carbonyl di-amide, - such as i-carbonyldiimidazole, further -s - N, N'-disubstituted on - oxygen atom, - optionally - on sulfur atom substituted; - -i-somočovmou - or - isothiocyanate, urea, íkde- - atom- - or oxygen is -SiR * - substituted, for example - ^one -lower alkytovým residue - especially - teřc.butylovým- radical, - phenyl (lower jalkylovým- ' the radical - or cycloalkyl radical - and - the substituents - on - the - atoms of the nitrogen N or N '- are - for example - -lower-alkyl ¹ radical, - especially - isopropyl - radical, - -cycloalkyl - - radical - - or -phenyl residue, - or any - other - - known and - suitable etherification procedures, such as reaction - of an acid salt * with - a reactive ester of an alcohol of the formula Rž-CH - and - strong · - inorganic acids or - strong -organic sulfonic acids ¹ -halides - acids such as - chlorides - acids - (produced - for example by the action of oc-alkyl chloride) - can be activated - esters - (consisting of, for example, - with an N-hydroxy compound derivative - containing - nitrogen, - as with N-hydroxysuccinimide-j or · mixed-anhydrides - (obtained for example - with lower-alkyl halogeno-esters - acids, - as -s-ethyl chloroformate - or - isobutyl chloroformate - -or- with - - halides

- haiogenioet. acids, such as - trichloroacetic acid chloride -, - can be converted by reaction with alcohols of the formula R 1 -CH 2 - optionally - in the presence of a base, such as pyridine, - - to - an ester-deflated carboxyl group - -—CCCR2.

In the - compound obtained - with an esterified group - of the formula - CCCR2 is - it is possible - to convert this group - to - another esterified- carboxyl group of this formula - for example by chloro-carboxy or -2-bromoethoxycarbonyl by treatment iodide salts such as sodium iodide in the presence of a suitable solvent such as acetone na-2-iodoethoxycarbonyl.

Mixed anhydrides can be produced by - a compound of formula I with a free-carboxyl group of formula -CCCR2, preferably a salt, in particular a salt of an alkali metal, for example a sodium salt, or - an ammonium salt, - for example - ¹ triethylammonium salt, - reacts with a reactive derivative, such as a hatogenide, for example chlorides, acids, / / with a lower alkyl ester of lialogenic acid or with a chloride lower alkanecarboxylic acids.

Preferably, physiologically-cleavable-ester-groups -CCCR2 are formed in any of the above methods.

The carboxyl group protected by an organic strength or stannyl group - may - be formed in a manner known per se - for example by the fact that - compounds of the formula 1 ° in which R 2 - represent hydrogen or - their - salts; - for example - alkali metal salts, - as - sodium salts, - react - with - suitable. fasting or stannylating agents (see, for example, British Patent Specification No. 1 073-530, or Dutch Unloading Document No. -6-7 / 1731 (07)).

The esterification reactions may be carried out in the presence or in the absence of an inert solvent, such as an optionally halogenated hydrocarbon, for example ^, methylene, ioFide, benzene, chlorobenzene, amide, for example dimethylformamide. - sulfoxide, - for example - dimethylsulfoxide, nitrile, - for example -acetonitrile, or the like - solvents, or - optionally - also in excess - alcohol - of the formula - R 2 - Depending on the method used - between -50 ° C and - depending on the method used ^. / 00 -celsius.

Procedure 1)

Conversion of the esterified carboxyl group by -CZR2, after cleavage of the ester of R2, to the free or in the form of a carboxy-salt present, i.e., such as, e.g. wherein - R2 represents - hydrogen - or - a cation; in the compound of formula 1 °, is carried out in a manner known per se, in particular by solvolysis, by hydrolysis, by alcoholysis or by acidolysis, or by reduction, such as by hydrogeholysis, or by chemical -reduction.

Thus, for example, a - target, (n-R) -alkoxycarbonyl group, a polycycloalkoxycarbonyl group, or a diphenylmethoxycarbonyl group can be treated by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid. or, optionally with the addition of a muculophilic compound, such as phenol or anisole, to the free carboxyl group. - optionally substituted - benzyloxykarbonylovoiu group may be - for example by treatment with hydrogen hydrogsnolýzou - at present - hydírogenačního of catalysts - such as (di · ⁱ Palau ovábor catalyst release. Far-can - specific - ways benzylioxykarbonylové substituted groups such as - 4 nitrOibenzyloxykarbonylovou- The group can also be converted to the free carboxyl group by chemical reduction, for example by the action of a metal alkali metal dithionite, for example sodium di-thionite, or by the action of a reducing metal, for example zinc, or a metal salt, such as magnesium salts, for example chromium (III) chloride, usually in the presence of a hydrogen releasing agent, which together with the metal makes it possible to produce a hydrogen content, such as acids, in particular acetic acids, as well as formic acids. acid or alcohol, preferably water is added · inného metal or metal salt. · as described above, you can also be converted into the second-lralogen · (·-lower alkoxycarbonyl. (optionally after conversion of the 2-bromo (loweralkoxycarbonyl) group to the 2-iodo (lower jalkoxycarbonyl group) or the acylmethoxycarbonyl group to the free carboxyl group, wherein the aroylmethoxycarbonyl group (e may also also be used) by the action of a nucleophilic agent, preferably a salt forming agent, such as sodium thiophenoxide or sodium iodide, cleavable Polyhalogenaryioxycarbonyl group, as a foam group, may be: and under mild basic conditions, such as by the action of dilute sodium hydroxide, or by the action of organic bases in the presence of water, to form a free carboxyl group.

Carboxyl group. Protected by, for example, levitation or stiffening forces can be released in the usual manner, for example by the action of 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, as regards the solvent, or optionally in an inert solvent, or in a mixture thereof, depending on the method, at a reduced or elevated temperature, for example. At temperatures between about -50 and 100 ° C.

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

Thus, the starting compounds of formula II in which R 5 represents hydrogen are known from DOS 2 151567. The starting compounds of formula II wherein R 5 represents methoxyl group or a group practicable to an imetho group, can be produced in a manner known per se, for example by introducing an eitherified mercapto group into compounds of formula II in which R 3 is hydrogen, by exchanging an ether of a mercapto group · For methoxy.

The starting compounds of the formula III are isolated. known, for example, from Belgian patents 852 971 and 853 5145, and from DOS 2 556 736 and 2; · 638028.

The starting compounds of the formula IV can be prepared by acylating the compounds of the formula II with an acid of the formula X - CH 2 - CO - A - COOH or a reactive functional derivative thereof, for example analogously to procedure a).

Starting materials of formula I,. wherein R 3 is a methoxy-replaceable group, in particular an etherified mercapto group, such as the methylthio group, required in the hj treatment, are conveniently produced from the corresponding compounds of formula IV ^: according to process b).

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

For enteral administration, tablets or gelatine capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbite, cellulose and / or glycine, and lubricating agents, for example silica, talc, stear. Or an acid thereof, such as. 'magnesium' or 'calcium salt of stearic acid, and / or with polyethylene glycol. Tablets also contain binders such as magnesium silicate, starches such as maize, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidine, and optionally substances allowing Disintegration of tablets such as starches, alginic acid or its. a salt, such as an alginate. sodium and / or effervescent mixtures, · adsorption agents, dyes; Flavorings and sweeteners. . Suppositories are mainly represented by emulsions or fat suspensions.

Pharmacologically. effective. The compounds of the invention are preferably used in the form of injectable, for example, intravenously or subcutaneously administrable preparations or in the form of mfusion solutions. Such solutions are. preferably isotonic. aqueous solutions or suspensions, wherein the compositions may be prepared prior to use from, for example, lyophilized preparations containing the active ingredient alone or together with a carrier. for example p. ' mannitem '. The pharmaceutical preparations can be sterilized and / or contain adjuvants, for example preservatives, stabilizers, wetting agents and / or emulsifiers, co-solvents, salts for regulating the osmotic pressure and / or buffers. Pharmaceutical preparations,. Which, if desired. They may contain other pharmacologically valuable substances in a manner known per se, for example by means of conventional mixing, dissolving or lyophilizing processes, and containing about 0.1 to about 100%, in particular about 1 to 10, about 50% by weight of the active substance, lyophilisates up to 100% by weight of the active substance. · Depending on the. The type of infection, the condition of the infected organism, a daily dose of about 0.5 g to about 5 g s.c. is used. for the treatment of · warm-blooded dogs weighing about 76 · kg.

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

Rf values for chromatography. thin layer:

DS: thin layer chromatography of the finished SL 254 silica gel plates. (product of Antec, BUfl-den).

The solvent systems used were of 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),

101:

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

101A:

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

In the derivatives of amino acids and 2-methyl-2-methoxyiminoacetic acid, the 2-amino-2-methoxyiminoacetic acid has a syn-confguration group. .

Example 1

a) To a solution of 1.14 g of 2- (2-chloroacetaniido-4-thiazolyl) -2-methoxyethoxyacetic acid - in 1.5 ml of tetrahydrofuran, add 0.085 g of N, N at -10 ° C. dicyclo-hexylcarbodiimide and 0.56 g of 1-liydroxybenztriazole at a temperature of about -5 to -10. The reaction mixture was stirred under nitrogen for 1 1/2 hours. After addition of a solution of 1.0 g of diphenylmethyl '7β-amino-34'-pheno4-carb (oxylic acid) in 15 ml of tetrahydrofuran, the reaction mixture is first stirred at the same temperature for 1 hour and then stirred at room temperature for 4 hours. The reaction mixture is filtered and the filtrate is evaporated in vacuo, the residue is taken up in ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and then the filtrate is concentrated in vacuo. Chromatography on silica gel using toluene with increasing proportions of ethyl acetate (up to -30%) yields 7β- [2-chloro-naphthamido-4-thiazolyl] -2-methoxyiminoacetamido] -3-cephem diphenylmethyl ester. -4-carboxylic acids.

DS:

Rf = 0.57 (ethyl acetate).

IR (methyl chloride): absorption bands at

3350, 3200, 1782, 1770 (arm),

1724, 1705, 1684, 1540 cm ¹ .

b) A mixture of 1.25 - g of diphenylmethyl 7β- [2- (2-chloroacetamide-4 ^ 1 ^ 1 ^ ^hia, ZOJ ^^^) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, 12 ml of methylene chloride, 0.68 ml of anisole and 3.4 ml of trifluoroacetic acid were stirred for 310 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 7β- [2- (2-chloroacetamido-4-thiazolyl) s-2-methoxyiminoacetaphthido] -3-cephem-4-carboxylic acid is filtered off, washed with diethyl ether and dried.

DS:

Rf value of 0.37 (mixture of n-butanol, glacial acetic acid and water -67: 10: 23).

(c) to a solution of 700 ml of 7β- [2- (2-chloro-amido-4-: thiazolyl) -2: -methoxyiminoacetamido] -3-cephem-4-carboxylic acid in 17 ml of N, N'- Dimethylacetamide (260 mg) was added and the reaction mixture was stirred at room temperature for 19 hours. After addition of 200 ml of diethyl ether and decantation of the solvent, the precipitate obtained is washed with 100 ml of diethyl ether and dissolved in 25 ml of water. The cloudy solution is cooled with ice and the pH is adjusted to 7 by the addition of sodium bicarbonate. The precipitate is filtered off, washed with water and the filtrate and washings are transferred to a column of 180 ml. 2 '. This column is washed with water and then with a mixture of water and isopropanol 85: 15. Fractions containing - 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetaphthamide] -3-cephem-4-carboxylic acid sodium salt they combine and evaporate. The sodium salt is then triturated with acetone, filtered and dried.

DS: _Rf value ~ O 19 (n-butanol: acetic -acid -ledové -a water 76: 10: 23).

UV spectrum (in ethanol):

A _m ax = 233 -NM (ε = 15 -500) -a -290 nm (broad) (ε = 5500).

Example 2

(a) To a solution of 3,3 / 1 g of 2- (2-tert-butoxycarbonyl-4-methoxy-4-hiazolyl) -2-methoxy-amino-acetic acid in 35 ml of tetrahydrofuran, add - 1,50 g of 1-hydroxybenztriazole and 27 g of NX-dicyclohexylcarbodiimide - and the reaction mixture was stirred at 0 ° C for 2 hours. To the reaction mixture was added a solution of 3.66 g of diphenylmethyl tert-amino-3-cephem-4-carboxylic acid tester in 45 ml of tetrahydrofuran, and the reaction mixture was further stirred at 0 ° C for 1 hour and at room temperature for 4 hours. room temperature. 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 the eluent and crystallization of the purified product from a mixture of -methyl-chloride and diethyl ether yields diphenylmethyl ester. 7 / 32- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxycarbaminoacetamido] -3-carboxylic acid-4-carboxylic acid, mp 154-157 degrees Celsius.

216037

DS: _Rf = 0.37 (toluene / ethyl acetate (1: 1)).

UV spectrum (in ethanol)

[Lambda] = 234 nm ([lambda] = 15,500) - 29.5 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) -Z-methoxyiminoacetic acid in 9 ml of methylene chloride and 0.26 ml of pyridine at -15 ° C was added 0.5 ml of diethyl phosphorobromidate under nitrogen. the mixture is stirred for 30; minutes at this temperature. After addition of 1.00 g of 7-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, aq. sodium bicarbonate solution and aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was purified by silica gel column 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. The obtained light beige, powdered 7β [2- [2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid trifluoroacetate is suspended in 90 ml of water. The pH of the suspension was adjusted to 7.1 by addition of 2N sodium hydroxide solution. The solution is filtered and the clear filtrate is chromatographed on 1200 ml of "Amiberlite 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 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-one. carboxylic acids.

IC spectra (in nujol): characteristic absorption bands at

3300 (wide), 1770, 1670, (wide), 1600, 11532, 1460 cm ^-1 .

A solution of 100 mg of the sodium salt obtained in 5 ml of water is brought to pH 3.5 by addition of a 0.5N hydrochloric acid solution. Unloaded

7β- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed thoroughly with water and acetone and dried under vacuum.

Example 5

A solution of 3.3 g of 7β- [2- (2-tert-butoxycarboinylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester in 3.5 ml of methylene chloride is stirred with 15 ml of methylene chloride. 4 ml of trifluoroacetic acid at 0 DEG C. for 30 minutes, then cold toluene is added and the mixture is evaporated in vacuo, the residue is digested with diethyl ether, the product is filtered off and dried, and the resulting yellow powder is dissolved in 10 ml of methanol. sodium methylhexanoate solution and to complete the precipitation of diethyl ether and the mixture is stirred under ice-cooling for 1 1/2 'hour to give the obtained N- [2- (2-tert-butoxycarbonylamino-44-thiazolyl) -2-methoxyiminoacetamido] -3-cephem- The 4-carboxylic acids are filtered off, washed well with diethyl ether and dried.

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

UV spectrum (in water):

Λmax = 233 nm (s —15 5'00), 290 nm nm (arm).

To convert to the free acid, 1.5 g of the obtained salt 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 is chromatographed on silica gel (deactivated with 5% water) using methylene chloride, a mixture of methylene chloride and ethyl acetate (increasing from 10 1 to 50%) and finally pure ethyl acetate. The resulting 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] ^-3-ce'fe, m-4-carboxylic acid The recrystallized from methanol, diethyl ether and hexane. Melting point about 210 ° C (decomposition).

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

UV spectrum (in ethanol):

Λmax = 260 nm (ε = 16,880),

232 nm (ε = 19,900),

224 nm (ε = 2θ! ООО).

IR (nujol): absorption bands at

3270, 3180, 1782, 1718, 16'54 cm ^1st

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 for 3 hours

216-37 hours at room temperature. A solution of 2.6 g of 7 _L 3- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 5 ml dimethylformamide was added to the mixture. and the reaction mixture was further stirred at room temperature for 1 hour. After concentration 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. The crude product obtained after evaporation in vacuo is chromatographed on silica gel. Elution of toluene containing 20 to 30% ethyl acetate afforded 7 / 3- (2- (2-tert-butoxycarbonylamino-4-thioazolyl) -2-methoxyiminoaoetamido) -3-cephem-4-carboxylic acid pivaloyloxymethyl ester.

DS: Rf ~ 0.61 (in ethyl acetate). UV-Sipectrum (in ethanol):

Amax = 234 nm (ε = 1600), 293 nm (arm).

IR (methylene chloride): absorption bands at

3380, 1789, 1773 (shoulder), 1725, 1680 ', 1638, 1545 cm -1.

Example 7

К 1.7 g pivaloyloxymethyl 7 _and e - [ '2- (2-tert-butoxycarbonyl] amino-4-thiazolyl) -2.-methoxyiminoacetamido] -3-cephem-4-carboxylic acid in 8.7 ml of methylene 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 resulting solution was washed with cold saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried under high vacuum. The obtained 7 / 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetaimido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester decomposes from about 130 ° C.

DS: _Rf value ~ 0.28 (ethyl acetate).

UV spectrum (in ethyl acetate):

Amax = 235 nm (ε = 16320), 295 nm (arm).

IR spectrum (in methylene chloride): characteristic absorption bands at

34801, 3390, 3330, 1782, 1753, 1680, 1620, 1530 cm &lt; ^{-1 &gt};.

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 for one hour at room temperature. To this suspension was then added 0.202 g of 7 / 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 3 ml of dimethylformamide and the mixture The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, the diluted solution was shaken with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel using toluene / ethyl acetate (1: 1) / ethyl acetate to give 7 / 3- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-d-pivaloyloxymethyl ester. carboxylic acids.

Example 9

а) To a solution of 7/3 '- [D, L-2-t-butoxycarbonylamino-2- (2-amino-4-thiazolyl) acetamido] -3-cephem- 4-Carboxylic acid and 2 ml of anisole in 10 ml of methylene chloride were added 10 ml of trifluoroacetic acid and the reaction mixture was stirred at 20-25 degrees Celsius for 1 hour, excluding moisture under a nitrogen atmosphere. After addition of 200 ml of diethyl ether to the solution cooled to 0 ° C, 7 / 3- [D, L-2-amino-2- (1,2-amino-4-thiazolyl) acetamido] -3-cephem-trifluoroacetate precipitated in crystalline form. The 4-carboxylic acid is filtered off, washed with diethyl ether and dried. The aqueous solution (25 ml) of crude trifluoroacetate was extracted three times with 15 ml of ethyl acetate, then the ethyl acetate extracts were adjusted at 0 ° C to pH 5.5 by addition of 2 N sodium hydroxide solution, concentrated to a volume of about 10 ml and isopropanol added dropwise. (40 mL). The precipitate formed is filtered off, reprecipitated from a 1: 4 water / acetone mixture and finally dissolved twice in a small amount of water to remove the organic solvent and evaporated on a rotary evaporator, after drying in a high vacuum as an amorphous powder dihydrate. 7 / 3- [D, L-2-amino-2- (2-amino-4-thiazolyl) acetamido] -3-cephem-4-carboxylic acid.

DS: _Rf value = (n-ibutanolu glacial acetic acid: water 67: 10 ': 23).

[α] ²⁰ = 76 ± 1 ° C (in 0.1 N hydrochloric acid solution: 0.33%).

UV spectrum (in 0,1 N hydrochloric acid solution):

Λ max = 250 nm, (ε = 12 400).

The starting material can be produced as follows:

(b) a solution of 24 g (5 mmol) of D, L-2-tert-butoxycarbonylamino-2- (2-trichloroethoxycarbonylamino-4-thiazolyl) acetic acid; and

0.56 ml of N-methylmorpholine in 50 ml of absolute methylene chloride, which is cooled to -20 DEG C., is added while stirring and excluding moisture, 0.615 ml of isobutyl chloroformate are added and the reaction mixture is allowed to react for 1 hour. 1.8-3 g (6 mmol) of diphenylmethyl ester of 7/3 amino-3-methyl-4-carboxylic acid diphenylmethyl ester are added in one portion at -15 ° C to the thus obtained mixed anhydride. After a reaction time of 3D minutes at -15 ° C and 2 1/2 hours at room temperature, the reaction mixture is diluted with 200 ml of ethyl acetate, washed twice with ice water and a saturated aqueous sodium chloride solution, and dried over sodium sulfate. Evaporate on a rotary evaporator to remove the solvent, whereupon 7 / 3- [D, L-2-tert-butoxycarbonylamino-2- (2-trifluoro-4-methoxycarbonylamino-4-thio) diphenylmethyl ester is obtained as an amorphous yellow powder. isoxyl) acetamido] -3-cephem-4-carboxylic acid.

DS: R value ₍ = 0.69 (on silica gel using ethyl acetate as solvent system)).

(c) To a solution of 3 · 0 g (3,76 mmol) of diphenylmethyl ester 7 / 3- [N-α-tert-butoxycarbonylamino-β-trichloroethoxycarbonylamino-4-thiazolyl) acetamido] -3-formyl-4-carbonyloxy acid in 30 ml of a 1: 1 mixture of acetonitrile and acetic acid, which is cooled to 0 ° C, 3 g of zinc powder are added in portions over ¹ minute with vigorous stirring. After 1 hour, the reaction mixture is diluted with 200 ml of ethyl acetate, the zinc powder is separated by filtration, and the filtrate is washed twice with ice water and saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and freed from the solvent on a rotary evaporator. 7-3- [D, L-2-t-butoxycarbonylamino-2-

- (- amino-4-thiazolyl] acetamido] -3-cephem-4-carboxylic acid of sufficient purity for processing in the next step of the synthesis.

DS: Rf value _r = 0i, 47 (silica gel, solvent system: ethyl acetate).

Example 10

To a solution of 2.40 g of diphenylmethyl ester 7/3

- [2- (2-tert-Butoxycarbonylamino) -4-thiazolyl-4-methoxyiminoaicetamido] -7a-methoxy-3-Cephem-4-carboxylic acid in 10 ml of methylene chloride is added 15 ml of trifluoroacetic acid and the reaction mixture is stirred at room temperature for 1 hour Then, the reaction mixture is poured onto ice, a cooled mixture of prtrolrthr (400 ml) and dirthylrthr (200 ml), the resulting trifluoroacetate is filtered off, washed with prtrolrthr and dried under high vacuum at room temperature. / 3-2- (2-amino-4-thiazolyl) ^{-2, me'thoxyi!} minoa.cetamido ^1] -Cα merhoxy-3 - cephem-4 -carboxylate acid are: suspended in 20 ml of water, adding The pH of the 1 N sodium bicarbonate solution is adjusted to 6.5, the suspension is stirred for 15 minutes at room temperature, after which a small amount of insoluble product is separated after treatment with activated carbon and filtration. The pH is adjusted to 6.0 and the solution obtained is concentrated on a rotary evaporator (under high vacuum) at 45 degrees Celsius. The aqueous solution is evaporated several times with ethanol and finally the addition of ethanol precipitates the sodium salt of 7β-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -α-methoxyl-3-cephem-4-carboxylic acid, filtered and washed thoroughly. The product can be further purified by dissolving in water and evaporating, optionally by precipitation with ethanol, melting at 199 DEG C. (decomposition).

DS: Rf value = 0.33, Rf value = 0.20 (solvent system 67), Ff value = 0.4.6 (solvent system 101), Rf value = 0.4, 4 ^ 5 (solvent system 1-1).

The starting material can be produced as follows:

The following reaction was carried out under a nitrogen atmosphere. Solution 4,90 · g of diphenylmethyl ester 7/3-t2- (2 - ethoxybutoxycarbonylaimino)

-4- (4-Hiazolyl) -2-methoxy- (4-acetamido) -3-cepham-4-carboxylic acid in 500 ml absolute tetrahydrofuran was cooled to -75 ° C (solid carbon dioxide bath * and acetone) and a dropwise cooled solution of lithium methoxide in methanol (210 ¹ mg of lithium dissolved in 20 · ml of methanol) is added dropwise over 2 minutes, raising the temperature to -70 ° C to form an orange-colored solution. Minutes at -75 DEG C., then 0.10 ml of tert-butyl hypochlorite is added and the solution is further stirred at -75 DEG C. After 8 minutes, an additional 0.60 ml of t-butyl hypochlorite is added to the solution. After 30 minutes, 10 ml of glacial acetic acid and a solution of 4.00 g of sodium thiosulphate in 5 ml of water are added dropwise, the cooling bath is removed and the solution is warmed to room temperature and diluted with ethyl acetate. 45 ° C, ethyl acetate The solution was washed successively with water, 1 N sodium bicarbonate solution and water, dried over sodium sulfate and the solvent was evaporated. The crude product is chromatographed on a 20-fold amount of silica gel. The fractions eluted with methylene chloride with 1% methyl acetate as eluent were combined. The product was dissolved in a small amount of ethyl acetate, precipitated with a mixture of control ether (500 ml) and diethyl ether (200 ml), filtered off and washed with petroleum ether.

Yield: 7 / 3-2- (2-1ΌΤϋ, 216937)

-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -7? -methoxy-3-cephem- ^; 4-carboxylic acids.

DS: (solvent system: toluene / ethyl acetate (3: 2)):

Rf value = 0.40.

Example 11

A capsule containing 0.250 g of 7 / 3- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamiido) -3-ceifem-4-carboxylic acid sodium salt is prepared as follows:

Ingredients (for 1Q0 ООО capsules):

7 / 3- (2-Amino-4-thiazolyl) -2-methoxyimino [cetamido] -3-cephem-4-carboxylic acid sodium salt 25 000 g wheat starch 2300 g magnesium stearate salt 1000 g

7 / 3- [2- (2-Amino-4-thiazolyl) -2-methoxy-aminoacetamido] -3-cephem-4-carboxylic acid sodium salt, wheat starch and magnesium stearate are mixed well and the mixture is filled into capsules size 1.

Example 12

A capsule containing 0.5 g of 7 / 3- (2- (2-aimino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid sodium salt is prepared as follows:

Ingredients (for 2Ю100 capsules):

7 / 1- [2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylate ^| boixylic acid poles vinylpyrrolidone corn starch magnesium stearate salt

7 / 3- [2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt is moistened with 300 ml of a solution of polyvinylpyrrolidone in 95% ethanol, mixture

1000,00 g

1'5,00 g

115,001 g

20.00 g is passed through a sieve; o 3 mm hole size and the granulate are dried under reduced pressure at 40-50 ° C. The dried granulate is passed through a 0.8 mm sieve, and corn starch and magnesium stearate are added and the mixture obtained is filled in a sliding mold. capsules (size 0).

Example 13

Dry ampoules or vials containing 0.5 g of sodium 7 /? - [2- (2-Amino-4-thiazolyl) -2-methoxyimino ⁱ acetamido] -3-cephem-4-carboxylic acid was prepared as follows :

Ingredients: (per ampoule or vial):

7 / 3- [2- (2-Amino-4-thioazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid, sodium salt 0.5 g miannit 0, 0.5 g

A sterile aqueous solution of 7- 3- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid and mannitol is sealed under aseptic conditions into a 5 ml vial or ml vials and tested.

Example 14

Dry ampoules or vials containing 0.25 g of 7 / 3- [2- (12-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt are prepared. as follows:

Composition (for 1 ampoule or vial):

7 / 3- [2 - (2-Amino-4-thiazolyl) -N-methoxyiminoacetamido] -3-cephem-4-carbonyl acid sodium salt 0.25 g mannitol 0.05 g

Aseptic aqueous solution of 7 / 3- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid and mannitol is filled into a 5 ml ampoule or aseptically under aseiptic conditions. ml flasks and the contents are sealed and tested.

Claims (9)

SUBJECT OF THE INVENTION A process for the preparation of 7-t-aminothiazolyl-acetamido-3-cephem-4-carboxylic acid derivatives of the general formula I, U) in which it is known A methylene or amino, hydroxy, sulfo, oxo or optionally carbamoylated hydroxyimino having up to 11 carbon atoms or methoxyimino substituted methylene, R3 is hydrogen, methoxy or C1-C6-substituted alkylthio, tolylthioscuipin or phenylthio; R @ 2 is hydrogen or a C1 -C7 alkyl esterifying group, an adamantyl radical, a phenylmethyl radical in which the phenyl is represented by one or two C1 -C4 alkyl, C1 -C4 alkoxy, hydroxy, halogen or nitro substituted phenynyl radicals, optionally halogen substituted benzoylmethyl radicals, polyhalophenyl radicals, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radicals, C 1 -C 4 alkanoyloxymethyl radicals in the alkanoyl moiety, C 1 -C 4 aminoalkanoyloxymethyl radical, C 1 -C 4 alkoxycarbonyloxymethyl radical, C 1 -C 4 alkoxycarbonyloxyethyl radical, C 1 -C 4 alkanoylthiomethyl radical alkanoyl C 1 -C 4 alkanoylaminomethyl radical in the alkanoyl group optionally substituted by halogen, benzoylammomethyl radical, phthalidyl radical, C 1 -C 4 alkoxymethyl radical, C 1 -C 4 -alkylalkyl radical or an amino group having from 3 to 8 carbon atoms in the cycloalkyl moiety, the amino group being substituted by two alkyl groups having 1 to 4 carbon atoms or an alkylene group having 2 to 8 carbon atoms optionally containing an oxo group, and salts thereof. The compound of formula (1) wherein: R 1 represents an acyl group of up to 18 carbon atoms, a mono-, di- or triphenylmethyl group or an organic silyl or stannyl group, and A, R 2 and R 5 have the meanings given in formula I, cleave the group R 1 and replace them with hydrogen, optionally converting the radical R 2 or A into another radical R 2 or A and / or to obtain a compound of the formula I optionally converted into a salt or the resulting salt is converted into a free compound or another salt. 2. The process of item 1 for producing compounds of formula I, wherein: A represents a methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxylminomethylene, carbamoylated hydroxylminomethylene or methoxyiminomethylene group, R 3 is hydrogen or methoxy; R2 is as defined in item 1, or a pharmaceutically acceptable salt thereof, characterized in that it is selected from a compound of formula (1) in which R @ 1 is lower alkanoyl of 1 to 4 carbon atoms or 2-haloalkanoyl of 1 to 4 atoms The compound of formula (I) is optionally converted to a pharmaceutically acceptable salt thereof, for example by solvolysis or reduction, and replaced with hydrogen. , 3. The method of item 1 for the preparation of compounds of formula I wherein R5 is hydrogen or methoxy, A is hydroxyiminomethyl, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene and R6 is hydrogen, diphenylmethyl or acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyl which can be cleaved under physiological conditions. or a phthalidyl group, or a salt thereof, characterized in that it is from a compound of the formula 1 ° in which R 1 is. Or a 2-haloalkanoyl group having 1 to 4 carbon atoms or a tert-butoxycarbonyl group and R2, R5 and A have the meaning given above, the R1 group is preferably cleaved off by treatment with an acidic reagent such as trifluoroacetic acid or by chemical reduction; optionally converted to a pharmaceutically acceptable salt. 4. The method of item 1 for the preparation of 7/3 [D, L-2-amino-2-i (2-amino-4-hiazolyl) acetamido] -3-cephem-4-carboxylic acid dihydrate, characterized by: by diphenylmethyl ester 7β [D, L-2-tert-butoxycarbonylamino-2- - (2-Amino-4''-thiazolyl) acetamido] -3-cephem-4-carboxylic acid is treated with anisole and trifluoroacetic acid. 5. The process of item 1 for the preparation of 7β-2- (2-amino-4-hiazolyl) -2-methoxyiminoacetamido] -7α-methoxy-3-cephem-4-carboxylic acid trifluoroacetate or a pharmaceutically acceptable salt thereof. characterized in that 7 / 3-2- (2-tert-butoxycarbonylamino-44 -riazolyl) -2-methoxyiminoacetamido] -7? -methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is treated with trifluoroacetic acid and then treated with trifluoroacetic acid; optionally converting the compound obtained into a pharmaceutically acceptable salt. 6. A process according to claim 1 for the preparation of amine-thiazolyl-acetamido-3-ethoxy-4-carboxylic acid derivatives of the formula I wherein R3 is hydrogen, A is methylene or amino, hydroxy, sulfo, oxo, hydroxyimino or methoxyimino substituted methylene and R2 represents hydrogen or a carboxyl group esterifying an alkyl radical of 1 to 7 carbon atoms, an adamantyl radical, a phenylmethyl radical, wherein the phenyl is represented by one or two optionally alkyl radicals of 1 to 4 carbon atoms, alkoxy of C1 to 4 carbon atoms, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen substituted benzoylmethyl radicals, polyhalophenyl radicals, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radicals, alkanoyloxymethyl radicals having 1 C 1-4 alkanoyl, C 1-4 alkanoyloxymethyl, phthalidyl or 1-ethyloxycarbonyloxyethyl, and salts of such compounds, characterized in that the compound is of the formula 1 °; wherein R 1 represents an acyl group of up to 18 carbon atoms, a mono-, di- or triphenylmethyl group or an organic silyl or stannyl group and R 2, A and R 3 have the meanings given in formula I, cleave the R 1 group and replace with hydrogen; of formula I converts the radical R 2 or A into another radical R 2 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 or another salt. 7. A method according to claim 6, characterized in that the 3.7 [2 '.-- 2-chloro · oraceta ^ι midot4 1-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid with thiourea and N, N'-dimethylacetamide and the obtained 7β- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is isolated or converted into a pharmaceutically usable salt, in particular sodium salt. 8. A process according to claim 1 for the preparation of 7,3-Minothiazolylacetamide-3-methyl-4-carboxylic acid derivatives of the formula I wherein R3 is hydrogen, A is methylene or amino, hydroxy, sulfo, oxo, hydroxyimino or methoxy substituted amino. and R 2 represents hydrogen or a carboxyl group esterifying an alkyl radical of 1 to 7 carbon atoms, an adamantyl radical, a phenylmethyl radical in which the phenyl is represented by one or two optionally C 1 -C 4 alkyl, a C 1 -C 4 alkoxy group Carbon atoms, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen-substituted benzoylmethyl, polyhalophenyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl , alkanoyloxyme (C 1 -C 4) -alkyl, (C 1 -C 4) -alkanoyloxymethyl, (C 1 -C 4) -alkanoyloxymethyl, (C 1 -C 4) -alkoxycarbonyloxymethyl, (C 1 -C 4) -alkoxycarbonyloxyethyl, alkanoylthiomethyl of 1 to 4 carbon atoms in the alkanoyl moiety, alkanoylaminomethyl of 1 to 4 carbon atoms in the alkanoyl moiety, the lower alkanoyl of 1 to 4 carbon atoms optionally substituted by halogen, benzoylaminomethyl, phthalidyl, alkoxymethyl, 1-4 carbon atoms in the alkoxy moiety, 2-aminoalkyl having 1 to 4 carbon atoms in alkyl, or 2-aminocycloalkyl having 3 to 4 carbon atoms; C 8 -C 8 cycloalkyl, wherein the amino group is substituted with two C 1 -C 4 alkyl groups or a C 2 -C 8 alkylene group optionally containing an oxo group, and salts of such compounds, characterized in that from a compound of the formula 1 ° in which R 1 represents an acyl group of up to 18 carbon atoms, a mono-, di- or triphenylmethyl group or an organic silyl or stannyl group, and R 2, A and R 3 have the meanings given in formula I, cleave this R 1 group and hydrogen, followed by optionally converting R 2 or A into another R 2 or A residue in the compound of formula I obtained, or optionally converting the compound of formula I into a salt or converting the obtained salt into a free compound or another salt. 9. A process according to claim 8, wherein the diphenylmethyl 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cep-4-carboxylic acid diphenylmethyl ester is treated with trifluoroacetic acid. acid and the obtained [3- (2- (2-amino-4-thiazolyl) -2-methoxyimino tamido) -3-cephem-4-carboxylic acid] is isolated or converted into a pharmaceutically acceptable salt, especially sodium salt. salt. ID 8. The method of claim 8, wherein the pivaloyloxymethyl ester is 7β- [2- - (1,2-tert-butoxycarbonylamino-4-thiazolyl) -N-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is treated with trifluoroacetic acid and the 7β- pivaloyloxymethyl ester obtained. - [2- (2-Amino-4-thiazolyl] -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is isolated or converted to a pharmaceutically acceptable salt.