CS216935B2 - Method of maling the derivatives of the 7-beta-aminothiazolylactamido-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

The present invention relates to a process for the preparation of novel 7β-aminothiazzlylacetamido-3-cephem-4-carboxylic acid derivatives which are not substituted at the 2-position of the 3-position of the cephem ring. These compounds have valuable pharmacological properties and can be used as antibiotics.

In particular, the invention relates to a process for the preparation of 7β-aminothiazolylacetamido-3-cephem-4-carboxylic acid derivatives. of formula I,

in which it means

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, αχο or optionally carbamoyl hydroxyimino having up to 11 carbon atoms or methoxyimino substituted methylene,

R3 is hydrogen, methoxy or a methoxy-substituted alkylthio group of up to 6 carbon atoms, - tolylthio or phenylthio, and

218935

R ₃ is hydrogen or a group esterifying karboxylovou- - alkyl - group having 1 - - up to 7 carbon atoms, adamantyl, - phenylmethyl residue, wherein the phenyl represented by one or two alkyl optionally having 1 to 4 carbon atoms, - C 1 -C 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 (C 1 -C 4) alkanoyl radical, (C 1 -C 4) alkanoyloxymethyl radical, (C 1 -C 4) alkoxycarbonyloxymethyl radical, (C 1 -C 4) alkoxycarbonyloxyethyl radical, alkanoylthiomethyl radical C 1 -C 4 alk anoylo-. an alkanoylaminomethyl radical having up to 4 carbon atoms in the alkanoyl group optionally substituted by halogen, a benzoylaminomethyl radical, a phthalidyl radical, an alkoxymethyl radical having 1 to 4 carbon atoms in the alkoxy radical, a 2-aminoalkyl radical having 1 to 4 carbon atoms in the alkyl moiety or 2-aminocycloalkyl -. a C 3 -C 8 radical in the cycloalkyl moiety wherein the amino group is substituted with two C 1 -C 4 alkyl radicals or an C 8 -C 8 alkylene group optionally containing an oxo group, and - salts of such compounds with salt-forming groups.

7β-Acylamino-3-cephem-4-carboxylic acid derivatives which are not substituted at the 3-position of the cephem ring, and a process for their preparation, are known from German Patent Nos. 2,151,567 and 2,223,667 and Swiss Patent Applications. No. 58 2709, No. 58 2710 and No. 58 5756. Compared to these compounds, in particular against [3- (N- (D-phenylglycyl)) amino-3-cep-4-carboxylic acid], the compounds according to the invention are distinguished in particular, increased stability to β-actamase.

Of the known 7/3 amino-3-substituted-3 -cephem-4-carboxylic acids acylated at the amino group at the 7β position with a 2- (2-amino-4-thiazolyl) acyl radical, it is known in particular 7 1/3 - [2 - ( 2-amino-4-thiazolyl-2-methoxyiminoacetamido] -3-acetoxymethyl-3-cephem-4-carboxylic acid (Cephotaxime) (e.g., DOS 2 702 501),

However, this compound is desacylated in vivo to about 40% to the corresponding 3-hydroxymethyl derivative, which is substantially less antibiotic-active. Appropriate inactivation of metabolisations of the compounds of the invention does not occur.

As used herein, the term "lower" in groups such as lower alkyl, lower alkylene, lower alkoxy, lower alkanoyl, and the like means that the corresponding groups are contained. ;

unless otherwise explicitly defined up to 7, preferably up to 4, carbon atoms.

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 sulpho groups, are optionally protected with cover groups which are 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 also under physiological conditions.

Protecting groups of this type, as well as 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., Schroder, and Lúbke, Academic Press, London, New York, 1965.

The amino protecting group is preferably an acyl group Ac, a mono-, di- or triarylmethyl 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 acids or semi- ¹ -carboxylic acids. % of carbonic acid. Such acyl groups are, for example, a lower alkanoyl group, such as a formyl, acetyl, propionyl group, a halogen (lower) alkanoyl group, such as a 2-haloacetyl group. in particular 2-chloro, 2-bromo, -2-iodo, 2,2-dichloro or 2,2-tri-chloroacetyl, phenylacetyl, phenoxyacetyl, thienylacetyl, benzoyl, 4-chloro,

A 4-methoxy- or 4-nitrobenzoyl group, a lower alkoxycarbonyl group, in particular a tert. (lower jalkoxycarbonyl, 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 tertiary alkyl, for example tert-butyl, lower alkoxy methoxy, hydroxy, halogen, for example chlorine 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-methoxyphenylmethoxycarbonyl, or 2-halo (lower Jalkoxycarbonyl, for example 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl or acylmethoxycarbonyl, in particular aroylcarbonyl), in particular aroylcarbonyl, wherein the aroyl group is is preferably optionally, - for example, by halogen, such as bromine, substituted by a benzoyl group, such as phenacyloxycarbonyl.

In the mono-, di- or triphenylmethyl group, the phenyl radicals are in particular optionally substituted phenyl radicals. Such groups are, for example, benzyl, diphenylmethyl or trityl.

Preferred acyl radicals R _{@ 1} are the acyl radicals of 2-haloacetic acid, in particular 2-chloroacetyl, and semi-esters of carbonic acid, in particular tert-butyloxycarbonyl, for example tert-butoxycarbonyl, optionally, for example, substituted benzyloxycarbonyl or diphenylmethoxycarbonyl, or 2-halogen (lower jalkoxycarbonyl, such as 2,2,2-trichloroethoxycarbonyl, as well as 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 sulfonic acids, such as p-toluenesulfonic acids.

Carbamoylated hydroxyimino group in the residue. A is a group of the partial formula —N — O — C (= OO — NHR4 ₎ wherein R4 is lower alkyl, cycloalkyl, aryl (lower) alkyl, or aryl.

In particular, the lower alkyl group R 4 is a lower alkyl group having 1 to 6 carbon atoms, such as a methyl, ethyl, propyl, butyl, pentyl or hexyl group, which groups may have a straight chain or a chain. branched. Branched lower 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 cycloheptyl.

The aryl (lower) alkyl group R ₄ is a group having from 7 to 10 carbon atoms and is, for example, benzyl, phenylethyl, phenylpropyl or phenylbutyl.

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

A preferred radical R @ 4 is ethyl, n-propyl, isopropyl, butyl, isobutyl, cyclohexyl and especially methyl.

The methoxy-replaceable group R3 is, for example, ethyl, propyl, butyl or, in particular, methylthio or phenyl or p-tolylthio.

The carboxyl group esterifying residue R2 is preferably readily cleavable under gentle conditions, including physiological. Such R 2 radicals are - in particular a tert-lower alkyl radical, for example a tert-butyl radical, an adamantyl radical, a phenylmethyl radical, in which the phenyl is preferably represented by one or two, optionally, for example tert-butyl, methoxy, hydroxy, halogen such as chloro and / or nitro, mono- or polysubstituted phenyl radicals, optionally as, for example, as mentioned above, substituted benzyl, for example 4-nitrobenzyl, or 4-methoxybenzyl, or for example as mentioned above, substituted diphenylmethyl, for example a benzhydryl or di (4-methoxyphenyl) methyl, or 2,2,2-trichlorotetyl radical, in particular a benzoylmethyl radical, in which the benzoyl radical is preferably optionally halogen, such as bromine, substituted with a benzoyl radical, such as a phenacyl radical or a polyhalophenyl radical a radical such as a pentachlorophenyl radical The radical R2 is furthermore a silyl an organic silyl group or a corresponding stannyl group. In these groups, the - atom - contains silicon optionally. a tin atom, preferably as a substituent, a methyl group, further a methoxy group and / or a halogen, for example chlorine. Suitable silyl or stannyl protecting groups are, in particular, trimethylsilyl, furthermore dimethyl-tert-butylsilyl, methoxymethylchlorosilyl- or dl (lower) alkyl halogensilyl, for example dimethylchlorosilyl, or correspondingly substituted stannyl groups, for example tri-n-butylstannyl.

Preferred protecting groups for R 2 are in particular tert-butyl, optionally, for example, as mentioned, substituted benzyl, for example

4-nitrobenzyl and diphenylmethyl.

The R3 moiety cleavable under physiological conditions imparts improved oral carboxylic acid absorption and / or prolonged efficacy to the active carboxylic acids themselves. Numerous such ester groups are known in the art of penicillins and cephalosporins. Mention may for example -C (= O) -O-R2 - where _R2 represents a methyl group substituted with acyl, acyloxy, acylthio, acylamino or etherified hydroxy group and optionally other organic residue, methyl group can be bonded with the carbonyl of the acyl or a 2-aminoaliphatic group.

In such groups, acyl is an organic carboxylic acid radical of up to about 18 carbon atoms and is represented, for example, by an optionally substituted alkanoyl group, a cycloalkanoyl group, an aroyl group, a heterocyclyl216935 carbonyl group, for example a heterocyclylcarbonyl group of carboxylic acid of formula I or biologically active penam-3. - or cephem-4-carboxylic acid, or an acyl radical of a semi-ester of carbonic acid. The etherified hydroxy group in the methyl group is a hydroxy group etherified with a hydrocarbon radical, especially a lower alkyl radical. An organic radical optionally substituting a methyl group. it 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 χ-lactone, 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 with two lower alkyl groups or an alkylene group optionally containing an oxo group. In such physiologically cleavable ester groups —C =Oj —O — R2, R2 is, for example, acetyloxymethyl or pivaloyloxymethyl, in particular α-amino is a lower (C1 -C4) -alkanoyloxymethyl group. in the alkanoyl moiety, for example, glycyloxymethyl, L-valyloxymethyl, L-leucyloxymethyl, 1-ethyloxycarbonyloxyethyl, acetylthiomethyl or pivaloylthiomethyl, lower alkanoylaminomethyl of 1 to 2; 4 carbon atoms in the alkanoyl moiety in which the lower C 1 -C 4 alkanoyl may be optionally substituted with a halogen such as chlorine, for example, acetylaminomethyl or 2,2-dichloroacetylaminomethyl, benzoylaminomethyl, or as an example for R2 containing lactone , phthalidyl, methoxymethyl, 2-aminoethyl, wherein the amino group is substituted with two lower alkyl groups of 1. or (C 2 -C 8) alkylene optionally containing an oxo group, such as 2-dimethylaminoethyl, 2-diethylaminoethyl or 2- (1-morpholinoethyl or 2-aminocycloalkyl, such as 2-dimethylaminocyclohexyl). , pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl and phthalidyl.

Salts are in particular salts of the compounds of formula I having a free carboxyl group, in particular metal salts or ammonium or ammonium salts, such as alkali metal salts and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts as well as ammonium salts ammonia or ammonium salts with suitable organic amines, the aliphatic, cycloaliphatic, cycloallphaticaliphatic or aralitic primary, secondary being suitable for the formation of the salt. or tertiary mono-, di- or polyamines, as well as heterocyclic bases such as lower alkylamines, for example triethylamine, hydroxy (lower) alkylamines, for example 2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tris- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids such as 4-aminobenzoic acid 2-diethylaminoethyl ester, lower alkylenamines such as 1-ethylpiperidine, cycloalkylamines such as dicyclohexylamine, or benzylamines such as N, N'-dibenzylethylenediamine, pyridine-type bases, colidine or quinoline.

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 trifluoroacetic acid, as well as with amino acids such as 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 inner 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 group, an amlnomethylene group or a sulfomethylene group, is present in the R, S- or preferably in the R-configuration. The optionally carbamoylated hydroxyimino- and methoxyiminomethylene group A is preferably in the syn-form (Z-form).

Compounds of formula (I) in which the carboxyl group is optionally sterilized in physiologically cleavable form and the functional groups of the A moiety 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 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 0.005 to -1 / ml, and against gramme, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, - Enterolbacter sp., Proteus sp. indole + 'and indole', Pseudomonas aeruginosa and Haemophilus influenzae, including against β-lactamase producing strains, at minimum concentrations <0.01 and 8 µg / ml, respectively. In vivo, by subcutaneous administration of 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. 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 origin216935 or infections, 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 preparation of antibiotic active compounds of formula I.

More particularly, the present invention relates to a process for the preparation of compounds of formula I wherein R 1 is hydrogen, C 1 -C 4 lower alkyl, C 1 lower alkanoyl. or 4-carbon (C 1 -C 4) alkanoyl, A is methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyimino-methylene, carbamoylated hydroxyiminomethylene, or methoxyiminomethylene, R ₃ is hydrogen or methoxy and R ₂ is hydrogen or a radical · cleavable under physiological conditions and their pharmaceutically usable salts as well as the corresponding compounds with protected functional groups.

Particular mention should be made of the compounds of the formula I in which Rr is in particular hydrogen and also a 2-halogen (lower) C1-C4 alkanoyl group such as a 2-chloro (lower) C1-C4 alkanoyl group, A is hydroxyiminomethylene, N-methylcarbamoyloxyiminomethylene or methoxyiminomethylene, R3 is hydrogen or methoxy and R2 is hydrogen or a physiologically cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalidyl compound, and a pharmaceutically acceptable salt thereof with protected functional groups.

In particular, the invention relates to a process for the preparation of the compounds of formula I described in the examples, the pharmaceutically usable salts thereof, as well as the starting materials and intermediates described therein.

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

Thus, the compounds of formula (I) are prepared by forming a compound of formula (VI),

in which

R1, R2, R3 and A have the meanings given in formula I, and wherein the double bond is in position

2,3 or in the 3,4-position and the functional groups are optionally protected, act as a heavy metal decarbonylating agent, after the reaction using the 2-cephemedivatives of formula VI, the decarbonylation product is heated to a temperature of 25 to 120 ° C; this product with a base and optionally in the resulting compound of formula I, radical R b or R 2 a is converted into another radical R _b or R 2 ¹ a, and / or the resulting compound of formula I is optionally converted into a salt or a resulting salt is converted into a free compound of formula I or another salt.

In particular, heavy metal complexes capable of binding carbon monoxide are used as decarbonylating agents in the decarbonylation of compounds of formula VI. Such heavy metal complexes are, in particular, platinum metal complexes, the platinum metal being understood in addition to platinum as, for example, iridium or rhodium, and also palladium and osmium. The platinum carbon monoxide-binding complex preferably contains organic ligands, which ligands may, in addition to the carbon atom, also be bound by a heteroatom, in particular a phosphorus atom, through the secondary valence (which forms non-covalent bonds) of the platinum metal atom. This complex may contain, in addition to these organic ligands, through the main valences (i.e., covalently) bonded substituents, such as heteroatoms, in particular halogen atoms, such as chlorine atoms, or carbonyl groups. Carbon monoxide-binding platinum metal complexes of this type make it possible to bind carbon monoxide by means of the main valences, i.e., by a covalent bond.

As platinum metal complexes, for example, phosphorus-containing platinum metal complexes are used, in particular platinum-metal phosphine complexes containing one, two or more phosphines. These phosphines contain as substituents preferably optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, in particular lower alkyl such as n-butyl, or especially optionally substituted phenyl such as phenyl. In addition to the phosphorus-containing moieties, for example phosphines, the platinum metal complexes may contain other organic ligands, especially those which can replace one, two or more phosphorus-containing ligands in the phosphorus-containing platinum metal complex, such as phosphines, such as suitable nitriles such as acetonitrile , in a non-covalent bond with a metal atom, and / or halogen atoms such as chlorine, or a carbonyl group in a covalent bond with a metal atom.

Preference is given to using bis-trisubstituted phosphine halides, iridium bis-trisubstituted phosphonyl halides or iridium tris-substituted phosphine halides, in particular rhodium tris-substituted phosphine halides, in which phosphine substituents are preferably lower alkyl radicals, for example n-butyl, and in particular phenyl, halides are mainly chlorides. Such platinum-group metal phosphine complexes which allow carbon monoxide to be bound by a covalent bond are, for example, platinum bis-triphenylphosphine chloride [(C ₆ H ₅ ) ₃ P] 2 PtCl 2 or iridium bis-triphenylphosphine carbonyl chloride [(С ₆ Н5) зР] 21г (СО) С1 and iridium trifenylfosfinchlorid tris [(C ₆ H 5] ₃ Р] 1гС1 _3, but in particular rhodium tris-trifenylfosfinchlorid [(C ₆ H _{5) 3} P] ₃ RhCl.

If desired or necessary, the decarbonylation can be carried out from the above heavy metal complexes in the presence of suitable catalysts or activating agents such as a Lewis acid such as boron trifluoride (which can be used with, for example, bis-triphenylphosphine platinum chloride); a metal such as sodium perchlorate (which can be used, for example, together with iridium bis-triphenylphosphinecarbonyl chloride).

The reaction is preferably carried out in the presence of inert solvents, in particular hydrocarbons, such as aliphatic or cycloaliphatic, especially aromatic hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons such as corresponding aliphatic or aromatic chlorinated hydrocarbons such as methylene chloride or chlorobenzene, ethers such as aliphatic, cycloaliphatic, cycloaliphatic or aromatic, further mixed ethers such as di-n-butyl ether, dioxane, diphenyl ether or anisole, nitriles such as aliphatic or aromatic nitriles such as acetonitrile or benzonitrile or ketones, especially aliphatic ketones such as lower alkanones such as acetone, ethyl methyl ketone or isobutyl methyl ketone or mixtures of such solvents. The reaction is carried out under cooling, at room temperature or with heating, for example at about 10 to about 150 ° C, such as at about 40 ° to about 120 ° C, further if necessary in a closed vessel and / or atmosphere an inert gas, for example under nitrogen or argon.

In the decarbonylation reaction, a 3-formyl-3-cephem- or 3-formyl-2-cephem derivative of formula VI can be used. If applicable

3-formyl-2-cefemderivative, the double bond isomerization must be carried out simultaneously with the deformylation or thereafter, which is achieved by raising the temperature to about 100 ° C and / or by the presence of a base.

Additional operations:

The compound of formula I obtained can be converted to another compound of formula I by converting the radicals R _b R ₂ or A, as defined above, into other radicals R _b R ₂ or A. This applies in particular to the cleavage of the protecting groups R ₁ and R ₂ and but also additional variations of residue 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 solvolysis, in particular hydrolysis, alcoholysis or acidolysis, or reduction , in particular by hydrogenolysis or chemical reduction, optionally simultaneously or gradually released.

Thus, for example, a tertiary (lower alkoxycarbonyl, polycycloalkoxycarbonyl or diphenylmethoxycarbonyl group) can be converted to a free carboxyl group by the addition of a nucleophilic compound such as phenol or anisole, optionally with the addition of a nucleophilic compound such as phenol or anisole. 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 with a reducing active metal, for example zinc, or metal salts such as chromium salts, for example chromium chloride, usually in the presence of an agent hydrogen, which together with the metal makes it possible to produce a nascent hydrogen, such as an acid, in particular acetic acid, as well as a formic acid, or an alcohol, preferably with the addition of water.

The 2-halogen (lower alkoxycarbonyl group [optionally after conversion of the 2-bromo (lower) alkoxycarbonyl group to 2-iodo (lower jalkoxycarbonyl)] or the acylmethoxycarbonyl group can also be converted to the free carboxyl group by treatment with a reducing metal or metal salt as described above. whereby the aroylmethoxycarbonyl group is optionally cleaved by treatment with a nucleophilic, preferably salt-forming agent, such as sodium thiophenoxide or sodium iodide, and the polyhalogenaryl216935 oxycarbonyl group, such as pentathiophenyloxycarbonyl, is converted under mild basic conditions such as by treatment with dilute sodium hydroxide; free carboxyl 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 the protecting group in various ways, for example by solvolysis or reduction. 2-Halogen (lower Jalkoxycarbonylamino) [optionally after conversion of 2-bromo [lower] alkoxycarbonyl to 2-iodo (lower) alkoxycarbonyl], acylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be carried out, for example, by treating with a suitable acetic acid in zinc , aroylmethoxykarbonylaminoskupina also by treatment with a nucleophilic, preferably salt-forming reagent, such thiophenoxide sodium, and 4-nitroberLzyloxykarbonylaminoskupma also treatment with an alkali metal dithionite, for example sodium dithionite, difenylmethoxykarbonylaminoskupina, tert. (lower) alkoxycarbonylamino or polycykloalkoxykarbonylaminoskupina with, for example formic or trifluoroacetic acid, optionally substituted benzyloxycarbonylamino, for example, by hydrogenolysis by treatment with hydrogen in the presence of a hydrocatalyst, a triarylmethyl group e.g. by treatment with an aqueous mineral acid and an amino group protected by an organic silyl or stannyl group, for example by hydrolysis or alcoholysis, and thereby released. A 2-haloacetyl group, such as a 2-chloroacetyl group, protected amino group can be released from the resulting condensation product by treatment with thiourea in the presence of a base or treatment with a thioxide such as thiourea alkali metal thioxide and subsequent solvolysis such as alcoholysis or hydrolysis.

A 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 capping groups may be selected such that they can all be removed simultaneously, for example acidolytically, such as with trifluoroacetic or formic acid, or reductively, such as with zinc and glacial acetic acid, or with hydrogen and a hydrogenation catalyst such as palladium on carbon as the catalyst.

By selecting suitable reaction conditions, the cryo group can also be removed selectively. Thus, for example, a diphenylmethoxycarbonyl group can be converted to a free carboxyl group by treatment with trifluoroacetic acid at 0 [deg.] C. whereas the tert-butoxycarbonylamino group present can be converted to the free amino group by the same reagent only at a higher temperature, e.g. time.

The described cleavage reactions 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 under a nitrogen atmosphere.

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

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 active oxides, such as manganese, chromium, nitrogen or sulfur oxides, 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 dicyclohexylcarbodiimide or oxygen; and peroxides, such as hydrogen peroxide, oxygen-containing acids, such as permanganic acid, chromic acid 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 Oppenauer 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, cyclohexanone or fluorenone. Another possibility of converting a hydroxymethylene group to an oxomethylene group is by dehydrogenation, for example by Raneylkl.

Depending on the oxidizing agent 216935a, the oxidation is carried out in water or in a solvent which optionally contains water at temperatures from about 0 ° to about 100 ° C.

In the compound of formula (I) in which A is an oxomethylene group, the functional group may be converted into a hydroxyimlnomethylene group in which the hydroxy group is present in an optionally protected or carbamoylated group, optionally with functional groups, by protecting with protected or O-carbamoylated hydroxylamine or O-methylhydroxylamine. form, optionally to a methoxyiminomethylene 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 atompher inert gas, - as in 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 tertiamine 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 is a methylene group, the methylene group can be converted to a hydroxyimino group, for example analogously to Belgian patent specification 855 953, by nitrosation, whereupon the hydroxy group is then optionally protected in a manner known per se , carbamoylated, or by methylation can be converted to a methoxy group. Furthermore, the methylene group A can be sulfonated to a sulfomethylene group, for example by treatment with sulfur trioxide-dioxane complex, for example analogously to DOS 2,638,028.

Salts of the compounds of formula (I) may 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-ethylcaproic acid or sodium bicarbonate, or with ammonia or a suitable organic amine, preferably stoichiometric amounts of only a small excess of salt-forming agent.

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 an acid. 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 embodiments in which the compounds obtained as intermediates are used as starting materials 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 VI are known or can be obtained analogously to known processes. Thus, they can be obtained analogously to Dutch patent 68 15631 or to Austrian patents 263 768 and 264 537.

The pharmacologically usable compounds of the invention can 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 carriers, and 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 lubricants, for example diatomaceous earth, talc, stearic acid or salts thereof, such as the magnesium or calcium salt of stearic acid, and / or polyethylene glycol. 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 substances which disintegrate the tablets as. are for example 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 injectable, for example intravenously or subcutaneously, administrable preparations or in the form of infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which preparations may be prepared, for example, from lyophilized preparations which contain the active ingredient alone or together with a carrier, for example mannitol, before use.

The pharmaceutical preparations may 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, may contain other pharmacologically valuable substances are produced in a manner known per se, for example by means of conventional pharmaceutical preparations.

21B935 by mixing, dissolving, or lyophilizing processes and containing about 0.1 to 100 why, especially about 1 to 50%. active ingredients, lyophilisates up to 100% active ingredient. V. depending on the type of infection, the condition of the infected organism, daily doses of about 0.5 g to about 5 g s are used. c. to treat warm-blooded weight of about 70 kg.

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

_Rf value on 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:

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

101 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

0.40 g of N- 2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-Z-methoxyiminoacetamido] -3-formyl-3-cephem-4-carboxylic acid diphenylmethyl ester is dissolved at 60 to 70 ° in 100 ml degassed benzene, 1 mol equivalent of tris-triphenylphosphine-rhodium chloride was added with vigorous stirring and the reaction mixture was refluxed for 5 hours. The reaction mixture was cooled, evaporated in vacuo and the residue taken up in methylene chloride. The separated bis-triphenylphosphine-rhodiumcarbonyl chloride is filtered off and the filtrate containing the cephem derivative is purified by thin layer chromatography on silica gel (solvent system: toluene / ethyl acetate) after evaporation. Washing zone visible under ultraviolet lamp. at 254 nm with an Rf value of 0.37, 7 / 3-2- (2 (tert-butoxycarbonylamino-4-thiazolyl) -2-Z-methoxyiminoacetamido) -3-cephem diphenylmethyl ester, after crystallization from methylene chloride / ether. 154 DEG-157 DEG.

Starting materials can be obtained as follows:

a) To a suspension of 41.07 g (151 mmol) of 7-aminocephalosporanic acid in 270 ml. of absolute methylene chloride was added 111 ml (453 mmol) of NO-bis-trimethylsilyl acetamide and the mixture was stirred at 25-30 ° C for 45 min.

until a clear solution is formed. (Hereafter referred to as solution A).

45,50 '. g (151 mmol) of 2- (2-tert-butyloxycarbonylaminothiazol-4-yl) -2-Z'-methoxyiminoacetic acid and 9.22 g (75.5 mmol) of 4-dimethylaminopyridine are largely dissolved in 300 ml of methylene chloride and pyridine (14.3 mL, 181 mmol) and diethyl phosphorobromidate (27.1 mL, 166 mmol) were added slowly at -15 to -20 °. The mixture was stirred at -15 to -20 ° for 30 '.

At this temperature, 14.3 ml of pyridine was added dropwise, followed by solution A. After the addition was complete, the reaction mixture was stirred for 2 1/2 hours at -20 °.

For working-up, the mixture is stirred into 1 liter of 0.5 M phosphate buffer (pH 7) and freed from methylene chloride in vacuo. Removal of the neutral portion by triplicating with 800 ml of ethyl acetate each time. In the aqueous phase, after acidification with concentrated phosphoric acid to pH 2 and saturation with sodium chloride, the product can be extracted with ethyl acetate (3.times.800 ml). The sodium sulfate-dried extracts gave 101.01 g of crude product as a yellowish foam upon evaporation.

For further purification, the amorphous material was digested successively five times in 1 liter of ether / hexane (1: 1) using a high speed stirrer. As insoluble material, 50.54 g (91 mmol) are obtained.

- [2- [2-tert-Butyloxycarbonylaminothiazol-4-yl) -2-Z-methoxyiminoacetamido] cephalosporanic acid as a beige powder.

b) A suspension of 10.0 g of 7 / 3-2- (2-tert-butyloxycarbonylaminothiazol-4-yl) -2-X-methoxyiminoacetamide orcephalosporanic acid. 150 ml of distilled water are brought to pH 7.4 by addition of 2N sodium hydroxide solution. The solution obtained is reacted for 5 hours with purified Bacterium subtilis esterase (strain ATCC 6333) at constant pH and 35 °. Then the reaction. The mixture was overlaid with cold ethyl acetate and adjusted to pH 2 with 5M phosphoric acid solution under ice-cooling. The separated aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were washed with water, dried over magnesium sulphate and concentrated to about 300 ml. After reaction with an excess of diphenyldiazomethane at room temperature for 3 hours, diphenyl dimethyl ester 7 / 3- is isolated by cooling and addition of a mixture of hexane and ether 1: 1.

[2- (2-tert-Butyloxycarbonylaminothiazol-4-yl) -2-Z-methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid and recrystallized from a mixture of acetone and cyclohexane.

UV spectrum (C ₂ H ₅ OH):

Λ _max = 235 (ε = 15,000), 295 nm (arm);

IC spectrum (in methylene chloride):

3400, 1790, 1778, 1729, 1680, 1640 (wide), 1543 cm ^-1 ;

DS: _Rf value ~ 0.28 (toluene: ethyl acetate 1: 1).

(c) 5 g of 7 / S- [2- (2-tert-butyloxycarbonylaminothiazol-4-yl) -2-Z-methoxyiminoacetamido] -3-hydroxymethyl-3-cephem-4-carboxylic acid diphenylmethyl ester is dissolved in 50 ml of absolute dlmethylsulphoxide 50 ml of acetic anhydride are added and the reaction mixture is left under nitrogen at room temperature for 5 hours. After concentration to about 50 ml in vacuo, the reaction mixture is normally treated with ethyl acetate, water, saturated sodium bicarbonate solution and saturated sodium chloride solution. Chromatography of the crude product on 150 g of silica gel eluting with toluene and 20 to 50% ethyl acetate gives diphenylmethyl 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-Z-methoxy-aminoacetamldo] -3-formyl-3- of cephem-4-carboxylic acid, as well as a small amount of the corresponding 2-cephemedevate as a by-product.

Collins oxidation with chromium trioxide dipyridine complex in absolute methylene chloride provides similar results.

Example 2

0.20 g of 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-formyl-2-cephem-4'-carboxylic acid diphenylmethyl ester was dissolved in 50 ° C at 60 ° C. ml of degassed benzene and 1 mol equivalent of tris-triphenylphosphine-rhodium chloride are added under vigorous stirring. After refluxing for 5 hours, the reaction mixture was evaporated and the residue was chromatographed on silica gel. A hardly separable mixture of the A ² / A ³ -3-H-cephem is obtained, which is taken up in methylene chloride and left to stand at room temperature for 5 hours after addition of 0.5 ml of triethylamine. Normal treatment with methylene chloride, 2N hydrochloric acid solution and saturated sodium chloride solution afforded crude N - [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-Z-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester an acid which is purified by preparative thin layer chromatography.

Example 3

In analogy to the above examples, the following compounds can be prepared using the corresponding starting materials:

(a) N - [2- (2-chloroacetamido-4-thiazolyl) -2-methoxyaiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester,

DS: R _f ~ 0.57 (ethyl acetate);

IC spectrum (methylene chloride):

absorption bands at 3350, 3200, 1782, 1770 (shoulder), 1724, 1705, 1684, 1540 cm ^-1 ;

b) 7 / 3- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester, m.p. 154-157 °;

DS: R _f ~ 0.37 (toluene: ethyl acetate = 1 ·· i);

UV spectrum (in ethanol):

Λ _max = 234 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 ;

c) 7 / 3- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester,

DS: R (0.61 (ethyl acetate);

UV spectrum (in ethanol):

Λ _max = 234 nm (ε = 1600), 293 nm (arm);

IR spectrum (methylene chloride): characteristic absorption bands at 3380, 1789, 1773 (shoulder), 1725, 1680, 1638, 1545 cm ^-1;

d) 2-tert-butoxycarbonylamino-2- (2-trichloroethoxycarbonylamino-4-thiazolyl) acetamido-3-cep-4-carboxylic acid diphenylmethyl ester as an amorphous yellow powder,

DS: R _f = 0.59 (silica gel, solvent system: ethyl acetate);

(e) 7 / 3- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -7a-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester,

DS: R _f = 0.40 (solvent system: toluene-ethyl acetate 3: 2);

b) diphenylmethyl 7, J3 [2- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3-cephem-4-carboxylic acid as a pale beige powder having a value R _f ~ 0.54 (solvent system: 52A), a decomposition temperature of about 150 °;

UV spectrum (in ethanol):

Λ max = 251 nm (ε = 12,900);

IR spectrum (methylene chloride): characteristic absorption bands at 3450, 3360, 3190 (shoulder), 1792, 1728, 1680, 1640, 1607, 1540, 1512 cm ^-1;

g) diphenylmethyl 7- [3- (2-amino-4-thiazolyl) acetamido] -3-cephem-4-carboxylic acid diphenyl ester, the crude product being digested with diethyl ether;

DS: R _f 0.29 (ethyl acetate), mp 105-115 ° (dec.),

UV Spectrum (ethanol):

Amas = 256nm (ε = 11100)

IR spectrum (in methylene chloride):

absorption bands at 3496, 3396, 1791, 1728, 1685, 1640, 1603, 1515 cm ⁴ ;

h) diphenylmethyl ester of 7 (3- [2- (2-amino-4-thiazolyl) [2 [N [methylcarbmoyloxyimino] [acetamido] -3-cephem-4-carboxylic acid as brownish crystals, m.p. ~ 150 ° (decomposition);

DS: _Rf ~ 0.45 (8: 2 chloroform / methanol)

IR (in methylene chloride): absorption bands at 3360, 1782 (broad), 1731, 1684, 1620, 1528 cm @ -1.

These compounds can be processed as follows.

Example 4

A mixture of 1.25 g of diphenylmethyl-7 / 3- (2- (2-chloro (tracetimidamide [4-thiazolyl) -2-methoxyiminoacetamido) -2-methoxy] amino) carboxylic acid, 12 mL of methylene chloride, 0.68 mL of anisole and 3.4 mL of tri The reaction mixture was further stirred for 45 minutes at the same temperature after the dropwise addition of 100 ml of diethyl ether. Excluded 7 (3 - (, 2- (2-chloroacetamide) [4 [thiazo [l]) -2-) methoxyiminoacetamido] -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).

To a solution of 700 mg of 7β-2- [2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido] -4-cephem-4-carboxylic acid in 17 ml of N, N'-dimethylacetamide was added 260 mg of thiourea and the reaction the 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 the washings are transferred to a 180 ml Amberlite XAD-2 column. This column is washed with water and then with a mixture of water and isopropanol 85: 15. The fractions containing the sodium salt of 7β-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidop S-cefem-α-carboxylic acid are combined. and evaporate. The sodium salt is then triturated with acetone, filtered off and dried.

DS: Rf ~ 0.19 (n-butanol / glacial acetic acid / water 67: 10: 23).

UV - petkrum (in ethane):

Amax = 233 nm (ε = 15,500) and 290 nm (wide) (ε = 5500).

Example 5

A solution of 15.0 g of diphenylmethyl 7 / 3- [2-

- (2-tert-butoxycarbonylamino) [4-thiazolyl] [2-methoxyiminoacetamido] -3-cephem [4-carboxylic acid in 75 ml of methylene chloride and 75 ml of trifluoroacetic acid is stirred for 1 hour at room temperature, then cold toluene is added and the mixture was evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried. The obtained light beige-powdery trifluoroacetate 7β-2- (2 [amino [4 [thiazolyl) -2-methoxyiminoacetamido] [3 [Cefem-4] carboxylic acid 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 "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 7 / 3--2- (2-amino-4-thiazolyl) [2-methoxyiminoacetamido] -3-cephem-4- carboxylic acids.

IR spectrum (in nujol):

characteristic absorbent bands at 3300 (wide), 1770, 1670, (wide), 1600, 1532, 1640 cm -1.

A solution of 100 mg of the sodium salt obtained in (5 ml of water is brought to pH 3.5 by the addition of 0.5 N hydrochloric acid solution). The precipitated 7 / 3- (2- (2-amino-2-amino-4-carboxylic acid)). (1) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid is filtered off, washed thoroughly with water and acetone and dried under vacuum.

Example 6

A solution of 3,3 g of diphenylmethyl 7 / 3- (2-

- (2-tert-butoxycarbooylamino-4-thiazolyl) -2-methoxyiminoacetamido] [3 [cephem [4-carboxylic acid] in 35 ml methylene chloride is stirred with 15.4 ml trifluoroacetic acid for 30 minutes at 0 °, then added cold toluene and the mixture was evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried. The resulting yellow powder was dissolved in 10 ml of methanol, a methanolic solution of sodium ethyl hexanoate was added, and diethyl ether was added to complete the precipitation, and the mixture was stirred under ice-cooling for 1/2 hour. The obtained 7β- [2- (2-tert-butoxycarbonylamino-4-thiazolyl] -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt is filtered off, washed well with diethyl ether and dried.

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

UV spectrum (in water):

Amax = 233 nm (ε - 15 500), 290 nm (arm).

To convert to the free acid, 1.5 g of the sodium salt obtained are 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, methylene chloride / ethyl acetate (increasing from 10 to 50% ^! ) And finally pure ethyl acetate. The obtained N- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-ethoxyiminoacetamide] -4-cephem-1-carboxylic acid was recrystallized from methanol / diethyl ether / hexane, m.p. .

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

UV-spectrum (in ethanol):

Ama ·: = 260 nm (ε - 16,880),

232 nm (ε = 19,900),

224 nm (ε = 20,000).

iC-spectrum (in nujol):

absorption bands at 3270, 3180, 1782, 1718, 1654 ^cm-first

Example 7

To a solution of 1.7 g of 7 / 3- [2- (2-tert-butoxycarbonylamino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid pivaloyloxymethyl ester in 8.7 ml of methylene chloride is added 8.7 ml of trifluoroacetic acid and the mixture was 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, and dried. 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-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid pivaloyloxymethyl ester is decomposed from about 130 °.

DS: Rf ~ 0.28 (in ethyl acetate).

UV-petkrum (in ethyl acetate):

Amax = 235 nm (ε = 16,320), 295 nm (arm).

IC-spetkrum (methylene chloride): characteristic absorption bands at 3480, 3390, 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 0.202 g of 7 / 3- [2- (2-amino-4-hiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt in 3 ml of dimethylformamide and the mixture was Stir 3 hours at room temperature. 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-pivaloyloxymethyl ester. 4-carboxylic acids.

Example 9

a) To a solution of 3.0 g (3.76 mmol) of 7 / 3- [D, L-2-tert-butoxycarbonylamino-2- (2-trichiorethoxycarbonylamino-4'-thiazolyl) acetamido] -3- [D, L-2-t-butoxycarbonylamino] acetamido] -3- Cr-4-carboxylic acid in 30 ml of a 1: 1 mixture of acetonitrile and acetic acid, which is cooled to 0 °, is added in portions of 3 g of zinc powder in vigorous stirring over about 10 minutes. After 1 hour, the reaction mixture is diluted with 200 ml of ethyl acetate, the zinc powder is separated by filtration, the filtrate is washed twice with ice water and a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated. The rotary evaporator was freed from the solvent to give diphenylmethyl ester (R, R) -2- (2-carboxylic acid, 2-carboxylic acid). amino-4-hiazolyl) acetamido] -3-cephem-4-carboxylic acid of sufficient purity to be processed in the next step of the synthesis.

DS: Rf value = 0.47 (silica gel, solvent system: ethyl acetate).

b) To a solution of 7 / 4β, 11,2-tert-butoxycarbonylamino-2- (2-amino-4-thiazolyl) acetamido] -3'-Cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole in 10 ml of methylene chloride are added 10 ml of trifluoroacetic acid and the reaction mixture is stirred for 1 hour at 20-25 ° C, excluding moisture under a nitrogen atmosphere. After addition of 200 ml of diethyl ether to the solution cooled to 0 °, 7/3-D, L-2-amino-2- (2-amino-4-hiazolyl) acetamido] -3-cephem-4- trifluoroacetate precipitated in crystalline form. The carboxylic acids are 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, and then the ethyl acetate extracts were adjusted to pH 0 at 0 ° with 2N sodium hydroxide solution.

5.5, concentrated to a volume of about 10 mL and isopropanol (-0 mL) was added dropwise. The precipitate formed is filtered off, reprecipitated from a 1: 1 mixture of water and acetone 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 amorphous. N - [D, L-2-amino-2- (2-amino-4-thiazolyl) acetamido] -3-cephem-4-carboxylic acid dihydrate powder.

DS: Rf value = 0.12 (n-butanol / glacial acetic acid / water 67: 10: 23).

[Ilai _O = 20 + 76 + T (0, lN hydrochloric acid: 0.33%).

UV spectrum (in 0.1N hydrochloric acid solution): λmax - 250 nm (ε = 12,400).

Example 10

To a solution of 2.40 g of diphenylmethyl ester of 7β- [2- [2- tert -butoxycarbonylamino [4-thiazolyl] -2-methoxyiminoacetamido] -4a-methoxy-3-cephem [4-carboxylic acid in 10 ml 15 ml of trifluoroacetic acid are added to the methylene chloride and the reaction mixture is stirred at room temperature for 1 hour with the exclusion of moisture. The reaction mixture was then poured onto an ice-cooled mixture of petroleum ether (400 mL) and diethyl ether (200 mL), the resulting trifluoroacetate was filtered off, washed with petroleum ether and dried under high vacuum at room temperature.

The crude 7-2- (2- [3- (4- (4-isolyl) -2-methoxyiminoacetamido) -7a-methoxy-3 [Cefem-4-carboxylic acid] trifluoroacetate was suspended in 20 mL of water by addition of 1N bicarbonate solution The pH of the solution was adjusted to 6.5, the suspension was stirred for 15 minutes at room temperature, after which a small amount of insoluble product was separated after treatment with activated carbon and filtration. A large amount of ethanol was added to the clear filtrate, the pH was adjusted to 6.0, and the solution was concentrated on a rotary evaporator (under high vacuum) at 45 °. The aqueous solution was evaporated several times with ethanol and finally the sodium salt of N - [2- (2-Amino [4-thiazolyl) [2-methoxyiminoacetamido] -7a'-methoxy-3 [cep-4-carboxylic acid] was added by adding ethanol. The mixture was washed thoroughly with ethanol, ethanol / diethyl ether (1: 1) and diethyl ether. The product can be further purified by dissolving in water and evaporating or precipitating with ethanol. Melting point: 199 DEG (decomposition).

DS: Rf value = 0.33, Rf value = 0.20 (solvent system 67), Rf value = 0.46 (solvent system 101), Rf value - 0.45 (solvent system 101A).

Example 11

A solution of 1,60 g of diphenylmethyl 7β- [2-

- (2-amino-4-hiazolyl) [2-hydroxyimmoacet [amido] -3 [Cefem [4] carboxylic acid in 15 ml methylene chloride is stirred for 30 minutes with 0.50 ml · anisole and 2.35 ml · trifluoroacetic acid in an ice bath, then 100 ml of cold toluene are added and the reaction mixture is evaporated in vacuo. The residue was digested with diethyl ether, the product was filtered off and dried. The obtained N- [4- (2-amino-4-thiazolyl) -2-hydroxyiminoacetamido] -3 [cephem-4-carboxylic acid trifluoroacetate was suspended in 10 ml of a 1: 2 mixture of water and methanol and pH of the suspension with the addition of · 10%! solution of triethylamine in methanol is adjusted to 4.1. After stirring at 0 ° for 30 minutes, the precipitated N - [(4-amino-1-thiazolyl) -2-hydroxyiminoacetamido] [3-cephem-4-carboxylic acid] is filtered off, washed with acetone and diethyl ether and dried. The temperature is about 170 ° (decomposition).

DS: Rf ~ 0.03 (solvent system 52A).

Example 12

A solution of 1,2 g of diphenylmethyl ester 7/3 [2-

- (2-Amino-4-hiazol-4-yl) acetamido] -3-cephem-4-carboxylic acid in 12 ml of methylene chloride, together with 0.39 ml of anisole and 1.83 ml of trifluoroacetic acid, is stirred for 30 minutes on ice. 100 ml of cold toluene is added and the mixture is evaporated in vacuo. The residue was digested with diethyl ether and the product was filtered off. The obtained 7/3 - trifluoroacetate [2- (2-amino-4-azyl) acetamido] -3 [cephem [4] carboxylic acid is suspended in 10 ml of a 1: 1 mixture of water and methanol. The pH of the slurry was adjusted to about 10% with 10% methanolic triethylamine

4. After stirring for 1 hour under ice-cooling, the precipitate is filtered off, washed with acetone and diethyl ether and dried. There was obtained 7 / 3- (2- (2-amino-4-hiazotyl) acetamido) -32 16 9 3 5

-cephem-4-carboxylic acid, m.p. 210 ° (dec.).

DS: _Rf value ~ 0.05 (solvent system 52A).

iC-spectrum (in nujol):

absorption bands at 3480 (wide), 3280, 1745 (shoulder), 1720, 1670, 1545 cm ¹ .

Example 13

A solution of 760 mg of 7 / 3- [2- (2-amino-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido] -3-cephem-4-carboxylic acid diphenylmethyl ester in 7 mL of methylene chloride is stirred with 0.21 mL of anisole and 1 ml of trifluoroacetic acid on an ice bath for 30 minutes, then 50 ml of cold toluene are added and the mixture is evaporated in vacuo. The residue was digested with diethyl ether, cooled with ice, filtered off and dried. The obtained 7 / 3- [2- (2-amino-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido] -3-cephem-4-carboxylic acid trifluoroacetate is suspended in about 6 ml of a 1: 4 mixture of water and methanol and The pH of the suspension is adjusted to about 4 by adding a 10% methanolic solution of triethylamine. After stirring at 0 ° for 30 minutes, 7 / 3- (2- (2-amino-4-thiazolyl) -2-N-methylcarbamoyloxyiminoacetamido) -S-cephem- The 4-carboxylic acid is filtered off and washed with diethyl ether, whereupon the yield is about 215 °.

DS: _Rf value ~ 0.24 (solvent system 52A).

IR (nujol): absorption bands at 1775 (shoulder), 1757, 1664, 1625 ^cm-first

Example 14

Capsules containing 0,250 g of sodium salt 7 / 3-

- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid is prepared as follows:

Ingredients (for 100,000 capsules): 7 / 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium wheat starch magnesium stearate

7 / 3- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid sodium salt, wheat starch and magnesium stearate are mixed well and filled into capsules size 1.

Example 15

Capsules containing 0,5 g of sodium 7 / 3- (2-

- (2-Amino-4-thiazolyl) -2-methoxyiminoacet-

000 g

500 g 100Og

1000,00 g

15,00 g

115, Og

20.00 g of amido] -3-cephem-4-carboxylic acid are prepared as follows:

Ingredients (for 2000 capsules):

7 / 3- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3-cephem-4-carboxylic acid sodium salt polyvinylpyrrolidone corn starch magnesium stearate

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 polyvinylpyrrolidine in 95% ethanol, sieved through a sieve of size 3 mm holes and the granulate is dried under reduced pressure at 40-50 °. The dried granulate is passed through a 0.8 mm sieve, corn starch and magnesium stearate are added, and the resulting mixture is filled into push-fit capsules (size 0).

Example 16

Dry ampoules or foils containing 0.5 g of 7 / 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt are prepared as follows:

Ingredients (per 1 inpull or flol): 7 / 3- [2- (2-amino-4-thlazolyl) -2-methoxyiminoacetamideb] -3-cephem-4-carboxylic acid sodium salt 0.5 g mannit 0.05 g

Sterile aqueous solution of 7./3-(2-(2-amino-4-thiazolyl)-2- (methoxyimino) acetamido] -3-cephem-4-carboxylic acid sodium salt and mannitol are sealed under acceptance conditions in a 5 ml ampoule or 5 ml and testing.

Example 17

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

Composition (for 1 ampoule or vial): 7 / 3- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid sodium salt 0,25 g mannitol 0,05 g

The sterile aqueous solution of 7 / 3- (2- (2-amino-4-thiazolyl) -2-methyl-oxyiminoacetamido] -3-cephem-4-carboxylic acid and mannitol sodium salt is filled into a 5 ml ampoule or 5 ml under aseptic conditions. The flask and contents are sealed and tested.

Claims (7)

CLAIMS 1. A process for the preparation of a .alpha.-amirrothiazole-3-cephem-4-carboxylic acid derivative of the formula (I): Wherein RfHN means 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 carbamoylated hydroxy-hydroxy of up to 11 carbon atoms or methoxyimino substituted methylene, R3 is hydrogen, methoxy or C1-C6-substituted alkylthio, tolylthio or phenylthio, and R 2 is hydrogen or a carboxyl group esterifying a C 1 -C 7 alkyl radical, an adamantyl radical, a phenylmethyl radical in which 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, polyhalophenyl radicals, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radicals, alkanoyloxymethyl radicals (C 1 -C 4) alkanoyl moiety, (C 1 -C 4) aminoalkanoyloxymethyl radical, (C 1 -C 4) alkoxycarbonyloxymethyl radical, (C 1 -C 4) alkoxycarbonyloxymethyl radical; carbon atoms in the alkoxy group, alkanoylthiomethyl (C 1 -C 4) alkanoyl radical, (C 1 -C 4) alkanoylaminomethyl radical optionally substituted by halogen, benzoylaminomethyl radical, phthalidyl radical, C 1 -C 4 alkoxymethyl radical, 2- (C 1 -C 4) aminoalkyl or (C 3 -C 8) 2-aminocycloalkyl radical of the cycloalkyl moiety, wherein the amino group is substituted with two C 1 -C 4 alkyl radicals or C 2 -C 8 alkylene; which optionally contains an oxo group, and salts of such compounds with salt-forming groups, characterized in that the compound of formula VI is S ~ | —Ζ I ⁷ NJ (VI) in which R _b , R 2, R 3 and A have the meanings given in formula I, and wherein the double bond is in the 2, 3 or 3, 4 position and the functional groups are optionally protected, act as a heavy metal complex by decaribonylating agent. the reaction using 2-cephemedivatives of formula (VI) heats the decarbonylation product at a temperature of 25 to 120 ° C or / and is treated with a base and optionally converted to another residue of R 1, R 2 or A in the compound of formula I 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 to another salt. 2. A process according to claim 1, wherein the compound of formula VI, wherein R3. is hydrogen or methoxy, R 2. has. as defined in (1), A represents methylene, aminomethylene, hydroxymethylene, sulfomethylene, hydroxyiminomethylene, carbamoylated hydroxyiminomethylene or methoxyiminomethyl and R 1 represents hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkanoyl Or a 2-haloalkanoyl group having from 1 to 4 carbon atoms, acting on a platinum metal complex such as a phosphorus-containing platinum metal complex, and unwanted protecting groups are cleaved in the compound of formula I obtained and the compound of formula I the free carboxyl group at the 4-position is optionally converted to a pharmaceutically acceptable salt. 3. A process according to claim 1, wherein the compound of formula VI wherein R3 is hydrogen or methoxy, R2 is hydrogen, diphenylmethyl or a physiologically cleavable acetyloxymethyl, pivaloyloxymethyl, 1-ethyloxycarbonyloxyethyl or phthalidyl group A represents a hydroxyiminomethylene group, an N-methylcarbamoyloxyiminomethylene group or a methoxyiminomethylene group, and Rt represents a hydrogen or a 2-haloalkanoyl group having from 1 to 4 carbon atoms, acts with a phosphorus-containing platinum metal complex. the carboxyl group at the 4-position is optionally converted to a pharmaceutically acceptable salt. 4. The process of claim 1 wherein the 3-formyl-3-cephem derivative of formula VI wherein R3 is hydrogen, R2 is diphenylmethyl, A is methoxyiminomethylene, and Rf is amino substituted by tert-butoxycarbonyl, with tris. - triphenylphosphine-rhodium chloride, the compound obtained is treated with trifluoroacetic acid and the resulting N- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3-cephem-4-carboxylic acid trifluoroacetate is optionally converted to the free compound, or to a pharmaceutically acceptable salt. 5. Method according to claim 1, characterized in that the derivative of 3-formyl [2-cephem of formula VI wherein R3 is hydrogen, A methoxyiminomethylenovou, R ₂ and R diphenylmethyl amino group substituted by a tert-butoxycarbonyl group treated tris [triphenylphosphinium chloride] and the resulting mixture of A2 / A3-3-H-cephem are treated with triethylamine, treated with trifluoroacetic acid and the obtained trifluoroacetate 7-2- (2 [amino-4-thiazolyl) - Optionally, the 2-methoxyiminoacetamido-3-carboxylic acid 4-carboxylic acid is converted to the free compound or a pharmaceutically acceptable salt thereof. 6. A process according to claim 1 for the preparation of 7-3-thiothiazolyl-acetamido-3-cephem-4-carboxylic acid derivatives of the formula I wherein R3 is hydrogen, R, hydrogen, C1-C4alkyl, acyl up to 18 carbon atoms, mono-, di- or triphenylmethyl, A is methylene or methylene substituted with amino, hydroxy, sulfo, oxo, hydroxyimino or methoxyimino, and R2 is hydrogen or a carboxy group esterifying an alkyl group having 1 up to 7 carbon atoms; a phenylmethyl radical in which phenyl is one or two optionally C1 -C4 alkyl, C1 -C4 alkoxy, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen substituted benzoylmethyl radicals, polyhalophenyl radicals, alkyl. C 1 -C 4 alkoxy, C 1 -C 4 alkoxy and / or halogen substituted silyl or stannyl radical, C 1 -C 4 alkanoyloxymethyl radical, C 1 -C 4 aminoalkanoyloxymethyl radical, phthalidyl radical or a 1-ethyloxycarbonyloxyethyl radical, and salts of such compounds. salt forming groups, characterized in that a compound of formula VI in which R1, R3, Y and R2 are as defined above and in which the functional groups are optionally protected is treated with a decarbonylating agent as a heavy metal complex, wherein, after the reaction using 2-cephemedivatives of formula VI, the decarbonylation product is heated to a temperature of 25 to 120 ° C and / or is treated with a base, whereupon optionally the residue R _b R 2 or A is converted into another the radical R _b or R 2 a, and / or the resulting compound of formula 'I is optionally converted into a salt or a resulting salt into the free compound of formula I or into another salt. 7. The method of claim 1 к production of derivatives of 7--aminothiazolylacetamido-3-cephem-4-carboxylic acid of formula I wherein R ₃ is hydrogen, R is hydrogen, alkyl having 1 to 4 carbon atoms or acyl having up to 18 alkyl or mono-, di- or triphenylmethyl group, a represents a methylene group or an amino, hydroxy, sulfo, oxo, hydroxyimino or methoxyimino group substituted methylene radical and R ₂ represents hydrogen or a carboxyl esterifying group, an alkyl radical having 1-7 carbon atoms, adamantyl, a phenylmethyl radical in which phenyl is one or two optionally C1-C4alkyl radicals, C1-C4alkoxy, hydroxy, halogen or nitro substituted phenyl radicals, optionally halogen-substituted benzoylmethyl radicals, polyhalophenyl radicals, alkyl radicals C 1 -C 4 alkoxy C 1 -C 4 and / or halogen substituted silyl or stannyl radical, C 1 -C 4 alkanoyloxymethyl radical, C 1 -C 4 aminoalkanoyloxymethyl radical, C 1 -C 4 alkanoylcarbonyloxymethyl radical alkanoyl moieties, C 1 -C 4 alkoxycarbonyloxyethyl, C 1 -C 4 alkanoylthiomethyl radical, C 1 -C 4 alkanoylaminomethyl radical in which the alkanoyl group is optionally substituted halogen, benzoylaminomethyl, phthalidyl, C 1 -C 4 alkoxymethyl, C 1 -C 4 2-aminoalkyl or C 3 -C 8 2-aminocycloalkyl radical in which the amino group is substituted by two alkyl radicals C 1-4 alkyl or alkylene with 2 to 8 carbon atoms optionally containing an oxo group, and salts of such compounds with salt-forming groups, characterized in that the compound of formula VI in which R _b R ₂ and A are as defined in formula I and in which they are The functional groups optionally protected are treated with a decarbonylating agent, such as a heavy metal complex, after the reaction using the 2-cephemedivatives of formula VI, the decarbonylation product is heated to 25 to 120 ° C and / or treated with a base, with a compound of formula I, the residue R 1, R ₂ or A is converted into another residue R _{b of} 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 of formula I or another salt.