CH626091A5 - Process for preparing enol derivatives - Google Patents

Abstract

There is described a novel process for preparing 7 beta -amino-3- or -2-cephem-3-ol-4-carboxylic acid compounds of the formula IA <IMAGE> or of the formula IB <IMAGE> where R@ is hydrogen or an amino-protective group R@, R@ is hydrogen or an acyl group Ac, or R@ and R@ together are a bivalent amino-protective group, R2 is hydroxyl or a radical R@ which together with the carbonyl group -C(=O)- forms a protected carboxyl group, and R3 is hydrogen, lower alkyl or optionally substituted alpha -phenyl(lower alkyl). The process comprises cyclising a 2-[4-(subst.thio)-3-acylamino-2-oxoazetidin-1-yl]-3-subst.amino-croton ic acid compound and solvolysing the 3-amino group in the resulting 7 beta -amino-3-(subst.amino)-3-cephem-4-carboxylic acid intermediate to the -O-R3 group.

Description

The present invention relates to a new process for the preparation of 7β-amino-3-cephem-3-ol-4-car-bonic acid compounds of the formula

0 = C ~! * 2

in which Rja represents hydrogen or an amino protecting group RXA, R ^ represents hydrogen or an acyl group Ac,

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or Ria and together represent a divalent amino protecting group, R2 stands for hydroxyl or one, together with the carbonyl group -C '(= 0) - represents a protected carboxyl group R2A, and Ra stands for hydrogen, lower alkyl or for optionally substituted a-phenyl lower alkyl, where R2 is not hydroxy if R0 is hydrogen, and the corresponding 2-cephemver compounds of the formula

0

wherein R /, R, b, R2 and R;> have the meanings given above, or salts of such compounds with salt-forming groups.

These antibiotics have valuable pharmacological properties or can be used as intermediates for the production of such. When administered parenterally and / or orally, they are effective against various gram-positive and gram-negative microorganisms, in particular against penicillin-resistant bacteria, with low toxicity.

These compounds are known from Swiss Patent Nos. 587 268 and 590 873. The known processes for the preparation of the abovementioned compounds have the disadvantages that they are difficult to access from fermentative, i.e. cephalosporin compounds obtainable only in low yield, in particular cephalosporin C, assume that certain intermediates require chromatography that is difficult to carry out industrially and that the overall yield is unsatisfactorily low.

The object of the invention is therefore to develop a new technically advanced method.

It has surprisingly been found that the compounds mentioned above can be prepared by protecting penicillins which can be produced by fermentation with high yield, in particular the 1-oxides of penicillin G or V and 6-amino-penicillanic acid, and their reactive groups in any known manner can easily be released after the reaction, it is assumed that the intermediates are obtained in high yields and sufficiently good purity, so that chromatography is unnecessary, and that the overall yield is significantly higher in all stages.

In 2-chephem compounds of the formula IB with the double bond in the 2,3-position, the optionally protected carboxyl group of the formula -C (= 0) -R2 preferably has the a configuration.

An amino protective group R, A is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl group, in particular the trityl group, and an organic silyl or an organic stannyl group. A group Ac, which can also represent a radical R ^ ',

represents primarily the acyl radical of an organic carboxylic acid, preferably having up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (including formic acid), and represents the acyl residue of a carbonic acid derivative.

A bivalent amino protecting group formed together by the radicals Rxa and R ^ is in particular the bivalent acyl radical of an organic dicarboxylic acid, preferably having up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl radical of a, preferably substituted in the a-position , e.g. an aromatic or heterocyclic radical containing a-aminoacetic acid, wherein the amino group is substituted via a, preferably substituted, e.g. two lower alkyl, such as methyl groups containing methylene radical is connected to the nitrogen atom. The radicals and Rxb together can also be an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably having up to 18 carbon atoms.

A protected carboxyl group of the formula -C (= 0) -R2A is primarily an esterified carboxyl group, but can also be a, usually mixed anhydride group or an optionally substituted carbamoyl or hydra-zinocarbonyl group.

The group R2A can therefore be a hydroxy group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= 0) grouping form an esterified carboxyl group. Such organic residues are e.g. aliphatic cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals.

The group R2A can also be an organic silyloxy radical, and a hydroxyl group etherified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a hydrocarbon radical which is optionally substituted by 1 to 3, preferably having up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen, such as chlorine-substituted silyloxy or stannyloxy group.

A radical R.sup.A forming a primarily mixed anhydride group with a -C (= 0) grouping is, for example, halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably having up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid semi-derivative, such as a carbonic acid semi-ester.

A radical R, A which forms a carbamoyl group with a -C (= 0) group is an optionally substituted amino group, in which substituents are optionally substituted monovalent or bivalent hydrocarbon radicals, preferably having up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic , Cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, further etherified or esterified Hydroxy, in which the etherifying or esterifying radicals, for example have the meanings given above and preferably up to 18

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Contain carbon atoms, as well as acyl residues, primarily from organic carboxylic acids and from carbonic acid derivatives, preferably with up to 18 carbon atoms.

One or both nitrogen atoms can be substituted in a substituted hydrazinocarbonyl group of the formula -C (= 0) -R2a, the substituents primarily being optionally substituted monovalent or bivalent hydrocarbon radicals, preferably having up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups, such as acyl radicals, primarily of organic carboxylic acids or of carbonic acid derivatives, preferably with up to 18 carbon atoms.

The general terms used in the above and following description have e.g. the following meanings:

An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid and a corresponding ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and also lower alkenyl or lower alkynyl, furthermore lower alkylidene, e.g. can contain up to 7, preferably up to 4 carbon atoms. Such residues can optionally be substituted by functional groups, e.g. by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, neideralkylene dioxy, optionally substituted phenyloxy or phenyl lower alkoxy, lower alkylthio or optionally substituted phenylthio, phenyl lower alkylthio, heterocyclylthio or heterocyclyl loweroxyalkoxy or halogeno, optionally carbonyl or oxyalkoxy, alkoxyalkoxy, optionally substituted, by oxo, nitro, optionally substituted amino, for example Niederalkylamino, di-Niederalkylamino, Niederalkylenamino, Oxaniederalkylenamino or Azaniederalkylenamino, as well as Acylamino, such as Niederalkanoylamino, Niederalkoxy-carbonylamino, Halo-geniederalkoxycarbonylamino, optionally substituted Phenylniederalkoxycarbonylamino, optionally substituted Carbamoylamino-alino-imino-aminocallamino, urocarbamylamino, urocarbamylamino, urocarbamylamino, urocarbonylamino, urocarbamylamino, urocarbamylamino, urocarbamylamino, urocarbamylamino, urocarbamylamino, urocarbamolamino, urocarbamolamino, urocarbamolamino, urocarbamylamino, urocarbamylamino, urocarbamylamino, urocarbylamino, urocarbylamino, urocarbamylamino, urocarbamol sulfoamino, azido, acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as carboxyl in salt form, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-lower alkyl or N, N-diniederalkylcarbamoyl, further optionally substituted Ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or Sülfo present in salt form, or optionally O-mono- or 0.0-disubstituted phosphono, in which substituent ducks e.g. optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where O-unsubstituted or O-monosubstituted phosphono can also be in salt-like alkali metal salt form, mono-, di- or poly-substituted.

A bivalent aliphatic residue, including the corresponding residue of a bivalent aliphatic carboxylic acid is e.g. Lower alkylene or lower alkenylene, optionally, e.g. such as an aliphatic radical indicated above, mono-, di- or poly-substituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur.

A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic

table-aliphatic radical in a corresponding organic carboxylic acid or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. mono-, bi- or polycyclic cycloalkyl or cyclo-alkenyl, further cycloalkylidene, or cycloalkyl or cyclo-alkenyl-lower alkyl or lower alkenyl, furthermore cycloalkyl-lower alkylidene or cycloalkenyl lower alkylidene, in which cycloalkyl and cycloalkylidene e.g. contains up to 12 such as 3-8, preferably 3-6 ring carbon atoms, while cyclo-alkenyl e.g. up to 12, such as 3-8, e.g. 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical e.g. can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned optionally substituted lower alkyl groups, or then, e.g. like the abovementioned aliphatic hydrocarbon radicals, can be mono-, di- or poly-substituted by functional groups.

An aromatic residue, including the aromatic residue of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon residue, e.g. a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, and also biphenylyl or naphthyl, which, if appropriate, e.g. how the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals can be mono-, di- or poly-substituted.

A bivalent aromatic residue, e.g. an aromatic carboxylic acid is primarily 1,2-arylene, especially 1,2-phenylene, which may optionally, e.g. how the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals can be mono-, di- or poly-substituted.

An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, furthermore an araliphatic ylidene radical, is e.g. an optionally substituted araliphatic hydrocarbon residue such as an optionally substituted e.g. up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radicals and primarily represent phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, furthermore phenyl-lower alkylidene, such radicals being e.g. Contain 1-3 phenyl groups and optionally, e.g. how the abovementioned aliphatic and cycloaliphatic radicals can be mono-, di- or poly-substituted in the aromatic and / or aliphatic part.

Heterocyclic groups, including those in heterocyclic aliphatic radicals, including heterocyclic or heterocyclic aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bicyclic or polycyclic aza, thia, oxa, thiaza, thiadiaza,

oxaza, diaza, triaza or tetrazacyclic residues of aromatic character, furthermore corresponding partially or completely saturated heterocyclic residues of this type, such residues optionally, e.g. how the above-mentioned cycloaliphatic radicals can be mono-, di- or poly-substituted. The aliphatic part in heterocyclic aliphatic residues has e.g. the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.

The acyl residue of a carbonic acid derivative is preferably the acyl residue of a corresponding half ester,

wherein the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or

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represents a heterocyclic aliphatic radical, primarily the acyl radical one optionally, e.g. in a- or ß-position, substituted lower alkyl half-ester of carbonic acid, and a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid optionally substituted in the organic radical. Acyl residues of a carbonic acid half ester are also corresponding residues of lower alkyl half esters of carbonic acid in which the lower alkyl part contains a heterocyclic group, e.g. contains one of the abovementioned heterocyclic groups of aromatic character, it being possible for both the lower alkyl radical and the heterocyclic group to be optionally substituted. The acyl radical of a carbonic acid derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group.

An etherified hydroxy group is primarily optionally substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified, hydroxyl groups, in particular lower alkoxy or halogen, furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocyclyloxy or heterocyclyl-lower alkoxy, in particular also optionally substituted phenyl lower alkoxy.

An optionally substituted amino group is e.g. Amino, Niederalkylamino, Diniederalkylamino, Nieder-alkylenamino, Oxaniederalkylenamino, Thianiederalkylenamino, Azaniederalkylenamino, Hydroxyamino, Niederalk-oxyamino, Niederalkanoyloxyamino, Niederalkoxycarbonylamino or Niederalkanoylamino.

An optionally substituted hydrazino group is e.g. Hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-loweralkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.

Lower alkyl is e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl e.g. Vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. Propargyl or 2-butynyl, and lower alkylidene e.g. Isopropylidene or isobutylidene can be.

Lower alkylene is e.g. 1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenyls e.g. 1,2-ethylene or 2-butene-1,4-ylene. Lower alkylene interrupted by heteroatoms is e.g. Oxane lower alkylene such as 3-oxa-l, 5-pentylene, thi-lower alkylene such as 3-thia-l, 5-pentylene or azane-lower alkylene such as 3-lower alkyl-3-aza-l, 5-pentylene, e.g. 3-methyl-3-aza-1,5-pentylene.

Cycloalkyl is e.g. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cyclo-alkenyl e.g. Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-,

2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclo-hexadienyl, and cycloalkylidene e.g. Cyclopentylidene or cyclohexylidene. Cycloalkyl-lower alkyl or lower alkenyl is e.g. Cyclopropyl-, cyclopentyl-, cyclohexyl- or cyclo-heptylmethyl, -1,1- or -1,2-ethyI, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl, while cycloalkenyl-lower alkyl or lower alkenyl, for example 1-, 2- or 3-cyclopentenyl-, 1-, 2- or

3-Cyclohexenyl- or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3-propyl, -vinyl or -allyl represents. Cycloalkyl-lower alkylidene is e.g. 3-cyclo-hexenylmethylene.

Naphthyl is 1- or 2-naphthyl, while biphenylyl e.g. 4-biphenylyl.

Phenyl-lower alkyl or phenyl-lower alkenyl is e.g. Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl,

Diphenylmethyl, trityl, styryl or cinnamyl, naphthyl-lower alkyl e.g. 1- or 2-naphthyimethyl, and phenyl-lower alkylidene e.g. Benzylidene.

Heterocyclic residues are primarily 5 substituted heterocyclic residues of aromatic character, e.g. corresponding monocyclic, monoaza, monothia or monooxacyclic radicals, such as pyrryl, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, further pyiridinium, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl, io bicyclic monoaza, monooxa or monothiacyclic residues such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzofuranyl, e.g. 2- or 3-benzofuranyl, or benzothienyl, e.g. 2- or 3-benzothienyl, monocyclic diaza, triaza, tels traza, oxaza, thiaza or thiadiazacyclic radicals such as imidazolyl, e.g. 2-imidazolyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, tetrazolyl, e.g. 1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g. 2-thia-20 zolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. l, 2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza- or thiaza-cyclic radicals such as benzimidazolyl, e.g. 2-benzimidazolyl, benzoxazolyl, e.g. 2-benzoxazolyl, or benzthiazolyl, e.g. 25 2-benzothiazolyl. Corresponding partially or completely saturated residues are e.g. Tetrahydrothienyl such as 2-tetrahydrothienyl, tetrahydrofuryl such as 2-tetrahydrofuryl or piperidyl, e.g. 2- or 4-piperidyl. Heterocyclic aliphatic radicals are heterocyclic groups, in particular the abovementioned 30-containing lower alkyl or lower alkenyl. The above heterocyclyl residues can e.g. by optionally substituted aliphatic or aromatic hydrocarbon radicals, especially lower alkyl, such as methyl, or optionally, e.g. phenyl substituted by halogen such as chlorine, 35 e.g. Phenyl or 4-chlorophenyl, or, e.g. like the aliphatic hydrocarbon radicals, be substituted by functional groups.

Lower alkoxy is e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-40 butyloxy, n-pentyloxy or tert-pentyloxy. These groups can be substituted, e.g. as in halogen-lower alkoxy, especially 2-halogen-lower alkoxy, e.g. 2,2,2-trichloro, 2-chloro, 2-bromo or 2-iodoethoxy. Lower alkenyloxy is e.g. Vinyloxy or allyloxy, lower alkylenedioxy e.g. 45 methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g. Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g. Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy - diphenylmethoxy, or heterocyclyloxy or heterocyclyl-50 lower alkoxy, e.g. Pyridyl-lower alkoxy, such as 2-pyridylmeth-oxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.

Lower alkylthio is e.g. Methylthio, ethylthio or n-5s butylthio, lower alkenylthio e.g. Allylthio, and phenyl-lower alkylthio e.g. Benzylthio, while mercapto groups etherified by heterocyclyl radicals or heterocyclylaliphatic radicals, in particular pyridylthio, e.g. 4-pyridylthio, imidazolylthio, thiazolylthio, e.g. 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g. l, 2,4-thiadiazol-3-ylthio or l, 3,4-thiadiazol-2-ylthio, or tetrazolylthio, e.g. 1 - Methyl-5-tetrazolylthio.

Esterified hydroxy groups are primarily halogen, e.g. Fluorine, chlorine, bromine or iodine, and lower alkoxycar-65 bonyloxy, e.g. Methoxycarbonyloxy, ethoxycarbonyloxy or tert-butyloxycarbonyloxy, 2-halogeno lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromo-ethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or aryl

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carbonyl, 2-halogeno lower alkoxycarbonyl or phenylnederalkoxycarbonyl radical, or one, optionally in salt, e.g. Alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, e.g. Methoxy, acyloxy, wherein acyl is primarily the acyl radical of a carbonic acid semi-ester, such as a lower alkoxycarbonyl, 2-halogeno lower alkoxycarbonyl or phenyl lower alkoxycarbonyl radical, and / or halogen, e.g. Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, one optionally, e.g. by lower alkyl, e.g. Methyl, and / or phenyl, which in turn has substituents such as halogen, e.g. Chlorine, substituted heterocyclic group such as a 4-isoxazolyl group, or preferably, e.g. by an optionally substituted such as halogen, e.g. Chlorine-containing lower alkyl radical N-substituted amino group, or n for 1, R1 for an optionally, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, e.g. Chlorine, containing phenyloxy, or lower alkyl group substituted by optionally protected amino and / or carboxy, e.g. for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, e.g. silylated such as tri-lower alkylsilylated e.g. trimethylsilylated, amino or acylamino, such as lower alkanoylamino, halogeno lower alkanoylamino or phthaloylamino, and / or silylated, such as tri-lower alkylsilylated, e.g. trimethylsilylated, or esterified, such as by lower alkyl, 2-halo-lower alkyl or phenyl-lower alkyl, e.g. Diphenylmethyl, esterified carboxy group, for a lower alkenyl group, for an optionally substituted, such as optionally, e.g. as indicated above, acylated hydroxy and / or halogen, e.g. Chlorine, further optionally protected, e.g. as indicated above, acylated amino lower alkyl such as aminomethyl, or optionally, e.g. as indicated above, acylated hydroxy and / or halogen, e.g. Chlorine, phenyloxy-containing phenyl group, optionally, e.g. by lower alkyl, such as methyl, or optionally protected, e.g. acylated, amino or aminomethyl, substituted pyridyl, e.g. 4-pyridyl, pyridinium, e.g. 4-pyridinium, thienyl, e.g. 2-thienyl, furyl, e.g. 2-furyl, imidazolyl, e.g. 1-imidazolyl or tetrazolyl, for example 1-tetrazolyl group, an optionally substituted lower alkoxy, e.g. Methoxy group, an optionally substituted, such as optionally protected, e.g. as stated above acylated, hydroxyl and / or halogen such as chlorine containing phenyloxy group, a lower alkylthio e.g. n-butylthio, or lower alkenylthio, e.g. Allylthio group, optionally, e.g. phenylthio, pyridylthio, e.g. 4-pyridiylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-yl-thio-, 1,2,4-thiadiazol-3-ylthio - such as 5-methyl-1,2,4-thidiazol-3-yIthio-, 1,3,4-thiadiazol-2-ylthio- such as methyl-1,3,4-thia-diazol-2-ylthio -, or 5-tetrazolylthio, such as l-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, for example Methoxy-carbonyl or ethoxycarbonyl, cyano or optionally, e.g. lower alkyl such as methyl or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g. Acetyl or propionyl or benzoyl group, or an azido group, and Rn and Rm for hydrogen,

or n for 1, R1 for lower alkyl or an optionally, as by optionally, e.g. as indicated above, acylated hydroxy and / or halogen, e.g. Chlorine, substituted phenyl, furyl, e.g. 2-furyl, thienyl, e.g. 2- or 3-thienyl,

or isothiazolyl, e.g. 4-isothiazolyl group, further for an L 1,4-cyclohexadienyl group, Rn for optionally protected or substituted amino, e.g. Amino, acylamino such as • lower alkoxycarbonylamino, 2-halogeno lower alkoxycarbo-5 nylamino or optionally substituted such as lower alkoxy, e.g. Phenyl-lower alkoxycarbonylamino containing methoxy or nitro, e.g. tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino or diphenylmethyloxycarbonylamino, aryl-lo sulfonylamino, e.g. 4-methylphenylsulfonylamino, trityl-amino, arylthioamino such as nitrophenylthioamino, e.g. 2-nitrophenylthioamino, or tritylthioamino or optionally substituted such as lower alkoxycarbonyl, e.g. Ethoxycarbonyl, or lower alkanoyl, e.g. Acetyl containing is 2-propylidene amino, such as l-ethoxycarbonyl-2-propylidene amino, or optionally substituted carbamoylamino such as guanidinocarbonylamino, or one optionally in salt, e.g. Alkali metal salt form of sulfoamino group, an azido group, optionally in salt, e.g. Al-20 potassium metal salt form or in protected, such as esterified form, e.g. as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, or as phenyloxycarbonyl, e.g. Diphe-; nylmethoxycarbonyl group present carboxyl group,

a cyano group, a sulfo group, an optionally functionally modified hydroxy group, with functionally modified hydroxy in particular acyloxy, such as formyloxy, and also lower alkoxycarbonyloxy, 2-halogeno lower alkoxycarbonyloxy or optionally substituted, such as lower alkoxy, e.g. Phenyl-lower alkoxycarbonyloxy containing methoxy, or nitro, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichloroethoxycarbonyloxy, 4-methoxybenzyloxycarbonyloxy or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, e.g. Methoxy, or phenyloxy, is an O-lower alkyl or O.O'-di-lower alkyl-35 phosphono group, e.g. O-methyl-phosphono or 0,0'-dimethylphosphono, or a halogen atom, e.g. Chlorine or bromine, and R111 for hydrogen, or n for 1, R1 and Rn each for halogen, e.g. Bromine, or lower alkoxycarbonyl, e.g. Methoxycarbonyl, and Rm for hydrogen, or n for 1.40 R1 for an optionally, e.g. by optionally, e.g. as indicated above, acylated hydroxy and / or halogen, e.g. Chlorine, substituted phenyl, furyl, e.g. 2-furyl, or thienyl, e.g. 2- or 3-thienyl, or isothiazolyl, e.g. 4-isothiazolyl group, further for a 1,4-cyclohexadienyl-45 grappe, Rn for optionally, e.g. as indicated above, protected aminomethyl, and R111 for hydrogen, or n for 1 and each of the groups R1, R11 and Rm for lower alkyl, e.g. Stand methyl.

Such acyl residues Ac are e.g. Formyl, cyclopentylcarbo-50 nyl, a-aminocyclopentylcarbonyl or a-amino-cyclohexyl-carbonyl (with optionally substituted amino group, e.g. sulfoamino group optionally in salt form, or one, by one, preferably slightly, e.g.

when treated with an acidic agent such as trifluoroacetic acid, reductive, e.g. when treated with a chemical reducing agent such as zinc in the presence of aqueous acetic acid or catalytic hydrogen, or hydrolytically cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid semi-ester such as lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, 2-halo-lower alkylcarbonyl, e.g. 2,2,2-trichloroethyloxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, e.g. Phen-acyloxycarbonyl, optionally substituted, such as lower alkoxy, e.g. Phenyl-lower alkoxycarbonyl containing methoxy or nitro, e.g. 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid halamide, such as carbamoyl or N-substituted, such as N-lower alkyl,

^ carbonylmethoxycarbonyloxy, e.g. Phenacyloxycarbonyloxy.

Lower alkoxycarbonyl is e.g. Methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert-pentyloxycarbonyl.

N-lower alkyl or N, N-di-lower alkyl carbamoyl is e.g. N-methylcarbamoyl, N-ethylcarbamoyl, N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl, while N-lower alkylsulfamoyl e.g. N-methylsulfamoyl or N, N-dimethylsulfamoyl.

A carboxyl or sulfo in alkali metal salt form is e.g. a carboxyl or sulfo in sodium or potassium salt form.

Lower alkylamino or di-lower alkylamino is e.g. Methylamino, ethylamino, dimethylamino or diethylamino, lower alkyleneamino e.g. Pyrrolidino or piperidino, oxa-lower alkyleneamino e.g. Morpholino, Thianiederalkylenami-no e.g. Thiomorpholino, and azane lower alkylene amino e.g. Piperazino or 4-methylpiperazino. Acylamino in particular represents carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. Methoxycarbonylamino, ethoxycarbonylamino or tert-butyloxycarbonylamino, halogen-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxy-carbonylamino, such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylalimino-, optionally for phthalylimino-no, such as for phthalylalimino-no, such as for phthalylimino, e.g. Sodium or ammonium salt form, present sulfoamino.

Lower alkanoyl is e.g. Formyl, acetyl, propionyl or pivaloyl.

O-lower alkyl phosphono is e.g. O-methyl or O-ethyl-phosphono, 0,0'-di-lower alkyl-phosphono, e.g. 0.0 - dimethyl-phosphono or O.O'-diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g. O-benzyl-phosphono, and O-lower alkyl-O'-phenyl-lower alkyl-phosphono, e.g. O-Ben-zyl-O'-methyl-phosphono.

Lower alkenyloxycarbonyl is e.g. Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. Adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or a-4-biphenyl-a-methyl-ethoxycarbonyl. Lower alkoxycarbonyl, wherein lower alkyl e.g. contains a monocyclic, monoaza, monooxa or monothiacyclic group is e.g. Furyl-lower alkoxycarbonyl, such as furfuryloxy-carbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyl-oxycarbonyl.

2-Lower alkyl and 2,2-di lower alkyl hydrazino is e.g. 2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino e.g. 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino, and lower alkanoylhydrazino e.g. 2-acetylhydrazino.

An acyl group Ac stands in particular for a N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4 which is preferably naturally pharmacologically active and which can be prepared in a naturally occurring or in a bio-, semi-synthetic or totally synthetic way carboxylic acid-containing acyl radical of an organic carboxylic acid, preferably having up to 18 carbon atoms, or an easily removable acyl radical, in particular a carbonic acid derivative.

An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula

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R11 O

I H

R1 - (C) n - C - (A)

I.

Rm where n is 0 and R1 is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably aromatic in character, a functionally modified, e.g. is esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or wherein n is 1, R1 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic aliphatic radical, in which the heterocyclic radical preferably has an aromatic character and / or a quaternary nitrogen atom, represents an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R11 and R111 is hydrogen, or wherein n is 1, R1 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably aromatic, Rn is an optionally functionally modified, e.g. esterified or etherified hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O.O'-disubstituted phos-phono group, or an azido group, and Rnl represents hydrogen, or in which n represents 1, each of the radicals R1 and R11 represents a functionally modified, preferably etherified or esterified, hydroxyl group or an optionally functionally modified carboxyl group, and Rnl represents hydrogen, or in which n represents 1, R1 is hydrogen or a optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rn and Rnl together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic bonded to the carbon atom by a double bond Represent hydrocarbon radical, or in which n is 1, and R1 is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, Rn one optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rm is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.

In the above-mentioned acyl groups of formula A e.g. n for 0 and Rr for hydrogen or an optionally, preferably in the 1-position, optionally protected amino, acylamino, in which acyl is primarily for the acyl radical of a carbonic acid semi-ester, such as a lower alkoxy

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e.g. N-methylcarbamoyl, as well as by trityl, furthermore by arylthio, e.g. 2-nitrophenylthio, arylsulfonyl, e.g. 4-methylphenylsulfonyl or 1-lower alkoxycarbonyl-2-propylidene, e.g. l-ethoxycarbonyl-2-propylidene, substituted amino group), 2,6-dimethoxybenzoyl, 5,6,7,8-tetrahydro-naphthoyl, 2-methoxy-l-naphthoyl, 2-ethoxy-l-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl , 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl - 4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl , 2-Chloräthylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl acrylyl, crotonyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butyl thioacetyl, Allylthioacetyl, methylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3 Bromopropionyl, aminoacetyl or 5-amino-5-carboxyvaleryl (with optionally substituted, for example as indicated, by a monoacyl or diacyl radical, for example an optionally halogenated lower alkanoyl radical such as acetyl or dichloroacetyl or phthaloyl, or phthaloyl, and / or optionally functionally modified, for example in salt, such as sodium salt, or in ester, such as lower alkyl -, e.g. Methyl or ethyl, or aryl-lower alkyl, e.g. Diphenylmethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxy-carbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, a-cyanopropionyl, 2-cyan-3,3-dimethyl-acrylylyl, phenyl -Azidophenylacetyl, 3-chlorophenyl-acetyl, 2- or 4-aminomethylphenyl-acetyl (with optionally substituted, for example as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxacetyl, phenylthioacetyl, bromophenylthio-acetyl -Phenyloxypropionyl, a-phenyloxyphenylacetyl, a-methoxyphenylacetyl, a-ethoxy-phenylacetyl, a-methoxy - 3,4-dichlorophenylacetyl, a-cyano-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxy-- phenylglycyl, 3,5-dichloro-4-hydroxy-phenylglycyl, a-amino - a- (1,4-cyclohexadienyl) acetyl, a-amino-a- (l-cyclohexenyl) acetyl, a-aminomethyl a-phenylacetyl or a-hydroxy-phenylacetyl, an amino acid present in these residues ppe if necessary, e.g. may be substituted as indicated above and / or an existing, aliphatic and / or phenolic bonded hydroxyl group optionally, analogously to the amino group, e.g. can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid semi-ester, or aO-methyl-phosphono-phenylacetyl or a-0,0-dimethylphospho-no-phenylacetyl, furthermore benzylthioacetyl, benzylthiopropionyl, a- Carboxyphenylacetyl (with optionally modified carboxy group, for example as indicated above), 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-meth-oxyphenyl) butyryl, 2-pyridylacetyl, 4-amino-pyridinium -acetyl (optionally with, for example, as substituted amino group substituted), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, a-carboxy-2-thienylacetyl or --Carboxy-3-thienylacetyl (optionally with a functional carboxyl group, for example as indicated above, modified), a - cyano-2-thienylacetyl, 4-amino-a- (2-thienyl) -acetyl, a-amino-no- a- (2-furyl) -acetyl or a-amino-a- (4-isothiazolyl) -acetyl (optionally with, for example as indicated above, see below substituted amino group), a-sulfophenylacetyl (optionally with, e.g. such as the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolylthioacetyl, l, 2,4-triazol-3-yl-thioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-l , 2,4-thia-diazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.

An easily removable acyl residue Ac, in particular a carbonic acid half-ester, is primarily one by Reduk626091

tion, e.g. when treated with a chemical reducing agent, or by acid treatment, e.g. with trifluoroacetic acid, an acyl radical of a half-ester of carbonic acid which can be split off, such as a lower alkoxycarbonyl group which is preferably branched and / or aromatically substituted at the carbon atom in the a-position to the oxy group or a methoxycarbonyl group substituted by arylcarbonyl, in particular benzoyl, or in the β-position lower alkoxycarbonyl radical substituted by halogen atoms, for example tert-butyloxycarbonyl, tert-pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl , e.g. Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the a-position is preferably multiply substituted, e.g. Diphenylmeth-oxycarbonyl or a-4-biphenylyl-a-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily a-furyl-lower alkoxycarbonyl, e.g. Furfuryloxycarbonyl.

A divalent acyl group formed by the two residues RjA and Rjb is e.g. the acyl radical of a lower alkane or lower alkenedicarboxylic acid, such as succinyl, or an o-arylenedicarboxylic acid, such as phthaloyl.

Another divalent radical formed by the groups R1A and R ^ is e.g. a, especially in the 2-position, substituted, e.g. optionally substituted phenyl or thienyl, and in the 4-position optionally by lower alkyl, such as methyl, mono- or disubstituted 1-oxo-3-aza-l, 4-butylene, e.g. 4,4-dimethyl-2-phenyl-l-oxo-3 - aza-1,4-butylene.

An etherified hydroxyl group R2A forms, together with the carbonyl grouping, a carboxyl group, which is preferably easily cleavable or easily converted into another functionally modified group, such as an esterified carboxyl group which can be converted into a carbamoyl or hydrazinocarbonyl group. Such a group R2A is e.g. Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which, together with the carbonyl group, forms an esterified carboxyl group which, particularly in 2-cephem compound, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group.

An etherified hydroxyl group R2A, which together with a -C (= 0) grouping forms a particularly easily cleavable esterified carboxyl group, is e.g. for 2-halo-lower alkoxy, wherein halogen preferably has an atomic weight of over 19. Such a residue together with the -C (= 0) grouping forms one when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g. with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group easily convertible into such and is e.g. 2,2,2-trichloroethoxy or 2-iodoethoxy, furthermore 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter.

An etherified hydroxyl group R2A, which together with the -C (= 0) grouping also forms a part of treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g. when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g. Sodium thiophenolate, which is an easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, in which aryl in particular represents an optionally substituted phenyl group, and preferably phenacyloxy.

The group R ,, A can also represent an arylmethox group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical

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means. Such a residue, together with the -C (= 0) grouping, forms an esterified carboxyl group which is readily cleavable on irradiation, preferably with ultraviolet light, under neutral or acidic conditions. An aryl group in such an arylmethoxy group is especially lower alkoxyphenyl, e.g. Methoxyphenyl (where methoxy is primarily in the 3-, 4- and / or 5-position), and / or especially nitrophenyl (wherein nitro is preferably in the 2-position). Such residues are especially lower alkoxy, e.g. Methoxy- and / or nitrobenzyloxy, primarily 3- or 4-methoxy-benzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy.

An etherified hydroxy group R2A can also represent a radical which, together with the -C (= 0) grouping, forms a group under acidic conditions, e.g. when treated with trifluoroacetic acid or formic acid, forms easily cleaved, esterified carboxyl group. Such a residue is primarily a methoxy group in which methyl is substituted by optionally substituted hydrocarbon residues, especially aliphatic or aromatic hydrocarbon residues such as lower alkyl, e.g. Methyl and / or phenyl, polysubstituted or monosubstituted by an electron-donating, substituent-containing carbocyclic aryl group or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa- or thiacycloaliphatic The rest is the ring member representing the position to the oxygen or sulfur atom.

Preferred polysubstituted methoxy groups of this type are tert-lower alkoxy, e.g. tert-butyloxy or tert-pentyloxy, optionally substituted diphenylmethoxy, e.g. Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, further 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above-mentioned substituted aryl group or the heterocyclic group e.g. a-Lower alkoxy - phenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or furfuryloxy, such as 2-furfuryloxy. A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is e.g. Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the a-position to the oxygen or sulfur atom, means e.g. 2-oxa- or 2-thi-lower alkylene or lower alkenyl having 5-7 ring atoms, such as 2-tetrahydro-furyl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs.

The etherified hydroxy group R2A can also represent a radical which, together with the -C (= 0) grouping, forms a hydrolytic, e.g. under weakly basic or acidic conditions, forms cleavable esterified carboxyl group. Such a radical is preferably an etherified hydroxyl group which forms an activated ester group with the -C (= (^ - grouping, such as nitrophenyloxy, for example 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, for example 4-nitrobenzyloxy, hydroxy-lower alkylbenzyloxy, for example 4-hydroxy-3,5-tert-butyl-benzyloxy, polyhalophenyloxy, for example 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyl-oxy, furthermore cyanomethoxy, and also acylaminomethoxy, for example phthaliminomethoxy or Succinyliminomethoxy.

The etherified hydroxyl group R2A can also be an esterified carboxyl group which together with the carbonyl group of the formula -C (= quine which can be split under hydrogenolytic conditions) and is, for example, optionally substituted, for example by lower alkoxy or nitro, substituted a-phenyl-lower alkoxy, such as benzyloxy, 4- Methoxybenzyloxy or 4-nitrobenzyloxy.

The group R2A can also be an etherified hydroxy group, together with the carbonyl grouping -C (= O) - an esterified carboxyl group which can be split under physiological conditions, primarily an acyloxy-5 methoxy group, in which acyl e.g. is the residue of an organic carboxylic acid, primarily an optionally substituted lower alkane carboxylic acid, or wherein acyloxy-methyl forms the residue of a lactone. Hydroxy groups etherified in this way are lower alkanoyloxy methoxy, e.g. Acetyloxy-10 methyloxy or pivaloyloxymethoxy, amino-lower alkanoyl-oxymethoxy, especially a-amino-lower alkanoyloxymeth-oxy, e.g. Glycyloxymethoxy, L-Valyloxymethoxy, L-Leucyl-oxymethoxy, also phthalidyloxy.

A silyloxy or stannyloxy group R2A preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halogeno-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups, such as 20 etherified hydroxy, as 15 substituents -, e.g. Lower alkoxy groups, or halo, e.g. Chlorine atoms, and primarily tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, halo-lower alkoxy - lower alkylsilyl, e.g. Chloro-methoxy-methyl-silyl, or tri-lower alkylstannyloxy, e.g. Tri-n-butylstannyloxy. 25 An acyloxy radical R2A together with a -C (= 0) grouping which forms a preferably hydrolytically cleavable mixed anhydride group contains e.g. the acyl residue of one of the above-mentioned organic carboxylic acids or carbonic acid half-derivatives, and is e.g. optionally, as by 30 halogen, e.g. Fluorine or chlorine, preferably in the a-position, substituted lower alkanoyloxy, e.g. Acetyloxy, pivaloyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy or ethoxycarbonyloxy.

A radical R2A, together with a -C (= 0) grouping which forms an optionally substituted carbamoyl or hydrazinocarbonyl group, is e.g. Amino, lower alkyl-amino or di-lower alkylamino such as methylamino, ethyl-amino, dimethylamino or diethylamino, lower alkylene-amino, e.g. Pyrrolidino or piperidino, oxane-lower alkylene-40 amino, e.g. Morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, e.g. 2-methylhydrazino or 2,2-dimethylhydrazino.

A lower alkyl group R.3 has up to 7, preferably up to 4 carbon atoms and is preferably methyl, or 45 also ethyl, n-propyl, hexyl or heptyl.

R o as a-phenyl-lower alkyl is in particular benzyl and diphenylmethyl, the substituents of the phenyl nuclei being e.g. esterified or etherified hydroxy, such as halogen, e.g. Fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, come into question.

Salts are in particular those of compounds of the formulas IA and IB with an acidic group, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts, such as alkali metal and earth 55, alkali metal, e.g. Sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di-60 or polyamines, and also heterocyclic bases for salt formation come into question, such as lower alkylamines, for example Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethyl amine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 65 4-aminobenzoic acid 2-diethylamino ethyl ester, lower alkylene amines, e.g. 1-ethyl piperidine, cycloalkylamines, e.g. Bi-cyclohexylamine, or benzylamines, e.g. N, N'-dibenzylethylenediamine, furthermore bases of the pyridine type, e.g. Pyridine,

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Collidia or quinoline, compounds of the formulas IA and IB, which have a basic group, can also acid addition salts, e.g. with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. Form trifluoroacetic acid or p-toluenesulfonic acid. Compounds of formulas IA and IB with an acidic and a basic group can also be used in the form of internal salts, i.e. in zwitterionic form. 1-Oxides of compounds of the formula IA with salt-forming groups can also form salts, as described above.

The compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such. Compounds of formula IA, wherein e.g. Rta stands for an acyl radical Ac and R ^ which are present in pharmacologically active N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem - 4-carboxylic acid compounds, or in which Rxa and Rab together form one preferably in the 2 position, e.g. by an aromatic or heterocyclic radical, and preferably in the 4-position, e.g. represented by 2 lower alkyl, such as methyl, substituted l-oxo-3-aza-l, 4-butylene radical, R2 is hydroxyl or an esterified carboxyl group which forms easily together with the carbonyl group under physiological conditions is R2A, and R® is lower alkyl, where in an acyl radical Rja optionally present functional groups, such as amino, carboxy, hydroxy and / or sulfo, are usually present in free form, or salt of such compounds with salt-forming groups, are parenteral and / or oral administration against microorganisms, such as gram positive bacteria, e.g. Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae, (e.g. in mice in doses of about 0.001 to about 0.02 g / kg s.c. or p.o.), and gram-negative bacteria, e.g. Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis, (e.g. in mice in doses of about 0.001 to about 0.15 g / kg sc or po), in particular also against penicillin-resistant bacteria, effective with low toxicity. These new connections can therefore e.g. in the form of antibiotic preparations, for the treatment of corresponding infections.

Compounds of the formula IB, in which R ^, R ^, R2 and Ra have the meanings given in connection with the formula IA, or compounds of the formula IA, in which R3 has the meaning given above, the radicals Rja and R ^ are hydrogen, or ^ is an amino protective group and R / 1 which is different from an acyl radical which occurs in pharmacologically active N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem-4-carboxylic acid compounds, or R / 1 is hydrogen, or R ^ and Rjb together one, preferably from one in the 2-position, eg by an aromatic or heterocyclic radical, and preferably in the 4-position, e.g. l-Oxo-3-aza-l, 4-butylene radical substituted by 2 lower alkyl, such as methyl, represent different bivalent amino protective groups, and R2 stands for hydroxyl, or Rta and Rj have the meanings given above, R2 for one, together with the -C (= 0) grouping represents a, preferably easily cleavable, protected carboxyl group-forming radical R2A, such a protected carboxyl group being different from a physiologically cleavable carboxyl group, and R, 3 having the meanings given above are valuable intermediates which are described in simple way, e.g. as described below, can be converted into the above pharmacologically active compounds.

The invention particularly relates to the production of

3-cephem compounds of the formula IA, in which Rja is hydrogen or preferably one which can be prepared in a fermentative (ie naturally occurring) or bio-, semisynthetic or totally synthetic, in particular pharmacologically active, such as highly active N-acyl derivative of a 6β-amino-penam Acyl radical containing 3-carboxylic acid or 7β-amino-3-cephem-4-carboxylic acid compound, such as one of the abovementioned acyl radicals of the formula A, in which R1, Rn, Rm and n have primarily the preferred meanings, R ^

represents hydrogen, or wherein R / and R ^ together preferably represent a 2-position, e.g. by an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, e.g. l-Oxo-3-aza-1,4-butylene radical substituted by two lower alkyl, such as methyl, represent R2 for hydroxyl, for optionally, preferably in the a-position e.g. with optionally substituted aryloxy such as lower alkoxyphenyloxy, e.g. 4-methoxyphenyloxy, lower alkanoyloxy, e.g. Acetyloxy or pivaloyloxy, a-amino lower alkanoyloxy, e.g. Glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, e.g. Benzoyl, or optionally substituted aryl such as phenyl, lower alkoxyphenyl, e.g. 4-methoxy-phenyl, nitrophenyl, e.g. 4-nitrophenyl, or biphenylyl, e.g. 4-biphenylyl, or in the β position by halogen, e.g. Chlorine, bromine or iodine, mono- or polysubstituted lower alkoxy such as lower alkoxy e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy or tert-pentyloxy, optionally substituted by lower alkoxy bis-phenyloxy-methoxy, e.g. Bis-4-methoxyphenyloxy-meth-oxy, lower alkanoyloxy-methoxy, e.g. Acetyloxymethoxy or pivaloyloxymethoxy, a-amino lower alkanoyloxy methoxy, e.g. Glycyloxy methoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, especially 1-phenyl-lower alkoxy, such as phenylmethoxy, such residues 1-3 optionally, e.g. phenyl radicals substituted by lower alkoxy such as methoxy, nitro or phenyl, e.g. Benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy,

4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, or 2-halogeno lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy, and for acyloxy, such as lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g. Acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, e.g. Tri-methylsilyloxy, or for optionally, e.g. amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g. Amino, lower alkyl or di-lower alkyl amino, such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g. 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R, 3, hydrogen, lower alkyl, especially methyl, or optionally, e.g. represented by halogen or lower alkoxy, substituted benzyl or diphenylmethyl, and the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups.

First of all, in a 3-cephem compound of the formula IA, and in a corresponding 2-cephem compound of the formula IB, or in a salt of such a compound with salt-forming groups R, a is hydrogen or one in fermentative ( ie naturally occurring) or biosynthetically producible N-acyl derivatives of 6ß-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem-4-carboxylic acid compounds containing acyl radical, in particular of the formula A, wherein R1, Rn , Rni and n have primarily the preferred meanings, such as one, for example by hydroxy, substituted phenylacetyl or phenyloxyacetyl radical, furthermore an optionally, e.g. through low

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alkylthio, or lower alkenylthio, and optionally substituted, such as acylated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl, e.g. 4-hydroxy-phenyl-acetyl, hexanoyl, octanoyl or n-butylthioacetyl, and especially 5-amino-5-carboxy-avleryl, in which the amino and / or the carboxyl groups are optionally protected and e.g. present as acylamino or esterified carboxyl, phenylacetyl or phenyloxyacetyl, or an acyl radical which occurs in highly effective N-acyl derivatives of 6β-amino-penam-3-carboxylic acid or 7ß-amino-3-cephem-4-carboxylic acid compounds, in particular of the formula A, wherein R1, R ", R111 and n primarily have the preferred meanings, such as formyl, 2-haloethylcarbamoyl, for example 2-chloro-ethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, for example 2-thienylacetyl, or tetrazolylacetyl, for example 1-tetrazolylacetyl, but especially in the a-position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, primarily monocyclic radical and by a functional group, primarily amino, carboxy, sulfo or hydroxy groups, acetyl, in particular phenylglycyl, in which phenyl optionally , for example by optionally protected hydroxy, such as acyloxy, for example optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by halogen, e.g. Chlorine, substituted phenyl e.g. Phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxy-phenyl (optionally also with a protected, such as acylated hydroxy group), and in which the amino group optionally also can be substituted and, for example represents a sulfoamino group, optionally in salt form, or an amino group which, as substituents, is a hydrolytically removable trityl group or primarily an acyl group, such as an optionally substituted carbamoyl or an optionally substituted ureidocarbonyl group, e.g. Ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g. Guanidinocarbonyl, or one, preferably light, e.g. when treating with an acidic agent, such as trifluoroacetic acid, further reductively, such as when treating with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid semi-ester, such as one of the above, for example optionally halogen or benzoyl substituted lower alkyloxycarbonyl, e.g. tert-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, or phenacyloxycarbonyl, optionally lower alkoxy or nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-methoxy-benzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid halamide, such as carbamoyl or N-methyl-carbamoyl, furthermore an arylthio or aryl-lower alkylthio radical, e.g. 2-nitrophenylthio or tritylthio, an arylsulfonyl radical which can be split off by means of electrolytic reduction, e.g. 4-methylphenylsulfonyl, or one with an acidic agent such as formic acid or aqueous mineral acid e.g. Hydrochloric or phosphoric acid, removable 1-lower alkoxycarbonyl or 1-lower alkanoyl-2-propylidene e.g. l-ethoxycarbonyl-2-propylidene, also contains a- (1,4-cyclohexadienyl) glycyl, «- (l-cyclohexenyl) glycyl, athie-nylglycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazo-lyl-glycyl, in which residues the amino group, for example may be substituted, protected or as indicated for a phenylglycyl radical, furthermore a-carboxy-phenylacetyl or a-carboxy-thienylacetyl, e.g. a-carboxy-2-thienylacetyl (optionally with a functionally modified, for example in salt, such as sodium salt form, or in ester, such as lower alkyl, for example methyl or ethyl, or phenyl-lower alkyl, for example diphenylmethyl ester form, present carboxyl group), "-Sulfo - phenylacetyl (optionally also with, for example, the sulfo group functionally modified like the carboxyl group), a-phospho-no, aO-methylphosphono- or a-0,0'-dimethylphospho-no-phenylacetyl, or a-hydroxy- phenylacetyl (optionally with a functionally modified hydroxy group, in particular with an acyloxy group, in which acyl can be split off or into one, preferably slightly, for example when treated with an acidic agent such as trifluoroacetic acid or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid such a convertible acyl radical, preferably a suitable acyl radical of a carbonic acid semi-ester, such as one of the abovementioned, for example optionally substituted by halogen or benzoyl Lower alkoxycarbonyl, e.g. 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl ,. also means formyl) and 1-amino-cyclo-hexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenylacetyl, or aminopyridiniumacetyl, e.g. 4-aminopyridiniumacetyl (optionally also with an amino group substituted, e.g. as indicated above), or pyridylthioacetyl, e.g. 4-pyridylthioacetyl, and Rab for hydrogen, or Rxa and R ^ together for one, preferably in the 2-position, optionally by protected hydroxy, such as acyloxy, e.g. optionally halogen-substituted lower alkoxy-carbonyloxy or lower alkanoyloxy, and / or by halogen, e.g. Chlorine, substituted phenyl e.g. Phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxy-phenyl (optionally also with a protected, for example acylated hydroxy group, substituted as indicated above) substituted l-oxo -3-aza-l, 4-butylene radical, which in the 4-position optionally contains two lower alkyl such as methyl, and R2 represents hydroxy, lower alkoxy, in particular a-polybranched lower alkoxy, for example tert-butyloxy, also methoxy or ethoxy, 2-halogeno-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3, optionally substituted by lower alkoxy or nitro phenyl radicals, e.g. 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g. Acetyloxymethoxy or pivaloyloxymethoxy, a-amino lower alkanoyloxymethoxy, e.g. Glycyloxy methoxy, 2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g. Ethoxycarbonyloxy, or lower alkanoyloxy, e.g. Acetyloxy, further tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, and R is hydrogen, lower alkyl, especially methyl, or optionally e.g. halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl.

The invention relates primarily to the preparation of 3-cephem compounds of the formula IA, in which Rta is hydrogen or an acyl group of the formula

O

II

Ra- (X) m-CH-C- (B)

I.

Rb wherein Ra is phenyl or hydroxyphenyl, e.g. 3- or 4-hydroxy-phenyl, furthermore hydroxy-chlorophenyl, e.g. 3-chloro-4-

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-hydroxy-phenyl- or 3,5-dichloro-4-hydroxy-phenyl, in which radicals hydroxy substituents are replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g. tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl can be protected, as well as thienyl, e.g. 2- or

3-thienyl, further pyridyl, e.g. 4-pyridyl, aminopyridinium, e.g. 4-aminopyridinium, furyl, e.g. 2-furyl, isothiazolyl, e.g. 4-isothiazolyl, or tetrazolyl, e.g. 1-tetrazolyl, or also 1,4-cyclohexadienyl or 1-cyclohexenyl, X represents oxygen or sulfur, m represents 0 or 1, and Rb represents hydrogen or, if m represents 0, amino,

and protected amino such as acylamino, e.g. a-poly-branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halogeno lower alkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbononylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy or nitro substituted phenyl lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonyl-amino or diphenylmethoxycarbonylamino, or 3-guanyl-ureido, also sulfoamino or tritylamino, and arylthio-amino, e.g. 2-nitrophenylthioamino, arylsulfonylamino, e.g.

4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl - 2-propylidenamino, e.g. l-ethoxycarbonyl-2-propylidene-amino, carboxy or in salt, e.g. Alkali metal, such as sodium salt, carboxy present as well as protected carboxy, e.g. esterified carboxy such as phenyl-lower alkoxy-carbonyl, e.g. Diphenylmethoxycarbonyl, sulfo or in salt, e.g. Alkali metal, such as sodium salt form of sulfo, as well as protected sulfo, hydroxy, as well as protected hydroxy, such as acyloxy, e.g. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbo-nyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbo-nyloxy, furthermore formyloxy, or O-lower alkylphosphono or O .O'-Diniederalkylphosphono, e.g. O-methylphosphono or 0.0'-dimethylphosphono, or a 5-amino-5-carboxyvaleryl radical, in which the amino and / or carboxy groups can also be protected and e.g. as acylamino, e.g. Lower alkanoylamino such as acetylamino, halogen lower alkanoylamino such as dichloroacetylamino, benzoylamino or phthaloylamino, or as esterified carboxy such as phenyl lower alkoxycarbonyl, e.g. Diphenylmethoxycarbonyl, where m is preferably 1 if Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and Rb is different from hydrogen if Ra is phenyl, hydroxyphenyl, hydroxy * chlorophenyl, thienyl, furyl, isothiazolyl, 1 Represents 4-cyclo-hexadienyl or 1-cyclohexenyl, R, b represents hydrogen, R2 primarily for hydroxy, furthermore for lower alkoxy, in particular a-polybranched lower alkoxy, for example tert-butyloxy, 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g. by lower alkoxy, e.g. Methoxy, substituted diphenylmethoxy, e.g. Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, further tri-lower alkylsilyloxy, e.g. Tri-methylsilyloxy, and R.3 is hydrogen, lower alkyl, e.g. Methyl, ethyl or n-butyl, and optionally, e.g. by halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl, and the corresponding 2-cephem compounds of the formula IB, or salts, in particular pharmaceutically usable, non-toxic salts of such compounds with salt-forming groups such as alkali metal, e.g. Sodium or alkaline earth metal, e.g. Calcium salts, or ammonium salts, including those with amines, of compounds in which

R2 represents hydroxy, and which contain a free amino group in the acyl radical of formula B.

First and foremost, in 3-cephem compounds

Formula IA, furthermore in corresponding 2-cephem compounds of the formula IB, and in salts, in particular in pharmaceutically usable, non-toxic salts of those compounds having salt-forming groups, such as in the salts Rxa for hydrogen mentioned in the preceding section, for the acyl radical of the formula B, in which Ra is phenyl and hydroxyphenyl, for example 4-hydroxyphenyl, thienyl, e.g. 2- or 3-thienyl, 4-isothiazolyl, 1,4-cyclohexadienyl or

1-cyclohexenyl, X is oxygen, m 0 or 1, and Rb is hydrogen or, if m is 0, amino, and also protected amino, such as acylamino, e.g. a-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or

2-halogeno lower alkoxycarbonylamino, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-iodoethoxycarbonylamino or 2-bromoethoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, e.g. 4-methoxybenzyloxycarbonylamino, or hydroxy, as well as protected hydroxy, such as acyloxy, e.g. a-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halogeno lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or for a 5-amino-5-carboxy- valeryl radical, in which the amino and carboxy group can also be protected and, for example as acylamino, e.g. Lower alkanoylamino such as acetylamino, halogen lower alkanoylamino such as dichloroacetylamino, benzoylamino or phthaloylamino or as esterified carboxy such as phenyl lower alkoxycarbonyl, e.g. Diphenylmethoxycarbonyl, preferably m being 1 when Ra is phenyl or hydroxyphenyl, Rxb is hydrogen, R2 is primarily hydroxy, further optionally halogen, e.g. Lower alkoxy substituted by chlorine, bromine or iodine, especially a-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, such as methoxy substituted diphenylmethyloxy, e.g. Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or p-nitrobenzyl-oxy, furthermore tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, and Ra means hydrogen, lower alkyl, especially methyl, or optionally halogen, e.g. Chlorine or bromine, or lower alkoxy, e.g. Methoxy, substituted benzyl or diphenylmethyl group.

The invention serves primarily for the preparation of 7β- (Da-amino-a-Ra-acetylamino) -3-lower alkoxy-3-cephem - 4-carboxylic acids, where Ra is phenyl, 4-hydroxyphenyl, 2-thienyl, 1 , 4-cyclohexadienyl or 1-cyclohexenyl, and lower alkoxy contains up to 4 carbon atoms and, for example Ethoxy or n-butyloxy, but primarily methoxy, and their inner salts, and especially 3-methoxy-7ß- (Da-phenylglycylamino) -3-cephem-4-carboxylic acid and its inner salt or for the preparation of 3-hydroxy-3-cephem-4-carboxylic acid compounds which can serve as intermediates for the preparation of these 3-lower alkoxy-3-cephem-4-carboxylic acid compounds; In the concentrations mentioned above, especially when administered orally, these 3-lower alkoxy compounds have excellent antibiotic properties, both against gram-positive and in particular against gram-negative bacteria with low toxicity.

According to the process of the invention, compounds of the formula IA, compounds of the formula IB and salts of such compounds having salt-forming groups are prepared by using a compound of the formula

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R

R

H

n v «

b / N-

H

i /

S-Y

O:

CH., R7

i L.Ü <®

V \ b

4th

0 = c-r ^

where Rf-, Rjb and R2A have the meanings given under formula IA, the group -N (R4a) (R4b) represents a secondary or tertiary amino group, and Y is a leaving group -S-R4, one with the sulfur atom attached to the thiogrup- pe -S- bonded group -S02-R5 or a group -S-S02 - Rn, in which R4 is an optionally substituted aromatic heterocyclic radical having up to 15 carbon atoms, and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical with one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond, is bonded to the thio group -S- or R4 represents an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18 carbon atoms and R5 is an optionally substituted one , aliphatic, cycloaliphatic, araliphatic or aromatic carbon radical having up to 18 carbon atoms, u After splitting off H-Y, cyclized and in the enamine of the formula (III) formed as an intermediate

/ 4 (in)

0-C — R,

in which the double bond can be in the 2,3- or 3,4-position, the amino group -N (R4a) (R4b) sol-volyses to the group -OR3, and optionally a compound obtained with a salt-forming group in a salt or a obtained one Salt converted into the free compound or into another salt.

In a compound of the formula II, the amino group -N (R4a) (R4b) can be in the trans- (crotonic acid configuration) or in the cis-position (isocrotonic acid configuration) to the carboxyl group.

In the group -S-R4, R4 is a monocyclic or bicyclic radical and can be substituted, for example, by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as fluorine or chlorine, or aryl, such as phenyl.

Such residues R4 are e.g. monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic residues of aromatic character, but especially monocyclic five-membered diazacyclic, oxazacyclic and thiazacyclic residues of aromatic character, and or in the first line is the corresponding benzo-diazacyclic or benzaztecyclic, benzoxte and has an aromatic character, in which R4 s a substitutable ring nitrogen atom, for example can be substituted by lower alkyl. Representative of such groups R4 are l-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2 -yl, l, 3-oxazol-2-yl, l, 3,4-oxadiazol-2-yl, l, 3,4,5-oxatriazol-2-yl, 2-quinolyl, • io l-methyl-benzimidazole -2-yl, benzoxazol-2-yl and especially benzthiazol-2-yl. Further groups R4 are acyl residues of organic carboxylic or thiocarboxylic acids, such as optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic, acyl or thioacyl groups with 15 to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g. Acetyl or propionyl, lower thio-alkanoyl, e.g. Thioacetyl or thiopropionyl, cycloalkane-carbonyl, e.g. Cyclohexane carbonyl, cycloalkane thiocarbonyl, e.g. Cyclohexanthiocarbonyl, benzoyl, thiobenzoyl, naphthylthylcarbonyl, naphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-pyridyl-thiocarbonyl, 2- or 3-thiothenoyl, 2- or 3-thiofuroyl, or correspondingly substituted, for example, by lower 25-alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl , Aryloxy, such as phenyloxy, mono- or poly-substituted acyl or thioacyl groups.

In the groups -S02-R5 and -S-S02-R5, R5 is an optionally substituted, in particular aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical having up to 18, preferably up to 10, carbon atoms. Suitable groups R5 are, for example, optionally substituted, such as by lower alkoxy, such as meth-35 oxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted alkyl, in particular lower alkyl, such as methyl -, Ethyl or butyl groups, alkenyl, such as allyl or butenyl groups, cycloalkyl, such as cyclopentyl or cyclohexyl groups, or 40 optionally by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl , such as phenyl, aryloxy, such as phenyloxy, or nitro, mono- or poly-substituted naphthyl or in particular phenyl groups, for example phenyl, o-, m- or preferably p-45 tolyl, o-, m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl.

In a starting material of the formula II, R2A preferably represents a group which forms an esterified carboxyl group, in particular which can be cleaved under mild conditions, with the -C (= 0) grouping, functional groups which may be present in a carboxyl protective group R2a in known way, eg can be protected as indicated above. A group R, A is e.g. in particular 55 an optionally halogen-substituted lower alkoxy group, such as methoxy, a-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halogeno-lower alkoxy, where halogen e.g. Represents chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy, or 2-iodoethoxy, or an optionally substituted such as lower alkoxy, e.g. Methoxy,

or 1-phenyl-lower alkoxy group containing nitro, such as optionally e.g. as indicated, substituted benzyloxy or diphenylmethoxy, e.g. Benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimeth-65oxydiphenylmethoxy, also an organic silyloxy or stannyloxy group such as tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy or halogen, e.g. Chlorine. In a starting material of the formula II, the radical is preferably

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R! 8- an amino protecting group R ^, such as an acyl group Ac, in which any free functional groups, e.g. Amino, hydroxyl, carboxyl or phosphono groups, in a manner known per se, amino groups e.g. by the abovementioned acyl, trityl, silyl or stannyl, and substituted thio or sulfonyl radicals, and hydroxyl, carboxy or phosphono groups, e.g. can be protected by the above-mentioned ether or ester groups, including silyl or stannyl groups, and Rjb hydrogen.

In a secondary amino group -N (R4a) (R4b) one of the substituents R4a and R4b is hydrogen and the other is an aliphatic, araliphatic or cycloaliphatic hydrocarbon radical which contains about up to 18, in particular up to 12 and preferably up to 7, carbon atoms. Aliphatic and araliphatic hydrocarbon radicals R4a or R4b are, for example, optionally substituted, e.g. lower alkoxy, such as methoxy, lower alkylthio, such as methylthio, cycloalkyl, such as cyclohexyl, aryl, such as phenyl or heterocyclyl, such as thienyl, substituted alkyl, especially lower alkyl, e.g. Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-ethoxyethyl, 2-methylthioethyl, cyclohexylmethyl, benzyl or thienylmethyl. Cycloaliphatic hydrocarbon radicals R4a or R4b are, for example, optionally substituted, e.g. cycloalkyl groups substituted by lower alkyl, such as methyl, lower alkoxy, such as methoxy, lower alkylthio, such as methylthio, cycloalkyl, such as cyclohexyl, aryl, such as phenyl or heterocyclyl, such as furyl, such as optionally substituted cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

In tertiary amino groups -N (R4a) (R4b) each of the substituents R4a and R4b denotes one of the aliphatic or cycloaliphatic hydrocarbon radicals indicated, where R4a and R4b can be the same or different, and where both substituents R4a and R4b by a carbon-carbon bond or via an oxygen, sulfur or optionally substituted, such as lower alkylated, for example methylated nitrogen atom can be linked.

Suitable tertiary amino groups N (R4a) (R4b) are, for example, dimethylamino, diethylamino, N-methyl-ethyl-amino, di-isopropylamino, N-methyl-isopropylamino, di-butylamino, N-methyl-isobutylamino, dicyclopropylamino, N-methyl- cyclopropylamino, dicyclopentylamino, N-methyl-cyclopentylamino, dicyclohexylamino, N-methyl-cyclo-hexylamino, N-methyl-cyclopentylamino, N-methyl-cyclo-hexylmethylamino, dibenzylamino, N-methylbenzylamino, N-cyclopropyl-azylamino , 1-pyrrolidinyl, 1-piperidyl, 1H-2,3,4,5,6,7-hexahydroazepinyl, 4-morpholine, 4-thiomorpholinyl, 1-piperazinyl or 4-methyl-1-piperazinyl.

The ring-closing reaction according to the invention of a compound of the formula II to a compound of the formula III is carried out in a suitable inert solvent, for example in an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon, such as methylene chloride, an ether , such as a di-lower alkyl ether, for example Diethyl ether, a di-lower alkoxy lower alkane such as dimethyloxyethane, a cyclic ether such as dioxane or tetrahydrofuran, an aliphatic, cycloaliphatic or aromatic nitrii such as aceto-nitrile, or in a mixture thereof, optionally in the presence of a moisture-absorbing agent, e.g. a dried molecular sieve, at room temperature or with heating to about 150 ° C, preferably to about 80 to about 100 ° C, if desired in an inert gas, such as nitrogen atmosphere.

The enamine of the formula III formed by the ring closure reaction can be isolated, optionally as a crude product, or solvolysed in the same reaction solution to give a compound of the formula IA or IB. In the enamine of the formula III which occurs as an intermediate, the double bond can be in the 2,3- or in the 3,4-position. A mixture of the two isomers can also be obtained. The crude product obtained can also already contain some solvolysis product of the formula IA or IB, if water or alcohols of the formula R®-OH are not completely excluded in the ring closure reaction. Solvolysis can be prevented by working in the presence of moisture-absorbing agents, such as dry molecular sieves. By carrying out the ring closure reaction in the presence of a compound R, 3rOH, in particular a lower alkanol, the compounds of the formula IA or IB can be obtained directly.

The solvolysis of enamines of the formula III obtained is carried out by adding water or an alcohol of the formula RrOH and, if appropriate, a catalytic to equimolar amount of an organic or inorganic acid, for example a carboxylic, sulfonic or mineral acid, such as formic, acetic or benzene -, methanesulfonic, p-toluenesulfonic, hydrochloric, sulfuric or phosphoric acid, at temperatures from about -10 ° to about 40 ° C, preferably at room temperature.

In the ring closure and solvolysis reaction according to the invention, depending on the starting material and reaction conditions, uniform compounds of the formula IA or IB or mixtures of compounds of the formula IA and IB can be obtained. Mixtures obtained can be prepared in a manner known per se, e.g. with the help of suitable separation methods, e.g. by adsorption and fractional elution, including chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, and further by fractional crystallization, solvent distribution, etc.

Obtained compounds of the formulas IA and IB, which are suitable intermediates for the preparation of pharmacologically active end products, can be converted into such active end products by various additional measures known per se.

In a compound of the formulas IA or IB obtained according to the invention, an a-phenyl-lower alkyl group Ra can easily be split off and replaced by hydrogen. Cleavage of an optionally substituted a-phenyl-lower alkyl, e.g. Benzyl or diphenylmethyl group takes place for example by acidolysis, e.g. by treatment with a suitable inorganic or organic acid, such as hydrochloric acid, sulfuric acid, formic acid or in particular trifluoroacetic acid, or by hydrogenolysis, for example by treatment with hydrogen in the presence of a catalyst, such as palladium. The resulting 3-hydroxy compounds are mainly in the 3-chefem form. An a-phenyl-lower alkyl group R, 3i can optionally be split off selectively, i.e. without a carboxyl protecting group R2A being split off simultaneously.

Enol ether, i.e. Compounds of the formula IA and / or IB in which R is lower alkyl are obtained from compounds of the formulas IA or IB in which R, 3; Hydrogen or a hydroxyl-protecting radical is, in the latter case by replacing this radical with hydrogen and then etherifying the free hydroxyl group by any method suitable for etherifying enol groups. The etherification reagent used is preferably a diazo compound of the formula Ra-N2 corresponding to the radical R, 3, primarily an optionally substituted

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diazo lower alkane, e.g. Diazomethane, diazoethane or diazo-n-butane, or an optionally substituted a-phenyl-diazo lower alkane, e.g. Phenyl- or diphenyl-diazome-than. These reagents are used in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g. Methylene chloride, a lower alkanol, e.g. Methanol, ethanol or tert-butanol, or an ether such as a lower alkyl ether, e.g. Di-; ethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent, under cooling, at room temperature or with gentle heating, further, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere applied.

Furthermore, enol ethers of the formula IA and / or IB can be obtained by treatment with a reactive ester of one, the lower alkyl radical or the optionally substituted a-phenyl-lower alkyl, e.g. Benzyl or diphenylmethyl radical Ra corresponding alcohol of the formula R, 3rOH form. Suitable esters are primarily those with strong inorganic or organic acids such as mineral acids e.g. Hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid or halogenated sulfuric acids, e.g. Fluorosulfuric acid, or strong organic sulfonic acids such as optionally e.g. lower alkanesulfonic acids substituted by halogen, such as fluorine, or aromatic sulfonic acids, e.g. optionally, e.g. benzenesulfonic acids substituted by lower alkyl such as methyl, halogen such as bromine and / or nitro, e.g. Methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid. These reagents, especially di-lower alkyl sulfates such as dimethyl sulfate, also lower alkyl fluorosulfates, e.g. Methyl fluorosulfate, or optionally halogen-substituted lower alkyl methanesulfonic acid e.g. Trifluoromethanesulfonic acid methyl esters are usually used in the presence of a solvent such as an optionally halogenated such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a mixture. Suitable condensing agents, such as alkali metal carbonates or hydrogen carbonates, e.g. Sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic bases, such as usually sterically hindered tri-lower alkylamines, e.g. N, N-diisopropyl-N-ethyl-amine (preferably together with lower alkyl halosulfates or optionally halogen-substituted methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g. at temperatures from about -20 ° C to about 50 ° C and, if necessary, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere is worked.

Enol ethers can also be treated with one or two etherified hydroxy groups of the formula Ra-0, i.e. with an appropriate acetal or orthoester, in the presence of an acidic agent. So you can e.g. gem-lower alkoxy lower alkanes such as 2,2-dimethoxypropane in the presence of a strong organic sulfonic acid such as p-toluenesulfonic acid and a suitable solvent such as a lower alkanol e.g. Methanol, or a lower alkyl or lower alkylene sulfoxide, e.g. Dimethyl sulfoxide, or tri-lower alkyl orthoformate, e.g. Triethyl orthoformate, in the presence of a strong mineral acid, e.g. Sulfuric acid,

or a strong organic sulfonic acid such as p-toluenesulfonic acid and a suitable solvent such as a lower alkanol e.g. Ethanol, or an ether, e.g. Use dioxane as etherifying agent and so get to compound 5 of formula IA and / or IB, where R, 3 | for lower alkyl, e.g. Is methyl or ethyl.

The enol ethers of the formula IA and / or IB can also be obtained if compounds of the formula IA in which Rj is hydrogen are mixed with tri-R3-oxonium salts io of the formula (R3) 13.0 © A © (so-called sea wine salts), as well as di-R? yO-carbenium salts of the formula (RaO) 2CH © A © or di-Ra-halonium salts of the formula (Rj3) 2 Hal © AQ, in which A © is the anion of an acid and Hai © is a halonium, in particular bromonium ion , treated. These are primarily tri-lower alkyloxonium salts, as well as di-lower alkoxycarbenium or di-lower alkyl halonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachloro-20 antimonates. Such reagents are e.g. Trimethyoxonium or triethyloxonium hexafluoroantimonate, hexachloranti-month, hexafluorophosphate, or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. These etherifying agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, e.g. Diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof if necessary in the presence of a base such as an organic base e.g. a preferably 30 sterically hindered tri-lower alkylamine e.g. N, N-diisopropyl-N-ethylamine, and with cooling, at room temperature or with gentle heating, e.g. at about -20 ° C to about 50 ° C, if necessary, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere. 35 The enol ethers of the formulas IA and / or IB can also be prepared by treating a compound of the formula IA, in which R, 3 is hydrogen, with a 3-substituted 1-R, 3-triazene compound (ie a compound of the formula Subst. N = N - NH-R,), where the substituent of the 3-40 nitrogen atom is an organic radical bonded via a carbon atom, preferably a carbocyclic aryl radical, such as an optionally substituted phenyl radical, for example Lower alkylphenyl, such as 4-methylphenyl. Such triazenes are 3-aryl-l-lower alkyl-triazenes, e.g. 45 3- (4-Methylphenyl) -l-methyl-triazene, 3- (4-methylphenyl) -l-ethyl-triazene, 3- (4-methylphenyl) -1-n-propyl-triazene or 3- (4th -Methylphenyl) -l-isopropyl-triazene, furthermore 3-aryl-l- (a - phenyl-lower alkyl) -triazenes, for example l-benzyl-3- (4-methyl-phenyl) triazene. These reagents are commonly used in the presence of inert solvents such as optionally halogenated hydrocarbons or ethers e.g. Benzene,

or solvent mixtures, and with cooling, at room temperature and preferably at elevated temperature, e.g. at about 20 ° C to about 100 ° C, if necessary, in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere used.

In the process according to the invention, as well as in additional measures to be carried out, if necessary, free functional groups which do not take part in the reaction can be present in the starting materials or in the compounds obtainable according to the process, e.g. free amino groups e.g. by acylation, tritylation or silylation,

free hydroxy or mercapto groups e.g. by etherification or starch, and free carboxyl groups e.g. by esterification, including silylation, temporarily protected in a manner known per se and released after the reaction, in a manner known per se, if desired, individually or together. So you can prefer

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e.g. Amino, hydroxy, carboxyl or phosphono groups in an acyl radical RXA or e.g. in the form of acylamino such as the above, e.g. 2,2,2-trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino, diphenylmethoxycarbonylamino or tert-butyloxycarbonylamino, of aryl or aryl-lower alkyl-thioamino, e.g. 2-nitrophenylthioamino, or arylsulfonylamino, e.g. 4-methylphenylsulfonylamino, or of 1-lower alkoxycarbonyl-2-propylidene amino groups, or of acyloxy, such as those mentioned above, e.g. tert-Butyloxycar-bonyloxy, 2,2,2-trichloroethoxycarbonyloxy or 2-bromo-ethoxycarbonyloxy groups, or of esterified carboxy, such as the above, e.g. Diphenylmethoxycarbonylgrup-pen, or O.O'-disubstituted phosphono-, such as the above, e.g. 0,0'-di-lower alkylphosphono, e.g. 0.0'-dimethylphosphono groups, protect and subsequently, if necessary after conversion of the protective group, e.g. a 2-bromoethoxycarbonyl into a 2-iodoethoxycarbonyl group, in a manner known per se and depending on the nature of the protective group, e.g. a 2,2,2-trichloroethoxycarbonylamino or 2-iodoethoxycarbonylamino group by treatment with suitable reducing agents, such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or tert.-butyloxycarbonylamino group by treatment with formic or trifluoroacetic acid, an aryl or arylamino group by treatment with a nuclophilic reagent, such as sulphurous acid, an arylsulfonylamino group by means of electrolytic reduction, a 1 - lower alkoxycarbonyl-2-propylidene amino group by treatment with aqueous mineral acid, or a tert.-butyloxycarbonyloxy group by treatment with ants or trifluoroacetic acid, or a 2,2,2-trichloroethoxycarbonyloxy group by treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or a diphenylmethoxycarbonyl group by treatment with formic or trifluoroacetic acid or by hydrogenolysis, or an O.O. '-disubstituted phosphono group d by treatment with an alkali metal halide, if desired, e.g. partially, split.

In a compound of the formula IA or IB which can be obtained according to the invention and has a protected, in particular esterified, carboxyl group of the formula -C (—0) -R2A, this can be carried out in a manner known per se, e.g. depending on the type of group R2a, are converted into the free carboxyl group. An esterified, e.g. by a lower alkyl radical, in particular methyl or ethyl, or by a benzyl radical esterified carboxyl group, in particular in a 2-cephem compound of the formula IB, can be obtained by hydrolysis in a weakly basic medium, e.g. by treatment with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, can be converted into a free carboxyl group. A carboxyl group esterified by a suitable 2-halogeno lower alkyl or an arylcarbonylmethyl group can e.g. by treatment with a chemical reducing agent such as a metal, e.g. Zinc, or a reducing metal salt such as a chromium II salt, e.g. Chromium-II chloride, usually in the presence of a hydrogen-donating agent which, together with the metal, can produce nascent hydrogen, such as an acid, primarily acetic and formic acid, or an alcohol, preferably water being added, a carboxyl group esterified by an arylcarbonylmethyl group also by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl grouping, for example by irradiation, preferably with ultraviolet light, for example below 290 mji if the arylmethyl group e.g. one in the 3-, 4- and / or 5-position, e.g. represents benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. over 290 mp, if the arylmethyl group e.g. means a benzyl radical substituted in the 2-position by a nitro group, a carboxyl group esterified by a suitably substituted methyl group such as tert-butyl or diphenylmethyl e.g. by treatment with a suitable acidic agent such as formic acid or trifluoroacetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group, furthermore a carboxyl group in anhydride form by hydrolysis, e.g. by treatment with an acidic or weakly basic aqueous agent, such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g. by treatment with hydrogen in the presence of a noble metal, e.g. Palladium catalyst to be split.

A e.g. Carboxyl group protected by silylation or stannylation can be used in a conventional manner, e.g. by treatment with water or an alcohol.

Compounds of the formula IA or IB obtained can be converted into other compounds of the formula IA or IB in a manner known per se.

In a compound obtained e.g. an amino protecting group RjA or R-t6, in particular an easily removable acyl group, in a manner known per se, e.g. an a-polybranched lower alkoxycarbonyl group such as tert-butyloxycarbonyl by treating with trifluoroacetic acid and a 2-halogeno-lower alkoxycarbonyl group such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treating with a suitable reducing metal or a corresponding metal compound, e.g. Zinc, or a chromium-II compound, such as chloride or acetate, are advantageously split off in the presence of a hydrogen-generating agent nascent with the metal or the metal compound, preferably in the presence of water-containing acetic acid.

Furthermore, in a resulting compound of formula IA or IB, wherein a carboxyl group of formula -C (= 0) - R2 preferably one, e.g. by esterification, including by silylation, e.g. represents a carboxyl group protected by reaction with a suitable organic halogen silicon or halogen-tin-IV compound, such as trimethylchlorosilane or tri-n-butyl-tin chloride, an acyl group R ^

or Rjb, in which free functional groups which may be present are optionally protected, are removed by treatment with an imide halide-forming agent, reaction of the resulting imide halide with an alcohol and cleavage of the imino ether formed, a protected, e.g. a carboxyl group protected by an organic silyl radical can be released in the course of the reaction.

The invention also relates to the use of the process according to the invention for the preparation of compounds of the formula IA or IB, in which R, a and Rtb are hydrogen and R2 and R; a have the meanings given under formula IA or IB, characterized in that in a compound obtained in which R 1 or Rtb represents an acyl group, a suitable acyl group by treating with an imide halide-forming agent, reacting the resulting imide halide with an alcohol and

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Splits off the imino ether formed and replaced by hydrogen.

Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are, above all, acid halides, such as acid bromides and in particular acid chlorides. These are primarily acid halides of inorganic acids, especially phosphorus-containing acids such as phosphoroxy, phosphorus tri and especially phosphorus pentahalides, e.g. Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also catechylphosphorus trichloride, and also acid halides, especially chlorides, of sulfur-containing acids or of carboxylic acids, such as thionyl chloride, phosgene or oxalyl chloride.

The reaction with one of the imide halide-forming agents mentioned is usually carried out in the presence of a suitable, in particular organic base, primarily a tertiary amine, e.g. a tertiary aliphatic mono- or diamine such as a tri-lower alkyl amine, e.g. Trimethyl, triethyl or N, N-diisopropyl-N-ethylamine, furthermore an N, N, N \ N'-tetraniederalkyl-lower alkylenediamine, e.g. -, N, N, N ', N'-tetramethyl-l, 5-pentylene-diamine or N, N, N \ N' - tetramethyl-l, 6-hexylenediamine, a mono or bicyclic mono- or diamine such as an N-substituted, e.g. N-lower alkylated, alkylene, azaalkylene or oxaalkylene amines, e.g. N-methylpiperidine or N-methylmorpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (di-azabicyclonones; DBN), or a tertiary aromatic amine such as a di-lower alkyl aniline , e.g. N, N-dimethyl-aniline, or primarily a tertiary heterocyclic, mono- or bicyclic base, such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent, such as an optionally halogenated, e.g. chlorinated, aliphatic or aromatic hydrocarbon, e.g. Methylene chloride. Approximately equimolar amounts of the imide halide-forming Miti J s and the base can be used; the latter can also be in excess or deficit, e.g. in about 0.2 to about 1-fold amount or then in an about to 10-fold, in particular an about 3 to 5-fold excess.

The reaction with the imide halide forming agent is preferably carried out with cooling, e.g. at temperatures from about -50 ° C to about + 10 ° C, but also at higher temperatures, i.e. e.g. up to about 75 ° C, if the stability of the raw materials and products allows an elevated temperature.

The imide halide product, which is usually processed further without isolation, is reacted according to the process with an alcohol, preferably in the presence of one of the bases mentioned, to give the imino ether. Suitable alcohols are e.g. aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g. chlorinated, or additional hydroxyl-containing, lower alkanols, e.g. Ethanol, propanol or butanol, especially methanol, furthermore 2-halogeno-lower alkanols, e.g. 2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol. Usually one is used, e.g. up to about 100-fold excess of the alcohol and preferably works under cooling, e.g. at temperatures from about -50 ° C to about 10 ° C.

The I.nino ether product can advantageously be subjected to cleavage without isolation. The imino ether can be cleaved by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, the latter being able to be carried out directly after imino ether formation if an excess of alcohol is used. Water or an alcohol, especially a lower alkanol, e.g. Methanol, or an aqueous mixture of an organic solvent such as an alcohol. One usually works in an acidic medium, e.g. at a pH of about 1 to about 5, which if necessary can be obtained by adding a basic agent such as an aqueous alkali metal hydroxide, e.g. Sodium or potassium hydroxide, or an acid, e.g. a mineral acid,

or organic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid.

The three-step process described above for splitting an acyl group is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert to the reactants, such as an optionally halogenated hydrocarbon, e.g. Methylene chloride, and / or in an inert gas atmosphere, such as a nitrogen atmosphere.

If the imide halide intermediate obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of with an alcohol 25, a compound of the formula IA or IB is obtained, in which both radicals Rja and R ^ represent acyl groups.

In a compound of formula IA or IB in which both 30 Rxa and Rj "are acyl groups, one of these groups, preferably the less sterically hindered, can be selectively removed, e.g., by hydrolysis or aminolysis.

In a compound of the formulas IA or IB, in which RtA and Ri »together with the nitrogen atom represent a phthalimine-35 dog group, this can e.g. by hydrazinolysis, i.e. when treating such a compound with hydrazine, be converted into the free amino group.

Certain acyl residues RXA of an acylamino group in compounds obtainable according to the invention, such as e.g. the 40 5-amino-5-carboxy-valeryl radical, wherein carboxyl, e.g. by esterification, especially by diphenylmethyl, and / or the amino group, e.g. protected by acylation, in particular by an acyl radical of an organic carboxylic acid, such as halogeno-lower alkanoyl, such as dichloroacetyl, or phthaloyl, can also be treated by treatment with a nitrosating agent, such as nitrosyl chloride, with a carbocyclic arene diazonium salt, such as benzene diazonium chloride , or with a positive halogen-donating agent, such as an N-halogen amide or imide, for example N-bromo-50 succinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro or cyano-lower alkane and adding a hydroxyl-containing agent, such as water or a lower alkanol, e.g. Methanol, or if 55 in the 5-amino-5-carboxy-valeryl radical RjA the amino group is substituted and the carboxy group is e.g. is protected by esterification, and Rjb preferably represents an acyl radical, but can also mean hydrogen, by standing in an inert solvent such as dioxane or a halo-60 genated aliphatic hydrocarbon, e.g. Methylene chloride, and, if necessary, working up the free or monoacylated amino compound by methods known per se.

A formyl group RtA can also be treated with an acidic agent, e.g. p-toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g. dilute ammonia, or a decarbonylating agent, e.g. Tris - (triphenylphosphine) rhodium chloride can be split off.

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A triarylmethyl such as the trityl group RXA can e.g. by treatment with an acidic agent such as a mineral acid e.g. Hydrochloric acid, be split off.

In a compound of formula IA or IB, in which Rja and R, 6 represent hydrogen, the free amino group can be substituted by methods known per se, primarily by acylation by treatment with acids, such as carboxylic acid, or reactive derivatives thereof.

If a free acid, preferably with protected, optionally present functional groups, such as an optionally present amino group, is used for the acylation, suitable condensing agents, such as carbodiimides, for example N, N'-di-ethyl-, N, N'- Dipropyl, N, N'-diisopropyl, N, N'-dicyclo-hexyl or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyl-diimidazole, or isoxazolinium salts, for example N-ethyl -5-phenylisoxazolinium-3'-sulfonate and N-tert-butyl-5-methyl-isoxazolinium perchlorate, or a suitable acylamino compound, e.g. 2-ethoxy-l-ethoxycarbonyl-l, 2-dihydro-quinoline.

The condensation reaction is preferably carried out in one of the anhydrous reaction media mentioned below, for example in methylene chloride, dimethylformamide or acetonitrile.

An amide-forming, functional derivative of an acid, preferably with protected optionally present groups, such as an optionally present amino group, is primarily an anhydride of such an acid, including, and preferably, a mixed anhydride. Mixed anhydrides are e.g. those with inorganic acids, especially with hydrohalic acids, i.e. the corresponding acid halides, e.g. Chlorides or bromides, further with hydrochloric acid, i.e. the corresponding acid azides, with a phosphoric acid, e.g. Phosphoric acid or phosphorous acid with a sulfuric acid e.g. Sulfuric acid, or with hydrocyanic acid. Other mixed anhydrides are e.g. those with organic acids such as organic carboxylic acids, such as with optionally, e.g. Lower alkane carboxylic acids substituted by halogen such as fluorine or chlorine, e.g. Pivalic acid or trichloroacetic acid, or with half esters, especially lower alkyl half esters, of carbonic acid, such as the ethyl or isobutyl half ester of carbonic acid,

or with organic, especially aliphatic or aromatic, sulfonic acids, e.g. p-toluenesulfonic acid.

Internal anhydrides such as ketenes, e.g. Use diketene, isocyanates (i.e. internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxy or amino groups, such as mandelic acid - O-carboxanhydride or the anhydride of 1-N-carboxyamino-cyclohexane carboxylic acid.

Further acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected, optionally present functional groups, such as esters with vinylogenic alcohols (i.e. enols), such as vinylogenic lower alkanols, or aryl esters, such as preferably, e.g. phenyl substituted by nitro or halogen such as chlorine, e.g. Pentachlorophenyl, 4-nitrophenyl or 2,4-di-nitrophenyl esters, heteroaromatic esters, such as benzotriazole esters, or diacylimino esters, such as succinylimino or phthalylimino esters.

Other acylation derivatives are e.g. substituted form-imino derivatives, such as substituted N, N-dimethylchloroform-imino derivatives of acids, or N-substituted N, N-diacylamines, such as an N, N-diacylated aniline.

Acylation with an acid derivative, such as an anhydride and especially with an acid halide, can be carried out in the presence of an acid binding agent, e.g. an organic base such as an organic amine, e.g. 5 a tertiary amine such as tri-lower alkylamine, e.g. Triethylamine, N, N-di-lower alkyl-aniline, e.g. N, N-dimethylaniline, or a pyridine-type base, e.g. Pyridine, an inorganic base, e.g. an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. io Sodium, potassium or calcium hydroxide, carbonai or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide.

The above acylation can be carried out in an aqueous or preferably non-aqueous solvent or solvent mixture, for example in a carboxylic acid amide such as N, N-di-lower alkyl amide, e.g. Dimethylformamide, a halogenated hydrocarbon, e.g. Methylene chloride, carbon tetrachloride or chlorobenzene, a 20 ketone, e.g. Acetone, an ester, e.g. Ethyl acetate, or a nitrii, e.g. Acetonitrile, or mixtures thereof, and, if necessary, at reduced or elevated temperature and / or in an inert gas, e.g. Nitrogen atmosphere.

In the above N-acylation reactions one can start from 25 compounds of the formulas IA or IB, in which R3i is lower alkyl or an optionally substituted a-phenyl-lower alkyl, e.g. Is benzyl or diphenylmethyl group and R2 has the above meaning, compounds with free carboxyl groups of the formula -C (= 0) -R2, where R2 is 30 hydroxy, also in the form of salts, e.g. Ammonium salts, such as with triethylamine, or in the form of a compound with a carboxyl group which is protected by reaction with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxyphosphorodihalide, such as methylphos-35 phosphorodichloride, ethylphosphorodibromide or methoxyphosphorodichloride can; in the acylation product obtained the protected carboxyl group can be isolated in a manner known per se, e.g. as described above, including by hydrolysis or alcoholysis.

An acyl group can also be introduced by combining a compound of the formula IA or IB, in which R ^ and R ^ together represent a ylidene residue (which can also be added subsequently, for example by treating a compound in which Rja 45 and Rjb is hydrogen) with an aldehyde , as can introduce an aliphatic, aromatic or araliphatic aldehyde), for example acylated according to the methods given above, and the acylation product, preferably in neutral or weakly acidic medium, hydrolyzed. 50 An acyl group can also be introduced in stages. So you can e.g. in a compound of formula IA or IB with a free amino group, a halogen-lower alkanoyl, e.g. Bromoacetyl group, or e.g. by treatment with a carbonic acid dihalide such as phosgene, 55 a halocarbonyl, e.g. Chlorocarbonyl group and introduce an N- (halogeno-lower alkanoxyl) or N- (halocarbonyl) amino compound thus obtainable with suitable exchange reagents, such as basic compounds, e.g. Tetrazole, thio compounds, e.g. 2-mercapto-l-methyl-imidazole, or 60 metal salts, e.g. Sodium azide or alcohols, such as lower alkanols, e.g. implement tert-butanol, and so arrive at substituted N-lower alkanoyl or N-hydroxycarbonyl-amino compounds.

In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and after acylation by means of methods known per se, e.g. released as described above.

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Acylation can also be accomplished by replacing an existing acyl group with another, preferably sterically hindered, acyl group, e.g. by the process described above, by preparing the imide halide compound, treating it with a salt of an acid and hydrolytically cleaving off one of the acyl groups present in the product thus obtainable, usually the less sterically hindered acyl group.

Furthermore, e.g. a compound of formula IA or IB, in which Rja represents a glycyl group, preferably substituted in the a-position, such as phenylglycyl, and R, b represents hydrogen, with an aldehyde, e.g. Formaldehyde, or a ketone such as lower alkanone e.g. React acetone, and thus arrive at compounds of formula IA or IB, wherein RjA and R; b together with the nitrogen atom represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position represent.

In a compound of formula IA or IB, wherein Rjft and R, b are hydrogen, the free amino group can also be introduced by introducing a triarylmethyl group, e.g. by treating with a reactive ester of a triaryl methanol, such as trityl chloride, preferably in the presence of a basic agent such as pyridine.

An amino group can also be protected by introducing a silyl and stannyl group. Such groups are introduced in a manner known per se, e.g. by treatment with a suitable silylating agent, such as with a dihalodi-lower alkyl silane, lower alkoxy-lower alkyl dihalosilane or tri-lower alkyl silyl halide, e.g. Dichloro-dimethylsilane, methoxy-methyl-dichloro-silane, tri-methylsilyl chloride or dimethyl-tert-butyl-silyl chloride, such silyl halide compounds preferably being in the presence of a base, e.g. Pyridine used, with an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) amine (see eg British patent No. 1 073 530), or with a silylated carboxamide, such as a bis-tri-lower alkylsilyl acetamide, for example Bis-trimethylsilyl-acetamide, or trifluorosilyl-acetamide, further with a suitable stannylating agent such as a bis (tri-lower alkyltin) oxide, e.g. Bis (tri-n-butyl tin) oxide, a tri-lower alkyl tin hydroxide, triethyl tin hydroxide, a tri-lower alkyl lower alkoxy tin, tetra-lower alkoxy tin or tetrano-lower alkyl tin compound, and a tri-lower alkyltin halide, e.g. Tri-n-butyltin chloride (see e.g. Dutch specification 67/11107).

In a compound of the formula IA or IB which is obtainable according to the process and which contains a free carboxyl group of the formula -C (= 0) -R2, such a compound can be converted into a protected carboxyl group in a manner known per se. So you get esters e.g. by treatment with a suitable diazo compound such as a diazo lower alkane, e.g. Diazomethane or diazobutane, or a phenyl-diazo-lower alkane, e.g. Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, e.g. Boron trifluoride, or also reacting with an alcohol suitable for esterification in the presence of an esterifying agent, such as a carbodiimide, e.g. Dicyclohexylcarbodiimid, and carbonyldiimidazole, further with an N, N'-disubstituted O- or. S-substituted isourea or isothiourea, wherein an O- and S-substituent e.g. Lower alkyl, especially tert-butyl, phenyl-lower alkyl or cycloalkyl, and N- or. N 'substituents e.g. Are lower alkyl, in particular iso-propyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a

capable esters of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid. In addition, acid halides, such as chlorides (prepared, for example, by treatment with oxalyl chloride), activated esters (formed, for example, with N-hydroxy nitrogen compound, such as N-hydroxysuccinimide), or mixed anhydrides (obtained, for example, with alkyl haloformates, such as ethyl chloroformate or isobutyl chloroformate). or with haloacetic acid halides, such as trichloroacetic acid chloride) by reaction with alcohols, optionally in the presence of a base, such as pyridine, into an esterified carboxyl group.

In a compound obtained with an esterified group of the formula -C (= 0) -R2, this can be converted into another esterified carboxy group of this formula, e.g. 2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt such as sodium iodide in the presence of a suitable solvent such as acetone in 2-iodoethoxycarbonyl.

Mixed anhydrides can be prepared by combining a compound of formula IA or IB with a free carboxyl group of formula -C (= 0) -R2, preferably a salt, especially an alkali metal, e.g. Sodium, or ammonium, e.g. Triethylammonium salt thereof with a reactive derivative such as a halide, e.g. the chloride, an acid, e.g. a alkyl haloformate or a lower alkanecarboxylic acid chloride.

In a compound which is obtainable according to the process and has a free carboxyl group of the formula -C (= 0) -R2, such a compound can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preference being given to reactive, functionally modified derivatives, such as the abovementioned acid halides, generally esters, as well as the abovementioned activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines.

A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, e.g. by using compounds of the formulas IA or IB, in which R2 is hydroxy, or salts, such as alkali metal, e.g. Sodium salts thereof, treated with a suitable silylating or stannylating agent such as one of the above-mentioned silylating or stannylating agents; see e.g. British Patent No. 1 073 530 and Dutch Patent No. 67/17107.

Modified functional substituents in groups R / 1, Rjb and / or R2, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or 0.0'-disubstituted phosphono groups, can also be prepared by methods known per se, e.g. the above described, release, or free functional substituents in groups R, A, R ^ 'and / or R2, such as free amino, hydroxyl, carboxy or phosphono groups, by methods known per se, e.g. Functionally acylate or esterify or substitute. For example, an amino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base, such as a tri-lower alkylamine, e.g. Triethylamine, convert into a sulfoamino group. Furthermore, the reaction mixture obtained by reacting an acid addition salt of a 4-guanylsemicarbazide with sodium nitrite, with a compound of formula IA or IB, wherein e.g. the amino protecting group RjA represents an optionally substituted glycyl group, and thus convert the amino group to a 3-guanyl ureido group. Compounds with aliphatic halogen, e.g. with a gee5

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if necessary, react substituted a-bromoacetyl grouping with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and thus obtain corresponding phosphono compounds.

Cephem compounds of the formula IA and IB obtained can be converted into 1-oxides of the corresponding 3-cephem compounds of the formula IA by oxidation with suitable oxidizing agents, such as those described below. Obtained 1-oxides of 3-cephem compounds of the formula IA can be reduced by reduction with suitable reducing agents, e.g. reduce those described below to the corresponding 3-cephem compounds of formula IA. In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, subsequently released again.

Cephem compounds obtained can be isomerized. Thus, obtained 2-cephem compounds of the formula IB, or mixtures of 2- and 3-cephemver compounds obtained, can be converted into the corresponding 3-cephem compounds of the formula IA by using a 2-cephemver compound of the formula IB, or a mixture consisting of a 2- and 3-cephem compound, in which free functional groups optionally, for example as indicated, may be temporarily protected, isomerized. You can e.g. Use 2-cephem compounds of the formula IB in which the group of the formula -C (= 0) -R2 represents a free or protected carboxyl group, it being possible for a protected carboxyl group to be formed during the reaction.

For example, a 2-cephem compound of the formula IB can be isomerized by treating it with a basic agent and isolating the corresponding 3-cephem compound of the formula IA from an equilibrium mixture of the 2- and 3-cephem compounds which may be obtained.

Suitable isomerizing agents are e.g. organic nitrogenous bases such as tertiary heterocyclic bases of aromatic character and primarily tertiary aliphatic, azacycloaliphatic or araliphatic bases such as N, N, N-tri-lower alkylamines e.g. N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine or N, N-diisopropyl-N-ethylamine, N-lower alkyl azacycloalkanes, e.g. N - methyl piperidine, or N-phenyl-lower alkyl-N, N-di-lower alkyl amines, e.g. N-benzyl-N, N-dimethylamine, as well as mixtures thereof, such as the mixture of a pyridine-type base, e.g. Pyridine, and an N, N, N-tri-lower alkylamine, e.g. Pyridine and triethylamine. Furthermore, inorganic or organic salts of bases, in particular of medium to strong bases with weak acids, such as alkali metal or ammonium salts of lower alkane carboxylic acids, e.g. Sodium acetate, triethylammonium acetate or N-methyl-piperidine acetate, as well as other analog bases or mixtures of such basic agents can be used.

The above isomerization with basic agents can e.g. in the presence of a derivative of a carboxylic acid suitable for the formation of a mixed anhydride, such as a carboxylic anhydride or halide, e.g. with pyridine in the presence of acetic anhydride. It is preferably carried out in an anhydrous medium, in the presence or absence of a solvent, such as an optionally halogenated, e.g. chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, bases used as reactants which are liquid under the reaction conditions can also serve as solvents at the same time,

if necessary, with cooling or heating, preferably in a temperature range from about - 30 ° C to about + 100 ° C, in an inert gas, e.g. Nitrogen atmosphere, and / or in a closed vessel.

The 3-cephem compounds of the formula IA thus obtainable can be prepared in a manner known per se, e.g. by adsorption and / or crystallization, from any 2-cephem compounds of the formula IB ab-5 still present.

The isomerization of 2-cephem compounds of the formula IB can also be carried out by oxidizing them in the 1-position, if desired, separating an available isomer mixture of the 1-oxides from 3-cephem compounds of the io formula IA and the 1 so obtainable Oxides of the corresponding 3-cephem compounds of the formula IA reduced.

Suitable oxidizing agents for the oxidation in the 1-position of 2-cephem compounds are inorganic 15 peracids, which have a reduction potential of at least +1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, in particular organic carboxylic acids a dissociation constant of at least 10-5 20 in question. Suitable inorganic peracids are periodic and persulfuric acid. Organic peracids are corresponding percarbonate and persulfonic acids which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and a carboxylic acid. It is advisable to use a large excess of the carboxylic acid if, e.g. Acetic acid is used as a solvent. Suitable peracids are e.g. Performic acid, peracetic acid, per-trifluoroacetic acid, permaleic acid, perbenzoic acid, mono-30 perphthalic acid or p-toluenesulfonic acid.

Oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least ICH using low concentrations, e.g. 35 1-2% and less, but also larger amounts of the acid can be used. The effectiveness of the mixture depends primarily on the strength of the acid. Suitable mixtures are e.g. those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid.

40 The above oxidation can be carried out in the presence of suitable catalysts. For example, the oxidation with percarboxylic acids is catalyzed by the presence of an acid with a dissociation constant of at least IO5, its effectiveness depending on its strength 45. Acids suitable as catalysts are e.g. Acetic acid, perchloric acid and trifluoroacetic acid. Usually at least equimolar amounts of the oxidizing agent are used, preferably a slight excess of about 10% to about 20%. The oxidation is carried out under mild conditions, e.g. at temperatures from about -50 ° C to about + 100 ° C, preferably from about -10 ° C to about + 40 ° C.

Oxidation of 2-cephem compounds to the 1-oxides of the corresponding 3-cephem compounds can also be accomplished by treating with ozone, as well as organic hypohalite compounds such as lower alkyl hypochlorites, e.g. tert-butyl hypochlorite, which can be obtained in the presence of inert solvents such as optionally halogenated hydrocarbons, e.g. Methylene chloride, and used at temperatures from about -10 ° C to about + 30 ° C, with periodate compounds such as alkali metal periodates, e.g. Potassium periodate, which is preferably used in an aqueous medium at a pH of about 6 and at temperatures from about -10 ° C. to about + 30 ° C., with iodobenzene-65 dichloride, which is preferably in an aqueous medium in the presence of an organic base, e.g. Pyridine, and with cooling e.g. at temperatures from about -20 ° C to about 0 °, or with any other oxidation

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22

be carried out medium, which is suitable for converting a thio into a sulfoxide grouping.

In the 1-oxides of 3-cephem compounds of the formula IA obtainable in this way, in particular in those compounds in which R ^, R / 'and R2 have the preferred meanings indicated above, the groups R ^, R, 1' and / or R2 are merged, split off or introduced within the defined framework. A mixture of isomeric a- and β-l-oxides can e.g. chromatographically, be separated.

The reduction of the 1-oxides of 3-cephem compounds of the formula IA can be carried out in a manner known per se by treatment with a reducing agent, if necessary in the presence of an activating agent. Possible reducing agents are: catalytically activated hydrogen, using noble metal catalysts which contain palladium, platinum or rhodium and which are optionally used together with a suitable support material, such as carbon or barium sulfate; reducing tin, iron, copper or manganese cations, which are in the form of corresponding compounds or complexes of inorganic or organic type, e.g. as tin (II) chloride, fluoride, acetate or formate, iron (II) chloride, sulfate, oxalate or succinate, copper (I) chloride, benzoate or oxide, or manganese (II) chloride , sulfate, acetate or oxide, or as complexes, for example with ethylenediamine tetraacetic acid or nitrilotriacetic acid; reducing dithionite, iodine or iron (II) cyanide anions, which in the form of corresponding inorganic or organic salts, such as alkali metal, e.g. Sodium or potassium dithionite, sodium or potassium iodide or iron - II-cyanide, or in the form of the corresponding acids, such as hydroiodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, furthermore esters, amides and halides of phosphinous, phosphonous or phosphorous acid, as well as phosphorus-sulfur compounds corresponding to these phosphorus oxygen compounds, in which organic residues are primarily aliphatic, aromatic or araliphatic residues, e.g. optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups such as e.g. Tri-phenylphosphine, tri-n-butylphosphine, diphenylphosphinous acid methyl ester, diphenylchlorophosphine, phenyldichlorophosphine, benzenephosphonous acid dimethyl ester, butanephosphonous acid methyl ester, phosphorous acid triphenyl ester, phosphorus acid trichloromethyl ester, phosphorus usdibromethyl ester, phosphorus reducing halosilane compounds which have at least one hydrogen atom bonded to the silicon atom and which, in addition to halogen, such as chlorine, bromine or iodine, also organic radicals, such as aliphatic or aromatic groups, e.g. optionally substituted lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc .; reducing quaternary chloromethyleneiminium salts, in particular chlorides or bromides, in which the iminium group is substituted by a bivalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N, N-diethyliminium chloride or N-chloromethylene pyrrolidinium chloride; and complex metal hydrides, such as sodium borohydride, in the presence of suitable activating agents, such as cobalt-II chloride, and borane dichloride.

As activating agents which are used together with those of the above-mentioned reducing agents which do not themselves have Lewis acid properties, i.e. which are primarily used together with the dithionite, iodine or iron - II-cyanide and the non-halogen-containing trivalent phosphorus reducing agents or in the catalytic reduction are, in particular, organic carbon and sulfonic acid halides, furthermore sulfur, phosphorus or Silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. Phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride, pivalic acid chloride, 4-Methoxyben-zoesäurechlorid, 4-Cyanbenzoesäurechlorid, p-toluenesulfonic acid chloride, methanesulphonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, Benzolphosphonigsäuredichlorid, dimethylchlorosilane or trichlorosilane, also suitable acid anhydrides , such as trifluoroacetic anhydride, or cyclic sultones such as ethane sultone, 1,3-propane sultone, 1,4-butane sultone or 1,3-hexane sultone.

The reduction is preferably carried out in the presence of solvents or mixtures thereof, the selection of which is primarily determined by the solubility of the starting materials and the choice of the reducing agent, e.g. Lower alkane carboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and e.g. optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. Benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkane carboxylic acid esters or nitriles, e.g. Ethyl acetate or acetonitrile, or amides of inorganic or organic acids, e.g. Dimethylformamide, dimethylacetamide or hexamethylphosphoramide, ether, e.g. Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g. Acetone, or sulfones, especially aliphatic sulfones, e.g. Dimethyl sulfone or tetramethylene sulfone, etc., together with the chemical reducing agents, these solvents preferably not containing water. It is usually carried out at temperatures from about -20 ° C. to about 100 ° C., and the reaction can be carried out at lower temperatures if very reactive activating agents are used.

In the 3-cephem compounds of the formula IA which can be obtained in this way, R / -, Rxb and / or R2 can be converted into other groups R ^, Rjb or R2 as described above.

Salts of compounds of the formulas IA and IB can be prepared in a manner known per se. Thus, salts of such compounds with acidic groups e.g. by treatment with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. form the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent. Acid addition salts of compounds of the formulas IA and IB with basic groups are obtained in the usual way, e.g. by treatment with an acid or a suitable anion exchange reagent. Internal salts of compounds of the formulas IA and IB which contain a salt-forming amino group and a free carboxyl group can e.g. by neutralizing salts such as acid addition salts to the isoelectric point, e.g. with weak bases, or by treatment with liquid ion exchangers. Salts of 1-oxides of compounds of the formula IA with salt-forming groups can be prepared in an analogous manner.

Salts can be converted into the free compounds in a conventional manner, metal and ammonium salts e.g. by treatment with suitable acids and acid addition salts e.g. by treating with a suitable basic agent.

Mixtures of isomers obtained can be separated into the individual isomers by methods known per se

5

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mixtures of diastereomeric isomers e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography} or other suitable separation processes. Racemates obtained can be separated in a customary manner, if appropriate after introducing suitable salt-forming groups, for example by forming a mixture of diastereomeric salts with optically active salt-forming agents, into the mixture diastereomeric salts and conversion of the salts into the free compounds or by fractional crystallization from optically active solvents into which the antipodes are separated.

The process also includes those embodiments according to which compounds obtained as intermediates are used as starting materials and the remaining process steps are carried out with them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction.

Such starting materials are preferably used and the reaction conditions are selected so that the compounds listed as particularly preferred at the outset are obtained.

In the starting compounds of the formula II, the leaving group Y is preferably a group -S02-R5, in which R5 5 has the stated meaning, but in particular the indicated preferred meaning.

The process according to the invention is distinguished from previously known processes in that it consists of inexpensive, easily accessible starting materials, such as, in particular, the 1-oxides of penicillins G or V which can be prepared by fermentation and 6-amino-penicillanic acid, the reactive groups of which on any one Protected in a known manner and can be easily released again after the reaction, starts, and the intermediate products according to the invention are produced in high yields. In particular, it also allows the direct preparation of compounds of the formula I in which R3 is hydrogen without the need to split off a hydroxyl protective group R131.

The starting materials of the formula II used according to the invention can be prepared, for example, according to the following reaction scheme.

24th

> a "K

Level 1 t) b /

> Ri

N ^ ^ Q _Y

XM /

I CR,

C-CH,

(V)

0

-c-i &

Level 2a,

Va: Y = Vb: Y = Vc: Y =

-s-r4

-S02-R5 -s-so2-r5

Level 2

v

R

a

1\

N

R

H h

Os

(VII) Vlla

S-Y CH0

■ N

'^ j ^ c - oh

0 = C "R2

=. -s-r.

Vllb: Y = "S02 ~ R5

Vile: Y

<-

-s-sop-rc

^ H H

Level 3 Kn] 't

1 \ 1 o Ç

0 = Ä— ~ N \ o

-C — CH.

(VI)

Via: Y = VIb: Y = VIc: Y =

v o = c-4

-s-r4 ~ S02 ~ R5

-s-so2-r5

R

1\

Level 4

N H H

y H — À /

S- '

Level 5a

Ott;

• N

Y "

f3

Level 5

-o-so2-r5

(VIII) 0 = C-R ^

Villa: y = VHIb: y =

-s-r,

4th

-so2-r5

Ville: y = -s-s02-r5

R

a

1\

N H H g _y

Kb 'Vf

-N

f:

3rd

0 = C-RA

0 =

(II)

lia: Y = -s-r

IIb: Y = -S02 "R5

Ile: Y = -S-S00-R,

/ b

25th

626m

Starting compounds of the formula IV are known or can be prepared by known processes.

Compounds of formula Va are also known or can be prepared according to Dutch patent 72.08671.

Compounds of the formula Vb can be obtained from compounds of the formula IV by reaction with a sulfinic acid of the formula HS02-R5 or a sulfonyl cyanide of the formula N = C - SO, -R5. Compounds of the formula IVc can be obtained from compounds of the formula IV by reaction with a thiosulfonic acid of the formula H-S-S02-R5. The reaction takes place in an inert solvent or solvent mixture, for example an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic Alcohol, such as lower alkanol, e.g. Methanol, ethanol, cyclohexanol or phenol, a polyhydroxy compound, e.g. a polyhydroxyalkane such as dihydroxy lower alkane e.g. Ethylene or propylene glycol, a lower ketone such as acetone or methyl ethyl ketone, an ethereal solvent such as diethyl ether, dioxane or tetrahydrofuran, a lower carboxylic acid amide such as dimethylform or dimethylacetamide, a lower di-alkyl sulfoxide such as dimethyl sulfoxide and the like or mixtures thereof.

The reaction takes place at room temperature or preferably at elevated temperature, e.g. at the boiling point of the solvent used, if desired in an inert gas, such as nitrogen atmosphere.

The reaction with the sulfonyl cyanide of the formula N = C-SO2-R0 is accelerated by adding compounds which provide halogen anions. Suitable compounds which provide halogen anions are, for example, quaternary ammonium halides, in particular chlorides and bromides, such as those which are optionally substituted on the lower alkyl groups, e.g. by aryl, such as phenyl, mono- or poly-substituted tetraniederalkylammonium halides, such as tetraethyl- or benzyl-triethylammonium chloride or bromide. The compounds providing halogen anions are added in amounts of about 1 to about 50 mole percent, preferably from about 2 to about 5 mole percent.

Compounds of formula Vb and Vc can also be obtained by using a compound of formula Va with a heavy metal sulfinate of formula Mn + (- S02-R5) n or with a heavy metal thiosulfonate of formula Mn + (~ S - S02-Rr)) n implements, in which M represents a heavy metal cation and n means the valence of this cation. Suitable heavy metal sulfinates or thiosulfonates are, in particular, those which have a greater solubility product in the reaction medium used than the heavy metal compounds of the formula Mn + (- S-R4) n formed during the reaction. Suitable heavy metal cations Mn + are especially those that form particularly poorly soluble sulfides. This includes, for example, the monovalent or divalent cations of copper, mercury, silver and tin, copper - ++ and silver + cations being preferred,

The heavy metal sulfinate or thiosulfonate can either be used as such or formed in situ during the reaction, for example from a sulfinic acid of the formula HSO, -Rn or a thiosulfonic acid of the formula H-S-SOa-R ,; or a soluble salt thereof, e.g. an alkali metal such as sodium salt and a heavy metal salt whose solubility product is greater than that of the resulting heavy metal sulfinate or thiosulfonate, e.g. a heavy metal nitrate, acetate or sulfate, e.g. Silver nitrate, mercury-II-diacetate or copper-II-sulfate or a soluble chloride, such as tin-II-chloride - dihydrate.

The reaction of a compound of formula Va with the heavy metal sulfinate of the formula Mn + (~ S-S02-R5) n or thiosulfonate of the formula Mn + (- S-S02-R5) n can be carried out in an inert organic solvent, in water or in a Solvent mixture consisting of water and a water-miscible solvent. Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as pentane, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cycloaliphatic or aromatic alcohols, such as lower alkanols, e.g. Methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds such as polyhydroxyalkanes, e.g. Dihydroxy-lower alkanes, such as ethylene or propylene glycol, carboxylic acid esters, e.g. Lower carboxylic acid lower alkyl esters, such as ethyl acetate, lower ketones, such as acetone or methyl ethyl ketone, ethereal solvents, such as dioxane, tetrahydrofuran or polyethers, such as dimethoxyethane, lower carboxamides, such as dimethylformamide, lower alkyl nitriles, such as acetonitrile or lower sulfoxides such as dimethyl sulfoxide. In water or in particular in mixtures of water and one of the solvents mentioned, including emulsions, the reaction usually proceeds much faster than in the organic solvents alone.

The reaction temperature is usually at room temperature, but can be reduced to slow the reaction or increased to accelerate, for example up to the boiling point of the solvent used, it being possible to work at normal or elevated pressure.

In a compound of formula V obtained, a group Rxa, Rjb or R2A can be converted into another group R1a, R ^ or R2a, analogous reactions can be used as indicated for the conversion of these groups in compounds of formula IA or IB .

In stages 2 and 3 or 2a, a compound of formula V can be converted into a compound of formula VII by oxidative degradation of the methylene group to an oxo group.

The oxidative cleavage of the methylene group in compounds of the formula V to form an oxo group can be carried out to form an ozonide compound of the formula VI by treatment with ozone. Ozone is usually used in the presence of a solvent such as an alcohol, e.g. a lower alkanol such as methanol or ethanol, a ketone, e.g. a lower alkanone such as acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. a halogeno lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and with cooling or gentle heating, e.g. at temperatures from about -90 ° C to about + 40 ° C.

An ozonide of the formula Via obtained as an intermediate can, optionally without isolation by conversion with a heavy metal sulfinate of the formula Mn + (_SO-R5) n or a -thiosulfonate of the formula Ma + (- S-S02-R5) n, analogously to the conversion of compounds of the formula Va to compounds of the formula Vb or Vc, are converted into a compound of the formula VIb or VIc.

An ozonide of formula V can be reductively cleaved in step 3 to a compound of formula VII, catalytically activated hydrogen, e.g. Hydrogen in the presence of a heavy metal hydrogenation catalyst such as Nikkei, furthermore palladium catalyst, preferably on a suitable support material such as calcium carbonate or carbon or chemical reducing agents such as reducing heavy5

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metals including heavy metal alloys or amalgams, e.g. Zinc, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or an alcohol, e.g. Lower alkanol, reducing inorganic salts such as alkali metal iodides e.g. Sodium iodide, in the presence of a hydrogen donor, such as an acid, e.g. Acetic acid, or reducing sulfide compound such as a lower alkyl sulfide, e.g. Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which may contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphines, e.g. Tri-n-butylphosphine, or triarylphosphines, e.g. Triphenylphosphine, furthermore phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkylphosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethylphosphite, or phosphoric acid triamides which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexane-lower alkylphosphide phosphoric acid , e.g. Hexamethylphosphoric acid tri-amide, the latter preferably in the form of a methanol adduct, or tetracyanethylene can be used. The usually non-isolated ozonide is normally cleaved under conditions used to make it, i.e. in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating.

Enol compounds of the formula VII can also be present in the tautomeric keto form.

An enol compound of the formula VHa can be converted by reaction with a heavy metal sulfinate of the formula Mn + (- S02. Or thiosulfate of the formula Mn + (- S-S02-R5) n, analogously to the conversion of compounds of the formula Va to compounds of the formula Vb or Vc, are converted into a compound of the formula Vllb or Vile.

In a compound of formula VII obtained, a group R, a, Rjb or R2A can be converted into another group R /, R, b or R "A, whereby analogous reactions can be used as for the conversion of these groups with compounds of Formula IA or IB is appropriate.

In the fourth stage, an enol compound of the formula VII obtained is converted into a compound of the formula VIII by esterification.

To prepare sulfonic acid esters of the formula VIII, a compound of the formula VII is esterified with a reactive functional derivative of a sulfonic acid of the formula KO-'X), R "where Rn has the meaning given under Y for R5.

Within the meaning of R5, these two groups in a compound of formula VIII can either be the same or different.

The reactive functional derivatives of a sulfonic acid of the formula H0-S02-R- are, for example, their reactive anhydrides, in particular the mixed anhydrides with hydrohalic acids, for example their chlorides, such as mesyl chloride and p-toluenesulfonic acid chloride.

The esterification is, preferably in the presence of an organic tertiary nitrogen base, such as pyridine, triethylamine or methyldiisopropylamine, in a suitable inert solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon, such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic Hydrocarbon, e.g. Methylene chloride, or an ether such as a di-lower alkyl ether, e.g. Diethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the reactivity of the esterifying reagent with cooling,

at room temperature or with slight warming, i.e. at temperatures from about -10 ° C to about + 50 ° C, further, if necessary, in a closed vessel and / or under an inert gas, e.g. Nitrogen atmosphere carried out. 5 The sulfonic acid ester of the formula VIII obtained can either be isolated or further processed in the same reaction mixture.

A compound of the formula Villa can, by conversion with a heavy metal sulfinate of the formula Mn + (- S02-R5) n io or thiosulfonate of the formula MM + C ~ S-S02-R5) n, analogously to the conversion of compounds of the formula Va Vb or Vc, are converted into a compound of the formula VHIb or Ville.

In a compound of formula VIII obtained, a group Rja, Rab or R2A can be converted into another group Rxa, Rib or R2A, analogous reactions can be used as indicated for the conversion of these groups in compounds of formula IA or V. .

20 In the 5th stage, a sulfonic acid ester of the formula VIII obtained is converted into a compound of the formula II by treatment with a primary or secondary amine of the formula H-N (R4a) (R4b).

The amination is carried out in a suitable inert organic solvent, such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon such as methylene chloride or an ether such as di-lower alkyl ether, e.g. Diethyl ether, or a cyclic ether, e.g. Tetrahydrofuran or dioxane, or a solvent mixture and, depending on the reactivity of group -0-S02-R5 and the amine used, at temperatures between about - 10 ° C and about 50 ° C, preferably at about 0 ° C to about 20 ° C, if necessary in a closed vessel and / or under an inert gas, eg Nitrogen atmosphere.

A compound of formula II can also be used in step 5a by treating a compound of formula VII with a salt of a primary or secondary amine of formula 40 H-N (R4a) (R4b), e.g. a hydrogen halide addition salt such as a hydrochloride in the presence of a tertiary base such as pyridine in a suitable solvent such as a lower alcohol e.g. absolute ethanol, at temperatures of about 20 to about 100 ° C, preferably at about 40 to about 45 60 ° C can be obtained.

A compound of the formula IIa can be reacted with a heavy metal sulfinate of the formula Mn + (~ S02-R5) n or thiosulfate of the formula Mn + ("S-S02-R5) n, analogously to the conversion of compounds of the formula Va to Vb or Vc can thus be converted into a compound of the formula IIb or Ile.

In a compound of formula II obtained, taking the enamine function into account, one group R, a, R, b or R2A can be converted into another group R, '1, R ^ or R2A over-55.

The pharmacologically useful compounds made according to the present invention can e.g. be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in admixture with inorganic or organic, solid or liquid, pharmaceutically usable excipients which are suitable for enteral or preferably parenteral administration. Thus, tablets or gelatin capsules are used which combine the active ingredient with diluents, e.g. Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or

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Polyethylene glycol; Tablets also contain binders, e.g. Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, traanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinyl pyrrolidone, and, if desired, disintegrants, e.g. Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colors, flavors and sweeteners. Furthermore, the new pharmacologically active compounds can be administered in the form of injectable, e.g. Use intravenously administered preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, these being e.g. from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. Mannitol can be prepared before use. The pharmaceutical preparations can be sterilized and / or adjuvants, e.g. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are used in a manner known per se, e.g. produced by means of conventional mixing-granulating, coating, solution or lyophilization processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active substance.

In connection with the present description, organic radicals designated “lower”, unless expressly defined, contain up to 7, preferably up to 4, carbon atoms; Acyl radicals contain up to 20, preferably up to 12 and primarily up to 7 carbon atoms.

The following examples serve to illustrate the invention; Temperatures are given in degrees Celsius. The cephem compounds mentioned in the examples have the R configuration in the 6- and 7-positions and the azetidinone compounds mentioned in the 3- and 4-positions.

example 1

A solution of 160 mg (0.23 mmol) of a mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-l-yl] -3- (l-pyrrolidyl) -crotonic acid - p-nitrobenzyl ester and the corresponding isocrotonic acid ester in 3 ml of dry acetonitrile is heated under nitrogen at 80 ° C. for about 4 hours until thin-layer chromatography (silica gel: toluene / ethyl acetate 1: 1) is no longer detectable. The heating bath is removed, the reaction mixture containing the 7β-phenoxyacet-amido-3-pyrrolidino-cephem-4-carboxylic acid p-nitrobenzyl ester, with p-toluenesulfonic acid (approx. 0.23 mmol) and 0.2 ml water added and stirring continued for 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is triturated at 0 ° C. with diethyl ether and gives the pale yellow 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-ni-trobenzyl ester. IR spectrum (methylene chloride): characteristic bands at 2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55; 7.45; 8.15 and 8.3 (i; NMR spectrum (deuterochloroform): 6 in ppm: 3.4 (2H, q, J = 17 Hz); 4.57 (2H, s); 5.06 (1H, d, J = 5 Hz); 5.35 (2H, q, J = 14 Hz); 5.7 (IH, dd, J = 5.10 Hz); 6.8 - 8.4 (10H, c) and 11.4 (1H, br. s.).

The starting materials can be obtained as follows:

a) A solution of 36.6 g (0.1 mol) of 6-phenoxyacet-amidopenicillanoic acid-l-oxide, 11.1 ml (0.11 mol) of triethylamine and 23.8 g (0.11 mol) of p -Nitrobenzyl bromide in 200 ml

Dimethylformamide is stirred for 4 hours at room temperature under nitrogen. The reaction solution is then introduced into 1.5 liters of ice water, the precipitate is filtered off, dried and recrystallized twice from ethyl acetate-methylene-5 chloride. The colorless, crystalline 6-phenoxy-acetamidopenicillanoic acid-p-nitrobenzyl ester-1β-oxide melts at 179-180 ° C.

b) A solution of 5.01 g (10 mmol) of 6-phenoxyacet-amidopenicillanoic acid p-nitrobenzyl ester-1β-oxide and 1.67 g of io (10 mmol) of 2-mercaptobenzothiazole in 110 ml of dry toluene is added for 4 hours Reflux cooked in a nitrogen atmosphere. The solution is concentrated to about 25 ml by distillation and diluted with about 100 ml of ether. The precipitated product is recrystallized from methylene-15 chloride ether and the 2- [4 - (benzothiazol-2-yldithio) -3-phenoxy-acetamido-2-oxoazetidine - l-yl] -3-methylene is obtained. p-nitrobenzyl butyric acid, melting point 138-141 ° C.

c) To a solution of 3.25 g (5.0 mmol) of 2- [4- (Benz-20 thiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -

-3-methylenebutyric acid p-nitrobenzyl ester in 200 ml acetone / water 9: 1 (v / v) 1.06 g of finely powdered silver nitrate is added. The solution of 890 mg (5 mmol) of sodium p-toluenesulfinate in 100 ml of the same solvent mixture is then introduced immediately (within ten minutes). A light yellow precipitate forms immediately. After stirring for one hour at room temperature, the mixture is filtered with the addition of Celite. The filtrate is diluted with water and extracted twice with ether. The combined ether-30 extracts are dried over sodium sulfate and, after concentration, give the pale yellow solid 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene butyric acid. p-nitrobenzyl ester. Thin layer chromatography on silica gel (toluene / ethyl acetate 2: 1): Rf value = 35 0.24; IR spectrum (in CH2C12): characteristic bands at 3.90, 5.56, 5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10 , 8,72,9,25,10,95 (i. The product can be used in the subsequent reaction without further purification.

The same compound can also be obtained by the following 40 methods:

ci) To a solution of 3.25 g (5.0 mmol) of 2- [4-benzothiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] --3-methylenebutyric acid-p- nitrobenzyl ester in 200 ml acetone / water 9: 1 (v / v), 1.58 g (1.2 equivalents) of silver p-45 toluenesulfinate are added in portions over 10 minutes. The suspension is stirred for one hour at room temperature, filtered and further processed as described in Example 1c). The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacet-amido-2-oxoazetidin-l-yl] -3-methylene-butyric acid p-nitro-50 benzyl ester is obtained in quantitative yield.

Silver p-toluenesulfinate is obtained as a colorless precipitate by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p-toluenesulfinate. The product is dried in a vacuum for 24 hours.

55 cii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-l-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared analogously to Example Ici) from 3.25 g 2- [4- (Benzothiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] - 3-methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 60 equivalents) copper II di-p-toluenesulfinate can be obtained in quantitative yield.

The copper-II-di-p-toluenesulfinate is obtained by reacting copper sulfate and sodium p-toluenesulfinate (2 equivalents) in water. After filtering off, the salt 65 is dried under vacuum at 60 ° C. for 12 hours.

ciii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared analogously to Example Ici) from 130 mg of 2- [ 4- (Benz-

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thiazol-2-yldìthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] - 3-methylenebutyric acid p-nitrobenzyl ester and 85 mg (2 equivalents) of tin-II-di-p-toluenesulfinate can be obtained.

The tin-II-p-di-p-toluenesulfinate is obtained by reacting tin-II-chloride (2H20) and sodium p-toluenesulfinate in water. After filtering off and washing with water, the salt is dried in vacuo at 50 to 60 ° C. for about 12 hours.

civ) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetami-do-2-oxoazetidin-l-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared analogously to Example Ici) from 130 mg of 2- [ 4- (Benzothiazol-2-yldithio) -3 -phenoxyacetamido-2-oxoazetidin-1-yl] --3-methylenebutyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II-di-p-toluenesulfinate were obtained will.

The mercury-II-di-p-toluenesulfinate is obtained by reacting mercury-II-di-acetate and sodium p-toluenesulfinate in water. After filtering off and washing with water, the salt is dried in vacuo at 50-60 ° C. for about 12 hours.

cv) A solution of 517 mg (1.02 mmol) of 6-phenoxy-acetamidopenicillanoic acid-p-nitrobenzyl ester-1β-oxide and 187 mg (1.2 mmol) of p-toluenesulfinic acid in 10 ml of 1,2-dimethoxyethane ( or dioxane) is refluxed for 4.5 hours in the presence of 3.5 g of a molecular sieve 3A and in a nitrogen atmosphere, whereupon a further 308 mg (1.98 mmol) of p-toluenesulfinic acid dissolved in 2 ml of 1,2-dimeth -oxyethane be added in five portions at 45 minute intervals. After 4.5 hours, the reaction mixture is poured into 100 ml of 5% aqueous sodium bicarbonate solution and extracted with ethyl acetate. The combined organic phases are washed with water and saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 2: 1 and gives the 2- [4- (p-toluenesulfonylthio) -3 -phenoxyacetamido-2-oxoazetidin-1 -yl] -3-methylene-butyric acid- p-nitrobenzyl ester.

evi) A mixture of 250 mg (0.5 mmol) of 6-phenoxy-acetamidopenicillanoic acid-p-nitrobenzyl ester 1-oxide, 110 mg (0.61 mmol) of p-toluenesulphonyl cyanide and 5 mg (0.022 mmol) of benzyl-triethylammonium chloride in 2 ml of dry, peroxide-free dioxane is stirred under argon at 110 ° C. for 4.5 hours. The solvent is evaporated off in vacuo and the remaining yellow oil is chromatographed on acid-washed silica gel. Elution with 30% ethyl acetate in toluene gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1-yl] -3-methylene-butter-acid-acid-p-nitrobenzyl ester.

evii) A mixture of 110 mg (0.61 mmol) of p-toluenesulfonyl cyanide and 4.5 mg (0.021 mmol) of tetraethylammonium bromide in 1 ml of pure dioxane is stirred at 110 ° C. under argon for 30 minutes. A suspension of 250 mg (0.5 mmol) of 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester-1β-oxide in 1 ml of dioxane is added and the resulting solution is stirred for 4 hours at 110 ° C. under argon. The solvent is removed in vacuo, the crude product is dissolved in ethyl acetate and washed with water and saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate and freed from the solvent in vacuo and gives crude 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l - yl] -3-methylenebutyric acid p-nitrobenzyl ester.

d) In a solution of 1.92 g (3.0 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3 - methylene-butyric acid-p -Nitrobenzylester in 30 ml dry methyl acetate at 1.18 ° C within 33 minutes 1.1

Equivalent ozone introduced. Excess ozone is then removed using a stream of nitrogen (15 minutes at -78 ° C). 2.2 ml of dimethyl sulfide (10 equivalents) are added and the solution warmed to room temperature. After standing for 5 hours, the solvent is distilled off in vacuo and the colorless oil which remains is taken up in 100 ml of benzene. The benzene solution is washed with three 50 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo. After recrystallization of the residue from toluene, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159-160 ° C. receive.

di) The crude 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester obtained in Example 1 .evii) is dissolved in 20 ml of methyl acetate and ozonized at -70 ° C until starting material is no longer available according to the thin layer chromatogram. A stream of nitrogen is then passed through the solution and heated to 0-5 ° C. A solution of 300 mg of sodium bisulfite in 5 ml of water is added and the mixture is stirred for about 5 minutes until no more ozonide can be detected with potassium iodide starch paper. The mixture is diluted with ethyl acetate, the aqueous phase is separated, and the organic phase is washed with water, dried over magnesium sulfate and freed from the solvent in vacuo. The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. The precipitate is filtered off and the filtrate is evaporated in vacuo. The residue is recrystallized from methanol and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 - yl] -3-hydroxycrotonic acid p-nitrobenzyl ester of melting point 159-160 ° C.

e) A solution of 641 mg (1 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-hy-hydroxycrotonic acid p-nitrobenzyl ester in 5 ml of dry Pyridine is cooled to -10 ° C. in an acetone-ice bath, 285 mg (1.5 mmol) of p-toluenesulfonyl chloride are added and the mixture is stirred under a nitrogen atmosphere for about 5 hours until thin layer chromatography (silica gel: toluene / ethyl acetate 1: 1) no starting material is detectable. The reaction solution is diluted with 50 ml of benzene, washed with water, ice-cold 10% aqueous citric acid solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido - 2-oxoazetidin-l-yl] -3-p-toluenesulfonyloxycrotonic acid p - nitrobenzyl ester of pale yellow color, which is sufficiently pure for further processing, is obtained . IR spectrum (methylene chloride): characteristic bands at 5.6; 5.8; 5.9; 6.55; 7.45; 8.55 and 8.75 [x; Nuclear Magnetic Resonance Spectrum (Deuterochloroform): 5 in ppm: 2.4 (6H, s); 2.45 (3H, s); 4.4 (2H, q, J = 15 Hz); 5.3 (2H, s); 5.3 (1H, dd, J = 5.10 Hz); 5.8 (1H, d, J = 5 Hz); 6.6 - 8.4 (18H, c>.

f) A solution of 80 mg (0.1 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3-p - toluenesulfonyloxy-crotonic acid-p- nitrobenzyl ester and 0.0175 ml pyrrolidine (0.21 mmol) in 2 ml dry tetrahydrofuran are stirred under a nitrogen atmosphere for about 1 hour until thin-layer chromatography (silica gel: toluene / ethyl acetate 1: 1) no longer shows any starting material. The reaction mixture is diluted with 10 ml of benzene, washed with twice 5 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 1: 1 and gives a mixture consisting of

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the colorless 2- [4- (p-toluenesulfonylthio) -3-phenoxyacet-amido-2-oxoazetidin-1 -yl] -3 - (1-pyrrolidyl) crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester. IR spectrum (methylene chloride): characteristic bands at 5.6; 5.95; 6.55; 7.45 and 8.75 [x; Nuclear Magnetic Resonance Spectrum (Deuterochloroform): 8 in ppm: 1.6-2.2 and 3.0-3.8 (8H, c); 2.08 and 2.27 (3H, s); 2.38 and 2.39 (3H, s); 4.42 (2H, q, J = 15 Hz) 4.8-6.0 (4H, c); 6.6 - 8.4 (14H, c).

The same compounds can also be obtained as follows:

fi) A solution of 256 mg (0.4 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-hydroxycrotonic acid-p- cooled to -10 ° C. Nitrobenzyl ester in 5 ml of dry methylene chloride is mixed with 0.1115 ml (0.8 mmol) of triethylamine under nitrogen and then 0.062 ml (0.8 mmol) of methanesulfonyl chloride. After one hour, 0.104 ml (1.24 mmol) of freshly distilled pyrrolidine is added and the mixture is stirred at -10 ° C. for a further 2 hours. The reaction solution is diluted with 20 ml of methylene chloride, washed with three times 15 ml of water, dried over sodium sulfate and evaporated in vacuo. The residue is triturated with diethyl ether and gives a mixture consisting of the slightly yellow 2- [4 - (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine - l-yl] -3- (l-pyrrolidyl) -crotonic acid -p-nitrobenzyl ester and the corresponding isocrotonic acid-p-nitrobenzyl ester, which can be used in this form in the next stage.

The methanesulfonic acid ester formed as an intermediate can also be isolated or prepared as follows:

fii) A solution of 128 mg (0.2 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-hydroxy-crotonic acid-cooled to -10 ° C. p-nitrobenzyl ester in 1 ml of dry methylene chloride is mixed with C, 042 ml (0.3 mmol) of triethylamine and 0.017 ml (0.22 mmol) of methanesulfonyl chloride under nitrogen and stirred at the same temperature for 30 minutes. The reaction mixture is diluted with 10 ml of methylene chloride, washed with 3 times 10 ml of saturated, aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The residue containing the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l -yl] -3-methanesulfonyloxy-crotonic acid p-nitrobenzyl ester and the corresponding iso-crotonic acid ester can be determined chromatographically Not clean instability well, but is pure enough to [eg to be able to be further processed according to example lfi)].

IR spectrum (methylene chloride): characteristic bands at 5.55; 5.7; 5.8; 6.55; 7.45; 8.55; 8.75 [r, NMR spectrum (deuterochloroform): 5 in ppm: 2.37 (3H, s); 2.39 and 2.5 (3H, s); 3.12 and 3.27 (3H, s); 4.39 and 4.41 (2H, s); 5.2 (IH, dd, J = 5.10 Hz); 5.25 (2H, s); 5.88 and 5.95 (1H, d, J = 5 Hz); 6.6 - 8.4 (15H, c).

Example 2

A solution of 148 mg (0.2 mmol) of a mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3- (N-methyl-cyclohexylamino ) - Crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester, in 3 ml of dry acetonitrile, is heated under nitrogen at 80 ° C for about 4 hours until thin-layer chromatography (silica gel: toluene / ethyl acetate 1: 1) is no longer detectable. The heating bath is removed, 38 mg (0.2 mmol) of p-toluenesulfonic acid and about 0.2 ml of water are added to the reaction mixture, and stirring is continued for 2 hours at room temperature. The reaction mixture is diluted with benzene, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is triturated at 0 ° C. with diethyl ether and gives the pale yellow 7ß-phenoxyacetamido-3-hydroxy - 3-cephem-4-carboxylic acid p-nitrobenzyl ester. IR spectrum (methylene chloride): characteristic bands at 2.95; 3.3; 5.6; 5.75 (sh); 5.9; 5.95 (sh); 6.55; 7.45; 8.15 and 8.3 (x; NMR spectrum (deuterochloroform): 5 in ppm: 3.4 (zH, q, J = 17 Hz); 4.57 (2H, s); 5.06 (IH, d, J = 5 Hz); 5.35 (2H, q, J = 14 Hz); 5.7 (1H, dd, J = 5.10 Hz); 6.8 - 8.4 (10H, c) and 11.4 (1H, br. s.).

The starting material can be obtained as follows:

A solution of 160 mg (0.2 mmol) of 2- [4- (p-toluenesul-f onylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-p - toluenesulfonyloxy-crotonic acid p-nitrobenzyl ester in 2 ml of dry tetrahydrofuran, 0.056 ml (0.42 mmol) of N-methyl-N-cyclohexylamine is added in a nitrogen atmosphere with stirring and stirring is continued for about 2 hours at room temperature until thin layer chromatography (silica gel: toluene / ethyl acetate 1: 1) no more starting material is detectable. The reaction solution is diluted with benzene, washed several times with water, dried over sodium sulfate and evaporated in vacuo. The residue is chromatographed on 10 g of acid-washed silica gel with benzene / ethyl acetate 3: 1. A mixture is obtained consisting of 2- [4- (p-toluenesulfonyl-i: hio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3- (N-methyl-cyclohexylamino) -crotonic acid-p- nitrobenzyl ester and the corresponding isocrotonic acid ester as a pale yellow oil. IR spectrum (methylene chloride): characteristic bands at 2.95; 3.4; 5.6; 5.8; 6.55; 7.4 and 8.75 {x.

Example 3

Analogously to Example 1, starting from a mixture consisting of the 2- [4-p- (toluenesulfonylthio) -3-phenoxy-acetamido) -2-oxoazetidin-1-yl] -3-cyclohexylamino-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester of 7β-phenoxyacetamido-3-cyclohexylamino-cephem-4-carboxylic acid p-nitrobenzyl ester (mixture of 2- and 3-cephem derivative) and from it the 7β-phenoxyacet-amido-3-hydroxy-3-cephem -4-carboxylic acid p-nitrobenzyl esters are produced.

The starting material can be obtained as follows:

a) A solution of 160 mg (0.2 mmol) of 2- [4-p- (toluenesulfonylthio) -3-phenoxyacetamido) -2-oxoazetidin-1-yl] -3-p-toluenesulfonyloxy-crotonic acid-p - Nitrobenzyl ester in 2 ml of dry tetrahydrofuran is mixed with 0.0577 ml (0.5 mmol) of cyclohexylamine under nitrogen and stirred for 1 hour at room temperature. The reaction solution is diluted with benzene, washed with water, dried over sodium sulfate and evaporated in vacuo. The residue, containing a mixture consisting of the 2- [4-p- (toluenesulfonylthio) -3-phenoxyacetamido) -2-oxoazetidin-l-yl] -3 - cyclohexylamino-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester , can be processed without cleaning. IR spectrum (methylene chloride): characteristic bands at 2.9; 3.4; 5.6; 5.9; 6.0; 6.25; 6.55; 7.45; 8,10 and 8,75 | x; Nuclear Magnetic Resonance Spectrum (Deuterochloroform): 5 in ppm: 1.8 - 2.0 (11H, c); 2.02 (3H, s); 2.35 (3H, s); 4.43 (2H, s); 4.95 (1H, dd, J = 5.10 Hz); 5.17 (2H, s); 5.80 (1H, d, J - 5 Hz); 6.6 - 9.2 (15H, c).

Example 4

a) To a solution of 485 mg of 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 10 ml of dry chloroform, cooled to 0 ° C., 3 ml of an ethereal diazo- methane solution (0.5 molar, 1.5 equivalents). The pale yellow solution is stirred at 0 ° C for 1 hour, to s

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Removal of excess diazomethane flushed with nitrogen and concentrated in vacuo. The residue is recrystallized from methylene chloride and gives the 7β-phenoxy-acetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester of melting point 140.5-142 ° C.

b) A solution of 250 mg (0.5 mmol) of 7β-phenoxy-acetamido-3-methoxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester in 2 ml of methanol / tetrahydrofuran 1: 1 becomes one during a Mixture of 5% palladium / carbon, pre-hydrogenated under atmospheric pressure, in 2 ml of the same solvent and hydrogenated for 3 hours at room temperature and atmospheric pressure. After this time, about 90% of the calculated amount of hydrogen is absorbed. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue is taken up in 10 ml of methylene chloride and extracted with 2 times 10 ml of 5% aqueous sodium bicarbonate solution. The combined bicarbonate extracts are neutralized at 0 ° C. with dilute hydrochloric acid and extracted with 3 times 10 ml of methylene chloride. The organic phase is dried over sodium sulfate and freed from the solvent in vacuo. After crystallization from chloroform / pentane, the residue gives the 7β-phenoxyacetamido-3-methoxy-3-cephem-4-carboxylic acid with a melting point of 173-174 ° C.

c) To a suspension of 2.55 g (7 mmol) of 7ß-phen-oxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 2.9 ml (22.4 mmol) of N, N-dimethylaniline in 11 ml of absolute methylene chloride are added under nitrogen at 20 ° C. to 0.7 ml (5.7 mmol) of dimethyl dichlorosilane and then stirred at the same temperature for 30 minutes. The resulting clear solution is cooled to −20 ° C., 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and the mixture is stirred for 30 minutes. At the same temperature, a pre-cooled (-20 ° C) mixture of 0.9 ml (7 mmol) N, N-dimethylaniline and 0.9 ml n-butanol is added, followed by 10 ml pre-cooled (- 20 ° C.) n-butanol is added and the mixture is then stirred for 20 minutes at −20 ° C. and 10 minutes without cooling. At about

- 10 ° C, 0.4 ml of water is added, the mixture is stirred for about 10 minutes in an ice bath (0 ° C), then 11 ml of dioxane is added, and after stirring for a further 10 minutes at 0 ° C, about 4.5 ml of tri-n-- Butylamine added in portions until the samples diluted with water assume a constant pH of 3.5. After stirring for 1 hour at 0 ° C., the precipitate is filtered off, washed with dioxane and recrystallized from water / dioxane. The 7β-amino-3-methoxy-ceph-3-em - 4-carboxylic acid hydrochloride dioxanate obtained has a melting point of over 300 ° C. Thin layer chromatogram: Rf value 0.17 (silica gel: system n-butanol / carbon tetrachloride / methanol / formic acid / water 30: 40: 20: 5: 5).

ci) A suspension of 11.75 g of 93% (corresponding to 10.93 g of 100%) 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 13.4 ml (12.73 g) N, N-Dimethyl-aniline in 47 ml abs. Methylene chloride (distilled over P205)

3.6 ml (3.87 g) of dimethyldichlorosilane are added at + 20 ° C. under nitrogen and the mixture is then stirred at the same temperature for 30 minutes. The now clear solution is cooled to -18 ° / -19 ° and mixed with 7.8 g of solid phosphorus pentachloride, the internal temperature being

- rises 10 °. After stirring for 30 minutes in a -20 ° bath, the clear solution is converted into a mixture of 47 ml of n-butanol (anhydrous, dried over Sikkan) and 4.4 ml (4.18 g) Dimethylaniline added dropwise. The inside temperature rises to -8 °. The mixture is stirred 30 minutes after - initially in the -20 ° bath, later in the ice bath (0 °), so that a final internal temperature of -10 ° is reached. A mixture of 47 ml of dioxane and 1.6 ml of water is added dropwise at this temperature (duration approx. 5

Minutes). The product slowly crystallizes out. After stirring for a further 10 minutes, the mixture is brought to a pH in an ice bath by adding portions of about 9.5 ml of tri-n-butylamine in about 1 hour (first 5 ml added in the first 5 minutes). Value brought and held between 2.2 and 2.4. The mixture is then filtered off, washed in portions with about 30 ml of dioxane, then about 15 ml of methylene chloride, and the crystalline 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate is thus obtained; Melting point above 300 ° C; UV spectrum (in 0.1 N sodium bicarbonate): Xmax = 270 mji (e = 7600); IR spectrum (Nujol): characteristic bands at 5.62; 5.80; 5.88; 6.26; 6.55; 7.03; 7.45; 7.72; 7.96; 8.14; 8.26; 8.45; 8.64; 8.97; 9.29; 10.40; 11.47 mji; [a] D20 = + 134 ° ± 1 ° (c = 1; 0.5 N sodium 15 bicarbonate solution).

From the hydrochloride dioxanate obtained, by adding a 20% aqueous solution thereof with 2 N sodium hydroxide solution to a pH of 4.1 (isoelectric point), the zwitterion of 7β-amino-3-methoxy-ceph-3-em- 4-car-20 bonic acid can be obtained, which is filtered off and dried and has a melting point of over 300 ° C. UV spectrum (in 0.1 N sodium bicarbonate solution) Xmax = 270 nm (e = 7600). Thin layer chromatogram: Rf value identical to that of the hydrochloride (silica gel, same system); 25 [a] D20 = + 232 ° ± 1 ° (c = 1; 0.5 N sodium bicarbonate solution).

d) A suspension of 1 g (2.82 mmol) of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate in 20 ml of dry methylene chloride is mixed with at room temperature under a nitrogen atmosphere 1.65 ml of bis (tri-methylsilyl) acetamide were added. After 40 minutes, the clear solution is cooled to 0 ° C. and 900 mg (4.37 mmol) of solid D-a-phenylglycyl acid chloride hydrochloride are added. Five minutes later, 0.7 ml (10 mmol) of propylene oxide 35 is added. The suspension is then stirred for 1 hour at 0 ° C. under a nitrogen atmosphere, then 0.5 ml of methanol is added, the 7β- (Da-PhenyIglycyl-amino) -3-methoxy-ceph-3-em-4-carboxylic acid- hydrochloride precipitates in crystalline form. The hydrochloride is filtered off, 40 is dissolved in 9 ml of water and the solution is adjusted to pH 4.6 with 1N sodium hydroxide solution. The precipitated dihydrate of the inner salt of 7β- (D-a-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid is filtered off, washed with acetone and diethyl ether and dried, melting point 174-176 ° 45 (decomposition); [a] D20 = + 132 ° (c = 0.714; in 0.1 N hydrochloric acid); Thin layer chromatogram (silica gel): Rf value - 0.18 (system: n-butanol / acetic acid / water 67: 10: 23). UV spectrum (in 0.1 N aqueous sodium bicarbonate solution)

Xmax = 269 m [i (s = 7000); IR spectrum (in mineral oil): 50 characteristic bands at 5.72; 5.94; 6.23 and 6.60 | i.

di) A suspension of 993 mg (4.32 mmol) of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid (inner salt) in 10 ml of methylene chloride is mixed with 1.37 ml (5.6 mmol ) N, N-bis (tri-methylsilyl) acetamide were added and the mixture was stirred for 45 minutes at room temperature under a nitrogen atmosphere. The clear solution is cooled to 0 ° C. and 1.11 g (5.4 mmol) of D-a-phenylglycyl acid chloride hydrochloride are added. After 5 minutes, 0.4 ml (5.6 mmol) of propylene oxide is added. The suspension is then stirred for 1 hour at 0 ° C. under a nitrogen atmosphere and then mixed with 0.6 ml of methanol. The crystallizing 7ß- (Da - phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid - hydrochloride is filtered off, dissolved in 15 ml of water at 0 ° C. and the solution is brought to about pH with 5 ml of 1N sodium hydroxide solution 4 ge-65 places. The solution, which has been warmed to room temperature, is brought to about pH 4.8 with triethylamine, whereupon the 7β- (D-a-phenylglycylamido) -3-methoxy-ceph-3-em-4-carboxylic acid crystallizes out in the form of the dihydrate.

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Example 5

Analogously to Example 4 d), conversion of 1.16 g (3 mmol) of 7β-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate obtainable according to the invention with 1.5 ml (6.2 mmol) bis- (trimethylsilyl) -acetamide and then a) with 765 mg (3.6 mmol) Da-Amino- (2-thienyl) -acetic acid chloride hydrochloride the 7ß- [Da-Amino-a- (2- thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, mp 140 ° (with decomposition); Thin layer chromatogram (silica gel; identification with iodine): Rf - 0.22 (system: n-butanol / acetic acid / water 67: 10: 23) and Rf ~ 0.53 (system: isopropanol / formic acid / water 77: 4: 19) ; Ultraviolet absorption spectrum: Xmax = 235 mji (s = 11400) and XSt! HuItel. = 272 mjx (e = 6100) in 0.1-n. Hydrochloric acid, and Xmax = 238 mp, (s = 11800) and X shoulder = 267 m p, (e = 6500) in 0.1-n. aqueous sodium hydrogen carbonate solution,

b) with 940 mg (4.5 mmol) of da-amino- (1,4-cyclohexadienyl) acetic acid chloride hydrochloride, the 7β- [da-amino- a- (1,4-cyclohexadienyl) acetylamino] -3-methoxy-3-cephem - 4-carboxylic acid in the form of the inner salt, mp 170 ° (with decomposition); Thin layer chromatogram (silica gel; identification with iodine): Rf ■ - ■ 0.19 (system: n-butanol / acetic acid / water 67: 10: 23) and Rf - 0.58 (system: isopropanol / formic acid / water 77: 4: 19); Ultraviolet absorption spectrum: Xmax = 267 m | i (s = 6300) in 0.1-n. Hydrochloric acid, and Xmax = 268 mji (e = 6600) in 0.1-n. aqueous sodium hydrogen carbonate solution, [a] D20 + 88 ° ± 1 ° (c = 1.06; 0.1 N hydrochloric acid), and c) with 800 mg (3.6 mmol) of da-amino-4-hydroxyphenyl-acetic acid chloride -hydrochloride, the 7β- [Da-amino-a- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-car-bonic acid in the form of the inner salt, F. = 243 - 244, 5 ° C (from the beginning of 231 ° sintering) (with decomposition); Thin layer chromatogram (silica gel; identification with iodine): Rf - 0.24 (system: n-butanol / acetic acid / water 67: 10: 23) and

Rf - 0.57 (system: isopropanol / formic acid / water 77: 4: 19); Ultraviolet absorption spectrum: Xmax = 228 m (i (s = 12000) and 271 mji, (s = 6900) in 0.1N hydrochloric acid, and

= 227 m | A (e = 10500) and XSchuIter = 262 m fi (e = 8000) in 0.1-n. aqueous sodium bicarbonate solution, f "] D20 = + 165 ° ± 1 ° (c = 1.3; 0.1 N hydrochloric acid).

Example 6

A solution of 158.2 g (0.2 mol) of a mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacet-amido-2-oxoazetidin-l-yl] -3- (l- pyrrolidyl) -crotonic acid diphenyl methyl ester and the corresponding isocrotonic acid ester in 1500 ml of dry acetonitrile is heated under nitrogen at 80 ° C. for about 5 hours until thin-layer chromatography (silica gel; toluene / ethyl acetate 1: 1) is no longer detectable. The heating bath is removed, the reaction mixture containing the 7β-phenoxyacetami-do-3-pyrrolidino-cephem-4-carboxylic acid diphenylmethyl ester is mixed with 200 ml of 0.1 N HCl and stirring is continued for 3 hours at room temperature. The reaction mixture is evaporated in vacuo.

The residue is taken up in ethyl acetate, washed successively with dilute sulfuric acid, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solution and dried over sodium sulfate. The solution is evaporated in vacuo and the crude 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester is purified by means of column chromatography (silica gel; toluene / ethyl acetate 4: 1); Thin layer chromatogram: Rf 0.24 (silica gel; toluene / ethyl acetate 1: 1).

The product obtained can be processed as follows:

i) The 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester obtained is taken up in methanol and an excess of ethereal diazomethane solution is added at 0.degree. After a reaction time of 5 minutes, the solution is evaporated down completely and the oily residue is chromatographed on silica gel thick-layer plates (toluene / ethyl acetate 3: 1). The silica gel of the zone at Rf = 0.19 is extracted with ethyl acetate and gives 7β-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid di-phenylmethyl ester: melting point 120 ° C. (from ether) IR spectrum (inCHCy: 3310.1775.1700.1690.1600 cm-1.

ii) The 7β-phenoxyacetamido-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester obtained can also be analogous to Example 4ai) using dimethyl sulfate and potassium bicarbonate according to the phase transfer method in the 7ß-phenoxy-acetamido-3-methoxy-ceph -3-em-4-carboxylic acid diphenyl methyl ester can be transferred.

iii) 0.87 ml of anisole is added to a solution of 2.0 g (3.78 mmol) of 7β-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride , cooled to 0 ° C. and left to stand for 1 hour after adding 1.2 ml of trifluoroacetic acid. The reaction mixture is concentrated in vacuo and the residue is crystallized from acetone / ether. The 7β-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid with a melting point of 170 ° C. (dec.) Is obtained.

The starting material can be produced as follows:

a) 100 g (27.3 mmol) of 6-phenoxyacetamido-peni-cillanic acid 1-oxide, 500 ml of dioxane and 58.4 g (30 mmol) of diphenylmethydiazomethane become the 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester after about 2 hours - received oxide; Melting point 144-146 ° C (ethyl acetate / petroleum ether).

b) Analogously to example lb), 292 g (55 mmol) of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-lß-oxide and 99 g (59.5 mmol) of 2-mercaptobenzothiazole become 2- [4 - (benzothiazole-2- yldithio) -3 -phenoxyacetamido-2-oxoazetidin - 1 -yl] -3-methylene-butyric acid diphenylmethyl ester obtained: melting point 140-141 ° C (from toluene / ether).

c) Analogous to Example lc), 10 g (14.7 mmol) of 2- [4 - (benzothiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine - l-yl] -3-methylenebutyric acid diphenylmethyl ester in 50 ml of ethyl acetate and 4.92 g (24.98 mmol) of finely powdered silver - p-toluenesulfinate after stirring for 7 hours at room temperature, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2 - oxo-azetidine- 1 -yl] -3-Methylenebutyric acid diphenylmethyl ester obtained. Rf = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (CHCy: 1782, 1740, 1695, 1340, 1150 cm-1.

d) Analogously to example ld), 10.8 g (16.2 mmol) of 12-

- [4- (pT oluenesulfonylthio) -3 -phenoxyacetamido-2-oxoazeti-din-l-yl] -3-methylenebutyric acid diphenylmethyl ester in 1 liter of methylene chloride and 1.1 equivalents of ozone of the 2- [4- (p-- T oluolsulf onylthio) -3 -phenoxyacetamido-2-oxoazetidin-l --yl] -3-hydroxycrotonic acid diphenylmethyl ester obtained; Melting point 142-143 ° C (from ether / pentane).

e) A solution of 134.4 g (0.2 mol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-hydroxycrotonic acid cooled to -10 ° C. Diphenylmethyl ester in 500 ml of dry methylene chloride is mixed with 34.8 ml (0.25 mol) of triethylamine under nitrogen and then with 24.5 ml (0.25 mol) of methanesulfonyl chloride. After 20 minutes, 47 ml (0.55 mmol) of freshly distilled pyrrolidine are added and the mixture is stirred at -10 ° C. for a further 2 hours. The reaction solution is washed three times with 150 ml of water, dried over sodium sulfate and in vacuo

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evaporated. The residue is dried to a foam and gives a mixture consisting of the slightly yellow

Diphenylmethyl 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti-din-l-yl] -3- (l-pyrrolidyl) -crotonic acid and the corresponding isocrotonic acid-diphenylmethyl ester, which are in this form in the next stage can be used.

Example 7

To a solution of 107.4 g (151.1 mmol) of 2- [4- (p-to-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] - 3-hydroxy-crotonic acid diphenylmethyl ester in 1 6 liters of methylene chloride are added dropwise at -10 ° C. to 29.2 ml (374.4 mmol) of methanesulfonyl chloride and then 52.2 ml (374.4 mmol) of triethylamine. After 30 minutes, 750 mmol of morpholine are slowly added dropwise at -10 ° C. and stirring is continued for a further 3 hours at -10 ° C. It is washed twice with 250 ml of 0.2 N HCl and saturated NaCl solution, the organic phase is dried with sodium sulfate, filtered, the filtrate is largely concentrated and mixed with 650 ml of methanol, whereupon crystallization begins. A crystalline mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3 - (1-morpholinyl) -crotonic acid - diphenylmethyl ester and the corresponding isocrotonic acid ester are isolated melting point 111-114 ° C (dec.).

Example 8

A solution of 74.1 g (0.1 mol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3- (l-mor-pholinyl) -crotonic acid -diphenylmethyl ester in 400 ml acetonitrile (over bas. A120; 3, dried) is heated under reflux for 7 hours. The solvent is then largely removed in vacuo and then replaced by 200 ml of cold, dry methanol. It crystallizes almost colorless

3-morpholino-7ß-phenoxyacetamido-3-cephem-4-carboxylic acid-diphenylmethyl ester from melting point 167-169 ° C.

Example 9

A solution of 6 g (10.24 mmol) of crystalline 3-Morpholino-7ß-phenoxyacetamido-3-cephem-4-carboxylic acid di-phenylmethyl ester in 100 ml of CH2C12 and 20 ml of methanol is mixed with 100 ml of 0.2 N HCl mixed and stirred intensively so that an emulsion is formed. After the reaction has ended (about 48 hours), the organic phase is separated off, dried and the solvent is removed in vacuo. A white foam of very pure 3-hydroxy-7β-phenoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl is obtained -ester of melting point 87-89 ° C.

Example 10

Analogously to Example 7, a crystalline mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3- (1-piperidinyl) -crotonic acid can be converted by reaction with piperidine -diphenylmethyl ester and the corresponding isocrotonic acid derivative from melting point 116 to 123 ° C (dec.).

Example 11

A solution of 11.1 g (15 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3- (1-piperidinyl) -crotonic acid diphenylmethyl ester is heated in 100 ml of dry acetonitrile under reflux for 5% hours. The solution is concentrated and 100 ml of cold, dry methanol are added, whereupon pure 3-piperidino-7β-phen-oxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester of melting point 184-188 ° C. (dec.) Crystallizes out.

Example 12

Analogously to Example 9, the 3-hydroxy-7β-phenoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester can also be prepared from the crystalline 3-piperidino-7β-phenoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester.

Example 13

Analogously to Example 7, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 - (1-pyrrolidinyl) -crotonic acid diphenyl methyl ester can be prepared by reaction with pyrrolidine.

Example 14

A solution of 14.5 g (20 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 - yl] -3- (l-pyrrolidinyl) -crotonic acid is heated -diphenylmethyl ester in 150 ml dry acetonitrile at 80 ° C until no more starting product can be detected by thin layer chromatography. The solvent is largely removed in vacuo and replaced by 100 ml of cold, dry methanol, whereupon the 3-pyrrolidino-7β-phenoxyacetamido-3-cephem-4-carbonate-diphenylmethyl ester, melting point 190-194 ° C., crystallizes out.

Example 15

Analogously to Example 9, the diphenylmethyl ester of 3-hydroxy can also be obtained from the crystalline 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti-din-l-yl] -3- (l-pyrrolidinyl) -crotonic acid Prepare -7ß-phenoxyacetamido-3-cephem-4-carboxylic acid diphenylmethyl ester.

Example 16

a) A solution of 6.83 g (10 mmol) of 2- [4- (benzothiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] -3- cooled to −20 ° C. Diphenylmethyl ester of hydroxycrotonic acid in 25 ml of methylene chloride is mixed with 0.971 ml (12.5 mmol) of methanesulfonyl chloride and then with 1.74 ml (12.5 mmol) of triethylamine. The reaction mixture is

Stirred at -20 ° C for 1H hours, after which 2.39 ml (27.5 mmol) of morpholine were added. The reaction mixture is stirred for a further hour at - 15 ° C and then warmed to room temperature. The mixture is diluted with 50 ml of methylene chloride, washed once with 40 ml of 2N HCl and three times with saturated saline. The organic phase is dried over sodium sulfate and evaporated. The crude product is chromatographed on 400 g of silica gel (Merck) with toluene / ethyl acetate (9: 1.3: 1.1: 1) and gives the 2- [4- (benzthiazol-2-yl) -3-phenoxyacetamido-2- -oxoazetidin-l-yl] -3- (l-morpholinyl) -crotonic acid-diphenyl-methyl ester.

b) A solution of 100 mg (0.133 mmol) of 2- [4- (benzothiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-l-yl] - 3- (l-morpholinyl) - Diphenylmethyl crotonic acid is heated in 5 ml of dry toluene at 70 ° C. for 24 hours. The solution is evaporated, the residue is dissolved in methylene chloride and diluted with methanol. The methylene chloride is slowly removed under vacuum, whereupon the product crystallizes from the remaining methanol. Diphenylmethyl 7β-phenoxyacetamido-3- (l-morpholinyl) -3-cephem-4-carbonate of melting point 172-173 ° C. is obtained.

c) To a solution of 10 mg (0.017 mmol) of 7β-phen-oxyacetamido-3- (l-morpholinyl) -3-cephem-4-carboxylic acid - diphenylmethyl ester in 5 ml of methylene chloride, 1 ml of 5N hydrochloric acid is added dropwise. The reaction mixture is stirred at room temperature for 30 minutes. The aqueous phase is separated off and the organic phase is washed with water, dried over sodium sulfate and evaporated. The 7β-phenoxyacetamido-3-hydroxy-3-cephem-

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-4-carboxylic acid diphenylmethyl ester. IR spectrum (in methylene chloride) ': characteristic absorption bands at 3410, 2925-2850, 1780, 1690, 1600, 1510, 1490, 1360, 1220, 1200 cm-1.

Example 17

Analogously to Examples 1 to 3 or 7 to 16, the following compounds can be prepared from suitable intermediates obtainable according to the invention:

7β-phenylacetamido-3-hydroxy-3-cephem-4-carboxylic acid - diphenylmethyl ester, IR spectrum (in CH2C12): bands at 2.95; 5.61; 5.77; 5.85; 5.95; 6.21 and 6.87 | i,

7-Amino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, IR spectrum (inCH2Cl2): bands at 5.58; 5.77 (shoulder); 6.02 and 6.22 fi,

Diphenylmethyl ester 7ß- (D-a-tert-butyloxycarbonylamino-a-phenylacetylamino) -3-hydroxy-3-cephem-4-carboxylic acid, IR spectrum (in CH2C12): bands at 2.94; 3.40; 5.62; 5.77; 5.75; 5.95; 6.21; 6.88 jx,

7β- [Da-tert-butyloxycarbonylamino-a- (4-hydroxyphe-nyl) acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid diphe-nylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 284 mfj, (e = 5100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.83 (sh); 5.88; 6.18; 6.67 (i,

Diphenyl methyl 7β- [Da-tert-butyloxycarbonylamino-a- (2-thienyl) -acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 283 mfj, (e = 5300) 5 infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 [x,

Diphenylmethyl ester of 7ß- [Da-tert-butyloxycarbonylamino-a- (3-thienyl) acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 283 mfi (e = 5300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 fi,

7ß- [D-a-tert-butyloxycarbonylamino-a- (2-furyl) acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 283 m fi, (e = 5300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 jx,

Diphenyl methyl ester 7ß- [Da-tert-butyloxycarbonylamino-a- (4-isothiazolyl) acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 250 mfj, (e = 12000) and 280 mfj, (s = 5800); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19;

6.66 (i ,,

7β- [Da-tert-butyloxycarbonylamino-a- (1,4-cyclohexadienyl) acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid - diphenylmethyl ester, IR spectrum (in CHClß): bands at 3380; 1780; 1690; 1610; 1590; 1470 cm-1,

Diphenylmethyl 7ß- (2-thienyl) acetylamino-3-hydroxy-3-cephem-4-carbonate, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 280 mfi (s = 5400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58; 5.82 (sh); 5.88; 6.17;

6.67 fi,

7β- (l-tetrazolyl) acetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in 95% strength aqueous ethanol): Xmax = 282 ml; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 fi,

7ß- (4-pyridylthio) acetylamino-3-hydroxy-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xm „v = 283 m fi;

Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.83 (sh); 5.88; 6.18; 6.67 (i,

Diphenylmethyl 7ß- (4-aminopyridinium-acetylamino) -3-hydroxy-3-ceph-em-4-carboxylic acid, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 282 mfj ,; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 fx,

Diphenyl methyl 7ß- [Da- (2,2,2-trichloroethoxycarbonyloxy) -a-phenyl-acetylamino] -3-hydroxy-3-cephem-4-carboxylic acid, ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 284 m fr, infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59; 5.87; 6.19; 6.66 n,

and analogously to Examples 4, 5 and 6 corresponding compounds etherified on the 3-hydroxy group, e.g.

3-methoxy-7ß-phenylacetamido-3-cephem-4-carboxylic acid - diphenylmethyl ester, IR spectrum (in CH2C12): bands at 2.94; 5.63; 5.83; 5.94; 6.26; 6.66 n,

3-methoxy-7β-amino-3-cephem-4-carboxylic acid diphenyl methyl ester (and salts thereof); IR spectrum (in dioxane): bands at 2.87; 5.62 and 6.26 p ,,

3-methoxy-7ß-phenylacetyIamino-3-cephem-4-carboxylic acid (or salts thereof); IR spectrum (in CH2C12): bands at 3.03; 5.60; 5.74; 5.92; 6.24; 6.67 fi,

3-methoxy-7ß- (D-a-tert-butyloxycarbonylamino-a-phe-nylacetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, mp. 162-163 ° C (diethyl ether),

3-methoxy-7ß- (D-a-phenylglycylamino) -3-cephem-4 - carboxylic acid (or salts thereof); Mp 174-176 ° C (with decomposition),

3-n-butyloxy-7ß-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, mp. 168-170 ° C (from CH2C12 / diethyl ether),

Diphenyl-methyl 3-n-butyloxy-7ß- (D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-cephem-4-carboxylic acid, IR spectrum (in CH2C12): bands at 2.88; 5.63; 5.84 (shoulder); 5.88; 6.26; 6.71 jjl,

3-n-butyloxy-7ß- (D-a-phenylglycylamino) -3-cephem-4 - carboxylic acid (or salts thereof); Mp 141-142 ° C (acetone / diethyl ether),

3-methoxy-7ß-phenylacetylamino-3-cephem-4-carboxylic acid methyl ester, mp. 171-174 ° C. (from CH2C12 / hexane),

Diphenylmethyl 3-ethoxy-7ß- (D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-cephem-3-carboxylic acid, IR spectrum (in CH2C12): bands at 2.96; 5.64; 5.90; 6.28; 6.73 [t,

3-ethoxy-7ß- (D-a-phenylglycylamino) -3-cephem-4-car-bonic acid (or salts thereof); UV spectrum (in 0.1 m NaHCQ solution): Xmax = 263 mp, (s = 5500),

Diphenyl-3-benzyloxy-7ß- (D-a-tert-butyloxycarbonylamino-a-phenyl-acetylamino) -3-cephem-4-carboxylic acid, IR spectrum (in CH2C12): bands at 2.96; 5.63; 5.88; 6.26; 6.72 fj ,,

3-Benzyloxy-7ß- (Da-phenylglycylamino) -3-cephem-4 - carboxylic acid (or salts thereof): UV spectrum (in 0.1 N NaHCO, solution): Xmax = 266 mfj, (e = 6500),

7ß- (5-Benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, IR spectrum (in CH2C12): bands at 5.65; 5.78; 6.03; 6.64 (1,

7ß- (D-a-tert-butyloxycarbonylamino-a-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid or salts thereof, IR spectrum (in CH2C12): bands at 3.00; 5.64; 5.92; 6.25; 6.72 fi,

Diphenyl methyl 7ß- [Da-tert-butyloxycarbonylamino-a- (2-thienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, IR spectrum (in CH2C12): bands at 2 , 94; 5.62; 5.85; 6.26; 6.72 | i,

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

626091

34

7ß- [Da-tert-butyloxycarbonylamino-a- (1,4-cyclohexadienyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid - diphenylmethyl ester, IR spectrum (in CH2C12): bands at 2.96; 5.64; 5.86; 5.90 (shoulder); 6.27; 6.73 | i,

7β- [D-a-amino-a- (l-cyclohexen-l-yl) acetylamino] -3 - methoxy-3-cephem-4-carboxylic acid or salts thereof,

7β- [Da-tert-butyloxycarbonylamino-a- (4-hydroxyphe-nyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphe-nylmethyl ester, IR spectrum (in CH2C12): bands at 2 , 83; 2.96; 5.64; 6.86; 5.91 (shoulder); 6.23; 6.28; 6.65; 6.72 yes

7β - [D - a-amino-a - (4-hydroxyphenyl) acetylamino] -3 - methoxy-3-cephem-4-carboxylic acid (or salts thereof), mp. 180 ° C. (with decomposition),

Diphenyl methyl 7ß- [Da-tert-butyloxycarbonylamino-a- (4-isothiazolyl) -5 -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, IR spectrum (in CH2C12): bands at 2 , 94; 5.65; 5.71 (shoulder); 5.88; 6.28; 6.73 \ i,

as well as the corresponding ceph-2-em compounds and the isomer mixtures consisting of the ceph-3-em and io the ceph-2-em compounds, and the 1-oxides of the corresponding ceph-3-em compounds.

Claims (17)

626091 ^> 1 $ / W O — i H C ^ N Y 0 = C-R ^ wherein R, a, R, b and R2A have the meanings given under formula IA, the group -N (R4a) (R4b) represents a secondary or tertiary amino group, and Y is a leaving group -S-R4, -S02-R5 or -S-S02-R5, in which R is an optionally substituted aromatic heterocyclic radical having up to 15 carbon atoms, and at least one ring nitrogen atom and optionally another ring hetero atom, which radical has one of its ring carbon atoms and a ring nitrogen atom through a double bond is connected to the thio group -S-5 or R4 is an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group having up to 18 carbon atoms and R5 is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic io hydrocarbon radical is up to 18 carbon atoms, with elimination of HY, cyclized and in the ge as an intermediate formed enamines of formula (III) 2. The method according to claim 1, characterized in that one uses starting materials of formula II, wherein 35 R2a an optionally substituted 1-phenyl-lower alkoxy group, such as benzyloxy, p-nitrobenzyloxy or diphenylmethoxy group, or an optionally halogen-substituted lower alkoxy group, such as methoxy, a-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halogeno-lower alkoxy, such as 40 2,2,2-trichloroethoxy. 2nd PATENT CLAIMS 1. Process for the preparation of 7β-amino-3-cephem - 3-ol-4-carboxylic acid compounds of the formula CUR. (IA) 0 = C ~ R, where Rja represents hydrogen or an amino protecting group RjA, R ^ represents hydrogen or an acyl group Ac, or Rj "and Rjh together represent a divalent amino protecting group, R2 represents hydroxy or one, together with the carbonyl group -C (= O) - a protected carboxyl group forming radical R2A, and Ra represents hydrogen, lower alkyl or optionally substituted a-phenyl-lower alkyl, where R2 is not hydroxy when R is hydrogen and the corresponding 2-cephem compounds of the formula 0-r, (IB) 0 »C ~ R, wherein Rja, R ^, R2 and R3, have the meanings given above, or salts of such compounds with salt-forming groups, characterized in that a compound of the formula R K ? .S-Y GH, ^ R7 3rd 626091 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,5,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3 , 4-oxadiazol-2-yl, 1,3,4,5-oxatriazol - 2-yl, 2-quinolyl, l-methyl-benzimidazol-2-yl, benzoxazol-2-yl and especially benzothiazol-2- yl means. 3. The method according to claim 1, characterized in that starting materials of the formula II are used, in which one of the radicals R4a or R4b is hydrogen and the other optionally, e.g. by lower alkoxy, such as methoxy, 45 deralkylthio, such as methylthio, cycloalkyl, such as cyclohexyl, aryl, such as phenyl or heterocyclyl, such as thienyl, substituted alkyl, especially lower alkyl, e.g. Methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, 2-ethoxyethyl, 2-methylthioethyl, cyclohexylmethyl, benzyl so or thienylmethyl, or an optionally, e.g. cycloalkyl group substituted by lower alkyl, such as methyl, lower alkoxy, such as methoxy, lower alkylthio, such as methylthio, cycloalkyl, such as cyclohexyl, aryl, such as phenyl or heterocyclyl, such as furyl, as optionally sub-55 substituted cyclopropyl, cyclopentyl, cyclohexyl or Cyclo-heptyl, or wherein -N (R4a) (R4b) dimethylamino, diethylamino, N-methyl-ethylamino, di-isopropylamino, N-methyl-isopropylamino, dibutylamino, N-methyl-isobutylamino, di-cyclopropylamino, N -Methyl-cyclopropylamino, dicyclo-6o pentylamino, N-methyl-cyclopentylamino, dicyclohexyl-amino, N-methyl-cyclohexylamino, dibenzylamino, N-methylbenzylamino, N-cyclopropyl-benzylamino, 1-aziridinyl, 1-pyrrolidinyl Piperidyl, lH-2,3,4,5,6,7-hexyhydroazepi-nyl, 4-morpholinyl, 4-thiomorpholinyl, 1-piperazinyl or 65 4-methyl-l-piperazinyl. 4. The method according to claim 1, characterized in that starting materials of formula II are used, in which Y is a group -S-R4, in which R4 l-methyl-imidazol-2-yl, Process according to claim 1, characterized in that starting materials of formula II are used, in which Y represents a group -S-R4, in which R4 is lower alkanoyl, e.g. Acetyl or propionyl, lower thioalkanoyl, e.g. Thioacetyl or thiopropionyl, cycloalkane carbonyl, e.g. Cyclohexane carbonyl, cycloalkane thiocarbonyl, e.g. Cyclohexanthiocar-bonyl, benzoyl, thiobenzoyl, naphthylcarbonyl, naphthyl-thiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-Pyridylthiocarbonyl, 2- or 3-thio-thenoyl, 2- or 3-thiofuroyl means or a corresponding substituted, for example by lower alkyl, such as methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as methoxy, aryl, such as phenyl, aryloxy , such as phenyloxy, mono- or polysubstituted acyl or thioacyl group. 6. The method according to claim 1, characterized in that starting materials of formula II are used, in which Y represents a group -S02-R5, in which R5 is optionally by lower alkoxy, such as methoxy, halogen, such as fluorine, Chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted alkyl, in particular lower alkyl, such as methyl, ethyl or butyl group, an optionally mono- or polysubstituted alkenyl, such as allyl, or butenyl group, or an optionally mono- or polysubstituted cycloalkyl, such as cyclopentyl or cyclohexyl group, or optionally by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy or nitro, mono- or poly-substituted naphthyl or in particular phenyl group, for example phenyl, o-, m- or preferably p-tolyl, o-, m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl represents p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl. 7. The method according to any one of claims 1 or 6, characterized in that starting materials of formula II are used, wherein Y is a group -S02-R5, wherein Rj is phenyl, p-tolyl, p-methoxyphenyl or p-nitrophenyl. 8. The method according to any one of claims 1 to 7, characterized in that the ring closure reaction of a compound of formula II to a compound of formula III is carried out in acetonitrile as a solvent. 9. The method according to any one of claims 1 to 8, characterized in that the solvolysis of enamines of the formula III obtained by adding water or an alcohol of the formula Rg-OH and a catalytic to equimolar amount of an organic or inorganic acid. 10. The method according to any one of claims 1 to 9, characterized in that one obtains a compound of formula IA, wherein R3. Hydrogen means converted into a compound of formula IA or IB by etherification, in which Rai means lower alkyl or optionally substituted a-phenyl-lower alkyl. 11. The method according to any one of claims 1 to 9, characterized in that in a compound obtained, wherein R, a or Rjb is an acyl group, a suitable acyl group is cleaved acidolytically and replaced by hydrogen. 12. The method according to any one of claims 1 to 9, characterized in that in a compound obtained in which Rta or R ^ is an acyl group, a suitable acyl group is reductively split off and replaced by hydrogen. 13. The method according to any one of claims 1 to 9, characterized in that protecting a free amino group in a compound obtained, e.g. acylated. 14. The method according to any one of claims 1 to 9, characterized in that in a compound obtained a protected carboxyl group of the formula -C (= 0) -R2A by alkaline or acidic hydrolysis, alcoholysis, acidolysis, or by treatment with a Reducing agent or converted into a free carboxyl group by irradiation. 15. The method according to any one of claims 1 to 9, characterized in that a compound of formula IA, wherein R ^ is hydrogen, R / hydrogen, an acyl group of the formula O II Ra- (X) m-CH-C- (B) I. Rb wherein Ra represents phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl, tetrazolyl or 1,4-cyclohexadienyl, in which radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, m represents 0 or 1, and Rb represents hydrogen or, if m denotes 0, optionally protected amino, carboxy, sulfo or hydroxyl, or O-lower alkylphosphono or O.O'-di-lower-alkylphosphono, or a 5-amino -5-carboxyvalaleyl means, in which the amino and carboxyl groups are optionally protected, and R2 and R3 have the meanings given in claim 1, produces. 15 20th 25th in which the double bond can be in the 2,3- or 3,4-position, the amino group -N (R4a) (R4b) to the group -OR ,, solvoly-30 siert, and optionally a compound with a salt-forming group obtained in a salt or a salt obtained is converted into the free compound or into another salt. 16. The method according to any one of claims 1 to 9, characterized in that the 7ß-phenoxyacetamido - 3-hydroxy-3-cephem-4-carboxylic acid p-nitrobenzyl ester is prepared. 17. Use of the process according to claim 1 for the preparation of compounds of the formula IA or IB, in which Rxa and Rtb are hydrogen and R2 and Rl3 have the meanings given in claim 1, characterized in that in a compound obtained, wherein Rxa or R ^ represents an acyl group, a suitable acyl group by treatment with an imide halide-forming agent, reacting the resulting imide halide with an alcohol and cleaving the imino ether formed and replaced by hydrogen.