CH605987A5 - Substd carboxylic acid derivs - Google Patents

Abstract

Substd carboxylic acid derivs broad spectrum antibiotics and inters

Description

  

  
 



   The present invention relates to a process for the preparation of enol ethers of 73-amino-cephem -3-ol-4-carboxylic acid compounds of the formula
EMI1.1
 wherein Rla represents hydrogen or an amino protective group R1A, and Rlb represents hydrogen or an acyl group Ac, or Rla and Rlb together represent a divalent amino protective group, R2A represents a protected carboxyl group together with the carbonyl group -C (= O) - And R3 is an optionally substituted hydrocarbon radical, and in which there is a C, Cq double bond in the 2,3- or in the 3,4-position,

   and also l-oxides of compounds of the formula in which the double bond is in the 3,4-position, or salts of such compounds with salt-forming groups.



   The enol derivatives of the present invention are ethers of 2-cephem-3-ol- or. 3-cephem-3-ol compounds.



   In 2-cephem compounds of the formula I with a double bond in the 2,3-position, the optionally protected carboxyl group of the formula -C (= O) -R2A preferably has the configuration.



   An amino protective group RIA is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl, in particular the trityl group, and an organic silyl and an organic stannyl group. A group Ac, which can also stand for a radical R1b, primarily represents the acyl radical of an organic carboxylic acid, preferably with 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), as well as the acyl radical of a carbonic acid half derivative.



   A divalent amino protective group formed together by the radicals Rla and Rlb is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, also the acyl radical of a preferably substituted, e.g. -aminoacetic acid containing an aromatic or heterocyclic radical, in which the amino group is via a, preferably substituted, e.g. two lower alkyl, such as methyl groups containing methylene radical is connected to the nitrogen atom.

  The radicals Rla and Rlb together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms.



     A protected carboxyl group of the formula -C <= O) - R2A is primarily an esterified carboxyl group, but can also represent a usually mixed anhydride group or an optionally substituted carbamoyl or hydrazinocarbonyl group.



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



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



   A radical R2A which forms a primarily mixed anhydride group with a -G (= O) group is in particular an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-derivative, such as a carbonic acid half-ester.



   One with one <(= O) grouping a carbamoyl group forming radical R2A is an optionally substituted amino group in which substituents are optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic, cycloaliphatic, cyclbaliphratic-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, furthermore etherified or esterified hydroxy,

   wherein the etherifying or esterifying residues e.g. have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, primarily of organic carboxylic acids and of carbonic acid half-derivatives, preferably with up to 18 carbon atoms.



   In a substituted hydrazinocarbonyl group of the formula -C (= O) -R2A, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or bivalent hydrocarbon radicals, preferably with 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 half derivatives, preferably with up to 18 carbon atoms.

 

   An optionally substituted hydrocarbon radical R3 is preferably a corresponding cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, but in particular an optionally substituted aliphatic hydrocarbon radical, and also a corresponding aromatic hydrocarbon radical.



   The general terms used in the description above and below have e.g. 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, as well as lower alkenyl or lower alkyl, furthermore lower alkylidene, e.g. can contain up to 7, preferably up to 4 carbon atoms.



  Such residues can optionally be replaced by functional groups, e.g. by free, etherified or esterified hydroxy or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phienylthio or phenyl-lower alkylthio, optionally substituted lower alikoxycarbonyloxy, optionally substituted lower alikoxycarbonyloxy, optionally substituted, further nitro, optionally substituted by z. Oxycarbonyloxy or lower alkanoyloxy or halogeno : B.

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or azaniederalklenamino, as well as acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halo-lower alkoxycarbonyiamino, optionally substituted phenyl-lower alkoxycarbonylumino, optionally substituted phenyl-lower alkoxycarbonylumino, optionally substituted, such as benzoyl-alkoxycarbonylamino, optionally substituted, such as benzoylocarbonylamino, modified, optionally, carbamoylaminoylamino, such as benzidoylalkarbonylamino, modified as benzidoylamino, optionally substituted, such as benzoylocarbonylamino, or optionally substituted carbamoylamino, such as benzidoyl alkarbonylamino, modified as benzidoylamino, optionally substituted, such as benzoylocarbonylamino, or optionally substituted carbamoylamino, such as benzidoyl alkarbonylamino, optionally substituted, such as benzoylocarbonylamino carboxyl present in salt form, esterified carboxyl, such as lower alkoxycarbonyl, optionally substituted carbamoyl, such as N-Niederaikyi- or N, N-Diniederalkylcarbamoyl,

   furthermore optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or salt-form sulfo, or optionally O-mono- or O, O-disubstituted phosphono, in which substituents e.g.



  optionally substituted lower alkyl, phenyl or phenyl lower alkyl, where unsubstituted or O-monosubstituted phosphono can also be present in salt, such as alkali metal salt form, being mono-, di- or polysubstituted.



   A divalent aliphatic radical, including the corresponding radical of a divalent aliphatic carboxylic acid, is e.g.



     Lower alkylene or lower alkenylene which may optionally, e.g.



  such as an aliphatic radical indicated above, mono-, di- or polysubstituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur.



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-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 hydrocarbyl, e.g.

   mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, furthermore cycloalkylidene, or Cyclbalkyl- or cycloalkenyl-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
Cycloalkenyl e.g. up to 12, such as 3 - 8, e.g. Has 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 cyclo aliphatic 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, mono-, di- or polysubstituted by functional groups.



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g. a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, and also biphenylyl or naphthyl, which optionally, e.g. like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted.



   A divalent aromatic radical, e.g. an aromatic carboxylic acid, is primarily 1,2-arylene, especially 1,2-phenylene, which may optionally, e.g. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals can be mono-, di- or polysubstituted,
An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, and also an araliphatic ylidene radical, is e.g. an optionally substituted araliphatic hydrocarbon radical such as an optionally substituted, e.g.

   Aliphatic hydrocarbon radical containing up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals and is primarily 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. like the abovementioned aliphatic and cycloallphatic radicals, can be mono-, di- or polysubstituted 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 bi- or polycyclic aza-, thia-, oxa-, thiaza-, thiadiaza-, oxaza-, diaza-, triaza- or tetrazacyciic radicals of aromatic character, and also corresponding partially or fully saturated radicals, these heterocyclic radicals optionally, for example like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted. The aliphatic part in heterocyclic-aliphatic radicals has e.g. the meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.



   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the organic radical of the ester group is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, e.g. lower alkyl half-ester of carbonic acid substituted in the n- or p-position, and a lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid which is optionally substituted in the organic radical.

  Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid in which the lower alkyl part is a heterocyclic group, e.g. one of the above-mentioned heterocyclic groups of aromatic character, it being possible for both the lower alky radical and the heterocyclic group to be optionally substituted. The acyr radical of a carbonic acid half 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 hydroxy groups, in particular lower alkoxy or halogen, and lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocyycloxy or heterocyloxy in particular also optionally substituted phenyl-lower alkoxy.



   An optionally substituted amino group is e.g.



  Amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino, thi-lower alkylenamino, aza-lower alkylenamino, hydroxyamilro, lower alkoxyamino, lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino.



   An optionally substituted hydrazino group is e.g. Hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino 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. Can be isopropylidene or isobutylidene.



   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 alkenylene e.g. 1,2-ethenylene or 2-buten-1,4-ylene. Lower alkylene interrupted by heteroatoms is e.g. Oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1, 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, cycloalkenyl e.g. Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene e.g. Cyclopentylidene or cyclohexylidene.



  Cycloalkyl-lower alkyl or lower alkenyl is e.g. Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -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-, - Represents 1,2- or -1,3-propyl, vinyl or allyl. Cyclo alkyl lower alkylidene is e.g. Cyclohexylmethylene, and cycloalkenyl lower alkylidene e.g. 3-cyclohexenylmethylene.



   Naphthyl is 1- or 2-naphthyl while biphenylyl is e.g. Represents 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-naphthylmenthyl, and phenyl lower alkylidene e.g. Benzylidene.



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, e.g. corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrrole, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. 2-, 3- or pyridyl, furthermore pyridinium, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl, bicyclic monoaza, monooxa or monothiacyclic radicals 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, tetraza, oxaza-, thiaza or thiadiazacyclic radicals, such as imidazolyl, iB. 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-thiazolyl, Isothia zoWI, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thia-diazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza or thiazacyclic radicals such as benzimidazolyl, e.g.

   2-benzimidazolyl, benzoxazolyl, e.g. 2-benzoxazolyl, or benzthlazoiyl, e.g. 2-benzothiazolyl.



  Corresponding partially or fully saturated radicals are e.g.



     Tetrahydrothienyl such as 2-tetrahydrothienyl, tetrahydrofuryl such as 2-tetrahydrofuryl, or piperidyl, e.g. 2- or 4-fiperidyl. Heterocyclic-aliphatic radicals are hetero - cyolic groups, in particular the above-mentioned containing lower alkyl or lower alkenyl. The above-mentioned heterocyclyl radicals can e.g. by optionally substituted aliphatic hydrocarbon radicals, especially lower alkyl, such as methyl, 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. -Butyloxy, n-pentyloxy or tert-pentyloxy. These groups can be substituted e.g. as in halo-lower alkoxy, especially 2-halo-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. Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, iB. Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g.

  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy e.g. Pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy.



   Lower alkylthio is e.g. Methylthio, ethylthio or n -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, e.g. 2-imidazolylthio, thiazolylthio, e.g. 2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g. 1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio, or tetrazolylthio, e.g. Are I-methyl-5-tetrazolylthio.



   Esterified hydroxy groups are primarily halogen, e.g. Fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g. Acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy, ethoxycarbonyloxy or tert. -Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, 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-dimethyl carbamoyl or N, N-diethylcarbamoyl, while N-lower alkylsulfamoyl e.g. Represents N-methylsulfamoyl or N, N-dimethylsulfamoyl.



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



   Lower alkylamino or di-lower alkylamino is e.g. Methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino e.g. Pyrrolidino or piperidino, oxane-lower alkylenamino e.g. Morpholino, thiane-lower alkyleneamine @ e.g. Thiomorpholino, and aza-lower alkylenamino e.g.

  Piperazino or 4-methylpiperazino. Acylamino is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. Methoxy carbonykmino, ethoxycarbonylamino or tert-butyloxycarbonylamino, halo-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such as phthalylamino, such as acetylamino or propionylamino, such as acetylamino or propionylamino, or optionally e.g. Sulfoamino present in the sodium or ammonium salt form.



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



     O-lower alkyl-phosphono is, for example: O-methyl- or O-ethyl-phosphono, O, O-di-lower alkyl-phosphono, e.g. 0,0-dimethylphosphono 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-benzyl-O-methyl-phosphono.



     Ni ederalkenyl oxycarbonyl is e.g. Vinyloxycarbonyl, while Cycloallkoxycarbonyl and Phenylniederalkoxycarbonyl, z.lB. Represents adamantyloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-diphenylyl-α-methyl-ethoxycarbonyl. Lower alkoxycarbonyl in which lower alkyl is e.g. a monocyclic, monoaza, monooxa or monothiacyclic group is e.g. Fuyl-lower alkoxycarbonyl, such as furfuryloxy carbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thenyloxycarbonyl.



     2-lower alkyl and 2,2-di-lower alkyl hydrazino is e.g.



     2-methylhyzino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino iB. 2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert-butyloxycarbonylhydrazino, and lower alkanoylhydrazino e.g. 2-acetylhydrazino.



   An acyl group Ac stands in particular for a naturally occurring or bio-, semi- or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem 4-carboxylic acid compound containing acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half 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
EMI4.1
 where n is 0 and RI is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, e.g.

   denotes esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or in which n is 1, RI 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 aromatic character and / or a quaternary nitrogen atom, 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 RII and RIII is hydrogen, or where 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 has aromatic character, RII an optionally functionally modified, eg

   esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and RITT stands for hydrogen, or in which n is 1, each of the radicals RI and R11 is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or in which n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   denotes aromatic or araliphatic hydrocarbon radical and R11 and RIII together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n stands for 1, and R1 an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic, -aliphatic, aromatic or araliphatic I (ohienwassersto ffrest or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have aromatic character, RII an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and R111 is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.



   In the above acyl groups of the formula A there are e.g. n for 0 and RI for hydrogen or an optionally, preferably in the 1-position by optionally protected amino, such as amino, acylamino, in which acyl primarily represents the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, or one, optionally in salt, iB. Alkali metal salt form present suifoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, one optionally, preferably by hydroxy, lower alkoxy, e.g. Methoxy, acyloxy, in which acyl primarily represents the acyl radical of a carbonic acid half-ester,

   such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, and / or halogen, e.g. Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl, an 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 a preferably, e.g. by an optionally substituted one such as halogen, e.g.

  Chlorine, lower alkyl radical containing N-substituted amino group, or n for 1, Rl for an optionally substituted, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, iB. 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 amino or acylamino, such as lower alkanoylamino or halo-lower alkanoylamino group, and;

  ; / or silylated or esterified carboxy group, for a lower alkenyl group, for an optionally substituted, such as optionally acylated, hydroxy and / or halogen, e.g. Chlorine, also optionally protected, such as acylated amino-lower alkyl, such as aminomethyl, or optionally substituted, such as optionally acylated hydroxy and / or halogen, e.g. Phenyl group containing chlorine containing phenyloxy, an optionally, e.g. by lower alkyl, such as methyl, or optionally protected, such as acylated amino or aminomethyl, substituted pyndyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl, an optionally substituted lower alkoxy, e.g.



  Methoxy group, an optionally, e.g. by optionally acylated hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g. n-butylthlo, or lower alkenylthio, e.g. Allylthio group, an optionally, e.g.

   by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthlo-, 1,2,4-triazol-3-ylthio-, 1,3,4, -triazol-2-ylthio-, 1 1,2,4-thiadiazole -3-ylthio-, such as 5-methylL1,2,4-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio-, such as 5-methyl-1,3,4-thiadiazol-2- ylthio, or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atoms, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, for example Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g. by 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 R11 and RIII for hydrogen, or n for 1, R1 for an optionally, e.g. by optionally acylated hydroxy and / or halogen, e.g.



  Chlorine, substituted phenyl, furyl, thienyl or 4-isothiazolyl group, furthermore for a 1,4-cyclohexadienyl group, R for optionally protected or substituted amino, e.g. acylated acylamino such as lower alkoxycarbonylamino, 2-halo lower alkoxycarbonylamino or phenyl lower alkoxycarbonylamino, e.g. tert-Butyloxycarbonylamino, 2,2,2 -Trichloräthoxycarbonylamino, 4-Methoxyb enzyloxycarbonylamino or Diphenylmethyloxycarbonylamino, Tritylamino, or optionally substituted carbamoylamino, like guanidinocarbonylamino, or one, optionally in Salzz.B. A sulfoamino group in alkali metal salt form, an azido group, an optionally in salt, e.g.

  Alkali metal salt form or in esterified form, e.g. as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as formyloxy, as well as lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or phenyl-lower alkoxycarbonyloxy, e.g. tert-butyloxycarbonyloxy, 2,2,2-trichlorocarbonyloxy, 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkyl phosphono group, e.g.



     O-methyl-phosphono or O, O-dimethylphosphono, or a halogen atom, e.g. Chlorine or bromine, and RIII for hydrogen, or n for 1, R1 and RII each for halogen, e.g. Bromine, or lower alkoxycarbonyl, e.g. Methoxycarbonyl, and RIII for hydrogen, or n for 1, RI for an optionally, e.g.



   by optionally acylated hydroxy and / or halogen, e.g. Chlorine, substituted phenyl, furyl, thienyl or 4-isothiazolyl group, furthermore for a 1-4-cyclohexadienyl group, RII for optionally, e.g. protected as stated above
Aminomethyl, and RIII for hydrogen, or n for 1 and each of the groups RI, RII and RIII for lower alkyl, e.g. Methyl stand.



   Such acyl radicals Ac are e.g. Formyl, cyclopentylcarbonyl, α-aminocyclopentylcarbonyl or α-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g. optionally in salt form, or a sulfoamino group, preferably slightly, e.g.

   when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethyloxycarbonyl , 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl, phenacyloxycarbonyl, 4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl- or N-methylcarbamoyl, as well as amino groups substituted by trityl, tetrahoxy-benzo-benzoyl, tetrahoxy-2-benzoethoxy) -Methoxy-naphthoyl, 2-ethoxy-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- Chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acryloyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, methylthioacetyl, ampionoacetyl, ampionyl, 3-propionyl, propionyl, propionyl, propionyl, 3-propionyl, propionyl, propionyl, propionyl, propionyl, propionyl, 3-propionyl, propionyl, propionyl, 3-propionyl, propionyl, propionyl, propionyl, 3-propionyl, propionyl, 3-bromoacetyl, 5-Amino-5-carboxyl-valeryl (with optionally, for example as indicated, such as by a monoacyl or diacyl radical, for example an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, e.g.

   in salt, such as sodium salt, or in ester, such as lower alkyl, e.g. Methyl or ethyl ', or aryl lower alkyl, e.g. Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonyl-acetyl, N-phenylcarbamoylacetyl, cyanoacetyl, ex-cyanopropionyl, 2-phenyl-3,3-acetyl-x-dimethyl-acrylyl nylacetyl, -azido-phenylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl (with optionally, e.g.

   as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, α-phenyloxy-propionyl, α-phenyloxy-acetyl, α-phenyloxyphenylacetety, α-ethoxy-phenylethoxyphenylacetety, α-phenyloxyphenylacetety, α-acetylethoxyphenylacetyl, α-phenyloxyphenylacetyl, α-phenyloxyphenylacetyl, α-acetylethoxyphenylacetyl

  ; -Methoxy-3,4-dichlorophenylacetyl, -Cyan-phenylacetyl, especially phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5-dichloro 4-hydroxyphenylglycyl, x-aminomethylmo-phenylacetyl or cc -Hydroxy-phenylacetyl, an amino group optionally present in these radicals, eg as indicated above, can be substituted and / or an aliphatic and / or phenolically bonded hydroxyl group which is present, if appropriate, 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 half ester), or?

  ; -O-methyl-phosphono-phenylacetyl or x-O, O-dimethyl-phosphono-phenylacetyl, also benzylthioacetyl,
Benzylthiopropionyl, -Carboxyphenylacetyl (with if necessary, e.g. as indicated above, functionally modified
Carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -pro pionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridiniumacetyl (optionally with, for example, as given above, substituted amino group ), 2-Thlenylacetyl, 3-Thlenylacetyl, 2-Tetrahydrothienylacetyl, 2-Furylacetyl, 1-Imidazolylacetyl, 1-Tetrazolylacetyl,? -Carboxy-2-thienyl-acetyl or?

    -Carboxy-3-thienylacetyl (optionally with a functionally modified carboxyl group, for example as indicated above), sc-cyano-2-thienylacetyl, α-amino-u; c- (2-thienyl) -acetyl, α-amino -? - (2-furyl) acetyl or? -amino-?

  ;-( 4-isothiazolyl) -acetyl (optionally with, for example, as stated above, substituted amino group), -Sulfophenylacetyl (optionally with, e.g. like the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolylthloacetyl, 1, 2,4-triazol-3-ylthioacetyl, 1,3, triazoi-2-ylthioacetyl, 5-methyl-1, 2,4thiadiazol-3-ylthioacetyl, 5-methyl'-1, 3,4-thia-diazol-2 -ylthfioacetyl or 1-methyl-5-tetrazolylthioacetyl.



   An easily cleavable acyl residue Ac, in particular a carbonic acid half-ester, is primarily one by reduction, e.g. when treated with a chemical reducing agent, or by acid treatment, e.g. with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl group which is multiply branched and / or aromatically substituted on the carbon atom in -position to the oxy group or a methoxycarbonyl group substituted by arylcarbonyl, in particular benzoyl radicals, or in the p-position by halogen atoms substituted lower alkoxycarbonyl radical, e.g. 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-bromo ethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g. Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily α-phenyl-lower alkoxycarbonyl, in which the -position is preferably polysubstituted, e.g. Diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily, α-furyl-lower alkoxycarbonyl, e.g. Furfuryloxycarbonyl.



   A divalent acyl group formed by the two radicals R1A and Rlb is e.g. the acyl radical of a lower alkane or lower alkene dicarboxylic acid, such as succinyl, or of an o-arylenedicarboxylic acid, such as phthaioyl.



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



   An etherified hydroxy group R2A together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified, such as 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 grouping forms an esterified carboxyl group which, in particular in 2-cephem compounds, is easily converted into a free carboxyl group or another functionally
Carboxyl group can be converted.



   An etherified hydroxy group R2A, which together with an -O (= O) group forms a particularly easily cleavable esterified carboxyl group, is, for example. for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19. Such a radical, together with the -C (= O) group, forms a, 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 which can be easily converted into such an and is, for example: B. 2,2,2-Trichloräthloxy or 2-Jodäthoxy, also
2-chloroethoxy or 2-1-bromoethoxy, which can easily be converted into the latter.



   An etherified hydroxy group RA which, together with the -C (= O) group, also has a role in 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, easily cleavable esterified carboxyl group, is an arylcarbonyknethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy.



   The group R2A can also stand for an arylmethoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical. Such a radical, together with the -C (= O) group, forms a upon irradiation, preferably with ultraviolet light, under neutral or acidic conditions easily cleavable, esterified carboxyl group. An aryl radical in such an arylmethoxy group contains, as substituents, in particular lower alkoxy, e.g. Methoxy (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or especially nitro (in the preferred phenyl radical preferably in the 2-position).

  Such radicals are primarily 3- or 4-methoxybenzyloxy, 3; 5-dimethoxybenzyloxy, 2-methylbenzyloxy or 4,5-dimethoxy-2-nitrobenzyloxy.



   An etherified hydroxy group R2A can also represent a radical which, together with the -C (= O) grouping, is an acidic group, e.g. when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms. Such a radical is primarily a methoxy group in which methyl. by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g.

  Methyl, or phenyl, polysubstituted or monosubstituted by a carbocyclic aryl group containing electron-donating substituents or a heterocyclic group of aromatic character containing oxygen or sulfur as a ring member, or then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic radical which means 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'-dimethoxy-diphenylmethoxy, furthermore 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above-mentioned substituted aryl group or the heterocyclic group is e.g. an x-lower alkoxyphenyl-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 l-adamantyl, and an oxa or thiacycloaliphatic radical mentioned above, in which methyl of the methoxy group is the ring member representing the α-position to the oxygen or sulfur atom, is e.g. 2-oxa- or 2-thia-lower alkylene or -nie deralkenylene with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs.

 

   The radical R2A can also represent an etherified hydroxyl group which, together with the -C (= O) group, forms a hydrolytic, e.g. under weakly basic or acidic conditions, cleavable esterified carboxyl group forms. Such a radical is preferably one which is etherified and which forms an activated ester group with the —C (= O) group
Hydroxy group such as nitrophenyloxy, e.g. 4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g. 4-nitrobenzyloxy, polyhalophenyloxy, e.g. 2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyano methoxy, and acylaminomethoxy, e.g. Phthaliminomethoxy or Succinyliminomethoxy.



   The group R2A can also represent an etherified hydroxyl group which, together with the carboxyl group of the formula -C (= O) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. optionally, e.g. sc-phenyl-lower alkoxy substituted by lower alkoxy or nitro, such as benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy.



   The group R2A can also be an etherified hydroxyl group which, together with the carbonyl group -C (= O) -, forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily lower alkanoyloxymethoxy, e.g. Acetyloxymethyloxy or pivaloylmethoxy.



   A silyloxy or stannyloxy group R2A preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araiiphatic hydrocarbon radicals, such as lower alkyl, cyeloalkyl, phenyl or phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, or tri-lower alkylstannyloxy, e.g. Tri-n-butylstannyloxy.



   An acyloxy radical R2A which together with a -C (= O) group forms a, preferably hydrolytically, cleavable mixed anhydride group contains e.g. the acyl radical of one of the above-mentioned organic carboxylic acids or carbonic acid half-derivatives, and is e.g. Lower alkanoyloxy, e.g. Acetyloxy, or lower alkoxycarbonyloxy, e.g. Ethoxycarbonyloxy.



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



   An optionally substituted aliphatic hydrocarbon radical R3 is in particular lower alkyl having up to 7, preferably up to 4 carbon atoms, such as ethyl, n-propyl, isopropyl or n-butyl and primarily methyl, furthermore lower alkenyl, e.g. Allyl, tertiary amino-lower alkyl in which the tertiary amino group is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3-di-lower alkylamino-lower alkyl, e.g. 2-dimethylaminoethyl, 2-diethyl aminoethyl or 3-dimethylaminopropyl, or etherified hydroxy-lower alkyl, in which the etherified hydroxy group, in particular lower alkoxy, is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3-lower alkoxy-lower alkyl, e.g. 2-methoxyethyl or 2-ethoxyethyl.

  An optionally substituted araliphatic hydrocarbon radical R3 is primarily an optionally substituted phenyl lower alkyl, in particular 1-phenyl lower alkyl radical with 1-3 optionally substituted phenyl radicals, such as benzyl or diphenylmethyl, where the substituents e.g. esterified or etherified hydroxy such as halogen, e.g. Fluorine, chlorine or bromine, or lower alkoxy, such as methoxy, are possible.



   Salts are in particular those of compounds of the formula I with an acidic group such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g.



  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, for example

  Triethylamine, hydroxy-lower alkylamines, e.g. 2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g. 4-aminobenzoic acid-2-dläthylaminoethyl ester, lower alkyleneamines, for example: B. 1-ethyl-piperidine, cycloalkylamines, e.g. Bicyclohexylamine, or benzylamines, e.g. N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g. Pyridine, collidine or quinoline.

  Compounds of formula I which have a basic group can also contain 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.



  Trifluoroacetic acid. Compounds of the formula I with one acidic and one basic group can also be used in the form of internal salts, i.e. in zwitterionic form. I-oxides of compounds of formula 1 with salt-forming groups can also form salts, as described above.



   The new compounds of the present invention have valuable pharmacological properties or can be used as intermediates for the preparation of such. Compounds of formula I wherein e.g.



     R13 stands for an acyl radical Ac and Rlb occurring in pharmacologically active N-acyl derivatives of 6u-amino-penam-3-carboxylic acid or 7p-amino-3-cephem-4-carboxylic acid compounds, or where Rla and Rlb together represent one in the 2-position preferably, for example by an aromatic or heterocyclic radical, and preferably in the 4 -position, e.g.

   L-oxo-3-aza-1,4-butylene radical substituted by 2 lower alkyl, such as methyl, R2A denotes hydroxyl or an etherified hydroxyl group which, together with the carbonyl group, forms an esterified carboxyl group which can easily be cleaved under physiological conditions, and R3 denotes the meaning given above has, and in which the double bond is preferably in the 3,4 position of the cephem ring, or salts of such compounds with salt forming groups, are against microorganisms such as gram-positive bacteria, e.g. Staphylococcus aureus, (e.g. in mice at doses of about 0.001 to about 0.02 g / kg po), and gram-negative bacteria, e.g. Escherichia coli (e.g. in mice in doses of about 0.001 to about 0.05 g / kg p.o.), also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, in particular also against penicillin-resistant bacteria.

  These new compounds can therefore be used accordingly, e.g. in the form of antibiotic preparations, use.



   Compounds of the formula I in which the double bond of the cephem ring is in the 2,3-position, or l-oxides of compounds of the formula I in which the double bond is in the 3,4-position and in which Rla, Rlb, R2A and R3 have the im Have the meanings given in connection with the formula I, or in which the double bond of the cephem ring occupies the 3,4 position, R3 has the meaning given above, the radicals Rla and Rlb are hydrogen, or Rla is an amino protective group different from the above-mentioned acyl radical and Rlb is hydrogen, or Rla and Rlb together one,

   represent divalent amino protective groups different from the abovementioned divalent radicals, and R2A stands for hydroxy, or Rla and Rlb have the meanings given above, R2A for a, together with the -C (= O) group, a, preferably easily cleavable, protected carboxyl group Forming radical represents, and R3 has the meanings given above, are valuable intermediates which in a simple manner, for example as described below, can be converted into the above-mentioned pharmacologically active compounds.



   Particularly valuable are the 3-cephem compounds of the formula 1, in which Rla is hydrogen or, preferably, a, in a fermentatively (ie naturally occurring) or bio-, semi- or totally synthetically producible, especially pharmacologically active, such as highly active N-acyl derivative of a 6ss- Amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound or an easily cleavable acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, Rlb stands for hydrogen, or in which R1a and Rlb together mean one in 2 Position preferably, e.g.

   by an aromatic or heterocyclic radical, and preferably in the 4-position, z.lB. L-oxo-3-aza-1,4-butylene radical substituted by 2 lower alkyl, such as methyl, R2A for hydroxy, for optionally, e.g. by optionally substituted
Aryloxy, such as lower alkoxyphenyloxy, e.g. 4-methoxyphenyl oxy, lower alkanoyloxy, e.g. Acetyloxy or pivaloyloxy, or arylcarbonyl, e.g. Benzoyl, or halogen, e.g. Chlorine,
Bromine or iodine, or optionally substituted aryl, such as
Phenyl, lower alkoxyphenyl, nitrophenyl or diphenyl substituted lower alkoxy such as lower alkoxy, e.g.

  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyl oxy or tert-pentyloxy, bis-phenyloxy-methoxy optionally substituted by lower alkoxy, e.g. Bis-4-methoxy phenyloxy-methoxy, phenacyloxy, lower alkanoyloxymethoxy, e.g. Acetyloxymethoxy or pivaloyloxymenthoxy, 2-halo lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-chloroethoxy, 2 43romethoxy or 2-iodoethoxy, optionally substituted
Phenyl-lower alkoxy, especially l-phenyl-lower alkoxy, such as
Phenylmethoxy, such radicals 1-3 optionally, e.g.



   phenyl radicals substituted by lower alkoxy such as methoxy, nitro or phenyl, e.g. Benzyloxy, 4-methoxy-benzyloxy, 2-iphenylyl-2-prnpyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, 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. Trimethylsilyloxy, or optionally, e.g. amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g.

  Amino, Nie deralkyl- or Diiederalkylamino, 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 R3 is lower alkyl, e.g.



   Methyl, ethyl, n-propyl, isopropyl or n-butyl, lower alkenyl, e.g. Allyl, optionally substituted Phenylnie deraikyl, in particular 1-phenyl-lower alkyl with 1 or 2, optionally, for example: B. by lower alkoxy, such as methoxy, substituted phenyl radicals, e.g. Benzyl or diphenylmethyl, and the l-oxides thereof, and also the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups.



   Primarily in a 3-cephem compound of the formula I, and in a corresponding 2-cephem compound, furthermore in an 1-oxide of the 3-cephem compound, or in a salt of such a compound with salt-forming compounds
Groups Rla for hydrogen or a fermentative (i.e.



  naturally occurring) or biosynthetically producible N-acyl derivatives of 6P-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds
Acyl radical, such as an optionally, e.g. by hydroxy, substituted phenylacetyl or phenyloxyacetyl radical, furthermore an optionally, e.g. by lower 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-Hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and especially 5-amino -5-carboxy-valeryl, in which the amino and / or the carboxyl groups are optionally protected and e.g. as acetylamino or

   esterified carboxyl are present, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 63-amino-penam-3-carboxylic acid or 7fi-amino-3-cephem-4-carboxylic acid compounds, such as formyl, haloethylcarbamoyl, e.g. 2-chloroethylcarbamoyl, cyanoacetyl, phenyiacetyi, thienylacetyl, e.g. 2-thienylacetyl, or tetrazolylacetyl, e.g. 1-tetrazolyl acetyl, especially phenylglycyl, in which phenyl optionally, e.g. by optionally protected hydroxy such as acyloxy, e.g. 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-phenyI (optionally with a protected, such as acylated hydroxy group), and in which the amino group is optionally substituted and e.g. represents a sulfoamino group which is optionally present in salt form or an amino group which, as substituents, is a hydrolytically cleavable trityl group or an optionally substituted carbamoyl group, such as an optionally substituted ureidocarbonyl group, e.g.

  Ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyi group e.g. Guanidinocarbonyl, or a, preferably light, e.g. when treating with an acidic agent, such as trifluoroacetic acid, or with a czhe- mischen reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the abovementioned, e.g.

   optionally halogen or benzoyl substituted lower alkyloxycarbonyl, e.g. 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 4-methoxybenzyl oxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl,

   also thienyl glycyl, wien-2- or z-3-thienylglycyl, -Furyiglycyl, such as a-2-furylglycyl, z4sothiazoiylglycyl, such as -4-isothiazolylglycyl, 1-amino-cyclohexylcarbonyi or amino-pyridinium, e.g. 4-aminopyridinium (optionally with, for example, as indicated above, substituted amino group), furthermore, x-carboxy-phenylacetyl or cc-carboxy-2-thienylacetyl (optionally with a functionally modified, e.g. 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: B.

  Diphenylmethyl ester form, present carboxyl group),, sc-sulfo-phenylacetyl (optionally with, e.g. like the carboxyl group, a functionally modified sulfo group), a-phosphono,? -O-methyl-phosphono or?

  ; -O, O-dimethyl-phosphono-pheylacetyl, or 5c-hydroxyphenylacetyl (optionally with a functionally modified hydroxyl group, in particular with an acyloxy group, in which acyl is one, preferably slightly, e.g. when treating with an acidic agent such as trifluoroacetic acid, or with a chemical Reducing agents, such as zinc in the presence of aqueous acetic acid, cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above-mentioned lower alkoxycarbonyl radicals, for example optionally substituted by halogen or benzoyl, for example

 

     2,2,2-trichloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert-butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), or pyridylthioacetyl, e.g. 4-pyridylthioacetyl, e.g. for an acyl radical of the formula A, and Rlb for hydrogen, or Rla and Rlb together for one, preferably in the 2-position, optionally protected by hydroxy, such as acyloxy, e.g.



  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 with a protected, such as acylated hydroxy group) substituted 1-oxo-3-aza-1, 4-butylene radical, which optionally contains two lower alkyl, such as methyl, in the 4-position, and R2A represents hydroxy, lower alkoxy, in particular α-poly-branched lower alkoxy, e.g. tert-butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, e.g.



  2,2,2-trichloroethoxy, 2-iodoethoxy or the 2-chloroethoxy or 2i-bromoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, e.g.



     4-methoxybenzyloxy, 4-niftobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenyimethoxy or trityloxy, and Ra is lower alkyl, e.g. Methyl, 1-phenyl lower alkyl, e.g.



  Benzyl or diphenylmethyl.



   The invention relates primarily to 3-cephem compounds of the formula I in which Rlb is hydrogen and R1a is hydrogen, cyanoacetyl, an acyl group of the formula
EMI9.1
 wherein Ar is phenyl, furthermore hydroxyphenyl, e.g. 3- or 4-hydroxyphenyl, or hydroxychlorophenyl, e.g. 3-chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, where in such radicals hydroxy substituents are replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g.



  tert-butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, as well as thienyl, e.g. 2- or 3-thienyl, also pyridyl, e.g. 4-pyridyl, aminopyridinium, e.g. 4-aminopyridinium, furyl, e.g. 2-furyl, isothiazolyl, e.g. 4-isothiazolyl, or tetrazolyl, e.g. l-tetrazolyl, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, when n is 0, optionally protected amino such as acylamino, e.g. α-polybranched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-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 3-guanylureido, also sulfoamino or tritylamino, optionally protected carboxy, e.g. esterified carboxy such as phenyl-lower alkoxycarbonyl e.g. Diphenylmethoxycarbonyl, optionally protected sulfo, as in alkali metal, e.g.

  Sodium salt form, sulfo present, optionally protected hydroxy such as acyloxy e.g. Alpha-polybranched lower alkoxycarbonyloxy, such as tert-butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also e.g. O-methylphosphono or O, O-dimethylphosphono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and / or carboxy groups are optionally protected and, for example. as acylamino, e.g. Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g.

  Diphenylmethoxycarbonyl, R2A is hydroxy, lower alkoxy, especially oc-polybranched lower alkoxy, e.g. 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'-dimethoxy-diphenylmethoxy, andi R, lower alkyl, e.g. Methyl, also means the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups.



   In 3 cephem compounds of the formula I, which are particularly valuable, and also in corresponding 2-cephem compounds, Rla is hydrogen, for the acyl radical of the formula B, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen or, when n represents 0, optionally protected amino, such as acylamino, e.g. o-poly-branched lower alkoxycarbonylamino, such as tert-butyloxycarbonylamino, or 2-halo-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-methoxybenzyloxycarbonyl.



  amino, or optionally protected hydroxy, such as acyl-.



  oxy, e.g. x-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, also formyloxy, or O-lower alkyl or O, O-di-lower alkyl phosphono, e.g. O-methylphosphono or O, O-dimethyl- -phosphono, or for a 5-amino-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected and e.g. as acylamino, e.g. Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, or phthaloylamino, or



  as an esterified carboxy such as phenyl-lower alkoxycarbonyl, e.g. Diphenylmethoxycarbonyl, Rlb represents hydrogen, R2A means hydroxy, optionally halogen in the 2-position, e.g. Chlorine, bromine or iodine substituted lower alkoxy, especially x-polybranched lower alkoxy, e.g. tert-butyloxy, or 2-halo-lower alkoxy, e.g. 2,2,2-trichloroethoxy, 2-joethoxy or 2-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethoxy, e.g. Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy and R3 represents lower alkyl, e.g. Methyl.



   The compounds of the formula I and l-oxides thereof, in which the double bond is in the 3,4-position, and their salts are obtained by reacting in a 3-cephem-3-ol compound of the formula
EMI9.2
 or in a 1-oxide thereof the 3-hydroxy group by etherification by means of a tri-R, -oxonium salt of the formula (R3) 30ss3Aa (VI) or a 3-substituted l-R3-triazene compound of the formula Subst.-N = N - NH - R, (VII), in which R3 has the meaning given under formula I, A8 is the anion of an acid and Subst. Is an aromatic radical, converted into a group of the formula - O - R3, and if desired, a compound obtained with salt-forming Group converted into a salt or a preserved salt in the free compound.

 

   In a starting material of the formula II, R2A preferably stands for an etherified hydroxy group R2A which can be cleaved, in particular under mild conditions, with the C (- 0) grouping and which forms an esterified carboxyl group, with any functional groups present in a carboxyl protective group R2A in known manner, for example as stated above, may be protected.

  A group R2A is e.g. in particular an optionally halogen-substituted lower alkoxy group such as x-polybranched lower alkoxy, e.g. tert-butyioxy, or 2-halo-lower alkoxy, in which halogen, e.g. Represents chlorine, bromine or iodine, primarily 2,2,2-chloroethoxy, 2-bromoethoxy, or 2-iodine ethoxy, or an optionally substituted one, such as lower alkoxy, z..B. Methoxy or nitro-containing l-phenylhiederalkoxy group, such as optionally, e.g. as indicated, substituted benzyloxy or diphenylmethoxy, e.g.

  Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy. In a starting material of the formula II, the radical Rla is preferably an amino protective group R1A, such as an acyl group Ac, in which any free functional groups present, for example: B. Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups e.g. by acylation, tritylation, silylation or stannylation, and hydroxy, carboxy or phosphono groups, e.g. may be protected by etherification or esterification, including silylation or stannylation, and Rlb is hydrogen.



   Starting materials of the formula II can be in the keto and / or in the enol form, the ring double bond in the latter being in the 2,3, but preferably in the 3,4 position. The starting materials of the formula II are usually converted from the enol form into the enol derivatives of the formula I. Furthermore, e.g. also use a mixture of a compound of the formula II and the corresponding 1-oxide as starting material and the product obtained is the mixture of a compound of the formula I and the corresponding 1-oxide.



   The conversion of the starting materials of the formula II into the enol derivatives can be carried out in a manner known per se.



   In the preparation according to the invention of the enol ethers of the formula I, starting materials of the formula II can be used in which Rla and Rlb are hydrogen, but in which Rla is preferably an amino protective group R1A.



   The enol ethers of the formula I can be obtained if starting materials of the formula II are treated with tri-R3-oxonium salts of the formula (R3) Ae (VI) (so-called sea wine salts), in which A8 is the anion of an acid. These are primarily tri-lower alkyloxonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachlorantimonates. Such reagents are e.g. Trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachlorantimonate, hexafluorophosphate, or tetrafluoroborate.



   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 a mixture thereof, if necessary, in the presence of a base such as an organic base, e.g. a, preferably sterically hindered, tri-lower alkylamine, e.g. N, N <Diisopropyl-N-ethyl-amine, and with cooling, at room temperature or with slight warming, e.g. B.  at about -200C to about 50C, if necessary, in a closed vessel and / or in an inert gas, e.g. B.  Nitrogen atmosphere. 



   The enol ethers of the formula I can also be prepared by treating starting materials of the formula II with a 3-substituted l-R3-triazene compound (IX) (i.e. H.  a compound of the formula Subst. -N = N - NH - R3), where the substituent of the 3-stick +. offatoms an aromatic radical, preferably a carbocyclic aryl radical, such as an optionally substituted phenyl radical, e.g. B.     Lower alkylphenyl, such as 4-methylphenyl. 

  Such triazene compounds are 3-aryl-1-lower alkyl-triazenes, e.g. B.  3- (4-methylphenyl) l -methyl-triazene, 3 (4-methylphenyl) -1 -ethyl-triazene, 3- (4-methylphenyl) -1-n-propyl-triazene or 3- (4-methylphenyl) - 1 -isopropyl-triazene, 3-aryl-1-lower alkenyl-triazenes, e.g. B.  3- (4-methylphenyl) allyl triazene, or 3-aryl-1-phenyl-lower alkyl-trazene, e.g. B.  3- (4-methylphenyl) -1-benzyl-triazene. 



  These reagents are usually in the presence of inert solvents, such as optionally halogenated hydrocarbons or ethers, eg. B.     Benzene, or solvent mixture, and with cooling, at room temperature and preferably at elevated temperature, iB.     at about 20 ° C. to about 100 ° C., if necessary, in a closed vessel and / or in an inert gas, e.g. B.     Nitrogen atmosphere used. 



   In the process according to the invention and in any additional measures to be carried out, if necessary, free functional groups not participating in the reaction can be present in the starting materials or in the compounds obtainable according to the process, e.g. B.  free amino groups e.g. B.  by acylation, tritylation or silylation, free hydroxyl or mercapto groups e.g. B.  by etherification or esterification, and free carboxyl groups e.g. B.  by esterification, inki.     Silylation, protected from being transient in a manner known per se and, if desired, released in a manner known per se after each reaction has taken place. 



   In a compound of the formula I obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= O) -R2A, this can be carried out in a manner known per se, e.g. B.  depending on the type of group R2A, can be converted into the free carboxyl group.  An esterified, e.g. B.  carboxyl group esterified by a lower alkyl radical, in particular methyl or ethyl, in particular in a 2-cephem compound of the formula I, can be obtained by hydrolysis in a weakly basic medium, e.g. B. 

   by treating with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. B.     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-halo-lower alkyl or an arylcarbonylmethyl group can e.g. B. 



  by treating with a chemical reducing agent such as a metal, e.g. B.     Zinc, or a reducing metal salt such as a chromium-1I salt, e.g. B.  Chromium-II-chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably adding water, a carboxyl group esterified by an arylcarbonylmethyl group, likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl group e.g. B.  by irradiation, preferably with ultraviolet light, e.g. B.  below 290 m {when the arylmethyl group z. B.  

   one optionally in the 3-, 4- and / or 5-position, e.g. B.  is benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. B.  over 290 m when the arylmethyl group z. B.  a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert. -Butyl or diphenylmethyl, esterified carboxyl group e.g. B.  by treatment with a suitable acidic agent such as formic acid or trifluoric acetic acid, optionally with the addition of a nucleophilic compound such as phenol or anisole, an activated esterified carboxyl group by hydrolysis, e.g. B. 

   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. B.  by treating with hydrogen in the presence of a noble metal, e.g. B.  Palladium catalyst, are cleaved. 



   A z. B.  Protected by silylation or stannylation carboxyl group can in a conventional manner, for. B.  can be released by treatment with water or an alcohol. 



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



   In a compound obtained, e.g. B.  an amino protective group R1A or  R11 ', in particular an easily cleavable acyl group, in a manner known per se, e.g. B.  a cs- polybranched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g. B. 

  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent nascent together with the metal or metal compound, preferably in the presence of acetic acid containing water.  Furthermore, in a compound of the formula I obtained in which a carboxyl group of the formula -C (= O) -R2 is preferably one, e.g. B.  by esterification, including by silylation, e.g. B. 

   by reaction with a suitable organic halosilicon or halogen-ztnn-IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, represents an acyl group R1A or Rlb, in which any free functional groups that may be present are optionally protected, by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleavage of the imino ether formed, a protected, e.g. B.  a carboxyl group protected by an organic silyl radical can be released during the reaction. 



     Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides.  There are primarily acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, eg. B.  Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechylphosphorus trichloride, and 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 said imide halide-forming agents is usually carried out in the presence of a suitable, in particular organic, base, primarily a tertiary amine, e.g. B.  a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, e.g. B.  Trimethyl, triethyl or ethyldiisopropylamine, also an N, N, N ', N' -tetraniederalkyl-lower alkylenediamine, e.g. B.  N, N, N ', N'-tetramethyl-d, 5-pentylenediamine or N, N, N', N'-tetramethyl- -1,6hexylenediamine, a mono- or bicyclic mono- or diamine, such as an N. -substituted, e.g. B.  N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, e.g. B. 



  N-methyl-piperidine or N-methyl-morpholine, also 2,3,4 6,7,8-hexahydropyrrol'ol, 2jpyrimidin (diazabicyclononen; DBN), or a tertiary aromatic amine such as a di-lower alkyl-aniline, z . B.    N, N-dimethylaniline, 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. B.  chlorinated, aliphatic or aromatic hydrocarbon, e.g. B.  Methylene chloride. 

  Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g. B.  in about 0.2 to about 1 times the amount or then in about to 10 times, in particular about 3 to 5 times, excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g. B.  carried out at temperatures from about 50 ° C. to about + 10 ° C., but also at higher temperatures, d. H.  z. B.  up to about 75 "C, if the stability of the starting materials and products allow an increased temperature. 



   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to form the imino ether.  Suitable alcohols are e.g. B.  aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g. B.  chlorinated, or additional hydroxyl-containing lower alkanols, e.g. B.  Ethanol, propanol or butanol, especially methanol, also 2-halo-lower alkanols, e.g. B. 



     2,2,2-trichloroethanol or 2-bromoethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol. 



     Usually one uses, e.g. B.  up to about 100-fold excess of the alcohol and preferably operates with cooling, e.g. B.  at temperatures from about -500C to about 10 C.    



   The imino ether product can advantageously be subjected to cleavage without isolation.  The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, by means of alcoholysis or, preferably, by means of hydrolysis.  It is preferable to use water or an aqueous mixture of an organic solvent such as an alcohol, especially a lower alkanol, e.g. B.  Methanol.  One usually works in an acidic medium, e.g. B.  at a pH of about
1 to about 5, which can be obtained, if necessary, by adding a basic agent such as an aqueous alkali metal hydroxide, e.g. B.  Sodium or potassium hydroxide, or an acid, e.g. B. 



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



   The above-described three-step process for splitting off 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 towards the reactants, such as an optionally halogenated hydrocarbon, e.g. B.  Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere. 

 

   If the intermediate imide halide product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula I is obtained in which both radicals Rla and Rlb are acyl groups
In a compound of the formula I in which both radicals Rla and Rlb are acyl groups, one of these groups, preferably the less sterically hindered one, e.g. B.  by hydrolysis or aminolysis, can be selectively removed. 



   In a compound of the formula I in which R1A and Rlb together with the nitrogen atom represent a phthalimido group, this can, for. B.  by hydrazinolysis, d. H.  at the
Treating such a compound with hydrazine into which free amino groups are converted. 



   Certain acyl radicals R1A of an acylamino group in compounds obtainable according to the invention, such as. B.  the 5-amino-5-carboxy-valeryl radical in which carboxyl, e.g. B.  by
Esterification, especially by diphenylmethyl, and / or the amino group, e.g. B.     by acylation, in particular by Haiogenniederaikanoyl, such as dichloroacetyl, optionally protected, can also by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzoidiazonium chloride, or with a positive halogen-donating agent such as an N-halo-amide ; or imide, e.g. B. 

  N-bromosuccinimide, preferably in a suitable solvent or solvent mixture such as formic acid, together with a nitro or cyano-lower alkane and adding the reaction product with a hydroxyl-containing agent such as water or a lower alkanol, e.g. B.  Methanol, or, if the amino group is unsubstituted in the 5-amino-5-carboxy-valeryl radical R1A and the carboxy group z. B.  is protected by esterification, and 'Rlb is preferably an acyl radical, but can also mean hydrogen, by leaving to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. B.     Methylene chloride and, if necessary, working up the free or monoacylated amino compound according to known methods
Methods to be split off. 



   A formyl group R1A can also be obtained by treatment with an acidic agent, e.g. B.  p-toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g. B.  dilute ammonia, or a decarbonylating agent, e.g. B. 



  Tris (triphenylphosphine) rhodium chloride, are split off. 



   A triarylmethyl, such as the trityl group R1A, can e.g. B. 



  by treating with an acidic agent such as a mineral acid, e.g. B.  Hydrochloric acid. 



   In a compound of the formula I in which Rla and Rlb are hydrogen, the free amino group can be obtained by acylation methods known per se, eg. B.  by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g. B.    Fluorides or chlorides, as well as pseudohalides, such as acids, correspond to the cyano carbonyl compounds, or anhydrides (including the internal anhydrides of carboxylic acids, i.e. H.  Ketenes, or from carbamic or thiocarbamic acids, d. H. 

  Iso cyanates or isothiocyanates, or mixed anhydrides, such as those that are z. B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, as well as with substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives, or an N-substituted N , N-diacylamine, such as an N, N-diacylated aniline, acylate, if necessary, in the presence of suitable condensing agents, when using acids such. B.  of carbodiimides, such as dicyclohexylcarbodiimide, when using reactive acid derivatives, e.g. B.  basic agents, such as triethylamine or pyridine, works, and if necessary also of salts such. B. 

  Ammonium salts of compounds of the formula I in which R2 is a hydroxyl group can start. 



   An acyl group can also be introduced by adding a compound of the formula I in which Rla and R1b together represent a ylidene radical (which can also be added subsequently, e.g. B.  by treating a compound in which Rla and Rlb are hydrogen with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde), e.g. B.  acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed. 



   An acyl group can also be introduced in stages.  So you can z. B.  in a compound of formula I with a free amino group a halo-lower alkanoyl, z. B.  Bromoacetyl group, or e.g. B.  by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl, e.g. B.  Chlorocarbonyl group, and an N - :( halogen-lower alkanoyl) - or     N- (halocarbonyl) -amino compound with suitable exchange reagents, such as basic compounds, e.g. B.     Tetrazole, thio compounds, e.g. B. 



     2-mercapto-1-methyl-imidazole, or metal salts, e.g. B.  Sodium azide or    Alcohols such as lower alkanols, e.g. B.  tert.  -Butanol, convert and so to substituted N-lower alkanoyl or    N-Hydroxycarbonylaaminoverbindungen arrive. 



  Furthermore, you can z. B.  a compound of the formula I in which Rla is a glycyl group, preferably substituted in the x position, such as phenylglycyl, and Rib is hydrogen, with an aldehyde, e.g. B.     Formaldehyde, or a ketone such as lower alkanone, e.g. B.  Acetone, and thus obtain compounds of formula 1 in which R1A and Rlb 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. 



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released by methods known per se after the acylation.  So you can preferably z. B.  Amino, hydroxy, carboxyl or phosphono groups in the acyl radical during the acylation reaction, for. B.  in the form of acylamino, such as those mentioned above, e.g. B.    2.2. 2-Trichloräthoxycarbonylamino-, 2 -Bromäthoxycarbonylamino-, 4-Meth, oxybenzyloxycarbonylamino, Diphenylmethoxycarbonylamino- or tert. -Butyloxycarbonylamino groups, from acyloxy, such as those mentioned above, e.g. B.  2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonylgruppen, of esterified carboxy, such as those mentioned above, e.g. B. 

  Diphenylmethoxycarbonyl groups, or    O, O-di-substituted phosphono, such as those mentioned above, e.g. B.  0,0 -Diniederalkylphosphono-, z. 'B.  O, O-dimethyl-phosphono groups, protect and subsequently, if necessary after conversion of the protective group, z. B.  a 2-Bromäthoxycarbonyl- in a 2-Jodäthoxycarbonylgruppe, z. B.  by treatment with suitable reducing agents such as zinc in the presence of aqueous acetic acid, or with trifluoroacetic acid, by hydrogenolysis or by treatment with an alkali metal halide, e.g. B.  partially, split. 

 

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



   In a compound of the formula I in which Rla and Rlb are hydrogen, the free amino group can also be removed by introducing a triarylmethyl group, e.g. B.  by treatment with a reactive ester of a triarylmethanol 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. B.  by treatment with a suitable silylating agent such as a dihalodiniedernylkyl-silane or tri-lower alkyl-silyl halide, e.g. B.    Dichloro dimethylsilane or trimethylsilyl chloride, or an optionally N-mono-lower alkylated, N, N -di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-lower alkylsilylated N- (tri-lower alkyl-silyl) - -amine, (see z. B.  British patent no.    1. 073. 530), or with a suitable stannylating agent, such as a bis (tri-lower alkyl tin) oxide, e.g. B. 

  Bis- (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g. B.       Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g. B.     Tri-n-butyl tin chloride (see e.g. B.  Dutch interpretation 67/11107).    



   In a compound of the formula I which can be obtained according to the process and which contains a free carboxyl group of the formula -C (= O) - -R2A, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se.  So you get z. B.  by treatment with a suitable diazo compound such as a diazo lower alkane, e.g. B.     Diazomethane or diazobutane, or a phenyldiazo lower alkane, e.g. B. 



  Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, such as. B.     Boron trifluoride, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B.     Dicyclohexylcarbodiimide and carbonyldiimidazole, furthermore with an N, N'-disubstituted O- or  5-substituted isourea or isothiourea, in which a 0- and S-substituent e.g. B.     Lower alkyl, especially tert. -Butyl, phenyl-lower alkyl or cycloalkyl, and N- or  N 'substituents e.g. B.    



  Are lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid, an ester. 

  Acid halides such as chloride (manufactured e.g. B.  by treatment with oxalyl chloride), activated esters (formed e.g. B.  nitrogen compounds with N-hydroxy, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g. B.  with haloformic acid lower alkyl esters, 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, are converted into an esterified carboxyl group. 



   In a compound obtained with an esterified group of the formula -C (= O) -R2A, this can be converted into another esterified carboxy group of this formula, e.g. B.  2-chloroethoxycarbonyl or 28romethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-iodoethoxycarb onyl.    



   Mixed anhydrides can be prepared by adding a compound of the formula I with a free carboxyl group of the formula -C (= O) -R2A, preferably a salt, in particular an alkali metal, e.g. B.  Sodium, or ammonium, e.g. B.  Triethylammonium salt thereof with a reactive derivative such as a halide, e.g. B.  the chloride, an acid, e.g. B.  a lower alkyl haloformate or a lower alkanecarboxylic acid chloride. 



   In a compound obtainable according to the process with a free carboxyl group of the formula C (= O) -R, A, this can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters , as well as the activated esters mentioned above, 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. B.  by using compounds of formula I in which RA is hydroxy, or salts such as alkali metal, e.g. B.     Sodium salts thereof treated with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see e.g. B.  British patent no.  1 073 530 or  Dutch exposition no.    67 / '17wo7.    



   Furthermore, modified functional substituents in groups R1A, R1b and / or R2A, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or O, O-disubstituted phosphono groups, can be carried out by methods known per se, e.g. B.     the above-described, release, or free functional substituents in groups R1A, R1b and / or R2A, such as free amino, hydroxy, carboxy or phosphono groups, by methods known per se, e.g. B.  Acylating or  Esterify or  Substitute, modify functionally.  So z. B.  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. B.  Triethylamine, convert into a sulfoamino group. 

  Furthermore, the reaction mixture of an acid addition salt of a 4ssuanylsemicarbazids with sodium nitrite with a compound of formula I, wherein z. B.  the amino protective group R1A represents an optionally substituted glycyl group, convert and so convert the amino into a 3-guanylureido group.  Furthermore, you can compounds with aliphatically bonded halogen, for. B.  with an optionally substituted 5C-bromo-acetyl grouping, with esters of phosphorous acid, such as tri-lower alkyl-phosphite compounds, and thus arrive at corresponding phosphono compounds. 



     Eirr obtainable according to the process mixture of a compound of formula I and the corresponding 1-oxide can with the help of suitable separation methods, for. B.  by chromatography (columns, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further by fractional crystallization, solvent distribution, etc.  be separated.  Furthermore, a mixture of a compound of the formula I and the corresponding 1-oxide can either be oxidized directly to the 1-oxide or reduced to a 3-cephem compound of the formula I. 

  These oxidation and reduction steps are described below in connection with the isomerization of a 2-cephem to the corresponding 3-cephem compound using a 1-oxide as an intermediate. 

 

   Obtained cephem compounds of the formula I in which the double bond is in the 2,3- or 3,4-position can be converted into 1-oxides of the corresponding 3-cephem compounds by oxidation with suitable oxidizing agents, such as those described below.  Obtained 1-oxides of 3-cephem compounds of the formula I in which the double bond is in the 3,4-position can be reduced by reduction with suitable reducing agents, such as. B.  reduce those described below to the corresponding 3-cephem compounds of the formula I.  In these reactions, care must be taken to ensure that, if necessary, free functional groups are protected and, if desired, are subsequently released again.   



   Obtained cephem compounds can be isomerized to who.  Thus obtained 2-cephem compounds of the formula I, in which the double bond is in the 2,3-position, can be converted into the corresponding 3-cephem compounds of the formula I, in which the double bond is in the 3,4-position, by converting a 2 -Cephemverbin'dung of the formula I, wherein free functional groups optionally, z. B.  as indicated, may be temporarily protected, isomerized.  You can z. B.  Set 2-cephem compounds of the formula I in which the group of the formula -C (= O) -R2A represents a free or protected carboxyl group, it being possible for a protected carboxyl group to also be formed during the reaction. .    



   For example, a 2-cephem compound of the formula I can be isomerized by treating it with a weakly basic
Treated funds and received from any
Equilibrium mixture of the 2- and 3-cephem compounds the corresponding 3-cephem compound of the formula I is isolated. 



   Suitable isomerizing agents are e.g. B.  organic nitrogen-containing bases, especially tertiary heterocyclic ones
Bases of aromatic character, primarily bases des
Pyridine type, such as pyridine itself, and collidines or lutidines, also quinoline, tertiary aromatic bases, e.g. B.  those of the aniline type such as N, N-Diniederaikylaniline, z. B.  N, N-dimethylaniline or N, N-diethylaniline, or tertiary aliphatic, azacycloaliphatic or araliphatic bases, such as N, N, N-tri-lower alkyiamines, e.g. B.    -N, N, N-trimethylamine, N, N-dimethyl-N-ethylamine, N, N, N-triethylamine or N, N -diisopropyl-N-ethylamine, N-Niederalkyi-azacycloalkane, z. B. 

  N-methyl-piperidine, or N-phenyl-lower-alkyl-N, N-di-lower alkyl-amines, e.g. B.  N-benzyl-N, N-dimethylamine, as well as mixtures thereof, such as the mixture of a base of the pyridine type and an N, N, N-tri-lower alkylamine, e.g. B.  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 alkanecarboxylic acids, eg. B.  Sodium acetate, triethyiammonium acetate or N-methyl-piperidine acetate, as well as other analogous bases or mixtures of such basic agents can be used. 



   The above isomerization with basic agents can, for. B. 



  in the presence of a derivative of a carboxylic acid which is suitable for the formation of a mixed anhydride, such as a carboxylic acid anhydride or carboxylic acid, e.g. B.  with pyridine in the presence of acetic anhydride.  It is preferable to work in an anhydrous medium, in the presence or absence of a solvent such as an optionally halogenated:

   z. B.  chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, or a solvent mixture, where used as the reactant.  Bases that are liquid under the reaction conditions can also serve as solvents, with cooling, at room temperature or with heating, preferably in a temperature range from about -300 ° C. to about + 100 ° C., in an Iuertgas-, z. B.  Nitrogen atmosphere, and / or in a closed vessel. 



   The 3-cephem compounds of the formula I obtainable in this way can be prepared in a manner known per se, for. B.  by adsorption and / or crystallization, separate from any 2-cephem compounds still present. 



   The isomerization of 2-cephem compounds of the formula I 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 formula I, and the 1- Oxides of the corresponding 3-cephem compounds are reduced. 



   Suitable oxidizing agents for the 1-position oxidation of 2-cephem compounds are inorganic ones
Peracids which have a reductone potential of at least + 1.5
Volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, especially organic carboxylic acids, with a dissociation constant of at least 10-5.  Suitable inorganic peracids are periodic and persulfuric acid.  Organic peracids are corresponding percarboxylic and persulfonic acids which can be added as such or formed in situ by using at least one equivalent of hydrogen peroxide and one carboxylic acid. 

  It is advantageous to use a large excess of the carboxylic acid if, for. B.  Acetic acid is used as a solvent.  Suitable peracids are e.g. B.  Performic acid, peracetic acid, trifluoroacetic acid, permaleic acid, perbenzoic acid, 3-chloroperbenzoic acid, monoperphthalic acid or p-toluene persulfonic acid. 



   The oxidation can also be carried out using hydrogen peroxide with catalytic amounts of an acid with a dissociation constant of at least 10-5, using low concentrations, e.g. B. 



     1-2% and less, but also larger amounts of acid can be used.  The effectiveness of the mixture depends primarily on the strength of the acid.  Suitable mixtures are e.g. B.  those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid. 



   The above oxidation can be carried out in the presence of suitable catalysts.  So z. B.  the oxidation with percarboxylic acids can be catalyzed by the presence of an acid with a dissociation constant of at least 10-5, the effectiveness of which depends on its strength.  Acids suitable as catalysts are, for. B.  Acetic acid, perchloric acid and trifluoroacetic acid.    Usually at least equimolar amounts of the oxidizing agent are used, preferably a small excess of about 10% to about 20%, larger excesses also being used, i. H.  up to 10 times the amount of the oxidizing agent or more. 

  The oxidation is carried out under mild conditions, e.g. B.  carried out at temperatures from about -500 ° C. to about 00 ° C., preferably from about -100 ° C. to about +40 ° C. 



   The oxidation of 2-cephem compounds to the 1 -oxides of the corresponding 3-cephem compounds can also be achieved by treatment with ozone, furthermore with organic hypohalite compounds, such as lower alkyl hypochlorites, e.g. B.    tert. -Butyl hypochlorite, which can be obtained in the presence of inert solvents, such as optionally halogenated hydrocarbons, e.g. B.    Methylene chloride, and used at temperatures from about -10 "C to about + 30" C, with periodate compounds such as alkali metal periodates, e.g. B. 

  Potassium periodate, which is preferably used in an aqueous medium at a pH of about 6 and at temperatures of about -100 ° C. to about + 30 ° C., with iodobenzene dichloride, which is used in an aqueous medium, preferably in the presence of an organic base, e.g. B.  Pyridine, and with cooling, e.g. B.  at temperatures from about -200C to about 0, or with any other oxidizing agent which is suitable for converting a thioin to a sulfoxide group. 

 

   In the 1-oxides of 3-cephem compounds of the formula I obtainable in this way, especially in those compounds in which R1a, Rlb and R2A have the preferred meanings given above, the groups Rla, RXb and / or R2A can be converted into one another within the framework set , split off or introduced.  A mixture of isomers a- and frl oxides can, for. B.  chromatographically, be separated. 



   The reduction of the 1-oxides of Ceph-3 -em compounds of the formula I 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 carrier material such as carbon or barium sulfate; reducing tin, iron, copper or manganese cations, which in the form of corresponding compounds or complexes of an inorganic or organic nature, e.g. B. 



  as tin (II) chloride, fluoride acetate or formate, iron (II) chloride, sulfate, oxalate or succinate, copper (II) chloride, benzoate or oxide, or manganese chloride, sulfate, acetate or oxide, or as complexes, e.g. B.     with ethylenediaminetetraacetic acid or nitrolotriacetic acid, can be used; reducing dithionite, iodine or iron (II) cyanide anions, which in the form of corresponding inorganic or organic salts, such as alkali metal, z. B. 

  Sodium or potassium dithionite, sodium or potassium iodide or -eines-Il- cyanide, or in the form of the corresponding acids, such as hydriodic acid, can be used; reducing trivalent inorganic or organic phosphorus compounds, such as phosphines, also esters, amides and halides of phosphinous, phosphonous or phosphorous acid, and phosphorus-sulfur compounds corresponding to these phosphorus-oxygen compounds, in which organic radicals are primarily aliphatic, aromatic or araliphatic radicals, e.g. B.  represent optionally substituted lower alkyl, phenyl or phenyl lower alkyl groups, such as. B. 

  Triphenylphosphine, tri-n-butylphosphine, methyl diphenylphosphinate, diphenylchlorophosphine, phenyldichlorophosphine, dimethyl benzene phosphonate, methyl butanephosphonate, triphenyl phosphate, trimethyl phosphate, phosphorus trichloride, phosphorus trichloride, etc. ; reducing halosilvanic 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 contain organic radicals such as aliphatic or aromatic groups, e.g. B.  may have optionally substituted lower alkyl or phenyl groups, such as chlorosilane, bromosilane, di- or trichlorosilane, di- or tribromosilane, diphenylchlorosilane, dimethylchlorosilane, etc. ;

   reducing quaternary chloromethylene iminium salts, in particular chlorides or bromides, in which the iminium group is substituted by one divalent or two monovalent organic radicals, such as optionally substituted lower alkylene or lower alkyl groups, such as N-chloromethylene-N, N-diethyi-iminiumchlo- rid 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. 



   As activating agents which are used together with those of the above-mentioned reducing agents which themselves do not have Lewis acid properties, i.e. H.  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 carboxylic and sulfonic acid halides, also sulfur, phosphorus or silicon halides with the same or greater second order hydrolysis constant than benzoyl chloride, e.g. B. 

  Phosgene, oxalyl chloride, acetic acid chloride or bromide, chloroacetic acid chloride; Pivalic acid chloride, 4-methoxybenzoyl, 4-Cyanbenzoesäurechlon-d, p-toluenesulfonyl chloride, methanesulfonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phenyldichlorophosphine, Benzolposphonigsäuredichlorid, dimethylchlorosilane or trichlorosilane, also suitable acid anhydrides, such as trifluoroacetic anhydride, or cyciische sultones, such Äthansulton, 1, 3-propane sultone, 1,4-butane sultone or 1,3-hexane sultone should be mentioned. 



   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. B.    Lower alkanecarboxylic acids or esters thereof, such as acetic acid and ethyl acetate, in the catalytic reduction, and z: B.  optionally substituted, such as halogenated or nitrated aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbons, e.g. B.  Benzene, methylene chloride, chloroform or nitromethane, suitable acid derivatives such as lower alkanecarboxylic acid esters or nitriles, e.g. B.  Ethyl acetate or acetonitrile, or amides of inorganic or organic acids, e.g. B. 

  Dimethylformamide or hexamethylphosphoramide, ethers, e.g. B.  Diethyl ether, tetrahydrofuran or dioxane, ketones, e.g.  Acetone, or sulfones, especially aliphatic sulfones, e.g. B.  Dimethyl sulfone or tetramethylene sulfone, etc. , together with the chemical reducing agents, these solvents preferably containing no water.  Usually, temperatures of about -20 ° C. to about 100 ° C. are used, and the reaction can be carried out at lower temperatures when using very reactive activating agents. 



   In the 3-cephem compounds of the formula I obtainable in this way, Rla, Rlb and / or R2A can, as described above, be converted into other groups Rla, Rlb or  R2A can be transferred, whereby it must be ensured that the 3-cephem compounds are significantly more sensitive to basic agents than the corresponding 2-cephem compounds. 



   Furthermore, 3-cephem compounds can be isomerized in a manner known per se to 2-cephem compounds, this reaction being effected by treatment with a base, preferably an organic base, such as a heterocyclic base, e.g. B.  Pyridine, and / or a tertiary amine such as a tri-lower alkylamine, e.g. B.  Triethylamine, and, if a free 3-cephem-4-carboxylic acid compound is used, additionally in the presence of a suitable acid derivative capable of forming a mixed anhydride group, such as a carboxylic acid anhydride such as lower alkanecarboxylic acid anhydride, e.g. B.  Acetic anhydride, can be carried out. 

  The desired 2-Ce phesu compound can be isolated in a manner known per se from an optionally obtained equilibrium mixture of the 2- and 3-cephem compounds. 



   Salts of compounds of the formula I can be prepared in a manner known per se.  So you can salts of compounds of formula I with acidic groups z. B.  by treating with metal compounds such as alkali metal salts of suitable carboxylic acid, e.g. B.     the sodium salt of a -ethyl'-caproic 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 formula I with basic groups are obtained in a customary manner, for. B.  by treatment with an acid or a suitable anion exchange reagent.  

  Internal salts of compounds of the formula I which contain a salt-forming amino group and a free carboxyl group can, for. B.  by neutralizing salts such as acid addition salts to the isoelectric point, e.g. B. 



  with weak bases, or by treating with liquid ones
Ion exchangers are formed.  Salts of 1 oxides of compounds of the formula I in which the double bond is in
3,4-position, with salt-forming groups can be prepared in an analogous manner. 



   Salts can be converted into the free compounds in the usual way, metal and ammonium salts z. B.   



  by treatment with suitable acids, and acid addition salts e.g. B.  by treating with a suitable basic agent. 



   Mixtures of isomers obtained can be separated into the individual isomers by methods known per se, mixtures of diastereomeric isomers, for. B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes.  Racemates obtained can be used in a customary manner, optionally after introducing suitable salt-forming groups, e.g. B.  by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds, or by fractional crystallization from optically active solvents into which 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 these, or the process is terminated at any stage; furthermore, starting materials can be used in the form of derivatives or formed during the reaction. 



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



   The inventive starting materials of the formula II can be, for. B.  can be prepared by adding the formula in a cephem compound
EMI16. 1
 wherein Rln is preferably an amino protecting group RtA, and wherein R2 is preferably hydroxy, but also represents a group R2A, the acetyloxymethyl group, z. B.     by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, converted into the hydroxymethyl group functionally modifies free carboxyl group of the formula -C (= O) -R2 in a suitable manner, e.g. B. 

  esterified by treatment with a diazo compound such as diphenyldiazomethane and the hydroxymethyl group, e.g. B.  by treating with a halogenating agent such as chlorinating agents, e.g. B.     Thionyl chloride, or iodizing agents such as N-methyl-N, N'-dicyclohexyl-carbodiimidium iodide, in a halomethyl z. B.     Chloromethyl resp.  Iodine converts methyl group.  A chloromethyl group is either directly, e.g. B.  by treating with a suitable chromium-II compound such as an inorganic or organic salt thereof, e.g. B. 

  Chromium (II) chloride or chromium (II) acetate, in a suitable solvent, such as dimethyl sulfoxide or then indirectly via the iodine ethyl group (which you can e.g. B.  by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted to the methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid. 

  The methylene group in a compound of the formula
EMI16. 2
 is oxidatively degraded using the process described below; in a thus obtainable cepham-3-one compound in which both radicals Rla and Rlb are hydrogen, the free amino group can be replaced by an appropriate protective group, e.g. B.  according to the procedure described above. 



   The oxidative splitting off of the methylene group in compounds of the formula VII with formation of an oxo group in the 3-position of the ring structure is preferably carried out with formation of an ozonide compound by treatment with ozone.  Ozone is preferably used in the presence of a solvent such as an alcohol, e.g. B.  a lower alkanol such as methanol or ethanol, a ketone, e.g. B.  a lower alkanone such as acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. B.  of a halogen. 



  lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, incl.  an aqueous mixture, as well as with cooling or gentle heating, e.g. B.  at temperatures from about -900C to about +40 "C.    



   An ozonide formed as an intermediate is split reductively, using catalytically activated hydrogen, e.g. B.     Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as a nickel or palladium catalyst, preferably on a suitable carrier material such as calcium carbonate or carbon, or chemical reducing agents such as reducing heavy metals, incl.  Heavy metal alloys or amalgams, e.g. B.     Zinc, in the presence of a hydrogen donor such as an acid, e.g. B.  Acetic acid, or an alcohol, e.g. B.  Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g. B.  Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g. B. 

  Acetic acid, or reducing organic compounds such as formic acid, a reducing sulfide compound such as a di-lower alkyl sulfide, e.g. B.     Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which can contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphines, e.g. B.     Tri-n-butylphosphine, or triarylphosphines, e.g. B.     Triphenylphosphine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds such as trimethyl phosphite, or phosphorous acid triamides,

   which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as Hexaniederalkylphosphigsäuretriamide, z. B.     Hexamethylphosphorigsäuretriamid, the latter preferably in the form of a methanol adduct, or tetracyanoethylene ver can use.  The cleavage of the ozonide, which is usually not isolated, normally takes place under the conditions that are used for its production, i.e. h in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating. 



   Depending on the nature of the oxidation reaction, a compound of the formula II or the corresponding 1-oxide or a mixture of the two compounds is obtained.  Such a mixture can be separated into the compound of the formula II and the corresponding l-oxide, or it can be oxidized to the uniform 1-oxide of a compound of the formula I. 



   A mixture of a compound of formula II with the corresponding 1-oxide can be prepared in a conventional manner, for. B.  by fractional crystallization or by chromatography (e.g. B.  Column chromatography, thin layer chromatography), into which the individual components are separated. 



   Furthermore, a mixture of a compound of the formula II and a 1-oxide thereof obtainable according to the process can also be oxidized directly to the 1-oxide of a compound of the formula II, the oxidizing agent described above being used for the preparation of l-oxide compounds. 



   In the inventive conversion of the starting materials of the formula II to the enol derivatives of the formula I of the present invention, the starting materials of the formula II do not need to be isolated after their preparation; they can preferably be converted directly into the compounds of the formula I in the form of the crude reaction mixture after preparation from the compounds of the formula VII. 



   The pharmacologically acceptable compounds of the present invention can e.g. B.  can be used for the production of pharmaceutical preparations which contain an effective amount of the active substance together or in a mixture with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral or, preferably, parenteral administration.  So you use tablets or gelatin capsules, which the active ingredient together with diluents, eg. B.  Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and lubricants, e.g. B.  Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binders, e.g. B. 

  Magnesium aluminum silicate, starches such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, Na triumcarboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g. B.     Starches, agar, alginic acid or a salt thereof, such as sodium alginate, and / or effervescent mixtures, or adsorbents, colorants, flavorings and sweeteners.  Preferably, the pharmacologically active compounds of the present invention are used in the form of injectable, e.g. B.  intravenously administrable preparations or from infusion solutions.  Such solutions are preferably isotonic aqueous solutions or suspensions, these e.g. B.  from lyophilized preparations which contain the active substance alone or together with a carrier material, e.g. B. 

  Mannitol, contained, can be prepared before use.  The pharmaceutical preparations can be sterilized and / or auxiliaries, e.g. B.    



  Contain preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers.  The present pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are made in a manner known per se, for. B.  by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes, and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilisates up to 100% of the active ingredient. 



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



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



   example 1
A solution of 0.050 g of 7-phenylacetylamino-cepham- -3-one-4 # -carboxylic acid diphenylmethyl ester and 0.020 g of l-methyl-3- (4-methylphenyl) -triazene in 5 ml of benzene is added for 2 hours Boiled under reflux.  After cooling, the mixture is evaporated under reduced pressure and the residue is purified by thin layer chromatography (silica gel; 1 × 20 cm; system: toluene / ethyl acetate 3: 1). 

  The zone (Rf # 0.18) visible under ultraviolet light (; 2 = 254 la) is eluted with acetone and 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, ultraviolet absorption spectrum (in ethanol) : #max = 264 IEL (n = 1300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 u, 5.63 IU, 5.83 R ", 5.94, 6.26 tu and 6168.    



   The starting material can be made as follows:
A solution of 0.50 g of 3-methylene-7p-phenylacetylamino-cepham-4α-carboxylic acid-diphenylmethyl ester in 100 ml of methanol is at -70 for 6.5 minutes with an oxygen-ozone stream containing 0.175 mmol / Min.  Ozone, treated.  The reaction mixture is mixed with 0.5 ml of dimethyl sulfide and stirred for one hour at 70 ° C., then for 2 hours at room temperature and evaporated to dryness.  The residue in methylene chloride is chromatographed on 15 g of silica gel.  The amorphous 7ss-phenylacetylamino-cepham-3-one is eluted with methylene chloride. 



     -4 # -carboxylic acid diphenylmethyl ester, thin-layer chromatography (silica gel): Rf # 0.47 (system: toluene / acetone / methanol / acetic acid 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95 a, 5.61; u 5.77, 5.85 y, 5.95 u, 6.21 i and 6.87; the compound shows a positive iron (III) chloride reaction, which suggests the presence of the enol form. 



   Example 2
A solution of 1.5 g of 3-methylene-7F-phenylacetylamino-cepham-4α-carboxylic acid p-nitrobenzyl ester in 300 ml of methylene chloride is treated with an oxygen-ozone mixture (0.26 mmol of ozone / Minute) and treated the reaction mixture with 1 ml of dimethyl sulfide.  The mixture is stirred for 30 minutes at 700 and for 2 hours at room temperature and then evaporated to dryness under reduced pressure.  The residue containing the 7ss-phenylacetylamino-cepham-3-one-4 # -carboxylic acid p-nitrobenzyl ester is taken up in 100 ml of benzene and triazene with an excess of 1-methyl-3- (4-methylphenyl) offset.  

  The mixture is stirred under reflux for 2 hours and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel.  The 3-methoxy-7frphenylacetylamino-3-cephem4-carboxylic acid -p-nitrobenzyl ester with Rf # 0.30 is eluted with toluene and increasing proportions of ethyl acetate (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): may = 260 mu (E = 13,000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 3.02 iu, 5.62 iu, 5.83, 5.93, 6.26 and 6.70, u-
Example 3
A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino-cepham-4x-carboxylic acid-2,2,2-trichloroethyl ester in 100 ml of methylene chloride is treated with an oxygen-ozone mixture at -70 for 8 minutes , 26 mmol ozone / minute) and treated the reaction mixture with 1 ml of dimethyl sulfide. 

  The mixture is stirred for 30 minutes at 70 and for 2 hours at room temperature and then evaporated to dryness under reduced pressure.  The residue containing the 7ss-phenylacetylamino-cepham-3-one-4 # -car- bonsäure-2,2,2-trichloroethyl ester is taken up in 100 ml of benzene and with an excess of 1-methyl-3- (4-methyl- phenyl) triazene added.  The mixture is stirred under reflux for 2 hours and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel. 

  The 3-methoxy-7p-phenylacetylamino-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester with Rf 0.32 is eluted with mixtures of toluene and increasing proportions of ethyl acetate (system: toluene / ethyl acetate 1: 1) ; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (# = 6340); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 3.02, 5.62, 5.83, 5.93, 6.26 and 6.70,
Example4
A solution of 15 g of 3-methylene-7ss- (D-α-tert. -butyloxy-carbonylamino-α-phenyl-acetylamino) -cephem-4α-carbon.    



  Diphenylmethyl acid ester in 1500 ml of methylene chloride is treated at 650 for 62 minutes with a mixture of oxygen and ozone containing 0.5 mmol of ozone per minute and then treated at 700 with 8.7 ml of dimethyl sulfide.  The mixture is stirred for 1 hour at 700 and for 2 hours at room temperature and evaporated under reduced pressure.  The residue containing the crude 7ss- (D-α-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino).    



     -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester, is dissolved in 350 ml of benzene and treated with 11 g of I-benzyl-3-8 (4-methylphenyl) -triazene, then refluxed for 4 hours.  After cooling, 100 ml of 2-n.  aqueous hydrochloric acid and washed with a saturated aqueous sodium chloride solution; the organic phase is dried over sodium sulfate and evaporated under reduced pressure. 

  The residue is chromatographed on 650 g of silica gel; with toluene containing 15% ethyl acetate the amorphous 3-benzyloxy-7ss- (D-α -tert), which is uniform according to thin layer chromatography. -butyloxycarbonylamino-α-phenyl-acetyiamino) -3-cephem-4-carboxylic acid phenymethyl ester eluted, thin-layer chromatogram (silica gel; development with iodine): Rf # 0.34 (system:

  Toluene / ethyl acetate 3: 1); [α] D20 = +7 + 1 (c = 0.97 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (# = 6800), and 264 (# = = 6800), and #Schlter = 280 m (± = 6300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.63, 5.88 and the like.     6.26 and 6.72.    



   Example 5
A solution of 0.5 g of 7ss- (D-? -Tert. -Butyioxycarbonylamino-phenyl-acetylamino) -3-methylene-cepham-4α-carboxylic acid p-nitrobenzyl ester in 100 ml of methylene chloride is treated for 4 minutes with an ozone-oxygen mixture containing 0.21 mmol of ozone in the minute, treated, then treated with 1 ml of dimethyl sulfide and then evaporated under reduced pressure.  The residue containing the 7ss- (D-α-tert. -Butyloxycarbonylamino- -α-phenylacetylamino) -cepham-3-one-4 # -carboxylic acid p-nitro-benzyl ester, is dissolved in 50 ml of benzene and 1-methyl-3- (4-methylphenyl) -triazene with an excess offset. 

  The mixture is stirred for 2 hours at reflux temperature and evaporated under reduced pressure and the residue is subjected to preparative layer chromatography (silica gel; system: toluene / ethyl acetate 1: 1; identification with ultraviolet light A, = 254).  This gives the 7ss- (D-α-tert. -Butyloxy-carbonylamino-phenyl-acetylamino) -3-methoxy-3-cephem--4-carboxylic acid p-nitrobenzyl ester with an Rf value of 0.35. 



   Example 6
A solution, cooled to 0, of 0.50 g of 7ss- (D-α-tert. -Butyloxycarbonylamino-ux -phenyl-acetylamino) -3-methylene-cepham-4c-carboxylic acid-2,2,2-trichloroethyl ester in 50 ml of methylene chloride is for 4 minutes with an ozone oxygen mixture containing 0.21 mmol of ozone per minute, treated, then treated with 0.5 ml of dimethyl sulfide and then evaporated under reduced pressure. 



  The residue containing the 7ss- (D-α-tert. -Butyloxycarbonylamino-α-phenylacetylamino) -cepham-3-one-4 # -carboxylic acid-2,2,2-trichloroethyl ester, is dissolved in 50 ml of benzene and treated with an excess of 1-methyl-3- (4 methylphenyl) triazene added.  It is evaporated under reduced pressure and the residue is subjected to preparative layer chromatography (silica gel; system: toluene / ethyl acetate 1: 1, identification with ultraviolet light A = 254). 

  The 7A- (D-5c-tert. -Butyloxycarbonylamino-5c-phenyl-acet amino) -3-methoxy-3-cephem-4-carboxylic acid-2,2,2-trichloro-ethyl ester with an Rf value of 0.40; UV spectrum (in 95% aqueous ethanol): #max = 257 (6000); IR spectrum (CH2Cl2): u. a.  Bands at 2.86; 5.62; 5.80; 5.85 and 6.26.    



   Example 7
Analogously to examples 1, 2 and 4, starting from corresponding cepham-3-one compounds by treatment with 1-methyl-3 - (- 4-methylphenyl) -triazene or  the corresponding ethyl, butyl or benzyl triazene the following compounds are obtained: 3 -n! -Butyloxy-7o-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, which after crystallization from a mixture of methylene chloride and diethyl ether in the form of colorless platelets melts at 168-1700, [α] D20 = +55 # 1 (c = 0.38 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): X, eax = 264 m (± = 7300);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.98, 5.62 u, 5.81, 5.92 pt, 6.25 la and 6.62.    



     
3-ethoxy-7p- (D-sc-tert. -butyloxycarbonylamino -; c-phenyl- acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, thin-layer chromatography (silica gel): Rf # 0.28 (system: toluene / ethyl acetate 3: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 ma (# = = 7000) and Man = 264 m (± = 6900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 Lt.     5.64 u, 5.90 u, 6.28 @ and 6.73.    



      3-n-Butyloxy-7ss- (D-α-tert. -butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester [X] D20 = + 110 # 10 (c = 0.98 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 264 m (± = 6100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.63, $ 5.84 (shoulder), 5.88, 6.26 and 6.71, 7p- [D-5c-tert. -Butyloxycarbonylamino -, - (4-hydroxy-phenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, thin-layer chromatogram (silica gel; identification with iodine): Rf # 0.35 (system :

  Toluene / ethyl acetate 1: 1); [α] D20 # -1 # 1 (c = 0.566 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol):) max = 276 mU (± = 7400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.83 u, 2.96, 5.64, 5.86 CL, 5.91 (shoulder), 6.23, 6.28, 6.65 and 6.72; 75- [D-cc-tert. -Butyloxycarbonylaminomx- (2-thienyl) -acetyl-mino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, thin-layer chromatogram (silica gel: identification with ultraviolet light A = 254 m); Rf ¯ 0.34 (system:

  Diethyl ether); [α] 20 D = +26 # 1 (c = 0.86 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol: #max = 240 mu (E = 12500) and 280 mu (E = 6000); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62, 5.85, 6.26, and 6.72, u;
7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; Melting point 1200C (from ether-IR spectrum (in CCHCCI-); 3310, 1775, 1700, 1690, 1600 cm- '. 



   7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester; Melting point 140.5-142 (from methylene chloride / ether) and from this by treating with hydrogen and palladium / carbon analogously to Example 8d) the 3-methoxy-7o-phenyloxyacetyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel ; System: n -butanol / acetic acid / water 75: 7.5: 21):

  Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66,
7ss-Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-2. 2,2-trichloroethyl ester; Thin-layer chromatogram (silica gel): Rf value 0.18 (toluene / ethyl acetate 3: 1); IR spectrum (in CHCl 3); 3310, 1775, 1700, 1690, 1600 cm-l, and from this by treatment with zinc and acetic acid analogous to Example 8c) the 3-methoxy-7ss-phenyloxyacetyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; System: n-butanol / acetic acid / water 75: 7.5: 21):

  Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 266 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66;
The compounds obtained according to Examples 1 to 7 can be further processed into the end products as follows:
Example 8 a) A mixture of 8.8 g of 3-methoxy-7ss- (D-α-tert. butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid are stirred for 15 minutes at 0, then 400 ml of pre-cooled toluene are added and reduced Pressure evaporated.  The residue is dried under high vacuum, digested with diethyl ether and filtered off. 

  The trifluoroacetate of 3-methoxy-7ss- (D-α-phenyl-glycylamino) -3- -cephem-4-carboxylic acid, which is dissolved in 20 ml of water, is thus obtained in powder form. 



   It is washed twice with 25 ml of ethyl acetate each time and the pH is adjusted with a 20% strength triethylamine solution
Methanol to about 5, a colorless precipitate forming.  The mixture is stirred in an ice bath for one hour and then added
Add 20 ml of acetone and leave to stand at about 4 for 16 hours.  The colorless precipitate is filtered off, washed with acetone and diethyl ether and reduced under reduced pressure
Print dried.  This gives the 3-methoxy-7- (D? A-phenyl-glycylamino) -3-cephem-4-carboxylic acid as an inner salt in the form of a microcrystalline powder, which is also contained in
In the form of a hydrate, F.  174-176 (with decomposition); [α] 20 D = + 149 (c = 1.03 in 0.1-n. 

  Hydrochloric acid); Thin-layer chromatogram (silica gel; developing with iodine): Rf ¯ 0.36 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30);
Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution):) ma.     = 267 (E = 6200); Infrared absorption spectrum (ini mineral oil): characteristic bands a. a.  at 5.72, 5.94, 6.23 11 and 6.60 ZL.    



   b) 256.3 g of 3-methoxy-7;, - (D a-tert. -butyl-oxycarbonylamino -, x-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester with a mixture of 250 ml of anisole in 1200 ml of methylene chloride and treated at 0 with 1200 ml of trifluoroacetic acid pre-cooled to 0.  The mixture is left to stand at 0 for 30 minutes and the reaction mixture is diluted over the course of 15 minutes with 12,000 ml of a 1: 1 mixture of diethyl ether and petroleum ether which has been cooled to 0. 

  The precipitated trifluoroacetic acid salt of 3-methoxy-7o- (D 5c-phenyl-glycylamino) -3-cephem4-carboxylic acid is filtered off, washed with diethyl ether, dried under reduced pressure and dissolved in 1900 ml of water.  The yellowish-colored impurities are removed by washing with 900 ml of ethyl acetate; the organic washing liquid is discarded and the aqueous solution (pH ¯ 1.5) is adjusted to pH 4.5 with a 20% solution of triethylamine in methanol. 

  The inner salt of 3-methoxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid crystallizes out as a dihydrate in the form of colorless prisms and is mixed with 1800 ml of acetone and 2- filtered off with stirring at 0 for hours, F.  175-177 (with decomposition); [α] D20 = +1380 # 10 (c = 1 in 0,1-n. 

  Hydrochloric acid); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): # max = 265 m (# = 6500); Infrared absorption spectrum (in mineral oil): bands at 2.72, 2.87, 3.14, 3.65, 5.68, 5.90, 6.18, 6.27, 6.37, 6.56, 6, 92, 7.16, 7.58, 7.74, 7.80, 8.12, 8.30, 8.43, 8.52, 8.65, 8.95, 9.36, 9.55, 9.70, 10. 02, 10.38, 10.77, 11.70, 12.01, 12.15, 12.48,, 12.60, "12.87 u, 13.45 and 14.30. 



      Microanalysis (C, 6H170, N3S, 2H2O;
Molecular weight: 399.42): calculated: C 48.11 8 5.30 N 10.52 S 8.03 found: C 47.86 H 5.27 N 10.47 S 8.00 c) 0.50 g 7ss - (D-α-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid-2,2,2-trichloroethyl ester dissolved in 25 ml of acetone: glacial acetic acid-water 1: 3: 1 for 1 hour at room temperature stirred with 2 g zinc dust.  The reaction mixture is filtered through Celite, washed with acetone and the filtrate is concentrated in vacuo.  The residue is taken up in ethyl acetate and extracted three times with water, the organic phase is dried over sodium sulfate and evaporated. 



  Chromatography of the crude product on 50 g of silica gel, which is deactivated by adding 5% water and eluting with CH 2 Cl 2 + 5% acetone, yields 0.34 g of 7ss- (D-? -Tert. -Butyl-oxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem-4-carboxylic acid, which is digested with ether to a colorless powder.  The product is identical to that obtained from the diphenyl methyl ester. 



   d) A solution of 250 mg of 7ss- (D-α-tert. -Butoxycarbonylamino-α-phenylacetylamino) -3-methoxy-3-cephem--4-carboxylic acid p-nitrobenzyl ester in 2 ml of a 1: 1 mixture of methanol and tetrahydrofuran is added to a suspension of 250 mg of prehydrogenated 5% strength Palladium / carbon catalyst given and hydrogenated at room temperature under normal pressure for 3 hours.  The catalyst is filtered off, washed with the same solvent mixture and the filtrate and washing liquid in vacuo a few.    

 

   steams.  The crude product obtained is dissolved in 10 ml of methylene chloride and the free acid is extracted twice with 10 ml of 5% strength aqueous sodium bicarbonate solution.  The bicarbonate extracts are neutralized at 0 with dilute hydrochloric acid and extracted three times with 10 ml of methylene chloride.  The organic phase is dried over sodium sulfate and the residue is triturated with diethyl ether.  The 7p- (D-IxStert. -Butyloxyvarbonylaminona-phenylacetylamino) -3- -methoxy-3-cephem-4-carboxylic acid, which is identical to the product obtained from the diphenylmethyl ester. 



   Example 9
A solution of 0.100 g of 7ss- (D-α-tert. -Butyloxycatrbonyl-amino-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester in 0.5 ml methylene chloride is mixed with 0.09 ml anisole and 0.100 ml trifluoroacetic acid and for 10 minutes at 0.     stirred and then diluted with 20 mol of a 1: 1 mixture of diethyl ether and pentane.  The fine precipitate is filtered off with a
Washed mixture of diethyl ether and pentane and dried under reduced pressure. 

  This gives the ma-tert.  -Butyloxycarbonylamino -x-phenyl-acetylamino) -3 - -methoxy-3-cephem-4-carboxylic acid in the form of a colorless powder, thin-layer chromatogram (silica gel; identification with iodine): Rf # 0.64 (system: n-butanol / acetic acid / Water 67:10:23); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 264 mu (± = 4100); In the infrared absorption spectrum (in methylene chloride): characteristic bands at 3.000, 5.64, 5.92, 6.25 and 6.72. 



   From the products obtained, the tert. -Butyloxycarbonyl group can be split off by treatment with anisole and trifluoroacetic acid according to Example 8. 



   Example 10
Analogously to Example 8, those obtained according to Example 7 can be used
Esters are saponified to the following free acids: a) A mixture of 0.06 g of 3-methoxy-7p-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is added for 5 ml Nuten left to stand at room temperature and then evaporated under reduced pressure.  The residue is taken to dryness twice together with a 1: 1 mixture of chloroform and toluene and chromatographed on 5 g of silica gel (containing about 5% water). 

  With methylene chloride containing 30-50% acetone the amorphous
3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid eluted and lyophilized from dioxane, ultraviolet absorption spectrum (in 95% strength aqueous ethanol): #max = 265 m (e = 5800); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03 @, 5.60, 5.74,
5.92, 6.24, and 6.67. 



   b) 3-n-Butyloxy-7ss-phenylacetylamino-3-cephem-4-car. 



   bonsäure, thin layer chromatogram: Rf = 0.75 (silica gel; ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11;
UV spectrum (ethanol): #max = 263 nm (# = 6400); IR spectrum (Nujol): characteristic bands at 2.95; 5.62;
5.81; 5.96; 6.24 ,.    



   c) A mixture of 2.70 g of 3-ethoxy-7ss- (D-α-tert. -butthloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 6.7 ml of anisole and 67 ml
Formic acid is used for one hour at room temperature.    



   ture stirred, diluted with 200 ml of toluene, then evaporated under reduced pressure and the residue under
Dried under high vacuum, digested with diethyl ether and filtered off.  The formate obtained as a brownish powder
3-ethoxy-7r, 3- (D-. os-phenyl-glycylamino) -3-cephem-4-carboxylic acid is dissolved in 8 ml of water, the aqueous phase is mixed with 2-n.  aqueous hydrochloric acid acidified with
10 ml of ethyl acetate washed with a 10%
Solution of triethylamine in methanol adjusted to a pH of about 5 and is evaporated under reduced pressure. 

  The residue is taken up in a small amount of methanol and the amorphous pale yellow 3-ethoxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid is precipitated as an inner salt by adding methylene chloride and diethyl ether Thin-layer chromatogram (silica gel): Rf # 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): # = 263 m, a (± = 5500).    



     d) A mixture of 0.5 g of 3-n-butyloxy-78- (D. cc-tert. -butyloxycarbonylamino-α-phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 1 ml of anisole and 15 ml of trifluoroacetic acid are left to stand for 15 minutes at 0, then diluted with 200 ml of cold toluene and under reduced pressure evaporated.  The residue is stirred with diethyl ether and the pulverulent, colorless residue is filtered off, washed with diethyl ether and dried under high vacuum.  The trifluoroacetate salt of 3-n-butyloxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid is thus obtained, which is dissolved in 5 ml of water. 

  The solution is washed twice with 10 ml of ethyl acetate each time and the pH of the aqueous phase is adjusted to 5.0 by adding a solution of triethylamine in methanol.  The solution is then evaporated under reduced pressure; the residue is taken up in a small amount of acetone and diluted with diethyl ether until it becomes cloudy. 

  The 3-n -butyloxy-7p- (D-phenylglycylamino) -3-cephem-4-carboxylic acid present in the form of the inner salt is obtained as a crystalline precipitate and filtered off, F.  141-142; Thin layer chromatogram (silica gel): Rf # 0.21 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): #max = 267 ma (s = 7300).    



   e) A mixture of 4.6 g of 3-bemyloxy-7P- (D-s-tert. -butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid, 250 ml of pre-cooled toluene, evaporated under reduced pressure, and the residue dried under high vacuum.  The product is stirred with diethyl ether and the powdery trifluoroacetate of 3-benzyloxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid is obtained, which is filtered off and in a 9: 1 mixture of Water and methanol is dissolved.  The pH is 2-n.  aqueous hydrochloric acid adjusted to 1.7; it is washed twice with 30 ml of ethyl acetate each time (the organic washing solutions are discarded), and the pH of the aqueous phase is adjusted to 5 by adding a 10% solution of triethylamine in methanol. 

  It is evaporated under reduced pressure, the residue is stirred with a mixture of acetone and diethyl ether, the powdery product is filtered off and washed with acetone and diethyl ether.  3-Benzyloxy-7- (Dz- -phenyl-glycylamino) -3-cephem-4-carboxylic acid is thus obtained in zwitterionic form, thin-layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): #max = 266 ma (± = 6500). 

 

   f) A mixture of 0.095 g of 7ss- [D-α-tert. -butyloxycarbonylamino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy--3 cephem-4-carboxylic acid diphenylmethyl ester, 0.25 ml of anisole and 5 ml of pre-cooled trifluoroacetic acid are added during
Stirred for 15 minutes at 0, then mixed with 50 ml of cold toluene and evaporated under reduced pressure.  The residue is stirred with diethyl ether and the powdery precipitate is filtered off and dried.  The salt of 7ss- [D-α-amino-α- (4-hydrocy-phenyl) -acetyl-amino] -3-methoxy-3-cephem-4-carboxylic acid with trifluoroacetic acid is dissolved in about 5 ml of water dissolved, the pH of the solution is adjusted by adding 2-n. 

  Hydrochloric acid is set to 1.5, and the aqueous solution is washed with 20 ml of ethyl acetate and its pH is adjusted to 5.0 by dropwise addition of a 20% strength solution of triethylamine in methanol, a colorless precipitate being formed .  It is diluted with 8 ml of acetone and the mixture is left to stand at 0 for 16 hours. 

  The precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. This gives the - [Da-Aminu-i- (4-hydroxy-pheIyl) -ace-methoxy -3-cephem-4-carboxylic acid in the form of the inner salt, F = 1800 (with decomposition); Thin-layer chromatogram (silica gel; identification with iodine): Rf N 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: #max = 228 m (± = 12000) and 271 m (E = 6800) in 0; 1-n. 

  Hydrochloric acid, and lmax = 227 (E = 10500) and shoulder = 262 mlu (E = 8000) in 0.1-n. 



  aqueous sodium hydrogen carbonate solution.    



   g) 3-methoxy-7ss- (2-thienyl) acetylamino-3-cephem-4-carboxylic acid, melting point 164-165 ° C. (from ethyl acetate / diethyl ether); Thin-layer chromatogram (silica gel. ; System: n-butanol / pyridine / acetic acid / water 38:24: 8:30): Rf = 0.5-0.6; Ultraviolet absorption spectrum (in 95% aqueous ethanol): lmax at 235 and 264 h) 3-methoxy-7ss-phenyloxyacetyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75 : 7.5: 21): Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Man = 266 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66. 



   The starting materials to be used in Examples 1 to 7 can be prepared as follows. 



   Example 11 a) A solution of 11.82 g of the crude sodium salt of 3-hydrocymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid (prepared by enzymatic deacetylation of the sodium salt of 3-acetyloxymethyl-7p-phenyiacetyl amino-3-cephem- 4-carboxylic acid with the help of a purified enzyme extract from Bacillus subtilis, strain ATCC 6633, and subsequent lyophilization of the reaction solution) in 200 ml of water is covered with 400 ml of ethyl acetate and acidified to a pH of 2 with concentrated aqueous phosphoric acid.  The aqueous phase is separated off and extracted twice with 150 ml of ethyl acetate each time.  The combined organic extracts are washed four times with 50 ml of water each time and dried over magnesium sulfate, then concentrated to about 400 ml. 



  The solution is mixed with excess diphenyldiazomethane, left to stand for 3 hours at room temperature and then the granular crystalline precipitate is filtered off.  The filtrate is concentrated to about 200 ml, cyclohexane is added while warm and, after cooling to room temperature, left to stand at about 4 for some time. 

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7P-phenylacetylamino-3 - -cephem-4-carboxylic acid diphenylmethyl ester obtained in this way melts at 176-176.5 (uncorr. ); 11.20 = 60 t 1 (c = 1.231% in chloroform); Thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light l 254 Rf = 0.42 (system: chloroform / acetone 4: 1), Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (System: methylene chloride / acetone 6: 1). 



   Dissolve 1.03 g of 3-hydroxymethyl-78-phenylacetylamino--3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N -methyl-N, N'-dicyclohexylcarbodiimidium iodide under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for a Hour at 35.     Another 1.05 g of N-methyl-N, N'-dicyclohexylcarbondiimidium iodide in 15 ml of absolute tetrahydrofuran are then added and the mixture is left to stand for 17 hours at room temperature under a nitrogen atmosphere.  The reaction mixture is freed from solvent on a rotary evaporator under reduced pressure.  The residue is taken up in methylene chloride and filtered through a column of 50 g of silica gel (addition of 10% distilled water); it is washed with 4 portions of 100 ml of methylene chloride each time. 

  The eluate is concentrated to a small volume and chromatographed on a silica gel column (90 g; deactivated by adding 10% distilled water).  With a total of 900 ml of a 3: 7 mixture of toluene and methylene chloride, non-polar impurities are eluted.  Elution with 2 portions of 200 ml of methylene chloride each gives the 3-iodomethyl-7, B- -phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester; the fractions which are uniform according to thin-layer chromatography are lyophilized from benzene, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.62 y, 5.82, 5.95, 6.70: \ L 7.32 lu and 8.16 p.    



   The iodination reagent used above can be prepared as follows:
In a 250 ml round-bottom flask with a magnetic stirrer, reflux condenser and attached nitrogen balloon, 42 g of freshly distilled N, N'-dicyclohexylcarbodiimld are dissolved in 90 ml of methyl iodide under a nitrogen atmosphere at room temperature and the colorless reaction mixture is stirred for 72 hours at a bath temperature of 70. 



  After the reaction time has elapsed, the excess methyl iodide is distilled off from the now red-brown solution under reduced pressure and the viscous, red-brown residue is dissolved in 150 ml of absolute toluene at 40 °.  The crystal mass which spontaneously crystallizes out within a few hours is separated from the mother liquor with the aid of a glass suction filter with an attached stick material balloon under exclusion of air, the reaction vessel is rinsed three times with 25 ml of absolute, ice-cold toluene each time and the same toluene is used to make the slightly yellowish crystal mass on the glass suction filter colorless to wash. 

  After drying at 0.1 mm Hg for 20 hours.  and room temperature the N-methyl -N, N'-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals, F.  111-113; Infrared absorption spectrum (in chloroform): characteristic bands at 4.72 p and 6.00, {. .    



   A solution of 0.400 g of 3-iodomethyl-7p-phenylacetyl-amino-3-cephem-4-carboxylic acid diphenylmethyl ester in 15 ml of 90% aqueous acetic acid is cooled to 0 in an ice bath and 2.0 g of zinc dust are added in portions while stirring well .  After a reaction time of 30 minutes at 0, the unreacted zinc dust is filtered off using a suction filter with a diatomaceous earth pad; the filter residue is suspended several times in fresh methylene chloride and filtered again.  The combined filtrates are concentrated under reduced pressure, treated with absolute toluene and evaporated to dryness under reduced pressure.  

  The residue is taken up with stirring in 50 ml of methylene chloride and 30 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution; the aqueous phase is separated off, extracted with two portions of 30 ml of methylene chloride each time and discarded.  The organic extracts are washed several times with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure.  The residue is chromatographed on a column of 22 g of silica gel (addition of 10% water).  The 3-methylene-7e, 3-phenylacetylamino-cephamAx-carboxylic acid diphenylmethyl ester is eluted with methylene chloride and methylene chloride containing 2% methyl acetate and crystallized from a mixture of methylene chloride and hexane, F. 



   144j-147; [α] 20 D = -18 # 1 (c = 0.715 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): max = 254 m (# = 1540) and 260 m (± = 1550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.65 u, 5.74 R ", 5.94, 6.26 and 6.67. 



   A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino. 



     -cepham-4α-carboxylic acid diphenylmethyl ester in 250 ml of methylene chloride is treated at -70 for 8/2 minutes with an oxygen-ozone mixture (0.265 mmol of ozone / minute) and the reaction mixture is treated with 1 ml of dimethyl sulfide.  The mixture is stirred for 30 minutes at 700 and for 1½ hours at room temperature and then evaporated to dryness under reduced pressure.  The residue, containing a mixture of 7ss-phenylacetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester and 7ss-phenyl acetylamino-cepham-3-one-4i-carboxylic acid diphenylmethyl ester-1-oxide, can be chromatographed be separated. 



   b) The 7ss- (D-α-phenyl-glycyl-amino) -cepham-3-one-4-carboxylic acid diphenylmethyl ester can be prepared in an analogous manner by using 3-acetyloxymethyl-7p- (Dtx-tert. -butyloxycarbonylamino-, K-phenylacetyl-amino) -3 - -cephem-4-carboxylic acid enzymatically cleaves the acetyioxymethyl group, the thus obtainable 3-hydroxymethyl-7, - (D- -a-tert. 

   -butyloxycarbonylamino-lx-phenylacetyl-amino) -3-cephem-4-carboxylic acid esterified with diphenyldiazomethane and in the 3-hydroxymethyl group of 3-hydroxymethyl-71p- (D- -z-tert.     -butyloxycarbonylamino-a-phenyiacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester replaced the hydroxyl group by treatment with N-methyl-N, N'-dicyclohexyl-carbodi-imidium iodide;

   the 3-iodomethyl group in 3-iodomethyl-7U, - (D-Ix-tert. -butyloxycarbonylamino-x-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid-diphenylmethyl ester is reductive, e.g. B.  converted to the methylene group by treatment with zinc in the presence of 90% aqueous acetic acid, and the 3-methylene-7ss- (D-α-tert. -butyloxy-carbonylamino-, a-phenylacetyl-amino) -cepham-4x-carboxylic acid-diphenylmethyl ester is added to the mixture of the 7ss- (D-α -tert) by treatment with ozone, followed by dimethyl sulfide. - -Butyloxycarbonylamino-, x-phenylacetyl-amino) -cepham-3- -one-4 # -carboxylic acid diphenylmethyl ester and the l-oxide thereof converted as follows:

  :
In a solution, cooled to -70, of 5.0 g of 3-methylene x74B- (D- x-tert. -butyloxyzarbonylamino-a-phenylacetylamino) -cepham-4α-carboxylic acid-diphenylmethyl ester in 500 ml of methylene chloride, with vigorous stirring for 1 hour, an oxygen-ozone stream containing 0.21 mmol of ozone /
Min.  initiated.  After another 10 min.  3 ml of dimethyl sulfide are added to the reaction mixture, the mixture is stirred for one hour at 65o and for 2 hours at room temperature and then evaporated under reduced pressure.  The
Crude product contains the 7- (D? A-tert. -Butyloxycarbonylamino-α-phenylacetyl-amino) -cepham-3-one-4 # -carboxylic acid-diphenylmethyl ester. 



   The raw material used for ozonization can also be produced as follows:
A chromatography column (diameter: 3 cm) is filled with 350 g of zinc grit, for 10 minutes with a
0.1 molar solution of mercury (II) chloride in 0.1 n.  Hydrochloric acid amalgamated and treated with plenty of water and finally with a small amount of l-n.     Washed hydrochloric acid.  A solution of 55 g of green chromium III chloride hexahydrate in 55 ml
Water and 11 ml 2-n.  Sulfuric acid is poured into the reduction tube and the flow rate is regulated so that a pure blue chromium chloride solution drips into the reaction vessel, which is kept under a nitrogen atmosphere. 

  The blue chromium (II) chloride solution is then mixed with a solution of 92 g of sodium acetate in 180 ml of air-free water, the solution turning red and finely crystalline chromium (II) acetate to precipitate acetate washed twice with 250 ml of air-free water each time.  A solution of 10.0 g of 3-acetyloxymethyl-7ss- (D-? -Tert) is added to the moist chromium (II) acetate. -butyloxy.    



  carbonyl-amino -, a-phenylacetyl-amino) -3-cephem-4-carboxylic acid in 200 ml of dimethyl sulfoxide, and the reaction mixture stirred for 15 hours under a nitrogen atmosphere at room temperature.  For working up, the reaction mixture is aerated for 30 minutes and, after the addition of 1000 g of a polystyrene sulfonic acid ion exchanger in the NaG form (Dowex 50 W) and 1000 ml of water, stirred for one hour.  After removing the ion exchanger, the pH of the solution is 6-n.  Hydrochloric acid adjusted to 2 and the aqueous phase extracted three times with 2000 ml of ethyl acetate each time. 

  The organic extracts are washed once with 1000 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. 



   The crude product obtained is dissolved in 100 ml of methanol and stirred with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene for 1 hour at room temperature. 



  The crude product obtained after evaporation is chromatographed on 500 g of silica gel; the 3-methylene-7ss- (D-α-tert. -butyloxycarbonylamino-a-phenylacetyl-amino) -cepham -4α-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of petroleum ether; after crystallization from a mixture of methylene dichloride and hexane, the product melts at 156-158; [α] D = -50 + 1 (c = 0.713, chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (# = 990>;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94,, 5.64, 5.74, 5.88 y (shoulder) and 6.71. 



   Similarly, the 7, - (D-, oc-tert. Butyloxycarbonyl-amino-z-phenylacetylamino) -cepham-3-one-4-carboxylic acid p- -nitrobenzyl ester and the 7ss- (D-? -Tert. -Butyloxycarbonyl-amino-α-phenylacetylamino) -cephem-3-one-4-carboxylic acid trichloroethyl ester. 



   c) A solution, cooled to 150, of 2.0 g of 3-methylene-7j3-phenylacetylamino-cepham-4x-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8% strength Solution of phosphorus pentachloride in methylene chloride and stirred for one hour under a nitrogen atmosphere at a temperature between 100 and -5.  The reaction mixture is then cooled to 250, mixed with 25 ml of absolute methanol and stirred for one hour at 100, then for 1.5 hours at room temperature. 



  80 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate are then added, the pH is adjusted to 2 with 20% aqueous phosphoric acid and the mixture is stirred at room temperature for 30 minutes. 



   The organic phase is separated off; the aqueous phase is extracted twice with 150 ml of methylene chloride each time and the organic solutions are combined, dried over sodium sulfate and evaporated.  The oily residue is taken up in 25 ml of ethyl acetate and a solution of 1.14 g of 4-methylphenylsulphonic acid monohydrate in 25 ml of ethyl acetate is added at 0 °.  It turns out a voluminous precipitate, which is filtered off with cold
Ethyl acetate and diethyl ether washed, dried and made from a mixture of methylene chloride and
Diethyl ether is recrystallized.  

  The 4-methylphenylsulfonate of -amino-3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester is obtained in this way in the form of colorless needles, F.  153-1550; [c = -14 ¯ 1 (c = 0.97 in methanol); Ultraviolet Absorption Spectrum (in ethanol): #max = 257 2L (= 1500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.5, 5, 60,, 8.50, 9.86 and 9.92. 



   A stream of oxygen and ozone (containing 0.35 mmol of ozone) is passed through a solution, cooled to 600, of 0.553 g of the 4-methylphenylsulfonate of 7p-amino-3-methylen-cepham--4α-carboxylic acid diphenylmethyl ester in 50 ml of methanol per minute).  After a further 5 minutes, 0.3 ml of dimethyl sulfide is added to the pale blue solution.  The mixture is stirred for 15 minutes at -70, for one hour at 120 and for one hour in an ice bath, then evaporated.  The residue is taken up in a small amount of methylene chloride, then diethyl ether is added until it becomes cloudy and the mixture is left to stand. 

  The microcrystalline, reddish colored powdery precipitate is filtered off and gives the 4-methylphenylsulfonate of 7,, 3-amino-cepham- -3-one - $ # - diphenylmethyl carboxylate, which is mainly in the enol form as 4-methylphenylsulfonate of 7p-amino - -3-cephem-3-ol-4-carboxylic acid diphenylmethyl ester is present, F = 143-145 (with decomposition); Thin layer chromatogram (silica gel) Rf ¯ 0.28 (system:

  Ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in ethanol): #max = 262 mU (= 3050) and 282 mu (E = 3020); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58, 5.77 (shoulder), 6.02 and 6.22. 



   A solution of 2.17 g (4.16 mM) of 4-methylsulfonate of 7f3-amino-cepham-3-one-4-carboxylic acid diphenylmethyl ester in 25 ml of methylene chloride is mixed with 1.04 ml (4.16 mM) of bis-trimethylsilyl -acetamide is added and the mixture is stirred at room temperature for 45 minutes under a nitrogen atmosphere (solution A). 



   A mixture of 1.50 g of D-α-tert. -Butylcarbonylamino- -x- (2-thienYl) acetic acid and 24 ml of methylene chloride are added at -20 C with 0.65 ml of N-methylmorpholine and 0.80 ml of isobutyl chloroformate and the solution at -200C for 45 minutes under a Stirred in a nitrogen atmosphere (solution B). 



   Solution A is cooled to -200C and solution B is added.  The combined solutions are stirred at 0 ° C. for 2¸ hours.  The reaction mixture is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on 70 g of silica gel with toluene / ethyl acetate 4: 1 and gives the -tert. -Butyloxycarbonylamino-, x- (2-thienyl) -acetylamino] -3-hydroxy-3-cephem-4, -carboxylic acid diphenylmethyl ester; Rf = 0.35 (silica gel; ethyl acetate); IR spectrum (chloroform): bands at 3380; 1780; 1690; 1610; 1590; 1470 cm-l. 



   d) Analogously to c), the following compounds can be obtained:
7p- [D-, x-tert. -ButyloxyzarbonylaminoSx- (4-hydroxyphenyl) -acetylamino] -cepham-3-one-4i-carboxylic acid diphenylmethyl ester;
7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-thienyl) -acetyl-amino] -cepham-3-one-4-carboxylic acid diphenylmethyl ester; 7i-phenoxyacetamido-cepham-3-one-4-carboxylic acid diphenylmethyl ester. 



   Example 12
In an analogous manner, the following compounds can be obtained using the suitable starting materials, optionally after additional conversions of a product obtained:
7ss- [D-α-tert. -Butyloxycarbonylamino-α (-4-isothiazolyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenyl-methyl ester, amorphous, [a1.20 = +26 # 1 (c = 0.65 in chloroform ); Thin-layer chromatogram (silica gel; identification with iodine): Rf ¯ 0.43 (system toluene / acetic acid. 



  ethyl ester 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): l, max = 250 m (± = 12200) and 280 mU (± = 5900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 lu, 5.65, 5.71 (shoulder), 5.88, 6.28 and 6.73; 3-methoxy-7ss-methoxycarbonylacetyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: ethyl acetate / acetic acid 9: 1): Rf = 0.5-0.6;

  Ultraviolet Absorption Spectrum (in methanol): #max at 265 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66 u; 7ss-bromocetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21): Rf = 0.25-0.35; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmas at 264 7ss - (α-carboxy-α-phenyl-acetylamino) -3-methoxy-3-cephem--4-carboxylic acid, thin layer chromatogram (silica gel; system: n -Butanol / pyridine / acetic acid / water 40: 24: 6: 30): 73-acetoacetylamino-3-methoxy-3 -cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 5: 21):

  Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 238 m and 265 m; 7ss-cyanoacetylamino-3-methoxy-3-cephem-4-carboxylic acid, melting point 150 - 155 C (from acetone / ethyl acetate / diethyl ether), thin-layer chromatogram (silica gel; system: n -butanol / pyridine / acetic acid / water 38:24: 8:30):

  Rf = 0.35-0.45; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 265 m (± = 5500); Infrared absorption spectrum (in mineral oil): characteristic bands at 3300, 2255, 1790, 1758, 1740, 1688, 1660 cm-1; [α] D = +180 (c = 1.055; methanol); 7ss - (α-cyano-propionylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n -butanol / pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.4-0.5; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 265 ma; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 and 5.66 7ss - (α-cyano-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21) Rf = 0.3-0.4; Ultraviolet absorption spectrum (in 95% aqueous ethanol): one at 267 mx; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.42 and 5.65; 7ss- (2-chloroethylamino-carbonylamino) -3-methoxy-3-cephem -4-carboxylic acid, thin-layer chromatogram (silica gel):

  Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75: 7.5: 21); Ultraviolet absorption spectrum (in ob 1 molar hydrochloric acid): #max at 266 m; 7ss-dichloroacetylamino-3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21): Rf = 0.40; Ultraviolet absorption spectrum (in 95% aqueous ethanol): lm3x at 264 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.67; 3-methoxy-7,3- (cc-sulfo, x-phenyl-acetylamino) -3-cephem-4- -carboxylic acid in the form of the disodium salt, thin-layer chromatogram (silica gel):

  Rf ¯ 0.10-0.20 (system: n -butanol / acetic acid / water 67:10:23); 3-methoxy-7ss - (α-phenylaminocarbonyl-acetylamino-3-methoxy-3-cephem4carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 67:10:23): Rf = 0.30; Ultraviolet absorption spectrum (in ethanol): #max at 241 m and 266 m; infrared absorption spectrum (in mineral oil): characteristic band at 5.56; 3-methoxy-79-methoxyacetylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: Ethyl acetate / pyridine / acetic acid / water 60: 20: 6: 11):

  Rf = 0.30; Ultraviolet absorption spectrum (in mineral oil): characteristic band at 5.64; 3-Methoxy-7ss - (, a-4-methylphenylthio-acetylarnino) -3 -cephem -4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 67:10:23):

  Rf = 0.45;
Ultraviolet absorption spectrum (in ethanol): max at 264 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.63;
7; -Benzoylacetylamino-3-methoxy-3-cephem-4-carboxylic acid,
Thin-layer chromatogram (silica gel; system: n-butanol / pyridtine / acetic acid / water 38: 24: 8: 30): Rf = 0.40; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 267 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66 ;;
7ss- (3-chloropropionylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21): Rf = 0.30;

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 265 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65; 7ss-chloroacetylamino-3-methoxy-3-cephem-4-carboxylic acid,
Thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30): Rf = 0.50; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max at 266 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65 |
7ss- (3-butenoyl-amino) -3-methoxy-4-cephem-4-carboxylic acid, thin layer chromatogram (silica gel; system: n-butanol /
Pyridine / acetic acid / water 38: 24: 8: 30):

  Rf = 0.65; 3ss-Methoxy-7ss - (α-methylthio-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30):
Rf = 0.60; Ultraviolet absorption spectrum (in 95% aqueous ethanol): i. max at 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.7; 7ss- (bis-methoxycarbonyl-acetylamino) -3-methoxy-3-cephem-
4-carboxylic acid, thin layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 38: 24: 8:30): Rf = 0.45;

  Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 268 m; Infrared absorption spectrum (in mineral oil): characteristic
Band at 5.64;
7ss-dibromoacetylamino-3-methoxy-3-cephem-4-carboxylic acid,
Thin-layer chromatogram (silica gel; system: n-butanol / acetic acid / water 75: 7.5: 21): Rf = 0.3 to 0.4; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 264 m; Infrared absorption spectrum (in mineral oil): characteristic band at
5.63,
3-Methoxy-7ss-pivalylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel):

  Rf # 0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max # 265 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66;
7ss - (α-Azido-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf - 0.4 - 0.5 (system: n-butanol / phridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max # 267 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.66, and 5.65 "u; 7ss - (α-O-O'-dimethyl-phosphono-α-phenyl-acetylamino) -3-methoxy-3- cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf # 0.4 (system: n-butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 95% ethanol): #max 3 266 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.66; u; 3-Methoxy-7ss- (5-methyl-3-phenyl-4-isoxazolyl-carbonylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel):

  Rf 0.3-0.4 (system: n-butanol / acetic acid / water 67:10:23); Infrared absorption spectrum (in mineral oil): characteristic band at 5.65 u 7ss- (4-aminomethylphenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf # 0.25-0.3 (System: n-butanol / acetic acid / water 67:10:23); Ultraviolet Absorption Spectrum (in 0.1 N hydrochloric acid): #max # 265 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.68; 7ss- (2,6-dimethoxy-benzoylamino) -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel):

  Rf - 0.50 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 265 ma; Infrared absorption spectrum (in mineral oil): characteristic band at 5.64; 7ss- [D-aα-tert. -Butyloxycarbonylamino-α- (3-thienyl) -acetyl-amino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester; Thin-layer chromatogram (silica gel): Rf # 0.3-0.4 (system:

  Diethyl ether); Ultraviolet absorption spectrum (in 95% aqueous ethanol): max = 238 m and 276 7ss- [D? -Amino-? (3-thienyl) acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf ¯ 0.2-0.3 (system: n-butanol / acetic acid / water 67:10:23 ); Ultraviolet absorption spectrum (in 0, l-n.     Hydrochloric acid): #max = 235 m and 270 7o- [D - tert. -Butyloxycarbonylarnino-lx- (2-furyl) -acetylamino] -3-methoxy-3-cephem 4-carboxylic acid diphenylmethyl ester; Thin-layer chromatogram (silica gel):

  Rf ¯ 0.35 (system: diethyl ether); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max ¯ 265 m; 7ss- [D-α-amino-α- (2-furyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid, thin layer chromatogram (silica gel): Rf ¯ 0.25 (system: n -Butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1 N hydrochloric acid): #max ¯ 265 m; 7ss- (D-α-hydroxy-α-phenyl-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, melting point 157 - 160 C (ethyl acetate / diethyl ether), thin-layer chromatogram (silica gel):

  Rf
0.35 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 95% aqueous ethanol):) max # 265 m (E = 6300); Infrared absorption spectrum (in mineral oil): characteristic bands at 3380, 1790, 1725, 1650, 1602, 1535 cm-l [α] D = +48 # 1 (c = 1.078; dioxane): 7ss- (1-amino-cyclohexyl carbonylamino) -3-methoxy-3-ce. 

 

  phem-4-carboxylic acid, as inner salt in amorphous form, thin-layer chromatogram (silica gel): Rf ¯ 0.2-0.25 (system: n-3utanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1-n.     Hydrochloric acid): man ¯ 264 mu; Infrared absorption spectrum (in mineral oil): characteristic band at 5.56; 3-methoxy-7ss- (4-pyridylthio-acetylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0, 25-0.30; Infrared absorption spectrum (in mineral oil): characteristic band at 5.65; 7ss - (α-4-Amino-pyridinium-acetylamino) -3-methoxy-3-cephem-4-carboxylic acid, as inner salt in amorphous form, thin layer chromatogram (silica gel):

  Rf = 0.20-0.3 (system: n-butanol / pyridine / acetic acid / water 42:24:30); Infrared absorption spectrum (in mineral oil): characteristic band at 5.65 t 3-methoxy-7ss- (1-tetrazoly-acetylamino) -3-cephem-4-carboxylic acid, melting point 142-1450C (from acetone / diethyl ether); Thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4:30): Rf = 0.35-0.45;
UV spectrum (alcohol): lmax = 264 rnx (± = 5800); IR spectrum (Nujol): bands at 3280, 1780, 1725, 1675, 1625, 1570, 845 cm-1; 3-Methoxy-7ss- (1-methyl-2-imidazolylthio-acetylamino) -3 -cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system; n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.3-0.4; Infrared absorption spectrum (in mineral oil):

  characteristic band at 5.66 u; 3-methoxy-7ss- (1,2,4-trazol-3-ylthio-acetylamino) -3-cephem -4carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30 ): Rf = 0.3-0.4; and 7p * azidoacetylamino -3-methoxy-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel; system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30): Rf = 0.40; Ultraviolet absorption spectrum (in ethanol): #max at 264 Infrared absorption spectrum (in mineral oil): characteristic bands at 4.65 v and 564 u.    



   The 3-cephem-3-ol compounds used in the alkylations in the above examples can also be alkylated according to the two following examples:
Example 13
A solution of 0.61 g of the crude 7ss- (D-α -tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) - -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester in 30 ml of absolute methylene chloride is mixed with 0.12 ml of diisopropylethylamine and 0.192 g of trimethyloxonium tetrafluoroborate and for 30 Stirred at -10 minutes under a nitrogen atmosphere; the oxonium salt gradually dissolves in the process. 

  The reaction mixture is poured onto a mixture of ice and a saturated aqueous sodium chloride solution; the aqueous mixture is extracted twice with 100 ml of methylene chloride each time and the organic phase is separated off, dried over sodium sulfate and evaporated under reduced pressure.  The residue is purified by means of preparative layer chromatography (silica gel; system: diethyl ether). 

  The zone which is visible under ultraviolet light () = 254 mL) and which is uniform by thin layer chromatography is isolated and stirred with 20 ml of diethyl ether; after stirring for 16 hours, the 7r- (D-5c-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -3-methoxy -3 -cephem-4-carboxylic acid-diphenylmethyl ester in finely crystalline form.  F 118-120.    

 

   Example 14
A solution of 0.100 g of the crude 7P- (D-sc-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -cepham-3-one-4 # - -carboxylic acid diphenylmethyl ester in 5 ml of nitromethane is mixed with 0.03 ml of diisopropylethylamine and a solution of 0.036 g of trimethyloxonium tetrafluoroborate in 0.5 ml of nitromethane and the mixture was stirred for 30 minutes under a nitrogen atmosphere and at -10.  The reaction mixture is worked up according to the method described in Example 28 and the crude product is purified by means of preparative layer chromatography.  This gives the 7g- (D-c-tert. - Butyloxycarbonylamino - phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, F.    118 - 1200.     

 

Claims (1)

PATENT CLAIM Process for the preparation of enol ethers of 7p-amino-cephem-3-ol-4-carboxylic acid derivatives of the formula EMI25.1 where R1a represents hydrogen or an amino protective group R1A, and Rlb represents hydrogen or an acyl group Ac, or Rla and Rlb together represent a divalent amino protective group, R2A represents a radical forming a protected carboxyl group together with the carbonyl group -C (= O) - , and R, represents an optionally substituted hydrocarbon radical, and in which there is a double bond in the 2,3 or 3,4 position, as well as l-oxides of compounds of the formula I in which the C, C double bond is in the 3,4 position stands, or salts of such compounds with salt-forming groups, characterized in that a 3-cephem-3-ol compound of the formula EMI25.2 or in an 1-oxide thereof the 3-hydroxyl group by etherification by means of a tri-R3-oxonium salt of the formula (R1) 10OAe (VI) or a 3-substituted 1-R3-triazene compound of the formula Subst.-N = N - NH - R3 (VII), in which R, which has the meaning given under formula I, AS is the anion of an acid and Subst. Is an aromatic radical, converted into a group of the formula -O-R3, and if desired, one obtained Compound with a salt-forming group converted into a salt or a salt obtained into the free compound. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula II are used in which Rla is an amino protective group R1A, which stands for an acyl group Ac, in which any free functional groups present may be protected, Rlb is hydrogen, and R2A is one with the -C (= O) grouping represents an etherified hydroxyl group which forms an esterified carboxyl group; where functional groups which may be present in an esterified carboxyl group of the formula -C (= O) -R2A can be protected. 2. The method according to dependent claim 1, characterized in that R2A represents an optionally substituted 1-phenyl-lower alkoxy, such as diphenylmethoxy group. 3. The method according to dependent claim 1, characterized in that R2A is an optionally halogen-substituted lower alkoxy group, such as an sc-polybranched lower alkoxy radical, e.g. tert. <Butyloxy, or a 2-halo-lower alkoxy radical, such as 2,2,2-trichloroethoxy. 4. Process according to claim, characterized in that enol ethers are prepared by treating the starting material of the formula II with a tri-R3-oxonium salt (VI), in which R 1 is lower alkyl. 5. The method according to dependent claim 4, characterized in that a tri-lower alkyl oxonium salt, in particular a corresponding tetrafluoroborate, is used. 6. The method according to claim, characterized in that enol ethers are prepared by treating the starting material of the formula II with a 3 -substituted 1-R3-tri-azene compound (VII), in which R is lower alkyl, lower alkenyl or phenyl-lower alkyl. 7. The method according to dependent claim 6, characterized in that a 3-aryl-1-lower alkyl-triazene, 3-aryl-1-nie deraWenyl-triazene or a 3-aryl-1-phenyl-lower alkyl-triazene, wherein aryl is preferred an optionally substituted phenyl, such as a Niederalkyiphenylrest is used. 8. The method according to patent claim Jch, characterized in that free amino groups not participating in the reaction are intermediately protected by acylation, tritylation or silylation, free hydroxyl or mercapto groups by etherification or esterification and free carboxyl groups by esterification in a starting material. 9. The method according to claim, characterized in that the protected carboxyl group -C (= O) -R2A in a compound obtained is converted into a free carboxyl group by solvolysis, reduction or photolysis. 10. The method according to claim, characterized in that in a compound obtained in which both radicals R1A and R1b are acyl groups, a suitable acyl group, e.g. split off by hydrolysis, aminolysis or hydrazinolysis and replaced by hydrogen. 11. The method according to claim, characterized in that a free amino group in a compound obtained is acylated by treatment with a carboxylic acid or a reactive, functional derivative thereof. 12. The method according to claim, characterized in that a compound obtained with a C, C double bond in the 2,3 position is isomerized to a corresponding compound with the C, C double bond in the 3,4 position. 13. The method according to dependent claim 12, characterized in that the isomerization is carried out by treatment with a weakly basic agent. 14. The method according to dependent claim 12, characterized in that the isomerization is carried out by oxidation of the 1-position and subsequent reduction of the 1 -oxide obtained of the corresponding 3-cephem compound. 15. The method according to claim or one of the dependent claims 1-14, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, furthermore the corresponding 2-cephem compounds, and salts of such compounds with salt-forming groups are prepared , wherein Rla is hydrogen or one, in a fermentatively or bio-, semi- or totally synthetically producible N-acyl derivative of a 6p-Amino.penam-3. carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound containing acyl radical or an easily cleavable acyl radical of a carbonic acid half derivative, Rlb stands for hydrogen, R, A hydroxy, optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino, and R3 represents lower alkyl or optionally substituted phenyl lower alkyl. 16. The method according to claim or one of the dependent claims 1-14, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, furthermore the corresponding 2-cephem compounds, and salts of such compounds with salt-forming groups are prepared in which Rla, R, b, R2A and R3 have the meanings given in dependent claim 15, or in which R2A and R3 have the meanings given in dependent claim 15 and R1a and R, b together are preferably in the 2 position and optionally in the 4 position substituted l-l-oxo-3-aza-1,4-butylene radical. 17. The method according to claim or one of the dependent claims 1-14, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, and corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups, wherein Rla is hydrogen, an acyl radical contained in fermentatively or biosynthetically producible N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7p-amino-3-cephem-4-carboxylic acid compounds, or an acyl radical occurring in highly effective N-acyl derivatives of 6p-amino-penam-3-carboxylic acid or 7p-amino.3 -cephem-4-carboxylic acid compounds, Rlb stands for hydrogen, R2A is hydroxy, lower alkoxy, 2 - Halo-lower alkoxy, phenyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkoxycarbonyloxy, and R3 is lower alkyl or 1-phenyl lower alkyl. 18. The method according to claim or one of the dependent claims 1-14, characterized in that 3-cephem compounds of the formula I according to claim or l-oxides thereof, and corresponding 2-cephem compounds, and also salts of such compounds with salt-forming groups in which R1a, R, b, R2A and R3 have the meanings given in dependent claim 17 or in which R, A and R3 have the meanings given in dependent claim 17 and Rla and Rlb together are substituted for one in the 2-position by optionally substituted phenyl l-oxo-3-aza-1,4-butylene radical which optionally contains two lower alkyl groups in the 4-position. 19. The method according to claim or one of the dependent claims 1-14, characterized in that 3-cephem compounds of the formula I according to claim or 1-oxides thereof, as well as corresponding 2-cephem compounds, and also salts of compounds with salt-forming groups, in which Rlh , R2A and R3 have the meanings given in dependent claim 17, and Rla represents hydrogen or a group of the formula EMI26.1 where n is 0 and R 'is hydrogen or an optionally substituted cycloaliphatic or aroma table hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, e.g. esterified or etherified hydroxy or mercapto group, or an optionally substituted amino group, or in which n is 1, Rl 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 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 R ″ and Rlll denotes hydrogen, or where n is 1, RT denotes 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 aromatic character, R11 an optionally functionally modified, eg esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and R111 is hydrogen, or in which n is 1 each of the radicals R1 and Rll is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R "'is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, Aromatic or araliphatic hydrocarbon radical and R11 and IRIIl together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n stands for 1, and Rl is an optionally substituted aliphatic, 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, R "an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RIlI denote hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 20. The method according to claim or one of the dependent claims 1-14, characterized in that 3 cephem compounds of the formula I according to claim or 1-oxides thereof, as well as corresponding 2-cephem compounds, furthermore salts of such compounds with salt-forming groups are prepared, in which Rlb, R2A and R3 have the meanings given in dependent claim 17 and R, a have the meanings given in dependent claim 19, or in which R2A and R have the meanings given in dependent claim 17 and R1a and Rlb together represent a phenyl optionally substituted in the 2-position -Oxo-3-aza-1,4-butylene radical, which optionally contains two lower alkyl groups in the 4-position. 21. The method according to claim or one of the subclaims 1-14, characterized in that 3-cephem or 2-cephem compounds of the formula I according to claim or salts of compounds with salt-forming groups in which Rlb is hydrogen, Rla is hydrogen, a Acyl group of the formula EMI27.1 wherein Ar is phenyl, hydroxyphenyl, hydroxychlorophenyl or 2-thienyl, where in such radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, n represents 0 or 1, and R represents hydrogen or, if n represents 0, stands for optionally protected amino, carboxy, sulfo or hydroxy, or O-lower alkylphosphono or O, O-di-lower alkylphosphono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected. R2A denotes hydroxy, lower alkoxy, 2-halo-lower alkoxy or optionally substituted diphenylmethexy, and R3 represents lower alkyl. 22. The method according to claim or one of the subclaims 1-14, characterized in that 3 cephem or 2-cephem compounds of the formula I according to claim or salts of compounds with salt-forming groups in which Rlb, R2A and R3 are the im Sub-claim 21 have given meanings, and Rla hydrogen, cyanoacetyl, an acyl group of the formula B according to sub-claim 21, wherein Ar is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazolyl or tetrazolyl, with hydroxy substituents in such radicals through Acyl groups can be protected, and X, n and! R has the meanings given in dependent claim 21, or denotes a 5-amino-5-carboxyvaleryl radical, wherein the amino and carboxy groups are optionally protected. 23. The method according to claim or one of the dependent claims 1-14, characterized in that 3 cephem or 2-tephem compounds of the formula I according to claim or salts of compounds with salt-forming groups in which R1 is hydrogen, the acyl radical of the formula B according to Dependent claim 21, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen, or, if n is 0, optionally protected amino or hydroxy, or O-lower alkyl or O, O-di-lower alkyl-phos- phono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected, R2A is hydroxy, is optionally halogen-substituted lower alkoxy or optionally lower alkoxy-substituted diphenylmethoxy, and R3 is lower alkyl. 24. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7o-phenylacetylamino-2-cephem-4oc-carboxylic acid diphenylmethyl ester is prepared 25. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7o-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester is prepared. 26. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7-phen, ylacetylamino-3-cephem-4-carboxylic acid or salts thereof are prepared. 27. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7 | p- (D-la-tert-butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem -4-carboxylic acid diphenylmethyl ester. 28. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7,3- (D-Ia-phlenylglycylamino) -3-cephem-4-carboxylic acid or salts thereof are prepared . 29. The method according to claim or one of the dependent claims 1-14, characterized in that the inner salt of 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3- -cephem-4-carboxylic acid is prepared. 30. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7ss- (D-α-tert-butyloxycarbonylamino-α-phenyl-acetylamaino) -2-cephem-4a- carboxylic acid diphenylmethyl ester. 31. The method according to claim or one of the dependent claims 1-14, characterized in that the 3-methoxy-7o- (D-, a-phenyl-glycylamino) -2-cephem-4a-carboxylic acid or salts thereof are prepared. 32. The method according to claim or one of the dependent claims 1-14, characterized in that the inner salt of 3-methoxy-7P- (D-.2-phenyl-glycylamino) -2- -cephem-4a-carboxylic acid is produced. 33. The method according to claim or one of the dependent claims 1-10 and 12-14, characterized in that the 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof are prepared.