CH590874A5 - Substd 7-beta-amino-cephamone carboxylic acid derivs - antibiotic inters - Google Patents

Abstract

Title cpds of formula I: (where R1 = H or an amine protecting gp.; R2 = H or acyl; or R1 + R2 tog. = a bivalent, amine protecting gp., and R4 = a carboxyl protecting gp., including enolic isomers, ketals, oxides, and salts of I) are prepd. (a) by oxidative fission of the 3-methylene derivs., or (b) by peracid oxidn and subsequent hydrolysis, from the 3-formyl ceph-2- or 3-em derivs.

Description

  

  
 



   The present invention relates to a process for the preparation of 7ss-acylamino-cepham-3-one-4-carboxylic acid derivatives of the formula
EMI1. 1
 wherein Ac represents an acyl group, and R2A represents a radical which forms a protected carboxyl group to be seeded with the carbonyl group -C (= O) -, and l-oxides of compounds of the formula I, or salts of such compounds with salt-forming groups, furthermore the use of compounds obtained according to the invention for the preparation of corresponding 3-ketal derivatives. 



   The present cepham-3-one compounds and the corresponding l-oxides can be used both in the keto form and in the enol form of the cephem-3-ol compounds of the formula
EMI1. 2
 which contain a double bond in 2,3- or in 3,4-position or are in a mixture of the two forms. 



   In the compounds of the formula I, as well as in the compounds of the formula Ia with a double bond in the 2,3-position, the protected carboxyl group preferably has the α-configuration. 



   An acyl group Ac 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), and represents the acyl radical of a carbonic acid half derivative. 



   A protected carboxyl group of the formula -C (= O) - R2t 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 hydroxy group etherified by an organic radical, in which the organic radical preferably contains 18 carbon atoms, which together with the -C (= O) group form an esterified carboxyl group.  Such organic residues are e.g.  B.  aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



   The group R2A can also represent an organic silyloxy radical as well as a hydroxyl 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 -C (= O) group is in particular an acyloxy radical in which acyl is the corresponding radical of an organic carboxylic acid, preferably with 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. 



   A radical R2A which forms a carbamoyl group with a -C (= O) group is an optionally substituted amino group in which substituents are optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, also etherified or esterified hydroxy, in which the etherifying or .  esterifying residues z. 

  B.  have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, 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 divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or divalent 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, preferably with up to 18 carbon atoms, are possible . 



   3-ketal derivatives, incl.  the 3-thioketal derivatives of compounds of the formula I are primarily corresponding compounds with glycols, thioglycols or dithioglycols, in particular corresponding aliphatic compounds such as lower alkylene glycols, thioglycols or dithioglycols, e.g.  B.  Glycol, thioglycol or dithioglycol. 



   The general terms used in the description above and below have e.g.  B.  following meanings:
An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, and a corresponding ylidene radical, is an optionally substituted, monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and lower alkenyl or lower alkynyl, also lower alkylidene, the z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  Such radicals can optionally be replaced by functional groups, e.g. 

  B.  by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyluiederalkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanitroloxy, optionally substituted by oxycarbonyloxy or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or halogen, furthermore z.  B. 

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, as well as acylamino, such as lower alkanoylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, azido, acyl, such as lower alkanol or benzoyl, such as alkoxyl, such as carboxyl, carboxy-modified carboxyl, such as alkoxyl, carboxy-modified carboxyl, such as carboxyl, if appropriate, carboxyl-carboxyl, such as alkoxyl, carboxyl, carboxy-substituted, such as carboxyl, carboxy-substituted, such as carboxyl, carboxy-substituted, carboxyl or carboxyl , optionally substituted carbamoyl, such as N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified sulfo, such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or O, O -disubstituted phosphono, wherein substituents, e.g. 

  B.     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 bivalent aliphatic residue, incl.  the corresponding residue of a divalent aliphatic carboxylic acid is z.  B.  Lower alkylene or lower alkenylene, which optionally, e.g.  B. 



  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-aliphatic hydrocarbon radical.  B. 



  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or  Cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, wherein cycloalkyl and cycloalkylidene z.  B.  contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl z.  B.  up to 12, such as 3-8, e.g.  B.  5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g.  B.  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, e.g. 

  B.  like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or poly-substituted by functional groups. 



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g.  B. 



  a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, and also biphenylyl or naphthyl, which optionally, for.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   A divalent aromatic radical, e.g.  B.  an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, which optionally, z.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, it can be nono-, di- or polysubstituted. 



   An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, also an araliphatic ylidene radical, is z.  B.  an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, e.g.  B.  Up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radicals and is primarily phenyl-lower alkyl or phenyl lower alkenyl, as well as phenyl-lower alkynyl, and also phenyl lower alkylidene, such radicals being e.g.  B.  1-3 phenyl groups and optionally, z.  B.  as the above mentioned aliphatic and cycloaliphatic 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 tetrazacyclic radicals of aromatic character, and also corresponding partially or fully saturated ones
Residues, these heterocyclic radicals optionally, for.  B.  like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted.  The aliphatic part in heterocyclic-aliphatic radicals has z.  B.  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, z.  B.  in a- or ss-position, substituted lower alkyl half esters of carbonic acid, and an optionally substituted lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half ester of carbonic acid 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. 

  B.  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic
Group can optionally be substituted.  The acyl 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 heterocyclyloxy or heterocyclyl-lower alkoxy, in particular also optionally substituted phenyl-lower alkoxy. 



   An optionally substituted amino group is e.g.  B. 



   Amino, Niederalkylamino, Diiederalkylamino, Niederalky lenamino, Oxaniederalkylenamino, Thianiederalkylenamino,
Aza-lower alkylenamino, hydroxyamino, lower alkoxyamino,
Lower alkanoyloxyamino, lower alkoxycarbonylamino or
Lower alkanoylamino. 

 

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



   Lower alkyl is e.g.  B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl or tert. -Butyl and n-pentyl,
Isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl z.  B.  Vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g.  B.  Propargyl or 2-butynyl and lower alkylidene e.g.  B.  Can be isopropylidene or isobutylidene. 



     Lower alkylene is e.g.  B.  1,2-ethylene, 1,2- or 1,3-propylene,
1,4-butylene, 1,5-pentylene or 1,6-hexylene, while Nie deralkenylen z.  B.    Is 1,2-athenylene or 2-buten-1,4-ylene. 



  Lower alkylene interrupted by heteroatoms is e.g.  B. 



  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.  B.  3-methyl-3-aza-1,5-pentylene. 



   Cycloalkyl is e.g.  B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and adamantyl, cycloalkenyl, e.g.  B.  Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene, e.g.  B.  Cyclopentylidene or cyclohexylidene.  Cycloalkyl-lower alkyl or lower alkenyl is e.g.  B.  Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3propyl, -vinyl or -allyl, while Cy , cloalkenyl-lower alkyl or lower alkenyl z.  B.  1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or -1,2-ethyl, -1,1- , -1,2- or -1,3-propyl, -vinyl or -allyl.  Cycloalkyl-lower alkylidene is e.g.  B. 



  Cyclohexylmethylene, and cycloalkenyl-lower alkylidene z.  B. 



  3 -cyclohexenylmethylene. 



   Naphthyl is 1- or 2-naphthyl, while biphenylyl is e.g.     B.  Represents 4-biphenylyl
Phenyl-lower alkyl or phenyl-lower alkenyl is, for.  B. 



  Benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl, phenyl lower alkylidene z.  B.  Benzylidene. 



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, e.g.  B.  corresponding monocyclic, monoaza-, monothla- or monooxacyclic radicals, such as pyrryl, e.g.  B.  2-pyrryl or 3 pyrryl, pyndyl, e.g.  B.  2-, 3- or 4-pyridyl, also pyridinium, thienyl, e.g.  B.  2- or 3-thienyl, or furyl, e.g.  B.  2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals such as indolyl, e.g.  B.  2- or 3-indolyl, quinolinyl, e.g.  B.  2 or 4-quinolinyl, isoquinolinyl, e.g.  B.  1-isoquinolinyl, benzofuranyl, e.g.  B.  2- or 3-benzofuranyl, or benzothienyl, e.g.  B.  2- or 3-benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as imidazolyl, e.g.  B.  2-imidazolyl, pyrimidinyl, e.g.  B.  2- or 4 pyrimidinyl, triazolyl, e.g. 

  B.    1,2,4-triazol-3 -yl, tetrazolyl, e.g.  B.  1- or 5-tetrazolyl, oxazolyl, e.g.  B.  2-oxazolyl, isoxazolyl, e.g.  B.  3-isoxazolyl, thiazolyl, e.g.  B.  2-thiazolyl, isothiazolyl, e.g.  B.  3-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g.  B.  1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, thiaza or oxazacyclic radicals such as benzimidazolyl, e.g.  B.  2-benzimidazolyl, benzoxazolyl, e.g.  B. 



  2-benzoxazolyl, or benzthiazolyl, e.g.  B.  2-benzothiazolyl.  Corresponding partially or fully saturated radicals are, for.  B.  Tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g.  B.  2- or 4-piperidyl. 



  Heterocyclic-aliphatic radicals are heterocyclic groups, in particular those containing lower alkyl or lower alkenyl.  The above-mentioned heterocyclyl radicals can, for.  B.  by optionally substituted aliphatic hydrocarbon radicals, in particular lower alkyl, such as methyl, or z.  B.  like the aliphatic hydrocarbon radicals, be substituted by functional groups. 



   Lower alkoxy is e.g.  B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy, tert.  Butyloxy, n-pentyloxy or tert. -Pentyloxy.  These groups can be substituted, e.g.  B.  as in halo-lower alkoxy, especially 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloro-, 2-bromo- or 2-iodoethoxy.  Lower alkenyloxy is e.g.  B.  Vinyloxy or allyloxy, lower alkylenedioxy, e.g.  B.  Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g.  B. 



  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g.  B.  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or heterocyclyloxy or heterocyclic lower alkoxy, e.g.  B.  Pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenylxoy. 



   Lower alkylthio is e.g.  B.    Methylthio, ethylthio or n-butylthio, lower alkenylthlo, e.g.  B.    Allylthio, and phenyl-lower alkylthio, e.g. B.  Benzylthio, while by heterocyclyl residues or heterocyclylaliphatic residues etherified mercapto groups, in particular imidazolylthio, z. B.     2-imidazolylthio, thiazolylthio, e.g.  B.  2-thiazolylthio, 1,2,4- or 1,3,4 thiadiazolylthio, e.g.  B.    1,2,4-thiadiazol-3-ylthio or 1,3,4 thiadiazol-2-ylthlo, or tetrazolylthio, e.g.  B.  Are 1-methyl-5tetrazolylthio. 



   Esterified hydroxy groups are primarily halogen, e.g.  B.  Fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g.  B.  Acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g.  B.  Methoxycarbonyloxy, athoxycarbonyloxy or tert. -Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g.  B.  2,2,2-Trichloräthoxycarbonyloxy, 2-Bromoäthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy or Phenylcarbonylmethoxycarbonyloxy, z.  B.  Phenacyloxycarbonyloxy. 



   Lower alkoxycarbonyl is e.g.  B.  Methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert. -Butyloxycarbonyl or tert. Pentyloxycarbonyl. 



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



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



   Lower alkylamino or di-lower alkylamino is e.g.  B. 



  Methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g.  B.  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g.  B.  Morpholino, thiane lower alkyleneamino, e.g.  B.  Thiomorpholino, and aza-lower alkylenamino, e.g.  B.  Piperazino or 4-methylpiperazino.  Acylamino is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g.  B. 



  Methoxycarbonylamino, Athoxycarbonylammo or tert. - Butyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, also for phthalimido, or optionally in salt, such as alkali metal, z.  B.  Sodium or ammonium salt form, present sulfoamino. 



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



   O-lower alkyl phosphono is e.g.  B.  0-methyl- or 0-ethyl-phosphono, O, O-di-lower alkyl-phosphono, e.g.  B.    0.0, - dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g. B.     O-benzyl-phosphono, and 0 lower alkyl-O-phenyl-phosphono, e.g.  B.  O-benzyl-O-methylphosphono. 

 

   Lower alkenyloxycarbonyl is e.g.  B.  Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenylniederalkoxycarbonyl z.  B.  Represents adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethoxycarbonyl.  Lower alkoxycarbonyl, wherein lower alkyl e.g.  B.  contains a monocyclic, monoaza-, monooxa- or monothiacyclic group, is z.  B.  Furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, e.g.  B.  2-thenyloxycarbonyl. 



   2-lower alkyl and 2,2-di-lower alkyl hydrazino are e.g.  B. 



  2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino, e.g.  B.  2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert. -Butyloxycarbonylhydrazino, and lower alkanoylhydrazino, e.g.  B.    2-acetylhydrazino.   



   An acyl group Ac stands in particular for a naturally occurring or bio-, semi-synthetic or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6B-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound - Acyl radical contained in an organic carboxylic acid 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 6ss-amino-penam-3-carboxylic acid or 7B-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI4. 1
 wherein 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, z. 

  B.  denotes esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or in which n is 1, Rt is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical in which the heterocyclic radical preferably has an aromatic character and / or a quaternary nitrogen atom, represents an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group,

   and each of the radicals RII and RIII is hydrogen, or in which n is 1, RI 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, z. 

  B.  esterified or etherified hydroxyl 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 azdio group or a halogen atom, and Rm is hydrogen, or in which n is 1, each of the radicals RI and RII is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RIII is hydrogen, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aliphatic,

   denotes aromatic or araliphatic hydrocarbon radical and Rz 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 Rt is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic -aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have aromatic character, RII an optionally substituted aliphatic, cycloaliphatic,

   cy Qoaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RHI hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 



   In the above acyl groups of the formula A, for.  B.  n for 0 and RI for hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z.  B.  Alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by hydroxy, lower alkoxy, z.  B.  Methoxy, and / or halogen, e.g.  B.  Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g.  B.  by lower alkyl, e.g.  B.  Methyl, and / or phenyl, which in turn have substituents such as halogen, e.g.  B.  Chlorine, can carry substituted heterocyclic group, such as a 4-isoxazolyl group, or a preferably, z.  B.  by an optionally substituted one such as halogen, e.g.  B. 

  Chlorine, lower alkyl containing N-substituted amino group, or n for 1, RI for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, e.g.  B. 



  silylated amino or acylamino and / or silylated or esterified carboxy group, an optionally substituted, preferably by halogen, such as chlorine, optionally substituted, such as hydroxy and / or halogen, e.g.  B.  Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, lower alkenyl group, optionally substituted one such as hydroxy, halogen, e.g.  B.  Chlorine, and / or optionally substituted, such as hydroxy and / or halogen, e.g.  B.  Phenyl group containing chlorine, containing phenyloxy, an optionally, e.g.  B.  by lower alkyl, such as methyl, amino or aminomethyl, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy, e.g.  B.  Methoxy group, an optionally, e.g. 

  B.  by hydroxy and / or halogen, such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g.  B.  n-butylthio, or lower alkenylthio, e.g.  B.  Allylthio group, an optionally, e.g.  B.  by lower alkyl such as methyl, substituted phenylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio, 1,2,4-thiadiazol-3-ylthio -, such as 5-methyl-1,2,4-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, especially chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, eg.  B. 

  Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g.  B.  by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g.  B. 



  Acetyl or propionyl, or benzoyl group, or an azido group, and RII and RIII for hydrogen, or n for 1, RI for an optionally, z.    B.     by hydroxy and / or halogen, e.g.  B.  Chlorine, substituted phenyl or thienyl group, also for a 1,4-cyclohexadienyl group, RII for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g.  B. 

 

  tert. -Butyloxycarbonylamino or 2,2,2-Trichloräthoxycar- bonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z.  B.  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z.  B.  Alkali metal salt form or in esterified form, e.g.  B.  as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl group, carboxyl group present, a cyano group, a sulfo group, an optionally functionally converted hydroxy group, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, z. 

  B.  tert. -Butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkyl-phosphono group, for example O-methylphosphono or O, O-dimethylphosphono, or a halogen atom, for example Chlorine or bromine, and Rm for hydrogen, or n for 1, RI and RII each for halogen, e.g.  B.  Bromine, or lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl, and Rm for hydrogen, or n for 1, and each of the groups RI, R and Rm for lower alkyl, e.g.  B.  Methyl stand. 



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



  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, cleavable or an acyl radical that can be converted into such, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2- Trichloräthyloxycarbonyl, 2-Bromäthoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino group substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, hexahydroxycarbonyl, benzyloxycarbonyl Methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5methyl-4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl,

   2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, 3-chloroacetyl, chloropropionyl, 3-chloroacetyl, 3-chloroacetyl, chloroacetyl, acetropyl, chloroacetyl, dibromoacetyl, chloroacetyl, acrylyl, crotonoyl, octanoyl, acrylyl, chloro-acetyl 5-Amino-5-carboxyl-valeryl (with optionally, e.g.    B; as indicated, as indicated by a monoacyl or diacyl radical, e.g.  B.  an optionally halogenated Niederal kanoylrest such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, z.  B.  in salt, such as sodium salt, or in ester, such as lower alkyl, e.g.  B.  Methyl or ethyl, or aryl lower alkyl, e.g.  B. 

  Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyano-propionyl, 2-cyano-3,3-dimethyl-ayl-phenyl, a-cyano-propionyl, a-cyano-3,3-dimethyl-arylacido, a-cyano-3,3-dimethyl-arylacido phenylacetyl, 3-chloro-phenylacetyl-, 4 aminomethylphenyl-acetyl, (with optionally, e.g. 

  B.  as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyl oxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-phenyloxyphenylacetyl, a-hydroxy-a-phenyl-phenoxy-phenoxy-phenoxy, a-methoxy-phenoxy-phenoxy-phenoxy, a-phenoxy-methyl-phenoxy-phenoxy-phenoxy, a-methyl-phenoxy-phenoxy-phenoxy-phenoxy-phenoxy-phenoxy, 4-trifluoromethylphenyloxyacetyl, -3,4-dichloro-phenylglycyl, a-cyano-phenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (the amino group in these radicals optionally z.  B.  as indicated above, may be substituted), a hydroxyphenylacetyl (where in these radicals the hydroxyl group optionally, similar to the amino group, e.g.  B. 



  can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester) or aO-methyl-phosphono-phenylacetyl or a O, O-dimethyl-phosphono-phenylacetyl, also benzylthio-acetyl, benzylthiopropionyl, a-carboxyphenylacetyl (with optionally, e.g.  B.  as indicated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4 amino-pyridinium acetyl (optionally with, e.g.  B.  as stated above, substituted amino group), 2-thienylacetyl, 2-tetrahydrothienylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with functional, e.g.  B. 



  as stated above, modified carboxyl group), α-cyano-2-thienylacetyl, -amino-2-thienylacetyl or α-amino-3thienylacetyl (optionally with, e.g.  B.  as stated above, substituted amino group), a-sulfo-phenylacetyl (optionally with, z.  B.  such as the carboxyl group, functionally modified sulfo group), 3-thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl-2-imidazolylthioacetyl, 1,2,4-triazol-3-ylthioacetyl, 1,3 , 4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl 1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl. 



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g.  B.  when treated with a chemical reducing agent, or by acid treatment, e.g.  B.  with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl radical, preferably multiply branched in the α-position or substituted by acylcarbonyl radicals, in particular benzoyl radicals, or in the β-position by halogen atoms, e.g.  B.  tert. -Butyloxycarbonyl, tert.  Pentyloxycarbonyl, phenacyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or a radical which can be converted into the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, furthermore, preferably polycyclic, cycloalkoxycarbonyl, e.g.  B. 

  Adamantyloxycarbonyl, optionally substituted phenyl-lower alkoxycarbonyl, primarily a-phenyl-lower alkoxycarbonyl, in which the a-position is preferably polysubstituted, e.g.  B.  Diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl, primarily u-furyl-lower alkoxycarbonyl, e.g.  B.  Furfuryloxycarbonyl. 



   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 carboxyl group, such as a carbamoyl or hydrazinocarbonyl group.  Such a group R2A is e.g. B.     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, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group. 



   An etherified hydroxy group R2A, which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for.  B.  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.  B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can easily be converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 

 

   An etherified hydroxy group R2A, which together with the -C ("0) '- grouping, also when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g.  B.  Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy 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 an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group contains, as substituents, in particular lower alkoxy, e.g.  B.  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-dimethoxy-benzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy. 



   An etherified hydroxy group R2A can also represent a radical which, together with the -C (= O) grouping, is an acidic group, e.g.  B.  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 is substituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g.  B. 

  Methyl or phenyl, polysubstituted or monosubstituted by a carbocyclic aryl group having an electron-donating substituent or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or then a ring member in a polycycloaliphatic hydrocarbon radical or the a- the aliphatic radical in an oxa- or thiacycloaliphatic radical Means position to the oxygen or sulfur atom representing ring member. 



   Preferred polysubstituted methoxy groups of this type are e.g.  B.  tert. -Butyloxy, tert. -Pentyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group, e.g.  B.  4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or    2-furvloxy is.  A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, for.  B. 

  Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member in the o-position to the oxygen or sulfur atom, means, for example, 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) 1 group, is a hydrolytic, e.g.  B.  under weakly basic or acidic conditions, forms cleavable esterified carboxyl group.  Such a radical is preferably an etherified hydroxyl group which forms an activated ester group with the -C (= O) grouping, such as nitrophenyloxy, e.g.  B.  4-nitrophenyloxy or 2,4-dinitrophenyloxy, nitrophenyl-lower alkoxy, e.g.  B.  4-nitrobenzyloxy, polyhalophenyloxy, e.g.  B.  2,4,6-trichlorophenyloxy, or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, e.g.  B.  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.  B. 



  optionally substituted a-phenyl-lower alkoxy, such as benzyloxy, 4-methoxy-benzyloxy or 4-nitrobenzyloxy. 



   The group R2A can also be a, together with the carbonyl group -C (= O) - forming an esterified carboxyl group cleavable under physiological conditions ver etherified hydroxyl group, primarily lower alkanoyloxymethoxy, z.  B.  Acetyloxymethyloxy or pivaloylmethoxy. 



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



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



   A radical R2A which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is z.  B.  Amine, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g.  B.  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g.  B.  Morpholino, hydroxyamino, hydrazino, 2-lower alkylhydrazino or 2,2-di-lower alkylhydrazino, e.g.  B.  2 methylhydrazino or 2,2-dimethylhydrazino. 



   Salts are in particular those of compounds of the formula I having 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.  B. 



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

  Compounds of the formula I which have a basic group can also contain acid addition salts, e.g.  B.  with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g.  B.  Trifluoroacetic acid.  Compounds of the formula I with one acidic and one basic group can also be used in the form of an inner salt, i.e.  H.  in zwitterionic form. 

 

   The novel compounds of the present invention are valuable intermediates which can be used to prepare compounds with pharmacological properties; they can, such as  B.  described below, can be converted into such. 



   The cepham-3-one compounds of the formula I, in which Ac is a, in a fermentative (i.e.  H. 



  naturally occurring) or bio-, semi- or totally synthetically producible, in particular pharmacologically active, such as highly active N-acyl derivative of a 6ss-anainopenam-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, in particular a carbonic acid half-ester, and R2A for optionally, z. B. , by optionally substituted aryloxy, e.g. B.  4th
Methoxyphenyloxy, lower alkanoyloxy, e.g. B.  Acetyloxy or
Pivaloyloxy, or arylcarbonyl, e.g. B.  Benzoyl, or halogen, e.g. B.  Chlorine, bromine or iodine, substituted lower alkoxy, such as Niederall; oxy, -z B. 

  Methoxy, methoxy, n-propyloxy, iso propyloxy, n-butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bis-phenyl oxy-methoxy optionally substituted by lower alkoxy, e.g. B.  Bis-4-methoxyphenyloxy-methoxy, phen acyloxy, lower alkanoyloxy-methoxy, e.g.  B.  Acetyloxy methoxy, or pivaloyloxymethoxy, or 2-halo-lower alkoxy, e.g. B.  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromo ethoxy or 2-iodoethoxy, for optionally substituted
Phenyl-lower alkoxy, especially 1-phenyl-lower alkoxy, such as pheny - - obeisolche radicals 1-3, if appropriate, e.g.    B.  may contain phenyl radicals substituted by lower alkoxy, such as methoxy, nitro or phenyl, e.g.  B. 

  Benzyloxy,
4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy, 4-nitro benzyloxy, diphenylmethoxy, 4,4'-diemthoxy-diphenyl methoxy or trityloxy, for acyloxy, such as lower alkoxycar bonyloxy, e.g.  B.  Methoxycarbonyloxy or Äthoxycarbonyl- oxy, or lower alkanoyloxy, z.  B.  Acetyloxy, for tri-lower alkylsilyloxy, e.g. B.  Trimethylsilyloxy, or where appropriate, e.g. B.  amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g.  B.  Amino, lower alkyl or di-lower alkylamino, such as methylamino or dimethylamino, hydrazino, 2-mederalkyl- or 2,2-di-lower alkylhydrazino, e.g. 

  B.  2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and the 1-oxides of
Cepham-3-one compounds of the formula I, such compounds being in the keto, d.  H.  the cepham-3-on, as well as in the enol, d.  H.  in the cephem-3-ol form can be present, furthermore the corresponding ketals with lower alkylene glycols, in particular with Glycol, and salts of such compounds with salt-forming groups. 



   In a Cepham-3-one connection, the
Formula I, furthermore in a corresponding 1-oxide, as well as in a ketal thereof with a lower alkylene glycol or in a salt of such a compound with salt-forming groups Ac for a fermentative (i.e.  H.  naturally occurring the) or biosynthetically producible N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds containing acyl radical, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted lower alkanoyl or Lower alkenoyl radical, e.g.  B.  4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino-5-carboxy-valeryl, in which the amiao and / or the carboxyl group are optionally protected and e.g. 

  B.  as acylamino or  esterified carboxyl are present, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-arnaopenam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, such as formyl, 2-chloroethylcarbamoyl , Cyanoacetyl, 2-thienylacetyl or 1-tetrazolylacetyl, especially phenylglycyl, in which phenyl is optionally substituted by optionally protected hydroxy, such as acyloxy, e.g.  B.  optionally halogen-substituted lower alkoxy carbonaloxy or lower alkanoyloxy, and / or halogen, e.g.  B. 



  Chlorine, substituted phenyl e.g.  B.  Phenyl, or 3- or 4-hydroxy-, 3-chloro-4-hydroxy- or 3,5-dichloro-4-hydroxyphenyl, optionally with protected hydroxyl groups, and in which the amino group is optionally substituted and e.g.  B.  is an optionally present in salt form sulfoamino group or an amino group which, as substituents, a hydraolytically cleavable trityl group or an optionally substituted carbamoyl, such as an optionally substituted ureidocarbonyl group, e.g.  B.  Ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g.  B. 



   Guanidinocarbonyl, or a, preferably light, e.g.  B. 



   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, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxy carbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. 
Butyloxycarbonyl or phenacyloxycarbonyl, or a carbon acid half-amide, such as carbamoyl or N-methylcarbamoyl, or in which the amino group is connected to the nitrogen atom of the 7ss-amino group by a methylene group, optionally lower alkyl, such as two methyls, furthermore thienylglycyl, such as 2- Thienylglycyl (optionally with, e.g.  B.  as stated above, substituted amino group), or 1-amino-cyclohexylcarbonyl (optionally with, e.g.  B. 



   as stated above, substituted amino group), also a
Carboxy-phenylacetyl or α-carboxy-2-thienylacetyl (if necessary with functionally modified, z.  B.  in salt, like
Sodium salt form, or in ester, such as lower alkyl, e.g.  B. 



   Methyl or ethyl, or phenyl lower alkyl, e.g.  B.  Diphenyl methyl ester form, present carboxyl group), a-sulfo phenylacetyl (optionally with, for.  B.  such as the carboxyl group, functionally modified sulfo group), a-phosphono, aO-methylphosphono or aO, O-dimethyl-phosphono phenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxyl group, in particular with an acyloxy group, in which acyl a , preferably light, e.g. 

  B.  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, cleavable or an acyl residue that can be converted into such a residue, preferably a suitable acyl residue of a carbonic acid half ester, such as 2,2,2-trichloroethoxycarbonyl, 2-chloroethoxy carbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. 
Butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), z.  B.  represents an acyl radical of the formula A, and R2A represents lower alkoxy, in particular a-polybranched lower alkoxy, e.g.  B.  tert-butyloxy, also methoxy or ethoxy, 2
Halo-lower alkoxy, e.g. 

  B.  2,2,2-trichloroethoxy, 2-iodine ethoxy or 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyl-lower alkoxy which can easily be converted into this
1-3 phenyl radicals, optionally substituted by lower alkoxy or nitro, e.g.  B.    4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenyl methoxy or trityloxy, lower alkanoyloxymethoxy, e.g.  B. 

 

   Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxy carbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyl oxy, e.g.  B.  Acetyloxy, dat
The invention relates primarily to cepham-3-one compounds of the formula I in which Ac is an acyl group of
formula
EMI7. 1
 wherein Ar is phenyl, also hydroxyphenyl, e.g.  B.  3- or 4-hydroxyphenyl, or hydroxy-chlorophenyl, e.g.  B.  3-chloro-4-hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, with hydroxy substituents in such radicals being replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g.  B. 



  tert. -Butyloxycarbonyl or 2,2,2-trichloroethoxycarbonyl, and 2-thienyl, X is oxygen or sulfur, n is 0 or 1, and R is hydrogen or, if n is 0, optionally protected amino such as acylamino, e.g.  B.  a-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.  B. 



  2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or 3-Guanylureido, also sulfoamino or tritylamino, optionally protected carboxy, z.  B.  esterified carboxy such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, optionally protected sulfo, as in alkali metal, e.g.  B.  Sodium salt form, sulfo present, optionally protected hydroxy such as acyloxy e.g.  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2 Halogenniederalkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-Niederalkylphosphono or O, O-Diiederalkylphosphono, z.  B. 

  O-methylphosphono or O, O-dimethylphosphono, or a 5-amino-5carboxy-valeryl radical, wherein the amino and carboxy groups are optionally protected and z.  B.  as acylamino, e.g.  B.  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.  B.  Diphenylmethoxycarbonyl, and R2A for lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally, e.g.  B.  by lower alkoxy, e.g.  B.  Methoxy, substituted diphenylmethoxy, e.g.  B. 

  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also the corresponding l-oxides thereof, such compounds in the keto, d.  H.  the cepham-3-one, as well as in the enol-, d.  H.  may be in the cephem-3-ol form, and also the corresponding ketals with lower alkylene glycols, in particular with glycol, and salts of such compounds with salt-forming groups. 



   In cepham-3-one compounds of the formula I or 1-oxides thereof, which are to be designated as particularly valuable, Ac stands 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, if n is 0, optionally protected amino such as acylamino, e.g.  B.  apolybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.  B.  2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino, or 2-Bromäthoxycarbonylamino, optionally protected hydroxy, such as acyloxy, z.  B.  a-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. 

  B.    O-methylphosphono or O, O-dimethyl-phosphono, or for a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected and z.  B. 



  as acylamino, e.g.  B.  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.  B.  Diphenylmethoxycarbonyl, are present, Rit and R2A is optionally halogen in the 2-position, z.  B.  Chlorine-, bromine- or iodine-substituted lower alkoxy, in particular α-poly-branched lower alkoxy, e.g.  B. 



  tert. -Butyloxy, or 2-halo-lower alkoxy, e.g.  B.  2,2,2 trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally lower alkoxy, such as methoxy-substituted diphenylmethyloxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy.  These compounds can be in the cepham-3-one or in the cephem-3-ol form, and furthermore, if they contain salt-forming groups, in the form of salts. 



   The compounds of formula 1, oxides and salts thereof are obtained by converting into a compound of formula
EMI8. 1
 wherein R2A has the meaning given under formula I, in a 1-oxide or a salt thereof, among intermediates
Protection of the 3-oxo group, the 7ss-amino group to a 7ss-
Acylamino group Ac-NH- acylated, and a compound obtained with a salt-forming group is isolated as a salt or as a free compound. 



   For acylation, the free oxo group can be protected in the form of a functionally modified enol group, such as a silylated or stannylated enol group or a ketal group.  The free amino group can be acylation methods known per se, for.  B.  by treating with carboxylic acids ACOH or reactive acid derivatives thereof, such as halides, e.g.  B.  Fluorides or
Chlorides, also pseudohalides, such as the cyanocarbonyl compounds corresponding to the acids, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H.  Ketenes, or from carbamic or thiocarbamic acids, d.  H.  Isocyanates or isothiocyanates, or mixed to hydrides, such as those that are z. 

  B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or iso butyl esters, or can be formed with trichloroacetic acid chloride), or activated esters, as well as with sub-substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives, or an N-substituted one
N, N-diacylamine, such as an N, N-diacylated aniline, acy late, if necessary, in the presence of suitable condensing agents, when using acids such.  B.  of carbodiimides such as dicyclohexylcarbodiimide
Use of reactive acid derivatives, e.g.  B.  Ba safe agents such as triethylamine or pyridine work. 



   An acyl group can also be introduced in stages.  So you can z.  B.  in a compound of the formula II a halogen-lower alkanoyl, z.  B.  Bromacetylgrup pe, or z.  B.  by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl, e.g.  B.  Chlorine carbonyl group, and a so obtainable N- (halogen-lower alkanoyl) - or  N- (halocarbonyl) -amino compound with suitable exchange reagents, such as basic
Connections, 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, and thus to substituted N-lower alkanoyl or  N-hydroxycarbonylamino compounds arrive. 

 

   In both respondents during the
Acylation reaction free functional groups can be temporarily protected in a manner known per se and released after the acylation by methods known per se.  So you can preferably z.  B.  Amino, Hy droxy, carboxyl or phosphono groups in the acyl radical during the acllation reaction z.  B.  in the form of acylamino, such as 2,2,2-Trichloräthoxycarbonylamino-, 2-Bromäthoxycar- bonylamino - or tert. -Butyloxycarbonylamino groups, from
Acyloxy, e.g.  B.  2,2,2-trichloroethoxycarbonyloxy- or 2
Bromoethoxycarbonyl groups, of esterified carboxy groups such as diphenylmethoxycarbonyl groups, or  O, O-disubstituted phosphono, such as O, O-di-lower alkylphosphono, e.g.  B.  0.0 dimethyl-phosphono groups, protect and subsequently, if necessary after conversion of 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.  Sodium iodide, such protected groups, optionally partially, cleave. 



   In a compound obtained with an esterified group of the formula -C (= O) -R2i, this can be converted into another esterified carboxy group of this formula, e.g.  B.  2-chloroethoxycarbonyl or 2-bromoethoxycarbonyl by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent, such as acetone, in 2-iodoethoxycarbonyl. 



   Modified functional substituents in groups Ac and / or R2A, such as acylated amino groups, acylated hydroxyl groups, esterified carboxy groups or O, O-disubstituted phosphono groups, can also be used, according to methods known per se, e.g.  B.  the above-described, release, or free functional substituents in groups Ac, and / or R2A, such as free amino, hydroxy, carboxy or phosphono groups, according to 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 4-guanylsemicarbazide with sodium nitrite with a compound of the formula I, wherein z.  B.  the amino protective group Ac represents an optionally substituted glycyl group, convert and thus convert the amino group into a 3 guanylureido group.  Furthermore, you can compounds with aliphatically bonded halogen, for.  B.  with an optionally substituted a-bromo-acetyl grouping, with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and thus arrive at corresponding phosphono 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 an acidic group z.  B.  by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, 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 basic and a free acidic group can, for.  B.  by neutralizing salts such as acid addition salts to the isoelectric point, e.g.  B. 



  with weak bases, or by treatment with liquid ion exchangers. 



   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 e.g.  B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes.  Racemates obtained can be used in the customary manner, optionally after introducing suitable salt-forming groups, eg.  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 them, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction. 



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



   The starting compounds of the formula II are obtained by reacting in a cepham compound of the formula
EMI9. 1
 where R1a is hydrogen or an amino protective group RtA, and R, A has the meaning given under formula I, or in a 1-oxide or a salt thereof, oxidatively splits off the methylene group in the 3-position, and, if desired, a mixture of a 3 -Oxocepham compound of the formula
EMI9. 2
 and the corresponding 1-oxide separates or oxidizes to the 1-oxide of a 3-oxocepham compound of the formula IV, if desired, converts a compound obtained into a ketal or converts the 3-oxo group into a protected enol group and, if appropriate, then cleaves off the amino protective group RtA, and / or if desired,

   a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, a mixture of isomers obtained is separated into the individual isomers. 



      In a starting material of the formula III, the protected carboxyl group of the formula -C (= O} -R2A in the 4-position preferably has the a-configuration. 



   In a starting material of the formula III, an amino protective group RIA is a group which can be replaced by hydrogen, primarily an acyl group Ac, and also a triaryl methyl group, in particular the trityl group, and an organic silyl group and an organic stannyl group.  Any free functional groups present in an acyl group Ac, e.g.  B.  Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups z.  B.  by acylating, tritylating, silylating or stannylating, and hydroxy, carboxy or phosphono groups, e.g.  B.  by etherification or esterification, incl. 

  Silylating or stannylating.    R2i preferably denotes an etherified hydroxyl group with the -C (= O) grouping, in particular under mild conditions, cleavable, esterified carboxyl group-forming, with any functional groups present in a carboxyl protecting group R2A in a manner known per se, e.g.  B.  as stated above, may be protected.  A group R2A is e.g.  B. 



  in particular an optionally substituted, such as lower alkoxy, e.g.  B.  Methoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as, if appropriate, e.g.  B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethoxy, or 4,4'-dimethoxy-diphenylmethoxy, and an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, or 2-halo-lower alkoxy, wherein halogen is e.g.  B.  Represents chlorine, bromine or iodine, primarily 2,2,2-trichloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy. 



   The oxidative degradation of the methylene group in a starting material of the formula III is preferably carried out with the 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.  a lower halogen 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 - 900 C 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 nickel, also palladium, 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, furthermore 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 trunethyl phosphite, or phosphorous acid triamides which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexane-lower alkyl zigsäuretriamide.  B. 

  Hexamethyl phosphorous acid triamide, the latter preferably in the form of a methanol adduct, or tetracyanoethylene.  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 type of oxidation reaction, a compound of the formula IV 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 IV and the corresponding 1-oxide, or it can be oxidized to the uniform 1-oxide of a compound of the formula IV. 



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



   Furthermore, an obtainable mixture of a compound of the formula IV and a 1-oxide thereof can also be oxidized directly to the 1-oxide of a compound of the formula IV.  Suitable oxidizing agents are inorganic peracids which have a reduction potential of at least + 1.5 volts and consist of non-metallic elements, organic peracids or mixtures of hydrogen peroxide and acids, 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, trifluoroperacetic 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 / 0 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 are 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%, with larger excesses, ie.  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.degree. C. to about + 1000.degree. C., preferably from about -100.degree. C. to about +400.degree.  Depending on the oxidizing agent used, one obtains the la or the 1ss oxide or a mixture of the two. 



   Ketal derivatives of compounds of the formula IV can be prepared in a manner known per se, e.g.  B.  by treating with a glycol, thioglycol or dithioglycol in the presence of an acidic catalyst such as p-toluenesulfonic acid, a Lewis acid such as zinc (II) chloride (especially when using thioglycol, usually using a water adsorbent such as sodium sulfate) or one acidic ion exchanger, usually in the presence of an inert solvent such as an optionally halogenated, such as chlorinated, preferably aliphatic hydrocarbon, or a suitable, optionally cyclic ether, e.g.  B.  Dioxane, or by ketal exchange, e.g.  B.  by treating with a ketal of a lower alkanone, e.g. 

  B.  2,2-ethylenedioxybutane, in the presence of a strong acid such as p-toluenesulfonic acid, or a ketal of a disubstituted formylamine compound, such as an N-formyl-N, N-dinie deralkyl-arains, e.g.  B.    (1,3-dioxolan-2-yl) -N, N-dimethylamine, in the presence of an acid, e.g.  B.  Acetic acid. 



   Ketal compounds of compounds of the formula IV can subsequently be cleaved in a manner known per se, ketals and thioketals z.  B.  by means of acid hydrolysis, such as with an aqueous inorganic or organic acid, e.g.  B.  Hydrochloric acid, formic acid or trifluoroacetic acid, usually in the presence of an inert solvent, such as an optionally halogenated, such as chlorinated, preferably aliphatic hydrocarbon, or a suitable, optionally cyclic ether, dithioketals z.  B.  by treatment with mercury (II) chloride (usually in the presence of an aqueous solvent, e.g.  B.  Acetone or dioxane) or with an N-haloamide such as N-bromosuccinimide. 



   Compounds of the formula IV that can be obtained are converted into compounds of the formula II by splitting off RtA, it being necessary to ensure that reaction conditions are selected under which the oxo group in the 3-position and the protected carboxyl group of the formula -C (= O) -R2t remain intact, with the oxo group also protected, e.g.  B.  can be protected in the form of a functionally modified enol group, such as a silylated or stannylated enol group, or a ketal group.  Furthermore, if necessary, free functional groups not participating in the reaction, free amino groups, for.  B.  by acylating, tritylating or silylating, free hydroxyl or mercapto groups e.g.  B.  by etherification or esterification, and free carboxyl groups e.g.  B.  by esterification, incl. 

  Silylating, be protected. 



   In a compound of the formula IV obtained, an amino protective group RtA, in particular an easily cleavable acyl group, is used in a manner known per se, e.g.  B.  an apolybranched 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 which noses together with the metal or the metal compound, preferably in the presence of aqueous acetic acid. 



  Furthermore, in a compound of formula IV obtained in which the oxo group is in the 3-position, e.g.  B.  in the form of a functionally modified, such as is protected in the form of a ketal group, an acyl group RtA, in which any free functional groups which may be present, amino groups e.g.  B.  in the form of acylamino groups or silylated amino groups, and / or carboxy groups e.g.  B.  in the form of esterified or silylated carboxy groups, protected, can be split off by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the amino ether formed. 



   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.  These are primarily acid halides of organic acids, especially of phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus ptahalides, eg.  B.  Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, as well as acid halides, in particular 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 preferably 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 Äthyldiisopropylaniin, also an N, N, N ', N'-Tetraniederalkyl-Niederalkylenediamins, z.  B. 



     N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N 'tetramethyl-1,6-hexyldiamine, 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-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclones; DBN), or a tertiary aromatic amine, such as one Di-lower alkyl aniline, e.g.  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, aliphati rule 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.  be present in about 0.2 to about 1-fold amount or then in about to 10-fold, in particular about 3 to 5-fold excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g.  B.  carried out at temperatures of about -500 ° C. to about + 10 ° C., but also at higher temperatures, d.  H.  z.  B.  up to about 750 C, if the stability of the starting materials and products allow an elevated 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, n-propanol, isopropanol or n-butanol, in particular methanol, also 2,2,2-trichloroethanol, 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-SO0 C to about 100 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.  It is preferred 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, if necessary, can be obtained 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 three-step process for cleaving an acyl group described above 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. 



   Certain acyl radicals R1A of an acylamino group in available compounds of the formula IV, 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 with halo-lower alkanoyl, such as dichloroacetyl, can also be protected by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen-donating agent such as an N-halogene 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 treating 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-5carboxy-valeryl radical RtA and the carboxy group z.  B.  is protected by esterification by.  Allowing 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 by methods known per se, are split off. 



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



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



   The starting materials of formula III can, for.  B.  be prepared by in a cephem compound of the formula
EMI12. 1
 where R2 preferably represents hydroxy, but also represents a group R2A, the acetyloxymethyl group, e.g.  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 tritolyl, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis, converted into the hydroxymethyl group, a functionally modifying free carboxyl group of formula -C ("0) '- 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 agent, e.g.  B.  Thionyl chloride, or an iodizing agent, e.g.  B.    N-methyl-N, N'-dicyclohexyl-carbodiimidium iodide into the halomethyl, e.g.  B.  Chloromethyl resp.  Converts iodomethyl group.  This chloromethyl group can either be used directly, e.g.  B.  by treating with a suitable chromium-II compound such as an inorganic or organic salt thereof, e.g.  B.  Chlorom-II-chloride or chromium II-acetate, in a suitable solvent such as dimethylsulfoxide, or then indirectly via the iodomethyl group (which can be used e.g. 

  B.  by treatment with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted into the methylene group of the starting material of the formula III by treatment with a suitable reducing agent such as zinc in the presence of acetic acid.  In a compound of the formula III obtained, an amino protective group RtA can split off as indicated above and replace it with hydrogen. 



   As mentioned above, the new compounds of the formula I and l-oxides thereof can be used as intermediates for the preparation of compounds with the cepham structure which either have valuable pharmacological properties or can in turn be used as intermediates. 



   So you can z.  B.  the compounds of formula I and l-oxides thereof into their enol derivatives, eg.  B.  by treatment with an optionally substituted diazo hydrocarbon compound of aliphatic character N2-RA such as a diazo lower alkane, e.g.  B.  Diazomethane, or a phenyl-diazo lower alkane, such as phenyldiazomethane, into an enol ether, or by treating with an acid HO-RA or preferably a suitable acid derivative such as halide, e.g.  B. 

  Chloride or anhydride, to convert into an enol ester and, if desired, in enol derivatives obtainable in this way, convert a protected carboxyl group of the formula -C (= O) -R2A in a manner known per se into a free carboxyl group and thus to cephem compounds of the formula
EMI12. 2
 which contain a double bond in the 2,3- or 3,4-position, and l-oxides of those compounds of the formula VI which contain a double bond in the 3,4-position and in which Ac has the meaning given above, R2A for Hydroxy or a radical R2A which forms a protected carboxyl group with the carbonyl group, and RA denotes an optionally substituted hydrocarbon radical of aliphatic character or an acyl group.  

  Compounds of the formula VI, in particular those in which Ac is an acyl radical contained in pharmacologically active N acyl derivatives of 6ss-amino-penam-3-carboxylic acid and 7ss-amino-3-cephem-4-carboxylic acid compounds, and R2A is hydroxy or a, together with the carbonyl grouping an etherified hydroxyl group which is cleavable under physiological conditions and which forms a carboxyl group, and RA has the meaning given above, as well as salts of such compounds, are against Mi ktoorganismen, such as gram-positive bacteria, z.  B.  Staphylococcus aureus, (e.g.  B.  in mice at doses of about 0.001 to about 0.02 g / kg p.  O. ), and gram-negative bacteria, e.g.  B. 



  Escherichia coli (e.g.  B.  in mice at doses of about 0.001 to about 0.05 g / kg p.    O.  >, also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, in particular against penicillin-resistant bacteria, effective, and can therefore, accordingly, z.  B.  in the form of antibiotic preparations, use. 



   The available, usable as intermediates 1 oxides of 3-cephem compounds of the formula VI can be obtained by reduction, e.g.  B.  by means of phosphorus trichloride, are converted into the 3 cephem compounds of the formula VI. 



   Furthermore, in the cepham compounds of the formula I and in l-oxides thereof, the oxo group in the 3-position, e.g.  B.  by treating with a suitable complex metal hydride, such as sodium borohydride, in the presence of a suitable solvent, such as an alcohol or ether, reduce to the hydroxyl group and, if desired, convert the hydroxyl group into an esterified, in particular into one esterified by an organic carboxylic acid, and / or convert a protected carboxyl group of the formula -C (= O) -R2i into the free carboxyl group. 

  In the thus obtainable cepham compound of the formula
EMI13. 1
 and an l-oxide thereof, in which RB is hydrogen or an acyl radical, the elements of a compound of the formula Rg — OH (VI), d.  H.  of water or an acid, under acidic resp.  basic conditions are split off, and the known 3-cephem compounds of the formula are obtained
EMI13. 2
 or.  1-oxides thereof, in which Ac and R2A have the meanings given above, and in which these radicals can be converted into one another in a manner known per se. 

  The
Compounds of the formula VII or salts thereof have ent neither valuable pharmacological, in particular antimicrobial properties, especially those in which
Ac stands for an acyl radical contained in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid and 7ss-amino-3-cephem-4-carboxylic acid compounds, and R2A is hydroxy or one, together with the carbonyl group, one below Under physiological conditions cleavable carboxyl group-forming etherified hydroxyl group, or salts thereof, or can be used as intermediate products for the preparation of the compounds mentioned with pharmacological properties. 



   The available 1
Oxides of the 3-cephem compounds of the formula VIII can according to Swiss Patent No.  582 710 by reduction, e.g.  B.  using phosphorus trichloride, in the 3
Cephem compounds of the formula VIII are converted. 



   In the above conversions of inventive
Compounds of the formula I to the compounds of the formula V or  Compounds of the formula I need not be isolated from the compounds of the formulas VI and VIII; they can be converted directly into the compounds of the formula V or in the form of the crude reaction mixtures after preparation from the compounds of the formula II.  VI and VIII transfer. 



   In connection with the present description, organic radicals denoted lower contain 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 invention; Temperatures are given in degrees Celsius. 



   example 1
A solution of 0.250 g of the 4-methylphenylsulfonic acid salt of 7ss-amino-cepham-3-one-4 $ -carboxylic acid-diphenyl-methyl ester, which is mainly in the enol form of 4-methylphenylsulfonate of 7ss-amino-3-cephem-3-ol- 4-carboxylic acid diphenylmethyl ester is present, 0.063 ml of trimethylchlorosilane and 0.044 ml of pyridine are added to 10 ml of methylene chloride and the mixture is stirred at room temperature for 30 minutes and then cooled to 0.  0.088 ml of pyridine and 0.092 ml of phenylacetic acid chloride are added, the mixture is left to react for one hour at 0 and for a further hour at room temperature and is diluted with 5 ml of a 1: 1 mixture of dioxane and water and stirred for 10 minutes. 

  It is diluted with 50 ml of methylene chloride, the phases are separated and the organic solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is chromatographed on silica gel; the 7ss phenylacetylamido-cephern-3-one-4ca? oonic acid-diphenylmethyl ester is eluted with methylene chloride; Thin layer chromatogram (silica gel): Rf N 0.55 (system:

  Ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in 950 / above aqueous ethanol): λ max = 283 m (e = 4400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 94 t, 5. 12 111, 5. 77, 5. 93 for 6. 21 jt and 6. 63.    



   The starting material can be made as follows:
A solution of 11.82 g of the crude sodium salt of 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid (prepared by enzymatic deacetylation of the sodium salt of 3-acetyloxymethyl-7-ss-phenylacetylamino3-cephem-4-carboxylic acid with the aid of a purified enzyme extract from Bacillus subtilis, strain ATCC 6633, and subsequent lyophilization in 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 it is warm and, after cooling to room temperature, left to stand at about 40 for some time. 

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176 = 176.50 (uncorr. ); [α] 20 D = -6 # 1 (c = 1.231% in chloroform); Thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light 225); 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). 



   1.03 g of 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide are dissolved under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for one hour at 350.  Another 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide in 15 ml of absolute tetrahydrofuran is 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 the 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 o / o 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 yields the 3-iodomethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester; the fractions which are uniform by thin-layer chromatography are lyophilized from benzene, infrared absorption spectrum (in methylene chloride: characteristic bands at 3. 00, 5. 62, 5. 82, 5. 95, 6. 70, 7. 32 and 8. 16. 



   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'-dicyclohexylcarbodiimide 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 700. 



  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 400 ° C.  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 attached nitrogen 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 colorless the slightly yellowish crystal mass on the glass suction filter to wash. 

  After drying for 20 hours at 0.1 mm Hg 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 and 6. 00, u.    



   A solution of 0.400 g of 3-iodomethyl-7ss-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 with thorough stirring.  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, with two portions of 30 ml each
Methylene chloride extracted 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-7ss-phenylacetylamino-cepham-4a-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.  144-147; [α] D20 = -18 # 1 (c = 0.715 in
Chloroform); Ultraviolet absorption spectrum (in 950% aqueous ethanol): ,, max = 254 m, a (e = 1540) and 260 m, u (± = 1550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 49, 5. 65, 5. 74 Lc,
5. 94, 6. 26 and 6. 67. 



   A solution, cooled to -150, of 2.0 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-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 80% 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 value to 2 with 20/0 aqueous phosphoric acid and the mixture is stirred for 30 minutes at room temperature. 



   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, at 0, a solution of 1.14 g of 4-methylphenylsulfonic acid monohydrate in 25 ml of methylene chloride is added.  A voluminous precipitate separates out, which is filtered off, washed with cold ethyl acetate and diethyl ether, dried and recrystallized from a mixture of methylene chloride and diethyl ether. 

  The 4-methylphenylsulfonate of the 7ss amino-3-methylen-cepham-4α-carboxylic acid diphenylmethyl ester is obtained in this way in the form of colorless needles, F.    153-1550; [a = - 140 + 10 (c = 0.97 in methanol); Ultraviolet Absorption Spectrum (in ethanol): ,, max = 257 u (e = 1500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.5, 5.60 1U, 5.73, 8.50, 9.68 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 4-methylphenylsulphonate of 7ss-amino-3-methylene-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 -700, for one hour at-120 and for one hour in an ice bath, then evaporated.  The residue is in a small amount
Methylene chloride added, then with until cloudy
Diethyl ether added and left to stand.  

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

  Ethyl acetate / pyndine / water 85: 10: 5); Ultraviolet absorption spectrum (in ethanol, \: #max = 262 m (e = 3050) and 282 m (e = 3020); infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58, u, 5.77 (shoulder), 6, 02 z and
6.22. 



      Example 2
In an analogous manner, the following compounds can be obtained when the suitable starting materials are selected:
7ss- [D-α-tert. -Butyloxycarbonylamino-α- (4-hydroxyphenyl) acetylamino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;
7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-thienyl) -acetyl amino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;
7ss- [D-α-tert. -Butyloxycarbonylamino-α- (3-thienyl) -acetyl amino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-furyl) -acetylamino cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (4-isothiazolyl) -acetyl amino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;

   7ss- [D-α-tert. -Butyloxycarbonylamino-α- (1,4-cyclohexanedienyl) acetylamino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- (2-thienyl) -acetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- (1-tetrazolyl) -acetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- (1-pyridylthio) -acetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;
7ss- (1-aminopyridinium) -acetylamino-cepham-3-one-4-carboxylic acid diphenylmethyl ester;
7ss- [D-α- (2,2,2-trichloroethoxycarbonyloxy) -α-phenyl-acetyl amino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;
7ss-Phenylacetylamino-cepham-3-one-4α-carboxylic acid diphenylmethyl ester-1-oxide, thin-layer chromatogram (silica gel):

  Rf = 0.22 (toluene / acetone / methanol / acetic acid system 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 69, 5. 58, 5. 76 (shoulder), 5. 83, 5. 97, 6. 22 and 6. 61; the compound shows a positive iron (III) chloride reaction, which suggests the presence of the enol form;
7ss- (D-α-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; Rf
Value of ¯ 0.5 (silica gel; system:

  Toluene / acetone / methanol / acetic acid 80:10: 4: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at
2. 94, 3. 40, 5. 62, 5. 77, 5. 75-5. 59 (broad band),
6th 21 and 6. 88; 7ss- (D-α-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) cepham-3-one-4 # -carboxylic acid 4-nitro-benzyl ester; 7ss- (D-α-tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) cepham-3-one-4 # -carboxylic acid 2,2,2-trichloroethyl ester; 7ss- (5-Benzoylamino-5-diphenylmethoxycarbonylvaleryl amino) -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester. 



   The compounds obtainable according to the invention can be further processed, for example, as follows:
Example 3 a) A solution of 1.0 g of 7ss-phenylacetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester in 100 ml of methanol is cooled to 0 and the mixture is treated with a solution of 0.10 g Sodium borohydride in 5 ml of water. 



  The reaction mixture is left to react at 0 for 30 minutes, the pH is adjusted to about 6 by adding acetic acid and the reaction mixture is evaporated under reduced pressure. 



     The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  Of the
The residue is chromatographed on 50 g of silica gel. 

  The 3 # -hydroxy-7ss-phenylacetylamino-cepham-4α-carbonic acid diphenylmethyl ester is eluted with a 2: 1 mixture of toluene and ethyl acetate, which, after crystallization from a mixture of acetone and dietary ether, melts at 157160; [α] D = + 80 # 1 (c = 0.492 in dioxane): #max =
258 m (e = 850); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 82, 2. 94, a, 5. 63, * 4,,
5. 74, 5. 92, 6. 25 and 6. 63. 



   b) A mixture of 0.312 g of 3 # -hydroxy-7ss-phenyl-acetylamino-cepham-4α-carboxylic acid diphenylmethyl ester in
15 ml of pyridine and 7 ml of acetic anhydride is during 16
Left to stand for hours at 0 and after adding 50 ml
Toluene evaporated under reduced pressure.  The residue is taken up in ethyl acetate; the organic solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. 

  The residue is purified by means of preparative thin layer chromatography; a 100 cm silica gel plate is used
Length and developed with a 1: 1 mixture of toluene and
Ethyl acetate.  The 3 $ -acetyloxy-7ss-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester is obtained with Rf = 0.47, which, after crystallization from a mixture of methylene chloride and pentane, melts at 162164; [α] 20 D = + 55 # 1 (c = 0.492 in chloroform);
Ultraviolet absorption spectrum (in 95/0 ethanol);

  ; AmaX = 253 m (# = 700), 258 m (# = 820) and 265 m (# =
660); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 96, 5. 66, 5. 77, 5. 97, 6. 28, b to and 6. 71 ,.    



   c) A mixture of 0.150 g of 3 # -acetyloxy-7ss-phenyl-acetylamino-cepham-4α-carboxylic acid diphenylmethyl ester and 5 ml of methylene chloride is mixed with 0.1 ml of triethylamine and left to stand for 16 hours at room temperature.  The reaction mixture is diluted with 100 ml of methylene chloride; the organic phase is with 50 ml of 2-n.     Hydrochloric acid and 50 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure.  Of the
The residue is purified by means of preparative thin-layer chromatography (2 silica gel plates 20 cm in length, system: toluene / ethyl acetate 3: 1). 

  A pale yellowish b1 is obtained with Rf = 0.36, which crystallizes from a mixture of methylene chloride and hexane.  The product is the 7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester, F.  161-163, [α] D20 = +30 # 1 (c = 0.968 in dioxane); Thin-layer chromatogram (silica gel; identification in ultraviolet light and with iodine vapor): Rf = 0.55 (system: toluene / acetone 4: 1), Rf = 0.35 (system: toluene / acetone 9: 1) and Rf = 0.40 (System:

  Toluene / ethyl acetate 4: 1); Ultraviolet absorption spectrum: #max = 258 m (# = 6100) and #min = 240 m (# = 5250) (in methylene chloride) and #max = 259 m (# = 6050) and #min = 239 m (# = 4950) ( in 95% aqueous ethanol); Infrared absorption spectrum: characteristic bands at 2. 90, 5. 57, 5. 76, 5. 91, 6. 09, 6. 66, 7. 13, 8. 12, 8. 63, 9. 07, 10. 43 and 12. 22 (in methylene chloride) and 3. 01, 5. 60, 5. 82, 6. 04, 6. 08 (shoulder), 6. 51, and 7. 13 (in mineral oil). 



   d) A solution of 0.566 g of 7ss-phenylacetylamino-3cephen-4-carboxylic acid diphenylmethyl ester in 2.5 ml of anisole and 10 ml of trifluoroacetic acid is left to stand for 20 minutes at room temperature and then several times with the addition of toluene until the trifluoroacetic acid is completely removed Taken dry.  The residue is taken up in ethyl acetate and 0.5 molar aqueous dipotassium hydrogen phosphate solution and the phases are separated.  The aqueous solution is washed twice with ethyl acetate and the organic solution twice with 0.5 molar aqueous dipotassium hydrogen phosphate solution.  The combined aqueous solutions are covered with fresh ethyl acetate and acidified with 20% aqueous phosphoric acid. 

  It is extracted with ethyl acetate, the organic solution is washed with a saturated aqueous sodium chloride solution and dried over
Magnesium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed on 50 times the amount of silica gel (washed with concentrated hydrochloric acid) and the 7ss-phenylacetylamino-3-cephem-4-carboxylic acid is eluted with methylene chloride containing 10-20% methyl acetate. 

  The fractions which are uniform according to thin-layer chromatography are crystallized from a mixture of methyl acetate and cyclohexane; the colorless crystals melt at 190-191; Thin-layer chromatogram (silica gel; development with iodine vapor or identification under ultraviolet light): Rf = 0.58 (system: n butanol / acetic acid / water 75: 7.5: 21), Rf = 0.265 (system: n butanol / ethanol / water 40: 10:50), Rf = 0.53 (system: n butanol / acetic acid / water 40:10:40), Rf = 0.43 (system: ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11) and Rf = 0.43 (system: ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10). 



   e) A solution of 1.94 g of 7ss-phenylacetylamino-3cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of absolute methylene chloride is cooled to - 150, then with 3.86 ml of absolute pyridine and 31.6 ml of an 8% solution of Phosphorus pentachloride in methylene chloride was added and the reaction mixture was stirred for 30 minutes at -10 and for a further 30 minutes at -50.  The golden yellow solution is cooled to -200 and 26.8 ml of absolute methanol are added so quickly that the internal temperature does not rise above -100.  The reaction mixture is stirred for one hour at -100, left to stand for a further hour at 25-30 and then 80 ml of a 0.5 molar aqueous potassium dihydrogen phosphate solution are added with vigorous stirring. 

  The pH of the two-phase reaction mixture is adjusted to 2 by the dropwise addition of 20% phosphoric acid, the mixture is stirred for 20 minutes at room temperature and the phases are separated.  The aqueous solution is washed twice with methylene chloride; the combined organic solutions are washed with two portions of 20 ml of water each and dried over anhydrous magnesium sulfate. 



   The solvent is removed under reduced pressure; the oily residue is applied to a column of 110 g of silica gel (5% water content).  It is eluted with methylene chloride phenylacetic acid methyl ester and with methylene chloride containing 3 0/0 acetic acid methyl ester the 7ss amino-3-cephem-4-carboxylic acid-diphenylmethylester, which is crystallized by dissolving in a small amount of methylene chloride and adding the solution to the warmth with diethyl ether (needle-shaped Crystals), washes with cold diethyl ether and dries, F.  153-154; Thin-layer chromatogram (silica gel): Rf = 0.50 (system: toluene / acetone 4: 1), Rf = 0.65 (system: toluene / acetone 2: 1), Rf = 0.40 (system:

  Toluene / ethyl acetate 1: 1) and Rf = 0.33 (toluene / diethyl ether system 1: 1); Ultraviolet absorption spectrum: #max = 257 m (# = 8150) and #min = 245 m (# = 7730) (in methylene chloride) and #max = 255 m (# = 5500) and #min = 236 m (# = 4650) ( in 95% ethanol);

  Infrared absorption spectrum: characteristic bands at 2. 91, 5. 61 tG, 5. 78 for 6. 11 to 7. 14 to 8. 15 to 8. 29 Al, 9. 14 and 9. 83 u (in methylene chloride) and at 2. 99, 5. 65, 5. 77, 6. 08, 7. 14, 7. 74, 7. 84, 8. 08, 8. 53, 9. 14, 9. 85 and 10. 35, ii (in mineral oil). 



   e) 0.380 g of 7ss-amino-3-cephen-4-carboxylic acid diphenylmethyl ester is poured over with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, and the clear solution is left during
Stand for 10 minutes at room temperature and then dilute with about 20 ml of absolute toluene.  The mixture is evaporated under reduced pressure; the residue is taken to dryness twice more together with toluene and then suspended in 5 ml of methanol, 5 ml of diethyl ether and 0.5 ml of water.  The pH of the suspension is adjusted to 3.5 by adding dropwise a 5% solution of triethylamine in methanol; the mixture is left to stand in an ice bath for 30 minutes and the fine precipitate is filtered using a suitable glass suction filter. 

  The pale beige-colored filter residue is washed with a mixture of methanol and methylene chloride, then with diethyl ether and dried under reduced pressure at 350 The 7ss-amino-3-cephem-4-carboxylic acid, which is obtainable as a fine microcrystalline powder, decomposes at 2150; Thin-layer chromatogram (silica gel; development with iodine): Rf = 0.12 (system: n-butanol / acetic acid / water 67:10:23), Rf = 0.28 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30) and Rf = 0.21 (system:

  Ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Infrared absorption spectrum (in mineral oil): characteristic bands at 3. 12 to 3. 80, 4. 12 (shoulder), 4. 92 to the 5th 54, 6. 05 u (shoulder), 6. 19 to 6. 55 tG, 7. 05 for the 7th 42, 8. 23, 8. 79 to 9. 55, 12. 08 tG, 12. 69 and 13. 04 tG.    



   f) A suspension of 0.070 g of 7ss-amino-3-cephem4-carboxylic acid in 2 ml of absolute methylene chloride is mixed with 0.031 g of triethylamine in 0.35 ml of methylene chloride, the suspension is diluted with 5 ml of absolute tetrahydrofuran and for 30 minutes, sometimes in an ultrasonic bath , touched. 



   0.102 g of tert is dissolved. -Butyloxycarbonyl-D-α-phenylglycine in 5 ml of absolute methylene chloride, mixed with 0.040 g of 4-methylmorpholine, and diluted with 10 ml of acetonitrile.  The mixture is cooled to -200 and, with stirring, 0.060 g of isobutyl chloroformate is added, whereupon the mixture is allowed to react at-150 for 30 minutes.  After cooling again to below -200, the milky suspension of the triethylammonium salt of 7ss-amino-3-cephem-4-carboxylic acid is then added.  The reaction mixture is stirred for 30 minutes at -150, for a further 30 minutes at 0 and finally for 2 hours at room temperature.  It is filtered, washed with acetonitrile, methylene chloride and diethyl ether and the filtrate is dried, which is evaporated to dryness. 

  The residue is taken up in ethyl acetate and water and the mixture is stirred by vigorous stirring and cooling with ice by adding 5 molar aqueous solution. Phosphoric acid acidified to pH 2.  The organic phase is separated off and washed four times with a small amount of a saturated aqueous sodium chloride solution. 

 

  The aqueous extracts are re-extracted with 2 portions of ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulfate and freed from the solvent under reduced pressure.  The residue is chromatographed on 10 g of silica gel (column; addition of 5% water). 

  Unreacted tert is eluted first. -Butyloxycarbonyl-D-a-phenylglycine with methylene chloride and methylene chloride containing increasing proportions of acetone, and then the 7ss- [N- (N-tert. -Butyloxycarbonyl-1) -α-phenylglycyl) -amino] -3-cephem-4-carboxylic acid, which is obtained in amorphous form; Ultraviolet absorption spectrum (in 950% ethanol): Am3n = = 252 m, a (e = 5100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.61, 5.85, 5.92 and 6.12; Thin-layer chromatogram (silica gel G; detection with iodine vapor): Rf = 0.6 = 0.7 (system: n-butanol / acetic acid / water 44:12:44). 



   g) A solution of 0.02 g of 7ss- [N- (N-tert. -Butyloxycar- bonyl-D-a-phenylglycyl) -amino] -3-cephem-4-carboxylic acid in 3 ml of pure trifluoroacetic acid is left to stand at room temperature for 15 minutes.  The resulting solution is evaporated in a rotary evaporator, the residue is taken to dryness twice with 20 ml of a 1: 1 mixture of chloroform and toluene to completely remove the trifluoroacetic acid and dried at 0.0001 mm Hg for 16 hours. 

  The 7ss- [N- (D-α-phenylglycyl) -amino] -3-cephem-4-carboxylic acid is obtained as a yellowish amorphous powder by adding an equivalent amount to a solution in water and methanol of the salt obtained with trifluoroacetic acid Triethylamine is added, evaporated and the residue digested with methylene chloride, thin-layer chromatogram (silica gel; development with iodine vapor): Rf = 0.29 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in water): #max = 250 m, a (e = 4300). 



   Example 4 a) A solution of 1.0 g of 7ss-phenylacetylamino-cepham 3-one-4α-carboxylic acid diphenylmethyl ester is taken up in 50 ml of methanol and an excess of diazomethane (in the form of a solution in diethyl ether) is added at 0. 



  The mixture is stirred for one hour at 0 and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel.  The 3-methoxy-7ss-phenyl acetylamino-2-cephem-4amcarboxylic acid diphenylmethyl ester with Rf = 0.57 is eluted with a 4: 1 mixture of toluene and ethyl acetate (system:

  Toluene / ethyl acetate 1: 1); F.  174 to 1770 after crystallization from a mixture of methylene chloride and pentane; Ultraviolet absorption spectrum (in 950% aqueous ethanol): im3x = 258 mn (e = 4310); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 96, 5. 60, 5. 71, 5. 92, 6. 15 and 6. 66; followed by 3-methoxy-7ss-phenylacetylamino-3cephem-4-carboxylic acid diphenylmethyl ester with Rf ¯ 0.37 (system: toluene / ethyl acetate 1: 1);

  Ultraviolet absorption spectrum (in 950 / o aqueous ethanol): λmax = 258 m (# = 6340), #max = 264 m (# = 6350) and #shoulder = 261 m (# = 5600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2. 94, 3. 02, 5. 62, 5. 67 (shoulder), 5. 81, 5. 92, 6. 23 and 6. 67. 



   b) A mixture of 0.06 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is left to stand for 5 minutes 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). 

  The amorphous 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid is eluted with methylene chloride containing 30-50% acetone and lyophilized from dioxane, ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 259 m (e = 4970) and 265 m, c (e = 4950); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3. 03 for the 5th 60, 5. 74, 5. 92, 6. 24 y and 6. 67.    



   The 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid can be prepared in an analogous manner by the 7ss- (D-α-tert. -Butyloxycarbonyl-amino-α-phenylacetyl-amino) -cepham-3-one-4α-carboxylic acid diphenylmethyl ester is treated with diazomethane, and after reacting with trifluoroacetic acid in the presence of anisole from the 3-methoxy-7ss- (Da-tert. -butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem-4 ° carboxylic acid diphenylmethyl ester, the desired 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid is obtained . 



   The 3-methoxy-7ss- (D-α-phenylglycyl-amino-3-cephem-4-carboxylic acid can also be obtained if the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester the phenylacetylamino group by treatment with phosphorus pentachloride in the presence of pyridine at about - 100, followed by methanol at about - 150 and hydrolysis at a pH of about 3 cleaves the free amino group in the 7ss-amino-3-methoxy-3-cephem- 4-carboxylic acid diphenylmethyl ester by treating with the mixed anhydride from a-tert. -Butyloxycarbonylamino-a-phenylacetic acid and isobutyl chloroformate acylated and in the 3-methoxy-7ss- (D-α-tert. -butyloxycarbonylamino?

  - phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester liberates the amino and carboxy groups by treatment with trifluoroacetic acid in the presence of anisole. 



   PATENT CLAIM 1
Process for the preparation of 7ss-acyl-amino-cepham-3-one-4-carboxylic acid derivatives of the formula
EMI17. 1
 wherein Ac represents an acyl group and R2A represents a radical which together with the carbonyl group -C (= O) - forms a protected carboxyl group, and 1-oxides of compounds of the formula I, or salts of such compounds with salt-forming groups, characterized that one in a compound of the formula
EMI17. 2
 wherein R2A has the meaning given under formula I, in a 1-oxide or a salt thereof, with intermediate protection of the 3-oxo group, the 7ss-amino group to a 7ss acylamino group Ac-NH- acylated, and a compound obtained with a salt-forming group as Salt or isolated as a free compound. 

 

      SUBCLAIMS
1.  Process according to patent claim I, characterized in that a starting material of the formula II is used in which the 3-oxo group is functional in the form of a

** WARNING ** End of DESC field could overlap beginning of CLMS **. 



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. obtained in amorphous form; Ultraviolet absorption spectrum (in 950% ethanol): Am3n = = 252 m, a (e = 5100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.61, 5.85, 5.92 and 6.12; Thin-layer chromatogram (silica gel G; detection with iodine vapor): Rf = 0.6 = 0.7 (system: n-butanol / acetic acid / water 44:12:44). g) A solution of 0.02 g of 7ss- [N- (N-tert-butyloxycarbonyl-Da-phenylglycyl) -amino] -3-cephem-4-carboxylic acid in 3 ml of pure trifluoroacetic acid is at room temperature for 15 minutes ditched. The resulting solution is evaporated in a rotary evaporator, the residue is taken to dryness twice with 20 ml of a 1: 1 mixture of chloroform and toluene to completely remove the trifluoroacetic acid and dried at 0.0001 mm Hg for 16 hours. The 7ss- [N- (D-α-phenylglycyl) -amino] -3-cephem-4-carboxylic acid is obtained as a yellowish amorphous powder by adding an equivalent amount to a solution in water and methanol of the salt obtained with trifluoroacetic acid Triethylamine is added, evaporated and the residue digested with methylene chloride, thin-layer chromatogram (silica gel; development with iodine vapor): Rf = 0.29 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in water): #max = 250 m, a (e = 4300). Example 4 a) A solution of 1.0 g of 7ss-phenylacetylamino-cepham 3-one-4α-carboxylic acid diphenylmethyl ester is taken up in 50 ml of methanol and an excess of diazomethane (in the form of a solution in diethyl ether) is added at 0. The mixture is stirred for one hour at 0 and then evaporated under reduced pressure. The residue is chromatographed on 50 g of silica gel. The 3-methoxy-7ss-phenyl acetylamino-2-cephem-4amcarboxylic acid diphenylmethyl ester with Rf = 0.57 is eluted with a 4: 1 mixture of toluene and ethyl acetate (system: Toluene / ethyl acetate 1: 1); F. 174 to 1770 after crystallization from a mixture of methylene chloride and pentane; Ultraviolet absorption spectrum (in 950% aqueous ethanol): im3x = 258 mn (e = 4310); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.60, 5.71, 5.92, 6.15 and 6.66; followed by 3-methoxy-7ss-phenylacetylamino-3cephem-4-carboxylic acid diphenylmethyl ester with Rf ¯ 0.37 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 950 / o aqueous ethanol): λmax = 258 m (# = 6340), #max = 264 m (# = 6350) and #shoulder = 261 m (# = 5600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 3.02, 5.62, 5.67 (shoulder), 5.81, 5.92, 6.23 and 6.67. b) A mixture of 0.06 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 0.05 ml of anisole and 1 ml of trifluoroacetic acid is left to stand for 5 minutes 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). The amorphous 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid is eluted with methylene chloride containing 30-50% acetone and lyophilized from dioxane, ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 259 m (e = 4970) and 265 m, c (e = 4950); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03 to 5.60, 5.74, 5.92, 6.24 y and 6.67. The 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid can be prepared in an analogous manner by using the 7ss- (D-α-tert-butyloxycarbonyl-amino- α-phenylacetyl-amino) -cepham-3-one-4α-carboxylic acid diphenylmethyl ester is treated with diazomethane and, after reaction with trifluoroacetic acid in the presence of anisole, the 3-methoxy-7ss- (Da-tert. -butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem-4 ° carboxylic acid diphenylmethyl ester, the desired 3-methoxy-7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid is obtained . The 3-methoxy-7ss- (D-α-phenylglycyl-amino-3-cephem-4-carboxylic acid can also be obtained if the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester the phenylacetylamino group by treatment with phosphorus pentachloride in the presence of pyridine at about - 100, followed by methanol at about - 150 and hydrolysis at a pH of about 3 cleaves the free amino group in the 7ss-amino-3-methoxy-3-cephem- Diphenylmethyl 4-carboxylate is acylated by treatment with the mixed anhydride of a-tert.-butyloxycarbonylamino-a-phenylacetic acid and isobutyl chloroformate and converted into 3-methoxy-7ss- (D-α-tert-butyloxycarbonylamino α). - phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester liberates the amino and carboxy groups by treatment with trifluoroacetic acid in the presence of anisole. PATENT CLAIM 1 Process for the preparation of 7ss-acyl-amino-cepham-3-one-4-carboxylic acid derivatives of the formula EMI17.1 wherein Ac represents an acyl group and R2A represents a radical which together with the carbonyl group -C (= O) - forms a protected carboxyl group, and 1-oxides of compounds of the formula I, or salts of such compounds with salt-forming groups, characterized that one in a compound of the formula EMI17.2 wherein R2A has the meaning given under formula I, in a 1-oxide or a salt thereof, with intermediate protection of the 3-oxo group, the 7ss-amino group to a 7ss acylamino group Ac-NH- acylated, and a compound obtained with a salt-forming group as Salt or isolated as a free compound. SUBCLAIMS 1. The method according to claim I, characterized in that a starting material of the formula II is used in which the 3-oxo group is in the form of a functional converted enol group, such as a silylated or stannylated enol group or in the form of a ketal group is intermediately protected, and wherein R2A is an etherified hydroxyl group forming an esterified carboxyl group with the -C (= O) s group, with any functional groups 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 the 3-oxo group is intermediately protected in the form of a silylated enol group. 3. The method according to dependent claim 1, characterized in that R2A represents an optionally substituted 1-phenyl-lower alkoxy, such as diphenylmethoxy group. 4. The method according to dependent claim 1, characterized in that R2A is an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy group, e.g. B. tert-butyloxy, or 2-halo-lower alkoxy group, such as 2,2,2-trichloroethoxy. 5. The method according to claim I, characterized in that acylation is carried out with a reactive acid derivative of a carboxylic acid Ac-OH, in which any functional groups present in the radical Ac are protected as intermediates. 6. The method according to dependent claim 6, characterized in that the reactive acid derivative used is an acid halide, in particular an acid chloride 7. The method according to dependent claim 6, characterized in that an anhydride is used as the reactive acid derivative, 8. The method according to dependent claim 6, characterized in that an activated ester is used as the reactive acid derivative. 9. The method according to claim I, characterized in that acylation is carried out with a carboxylic acid AcOH in the presence of a carbodiimide, such as dicyclohexylcarbodiimide. 10. The method according to claim I, characterized in that acylation is carried out with a reactive acid derivative of an acid Ac-OH in the presence of a basic agent such as triethylamine or pyridine. 11. The method according to claim I or one of the dependent claims 1-10, characterized in that compounds of the formula I according to claim I or 1 oxides thereof, as well as salts of such compounds with salt-forming groups, wherein Ac is a fermentative or bio- , semi- or totally synthetically producible N-acyl derivative of a 6ss-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, and R2A is optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino. 12. The method according to claim I or one of the dependent claims 1-10, characterized in that compounds of the formula I according to claim I or 1-oxides thereof, furthermore salts of those compounds with salt-forming groups, in which Ac is a fermentatively or biosynthetically producible N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem4-carboxylic acid compounds, or an acyl radical contained in highly effective N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3 -cephem-4-carboxylic acid compounds occurring acyl radical, and R2A is lower alkoxy, 2-halo-lower alkoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, Means lower alkoxycarbonyloxy or lower alkanoyloxy. 13. The method according to claim I or one of the subclaims 1-10, characterized in that compounds of the formula I according to claim I, or 1-oxides thereof, and also salts of those compounds with salt-forming groups, wherein R2A is those given in claim I. Has meanings, and Ac for a group of the formula EMI18.1 where n is 0 and RI is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably aromatic rule, a functionally modified, z. B. ver esterified or etherified hydroxy or mercapto group, or an optionally substituted amino group, or wherein n is 1, RI is hydrogen or a given if substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic Hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably aromatic 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 R and RIII is hydrogen, or where n is 1, RI is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, wherein the heterocyclic radical preferably has aromatic character, RII is an optionally functionally modified, z. B. esterified or etherified hydroxyl or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or O-disubstituted phosphorus group, an azido group or a halogen atom, and RIII stands for hydrogen, or wherein n is 1, each of the radicals RI and RII is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified one Is carboxyl group, and RIII is hydrogen, or where n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and RII and RIII together represent an optionally substituted aliphatic, cyclo aliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical connected by a double bond to the carbon atom, or where n is 1, and Rt is an optionally substituted aliphatic different, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical 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 arali phatic hydrocarbon radical and Rm is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 14. The method according to claim I or one of the subclaims 1-10, characterized in that compounds of the formula I according to claim I, or the 1-oxides thereof, and also salts of compounds with salt-forming groups in which Ac is an acyl group of the formula EMI19.1 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 0-lower alkylphosphono or O, O-di-lower alkyl-phosphono, or a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected, and R2i lower alkoxy, 2-halo-lower alkoxy or optionally substituted diphenylmethoxy. 15. The method according to claim I or one of the subclaims 1-10, characterized in that compounds of the formula I according to claim I or 1-oxides, furthermore salts of those compounds with salt-forming groups, wherein the acyl radical of the formula B according to subclaim 14 corresponds to where 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-phosphono, or a 5- Amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected, and R2A denotes lower alkoxy which is optionally halogen-substituted in the 2-position or optionally lower alkoxy-substituted diphenylmethoxy. 16. The method according to claim I or one of the dependent claims 1-10, characterized in that the 7ss-phenyl-acetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester is prepared. 17. The method according to claim I or one of the dependent claims 1-10, characterized in that the 7B-phenylacetamino-cepham-3-one-4a-carb onsäurediphenyl- methylester-1-oxide is prepared. PATENT CLAIM II Use of the compounds of formula I obtained by the process of claim I for the preparation of 3-ketals, characterized in that they are treated with a glycol, thioglycol or dithioglycol in the presence of an acidic catalyst