CH590873A5 - 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 7 t3-amino-cepham-3-one-4-carboxylic acid derivatives of the formula
EMI1. 1
 where Rt represents hydrogen or an amino protective group, and Rf represents hydrogen or an acyl group, or R1 and Rb together represent a divalent amino protective group, R2 represents a radical which together with the carbonyl group -C (= O) - forms a protected carboxyl group, and / or 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 / or the corresponding l-oxides can be used both in 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 amino protective group is a group which can be replaced by hydrogen, primarily an acyl group, also a tri-methyl group, especially the trityl group, and an organic silyl and an organic stannyl group.  An acyl group 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 (incl.  Formic acid), as well as the acyl radical of a carbonic acid half derivative. 



      A bivalent amino protective group formed by the radicals Rg and Rlb together is in particular the divalent acyl radical of an organic dicarboxylic acid, preferably with up to 18 carbon atoms, primarily the diacyl radical of an aliphatic or aromatic dicarboxylic acid, furthermore the acyl radical of an a-position substituted, e.g.  B. 



  an aromatic or heterocyclic radical containing a-aminoacetic acid, wherein the amino group via a, preferably substituted, z.  B.  two lower alkyl, such as containing methyl groups, methylene radical is connected to the nitrogen atom.  The radicals R1 and Rb together can also represent an organic, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic ylidene radical, preferably with up to 18 carbon atoms. 



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



   The group R2A can be a hydroxyl group which is etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= O) group forms an esterified carboxyl group.  Such organic residues are e.g.  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 R2 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, further 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 and 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 alkenyldioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy, optionally substituted, nitro, furthermore optionally substituted by oxo or halogeno-oxycarbonyloxy, nitro, furthermore optionally substituted by oxo or halogeno-oxycarbonyloxy , e.g.  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 guanidinecarbonylamino, azido, acyl, such as lower alkanoyl or benzoyl, such as lower alkanoyl or benzoyl, such as lower alkanoyl or benzoyl, carboxyl in the form of lower alkanoyl, such as carboxyl, optionally functional, modified, such as carboxyl, such as 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 in salt form, or optionally O-mono- or O, O-disubstituted phosphono , wherein substituents e.g. 

  B.  represent 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, 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, e.g.  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 polysubstituted by functional groups. 



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g.  B.  a mono-, bi- or polycyclic aromatic hydrocarbon radical, in particular phenyl, and 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, can be mono-, 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, furthermore phenyl-lower alkylidene, such radicals being e.g.  B.  1-3 phenyl groups and optionally, z.  B.  like the abovementioned 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 radicals, these heterocyclic radicals optionally, z.  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 (3-position, substituted lower alkyl half-ester of carbonic acid, as well as a lower alkenyl-, cycloalkyl-, phenyl- or phenyl-lower-alkyl-half-ester of carbonic acid which is optionally substituted in the organic radical.  Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g.  

  B.  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may 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 hydroxyl group is primarily optionally substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, and also lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocycoxyloxy, especially heterocyclyloxy or heterocyclyl lower alkoxy also optionally substituted phenyl-lower alkoxy. 



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



  Amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino, thian-lower alkylenamino, 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 alkylhydrazino, 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 lower alkenylene z.  B.  1,2-ethenylene 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 alkyl3-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, as well as adamantyl, cycloalkenyl z.  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 -1,3-propyl, vinyl or allyl, while cycloalkenyl lower alkyl or lower alkenyl e.g.    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-, - Represents 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-, monothia- 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 diazn, triaza, tetraza, thlaza, 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, isooxazolyl, 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, for.  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 z.  B.  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy e.g.  B.  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy z.  B.    Pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfu acyloxy or thienyl-lower alkoxy, such as 2-thenyloxy. 



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



   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, ethoxycarbonyloxy or tert.  Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g.  B.  2,2,2-Trichloräthoxycarbonyloxy, 2-Bromoäthoxycarbo nyloxy or 2-Jodäthoxycarbonyloxy, or phenylcarbonyl methoxycarbonyloxy, z.  B.  Phenacyloxycarbonyloxy. 



   Lower alkoxycarbonyl is e.g.  B.  Methoxycarbonyl, ethoxy carbonyl, 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 alkylsul famoyl z.  B.  Represents N-methylsulfamoyl or N, N-dimethylsulfamoyl. 



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



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

 

   Methylamino, ethylamino, dimethylamino or diethyl amino, lower alkylenamino z.  B.  Pyrrolidino or piperidino, Oxaniederalkylenamino z.  B.  Morpholino, thiane lower alkyleneamino, e.g.  B.  Thiomorpholino, and aza-lower alkylenamino e.g.  B. 



   Piperazino or 4-methylpiperazino.  Acylamino stands for carbamoylamino, Niederalkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, Guanidi nocarbonylamino, Niederalkoxycarbonylamino z.  B.  Methoxy carbonylamino, ethoxycarbonylamino or tert. -Butyloxycar bonylamino, 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.  O-methyl- or O-ethyl-phosphono, O, O-di-lower alkyl-phosphono z.  B. 



  O, O-dimethylphosphono or O, O-diethylphosphono, O-phenyl-lower alkyl-phosphono, e.g.  B.  O-benzyl-phosphono, and O-lower alkyl-O-phenyl-lower alkyl-phosphono e.g.  B. 



  O-benzyl-O-methyl-phosphono. 



   Lower alkenyloxycarbonyl is e.g.  B.  Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenylniederalkoxycarbonyl z.  B.  Adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methyl-ethoxycarbonyl represents.  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- acetylhydra tin.    



   An acyl group Ac stands in particular for a naturally occurring or bio-, semi- or totally synthetically producible, preferably pharmacologically active N-acyl derivative of a 6 (3-amino-penam-3-carboxylic acid or 7 7ss-amino-3- cephem-4-carboxylic acid compound containing acyl radical of 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 6 6ss-amino-penam-3-carboxylic acid or 7 7ss-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI4. 1
 wherein n is 0 and Rl 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, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical , in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, represents an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group,

   and each of the radicals R ″ and Rlll denotes hydrogen, or in which n is 1, Rl denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character, R11 is an optionally functionally modified, z. 

  B.  esterified or etherified hydroxy or mercapto group, an optionally substituted amino group, an optionally functionally modified carboxyl group or sulfo group, an optionally O-mono- or O-disubstituted phosphono group, an azido group or a halogen atom, and Rlll is hydrogen, or where n is 1, each of the radicals Rl and R11 is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R "1 is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and R "and Grill together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or where n stands for 1, and Rl is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, Rll an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and RIII is 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-isoxazoyl group, or a preferably, z.  B.  by an optionally substituted one such as halogen, e.g.  B. 

  Chlorine, containing lower alkyl radical N-substituted amino group, or n for 1, Rl for an optionally substituted, preferably by halogen, such as chlorine, optionally substituted, such as hydroxy and / or halogen, z.  B.  Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, such as 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, a lower alkenyl group, an 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, pyndinium, thienyl, 1-imidazolyl or 1-tetrazolyl, 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, 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 and 1-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, e.g.  B. 



  Methoxycarbonyl or ethoxycarbonyl, cyano or give also, z.  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 R11 and Rm for hydrogen, or n for 1, Rt 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, Rll for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g. 

  B.  tert. -Butyloxycarbonylamino or 2,2,2-trichloroethoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidine carbonylamino, 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 modified hydroxyl group, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g.  B.  tert. -Butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or 0,0 di-lower alkyl-phosphono group, e.g. 

  B.  O-methyl-phosphono or O, O-dimethylphosphono, or a halogen atom, e.g.  B. 



  Chlorine or bromine, and Rlll for hydrogen, or n for 1, R 'and RIl each for halogen, z.  B.  Bromine, or lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl, and Rul for hydrogen, or n for 1, and each of the groups Rl, R11 and Rlll for lower alkyl, e.g.  B.  Methyl. 



   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 one, by a, preferably slightly, 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, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethyloxycarbonyl , 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino groups substituted by trityl), 2,6 dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, hexoxy-carbonyl-carbonyl,

   5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3 - (2-chloropheny) -5-methyl-4-isoxazolylcarbonyl-, 3- (2,6 dichlorophenyl) -S -methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, Acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl or 3-chloropropionyl-bromoacetyl 5-carboxyl-valeryl (with optionally, e.g.  B.  as indicated, as indicated by a monoacyl or diacyl radical, e.g.  B.  an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, e.g.  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.  Diphenylmethyl ester form, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, a-cyano-acetylacetyl, azlyl-phenyl, a-cyano-acetyl, azlyl-phenido-a-a-acetyl-phenido, 2-cyano-a-acetyl, azlyl, 2-cyano-a-acetyl-phenido 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl (with optionally, e.g. 

  B.  as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-phenyloxyphenylacetyl, a-hydroxy-a-phenoxy-phenoxy-phenoxy, a-hydroxy-a-phenyl-phenoxy-phenoxy-phenoxy, a-ethoxy-phenoxy-phenoxy-phenoxy-phenoxy, a-methyl-phenoxy-phenoxy-phenoxy-phenoxy-phenoxy-phenoxy, -3,4-dichloro-phenylacetyl, a-cyano-phenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (where in these radicals the amino group may 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-0,0-dimethyl-phosphono-phenylacetyl, furthermore benzylthioacetyl, benzylthiopropionyl, a-carboxyphenylacetyl (with optionally , e.g.  B.  as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium 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), from cyano 2-thienylacetyl, α-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-imidazolyl-thioacetyl, 1,2,4-triazol-3-ylthloacetyl, 1,3 , 4-triazol-2-ylthloacetyl, 5-methyl-1,2,4-thiadiazol-3 -ylthioacetyl, 5-methyl 1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthio- acetyl. 



   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 multi-branched in the a-position or by acylcarbonyl, especially benzoyl radicals, or substituted in (3-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 α-furyl-lower alkoxycarbonyl, e.g.  B.  Furfuryloxycarbonyl. 



   A divalent acyl group formed by the two radicals Rt and R, is z.  B.  the acyl radical of a lower alkane or lower alkene dicarboxylic acid, such as succinyl, or an o-aryldicarboxylic acid, such as phthaloyl. 

 

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



   An etherified hydroxyl group RA forms, together with the carbonyl group, 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 one in such an easily convertible carboxyl group and is z.  B.  2,2,2-chloroethoxy 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 (= O) -t grouping, also produces a chemical reducing agent 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, 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, is polysubstituted or monosubstituted by a carbocyclic aryl group having electron-donating substituents or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or is then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa- or thiacycloaliphatic The remainder is the ring member representing the a-position to the oxygen or sulfur atom. 



   Preferred polysubstituted methoxy groups of this type are e.g.  B.  tert. -Butyloxy, tert. -Pentyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or 2- (4-biphenylyl) -2propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group, e.g.  B.  4-methoxybenzyloxy or 3,4-dimethoxy-benzyloxy, or  2-Furyloxy is.  A polycycloaliphatic carbon hydrogen radical in which methyl of the methoxy group is a, preferably three-fold, 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 representing the a-position to the oxygen or sulfur atom, means e.g.  B.  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) grouping, 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 R2 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 alkylstannyloxy, e.g.  B.  Tri-nbutylstannyloxy. 



   An acyloxy radical RA forming a, preferably hydrolytically, cleavable mixed anhydride group together with a -C (= O) grouping 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.  Ethoxycarbonyloxy. 



   A radical RA which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is z.  B.  Amino, 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, and 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-diethyl aminoethyl 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 formula 1 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 RIA is hydrogen or, preferably, 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 6 p-amino-penam-3-carboxylic acid or 7 P-amino-3-cephem-4-carboxylic acid compound or an acyl radical easily cleavable acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, Rb stands for hydrogen, and R2A for optionally, e.g.  B.  by optionally substituted aryloxy, e.g.  B.  4-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 lower alkoxy, e.g.  B. 



  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert. -Butyloxy or tert. -Pentyloxy, bis-phenyloxy-methoxy optionally substituted by lower alkoxy, e.g.  B.  Bis4-methoxyphenyloxy-methoxy, phenacyloxy, lower alkanoyloxy-methoxy, e.g.  B.  Acetyloxymethoxy or pivaloyloxymethoxy, or 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, for optionally substituted phenyl-lower alkoxy, in particular l-phenyl-lower alkoxy, such as phenylmethoxy, such radicals 1-3 optionally, 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-porpyl- oxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxydiphenylmethoxy or trityloxy, for acyloxy, such as lower alkoxycarbonyloxy, e.g.  B. 

  Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy, for tri-lower alkylsilyloxy, e.g.  B.    Tnmethylsilyloxy, or optionally, 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-lower alkyl or 2,2-di-lower alkylhydrazino, e.g.  B.  2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and the 1-oxides of the cepham3- one compounds of the formula I, such compounds in the keto, ie.  H.  the cepham-3-on, as well as in the enol, d.  H. 



  may be in the cephem-3-ol form, as well as salts. of such compounds with salt-forming groups. 



   In a cepham-3-one compound of the formula I, furthermore in a corresponding 1-oxide, or in a salt of such a compound with salt-forming groups R? for hydrogen or one in fermentative (i.e.  H.  naturally occurring) or biosynthetically producible N-acyl derivatives of 6 6P-amino-penam-3-carboxylic acid or 7 p-amino-3-cephem-4-carboxylic acid compounds containing acyl radical, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, furthermore an optionally substituted lower alkanoyl radical or lower alkenoyl radical, e.g.  B. 



  4-Hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butylthio acetyl, and in particular 5-amino-5-carboxy-valeryl, in which the amino 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 6 (3-amino-penam-3-carboxylic acid or 7 (3-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 alkoxycarbonyloxy 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 hydroxy groups, and in which the amino group is optionally substituted and e.g.  B.  represents an optionally present in salt form sulfoamino group or an amino group which, as substituents, is a hydrolytically 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, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethyloxycarbonyl, 2 -Chloräthoxycarbonyl, 2-bromoethoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, or in which the amino group is connected to the nitrogen atom of the 7 7-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, z. 

  B.  as indicated above, substituted amino group), also a-carboxy-phenylacetyl or a-carboxy-2-thienylacetyl (optionally with functionally modified, e.g.  B.  in salt, such as sodium salt form, or in ester, such as lower alkyl, e.g.  B.  Methyl or ethyl, or phenyl lower alkyl, e.g.  B.  Diphenylmethylesterform, present carboxy group), a-sulfo-phenylacetyl (optionally with, z.  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 hydroxy 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, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as 2,2,2-trichloroethoxycarbonyl, 2 - chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or Phenacyloxycarbonyl, also means formyl), z.  

  B.  for an acyl radical of the formula A, and Rlb for hydrogen, and R2 represents lower alkoxy, in particular a-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z.  B. 



  2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyhliederalkoxy with 1-3 phenyl radicals, optionally substituted by lower alkoxy or nitro z.  B. 



  4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyl oxymethoxy, e.g.  B.  Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy. 



   The invention relates primarily to cepham-3-one compounds of the formula I, in which Ri denotes hydrogen, R, hydrogen, an acyl group of the formula
EMI8. 1
 wherein Ar is phenyl, also hydroxyphenyl, e.g.  B.  3- or 4-hydroxyphenyl, or hydroxy-chlorophenyl, e.g.  B.  3-chloro-4hydroxyphenyl- or 3,5-dichloro-4-hydroxyphenyl, with hydroxy substituents in such radicals replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g.  B. 



     tert. -Butyloxycarbonyl or 2,2,2-Trichloräthoxycarbonyl, can be protected, and 2-thienyl is, 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-poly-branched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.  B.  2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Brom äthoxycarbonylamino, 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 AlkalimetaU-, z.  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-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbo- nyloxy or 2-bromoethoxycarbonyloxy, also formyloxy, or O-lower alkylphosphono or O, O-di-lower alkylphosphono, z.  B. 

  O-methylphosphono or O, O-dimethylphosphono, or 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, and R2A for lower alkoxy, msbe- special α-polybranched lower alkoxy, z.  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 1-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, as well as 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, R is hydrogen, for the acyl radical of the formula B, in which Ar is phenyl, X is oxygen, n is 0 or 1, and R is hydrogen or, if n 0 represents 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, optionally protected hydroxy, such as acyloxy, z. 

  B.    a-polybranched lower alkoxycarbonyloxy, such as tert.  Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyl- oxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbo- nyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or O-lower alkyl or O, O-di-lower alkyl-phosphono, z.  B. 



  O-methylphosphono or O, O-dimethyl-phosphono, mean, 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, Rlb represents hydrogen, and R2A optionally in 2-control means halogen, e.g.  B.    Chlorine-, bromine- or iodine-substituted lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.    tert. -Butyloxy, or 2-halo-lower alkoxy, z. 

  B.    2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or optionally mederalkoxy, such as methoxy-substituted diphenylmethyloxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy.     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 7ss-amino-cepham-3-one-4-carboxylic acid derivatives of the formula I and / or 1-oxides of compounds are obtained by converting in a cepham compound of the formula
EMI8. 2
 or in a 1-oxide thereof the methylene group in the 3-position is replaced by the oxo group by treatment with ozone and subsequent reductive cleavage of the ozonide formed as an intermediate, and a compound obtained with a salt-forming group is isolated as a salt or as a free compound. 



   In a starting material of the formula II, 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 II, an amino protective group is in particular an acyl group, in which there are also free functional groups present, e.g.  B.  Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups, e.g.  B.  by acylation, tritylation, silylation or stannylation, and hydroxy, carboxy or phosphono groups, e.g.  B.  by etherification or esterification, incl. 

  Silylation or stannylation, can be protected, and R1b for hydrogen, while R2A is preferably for a, with the -C (= O) group an, in particular under mild conditions, cleavable, esterified carboxyl group-forming etherified hydroxy group R2A, where optionally existing functional groups in a carboxyl protecting group R2A in a manner known per se, for.  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-phenylnie- deralkoxy group, such as, if appropriate, z.  B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  

  Benzyl, 4-methoxybenzyl, 4-nitrobenzyl, diphenylmethoxy or 4,4'-dimethoxyldiphenylmethoxy, 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 z.  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.    Triethylsilyloxy.    



   The oxidative degradation of the methylene group in a starting material of the formula II is 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 -90oC to about + 400C.    



   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 trimethyl phosphite, or phosphorous acid triamides, which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as hexanide alkyl phosphites .  B. Hexamethylphosphorigsäuretriamid, 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 I or the corresponding 1-oxide or a mixture of the two compounds is obtained according to the invention. 



  Such a mixture can be separated into the compound of the formula I and the corresponding 1-oxide, or it can be oxidized to the uniform 1-oxide of a compound of the formula I. 



   A mixture of a compound of the formula I 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, a mixture of a compound of the formula I and a 1-oxide thereof obtainable according to the process can also be oxidized directly to the 1-oxide of a compound of the formula I. 



  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 percarbonic 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% and less, but also larger amounts of acid can be used. 



  The effectiveness of the mixture depends primarily on the strength of the acid.  Suitable mixtures are e.g.  B. 



  those of hydrogen peroxide with acetic acid, perchloric acid or trifluoroacetic acid. 



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

  B.  carried out at temperatures from about −50 ° C. to about + 100 ° C., preferably from about −10 ° C. to about + 400 ° C.  Depending on the oxidizing agent used, the 1 a or 1 t 3 oxide or a mixture of the two is obtained.    



   Ketal derivatives of compounds of the formula I 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 chlorites, 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 formyl amine compound such as an N-formyl-N, N-di-lower alkylamine, 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 I 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 I obtainable according to the invention can be converted into other compounds of the formula I, 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) RA2 remain intact where the oxo group is 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 acylation, tritylation or silylation, free hydroxyl or mercapto groups e.g.  B.  by etherification or esterification, and free carboxyl groups e.g.  B.  by esterification, incl.  Silylating, be protected. 



   In a compound obtained, e.g.  B.  an amino protective group Rl or    Rb, in particular an easily cleavable acyl group, in a manner known per se, e.g.  B.  an α-polybranched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2, 2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, eg.  B.  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent nascent together with the metal or metal compound, preferably in the presence of acetic acid containing water. 

  Furthermore, in a compound of formula I 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 ltl or Rb, in which any free functional groups present, if appropriate, amino groups z.  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, are protected by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the imino 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 inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, e.g.  B.  Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechylphosphorus trichloride, and acid halides, especially chlorides, of sulfur-containing acids or 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 ethyldiisopropylamine, also an N, N, N ', N' Tetraniederalkyl-lower alkylenediamine, 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-methylpiperidine or N-methyl-morpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonones; 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, aliphatic or aromatic hydrocarbon, e.g.  B.  Methylene chloride.  Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g. 

  B.  in about 0.2 to about 1 times the amount or then in about to 10 times, in particular a 3 to 5 times, excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g.  B.  carried out at temperatures from about - 50oC to about + 10oC, but also at higher temperatures, d.  H.  z.  B.  up to about 750C, 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 - 50oC to about + 10oC. 



   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 preferable to use water or an aqueous mixture of an organic solvent such as an alcohol, especially a lower alkanol, e.g.  B.  Methanol.  One usually works in an acidic medium, e.g.  B.  at a pH of about 1 to about 5 which, 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. 



   If the intermediate imide halide product obtainable by the above process is reacted with a salt such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula I is obtained in which both radicals R 1 and R b are acyl groups represent. 

 

   In a compound of the formula I in which both radicals R and R, b represent acyl groups, one of these groups, preferably the less sterically hindered one, e.g.  B.  by hydrolysis or aminolysis, can be selectively removed. 



   Certain acyl radicals R, a of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5-amino5-carboxy-valeryl radical in which carboxyl, e.g.  B.  by esterification, in particular by diphenylmethyl, and / or the amino group, e.g.  B.  protected by acylation, in particular with halo-lower alkanoyl, such as dichloroacetyl, can also be achieved 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-releasing agent such as an N-halogen 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 the reaction product is mixed with a hydroxyl-containing agent such as water or a lower alkanol, e.g.  B.  Methanol, or, if in the 5-amino-5-carboxy-valeryl radical Rt, the amino group is unsubstituted and the carboxy group z.  B.  is protected by esterification, and Rlb is preferably an acyl radical, but can also mean hydrogen, 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 Rt can e.g.  B. 



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



   Furthermore, you can z.  B.  in a compound of the formula I in which Rt and R, b are hydrogen, and the oxo group in the 3-position is preferably, e.g.  B.  as indicated, is protected, the free amino group by acylation methods known per se, eg.  B.  by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g.  B.  Fluorides or chlorides, also pseudohalides, such as 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 anhydrides, such as those which z. 

  B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, as well as with substituted formimino derivatives, such as substituted N, N dimethylchloroformimino derivatives, or an N-substituted N, N- Diacylamine, such as an N, N-diacylated aniline, acylate, if necessary, in the presence of suitable condensing agents, when using acids such.  B. 



  of cabodiimides, such as dicyclohexylcarbodiimide, when using reactive acid derivatives, e.g.  B.  basic agents such as triethylamine or pyridine works. 



   An acyl group Ac can also be introduced by adding a compound of the formula I in which R? and R, b together for a ylidene residue (which can also be added subsequently, e.g.  B. 



  by treating a compound in which Rl and Rb are hydrogen with an aldehyde such as an aliphatic, aromatic or araliphatic aldehyde), e.g.  B.  acylated by the methods given above, and the acylation product, preferably in a neutral or weakly acidic medium, hydrolyzed. 



   An acyl group can also be introduced in stages.  So you can z.  B.  in a compound of formula I with a free amino group a halo-lower alkanoyl, z.  B.  Bromoacetyl group, or e.g.  B.  by treating with a carbonic acid dihalide such as phosgene, a halocarbonyl, e.g.  B.  Chlorocarbonyl group, and a so obtainable N- (halo-lower alkanoyl) or  N- (halocarbonyl) amino compound with suitable exchange reagents, such as basic compounds, e.g.  B.  Tetrazole, thio compounds, e.g.  B.  2-mercapto-1-methyl-imidazole, or metal salts, e.g.  B. 



  Sodium azide or  Alcohols such as lower alkanols, e.g.  B.  tert.  Butanol, implement and so to substituted N-Niederalkanoylbzw.  N-hydroxycarbomylamino compounds arrive.  Furthermore, you can z.  B.  a compound of the formula I in which R, a is a glycyl group, preferably substituted in the a-position, such as phenylglycyl, and R, b is hydrogen, with an aldehyde, e.g.  B.  Formaldehyde, or a ketone such as lower alkanone, e.g.  B.  Acetone, and thus obtain compounds of the formula I in which Rt and Rbb together represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position. 



   In both reactants, free functional groups can be temporarily protected in a manner known per se during the acylation reaction and can be released after the acylation by methods known per se. 



   So you can preferably z.  B.  Amino, hydroxy, carboxyl or phosphono groups in the acyl radical during the acylation reaction, e.g.  B.  in the form of acylamino, such as 2,2,2 trichloroethoxycarbonylamino, 2-bromoethoxycarbonylamino or tert. -Butyloxycarbonylamino groups, from acyloxy, e.g.  B. 



  2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonylgruppen, of esterified carboxy, such as diphenylmethoxycarbonyl groups, or  O, O-disubstituted phosphono, such as O, O-di-lower alkylphosphono, e.g.  B.  O, O-dimethyl-phosphono groups, protect and subsequently, if necessary after conversion of the protective group, e.g.  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 trffluoroacetic acid, by hydrogenolysis or by treatment with an alkali metal halide, e.g.  B.  Sodium iodide, such protected groups, optionally partially, cleave. 



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



   In a compound of the formula I in which Rt and Rib are hydrogen, the free amino group can also be removed by introducing a triatylmethyl group, e.g.  B.  by treatment with a reactive ester of a triatylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine. 



   An amino group can also be protected by introducing a silyl and stannyl group.  Such groups are introduced in a manner known per se, e.g.  B.  by treatment with a suitable silylating agent such as a dihalodin lower alkyl silane or tri lower alkyl silyl halide, e.g.  B. 



  Dichloro-dimethylsilane or trimethyl-silyl chloride, or an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkyl-silyl) -amine (see e.g.  B.  British patent no.  1073 530), or with a suitable stannylating agent such as a bis (tri-lower alkyl tin) oxide, e.g.  B.  Bis (tri-n-butyl-tin) oxide, a tri-lower alkyltin hydroxide, e.g.  B.  Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy-tin, tetra-lower alkoxy-tin or tetra-lower alkyl-tin compound, and a tri-lower alkyl tin halide, e.g.  B.  Tri-n-butyl tin chloride (see e.g.  B.  Dutch publication 67/17107). 

 

   In a compound obtained with an esterified grouping of the formula -C (= O) -R, 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. 



   Furthermore, modified functional substituents in groups Rt, Rbl and / or R2A, such as acylated amino groups, acylated hydroxy groups, esterified carboxy groups or O, O-disubstituted phosphono groups, according to methods known per se, eg.  B.  the above-described, release, or free functional substituents in groups Rla, R, b and / or R2, such as free amino, hydroxy, carboxy or phosphono groups, according to methods known per se, e.g.  B.  Acylating or esterifying 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 R, a 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 these, 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 materials of the formula II used according to the invention can, for.  B.  be prepared by in a cephem compound of the formula
EMI12. 1
 wherein Rt is an amino protective group, Rlb has the meaning given under formula I, R2 preferably stands for hydroxy, but also stands for a group R2A which is acetyloxymethyl group, e.g.  B.  converted into the hydroxymethyl group by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis functionally modifies free carboxyl group of the formula -C (= O) -R2 in a suitable manner, e.g. 

  B.  esterified by treatment with a diazo compound such as diphenyldiazomethane and the hydroxymethyl group, e.g.  B.  by treating with a halogenating agent such as chlorinating agent, e.g.  B.  Thionyl chloride, or an iodinating agent, e.g.  B.  N-methyl-N, N'-dicyclohexylcarbodiimidium 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.    Chromium H chloride or chromium II acetate, in a suitable solvent, such as dimethyl sulfoxide, or then directly via the iodomethyl group (which you can 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 II by treatment with a suitable reducing agent such as zinc in the presence of acetic acid. 



   As mentioned above, the new compounds of the formula I and / or 1-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 into their enol derivatives, e.g.  B.  by treatment with an optionally substituted diazo hydrocarbon compound of aliphatic character, 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 treatment with an acid or, preferably, a suitable acid derivative such as halide, e.g.  B. 

  Convert chloride or anhydride 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 into cephem compounds of the formula
EMI13. 1
 which contain a double bond in the 2,3- or 3,4-position and / or 1-oxides of those compounds of the formula IV which contain a double bond in the 3,4-position, and in which Rt and R, the above have given meanings, R2 stands for hydroxy or for a radical R2 which forms a protected carboxyl group with the carbonyl group, and RA stands for an optionally substituted hydrocarbon radical of aliphatic character or an acyl group. 



  Compounds of the formula IV, in particular those in which Rt is an acyl radical contained in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid and 7t3-amino-3-cephem-4-carboxylic acid compounds, Rb is hydrogen , and R2 represents hydroxyl or a, together with the carbonyl group, a carboxyl group forming a cleavable under physiological conditions, etherified hydroxyl group, and RA has the meaning given above, as well as salts of such compounds, are against microorganisms such as gram-positive bacteria, e.g.  B. 



  Staphylococcus aureus, (e.g.  B.  in mice at doses from 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, especially also against penicillin-resistant bacteria, and can therefore be used accordingly, e.g.  B.  in the form of antibiotic preparations, use. 



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



   Furthermore, in the cepham compounds of the formula I and / or in 1-oxides thereof, the oxo group in the 3-position, e.g.  B.  by treatment 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) -R2 into the free carboxyl group. 

  In the thus obtainable cepham compound of the formula
EMI13. 2
 and / or the 1-oxide thereof, in which RB is hydrogen or an acyl radical, the elements of a compound of the formula -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. 3
 and / or 1-oxides thereof, in which Rast, Rb and R2 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 either have valuable pharmacological, in particular antimicrobial properties, in particular those in which Rt represents a pharmacologically active N-acyl derivative of 6 6ss-amino-penam-3-carboxylic acid and 7 P-amino3- cephem-4-carboxylic acid compounds, Rb is hydrogen, and R2 is hydroxy or an etherified hydroxyl group which, together with the carbonyl grouping, forms an etherified hydroxyl group which can be cleaved under physiological conditions, or salts thereof, or can be used as intermediates for the preparation of the compounds mentioned with pharmacological properties be used. 



   The oxides of the 3-cephem compounds of the formula VIII which can be used as intermediates can be obtained according to Swiss Patent No.  582 710 by reduction, e.g.  B.  by means of phosphorus trichloride, are converted into the 3-cephem compounds of the formula VII. 



   In the above conversions of compounds of the formula I according to the invention to the compounds of the formula IV or  Compounds of the formula I do not need to be isolated from the compounds of the formulas V and VII; they can be converted directly into the compounds of the formula IV or in the form of the crude reaction mixtures after preparation from the compounds of the formula II.  V and VII 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 0.50 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 100 ml of methanol is at -700 for 6.5 minutes with an oxygen-ozone stream containing 0.175 mmol / min Ozone, treated.  The reaction mixture is mixed with 0.5 ml of dimethyl sulfide and stirred for one hour at -700, then for 2 hours at room temperature and evaporated to dryness.  The residue in methylene chloride is chromatographed on 15 g of silica gel. 

  The amorphous 7 P-phenylacetylamino-cepham-3-one-4 a-carboxylic acid diphenylmethyl ester is eluted with methylene chloride, thin layer chromatography (silica gel): Rf - 0.47 (system: toluene / acetone / methanol / acetic acid 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.61, 5.77 I1, 5.85 I1, 5.95, 6.21 11 and 6.87 II; the compound shows a positive iron (III) chloride reaction, which suggests the presence of the enol form. 



   With methylene chloride containing 10% acetone, a more polar compound can be eluted which is very probably identical to the 7ss-phenylacetylamino-cepham-3-one-4α-carboxylic acid diphenylmethyl ester-1-oxide, thin-layer chromatogram (silica gel): Rf = 0.22 (system: toluene / acetone / methanol / acetic acid 80: 10: 5: 5); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 Il, 5.58, 5.76 Il (shoulder), 5.83 I1, 5.97 I1, 6.22 and 6.61 p; the compound shows a positive iron (III) chloride reaction, which suggests the presence of the enol form. 



   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-7ss-phenylacetylamino3-cephem-4-carboxylic acid using a purified enzyme extract from Bacillus subtilis, strain ATCC 6633, and subsequent lyophilization of the reaction solution) in 200 ml of water is covered with 400 ml of ethyl acetate and acidified to a pH of 2 with concentrated aqueous phosphoric acid.  The aqueous phase is separated off and extracted twice with 150 ml of ethyl acetate each time.  The combined organic extracts are washed four times with 50 ml of water each time and dried over magnesium sulfate, then concentrated to about 400 ml. 

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

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenyl-acetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176-176.50 (uncorr. ); [c:] 2O = -6 + lo (c = 1.231% in chloroform); Thin layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light 254m); Rf = 0.42 (system: chloroform / acetone 4: 1), Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (system: methylene chloride / acetone 6: 1). 



   Dissolve 1.03 g of 3-hydroxymethyl-7B-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for one hour at 35. Another 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium chloride in 15 ml of absolute tetrahydrofuran are then added and the mixture is left to stand for 17 hours at room temperature under a nitrogen atmosphere.  The reaction mixture is freed from 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% distilled water); it is rewashed with 4 portions of 100ml each of methylene chloride. 

  The eluate is concentrated to a small volume and chromatographed on a silica gel column (90 g; deactivated by adding 10% distilled water). 



  With a total of 900 ml of a 3: 7 mixture of toluene and methylene chloride, non-polar impurities are eluted.  Elution with 2 portions of 200 ml of methylene chloride each gives the 3-iodomethyl-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 Il, 5.82 Il, 5.95 Il, 6.70 Il, 7.32 F and 8.16 . 



   The iodination reagent used above can be prepared as follows:
In a 250 ml round bottom flask with 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 70O.  After the reaction time has elapsed, the excess methyl iodide is distilled off from the now red-brown solution under reduced pressure and the viscous, red-brown residue is dissolved in 150 ml of absolute toluene at 40 °. 

  The crystal mass which spontaneously crystallizes out within a few hours is separated from the mother liquor with the aid of a glass suction filter with 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 at 0.1 mm Hg for 20 hours.  and room temperature the N-methyl-N, N'-dicyclohexylcarodiimidium iodide is obtained in the form of colorless crystals, F.    111-113; Infrared absorption spectrum (in chloroform): characteristic bands at 4.72 y and 6.00 y.    



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

  The residue is taken up with stirring in 50 ml of methylene chloride and 30 ml of a 0.5 molar aqueous dipotassium hydrogen phosphate solution; the aqueous phase is separated off, extracted with two portions of 30 ml of methylene chloride each time and discarded.  The organic extracts are washed several times with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated under reduced pressure.  The residue is chromatographed on a column of 22 g of silica gel (addition of 10% water). 

  The 3-methylene-7ss-phenylacetylamino-cepham-4α-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 "; [a] D = -180+ 10 (c = 0.715 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol); hmax = 254 mF (e = 1540) and 260 mF (E = 1550);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 y, 5.65, 5.74 Il, 5.94 Il, 6.26 F and 6.67 Il.    

 

   Example 2
A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 250 ml of methylene chloride is treated with an oxygen-ozone mixture (0.265 mmol of ozone / min ) and treated the reaction mixture with 1 ml of dimethyl sulfide.  The mixture is stirred for 30 minutes at -70 and for 11/2 hours at room temperature and then evaporated to dryness under reduced pressure. 

  The residue, containing a mixture of 7 ß-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester and 7 7ss-phenylacetylamino-cepham-3-on-4a-carboxylic acid diphenylmethyl ester-1-oxide, is in 50 ml of methanol were added and an excess of diazomethane (in the form of a solution in diethyl ether) was added at 00.  The mixture is stirred for one hour at 00 and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel. 

  The 3-methoxy-7-s-phenylacetylamino-2-cephem-4 a-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of toluene and ethyl acetate with Rf = 0.57 (system: toluene / ethyl acetate 1: 1); ; F.    174-177 after crystallization from a mixture of methylene chloride and pentane; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 mF (e = 4310);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 Il, 5.60, 5.71 R 5.92 I1, 6.15 11 and 6.66 i ±; followed by 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf ¯ 0.37 (system:

  Toluene / ethyl acetate 1: 1) '; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (E = 6340), #max = 264 m, a (e = 6350) and shoulder = 261 m (e = 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; and with ethyl acetate the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid-diphenylmethylester-1-oxide with Rf = 0.31 (system:

  Ethyl acetate); F.  152-155 after crystallization from a mixture of acetone and diethyl ether; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 288 m1k (e = 3610) and #shoulder = 247 mp; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 1k, 5.59, 5.81, 5.95, 6.22 F and 6.61. 



   Example 3
A solution of 0.50 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 50 ml of methanol is treated at -700 with an oxygen-ozone mixture until it begins to turn blue.  The excess ozone is driven off with nitrogen and the reaction mixture is mixed with 0.5 ml of dimethyl sulfide and stirred for 11/2 hours at room temperature. 

  It is then evaporated to dryness under reduced pressure, the residue, containing a mixture of the 7P-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester and the 7 7ss-phenylacetylamino-cepham-3-one4 a- carboxylic acid diphenymethyl ester-1 oxide, in 10 ml of pyridine, treated with 5 ml of acetic anhydride and left to stand for 16 hours at 0O.  It is evaporated to dryness under high vacuum; the residue is taken up in ethyl acetate 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 30 g of silica gel, the 3-acetyloxy-7-s-phenyl-acetylamino-3-cephem-4-carboxylic acid diphenylethyl ester being eluted with a 4: 1 mixture of toluene and ethyl acetate.  The product is crystallized from a mixture of acetone and diethyl ether, F.    1581600; Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 mF (e = 6580) and 164 m1k (e = 6550);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.59 ll, 5.69 F (shoulder), 5.78, 5.91, 6.061k (shoulder) and 6.67 1k
Example 4
A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 100 ml of methanol is treated at -70 with an oxygen-ozone mixture until the onset of blue coloration, and the excess ozone with Nitrogen expelled.  The reaction mixture is mixed with 0.4 ml of dimethyl sulfide and stirred for 30 minutes at room temperature. 

  Then it is cooled to oil and the reaction mixture, containing the 7ss-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester and the 7 P-phenylacetylamino-cepham-3-one-4 a-carboxylic acid diphenylmethyl ester-1- oxide, with a solution of 0.10 g of sodium borohydride in 5 ml of water.  The mixture is left to react for 30 minutes at 0 °, 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.  The residue is chromatographed on 50 g of silica gel. 

  With a 2: 1 mixture of toluene and ethyl acetate, the 3 # -hydroxy-7ss-phenylacetylamino-cepham-4α-carboxylic acid diphenylmethyl ester is eluted, which after crystallization from a mixture of acetone and diethyl ether melts at 157-160; [a] D = +80 # 1 (c = 0.492 in dioxane): #max = 258 m1k (e = 850); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.82, 2.94, 5.63, 5.74, 5.92, 6.25 and 6.63. 



   Example 5
A mixture of 0.312 g of 3t-hydroxy-7ss-phenylacetylamino-cepham-4a-carboxylic acid diphenylmethyl ester in 15 ml of pyridine and 7 ml of acetic anhydride is left to stand for 16 hours at 0 and, after addition of 50 ml of 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 silica gel plate 100 cm long is used and developed with a 1: 1 mixture of toluene and ethyl acetate. 

  The 3 # -acetoxy-7ss-phenylacetyamino-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 162-1640; [α] 20 D = + 55o f la (c = 0.492 in chloroform); Ultraviolet absorption spectrum (in 95% ethanol): #max = 253 m (# = 700), 258 m (# = 820) and 265 m1k (2 = 660); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.66, 5.77, 5.97, 6.28 and 6.71. 



   Example 6
A mixture of 0.150 g of 3t-acetyloxy-7ss-phenylacetylamino-cepham-4a-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.  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). 

 

  With Rf = 0.36, a pale yellowish oil is obtained which crystallizes from a mixture of methylene chloride and hexane. 



  The product is the 7 P-phenylacetylamino-3-cephem4-carboxylic acid diphenylmethyl ester, F.  161-163, [α] 20 D = + 30O + 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 my (E = 6100) and #max = 259 my (± = 5250) (in methylene chloride) and #max = 259 mFt (E = 6050) and #min = 239 my (e = 4950) ( in 95% aqueous ethanol); Infrared absorption spectrum:

   characteristic bands at 2.90, 5.57, 5.76 y, 5.91 1, 6.09 y, 6.66, 7.13, 8.12, 8.63, 9.07, 10.43> and 12.22, (in methylene chloride) and 3.01, 5.60 y, 5.82, 6.04 H 6.08 F (shoulder), 6.51 and 7.13 (in mineral oil). 



   Example 7
A solution of 0.566 g of 7t3-phenylacetylamino-3-cephem-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 to dryness.  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 is washed 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, 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 = 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). 



   Example 8
A solution of 1.94 g of 7-P-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 100 ml of absolute methylene chloride is cooled to -15, then with 3.86 ml of absolute pyridine and 31.6 ml of an 8% solution of phosphorus pentachloride in methylene chloride and the reaction mixture stirred for 30 minutes at -10 'and for a further 30 minutes at -5.  The golden yellow solution is cooled to -20 'and 26.8 ml of absolute methanol are added so quickly that the internal temperature does not rise above -10'.  The reaction mixture is stirred for one hour at -10 ', left to stand for a further hour at 25-300 and then mixed with 80 ml of a 0.5 molar aqueous potassium hydrogen phosphate solution with vigorous stirring. 

  The pH of the two-phase reaction mixture is adjusted to 2 by the dropwise addition of 20% strength 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 elutes with methylene chloride phenylacetic acid methyl ester and with methylene chloride containing 3% acetic acid methyl ester the 7 ß-amino-3-cephem-4-carboxylic acid diphenylmethyl ester, which is crystallized by dissolving 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.  153-1540; 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 (system:

  Toluene / diethyl ether 1: 1); Ultraviolet absorption spectrum: #max = 257 my (± = 8150) and #min = 245 mF (± = 7730) (in methylene chloride) and #max = 255 m (# = 5500) and #min = 236 my (± = 4650) ( in 95% ethanol);

  Infrared absorption spectrum: characteristic bands at 2.91, 2.97, 5.61, 5.78 y, 6.11 y, 7.14, 8.15 ij, 8.29, 9.14, and 9.83 11 ( in methylene chloride) and at 2.99, 5.65, 5.77, 7.14, 7.74 ij, 7.84, 8.08 I1, 8.53 y, 9.14 y, 9.85 11 and 10.35 (in mineral oil). 



   Example 9
0.380 g of diphenylmethyl 7ss-amino-3-cephem-4-carboxylate is poured over with 2 ml of anisole and 8 ml of absolute trifluoroacetic acid, the clear solution is left to stand for 10 minutes at room temperature and then diluted 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 at 35O under reduced pressure. 

  The 7 ß-amino-3-cephem-4-carboxylic acid, which is thus available 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, 3.80, 4.12 (shoulder), 4.92, 5.54, 6.05 ju (shoulder), 6.19, 6.55, 7, 05 for 7.42 jt, 8.23 y, 8.79 Il, 9.55 Il, 12.08 y, 12.69 and 13.04 Il.    

 

   Example 10
A suspension of 0.070 g of 7ss-amino-3-cephem-4-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 -20 and, while stirring, 0.060 g of isobutyl chloroformate is added, whereupon the mixture is allowed to react at -15 for 30 minutes.  After cooling again to below -20 ', the milky suspension of the triethylammonium salt 7 P-amino-3-cephem-4-carboxylic acid is then added.  The reaction mixture is stirred for 30 minutes at -15 ', 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 acidified to pH 2 by adding 5 molar aqueous phosphoric acid, while stirring vigorously and cooling with ice.  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-α-phenylglycine with methylene chloride and methylene chloride, containing increasing proportions of acetone, and then the 7 8- [N- (N-tert. -Butyloxycarbonyl-D-α-phenylglycyl) -amino] -3-cephem-4-carboxylic acid, which is obtained in amorphous form; Ultraviolet absorption spectrum (in 95% ethanol): Xmax = 252 my (± = 5100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.61 Il, 5.85 F1, 5.99 gu 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). 



   Example 11
A solution of 0.02 g of 7- [N- (N-tert. Butyloxycarbonyl-D-α-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 0.001 mm Hg for 16 hours. 

  The 7 ss- [N- (D-α-phenylglycyl) -amino] -3-cephem-4-carboxylic acid is obtained as a yellowish amorphous powder by adding to a solution in water and methanol of the salt obtained with trifluoroacetic acid with an equivalent The amount of triethylamine is added, evaporated and the residue digested with methylene chloride, thin-layer chromatography (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): Xmax = 250 m (E = 4300). 



   Example 12
In an analogous manner, if suitable starting materials are selected and, if appropriate, after additional conversion, the following compounds can be obtained: 7ss-Phenylacetylamino-3-cephem-4-carboxylic acid [di (4-methoxyphenyl) methyl] ester;
7 P-phenylacetylamino-3-cephem-4-carboxylic acid benzyl ester;
7ss-phenyloxyacetylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system: n-butanol / acetic acid / water 75,: 7.5: 21); 7 ss- (ss-thienylacetyl-amino) -3 -cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8 : 30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Xmax at 237 m;

  Infrared absorption spectrum (in mineral oil): characteristic band at 5.62 p; 7ss- (1-tetrazolylacetylamino) -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4: 30); Ultraviolet Absorption Spectrum (in methanol): Xmax at 255 m; 7 ss- (1-methyl-2-imidazolylthio-acetyl) -amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.3-0.4 (system: n-butanol / pyridine / acetic acid / Water 42: 24: 4: 30); Ultraviolet Absorption Spectrum (in methanol): Xmax at 252 mull;

   7ss - (α-phenyl-α-2,2,2-trichloroethoxycarbonyloxy-acetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester; 7ss - (α-hydroxy-α-phenylacetyl-amino) -3-cephem-4-carboxylic acid; 7 t3- (4-pyridylthioacetyl-amino) -3-cephem-4-carboxylic acid, amorphous; Thin-layer chromatogram (silica gel): Rf = 0.35-0.45 (system: n-butanol / pyridine / acetic acid / water 42: 24: 4:30), infrared absorption spectrum (in mineral oil): characteristic band at 5.62; 7ss-acetoacetyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75: 7.5: 21);

  Ultraviolet absorption spectrum (in 0.1-m.  aqueous sodium hydrogen carbonate solution): #max at 238 mF and 265 m; 7ss-cyanoacetylamino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.45-0.55 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 254 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.32 and 5.60 ll; 7 ss-a-cyanopropionyl-amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Pf = 0.5-0.6 (system: n-butanol / pyridine / acetic acid / water 38: 24: 8: 30 );

  Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 254 mull; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 p and 5.62 'L; 7 ss- (a-cyano-phenylacetyl) -amino-3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.3-0.4 (system: n-butanol / acetic acid / water 75: 7.5 : 21); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): has at 260 m;

  Infrared absorption spectrum (in mineral oil): characteristic bands at 4.42 F and 5.62; 7ss - [α- (N-tert. -Butyloxycarbonyl-amino) -α-2-thienyl-acetyl] -amino] -3-cephem-4-carboxylic acid, thin-layer chromatogram (silica gel): Rf = 0.5-0.6 (system: ethyl acetate / pyridine / acetic acid / Water 62: 21: 6: 11); 7 P- (cr-amino-a-2-thienylacetyl) -amino-3-Lcephem-4-carboxylic acid as zwitterion, thin-layer chromatogram (silica gel): Rf = 0.4-0.5 (system:

  Ethyl acetate / methyl ethyl ketone / formic acid / water 50: 30: 10: 10); and 7 ß-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester-1-oxide, F.  198-202 (uncorr. ); [cL] 20 D = + 1120 + 10 (c = 0.667 in chloroform); Ultraviolet absorption (95% aqueous ethanol): #max = 264 mF (E = 6860) and Xmin = 240 my (E = 3930). 

 

   Example 13
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 are 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 ml (E = 4950); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.60, 5.92 ij, 6.24 CL and 6.67 Il.    



   The 3-methoxy-7ss- (D-a-phenylglycyl-amino) -3-cephem-4-carboxylic acid can be prepared in an analogous manner by 3-acetyloxymethyl-7ss- (D-α-tert. -butyloxy-carbonylamino-a-phenylacetyl-amino) -3 -cephem-4-carboxylic acid enzymatically cleaves the acetyloxymethyl group, the thus obtainable 3-hydroxymethyl-7ss- (D-α-tert. -butyloxycarbonyl-amino-α-phenylacetyl-amino) -3-cephem-4-carboxylic acid esterified with diphenyldiazomethane and in the 3-hydroxymethyl group of 3-hydroxymethyl-7ss- (D-α-tert. -butyloxycarbonyl-amino-a-phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester replaced the hydroxyl group by treatment with N-methyl-N, N'-dicyclohexyl-caarbodiimidium iodide;

   the 3-iodomethyl group in 3-iodomethyl-7ss- (D-a-tert. - butyloxycarbonylamino-α-phenylacetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester is reductively, e.g.  B.  by treatment with zinc in the presence of 90% aqueous acetic acid, converted into the methylene group, and the 3 - methyllene-7 ss- (D - a-tert. -butyloxycarbonylamino-a-phenyl acetyl-amino) -cepham-4 a-carboxylic acid-diphenylmethyl ester is converted by treatment with ozone, followed by dimethyl sulfide to the mixture of the 7 P- (D-a-tert. -Butyloxycarbonylamino-a phenylacetyl-amino) -cepham-3-one-4-carboxylic acid diphenylmethyl ester and the 1-oxide thereof;

   the latter is separated off by chromatography, the 7 B- (D-a-tert. -Butyloxycarbonyl-amino-a-phenylacetyl-amino) -cepham-3-one-4acarboxylic 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-phenylacetyl-amino) -3-cephem-4-carboxylic acid-diphenylmethyl ester the desired 3-methoxy 7ss- (D-α-phenylglycyl-amino) -3-cephem-4-carboxylic acid.    



   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 is cleaved by treatment with phosphorus pentachloride in the presence of pyridine at about -10 ', followed by methanol at about -15' and hydrolysis at a pH of about 3, the free amino group in 7ss-amino-3-methoxy-3- diphenylmethyl cephem-4-carboxylate by treating with the mixed anhydride from α-tert. -Butyloxycarbonylamino-?

  ; -phenyl acetic acid and isobutyl chloroformate acylated and in the 3-methoxy-7 p- (D-a-tert.  -butyloxycarbonylamino-a-phenylace tyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester liberates the amino and carboxy groups by treatment with trifluoroacetic acid in the presence of anisole. 



   Example 14
A stream of oxygen and ozone (containing 0.35 mmol of ozone) is passed through a cooled solution of 0.553 g of 4-methylphenylsulphonate of 7B-amino-3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester in 50 ml of methanol for 4 minutes per minute).  After a further 5 minutes, 0.3 ml of dimethyl sulfide is added to the pale blue solution.  The mixture is stirred for 15 minutes at -70, for one hour at -12 'and for one hour in an ice bath, then evaporated.  The residue is taken up in a small amount of methylene chloride, then diethyl ether is added until it becomes cloudy and the mixture is left to stand. 

  The microcrystalline, reddish colored powdery precipitate is filtered off and gives the 4-methylphenylsulphonate of 7 p-amino-cepham-3-one-4 a-carboxylic acid diphenylmethyl ester, which is mainly in the enol form as 4-methylphenylsulphonate of 7ss-amino 3-cephem-3- ol-4-carboxylic acid diphenylmethyl ester is present, F.  = 143 1450 (with decomposition); Thin layer chromatogram (silica gel) Rf ¯ 0.28 (system:

  Ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in ethanol): #max = 262 my (E = 3050) and 282 ml (E + 3020); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.58 I1, 5.77 11 (shoulder), 6.02 y and 6.22 CL.    



   The starting material can be made as follows:
A solution, cooled to -15, of 2.0 g of 3-methylene-7ss-phenylacetylamino-cepham-4 a-carboxylic acid diphenylmethyl ester in 80 ml of absolute methylene chloride is mixed with 3.2 ml of absolute pyridine and 32 ml of an 8% solution Phos phorpentachlorid added to methylene chloride and stirred for one hour under a nitrogen atmosphere at a temperature between -10 'and -5.  The reaction mixture is then cooled to -25, mixed with 25 ml of absolute methanol and stirred for one hour at -10 ', then for 1.5 hours at room temperature. 

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



   The organic phase is separated off; the aqueous phase is extracted twice with 150 ml of methylene chloride each time and the organic solutions are combined, dried over sodium sulfate and evaporated.  The oily residue is taken up in 25 ml of ethyl acetate and a solution of 1.14 g of 4-methylphenylsulfonic acid monohydrate in 25 ml of methylene chloride is added at 0O.  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. 

  This gives the 4-methylphenylsulfonate of 7-amino-3-methylene-cepham-4-a-diphenylmethyl ester in the form of colorless needles, F.  153-155; [a] D = -140 + 1 (c = 0.97 in methanol); Ultraviolet Absorption Spectrum (in ethanol): #max = 257 F (E = 1500);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.5, 5.60 y, 5.73 Il, 8.50, u, 9.68 and 9.92
Example 15
In a solution, cooled to -70, of 5.0 g of 3-methylene-7ss- (D-? -Tert. -butyloxycarbonylamino-α-phenyl-acetylamino) -cepham-4α-carboxylic acid diphenylmethyl ester in 500 ml of methylene chloride is passed in an oxygen-ozone stream containing 0.21 mmol of ozone / min with vigorous stirring for one hour.  After a further 10 minutes, 3 ml of dimethyl sulfide are added to the reaction mixture, the mixture is stirred for one hour at -65 'and for 2 hours at room temperature and then evaporated under reduced pressure. 

  The crude product, which the 7t3- (D-a-tert. -Butyloxycar- bonylamino-a-phenylacetyl-amino) -cepham-4-one-4M-carboxylic acid diphenylmethyl ester, in 150 ml of methanol is treated with an excess amount of a solution of diazomethane in diethyl ether at 0O and stirred for 15 minutes and then evaporated.  A yellowish foam is obtained which is chromatographed on 200 g of silica gel.  

  With a 3: 1 mixture of toluene and ethyl acetate, the amorphous 3-methoxy-7ss- (D-a- tert.  -butyloxycarbonylamino-a-phenylacetyl-amino) -3-cephem4-carboxylic acid diphenylmethyl ester Thin-layer chromatogram (silica gel): Rf = 0.22 (system: toluene / ethyl acetate 3: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.60 Il, 5.85 y, 6.23 and 6.70, u.    



   The starting material can be made as follows:
A chromatography column (diameter: 3 cm) is filled with 350 g of zinc grit, for 10 minutes with a 0.1 molar solution of mercury (II) chloride in 0.1N.  Hydrochloric acid amalgamated and with a lot of water and finally with a small amount of 1-n.  Washed hydrochloric acid.  A solution of 55 g of green chromium m-chloride hexahydrate in 55 ml of water and 11 ml of 2-n.  Sulfuric acid is poured into the reduction tube and the flow rate is regulated in such a way that a chromium (II) chloride solution of a pure blue color drips into the reaction vessel, which is kept under a nitrogen atmosphere. 

  The blue chromium (II) chloride solution is then mixed with a solution of 92 g of sodium acetate in 180 ml of air-free water, the solution turning red and finely crystalline chromium (II) acetate precipitating out. 



   When the precipitation is complete, the supernatant solution is removed and the chromium (II) acetate is washed twice with 250 ml of air-free water each time.  A solution of 10.0 g of 3-acetyloxymethyl-7ss- (D-a-tert. - butyloxycarbonyl-amino-a-phenylacetyl-amino) -3 -cephem-4carboxylic acid in 200 ml of dimethyl sulfoxide, and the reaction mixture stirred for 15 hours under a nitrogen atmosphere at room temperature.  For working up, the reaction mixture is aerated for 30 minutes and, after the addition of 1000 g of a polystyrene sulfonic acid ion exchanger in the Na form (Dowex 50 W) and 1000 ml of water, stirred for one hour.  After removing the ion exchanger, the pH of the solution is 6-n. 

  Hydrochloric acid adjusted to 2 and the aqueous phase extracted three times with 2000 ml of ethyl acetate each time.  The organic extracts are washed four times with 1000 ml of a saturated aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. 



   The crude product obtained is dissolved in 100 ml of methanol and stirred with a solution of 6 g of diphenyldiazomethane in 30 ml of benzene for 1 hour at room temperature.  The crude product obtained after evaporation is chromatographed on 500 g of silica gel; the 3-methylene-7ss- (D-a-tert. - butyloxycarbonylemino-a-phenylacetyl-aminoj-cepham-4a-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of petroleum ether; after crystallization from a mixture of methylene dichloride and hexane, the product melts at 156-158; [a] D = -50 '+1 (C = 0.713, chloroform);

  Ultraviolet absorption spectrum in 95% aqueous ethanol: Xmax = 258 (± = 990); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 Il, 5.64, 5.74, 5.88 y (shoulder) and 6.71>.    



   Example 16
A solution of 0.400 g of 7 p- (D-a-tert. -Butyloxycarbo nylamino-a-phenyl-acetylamino) -3-methylen-cepham-4 acarboxylic acid-diphenylmethyl ester in 40 ml of methylene chloride is cooled to 0O, and 0.0835 g of tetracyanoethylene is added.  The yellow solution is treated at 0 with an oxygen / ozone mixture until 0.773 mmol of ozone has been consumed and then evaporated to dryness under a high vacuum at about 350. 

  The residue containing the 7B- (D-a-tert. -Butyloxycarbonylamino-a-phenylacetylamino) -cepham 3-one-4% carboxylic acid diphenylmethyl ester, is taken up in 50 ml of methanol, treated with a solution of diazomethane in diethyl ether until it remains yellow and then evaporated under reduced pressure at about 350. 



  0.1 g of the residue is worked up by means of a layer chromatogram (silica gel; system: ethyl acetate / toluene 1: 1), the methoxy-7 ss- (D-α -terting with Rf ¯ 0.5. - Butyloxycarbonylamino-a-phenyl-acetylamino) -3-cephem-4carboxylic acid diphenylmethyl ester, which is identical to the product of Example 4, and with Rf ¯ 0.6 the 7 ss- (D-a-tert.  Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methylene cepham-4α-carboxylic acid diphenylmethyl ester. 



   Example 17
A solution of 0.2 g of 7ss- (D-a-tert. -Butyloxycarbo- nylamino- a-phenyl-acetylamino) -3 -methylene-cepham-4 acarboxylic acid diphenylmethyl ester in 3 ml of methylene chloride is cooled to -22 'and initially mixed with 0.026 ml of pyridine and then with an ozone-oxygen mixture up to Passing 1.31 mmol of ozone treated.  The reaction mixture is evaporated to dryness under high vacuum and the residue is purified by thin layer chromatography. 

  The 7 ss- (D- α -tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -cepham-3-one-4t-carboxylic acid diphenylmethyl ester has an 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, 5.75-5.95 p (broad band), 6.21 F and 6.88 Il.    



   Example 18
The preparation of the 7 P- (D-a-tert. -Butyloxycarbonyl-amino-a-phenyl-acetylamino) -cepham-3-one-411-carboxylic acid diphenylmethyl ester from the 7 P- (D-a-tert. -Butyloxycar- bonylamino- a-phenyl-acetylamino) -3 -methylene-cepham-4 a-carboxylic acid diphenylmethyl ester is advantageously carried out continuously:
A 1% solution of 7ss- (D-α -tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -3-methylene-cepham-4-α-carboxylic acid-diphenylmethyl ester in methylene chloride by a with solids (e.g.  B. 

  Raschig Ringen) filled, cooled to 0O reactor tube (about 3 cm diameter) flow through and passes through an ozone-oxygen mixture in countercurrent, which delivers 0.245 mmol of ozone per minute.  The gas flow is regulated so that 700 ml of the gas mixture flow through the reactor tube per hour.  The residence time of the solution of the 7ss- (D-a-tert. -Butyloxy-carbonylamino-a-phenyl-acetylamino) -3 -methylene-cepham-4-carboxylic acid diphenylmethyl ester in the reactor tube
15 seconds.  The reaction solution with the ozonide is allowed to flow directly into a receiver with a solution of dimethyl sulfide in methylene chloride until it contains an excess of 5% dimethyl sulfide; then the template is changed. 

  The solution of the 7 p- (D-a-tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) -cepham 3-one-4 # -carboxylic acid-diphenylmethyl ester is evaporated under reduced pressure at about 350 and the residue, e.g.  B.  as described in Example 4, taken up in methanol and treated with a solution of diazomethane in diethyl ether.  The 3-methoxy-7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, which is identical to the product of Example 4. 

 

   Example 19
A mixture of 5 g of 3-methylene-7ss- (D-a-tert. -butyl-oxycarbonylamino-a-phenyl-acetylamino) -cepham-4-a-carboxylic acid diphenylmethyl ester and 500 ml of methylene chloride is treated at -70 with 1.15 equivalents of ozone according to the method described in the preceding examples, then treated with 2 ml of dimethyl sulfide and stirred for one hour at -70 and 2 hours at room temperature, then evaporated under reduced pressure.  The residue containing the 7ss- (D-a-tert. -Butyloxycarbonyl-amino-a-phenyl-acetylamino) -cepham-3-one-45-carboxylic acid diphenylmethyl ester, is dissolved in 150 ml of methanol and treated at 0O with a solution of diazonobutane in diethyl ether until it remains yellow. 

  After 15 minutes the solution is evaporated under reduced pressure and the residue is purified by means of preparative layer chromatography (silica gel; 1.5 mm thick; plates 16 × 100 cm; system: toluene / ethyl acetate 75:25).  The zone visible under ultraviolet light with an Rf value of about 0.35 gives the -3-n-butyloxy-7ss- (D-α-tert. -butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester which is purified again by means of repeated chromatography on silica gel and lyophilized from dioxane, (a] 20 = + 11o + 1 (c = 0.98 in chloroform); ultraviolet absorption spectrum (in 95% aqueous ethanol); #max = 264 m (± = 6100);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 5.63 y, 5.84 ii (shoulder), 5.88, 6.26> and 6.71,
Example 20
A solution of 0.258 g of 3-methylene-7ss-phenylacetyl-amino-cepham-4-a-carboxylic acid-diphenylmethyl ester-1-oxide in 50 ml of methanol is at -65 with an oxygen / ozone mixture (20 mmol of ozone per minute) Treated to remain blue.  The reaction mixture is then treated with 0.5 ml of dimethyl sulfide, stirred for 20 minutes at -65 and 30 minutes at room temperature and evaporated under reduced pressure. 

  The residue, containing the 7ss-phenylacetamino-cepham-3-one-4 # -carboxylic acid-diphenylmethyl ester-1-oxide, is taken up in 20 ml of methanol and at 0O until it turns yellow with an ethereal solution of diazomethane in Diethyl ether added.  After standing for 15 minutes, the reaction mixture is evaporated under reduced pressure. 

  The residue is purified by means of preparative layer chromatography; the zone visible under ultraviolet light (k = 254 ml) with Rf ¯ 0.20 (system: ethyl acetate; identification with iodine) is eluted with a 1: 1 mixture of acetone and methanol and this gives 3-methoxy-7ss -phenylacetylamino-3-cepham-4-carboxylic acid diphenylmethyl ester-1-oxide, ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 276 m (± = 7500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 Cl, 5.56 y, 5.81 y.     5.92, 6.22 and 6.67 ij.    



   The starting material used in the above example can be prepared as follows: A solution, cooled to 0O, of 0.50 g of 3-methylene-7 B-phenylacetylamino-cepham-4 a-carboxylic acid diphenylmethyl ester in 50 ml of methylene chloride is mixed with a solution of 0.19 g of 3-chloroperbenzoic acid in 10 ml of methylene chloride were added and the mixture was stirred in an ice bath under a nitrogen atmosphere for 30 minutes.  The reaction mixture is diluted with 100 ml of methylene chloride, washed twice with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and with 50 ml of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel. 

  The 3-methylene-7-P-phenylacetylaminocepham-4 a-carboxylic acid diphenyl methyl ester 1-oxide is eluted with methylene chloride containing 3l5% acetone and crystallized from a mixture of acetone, diethyl ether and hexane, F = 172-175; [α] 20 D = -68 (c = 0.925 in chloroform); Thin-layer chromatogram (silica gel; identification with iodine): Rf ¯ 0.25 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): no specific absorption;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 y, 5.60, 5.74 Il, 5.92, 6.24 y, 6.63 11 and 9.60.    



   Example 21
A solution of 8.2 g of 7ss- (D-a- tert.  -Butyloxycarbonylamino-a-phenyl-acetylamino) -3 methylenceepham-4a-carboxylic acid diphenylmethyl ester in 800 ml of methylene chloride is treated for 34 minutes with an oxygen / ozone stream (0.49 in moles of ozone per minute), then with 3.5 ml of dimethyl sulfide are added and the mixture is stirred at -70 'for one hour and at room temperature for 2 hours. 

  After evaporation under reduced pressure, the oily residue containing the 7ss- (D-a- tert. -Butyloxycarbonylamino-a-phenylacetylamino) -cepham-3-on-45-carboxylic acid diphenylmethyl ester, dissolved in 300 ml of benzene, mixed with 3.28 g of 1-ethyl-3- (4-methylphenyl) -triazene and for one hour under one Refluxed nitrogen atmosphere, then evaporated under reduced pressure. 

  The residue is chromatographed on 360 g of silica gel, the amorphous 3-ethoxy-7ss- (D-α-tert. -butyloxycarbo- nylamino- a-phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 4: 1 mixture of toluene and ethyl acetate, thin layer chromatography (silica gel): Rf ¯ 0.28 (system:

  Toluene / ethyl acetate 3: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 m (# = 7000) and hmax = 264 mF (± = 6900);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.64, 5.90 lt, 6.28 lt and 6.73,
Example 22
A solution of 15 g of 3-methylene-7ss- (D-α-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) -cepham-4a-carboxylic acid diphenylmethyl ester in 1500 ml of methylene chloride is treated at -65 'for 62 minutes with a mixture of oxygen and ozone containing 0.5 mmol of ozone per minute and then treated at -70 mixed with 8.7 ml of dimethyl sulfide.  The mixture is stirred for 1 hour at -70 and for 2 hours at room temperature and evaporated under reduced pressure. 

  The residue containing the crude 7ss- (D-a-tert. -Butyloxycarbonylamino-a-phenyl-acetyl-amino) -cepham-3-one-4t-carboxylic acid diphenylmethyl ester, is dissolved in 350 ml of benzene and mixed with 11 g of 1-benzyl-3 (4-methylphenyl) -triazene, then during Boiled under reflux for 4 hours.  After cooling, 100 ml of 2-n. 



  aqueous hydrochloric acid and washed with a saturated aqueous sodium chloride solution; the organic phase is dried over sodium sulfate and evaporated under reduced pressure.  The residue is chromatographed on 650 g of silica gel; with toluene containing 15% ethyl acetate, the amorphous 3-benzyloxy-7ss- (D-? -tert), which is uniform according to thin layer chromatography. -butyloxycarbonylamino-α-phenyl acetylamino) -3-cephem-4-carboxylic acid-diphenylmethyl ester eluted, thin-layer chromatogram (silica gel); Development with iodine): Rf - 0.34 (system:

  Toluene / ethyl acetate 3: 1); [ujn2l = + 70 + 1 (c = 0.97 in chloroform); Ultraviolet absorption spectrum (in 95% aqueous ethanol): #max = 258 my (± = 6800), and 264 mlt (± = 6800, and # shoulder =
280 mlt (± = 6300); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 lt 5.63 lt 5.88,
6.26 lt and 6.72 Il.    

 

   Example 23
A solution of 1.59 g of 7t3- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester in 150 ml
Methylene chloride is cooled to -70 'and under vigorous
Stir for 12 minutes and 43 seconds with a
Mixture of ozone and oxygen containing 0.2 mmol of ozone per minute then treated with 1 ml of dimethyl sulfide.  The mixture is stirred for 5 minutes at -70 and for 30 minutes at room temperature and evaporated under reduced pressure.  The residue, containing the 7ss- (5-benzoylamino-5-diphenylmetjoxycarbonyl-valeryl-amino) -cepham-3-one-4-t-carboxylic acid diphenylmethyl ester, is dissolved in 40 ml of methanol, cooled in an ice bath and added until it remains Yellow coloration with a solution of diazomethane in diethyl ether. 



  The reaction mixture is evaporated under reduced pressure and the residue is chromatographed on 100 g of silica gel.  The 7 ss- (5-benzoylamino-5-diphenylmethoxycarbonyl valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is eluted with a 1: 1 mixture of toluene and ethyl acetate and obtained as an amorphous product, thin-layer chromatogram (Silica gel): Rf = 0.45 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): shoulder = 258 ml (± = 7450), 264 my (E = 7050) and 268 mp (E = 6700); tInfrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5th , 78, 6.03 y and 6.64.    



   The starting material can be made as follows:
A solution of 50 g of the sodium salt of Cephalosporin C in 1500 ml of 10% strength aqueous dipotassium hydrogen phosphate is diluted with 1200 ml of acetone and 21 g of benzoyl chloride are added at 0 ".  The mixture is stirred for 30 minutes at 0 and for 45 minutes at 20, the pH being kept constant at 8.5 by adding a 50% strength aqueous tripotassium phosphate solution.  It is concentrated to about half the volume under reduced pressure, washed with ethyl acetate, acidified to pH 2.0 with 20% aqueous phosphoric acid and extracted with ethyl acetate. 

  The organic phase is dried and evaporated under reduced pressure; the residue, recrystallized from acetone, gives the N-benzoyl-cephalosporin C, F, 117-119 "; thin-layer chromatogram (silica gel): Rf = 0.37 (system: n butanol / acetic acid / water 75: 7.5: 21) and Rf: 0.08 (system ethyl acetate / pyridine / acetic acid / water 62: 21: 6: 11). 



   A solution of 4.7 g of N-benzoyl-cephalosporin C in 85 ml of 0.5 molar aqueous dipotassium hydrogen phosphate solution and 9 ml of dimethylformamide is stirred together with 4.7 g of aluminum amalgam for 45 minutes at pH 6.0 and 45O, the pH is kept constant by adding 20% aqueous phosphoric acid.  100 ml of ice are added, a layer of cold ethyl acetate is added and the pH is adjusted to 2.0 with concentrated phosphoric acid.  The mixture is saturated with sodium chloride, the organic layer is separated off and the aqueous phase is washed twice with ethyl acetate. 



   The combined organic extracts, washed with saturated aqueous sodium chloride solution and dried over sodium sulphate, give a residue on evaporation under reduced pressure, which is crystallized in ethyl acetate.  It is slowly diluted with 15 ml of a 2: 3 mixture of ethyl acetate and hexane, filtered after standing for 2 hours at -5 'and, after crystallization from a 1: 4 mixture of ethyl acetate and diethyl ether, the 7ss- (5-benzoylamino-5 - carboxy-valerylamino) -3-methylencepham-4a-carboxylic acid, F. 



     82-89 "(with decomposition); thin layer chromatogram (silica gel): Rf = 0.53 (system: n-butanol / acetic acid / water 75: 7.5: 21), and Rf = 0.08 (system: ethyl acetate / pyridine / Acetic acid / water 62: 21: 6: 11). 



   The aluminum amalgam used above can be prepared as follows: A mixture of 3.3 g of aluminum grit and 100 ml of 50% aqueous sodium hydroxide solution is shaken for 30 seconds and, after the supernatant liquid has been decanted off, washed three times with 300 ml of water each time.  The residue is treated for 3 minutes with 130 ml of a 0.3% strength aqueous mercury (II) chloride solution and washed three times with 300 ml of water each time.  The entire treatment is repeated once and the aluminum amalgam is finally washed three times with tetrahydrofuran.  About 15 ml of ethyl acetate are used to transfer the product into the reaction vessel. 



   A solution of 2.3 g of 7 ss- (5-benzoylamino-5-carboxy-valeryl-amino) -3-methylen-cepham-4? -Carboxylic acid in 25 ml of dioxane is added dropwise within 10 minutes with a solution of 2.5 g diphenyldiazomethane in 10 m @ n-pentane are added. 



  The mixture is stirred for 30 minutes at room temperature, the excess diphenyldiazomethane is decomposed by adding a few drops of acetic acid (glacial acetic acid) and the solution is evaporated under reduced pressure.  The residue is chromatographed on 80 g of silica gel, the 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methylene-cepham-4a-carboxylic acid diphenylmethyl ester being eluted with a 3: 1 mixture of toluene and ethyl acetate and then crystallized from a mixture of methyl acetate and cyclohexane, F.  180-181; Thin-layer chromatogram (silica gel): Rf = 0.24 (system toluene / ethyl acetate 2: 1); Ultraviolet absorption spectrum (in 95% strength aqueous ethanol): no characteristic bands;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.66, 5.76 ii, 5.95 Il, 6.03, a, 6.64 CL and 6.70 p.    



   Example 24
A solution of 0.400 g of 7ss- (D-a- tert. -Butyloxycarbonylamino-α-phenyl-acetylamino) -3-methylene-cepham-4 a-carboxylic acid diphenylethyl ester in 40 ml of methylene chloride is treated with an ozone-oxygen mixture containing 0.21 mmol of ozone per minute for 3.6 minutes , treated, then treated with 0.5 ml of dimethyl sulfide and then evaporated under reduced pressure. 



  The residue containing the 7ss- (D-a-tert. -Butyloxycarbo- nylamino-a-phenylacetylamino) -cepham-2-one-45-carboxylic acid diphenylmethyl ester, is dissolved in 10 ml of methanol and treated with a solution of diazomethane in diethyl ether until it remains yellow.  It is evaporated under reduced pressure and the residue is subjected to the preparative
Layer chromatography (silica gel; system: toluene-acetic acid ethyl ester 1: 1; identification with ultraviolet light: A = 254). 



   A mixture of the 7ss- (D-a-tert. -Butyloxy-carbonylamino-a-phenyl-acetylamino) -3 -methylene-cepham
4a-carboxylic acid diphenylmethyl ester and the 7ss- (D-a- tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-2-cephem-4 a-carboxylic acid diphenylmethyl ester, both with an Rf value of 0.55,

   then the 7ss- (D-a-tert. - Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy
3-cephem-4-carboxylic acid diphenylmethyl ester with a
Rf value of 0.45 and finally a mixture of the 7ss- (D-a tert. -Butyloxycarbonylamino- a-phenyl-acetylamino)
3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester 1B-oxyds with an Rf value of 0.17 and -la-oxyds with an Rf value of 0.07. 

  Instead of the 7ss- (D-a-tert. -
Butyloxycarbonylamino-a-phenylacetylamino) -3-methylene-cepham-4α-carboxylic acid diphenylmethyl ester can be obtained in the above process as the 7ss- (D-a-tert. -Butyloxycarbonyl-amino-a-phenyl-acetylamino) -3-methylene-cepham-4a-carboxylic acid 4-nitro-benzyl ester or the 7 p- (D-a-tert. -Butyl-oxycarbonylamino-a-phenyl-acetylamino) -3 -methylene-cepham-4α-carboxylic acid-2,2,2-trichloroethyl ester, which can be obtained by
Treating the sodium salt of the 7ss- (D-a-tert. -
Butyloxycarbonylamino- o-phenyl-acetylamino) -3-methylene-cepham-4a-carboxylic acid with 4-nitro-benzyl bromide or 

 

      of a reactive, mixed anhydride of the 7 7ss- (D-a-tert. -Butyloxycarbonylamino-a-phenyl-acetyamino)
3-methylene-cepham-4a-carboxylic acid with 2,2,2-trichloroethanol can be used as starting materials and via the 7ss- (D-? -Tert. -Butyloxycarbonylamino-?

  ; -phenyl-acetylamino) -cepham-3-one-4t-carboxylic acid 4-nitrobenzyl ester or  the 7 B- (D-a-tert. -Butyloxycarbonyl-amino-a-phenyl-acetylamino) -cepham-3-one-4t-carboxylic acid-2,2,2-trichloroethyl ester of 7 B- (Da-tert, -Butyl-oxycarbonylamino-a-phenyl-acetylamino ) -3-methoxy-3-cephem-4-carboxylic acid 4-nitro-benzyl ester or  the 7ss- (D-a-tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) 3-methoxy-3-cephem-4-carboxylic acid 2,2,2-trichloroethyl ester. 



   Example 25
A solution of 0.250 g of the 4-methylphenylsulphonic acid salt of 7 ß-amino-cepham-3-one-4 # -carboxylic acid diphenyl-methyl ester, which is mainly in the enol form of 4-methylphenylsulphonate of 7 B-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 0O.  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 it 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 7 7ss-phenylacetylaminocepham-3-one-4 # -carboxylic acid diphenylmethyl ester is eluted with methylene chloride; Thin-layer chromatogram (silica gel): Rf - 0.55 (system: ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 283 mF (E = 4400);

  In infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ij, 5.12 l, 5.77 Il, 5.93 y, 6.21 p and 6.63 p.    



   Example 26
In an analogous manner, the following compounds can be obtained when the suitable starting materials are selected: 7 ss- [D-a-tert. -Butyloxycarbonylamino-a- (4-hydroxyphenyl) -acetylamino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-thienyl) acetylamino] -cepham-3-one-4, 5-carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (3-thienyl) acetylaminol -cepham3-one-4kcarboxylic acid diphenylmethyl ester; 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (2-furyl) acetylamino-cepham-3-one-4 # -carboxylic acid diphenylmethyl ester;

   7 ss- [D -a-tert.  -Butyloxycarbonylamino-α- (4-isothiazolyl) -acetylamino] -cephame-3-one-4t-carboxylic acid diphenylmethyl ester; 7 ss- [D-a-tert. -Butyloxycarbonylamino-a- (1,4-cyclohexadienyl) -acetylamino] -cepham-3-one-4 5-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; 7 B- (4-aminopyridinium-acetylamino) -cepham-3-one-45-carboxylic acid diphenylmethyl ester;

   and 7ss- [D-α- (2,2,2-trichloroethoxycarbonyloxy) -α-phenyl-acetylamino] -cepham-3-one-4t-carboxylic acid diphenyl-methyl ester. 



   PATENT CLAIM I
Process for the preparation of 7 t3-amino-cepham-3-one-4-carboxylic acid derivatives of the formula
EMI22. 1
 where R1 represents hydrogen or an amino protective group, and Ru represents hydrogen or an acyl group, or R1 and Rb together represent a divalent amino protective group, R2 represents a radical which, together with the carbonyl group -C (= O) -, forms a protected carboxyl group, and / or 1-oxides of compounds of the formula I, or salts of such compounds with salt-forming groups, characterized in that

   that in a cepham compound of the formula
EMI22. 2
 or in a 1-oxide thereof the methylene group in the 3-position is replaced by the oxo group by treatment with ozone and subsequent reductive cleavage of the ozonide formed as an intermediate, and a compound obtained with a salt-forming group is isolated as a salt or as a free compound. 



   SUBCLAIMS
1.  Process according to claim I, characterized in that a starting material of the formula II is used, in which Rl is an amino protective group which stands for an acyl group, in which any free functional groups which may be present can be protected, Rb is hydrogen, and RzA is a with -C ( = O) grouping represents an etherified hydroxyl group which forms an esterified carboxyl group, it being possible for any functional groups present in an esterified carboxyl group of the formula -C (O) - R2A to be protected. 

 

   2.  Process according to dependent claim 1, characterized in that R2 represents an optionally substituted 1-phenyl-lower alkoxy group, such as the diphenylmethoxy group. 



   3.  Process according to dependent claim 1, characterized in that R2A is an optionally halogen-substituted lower alkoxy group, such as an α-polybranched lower alkoxy group, e.g.  B.  tert. -Butyloxy, or a 2-halo-lower alkoxy group, such as 2,2,2-trichloroethoxy. 



   4th  Process according to claim I, characterized in that an ozonide obtainable as an intermediate product is used

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. amino-a-phenyl-acetylamino) -cepham-3-one-4-t-carboxylic acid-2,2,2-trichloroethyl ester 7 B- (Da-tert, -butyloxycarbonylamino-a-phenyl-acetylamino) -3 -methoxy-3-cephem-4-carboxylic acid-4-nitro-benzyl ester or the 7ss- (Da-tert-butyloxycarbonylamino-a-phenyl-acetylamino) 3-methoxy-3-cephem-4-carboxylic acid-2,2, 2-trichloroethyl ester obtained. Example 25 A solution of 0.250 g of the 4-methylphenylsulphonic acid salt of 7 ß-amino-cepham-3-one-4 # -carboxylic acid diphenyl-methyl ester, which is mainly in the enol form of 4-methylphenylsulphonate of 7 B-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 0O. 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 it 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 7 7ss-phenylacetylaminocepham-3-one-4 # -carboxylic acid diphenylmethyl ester is eluted with methylene chloride; Thin-layer chromatogram (silica gel): Rf - 0.55 (system: ethyl acetate / pyridine / water 85: 10: 5); Ultraviolet absorption spectrum (in 95% aqueous ethanol): Xmax = 283 mF (E = 4400); In infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 ij, 5.12 l, 5.77 Il, 5.93 y, 6.21 p and 6.63 p. Example 26 In an analogous manner, the following compounds can be obtained when the suitable starting materials are selected: 7 [D-a-tert-butyloxycarbonylamino-a- (4-hydroxyphenyl) -acetylamino] -cepham-3-one-4 # -carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert-butyloxycarbonylamino-α- (2-thienyl) acetylamino] -cepham-3-one-4, 5-carboxylic acid diphenylmethyl ester; 7ss- [D-α-tert-butyloxycarbonylamino-α- (3-thienyl) acetylaminol -cepham3-one-4kcarboxylic acid diphenylmethyl ester; 7ss- [D-α-tert-butyloxycarbonylamino-α- (2-furyl) acetylamino-cepham-3-one-4 # carboxylic acid diphenyl-methyl ester; 7 ss- [D -a-tert. -Butyloxycarbonylamino-α- (4-isothiazolyl) -acetylamino] -cephame-3-one-4t-carboxylic acid diphenylmethyl ester; 7 ss- [Da-tert-butyloxycarbonylamino-a- (1,4-cyclohexadienyl) -acetylamino] -cepham-3-one-4 5-carboxylic acid diphenylmethyl ester 7ss- (2-thienyl) -acetylamino-cepham- 3-on-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; 7 B- (4-aminopyridinium-acetylamino) -cepham-3-one-45-carboxylic acid diphenylmethyl ester; and 7ss- [D-α- (2,2,2-trichloroethoxycarbonyloxy) -α-phenyl-acetylamino] -cepham-3-one-4t-carboxylic acid diphenyl-methyl ester. PATENT CLAIM I Process for the preparation of 7 t3-amino-cepham-3-one-4-carboxylic acid derivatives of the formula EMI22.1 where R1 represents hydrogen or an amino protective group, and Ru represents hydrogen or an acyl group, or R1 and Rb together represent a divalent amino protective group, R2 represents a radical which, together with the carbonyl group -C (= O) -, forms a protected carboxyl group, and / or 1-oxides of compounds of the formula I, or salts of such compounds with salt-forming groups, characterized in that that in a cepham compound of the formula EMI22.2 or in a 1-oxide thereof the methylene group in the 3-position is replaced by the oxo group by treatment with ozone and subsequent reductive cleavage of the ozonide formed as an intermediate, and a compound obtained with a salt-forming group is isolated as a salt or 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 Rl is an amino protective group which stands for an acyl group, in which any free functional groups that may be present can be protected, Rb is hydrogen, and RzA is a with - C (= O) grouping represents an etherified hydroxyl group which forms an esterified carboxyl group, it being possible for functional groups which may be present in an esterified carboxyl group of the formula -C (O) - R2A to be protected. 2. The method according to dependent claim 1, characterized in that R2 represents an optionally substituted 1-phenyl-lower alkoxy group, such as the diphenylmethoxy group. 3. The method according to dependent claim 1, characterized in that R2A is an optionally halogen-substituted lower alkoxy group, such as an α-polybranched lower alkoxy group, e.g. B. tert-butyloxy, or a 2-halo-lower alkoxy group, such as 2,2,2-trichloroethoxy. 4. The method according to claim I, characterized in that one obtainable as an intermediate ozonide by treating with catalytically activated hydrogen, with a reducing heavy metal, heavy metal alloy or heavy metal amalgam in the presence of a hydrogen donor, a reducing inorganic salt in the presence of a hydrogen donor or a reducing organic compound such as formic acid, a reducing sulfide compound or a reducing organic phosphorus compound, into a compound of Formula 1 or its l-oxide transferred. 5. The method according to claim I, characterized in that a mixture obtained of a compound of formula I and a corresponding l-oxide thereof is oxidized to the 1-oxide of the compound of formula I by treatment with a peracid or hydrogen peroxide. 6. The method according to claim I, characterized in that a free amino group is acylated in a compound obtained. 7. The method according to claim I, characterized in that a starting material of the formula II is used in the form of derivatives in which functional groups are protected. 8. The method according to claim I or one of the dependent claims 1-7, characterized in that compounds of the formula I according to claim I or l-oxides thereof, and salts of those compounds with salt-forming groups in which Rl is hydrogen or one in one Rlb represents a fermentative or bio-, semi- or totally synthetically producible N-acyl derivative of a 6 p-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound or an easily cleavable acyl radical of a carbonic acid half derivative represents hydrogen, and R2A optionally substituted lower alkoxy, optionally substituted phenyl-lower alkoxy, Acyloxy, tri-lower alkylsilyloxy, or optionally substituted amino or hydrazino. 9. The method according to claim I or one of the dependent claims 1-7, characterized in that compounds of the formula I according to claim I or l-oxides thereof, furthermore salts of those compounds with salt-forming groups, in which Rt is hydrogen, one in fermentative or Biosynthetically producible N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-3-carboxylic acid compounds, or an acyl radical contained in highly effective N-acyl derivatives of 6 t3-amino-penam-3-carboxylic acid or 7 7ss-amino-3-cephem-4-carboxylic acid compounds is acyl radical, R1b is hydrogen, and R2 is lower alkoxy, 2-halo-lower alkoxy, Phenylacyloxy, l-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxy. 10. The method according to claim I or one of the dependent claims 1-7, characterized in that compounds of the formula I according to claim I, or l-oxides thereof, and also salts of those compounds with salt-forming groups in which Rlb and R, A are prepared in dependent claim 9 have opposite meanings, and Rl represents hydrogen or a group of the formula EMI23.1 where n is 0 and Rl 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. esterified or etherified hydroxy or mercapto group, or an optionally substituted amino group, or where n is 1, R 'is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or represents an azido group, and each of the radicals R11 and R111 is hydrogen, or where n is 1, Rl 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 The remainder preferably has aromatic character, Rll 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 azido group or a halogen atom, and Rlll represents hydrogen, or where n is 1, each of the radicals Rl and Rll is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R "'is hydrogen, or where n is 1, Rl is hydrogen or an optionally substituted aliphatic , is cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and R11 and R111 together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, or where Rl is 1, and where n is 1, and substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical in which heterocyclic radicals preferably have an aromatic character, Rll an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical and Rlll is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical. 11. The method according to claim I or one of the dependent claims 1-7, characterized in that compounds of the formula I according to claim I, or the l-oxides thereof, and also salts of compounds with salt-forming groups in which Rl is hydrogen, is prepared R? Hydrogen, an acyl group of the formula EMI23.2 wherein Ar is phenyl, hydroxyphenyl, hydroxy-chlorophenyl or Represents 2-thienyl, where hydroxysubstituent can be protected by acyl radicals in such radicals, X represents oxygen or sulfur, n represents 0 or 1, and R represents water substance or, if n is 0, optionally protected amino, carboxy, sulfo or hydroxy, or O-lower alkylphosphono or O, O-di-lower alkylphosphono, or denotes a 5-amino-5-carboxy-valeryl radical in which the amino and carboxy groups are optionally protected, and R2 denotes lower alkoxy, 2-halo-lower alkoxy or optionally substituted diphenylmethoxy. 12. The method according to claim I or one of the subclaims 1-7, characterized in that compounds of the formula I according to claim I or 1-oxides, furthermore salts of compounds with salt-forming groups in which Rl is hydrogen, the acyl radical of the formula B, is prepared according to dependent claim 11, wherein 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, represents, Rlb represents hydrogen, and R2A denotes lower alkoxy which is optionally halogen-substituted in the 2 position or optionally lower alkoxy-substituted diphenylmethoxy. 13. The method according to claim I or one of the dependent claims 1-4 and 6-7, characterized in that 7 P-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester is prepared. 14. The method according to claim I or one of the subclaims 1-7, characterized in that the 7,3-phenylacetylamino-cepham-3-one-4 a-carboxylic acid diphenyl methyl ester 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 or thioketals, characterized in that they are reacted with a glycol, thioglycol or dithioglycol in the presence of an acidic catalyst.