CH602635A5 - 7-Amino-3-hydroxy-2(or 3)-cephem-4-carboxylic acid derivs prepn - Google Patents

Abstract

7-Amino-3-hydroxy-2(or 3)-cephem-4-carboxylic acid derivs prepn by cyclizing 3-alkoxy-2-(2-oxo-3-amino-4-thio-1-azetidinyl)-crotonic acid derivs

Description

  

  
 



   The present invention relates to a process for the preparation of 2- (3-amino-2-oxo-4-sulfonylthio-1-azetidinyl) -3-methylene-butyric acid compounds of the formula
EMI1. 1
 where Rta represents hydrogen or an amino protective group R, A and Rjb represents hydrogen or an acyl group Ac, or Rta and Rtb together represent a divalent amino protective group, R2A represents a radical which together with the carbonyl group -C (= O) - forms a protected carboxyl group and Y denotes a group of the formula -SO2-R bonded to the thio group -S- by the sulfur atom, or a group -S-SO2-R,

   wherein R5 represents an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms, and also their salts. 



   An amino protective group R1A is a group which can be replaced by hydrogen, primarily an acyl group Ac, furthermore a triarylmethyl, in particular the trityl group, and an organic silyl or an organic stannyl group. 



  A group Ac, which can also stand for a radical Rtb, 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 divalent amino protective group formed by the radicals R, a and RXb 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, and also the acyl radical of a preferably substituted in a position , 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 methyl groups containing methylene radical is connected to the nitrogen atom. 

  The radicals Rta and Rjb 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 therefore be a hydroxy group etherified by an organic radical, in which the organic radical preferably contains up to 18 carbon atoms, which together with the -C (= 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 and 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 halogen , such as chlorine-substituted silyloxy or stannyloxy groups. 



   A radical R2A which forms a primarily mixed anhydride group with a -C (= O) group is, for example, halogen, such as chlorine or an acyloxy radical, in which acyl is the corresponding radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, such as a 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 bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or bivalent aliphatic, cycloaliphatic, cycloaliphatic aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms and / or functional groups, such as optionally functionally modified, in particular free hydroxy, furthermore etherified or esterified hydroxy, in which the etherifying ones or.  esterifying residues z. 

  B.  have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, primarily of organic carboxylic acids and of carbonic acid half-derivatives, preferably with up to 18 carbon atoms. 



   In a substituted hydrazinocarbonyl group of the formula -C (= O) -R2A, one or both nitrogen atoms can be substituted, the substituents primarily being optionally substituted monovalent or 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, primarily of organic carboxylic acids or of carbonic acid semi-derivatives, preferably with up to 18 carbon atoms, are possible. 

 

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

  B.  by free, etherified or esterified hydroxy or
Mercapto groups, such as lower alkoxy, lower alkenyloxy, Nie deralkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio, phenyl-lower alkylthio, heterocyclylthio or heterocyclyl-lower alkylthio, furthermore nitro, nitro, optionally substituted nitro, amino, nitro, optionally substituted by oxo, nitro, or alkoxycarbonyloxy, optionally substituted, nitro, nitro, optionally nitro, or alkoxycarbonyloxy, optionally substituted, nitro, optionally substituted by oxyloxy, or alkoxycarbonyloxy, optionally substituted, nitro, optionally nitro, or alkoxycarbonyloxy, optionally substituted by lower alkoxycarbonyloxy.  B. 

  Lower alkylamino, di-lower alkylamino, lower alkylenamino, oxaniederalkylenamino or aza-loweralkylenamino, as well as acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halo-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted, optionally substituted carbamoylamino, optionally substituted, optionally substituted carbamoylamino-alcoalamino, optionally substituted carbamoylamino-amino, optionally substituted carbamoylamino-amino, furthermore, optionally substituted carbamoylamino-amino, such as alkidoylamino-carbonamino, such as alkidoylamino-carbonamino, such as alkidoylamino-carbonamino, such as alkidoylamino-carbonamino, such as alkidoylamino-carbonamino, such as alkidoylamino-carbonamino, as Lower alkanoyl or benzoyl, optionally functionally modified carboxyl such as carboxyl present in salt form, esterified carboxyl such as lower alkoxycarbonyl, optionally substituted carbamoyl such as N-lower alkyl- or N, N-di-lower alkylcarbamoyl, also optionally substituted ureidocarbonyl or guanidinocarbonyl, or cyano, optionally functionally modified Sulfo,

   such as sulfamoyl or sulfo present in salt form, or optionally O-mono- or O, O-disubstituted phosphono, wherein substituents z.  B.  optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where O-unsubstituted or O-monosubstituted phosphono can also be present in salt or alkali metal salt form, be 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 abovementioned aliphatic radical, mono-, di- or polysubstituted and / or interrupted by heteroatoms such as oxygen, nitrogen or sulfur. 



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid, or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical.  B.  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or  Cycloalkyl or cycloalkenyl lower alkyl or lower alkenyl, also cycloalkyl lower alkylidene or cycloalkenyl lower alkylidene, wherein cycloalkyl and cycloalkylidene z.  B.  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.  may 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 also biphenylyl or naphthyl, which optionally, for.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   A divalent aromatic radical, e.g.  B.  an aromatic carboxylic acid, is primarily 1,2-arylene, in particular 1,2-phenylene, which optionally, z.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, 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 and phenyl-lower alkynyl, and also 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 heterocyclic radicals of this type, such 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 8-position, substituted lower alkyl half-ester of carbonic acid, and also 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.  one of the abovementioned heterocyclic groups of aromatic character, it being possible for both the lower alkyl radical and the heterocyclic group to be optionally substituted.  The acyl radical of a carbonic acid half derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group. 



   An etherified hydroxy group is primarily optionally substituted lower alkoxy, in which substituents are primarily free or functionally modified, such as etherified or esterified hydroxyl groups, in particular lower alkoxy or halogen, and lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocycoxyloxy or heterocyclyl lower 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-n-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 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 alkyl-3-aza-1,5-pentylene, e.g.  B.  3-methyl-3-aza-1,5-pentylene. 



   Cycloalkyl is e.g.  B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, 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 z.  B.  Cyclopentylidene or cyclohexylidene.    CycloaLkyl-lower alkyl or lower alkenyl is z.  B.  Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl, -1,1-, -1,2- or -1,3propyl, -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, -1,1-1 , 2- or -1,3-propyl, vinyl or allyl.  Cycloalkyl-lower alkylidene is e.g.  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, styryl or cinnamyl, naphthyl-lower alkyl z.  B.  1- or 2-Naphthylmnethyl, and Phenylniederalkyliden 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, pyridyl, e.g.  B.  2-, 3- or 4-pyridyl, also pyridinium, thienyl, e.g. B.     2- or 3-thienyl, or furyl, e.g.  B.  2 furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals, such as indolyl, e.g.  B.  2- or 3-indolyl, quinolinyl, e.g.  B.  2- or 4-quinolinyl, isoquinolinyl, e.g.  B.  1-isoquinolinyl, benzofuranyl, e.g.  B.  2- or 3-benzofuranyl, or benzothienyl, e.g.  B.  2- or 3-benzothienyl, monocyclic diaza, triaza, tetraza, oxaza-, thiaza or thiadiazacyclic radicals, such as imidazolyl, e.g.  B.  2-imidazolyl, pyrimidinyl, e.g.  B.  2- or 4-pyrimidinyl, triazolyl, e.g.  B.  1,2,4-triazol-3-yl, tetrazolyl, e.g. 

  B.  1- or 5-tetrazolyl, oxazolyl, e.g.  B.  2-oxazolyl, isoxazolyl, e.g.  B.  3- or 4-isoxazolyl, thiazolyl, e.g.  B.  2-thiazolyl, isothiazolyl, e.g.  B.  3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g.  B.    1, S4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza- or thiazacyclic radicals, such as benzimidazolyl, e.g.  B.  2-benzimidazolyl, benzoxazolyl, e.g.  B.    2-benzoxazolyl, or benzthiazolyl, e.g.  B.  2 benzthiazolyl.  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 or aromatic hydrocarbon radicals, in particular lower alkyl, such as methyl, or optionally, e.g.  B.  by halogen such as chlorine, substituted phenyl, e.g.  B.  Phenyl or 4-chlorophenyl, or, e.g.  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-chloro-, 2-bromo- or 2-iodoethoxy.  Lower alkenyloxy is e.g.  B.  Vinyloxy or allyloxy, lower alkylenedioxy e.g.  B.  Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g.  B.  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g.  B.  Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or heterocyclyloxy or heterocyclyl-lower alkoxy, e.g.  B.    Pyridyl-lower alkoxy, such as 2-pyridylmethoxy, furyl-lower alkoxy, such as furfuryloxy, or thienyl-lower alkoxy, such as 2-thenyloxy. 



   Lower alkylthio is e.g.  B.  Methylthio, ethylthio or n-butylthio, lower alkenylthio z.  B.    Allylthio, and phenyl lower alkylthio e.g.  B.    Benzylthio, while mercapto groups etherified by heterocyclyl radicals or heterocyclylaliphatic radicals, in particular pyridylthio, e.g.  B.  4-pyridylthio, imidazolthio, thiazolylthio, e.g.  B.  2-thiazolylthio, 1,2,4- or 1,3,4-thiadiazolylthio, e.g.  B.  1,2,4-thiadiazol-3-ylthio or 1,3,4-thiadiazol-2-ylthio, or tetrazolylthio, e.g.  B.  Are 1-methyl5-tetrazolylthio. 



   Esterified hydroxy groups are primarily halogen, e.g.  B.  Fluorine, chlorine, bromine or iodine, and Niederalkoxycar b onyloxy, z.  B.    Methoxycarbonyloxy, ethoxycarbonyloxy or tert. -Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g.  B.  2,2,2-Trichloräthoxycarbonyloxy, 2-Brom äthoxycarbonyloxy or 2-Jodäthoxycarbonyloxy, or Arylcarbonylmethoxycarbonyloxy, z.  B.  Phenacyloxycarbonyloxy. 



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



   N-lower alkyl- or N, N-di-lower alkyl-carbamoyl is e.g.  B. 



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



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



   Lower alkylamino or di-lower alkylamino is e.g.  B.  Methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino z.  B.  Pyrrolidino or piperidino, Oxaniederalkylenamino z. B.     Morpholino, thiane lower alkyleneamino 113.     Thiomorpholino, and aza-lower alkylenamino e.g.  B.  Piperazino or 4-methylpiperazino.  Acylamino is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g.  B. 

 

  Methoxycarbonylamino, ethoxycarbonylamino or tert. -Butyloxycarbonylamino, halo-lower alkoxycarbonylamino, such as 2,2,2-trichloroethoxycarbonylamino, phenyl-lower alkoxycarbonylamino, such as 4-methoxybenzyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, also for phthalimido, or optionally in salt, such as alkali metal.  B.  Sodium or ammonium salt form, present sulfoamino. 



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



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



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



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



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



   An acyl group Ac stands in particular for an N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound which is naturally occurring or which can be bio-, semi-synthetically or totally synthetically produced, preferably pharmacologically active contained acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, or an easily cleavable acyl radical, in particular a carbonic acid half derivative. 



   An acyl radical Ac contained in a pharmacologically active N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI4. 1
 wherein n is 0 and RI is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, z. 

  B.  denotes esterified or etherified hydroxy or mercapto or an optionally substituted amino group, or in which n is 1, RI is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical in which the heterocyclic radical preferably has aromatic character and / or a quaternary nitrogen atom, 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 Rll and Rlll is hydrogen, or where n is 1, Rt is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical is preferably aromatic in character has, RII an optionally functionally modified, z. 

  B.  esterified or etherified hydroxy or mercapto group, such as a halogen atom, an optionally substituted amino group, an optionally functionally modified carboxyl or sulfo group, an optionally O-mono- or O, O'-disubstituted phosphono group, or an azido group, and RIIt denotes hydrogen or where n is 1, each of the radicals RI and RII is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and RITT is hydrogen, or where n is 1, RI is hydrogen or an optionally substituted one aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

   aromatic or araliphatic hydrocarbon radical and Ril R111 together represent an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n stands for 1, and RI is an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which heterocyclic radicals preferably have an aromatic character, RII an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

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



   In the above acyl groups of the formula A, for.  B.  n is 0 and RI is hydrogen or an optionally, preferably in the 1-position by optionally protected amino, acylamino, in which acyl is primarily the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, 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, acyloxy, wherein acyl is primarily the acyl radical of a carbonic acid half-ester, such as a lower alkoxycarbonyl, 2-halo-lower alkoxycarbonyl or phenyl-lower alkoxycarbonyl radical, and / or halogen, e.g.  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 has substituents such as halogen, e.g.  B.  Chlorine, may carry substituted heterocyclic group, such as a 4-isoxazolyl group, or a preferably, z.  B.  by an optionally substituted one such as halogen, e.g.  B.  Chlorine, lower alkyl containing N-substituted amino group, or n for 1, Rt for an optionally substituted, preferably by halogen, such as chlorine, by optionally substituted, such as hydroxy, acyloxy, in which acyl has the meaning given above, and / or halogen, e.g.  B.  Chlorine, phenyloxy containing, or optionally protected amino and / or carboxy substituted lower alkyl group, e.g.  

  B.  for a 3-amino-3-carboxy-propyl radical with optionally protected amino and / or carboxy group, e.g.  B.  silylated, such as tri-lower alkylsilylated, e.g.  B. 



  trimethylsilylated, amino or acylamino, such as lower alkanoylamino, halo-lower alkanoylamino or phthaloylamino, and / or silylated, such as tri-lower alkylsilylated, e.g.  B.  trimethylsilylated, or esterified, such as by lower alkyl, 2-halo-lower alkyl or phenyl-lower alkyl, e.g.  B.  Diphenylmethyl, esterified carboxy group, for a lower alkenyl group, for an optionally substituted, such as optionally, e.g.  B.  as indicated above, acylated hydroxy and / or halogen, e.g.  B.  Chlorine, also optionally protected, e.g.  B.  as indicated above, acylated amino lower alkyl, such as aminomethyl, or optionally, e.g.  B.  as indicated above, acylated hydroxy and / or halogen, e.g.  B.   



  Phenyl group containing chlorine, containing phenyloxy, an optionally, z.  B.  by lower alkyl, such as methyl, or optionally protected, e.g.  B.  acylated, amino or aminomethyl, substituted pyridyl, e.g.  B.  4-pyridyl, pyridinium, e.g.  B.  4-pyridinium, thienyl, e.g.  B.  2-thienyl, furyl, e.g.  B.  2-furyl, imidazolyl, e.g.  B.  1 imidazolyl, or tetrazolyl, e.g.  B.  1-tetrazolyl group, an optionally substituted lower alkoxy, e.g.  B.  Methoxy group, an optionally substituted, such as optionally protected, e.g.  B.  acylated, hydroxy and / or halogen, such as chlorine, containing phenyloxy group a lower alkylthio, z.  B.  n-butylthio, or lower alkenylthio, e.g.  B.    Allylthiogmppe, optionally, z.  B.  by lower alkyl, such as methyl, substituted phenylthio, pyridylthio, e.g. 

  B.  4-pyridylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio-, 1, 2,4-thiadiazol-3-ylthio-, such as 5-methyl-1, 2,4-thidiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, such as methyl-1,3,4-thiadiazol-2-ylthio, or 5-tetrazolylthio - Such as 1-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxyl group, such as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g.  B.  by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g.  B. 

  Acetyl or propionyl, or benzoyl group, or an azido group, and Rll and Rlll for hydrogen, or n for 1, RI for lower alkyl or an optionally, as by optionally, z.  B.  as indicated above, acylated hydroxy and / or halogen, e.g.  B.  Chlorine, substituted phenyl, furyl, e.g.  B.  2-furyl, thienyl, 2.  B.    2 or 3-thienyl, or isothiazolyl, e.g.  B.  4-isothiazolyl group, also for a 1,4-cyclohexadienyl group, RII for optionally protected or substituted amino, e.g.  B.  Amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, e.g.  B.  Methoxy or nitro containing phenyl lower alkoxycarbonylamino, e.g. 

  B.  tert. -Butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxy.    



  benzyloxycarbonylamino or diphenylmethyloxycarbonylamino, arylsulfonylamino, e.g.  B.  4-methylphenylsulfonylamino, tritylamino, arylthioamino, such as nitrophenylthioamino, e.g.  B.  2-nitrophenylthioamino, or tritylthioamino or optionally substituted, such as lower alkoxycarbonyl, e.g.  B.  Ethoxycarbonyl, or lower alkanoyl, e.g.  B.  Acetyl, containing 2-propylideneamino, such as 1-ethoxycarbonyl-2-propylidenamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt, e.g.  B.  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z.  B.  Alkali metal salt form or in protected, such as esterified form, e.g.  B.  as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl, or as phenyloxycarbonyl, z.  B. 

  Diphenylmethoxycarbonylgruppe present carboxyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxy group, where functionally modified hydroxy, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy or optionally substituted, such as lower alkoxy, e.g.  B.  Methoxy, or nitro containing phenyl-lower alkoxycarbonyloxy, e.g.  B.  tert. -Butyloxycarbonyloxy, 2,2,2-Trichloräthoxycarbonyloxy, 4-Methoxybenzyloxycarbonyloxy or Diphenylmethoxycarbonyloxy, or optionally substituted lower alkoxy, z.  B.  Methoxy, or phenyloxy, an O-lower alkyl or O, O'-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 R111 for hydrogen, or n for 1, R1 and RI1 each for halogen, e.g.  B.  Bromine, or lower alkoxycarbonyl, e.g.  B. 



  Methoxycarbonyl, and RIII for hydrogen, or n for 1, RI for an optionally, z.  B.  by optionally, e.g.  B. 



  as indicated above, acylated hydroxy and / or halogen, e.g.  B.  Chlorine, substituted phenyl, furyl, e.g.  B.  2-furyl, or thienyl, e.g.  B.  2- or 3-thienyl, or isothiazolyl, e.g.  B.  4 isothiazolyl group, also for a 1,4-cyclohexadienyl group, RIT for optionally, z.  B.  as indicated above, protected aminomethyl, and RIIt for hydrogen, or n for 1 and each of the groups R I, Rll and Rlll for lower alkyl, e.g.  B.  Methyl stand. 



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



  when treating with an acidic agent such as trifluoroacetic acid, reductively, e.g.  B.  when treating with a chemical reducing agent such as zinc in the presence of aqueous Es acetic acid, or catalytic hydrogen, or hydrolytically cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as lower alkoxycarbonyl, e.g.  B.  tert. -Butyloxycarbonyl, 2-halo-lower alkylcarbonyl, e.g.  B.  2,2,2-Trichloräthyloxycarbonyl, 2-Bromoäthoxycarbonyl or 2-Jod äthoxycarbonyl, Arylcarbonylmethoxycarbonyl, z.  B.  Phenacyloxycarbonyl, optionally substituted, such as lower alkoxy, e.g.  B.  Methoxy, or nitro-containing phenyl-lower alkoxycarbonyl, e.g.  B.  4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide such as carbamoyl or N-substituted, such as N-lower alkyl, e.g.  B. 

  N-methylcarbamoyl, as well as by trityl, also by arylthio, z.  B.  2-nitrophenylthio, arylsulfonyl, e.g.  B.  4-methylphenylsulphonyl or 1-lower alkoxycarbonyl-2-propylidene, e.g.  B.    1-ethoxycarbonyl-2-propylidene, substituted amino group), 2,6-dimethoxybenzoyl, 5,6,7, 8-tetrahydro-naphthoyl, 2-methoxy-1-naphthoyl, 2-ethoxy-1-naphthoyl, benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 5-methyl-3-phenyl-4-isoxazolylcarbonyl, 3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolyl-carbonyl , 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, methylthioacetyl, chloroacetyl,

   Bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxy-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. 

  Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, 2-cyano-3,3-dimethyl-aclylacetyl, 2-cyano-3,3-dimethyl-aclyyl, 2-cyano-3,3-dimethyl-acyl Azidophenylacetyl, 3-chlorophenylacetyl, 2 or 4-aminomethylphenyl-acetyl (with optionally, e.g.  B. 

 

  as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenyl, a-phenyloxyphenyl, a-phenyloxyphenyl, a-phenyloxyphenyl, a-phenyloxyphenyl, a-phenyloxyphenyl, 4-phenoxy , a-cyano-phenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl, 3,5 dichloro-4-hydroxyphenylglycyl, a-amino-a- (1,4-cyclohexadienyl) acetyl, a-aminomethyl-a-phenylacetyl or a-hydroxyphenylacetyl, an amino group optionally present in these radicals, e.g.  B.  as stated above, may be substituted and / or an existing, aliphatic and / or phenolically bonded hydroxyl group, if appropriate, analogously 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 a-O-methyl-phosphono-phenylacetyl or a-O, O-dimethylphosphono-phenylacetyl, also benzylthioacetyl, benzylthiopropionyl, a-carboxyphenylacetyl (with optionally, e.g.  B.  as indicated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, z.  B.  as stated above, substituted amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetrahydrothienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3-thlenylacetyl (optionally with functional, e.g. 

  B.  as stated above, modified carboxyl group), a-cyano-2-thienylacetyl, a-amino-a- (2-thienyl) -acetyl, a-amino-a- (2-furyl) -acetyl or a-amino-a- (4 -isothiazolyl) -acetyl (optionally with, e.g.  B.  as stated above, substituted amino group), a-sulfophenylacetyl (optionally with, e.g.  B.  such as the carboxyl group, functionally modified sulfo group), 3-methyl-2-imidazolylthioacetyl, 1,2,4-triazol-3 -ylthioacetyl, 1,3,4-triazol-2-ylthioacetyl, 5-methyl-1,2,4 -thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1-methyl-5-tetrazolylthioacetyl.    



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a through-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 group which is multiply branched and / or aromatically substituted on the carbon atom in a position to the oxy group or a methoxycarbonyl group substituted by aryl carbonyl, in particular benzoyl radicals, or substituted in the 8-position by halogen atoms Lower alkoxycarbonyl radical, 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 R1A and Rtb is z.  B.  the acyl radical of a lower alkane or lower alkene dicarboxylic acid, such as succinyl, or an arylenedicarboxylic acid, such as phthaloyl. 



   Another bivalent radical formed by the groups RtA and Rlb 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-1,4-butylene radical, e.g.  B.  4,4-dimethyl-2-phenyl-1-oxo-3aza-1,4-butylene. 



   An etherified hydroxy group R2A together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified 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) grouping, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can be easily converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2 chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



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



   The group R2A can also stand for an arylmethoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the -C (= O) group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group is in particular lower alkoxyphenyl, e.g.  B.  Methoxyphenyl (where methoxy is primarily in the 3-, 4- and / or 5-position), and / or especially nitrophenyl (where nitro is preferably in the 2-position). 



  Such radicals are especially lower alkoxy, e.g.  B.  Methoxy- and / or nitro-benzyloxy, primarily 3- or 4-methoxybenzyloxy, 3,5-dimethoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy. 



   An etherified hydroxy group R2A can also represent a radical which, together with the -C (= 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 and / or phenyl, polysubstituted or monosubstituted by an electron donating carbocyclic aryl group having substituents or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member, or then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic radical which means the a-position to the oxygen or sulfur atom representing the ring member. 

 

   Preferred polysubstituted methoxy groups of this type are tert. Lower alkoxy, e.g.  B.  tert. -Butyloxy or tert. Pentyloxy, optionally substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, furthermore 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group is e.g.  B.    a-Niederalkoxy-pheny1- lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethoxybenzyloxy, or  Furfuryloxy, as is 2-furfuryloxy.  A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, for.  B. 

  Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the a-position to the oxygen or sulfur atom, means e.g.  B.  2-oxa- or 2-thian lower alkylene or lower alkenylene with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl 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, hydroxy-lower alkyl-benzloxy, e.g.  B.  4 hydroxy-3,5-tert. -butyl-benzyloxy, polyhalophenyloxy, e.g.  B.  2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyanomethoxy, and acylaminomethoxy, z.  B. 



  Phthaliminomethoxy or succinyliminomethoxy. 



   The group R2A can also represent an etherified hydroxyl group which, together with the carbonyl group of the formula -C (= O) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g.  B. 



  optionally, e.g.  B.  a-phenyl-lower alkoxy substituted by lower alkoxy or nitro, such as benzyloxy, 4-methoxybenzyloxy 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 an acyloxymethoxy group, wherein acyl z.  B.  denotes the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or in which acyloxymethyl forms the residue of a lactone.  Hydroxy groups etherified in this way are lower alkanoyloxy methoxy, e.g.  B.  Acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, in particular α-amino-lower alkanoyloxymethoxy, e.g.  B.  Glycyloxymethoxy, L-valyloxymethoxy, L-leucycloxymethoxy, other phthalidyloxy. 



   A silyloxy or stannyloxy group R2A preferably contains, as substituents, optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups, such as etherified hydroxy, e.g.  B.  Lower alkoxy groups, or halogen, e.g.  B.  Chlorine atoms, and is primarily tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyl, e.g.  B.  Chloro-methoxy-methyl-silyl, or tri-lower alkylstannyloxy, e.g.  B.  Tri-n-butylstannyloxy. 



   An acyloxy radical R2A, which together with a -C (= O) grouping forms a, preferably hydrolytically, cleavable mixed anhydride group contains z.  B.  the acyl radical of one of the above organic carboxylic acids or carbonic acid half derivatives, and is z.  B.  optionally, such as by halogen, e.g.  B.  Fluorine or chlorine, preferably in the a-position, substituted lower alkanoyloxy, e.g.  B.  Acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g.  B. 



  Methoxycarbonyloxy or 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-Nie deralkylhydrazino or 2,2-di-lower alkylhydrazino, e.g.  B.  2 methylhydrazino or 2,2-dimethylhydrazino. 



   In the groups -SO2-Rs and -S-SO2-Rs, W is an optionally substituted, in particular aliphatic, cycloaliphatic, araliphatic or aromatic, hydrocarbon radical with up to 18, preferably up to 10, carbon atoms. 

  Suitable groups Rs are, for example, optionally substituted, such as by lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted alkyl, in particular lower alkyl, such as methyl, ethyl - or butyl groups, alkenyl, such as allyl or butenyl groups, or cycloalkyl, such as cyclopentyl or cyclohexyl groups, or optionally by lower alkyl, such as methyl, lower alkoxy, such as methoxy, halogen, such as fluorine, chlorine or bromine, aryl, such as phenyl, Aryloxy, such as phenyloxy, or nitro, mono- or polysubstituted naphthyl or, in particular, phenyl groups, for example phenyl, o-, m- or preferably p-tolyl, o-, moderately preferably p-methoxyphenyl, o-, m- or p-chlorophenyl , p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl. 



   In a compound of the formula IV, R2A preferably stands for an etherified hydroxyl group with the -C (= O) grouping, in particular under mild conditions, cleavable, esterified carboxyl group-forming, with any functional groups present in a carboxyl protective group R2A per se known manner, e.g.  B.  as stated above, may be protected.  A group R2A is e.g.  B.  in particular an optionally halogen-substituted lower alkoxy group such as methoxy, α-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, or an optionally substituted one, such as lower alkoxy, e.g.  B. 



  Methoxy, or nitro-containing 1-phenyl-lower alkoxy group, such as, if appropriate, e.g.  B.  as indicated, substituted benzyloxy or diphenylmethoxy, e.g.  B.  Benzyloxy, 4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also an organic silyloxy or stannyloxy group, such as tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy or halogen, e.g.  B.  Chlorine.  In a compound of the formula IV, the radical Rta is preferably an amino protective group RlA, such as an acyl group Ac, in which any free functional groups present, e.g.  B.  Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups z.  B. 

 

  by the above acyl, trityl, silyl or stannyl, and substituted thio or sulfonyl radicals, and hydroxy, carboxy or phosphono groups, for.  B.  through the above-mentioned ether or ester groups, incl.  Silyl or stannyl groups, and Rtb is hydrogen. 



   The inventive method is characterized in that a compound of the formula
EMI7. 1
  where Rta, R, b and R2A have the above meaning and R4 is an optionally substituted aromatic heterocyclic radical having up to 15, preferably up to 9 carbon atoms, and at least one ring nitrogen atom and optionally one further ring heteroatom, such as oxygen or sulfur, which radical is with one of its ring carbon atoms which is connected to a ring nitrogen atom by a double bond, is bonded to the thio group -S-, or an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18 carbon atoms, with a heavy metal sulfinate Formula Mn + (- s02-Rs) n or 

   with a heavy metal thiosulfonate of the formula Mn + (- S-SO2-Rs) n, where M is a heavy metal cation and n is the valence of this cation. 



   In the group -S-R4, R4 is an optionally substituted aromatic heterocyclic radical with up to 15, preferably up to 9 carbon atoms, and at least one ring nitrogen atom and optionally a further ring heteroatom, such as oxygen or sulfur, which radical with one of its ring carbon atoms, which with a ring nitrogen atom is connected by a double bond to the thio group -S- is bonded.  Such radicals are monocyclic or bicyclic and can be substituted, for example, by lower alkyl, such as methyl or ethyl, lower alkoxy, such as methoxy or ethoxy, halogen, such as fluorine or chlorine, or aryl, such as phenyl. 



   Representative for such groups R4 are 1-methylimidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5 thiatriazol-2-yl, 1 , 3-0xazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl, benzoxazole 2-yl and especially benzthiazol-2-yl.  Further
Groups R4 are acyl radicals of organic carboxylic or thiocarboxylic acids, such as optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic, acyl or thioacyl groups with up to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g.  B.  Acetyl or propionyl, lower thioalkanoyl, e.g.  B.  Thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g.  B.  Cyclohexanecarbonyl, cycloalkanethiocarbonyl, e.g.  B. 

  Cyclohexanthiocarbonyl, benzoyl, thiobenzoyl, naphthylcarbonyl, naphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3 or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, 2- or 3-thiofuroyl, or correspondingly substituted ones, for example by lower alkyl such as methyl, halogen such as fluorine or chlorine, lower alkoxy such as methoxy, aryl such as phenyl, aryloxy such as phenyloxy, mono- or poly-substituted acyl - or thioacyl groups. 



   Suitable heavy metal sulfinates or  thiosulfonates are in particular those which have a greater solubility product in the reaction medium used than the heavy metal compounds of the formula Mnf (-S-R4) n formed during the reaction.     Suitable heavy metal cations Mn + are in particular those which form particularly sparingly soluble sulfides.  These include, for example, the monovalent or divalent cations of copper, mercury, silver and tin, with copper and silver + cations being preferred. 



   The heavy metal sulfinate or  thiosulfonate can either be used as such or formed in situ during the reaction, for example from a sulfinic acid of the formula HSO2-Rs or  a thiosulfonic acid of the formula H-S-SO, -R, or a soluble salt thereof, e.g.  B.  an alkali metal salt, such as sodium, and a heavy metal salt, the solubility product of which is greater than that of the heavy metal sulfinate or  thiosulfonate, for example a heavy metal nitrate, acetate or sulfate, e.g.  B. 



  Silver nitrate, mercury (II) diacetate or copper (II) sulfate or a soluble chloride such as tin (II) chloride dihydrate. 



   The reaction of a compound of the formula IVa with the heavy metal sulfinate of the formula Mn + (- SO2-Rs) n or 



  thiosulfonate of the formula Mn + (- S-SO2-R5) n can be carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent.  Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cycloaliphatic or aromatic alcohols such as lower alkanols, e.g.  B.  Methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds such as polyhydroxyalkanes, e.g.  B.  Dihydroxy lower alkanes such as ethylene or propylene glycol, carboxylic acid esters, e.g.  B. 

  Lower carboxylic acid lower alkyl esters such as ethyl acetate, lower ketones such as acetone or methyl ethyl ketone, ethereal solvents such as dioxane, tetrahydrofuran or polyethers such as dimethoxyethane, lower carboxamides such as dimethylformamide, lower alkyl nitriles such as acetonitrile or lower sulfoxides such as dimethyl sulfoxide.  In water or especially in mixtures of water and one of the solvents mentioned, incl.  in emulsions, the reaction is usually much faster than in the organic solvents alone. 



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



   In a compound of the formula IVb obtained, one group Rta, Rtb or R2A can be converted into another group R. a, Rtb or R2A can be converted, it being possible to use reactions analogous to those indicated for the conversion of these groups for compounds of the formula IA or IB. 



   The compounds of the formula IVb which can be prepared according to the invention are valuable intermediates which, for example, according to the reaction scheme below, can be converted into the pharmacologically valuable 7fl-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula IA or  can be converted into the corresponding 7fl-amino-2-cephem-3-ol-4-carboxylic acid compounds of the formula IB, which are also suitable as intermediate. 

 

   The process shown in the reaction scheme is distinguished from previously known processes in that it uses cheap, easily accessible starting materials, such as in particular the 1-oxides of penicillins G or V, which can be produced by fermentation, and 6-amino-penicillanic acid, whose reactive groups are based on any protected in a known manner and can be easily released again after the reaction, goes out, and the preparation of the intermediates required according to the invention is carried out with high yields.   



  Reaction scheme
EMI9. 1
  
EMI10. 1

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



   Compounds of the formula IVa are also known or can, according to Dutch patent specification 72. 08671. 



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



   The oxidative splitting off of the methylene group in compounds of the formula IV with the formation of an oxo group can be carried out with the formation of an ozonide compound of the formula V by treatment with ozone.  Ozone is usually used in the presence of a solvent such as an alcohol, e.g.  B.  a lower alkanol such as methanol or ethanol, a ketone, e.g.  B.  a lower alkanone such as acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g.  B.  a lower halogen alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, incl.  an aqueous mixture, as well as with cooling or gentle heating, e.g.  B.  at temperatures from about -900 C to about +400 C. 



   An ozonide of the formula V can be split reductively in step 3 to give a compound of the formula VI, using catalytically activated hydrogen, e.g.  B.  Hydrogen in the presence of a heavy metal hydrogenation catalyst, such as nickel, also palladium catalyst, preferably on a suitable carrier material, such as calcium carbonate or carbon or chemical reducing agents, such as reducing heavy metals incl.  Heavy metal alloys or amalgams, e.g.  B. 



  Zinc, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or an alcohol, e.g.  B.  Lower alkanols, reducing inorganic salts such as alkali metal iodides, e.g.  B.  Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or reducing 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-butyl-phosphine, or triarylphosphines, e.g.  B. 

  Triphenylphosphine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides, which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexane-lower alkyl phosphorous acid triamides.  B.  Hexamethyl phosphorous triamide, the latter preferably in the form of a methanol adduct, or tetracyanoethylene can be used.  The cleavage of the ozonide, which is usually not isolated, is normally carried out under the conditions that are used for its production, i.  H.  in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating. 



   Eno compounds of the formula VI can also exist in the tautomeric keto form. 



   In a compound of the formula VI obtained, a group Rta, Rgb or R2A can be converted into another group Rta, Rtb or R2A, it being possible to use reactions analogous to those indicated for the conversion of these groups in the case of compounds of the formula IA or IB. 



   In the 4th  Step, an enol compound of the formula VI obtained is converted by etherification into a compound of the formula II in which R30 is lower alkyl or a hydroxy protecting group, e.g.  B.  as defined for Ra under formula IA or IB. 



   For the preparation of lower alkyl and optionally substituted a-Phenylniederalkylenoläthern of the formula II is used as an etherifying agent, for example, a corresponding diazo compound, z. B.     a diazo lower alkane such as diazomethane, diazoethane, diazo-n-butane or an optionally substituted a-phenyldiazo lower alkane, e.g.  B.  Phenyl or diphenyl diazomethane.  These reagents are used in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated aliphatic hydrocarbon, e.g.  B. 



  Methylene chloride, a lower alkanol, e.g.  B.  Methanol, ethanol or tert. -Butanol, or an ether such as a di-lower alkyl ether, e.g.  B.  Diethyl ether, or a cyclic ether, e.g.  B.  Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent with cooling, at room temperature or with slight warming, further, if necessary, in a closed vessel and / or under an inert gas, e.g.  B.  Nitrogen atmosphere applied. 



   Furthermore, lower alkylenol ethers of the formula II substituted a-phenyl lower alkylenol ethers of the formula II can be formed by treating an enol compound of the formula VI with a reactive ester of a corresponding alcohol of the formula R3 -OE.  Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g.  B.  Hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid or halosulfuric acids, eg.  B. 



  Fluorosulfuric acid, or strong organic sulfonic acids, such as, if appropriate, e.g.  B.  by halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as.  B.  optionally, e.g.  B.  benzenesulfonic acids substituted by lower alkyl, such as methyl, halogen, such as bromine, and / or nitro, e.g.  B.  Methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid.  These reagents, especially di-lower alkyl sulfates, such as dimethyl sulfate, also lower alkyl fluorosulfates, e.g.  B.  Methyl fluorosulphate, or optionally halogen-substituted methanesulphonic acid lower alkyl ester, e.g.  B.  Trifluoromethanesulfonic acid methyl ester are usually in the presence of a solvent, such as an optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, eg.  B. 

  Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a solvent mixture is used.  It is preferred to use suitable condensing agents, such as alkali metal carbonates or hydrogen carbonates, e.g.  B.  Sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic bases such as, usually sterically hindered, tri-lower alkylamines, e.g.  B. 



     N, N-diisopropyl-N-ethylamine (preferably together with lower alkyl halosulfates or optionally halogen-substituted methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g.  B.  at temperatures of about -200 C to about 500 C and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B.  Nitrogen atmosphere is worked. 



   Lower alkylenol ethers of the formula II can also be prepared by treating an enol compound of the formula VI with a compound containing two or three lower alkyl-etherified hydroxy groups of the formula R3 -O on the same carbon atom of aliphatic character;  H.  with a corresponding acetal or orthoester, in the presence of an acidic agent.  So you can z.  B.  gem lower alkoxy lower alkanes, such as 2,2-dimethoxy-propane, in the presence of a strong organic sulfonic acid, such as p-toluenesulfonic acid, and a suitable solvent, such as a lower alkanol, e.g.  B.  Methanol, or a di-lower alkyl or lower alkylene sulfoxide, e.g.  B.  Dimethyl sulfoxide, or tri-lower alkyl orthoformate, e.g.  B.  Triethyl orthoformate, in the presence of a strong mineral acid, e.g.  B. 

  Sulfuric acid, or a strong organic sulfonic acid such as p-toluenesulfonic acid and a suitable solvent such as a lower alkanol, e.g.    13.  Ethanol, or an ether, e.g.  B.  Dioxane, used as an etherifying agent and so arrive at compounds of the formula II in which R3 is lower alkyl, e.g.  B.  Methyl resp.  Ethyl stands. 



   The lower alkylenol ethers of the formula II can also be obtained by using enol compounds of the formula VI with tri-lower alkyloxonium salts of the formula (R30) 30G3Ae (so-called sea wine salts), as well as di-RsO-carbenium salts of the formula (RO) CHAe, or di-R-- Halonium salts of the formula (R3O) 2Hal® Ae, in which Ae is the anion of an acid and Hal is a halonium, in particular bromonium ion, and R3 is lower alkyl. 

  These are primarily tri-lower alkyloxonium salts, as well as di-lower alkoxycarbenium or di-lower alkylhalonium salts, in particular the corresponding salts with complex, fluorine-containing acids, such as the corresponding tetrafluoroborates, hexafluorophosphates, hexafluoroantimonates or hexachlorantimonates.  Such reagents are e.g.  B.  Trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachlorantimonate, hexaffuophosphate or tetrafluoroborate, dimethoxy carbenium hexaffuorophosphate or dimethylbromonium hexa buoroantimonate.     These etherifying agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, e.g.  B. 

  Diethyl ether, tetrahydrofuran or methylene chloride, or in a mixture thereof, if necessary, in the presence of a base such as an organic base, e.g.  B.  a, preferably sterically hindered, tri-lower alkylamine, e.g.  B.  N, N-diisopropyl-N äthyl-amine, and with cooling, at room temperature or with gentle heating, for.  B.  at about -200 C to about 500 C, if necessary, in a closed vessel and / or in an inert gas, e.g.  B.  Nitrogen atmosphere. 



   Compounds of the formula II in which the hydroxyl protective group R3 is a 2-oxa or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical, are by acid-catalyzed, for example by a strong mineral acid such as sulfuric acid or hydrochloric acid-catalyzed addition of a, fl-unsaturated aliphatic or cycloaliphatic ethers or thioethers, such as 1-lower alkoxy-lower alkenes, e.g.  B.  1-methoxyethene or l-methoxypropene, l-lower alkylthio-lower alkenes, such as l-methylthio-ethene or l-methylthio-propene, oxa- or thia-cyclone-lower alk-2-enes or -2,4-dienes with 5-7 ring atoms, z. B.     2,3-dihydrofuran, 2H-pyran, 3,4-dihydro-2H-pyran or corresponding analogous sulfur compounds, to the 3-hydroxy group of a compound of formula VI. 

  The addition can be carried out in an excess of the unsaturated ether or thioether and optionally in an inert organic solvent, for example an aliphatic, cycloaliphatic or aromatic hydrocarbon such as pentane, hexane, cyclohexane, benzene, toluene and the like, with the exclusion of water. 



   Formula II includes silyl or stannyl ethers;  H. 



  Compounds of the formula II in which R3 is a substituted silyl or stannyl group are obtained by any method suitable for silylation or stannylation of enol groups, for example by treatment with a suitable silylating agent, such as with a dihalo gendiniederilkyl-silane, lower alkoxy-lower alkyl-dihalosilane or Tri-lower alkyl silyl halide, e.g.  B.  Dichloro-dimethylsilane, methoxymethyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert. -butyl-silyl chloride, where such silyl halide compounds are preferably used in the presence of a base, e.g.  B. 

  Pyridine, used, with an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkyl-silylated N- (tri-lower alkylsilyl) -amine (see e.g.  B.  British patent no.  1 073 530), e.g.  B.  with a hexaniederalkyldisilazane, such as hexamethyldisilazane, or with a silylated carboxamide, such as a bis-triiederalkylsilyl-acetamide, e.g.  B.  Bis-trimethylsilyl-acetamide, or Triffuorsilylacetamid, also with a suitable stannylating agent, such as a bis (tri-lower alkyl-tin) oxide, z.  B.  Bis (tri-n-butyl-tin) oxide, a tri-lower alkyl-tin hydroxide, e.g.  B. 

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

 

   In a compound of the formula II obtained, a group Rta, Reib, R2A or R3 can be converted into another group Rta, R> b, R2A or R3, it being possible to use reactions analogous to those used for the conversion of these groups in compounds of the formula IA or IV is indicated. 



   According to step 5, compounds of the formula II can be used to prepare 7B-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula IA, in which Rja and Rtb are hydrogen or an acyl group Ac, or R, a and Rtb together represent a divalent amino protective group, R2 represents hydroxy or a radical R2A which forms a protected carboxyl group together with the carbonyl group -C (= O) -, and R3 represents hydrogen or lower alkyl or a hydroxy protective group R3o, as well as l-oxides of 3-cephem compounds of the formula IA,

   and the corresponding 2-cephem compounds of the formula IB, in which R1a, Rtb, R2 and R3 have the meanings given above, or salts of such compounds with salt-forming groups. 



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



   A lower alkyl group R3 has up to 7, preferably up to 4 carbon atoms and is in particular methyl, or else ethyl, n-propyl, hexyl or heptyl. 



   A hydroxyl protecting group R is, for example, an easily split off 2-oxa- or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical, an easily split off substituted silyl or stannyl group, or an also easily split off optionally substituted a-phenyl-lower alkyl such as optionally substituted benzyl or Diphenylmethyl group. 



   The 2-oxa- or 2-thia-aliphatic or -cycloaliphatic hydrocarbon radical R3 is primarily a 1-lower alkoxy-1-lower alkyl or 1-lower alkylthio-1-lower alkyl radical, such as 1-methoxy-1-ethyl, 1-ethoxy -l-ethyl, l-methylthio-l-ethyl or l-ethylthio-l-ethyl, or a 2-oxa or 2-thianiederalkylene or lower alkenylene radical, with 5-7 ring atoms, such as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3 dihydro-2-pyranyl or a corresponding analogous sulfur compound. 



   Easily split off silyl or stannyl groups R3 are preferably substituted by optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, halo-lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, or optionally modified functional groups such as etherified hydroxy, z .  B.  Lower alkoxy groups, or halogen, e.g.  B.  Chlorine atoms, substituted.  Representative of such groups are primarily tri-lower alkylsilyl, such as trimethylsilyl, halo-lower alkoxy-lower alkylsilyl, such as chloromethoxymethylsilyl, or also tri-lower alkylstannyl, such as tri-butylstannyl. 



   Salts are in particular those of compounds of the formulas IA and IB with an acidic group, such as a carboxy, sulfo or phosphono group, primarily metal or ammonium salt, such as alkali metal and alkaline earth metal, e.g.  B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, e.g.  B.  Triethylamine, hydroxy-lower alkylamines, e.g.  B.  2-hydroxyethylamine, bis (2-hydroxyethyl) amine or tris (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g.  B.  4-aminobenzoic acid-2-diethylamino-ethyl ester, lower alkyleneamines, e.g. 

  B.  1-ethyl-piperidine, cycloalkylamines, e.g.  B.  Bicyclohexylamine, or benzylamines, e.g.  B.  N, N'-dibenzylethylenediamine, also bases of the pyridine type, e.g.  B.  Pyridine, collidine or quinoline, compounds of the formulas IA and IB, which have a basic group, can also 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.  Form trifluoroacetic acid or p toluenesulfonic acid.  Compounds of the formulas IA and IB with an acidic and a basic group can also be used in the form of internal salts, i.e.  H.  in zwitterionic form.  1-Oxides of compounds of the formula IA with salt-forming groups can also form salts, as described above. 



   The compounds of the formulas IA or  IB have valuable pharmacological properties or can be used as intermediates for the preparation of such.  Compounds of formula IA, wherein z.  B.    R, a for an acyl radical Ac and Rtb occurring in pharmacologically active N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7iB-amino-3-cephem-4-carboxylic acid compounds, or in which Rta and Rtb together represent one in the 2-position, e.g.  B.  by an aromatic or heterocyclic radical, and preferably in the 4-position, e.g. 

  B.  L-oxo-3-aza-1,4-butylene radical substituted by 2 lower alkyl, such as methyl, R2 denotes hydroxy or an etherified hydroxy group R2A which forms an esterified carboxyl group easily cleavable under physiological conditions together with the carbonyl group, and R3 denotes lower alkyl, where any functional groups present in an acyl radical R, a, such as amino, carboxy, hydroxyl and / or sulfo, are usually present in free form, or salts of such compounds with salt-forming groups are, in the case of parenteral and / or oral administration, against microorganisms such as gram positive bacteria, e.g.  B.  Staphylococcus aureus, Streptococcus pyogenes and Diplococcus pneumoniae (e.g.  B.  in mice at doses from about 0.001 to about 0.02 g / kg s.  c.  or p.  O. ), and gram-negative bacteria, e.g. 

  B.    Escherichia coli, Salmonella typhimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettgeri and Proteus mirabilis, e.g.  B.  in mice at doses from about 0.001 to about 0.15 g / kg s.  c.  or p.  O. ), especially against penicillin-resistant bacteria, with low toxicity.  These new compounds can therefore, for.  B.  in the form of antibiotic preparations for the treatment of corresponding infections use. 



   Compounds of the formula IB or l-oxides of compounds of the formula IA in which Rta, Rtb, R2 and R3 have the meanings given in connection with the formula IA, or compounds of the formula IA in which R3 has the meaning given above, the radicals Rza and R1b is hydrogen, or Rla is an acyl radical different from an acyl radical occurring in pharmacologically active N-acyl derivatives of 6B-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and Rtb is hydrogen , or R, a and Rtb together one, of one in the 2-position preferably, e.g. 

  B.  by an aromatic or heterocyclic radical, and preferably in the 4 position, e.g.  B.  by 2 lower alkyl, such as methyl, substituted l-oxo-3-aza-1,4-butylene radical represent different divalent amino protective groups, and R2 stands for hydroxy, or R1 and R, b have the meanings given above, R2 for one, together with the -C (= O) group represents a preferably easily cleavable, protected carboxyl group-forming radical R2A, where a carboxyl group protected in this way is different from a physiologically cleavable carboxyl group, and R3 has the meanings given above, are valuable intermediates which in a simple way, e.g.  B.  as described below, can be converted into the above-mentioned pharmacologically active compounds. 

 

   The invention relates in particular to intermediates of the formula IVb, suitable for the preparation of 3-cephem compounds of the formula IA, in which Rta is hydrogen or, preferably, one 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 6B-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound containing acyl radical, such as is one of the above acyl radicals of the formula A, where in this Rl, Rll, Grill and n primarily have the preferred meanings, RXb is hydrogen,

   or wherein Rta and R, b together are preferably in the 2 position, e.g.  B.  by an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, e.g.  B.  represented by two lower alkyl, such as methyl, substituted 1-oxo-3-aza-1,4-butylene radical, R2 for hydroxy, for optionally, preferably in a-position z.  B.  by optionally substituted aryloxy, such as lower alkoxyphenyloxy, e.g.  B.  4-methoxyphenyloxy, lower alkanoyloxy, e.g.  B. 



  Acetyloxy or pivaloyloxy, α-amino lower alkanoyloxy, e.g.  B. 



  Glycyloxy, L-valyloxy or L-leucyloxy, arylcarbonyl, e.g.  B. 



  Benzoyl, or optionally substituted aryl such as phenyl, lower alkoxyphenyl, e.g.  B.  4-methoxyphenyl, nitrophenyl, e.g.  B.  4-nitrophenyl, or biphenylyl, e.g.  B.  4-biphenylyl, or in position by halogen, e.g.  B.  Chlorine, bromine or iodine, mono- or polysubstituted 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.  Bis-4-methoxyphenyloxy-methoxy, lower alkanoyloxy-methoxy, e.g.  B.  Acetyloxymethoxy or pivaloyloxymethoxy, α-amino-lower alkanoyloxy-methoxy, e.g.  B.  Glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, especially 1-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-propyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, or 2-halo-lower alkoxy, e.g.  B. 



  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy, and for acyloxy, such as lower alkoxycarbonyloxy, z.  B.  Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, or optionally, e.g.  B.  by lower alkyl, such as methyl, or hydroxy substituted amino or hydrazino, 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 R3 is hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, e.g.  B. 



  Trimethylsilyl, or optionally, e.g.  B.  by halogen or lower alkoxy, substituted benzyl or diphenylmethyl, and the 1-oxides thereof, furthermore the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups. 



   First and foremost, intermediate products of the formulas IVb or  in a 3-cephem compound of the formula IA, and in a corresponding 2-cephem compound of the formula IB, furthermore in a 1-oxide of a 3-cephem compound of the formula IA, or in a salt of such a compound with salt-forming groups Rta for hydrogen or one in fermentative (i.e.  H.  naturally occurring) or biosynthetically producible N-acyl derivatives of 6B-amino-penam- 3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, in particular of the formula A, in which RI, Ril, Rlll and n primarily have the preferred meanings, such as an optionally, e.g. 

  B.  by hydroxy, substituted phenylacetyl or phenyloxyacetyl radical, also an optionally, z.  B.  by lower alkylthio, or lower alkenylthio, and optionally substituted, such as acylated amino and / or functionally modified, such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, e.g.  B.  4-Hydroxy-phenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino5-carboxy-valeryl, in which the amino and / or the carboxyl groups 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 6B-amino-penam-3-carboxylic acid or 7ss-amino3-cephem-4-carboxylic acid compounds, in particular of the formula A, in which Rl, Ril, Rlll and n primarily have the preferred meanings such as formyl, 2-haloethylcarbamoyl, e.g.  B.  2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, e.g.  B.  2-thienylacetyl, or tetrazolylacetyl, e.g. 

  B.  l-Tetrazolylacetyl, but especially in a-position by a cyclic, such as a cycloaliphatic, aromatic or heterocyclic, primarily monocyclic radical and by a functional group, primarily amino, carboxy, sulfo or hydroxyl groups, substituted acetyl, in particular phenylglycyl, in which Phenyl optionally, e.g.  B.  by optionally protected hydroxy, such as acyloxy, e.g.  B.  optionally halogen-substituted lower alkoxycarbonyloxy or lower alkanoyloxy, and / or by 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 also with a protected, such as acylated hydroxy group), and in which the amino group can optionally also be substituted and Z. 

  B.  an optionally present in salt form or an amino group which is a hydrolytically cleavable trityl group or primarily an acyl group, such as 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, further reductive, such as when treating with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or with catalytic hydrogen, or hydrolytically cleavable or an acyl radical that can be converted into such, preferably a suitable acyl radical Carbonic acid half-ester, such as one of the above, e.g.  B.  optionally halogen or benzoyl-substituted lower alkyloxycarbonyl radicals, e.g.  B.  tert. -Butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, or phenacyloxycarbonyl, optionally lower alkoxy or nitro-substituted phenyl-lower alkoxycarbonyl, e.g. 

  B.  4-methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, and also a cleavable arylthio or aryl-lower alkylthio radical, e.g.  B.  2-nitrophenylthio or tritylthio, an arylsulfonyl radical which can be split off by means of electrolytic reduction, e.g.  B.  4-methylphenylsulfonyl, or one with an acidic agent such as formic acid or aqueous mineral acid, e.g.  B.  Hydrochloric or phosphoric acid, cleavable l-lower alkoxycarbonyl or l-lower alkanoyl-2-propylidene radical, e.g.  

  B.    1-ethoxycarbonyl-2-propylidene, also contains a- (1,4-cyclohexadienyl) -glycyl, a-thienylglycyl, such as a-2- or a-3-thienylglycyl, a-furylglycyl ,.    



  such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazolylglycyl, where in such radicals the amino group, e.g.  B.  as indicated for a Phenylglycyfrest, substituted or protected, also α-carboxy-phenylacetyl or a-carboxy-thienylacetyl, z.  B.  a-Carboxy-2-thienylacetyl (if necessary with functionally modified, z.  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 carboxyl group), a-sulfo-phenylacetyl (optionally also with, z. 

  B.  such as the carboxyl group, functionally modified sulfo group), a-phosphono, aO-methylphosphono- or aO, O'-dimethylphosphono-phenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxy group, in particular with an acyloxy group, in which acyl is, preferably easy, e.g.  B.  when treating with an acidic agent such as trifluoroacetic acid, or with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, cleavable or convertible into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as one of the above, e.g.  B.  lower alkoxycarbonyl radical optionally substituted by halogen or benzoyl, e.g. 

  B.  2,2,2-Trichloräthoxycarbonyl, 2-Chloräthoxyvarbonyl, 2-Bromoäthoxycarbonyl, 2-Jodäthoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), and l-amino-cyclohexylcarbonyl, aminomethylphenylacetyl, such as 2- or 4-aminomethylphenylacetyl, or aminopyridinium acetyl, z.  B.  4-aminopyridinium acetyl (optionally also with, e.g.  B.  as stated above, substituted amino group), or pyridylthioacetyl, e.g.  B.  4-pyridylthioacetyl, and R, b for hydrogen, or Rta and Rtb together for one, preferably in the 2-position, optionally by protected hydroxy, such as acyloxy, e.g.  B.  optionally halogen-substituted lower alkoxy-carbonyloxy or lower alkanoyloxy, and / or by 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 also with protected, e.g.  B.  as stated above, acylated hydroxy group) substituted l-oxo-3-aza-1,4-butylene radical, which optionally contains two lower alkyls, such as methyl, in the 4-position, and R2 represents hydroxy, lower alkoxy, in particular a-polybranched lower alkoxy, e.g. .  B.    tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, l-phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, e.g.  B.  4-methoxybenzyloxy, 4-nitrobenzyloxy,
Diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g.  B. 

  Acetyloxyme thoxy or pivaloyloxymethoxy, α-amino lower alkanoyloxy methoxy, e.g.  B.  Glycyloxymethoxy, 2-phthalidyloxymethoxy, lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy, also tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, is, and R3 is hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, z.  B.  Trimethylsilyl, or optionally e.g.  B.  by halogen, such as chlorine or bromine, or lower alkoxy, such as methoxy, substituted benzyl or diphenylmethyl. 



   The invention relates primarily to intermediates of the formula IVb, suitable for the preparation of 3-cephem compounds of the formula IA, in which Rta is hydrogen or an acyl group of the formula
EMI14. 1
 wherein Ra is phenyl or hydroxyphenyl, e.g.  B.  3- or 4-hydroxyphenyl, also hydroxy-chlorophenyl, z.  B.  3-chloro-4-hydroxyphenyl or 3,5-dichloro-4-hydroxyphenyl, with hydroxy substituents in such radicals being replaced by acyl radicals, such as optionally halogenated lower alkoxycarbonyl radicals, e.g.  B. 



  tert. -Butyloxycarbonyl or 2,2,2-Trichloräthoxycarbonyl, can be protected, as well as thienyl, z.  B.  2- or 3-thienyl, also pyridyl, e.g.  B.  4-pyridyl, aminopyridinium, e.g.  B.  4 aminopyridinium, furyl, e.g.  B.  2-furyl, isothiazolyl, e.g.  B.  4 isothiazolyl, or tetrazolyl, e.g.  B.  L-tetrazolyl, or 1,4-cyclohexadienyl, X is oxygen or sulfur, m is 0 or 1, and Rb is hydrogen or, if m is 0, for amino, and protected amino, such as acylamino, e.g.  B.  a-polybranched lower alkoxycarbonylamino, such as tert. -Butyloxycarbonylamino, or 2-halo-lower alkoxycarbonylamino, e.g.  B.  2,2,2-Trichloräthoxycarbonylamino, 2-Jodäthoxycarbonylamino or 2-Bromäthoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, z. 

  B.  4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamine, or 3-guanylureido, also sulfoamino or tritylamines, and arylthioamino, e.g.  B.  2-nitrophenylthioamino, arylsulfonylamino, e.g.  B.  4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl-2-propylideneamino, e.g.  13.  1-Ethoxycarbonyl-2-propylideneamino, carboxy or in salt, e.g.  B. 



  Carboxy in alkali metal, such as sodium salt form, as well as protected carboxy, e.g.  B.  esterified carboxy such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, sulfo or in salt, e.g.  B.  Alkali metal, such as the sodium salt form present Sulfe, as well as protected sulfo, hydroxy, and protected hydroxy, such as acyloxy, e.g.  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2-trichlor äthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-bromo äthoxycarbonyloxy, also formyloxy, or O-Niederalkylphosphono or O, O'-Diiederalkylphosphono, z. B.       O-methylphosphono or O, O'-dimethylphosphono, or a 5-amino-5-carboxyvaleryl radical, in which the amino and / or carboxy groups can also be protected and z. 

  B.  as acylamino, e.g.  B.  Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino or phthaloylamino, or  as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g.  B.  Diphenylmethoxycarbonyl, are present, where m is preferably 1 when Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl or pyridyl, and m is 0 and Rb is different from hydrogen when Ra is phenyl, hydroxyphenyl, hydroxychlorophenyl, thienyl, furyl, isothiazolyl or 1 , 4 is cyclohexadienyl, Rjb is hydrogen, R2 primarily for hydroxy, also for lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, 2-halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, 2-iodine ethoxy or 2-bromoethoxy, or optionally, e.g.  B.  by lower alkoxy, e.g.  B. 

  Methoxy, substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, also tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, and R3 is hydrogen, lower alkyl, e.g.  B.  Methyl, ethyl or n-butyl, and tri-lower alkylsilyl, e.g.  B.  Trimethylsilyl, as well as the l-oxides of such 3-cephem compounds of the formula IA, also of the corresponding 2-cephem compounds of the formula IB, or salts, in particular the pharmaceutically usable, non-toxic salts of such compounds with salt-forming groups, such as alkali metal, e.g.  B.  Sodium or alkaline earth metal, e.g.  B.  Calcium salts, or ammonium salts, incl.  those with amines, of compounds in which R2 is hydroxy, and which contain a free amino group in the acyl radical of the formula B. 

 

   First and foremost, intermediate products of the formulas IVb or  in 3-cephem compounds of the formula IA, furthermore in corresponding 2-cephem compounds of the formula IB, and in salts, in particular in pharmaceutically acceptable, non-toxic salts of such compounds with salt-forming groups, as mentioned in the section above Salts RXa for hydrogen, for the acyl radical of the formula B, in which Re is phenyl and hydroxyphenyl, e.g.  B.  4-hydroxyphenyl, thienyl, e.g.  B.  2- or 3-thienyl, 4-isothiazolyl or 1,4-cyclohexadienyl, X is oxygen, m is 0 or 1, and Rb is hydrogen or, when m is 0, amine, and 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-Jodäthoxyvar- bonylamino or 2-Bromäthoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, z.  B.  4-methoxybenzyloxycarbonylamines, or hydroxy, and protected hydroxy, such as acyl. 



  oxy, e.g.  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or for a 5-amino-5-carboxy-valeryl radical, in which the amino group and protected can be and z.  B.  as acylamino, e.g.  B.  Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or phthaloylamino, or  as an esterified carboxy, such as phenyl-lower alkoxycarbonyl, e.g.  B. 



  Diphenylmethoxycarbonyl, are present, where m is preferably 1 when Ra is phenyl or hydroxyphenyl, RXb is hydrogen, R2 is primarily hydroxy, also optionally in the 2-position halogen, e.g.  B.  Chlorine-, bromine- or iodine-substituted lower alkoxy, especially apolybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, or 2 halo-lower alkoxy, e.g.  B.  2,2,2-trichloroethoxy, such as methoxy-substituted diphenylmethyloxy, e.g. B.  Diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, or p-nitrobenzyloxy, also tri-lower alkylsilyloxy, e.g.  B.  Trimethylsilyloxy, and R3 is hydrogen, lower alkyl, especially methyl, tri-lower alkylsilyl, e.g.  B.  Trimethylsilyl. 



   The invention relates primarily to intermediates of the formula IVb, suitable for the preparation of 7ss- (Da-amino-a-Ra-acetylamino) -3-lower alkoxy-3-cephem-4-carboxylic acids, wherein Ra is phenyl, 4- Hydroxyphenyl, 2-thienyl or 1,4-cyclohexadienyl and lower alkoxy contains up to 4 carbon atoms and z.     Ethoxy or n-butyloxy, but primarily methoxy, and internal salts thereof, and especially of 3-methoxy-7B- (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid and its internal salt thereof ; In the above-mentioned concentrations, especially when administered orally, these compounds have excellent antibiotic properties, both against gram-positive and in particular against gram-negative bacteria, with low toxicity. 



   According to step 5 of the above reaction scheme, compounds of the formula IA, their l-oxides, compounds of the formula IB and salts of such compounds with salt-forming groups are prepared by adding a compound of the formula
EMI15. 1
 where Rta, R, b and R2A have the meanings given under formula IA, R3O stands for lower alkyl or a hydroxyl protecting group, and Y has the meanings given under formulas IVb and IVc, treated with a base and, if desired, in a base Compound of the formula IA or IB converts the protected carboxyl group of the formula -C (= O) -RaA into the free or into another protected carboxyl group, and / or, if desired,

   the protected hydroxyl group -OR, o is converted into a free hydroxyl group and / or the resulting free hydroxyl group or the protected hydroxyl group -O-RS converted into a lower alkoxy group -O-R3, and / or, if desired, within the definition of the end products The compound obtained is converted into another compound, and / or, if desired, a compound obtained with a salt-forming group is converted into a salt or a salt obtained is converted into the free compound or into another salt, and / or, if desired, a mixture obtained from separates isomeric compounds into the individual isomers. 



   In a compound of the formula II, the -O-R3 group can be in the trans (crotonic acid configuration) or cis (isocrotonic acid configuration) position to the carboxyl group. 



   In a starting material of the formula II, R30 preferably denotes lower alkyl, in particular methyl, or, as a hydroxyl protective group, preferably a substituted silyl group, in particular the trimethylsilyl group. 



   Bases suitable for the ring closure reaction are, in particular, strong organic or inorganic bases.  Particularly noteworthy are bicyclic amidines, such as diazabicycloalkenes, e.g.  B.  1,5-diazabicyclo [4. 3. 0] non-5-ene or 1,5 diazabicyclof5. 4th 0] undec-5-ene, substituted, e.g.  B.  by lower alkyl polysubstituted guanidines, such as tetramethylguanidine, also metal bases, such as hydrides, amides or alcoholates of alkali metals, especially lithium, sodium or potassium, for example sodium hydride, lithium di-lower alkylamides, such as lithium diisopropylamide, potassium lower alkanolates, such as potassium tert. -butylate.  Compounds of formula II in which R2A is halogen, e.g.  B. 

  Chlorine, means, can also with a tertiary organic nitrogen base, e.g. B.     a tri-lower alkylamine, such as triethylamine, are cyclized, in the presence of an alcohol such as a lower alkanol, e.g.  B.  tert. -Butanol, the corresponding ester of formula IA and / or IB can be obtained. 



   The reaction of stage 5 is carried out in a suitable inert solvent, for example in an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluene, a halogenated hydrocarbon such as methylene chloride, an ether such as a di-lower alkyl ether, e.g.  B.  Diethyl ether, a Diniederalkoxyniederalkan such as dimethyloxy ethane, a cyclic ether such as dioxane or tetrahydrofuran or a lower alkanol, z.  B.  Methanol, ethanol or tert. -Butanol, or in a mixture thereof, at room temperature or with gentle heating to 40 to 500, if desired in an inert gas, such as nitrogen atmosphere. 

 

   In the ring closure reaction of stage 5, single compounds of the formula IA or IB or mixtures of compounds of the formula IA and IB can be obtained, depending on the starting material and reaction conditions.  Mixtures obtained can in a manner known per se, for.  B.  using suitable separation methods, e.g.  B.  through adsorption and fractionated elution, incl.  Chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, further by fractional crystallization, solvent distribution, etc.  be separated.   



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



   In a compound of the formula IA or IB obtained, a hydroxyl protective group R3 can easily be split off and replaced by hydrogen.  A 2-oxa- or 2-thiaaliphatic or cycloaliphatic hydrocarbon radical can, for example, by acid hydrolysis, a silyl or stannyl group by hydrolysis, alcoholysis or acidolysis, for example by treatment with water or with an alcohol, such as methanol or ethanol, or with a Acid, such as acetic acid, are split off.  A hydroxy protecting group R3 can optionally be split off selectively, d.  H.  without a carboxyl protecting group R2A being split off at the same time. 



   Enol ether, d.  H.  Compounds of the formula IA and / or IB, in which R3 is lower alkyl, are obtained from compounds of the formulas IA or IB, in which R3 is a radical protecting hydroxyl groups, by replacing this radical with hydrogen and subsequent etherification of the free hydroxyl group according to any, for etherification processes suitable for enol groups, for example those given in step 4.  The etherifying reagent used is preferably a diazo compound of the formula R3-N2 corresponding to the optionally substituted hydrocarbon radical R, primarily an optionally substituted diazo lower alkane, e.g.  B.  Diazomethane, diazoethane or diazo-n-butane. 



   In the present process, and in any additional measures to be carried out, if necessary, free functional groups not participating in the reaction in the starting materials or in the compounds obtainable according to the process, eg.  B.  free amino groups z.  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.  Silylation, protected from transient in a manner known per se and, in each case after the reaction has taken place, released in a manner known per se, if desired, individually or together.  So you can preferably z.    B.    



  Amino, hydroxy, carboxyl or phosphono groups in an acyl radical R1A or    Rtb e.g.     B.  in the form of acylamino, such as those mentioned above, e.g.  B.    2,2,2-Trichloräthoxycarbonyl- amino-, 2-Bromoäthoxycarbonylamino-, 4-Methoxybenzyloxycarbonylamino-, Diphenylmethoxycarbonylamino- or tert.  Butyloxycarbonylamino, of aryl or aryl lower alkylthioamino, e.g.  B.  2-nitrophenylthioamino, or arylsulfonyl amino, e.g.  B.  4-methylphenylsulfonylamino, or of 1 lower alkoxycarbonyl-2-propylideneamino, or  from
Acyloxy, such as those mentioned above, e.g.  B.  tert. -Butyloxycarbonyl oxy, 2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoethoxy carbonyloxy groups, or  of esterified carboxy, such as those mentioned above, e.g.  B.  Diphenylmethoxycarbonyl groups, or 



   O, O'-disubstituted phosphono such as the above, e.g.  B. 



   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-bromo ethoxycarbonyl into a 2-iodo-ethoxycarbonyl group, in a manner known per se and depending on the type of protective group, e.g.  B.  a 2,2,2-Trichloräthoxycarbonylamino- or 2-Jod äthoxycarbonylaminogruppe by treatment with suitable
Reducing agents such as zinc in the presence of aqueous acetic acid, a diphenylmethoxycarbonylamino or tert. 
Butyloxycarbonylamino group by treatment with formic or trifluoroacetic acid, an aryl or aryl lower alkylthioamino group by treatment with a nucleophilic reagent, such as sulfurous acid, an arylsulfonylamino group by means of electrolytic reduction,

   a l-lower alkoxycarbonyl-2-propylideneamino group by treatment with aqueous mineral acid, or  a tert. -Butyloxycarbonyloxy group by treatment with formic or trifluoroacetic acid, or a 2,2,2-Trichloräthoxycarbonyloxygruppe by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, or  a diphenylmethoxycarbonyl group by treatment with formic or trifluoroacetic acid or by hydrogenolysis, or 



  an O, O'-disubstituted phosphono group by treatment with an alkali metal halide, if desired, e.g.    B '.     partially, split. 



   In a compound obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= O) -R2A, this can be carried out in a manner known per se, e.g.  B.  depending on the type of group R2A, can be converted into the free carboxyl group.  An esterified, e.g.  B.  carboxyl group esterified by a lower alkyl radical, in particular methyl or ethyl, can be obtained by hydrolysis in a weakly basic medium, e.g.  B.  by treatment with an aqueous solution of an alkali metal or alkaline earth metal hydroxide or carbonate, e.g.  B.  Sodium or potassium hydroxide, preferably at a pH of about 9 to 10, and optionally in the presence of a lower alkanol, can be converted into a free carboxyl group.  A carboxyl group esterified by a suitable 2-halo-lower alkyl or an arylcarbonylmethyl group can e.g. 

  B.  by treating with a chemical reducing agent such as a metal, e.g.  B.  Zinc, or a reducing metal salt, such as a chromium-II salt, e.g.  B.  Chromium-II-chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably adding water, a carboxyl group esterified by an arylcarbonylmethyl group, likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl group e.g.  B.  by irradiation, preferably with ultraviolet light, e.g.  B.  below 290 m, u when the arylmethyl group z.  B.  one optionally in the 3-, 4- and / or 5-position, e.g. 

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

  B.  by treatment with an acidic or weakly basic aqueous agent such as hydrochloric acid or aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer from pH about 7 to about 9, and a hydrogenolytically cleavable esterified carboxyl group by hydrogenolysis, e.g.  B.  by treating with hydrogen in the presence of a noble metal, e.g.  B.  Palladium catalyst, are cleaved. 



   A z.  B.  protected by silylation or stannylation
Carboxyl group can in the usual way, for.  B.  can be released by treatment with water or an alcohol. 



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



   In a compound obtained, e.g.  B.  an amino protecting group RtA or    Rtb, in particular an easily cleavable acyl group, in a manner known per se, for.  B.  an apolybranched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treating with trifluoroacetic acid and a 2-halo-lower alkoxycarbonyl group, such as 2,2,2-tri chloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treating with a suitable reducing metal or corresponding metal compound, for.  B.  Zinc, or a chromium (II) compound, such as chloride or acetate, advantageously in the presence of an agent which nascent together with the metal or the metal compound, preferably in
Presence of hydrous acetic acid, split off who the. 



   Furthermore, in a compound of the formula
IA or IB, in which a carboxyl group of the formula -C (= O) -R2 is preferably one, e.g.  B.  by esterification, including by silylation, e.g.  B.  by reaction with a suitable organic halosilicon or halogen-tin-IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, is a protected carboxyl group, an acyl group Rta or Rtb, in which any free functional groups that may be present are optionally protected, by treating with an imide halide-forming agent, reaction of the resulting imide halide with an alcohol and cleavage of the imino ether formed, are cleaved, with a protected, z. 

  B.  a carboxyl group protected by an organic silyl radical can be released during the reaction. 



   Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides.  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 tri chloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, especially chlorides, of sulfur-containing acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride. 



   The reaction with one of the said imide halide-forming agents is usually carried out in the presence of a suitable, in particular organic base, primarily a tertiary amine, e.g.  B.  a tertiary aliphatic mono- or diamine, such as a tri-lower alkyl amine, e.g.  B.  Trimethyl, triethyl or N, N-diisopropyl-N-ethylamine, also an N, N, N ', N'-tetraniederalkyl-lower alkylenediamine, e.g.  B. 



     N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N 'tetramethyl-1,6-hexylenediamine, 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-methylmorpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine such as a 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.  be present in about 0.2 to about 1 times the amount or then in about to 10 times, in particular about 3 to 5 times, excess. 



   The reaction with the imide halide forming agent is preferably carried out with cooling, e.g.  B.  carried out at temperatures of about -500 C to about + 100 C, but also at higher temperatures, d.  H.  z.  B.  to about 750 C, can work if the stability of the starting materials and
Allow products to increase temperature. 



   The imide halide product, which is usually processed further without isolation, is reacted according to the process with an alcohol, preferably in the presence of one of the bases mentioned above, to give the imino ether.  Suitable Alko hole are z.  B.  aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g.  B.  chlorinated, or additional hydroxyl groups have de, lower alkanols, e.g.  B.  Ethanol, propanol or butanol, especially methanol, also 2-halo-lower alkanols, e.g.  B.    2,2,2-trichloroethanol or 2-bromoethanol and, if appropriate, substituted phenyl-lower alkanols, such as benzyl alcohol.  Usually one uses, e.g.  B.  until about
100-fold, excess of the alcohol and works vorzugswei se under cooling, z. 

  B.  at temperatures from about -500 C to about 100 C. 



   The imino ether product can advantageously be subjected to cleavage without isolation.  The split of the
Imino ethers can be obtained by treatment with a suitable hydroxy compound, preferably by means of hydrolysis, furthermore by alcoholysis, the latter being able to take place directly after the imino ether formation when using an excess of the alcohol.  It is preferred to use water or an alcohol, especially a lower alkanol, e.g.  B.  Methanol, or an aqueous mixture of an organic solvent such as an alcohol. 



   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 described above for splitting off an acyl group is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert to 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 imide halide intermediate product obtainable by the above process is reacted with a salt, such as an alkali metal salt of a carboxylic acid, especially a sterically hindered carboxylic acid, instead of an alcohol, a compound of the formula IA or IB is obtained in which both radicals Rla and Rlb Represent acyl groups. 



   In a compound of the formula IA or IB in which both radicals Rla and Rlb are acyl groups, one of these groups, preferably the less sterically hindered one, e.g.  B. 

 

  by hydrolysis or aminolysis, can be selectively removed. 



   In a compound of the formulas IA or IB, in which R1A and Rlb together with the nitrogen atom represent a phthalimido group, this can, for.  B.  by hydrazinolysis, d.  H.  when treating such a compound with hydrazine, are converted into the free amino group. 



   Certain acyl radicals RlA of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5-amino-5-carboxy-valeryl radical in which carboxyl, e.g.  B.  by esterification, especially by diphenylmethyl, and / or the amino group, e.g.  B.  by acylation, in particular by an acyl radical of an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl, or phthaloyl, are optionally protected, can also be treated with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen donating agents such as an N-halo-amide or imide, e.g.  B. 

  N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid, together with a nitro or cyano-lower alkane and treating the reaction product 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 R, A is substituted for the amino group 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 formyl group RtA can also be obtained by treating with an acidic agent e.g.  B.  p-toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g.  B.  dilute ammonia, or a decarbonylating agent, e.g.  B. 



  Tris (triphenylphosphine) rhodium chloride, are split off. 



   A triarlylmethyl, such as the trityl group RlA, can e.g.  B. 



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



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



   If a free acid, preferably with protected, optionally present functional groups, such as an optionally present amino group, is used for the acylation, suitable condensing agents such as carbodiimides, for example N, N'-diethyl-, N, N'-dipropyl, are usually used -, N, N'-diisopropyl-, N, N'-dicyclohexyl- or N-ethyl-N'-3-dimethylaminopropyl-carbodiimide, suitable carbonyl compounds, for example carbonyldiimidazole, or isoxazolinium salts, for example N-ethyl-5-phenylisoxazolinium-3 '-sulfonate and N-tert. -Butyl-5-methylisoxazolinium perchlorate, or a suitable acylaniino compound, e.g.  B.    2-ethoxy-1-ethoxycarbonyl-1, 2-dihydroquinoline. 



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



   An amide-forming, functional derivative of an acid, preferably with protected optional groups, such as an optional amino group, is primarily an anhydride of such an acid, including, and preferably, a mixed anhydride.  Mixed anhydrides are e.g.  B.  those with inorganic acids, especially with hydrohalic acids, d.  H.  the corresponding acid halides, e.g.  B.  chlorides or bromides, also with hydrazoic acid, d.  H.  the corresponding acid azides with a phosphorus acid, e.g.  B. 



  Phosphoric acid or phosphorous acid, with a sulfuric acid, e.g.  B.  Sulfuric acid, or with hydrocyanic acid.  Other mixed anhydrides are e.g.  B.  those with organic acids, such as organic carboxylic acids, such as with optionally, e.g.  B.  by halogen, such as fluorine or chlorine, substituted lower alkanecarboxylic acids, e.g.  B.  Pivalic acid or trichloroacetic acid, or with half-esters, especially lower alkyl half-esters, of carbonic acid, such as the ethyl or isobutyl half-ester of carbonic acid, or with organic, especially aliphatic or aromatic, sulfonic acids, e.g.  B.  p-toluenesulfonic acid. 



   Furthermore, as acylating agents, internal anhydrides such as ketenes, e.g.  B.  Diketene, isocyanates (d.  H.  internal anhydrides of carbamic acid compounds) or internal anhydrides of carboxylic acid compounds with carboxy-substituted hydroxyl or amino groups, such as mandelic acid-O-carboxy anhydride or the anhydride of 1-N-carboxyamino-cyclohexanecarboxylic acid. 



   Further acid derivatives suitable for reaction with the free amino group are activated esters, usually with protected functional groups that may be present, such as esters with vinylogous alcohols (i.e.  H.  Enols), such as vinylogous lower alkanols, or aryl esters, such as, preferably, e.g.  B.  by nitro or halogen, such as chlorine, substituted phenyl esters, e.g.  B.  Pentachlorophenyl, 4-nitrophenyl or 2,4-dinitrophenyl esters, heteroaromatic esters such as benzotriazol esters, or diacylimino esters such as succinylimino or phthalylimino esters. 



   Further acylation derivatives are e.g.  B.  substituted formimino derivatives, such as substituted N, N-dimethylchloroformimino derivatives of acids, or N-substituted N, N-diacylamines, such as an N, N-diacylated aniline. 



   The acylation with an acid derivative such as an anhydride and especially with an acid halide can be carried out in the presence of an acid binding agent, for example an organic base such as an organic amine, e.g.  B. 



  a tertiary amine such as tri-lower alkylamine, e.g.  B.  Triethylamine, N, N-di-lower alkyl-aniline, e.g.  B.  N, N-dimethylaniline, or a pyridine-type base, e.g.  B.  Pyridine, an inorganic base, for example an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g.  B.  Sodium, potassium or calcium hydroxide, carbonate or bicarbonate, or an oxirane, for example a lower 1,2-alkylene oxide, such as ethylene oxide or propylene oxide. 



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



   In the above N-acylation reactions one can start from compounds of the formulas IA or IB, in which R3 is lower alkyl and R2 has the above meaning, where compounds with free carboxyl groups of the formula -C (= O) -R2, in which R2 is hydroxy, also in the form of salts, e.g.  B.  Ammonium salts, such as with triethylamine, or in the form of a compound with a carboxyl group protected by reaction with a suitable organic phosphorus halide compound, such as with a lower alkyl or lower alkoxy phosphorus dihalide such as methyl phosphorus dichloride, ethyl phosphorus dibromide or methoxyphosphorus dichloride, can be used; in the acylation product obtained, the protected carboxyl group in a manner known per se, for.  B.  as described above, incl.  by hydrolysis or alcoholysis. 

 

   An acyl group can also be introduced by adding a compound of the formula IA or IB, where Rla and Rlb together represent a ylidene radical (which can also be added subsequently, e.g.  B.  by treating a compound in which Rta and Rtb 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 IA or IB with a free amino group a halogen-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, convert and so to substituted N-lower alkanoyl or  N-hydroxycarbonylamino compounds arrive. 



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



   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 obtainable in this way, usually the less sterically hindered acyl group. 



   Furthermore, you can z.  B.  a compound of the formula IA or IB, wherein Rla is a glycyl group, preferably substituted in a-position, such as phenylglycyl, and Rlb is hydrogen, with an aldehyde, e.g.  B.  Formaldehyde, or a ketone such as lower alkanone, e.g.  B.  Acetone, react and thus arrive at compounds of the formula IA or IB in which R1A and R1b together with the nitrogen atom represent a 5-oxo-1,3-diaza-cyclopentyl radical which is preferably substituted in the 4-position and optionally substituted in the 2-position. 



   In a compound of the formula IA or IB in which Rla and Rtb are hydrogen, the free amino group can also be removed by introducing a triarylmethyl group, e.g.  B.  by treatment with a reactive ester of a triarylmethanol such as trityl chloride, preferably in the presence of a basic agent such as pyridine. 



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



  Dichloro-dimethylsilane, methoxymethyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert. -butyl-silyl chloride, where such silyl halide compounds are preferably used in the presence of a base, e.g.  B.  Pyridine, used, with an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsllyl) -amine (see e.g.  B. 



  British patent no.  1073 530), or with a silylated carboxamide, such as a bis-triniederalkylsilyl-acetamid, z.  B.  Bis-trimethylsilyl-acetamide, or trifluorosilylacetamide, also with a suitable stannylating agent, such as a bis (tri-lower alkyltin) oxide, e.g.  B.  Bis (tri-n-butyltin) oxide, a tri-lower alkyl-tin hydroxide, e.g.  B.  Triethyl-tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g.  B.  Tri-n-butyl-tin chloride (see e.g.  B.  Dutch interpretation 67/11107). 



   In a compound of the formula TA or IB obtainable according to the process which contains a free carboxyl group of the formula -C (= O) -R2, such a carboxyl group can be converted into a protected carboxyl group in a manner known per se.  So you get esters z.  B.  by treating with a suitable diazo compound such as a diazo lower alkane, e.g.  B.  Diazomethane or diazobutane, or a phenyldiazo lower alkane, e.g.  B.  Diphenyldiazomethane, if necessary, in the presence of a Lewis acid, such as.  B. 

  Boron trifluoride, or reacting with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B.     Dicyclohexylcarbodiimide and carbonyldiimidazole, furthermore with an N, N'-disubstituted O- or    S-substituted isourea or isothiourea, in which a 0- and S-substituent e.g.  B.  Lower alkyl, especially tert.  Butyl, phenyl-lower alkyl or cycloalkyl, and N- or  N 'substituents e.g.  B.  Are lower alkyl, especially isopropyl, cycloalkyl or phenyl, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.  Furthermore, acid halides, such as chlorides (produced e.g. 

  B.  by treatment with oxalyl chloride), activated esters (formed e.g.  B.  with N-hydroxy nitrogen compound, such as N-hydroxy-succinimide) or mixed anhydrides (obtained e.g.  B.  with haloformic acid lower alkyl esters, such as ethyl chloroformate or isobutyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride), by reaction with alcohols, optionally in the presence of a base such as pyridine, are converted into an esterified carboxyl group. 



   In a compound obtained with an esterified group of the formula -C (= O) -R2, 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. 



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



   In a compound obtainable according to the process with a free carboxyl group of the formula -C (= O) -R2, this can also be converted into an optionally substituted carbamoyl or hydrazinocarbonyl group, preferably reactive, functionally modified derivatives, such as the above-mentioned acid halides, generally esters, as well as reacts the above activated esters, or mixed anhydrides of the corresponding acid with ammonia or amines, including hydroxylamine, or hydrazines. 

 

   A carboxyl group protected by an organic silyl or stannyl group can be formed in a manner known per se, 113.     by adding compounds of the formulas IA or IB in which R2 is hydroxy, or salts such as alkali metal, e.g.  B.  Sodium salts thereof treated with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see e.g.  B.  British patent no.  1073 530 or  Dutch exposition no.  67/17107. 



   You can also modified functional substituents in groups RlA, Rlb and / or R2, such as substituted amino groups, acylated hydroxyl groups, esterified carboxy groups or O, O'-disubstituted phosphono groups, according to methods known per se, for.  B.  the above-described, release, or free functional substituents in groups R1A, Rlb and / or R2, such as free amino, hydroxy, carboxy ode phosphono groups, according to methods known per se, eg.  B. 



  Acylating or  Esterify or  Substitute, modify functionally.  So z.  B.  an amino group by treatment with sulfur trioxide, preferably in the form of a complex with an organic base such as a tri-lower alkylamine, e.g.  B.  Triethylamine, convert into a sulfoamino group.  Furthermore, the reaction mixture, obtained by reacting an acid addition salt of a 4-guanylsemicarbazide with sodium nitrite, with a compound of formula IA or IB, wherein z.  B.  the amino protective group R1A 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 α-bromoacetyl group, with esters of phosphorous acid, such as tri-lower alkyl phosphite compounds, and thus arrive at corresponding phosphono compounds. 



   Salts of compounds of the formulas IA and IB can be prepared in a manner known per se.  So you can salts of such compounds with acidic groups z.  B. 



  by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g.  B.  the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of the formulas IA and IB with basic groups are obtained in the customary manner, for.  B.  by treatment with an acid or a suitable anion exchange reagent.  Internal salts of compounds of the formulas IA and IB which contain a salt-forming amino group and a free carboxyl group can, 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 of 1-oxides of compounds of the formula IA with salt-forming groups can be prepared in an analogous manner. 



   Salts can be converted into the free compounds in 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 diastereomeric salts with optically active salt-forming agents, separating the mixture into the diastereomeric salts and converting the salts to the free compounds, or by fractional crystallization from optically active solvents into which antipodes are separated. 



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



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



   In the starting compounds of the formula II, the leaving group Y is preferably a group —SO2-R5, in which R has the meaning given, but especially the preferred meaning given. 



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



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



  The cephem compounds mentioned in the examples have the R configuration in the 6- and 7-positions and the azetidinone compounds mentioned in the 3- and 4-positions. 



   example 1
For the solution of 133 mg (0.2 mM) of an isomer mixture consisting of 2- [4 - (- p-Toluenesulfonylthlo) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid-p nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of approximately 4: 1 in 4 ml of dry tetrahydrofuran, a solution of 60 pol (2 equivalents) 1,5-diazobicyclo [5. 4th 0] undec-5-ene in 1 ml of tetrahydrofuran was added dropwise.  After allowing to stand at room temperature for 40 minutes, it is diluted with 20 ml of benzene, cooled in an ice bath and stirred for 10 minutes with 10 ml of a 10 8/0 citric acid solution. 

  The organic layer is separated, washed in sequence with saturated saline solution, 10% sodium bicarbonate solution and saline solution.  The solution, dried over magnesium sulfate, is concentrated in vacuo and the yellow oil obtained is chromatographed on 4 g of acid-washed silica gel (2 kg of silica gel, stirred three times with 21% concentrated hydrochloric acid for 10 minutes, decanted, washed neutral with distilled water, rewashed with methanol and 60 hours activate at 1200) with benzene / ethyl acetate 5: 1 as eluent.  The fractions containing the isomer mixture are combined and concentrated in vacuo. 

  A semi-solid isomer mixture is obtained, consisting of the 7B-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester and the 7B-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid pnitrobenzyl ester in a ratio of about 1: 3, which can be separated into the two isomers on Woelm silica gel (activity III) with benzene / ethyl acetate 5: 1.  The faster running 7fl-phenoxyacetamido-3-methoxy-ceph2em4carbonsäu re-p-nitrobenzyl ester is recrystallized from methylene chloride / ether and has a melting point of 129-131.50 C.  The slower running 7B-phenoxyacetamido-3-methoxy-ceph-3em-4-carboxylic acid p-nitrobenzyl ester has a melting point of 140.5-1420 ° C. (from methylene chloride / ether). 

 

   The products can be further processed as follows:
A solution prepared at 0 C of 555 mg (1.11 mmol) of a crude mixture, consisting of the 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid p-nitrobenzyl ester and the 7fl -Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1 in 33 ml of tetrahydrofuran, 16 ml of a 0.1 N potassium hydroxide solution pre-cooled to 0 C are added with stirring. 



  The mixture is stirred for a further 5 minutes at 0 ° C., then 100 ml of ice water and 100 ml of precooled methylene chloride are added and the mixture is briefly stirred.  Addition of 1 ml of saturated aqueous sodium chloride solution causes the two phases to separate.  The organic phase is separated off, the aqueous phase is washed again with 20 ml of methylene chloride, then covered with 50 ml of methylene chloride and acidified with 20 ml of 2N hydrochloric acid.  After shaking, the organic phase is separated off and the hydrochloric acid solution is extracted twice with 10 ml of methylene chloride each time.  The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo. 



  The residue is recrystallized from methylene chloride / diethyl ether / pentane and gives 7fl-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid with a melting point of 1421450 C. 



   The starting materials can be obtained as follows: a) A solution of 36.6 g (0.1 M) 6-phenoxyacetamido penicillanic acid 1B-oxide, 11.1 ml (0.11 M) triethylamine and 23.8 g (0 , 11 M) p-nitrobenzyl bromide in 200 ml of dimethylformamide is stirred for 4 hours at room temperature under nitrogen.  The reaction solution is then introduced into 1.5 l of ice water, the precipitate is filtered off, dried and recrystallized twice from ethyl acetate-methylene chloride.  The colorless, crystalline 6-phenoxyacetamido penicillanic acid p-nitrobenzyl ester 14-oxide melts at 1791800 C. 



   b) A solution of 5.01 g (10 mM) of 6-phenoxyacetamido penicillanic acid p-nitrobenzyl ester-1jB-oxide and 1.67 g (10 mM) of 2-mercaptobenzothiazole in 110 ml of dry toluene is refluxed for 4 hours in a nitrogen atmosphere cooked.  The solution is reduced to approx. 



  25 ml concentrated and with approx.  100 ml of ether diluted.  The precipitated product is recrystallized from methylene chloride-ether and the 2- [4- (benzthiazol-2-yldithio) 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester is obtained Melting point 138-1410 C. 



   c) To a solution of 3.25 g (5.0 mM) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 methylenebutyric acid p-nitrobenzyl ester in 200 ml of acetone / water 9: 1 (v / v) is added to 1.06 g of finely powdered silver nitrate.  Immediately thereafter, the solution of 890 mg (5 mM) sodium p-toluenesulfinate in 100 ml of the same solvent mixture is added (within ten minutes).  A light yellow precipitate forms immediately.  After stirring for one hour at room temperature, it is filtered with the addition of Celite.  The filtrate is diluted with water and extracted twice with ether. 

  The combined ether extracts are dried over sodium sulfate and, after concentration, give the pale yellow solid 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoacetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester.  Thin-layer chromatogram on silica gel (toluene / ethyl acetate 2: 1): Rf value = 0.24; IR spectrum (in CH2Cl2): characteristic bands at 3,90,5,56,5.70, 5.87, 6.23, 6.53, 6.66, 7.40, 7.50, 8.10 , 8.72, 9.25, 10.95, and the like    



  The product can be used in the subsequent reaction without further purification. 



   The same compound can also be obtained by the following methods: ci) To a solution of 3.25 g (5.0 mM) 2- [4- (Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine-1- yl] -3-methylenebutyric acid p-nitrobenzyl ester in 200 ml acetone / water 9: 1 (V is added 1.58 g (1.2 equivalents) silver p-toluenesulfinate in portions over 10 minutes. 



  The suspension is stirred for one hour at room temperature, filtered and processed further as described in Example 1c).  The 2-r4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid p-nitrobenzyl ester is obtained in quantitative yield. 



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



   cii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared from 3.25 g of 2- [4- (Benzthiazol-2yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 1.87 g (2 equivalents) of copper (II) di-p-toluenesulfinate can be obtained in quantitative yield. 



   The copper (II) di-p-toluenesulfinate is obtained by reacting copper sulfate and sodium p-toluenesulfinate (2 equivalents) in water.  After filtering off, the salt is dried in vacuo at 600 ° C. for 12 hours. 



   ciii) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido- 2-oxoazetidin-1-ylj-3-methylenebutyric acid p-nftrobenzyl ester can also be prepared analogously to Example lci) from 130 mg 2- [4- (Benzthiazol2- yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 -methylene butyric acid p-nitrobenzyl ester and 85 mg (2 equivalents) tin-II-di-p-toluenesulfinate are obtained. 



   Tin-II-di-p-toluenesulfinate is obtained by reacting tin-II-chloride (2 H2O) and sodium p-toluenesulfinate in water.  After filtering off and washing with water, the salt is dried in vacuo at 50-600 ° C. for about 12 hours. 



   civ) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 -methylene butyric acid p-nitrobenzyl ester can also be prepared from 130 mg of 2-t4- (benzthiazole- 2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II-di-p-toluenesulfinate can be obtained. 



   Mercury-II-di-p-toluenesulfinate is obtained by reacting mercury-II-di-acetate and sodium p-toluenesulfinate in water.  After filtering off and washing with water, the salt is dried in vacuo at 50-600 ° C. for about 12 hours. 



   d) In a solution of 1.92 g (3.0 mM) 2- [4- (p-toluene sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-methylene-butyric acid-p- Nitrobenzyl esters in 30 ml of dry methyl acetate are introduced at -780 C within 33 minutes, 1.1 equivalents of ozone.  Immediately afterwards, excess ozone is removed using a stream of nitrogen (15 min.  at -780 C) removed.  2.2 ml of dimethyl sulfide (10 equivalents) are added and the solution is warmed to room temperature.  After standing for 5 hours, the solvent is distilled off in vacuo and the colorless oil that remains is taken up in 100 ml of benzene.  

  The benzene solution is washed three times with 50 ml portions of saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo.  After the residue has been recrystallized from toluene, the 2- [4- (p-toluenesulfonyl thio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-hydroxycrotonic acid p-nitrobenzyl ester with a melting point of 159-1600 ° C. is obtained. 



   di) The crude 2- [4- (p-toluene sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester obtained according to Example lc) is dissolved in 20 ml of methyl acetate and ozonated at 700 C until, according to thin-layer chromatography, there is no longer any starting material.  A stream of nitrogen is then passed through the solution and the solution is heated to 0-50 ° C.  A solution of 300 mg of sodium bisulfite in 5 ml of water is added and the mixture is stirred for about 5 minutes until ozonide can no longer be detected with potassium iodide starch paper.  The mixture is diluted with ethyl acetate, the aqueous phase is separated and the organic phase is washed with water, dried over magnesium sulfate and freed from the solvent in vacuo. 



  The crude product is dissolved in 3 ml of methylene chloride and
15 ml of toluene were added.  The precipitate is filtered off and the filtrate is evaporated in vacuo.  The residue is recrystallized from methanol and gives the 2- [4- (p-toluenesulfonyl thio) -3-phenoxyacetamido-2-oxoazeüdin 1-yl] -3-hydroxycrotonic acid p-nitrobenzyl ester with a melting point of 159
1600 c. 



   e) A solution of 1.93 g of 2- [4- (p-toluenesulfonylthio) -3phenoxyacetamido-2-oxoazetidin-1-yl] -3-oxobutyric acid pnitrobenzyl ester (3.0 mM) in 15 ml of dry chloroform is brought to 0 C. and 6 ml of an ethereal diazomethane solution (0.75 molar, corresponding to 1.5 equivalents) were added over the course of 10 minutes.  The mixture is stirred for two hours at 0, excess diazomethane is removed with a stream of nitrogen and the solvent is stripped off in vacuo.  The crude product is purified by filtration through Woelm silica gel (activity III, 40-fold amount) with benzene / ethyl acetate 5: 1.  The colorless oil obtained after the solvents have been distilled off crystallizes on standing. 



  After recrystallization from methylene chloride-ether, an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1-yl-3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of approximately 4: 1. 



  Melting point of the mixture 155-156.50 C. 



   Example 2
A solution of 279 mg of 2 - (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and
1 ml of hexamethyldisilazane is for one hour on
Heated to reflux, evaporated in vacuo and the oily
Residue getrock net in a high vacuum for one hour.  The silylated crude product consists of 2- [4- (p-To luolsulfonylthlo) -3-phenoxyacetamido-2. oxoazetidin-1-ylj-3 - trimethylsilyloxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. 



   The crude product obtained is taken up in 3 ml of dry chloroform, cooled to 0 C and, under nitrogen and with stirring, with 0.069 ml (0.47 mmol) of 1,5-diazabicy clo [5. 4th 0] undec-5-en added.  After a reaction time of 1 hour, 0.3 ml of acetic acid is added to the solution and it is diluted with chloroform.  The chloroform solution is diluted with
Sulfuric acid, water and dilute sodium bicarbonate solution.  The aqueous phases are extracted with chloroform, the combined organic phases over
Dried sodium sulfate and concentrated in vacuo.  The crude 7B-phenoxyacetamido-3-hydroxy-ceph-3 em-4-carboxylic acid diphenylmethyl ester is obtained.  Rf value: 0.13 (silica gel; toluene / ethyl acetate 3: 1). 



   The crude product obtained is taken up in methanol and treated with an excess of ethereal diazo methane solution at 0 C.  After a reaction time of 5 minutes, the solution is completely concentrated and the oily residue is chromatographed on silica gel thick-layer plates (toluene / ethyl acetate 3: 1).  The silica gel of the zone at Rf = 0.19 is extracted with ethyl acetate and yields 7jB-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester; Melting point 1200 C (from ether); IR spectrum (in CHCl3): 3310, 1775, 1700, 1690, 1600 cm-l.    



   The starting material is prepared as follows: a) From 100 g (27.3 mM) 6-phenoxyacetamido-penicillanic acid 11B-oxide, 500 ml dioxane and 58.4 g (30 mM) diphenylmethyldiazomethane, after about 2 hours, the 6- Phe noxyacetamidopenicillanic acid diphenylmethyl ester-1, oxide obtained; Melting point 144-1460 C (ethyl acetate / petroleum ether). 



   b) Analogously to Example lb) is from 292 g (55 mM) 6-Phe noxyacetamido-penicillanic acid diphenylmethyl ester 1,8-oxide and 99 g (59.5 mM) 2-mercaptobenzothiazole of 2- [4- (benzothiazole- 2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester; Melting point 140-1410 C (from toluene / ether).    



   c) Analogously to Example lc), from 10 g (14.7 mM) 2- [4 (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin 1-yl] -3-methylenebutyric acid diphenylmethyl ester in 50 ml ethyl acetate, 4.92 g (24.98 mM) finely powdered silver ptoluenesulfinate and stirring for 7 hours at room temperature of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid -diphenylmethyl ester obtained.  Rf = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (CHCl1): 1782, 1740, 1695, 1340, 1150 cm-1. 



   The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2oxo-azetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester can also be prepared as follows: ci) A suspension of 106.5 g of 6-phenoxyacetamido penicillanic acid Diphenylmethylester-1jB-oxide and 33.8 g of 2 mercaptobenzothiazole in 900 ml of toluene and 9 ml of glacial acetic acid are boiled under nitrogen for 2 hours on a water separator, about 4.5 ml of water being separated out.  The solution is cooled to room temperature, a total of 85.5 g of silver p-toluenesulfinate are added in portions over the course of 1 hour and the mixture is then stirred at 220 for a further 2 hours.  The mixture is filtered through Hyflo and the filtrate is washed twice with saturated aqueous sodium chloride solution. 

  The organic phase is dried over magnesium sulfate, concentrated in vacuo to about 1 liter, decolorized with 30 g of Norit and evaporated.  The yellow foam obtained is crystallized from methylene chloride / diethyl ether.  Melting point 79-820 C.  Rf value = 0.55 (silica gel; toluene / ethyl acetate 3: 1).  Further amounts of the substance can be obtained from the mother liquors by crystallization from methylene chloride / diethyl ether. 



   d) Analogously to Example ld), from 10.8 g (16.2 mM) 2- [4- (p toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] 3-methylenebutyric acid diphenylmethyl ester in 1 1 methylene obtained chloride and 1.1 equivalents of ozone of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester; Melting point 142-1430 C (from ether / pentane). 



   Ozonation can also be carried out at 0 C:
In a solution of 9.23 g (13.8 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine-1 -ylj -3 -methylene butyric acid diphenylmethyl ester in 960 ml of methylene chloride is at 0 C initiated 15.2 mmol of ozone within 19 minutes.  The clear reaction solution is mixed with 10 ml of dimethyl sulfide and stirred at 50 ° C. for 20 minutes.  After concentration in a water jet vacuum and drying of the residue in a high vacuum, a pale yellow foam results which crystallizes from methylene chloride / hexane: melting point of the 2- [4- (p-toluenesulfonylthio) -3phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy Crotonic acid diphenylmethyl ester is 13e1380 C.  

  Thin layer chromatogram: Rf value - 0.46 (silica gel; toluene / ethyl acetate 3: 1).   



   Example 3
A solution of 301 mg (0.462 mmol) of 2- [4- (p-toluene sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 3 ml of 1,2-dimethoxy ethane 0.12 ml of bis-trimethylsilyl-acetamide (0.508 mmol) is added under a nitrogen atmosphere and the mixture is stirred at room temperature for one hour.  The solution is completely concentrated and the oily residue is dried in a high vacuum for one hour.  The silylated Rohpro product is taken up in 3 ml of dried 1,2-dimethoxyethane and after cooling to 0 C with 0.075 ml (0.508 mmol) of 1,5-diazabicyclo [5. 4th 0] undec-5-en added.  After 6
Hours reaction time at 0 C under a nitrogen atmosphere is mixed with 0.3 ml of acetic acid and diluted with methylene chloride. 

  The methylene chloride solution is successively mixed with dilute sulfuric acid, water and dilute
Washed bicarbonate solution.  The aqueous phases are extracted with methylene chloride, and the combined organic phases are dried with sodium sulfate, concentrated in vacuo and dried in a high vacuum.  The crude 74-phenoxyacetamido-3-hydroxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained.  The solution of the crude product in chloroform is mixed with an excess of an ethereal diazomethane solution at 0 C and left to stand at 0 C for 5 minutes.  It is then completely concentrated and the residue is chromatographed on silica gel as in Example 2. 



  The 7, B-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is obtained; Rf value = 0.19 (silica gel; toluene / ethyl acetate 3: 1); Melting point 1200 C (from ether); IR spectrum (in CHCl3): 3310, 1775, 1710, 1690, 1600 cm-t.    



   Example 4
A solution of 100 mg (0.15 mmol) of an isomer mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3 phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding Isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane is stirred with 0.045 ml (0.3 mmol) of 1,5-diazabicyclo [5. 4th 0] undec-5-en added.  The solution is stirred under nitrogen at room temperature for 40 minutes, then cooled with ice and mixed with 0.1 ml of acetic acid.  The solution diluted with methylene chloride is washed successively with dilute sulfuric acid, water and dilute bicarbonate solution.  The aqueous phases are extracted with methylene chloride.  The combined organic phases are dried with sodium sulfate, concentrated and freed completely from the solvent in a high vacuum. 

  The oily residue is chromatographed on a silica gel thick layer plate (mobile phase toluene / ethyl acetate 3: 1, developed once).  The two zones at Rf = 0.19 resp.  0.4 are extracted together with ethyl acetate and the resulting solution is completely concentrated.  An oily product is obtained which is composed of 7fl-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid-diphenylmethyl ester and the isomer 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid-diphenylmethyl ester in the ratio 1: 4 exists. 



  Rf value = 0.14 or  0.32 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (in CHCl. ): 3400, 3310, 1785, 1770, 1750, 1710, 1690, 1630, 1600 cm- '. 



   The isomer mixture used as starting material can be obtained via the corresponding 2-benzoxazole derivatives as follows: aviii) A solution of 10 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester-1, B-oxide and 3 g of 2-mercaptobenzoxazole in 25 ml of dry tetrahydrofuran is completely evaporated in vacuo.  The remaining foam is heated to 1200 ° C. (oil bath temperature) in a water jet vacuum for 70 minutes.  After cooling, the melt residue is chromatographed on 500 g of acid-washed silica gel with toluene / ethyl acetate 6: 1 and then 3: 1. 

  The 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-methylene-butyric acid diphenylmethyl ester is obtained in the form of a white foam; IR spectrum (methylene chloride): characteristic bands at 5.6, 5.75, 5.90, 6.7 p.    



   aix) Analogously to one of Examples 1c) to lciv) or analogously to Example 2c), the 2- [4- (benzoxazol-2-yldithio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester converted into the 2- [4- (p-toluenesulfonylthlo) -3-phenoxy-acetamido-2-oxo-azetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester, which according to Example 2d is converted into the 2 [4- (p- Toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester is converted. 



   - a) The isomer mixture used as starting material can analogously to Example le) from 4 g (6.14 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3 hydroxycrotonic acid -diphenylmethylester and an excess of ethereal diazomethane solution can be obtained.  The isomer mixture obtained, consisting of the 2- [4- (p-toluenesulfonylthlo) -3-phenoxyacetamido-2-oxoazetidin1ylj3 methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester (about 3: 1) crystallizes from ethyl acetate / pentane and has a melting point of 150 ° C . 



   Example 5
A solution of 300 mg (0.45 mmol) of the crystallized isomer mixture obtainable according to Example 4a), consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy -crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-dimethoxyethane is added at room temperature under nitrogen with 0.134 ml (0.9 mmol) of 1,5-diazabicyclo [5. 4th 0] undec-5-ene stirred.  After a reaction time of 40 minutes, the solution is cooled to 0 ° C. and 0.4 ml of acetic acid and then 180 mg (1.36 mmol) of m-chloroperbenzoic acid (85 e / oig) are added. 

  The solution is stirred for 10 minutes at 0 C under nitrogen, diluted with chloroform and washed with dilute sulfuric acid / sodium thiosulfate, water and dilute sodium bicarbonate solution.  The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate, concentrated in vacuo and freed from the solvent in a high vacuum.  The crude product obtained is separated on silica gel thick-layer plates (mobile phase ethyl acetate, developed once).  The silica gel of the zone at Rf = 0.51 is extracted with ethyl acetate, the resulting solution is concentrated and the residue is dried in a high vacuum.  

  The oily residue obtained is 7,8-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-l, B-oxide, which crystallizes from methylene chloride / pentane, melting point 1151200 C. 



   By extracting the silica gel of the zone at Rf = 0.22 with ethyl acetate, concentrating the solution on a rotary evaporator and drying the oily residue, the 7fl-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester can be obtained -la-oxide, melting point 1751800 (from chloroform). 



   The 1-oxides obtained can be processed further as follows: a) A solution of 150 mg (0.275 mmol) of 7B-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester lss oxide in 3 ml After cooling to 0 C, methylene chloride and 0.1 ml of dimethylformamide are treated with 188 mg (1.37 mmol) of phosphorus trichloride.  The solution is stirred at 0 C for 30 minutes, diluted with methylene chloride and washed with aqueous sodium bicarbonate solution.  The aqueous phase is extracted with methylene chloride, the combined organic phases are dried over sodium sulfate and concentrated in vacuo.  The obtained crude 7,8-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester is recrystallized from ether; Melting point 1200 C. 



   b) A solution of 2.0 g (3.78 mmol) of 7fl-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester in 5 ml of methylene chloride is mixed with 0.87 ml of anisole , cooled to 0 C and left to stand for 1 hour after adding 1.2 ml of trifluoroacetic acid.  The reaction mixture is concentrated in vacuo and the residue is crystallized from acetone / ether.  The 7fl-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid with a melting point of 1700 C (dec. ). 



   c) To a suspension of 2.55 g (7 mmol) of 7, B-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 2.9 ml (22.4 mmol) of N, N- Dimethylaniline in 11 mol of absolute methylene chloride is given under nitrogen at 200 ° C. 0.7 ml (5.7 mmol) of dimethyl dichlorosilane and then stirred for 30 minutes at the same temperature.  The resulting clear solution is cooled to -200 ° C., 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and the mixture is stirred for 30 minutes. 

  At the same temperature, a pre-cooled (-200 C) mixture of 0.9 ml (7 mmol) of N, N-dimethylaniline and 0.9 ml of n-butanol is added within 2 to 3 minutes, followed by a rapid 10 ml of pre-cooled (-200 C) n butanol was added and the mixture was then stirred for 20 minutes at -200 C and for 10 minutes without cooling.  At about 100 ° C., 0.4 ml of water is added, stirred for about 10 minutes in an ice bath (00 ° C.), then 11 ml of dioxane are added and after a further 10 minutes of stirring at 0 ° C., approx.  4.5 ml of tri-n-butylamine were added in portions until the samples diluted with water assume a constant pH value of 3.5.  To
Stirring at 0 C for 1 hour, the precipitate is filtered off, washed with dioxane and recrystallized from water / dioxane. 

  The 74-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate obtained has a melting point of over 3000 C.  Thin-layer chromatogram: Rf value 0.17 (silica gel; system n-butanol / carbon tetrachloride / methanol / formic acid / water 30: 40: 20: 5: 5). 



   The zwitterion of 7B-amino-3-methoxy-ceph-3-em can be obtained from the hydrochloride-dioxanate obtained by adding 2N sodium hydroxide solution to a 20% strength aqueous solution thereof up to a pH of 4.1 (isoelectric point) -4-carboxylic acid can be obtained, which, filtered off and dried, has a melting point of over 3000 C.    W spectrum (in 0.1 N sodium bicarbonate solution) im32c = 270 nm (± = 7600). 



  Thin-layer chromatogram: Rf value identical to that of the hydrochloride (silica gel, same system); [a] D20 = + 2320 + 10 (c = 1; 0.5 N sodium bicarbonate solution). 



   d) A suspension of 1 g (2.82 mmol) of 7B-amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride-dioxanate in 20 ml of dry methylene chloride is added at room temperature under a nitrogen atmosphere with 1.65 ml Bis (trimethylsilyl) acetamide added.  After 40 minutes the clear solution is cooled to 0 C and treated with 900 mg (4.37 mmol) of solid D-α-phenylglycylic acid chloride hydrochloride.  Five minutes later, 0.7 ml (10 mmol) of propylene oxide are added.  The suspension is then stirred for 1 hour at 0 C under a nitrogen atmosphere, then with
0.5 ml of methanol are added, the 7,5- (D-α-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride precipitating in crystalline form. 

  The hydrochloride is filtered off, dissolved in 9 ml of water and the solution is adjusted to pH 4.6 with 1N sodium hydroxide solution.  The precipitating dihydrate of the inner salt of 7ss- (D-a-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid is filtered off, washed with acetone and diethyl ether and dried, melting point 17P1760 (decomposition); [a] D20 = + 1320 (c = 0.714; in 0.1 N hydrochloric acid); Thin-layer chromatogram (silica gel): Rf value 0.18 (system: n-butanol / acetic acid / water 67:10:23).  UV spectrum (in 0.1 N aqueous sodium bicarbonate solution) max = 269 u (e = 7000); IR spectrum (in mineral oil): characteristic bands at 5.72, 5.94, 6.23 and 6.60.    



   Example 6
A solution of 200 mg (0.254 mM) 2- [4- (p-toluenesulfonylthio) -3- (D-a-tert. -butyloxycarbonylamino-a-phenylacetyl-amino) -2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester in 2 ml dimethylformamide is mixed with 57 μl (0.38 mM) 1,5-diazabicyclo [5. 4th 0] undec-5-ene stirred for 30 minutes at room temperature, then mixed with ethyl acetate and washed with water and 2N hydrochloric acid until acidic and with saturated aqueous sodium chloride solution until neutral.  The organic phase is dried over sodium sulfate and evaporated in vacuo.  The residue is chromatographed on silica gel thick-layer plates using toluene / ethyl acetate 1: 1 as the mobile phase. 

  The 7fl- (D-a-tert. -Butylcarbonylamino a-phenylacetylamino) -3-methoxy-ceph-2-em-4o-carboxylic acid diphenylmethyl ester of melting point 166-1680 C (methylene chloride / pentane); Thin-layer chromatogram (silica gel; diethyl ether): Rf value - 0.51; UV spectrum (in ethanol): Man = 257 m, (± = 3500); IR spectrum (in methylene chloride: characteristic bands at 2.96, 5.63, 5.74, 5.85 (shoulder), 5.92, 6.16, 6.64 and 6.72,; and the 7B- (Da-tert. - Butylcarbonylamino-a-phenyl-acetylamino) -3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester of melting point 162-1630 C (diethyl ether);

  Thin-layer chromatogram: Rf value: - 0.33 (silica gel; diethyl ether); UV spectrum (in ethanol) max = 265 m, (e = 6600); 280 m (shoulder) (e = 6200); IR spectrum (in methylene chloride): 2.92, 5.58, 5.64 (shoulder), 5.82, 6.22 and 6.67 y. 



   The compounds obtained can be processed further as follows: a) A mixture of 8.8 g (7B- (D-a-tert. -Butyloxycarbo- nylamino-a-phenyl-acetylamino) -3-methoxy-3-cephem-4carboxylic acid diphenylmethyl ester, 8.6 ml of anisole and 145 ml of trifluoroacetic acid is stirred for 15 minutes at 0 C, then 400 ml of pre-cooled toluene are added and evaporated under reduced pressure.  The residue is dried under high vacuum, digested with diethyl ether and filtered off.  The trifluoroacetate of 7B- (D-a-phenyl-glycylamino) -3-methoxy-3-cephem-4-carboxylic acid, which is dissolved in 20 ml of water, is thus obtained in powder form. 

 

  It is washed twice with 25 ml of ethyl acetate each time and the pH value is adjusted to about 5 with a 20% strength triethylamine solution in methanol, a colorless precipitate being formed.  The mixture is stirred for one hour in an ice bath, then 20 ml of acetone are added and the mixture is left to stand at about 40 ° C. for 16 hours.  The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure.  The 7,8- (N-a-phenyl-glycylamino) -3-methoxy-3-cephem-4-carboxylic acid is obtained in the form of a microcrystalline powder as an inner salt, which is also present in the form of a hydrate, F.    17P1760 C (with decomposition); [a] D20 = + 1490 (c = 1.03 in 0.1-n. 

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



   b) A mixture of 0.063 g of 7ss- (D-a-tert. -Butyloxycar bonylamino-a-phenylacetylamino) -3-methoxy-2-cephem-4a-carboxylic acid diphenylmethyl ester, 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid is left to stand for 15 minutes at 0 C and then evaporated under reduced pressure. 



  The residue is digested with diethyl ether, filtered off and dried.  The colorless and powdery trifluoroacetate of 7ss- (Da-phenyl-glycylamino) -3-methoxy-2-cephem-4a-carboxylic acid obtainable in this way is dissolved in 0.5 ml of water and the pH of the solution is adjusted by adding a dropwise 10 0 / own solution of triethylamine in methanol adjusted to about 5.  The mixture is stirred for one hour in an ice bath, the colorless precipitate is filtered off and dried in a high vacuum. 

  The 7ss- (Da-phenyl-glycylamino) -3-methoxy-2-cephem-4a-carboxylic acid is thus obtained as an inner salt, thin-layer chromatogram (silica gel; development with iodine): Rf 0.44 (system: n-butanol / Pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): shoulder = 260, u.    



   c) A solution of 0.63 g of 7ss- (D-a- tert. -Butyloxycarbonylamino-a-phenyl-acetylamino) -3-methoxy-2-cephem-4a-carbon & ure-diphenylmethyl ester in 25 ml of methylene chloride is mixed with a solution of 0.20 g of 3-chloroperbenzoic acid in 5 ml of methylene chloride.  The mixture is stirred for 30 minutes at 0 C, mixed with 50 ml of methylene chloride and washed successively with 25 ml each of a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. 



  The organic phase is dried over sodium sulfate and evaporated under reduced pressure.  The residue is crystallized from a mixture of methylene chloride and diethyl ether; this gives the 7ss- (D-a-tert. -Butyloxycarbo- nylamino-a-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester-l-oxide in the form of colorless needles, F.    172-1750 C; Thin-layer chromatogram (silica gel): Rf - 0.44 (system:

  Ethyl acetate; Development with iodine vapor); Ultraviolet Absorption Spectrum (in ethanol) max = 277 mlt (e = 7200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 cm, 5.56 lot, 5.71 lot, 5.83 lot, 5.90, u, 6.27 lot and 6.67 lt.    



   d) A solution of 1.30 g of 7B- (D-a- tert. -Butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester-1-oxide in 30 ml of dimethylformamide is mixed with 2.80 g of phosphorus trichloride with exclusion of air.  After standing for 15 minutes, the reaction mixture is poured onto a mixture of ice and an aqueous dipotassium hydrogen phosphate solution; the aqueous mixture is twice with each
100 ml of ethyl acetate extracted.  The organic extract is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 

  The residue is chromatographed on silica gel; one elutes with diethyl ether the amorphous 7ss- (D-a- tert. -Butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester as thin-layer chromatographically pure substance, Rf-0.39 (system: diethyl ether; development with iodine vapor); [a] D = 10 + 10 (c = 0.981 in chloroform); Ultraviolet absorption spectrum (in methanol): imax = 264 lt (e = 6300); Infrared absorption spectrum (in methylene chloride): characteristic
Bands at 2.94 lt, 5.62 in, 5.84, 5.88, v, 6.25 lt and 6.70. 



   The starting material can be obtained as follows: e) A solution, cooled to 150 ° C., of 31.2 g (0.12 mmol) of D-N-tert. -Butyloxycarbonyl-phenylglycine and 16.7 ml (0.12 mmol) of triethylamine in 300 ml of tetrahydrofuran are mixed with 16.5 ml (0.12 mmol) of isobutyl chloroformate and stirred at -100 ° C. for 30 minutes.  A solution of 21.6 g (0.10 mmol) 6-amino-penicillanic acid and 15.4 ml (0.11 mmol) triethylamine in 300 ml tetrahydrofuran / water 2: 1 is then added.  The reaction mixture is stirred for 1 hour at 0 C and 2 hours at room temperature, the pH value being adjusted to approx.  6.9 is kept constant. 

  The reaction mixture is adjusted to pH 2.0 with phosphoric acid at 50 C, saturated with sodium chloride and extracted three times with 500 ml of ethyl acetate each time, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.  The crude N-tert obtained in the form of a light yellow foam. -Butyloxycarbonyl-ampicillin has the Rf value in the thin-layer chromatogram - 0.65 (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10. 



   f) A solution of 57.22 g of crude N-tert. -Butyloxycarbonyl-ampicillin in 100 ml of glacial acetic acid is added within 10 minutes with 21.6 ml of 30/0 hydrogen peroxide (0.25 M) and stirred for 2.5 hours at room temperature.  The reaction mixture is then poured onto 21 ice water, the N-tert which is obtained in the form of a voluminous precipitate. -Butyloxycarbonyl-ampicillin-1 oxide filtered off, washed well with water and dried in vacuo. 



  By extracting the filtrate with ethyl acetate, additional amounts of crude N-tert. -Butylcarbonyl-ampicillin-1 oxide can be obtained.  Thin layer chromatogram (silica gel; ethyl acetate / n-butanol / pyridine / acetic acid / water 42:21:21: 6:10); Rf value - 0.30. 



   g) A mixture of 67.7 g of crude N-tert. -Butyloxycarbonyl-ampicillin-1-oxide in 380 ml of dioxane is mixed with a solution of 42 g (0.23 M) of diphenyldiazomethane in 130 ml of dioxane and stirred for 2.5 hours at room temperature.  After adding 5 ml of glacial acetic acid, it is evaporated in vacuo.  The residue is digested with petroleum ether, the petroleum ether extract is discarded and the residue is crystallized from methylene chloride / ether / hexane. 

  The N-tert is obtained.    Butyloxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester of melting point 164-1660 ° C; JD20 = +1170: 1:10 (c = 1, CHCl3); IR spectrum (methylene chloride): characteristic bands at 2.91, 2.94, 5.54, 5.69, 5.82 (shoulder), 5.88, 6.60, 6.68, u; Thin layer chromatogram: Rf value - 0.23 (silica gel; toluene / ethyl acetate 3: 1). 



   h) A mixture of 11.2 g (17.7 mmol) of N-tert. -Butyl oxycarbonyl-ampicillin-1-oxide-diphenylmethyl ester and 3.26 (19.5 mmol) mercaptobenzothiazole in 170 ml of toluene is boiled for 3 hours in a reflux apparatus with a water separator and then evaporated.  The residue is chromatographed on silica gel with toluene / ethyl acetate 3: 1 as the eluent and gives the amorphous 2- [4- (benzthi azol-2-yldithio) -3- (3 a-tert. -butyloxycarbonylamino-a-phenyl acetylamino) -2-oxoazetidin-1-ylj-3-methylenebutyric acid diphenylmethyl ester, thin-layer chromatogram: Rf value 0.37 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.64, 5.76,
5.86 (shoulder), 5.91 and 6.71. 

 

   i) A solution of 2.34 g (3.0 mmol) 2- [4- (benzthiazole
2-yldithio) -3 - (a-tert. -butyloxycarbonylamino-a-phenyl-acetyl amino) -2-oxoazetidin-1-yl] -3-methylen-butyric acid-diphenyl methyl ester in 30 ml acetone / water 9: 1 at 0 C with
0.868 g (3.46 mmol) of silver toluenesulfinate were added and the mixture was stirred in an ice bath for 1 hour.  The precipitate which has separated out is filtered off.  The filtrate is taken up in toluene and extracted with saturated aqueous sodium chloride solution.   



  The organic phase is dried over sodium sulfate and, after evaporation, gives the amorphous 2- [4- (p-toluenesulfonylthio) -3- (a-tert. -butyloxycarbonylamino-a-phenyl-acetylamino) -2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester, thin-layer chromatogram: Rf value 0.33 (silica gel; toluene / ethyl acetate 3: 1); IR spectrum (methylene chloride): characteristic bands at 2.93, 5.57, 5.70, 5.82, 6.21, 6.65 lot.    



   j) In a solution of 2.30 g (3.0 mmol) of 2- [4- (p-toluenesulfonylthio) -3- (a-tert. -butyloxycarbo nylamino-a-phenylacetylamino) -2-oxoazetidin-1-ylj-3-methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride, an ozone / oxygen stream (0.5 mmol of ozone per minute) is introduced for 7 minutes .  After 1 ml of dimethyl sulfide has been added, the solution is stirred for a further hour without cooling and then evaporated in vacuo. 

  The residue is recrystallized from methylene chloride / ether / hexane and gives the 2- [4- (p-toluenesulfonylthio) -3- (a-tert. -butyloxy-carbonylaTnino-a-phenyl-acetylamino) -2-oxoazetidine-1-yl-3-diphenylmethyl hydroxycrotonate of melting point 182-1840 ° C; UV spectrum (ethanol): Amax = 259 mlt (± = 13,400); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.59, 5.83, 5.92, 6.03 (shoulder), 6.18, 6.68 lot; Thin-layer chromatogram: Rf value 0.55 (silica gel; toluene / ethyl acetate 1: 1). 



   k) A solution of 0.54 g (0.7 mmol) 2- [4- (p-toluenesulfonylthio) -3 - (a-tert. -butyloxycarbonylamino-a-phenyl acetylamino) -2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml of methylene chloride / methanol 1: 1 is stirred at 0 C with an excess of an ethereal diazo methane solution for 15 minutes and then in Evaporated in vacuo. 

  Preparative layer chromatography of the residue on silica gel with toluene / ethyl acetate 1: 1 as the mobile phase and elution of the zone visible in UV light yields the 2- [4- (p-toluenesulfonylthio) -3- (a-tert. -butyloxycarbonylamino-a-phenyl-acetylamino) -2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester, which is recrystallized from methylene chloride / diethyl ether / hexane.  Melting point 204-2060 C; UV spectrum (ethanol): max = 259 mlt (e = 16,000); IR spectrum (Nujol): characteristic bands at 2.93, 5.58, 5.80, 5.84, 5.93, 6.24, 6.57 lt; Thin-layer chromatogram: Rf value ¯ 0.33 (silica gel; toluene / ethyl acetate 1: 1). 



   Example 7
A mixture of 670 mg (1 mmol) 2- [4- (p-toluene sulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester, 6.7 ml 1, 2-dirnethoxyethane and 0.22 ml 1,5-diazabicyclo [5. 4th 0] undec-5-en is stirred for 25 minutes at room temperature under a nitrogen atmosphere.  The reaction mixture is diluted with toluene and washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. 

  The residue gives, after preparative thick layer chromatography on silica gel with toluene / ethyl acetate 1: 1, the 7B-penhylacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester with a melting point of 166-1690 C (from methylene chloride /
Hexane), UV spectrum (ethanol): imax = 258 mlt (e =
4500); IR spectrum (methylene chloride): characteristic
Bands at 2.93, 5.62, 5.73, 5.93, 6.66 lt; Rf value -c 0.54 (silica gel;

  System toluene / ethyl acetate 1: 1) and the amorphous 7ss-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester, UV spectrum (ethanol): imax =
258 mlt (e = 6350), 264 mlt (e = 6350), 282 mjlb (e = 5600) (shoulder); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83, 5.94, 6.26, 6.66 lt; Rf value 0.37 (silica gel; system toluene / ethyl acetate 1: 1), in a ratio of 8: 1. 



   Further processing can be carried out as follows:
The 7ss-phenylacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester can analogously to Example 6c) into the 7ss-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-1 oxide from melting point 152-1550 (from acetone / diethyl ether); Rf value 0.31 (silica gel; system: ethyl acetate); W spectrum (in 95% ethanol): man = 288 m, u (e = 3610) and shoulder at = 247 mlt; IR spectrum (methylene chloride): characteristic bands at 2.94, 5.59, 5.81, 5.95, 6.22 and 6.61, u. 



   A purer product consisting mainly of the 7B-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester 1fl-oxide can be obtained as follows:
A solution of 6.7 g (10 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxyisocrotonic acid diphenylmethyl ester in 67 ml of abs.  Tetrahydrofuran is stirred with 2.28 ml (15 mmol) of 1,5-diazabicyclo [5.4.0] and dec-5-ene for 15 minutes at 200 ° C., treated with 0.7 ml of glacial acetic acid and then evaporated in vacuo.  The oily, dark residue is dissolved in 30 ml of methylene chloride and extracted successively with 15 ml of water, 10 ml of 0.5 N hydrochloric acid, 10 ml of saturated aqueous sodium bicarbonate solution and 10 ml of water. 

  The aqueous phases are re-extracted with 10 ml of methylene chloride, the organic extracts are combined and stirred at 0 ° C. with 2.24 ml of 40% peracetic acid in an ice bath for 15 minutes.  The reaction mixture is then mixed with a solution of 1.50 g (6 mmol) of sodium thiosulfate pentahydrate in 20 ml of water, stirred for 10 minutes and the aqueous phase is separated off. 



  The organic phase is washed with 10 ml of water, dried over sodium sulfate and evaporated in vacuo.  Crystallization of the solid residue from methylene chloride / petroleum ether gives the 7ss-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester-lss oxide with a melting point of 175-1760 ° C .; Thin layer chromatogram (silica gel): Rf value - 0.1 (toluene / ethyl acetate 1: 1); UV spectrum (ethanol): III = 279 mlt (8 = 7300); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.56, 5.78, 5.91, 6.20, 6.67.    



   The 7B-phenyl-acetamido-3-methoxy-ceph-3-em-carboxylic acid diphenylmethyl ester can be obtained from the 1-oxides analogously to Example 6e. 



   The crude 7ss-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid can be obtained from the latter by saponification analogously to Example 6e), which is obtained by chromatography on silica gel (containing 5% water) with methylene chloride 30-50 IO / o acetone, and subsequent lyophilization from dioxane can be purified, UV spectrum (in 95/0 strength ethanol): max = 265 with (e = 5800); IR spectrum (methylene chloride): characteristic bands at 3.03, 5.60, 5.74, 5.92, 6.24 and 6.67. 

 

   The starting material and the intermediate products can be prepared as follows: a) A mixture of 37.24 g (0.1 mol) of penicillin G potassium salt in 90 ml of water, 7.3 ml of acetone and 150 ml of chloroform is stirred at 0 ° C. 19.4 ml of 40% peracetic acid were added within 40 minutes.  After a further 15 minutes, 28 g (0.15 mol) of benzophenone hydrazone, then 6.3 ml of 10 / above aqueous potassium iodide solution and then a mixture of 32.5 ml of 10% sulfuric acid dropwise over 1.5 hours are added at the same temperature and 28 ml 40 less peracetic acid added. 



  After the addition is complete, the mixture is stirred for 30 minutes at 0 C, warmed to 150 and diluted with 400 ml of chloroform.  The aqueous phase is separated off and the organic phase is washed successively with 300 ml of 5-point aqueous sodium bisulfite solution, 300 ml of saturated aqueous sodium bicarbonate solution and 300 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The evaporation residue is recrystallized from ethyl acetate / petroleum ether and gives the 6-Phc.    



  nylacetamidopenicillanic acid diphenylmethyl ester-lss-oxide, melting point 1390 C; Thin-layer chromatogram (silica gel): Rf value c 0.40 (system toluene / ethyl acetate 1: 1); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.56, 5.70, 5.92 and 6.57 p.    



   b) A mixture of 5.165 g (10 mmol) of 6-phenylacet amidopenicillanic acid diphenylmethyl ester 1ss oxide in 50 ml of toluene and 0.5 ml of glacial acetic acid is mixed with 1.83 g (11 mmol) of 2-mercaptobenzothiazole and 2 hours in a boiled with a water separator provided reflux apparatus. 



  On cooling, the 2- [4- (benzthiazol-2-yldithio) 3-phenylacetamido-2-oxoazetidin-1-ylj-3-methylene-butyric acid diphenylmethyl ester spontaneously crystallizes out.  After recrystallizing once from methylene chloride / diethyl ether, crystals with a melting point of 13P1360 C are obtained; Thin-layer chromatogram (silica gel): Rf value c 0.52 (system toluene-ethyl acetate 1: 1); UV spectrum (ethanol): max = 269 m, (e = 12700); IR spectrum (methylene chloride): characteristic bands at 2.90, 5.60, 5.72, 5.92 and 6.61.    



   c) The product obtained under b) does not need to be isolated for further processing.  After cooling, the reaction mixture can be diluted directly with 30 ml of toluene, set ver with 3.95 g (15 mmol) of silver p-toluenesulfinate and stirred for 2 hours at room temperature.  The yellow precipitate which has separated out is filtered off through Hyflo and washed with toluene.  The filtrate is extracted with saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated in vacuo.  The evaporation residue is taken up in toluene and petroleum ether is added.  The precipitate is filtered off and recrystallized from ethyl acetate / petroleum ether. 

  The resulting 2- [4- (p toluenesulfonylthlo) -3-phenylacetamido-2-oxoazetidin-1-yU-3-methylene-butyric acid diphenylmethyl ester has a melting point of 750 ° C .; Thin-layer chromatogram (silica gel): Rf value c 0.47 (system toluene / ethyl acetate 1: 1); UV spectrum (ethanol): imax = 259 m, a (e = 4300); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.63 X.    



   d) A solution of 655 mg (1 mM) 2- [4- (p-toluene sulfonylthio) -3 -phenylacetamido-2-oxoazetidin-1-yl] -3 -methylenebutyric acid diphenylmethyl ester in 65 ml methylene chloride is at 650 ° C. treated with an ozone / oxygen mixture to a light blue color.  After adding 0.5 ml of dimethyl sulfide, the mixture is allowed to warm to room temperature and evaporated in vacuo.  The crude 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester, Rf value c 0.46 (silica gel; system toluene / ethyl acetate 1: 1); IR spectrum (methylene chloride): characteristic bands at 2.95, 5.60, 5.98, 6.18, 6.61, a, can be processed further without further purification. 

 

   e) The crude product obtained under d) is dissolved in 20 ml of methanol and ethereal diazomethane solution is added at 0 ° C. until it remains yellow.  After the solvent has been evaporated off in vacuo, the residue is purified by preparative thick layer chromatography on silica gel using toluene / ethyl acetate 1: 1 as the mobile phase.  The 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2- oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester, Rf value 0.2 (silica gel; system toluene / ethyl acetate 1: 1); IR spectrum (methylene chloride): characteristic bands at 2.94, 5.61, 5.96, 6.24, 6.62 p, in addition to a little 2- [4- (p-toluene sulfonylthio) -3-phenylacetamido-2 -oxoazetidin-1-yl-3-methoxy-isocrotonic acid-diphenylmethyl ester.  

 

Claims (1)

PATENT CLAIM Process for the preparation of 2- (3-amino-2-oxo-4-sulphonylthio-1-azetidinyl) -3-methylene-butyric acid compounds of the formula EMI27.1 wherein R, a represents hydrogen or an amino protective group R, A and Rtb represents hydrogen or an acyl group Ac or R1 "and Rtb together represent a divalent amino protective group, R, A represents one, together with the carbonyl group -C (= O) - one protected carboxyl group, and Y is a group of the formula -S02-R bonded with the sulfur atom to the thio group -S-, or a group -S-SO2-R, in which R5 is an optionally substituted, aliphatic, cycloaliphatic, represents araliphatic or aromatic hydrocarbon radicals with up to 18 carbon atoms, and their salts, characterized in that a compound of the formula EMI27.2 where R, a, Rtb and RA have the above meanings and Rd is an optionally substituted aromatic heterocyclic radical with up to 15 carbon atoms and at least one ring nitrogen atom and optionally one further ring heteroatom, which radical is with one of its ring carbon atoms that with a ring nitrogen atom through a double bond is connected, is bonded to the thio group -S-, or is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18 carbon atoms, with a heavy metal sulfinate of the formula Mnf (-S08-Rs) n or with a heavy metal thiosulfonate of the formula Mn + (- S-SO2-Rs) n, where M is a heavy metal cation and n is the valence of this cation. SUBCLAIMS 1. The method according to claim, characterized. net that starting materials of the formula IVa are used in which Rja is an amino protective group R, A, which stands for an acyl group Ac, in which any free functional groups that may be present can be protected, Rtb is hydrogen, R2A is one with the -C (= O) -Grouping represents an esterified carboxyl group-forming etherified hydroxyl group, where optionally present functional groups in an esterified carboxyl group of the formula -C (= O) -R2A can be protected, and where R4 is an optionally substituted aromatic heterocyclic radical with up to 9 carbon atoms, and at least a ring nitrogen atom and optionally a further ring heteroatom, such as oxygen or sulfur, which radical is with one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond, is bound to the thio group -S-. 2. The method according to claim, characterized in that R2A is an optionally substituted 1-phenyl-lower alkoxy, such as benzyloxy, p-nitrobenzyloxy or diphenylmethoxy group, or an optionally halogen-substituted lower alkoxy group, such as methoxy, a-polybranched lower alkoxy, e.g. B. tert-butyloxy, or 2-halo-lower alkoxy, such as 2,2,2-trichloroethoxy. 3. The method according to claim, characterized in that R4 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4 thiadiazol-2-yl, 1,3,4,5- Thiatriazol-2-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl or 1-methyl- means benzimidazol-2-yl. 4. The method according to claim, characterized in that R4 is an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group with up to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, e.g. B. acetyl or propionyl, lower thioalkanoyl, e.g. B. thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g. B. cyclohexanecarbonyl, cyclo. alkanthiocarbonyl, e.g. B. Cyclohexanthiocarbonyl, benzoyl, thiobenzoyl, naphthylcarbonyl, naphthylthiocarbonyl, heterocyclic carbonyl or thiocarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3 or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, 2- or 3-thiofuroyl or a correspondingly substituted one, for example by lower alkyl such as methyl, halogen such as fluorine or chlorine, lower alkoxy such as methoxy, aryl such as phenyl, aryloxy such as phenyloxy, mono- or represents a polysubstituted acyl or thioacyl group. 5. The method according to claim, characterized in that R4 is benzthiazol-2-yl. 6. The method according to claim, characterized in that R4 is benzoxazol-2-yl. 7. The method according to claim, characterized in that one reacts with a heavy metal sulfinate of the formula Mn + (- SOeR3n, wherein M is copper, mercury, silver or tin, n 1 or 2, and wherein R5 is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or is an aromatic hydrocarbon radical having up to 18, preferably up to 10 carbon atoms. 8. The method according to claim, characterized in that one reacts with a heavy metal thiosulfonate of the formula Mn + (- S-SO2-Rs) n, in which M is copper, mercury, silver or tin, n 1 or 2, and in which R5 is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18, preferably up to 10 carbon atoms. 9. The method according to claim, characterized in that one reacts with a heavy metal sulfinate of the formula CU2 + (- SO2-Rs) 2 or Ag + (- SO2-Rs), in which R is optionally substituted by lower alkoxy, halogen, aryl or aryloxy, mono- or polysubstituted lower alkyl, alkenyl or cycloalkyl group, or a naphthyl or, in particular, phenyl group optionally mono- or poly-substituted by lower alkyl, lower alkoxy, halogen, aryl, aryloxy or nitro, for example phenyl, o-, m- or preferably p-tolyl, o- , m- or preferably p-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2-naphthyl. 10. The method according to claim, characterized in that one reacts with a heavy metal sulfinate of the formula CU2 + (- SO2-Rs) 2 or Ag + (- SO-R5), in which Rs is phenyl, p-tolyl, p-methoxyphenyl or p-nitrophenyl . 11. The method according to claim, characterized in that the reaction is carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. 12. The method according to claim, characterized in that the reaction is carried out at room temperature. 13. The method according to claim or one of the dependent claims 1-12, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl] -3-methylenebutyric acid-p -nitrobenzyl ester. 14. The method according to claim or one of the dependent claims 1-12, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti- din-1-yl] -3-methylenebutyric acid diphenylmethyl ester manufactures. 15. The method according to claim or one of the dependent claims 1-12, characterized in that the 2- [4- (p-toluenesulfonylthio) -3 - (Da-tert.-butyloxycarbonyl-amino-a-phenylacetamido) -2-oxoazetidine -1 -yl] -3-methylenebutyric acid diphenylmethyl ester. 16. The method according to claim or one of the dependent claims 1-12, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester is prepared.