CH605737A5 - 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-thio-1-azetidinyl) -3-substituted-hydroxy-crotonic acid compounds of the formula
EMI1.1
 where R1a represents hydrogen or an amino protective group R1A, and Rb represents hydrogen or an acyl group Ac, or Rl and R together represent a divalent amino protective group, RA represents hydroxy or a protected one together with the carbonyl group -C (= 0)
Is a carboxyl group-forming radical, and R3 is lower alkyl, or a hydroxy protecting group, and Y is a leaving group -S-R4, -SO-R5 or -S-SO2-R5, wherein R4 is an optionally substituted aromatic heterocyclic
Remainder with up to 15 carbon atoms,

   and at least one
Ring nitrogen atom and optionally a further ring heteroatom, which radical is with one of its ring carbon atoms, the one with a ring nitrogen atom through a
Double bond is bonded to the thio group -5-, and R5 is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms, as well as their salts.



   An amino protective group Rl is a group which can be replaced by hydrogen, primarily an acyl group Ac, also 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 Rb, primarily represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic -aliphatic carboxylic acid (including formic acid), as well as the acyl radical of a carbonic acid semi-derivative.



   A divalent amino protective group formed by the radicals R1 and R1 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, z. B.



  an aromatic or heterocyclic radical containing a-aminoacetic acid, in which the amino group is connected to the nitrogen atom via a, preferably substituted, for example two lower alkyl, such as methyl group-containing methylene radical. The radicals R1a and R1b 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.
A protected carboxyl group of the formula -C (= OFR2 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 hydroxyl 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, and also heterocyclic or heterocyclic-aliphatic radicals.



   The group R2 can also represent an organic silyloxy radical, as well as a hydroxy group etherified by an organometallic radical, such as a corresponding organic stannyloxy group, in particular a hydrocarbon radical optionally substituted by 1 to 3, preferably with up to 18 carbon atoms, such as aliphatic hydrocarbon radicals, and optionally by halogen , such as chlorine-substituted silyloxy or stannyloxy group.



   A radical R2 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 R 2 which forms a carbamoyl group with a -C (= O) grouping is an optionally substituted amino group in which substituents are optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or 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 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 bivalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted, monovalent or bivalent aliphatic , cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms, furthermore corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups such as acyl radicals, primarily from organic carboxylic acids or from carbonic acid with half derivatives, preferably up to 18 carbon atoms.

 

   A lower alkyl group R3 has up to 7, preferably up to 4 carbon atoms and is in particular methyl.



   A hydroxyl protecting group R3 is, for example, an easily split off 2-oxa or 2-thia-aliphatic or cycloaliphatic hydrocarbon radical, or an easily split off substituted silyl or stannyl group.



   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 radicals 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, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylthio or optionally substituted phenylthio, phenyl-lower alkylthio, heterocyclyl-oxythio or, optionally, heterocyclyl-oxythio or, optionally substituted halogeno-alkyloxy-or, optionally-substituted-oxycarbonyloxy-lower alkyl, or oxycarbonyloxy, or optionally substituted halogeno-oxycarbonyloxy, or optionally substituted halo-alkyloxythio, or optionally substituted halogeno-oxycarbonyloxy, or optionally substituted halogeno-oxycarboyloxy, or optionally substituted halogeno-oxycarboyloxy, or optionally substituted halogeno-oxycarbonyloxy, or optionally substituted halogeno-oxycarboyloxy, or optionally substituted halogeno-oxy-oxyloxy, or optionally substituted halogeno-alkyloxy, or optionally substituted halo-alkyloxy , also by oxo, nitro, optionally substituted amino, e.g. B.



   Lower alkylamino, di-lower alkylamino, lower alkylenamino,
Oxaniederalkylenamino or Azaniederalkylenamino, as well as
Acylamino, such as lower alkanoylamino, lower alkoxycarbonylamino, halo-lower alkoxycarbonylamino, optionally substituted phenyl-lower alkoxycarbonylamino, optionally substituted carbamoylamino, ureidocarbonylamino or guanidinocarbonylamino, also optionally in salt, such as alkali metal salt form, sulfoamino,
Acyl, such as lower alkanoyl or benzoyl, optionally functionally modified carboxyl, such as that present in salt form
Carboxyl, 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 in salt form, or optionally 0
Mono- or 0,0-disubstituted phosphono, wherein substituents are z. B. optionally substituted lower alkyl, phenyl or phenyl-lower alkyl, where 0-unsubstituted or 0-monosubstituted phosphono can also be in salt or alkali metal salt form, be mono-, di- or polysubstituted.



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



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid, or a corresponding cycloaliphatic or cycloaliphatic-aliphatic ylidene radical is an optionally substituted, mono- or bivalent cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical. B. mono-, bi or polycyclic cycloalkyl or cycloalkenyl, also cycloalkylidene, or cycloalkyl or cycloalkenyl-lower alkyl or -lower alkenyl, also cycloalkyl-lower alkylidene or cycloalkenyl-lower alkylidene, wherein cycloalkyl and cycloalkylidene e.g. contains up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl z. B. up to 12, such as 3-8, e.g.

  B. 5-8, preferably 5 or 6 ring carbon atoms and 1 to 2 double bonds and the aliphatic part of a cycloaliphatic-aliphatic radical z. B. can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. B. by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, e.g. B. like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or poly-substituted by functional groups.



   An aromatic radical, including the aromatic radical of a corresponding carboxylic acid, is an optionally substituted aromatic hydrocarbon radical, e.g. B. a mono-, bis or polycyclic aromatic hydrocarbon radical, in particular phenyl, and also biphenylyl or naphthyl, which may optionally, for. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted.



   A divalent aromatic radical, e.g. B. an aromatic carboxylic acid, is primarily 1,2-arylene, especially 1,2-phenylene, which may optionally, for. B. as the above-mentioned aliphatic and cycloaliphatic hydrocarbon radicals, 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 having aliphatic hydrocarbon radicals and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, and phenyl-lower alkynyl, also phenyl lower alkylidene, such radicals z. Contain 1-3 phenyl groups and optionally, e.g. 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 s-position, substituted lower alkyl half esters of carbonic acid, and a lower alkenyl, cycloalkyl, phenyl or phenyl lower alkyl half ester of carbonic acid which is optionally substituted in the organic radical. Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g.

  B. one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted. The acyl radical of a carbonic acid half derivative can also be an optionally N-substituted carbamoyl group, such as an optionally halogenated N-lower alkylcarbamoyl group.



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



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



  Amino, lower alkylamino, di-lower alkylamino, lower alkylenamino, oxane-lower alkylenamino, thian-lower alkylenamino, aza-lower alkylenamino, hydroxyamino, lower alkoxyamino, lower alkanoyloxyamino, lower alkoxycarbonylamino or lower alkanoylamino.



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



  Hydrazino, 2-lower alkylhydrazino, 2,2-di-lower alkylhydrazino, 2-lower alkoxycarbonylhydrazino or 2-lower alkanoylhydrazino.



   Lower alkyl is z..B. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while lower alkenyl z. B. vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl, lower alkynyl e.g. B. propargyl or 2-butynyl, and lower alkylidene z. B. 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-ethylene 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 azo-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. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl e.g. Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene e.g. Cyclopentylidene of the cyclohexylidene.



  Cycloalkyl-lower alkyl or lower alkenyl is e.g. Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1 or 1-, 2-ethyl, -1,1-, -1,2- or-1,3-propyl, -vinyl or -allyl, while cycloalkenyl lower alkyl or - lower alkenyl z. B. 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenylmethyl, -1,1- or 1-2, -ethyl, -1, Represents 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-naphthylmethyl, and phenyl lower alkylidene z. B. benzylidene.



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character.



  z. B. corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, e.g. 2-pyrryl or 3-pyrryl, pyridyl, e.g. B. 2-, 3- or 4-pyridyl, also pyridinium, thienyl, z. 2- or 3-thienyl, or furyl, e.g. 2-furyl, bicyclic monoaza, monooxa or monothiacyclic radicals such as indolyl, e.g. 2- or 3-indolyl, quinolinyl, e.g. 2- or 4-quinolinyl, isoquinolinyl, e.g. 1-isoquinolinyl, benzofuranyl, e.g. 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, z. B. 2 imidazolyl, pyrimidinyl, e.g. 2- or 4-pyrimidinyl, triazolyl, e.g. 1,2,4-triazol-3-yl, tetrazolyl, e.g.

  1- or 5-tetrazolyl, oxazolyl, e.g. 2-oxazolyl, isoxazolyl, e.g. 3- or 4-isoxazolyl, thiazolyl, e.g. 2¯thiazolyl, isothiazolyl, e.g. 3- or 4-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. 1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, oxaza or thiazacyclic radicals such as benzimidazolyl, e.g. 2-benzimidazolyl, benzoxazolyl, e.g. 2-benzoxazolyl, or benzthiazolyl, e.g. 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. Heterocyclischaliphatic radicals are heterocyclic groups, especially the above-mentioned lower alkyl or lower alkenyl containing.



  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, z. 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. Methylenedioxy, ethylenedioxy or isopropylidenedioxy, cycloalkoxy, e.g.



  Cyclopentyloxy, cyclohexyloxy or adamantyloxy, phenyl-lower alkoxy, e.g. Benzyloxy, 1- or 2-phenylethoxy, diphenylmethoxy or 4,4'-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. like 2-thenyloxy.



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



   Esterified hydroxy groups are primarily halogen, e.g. B. fluorine, chlorine, bromine or iodine, and Niederalkoxycarbonyloxy, z. B. methoxycarbonyloxy, ethoxycarbonyloxy or tert. Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. 2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or arylcarbonylmethoxycarbonyloxy, e.g. Phenacyloxycarbonyloxy.



   Lower alkoxycarbonyl is e.g. 13. Methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert. Butyloxycarbonyl or tert-pentyloxycarbonyl.



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



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



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

 

   Lower alkylamino or di-lower alkylamino is e.g. B. methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino z. E.g. pyrrolidino or piperidino, oxaniederalkylenamino e.g. Morpholino, thiane lower alkyleneamino e.g. B. Thiomorpholino, and Azaniederalkylenamino z. B. piperazino or 4-methylpiperazino.

  Acylamino is especially carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino, e.g. 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, if appropriate, phthalimetallamino, such as acetylamino or propionylamino, e.g. 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. 0-methyl or O-ethylphosphono, O, O'-di-lower alkyl-phosphono, z. B. 0,0-dimethylphosphono or O, O'-diethylphosphono, O-phenyl lower alkyl phosphono, z. B. O-benzyl-phosphono, and O-lower alkyl-O'phenyl-lower alkyl-phosphono, e.g. B. O-benzyl-O¯methylphosphono.



   Lower alkenyloxycarbonyl is e.g. Vinyloxycarbonyl, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl, e.g. Adamantyloxycarbonyl, benzyloxycarbonyl, 3-methoxybenzyloxycarbonyl, diphenylmethoxycarbonyl or α-4 biphenyl-a-methyl-ethoxycarbonyl represents. Lower alkoxycarbonyl, wherein lower alkyl e.g. 13. Contains a monocyclic, monoaza-, monooxa- or monothiacyclic group, is z. B.



  Furyl-lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl-lower alkoxycarbonyl, such as 2-thienyloxycarbonyl.



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



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



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

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

   and each of the radicals R ″ and Riii denotes hydrogen, or where n is 1, Rl denotes an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical or an optionally substituted heterocyclic or heterocyclic-aliphatic radical, in which the heterocyclic radical preferably has an aromatic character, R "is 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 0-mono- or 0,0'-disubstituted phosphono group, or an azido group, and Rl ] is hydrogen, or in which n is 1, each of the radicals Rl and R <l is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or where n is 1, R 'is hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic,

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

   aromatic or araliphatic hydrocarbon radical and R "'denotes hydrogen or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical.



   In the above acyl groups of the formula A, for. B.



  n for 0 and R 'for 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, e.g.



  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, where 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, an optionally, z. B. by lower alkyl, e.g. Methyl and / or phenyl which in turn has substituents such as halogen, e.g. 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, R '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, containing phenyloxy, or by 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, z. B. silylated, such as tri-lower alkylsilylated, e.g.

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

  As indicated above, acylated hydroxy and / or halogen, e.g. Phenyl group containing chlorine, containing phenyloxy, an optionally, z. By lower alkyl, such as methyl, or optionally protected, e.g. acylated as indicated above,
Amino or aminomethyl, substituted pyridyl, e.g. 13.4-
Pyridyl, pyridinium, e.g. 4-pyridinium, thienyl, e.g. B. 2
Thienyl, furyl, e.g. 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, z. B. acylated as indicated above, hydroxy and / or halogen, such as
Chlorine containing phenyloxy group, a lower alkylthio e.g. n-butylthio, or lower alkenylthio, e.g.

  Allylthio group, an optionally, e.g. by lower alkyl, like
Methyl, substituted phenylthio, pyridylthio, e.g. 4-pyridyl thio, 2-imidazolylthio, 1,2,4-triazol-3-ylthio, 1,3,4-triazole
2-ylthio-, 1, 2,4-thiadiazol-3-ylthio- such as 5-methyl-1,2,4-thiadiazol-3-ylthio-, 1,3,4-thiadiazol-2-ylthio- such as 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 converted carboxyl group such as lower alkoxycarbonyl, z. B.



   Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, e.g. by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g. B. acetyl or propionyl, or benzoyl group, or an azido group, and R "and R" 'for hydrogen, or n for 1, R' 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. 2-furyl, thienyl, e.g. B. 2- or 3-thienyl, or isothiazolyl, e.g.

  B. 4-isothiazolyl group, also for a 1,4 cyclohexadienyl group, R "for optionally protected or substituted amino, for example amino, acylamino, such as lower alkoxycarbonylamino, 2-halo-lower alkoxycarbonylamino or optionally substituted, such as lower alkoxy, e.g. methoxy, or nitro containing Phenyl-lower alkoxycarbonylamino, e.g. tert-butyloxycarbonylamino, 2,2,2-trichloroethoxycarbonylamino, 4-methoxybenzyloxycarbonylamino or diphenylmethyloxycarbonylamino, arylsulphonylamino, e.g. 4-methylphenylsulphonylamino, or tritylaminothio, e.g. optionally substituted, such as lower alkoxycarbonyl, for example ethoxycarbonyl, or lower alkanoyl, for example



  Acetyl, containing 2-propylideneamino, such as 1-ethoxycarbonyl-2-propylideneamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt, e.g. B. alkali metal salt form
Sulfoamino group, an azido group, an optionally in salt, z. B.

  Alkali metal salt form or in protected, such as esterified form, e.g. as lower alkoxycarbonyl, e.g. Methoxycarbonyl or ethoxycarbonyl, or as phenyloxycarbonyl, e.g. Diphenylmethoxycarbonyl group present carboxyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxy group, where functionally modified hydroxy especially acyl oxy, such as formyloxy, and lower alkoxycarbonyloxy, 2
Halogenniederalkoxycarbonyloxy or optionally substituted, such as lower alkoxy, e.g. B. methoxy, or nitro-containing phenylniederalkoxycarbonyloxy, 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 0,0'-di-lower alkyl-phosphono group, e.g. B. 0-methyl-phosphono or 0,0'-dimethylphosphono, or a halogen atom, e.g. B. chlorine or bromine, and R "'for hydrogen, or n for 1, R' and R" each for halogen, e.g. B. bromine, or lower alkoxycarbonyl, e.g. B.



  Methoxycarbonyl, and R1 ″ for hydrogen, or n for 1, R 'for an optionally acylated hydroxyl and / or halogen, eg chlorine, substituted phenyl, furyl, e.g. 2-furyl, or thienyl, e.g.



  2- or 3-thienyl, or isothiazolyl, e.g. B. 4-isothiazolyl group, also for a 1,4-cyclohexadienyl group, Rll for optionally, z. B. as stated above, protected aminomethyl, and R "'is hydrogen, or n is 1 and each of the groups R', R" and R "'are lower alkyl, for example methyl.



   Such acyl radicals Ac are z. B. formyl, cyclopentylcarbonyl, a-aminocyclopentylcarbonyl or a-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g.



  optionally present in salt form sulfoamino group, or one, by a, preferably slightly, z. When treating with an acidic agent such as trifluoroacetic acid, reductive, e.g. on treatment with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, or catalytic hydrogen, or hydrolytically cleavable or an acyl radical which can be converted into such, preferably a suitable acyl radical of a carbonic acid half ester, such as lower alkoxycarbonyl, e.g. tert-butyloxycarbonyl, 2-halo-lower alkylcarbonyl, e.g. 2,2,2-trichloroethyloxycarbonyl, 2-bromoethoxycarbonyl or 2-iodoethoxycarbonyl, arylcarbonylmethoxycarbonyl, e.g. 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. 2-nitrophenylthio, arylsulfonyl, e.g. B. 4-methylphenylsulfonyl 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) -5methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl , Propionyl, butyryl, pivaloyl, hexanoyl, octanoyl, acrylyl, cortonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, butylthioacetyl, allylthioacetyl, methylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropyl, 3-chloropropionyl, dibromoacetyl, 3-chloropropyl, dibromoacetyl, 3-chloropropyl -5-carboxy-valeryl (with optionally, for example as indicated, as represented 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, z. B. in salt, such as sodium salt, or in ester, such as lower alkyl, z. Methyl or ethyl, or aryl lower alkyl, e.g. Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bis-methoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, 2-cyano-3,3-dimethyl-acrylacetyl <a-bromophenylacetyl, a-azidophenylacetyl, 3-chlorophenylacetyl, 2 or 4-aminomethylphenylacetyl (with if necessary, e.g.

 

  as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenylacetyl, a-phenyloxyphenylacetyl, a-phenyloxyphenylacetyl, a-methoxyphenylethoxy, a-phenyloxyphenylacetyl, a-methoxyphenylethoxy, a-phenyloxyphenylacetyl, a-methoxyphenylethyl, a-methoxyphenylethyl, a-methoxyphenylethyl, a-methoxyphenylethoxy, a-methoxyphenylethyl a-Cyano-phenylacetyl, especially 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 indicated above, can be substituted and / or an existing, aliphatic and / or phenolically bonded hydroxyl group optionally, analogously to the amino group, e.g. can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester), or a-O-methyl-phosphono-phenylacetyl or a-0,0-dimethylphosphonophenylacetyl, also benzylthioacetyl, benzylthiopropionyl, a
Carboxyphenylacetyl (with a carboxy group that is functionally modified, for example, as indicated above), 3
Phenylpropionyl, 3- (3-cyanophenyl) propionyl, 4- (3-methoxy phenyl) butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, e.g.

  B. as indicated above, substituted
Amino group), 2-thienylacetyl, 3-thienylacetyl, 2-tetra hydrothienylacetyl, 2-furylacetyl, I-imidazolylacetyl, 1-tetra zolylacetyl, α-carboxy-2-thienylacetyl or α-carboxy-3 thienylacetyl (optionally with functional, e.g. given above, modified carboxyl group), a-cyano-2-thienylacetyl, a-amino-a- (2-thienyl) -acetyl, a-amino-a- (2furyl) -acetyl or a-amino-a- (4-isothiazolyl ) -acetyl (if necessary with, for example, as stated above, substituted amino group), a-sulfophenylacetyl (if necessary with, e.g.

  B. like that
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-thiadiazole - 3 ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1 methyl-5-tetrazolylthioacetyl.



   An easily cleavable acyl radical Ac, especially one
Carbonic acid half-ester is primarily a reduction, e.g. 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 one, preferably on the carbon atom in a position to
Oxy group multiply branched and / or aromatically substituted lower alkoxycarbonyl group or a methoxycarbonyl group substituted by arylcarbonyl, in particular benzoyl, or lower alkoxycarbonyl group substituted in the s-position by halogen atoms, e.g.

  B. tert-Butyloxycarbonyl, tert-Pentyloxycarbonyl, Phenacyloxycarbonyl, 2,2,2 Trichloräthoxycarbonyl or 2-Jodäthoxycarbonyl or a radical convertible in the latter, such as 2-chloro- or 2-bromoethoxycarbonyl, also, preferably polycyclic, cycloalkoxycarbonyl, z. 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 a 4-biphenylyl-a-methyl-ethyloxycarbonyl, or furyl-lower alkoxycarbonyl; primarily a-furyl-lower alkoxycarbonyl, e.g. B.



  Furfuryloxycarbonyl.



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



   A further divalent radical formed by the groups R1A and R1b is e.g. 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-3-aza-1,4butylene. A.
An etherified hydroxy group R2 together with the carbonyl group forms an esterified carboxyl group, preferably easily cleavable or easily converted into another functionally modified carboxyl group, such as into a carbamoyl or hydrazinocarbonyl group. Such a group R 2 is e.g. B.

  Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl group 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 RA2 which together with a -C (= O) group forms a particularly easily cleavable esterified carboxyl group, is available, for. B. for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19. Such a radical, together with the -C (= O) group, forms a, when treated with chemical reducing agents under neutral or weakly acidic conditions, e.g. B. with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or one in such an easily convertible esterified carboxyl group 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 R A2 ç which, together with the -C (= O) grouping, also results in treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g. 13. when treating with zinc in the presence of aqueous acetic acid, also when treating with a suitable nucleophilic reagent, e.g. B. sodium thio phenolate, easily cleavable esterified carboxyl group is an arylcarbonylmethoxy group, wherein aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy.



   The group R 2 can also stand for an aryl methoxy group, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical. Such a residue, together with the -C (= O) -
Grouping an esterified carboxyl group which can be easily cleaved upon irradiation, preferably with ultraviolet light, under neutral or acidic conditions. An aryl radical in such an arylmethoxy group is in particular lower alkoxy phenyl, e.g. B. Methoxyphenyl (where methoxy is primarily in
3-, 4- and / or 5-position), and / or especially Nitrophe nyl (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-di methoxybenzyloxy, 2-nitrobenzyloxy or 4,5-dimethoxy-2 nitro-benzyloxy.



   An etherified hydroxy group RA can also represent a radical which, together with the -C (= O) grouping, is a radical under acidic conditions, e.g. when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified
Forms carboxyl group. Such a remainder is primarily one
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 by a,
Electron-donating, substituent-containing carbocyclic aryl group or a heterocyclic group of aromatic character having oxygen or sulfur as a ring member is monosubstituted, or then a ring member in a polycyclo aliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic radical which is in the a position Means ring member representing oxygen or sulfur atom.



   Preferred polysubstituted methoxy groups of this type are tert-lower alkoxy, e.g. B. tert-butyloxy or tert-pentyl oxy, optionally substituted diphenylmethoxy, e.g. Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, also 2- (4-biphenylyl) -2-propyloxy, while a methoxy group containing the above substituted aryl group or the heterocyclic group e.g. B. x-lower alkoxy-phenyl-lower alkoxy, such as 4-methoxybenzyloxy or 3,4-dimethylbenzyloxy, or furfuryloxy, such as 2-furfuryloxy. A polycycloaliphatic hydrocarbon radical in which methyl of the methoxy group is a, preferably triple, branched ring member is, 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-thianiederalkylen or -niederalkenylen with 5-7 ring atoms, like 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogues.



   The radical R2A can also represent an etherified hydroxyl group which, together with the -C (= O) group, forms a hydrolytic, e.g. under weakly basic or acidic conditions, 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. 4-nitrophenyloxy or 2,4 dinitrophenyloxy, nitrophenyl lower alkoxy, e.g. 4-nitrobenzyloxy, hydroxy-lower alkyl-benzyloxy, 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 R A2 can also represent an etherified hydroxyl group which, together with the carbonyl group of the formula C (= 0) - forms an esterified carboxyl group which can be cleaved under hydrogenolytic conditions, and is e.g. B.



  optionally, e.g. B. by lower alkoxy or nitro, substituted xx-phenyl-lower alkoxy, such as benzyloxy, 4-methoxybenzyloxy or 4-nitrobenzyloxy.



   The group R 2 can also be an etherified hydroxyl group which, together with the carbonyl group -C (= 0) - forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily an acyloxymethoxy group, in which acyl z. B. denotes the residue of an organic carboxylic acid, primarily an optionally substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the residue of a lactone. Hydroxy groups so etherified are lower alkanoyloxy methoxy, e.g. Acetyloxymethyloxy or pivaloyloxymethoxy, amino-lower alkanoyloxymethoxy, in particular α-amino-lower alkanoyloxymethoxy, e.g. B. Glycyl oxymethoxy, L-Valyloxymethoxy L-Leucykoxymethoxy, also phthalidyloxy.

  A.
A silyloxy or stannyloxy group R 2 contains, as substituents, preferably 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. Chlorine atoms, and is primarily tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy, halo-lower alkoxy-lower alkylsilyl, e.g. Chloro-methoxy-methyl-silyl, or tri-lower alkylstannyloxy, e.g. Tn-n-butylstannyloxy.



   An acyloxy radical R2A which together with a -C (= O) group forms a, preferably hydrolytically, cleavable mixed anhydride group contains e.g. the acyl radical of one of the above organic carboxylic acids or carbon acid half derivatives, and is, for. B. optionally, such as by halogen, e.g. 13. Fluorine or chlorine, preferably in the c'-position, substituted lower alkanoyloxy, e.g. B. acetyloxy, pivalyloxy or trichloroacetyloxy, or lower alkoxycarbonyloxy, e.g. B.



  Methoxycarbonyloxy or ethoxycarbonyloxy.



   A radical R2 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, z. B. pyrrolidino or piperidino, Oxaniederalkylenamino, z. Morpholino, hydroxyamino, hydrazino, 2-lower alkyl hydrazino or 2,2-di-lower alkyl hydrazino, e.g. 2 methylhydrazino or 2,2-dimethylhydrazino.



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



   The 2-0xa- 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 -1-ethyl, 1-methylthio1-ethyl or 1-ethylthio-1-ethyl, or a 2-0xa- or 2-thia-lower alkylene 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 cleavable 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, e.g. Lower alkoxy groups, or halogen, e.g. 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-nbutylstannyl.



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



   In a compound of the formula II, a leaving group Y is, for example, a group -S-R4, a group -S02-R5 bonded to the thio group -5- by the sulfur atom, or a group -S802-R5.



   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 which thio group 8- 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 of such groups R4 are 1-methyl-imidazol-2-yl, 1,3-thiazol-2-yl, 1,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl , 1,3-0xazol-2-yl, 1,3,4-oxadiazol-2-yl, 1,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1-methylbenzimidazol-2-yl, benzoxazole -2-yl and especially benzthiazol-2-yl.



  Further groups R4 are 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. Acetyl or propionyl, lower thioalkanoyl e.g. Thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g. Cyclohexanecarbonyl, cycloalkanethiocarbonyl, e.g. 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 corresponding substituted, for example by lower alkyl, such as methyl, halogen,

   such as fluorine or chlorine, lower alkoxy such as methoxy, aryl such as phenyl, aryloxy such as phenyloxy 'mono- or poly-substituted acyl or thioacyl groups.



   In the groups -SO2-Rs and -S-SO2-Rs, Rs is an optionally substituted, 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, H logs, such as fluorine, chlorine or bromine, aryl, such as phenyl, aryloxy, such as phenyloxy, mono- or polysubstituted alkyl, especially 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 poly-substituted naphthyl or especially phenyl groups , for example phenyl, o-, m- or preferably p-tolyl, o-, m- or preferably p-methoxyphenyl, o-, moderate p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl, p-nitrophenyl or 1- or 2 -Naphthyl.

  A.
In a compound of the formula II, R is preferably 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 RA in a manner known per se, for example may be protected as stated above. A group R is e.g. B. in particular special an optionally halogen-substituted Niederalk oxygruppe, such as methoxy, a-polybranched lower alkoxy, z. B.



   tert-butyloxy, or 2-halo-lower alkoxy, in which halogen is e.g. Represents chlorine, bromine or iodine, primarily 2,2,2-tri chloroethoxy, 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 where appropriate, e.g. B. as indicated, substituted benzyloxy or
Diphenylmethoxy, e.g. Benzyloxy, 4-methoxybenzyloxy, 4
Nitrobenzyloxy, diphenylmethoxy or 4,4'-dimethoxydiphenylmethoxy, also an organic silyloxy or stannyl oxy group, such as tri-lower alkylsilyloxy, e.g. Trimethylsilyloxy or halogen, e.g. Chlorine.

  In a starting material of the formula II, the radical Ra preferably denotes an A amino protective group lt1 A, such as an acyl group Ac, in which any free functional groups present, e.g. 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 z. B. by the above-mentioned ether or ester groups, including silyl or stannyl groups, can be protected, and Rb hydrogen.



   In a compound of the formula II, R3 preferably denotes lower alkyl, in particular methyl, or, as a hydroxyl protective group, preferably a substituted silyl group, in particular the trimethylsilyl group.



   The inventive method is characterized in that one in a compound of the formula
EMI8.1
 wherein R1a, R1b, R2A and Y have the abovementioned meaning, converts the enol group into a group -OR3 by etherification, and converts a compound obtained with a salt-forming group into a salt or a salt obtained into the free compound or into another salt.



   For the preparation of lower alkylenol ethers of the formula II, the etherifying reagent used is preferably a diazo lower alkane R3-N2, e.g. B. diazomethane, diazoethane or diazo-n-butane. 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, z. 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. brought nitrogen atmosphere to use.



   Furthermore, 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 lower alkanol of the formula R3-OH. Suitable esters are primarily those with strong inorganic or organic acids such as mineral acids, e.g. Hydrogen halide acids, such as hydrochloric, hydrobromic or hydroiodic acid, also sulfuric acid or halosulfuric acids, e.g. Fluorosulfuric acid, or strong organic sulfonic acids, such as optionally, e.g. by halogen, such as fluorine, substituted lower alkanesulfonic acids, or aromatic sulfonic acids, such as.

  E.g. optionally, e.g. benzenesulfonic acids substituted by lower alkyl such as methyl, halogen such as bromine and / or nitro, e.g. Methanesulfonic, trifluoromethanesulfonic or p-toluenesulfonic acid.



  These reagents, especially di-lower alkyl sulphates, such as dimethyl sulphate, and also lower alkyl fluorosulphates, e.g. Methyl fluorosulphate, or optionally halogen-substituted methanesulphonic acid lower alkyl esters, e.g. Methyl trifluoromethanesulfonate are usually prepared in the presence of a solvent such as an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a mixture is used.

  Suitable condensing agents, such as alkali metal carbonates or hydrogen carbonates, e.g. Sodium or potassium carbonate or hydrogen carbonate (usually together with a sulfate), or organic bases such as, usually sterically hindered, tri-lower alkylamines, e.g. N, N-diisopropyl-N-ethylamine (preferably together with lower alkyl halogen sulfates or optionally halogen-substituted methanesulfonic acid lower alkyl esters), with cooling, at room temperature or with heating, e.g. B. at temperatures of about -20 "C to about 50 C and, if necessary, in a closed vessel and / or in an inert gas, e.g.



   Nitrogen atmosphere is worked.



   Niederalkylenoläther of the formula II can also by
Treating an enol compound of the formula VI having two or three lower alkyl etherified hydroxy groups of the formula on the same carbon atom of aliphatic character
R3-O containing compound, i.e. H. with a corresponding acetal or orthoester, in the presence of an acidic agent. So you can e.g. 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.



  Methanol, or a di-lower alkyl or lower alkylene sulfoxide, e.g. B. dimethyl sulfoxide, or orthoformic acid tri-lower alkyl ester, z. B. triethyl orthoformate, in
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, z. B. ethanol, or an ether, e.g. As dioxane, use as an etherifying agent and thus arrive at compounds of the formula II in which R3 is lower alkyl, e.g. B. methyl or



  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 (R3) 3 O <Ae (so-called sea wine salts), as well as di-R3O-carbenium salts of the formula (R3o) 2 CHeAn, or di-R3-halonium salts of the formula (R3) 2 Hal &commat; As where Ae is the anion of an acid and Hals is a halonium, in particular bromonium ion and R3 signify 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 hexachloroantimonates.

  Such reagents are z. B. trimethyloxonium or triethyloxonium hexafluoroantimonate, hexachlorantimonate, hexafluorophosphate, or tetrafluoroborate, dimethoxycarbenium hexafluorophosphate or dimethylbromonium hexafluoroantimonate. These etherifying agents are preferably used in an inert solvent such as an ether or a halogenated hydrocarbon, e.g. 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-ethyl-amine, and with cooling, at room temperature or with gentle heating, for.

  B. at about -20 C to about 50 C, if necessary, in a closed vessel and / or in an inert gas e.g.



  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 or, B-unsaturated aliphatic or Cylcoaliphatic ethers or thioethers, such as l-lower alkoxy-lower alkenes, e.g. B. 1 methoxy-ethene or 1-methoxypropene, 1-lower alkylthio-lower alkenes, such as 1-methylthio-ethene or I-methylthio-propene, oxa- or thia-cycloniederalk-2-enes or -2,4-serve with 5-7 ring atoms , e.g. 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 made.

  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.



   The formula II includes silyl-. or stannyl ether, d. H.



  Compounds of the formula II in which R is a substituted silyl or stannyl group are obtained by any method suitable for the silylation or stannylation of enol groups, for example 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. 13. Dichloro-dimethyl-silane, methoxymethyl-dichloro-silane, trimethylsilyl chloride or dimethyl-tert-butyl-silyl chloride, such silyl halide compounds preferably in the presence of a base, for. 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 alkylsilyl) -amine (see e.g. British Patent No.



  1 073 530), e.g. with a hexaniederalkyldisilazane, such as hexamethyldisilazane, or with a silylated carboxamide, such as a bis-triiederalkylsilyl-acetamide, e.g. B. bis-trimethylsilyl-acetamide, or trifluorosilylacetamide, also with a suitable stannylating agent such as a bis (tri-lower alkyltin) oxide, e.g. 13. bis (tri-n-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g. 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. Dutch Auslegeschrift 67/11107).



   A compound of the formula IIa, in which R3 is lower alkyl or a hydroxyl group protective radical, and Y is an S-R4 radical, can be obtained by reaction with a heavy metal sulfine of the formula Mn + (- SO2Rs) n or thiosulfonate of the formula M + (S-SO2R5) n , analogous to the conversion of compounds of the formula IVa to IVb or IVc, can be converted into a compound of the formula IIb or IIc.



   In a compound of the formula II obtained, a group R1a, R1b, R2A or R3 can be converted into another group R1a, R 1, R2 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 IB is specified.



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

 

   The method shown in the reaction scheme, which also includes the preparation of the starting materials of the formula VI used according to the invention, is distinguished from previously known methods in that it is based on 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, the reactive groups of which can be protected in any known manner and easily released again after the reaction, runs out, and the intermediate products required according to the invention are prepared with high yields.



  Reaction scheme
EMI10.1
  
EMI11.1

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



   Intermediate products of the formula IVa are also known or can be prepared according to Dutch patent 7,208,671.



   Intermediate products of the formula IVb can be obtained from compounds of the formula III by reaction with a sulfinic acid of the formula HSO2-lt5. Compounds of the formula IVc can be obtained from compounds of the formula III by reaction with a thiosulfonic acid of the formula H4402-Rs. The reaction takes place in an inert solvent or solvent mixture, for example an optionally halogenated, such as chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as pentane, hexane, cyclohexane, benzene, toluene, methylene chloride, chloroform or chlorobenzene, an aliphatic, cycloaliphatic or aromatic alcohol, such as lower alkanol, e.g. B. methanol, ethanol, cyclohexanol or phenol, a polyhydroxy compound, e.g. B. a polyhydroxyalkane, such as dihydroxy lower alkane, e.g. B.

  Ethylene or propylene glycol, a lower ketone such as acetone or methyl ethyl ketone, an ethereal solvent such as diethyl ether, dioxane or tetrahydrofuran, a lower carboxylic acid amide such as dimethylformamide or dimethylacetamide, a lower dialkyl sulfoxide such as dimethyl sulfoxide and the like or mixtures thereof.



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



   Compounds of the formula IVb and IVc can also be obtained by mixing a compound of the formula IVa with a heavy metal sulfinate of the formula M "+ (- SO, -R,), or with a heavy metal thiosulfonate of the formula Mn + (- S-SO2-Rs) n converts, in which M is a heavy metal cation and n is the valency of this cation. Suitable heavy metal sulfinates or thiosulfonates are in particular those which have a greater solubility product in the reaction medium used than the heavy metal compounds of the formula Mn + (- S-R4 ) n. Suitable heavy metal cations Mn + are in particular those which form particularly sparingly soluble sulfides.

  These include, for example, the mono- 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 a sulfinic acid of the formula HSO2-Rs or a thiosulfonic acid of the formula H-S-SO2-Rs or a soluble salt thereof, e.g. B. an alkali metal, such as sodium salt, and a heavy metal salt whose solubility product is greater than that of the resulting heavy metal sulfinate or thiosulfonate, for example a heavy metal nitrate, acetate or sulfate, z. 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-SO2Rs) n can be carried out in an inert organic solvent, in water or in a solvent mixture consisting of water and a water-miscible solvent. Suitable inert organic solvents are, for example, aliphatic, cycloaliphatic or aromatic hydrocarbons such as pentane, hexane, cyclohexane, benzene, toluene, xylene, or aliphatic, cycloaliphatic or aromatic alcohols such as lower alkanols, e.g. Methanol, ethanol, cyclohexanol or phenol, polyhydroxy compounds such as polyhydroxyalkanes, e.g. B. dihydroxy lower alkanes such as ethylene or propylene glycol, carboxylic acid esters, eg. 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, in particular, in mixtures of water and one of the solvents mentioned, including in emulsions, the reaction usually proceeds 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 IV obtained, a group R1a, R1b or R2A can be converted into another group R1a, R1b or R2A, it being possible to use reactions analogous to those given for the conversion of these groups for compounds of the formula TA or IB.



   In stages 2 and 3 or 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 enolized 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 halo-lower alkane, such as methylene chloride or carbon tetrachloride, or a solvent mixture, including an aqueous mixture, and with cooling or gentle heating, for. B. at temperatures from about -90 C to about +40 C.



   An ozonide of the formula Va obtained as an intermediate can, if appropriate without isolation, by conversion with a heavy metal sulfinate of the formula Mn + (- SO-Rs) n or a thiosulfonate of the formula Mn + (- S-SO2-R5) n, analogously to the conversion of compounds of formula IVa to compounds of formula IVb or IVc, into a compound of formula Vb or



  Vc to be transferred.



   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 coal or chemical reducing agents such as reducing heavy metals including heavy metal alloys or amalgams, z. B.



  Zinc, in the presence of a hydrogen donor such as an acid, e.g. Acetic acid, or an alcohol, e.g. 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. 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 may contain 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, furthermore phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides, which optionally contain substituted aliphatic hydrocarbon radicals as substituents, e.g. hexane-lower alkyl phosphorous acid triamides. Hexamethyl-phos phorigsäuretriamid, 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.



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



   An enol compound of the formula IVa can be obtained by reacting with a heavy metal sulfinate of the formula Mn + (- SO2-Rs) n or thiosulfonate of the formula M0 + (S-SO2R5) n, analogously to the conversion of compounds of the formula IVa to compounds of the formula IVb or IVc, can be converted into a compound of the formula VIb or VIc.



   In a compound of the formula VI obtained, a group R1a, R1b or R2A can be converted into another group R1a, R1b or R2A, it being possible to use reactions analogous to those indicated for the conversion of these groups for compounds of the formula IA or IB .



   According to step 5, the compounds of the formula II obtainable according to the invention can be used for the preparation of 7ss-amino-3-cephem-3-ol-4-carboxylic acid compounds of the formula Ia, A in which R 1 represents hydrogen or an amino protective group according to R, and R1b for Is hydrogen or an acyl group Ac, or R l and R 1 together represent a divalent amino protective group, R2 stands for hydroxy or a Res R2A which forms a protected carboxyl group together with the carbonyl group -C (= O), and R3 stands for hydrogen, lower alkyl or represents a hydroxy protecting group, and 1 oxides of 3-cephem compounds of the formula IA, and the corresponding 2-cephem compounds of the formula IB, in which RT,

   R, 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 oc configuration.



   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, and ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic Bases for salt formation come into question, such as lower alkylamines, for. 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. 1-ethyl-piperidine, cycloalkylamines, e.g. Bicyclohexylamine, or benzylamines, e.g. 13. N, N'-dibenzylethylenediamine, also bases of the pyridine type, e.g. Pyridine, collidine or quinoline, compounds of the formulas IA and IB which have a basic group can also be acid addition salts, e.g. with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g. B.



  Form trifluoroacetic acid or p-toluenesulfonic acid. Compounds of the formulas IA and IB with an acidic and an 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 formula IA or IB have valuable pharmacological properties or can be used as intermediates for the preparation of such.



  Compounds of formula IA wherein e.g. R1 for an acyl radical Ac occurring in pharmacologically active N-acyl derivatives of 6ss-aminopenam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and Rb R for hydrogen, or in which lt 1 and lt together are in the 2-position, e.g. B. by an aromatic or heterocyclic radical, and preferably in the 4-position, for. B.

 

  1-oxo-3-aza1,4-butylene radical substituted by 2 lower alkyl, such as methyl, R2 is 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 is lower alkyl, where in Any functional groups present in an acyl radical R1a, such as amino, carboxy, hydroxy and / or sulfo, are usually present in free form, or salts of such compounds with salt-forming groups, are against microorganisms such as gram-positive bacteria in the case of parenteral and / or oral administration , e.g. Staphylococcus aureus, Streptococcus pyogenes and Dinlococcus Dneumoniae, (e.g.

  B. in mice at doses from about 0.001 to about
0.02g / kg s.c. or o.o.), and gram-negative bacteria, e.g.



     Eschericbia coli. Salmonella thimurium, Shigella flexneri, Klebsiella pneumoniae, Enterobacter cloacae, Proteus vulgaris, Proteus rettoeri and Proteus mirahilis, (e.g. in mice in doses of about 0.001 to about 0.15 g / kg s. C: or p. O.) especially effective 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 1-oxides of compounds of the formula IA, in which R 1, Ro, R2 and It3 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 R1a and R1b stand for hydrogen, or Ra is an acyl radical different from an acyl radical occurring in pharmacologically active N acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and ltb denotes hydrogen, or lta and lt b together one, from one
1 1 in the 2-position preferably, for.

  By an aromatic or heterocyclic radical, and preferably in the 4-position, e.g.



   1-oxo-3-aza substituted by 2-lower alkyl, such as methyl
1,4-butylene radicals represent different divalent amino protective groups, and R2 stands for hydroxy, or R1a and R1b have the meanings given above, R2 for a radical, together with the -C (= O) group, represents a preferably easily cleavable, protected carboxyl group-forming radical lt 2 , wherein 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 that can be easily obtained, for example as described below, can be converted into the above-mentioned pharmacologically active compounds.



   The invention relates in particular to intermediates of the formula II, suitable for the production of 3-cephem compounds of the formula IA, in which R is hydrogen or, preferably, one which can be produced by fermentation (ie naturally occurring) or bio-, semi- or totally synthetically, in particular pharmacologically active , such as a highly active N-acyl derivative of a 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compound containing acyl radical, such as one of the above acyl radicals of the formula A, in which RI, RII, RIII and in the strictest sense have the preferred meanings, R1b stands for hydrogen, or in which R1a and b R, together preferably have one in the 2-position, for example by an aromatic or heterocyclic radical, such as phenyl, and preferably in the 4-position, e.g.

  B. by two lower alkyl, such as methyl, substituted 1-oxo-3-aza-1,4-butylene radical represent, R2 for hydroxy, for optionally, preferably in a
Position z. B. by optionally substituted aryloxy, such as
Lower alkoxyphenyloxy, e.g. 4-methoxyphenyloxy, lower alkanoyloxy, e.g. Acetyloxy or pivaloyloxy, α-amino lower alkanoyloxy, e.g. B. glycyloxy, L-valyloxy or L-leucyl oxy, arylcarbonyl, e.g. B. benzoyl, or optionally substituted aryl such as phenyl, lower alkoxyphenyl, z. B. 4-meth oxyphenyl, nitrophenyl, e.g. B. 4-nitrophenyl, or biphenylyl, e.g. 4-biphenylyl, or in the ss-position by halogen, e.g.



   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, bisphenyloxy-methoxy optionally substituted by lower alkoxy, e.g. 13. Bis-4-methoxyphenyloxy-methoxy, lower alkanoyloxy-methoxy, e.g. Acetyloxymethoxy or pivaloyloxymethoxy, z-amino lower alkanoyloxy methoxy, e.g. Glycyloxymethoxy, phenacyloxy, optionally substituted phenyl-lower alkoxy, in particular 1-phenyl-lower alkoxy, such as phenylmethoxy, such radicals 1-3 optionally, e.g. Phenyl radicals substituted by lower alkoxy such as methoxy, nitro or phenyl, e.g.



  Benzyloxy, 4-methoxy-benzyloxy, 2-biphenylyl-2-propyloxy, 4-nitro-benzyloxy, diphenylmethoxy, 4,4'-dimethoxy-diphenylmethoxy or trityloxy, or 2-halo-lower alkoxy, e.g.



  2,2,2-trichloroethoxy, 2-chloroethoxy, 2-bromoethoxy or 2-iodoethoxy, also for 2-phthalidyloxy, as well as for acyloxy, such as lower alkoxycarbonyloxy, e.g. Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g. B. acetyloxy or pivaloyloxy, for tri-lower alkylsilyloxy, e.g. B. trimethylsilyloxy, or for optionally, e.g. Amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g. Amino, lower alkyl or di-lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g. 2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R3 is hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, e.g. B.

  Trimethylsilyl, and the 1-oxides thereof, furthermore the corresponding 2-cephem compounds of the formula IB, or salts of such compounds with salt-forming groups.



   In an intermediate of the formula II, or in a 3-cephem compound of the formula IA, as well as in a corresponding 2-cephem compound of the formula IB, and also in a 1-oxide, a 3-cephem compound is primarily Formula TA, or in a salt of such a compound with salt-forming groups R1a for hydrogen or in a fermentative (ie

   naturally occurring) or biosynthetically producible N-acyl derivatives of 6ss-amino-penam- 3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds containing acyl radical, in particular of the formula A, wherein Rl, Ril, R "' and n primarily have the preferred meanings, such as an optionally substituted, for example by hydroxy, phenylacetyl or phenyloxyacetyl radical, furthermore an optionally, e.g. by lower alkylthio or lower alkenylthio, and optionally substituted, such as acylated amino and / or functionally modified such as esterified carboxyl, substituted lower alkanoyl or lower alkenoyl radical, e.g.

  B. 4-hydroxyphenylacetyl, hexanoyl, octanoyl or n-butylthioacetyl, and in particular 5-amino-5-carboxy-valeryl, wherein the amino and / or the carboxyl groups are optionally protected and z. B. present as acylamino or esterified carboxyl, phenylacetyl or phenyloxyacetyl, or an acyl radical occurring in highly effective N-acyl derivatives of 6ss-amino-penam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds, in particular of the formula A, where Rr, RII, Rlll and n primarily have the preferred meanings, such as formyl, 2-haloethylcarbamoyl, for example 2-chloroethylcarbamoyl, cyanoacetyl, phenylacetyl, thienylacetyl, e.g. B. 2-thienylacetyl, or tetrazolylacetyl, e.g.

  B. 1 tetrazolylacetyl, but especially in the o: 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 substituted acetyl, in particular phenylglycyl, wherein phenyl optionally, z. 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 optionally also can be substituted and z.

  B. is an optionally present in salt form sulfoamino group 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, z. B. ureidocarbonyl or N'-trichloromethylureidocarbonyl, or an optionally substituted guanidinocarbonyl group, e.g. B.

  Guanidinocarbonyl, or a, preferably light, e.g. 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. optionally halogen or
Benzoyl-substituted lower alkyloxycarbonyl radicals, e.g.

  B. tert. Butyloxycarbonyl, 2,2,2-Trichloräthyloxycarbonyl, 2-Chloräth- oxycarbonyl, 2-Bromäthoxycarbonyl, 2-Jodäthoxycarbonyl, or phenacyloxycarbonyl, optionally lower alkoxy or nitro-substituted phenyl-lower alkoxycarbonyl, z. 13. 4-Methoxybenzyloxycarbonyl or diphenylmethoxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methyl carbamoyl, also an arylthio or aryl-lower alkylthio radical which can be cleaved off with a nucleophilic reagent, such as hydrocyanic acid, sulfuric acid or thioacetic acid amide, e.g.



   2-nitrophenylthio or tritylthio, one by means of electrolytic
Reduction of cleavable arylsulfonyl radical, e.g. B. 4-methyl phenylsulfonyl, or one with an acidic agent such as formic acid or aqueous mineral acid, e.g. B. hydrogen chloride or phosphoric acid, cleavable 1-lower alkoxy carbonyl or l-lower alkanoyl-l-propylidene radical, z. B. 1
Ethoxycarbonyl-2-propylidene, also contains xx- (1,4-cyclohexadienyl) -glycyl, a-thienylglycyl, such as or-2- or <x-3-thienylglycyl, a-furylglycyl, such as a-2-furylglycyl, a-isothiazolylglycyl, such as a-4-isothiazolyl-glycyl, with the
Amino group, e.g.

  B. as indicated for a phenylglycyl radical, substituted or protected, also a-carboxy-phenyl-acetyl or a-carboxy-thienylacetyl, z. B. a-Carboxy-2-thienyl acetyl (optionally with a functionally modified one, e.g. in
Salt, such as sodium salt form, or in ester, such as lower alkyl, e.g. B. methyl or ethyl, or phenyl lower alkyl, z. B. Diphenylmethylesterform, present carboxyl group), o-sulfo-phenylacetyl (optionally with, z.

  B. like the carboxyl group, functionally modified sulfo group), <z-Phos- phono, a-0-methylphosphono- or ar-0,0¯-dimethylphos- phono-phenylacetyl, or a-hydroxyphenylacetyl (optionally with a functionally modified hydroxyl group, in particular with an acyloxy group, in which acyl is one, preferably light , e.g.  B.  when treating with an acidic agent, such as trifluoresetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical that can be split off or converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half-ester, such as one of the abovementioned, e.g. 

  B.  lower alkoxycarbonyl radical optionally substituted by halogen or benzoyl, e.g. B.  2,2,2-trichlorethoxycarbonyl, 2-chloroethoxycarbonyl, 2-bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl or phenacyloxycarbonyl, also means formyl), and 1-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 R1b for hydrogen, or R1a and R1b together for one, preferably in the 2-position, optionally protected by 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 1-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 os-polybranched lower alkoxy, z. B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z.  B. 



  2,2,2-trichloroethoxy, 2-iodoethoxy or the easily convertible into this 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-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.  Acetyloxymethoxy or pivaloyloxymethoxy, α-amino lower alkanoyloxymethoxy, 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, and R3 represents hydrogen, lower alkyl, especially methyl, or a hydroxy protecting group, such as tri-lower alkylsilyl, e.g. 

  B. 



  Trimethylsilyl. 



   The invention relates primarily to intermediates of the formula II, suitable for the preparation of 3-cephem compounds of the formula IA, in which R1 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-4hydroxyphenyl- 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.     1-tetrazolyl, or 1,4 cyclohexadienyl, X represents oxygen or sulfur, m represents 0 or 1, and Rb represents hydrogen or, if represents, 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-Bromoäthoxycarbonylamino,

   or optionally lower alkoxy or nitro substituted phenyl-lower alkoxycarbonylamino, e.g.  B.  4-methoxybenzyloxycarbonylamino or diphenylmethoxycarbonylamino, or 3-guanylureido, also sulfoamino or tritylamino, and arylthioamino, e.g. B. 



  2-nitrophenylthioamino, arylsulfonylamino, e.g.  B.  4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl-2-propylideneamino, e.g. B.  l-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 sodium salt form present sulfo, as well as protected sulfo, hydroxy, and protected hydroxy, such as acyloxy, z.  B. 



      -Polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-Halogenniederalkoxycarbonyloxy, such as 2,2,2-Trichloräthoxycarbonyloxy, 2-Jodäthoxycarbonyloxy or 2-Bromäthoxycarbonyloxy, also formyloxy, or 0 Niederalkylphosphono or 0,0'-Diiederalkylphosphono, z.  B. 



  0-methylphosphono or 0,0'-dimethylphosphono, or a 5-amino-5-carboxyvaleryl radical, in which the amino and / or carboxy groups can also be protected and 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-Cyclohexadienyl, R is hydrogen, R2 primarily for hydroxy, also for lower alkoxy, in particular a-polybranched lower alkoxy, e.g. B.     tert. -Butyloxy, 2-halo-lower alkoxy, e.g. B.     2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy,

   or optionally, e.g. B.     by lower alkoxy, e.g.  B.  Methoxy, substituted diphenylmethoxy, e.g. B.     Diphenylmethoxy or 4,4'-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 1-oxides of those for cephem compounds of the formula TA, furthermore the corresponding 2-cephem compounds of the formula IB, or salts, in particular the pharmaceutically acceptable, 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 formula II 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 in the salts R1 for mentioned in the previous section Hydrogen, for the acyl radical of the formula B, in which Ra 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, 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 oder2-Brom äthoxycarbonylamino, or optionally lower alkoxy- or nitro-substituted phenyl-lower alkoxycarbonylamino, z. B.     4 methoxybenzyloxycarbonylamino, or hydroxy, as well as protected hydroxy such as acyloxy, e.g. 

  B.  a-polybranched lower alkoxycarbonyloxy, such as tert. -Butyloxycarbonyloxy, or 2-halo-lower alkoxycarbonyloxy, such as 2,2,2-trichloroethoxycarbonyloxy, 2-iodoethoxycarbonyloxy or 2-bromoethoxycarbonyloxy, furthermore formyloxy, or for a 5-amino- 5-carboxy-valeryl radical, in which the carboxy and zino can also be protected.  B.  as acylamino, e.g.  B. 

  Lower alkanoylamino, such as acetylamino, halo-lower alkanoylamino, such as dichloroacetylamino, benzoylamino, or pththaloylamino, or  as an esterified carboxy, such as phenyl lower alkali. - oxycarbonyl, e.g. B.     Diphenylmethoxycarbonyl, where m preferably denotes 1 when Ra is phenyl or hydroxyphenyl, R b denotes hydrogen, R2 primarily denotes
Hydroxy, also optionally in the 2-position halogen, z.  B. 



   Chlorine, bromine or iodine-substituted lower alkoxy, in particular a-polybranched lower alkoxy, e.g.  13.     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'-dimethoxy-diphenylmethoxy, or p-nitrobenzyloxy, also tri-lower alkylsilyloxy, e.g. B.  Trimethylsilyl oxy and R3 is hydrogen, lower alkyl, especially methyl, tri-lower alkylsilyl, e.g. B.  Trimethylsilyl.    



   The invention relates primarily to intermediates
Formula II, suitable for the preparation of 7, B- (D- Ra-acetyl-amino) -3-lower alkoxy-3-cephem-4-carboxylic acids, where Ra is phenyl, 4-hydroxyphenyl, 2-thienyl or 1,4 -Cyclohexa dienyl, and lower alkoxy contains up to 4 carbon atoms and z. B.     Ethoxy or n-butyloxy, but primarily methoxy, and the inner salts thereof, and especially the 3-methoxy-7ss- (D-ac-phenyl-gylcylamino) -3-cephem-4carboxylic acid and the inner salt thereof, In the above-mentioned concentrations, especially when administered orally, these compounds have excellent antibiotic properties, both against gram-positive and especially against gram-negative bacteria, with low toxicity. 



   According to step 5 of the above reaction scheme, compounds of the formula IA and salts of such compounds with salt-forming groups are prepared by adding a compound of the formula II prepared according to the invention, in which R1a, R1b and R2A have the meanings given under formula IA, R3 for lower alkyl or a Hydroxy protective group, and Y is a leaving group, treated with a base, and, if desired, in a compound of formula IA or IB obtained, the protected carboxyl group of formula -C (= O) -RA is converted into the free or into another protected carboxyl group , and / or, if desired,

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



   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-diazabicyclo [5. 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, in particular lithium, sodium or potassium, for example sodium hydride, lithium di-lower alkyl amides, such as lithium diisopropylamide, potassium lower alkanolates, such as potassium tert. -butylate.  Compounds of formula II in which
A R 2 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 dimethyloxyethane, 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 50 ", 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.     by adsorption and fractionated
Elution, incl.  Chromatography (column, paper or plate chromatography) using suitable adsorbents, such as silica gel or aluminum oxide, and eluents, also through 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 lt3 can easily be split off and through
Hydrogen to be replaced.    A 2-oxa- or 2-thia-aliphatic 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 an acid like
Acetic acid, are split off.  The splitting off of a hydroxyl protecting group R3 can optionally be carried out selectively
A men will be, d.  H.  without a carboxyl protecting group R2 being split off at the same time. 



     Enol ether, d.  H.  Compounds of the formula TA and / or IB, in which R3 stands for 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 desired, 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 R3, 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 e.g.  13.  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, temporarily protected 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 Rt or  R b z.  B. 



  in the form of acylamino, such as those mentioned above, e.g.  B.  2,2,2, -Trichloräthoxycarbonylamino-, 2-Bromoäthoxycarbonylamino-, 4 Methoxybenzyloxycarbonylamino-, Diphenylmethoxycarbonylamino- or tert. -Butyloxycarbonylamino-, of aryl- or aryl-lower alkylthioamino-, e.g.    13.     2-nitrophenylthioamino, or arylsulfonylamino, e.g. B.     4-methylphenylsulfonylamino, or 1-lower alkoxycarbonyl-2-propylideneamino groups, or 



  of acyloxy, such as those mentioned above, e.g.  B.  tert. -Butyloxycarbonyloxy, 2,2,2-Trichloräthoxycarbonyloxy- or 2-Bromoäthoxycarbonyloxygruppen, 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.    0,0'-di-lower alkylphosphono-, e.g.  B.  0,0'-dimethyl-phosphono groups, protect and subsequently, optionally after conversion of the protective group, e.g.  B.  a 2-bromoethoxycarbonyl in 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-Jodäthoxycarbonylaminogruppe 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 sulphurous acid, an arylsulfonylamino group by means of electrolytic reduction, a 1-lower alkoxycarbonyl-2propylidene amino group by treatment with aqueous mineral salts.  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  a 0,0'-disubstituted phosphono group by treatment with an alkali metal halide, if desired, e.g.  13.     partially, split. 



   In a compound obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= O) RA2, this can be carried out in a manner known per se, e.g. B.     depending on the type of group according to 2A, 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.     under 290 if the arylmethyl group z.  

  B.  one optionally in the 3, 4 and / or 5 position, e.g. B.     is benzyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g.  B.  over 290 m> if the arylmethyl group z.  B.  a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert. -Butyl or diphenylmethyl, esterified carboxyl group e.g. B. 

   by treatment with a suitable acidic agent such as formic acid or 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 water in the presence of a noble metal, e.g.  B.  Palladium catalyst, are cleaved. 



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



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



   In a compound obtained, e.g. B.     an amino protecting group R A or  Rb in particular is an easily cleavable acyl group, in a manner known per se, eg. B.     an α-polybranched lower alkoxycarbonyl group, such as tert. -Butyloxycarbonyl, by treatment with trifluoroacetic acid and a 2 halo-lower alkoxycarbonyl group, such as 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl, or a phenacyloxycarbonyl group by treatment with a suitable reducing metal or corresponding metal compound, e.g. B.    



  Zinc, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating agent nascent together with the metal or metal compound, preferably in the presence of acetic acid containing water. 



   Furthermore, in a compound of the formula IA or IB obtained in which a carboxyl group of the formula (= O) -R2 is preferably one, e.g. B.     by esterification, including by silylation, e.g.  B.  by reacting 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 lt or lt, in which any free functional groups that may be present are optionally protected, by treatment with an imide halide-forming agent, reacting the resulting imide halide with an alcohol and cleaving the formed
Imino ethers, are split off, 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 inorganic acid halides
Acids, especially phosphorus acids, such as phosphorus oxy-, phosphorus tri- and especially Phosphorpentahalogeni de, z. B.     Phosphorus oxychloride, phosphorus trichloride, and primarily
Line phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, especially chloride, 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-, triithyl- or N, N-diisopropyl-N-ethyl-amine, also a 9, N, N ', N'-tetraniederalkyl- lower alkylenediamine, z.  B. 



     9, N, N ', N'-tetramethyl-1,5-pentylenediamine or 9, N, N', N'-tetramethyl-1,6-hexylenediamine, a mono- or vicyclic mono- or diamine, such as an N. -substituted,. B.     N-lower alkylated, alkylene, azaalkylene or oxa ilkylenamins, e.g.  B. 

  N-methylpiperidine the N-methylmorpholine, werner 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (Dia rabicyclononen; DBN), or a tertiary aromatic amine such as a di-lower alkyl aniline, z. B.     N, N-dimethyl miline, or primarily a tertiary heterocyclic, nono- 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.  You can use approximately equimolar amounts of the imide halide-forming agent and the base; but the latter can also be in but or deficit, z.  B.  in about 0.2 to about 1-fold amount or then in about to 10-fold, in particular about 3 to 5-fold excess. 



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



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



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



  Usually one uses, e.g.  B.  up to about 100 times, excess of the alcohol and preferably works with cooling, e.g. B.  Temperatures from about -50 "C to about 10 C. 



   The imino ether product can advantageously be subjected to cleavage without isolation.  The cleavage of the imino ether can be achieved by treatment with a suitable hydroxy compound, 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 for cleaving an acyl group described above is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert towards the reactants, such as an optionally halogenated hydrocarbon, e.g. B. 



  Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere.   



   If one uses the one obtainable by the above procedure
Imide halide intermediate instead of with an alcohol with a salt, such as an alkali metal salt of a carboxylic acid, in particular a sterically hindered carboxylic acid, a compound of the formula IA or IB is obtained, in which both
Rests R1 and lt 1 represent acyl groups. 



   In a compound of formula IA or IB in which both
R 1 and R b radicals represent acyl groups, one of these
Groups, preferably the less sterically hindered, e.g.  B. 



   by hydrolysis or aminolysis, can be selectively removed. 



   In a combination of the formula IA or IB.  where RA and and Rs 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 R of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5th
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, especially by a
Acyl radical of an organic carboxylic acid, such as halo-lower alkanoyl, such as dichloroacetyl, or phthaloyl, optionally protected, can also be obtained by treating with a nitrosating agent, such as nitrosyl chloride, with a carbocyclic arene diazonium salt, such as benzene diazonium chloride, or with a positive halogen-donating agent, such as an N
Halo-amide or -imide, e.g.    13.     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
A.
R, the amino group substituted and the carboxy group z.  B. 



  is protected by esterification, and Rt is preferably an acyl radical, but can also mean hydrogen, by leaving to stand in an inert solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g.  B.
Methylene chloride and, if necessary, working up the free or monoacylated amino compound by methods known per se, are split off. 



   A.
A formyl group R 1 can also be obtained by treatment with an acidic agent, e.g.  B.  p. Toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g.  B.  diluted
Ammonia, or a decarbonylating agent, e.g.  B.  Tris (triphenylphosphine) rhodium chloride, are split off. 



   A triarylmethyl, such as the trityl group RX, can e.g.    13.    



  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 R 1 and b Rt 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-, 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-5phenylisoxazolinium 3'- sulfonate and N-tert. -Butyl-S-methyl isocazolinium perchlorate, or a suitable acylamino 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.    13.     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. 13.     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-0-carboxy anhydride or the anhydride of 1-N-carboxamino-cyclohexanecarboxylic acid, use. 



   Other 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 ester, or
Diacylimino esters, such as succinylimino or phthalylimino esters. 



   Further acylation derivatives are e.g. B.  substituted form imino 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 one
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 of
Compounds of the formulas IA or IB start, in which R3
Is lower alkyl and R2 has the above meaning, where connec tions with free carboxyl groups of the formula -C (= O) -R2, where R2 is hydroxy, also in the form of salts, eg.  B. 



   Ammonium salts, such as with triethylamine, or in the form of a
Compound with one by reacting with a suitable organic phosphorus halide compound, such as with one
Lower alkyl or lower alkoxy phosphorus dihalide, such as methyl phosphorus dichloride, ethyl phosphorus dibromide or methoxyphosphorus dichloride, protected carboxyl group can be used; in the acylation product obtained, the protected carboxyl group can be known per se
Way, e.g.  B.  as described above, incl.  by hydrolysis or
Alcoholysis, are released. 



   An acyl group can also be introduced by adding a compound of the formula IA or IB, where R t and R, together for a ylidene radical (which can also be added subsequently, e.g.  B.  by treating a compound wherein lt and lt b1
Represents hydrogen, with an aldehyde, such as an aliphati rule, aromatic or araliphatic aldehyde can introduce) is, for. B.     acylated by the methods given above, and the acylation product, preferably in 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 halogen carbonyl, z. B.  Chlorocarbonyl group, and a so obtainable N- (halo-lower alkanoyl) or    N- (Ilalogen carbonyl) - amino compound with suitable exchange reagents, such as basic compounds, eg. 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 succeeded. 



   In both reactants can free functional
Groups temporarily protected during the acylation reaction in a manner known per se and after the acylation by means of methods known per se, eg. 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 thus obtainable, usually the less sterically hindered acyl group. 



   Furthermore, you can z. B.  a compound of the formula IA or IB, in which lt 1 is a glycyl group, preferably substituted in the a-position, such as phenylglycyl, and R b is hydrogen, with an aldehyde, e.g.  B.  Formaldehyde, or a ketone such as lower alkanone, e.g.       13.     Acetone, react and so get to Verbin @@@ @@@ b compounds of the formula TA or IB, where Rt and R, together with the nitrogen atom, a, preferably substituted in the 4-position, optionally substituted in the 2-position 5-oxo Represent 1,3-diaza-cyclopentyl radical. 



   In a compound of the formula IA or IB, in which R1 @ and lt 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 treating 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, such silyl halide compounds preferably in the presence of a base, for.    13.     Pyridine, used, with an optionally N-mono-lower alkylated, N, N-di-lower alkylated, N-tri-lower alkylsilylated or N-lower alkyl-N-tri-lower alkylsilylated N- (tri-lower alkylsilyl) -amine (see e.g.  B.  British patent no. 



  1 073 530), or with a silylated carboxamide, such as a bis-tri-lower alkylsilyl-acetamide, e.g.  B.  Bis-trimethylsilylacetamide, or trifluorosilylacetamide, furthermore with a suitable stannylating agent such as a bis (tri-lower alkyltin) oxide, e.g. B.     Bis (tri-n-butyl-tin) oxide, a tri-lower alkyltin hydroxide, e.g. B.     Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g.  B.  Tri-n-butyl tin chloride (see e.g.  B.  Dutch 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-hydroxysuccinimide) 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) -R1, 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 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, e.g. B.  by making compounds of the formulas
IA or IB, where R2 is hydroxy, or salts such as alkali metal, z.  B.  Sodium salt thereof treated with a suitable silylating or stannylating agent such as one of the aforementioned silylating or stannylating agents; see e.g.  B. 



   British patent no.  1 073 530 or  Dutch exposition no.  67/17107. 



   Furthermore, modified functional substituents in groups R1A, R1b and / or R2, such as substituted amino groups, acylated hydroxyl groups, esterified Carboxygrup pen or 0,0'-disubstituted phosphono groups, according to methods known per se, for. B.     the above-described, release, or free functional substituents in groups according to A, according to 1
1 1 and / or lot2, such as free amino, hydroxy, carboxy or Phos phonogruppen, according to known methods, for.  B.  Acylie ren 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 lt 1 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 a-ethyl caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of the 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, for.  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 these, or the process is terminated at any stage; furthermore, starting materials in the form of derivatives can be used or formed during the reaction. 



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



   In the intermediate products of the formula II which can be prepared according to the invention, the leaving group Y is preferably a group SO, -R ,, in which Rs has the meaning given, but in particular 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-toluenesulfonylthio) -3-phenoxy-acet-amido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-p nitrobenzyl ester and the corresponding isocrotonic acid ester in a ratio of approximately 4: 1 in 4 ml of dry tetrahydrofuran is a solution of 60> l (2 equivalents) 1,5-diazabicyclo [5. 4th 0] undec-5-ene in 1 ml of tetrahydrofuran was added dropwise.  After standing at room temperature for 40 minutes, the mixture is diluted with 20 ml of benzene, cooled in an ice bath and stirred for 10 minutes with 10 ml of a 10% citric acid solution above.  

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

  A semisolid isomer mixture is obtained consisting of the 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester and the 7ss-phenoxyacetamido-3-methoxy-ceph-2em-4-carboxylic acid p-nitrobenzyl 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 7ss-phenoxyacetamido-3-methoxy-ceph-2 em-4-carboxylic acid p-nitrobenzyl ester is recrystallized from methylene chloride / ether and has the melting point
129-131.5 "C.  The slower running 7ss-phenoxyacetamido.    



  3- methoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester has a melting point of 140.5-142 ° 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 7B-phenoxyacetamido-3-methoxy-ceph-3-em-4carboxylic acid p-nitrobenzyl ester in a ratio of about 3: 1 in 33 ml of tetrahydrofuran is added with stirring with 16 ml of a 0.1 N potassium hydroxide solution precooled to 0 C.  The mixture is stirred for a further 5 minutes at 0 C, then treated with 100 ml of ice water and 100 ml of precooled methylene chloride and 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 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid with a melting point of 142-145 C.    



   The starting materials can be obtained as follows: a) A solution of 36.6 g (0.1 M) 6-phenoxyacetamidopenicillanic acid lss-oxide, 11.1 ml (0.11 M) triethylamine and 23.8 g (0.1 M) 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-phenoxyacetamidopenicillanic acid pnitrobenzyl ester lss oxide melts at 179-180 C. 



   b) A solution of 5.01 g (10 mM) 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester lss-oxide and 1.67 g (10 mM) 2-mercaptobenzothiazoline 110 ml dry toluene is refluxed in a nitrogen atmosphere for 4 hours.  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-methylen-butyric acid p-nitrobenzyl ester with a melting point of 138 is obtained -141 "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-oxoazetidin-1-yl] -3-methylenebutyric acid 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 p.  The product can be used in the subsequent reaction without further purification. 



   The same compound can also be obtained by the following methods: cl) 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 / v), 1.58 g (1.2 equivalents) silver ptoluenesulfinate is added 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- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric 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 analogously to Example 1cI) from 3.25 g 2- [4 ( Benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin 1-yl] -3-methylenebutyric acid-p-nitrobenzyl ester and 1.87 g (2 equivalents) copper-II-di-p-toluenesulfinate can be obtained in quantitative yield. 



   Copper (II) di-p-toluenesulfinate is produced by reacting copper sulfate and sodium p-toluenesulfinate (2 eq. ) obtained in water.  After filtering off, the salt is dried in vacuo at 60 ° C. for 12 hours. 



     cIII) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2- oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared analogously to Example 1cI) from 130 mg 2- [4 (benzthiazole- 2-yldithio) -3-phenoxyacetamido-2-oxazeti din-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 85 mg (2 equivalents) tin-II-di-p-toluenesulfinate are obtained. 



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



   cIV) The 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester can also be prepared analogously to Example 1cI) from 130 mg 2- [4 (benzthiazole- 2-yldithio) -3-phenoxyacetamido-2 oxoazetidin1-yl] -3-methylenebutyric acid p-nitrobenzyl ester and 102 mg (2 equivalents) of mercury-II-di-p-toluenesulfinate. 

 

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



   cV) A solution of 517 mg (1.02 mM) 6-phenoxyacetamidopenicillanic acid p-nitrobenzyl ester lss-oxide and 187 mg (1.2 mM) p-toluenesulfinic acid in 10 ml 1,2-dimethoxyethane (or dioxane) is made 4.5 hours in the presence of 3.5 g of a molecular sieve 3A and heated under reflux in a nitrogen atmosphere, whereupon a further 308 mg (1.98 mM) of p-toluenesulfinic acid dissolved in 2 ml of 1,2-dimethoxyethane in five portions in 45 minutes Intervals are added.  After 4.5 hours, the reaction mixture is poured into 100 ml of the above aqueous sodium bicarbonate solution and extracted with ethyl acetate.  The combined organic phases are washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated. 

  The residue is chromatographed on silica gel thick-layer plates with toluene / ethyl acetate 2: 1 and gives the 2- [4- (p toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid p-nitrobenzyl ester. 



   d) In a solution of 1.92 g (3.0 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3methylene-butyric acid p-nitrobenzyl ester 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 -78 "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 dissolved in
100 ml of benzene added.  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-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-hydroxycrotonic acid p-nitrobenzyl ester with a melting point of 159-160 ° C. is obtained . 



     dl) The crude 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3methylenebutyric acid-p-nitrobenzyl ester obtained according to Example lc) is dissolved in 20 ml of methyl acetate and at -70 "C. Ozonated 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 0-5 ° C.  A solution of 300 mg of sodium bisulfite in 5 ml of water is added and the mixture is stirred for about 5 minutes until ozonide is no longer detectable with potassium iodide starch paper.  The mixture is diluted with ethyl acetate, the aqueous phase is separated, and the organic phase is washed with water, dried over magnesium sulfate and freed from the solvent in vacuo. 

  The crude product is dissolved in 3 ml of methylene chloride and 15 ml of toluene are added. 



  The precipitate is filtered off and the filtrate is evaporated in vacuo.  The residue is recrystallized from methanol and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid p-nitrobenzyl ester with a melting point of 159-160 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. cooled 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) - 3phenoxyacetamido-2-oxoazetidin-1-yl] - 3-methoxycrotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid ester in the ratio of about 4: 1.  Melting point of the mixture 155-156.5 C. 



   Example 2
A solution of 279 mg of 2- [4- (p-toluenesulfonylthio) - 3phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid rediphenylmethyl ester (0.428 mmol) in 4 ml of chloroform and 1 ml of hexamethyldisilazane is added for one hour heated to reflux, evaporated in vacuo and the oily residue dried in a high vacuum for one hour. 



  The silylated crude product consists of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -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-diazabicyclo [5. 4th 0] -undec-5-ene added.  After a reaction time of 1 hour, 0.3 ml of acetic acid is added and the solution is diluted with chloroform.  The chloroform solution is washed with dilute sulfuric acid, water and dilute sodium bicarbonate solution.  The aqueous phases are extracted with chloroform, the combined organic phases are dried over sodium sulfate and concentrated in vacuo.  The crude 7ss-phenoxyacetamido-3-hydroxy-ceph-3em-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 an excess of ethereal diazomethane solution is added 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 7ss-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-9.    



   The starting material is prepared as follows. 



   a) From 100 g (27.3 mM) 6-phenoxyacetamidopenicillanic acid 1ss oxide, 500 ml dioxane and 58.4 g (30 mM) diphenylmethyldiazomethane, after about 2 hours, 6-phenoxyacetamidopenicillanic acid diphenylmethyl ester 1ss oxide receive; Melting point 144-146 C (ethyl acetate / petroleum ether). 



   b) Analogously to Example lb), 292 g (55 mM) 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester 1ss-oxide and 99 g (59.5 mM) 2-mercaptobenzothiazole or 2- [4- (benzthiazol-2-yldithio) - 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester obtained; Melting point 140-141 "C (from toluene / ether). 



   c) Analogously to Example 1c), 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 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3 -methylene butyric acid diphenylmethyl ester obtained.  Rf value = 0.28 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (CHCl3): 1782, 1740, 1695, 1340, 1150 cm-1.    



   d) Analogously to Example ld), from 10.8 g (16.2 mmol) of 2- [4 (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester in 11-methylene chloride and 1.1 equivalents of ozone of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxozaetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester; Melting point 142-143 "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-oxoazetidin-1 -yl] -3methylenebutyric acid diphenylmethyl ester in 960 ml of methylene chloride is at 0 C within 15.2 mmol of ozone was introduced over a period of 19 minutes.  10 ml of dimethyl sulfide are added to the clear reaction solution and the mixture is stirred at 5 ° C. for 20 minutes.  After concentration in a water jet vacuum and drying the residue in a high vacuum, a light 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 134-138 "C. 

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



   The same connection can also be made according to the following
Methods are obtained: dI) A solution of 684 mg (1 mmol) 2- [4- (Benzthiazole
2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml acetone / water
9: 1 (v / v) becomes with 341 mg (1.3 mM) silver p-toluenesulfinate 60
Stirred minutes at room temperature.  The yellow reaction mixture is mixed with 50 ml of acetone and filtered.  The filtrate is evaporated in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 4: 1.  The obtained 2- [4- (p-toluenesulfonylthio)
3-phenoxyacetamido-2-oxoazetidin-1-yl] - 3-hydroxycrotonic acid diphenylmethyl ester is recrystallized from ether / pentane and melts at 142-143 C. 



   dII) A solution of 72.9 mg (0.1 mM) of the crude Ozo nids, obtained by ozonization of 68.1 mg (0.1 mM) 2- [4 (Benzthiazol-2-ylthio) -3-phenoxyacetamido- 2-oxoazetidin-1 yl] -3-methylenebutyric acid diphenylmethyl ester in ethyl acetate and evaporation of the solvent, in 2 ml of acetone / water
9: 1 (v / v) is stirred with 35 mg (1.3 equivalents) of silver p-toluenesulfinate for one hour at room temperature.  The reaction mixture is diluted with 3 ml of acetone and filtered.  The
0.2 ml of dimethyl sulfide are added to the filtrate and the mixture is stirred for two hours at room temperature (until the iodine-starch reaction is negative).  After removing the solvent in vacuo, the residue is chromatographed on 3 g of acid-washed silica gel with toluene / ethyl acetate 4: 1. 

  The 2 [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester is recrystallized from ether / pentane and melts at 142-143 "C.    



  After repeated recrystallization from methylene chloride / diethyl ether, a melting point of 144 145 ° C. (corrected) is obtained; [or120 = -68 "f 1" (c = 1; chloroform); Thin-
D layer chromatogram: Rf value = 0.81 (silica gel; methylene chloride / ethyl acetate 8: 2); UV spectrum (ethyl alcohol): man = 261 nm (e = 14,400); IR spectrum (Nujol): characteristic bands at 3 00 5 56 5 3.00; 5.56; 5.93; 5.98; 6.06; 6.19; 6.25; 6.54; 6.70; 6.82; 7.02; 7.47; 8.03; 8.76; 9.53; 10.23; 10.60; 12.30; 13.26; 14.30, it.    



   Example 3
A solution of 301 mg (0.462 mmol) of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid-diphenylmethyl ester in 3 ml of 1,2-dimethoxyethane is under a nitrogen atmosphere with 0, 12 ml of bistrimethylsilyl acetamide (0.508 mmol) were added and the mixture was 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 crude 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 a reaction time of 6 hours at 0 ° C. under a nitrogen atmosphere, 0.3 ml of acetic acid is added and the mixture is diluted with methylene chloride. 

  The methylene chloride solution is washed successively with dilute sulfuric acid, water and dilute 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 7ss-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 7ss-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 120 "C (from ether) IR spectrum (in CHCl3): 3310, 1775, 1710, 1690, 1600 cm¯l.    



   Example 4
A solution of 100 mg (0.15 mmol) of an isomer mixture consisting of the 2- [4- (p-toluenesulfonylthio) -3phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml 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 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 7ss-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 a ratio of 1 : 4 exists.    Rf value = 0.14 or  0.32 (silica gel, toluene / ethyl acetate 3: 1); IR spectrum (in CHCl3): 3400, 3310, 1785, 1770, 1750, 1710, 1690, 1630, 1600 cm-t.    



   a) The isomer mixture used as starting material can analogously to Example le) from 4 g (6.14 mM) 2- [4- (p-toluene sullonylthio) -3- phenoxyacetamido-2- oxo-azetidin-1-yl] -3- hydroxycrotonic acid diphenylmethyl ester and an excess of ethereal diazomethane solution can be obtained.  The isomer mixture obtained consisting of the 2- [4-toluenesulfonylthio) -3-phenoxyacetarnido-2- oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester (about 3: 1) crystallizes from ethyl acetate / pentane and has the Melting point 150-152 "C. 



   The isomer mixture used as starting material or  the crotonic and isocrotonic acid derivatives can also be obtained as follows: aI) A solution of 698 mg (1 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-ylthio) -3-phenoxyacetamido-2- oxoazetidine- 1-ylj-3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in 20 ml acetone / water 9: 1 (v / v) is mixed with 341 mg (1.3 mM) silver p-toluenesulfinate for 1 hour at room temperature touched.  The yellow reaction mixture is diluted with 50 ml of acetone and filtered.  The filtrate is evaporated in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. 

 

  An isomer mixture is obtained consisting of the 2- [4- (p-toluenesulfonylthio) -3- phenoxyacetamido-2- oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the 2 [4- (p-toluenesulfonylthio) -3 phenoxyacetamido- 2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester.    



   aII) The reaction described under aI) can also be carried out in tetrahydrofuran instead of acetone / water, it being necessary to stir for about 24 hours at room temperature.   



   aIII) A solution of 336 mg (0.5 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester in 4 ml of ethylene chloride 0.21 ml (1.2 mM) of ethyl diisopropylamine and 0.12 ml (1.5 mM) of fluorosulfonic acid methyl ester are added at 0 C and the mixture is stirred for 30 minutes at 0 C and a further 30 minutes at room temperature .  The reaction mixture is diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution and dilute aqueous sodium bicarbonate solution and dried over sodium sulfate. 

  The residue remaining after evaporation is chromatographed on silica gel.    Toluene / ethyl acetate 4: 1 initially elutes some starting material.     With toluene / ethyl acetate 1: 1, an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3- phenoxyacetamido-2- oxoazetidin-1-yl] -3-crotonic acid-diphenylmethyl ester and the corresponding isocrotonic acid- diphenyl methyl ester, isolated. 



   aIV) a solution of 300 mg (0.447 mM) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoaceti hydroxycrotonic acid diphenylmethyl ester in 4 ml acetone is mixed with 76 mg (0.55 mM) potassium carbonate and 0.088 ml (0.92 mM) dimethyl sulfate were added and the mixture was stirred at room temperature for 5 hours.  The solution is diluted with ethyl acetate, washed with water and dried over sodium sulfate.  After removing the solvent, the residue is recrystallized from ethyl acetate / pentane and yields an isomer mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. 



   aV) A solution of 6.73 g of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester (crystalline) in 67 ml of absolute tetrahydrofuran is at 20 C with 1.57 g of N, N'-dinitroso-N, N'-dimethyloxamide and then with a solution of 0.57 ml (0.51 g) of ethylenediamine in 5 ml of tetrahydrofuran within 15 minutes.  After the addition, the mixture is stirred for 1 hour at 0 ° C., 0.53 ml (11 mmol) of glacial acetic acid and 6.7 g of Celite are added and the mixture is filtered off.  The residue is washed 5 times with 20 ml of tetrahydrofuran each time.  Filtrate and washing liquids are combined, to approx.  Concentrated to 20 g and mixed with 20 ml of hexane.  The crystals are filtered off, washed with tetrahydrofuran / hexane 1: 2 and dried in a high vacuum. 



   The crystals consist mainly of the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester.  A sample is recrystallized from ethyl acetate / diethyl ether and gives the following analytical data: melting point 167-169 C; [α] D20 = -30 # 1 (c = 1; methylene chloride); Thin layer chromatogram:

  Rf value = 0.57 (silica gel; methylene chloride / ethyl acetate / glacial acetic acid 60/40: 1); UV spectrum (ethyl alcohol): γ max = 260 my (e = 16,600); IR spectrum (Nujol): characteristic bands at 2.97; 5.62; 5.90; 6.27; 6.61; 6.66; 7.17; 7.53; 7.70; 7.96; 8.02; 8.20; 8.80; 9.20; 10.26; 12.24; 13.30, u.     NMR spectrum (100 megahertz / in CDCl3): 8 2.32 (s / CH3); 2.34 (s / CH3); 3.73 (s / OCHe); 4.30 / 4.44 (AB; J = 5 / azetidine-4-CH -); 6.8-7.5 (m / 19 aromatic H, NH) ppm. 



   In addition to a little isocrotonic acid derivative, the mother liquor mainly contains 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester; which after chromatographic purification on silica gel has a melting point 146-148 (corr. , from ethyl acetate / hexane);

  NMR spectrum (100 megahertz / in CDCl3) / b 2.08 (s / vinyl-CH3); 2.26 (s / aromat.  -CH3); 3.70 (s / -OCH3); 4.47 (s / -OCH2CO -); 4.94 (dd / J = 5 and 8 / azetidine-3-CH -); 5.83 (d / J = 5 / azetidine-4-CH -), 6 , 8-7.5 (m / 19 aromatic H, -NH-) ppm; [α] 20 = +21 # 1; (c = 1;

  ;
Methylene chloride) D aVI) A suspension of 6.72 g (10 mmol) 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1- yl] -3-hydroxycrotonic acid diphenylmethyl ester (crystalline) and 0 , 36 g (1 mmol) of tetra-butylammonium iodide in 100 ml
Toluene with 3.78 g (30 mmol) of dimethyl sulfate and 30 ml
20 percent    aqueous potassium bicarbonate solution added, and 4
Vigorously stirred for hours at room temperature.  The solid substance goes into solution within the first 15 minutes
Mixture is diluted with toluene and saturated with aqueous
Washed sodium chloride solution. 

  After drying the organic phase with sodium sulfate and concentrating, it is obtained through
Crystallization from ethyl acetate / diethyl ether 2- [4- (p toluenesulfonylthio) -3- phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester. 



   aVII) A suspension of 3.36 g (5 mmol) 2- [4- (p-
Toluenesulfonylthio) -3- phenoxyacetamido-2- oxoazetidin-1- yl] -3-hydroxy-crotonic acid diphenylmethyl ester (crystalline) in, 15 ml of carbon tetrachloride and 10 ml of water is mixed with 1.08 g (3 mmol) of tetrabutylammonium iodide and 1.9 ml (2.52 g
20 mmol) of dimethyl sulfate are added.  For the mixture, which is vigorously stirred at room temperature, an automatic
Add enough 1N sodium hydroxide solution to the titrator so that the pH remains constant at 7.0.  Over the course of 4-5 hours will be
1.5-2 equivalents of sodium hydroxide solution consumed.  The mixture is diluted with ethyl acetate and water and mixed with a little common salt.  The organic phase is dried over sodium sulfate and evaporated. 

  The residue becomes from little
1: 1 ethyl acetate / hexane crystallizes and gives the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester. 



   The isomer mixture used as starting material can also be obtained via the corresponding 2-benzoxazole derivatives as follows: aVIII) A solution of 10 g of 6-phenoxyacetamido-penicillanic acid diphenylmethyl ester 1ss-oxide and 3 g of 2-mercapto benzoxazole in 25 ml of dry tetrahydrofuran is completely evaporated in vacuo.  The remaining foam is heated in a water jet vacuum to 120 ° C. (bath temperature) for 70 minutes.  The melt residue will appear after cooling
500 g of acid-washed silica gel with toluene / ethyl acetate 6: 1 and then 3: 1 chromatographed. 

  The 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -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. 



      aIX) In a solution, cooled to 70 ° C., of 3.35 g of 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine
1-yl] -3-methylene-butyric acid diphenylmethyl ester in 125 ml
About one equivalent of ozone (in the form of a 02/03 mixture) is introduced into ethyl acetate until no more starting material can be detected by thin-layer chromatography (silica gel; toluene / ethyl acetate 3/1).  The solution is evaporated to about 50 ml in vacuo, 5 ml of dimethyl sulfide are added and the mixture is stirred until no further reaction is obtained in the potassium iodide starch test.  The mixture is evaporated in vacuo, the
The residue was dissolved in 150 ml of benzene and washed with water. 

 

   The organic phase is dried over sodium sulfate and evaporated.  The residue is acid washed onto 150 g
Silica gel chromatographed with toluene / ethyl acetate 4: 1. The 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenyl methyl ester is obtained in the form of a white foam; IR spectrum (methylene chloride): characteristic bands at 5.60.5.90,
6.0. 



   aX) To a solution of 1.7 g of 2- [4- (benzoxazol-2-yl-diethio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 12.5 ml of methylene chloride is added dropwise to an ethereal diazomethane solution with stirring at 0 ° C. until no more starting material can be detected by thin layer chromatography (silica gel; toluene / ethyl acetate 3: 1).  The mixture is evaporated in vacuo and the residue is chromatographed on 80 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. 

  An isomer mixture is obtained consisting of the 2- [4- (benzoxazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of about 5: 1; IR spectrum (methylene chloride): characteristic bands at 5.60,5.85 sh, 5,90,6,40,6,65. 



   aXI) A solution of 682 mg (1 mM) of an isomer mixture consisting of 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding diphenylmethyl isocrotonate in 20 ml of acetone / water 9: 1 (v / v) is stirred with 350 mg (1.3 mM) of silver p-toluenesulfinate for 90 minutes at room temperature.  The mixture is filtered through Celite #, the filtrate concentrated in vacuo to 5 ml and extracted with 30 ml of methylene chloride.  The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. 

  The residue is chromatographed on 30 g of acid-washed silica gel with toluene-ethyl acetate 1: 1 and gives an isomer mixture consisting of 2 [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazcti-din-1-yl] -3-methoxy -crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. 



   Example S.
A solution of 300 mg (0.45 mmol) of the crystallized isomer mixture obtainable according to Example 4a) consisting of the 2- [4- (p-toluenesulfonylthio-3-phenoxacetamido-2oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid ester in 4 ml of dry 1,2-l) imethoxyethane 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%) 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 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester isoxide, which crystallizes from methylene chloride / pentane, melting point 115-120 ° 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 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester 1a: oxide, melting point 175-180 (from chloroform). 



   The 1-oxides obtained can be further processed as follows: a) a solution of 150 mg (0.275 mmol) of 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester-lss-oxide in 3 ml of methylene chloride and 0.1 ml of dimethylformamide are added, after cooling to 0 C, 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 resulting crude 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid nylmethylester is recrystallized from ether; Melting point 120 C. 



   b) A solution of 2.0 g (3.78 mmol) of 7ss-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 0 C cooled and after the addition of 1.2 ml of trifluoroacetic acid left to stand for 1 hour.  The reaction mixture is concentrated in vacuo and the residue is crystallized from acetone / ether.  The 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid with a melting point of 170 ° C. is obtained (decomp. ).    



   c) To a suspension of 2.55 g (7 mmol) of 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid and 2.9 ml (22.4 mmol) of N, N-dimethylaniline in 11 ml of absolute methylene chloride are added under nitrogen at 20 ° C. to 0.7 ml (5.7 mmol) of dimethyl dichlorosilane and then stirred for 30 minutes at the same temperature.     The resulting clear solution is cooled to 20 ° C., 1.6 g (7.7 mmol) of solid phosphorus pentachloride are added and the mixture is stirred for 30 minutes. 

  At the same temperature, a pre-cooled (-20 C) mixture of 0.9 ml (7 mmol) of N, N-dimethylaniline and 0.9 ml of n-butanol is added within 2 to 3 minutes, followed by quickly 10 ml of pre-cooled (20 C) ) added n-butanol and then stirred for 20 minutes at 20 C and 10 minutes without cooling.  At about 10 C, 0.4 ml of water is added, stirred for about 10 minutes in an ice bath (0 C), then 11 ml of dioxane are added and after a further 10 minutes of stirring at 0 C for approx. 4.5 ml of tri-n-butylamine are added in portions until the samples diluted with water have a constant pH value of 3.5. 

  After stirring at 0 C for 1 hour, the precipitate is filtered off, washed with dioxane and recrystallized from water / dioxane.  The 7ss-amino-3-methoxy-ceph3-em-4-carboxylic acid hydrochloride dioxanate obtained has a melting point of over 300 C.  Thin-layer chromatogram: Rf value 0.17 (silica gel; system n-butanol / carbon tetrachloride / methanol / formic acid / W 30: 40: 20: 5: 5). 



   d) A suspension of 1 g (2.82 mmol) of 7ss-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 is added.  After 40 minutes the clear solution is cooled to 0 ° C. and 900 mg (4.37 mmol) of solid D-α-phenylglycylic acid chloride hydrochloride are added.  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, 0.5 ml of methanol is then added, the 7ss-α-phenylglycylamino) -3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride in crystalline form fails.  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-α-phenylgylcylamino) -3-methoxy-ceph3-em-4carboxylic acid is filtered off, washed with acetone and diethyl ether and dried, melting point 174-176 (decomposition); [a] 20 = +132 (c = 0.714; in 0.1 N hydrochloric acid);
D 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) Arnax 2 = 269 cm (e = 7000); IR spectrum (in mineral oil):

   characteristic bands at 5.72, 5.94, 6.23 and 6.60.    



   Example 6
To a solution of 0.697 g (1.0 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3 phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding diphenylmethyl isocrotonate in 4 ml of dry tetrahydrofuran, the solution of 0.228 g (1.5 mM) of 1,5-diazabicyclo [5. 4th 0] -undec-5-ene given in 10 ml of tetrahydrofuran.  The mixture is stirred for 40 minutes at room temperature, diluted with 200 ml of benzene and washed successively with dilute hydrochloric acid, sodium bicarbonate solution and water.  The organic phase is dried over sodium sulfate and the solvent is removed in vacuo.  The crude product obtained is chromatographed on 30 g of acid-washed silica gel. 

  Toluene / ethyl acetate 7: 1 first elutes 2-mercaptobenzothiazole and then the 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester.  IR spectrum (in CH2Cl2): 5.60, 5.74, 5.90, 8.28.    



   The ester obtained can be converted into the free acid as follows: i) A mixture of 53 mg (0.1 mmol) of 7B-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester, 0.07 ml Trifluoroacetic acid, 0.06 ml of anisole and 0.5 ml of methylene chloride is stirred at 0 ° C. for 15 hours.  The mixture is diluted 3: 1 with 5 ml of pentane / diethyl ether and shaken vigorously.  The precipitating white, amorphous 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid is filtered off and washed with pentane / diethyl ether 3: 2.  IR spectrum (CH 2 Cl 2): 5.60, 5.90, 8.28.    



   The starting material can be obtained as follows: a) In the solution of 681 mg (1.0 mM) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidine- 1 -yl] -3-methylene-butyric acid diphenylmethyl ester in 30 ml of ethyl acetate is passed in 1 equivalent of ozone (diluted with oxygen).  The reaction solution is allowed to warm up, it is concentrated in vacuo to 10 ml, 1.0 ml of dimethyl sulfide is added and it is stirred for 15 hours at room temperature.  Solvent and excess reagent are removed in vacuo and the residue is chromatographed on 30 g of acid-washed silica gel with toluene / ethyl acetate 4: 1 (15 ml fractions).  The 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester is obtained as a solid amorphous substance. 



     [a] = 1300 + 1 "(CHCls; c = 0.8) IR spectrum (CH2Cl2): 2.95, 5.60, 5.92, 6.04, 8.10.    



   b) A solution of crude 2- [4- (benzthiazol-2-yl-dithio) 3-phenoxyacetamido-2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester, obtained by ozonization of 681 mg (1, 0 mM) 2- [4- (Benzthiazol-2-yldithio) -3-phen oxyacetamido-2-oxo-azetidin-1-yl] -3 methylene-butyric acid diphenylmethyl ester, in 5 ml of methylene chloride is distilled at 0 C with an ethereal Diazomethane solution (containing 1.3 mM diazomethane) was added.  The mixture is stirred for one hour at 0 C, washed with water and the organic layer is dried over sodium sulfate.  The solvents are removed in vacuo and the residue is chromatographed on 35 g of acid-washed silica gel with toluene / ethyl acetate 2: 1. 

  An isomer mixture is obtained consisting of the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. 



  IR spectrum (in CH 2 Cl 2): 5.60.5.88.6.67, 9.15, 9.92.    



   Example 7
Analogously to Example 4, from 200 mg (0.307 mM) of an isomer mixture consisting of 2 - [- 4 (p-toluenesulfonylthio) -3phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocro tonic acid-2,2,2-trichloroethyl ester and 0.09 ml (0.6 mM) 1,5 diazabicyclo [5. 4th 0] undec-5-en by stirring for 30 minutes at room temperature in 3 ml of 1,2-dimethoxyethane, the isomer mixture consisting of the 7B-phenoxyacetamido-3-methoxyceph-2-em-4-carboxylic acid 2,2,2-trichloroethyl ester and the 74-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid 2,2,2-trichloroethyl ester (in a ratio of about 1: 1). 



  Rf values = 0.36 or  0.18 (silica gel; toluene / ethyl acetate 3: 1).    



   The starting material can be obtained as follows: a) Analogously to Example 1b), 498 mg (1 mM) of 6-phenoxyacetamido-penicillanic acid 2,2,2-trichloroethyl ester and 200.7 mg (1.2 mM) of 2-mercaptobenzothiazole are obtained 2- [4- (Benz thiazol-2-yl-dithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid 2,2,2-trichloroethyl ester was obtained; Melting point 144-149 "C (from methylene chloride / pentane), Rf value = 0.5 (silica gel; ether). 



   b) Analogously to Example 6a), from 647 mg (1 mM) 2- [4 (benzthiazol-2-yldithio) -3-phenoxyacetamido-2- oxo-azeti din-1-yl] -3-methylenebutyric acid 2.2, 2-trichloroethyl ester and 1.2 equivalents of ozone and subsequent cleavage of the ozonide with dimethyl sulfide of 2- [4- (benzthiazol-2-yldithio) 3-phenoxyacetamido-2-oxoazetidin 1-yl] -3-hydroxycrotonic acid-2,2,2 -trichloroethyl ester produced; Melting point 129-130 C (ether / petroleum ether). 



   c) Analogously to Example 6b), from 5 g (7.71 mM) 2-4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] 3- hydroxycrotonic acid-2,2,2- trichloroethyl ester and an excess of diazomethane, the isomer mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester; Melting point 170-174 C (from methylene chloride / ether). 



   d) Analogously to Example 1c), 1.9 g (2.87 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 is obtained - Methoxycrotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2-trichloroethyl ester by stirring for five hours at room temperature with 0.8 g (4.05 mM) of silver ptoluenesulfinate in 35 ml of acetonitrile / ethyl acetate 3: 4 an isomer mixture consisting of the 2- [4- (p-toluenesulfonyl thio) -3 - phenoxyacetamido-2-oxoazetidine-1-yl -3 - methoxycrotonic acid 2,2,2-trichloroethyl ester and the corresponding isocrotonic acid 2,2,2 -trichloroethyl ester obtained; Melting point 155-158 C (from ethyl acetate / ether). 



   Example 8
A solution of 100 mg (0.146 mmol) 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] 3-hydroxycrotonic acid diphenylmethyl ester in 2 ml dry methylene chloride is at 0 C with 0 , 02 ml (0.16 mmol) of trimethylchlorosilane were added.  0.0477 ml (0.32 mmol) of 1.5 diazabicyclo [5] were added to this solution under nitrogen and with stirring. 4th 0] undec-5-ene and stirring is continued at 0 C for 1 hour.  After adding 0.2 ml of acetic acid, the mixture is diluted with methylene chloride.  The organic phase is washed successively with dilute sulfuric acid, water and aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated to dryness in vacuo. 

 

   The resulting crude 7B-phenoxyacetamido-3-hydroxyceph-3-em-4-carboxylic acid diphenylmethyl ester is dissolved in methanol and an ethereal diazomethane solution is added at 0.degree.  After 10 minutes, the solution is carefully concentrated and the residue is dried in a high vacuum.  The residue is purified by thick layer chromatography (toluene / ethyl acetate 3: 1, silica gel).  After eluting the silica gel of the zone at Rf = 0.17 with ethyl acetate and concentrating the solution on a rotary evaporator, the 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester is obtained; Melting point 1200 C (from ether). 



   Example 9
A solution of 367 mg (0.5 mM) of a mixture consisting of the 2- [4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester , and 152 mg (1.0 mM) 1,5-diazabicyclo [5. 4th 0] undec-5-ene in 10 ml of dry tetrahydrofuran is stirred for 40 minutes at room temperature.  The reaction mixture is diluted with benzene, washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution, dried over sodium sulfate and freed from the solvent in vacuo. 

  The residue is chromatographed on acid-washed silica gel with toluene / ethyl acetate 7: 1 as the eluent, pure diphenylmethyl 7B-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid being obtained.    By elution with toluene / ethyl acetate 2: 1, a mixture is then isolated which, in addition to the 7B-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester, also the 7ss-phenoxyacetamido-3-methoxy-ceph- Contains 3-em-4-carboxylic acid diphenylmethyl ester. 



   The starting materials can be prepared as follows: a) Analogously to Example 4aI) is obtained from 348.5 mg (0.5 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2ylthio) -3-phenoxyacetamido-2-oxoazetidine - 1-yl] - 3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 200 mg (0.68 mM) silver p-nitrobenzenesulfinate by stirring for one hour at 60 C in 10 ml acetone / water 9: 1 a mixture, consisting of the 2- [4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetamido2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester. 



   Silver p-nitrobenzenesulfinate is obtained by combining aqueous solutions of equimolar amounts of silver nitrate and sodium pnitrobenzenesulfinate.  The precipitate is filtered off and dried in vacuo at 50-60 ° C. for 24 hours. 



   Example 10
Analogously to Example 9, 351.5 mg (0.5 mM) of an isomer mixture consisting of the 2- [4- (p-methoxybenzene sulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester is obtained and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1 mM) 1,5-diazabicyclo [5. 4th 0] undec-5-en a mixture consisting of the 7B-phenoxyacetamido-3-methoxy-ceph-2em-4-carboxylic acid diphenylmethyl ester and the 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4- carboxylic acid diphenylmethyl ester, which can be separated into the two isomers by chromatography. 



   The starting materials can be obtained as follows: a) Analogously to Example 4aI), 697 mg (1 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2yl-thio) -3-phenoxyacetamido-2-oxoazetidine-1 -yl] - 3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 361 mg (1.3 mM) silver p-methoxybenzenesulfinate by one-time stirring at room temperature in 20 ml acetone / water 9: 1 a mixture consisting of the 2- [4- (p-methoxybenzenesulfonylthio) -3phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester.  IR spectrum (in CH2C12): characteristic bands at 5,60,5,88,6,18,8,76, u.    



   Silver p-methoxybenzenesulfinate is obtained by combining aqueous solutions of equimolar amounts of silver nitrate and sodium p-methoxybenzenesulfinate.  The precipitate is filtered off and dried in vacuo at 50-60 ° C. for 24 hours. 



     aI) Analogously to Example 2dI), 684 mg (1 mM) 2- [4 (benzthiazol-2-yl-thio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid, diphenylmethyl ester and 361 mg ( 1.3 mM) silver p-methoxybenzenesulfinate by stirring for one hour at room temperature in 20 ml of acetone / water 9: 1 of 2- [4- (p-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1yl] -3-hydroxy- crotonsäuru-diphenylmethyl ester obtained, which according to example ld) with diazomethane in a mixture consisting of the 2- [4- (p-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester is converted. 

  IR spectrum (in CH 2 Cl 2): characteristic bands at 5.60, 5.88, 6.18, 8.76.    



   Example 11
Analogously to Example 9, 336.3 mg (0.5 mM) of an isomer mixture consisting of 2- (4-benzenesulfonylthio-3phenoxyacetamido-2- oxoazetidin-1-yl) - 3-methoxycrotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester, and 152 mg (1 mM) 1,5-diazabi cyclo [5. 4th 0] undec-5-en a mixture consisting of the 7ss-phenoxy-acetamido-3-methoxy-ceph-2-em-4-carboxylic acid diphenylmethyl ester and the 7ss-phenoxyacetamido-3-methoxy-ceph-3-em -4-carboxylic acid diphenylmethyl ester, obtained, which can be separated into the two isomers by chromatography. 



   The starting materials can be obtained as follows: a) Analogously to Example 4aI), 697 mg (1 mM) are converted into one
Isomer mixture consisting of the 2- [4- (benzthiazol-2-yl-thio) - 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrontonic acid diphenylmethyl ester, and 324 mg (1.3 mM) silver benzene sulfinate by stirring for 90 minutes
Room temperature in 20 ml of acetone / water 9: 1, a mixture consisting of the 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonic acid diphenyl methyl ester and the corresponding isocrotonic acid - Diphenylmethylester obtained.  IR spectrum (in CH2C12): characteristic bands at 5.60.5.88.8.74 ju.    



   Silver benzene sulfinate is obtained by combining aqueous solutions of equimolar amounts of silver nitrate and sodium benzene sulfinate.  The precipitate is filtered off and dried in vacuo at 50-60 ° C. for 24 hours. 



     al) Analogously to Example 2dI), from 697 mg (1 mM) 2- [4 (benzthiazol-2-ylthio) -3-phenoxyacetaxido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid diphenylmethyl ester and 324 mg (1.3 mM) silver benzene sulfinate obtained by stirring for 90 minutes at room temperature in 20 ml acetone / water 9: 1 of the 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-hydroxy-crotonic acid diphenylmethyl ester , according to Example ld) with diazomethane in a mixture consisting of the 2- (4-benzenesulfonylthio- 3-phenoxyacetamido-2-oxoazetidin-1-yl) -3-methoxycrotonic acid-diphenylmethyl ester and the corresponding isocrotonic acid-diphenylmethyl ester , is transferred.  

  IR spectrum (in CH2Cl2): characteristic bands at 5.60, 5.88, 8.74.      



   Example 12
A mixture of 141 mg (0.2 mM) 2- [4- (o-methoxy. - benzenesulfonylthio) - 3-phenoxyacetamido-2-oxoazetidin-1 -yl] -
3-methoxy-crotonic acid diphenylmethyl ester and 61 mg (0.4 mM) 1,4-diazabicyclo [5. 4th 0] undec-5-ene in 4 ml of dry tetrahydrofuran is stirred for 70 minutes at room temperature.  Working up analogously to Example 10 gives a raw mixture consisting of the 7B-phenoxyacetamido-3-methoxy-ceph-2- em-4a-diphenylmethyl ester and the 7B-
Phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid di phenylmethyl ester in a ratio of about 4.4: 1 that by
Chromatography on silica gel analogous to Example 10 in the two
Isomers can be separated. 



   The two connections are created in roughly the same way
Ratio if 141 g (0.2 mM) of 2- [4- (o-methoxy benzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 yl] -3-methoxy-isocrotonic acid diphenylmethyl ester are treated analogously. 



   The two isomeric starting materials can be obtained as follows: a) 3.49 g (5 mM) of an isomer mixture consisting of 2- [4- (benzthiazol-2-ylthio) - 3-phenoxyacetamido-2 oxoazetidin-1 -yl] - 3-methoxy-crotonic acid diphenylmethyl ester and the corresponding isocrotonic acid diphenylmethyl ester in a ratio of about 4: 1 is mixed with 1.82 g (6.5 mM) silver o methoxybenzenesulfinate in 100 ml acetone / water 9: 1 for 130 minutes stirred at room temperature.  The mixture is filtered and the filtrate is evaporated in vacuo.  The residue is on 140 g of acid-washed silica gel with toluene /
Ethyl acetate 1: 1 chromatographed. 

  50 ml of fractions are collected, of which fractions 7 to 13 contain pure 2- [4 (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester, IR -Spectrum (CH2Cl2): 5.60,5,90,8,72,915, u, and
Fraction 25 and the following fractions pure 2- [4- (o
Methoxybenzenesulfonylthio) - 3-phenoxyacetamido-2-oxoazeti din-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester, IR spectrum (CH2Cl2): 5.60, 5.90, 8.20, 8.30, 8.72, 9.80.     Fractions 14 through 24 contain mixtures of the two
Isomers. 



     al) Analogously to Example 2dI), from 684 mg (1 mM) 2- [4 (benzthiazol-2-ylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] - 3-hydroxycrotonic acid diphenylmethyl ester and 361 mg ( 1.3 mM) silver o-methoxybenzenesulfinate by one hour
Stir in 20 ml of acetone / water 9: 1 at room temperature
2- [4- (o-Methoxybenzenesulfonylthio) -3-phenoxyacetamido-2 oxoazetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester, which is methylated with diazomethane according to Example 1d). 

  Chromatography on acid-washed silica gel with toluene / ethyl acetate 1: 1 first gives the pure 2- [4- (o methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoaze tidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester, IR -Spectrum (CH2Cl2): 5.60, 5.90, 8.72, 9.15, and on it the pure 2- [4- (o-methoxybenzenesulfonylthio) - 3-phen oxyacetamido-2- oxoazetidin-1 -yl] - 3-methoxy-crotonic acid diphenylmethyl ester, IR spectrum (CH2Cl2): 5.60, 5.9Q 8.20,
8.30, 8.72, 9.80.  The last fractions contain mixtures of the two isomers. 



   Example 13
A mixture of 57 mg (0.1 mM) of crude 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidine
1-yl] -3-methoxy-isocrotonic acid chloride and 43 mg (0.3 mM)
1,5-diazabicyclo [5. 4th 0] - undec-5-en in 2 ml of dry
Methylene chloride is stirred at room temperature for 80 minutes.    



   The mixture is diluted with methylene chloride, washed with dilute hydrochloric acid and water, dried over sodium sulfate and freed from the solvent in vacuo.  The residue is dissolved in 0.5 ml of methylene chloride, 5 ml of pentane / diethyl ether 3: 1 are added and the mixture is shaken.  The precipitate is filtered off and washed with pentane / diethyl ether 3: 1.  It consists of the fairly pure 7ss-phenoxyacctamido-3-methoxy-ceph-2-em-4a-carboxylic acid. 



   The starting material can be obtained as follows: a) A mixture of 703 mg (1 mM) of pure 2- [4- (o methoxybenzenesulfonylthio) - 3-phenoxyacetamido-2- oxoaze tidin-1-yl] - 3-methoxy-isocrotonic acid- Diphenylmethyl ester, 0.7 ml of trifluoroacetic acid and 0.66 ml of anisole in 4 ml of methylene chloride is stirred at 0 ° C. for 3 hours.  The mixture is then mixed with 50 ml of pentane / diethyl ether 3: 1 and shaken vigorously.  The white precipitate of pure 2- [4- (o methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid is filtered off and washed with pentane / diethyl ether 3: 1.  IR spectrum (CH2Cl2): 5.60, 5.93, 6.25, 8.72.    



   b) To a solution of 54 mg (0.1 mM) 2- [4- (o-Methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid in 0.5 ml of a 10 % oxalyl chloride solution in dioxane, a drop of dimethylformamide in dioxane is added, whereupon gas is immediately evolved.  The mixture is stirred for 2 hours at room temperature and the solvent and excess oxalyl chloride are evaporated off in vacuo.  The residue is dried in a high vacuum and gives the 2- [4- (o-methoxybenzenesulfonylthio) 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonyl chloride in the form of a slightly orange-colored foam, IR spectrum (CH2Cl2 ): 5.60, 5.90, 8.70.    



   Example 14
A solution of 200 mg (0.254 mM) 2- [4- (p-toluenesulfonylthio) - 3- (D-a-tert. -butyloxycarbonylamino-a-phenylacetylamino) - 2-oxoazetidin-1-yl] -3-methoxycrotonic acid diphenylmethyl ester in 2 ml of dimethylformamide is treated with 57 (0.38 mM) 1,5-diazabicyclo [5. 4th 0] undec-5-ene stirred for 30 minutes at room temperature, then treated 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 7ss- (D-α-tert is obtained.     Butylcarbonylamino-a-phenylacetylamino) -3-methoxy-ceph-2-em-4x-carboxylic acid diphenylmethyl ester of melting point 166-168 C (methylene chloride / pentane); Thin-layer chromatogram (silica gel; diethyl ether): ltf value 0.5 1; UV spectrum (in ethanol): γ = 257 m (e = 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 7ss- (D-a-tert. Butylcarbonylamino-a-phenyl-acetylamino) -3methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester of melting point 162-163 C (diethyl ether); Thin layer chromatogram:

  Rf value: - 0.33 (silica gel; diethyl ether); UV spectrum (in ethanol) Ämax = 265 nyl (e = 6600); 280 nqu (shoulder) (e = 6200); IR spectrum (in methylene chloride): 2.92, 5.58, 5.64 (shoulder), 5.82, 6.22 and 6.67.    

 

   The compounds obtained can be further processed as follows: a) A mixture of 8.8 g of 7, B- (D-x-tert.     Butyloxycarbonyl amino-a-phenyl-acetylamino) - 3-methoxy-3-cephem-4-carboxylic 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 trifluoro acetate of 7ss- (D-α-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 4 ° C. for 16 hours.  The colorless precipitate is filtered off, washed with acetone and diethyl ether and dried under reduced pressure. 



  The 7ss- (D-a: -phenyl-glycylamino) -3-methoxy-3-cephem-4-carboxylic acid is thus obtained in the form of a microcrystalline powder as an inner salt, which is also present in the form of a hydrate, F. 174-176 C (with decomposition); [α] 20 = +149 (c = 1.03 in 0.1-n. Hydrochloric acid); Thin-layer chromatogram (silica gel; developing with iodine): Rf¯0.36 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): Ämax = 267 (e = 6200); Infrared absorption spectrum (in mineral oil): characteristic bands a. a.  at 5.72, 5.94, 6.23 and 6.60. 



      b) A mixture # n 0.063 g of 7ss- (D-α-tert. Butyloxycarbonylamino-α-phenylamino) -3-methoxy-2-cephem-4α-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 de 7ss- (D-α-phenyl-glycylamino) -3-methoxy-2-cephem-4α-carboxylic acid thus obtainable is dissolved in 0.5 ml of water and the pH of the solution is adjusted dropwise Addition of a 10% 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- (D-α-phenyl-glycylamino) -3-methoxy-2-cephem-4x-carboxylic acid is thus obtained as an inner salt, thin-layer chromatogram (silica gel; development with iodine): Rf¯0.44B (system: n butanol / Pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): γ shoulder = 260. 



   c) A solution, cooled to 0 C, of 0.63 g of 7ss- (D-? - tert.    Butyloxycarbonylamino-α-phenyl-acetylamino) -3-methoxy-2-cephem-4a-carboxylic acid 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; the 7ss- (D-α-tert. -Butyloxycarbonylamino- a- phenyl-acetyl-amino) - 3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester- 1-oxide in the form of colorless needles, F. 



     172 175 C; Thin-layer chromatogram (silica gel): Rf-0.44 (system: ethyl acetate; development with iodine vapor); Ultraviolet absorption spectrum (in ethanol): γ max = 277 m (# = 7200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.56, 5.71, 5.83, 5.90, 6.27 and 6.67.    



   d) A solution, cooled to 10 "C, of 1.30 g of 7ss- (D-α-tert-butyloxycarbonylamino-α-phenyl-acetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester- 1oxide in 30 ml of dimethylformamide is mixed with 2.80 g of phosphorus trichloride with the 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 extracted twice with 100 ml of ethyl acetate each time.  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 represents the amorphous 7ss- (D-? -Tert. -Butyloxycarbonyl-amino-α-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 Ioddamp) ; [α] D = 1 + 1 (c = 0.981 in chloro form); Ultraviolet absorption spectrum (in ethanol): γ = 264 (# = 6300; infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 5.62,, 5.84,
5.88, 6.25 and 6.70. 



   The starting material can be obtained as follows: e) A solution, cooled to -15 ° C., of 31.2 g (0.12 mmol) of D-N-tert. Butyloxycarbonylphenylglycine 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 the mixture is stirred at -10 ° C. for 30 minutes.  A solution of 21.6 g (0.10 mmol) of 6-aminopenicillanic acid and 15.4 ml (0.11 mmol) of triethylamine in 300 ml of tetrahydrofuran / water 2: 1 is then added.  The reaction mixture is 1
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 at 5 ° C. with phosphoric acid, 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 ¯0.65 in the thin layer chromatogram (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
21.6 ml of 30% hydrogen peroxide (0.25 M) are added and
Stirred for 2.5 hours at room temperature.  The reaction mixture is then poured onto 2 l of ice water that is dissolved in
Form of a voluminous precipitate accumulating N-tert. Bu tyloxycarbonyl-ampicillin-1-oxide filtered off, washed well with water and dried in vacuo.  By extracting the
Filtrates with ethyl acetate can tert additional amounts of crude N. 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. Butyloxycarbo nyl 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 from methylene chloride /
Ether / hexane crystallized. 

  The N-tert is obtained. Butyloxy carbonyl-ampicillin-1-oxide-diphenylmethyl ester of melting point 164-166 C; [α] D20 = + 117 # 1 (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; Thin-layer chromatogram: Rf value 0.23 (silica gel;
Toluene / ethyl acetate 3: 1). 

 

  0 h) A mixture of 11.2 g (17.7 mmol) of N-tert. Butyloxy carbonyl-ampicillin-1-oxide-diphenylmethyl ester and 3.26 (19.5 mmol) mercaptobenzothiazole in 170 ml of toluene is 3
Boiled for 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- (benzthiazol-2 yldithio) - 3- (a: -tert). butyloxycarbonylamino-a: - phenylacetyl amino) -2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester, thin-layer chromatogram:

  Rf Wert¯0.37 (silica gel; toluene / ethyl acetate 3: 1); Ilt 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) of 2- [4- (Benzthiazol2-yldithio) -3- (α-tert. butyloxycarbonylamino-α-phenyl acetylamino) -2-oxoazetidin-1-yl] -3-methylen-butyric acid diphenylmethyl ester in 30 ml acetone / water 9: 1 is mixed with 0.868 g (3.46 mmol) silver toluenesulfinate at 0 ° C and 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-toluene sulfonylthio) -3 - (a-tert. butyloxycarbonylamino-a-phenylace tylamino) - 2-oxoazetidin-1-yl] -3-methylene-butyric acid-diphenylmethyl ester, thin-layer chromatogram: Rf Wert¯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.    



   j) In a solution, cooled to -70 ° C., of 2.30 g (3.0 mmol) of 2- [4- (p-toluenesulfonylthio) -3- (a-tert. butyloxy carbonylamino-a-phenylacetylamino) - 2-oxoazetidin-1-yl] -3methylene-butyric acid diphenylmethyl ester in 230 ml of methylene chloride, an ozone / oxygen stream (0.5 mmol of ozone per minute) is passed in for 7 minutes.  After adding 1 ml of dimethyl sulfide, the solution is stirred for a further 1 hour without cooling, then evaporated in vacuo. 

  The residue is crystallized from methylene chloride / ether / hexane and gives the 2- [4- (p-toluenesulfonylthio) -3- (a-tert. butyloxycarbonylamino-a-phenyl-acetylamino) -2-oxoazetidin-1-yl] 3-hydroxycrotonic acid diphenylmethyl ester of melting point 182-184 ° C; UV spectrum (ethanol): γ max = 259 m (e = 13 400); IR spectrum (methylene chloride): characteristic bands at 2,92,5,59,5,835,5,92,6.03 (shoulder), 6.18, 6.68; Thin-layer chromatogram: Rf value 0.55 (silica gel; toluene / ethyl acetate 1: 1).    



   k) A solution of 0.54 g (0.7 mmol) of 2- [4- (p-toluene sulfonylthio) -3 - (α-tert. butyloxycarbonylamino-α-phenylacetylamino) -2-oxo-azetidin-1-yl] -3-hydroxycrotonic acid diphenylmethyl ester in 20 ml methylene chloride / methanol 1: 1 is stirred at 0 ° C. with an excess of an ethereal diazomethane solution for 15 minutes and then evaporated in a vacuum.  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. butyloxycarbonyl amino-α-phenyl-acetylamino) -2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester, which is recrystallized from methylene chloride / diethyl ether / hexane. 

  Melting point 204206 "C; UV spectrum (ethanol): γ max = 259 m (e = 16,000); IR spectrum (Nujol): characteristic bands at 2.93, 5.58, 5.80, 5.84 , 5.93, 6.24, 6.57; thin layer chromatogram: ltf value 0.3 3 (silica gel; toluene / ethyl acetate 1: 1). 



      Example 15
A mixture of 670 mg (1 mmol) 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3methoxycrotonic acid diphenylmethyl ester, 6.7 ml 1,2-dimethoxyethane and 0 , 22 ml 1,5-diazabicyclo [5. 4th 0] undec-5en 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. 

  After preparative thick layer chromatography on silica gel, the residue yields with
Toluene / ethyl acetate 1: 1 the 7ss-phenylacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid diphenylmethyl ester from
Melting point 166-169 "C (from methylene chloride / hexane), UV
Spectrum (ethanol): γ max = 258 m (± = 4500), IR spectrum (methylene chloride): characteristic bands at 2.93, 5.62,
5.73, 5.93, 6.66, Rf -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): γ max = 258 m (e = 6350), 264 m, (# = 6350), 282 m (e = 5600) (shoulder), IR spectrum (methylene chloride): characteristic bands at 2.94, 5.63, 5.83,
5,94,6,26,6,66, 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-4α-carboxylic acid diphenylmethyl ester can be converted into the 7ss-phenylacetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenylmethyl ester analogously to Example 17c) 1-oxide, melting point 152-155 "(from acetone / diethyl ether), Rf value 0.31 (silica gel; system: ethyl acetate), UV spectrum (in 95% ethanol): γ max = 288 m ( # = 3610) and shoulder at γ = 247 m; IR
Spectrum (methylene chloride): characteristic bands at 2,94,5,59,5,81,5,95,6,22 and 6,61. 



   A purer product that consists mainly of the 7ss-phenyl acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester-1ss-oxide can be obtained as follows:
A solution of 6.7 g (10 mmol) of 2- [4- (p-toluenesulfonyl thio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester in 67 ml of abs.  Tetrahydrofuran is mixed with 2.28 ml (15 mmol) of 1,5-diazabicyclo [5. 4th 0] undec-5-ene stirred for 15 minutes at 20 ° 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-phenyl-phenyl-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid diphenyl methyl ester-lss-oxide with a melting point of 175-176 "C; thin-layer chromatogram (Silica gel): Rf value ¯0.1 (toluene / ethyl acetate 1: 1); UV spectrum (ethanol): γ = 270 m (e = 7300); IR spectrum (methylene chloride): characteristic
Bands at 2.94; 5.56; 5.78; 5.91; 6.20; 6.67.    



   From the 1-oxides, analogously to Example 14e) of the 7ss-
Phenylacetamido-3-methoxy-ceph-3-em-carboxylic acid-diphenylmethyl ester are obtained. 

 

   The crude 7ss-phenylacetamido-3-methoxy-ceph-3-em-4 carboxylic acid can be obtained from the latter by saponification analogously to Example 14a), which can be obtained by chromatography
Silica gel (containing 5% water) with methylene chloride, containing 30-50% acetone and subsequent lyophilization
Dioxane can be purified, UV spectrum (in 95%
Ethanol): Amax = 265 m (± = 5800); IR spectrum (methylene chloride): characteristic bands at 3.03, 5.60, 5.74, 5.92,
6.24 and 6.67, etc.    



   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 within 40 Minutes with 19.4 ml of 40 percent peracetic acid.  After a further 15 minutes, 28 g (0.15 mol) of benzophenone hydrazone, then 6.3 ml of 1 percent aqueous potassium iodide solution and then within 1.5 hours a mixture of 32.5 ml of 10 percent sulfuric acid and dropwise at the same temperature 28 ml of 40 percent peracetic acid are added.  After the addition is complete, the mixture is stirred for 30 minutes at 0 C, warmed to 15 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 percent 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 phenylacetamidopenicillanic acid diphenyl methyl ester oxide, melting point 139 "C; thin-layer chromatogram (silica gel): Rf value -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. 



   b) A mixture of 5.165 g (10 mmol) of 6-phenylamidophenicillanic acid-diphenylmethylester-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 one with a reflux apparatus provided with a water separator.  On cooling, the 2- [4 (benzthiazol-2-yldithio) -3phenylacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester crystallizes out spontaneously. 

  After recrystallizing once from methylene chloride / diethyl ether, crystals with a melting point of 134-136 C are obtained; Thin-layer chromatogram (silica gel): Rf value -0.52 (toluene / ethyl acetate system 1: 1), UV spectrum (ethanol): γ max = 269 m (e = 12,700); 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, mixed 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 by shaking with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo.  The evaporation residue is taken up in toluene and petroleum ether is added. 

  The precipitate is filtered off and umkri crystallized from ethyl acetate / petroleum ether.     The resulting 2- [4- (p-toluenesulfonylthio) -3phenylacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid diphenylmethyl ester has a melting point of 75 ° C .; Thin-layer chromatogram (silica gel): Rf value ¯0.47 (system toluene / ethyl acetate 1: 1), UV spectrum (ethanol): AmaX = 259 m (± = 4300); IR spectrum (methylene chloride): characteristic bands at 2.92, 5.62, 5.74, 5.94 and 6.63. 



   d) A solution of 655 mg (1 mM) 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid diphenylmethyl ester in 65 ml methylene chloride is at -65 ° 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 -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, can be processed further without further purification. 



   e) The crude product obtained under d) is dissolved in 20 ml of methanol and mixed with ethereal diazomethane solution 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-methoxy-crotonic 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, in addition to a little 2-14- (p-toluenesulfonylthio) -3phenylacetamido-2-oxoaceztidine -1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester. 



   Example 16
To a solution of 6.06 g (10 mmol) of a 3: 1 mixture of the isomeric 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 methoxy-croton- and Isocrotonic acid benzyl ester and 2.33 g (15 mmol) of p-toluenesulfinic acid in 200 ml of absolute tetrahydrofuran are stirred at room temperature with 5.20 ml (35 mmol) of 1,5-diazabicyclo [5. 4th 0] undec-5-en given.  The mixture is continued for 40 minutes at room temperature, treated with 500 ml of methylene chloride and successively with 200 ml of 0. 5 N hydrochloric acid, 200 ml water, 200 ml 0.5 N sodium bicarbonate and 200 ml water.  The methylene chloride phase is dried over sodium sulfate and evaporated in vacuo. 

  The residue is chromatographed on 200 g of acid-washed silica gel toluene / ethyl acetate 3: 1, the 7B-phenoxyacetamido-3-methoxy-ceph-2 em-4ar-carboxylic acid benzyl ester of melting point 148-151 ° C. being obtained by adding diethyl ether to the fractions becomes.    IR spectrum (methylene chloride): characteristic bands at 5.60, 5.75, 5.90, 8.25; [a] 2 = +284 # 1 (c = 1; chloroform).     D.
Toluene / ethyl acetate 2: 1 elutes the 7B-phenoxyacetamido-3-methoxy-ceph-3, which can also be precipitated with diethyl ether.  em4-caronic acid benzyl ester of melting point 89-91 "C;

  IR spectrum (methylene chloride): characteristic bands at 5.60, 5.85, 5.90; [a] 20 = +470 j 10 (c = 1; chloroform). 



   D.
The ratio of the Ceph-2-em to the Ceph-3-em connection is about 3: 1. 



   The connections can be further processed as follows:
One at. 0 "C prepared solution of 454 mg (1 mmol) of an approx.  3: 1 mixture of 7B-phenoxyacetamido-3-methoxy-ceph-2-em-4-carboxylic acid benzyl ester and 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylic acid benzyl ester in 30 ml of tetrahydrofuran 15 ml of pre-cooled 0.1 N potassium hydroxide solution are added while 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 stirred vigorously.  Addition of a little saturated aqueous sodium chloride solution causes a separation into two phases. 

  The methylene chloride phase is separated off and the aqueous phase is washed with a further 30 ml of methylene chloride.  The aqueous phase is covered with a layer of 50 ml of methylene chloride, treated with 10 ml of 2N hydrochloric acid and shaken thoroughly.  After the organic phase has been separated off, it is extracted twice more with 30 ml of methylene chloride each time.  The combined methylene chloride extracts are dried over sodium sulfate and evaporated in vacuo.  

  The white foam obtained crystallizes on addition of chloroform and diethyl ether and gives 7ss-phenoxyacetamido-3-methoxy-ceph-2- cm-4a-carboxylic acid with a melting point of 142 ° C. (decomposition).       IR spectrum (KBr): characteristic bands at 5.65, 5.75.5.95
The starting material can be prepared as follows: a) To a solution of 36.6 g (0.1 mol) of 6-phenoxyacetamidopenicillanic acid 1B-oxide in 150 ml of dry dimethylformamide is added 20 ml (14.6 g of 0.145 mol ) Triethylamine and 17 ml (24.5 g, 0.143 mol) of benzyl bromide were added.  The mixture is stirred for 20 hours at room temperature, then ice water is poured. 

  The precipitate is sucked off, with approx.  1000 ml of water washed, dried in vacuo at 40 for 2 days, then taken up in 200 ml of methylene chloride and dried again with sodium sulfate.  The white foam remaining after evaporation of the solvent in vacuo is dissolved in 150 ml of ethyl acetate and left to stand first at room temperature, then at, whereupon pure 6-phenoxyacetamidopenicillanic acid benzyl ester lss oxide crystallizes.  Melting point 13F140 C; IR spectrum (methylene chloride); characteristic bands at 5.55.5.75.5.90, u; [] 20 = +174 # 1 (c = 1, chloroform). 

  D.
From the mother liquor can be based on chromatography
250 g of acid-washed silica gel with toluene-ethyl acetate (1: 1) further amounts of the crystalline benzyl ester-lss-oxide are obtained. 



   b) 4.56 g of 10 mmol) 6-phenoxyacetamido-penicillanic acid benzyl ester lss oxide and 1.84 g (11 mmol) of 2-mercaptobenzothiazole are refluxed in 100 ml of toluene for 5 hours (bath temperature 135).  The mixture is left to stand, whereupon the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylenebutyric acid benzyl ester crystallizes out.  The crystals are filtered off with suction, washed with 50 ml of toluene and dried in a high vacuum. 



  Further amounts of the crystalline product can be obtained by chromatography of the mother liquor on 70 g of acid-washed silica gel with toluene-ethyl acetate (3: 1). 



  Melting point of the pure product 150¯153 C; IR spectrum (methylene chloride): characteristic bands at 5.60,
5,75,5,90; [or] = 1120 fl "(c = 1; chloroform). 



   D c) By a solution of 6.06 g (10 mmol) 2- [4- (Benz thiazol-2-yldithio) -3-phenoxy-acetamido-2-oxoazetidin-l-yl]
3- methylenebutyric acid benzyl ester in 300 ml methylene chloride is passed through an oxygen / ozone mixture at C until the starting material is completely ozonated (control by means of thin layer chromatography, silica gel,
Toluene / ethyl acetate 1: 1).  To the mixture is then 50 ml
10% aqueous sodium bisulfite solution was added and the mixture was stirred (5 min) until no ozonide can be detected with potassium iodide starch.  300 ml of water are added to the mixture and the product is distributed between the two phases formed.  The organic phase is dried over sodium sulfate and freed from the solvent. 

  The residue is in
100 ml of ether-pentane (1: 1) triturated at 0 C, whereupon the 2 [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxy-crotonic acid benzyl ester crystallized out, melting point 58-62 C; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.90, 6.00 y [a] 20 20 -92 # 1 (c = 1, chloroform).     D d) 6.08 g (0.01 mol) 2- [4- (benzthiazol-2-yldithio) - 3 phenoxyacetamido-2- oxoazetidin-1-yl] - 3-hydroxy-crotonic acid benzyl ester and 3.50 g ( 0.013 mol) of silver p-toluene sulfinate are dissolved in 200 ml of acetone-water (9: 1) for 60
Stirred minutes at room temperature. 

  The educated yellow one
The precipitate is filtered off through cellite, the residue is washed with acetone and the filtrate is reduced to a volume of approx.  20 ml concentrated.  The product is then partitioned between methylene chloride and dilute aqueous sodium sulfate solution.  The organic phase is dried over sodium sulfate and the solvent is evaporated off in vacuo.  The residue was taken up in 70 ml of ethyl acetate, if necessary with warming, filtered from something insoluble and evaporated again. 

  By adding 100 ml of ether pentane at 0 C, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-hydroxy-crotonic acid benzyl ester crystallizes with a melting point of 151-152 C; IR spectrum (methylene chloride): characteristic bands at 5.60, 5.90, 6.00, = -16 # 1 (c = 1; chloroform).    



   D e) To a solution of 5.97 g (0.01 mol) of pure 2- [4- (p toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 yl] -3-hydroxy-crotonic acid, benzyl ester in 50 ml Methylene chloride is added dropwise to an ethereal diazomethane solution with stirring at 0 ° C. until the starting material is completely methylated (control: thin layer chromatography on silica gel, toluene / ethyl acetate 1: 1).     Excess diazomethane is neutralized with a few drops of glacial acetic acid (avoid excess glacial acetic acid), after which the mixture is evaporated in vacuo. 

  The yellowish, foam-like residue is crystallized from diethyl ether / pentane (1: 1) and an isomer mixture is obtained consisting of 2- [4- (p-toluenesulfonylthio) - 3-phenoxyacetamido-2- oxoazetidin-1-yl] - 3-methoxy-crotonic acid benzyl ester and the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3 methoxy-isocrotonic acid benzyl ester in a ratio of about 3: 1. 



   The two isomers can be separated by repeated chromatography on silica gel with toluene / ethyl acetate 1: 1.  The resulting 2- [4- (p-toluenesulfonylthio) 3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid benzyl ester has a melting point of 166-168 ° C .; [a] 20
D = -36 # 1 (c = 1; chloroform); IR spectrum (methylene chloride): characteristic bands at 5.60, 5.80, 5.90, 8.72; NMR spectrum (chloroform): characteristic bands at 2.12 (s): 5.00 (dd); 5.90 (d) ppm; Thin-layer chromatogram: Rf value ¯0.10 (silica gel; toluene / ethyl acetate 1: 1). 



  The obtained 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrntonic acid benzyl ester has the melting point 59-63 ° C; [a] 20 = - 10110 (c = 1;
D.
Chloroform); IR spectrum (methylene chloride): characteristic bands at 5.60, 5.87 sh. 5,90,8,72; NMR spectrum (chloroform): characteristic bands at 2.32 (s), 5.45 (d, d),
5.72 (d) ppm; Thin layer chromatogram: Rf value-0.13 (silica gel:

  Toluene / ethyl acetate 1: 1)
Example 17
A solution of 534 mg (1 mmol) of a mixture consisting of 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2 oxoazetidin-1 -yl] -3-methoxy-isocrotonic acid methyl ester and 2- [4- ( p-Toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeti din-1-yl] -3-methoxy-crotonic acid methyl ester in a ratio of about 4: 1 in 20 ml of tetrahydrofuran is added with stirring with 302 mg (2 mmol) 1.5 -Diazabicyclo [5th 4th 0] - undec-5-ene added and stirred for 40 minutes.  The mixture is diluted with 70 ml of methylene chloride and washed successively with dilute hydrochloric acid, water, dilute aqueous sodium bicarbonate solution and again water.  The organic phase is dried over sodium sulfate and evaporated in vacuo. 

  The residue is acid-washed on 15 g: silica gel with toluene / ethyl acetate 2: 1 and then 1: 1 chromatographed, initially the pure 7B-phenoxyacetamido-3-methoxyceph-2-em-4a-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.70.5.90.8.25, and then the pure 7ss-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid methyl ester, IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90, 7.10 u in the form of colorless foams. 

 

   The compounds obtained can be further processed as follows:
To a solution, cooled in an ice bath, of 382 mg of 7ss-phenoxyacetamido-3-methoxy-ceph-2-em-4a-carboxylic acid methyl ester in 30 ml of tetrahydrofuran, 15 ml of cooled 0.1 N aqueous potassium hydroxide solution is added with stirring. 



  After 5 minutes, 100 ml of water and 70 ml of methylene chloride are added and the mixture is acidified by adding 10 ml of N aqueous hydrochloric acid.  The methylene chloride phase is separated off and the aqueous phase is extracted with 30 ml of methylene chloride.  The combined organic phases are dried over sodium sulfate and evaporated in vacuo.  The residue is crystallized from chloroform / diethyl ether and gives the 7B-phenoxyacetamido-3-methoxy ceph-2-em-4? carboxylic acid of melting point 142 "(decomposition). 



   The same compound with a melting point of 142 "(decomposition) is obtained when the methyl 7ss-phenoxyacetamido-3-methoxy-ceph-3-em-4-carboxylate is saponified with 0.1 N potassium hydroxide solution as described above. 



   The starting materials can be prepared as follows: a) A solution of 19.25 g (50 mmol) of 6-phenoxyacetamidopenicillanic acid methyl ester lss oxide and 9.4 g (55 mmol) of 2-mercaptobenzothiazole in 500 ml of dry toluene is used Boiled under reflux for 8 hours and then concentrated in vacuo.  The residue is dissolved in 400 ml of ethyl acetate while warming (-80 "), treated with 0.2 g of activated charcoal and suction filtered through an electrically heated glass frit.  On cooling, the methyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid, melting point 132 1340 ° C., separates out.  Further amounts of this compound can be obtained from the mother liquors (melting point 1351370 ° C.). 



   b) By a solution of 20.6 g (40 mmol) of 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methylene-butyric acid methyl ester in 400 ml Acetone is passed through an ozone / oxygen mixture at - 200 ° C. until no more starting material can be detected by thin layer chromatography (silica gel, toluene / ethyl acetate 1: 1).  The mixture is then mixed with 40 ml of dimethyl sulfide and stirred for 3 days at room temperature until no more ozone can be detected with potassium iodide starch.  The mixture is concentrated in vacuo and the liquid residue is poured onto 400 ml of ice water.  The precipitate is filtered off, washed with 200 ml of ice water, dried in vacuo and crystallized at 0 ° C. from diethyl ether / pentane. 

  The methyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-hydroxycrotonate obtained has a melting point of 127 130 C; IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.90, 600, 8.10.     Further amounts of the product can be obtained by chromatography of the mother liquors on silica gel with toluene / ethyl acetate 3: 1. 



   c) To a solution of 4.85 g (0.01 mol) of 2- [4- (benzothiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidine-1-yl'3-hydroxycrotonic acid methyl ester in 50 ml of methylene chloride at 0 C with stirring, enough ethereal diazomethane solution is added until no more starting material can be detected by thin layer chromatography (silica gel, toluene / ethyl acetate 1: 1) after stirring for 15 minutes.  Excess diazomethane is neutralized with the minimum amount of acetic acid and the mixture is evaporated in vacuo. 

  The residue consists of a mixture of 2- [4- (Benzthiazol2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3methoxy-isocrotonic acid methyl ester and 2- [4- (Benzthiazol-2-yldithio-3-phenoxyacetamido -2-oxoazetidin-1-yl] -3-methoxy-crotonic acid methyl ester in a ratio of about 4: 1.  IR spectrum (in methylene chloride): characteristic bands at 5.60, 5.85, 5.90, 9.05, 10.00.    



   d) A mixture of 5.03 g (0.01 mol) of a mixture consisting of the 2- [4- (Benzthiazol-2-yldithio) - 3-phenoxyacetamido-2- oxoazetidin- 1 -yl] - 3-methoxy- isocrotonic acid methyl ester and the corresponding crotonic acid methyl ester in a ratio of about 4: 1.3.50 g (0.013 mol) silver ptoluenesulfinate and 200 ml acetone / water 9: 1 is stirred for 40 minutes at room temperature and then filtered through cellite. 



  The filter residue is washed with acetone and the combined filtrates are concentrated in vacuo to a volume of about 20 ml.  After adding 100 ml of methylene chloride and 100 ml of dilute aqueous sodium sulfate solution, the mixture is shaken, the aqueous phase is separated off and the methylene chloride phase is dried over sodium sulfate and evaporated in vacuo.  For purification, the residue is triturated with diethyl ether / pentane at 0 ° C. and filtered off.  A mixture of 2- [4- (p-toluenesulfonylthio) - 3-phenoxyacetamido-2- oxoazetidin-l-yl) - 3-methoxy-isocrotonic acid methyl ester and 2- [4- (p-toluenesulfonylthio) - 3- phenoxyacetamido-2oxoazetidin-1-yll-3-methoxy-crotonic acid methyl ester in a ratio of about 4: 1 in the form of a white powder.  IR spectrum (in methylene chloride) characteristic bands at 5.60, 5.85.5.90.8.75. 



   Example 18
The following compounds can be prepared analogously from suitable intermediates according to the invention: 7B-Amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester or salts thereof, 3-n-butyloxy-7ss-phenylacetylamino-3-cephem-4- diphenylmethyl carboxylate, 3-n-butyloxy-7ss- (Da-tert. -butyloxycarbonylamino-a-phenyl-acetyl-amino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 3-n-butyloxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid or salts thereof, 3-methoxy-7ss-phenylamino-3-cephem-4-carboxylic acid methylser 3-ethoxy-ss- (D0? -tert. -butyloxycarbonylamino-?

  ; -phenyl-acetylamino) -3-cephem-4-carboxylic acid diphenylmethyl ester, 3-ethoxy-7ss- (Da-phenyl-glycylamino) -3-cephem-4-carboxylic acid or salts thereof, 3-benzyloxy-7ss- (D -? -trt.  butyloxycarbonylamino-α-phenyl-acetylamino) -3-cephem-4-carboxylic acid-diphenylmethyl ester, 3-benzyloxy-7ss- (D-α-phenyl-glycylamino) -3-cephem-4-carboxylic acid or salts thereof , 7B- (5-Benzoylamino-5-diphenylmethoxycarbonylvalerylamino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7ss- (D-α-tert. -Butyloxycarbonylamino-?

  ; -phenylacetyl-amino) -3-methoxy-3-cephem-4-carboxylic acid or salts thereof, 7ss- [D-a-tert. -Butyloxycarbonylamino-a- (2-thienyl) -acetyl-amino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (1,4-cyclohexadienyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid-diphenylmethyl ester, 7ss- [Da-amino-a- (2-thienyl) -acetylamino ] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, 7ss- [D-amino-a- (1,4-cyclohexadienyl) -acetylamino] -3 methoxy-3-cephem-4-carboxylic acid in the form of the inner
Salt. 

 

      7ss- [D-α-amino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, 7ss- [D-α- Amino-alpha- (1-cyclohexen-1-yl] acetylamino] -3-methoxy-3-cephem-4-carboxylic acid or salts thereof,
7ss- [D-α-tert. -Butyloxycarbonylamino-α- (4-hydroxyphenyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenyl methyl ester, 7ss- [D-α-tert. -Butyloxycarbonylamino-α- (4-isothiazolyl) -acetylamino] -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester, 7ss- (D-α-tert. -Butyloxcarbonylamino-?

  ; -phenylacetylamino) 3- methoxycarbonyloxy-3- cephem-4-carboxylic acid diphenylmethyl ester, as well as the corresponding Ceph-2-em compounds and the isomer mixtures consisting of the Ceph-3-em and the Ceph-2-em compounds, as well the 1-oxides of the corresponding Ceph-3-em compounds.  

 

Claims (1)

PATENT CLAIM Process for the preparation of 2- (3-amino-2-oxo-4-thio 1-azetidinyl) -3- substituted-hydroxy-crotonic acid compounds of the formula EMI34.1 where lt represents hydrogen or an amino protective group RA, and lt1 represents hydrogen or an acyl group Ac, or R1a and R1b together represent a divalent amino protective group, R2A represents hydroxy or a radical R2A which together with the carbonyl grouping-C (=) - forms a protected carboxyl group R3 represents lower alkyl or a Hydroxy protecting group and Y is a leaving group S-R4, -5O2-R5 or -S-SO2R5, where R4 is an optionally substituted aromatic heterocyclic radical with up to 15 Carbon atoms, and at least one ring nitrogen atom and optionally a further ring heteroatom, wel cher radical with one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond, is bonded to the thio group -5-, and Rs is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms, as well as their salts, characterized in that one in a compound of the formula EMI34.2 whereinlta, ltb, lt 2 and Y have the abovementioned meaning 1 1 2, the enol group is converted into a group -OR3 by etherification, and optionally converting a compound obtained with a salt-forming group into a salt or a salt obtained into the free compound or into another salt. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula VI are used in which R1 is an amino protective group R A1, which stands for an acyl group Ac, in which any free functional groups that may be present may be protected, Rb is hydrogen A is one with the -C (= O) group represents an etherified hydroxyl group which forms an esterified carboxyl group, it being possible for functional groups which may be present in an esterified carboxyl group of the formula -C (= O) -R 2A to be protected, and Y is an -S-R4 group , a group -SO2-lt5 bonded with the sulfur atom to the thio group -S or a group -S-SO2-Rs. 2. The method according to claim, characterized in that A that in a starting material of the formula VI R 2 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, is. 3. The method according to claim, characterized in that in a starting material of the formula VI Y is a group -S-R4, wherein R4 is an optionally substituted aromatic heterocyclic radical with 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 is bonded to one of its ring carbon atoms, which is connected to a ring nitrogen atom by a double bond, to the thio group -S-. 4. The method according to claim, characterized in that in a starting material of the formula Vi 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, 1-methyl- benzimidazole 2-yl, means. 5. The method according to claim, characterized in that in a starting material of the formula VI R4 an optionally substituted aliphatic, cycloaliphatic, arali phatic or aromatic acyl or thioacyl group with up to 18, preferably up to 10, carbon atoms, such as lower alkanoyl, z . B. acetyl or propionyl, lower thioalkanoyl, e.g. B. Thioacetyl or thiopropionyl, cycloalkanecarbonyl, e.g. B. Cyclohexanecarbonyl, cycloalkanethiocarbonyl, e.g. 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 corresponding substituted, for example by lower alkyl, such as Methyl, halogen, such as fluorine or chlorine, lower alkoxy, such as Methoxy, aryl such as phenyl, aryloxy such as phenyloxy, mono or polysubstituted acyl or thioacyl group. 6. The method according to claim, characterized in that in a starting material of the formula VI R4 benzothiazole 2-yl is. 7. The method according to claim, characterized in that in a starting material of the formula VI R4 benzoxazole 2-yl is. 8. The method according to claim, characterized in that in a starting material of the formula VI Y is a group -SO2-Rs, where Rs is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 10 carbon atoms. 9. The method according to claim, characterized in that in a starting material of the formula VI Y is a group -S-SO2-lt5, wherein Rs is an optionally substituted, aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 10 carbon atoms. 10. The method according to claim, characterized in that in a starting material of the formula VI Rs an optionally lower alkoxy, halogen, aryl or aryloxy, mono- or polysubstituted lower alkyl, alkenyl or cycloalkyl group, or optionally lower alkyl, lower alkoxy, halogen, aryl , Aryloxy or nitro mono- or polysubstituted naphthyl or in particular phenyl group, for example phenyl, o- or m-tolyl, o- or m-methoxyphenyl, o-, m- or p-chlorophenyl, p-biphenylyl, p-phenoxyphenyl , or 1- or 2-naphthyl. 11. The method according to claim, characterized in that in a starting material of the formula VI Y is a group -S02-R5, in which Rs is phenyl, p-tolyl, p-methoxyphenyl or p-nitrophenyl. 12. The method according to claim, characterized in that the etherification is carried out with a diazo lower alkane corresponding to R3. 13. The method according to claim, characterized in that diazomethane is used as the etherifying agent. 14. The method according to claim, characterized in that the etherification is carried out with a reactive ester of an alcohol of the formula R3-OH. 15. The method according to claim, characterized in that a di-lower alkyl sulfate is used as the etherifying agent. 16. The method according to claim, characterized in that the etherifying agent used is dimethyl sulfate. 17. The method according to claim, characterized in that the etherifying agent used is trimethylchlorosilane or hexamethyldisilazane. 18. The method according to claim, characterized in that in a compound of the formula II, in which Y is a group -S-lt4, this is obtained by treatment with a Schwerm.etallsullinat of the formula M "+ (-SOzR5) n, in which Mn + represents a heavy metal cation in which n is 1 or 2, and Rs is an optionally substituted aliphatic, cycloaliphatic, araliphatic or aromatic hydrocarbon radical with up to 18 carbon atoms, converted into a group -SO2-Rs. 19. The method according to claim, characterized in that in a compound of formula II obtained in which R2A forms a protected carboxyl group together with the carbonyl group-C (= O), this is converted into a free carboxyl group. 20. The method according to claim or one of the dependent claims 1-19, characterized in that amino-2-oxo-4-thio-1-azetidinyl) -3-substituted-hydroxycrotonic acid compounds of the formula II or salts thereof are prepared in which Ra denotes hydrogen, Rb denotes an acyl group of the formula 1 EMI35.1 where Ra is phenyl, hydroxyphenyl, hydroxy-chlorophenyl, thienyl, pyridyl, aminopyridinium, furyl, isothiazyl, tetra silyl or 1,4-cyclohexadienyl, wherein in such radicals hydroxy substituents can be protected by acyl radicals, X represents oxygen or sulfur, m for 0 or 1 and Rb is hydrogen or, if 0 is, optionally protected amino, carboxy, sulfo or hydroxy, or 0-lower alkylphosphono or 0,0'-di-lower alkylphosphono, or denotes a 5-amino-5-carboxy-valeryl radical, in which the amino and carboxy groups are optionally protected, R A2 is hydroxy, lower alkoxy, 2-halo-lower alkoxy, phenacyloxy, 1-Phenyl-lower alkoxy with 1-3 phenyl radicals optionally substituted by lower alkoxy or nitro, lower alkanoyloxymethoxy, α-amino-lower alkanoyloxymethoxy, lower alkoxycarbonyloxy or lower alkanoyloxy, R3 is lower alkyl or tri-lower alkylsilyl, and Y has the meanings given in the dependent claims 6, 7 or 11. 21. The method according to claim or one of the dependent claims 1-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3 - phenoxyacetamido-2- oxo azetidin-1-yl] -3- methoxy crotonic acid p-nitrobenzyl ester, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-methoxy-isocrotonic acid p-nitrobenzyl ester or a mixture of isomers thereof. 22. The method according to claim or one of the sub-claims 1-11 or 17, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxy-acetamido-2-oxoazetidin-1-yl] -3-trimethylsilyloxycrotonic acid - Diphenylmethyl ester, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-trimethylsilyloxyisocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 23. The method according to claim or one of the sub-claims 1-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazeitidin- 1-yl] -3-methoxy Crotonic acid diphenylmethyl ester, the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid rediphenylmethyl ester or a mixture of isomers thereof. 24. The method according to claim or one of the sub-claims 1-3, 6 or 12-16, characterized in that the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido 2-oxazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester, 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 25. The method according to claim or one of the sub-claims 1-3, 6 or 12-16, characterized in that the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido 2- oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloroethyl ester, 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl ] -3-methoxy-isocrotonic acid-2,2,2 trichiorethyl ester or an isomer mixture thereof. 26. The method according to claim or one of the sub-claims 1-3, 6, 12-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2 oxoazetidin-1-yl] -3-methoxy-crotonic acid-2,2,2-trichloroethyl ester, 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid-2,2 , 2-trichloroethyl ester or a mixture of isomers thereof. 27. The method according to claim or one of the sub-claims 1-3, 6 or 17, characterized in that the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2 oxoazetidin-1-yl] -3 - trimethylsilyloxy-crotonic acid diphenyl methyl ester, the 2- [4- (benzthiazol-2-yldithio) -3-phenoxy acetamido-2-oxoazetidin-1-yl] -3-trimethylsilyloxy-isocrotonic acid diphenyl methyl ester or a mixture of isomers thereof. 28. The method according to claim or one of the dependent claims 1-3, 6 or 19, characterized in that the 2- [4- (benzthiazol-2-yldithio) - phenoxyacetamido-2- oxo azetidin- 1 -yl] -3- methoxy-crotonic acid, which produces 2- [4- (benzthiazol2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid or a mixture of isomers thereof. 29. The method according to claim or one of the dependent claims 1-16 or 18, characterized in that the 2- [4- (p-nitrobenzenesulfonylthio) -3- phenoxyacetamido-2 oxoazetidin- 1 -yl] -3 - methoxy-crotonic acid- diphenylmethyl ester, the 2- [4- (p-nitrobenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1 -yl] -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 30. The method according to claim or one of the sub-claims 1-16 or 18, characterized in that 2 [4- (p-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-crotonic acid diphenylmethyl ester, the 2- [4- (p-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-ylj-3-methoxy-isocrotonic acid rediphenylmethyl ester or a mixture of isomers thereof. 31. The method according to claim or one of the sub-claims 1-16 or 18, characterized in that the 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxo-azetidin-1-yl) -3-methoxy-crotonic acid diphenylmethyl ester, the 2- (4-benzenesulfonylthio-3-phenoxyacetamido-2-oxo azetidin-1-yl) -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 32. The method according to claim or one of the sub-claims 1-16 or 18, characterized in that the 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy -crotonic acid diphenylmethyl ester, the 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 33. The method according to claim or one of the dependent claims 1-16, 18 or 19, characterized in that the 2- [4- (o-methoxybenzenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy -isocrotonic acid and the corresponding isocrotonic acid. 34. The method according to claim or one of the dependent claims 1-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3- (D-α-tert.butyloxycarbonylamino-> z-phenylacetamido ) -2-oxoazetidin-1 -yl] -3-methoxycrotonic acid diphenylmethyl ester. 35. The method according to claim or one of the dependent claims 1-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxo-azetidin-1-yl] -3-methoxy -crotonic acid diphenylmethyl ester, the 2- [4- (p-toluenesulfonylthio) -3-phenylacetamido-2-oxo azetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof. 36. The method according to claim or one of the dependent claims 1-3, 6 or 12-16, characterized in that the 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido2-oxqazetidin-1-yl] -3 methyl methoxy-crotonate, the methyl 2- [4- (benzthiazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonate or a mixture of isomers thereof. 37. The method according to claim or one of the dependent claims 1-16 or 18, characterized in that the 2- [4- (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxo azetidin-1-ylj-3-methoxy-crotonic acid - methyl ester, the 2- [4 (p-toluenesulfonylthio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid methyl ester or a mixture of isomers thereof. 38. The method according to claim or one of the dependent claims 1-3, 7 or 12-16, characterized in that the 2- [4- (benzoxazol-2-yldithio) -3- phenoxyacetamido2- oxoazetidine-1 -ylj -3 - methoxy-crotonic acid diphenylmethyl ester, the 2- [4- (benzoxazol-2-yldithio) -3-phenoxyacetamido-2-oxoazetidin-1-yl] -3-methoxy-isocrotonic acid diphenylmethyl ester or a mixture of isomers thereof