CH590879A5 - Substd carboxylic acid derivs - broad spectrum antibiotics and inters - Google Patents

Abstract

Title cpds are of formula I: where R1 = an amine protecting gp., R2 = H or acyl; or R1 + R2 tog. = a bivalent amine protecting gp.; R3 = an opt. subst. hydrocarbon residue, or acyl; and R4 = OH or a carboxyl protecting gp I are prepd. by acylating the corresp. 7 beta-amines (I, R1 = R2 = H).

Description

  

  
 



   The present invention relates to a process for the preparation of O-substituted 7ss-amino-cephem-3-ol4-carboxylic acid compounds of the formula
EMI1. 1
 where R2 stands for hydroxy or a radical RA which together with the carbonyl group -C (= 0) forms a protected carboxyl group and R3 stands for an optionally
2 substituted hydrocarbon radical or an acyl group, and salts of such compounds. 



   A protected carboxyl group of the formula -C (= O) -R 2A 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 R A can be one through an organic radical
2 etherified hydroxy group, in which the organic radical preferably contains 18 carbon atoms which, together with the -C (= O) grouping, forms an esterified carboxyl group. Such organic radicals are e.g. B.  aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, as well as heterocyclic or heterocyclic-aliphatic radicals. 



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



   A radical R A which forms a primarily mixed anhydride group with a -C (= O) group is ins
2 is a special acyloxy radical, corresponding to acyldene of an organic carboxylic acid, preferably with 18 carbon atoms, such as an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid or a carbonic acid half-denvate, such as a carbonic acid half-ester. 



   A radical R A. which forms a carbamoyl group with a -C (= O) group.  is a possibly substi
2 tuierte amino group, in which substituents optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 carbon atoms, such as optionally substituted monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms.    



   material 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  ver estemden residues z.  B.  have the meanings given above and preferably contain up to 18 carbon atoms, as well as acyl radicals, preferably with up to 18 carbon atoms. 



   In a substituted hydrazinocarbonyl group of the formula -C (= O) -RA, one or both nitrogen atoms can be substituted
2 be tuiert, where as substituents primarily optionally substituted monovalent or divalent hydrocarbon radicals, preferably with up to 18 hydrocarbon atoms, such as optionally substituted, monovalent or divalent aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals with up to 18 carbon atoms corresponding heterocyclic or heterocyclic-aliphatic radicals with up to 18 carbon atoms, and / or functional groups, such as acyl radicals, preferably with up to 18 carbon atoms, are possible. 



   An optionally substituted hydrocarbon radical R3 is preferably a corresponding cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, but in particular an optionally substituted aliphatic hydrocarbon radical, and also a corresponding araliphatic hydrocarbon radical.  An acyl group R3 is primarily the acyl radical of an organic carboxylic acid, incl. 



  Formic acid, such as a cycloaliphatic, cycloaliphatic-aliphatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, in particular the acyl radical of an aliphatic carboxylic acid, also an aromatic carboxylic acid, and a carbonic acid half derivative.    



   The general terms used in the description above and below have e.g. B.  following meanings:
An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, and a corresponding ylidene radical, is an optionally substituted monovalent or divalent aliphatic hydrocarbon radical, in particular lower alkyl, and lower alkenyl or lower alkynyl, furthermore 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 or phenyl-lower alkylthio, optionally substituted lower alkoxycarbonyloxy or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or lower alkanitroloxy, optionally substituted by oxycarbonyloxy, or halogen, furthermore .  z.  B. 

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

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



   A bivalent aliphatic residue, incl.  the corresponding residue of a divalent aliphatic carboxylic acid is z.  B. 



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



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



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

  B.  5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z.  B.  can contain up to 7, preferably up to 4 carbon atoms.  The above cycloaliphatic or cycloaliphatic-aliphatic
Remnants 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, for.  B.  like the above, aliphatic
Hydrocarbon radicals, mono-, di- or poly-substituted by functional groups. 



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



   A divalent aromatic radical, e.g.  B.  an aromatic one
Carboxylic acid, is primarily 1,2-arylene, especially 1,2
Phenylene, optionally, e.g.  B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, mono-, di- or polysubstituted. 



   An araliphatic radical, including the araliphatic radical in a corresponding carboxylic acid, and also an araliphatic radical
Ylidene residue is e.g.  B.  an optionally substituted arali phatischer hydrocarbon radical, such as an optionally substituted, z.  B.  up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals pointing aliphatic hydrocarbon radical and is primarily phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl, also phenyl-lower alkylidene, such radicals being e.g. B.  1-3 phenyl groups and optionally ge, z.  B.  like the abovementioned aliphatic and cyclo aliphatic radicals, in the aromatic and / or aliphatic part can be mono-, di- or polysubstituted. 



   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 tetraza-cyclic radicals of aromatic character, furthermore corresponding partially or fully saturated radicals, these heterocyclic radicals optionally, e.g.  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, B-position, substituted lower alkyl half-ester of carbonic acid, as well as a lower alkenyl-, cycloalkyl-, phenyl- or phenyl-lower-alkyl-half-ester of carbonic acid which is optionally substituted in the organic radical.  Acyl radicals of a carbonic acid half ester are also corresponding radicals of lower alkyl half esters of carbonic acid, in which the lower alkyl part is a heterocyclic group, e.g. 

  B.  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group may optionally be substituted.  The acyl radical of a carbon 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, furthermore lower alkenyloxy, cycloalkyloxy or optionally substituted phenyloxy, and also heterocyclyloxy, especially also optionally heterocyclyloxy or heterocyclyln 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 alkoxyakino, lower alkanoyloxiamino, lower alkoxycarbonylamino or lower alkanoylamino. 



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



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



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



   Lower alkylene is e.g. B.     1,2-ethylene, 1,2- or 1,3-propylene, 1,4-butylene, 1,5-pentylene or 1,6-hexylene, while lower alkenylene z.  B.    1,2-ethenylene or 2-buten-1,4-ylene.  Lower alkylene interrupted by heteroatoms is e.g.  B. 



  Oxane-lower alkylene, such as 3-oxa-1,5-pentylene, thian-lower alkylene, such as 3-thia-1,5-pentylene, or aza-lower alkylene, such as 3-lower alkyl-3-aza-1,5-pentylene, e.g.  B.  3-methyl-3-aza-1,5-pentylene. 



   Cycloalkyl is e.g.  B.  Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl, cycloalkenyl z.  B.  Cyclopropenyl, 1-, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl, 3-cycloheptenyl or 1,4-cyclohexadienyl, and cycloalkylidene e.g.  B.  Cyclopentylidene or cyclohexylidene. 

 

  Cycloalkyl-lower alkyl or lower alkenyl is e.g.  B.  Cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1 or -1,2-ethyl, -1,1-, -1,2- or 1,3-propyl, -vinyl or -allyl, while cycloalkenyl-lower alkyl or -lower alkenyl e.g.  B.  1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenely- or 1-, 2- or 3-cycloheptenylmethyl, -1,1, or -2,3-ethyl, -1,1- , -1,2- or 1-3, -propyl, -viny! or -allyl.  Cycloalkyl lower alkylidene is e.g.  B.  Cyclohexylmethylene, and cycloalkenyl lower alkylidene z.  B.  3-cyclohexenylmethylene.   



   Naphthyl is 1- or 2-naphthyl, while biphenylyl, e.g. B. 



  Represents 4-biphenylyl. 



   Phenyl-lower alkyl or phenyl-lower alkenyl is, for.  B. 



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



   Heterocyclic radicals are primarily optionally substituted heterocyclic radicals of aromatic character, e.g.  B.  corresponding monocyclic, monoaza-, monothia- or monooxacyclic radicals, such as pyrryl, e.g. B.  2-pyrryl or 3-pyrryl, pyridyl, e.g.  B.  2-, 3- or 4-pydridyl, also pyridinium, thienyl, e.g. B.  2- or 3-thienyl, or furyl, e.g. B.     2-furyl, bicyclic monoaza-, monooxa- or monothiacyclic radicals such as indolyl, e.g.  B.  2- or 3-indolyl, quinolinyl, e.g. 

  B.  2- or 4-quinolinyl, isoquinolinyl, e.g. B.    1-isoquinolinyl, benzofuranyl, e.g. B.     2- or 3-benzofuranyl, or benzothienyl, e.g. B.  2- or 3 benzothienyl, monocyclic diaza, triaza, tetraza, thiaza, thiadiaza or oxazacyclic radicals, such as imidazolyl, e.g. B.  2 imidazolyl, pyrimidinyl, e.g. B.  2- or 4-pyrimidinyl, triazolyl, e.g. B.  1,2,4-triazol-3-yl, tetrazolyl, e.g. B.  1- or 5-tetrazoylyl, oxazolyl, e.g. B.  2-oxazolyl, isocazolyl, e.g. B.     3-isoxazolyl, thiazolyl, e.g. B.  2-thiazolyl, isothiazolyl, e.g. B.  3-isothiazolyl or 1,2,4- or 1,3,4-thiadiazolyl, e.g. B.  1,2,4-thiadiazol-3-yl or 1,3,4-thiadiazol-2-yl, or bicyclic diaza, thiaza or oxazacyclic radicals such as benzimidazolyl, e.g. B.  2 benzimidazolyl, benzoxazolyl, e.g. B. 

   2-benzoxazolyl, or benzthiazolyl, e.g. B.  2-benzothiazolyl.  Corresponding partially or fully saturated radicals are, for.  B.     Tetrahydrothienyl, such as 2-tetrahydrothienyl, tetrahydrofuryl, such as 2-tetrahydrofuryl, or piperidyl, e.g. B.  2- or 4-piperidyl.  Heterocyclic-aliphatic radicals are heterocyclic groups, in particular those containing lower alkyl or lower alkenyl. 



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



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



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



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



   Esterified hydroxy groups are primarily halogen, e.g.  B.  Fluorine, chlorine, bromine or iodine, as well as lower alkanoyloxy, e.g.  B.  Acetyloxy or propionyloxy, lower alkoxycarbonyloxy, e.g.  B.  Methoxycarbonyloxy, ethoxycarbonyloxy or tert.  Butyloxycarbonyloxy, 2-halo-lower alkoxycarbonyloxy, e.g. B.  2,2,2-trichloroethoxycarbonyloxy, 2-bromoethoxycarbonyloxy or 2-iodoethoxycarbonyloxy, or phenylcarbonylmethoxycarbonyloxy, e.g. B.  Phenacyloxycarbonyloxy. 



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



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



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



   A carboxyl or sulfo present in alkali metal salt form is e.g.  B.  one present in the 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.  B.  Pyrrolidino or piperidino, Oxaniederalkylenamino z.    B.  Morpholino, thiane lower alkyleneamino, e.g. B.  Thiomorpholino, and aza-lower alkylenamino e.g. B. 



   Piperazino or 4-methylpiperazino.     Acylamino particularly represents carbamoylamino, lower alkylcarbamoylamino, such as methylcarbamoylamino, ureidocarbonylamino, guanidinocarbonylamino, lower alkoxycarbonylamino z.  B.  Methoxycarbonylamino, ethoxycarbonylamino or tert. -Butyloxycarbonylamino, lower alkanoylamino, such as acetylamino or propionylamino, also for phthalimido, or optionally in salt, such as alkali metal, z.  B.  Sodium or ammonium salt form, present sulfoamino. 



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



   O-lower alkyl phosphono is e.g.  B.  O-methyl- or 0-ethyl-phosphono, 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 0 lower alkyl-O-phenyl-phosphono z.  B.  O-benzyl-O-methylphosphono. 



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



   2-lower alkyl and 2,2-di-lower alkyl hydrazino are e.g.  B.  2-methylhydrazino or 2,2-dimethylhydrazino, 2-lower alkoxycarbonylhydrazino e.g. B.  2-methoxycarbonylhydrazino, 2-ethoxycarbonylhydrazino or 2-tert. -Butyloxycarbonylhydrazino, and lower alkasnoylhydrazino e.g. B.  2-acetylhydrazino. 



     
An etherified hydroxy group R A forms together with
2 of the carbonyl group has a, preferably easily cleavable or easily another functionally modified carboxyl group, such as an esterified carboxyl group which can be converted into a carbamoyl or hydrazinocarbonyl group.  Such a group A R 2 is e.g.  B.  Lower alkoxy, such as methoxy, ethoxy, n-propyloxy or isopropyloxy, which together with the carbonyl grouping forms an esterified carboxyl group which, especially in 2-cephem compounds, can easily be converted into a free carboxyl group or into another functionally modified carboxyl group. 

 

     
An etherified hydroxy group R A, which together
2 forms a particularly easily cleavable esterified carboxyl group with a -C (= O) grouping, is z.  B.  for 2-halo-lower alkoxy, in which halogen preferably has an atomic weight of more than 19.  Such a radical, together with the —C (= O) grouping, forms a, upon treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g. B.  with zinc in the presence of aqueous acetic acid, easily cleavable esterified carboxyl group or an esterified carboxyl group which can be easily converted into such and is z.  B.  2,2,2-trichloroethoxy or 2-iodoethoxy, also 2-chloroethoxy or 2-bromoethoxy, which can easily be converted into the latter. 



   An etherified hydroxyl group R 2 X which, together with the -C (= O) grouping, also results in treatment with chemical reducing agents under neutral or weakly acidic conditions, e.g.  B.     when treating with zinc in the presence of aqueous acetic acid, further when treating with a suitable nucleophilic reagent, e.g.  B.  Sodium thiophenolate, easily cleavable esterified carboxyl group, is an arylcarbonylmethoxy group, in which aryl is in particular an optionally substituted phenyl group, and preferably phenacyloxy. 



   The group R A can also represent an aryl methoxy group
2, in which aryl is in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the = = O) group, forms an esterified carboxyl group which can be easily cleaved under neutral or acidic conditions on irradiation, preferably with ultraviolet light.  An aryl radical in such an arylmethoxy group contains, as substituents, in particular lower alkoxy, e.g.  B.  Methoxy (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or especially nitro (in the preferred phenyl radical preferably in the 2-position).  Such radicals are primarily 3 or 4-methoxybenzyloxy, 3,5-dimethoxy-benzyloxy, 2-nitro-benzyloxy or 4,5-dimethoxy-2-nitro-benzyloxy. 



     An etherified hydroxy group R A can also be a radical
Represent 2, which together with the -C (= O) grouping under acidic conditions, e.g.  B.  when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms.  Such a radical is primarily a methoxy group in which methyl is substituted by optionally substituted hydrocarbon radicals, in particular aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g.  B. 



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



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



  Adamantyl, such as 1-adamantyl, and an above-mentioned oxa- or thiacycloaliphatic radical, in which methyl of the methoxy group is the ring member representing the a-position to the oxygen or sulfur atom, means e.g. B.  2-tetrahydrofuryl, 2-tetrahydropropyranyl or 2,3-dihydro-2-pyranyl or corresponding sulfur analogs. 



     
The R A radical can also be an etherified hydroxyl group
Represent 2, which together with the -C (= O) group a hydrolytic, z.  B.  Under weakly basic or acidic conditions, cleavable esterified carboxyl group forms. 



  Such a radical is preferably one with the -C (= O) -Grup pierung an activated ester group-forming etherified Hy droxygruppe, such as nitrophenyloxy, z.  B.  4-nitrophenyloxy or 2,4-dinitropheflyloxy, nitrophenyl-lower alkoxy, e.g.  B.  4th
Nitrobenzyloxy, polyhalophenyloxy, e.g. B.  2,4,6-trichlorophenyloxy or 2,3,4,5,6-pentachlorophenyloxy, also cyano methoxy, and acylaminomethoxy, z.  B.  Phthaliminomethoxy or succinyliminomethoxy. 



   The group R2A can also be one, together with the
Carboxyl group of the formula -C (= OF represent an etherified hydroxyl group which can be cleaved under hydro genolytic conditions and which forms an esterified carboxyl group, and is z. B. 



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



      A.
The group R2A can also form an esterified carboxyl group which can be cleaved under physiological conditions together with the carbonyl group —C (0). 



  ethereal hydroxy group, primarily lower alkanoyloxymethoxy, e.g.  B.  Acetyloxymethyloxy or pivaloylmethoxy.  A.
A silyloxy or stannyloxy group R2 preferably contains optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such as lower alkyl, cycloalkyl, phenyl or phenyl-lower alkyl groups, and is primarily tri-lower alkylsilyloxy, e.g. B.    Trimethylsilyloxy, or tri-lower alkylstannyloxy, e.g.  B.  Tri-n-butylstannyloxy. 



   A mixed anhydride which can be cleaved, preferably hydrolytically, together with a -C (= O) group
A group-forming acyloxy radical R2 contains z. B.  the acyl radical of one of the above organic carboxylic acids or carbonic acid half derivatives, and is z. B.  Lower alkanoyloxy, e.g. B.  Acetyloxy, or lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy. 



   A radical R A2 which, together with a -C (= O) grouping, forms an optionally substituted carbamoyl or hydrazinocarbonyl group is z.  B.  Amino, lower alkylamino or di-lower alkylamino, such as methylamino, ethylamino, dimethylamino or diethylamino, lower alkylenamino, e.g. B.  Pyrrolidino or piperidino, oxaniederalkylenamino, e.g.  B.  Morpholino, hydroxyamino, hydrazino, 2-lower alkyl hydrazino or 2,2-di-lower alkyl hydrazino, e.g. B.  2 methylhydrazino or 2,2-dimethylhydrazino. 



   An optionally substituted aliphatic hydrocarbon radical R3 is in particular lower alkyl, such as ethyl, n-propyl and primarily methyl, furthermore tert. -Amino-lower alkyl, wherein the tert. -Amino group is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3 di-lower alkylamino-lower alkyl, e.g. B.    2-dimethylaminoethyl, 2-diethylaminoethyl or 3-dimethylaminopropyl, or ver etherified hydroxy-lower alkyl, in which the etherified hydroxy group, in particular lower alkoxy, is separated from the oxygen atom by at least two carbon atoms, such as 2- or 3 lower alkoxy-lower alkyl, e.g. B.  2-methoxyethyl or 2-ethoxyethyl.  

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



   The acyl radical R3 of an aliphatic carboxylic acid is primarily optionally substituted lower alkanoyl, e.g.  B. 



  Acetyl, propionyl or pivaloyl, such radicals such.  B.  by esterified or etherified hydroxy, e.g.  B.  Halogen, such as fluorine or chlorine, or lower alkoxy, e.g.  B.  Methoxy or ethoxy, may be substituted.  The acyl radical R3 of an aromatic carboxylic acid is z.  B.  optionally substituted benzoyl, such as benzoyl, or by esterified or etherified hydroxy, e.g.  B. 



  Halogen, such as fluorine or chlorine, or lower alkoxy, e.g. B.  Methoxy or ethoxy, or lower alkyl, e.g. B.  Methyl, substituted benzoyl. 



   Salts are in particular those of compounds of the formula I having a free carboxy group, primarily metal or ammonium salts such as alkali metal and alkaline earth metal, e.g. B.  Sodium, potassium, magnesium or calcium salts, as well as ammonium salts with ammonia or suitable organic amines, with primarily aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and araliphatic primary, secondary or tertiary mono-, di- or polyamines, and heterocyclic bases for the salt formation come into question, such as lower alkylamines, e.g. B.  Triethylamine, hydroxy-lower alkylamines, e.g. B.  2-hydroxyethylamine, bis- (2-hydroxyethyl) amine or tri- (2-hydroxyethyl) amine, basic aliphatic esters of carboxylic acids, e.g.  B.  4-aminobenzoic acid-2-diethylaminoethyl ester, lower alkyleneamines, e.g.  B.  1-ethyl-piperidine, cycloalkylamines, e.g.  B.  Bicyclohexylamine, or benzylamines, e.g. 

  B.    N, N'-dibenzyl-ethylenediamine, also bases of the pyridine type, e.g.  B.  Pyridine, collidine, or quinoline.  Compounds of the formulas can also contain acid addition salts, e.g. B.  with inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, e.g.  B.  Trifluoroacetic acid.  Compounds of the formula I with a free carboxy group can also be used in the form of an inner salt, i.e.  H.     in zwitterionic form. 



     I-oxides of compounds of the formula I with salt-forming groups can also form salts, as described above. 



   The novel compounds of the present invention can be used as intermediates in the preparation of pharmacologically useful compounds.  Compounds of the formula II which can be prepared therefrom by reacylation z. B. , where RA is an acyl radical Ac occurring in pharmacologically active N acyl derivatives of 6ss-amino-pe-nam-3-carboxylic acid or 7ss-amino-3-cephem-4-carboxylic acid compounds and Rb is hydrogen, R2 is hydroxy or one together with the carbonyl group forms an etherified hydroxyl group RA which is easily cleavable under physiological conditions and forms an esterified carboxyl group
2 and R3 has the meaning given above, and in which the double bond is preferably in the 3,4-position of the cephem ring,

   or salts of such compounds with salt-forming groups are against microorganisms such as gram-positive bacteria, e.g. B.  Staphylococcus aureus, (e.g. B.  in mice at doses of about 0.001 to about 0.02 g / kg p. O. ), and gram-negative bacteria, e.g.  B.  Escherichia coli (e.g.  B.  in mice at doses of about 0.001 to about 0.05 g / kg p. O. ), also Klebsiella pneumoniae, Proteus vulgaris or Salmonella typhosa, in particular also against penicillin-resistant bacteria. 



   The 3-cephem compounds of the formula I in which R2 is hydroxy, for optionally, e.g. B.     by optionally substituted aryloxy, e.g.  B.  4-methoxyphenyloxy, lower alkanoyloxy, e.g. B.  Acetyloxy or pivaloyloxy, or arylcarbonyl, e.g. B.  Benzoyl, or halogen, e.g.  B.  Chlorine, bromine or iodine, substituted lower alkoxy, such as lower alkoxy, e.g.  B. 



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

  Methoxycarbonyloxy or ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B.  Acetyloxy, for tri-lower alkylsilyloxy, e.g. B.    Trimethylsilyloxy, or optionally, e.g.  B.  amino or hydrazino substituted by lower alkyl such as methyl or hydroxy, e.g.  B.  Amino, lower alkyl or di-lower alkylamino such as methylamino or dimethylamino, hydrazino, 2-lower alkyl or 2,2-di-lower alkylhydrazino, e.g.  B.  2-methylhydrazino or 2,2-dimethylhydrazino, or hydroxyamino, and R3 is lower alkyl, e.g.  B.  Methyl or ethyl, optionally substituted phenyl-lower alkyl, in particular 1-phenyl-lower alkyl with 1 or 2, optionally, e.g.  B.  by lower alkoxy, such as methoxy, substituted phenyl radicals, e.g. B.  Benzyl or diphenylmethyl, or lower alkanoyl, e.g.  B.  Aectyl or propionyl, and optionally, e.g. 

  B.  by lower alkyl such as methyl, lower alkoxy, e.g. B.    Meffioxy, or halogen, e.g. B.  Represents fluorine or chlorine, substituted benzoyl, or salts of such compounds. 



   Primarily in a 3-cephem compound of the formula I, or in a salt of such a compound, R2 is hydroxy, lower alkoxy, in particular α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, also methoxy or ethoxy, 2-halo-lower alkoxy, z.  B.  2,2,2-trichloroethoxy, 2 iodoethoxy or the easily convertible 2-chloroethoxy or 2-bromoethoxy, phenacyloxy, 1-phenyl-lower alkoxy with 1-3 phenyl radicals, optionally substituted by lower alkoxy or nitro z. B.  4-methoxybenzyloxy, 4-nitrobenzyloxy, diphenylmethoxy, 4, 4'-D imethoxy-diphenylmethoxy or trityloxy, lower alkanoyloxymethoxy, e.g.  B.  Acetyloxymethoxy or pivaloyloxymethoxy, lower alkoxycarbonyloxy, e.g.  B.  Ethoxycarbonyloxy, or lower alkanoyloxy, e.g.  B. 



  Acetyloxy and R3 is lower alkyl, e.g.  B.  Methyl, 1-phenyl lower alkyl, e.g.  B.  Benzyl or diphenylmethyl, lower alkanoyl, e.g. B.  Acetyl or propionyl, or benzoyl. 



   The invention relates primarily to 3-cephem compounds of the formula I in which
R2 represents hydroxy, lower alkoxy, especially α-polybranched lower alkoxy, e.g.  B.  tert. -Butyloxy, 2-halo-lower alkoxy, e.g. B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromo ethoxy, or optionally, z.  B.  by lower alkoxy, e.g.  B. 



  Methoxy, substituted diphenylmethoxy, e.g.  B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 is lower alkyl, e.g.  B.  Methyl, or lower alkanoyl, e.g.  B.  Acetyl or propionyl, also denotes the corresponding 2-cephem compounds, or salts of such compounds with salt-forming groups. 

 

   In as particularly valuable to 3-cephem compounds of the formula I, R2 is hydroxy, optionally halogen in the 2-position, e.g. B.  Chlorine, bromine or iodine substituted lower alkoxy, especially Åa polybranched lower alkoxy, e.g. B.    



  tert. -Butyloxy, or 2-halo-lower alkoxy, e.g. B.  2,2,2-trichloroethoxy, 2-iodoethoxy or 2-bromoethoxy, or given. 



  if lower alkoxy, such as methoxy-substituted diphenylmethyloxy, e.g. B.  Diphenylmethoxy or 4,4'-dimethoxy-diphenylmethoxy, and R3 means lower alkyl, e.g. B.  Methyl, or lower alkanoyl, e.g.  B.  Acetyl. 



   The compounds of the formula I and their salts are obtained by converting into a compound of the formula
EMI6. 1
   where R A is an acyl group Ac and R b is hydrogen
1 A 1 tet, or where R A and R b together with the nitrogen
1 1 atom represent a phthalimido group, and where R2 and R3 have the meanings given under formula I, the acylated 7ss-amino group is converted into a free 7ss-amino group by deacylation and a compound obtained is isolated as a salt or in free form. 



   An acyl group Ac primarily represents the acyl radical of an organic carboxylic acid, preferably with up to 18 carbon atoms, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid (incl. 



  Formic acid), as well as the acyl radical of a carbonic acid half derivative. 



   An acyl group Ac stands in particular for an acyl radical of an organic acid or 7-amino-3-cephem-4-carboxylic acid compound contained in a naturally occurring or bio-, semi- or totally synthetically producible N-acyl derivative of a 6-amino-penam3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound Carboxylic acid or an easily cleavable acyl radical, in particular a carbonic acid half derivative.    



   An acyl radical Ac contained in an N-acyl derivative of a 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compound is primarily a group of the formula
EMI6. 2
 wherein n is 0 and Rl is hydrogen or an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, z. 

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

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

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

   aromatic or araliphatic hydrocarbon radical and R ″ and Rlll 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, Rll 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 abovementioned acyl groups of the formula A, for. B.  n for 0 and R1 for hydrogen or an optionally, preferably in the 1-position by amino or a, optionally in salt, z.  B.  Alkali metal salt form present sulfoamino group, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by hydroxy, lower alkoxy, z.  B.  Methoxy, and / or halogen, e.g.  B. 



  Chlorine, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g.  B.  by lower alkyl, e.g.  B. 



  Methyl, and / or phenyl, which in turn have substituents such as halogen, e.g.  B.  Chlorine, can carry substituted heterocyclic group, such as a 4-isocazolyl 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, Rl for a 3-amino-3carboxy-propyl radical with optionally protected amino and / or carboxy group, z.  B.  silylated amino or acylamino and / or silylated or esterified carboxy group, an optionally substituted, preferably by halogen, such as chlorine, optionally substituted, such as hydroxy and / or halogen, e.g.  B.  Chlorine, phenyloxy containing, amino and / or carboxy, substituted lower alkyl group, lower alkenyl group, optionally substituted one such as hydroxy, halogen, e.g.  B. 

 

  Chlorine, and / or optionally substituted, such as hydroxy and / or halogen, e.g.  B.  Phenyl group containing chlorine, containing phenyloxy, an optionally, z. B.     through down. alkyl, such as methyl, amino or substituted pyridyl, pydridi nium, thienyl, 1-hnidazolyl or 1-tetrazolyl, an optionally substituted lower alkoxy, e.g.  B.     Methoxy group, an optionally, e.g.  B.    by hydroxy and / or halogen such as chlorine, substituted phenyloxy group, a lower alkylthio, e.g.  B.  n-butylthio, or lower alkenylthio, e.g.  B. 

  Allylthio group, an optionally, e.g. B.       by lower alkyl, such as methyl, substituted phenylthio-, 2-imidazolylthio-, 1,2,4-triazol-3-ylthio-, 1,3,4-triazol-2-ylthio-, 1,2,4-thiadiazol-3- ylthio, such as 5-methyl-1, 2,4-thiadiazol-3-ylthio, 1,3,4-thiadiazol-2-ylthio, such as 5-methyl-1,3,4-thiadiazol-2-ylthlo- , or 5-tetrazolylthio, such as 1-methyl-5-tetrazolylthio group, a halogen, in particular chlorine or bromine atom, an optionally functionally modified carboxy group, such as lower alkoxycarbonyl, e.g. B. 



  Methoxycarbonyl or ethoxycarbonyl, cyano or optionally, z. B.  by lower alkyl, such as methyl, or phenyl, N-substituted carbamoyl, an optionally substituted lower alkanoyl, e.g. B.  Acetyl or propionyl, or benzoyl group, or an azido group, and Rlt and R "'for hydrogen, or n for 1, Ru for an optionally, z. B.  by hydroxy and / or halogen, e.g. B.  Chlorine, substituted phenyl or thienyl group, also for a 1,4-cyclohexadienyl group, Ril for optionally substituted amino, such as lower alkoxycarbonylamino or 2-halo-lower alkoxycarbonylamino, e.g.  B. 



  tert. -Butyloxycarbonylamino or 2,2,2-Trichloräthoxycarbonylamino, or optionally substituted carbamoylamino, such as guanidinocarbonylamino, or one, optionally in salt z.  B.  Alkali metal salt form present sulfoamino group, an azido group, an optionally in salt, z. B. 



  Alkali metal salt form or in esterified form, e.g.  B.     as lower alkoxycarbonyl, e.g.  B.  Methoxycarbonyl or ethoxycarbonyl group, present carboxyl group, a cyano group, a sulfo group, an optionally functionally modified hydroxyl group, in particular acyloxy, such as formyloxy, and lower alkoxycarbonyloxy or 2-halo-lower alkoxycarbonyloxy, e.g.  B.  tert. -Butyloxycarbonyloxy or 2,2,2-trichlorocarbonyloxy, or optionally substituted lower alkoxy or phenyloxy, an O-lower alkyl or O, O-di-lower alkylphosphono group, e.g. B.  O-methyl-phosphono or O, O-dimethylphosphono, or a halogen atom, e.g.  B.  Chlorine or bromine, and Rlll for hydrogen, or n for 1, Rl and Rir each for halogen, z. B.  Bromine, or lower alkoxycarbonyl, e.g. B. 

  Methoxycarbonyl, and Rlll for hydrogen, or n for 1 and each of the groups Rl, Rll and Rlll for lower alkyl, e.g.  B.     Methyl stand. 



   Such acyl radicals Ac are z. B.  Formyl, cyclopentylcarbonyl, oc-amino-cyclopentylcarbonyl or ar-amino-cyclohexylcarbonyl (with optionally substituted amino group, e.g.  B. 



  optionally present in salt form sulfoamino group, or one, by a, preferably slightly, z. B.  when treating with an acidic agent, such as trifluoroacetic acid, or with a chemical reducing agent, such as zinc in the presence of aqueous acetic acid, an acyl radical which can be split off or which can be converted into such an acyl radical, preferably a suitable acyl radical of a carbonic acid half ester, such as 2,2,2 trichloroethyloxywbonyl, 2 -Bromoethoxycarbonyl, 2-iodoethoxycarbonyl, tert. -Butyloxycarbonyl, phenacyloxycarbonyl, or a carbonic acid half-amide, such as carbamoyl or N-methylcarbamoyl, as well as amino group substituted by trityl), 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, 5-ethoxy-naphthoyl, benzyloxyloxycarbonyl, Methyl-3-phenyl-4isoxazolylcarbonyl,

   3- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 3- (2,6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2-chloroethylaminocarbonyl, acetyl, propionyl, butyryl, hexanoyl, octanoyl, acrylyl , Crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl. 



  Allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl or 5-amino-5-carboxyl-valeryl (with optionally, e.g. B.  as indicated, as indicated by a monoacyl ode diacyl radical, z. B.  an optionally halogenated lower alkanoyl radical, such as acetyl or dichloroacetyl, or phthaloyl, substituted amino group and / or optionally functionally modified, e.g. B.     in salt, such as sodium salt, or in ester, such as lower alkyl, e.g.  B.     Methyl or ethyl, or aryl lower alkyl, z. B. 

  Diphenylmethylesterform, present carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, bismethoxycarbonylacetyl, N-phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl, azo-acetyl, -phenyl-aclylacido, 2-cyano-3,3-dimethyl-aclyyl, 2-cyano-3,3-dimethyl-aclyyl, 2-cyano-3,3-dimethyl-aclyyl, phenyl-phenyl-phenyl-phenyl, azo-acetyl, -phenyl-acetyl, azo-acetyl, phenyl-phenyl-acetyl, a-cyano-3,3-phenyl-acetyl, azidoacetyl, methoxycarbonylacetyl, methoxycarbonylacetyl, 3-chlorophenylacetyl, 4-aminomethylphenyl-acetyl, (with optionally, e.g. B. 

   as indicated, substituted amino group), phenacylcarbonyl, phenyloxyacetyl, 4-trifluoromethylphenyloxyacetyl, benzyloxyacetyl, phenylthioacetyl, bromophenylthioacetyl, 2-phenyloxypropionyl, a-phenyloxyphenoxy-phenoxy, 3-phenyloxyphenoxy-phenoxy-3-a-acetyl-a-phenoxy-phenoxy-phenoxy-3-a-ethyl-a-phenoxy-phenoxy-3-acetyl-a-methyl-phenoxy-phenoxy-phenoxy-3-a-methyl-a-phenoxy-phenoxy-phenoxy-3-a-ethyl-a-phenoxy-phenoxy-phenoxy-3-a-methyl-phenoxy-phenoxy-phenoxy-3-a-methyl-phenoxy-acetyl , 4-dichloro-phenylacetyl, a-cyanophenylacetyl, in particular phenylglycyl, 4-hydroxyphenylglycyl, 3-chloro-4-hydroxyphenylglycyl or 3,5-dichloro-4-hydroxyphenylglycyl (the amino group in these radicals optionally, e.g. 

  B.     as indicated above, may be substituted), a-hydroxyphenylacetyl (where in these radicals the hydroxyl group optionally, similar to the amino group, e.g. B.  can be protected by a suitable acyl radical, in particular by formyl or an acyl radical of a carbonic acid half ester) or a-O-methylphosphono-phenyl-acetyl or a-O, O-dimethyl-phosphonophenylacetyl, also benzylthioacetyl, benzylthiopropionyl, a-carboxyphenylacetyl (with optionally, z. B.  as stated above, functionally modified carboxy group), 3-phenylpropionyl, 3- (3-cyanophenyl) -propionyl, 4- (3-methoxyphenyl) -butyryl, 2-pyridylacetyl, 4-aminopyridinium acetyl (optionally with, e.g. B. 

   as stated above, substituted amino group), 2-thienylacetyl, 2-tetrahydrothienylacelyl, x-carboxy-2-thienylacetyl or α-carboxy-3-thienylacetyl (optionally with functional, e.g.  B.     as stated above, modified carboxyl group), α-cyano-2-thienylacetyl, α-amino-2-thienylacetyl or α-amino-3-thienylacetyl (optionally with, e.g. B.  as stated above, substituted amino group), a-sulfo-phenylacetyl (optionally with, e.g. B. 

   such as the carboxyl group, functionally modified sulfo group), 3 thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-tetrazolylacetyl, 3-methyl-2-imidazolylthloacetyl, 1,2,4-triazol-3 -ylthioacetyl, 1,3, 4-triazol-2-ylthioacetyl, 5-methyl-1,2,4-thiadiazol-3-ylthioacetyl, 5-methyl-1,3,4-thiadiazol-2-ylthioacetyl or 1 methyl-5-tetrazolylthioacetyl. 



   An easily cleavable acyl radical Ac, in particular a carbonic acid half-ester, is primarily a reduction, e.g. B.  when treated with a chemical reducing agent, or by acid treatment, e.g.  B.  with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as one, preferably multiply branched in the a-position or by acylcarbonyl, especially benzoyl radicals, or in the ss position by halogen atoms substituted Niederalkoxycar bonyl radical, z.  B.     tert. -Butyloxycarbonyl, tert. -Pentyloxycarbonyl, Phenacyloxycarbonyl, 2,2,2-Trichloräthoxycarbonyloder2-Jod äthoxycarbonyl 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. 



   In a starting material of the formula II, the radical R A preferably denotes an acyl group Ac in which any free functional groups present, e.g. B.       Amino, hydroxy, carboxyl or phosphono groups, in a manner known per se, amino groups z.  B.  by acylating, tritylating, silylating or stannylating, and hydroxy, carboxy or phosphono groups, e.g.  B.  by etherification or esterification, incl.  Silylating or stannylating, may be protected, and Rb is hydrogen. 



   1
In a starting material of the formula II, R2 preferably represents an esterified carboxyl with the —C (= O) grouping, in particular an esterified carboxyl which can be cleaved under mild conditions
A group-forming, etherified hydroxy group R 2, with any functional groups present in a Carb oxyl protective group R A in a manner known per se, e.g.  B.  how
2 A above, may be protected.  A group R 2 is e.g.  B.  in particular an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, e.g. B. 



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



   A compound of the formula II is deacylated to a compound of the formula I in a manner known per se. 



   So an easily cleavable acyl group, in a conventional manner, for.  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 the metal compound, preferably in the presence of hydrous acetic acid.  Furthermore, in a compound of the formula II in which a carboxyl group of the formula -C (= O) -R2 is preferably one, e.g. 

  B.  by esterification, including by silylation, e.g.  B.  by reaction with a suitable organic halosilicon or halotin IV compound, such as trimethylchlorosilane or tri-n-butyltin chloride, represents an acyl group R A b R1.  or R1, if any free functional groups present are optionally protected, are cleaved off by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the imino ether formed, a protected, e.g.  B.  a carboxyl group protected by an organic silyl radical can be released during the reaction. 



   Imide halide-forming agents in which halogen is bonded to an electrophilic central atom are primarily acid halides, such as acid bromides and especially acid chlorides. 



  These are primarily acid halides of inorganic acids, especially phosphorus-containing acids, such as phosphorus oxy-, phosphorus tri- and especially phosphorus pentahalides, e.g. B.  Phosphorus oxychloride, phosphorus trichloride, and primarily phosphorus pentachloride, also pyrocatechyl phosphorus trichloride, and acid halides, in particular chlorides, of sulfur-containing acids or of carboxylic acids such as thionyl chloride, phosgene or oxalyl chloride. 



   The reaction with one of the said imide halide-forming agents is preferably carried out in the presence of a suitable, in particular organic, base, primarily a tertiary amine, e.g.  B.  a tertiary aliphatic mono or diamine, such as a tri-lower alkyl amine, e.g.  B.  Trimethyl, triethyl or ethyl diisopropylamine, also an N, N, N ', N' tetraniederalkyl-lower alkylenediamine, e.g. B.  N, N, N ', N'-tetramethyl-1,5-pentylenediamine or N, N, N', N'-tetramethyl-1,6hexyldiamine, a mono- or bicyclic mono- or diamine, such as an N- substituted, e.g.  B.    N-lower alkylated, alkylene, azaalkylene or oxaalkylene amine, e.g.  B.  N-methylpiperidine or N-methylmorpholine, also 2,3,4,6,7,8-hexahydro-pyrrolo [1,2-a] pyrimidine (diazabicyclonones; DBN), or a tertiary aromatic amine, such as a diene lower alkylaniline, e.g. B. 

  N, N-dimethylaniline, or primarily a tertiary heterocyclic, mono- or bicyclic base such as quinoline or isoquinoline, especially pyridine, preferably in the presence of a solvent such as an optionally halogenated, e.g. B.  chlorinated, aliphatic or aromatic hydrocarbon, e.g.  B.  Methylene chloride.  Approximately equimolar amounts of the imide halide-forming agent and the base can be used; but the latter can also be in excess or deficiency, e.g.  B.  be present in about 0.2 to about 1-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 + 100 C, but also at higher temperatures, d.  H.  z.  B.  up to about 75 "C, if the stability of the starting materials and products allow an increased temperature. 



   The imide halide product, which is usually processed further without isolation, is, according to the process, reacted with an alcohol, preferably in the presence of one of the abovementioned bases, to form the imino ether.  Suitable alcohols are e.g.  B.  aliphatic and araliphatic alcohols, primarily optionally substituted, such as halogenated, e.g.  B. 



  chlorinated, or additional hydroxyl-containing lower alkanols, e.g.  B.  Ethanol, n-propanol, isopropanol or n-butanol, in particular methanol, also 2,2,2-trichloroethanol, and optionally substituted phenyl-lower alkanols, such as benzyl alcohol.  Usually one uses, e.g.  B. 



  up to about 100-fold excess of the alcohol and preferably operates with cooling, e.g.  B.  at temperatures from about -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 Hydroxyverbindyng.  It is preferable to use water or an aqueous mixture of an organic solvent such as an alcohol, especially a lower alkanol, e.g.  B.  Methanol.  One usually works in an acidic medium, e.g.  B.  at a pH of about 1 to about 5 which, if necessary, can be obtained by adding a basic agent such as an aqueous alkali metal hydroxide, e.g.  B. 

 

  Sodium or potassium hydroxide, or an acid, e.g.  B.  a mineral acid, or organic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, trifluoroacetic acid or p-toluenesulfonic acid. 



   The three-step process for cleaving an acyl group described above is advantageously carried out without isolating the imide halide and imino ether intermediates, usually in the presence of an organic solvent which is inert to the reactants, such as an optionally halogenated hydrocarbon, e.g.  B.  Methylene chloride, and / or in an inert gas atmosphere such as a nitrogen atmosphere.   



   In a compound of the formula I in which RA and R bl
1 1 represent a phthalimido group together with the nitrogen atom, 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 A of an acylamino group in compounds obtainable according to the invention, such as.  B.  the 5 amino-5-carboxy-valeryl radical in which carboxyl, e.g. B.  by esterification, especially by diphenylmethyl, and / or the amino group, e.g. B.  by acylation, especially by halo-lower alkanoyl, such as dichloroacetyl, can also be protected by treatment with a nitrosating agent such as nitrosyl chloride, with a carbocyclic arene diazonium salt such as benzene diazonium chloride, or with a positive halogen-donating agent such as an N-halo-amide or imide, e.g. B. 

  N-bromosuccinimide, preferably in a suitable solvent or solvent mixture, such as formic acid together with a nitro or cyano-lower alkane and adding a hydroxy-containing agent, such as water or a lower alkanol, e.g. B.  Methanol, or if the amino group in the 5-amino-5-carboxy-valeryl radical R A is unsubstituted and the carboxy group z.  B.  is protected by esterification, and R b is hydrogen, by standing in an inert 1 solvent such as dioxane or a halogenated aliphatic hydrocarbon, e.g. B.  Methylene chloride and, if necessary, working up the free or monoacylated amino compound according to methods known per se, are split off. 



      A.
A formyl group R1 can also be obtained by treatment with an acidic agent, e.g. B.  p-toluenesulfonic or hydrochloric acid, a weakly basic agent, e.g.  B.  dilute ammonia, or a decarbonylating agent, e.g. B.  Tris (triphenylphosphine) rhodium chloride, are split off. 



   - In the process according to the invention, as well as 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. B. 



  by acylated, trityllerene or silylated, free hydroxy 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, if desired, released in a manner known per se in each case after the reaction has taken place. 



   In a compound of the formula I obtainable according to the invention with a protected, in particular esterified, carboxyl group of the formula -C (= O) -R A, this can in itself
2 A in a known manner, e.g.  B.  depending on the type of group R 2A, can be converted into the free carboxyl group.  An esterified, e.g.  B. 



  carboxyl group esterified by a lower alkyl radical, especially methyl or ethyl, especially in a 2-cephem compound of the formula I, 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, for example.     by treating with a chemical reducing agent such as a metal, e.g. B. 

  Zinc, or a reducing metal salt, such as a chromium-II salt, e.g. B.    Chromium-II-chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic and formic acid, or an alcohol, preferably adding water, a carboxyl group esterified by an arylcarbonylmethyl group, likewise by treatment with a nucleophilic, preferably salt-forming reagent, such as sodium thiophenolate or sodium iodide, a carboxyl group esterified by a suitable arylmethyl group e.g.  B.  by irradiation, preferably with ultraviolet light, e.g. B.  below 290 mK 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 nyc when the arylmethyl group z.  B.  a benzyl radical substituted in the 2-position by a nitro group, a by a suitably substituted methyl group, such as tert. -Butyl or diphenylmethyl, esterified carboxyl group e.g. 

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



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



   Salts of compounds of the formula I can be prepared in a manner known per se.  So you can salts of compounds of formula I with acidic groups z.  B.  by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g.  B.  the sodium salt of α-ethylcaproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts of compounds of the formula I with basic groups are obtained in a customary manner, for.  B.  by treatment with an acid or a suitable anion exchange reagent.  Internal salts of compounds of the formula I which contain a 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 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 diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds, or by fractional crystallization from optically active solvents into which antipodes are separated.   



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



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



   The starting materials of the formula II used according to the invention can, for.  B.  be prepared by in a cephem compound of the formula
EMI10. 1
 wherein R al preferably represents an amino protective group R A1, and wherein R2 preferably represents hydroxy, but also represents a group R A2, the acetyloxymethyl group, z.  B. 



  converted into the hydroxymethyl group by hydrolysis in a weakly basic medium, such as with an aqueous sodium hydroxide solution at pH 9-10, or by treatment with a suitable esterase, such as a corresponding enzyme from Rhizobium tritolii, Rhizobium lupinii, Rhizobium japonicum or Bacillus subtilis functionally modifies free carboxyl group of the formula = = O) -R2 in a suitable manner, e.g.  B.    



  esterified by treatment with a diazo compound such as diphenyldiazomethane and the hydroxymethyl group, e.g.  B. 



  by treating with a halogenating agent such as chlorinating agents, e.g.  B.  Thionyl chloride, or iodizing agents such as N-methyl-N, N'-dicyclohexyl-carbodiimidium iodide, in a halomethyl z.  B.  Chloromethyl resp.  Converts iodomethyl group.  A chloromethyl group is either directly, e.g.  B. 



  by treating with a suitable chromium-II compound such as an inorganic or organic salt thereof, e.g.  B. 



     Chromium-II-chloride or chromium-II-acetate, in a suitable solvent such as dimethylsulfoxide or then indirectly via the iodomethyl group (which you can e.g.  B.  by treating the chloromethyl compound with a metal iodide such as sodium iodide in a suitable solvent such as acetone), and the iodomethyl group converted to the methylene group by treatment with a suitable reducing agent such as zinc in the presence of acetic acid.  The methylene group in a compound of the formula
EMI10. 2
 is oxidatively degraded using the process described below; in a cepham-3-one compound obtainable in this way, in which both radicals R a and R b are hydrogen,
1 1 can the free amino group by an appropriate protecting group, for.  B.  following the procedure described below. 



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

  B.     at temperatures of about -90 "C to about + 4ovo C. 



   An ozonide formed as an intermediate is split reductively, using catalytically activated hydrogen, e.g.  B. 



  Hydrogen in the presence of a heavy metal hydrogenation catalyst such as nickel, also palladium, preferably on a suitable carrier material such as calcium carbonate or carbon, or chemical reducing agents such as reducing heavy metals, incl.  Heavy metal alloys or amalgams, e.g.  B. 



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



  Sodium iodide, in the presence of a hydrogen donor such as an acid, e.g.  B.  Acetic acid, or reducing organic compounds such as formic acid, a reducing sulfide compound such as a di-lower alkyl sulfide, e.g.  B.  Dimethyl sulfide, a reducing organic phosphorus compound, such as a phosphine, which may contain optionally substituted aliphatic or aromatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphines, e.g.  B.  Tri-n-butylphosphine, or triarylphosphines, e.g.  B. 

  Triphenylphosphine, furthermore phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, such as tri-lower alkyl phosphites, usually in the form of corresponding alcohol adduct compounds, such as trimethyl phosphite, or phosphorous acid triamides which optionally contain substituted aliphatic hydrocarbon radicals as substituents, such as hexa-lower alkyl phosphites .  B.  Hexamethylphos phorigsäuretriamid, the latter preferably in the form of a methanol adduct, or tetracyanoethylene. 

  The cleavage of the usually not isolated ozonide normally takes place under the conditions which are used for its preparation, i.  H.  in the presence of a suitable solvent or solvent mixture, and with cooling or gentle heating.   



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



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



   The compounds of the formula II are obtained by adding a cepham-3-one compound of the formula
EMI11. 1
 or a corresponding enol with a double bond in the 2,3 or 3,4-position, or a 1-oxide of such compounds, converted into an enol derivative with a functionally modified hydroxyl group of the formula -O-R3 in the 3-position, and, if desired , in a compound of the formula I obtained, the protected carboxyl group of the formula-C (= O> RA in 2 'converts the free or into another protected carboxyl group, and / or, if desired, a compound of the formula II obtained into another compound of the formula II transferred, and / or, if desired,

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



   In a keto starting material of the formula VIII, the protected carboxyl group of the formula -C (= O) -R A in the 4 position preferably has the a-configuration.  2
Cepham-3-one starting materials of the formula VIII can be in the keto and / or in the enol form; The starting materials of the formula VIII are converted from the enol form into the enol derivatives of the formula II.  Furthermore, a mixture of a compound of the formula VIII and the corresponding enol can be used as starting material and the product obtained is the mixture of a compound of the formula II and the corresponding 1-oxide. 



   The conversion of the starting materials of the formula VIII into the enol derivatives is carried out in a manner known per se. 



   Enol ether, d.  H.     Compounds of the formula II in which R3 stands for an optionally substituted hydrocarbon radical are obtained by a process suitable for etherifying enol groups, it being possible to use starting materials of the formula VIII in which R a and R b are
1 1 are hydrogen, but preferably Ra for one
R A stands.  Preferably, 1 amino protective group R 1A is used as the etherifying reagent a diazo compound of the formula R3-N2 (III) corresponding to the optionally substituted hydrocarbon radical R3, primarily an optionally substituted diazo lower alkane, e.g.  B.  Diazomethane or diazoethane, also an optionally substituted phenyl-diazo lower alkane, such as a 1-phenyl diazo lower alkane, e.g.  B.  Phenyldiazomethane or diphenyldiazomethane. 

  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 Diniederalkyläthers, z.  B.  Diethyl ether, or a cyclic ether, e.g.  B.  Tetrahydrofuran or dioxane, or a solvent mixture, and depending on the diazo reagent with cooling, at room temperature or with slight warming, further, if necessary, in a closed vessel and / or under an inert gas, e.g. B.  Nitrogen atmosphere applied. 



   Furthermore, enol ethers of the formula II can be formed by treatment with a reactive ester of an alcohol of the formula R3XH (IV) corresponding to the optionally substituted hydrocarbon R3.  Suitable esters are primarily those with strong inorganic or organic acids, such as mineral acids, e.g.  B.  Hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acid, or strong organic sulfonic acids such as methanesulfonic or p-toluenesulfonic acid.  These reagents, particularly lower alkyl halides, e.g.  B.  Methyl iodide, or corresponding phenyl lower alkyl halides, are usually in the presence of a solvent such as an optionally halogenated, such as chlorinated aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. B. 

  Methylene chloride, an ether such as dioxane or tetrahydrofuran, or a lower alkanol such as methanol, or a solvent mixture, preferably using suitable condensing agents such as a silver salt, e.g.  B.  Silver nitrate, silver perchlorate or silver tetrafluoroborate, used, and with cooling, at room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g.  B. 



  Nitrogen atmosphere applied. 



   Enol esters, d.  H.  Compounds of the formula II in which R3 is an acyl group are obtained by any process suitable for esterifying enol groups, at least R 1 in the starting material of the formula VIII being different from hydrogen, if one does not want to risk simultaneous acylation of a free amino group.     Carboxylic acids of the form R3OH (V) corresponding to the acyl radical R3 or reactive acid derivatives thereof, such as halides, e.g.  B.  Fluorides or chlorides, as well as pseudohalides, such as cyanocarbonyl compounds or anhydrides corresponding to the carboxylic acids (including the internal anhydrides of carboxylic acids, i.e.  H.     Ketenes, or from carbamic or thiocarbamic acids, d. 

  H.  Isocyanates or isothlocyanates, or mixed anhydrides, such as those which are e.g.  B.  with haloformic acid lower alkyl, such as chloroformic acid ethyl esters or isobutyl esters, or with trichloroacetic acid chloride are to be understood), or activated esters, such as esters with vinylogous alcohols (d. H.  Enols), e.g. B. 

 

  Esters of lower alkanecarboxylic acids with vinylogous lower alkanols (enol form of lower alkanols or lower alkanols), e.g.  B.  with isopropenyl acetate, if necessary, in the presence of suitable condensing agents, when using acids such.  B.  of carbodiimide compounds, such as dicyclohexylcarbodiimide, or carbonyl compounds, such as diimidazolylcarbonyl, when using reactive acid derivatives z.  B.  of basic agents such as tri-lower alkylamines, e.g.  B.  Triethylamine, or heterocyclic bases, e.g. B.  Pyridine, and when using esters with vinylogous alcohols in the presence of an acidic agent such as a mineral, e.g.  B.  Sulfuric acid or a strong sulphonic, e.g.  B.  p-toluenesulfonic acid, works. 

  The acylation reaction can be carried out in the absence or in the presence of a solvent or solvent mixture, with cooling, at room temperature or with heating, and, if necessary, in a closed vessel and / or in an inert gas, e.g. B. 



  Nitrogen atmosphere.  Suitable solvents are e.g.  B.  optionally substituted, in particular optionally chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbons, such as benzene or toluene, it also being possible to use suitable esterification reagents, such as acetic anhydride, as diluents. 



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



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



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



   For example
A solution of 0.514 g of 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 30 ml of methylene chloride is cooled to - 100 and with 0.8 ml of absolute pyridine and 8.0 ml of an 8% solution of Phosphorus pentachloride added to methylene chloride.  The reaction mixture is stirred for one hour at -100 to -50, then cooled to -30 "and mixed with 5 ml of methanol.  The mixture is stirred for one hour at -100 bis, one hour 0 and one hour at room temperature. 

  20 ml of a 0.5 molar aqueous potassium hydrogen phosphate solution are added, the mixture is stirred at pH 2.4 for 30 minutes, diluted with methylene chloride, the aqueous phase is separated off and extracted with methylene chloride.  The combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is digested with diethyl ether and left to stand at 0 for 16 hours; the precipitate is filtered off, washed with diethyl ether and dried. 

  The 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as a light beige powder, thin-layer chromatogram (silica gel; developed with iodine vapor): Rf-0.17 (system: ethyl acetate); Ultraviolet absorption spectrum (in 95% aqueous ethanol) / max = 258 m, u (e = 5250) and 264 m, u (s = 5300 AS ° huler = 29O m, u (e = 5200); infrared absorption spectrum (in dioxane): characteristic bands at 2.87 y (broad), 5.62 K, 5.85 Iz and 6.26 Cl.    



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

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

  The precipitate is filtered off and recrystallized from a mixture of acetone and cyclohexane; the 3-hydroxymethyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester thus obtained melts at 176-176.5 (uncorr. ); yes] 20 -6 "fl" (c = 1.231% in
D chloroform); Thin-layer chromatogram (silica gel; detection with iodine vapor or ultraviolet light A 254); Rf = 0.42 (system: chloroform / acetone 4: 1), Rf = 0.43 (system: toluene / acetone 2: 1), and Rf = 0.41 (system: methylene chloride / acetone 6: 1). 



   1.03 g of 3-hydroxymethyl-7ss-phenylacetylamino-3cephem-4-carboxylic acid diphenylmethyl ester and 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide are dissolved under a nitrogen atmosphere in 25 ml of absolute tetrahydrofuran and heated for one hour at 35 ".     Another 1.05 g of N-methyl-N, N'-dicyclohexylcarbodiimidium iodide in 15 ml of absolute tetrahydrofuran is then added and the mixture is left to stand for 17 hours at room temperature under a nitrogen atmosphere.  The reaction mixture is freed from the solvent on a rotary evaporator under reduced pressure.  The residue is taken up in methylene chloride and filtered through a column of 50 g of silica gel (addition of 10% distilled water); it is washed with 4 portions of 100 ml of methylene chloride each time. 

  The eluate is concentrated to a small volume and chromatographed on a silica gel column (90 g; deactivated by adding 10% distilled water).  With a total of 900 ml of a 3: 7 mixture of toluene and methylene chloride, non-polar impurities are eluted.  Elution with 2 portions of 200 ml of methylene chloride each yields the 3-iodine methyl-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester; the fractions which are uniform according to thin-layer chromatography are lyophilized from benzene, infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.00 iL, 5.62, 5.82, 5.95 C1, 6.70 u, 7.32 y and 816N
The iodination reagent used above can be prepared as follows:
In a 250 ml round bottom flask with magnetic stirrer, reflux condenser and attached nitrogen balloon, 42 g of freshly distilled N, N'-dicyclohexylcarbodiimide are dissolved in 90 ml of methyl iodide under a nitrogen atmosphere at room temperature and the colorless reaction mixture is stirred for 72 hours at a bath temperature of 70.  After the reaction time has elapsed, the excess methyl iodide is distilled off from the now red-brown solution under reduced pressure and the viscous, red-brown residue is dissolved in 150 ml of absolute toluene at 40 °.  

  The crystal mass which spontaneously crystallizes out within a few hours is separated from the mother liquor with the aid of a glass suction filter with attached nitrogen balloon under exclusion of air, the reaction vessel is rinsed three times with 25 ml of absolute, ice-cold toluene each time and the same toluene is used to colorless the slightly yellowish crystal mass on the glass suction filter to wash.  After drying at 0.1 mm Hg for 20 hours.  and room temperature the N-methyl-N, N-dicyclohexylcarbodiimidium iodide is obtained in the form of colorless crystals, F 111-113; Infrared absorption spectrum (in chloroform): characteristic bands at 4.72 C1 and 6.00 cm.      



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

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

  The 3-methylene-7ss-phenylacetylamino-cephem-4a-carboxylic acid-diphenylmethyl ester is eluted with methylene chloride and methylene chloride containing 2% methyl acetate and crystallized from a mixture of methylene chloride and hexane, F. 144-147; [α] = 180 i10 (c = 0.715 in chloroform);

  Ultraviolet absorption spectrum (in 95% aqueous ethanol): AmaX = 254 my (s = 1540) and 260 my (± = 1550); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 C (, 5.65, 5.74, 5.94, 6.26 y and 6.67 p.    



   A solution of 1.0 g of 3-methylene-7ss-phenylacetylamino cepham-4α-carboxylic acid diphenylmethyl ester in 250 ml of methylene chloride is treated with an oxygen-ozone mixture (0.265 mmol ozone / minute) at -70 for 8+ minutes and 1 ml of dimethyl sulfide is added to the reaction mixture.  The mixture is stirred for 30 minutes at 700 and for 1+ hours at room temperature and then evaporated to dryness under reduced pressure.  The residue, containing a mixture of 7ss-phenylacetylamino-cepham-3-one-4a-carboxylic acid diphenylmethyl ester and 7ss-phenylacetylamino.    



  cepham-3-one-4-carboxylic acid diphenylmethyl ester-1-oxide, is taken up in 50 ml of methanol and, at 0, an excess of diazomethane (in the form of a solution in diethyl ether) is added.  The mixture is stirred for one hour at 0 and then evaporated under reduced pressure.  The residue is chromatographed on 50 g of silica gel. 

  A 4: 1 mixture of toluene and ethyl acetate is used to elute the 3-methoxy-7ss-phenylacetylamino-2-cephem-4a-carboxylic acid diphenylmethyl ester with Rf = 0.57 (system: toluene / ethyl acetate 1: 1); F. 174-177 after crystallization from a mixture of methylene chloride and pentane; Ultraviolet absorption spectrum (in 95% aqueous ethanol): Ämix = 258 m, u (± = 4310); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 5.60, 5.71, 5.92, 6.15 and 6.66; followed by 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester with Rf¯0.37 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): AmaX = 258 m (# = (: 6340), Äx = 264m (± = 6350) and Ashoulder = 261m (: = 5600); infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94, 3.02, 5.62, 5.67 (shoulder), 5.81, 5.92, 6.23 and 6.67; and with ethyl acetate the 3-methoxy-7ss-phenylacetylamino-3- cephem-4-carboxylic acid diphenylmethyl ester-1 -oxide with Rf = 0.31 (system:

  Ethyl acetate); F.  152-155 after crystallization from a mixture of acetone and diethyl ether; Ultraviolet absorption spectrum (in 95% aqueous ethanol): # max = 288 IIYL (8 = 3610) and ASchulbr = 247 mi infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 p, 5.59 L, 5.81 H 5 , 95 K 6.22 Cr and 6.61. 



   Example 2
A solution of 0.263 g of 7ss- (5-benzoylamino-5-diphenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester in 13 ml of methylene chloride is cooled to -100 and mixed with 0.132 ml of pyridine and 3 , 52 ml of an 8% solution of phosphorus pentachloride in methylene chloride.  The mixture is stirred for one hour at -10 ", then cooled to 300, 2.2 ml of cooled methanol are quickly added and stirring is continued for 30 minutes at 100 and -5.  The reaction mixture is then mixed with 6.5 ml of a 0.5 molar aqueous solution of potassium dihydrogen phosphate, stirred for 5 minutes at room temperature and the phases are separated. 

  The aqueous phase is washed with methylene chloride; the combined methylene chloride phases are washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is dissolved in methanol and diethyl ether is added to the solution until it becomes slightly cloudy.  The 7pp amino-3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is obtained as an amorphous precipitate, thin-layer chromatogram (silica gel): Rf = 0.17 (system: ethyl acetate; development with iodine): ultraviolet absorption spectrum (in 95% - strength aqueous ethanol): A max = 258 (# = 5700); Infrared absorption spectrum (in dioxane): characteristic bands at 2.87, 5.62 jC, 5.85 y and 6.26. 



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

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



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

 

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



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



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



  About 15 ml of ethyl acetate are used to transfer the product into the reaction vessel. 



   A solution of 2.3 g of 7ss- (5-benzoylamino-5-carboxyvaleryl-amino) -3-methylene-cepham-4a-carboxylic acid in 25 ml
A solution of 2.5 g of diphenyldiazomethane in 10 ml of n-pentane is added dropwise to dioxane over a period of 10 minutes. 



  The mixture is stirred for 30 minutes at room temperature, the excess diphenyldiazomethane is decomposed by adding a few drops of acetic acid (glacial acetic acid) and the solution is evaporated under reduced pressure.  The residue is chromatographed on 80 g of silica gel, the 7ss- (5-benzoylamino-5-di-phenylmethoxycarbonyl-valeryl-amino) -3-methylene-cepham a-carboxylic acid diphenylmethyl ester with a 3: 1 mixture of toluene and ethyl acetate eluted and then crystallized from a mixture of methyl acetate and cyclohexane, F.  1801810; Thin-layer chromatogram (silica gel): Rf = 0.24 (system:

  Toluene / ethyl acetate 2: 1); Ultraviolet absorption spectrum (in 95% aqueous ethanol): no characteristic bathing; Infrared absorption spectrum (in methylene chloride): characteristic bathing at 6.55y, 5.76K, 5.95, 6.03u, 6.64cm and 670lt
A solution of 1.59 g of 7ss- (5-benzoylamino-5-diphenyl methoxycarbonyl-valeryl-amino), 3 -methylene-cepham-4a-carboxylic acid diphenylmethyl ester in 150 ml of methylene chloride is cooled to -70 "and while stirring vigorously during Treated for 12 minutes and 43 seconds with a mixture of ozone and oxygen containing 0.1 mmol of ozone per minute, then treated with 1 ml of dimethyl sulfide. 

  The mixture is stirred for 5 minutes at 700 and for 30 minutes at room temperature and evaporated under reduced pressure.  The residue, containing the 7ss- (5-benzoylamino-5-diphenylmethoxycarbonylvaleryl-amino) -cepham-3-one-4-carboxylic acid diphenylmethyl ester, is dissolved in 40 ml of methanol, cooled in an ice bath and mixed until it remains yellow with a solution of diazomethane in diethyl ether.  The reaction mixture is evaporated under reduced pressure and the residue is 100 g
Chromatographed silica gel. 

  The 7ss- (5-benzoylamino-5-di phenylmethoxycarbonyl-valeryl-amino) -3-methoxy-3-cephem-4-carboxylic acid diphenylmethyl ester is with a
1: 1 mixture of toluene and ethyl acetate eluted and obtained as an amorphous product, thin-layer chromatogram (silica gel): Rf = 0.45 (system: toluene / ethyl acetate
1: 1); Ultraviolet absorption spectrum (in 95% aqueous
Ethanol): Asehuer = 258 mfe (e = 7450), 264 mju (8 = 7050) and
268 mfe (: = 6700); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65 CL, 5.78 Cc, 6.03 ju and 6.64 lt.    



   Example 3
A suspension of 1.65 g of 7ss-amino-3-methoxy-3cephem-4-carboxylic acid diphenylmethyl ester and 2 ml of anisole is mixed with 20 ml of precooled trifluoroacetic acid and stirred in an ice bath for 15 minutes.  It is diluted with 100 ml of cold toluene and the reaction mixture is evaporated under reduced pressure.  The dark brown residue is dried under high vacuum and stirred with diethyl ether; the precipitate is filtered off, washed with acetone and diethyl ether and dried.  The thus obtainable salt of 7ss amino-3-methoxy-3-cephem-4-carboxylic acid and trifluoroacetic acid is dissolved in 10 ml of water; the aqueous solution is washed twice with 10 ml of ethyl acetate each time, and brought to a pH of 4.5 by adding a 10% solution of triethylamine in methanol. 

  Dilute with 10 ml of acetone; the mixture is stirred at 0 for one hour.  The precipitate is filtered off, washed with a 1: 2 mixture of acetone and diethyl ether and dried in a high vacuum and gives the 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid in the form of the inner salt, thin-layer chromatogram (silica gel) : Ruf¯0.16 (system: n butanol / acetic acid / water 67:10:23); Ultraviolet absorption spectrum (in 0.1-n.  Hydrochloric acid): An ,. X = 261 mlt 5400).    



   In the 7ss-amino-3-methoxy-3-cephem-4-carboxylic acid which can be prepared by the above process, treatment with trimethylchlorosilane can convert the carboxyl group and, if an excess of the silylating agent is used, also the amino group into the carboxyl group protected by a trimethylsilyl group and, if appropriate, converting protected amino group in the same way, and acylating the amino group in the trimethylsilylated 7ss amino-3-methoxy-3-cephem-4-carboxylic acid by treatment with phenylacetyl chloride; after the usual work-up in the presence of water, the 3-methoxy-7ss-phenylacetylamino-3-cephem-4-carboxylic acid is obtained. 



   Example 4
To a suspension of 2.55 g (7 mmol) of 7ss-phenoxy-acetamido-3-methoxy-ceph-3-em-4-carboxylic acid (obtained from 0.25 mmol of phenyloxyacetyl chloride and 0.25 mmol of 7ss-amino3-methoxy- 3- cephem-4-carboxylic acid in methylene chloride at -15 "and in the presence of 0.5 mmol of triethylamine) and 2.9 ml (22.4 mmol) of N, N-dimethylaniline in 11 ml of absolute methylene chloride under nitrogen at 20.degree 0.7 ml (5.7 mmol) of dimethyl dichlorosilane were added and the mixture was 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, then quickly 10 ml of pre-cooled (- 20 "C) n-butanol is added and the mixture is then stirred for 20 minutes at -20" C and 10 minutes without cooling.  At about - 100 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 were added in portions until the samples diluted with water assume 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-Amino3-methoxy-ceph-3-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 / water 30: 40: 20: 5: 5). 



   Example S.
A suspension of 11.75 g of 93 percent (corresponds to 



  10.93 g of 100%) 7ss-phenoxyacetamido-3-methoxy-ceph3-em-4-carboxylic acid and 13.4 ml (12.73 g) of N, N-dimethylaniline in 47 ml of abs.  Methylene chloride (distilled over P2O5) is treated with 3.6 ml (3.87 g) of dimethyl dichlorosilane at +20 C under nitrogen and then stirred for 30 minutes at the same temperature.  The now clear solution is cooled to - 180/190 and treated with 7.8 g-solid phosphorus pentachloride, the internal temperature rising to - 100. 

  After 30 minutes of stirring in the - 200 bath, the clear
Solution within approx.  7 minutes, to one chilled to - 200
Mixture of 47 ml of n-butanol (anhydrous, dried over Sikkan) and 4.4 ml (4.18 g) of dimethylaniline were added dropwise.  The internal temperature rises to -8 ". The mixture is stirred 30 minutes later - initially in a -200 bath, later in an ice bath (0), so that a final internal temperature of -100 is reached.  At this
Temperature becomes a mixture of 47 ml of dioxane and 1.6 ml
Water was added dropwise (duration about 5 minutes).  The product slowly crystallizes out. 

  After stirring for a further 10 minutes, the mixture is poured into an ice bath by adding approx.  9.5 ml tri-n-butylamine within approx.  1 hour (first
5 ml) added in the first 5 minutes) brought to a pH between 2.2 and 2.4 and maintained.  It is then filtered off, washed in portions with approx.  30 ml dioxane, then approx.  15 ml of methylene chloride and thus receives the crystalline 7ss
Amino-3-methoxy-ceph-3-em-4-carboxylic acid hydrochloride dioxanate; Melting point above 300 C;

  UV spectrum (in 0.1 N
Sodium bicarbonate): 1S, X = 270 mfe (e = 7600); IR spectrum (Nujol): characteristic bands at 5.62; 5.80; 5.88; 6.26;
6.55; 7.03; 7.45; 7.72; 7.96; 8.14; 8.26; 8.45; 8.64; 8.97; 9.29; 10.40; 11.47 my; Ez 20 = + 1340 l10 (c = 1; 0.5NNa-
D trium bicarbonate solution).    

 

   The zwitterion of the 7ss-amino-3-methoxy-ceph-3-em can be obtained from the hydrochloride dioxanate obtained by adding 2N sodium hydroxide solution to a 20% strength aqueous solution thereof up to a pH of 4.1 (isoelectric point) -4- carboxylic acid are obtained, which is filtered off and dried, has a melting point of over 3000 C, UV spectrum (in 0.1 N sodium bicarbonate solution) A. , SX = 270 nm (e = 7600).     Thin-layer chromatogram: Rf value identical to that of the hydrochloride (silica gel, same system); [aj 20 = +232 +1 (c = 1; 0.5 N sodium bicarbonate solution).     D.

 

Claims (1)

PATENT CLAIM Process for the preparation of 7ss-amino-cephem-3- 01-4carboxylic acid compounds of the formula EMI15.1 where R2 stands for hydroxy or a radical R2 which forms a protected carboxyl group A together with the carbonyl group (= 0), and R3 stands for an optionally substituted hydrocarbon radical or an acyl group, and salts of such compounds, characterized in that one .in a compound of the formula EMI15.2 where R A is an acyl group Ac and R b is hydrogen, 1 1 or where R A 'and R bl together with the nitrogen atom 1 1 represent a phthalimido group, and in which R2 and R3 have the meanings given under formula I, the acylated 7ss amino group is converted into a free 7ss amino group by deacylation and a compound obtained is isolated as a salt or in free form. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of the formula II are used in which R represents the acyl radical of an organic carboxylic acid, in which1 any free functional groups present are protected, R b is hydrogen, and R 2A is one with 1 2 -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) -RA to be protected. 2. The method according to claim, characterized in that A that starting materials of the formula II are used in which R1 is phenylacetyl, phenyloxyacetyl or 5-monoacylamino-5aryl-lower alkoxycarbonylvaleryl. 3. The method according to claim, characterized in that A represents an optionally substituted 1-phenyl lower alk R2 oxy, wle diphenylmethoxy group. 4. The method according to claim, characterized in that R A that R 2 is an optionally halogen-substituted lower alkoxy group, such as a-polybranched lower alkoxy, e.g. B. tert-butyloxy, or 2-halo-lower alkoxy, such as 2,2,2-trichloroethoxy represents. 5. The method according to claim, characterized in that a compound of the formula II is deacylated by hydrolysis, aminolysis or hydrazinolysis. 6. The method according to claim, characterized in that one carries out the deacylation of a suitable acyl group R A in a compound of formula II by treatment with an imide halide-forming agent, reacting the imide halide formed with an alcohol and cleaving the imino ether formed. 7. The method according to dependent claim 6, characterized in that the imide-halide-forming agent used is phosphorus pentachloride. 8. The method according to claim, characterized in that the protected carb oxyl group -C (= O) -RA in a compound obtained by solvolysis, reduction or 2 Photolysis converted into a free carboxyl group. 9. The method according to claim or one of the dependent claims 1-8, characterized in that 3-cephem compounds of the formula I according to claim, as well as salts of compounds in which R2 is hydroxy, optionally substituted lower alkoxy or optionally substituted phenyl-lower alkoxy, and R3 is lower alkyl , optionally substituted phenyl-lower alkyl, lower alkanoyl or benzoyl. 10. The method according to claim or one of the dependent claims 1-8, characterized in that 3-cephem compounds of the formula I according to claim or salts of those compounds are prepared in which R2 is hydroxy, lower alkoxy, 2-halo-lower alkoxy or optionally substituted diphenylmethoxy and R3 represents lower alkyl or lower alkanoyl. 11. The method according to claim or one of the subclaims 1-8, characterized in that 3-cephem compounds of the formula I according to claim or salts of such compounds are prepared in which R2 is hydroxy, optionally lower alkoxy which is halogen-substituted in the 2-position or optionally lower alkoxy is substituted diphenylmethoxy, and R3 is methyl. 12. The method according to claim or one of the dependent claims 1-7, characterized in that the 3-methoxy-7ss-amino-3-cephem-4-carboxylic acid diphenylmethyl ester is prepared.