CH562250A5 - 7-(n-acylamino) 2,2-dimethylceph-3-em 4-car boxylic acid - derivs antibiotic intermediates - Google Patents

Abstract

Cephem derivs. of formula (I) and their salts, where R is acyl and R2 a carboxyl protecting group e.g. an ester, anhydride, silyl or stannyl residue, are intermediates for broad spectrum antibiotics. (I) are prepd. by acylating the N-unsubstd. analogues of (I) with a reactive deriv. of the acid.

Description

  

  
 



   The present invention relates to a process for the preparation of 7- (N-acyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acids and their esters of the formula I
EMI1. 1
 where Ac represents an acyl group and R2 represents hydrogen, or an organic radical R- which together with the C (= O-grouping forms an esterified carboxyl group. t stands, as well as salts of such compounds, with salt-forming groups. 



   A group Ac primarily represents the acyl radical of an organic carboxylic acid, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid and the acyl radical of a carbonic acid half derivative.    



   A residue RnA is e.g. B.  an organic radical which, together with the carboxyl group, forms an esterified carboxyl group, preferably easily cleavable; such radicals can be aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, in particular optionally substituted hydrocarbon radicals of this type, and also heterocyclic or heterocyclic-aliphatic radicals. 



   An aliphatic radical, including the aliphatic radical of a corresponding organic carboxylic acid, which term also includes formic acid, is an optionally substituted aliphatic hydrocarbon radical, such as an alkyl, alkenyl or alkynyl, in particular a lower alkyl or lower alkenyl, and also a lower alkynyl radical, the z. B.    



  can contain up to 7, preferably up to 4 carbon atoms.  Such radicals can optionally be replaced by functional groups, e.g. B.  by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy * Niederalkvlendioxy-, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto or optionally substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxycarbonyloxy or lower alkoxycarbonyloxy Halogen atoms, also through oxo groups, azido groups, acyl, such as lower alkanoyl or benzoyl groups,

   optionally functionally modified carboxy groups such as carboxyl groups present in salt form or lower alkoxycarbonyl, optionally N-substituted carbamyl.     or cyano groups, or optionally functionally modified sulfo groups, such as sulfamoyl groups or sulfo groups present in salt form, can be mono-, di- or polysubstituted. 



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid, is an optionally substituted cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radical, e.g. B. 



  a mono-, bi- or polycyclic cycloalkyl or cycloalkenyl group, or  Cycloalkyl or cycloalkenyl-lower alkyl or lower alkenyl group, wherein a cycloalkyl radical z. B.  up to
12, such as 3-8, preferably 3-6, ring carbon atoms, while a cycloalkenyl radical z. B.  up to 12, such as 3-8, e.g. B.    5-8, preferably 5 or 6, ring carbon atoms and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z. B.  may contain up to 7, preferably up to 4, carbon atoms. 

  The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. B.  by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned, optionally substituted lower alkyl groups, or then, for. B.  like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups. 



   The 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 a phenyl, and a biphenylyl or naphthyl radical, which optionally, for. B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   The araliphatic radical, including the araliphatic radical in a corresponding carboxylic or sulfonic acid, is z. B.  an optionally substituted araliphatic hydrocarbon radical, such as an optionally substituted, e.g. B.  Up to three, optionally substituted mono-, bi- or polycyclic, aromatic hydrocarbon radicals containing aliphatic hydrocarbon radicals and is primarily a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl radical, such radicals z. B.  1-3 phenyl groups and optionally, z. B.  like the abovementioned aliphatic and cycloaliphatic radicals, can be mono-, di- or polysubstituted in the aromatic and / or aliphatic part. 



   Heterocyclic groups, including those in heterocyclic-aliphatic radicals, including heterocyclic or heterocyclic-aliphatic groups in corresponding carboxylic acids, are in particular monocyclic, as well as bi- or polycyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza- , triaza or tetrazacyclic radicals of aromatic character, which 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 ss-position, substituted lower alkyl half esters of carbonic acid (i.e. H.  a lower alkoxycarbonyl radical which is optionally substituted in the lower alkyl moiety, preferably in the ce- and also in the 13-position), and one optionally in the lower alkenyl, cycloalkyl, phenyl or 



     Phenyl-lower-alkyl part-substituted lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl half-ester of carbonic acid (i.e. H.  an optionally in lower alkenyl, cycloalkyl, phenyl or    Phenyl-lower alkyl part-substituted lower alkenyloxycarbonyl, cycloalkoxycarbonyl, phenyloxycarboxycarbonyl or phenyl-lower alkoxycarbonyl 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, e.g. B.  contains one of the above-mentioned heterocyclic groups of aromatic character, it being possible for both the lower alkyl part and the heterocyclic group to be optionally substituted.  

  Acyl residues of carbonic acid half derivatives are also optionally N-substituted carbamoyl groups. 



   A lower alkyl radical is e.g. B.  a methyl, ethyl, n-propyl.   



  Isopropyl, n-butyl, isobutyl, sec. -Butyl- or tert. -Butyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while a lower alkenyl z. B.  a vinyl, allyl, isopropenyl, 2- or 3-methalallyl or 3-butenyl group, and a lower alkynyl radical e.g. B.  may be a propargyl or 2-butynyl group. 



   A cycloalkyl group is e.g. B.  a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl and adamantyl group, and a cycloalkenyl, e.g. B.  a 2-cyclopentyl, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl group.  A cycloalkyl-lower alkyl or -niederalkenylrest is z. B.  a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, -1,1- or -1,2-ethyl-, -1,1-, -1,2- or -1,3-propyl-, -vinyl- or allyl group, while a cycloalkenyl lower alkyl or lower alkenyl group, e.g. B.  a 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or 1-, 2- or 3-cycloheptenyl-methyl-, -1,1 or -1,2-ethyl-, -1, Represents 1-, -1,2- or -1,3-propyl, vinyl or allyl group. 



   A naphthyl radical is a 1- or 2-naphthyl radical, while a biphenyl group z. B.  represents a 4-biphenylyl radical. 



   A phenyl-lower alkyl or phenyl-lower alkenyl radical is, for. B.  a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical. 



   Heterocyclic radicals are e.g. B.  monocyclic, monoaza-, monothia- or monooxacyclic radicals of aromatic character, such as pyridyl, z. B.  2-pyridyl, 3-pyridyl or 4-pyridyl, furthermore pyridinium, thienyl, z. B.  2-thienyl radicals, or furyl, e.g. B.  2-furyl radicals, or bicyclic monoazacyclic radicals of aromatic character, such as quinolinyl, e.g. B. 



  2-quinolinyl or 4-quinolinyl radicals, or isoquinolinyl, e.g. B. 



  1-Isoquinolinyl radicals, or monocyclic diaza, triaza, tetraza, thiaza or oxazacyclic radicals of aromatic character.  such as pyrimidinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl radicals.  Heterocyclischaliphatic radicals are heterocyclic groups, especially the lower alkyl or lower alkenyl radicals containing the above. 



   Etherified hydroxyl groups are primarily lower alkoxy, e.g. B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec. -Butyloxy-, tert.  Butyloxy, n-pentyloxy or tert. -Pentyloxy groups, as well as substituted lower alkoxy, such as halo-lower alkoxy, in particular 2-halo-lower alkoxy, z. B.  2,2,2-trichloro, 2 bromine or 2-iodoethoxy groups, also lower alkenyloxy, z. B.  Vinyloxy or allyloxy groups, lower alkylenedioxy, e.g. B.  Methylene, ethylene or isopropylidenedioxy groups, cycloalkoxy, e.g. B.  Cyclopentyloxy, cyclohexyloxy or adamantyloxy groups, phenyloxy groups, phenyl-lower alkoxy, e.g. B. 

  Benzyloxy or 1- or 2-phenylethoxy groups, or by monocyclic, monoaza-, monooxa- or monothiacyclic groups of aromatic character substituted lower alkoxy, such as pyridyl-lower alkoxy, z. B.  2-pyridylmethoxy, furyl-lower alkoxy, e.g. B.  Furfuryloxy, or thienyl lower alkoxy, e.g. B.  2-thenyloxy groups, to be understood. 



   As etherified mercapto groups, lower alkyl mercapto, z. B. Methylmercapto-, Athylmercapto- or n-butylmercapto groups, lower alkenylmercapto-, z. B.  Allyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto, e.g. B.  Benzyl mercapto groups. 



   Esterified hydroxy groups are primarily halogen, e.g. B.  Fluorine, chlorine, bromine or iodine atoms, and lower alkanoyloxy, z. B.  Acetyloxy or propionyloxy groups. 



   Substituted amino groups are mono- or disubstituted
Amino groups in which the substituents are primarily optionally substituted monovalent or divalent aliphatic, cycloaliphatic hydrocarbon radicals and acyl groups.  Such amino groups are in particular lower alkylamino or di-lower alkyl-amino, e.g. B. 



  Methylamino, ethylamino, dimethylamino or diethylamino groups, or optionally by heteroatoms such as oxygen, sulfur or optionally, e.g. B.  lower alkyleneamino groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiomorpholino or 4-methylpiperazino groups.  Substituted amino groups are also acylamino, especially lower alkanoylamino, such as acetylamino or propionylamino groups, or optionally in salt, such as alkali metal, z. B.  Sodium or ammonium salt form, sulfamino groups present. 



   A lower alkanoyl radical is e.g. B.  an acetyl or propionyl group. 



   A carboxyl group present in salt form is e.g. B.  a carboxyl group present in alkali metal or ammonium salt form. 



   A lower alkoxycarbonyl radical is e.g. B.  a methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, tert. -Butyloxycarbonyl- or tert. Pentyloxycarbonyl group. 



   Optionally N-substituted carbamoyl groups are e.g. B. 



  N-lower alkyl- or N, N-di-lower alkyl-carbamoyl-, such as N-methyl-, N-ethyl-, N, N-dimethyl- or N, N-diethylcarbamoyl-, and N-halo-lower alkylcarbamoyl-, e.g.  B.  N-2 chloroethylcarbamoyl groups. 



   A sulfamoyl group may optionally be substituted and e.g. B.  represent an N-lower alkyl-sulfamoyl, such as N-methyl or N, N-dimethylsulfamoyl group.  Sulfo groups present in salt form are e.g. B.  in alkali metal, e.g. B.  Sulfo groups present in the sodium salt form. 



   A Niederalkenyloxycarbonylrest is z. B.  the vinyloxycarbonyl group, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl groups, in which the cycloalkyl or 



  Phenyl-lower alkyl radical have the above meaning, e.g. B. 



  Represent adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-biphenylyl-α-methylethoxycarbonyl groups.  Lower alkoxycarbonyl groups in which the lower alkyl radical z. B.  contains a monocyclic, monoaza-, monooxa- or monothiacyclic group are, for. B. 



  Furyl lower alkoxycarbonyl, such as furfuryloxycarbonyl or thienyl lower alkoxycarbonyl, e.g. B.  Thenyloxycarbonyl groups. 



   A radical R2 together with the -C (= O) -O- group preferably forms a, under neutral or acidic, aqueous conditions on treatment with a reducing metal, a reducing metal alloy, e.g. B.  a reducing metal amalgam, or a metal salt, upon irradiation, preferably with ultraviolet light, or upon treatment with an acidic and weakly basic agent, or under neutral conditions hydrolytically or alcoholytically, easily cleavable esterified carboxyl group. 



   An organic radical R2 is e.g. B.  the group Rosa, which denotes a 2-halo-lower alkyl radical, in which halogen preferably has an atomic weight of more than 19; such a
The remainder forms, together with the -C (= O) -O grouping, a, when treated with a reducing agent, a reducing metal alloy, e.g. B.  a reducing metal amalgam or a metal salt, 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 that can easily be converted into such a group.  The radical K can be one, two or more halogen, e.g. B.  Chlorine, bromine or iodine atoms contain, in particular 2-chlorine, but also 2-bromo-lower alkyl radicals, several, preferably three chlorine or  

  Contain bromine atoms, while a 2-iodine-lower alkyl radical has primarily only one iodine atom.  The radical R ″ represents in particular a 2-polychloro-lower alkyl, such as 2-polychloroethyl radical, primarily the 2,2,2-trichloroethyl radical, and the 2,2,2-trichloro-1-methyl-ethyl radical, but it can also z. B.  a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, e.g. B.  the 2,2,2 tribromoethyl, also the 2-bromoethyl radical, or a 2-iodine lower alkyl.  in particular the 2-iodoethyl radical. 



   Another group RA which, together with the -C (= O) O grouping, produces a upon treatment with one of the above-mentioned metallic reducing agents under neutral or weakly acidic conditions, e.g. B.  when treated with zinc in the presence of aqueous acetic acid, represents easily cleavable esterified carboxyl group, is an arylcarbonylmethyl group Rb.     In this, the aryl radical stands for a bi- or polycyclic, but in particular a monocyclic, optionally substituted aromatic hydrocarbon radical, e.g. B.  an optionally substituted phenyl group.  Substituents of such groups are e.g. B.  optionally substituted hydrocarbon radicals such as lower alkyl, e.g. B.  Methyl, ethyl or isopropyl.  also trifluoromethyl, phenyl or phenyl lower alkyl.  z. B. 

  Benzyl or phenylethyl radicals, or functional groups such as free or functionally modified carboxyl groups, e.g. B.  Carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, also carbamoyl or cyano groups, optionally functionally modified, such as esterified hydroxyl or mercapto groups, e.g. B.  Halogen atoms, or etherified hydroxy or mercapto groups, such as lower alkoxy, e.g. B.  Methoxy, ethoxy, n-propyloxy, isopropyloxy.  n-butyloxy or tert. -Butyloxy groups, and / or optionally substituted amino, such as di-lower alkyl, z. B. 



  Dimethylamino or diethylamino, or lower alkanoylamino.  z. B.  Acetylamino groups. 



   The methyl part of an arylcarbonylmethyl radical Rob is preferably unsubstituted, but can also be an organic radical.  z. B.  an optionally substituted aliphatic hydrocarbon radical such as a lower alkyl, e.g. B.  Methyl ethyl.     n-propyl, isopropyl, n-butyl or tert. -Butyl group, or a cycloaliphatic, aromatic or araliphatic radical, such as an aryl, z. B.  optionally substituted phenyl group.  and an optionally substituted cycloalkyl, e.g. B.    Cvclohexylgruppe, or an optionally substituted phenyl-lower alkyl, e.g. B.  Benzyl group, as a substituent. 



   An arylcarbonylmethyl radical R is preferably the unsubstituted phenacyl radical, but it can also be one which is substituted in the aromatic part.  as by lower alkyl, e.g. B.  Methyl groups, lower alkoxy, e.g. B.  Methoxy groups, or halogen, e.g. B.  Represent fluorine, chlorine or bromine atoms, substituted phenacyl radical. 



   The group RA can also represent the group Rg, which represents an arylmethyl group, in which aryl denotes a bi- or polycyclic, but in particular a monocyclic, preferably substituted aromatic hydrocarbon radical.  Such a radical, together with the -C (= O) -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 is primarily an optionally substituted phenyl group.  but can also be a naphthyl, such as 1- or 2-naphthyl group.  Substituents of such groups are e.g. B. 



  optionally substituted hydrocarbon radicals, such as lower alkyl, phenyl or phenyl-lower alkyl radicals, which may optionally contain functional groups, such as those below, as substituents, or primarily functional groups, such as free or functionally modified carboxyl groups.  z. B.  Carboxy, lower alkoxycarbonyl, such as methoxycarbonyl or ethylcarbonyl, carbamoyl or
Cyano groups, optionally substituted amino, such as di-lower alkylamino groups, or acyl, such as lower alkanoyl, e.g. B. 



  Acetyl groups, especially esterified hydroxy or mercapto groups, such as acyloxy, e.g. B.  Lower alkanoyloxy, such as acetyloxy groups, or halogen, e.g. B.  Fluorine, chlorine or bromine atoms, primarily etherified hydroxy or mercapto groups, such as lower alkoxy, e.g. B.  Methoxy, ethoxy, n propyloxy, isopropyloxy, n-butyloxy or tert. -Butyloxy-, also lower alkylmercapto-, z. B.  Methyl mercapto or ethyl mercapto groups (which are primarily in the 3-, 4- and / or 5-position in the case of the preferred phenyl radical) and / or above all nitro groups (in the case of the preferred phenyl radical, preferably in the 2-position). 



   The methyl part of an arylmethyl radical Ro can optionally, for. B.  like the methyl part in an arylcarbonylmethyl radical Ro preferably have an optionally substituted hydrocarbon radical as a substituent. 



   A radical R is preferably an optionally substituted α-phenyl-lower alkyl or benzhydryl radical, such as an optionally substituted by lower alkoxy, such as methoxy groups, preferably in the 3-, 4- and / or 5-position, and / or by nitro groups, preferably in the 2nd position Position, substituted 1-phenyl ethyl or benzhydryl, primarily benzyl radical, in particular the 3- or 4-methoxybenzyl, 3,5-dimethoxy-benzyl, 2-nitrobenzyl or 4,5-dimethoxy-2 -nitro-benzyl radical. 



   A group RA can also represent the remainder of Rod, which, together with the - C (= O) - O grouping, is a product under acidic conditions, e.g. B.  when treated with trifluoroacetic acid or formic acid, easily cleavable, esterified carboxyl group forms. 

  Such a radical Rod is primarily a methyl group which is polysubstituted by optionally substituted hydrocarbon radicals or by one having electron-donating substituents.  carbocyclic aryl group or a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or then a ring member in a polycycloaliphatic hydrocarbon radical or in an oxa or thiacycloaliphatic radical which is the ct position to the oxygen or sulfur atom. 



   Substituents of polysubstituted, e.g. B.  di- or trisubstituted methyl groups 12; are primarily optionally substituted aliphatic or aromatic hydrocarbon radicals, such as lower alkyl, e.g. B.  Methyl or ethyl groups, as well as phenyl or biphenylyl, z. B.  4-biphenylyl groups.  Polysubstituted methyl groups Rod are e.g. B.  tert. -Butyl- or tert.  Pentyl and benzhydryl or 2- (4-biphenylyl) -2-propyl radicals. 



   An electron-donating, substituent-containing carbocyclic aryl group in the aryl radical is a bi- or polycyclic, in particular monocyclic, aryl, e.g. B.  Naphthyl and primarily phenyl radical.  Electron-donating substituents, which are preferably in the p- and / or o-position of the aryl radical, are, for. B.  free or preferably functionally modified, such as esterified and primarily etherified hydroxy groups, such as lower alkoxy, e.g. B.  Methoxy, also ethoxy or isopropyloxy groups, as well as corresponding free or functionally modified mercapto groups, also aliphatic, cycloaliphatic, aromatic or araliphatic, optionally suitably substituted hydrocarbon radicals, especially lower alkyl, e.g. B.  Methyl or tert.  Butyl groups, or aryl, e.g. B.  Phenyl groups. 

 

   A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members can be bi- or polycyclic, but is primarily monocyclic and is primarily a furyl, e.g. B.  2-furyl radical, or a thienyl, e.g. B.  2-thienyl radical. 



   Polycycloaliphatic hydrocarbon radicals in which the methyl group Ro is a preferably three-branched ring member are, for. B.  Adamantyl, such as 1-adamantyl radicals. 



   An oxa and thiacycloaliphatic radical linked in the a position is primarily a 2-oxa or 2-thiacycloalkyl and 2-oxa or 2-thiacycloalkenyl group, in which the methyl group Rd is the one adjacent to the ring oxygen or ring sulfur atom with the oxygen atom the group of the formula - - 12; represents linked ring member, and which preferably contains 4-6 ring carbon atoms.  Such residues are e.g. B.  2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3 dihydro-2-pyranyl radicals or corresponding sulfur analogs. 



   Preferred radicals Ro are tert. -Butyl-, tert. Pentyl, 4 methoxybenzyl and 3,4-dimethoxybenzyl radicals, and 1 adamantyl, 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl groups.    



   The remainder RÄ can also be group 12; represent, which together with the - C (= O grouping under weakly basic conditions, e.g. B.  at pH 7-9, forms cleavable esterified carboxyl group.  Such a radical Ro is preferably a radical which forms an activated ester with the -C (= O) -O grouping, in particular a hydrocarbon, in particular aliphatic or aromatic hydrocarbon radical substituted by electron-attracting groups.  Electron-attracting groups are primarily nitro groups or, advantageously, functionally modified carboxyl or sulfo groups, such as cyano or sulfamoyl groups, and also halogen, e.g. B. 

  Chlorine atoms; these preferably substitute the z-position of the hydrocarbon radical or are in conjugation with this via, preferably aromatic, double bonds.  Preferred radicals Ro are nitrophenyl, e.g. B.  4-nitrophenyl or 2,4-dinitrophenyl or polyhalophenyl, e.g. B.  2,4,6-trichlorophenyl or 2,3,4,5,6 pentachlorophenyl and also cyanomethyl radicals. 



   The group R2 can also represent a radical which, together with the carboxyl group -C (= O) -O-, forms an esterified carboxyl group which can be cleaved under physiological conditions, primarily a methyl radical substituted by an acyloxy group, in which the acyl radical is the acyl radical of an organic carboxylic acid, such as an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid, wherein the organic radicals have the above meaning, in particular a lower alkanoyl, z. B.  Acetyl radical, as well as the acyl radical of a carbonic acid half derivative means. 



   Salts of compounds obtainable according to the process are, in particular, those of compounds of the formula I in which R2 is hydrogen; these are 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, aliphatic, cycloaliphatic, cycloaliphatic-aliphatic and aliphatic primary, secondary or tertiary mono-, di- or polyamines for the salt formation in question come, such as lower alkylamines, e.g. B.  Triethylamine, hydroxy lower alkylamines, e.g. B.  2-hydroxy ethylamine, bis (2-hydroxyethyl) amine or tri- (2-hydroxy ethyl) amine, basic aliphatic esters of carboxylic acids, e.g. B.  4-aminobenzoic acid-2-diethyl ester, alkylene amines, e.g. B. 



  1-ethyl-piperidine, cycloalkylamines, e.g. B.    Bicyclohexylamine, or benzylamines, e.g. B.  N, N'-dibenzyl-ethylenediamine.  The compounds of formula I in which the acyl group Ac contains a basic radical 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 acid.  Furthermore, compounds in which R2 is hydrogen and which have a basic group in the acyl radical can be in the form of internal salts, i.e.  H.  in the zwitterionic form. 



   The compounds of the formula I obtainable according to the invention, in particular those in which the group R2 represents hydrogen or an organic radical which can easily be split off under physiological conditions, show valuable pharmacological properties.  They are primarily effective against gram-positive bacteria such as Staphylococcus aureus and against gram-negative bacteria such as Escherichia coli, including penicillin-resistant bacteria of this type, and can be used in accordance with infections caused by such microorganisms. 

  It should be noted that, in contrast to known 7 (N-acylamino) -ceph (3) em-4-carboxylic acid compounds that are effective against microorganisms, the isomerization of the double bond, which in the known compounds of the cephem series leads to the pharmacologically inactive ceph (2) em compounds leads, cannot take place in the compounds of formula I because of the double substitution in the 2-position. 



   Compounds of the formula I in which R2 together with the - C (= O) - O group represents a removable organic radical, and valuable intermediates which can easily be converted into the pharmacologically active compounds of the formula by converting an organic radical R2 into a hydrogen atom I get convicted. 



   Particularly valuable are compounds of the formula I in which Ac stands for an acyl radical of an organic carboxylic acid containing pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid and 7-amino-cephalosporanic acid compounds and R2 stands for hydrogen or an organic carboxylic acid that can be easily cleaved under physiological conditions Rest means. 



   Such an acyl radical is primarily a group of the formula
EMI4. 1
 where n is 0 and Rl is an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, preferably etherified hydroxyl or mercapto group or an optionally substituted amino group, or in which n is 1, R 'is hydrogen or an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, an optionally functionally modified, preferably etherified or esterified hydroxyl or mercapto group,

   represents an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R ″ and R111 is hydrogen, or where n is 1, Rl is an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted one heterocyclic radical, preferably of aromatic character, R11 denotes an optionally functionally modified, preferably etherified, hydroxyl or mercapto group, an optionally substituted amino group or an optionally functionally modified carboxyl group, and R'11 denotes hydrogen, or in which n denotes 1,

   each of the radicals R 'and R'l is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R "' is hydrogen, or in which n is 1, Rl is hydrogen or an optionally substituted aliphatic hydrocarbon radical, and R "and R" 'together represent an optionally substituted aliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n is 1, and Rl is an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical,

   preferably of aromatic character, R "denotes an optionally substituted aliphatic or aromatic hydrocarbon radical and RIII is hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon radical. 



   In the above acyl groups of the formula Ia, for. B.  n for 0 and Rl for an optionally, preferably in the 1-position by amino or one, optionally in salt, z. B. 



  Alkali metal salt form present sulfoamino group, substituted cycloalkyl group having 5-7 ring carbon atoms, an optionally, preferably by lower alkoxy, substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, z. B.  by lower alkyl and / or phenyl groups, which in turn have substituents such as halogen, e.g. B.  Chlorine, can carry substituted, heterocyclic group, such as a 4 isoxazolyl, or a preferably, z. B.  by an optionally substituted one such as halogen, e.g. B. 

  Chlorine-containing lower alkyl radical N-substituted amino group, or n for 1, Rl for an optionally substituted lower alkyl group, preferably by halogen, such as chlorine, optionally substituted phenyloxy, amino and / or carboxy, a lower alkenyl group, an optionally substituted one, such as hydroxy, halogen , e.g. B.  Chlorine, or optionally substituted phenyloxy-containing phenyl group, an optionally, z. B. 



  by amino, substituted pyridyl, pyridinium, thienyl, 1 imidazolyl or 1-tetrazolyl group, an optionally substituted lower alkoxy or phenyloxy group, a lower alkyl mercapto or lower alkenyl mercapto group, an optionally, z. B.  by lower alkyl, substituted phenylmercapto-.  2-imidazolyl mercapto or 1,2,4-triazol-3-yl mercapto group, a halogen, in particular chlorine or bromine atom, a carboxy, lower alkoxycarbonyl, cyano or optionally, e.g. B. 

   by phenyl, N-substituted carbamoyl group, an optionally substituted lower alkanoyl or benzoyl group, or an azido group, and R "and R111 for hydrogen, or n for 1, Rl for an optionally substituted phenyl or thienyl group, R" for an amino or Cyano group, optionally in salt, z. B.  Alkali metal salt form present carboxyl or sulfoamino group, or an optionally substituted lower alkoxy or phenyloxy group, and R "'for hydrogen, or n for 1, Rl and R" each for a halogen, z. B.  Bromine atom, or a Niederalkoxycar bonyl- z. B. 

  Methoxycarbonyl group, and R'l 'is hydrogen, or n is 1, and each of the groups R', R "and R" 'is a lower alkyl group. 



   The above acyl groups can e.g. B.  by the radical of the formula Y - (CmH7m) - C (= 0) -, in which m is 0, 1 or 2, preferably 1, and a carbon atom of a, preferably unbranched, alkylene radical of the formula - (CmH2m) - z . B.     by an optionally substituted amino group, a free, etherified or esterified hydroxy or mercapto group, a free or functionally modified carboxyl group or an oxo group, e.g. B.  can be substituted by one of the above groups of this type, and wherein Y is a, optionally in the nucleus, z. B.  such as the above alkylene radical, as well as aromatic or cycloaliphatic hydrocarbon radicals substituted by nitro or optionally functionally modified sulfo groups, such as phenyl or cycloalkyl radical, or an optionally, z. B. 

   As the above aromatic or cycloaliphatic radical, substituted heterocyclic group, preferably of aromatic character, such as an optionally substituted pyridyl, pyridinium, thienyl, furyl, imidazolyl, tetrazolyl or isoxazolyl group, furthermore one, optionally substituted as indicated , aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, e.g. B.  aromatic character, etherified hydroxyl or mercapto group means. 



  Such acyl radicals are, for. B. 



  2,6-dimethoxybenzoyl-, tetrahydronaphthoyl-, 2-methoxy-naphthoyl-, 2-ethoxy-naphthoyl-, cyclopentylcarbonyl-, a-amino-cydopentylcarbonyl- or a-amino-cyclohexylcarbonyl (optionally with substituted amino, e.g. B.  a sulfoamino group, optionally present in salt form), benzyloxycarbonyl, hexahydrobenzyloxycarbonyl, 2-phenyl-5-methyl-4-isoxazolylcarbonyl, 2- (2-chlorophenyl) -5-methyl-4-isoxazolylcarbonyl, 2- (2 , 6-dichlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, phenylacetyl-, phenacylcarbonyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl-, 2-phenyloxypropionyl-, a-phenyloxy-phenylacetyl-, a-ethoxy-phenyl-phenyl -Methoxy-3, 4-dichloro-phenylacetyl-, a-cyano-phenylacetyl-, phenylglycyl (optionally with substituted amino,

   such as a sulfoamino group, optionally present in salt form), benzylthioacetyl, benzylthiopropionyl, α-carboxyphenylacetyl (optionally with functionally modified, e.g. B.  carboxyl group present in salt form), 2-pyridylacetyl-, 4-aminopyridiniumacetyl-, 2-thienylacetyl-, α-carboxy-2thienylacetyl- or α-carboxy-3-thienylacetyl- (optionally with functionally modified, e.g. B. 

   carboxyl group present in salt form), a-cyano-2-thienylacetyl-, a-amino-2-thienylacetyl- or a-amino-3-thienylacetyl- (optionally with substituted amino, e.g. B. , optionally present in salt form, sulfoamino group), 3-thienylacetyl-, 2-furylacetyl-, 1-imidazolylacetyl-, 1-methyl-5-tetrazolylacetyl-, 3-methyl-2imidazolylthioacetyl- or 1,2,4-triazole-3- yl-thioacetyl group.    



  An acyl radical is e.g. B.  also a group of the formula CnH2n + 1 = = 0) - or CnH2n-1-C (= 0) -, where n is an integer up to 7 and the chain is straight or branched and optionally interrupted by an oxygen or sulfur atom and / or z. B.  by halogen atoms, free or functionally modified carboxyl, such as lower alkoxycarbonyl or cyano groups, free or substituted amino groups, or oxo, azido or nitro groups, can be substituted, e.g. B.  

   a propionyl, butyryl, hexanoyl, octanoyl, acrylyl, crotonoyl, 3-butenoyl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl, chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl, 5-amino-5-carboxy-valeryl (optionally with substituted amino and / or optionally functionally modified carboxyl group), azidoacetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl , Bismethoxycarbonylacetyl-, N-Phenylcarba moylacetyl-, cyanoacetyl-, a-cyanopropionyl or 2-cyano-3-dimethylacrylyl group, also a radical of the formula Z-NH-CO-, wherein Z is an optionally substituted aromatic or aliphatic hydrocarbon radical, in particular one optionally substituted by lower alkoxy groups and / or halogen atoms, lower alkyl radical, e.g. 

  B.  the N-2-chloroethylcarbamoyl radical, means. 



   First and foremost, acyl groups Ac are the acyl groups occurring in highly effective N-acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-3-cephem-4-carboxylic acid compounds, such as 2-chloroethylcarbamoyl, cyanoacetyl, phenylglycyl ( optionally with substituted amino group), 2 thienylacetyl-, a-amino-2-thienylacetyl- (optionally with substituted amino group), 1-aminocyclohexylcarbonyl (optionally with substituted amino group) or the a-carboxy-phenyl-acetyl- or a-carboxy-2 thienylacetyl radical (optionally with substituted carboxy group). 



   The compounds of the formula I can be obtained according to the invention by reacting in a 7-amino-ceph (3) em compound of the formula
EMI6. 1
 wherein R2 represents a hydrogen atom or an organic radical R2 which together with the -C (= O) -O group forms an esterified carboxyl group, or acylates the free amino group in a salt thereof.  If desired, the esterified carboxyl group of the formula - C (= 0) - 0 - RA in a compound obtained can be converted into a free carboxyl group by treatment with an ester-splitting agent. 



   In the starting material, an organic radical R2 is in particular a radical which forms an easily cleavable esterified carboxyl group with the - C (= O) - O group, such as one of the groups mentioned above. 



   The acylation of the free amino group in the starting material of the formula II can be carried out according to acylation methods known per se, eg. B.  by treating with carboxylic acids or reactive functional carboxylic acid derivatives thereof such as carboxylic acid halides, e.g. B.  Carboxylic acid chlorides, or anhydrides (including the internal anhydrides of carboxylic acids, i.e.  H.  Ketenes, or from carbamic or thiocarbamic acids, d.  H. 

  Isocyanates or isothiocyanates, or mixed anhydrides, such as those that can be formed with chloroformic acid lower alkyl esters or trichloroacetic acid chloride, are to be understood) or activated esters, such as esters with N-hydroxy amides or imides, such as N-hydroxysuccinic acid imide, or with electrons -attractive substituents containing alcohols or phenols, e.g. B.  4-nitrophenol or cyanomethanol, using, if necessary, suitable condensing agents, acids, e.g. B.  in the presence of carbodiimides such as dicyclohexylcarbodimide, and acid halides and anhydrides in the presence of basic agents such as triethylamine or pyridine.  Free functional groups can be intermediately protected in both reactants. 



   Connections obtained can be converted into one another within the defined framework.  So z. B.  in a compound of the formula I obtainable according to the process, in which R2 represents a group R2A, an esterified carboxyl group of the formula - C (= 0 - RZ) is converted into a free carboxyl group. 



   So you can z. B.  a carboxyl group esterified by a radical Ro or R, b by treatment with one of the said metallic reducing agents in the presence of at least an equimolar amount, usually in the presence of an excess of water.  You work under mild conditions, usually at room temperature or even with cooling. 



   Reducing metals, as well as reducing metal alloys or amalgams, and also strongly reducing metal salts are z. B.  Zinc, zinc alloys, e.g. B.  Zinc copper, or zinc amalgam, also magnesium, which are preferably used in the presence of hydrogen-releasing agents which are able to generate hydrogen nascent together with the metals, metal alloys and amalgams, zinc, e.g. B.  advantageously in the presence of acids such as organic carbon, e.g. B.  Lower alkanecarboxylic acids, primarily acetic acid, or acidic agents such as ammonium chloride or pyridine hydrochloride, preferably with the addition of water, and in the presence of alcohols, especially aqueous alcohols such as lower alkanols, e.g. B. 

  Methanol, ethanol or isopropanol, which can optionally be used together with an organic carboxylic acid, and alkali metal amalgams, such as sodium or potassium amalgam, or aluminum amalgam in the presence of moist solvents such as ethers or lower alkanols. 



   Strongly reducing metal salts are primarily chromium II salts, e.g. B.  Chromium (II) chloride or chromium (II) acetate, preferably in the presence of aqueous media containing water-miscible organic solvents such as lower alkanols, carboxylic acids such as lower alkanecarboxylic acid, or derivatives such as optionally substituted, e.g. B.  lower alkylated, amides thereof, or ethers, e.g. B.  Methanol, ethanol, acetic acid, dimethylformamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether can be used. 



   In a compound of formula I obtainable according to the process, in which R2 represents a group Rc, the esterified carboxyl group of formula -C (= O) ORc can be cleaved by irradiation with light, preferably with ultraviolet light.  Depending on the type of substituent Rc, longer or shorter-wave light is used.  So z. B. 



  Groups of the formula -C (= O) -O-RO, in which reins are substituted by a nitro group in the 2-position of the aryl radical, optionally further substituents such as lower alkoxy, e.g. B. 



  Methoxy groups, having arylmethyl, especially benzyl radical, z. B.  the 4,5-dimethoxy-2-nitro-benzyl radical, represents, by irradiation with ultraviolet light with a wavelength range of over 290 mF, those in which Rg z. B.  one optionally in the 3-, 4- and / or 5-position, e.g. B.  arylmethyl substituted by lower alkoxy and / or nitro groups, e.g. B.  Benzyl radical, is cleaved by irradiation with ultraviolet light with a wavelength range below 290 mF.  

  In the first case, a high-pressure mercury vapor lamp is used, preferably using Pyrex glass as the filter, e.g. B.  at a main wavelength range of about 315 mull, in the latter case with a low-pressure mercury vapor lamp, e.g. B.  with a main wavelength range of about 254 m.    



   The irradiation reaction is carried out in the presence of a suitable polar or non-polar organic solvent or a mixture; Solvents are e.g. B.  optionally halogenated hydrocarbons, such as optionally chlorinated lower alkanes, e.g. B.  Methylene chloride, or optionally chlorinated benzenes, e.g. B.  Benzene, and also alcohols such as lower alkanols, e.g. B.  Methanol, or ketones, such as lower alkanones, e.g. B.  Acetone.  The reaction is preferably carried out at room temperature or, if desired, with cooling, usually in an inert gas, e.g. B.  Nitrogen atmosphere.  It is preferably carried out in the presence of water; but you can also treat the irradiation product subsequently with water, for. B.  by working up the product obtained in the presence of water. 



   In a compound of the formula I obtainable according to the invention, in which R2 represents a group Rod, the grouping of the formula - C (= O) - O - RU can be removed by treatment with an acidic agent, in particular with an acid such as a strong organic carboxylic acid, e.g. . B.  an optionally substituted, preferably containing halogen atoms, lower alkanecarboxylic acid, such as acetic acid or trifluoroacetic acid, also with formic acid or a strong organic sulfonic acid, e.g. B.  p-toluenesulfonic acid. 



  Usually, an excess of an acidic reagent which is liquid under the reaction conditions is used as the diluent and the reaction is carried out in the presence of at least an equivalent amount of water, and at room temperature or with cooling, e.g. B.  to about - 20C to about + 10oC.    



   An esterified carboxyl group of the formula -C (= O) -O-RO in a compound obtainable according to the process can under weakly basic conditions, e.g. B.  at a pH of about 7 to about 9 by treating with a weakly basic agent such as an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, or a suitable buffer solution such as a dipotassium hydrogen phosphate buffer, in the presence of water and preferably an organic solvent such as methanol or acetone to be split. 



   Before an esterified carboxyl group of the formula - C (= O) - O-Rz is cleaved, it can be converted into another esterified carboxyl group in a starting material obtained in a manner known per se.  So you can z. B.  in a residue 12 representing the group RA; an aliphatically bonded chlorine or bromine atom, as in a 2-bromoethyloxy radical Ro z. B.  by treating with an iodized salt such as an alkali metal, e.g. B.  Potassium iodide, in a suitable solvent such as acetone, replace this with an iodine atom. 



   In a compound with a group of the formula -C (= O) -O-R2, where R2 is hydrogen, the free carboxyl group can be used in a manner known per se, e.g. B.  by treating with a diazo compound such as a diazonie deralkan, e.g. B.  Diazomethane or diazoethane, or a phenyl-diazo-lower alkane, e.g. B.  Phenyldiazomethane or diphenyldiazomethane, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. B.  Dicyclohexylcarbodiimide, as well as carbonyldiimidazole, or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid, as well as a strong organic sulfonic acid.  Furthermore, acid halides, such as chlorides (produced e.g. B. 



  by treatment with oxalyl chloride), or activated esters, e.g. B.  those with N-hydroxy nitrogen compounds, or z. B. 



  mixed anhydrides formed with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride, are converted into esters by reaction with alcohols, optionally in the presence of a base such as pyridine. 



   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, wherein R2 is hydrogen, z. B.  by treating with metal compounds such as alkali metal salts of suitable carboxylic acids, e.g. B.  the sodium salt of a-ethyl-caproic acid, or with ammonia or a suitable organic amine, preferably using stoichiometric amounts or only a small excess of the salt-forming agent.  Acid addition salts are usually obtained, for. B.  by treatment with an acid or a suitable ammonium exchange reagent.  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 prepared by methods known per se, e.g. B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes, can be separated into the individual isomers.  Racemates obtained can in the usual way, optionally after the temporary introduction of 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 starting materials are used in the form of reaction mixtures formed under the reaction conditions. 



   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 process can, for. B.  be prepared by adding a penam-3-carboxylic acid compound IIIa having the formula
EMI7. 1
 wherein Aco stands for the acyl radical of an organic carboxylic acid, primarily for an acyl radical occurring in naturally occurring or biosynthetically available N-acyl derivatives of 6-aminopenicillanic acid, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted lower alkanoyl or lower alkanoyl radical, e.g. B. 

   the 4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxyvaleryl, n-butylmercaptoacetyl or allylmercaptoacetyl, and in particular the phenylacetyl or phenyloxyacetyl radical, and in which there is free functional groups , such as hydroxyl, mercapto and, in particular, amino and carboxyl groups, optionally in the acyl radical Ac, e.g. B.  by acyl groups or 

 

  are protected in the form of ester groups, and Ro stands for a carboxyl group - C (= O) - OH (compound IIIa), or a salt thereof into the corresponding acid azide compound with the formula III, wherein Ro denotes the azidocarbonyl radical-C (= O) - N3 represents (compound IIIb), converted, this with elimination of nitrogen to the corresponding isocyanate compound with the formula III, in which Ro denotes the isocyanato group N = C = O (compound IIIc), converted and simultaneously or subsequently with a compound of the formula H-Xo (IV) treated. 

  In the compound of the formula IV, X0 denotes an etherified hydroxyl or mercapto group of the formula -0-12, -0-12 ;, -0-12; which, together with a carbonyl group, forms an esterified carboxyl or thiocarboxyl group which can easily be cleaved under mild, in particular neutral to weakly acidic conditions; or -O-R0c, wherein pink, R0b and 12; have the meanings given above and in particular represent the 2,2,2-trichloroethyl or 2-iodoethyl, as well as the 2-bromoethyl radical which can be converted into these, and also the phenacyl or 4,5-dimethoxy-2-nitrobenzyl radical. 



   A penam compound of the formula is obtained in this way
EMI8. 1
 in which, if desired, an acyl radical Ac, z. B.  by the method described above, replace with hydrogen and the free amino group, e.g. B.  can re-acylate by acylation methods known per se, and when the esterified carboxyl group of the formula - C (= O) -X0 is cleaved in the presence of water into a penam compound of the formula
EMI8. 2
 is transferred.  If a compound of the formula VI is treated with a hydride reducing agent which is inert towards amide groups, a compound of the formula is obtained
EMI8. 3
 in which, optionally after converting the acylamino group of the formula Ac-HN- into a free amino group and reacylation of the free amino group, the primary hydroxyl group is converted into a hydroxyl group esterified by the acyl radical of the formula -C (= O) -X. 

  A 4ss- (2-0- esterified hydroxymethyl-2-propylmercapto) -3ss N-Ac-amino-azetidin-2-one of the formula which can be obtained in this way
EMI8. 4th
 is made with a compound of the formula
EMI8. 5
 wherein Rc is one of the above-mentioned organic radicals R2A which form an easily cleavable esterified carboxyl group with the carboxyl group, in particular a group of the formula 12 ;, Rob, R, or Rd, or a reactive derivative thereof reacted, and in the compound thus prepared formula
EMI8. 6th
 the secondary hydroxy group is converted into a reactive esterified hydroxy group. 



   A compound of the formula
EMI9. 1
 in which in an acyl radical Ac, free, reactive functional groups which may be present may be protected, and in which Z is a reactive, esterified hydroxyl group, primarily a halogen, in particular chloro or bromine atom, and an organic sulfonyloxy, e.g. B.  4-methylphenylsulfonyloxy or methylsulfonyloxy group, is with a phosphine compound of the formula
EMI9. 2
 wherein each of the radicals Ra, Rb and Rc represents an optionally substituted hydrocarbon radical, reacted and in the resulting phosphoranylidene compound of the formula
EMI9. 3
 optionally after cleavage of the elements of an acid H-Z from a phosphonium salt compound of the formula available as an intermediate
EMI9. 4th
 the esterified carboxyl group of the formula -C (= O) -X cleaved. 

  A phosphorarylidene compound of the formula is obtained in this way
EMI10. 1
 in which the carbinol group of the formula - CH2 - OH is oxidized to the formyl group of the formula - CHO, with simultaneous ring closure with formation of a Ceph (3) em compound of the formula
EMI10. 2
 takes place.  In this connection, the group Aco can be split off in a manner known per se by treating with an imide halide-forming agent, converting the imide halide contained into the corresponding imino ether and cleaving the latter, and, if desired, in a manner known per se, an easily replaceable by hydrogen organic radical Rf is replaced by hydrogen, and, if desired, this by a radical R other than hydrogen. B. 



   The conversion of an acid compound IIIa or a suitable salt, in particular an ammonium salt, into the corresponding acid azide IIIb can, for. B.  by converting it into a mixed anhydride (e.g. B.  by treating with a haloformic acid lower alkyl ester, such as ethyl chloroformate, or with trichloroacetic acid chloride in the presence of a basic agent such as triethylamine or pyridine) and treating such an anhydride with an alkali metal azide, such as sodium azide, or an ammonium azide, e.g.  B. 



  Benzyltrimethylammonium azide.  The so obtainable acid azide compound IIIb can in the presence or absence of a compound of formula IV under the reaction conditions, for.  B.  when heated, into the desired isocyanate compound-
IIIc, which usually does not need to be isolated and can be converted directly into the desired compound of formula V in the presence of a compound of formula IV. 



   The reaction with a compound of the formula IV, in particular with an alcohol of the formula Ra-OH, 12; -OH or    12; - OH, as with a 2-haloethanol 12; - OH, e.g. B. 



  with 2,2,2-trichloro- or 2-bromoethanol, an arylcarbonylmethanol 12; - OH, e.g. B.  Phenacyl alcohol, or an aryl methanol Ro-OH, e.g. B.  4,5-dimethoxy-2-nitrobenzyl alcohol is optionally dissolved in an inert solvent, e.g. B.  in a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzyl, preferably with heating. 



   The cleavage of an esterified carboxyl group of the formula -C (= O) -Xo in a compound of the formula V is carried out as described above for the cleavage of an esterified carboxyl group -C (= O) -O-R2.  If XO is the group -0-12; or -0 - 12; represents, the cleavage by treatment with one of the above metallic reducing agents, z. B.  Zinc, or 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 acid, or an alcohol, preferably adding water, and if XO is a group of the formula ORo represents, by irradiation, preferably with ultraviolet light, with shorter-wave ultraviolet light, e.g. B.  below 290 mF, works when Ro z. B.  one optionally in the 3-, 4- and / or 5-position, e.g. B.  arylmethyl radical substituted by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. B. 



  over 290 mF when Ro z. B.  means an arylmethyl radical substituted in the 2-position by a nitro group. 



   An amide group non-reducing hydride reducing agents are primarily boron-containing hydrides, such as. B. 



  Diborane and especially alkali metal or alkaline earth metal borohydrides, especially sodium borohydride.  Complex organic aluminum hydrides such as alkali metal tri-lower alkoxy aluminum hydrides, e.g. B.  Lithium tri-tert. -butyloxy aluminum hydride can also be used. 



   These reducing agents are preferably used in the presence of suitable solvents or mixtures thereof, alkali metal borohydrides e.g. B.  in the presence of solvents containing hydroxy or ether groups, such as lower alkanols, e.g. B.  Methanol or ethanol, as well as isopropanol, also tetrahydrofuran or diethylene glycol dimethyl ether, if necessary, with cooling or heating. 



   In the compound of formula VII obtained, the primary hydroxyl group is acylated in a manner known per se, the usual acylating agents being used in the acylation reaction, in particular suitable reactive derivatives of acids which, if necessary, in the presence of a, preferably basic agent, such as a organic tertiary base, e.g. B.  Triethylamine or pyridine can be used.  Reactive derivatives of acids are e.g. B.  Anhydrides, incl.  internal anhydrides, such as ketenes, or isocyanates, or mixed, especially with haloformic acid esters, e.g. B.  Ethyl chloroformate, or haloacetic acid halides, e.g. B. 

  Trichloroacetic acid chloride, anhydrides that can be prepared, also halides, primarily chlorides, or reactive esters such as esters of acids with alcohols or phenols containing electron-attracting groups, and with N-hydroxy compounds, e.g. B.  Cyanmethanol, p-nitrophenol or N-hydroxysuccinimide.  The acylation reaction can be carried out in the presence or absence of solvents or solvent mixtures, if necessary with cooling or heating, in a closed vessel under pressure and / or in an inert gas, e.g. B.  Nitrogen atmosphere, optionally carried out in stages. 

 

   The addition of the glyoxylic acid compound to the nitrogen atom of the lactam ring of a compound of the formula VIII takes place preferably at elevated temperature, primarily from about 50 ° C. to about 1500 ° C., in the absence of a condensing agent and / or without the formation of a salt.  In this case, instead of the free glyoxylic acid compound, a reactive oxo derivative thereof, primarily a hydrate, can be used, water formed when using the hydrate, if necessary by distillation, e.g. B.  azeotropic, can remove. 



   Preferably one works in the presence of a suitable solvent, such as. B.  Dioxane or toluene, or solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the atmosphere of an inert gas such as nitrogen. 



   In a compound of the formula X, the secondary hydroxyl group can be converted in a manner known per se into a reactive hydroxyl group esterified by a strong acid, in particular into a halogen atom or into an organic sulfonyloxy group.  This esterification can, for. B.  by treating the hydroxy compound with a suitable halogenating agent such as a thionyl halide, e.g. B.    chloride a phosphorus oxyhalide, especially chloride or a halophosphonium halide, such as triphenylphosphonium dibromide, or -diiodide, and by treating with a suitable organic sulfonic acid halide, such as chloride, preferably in the presence of a basic, primarily an organic basic agent such as an aliphatic tertiary amine, e.g. . B. 

  Triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g. B.  Pyridine or collidine.  It is preferred to work in the presence of a suitable solvent, e.g. B.  Dioxane or tetrahydrofuran, or a mixed solvent, if necessary with cooling and / or in the atmosphere of an inert gas such as nitrogen. 



   In a compound obtained with a reactive esterified hydroxyl group, this can be converted into another reactive esterified hydroxyl group in a manner known per se.  So you can z. B.  a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, in particular with an inorganic bromide or iodide salt such as lithium bromide, preferably in the presence of a suitable solvent such as ether, with a bromine or iodine reagent.  Replace iodine atom. 



   In the phosphine compound of the formula XI, each of the groups represents Ra.  Rb and Rc an optionally, e.g. B.  by etherified or esterified hydroxyl groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl or an optionally substituted.  z. B.  phenyl radical substituted by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxyl groups, such as lower alkoxy groups, or halogen atoms, or nitro groups. 



  The reaction of a compound of the formula Ia with the phosphine compound in which each of the groups Ra, Rb and Rc is primarily phenyl and a lower alkyl, especially the n-butyl radical, is preferably carried out in the presence of a suitable inert solvent, such as an aliphatic , cycloaliphatic or aromatic hydrocarbon, e.g. B.  Hexane, cyclohexane, benzene or toluene, or an ether, e.g. B.  Dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture made.  If necessary, one works under cooling or at elevated temperature and / or in the atmosphere of an inert gas such as nitrogen. 



   An intermediately formed phosphonium salt compound of formula XIIa usually spontaneously loses the elements of the acid H-Z: if necessary, the phosphonium salt compound can be removed by treatment with a weak base such as an organic base, e.g. B.  Diisopropylethylamine or pyridine, decomposed and converted into the phosphoranylidene compound of the formula XII. 



   The cleavage of the esterified carboxyl group of the formula -C (= O) -X in a compound of the formula XII can, for.  B. 



  be carried out in the manner described above and adapted to the type of group X; d. H.  a group of the formula - C (= O) - 0 - Rg or -C (= O) -0-12; can be obtained by treatment with one of the above-mentioned metallic
Reducing agent, a group of the formula -C (= O) -O-R> by irradiation, and a group of the formula -C (= O) - 0 - R, d or  - C (= O) - 0 - Ro by treating with an acidic resp.  weakly basic agents are split. 

  In a compound of the formula XII, the esterified carboxyl groups of the formulas -C (= O) -X and C (= O) OR2 preferably differ from one another in such a way that the esterified carboxyl group of the formula - C (= O) - 0 - RB, remains intact. 



   The oxidation of the primary carbinol group in a compound of the formula XIII, which takes place with simultaneous ring closure to a compound of the formula Ia, can surprisingly by treatment with an oxidizing sulfoxide compound, such as a di-lower alkyl sulfoxide, in particular dimethyl sulfoxide, in the presence of a dehydrating or dehydrating agent , such as an acid anhydride, especially acetic anhydride, a carbodiimide or ketenimine, or sulfur trioxide.  It is preferred to use an excess of the oxidizing agent which, if liquid under the reaction conditions, can also be used as a diluent. 

  The reaction is preferably carried out in an approximately 1: 1 mixture of dimethyl sulfoxide and acetic anhydride, working with cooling if desired, but mostly at room temperature or at a slightly elevated temperature. 



   In a compound of the formula I obtained, the acyl group Aco, in which any free functional groups which may be present, can preferably be protected.  by treating with an imide halide forming agent such as a suitable inorganic acid halide, e.g. B.  Phosphorus pentachloride, preferably in the presence of a basic agent such as pyridine, reacting the resulting imide halide with an alcohol such as lower alkanol, e.g. B.  Methanol, and cleavage of the imino ether formed in an aqueous medium, preferably under acidic conditions. 



   In a starting material of the formula II obtained, in which the - C (= 0) OR 2 s grouping is an esterified carboxyl group, this can be carried out in a manner known per se, e.g. B. 



  as described above, converted into the free carboxyl group, e.g. B.  by treatment with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, a compound of the formula II having an esterified carboxyl group of the above formula, in which RB stands for a radical which, together with the carboxyl group, forms a reductively removable esterified carboxyl group, e.g. B.  the phenacyl, 2,2,2-trichloroethyl or 2-iodoethyl radical (the latter before cleavage of the esterified carboxyl group z. B.  from a corresponding 2-bromoethyl radical, e.g. B. 

   by treating with an alkali metal iodide such as sodium iodide in the presence of a suitable solvent such as acetone), or by treating with an acidic agent such as trifluoroacetic acid, a compound of formula X having an esterified carboxyl group of the above formula, wherein RB for one, together with the carboxyl group, forming an esterified carboxyl group cleavable in the presence of a suitable acidic agent, e.g. B.  the tert. -Butyloxy group. 

 

   In a starting material of the formula II obtained, a free carboxyl group -C (= O) -O-RB can be used in a manner known per se, e.g. B.  as stated above, can be converted into an esterified carboxyl group and the latter into another carboxyl group.  Silyl and stannyl groups Rf can also be introduced in a manner known per se, e.g. B. 



  by treating compounds of formula II in which R2 is hydrogen, as well as salts such as alkali metal, e.g. B. 



  Sodium salts thereof with a suitable silylating agent such as a tri-lower alkyl silyl halide, e.g. B.  Trimethylsilyl chloride, or an N- (tri-lower alkyl-silyl) -N-Rd-N-Re-amine, in which Rd is a hydrogen atom or a lower alkyl group and Re is a hydrogen atom, a lower alkyl group or a tri-lower alkyl-silyl group (see e.g. B.  British patent no.  1 073 530), or with a suitable stannylating agent such as bis (tri-lower alkyl-tin) oxide, e.g. B.  Bis- (trin-butyl-tin) oxide, a tri-lower alkyl tin hydroxide, e.g. B. 



  Triethyl tin hydroxide, a tri-lower alkyl-lower alkoxy tin, tetra-lower alkoxy-tin or tetra-lower alkyl tin compound, and a tri-lower alkyl tin halide, e.g. B.  Trin-butyl tin chloride (see e.g. B.  Dutch publication 67/17107). 



   In the preparation of the starting material, if necessary, free functional groups not participating in the reaction in the reactants, e.g. B.  free hydroxy, mercapto or amino groups, e.g. B.  by acylation, and free carboxy 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. 



   Compounds of the formula I obtainable according to the method with pharmacological effects can be, for. B.  can be used in the form of pharmaceutical preparations which contain them in admixture with a solid or liquid pharmaceutical carrier material and which are suitable for enteral, parenteral or topical administration. 



  Suitable carriers which are inert towards the active substances are, for. B.  Water, gelatin, saccharides such as lactose, glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known carriers.  The preparations can be in solid form, e.g. B.  as tablets, dragees, capsules or suppositories, or in liquid form, e.g. B.  as solutions, suspensions or emulsions.  They can be sterilized and / or contain auxiliaries, such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers.  They can also contain other pharmacologically usable substances. 



  The pharmaceutical preparations which are also encompassed by the present invention can be produced in a manner known per se. 



   The invention is described in the following examples.  The temperatures are given in degrees Celsius. 



   example 1
A suspension of 0.080 g of 7-amino-2,2-dimethylceph (3) em-4-carboxylic acid in 2 ml of absolute methylene chloride is mixed with 0.0354 g of triethylamine in 0.36 ml of methylene chloride.  The suspension is diluted with 5 ml of absolute tetrahydrofuran and stirred for 30 minutes, sometimes in an ultrasonic bath. 



   0.113 g of tert is dissolved. -Butyloxycarbonyl-D-a-phenylglycine in 5 ml of absolute methylene chloride, mixed with 0.0455 g of 4-methylmorpholine, diluted with 10 ml of acetonitrile and cooled to -200.  0.0605 g of isobutyl chloroformate is added with stirring, whereupon the mixture is allowed to react at-150 for 30 minutes.  After cooling again to below -200, the milky suspension of the tri-ethylammonium salt of 7-amino-2,2-dimethyl-ceph (3) em4-carboxylic acid is added and the reaction mixture is stirred for 30 minutes at-150 and for a further 30 minutes 0O and finally for 2 hours at room temperature. 



  Unreacted starting material is filtered off, washed with acetonitrile, methylene chloride and diethyl ether and dried.  The filtrate is evaporated to dryness and the residue is taken up in ethyl acetate and water. 



  With thorough stirring and cooling with ice, the mixture is acidified to pH 2 by adding 5 molar aqueous phosphoric acid. 



  The organic phase is separated off and washed four times with a small amount of a saturated aqueous sodium chloride solution.  The aqueous extracts are back-extracted with 2 portions of ethyl acetate and the combined organic extracts are dried over anhydrous magnesium sulfate and freed from the solvent under reduced pressure. 



   The yellowish foam obtained as residue is chromatographed on 10 g of silica gel (column; addition of 5% water). 



  With nine 40 ml portions of methylene chloride, containing 1-4% acetone, a mainly unreacted tert. -Butyloxycarbonyl-D-a-phenylglycine existing material eluted, with three 40 ml portions of methylene chloride containing 5% acetone, a mixture of the tert. -Butyloxycarbonyl-D-aphenylglycine and the 2,2-dimethyl-7- [N- (N-tert. -butyloxy-carbónyl-D-a-phenylglycyl) -amino] -ceph (3) em-4-carboxylic acid of the formula
EMI12. 1
 receive. 



   The pure product is obtained with methylene chloride containing 750% acetone, infrared absorption spectrum (in methylene chloride): characteristic bands at 2.94 y, 3.32 Il, 5.60 K, 5.86, 5.92 Il, 6.12 E , 6.62 F (shoulder), 6.69 II, 7.18 I1, 7.31 y, 7.80 1, 8.21 I1, 8.60 y, 9.10 11 and 9.52 II; Thin-layer chromatogram (silica gel with added calcium sulfate;

  Detection with iodine vapor or by spraying with trifluoroacetic acid, followed by ninhydrin / collidine reagent): Rf = 0.67 (system n-butanol / acetic acid / water 75: 7.5: 21), Rf = 0.71 (system n- Butanol / acetic acid / water 44:44), Rf = 0.58 (system ethyl acetate / pyridine / acetic acid / water 62: 21: 6 11) and Rf = 0.68 (system ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6 10); Ultraviolet absorption spectrum (in ethanol) fmax 256 mss (E = 5700). 

 

   Example 2
A solution of 0.0237 g of 2,2-dimethyl-7- [N- (N-tert.    butyloxycarbonyl-D-z-phenylglycyl) -aminoj-ceph (3) em-4-carboxylic acid (uniform by thin layer chromatography and lyophilized from benzene) in 5 ml of pure formic acid is left to stand at room temperature for 2 hours.  The clear, colorless solution is freeze-dried in a high vacuum and the lyophilizate is dried at 0.001 mm Hg and at 35 for 16 hours to completely remove the formic acid. 

  The 2,2-dimethyl-7- [N- (D-a-phenylglycyl) -amino] -ceph (3) em-4-carboxylic acid in the zwitterionic form of the formula
EMI13. 1
 is obtained in the form of a fine white powder; Thin-layer chromatography (silica gel with calcium sulfate addition; detection by means of ultraviolet light or ninhydrin / collidine reagent): Rf = 0.29 (system n-butanol / acetic acid / water 67: 10: 23), Rf = 0.34 (system n-butanol / pyridine / Acetic acid / water 42: 24: 4: 30) and Rf = 0.16 (system ethyl acetate / n-butanol / pyridine / acetic acid / water 42: 21: 21: 6: 10); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90, 3.09, 3.22, 5.61, 5.89, 6.12, 6.52, 7.10, 7.32, 7.79, 7 , 92, 8.15, 8.50, 9.05, 9.54, 9.80, 13.64 and 14.37. 



     Example 3
The 7-amino-2,2-dimethyl-ceph (3) em-4-carboxylic acid can be N-acylated and converted into 7- (N-acyl-amino) -2,2-dimethyl-ceph (3 ) em- 4-carboxylic acids of the formula
EMI13. 2
 be transferred:
Variant A 0.4 mmol of an acid [AcOHj is dissolved in 0.2 ml of absolute methylene chloride with the addition of 0.056 ml (0.4 mmol) of triethylamine [stock solution: 28.0 ml (200 mmol) of triethylamine, with methylene chloride to 100 ml diluted] dissolved. 

  0.0452 ml (0.4 mmol) of trichloroacetic acid chloride in 0.2 ml of methylene chloride [stock solution 22.6 ml (200 mmol) of trichloroacetic acid chloride, diluted to 100 ml with methylene chloride] are added to the solution, which has been cooled to -15 -15 stirred.  The solution with the mixed anhydride [Ac-OC (= O) -CCl3] is treated with a finely dispersed slurry, cooled to -15, of 0.046 g (0.2 mmol) -7-amino-2,2-dimethyl-ceph (3 ) em-4-carboxylic acid and 0.056 ml (0.4 mmol) of triethylamine in 0.4 ml of methylene chloride and vibrated for 30 minutes at -15 and then for 30 minutes at 20 in the ultrasonic bath. 

  The usual brown reaction solution is evaporated to dryness under reduced pressure, and the residue obtained is partitioned between 2 ml of a 10% aqueous dipotassium hydrogen phosphate solution (pH 8.9) and 1 ml of ethyl acetate.  The aqueous phase is adjusted to pH 2.6 with 20% aqueous phosphoric acid and then extracted exhaustively with ethyl acetate.  The ethyl acetate extract (6-10 ml) is washed with water and dried over sodium sulfate and evaporated under reduced pressure.  The residue is chromatographed preparatively on a thin-layer plate on silica gel in a suitable solvent system for 2-5 hours. 

  After the plate has been dried at room temperature in a nitrogen atmosphere, the silica gel zone absorbing under the ultraviolet light (254 m) is mechanically detached from the plate and extracted three times with 1030 ml of ethanol or methanol.  After the extract has been evaporated under reduced pressure, the 7- (N-acylamino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid is obtained as a beige or almost colorless residue. 



   If the thin-layer plate has more than one zone which absorbs ultraviolet light, the individual zones are processed separately, as described above. 



  A sample of the material resulting from the different zones is tested against Staphylococcus aureus in the plate diffusion test.  The material from the microbiologically most active zone is subjected to another preparative thin-layer separation, whereby the chromatographically uniform product can be isolated. 



     Variant B
0.2 mmol of the sodium salt of an acid [AcONa] in 0.2 ml of absolute dimethylformamide is mixed with 0.2 mmol of trichloroacetyl chloride as in variant A and a solution of 0.2 mmol of 7-amino-2,2- dimethyl-ceph (3) em-4-carboxylic acid and 0.2 mmol of triethylamine in 0.2 ml of dimethylformamide as in variant A and worked up. 



     Variant C
A mixture of 0.25 mmol of an acid chloride [AcCl] in 0.2 ml of methylene chloride is added to a solution, cooled to -15, of 0.046 mg (0.2 mmol) of 7-amino-2,2-dimethyl-ceph (3) em-4-carboxylic acid and 0.070 ml (0.5 mmol) of triethylamine in 0.5 ml of methylene chloride were added and reacted and worked up as in variant A. 



     Example 4
If in the process of Example 3, variant B, the sodium salt of methyl malonate is used as the acylated starting material, the 2,2-dimethyl-7- (N-methoxycarbonylacetyl-amino) -ceph (3) em-4- carboxylic acid of the formula XA, wherein Ac is the remainder of the formula
EMI13. 3
 means, and which in the thin layer chromatogram (silica gel; ystem ethyl acetate / acetic acid 9: 1) has an Rf value of 0.55; Ultraviolet Absorption Spectrum (in methanol): #max at 258 m; [infrared absorption spectrum (in mineral oil):

   characteristic bands at 5.57. 



   Example 5
If in the process of Example 3, variant B, the sodium salt of the ethyl malonic acid half-ester is used as the acylating starting material, the 7- (N-ethoxycarbonylacetyl-amino) -2,2imethyl-ceph (3) em-4-carboxylic acid is obtained Formula XA, where Ac is the remainder of the formula
EMI13. 4th
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 42: 24: 4: 30) has its Rf value of 0.57; Ultraviolet Absorption Spectrum (in methanol): #max at 259 mull; Infrared absorption spectrum (in mineral oil): characteristic band at 5.58.    



   Example 6
If, in the process of Example 3, variant C, the bromoacetic acid chloride is used as the acylating starting material, the 7- (N-bromoacetylamino) -2,2-dimethylceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI14. 1
 and which in the thin-layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.30-0.34; Ultraviolet absorption spectrum (0.1 molar aqueous sodium hydrogen carbonate solution): Bmax at 258 ml.    



   Example 7
A mixture of 0.1394 g (0.4 mmol) of 7- (N-bromoacetylamino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid in 0.5 ml of methanol and 0.047 g (0.5 mmol ) 4-Aminopyridine is reacted in the presence of 0.048 g (0.5 mmol) of diisopropylethylamine at 40O until the reaction has ended (control by means of thin-layer chromatography).  It is evaporated and the residue is subjected twice to preparative thin-layer chromatography (silica gel). 

  The 7- [N- (4-aminopyridinium-acetyl) -amino] -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, which can be obtained in this way,
EMI14. 2
 shows an Rf value of 0.25-0.4 in a thin layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 42: 24: 4:30); Ultraviolet Absorption Spectrum (in water): Xmax at 266 mull; Infrared absorption spectrum (in mineral oil): characteristic band at 5.63 tj.    



   Example 8
If the malonic acid-N-phenyl-half-amide is used as acylating starting material in the process of Example 3, variant A, the 2,2-dimethyl-7- [N- (N-phenylaminocarbonylacetyl) -amino] -ceph (3) em is obtained -4-carboxylic acid of the formula XA, in which Ac is the remainder of the formula
EMI14. 3
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / acetic acid / water 67: 10: 23) has an Rf value of 0.41; Ultraviolet Absorption Spectrum (in methanol): Amax at 241 ml and 256 ml; Infrared absorption spectrum (in mineral oil): characteristic band at 5.62 y.    



   Example 9
If in Example 3, variant C, the methoxyacetic acid chloride is used as the acylating starting material, the 2,2-dimethyl-7 - (N-methoxyacetylamino) ceph (3) em-4-carboxylic acid of the formula XA, in which Ac denotes Remainder of the formula
EMI14. 4th
 denotes, and which in the thin layer chromatogram (silica gel; system ethyl acetate / pyridine / acetic acid / water 60: 20: 6 11) has an Rf value of 0.36; Ultraviolet absorption spectrum (in dioxane): Bmax = 257 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.59.    



   Example 10
If in Example 3, variant C, the phenyloxyacetyl chloride is used as the acylating starting material, the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI14. 5
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.44. 

 

   Example 11
If in Example 3, variant C, the 4-methylphenylthio-acetic acid chloride is used as the acylating starting material, the 2,2-dimethyl-7- (N-4-methylphenylthioacetylamino) -ceph (3) em-4-carboxylic acid is obtained of the formula XA, where Ac is the remainder of the formula
EMI14. 6th
 and which in the thin-layer chromatogram (silica gel; system n-butanol / acetic acid / water 67: 10: 23) has an Rf value of 0.50; Ultraviolet absorption spectrum (in methanol): λ max at 249 mull; Infrared absorption spectrum (in mineral oil): characteristic band at 5.62.    



   Example 12
A 10% slurry of 0.0697 g of 7-amino-2,2dimethyl-ceph (3) em-4-carboxylic acid and 0.0202 g (0.2 mmol) of triethylamine in methylene chloride is treated with a 10% solution of 0.0218 g (0.26 mmol) of diketene in methylene chloride and vibrated for one hour at 22 in an ultrasonic bath; A clear solution is obtained after about 30 minutes. 



  The reaction mixture is worked up according to the method of Example 3, variant A, and the 7- (N-acetoacetylamino) -2,2-dimethylceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder, is obtained the formula
EMI15. 1
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.35; Ultraviolet absorption spectrum (in 0.1-m aqueous
Sodium hydrogen carbonate solution): i max at 238 m and 269 m. 



   Example 13
If benzoylacetic acid is used as acylating starting material in the process of Example 3, variant A, the 7- (N-benzoylacetylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI15. 2
 denotes, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.60; Ultraviolet absorption spectrum (in 0.1 molar sodium hydrogen carbonate solution): J.  ax 239 mic; Infrared absorption spectrum (in mineral oil): characteristic band at 5.67 tt.    



   Example 14
If cyanoacetic acid is used as acylating starting material in the process of Example 3, variant A, 7- (N-cyanoacetylamino) -2,2 dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI15. 3
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.53; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 258 mull; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.33 and 5.60, u.    



   Example 15
If in Example 3, variant C, the o-cyanopropionic acid chloride is used as the acylating starting material, the 7- (Na-cyanopropionyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula is obtained XA, where Ac is the remainder of the formula
EMI15. 4th
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.59; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): #max at 257 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.44 l and 5.64, u.    



   Example 16
If a-cyano-phenylacetic acid is used as acylating starting material in the process of Example 3, variant A, 7 - (Na-cyano-phenylacetylamino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid is obtained of the formula XA, where Ac is the remainder of the formula
EMI15. 5
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.38; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): imax at 260 m; Infrared absorption spectrum (in mineral oil): characteristic bands at 4.40 and 5.64 y.    



   Example 17
A 10% suspension of 0.0697 g (0.2 mmol) 7-amino-2,2-dimethyl-ceph (3) em-4-carboxylic acid and 0.0429 g (0.3 mmol) tri-n- butylamine in dimethylformamide is mixed with an above solution of 0.0422 g (0.4 mmol) of 2 chloroethyl isocyanate in dimethylformamide and the mixture is vibrated for one hour at 22 in an ultrasonic bath. 

  The process described in Example 3, variant A, is then worked up and the 7- [N- (2-chloroethylaminocarbonyl) amino] -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula is obtained XA, where Ac is the remainder of the formula
EMI15. 6th
 means, and the thin-layer chromatogram (silica gel) Rf values of 0.53 (system n-butanol / acetic acid / water 75: 7.5: 21) and of 0.70 (system n-butanol / pyridine / acetic acid / water 38: 24: 8:30); Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): hmax at 258 m.    



   Example 18
If in Example 3, variant C, the 2-thienylpionyl chloride is used as the acylating starting material, the 7- (N-3-chloropropionylamino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula is obtained XA, where Ac is the remainder of the formula
EMI16. 1
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.30; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Xmax at 256 mp; Infrared absorption spectrum (in mineral oil): characteristic band at 5.62 Il.    



   Example 19
If, in Example 3, variant C, the chloroacetic acid chloride is used as the acylating starting material, the 7- (N-chloroacetylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder the formula
EMI16. 2
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.61; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Amax at 257 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.62 Il.    



   Example 20
If dichloroacetic acid is used as acylating starting material in the process of Example 3, variant A, the 7- (N-dichloroacetylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI16. 3
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.54; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Xmax at 257 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.70 Il.    



   Example 21
If in Example 3, variant C, the 2-propenecarboxylic acid chloride is used as the acylating starting material, the 7- (N-butenoylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI16. 4th
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.65. 



   Example 22
If in Example 3, variant C, the phenylacetic acid chloride is used as the acylating starting material, the 2,2-dimethyl-7- (N-phenylacetylamino) -ceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder the formula
EMI16. 5
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8: 30) has an Rf value of 0.62. 



   Example 23
If in Example 3, variant C, the 2-thienyl acetyl chloride is used as the acylating starting material, the 2,2-dimethyl-7- (N-2-thienylacetylamino) ceph (3) em-4-carboxylic acid of the formula is obtained XA, where Ac is the remainder of the formula
EMI16. 6th
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) has an Rf value of 0.59; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution: A max at 235 m; infrared absorption spectrum (in mineral oil): characteristic band at 5.64 μl.    



   Example 24
If, in the process of Example 3, variant A, methylthioacetic acid is used as the acylating starting material, 2,2-dimethyl-7- (N-methylthioacetylamino) -ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI16. 7th
 means, and which in the thin-layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38:24 8:30) has an Rf value of 0.60; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Xmax at 256 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.7.    

 

   Example 25
If in Example 3, variant C, the bis-methoxycarbonyl-acetic acid chloride is used as the acylating starting material, the 7- (N-bis-methoxycarbonylacetyl-amino) 2,2-dimethyl-ceph (3) em-4-carboxylic acid is obtained Formula XA, where Ac is the remainder of the formula
EMI17. 1
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 38: 24: 8: 30) has an Rf value of 0.57; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Amax at 249 my; Infrared absorption spectrum (in mineral oil): characteristic band at 5.57 u.    



  The bis-methoxycarbonyl acetic acid chloride used as an acylating agent is prepared by reacting the sodium salt of dimethyl malonate in tetrahydrofuran with phosgene at -10. 



   Example 26
If in the process of Example 3, variant A, phenylmalonic acid is used as the acylating starting material, the 7- (Na-carboxy-phenylacetyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula XA is obtained where Ac is the remainder of the formula
EMI17. 2
 means.  and which in the thin-layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has two zones: The faster moving zone with Rf = 0.45 contains the 2,2-dimethyl-7- (N- phenylacetyl) amino) -ceph (3) em-4-carboxylic acid and the slower moving zone with Rf = 0.26 the desired 7- (N-α-carboxy-phenylacetyl-amino) -2,2-dimethyl-ceph ( 3) em-4-carboxylic acid. 



   Example 27
If in the process of Example 3, variant B, the sodium salt of DL-a- (N-tert. -Butyl-oxycarbonyl-amino) -2-thienylacetic acid as acylating starting material, the 2,2-dimethyl-7- [N-a- (N-tert. -butyloxycarbonyl-amino) -2-thienylacetyl-amino] -ceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder of the formula
EMI17. 3
 means, and which is purified by thin layer chromatography (silica gel) and in the system ethyl acetate / pyridine / acetic acid / water (62: 21: 6 11) an Rf value of 0.54 and in the system ethyl acetate / n-butanol / pyridine / acetic acid / water (42: 21: 21: 6: 10) has an Rf value of 0.66. 

  It can be converted into the 7- [N - (α-amino-2-thienylacetyl) -amino] -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac the rest of the formula
EMI17. 4th
 means to be convicted; this is present as a zwitterion and in the thin-layer chromatogram (silica gel) in the system ethyl acetate / methyl ethyl ketone / formic acid / water (50: 30: 10 10) has an Rf value of 0.47.    



   Example 28
A solution of the 7- (N-bromoacetyl-amino) -2,2-dimethylceph (3) em-4-carboxylic acid (about 0.15 mmol) in 0.3 ml of a solution of obtainable by the method described in Example 6 17.3 ml of diisopropylethylamine in 100 ml of methylene chloride are mixed with 0.0126 g (0.18 mmol) of tetrazole in 0.3 ml of dimethylformamide and allowed to react for 30 minutes at room temperature.  The process described in Example 3 is worked up and the 2,2-dimethyl-7- (N-1-tetrazolylacetylamino) -ceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder of the formula, is obtained
EMI17. 5
 means, and those in the thin layer chromatogram [silica gel; System n-butanol / pyridine / acetic acid / water (42: 24: 4: 30)] has an Rf value of 0.50; Ultraviolet absorption spectrum (in methanol): bmax at 257 mull.    



   Example 29
A solution of the 7- (N-bromoacetyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid (about 0.15 mmol) obtainable by the method described in Example 6 is placed in 0.3 ml a solution of 17.3 ml of diisopropylethyl-amine in 100 ml of methylene chloride with 0.0205 g (0.18 mmol) of 2-mercapto-1-methyl-imidazole in 0.3 ml of dimethylformamide according to the method described in Example 28, wherein if allowed to react for 7 hours at 200, the 7- [N- (1-methyl-2-imidazolyl-thioacetyl) -amino] -2,2-dimethyl-ceph (3) em-4-carboxylic acid of the formula is obtained XA, where Ac is the remainder of the formula
EMI17. 6th
 means, and those in the thin layer chromatogram [silica gel; System n-butanol / pyridine / acetic acid / water (42: 24: 4:

   30)] has an Rf value of 0.37; Ultraviolet absorption spectrum (in methanol): kmax at 253 m
Example 30
A solution of the 7- (N-bromoacetylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid (about 0.15 mmol) obtainable by the process described in Example 6 is placed in 0.3 ml of a solution 17.3 ml of diisopropylethyl-amine in 100 ml of methylene chloride with 0.0182 g (0.18 mmol) of 3-mercapto-1,2,4-triazole according to the method described in Example 28, being carried out for 7 hours at 20 lets react, the 2,2-dimethyl-7- [N- (1,2,4-triazol-3-yl-thioacetyl) -amino] -ceph (3) em-4-carboxylic acid of the formula XA is obtained, wherein Ac is the remainder of the formula
EMI18. 1
 means, and those in the thin layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 42: 24: 4:

   30) has an Rf value of 0.52; Ultraviolet Absorption Spectrum (in methanol): Amax at 254 mp.    



   Example 31
If in Example 3, variant C, the dibromoacetic acid chloride is used as the acylating starting material, the 7- (N-dibromoacetylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acid of the formula XA, in which Ac denotes, is obtained Remainder of the formula
EMI18. 2
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / acetic acid / water 75: 7.5: 21) has an Rf value of 0.44; Ultraviolet absorption spectrum (in 0.1 molar aqueous sodium hydrogen carbonate solution): Amax at 253 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.61. 



   Example 32
A solution prepared at 30 of the 7- (N-bromoacetyl-amino) -2,2-dimethyl-ceph (3) em-4-carboxylic acid (about 0.15 mmol) prepared by the method described in Example 6 in 10 ml of ethanol and 0.3 ml of water are mixed with a solution of 0.03 g of sodium azide in 0.5 ml of water.  The mixture is stirred for 15 hours at room temperature and in the absence of light, and the reaction mixture is worked up by the method described in Example 3. 

  The 7- (N-azidoacetylamino) -2,2-dimethylceph (3) em-4-carboxylic acid of the formula XA, in which Ac is the remainder of the formula, is thus obtained
EMI18. 3
 means, and which in the thin layer chromatogram (silica gel; system n-butanol / pyridine / acetic acid / water 42: 24: 4: 30) has an Rf value of 0.50; Ultraviolet Absorption Spectrum (in methanol): #max at 258 m; Infrared absorption spectrum (in mineral oil): characteristic band at 5.58.    



   Example 33
The starting material used in the above examples can e.g. B.  can be produced as follows:
15 ml of a sulfonic acid type ion exchanger (HForm) are introduced into the triethylammonium salt form by treatment with a solution of 5 ml of triethylamine in 100 ml of water, the column is washed neutral with 300 ml of water and treated with a solution of 2 g of the sodium salt of Penicillin-G in 10 ml of water and then eluted with water. 



  A volume of 45 ml is withdrawn and lyophilized at a pressure of 0.01 mm Hg.  The crude triethylammonium salt of penicillin-G thus obtained is dissolved in methylene chloride, and the solution is dried over sodium sulfate, filtered and evaporated. 



   A solution of the penicillin-G-triethylammonium salt thus obtainable in a mixture of 40 ml of methylene chloride and 40 ml of tetrahydrofuran is cooled to -10> and 2.9 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran are slowly added with stirring.  The mixture is stirred for 90 minutes at -5 to 0, then treated with a solution of 0.395 g of sodium azide in 4 ml of water and the mixture is stirred for 30 minutes at -5 to 0.     It is diluted with 100 ml of ice water and extracted three times with 75 ml of methylene chloride each time; the organic extracts are washed with water, dried and evaporated at room temperature under reduced pressure. 

  The amorphous penicillin G-azide is thus obtained, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05 y, 4.71, 5.62 II, 5.80 y, 5.94 y, 6.69 and 8, 50.    



   A solution of 1.72 g of the penicillin G azide in 30 ml of benzene is mixed with 1.5 ml of 2,2,2-trichloroethanol and stirred at 70 for 25 hours.  A regular evolution of nitrogen is observed during the first 15 minutes and after a few hours the product separates out of the solution.  The mixture is diluted with 60 ml of hexane while stirring, cooled and filtered after 15 minutes.  The filter residue is washed with a 2: 1 mixture of benzene and hexane and with cold ether. 

  The pure 2,2-dimethyl-6- (N-phenylacetyl-amino) -3 (N-2,2,2-trichloroethoxycarbonyl-amino) -penam, which melts at 223-223.50; [a] 20 = + 172> (c = 1.018 in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04 Il, 5.61 Il, 5.77 y, 6.97 pl, 6.70, 8.30 H 9.17 Il, 9.62 and 11.85. 



   The product can also be obtained by heating 0.03 g of penicillin G azide in 2 ml of benzene to 70 for 20 minutes, the 3-isocyanato-2,2-dimethyl-6- by evaporating the reaction mixture under reduced pressure (N-phenylacetyl-amino) -penam [infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06 y, 4.48 Il, 5.62, 5.96 y, 6.70 C1] and this according to the example 4 by reacting with 2,2,2-trichloroethanol into the desired 2,2-dimethyl-6- (N-phenylacetyl-amino) 3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam . 

 

   A solution of 2.49 g of 2,2-dimethyl-6- (N-phenyl acetyl-amino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino) -pen- am in 50 ml of dimethylformamide, 25 ml Acetic acid and 5 ml of water are prepared at room temperature, then cooled to 0> and, while stirring, a total of 25 g of zinc dust is added in portions within 10 minutes.  The mixture is stirred at 0> for 20 minutes, then the mixture is filtered into a template of 500 ml of a saturated aqueous sodium chloride solution and the filter residue is washed out with 25 ml of acetic acid.  The filtrate is extracted three times with 300 ml of benzene each time; the organic extracts are washed with water, dilute aqueous sodium hydrogen carbonate solution and water, combined, dried and evaporated under reduced pressure. 

  The residue is chromatographed on 45 g of acid-washed silica gel.  Fractions of 100 ml each are taken, using 300 ml of benzene, 300 ml of a 9: 1, 500 ml of a 4: 1, 600 ml of a 2: 1 and 200 ml of a 1: 1 mixture of benzene and ethyl acetate and 100 ml of ethyl acetate washes out.  Fractions 8 and 9 contain crystalline starting material, while the 3-hydroxy-2,2-dimethyl-6- (N-phenylacetyl-amino) -penam is obtained from fractions 11-15 as a colorless oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90 Lt, 3.05, 5.64 Lt, 5.99, 6.70 and 9.28, etc.    



   A solution of 0.3 g of 3-hydroxy-2,2-dimethyl-6- (N-phenylacetyl-amino) -penam in 8 ml of tetrahydrofuran is at 0> with 0.5 ml of a solution of 0.38 g of sodium borohydride in 5 ml Treated water.  The reaction mixture is stirred at 0> for 20 minutes, then acidified with 20 drops of acetic acid and diluted with 50 ml of methylene chloride.  The organic solution is washed with a saturated aqueous sodium chloride solution, dried and evaporated. 

  After crystallization from benzene, the residue gives 4ss- (2-hydroxymethyl-2-propyl-mercapto) -3ss (N-phenylacetyl-amino) -azetidin-2-one, which melts at 129-129.50; [α] 20 D = 1 # 1 (c = 0.984 in chloroform): Ultraviolet absorption spectrum (in ethanol): #max = 252 mZ (E = 170), 258 m (E = 200) and 265 m (E = 150); Infrared absorption spectrum:

   characteristic bands in methylene chloride at 2.75, 2.92, 5.61, 5.97, 6.23, 6.62, 6.68 Lt (shoulder) and 9.48, u, and in mineral oil at 3.12 IFt, 3. 18 u (shoulder), 3.23, u, 5.62, 5.75 Lt 6.08, 6.23 Il, 6.42 Lt.     8.02 Lt and 9.45; Thin layer chromatogram (silica gel): Rf = 0. 10 (chloroform / acetone 4: 1), Rf = 0.33 (chloroform / methanol 19 1) and Rf = 0.63 (chloroform / methanol 9: 1).    



   A solution of 1.55 g of 413- (2-hydroxymethyl-2-propyl-mercapto) -3ss- (N-phenylacetylamino) -azetidin-2-one and 1.42 g of 2,2,2-trichloroethyl chloroformate in 20 ml of absolute tetrahydrofuran is cooled to 0> and, while stirring, a solution of 0.81 ml of absolute pyridine (0.79 g) in 10 ml of absolute tetrahydrofuran is added over the course of 3 minutes.  After the addition has ended, the temperature is allowed to rise to about 20 and stirring is continued for 2 hours.  The reaction mixture is diluted with 150 ml of methylene chloride and 40 ml of water, shaken and the phases are separated. 

  The aqueous phase is washed twice with 50 ml of methylene chloride each time and the combined organic phases are washed twice with 30 ml of water each time, dried over magnesium sulfate and freed from the solvent under reduced pressure.  The residue is chromatographed on a column of 165 g of silica gel.  Bis (2,2,2-trichloroethyl) carbonate and a little 2,2,2-trichloroethanol are washed out with a 19: 1 mixture of methylene chloride and methyl acetate; the 3ss- (N-phenylacetylamino) -40- [2- (2,2,2-trichloroethoxyloxy-carbonyloxymethyl) -2-propylmercapto] -azetidin-2-one is obtained as an amorphous and thin-layer chromatographically pure product with a 9: 1 -Mixture of methylene chloride and methyl acetate eluted and lyophilized from benzene. 

  The lyophilizate is dried in a high vacuum for 20 hours at room temperature; [α] D20 = -3 # 1 (c = 1.097 in chloroform): Thin-layer chromatogram (silica gel): Rf = 0.24 (toluene / ethyl acetate 1: 1) and Rf = 0.78 (chloroform / acetone 2 1 ); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91 Il, 5.61, 5.64 Lt (shoulder), 5.93, 6.62, 7.22 Fa, 8.08, 10.00 Lt and 12, 25 Lt.    



   A solution of 3.2 g of glyoxylic acid tert. Butyl ester hydrate in 80 ml of toluene is concentrated to half the volume to remove water and, after cooling, with 0.880 g of 3ss- (N-phenylacetylamino) -4ss- (2- [2,2,2-trichloroethoxycarbonyloxymethyl) -2 propylmercapto] azetidin -2-one added.  The mixture is then heated at 90 for 4 1/2 hours and, after cooling, the reaction mixture is drawn onto a column of 120 g of silica gel. 

  The α-hydroxy-α - {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,22-trichloroethoxy-carbonyloxymethyl) - is eluted with a 3: 1 mixture of toluene and ethyl acetate. 2-propylmercapto] -1-azetidinyl} -a-hydroxy-acetic acid -tert.  butyl ester, which in the thin layer chromatogram (silica gel) shows an Rf value of 0.36 (benzene / ethyl acetate system 1: 1) and is a uniform product that can be processed without further purification. 



   A solution, cooled to -10, of 0.932 g of a-hydroxy a- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxycarbonyloxymethyl) -2-propylmercapto] - 1 - azetidinyl} acetic acid tert. butyl ester in 18 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is mixed with 0.366 ml of pyridine and then with a solution of 0.328 ml of thionyl chloride in 10 ml of a 1: 1 mixture of dioxane and tetrahydrofuran.  The reaction mixture is stirred for one hour at 0 and for a further hour at room temperature; the resulting precipitate is filtered off and the filtrate is evaporated in a rotary evaporator. 

  The oily residue containing the α-chloro-α - {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2, -2-trichloroethoxycarbonyloxymethyl) -2-propylmercapto] 1 -acetidinyl } -acetic acid tert.  -butyl ester, is evaporated to dryness twice with 50 ml of benzene each time, then taken up in 20 ml of dioxane and heated to 55 for 17 hours with 0.769 g of triphenylphosphine and 0.122 ml of pyridine.  After cooling, the reaction mixture is filtered through a diatomaceous earth preparation and the filtrate is evaporated to dryness.  A dark brown oily residue is obtained, which is chromatographed on 25 times the amount of silica gel. 

  The α- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] -1-azetidinyl} - is eluted with ethyl acetate. a-triphenylphosphoranylidene-acetic acid-tert. butyl ester; Thin-layer chromatogram (silica gel): Rf = 0.16 (benzene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04 Il, 3.45, 5.68 GF1, 5.96 Lt, 6.14 and 6.63 Lt; Ultraviolet absorption spectrum (in ethanol): final absorption at 220 m.    

 

   A solution of 0.614 g of a- {2-oxo-3ss- (N-phenylacetylamino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] - cooled to about 15> 1 azetidinyl} -α-triphenylphosphoranylidene-acetic acid-tert. Butyl ester in 30 ml of glacial acetic acid is mixed with 6.0 g of zinc dust and 3.0 ml of water and stirred for 30 minutes at about 15.  The zinc dust is filtered off and the filtrate is evaporated in a rotary evaporator.  The residue is taken up in 250 ml of benzene and washed with 75 ml of distilled water, 75 ml of a saturated aqueous sodium hydrogen carbonate solution and 75 ml of distilled water.  The aqueous phases are re-extracted with 100 ml of benzene and the combined organic extracts are dried over magnesium sulfate and evaporated. 

  The residue obtained is α- [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3ss (N-phenylacetyl-amino) -1-azetidinyl] -α-triphenyl-phosphoranylidene-acetic acid-tert.  butyl ester, thin-layer chromatogram: Rf = 0.145 (ethyl acetate); Infrared absorption spectrum (methylene chloride): characteristic bands at 3.00, 3.47, 5.68, 6.00, 6.10 Lt and 6.61; which is further processed without cleaning. 



   A solution of 0.5205 g of α- [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3 P- (N-phenylacetylamino) 1-azetidinyl] -a-triphenylphosphoranylidene-acetic acid-tert. Butyl ester in 10 ml of absolute dimethyl sulfoxide is mixed with 10 ml of acetic anhydride and left to stand for 16 hours under a nitrogen atmosphere at room temperature, then heated for 2 hours at 50 and evaporated to dryness.  The residue is purified by means of preparative thin layer chromatography (silica gel; plates 100 cm × 10 cm × 1.5 mm). 

  It is developed with a 2: 1 mixture of toluene and ethyl acetate and the desired 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em is obtained
4-carboxylic acid tert.  -butyl ester, Rf approximately 0.55-0.58, of the non-isolated a- [4ss- (2-formyl-2-propylmercapto) -2-oxo-3 ss- (N-phenyl - acetylamino) -1-azetidinyl] - α-triphenylphosphoranylidene-acetic acid-tert. -butyl ester is formed and crystallized when sprayed with ethanol. 



  The colorless crystals melt at 86-90, re-solidify and finally melt at 159-162; [α] D20 = +95 + 100 (c = 0.1 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.38 (system: hexane / ethyl acetate 3: 2); Ultraviolet Absorption Spectrum (in ethanol): Amax 258 m (E = 7100); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.44, 5.62, 5.82, 5.92, 6.11, 6.67, 7.18, 7.34, 7.75 Lt and 8.66 Lt
A solution of 0.58 g of 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-4-carboxylic acid-tert. -butyl ester in 10 ml of absolute trifluoroacetic acid is left to stand for one hour at room temperature. 

  The pale yellow solution is evaporated under reduced pressure and the residue is taken to dryness twice with a small amount of absolute toluene.  The residue is chromatographed on 30 g of silica gel (5% water; column).  With methylene chloride containing 2-4% acetone, impurities are washed out; with 19 1 and 9: 1 mixtures of methylene chloride and acetone, the chromatographically pure 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-4-carboxylic acid and with 4 1- and 1 : 1 mixtures of the same solvent mixture slightly contaminated product eluted. 

  The pure acid is obtained as a colorless, vitreous material; Ultraviolet absorption spectrum (in ethanol): Amax = 257 m, u (E = 6450) and kamin = 232 m, u (E = 4400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90 Lt 5.57, 5.72, 5.83, 5.90 Lt 6.11, 6.64, 7.08, 7.31, 8.20 and 9 , 08; Thin-layer chromatogram (silica gel):

  Rf = 0.41 (system n butanol / ethanol / water 40 10:50), Rf = 0.68 (system n butanol / acetic acid / water 44:44), Rf = 0.53 (system ethyl acetate / pyridine / acetic acid / Water 62: 21: 6 11), Rf = 0.62 (system n-butanol / pyridine / acetic acid / water 38: 24: 8:30) and Rf = 0.61 (system n butanol / acetic acid / water 75: 7 , 5:21). 



   If the 2,2-dimethyl-7- (N-phenylacetylamino) -ceph (3) em-4-carboxylic acid is mixed with a slight excess of a 3 molar solution of the sodium salt of a-ethylcaproic acid in methanol, the result is at Dilute with acetone the sodium salt of 2,2-dimethyl-7- (N-phenylacetylamino) -ceph (3) em-4-carboxylic acid, which is at 2180 (uncorr. ) decomposes; Ultraviolet absorption spectrum (in water): Xmax 252 m, u (e = 7300) and #min = 232 m, u (E = 5500); Infrared absorption spectrum (in mineral oil): characteristic bands at 2.99, 5.65, 5.98, 6.92, 6.50, 6.67, 7.05, 7.29, 8.64, 9.03 and 9 , 48. 



   A solution of 0.347 g of 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-4-carboxylic acid (lyophilized from dioxane and dried under high vacuum at 30) in 20 ml of absolute methylene chloride is mixed with 0.239 g Trimethylchlorosilane and 0.158 g of absolute pyridine were added and the mixture was stirred at room temperature for 60 minutes.  The almost colorless solution is cooled to below -200, whereupon a solution of 1.07 g of absolute pyridine in 9.9 ml of methylene chloride and 7.8 ml of an 8% solution of phosphorus pentachloride in absolute methylene chloride is added one after the other.  The mixture is stirred for 60 minutes at -10 to 120, the solution turning a pale yellow.  After cooling again to about -200, 5 ml of absolute methanol are allowed to flow in and the mixture is stirred for 25 minutes at -100, then for 35 minutes at room temperature. 

  5 ml of water are added, the pH of the reaction mixture is increased from 1.8 to 2.2 by the dropwise addition of diethylamine, and it is stirred for 20 minutes at room temperature.  The pH value is increased to 3.4 by adding more triethylamine, the cloudy, two-phase mixture is stirred for 90 minutes while cooling in an ice bath and then filtered.  The filter residue is washed with methanol, methylene chloride and diethyl ether and dried in a vacuum desiccator. 

  The 7-amino2,2-dimethyl-ceph (3) em-4-carboxylic acid is thus obtained; Ultraviolet absorption spectrum (in 0.1-n.  aqueous sodium hydrogen carbonate solution): #max = 254 m, u (E = 6350) and kamin = 234 with (E = 4250); Infrared absorption spectrum: characteristic bands at 3.10, 3.75, 5.51, 6.17, 6.52, 7.03, 7.30 and 7.40 (in mineral oil) and at 2.88, 3.10, 3.82, 5.52, 6.17, 6.50, 6.82, 7.04, 7.40, 8.13, 9.57, 12.10 and 12.67 (in potassium bromide); Paper chromatogram (running distance 24 cm, system n-propanol / water 7: 3; detection with ninhydrin / collidine reagent): Rf = 0.44 thin-layer chromatogram (cellulose; running distance 15.5 cm; system n-butanol / water / ethanol; detection with Reindel-Hoppe reagent); Rf = 0.37. 



   The starting material can also be made as follows:
A solution of 2.625 g of penicillin-V in 30 ml of tetrahydrofuran is mixed with 5.31 ml of a 10 ml solution of 2 ml of triethylamine in tetrahydrofuran while stirring and cooling to 100.  3.6 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran are then slowly added at -10 and, after the addition is complete, the mixture is stirred at -10 to -5o for 90 minutes. 



   The reaction mixture is treated with a solution of 0.51 g of sodium azide in 5.1 ml of water, stirred for 30 minutes at 0 ° to -5 ° and diluted with 150 ml of ice water. 

 

  It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 25 and under reduced pressure.  The amorphous penicillin V-azide is thus obtained as a slightly yellowish oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 4.70, 5.61, 5.82 (shoulder), 5.93, 6.26, 6.71, 8.50 and 9.40. 



   A solution of 2.468 g of the penicillin V-azide in 30 ml of benzene is heated to 70 ° for 30 minutes.  The pure 3-isocyanato-2,2-dimethyl-6- (N-phenyloxyacetylamino) -penam can be obtained by evaporating the solution under reduced pressure; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03 Il, 4.46, 5.59, 5.93, 6.26, 6.62, 6.70, 7.53, 8.28, 8.53, 9.24 and 9.40. 



   The above solution of 3-isocyanato-2,2-dimethyl-6- (Nphenyloxyacetyl-amino) -penam is mixed with 3.4 ml of a 10 ml solution of 2 ml of 2,2,2-trichloroethanol in benzene and the reaction mixture during Maintained at 70 for 95 minutes. 



  The solvent is removed under reduced pressure and the residue is purified on 40 ml of acid-washed silica gel (column).  It is washed with 300 ml of benzene and 300 ml of a 19: 1 mixture of benzene and acetic acid ethereal ester by-products and the pure 2,2-dimethvi-6- (N-phenyloxyacetyl-amino) -3- (N-2, 2,2-trichlorethoxy-carbonyl-amino) -penam with 960 ml of a 9: 1 mixture of benzene and ethyl acetate. 

  The product melts at 169-171 (decompose); [α] 20 D = +83 (c = 1.015 in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.5 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.62, 5.77, 5.93, 6.27, 6.62, 6.70, 8.30, 9.23 and 9.50. 



   A solution of 3 g of crystalline 2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -3- (N-2,2,2-trichloroethoxycarbonyl-amino) -penam in 65 ml of 90% aqueous acetic acid and 30 ml of dimethylformamide is 32.6 g of zinc dust were added within 20 minutes while cooling in ice and the mixture was stirred for 20 minutes.  The excess zinc is filtered off and the filter residue is washed with benzene; the filtrate is diluted with 450 ml of benzene, washed with a saturated aqueous sodium chloride solution and water, dried and evaporated under reduced pressure.  The residue is purified on a column of 45 g of acid-washed silica gel. 



  It is eluted with 100 ml of benzene and 400 ml of a 9: 1 mixture of benzene and ethyl acetate and apolar products are obtained.  Starting material is washed out with 100 ml of a 4: 1 mixture of benzene and ethyl acetate, and with a further 500 ml of the 4: 1 mixture of benzene and ethyl acetate, and with 200 ml of a 2: 1 mixture of benzene and ethyl acetate, the 3 Hydroxy-2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -penam, which crystallizes spontaneously as a hydrate and, after trituration with water-saturated ether, melts indistinctly in the range of 62-850. 



   If chromatographed but non-crystalline 2,2-dimethyl-6- (N-phenyloxyacetyl-amino) -3 (N-2,2,2-trichloroethoxycarbonyl-amino) -penam is used and reduced in dilute acetic acid without the addition of dimethylformamide, the pure product is obtained, which melts at 62-70>; Thin-layer chromatogram (silica gel): Rf = 0.35 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.93, 3.09, 5.65, 5.96, 6.29, 6.65, 6. 75 u.     8th. 57 u, Lt> 9. 27, 10.00 and 11.95. 



   A solution of 0.18 g of 3-hydroxy-2,2-dimethyl-6- (Nphenyloxyacetyl-amino) -penam hydrate in 5 ml of tetrahydrofuran is treated at 0 with 0.3 ml of a solution of sodium borohydride in 5 ml of water.  The mixture is stirred for 20 minutes at 0O, then adjusted to pH ¯ 4 by adding 12 drops of acetic acid and diluted with 50 ml of methylene chloride.  The organic solution is washed twice with saturated aqueous sodium chloride solution, the aqueous washing liquids are backwashed with methylene chloride and the combined organic solutions are dried and evaporated under reduced pressure. 

  The crystalline residue is crystallized from a mixture of methylene chloride and ether to give the 4ss- (2-hydroxymethyl-2-propyl-mercapto) -3ss- (N-phenyloxyacetyl) -amino) -azetidin-2-one which obtained after repeated recrystallization in needles, F.  156-157; [α] D20 = +130 # 1 (c = 0.708 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59, 5.93, 6.26, 6.62, 6.70, 7.53, 8.28, 8.53, 9 , 24 and 9.40. 



   A solution of 0.4 g of 4ss- (2-hydroxymethyl-2-propylmercapto) -3ss- (N-phenyloxyacetyl-amino) azetidin-2-one and 0.52 g of 2,2,2-trichloroethoxycarbonyl chloride in 6 ml dry tetrahydrofuran is slowly mixed with a solution of 0.6 ml of pyridine in 4 ml of dry tetrahydrofuran with stirring and at 0.  After the addition has ended, the mixture is stirred for 3 hours, then diluted with 100 ml of methylene chloride; the organic solution is washed with water, dried and evaporated.  The residue is chromatographed on 40 g of acid-washed silica gel.  By-products, mainly the bis2,2,2-trichloroethyl carbonate, are washed out with benzene, and 9 1 and 4: 1 mixtures of benzene and ethyl acetate. 



  The 3ss- (N-phenyloxyacetylamino) -4ss- [2- (2,2,2trichlorethoxy-carbonyloxymethyl) 2-propylmercapto-azetidin-2-one is eluted with a 1: 1 mixture of benzene and ethyl acetate and from recrystallized from a mixture of ether and pentane, F.  93-95; [α] 20 D = -6> +1 (c = 1.17 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.63, 5.68, 5.92, 6.26, 6.69, 6.70, 7.25 and 8.08. 



   A solution of 0.4 g glyoxylic acid tert. Butyl ester hydrate in 5 ml of toluene is dried azeotropically by distilling off 2 ml of toluene under normal pressure.  The mixture is cooled to 90 and 0.121 g of 3ss- (N-phenyloxyacetyl-amino) -4ss- [2-2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propyl-mercapto] -azetidin-2-one in 2 ml of anhydrous Toluene too.  The mixture is heated at 90 for 90 minutes; the volatile constituents are distilled off under a pressure of 0.01 mm Hg.  The oily residue is taken up in a mixture of benzene and pentane and washed with water.  The organic phase is dried and the solvent is distilled off under reduced pressure. 

  The residue is chromatographed on 3.5 g of acid-washed silica gel, and the amorphous mixture of the isomers of α-hydroxy-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- ( 2,2,2-trichlorethoxy-carbonyloxymethyl) -2-propyl mercapto] -1-azetidinyl} -acetic acid-tert. butyl ester by eluting with a 4: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.64, 5.80, 5.94, 6.27, 7.32, 8.17 and 8.69. 



   A solution of 0.254 g of α-hydroxy-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] - 1 -azetidinyl} acetic acid tert-butyl ester in 5 ml of dioxane (dried by filtering through aluminum oxide, activity I) is cooled to 0 and treated with 0.320 g of polymeric Hünig base (diisopropylaminomethylene polystyrene; prepared by heating a mixture of 100 g of chloromethyl polystyrene [J.  At the.  Chem.  

  Soc.  85, 2149 (1963)], 500 ml of benzene, 200 ml of methanol and 100 ml of diisopropylamine to 150 ml with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and triethylamine, 1000 ml of methanol, 1000 ml of methanol and drying for 16 hours at 100/10 mm Hg; the product neutralizes 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) and 0.6 ml of a solution of thionyl chloride in dry dioxane (1 ml of thionyl chloride per 10 ml of solution) is added.  After 2 hours the mixture is filtered, the filter residue is washed with dry dioxane and the filtrate is evaporated to dryness under high vacuum. 

  The residue containing the α-chloro-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] - 1 -azetidinyl) acetic acid tert. butyl ester, is dissolved in 5 ml of dioxane, 0.2 g of triphenylphosphine and 0.2 g of the polymeric Hünig base are added and the mixture is stirred at 55 for 16 hours.  It is filtered, the filter residue is washed with benzene and the filtrate is evaporated under reduced pressure.  The residue is chromatographed on 15 g of acid-washed silica gel. 

  The fractions washed out with a 4: 1 mixture and the first with a 2: 1 mixture of benzene and ethyl acetate contain unreacted starting material, while the other fractions with the 2: 1 mixture of benzene and ethyl acetate and with a 1: 1 mixture of the same solvents, fractions eluted the amorphous α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2trichlorethoxy-carbonyloxy-methyl) -2-propylmercapto ] - 1-azetidinyl} - α-triphenylphosphoranylidene-acetic acid-tert. -butyl ester, infrared absorption spectrum (in methylene chloride): contain characteristic bands at 3.03, 5.69, 5.94, 6.2 Lt and 8.9 Lt and the other fractions contain some triphenylphosphine oxide. 



   A solution of 0.127 g of a- (2-oxo-3P- (N-phenyloxyacetyl-amino) -4P- [2- (2,2,2-trichlorethoxycarbonyloxymethyl) -2-propylmercapto] -1-azetidinyl} -? -triphenylphosphoranylidene-acetic acid-tert. Butyl ester in 10 ml of 90% aqueous acetic acid is mixed with 1.0 g of zinc dust and stirred at 0> for 30 minutes.  The mixture is filtered, the filtrate is diluted with 100 ml of benzene, washed with water, a dilute aqueous sodium hydrogen carbonate solution and water and the aqueous solutions are re-extracted with benzene. 

  The combined organic solutions are evaporated under reduced pressure to give the amorphous a- [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3ss- (N-phenyloxyacetylamino) -1-azetidinyl] -α-triphenyl - phosphoranylideneacetic acid tert.  -butyl ester as a colorless, gummy substance; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 Lt 5.69, 5.97 Lt 6.12, 6.55 Lt 6.69 Lt 7.33, 7.50, 8.55 Lt 9.03, 9 , 23 Lt and 9.40. 



   A solution of 0.0530 g of a- [4B- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3-ss- (N-phenyloxyacetylamino) -1-azetidinyl] -a-triphenylphosphoranylidene-acetic acid tert. Butyl ester in 1 ml of absolute dimethyl sulfoxide and 1 ml of acetic anhydride is left to stand for 16 hours at room temperature, then heated for 90 minutes at 50 and evaporated under high vacuum. 

  The residue is purified by means of preparative thin layer chromatography (silica gel plates 20 cm × 20 cm × 1.5 mm; toluene / ethyl acetate system 9 1).     Elution of the strip that is active under ultraviolet light with methanol yields the thin layer chromatography (Rf = 0.44; silica gel;

  System hexane / ethyl acetate 3: 2) pure 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) ceph (3) em-4-carboxylic acid tert. butyl ester ultraviolet absorption spectrum (in ethanol): λ max = 263 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.61 y, 5.83 Lt, 5.91, 6.11 Lt and 6.26 ll; of the α- [4ss - (- Formyl-2-propylmercapto) -2-oxo-3ss- (N-phenyloxyacetyl-amino) -1-azetidinyl] -α-triphenylphosphoranylidene obtained by ring closure from the intermediate and not isolated acetic acid tert. -butyl ester is formed. 



   A solution of 0.0146 g of 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid-tert. butyl ester in 1 ml of trifluoroacetic acid is left to stand at 230 for one hour, then evaporated under reduced pressure. 



  The oily residue is taken to dryness twice with a mixture of toluene and chloroform and dried under reduced pressure.  This gives the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.34 Lt 3, 49, 5.62 Il, 5.64 Lt 5.92, 6.12 Lt 6.27, 6.61 pounds 6.72. 



   In the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid obtainable in this way, the acylated amino group can be converted into the free amino group as shown above, and the 7-amino group is obtained -2,2 dimethyl-ceph (3) em-4-carboxylic acid.    



   PATENT CLAIM 1
Process for the preparation of 7- (N-acylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acids and their esters of the formula 1
EMI22. 1
 where Ac represents an acyl group, and R2 represents hydrogen or an organic radical RA2 which together with the - C (= O) -O group forms an esterified carboxyl group, or salts of such compounds with salt-forming groups, characterized in that in a 7-amino-ceph (3) em compound of the formula II
EMI22. 2
 or acylated the free amino group in a salt thereof. 

 

   SUBCLAIMS
1.  Process according to claim I, characterized in that R2 in the starting material of the formula II according to claim I represents an organic radical R2A which represents a radical which forms an easily cleavable esterified carboxyl group with the - C (= O) - O group. 



   2.  Process according to claim I, characterized in that R2 in the starting material of the formula II according to

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. lized 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) and treated with 0.6 ml of a solution of thionyl chloride in dry dioxane (1 ml of thionyl chloride per 10 ml of solution). After 2 hours the mixture is filtered, the filter residue is washed with dry dioxane and the filtrate is evaporated to dryness under high vacuum. The residue containing the α-chloro-α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2-trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] - 1 -azetidinyl) -acetic acid tert-butyl ester is dissolved in 5 ml of dioxane, 0.2 g of triphenylphosphine and 0.2 g of the polymeric Hünig base are added and the mixture is stirred at 55 for 16 hours. It is filtered, the filter residue is washed with benzene and the filtrate is evaporated under reduced pressure. The residue is chromatographed on 15 g of acid-washed silica gel. The fractions washed out with a 4: 1 mixture and the first with a 2: 1 mixture of benzene and ethyl acetate contain unreacted starting material, while the other fractions with the 2: 1 mixture of benzene and ethyl acetate and with a 1: 1 mixture of the same solvents, fractions eluted the amorphous α - {2-oxo-3ss- (N-phenyloxyacetyl-amino) -4ss- [2- (2,2,2trichlorethoxy-carbonyloxy-methyl) -2-propylmercapto ] -1-azetidinyl} -α-triphenylphosphoranylidene-acetic acid, tert-butyl ester, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.69, 5.94, 6.2 Lt and 8.9 Lt contain and the other fractions have some triphenylphosphine oxide. A solution of 0.127 g of a- (2-oxo-3P- (N-phenyloxyacetyl-amino) -4P- [2- (2,2,2-trichlorethoxycarbonyloxymethyl) -2-propylmercapto] -1-azetidinyl} -triphenylphosphoranylidene-acetic acid tert-butyl ester in 10 ml of 90% aqueous acetic acid is mixed with 1.0 g of zinc dust and stirred at 0> for 30 minutes. The mixture is filtered, the filtrate is diluted with 100 ml of benzene, washed with water, a dilute aqueous sodium hydrogen carbonate solution and water and the aqueous solutions re-extracted with benzene. The combined organic solutions are evaporated under reduced pressure to give the amorphous a- [4ss- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3ss- (N-phenyloxyacetylamino) -1-azetidinyl] -α-triphenyl - phosphoranylideneacetic acid tert. -butyl ester as a colorless, gummy substance; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 Lt 5.69, 5.97 Lt 6.12, 6.55 Lt 6.69 Lt 7.33, 7.50, 8.55 Lt 9.03, 9 , 23 Lt and 9.40. A solution of 0.0530 g of tert-butyl a- [4B- (2-hydroxymethyl-2-propylmercapto) -2-oxo-3-ss- (N-phenyloxyacetylamino) -1-azetidinyl] -a-triphenylphosphoranylidene acetic acid in 1 ml of absolute dimethyl sulfoxide and 1 ml of acetic anhydride is left to stand for 16 hours at room temperature, then heated for 90 minutes at 50 and evaporated under high vacuum. The residue is purified by means of preparative thin layer chromatography (silica gel plates 20 cm × 20 cm × 1.5 mm; toluene / ethyl acetate system 9 1). Elution of the strip that is active under ultraviolet light with methanol yields the thin layer chromatography (Rf = 0.44; silica gel; System hexane / ethyl acetate 3: 2) pure 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) ceph (3) em-4-carboxylic acid tert-butyl ester Ultraviolet absorption spectrum (in ethanol): A max = 263 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.61 y, 5.83 Lt, 5.91, 6.11 Lt and 6.26 ll; of the α- [4ss - (- Formyl-2-propylmercapto) -2-oxo-3ss- (N-phenyloxyacetyl-amino) -1-azetidinyl] -α-triphenylphosphoranylidene obtained by ring closure from the intermediate and not isolated -acetic acid tert-butyl ester is formed. A solution of 0.0146 g of 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid tert-butyl ester in 1 ml of trifluoroacetic acid is left to stand at 230 for one hour, then under evaporated under reduced pressure. The oily residue is taken to dryness twice with a mixture of toluene and chloroform and dried under reduced pressure. This gives the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.34 Lt 3, 49, 5.62 Il, 5.64 Lt 5.92, 6.12 Lt 6.27, 6.61 pounds 6.72. In the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid obtainable in this way, the acylated amino group can be converted into the free amino group as shown above, and the 7-amino group is obtained -2,2 dimethyl-ceph (3) em-4-carboxylic acid. PATENT CLAIM 1 Process for the preparation of 7- (N-acylamino) -2,2dimethyl-ceph (3) em-4-carboxylic acids and their esters of the formula 1 EMI22.1 where Ac represents an acyl group, and R2 represents hydrogen or an organic radical RA2 which together with the - C (= O) -O group forms an esterified carboxyl group, or salts of such compounds with salt-forming groups, characterized in that in a 7-amino-ceph (3) em compound of the formula II EMI22.2 or acylated the free amino group in a salt thereof. SUBCLAIMS 1. The method according to claim I, characterized in that R2 in the starting material of the formula II according to claim I represents an organic radical R2A which represents a radical which forms an easily cleavable esterified carboxyl group with the - C (= O) - O group. 2. The method according to claim I, characterized in that R2 in the starting material of the formula II according to Claim I stands for a group RA which, together with the -C (= O) -O- group, has a reducing metal, e.g., a reducing metal alloy, when treated under neutral or acidic aqueous conditions with a reducing metal. a reducing metal amalgam or a metal salt when irradiated. when treated with an acidic or weakly basic agent, easily cleavable esterified carboxyl group forms. 3. The method according to claim I, characterized. acylating the amino group by treatment with a carboxylic acid or a reactive functional carboxylic acid derivative thereof. 4. The method according to claim I, characterized in that the amino group is acylated by treatment with a carboxylic acid halide. 5. The method according to claim I, characterized in that the amino group is acylated by treatment with a carboxylic acid chloride. 6. The method according to claim I, characterized. that the amino group is acylated by treatment with an anhydride of a carboxylic acid. 7. The method according to claim I, characterized in that the amino group is acylated by treatment with an internal anhydride or a mixed anhydride of a carboxylic acid. 8. The method according to claim I, characterized. that the amino group is acylated by treatment with an activated ester of a carboxylic acid. 9. The method according to claim I, characterized in that acylation is carried out in the presence of a condensing agent. 10. The method according to claim I, characterized in that free functional groups are intermediately protected in the reactants. 11. The method according to claim I, characterized in that compounds of the formula I according to claim I or salts of such compounds with salt-forming groups in which Ac is an acyl group which in a pharmacologically active N-acyl derivative of 6-aminopenicillan or 7 -Amino-cephalosporanic acid or which is an acyl radical that can be easily split off under acidic conditions or by reductive action, and R2 is hydrogen or an organic radical which, together with the carbonyloxy grouping, is a, when treated with an acidic agent or when treated with a reducing metal reducing metal alloy, e.g. a reducing metal amalgam, or a metal salt, under neutral or weakly acidic, aqueous conditions, forms an esterified carboxyl group which can be cleaved or which can easily be converted into this esterified carboxyl group. 12. The method according to claim I, characterized in that compounds of the formula I according to claim I or a salt of such compounds with salt-forming groups is prepared, wherein Ac is either a naturally occurring, biosynthetically producible or highly effective N-acyl derivative of 6-amino -penam-3carboxylic acid or 7-amino-ceph (3) em-4-carboxylic acid compounds containing acyl radical or an acyl radical that can be easily split off under acidic conditions or reductively, and R2 represents hydrogen, a methyl radical polysubstituted by optionally substituted hydrocarbon radicals, the 2 , 2,2-trichloroethyl radical, the iodoethyl radical or the easily convertible 2-bromoethyl radical, or the phenacyl radical. 13. The method according to claim I or one of the dependent claims 1-10, characterized in that compounds of the formula I according to claim I, in which Ac is a group of the formula EMI23.1 where n is 0 and Rl is an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably of aromatic character, a functionally modified, preferably etherified hydroxyl or mercapto group or an optionally substituted amino group, or in which n is 1, Rl is hydrogen or an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, represents an optionally functionally modified, preferably etherified or esterified hydroxy or mercapto group, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R ″ and Rl'l denotes hydrogen, or in which n is 1 Rl denotes an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, R11 denotes an optionally functionally modified, preferably etherified hydroxyl or mercapto group, an optionally substituted amino group or an optionally functionally modified carboxyl group, and R111 is hydrogen, or in which n is 1, each of the radicals Rl and R "is a functionally modified, preferably etherified or esterified hydroxyl group, or an optionally functionally modified carboxyl group, and R'11 is hydrogen, or in which n is 1 Rl is hydrogen or an optionally substituted aliphatic hydrocarbon radical, and R "and R" 1 together represent an optionally substituted aliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n is 1, and R 'is an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, R "is an optionally substituted aliphatic or aromatic hydrocarbon radical and R" 1 is hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon radical, and R has the meaning given in dependent claim 12. 14. The method according to claim I or one of the dependent claims 1-10, characterized in that compounds of the formula I according to claim I, in which Ac represents a radical of the formula Y (CmH2m) -C (= O) -, in which m is 0, 1 or 2, and a carbon atom of the group - (CmH2m) - can be substituted by an optionally substituted amino group, a free, etherified or esterified hydroxy or mercapto group, a free or functionally modified carboxyl group or an oxo group, and in which Y is optionally in the nucleus by an optionally substituted amino group, a free, etherified or esterified hydroxyl or mercapto group, a free or functionally modified carboxyl group, a nitro or an optionally functionally modified sulfo group, aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, preferably of aromatic character, or by an aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, preferably of aromatic character, optionally substituted as indicated ethereal hydroxyl or mercapto group, or a group of the formula CnH2n + lC (= O) - or CaH2n-1-C (= represents, where n is an integer up to 7, and the chain is straight or branched and optionally from one Oxygen or sulfur atom interrupted and / or by halogen atoms, free or functionally modified carboxyl, such as lower alkoxycarbonyl or cyano groups, free or substituted amino groups, or oxo, azido or nitro groups can be substituted, and R2 has the meaning given in dependent claim 12. 15. The method according to claim I or one of the sub-claims 1-10, characterized in that compounds of the formula I according to claim I, in which Ac represents an optionally substituted phenylacetyl, phenyloxyacetyl, lower alkanoyl or lower alkenoyl radical, and R2 represents hydrogen , the tert-butyl group, the 2,2,2 trichloroethyl radical, the iodoethyl radical, or the phenacyl radical. 16. The method according to claim I or one of the dependent claims 1-10, characterized in that the 2,2-dimethyl-7- (N-phenylacetyl-amino) -ceph (3) em-carboxylic acid is prepared. 17. The method according to claim I or one of the dependent claims 1-10, characterized in that the 2,2-dimethyl-7- (N-phenyloxyacetyl-amino) -ceph (3) em-4-carboxylic acid is produced 18. The method according to claim I or one of the dependent claims 1-10, characterized in that the 2,2 dimethyl-7- [N- (N-tert -butyloxycarbonyl-D -a-phenyl-glycyl) - amino] - ceph (3) em-4-carboxylic acid. 19. The method according to claim I or one of the dependent claims 1-10, characterized in that the 2,2-dimethyl-7- [N- (D-a-phenylglycyl-amino] -ceph (3) em-4-carboxylic acid) is prepared . PATENT CLAIM II Use of the compounds of the formula I obtained by the process of claim I, in which R2 is an organic radical R2 which forms an esterified carboxyl group together with the - C (= O) - O group, for the preparation of compounds of the formula I in which Ac has the meaning given in claim 1 and R2 stands for hydrogen, characterized in that the esterified carboxyl group of the formula - C (= 0) - O-Rk is converted into a free carboxyl group by treatment with an ester-splitting agent.