CH542842A - Bis-(cis-3-amino-2-oxo-4-azetidinyl)-disulphide cpds, esp-6-apa - or 7-acsa acylderivs - inters for antibacterials - Google Patents

Abstract

Cpds. (I): where Ra1 = H or an amino-protecting gp. RA1; Rb1 = H or acyl or RA1 + Rb1 form together a bivalent amino-protecting gp.) or salts of (I) are prepd. by oxidising a cpd. (II) (where Y = ylidene residue). When RA1 and Rb1 in (I) form an ylidene, an amino-protecting group is opt. introduced and/or salts may be formed or exchanged and/or mixtures of isomers may be separated. Pref. cpds. (I) Y= mono- or disubstd. methylene with mon- or bivalent aliphatic hydrocarbon residues as substituents. The pref. oxidation agents are halogens esp. iodine and also heavy metal carboxylates with UV-irradiation; O2 with heavy metal catalysts or a hypohalite cpd. (I) may be used as intermediates in the synthesis of anti-bacterially-active cpds. with activity against Gram-pos and Gram-neg bacteria.

Description

  

  
 



   The present invention relates to a process for the preparation of bis (cis-3-amino-2-oxo-4-azetidinyl) -dusulphide compounds of the formula
EMI1. 1
 wherein Ac represents an acyl group. 



   An acyl 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. 



   An 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, e.g. B. 



  can contain up to 7, preferably up to 4 carbon atoms.  Such radicals can optionally be replaced by functional groups, e.g. B.  by free, etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy. 

  Lower alkyl mercapto or optionally substituted phenyl mercapto or phenyl lower alkyl mercapto, lower alkoxycarbonyioxy or lower alkanoyloxy groups, or halogen atoms, furthermore by oxo groups, nitro groups, optionally substituted amino groups, azido groups, acyl groups, such as lower alkanoyl or benzoyl groups, optionally functionally modified carboxyl groups such as carboxyl groups, such as carboxyl groups which are functionally modified 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, mono-.  be di- or polysubstituted.  A divalent aliphatic hydrocarbon radical is e.g. B.  a lower alkylene or lower alkenylene radical. 



   A cycloaliphatic or cycloaliphatic-aliphatic radical in a corresponding organic carboxylic acid is an optionally substituted 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.  contains 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.  Has 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z. B.  can contain up to 7, preferably up to 4 carbon atoms. 

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



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



   The aliphatic radical in a corresponding carboxylic 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 such. 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, in corresponding carboxylic acids are in particular monocyclic, as well as bi- or polycyclic, aza-, thia-.     oxa-, thiaza, oxaza-, diaza, triaza, or tetrazacyclic radicals, preferably of aromatic character, which may optionally, for. B.  like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted.  The aliphatic part in heterocyclic-aliphatic radicals has z. B.  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 carbonic acid 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 p position, substituted lower alkyl half esters of carbonic acid (i.e. H.  a lower alkoxycarbonyl radical optionally substituted in the lower alkyl moiety, preferably in the o- or p-position), and one optionally substituted in the lower alkenyl, cycloalkyl, phenyl or 

  Phenyl-lower alkyl part-substituted lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl semiesters of carbonic acid (i.e. H.  an optionally in lower alkenyl, cycloalkyl, phenyl or    Phenyl-lower alkyl part-substituted lower alkenyloxycarbonyl, cycloalkoxycarbonyl, phenyloxycarbonyl 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, both the lower alkyl radical and the heterocyclic group being optionally substituted;

   such acyl radicals are u in the lower alkyl part.  lower alkoxycarbonyl groups which are optionally substituted in the heterocyclic group and which contain a heterocyclic group of aromatic character in the lower alkyl radical. 



   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 group, while a lower alkenyl radical z. B.  a vinyl, allyl, isopropenyl, 2- or 3-methalallyl or 3-butenyl group, and a lower alkynyl radical e.g. B.  may be propargyl or 2-butynyl. 



   A lower alkylene group is e.g. B.  a 1,4-butylene or 1,5-phenylene radical, and a lower alkenylene radical z. B.  a 2-buten-1, 4-ylene radical. 



   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- od.  -1,2-ethyl, -1,1-, -1,2- or-l, 3-propyl, vinyl or ally] group, while a cycloalkenyl-lower alkyl or -niedernlkenylgruppe, z. 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 , 1-, -1,2- or -1,3-propyl, vinyl or allyl group. 



   A naphthyl radical is a 1- or 2-naphthyl radical, while a biphenylyl group is e.g. 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, styry] 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.  z. 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.  I-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.  Heterocyclic-aliphatic radicals are heterocyclic groups, especially the lower alkyl or lower alkenyl radicals containing the above. 



   Among etherified hydroxyl groups are primarily lower alkoxy.  z. 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 Nie deralkenyloxy, 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-, ethylmercapto- or n-Bu tylmercaptogruppen, Niederalkenylmercapto-, z. B. 



     Ally] 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 monovalent or divalent, optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic 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, for. 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, sulfoamino 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, iso propyloxycarbonyl, tert. -Butyloxycarbonyl- or tert.  Pentyloxycarbonyl group. 



   Optionally N-substituted carbamyl groups are e.g. B.  N-lower alkyl- or N, N-di-lower alkyl-carbamyl-, such as N-methyl-, N-ethyl-, N, N-dimethy. l- or N, N-diethylcarbamyl groups. 



   A sulfamyl 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-biphenyl yl-oc-methylethoxycarbonyl groups.  Lower alkoxycarbonyl groups in which the lower alkyl radical z. B.  contains a monocyclic, monoaza-, monooxa- or monothiacyolische group are, for. B.  Furyl lower alkoxycarbonyl, such as furfuryloxycarbonyl, or Thie nyiniederalkoxycarbonyl, z. B.    2-thenyloxycarbonyl groups. 

 

   As shown below, the new disulfide compounds of the formula I provide valuable intermediates
Manufacture of pharmacologically active compounds. 



   Particularly valuable as intermediates are compounds of the formula I in which the acyl group Ac represents a naturally occurring or synthetically producible N-acyl derivative of the 6-amino-penicillanic acid or 7-amino-cephalosporanic acid compounds contained in a preferably pharmacologically active men
Acyl radical or an easily cleavable acyl radical. 



   An acyl radical Ac contained in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalospo ranoic acid or an acyl radical which can be converted into these is primarily a group of the formula
EMI3. 1
 where n is 0 and R1 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 , RI 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, an optionally functionally modified carboxyl group, an acyl group, an optionally substituted amino group or an azido group, and each of the radicals R13 and R332 is hydrogen, or where n is 1, Rr is an optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, RII is an optionally functionally modified, preferably etherified, hydroxyl or mercapto group,

   is an optionally substituted amino group or an optionally functionally modified carboxyl group, and Rlll is hydrogen, or where n is 1, each of the radicals Rl and RI 'is a functionally modified, preferably etherified or esterified hydroxyl group or an optionally functionally modified carboxyl group, and R113 represents hydrogen, or in which n represents 1, R1 represents hydrogen or an optionally substituted aliphatic hydrocarbon radical, and R11 and R311 together represent an optionally substituted aliphatic hydrocarbon radical connected to the carbon atom by a double bond,

   or where 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, R33 is an optionally substituted aliphatic or aromatic hydrocarbon radical and R311 is hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon radical. 



   In the above definitions, an aliphatic hydrocarbon radical means e.g. B.  a straight-chain or branched lower alkyl, as well as lower alkenyl or lower alkynyl group.  Such a radical, in particular a lower alkyl radical, can be used as substituents, for. B.  optionally substituted cycloaliphatic or aromatic hydrocarbon radicals, e.g. B. 

  Phenyl radicals, or optionally substituted heterocyclic radicals, preferably of aromatic character, also optionally functionally changed, preferably etherified or esterified hydroxy or mercapto, z. B.  Hydroxy or mercapto groups etherified by optionally substituted aliphatic, aromatic or araliphatic hydrocarbon radicals and heterocyclic or heterocyclic-aliphatic groups, such as optionally substituted lower alkoxy, phenyloxy, phenyl-lower alkoxy or lower alkyl mercapto groups, or halogen atoms, nitro groups, such as optionally substituted amino groups Dinicderalkyl-amino, alkylenamino, lower alkanoyl-amino or sulfoamino groups, acyl, e.g. B.  optionally substituted lower alkanoyl or benzoyl radicals, or optionally functionally modified carboxyl, e.g. B. 

  Lower alkoxycarbonyl, carbamoyl or cyano groups, azido groups or optionally functionally modified sulfo, e.g. B.  Sulfamoyl groups. 



   A cycloaliphatic hydrocarbon radical preferably contains 3-7 ring carbon atoms and is an optionally, z. B.  by aliphatic radicals or then, e.g. B. 



  like the big aliphatic radical, cycloalkyl- substituted by functional groups.  as well as cycloalkenyl groups, primarily with 5 or 6 ring carbon atoms.  Such a cycloaliphatic radical preferably contains.  primarily a cycloalkyl radical, as a substituent an amino group in the 1-position. 



   The abovementioned aromatic hydrocarbon radicals are in particular optionally substituted, bicyclic, but primarily monocyclic aromatic hydrocarbon radicals, which can be partially saturated, such as naphthyl or tetrahydronaphthyl, primarily phenyl radicals.  These residues can e.g. B.  by optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon, z. B. 

  Lower alkyl, trifluoromethyl or optionally substituted cycloalkyl or phenyl radicals, or by functional groups, such as optionally functionally modified, e.g. B.  Etherified or esterified, hydroxyl or mercapto, nitro groups, optionally substituted amino groups, acyl groups, optionally functionally modified carboxyl or optionally functionally modified sulfo groups, e.g. B.  the above-mentioned functional groups of this type may be substituted. 



   An optionally substituted heterocyclic radical, preferably of aromatic character, is primarily a monocyclic monoaza-, monothia-, monooxa-, diaza, oxaza-, thiaza, triaza or tetrazacyclic radical, preferably of aromatic character, e.g. B.  a pyridyl, pyridinium, thienyl, furyl, imidazolyl, isozolyl, thiazolyl, triazolyl, tetrazolyl or isoxazolyl radical, the z. B.  how one of the above aromatic radicals can be substituted. 

 

   An etherified hydroxy or mercapto group contains as an etherifying radical z. B.  an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical, and means z. B.  an optionally substituted lower alkoxy, lower alkenyloxy, phenyloxy, phenyl-lower alkoxy, lower alkyl mercapto, lower alkenyl mercapto, phenyl mercapto or phenyl lower alkyl mercapto group.     Further, a hydroxyl and especially mercapto group ver ethereal radicals are optionally substituted heterocyclic groups, preferably of aromatic character, such as. B.  the above-mentioned heterocyclic radicals. 



   Esterified hydroxyl groups are e.g. B.  Hydroxy groups esterified by inorganic or organic acids, in particular halogen atoms, and also lower alkanoyloxy or benzoyloxy groups which may be substituted. 



   Substituted amino groups contain as substituents one or two optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, wherein such radicals, in particular aliphatic radicals, can also be bivalent, and are, for. B.  optionally, such as by halogen atoms, substituted lower alkyl or di-lower alkylamino groups or optionally substituted lower alkyleneamino groups with 5-7 ring members, in which the carbon atoms of the lower alkylene radical are replaced by an oxygen or sulfur atom or, optionally a substituent, e.g. B. 



  a lower alkyl group, nitrogen atom may be interrupted. 



   Optionally functionally modified carboxyl groups are z. B.  esterified or amidated carboxyl groups, such as lower alkoxycarbonyl or optionally N-substituted, such as N-lower alkyl or N, N-di-lower alkylcarbamoyl groups, and also cyano groups. 



   An acyl group is e.g. B.  an optionally substituted lower alkanoyl, lower alkenoyl or benzoyl group. 



   In the above-mentioned functional groups substituted by organic radicals, such as etherified hydroxyl or mercapto groups or substituted amino groups, the organic radicals, e.g. B.  aliphatic, cycloaliphatic or aromatic groups, and optionally heterocyclic radicals, e.g. B.  like the above radicals of this type, be substituted. 



   In the above acyl groups of the formula Ib, for. B.  n for 0 and RI 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 with 5-7 ring carbon atoms, an optionally, preferably by lower alkoxy, substituted phenyl, naphthyl or Te trahydronaphthyl group, an optionally, z. B.  by lower alkyl and / or phenyl groups, which in turn sub substituents such as halogen, z. B.  Chlorine, can carry sub-substituted heterocyclic group, such as a 4-isoxazolyl, or preferably, for. 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, RI for an optionally substituted phenyloxy, preferably by halogen, such as chlorine,
Amino and / or carboxy, substituted Niederalkylgrup pe, a lower alkenyl group, an optionally sub-substituted, such as hydroxy, halogen, z. B. 

  Chlorine, or optionally substituted phenyloxy-containing phenyl group, an optionally, z. B.  by amino, substituted pyridyl, pyridinium, thienyl, 1-imidazolyl or l-tetrazolyl group, an optionally substituted Nie deralkoxy or phenyloxy group, a Niederalkylmer capto or lower alkenyl mercapto group, an optionally, z. B.  by lower alkyl.  substituted Phenylmer capto, 2-imidazolylmercapto or 1, 2,4-triazol-3 -ylmercapto group, a halogen, in particular chlorine or
Bromine, a carboxy, lower alkoxycarbonyl, cyano or optionally, e.g. B. 

   substituted by phenyl, N-
Carbamoylgruppe, an optionally substituted Nie deralkanoyl- or benzoylgruppe, or an Azidogrup pe, and RII and RIIt for hydrogen, or n for 1, RI for an optionally substituted phenyl or thienyl group, RII for an amino or cyano group, a given in Salt, e.g. B.  Alkali metal salt form present carboxyl or sulfoamino group, or an optionally substituted lower alkoxy or phenyloxy group, and RIII for hydrogen, or n for 1, RI and R each for a halogen, z. B.  Bromine atom, or a lower alkoxycarbonyl, e.g. 

  Methoxycarbonyl group, and RIII stands for hydrogen, or n stands for 1, and each of the groups RT, RII and RIII stand for a lower alkyl group. 



   The above acyl groups can e.g. B.  by the radical of the formula RIV- (CmH2m) -C (= O) -, 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.  by one of the above groups of this type, can be substituted, and wherein RIV is a, optionally in the core, 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. 

   such as the above aromatic or cycloaliphatic radical, substituted heterocyclic group, preferably of aromatic character, such as an optionally substituted pyridyl, pyndinimn, thienyl, furyl, imidazolyl, tetrazolyl or isoxazolyl group, also one, by one, optionally as indicated substituted, aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, z. 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-cyclopentylcarbonyl- or a-amino-cyclohexylcarbonyl- (optionally with substituted amino group, such as one, optionally in salt, such as alkali metal salt form present sulfoamino group or an acylamino group, in which the acyl radical is preferably an easily cleavable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethoxycarbonyl, phenacyl oxycarbonyl or tert. -Butyloxycarbonylrest), benzyloxycarbonyl-, hexahydrobenzyloxycarbonyl-, 2-phenyl-5-methyl-4-isoxazolylcarbonyl-,

   2- (2-chlorophenyl) -5 -methyl- 4 -isoxazolylearbonyl-, 2- (2,6-dichlorophenyl) -5- methyl-4-isoxazolylcarbonyl-, phenylacetyl-, phenacylcarbonyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl- , 2-phenyloxypropionyl-, a -phenyloxy-phenylacetyl-, a-methoxy-phenylacetyl-, a-ethoxy-phenylacetyl-, a-methoxy-3,4-dichloro-phenylacetyl-, z-cyano-phenyl- acetyl-, phenylglycyl- (optionally with, e.g. B.  as stated above, substituted amino group), benzylthioacetyl, benzyltbiopropionyl, a-Garboxyphenylacetyl- (if necessary with functionally modified, as in salt, z. B. 

  Alkali metal salt form present or esterified carboxyl group), 2-pyridylacetyl-, 4-aminopyridiniumacetyl-, 2-thienylacetyl-, α-carboxy-2-thienylacetyl- or α-carboxy-3-thienylacetyl- (optionally with, e.g. B.  as stated above, functionally modified carboxyl group), a-cyano-2-thienylacetyl-, a-amino-2-thienylacetyl- or a-amino-3-thienylacetyl- (optionally with, e.g. B.  as stated above, substituted amino group), 3
Thienylacetyl, 2-furylacetyl, 1-imidazolylacetyl, 1-methyl-5 tetrazolylacetyl, 3-methyl-2-imidazo-wlthioacetyl or 1,2,4-triazol-3-yl-thioacetyl.     An acyl radical is e.g. B.  

   also a group of the formula CnH2n +, - C (= O) - or CnH2n 1-C (= O) -s in which 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, ethoxyearb , Bismethoxyvarbonylacetyl, N - phenylcarbamoylacetyl, cyanoacetyl, cc-cyanopropionyl or 2-cyano-3-dimethylacrylyl group, also a radical of the formula RV-NH-CO-,

   wherein Rv is an optionally substituted aromatic or aliphatic hydrocarbon radical, in particular an optionally substituted lower alkyl radical, preferably by lower alkoxy groups and / or halogen atoms, e.g. B.  the N-2-chloroethylcarbamoyl radical, means. 



   An easily cleavable acyl residue Ac 'is primarily a by reduction z. B.  when treating with a chemical reducing agent, or by acid treatment, e.g. B.  with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl, preferably multiple branched or substituted by halogen atoms, z. B. 

   tert. -Butyloxycarbonyl-, tert. -Pentyloxyvarbonyl-, 2,2,2-Trichloräthoxycarbo- nyl- or 2-Jodäthoxyvarbonylrest or a remainder which can be converted into the latter such as the 2-Bromoäthoxyearbonylrest, a, preferably polycyclic cycloalkoxycarbonyl, z. B. 

  Adamantyloxycarbonyl, a phenyl-lower alkoxy carbonyl, primarily α-phenyl-lower alkoxycarbonyl radical; wherein the x-position is preferably polysubstituted, e.g. B.  the diphenyl-methoxycarbonyl or x-4-biphenylyl-α-methyl-ethyloxycarbonyl radical, or a furyl-lower alkoxycarbonyl, primarily x-furyl-lower alkoxycarbonyl, e.g. B.    Furfuryloxyvarbonyl residue.    



   In a compound of the formula I, the group Ac is primarily a naturally occurring or biosynthetically producible N-acyl derivative of 6-amino-penam-3-carboxylic acid or 7-amino-ceph-3-em-4- -carboxylic acid compounds containing acyl radical, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, also an optionally substituted lower alkanoyl or lower alkenoyl radical, e.g. B. 

   the 4-Hy droxy-phenylacety} -, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valeryl, n-butylmercaptoacetyl or allylmercaptoacetyl, and especially the phenylacetyl or phenyloxyacetyl radical, an in highly effective N acyl derivatives of 6-amino-penam-3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical, such as the 2-chloroethylcarbamoyl, cyanoacetyl,

   Phenylglycyl- (optionally with substituted amino group), 2-thienylacetyl-, α-amino-2-thienylacetyl- (optionally with substituted amino group), 1-amino-cyclohexylcarbonyl- (optionally with substituted amino group), x-carboxy-phenylacetyl- (optionally with substituted carboxyl group) or a -carboxy-thienylacetyl radical (optionally with a protected carboxyl group), or a slightly, especially under acidic conditions, e.g. B.  when treating with trifluoroacetic acid, or reductively, e.g. B. 

   when treating with zinc in the presence of aqueous acetic acid, cleavable acyl radical of a carbonic acid half ester, such as the tert. -Butyl oxycarbonyl, 2,2,2-Trichloräthoxyvarbonyl- or 2-Jod- äthoxycarbonyl- or the convertible in the latter 2 bromoethoxycarbonyl.    



   The new disulfide compounds of the formula I can surprisingly be obtained by adding a compound of the formula
EMI5. 1
 wherein Y represents an optionally substituted methylene group, with oxidation.  Cleavage of a group bonded to the nitrogen and acylation in any order, converted into the corresponding compound of the formula I. 



   In a starting material of the formula II, Y is preferably a mono- or disubstituted methylene group, with substituents preferably optionally substituted, mono- or divalent hydrocarbon radicals, primarily corresponding aliphatic hydrocarbon freshness, such as lower alkyl.  z. B.  Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl groups, also lower alkylene, e.g. B.    1,4-butylene or 1,5-pentylene groups, as well as corresponding cycloaliphatic, cycloali phatic-aliphatic, aromatic or araliphatic hydrocarbon radicals, such as cycloalkyl, z. B.  Cyclopcntyl or cyclohexyl, phenyl or phenyl lower alkyl, e.g. B. 



  Benzyl or phenylethyl groups.  Y is primarily the isopropylidene or isobutylidene group, i.e. H. 



  for a methylene radical substituted by two methyl groups or one isopropyl group. 



   Oxidizing agents used in accordance with the process are primarily those which are used to form disulphad compounds under conditions under which the p-lactam ring is not influenced.  These are in particular halogen, such as bromine and primarily iodine which is advantageously used in the presence of organic solvents, e.g. B.  optionally substituted hydrocarbons, such as aromatic hydrocarbons, e.g. B. 



  Benzene, ethers, such as cyclic ethers, e.g. B.  Tetrahydrofuran or dioxane, alcohols such as lower alkanols, e.g. B. 



  Methanol or ethanol, or carboxylic acids such as lower alkanecarboxylic acids, e.g. B.  Acetic acid.  or solvent mixtures and optionally in the presence of water, with cooling (e.g. B.  Temperatures up to about 30 ° C), at room temperature or with gentle heating, further if necessary under an inert gas such as nitrogen atmosphere. 

 

   Further oxidizing agents suitable for the oxidation of starting materials are oxidizing heavy metal carboxylates, preferably lead IV carboxylates, such as lead IV alkanoates, especially lower alkanoates and primarily lead tetraacetate, also lead tetrapropionate or lead tetrastearate, and optionally substituted lead traben zoates, e.g. B.  Lead tetrabenzoate or lead tetra-3-bromobenzoate, as well as thallium-III-carboxylates, e.g. B. 

  Thallium-III-acetate, or silver-II-carboxylates, such as mercury-II acetate, these oxidizing agents, if desired, in situ, e.g. B.  can be formed by the reaction of lead dioxide or mercury oxide with an organic carboxylic acid such as acetic acid. 



   The above heavy metal carboxylates, in particular the corresponding lead-V compounds, are advantageously used in the presence of a light source, preferably using ultraviolet and longer-wave, such as visible light, optionally with the addition of suitable sensitizers.  The UV light preferably has a main wavelength range of over 280 mp, primarily from about 300 m: \ L to about 350 raC1; this can e.g. B.  by suitable filtering of the ultraviolet light through an appropriate filter, e.g. B. 



  Pyrex filters, or by suitable solutions, such as salt solutions, or other, shorter-wave light-absorbing liquids, such as benzene or toluene.  The ultraviolet light is preferably generated by means of a high pressure mercury vapor lamp. 



   The oxidation with a heavy metal carboxylate oxidizing agent is usually carried out in the presence of a suitable diluent such as benzene, acetonitrile or acetic acid, if necessary, with cooling or with heating and / or in an inert gas atmosphere. 



   Furthermore, as an oxidizing agent in the above reaction, oxygen (e.g. B.  as pure oxygen or in the form of air) in the presence of a heavy metal used as a catalyst, e.g. B.  Copper (II) or iron (III) salt, such as iron (III) chloride or iron (III) sulfate, and preferably in the presence of a solvent such as acetic acid, hypohalite compounds, in particular Al kaiinaetallhypohaiogenite, z. B. 

  Sodium hypojodite and organic hypohalites, such as tert.  -Butyl hypohalite, suitable iron (III) salts and complexes, such as iron (III) chloride, preferably in the presence of an organic solvent, e.g. B.  Ether, acetic acid, or ethanol, and optionally water, or potassium ferricyanide, 1,2
Diiodoethane in the presence of an organic solvent z. B.  Acetone, tetrahydrofuran or ethanol, or
Thiocyanogen in the presence of a suitable organic
Solvent, e.g. B.  Acetic acid, can be used. 



   In a disulfide compound which can be obtained as an intermediate according to the process and in which the amino group is optionally mono- or disubstituted
Methylene group is substituted, this can in the presence of water, d. H.  So even during the Oxydationsreak tion, if this is carried out in the presence of water, are replaced by hydrogen. 



   In a disulfide compound obtainable according to the process, amino groups which are either unsubstituted or each contain an optionally substituted methylene radical as a substituent are known per se
Methods, e.g. B.  by treating with carboxylic acids or reactive acid derivatives thereof such as halides, e.g. B.  Chlorides, anhydrides (including the internal
Anhydrides of carboxylic acids, d. H.  Ketenes, or from
Carbamic or thiooarbamic acids, d. H.  Isocyanates or isothiocyanates, or mixed anhydrides, such as those which z. B.  with chloroformic acid lower alkyl esters or trichloroacetic acid chloride are to be understood) or acylated acylated esters. 



   It works, if necessary, in the presence of suitable condensing agents, using acids such. B.  in the presence of carbodiimides, such as di cyclohexylcarbodiimide, and when using reactive acid derivatives z. B.  in the presence of basic agents such as triethylamine or pyridine. 



   An acyl group can also be introduced stepwise; z. B.  you can in an amino group a halo gene-lower aikanoyl, z. B.    Bromoacetylgmppe, and a thus obtainable N-halo-lower alkanoylamino compound with suitable exchange reagents, such as basic compounds, e.g. B.  Tetrazole, thio compounds, e.g. B.    2-mercapto-1-methyl4-midazole, or metal salts, e.g. B.  Sodium azide, react and thus arrive at substituted N lower alkanoylamino compounds. 

  Furthermore, an amino compound obtainable according to the process can be reacted with a carbonyl dihalide, such as phosgene, and the halogen, e.g. B.    Chlorocarbonylamino compound with an alcohol, e.g. B.    tert.  -Butanol, treat, and so gradually an etherified hydroxycarbonyl, z. B. 



  the tert.  Butyloxycarbonyl group, into the amino group. 



   In both of the compounds taking part in the acylation, free functional groups can be temporarily protected during the acylation reaction in a manner known per se and released in a manner known per se after the acylation. '
In the oxidation reaction or in the work-up of the acylation product, an optionally substituted methylene radical formed, possibly in modified form, is split off. 



   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 know in customary, 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 the antipodes are separated. 



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



   Such starting materials are preferably used and the reaction conditions are chosen so that one of those listed at the beginning as being particularly preferred
Connections. 



   . The starting materials of the
Formula II, in which Y represents a disubstituted methylene group, are known (see e.g. B.  Austrian patent no.  264 533) or can be made according to those known for the
Compounds used methods are made. 

 

  Starting materials in which Y is an unsubstituted or monosubstituted methylene group can, for. B.  be obtained when a compound of the formula II, in which Y is a disubstituted methylene group, with an aldehyde or a reactive derivative, such as a hydrate or a reactive polymer
Reacts product of such an aldehyde.  This reaction is usually carried out in a solvent such as one with
Water-miscible organic solvent such as a water-miscible alcohol or ether, e.g. B.  Dioxane, or made in a suitable mixture of solvents. 

  It is preferable to add water and operate in the presence of an acidic agent such as an inorganic or organic acid, e.g. B.  an organic carboxylic or preferably sulphonic acid such as p toluenesulphonic acid, if desired or necessary, with cooling or preferably heating and / or in a closed vessel and / or in an inert gas atmosphere, e.g. B.  under nitrogen. 



   The starting material of the formula II, in which Y stands for a methylene radical substituted by the isopropyl group, can be prepared from readily available starting materials if a penam-3-carboxylic acid compound IIIa with the formula
EMI7. 1
 in which Aca represents the acyl radical of an organic carboxylic acid, in which free functional groups such as hydroxyl, mercapto and, in particular, amino and carboxyl groups, optionally, e.g. B.  by acyl groups or 

   in the form of ester groups, are protected, 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, in which Ro represents the azido carbonyl radical -C (= O) - N3 represents (compound IIIb) converted, this with elimination of nitrogen to the corresponding isocyanate compound with the formula III, where Ro is the isocyanato group -N = C = O (compound IIIc) and converted simultaneously or subsequently with a compound of the formula H-X1 ( IV), in which X represents a hydroxy or mercaptocarbonyl group which is substituted together with the carbonyl group in the isocyanato group and which can be cleaved under neutral or acidic conditions,

   and in a compound obtained, if necessary or desired, an acyl radical Aca is replaced by hydrogen and, if desired, this is replaced by an acyl group which can be split off in the following step.  In the penam compound of the formula thus obtainable
EMI7. 2
 where R1 "is hydrogen or an acyl group Ac" which can be split off under the reaction conditions of the following process step, the group of the formula -C (= O) -X1 is split under neutral or weakly acidic conditions with simultaneous or subsequent treatment with water and the optionally formed 4,4-dimethyl-5-thia-2,7-diaza-bicyclo [4. 2. 0] oct- -2-en-8-one separated or reduced in this the carbon-nitrogen double bond. 



   An acyl group Aca occurring in the compounds of the formula III can represent any acyl radical of an organic carboxylic acid with optionally protected functional groups, primarily an acyl radical contained in naturally occurring or biosynthetically producible N-acyl derivatives of the 6-aminopenam-3-carboxylic acid compounds, such as a monocyclic arylacetyl or aryloxyacetyl, also an optionally substituted lower alkanoyl or lower alkenoyl, z. B.  the 4-hydroxyphenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valeroyl, n-butylmercaptothioacetyl or allylmercaptothioacetyl, in particular the phenylacetyl or phenyloxyacetyl, or then one, preferably below Acyl radical that can easily be split off under acidic conditions, such as the acyl radical of a half ester of carbonic acid, e.g. B. 

   the tert. -Butyloxycarbonyl- rest. 



   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 in the presence of a basic agent such as triethylamine) 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.  on heating, are converted into the desired isocyanate compound IIIb, which usually does not need to be isolated and can be converted directly into the desired compound of the formula V in the presence of a compound of the formula IV. 



   Substituted hydroxyl or mercapto groups X1 are primarily etherified hydroxyl and mercapto groups which, together with the carbonyl group, form a functionally modified, primarily esterified, carboxyl and thiocarboxyl group which can be cleaved under neutral or weakly acidic conditions. 



   The group X3 represents e.g. B.  represents the radical of the formula -OR, "which, together with the carbonyl group, represents an esterified carboxyl group which can easily be cleaved when treated with chemical reducing agents under neutral or weakly acidic conditions has over 19, 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-methylethyl radical, but can also z. B.  a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, such as 2,2,2-bromoethyl, also the 2 bromoethyl radical, or a 2-iodo-lower alkyl, e.g. B. 

   in particular the 2-iodoethyl radical. 



   Another group X1, which together with the carbonyl group represents an esterified carboxyl group which can easily be cleaved when treated with chemical reducing agents under neutral or weakly acidic conditions, is the group -OR, b, in which Rob is an arylcarbonylmethyl group and preferably the unsubstituted phenacyl radical, as well as an im aromatic moiety, such as phenacyl radical substituted by lower alkyl or lower alkoxy groups, or halogen atoms. 



   The group Xt can also represent the radical of the formula -O-R, "which, together with the carbonyl grouping, represents an esterified carboxyl group which can be easily cleaved under neutral or weakly acidic conditions when irradiated.  In this group, RoC stands for an arylmethyl group, in which aryl denotes an optionally substituted phenyl group, the substituents of which are primarily functional groups, such as free or functionally modified carboxyl groups, e.g. B. 



     Carboxy, lower alkoxycarbonyl, carbamoyl or cyano groups, optionally substituted amino, such as di-lower alkyl-am. ino groups, or acyl, such as lower alkanoyl groups, but especially optionally functionally modified, especially esterified hydroxyl or mercapto groups, such as acyloxy, e.g. B.  Lower alkanoyloxy groups, or halogen atoms and primarily etherified hydroxyl or mercapto groups, such as lower alkoxy groups, also lower alkylthio groups (which are primarily in the 3-, 4- and / or 5-position in the preferred phenyl radical) and / or above all nitro groups (in the preferred phenyl radical preferably in the 2-position). 



  Such groups ROe are in particular 1-phenylethyl or benzhydryl, primarily benzyl, substituted by lower alkoxy groups, such as methoxy groups, preferably in the 3-, 4 and / or 5-position, and / or by nitro groups, preferably in the 2-position, in particular the 3- or 4-methoxybenzyl, 3,5-dimethoxy-benzyl, 2-nitrobenzyl or 4,5-dimethoxy-2-nitro-benzyl radical. 



   A group X1 can also represent the radical of the formula -O-R, d which, together with the carbonyl group, forms an esterified carboxyl group which can easily be cleaved under acidic conditions.  Such a radical Rod is primarily a methyl group which is monosubstituted by a carbocyclic aryl group having electron-donating substituents or by a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or then in an oxa- or thiacycloaliphatic radical denotes the oc-position to the oxygen or sulfur atom representing ring member. 



   An oarbocyclic aryl group containing electron-donating substituents in the aryl radical is primarily the phenyl radical, with suitable substituents which are preferably in the p- and / or o-position of the phenyl radical, e.g. B.  free or preferably functionally modified, such as esterified and primarily etherified hydroxy groups, such as lower alkoxy groups, as well as corresponding free or functionally modified mercapto groups, also aliphatic, cycloaliphatic, aromatic or araliphatic, optionally suitably substituted hydrocarbon radicals, in particular lower alkyl groups, or aryl, e.g. B.  Phenyl groups. 



   A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members is primarily a furyl, e.g. B.  2-furyl radical, or a thienyl, e.g. B.  2-thienyl radical. 



   An oxa and thiacycloaliphatic radical linked in the o, position is primarily a 2-oxa or 2 thiacycloalkyl and 2-oxa or 2-thiacycloalkenyl group, in which the methyl group Rod represents the ring member adjacent to the ring oxygen or ring sulfur atom , and which preferably contains 4-6 ring carbon atoms, primarily a 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro -2-pyranyl radical or a corresponding sulfur analog. 



   Preferred radicals Rod are 4-methoxyhenzyl and 3,4 dimethoxyhenzyl radicals, as well as 2-tetrahydrofuryl, 2-tetrahydropyranyl or 2,3-dihydro-2-pyranyl groups. 



   The reaction of a compound of the formula IIIc with a compound of the formula IV, in particular with a 2-halogenoethanol ROa-OH, e.g. B.  with 2,2,2-trichloro- or 2-bromoethanol, an arylcarbonylmethanol R, b-OH, z. B.  Phenacyl alcohol, or an aryl methanol R, "- OH or R, d-OH, e.g. B.    4,5-Dimethexy-2-nitrobenzyl alcohol or 4-methoxy-benzyl 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 chlorobenzene, preferably with heating. 



   An acyl group Ac "which can be split off under the reaction conditions of the conversion of a compound of the formula V into the starting material of the formula II, in which Y is a 1-isobutylidene group, is z. B.  a group of the formula -C (= O) -X1, in which X1 has the meaning given above, in particular a group of the formula -C (= O) -O-ROa, -C (= O) -O-Rob -C ( = O) O ROe or -C (= O) -OR, d, in which pink, R, b, ROe and Rod have the meanings given above, but can also represent any other acyl group which can be split off under the reaction conditions mentioned,

   in particular an R, "- O-C (= O) grouping which can be split off under acidic conditions, in which ROe is preferably a methyl radical which is multiply substituted in the, position, such as a lower alkyl group which is multiply branched in the a-position, e.g. B.  tert. -Butyl- or tert.  Pentyl group, a cycloalkyl, e.g. B.  Adamantyl group, a polyarylmethyl, e.g. B.  Benzhydryl or trityl, and also a 2- (4-biphenylyl) -1-methyl-ethyl group. 

  The above-mentioned ROe-O-C (= O) groups can be split off, in particular in the presence of oxygen-containing acids, primarily from strong organic carboxylic acids such as trifluoroacetic acid and formic acid, or from strong organic sulfonic acids such as p-toluenesulfonic acid, i.e. H.  can be replaced by hydrogen. 



   An acyl group Ac which cannot be split off under the reaction conditions of the subsequent process step, in particular an acyl group different from the radical of the formula -C (= O) -XI, can, if desired, after protection of functional groups in such a radical ( z. B.  by acylation, esterification or silylation) or after the release of protected functional in such a residue (e.g. B. 

 

  by hydrolysis, reduction or treatment with an acid), e.g. B.  by treating with a suitable inorganic acid halide such as phosphorus pentachloride, preferably in the presence of a basic agent such as pyridine, to form an imide halide, reacting the imide halide with an alcohol such as lower alkanol, e.g. B.  Methanol, and cleavage of the iminoether z. B.  are split off in an aqueous medium, preferably under acidic conditions.  The acyl radical of a suitable half ester of carbonic acid, such as a carbo-lower alkoxy which can be cleaved under acidic conditions, e.g. B.  the carbo-tert. -butyloxy- and carbo-tert. -pentyloxy-, Carboadamantyloxy- or Carbodiphenylmethoxyrestes, z. B.  be split off by treatment with trifluoroacetic acid.   



   The cleavage of the group -C (= O) -XI in an intermediate of the formula V depends on the nature of this group, the cleavage being carried out in the presence of at least one mole, normally an excess of water, or the reaction product being treated subsequently with water . 



   The cleavage of an esterified carboxyl group of the
Formula -C (= O) -XI, which in a compound of formula V can also represent the radical Ac ", and in which X1 represents the group -OR," or -OR, u, is obtained by treatment with a chemical reducing agent 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. 



   Chemical reducing agents are e.g. B.  suitable reducing metals, as well as reducing metal compounds, e.g. B.  Metal alloys or amalgams, as well as strongly reducing metal salts.  Zinc, zinc alloys, e.g. B.  Zinc copper, or zinc amalgam, also magnesium, which are preferably used in the presence of hydrogen-releasing agents that are able to generate hydrogen nascent together with the metals, metal alloys and amalgams, zinc z. 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 compounds, 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 acids 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 the formula V.  where X1 represents a radical of the formula -O-R, ", the group of the formula -C (= O) -Xl, which can also represent the group Aco, can be cleaved by irradiation with light, preferably with ultraviolet light.  Depending on the type of substituent Ror, longer or shorter wavelength light is used.  So z. B.  Groups of the formula -C (= O) -O-R, ', where ROe is a substituted by a nitro group in the 2-position of the aryl radical, optionally further substituents, such as lower alkoxy, z. 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 mi, those in which R0e is optionally in the 3-, 4- and / or 5-position, e.g. B.  by lower alkoxy and / or nitro groups, substituted arylmethyl, z. B.  Benzyl radical, is cleaved by irradiation with ultraviolet light with a wavelength range of less than 290 m e. 

  It works in the first case with a high pressure mercury vapor lamp, preferably using Pyrex glass as a filter, for. B.  at a Hauptwellenlängenbe rich of about 315 mp.     in the latter case with a low pressure mercury vapor lamp, e.g. B.  with a main wavelength range of about 254.    



   The irradiation reaction is carried out in the presence of a suitable polar or apolar organic solvent or a mixture: Solvents are e.g. B.  optionally halogenated hydrocarbons, such as optionally chlorinated lower alkanes.  z. B. 



  Methylene chloride.  or optionally chlorinated benzene, e.g. B.  Benzene, also alcohols such as Niedenilkanole, z. l3.    



  Methanol.  or ketones such as lower alkanones, e.g. B.  Acetone. 



  The reaction is preferably carried out at tin temperature or, if necessary.  with cooling, usually in an inert gas, e.g. B.    Nitrogen atmosphere.     by.  It is preferably carried out in the presence of water; But you can also treat the Rcslrahlu npsprodu kt subsequently with water, for. B.  by working up the product obtained in the presence of water. 



   In a compound of formula V.  wherein X, represents a group of the formula -O-R "I '.    can be the grouping of the formula -C (= O) -O-R "ti, which can also represent the group AcO.  by treating with an acidic agent, especially an acid such as a strong organic cajoic acid, e.g. B.  an optionally substituted lower alkanecarboxylic acid, preferably containing halogen atoms.  such as acetic acid or trifluoroacetic acid, furthermore with formic acid or a strong organic sulfonic acid.    ,.  13.       p-ToluolsulfonsÅaulez are cleaved. 

  An excess of an acidic reagent which is liquid under the reaction conditions is usually used as the diluent and the reaction is carried out in the presence of at least an equivalent amount of water.  as well as at room temperature or with cooling, e.g. B.  to about -200C to about t100C.     If Aca in the starting material represents a group of the formula -C (= O) -O ROe, such a group can be split off at the same time during the treatment with the acidic agent. 



   The 4,4-dimethyl-5-thia-2,7-diazabicyclo [4. 2. O] oct-2-en-8-one, which in particular in the non-reductive cleavage of a group of the formula -C (= O) -X, in a compound of the formula V, wherein X is the group of the formula -OR "' or -OR, d, also in the cleavage of a group of the formula -C (= O) -X, in a compound of the formula V, in which X is the group of the formula -OR. ,: l represents, occurs with the help of a strongly reducing metal salt. 



  can be converted into the desired 3-isopropyl-4-thia-2,6-diazabicyclo [3. 2. Ojheptan-7-one can be converted or then separated from a mixture with the latter.  To reduce the carbon-nitrogen double bond in the 4th 4-dimethyl-5-thia- -2,7-diazabicyclo [4. 2. 0] oct-2-en-8-one, which with simultaneous rearrangement to 3-isopropyl-4-thia-2,6-diazabicyclo [3. 2. 0] heptan-7-one runs, preferably chemical reducing agents, primarily reducing metal or metal compounds, such as those mentioned above, preferably in the presence of hydrogen donating agents, in particular zinc in the presence of an acid such as acetic acid, or an alcohol. 

 

   A mixture of 3-isopropyl-4-thia-2,6-diazabicyclo [3. 2. 0] heptan-7-one and 4,4-dimethyl-5-thia-2,7-diazabicyclo [4. 2. 0] oct-2-en-8-one, as it is primarily in a reductive cleavage of the group of the formula -C (= O) -X1 in a starting material of the formula V, wherein X1 is a group of the formula -OR, a or -OR, h means, arises, can by known separation methods, for. B.  by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes and the individual compounds are separated. 



   In the preparation of the starting materials of the formula II, intermediate products can be converted into one another at suitable stages.  So z. B.  an aliphatically bonded chlorine, especially bromine atom, in the radical X1, such as the 2-bromoethyloxy radical, e.g. B.  by treating with a suitable iodized salt such as an alkali metal, e.g. B. 



  Potassium iodide, replaced with an iodine atom in a suitable solvent such as acetone, e.g. B.  the 2-bromoethyl radical can be converted into the 2-iodoethyl radical. 



   Furthermore, in a compound of the formula V in which RO is hydrogen, this can be replaced by an acyl group AcO which can be split off under the reaction conditions and replaced by hydrogen, e.g. B.  using acylation processes known per se. 



   As mentioned, the compounds of the formula I are valuable intermediates which are particularly useful for the preparation of pharmacologically valuable compounds, e.g. B.  of the 7P-amino-ceph-3-em-4-carboxylic acid type and N-acyl derivatives thereof, the latter in particular, having effects against microorganisms such as gram-positive and gram-negative bacteria. 



   Thus, a compound of the formula I in which Ac stands for an amino protective group R1A can be mixed with an oxirane compound of the formula
EMI10. 1
 wherein each of the groups R3, R4, R and R6 is hydrogen or an organic radical bonded via a carbon atom, preferably at least one of the radicals R3, R4, R5 and R6 being hydrogen, with simultaneous treatment with a reducing agent;

   a compound of the formula is thus obtained
EMI10. 2

In a compound of the formula VII, in which of the radicals R3, R4, R3 and R6 at least R6 is hydrogen, the hydroxy group is converted into a hydroxy group esterified by the acyl radical of the formula -C (= O) -X2, in which X3 is a etherified hydroxyl or mercapto group, which together with the carbonyl group forms an esterified carboxyl or thiocarboxyl group which can be cleaved under mild conditions. 

  The thus obtainable compound of the formula
EMI10. 3
 is made with a compound of the formula
EMI10. 4th
 wherein R2A represents an organic radical of an alcohol or phenol compound which together with the -C (= O) -O grouping forms an esterified carboxyl group, or a reactive derivative thereof and is converted into the addition compound of the formula
EMI10. 5
 the secondary hydroxy group is converted into a reactive esterified hydroxy group. 

  The reactive ester of the formula
EMI10. 6th
 wherein Z is a reactive esterified hydroxy group, primarily a halogen, especially chlorine or bromine atom, and an organic sulfonyloxy, e.g. B.  4 represents methylphenylsulfonyloxy or methylsulfonyloxy, one sets with a phosphine compound of the formula
EMI10. 7th
  wherein each of the radicals Ra, Rb and Re stands for an optionally substituted hydrocarbon radical, and thus obtained, if necessary, after cleavage of the elements of an acid of the formula H-Z (XIIIa) from a phosphonium salt compound of the formula available as an intermediate
EMI11. 1
 the phosphoranylidene compound of the formula
EMI11. 2
 in which one cleaves the esterified carboxyl group -C (= O) -X2. 

  A compound of the formula is obtained in this way
EMI11. 3
 in which the hydroxyl group is oxidized to the oxo group.  In a ceph-3-em compound of the formula obtainable in this way
EMI11. 4th
 in which Rl represents an amino protective group R, A, and R3 represents the organic radical R2A, and the carbonyl compound of the formula formed by ring closure from the but not isolated carbonyl compound of the formula which is formed under the reaction conditions
EMI11. 5
 arises can, if desired, split off the amino protective group R1A and, if appropriate, protect the free amino group in a compound obtainable in this way, and / or if desired,

   an ester grouping of the formula -C (= O) -O-RA in the free carboxyl group or in another ester grouping of the formula -C (= O) -O-R. . A converted, and optionally a free carboxyl group into an esterified carboxyl group of the formula -C (= O) -O-R? converted, and / or, if desired, a compound obtained with a salt-forming group in a salt or a salt obtained in the free compound or in another salt, and / or, if desired, a mixture of isomers obtained are separated into the individual isomers. 



   An organic radical R3, R ,, R, and / or Rfi is primarily an optionally substituted hydrocarbon radical, in particular an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radical, in particular an optionally, z. B.  by free or functionally modified, such as etherified or esterified hydroxyl or mercapto groups, e.g. B.  Lower alkoxy, lower alkylthio or lower alkanoyloxy groups or halogen atoms, or optionally functionally modified carboxyl groups, such as lower alkoxycarbonyl, carbamyl or cyano groups substituted lower alkyl, primarily methyl, or an optionally, z. B.  such as the above-mentioned lower alkyl radical or by lower alkyl radicals, substituted phenyl or phenyl lower alkyl, e.g. B. 

  Benzyl radical. 



   The reducing agents used in the preparation of compounds of the formula VII from compounds of the formula I by treatment with an oxirane compound of the formula VI are primarily chemical reducing agents such as. B.  the above, especially zinc in the presence of the above aqueous acetic acid, in question, where one. under mild conditions, e.g. B.  works at room temperature or even under cooling. 



   In a compound of the formula VII, the hydroxy group is converted into the acyloxy group of the formula -OC (= O) -X2, in particular into a group of the formula -O-Cf = O) -O-ROa, -OC (= O) - by acylation OR, h, -OC (= O) - -O-ROe, -OC (= O) -Rod or -OC (= O) -O-Roe where Rosa, Rob, Rote, Rod and ROe have the meanings given above and primarily for 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, phenacyl, 4,5-dimethoxy-2-nitro-benzyl or tert. -Butyl residues are,

   furthermore into a group of the formula -OC (= O) -OR, ', in which Rof stands for an organic radical which, together with the carboxyl group, forms an esterified carboxyl group which can be cleaved under hydrolytic conditions, such as an activated ester grouping, and in particular a cyanomethyl-, 4-nitrophenyl -, 4-nitrobenzyl, phthalimidomethyl or succinimidomethyl group means converted. 



   The acylation reaction can be carried out in a manner known per se, e.g. B.  such as the acylation of an amino group described above, are carried out, using the usual acylating agents, especially suitable reactive derivatives of acids, if necessary, in the presence of a preferably basic agent, such as an 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, od. 



     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, 4-nitrophenol or N-hydroxysuccinimide.  The acyl group can also be introduced in stages; so you can z. B.  a compound of formula VII with a carbonic acid halide.  z. B.  Phosgene, treat and the so he available compound of formula VIII, wherein X is a halogen, z. B.  Chlorine atom, with a suitable alcohol, e.g. B.    2,2,2-trichloroethanol, tert. -Butanol or phenacyl alcohol, convert into the desired compound of formula VIII. 

  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. 



   In a glyoxylic acid compound of the formula IX, the radical R2A primarily represents a group Rosa, R, b, R "C, Rod, ROe or Rof.    



   The addition of the Glyoxylsäu ester compound of the formula IX to the nitrogen atom of the lactam ring of a compound of the formula VIII takes place preferably at elevated temperature, primarily at 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 ester compound, a reactive oxo derivative thereof, primarily a hydrate, can be used. 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. 



  One uses z. B.  suitable halogenating agents 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 a suitable organic sulfonic acid halide, such as chloride, the reaction 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 solvent mixture, if necessary, with cooling and / or in the atmosphere of an inert gas such as nitrogen. 



   In a compound of the formula XI obtained, a reactive esterified hydroxy group Z can be converted in a manner known per se into another reactive esterified hydroxy group.  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 a compound of the formula XII, each of the groups Ra, Rb and Re is primarily an optionally, e.g. B.  by etherified or esterified hydroxy groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl radical or an optionally 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 XI with the phosphine compound of the formula XII, in which each of the groups Ra, Rb and Re is primarily phenyl and a lower alkyl, in particular n-butyl, 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 with cooling or at elevated temperature and / or in the atmosphere of an inert gas such as nitrogen. 



   A phosphonium salt compound of the formula XIII formed as an intermediate usually spontaneously loses the elements of the acid of the formula H-Z XIIIa; if necessary, the phosphomum salt compound can be treated 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 XIV. 



   The cleavage of the esterified carboxyl group of the formula -C (= O) -X, in a compound of the formula XIV can be carried out in various ways, depending on the nature of the group X2.  For example, a grouping -C (= O) -X2, wherein X2 is the group of the formula -O-R, "or O Rob, by treatment with a chemical reducing agent, e.g. B.  one of the above-mentioned reducing agents, such as zinc, which is advantageously in the presence of an acid or an alcohol, optionally with the addition of water, e.g. B.  in the presence of aqueous acetic acid, is used, and a grouping of the formula -C (= O) -X.     wherein X2 represents the group of the formula -O-R ,, c by irradiation with light, in particular with ultraviolet light, cleave;

   these cleavage reactions can be carried out according to the methods described above. 



   An esterified carboxyl group of the formula -C (= O) -O-R, or -C (= O) -O-Roe can be obtained 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 that is liquid under the reaction conditions is used as a diluent and works at room temperature or under Küh len, eg. B.  to about -20uC to about 10oC.    



   An esterified carboxyl group -C (= O) -O-R, 'can hydrolytically under neutral or weakly acidic or basic conditions, e.g. B.  at a pH of from about 4 to about 9, e.g. B.  by treating with water, a weakly acidic agent such as a weak acid or a weakly acidic buffer solution, or a weakly basic agent such as an alkali metal hydrogen carbonate such as sodium hydrogen carbonate, or a suitable buffer (pH about 7 to about 9) such as a Dipotassium hydrogen phosphate buffer, in the presence of water and preferably an organic solvent such as methanol or acetone, are cleaved. 



   In a compound of the formula XIV, the esterified carboxyl groups of the formulas -C (+ O) -X2 and -C (= 0) -O-R2 'preferably differ from one another in such a way that under the conditions of cleavage of the esterified carboxyl group of the formula - C (= 0) -X2 the esterified carboxyl group of the formula -C (= O) -O-R2A remains intact. 

  Provides z. B.  the esterified carboxyl group of the formula -C (= O) -X2 is one of the esterified carboxyl groups that can be cleaved when treated with a chemical reducing agent such as zinc in the presence of aqueous acetic acid, e.g. B.  a grouping of the formula -C (= O) - -O-R, "or-C (= O) -O-ROb, in which ROa preferably represents the 2nd 2. 2-trichloroethyl or 2-iodoethyl or the 2-bromoethyl radical which can easily be converted into the latter and Rob are primarily the phenacyl group, the esterified carboxyl group of the formula -C (= O) -O-R2A z. B.  for one of the esterified carboxyl groups —C (= O) —O — R2A, cleavable on treatment with a suitable acid such as trifluoroacetic acid, e.g. B. 

   for a grouping of the formula -C (= O) -O-ROd, in which Rod is preferably the tert. -Butyl group. 



   The oxidation of a compound of the formula XV can surprisingly be carried out by treatment with an oxidizing organic sulfoxide compound in the presence of agents with dehydrating or water-absorbing properties.  The oxidizing sulfoxide compounds are primarily aliphatic sulfoxide compounds, such as di-lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides, e.g. B.  Tetramethylene sulfoxide.  Agents with water-removing or water-absorbing properties are primarily acid anhydrides, in particular anhydrides of organic, aliphatic or aromatic carboxylic acids, e.g. B. 

  Anhydrides of lower alkene carboxylic acids.     especially acetic anhydride.  also propionic acid canhydlide.     or benzoic anhydride, and anhydrides of inorganic acids, in particular of phosphoric acids, such as phosphorus pentoxide.  The above anhydrides.  primarily from organic carboxylic acids.  z. B.    Acetic acid callhydride, are preferably used in about a 1: 1 mixture with the sulfoxide oxidizing agent. 

  Other dehydrating eder-absorbing agents are carbodiimides, primarily dicyclohexylcarbodiimide.    also diisopropylcarbodiimide, or ketenimine, z. B.    Diphenyl-N-p-toylketenimine: these reagents are preferably used in the presence of acidic catalysts, such as phosphoric acid or pyridinium trifluoroacetate or phosphorus. 



  Sulfur trioxide can also be used as a water releasing or absorbing agent, usually in the form of a complex, e.g. B.  with pyridine. 



   Usually the sulfoxide oxidizing agent is used in excess.    Sulphoxide compounds liquid under the reaction conditions.     in particular the dimethyl sulfoxide, z. B.  also serve as a solvent: inert diluents such as benzene or mixtures of solvents could also be used as solvents. 



   The above oxidation reaction is carried out, if desired, with cooling, but mostly at room temperature or at a slightly elevated temperature.  In this case, an aldehyde compound of the formula XVIa obtainable as an intermediate product according to the process is ring-closed directly under the reaction conditions and without being isolated to give the 7S-amino-ceph-3-em-4-carboxylic acid compound of the formula XVI. 



   In a compound of the formula XVI obtained, a protecting group R2A, in particular an easily cleavable acyl group, can be a tcrt in a manner known per se.  Butyloxycarbonyl group e.g. B.  by treatment with trifluoroacetic acid, and a 2,2,2-Trichloräthoxycarbonyl- group by treatment with a suitable metal or a metal compound, z. B.  Tin, or a chromium-II compound such as chloride or acetate.     advantageously in the presence of a hydrogen-generating, hydrogen-releasing agent which nascent together with the metal or the metal compound, preferably hydrous acetic acid. 

 

  Furthermore, in a compound of the formula XVI obtained in which a carboxyl group -C (= O) -O-R2 is preferably a z. B.  by esterification, including by silylation or stannylation, e.g. B.  with a suitable organic halosilicon or halogen-tin-IV compound, such as trimethylchlorosilane, protected carboxyl group, a suitable acyl group R1, in which any free functional groups present are preferably protected, by treatment 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 are split off in an aqueous or alcoholic medium, preferably under acidic conditions.  A triarylmethyl, e.g. B.  Trityl group R, A can e.g. B.  by treating with an acidic agent such as a mineral acid, e.g. B. 



  Hydrochloric acid. 



   In a compound of the formula XVI in which R1 is hydrogen, the free amino group can be replaced by substitution processes known per se, e.g. B.  as described above, protected, in particular acylated. 



   In a compound of the formula XVI with an esterified carboxyl group, the latter e.g. B.  represents an esterified carboxyl group of the formula -C (= O) -O-R2A which can easily be converted into the free carboxyl group, this can be carried out in a manner known per se, e.g. B.     Depending on the nature of the esterifying radical R, A, are converted into the free carboxyl group, a grouping of the formula -C (= O) - -O-R, "or -C (= O) -O-Rol) z. B.  by treating with a chemical reducing agent such as a metal, e.g. B.  Zinc, or a reducing metal salt, such as a chromium-II salt, e.g. B. 

  Chromium (II) chloride, usually in the presence of a hydrogen-donating agent that is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic acid, or an alcohol, preferably adding water, a group of the formula - C (= O) -O-Roe e.g. B. 



  by irradiation, preferably with ultraviolet light, wherein one with shorter-wave ultraviolet light, for. B. 



  below 290 mlpl, works when ROe 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 mu, if ROe z. B.  is an arylmethyl radical substituted in the 2-position by a nitro group, a grouping -C (= O) -O-Rod or -C (= O) - -O-R, "z. B.  by treatment with an acidic agent such as formic acid or trifluoroacetic acid and a grouping -C (= O) -O-Ror e.g. B.  by hydrolysis, depending on the type of radical ROr z. B. 

   by treatment with an aqueous, weakly acidic or weakly basic agent such as aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer. 



   In a compound of the formula XVI, a grouping of the formula -C (= O) -O-R2A can be converted into another of this formula, e.g. B.  a 2-bromoethoxycarbonyl group of the formula -C (= O) -O-Roa by treatment with an iodine salt, such as sodium iodide, in the presence of a suitable solvent such as acetone, into a 2-iodine ethoxycarbonyl group. 



   A z. B.  Amino or carboxyl group protected by silylation can be used in a conventional manner, e.g. B.  can be released by treatment with water or an alcohol. 



   In a compound of the formula XVI with a group of the formula -C (= O) -O-R2, wherein R3 is hydrogen, the free carboxyl group can be in a manner known per se, for. B.  by treating with a diazo compound such as a diazo lower alkane, e.g. B.  Diazomethane or diazoethane, or a phenyl-diazo-lower alkane, e.g. B.  Phenyldiazomethane or Diphenyldiazometban, or by reacting 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. 



   In the above process steps, if necessary, free functional groups not participating in the reaction in the reactants, e.g. B. 'free -IIy- droxy-, mercapto and amino groups, z. B.  by acylation, tritylation or silylation, and free carboxyl groups e.g. B.  by esterification, incl.  Silylation, temporarily protected in a manner known per se and, if desired, released in a manner known per se in each case after the reaction has taken place. 



   The compounds of the formula XVI, especially those in which R1 is an acyl radical contained in pharmacologically active, naturally occurring or biosynthetically or semi- or totally synthetically producible N-acyl derivatives of 6-aminopenicillanic acid or 7-aminocephalosporanic acid compounds, and R3 is hydrogen or an organic radical R2A which can easily be split off under physiological conditions are resistant to microorganisms such as gram-positive bacteria, e.g. B.  Staphylococcus aureus, and gram negative bacteria, e.g. B.  Escherichia coli, in particular against penicillin-resistant bacteria, e.g. B.    versus. Staphylococcus aureus effective in dilutions up to 0.0001 / ml. 



   Such compounds with pharmacological effects can e.g. 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 ones 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 solution of 1.64 g of 3-isopropyl-4-thia-2,6-diazabicyclo [3. 2. 0] heptan-7-one in 33 ml of a 1: 1 mixture of acetic acid and water is added within 10 minutes with 71.7 ml of a 0.5-n.  Solution of iodine in ethanol are added, the mixture is left to stand at room temperature for one hour and then concentrated under reduced pressure. 



  The residue, dried under high vacuum, contains the bis (cis-2-oxo-3ss-amino-4ss-azetidinyl) disulfide of the formula
EMI15. 1
 and is suspended in 90 ml of acetonitrile and treated with 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride at Oo.  It is left to stand for 15 minutes at 0 and for one hour at room temperature and then evaporated under reduced pressure.  It is triturated for 30 minutes with 10 ml of a 1: 1 mixture of dioxane and water and the residue is taken up in ethyl acetate; the solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried and evaporated. 

  The oily residue is chromatographed on 100 g of pure silica gel; the oily bis- (cis-2-oxo-3X-phenylacetylamino-4-azetidinyl) disulfide is eluted with a 19: 1 mixture of ethyl acetate and acetone and converted into a finely powdered amorphous form by lyophilization; Thin-layer chromatogram (silica gel): Rf 0.36 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.08 u, 5.62 u, 5.97, u and 6.51 e.    



   The starting material can be made as follows:
15 ml of a sulfonic acid ion exchanger (H form) 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 -100 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 -50 to 00, 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 00.  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 obtained in this way, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, tt, 4.71, 5.62 pt, 5.80, 5.94, 6.69 tt and 8. 50. 



   A solution of 1.72 g of penicillin G azide in 30 ml of benzene is mixed with 1.5 ml of 2. 2,2-trichloroethanol was added and the mixture was stirred at 700 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.  It is diluted with 60 ml of hexane while stirring.  cools u.  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-6p-phenylacetylamino-3- (2,2,2-trichlorethoxycarbonylamino) -penam is obtained, which melts at 223-223.50; [α] D20 = = t 1720 (c = 1.018 in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04 t, 5.61 1, 5.77 st, 6.97, u, 6.70, 8.30 1l, 9.17 to 9.62> and 11, 85 t.    



   The product can also be obtained by heating 0.03 g of penicillin-G azide in 2 ml of benzene to 700 for 20 minutes, and evaporating the reaction mixture under reduced pressure to obtain the 3-isocyanato-2,2-dimethyl-6ss- phenylacetylamino penam; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06 j, 4.48, 5. 62>, 5.96 and 6.70, u; and this by repositioning with 2. 2. 2-trichloroethanol in the desired 2. 2-Dimethyl-6-phenylacetylamino-3 - (2,2,2-trichloroethoxycarbonylamino) -penam transferred. 



   A solution of 11.0 g of 2. 2-dimethyl-6-phenylacetylamino-3- (2.2.2. trichlorethoxycarbonylamino) penam in a mixture of 240 ml of anhydrous methylene chloride and 25.6 ml of pyridine is added under a nitrogen atmosphere at - 100 with 166 ml of a 10% solution of phosphorus pentachloride in methylene chloride and then stirred for 30 minutes at 0.  Then 120 ml ml of absolute methanol are added with strong cooling (- 100) and stirring is continued for 2 hours.  80 ml of water are added, the pH value (measured in samples diluted with water) is adjusted with about 9 ml of a 2-n.  aqueous sodium hydroxide solution to 3. 3 and let react for one hour at 00 and for another hour at 200. 

  It is then poured into 500 ml of a l-m while stirring.     aqueous dipotassium hydrogen phosphate buffer solution and the pH value is adjusted from 6.5 to 7.0 by adding 50% aqueous tripotassium phosphate solution.  The aqueous phase is separated off and washed twice with 200 ml of methylene chloride each time; the three organic solutions are each washed twice with water, combined, dried over sodium sulfate and evaporated under reduced pressure.  The crystalline residue is taken up in 40 ml of a 1: 1 mixture of benzene and hexane; the mixture is cooled at 00 for 15 minutes and the precipitate is filtered off. 

  The 65-amino-2,2-dimethyl-3- (2.2. 2-trichlorethoxycarbonylamino) -penam, which at 1791800 (corr. ) melts; Infrared absorption spectrum: characteristic bands (in methylene chloride) at 2.90 tt, 5.58 u, 6.62, 7.17, 7.27>, 8.32, 8.46 11, 8.82 u, 9.25 u and 9.62 p; (in Nujol) at 2.95%, 3.01 u, 3.11 it, 5.64>, 5.80 Lt, 6.35, 7.60 u, 7.87>, 8.00, 8, 27 u, 8.65 u, 8.70, 9.16 u and 9.57 X; Thin-layer chromatogram (silica gel):

  Rf = 0.17 (in the toluene / acetone system 8: 2) and Rf = 0.43 (in the toluene / acetone 6: 4 system); characteristic yellow coloration with ninhydrin collidine (free amino group).   



   A mixture of 0.05 g of 6p-amino-2,2-dimethyl-3- (2,2,2-trichloroethoxycarbonylamino) -2,2-dimethyl-penam and 0.1 g of zinc dust in 2 ml of a 1: 1 Mixture of acetone and water is fibrated after adding 0.2 ml of acetic acid at 200 for one hour with 45 kHz (ultrasound), then diluted with 50 ml of water.  It is extracted with 50 ml of ethyl acetate, the organic extract is dried over sodium sulfate and evaporated under reduced pressure.  The residue is recrystallized from a mixture of methylene chloride and hexane and 3-isopropyl-4-thia-2,6-diazabicy clo [3. 2. 0] heptan-7-one, F.    151-1550; Thin-layer chroma togramim: Rf = 0.17 (system: toluene / acetone 8: 2) and Rf = 0.38 (system: toluene / acetone 6: 4). 



   In the above process, 0.2 g of ammonium chloride or 0.2 g of pyridine hydrochloride can be used in place of acetic acid. 



   Example 2
A solution of 0.317 g of 3,3-dimethyl-4-thia-2,6- -diazabicyclo [3. 2. 0] heptan-7-one in 3.0 ml of methylene chloride is mixed with 0.254 g of iodine in 12.0 ml of benzene; this immediately forms a voluminous brown precipitate. 



  The mixture is shaken from time to time for 10 minutes at room temperature, then filtered and the filter residue, which contains the hydroiodide salt of bis (cis-3, Bs -isopropylideneamino-2-oxo-4p-azetidinyl) disulfide, with benzene and pentane washed and suspended in 8.0 ml of acetonitrile.  2.0 ml of pyridine are added to the suspension, a clear yellow solution being obtained, which is cooled to +100, and 0.4 ml of phenylacetic acid chloride is added dropwise with stirring.  The reaction mixture is left to stand for 20 minutes at room temperature, then concentrated under reduced pressure to a weight of 1.9 g.  The yellow syrupy residue is taken up in 50 ml of ethyl acetate and the solution is washed with 50 ml of water and then evaporated. 

  The residue is crystallized from a mixture of methanol, methylene chloride and hexane.  The bis- (cis-2-oxo-3p-phenylacetylamino-4f3- -azetidinyl) disulfide melts after recrystallization from acetone and methylene chloride at 152-1550 (analysis preparation: 156.5-158.50).    



   Example 3
A solution of 10.0 g of 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one in 200 ml of a 1: 1 mixture of acetic acid and water is added dropwise over 15 Minutes with 436 ml of a 0.2 molar solution of iodine in ethanol and evaporated after one hour at room temperature under reduced pressure.  The residue, containing the bis- (cis-3p-amino-2-oxo-4p-azetidinyl) disulfide, is dried under high vacuum and processed further without purification. 



   The crude product obtainable by the above process is dissolved in 200 ml of a 1: 1 mixture of tetrahydrofuran and water, treated with 8.4 ml of triethylamine and slowly N -terted to a mixture cooled to -100. -Butyloxycarbonyl-D-sc-phenylglycine, 8.95 ml of triethylamine and 8.40 g of isobutyl chloroformate in 170 ml of tetrahydrofuran were added dropwise.  After one hour at 0 and a further hour at room temperature, the reaction mixture is concentrated to half and taken up in 800 ml of ethyl acetate.  It is washed twice with 200 ml each of a saturated aqueous sodium hydrogen carbonate solution and twice with 200 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.  The residue is chromatographed on 500 g of silica gel. 

  The bis- [cis-3p- (N-tert. -butyloxyzarbonyl-D-x-phenylglycyl) -amino-2-oxo-4ss-azetidinyl] -disulfide is eluted with ethyl acetate.  The amorphous product melts at 163-1660 with decomposition; [D30 = + 1450 + 10 (c = 0.930 in chloroform); Thin-layer chromatogram (silica gel; development with iodine vapor): Rf 0.33 (system:

  Ethyl acetate); Ultraviolet Absorption Spectrum (in ethanol):); max = 257 mp, (z = 2200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90 Il, 2.98 tls 3.34, u, 5.63, 5.90! 1, 6.68 u 7.29 y, 8.11, p, 8 , 58 y and 9.53.    



   The bis- (cis-2-oxo-3-acylamino -4p-azetidinyl) disulfides of the above examples can be further processed as follows:
A: A solution of 0.35 g of bis (cis-2-oxo-3i-phenyl-acetylamino-4ss-azetidinyl) disulfide in 16 ml of a 9: 1 mixture of acetic acid and water is at about 50 with about 3.2 g of ethylene oxide, then mixed with 3.5 g of zinc dust.  The reaction mixture is stirred for 15 minutes at about 50 and for 30 minutes at room temperature, then filtered.  The filter residue is washed with acetone and the filtrate is evaporated.  The residue is taken up in about 150 ml of ethyl acetate and the solution is washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and with 100 ml of a saturated aqueous sodium chloride solution, dried and evaporated. 

  The residue is chromatographed on 50 g of silica gel together with a crude product obtained in an analogous manner from 0.58 g of bis (cis-2-oxo-3p-phenylacetylamino-4p-azetidinyl) disulfide.  The 4ss- (2-hydroxyethyl mercapto) -3, B-phenylacetylamino-azetidin-2-one is eluted with a 19: 1 mixture as a uniform product which, after crystallization from a mixture of acetone and diethyl ether, melts at 141-1420 ; [a] 20 D = +440 + 20 (c = 0.571 in ethanol); Thin layer chromatography (silica gel; developing with iodine): Rf 0.45 (system:

  Ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.01, 5.68 Lt, 6.01>, 6.431> and 6.52.    



   A solution of 0.61 g of 4. (2. Hydroxyethyl mercapto).    



     -3l-phenylacety1amino-azetidin-2-one in 10 ml of tetrahydrofuran is added dropwise at 0 with 1.38 g of 2,2,2-trichloroethyl chloroformate in 5 ml of tetrahydrofuran, then with 1.06 g of pyridine in 5 ml of tetrahydrofuran. 



  The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes at 0 and for 2 hours at room temperature.  then taken up in 150 ml of methylene chloride.  It is washed with a saturated aqueous sodium chloride solution, dried and evaporated.  The residue is chromatographed on 50 times the amount of silica gel; the 3-phenyl-acetylamino-4 - [2- (2,2,2-trichloroethoxycarbonyloxy) -äthylmercaptoj-azetidin-2-one is eluted with a 1: 1 mixture of methylene chloride and ethyl acetate.  

  After crystallization and recrystallization once from diethyl ether, the product is obtained in the form of colorless needles, F.    99 1010; Thin-layer chromatogram (silica gel): Rf to 0.46 (system: ethyl acetate; development with iodine); [] D20 = + 30 + 20 (c = 0.518 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88 Il, 5.58 y, 5.64, u, 5.92. C1 and 6.62 u.   



   A mixture of 1.0 g of 3j3-Phenylacetylamino-4- [2- - (2,2,2 -trichloräthoxycarbonyloxy) - ethylmercapto] -azet- idin-2-one and 3. 0 g glyoxylic acid tert. Butyl ester hydrate in 50 ml of benzene is refluxed for 16 hours with separation of water, then cooled and washed twice with 25 ml of distilled water each time, dried over sodium sulfate and evaporated. 



  The x-hydroxy-31- (2-oxo-39-phenylacetylamino-4p- [2- (2,2,2-trichlorethoxycarbonyloxy) -äthylmer capto] -l-acetidinyl) -acetic acid-tert is obtained. -butyl ester which is processed further without purification. 



   The crude α-hydroxy-α - {2-oxo-3ss-phenylacetylamino-4ss- [2- (2,2, - 2-trichloroethoxycarbonyloxy) - ethylmercaptoj - 1-azetidinyl} -acetic acid-tert. Obtainable by the above process . -butyl ester is dissolved in 20 ml of a 1: 1 mixture of dioxane and tetrahydrofuran and at - 100 dropwise with 0.54 ml of pyridine in 2 ml of dioxane and 0.48 ml of thionyl chloride in 10 ml of a 1: 1 mixture of dioxane and Tetrahydrofuran added. 

  The reaction mixture is stirred for 30 minutes at -100 to -50 and for one hour under a nitrogen atmosphere, the precipitate is filtered off and the filtrate with the 31-chloro-x- (2-oxo-3p-phenylacetylamino-4ss- [2-2 , 2,2-trichloräthoxycarbonyloxy) -äthylmercaptol- - 1 -azetidinyl} -acetic acid-tert. -butyl ester evaporated: the product is further processed in its raw state. 



   A solution of the crude α-chloro-α - {2-oxo-3ss-phenylacetylamino-4ss- [2 - (2,2,2-trichloroethoxycarbonyloxy) -ethylmercapto] -1- -azetidinyl} obtainable by the above process acetic acid tert. butyl ester in 30 ml of a 1: 1 mixture of dioxane and tetrahydrofuran is mixed with 1.15 g of triphenylphosphine and 0. 35 ml of pyridine are added and the mixture is heated at 500 for 2 hours, then evaporated to dryness. 

  The residue is chromatographed on 30 g of pure silica gel, using a 1: 1 mixture of toluene and ethyl acetate to give the α- (2-oxo -3ss-phenylacetylamino-4,3- [2- (2.2 , 2 - trichloräthoxycarbo- nyloxy) - ethyl mercapto] - 1 - azetidinyl} - o-triphenylphos- phoranylideneacetic acid-tert. -butyl ester is eluted, which is contaminated with a little triphenylphosphine oxide and can be purified by preparative thin-layer chromatography (silica gel; development with iodine), Rf 0.57 (system:

  Toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.42>, 5.68 it, 5.97 Il, 6.10 l and 6.65 Il.    



   A mixture of 0.225 g of x- (2-oxo-3P-phenylacetylamino-4ss- [2- (2,2,2-trichlorethoxycarbonyloxy) ethylmercapto] -1-azetidinyl} -x - triphenylphosphoranylidene - acetic acid tert. butyl ester in 10 ml of a 9: 1 mixture of acetic acid and water is mixed with 3.0 g of zinc dust and stirred at 150 for 45 minutes.  It is filtered and the filtrate is evaporated; the residue is taken up in 50 ml of ethyl acetate and the solution is washed with 25 ml of a saturated aqueous sodium hydrogen carbonate solution and twice with 25 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 

  This gives the x- [43- (2-hydroxyethylmercapto) -2-oxo-3ss-phenylace tylamino-1-acetidinyl] -α-triphenylphosphoranylidene-acetic acid-tert. butyl ester; Thin-layer chromatogram (silica gel; development with iodine): Rf 0.24 (system: toluene / acetone 1: 1). 



   A mixture of 0.221 g of the crude - [4ss- (2-Hydroxy-ethylmercapto) -2-oxo-3ss-phenylacetylamino-1-azetidinyl] -α-triphenylphosphoranylidene-acetic acid - tert. Butyl ester in 5 ml of dimethyl sulfoxide and 5 ml of acetic anhydride is left to stand for 16 hours at room temperature, then concentrated under reduced pressure.  The residue is taken up in 100 ml of toluene: the organic solution is washed three times with 50 ml of distilled water each time, dried over sodium sulfate and evaporated. 

  The oily residue is chromatographed on 10 g of silica gel; the desired 7w-phenylacetylamino-ceph-3-em-4-carboxylic acid - tert.  -butyl ester, which is obtained by ring closure from the intermediate and unisolated α- (4ss-Formylmethylmercapto-2-oxo-3ss- - phenylacetylamino - 1 -azetidinyl) - - triphenylphosphoranylidene-acetic acid-tert. -butyl ester forms.  is eluted with a 4: 1 mixture of toluene and ethyl acetate: Thin-layer chromatogram (silica gel): Rf 0.48 (system:

  Toluene / ethyl acetate 1: 1); Ultraviolet Absorption Spectrum (in pure ethanol): #max 258 my; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00 II, 3. 48 lt.  5.62 lt.     5.81 t,
5.93 Il, 6.10 y, 6.67, 7.15 u, 7.31 'St, 7.70,.       8.65 lt and 9.03p. 



   A mixture of 0.03 g - phenylacetylamino -ceph - -3-em-4-carboxylic acid-tert. Butyl ester and 0.5 ml of trifluoroacetic acid are allowed to stand at room temperature for one hour.     The trifluoroacetic acid is then removed under reduced pressure and the residue is taken to dryness twice with 5 ml each of a mixture of benzene and chloroform.  The residue becomes chromium on 5 silica gel. .  graphed and the 7n-phenylacetylamino-ceph3 -em4-carboxylic acid with methylene chloride, containing 5% acetone, eluted; Thin-layer chromatogram (silica gel: development with iodine): Rf 0.49 (system: n-butanol / pyridine / vinegar. dl itre / water 40: 24: 6: 30). 



   B: A solution of 5.63 g of bis- [cis-3 (- (N-tert. -butyl- oxycarbonyl- D -? - phenylglycyl) -amino-2-oxo- - 4 - azetidi- nyl] disulfide in 190 ml of a 9: l mixture of acetic acid and water is mixed with about 60 g of ethylene oxide and 56 g of zinc dust added, and stirred vigorously for one hour at room temperature.  It is filtered and the filtrate is concentrated, taken up in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. 

  The residue is chromatographed on 150 g of silica gel; it is eluted with ethyl acetate and the 3P- (N-tert.  -Butyloxycarbonyl - D-. z-phenylglycyl) -amino-4B- - (2-hydroxyethylthio) -azetidin-2-one, which melts at 130-1310 after crystallization from a mixture of acetone and diethyl ether; [oc] 20 D = 640 + 20 (c = 0622 0.622 in ethanol); Thin-layer chromatogram (silica gel; development with iodine vapor): Rf 0.47 (system:

  Ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90 ll, 3.00 u, 3.25 ll, 3.34, 5.61 u, 5.83 u, 5.91, a, 6.68 j "7 , 29, 8.58 lt and 9.02 p.    

 

   A solution, cooled to 00, of 4.80 g of 3a- (N-tert. -Butyloxycarbonyl -D - - phenylglycyl) -amino -4p- (2-hydroxyethylthio) -azetidin-2-one and 7.74 g of chloroformic acid-2,2,2-trichloroethyl ester in 100 ml of tetrahydrofuran within 10 minutes with a solution of 5.9 g of pyridine in 50 ml of tetrahydrofuran, stirred while
15 minutes at 00 and for 30 minutes at room temperature and concentrated.  It is taken up in 500 ml of methylene chloride, washed twice with 100 ml of a saturated aqueous sodium chloride solution and evaporated. 

  The residue is chromatographed on 300 ml of silica gel; one elutes with a 4: 1 mixture of methylene chloride and ethyl acetate the non-crystalline 3p- (N-tert.    -Butyloxycarbonyl-D-α-phenylglycyl) -amino-4ss- [2,2,2- - trichlorethoxycarbonyloxy) - ethylthio] - azetidin -2-one, thin-layer chromatogram (silica gel; development with iodine vapor): Rf 0.55 (system : Ethyl acetate) and Rf 0.19 (system: toluene / ethyl acetate 1: 1): infrared absorption spectrum (in methylene chloride): characteristic bands at 3. 00 Il, 3.35 u, 3.42, 5.61,
5.66 lt, 5.85 1r, 5.92, 6.75 u.  7.06 It, 8.14 and 8.61. 



   A mixture of 13.5 g of glyoxy acid tert is dehydrated. butyl ester hydrate in 160 ml of toluene by distilling off about 80 ml of toluene.  gives to 5.29 g 3p- (N- -tert. -Butyloxycarbonyl-D -? - phenylglycyl) -amino - (2. 2,2-trichlorethoxycarbonyl oxy) -äthylthio] -azetidin-2-one and heated the reaction mixture for 16 hours under a nitrogen atmosphere at 900.  After this
Cooling is diluted with toluene to a volume of
150 ml, washed five times with 100 ml of water each time, dried over sodium sulfate and evaporated. 

  The residue contains the x-l 3p- (N-tert. Buty1-oxycarbonyl-D-phenylglycyl) -amino-4g- [2- (222-trichloroethoxycarbonyl-oxy) -ethio] -2-oxo-1-acetidinyl} -z.     - hyd roxy - acetic acid tert. -butyl ester and is processed further without purification. 



   The oily product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane and, at about -50, 2.24 ml of pyridine and 2.00 ml of thionyl chloride in a 1: 1 mixture are added over the course of 10 minutes of tetrahydrofuran and dioxane.  After standing at -5 for 30 minutes, the cooling bath is removed; the mixture is stirred for a further hour at room temperature, filtered through a diatomaceous earth preparation and evaporated. 



  The residue contains the 2-chloro-a- (3P- (N-tert. -Butyloxycarbonyl- D - phenylglycyl) -amino- 4ss- [2- (2,2,2-trichlorethoxycarbonyloxy) -ethylthio] -2-oxo-1 -azetinyl} -acetic acid-tert. -butyl ester and is processed further without purification. 



   The above crude product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane, 4.86 g of triphenylphosphine and 0.75 ml of pyridine are added and the mixture is heated at 500 for 10 hours under a nitrogen atmosphere.  The dark red solution is concentrated, the residue is taken up in methylene chloride and the mixture is washed twice with 100 ml of water and then evaporated. 

  The residue is chromatographed on 200 g of silica gel, d n α-( 3ss- (N-tert. -Butyl oxycarbonyl-D - i. -phenylelycyl) -amino-4ss- [2- (2,2,2-trichloroethoxycarbonyloxy) - ethylthio] - - 2-oxo-1-azetidinyl} - -a triphenylphosphoranylidene-acetic acid -tert. - butyl ester eluted with a 1: 1 mixture of toluene and ethyl acetate; Thin-layer chromatogram (silica gel; development with iodine vapor): Rf 0. 25 (system:

  Toluene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.44 Il, 5.67 it, 5.86 Lt, 5.92 t, 6. 14 "and 6.76 TL.    



   A solution of 1.74 g. -} 3- (N-tert. -Butyloxycar- bonyl - D - - phenylglycyl) amino - 43 - [2 - (2,2,2 - trichloroethoxycarbonyloxy) ethylthio] -2-oxo 1 -azetidinyl} - α-triphenylphosphoranylidene-acetic acid- tert. butyl ester in 65 ml of a 9: 1 mixture of acetic acid and water is mixed with 12 g of zinc dust and stirred for one hour at room temperature.  It is filtered through a diatomaceous earth preparation, the filtrate is evaporated and the residue is taken up in 500 ml of ethyl acetate. 

  It is washed twice with 100 ml of a saturated aqueous sodium chloride solution and with 100 ml of a saturated aqueous sodium chloride solution.  the organic phase is dried over sodium sulfate and evaporated. 



  The α- [3α- (N-tert. -Butyloxycarbonyl-D-α-phenylglycyl) -amino-4a - (2-hydroxyethylthio) -2-oxo-1-azetidinyl] - z - (triphenylphosphoranylidene) -acetic acid -tert. -buty] ester, thin layer chromatogram (silica gel; development with iodine vapor): Rf 0.29 (system: toluene / acetone 3: 2); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00 and 3.42, 5.68 e, 5.86, 5.93, 6.16 Il, 6.75 u and 8.75 y, respectively.    



     A mixture of 1.53 g of crude α- [3α- (N-tert. -Butyloxycarbonyl-D-a-phenylglycyl) -amino-4sc - (2-hydroxyethyl thio) -2-oxo-1-azetidinyl] - - (triphenylphosphoranylidene) acetic acid tert. Butyl ester in 60 ml of a 1: 1 mixture of dimethyl sulfoxide and acetic anhydride is left to stand for 16 hours at room temperature under a nitrogen atmosphere, then kept at 500 for a further 2 hours.  It is concentrated, taken up in 500 ml of toluene and washed three times with 100 ml of water each time.  The organic phase is dried over sodium sulfate and evaporated. 

  The residue is chromatographed on 120 g of silica gel and the 7ss- (N-tert. -Butyloxycarbonyl-D-α-phenylglycyl) -amino-ceph-3-em-4-carboxylic acid - tert. butyl ester with an 8: 2 mixture of toluene and ethyl acetate eluted.  The product crystallizes from a mixture of diethyl ether and pentane, F.  159 1610; [a] D20 = + 290 + 20 (c = 0.521 in chloroform); Thin-layer chromatography (silica gel; development with iodine vapor): Rf 0.67 (system: toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in ethanol); #max = 255 rult (± = 5400):

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.68 tt, 2.89 lt '3.33, 5.57, 5 * 79! T, 5.88 u, 6.08, 6.22, 6.70, 7.15, 7.28 t, 7.68, 8.04 u, 8.64, 9.05 ", 9.52 and 9.79. 



   A mixture of 0.6367 g of 7b- (N-tert. -Butyloxycarbonyl-D-a-phenylglycyl) -amino-ceph-3-em-4-carboxylic acid -tert. Butyl ester in 30 ml of trifluoroacetic acid is left to stand for 15 minutes at room temperature, then 100 ml of toluene are added and the mixture is evaporated.  The residue is taken up again in 100 ml of a 3: 1 mixture of toluene and methanol, evaporated under reduced pressure and dried under high vacuum. 

 

  The white powdery residue is dissolved in 5 ml of methanol and treated with 13 ml of the above solution of triethylamine in diethyl ether, a voluminous new precipitate being formed.  The solvent is evaporated off under reduced pressure, the residue is slurried in methylene chloride and suction filtered.  It is washed with about 150 ml of methylene chloride and dried under high vacuum.  The 7p- (D - =, - phenylglycyl) -amino-ceph-3-em-4-carboxylic acid is obtained in the zwitterionic form as a pale yellowish, amorphous powder, thin-layer chromatogram (silica gel; development with iodine vapor): Rf for 0.29 (system: n-butanol / pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in water): #max = 250 m (e = 4300).  

 

Claims (1)

PATENT CLAIM Process for the preparation of bis-azetidinyl disulfide compounds of the formula EMI18.1 wherein Ac represents an acyl group, characterized in that one is a compound of the formula EMI19.1 in which Y represents an optionally substituted methylene group, converted into the corresponding compound of the formula I with oxidation, cleavage of a group bonded to the nitrogen and acylation in any order. SUBCLAIMS 1. The method according to claim, characterized in that in a starting material of the formula II, the group Y is a mono- or disubstituted methylene group, in which the substituents are optionally substituted. represent mono- or divalent hydrocarbon radicals. 2. The method according to claim or dependent claim 1, characterized in that the methylene group Y is substituted by two methyl radicals or one isopropyl group. 3. The method according to claim, characterized in that halogen is used as the oxidizing agent. 4. The method according to claim and dependent claim 3, characterized in that iodine is used. 5. Method according to claim. characterized in that oxidizing black metal carboxylates are used as oxidizing agents. 6. The method according to claim uild dependent claim 5, characterized in that lead tetraacetate is used. 7. The method according to claim and dependent claim 5, characterized. that oxidizing heavy metal carboxylates are used in the presence of ultraviolet light. 8. Method according to claim. characterized. that oxygen is used in the presence of a heavy metal catalyst as an oxidizing agent. 9. Method according to claim. characterized in that one uses hypohalotrenic compound as an oxidizing agent. 10. Method according to claim. characterized in that iron III salts are used as oxidizing agents. 11. The method according to claim, characterized in that one uses diiodoethane as an oxidizing agent. 12. Method according to claim. characterized in that thiocyanogen is used as the oxidizing agent. 13. Method according to Patentaii.; Pruch. characterized in that one with an acid halide, an acid anhydride odc. acylated an activated ester. 14. Method according to claim. characterized in that one in naturally occurring or biosynthetically preparable or in highly effective N-acyl derivatives oll 6-amino-perant-3-carboxylic acids or 7-amino-ceph-3-em-4-carbon.uren occurring acyl radical or a slightly introduces cleavable acyl radical of a carbonic acid half ester. 15. The method according to claim or dependent claim 14, characterized. that one has the N-tert. -Butyloxycarbonyl-D-ex-phenylglycylrcst.