CH561727A5 - Thiazabicyclic compns - Google Patents

Abstract

Compds of formula (I) (where R1 = H or ester residue; R2 is H or acyl and R is methylene mono- or di-substd. aromatic-heterocyclic a heterocyclic-aliphatic residues opt. substd. by hydrocarbon residues themselves opt. substd) are prepd. by ring closure of an appropriately substd. 2, 6-diazo-bicyclo 3.2.0 heptane to form the "cephem" ring system. Medicaments are in forms suitable for enteral or parenteral administration.

Description

  

  
 



   The present invention relates to the preparation of 7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid compounds of the formula
EMI1. 1
 where R1 represents a hydrogen atom or the organic radical of an alcohol, R2 represents an acyl radical and R a methylene radical substituted by one or two optionally substituted hydrocarbon radicals, optionally substituted heterocyclic or heterocyclic-aliphatic radicals in which heterocyclic groups have an aromatic character, or functional groups represents, as well as salts of such compounds with salt-forming groups. 



   The compounds of the formula I have the configuration of 7-aminocephalosporanic acid. 



   The group R1 can mean the organic radical of any alcohol, but in particular an optionally substituted aliphatic or araliphatic hydrocarbon radical. 



   The group R2 primarily represents the acyl radical of an organic carboxylic acid, e.g. B.  a carbonic acid half-derivative or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid. 



   A hydrocarbon radical substituting the methylene group R is primarily an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic araliphatic or heterocyclic-aliphatic hydrocarbon radical, such a hydrocarbon radical also being of a divalent nature and e.g. B.  may represent a divalent aliphatic hydrocarbon radical. 

  A functional substituent of the methylene group R is e.g. B.  a ver etherified hydroxy and mercapto group, e.g. B.  one by an optionally substituted aliphatic, and aromatic or araliphatic hydrocarbon radical ver etherified hydroxyl and mercapto group, or by an organic carboxylic acid, for. B.  an aliphatic, aromatic or araliphatic carboxylic acid esterified hydroxyl and mercapto group, and also an acyl radical, in particular the acyl radical of an aliphatic, aromatic or araliphatic carboxylic acid. 



   An aliphatic hydrocarbon radical is an alkyl, alkenyl or alkynyl, in particular a lower alkyl or lower alkenyl, and also a lower alkynyl radical, the z. B.  can contain up to 7, preferably up to 4 carbon atoms. 



  Such radicals can optionally be replaced by functional groups, e.g. B.  by 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 given. 



  if substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, and halogen atoms, furthermore by nitro groups, optionally substituted amino groups or optionally functionally modified carboxy groups, such as carboxy lower alkoxy, optionally N-substituted carbamyl, or cyano groups, mono-, di- or be polysubstituted. 



   Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals are, for. B.  mono-, bi- or polycyclic cycloalkyl or cycloalkenyl groups, or  Cycloalkyl or cycloalkenyl-lower alkyl or -niederalkenylgruppen, wherein cycloalkyl radicals z. B.  contain up to 12, such as 3-8, preferably 3-6 ring carbon atoms, while cycloalkenyl radical z. B.  have up to 12, such as 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of cycloaliphatic-aliphatic radicals 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. B.  the above-mentioned, optionally substituted lower alkyl groups, or then, like the above-mentioned aliphatic hydrocarbon radicals, be mono-, di- or polysubstituted by functional groups. 



   An aromatic hydrocarbon radical is e.g. B.  a monocyclic or bicyclic aromatic hydrocarbon radical, in particular a phenyl, and a biphenylyl or naphthy radical, which optionally, z. B.  like the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be mono-, di- or polysubstituted. 



   An araliphatic hydrocarbon radical is an optionally substituted one, e.g.     to three, optionally substituted, mono- or bicyclic, 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 containing 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. 



   A divalent aliphatic hydrocarbon radical is primarily a lower alkylene, and a lower alkenyl radical, the z. B.  contains up to 8, preferably 4 to 5 carbon atoms, and, if desired, e.g. B.  such as the above-mentioned cycloaliphatic radicals, may be substituted. 



   The heterocyclic part of a heterocyclic or heterocyclic-aliphatic radical is in particular a monocyclic, as well as bicyclic or polycyclic aza-, thia-, oxa-, thiaza-, oxaza- or diazacyclic radical of aromatic character, which is optionally z. B.  as the above-mentioned cycloaliphatic radicals can be mono-, di- or polysubstituted.  The aliphatic part in heterocyclic-aliphatic radicals has z. B.  the meaning given for the corresponding cycloaliphatic or araliphatic radicals. 



   The acyl radical of a carbonic acid half derivative is preferably the acyl radical of a corresponding half ester, in which the esterifying organic radical is an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic aliphatic radical, primarily the radical of an optionally substituted lower alkyl half ester of carbonic acid (i.e. H.  a carbo-lower alkoxy radical optionally substituted in the lower alkyl part), and one optionally 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.  a in lower alkenyl, cycloalkyl, phenyl or  

  Phenyl-lower alkyl part of optionally substituted carbon-lower alkenyloxy, carbocycloalkoxy, carbo-phenyloxy or carbo-phenyl-lower alkoxy radical).  Acyl radicals of a carbonic acid half-ester are also acyl radicals of lower alkyl half-esters of carbonic acid, in which the lower alkyl part is a heterocyclic, e.g. B.  contains one of the above-mentioned heterocyclic groups of aromatic character, it being possible for the lower alkyl radical and the heterocyclic group to be optionally substituted.  Such acyl radicals are optionally substituted carbo-lower alkoxy groups in the lower alkyl part and in the heterocyclic group which contain a heterocyclic group of aromatic character in the lower alkyl radical; heterocyclic groups of this type are described in more detail below. 



   The acyl radical of an aliphatic carboxylic acid is z. B.  the corresponding remainder of an optionally, z. B.  such as the above-mentioned aliphatic hydrocarbon radicals, substituted alkane, as well as alkene or alkyne, primarily lower alkane, and lower alkene or lower alkyne carboxylic acid, the z. B.  can contain up to 7, in particular up to 4 carbon atoms. 



   The acyl radical of a cycloaliphatic or cycloaliphatic-aliphatic carboxylic acid is z. B.  the acyl radical of an optionally, z. B.  such as the aforementioned cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals, substituted cycloalkanoic or cycloalkenecarboxylic acid, or 



  Cycloalkyl or cycloalkenyl-lower alkane or -niederalkencarbonsäure, where a cycloalkyl or cycloalkenyl radical, and the aliphatic part of cycloaliphatic-aliphatic carboxylic acids z. B.  have the number of carbon atoms and / or double bonds specified above for corresponding radicals and optionally, for example  as indicated, may be substituted. 



   The acyl radical of an aromatic carboxylic acid is primarily the radical of a mono- or bicyclic aromatic carboxylic acid, which optionally, z. B.  such as the above-mentioned cycloaliphatic radical, may be substituted. 



   In the acyl radical of an araliphatic carboxylic acid, the araliphatic part has z. B.  the above meaning; an araliphatic carboxylic acid means primarily a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid, in which the phenyl radical and the aliphatic part optionally, e.g. B.  like the aforementioned cycloaliphatic resp.  aliphatic groups, can be substituted. 



   The acyl radical of a heterocyclic carboxylic acid is in particular the radical of such an aromatic character in which the heterocyclic radical can preferably be monocyclic, as well as bi- or polycyclic and primarily for an optionally, z. B.  as the above-mentioned cycloaliphatic radical, substituted mono-, as well as bi- or polycyclic aza-, oxa-, thia-, diaza-, oxaza- or thiazacyclic radical.  In a heterocyclic-aliphatic carboxylic acid, the heterocyclic radical has the meaning given above, while the aliphatic part such. B.  in an araliphatic carboxylic acid represents an optionally substituted lower alkyl or lower alkenyl radical. 



   A hydroxyl group etherified by an optionally substituted aliphatic hydrocarbon radical is, for example.     an alkoxy, as well as alkenyloxy or alkynyloxy, in particular a lower alkoxy, and also lower alkenyloxy or lower alkynyloxy group, the alkyl, alkenyl or alkynyl, especially lower alkyl, lower alkenyl or lower alkynyl radicals of these groups such as the aliphatic hydrocarbon radicals given above functional groups, such as etherified or esterified hydroxyl or mercapto groups, nitro groups, substituted amino groups or functionally modified carboxy groups, can be mono-, di- or polysubstituted. 



   Etherified hydroxyl groups are further optionally substituted phenyloxy, phenyl-lower alkoxy or phenyl-lower alkenyloxy groups, it being possible for the hydrocarbon radicals of hydroxyl groups etherified in this way to be mono-, di- or poly-substituted as indicated above by hydrocarbon or functional groups. 



   A lower alkyl radical is e.g. B.  a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec. -Butyl- or tert. -Bu tyl, and n-pentyl, isopentyl, n-hexyl, isohexyl or n-heptyl, while a lower alkenyl z. B.  a Vi nyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butene nyl group.     and a lower alkynyl radical, for example.     a propargylic or
Can be 2-butynyl group. 



   Optionally substituted aliphatic hydrocarbon radicals, especially lower alkyl groups, which u. a.  also cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic
Can substitute radicals, contain z. B.  the above
Substituents and are e.g. B.  Halo-lower alkyl groups such as mono-, di- or polyhalogenated lower alkyl, e.g. B.  Methyl, ethyl, or 1- or 2-propyl groups; Rests of this type, in particular special 2-halo-lower alkyl radicals such as 2,2,2-trichloroethyl or 2-iodoethyl groups, primarily represent halogenated lower alkyl radicals R1, or form the organic part of corresponding 2-halo-lower alkoxy groups R. 



   A cycloalkyl group is e.g. B.  a cyclopropyl, cyclo butyl, cyclopentyl, cyclohexyl or cycloheptyl, and
Adamantyl group and a cycloalkenyl z. B.  a 2- or
3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cyclo heptenyl group.  A cycloalkyl-lower alkyl or -niederalke nylrest is z. B.  a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl-methyl-, -1,1- or -1,2-ethyl-, -1,1-, -1,2 or -1,3-propyl-, -vinyl- or -allyl group, while a
Cycloalkenyl-lower alkyl or lower alkenyl group e.g. B.  a
1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl- or
1-, 2- or 3-cycloheptenyl-methyl-, -1,1- or -1,2-ethyl-, -1,1-, -1,2- or -1,3-propyl-, -vinyl- or allyl group. 



   A naphthyl radical is a 1- or 2-naphthyl radical, while a biphenylyl is primarily a 4-biphenylvi group. 



   A phenyl-lower alkyl or phenyl-lower alkenyl radical is, for. B. 



   a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpro pyl, diphenylmethyl, trityl, 1- or 2-naphthylmethyl,
Styryl or cinnamyl radical. 



   A lower alkylene or lower alkenylene radical is z. B. 



   by a 1,2-ethylene, 1,3-propylene, 2,2-dimethyl-1,3-propylene, 1,4-butylene, 1- or 2-methyl-1,4-butylene , 1,4-dimethyl-1,4-butylene-, 1,5-pentylene-, 1-, 2- or 3-methyl-1,5-pentylene-, 1,6-hexylene-, 2- Buten-1,4-ylene or 2- or 3-penten-1,5-ylene group. 



   Heterocyclic radicals of aromatic character are z. B. 



   monocyclic monoaza-, monothia- or monooxacyclic
Residues of aromatic character, such as pyridyl, e.g. B.  2-, 3- or
4-pyridyl radicals, thienyl, e.g. B.  2-thienyl radicals, or furyl, e.g. B. 



   2-furyl radicals, or bicyclic, monoazacyclic radicals aromatic character, such as quinolinyl, z. B.  2-quinolinyl or
4-quinolinyl radicals, or isoquinolinyl, e.g. B.  1-Isoquinolinyl radicals, or monocyclic thiaza or oxazacyclic radicals of aromatic character, such as oxazolyl, isoxazolyl, thiazo lyl or isothiazolyl radicals.  Heterocyclischaliphatic radicals are heterocyclic radicals such as those containing
Lower alkyl or lower alkenyl radicals. 

 

   Among etherified hydroxy groups are primarily
Lower alkoxy, e.g. B.  Methoxy, ethoxy, n-propyloxy, iso propyloxy, 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-trichloroethoxy or 2-iodoethoxy groups, also lower alkenyloxy, z. B.  Vi nyloxy or allyloxy groups, lower alkylenedioxy, e.g. B. 



   Methylene or ethylenedioxy groups, phenyloxy groups, or 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 pyndyl-lower alkoxy, z. B.  2-pyridylmethoxy, furyl-lower alkoxy, e.g. B. 



  Furfuryloxy, or thienyl-lower alkoxy, e.g. B.  2-thienyloxy groups. 



   Among the etherified mercapto groups are lower alkyl mercapto, e.g. B.  Methyl mercapto or ethyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto, zrB.     Benzyl mercapto groups. 



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



   Substituted amino groups are mono- or disubstituted amino groups in which the substituents are primarily optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals.  Such amino groups are in particular lower alkylamino or di-lower alkylamino, e.g. B.  Methylamino, ethylamino, dimethylamino or diethylamino groups, or, optionally by heteroatoms, such as oxygen, sulfur or optionally, e.g. B.  lower alkyl groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiamorpholino or 4-methylpiperazino groups. 



   A carbo-lower alkoxy radical is z. B.  a carbomethoxy, carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy, carbo-tert. -butyloxy- or carbo-tert. -pentyloxy group.    



   Optionally N-substituted carbamyl groups are, for example.    



  N-lower alkyl or N, N-di-lower alkyl-carbamyl, such as N-methyl, N-ethyl, N, N-dimethyl or N, N-diethylcarbamyl groups. 



   A carbo-lower alkenyl radical is z. B.  the carbovinyloxy group, while carbo-cycloalkoxy and carbo-phenyl-lower alkoxy groups, in which the cycloalkyl or  Phenyl lower alkyl radical have the above meaning, e.g. B.  Represent carboadamantyloxy or carbo-benzyloxy groups. 



  Carboxylic lower alkoxy groups in which the lower alkyl radical is substituted by monocyclic, monoaza, monooxa or monothiacyclic groups are, for. B.     Carbo-furyl-lower alkoxy, such as carbofurfuryloxy, or carbo-thienyl-lower alkoxy, e.g. B.  Carbo-2-thenyloxy groups. 



   A lower alkanoic or lower alkene carboxylic acid is e.g. B.    



  Acetic, propionic, butyric, isobutteric, valeric, pivalic or acrylic acid, while a cycloalkane or cycloalkene or 



  Cycloalkyl or cycloalkenyl-lower alkane or lower alkenecarboxylic acid z. B.  means a cyclopentane, cyclohexane or 3-cyclohexenecarboxylic acid, cyclopentylpropionic, cyclohexyl acetic, 3-cyclohexenyl acetic or hexahydrocinnamic acid,
A mono- or bicyclic aromatic carboxylic acid is e.g. B.     Benzoic acid or 1- or 2-naphthalenecarboxylic acid, and a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid z. B.     Phenylacetic, phenylpropionic or cinnamic acid. 



   As heterocyclic carboxylic acids are nicotinic or isonicotinic acid, 2-thiophene, 2-furan, 2- or 4-quinoline or 1-isoquinoline carboxylic acid, and as corresponding lower alkanoic or lower alkene carboxylic acids substituted by heterocyclic radicals, for. B.  called 2-, 3- or 4-pyridyl acetic, 2-thienyl acetic, 2-furyl acetic, 2-furyl acetic or 2-furylacrylic acid. 



   The compounds of the present invention can exist in the form of mixtures of isomers or as pure isomers. 



   The compounds according to the invention have valuable, primarily pharmacological properties.  For example, compounds of the formula I in which R1 is preferably a hydrogen atom and an acyl radical R2 is in particular one of the acyl radicals occurring in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acids or 7-amino-cephalosporanic acids are against microorganisms, especially against gram -positive bacteria such as Staphylococcus aureus and Proteus vulgaris are effective.  In vitro tests with these compounds show, for. B.     Growth inhibiting effects on the above-mentioned organisms in dilutions up to 0.0001%. 



   The compounds of the formula I, in particular those in which R1 is a preferably easily split off organic residue of an alcohol and R2 represents a hydrogen atom or an acyl residue, or in which R1 stands for a hydrogen atom and R2 is a preferably easily split off acyl residue, e.g. .     represents the acyl radical of a carbonic acid half-derivative, in particular a carbonic acid half-ester, are valuable intermediate products which can be converted in a manner known per se into the above-mentioned pharmacologically active compounds. 



   In contrast to the known 7-amino-cephalosporanic acid compounds, which also have the 7-amino-8-oxo-5-thia-1 -azabicyclo [4,2, Ojoct-2-en-2-carboxylic acid basic structure, can in the present compounds an isomerization to the corresponding A3w4 compounds does not take place; It is known that this isomerization, which does not lead to the structurally more stable A3 4 isomers in the 7-amino-cephalosporanic acid series, is associated with a complete loss of pharmacological activity. 



   The invention relates primarily to compounds of the formula
EMI3. 1
 with the configuration of 7-amino-cephalosporanic acid or salts of such compounds with salt-forming groups, wherein R ', for a hydrogen atom, a lower alkyl, such as methyl or ethyl, especially tert. -Butyl-, and tert. -Pentyl, a halo-lower alkyl, primarily a 2-halo-lower alkyl, such as 2,2,2-trichloroethyl, a cycloalkyl, z. B.     Adamantyl radical, or a phenyl-lower alkyl, in particular diphenylmethyl radical, in particular an easily cleavable radical of the above type, R'2 is an acyl radical, especially one occurring in pharmacologically active N-acyl derivatives of 6-aminopenicillanic acid or 7-aminocephalosporanic acid Acyl radical, such as. B.  

   represents the radical of the formula Y- (CmH2m) -CO-, wherein m is an integer from 0 to 4, preferably 1, and one carbon atom of a preferably unbranched alkylene radical of the formula - (CmH2m) - is optionally substituted by an optionally substituted one Amino group, a free, etherified or esterified hydroxyl or mercapto group or a free or functionally modified carboxyl group, e.g. B.  may be substituted by one of the above groups of this type, and wherein Y is optionally in the nucleus, e.g. B. 

   such as the above alkylene radical, as well as by sulfo or nitro groups, substituted aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, preferably aromatic, or a hydroxy or mercapto group etherified by an aromatic or cycloaliphatic hydrocarbon radical or a heterocyclic radical, z. B. 



  a 2,6-dimethoxybenzoyl-, tetrahydronaphthoyl-, 2-methoxy-naphthoyl-, 2-ethoxy-naphthoyl-, phenylacetyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl-, 2-phenyloxypropionyl-, a-phenoxy-phenoxy- phenylacetyl-, methoxy-3, 4-dichlorophenylacetyl- oc-cyano-phenylacetyl- having phenyiglycyl- (optionally with protected amino group), benzyloxycarbonyl-, benzylthioacetyl-, benzylthiopropionyl-, hexahydrobenzylopentanoyl-, cyclopentanoxycarbonyl-, cyclopentanoyl or x-amino-cyclohexanoyl (optionally with a protected amino group), 2-thienylacetyl, a-cyano-2-thienylacetyl,, 0c-amino-2-thienyl-acetyl (optionally with a protected amino group), 3-thienylacetyl,

   2-furylacetyl, 2-phenyl-5-methylisoxazolyl-carbonyl or 2- (o-chlorophenyl) -5-methyl-isoxazolyl-carbonyl group, or a radical of the formula CnH2nslCO- or CnH2n, CO, where n is an integer up to 7 and the chain is straight or branched and optionally interrupted by an oxygen or sulfur atom or z. B.  may be substituted by halogen atoms, trifluoromethyl, free or functionally modified carboxyl, such as cyano, free or substituted amino or nitro groups, e.g. B. 

   a propionyl-, butyryl-, hexanoyl-, octanoyl-, butylmercapto-acetyl-, acrylyl-, crotonyl-, 2-pentennyl-, allylmercapto-acetyl-, chloroacetyl-, 3-chloropropionyl-, 3-bromo-propionyl-, aminoacetyl -, 2-carboxypropionyl, cyanoacetyl or 2-cyano-3-dimethyl-acroyl group, or a radical of the formula Z-NH-CO-, wherein Z represents an optionally substituted aromatic or aliphatic hydrocarbon radical, in particular a lower alkyl radical substituted by lower alkoxy groups and / or halogen atoms means, or then an easily cleavable acyl radical, especially the radical of a half ester of carbonic acid, such as a carbo-lower alkoxy, e.g. B.  Carbo-tert. -butyloxy-, carbo-tert. -pentyloxy or carbo-2,2,2-trichloroethyloxy radical, a carbo-cycloalkoxy, z. B. 

  Carbo-adamantyloxy, a carbo-phenyl-lower alkoxy, e.g. B.  Carbo-diphenylmethoxy, or a Carbo-furylniederalkoxy-, z. B.  Carbo-furfuryloxy, and R 'is a by lower alkyl, especially methyl, and lower alkanoyl, especially acetyl or propionyl, or by, optionally substituents, z. B.  those indicated above, such as aliphatic hydrocarbon radicals, e.g. B.  Lower alkyl groups, or etherified or esterified hydroxyl groups, e.g. B.    Lower alkoxy groups or halogen atoms, or phenyl groups containing nitro groups, as well as benzoyl groups are substituted methylene groups, these being only one (e.g. B.  a phenyl group) or up to two (e.g. B.  Lower alkyl groups) of the above-mentioned substituents may contain. 



   7-NR "2-amino-8-oxo -4-methylene-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids are particularly valuable as pharmacologically active substances and as intermediates or lower alkyl esters thereof, as well as salts such compounds with salt-forming groups in which R "2 is the acyl radical of a pharmacologically active 6-N-acylamino-penicillanic acid or 7-N-acylamino-cephalosporanic acid compound, such as one of the above radicals, or a carbo- lower alkoxy, especially the carbo-tert. -butyloxy group, the methylene group is substituted in the 4-position by one or two lower alkyl, especially methyl radicals, or by a phenyl radical optionally containing lower alkyl, lower alkoxy or nitro groups or halogen atoms, and the lower alkyl radical of the ester group is optionally, preferably in the 2-position ,

   may have one or more halogen atoms, and primarily for the tert. -Butyl-, and the 2,2,2-trichloroethyl radical. 



   The compounds of the present invention can be obtained by using a compound of the formula
EMI4. 1
 wherein R1 and R have the meanings given above, acylates the amino group.  If desired, an organic radical Rl of an alcohol in a compound obtained can be replaced by hydrogen or converted into another organic radical corresponding to the group R1, and / or, if desired, a compound containing salt-forming groups into a salt or a salt obtained into the free compound or converted into another salt, and / or, if desired, a mixture of isomers obtained can be separated into the individual isomers. 



   In the starting material of the formula II, R1 is primarily a hydrogen atom or an easily split off organic residue of an alcohol, e.g. B.  a reductively cleavable organic radical of an alcohol, e.g. B.  a 2-halo-lower alkyl, such as the 2,2,2-trichloroethyl radical, or an organic radical of an alcohol which can be split off under acidic conditions, such as a methyl radical which is polysubstituted by aliphatic or aromatic, optionally substituted hydrocarbon radicals, e.g. B.  the benzhydryl, trityl, tert. -Butyl-, tert. Pentyl or adamantyl radical. 



   The acylation of the free amino group can be carried out by methods known per se, e.g. B.  by treating with an acid, especially an organic carboxylic acid or acid derivative thereof, such as a halide, e.g. B.     Chloride, anhydride (including the internal anhydride of an organic carboxylic acid, i.e. H.  a ketene, or that of a carbamic or thiocarbamic acid, d. H.  an isocyanate or isothiocyanate, as well as a mixed anhydride is to be understood), or an activated ester.  If necessary, e.g. B.  when using the free acid as acylating agent, suitable condensing agents such as carbodiimides, e.g. B.     Dicyclohexylcarbodiimide, are used. 



   If desired, a starting material formed under the conditions of its preparation can be acylated without isolation. 



   In a compound obtainable according to the process, a suitably esterified carboxyl group can be released in a manner known per se.  So a z. B.  a polysubstituted methyl group, such as the benzhydryl, tert. -Butyl-, tert.  Esterified carboxyl group containing pentyl or adamantyl group can be liberated by treatment with an acid such as trifluoroacetic acid.  This reaction can be carried out simultaneously with the inventive, i. H.  ring closure carried out under acidic conditions, especially in the presence of trifluoroacetic acid.  Furthermore, z. B.  a carboxyl group esterified by a 2-halo-lower alkyl group, such as the 2,2,2-trichloroethyl group, reductively, e.g. B. 

 

  by treatment with a chemical reducing agent such as nascent hydrogen, e.g. B.  by the action of metals, metal alloys or amalgamations on hydrogen-releasing agents such as zinc, zinc alloys, e.g. B.  Zinc copper, or zinc amalgam in the presence of acids such as organic carboxylic acids, especially lower alkanecarboxylic acids, e.g. B.  Acetic acid, such as 90% aqueous acetic acid, or alcohols, such as lower alkanols, optionally in the presence of acids, or alkali metal, e.g. B.  Sodium or potassium amalgam or aluminum amalgam, in the presence of moist ether or lower alkanols, furthermore with reducing metal salts such as 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, lower alkanecarboxylic acid or ethers, e.g. B.  Methanol, ethanol, acetic acid, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether are released. 



   Compounds with a free carboxyl group can in a conventional manner, for. B.  in their salts, such as B.  Sodium or potassium, alkali or alkaline earth metal, e.g.     Calcium or magnesium, or ammonium salts, are converted, e.g. B.  be released with or from ammonia or amines. 



   Free carboxy groups can be prepared by methods known per se, e.g. B.  by treating with a diazo compound such as a diazo-lower alkane, for example, diazomethane or diazo ethane, or a phenyl-diazo-lower alkane, e.g. B.  Phenyldiazomethane or diphenyldiazomethane, or by reacting with a hydroxy compound suitable for esterification, such as. B.  an alcohol, 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 or the acid with a reactive ester of the hydroxy compound, especially an alcohol, and a strong inorganic acid or a strong organic sulfonic acid. 

  Furthermore, acid halides, in particular chlorides, and activated esters, such as. B.     Esters with N-hydroxy nitrogen compounds, or mixed anhydrides formed with haloformic acid esters, can be converted into esters by reaction with hydroxy compounds such as alcohols, optionally in the presence of a base such as pyridine. 



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. B.  separated into the individual isomers by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other methods.  Racemates obtained can in the usual way, for. B.  be separated 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 in the antipodes, preferably the more active antipode isolated. 



   The process also includes those embodiments according to which starting materials are used in the form of derivatives or are formed during the reaction. 



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



   The starting materials used according to the process can be, for. B.  after that in switzerland.  Patent No.    537415 can be prepared by adding a compound of the formula
EMI5. 1
 wherein Ro2 represents an acyl radical Ac which is split off under the acidic conditions of the process under which the starting materials of the formula II are prepared, R represents an organic radical and Ri represents a hydrogen atom, or R ″ and R4 together represent a disubstituted carbon atom with a glyoxylic acid ester of the formula O = CH- -COORO, (III), in which R 1 is the organic radical of an alcohol, in particular one of the above-mentioned easily cleavable radicals,

   or a derivative, e.g. B.  a hydrate thereof is reacted at an elevated temperature, primarily at about 50 "C to about 1500C, in the absence of a condensing agent and / or without the formation of a salt, the water formed when the hydrate is used, if necessary, by distillation, z. B.  azeotropic, can remove. 



   An acyl radical which can be split off under acidic conditions is in particular, for example.     the carbo-tert. -butyloxy-, as well as Carbo4eft- -pentyloxy-, Carbo-vinyloxy-, Carbo-adamantyloxy- or Carbo-furfuryloxy radical.    



   An optionally substituted hydrocarbon radical R represents primarily a cleavable, preferably unsaturated aliphatic hydrocarbon radical, such as lower alkenyl, especially 2-propenyl radical, or a hetero radical, e.g. B.  by an etherified or esterified hydroxyl group, e.g. B.  a lower alkoxy or lower alkanoyloxy group or a halogen atom, or a halogen atom-substituted aliphatic hydrocarbon radical, such as lower alkyl, e.g.     Methyl, ethyl, n-propyl or isopropyl radical, as well as a corresponding cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical, preferably unsaturated in the linkage position or substituted by a hetero radical. 



   Substituents of a disubstituted carbon atom, which is represented by the two radicals R8 and R4 together, are optionally substituted hydrocarbon radicals, such as optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals.  The two substituents of the disubstituted carbon atom can also be taken together and z. B.  represent an optionally substituted and / or interrupted by heteroatoms divalent, aliphatic hydrocarbon radical.  The two radicals R8 and R4 together represent a carbon atom which is preferably disubstituted by lower alkyl, in particular methyl groups. 



   In such a obtainable compound of the formula
EMI5. 2
  can the hydroxy group by treatment with a suitable th esterifying agent, for. B.  a halogenating agent such as a thionyl halide, e.g. B.  chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium halide such as triphenylphosphine dibromide or iodide, or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily an organic basic agent, such as an aliphatic tertiary amine, z. B.  Triethylamine or diisopropyl ethylamine, or a heterocyclic base of the pyridine type, e.g. B.  Pyridine or collidine, can be converted into a reactive esterified hydroxyl group, primarily into a halogen atom, or into an organic sulfonyloxy group. 



   By implementing such an available.  Compound of formula
EMI6. 1
 wherein X is the reactive esterified hydroxyl group, primarily a halogen, especially a chlorine or bromine, and an iodine atom, but also an organic, primarily an aliphatic or aromatic sulfonyloxy, z. B.  an optionally substituted lower alkylsulfonyloxy, such as methylsulfonyloxy, ethylsulfonyloxy or 2-hydroxy-ethylsulfonyloxy, or an optionally substituted phenylsulfonyloxy, z. B.  4-methylphenylsulfonyloxy, 4-bromo-phenylsulfonyloxy or 3-nitro-phenylsulfonylox group, with a phosphine compound of the formula
EMI6. 2
 wherein each of the groups Ra, Rb and RG represents an optionally substituted hydrocarbon radical, primarily an optionally substituted lower alkylene or phenyl, e.g. B. 



  n-Butyl or phenyl radical, preferably in the presence of an inert solvent, is obtained, if necessary, after the elements of the acid of the formula H-x have been split off, which, for. B.  by treatment with a weak, especially an organic base, e.g. B.  Diisopropylethylamine or pyridine can be done, a phosphoranylidene compound of the formula from a phosphonium salt compound available as an intermediate
EMI6. 3
   When treating with a compound of the formula
EMI6. 4th
 wherein Ro stands for one, containing at least one hydrogen atom, by one or two optionally substituted hydrocarbon radicals, optionally substituted heterocyclic radicals or optionally substituted heterocyclicaliphatic radicals, in which one heterocyclic group has aromatic character,

   or functional groups substituted methyl radical, or a reactive derivative, in particular a hydrate thereof, preferably at elevated temperature, e.g. B.  at about 50 "C to about 150" C, compounds of the formula IVa are obtained from compounds of the formula
EMI6. 5
 which can be obtained by ring closure under acidic conditions, e.g. B. 



  by treatment with a strong, preferably oxygen-containing inorganic or organic acid, e.g. B.  organic carboxylic or sulfonic acid, in particular with a strong, preferably halogen-substituted lower alkanecarboxylic acid, optionally substituted by hetero radicals, such as an a: haloacetic acid or cc-halopropionic acid, in which halogen preferably denotes fluorine and chlorine, primarily trifluoroacetic acid, being in the absence or in the presence of an inert solvent, e.g. B. 

  Dioxane, or a mixture of diluents, preferably with cooling, e.g. B.  at temperatures from about -300 ° C. to about + 10 ° C., preferably at about -25 ° C. to about OOC, if necessary, can work in an inert gas atmosphere, into compounds of the formula II.  In these an easily cleavable residue RO, in a manner known per se, z. B.  as stated above, are split off. 



   The intermediates of the formula (IIIa) used in the preparation of the starting materials, in which R3 and R4 together represent a disubstituted carbon atom, are known.  Others in which R8 is a removable organic radical and R4 is a hydrogen atom can, for. B.  be obtained if the carboxyl group in a 6-N-acylamino-18-penicillanic acid compound is converted into an isocyanato group in a manner known per se, the compound thus obtained with a 2-halo-lower alkanol, e.g. B. 

 

     2,2,2-TA-chloroethanol or 2-iodoethanol, treated, and in the 6-acylamino-2- (N-carbo-2-halo-lower alkoxy-amino) -3, 3 -dimethyl-4-thia formed in this way - 1 -azabicyclo [3.2-0] heptan-7-one compound the substituent in the 2-position by treatment with a chemical reducing agent, e.g. B.  Zinc in the presence of 90% acetic acid splits.  The corresponding 6-acylamino-2-hydroxy-3,3-dimethyl-4-thia-1-azabicyclo [3.2.0] heptan-7-one compound is obtained in this way, which is obtained on treatment with a heavy metal acylate oxidizing agent , in particular a lead IV carboxylate, such as lower alkanoate, for example.  Lead retraacetate, usually under illumination, preferably with ultraviolet light, can be converted into a 3-acylamino -2- (2-acyloxy-2-propylmercapto) -1-formyl-azetidin-4-one compound. 

  By heating, the acyloxy group can, if desired, be split off together with hydrogen and with formation of the 2-propenyl mercapto group in the form of the corresponding acid.  The formyl group attached to the ring nitrogen atom can be removed by treatment with a suitable decarbonylating agent such as a tris (tri-organically substituted phosphine) rhodium halide, e.g. B.  Tris (triphenylphosphine) rhodium chloride, in a suitable solvent, e.g. B.  Benzene, or with conversion into the carbinol group z. B.  by treatment with catalytically activated hydrogen in the presence of a palladium catalyst and glacial acetic acid or hydrochloric acid tetrahydrofuran. 

  If desired, in a compound obtainable by the above process, the 2-acyloxy-2-propyl radical by treating with a weakly basic agent such as an alkali metal hydrogen carbonate or pyridine, in the presence of a reactive ester of an alcohol such as a suitable halide, by another organic residue can be replaced. 



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



   Example I.
A solution of 0.1211 g of the isomer A of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid-tert. Butyl ester in 1.2 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 21 hours, then diluted with 9 ml of dioxane.  The mixture containing the 7-amino-4enzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) is with a solution of 0.129 g of phenyloxyacetyl chloride in 1 ml of dioxane was added.  After standing at room temperature for 21% hours, the reaction mixture is treated with 1 ml of water and left to stand for a further hour. 

  The volatile components are removed by lyophilization under high vacuum and the residue is chromatographed on 9 g of acid-washed silica gel.  With a 100: 5 mixture of benzene and acetone, phenyloxyacetic acid and a small amount of a neutral material and with a 2: 1 mixture of benzene and acetone the 4-benzylidene-7-N-phenyloxyacetyl amino-8-oxo-5- thia-1 -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI7. 1
 eluted which, after recrystallization from a mixture of acetone and benzene, melts in the form of yellowish crystals at 191-1930 (decomposition); Thin layer chromatogram:

  Rf 0.36 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol, # max349 m and 250-265 m (shoulder); in potassium hydroxide / ethanol, # max345 m and 250-265 m (shoulder); and in hydrogen chloride / ethanol, # max357 m and 250-265 m (shoulder); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.204.15, 5.62, 5.70 (shoulder), 5.82-5.95, 6.00 + (shoulder), 6.106.15 ç and 6.23-6.3311 (inflection). 



   Example 2
A solution of 0.5625 g of the isomer A of cc- (2-carbo- tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3, 2to] heptyl) ax- (phenylacetylmethylene) acetic acid tert. Butyl ester in 4 ml of trifluoroacetic acid pre-cooled to -20 is left to stand for 20 hours at 200 and for one hour at room temperature.  It is diluted with 30 ml of dry dioxane, and the mixture, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of 7-Amino-cephalosporic acid), with a solution of 0.5 g of freshly distilled phenylacetic acid chloride in 5 ml of dioxane. 

  The reaction mixture is left to stand for 3 hours at room temperature, then 2 ml of water are added; it is left to stand for one hour at room temperature, then cooled to -100 and the volatile components are evaporated by lyophilization under high vacuum.  The residue is taken up in 4 ml of benzene, whereupon crystallization begins. 

  The crystalline material is filtered off after 24 hours and washed with benzene; the 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) of the formula
EMI7. 2
 after recrystallization from 90% aqueous ethanol at 224. 2260 melts; Thin layer chromatogram:

  Rf 0.30 (silica gel; in the system toluene / acetic acid / water 5: 4: 1); Ultraviolet absorption spectrum: in ethanol, #max 353 m11 and 250-265 m11 (shoulder); in potassium hydroxide / ethanol, # max347 m, 250.265 m and 240 m (shoulder); and in hydrogen chloride / ethanol, # max358 m and 250-265 m infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 (shoulder), 3.10-4.1011, 5.65, 5.75 (shoulder), 5 , 80 x (shoulder), 5.90-5.95 e, 6.00 u (shoulder), 6.15, 6.24 (shoulder), 6.28 (shoulder), 6.55, 6.65 and 6.73 (shoulder).    

 

   The mother liquor is chromatographed on 10 g of acid-washed silica gel; with a 100: 5 mixture of benzene and acetone is phenylacetic acid together with a yellow neutral material and then with a 2: 1 mixture of benzene and acetone another amount of 4-benzylidene-7-N-phenylacetyl-amino-8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid eluted, which crystallized after adding a little acetone, F.    223. 2250.    



   Example 3
A solution of 0.0917 g of the isomer A of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicydo- [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid-tert. Butyl ester in 1 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 21 hours, then diluted with 7 ml of dioxane.  The mixture obtained, containing the 7-amino-4-benzylidene-8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) is treated with 10 drops of acetic acid chloride.  The reaction mixture is left to stand for 3 hours at room temperature, the excess acetic acid chloride is removed under reduced pressure (oil pump) and 0.8 ml of water is added. 

  After a further hour at room temperature, the volatile components are evaporated under reduced pressure (± S1 pump) and the residue is dissolved in 0.7 ml of benzene.  The 7-N-acetyl-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of formula
EMI8. 1
 crystallizes out, F.  160-1640; Thin-layer chromatogram: Rf 0.16 (silica gel; in the system toluene / acetic acid / water 5: 4: 1);

  Ultraviolet absorption spectrum: in ethanol, #max 354 mlr and 250-265 mlt (shoulder); in ethanol / potassium hydroxide, #ma 346 m, 250-265 m and 250 m (shoulder), and in ethanol / hydrogen chloride, #max 357 m! and 250-265 ms, (shoulder); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.15-4.20, 5.63-5.71, 5.75 (shoulder), 5.80-5.94 (inflection), 6.00 (shoulder), 6.04-6.13 and 6.40-6.70 (inflection). 



   The mother liquor is chromatographed on 5 g of acid-washed silica gel; a further amount of the desired 7 -N-acetylamino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- is eluted with a 4: 1 mixture of benzene and acetone en-2-carboxylic acid together with a neutral product which is enriched in the first fractions. 



   Example 4
A suspension, cooled in ice water, of 0.0198 g of 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2- carboxylic acid in 1.5 ml of methanol is treated in portions with an excess of a 2% solution of diazomethane in ether; the development of nitrogen starts immediately u.  the solid material dissolves.  The addition of diazomethane is stopped as soon as the yellow discoloration persists for 2-3 minutes.  The volatile components are removed in a rotary evaporator and the residue is crystallized by adding a few drops of methanol. 

  The 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester (configuration of the 7th -Amino-cephalosporanic acid) of the formula
EMI8. 2
 melts at 193-195.5; [alD20 = -325 + 10 (c = 1 in chloroform); Thin layer chromatogram:

  Rf = 0.22 (silica gel; in the system hexane / ethyl acetate 2: 1); Ultraviolet absorption spectrum: in ethanol #max 360 mm (± = 24800) and 262 mS (± = 8100; shoulder); in potassium hydroxide / ethanol #max 3.62 mlt and 250 mlQ (shoulder); and in hydrogen chloride / ethanol #max 362 m and 250-265 m (shoulder);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 5.62 lt, 5.82, 5.95, 6.00 (shoulder), 6.24 + z, 6.30 (shoulder), 6.62 lt (Shoulder) and 6,656,73, u-
Example p
A mixture of 0.1158 g of a- (2-carbo-tert. -butyloxy-3,3- -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (isobutyrylmethylene) -acetic acid-tert. Butyl ester (isomer A) in 1 ml of pre-cooled trifluoroacetic acid is left to stand at 200 for 22 hours. 

  5 ml of dry dioxane are added and the mixture containing the 7-amino -4-isopropylidene-8-oxo-5-thia-1 is treated. azabicyclo [4,2, O] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid), with 0.123 g of phenylacetyl chloride.  After standing for 3 hours at room temperature, 10 drops of water are added and, after a further hour, the volatile components are distilled off under high vacuum.  The oily residue is chromatographed on 10 g of acid-washed silica gel. 



  With a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral product are eluted.  The 4-isopropylidene-7-N-phenylacetyl-amino-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI8. 3
 is washed out with a 2: 1 mixture of benzene and acetone. 

  After crystallization from benzene, containing a small amount of acetone, it melts at 216-219; Infrared absorption spectrum: in ethanol,). max 326 mlt; in potassium hydroxide / ethanol, lmax 317 mlt; and in hydrogen chloride / ethanol, lmsx 332 mull; Infrared absorption spectrum (in potassium bromide):

   characteristic bands at 3.00 lt (shoulder), 3.15-4.35 p,
5.60, 5.65 (shoulder), 5.90, 6.04, 6.25, 6.30 (shoulder) and 6.45-6.55 1t-
Example 6
A mixture of 0.128 g of the isomer A of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - [(4-nitro-phenylacetyl) -methylene] -acetic acid- -tert. Butyl ester in 1 ml of trifluoroacetic acid is left to stand at 200 for 44 hours. 

  The orange-colored reaction mixture containing the 1-amino-4- (4-nitrobenzylidene) - -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7th -Amino-cephalosporanic acid), is then diluted with 5 ml of dry dioxane and mixed with a solution of 0.155 g of phenylacetyl chloride in 2 ml of dioxane.  After standing for three hours at room temperature, 0.5 ml of water is added and, after a further 60 minutes at room temperature, the volatile components are removed under an oil pump vacuum.  A few drops of methylene chloride and benzene are added to the residue; an orange-yellow precipitate forms, which is filtered off and washed on the filter with a few drops of methylene chloride. 

  This gives 4- (4-nitro-benzylidene) -7-N-phenylacetyl-amino-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid ( Configuration of 7-amino-cephalosporanic acid) of the formula
EMI9. 1
 which, after recrystallization from a mixture of acetone and benzene, melts at 202-204; I Ultraviolet absorption spectrum in ethanol: #max 390 m and 273 m (weak), in potassium hydroxide / ethanol: lm. x 398 m and about 275 (weak), u.  in hydrochloric acid / ethanol: man 392 and about 275 m (weak);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.9-4.2 (broad), 5.60-5.65, 5.80-6.0, 6.05, 6.25, 6.60 y and 7 , 45,.    



   Example 7
A solution of 0.023 g of crude 4- (4-nitro-benzylidene) -7-N-phenylacetyl -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- obtained from crystallization mother liquor en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) in 1 ml of methanol is treated with an excess of diazomethane in ether and left to stand for a few minutes at room temperature, then evaporated in a rotary evaporator. 



   The residue is purified by means of thin layer chromatography (silica gel plate; 20 × 10 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate and with ethyl acetate alone.  The orange band is extracted with ethyl acetate and the 4- (4-nitro-benzylidene) -7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- is obtained. en-2-carboxylic acid methyl ester (configuration of 7-amino-cephalosporanic acid) of the formula
EMI9. 2
 which crystallizes after standing for a long time, F.    185-187 (with decomposition);

  Ultraviolet absorption spectrum in ethanol: #max 382 m and 278 m (shoulder), in potassium hydroxide / ethanol: max 380 mull and 278 m (shoulder), and in hydrochloric acid / ethanol: #max 378 m and 278 m (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.60, 5.81, 5.95 (, 6.24-6.30, 6.60-6.65, 6.70 (shoulder) and 7.46 t
Example 8
A solution of 0.12 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2, 0] heptyl-α - [(4-methoxy-phenylacetyl) -methylene] -acetic acid-tert. Butyl ester in 1 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 2 hours. 

  The reaction mixture containing the 7-amino-4- (4-methoxybenzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino -cephalosporanic acid), 5 ml of dioxane are added and the mixture is treated with a solution of 0.154 g of phenylacetyl chloride in 2 ml of dry dioxane.  After 3 hours at room temperature, 10 drops of water are added and the solution is left to stand for a further hour.  The volatile components are then evaporated off under high vacuum and the oily residue is chromatographed on 10 g of acid-washed silica gel (column). 



  The excess phenylacetic acid is washed out with benzene containing 5% acetone, together with a yellow colored product.  The 4- (4-methoxybenzylidene) -7-N-phe nylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) of the formula
EMI9. 3
 is eluted with a 2: 1 mixture of benzene and acetone and, after crystallization from a mixture of acetone and benzene, melts as a yellow product at 201-203; Ultraviolet absorption spectrum in ethanol: lmax 366 CL and 275 (shoulder), in potassium hydroxide / ethanol: one 356 m and 272 m (shoulder), and in hydrochloric acid: ethanol: #max 372 m and 277 m (shoulder);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.95 (shoulder), 3.014.40, 5.64-5.70, 5.75 (inflection), 6.04-6.10, 6.28 and 6.61
Example 9
A mixture of 0.0052 g of 4- (4-methoxybenzylidene) -7-N -phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid (Configuration of 7-amino-cephalosporanic acid) in 2 ml of methanol is mixed with 2 ml of a 2% ethereal diazomethane solution.  The mixture is left to stand for 3 minutes at room temperature, the volatile components are then evaporated and the residue is crystallized from a mixture of methanol and ether. 

  The 4- (4-methoxybenzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4,2.0] oct-2-carboxylic acid methyl ester (configuration of the 7-amino -cephalosporanic acid) of the formula
EMI10. 1
 melts at 210-2110; Ultraviolet absorption spectrum in ethanol: #max 378 m and 278 nu (shoulder), in potassium hydroxide / ethanol): lmax 376 m and 278 m (shoulder), and in hydrochloric acid / ethanol: one 374 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 5.60, 5.80, 5.91, 6.26, 6.60-6.65 and 7.12. 



   Example 10
A solution of 0.232 g of the isomer A of a- (2-carbo-tert. -butyloxy-3, 3 -dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) -? - [(4-chlorophenylacetyl) -methylene] - - acetic acid tert. butyl ester in 2 ml of trifluoroacetic acid for 21 hours at 200.  After a further 20 minutes at room temperature, 15 ml of dry dioxane are added and 0.25 g of freshly distilled phenylacetyl chloride is added to the mixture containing the 7-amino-4- (4-chlorobenzylidene) -8-oxo-5-thia-1 -azabicyclo [4,2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (4-chlorobenzylidene) - # -cephem-4-carboxylic acid. 

  The reaction solution is kept at room temperature for 3 hours, then 0.3 ml of water is added and the mixture is left to stand at room temperature for one hour.  The volatile constituents are removed under reduced pressure (oil pump, room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel. With 250 ml of a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral by-product are washed out. 

  With a 2: 1 mixture of benzene and acetone, the 4- (4-chlorobenzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en-2- carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2- (4-chlorobenzylidene) -7-N-phenylacetylamino -A3-cephem-4-carboxylic acid of the formula
EMI10. 2
 eluted, which crystallizes in the form of yellowish crystals on addition of a little benzene and ethyl acetate, F.    226-227; Ultraviolet Absorption Spectrum: Imar 359 (in ethanol); #max 351 m (in potassium hydroxide / ethanol) and lmax 362 mp (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.85-4.30 (broad), 3.02, 5.62, 5.88, 6.15, 6.26 j ", 6.55 pr, and 6.70 . 



   Example 11
A solution of 0.3285 g of the isomer A (trans) of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) rn- (cyclohexyl-acetyl-methylene) -acetic acid-tert. Butyl ester in 2.3 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 16 hours. 



  The reaction mixture containing the 7-amino-4-cyclohexyl methylene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) or 7-amino-2-cyclohexylmethylene-A3-cephem-4-carboxylic acid, 0.13 g of phenylacetyl chloride in 14 ml of dioxane is added and the mixture is kept at room temperature for 3 hours. 



  After a further hour, 0.3 ml of water is added, the volatile components are removed under reduced pressure (oil pump: room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel.  Phenylacetic acid and a small amount of neutral substances are removed with a 100: 5 mixture of benzene and acetone, and the 4-cyclohexylmethylene-7-N-phenylacetyl-amino-8-oxo is eluted with a 2: 1 mixture of benzene and acetone -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-cyclohexylmethylene-7-N-phenylacetyl-amino-dS3-cephem -4-carboxylic acid of the formula
EMI10. 3
 which, after crystallization from benzene, melts at 120-121; Ultraviolet absorption spectrum:

   ) max 317 m (in ethanol), #max 309 m (in potassium hydroxide / ethanol) and #max 309 r (in potassium hydroxide / ethanol) and #max 323 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 3.45 ,, 3.53, 2.85-4.3 (broad), 5.61, 5.70-5.85 (broad), 5, 94 6.05 p (shoulder), 6.24 IL and 6.60-6.70 y.    



   Example 12
A mixture of 0.4 g of a- (2-Carbo-terL-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid-tert. butyl ester in 4 ml of trifluoroacetic acid is left to stand at -20 for 20 hours; the trifluoroacetic acid is removed under reduced pressure (oil pump) and the orange residue containing the 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2-benzylidene- # -cephem- 4-carboxylic acid, mixed with 4 ml of a solution, cooled to 150, of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride.  (The mixed anhydride can be obtained as follows:

  A mixture of 1.45 g of cyanoacetic acid in 3 ml of methylene chloride is mixed with 1.1 ml of triethylamine and the resulting solution, cooled to -5, is added with stirring to a solution of 1.45 g of trichloroacetyl chloride in 3 ml of methylene chloride which is kept at 150.  A suspension is thus obtained which is brought to a volume of 14 ml at 150 with methylene chloride and is used in this form).  The reaction mixture is mixed with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride, stirred for 2 hours at room temperature and then diluted with 30 ml of ethyl acetate. 

  It is washed with a concentrated sodium chloride solution containing hydrochloric acid in water (15 ml of the sodium chloride solution contains 1.5 ml of l-n.     Hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  About 1 ml of ethyl acetate is added to the residue and the mixture is carefully diluted with ether and then left to stand.  The crystalline 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-en-2-carboxylic acid (configuration of 7-amino -cephalosporanic acid) or 2-benzylidene-7-N-cyanoacetylamino- # -cephem-4-carboxylic acid of the formula
EMI11. 1
 F.    215-216 (with decomposition). 



   The residue from the mother liquor is chromatographed on 20 g of acid-washed silica gel, using a 100: 5 mixture of benzene and acetone, neutral components, cyanoacetic acid and trichloroacetic acid and a 2: 1 mixture of benzene and acetone, a further amount of the desired product eluted, which, after crystallizing from ethyl acetate and ether, melts at 225-2270 (decomposition); Ultraviolet absorption spectrum: # max @ 353 n and 240-265 m (broad shoulder) (in ethanol), #max 346 m and 248 rns (shoulder) (in potassium hydroxide / ethanol) and @max 356 m and 247 m (shoulder) (in Hydrogen chloride / ethanol);

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90-4.20, 4.42, 5.60 m, 5.855.90, 5.98, 6.22 and 6.45. 



   Example 13
A solution of 0.023 g of 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclol4,2,0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid ) in about 2 ml of methanol is treated with a large excess of a 2% solution of diazomethane in ether.  After standing for two minutes at room temperature, the excess of the diazomethane and the solvents are evaporated and the crystalline residue is purified by preparative thin layer chromatography on a silica gel plate using a 95: 5 mixture of chloroform and methanol. 

  The 4-benzylidene-7-N-cyanoacetylamino -8-oxo-5-thia-1-azabicyclo [4,2.0] oct-2-ene-carboxylic acid methyl ester (configuration of the 7-amino-cephalosporanic acid) or 2- Benzylidene-7-N-cyanoacetyl-amino- & -cephem. 4-carboxylic acid methyl ester of the formula
EMI11. 2
 is obtained in crystalline form, F.  232-234;

  Ultraviolet absorption spectrum: #max 356 m and 247-265 mlt (broad shoulder) (in ethanol), # max364; m; and 253 mp (in potassium hydroxide / ethanol) and #max 364 m and 254 with (when acidifying the alkaline sample with hydrogen chloride / ethanol); Infrared absorption spectrum (in mineral oil): characteristic bands at 3.1, 5.60-5.64, 5.80 Iz 5.98! 1Q, 6.20, 6.45 and 6.50 L (shoulder). 



   Example 14
A mixture of 0.328 g of a- (2-Carbo-tert-butyloxy-3,3- -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α- (4-nitrophenylacetyl-methylene) -acetic acid-tert. Butyl ester and 3 ml of trifluoroacetic acid is left to stand at 200 for 44 hours. 

  The trifluoroacetic acid is removed under reduced pressure (oil pump) and the residue, containing the 7-amino-4- (4-nitrobenzylidene) -8-oxo-5-thia-1-azabicyclo- [4.2.0] oct-2 -en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (4-nitro-benzylidene) - # - -cephem-4-carboxylic acid, with 3 ml of a solution of the mixed anhydride of cyanoacetic acid and Trichloroacetic acid in methylene chloride (preparation, see Example 12), followed by 1.5 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.  

  The reaction mixture is kept at room temperature for 2 hours, then diluted with 15 ml of ethyl acetate and treated with concentrated aqueous sodium chloride solution containing hydrochloric acid (10 ml of sodium chloride solution contain 1 ml of l-n.     Hydrochloric acid) and washed with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The residue is chromatographed on 10 g of acid-washed silica gel. 

  With a 100: 5 mixture of benzene and acetone, the excess of cyanoacetic acid and trichloroacetic acid and an orange neutral component and with a 2: 1 mixture of benzene and acetone the amorphous yellow-orange 7-N-cyanoacetylamino-4- (4-nitro-benzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-en-2-carboxylic acid (configuration of the 7-amino. cephalosporanic acid) or 7-N-cyanoacetylamino-2- (4-nitro-benzylidene) -A8-cephem-4-carboxylic acid of the formula
EMI12. 1
 eluted;

  Ultraviolet absorption spectrum: #max 388 m and 275 m (in ethanol), #max 453 mL and 263 m (in potassium hydroxide / ethanol) and lmax 420 m and 263 mv, (after acidifying the alkaline sample with hydrogen chloride / ethanol); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.8-4.2, 5.60-5.65, 5.80-6.07 4, 6.25 x, 6.60 and 7.45 p.    



   Example 15
A solution of 0.058 g of the isomer A of 0c- (2-Carbo- -tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid-tert. -butyl ester in 1.5 ml of acetic acid, which contains 0.015 g of p-toluenesulfonic acid, is left to stand for 18 hours at room temperature, then diluted with 12 ml of dioxane. The solution obtained is with 0.08 g of phenylacetyl chloride and after 3 hours with 0 , 5 ml of water added.  The reaction mixture is left to stand for one hour at room temperature, the volatile components are then evaporated off under high vacuum and at room temperature, and the residue is chromatographed on 10 g of acid-washed silica gel. 



  With a 100: 5 mixture of benzene and acetone, the excess phenylacetic acid and a neutral fraction, which contains a small amount of 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [ 4.2.0] oct-2-en-2-carboxylic acid tert. -butylesters (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7-N-phenylacetyl -amino- # -cephem-4-carboxylic acid tert. butyl ester of the formula
EMI12. 2
 contains; Ultraviolet absorption spectrum: #max 356 according to (in ethanol, potassium hydroxide / ethanol or hydrogen chloride ethanol). 

  The 4-benzylidene-7-N-phenylacetyl-amino-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-ene is eluted with a 2: 1 mixture of benzene and acetone -2-carboxylic acid, which is identical to the product of the process described in Example 2. 



   Example 16
A mixture of 0.35 g of the isomer A of a- (2-Carbo 4ert -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3.2, 0] heptyl) -α- (isobutyrylmethylene) -acetic acid-tert. Butyl ester in 2.8 ml of trifluoroacetic acid is left to stand at -20 for 24 hours and the trifluoroacetic acid is then distilled off in a high vacuum at room temperature. 

  The residue containing the 7-amino-4-isopropylidene-8-oxo-5-thia- -1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 7-Amino-2-isopropylidene-A3-cephem-4-carboxylic acid is mixed with 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation: see Example 12), then with 2 ml of a solution of 0, Treated 3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.  The resulting solution is left to stand for 2 hours at room temperature.  It is diluted with 40 ml of ethyl acetate and the organic solution is washed with 15 ml of water, 2 ml of 2-n.  Hydrochloric acid and twice with a saturated aqueous sodium chloride solution. 

  The aqueous phases are extracted with a small amount of ethyl acetate and the combined organic solutions are dried over sodium sulphate and then evaporated.  The residue is treated with a mixture of benzene and acetone; 7-N-cyanoacetyl-amino-4-isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7th -Amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino-2-isopropylidene- # -cephem-4-carboxylic acid of the formula
EMI12. 3
 F.  over 2750; Ultraviolet absorption spectrum: in ethanol #max 327 m; in ethanol / potassium hydroxide #max 320 m; and in ethanol / hydrogen chloride #max 333 m;

  Infrared absorption spectrum (potassium bromide): characteristic bands at 2.90-4.20, 5.64, 5.75 (shoulder), 5.98, 6.22-6.40 and 6.45. l-
The mother liquor is purified on 10 g of acid-washed silica gel; with a 100: 5 mixture of benzene and acetone is prewashed and with a 2: 1 mixture of benzene and acetone, after treatment with a few drops of benzene and acetone, a further amount of 7-N-cyanoacetyl-amino-4 is obtained -isopropylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid. 



   Example 17
A mixture of 0.42 g of isomer A of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) -α - [(4-chlorophenylacetyl) -methylene] -es - Acetic acid tert. -butylesters in 3.1 ml of trifluoroacetic acid during 23 hours at -20 and then the trifluoroacetic acid is distilled off under high vacuum at room temperature. 



  The residue containing the 7-amino-4- (4-chlorobenzylidene) 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) or 7-amino-2- (4-chlorobenzylidene) - # -cephem-4-carboxylic acid, 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation: see Example 12) are added, then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride. The solution is left to stand for 2 hours at room temperature, then diluted with 40 ml of ethyl acetate and shaken with 15 ml of water, with 2 ml of a 2- n. 

  Hydrochloric acid and twice with a concentrated aqueous sodium chloride solution; the aqueous solutions are each extracted with a small amount of ethyl acetate.  The combined organic solutions are dried over sodium sulfate and evaporated; the residue is treated with 3 ml of ethyl acetate and 4 ml of ether and the 4- (4-chlorobenzylidene) -7-N-cyanacetyl-amino-8-oxo-5-thia-1 -azabicyclo [4.2, 0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2 - (- 4-chlorobenzylidene) -7-N-cyanoacetylamino- # -ce- phem-4-carboxylic acid of the formula
EMI13. 1
 F.  252-253;

  Ultraviolet absorption spectrum: in ethanol #max 358 m; in ethanol / potassium hydroxide #max 365 m, and after acidifying the ethanol / potassium hydroxide sample with hydrogen chloride #max 369 m; Infrared absorption spectrum (potassium bromide): characteristic bands at 2,874.30, 5.60, 5.65 (shoulder), 5.85 (shoulder), 6.00, 6.39-6.42, 6.47 4 (shoulder) and 6.57-6.62 (shoulder). 



   The residue from the mother liquor is chromatographed on 10 g of acid-washed silica gel.  It is pre-washed with a 95: 5 mixture of benzene and ethyl acetate and a further amount of 4- (4-chlorobenzylidene) -7-N-cyanoacetyl-amino-8-oxo is eluted with a 2: 1 mixture of benzene and ethyl acetate -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, which is purified by crystallization from a mixture of ethyl acetate and ether.    



   Example 18
A mixture of 0.367 g of isomer A of α- (2-carbo- tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo - [3.2.0] heptyl) -? - [(3-phenylpropionyl) -methylene] - acetic acid -: ert - butyl ester in 3 ml of trifluoroacetic acid is left to stand at 200 for 22 hours and the trifluoroacetic acid is then distilled off under high vacuum at room temperature. 

  The residue, containing the 7-amino-8-oxo-4- (2-phenyl-1,1-ethylidene) -5-thia-1-azabicyclo [4.2.0] oct-2-ene-carboxylic acid ( Configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (2-phenyl-l, l-ethylidene) -A3-cephem-4-carboxylic acid, is mixed with 4 ml of a pre-cooled solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in Methylene chloride (manufacture:

   see Example 12), then treated with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride. After standing for 2 hours at room temperature, it is diluted with 40 ml of ethyl acetate and the mixture with 15 ml of water, with 2 ml of 2 -n.     Hydrochloric acid and washed twice with a saturated aqueous sodium chloride solution;

   the aqueous solutions are each extracted with ethyl acetate. The combined organic solutions are dried over sodium sulfate and evaporated. The 7-N-cyanoacetylamino-4- (2-phenyl-1,1-ethylidene) -8-oxo-5-thia- 1-azabicyclo [4,2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-N-cyanoacetyl-amino-2- (2-phenyl-1,1-ethylidene ) -d3-co phem4-carboxylic acid of the formula
EMI13. 2
 by triturating the residue with benzene, F.  217-2180 (with decomposition);

  Ultraviolet absorption spectrum: in ethanol and ethanol / hydrogen chloride #max 323 mz and in ethanol potassium hydroxide l "", x y 315 m; Infrared absorption spectrum (potassium bromide): characteristic bands at 2.854.20iz, 5.58, 5.62 (shoulder), 5.81 (shoulder), 5.97, 6.05 (shoulder), 6.25 and 6.40. 



   The residue of the mother liquor is chromatographed on 10 g of acid-washed silica gel.  With a 2: 1G mixture of benzene and acetone, cyanoacetic acid and trichloroacetic acid are washed out and a further amount of the 7-N-cyanoacetylqmino-4- (2-phenyl-1,1- is eluted with a 2: 1 mixture of benzene and acetone ethylidene) -8-oxo- -5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid, which is purified by trituration with benzene. 



   Example 19
A mixture of 0.2 g of the isomer A (trans) of the a- (2- -carbo-tert. -butyloxy-3,3-methyl-7-oxo4-thia-26-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetyl-methylene) -acetic acid- tert-butyl ester in 1 , 5 ml of trifluoroacetic acid is left to stand at -20 for 19 hours.  The trifluoroacetic acid is evaporated at room temperature, finally under high vacuum. The residue, which is 7-amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (Configuration of 7-amino-cephalosporanic acid) or 7-amino -2-benzylidene- # -cephem-4-carboxylic acid is dissolved in 2 ml of methylene chloride which contains 0.11 ml of triethylamine. 

 

   A solution of 0.052 ml of isobutyl chloroformate in 0.5 ml of tetrahydrofuran is added at -10 with 0.101 g of D-N-carbo-tert. -butyloxy-phenylglycine and 0.055 ml of triethylamine in 2 ml of tetrahydrofuran are added; after 10 minutes, the above-mentioned solution of the cyclization product is added.    



  The mixture obtained is left to stand at 100 for one hour and at room temperature for a further hour.  The volatile components are distilled off under reduced pressure, the residue is dissolved in 25 ml of ethyl acetate and extracted 3 times with water.  The combined aqueous extracts are with 2-n.  Hydrochloric acid acidified to pH 3 and extracted with ethyl acetate.  The organic solution is dried over sodium sulfate and evaporated under reduced pressure. 

  The residue is chromatographed on 3 g of acid-washed silica gel, using a mixture of benzene and ethyl acetate with a proportion of ethyl acetate increasing from 2% -50% as the mobile phase. In this way, first D-phylglycine and then the non-crystalline 4- Benzylidene-7-N- (N-carbo-tert. -butyloxy-D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) or 2 -Benzylidene-7-N- (N-car bo-tert. -butyloxy-D-phenyl-glycyl) - # -cephem-4-carboxylic acid, ultraviolet absorption spectrum:

   in ethanol #max 352 m, in ethanol / potassium hydroxide lniax 347 r4x, and in ethanol / hydrogen chloride #max 359 monthly; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 2.80-4.40 tL '5.60 ol ,, 5.80 (shoulder), 5.85-5.95, 6.05.    



  (Shoulder), 6.20-6.30 and 6.65-6.75. 



   A further amount of this product can be isolated from the residue of the first ethyl acetate solution; it contains a small amount of 4-benzylidene-7-N- (N-carbo-tert. -butyloxy-D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid tert. -butyl ester (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7 -N- (N-carbo-tert. -butyloxy-D-phenyl-glycyl) -amino- # -ce- phem4-carboxylic acid tert. butyl ester. 



   A mixture of 0.0304 g of 4-benzylidene-7-N- (N-carbo -tert. -butyloxy-D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and 0.4 ml of formic acid (99%) left to stand for 2¸ hours at room temperature.  The formic acid is then removed under reduced pressure (water bath) and the residue is dried at 500 ° C. under high vacuum (diffusion pump). 

  The non-crystalline 4-benzylidene-7-N- (D-phenyl-glycyl) -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene is obtained in this way -2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2-benzylidene-7-N- (D-phenyl-glycyl) -amino-A8-cephem-4-carboxylic acid of the formula
EMI14. 1
 which you can get in the form of a salt incl.  an inner salt can be obtained; Ultraviolet absorption spectrum: in ethanol two 347 m, in ethanol / potassium hydroxide #max 346 m, and in ethanol / hydrogen chloride #max 357 m; Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.95-4.30, 5.60-5.72, 5.90-6.00, 6.25-6.65 and 6.70 (shoulder). 



   Example 20
A solution of 0.255 g of the isomer A (trans) of the a- (2 -carbo-tert.  -butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) - [(4-chlorobuty-methylene / acetic acid- tert. Butyl ester in 5 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 20 hours.  4 ml of trifluoroacetic acid are evaporated and the solution containing the 7-amino-4- (3-chloro-1,1-propylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- (3-chloro-1,1-propylidene) -A3-cephem4-carboxylic acid is mixed with 15 ml of dioxane and 0 Treated 25 g of phenylacetic acid chloride. 

  The reaction mixture is left to stand at room temperature for 3 hours, then treated with 0.1 ml of water and, after a further hour, evaporated under reduced pressure.  The residue is chromatographed on 10 g of acid-washed silica gel; phenylacetic acid and neutral components are washed out with a 19: 1 mixture of benzene and acetone and with a 2:

  : 1 mixture of benzene and acetone the 4- (3-chloro-1,1-propylidene) -7-N-phenylacetylamino-8- -oxo-5-thia-1-azabicyclot4,2,0] oct-2- en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 2- (3-chloro-1,1-propylidene) -7-N-phenylacetyl-amino-A3-cephern-4-carboxylic acid of the formula
EMI14. 2
 eluted, which crystallizes in platelets on standing, F.  84-870; Thin-layer chromatogram (silica gel; system toluene / acetic acid / water 5: 5: 1): Rf = 0.34; Ultraviolet absorption spectrum: in ethanol #max 314 m, and in ethanol / potassium hydroxide #max 306 m; Infrared absorption spectrum (potassium bromide): characteristic bands at 2.804.10, 5.55-5.70, 6.05, 6.24 and 6.50-6.60. 



   A solution of 0.03 g of 4- (3-chloro-1,1-propylidene) -7-N- -phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acid in 2 ml of tetrahydrofuran is treated with a solution of 0.05 g of diazomethane in 2.5 ml of ether.  After standing for 5 minutes at room temperature, the solvents are evaporated off under reduced pressure. 

  The residue crystallizes on standing and, after recrystallization from a mixture of methylene chloride and hexane, gives 4- (3-chloro-1,1-propylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia-1 Azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester of the formula
EMI14. 3
 in yellow needles, F.  174-1760; [am20 = +58 + 20 (c = 0.59 in chloroform); Thin-layer chromatogram (system: benzene / ethyl acetate 1: 1):

  Rf = 0.43; Ultraviolet absorption spectrum: lma: 321 m (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.97 + z, 3.30-3.50, 5.61, 5.81, 5.94, 6.23 and 6.74
The starting materials used in the above examples can, for example.  can be produced as follows:
Example 21
A mixture of 5 g of 2-carbo-tert. -butyloxy-3,3-dimethyl -4-thia-2,6-diaza-bicyclo [3.2.0] heptan-7-one and 5.5 g glyoxylic acid tert. butyl ester hydrate in 40 ml of dioxane is stirred in a closed vessel for 13¸ hours at 95 and then evaporated. 

  The residue is dissolved in 1000 ml of pentane, washed three times with 500 ml of water and once with 200 ml of a saturated aqueous sodium chloride solution, dried over dry sodium sulfate and evaporated.  This gives an approximately 50:50 mixture of the two isomers of x- (2-Carbo4ert.     -butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) -α-hydroxy-acetic acid-tert. butyl ester of the formula
EMI15. 1
 0.9 g of the mixture obtained is crystallized from pentane and recrystallized from a mixture of ether and pentane, an isomer of the above compound, F.    134-1370, obtained; tCC] D = 3650 + 10 (c = 1.102 in chloroform); Thin layer chromatogram:

  Rf = 0.49 in a 1: 1 mixture of benzene and ethyl acetate; Infrared spectrum (in methylene chloride), bands at 2.94, 5.62, 5.77 and 5.85. 



   Example 22
A mixture of 6 g of a 1: 1 mixture of the isomers of sc- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- -diaza-6-bicyclo [3.2.0] heptyl) -α-hydroxy-acetic acid-tert. -butyl esters and 10.5 g of the so-called.   Polystyrene Hünig base (prepared by heating a mixture of 100 g of chloromethyl polystyrene [J.  At the.  Chem. 

  Soc.  85, 2149 (1963) 1, 500 ml of benzene, 200 ml of methanol and 100 ml of diisopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3 l mixture of dioxane and triethylamine, 1000 ml of methanol and 1000 ml of dioxane and 1000 ml of methanol and drying for 16 hours at 100/10 mm Hg, the product neutralizes 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) in a 1: 1 mixture of dioxane and tetrahydrofuran stirred for 20 minutes.  After cooling, it is treated dropwise within 20 minutes with a solution of 6 g of thionyl chloride in 50 ml of dioxane and the mixture is stirred at 20 for 140 minutes, then filtered. 

  The filtrate is evaporated, the residue is taken up in 200 ml of pentane and the solution is treated with 1 g of an activated charcoal preparation, then filtered.  This gives an approximately 1: 1 mixture of the isomers of a- (2-carbo-tert. -butyloxy-3. 3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α-chloro-acetic acid tert. butyl ester. 



   Example 23
A solution of 11.3 g of a crude mixture of the isomers of a- (2-carbo-tert. -butyloxy-3, 3 -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α-chloro-acetic acid-tert. - Butyl ester in 150 ml of absolute dioxane is mixed with 11.4 g of triphenylphosphine and 10.8 g of polystyrene Hünig base or diisopropylaminomethyl polystyrene (prepared by heating a mixture of 100 g of chloromethyl polystyrene [J.  At the. 



  Chem.  Sac. , 85, 2149 (1963)], 500 ml of benzene, 200 ml of methanol and 100 ml of diisopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and triethylamine, 1000 ml of methanol, 1000 ml of dioxane and 1000 ml of methanol and drying for 16 hours at 100/10 mm Hg; the product neutralizes 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water), stirred for 17 hours under a nitrogen atmosphere at 55, then cooled and filtered through a glass filter. 

  It is washed with 100 ml of benzene; the filtrate is evaporated under a water jet vacuum; the residue is dried under high vacuum, dissolved in 100 ml of a 9: 1 mixture of hexane and ethyl acetate and chromatographed on a column (height 48 cm; diameter 6 cm) with acid-washed silica gel.  With 2000 ml of a 3: 1 mixture of hexane and ethyl acetate, triphenylphosphine and some triphenylphosphine sulphide are added, with a further 4000 ml of the 3: 1 mixture of hexane and ethyl acetate the a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid-tert.    



  -butyl ester of the formula
EMI15. 2
 eluted; a further amount of the impure product can be obtained with 1500 ml of the same solvent mixture. 



  In the thin layer chromatogram (silica gel; system: 1: 1 mixture of benzene and ethyl acetate) the product has an Rf value of 0.5 and crystallizes from a mixture of ether and pentane, F.  121-122; [α] D = -219 # 1 (c = 1.145 in chloroform); Ultraviolet absorption spectrum (in ethanol): #max = 225 m (# = 30,000) and 260 m (# = 5400); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.76, 5.80 (shoulder), 5.97, 6.05, (shoulder) and 6.17.  A further amount of the product can be isolated from the mother liquor by crystallization in an ether-pentane mixture. 

 

   Example 24
A solution of 2 g of a- (2-Carbo-tert-butyloxy-3,3-dllnethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α- (triphenylphosphoranylidene) acetic acid tert.  Butyl ester and 0.7 g of benzylglyoxal in 30 ml of dry toluene are heated under a nitrogen atmosphere for 23 hours at 800 (bath temperature), then a further amount of 0.2 g of benzylglyoxal is added and the mixture is heated at 80 for 22 hours.  The solvent is removed under reduced pressure and the viscous residue is chromatographed on a column containing 60 g of acid-washed silica gel. 

  With 450 ml of benzene, the excess benzylglyoxal, with 250 ml (10 fractions) of a 95: 5 mixture of benzene and ethyl acetate, a mixture of the isomers of sc- (2-carbo-tert. - -butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -s- (phenylacetylmethylene) -acetic acid-tert. butyl ester of the formula
EMI16. 1
 and washed out a more polar material with another amount of the same solvent mixture. 



   The above mixture of isomers is chromatographed again on 60 g of acid-washed silica gel, washing with a 99: mixture of benzene and ethyl acetate.  A product consisting mainly of benzylglyoxal is obtained, then with 125 ml a fraction I consisting mainly of isomer A, with 250 ml a fraction II consisting of a mixture of the two isomers and with 300 ml a fraction consisting mainly of isomer B III. 

  The above three fractions are recrystallized from hexane, from fraction I the isomer A; F.  108-110; Thin-layer chromatogram: Rf 0.49 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum: man 299 (in ethanol), 337 m (in potassium hydroxide / ethanol) and 337 m (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.83 (shoulder), 5.85-5.95 y and 6.29; and from fractions II and III the isomer B; F.  156 1570; Thin layer chromatogram:

  Rf 0.42 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum:). ma 294 m (in ethanol), 335 m (potassium hydroxide / ethanol) and 335 mll (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.80 Cr (shoulder), 5.84-5.96 and 6.34; is obtained.  Further amounts of the two isomers can be isolated from the mother liquors in the same way. 



   Example 25
A solution of 0.0162 g of the isomer B of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3, 2.0] heptyl). a- (phenylacetylmethylene) acetic acid 4ert.     Butyl ester in 10.6 ml of benzene is irradiated with ultraviolet light in a vessel made of Pyrex glass under a nitrogen atmosphere at room temperature.  After 90 minutes the solvent is distilled off; according to  Nuclear magnetic resonance spectrum, the non-crystalline residue consists of an approximately 42:58 mixture of isomer A and isomer B of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid tert. butyl ester.    



   Crystalline isomer B and fractions consisting mainly of isomer B of a- (2-carbo-tert. -butyloxy-3,3-dimethyl- -7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetyl-methylene) -acetic acid-tert. -butylesters can be converted in the same way to isomer mixtures containing isomer A and isomer B of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α-phenyl-acetylmethylene) -acetic acid-tert.  -butylesters are isomerized. 



   Example 26
1 g of α- (2-carbo-tert. -butyloxy-3,3-dimethyl- -7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenyl-phosphoranylidene) -acetic acid-tert. -butyl ester under nitrogen with 0.65 g isopropylglyoxal in 7 ml toluene and left to stand at 90 for 8 days.  The solvent and the excess of isopropylglyoxal are removed under reduced pressure at 50 and the residue is chromatographed on 50 g of acid-washed silica gel; it is washed out with a 4: 1 mixture of hexane and ethyl acetate. 

  With the first 150 ml the isomer A (trans) of the os- (2-Carbo- is -tert.  -butyloxy-3, 3 -dimethyl-7-oxo -4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (isobutyrylmethylene) -acetic acid-tert. -butyl- esters of the formula
EMI16. 2
 washed out, which after crystallization from a mixture of hexane and ethyl acetate melts at 133-134; Ultraviolet absorption spectrum: in ethanol #max 294 mpw; in potassium hydroxide / ethanol lmax 330 mt; and in hydrogen chloride / ethanol #max 330 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62 qz, 5.80, (shoulder); 5.84-5.94 and 6.26. 



   The isomer B (cis) of the α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (isobutyrylmethylene) -acetic acid-tert . Butyl ester is obtained on further washing with the same solvent mixture and, after crystallization from a mixture of hexane and ethyl acetate, melts at 146-147;

  Ultraviolet spectrum: in ethanol #max 289 m; in potassium hydroxide / ethanol #maox 328 m; and hydrogen chloride / ethanol) #max 328 ml; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60-5.66, 5.75 2 (shoulder), 5.85-5.95 L and 6.31 11
Example 27
A mixture of 0.05 g of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo. 4-thia-2.6. diaza-6. bicyclo [3, 2.0] heptyl) - (triphenylphosphoranylidene) acetic acid tert. -butyl ester u.  0.0355 g of 4-nitrobenzyl-glyoxal in 0.6 ml of toluene is heated at 80 for 7 hours. 

  The solvent is then distilled off under reduced pressure and the residue is chromatographed on a thin-layer silica gel plate (20 × 20 × 0.15 cm), developing with a 2: 1 mixture of hexane and alkyl acetate.  Two yellow bands are obtained, the upper one being the isomer A of α- (2-carbo-tert. -butyl-oxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - [(4-nitro-phenylacetyl) - methylene] acetic acid tert. butyl ester of the formula
EMI17. 1
 with Rf value = 0.41; Ultraviolet absorption spectrum: lmax 288 m (broad; in ethanol), and #max 505 mp, 262 m (potassium hydroxide / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.83 1 (shoulder), 5.88-5.92, 5.97 (shoulder), 6.28-6.33 Ii, 6.59 Ii and 7.45 tl; and the lower isomer B of the a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -a - [(4th. nitro. phenylacetyl). methylenej. acetic acid -tert. butyl ester of the formula
EMI17. 2
 as yellow, glass-like products. 

  The isomer B crystallizes from hexane, F.    173; Rf value: 0.29; Ultraviolet absorption spectrum in ethanol: lmax 293 rfl ±, and in potassium hydroxy / ethanol: #max 335 m and 285 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62 Ii (shoulder), 5.83-5.92, 6.30-6.35 tl, 6.59 Il and 7.45. 



   The 4-nitrobenzylglyoxal used as starting material above can be prepared as follows: A solution of about 4 g of diazomethane in 200 ml of dry ether is under
Stir dropwise with 6 g of 4-nitrophenyacetyl chloride in
80 ml of dry tetrahydrofuran are added, the temperature being maintained at 0-50 by stirring in an ice-water bath. After about 30 minutes, the addition is complete; the reaction mixture is stirred for a further 15 minutes at 0-5 and then evaporated in a rotary evaporator. 



  The solid residue is dissolved in a mixture of methylene chloride and ether, the small amount of solid material is filtered off and the filtrate is evaporated.  This gives the 4-nitrobenzyl-diazomethyl-ketone, which, after crystallization from a mixture of ether and hexane, melts at 90-920; Infrared absorption spectrum (in methylene chloride); characteristic bands at 4.78, 6.10, 6.26, 6.58 tl and 7.45
A solution of 3 g of 4-nitrobenzyl diazomethyl ketone in
100 ml of a 1: 1 mixture of ether and methylene chloride is mixed with a solution of 4.22 g of triphenylphosphine in 100 ml of ether. 

  After about 5 minutes the 1- (4-nitrophenyl) -3- (triphenylphosphoranylidene-hydrazono) -acetone crystallizes out at room temperature; the mother liquor is filtered and concentrated, from which a further amount of the desired product crystallizes.  The crude product is crystallized from a mixture of 50 ml of methylene chloride and 250 ml of hexane, F.  160-165.  Ultraviolet absorption spectrum (in ethanol): #max 320 m and 270-275 m (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 Ii (shoulder), 6.14-6.20 y, 6.32, 6.67-6.74 Ii and 7.45,.    



   A suspension of 0.467 g of 1- (4-nitrophenyl) -3- (triphenylphosphoranylidene hydrazono) acetone in 3 ml of tetrahydrofuran is mixed with 0.21 g of powdered sodium nitrite and 1.2 ml of water.  The mixture is cooled to 0-5 and added dropwise over 2 minutes with 2.2 ml of 2-n.  Hydrochloric acid is added, forming an emulsion.  After 60 minutes at 0-5, the aqueous layer is separated off and extracted four times with 10 ml of methylene chloride each time.  The combined organic solutions are washed twice with 10 ml of saturated aqueous sodium chloride solution each time and evaporated; the residue is chromatographed on 20 g of acid-washed silica gel. 

  The crystalline, enolized 4-nitrobenzylglyoxal is eluted with 600 ml of benzene; Ultraviolet absorption spectrum in ethanol: #max 343 m, in potassium hydroxide / ethanol: 444 mp, and in hydrochloric acid / ethanol: #max 343 mt; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 5.98 1, 6.0611, 6.28, 6.60 and 7.47: and with 350 ml of a 9: 1 mixture of benzene and ethyl acetate the hydrate of 4-nitrobenzylglyoxal as a non-crystalline, syrupy material;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.01, 5.82, 6.2711, 6.61 and 7.47. 



   Example 28
A mixture of 0.872 g of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid-tert . butyl ester and 0.611 g of 4-nitrobenzyl glyoxal hydrate in 10.5 g of toluene is heated at 80 for 6¸ hours.  The solvent is distilled off under reduced pressure and the residue is chromatographed on 50 g of acid-washed silica gel.  

  With 1300 ml of benzene and 500 ml of a 98.5: 1.5 mixture of benzene and ethyl acetate, the isomer A of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxoXthia-2,6-diaza-6-bicyclo [3 2.0] heptyl) - [(4-nitro-phenylacetyll) -methylene] - -acetic acid-tert. butyl ester, with 200 ml of a 96: 4 mixture of benzene and ethyl acetate, a mixture of the two isomers A and B that - (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α - [(4-nitro-phenylacetyl) -methylene] acetic acid tert. -butyl ester and with another 400 ml of 96:

   4 mixture of benzene and ethyl acetate the isomer B of a- (2-carbo-tert.  -butyloxy- -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - - [(4-nitro-phenylacetyl) - methylene] acetic acid tert. butyl ester together with a small amount of isomer A eluted. 



  The mixture is separated by means of thin layer chromatography (4 silica gel plates; 20 × 20 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate; a further amount of isomer A is thus obtained; Rf = 0.41; and of isomer B; Rf = 0.29.  The latter is combined with the almost pure isomer B from the chromatogram and crystallized from hexane, F.  173. 



   Example 29
A mixture of 0.714 g of cc- (2-carbo-tert, -butyloxy-3,3- -dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α- (triphenylphosphoranylidene) acetic acid tert. Butyl ester and 0.67 g of 4-methoxybenzylglyoxal hydrate in 8.6 ml of toluene is heated at 80 for 3¸ hours, then evaporated under reduced pressure.  The residue is chromatographed on 50 g of acid-washed silica gel. 

  The excess 4-methoxybenzyl-glyoxal in anhydrous form is washed out with 500 ml of benzene, while the almost pure isomer A of α- (2-carbo-tert. Is obtained with 800 ml of a 99: 1 mixture of benzene and ethyl acetate. -butyloxy-3,3-dimethyl-7- -oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - [(4-methoxy-phenylacetyl) - methylene] acetic acid tert. butyl ester of the formula
EMI18. 1

F.    105-107 after recrystallization from a mixture of ethyl acetate and hexane; Ultraviolet absorption spectrum in ethanol: #max 298 m, u, 288 m t (shoulder) u.  225 m (shoulder), u.  in potassium hydroxide / ethanol: #max 340 m;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, 5.82 c (shoulder), 5.87-5.97, 6.23, 23 (shoulder), 6.28 pw "6.63 u.  6.77; with another 400 ml of the 99: 1 mixture of benzene u. 

  Ethyl acetate a mixture of the isomers A and B and with 300 ml of a 98: 2 mixture of benzene and ethyl acetate the isomer B of a- (2-carbo-tert. -butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6- -diaza-6-bicyclo [3.2.0] heptyl) - α - [(4-methoxyphenylacetyl) -methylene ] acetic acid tert. butyl ester of the formula
EMI18. 2
 washes out; the pure isomer B obtained from the mixture fraction by recrystallization from hexane and the pure isomer B obtained in the same way from the fraction of the isomer B melts at 169-170; Ultraviolet absorption spectrum in ethanol: #max 289 m (wide) and 227 m (shoulder), and in potassium hydroxide / ethanol: #max 343 m;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59, 5.75 tl (shoulder), 5.80-5.93, 6.24 (shoulder), 6.3011 and 6.60. 



   Using preparative thin-layer chromatography and developing with a 2: 1 mixture of hexane and ethyl acetate, further amounts of the two isomers A and B of a- (2-carbo-tert.  -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3, 2.0] heptv1) - [(4-methoxyphenylacetyl) -methylene] - acetic acid tert. -butyl ester can be obtained. 



   The 4-methoxybenzyl glyoxal hydrate used as starting material in the above example can be obtained as follows:
A solution of 7.43 g of 4-methoxyphenylacetyl chloride in 100 ml of dry ether is added dropwise to a solution, cooled to 0-5, of 6 g of diazomethane in 300 ml of ether.  The reaction mixture is stirred for a further 30 minutes, finally without cooling.  The excess of diazomethane and the solvent are removed under reduced pressure in a rotary evaporator and the residue is dissolved in 100 ml of ether and the small amount of waxy material is filtered off. 

  After evaporating the filtrate, 4-methoxy-benzyl-diazomethyl ketone is obtained; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.79, 6.10, 6.22 (shoulder), 6.62 and 7.73-7.45.     that is processed further without cleaning. 



   A solution of 7.52 g of 4-methoxybenzyl diazomethyl ketone in 300 ml of ether is mixed with 11.1 g of triphenylphosphine in 200 ml of ether.  The reaction mixture is stirred at room temperature, a crystalline precipitate forming after a few minutes, which is filtered off after an hour and washed with cold ether.  This gives 1 - (4-methoxyphenyl) -3 - (triphenylphosphoranylidene-hy- drazono) acetone, which melts at 111-112; Infrared absorption spectrum (in methylene chloride3: characteristic bands at 4.80.  6.05 ti (shoulder), 6.14 y, 6.2411 (shoulder) and 7.73-7.45; that is processed further without cleaning. 



   A solution of 1.82 g of 1- (4-methoxyphenyl) -3- (triphenyl-phosphoranylidene-hydrazono) -acetone in 12 ml of tetrahydrofuran is mixed with 0.84 g of powdered sodium nitrite and the mixture is diluted with 5 ml of water.  The resulting suspension is cooled to 0-5, dropwise over 7 minutes with 8.8 ml of 2-n.  Treated hydrochloric acid and then kept at 0-5 for a further 30 minutes.  The aqueous phase is washed twice with methylene chloride; the combined organic solutions are washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure.  The oily residue is chromatographed on 40 g of acid-washed silica gel. 

  A small amount of a by-product is washed out with benzene and with 1200 ml of a 95: 5 mixture of benzene and ethyl acetate, the 4-methoxybenzylglyoxal is obtained mainly in the form of the hydrate, the oily product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96 y, 5.79-5.84, 6.23 and 6.63. 

  The anhydrous product melts after recrystallization from a mixture of chloroform and hexane at 139-1400; Ultraviolet absorption spectrum in ethanol or hydrochloric acid / ethanol: lmax 333 mn, and in potassium hydroxide / ethanol: #max 367 mn; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 5.97, 6.09 y, 6.24 y, 6.61 tL and 7.15. 



   Example 30
A solution of 0.8 g of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenyl-phosphoranylidene) -acetic acid tert . Butyl ester and 1.2 g of the crude 4-chlorobenzyl glyoxal hydrate in 12 ml of toluene is heated at 800 for 5 hours.  The solvent is distilled off under reduced pressure and the syrupy residue is dissolved in about 4 ml of benzene.  The resulting crystalline precipitate, consisting of the enol of 4-chlorobenzyl-glyoxal, is filtered off and the filtrate is chromatographed on a column of 50 g of acid-washed silica gel. 

  A further amount of 4-chlorobenzyl-glyoxal is eluted with 500 ml of benzene and a mixture of the isomers of α- (2-carbo-tert.) Is eluted with 200 ml of benzene and 800 ml of a 97: 3 mixture of benzene and ethyl acetate. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,50] heptyl) m [(4-chlorophenylacetyl) methylene] acetic acid -Tert. -butyl ester, which is chromatographed on a further 50 g of acid-washed silica gel using benzene and benzene containing 5% ethyl acetate and then separated by preparative thin-layer chromatography (system hexane: ethyl acetate 2: 1). 

  The non-crystalline isomer A (trans) of 0c- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3. 2. 0] heptyl) rn - [(4-chlorophenylacetyl) -methylene] -acetic acid-tert. butyl ester of the formula
EMI19. 1
 which shows the following bands in the ultraviolet absorption spectrum: #max 300 m (in ethanol); #max 342 m (in potassium hydroxide / ethanol); and #max 338 m (when adding hydrogen chloride to the previous sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60, 5.75 Ii (shoulder), 5.80-5.92 ti (broad), 6.26 11, and 6.70; and the crystalline isomer B (cis) of the α- (2-carbo-tert. -butyl-oxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] hep tyl) - α - [(4-chlorophenyl-acetyl) -methylene] acetic acid tert. -butyl- esters of the formula
EMI19. 2
 which, after recrystallization from hexane, melts at 178-1790; Ultraviolet absorption spectrum: max 295 m (in ethanol); #max 337 m (in potassium hydroxide / ethanol);

   and #max 337 m (when adding hydrogen chloride to the previous sample); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59, 5.75 (shoulder), 5.78-5.94,; 6.07 tl (shoulder), 6.31 y and 6.70 t.     Isomer A is processed further without purification
The 4-chlorobenzylglyoxal hydrate can be prepared as follows:
A solution of 16.5 g of 4-chlorophenylacetyl chloride in 150 ml of dry ether is added dropwise with vigorous stirring and while cooling in an ice-water bath to about 11 g of diazomethane in 500 ml of ether.  After reacting at 5-10 for 30 minutes, the diazomethane and the solvent are distilled off under reduced pressure. 



  The 4-chlorobenzyl-diazomethyl ketone available as a yellowish crystalline residue; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.84, 6.22, 6.80 and 7.47; is processed further without cleaning. 



   A solution of 17 g of 4-chlorobenzyl diazomethyl ketone in 150 ml of ether is added at room temperature to a solution of 23.5 g of triphenylphosphine in 300 ml of ether.  The yellowish crystalline precipitate is filtered off after 20 minutes, washed with ether and recrystallized from a mixture of methylene chloride and ether; the 1 - (4-chlorophenyl) -3 - (triphenylphosphoranylidene-hydiazono) acetone thus obtainable melts at 130-131; Ultraviolet absorption spectrum: #max 320 m3x (ethanol); Man 320 man (potassium hydroxide / ethanol); and #max 255-278 rn (broad shoulder) (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.76, 6.03 (shoulder), 6.12 4Q, 6.28 (shoulder) and 6.65-6.75 + t.    

 

   A suspension of 8 g of 1- (4-chlorophenyl) -3- (triphenyl -phosphoranylidene-hydrazono) -acetone and 3.6 g of sodium nitrite in 51 ml of tetrahydrofuran and 22 ml of water is stirred and cooled in an ice-water bath (10 -13) drop by drop within about 10 minutes with 37 ml of 2-n.  Hydrochloric acid is added, 2 phases being formed.  The mixture is stirred for 30 minutes at room temperature, the organic layer is separated off and the aqueous phase is extracted several times with methylene chloride.  The combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure.  A syrupy residue is obtained which is chromatographed on 60 g of acid-washed silica gel. 

  The crude 4-chlorobenzylglyoxal hydrate is extracted with benzene and a 95: 5 mixture of benzene and ethyl acetate; Ultraviolet absorption spectrum: man 222 ml (in ethanol); #max 365 m (in potassium hydroxide / ethanol); and #max 316 ml (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.87-4.3, 5.77, 6.27 and 6.72; and processed further without cleaning. 

  The anhydrous 4-chlorobenzylglyoxal in the enol form melts after recrystallization from methylene chloride at 144-1470; Ultraviolet Absorption Spectrum: #max 316 mli (in ethanol); one 364 m (in potassium hydroxide / ethanol); and #max 316 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92, 5.97, 6.07, 6.29 and 6.71.    



   Example 31
A solution of 2.5 g of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid-tert . Butyl ester and 1.3 g of cyclohexylmethyl glyoxal hydrate in 50 ml of toluene are heated to 80 for 4 hours and the solvent is evaporated off under reduced pressure.  The syrupy residue is triturated with ether, the resulting triphenylphosphine oxide is filtered off and the filtrate is evaporated.  The residue is chromatographed on 120 g of acid-washed silica gel, washing with a 98: 2 and a 9: mixture of hexane and ethyl acetate. 

  The isomer A (trans) of a- (2-carbo-tert. -butyloxy--3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (cyclohexyl-acetyl-methylene) -acetic acid-tert. butyl ester of the formula
EMI20. 1
 by means of preparative thin-layer chromatography (plates 20 X 20 X 0.15 cm; silica gel; benzene system:

  Acetone 98: 2) is purified and obtained in syrupy form; [] D20 = 4510 + 10 (c = 0.87 in chloroform); Ultraviolet Absorption Spectrum: #max 297 ml (in ethanol); lmax 334 m (in potassium hydroxide / ethanol); and #max 334 (when adding hydrogen chloride to the alkaline to the sample); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45>, 3.50, 5.61, 5.78 w, (shoulder), 5.805.95, 6.07 (shoulder) and 6.28.    



   The isomer B (cis) of the α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (cyclohexylacetyl-methylene) -acetic acid -Tert.  butyl ester of the formula
EMI20. 2
 is eluted as the second product and crystallized from hexane, F.  154-1550; F] D = -232 + 10 (c = 0.8 in chloroform); Ultraviolet absorption spectrum: #max 288 ml (in ethanol), #max 333 m (in potassium hydroxide / ethanol); and #max 333 m (when adding hydrogen chloride to the above alkaline to the sample); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.44, 3.53, 5.60, 5.75 (shoulder), 5.80-5.93, 6.05 (shoulder) and 6.31. 



   The cyclohexylmethylglyoxal hydrate used as starting material can be prepared as follows: A solution of 19.8 g of cyclohexyl acetyl chloride (b.p.  98-1000 / 23 mm Hg) in 150 ml of dry ether is slowly added to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether, while cooling to 0-5 in an ice-water bath.  The excess of the diazomethane and the ether are distilled off under reduced pressure and the residue obtained is cyclohexylmethyl diazomethyl ketone; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45, 3.5211, 4.75, 30 and 6.12; that is processed further without cleaning. 



   A solution of 32 g of triphenylphosphine in 450 ml of ether is stirred all at once with a solution of 20 g of cyclohexylmethyl diazomethyl ketone in 100 ml of ether. After stirring for 30 minutes at room temperature, the solvent is evaporated under reduced pressure.  The l-cyclohexyl-3- (triphenylphosphoranylidene-hydrazono) -acetone, available as an oily residue, crystallizes in the cold from ether, F.  58-62; Ultraviolet absorption spectrum: lmax 314 mp, 2.62-2.75 m and 223 ml (in ethanol and in potassium hydroxide / ethanol), and #max 257-275 m and 230 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 3.56, 4.76, 6.15 and 6.67. 



   A mixture of 15 g of 1-cyclohexyl-3- (triphenylphos- phoranylidene-hydrazono) acetone and 7.37 g of sodium nitrite in 120 ml of tetrahydrofuran and 42 ml of water is slowly added with stirring and cooling to 10-13 (ice-water bath) 77 ml 2-n.  Hydrochloric acid added.  After a further 30 minutes at room temperature, the organic solution is separated off and the aqueous phase is extracted with methylene chloride.  The combined organic solutions are dried over sodium sulfate and evaporated under reduced pressure.  The syrupy residue is treated with ether, the resulting triphenylphosphine oxide is filtered off and the filtrate is evaporated.  

  The residue is chromatographed on an acid-washed silica gel column (120 g), the cyclohexylmethyl glyoxal hydrate being eluted as a syrupy product with about 3000 ml of a 97: 3 mixture of hexane and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90-4.1 11 (broad); 3.47, 3.53 ps, and 5.8011; and processed further without cleaning.      



   Example 32
A solution of 1.5 g of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid-tert .  Butyl ester and 1.0 g of 2-phenylethyl glyoxal hydrate in 20 ml of toluene is heated at 800 for 2 hours and then left to stand for 16 hours at room temperature.  The toluene is removed under high vacuum and the residue separated by means of preparative thin-layer chromatography; silica gel plates (100 X 20 X 0.15 cm) are used and developed with a 4: 1 mixture of hexane and ethyl acetate. 

  This gives the less polar isomer A (trans) of the a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo- [3.2.0] heptyl) -α - [(3-phenyl-propionyl) -methylene ] -acetic acid- tert-butyl ester of the formula
EMI21. 1
 which crystallizes spontaneously and, after recrystallization, from hexane melts at 100-102; [α] 20 D = 4280 + 10 (c = 1 in chloroform); Ultraviolet Absorption Spectrum (in ethanol): #max 292 m (# = 11100);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.80 (shoulder), 5.85-5.93 L and 6.2711. Another amount can be obtained from the crystallization mother liquor. 



   The more polar fraction, which also crystallizes spontaneously, is recrystallized from hexane and gives the isomer B (cis) of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2,0] heptyl) α - [(3-phenyl-propionyl) -ethylene ] acetic acid tert. butyl ester of the formula
EMI21. 2
 F.    129-130; [a] 20 D = -358 + 10 (c = 1.04 in chloroform); Ultraviolet absorption spectrum (in ethanol): ma: 289 (± = 18200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.75 (shoulder), 5.82-5.94 and 6.2711.    



   The 2-phenylethylgly oxalhydrate used as the starting material can be prepared as follows:
A solution of 4.8 g of diazomethane in 240 ml of ether is added within 20 minutes and with vigorous stirring with a solution of 7.1 g of dihydrocinnamyl chloride in 100 ml of ether, the reaction mixture being cooled to -5.  The mixture is stirred for 15 minutes without cooling and the volatile components are distilled off under reduced pressure.  The oily residue obtained is 2-phenylethyl diazomethyl ketone; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.76 Ir, 6.11, 6.1611 (shoulder) and 6.69. 



   A solution of 7.45 g of the crude 2-phenylethyl-diazomethyl ketone in 200 ml of ether is treated at room temperature with a solution of 11 g of triphenylphosphine in 200 ml of ether. The mixture is stirred for 2 hours and the crystalline 1-benzyl-34triphenylphosphoranylidene-hydrazono is filtered acetone, which melts at 105 after recrystallization from ether; Ultraviolet absorption spectrum (in ethanol): #max 316m, 265-280 m (shoulder) and 223 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 and 6.63. 



   4.16 g of powdered sodium nitrite are suspended in a solution of 8 g of 1-benzyl-3- (triphenylphosphoranylidene-hydrazono) -acetone in 60 ml of tetrahydrofuran and 30 ml of water and the suspension, with vigorous stirring, with 44 ml of 2-n.    Hydrochloric acid added; the addition takes 15-20 minutes, cooling to 10-15. After a further 15 minutes at room temperature, extraction is carried out with ether; the ether extract is washed with a concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on 100 g of silica gel (column), using 98 2 and 95:

   5 mixtures of benzene and ethyl acetate are eluted. This gives 2-phenylethyl glyoxane hydrate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88, 3.00-4.30 (broad) and 5.77-5.86. 



   Example 33
A solution of 0.77 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo4-thia-26-diaza-6-bicycloE3, 2.0] heptyl) a- ( triphenylphosphoranylidene) acetic acid tert. Butyl ester and 0.92 g of 3-chloropropyl glyoxal hydrate in 23 ml of toluene are left to stand at 500 for 6 hours.  The solvent is evaporated off under reduced pressure and the oily residue is purified by preparative thin layer chromatography (silica gel plates 100 X 20 X 0.15 cm; system: hexane / ethyl acetate 4: 1). 

  The least polar fraction (Rf = 0.38) represents the isomer A (trans) of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- diaza-6-bicyclo [3.2.0] heptyi) - [(4-chlorobutyry-methylene] -acetic acid 4- butyl esters of the formula
EMI21. 3
  represents, which is obtained as a colorless oil; Thin-layer chromatogram (system: hexane / ethyl acetate 2: 1): Rf = 0.48; Ultraviolet absorption spectrum: l. max 295 ntt (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.42, 5.62, 5.80-5.95 z and 6.27 p.    



   The isomer B (cis) of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-chlorobutyryl) -methylene ] acetic acid tert. butyl ester of the formula
EMI22. 1
 is obtained in the form of a colorless oil as the more polar fraction (Rf = 0.23); Thin-layer chromatogram (system hexane / ethyl acetate 2: 1):

  Rf = 0.42; Ultraviolet absorption spectrum: lmax 295 m (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.42 z, 5.61, 5.78-5.94 p and 6.31 f
A mixture of 0.29 g of isomer B of cs- (2-carbo- -tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-chlorobutyryl) -methylene] -acetic acid -Tert. Butyl ester in 130 ml of benzene is irradiated with a high-pressure mercury vapor lamp in a Pyrex glass jacket at room temperature for 3 hours and then evaporated under reduced pressure. 

  The crude mixture of the two isomers A and B of α- (2-carbo-tert. -butyloxy-3,3-dimethyl- -7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-chlorobutyryl) -methylene ] acetic acid tert.  -butyl ester is determined by means of preparative thin layer chromatography, e.g. B.  as described above, separated and thus a further amount of the desired isomer A (trans) is obtained. 



   The 3-chloropropylglyoxal used in the above example can be made as follows:
A solution of 10 g of 4-chlorobutyryl chloride in 150 ml of dry ether is slowly added with stirring and cooling to 0 to 5 in an ice-methanol bath to a solution of 12.3 g of diazomethane in 500 ml of ether.  After a further 5 minutes at 0 to 5, the solution with the 3-chloropropyl-diazomethyl ketone is concentrated under reduced pressure to a volume of 150 ml and immediately treated with a solution of 22.8 g of triphenylphosphine in 200 ml of ether. 

  The 1- (3 -chloropropyl) -3- (triphenylphosphoranyllden-hydrazono) -acetone crystallizes out, F.  103-1040; Ultraviolet absorption spectrum: man 320 mop and 228 m (in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 y and 6.64,.     Another amount of the desired product can be isolated from the mother liquor. 



   A mixture of 6 g of 1- (3-chloropropyl) -3- (triphenylphos- phoranyliden-hydrazono) -acetone and 3.1 g of sodium nitrite in 55 ml of tetrahydrofuran and 30 ml of water is slowly stirred with 22 ml of 2-n.  Hydrochloric acid is added, the addition being carried out with cooling to 13-150 in an ice-water bath. 

  After a further 15 minutes at room temperature, the mixture is extracted three times with 150 ml of ether each time; the combined ether extracts are washed five times with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The oily yellow precipitate is chromatographed on 100 g of acid-washed silica gel (column); the pure 3-chloropropyl glyoxal hydrate is eluted with a 95: 5 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90-4.0 lt (broad), 3.45 and 5.81 e.g.    



   Example 34
A solution of 0.3784 g of the isomer A (trans) of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl-α - [(4-tert. -butyl-phenyl) -acetylmethy- len] -acetic acid-tert. Butyl ester in 3 ml of pre-cooled trifluoroacetic acid is left to stand at 200 for 20 hours. 

  The trifluoroacetic acid is distilled off under reduced pressure and at room temperature and the residue, which contains the 7 amino-4- (4-tert. -butyl-benzylidene) -8-oxo-5-thia -1-azabicyclo [4,2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-amino-2- ( 4-tert. -butyl -benzylidene) - # -cephem-4-carboxylic acid, is treated with 4 ml of a solution of the mixed anhydride of cyanoacetic acid and trichloroacetic acid in methylene chloride (preparation see Example 12), the temperature being kept at 10O.  After the addition, 2 ml of a solution of triethylamine and triethylammonium acetate in methylene chloride (preparation, see Example 12) are added and the resulting reaction mixture is stirred for 2 hours without cooling. 

  It is treated with 40 ml of ethyl acetate and the mixture is washed with dilute hydrochloric acid and a saturated aqueous sodium chloride solution.  The organic solution is dried over sodium sulfate and evaporated.  The residue is chromatographed on a column of 10 g of acid-washed silica gel; with a 95: 5 mixture of benzene and acetone, trichloroacetic acid, cyanoacetic acid and some neutral by-products are washed out. 

  With a 2: l mixture of benzene and ethyl acetate, the crude 7-N -cyanoacetylamino-4- (4-tert. -butyl-benzylidene) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-N-cyanoacetylamino-2 - - (4-tert. -butyl-benzylidene) - # -cephem-4-carboxylic acid of the formula
EMI22. 2
 eluted as an amorphous product; Ultraviolet absorption spectrum: #max 361 mp, (in ethanol), lmax 352 mi (in ethanol / potassium hydroxide) and lmax 363 m (in ethanol / hydrogen chloride);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90-4.35 p, 3.40, 5.60-5.68, 5.75-5.90 1x, 6.05 Ii (shoulder), 6.25 tl and 6.40-6.65 z.    



   A solution of the material obtained in 2 ml of acetone is mixed with 1 ml of a 10% strength solution of the sodium salt of α-ethyl-caproic acid in acetone and with ether.  The dark colored product is discarded and the beige colored sodium salt of 7-N-cyanoacetyl-amino-4- (4-tert. -butyl-benzylidene) -8-oxo-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) or 7-N-cyanoacetylamino-2 - (4-tert. -butyl-benzylidene) -A3-cephem-4-carboxylic acid is filtered off, F.     > 2400; Ultraviolet absorption spectrum: one 352 m (in ethanol), and max 363 m (in ethanol / hydrogen chloride);

  Infrared absorption spectrum (potassium bromide): characteristic bands at 2.80-4.0, 3.40 p 4.52 s "5.65-5.70 1e, 5.90 (shoulder) and 6.03 6.55.    



   The, - (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - α - [(4-tert. -butylphenyl) -acetylmethylene] -acetic acid-tert. -butyl ester, which is used as starting material in the above process, can be prepared as follows: A solution of 1.5 g of a- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid-tert. butyl ester and 1.5 g of 4-tert. -Butyl-benzyl-glyoxal hydrate in 15 ml of toluene is heated for 90 minutes at 80 under a nitrogen atmosphere. 

  The solvent is then evaporated off under reduced pressure and the residue is chromatographed (preparative thin-layer chromatography; 3 silica gel plates 100 X 20 X 0.15 cm) using a 4: 1 mixture of hexane and ethyl acetate as the mobile phase. 

  The isomer A (trans) of a- (2 -carbo-tert is obtained in this way. -butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -? - [(4-tert. -butyl-phenyl) -acetylmethylene] - -acetic acid-tert. butyl ester of the formula
EMI23. 1
 as amorphous foam; Thin-layer chromatogram (silica gel; system hexane / ethyl acetate 4: 1):

  Rf = 0.58; Ultraviolet absorption spectrum:). mas 298 m (in ethanol), #max 338 m (in ethanol / potassium hydroxide), and #max 338 m (when adding hydrogen chloride to the ethanol / potassium hydroxide sample); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.40, 5.62, 5.78, (shoulder), 5.82-5.92 left and 6.27; and the isomer B (cis) the α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6- -diaza-6-bicyclo [3.2.0] heptyl) -? - [(4-tert. -butylphenyl) acetyl methylene] acetic acid tert. butyl ester of the formula
EMI23. 2
 which, after recrystallization from hexane, melts at 153; [] 20 D = 3280 + 10 (c = 0.888 in chloroform); Thin-layer chromatogram (silica gel; system hexane / ethyl acetate 4: 1): Rf = 0.44;

  Ultraviolet absorption spectrum: #max 295 m (# = 18300) (in ethanol), max 338 m (in ethanol / potassium hydroxide) and #max 338 m (when acidifying the ethanol / potassium hydroxide sample with hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40 +, 5.60, 5.72 y (shoulder), 5.80-5.92 in and 6.28. 



   The 4-tert used in the preparation of the starting material. -Butylbenzyl glyoxal hydrate can be prepared as follows: A solution of 10.6 g of 4-tert. -Butyl-phenylacetic acid chloride (produced by heating a mixture of
10 g 4-tert. -Butyl-phenylacetic acid with 60 ml of thionyl chloride to 600 for 3 hours, removal of the excess of thionyl chloride under reduced pressure and repeated evaporation of a mixture of the residue in benzene to remove the last traces of thionyl chloride) in 100 ml of dry ether slowly becomes a solution of 8.3 g of diazomethane added to 300 ml of ether.  After standing at -5 for 10 minutes, the excess of the diazomethane and the ether is distilled off under reduced pressure and at room temperature. 

  The yellow oily residue represents the 4-tert. - -Butyl-benzyl-diazomethyl ketone, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40 ii, 3.50 ti (shoulder), 4.72, 6.10 and 7.38,; and is processed further without cleaning. 



   A solution of 10.9 g of 4-tert. -Butylbenzyl diazomethyl ketone in 200 ml of dry ether and a mixture of 13.2 g of triphenylphosphine in 200 ml of dry ether are combined and stirred at room temperature for about 30 minutes. The 1- (4-tert. -Butylphenyl) -3- (triphenylphosphoranylidene) acetone precipitates, F.    129-130 after recrystallization from hexane; Ultraviolet absorption spectrum (in ethanol): #max 314 m (# = 7900) and #max 258 m (# = 16600); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.40 y, 4.72 y, 6.00 (shoulder), 6.70 and 6.60.  Another amount of the product can be obtained by concentrating the mother liquor. 

 

   A solution of 9.6 g 1- (4-tert. -Butylphenyl) -3- (triphenylphosphoranylidene) acetone in 60 ml tetrahydrofuran and 44 ml water is treated with 4.2 g sodium nitrite; the suspension is stirred at 10-130, with 44 ml of 2-n. 



  Hydrochloric acid is added dropwise.  After a further 10 minutes at 10, the organic layer is separated and the aqueous solution is extracted with methylene chloride.  The organic solutions are combined and evaporated; the residue is crystallized from ether, and the product obtainable from the mother liquor is chromatographed on 80 g of acid-washed silica gel. 

  With benzene and a 96: 4 mixture of benzene and ethyl acetate, the non-crystalline 4-tert.  -Butylbenzyl glyoxal hydrate eluted; Ultraviolet absorption spectrum: #max 250-275 m (in ethanol), #max 364 m (in ethanol / potassium hydroxide), and #max 322 mi (in ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.85-4.20, 3.40, 5.76, 6.60 and 7.30; Thin-layer chromatogram (silica gel; system benzene / ethyl acetate 1: 1): Rf = # 0.57 (smeared); and processed further without cleaning. 



   In an analogous manner, the following compounds can be obtained when the suitable starting materials are selected: 2-Ethylidene -7-phenylacetylamino-ceph-3-em4-carboxylic acid, F.    95. 980 after recrystallization from a mixture of benzene and acetone; Thin layer chromatogram (silica gel): Rf = 0.33 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 318 m (in ethanol), lmax = 300 m (in ethanol / potassium hydroxide) and #max = 322 m (in ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 3.29, 5.58, 5.75 (shoulder), 5.90, 6.21, 6.64 and 7.06 g ti;
7-Phenylacetylamino-2- (1,1-propylidene) -ceph-3-em-4-carboxylic acid, F.    102-105 after recrystallization from benzene; Thin-layer chromatogram (silica gel):

  Rf = 0.36 (system: acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 318 m (in ethanol), #max = 312 m (in ethanol / potassium hydroxide) and #max = 318 m (ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 3.30-3.50, 5.60 x, 5.66-5.76 s "5.91, 6.22'L and 6.64;
2-Ethylidene-7-cyanoacetylamino-ceph-3-em-4-carboxylic acid, F.  222-2250 after recrystallization from acetone; Thin-layer chromatogram (silica gel): Rf = 0.12 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 319 m (in ethanol), #max = 310 m (in ethanol / potassium hydroxide) and #max = 320 m (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.10, 3.30 ii, 4.45 ii, 5.6011, 5.90, 6.00, 6.25 Ii and 6.40;
7-cyanoacetylamino-2- (1,1-propylidene) -ceph-3-em-4-carboxylic acid, amorphous; Thin layer chromatogram (silica gel): Rf = 0.18 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 317 ml (in ethanol), lmax = 311 ml (ethanol / potassium hydroxide) and #max = 321 (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.10, 3.30, 3.41, 4.45, 5.60, 5.86, 6.02, 6.25 and 6.41;
2-ethylidene-7-bromoacetylamino-ceph-3-em-4-carboxylic acid, amorphous; Thin-layer chromatogram (silica gel): Rf = 0.24 (system:

  Acetic acid / toluene / water 5: 5: 1); Ultraviolet absorption spectrum: #max = 315 m (ethanol), #max = 314 m (ethanol / potassium hydroxide) and #max = 323 m (ethanol / hydrogen chloride); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06 (broad), 5.58, 5.67 Ii '5.81 j "6.23 ti and 6.42-6.62; and
2-Ethylidene-7- (1-tetrazolylacetylamino) -ceph-3-em-4-carboxylic acid, F.  238-240 after recrystallization from acetone; Thin-layer chromatogram (silica gel):

  Rf = 0.19 (system: acetic acid / water / toluene 5: 5: 1); Ultraviolet absorption spectrum: #max = 318 m (ethanol), #max = 308 m (ethanol / potassium hydroxide) and #max = 319 mli (ethanol / hydrogen chloride); Infrared absorption spectrum (potassium bromide): characteristic bands at 3.05, 3.20-3.45, 5.66, 5.8511, 5.95 tL, 6.24 Ii and 6.48.    



   The following compounds can be used as starting materials to produce the above compounds:
Isomer A of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7- -oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (n-butyryl-methylene) -acetic acid- tert. -butylesters, F.  109-1100 after recrystallization from hexane; [] D20 = -511 + 2 (in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.62 (system:

  Hexane / ethyl acetate 2: 1); Ultraviolet Absorption Spectrum (ethanol): #max = 292 my (# = 9900); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.36, 5.60, 5.80 (shoulder), 5.845.93 and 6.25; the corresponding isomer B melts after recrystallization from hexane at 126-127; [α] 20 D = -424 + 2 (in chloroform); Thin-layer chromatogram (silica gel): Rf = 0.56 (system:

  Hexane / ethyl acetate 2: 1); Ultraviolet Absorption Spectrum (ethanol): #max = 286 (# = 17700); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.38, 5.60, 5.76 Ii (shoulder), 5.82-5.95 and 6.27; and
Isomer A of α- (2-carbo-tert. -butyloxy-3,3-dimethyl-7- -oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α-propionylmethylene acetic acid tert. -butylesters, F.  126-1270 after recrystallization from hexane; [] D20 = -524 + 1 (chloroform); Thin-layer chromatogram (silica gel):

  Rf = 0.64 (system: hexane / ethyl acetate 2: 1); Ultraviolet Absorption Spectrum (in ethanol): #max = 289 m (# = 9500); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.34, 5.62, 5.82 (shoulder), 5.85-5.95 and 6.28; the corresponding isomer B melts at 151-153 after recrystallization from hexane; ta]] 20 = - 410 f 10 (chloroform); Thin-layer chromatogram (silica gel): Rf = 0.57 (system: hexane / ethyl acetate); Ultraviolet Absorption Spectrum (ethanol): #max = 286 m (± = 17150); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43, 5.61, 5.80 (shoulder), 5.85, u-5.95 and 6.29.  

 

Claims (1)

PATENT CLAIM Process for the preparation of 7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid and esters thereof of the formula EMI24.1 where R1 represents a hydrogen atom or the organic radical of an alcohol R1OH, R2 represents an acyl radical and R represents a methylene radical substituted by one or two optionally substituted hydrocarbon radicals or optionally substituted heterocyclic radicals in which heterocyclic groups have an aromatic character, or functional groups, and Salts of such compounds with salt-forming groups, characterized in that in a compound of the formula EMI25.1 acylated the amino group. SUBSCRIBED 1. The method according to claim, characterized in that the organic radical R1 in a compound obtained is replaced reductively or under acidic conditions by hydrogen or in a compound in which R 1 is hydrogen, this is replaced by a compound by an organic radical R 1. 2. The method according to claim, characterized in that a compound containing salt-forming groups is converted into a salt or a salt obtained is converted into the free compound or into another salt. 3. The method according to claim, characterized in that a mixture of isomers obtained is separated into the individual isomers or individual isomers obtained are isomerized to give an isomer mixture. 4. The method according to claim, characterized in that the free amino group in the starting material is acylated by treatment with organic carboxylic acids or with reactive, functional acid derivatives thereof 5. The method according to dependent claim 4, characterized in that halides, anhydrides or activated esters are used as reactive, functional acid derivatives 6. The method according to claim, characterized in that starting materials are used in the form of a raw reaction mixture obtainable under the action conditions. 7. The method according to claim or one of the dependent claims 1-6, characterized in that compounds of the formula EMI25.2 wherein R'1 denotes a hydrogen atom or a lower alkyl, halo-lower alkyl, cycloalkyl or phenylene-lower alkyl radical, R'2 represents an acyl radical and R 'represents a methylene group substituted by lower alkyl, lower alkanoyl or optionally substituted phenyl or benzoyl radicals, or salts of such compounds with salt-forming groups. 8. The method according to claim or one of the subclaims 1-6, characterized in that compounds of the formula Ia according to subclaim 7 or salts of compounds with salt-forming groups in which R'1 is a hydrogen atom or an easily cleavable lower alkyl, halo-lower alkyl , Cycloalkyl- or phenyl-lower alkyl radical, R'2 represents an acyl radical occurring in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, or an easily cleavable acyl radical and R 'represents one, by one or two lower alkyl radicals or a substituted methylene group optionally containing lower alkyl, lower alkoxy or nitro groups or halogen atoms 9. Process according to claim or one of the dependent claims 1-6, characterized in that 7-NR "2 -amiflo-8-oxo-methylene-5-thia-1 -azabicyclo [4,2,0] oct-2-en- 2 -carboxylic acids or lower alkyl esters thereof, as well as salts of those compounds with salt-forming groups in which R "2 is the acyl radical of a pharmacologically active 6-N-acylamino-penicillanic acid or 7-N-acylamino-cephalosporanic acid compound or a carbo-lower alkoxy group, the methylene group in the 4-position by one or two lower alkyl radicals or by an optionally lower alkyl, Phenyl radical containing lower alkoxy or nitro groups or halogen atoms is substituted and the lower alkoxy radical of the ester group can optionally have one or more halogen atoms in the 2-position. 10. The method according to claim or one of the dependent claims 1-6, characterized in that 7-NR "2 -amino -8-oxo-4-methylene-5-thia- 1 -azabicyclo [4.2.0] oct- 2-en-2-carboxylic acids or lower alkyl esters thereof, as well as salts of compounds with salt-forming groups in which R "2 has the meaning given in dependent claim 9, the methylene group in the 4-position by one or two methyl radicals or by an optionally lower alkyl -, Lower alkoxy or nitro groups or halogen atoms containing phenyl radical is substituted and the lower alkyl radical of the ester group for the tert. -Butyl or the 2,2,2-trichloro ethyl radical. 11. The method according to claim or one of the dependent claims 1-6, characterized in that the 4- (4 -nitrobenzylidene) -7.N-phenylacetyl-amino-8-oxo-5-thia-l -aza bicyclo [4, 2.0] oct-2-ene-2-carboxylic acid. 12. The method according to claim or one of the dependent claims 1-6, characterized in that the 4 .Benzylidene-7-N-phenyloxyacetyl-amino-8-oxo-5-thia-l -azabi cyclo (4,2,0] oct-2-ene-2.carboxylic acid produces 13. The method according to claim or one of the dependent claims 1-6, characterized in that the 4 -benzylidene-7-N-phenylacetyl-amlno-8-oxo-5-thia-1-azabicyclo [4,2.0] oct -2-en-2-carboxylic acid produces 14. The method according to claim or one of the dependent claims 1-6, characterized in that the 7-N -acetylamino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2 -en-2-carboxylic acid produces 15th Process according to claim or one of the dependent claims 1-6, characterized in that the 4- (4 -methoxybenzylidene) -7-phenylacetyl-amino-8-oxo -5-thia-1-azabicyclo [4,2,0] oct -2-en-2-carboxylic acid produces 16. The method according to claim or one of the dependent claims 1-6, characterized in that the 4-isopropylidene-7.N-phenylacetyl-amino.8.oxo-5-thia-1-azabicyclo [4,2,0] oct-2-en-2-carboxylic acid produces