CH542841A - 3-amino-4-(2-hydroxyethylthio)-2-oxo-azetidine derivs-pref contng ant - n-acyl derivs -intermediates for cpds with antibacterial activity - Google Patents

Abstract

Cpds. of gen form (I) where Ra1 = H or an amino-protecting group RA1; Rb1 = H or an acyl group Ac1; or Ra1 + Ra1 Rb1 for a bivalent amino-protecting group; R2 = H or acyl Ac2; each or R3 and R4 = H or an organic residue bound via a C-atom; or salts of (I) with salt-forming groups, are prepd. by reacting a bis(cis-3-N-RA1- N-Rb1-amino-2-oxo-4-azetidinyl)-disulphide of formula (II) with an oxiran cpd (III) and simultaneous reaction with a reducing agent. In cpd. (I) where R2 = H the OH gp. may be exchanged for acyloxy and/or when RA1 and/or Rb1a = Ac or RA1 + Rb1 = a bivalent amino-protecting group these may be split off and/or the free amino group may be protected and/or a salt may be exchanged for a free cpd. or another salt and/or a free cpd. may be exchanged for a salt and/or an isomeric mixture may be separated into isomers. The preferred reducing agents used are Zn, its alloys or amalgams or Mg, pref. in the presence of acids, acid agents or alcohols pref. with addition of water. Other reducing agents are alkalimetal- or Al amalgams in the presence of moist solvents or Cr II cpds. pref. in aqueous medium. The pref. acyl group Ac1 is an N-acyl deriv of a 6-APA or 7-amino-ceph-alosporanic acid cpd-contg. acyl gp. of an organic carboxylic acid or of a carbonic acid semi-deriv. (I) are intermediates in the synthesis of other cpds. esp. those of the type 7beta-amino-ceph-3-em-4-carboxylic acid and its N-acyl derivs which have ant-microbial activity such as against Gram-+ve and Gram-ve bacteria. In an example ethyleneoxide and Zn-dust are added to bis-(cis-2-oxo-3beta-phenylacetylemino-4beta-azetidinyl)-disulphi- de in aq. acetic acid to give 4beta-(2-hydroxyethylthio)-3beta-phenylacetylamino-azetidin-2-one.

Description

  

  
 



   The present invention relates to a process for the preparation of 3-amino-4- (2-hydroxyethylmercapto) -2- -oxo-azetidine compounds of the formula
EMI1.1
 where Rz represents an acyl group, R2 represents hydrogen, and each of the radicals R3 and R represents hydrogen or an organic radical bonded via a hydrocarbon atom, or salts of such compounds with salt-forming groups, and their use for the preparation of corresponding compounds in which the Hydroxy group is acylated by a group -C (= O) X.



   An acyl group R 1 primarily represents the acyl radical of an organic carboxylic acid, in particular the acyl radical of an optionally substituted aliphatic, cycloaliphatic. cycloaliphatic-aliphatic, aromatic. araliphatic. heterocyclic or heterocyclic-aliphatic carboxylic acid, as well as the acyl radical of a carbonic acid halide.



   An organic radical bonded via a carbon atom is primarily an optionally substituted hydrocarbon radical, in particular an optionally substituted aliphatic one. also cycloaliphatic cyclic aliphatic-aliphatic, aromatic or arclliph.ltischer hydrocarbon radical.



   An aliphatic radical, including the corresponding radical of an aliphatic carboxylic acid, which includes formic acid, is an optionally substituted aliphatic hydrocarbon radical such as an alkyl, alkenyl or alkynyl, especially a lower alkyl or lower alkenyl, and also a lower alkynyl radical . the e.g. can contain up to 7, preferably up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g. by free, etherified or esterified hydroxyl or mercapto groups.



  such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy. optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkyl mercapto or optionally substituted phenyl mercapto or phenyl lower alkyl mercapto, lower alkoxyearbonyloxy or lower alkanoyloxy groups, or halogen atoms, furthermore by oxo groups, nitro groups. optionally substituted amino groups. Azido groups.

  Acyl-. such as lower alkanoyl or benzoyl groups. optionally functionally converted from carboxy groups. as in salt form are the carboxyl groups or lower alkoxycarbonyl, optionally N-substituted carbamyl or cyano groups, or optionally functionally modified sulfo groups. such as sulfamoyl groups or sulfo groups present in salt form, be mono-, di- or polysubstituted.



   A cycloaliphatic or cycloaliphatic-aliphatic radical, including the corresponding radical of a cy tltaliphatic or cycloaliphatic-aliphatic carminic acid, is an optionally substituted or cyclo aliphatic-aliphatic hydrocarbon radical. e.g. a m,) no-. bi- or polycyclic cycloalkyl or cycloalkene n-I-ru ppe. or.

  Cycloalkyl or cycloalkenyl, lower alkyl or lower alkenyl group in which a cycloalkyl radical is e.g. contains up to 12, such as 3-8, preferably 3-6, ring carbon atoms, while a cycloalkenyl radical e.g. up to 12, such as 3-8, e.g. Has 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of a cycloaliphatic-aliphatic radical z.'B. can contain up to 7, preferably up to 4 carbon atoms. The above cycloaliphatic or cycloaliphatic-aliphatic radicals can, if desired, e.g. by optionally substituted aliphatic hydrocarbon radicals, such as by the above-mentioned optionally substituted lower alkyl groups, or then, e.g. like the abovementioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups.



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



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



   Heterocyclic groups, including those in heterocyclic-aliphatic radicals, in corresponding carboxylic acids are, in particular, monocyclic, as well as bi- or polycyclic, aza-, thia-. oxa-, thiaza-, oxaza-, diaza-. triaza or tetrazacyclic radicals, preferably of aromatic character, which optionally, e.g. like the above-mentioned cycloaliphatic radicals, can be mono-, di- or polysubstituted. The aliphatic part in heterocyclic-aliphatic radicals has e.g. meaning given for the corresponding cycloaliphatic-aliphatic or araliphatic radicals.



   The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of a carbonic acid half-ester, in which the organic radical of the ester group represents an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical or a heterocyclic-aliphatic radical, primarily the acyl radical of an optionally, e.g. in a- or 8-position, substituted lower alkyl half-ester of carbonic acid (i.e. a lower alkoxycarbonyl radical which may be substituted in the lower alkyl moiety, preferably in a- or in B-position), as well as one optionally in the lower alkenyl, cycloalkyl, phenyl or

  Phenyl-lower alkyl part-substituted lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl balbesters of carbonic acid (ie a lower alkenyloxycarbonyl, cycloalkoxycarbonyl, phenyloxycarbonyl or phenyl optionally substituted in the lower alkenyl, cycloalkyl, phenyl or phenyl-lower alkyl part lower alkoxycarbonyl radical).



  Acyl radicals of a carbonic acid half-ester are also corresponding radicals of lower alkyl half-esters of carbonic acid, in which the lower alkyl part is a heterocyclic, e.g.



  contains one of the above-mentioned heterocyclic groups of aromatic character, both the lower alkyl radical and the heterocyclic group being optionally substituted; such acyl radicals are optionally substituted lower alkoxycarbonyl groups in the lower alkyl part and in the heterocyclic group, which contain a heterocyclic group of aromatic character in the lower alkyl radical.



   A lower alkyl radical is e.g. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as n4 entyl, isopentyl, n-hexyl, isohexyl or n- Heptyl group, while a lower alkenyl group, for example a vinyl, allyl, isopropenyl, 2- or 3-methalallyl or 3-butenyl group, and a lower alkynyl radical e.g. may be propargyl or 2-butynyl.



   A lower alkylene radical is e.g. a 1,4-butylene or 1,5-pentylene radical, and a lower alkenylene radical e.g. a 2-butene-1,4-ylene radical.



   A cycloalkyl group is e.g. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, as well as adamantyl group, and a cycloalkenyl, e.g.



  a 2-cyclopentyl, 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl group. Cycloalkyl, lower alkyl or lower alkenyl is e.g. a cyclopropy] -, cyclopentyl-, ICyclohexyl- or cycloheptylmethyl-, -1,1- or -1,2-ethyl-, -1,1-, -1,2- or -1.3-propyl-, -vinyl- or allyl group, while a cycloalkenyl-lower alkyl or lower alkenyl group, e.g. a 1-, 2- or 3-cyclopentenyl-, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl-, -1,1- or -1,2 ethyl-, -1, Represents 1-, -1,2- or -1,3-propyl, vinyl or allyl group.



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



   A phenyl-lower alkyl or t-phenyl-lower alkenyl radical is e.g. a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3henylpropyl-. Diphenylmethyl, trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.



   Heterocyclic radicals are e.g. monocyclic. monoaza-, monothia- or monooxacyclic radicals of aromatic character. such as pyridyl, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl, furthermore pyridinium, thienyl, e.g. 2-thienyl radicals, or furyl, e.g. 2-furyl residues. or bicyclic monoazacyclic radicals of aromatic character such as quinolinyl, e.g. 2-quinolinyl or 4-quinolinyl radicals. or isoquinolinyl, e.g. 1 -isoquinolinyl radicals, or monocyclic diaza-, triaza-, tetraza-. thiaza- or oxazacyclic radicals of aromatic character, such as pyrimidinyl, triazolyl. Tetrazolyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl radicals.

  Heterocyclic-aliphatic radicals are heterocyclic groups, especially the lower alkyl or lower alkenyl radicals containing the above.



   Among etherified hydroxy groups are primarily lower alkoxy, e.g. Methoxy-. Ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy, n-pentyloxy or tert-pentyloxy groups, and substituted lower alkoxy, such as halo-lower alkoxy -, in particular 2-halo-lower alkoxy-, for example: B. 2,2,2-trichloro, 2-bromo or 2-iodoethoxy groups, also lower alkenyloxy, e.g. Vinyloxy or allyloxy groups, lower alkylenedioxy, e.g. Methylene, ethylene or isopropylidenedioxy groups, cycloalkoxy, e.g.

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



   As etherified mercapto groups, lower alkyl mercapto, e.g. Methyl mercapto, ethyl mercapto or n-butyl mercapto groups, lower alkenyl mercapto, e.g.



     Allyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto, e.g. Benzyl mercapto groups. to call.



   Esterified hydroxy groups are primarily halogen, e.g. Fluorine, chlorine, bromine or iodine atoms, as well as lower aikanoyloxy, e.g. Acetyloxy or +> ropionyloxy groups.



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



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



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



   A carboxyl group present in salt form is e.g.



  a carboxyl group present in alkali metal or ammonium salt form.



   A lower alkoxycarbonyl radical is e.g. a methoxycarbonyl, ethoxycarbonyl, nJ propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl or tert. - pentyloxycarbonyl group.



   Optionally N-substituted carbamyl groups are, for example. N-lower alkyl or N, N-l-di-lower alkyl-carbamyl, such as N-methyl, N-ethyl, N, N-dimethyl or N, N-diethylcarbamyl groups.



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

 

   A lower alkyloxycarbonyl radical is e.g. the vinyloxycarbonyl group, while cycloalkoxycarbonyl and phenyl-lower alkoxycarbonyl groups, in which the cycloalkyl or phenyl-lower alkyl radical have the aforementioned meaning. e.g. Adamantyloxycarbonyl, benzyloxycarbonyl, diphenylmethoxycarbonyl or α-4-Biphe nylyl-α-methyl-ethox¯ycarbonyl groups represent. Lower alkoxycarbonyl groups in which the lower alkyl radical is e.g. contains a monocyclic, monoaza, monooxa or monothiacyclic group are e.g. Furyl lower alkoxycarbonyl, such as furfuryloxycarbonyl, or thienyl lower alkoxycarbonyl, e.g. 2-thenyloxycarbonyl groups.



   Salts of compounds of the formula are in particular acid addition salts of those compounds in which R1 is hydrogen; suitable acids are primarily inorganic acids such as hydrohalic acids, e.g. Hydrogen chloride, hydrogen bromide or.



  Hydroiodic acids, sulfuric acid or phosphoric acids, as well as strong organic carboxylic or sulfonic acids.



   The compounds of formula I provide. as shown below, are valuable intermediates for the production of pharmacologically active compounds.



   The invention also relates, as new compounds, to those of the formula I in which Rl. R2, R, and R4 have the meanings given above.



   Particularly valuable as intermediate products are compounds of the formula I in which RX denotes hydrogen or the acyl group Ac ', which represents a, in a preferably pharmacologically active, naturally occurring or synthetically producible N-acyl derivative of the 6-amino penicillanic acid or 7-amino cephalos poransäureverbindungen containing acyl radical or an easily cleavable acyl radical, R. represents hydrogen or an easily cleavable acyl radical of the formula -C (= O) -Xl, where X1 represents an etherified hydroxyl or mercapto group which, together with the carbonyl grouping, is a mild one Conditions means cleavable esterified carboxyl or thiocarboxyl group, and each of the groups R2 and R, hydrogen or an optionally, for example

   by free or functionally modified, such as etherified or esterified hydroxyl or mercapto groups, e.g. Lower alkoxy, lower alkylthio or lower alkanoyloxy groups or halogen atoms, or optionally functionally modified carboxyl groups.



  such as lower alkoxycarbonyl, carbamyl or cyano groups substituted lower alkyl, primarily methyl, or an optionally. e.g. like the above-mentioned lower alkyl radical or phenyl or phenyl-lower alkyl substituted by lower alkyl radicals. e.g. Benzyl radical. means, where and at most one of the radicals R2 and R, stands for an optionally substituted phenyl or phenyl-lower alkyl radical. New compounds among the particularly emphasized compounds are those of the formula I in which R1, R, R2 and R4 have the meanings just given, preferably at most one of the radicals R3 and R4 being an optionally substituted phenyl or phenyl-lower alkyl radical.



   An acyl radical Ac 'contained in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid or an acyl radical which can be converted into these is primarily a group of the formula
EMI3.1
 wherein n is 0 and R1 is an optionally substituted cycloaliphatic or aromatic hydrocarbon radical, or an optionally substituted heterocyclic radical, preferably an aromatic character. a functionally modified, preferably etherified hydroxyl or mercapto group or an optionally substituted amino group, or in which n is 1, R1 is hydrogen or an optionally substituted aliphatic group.

   cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, an optionally functionally modified, preferably etherified or esterified hydroxyl or mereapto group, an optionally functionally converted carboxyl group, an acyl group. is an optionally substituted amino group or an azido group, and each of the radicals R and R11 is hydrogen, or in which n is 1, Rl is an optionally substituted aliphatic.

   Cycloal iphatical or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical, preferably of aromatic character, R "denotes a level or functionally modified, preferably etherified hydroxyl or mercapto group, a given subsection of amino or a given group of amino acids optionally denotes a functionally separated carboxyl group, and R "'denotes hydrogen, or in which n denotes
1 stands,

   each of the radicals Rl and R "denotes a functionally modified, preferably vcrilhcl-Lc or esterified hydroxyl group or an optionally fully modified carboxyl group. and R" 'represents Wnssloff, or in which n is 1, R' is hydrogen or an optionally substituted a lipha I mean hydrocarbon radical.

   and R "and R't 'together represent an optionally substituted aliphatic hydrocarbon radical linked to the carbon atom by a double bond, or in which n is
1 and Rl is an optionally substituted aliphatic. cycloaliphatic or aromatic hydrocarbon radical or an optionally substituted heterocyclic radical,

   preferably of aromatic character, Rti is an optionally substituted aliphatic or aromatic hydrocarbon radical and R'Tl is hydrogen or an optionally substituted aliphatic or aromatic hydrocarbon radical.



     In the above definitions, an aliphatic hydrocarbon radical z 13 means a straight chain or branched lower alkyl. as well as lower alkenyl or lower alkynyl group. Such a residue. In particular a Nie derulkylrest. can be used as substituents e.g. optionally substituted cycloaliphatic or aromatic hydrocarbon radicals, e.g. Phenyl radicals, or optionally substituted heterocyclic radicals, preferably of aromatic character, also optionally functionally modifiedc. preferably etherified or esterified hydroxy or mercapto, e.g. by optionally substituted aliphatic, aromatic or araliphatic hydrocarbon radicals.

   and also heterocyclic or heterocyclic-aliphatic groups, etherified hydroxyl or mercapto groups, such as optionally substituted lower alkoxy, phenyloxy, phenyl-lower alkoxy or lower alkyl mercapto groups. or halogen atoms, nitro groups, optionally substituted amino, such as di-lower alkyl-amino, alkylenamino. Lower alkanoyl amino or sulfonic amino groups, acyl, e.g. optionally substituted lower alkanoyl or benzoyl radicals, or optionally functionally modified carboxyl, e.g. B.



  Lower alkoxycarbonyl, carbamoyl or cyano groups.



  Azido groups or optionally functionally modified sulfo, e.g. Sulfamoyl groups. contain.



   A cycloaliphatic hydrocarbon radical preferably contains 3-7 ring carbon atoms and is an optionally, e.g. by aliphatic 'radicals or then, e.g. like the above aliphatic radical, cycloalkyl and cycloalkenyl groups substituted by functional groups, primarily with 5 or 6 'ring carbon atoms. Such a cycloaliphatic radical, primarily a cycloalkyl radical, preferably contains an amino group in the 1-position as a substituent.



   The abovementioned aromatic hydrocarbon radicals are in particular optionally substituted, bicyclic, but primarily monocyclic aromatic hydrocarbon radicals, some of which may be saturated, such as naphthyl or tetrahydronaphthyl, primarily phenyl radicals. These residues can e.g. by optionally substituted aliphatic, cycloaliphatic or aromatic hydrocarbon, e.g. Lower alkyl, trifluoromethyl or optionally substituted cycloalkyl or phenyl radicals, or by functional groups, such as optionally modified, e.g.



  etherified or esterified, hydroxyl or mercapto, nitro groups, optionally substituted amino groups, acyl groups, optionally functionally modified carboxyl or optionally functionally modified sulfo groups, e.g. the above-mentioned functional groups of this type may be substituted.



   An optionally substituted heterocyclic radical, preferably of aromatic character, is primarily a monocyclic monoaza, monothia, mono oxa, 'B, diaza, oxaza, thiaza, triaza or tetrazacyclic radical, preferably of aromatic character, e.g.



  a pyridyl, fyridinium, thienyl, furyl, imidazolyl, isozolyl, thiazolyl, triazolyl, tetrazolyl or isoxazolyl radical, which is e.g. how one of the above aromatic radicals can be substituted.



   An etherified hydroxy or mercapto group contains as an etherifying radical e.g. an optionally substituted aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon radical, and means et e.g. an optionally substituted lower alkoxy, ied eralkenyloxy, phenyloxy, phenyl-lower alkoxy, lower alkyl mercapto, lower alkenyl mercapto, phenyl mercapto or phenyl lower alkyl mercapto group. Further radicals etherifying a hydroxyl and, in particular, mercapto group are optionally substituted heterocyclic C; groups, preferably of aromatic character, such as e.g. the above-mentioned heterocyclic radicals.



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



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



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



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



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



   In the abovementioned acyl groups of the formula Ib, iB. n for 0 and RI for one optionally, preferably in the 1-position by amino or one, optionally in salt, z.lB. Alkali metal salt form, substituted cycloalkyl group with 5-7 ring carbon atoms, an optionally, preferably by lower alkoxy, sulfo-substituted phenyl, naphthyl or tetrahydronaphthyl group, an optionally, e.g. by lower alkyl and / or phenyl groups, which in turn have substituents such as halogen, e.g.

  Chlorine, substituted heterocyclic group, such as a 4-isoxazolyl, or a preferably, e.g. by an optionally substituted one such as halogen, e.g.



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



  Chlorine, or optionally substituted phenyloxy-containing phenyl group, an optionally, e.g. by amino, substituted pyridyl, pyridinium, thienyl, 1 imidazolyl or 1 -etrazolyl group, an optionally substituted lower alkoxy or phenyloxy group, a lower alkyl mercapto or lower alkenyl mercapto group, an optionally, e.g. by lower alkyl, substituted phenyl mercapto, 2-imidazolyl mercapto or 1,2, 4-triazol-3-yl mercapto group, a halogen, especially chlorine or chromate atom, a carboxy, lower alkoxycarbonyl, cyano or optionally, e.g.

   by phenyl, N-substituted carbamoyl group, an optionally substituted lower alkanoyl or benzoyl group, or an azido group, and Rn and RI for hydrogen, or n for 1, Rt for an optionally substituted EPhenyl or thienyl group, RII for an amino or Cyan grul * e, one optionally in salt, e.g. In alkali metal salt form, carboxyl or sulfoamino group, or an optionally substituted lower alkoxy or phenyloxy group, and RIII for hydrogen, or n for 1, Ri and RII each for a halogen, e.g. Bromine atom,

   or a lower alkoxycarbonyl, e.g. Methoxycarbonyl group, and RIII is hydrogen, or n is 1, and each of the groups Rt, RII and RIII is a lower alkyl group.

 

   The above acyl groups can e.g. by the radical of the formula RIV- (Cm H2m) -C (= O) -, where m m stands for 0, 1 or 2, preferably 1, and a carbon atom of a preferably unbranched alkylene radical of the formula (CmlH2m) - e.g. by an optionally substituted amino group, a free, etherified od.



  esterified hydroxyl or mercapto group, a free or functionally modified carboxyl group or an oxo group, iB. can be substituted by one of the above groups of this type, and in which RIV is a, optionally in the nucleus, e.g. such as the above alkylene radical, as well as aromatic or cycloaliphatic hydrocarbon radicals substituted by nitro or optionally functionally modified sulfo groups, such as phenyl or cycloalkyl radical, or an optionally, e.g. like the above aromatic or cycloaliphatic radical, substituted heterocyclic group, preferably of aromatic character. such as an optionally substituted pyridyl, pyridinium. Thienyl., Furyl, imidazolyl.

  Tetrazolyl or isoxazolyl group, furthermore one, by an aromatic or cycloaliphatic hydrocarbon radical or heterocyclic radical, optionally substituted as indicated, e.g. aromatic character, etherified hydroxyl or mercapto group means. Such acyl radicals are e.g. 2,6-dimethoxybenzoyl, tetrahydronaphthoyl, 2-methoxy-naphthoyl, 2-ethoxy-naphthoyl, cyclopentylcarbonyl, -amino-cyclopentylcarbonyl- or x-amino-cyclohexylcarbonyl- (optionally with substituted amino group. Like one, optionally sulfoamino group or an acylamino group present in salt, such as alkali metal salt form, in which the acyl radical is preferably an easily cleavable acyl radical of a carbonic acid half ester, such as 2,2,2-trichloroethoxycarbonyl.

  Phenacyloxycarbonyl or tert-butyloxycarbonyl radical). Benzyloxycarbonyl-, hexahydrobenzyloxycarbonyl-, 2-phenyl-5-methyl-4-isoxazolylcarbonyl-, 2- (2- chlorophenyl) -5-methyl-4-isoxazolylcarbonyl-, 2- (2,6-dichlorophenyl) -5-methyl -4-isoxazolylcarbonyl-, phenylacetyl-, phenacylcarbonyl-, phenyloxyacetyl-, phenylthioacetyl-, bromophenylthioacetyl-, 2-phenyloxypropionyl-, a- -phenyloxy-phenylacetyl-, x methoxyphenylacetyl-, a-methoxy -3,4-dichloro-phenylacetyl-, -Cyan-phenylacetyl-, phenylglycyl- (optionally with, e.g.

   as stated above, substituted amino group), benzylthioacetyl, benzyltbiopropionyl, x-carboxy-phenylacetyl (optionally with a functionally modified carboxy group, as present in salt, eg alkali metal salt form or esterified), 2-. pyridylacetyl, 4- Amino-pyridinium acetyl, 2-thienylacetyl, oc-carboxy -2-thienylacetyl or * carboxy-3-thienylacetyl (optionally with, for example, functionally modified carboxyl group as indicated above). α-cyano-2-thienylacetyl-, sc- -amino-2-thienylacetyl- or x-amino-3-thienylacetyl- (optionally with, e.g.

   as stated above, substituted amino group), 3-thienylacetyl-, 2-furylacetyl-, 1-rmidazolylacetyl-, 1-methyl-5-tetrazolylacetyl-. 3-methyl -2-imidazolylthioacetyl or 1, 2,4-triazol-3-yl-thioacetyl group.

  An acyl residue is e.g. also a group of the formula CnHen + 1-C (= O) - or C * H2 "1-C (= O) -. in which is an integer up to 7 and the chain is straight or branched and optionally from an oxygen or Sulfur atom interrupted and / or, for example, halogen atoms, free or functionally modified carboxyl groups, such as lower alkoxycarbonyl or cyano groups, free or substituted amino groups, or oxo, azido or nitro groups, can be substituted, for example propionyl, butyryl, lexanoyl -, octanoyl, acrylyl, crotonoyl, 3 butenovl, 2-pentenoyl, methoxyacetyl, methylthioacetyl, butylthioacetyl, allylthioacetyl.

  Chloroacetyl, bromoacetyl, dibromoacetyl, 3-chloropropionyl, 3-bromopropionyl, aminoacetyl, 5-amino-5-carboxy-valeryl (optionally with substituted amino and / or optionally functionally modified carboxyl group).



  Azidoacetyl, carboxyacetyl, methoxycarbonylacetyl.



  Ethoxylcarbonylacetyl, bismethoxycarbonylacetyl, N phenylcarbamoylacetyl, cyanoacetyl, α-cyanopropionyl or 2-cyano-3-dimethylacrylyl group, also a radical of the formula RV-NH <O-, where RV is an optionally substituted aromatic or aliphatic hydrocarbon radical, in particular one. optionally lower alkyl radical, preferably substituted by lower alkoxy groups and / or halogen atoms, e.g. the N-2-chloro ethylcarbamoyl radical means.



   An easily cleavable acyl residue Ac 'is primarily one by reduction, e.g. by treatment with a chemical reducing agent, or by acid treatment, e.g. with trifluoroacetic acid, cleavable acyl radical of a half ester of carbonic acid, such as a lower alkoxycarbonyl, preferably multiply branched or substituted by halogen atoms. e.g. tert-butyloxycarbonyl, tert-pentyloxycarbonyl, 2.2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl radical or a radical which can be converted into the latter, such as 2-bromoethoxycarbonyl radical, a, preferably polycyclic cycloalkoxycarbonyl, e.g.

  Adamantyloxycarbonyl radical, a phenyl-lower alkoxycarbonyl, primarily phenyl-lower alkoxycarbonyl radical, in which the a-position is preferably polysubstituted. e.g. the diphenyl-methoxycarbonyl or a4-biphenylyl-a-methyl-ethyloxycarhonyl radical, or a furyl-lower alkoxy carbonyl, primarily sc-furyl-lower alkoxycarbonyl. e.g. Furfuryloxycarbonyl radical.



   The hydroxy group -O-R can be converted into an acyloxy group -O-C (= O) -X, in which the group -C (= O) -X1 is an esterified carboxyl group which can be cleaved under mild conditions.



   In an esterified carboxyl group of the formula -C (= O) -XI the group X1 is e.g. represents the remainder of the formula -O-R, "which, together with the carbonyl group, represents an esterified carboxyl group which can be easily cleaved when treated with chemical reducing agents under neutral or weakly acidic conditions.



  In this group, Rna denotes a 2-halo-lower alkyl radical in which halogen preferably has an atomic weight of more than 19, in particular a 2-polychloro-lower alkyl, such as 2-polychloroethyl radical, primarily the 2.2,2-trichloroethyl radical and the 2.2.2 radical -Trichlor-1-methylwäthylrest, but can also, for example a 2-bromo-lower alkyl, such as 2-polybromo-lower alkyl, such as 2,2.2-bromoethyl, and also the 2-bromoethyl radical. or a 2 iodine-lower alkyl, e.g. in particular the 2-iodo-ethyl radical.



  mean.



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

 

   The group X1 can also represent the radical of the formula -O-R, 'which, together with the carbonyl group, represents an esterified carboxyl group which can be easily cleaved upon irradiation under neutral or weakly acidic conditions. In this group, R represents an arylmethyl group, in which aryl represents an optionally substituted phenyl group. their substituents are primarily functional groups, such as free or functionally modified carboxyl groups. e.g.



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



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



   A group X1 can also represent the radical of the formula -O-Ro ('which, together with the carbonyl grouping, forms an esterified carboxyl group that is easily cleavable under acidic conditions. Such a radical Rod is primarily a methyl group, which is formed by an electron donating Carbocyclic aryl group having substituents or monosubstituted by a heterocyclic group of aromatic character having oxygen or sulfur atoms as ring members, or in an oxa or thiacycloaliphatic radical which means the ring member representing the position relative to the oxygen or sulfur atom.



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



   A heterocyclic group of aromatic character containing oxygen or sulfur atoms as ring members represents primarily a furyl, e.g. 24 furyl, or a thienyl, e.g. 2-thienyl radical.



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



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



   An esterified carboxyl group of the formula -C (= O) -X1 which can likewise be cleaved under acidic conditions is the group of the formula -C (= O) -OR, ", in which ROe is preferably a methyl radical which is polysubstituted in the sc position, such as a - Position of multiply branched lower alkyl, e.g. tert-butyl or tert-pentyl, a cycloalkyl, e.g. adamantyl group, a polyarylmethyl, e.g. benzhydryl or trityl, furthermore a 2- (4-biphenyl- yl) -l - methyl-ethyl group.



   Another easily cleavable esterified carboxyl group of the formula -C (= O) -X1 is a group of the formula -C (= O) -O-Rof, in which Rof represents an esterified carboxyl group which can be cleaved under hydrolytic conditions together with the carboxyl group, such as an organic radical forming an activated ester group and in particular denotes a cyanomethyl, 4-nitrophenyl, 4-nitrobenzyl, phthalimidomethyl or succinimidomethyl group.



   In a compound of the formula I, the group R1 is primarily an acyl radical contained in naturally occurring or biosynthetically producible fN acyl derivatives of 6Jamino-penam-3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds, such as an optionally substituted phenylacetyl or phenyloxyacetyl radical, furthermore an optionally substituted lower alkanoyl or lower alkenoyl radical, for example



  the 4-hydroxy-phenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5-amino-5-carboxy-valeryl, n-butylmercaptoacetyl or allylmercaptoacetyl, and in particular the phenylacetyl or phenyloxyacetyl radical, a highly effective N-acyl derivative 16-amino-penam- -3-carboxylic acid or 7-amino-ceph-3-em-4-carboxylic acid compounds occurring acyl radical, such as the 2-chloroethylcarbamoyl, cyanoacetyl, phenylglycyl (optionally with substituted amino group),

   2-thienylacetyl, amino-2-thienylacetyl (optionally with substituted amino group), 1-aminocyclohexylcarbonyl (optionally with substituted amino group), cc-carboxy-phenylacetyl (optionally with substituted carboxyl group) or α-carboxy-thienylacetyl radical (optionally with a protected carboxyl group), or a slightly, especially under acidic conditions, e.g. at the   ;

  ; Treatment with trifluoroacetic acid, or reductive, e.g. on treatment with zinc in the presence of aqueous acetic acid, cleavable acyl radical of a carbonic acid half-ester, such as tert-butyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycarbonyl or the 2-bromoethoxycarbonyl radical which can be converted into the latter, and R2 represents hydrogen, while each of the groups R3 and R4 represents hydrogen or a lower alkyl, primarily methyl or ethyl group.

  In the corresponding acylated compounds the group -C (= O) X1 represents an easily, e.g. as indicated, cleavable acyl radical of a carbonic acid half ester, such as a radical of the formula -C (= O) -O-Roa, -C (= O) -OR, b or -C (= O) -OR, ", for example the tert. -Butyloxycarbonyl-, 2,2,2-Trichloräthoxycarbonyl- or 2-Jodäthoxycarbonyl- or the convertible in the latter 2-Bromoethoxycarbonyl.



   According to the invention, the mercapto alcohol compounds of the formula I will behave if a bis (cis-3 - R1A-amino-2-oxo-4-azetigdinyl) disulfide compound of the formula
EMI6.1
 with an oxirane compound of the formula
EMI6.2
  with simultaneous treatment with a reducing agent.



   The reducing agents used are primarily chemical reducing agents, e.g. suitable reducing metals, as well as reducing metal compounds, e.g.



  Metal alloys or amalgams, as well as strongly reducing metal salts. Zinc, zinc alloys, e.g. Zinc copper, or zinc amalgam, and also magnesium, which are preferably used in the presence of hydrogen-releasing agents which are able to generate hydrogen nascent together with the metals, metal alloys and amalgams, zinc e.g. advantageously in the presence of acids such as organic carbonic, e.g. Lower alkanecarboxylic acids.



  primarily acetic acid, or acidic agents such as ammonium chloride or ipyridine hydrochloride, preferably with the addition of water, and in the presence of alcohols, especially aqueous alcohols such as lower alkanols, e.g. Methanol, ethanol or isopropanol, which can optionally be used together with an organic carboxylic acid, and alkali metal amalgams, such as sodium or potassium amalgam, or <Aluminum amalgam, preferably in the presence of moist solvents such as ethers or lower alkanols.



   Strongly reducing metal salts are primarily Chrom4l compounds, e.g. Chromium-II-chloride or chromium-II-acetate, preferably in the presence of aqueous media containing water-miscible organic solvents, such as lower alkanols, carboxylic acids, such as lower alkanecarboxylic acids or derivatives, such as optionally substituted, e.g. lower alkylated, amides thereof, or ethers, e.g. Methanol, ethanol, acetic acid, dimethylformamide, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether or diethylene glycol dimethyl ether can be used.



   The reaction according to the invention is preferably carried out in the presence of a solvent, primarily a water-miscible solvent such as a lower alkanol, e.g. Ethanol, an ether, e.g. Tetrahydrofuran, or a lower alkanecarboxylic acid, e.g. Acetic acid, or a solvent mixture, usually carried out in the presence of water, being carried out under mild conditions, usually at room temperature or with cooling, e.g. at about -200C to about +1 00C, if necessary also at an elevated temperature, e.g. at temperatures up to about 1000C, and / or in a closed vessel and / or in an inert gas, e.g. Nitrogen atmosphere works.



   In a compound of the formula I obtainable according to the process, the free hydroxyl group can be removed by methods known per se, e.g. by treatment with a carboxylic acid of formula X1-COOH or reactive acid derivatives thereof such as halides, e.g. Chlorides, anhydrides (including the internal anhydrides of carboxylic acids, ie ketenes, or of carbamic or thiocarbamic acids, ie isocyanates or isothiocyanates, or mixed anhydrides, such as those that can be formed, for example, with chloroformic acid lower alkyl esters or trichloroacetic acid chloride) or activated Esters are acylated.

  If necessary, one works in the presence of suitable condensing agents, when using acids e.g. in the presence of carbodiimides, such as dicyclohexylcarbodiimide, u. when using reactive acid derivatives e.g. in the presence of basic agents such as triethylamine or pyridine.



   An acyl group can also be introduced stepwise; for example, a compound obtainable according to the process can be reacted with a carbonyl dihalide, such as phosgene, and the halogen, e.g. Chlorocarbonyloxy compound with an alcohol, e.g. 2,2,2-trichloroethanol, 2-bromoethanol, phenacyl alcohol or tert. Butanol, and so gradually an etherified hydroxycarbonyl, e.g. the 2,2,2-Trich loräthoxycarbonyl-, 2aBromäthoxycarbonyl-, Phenacyloxycarbonyl- or tert. Butyloxycarbonyl group, into the hydroxyl group.

  The acylation reaction can be carried out in the presence or absence of solvents or solvent mixtures, if necessary, with cooling or heating, in a closed vessel under pressure and / or in an inert gas, e.g. Nitrogen atmosphere, optionally carried out in stages.



   Salts of compounds of the formula 1 can be prepared in a manner known per se, acid addition salts of compounds with basic groups e.g.



  by treatment with an acid or a suitable anion exchange reagent. Salts can be converted into the free compounds in the usual way, acid addition salts e.g. by treating with an appropriate barbaric means.



   Mixtures of isomers obtained could be obtained by methods known per se, e.g. by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes, are separated into the individual isomers. Racemates obtained can usually, if appropriate, after the introduction of salt-forming groups at a temporary rate, e.g. 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.



  be separated into the antipodes.

 

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



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



   The starting materials of the formula II used according to the method are obtained when a compound of the formula
EMI7.1
 wherein Y represents an optionally substituted methylene group, oxidizes, and in a compound of the formula obtained, suitable sensitizers are used. The UV light preferably has a main wavelength range of over 280 my, primarily from about 300 m to about 350 Ilr;

  ; this can e.g. by suitably filtering the ultraviolet light through an appropriate filter, e.g. Pyrex filters, or by suitable solutions, such as salt solutions, or other, shorter-wave light absorbing liquids, such as benzene or toluene. tThe ultraviolet light is preferably generated by means of a high pressure mercury vapor lamp.



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



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



  potassium metal hypohalites, e.g. Sodium hypoiodite, as well as organic hypohalites, such as tert-butyl hypohalite, suitable iron (III) salts and complexes, such as iron (III) chloride, preferably in the presence of an organic solvent, e.g. Ether, acetic acid, or ethanol, and optionally water, or potassium ferricyanide, 1,2 diiodoethane in the presence of an organic solvent e.g. Acetone, tetrahydrofuran or ethanol, or thiocyanogen in the presence of a suitable organic solvent, iB. Acetic acid, can be used.



   In a disulfide compound of the formula IIa obtainable according to the process in which the radicals R1a and R1b together represent an optionally substituted methylene group, such a methylene group can be replaced hydrolytically by hydrogen; If the oxidation reaction is carried out in the presence of water, this cleavage can already take place during this.



   In a disulfide compound of the formula Ha obtainable according to the process, in which the amino groups are unsubstituted or contain an optionally substituted methylene radical as a substituent, these groups can be converted by methods known per se, e.g. as described above, protected, e.g. be acylated. An optionally substituted methylene radical formed by the groups R1a and R1b, possibly in modified form, can be split off.



   The intermediates of the formula III, in which Y represents a disubstituted methylene group, required to prepare the starting materials are known (see e.g. Austrian Patent No. 264 533) or can be prepared by the processes used for the known compounds. Compounds in which Y is an unsubstituted or monosubstituted methylene group can e.g. are obtained when a compound of the formula III, in which Y is a disubstituted methylene group, is reacted with an aldehyde or a reactive derivative such as a hydrate or a reactive polymeric product of such an aldehyde.

  This reaction is usually carried out in a solvent such as a water-miscible organic solvent such as a water-miscible alcohol or ether, e.g. Dioxane, or made in a suitable mixture of solvents.



  It is preferable to add water and work in
EMI8.1
 wherein R1a and R1b represent hydrogen or together represent an optionally substituted methylene group, if desired, after cleavage of the latter, introduces the acyl group tR1 into the amino group.



   In a compound of the formula III, Y is preferably a mono- or disubstituted methylene group, where substituents are preferably optionally substituted, mono- or divalent hydrocarbon radicals, primarily corresponding aliphatic hydrocarbon radicals, such as lower alkyl, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl groups, also lower alkylene, e.g. 1,4-butylene or 1,5-pentylene groups, as well as corresponding cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals, such as cycloalkyl, e.g. Cyclopentyl or cyclohexyl, IPhenyl or phenyl lower alkyl, e.g.



  Benzyl or phenylethyl groups. Y is primarily the isopropylidene or isobutylidene group, i. for a methylene radical substituted by two methyl groups or one isopropyl group.



   Oxidizing agents used according to the method are primarily those which are used to form disulfide compounds under conditions under which the lactam ring is not affected. In particular, these are halogen, such as bromine and primarily iodine, which can advantageously be used in the presence of organic solvents, e.g.

   optionally substituted hydrocarbons such as aromatic hydrocarbons, e.g. Benzene, ethers such as cyclic ethers, e.g. Tetrahydrofuran or dioxane, alcohols such as lower alkanols, e.g. Methanol or ethanol, or carboxylic acids, such as Niederalkancaibonsäuren, z.'B. Acetic acid, or solvent mixtures and optionally in the presence of water, with cooling (e.g. temperatures up to about -30 ° C.), at room temperature or with slight warming, further, if necessary, under an inert gas such as nitrogen atmosphere.



   Further oxidizing agents suitable for the oxidation of starting materials are oxidizing heavy metal carboxylates, preferably lead IV carboxylates, such as lead IV alkanoates, in particular lower alkanoates and primarily lead tetraacetate, also lead tetrapropionate or lead tetrastearate, and optionally substituted lead trabenzoates, iB. Lead tetrabenzoate or lead tetra-3-bromobenzoate, as well as thallium III-carboxylates, e.g. Thallium III acetate, or mercury II carboxylates such as mercury II acetate, these oxidizing agents, if desired, in situ, e.g. can be formed by the reaction of lead dioxide or mercury-II-oxide with an organic carboxylic acid such as acetic acid.

 

   The above heavy metal carboxylates, in particular the corresponding lead 1V compounds, are advantageously used in the presence of a light source, preferably with ultraviolet and longer-wave, such as visible light, optionally with the addition of an acidic agent such as an inorganic or organic acid, e.g. an organic carboxylic or preferably sulphonic acid such as p-toluenesulphonic acid, if desired or necessary, with cooling or preferably heating and / or in a closed vessel and / or in an inert gas atmosphere, e.g. under nitrogen.



   The compound of the formula III, in which Y is a methylene radical substituted by the isopropyl group, can be prepared from readily available starting materials if a penam-3-carboxylic acid compound IVa of the formula
EMI9.1
 in which Aca represents the acyl radical of an organic carboxylic acid, in which free functional groups, such as hydroxyl, mercapto and, in particular, amino and carboxyl groups, optionally, e.g. by acyl groups or

   in the form of ester groups, are protected, and Ro is a carboxyl group -C (= O) -OH (compound IVa) or a salt thereof into the corresponding acid azide compound with the formula IV. wherein Ro is the azidocarbonyl radical -C (= O) - N3 represents (compound IVb) converted, this with elimination of nitrogen to the corresponding isocyanate compound with the formula IV, in which Ro is the isocyanato group -N = C = O (compound IVc) and simultaneously or subsequently with a compound of the formula HX (V) in which X2 represents a hydroxy or mercaptocarbonyl group which is substituted together with the carbonyl group in the isocyanato group and which can be cleaved under neutral or acidic conditions, and in a compound obtained,

   if necessary or desired, an acyl radical Ac is replaced by hydrogen and, if desired, this is replaced by an acyl group which can be split off in the following step. In the thus obtainable Pe naming compound of the formula
EMI9.2
 where Rl is hydrogen or an acyl group Ac "which can be split off under the reaction conditions of the following process step, the group of the formula -C (= O) -X2 is split under neutral or weakly acidic conditions with simultaneous or subsequent treatment with water and the 4 , 4-Dimethyl-5-ffi ia-2,7-d iaza-bicyclo [4.2.0] oct-2-en-8-one is separated off or the carbon-nitrogen bond is reduced in this.



   An acyl group AQ occurring in the compounds of the formula IV can represent any acyl radical of an organic carboxylic acid with optionally protected functional groups, primarily an acyl radical contained in naturally occurring or biosynthetically producible N-acyl derivatives of the 6-aminopenam-3-carboxylic acid compounds, such as a monocyclic arylacetyl or aryloxyacetyl, further an optionally substituted lower alkanoyl or lower alkenoyl, eg the 4-hydroxy-phenylacetyl, hexanoyl, octanoyl, 3-hexenoyl, 5> amino-5-carboxy-valeroyl, n-butyl mercaptothioacetyl or allyl mercaptothioacetyl, in particular the phenylacetyl or phenyloxyacetyl, or then one, preferably under acidic conditions easily cleavable acyl residue.

   like the acyl residue of a half ester of carbonic acid, iB. the tert-butyloxycarbonyl radical.



   The conversion of an acid compound 1Va or a suitable salt, in particular an ammonium salt, into the corresponding acid azide 1Vb can e.g.



  by converting it into a mixed anhydride (e.g. by treating with a lower alkyl haloformate such as ethyl chloroformate in the presence of a basic agent such as triethylamine) and treating such anhydride with an alkali metal azide such as sodium azide. The acid azide compound Wb obtainable in this way can be used in the presence or absence of a compound of the formula V under the reaction conditions, e.g. on heating, are converted into the desired isocyanate compound IVc, which usually does not need to be isolated and can be converted directly into the desired compound of the formula VI in the presence of a compound of the formula V.



   Substituted hydroxyl or mercapto groups X are primarily etherified hydroxyl and mercapto groups which, together with the carbonyl group, form a functionally modified, primarily esterified, carboxyl and thiocarboxyl group which can be cleaved under neutral or weakly acidic conditions. These are in particular the groups of the formula -O-R, ", -O-R, b, -O-R," and Rod, in which pink, R, b, ROe and Rod have the meanings given above.



   The reaction of a compound of formula IVc with a compound of formula V, especially with a 2-haloethanol R0aOH, e.g. with 2,2,2-trichloro- or 2-bromoethanol, an arylcarbonylmethanol R, b-OH.



  e.g. Phenacyl alcohol, or an aryl methanol Roe-0H or R, d-OH, e.g. 4,5-dimethoxy-2-nitro-benzyl alcohol or 4s-methoxy-benzyl alcohol is optionally dissolved in an inert solvent, e.g. in a halogenated hydrocarbon, such as carbon tetrachloride, chloroform or methylene chloride, or in an aromatic solvent such as benzene, toluene or chlorobenzene, preferably with heating.



   An acyl group Ac "which can be split off under the reaction conditions of the conversion of a compound of the formula VI into a compound of the formula III, in which Y is a 1 -isobutylidene group, is, for example
Group of the formula -C (= O) -X2, in which X1 has the meaning given above, in particular a group of the formula -C (= O) -O-Roa7 -C (= O) -OqRob7 -C (= O) - O-Roe or -C (= O) -O-Rnd, in which ROa, Roh, ROe and Rod have the meanings given above, but can also represent any other acyl group which can be split off under the reaction conditions mentioned,

   in particular a ROe-O-C (= O) group which can be split off under acidic conditions. The latter can be split off, in particular in the presence of oxygen-containing acids, primarily from strong organic carboxylic acids such as trifluoroacetic acid and formic acid, or from strong sulfonic acids such as p-toluenesulfonic acid, i.e. can be replaced by hydrogen.



   An acyl group Aca which cannot be split off under the reaction conditions of the subsequent process step, in particular an acyl group different from the radical of the formula -C (= O) -X, can be used in a manner known per se, e.g. as described above, can be replaced by hydrogen.



   The cleavage of the group -C (= O) -X5 in an intermediate of the formula VI depends on the type of this group, the cleavage being carried out in the presence of at least one mole, normally an excess, of water, or that Reaction product subsequently treated with water.



   The cleavage of an esterified carboxyl group of the formula -C (= O) -X2, which in a compound of the formula VI can also represent the radical Ac ", and in which X represents the group -OR," or OJRoh, is carried out by treating with a chemical reducing agents in the presence of at least an equimolar amount, usually in the presence of an excess of water. You work under mild conditions, usually at room temperature or even with cooling.



   Reducing agents are the reducing agents of this type mentioned in the process according to the invention described above, such as reducing metals, metal alloys or metal compounds, preferably in the presence of hydrogen-donating agents, primarily zinc in the presence of aqueous acetic acid.



   In a compound of the formula VI, in which X represents a radical of the formula -O1RoC, the group of the formula -C (= O) -X2, which can also represent the group Ac ", can be obtained by irradiation with light, preferably with ultraviolet light, Depending on the nature of the substituent ROt, longer or shorter wavelength light is used. For example, groups of the formula -C (= O) -OR, ", in which ROe one substituted by a nitro group in the 2-position of the aryl radical, are optionally further substituents, such as lower alkoxy, e.g.

  Arylmethyl, especially benzyl, radical containing methoxy groups, e.g. the 4,5-dimethoxy-2-nitro-benzyl radical, represents, by irradiation with ultraviolet light with a wavelength range of over 290 m, p, those in which ROe has one optionally in the 3-, 4- and / or 5-position, e.g. arylmethyl substituted by lower alkoxy and / or nitro groups, e.g. Benzyl radical, is cleaved by irradiation with ultraviolet light with a wavelength range of less than 290 mu.

  In the first case one works with a high pressure mercury vapor lamp, whereby one preferably uses Pyrex glass as filter, for example: at a main wavelength range of about 315 mu, in the latter case with a low-pressure mercury vapor lamp, e.g. at a main wavelength range of about 254 mu.



   The irradiation reaction is carried out in the presence of a suitable polar or non-polar organic solvent or a mixture; Solvents are e.g. optionally halogenated hydrocarbons, such as optionally chlorinated lower alkanes, e.g. Methylene chloride, or optionally chlorinated benzenes, e.g.



  Benzene, also alcohols such as lower alkanols, e.g. Methanol, or ketones, such as lower alkanones, e.g. Acetone.



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



   In a compound of the formula VI, in which X represents a group of the formula O-Rod, the grouping of the formula -C (= O) -OR, d, which can also represent the group Ac, can, by treatment with an acidic agent, in particular with an acid such as a strong organic carboxylic acid, e.g. an optionally substituted, preferably halogen-containing, lower alkanecarboxylic acid, such as acetic acid or trifluoroacetic acid, furthermore with formic acid or a strong organic sulfonic acid, e.g. p-toluenesulfonic acid.

  Usually, an excess of an acidic reagent that is liquid under the reaction conditions is used as the diluent and the reaction is carried out in the presence of at least an equivalent amount of water, as well as at room temperature or with cooling, e.g. to about -20WC to about + 100C. If Ace in the starting material represents a group of the formula -C (= O) -O-Roe, such a group can be split off at the same time during the treatment with the acidic agent.



   The 4,4-dimethyl-5-thia-2,7diazabicyclo [4,2,0l oct-2-en-8 - one which may be formed as an intermediate product, which is particularly useful in the non-reductive cleavage of a group of the formula -C (= O) -X2 in a compound of the formula VI, in which X2 is the group of the formula O ROe or -OR, d, furthermore also in the cleavage of a group of the formula -C (= O) -X2 in a compound of the formula in which X represents the group against formula -OR, ", occurs with the help of a strongly reducing metal salt,

   can be converted into the desired 3-isopropyl-4-thia-2,6-diazabicydo [3,2,0hep-tan-7-one by exhaustive reduction or then separated from a mixture with the latter. One uses to reduce the carbon / nitrogen double bond in 4,4-dimethyl-5-thia-2,7-diaabicyclo [4,2,0] oct-2-en-8-one, which with simultaneous rearrangement to 3-isopropyl-4-thia-2,6-diazabicyclo [3, 2.0] heptan-7-one, preferably chemical reducing agents, primarily reducing metal or metal compounds, such as those mentioned above, preferably in the presence of hydrogen donating agents Agents, especially zinc in the presence of an acid such as acetic acid or an alcohol.

 

     A mixture of 3-isopropyl-4-thia-2,6-diazabicyclo [3,2,0] heptan-7-one and 4,4-dimethyl-5-thia-2,7-diazabicyclo [4, 2.0] oct-2-en-8-one, as occurs primarily in a reductive cleavage of the group of the formula -C (= O) -X2 in a starting material of the formula VI, in which X2 is a group of the formula O ROa or -OR, b means, arises, can according to separation methods known per se, for example by fractional crystallization, adsorption chromatography (column or thin-layer chromatography) or other suitable separation processes and the individual compounds are separated.



   In the preparation of compounds of the formula VI, intermediate products can be converted into one another at suitable stages. E.g. an aliphatically bonded chlorine, especially bromine, atom in the radical X2, such as the 2-bromo-ethyloxy radical, e.g. by treating with a suitable iodized salt. such as an alkali metal, e.g. Potassium iodide, replaced by an iodine atom in a suitable solvent such as acetone, e.g. the 2zBromäthylrest can be converted into the 2-iodoethylrest.



   Furthermore, you can in a compound of formula VI.



  where R1 is hydrogen, this is replaced by an acyl group Aco which can be split off under the reaction conditions and can be replaced by hydrogen, e.g. using acylation processes known per se.



   As mentioned, the compounds of formula 1 are valuable intermediates which are particularly useful for the preparation of pharmacologically valuable compounds, e.g. of the 7ss amino-ceph-3-em-4-carboxylic acid type and Nt acyl derivatives thereof. the latter in particular, with effects against microorganisms, such as gram-positive and gram-negative bacteria, can be transferred.



   For example, a compound of the formula I in which the radical R is the acyl radical of the formula -C (= O) -Xl can be mixed with a compound of the formula
EMI11.1
 wherein RA represents an organic radical of an alcohol or phenol compound which, together with the -C (= ()) - O- grouping, forms an esterified carboxyl group, or a reactive derivative thereof, and in the addition compound of the formula
EMI11.2
 convert the secondary hydroxy group into a reactive esterified hydroxy group.

  The reactive ester of the formula
EMI11.3
 in which Z is a reactive esterified hydroxyl group, primarily a haloene, especially chlorine or bromine atom, and an organic sulfonyloxy group. z. 13. 4 Mcuss is Iphenylsulfonyloxy or Methlylsulfonyloxygrup- pe. sets flat with one of the phosphine compounds of the formula
EMI11.4
 wherein each of the radicals R;

  ; t, R "and R,. stand for an optionally substituted hydrocarbon radical, and thus if necessary, after splitting off the elements, obtain an acid of the formula H-Z (Xla) from a phosphonium salt compound of the formula available as an intermediate
EMI11.5
  the phosphoranylidene compound of the formula
EMI12.1
 in which one cleaves the esterified carboxyl group -C (= O) -Xl. A compound of the formula is obtained in this way
EMI12.2
 in which the hydroxyl group is oxidized to the oxo group.

  In a Ccph-3-em compound of the formula obtainable in this way
EMI12.3
 in which R7 stands for the organic radical RA, and the ring closure from the carbonyl compound of the formula which is formed under the reaction conditions but is not isolated
EMI12.4
 arises, if desired, the acyl group R1 can be split off and optionally protected the free amino group in a compound obtainable in this way, and / or, if desired, an ester grouping of the formula -C (= O) -O-RTA in the free carboxyl group or in another ester grouping of the formula -C (= O) -O-RTA converted,

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



   In a compound of the formula I to be used as starting material in which of the radicals R5, R4, RU and R6 at least R6 is hydrogen and the radical R2 is the acyl radical of the formula -C (= O) -X1, the acylated hydroxyl group is in particular a group of the formula -OC (= O) -O-R05, -OC (= O) -OR, h, -OC (= O) -OR, C, -OC (= O) -Rod, -OC (= O) O.R0e or.



  -OC (= O) -O-RoÚ, where R0a, IR, b, Rote, Rod, ROe and red have the meanings given above and primarily for 2,2,2-trichloroethyl, 2-bromoethyl, 2-iodoethyl, phenacyl, 4,5-dimethoxy-2-nitro-benzyl or tert-butyl radicals.



   In a glyoxylic acid compound of the formula VII, the radical RA is primarily a group ROa, Rou, R, C, Rod, ROe and RoÚ.



   The addition of the glyoxylic ester compound of the formula VII to the nitrogen atom of the lactam ring of a compound of the formula I takes place preferably at elevated temperature, primarily at about 50 ° C. to about 1500 ° C., in the absence of a condensing agent and / or without the formation of a salt. Instead of the free glyoxylic acid ester compound, it is also possible to use a reactive oxo derivative thereof, primarily a hydrate, it being possible, if necessary, to remove water formed when using the hydrate by distillation, e.g. azeotropically.

 

   It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or toluene, or solvent mixture, if desired or necessary, in a closed vessel under pressure and / or in the atmosphere of an inert gas such as nitrogen.



   In a compound of the formula VIII, the secondary hydroxyl group can be converted in a manner known per se into a reactive hydroxyl group esterified by a strong acid, in particular into a halogen atom or into an organic sulfonyloxy group. being transformed. One uses e.g. suitable halogenating agents such as a thionyl halide, e.g. -chloride. a phosphorus oxyhalide. especially chloride. or a haloene phosphonium halide, such as triphenylphosphonium dibromide or diiodide. as well as a suitable organic sulfonic acid halide.

   such as chloride, the reaction preferably in the presence of a basic, primarily an organic basic agent. wic an aliphatic tertiary amine, zjB. Trietlylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type. z, B. Pyridine or collidine.



  It is preferred to work in the presence of a suitable solvent, e.g. Dioxane or tetrahydrofuran.



  or a solvent mixture. if necessary. with cooling and / or in the numosphere of an inert gas such as nitrogen.



   In a compound of the formula IX obtained, a reactive esterified hydroxy group Z can be converted in a manner known per se into another reactive esterified hydroxy group. So you can, for example. a chlorine atom by treating the corresponding chlorine compound with a suitable bromine or iodine reagent, in particular with an inorganic bromide or iodide salt such as lithium bromide. preferably in the presence of a suitable solvent, such as ether, replace with a bromine or iodine atom.



   In a compound of the formula X, each of the groups Ra, R1, upd Rc is primarily an optionally, e.g. by etherified or esterified hydroxyl groups, such as lower alkoxy groups or halogen atoms, substituted lower alkyl radical or an optionally, z.E. by aliphatic hydrocarbon radicals, such as lower alkyl groups, or etherified or esterified hydroxyl groups. such as lower alkoxy groups or halogen atoms, or nitro groups, substituted phenyl radicals.



   The reaction of a compound of the formula IX with the phosphine compound of the formula X, in which each of the groups Ra, Rb and Re is primarily phenyl and a lower alkyl, especially the n-butyl radical, is preferably carried out in the presence of a suitable inert solvent how eir. aliphatic, cycloaliphatic t, the aromatic hydrocarbon, e.g.



  Hexane, cyclohexane. Benzene or toluene, or an ether, e.g. Dioxane. Tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture made. If necessary, one works with cooling or at elevated temperature and / or in the atmosphere of an inert gas such as nitrogen.



   A phosphonium salt compound of the formula XI formed as an intermediate usually spontaneously loses the elements of the acid of the formula H-Z (XIa); if necessary, the phosphonium salt compound can be prepared by treating with a weak base such as an organic base, e.g. Diisopropylethylamine or pyridine, decomposed and converted into the phosphoranylidene compound of the formula XII.



   The cleavage of the esterified carboxyl group of the formula -C (= O) -X1 in a compound of the formula XII can be carried out in various ways depending on the nature of the group X1. Thus, a grouping -C (= O) -X1 in which X1 is the group of the formula -O-Rc, or OkRob, can be obtained by treatment with a chemical reducing agent, e.g. one of the abovementioned reducing agents, such as zinc, which is advantageously used in the presence of an acid or an alcohol, optionally with the addition of water, e.g. in the presence of aqueous acetic acid. and a grouping of the formula -C (O) -X1. wherein X represents the group of the formula O-R "t by irradiation with light, in particular with ultraviolet light, cleave:

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



   An esterified carboxyl group of the formula -C (= O) .OR or -C (= O) -O-Red can be obtained by treatment with an acidic agent. especially with an acid such as a strong organic carboxylic acid. e.g.



  an optionally substituted lower alkanecarboxylic acid, preferably containing halogen atoms, such as acetic acid or trifluoroacetic acid. also with formic acid or a strong organic sulfonic acid, e.g. 13. p-To luenesulfonic acid, are cleaved. An excess of an acidic reagent which is liquid under the reaction conditions is usually used as a diluent and the reaction is carried out at room temperature or with cooling, e.g. to about -2 () 'C to about + 100C.



   An esterified carboxyl group -C (= O) -O-RI, 'can be hydrolytically carried out under neutral or weakly acidic or basic conditions, e.g. at a pH of about 4 to about 9. zsB. by treating with water, a weakly acidic agent. such as a weak acid or a weakly acidic buffer solution, or a weakly acidic agent such as an alkali metal hydrogen carbonate. such as sodium hydlogellic calcium carbonate or a suitable buffer (pH about 7 to about 9). such as a dipotassium hydrogen phosphate buffer.

   in the presence of water and preferably an organic solvent such as methanol (or acetone.



   In a compound of the formula XII, the esterified carboxyl groups of the formulas -C (-O) -X, and -C. (= O) -O-R7A preferably differ from one another so that under the conditions of cleavage of the esterified carboxyl group of the formula -C (= O) -Xl, the esterified carboxyl group of the formula -C (= O) -O -R, remains intact.

  Provides zJB. the esterified carboxyl group of the formula -CfO) -X, one of those when treated with a chemical reducing agent such as zinc in the presence of aqueous acetic acid. cleavable esterified carboxyl group, e.g. a grouping of the formula -C (= O) -OR "" or -C (= O) -OR "', in which Roa is preferably for 2,2,2-trichloroethyl or 2-iodoethyl or the easily convertible into the latter 2-Bromoethyl radical and Ra primarily represent the phenacy group, the esterified carboxyl group of the formula -C (= O) -O-R7A, for example, represents one of the esterified carboxyl groups that can be cleaved when dealing with a suitable acid, such as trifluoroacetic acid - C (= O) -O-R7A, e.g.

   for a grouping of the formula -C (= O) -O-Ratls in which Rad preferably represents the tert-butyl group.

 

   The oxidation of a compound of the formula XII can surprisingly be carried out by treatment with an oxidizing organic sulfoxide compound in the presence of agents with dehydrating or water-absorbing properties. As oxidizing sulfoxide compounds are primarily aliphatic sulfoxide compounds in question, such as di-lower alkyl sulfoxides, primarily dimethyl sulfoxide, or lower alkylene sulfoxides, e.g. Tetramethylene sulfoxide.



  Agents with dehydrating or absorbing properties are primarily acid anhydrides, in particular anhydrides of organic, such as aliphatic or aromatic carboxylic acids, e.g. Anhydrides of lower alkanecarboxylic acids, especially acetic anhydride. also propionic anhydride, or benzoic anhydride, and anhydrides of inorganic acids, especially phosphoric acids, such as phosphorus pentoxide. The above anhydrides, primarily from organic carboxylic acids, e.g. Acetic anhydride, are preferably used in about a 1: 1 mixture with the gulfoxide oxidizing agent.

  Further dehydrating or absorbing agents are carbodiimides, primarily dicyclohexylcarbodiimide, also diisopropylcarbodiimide, or ketenimines, e.g. DiphenyliN-p-tolylketenimin, these reagents are preferably used in the presence of acidic catalysts such as phosphoric acid or pyridinium trifluoroacetate or phosphate. Sulfur trioxide can also be used as a dehydrating or absorbing agent, usually in the form of an I complex, eg. with pyridine.



   Usually, the 'sulfoxide oxidizing agent is used in excess.' Sulphoxide compounds which are liquid under the reaction conditions, especially dimethyl sulphoxide, can e.g. also serve as a solvent; inert diluents such as benzene or mixtures of solvents can also be used as solvents.



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



   In a compound of the formula XIV obtained, an acyl group R1, in particular an easily cleavable acyl group, in a manner known per se, a tert. -Butyloxycarbonyl group e.g. by treatment with trifluoroacetic acid and a 2,2,2-trichloroethoxycarbonyl group by treatment with a suitable metal or metal compound, e.g. Tin, or a chromium (II) compound, such as chloride or acetate, can advantageously be split off in the presence of a hydrogen-generating, hydrogen-releasing agent, preferably of hydrous acetic acid, which noses together with the metal or the metal compound.

  Furthermore, in a compound of the formula XIV obtained in which a carboxyl group -C (= O) -OqR7 is preferably a zjB. by esterification, including by silylation or stannylation, e.g. with a suitable organic halosilicon or halo-tin-IV compound, such as trimethylchlorosilane, is a suitable acyl group R1, in which any free functional groups present are preferably protected, by treatment with an imide halide-forming agent, such as a suitable inorganic acid halide, e.g. Phosphorus pentachloride, preferably in the presence of a basic (agent such as pyridine, reaction of the imide halide formed with an alcohol such as lower alkanol, iB.

  Methanol, and cleavage of the imino ether formed in an aqueous or alcoholic medium, preferably under acidic conditions, are split off. A triarylmethyl group R1 can e.g. be split off as described above.



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



   In a compound of the formula XIV with an esterified carboxyl group, the latter z) B. represents an esterified carboxyl group of the formula -C (= O) -O-R7A which can easily be converted into the free carboxyl group, this can be carried out in a manner known per se, e.g.

   Depending on the type of esterifying radical R7A into which the free carboxyl group is converted, a grouping of the formula -C f = O) OR0a or C (= o) O Rob z.lB. by treatment with a chemical reducing agent, such as a metal, e.g. Zinc, or a reducing metal salt such as a chromium-II salt, e.g. Chromium-II-chloride, usually in the presence of a hydrogen-donating agent which is able to generate nascent hydrogen together with the metal, such as an acid, primarily acetic acid, or an alcohol, preferably adding water, a group of the formula -C (= O) -O ROe e.g.

   by irradiation, preferably with ultraviolet light, with shorter-wave ultraviolet light, for example. below 290 mp "if ROe is, for example, an arylmethyl radical optionally substituted in the 3-, 4- and / or 5-position, e.g. by lower alkoxy and / or nitro groups, or with longer-wave ultraviolet light, e.g. over 290 mF, if R00 e.g.

   is an arylmethyl radical substituted in the 2-position by a nitro group, a grouping C (= O) O Rod or -C (= O) O ROe iB. by treatment with an acidic agent such as formic acid or trifluoroacetic acid and a moiety -C (= O) -O-Rof e.g. by hydrolysis, e.g. by treatment with a weakly acidic or weakly basic agent, such as aqueous sodium hydrogen carbonate or an aqueous potassium phosphate buffer.



   In a compound of the formula XIV, a grouping of the formula -C (= O) -O-R7A can be converted into another of this formula, e.g. a 2-bromo ethoxycarbonyl group of the formula -C (= O) -O Roa by treatment with an iodine salt such as sodium iodide, in the presence of a suitable solvent such as acetone, into a 2-iodoethoxycarbonyl group.



   E.g. carboxyl group added by silylation can be added in a conventional manner, e.g. can be released by treatment with water or an alcohol.



   In a compound of the formula XIV with a group of the formula -C (= O) -O-R7, in which R7 stands for hydrogen, the free carboxyl group can be used in a manner known per se, e.g. by treating with a diazo compound such as a diazo lower alkane, e.g. Diazomethane or diazoethane, or an IPhenyl-diazo-lower alkane, e.g. Phenyldiazomethane or viphenyldiazomethane, or by reaction with an alcohol suitable for esterification in the presence of an esterifying agent such as a carbodiimide, e.g. Dicyclohexyicarbodllmid, and carbonyldiimidazole,

   or by any other known and suitable esterification process, such as reaction of a salt of the acid with a reactive ester of an alcohol and a strong inorganic acid and a strong organic sulfonic acid. Acid halides such as chlorides (prepared e.g. by treatment with oxalyl chloride) or activated esters, e.g. those with N-Hydroxystick substance compounds, or e.g. mixed anhydrides formed with haloformic acid lower alkyl esters, such as ethyl chloroformate, or with haloacetic acid halides, such as trichloroacetic acid chloride, are converted into esters by conversion with alcohols, optionally in the presence of a base such as pyridine.

 

   In the above process steps, if necessary, free functional groups not participating in the reaction in the reaction participants, e.g. free hydroxy, mercapto and amino groups, e.g. by acylating, tritylating or silylating, and free carboxyl groups ziB. temporarily protected by esterification, including silylation, in a manner known per se and, if desired, released in a manner known per se after each reaction has taken place.



   The compounds of the formula XIV, in particular those in which R1 is an acyl radical contained in pharmacologically active, naturally occurring or biosynthetically or semi- or totally synthetically producible N acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalic-acid compounds, and R7 is hydrogen or an organic radical R7A which can be easily split off under physiological conditions are against microorganisms such as gram-positive bacteria, for example Staphylococcus aureus, and gram-negative bacteria, e.g. Escherichia coli, in particular also against penicillin-resistant bacteria, e.g.

   effective against Staphylococcus aureus in dilutions up to 0.0001 / ml.



   Such compounds with pharmacological effects can i be used in the form of pharmaceutical preparations which they contain in admixture with a solid or liquid pharmaceutical carrier material and the like. which are suitable for enteral, parenteral or topical administration. Suitable carrier substances which are inert towards the active substances are e.g. Water, gelatin, saccharides such as lactose, glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known ones Carriers. The preparations can be in solid form, e.g. as tablets, dragees, capsules or suppositories, or in liquid form, e.g.



  as solutions, suspensions or emulsions.



  They can be sterilized and / or contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, solubilizers, salts to regulate the osmotic pressure and / or buffers. They can also contain other pharmacologically usable substances. The pharmaceutical preparations which are also encompassed by the present invention can be produced in a manner known per se.



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



   example 1
A solution of 0.35 g of bis (cis-2-oxo-3p-phenylacetylamino-45-azetidinyl) disulfide in 16 ml of a 9: 1 mixture of acetic acid and water is added at about 5 to about 3.2 g Ethylene oxide, then mixed with 3.5 g zinc dust. The reaction mixture is stirred for 15 minutes at about 50 and for 30 minutes at room temperature, then filtered. The filter residue is washed with acetone and the filtrate is evaporated. The residue is taken up in about 150 ml of ethyl acetate and the solution is washed with 50 ml of a saturated aqueous sodium hydrogen carbonate solution and with 100 ml of a saturated aqueous sodium chloride solution, dried and evaporated.

  The residue is chromatographed on 50 g of silica gel together with a crude product obtained in an analogous manner from 0.58 g of bis (cis-2-oxo-3, -phenylacetylamino-41-azetidinyl) disulfide. The 4p- (2- -hydroxyethylthio) -3β-phenylacetylamino-azetidin-2-one is eluted with a 19: 1 mixture as a uniform product which, after crystallization from a mixture of acetone and diethyl ether, melts at 1411420; [D2O = +440 + 20 (c = 0.571 in ethanol); Thin-layer chromatography (silica gel; developing with iodine): Rf 0.45 (system: ethyl acetate / acetone 1: 1);

  Infrared absorption spectrum (in mineral oil): characteristic bands at 3.01 4, 5.68 SL, 6.01, 6.43> and 6.52 p.



   The starting material can be made as follows:
15 ml of a sulfonic acid type ion exchange
0+ shear (H form) by treating with a solution of 5 ml of triethylamine in 100 ml of water in the triethyl ammonium salt form, the column was washed neutral with 300 ml of water and treated with a solution of 2 g of the sodium salt of penicillin-G in 10 ml of water and then eluted with water. A volume of 45 ml is withdrawn and lyophilized at a pressure of 0.01 mm Hg. The crude triethylammonium salt of iPenicillin-G thus obtained is dissolved in methylene chloride, and the solution is dried over sodium sulfate, filtered and evaporated.



   A solution of the penicillin G-triethyl thus obtainable.



  ammonium salt in a mixture of 40 ml of methylene chloride and 40 ml of tetrahydrofuran is cooled to -100 and slowly mixed with 2.9 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran with stirring. The mixture is stirred for 90 minutes at -50 to 00, then treated with a solution of 0.395 g of sodium azide in 4 ml of water and the mixture is stirred for 30 minutes at -50 to 00. It is diluted with 100 ml of ice water and extracted three times with 75 ml each time Methylene chloride; the organic extracts are washed with water, dried and evaporated at room temperature under reduced pressure.

  The amorphous penicillin-G azide is obtained in this way, infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05 y 4.71;, u, 5.62 p, 5.80, 5.94, 6.69 u and 8.50.



     A solution of 1.72 g of penicillin-G azide in 30 ml of benzene is mixed with 1.5 ml of 2,2,2-trichloroethanol and stirred at 700 for 25 hours. A regular evolution of nitrogen is observed during the first 15 minutes and after a few hours the product separates out of the solution. The mixture is diluted with 60 ml of hexane while stirring, cooled and filtered after 15 minutes. The filter residue is washed with a 2: 1 mixture of benzene and hexane and with cold ether.

  The pure 2,2-dimethyl - - phenylacetylamino-342,2,2 - trichlorethoxycarbonylamino) -penam is obtained, which melts at 223-223.50; [] D20 = + 1720 (c = 1.018 in ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.61, 5.77 11, 697, 6.70, 8.30, 9.17 CL, 9.62 and 11.85 qu.

 

   The product can also be obtained by heating 0.03 g of penicillin G azide in 2 ml of benzene to 700 for 20 minutes, evaporating the reaction mixture under reduced pressure to give the 3-isocyanato-2,2-dimethyl-6? -phenyl-acetylamino - penam; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06 l, 4.48, 5.62 u, 5.96 p and or iwiierold and this by reaction with 2.2.2 trichloroethanol into the desired 2,2-dimethyl -6p-phenylacetylamino-3 - (2,2,2 - trichlorethoxycarbonylamino) -penam transferred.



   A solution of 1.1.0 g of 2,2-dimethyl-60-phenylacetyl-amino-3- (2,2,2-trichlorethoxycarbonylamino) - penam in a mixture of 240 ml of anhydrous methylene chloride and 25.6 ml of pyridine is under 166 ml of a 10% solution of phosphorus pentachloride in methylene chloride were added in a nitrogen atmosphere at - 100 and the mixture was then stirred at 0 for 30 minutes.



  Then 120 ml of absolute methanol are added with strong cooling (- 100) and stirring is continued for 2 hours. 80 ml of water are added, the pH value (measured in samples diluted with water) is adjusted with about 9 ml of a 2-n. aqueous sodium hydroxide solution to 3.3 and allowed to react for one hour at 00 and for another hour at 200. It is then poured into 500 ml of a 1-m while stirring. aqueous di potassium hydrogen phosphate buffer solution and adjusts the pH by adding 50% aqueous tripotassium phosphate solution from 6.5 to 7.0. The aqueous phase is separated off and washed twice with 200 ml of methylene chloride each time; the three organic solutions are each washed twice with water, combined, dried over sodium sulfate and evaporated under reduced pressure.

  The crystalline residue is taken up in 40 ml of a 1: 1 mixture of benzene and hexane; the mixture is cooled at 00 for 15 minutes and the precipitate is filtered off. The 6β-amino-2,2-dimethyl-3 (2,2,2-trichloroethoxyzarbo-nylamino) -penam is obtained in this way, which melts at 1791 800 l (corr.);

  In the infrared absorption spectrum: characteristic bands (in methylene chloride) at 2.90, 5.58 1F, 6.62, 7.17 y, 7.27, 1l,
8.32 8.46, p, 8.82 gel, 9.25 III and 9.62! P; (in Nujol) at
2.95, 3.01, 3.11 III, 5.64, 5.80, 6.35 Il, 7.60 Il,
7.87, 8.00, 8.27, 8.65, i, 8.70 9.16 and 9.57 11; Thin-layer chromatogram (silica gel):

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



   A mixture of 0.05 g of 6h amino-2,2-dimethyl-3- (2,2,2-trichloroethoxycarbonylamino) -penam and 0.1 g of zinc dust in 2 ml of a 1: 1 mixture of acetone and water is after Addition of 0.2 ml of SEacetic acid fibrated at 200 for one hour at 45 kHz (ultrasound), then diluted with 50 ml of water. It is extracted with 50 ml of ethyl acetate, the organic extract is dried over sodium sulfate and evaporated under reduced pressure.

  The residue is recrystallized from a mixture of methylene chloride and hexane and 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] -heptan-7-one, mp 151-1550; Thin-layer chromatogram: Rf = 0.17 (system: toluene / acetone 8: 2) and Rf = 0.38 (system: toluene / tacetone 6: 4).



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



   A solution of 1.64 g of 3-isopropyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one in 33 ml of a 1: 1 mixture of acetic acid and water is made within 10 minutes with 71.7 ml of a 0.5 n. Solution of iodine in ethanol are added, the mixture is left to stand at room temperature for one hour and then concentrated under reduced pressure. The residue with the bis (cis-2-oxo-3ss-amino-azetidin-4ss-yl) disulfide, dried under high vacuum, is suspended in 90 ml of acetonitrile, and 4.5 ml of pyridine and 4.5 ml of phenylacetic acid chloride are added at 0 . It is left to stand for 15 minutes at 00 and for one hour at room temperature and the like. then evaporated under reduced pressure.

  It is triturated for 30 minutes with 10 ml of a 1: 1 mixture of dioxane and water and the residue is taken up in ethyl acetate; the solution is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried and evaporated.

  The oily residue is chromatographed on 100 g of pure silica gel; the oily bis- (cis-2-oxo-3β-phenylacetylamino-4ss-azetidinyl) disulfide is eluted with a mixture of ethyl acetate and acetone and converted into a finely powdered amorphous form by lyophilization: thin-layer chromatogram (silica gel): Rf for 0.36 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.08, 5.62, 5.97, 11 and 6.51 l.



   The bis - '(cis-2-oxo-3-phenylacetylamino-4 -azetidin-yl) disulfide can also be obtained as follows:
A solution of 0.317 g of 3,3-dimethyl-4-thia-2,6-diazabicyclo [3.2.0] heptan-7-one in 3.0 ml of methylene chloride is mixed with 0.254 g of iodine in 12.0 ml of benzene ; this immediately forms a voluminous brown precipitate.



  The mixture is shaken from time to time for 10 minutes at room temperature, then filtered, and the filter residue is washed with benzene and pentane and suspended in 8.0 ml of acetonitrile. 2.0 ml of pyridine are added to the suspension, a clear yellow solution being obtained, which is cooled to +100, and 0.4 ml of phenylacetic acid chloride is added dropwise with stirring.



  The reaction mixture is left to stand for 20 minutes at room temperature, then concentrated under reduced pressure to a weight of 1.9 g.



  The yellow syrupy residue is taken up in 50 ml of ethyl acetate and the solution is washed with 50 ml of water and then evaporated. The residue is crystallized from a mixture of methanol, methylene chloride and hexane. The bis- (cis-2-oxo-38-phenylacetylamino-4β-acetidinyl) disulfide melts after recrystallization from acetone and methylene chloride at 1521550 (analysis preparation: 156.5-158.5).



   Example 2
A mixture of 0.10 g of bis (cis-2-oxo-3,3-phenylacetylamino-4ss-azetidinyl) disulfide and 1.0 g of 1,2-propylene oxide in 5 ml of glacial acetic acid and 0.5 ml of water 1.0 g of zinc dust is added at 0. The reaction mixture is stirred for 30 minutes at about 0 and for a further 30 minutes at room temperature, then filtered through a diatomaceous earth preparation. It is washed with acetone and the filtrate is evaporated. The residue is taken up in 100 ml of ethyl acetate; the organic solution is washed with 50 ml of water, 50 ml of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated aqueous sodium chloride solution; the aqueous washing solutions are back-extracted with 100 ml of ethyl acetate.

  The combined organic solutions are dried over sodium sulfate and evaporated; the residue is chromatographed on 10 g of silica gel. It is eluted with ethyl acetate containing 5% acetone and the chromatographically uniform 4. (2-hydroxypropyl mercap.



     to) -3p -phenylncetylnmino-azetidin-2-yne, which crystallizes when sprayed with methylene chloride and melts in the form of colorless crystals at 102-106; Thin-layer chromatogram (silica gel): Rf 0.44 (system: ethyl acetate / acetone 1: 1; development with iodine).



   Example 3 A mixture of 0.10 g of bis (cis-2-oxo-3,8-phenylacetylamino-azetidinyl) disulfide and 1.0 g of 1,2-butylene oxide in 5 ml of glacial acetic acid and 0.5 ml of water 1.0 g of zinc dust is added. The reaction mixture is stirred for 30 minutes at about 0 and for a further 30 minutes at room temperature, then filtered through a diatomaceous earth preparation. It is washed with acetone and the filtrate is evaporated. The residue is taken up in 100 ml of ethyl acetate; the organic solution is washed with 50 ml of water of a saturated aqueous sodium hydrogen carbonate solution and 50 ml of a saturated aqueous sodium chloride solution; the aqueous washing solutions are back-extracted with 100 ml of ethyl acetate.

  The combined organic solutions are dried over sodium sulfate and evaporated; the residue is chromatographed on 10 g of silica gel. It is eluted with ethyl acetate and ethyl acetate containing 5% acetone and the chromatographically uniform 4p- (2-hydroxybutylmercapto) -3β-phenylacetylamino-azetidin-2-one, which is crystallized from a mixture of methylene chloride and hexane and is obtained at 108 -117 melts; Thin-layer chromatogram (silica gel): iRf 0.49 (system: ethyl acetate / acetone 1: 1; development with iodine).

  According to the NMR spectrum, the substance consists of a mixture (approx. 1: 1) of the two diastereoisomeric compounds, which differ in the configuration at the carbon atom substituted by the hydroxyl group.



   Example 4
A solution of 0.61 g of 4p- (2-hydroxyethylmer-capto) 3β-phenylacetylamino-azetidin-2-one in 10 ml of tetrahydrofuran is added dropwise at 0 to 1.38 g of chloroformic acid-2,2,2-trichloroethyl ester in 5 ml of tetrahydrofuran, then 1.06 g of pyridine in 5 ml of tetrahydrofuran. The reaction mixture is stirred under a nitrogen atmosphere for 15 minutes at 0 ° and for 2 hours at room temperature, then taken up in 150 ml of methylene chloride. It is washed with a saturated aqueous sodium chloride solution, dried and evaporated.

  The residue is chromatographed on 50 times the amount of silica gel; the 30- -phenylacetylamino-4β - [2- (2,2,2-trichloroethoxycarbonyl-oxy) -ethylmercaptol-azetidin-2-one is eluted with a 1: 1 mixture of methylene chloride and ethyl acetate.

  After crystallization and single recrystallization from diethyl ether, the product is obtained in the form of colorless needles, mp 99-101; Thin-layer chromatogram (silica gel): Rf 0.46 (system: ethyl acetate; development with iodine); [iD20 = +30 + 20 (c = 0.518 in chloroform);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.88 ir, 5.58, 5.64, 5.92 and 6.62
Example 5
A solution of 5.63 g of bis- [ds-3p '- (N-tert-butyl oxycarbonyl-D <-phenylglycyl) -amino-2-oxo-4,8-azetidi- nyl] disulfide in 190 ml of a 9: 1X mixture of acetic acid and water is mixed with about 160 g of ethylene oxide and 56 g of zinc dust, and strongly for one hour at room temperature touched. It is filtered and the filtrate is concentrated, taken up in ethyl acetate, washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.

  The residue is chromatographed on 150 g of silica gel; the elution is carried out with ethyl acetate to give 3β (N-tert-butyloxycarbenyl-D-α-phenylglycyl) -amino-4β (2-hydroxyethylthio) -azetidin-2-one which, after crystallization from a mixture of Acetone and diethyl ether melt at 13G131; to] D20 = 64 + 20 (c = 0.622 in ethanol): Thin-layer chromatogram (silica gel; s development with iodine vapor):

  Rf ¯ 0.47 (system: ethyl acetate / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 3.00, 3.25, 3.34, 5.61, 5.83, 5.91, 6.68, 7.29, 8.58 and 9.02 A.



   Example 6
A solution, cooled to 0, of 4.80 g of 3z- (N-tert-butyloxycarbonyl-D - a - phenylglycyl) -amino--4j- (2-hydroxyethylthio) -azetidin-2-one and 7.74 g is added 2,2,2-trichloroethyl chloroformate in 100 ml of tetrahydrofuran within 10 minutes with a solution of 5.9 g of pyridine in 50 ml of tetrahydrofuran, stirred for 15 minutes at 0 and for 30 minutes at room temperature and concentrated. It is taken up in 500 ml of methylene chloride, washed twice with 100 ml of a saturated aqueous sodium chloride solution and evaporated.



  The residue is chromatographed on 300 ml of silica gel; a 4: 1 g mixture of methylene chloride and ethyl acetate is used to elute the non-crystalline 3,8- (N-tert-butyloxycarbonyl-de-phenylglycyl) -amino- - 12 (2,2,2-trichloroethoxycarbonyloxy) -ethylthiol -azeti- din-2-one, thin layer chromatogram (silica gel, development with iodine vapor): Rf 0.55 (system: ethyl acetate) and Rf 0.19 (system:

  Toluene / ethyl acetate 1: 1): infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00 3.35, 3.42, 5.61, 5.66}, 5.85, 5.92 y, 6 , 75, 7.06 and 8.14 y and 8.61 p, respectively.



   The starting material can be obtained as follows:
A solution of 10.0 g of 3Jisopropyl-4-thia-2,6-diazabicyclo [3.24] heptan-7-one in 200 ml of a 1: 1 mixture of (acetic acid and water is added dropwise over 15 minutes 436 ml of a 0.2 molar solution of iodine in ethanol are added and the mixture is left to stand for one hour at room temperature and evaporated under reduced pressure. The residue, containing the bis-3ss-amino-2-oxo-4g8-azetidinyl) disulfide, is removed under high vacuum dried and processed further without cleaning.



   The crude product obtainable by the above process is dissolved in 200 ml of a 1: 1 mixture of tetrahydrofuran and water, mixed with 8.4 ml of triethylamine and slowly added to a mixture of N -tert.-butyloxycarbonyl-Da-phenyglycine, 8, cooled to 100 95 ml of triethylamine and 8.40 g of isobutyl chloroformate were added dropwise to 170 ml of tetrahydrofuran. After one hour at 0 and a further hour at room temperature, the reaction mixture is concentrated to half and taken up in 800 ml of ethyl acetate. It is washed twice with 200 ml each of a saturated aqueous sodium hydrogen carbonate solution and twice with 200 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue is chromatographed on 500 g of silica gel.

  The bis-lcis-3 | ss- (N-tert-butyloxyvarbonyl-D-α-phenylglycyl) -amino-2-oxo-4β-acetidinyl] -disulfide is eluted with ethyl acetate. The amorphous product melts at 1631,660 with decomposition; {%] 20 D = + 1450 i 10 (c = 0.930 in chloroform); Thin-layer chromatogram (silica gel; development with iodine vapor): Rf to 0.33 (system:

  Ethyl acetate); Ultraviolet Absorption Spectrum (in ethanol): #max = = 257 mu (s = 2200); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 2.98, 3.34 i, 5.63 Lt, 5.90, 6.68, u, 7.29, 8.11 u, 8.58 tt and 9 , 53 Lt.



   Example 7
A mixture of 0.71 g of 4p (2-hydroxypropylthio) -3β-phenyl-acetylamino-azetidin-2-one in 25 ml of tetrahydrofuran is mixed at 0 with 0.72 ml of chloroformic acid -2,2,2-trichloroethyl ester and 0 , 83 ml of pyridine in 15 ml of tetrahydrofuran were added. The mixture is stirred for 30 minutes at 0 and for 45 minutes at room temperature, concentrated under reduced pressure to about a quarter of the volume, diluted with methylene chloride and washed with a saturated aqueous sodium chloride solution. The organic solution is dried over magnesium sulphate and evaporated under reduced pressure.

  The crude product is chromatographed on 90 g of silica gel, the 3: -Pheny1acetylamino-4- [2- - (2,2,2-trichloräthoxycarbonyloxy) -propylthio] -azetidin-2- -one with methylene chloride and methylene chloride, containing 10% up to 20% ethyl acetate eluted, thin-layer chromatogram (silica gel):

  Rf = 0.53 (system: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03 u, 3.46 l, 5.62 lt, 5.67 ll, 5, &, 5.92 and 6.70 lt
Example 8
A mixture of 1 g of bis- [cis-3β-phenylacetylamino-2-oxo-40-azetidinyl] disulfide in 50 ml of acetic acid and 5 ml of water is mixed with 1.1 g of 3W fluorine-1,2-propylene oxide and
10 g zinc dust added.

  The mixture is stirred for 1 hour at room temperature, filtered, the filtrate is concentrated and the residue is taken up in ethyl acetate; The organic solution is mixed with an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. washed, dried and evaporated. The crude product is chromatographed on 40 g of silica gel and the 4β- (3-fluoro-2-hydroxypropylthio) -3β-phenylacetylamino-azetidin-2-one is eluted with ethyl acetate, thin-layer chromatogram (silica gel): Rf = 0 , 31 (system: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02 Lt, 3.43, 5.63 Lt '5.90 (broad), 6.70 and 7.16.



   Example 9
A mixture of 0.330 g of 4P- (3-fluoro-2-hydroxy-propylthio) -3β-phenylacetylamino-azetidin-2-one in 20 ml of tetrahydrofuran is mixed at 0 with 0.495 g of chloroformic acid-2,2,2- trichloroethyl ester and then a solution of 0.370 g of pyridine in 10 ml of tetrahydrofuran was added dropwise. The mixture is stirred for 30 minutes at 0 and for 45 minutes at room temperature, filtered through a diatomaceous earth preparation and the filtrate is evaporated to dryness under reduced pressure.

  The residue is taken up in 300 ml of ethyl acetate, the organic solution is washed with aqueous sodium hydrogen carbonate solution and aqueous sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on 30 g of silica gel and the 4β- [3-fluoro-2- (2.2, 2-trichlorethoxycarbonyloxy) propylthio] -3p-phenylacetylamino-azetidin -2-one eluted with a 1 1 mixture of methylene chloride and ethyl acetate, thin-layer chromatogram on silica gel): Rf = 0.52 (system: ethyl acetate); Infrared absorption spectrum (in, methylene chloride): characteristic bands at 3.02, 3.45, 5.60 Il, 5.78, 5.92, 6.74 and 7.08.



   The compounds of the present invention can e.g. are further processed as follows: A. A mixture of 1.0 g of 3ss-phenylacetylamino--4β - [2- (2,2,2-trichloroethoxycarbonyloxy) -ethylmercapto] -azetidin-2-one and 3.0 g of glyoxylic acid- tert-butyl ester hydrate in 50 ml of benzene is refluxed for 16 hours with separation of water, then cooled and washed twice with 25 ml of distilled water each time, dried over sodium sulfate and evaporated. Α-Hydroxy-α - {2-oxo-3β-phenylacetylamino-4β - [2- (2,2,2-trichloroethoxycarbonyloxy) -ethylmercapto] -1 -acetidinyl} -acetic acid is thus obtained tert-butyl ester, which is processed further without purification.



   The crude α-hydroxy-α - {- 2-oxo-3β-phenylacetylamino-4ss- [2- - (2,2,2-trichloroethoxycal'bonyloxy) -ethylmercnptoj-1-acetidinyl} obtainable by the above process -acetic acid tert-butyl ester is dissolved in 20 ml of a 1: 1 mixture of dioxane and tetrahydrofuran and added dropwise at -10 ml with 0.54 ml of pyridine in 2 ml of dioxane and 0.48 ml of thionyl chloride in 10 ml of a 1 mixture added by 'dioxane and tetrahydrofuran.



  The reaction mixture is stirred for 30 minutes at 100 to -50 and for one hour under a nitrogen atmosphere, the precipitate is filtered off and the filtrate is treated with the? -Chloro-? - {2-oxo-3ss-phenylacetylamino-4? - [2- (2,2,2 - trichlorethoxycarbonyloxy) - ethyl mercapto] -l -azetidinyl) -acetic acid tert-butyl ester evaporated; the product is processed further in its raw state.



   A solution of the crude α-chloro-α - {2-oxo-3β-phenylacetylamino-4β - - [2- (2,2,2-trichloroethoxycarbonyloxy) -ethylmercapto] -1- - obtainable by the above process azetidinyl} -acetic acid tert-butyl ester in 30 ml of a 1: 1X mixture of dioxane and tetrahydrofuran is mixed with 1.15 g of triphenylphosphine and 0.35 ml of pyridine and heated at 500 for 2 hours, then evaporated to dryness.

  The residue is chromatographed on 30 g of pure silica gel, using a 1: 1 mixture of toluene and ethyl acetate to obtain the a- {2-oxo-3 - phenylacetylamino - 4 - [2 - (2,2,2-trichloro- äthoxycarbonyloxy) -äthyl-mercapto] -1-azetidinyl} - - triphenylphosphoranylidene-acetic acid tert-butyl ester eluted, which is contaminated with a little triphenylphosphine oxide and can be purified by means of preparative thin layer chromatography (silica gel; development with iodine), Rf to 0 .57 (system: toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, 3.42, 5.68, 5.97 Lt, 6.10 lt and 6.65.

 

   A mixture of 0.225 g of α - {2-oxo-3β-phenylacetyl-amino-4p- [2- (2,2,2-trichloroethoxycarbonyloxy) -ethylmer capto] -1-acetidinyl) -sn-triphenylphosphoranylidene-acetic acid tert-butyl ester in 10 ml of a 9: 1 mixture of acetic acid and water is mixed with 3.0 g of zinc dust and stirred at 150 for 45 minutes. It is filtered and the filtrate is evaporated; the 'residue is taken up in 50 ml of ethyl acetate and the solution is washed with 25 ml of a saturated aqueous sodium hydrogen carbonate solution and twice with 25 ml each of a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated.

  The tert-butyl x- [4,3- (2-hydroxy-ethylmercapto) -2-oxo-3β-phenyl-ncetylamino-1-acetidinyl] - triphenylphosphoranylidene-acetic acid is obtained in this way; Thin-layer chromatogram (silica gel; development with iodine): Rf 0.24 (system:
Toluene / acetone 1: 1).



   A mixture of 0.221 g of the crude α- [4β- (2-hydroxyethylmercapto) -2-oxo-3B-phenylacetylamine ino-1-azetidinyl] -α - triphenylphosphoranylidene-acetic acid tert-butyl ester in 5 ml of dimethyl sulfoxide and 5 ml of acetic anhydride is left to stand for 16 hours at room temperature, then concentrated under reduced pressure. The residue is taken up in 100 ml of toluene; the organic solution is used three times each
Washed 50 ml of distilled water, dried over sodium sulfate and evaporated.

  The oily residue is chromatographed on 10 g of silica gel: the desired one
7β-Phenylacetylamino-ceph-3-em-4-carboxylic acid tert-butyl ester, which is obtained by ring closure from the intermediate obtained and not isolated .- (4-Formylmethylmer-capto-2-oxo-3β-phenylacetylamino - 1 -azetidinyl) -x-triphenylphosphoranylidene - acetic acid - forms tert-butyl ester, is eluted with a 4: mixture of toluene and ethyl acetate; Thin layer chromatogram (silica gel): Rf 0.48 (system:

  Toluene / ethyl acetate
1: 1); Ultraviolet absorption spectrum (in neat ethanol): #max 258 mu; Infrared absorption spectrum (in 'methylene chloride): characteristic bands at 3.00, 3.48,
5.62 Lt 5.81 1l, 5.93, 6.10, 6.67, 7.15 Il, 7.31, 7.70 Il, 8.65 and 9.03.



   A mixture of 0.03 g of 7p-phenylacetylamino-ceph--3-em-4-carboxylic acid tert-butyl ester and 0.5 ml of trifluoroacetic acid is left to stand for one hour at room temperature. The trifluoroacetic acid is then removed under reduced pressure and the residue is taken to dryness twice with 5 ml each of a mixture of benzene and chloroform. The residue is chromatographed on 5 g of silica gel and the 7β-phenyl-acetylamino-ceph-3-em-4-carboxylic acid is eluted with methylene chloride containing 5% acetone; Thin-layer chromatogram (silica gel: development with iodine): Rf 0.49: system: n-butanol / pyridine / acetic acid / water 40: 24: 5: 30)
B.

  A mixture of 13.5 g of glyoxy acid tert-butyl ester hydrate in 160 ml of toluene is dehydrated by distilling off about 80 ml of toluene, and 5.29 g of 3β- (N-tert-butyloxycarbonyl-D-α ; - phenylglycyl) amino-4β - -2- (2,2,2-trichloroethoxycarbonyloxy) -ethylthiol-azetidin -2-one and the reaction mixture is heated for 16 hours under a nitrogen atmosphere at 900. After cooling, it is diluted with toluene to a volume of 150 ml, washed five times with 100 ml of water each time, dried over sodium sulfate and evaporated. The residue contains the α- {3β- (N-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino-4β - [2- (2,2,2-trichloroethoxycarbonyl-oxy) -ethylthio] -2-oxo-1-azetidinyl} -α-hydroxy-acetic acid-tert-butyl ester and is processed further without purification.



   The oily product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane and, at about -50, 2.24 ml of pyridine are added and within 10
Minutes with 2.00 ml of thionyl chloride in a 1: 1 mixture of tetrahydrofuran and dioxane. After standing at -5 for 30 minutes, the cooling bath is removed; the mixture is stirred for a further hour at room temperature, filtered through a diatomaceous earth preparation and evaporated. The residue contains the α-chloro-α - {3β- (N-tert-butyloxycarbonyl-D-sc-phenylglycyl) -ami - [2- (2,2,2- -trichloroethoxycarbonyloxy) -ethylthio] - 2-oxo-I-azetinyl} - -acetic acid tert-butyl ester and is processed further without purification.



   The above crude product is dissolved in 100 ml of a 1: 1 mixture of tetrahydrofuran and dioxane. 4.86 g of triphenylphosphine and 0.75 ml of pyridine are added and the mixture is warmed under a nitrogen atmosphere for 1 () hours at 500 °. The dark red solution is concentrated.



  the residue is taken up in methylene chloride and the mixture is washed twice with 100 ml of water and then evaporated. The residue is chromatographed on 200 g of silica gel. with the a- \ 3ss- (N-tcrt.- -Butyloxycarbonyl-D-α-phenylglycyl) -amino-4p- [2- (2,2,2- -trichloräthoxycarbonyloxy) -äthylthio] - 2 - oxo- 1 -nzetidi- nyl, - z-triphenylphosphoranylidene-acetic acid tert-butyl ester eluted with a 1: 1 mixture of toluene and ethyl acetate;

  Thin-layer chromatogram (Si silica gel; development with iodine vapor): IRf to 0.25 (system: toluene / ethyl acetate 1: 1); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.00, 3.44 tj, 5.67 lt. 5.86 ji, 5.92 lt. 6.14 lt and
6.76 Lt
A solution of 1.74 g - {3- (N-tert-Butyloxycar bonyl- Dx-phenylglycyl) -am ino-4p - [2 - (2,2,2-trichloräth- oxycarbonyloxy) -äthylthio] -2- oxo-1-azetidinyl} -α-triphenylphosphoranylidene-acetic acid tert-butyl ester in 65 ml of a 9: 1 mixture of acetic acid and water is mixed with 12 g of zinc dust and stirred for one hour at room temperature.

  It is filtered through a diatomaceous earth preparation, the filtrate is evaporated and the residue is taken up in 5 × 0 ml of ethyl acetate. It is washed twice with 100 ml of a saturated aqueous sodium hydrogen carbonate solution and with 100 ml of a saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulfate and evaporated.



  The α [3α- (N-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino-4α- (2-hydroxyethylthio) -2-oxo-1-acetidinyl] - z - is thus obtained (triphenylphosphoranylidene) - acetic acid -tert.-butyl ester. Thin layer chromatogram ni (silica gel: developing with iodine vapor): Rf ¯ () .29 (system: toluene / acetone 3: 2); Infrared absorption spectrum (in methylene.



  chloride): characteristic bands at 3.00! t, 3.42, 5.68, 5.86 u, 5.93, 6.16 i, 6.75 to and 8.75 t.



   A mixture of 1.53 g of crude α- [3α- (N-tert-butyl-oxycarbonyl-D-phenylglycyl) -amino-4q, - (2-hydroxy-ethylthio) -2-oxo- 1 - azetidinyl] - x- (triphenylphosphoranylden) -acetic acid tert-butyl ester in 60 ml of a 1: 1 mixture of dimethyl sulfoxide and acetic anhydride is left to stand for 16 hours at room temperature under a nitrogen atmosphere, then kept at 500 for a further 2 hours . It is concentrated, taken up in 500 ml of toluene and washed three times with 100 ml of water each time.



  The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on 120 g of silica gel and the 7P- (N-tert-butyloxycarbony] - -D-a-phenylglycyl) -amino-ceph.3-em-4-carboxylic acid-tert. butyl ester with an 8: 2 mixture of toluene and ethyl acetate eluted. The product crystallizes from a mixture of diethyl ether and pentane.

  F. 159 1610; [am20 = +290 20 (c = 0.521 in chloroform): thin layer chromatography (silica gel; development with iodine vapor): Rf ¯ 0.67 (system: toluene / ethyl acetate 1: 1); Ultraviolet Absorption Spectrum (in ethanol): #max = 255 m (e = 5400);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.68,
2.89, 3.33, 5.57, 5.79, 5.88, 6.08, 6.22 Lt 6.70, 7.15, 7.28, F, 7.68 1l, 8.04 "8.64 Il, 9.05, 9.52 iu and 9.79 Lt
A mixture of 0.6367 g of 7p- (N-tert-butyloxycarbonyl-D-x-phenylglycyl) -amino-ceph-3-em-4-carboxylic acid-tert-butyl ester in 30 ml of trifluoroacetic acid is during
Left to stand for 15 minutes at room temperature, then treated with 100 ml of toluene and evaporated.

  The residue is taken up again in 100 ml of a 3: 1 mixture of toluene and methanol, evaporated under reduced pressure and dried under high vacuum.



   The white powdery residue is dissolved in 5 ml of methanol and 13 ml of an above solution of
Triethylamine is added to diethyl ether, a voluminous new precipitate being formed. The 'solvent is evaporated off under reduced pressure, the residue slurried in methylene chloride and suction filtered. It is washed with about 150 ml of methylene chloride and dried under high vacuum. This gives 70- (D-2.Phenylglycyl) -amino-ceph-3-em-4-carboxylic acid in the zwitterionic form as a pale yellowish, amorphous powder, thin-layer chromatogram (silica gel; development with iodine vapor): Rf to 0, 29 (system: n-butanol /
Pyridine / acetic acid / water 40: 24: 6: 30); Ultraviolet absorption spectrum (in water): 1 ,,,, ax = 250 m, ° (± = 4300).



   C. A mixture of 0.706 g of 3β-phenylacetylamino--4ss- [2- (2,2,2-trichloroethoxy-carbonyloxy) -propylthio] -azetidin-2-one and 2.7 g of anhydrous tert-butyl glyoxylate in 50 ml of toluene is heated under nitrogen at 900 for 16 hours and then diluted to a volume of 300 ml with toluene. It is washed five times with 50 ml of water each time, dried over sodium sulfate and evaporated under reduced pressure. The crude oc- - {2-Oxo-3p-phenylacetylamino -4ss - [2 - (2,2,2 - trichloroethoxycarbonyloxy) propylthio] -l -azetidinyl) -a-hydroxy- -acetic acid-tert. -butyl ester is processed further without purification.



   A solution of 1.73 of the crude α- {2-oxo-3β-phenyl-acetylamino-4p- [2 - (2,2,2-trichloroethoxy-carbonyloxy) -propylthio] -1-acetidinyl} -α -hydroxy-acetic acid-tert. - Butyl ester in 25 ml of a 1: 1 mixture of tetrahydrofuran and dioxane is added at 50 and in a nitrogen atmosphere with 0.37 ml of pyridine and 0.33 ml of thionyl chloride in 10 ml of tetrahydrofuran and for 30 minutes at -50 and for 1 hour stirred at room temperature. The pyridine hydrochloride is filtered off and the filter residue is washed with diethyl ether. The filtrate is taken to dryness under reduced pressure and dried under high vacuum.



  The α-chloro-α - {2-oxo-3β-phenylacetylamino-4β- [2- (2,2,2-trichloroethoxy-carbonyloxy) -propylthio] -1-azetidinyl} -acetic acid-tert. -Butyl ester is obtained as a dark oil and processed further without purification.



   The α-chloro-α - {2-oxo-3β-phenylacetylamino-4} - [2- (2,2,2-trichloroethoxycarbonyloxy) -propylthio] -1-acetidinyl obtainable as the crude product by the above process } tert-butyl acetic acid ester in 25 ml of a 1: 1 mixture of tetrahydrofuran and dioxane is mixed with 0.812 g of triphenylphosphine and 0.12 ml of pyridine and kept at 500 for 10 hours. It is diluted with 300 ml of methylene chloride, the organic solution is washed twice with 100 ml of water each time, dried over sodium sulfate and evaporated.

  The crude product is chromatographed on 70 g of silica gel; with a 1: 1 mixture of toluene and ethyl acetate, the? - {2-Oxo-3? -phenylacetylamino-4? - [2 - (2,2,2 - trichloroethoxycarbonyloxy) propylthio] - 1 -azetidinyl) -a-triphenyl-phosphoranylidene - acetic acid - tert. butyl ester eluted, thin-layer chromatogram (silica gel): Rf = 0.22 (system: toluene / ethyl acetate 1: 1); Infrared absorption spectrum in methylene chloride): characteristic bands at 3.02,, 3.45, 5.67 u, 5.85, 5.91 u, 6.15 Lt and 6.75, u.



   A mixture of 0.562 g of a- {2-oxo-3p-phenylacetylamino-4ss- [2 - (2,2,2-trichlorethoxycarbonyloxy) - propylthio] -1-azetidinyl} - sc - triphenylphosphoranylidene - acetic acid tert .-Butyl ester in 20 ml of a 9: 1 mixture of acetic acid and water is mixed with 4 g of zinc dust and stirred for 1 hour at room temperature.



  The zinc is filtered off, washed with acetone and evaporated to dryness under reduced pressure. The residue is taken up in 300 ml of ethyl acetate, the organic solution is washed twice with 50 ml of an aqueous 1 sodium hydrogen carbonate solution each time and once with 50 ml of a saturated aqueous sodium chloride solution, dried and evaporated.

  The α- [4β- (2-hydroxypropylthio) -2-oxo-3β-phenylacetylamino-1-azetidinyl] - z - triphenylphosphoranylidene acetic acid - tert. - butyl ester, thin layer chromatogram (silica gel): Rf = 0.38 (system: toluene / acetone 1: 1); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 3.44. , 5.67 u, 5.86, 5.93 u, 6.17 Lt and 6.75.



   D. A mixture of 0.203 g of 4p- [3-fluoro-2- (2,2,2- trichloroethoxycarbonyloxy) propylthio] - 3p-phenylacetylamino-azetidin-2-one in 20 ml of toluene is treated with 0.730 U of anhydrous glyoxylic acid tert-butyl ester is added and the mixture is heated at 900 for 15 hours in a nitrogen atmosphere, then diluted with 150 ml of toluene. It is washed five times with 30 ml of water each time and dried over Ma.



  magnesium sulfate and evaporated. The crude oc- {4- [3-fluoro -2- (2,2,2-trichloroethoxycarbonyloxy) -propylthio] -2-oxo -3β-phenylacetylamino-1-azetidinyl} - - hydroxy - acetic acid tert. -butyl ester is processed further without purification.



   A mixture of 0.36 g of ss- {4p- [3-tFluo-2- (2,2,2-tri chloroethoxycarbonyloxy) propylthio] -2-oxo W 3 -phenyl.



     acetylamino-l-azetidinyl} -a-hydroxy-acetic acid-tert. - bu.



  tyl ester in 10 ml of a 1: 1 mixture of tetrahydro furan u. Dioxane is added at -5 with 0.08 ml of pyridine and 0.07 ml of thionyl chloride u. for 30 minutes at -50 a. Stirred for 1 hour at room temperature under a nitrogen atmosphere. It is filtered from pyridine hydrochloride, the filtrate is evaporated to dryness under reduced pressure and. dries the residue under high vacuum. The crude α-chloro-α- {4β- [3-fluoro-2- (2 2,2-trichloroethoxycarbonyloxy) propionylthio] -2-oxo -phenylacetylamino-1-azetidinyl) acetic acid - tert. - butyl ester is processed further without cleaning.



   The crude α-chloro-x- {40- [3-fluoro-2 - (2,2,2-trichloroethoxycarbonyl-oxy) -propylthio] -2-oxo-3p-phenylacetylamino-1-azetidinyl obtainable by the above process } tert-butyl acetate is taken up in 15 ml of a mixture of tetrahydrofuran and dioxane, 0.170 g of triphenylphosphine and 0.03 ml of Pyridii are added and the mixture is heated to 500 for 10 hours. Mai concentrates, dilutes with methylene chloride and washes twice with 50 ml of water each time. The organic phase is dried over magnesium sulfate and evaporated and the residue is chromatographed on 15 g of silica gel.

  With a 1: 1 mixture of toluene and ethyl acetate, the α- {4β- [3-fluoro-2- (2,2,2-trichloroethoxycar bonyloxy) -propylthio] -2-oxo-3β-phenylacetylamino is obtained -1-aze tidinyl} -α-triphenylphosphoranylidene-acetic acid tert-butyl ester eluted, thin-layer chromatogram (silica gel): Rf = 0.5 (system: toluene-ethyl acetate 1: 1).



   A mixture of 0.105 g? - {4? - [3-fluoro-2- (2,2,2-trichloroethoxycarbonyloxy) -propylthio] -2-oxo-3x-phenylamino-1-acetidinyl) -? - triphenylphosphoranylidene-acetic acid tert-butyl ester in 10 ml of a 9: 1 mixture of acetic acid and water is treated with 1 g of zinc dust, kept at room temperature for 45 minutes and filtered through a diatomaceous earth preparation.



  It is washed with acetone, the filtrate is evaporated and taken up in ethyl acetate. The organic solution is washed with an aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried and evaporated. The residue is purified by means of preparative thin-layer chromatography (silica gel; system: toluene; acetone 1: 1). The band with Rf = 0.5 identified under the ultraviolet light is scratched out and extracted with a 9: 1 mixture of acetone and methanol.

  It is filtered and evaporated to give the α- [4β- (3-fluoro-2-hydroxy-propylthio) -2-oxo-39-phenylacetylamino-1-azetidinyl] "-triphenylphosphoranylidene-acetic acid-tert. butyl ester, which shows the following characteristic bands in the ultraviolet absorption spectrum (in methylene chloride): 3.00 it, 3.44, 5.67, 5.85 (broad), 6.21 t, 6.71 l and 7.30.



   PATENT CLAIM I
Process for the preparation of 3-amino-4- (2-hydroxy-ethylthio) -2-oxo-azetidine compounds of the formula
EMI21.1
 wherein k1 represents an acyl group. R @ stands for hydrogen, and each of the radicals R3 and R4 stands for hydrogen or an organic radical bonded via a carbon atom, or salts of such compounds with salt-forming groups, characterized in that a bis (cis-3-N- R1-amino-2-oxo-4-azetidinyl).



  disulfide compound of the formula
EMI21.2
 with an oxirane compound of the formula
EMI21.3
 with simultaneous treatment with a reducing agent.



   SUBSTANTIAL CLAIMS Method according to claim 1. characterized. that you can use reducing metals or metal compounds. like metal alloys. -amalgams or salts used as reducing agents.



      2. The method according to patent claim 1 or sub-claim 1, characterized. that nian zinc. Zinc alloys or zinc amalgam or magnesium. preferably in the presence of hydrogen donating agents such as acids. acidic agents or alcohols. preferably used with the addition of water as a reducing agent.



   3. The method according to claim 1 or one of the preceding subclaims. dlulch marked.



  that one zinc in the presence of a lower alkyl carboxylic acid. especially acetic acid. or an alcohol. like lower alkanol. preferably used with the addition of water as a reducing agent.



   4. The method according to claim 1 or sub-claim 1. characterized in that one Alkalime- @allamalgame or Alulllin iumanla Iga m. preferably used in the presence of moist solvents as a reducing agent.



   5. The method according to claim 1 or sub-claim 1, characterized in that Chroni-lf compounds, e.g. Chromium-II-chloride or Chrolll-II-acetate. preferably ir; Presence of aqueous media used as reducing agent.



     (). Method according to claim 1, characterized. that nian compounds of the formula I where R, a. in a preferably pharmacologically active, naturally occurring or synthetically producible N-acyl derivative of 6-amino-penicillanic acids or 7-aminocephalosporanic acid or an easily cleavable acyl radical of a carbonic acid half derivative. R represents hydrogen. and each of the groups R :, and R, denotes hydrogen or an optionally substituted lower alkyl, phenyl or phenyl-lower alkyl radical.



   7. The method according to claim I or dependent claim 6, characterized in that compounds of the formula I are prepared in which R, and R, have the meanings given in dependent claim 6 and R3 is hydrogen.



   8. The method according to claim I or dependent claim 6, characterized in that compounds of the formula 1 are prepared in which R represents a naturally occurring or biosynthetically producible or highly effective N-acyl derivative of 6-amino-penam-3-carboxylic acids or 7- Amino-ceph-3-em-4-carboxylic acids occurring acyl radical or an easily cleavable acyl radical of a carbonic acid half-ester, R2 is hydrogen, R .., hydrogen and R, hydrogen, a lower alkyl group which is optionally substituted by halogen or a phenyl lower alkyl group mean.

 

   9. The method according to claim I or dependent claim 6, characterized in that compounds of the formula I are prepared in which Rl, R2 and Ra have the meanings given in dependent claim 8, and R4 is hydrogen or a lower alkyl group.



   10. The method according to claim 1, characterized in that the 4β- (2-hydroxyethylthio) -3β-phenylacetylamino-azetidin-2-one is prepared.



   11. The method according to claim I, characterized in that the 4S- (2-hydroxypropylthio) -3β-phenylacetylamino-azetidin-2-one is prepared.

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. ethyl ester eluted, thin-layer chromatogram (silica gel): Rf = 0.5 (system: toluene-ethyl acetate 1: 1). A mixture of 0.105 g? - {4? - [3-fluoro-2- (2,2,2-trichloroethoxycarbonyloxy) -propylthio] -2-oxo-3x-phenylamino-1-acetidinyl) -? - triphenylphosphoranylidene-acetic acid tert-butyl ester in 10 ml of a 9: 1 mixture of acetic acid and water is treated with 1 g of zinc dust, kept at room temperature for 45 minutes and filtered through a diatomaceous earth preparation. It is washed with acetone, the filtrate is evaporated and taken up in ethyl acetate. The organic solution is washed with an aqueous sodium hydrogen carbonate solution and a saturated sodium chloride solution, dried and evaporated. The residue is purified by means of preparative thin-layer chromatography (silica gel; system: toluene; acetone 1: 1). The band with Rf = 0.5 identified under the ultraviolet light is scratched out and extracted with a 9: 1 mixture of acetone and methanol. It is filtered and evaporated to give the α- [4β- (3-fluoro-2-hydroxy-propylthio) -2-oxo-39-phenylacetylamino-1-azetidinyl] "-triphenylphosphoranylidene-acetic acid-tert. butyl ester, which shows the following characteristic bands in the ultraviolet absorption spectrum (in methylene chloride): 3.00 it, 3.44, 5.67, 5.85 (broad), 6.21 t, 6.71 l and 7.30. PATENT CLAIM I Process for the preparation of 3-amino-4- (2-hydroxy-ethylthio) -2-oxo-azetidine compounds of the formula EMI21.1 wherein k1 represents an acyl group. R @ stands for hydrogen, and each of the radicals R3 and R4 stands for hydrogen or an organic radical bonded via a carbon atom, or salts of such compounds with salt-forming groups, characterized in that a bis (cis-3-N- R1-amino-2-oxo-4-azetidinyl). disulfide compound of the formula EMI21.2 with an oxirane compound of the formula EMI21.3 with simultaneous treatment with a reducing agent. SUBSTANTIAL CLAIMS Method according to claim 1. characterized. that you can use reducing metals or metal compounds. like metal alloys. -amalgams or salts used as reducing agents. 2. The method according to patent claim 1 or sub-claim 1, characterized. that nian zinc. Zinc alloys or zinc amalgam or magnesium. preferably in the presence of hydrogen donating agents such as acids. acidic agents or alcohols. preferably used with the addition of water as a reducing agent. 3. The method according to claim 1 or one of the preceding subclaims. dlulch marked. that one zinc in the presence of a lower alkyl carboxylic acid. especially acetic acid. or an alcohol. like lower alkanol. preferably used with the addition of water as a reducing agent. 4. The method according to claim 1 or sub-claim 1. characterized in that one Alkalime- @allamalgame or Alulllin iumanla Iga m. preferably used in the presence of moist solvents as a reducing agent. 5. The method according to claim 1 or sub-claim 1, characterized in that Chroni-lf compounds, e.g. Chromium-II-chloride or Chrolll-II-acetate. preferably ir; Presence of aqueous media used as reducing agent. (). Method according to claim 1, characterized. that nian compounds of the formula I where R, a. in a preferably pharmacologically active, naturally occurring or synthetically producible N-acyl derivative of 6-amino-penicillanic acids or 7-aminocephalosporanic acid or an easily cleavable acyl radical of a carbonic acid half derivative. R represents hydrogen. and each of the groups R :, and R, denotes hydrogen or an optionally substituted lower alkyl, phenyl or phenyl-lower alkyl radical. 7. The method according to claim I or dependent claim 6, characterized in that compounds of the formula I are prepared in which R, and R, have the meanings given in dependent claim 6 and R3 is hydrogen. 8. The method according to claim I or dependent claim 6, characterized in that compounds of the formula 1 are prepared in which R represents a naturally occurring or biosynthetically producible or highly effective N-acyl derivative of 6-amino-penam-3-carboxylic acids or 7- Amino-ceph-3-em-4-carboxylic acids occurring acyl radical or an easily cleavable acyl radical of a carbonic acid half-ester, R2 is hydrogen, R .., hydrogen and R, hydrogen, a lower alkyl group which is optionally substituted by halogen or a phenyl lower alkyl group mean. 9. The method according to claim I or dependent claim 6, characterized in that compounds of the formula I are prepared in which Rl, R2 and Ra have the meanings given in dependent claim 8, and R4 is hydrogen or a lower alkyl group. 10. The method according to claim 1, characterized in that the 4β- (2-hydroxyethylthio) -3β-phenylacetylamino-azetidin-2-one is prepared. 11. The method according to claim I, characterized in that the 4S- (2-hydroxypropylthio) -3β-phenylacetylamino-azetidin-2-one is prepared. 12. The method according to claim 1 thereby ge indicates that the 3β- (N-tert-butyloxycarbonyl- -D-t22-pheny] glycyl) -amino-4,3- (2-hydroxyethylthio) -azetidin-2-one- is prepared. 13. The method according to claim I, characterized in that the 3β-phenylacetylamino-4q- (3-fluorine-2-hydroxypropylthio) -azetidin-2-one is prepared. 14. The method according to claim I, characterized in that a compound obtained with a salt-forming group is converted into a salt. PATENTA: NSPRUC H II Use of a compound of the formula I obtainable according to claim I, in which R2 is hydrogen, for the preparation of compounds of the formula (1) in which R2 is an acyl group of the formula -C (= O) -X1 which can be split off under mild conditions, characterized in that the free hydroxyl group is esterified by treatment with such a carboxylic acid or a reactive acid derivative thereof that the group is cleavable under mild conditions. SUBCLAIMS 15. Use according to claim II, characterized in that it is reacted with an anhydride of the acid. 16. Use according to claim II or dependent claim 1, characterized in that it is reacted with a halide of the acid. 17. Use according to claim II, or one of the preceding subclaims, characterized in that it is reacted with a chloride of the acid. 18. Use according to claim II, characterized in that the esterification is carried out in the presence of a condensing agent. 19. Use according to claim II, characterized in that the reaction is carried out with a carbonic acid half ester of the formula X1-COOH or a reactive derivative thereof, in which the radical X1 is a radical bonded via oxygen. 20. Use according to claim II, characterized in that it is reacted with a carbonic acid half ester of the formula X1-COOH or a reactive derivative thereof, in which the radical X is the 2,2,2-tri chloroethoxy radical. 21. Use according to claim II, characterized in that the 3p-phenylacetylamino-4p- [2- - (2,2,2-trichlorethoxycarbonyloxy) ethylthio] -azetidin - 2 -one produces nlan. 22. Use according to claim 1-1, characterized in that the 3p- (N-tert-butyloxycarbonyloxy: -phenylglycyl) -amino-4 - [2- (2,2,2-trichloroethoxycarbonyloxy) - ethylthio] -azetidin-2-one produces. 23. The method according to claim II, characterized in that the 3- (N-tert-butyloxycarbonyl-D-α-phenylglycyl) -amino-4β - [2- (2,2,2-trichloroethoxycarbonyloxy) -äthylthio] -azetidin-2-one produces. 24. The method according to claim II, characterized in that the 3p-phenylacetylamino-4,8- - [2- (2,2,2-trichlorethoxycarbonyloxy) - propylthio] - azetidin-2-one is prepared. 25. The method according to claim II, characterized in that the 3ss-phenylacetylamino-4ssç [3- -fluoro - 2- (2,2,2 - trichlorethoxycarbonyloxy) - propylthio] -azetidin-2-one is prepared.