CH500233A - Alpha-hydroxy-2-oxo-1-azetidinemethane-carboxylic acids - inters for pharmaceuticals e.g. antibiotics - Google Patents

Abstract

New: Alpha-hydroxy-2-oxo-1-azetidinemethane-carboxylic acids of formula (where R1 is H or organic residue of alcohol, R2 is H or acyl, R3 is opt. substd. hydrocarbon residue and R4 is H if R2 is acyl, or R3 and R4 together stand for disubstituted carbon if R2 is H or acyl) and their salts. Produced by reacting 1-unsubstituted azetidine-2-one cpds. of formula (where R2A is acyl) with a cpd. of formula O=CH-COOR1A (where R1A is residue of alcohol) or with a reactive derivative thereof and opt. splitting off acyl groups R2A and opt. acylating free N-atom in cpd. obtained, and/or converting ester obtained to free carboxylic acid, opt. converting salt to free cpd. or different salt and/or separating isomers from mixture. Products useful intermediates in production of pharmaceuticals, such as antibiotics.

Description

  

  
 



  Process for the preparation of phosphorus-containing acetic acid compounds
The present invention relates to a process for the preparation of phosphorane compounds of the formula
EMI1.1
 where R1 represents the organic radical of an alcohol, R2 represents an acyl radical, R3 represents an organic radical and R4 represents a hydrogen atom, or the two groups R8 and R4 together represent a disubstituted carbon atom, and each of the groups Ra, Rb and RG represents an organic radical means, as well as salts of such compounds with salt-forming groups.



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



   An acyl radical R2 is primarily that of an organic carboxylic acid, in particular a carbonic acid half derivative or an optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid.



   An organic radical Rs is an optionally substituted hydrocarbon radical, primarily an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radical which can be split off, is unsaturated in the linkage position or substituted by a hetero radical.



   Substituents of a disubstituted carbon atom, which is represented by the two radicals R3 and R4 together, are optionally substituted hydrocarbon radicals, such as optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic hydrocarbon radicals. The two substituents of the disubstituted carbon atom can also be taken together and z. B. represent an optionally substituted and / or interrupted by heteroatoms, divalent, aliphatic hydrocarbon radical.



   Organic radicals Ra, Rb and Re are primarily optionally substituted aliphatic or aromatic, and also optionally substituted cycloaliphatic, cycloaliphatic-aliphatic or araliphatic hydrocarbon radicals.



   An aliphatic hydrocarbon radical is an alkyl, alkenyl or alkynyl, in particular a lower alkyl or lower alkenyl, and also a lower alkynyl radical, the z. B. can contain up to 7, preferably up to 4 carbon atoms. Such radicals can optionally be replaced by functional groups, e.g.

  B. by etherified or esterified hydroxyl or mercapto groups, such as lower alkoxy, lower alkenyloxy, lower alkylenedioxy, optionally substituted phenyloxy or phenyl-lower alkoxy, lower alkylmercapto or optionally substituted phenylmercapto or phenyl-lower alkylmercapto, lower alkoxycarbonyloxy or lower alkanoyloxy groups, and can also be mono-, di- or poly-substituted by nitro groups, substituted amino groups or functional converted carboxy groups, such as carbo-lower alkoxy, optionally N-substituted carbamyl or cyano groups.



   Cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals are, for. B. Cycloalkyl or cycloalkenyl groups, or cycloalkyl or cycloalkenyl-lower alkyl or lower alkenyl groups, in which cycloalkyl radicals e.g. Contain 3-8, preferably 3-6 ring carbon atoms. while cycloalkenyl radicals e.g. 5-8, preferably 5 or 6 ring carbon atoms, and 1 to 2 double bonds, and the aliphatic part of cyclo aliphatic-aliphatic radicals e.g. 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. B.



  the above-mentioned, optionally substituted lower alkyl groups, or then, like the above-mentioned aliphatic hydrocarbon radicals, mono-, di- or polysubstituted by functional groups.



   An aromatic hydrocarbon radical is a mono- or bicyclic aromatic hydrocarbon radical, in particular a phenyl, and a 1- or
2-naphthyl group which may optionally, e.g. such as the abovementioned aliphatic and cycloaliphatic hydrocarbon radicals, can be substituted.



   An araliphatic hydrocarbon radical is a z. B. up to three, optionally substituted, mono- or bicyclic, aromatic hydrocarbon radicals, optionally substituted aliphatic hydrocarbon radical and is primarily a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl radical, where such radicals 1- Contain 3 phenyl groups and optionally, z. B. as the above-mentioned aliphatic and cycloaliphatic radicals, in the aromatic and aliphatic part can be substituted.



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



   The acyl radical of a carbonic acid half-derivative is preferably the acyl radical of a corresponding half-ester, such as an optionally substituted aliphatic half-ester, primarily an optionally substituted lower alkyl half-ester of carbonic acid, i.e. H. a carbo-lower alkoxy radical which is optionally substituted in the lower alkyl part. An aliphatic carboxylic acid is in particular an optionally, z. B. as the above-mentioned aliphatic hydrocarbon radicals, substituted alkane, as well as alkene or alkyne, primarily lower alkane, and lower alkene or lower alkyne carboxylic acid, the z. B. can contain up to 7, in particular up to 4 carbon atoms. A cycloaliphatic or cycloaliphatic-aliphatic carboxylic acid is an optionally z.

  B. as the above-mentioned cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals, substituted cycloalkane or cycloalkenecarboxylic acid, or cycloalkyl or cycloalkenyl lower alkanoic or lower alkenyl carboxylic acid, where a cycloalkyl or cycloalkenyl radical, as well as the aliphatic part of cycloaliphatic-aliphatic-aliphatic acids, e.g. have the number of carbon atoms and / or double bonds indicated above for corresponding radicals and may optionally be substituted as indicated. An aromatic carboxylic acid is primarily a mono- or bicyclic aromatic carboxylic acid which may optionally, e.g. B. as the above-mentioned cycloaliphatic radical, may be substituted. In an araliphatic carboxylic acid, the araliphatic part has e.g.

  B. the above meaning; an araliphatic carboxylic acid means primarily a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid, in which the phenyl radical and the aliphatic part optionally, e.g. as the above-mentioned cycloaliphatic or aliphatic groups can be substituted. A heterocyclic carboxylic acid is in particular one of aromatic character in which the heterocyclic radical can be monocyclic or bicyclic and primarily for an optionally, e.g. such as the above-mentioned cycloaliphatic radical, substituted mono- or bicyclic, monoaza, monooxa, monothia, diaza, oxaza or thiazacyclic radical, primarily a pyridyl, thienyl, furyl, quinolyl or isoquinolyl radical.



  In a heterocyclic aliphatic carboxylic acid, the heterocyclic radical has the meaning given above, while the aliphatic part such. B. in an araliphatic carboxylic acid for an optionally substituted lower alkyl and lower alkenyl radical.

 

   A lower alkyl radical is e.g. B. a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, as well as n-pentyl, isopentyl, n-hexyl , Isohexyl or n-heptyl group, while a lower alkenyl radical z. A vinyl, allyl, isopropenyl, 2- or 3-methallyl or 3-butenyl group, and a lower alkynyl radical e.g. may be propargyl or 2-butynyl.



   A cycloalkyl group is e.g. B. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl group, and a cycloalkenyl z. B. a 2- or 3-Cyclopentrl, 1-, 2- or 3-Cyclohexenyl or 3-Cycloheptenylgruppe.



  A cycloalkyl-lower alkyl or -niederalkenylrest is z. B. a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl-methyl, ethyl, propyl, vinyl, or allyl group, while a cyclo alkenyl-lower alkyl or -niederal kenyligruppe z. B. represents a 1-, 2 or 3-cyclopentyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenyl-methyl, -ethyl, -propyl, -vinyl or -allyl group.



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



   A Mederalkylen- or Niederalkenylenrest z. B. by a 1,2-ethylene, 1,3-propylene, 2,2-dimethyl - 1, 3-propylene, 1,4-butylene, 1- or 2-methyl-1,4- butylene, 1,4-dimethyl-1,4-butylene, 1,5-pentylene, 1-, 2- or 3-methyl-1,5-pentylene, 1,6-hexylene, 2-butene -1,4-ylene or 2- or 3-penten-1,5-ylene group.



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



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



  Acetic, propionic, isobutyric, valeric, pivalic or acrylic acid, while a cycloalkane or cycloalkenyl or



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



  As pyridine, thiophene, furan, quinoline or isoquinoline carboxylic acids are nicotinic or isonicotinic acid, 2-thiophene, 2-furan, 2- or 4-quinoline or 1-isoquinoline carboxylic acid, and the corresponding pyridyl, furyl, Thienyl, quinolyl or isoquinoly-lower alkane or -niederalkencarbonsäuren z. B. called 2-, 3- or 4-pyridyl acetic acid, 2-thienyl acetic acid, 2-furyl acetic acid or 2-furylacrylic acid.



   Optionally substituted aliphatic hydrocarbon radicals, in particular lower alkyl groups, which u. a. can also substitute cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radicals, contain the above-mentioned substituents and are z. Halo-lower alkyl groups such as mono-, di- or trihalogenated lower alkyl, e.g. Methyl, ethyl, or 1- or 2-propyl groups; Residues of this type, in particular 2-halo-lower alkyl radicals such as 2,2,2-trichloroethyl or 2-iodoethyl groups, primarily represent halogenated lower alkyl radicals R.



   Other substituted aliphatic hydrocarbon radicals, such as the aliphatic hydrocarbon radicals R3 substituted by hetero radicals in the linked position, are primarily lower alkyl groups containing ether or esterified hydroxy groups in the linked position, such as lower alkoxy or lower alkanoyloxy groups or halogen atoms containing lower alkyl, such as lower alkyl, such as Ethyl, propyl or isopropyl radicals.



  These, as well as aliphatic hydrocarbon radicals R3 which are unsaturated in the linkage position, in particular the 2-propenyl radical, can preferably be removed under acidic conditions, an alkanoyloxy group also under alkaline conditions, and by treatment with mercaptide-forming heavy metal salts, such as mercury or cadmium salts, e.g. the corresponding halides or lower alkanoyloxy compounds, split off.



   Among the etherified hydroxy and mercapto groups are lower alkoxy, e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy groups, lower alkenyloxy, e.g. B. vinyloxy or allyloxy groups, lower alkylenedioxy, z. B. Methvlenoder Ethylenedioxygruppen, phenyloxy groups, phenyl-lower alkoxy, z. Benzyloxy or 1- or 2-phenyl ethoxy groups, lower alkyl mercapto, e.g. Methyl mercapto or ethyl mercapto groups, phenyl mercapto groups or phenyl-lower alkyl mercapto, e.g. B.



     Benzyl mercapto groups. Esterified hydroxyl groups are primarily halogen e.g.



  Fluorine-. Chlorine, bromine or iodine atoms, and lower alkanyloxy, z. B. Ättyloxy- or propionyloxy groups.



   Substituted amino groups are mono- or disubstituted amino groups in which the substituents are primarily optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals.

  Such amino groups are in particular lower alkyl amino or di-lower alkyl amino, z. 3. Methyiamino, ethylamino, dimethylamino or diethylammograms, or optionally by heteroatoms, such as oxygen, sulfur or optionally, e.g. lower alkyleneamino groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiamorpholino or methylpiperazino groups.



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



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



   The compounds according to the invention are novel intermediates of the Wittig type which are suitable for the preparation of valuable compounds which primarily have pharmacological activity. So you can e.g. in compounds of the formula I in which Rt is preferably a reductively cleavable organic radical of an alcohol, Rla, such as a 2-halo-lower alkyl, e.g. the 2,2,2-trichloroethyl radical, or then an organic radical of an alcohol which can be split off under acidic conditions, such as a methyl radical which is polysubstituted by aliphatic or aromatic, optionally substituted hydrocarbon radicals, e.g. the benzhydryl, trityl or tert-butyl radical,

   and R2 represents an acyl radical that can be split off under acidic conditions, R2a, such as the carbo-tert-butyloxy radical, by treatment with glyoxylic acid compounds, preferably at elevated temperature (50-150 ° C.) and in an inert solvent such as dioxane, toluene, xylene or diethylene glycol dimethyl ether, optionally with the addition of a suitable carboxylic acid, such as benzoic acid, replace the phosphoranylidene radical with an optionally functionally modified carboxymethylene radical. The resulting double bond in a compound obtainable in this way can e.g. by treatment with catalytically activated hydrogen, e.g.

  In the presence of a noble metal such as palladium catalyst with nascent hydrogen, e.g. by treating with a suitable zinc compound such as zinc, zinc amalgam or zinc copper in the presence of a hydrogen donating agent such as a weak carboxylic acid, e.g. Acetic acid, or a lower alkanol such as methanol, ethanol or isopropanol, if included, an aqueous mixture thereof, or with a homogeneous hydrogenation catalyst such as transition metal hydrides, e.g. corresponding chromium (III), manganese (II), iron (III), cobalt (II) or nickel (II) compounds or complexes, such as carbonyl, cyano or phosphine complexes thereof, are saturated.

  By treating with a strong, preferably oxygen-containing inorganic or organic acid, primarily trifluoroacetic acid, in the presence of an anhydride of a strong acid, such as trifluoroacetic anhydride, followed by a suitable acid anhydride, in particular acetic anhydride, a compound of the formula which can be obtained in this way can be obtained
EMI4.1
 wherein Rd represents a hydrogen atom or one of the removable organic radicals of alcohols mentioned for the group R3, optionally after cleavage of an acyl group R2a and / or conversion of an intermediate of the formula A, wherein Rd represents a hydrogen atom, into a reactive derivative, such as an acid halide, e.g.

  Chloride (e.g. 13. using thionyl chloride or oxalyl chloride) or a mixed anhydride, e.g. B. with a carbonic acid lower alkyl half ester such as ethyl half ester (e.g.



  using a haloformic acid lower alkyl ester) or a lower alkanecarboxylic acid, such as acetic acid (for example using an appropriate anhydride), with cleavage of the R3-S-13 bond and the -N-R4 bond, to give a compound of the formula
EMI4.2
 close the ring. The latter, primarily those in which Rta is a hydrogen atom and R2a is an acyl group, are resistant to various microorganisms, e.g. against Gram-positive and Gram-negative bacteria, such as Staph.aureus, Proteus vulgaris and Bacillus megatherium, have antibiotics and can be used accordingly.

 

   Furthermore, compounds of the formula I can be mixed with carboxyaldehyde compounds of the formula
EMI4.3
 wherein R is a carbon atom which, in addition to at least one hydrogen atom, contains optionally substituted aromatic and aliphatic hydrocarbon radicals such as phenyl and lower alkyl groups, or tautomers or reactive derivatives thereof, such as e.g. React hydrates or enols thereof, wherein the reaction is preferably carried out like the addition reaction described above.



  The compounds of the formula thus obtained
EMI5.1
 wherein R, Rta, R2a, Rs and R4 have the meanings given above, where R stands in particular for a carbon atom which, in addition to at least one hydrogen atom, preferably has one or two lower alkyl groups or one optionally as indicated above, e.g. by hydrocarbon radicals, such as lower alkyl groups, or by functional groups, such as etherified or esterified hydroxyl groups, e.g. Lower alkoxy groups or halogen atoms, or nitro groups substituted phenyl groups, optionally also together with a NiederalkyDgruppe, or an acyl, z.

  An optionally substituted benzoyl group, as substituent, by treatment with a suitable acidic agent, e.g. Trifluoroacetic acid, close the ring. In compounds of the formula obtainable in this way
EMI5.2
 wherein Ra is an optionally substituted hydrocarbon radicals, optionally substituted heterocyclic or heterocyclic-aliphatic radicals in which heterocyclic groups have aromatic character, or functional groups mono- or disubstituted carbon atom, an organic group Rl can be replaced by hydrogen and / or a hydrogen Rl and / or R2 can be replaced by an organic group Rt or an acyl radical R2, in particular by a suitable acyl radical.



   Compounds of type (E), in particular those in which R1 represents a hydrogen atom and R2 represents a suitable, in particular one in pharmacologically active 6-acylamino-penicillanic or 7-acylamino-cephalosporanic acid derivatives, an acyl radical of an organic carboxylic acid has excellent, compared to different types Microorganisms, in particular against gram-positive bacteria such as Staph.aureus and Proteus vulgaris, have antibiotic effects and can be used accordingly.



   The invention relates primarily to compounds of the formula
EMI5.3
 and
EMI5.4
 wherein R1, for a lower alkyl, such as methyl, ethyl or tert-butyl radical, a halo-lower alkyl, primarily a 2-halo-lower alkyl, such as 2,2,2-trichloroethyl, or a phenyl lower alkyl, in particular diphenylmethyl radical, R2, an acyl radical, in particular the acyl radical of an organic carboxylic acid, which occurs in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, such as phenylacetyl, phenyloxyacetyl, a protected amino group containing phenylglycyl, thienylacetyl, z.

  B. 2-thienylacetyl, chloroethyl-carbamoyl or cyanoacetyl radical, or then an easily cleavable acyl radical, especially the radical of a half-ester of carbonic acid, such as a carbo-lower alkoxy, e.g.



  Carbo-tert-butyloxy radical, each of the radicals R3 and R, stands for a lower alkyl, in particular methyl radical, R3, a 2-propenyl or 2-lower alkanoyloxy2-propyl group and each of the groups Ra ', Rb' and Rc 'represents a lower alkyl or phenyl radical.



   Particularly valuable as intermediate products are the a- (Tri-R-phosphoranylidene) -a- (2-carbo-lower alkoxy-3,3-dimethyl-7-oxo-4-thia 2,6-diaza-6-bicyclo [3, 2.0] heptyl) - acetic acid lower alkyl ester, in which the lower alkyl radical of the ester grouping can optionally have one or more halogen atoms, preferably in the 2-position, and is primarily the tert-butyl or 2,2,2-trichloroethyl radical, while the carbo-lower alkoxy radical in the 2-position preferably represents the carbo-tert-butyloxy radical and R stands for a lower alkyl or phenyl group.
EMI6.1




  NEN can be obtained in a surprising manner if a reactive ester of an α-hydroxy-2-oxo-1-azetidine methanecarboxylic acid ester of the formula
EMI6.2
 wherein X represents a reactive esterified hydroxy group with a phosphine compound of the formula
EMI6.3
 converts, and a phosphonium salt compound obtainable as an intermediate product by treatment with a weak base with elimination of the elements of the acid H-X in the corresponding Phosphoranver binduilg. If desired, an obtained mixture of isomers can be converted into the individual isomers.



   In the starting material of the formula IIa, a group X primarily represents a halogen, in particular a chlorine or bromine, and an iodine atom; X can also represent an organic, primarily an aliphatic or aromatic sulfonyloxy, e.g. B. an optionally substituted lower alkyl sulfonyloxy, such as methylsulfonyloxy, Athylsulfonyloxy or 2-hydroxy-ethylsulfonyloxy, or an optionally substituted phenylsulfonyloxy, z. B.



  4-methylphenylsulfonyloxy, 4-bromo-phenylsulfonyloxy or 3-nitro-phenylsulfonyloxy group. In the phosphine compound of the formula IIb the radicals Ra, Rb and R have the meanings given above and are primarily optionally substituted lower alkyl or phenyl radicals, e.g.



  n-butyl or phenyl groups.



   The above reaction is preferably carried out in the presence of a suitable inert solvent such as an aliphatic, cycloaliphatic or aromatic hydrocarbon such as hexane, cyclohexane, benzene or toluoyl, or an ether such as dioxane, tetrahydrofuran or diethylene glycol dimethyl ether, or a solvent mixture. It is preferably carried out at an elevated temperature, e.g. B. at a temperature of about 500 C to about
EMI6.4
 ert gas, such as nitrogen.



   An intermediately formed phosphonium salt compound of the formula
EMI6.5
 usually spontaneously loses the elements of the acid H-X; if necessary, the phosphonium salt compound can be prepared by treating with a weak base such as an organic base, e.g. B. diisopropylethylamine or pyridine are decomposed.



   Mixtures of isomers obtained can be prepared by methods known per se, e.g. by fractional crystallization, adsorption chromatography (column or thin layer chromatography) or other suitable separation processes, can be separated into the individual isomers. Racemates obtained can in the usual way, for. B. by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the mixture into the diastereoisomeric salts and converting the separated salts into the free compounds or by fractional crystallization from optically active solvents into the antipodes.

 

   The process also includes those embodiments according to which compounds obtained as intermediates, e.g. the above-mentioned phosphonium salt compounds of the formula III, used as starting materials and the remaining process steps, e.g. B. the cleavage of the elements of the acid H-X from the compounds of the formula III by treatment with a weak base, 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 used according to the process are obtained by using a compound of the formula
EMI6.6
  with a glyoxylic acid ester or a reactive derivative, e.g. a hydrate thereof is reacted at an elevated temperature, primarily at about 500 ° C. to about 150 ° C., in the absence of a condensing agent and / or without the formation of a salt, water formed when the hydrate is used, if necessary, by distillation , e.g. azeotropic, can remove.



   In such a obtainable compound of the formula
EMI7.1
 the hydroxy group is removed by treatment with a suitable esterifying agent, e.g. a halogenating agent such as a thionyl halide, e.g. chloride, a phosphorus oxyhalide, especially chloride, or a halophosphonium halide such as triphenylphosphine dibromide or iodide, or a suitable organic sulfonic acid halide such as chloride, preferably in the presence of a basic, primarily an organic basic agent, such as an aliphatic tertiary amine , e.g. Triethylamine or diisopropylethylamine, or a heterocyclic base of the pyridine type, e.g. Pyridine or collidine, converted into a reactive esterified hydroxyl group.



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



     2,2,2-trichloroethanol or 2-iodoethanol, treated and in the 6-acylamino-2- (2-halo-lower alkoxycarbonyl-amino) -3,3-dimethyl-4-thia-1-azabicyclo [3, 2.0] heptan-7-one compound the substituents in the 2-position by treatment with a chemical reducing agent, for example Zinc in the presence of 90% acetic acid cleaves. The corresponding 6-acylamino-2-hydroxy-3, 3-dimethyl-4-thia-1-azabicyclo [3.2.0] heptan-7-one compound, which is oxidizing agent when treated with a heavy metal acylate, is obtained. especially a lead IV carboxylate, such as lower alkanoate, e.g. B.

  Lead tetraacetate, usually with illumination, preferably with ultraviolet light, can be converted into a 3-acylamino-2- (2-acyloxy-2-propylmercapto) -1-formyl-azetidin-4-one compound. If desired, the acyloxy group can be cleaved off by heating with the introduction of a double bond in the 2-propyl mercapto group together with a hydrogen atom in the form of the corresponding acid. The formyl group attached to one of the nitrogen atoms can be nylated by treatment with a suitable decarbonylating agent such as a tris (tri-organically substituted phosphine) rhodanium halide, e.g. Tris (triphenylphosphine) rhodium chloride, in a suitable solvent, e.g. B. benzene, or with conversion into the carbinol group z.

  B. by treatment with catalytically activated hydrogen in the presence of an acidic reagent, such as hydrogen in the presence of a palladium catalyst and glacial acetic acid or hydrochloric acid tetrahydrofuran, can be removed. If desired, the 2-acyloxy-2-propyl radical in a compound obtainable by the above process can be obtained by treating with a weakly basic agent such as an alkali metal hydrogen carbonate or pyridine in the presence of a reactive ester of an alcohol such as a suitable halide another organic residue can be replaced.



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



   example 1
A solution of 11.3 g of a crude mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimefllyl-7-oxo-4-thia-2, oediaza-6-btcyclo [3.2 , Oj-heptyl a-chloro-acetic acid tert-butyl ester in 150 ml of absolute dioxane is mixed with 11.4 g of triphenylphosphine and 10.8 g of polystyrene Hünig base or diisopropylaminomethyl polystyrene (prepared by heating a mixture of 100 g of chloromethyl polystyrene [J. .Am.Chem.Soc., 85, 2149 (1963) 1, 500 ml of benzene, 200 ml of methanol and 100 ml of diisopropylamine to 1500 with shaking, filtering, washing with 1000 ml of methanol, 1000 ml of a 3: 1 mixture of dioxane and Triethylamine, 1000 ml of methanol, 1000 ml of dioxane and 100 ml of methanol and drying for 16 hours at 100/10 mm Hg;

   the product neutralized 1.55 milliequivalents of hydrochloric acid per gram in a 2: 1 mixture of dioxane and water) added, stirred for 17 hours under a nitrogen atmosphere at 55 ", then cooled and filtered through a glass filter. It is washed with 100 ml of benzene; the filtrate is evaporated under a water jet vacuum; the residue is dried under high vacuum, dissolved in 100 ml of a 9: 1 mixture of hexane and ethyl acetate and chromatographed on a column (height 48 cm; diameter 6 cm) with acid-washed silica gel.

  With 2000 ml of a 3: 1 mixture of hexane and ethyl acetate, triphenylphosphine and a little triphenylphosphine sulfide are added, with a further 4000 ml of the 3: 1 mixture of hexane and ethyl acetate, a- (2r-carbo-tert-butyl-oxy-3 3 - dimethyl-7-oxo-4thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a- (triphenylphosphoranylidene) acetic acid tert-butyl ester of the formula
EMI8.1
 eluted; a further amount of the impure product can be obtained with 1500 ml of the same solvent mixture.

  The product has an Rf value of 0.5 in a thin-layer chromatogram (silica gel; system 1: 1 mixture of benzene and ethyl acetate) and crystallizes from a mixture of ether and pentane, mp 121-122; [a] D = -2190 + 10 (c = 1.145 in chloroform); Ultraviolet absorption spectrum (in ethanol): Man = 225 m (e = 30,000) and 260 m, (e = 5400);

  Infrared absorption spectrum (In methylene chloride): characteristic bands at 5.76, 5.80 (shoulder), 5.97jt, 6.05u (shoulder) and 6.17. A further amount of the product can be isolated from the mother liquor by crystallization in a Sither-Pentan mixture.



   Example 2
A solution of 0.1 g of a- (2-carbo-tert-butyloxy-3, 3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptyl) -a-chloro-acetic acid 2,2,2-trichloroethyl ester in 3 ml of dry benzene (after treating with sodium and filtering through aluminum oxide, neutral, activity I) is treated with 0.072 g of freshly distilled trin-butyl-phosphine and that The mixture was stirred for 25 hours at room temperature.

  The product obtained is chromatographed on silica gel, using a 9: 1 mixture of benzene and ethyl acetate to give a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6- diaza-6 bicyclo [3.2.0] heptyl) a- (tri-n-butyl-phosphoranylidene) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI8.2
 which is processed further without cleaning,
Example 3
A mixture of 0.735 g of polystyrene Hünig base in 10 ml of dioxane (treated with neutral aluminum oxide, activity I) is mixed with 0.34 g of triphenylphosphine recrystallized from hexane, then with 0.5 g of a- (2-carbo-tert-butyloxy -3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2.0] heptyl)? -Chloroacetic acid-2,2,2-trichloroethyl ester and treated for 17 hours stirred at 600 under a nitrogen atmosphere.

  The mixture is filtered through a glass filter, and the filter residue is washed twice with 5 ml of methylene chloride each time and once with 5 ml of benzene. The filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel. Triphenylphosphine, starting material and dehalogenated starting material are washed out with benzene and a 19: 1 mixture of benzene and ethyl acetate.

  The desired a- (2-carbo-tert-butyloxy-3,3 dimethyl-7exo-4-thia-2,6Ziaza-6-bicyclo [3.2.0] heptyl) - a- (triphenyl-phosphoranylidene) acetic acid 2,2,2-trichloroethyl ester of the formula
EMI8.3
 obtained with a 9: 1 mixture of benzene and ethyl acetate in oily form, which, after crystallizing twice from a methylene chloride-pen tane mixture, melts at 2050; [a] 20D = -1920 + 10 (c = 1.054 in chloroform); Thin-layer chromatogram (silica gel): Rf 0.54 in the benzene-acetic acid ethyl ester system (3: 1); Ultraviolet absorption spectrum (in ethanol): AmaX = 225m (e = 30,100) and 265 my (e = 5760);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, u, 5.85, u and 6.10. More polar components are washed out using a 4: 1 mixture of benzene and ethyl acetate.

 

   Example 4
A mixture of 0.104 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl-a 2,2,2-trichloroethyl bromoacetate and triphenylphosphine (1.3 equivalents) in 0.2 ml of benzene at 25 give a colorless precipitate within 20 minutes. After one hour, the precipitate is filtered off, the precipitate four times at 0.5 ml of a 1: 1 mixture of benzene and hexane and dried.

  A- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a is obtained in this way - (triphenylphosphonium) acetic acid 2,2,2-trichloroethyl ester bromide, which after treatment with aqueous sodium carbonate solution gives the crude a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4 -thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - -actriphenylphosphoranylidene) = acetic acid ester-2,2,2-trichloro-ethyl ester which, after crystallization from hexane, melts at 201-202.



   Example 5
A solution of 0.115 g of the crude mixture of the isomers of α-chloro-α- (α-isopropylmercapto-4-oxo-3-aN-phenyloxyacetyl-amino-1-azetidinyl) -acetic acid tert-butyl ester in 2 ml 0.12 g of triphenylphosphine and 0.11 g of polystyrene Hünig base are added to dioxane, and the mixture is stirred at 55 "for 16 hours, then filtered. The filter residue is washed with benzene and the filtrate is evaporated to dryness under reduced pressure. The residue is evaporated to dryness Chromatographed on 5 g of acid washed silica gel.

  The excess triphenylphosphine is washed out with 40 ml of benzene, and with a 1: 1 mixture of benzene and ethyl acetate, as well as with ethyl ester, the desired a- (2a-isopropylmercapto-oxo-3 a-N-phenyloxyacetyl-amino-1 is obtained -azetidinyl) a-triphenylphosphoranylididenessigsäuretert. -butyl ester of the formula
EMI9.1
 as a colorless oil; Infrared absorption spectrum (in methylene chloride); characteristic bands 3.05, 5.71, u, 5.94, u, 6.17, 6.58, m, 6.72At, 7.34, u, 8.60, s and 9.03 ,.



   The starting materials used in the above examples can be produced as follows:
Example 6
A solution of 3 g of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclot3,2,0] -heptan-7-one in 23.3 ml of dry dioxane becomes treated with 5.2 g of glyoxylic acid-2,2,2-trichloroethyl ester hydrate; the reaction vessel is closed and heated for 7 hours at a bath temperature of 95 ". The pale yellowish, clear reaction solution is diluted with 150 ml of benzene and washed three times with 150 ml of water each time, emulsions which occur can be easily removed by adding 20 ml of a concentrated aqueous solution can be broken by sodium chloride.

  The combined aqueous solutions are washed with 150 ml of benzene; the combined organic solutions are dried with sodium sulfate and evaporated under reduced pressure.



  The viscous residue is dissolved in 60 ml of a 3: 1 mixture of pentane and ether, the higher-melting isomer of a- (2-carbo-tert-butyloxy-3,3-dimdchyl-7 <xo 4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a-hydroxy-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI9.2
 crystallized in prisms which are filtered off at the beginning of the appearance of needle-shaped crystals and melt at 141-146; analytical preparation F. 146-1470; [a] D20 = -307 "1 10 (c = 0.938 in chloroform); infrared spectrum (in methylene chloride) bands at 2.7, 5.6, 5.68, 5.85, 7.32, 8.65 and 9 , 4p ±.



  The clear filtrate is evaporated and the residue is recrystallized from 50 ml of a 5/1 mixture of pentane and ether, the lower-melting isomer of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7 oxo -4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl-α-hydroxy-acetic acid-2,2,2-trichloroethyl ester, which melts in colorless needles at 125-1290; analytical preparation : F. 126-1290; [a] D = -187 "+20 (c = 0.625 in chloroform); infrared absorption spectrum (in methylene chloride) bands at 2.8, 5.6, 5.84, 7.3 and 7, 64.



   After 2 days, further crystalline material is obtained from the mother liquor, which, after recrystallization from a 3: 1 mixture of pentane and ether in prisms, melts at 140-145 and is identical to the higher-boiling isomer. A further amount of the needle-shaped, low-melting isomer, mp 127-1310, is obtained from the filtrate.



   Example 7
A mixture of 5 g of 2-carbo.tert.-butyloxy-3, 3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2.0] heptan-7-one and 5.5 g of glyoxylic acid tert-butyl ester hydrate in 40 ml of dioxane is stirred in a closed vessel for 13 1/2 hours at 95 "and then evaporated.



  The residue is dissolved in 1000 ml of pentane, washed three times with 500 ml of water and once with 200 ml of a saturated aqueous sodium chloride solution, dried over dry sodium sulfate and evaporated.



  An approximately 50:50 mixture of the two isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo is thus obtained [3,2,0) heptyl-α-hydroxy-acetic acid tert-butyl ester of the formula
EMI10.1
 0.9 g of the mixture obtained is crystallized from pentane and recrystallized from a mixture of ether and pentane to give an isomer of the above compound, F. 13X137; [a] D = -3650 + 10 (c = 1.102 in chloroform); Thin-layer chromatogram: Rf = 0.49 in a 1: 1 mixture of benzene and ethyl acetate; Infrared spectrum (in methylene chloride), bands at 2.94, 5.62, 5.77 and 5.85.



   Example 8
A solution of 0.25 g of the glyoxylic acid tert-butyl ester hydrate in 5 ml of toluene is concentrated to a volume of about 3 ml under normal pressure. After cooling to 900, 0.069 g of 2a-isopropylmercapto-3 aN-phenyloxyacetylamino-azetidin-4-one is added and the mixture is diluted after 2 hours with 20 ml of benzene and washed three times with 20 ml of water each time, the aqueous washing solutions are mixed with 10 ml benzene: backwashed and the combined benzene solutions dried and evaporated.

  The residue is degassed at a pressure of o; os mm Hg; the amorphous mixture of the two isomers of the α-hydroxy-α- (2α-isopropylmercapto-4-oxo-3 a-N-phenyloxyacetyl-amino-1-acetidinyl) -acetic acid tert-butyl ester of the formula is thus obtained
EMI10.2
 which still contains a small amount of the glyoxylic acid tert-butyl ester hydrate; Infrared absorption spectrum (in methylene chloride); characteristic bands at 2.83, 2.98, 3.05, 5.65, 5.78p, 5.93, 6.26, 6.60, 6.71, 7.31, 8.65 and 9.23y.



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



   The reaction mixture is treated with a solution of 0.51 g of sodium azide in 5.1 ml of water, stirred for 30 minutes at 0 to -5 and diluted with 150 mol of ice water. It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 15 and under reduced pressure. The amorphous penicillin V-azide is thus obtained as a slightly yellowish t1; Infrared absorption spectrum (in methylene chloride); characteristic bands at 3.04, 4.70, 5.61, 5.82 (shoulder), 5.93, 6.26, 6.61, 6.71, 8.50 and 9.40.



   A solution of 2.468 g of penicillin-V-azide-s in 30 ml of benzene is heated to 70 for 30 minutes. The pure 2-isocynato-3,3-dimethyl-6 (N-phenyloxyacetyl-amino) -4-thia-1azabicyclo [3,2,0] heptan-7-one can be obtained by evaporating the solution under reduced pressure; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.46, 5.59, 5.93, 6.26, 6.62, u, 6.70, 7.53, 8.28, 8.53 , 9.24 and 9.40.

 

   The above solution of the 2-isocyanato-3,3aimethyl-6- (N-phenyloxyacetyl-amino) -4-thiaazabicyclo [3.2.0] heptan-7-one is mixed with 3.4 mg of a 10 ml solution of 2 mol 2,2,2-trichloroethanol in benzene and the reaction mixture kept at 700 for 95 minutes.



  The solvent is removed under reduced pressure and the residue is purified on 40 ml of acid-washed silica gel (column). It is washed with 300 ml of benzene and 300 ml of a 19: 1 mixture of benzene and ethyl acetate by-products and the pure 2- (N-carbo-2,2,2-trichloroethoxy-amino) -3,3-dimethyl-6 is eluted - (N-phenyloxyacetyl-amino) 4-thia-1-azabicyclo [3,2,0] heptan-7-one of the formula
EMI10.3
  with 960 ml of a 9: 1 mixture of benzene and ethyl acetate.

  After recrystallization from a mixture of ether and pentane, the product melts at 169-171 (with decomposition, \; [a] D20 = +83 (c = 1.015 in chloroform); thin-layer chromatogram (silica gel): Rf = 0.5 in 1 1 -Mixture of benzene and ethyl acetate;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05y, 5.62, 577, u, 5.93, z, 6.27, 6.62, 6.70, a, 8.30, u, 9.23 , and, 9s508-
The last fractions eluted with a 9: 1 mixture of benzene and ethyl acetate contain a small amount of the product isomeric with the above compound in the 2-position.



   A solution of 3 g of crystalline 2- (N-carbo-2,2,2-trichloroethoxy-amino3-3,3-dimethyl-6- (N-phenyloxy-acetyl-amino) -4-thia-1-azabicyclo [3 , 2.0) heptan-7-one in 65 ml of 900% aqueous acetic acid and 30 ml of dimethylformamide are mixed with 32.6 g of zinc dust within 20 minutes while cooling with ice and stirred for 20 minutes. The excess zinc is filtered off and the filter residue is washed with benzene; the filtrate is diluted with 450 ml of benzene, washed with a saturated sodium chloride solution and water, dried and evaporated under reduced pressure. The residue is purified on a column of 45 g of acid-washed silica gel. It is eluted with 100 ml of benzene and 400 ml of a 9: 1 mixture of benzene and ethyl acetate apolar products.

  Starting material is washed out with 100 ml of a 4: 1 mixture of benzene and ethyl acetate and with another 500 ml of the 4: 1 mixture of benzene and ethyl acetate, and with 200 ml of a 2: 1 mixture of benzene and ethyl acetate, the 2- Hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) 4-thia-1-azabicyclo [3, 2,0] heptan 7-one of the formula
EMI11.1
 which crystallizes spontaneously as a hydrate and, after trituration with water-saturated ether, melts indistinctly in the range of 62-85.



   If chromatographed but not crystalline starting material is used and reduced in dilute acetic acid without the addition of dimethylformamide, the pure product is obtained, which melts at 62-70; Thin-layer chromatogram (silica gel): Rf = 0.35 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride); characteristic bands at 2.93, 3.09, 5.65, 5.96, u, 6.29, u, 6.65, u, 6.75, 8.57, 9.27, 10.00 and 11.95 .



   A solution of 0.065 g of 3,3-dimethyl-2-hydroxy-6 (N-phenyloxyacetyl-amino> 4-thia-1- azabicyclo [3.2.0] heptan-7-one in 5 ml of benzene is mixed with 0, 15g lead tetraacetate containing 10 o / o acetic acid, treated and the yellow solution illuminated with a high pressure mercury vapor lamp (80 watt) in a water-cooled Pyrex glass jacket. After 10 minutes the yellow color disappears and a partially flaky white, partially rubbery yellow precipitate forms The mixture is diluted with benzene, washed with water, dilute aqueous sodium hydrogen carbonate solution and water and evaporated under reduced pressure.

  The 1-formyl-2- (2-acetyloxy-2-propyl-mercapto) -3 (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula is obtained in this way
EMI11.2
 as a slightly yellowish, rubbery product; Infrared absorption spectrum - (in methylene chloride): characteristic bands at 3.05, 5.56, 5.78,

   5.90, 6.27, 6.62y, 6.71y, 7.33, 7.67, u, 8.92, lt, 9.24, and 9.82, ez
A solution of 0.051 g of 1-formyl-2- (2-acetyloxy-2- (propylmercapto) - 3- (N-phenyloxyacetyl-amino) azetidin-4-one in 3 ml of anhydrous benzene is mixed with 0.13 g of Tris-Tri Treated phenyl-phosphine-rhodium chloride and refluxed for 3 hours. The initially red solution turns brown, with a small amount of a precipitate. After cooling, this is filtered off and the filtrate evaporated under reduced pressure.

  The residue is chromatographed on 5 g of acid-washed silica gel, fractions of 5 ml each being taken. It is eluted with 10 ml of benzene, 30 ml of a 9: 1, 25 ml of a 4: 1 and 10 ml of a 1: 1 mixture of benzene and ethyl acetate, then with 25 ml of ethyl acetate.



  Fractions 2-6 give a rhodium complex with a strong CO absorption at 5.18 in the infrared spectrum. A small amount of the 1-formyl-2-isopropenylmercapto-3 (N-phenyloxy-acetyl-amino) -azetidin-4-one can be isolated from fractions 10-12, while the 2-isopropenylmercapto-3 can be isolated from fractions 15-17 3 - (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula
EMI12.1
 as an amorphous product.



   The product can be obtained in crystalline form if the eluting solution is filtered through 0.5 g of acid-washed silica gel and the product is eluted with a 1: 1 mixture of benzene and ethyl acetate, mp 156-1580; [a] 20 D = -700 1 20 (c = 0.665 in chloroform); Infrared absorption spectrum, rum (in methylene chloride): characteristic bands at 3.07, 5.65, 5.96, 6.29, 6.59, 6.74, u, 8.19, 9.25 and 9.92.



   A solution of 0.08 g of 2a-isopropenylmercapto-3mN-phenyloxyacetylmamino-azetidin-4-one in 10 ml of ethyl acetate is mixed with 0.1 g of a 10% palladium-on-cobl> catalyst and the mixture in a Stirred in a hydrogen atmosphere, then filtered. The filtrate is evaporated and the crystalline residue is recrystallized from a mixture of methylene chloride and ether.

  The 2a-isopropylmercapto-3-N-phenylacetylamino-azetidin-4-one of the formula is obtained in this way
EMI12.2
 which melts at 128-130 and 1430 (double melting point); [a] D20 = -480 + 10 (c = 0.785 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.63, 5.93, 6.26, 6.58, 6.70, 8.15, u, 9.21 and 9.41.



   Example 9
A solution of 1.84 g of the higher melting isomer of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0 ] heptyl) -a-hydroxyBessi! gäur- 2,2,2-trichloro-ethyl ester in 20 ml of a 1: 4 mixture of dry dioxane and tetrahydrofuran is added with 12 ml of a freshly prepared 1-molar solution of triethylamine in dioxane. The mixture is cooled from -150 and treated dropwise with the exclusion of atmospheric moisture with 8 ml of a freshly prepared 1 molar solution of thionyl chloride in dioxane, then stirred for 5 minutes at -15 ".

  After warming to room temperature and stirring for 10 minutes at 20, it is diluted with 60 ml of toluene and the mixture is filtered through a glass filter. The clear filtrate is evaporated under reduced pressure and with a bath temperature below 45. The residue is dried for 2 hours at 25 / 0.01 mm Hg, then triturated three times with 60 ml of boiling pentane each time; the solution is stirred for 10 minutes with 0.3 g of an activated carbon preparation and filtered through a glass filter.



  After evaporation, the residue is crystallized from pentane; the α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α thus obtained ; -chloro-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI12.3
 after repeated recrystallization from pentane, it melts at 131-1360; Analysis preparation 130-131; [a] 20 D = -3070 + 1 (c = 0.091 in chloroform); Infrared spectrum (in methylene chloride), bands at 5.60, 5.64 and 5.85.



   Example 10
A mixture of 6 g of a 1: 1 mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -α-hydroxy-acetic acid tert-butyl ester and 10.5 g of the so-called polystyrene Hünig base in a 1: 1 mixture of dioxane and tetrahydrofuran is stirred for 20 minutes. After cooling, it is treated dropwise within 20 minutes with a solution of 6 g of thionyl chloride in 50 ml of dioxane and the mixture is stirred at 200 for 140 minutes, then filtered. The filtrate is evaporated, the residue is taken up in 200 ml of pentane and the solution is treated with 1 g of an activated charcoal preparation, then filtered.

  An approximately 1: 1 mixture of the isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [ 3,2,0] heptyl) - a-chloro-acetic acid-tert-butyl ester, which is further processed without purification.



   Example 11
A solution of 0.165 g of a- (2-carbo-tert, -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a-chloro-acetic acid-2,2,2-trichloroethyl ester in 30 ml of dry ether is mixed with 0.22 g of dry lithium bromide and the suspension is stirred at 250 for 150 minutes. The filtered solution is diluted with 20 ml of pentane, then filtered again and evaporated. The residue is treated with 20 ml of a 9: 1 mixture of boiling pentane and ether and filtered, and the clear filtrate is evaporated.



  The α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - is thus obtained a-bromo-acetic acid-2,2,2-trichloroethyl ester of the formula
EMI13.1
 which, after crystallization from pentane, melts at 119-120 (with decomposition).



   Example 12
A solution of 0.115 g of the crude mixture of the isomers of u-hydroxy-a- (2a-isopropylmercapto-4-oxo-3a-N-phenyl-oxyacetyl-amino-1-azetidinyl) -acetic acid tert-butyl ester (approx , 1 g of the two epimers) in 2.4 ml of anhydrous dioxane are mixed with 0.1 g of polystyrene Hünig base and cooled to 0 while stirring.



  0.06 g of thionyl chloride in 0.5 ml of dioxane is added, stirring is continued for 21/4 hours at room temperature and the mixture is filtered; the filter residue is washed with dioxane and the filtrate is evaporated under reduced pressure. The residue contains the mixture of the isomers of a-chloro-a- (2a-isopropylmercapto-4-oxo3a-N-phenyloxyacetyl-amino-1-azetidinyl) -acetic acid tert-butyl ester of the formula
EMI13.2
 which shows the following characteristic bands in the infrared absorption spectrum (in methylene chloride): 3.05, 5.63It, 5.75, u, 5.93, 6.25, 6.70, 7.30 and 8.7Qt.



   The compounds obtainable according to the invention can be converted into pharmacologically active compounds as follows:
Example 13
A solution of 0.301 g of a- (2-carbo-tert-butyloxy 3,3-dimethyl-7-oxo4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) a- (triphenylphosphoranyEdene - 2,2,2-trichloro-ethyl acetate and 0.3 g of liquid tert-butyl glyoxylate (mainly in the form of the hydrate) is stirred for 22 hours at 50, then diluted with benzene and washed with water, dried and The crude product is taken up in benzene and filtered through a column of 3 g of acid-washed silica gel.

  The pure mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-ziaza-6-bicyclo (3.2.0 ] heptyl-a- (carbo-tert-butyloxymethylene) acetic acid 2,2,2-trichloroethyl ester of the formula
EMI13.3
 receive.

  Crystallization from ether gives isomer A, which melts after renewed recrystallization in 1890; [a] D20 = -3290 + 20 (c = 0.558 in chloroform); Thin layer chromatogram (SiLiagel9: t¯ 0.64 in a 3: 1 mixture of benzene and ethyl acetate; ultraviolet absorption spectrum (in ethanol): A max = 270met (e = 17 600>; infrared absorption spectrum (in methylene chloride); characteristic bands at 5.61, 5.68 (shoulder), 5.75, b (shoulder), 5.87, 6, l7t, 7.27, 7.37,, 8.70, and 9.32.

  Crystallization of the mother liquor residue results in a crystalline mixture of isomers, from which isomer B can be removed by washing out in cold ether; from the filtrate, after evaporation and crystallization from a Sither pentane mixture, isomer B is obtained in fine needles, mp 119-120; [a] D20 = 3630 1 10 (c = 1.213 in chloroform; thin-screen chromatogram (silica gel): Rf 0.64 in a 3: 1 mixture of benzene-ethyl acetate;

  Ultraviolet absorption spectrum (in ethanol): A max 279 m, (e = 8900; infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.75, 5.87, 6.15, 7.31, 8.65 , 9.05 and 9.30.



   The above reaction can also be carried out as follows: A mixture of 5.04 g of a- (2-carbo-tert-butyl-oxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3,2,0] heptyl-a- (triphenyl-phosphoranylidene) -acetic acid2,2,2-trichloroethyl ester in 15 ml of absolute toluene (prepared at 60) is stirred and in a nitrogen atmosphere with a solution of 4, 5 g of tert-butyl glyoxylate in 10 ml of absolute toluene are added and the mixture is heated at 600 for 15 hours.

  After evaporation of the solvent under reduced pressure, the oily residue in benzene is filtered through a column (diameter: 3 cm; height: 32 cm) of 100 g of acid-washed silica gel. The pure mixture of the isomers A and B of a- (2-Carbo-tert-butoxy-3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] Heptyl-α- (carbo-tert-butyloxymethylene) -acetic acid-2,2,2-trichloroethyl ester is obtained with 500 ml of benzene and an impure mixture of isomers with a further 750 ml of benzene. The pure product is obtained by crystallization as described above Process the pure isomer A, F. 191, from the mother liquor the pure isomer B (F.



     120-121); A further amount of isomer B can be obtained from the impure mixture.



   Example 14
A mixture of 0.035 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl-α- (Triphenylphosphoranylidene) acetic acid 2,2,2-trichloroethyl ester and 0.036 g glyoxylic acid 2,2,2-trichloroethyl ester hydrate in 0.5 ml toluene is heated for 5 hours and under a nitrogen atmosphere at 500. After diluting with benzene and Washing with water gives a residue from the organic solution, which is purified by filtering through 0.7 g of acid-washed silica gel.

  The mixture of the two isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0 ] heptyl) - a- (carbo-2,2,2-trichloroethoxymethylene) acetic acid-2,2,2-trichloroethyl ester of the formula
EMI14.1
 by washing out with 20 ml of benzene; Thin-layer chromatogram (silica gel): Rf 0.7 in a 3: 1 mixture of benzene and ethyl acetate. Crystallization from an ether-pentane mixture gives an isomer as a crystalline product which melts at 176-1770 and very probably has the configuration of maleic acid.



   Example 15
A solution of 0.212 g of a- (2-carbo-tert-butyloxy-3, 3, dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a- (triphenylphosphoranylidene) -acetic acid 2,2,2-ethyl ester in 0.5 g of ethylene glycol dimethyl ether is reacted in a closed glass tube for 17 hours at 600 with glyoxylic acid ethyl ester hemiethylacetal.



  It is then diluted with 1 ml of xylene and evaporated under reduced pressure. The residue is chromatographed on silica gel (column 1.8 cm in diameter and 20 cm in length), eluting with a 95: 5 mixture of benzene and ethyl acetate. This gives a 5: 1 mixture of the two isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo 4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) - a- (carbäthoxymethylene) acetic acid-2,2,2trichloroethyl ester of the formula
EMI14.2
 which, after recrystallization from pentane, melts at 950; Ultraviolet absorption spectrum (in ethanol): Amax = 277 mH (e = 10,550); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 5.65, 5.85, 5.90 and 6.20, lz.



   Example 16
A solution of 0.5 g of a- (2-Carbo-tert-butyloxy-3,3, -dimethyl-7-oxo-4-thia2,6-diaza-6-bicyclo [3.2.0] heptyl) a- (triphenylphosphoranylidene) -acetic acid tert-butyl ester in 5 ml of dry dioxane is reacted with 0.6 g of 2,2,2-trichloroethyl ester hydrate under a nitrogen atmosphere at 600 for 18/4 hours. The solvent is then removed under reduced pressure; the residue is diluted with 10 ml of benzene, the excess of glyoxylic acid ester crystallizing out and being filtered off. The filtrate is washed three times with 10 ml of water, the washing liquids are backwashed with benzene and the organic solutions are dried over sodium sulfate and evaporated.

  The crude product is chromatographed on silica gel (column 1.8 cm in diameter and 15 cm in height), eluting with 150 ml of benzene, 100 ml of a 49: 1 mixture and 100 ml of a 19: 1 mixture of benzene and ethyl acetate.



  A 4: 1 mixture of the two isomers of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3 , 2.0] heptyl) -a- (carbo-2,2,2-trichloroethoxymethylene) acetic acid tert-butyl ester of the formula
EMI15.1

From the fractions which contain the majority of the isomer A, this is obtained by crystallization from pentane, mp 130-1310; [a] 20 D = -3710 + 10 (c = 1.061 in chloroform); Thin-layer chromatogram (silica gel): Rf 0.5 in a 3: 1 mixture of benzene and hexane; Ultraviolet absorption spectrum (in ethanol): lmax = 287 m (e = 10.950);

  Infrared absorption spectrum (in methylene chloride); characteristic bands at 5.65y, 5.83, 5.90 and 6.20. The other isomer shows an Rf value of 0.3 in the thin-layer chromatogram.



   Example 17
A mixture of 4 g of a- (2-carbo-tert-4utyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptal) -a- (Triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.9 g of glyoxylic acid hydrate in 80 ml of absolute dioxane is kept for 3 hours at room temperature under a nitrogen atmosphere and then evaporated at a bath temperature of 450 under reduced pressure. The residue is dissolved in 150 ml of ether and extracted three times with 40 mol of 1 aqueous sodium carbonate each time.

  The aqueous extracts are washed with 150 mg of ether, treated with 20 ml of a concentrated phosphate buffer solution (pH 6) and with 63.2 ml of 2-n. aqueous sulfuric acid acidified to pH 6-5, then extracted four times with 150 mg ether each time. The ether extracts are dried over sodium sulfate and evaporated; the mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3, 2.0] heptyl is obtained in this way ) -a- (carboxymethylene) -acetic acid tert-butyl ester of the formula
EMI15.2
 which consists of about 65 o / o of isomer A. and 35 o / o of isomer B.

  Chromatography on acid-washed silica gel is used to elute first isomer A with a 4: 1 mixture of hexane and ethyl acetate, which, after being recrystallized three times from pentane, melts at 1300; [a] 20 D = -457 1 10 (c = 1 in chloroform); Thin-layer chromatogram (silica gel; system toluene: acetic acid: water 5: 4: 1); Rf = 0.40; Ultraviolet Absorption Spectrum (in ethanol): 2 max = 277 my (e = 8850);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.55u, 5.80-5.95 and 6.25, u; then isomer B, which, after crystallizing three times from pentane, melts at 1770; [a] 20 D = 4310 + 10 (c = 1.041 in chloroform); Thin-layer chromatogram (silica gel; system toluene: acetic acid: water 5: 4: 1): Rf = 0.47; Ultraviolet Absorption Spectrum (in ethanol): #max = 270 nyl (e = 17,000); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65kl, 5.80-5.95, u and 6.25 (strong).



   Example 18
A solution of 2 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptyl) -a - (Triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.7 g of benzylglyoxal (in enol form) in 30 ml of dry toluene is heated under a nitrogen atmosphere for 23 hours at 80 (bath temperature), then with a further amount of 0.2 g Benzylglyoxal added; the mixture is heated at 80 for 22 hours. The solvent is removed under reduced pressure and the viscous residue is chromatographed on a column containing 60 g of acid-washed silica gel.

  With 450 ml of benzene the excess benzylglyoxal, with 250 ml (10 fractions) of a 95: 5 mixture of benzene and ethyl acetate a mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl- 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- (phenylacetylmethylene) -acetic acid tert-butyl ester of the formula
EMI16.1
 and washed out a polar material with another amount of the same solvent mixture.



   The above mixture of isomers is chromatographed again on 60 g of acid-washed silica gel, washing out in a 99: 1 mixture of benzene and ethyl acetate. A product consisting mainly of benzylglyoxal is obtained in the forerun, then with 125 ml a fraction I consisting mainly of isomer A, with 250 ml of a fraction II consisting of a mixture of the two isomers and with 300 ml a fraction consisting mainly of isomer B III.

  The above three fractions are recrystallized from hexane, from fraction I the isomer A; F. 109-110; [a] D20 = -4520 + 1 (c = 1 in chloroform); thin layer chromatogram; Rf = 0.49 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum: R max 297 my (e = 11,000) (in sithanol), 337 m (in potassium hydroxide / ethanol) and 337 m, u (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride); characteristic bands at 5.63, 5.83, (shoulder), 5.85-5.95, u and 6.29; and from fractions II and III the isomer B;

  F. 157-1580; [CLJD20 = 3630 + 0.7 (c = 1 in chloroform); Thin-layer chromatogram: Rf = 0.42 (silica gel; in the system hexane: ethyl acetate 2: 1); Ultraviolet absorption spectrum; # max 294 mM (e = 19,300) (in ethanol), 335 my (potassium hydroxydiAthanol) and 335 m (when acidifying a basic solution in ethanol); Infrared absorption spectrum (in methylene chloride); characteristic bands at 5.63, 5.80, es (shoulder), 5.8v5.96, u and 6.34, u; is obtained. Further amounts of the two isomers can be isolated from the mother liquors in the same way.



   Example 19
A solution of 0.0162 g of the isomer B of cl- (2-Carbbtert, -butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0 ] heptyl) α- (phenylacetylmethylene) -acetic acid tert-butyl ester in 10.6 ml of benzene is irradiated with ultraviolet light in a vessel made of Pyrex glass under a nitrogen atmosphere at room temperature. After 90 minutes the solvent is distilled off; According to the nuclear magnetic resonance spectrum, the non-crystalline residue consists of an approximately 42:58 mixture of isomer A and isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) cr- (phenylacetylmethylene) acetic acid tert-butyl ester.



   Crystalline isomer B and fractions consisting mainly of isomer B of a- (2-carbo-tert-butyloxy, 3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0 ] heptyl) -a- (phenylacetylmethylene) - acetic acid tert-butyl ester can be used in the same way to form isomer mixtures containing isomer A and isomer B of a- (2-carbo-tert, -butyloxy-3,3dimethyl- 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0} heptyl) a- (phenylacetylmethylene) -acetic acid tert-butyl ester can be isomerized.

 

   Example 20
1 g of a- (2-Carboatert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo C3,2,0] heptyl) -a- ( triphenylphosphoranylidene) - tert-butyl acetate under nitrogen with 0.65 g of isopropylglyoxal (in enol form) in 7 ml of toluene and left to stand at 900 for 8 days. The solvent and the excess of isopropylglyoxal are removed under reduced pressure at 500 and the residue is chromatographed on 50 g of acid-washed silica gel; it is washed with a 4: 1 mixture of hexane and ethyl acetate.

  With the first 150 ml the isomer A (trans) of the α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicydo [ 3,2,0) heptyl) - a- (isobutyriyl-methylene) -acetic acid tert-butyl ester of the formula
EMI17.1
 washed out, which after crystallization from a mixture of hexane and ethyl acetate melts at 133-134;

  Ultraviolet absorption spectrum; 2 max 294 mR (in ethanol); Ä max 330 m, (in potassium hydroxide / ethanol) and Ä max 330 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride); characteristic bands at 5.62, 5.80 (shoulder); 5.84-5.94, and 6.26.



   The isomer B (cis) of a- (2-Carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia 2,6-diaza-6-bicyclo [3,2,0) heptyl) - a- (Isobutyrylmethylene) -acetic acid tert-butyl ester is obtained on further washing with the same solvent mixture and melts after crystallization from a mixture of hexane and ethyl acetate at 146-147; Ultraviolet absorption spectrum; A max m, b (in ethanol); Ä max 328 m, u (in potassium hydroxide / ethanol) and A max 328 m, b (in C-hydrochloric acid / ethanol); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 5.60-5.66, 5.75jt (shoulder), 5.85-5.95 and 6.31.



   Example 21
A mixture of 0.05 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.0355 g of 4-nitrobenzyl-glyoxal in 0.6 ml of toluene are heated at 80 for 7 hours. The solvent is then distilled off under reduced pressure and the residue is chromatographed on a thin-layer silica gel plate (20 x 20 x 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate.

  Two yellow bands are obtained, the upper one being the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) -α [(4-nitro-phenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI17.2
 with Rf value = 0.41; Ultraviolet absorption spectrum:

  A max 288 m, u (wide; in ethanol), and # max 505 m, u and 262 m, u (potassium hydroxide / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.63, u, 5.83 (shoulder), 5.88-5.92u, 5.97 (shoulder), 6.28-6.33, 6.59 and 7 , 45, u; and the lower isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bacyclo [3,2,0] heptyl ) -? - [(4-nitro-phenylacetyl) -methylene] -acetic acid-tert-butyl ester of the formula
EMI18.1
 as yellow, glass-like products.

  Isomer B crystallizes from hexane, mp 1730; Rf value: 0.29; Ultraviolet absorption spectrum in ethanol; Ä max 293 m, ez and in potassium hydroxide / ethanoi: Ä max 335 m, and 285 mjt; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.62, 5.77 (shoulder), 5.83-5.92, u, 6.30-6.35, 6.59 and 7.45.



   The 4-nitro-benzylglyoxal used as starting material above can be prepared as follows: 6 g of 4-nitrophenylacetyl chloride in 80 ml of dry tetrahydrofuran are added dropwise to a solution of about 4 g of diazomethane in 200 ml of dry ether, while stirring and an ice water bath keeps the temperature at 0-5.



  The addition is complete after about 30 minutes; the reaction mixture is stirred for a further 15 minutes at 0-5 "and then evaporated in a rotary evaporator. The solid residue is dissolved in a mixture of methylene chloride and ether, the small amount of solid material is filtered off and the filtrate is evaporated. This gives 4-nitrobenzyl diazomethyl ketone, which melts at 90-920 after crystallization from a mixture of ether and hexane; infrared absorption spectrum (in methylene chloride); characteristic bands at 4.78, 6.10, 6.26 and 7.45, and the like.



   A solution of 3 g of 4-nitrobenzyl diazomethyl ketone in 200 mol of a 1: 1 mixture of ether and methylene chloride is mixed with a solution of 4.22 g of triphenylphosphine in 100 ml of ether. After about 5 minutes, the 1- (4-nitrophenyl) -3- (triphenylphosphoranylidene hydrazino) acetone crystallizes out at room temperature; the mother liquor is filtered and concentrated, from which a further amount of the desired product crystallizes.

  The crude product is crystallized from a mixture of 50 ml of methylene chloride and 250 ml of hexane, mp 160-1650; Ultraviolet absorption spectrum (in ethanol): A max 320 nyc and 270-275 m, (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 6.10 (shoulder), 6.14-6.20, 6.32, 6.67-6.74, u and 7.45.



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

  The crystalline, enolized 4-nitrobenzylglyoxal, mp 163-164, is eluted with 600 ml of benzene; Ultraviolet absorption spectrum in ethanol: max 343 m, in potassium hydroxide / ltthanol: 444 mbt, and in hydrochloric acid / ethanol: 2 max 343 m; in infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.02, 5.98, 6.06, 6.28, 6.60 and 7.47; and with 350ml of a 9: 1 mixture of benzene and ethyl acetate of the hydrate of 4-nitrobenzylglyoxal as a non-crystalline, simpartous material; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 5.98, 6.06, 6.28, and 7.47etz.



   Example 22
A mixture of 0.872 g of a- (2-carbo-tert-butyloxy3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] -heptyl) -aXtriphenylphosphoranylidene ) - Acetic acid tert-butyl ester and 0.611 g of 4-nitobe (nzyl-glyoxal-hydrate in 10.5 g of toluene are heated at 800 for 6 1/2 hours.



  The solvent is distilled off under reduced pressure and the residue is chromatographed on 50 g of acid-washed silica gel. With 1300 ml of benzene and 500 ml of a 98.5: 1.5 mixture of benzene and ethyl acetate, the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia- 2,6-diaza-6bicyclo [3,2,0] -heptyl) -a - [(4-nitrophenylacetyl) -methylene] -acetic acid tert-butyl ester, with 200 ml of a 96: 4 mixture of benzene and ethyl acetate a mixture of both isomers A and B of a- (2-carbo-tert-butyloxy-3,3-dimethyl 7.oxo-4-thia-2,6-diaza-6-bicyclol3,2,0] -heptyl) -a - [(4-nitro-phenylacetyl) methylene] -acetic acid tert-butyl ester and with another 400ml of 96:

  : 4-mixture of benzene and ethyl acetate the isomer B of α- (2-carbo-tert-butyloxy-3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3, 2.0] heptyl) -? - [(4-mtro-phenylacetyl) - methylene] -acetic acid tert-butyl ester together with a small amount of the isomer A eluted. The mixture is separated by thin layer chromatography (4 silica gel plates; 20 X 20 X 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate; a further amount of isomer A is thus obtained; Rf = 0.41; and of isomer B; Rf = 0.29. The latter is combined with the almost pure isomer B from the chromatogram and crystallized from hexane, mp 1730.



   Example 23
A mixture of 0.714 g of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 0.67 g of 4-methoxybenzylglyoxal hydrate in 8.6 ml of toluene are heated at 800 for 3 1/2 hours and then evaporated under reduced pressure. The residue is chromatographed on 50 g of acid-washed silica gel.

  The excess 4-methoxybenzyl-glyoxal in anhydrous form is washed out with 500 ml of benzene, while the almost pure isomer A of a- (2-carbo-tert.- is obtained with 800 ml of a 99: 1 mixture of benzene and ethyl acetate. butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - CL- [(4-methoxyphenylacetyl) -methylene] acetic acid-tert .-butyl ester of the formula
EMI19.1
 F. 105-107 after recrystallization from a mixture of ethyl acetate and hexane;

  Ultraviolet absorption spectrum in ethanol: A max 298 m, u, 288 mjt (shoulder) and 225 m, (shoulder), and in potassium hydroxide / ethanol: X max 340 m;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at S, 63u, 5.82 (shoulder), 5.87-5.97, 6.23 (shoulder), 6.28, 6.63 and 6.77; with a further 400 ml of the 99: 1 mixture of benzene and ethyl acetate a mixture of the isomers A and B with 300 ml of a 98: 2 mixture of benzene and ethyl acetate the isomer B of the α- (2-carbo-tert.- butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2.0] heptyl) -α- [(4-methoxyphenylacetyl) -methylene] -acetic acid tert. butyl ester of the formula
EMI19.2
 washes out; the pure isomer B obtained from the mixed fraction and the pure fraction of the isomer B by recrystallization from hexane melts at 169-170; Ultraviolet absorption spectrum:

  A max 289 with (wide) and 227 m, cz (shoulder) (in ethanol), and A max 343 m, ct (in potassium hydroxide / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59jt, 5.75 (shoulder), 5.80-5.93, u, 6.24y (shoulder), 6.3Qt and 6.60.



   From the combined mother liquors, additional amounts of the two isomers A and B of α- (2-carbo-tert-butyloxy-3,3-dimethyl- (2-carbo-tert-butyloxy-3,3-dimethyl-) can be obtained from the combined mother liquors by means of preparative thin layer chromatography and developing with a 2: 1 mixture of hexane and ethyl acetate. 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -α- [(4-methoxyphenylacetyl) -methylene] -acetic acid tert-butyl ester can be obtained .



   The 4-methoxybenzyl glyoxal hydrate used as starting material in the above example can be obtained as follows:
A solution of 7.43 g of 4-methoxyphenylacetyl chloride in 100 ml of dry ether is added dropwise to a solution, cooled to 050, of 6 g of diazomethane in 300 ml of ether. The reaction mixture is stirred for a further 30 minutes, finally without cooling. The excess of diazomethane and solvent are removed under reduced pressure in a rotary evaporator and the residue is dissolved in 100 ml of ether and the small amount of waxy material is removed.

  After evaporating the filtrate, 4-methoxy-benzyl-diazomethyl ketone is obtained; Infrared absorption spectrum (in methylene chloride); characteristic bands at 4.79, u, 6.10, 6.22 (shoulder), 6.62 and 7.72-7.45, z; that is processed further without cleaning.



   A solution of 7.52 4-methoxybenzyl diazomethyl ketone in 300 ml of ether is mixed with 11.1 g of triphenylphosphine in 200 ml of ether. The reaction mixture is stirred at room temperature, a crystalline precipitate forming after a few minutes, which is filtered off after an hour and washed with cold ether. This gives 1- (4-methoxyphenyl) -3- (triphenylphosphoranylidene-hydrazono) acetone, which melts at 111-112; Infrared absorption spectrum (in methylene chloride): characteristic bands at 4.80-6.05 (shoulder), 6.14, 6.24u (shoulder) and 6.63-6.70, u; and is processed without further cleaning.



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

  A small amount of a by-product is washed out with benzene and with 1200 ml of a 95: 5 mixture of benzene and ethyl acetate, the 4-methoxybenzylglyoxal is obtained mainly in the form of the hydrate, the oily product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, u, 5.79-5.84, 6.32 and 6.63m.

  The water-free product melts after recrystallization from a mixture of chloroform and hexane at 139-140; Ultra-absorption spectrum in ethanol or hydrochloric acid / ethanol; Ä max 333 m, and in potassium hydroxide / ethanol: 2 max 367 m; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.00, u, 5.97t, 6.09, h, 6.61, u and 7.15 e.g.



   Example 24
A solution of 0.8 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) α- (triphenylphosphoranylidene) -acetic acid tert-butyl ester and 1.2 g of the crude 4-chlorobenzyl-glyoxal hydrate in 12 ml of toluene are heated at 80 "for 5 hours.



  The solvent is distilled off under reduced pressure and the syrupy residue is dissolved in about 4 ml of benzene. The resulting crystalline precipitate, consisting of the enol of 4-chlorobenzylglyoxal, is filtered off and the filtrate is chromatographed on a column of 50 g of acid-washed silica gel. A further amount of 4-chlorobenzyl-glyoxal is eluted with 500 ml of benzene and with 200 ml of benzene and 800 ml of a 97:

  : 3-mixture of benzene and ethyl acetate a mixture of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2 , 0] -heptyl) a- [(4-chlorophenylacetyl) -methylene) - acetic acid tert-butyl ester isomers washed out, which is chromatographed on a further 50 g of acid-washed silica gel using benzene and benzene containing 5 O / o ethyl acetate and then separated by preparative thin-layer chromatography (system hexane: ethyl acetate 2: 1).

  The non-crystalline isomer A (trans) of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3 , 2.0] heptyl) a- [(4-chlorophenylacetyl) -methylene] -acetic acid tert-butyl ester of the formula
EMI20.1
  which shows the following bands in the ultraviolet absorption spectrum: 2 max 300 m, xt (in ethanol); A max 342 mM (in potassium hydroxide / ethanol); and 2 max 338 m, b (when adding hydrogen chloride to the previous sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.60, 5.75, (shoulder), 5.80-5.92, u (broad), 6.26, and 6.70; and the crystalline isomer B (cis) of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-2,6-diaza-6bicyclo [3,2,0] -heptyl) -α ; - [(4-Chlorophenyl acetyl) methylene] acetic acid tert-butyl ester of the formula
EMI21.1
 which, after recrystallization from hexane, melts at 178-179; Ultraviolet absorption spectrum:

  A max 295 my (in ethanol); A max 337 µm (in potassium hydroxide ethanol); and A max 337 m, b (when hydrogen chloride is added to the previous sample); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.59, 5.75 (shoulder), 5.78-5.94, u, 6.07 (shoulder), 6.31 and 6.70 ,. Isomer A is processed further without purification.



   The 4-chlorobenzylglyoxal hydrate can be prepared as follows:
A solution of 16.5 g of 4-chlorophenylacetyl chloride in 150 ml of dry ether is added dropwise with vigorous stirring and while cooling in an ice-water bath to about 11 g of diazomethane in 500 ml of ether. After reacting at 5-10 for 30 minutes, the diazomethane and the solvent are distilled off under reduced pressure. The 4-chlorobenzyl-diazomethyl ketone available as a yellowish crystalline residue; Infrared absorption spectrum (in methylene chloride); characteristic bands at 4.84, 6.22, 6.80 and 7.47; is processed further without cleaning.



   A solution of 17 g of 4-chlorobenzyl diazomethyl ketone in 150 ml of ether is added at room temperature to a solution of 23.5 g of triphenylphosphine in 300 ml of ether. The yellowish crystalline precipitate is filtered off after 20 minutes, washed with ether and recrystallized from a mixture of methylene chloride and ether;

   the 1 - (4-chlorophenyl) -3- (triphenylphosphoranylidene hydrazono) acetone thus obtainable melts at 130-131 "; ultraviolet absorption spectrum: A max 320 m, u (ethanol); A max 320 mc4 (potassium hydroxide-l2ithanol); and A max 255-278 m, u (broad shoulder) (in hydrogen chloride / ethanol); infrared absorption spectrum (in methylene chloride): characteristic bands at 4.76, u, 6.03 (shoulder), 6.12, 6.28 (shoulder ) and 6.65-6.75, b.



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

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

  The anhydrous 4-chlorobenzylglyoxal in the enol form melts after recrystallization from methylene chloride at 144-147; Ultraviolet absorption spectrum A max 316 m, u (in ethanol); A max 364 m (in potassium hydroxide / ethanol); and A max 316 m, u (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.92u, 5.97, 6.07, 6.29 and 6.71.

 

   Example 25
A solution of 2.5 g of a- (2-carbo-tert-butyloxy-3,3dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2.0] heptyl) -? - (Triphenylphosphoranyliden) - acetic acid tert-butyl ester and 1.3 g of cyclohexylmethyl glyoxal hydrate in 50 ml of toluene are heated to 80 "for 4 hours and the solvent is evaporated off under reduced pressure. The syrup-containing residue is triturated with ether, the The resulting triphenylphosphine oxide is filtered off and the filtrate is evaporated.The residue is chromatographed on 120 g of acid-washed silica gel, washing with a 98: 2 and a 9: 1 mixture of hexane and ethyl acetate.

  The isomer A (trans) of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2, 0] heptyl) -α- (cyclohexylacetyl-methylene) -acetic acid tert-butyesters of the formula
EMI22.1
 which is purified by means of preparative thin layer chromatography (plates 20 X 20 X 0.25 cm; silica gel; system benzene: acetone 98: 2) and obtained in a syrupy form; [a1D2 = -451 1 1 (c = 0.87 in chloroform); Ultraviolet absorption spectrum: A max 297 m, cz (in ethanol); A max 334 m (in potassium hydroxide / ethanol); and # max 334 m, b (when adding hydrogen chloride to the alkaline sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.45, u, 3.50, 5.61, 5.78 (shoulder), 5.80-5.95, z, 6.07 (shoulder) and 6.28 .



   The isomer B (cis) of a- (2-Carbo-tert-butyloxy-3, 3 -dimethyl-7-oxo-4-thia2,6-diaza-6bicyclo [3.2.0] heptyl) -? - (Cyclohexyl acetyl methylene) acetic acid tert-butyl ester of the formula
EMI22.2
 is eluted as the second product and crystallized from hexane, mp 154-1550; [a] D = -2320 + 10 (c = 0.8 in chloroform); Ultraviolet absorption spectrum A max 288 m, u (in ethanol), A max 333 m, (in potassium hydroxide / ethanol) and A max 333 m, u (when hydrogen chloride is added to the above alkaline sample);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.44, 3.53, 5.60, 5.75 (shoulder), 5.80-5.93, a, 6.05 (shoulder) and 6.31.



   The cyclohexylmethylglyoxal hydrate used as starting material can be prepared as follows:
A solution of 19.8 g of cyclohexyl acetyl chloride (boiling point 98-100 / 23mm Hg) in 150 ml of dry ether is slowly added to a vigorously stirred solution of 11 g of diazomethane in 500 ml of ether while cooling to 0-5 in an ice water bath . The excess of the diazomethane and the ether are distilled off under reduced pressure and the residue obtained is cyclohexylmethyl diazomethyl ketone; Infrared spectrum (in methylene chloride): characteristic bands at 3.45, 3.52, 4.75 and 6.12; that is processed further without cleaning.



   A solution of 32 g of triphenylphosphine in 450 ml of ether is mixed all at once with a solution of 20 g of cyclohexylmethylaiazomethyl ketone in 100 ml of ether while stirring. After stirring for 30 minutes at room temperature, the solvent is evaporated off under reduced pressure. The 1-cyclohexyl-3- (triphenylphosphoranylidene-hydraz; ono) -acetone, obtainable as an oily residue, crystallizes in the cold from ether.

  F. 58-620; Ultraviolet absorption spectrum: max m 2.62-2.75 m, and 223 m, ll (in ethanol and in potassium hydroxide / ethanol), and A max 257-275 nyl and 230 m (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.43m, 3.56, 4.67, u, 6.15 and 6.67.



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

  The residue is chromatographed on an acid-washed silica gel column (120 g), the cyclohexylmethyl glyoxal hydrate being eluted as a syrupy product with about 3000 ml of a 97: 3 mixture of hexane and ethyl acetate; Infrared absorption spectrum (in methylene chloride); characteristic bands at 2.90-4.1, b (broad); 3.47, u, 3.53, and 5.80 cm; and processed further without cleaning.



   Example 26
A solution of 2.55 g of the mixture of the isomers ren des a (2-Carbbtert.-Butyloxy-3,3-dimethyl-7exo- $ thia-2,6-diaza-6-bicyclo [3,2,0] heptyl ) - a- (carboxymethylene) -acetic acid tert-butyl ester in 80 ml of a 9: 1 mixture of acetic acid and water is mixed with 0.5 g of zinc dust every 15 minutes at room temperature and with vigorous stirring until the reduction is complete. After an hour, only a small amount of starting material can be detected; the addition of zinc dust is interrupted and stirring is continued at room temperature for 2 hours and then 60 ml of water and 60 ml of methylene chloride are added. It is filtered through cotton wool and then extracted four times with 100 ml of methylene chloride each time.

  The combined methylene chloride solutions are dried over sodium sulphate and evaporated at 450 under reduced pressure. The residue is repeatedly mixed with benzene and this is evaporated in each case until the acetic acid is completely removed. The crude residue is filtered through acid-washed silica gel (diameter: 4 cm; height 10 cm), eluting with a 2: 1 mixture of hexane and ethyl acetate; the mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0lheptyl) - a- (carboxymethyl) -acetic acid tert-butyl ester of the formula
EMI23.1
 which can be largely separated by crystallization from ether and hexane.

  Isomer A is obtained first, which, in somewhat impure form, melts at 169-171 after recrystallization from the ether-hexane mixture.



   The first mother liquor predominantly contains the isomer B, which can be purified as follows: A solution of 0.1983 g of the mother liquor residue containing the isomer B in 5 ml of methylene chloride is mixed with 2.26 mol of a solution of 1.9836 g of cyclohexylamine in 100 mg of ether are added and the solution is evaporated. The residue is taken up in methylene chloride and filtered, the filtrate is evaporated and the residue is crystallized from a mixture of methylene chloride and acetone. The crystalline material thus obtainable and that of the first work-up of the mother liquor are dissolved in 5 mol of methylene chloride with 5 ml of water containing 0.5 ml of 2-n. Sulfuric acid, shaken and the aqueous phase washed back with 10 ml of methylene chloride.

  The organic solutions are washed with 10 ml of water, dried over sodium sulfate and evaporated; the pure isomer B of a- (2-CarboHtert.-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3,2,0] heptyl) -a is obtained in this way - (carboxymethyl) acetic acid tert-butyl ester, m.p. 116-1170; [a] D20 = -2520 + 1 "(c = 0.924 in chloroform); thin-layer chromatogram; Rf = 0.35-0.33 (system toluene: acetic acid: water 5: 4: 1); infrared absorption spectrum (in methylene chloride): characteristic Bands at 5.68, u, 5.78 good and 5.85-5.90, b.



   Example 27
A solution of 0.065 g of the isomer mixture of a- (2-carbo-tert-butyloxy-3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) - a- (carbäthoxxymelylen) -essigsäure- 2,2,2-trichloroethyl ester in 2 ml of a 4: 1 mixture of hexane and methylene chloride is mixed with about 2 molar equivalents of cobalt hydrocarbonyl in hexane at room temperature for one hour in a carbon monoxide-nitrogen atmosphere. The reducing agent is prepared as follows: a solution of 0.39 g of dicobalt octacarbonyl in 10 ml of dry hexane is mixed with 3 ml of dimethylformamide under a nitrogen atmosphere and stirred for half an hour. A two-phase system is obtained, the upper layer is colorless, the lower red. Then, while cooling in an ice bath, 8 mol of a 1: 1 mixture of concentrated hydrochloric acid and 2-n.

  Hydrochloric acid was added and the mixture was stirred at 0 for one hour. The blue acid layer is peeled off and the yellow hexane solution is washed three times with 1 ml of water. The hexane solution contains 1.47 mmol cobalt hydrocarbony] and is used in this form.



   The reaction mixture is then filtered through a column (height: 7 cm, diameter: 2 cm) of silica gel and washed out with benzene (cobalt derivatives) and with 20 mol of a 3: 1 mixture of benzene and ethyl acetate. A crude product is obtained from the latter mixture, which is in turn chromatographed on silica gel and eluted with 49: 1, 19: 1 and 4: 1 mixtures of benzene and ethyl acetate.

  The isomer A of a- (2-carbo-tert-butyoxy-3,3dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptyl) -a- (carbäthoxymethyl) acetic acid - 2,2,2-trichloroethyl ester of the formula
EMI24.1
 which melts after crystallization from pentane at 900, and a mixture of isomer B with some isomer rem A, and a small amount of 2-carbo-tert-butyloxy-3,3-dimethyl 4-thia-2,6-diaza -bicyclo [3.2.0] heptan-7-one.



   Example 28
A hexane solution of 1.47 mmol of cobalt hydrocarbonyl is mixed with 0.2 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2 , 0] heptyl) -a- (carbo-tert-butyl-oxy-methylene) -acetic acid-2,2,2trichloroethyl ester in 2ml of a 4: 1 mixture of hexane and methylene chloride; the reaction mixture turns dark brown. After 30 minutes at room temperature, filter through silica gel.

  The cobalt compounds are washed out with benzene until the silica gel is colorless, then it is eluted with a 9: 1 mixture of benzene and ethyl acetate, a mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3- dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0) heptyl) - a- (carbo-tert-butyloxymethyl) acetic acid 2,2,2-trichloroethyl ester of the formula
EMI24.2
 and the 2-carbo-tert-butyloxy-3,3dimethyl-4-thia-2,6-diaza bicyclo [3.2.0] heptan-7-one is eluted with a 3: 1 mixture of benzene and ethyl acetate.

  Crystallization from a mixture of methylene chloride and pentane gives a mixture of the two isomers, mp 95-1050, and after a further crystallization isomer A, mp 1080; [a] 20 D = -2400 + 10 (c = 0.452 in chloroform); Ultraviolet absorption spectrum (in ethanol): A max = 230 m (weak); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65.4, 5.70, 5.85u and 5.90.



   Example 29
A mixture of 0.0414 g of a- (2-carbo-tert-butyloxy3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] -heptyl) - A- (carbo-tert-butyloxy methylene-acetic acid-2,2,2-trichloro-ethyl ester in 4 ml acetic acid ethyl ester is in the presence of 0.0524 g of a 10 0 / o palladium-on-carbon catalyst at 30 for 45 Hydrogenated under atmospheric pressure for minutes, after filtering the filtrate is evaporated and the residue is purified by filtering through 1.2 g of acid washed silica gel.

  Apolar material is eluted with 15 ml of benzene and the major part of the isomer mixture of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2 , 0] heptyl) -a- (carbo-tert-butyloxy-methyl) -acetic acid2,2,2-trichloroethyl ester with 5 ml of a 9: 1 mixture of benzene and ethyl acetate, which melts at 90-960 after crystallization from pentane .



   Example 30
A solution of 1.98 g of dicobalt octacarbonyl in 25 ml of hexane is mixed with 6 ml of dimethylformamide while stirring in a nitrogen atmosphere. After 30 minutes, two phases form, an upper yellow and a lower red. The mixture is cooled to 0 while stirring with 10 ml of a 1: 1 mixture of 2-n. Hydrochloric acid and concentrated hydrochloric acid are added and the mixture is kept at about 0 for one hour.



  The blue acid layer is peeled off, the mixture which remains is washed three times with 5 ml of water and then dried with a little sodium sulfate.



   A solution of 1.039 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0] heptyl) -a - (Carbo-tert-butyloxymethylene) -acetic acid-2,2,2-trichloroethylester in 3 ml of methylene chloride and 4 ml of n-hexane is mixed in a nitrogen atmosphere with the cobalt hydrocarbonyl solution prepared by the above process and the mixture for 15 Stirred for minutes at room temperature, then filtered through acid washed silica gel.

  The column (2 cm diameter, height: 25 cm) is washed colorless with benzene and then the mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia- 2,6-diaza-6bicyclo [3.2.0] heptyl) -a- (carbo tert-butyloxymethyl) -acetic acid-2,2,2-trichloroethyl ester eluted with a 10: 1 mixture of benzene and acetic acid ethyl ester. Repeated crystallization from pentane gives isomer A, which melts at 108-110; the mother liquor contains mainly a 1: 1 mixture of the two isomers.

  The isomer A has the following configuration:
EMI25.1

Example 31
A solution of 0.205 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diazam6-bicyclo [3.2.0] heptyl) - a- (Carbo-tert-butyloxymethylene) -acetic acid-2,2,2-trichloroethyl ester (mixture of the two isomers) in 6 ml of a 4: 1 mixture of hexane and methylene chloride is mixed with 3 equivalents of cobalt hydrocarbonyl in 10 ml of hexane under a nitrogen atmosphere at room temperature 3 equivalents of cobalt hydrocarbonyl in 10 ml of hexane are added, then filtered through a column of silica gel (2 cm in diameter and 8 cm in length), cobalt compounds being washed out with benzene and reduction products with a 3: 1 mixture of benzene and ethyl acetate.

  The crude product is again filtered on silica gel (diameter of the column: 1 cm; height: 25 cm), prewashing with 100 ml of benzene and eluting an isomer of the starting material with 150 ml of a 99: 1 mixture of benzene and ethyl acetate 200 ml of a 49: 1 mixture of benzene and ethyl acetate, the isomeric bath a- (2-carbotert-butyioxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3, 2.0] heptyl) -a- (carbo-tert-butyloxymethyl) -acetic acid-2,2,2-trichloroethyl ester, followed by a mixture of the two isomers and pure isomers B, and then with 80 ml of a 4: 1- Mixture of benzene and ethyl acetate add a small amount of 2-carbo-tert-butyloxy-3,3-dimethyl-4-thia-2,6-diaza-bicyclo [3.2.0] heptan-7-one.



  The isomer B has the following configuration:
EMI25.2
 and, after crystallization from pentane, melts at 92-93; [a] 20 D = 1970 in 10 (c = -197 in chloroform); Ultraviolet absorption spectrum (in ethanol): weak absorption at 230-240 mc; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.65, 5.725, and 5.85-5.951r.



   Example 32
A mixture of 0.035 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6 bicyclo [3, 2.0) heptyl) -a- (carbo- tert-butyloxymethyl) acetic acid-2,2,2trichloroethyl ester (Example 30) and 2 ml of pre-cooled trifluoroacetic acid is left to stand for 25 minutes at 0, then evaporated under high vacuum and with 3 ml of a saturated aqueous solution of Sodium acetate added.

 

  The reaction mixture is extracted with methylene chloride, the organic solution is dried over sodium sulfate and evaporated. The residue crystallizes from a mixture of ether and pentane and gives the 3,3-dimethyl-7-oxo-4-thia-2,6diaza-6-bicyclo [3,2,0] heptyl-a- (carbo-tert. - Butyloxy-methyl) -acetic acid-2,2,2-trichloroethyl ester of the formula
EMI25.3
  which melts at 136-138; [a] D 20 = -112 + 2 "(c = 0.625 in chloroform); thin layer chromatography (silica gel): Rf = 0.25 in a 3: 1 mixture of benzene and ethyl acetate;

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.12, 5m74, u, 5.84cm and 7.34u.



   Example 33
A mixture of 0.75 g of the isomer mixture of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza4-bicyclo [3.2.0] heptyl) - a- (carboxymethylene) -acetic acid tert-butyl ester in 20 ml of a 9: 1 mixture of acetic acid and water is treated within 31/2 hours with small amounts of a total of 4 g of zinc at room temperature, then with 20 mm of water are added and the mixture is filtered through cotton wool. It is extracted three times with 30 ml of methylene chloride each time. The organic extracts are dried over sodium sulphate and evaporated, acetic acid residues being removed azeotropically together with benzene under reduced pressure; the latter operation is repeated five times.

  The residue is filtered through a silica gel column (1.8 cm diameter; 5.5 cm height), eluting with a 1: 1 mixture of hexane and ethyl acetate and finally with ethyl acetate.



  A 1: 1 mixture of the isomer of a- (2-carbo-tert-butyloxy-3,3dimethyl-7-oxo-4-thia-2,6-diaza-6 bicyclo [3.2.0 ] heptyl) -a- (carboxymethyl) -acetic acid tert-butyl ester.



  Crystallization from a mixture of ether and hexane at room temperature gives isomer A, which, after recrystallization from hexane (0), melts at 169-173 (analysis preparation: 172-173); [a] D20 = -295 "+ 10 6 (c = 1.168 in chloroform); thin layer chromatogram (silica gel): Rf = 0.35 in a 5: 4: 1 mixture of toluoyl, acetic acid and water; infrared absorption spectrum (in methylene chloride) : characteristic bands at 5.68y, 5.72, z and 5.90.



   The mother liquor from the above crystallization of the isomer mixture is concentrated and left to stand at room temperature for 16 hours, after which a further amount of isomer A is obtained. The filtrate is evaporated and recrystallized from hexane (0; 7 days); this gives the isomers B, F.



     116-1170; [a] D20 = -2520 + 10 (c = 0.924 in chloroform); Thin layer chromatogram (silica gel): Rf = 0.35-0.33 in a 5: 4: 1 mixture of toluene, acetic acid and water; Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.68, 5m78, and 5.85-5.90 e.g.



   The separation of 0.583 g of the mixture of the isomers of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6> bicyclo [3.2, 0] heptyl] - a- (carboxymethyl) -acetic acid tert-butyl ester can also be carried out chromatographically on acid-washed silica gel (column: 3 cm diameter; and 35 cm height), 300 ml of a 40: 1, 300 ml a 19: 1, 450 ml of a 9: 1, 300 ml of a 4: 1, 300ml of a 3: 1, 300ml of a 2: 1 and 300 ml of a 1: 1 mixture of hexane and ethyl acetate and 400 The isomer A is washed out with the 3: 1 and 2: 1 mixture before the isomer B and, after crystallization from hexane, melts at 172-1730.



   An extensive separation of the two isomers A and B of a- (2-carbo-tert-butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6bicyclo [3,2,0] heptyl) -a- (carboxymethyl) acetic acid tert-butyl ester can, for. B. can also be carried out if 0.1 g of the 1: 1 isomer mixture in 3 ml of methylene chloride with 1.16 ml of a 100 ml solution of 1.9836 g of cyclohexylamine in ether (1 equivalent) is added. The main part of the isomer A precipitates as a gel and is mixed with 2 ml of methylene chloride and 1.2 ml of water containing 0.12 ml of 2-n. aqueous sulfuric acid, shaken. The organic phase is washed with 2.5 ml of water and the aqueous phase with 2.5 ml of methylene chloride; the organic extracts are combined, dried over sodium sulfate and evaporated; a 7: 1 mixture of isomers A and B is obtained.



   Example 34
A mixture of 0.027 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - (a-carboxymethyl) -acetic acid tert-butyl ester and 1 ml of precooled trifluoroacetic acid are kept at -10 for 30 minutes, then evaporated under high vacuum at -10 "and mixed with 10 ml of ether ml and washed once with 1 ml of saturated aqueous sodium hydrogen carbonate solution, then mixed with 4 ml of a saturated phosphate buffer solution pH5-6 and with 3.75 ml of 2-n.



  aqueous sulfuric acid adjusted to pH 6. It is extracted twice with 10 ml of ether each time, the organic phase is washed once with 2 ml of water, dried over sodium sulfate and evaporated. The non-crystalline isomer A of a- (3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a- (carboxymethyl) is obtained in this way ) tert-butyl acetic acid ester of the formula
EMI26.1
 which in the thin layer chromatogram (silica gel) has an Rt = 0.31 in a 5: 5: 1 mixture of toluene, acetic acid and water.



   Example 35
A mixture of 0.105 g of isomer B of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7 oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) -a- (carboxymethyl) -acetic acid tert-butyl ester and 2.5 ml trifluoroacetic acid pre-cooled to -80 are kept at -10 "for 35 minutes, then evaporated under high vacuum. The crude product is mixed with 40 ml of a 1: 1 - Mixture of saturated aqueous sodium hydrogen carbonate solution and ether at 0; the ether phase is washed with 5 ml of saturated aqueous sodium hydrogen carbonate solution and 5 ml of water, then treated with 3 ml of a concentrated phosphate buffer solution (pH 6) and adjusted to pH 5 with 2N aqueous sulfuric acid -6, then extracted 3 times with 15 ml of ether each time.

  The combined ether solutions are washed with 5 ml of water, dried over sodium sulfate and evaporated. After recrystallization from a mixture of ether, methylene chloride and hexane, the isomer B of cr- (3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3,2,0] heptyl) <a- (carboxylmethyl) -acetic acid tert-butyl ester, mp 137-138; [a] 20 D = -1070 + 10 (c = 0.7 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 5.70, 5.78, 7.30y and 8.70.



   Example 36
A mixture of 0.025 g of isomer B of 3,3-dimethyl-7-oxo-4-thia-2,6-diaza 6-bicyclo [3, 2.0] heptyl) -a- (carboxymethyl) -acetic acid-tert .-Butyl ester (Example 24) and 1 ml of trifluoroacetic acid are kept at 0 for 18 hours, then evaporated under reduced pressure, and 1 ml of dioxane is added to the residue and an ether solution of diazomethane is added to saturation.

  After a reaction time of 3 minutes, it is evaporated under reduced pressure, the residue is filtered through a silica gel column (diameter: 0.8 cm; height: 10 cm), eluting with a 2: 1 mixture of hexane and ethyl acetate; the isomer B of 3,3-dimethyl-7-oxo-4-thia-2,6-diaza 6-bicyclo [3, 2.0] heptyl) -a (carbomethoxymethyl) -acetic acid obtained as the crude product. butyl ester of the formula
EMI27.1
 After recrystallization from a mixture of ether, methylene chloride and hexane, it melts at 1361370.



   Example 37
A solution of 0.1056 g of the isomer A of a- (2-carbo-tert-butyloxy-3, 3-dimethyl-7-ox4thia-2, 6-diaza-6-bicyclo [3 2, O] -heptyl) a- (Carbo-tert-butyloxymethyl) -acetic acid2,2,2-trichloroethyl ester in 1.6 ml of an 84:16 mixture (parts by weight) of trifluoroacetic acid and trifluoroacetic anhydride is treated after standing for two hours at room temperature with 12 ml of acetic anhydride and after one hour Stand at room temperature under high vacuum without heating. The residue is dissolved four times in a mixture of methylene chloride and benzene and each time taken to dryness.

  The residue crystallizes from chloroform and gives the 7a-trifluoroacetylamino-4, 8-dioxo-l-aza-5-thia-2ss-bicyclo [4.2.0] octane carboxylic acid 2,2,2-trichloroethyl ester of the formula
EMI27.2
 F. 175-176; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.60, 5.69, x, 5.79, 5.94u and 6.56.



   Example 38
A solution of 0.017 g of 7a-trifluoroacetylamino-4,8dioxo-1-aza-5-thia-2ss bicyclo (4,2,0] octane carboxylic acid 2,2,2-trichloroethyl ester in 1 ml 90% aqueous acetic acid is treated within 5 minutes with 0.17 g of activated zinc dust After 50 minutes, 10 ml of ethyl acetate are added, the mixture is filtered and the filter residue is washed with 10 ml of ethyl acetate.

 

  The organic filtrate is washed with 4 ml of a saturated aqueous sodium chloride solution, dried and evaporated under reduced pressure. The oily 7a-trifluoroacetylamino-4,8dioxo-1-aza-5-thia-2ss bicyclo [4.2.0] octane carboxylic acid of the formula is obtained in this way
EMI27.3
 the bands characteristic in the infrared absorption spectrum (in potassium bromide) at 5.64, a, 5.83, 5.95, 6.47, u, 7.12, 8.12, z, 8.60, 9.60 and 10.00 exhibit.



   This compound shows the effects indicated in the description against gram-positive and gram-negative microorganisms, in particular against Staph. aureus, Proteus vulgaris and Bacillus megatherium.



   Example 39
A solution of 0.05 g of isomer B of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2, 0] heptyl) -a (carbo-tert-butyloxy-methyl) -acetic acid-2,2,2-trichloroethyl ester in 0.8 ml of an 84:16 mixture (parts by weight) of trifluoroacetic acid and trifluoroacetic anhydride is left for 2 hours at room temperature left and then treated with 2 mol of acetic anhydride. After one hour (room temperature) the volatile components are removed under high vacuum without heating and the residue is dissolved in methylene chloride and benzene. The solution is taken to dryness and this process is repeated three times.

  The residue is crystallized from chloroform, the 7a-N-trifluoroacetylamino-4,8-dioxo5-thia-1-azabicyclo [4.2.0] octane2ss-carboxylic acid 2,2,2-trichloroethyl ester of the formula
EMI28.1
 receives. The mother liquor is chromatographed on acid-washed silica gel, a further amount of the desired product being eluted with a 9: 1 mixture of benzene and ethyl acetate and recrystallized from chloroform, mp 183-187; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.08, u, 5.61, 5.7l, 5.79, 5.94, u and 6.56, u.



   Example 40
A solution of 0.1211 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-3,6-diaza-6-bicyclo [3.2 , 0] heptyl) -a- (phenylacetylmethylene) -acetic acid tert-butyl ester in 1.2 ml of precooled trifluoroacetic acid is left to stand for 21 hours at -20 ", then diluted with 9 ml of dioxane. The mixture containing the 7-amino 4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-aminocephalosporanic acid) is treated with a solution of 0.129 g of phenyloxyacetyichloride in 1 ml of dioxxane are added After standing at room temperature for 2 1/2 hours, the reaction mixture is treated with 1 ml of water and left to stand for a further hour.

  The volatile components are removed by lyophilization under high vacuum and the residue is chromatographed on 9 g of acid-washed silica gel. With a 100: 5 mixture of benzene and acetone phenyloxyacetic acid and a small amount of a neutral material and with a 2: 1 mixture of benzene and acetone the 4-renzylidene-7-N-phenyloxyacetyl-amino-8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI28.2
 eluted which, after recrystallization from a mixture of acetone and benzene, melts in the form of yellowish crystals at 191-193 (decomposition); Thin layer chromatogram: Rf. 0.36 (silica gel); in the system toluene / acetic acid / water 5: 4: 1);

  Ultravuolet absorption spectrum; in ethanol, Ä max 349 m, u and 250265 with (shoulder); in potassium hydroxide / ethanol, A max 345 mu and 25s265 mu (Sohulter); and in hydrogen chloride, A max 357 m and 250-265 mz (shoulder); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.20-4.15, u, 5.621 ', 5.70, u (shoulder), 5.82-5.95, 6.00 ( Shoulder), 6.10-6.15 and 6.23-6.33, xl (inflection).



   Example 41
A solution of 0.5625 g of isomer A of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-12,6-diaza-6bicyclo [3.2.0] heptyl ) -a (phenylacetylmethylene) -acetic acid tert-butyl ester in 4 ml of pre-cooled trifluoroacetic acid is left to stand for 20 hours at -20 "and for one hour at room temperature. It is diluted with 30 ml of dry dioxane and the mixture containing the 7th -Amino-4-benzylidene-8-oxo-5-thia-1-azabicyclo- [4,2,0] -oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid), with a solution of 0.5 g of freshly distilled phenylacetic acid chloride in 5 ml of dioxane.

  The reaction mixture is left to stand for 3 hours at room temperature, then 2 ml of water are added; the mixture is left to stand for one hour at room temperature, then cooled to -10 "and the volatile components are evaporated off by lyophilization under high vacuum. The residue is taken up in 4 ml of benzene, whereupon crystallization begins.

  The crystalline material is filtered off after 24 hours and washed with benzene; the 4-benzylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid (configuration of the 7-amino -cephalosporanic acid) of the formula
EMI29.1
 which, after recrystallization from 90% aqueous ethanol, melts at 224-226; Thin layer chromatogram; Rf 0.30 (silica gel; in the system toluene / acetic acid / water 5: 4: 1);

  Ultraviolet absorption spectrum: in methanol, 2 max 353 mjt and 250-265 mtt (shoulder); in potassium hydroxide / sithanol, 2 max 347 mid, 250-265 m, b and 240 m, u (shoulder); and in hydrogen chloride / ethanol, R max 358 m and 250-265 mp;

  Infrared absorption spectrum (in potassium bromide): characteristic bands at 3.00 (shoulder), 3.10-4.10, u, 5.65, 5.7 (shoulder), 5.80 (shoulder), 5.90- 5.95ix, 6.00 (shoulder), 6.15, 6.24 (shoulder), 6.28 (shoulder), 6.55, 6.65 and 6.73 (shoulder).



   The mother liquor is chromatographed on 10 g of acid-washed silica gel; with a 100: 5 mixture of benzene and acetone becomes phenylacetic acid along with a yellow neutral material and then with a 2: 1 mixture of benzene and acetone another amount of -benzylidene-7-N-phenylacetyl-amino-8-oxo -5-thia-1-azabicyclo [4,2,0] -oct2-en-2-carboxylic acid eluted, which crystallized after adding a little acetone, m.p. 223-2250.



   Example 42
A solution of 0.0917 g of isomer A of α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2, 0] heptyl) -α- (phenylacetylmethylene) -acetic acid tert-butyl ester in 1 ml of precooled trifluoroacetic acid is left to stand for 21 hours at -20 ", then diluted with 7 mol of dioxane. The mixture obtained, containing the 7A-mino-4 Benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of 7-aminocephalosporanic acid) is added to 10 drops of acetic acid chloride and the reaction mixture is left Stand for 3 hours at room temperature, remove the excess acetic acid chloride under reduced pressure (oil pump) and add 0.8 ml of water.

  After a further hour at room temperature, the volatile components are evaporated off under reduced pressure (oil pump) and the residue is dissolved in 0.7 ml of benzene. 7-N-Acetyl-amino-4-benzylidene-8-oxo-5-thia-1 -azabicyclo [4,2,0] - oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) the formula
EMI29.2
 crystallizes out, mp 160-164, thin-layer chromatogram: Rf 0.16 (silica gel; in the system toluene / acetic acid / water 5: 4: 1);

  Ultraviolet absorption spectrum: in ethanol, A max 354 m, and 250-265 m, u (shoulder); in ethanol / potassium hydroxide, max 346 m, u, 250-265 m, 4 and 240, u (shoulder), and in ethanol / hydrogen chloride, max 357 m, and 250-265 m, (shoulder); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.90 (shoulder), 3.15-4.20, u, 5.63-5.71, u, 5.75 (shoulder), 5.80-5.94u (Inflection), 6.00 (shoulder), 6.04-6.13 and 6.40-6.70, u (inflection).

 

   The mother liquor is chromatographed on 5 g of acid-washed silica gel; a further amount of the desired 7-N-acetylamino-4-benzylidene-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-ene is eluted with a 4: 1 mixture of benzene and acetone -2-en-3-carboxylic acid together with a neutral product that is enriched in the first fractions.



   Example 43
A suspension, cooled in ice water, of 0.0198 g of 4-benzylidene-7-N-phenylacetyl-amino8-oxo-5-thia-1-aza-bicyclo [4.2.0) oct2-en-2-carboxylic acid in 1 , 5 ml of methanol is treated in portions with an excess of a 2% solution of diazomethane in ether; the development of nitrogen starts immediately and the solid material dissolves. The addition of diazomethane is stopped as soon as the yellow discoloration persists for 2-3 minutes. The volatile components are removed in a rotary evaporator and the residue is crystallized by adding a few drops of methanol.

  The 4-benzylidene-7-N-phenylacetyl-amino8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid methyl ester obtained in this way (configuration of the 7-amino-cephalosporanic acid ) of the formula
EMI30.1
 melts at 193-195.5; [a] D20 = -3250 + 10 (c = 1 in chloroform); Thin-layer chromatogram: Rt = 0.22 (silica gel; in the system hexane: ethyl acetate 2: 1);

  Ultraviolet absorption spectrum (in ethanol): max 360 m, b (e = 24,800) and 262 m (e = 8100); Ä 362 362 m, u and 250 m, b (shoulder) (in potassium hydroxide ethanol); and A max 362 m, t and 250-265 m, t (shoulder) (in hydrogen chloride / ethanol); Infrared absorption spectrum (in methylene chloride); characteristic bands at 3.06J ±, 5.62,, 5.82,, 5.95, 6.00 (shoulder), 6.62 (shoulder) and 6.65-6.73, c.



   Example 44
A mixture of 0.1158 g of a- (2¯carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl ) - a- (isobutyrylmethylene) -acetic acid tert-butyl ester (isomer A) in 1 ml of precooled trifluoroacetic acid is left to stand at -200 for 22 hours.



  5 ml of dry dioxane are added and the mixture, containing the 7-amino-4-isopropylidene-8-oxo-5-thia-il-azabicyclo [, 2.0] oct-en-2-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) with 0.123 g of phenacetyl chloride. After standing for 3 hours at room temperature, 10 drops of water are added and, after a further hour, the volatile components are distilled off under high vacuum. The oily residue is chromatographed on 10 g of acid-washed silica gel. With a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral product are eluted.

  The 4-isopropylidene-7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo- [4,2,0] .oct-2-en-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of formula
EMI30.2
 is washed out with a 2: 1 mixture of benzene and acetone. Upon crystallization from benzene containing a small amount of acetone, it melts at 216-219; Infrared absorption spectrum: in ethanol, 2,326,326 m; in potassium hydroxide ethanol, max 317 nyl; and in hydrogen chloride / ethanol, R max 332 m, t; Infrared absorption spectrum (in potassium bromide):

   characteristic bands at 3.00 (shoulder), 3.15-4.35, u, 5.60, 5.65 (shoulder), 5.90, t, 6.04, t, 6.25, 6.30 , (Shoulder) and 6.45-6.55, lz.



   Example 45
A mixture of 0.128 g of the isomer A of a- (2-Carbo-tert-butyoxy-3,3-diemthyl7-oxo-4-thia-2,6-diaza-6bicyclo [3.2.0] -heptyl) - [(4-nitro-phenylacetyl) .methylene] -acetic acid tert-butyl ester in 1 ml trifluoroacetic acid is left to stand at 200 for 44 hours. The orange-colored reaction mixture containing the 7-amino-4- (4-nitrobenzylidene) -8-oxo5-thia-1-azabicyclo [4,2,0] -oct-2-ene 2-carboxylic acid (configuration of the 7-amino cephalosporanic acid), is then diluted with 5 ml of dry dioxane and mixed with a solution of 0.155 g of phenylacetyl chloride in 2 ml of dioxane. After standing for three hours at room temperature, 0.5 ml of water is added and, after a further 60 minutes at room temperature, the volatile components are removed under an oil pump vacuum.

  A few drops of methylene chloride and benzene are added to the residue; an orange-yellow precipitate forms, which is filtered off and washed on the filter with a few drops of methylene chloride. This gives 4- (4.nitro-benzylidene) -7-N-phenylacetyl-amino-8-oxo-5-thia -1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI31.1
 which, after recrystallization from a mixture of acetone and benzene, melts at 202-204;

  Ultraviolet absorption spectrum in ethanol: 2 max 390 mM (weak); in potassium hydroxide / ethanol: Ä max 398 m, b and about 275 with (weak); and in hydrogen chloride / ethanol: t max 392 m, and about 275 m, t4 (weak); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.9-4.2 it (broad), 5.60-5.65 it, 5.80-6.0, u, 6.05, 6.25, 6, 60, and 7.45.



   Example 46
A solution of 0.023 g of crude 4- (4.nitro-benzylidene) -7-N-phenylacetylamino-8-oxo-5-thia-1azabicyclo [4.2.0] oct-2-ene-2- obtained from crystallization mother liquor carboxylic acid (configuration of 7-amino-cephalosporanic acid) in 1 mol of methanol is treated with an excess of diazomethane in ether and left to stand for a few minutes at room temperature, then evaporated in a rotary evaporator.



   The residue is purified by means of thin layer chromatography (silica gel plate; 20 × 10 × 0.15 cm), developing with a 2: 1 mixture of hexane and ethyl acetate and with ethyl acetate alone. The orange band is extracted with ethyl acetate and the 4- (4-nitro-benzylidene) -7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acid methyl ester configuration of 7-amino-cephalosporanic acid) of the formula
EMI31.2
 which crystallizes after standing for a long time, F. 185-187 (with decomposition);

  Ultraviolet absorption spectrum in ethanol: A max 382 with and 278 with (shoulder), in potassium hydroxide / ethanol: A max 380 with and 278 with (shoulder), and in hydrogen chloride / ethanol: A max 378 with and 278 with (shoulder); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.60m, 5.81, u, 5.95, m, 6.24-6.30y, 6.60-6.65, u, 6.7 (Shoulder) and 7.46.

 

   Example 47
A solution of 0.12 g of the isomer A of α - [(4-methoxy-phenylacetyl) -methylene] - 7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2.0] heptyl) - a- [(4-methoxyphenyacetyl) -methylene] - acetic acid tert-butyl ester in 1 ml of pre-cooled trifluoroacetic acid is left to stand at -20 for 2 hours. The reaction mixture containing the 7-amino-4- (4-methoxybenzylidene) 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid), 5 ml of dioxane are added and the mixture is treated with a solution of 0.154 g of phenylacetyl chloride in 2 ml of dry dioxane. After 3 hours at room temperature, 10 drops of water are added and the solution is left to stand for a further hour.

  The volatile components are then evaporated off under high vacuum and the oily residue is chromatographed on 10 g of acid-washed silica gel (column). The excess phenylacetic acid is washed out with benzene containing 5% acetone, together with a yellow colored product.

  The 4- (4-methoxybenzylidene) -7- N phenylacetylamino-8-oxo5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (configuration of the 7-amino-cepahlosporanoic acid) of the formula
EMI32.1
 is eluted with a 2: 1 mixture of benzene and acetone and, after crystallization from a mixture of acetone and benzene, melts as a yellow product at 201-203; Ultraviolet absorption spectrum in ethanol; max 366 lt and 275 with (shoulder), in potassium hydroxydlethanol: A max 356 with and 272 with (shoulder), and in hydrogen chloride / ethanol:

  A max 372 with and 277 with (shoulder); Infrared absorption spectrum in potassium bromide): characteristic bands at 2.95 (shoulder), 3.01-, 4.40 lt, 5.64-5.70 lt, 5.75 lt (inflection), 6.04-6.10, u, 6.28 and 6.61.



   Example 48
A mixture of 0.0052 g of 4- {4-methoxybenzylidene) - 7-N-phenylacetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (Configuration of 7-aminobcephalosporanic acid) in 2 ml of methanol is mixed with 2 ml of the above 2 ethereal diazomethane solution. The mixture is left to stand for 3 minutes at room temperature, the volatile components are then evaporated and the residue is crystallized from a mixture of methanol and ether.

  The methyl 4- (4-methoxybenzylidene) -7-N-phenylacetylamino-8-oxo-5-thia-1-azabicyclo [4,2.0] oct-2-en-2-carboxylate (configuration of 7-amino-cephalosporanic acid) of the formula
EMI32.2
 melts at 210-211; Ultraviolet absorption spectrum in ethanol: A max 378 with and 278 mp (shoulder), in potassium hydroxide / ethanol: A max 376 with and 278 with (shoulder), and in hydrogen chloride / ethanol: A max 374 with; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.02, 5.60, 5.80, 5.91, 6.26, 6.60-6.65ia and 7.12.



   Example 49
A solution of 0.232 g of the isomer A of a- (2-carbo-tert-butyloxy-3,3-methyl-7-oxo-4-thia-2,6-diazaabicyclo [3.2, 0] heptyl) -? - [(4-chlorophenylacetyl) -methylene] - acetic acid tert-butyl ester in 2 ml of trifluoroacetic acid for 21 hours at -20. After a further 20 minutes at room temperature, 15 ml of dry dioxane are added and 0.25 g of freshly distilled phenylacetyl chloride is added to the mixture that contains the 7-amino-4- (4-chlorobenzylidene) -8-oxo-5-thia-1 -azabicyclo [4.2.0] oct-en-2-carboxylic acid (configuration of 7-amrinotcephalosporanic acid) contains. The reaction solution is kept at room temperature for 3 hours, then 0.3 ml of water is added and the mixture is left to stand at room temperature for one hour.

  The volatile constituents are removed under reduced pressure (oil pump, room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel. With 250 ml of a 100: 5 mixture of benzene and acetone, phenylacetic acid and a small amount of a neutral by-product are washed out.

  With a 2: 1 mixture of benzene and acetone, the 4- (4-chlorobenzylidene) -7-N-phenylacetyl-amino 8-oxo-5-thia-1-azabicydo [4.2.0] oct-2- en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid) of the formula
EMI33.1
 eluted, which crystallizes in the form of yellowish crystals on addition of a little benzene and ethyl acetate, F. 226-227 "; Ultraviolet absorption spectrum: 2 max 359 my (in ethanol); R max 351 zenite (in potassium hydroxide / ethanol) and i max 362 mXt (in hydrogen chloride / ethanol);

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



   Example 50
A solution of 0.3285 g of the isomer A (trans) of a- (2-Carbo4ert, .butyloxy-3,3-dimethyl7-oxo-4-thia-2,6-diaza-6-bicyclo [3.2, 0] heptyl) - a- (cyclohexylacetyl-methylene) -acetic acid tert-butyl ester in 2.3 ml of precooled trifluoroacetic acid is left to stand at -20 for 16 1/2 hours. The reaction mixture containing the 7-amino-4-cyclohexylmethylene 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) is mixed with 0.13 g of phenylacetyl chloride in 14 ml of dioxane and kept at room temperature for 3 hours. After a further hour, 0.3 ml of water is added, the volatile components are removed under reduced pressure (oil pump; room temperature) and the residue is chromatographed on 10 g of acid-washed silica gel.

  Phenylacetic acid and a small amount of neutral substances are removed with a 100: 5 mixture of benzene and acetone, and the 4-cyclohexylmethylene-7-N-phenylacetylamino8-oxo-5-thia is eluted with a 2: 1 mixture of benzene and acetone -1-azabicyclo [4.2.0] oct 2-en-2-carboxylic acid configuration of the 7-amino-cephalosporanic acid) of the formula
EMI33.2
 which, after crystallization from benzene, melts at 120-121; Ultraviolet absorption spectrum: 2 max 317 with (in ethanol), 2 max 309 with (in potassium hydroxide / ethanol) and R max 323 m, u (in hydrogen chloride / ethanol);

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.96, 3.45, 3.53, 2.85-4.3, u (broad), 5.61, 5.70-5.85, cz (broad) m 5.94, 6.05, (shoulder), 6.24 and 6.60-6.70, b.



   Example 51
A mixture of 0.4 g of cc- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza-6bicyclo [3.2.0] heptyl) - α- (phenylacetylmethylene) -acetic acid tert-butyl ester in 4 ml of trifluoroacetic acid is left to stand for 20 hours at -20 "; the trifluoroacetic acid is removed under reduced pressure (oil pump) and the orange residue containing the 7-amino-4-benzylidene -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-en-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) with 4 ml of a cooled to -15 solution of the mixed Anhydride of cyanoacetic acid and trichloroacetic acid are added in methylene chloride. (The mixed anhydride can be obtained as follows:

  A mixture of 1.45 g of cyanoacetic acid in 3 ml of methylene chloride is mixed with 1.1 ml of triethylamine and the resulting solution, cooled to -5 ", is added to a solution of 1.45 g of trichloroacetyl chloride in 3 ml of methylene chloride kept at -15" This gives a suspension which, at -15 ", is brought to a volume of 14 ml with methylene chloride and is used in this form). The reaction mixture is mixed with 2 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride, stirred for 2 hours at room temperature and then diluted with 30 mm of ethyl acetate.

  It is washed with a concentrated sodium chloride solution containing hydrochloric acid in water (15 ml of the sodium chloride solution contains 1.5 ml of 1N hydrochloric acid) and with concentrated aqueous sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. About 1 ml of ethyl acetate is added to the residue and the mixture is carefully diluted with ether and then left to stand.

  The crystalline 4-benzylidene-7-N-cyanoacetylamino8-oxo-5-thia-1-azabicyclo [4,2,0] -oct 2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) is obtained in this way formula
EMI34.1
 The residue from the mother liquor is chromatographed on 20 g of acid-washed silica gel, with a 100: 5 mixture of benzene and acetone neutral components, cyanoacetic acid and trichloroacetic acid and a further amount of the desired product with a 2: 1 mixture of benzene and acetone eluted, which, after crystallization from ethyl acetate and ether, melts at 225-227 (decomposition); Ultraviolet absorption spectrum:

  : s max 353 m and 240-265 m (wide shoulder) (in methanol), 2 max 346 nyc and 248 m (shoulder) (in potassium hydroxide / ethanol) and Ä max 356 m, and 247 m, lt (shoulder ) (in hydrogen chloride / ethanol); Infrared absorption spectrum): characteristic bands at 2.90-4.20, m, 4.41, 5.60, 5.85-5.90, u, 5.98, 6.22 and 6.45.



   Example 52
A solution of 0.023 g of 4-benzylidene-7-N-cyanoacetyl amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino cephalosporanic acid) in about 2 ml of methanol is treated with a large excess of a 2% solution of diazomethane in ether. After standing for two minutes at room temperature, the excess of the diazomethane and the solvents are evaporated and the crystalline residue is purified by preparative thin-layer chromatography on a silica gel plate, using a 95: 5 mixture of chloroform and methanol.



  The 4-benzylidene-7-N-cyanoacetylamino-8-oxo-5-thia-1-azabicyclo [4,2,0] -oct-2-en-2-carboxylic acid methyl ester (configuration of the 7-aminocephalosporanic acid) of the formula
EMI34.2
  is obtained in crystalline form, F. 232-234; Ultra violet absorption spectrum: 2 max 356 m, z and 247-265 nqu (broad shoulder) (in ethanol), Ä 364 364 m, and 253 m, 4 (in potassium hydroxide / ethanol) and A max 364 m and 254 m, 4 (when acidifying the alkaline sample with hydrogen chloride / ethanol);

  Infrared absorption spectrum (in mineral oil): characteristic bands at 3.1 it, 5.60-5.64, u, 5.80 ist, 5.98 ist, 6.20lot, 6.45etc and 6.50 (shoulder).



   Example 53
A mixture of 0.328 g of a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza 6-bicyclo [3.2.0] heptyl) -a - (4-nitrophenylacetyl-methylene) -acetic acid tert-butyl ester and 3 ml trifluoroacetic acid are left to stand at -20 "for 44 hours. The trifluoroacetic acid is removed under reduced pressure (oil pump) and the residue containing the 7-amino-4 - (4-nitrobenzylidene) -8-oxo5-thia-1-azabicyclo [4,2.0] oct-en-2-carboxylic acid (configuration of 7-amino-cephalosporanic acid), with 3 ml of a solution of the mixed anhydride of cyanoacetic acid and Trichloroacetic acid in methylene chloride (for preparation, see Example 55), followed by 1.5 ml of a solution of 0.3 ml of acetic acid and 1 ml of triethylamine in 6 ml of methylene chloride.

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

  With a 100: 5 mixture of benzene and acetone, the excess of cyanoacetic acid and trichloroacetic acid and an orange neutral component and with a 2: 1 mixture of benzene and acetone the amorphous yellow-orange 7-N-cyanoacetylamino-4- (4-nitro -benzylidene) - 5-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid (configuration of the 7-amino-cephalosporanic acid) of the formula
EMI35.1
 eluted;

  Ultraviolet absorption spectrum: A max 388 with and 275 with (in ethanol), A m3x 453 with and 263 with (in potassium hydroxide / X2ithanol) and A max 420 with and 263 with (after acidifying the alkaline sample with hydrogen chloride / ethanol); Infrared absorption spectrum (in potassium bromide): characteristic bands at 2.84.2is, 5.60-5.65, u, 5.80-6.07, lt, 6.25, 6.60 and 7.45.



   Pharmacologically active compounds of the above type are preferably used in the form of pharmaceutical preparations which contain them in admixture with a solid or liquid pharmaceutical carrier material and which are suitable for enteral or parenteral administration. Suitable carriers which are inert towards the active substances are, for. B. water, gelatin, saccharides such as lactose, glucose or sucrose, starches such as corn, wheat or arrowroot starch, stearic acid or salts thereof such as magnesium or calcium stearate, talc, vegetable fats and oils, alginic acid, benzyl alcohols, glycols or other known carriers. The preparations can be in solid form, e.g. B. as tablets, dragees, capsules or suppositories, or in liquid form, e.g. B. as solutions, suspensions or emulsions.

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

 

Claims (1)

PATENT CLAIM Process for the preparation of phosphoranylidene compounds of the formula EMI35.2 where R represents the organic radical of an alcohol R-oH, R2 represents an acyl radical, R3 represents an organic radical and R4 represents a hydrogen atom, or the two groups R3 and R4 together represent a disubstituted methylene group, and each of the groups Ra, Rb and Re means an organic radical, characterized in that one is a reactive ester of an α-hydroxy-2-oxo-1-azetidine-methane carboxylic acid ester of the formula EMI36.1 wherein X is a reactive esterified hydroxy group, with a phosphine compound of the formula EMI36.2 and converts a phosphonium salt compound obtained as an intermediate into the corresponding phosphoranylidene compound by treatment with a weak base with elimination of the elements of the acid H-X. SUBCLAIMS 1. The method according to claim, characterized in that starting materials of formula IIa are used in which X is a halogen atom or an organic, such as an aliphatic or aromatic sulfonyloxy group. 2. The method according to claim, characterized in that phosphine compounds of the formula IIb are used in which the radicals Ra, Rb and RG are optionally substituted lower alkyl or phenyl radicals, such as n-butyl or phenyl groups. 3. The method according to claim, characterized in that the reaction is carried out at elevated temperature, for. B. at a temperature of 500 C to 1500 C, optionally in the atmosphere of an inert gas such as nitrogen. 4. The method according to claim, characterized in that a mixture of isomers obtained is converted into the individual isomers. 5. The method according to claim, characterized in that starting materials are used in the form of a crude reaction mixture obtainable under the reaction conditions. 6. The method according to claim or one of the dependent claims 1-5, characterized in that compounds of the formula EMI36.3 wherein Rl stands for a lower alkyl, halo-lower alkyl or phenyl-lower alkyl radical, R2 stands for an acyl radical, each of the radicals R3 and R6 stands for a lower alkyl radical and each of the groups R'a, R'b and RTG stands for a lower alkyl or phenyl radical , manufactures. 7. The method according to claim or one of the subclaims 1-5, characterized in that compounds of the formula Ia shown in subclaim 6, wherein R1 is the tert-butyl or 2,2,2-trichloroethyl radical, R2, the Acyl radical of an organic carboxylic acid, which occurs in pharmacologically active N-acyl derivatives of 6-amino-penicillanic acid or 7-amino-cephalosporanic acid, or the acyl radical of a half ester of carbonic acid, such as a carbo-lower alkoxy, e.g. B. Carbo-tert-butyloxy radical, means that each of the radicals R5 and R5 stands for the methyl radical and each of the groups R'a, R'b and R'G means a lower alkyl or phenyl radical. 8. The method according to claim or one of the subclaims 1-5, characterized in that a- (tri-R-phosphoranylidene) -a- (2-carbo- lower alkoxy-3,3-dimethyl-7-oxo-4-thia -2,6-diaza-6-bicyclo [3.2.0] heptyl) -acetic acid lower alkyl ester, in which the lower alkyl radical of the ester group can optionally have one or more halogen atoms, preferably in the 2-position, and R stands for a lower alkyl or phenyl group , manufactures. 9. The method according to claim or one of the dependent claims 1-5, characterized in that a- (tri-R-phorphoranylidene) -a- (2-carbo lower alkoxy-3, 3-dimethyl-7-oxo-4-thia- 2,6-diaza-6-bicyclo [3, 2,0] heptyl) acetic acid lower alkyl ester, in which the lower alkyl radical of the ester group stands for the tert-butyl or 2,2,2-trichloroethyl radical, while the carbo-lower alkoxy radical in the 2-position is preferably the carbo-tert-butyloxy radical and R is a lower alkyl or phenyl group. 10. The method according to claim or one of the dependent claims 1-5, characterized in that a- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza- 6-bicyclo [3 2,0] -heptyl) - a- (triphenyl-phopshoranylidene) -acetic acid tert-butyl ester. 11. The method according to claim or one of the dependent claims 1-5, characterized in that α (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza- 6-bicyclo [3.2.0] heptyl) - a- (tri-n-butyl-phosphoranylidene) acetic acid-2,2,2-trichloroethyl ester. 12. The method according to claim or one of the dependent claims 1-5, characterized in that α- (2-carbo-tert-butyloxy-3,3-dimethyl-7-oxo-4-thia-2,6-diaza -6-bicyclo [3.2.0] heptyl) - a- (triphenyl-phosphoranylidene) acetic acid-2,2,2-trichloroethyl ester.