CH542876A - 2-hydroxy-3-,3-dimethyl-6-acylamino-4-thia-1-axa - bicyclo(3,2,0)heptan-7-ones and their esters useful as - Google Patents

Abstract

2 hydroxy 3,3 dimethyl 6 acylamino 4 thia 1 aza bicyclo 3,2,0 heptan 7 ones and their esters useful as intermediates for antibacterials. G3A. Are new cpds. of formula (I) having the configuration of 6-amino-penicillanic acid (where Ac is the acyl residue of an organic acid, pref. an acyl residue occuring in a pharmacologically active N-acyl deriv. of 6-aminopenicillanic acid or 7-aminocephalosporanic acid, or the readily removable acyl residue of a carbonic acid half-ester) and their O-esters, and may be in the form of mixtures of isomers or as pure isomers. The cpds. are prepd. by cleaving the group X from a cpd. (II) (where X is a subst. hydroxy or mercapto group which is cleavable under neutral or weakly acidic conditions, pref. a group -O-Ro in which Ro is 2-halo-(lower alkyl) in which the halogen has an atomic wt. >19) under neutral or weakly acidic conditions in the presence of H2O, and, if desired, acylating the free OH group in the resulting (I) and/or in cpds. obtained contng. acylamino residues having protected functional groups freeing such groups, and/or separating a resulting isomer mixture into the individual isomers.

Description

  

  
 



   The present invention relates to a process for the preparation of 2-Hydfl) x -3 3-dimetbvl-6-N-Ac-amino-4-thia-I-azahicaclo I3.7,01 heptan-7-ones (configuration of the 6 aminopenicillans .iure) of the formula
EMI1.1
 wherein Ac is the acyl radical of an organic carboxylic acid AcOH. in which functional groups which may be present and which are reactive under the reaction conditions are protected, as well as esters of such compounds.



   An acyl radical of an organic carboxylic acid AcOH is in particular the acyl radical of a carbonic acid halide derivative or an optionally substituted aliphatic one. cycloaliphatic. cycloaliphatic-aliphatic aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic carboxylic acid.



   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. a carbo-lower alkoxy group which is optionally substituted in the lower alkyl radical.



   An aliphatic carboxylic acid is in particular an optionally substituted alkane, as well as alkene or alkyne, primarily lower alkane. as well as lower alkene or lower alkyne carboxylic acid. the e.g. can contain up to 7, preferably up to 4 carbon atoms.



   A cycloaliphatic or cycloaliphatic-aliphatic carboxylic acid is an optionally substituted cycloalkane or cycloalkene carboxylic acid, or cycloalkyl or cycloalkenyl-lower alkanoic or lower alkene carboxylic acid.



   An aromatic carboxylic acid is primarily an optionally substituted monocyclic and bicyclic aromatic carboxylic acid.



   An araliphatic carboxylic acid means primarily a monocyclic and bicyclic araliphatic carboxylic acid, in particular a phenyl-lower alkanoic or phenyl-lower alkene carboxylic acid in which a phenyl radical and the aliphatic part can optionally 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 substituted monocyclic or bicyclic, aza-. oxa-, thia-, diaza-, oxaza- or thiazacyclic radical.



   In a heterocyclic-aliphatic carboxylic acid the heterocyclic radical has the meaning given above, while the aliphatic part e.g. as in an araliphatic carboxylic acid stands for an optionally substituted lower alkyl and lower alkenyl radical.



   Aliphatic radicals of aliphatic carboxylic acids are primarily aliphatic hydrocarbon radicals, such as alkyl, alkenyl or alkynyl, especially a lower alkyl or lower alkenyl, as well as lower alkynyl radicals, which are optionally replaced by functional groups, e.g. free, 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 groups, lower alkoxy-carhonyloxy or lower alkoxy-carhonyloxy or lower alkoxy-carhonyloxy , as well as halogen atoms. furthermore by nitro groups. free or substituted amino groups, free or functionally modified carboxy groups, such as carbo-lower alkoxy.

  optionally N-substituted carbamoyl and / or cyano groups, monodi- or polysubstituted.



   Cycloaliphatic or cycloaliphatic-aliphatic radicals in corresponding carboxylic acids are cycloaliphatic or cycloaliphatic-aliphatic hydrocarbon radicals, e.g.



  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-X.



  preferably 5 or 6 ring carbon atoms. as well as 1 to 2 double bonds, and the aliphatic part of cycloaliphatic-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, e.g. the above optionally substituted lower alkyl groups, or then, like the abovementioned aliphatic hydrocarbon radicals, be substituted by functional groups.



   The aromatic radical of an aromatic carboxylic acid is a monocyclic as well as 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 radicals, can be substituted.



   In an araliphatic carboxylic acid the araliphatic radical is an araliphatic hydrocarbon radical, in particular an e.g. up to three optionally substituted, monocyclic ones.



  and also optionally substituted aliphatic hydrocarbon radicals containing bicyclic, aromatic hydrocarbon radicals. It is primarily a phenyl-lower alkyl or phenyl-lower alkenyl, as well as phenyl-lower alkynyl radical, such radicals containing 1-3 phenyl groups and optionally, e.g. as the above-mentioned aliphatic and cycloaliphatic radicals can be substituted in the aromatic and aliphatic part.



   The heterocyclic radical of a heterocyclic or heterocyclic-aliphatic carboxylic acid is primarily a mono- or bicyclic heterocyclic radical of aromatic character with nitrogen, oxygen and / or sulfur atoms as ring members, in particular monocyclic and bicyclic monoaza-, monooxa-, monothia-, diaza, oxaza or thiazacyclic radicals of aromatic character. These heterocyclic or heterocyclic-aliphatic radicals can optionally, e.g. like the abovementioned aliphatic and cycloaliphatic radicals, be substituted in the heterocyclic and aliphatic part.

 

   A carbo-lower alkoxy radical is e.g. a carbomethoxy.



  Carbethoxy, carbo-n-propyloxy, carbo-isopropyloxy or carbo-tert-butyloxy group.



   A lower alkyl radical is e.g. B. a methyl, ethyl, in-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 group, for example 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. a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group, and a cycloalkenyl group e.g. B. a 2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 3-cycloheptenyl group. Cycloalkyl, lower alkyl or lower alkenyl is e.g. a cyclopropyl, cyclopentyl, cyclohexyl or cycloheptylmethyl, ethyl, propyl, vinyl or allyl group. while a cycloalkenyl, lower alkyl or lower alkenyl group is e.g.



  represents a 1-2- or 3-cyclopentenyl, 1-, 2- or 3-cyclohexenyl or 1-, 2- or 3-cycloheptenylmethyl-, -ethyl-, -propyl-, vinyl- or -allyl group.



   A phenyl-lower alkyl or phenyl-lower alkenyl radical is e.g. a benzyl, 1- or 2-phenylethyl, 1-, 2- or 3-phenylpropyl-, diphenylmethyl- or -ethyl-. Trityl, 1- or 2-naphthylmethyl, styryl or cinnamyl radical.



   Heterocyclic radicals in acyl groups of heterocyclic and heterocyclic-aliphatic carboxylic acids are i.a.



  Pyridyl, e.g. 2-, 3- or 4-pyridyl, furyl, e.g. 2-furyl, thienyl, e.g. 2-thienyl, pyrimidyl, e.g. 2- or 4-pyrimidyl oxazolyl, e.g. 2-oxazolyl, thiazolyl, e.g. 2-thiazolyl, or quinolyl, e.g. 2- or 4-quinolyl radicals. Aliphatic radicals in heterocyclic-aliphatic groups are primarily lower alkyl and lower alkenyl, e.g. Methyl, ethyl propyl or vinyl radicals.



   Among the etherified hydroxy and mercapto groups mentioned as substituents of the abovementioned aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radicals are lower alkoxy groups, e.g. Methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy or isobutyloxy groups, lower alkenyloxy, e.g. Vinyloxy or allyloxy groups, lower alkylenedioxy groups, e.g. Methylene or ethylenedioxy groups, phenyloxy, phenyl-lower alkoxy, e.g. Benzyloxy or 1- or 2-phenylethoxy groups, lower alkyl mercapto, e.g. Methyl mercapto or ethyl mercapto groups, phenyl mercapto groups, phenyl-lower alkyl mercapto, e.g. Benzyl mercapto groups.



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



   Substituted amino groups are mono- or disubstituted amino groups in which the substituents are primarily optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic radicals, as well as acyl radicals. Such amino groups are in particular lower alkylamino or di-lower alkylamino, e.g. Methylamino, ethylamino, dimethylamino or diethylamino groups, or optionally by heteroatoms such as oxygen, sulfur or optionally, e.g.



  lower alkyleneamino groups interrupted by lower alkyl groups, substituted nitrogen atoms, such as pyrrolidino, piperidino, morpholino, thiamorpholino or 4-methylpiperazino groups, as well as carbo-lower alkoxyamino, e.g.



  Carbomethoxyamino, carbethoxyamino or carbo-tert-butyloxyamino groups, the lower alkyl radical being optionally substituted by halogen, e.g. Chlorine atoms, e.g. as in the Carbo2,2,2-trichloroethoxy-amino radical, or by phenyl groups e.g. as can be substituted in the carbobenzyloxyamino radical.



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



   Esters of compounds of the formula I are those with organic sulfonic acids, such as lower alkanoic or aryl sulfonic acids, for example methane or ethanesulfonic acid, benzene or toluenesulfonic acid, and also with organic carboxylic acids, such as aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aromatic, araliphatic, heterocyclic or heterocyclic -aliphatic carboxylic acids which contain the above acyl radicals, such as lower alkanecarboxylic acids, which optionally as indicated, for example



  by halogen atoms, such as formic acid, propionic acid, pivalic acid, diethylacetic acid or chloroacetic acid, cycloalkanecarboxylic acids such as cyclopentane or cyclohexane carboxylic acid, cycloalkyl-lower alkanoic acids such as cyclohexylacetic acid, aromatic and araliphatic carboxylic acids as indicated, e.g. may be substituted by lower alkyl or lower alkoxy groups, halogen atoms, nitro, carbamoyl or nitrile groups, e.g. Benzoic acid, naphthoic acid, phenylacetic acid, phenylpropionic acid or cinnamic acid, optionally substituted carboxylic acids containing heterocyclic radicals, e.g. Pyridine, furan or thiophene carboxylic acids, 2-pyridyl acetic acid, 3- (2-furyl) propionic acid.



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



   The new compounds can serve as intermediates for the preparation of pharmacologically active compounds.



   Compounds of the formula are particularly valuable
EMI2.1
 wherein Ac 'is a carbo-lower alkoxy group which may optionally be substituted in the lower alkyl radical by halogen atoms, in particular the carbo-tert-butyloxy radical, or the acyl radical of a pharmacologically active 6-N-acylamino-penicillanic acid or 7-N-acylamino-cephalosporanic acid , wherein any functional groups which are reactive under the reaction conditions are protected, such as the phenylacetyl, phenyloxyacetyl, phenylglycyl, 2-thienylacetyl, cyanoacetyl or 3-chloropropionyl radical.

 

   The new compounds are obtained by using a compound of the formula
EMI2.2
 wherein Ro represents a 2-halo-lower alkyl radical wherein halogen has an atomic weight greater than 19, treated with a chemical reducing agent in the presence of water. If desired, the hydroxyl group in the 2-position in a compound obtained can be acylated, and / or, in a compound obtained with a radical Aco containing protected functional groups, these groups can be converted into the free functional groups, and / or, if desired, a obtained one Isomer mixture are separated into the individual isomers.



   In the above starting material there are free functional groups in the acyl radical Ac, which are protected during the reaction, primarily free hydroxy groups. Mercapto and amino, as well as carhoxy groups. The latter are e.g. by transferring to a. e.g. under acidic conditions, easily cleavable esters, such as an optionally substituted aliphatic or aromatic hydrocarbon radicals polysllbstittliertell Níethylester. such as the tert-butyl ester, or in a e.g. reductively cleavable ester. such as a 2-halo-lower alkyl-.

   in particular the 2,2,2-trifluorethyl ester, the others e.g. by converting into easily cleavable acyl derivatives. such as carbo-lower alkoxy which can be split under acidic conditions. e.g. Carbo-tert-butyloxyden.vate, or reductively cleavable carbo-2-halo-lower alkoxy, such as carbo-2,2,2 trichlorithosq derivatives. geschiitot.



   In the starting material, the halogen atom in a 2-halo-lower alkyl radical is a bromine or iodine. especially a chlorine atom. and the remainder is preferably a 2-polychloro lower alkyl. like a 2-polychloroethyl radical. primarily the 2.2 .'-Trichloriithylrest. but can also e.g. a 2-iodo-lower alkyl radical. e.g. mean the 2-iodoethyl radical.



   The treatment of the starting material with the chemical reducing agent is carried out under mild conditions.



  usually carried out at room temperature or with cooling.



  Particularly suitable reducing agents are nasal hydrogen. receive e.g. through the action of metals, metal alloys or amalgams on hydrogen-releasing agents. like zinc. Zinc alloys, e.g. Zinc copper, or zinc amalgam in the presence of acids, such as organic carbon dioxide. such as lower alkanoic acid. e.g. Acetic acid, with the addition of water. or from alcohols such as lower alkoxides, e.g. Methanol or ethanol, with the addition of water, as well as alkali metal amalgams, such as sodium or potassium amalgam, or aluminum amalgam on moist solvents such as ether or lower alkanols.



   Strongly reducing metal salts, such as chromium-II compounds, can also be used. e.g. Chromium (II) chloride or chromium (II) acetate, preferably in the presence of aqueous media containing water-miscible media. organic solvents such as lower alkanols. Lower alkanecarboxylic acids or ethers, e.g. Methanol, ethanol, acetic acid, tetrahydrofuran, dioxane. Use ethylene glycol dimethyl ether or diethylene glycol dimethyl ether as chemical reducing agents.



   In a compound obtainable according to the process, the hydroxyl group in the 2-position can, if desired, be acylated in a manner known per se. The usual acylating agents, such as acids or their reactive derivatives, are used for this purpose, e.g. in the presence of a suitable condensing agent such as a carbodiimide, e.g.



  Dicyclohexylcarbodiimide, and if necessary, in the presence of a basic agent such as an organic tertiary base, e.g. Triethylamine or pyridine. Reactive derivatives of acids are anhydrides, including internal anhydrides, such as ketenes, isocyanates or isothiocyanates, or mixed, in particular with haloformic acid esters, e.g. Ethyl chloroformate anhydrides, also halides, primarily chlorides, or reactive esters, such as esters of acids with alcohols or phenols containing electron-withdrawing groups, and with N-hydroxy compounds, e.g. Cyanmethanol, p-nitrophenol or N-hydroxysuccinimide.

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



   In the acyl radical Ac of a compound obtainable according to the process, protected functional groups, e.g. B. a by treatment with acid or reductively cleavable carbo lower alkoxyamino, such as the carho-tert-butyloxyamino or carho-2,2,2-trichlorathoxyamino group, are converted into the corresponding free groups, these e.g. by
Treatment with the abovementioned chemical reducing agents (it being possible for such a residue to be split off simultaneously with the process-related reaction). those e.g. by treating with trifluoroacetic acid.



   Mixtures of. Obtained by the above procedures
Isomers 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 be processed in a conventional manner, e.g.



   by forming a mixture of diastereoisomeric salts with optically active salt-forming agents, separating the
Mixture into the diastereoisomeric salts and conversion of the separated salts into the free compounds or by fractional crystallization from optically active solvents into which the antipodes are separated.



   The above processes also include those embodiments, according to which starting materials are used in the form of raw reaction mixture obtainable under the reaction conditions.



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



   The starting materials used according to the process are primarily
Line the compounds of the formula
EMI3.1
 wherein RO is a 2-haloethyl, especially a 2-polychloroethyl and primarily a 2,2,2-trichloroethyl radical.



   These starting materials can be prepared if a 3,3-dimethyl-6-N-Ac-amino-7-oxo-4-thia-1-aza-2-bicyclo [3,2,0] heptanecarboxylic acid (e.g. a 6 -N-Ac-aminopenicillanic acid compound) or a suitable salt, in particular an ammonium salt thereof, into a mixed anhydride, e.g. by treatment with a halogen formic acid - lower alkyl ester, such as ethyl chloroformate, in the presence of a basic agent, such as triethylamine, and the reactive derivative thus formed with a metal azide, such as sodium azide, or an ammonium azide, e.g., benzyltrimethylammonium azide, is reacted. The 3,3-dimethyl-6-N-Ac-amino-7-oxo-4-thia-1-aza-2-bicyclo [3.2.0] heptanecarboxylic acid azide obtainable in this way is treated with one of the 2 halo-lower alkyl groups -Halogen lower alkanol treated.

 

   The reaction with a 2-halo-lower alkanol, especially a 2-haloethanol, e.g. with 2,2,2 trichloroethanol, optionally in an inert solvent, e.g. a halogenated hydrocarbon such as carbon tetrachloride, chloroform or methylene chloride, or an aromatic solvent such as benzene, toluene or chlorobenzene, preferably carried out with heating. The azide decomposes with evolution of nitrogen and is deposited to form 2-isocyanato-3, 3-dimethyl-6-N-Ac-amino-4-thia-1-azabicyclo [3,2,0] heptane-7- which is usually not isolated on compound, which then reacts with the 2-halo-lower alkanol.



   As mentioned above. For example, the compounds of the present invention can be used as starting materials for the preparation of other compounds which can be used either as pharmacologically active or as intermediates.



   So you can e.g. for the preparation of l-formyl-2- (2-R, carbonyloxy-2-propylmercapto) -3-N-Ac-amino-azetidin-4-one compounds of the formula
EMI4.1
 in which Ac has the meaning given above and R1 is an organic radical, serve.



   An organic radical R <is an optionally substituted hydrocarbon radical, primarily an optionally substituted aliphatic or aromatic hydrocarbon radical.



   An aliphatic hydrocarbon radical is particularly a lower alkyl, e.g. Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl radical.



   An aromatic hydrocarbon radical is primarily a monocyclic aromatic hydrocarbon radical, such as a phenyl or a phenyl radical substituted by aliphatic hydrocarbon radicals, in particular lower alkylphenyl radical, e.g. 2-, 3- or 4-methylphenyl, ethylphenyl or isopropylphenyl, but can also be a bicyclic aromatic hydrocarbon radical, e.g. be a naphthyl radical or a naphthyl radical substituted by aliphatic hydrocarbon radicals. These aromatic radicals can optionally be e.g. be substituted by etherified and esterified hydroxy or mercapto groups, or amino groups of the type mentioned above, trifluoromethyl and / or nitro groups.



   The compounds of the above type can exist in the form of mixtures of isomers or of pure isomers.



   These compounds show valuable pharmacological properties; in particular, in dilutions up to (), Ot% they are effective against both gram-positive bacteria. such as Staphylococcus aureus, as well as against gram-negative bacteria such as Proteus vulgaris, and can therefore be used as antibacterial agents. They also serve as intermediate products for the production of valuable, e.g.



  pharmacologically active compounds.



   Compounds of the formula are particularly valuable
EMI4.2
 where Ac 'has the meaning given above and R, for a lower alkyl, in particular the methyl radical. stands.



   The above compounds of the formula III are obtained if a 2-hydroxy-3 3-dimethyl-6-N-Ac-amino-4 thia-1 -azabicyclo [3,7.01 heptan-7-one prevention of the formula
EMI4.3
 treated with an oxidizing agent donating the acyloxy group of the formula -O-C (= O) -R1, and, if desired.



  in a compound obtained with a radical Ac having protected functional groups, this group is released, and / or, if desired, a mixture of isomers obtained is separated into the individual isomers.



   Oxidizing agents which donate acyloxy groups are preferably oxidizing heavy metal carboxylates, preferably lead IV carboxylates, such as lead IV alkanoates, primarily lead tetraacetate, and lead tetrapropionate or lead tetrastearate, and optionally substituted lead trabenzoates, e.g. Lead tetrabenzoate or lead tetra-3-bromobenzoate. as well as thallium lil carboxylates, e.g. Thallium-lil-acetate, or mercury-II-carboxylate, such as mercury-lil-acetate. These oxidants can also be used in situ, e.g. B. by reaction of lead dioxide or mercury-II-oxide with an organic carboxylic acid. such as acetic acid.



  These heavy metal carboxylates, in particular the corresponding lead IV compounds, are advantageously used in the presence of a light source, e.g. works with ultraviolet or longer-wave, such as visible light, optionally with the addition of suitable sensitizers. In this case, UV light preferably has a main wavelength range of over 280 nn, u, primarily from about 300 mI <to about 350, which can e.g. by suitably filtering the ultraviolet light through an appropriate filter, e.g. Glass filter. or by suitable solutions, such as salt solutions, or other liquids which absorb light for a short time, such as benzene or toluene. The ultraviolet light is preferably generated by means of a high pressure mercury vapor lamp.



   The above reaction can e.g. be carried out in such a way that the starting material is mixed with the necessary amount of the oxidizing agent which donates an acyloxy group, usually in the presence of a suitable diluent such as benzene, acetonitrile or acetic acid. if necessary, treated with cooling or with heating, and / or in an inert gas atmosphere.



   In a compound obtained, protected functional groups of an Ac NH group can be released in the manner shown above.



   As mentioned, the above-mentioned 1-formyl-2- (2-RI-carbonyloxy-2-propylmercapto) -3-N-Ac-amino-azetidin-4one compounds of the formula III can also be used as intermediates for the preparation of pharmacologically active compounds, in particular of l-R2-2-R3-mercapto-3-N-Ac-amino-azetidin-4-one compounds of the formula
EMI5.1
 where R denotes hydrogen or the acyl radical Ac, R2 represents a hydrogen atom or a formyl group, and R3 represents an optionally monounsaturated isopropyl radical, with the proviso that R denotes an acyl radical Ac.



  if R3 stands for the isopropenyl radical, can be used.



   The compounds of the above type can exist in the form of mixtures of isomers or of pure isomers.



   Compounds of the formula IV. In which R is an acyl radical. show valuable pharmacological properties; in particular, they are effective against both gram-positive bacteria in dilutions up to 0.01%. such as Staphylococcus aureus, as well as against gram-negative bacteria such as Proteus vulgaris, and can therefore be used as antibacterial agents. They also serve as intermediate products for the production of valuable, e.g. pharmacologically active compounds.



   Compounds of the formula are particularly valuable
EMI5.2
 where Ac 'has the meaning given earlier.



   The compounds of the formula IV can be obtained by using compounds of the formula
EMI5.3
 wherein Ac and R, have the meanings given above, thermally decomposed and, if desired, saturates the double bond in the isopropenyl radical in a compound obtained, and / or, if desired, splits off the formyl group in a compound obtained. and or. if desired in a preserved compound. in which R3 represents the isopropyl radical, an Ac-NH group cleaves. and, if desired. acylated the released amino group, and / or.



  if wanted. in a compound obtained with an acyl radical containing protected functional groups, these groups are released. and or. if desired, a mixture of isomers can be broken down into the individual isomers.



   The thermal decomposition of the starting material is preferably carried out in the presence of an inert solvent or solvent mixture, in particular a suitable aliphatic or aromatic hydrocarbon such as high-boiling petroleum ether, benzene, toluene or xylene, at temperatures from about 50 ° C. to about 150 ° C., preferably from about 70 ° to made about 170 ". You can, if desired, in an inert gas. like nitrogen atmosphere.



   In a compound of the formula IV obtainable according to the process, in which R3 stands for the isopropenyl radical, this can be reductively, preferably by treatment with catalytically activated hydrogen, e.g. with hydrogen in the presence of a noble metal catalyst containing e.g. Palladium or platinum, if necessary, under increased pressure and / or with heating, can be converted into the isopropyl radical.



   In an available compound in which R2 stands for a formyl radical, this can be obtained by decarbonylation, e.g.



  by treatment with a complex transition metal compound which can form a stable complex with carbon monoxide, such as a trisubstituted trisphosphine rhodium halide, such as tris.triphenylphosphine rhodium chloride. This reaction is preferably carried out in a suitable inert solvent or solvent mixture, e.g. in benzene. being, if desired, in an inert gas. e.g. Nitrogen atmosphere, works. The decarbonylation reaction, which is preferably carried out at elevated temperature, can also be applied directly to the starting material of the formula III; Under these conditions thermal decomposition occurs with formation of the isopropenyl radical and the formyl group is split off at the same time.



   In compounds of the formula IV in which R2 stands for the formyl radical, this can also be achieved by hydrolysis.



  Alcoholysis, ammonolysis or aminolysis can be replaced by hydrogen. The hydrolysis can e.g. by treatment with a suitable inorganic base such as an alkali metal or alkaline earth metal hydroxide or carbonate, e.g. Sodium, potassium, calcium or barium hydroxyl or carbonate. as well as an alkali metal hydrogen carbonate, e.g. Sodium or potassium hydrogen carbonate, can be carried out in an aqueous medium. Alcoholysis with alcohols such as lower alkanols.



  e.g. Methanol or ethanol, as well as mercaptans, are preferably used in the presence of corresponding alcoholates or thiolates, such as alkali metal lower alkanolates. e.g.



  Sodium methylate or ethylate, and weakly basic acylates, such as alkali metal lower alkanoates. e.g. Sodium acetate.



   The ammonolysis with ammonia, as well as with quaternary ammonium hydroxides, e.g. Benzyltrimethylammonium hydroxide or tetrabutylammonium hydroxide also leads to the removal of a formyl group R2. When using ammonia one works e.g. in a two-phase system; the ammonia, which is preferably used in the form of an aqueous solution, enters the organic phase in low concentration and causes the formyl group to be split off. Aminolysis can be done with amines. especially primary or secondary, primarily aliphatic or aromatic amines, e.g. Ethylamine, diethylamine. Pyrrolidine or aniline.



   In a compound of the formula IV obtainable in this way, can.



  an appropriate acylamino moiety, if desired. e.g.



  a carbo-lower alkoxyamino group which can be cleaved by treatment with acid or reductively, such as the carbo-tert-butyloxyamino or carbo-2,2,2-trichloroethoxyamino group, are cleaved, these e.g. by treating with the above chemical reducing agents, those e.g. by treating with trifluoroacetic acid. If desired, a free amino group thus formed can e.g. how to acylate the above hydroxyl group; protected functional groups can be released as indicated. These additional measures are carried out on compounds in which R3 is the isopropyl radical.

 

   Compounds of the formula IV in which R3 stands for the isopropenyl radical, primarily those in which Ac is an acyl radical which can be split off easily, especially under acidic conditions, such as a suitable acyl radical of a carbonic acid half-ester, e.g. one optionally substituted in the lower alkyl part, preferably in its a-position, carbo-lower alkoxy radical, and one, optionally in the lower allenyl, cycloalkyl. Phenyl or phenyl-lower alkyl part-substituted carbo-lower alkenyloxy, carbocycloalkyl.



  Carbo-phenyloxy or carbo-phenyl-lower alkoxy radical, or a Car'oo-lower alkoxy radical having a heterocyclic group of aromatic character in the lower alkyl moiety, preferably in the a-position, and R2 is a hydrogen atom, can also be used in compounds of the formula
EMI6.1
 especially in those in which R has the meaning given above; Compounds of this type are known, e.g. as valuable intermediate products in the synthetic production of 7-acylamino-cephalosporanic acid compounds; see e.g. Austrian patents No. 263 768 and 264 537.



   They are obtained by using compounds of the formula IV in which R3 is the bsopropenyl radical and Ac is preferably one of the above. is easily split off radical, and R2 is a hydrogen, treated with a strong, oxygen-containing acid, and, if desired, acylated in a compound of the formula V obtained with an unsubstituted nitrogen atom in the 3-position.



   The ring closure can be achieved by treating with a strong inorganic or organic. oxygen-containing acid, such as organic carboxylic or sulfonic acid, in particular a strong lower alkanecarboxylic acid, optionally substituted by hetero radicals, preferably by halogen atoms. such as an n-halo-acetic or ou-halo-propionic acid, in which halogen is preferably fluorine and chlorine. primarily trifluoroacetic acid are effected, in the absence or presence of an inert solvent such as dioxane, or a mixture of diluents. and, if necessary, with cooling, e.g. at temperatures from about -300 to about + 10 C, and / or in an inert gas. e.g.



  Nitrogen atmosphere, works.



   Acylation of an unsubstituted nitrogen atom in a compound obtainable according to the process can e.g. as described above, if desired, carried out in stages.



   Furthermore, the compounds of the formula I can be used for the preparation of 2- (2-hydroxymethyl-2-propylmercapto) -3aminoazetidin-2-one compounds of the formula
EMI6.2
 wherein R has the above meaning and O-esters of such compounds are used.



   Esters are primarily those with the organic carboxylic acids mentioned above.



   Compounds of formula VI. in which R represents the acyl radical, with any free functional groups present in the Ac radical preferably being protected, are valuable intermediates. So you can u. a. can be used for the preparation of compounds of the formula
EMI6.3
 in which each of the groups Ac and Ac2 denotes the residue of an organic carboxylic acid. in particular of compounds of the formula
EMI6.4
 wherein Ac 'has the meaning given above and each of the radicals Ac' and Ac'2 stands for a lower alkanoyl radical.

  These products are effective against both gram-positive and gram-negative bacteria. especially against Staphylococcus aureus and Proteus vulgaris. and can accordingly be used as antibacterially active substances: they are obtained when compounds of the formula V. in which R represents the acyl radical Ac, or esters with carboxylic acids thereof are acylated at elevated temperature. Anhydrides or halides are used as acylating agents. such as chlorides, of organic carboxylic acids, and operates preferably at temperatures of about 40 "C to about 150" C. in particular in a temperature range from about 60 "C to about 120" C and in the presence of a suitable organic. especially tertiary base such as pyridine.



   Compounds of the formula are particularly valuable as intermediates
EMI6.5
 wherein Ac 'has the meaning given above, and esters thereof with lower alkanecarboxylic acids.



   The above compounds can be obtained by adding a 2-hydroxy-3,3-dimethyl-6-N-Ac-amino-4-thia-1azabicyclo [3.2.0] heptan-7-one compound of the formula I. treated with an amide group non-reducing hydride reducing agent and, if desired, esterifying the hydroxyl group in a compound obtained, and / or if desired. in a compound obtained with an Ac-NH grouping this cleaves and, if desired, acylates the released amino group, and / or, if desired, releases these groups in a compound obtained with an acyl radical containing protected functional groups, and / or, if desired. a mixture of isomers obtained is split into the individual isomers.



   Amide groupings non-reducing hydride Reducing agents are primarily boron-containing hydrides such as e.g. Diborane, primarily alkali metal or alkaline earth metal borohydrides, primarily sodium borohydride. Complex organic aluminum hydrides such as alkali metal -triniederalkoxyaluminiumhydride, z. B. Lithium tri-tert-butyloxy aluminum hydride. can also be used.



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



   In a compound thus obtainable e.g. the free hydroxyl group is esterified and / or the acylamino group is cleaved and, if desired, acylated again by the processes described above; protected functional groups can, as indicated, be released.



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



   Example I.
A solution of 3 g of crystalline 2- (N-carbo-2,2,2trichloroethoxy-amino) -3,3-dimethyl-6- (N-phenyloxy-acetylamino) -4-thia-1-azabicyclo [3.2, 0] heptan-7-one in 65 ml of 90% 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 aqueous sodium chloride solution and water. dried and evaporated under reduced pressure. The residue is purified on a column of 45 g of acid-washed silica gel. It is obtained with 100 ml of benzene and 10O ml of a 9: 1 mixture of benzene and ethyl acetate, and apolar products are obtained.

  Starting material is washed out with 100 ml of a 4: 1 mixture of benzene and ethyl acetate and with a further 500 ml of the 4: 1 mixture of benzene and ethyl acetate. and with 200 ml of a 2: 1 mixture of benzene and ethyl acetate, 2-hydroxy-3,3-dimethyl6- (N-phenyloxyacetylamino) -4-thia-1-azabicyclo [3.2.0] heptane is obtained -7-one (configuration of 6-aminopenicillanic acid) der
EMI7.1
   which crystallizes spontaneously as a hydrate and, after trituration with water-saturated ether, melts indistinctly in the range of 62-85.



   If chromatographed but non-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 2.93I. 3.091. 5.65, 5.96, 6.29, 6.65, 6.75, 8.57, 9.27, 10.00 and 11.95se.



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



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



  It is extracted three times with methylene chloride; the organic extracts are washed with water, dried and evaporated at 25 and under reduced pressure. The amorphous penicillin V-azide is thus obtained as a slightly yellowish oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 4.70u, 5.61u, 5.82 (shoulder), 5.93, u, 6.26, u, 6.61, et, 6.71, u, 8.50, u and 9.40, u.



   A solution of 2.468 g of the penicillin V azide in 30 ml of benzene is heated to 70 for 30 minutes. The pure 2-isocyanato-3,3-dimethyl-6- (N-phenyloxyacetylamino) -4-thia-1-azabicyclo [3,2.01 heptan-7-one can be obtained by evaporating the solution under reduced pressure.



  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, u, 4.46H, 5.59, u, 5.93H, 6.26y, 6.6 ', u, 6.70, u, 7.53y, 8.28ju, 8.53jr, 9.24, u and 9, M).



   The above solution of the 2-isocyanato-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3,2,0] heptan7-one is mixed with 3.4 ml of a 10 ml solution of 2 ml of 2,2,2-trichloroethanol in benzene are added and the reaction mixture is kept at 70 "for 95 minutes. The solvent is removed under reduced pressure and the residue is purified on 40 ml of acid-washed silica gel (column). It is washed with 300 ml of benzene and 300 ml 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- (N-phenyloxyacetyl-amino) - 4-thia-1-azabicyclo [3.2.0] heptan-7-one of the formula
EMI7.2
 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) [o] 20 = +83 "(c = 1.015 in chloroform); thin
D layer chromatogram (silica gel): Rf = 0.5 in a 1: 1 mixture of benzene and ethyl acetate: infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.62,,,,, 6.27, 6.62 , 6.70, 8.30, 9.23 and 9.50.



   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.



   Example 2
A solution of 2.49 g of 2- (N-Carbo-2, 2, 2-trichloroethoxy-amino) -3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo [3 , 2.0] heptan-7-one in 50 ml of dimethylformamide, 25 ml of acetic acid and 5 ml of water is prepared at room temperature, then cooled to 00 and mixed with a total of 25 g of zinc dust in portions within 10 minutes while stirring.



  The mixture is stirred at 0 for 20 minutes, then the mixture is filtered into a receiver of 500 ml of a saturated aqueous sodium chloride solution and the filter residue is washed out with 25 ml of acetic acid. The filtrate is extracted three times with 300 ml of benzene each time; the organic extracts are washed with water, dilute aqueous sodium hydrogen carbonate solution and water, combined, dried and evaporated under reduced pressure. The residue is chromatographed on 45 g of acid-washed silica gel. Fractions of 100 ml each are taken, using 300 ml of benzene, 300 ml of a 9: 1, 500 ml of a 4: 1, 600 ml of a 2: 1 and 200 ml of a 1: 1 mixture of benzene and ethyl acetate and Washes out 100 ml of ethyl acetate.



  Fractions 8 and 9 contain crystalline starting material, while the 2-hydroxy-3,3-dimethyl-6- (N-phenylacetylamino) -4-thia-1-aza-bicyclo [3.2.0] heptan-7-one (Configuration of 6-aminopenicillanic acid) of the formula
EMI8.1
 obtained from fractions 11-15 as a colorless oil; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, u, 3.05,, 5.64y, 5.99, u, 6.70, u and 9.28.



   The starting material can be obtained as follows:
15 ml of a sulfonic acid type ion exchanger (11 + form) are introduced into the triethylammonium salt form by treatment with a solution of 5 ml of triethylamine in 100 ml of water, the colon is washed neutral with 300 ml of water and treated with a solution of 2 g of the Sodium salt of penicillin-G in 10 ml of water and then eluted with water. A volume of 45 ml is withdrawn and lyophilized at a pressure of 0.01 mm Hg. The crude triethylammonium salt of penicillin-G thus obtained is dissolved in methylene chloride, the solution is dried over sodium sulfate, filtered and evaporated.



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

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



   A solution of 1.72 g of penicillin G azide in 30 ml of benzene is mixed with 1.5 ml of 2,2,2-trichloroethanol and stirred for 25 hours at 70 ". During the first 15 minutes, a regular development of Nitrogen was found and after a few hours the product separates from the solution. It is diluted with stirring with 60 ml of hexane, cooled and filtered after 15 minutes. The filter residue is washed with a 2: 1 mixture of benzene and hexane and with cold ether .

  The pure 2 (N-carbo-2, 2, 2, -trichloroethoxy-amino) -3,3-dimethyl-6- (Nphenylacetylamino) -4-thia-1-azabicyclo [3.2.0] heptane is obtained in this way -7-one of the formula
EMI8.2
    20 which melts at 223-223.5 "; [lx] D = + 1720 (c = 1.018 in
Ethanol); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, ce, 5.61, u, 5.77, u, 6.57, u, 6.70, u, 8.30, 9.17, 9.62 and 11.85.



   The product can also be obtained by adding 0.03 g of des
Penicillin G azide in 2 ml of benzene heated to 70 "for 20 minutes, the 2-isocyanato-3,3-dimethyl-6- (N phenylacetyl-amino) -4-thia-1- by evaporation of the reaction mixture under reduced pressure azabicyclo [3.2.0] heptan-7-one;
Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.06, 4.48, 5.62, 5.96 and 6.70; obtained and this according to the method shown in Example 1 by reacting with 2,2,2-trichloroethanol into the desired 2- (N carbo-2, 2, 2-trichloroethoxy-amino) -3,3-dimethyl-6- (N phenylacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one transferred.



   Example 3
A solution of 0.5 g of 2- (N-carbo-2, 2, 2-trichloroethoxy amino) -3,3-dimethyl-6- (N-carbo-tert.-butyloxy-amino) -4 thia-1- azabicyclo [3.2.0] heptan-7-one (configuration of the 6 amino penicillanic acid) in 5 ml of tert-butanol is mixed with 4 ml
Acetic acid and 1 ml of water. After cooling in an ice bath, stir for 15 minutes
5 g zinc dust added in small portions. The mixture is stirred for a further 30 minutes at 00 and then filtered into a receiver of 70 ml of saturated aqueous sodium chloride solution.



  The residue is washed with methylene chloride and the aqueous phase of the filtrate is extracted with the same solvent. The organic extracts are washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The thus obtained
The crude product can be purified by chromatography on 10 g acid-washed silica gel, first pre-washing with a 9: 1 mixture of benzene and ethyl acetate and then the 2-hydroxy with the same solvent mixture and a 4: 1 mixture of benzene and ethyl acetate 3.3-dimethyi-6- (N-carho-tert-butyloxy-amino) -4-thia-I-azahicyclo [3,2.01 -heptan-7-one (configuration of the 6-amino-penicillanic acid) of the formula
EMI9.1
 eluted as a colorless oil.

  This crystallizes from a mixture of ether and pentane. F. 106-1 10 "(sintering from 10 ()); [al 20 + 1150 :::: 1 (c = 0.858 in chloroform); thin layer
D chromatogram (silica gel): Rf 0.53 in a 1: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.91.



  3.04, m 5.64, 5.84, 6.68, 7.33 and 8.60.



   The starting material used above can be made as follows:
A suspension of 0.5 g of crude 6-aminopenicillanic acid in 4 ml of chloroform (freshly distilled over phosphorus pentoxide) is treated with 1 ml of hexamethyldisilazane of the formula [(CH3) 3Si] 2NH and 1 ml of chloroform dried over phosphorus pentoxide; the reaction mixture is refluxed for 2 hours with exclusion of atmospheric moisture, then cooled to 0 "and, after the addition of 1.7 ml of a 10 ml solution of 2 ml of triethylamine in chloroform, treated with 0.385 g of distilled tert.-butyl fluoroformate .



  The mixture is kept for 30 minutes at 09C, then for 90 minutes at room temperature and diluted with cold methylene chloride. The organic solution is washed with cold aqueous 10% strength citric acid and water, the aqueous washing liquids being backwashed with cold methylene chloride. The combined organic extracts are extracted twice with a dilute aqueous sodium hydrogen carbonate solution and, immediately after being separated off, acidified with citric acid in the presence of methylene chloride and at O ". The organic phase is separated off, dried and evaporated; the pure amorphous 6- (N- Carbo-tert-butyloxy-amino) penicillanic acid.

  Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.63, 5.82, 6.67, 7.32 and 8.60.



   The 6- (N-carbo-tert-butyloxy-amino) penicillanic acid obtained is dissolved in 10 ml of methylene chloride and treated with 0.43 ml of a 10 ml solution of 2 ml of triethylamine in methylene chloride. On evaporation, the amorphous residue obtained is 6- (N-carbo-tert-butyloxy-amino) penicillanic acid triethylammonium salt; Infrared spectrum (in methylene chloride): characteristic bands at 3.05, 5.67, 5.86, 6.17, 6.67, 7.32 and 8.53.



   A solution of 0.226 g of 6- (N-carbo-tert-butyloxyamino) -penicillanic acid triethylammonium salt in 5 ml of tetrahydrofuran is treated at - 10 with 0.26 ml of a 10 ml solution of 2 ml of ethyl chloroformate in tetrahydrofuran. After stirring for 90 minutes at -S0bis -10, it is treated with a solution of 0.04 g of sodium azide in 0.4 ml of water. The mixture is stirred for a further 30 minutes at -5 to 0, then diluted with 20 ml of ice water and extracted with methylene chloride.

  The organic extract is dried and evaporated at a temperature below 25 under reduced pressure; the crude 6- (N-carbo-tert-butyloxy-amino) penicillanic acid azide is thus obtained as a residue; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 4.70, 5.62, .3, 6.16, 7.32, 8.60 and 9.40, lt.



   The crude product obtained above is dissolved in 5 ml of benzene, stirred for 5 minutes at 70 and a small amount of the solvent is evaporated off; According to the infrared spectrum (in methylene chloride; characteristic bands at 3.03, 4.48, 5.61, 5.83, 6.67, 7.31, 7.55Xt and 8.62) is the rearrangement into the 2-isocyanato -3,3-dimethyl-6- (N-carbo-tert-butyloxyamino) -4-thia-1-azabicyclo [3,2,0] heptan-7-one complete.



  The warm benzene solution is mixed with 0.2 ml of 2,2,2-trichloroethanol; the reaction mixture is stirred for a further 90 minutes at 70 "and then evaporated under reduced pressure. This gives 2- (N-carbo-2,2,2-trichloroethoxy-amino) -3,3-dimethyl- 6- (N-carbo-tert-butyloxy-amino) -4-thia-1-azabicyclo- [3.2.0] heptan-7-one der
formula
EMI9.2
 which, after recrystallization from a mixture of ether and pentane, melts at 165-167; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.63, 5.81, 5.84, 6.69, 7.34, 8.65, 9.16 and 9.59, and the like.



   Example 4
A solution of 1.04 g of 2- (N-Carbo-2-iodethoxy-amino) 3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one in 6 ml of tetrahydrofuran is mixed with 60 ml of 90% strength aqueous acetic acid, cooled to 0 and treated with 8 g of zinc dust. The reaction mixture is placed in an ultrasonic bath at 00 for 15 minutes and then filtered through a diatomaceous earth preparation (Celite) and washed with 100 ml of methylene chloride. The combined filtrates are evaporated under reduced pressure and the residue is taken up in 100 ml of methylene chloride and about 70 ml of a 0.5 m. Dipotassium hydrogen phosphate solution saturated with sodium chloride. The aqueous phase is extracted twice with 100 ml of methylene chloride each time.

  The organic extracts are washed with 50 ml each of the 0.5 m. Sodium chloride-saturated dipotassium hydrogen phosphate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated under reduced pressure. The residue is lyophilized from benzene; the colorless 2-hydroxy-3,3dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3,2,0] heptan-7-one (configuration of the 6-amino-penicillan acid), which melts as a hydrate after trituration with water-saturated ether in the range of 62-85; the anhydrous product melts at 62-70.



   The raw material is produced as follows:
A mixture of 16 g of penicillin V-azide in 160 ml of absolute benzene is mixed with 3.3 ml of freshly distilled 2-bromoethanol and heated to 60-65 for 40 minutes, then cooled to room temperature within one hour. The solvent is evaporated off under reduced pressure and the residue is chromatographed on 390 g of silica gel.

  With 19: 1 and 9: 1 mixtures of methylene chloride and ethyl acetate, the 2- (N-carbo-2-bromoethoxyamino) -3,3-dimethyl-6- (N-phenyloxyacetylamino) -4-thia-1azabicyclo is obtained [3,2,0] heptan-7-one of the formula
EMI10.1
 eluted and crystallized from a mixture of methylene chloride and cyclohexane, mp 128.5-129 (corr.); [α] 20 / D = +90 # 1 (c = 0.933 in chloroform); Thin layer chromatography (silica gel):

  Rf = 0.41 (toluene / acetone system 3: 1), Rf = 0.70 (toluene / acetone system 1: 1), and Rf = 0.52 (toluene / ethyl acetate system 1: 1), ultraviolet absorption spectrum (in ethanol ): #max 262 m (e = 940), 268 m, (± = 1260) and 275 m (# = 1060), and Amin 246247 m (8 = 445), 264 m (e = 930) and 270 m ( r = 810); Infrared absorption spectrum (in mineral oil):

   characteristic bands at 2.98, 5.62, 5.82, 5.93, 6.24, 6.48, 6.64, 6.90, 7.61, 8.00, 8.10, 8.28 , 8.49, 11.80, 13.28, 14.59 and 15.04, and the like.



   7.56 g of 2- (N-carbo-2-bromoethoxy-amino) 3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptane are poured over them -7-one with a solution of 9.6 g of sodium iodide in 48 ml of absolute acetone and the clear solution is heated to 35 for 16 hours under a nitrogen atmosphere; After just 5 minutes, a white, fine-grain precipitate begins to separate out. After the reaction has ended, the acetone is evaporated off under reduced pressure and the residue is shaken with 10 ml of water and 350 ml of ethyl acetate. The organic solution is washed three times with water; the aqueous phases are washed with 70 ml of ethyl acetate each time and the combined organic solutions are dried over anhydrous magnesium sulfate and concentrated under reduced pressure.

  The concentrated solution is gently warmed together with about 70 ml of methylene chloride, then about 400 ml of cyclohexane are added. After cooling to room temperature, the precipitate (long colorless needles) is filtered off, washed with a 1: 4 mixture of ether and cyclohexane and dried under reduced pressure.

  This gives 2- (N-carbo-2-iodethoxyamino) -3,3-dimethyl-6- (N-phenyloxyacetylamino) -4-thia- 1- azabicyclo [3,2,0] heptane-7- on the formula
EMI10.2
 which, after crystallization from a mixture of methylene chloride and cyclohexane, melts at 154-155 "; f80" +1 "(c = 1.031 in chloroform); thin-layer chromatogram (silica gel):

  Rf = 0.35 (system toluene / ether 1: 1), Rf = 0.65 (system toluene / acetone 4: 1) r Rf = 0.81 (system toluene / acetone 1: 1), and Rf = 0, 66 (system toluene / ethyl acetate 1: 1); Ultraviolet absorption spectrum (in ethanol): man 260 m, et (8 = 1440), 267 m 1690) and 274 m (8 = 1350), and imin 242 m, u (8 = 970), 263 m (# 1380) and 271 m, (8 = 1100); Infrared absorption spectrum: characteristic bands at 2.90, 5.57, 5.77, 5.89, 6.24 (shoulder), 6.61, 6.648 (shoulder), 6.67, 8.17, 8.27, 8 , 47, 9.27 and 9.42 (in methylene chloride) and at 2.95 (shoulder). 2.98. 5.67.



  5.78, 5.92, 6.24, 6.51, 6.62 and 6.68 (in mineral oil).



   In an analogous manner, when treating 2- (N-Carbo2-iodethoxy-amino) -3,3-dimethyl-6- (N-phenylacetyl-amino) 4-thia-1-azabicyclo [3.2.0] heptane 7-one with zinc dust in the presence of 90% aqueous acetic acid gives 2-hydroxy3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo 13,2,01 heptan-7-one (configuration of 6-Amino-penicillanic acid) are obtained: colorless 01: infrared absorption spectrum (in methylene chloride): characteristic bands at 2.90, 3.05, 5.64, 5.99. 6.70 and 9.28.



   The 2- (N-carho-2-iodoethoxy-amino) -3,3-dimethyl-6- (N-phenylacetyl-amino) 4-thia-1 -azahicyclo [3,2,0) heptan-1 used as starting material -on can be obtained as follows:
The yellow solution of 23 g of crude 2-isocyanato-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1 -azabicyclo [3.2.0 ] heptan7-one (configuration of 6-amino-penicillanic acid) in 230 ml of benzene is mixed with 4.9 ml of 2-bromoethanol and 0.1 ml of tributyl tin oxide and left to stand for 2 hours at room temperature, then evaporated.

  The residue is taken up in methylene chloride and chromatographed on 350 g of silica gel (column). The 2- (N-carbo-2-bromoethoxy-amino) -3,3-dimethyl-6- (N-phenylacetyl-amino) 4-thia- 1 -azabicyclo [3.2.0] heptane-7- is eluted on (configuration of the 6 amino penicillanic acid) of the formula
EMI11.1
 with a 9: 1 mixture of methylene chloride and ethyl acetate.

  After recrystallization from a mixture of methylene chloride and cyclohexane or acetone and cyclohexane, the product melts at 149-150: [al 2D0 = +99 # 10 (c = 1.008 in chloroform): thin layer chromatogram (silica gel): Rf = 0.51 (toluene system / Ethyl acetate 1: 1), Rf = 0.32 (system toluene / acetone 4: 1) and Rf = 0.71 (system toluene-acetone 1: 1):

  Ultraviolet absorption spectrum (in ethanol): #max 252 m (# = 300), 258 midd (e = 270) and 265 m (# = 180): Infrared absorption spectrum: characteristic bands at 2.91, 5.58, 5.77, 6.62 6.62 (shoulder), 6.66, 8.21, 8.30, 8.48, 9.32 and 9.64 (in methylene chloride) and at 2.93, 2.95, 3.01 , 5.62, 5.79, 5.82 (shoulder), 5.91, 5.98, 6.53, 6.57. 6.68 and 7.36 (in mineral oil).



   5.265 g of 2- (N-Carbo-2-bromoethoxyamino) 3 are poured over. 3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one with a solution of 6.9 g of sodium iodide in 34.5 ml of purified acetone and lets stand for 16 hours at 30: after a few minutes a dense precipitate of sodium bromide begins to form. After the reaction has ended, the solvent is evaporated off under reduced pressure and the residue is taken up in 30 ml of water and 70 ml of ethyl acetate. The golden yellow organic phase becomes 0.1-n after adding a few drops.

 

  shaken aqueous sodium thiosulfate solution; the aqueous phase is separated off and washed twice with 50 ml of ethyl acetate each time. The combined organic solutions are washed twice with 20 ml of water each time, dried over magnesium sulfate and concentrated to a volume of 20-30 ml. It is diluted with 50 ml of methylene chloride and treated with 200 ml of hot cyclohexane, the mixture is cooled to room temperature and then left to stand at 4 for one hour. The colorless needles are filtered off and washed with a 4: 1 mixture of cyclohexane and ether.

  The 2- (N-carbo-2-iodoethoxy-amino) -3, 3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan7-one is obtained (Configuration of 6-amino penicillanic acid) of the formula
EMI11.2
  that after crystallization from methyl acetate and cyclohexane at 153-154 schmil [α] D20 20 = +89 +1
D (c = 1.011 in chloroform); Thin-layer chromatogram (silica gel):

  Rf = 0.56 (toluene / ethyl acetate system 1: 1), Rf = 0.35 (toluene / acetone system 4: 1) and Rf = 0.74 (toluene / acetone 1: 1 system); Ultraviolet absorption spectrum (in ethanol): one 252 m (z = 815), 258 my (± = 775), 264 m (e = 600) and 335 m (e = 45); Infrared absorption spectrum:

   characteristic bands at 2.90, 5.58, 5.76,. 6.651 (, 6.85, 8.18, 8.34, 8.47 and 9.378 (in methylene chloride) and 2.97y (shoulder), 3.03, 5.62, 5.87, 6.58, 6, 59, 6.67, 7.65, 8.01, 9.67 and 12.92 (in mineral oil)
Example 5
A solution of 0.14 g of 2-hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1 -azahicyclo [3,2,0j heptan7-one in 2 ml of dry benzene is mixed with 1 ml Acetic anhydride and 0.2 ml of pyridine are added and the mixture is heated to 50 for 2 hours. It is then evaporated under reduced pressure and the residue is purified by chromatography on 1 g of acid-washed silica gel.

  It is eluted with 10 ml of benzene and 40 ml of a 19: 1 mixture of benzene and ethyl acetate and the pure 2-acetyloxy-3, 3dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [ 3,2,01 heptan-7-one of the formula
EMI12.1
 which after crystallization from a mixture of ether and pentane and recrystallization from ether melts at 129-131; [a] 20 = + 85 # 1 (c = 1.135 in chloroform);
D Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.61, 5.74, 5.94, 6.28, 6.64, 6.72, 8.32 and 9.62.



   Example 6
A solution of 0.132 g of 2-Wydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan7-one in 2 ml of benzene is 0.75 ml a 10 ml solution of 1 ml of benzoyl chloride in benzene and 0.1 ml of pyridine and the mixture was stirred at room temperature for 20 hours, then diluted with benzene and 0.5-n. Hydrochloric acid, dilute aqueous sodium hydrogen carbonate solution and water. The aqueous washing solutions are washed with benzene; the combined benzene solutions are dried and evaporated under reduced pressure.

  The residue is chromatographed on 2.5 g of acid-washed silica gel, washing off non-polar impurities with 60 ml of benzene and 2-benzoyloxy-3,3-dimethyl-6- (N-phenyloxyacetyl with 15 ml of a 9: 1 mixture of benzene and ethyl acetate -amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one of the formula
EMI12.2
 eluted, which is obtained as a slightly yellowish amorphous product; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.60, 5.80, 5.92, 6.26, 6.62, 6.70, 8.28, 8.50, 9.20, 9 , 36 and 10.20.



   Example 7
A solution of 0.14 g of 2-hydroxy-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one in 2 ml of anhydrous benzene becomes 1 ml of acetic anhydride and 0.2 ml of pyridine are added and the mixture is heated at 50 "for 2 hours, then concentrated under reduced pressure.

  The residue is filtered through a column of 10 g of acid-washed silica gel; with 30 ml of a 19: 1 mixture of benzene and ethyl acetate and 10 ml of a 9: 1 mixture of benzene and ethyl acetate, the amorphous 2-acetyloxy-3,3-dimethyl-6- (N-phenylacetylamino) -4-thia - 1-azabicyclo [3,2,0] heptan-one of the formula
EMI12.3
  eluted; Infrared spectrum (in methylene chloride): characteristic bands at 3.06, 5.62, 5.76, 5.98, 6.70, 7.35, 8.28, and 9.60; the product contains about 10% of the 2-position epimeric compound.



   Example 8
A solution of 0.123 g of 2-hydroxy-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1 -azabicyclo [3.2.0] heptan-7-one in 2 ml of anhydrous benzene is mixed with 0 , 1 ml of pyridine and 0.75 ml of a 10 ml solution of 1 ml of benzoyl chloride in benzene are added and the mixture is stirred at room temperature for 16 hours. It is diluted with benzene, the solution is diluted with 0.5-n. Hydrochloric acid, dilute aqueous sodium hydrogen carbonate and water and the aqueous washing liquids extracted with benzene. The organic solutions are combined, dried and concentrated under reduced pressure. The residue is chromatographed on 2.5 g of acid-washed silica gel.

  The 2-benzoyloxy-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1 -azabicyclo [3,2,0] heptan-7-one of the formula
EMI13.1
 is washed out as a yellow oil with 19: 1 and a 9: 1 mixture of benzene and ethyl acetate; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, u 5.60y, 5.80y, 5.97, a, 6.65, u, 9.18, u, 9.34, u, 9.72 and 10 , 15, u.



   Example 9
A solution of 0.065 g of 2-hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan7-one in 5 ml of benzene is mixed with 0.15 g Lead tetraacetate containing 10% acetic acid treated and the yellow solution illuminated with a high pressure mercury vapor lamp (80 watts) in a water-cooled Pyrex glass jacket. After 10 minutes the yellow color disappears and a partly flaky and white, partly rubbery and yellow precipitate forms. It 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
EMI13.2
 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, 6.62, 6.71, 7.33, 7.67, 8.92, 9 , 24, and 9.82.



   Example 10
A solution of 0.1 g of 2-hydroxy-3, 3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1 -azabicyclo [3.2.0] heptan-7-one in 10 ml of benzene is with 0.24 g of lead tetraacetate, containing 10 8 / c acetic acid, treated and the yellow mixture illuminated at 10 "C with stirring with a high pressure mercury vapor lamp (80 watt) in a water-cooled Pyrex glass jacket. After 20 minutes, no more tetravalent lead compounds can be detected and the reaction mixture is colorless, with a yellowish precipitate having settled on the walls of the vessel.

  It is diluted with benzene, washed with water and dilute aqueous sodium hydrogen carbonate solution and evaporated under reduced pressure at a temperature below 25-309. The amorphous 1-formyl-2- (2-acetyloxy-2-propyl-mercapto) -3- (n-phenylacetyl) is obtained in this way -amino) -azetidin-4-one of the formula
EMI13.3
   Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.56, 5.78, 5.87, 6.69Cl, 7.33Cr, 7.68, 8.57, 8.93 and 9.84, and the like.



      Example 11
A solution of 0.3 g of 2-hydroxy-3, 3-dimethyl-6- (Ncarbo-tert-butyloxy-amino) -4-thia-1 -azabicyclo [3.2.0] heptan-7-one ( Configuration of 6-amino-penicillanic acid) in 125 ml of anhydrous benzene is mixed with 1 g of vacuum-dried lead tetraacetate and 0.09 ml of pyridine and the mixture at about 12-15 "with a high-pressure mercury vapor lamp (Hanau; type Q 81; 80 watts) in one A water-cooled Pyrex glass jacket is illuminated, while it is kept moving by passing an oxygen-free nitrogen atom through it, a white precipitate of lead diacetate is formed; a small amount of a rubbery black product, which very likely contains metallic lead, is deposited on the Pyrex glass jacket and becomes over time Scraped off time.

  After one hour the entire amount of lead tetraacetate is used up; the mixture is filtered, the filtrate washed with dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure. The crude 1-formyl-2x- (2acetyloxy-2-propylmercapto) -3a- (N-carbo-tert-butyloxyamino) -azetidin-4-one of the formula is obtained in this way
EMI14.1
 which is available as an amorphous product and is further processed without cleaning; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, 5.56, 5.88, 6.70, u, 7.33y and 8.70.



   Example 12
A solution of 0.5 g of the hydrate of 2-hydroxy-3,3 dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1 -azabicyclo [3,2.01 heptan-7-one (configuration of 6-aminopenicillanic acid) in 125 ml of anhydrous benzene is treated with 1.15 g of lead tetraacetate (containing 10% acetic acid) and the mixture is illuminated at about 15 "with a high-pressure mercury vapor lamp (80 watts) in a water-cooled Pyrex glass jacket, using a slow current After 141 hours the originally yellow solution becomes colorless, the reaction to potassium iodide starch paper is negative.

  The reaction mixture is filtered, the filtrate is diluted with benzene and washed with water, dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure. The residue contains 1-formyl-2a- (2 acetyloxy-2-propyl-mercapto) -3a- (N-phenyloxyacetylamino) -azetidin-4-one, which is processed further without purification.



   Example 13
A solution of 1 g of the hydrate of 2-hydroxy-3,3dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1 -azabicyclo [3,2,0] heptan-7-one (configuration of the 6- Aminopenicillanic acid) in 125 ml of anhydrous benzene is treated with 0.3 ml of pyridine and 2.6 g of lead tetraacetate dried under reduced pressure; the mixture is illuminated at about 15 'with a high pressure mercury vapor lamp (80 watts) in a water-cooled Pyrex glass jacket, a slow stream of nitrogen washed over pyrrogallol being passed through. After 3 hours the test for potassium iodide starch paper is only weakly positive.

  The mixture is filtered, washed with 100 ml each of a dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure; the crude product contains 1-formyl-2a- (2-acetyloxy-2-propyl-mercapto) -3a- (Nphenyloxyacetyl-amino) -azetidin-4-one, which is processed further without purification.



   Example 14
A solution of 0.5 g of the hydrate of 2-hydroxy-3,3 dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one (configuration of the 6-aminopenicillanic acid) and 2.1 g of lead trabenzoate in 160 ml of anhydrous benzene, through which a stream of oxygen-free nitrogen is passed, is illuminated at 15 with a high-pressure mercury vapor lamp (Hanau Q 81; 70 watts) in a water-cooled Pyrex glass jacket. The originally dark yellow solution becomes colorless after about 12 hours; only a small amount of a flaky precipitate forms, which is filtered off. The filtrate is washed with water, dilute aqueous sodium hydrogen carbonate solution and again with water, dried and evaporated under reduced pressure.

  The residue containing the 1-formyl-2a- (2benzoyloxy-2-propyl-mercapto) -3a- (N-phenyloxyacetylamino) -azetidin-4-one of the formula
EMI14.2
 is processed further without cleaning.



   Example 15
A mixture of 0.12 g of 1-formyl-2- (2-acetyloxy-2propylmercapto) -3- (N-phenyloxy-acetyl-amino) -azetidin-4one in 12 ml of anhydrous benzene is heated to 80 "for 6 hours and then evaporated under reduced pressure.



  1-Formyl-2isopropenylmercapto-3- (N-phenyloxyacetyl-amino) -azetidin4-one of the formula is obtained as a slightly bleached oily product
EMI15.1
 which can be purified by chromatography on acid-washed silica gel and eluting with a 9: 1 mixture of benzene and ethyl acetate. The amorphous product shows the following characteristic bands in the infrared absorption spectrum (in methylene chloride): 3.05, 5.56, 5.88, 6.28, 6.72 and 7.68.



   Example 16
A mixture of 0.075 g of 1-formyl-2- (2-acetyloxy-2propylmercapto) -3- (N-phenylacetyl-amino) -azetidin-4-one and 7.5 ml of anhydrous benzene is refluxed for 62 hours and then evaporated under reduced pressure. The amorphous 1-formyl-2isopropenylmercapto-3- (N-phenylacetyl-amino) -azetidin-4one of the formula is obtained in this way
EMI15.2
 the infrared absorption spectrum (in methylene chloride) shows characteristic bands at 3.05, 5.56, 5.90, 6.70 and 7.70.



   Example 17
The crude product obtainable by the process of Example 13 and containing the 1-formyl-2a- (2-acetyloxy-2propyl-mercapto) -3a- (N-carbo-tert-butyloxy-amino) azetidin-4-one is in 15 ml Dissolved toluene and heated at 90 "for 17 hours in a nitrogen atmosphere. The mixture is evaporated under reduced pressure and the crude 1-formyl-2a-isopropenylmercapto-3ec- (N-carbo-tert-butyloxyamino) -azetidin-4-one is obtained formula
EMI15.3
 as an amorphous product which has the following characteristic bands in the infrared spectrum (in methylene chloride): 3.03, u.



     5.55, 5.85, 6.69 and 7.32.



   Example 18
A solution of the crude 1-formyl-2a- (2-acetyloxy-2-propyl mercapto) -3a- (N-phenyloxyacetyl-amino) -azetidin-4-one obtainable by the method of Example 12 is dissolved in 50 ml of anhydrous benzene ; the solution is kept at 80 "for 17 hours and again evaporated to dryness. In addition to a small amount of 1 -formyl-2a- (2-acetyloxy-2-propylmercapto) -3 a- (N-phenyloxyacetyl-amino) - azetidin-4-one mainly the 1 -formyl-2a-isopropenyl-3a- (N-phenyloxyacetyl-amino) azetidin-4-one; the crude product is processed further without purification.



   Example 19
The crude 1-formyl-2a- (2-acetyloxy-2-propyl-mercapto) -3a- (Nphenyloxyacetyl-amino) -azetidin-4-on¯, which can be obtained by the process of Example 13, is dissolved in 50 tal toluene and used for 16 Maintained at 90 "for hours under a nitrogen atmosphere, then evaporated under reduced pressure. The residue contains the 1-formf l-2a-isopropenylmercapto-3a- (N-phenyloxyacetyl-amino) azetidin-4-one, which is processed further without purification.



   Example 20
A solution of 0.741 g of the residue obtainable by the process of Example 14, containing 1-formyl-2a- (2-benzoyloxy-2-propylmercapto) -3a- (N-phenyloxyacetyl-amino) -azetidin-4-one in 25 ml of toluene heated for 16 hours at 90 ", then cooled and diluted with benzene. The organic solution is washed with dilute aqueous sodium hydrogen carbonate solution and water, dried and evaporated under reduced pressure.



  The 1-formyl-2a-isopropenylmercapto-3a- (N-phenyloxyacetylamino) -azetidin-4-one obtained as residue is processed further without purification.



   Example 21
A solution of 0.35 g of the crude 1-formyl-2a-isopropenylmercapto-3a- (N-phenyloxyacetyl-amino) -azetidin-4-one obtainable by the method of Example 18 in 7.5 ml of tetrahydrofuran is cooled to 150 , diluted with 7.5 ml of methanol and added dropwise over one hour with 1 ml of a 0.1-n. treated with aqueous sodium hydroxide solution. The reaction mixture is stirred for 20 minutes at -15 ", then diluted with 100 ml of methylene chloride and washed with water; the aqueous solution is backwashed with methylene chloride. The combined organic solutions are dried and evaporated under reduced pressure.

  The residue is crystallized from benzene; the 2a-isopropenylmercapto-3a- (N-phenyloxyacetyl-amino) -azetidin-4-one thus obtained melts at 157-158 after recrystallization from a mixture of methylene chloride and ether. The residue from the mother liquors is chromatographed on 5 g of acid-washed silica gel; it is washed with 20 ml of benzene, 60 ml of a 9: 1 mixture of benzene and ethyl acetate and 50 ml of a 4: 1 mixture of benzene and ethyl acetate apolar by-products and with another 50 ml of the same mixture a further amount of 2a-isopropenylmercapto-3a - (N-phenyloxyacetyl-amino) -azetidin-4-ones from; Strongly polar substances are eluted with ethyl acetate.

 

   Example 22
The crude product obtainable by the process of Example 19, containing the 1-formyl-2a-isopropenylmercapto-3a- (N-phenyloxyacetyl-amino) -azetidin-4-one, is dissolved in 45 ml of methylene chloride, with 45 ml of water and 0, Treated 9 ml of concentrated aqueous ammonia and stirred vigorously at room temperature for 5 hours. The aqueous phase is washed twice with 50 ml of methylene chloride each time and the combined organic solutions are dried and evaporated under reduced pressure.

  The residue is recrystallized from a mixture of methylene chloride and ether and gives the pure 2 <x -isopropenylmercapto-3c- (N-phenyloxyacetyl-amino) -azetidin-4-one, F. 157-1609 The semi-crystalline mother liquor is chromatographed on acid-washed silica gel and gives another amount of the desired product.



   Example 23
The crude 1-formyl-2a-isopropenylmercapto-3a- (N-carbo-tert-butyloxy-amino) -azetidin-4-one obtainable by the process of Example 17 is dissolved in 10 ml of methylene chloride, the solution is made with 10 ml Diluted water and treated with 10 drops of concentrated aqueous ammonia. The reaction mixture is stirred vigorously at room temperature for 4 hours and then separated into the two layers; the aqueous phase is washed with methylene chloride and the organic solutions are combined, dried and evaporated. The residue is chromatographed on 15 g of acid-washed silica gel, eluting with chloroform.

  Fewer polar by-products are first eluted in the forerun, then the desired 2xx-isopropenylmercapto-3a- (N-carbo-tert-butyloxy-amino) azetidin-4-one of the formula is obtained
EMI16.1
 which after crystallization from cold ether melts at 141 ° and after sublimation (1281320 / 0.001 mm Hg) at 142-144; [0: iD = - 26 "+ 1" (c = 0.883 in chloroform); Ultraviolet absorption spectrum (in ethanol): ,, = 223 m, u (e = 4840); Infrared absorption spectrum (in methylene chloride):

   characteristic bands at 3.03, 5.63, 5.84, 6.22, 6.67, (7.32, a, 7.57, u, 8.64, u, 9.45, m, and 11.651 u.



   Example 24
A solution of 0.56 g of the crude 1 -formyl-2a-isopropenyl-3a- (N-phenyloxyacetyl-amino) -azetidin-4-one obtainable by the method of Example 20 in 20 ml of methylene chloride is mixed with 20 ml of water and 0 , 45 ml of concentrated aqueous ammonia solution are added and the mixture is stirred vigorously at room temperature for 4 hours. The two layers are separated; the aqueous phase is washed with methylene chloride and the combined organic solutions are dried and evaporated.

  The crystalline residue is dissolved in chloroform and filtered through 4 g of acid-washed silica gel, first an apolar yellow fraction and then, when washed with chloroform, the pure, crystalline 2a-isopropenyl-3a- (N-phenyloxyacetyl-amino) azetidin-4-one is, F. 157-1589 The yellow fraction is chromatographed on 10 g of acid-washed silica gel, washing with chloroform; after non-polar impurities, a further amount of the desired product can be obtained in this way.



   Example 25
A mixture of 0.1 g of 1-formyl-2-isopropenylmercapto-3- (N-phenyloxyacetyl-amino) -azetidin-4-one in 5 ml of ethyl acetate is gen for one hour in the presence of 0.2 g of a 10% Hydrogenated palladium-on-carbon catalyst, then filtered and the filtrate evaporated under reduced pressure. The residue is purified by chromatography on 5 g of acid-washed silica gel and the 1-formyl-2-isopropylmercapto-3- (N-phenyloxyacetylamino) -azetidin-4-one of the formula is eluted
EMI16.2
 with a 4: 1 mixture of benzene and ethyl acetate.



  30% of the product thus obtainable is starting material; the infrared absorption spectrum (in methylene chloride) shows characteristic bands at 3.04, 5.56, 5.89, 6.26, 6.63, 6.72 and 7.67 cm.



   Example 26
A mixture of 0.5 g of a 10% palladium-on-carbon catalyst in 5 ml of ethyl acetate is pre-hydrogenated at 25, 14.3 ml of hydrogen being taken up.



  Then 0.063 g of 1-formyl-2-isopropenyl-mercapto-3 (N-phenylacetyl-amino) -azetidin-4-one in 2 ml of ethyl acetate is added and the mixture is further hydrogenated at 30 for 22 hours. After filtering and evaporating the solvent, the residue is chromatographed on 5 g of acid-washed silica gel.

  It is eluted with 10 ml of benzene and 10 ml of a 4: 1 mixture of benzene and ethyl acetate and by-products are obtained with a further 15 ml of the mixture of 1-formyl-2-isopropylmercapto-3- (N-phenylacetylamino) -azetidin-4-one the formula
EMI16.3
 as a colorless oil showing characteristic bands at 3.04, 5.56, 5.92, 6.18, 7.24 and 7.68 in the infrared absorption spectrum (in methylene chloride).



   Example 27
A solution of 0.051 g of 1-formyl-2- (2-acetyloxy-2propylmercapto) -3- (N-phenyloxyacetyl-amino) -azetidin-4one in 3 ml of anhydrous benzene is treated with 0.13 g of tristriphenylphosphine rhodium chloride and during 3 Boiled under reflux for hours. The initially red solution turns brown, with a small amount of precipitate forming. After cooling, this is filtered off and the filtrate is 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 absorption spectrum. A small amount of the l-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
EMI17.1
 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 treated with a 1: 1 mixture of
20 Benzene and ethyl acetate eluted, m.p. 156-158 "; [a] l D = -70" # 2 (c = 0.665 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.07, 5.65, 5.96, 6.29, 6.59, 6.74, 8.19, 9.25 and 9.92S>.



   Example 28
A solution of 0.08 g of 2a-isopropenylmercapto-3a- (Nphenyloxyacetyl-amino) -azetidin-4-one in 10 ml of ethyl acetate is for 45 minutes in the presence of 0.1 g of a 10% palladium-on-carbon Stirred catalyst in a hydrogen atmosphere; the absorption of hydrogen stops after about 25 minutes. The reaction mixture is filtered and the filtrate is evaporated.

  The crystalline residue is recrystallized from a mixture of methylene chloride and ether; the 2a-isopropylmercapto-3a- (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula which can be obtained in this way
EMI17.2
 melts at 128-130 and 143 "(double melting point); infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05Xt, 5.63, 5.93, 6.26, 6.58, 6.70, 8.15, 9 , 21 and 9.41.



   Example 29
A solution of 0.05 g of 2a-isopropenylmercapto-3a- (Ncarbo-tert-butyloxy-amino) -azetidin-4-one in 0.5 ml of cold trifluoroacetic acid is kept at 0 "for 15 minutes; the solution is slightly discolored yellowish and is then diluted with a solution of 1 g of crystalline sodium acetate in 2 ml of water, extracted three times with 10 ml of methylene chloride each time; the combined organic extracts are dried and evaporated under reduced pressure; the acetic acid is removed at 0.001 mm Hg.

  4,4-Dimethyl-azetidino [3,2-d] thiazolidin-2-one of the formula is obtained in this way as a colorless oil
EMI17.3
 that crystallizes on addition of benzene and after recrystallization
20size from benzene melts at 115-117; [aj D = +8 +1 (c = 0.845 in chloroform); Thin layer chromatography (silica gel; system: 1: 1 mixture of benzene and ethyl acetate): Rf = 0.13; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.68 (potassium bromide) and 5.78.



   Example 30
A solution of 0.15 g of 4,4-dimethyl-azetidino [3,2-d] thiazolidin-2-one in 10 ml of dry tetrahydrofuran (freshly filtered through a column with aluminum oxide, activity I) is cooled to 0. Phosgene is passed through the cold solution for 5 minutes and the reaction mixture is stirred for a further 30 minutes with exclusion of atmospheric moisture; the initially appearing precipitate dissolves again. It is then evaporated and the residue is chromatographed on 3 g of acid-washed silica gel. The desired 3-chlorocarbonyl-4,4-dimethyl-azetidino [3,2-d] thiazolidin-2-one of the formula
EMI17.4
 is eluted with benzene and a 9: 1 mixture of benzene and ethyl acetate and crystallizes spontaneously.

  It is recrystallized from a mixture of benzene and hexane and melts at 178-180 (conversion at 140-160; infrared absorption spectrum (in methylene chloride): characteristic bands at 3.04, u, 5.62, u, 5.74, u, 7.48, u, 8.28, u and 11.84.



   A solution of 0.1 h of 3-chlorocarbonyl-4,4-dimethyl-azetidino [3,2-d] thiazolidin-2-one in 10 ml of tert-butanol is mixed with 0.2 g of calcium carbonate and for 2+ days at 90 "bath temperature and with stirring in a closed vessel. After cooling, the mixture is filtered, the residue is washed with benzene and the filtrate is evaporated under reduced pressure. The residue is taken up in benzene; the organic solution is washed with water and dried The residue is redissolved in benzene and chromatographed on 1 g of acid-washed silica gel.

  With 9: 1 and 4: 1 mixtures of benzene and Es, ethyl acetate, the 3-carbo-tert. butyloxy-4,4-dimethyl-azetidino [3,2-dl thiazolidin-2-one of the formula
EMI18.1
 eluted and recrystallized from a mixture of ether and pentane, F. 1 17-120 "(analytical preparation: 120.5); [a] 20 = -274" (c = 0.522 in chloroform); Thin film
D chromatogram (silica gel; system 1: 1 mixture of benzene and ethyl acetate): Rf = 0.15; Infrared absorption spectrum (in methylene chloride): characteristic bands at 2.95, 5.62, 5.90, 7.25, 7.35, 7.75, 8.65, 9.36, 10.60, 11.65 and 12 , 30.



   Example 31
A solution of 0.18 g of 2-hydroxy-3,3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan7-one hydrate in 5 ml of tetrahydrofuran is at 00 mixed with 0.3 ml of a solution of 0.38 g of sodium borohydride in 5 ml of water. The mixture is stirred at 0 for 20 minutes, then adjusted to pH X 4 by adding 12 drops of acetic acid and diluted with 50 ml of methylene chloride. The organic solution is washed twice with saturated aqueous sodium chloride solution, the aqueous washing liquids are backwashed with methylene chloride and the combined organic solutions are dried and evaporated under reduced pressure.

  The crystalline residue is recrystallized from a mixture of methylene chloride and ether, the 2- (2-hydroxymethyl-2propylmercapto) -3- (N-phenyloxyacetyl-amino) -azetidin-4one of the formula
EMI18.2
 obtained after repeated recrystallization in needles, F. 156-157 "; [a] 20 = +130" + 1 "(c = 0.708
D in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03Cl, 5.65CL, 5.94, 6.26, 6.58, 6.70, 8.15, 8.27 and 9.43y.



   Example 32
A solution of 0.3 g of 2-hydroxy-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1-azabicyclo [3.2.0] heptan-7-one in 8 ml of tetrahydrofuran is at 00 treated with 0.5 ml of a solution of 0.38 g of sodium borohydride in 5 ml of water. The reaction mixture is stirred at 0 for 20 minutes, then acidified with 20 drops of acetic acid and diluted with 50 ml of methylene chloride. The organic solution is washed with a saturated aqueous sodium chloride solution, dried and evaporated.

  After crystallization from benzene, the residue gives 2- (2-hydroxymethyl-2-propylmercapto) -3- (N-phenylacetyl-amino) -azetidin-4-one of the formula
EMI18.3
 that melts at 120-133; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 3.15, 5.65, 6.00, 6.65, 7.45 and 9.45, and the like.



   Example 33
A solution of 0.08 g of 2-hydroxy-3, 3-dimethyl-6- (Ncarbo-tert-butyloxy-amino) -4-thia-1 -azabicyclo [3.2.0] heptan-7-one ( Configuration of 6-amino-penicillanic acid) in 5 ml of tetrahydrofuran is added at 0 0 with 0.13 ml of a solution of 0.38 g of sodium borohydride in 5 ml of water. The reaction mixture is stirred for 20 minutes at room temperature, then acidified with 5 drops of acetic acid and diluted with methylene chloride. The organic phase is washed with a saturated aqueous common salt solution, dried and evaporated under reduced pressure.

  The residue is chromatographed on 0.5 g of acid-washed silica gel, washing off apolar by-products with 5 ml of benzene and 9: 1 and 4: 1 mixtures of benzene and ethyl acetate, and with 10 ml of a 1: 1 mixture of benzene and ethyl acetate and 5 ml of ethyl acetate, the armophe 2a- (2-hydroxymethyl-2propylmercapto) -3a- (N-carbo-tert-butyloxy-amino) azetidin-4-one of the formula
EMI18.4
 eluted; Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.63, 5.83, 6.63, 7.31, 8.60 and 9.43, ee.

 

   Example 34
A solution of 0.05 g of 2- (2-hydroxymethyl-2propylmercapto) -3- (N-phenyloxyacetyl-amino) -azetidin-4on in a mixture of 0.5 ml of acetic anhydride and 0.1 ml of pyridine is at Left to stand at room temperature. The vaporizable components are then distilled off under an oil pump vacuum; after adding a few ml of toluene, it is distilled off again.

  The 2- (2-acetyloxymethyl-2-propyl mercapto) -3- (N-phenyloxyacetylamino) -azetidin-4-one of the formula obtained as a crystalline residue
EMI19.1
 is recrystallized from a mixture of methylene chloride and ether, F.122; [α] D 20 = -38 * 1 0 (c = 0.988 in
D chloroform): infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.64, 5.77, 5.93, 6.26, 6.58, 6.71, 7.27 and 8.15.



   Example 35
A solution of 0.056 g of 2a- (2-hydroxymethyl-2 propylmercapto) -3x- (N-phenyloxyacetyl-amino) -azetidin-4one in 1 ml of tetrahydrofuran is diluted to one volume with 0.2 ml of a solution of 2 ml of ethyl chloroformate of 10 ml with tetrahydrofuran, and treated with 0.1 ml of pyridine, while stirring at room temperature. A gummy precipitate forms immediately, which solidifies in the course of the reaction. After 4 hours, it is diluted with methylene chloride, washed with water, dried and evaporated under reduced pressure.

  The 2a- (2-ethoxycarbonyloxymethyl-2-propylmercapto) -3a- (N-phenyloxyacetylamino) -azetidin-4-one of the formula is obtained in this way
EMI19.2
 which melts after recrystallization from a mixture of methylene chloride and ether at 103-105; [α] 20 chloride and ether melt at 103-1050; D D0 = 110 + 1 (c = 1.133 in chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.05, 5.63, 5.75, 5.94, 6.27, 6.60, 6.72, 8.18 / c and 9.88.



   Example 36
A solution of 0.4 g of 2a- (2-hydroxymethyl-2 propylmercapto) -3a- (N-phenyloxyacetyl-amino) -azetidin-4-one and 0.52 g of 2,2,2-trichloroethoxycarbonyl chloride in 6 ml dry tetrahydrofuran is slowly mixed with a solution of 0.6 ml of pyridine in 4 ml of dry tetrahydrofuran with stirring and at 0. After the addition has ended, the mixture is stirred for 3 hours, then diluted with 100 ml of methylene chloride; the organic solution is washed with water, dried and evaporated. The residue is chromatographed on 40 g of acid-washed silica gel. With benzene and 9: 1 and 4: 1 mixtures of benzene and ethyl acetate, by-products, mainly bis-2,2,2 trichloroethyl carbonate, are washed out.

  The 2a- [2- (2,2,2 trichloroethoxy-carbonyloxymethyl) -2-propylmercapto] -3a- (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula
EMI19.3
 is eluted with a 1: 1 mixture of benzene and ethyl acetate and recrystallized from a mixture of ether and pentane, mp 93950; [a] 20 = 6 ¯1 (c = 1.17 in
D chloroform); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3.03, 5.63, 5.68, 5.92, 6.26, 6.69, 6.70, 7.25 and 8.08.



   Example 37
A solution of 0.02 g of 2- (2-hydroxymethyl-2propylmercapto) -3- (N-phenyloxyacetyl-amino) -azetidin-4on in a mixture of 0.2 ml of acetic anhydride and 0.05 ml of pyridine is for 5¸ hours heated at 70 "under anhydrous conditions. The solvents are evaporated at a pressure of 1 mm Hg; the residue is dissolved in toluene and the solvent is again evaporated under reduced pressure.

  The 1 -acetyl-2- (2-acetyloxymethyl-2-propylmercapto) -3- (N-phenyloxyacetyl-amino) -azetidin-4-one of the formula is obtained
EMI20.1
 as a colorless amorphous residue: Ruf = 0.55 (silica gel plates: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3, () 5, tt, 5.58, 5.77x, 5.84, 5.92, 6.27, 6.62, 6.72, zu and 7.29set .



   PATENT CLAIM 1
Process for the preparation of 2-hydroxy-3,3-dimethyl-6-N-Ac-amino-4-thia-1-azabicyclo [3,2,01 heptan-7-ones of the formula
EMI20.2
 in which Ac is the acyl radical of an organic carboxylic acid AcOH, in which functional groups which may be present and which are reactive under the reaction conditions are protected, characterized in that a compound of the formula
EMI20.3
    wherein Ro represents a 2-halo-lower alkyl radical, wherein
Halogen has an atomic weight of over 19, with one
Treated reducing agent in the presence of water.



   SUBCLAIMS
1. The method according to claim I, characterized in that starting materials are used in which the halogen atom in a 2-halo-lower alkyl radical Ro is a chlorine,
Is bromine or iodine atom.



   2. The method according to claim I, characterized in that starting materials are used in which R is a
Represents 2-polychloro-lower alkyl radical.



   3. The method according to claim 1, characterized in that starting materials are used in which the radical R is the 2,2,2-trichloroethyl radical.



     A. The method according to claim l, characterized in that nascent hydrogen is used as the reducing agent.



   5. The method according to claim 1, characterized in that the starting materials are treated with nascent hydrogen, obtained by the action of metals, metal alloys or amalgams on hydrogen-releasing agents, in the presence of water.



   6. The method according to claim 1, characterized in that the starting materials are treated with nascent hydrogen, obtained by the action of zinc, zinc alloys or zinc amalgam on acids or alcohols, with the addition of water.



   7. The method according to claim 1, characterized in that the starting materials with zinc and acetic acid, with the addition of water. treated.



   8. The method according to claim 1, characterized in that the starting materials are treated with alkali metal amalgams or aluminum amalgams and moist solvents. according to patent application 1, thereby marked
9. Method net that the starting materials with chromium II compounds, in the presence of aqueous media. treated.



   10. The method according to claim 1, characterized in that starting materials are used in the form of raw reaction mixtures obtainable under the reaction conditions.



   11. The method according to claim 1, characterized in that an isomer mixture obtained is separated into the individual isomers.



   12. The method according to claim I or one of the dependent claims 1-11, characterized in that compounds of the formula
EMI20.4
 where Ac 'denotes a carbo-lower alkoxy group or the acyl radical of a pharmacologically active 6-N-acylamino-penicillanic acid or 7-N-acylamino-cephalosporanic acid, in which any functional groups which are reactive under the reaction conditions are protected. manufactures.

 

   13. The method according to claim 1, or one of the dependent claims 1-11, characterized in that 2 hydroxy-3, 3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia1-azabicyclo [3.2.0 ] heptan-7-one produces.



   14. The method according to claim I or one of the dependent claims 1-11, characterized in that 2

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



   

 

Claims (1)

** WARNING ** Beginning of CLMS field could overlap end of DESC **. EMI20.1 as a colorless amorphous residue: Ruf = 0.55 (silica gel plates: ethyl acetate); Infrared absorption spectrum (in methylene chloride): characteristic bands at 3, () 5, tt, 5.58, 5.77x, 5.84, 5.92, 6.27, 6.62, 6.72, zu and 7.29set . PATENT CLAIM 1 Process for the preparation of 2-hydroxy-3,3-dimethyl-6-N-Ac-amino-4-thia-1-azabicyclo [3,2,01 heptan-7-ones of the formula EMI20.2 in which Ac is the acyl radical of an organic carboxylic acid AcOH, in which functional groups which may be present and which are reactive under the reaction conditions are protected, characterized in that a compound of the formula EMI20.3 wherein Ro represents a 2-halo-lower alkyl radical, wherein Halogen has an atomic weight of over 19, with one Treated reducing agent in the presence of water. SUBCLAIMS 1. The method according to claim I, characterized in that starting materials are used in which the halogen atom in a 2-halo-lower alkyl radical Ro is a chlorine, Is bromine or iodine atom. 2. The method according to claim I, characterized in that starting materials are used in which R is a Represents 2-polychloro-lower alkyl radical. 3. The method according to claim 1, characterized in that starting materials are used in which the radical R is the 2,2,2-trichloroethyl radical. A. The method according to claim l, characterized in that nascent hydrogen is used as the reducing agent. 5. The method according to claim 1, characterized in that the starting materials are treated with nascent hydrogen, obtained by the action of metals, metal alloys or amalgams on hydrogen-releasing agents, in the presence of water. 6. The method according to claim 1, characterized in that the starting materials are treated with nascent hydrogen, obtained by the action of zinc, zinc alloys or zinc amalgam on acids or alcohols, with the addition of water. 7. The method according to claim 1, characterized in that the starting materials with zinc and acetic acid, with the addition of water. treated. 8. The method according to claim 1, characterized in that the starting materials are treated with alkali metal amalgams or aluminum amalgams and moist solvents. according to patent application 1, thereby marked 9. Method net that the starting materials with chromium II compounds, in the presence of aqueous media. treated. 10. The method according to claim 1, characterized in that starting materials are used in the form of raw reaction mixtures obtainable under the reaction conditions. 11. The method according to claim 1, characterized in that an isomer mixture obtained is separated into the individual isomers. 12. The method according to claim I or one of the dependent claims 1-11, characterized in that compounds of the formula EMI20.4 where Ac 'denotes a carbo-lower alkoxy group or the acyl radical of a pharmacologically active 6-N-acylamino-penicillanic acid or 7-N-acylamino-cephalosporanic acid, in which any functional groups which are reactive under the reaction conditions are protected. manufactures. 13. The method according to claim 1, or one of the dependent claims 1-11, characterized in that 2 hydroxy-3, 3-dimethyl-6- (N-phenyloxyacetyl-amino) -4-thia1-azabicyclo [3.2.0 ] heptan-7-one produces. 14. The method according to claim I or one of the dependent claims 1-11, characterized in that 2 Hydroxy-3,3-dimethyl-6- (N-phenylacetyl-amino) -4-thia-1 azabicyclo [3,2,0] heptan-7-one. 15. The method according to claim I or one of the dependent claims 1-11, characterized in that 2 hydroxy-3,3-dimethyl-6- (N-carbo-tert.-butyloxy-amino) -4 thia-1-azabicyclo [ 3,2,0] heptan-7-one. PATENT CLAIM II Use of a compound of the formula I obtained by the process of claim I for the preparation of a compound of the formula 1 in which the hydroxyl group is esterified in the 2-position, characterized in that in a compound of the formula I obtained, the hydroxyl group in the 2-position acylated.