IE60388B1 - Process for the manufacture of optically active acyloxyazetidinones - Google Patents

Abstract

(4R)-3,4-trans-disubstituted azetidinones of the formula <IMAGE> in which R1 denotes hydrogen or lower alkyl, R2 denotes hydrogen or a hydroxyl-protecting group R, R3 denotes phenyl, substituted phenyl or lower alkyl and R4 denotes hydrogen or an amino-protecting group R, are valuable intermediates for the preparation of optically active penem or carbapenem compounds which act as antibiotics. The processes comprise the ring closure between carbon atoms 3 and 4 of the azetidinone ring.

Description

Process for the manufacture of optically active acyloxvazetidinones The present invention relates to a process for the manufacture of (4R)~3,4-trans-disubstituted azetidinones of the formula Ri- (I) in which Rj is hydrogen or Ch~C4alkyl, R2 is hydrogen or a hydroxy-protecting group R^, R3 is phenyl, phenyl that is mono- to tri~substituted hy C^-C^alkoxy, C1-=C4alkyl and/or by halogen, or is 4-nitrophenyl and R4 is hydrogen or an amino-protecting group Rjl, and to the novel compounds of the formula Ϊ in which Rj, R2, R3 and R4 have the meanings indicated.

The general definitions used within the ambit of this invention preferably have the following meanings: The term lower88 used in connection with groups or radicals, for example lower alkyl, lower alkoxy, lower alkanoyl etc, , denotes that the groups or radicals so designated, unless expressly defined otherwise, contain up to and including 7, preferably up to and including 4, carbon atoms.

Cj-C^alkyl Ri is preferably methyl, also ethyl, npropyl? isopropyl? n-butyl? isobutyl or tert-butyl. is preferably methyl or also hydrogen.

R2 i® preferably hydrogen.

Hydroxy-protecting groups R2an<^ their introduction and removal are described, for example, in Protective Groups in Organic Chemistry, Plenum Press, London and New York 1973? and in Protective Groups in Organic Chemistry? Wiley, New York 1974.

A hydroxy-protecting group is, for example, the acyl group of a substituted carboxylic or sulphonic acid, for example lower alkanoyl substituted by halogen, such as fluorine or chlorine, for example 2,2-dichloro- or 2.2.2- trifluoro-acetyl, the acyl group of a lower alkylor lower alkenyl-carbonic acid semiester that is unsubstituted or substituted, for example, by halogen, for example chlorine, phenyl or by p-nitrophenyl, for example 2.2.2- trichloroethoxycarbonyl, allyloxvcarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, aroyl, such as benzoyl? that is unsubstituted or substituted, for example? by nitro, halogen or lower alkoxy, for example 4-nitro-? 3,5-dinitro-? 4-chloro- or 4-methoxy-benzoyl, lower alkanesulphonyl, such as methanesulphonyl, arylsulphonyl? such as toluenesulphonyl, 2* oxa- or 2-thiacycloalkyl having from 5 to 7 ring atoms, for example 2tetrahydrofuryl or 2-tetrahydropyranyl or a thia analogue thereof, 1-lower alkoxy-lower alkyl, for example methoxymethyl or 1-ethoxyethyl, or a silyl group trisubstituted by lower alkyl, aryl-lower alkyl and/or aryloxy.

R2 is preferably the substituted acyl group of a carbonic acid semiester, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonvl or pnitrobensyloxyearbonyl, benzoyl mono- or di-substituted by nitro, for example 4-nitro- or 3,5-dinitro-benzoyl, or a silyl group substituted by the groups mentioned, for example tri-lower alkylsilyl, such as trimethyl- or triethy1-siXyX, di-lower alkyl-tri-lower alkyImethy1silyl, for example dimethyl- or diethyl-(2-efchyX-2~ propyl)silyl, dimethyl-(tert-butyl)silyl or dimethyl(2,3-dimethyXbut-2-yl) silyl , diaryl- (lower alkyl) silyl, for example diphenyl-(tert-butyl)silyl, aryl-(di-lower alkyl)silyl, for example tert-buty1-methy1-phenyIsilvl, and tri-lower alkylaryloxy-(di-lower alkyl)silyl, for example 2,4,6-tri-(tert-butyl)phenoxy(dimethyl)silyl.

Especially preferred protecting groups R2are» because they are particularly easy to remove, 2,2,2trichloroethoxycarbonyl, allyloxycarbonyl and 3,5dinitrobenzoyl.

Substituted phenyl R3 is mono- to tri-substituted by C1-C4alkoxy, for example methoxy, Ch-Chalky1, for example methyl, and/or by halogen, for example chlorine, for example 4-methoxy- or 4-n.itro-phenyX, 2-, 3- or 4-chlorophenyl or 4-tolyl. R3 is preferably phenyl.

An amino-protecting group R| is preferably arylmethyl or aryl that can be removed by oxidation, aryl preferably being phenyl substituted by one or more, for example two, lower alkoxy groups, for example methoxy, and being especially 4-methoxybenzyl or 2,4-dimethoxybenzyl or 4-methoxyphenyl or 3,4-dimethoxyphenyl.

Tha invention relates preferably to compounds of the formula Ϊ in which Ri is hydrogen or methyl, R2 ^-s hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl or 3,5-dinitrobenzoyl, R3 is phenyl and R4 is hydrogen or p-methoxyphenyl.

House, Modern Synthetic Reactions, 2nd Ed., pages 321-328; Hontury, M., et al., Tetrahedron 33, 2819-2824 (1977); and Momose, T., et al., Chem. Pharmac. Bull, 26, 2589-2593 (1978) demonstrate that acetyl- or benzoylsubstituted cyclic compounds undergo a Baver-Villiger reaction when treated with per acids, whereas in the case of acetyl-substituted starting compounds the acetoxysubstituted products are always obtained, those references indicate that, in the case of benzoyl-substituted cycles having four ring members, a reaction to form the phenyloxycarbonyl product is to be expected. In contrast to that result,» benzoyloxy-substituted cycles having four ring members are formed in the case of the process according to the invention.

The process according to the invention is characterised in that a compound of the formula (II), in which Rj, R2, ^3 R4 have the meanings mentioned under formula I, is subjected to a Bayer-Villiger reaction by treatment with a per acid, and, if desired, in an obtainable compound of the formula I in which R2 is hydrogen the free hydroxy group is converted Into a protected hydroxy group OR2 and/or, if desired, in an obtainable compound of the formula I the hydroxy-protecting group R2 and/or the amino-protecting group R| are (is) removed.

Preferably, in a starting material of the formula II, Ηχ is hydrogen or methyl, R2 is hydrogen or one of the mentioned hydroxy-protecting groups R£, such as 2f2,2-trichloroethoxycarbonvl, allyloxycarbonyl, 3,5dinitrobenzoyl, dimethyl-tert-butylsilyl or dimethvl-2,2dimethylbut-2-ylsilyl, R4 is hydrogen or an aminoprotecting group R4, especially p-methoxyphenyl, and R3 is phenyl.

Organic per acids, inorganic per acids or iminopercarboxylic acids or salts thereof, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, can be used in the reaction, for example unsubstituted or halogenated lower alkanepercarboxylic acids, such as peracetic acid or trifluoroperaeetic acid, aromatic per acids that are unsubstituted or mono- or di-substituted by nitro and/or halogen, such as perbensoic acid, p-nitroperbensoic acid, m-chloroperbensoic acid, 3,5-dinitroperbenzoic acid, monoperphthalic acid or a salt thereof, for example magnesium monoperphthalate, peroxosulphuric acids, for example peroxosulphuric acid, or trihaloiminoperacefcic acids, for example trichloro- or tri-fluoro-iminoperacetic acid. Peracetic acid, m-chloroperbensoic acid and monoperphthaiic acid are preferred.

The per acids can also be formed in situ, for example from the corresponding acid or an acidic salt thereof and hydrogen peroxide. The iminopercarboxylic acids especially are customarily manufactured in situ, for example from the corresponding nitriles and hydrogen peroxide, preferably in the presence of a weakly acidic buffer, for example potassium hydrogen phosphate. The reaction takes place in a customary solvent, for example a halogenated hydrocarbon, such as methylene chloride or chloroform, an ester, such as ethyl acetate, a liquid acid, such as glacial acetic acid, or an alcohol, such as a lower alkanol, for example ethanol, at temperatures of from approximately 0* to approximately 100 "C, where appropriate in an inert gas atmosphere, and, where appropriatef under pressure, for example at approximately up to 10 bar.

The hydroxy-protecting group R-) can be introduced in a manner known per se. for example by reacting a compound of the formula X in which is hydrogen and R4 is preferably an amino-protecting group Ra with a reactive derivative of an acid whose acyl group is the hydroxy-protecting group, for example by reaction with an anhydride, for example trifluoroacetic acid anhydride, a mixed anhydride, for example an acid halide, for example 2,2-dichloroacetyl chloride, a mixed anhydride of a carbonic acid semiester, for example 2,2,2trichloroethyl-, allyl-, phenyl- or p-nitrophenylchloroformate, by reaction with 1,2-dihvdrofuran or 1,2dihydropyran in the presence of an acid, for example ptoluenesulphonic acid, or by reaction with a halosilane, for example a tri-lower alkylhalosilane, such as trimethylchloro- or dimathyl-tert-butylchloro-silane.

In an obtainable compound of the formula I, the removal of the protecting group R£ is carried out in a manner known oer se, for example by solvolysis, for example acidolysis, reduction or oxidation.

The acyl group R2 can be hydrolysed under acidic or alkaline conditions, depending on the meaning of R£, for example with acids, such as formic or trifluoroacetic acid, or with bases, such as an alkali metal hydroxide or carbonate, for example sodium bicarbonate, a bicyclic amidine, such as l,5-diazabicyclo[5.4.0]undec-5-ene, or an alkali metal halide. A 2-oxa- or 2-thia-cycloalkyl group is removed in th® presence of acids.

Halo-lower alkoxycarbonyl, and benzyloxycarbonyl Rj> that is unsubstituted or substituted by nitro can be removed and replaced by hydrogen by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a suitable hydrogenation catalyst, for example platinum oxide or palladium, or by treatment with chemical reducing agents, such as zinc in the presence of aqueous acetic acid.

The silyl group R2 substituted as indicated can be removed in the presence of solvents containing hydroxy groups under neutral, acidic or alkaline conditions, or especially by treatment with a salt of hydrofluoric acid that yields fluoride anions, such as with an alkali metal fluoride, for example sodium fluoride, where appropriate in the presence of a macrocyclic polyether (’’crown ether'8) L, or with the fluoride of an organic quaternary base, such as tetra-lower alkylaxnmonium fluoride, for example tetrabutylammonium fluoride.

The conversion of the lower alkenyloxvcarbonyloxy group -OR-S into hydroxy, lower alkenyl being especially allyl, is preferably carried out with an acceptor of lower alkenyl groups in the presence of tetrakis-triphenylphosphine-palladium and, where appropriate, in the presence of triphenylphosphine. Suitable acceptors of lower alkenyl groups, such as, especially, the allyl 2Q group, are, for example, amines, such as, especially, sterically hindered amines, for example tert-butylamine, also tri-lower alkvlamines, for example triethylamine, morpholine or thiomorpholine, aliphatic or cycloaliphatic /3-dicarbonyl compounds, for example acetylacetone, ethyl ?5 acetoacetate or dimedone, also lower alkanecarboxylic acids, for example acetic acid or propionic acid, A preferred acceptor is dimedone. The reaction is carried out with from 1.5 to 10 molar equivalents of the acceptor of lower alkenyl groups in the presence of from 2 to 10 jq mol%, especially from 5 to 8 mol% (based on the starting compound of the formula Ϊ) of tetrakis-tripheny1phosphine-palladium catalyst, optionally in the presence of up to 50 mol% of triphenylphosphine in an inert solvent, such as an ether, for example dioxan or 5 especially tetrahydrofuran, a halogenated hydrocarbon, for example methylene chloride, a lower alkanol, for example ethanol, an ester, for example ethyl acetate, or in a mixture thereof at room temperature or at slightly elevated or reduced temperature, for example at from approximately 0’ to approximately 40 °C, preferably at from approximately 20° to approximately 25°C, if necessary in an inert gas atmosphere, such as a nitrogen or argon atmosphere.

The arylmethy1 group R|, for example 4-methoxy- or 2.4- dimethoxy-benzyl, is removed, for example, by oxidation, for example by reaction with a strong oxidising agent, for example an inorganic peroxo salt, for example sodium or potassium peroxodisulphate, in the presence of an acidic salt, for example dipotassium hydrogen phosphate, and, where appropriate, in the presence of a catalyst, for example a metal salt, for example an iron(II) and/or copper(II) salt, for example iron(II) sulphate heptahydrate and/or copper(II) acetate hydrate, or especially by reaction with a cerium(IV) salt, for example cerium(IV) iodate, cerium(IV) nitrate (CeOK(NO3)3), cerium(IV) sulphate or preferably with diammonium cerium (IV) hexanitrate,, for example in aqueous-organic media, preferably in aqueous acetonitrile.

The aryl group R^, for example 4-methoxyphenyl or 3.4- dimethoxyphenyl, is preferably removed by oxidation, for example by ozonolysis in ethyl acetate and subsequent decomposition of the resulting ozonides by reduction with a reducing agent, for example sodium thiosulphate, or by reaction with a cerium(IV) salt, for example diammonium cerium(IV) hexanitrate.

R4, irrespective of the meaning of R£, can be removed either selectively or together with R$.

Th® described cleavage reactions are carried out under conditions known per se, if necessary while cooling or heating'and, where appropriate, in an inert gas atmosphere, for example a nitrogen atmosphere.

The present invention relates preferably to a process for the manufacture of compounds of the formula I in which Ri_ is hydrogen or methyl, R2s hydrogen or a hydroxy-protecting group R$, for example the substituted acyl group of a carbonic acid semiester, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, 4-nitro- or 3,5dxnitro-benzoyl, or tri-lower alkylsilyl, for example trimethylsilyl, dimethyl-tert-butylsilyl, or dimethyl™ (2?3-dimefchyIbut-2-yl)"-silyl, R3 is phenyl or methyl and Ra is hydrogen or an amino-protecting group Ri, example 4-methoxybenzyl, 2,4-dimethoxybenzyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl, and in which the l’-carbon atom of the side chain has the R- or S-configuration if Ri represents lower alkyl.

Compounds of the formula I, especially those in which Ri is hydrogen or methyl, r2 is hydrogen or also a hydroxy-protecting group R2 and R4 is hydrogen, are valuable intermediates which can be further processed in a manner known per se to form antibiotically active penem or carbapenem compounds. The further processing is carried out analogously to that of known azetidinone compounds of the formula I in which R3 represents methyl, for example as described by T. Hayashi et al-, Chem.

Pharm. Bull. 29, 3158, 1981, or as described in European Patent Applications Nos. 42026 (for penems) and 78026 (for earbapenems).

The invention also relates to the starting compounds of the formula II, especially those in which Ri, R2, R3 and R4 have the preferred meanings, and to processes for their manufacture.

Preferred are starting compounds of the formula II in which Ri is hydrogen or methyl, R2 is hydrogen or a hydroxy-protecting group R2, R3 is phenyl and R4 is hydrogen or an amino-protecting group R|.

Very preferred is a starting compound of formula II in which Rj is methyl, R2 is hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, tert"butyldimethylsilyl, dimethvl-2,3-dimethy.lbut-2-ylsilyl or 3,5-dinitrobenzoyl, R3 is phenyl and R4 is hydrogen or u-methoxyphenyl.

The process for the manufacture of compounds of the formula II is characterised in that: a) an c-carbanion of a compound of the formula (III) in which Rlr R3 and R4alkyl, especially methyl, the 3-carbon atom has the R- or the S-configuration, or a compound of the formula (IV) , in which Rj, R3 and R| have the meanings mentioned under formula I, R§ is a hydroxy-protecting group that cannot be removed under th© conditions of the cyclisation process and X is a nucleofugal leaving group, and the 2carbon atom has the R-configuration and, if Ηχ is C^-C^alkyl, the 3-carbon atom has the R- or the Sconfiguration, is cyclised, or b) a cis-compound of the formula in which R^, R2, R3 and R4 have the meanings given under formula II, is isomerised, and. if desired, the aminoprotecting group R4 is removed and replaced by hydrogen and/or, if desired, an obtainable compound of the formula II is converted into a different compound of the formula II.

In a starting material of the formula Iv, a hydroxyprotecting group R^ that cannot be removed under the conditions ox the cyclisation process is one of the acyl groups mentioned under R£ of a substituted carboxylic or sulphonic acid, for example 2,2,2-tri-fluoroacetyl, the substituted acyl group of a carbonic acid semiester, for example p-nitrobenzyloxycarbonyl, 2-tetrahydro-furyl or -pyranyl, or 1-lower alkoxy-lower alkyl, for example, methoxymethyl or l-ethoxyethyl, or an unsubstituted or substituted aroyl group, for example a 4-nitrobenzoyl or 3,5-dinitrobenzoyl group, and a suitable nucleofugal leaving group X is, for example, halogen, for example chlorine, bromine or iodine, lower alkanoyloxy, for example acetoxy, arvlsulphonyXoxy, for example phenylsulphonyloxv or tosyloxy, or lower alkylsulphonyloxv, for example mesyloxy.

The c-carbanion of a compound of the formula III or IV is to be understood as being an anion in which the negative charge is on the carbon atom in ©-position with respect to the -CO-R3 group, that is to say a corresponding compound having the partial formula -N-CH®-CO~R3.

Such carbanions are manufactured in situ by treating a compound of the formula III or IV in a suitable solvent with a base that forms such carbanions. Such bases are, for example, alkali metal bases, such as hydroxides or carbonates of sodium, potassium or lithium, or organic alkali metal compounds, for example lower alkyllithium compounds, such as n-butyl- or tert-butyl-lithium, alkali metal amides, for example lithium diisopropylamide or ditert-butylamide, and especially alkali metal amides in which two hydrogen atoms have been replaced by silyl groups, for example trimethylsilyl groups, for example lithium, sodium or potassium bis-(trimethylsilyl)-amide.

Further bases are organic nitrogen bases, for example amidines, such as 1,5-diazabicyclo[4.3.0]non-5ene and 1,5-diazabicyclo[5.4.0]undac-5-ene, and reagents that yield fluoride ions in an aprotic organic solvent and are suitable especially for the manufacture of carbanions of the compounds of the formula III.

A reagent that yields fluoride ions in an aprotic organic solvent is preferably a tetra-lower alkylammonium fluoride, especially tetra-n-butylammoniuxn fluoride.

Suitable solvents for the carbanion formation are, for example, hydrocarbons, such as benzene or toluene, halogenated hydrocarbons, such as methylene chloride or chloroform, ethers, such as dioxan, tetrahydrofuran or dimethoxyethane, amides, such as dimethylformamide or hexamethylphosphoric acid triamide, sulphoxides, such as dimethyl sulphoxide or nitriles, such as acetonitrile, or mixtures thereof. The reaction can also be carried out under phase transfer conditions, for example in the system consisting of methylene chloride and 50% sodium hydroxide solution in the presence of a phase transfer catalyst, such as benzyltriethylammoniura chloride or tetrabutylammonium bisulphate. The reaction temperature also depends on the base used and is approximately from -80’ to 80°C. The operation is preferably carried out under an inert gas atmosphere, for example an argon or nitrogen atmosphere.

During the process, an inversion of the configuration at the 2-carbon atom of the starting material takes place so that a 3S-compound of the formula II is formed from a 2R-compound of the formula III or IV. The configuration of the I-1 -carbon atom (R^ = Ci-C^alkyl) in the side chain remains unaltered. For example, 3S-azetidinones of the formula II are obtained from R-glycidic acid amides of the formula III or (3S-113 R) -3-hydroxyethylazatidinones of the formula II are obtained from (2R,3R)-2,3-epoxybutyric acid amides of the formula III.

The isomerisation process b) takes place in a suitable solvent or solvent mixture in the presence of a base. Suitable solvents and bases and also the reaction conditions are the same as those that may be used for the cyclisation process a) . Aprotic dipolar solvents, such as dimethylformamide, N-methylpyrrolidine, dimethyl sulphoxide or the like,, are preferably used. Suitable bases are especially potassium carbonate or 1,5-diazabicvclo[5.4.0)undec-5~ene, it also being possible to carry out the operation under the mentioned phase transfer conditions.

The cis-compounds of the formula II’ may be formed as secondary products in the cyclisation reaction a).

They can be separated off in customary manner, for example by chromatography.

Compounds of the formula III can be manufactured in a manner known per se by reacting compounds of the formula VII r4n:h-ch2-1-r3 (vii) in which R3 and R^ have the meanings mentioned under formula V with epoxy acids of the formula Η (VIII) or salts thereof in a manner analogous to that indicated below for the reaction of a carboxylic acid of the formula VI with an amine of the formula vu. The epoxy acids of the formula VUI are known or can be manufactured in a manner known per se.

In a preferred embodiment of the process, starting materials of the formula III are manufactured in situ, under the mentioned carfoanion-forming conditions and with Ί θ a Walden inversion at the 2-carbon atom, from compounds of the formula (V) in which R^, R3, Rj, and X have the meanings mentioned, R^8 is hydrogen or a hydroxy-protecting group that can be removed under the conditions of the epoxide formation, and in which the 3-carbon atom has the R- or the Sconfiguration if Ri is Ci-Chalky1.

In a compound of the formula v, a hydroxy-protecting group R®i' that can be removed under the conditions of the epoxide formation is a tri-lower alkylsilyl group, for example dimethyl-tert-butylsily.1 or trimethylsilyl. X is preferably halogen, for example chlorine or bromine, lower alkanesulphonyloxy, for example mesyloxy, or arylsulphonyloxy, for example tosyloxy.

The removal of R^’-X in which R|· is hydrogen is effected using one of the mentioned carfoanion-forming bases, for example sodium or potassium hydroxide or sodium or potassium carbonate, preferably using an amidine, for example 1,5-diazabicyclo[5,4.0)undec~5~ene, or also using a tetra-lower alkylammonium fluoride, for example dehydrated tetra-n-butvlammonium fluoride. If R^" is a tri-lower alkylsilyl group that can be removed under the conditions of the epoxide formation, a tetra-lower alkylammonium fluoride is preferably used.

The reaction to form an epoxy compound of the formula III is preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxylic acid amide, for example dimethyl *formamide, a halogenated hydrocarbon, for example methylene chloride, chloroform, carbon tetrachloride or chlorobenzene, a ketone, for example acetone, a cyclic ether, for example dioxan or tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, where appropriate at reduced or elevated temperature, for example in a temperature range of from approximately -40°C to approximately +100°C, preferably from approximately -10°C to approximately +50'C, and, where appropriate, under an inert gas atmosphere, for example a nitrogen atmosphere.

In the reaction according to this process, the configuration at the 2-carbon atom is reversed, whereas the configuration of the 3-carbon atom (Ri = Cj-G^alkyl) is retained. The (2R,3R) -compounds of the formula III are formed from 2S-halogen-3R-hydroxvcarfooxylic acid amides of the formula V. The same applies to the 2S~halogen-3Shydroxycarboxylic acid amides of the formula .III.

The epoxide of the formula III can also be isolated after its manufacture by removing from a compound of the formula V.

The conversion of a compound of the formula V in which Hl ’ is hydrogen into an epoxy compound of the formula III and the isolation thereof are carried out in a manner known aar se. for example under the reaction conditions known from steroid chemistry, see C Djerassi et al. 'Steroid Reactions", Holden Day, San Francisco 1963, pages 606-613, especially by means of one of the amidines mentioned, such as 1,5-diasabicvclo[5.4.0]undec5-ene. If the compound of the formula III is to be isolated before being further processed, it is preferable to us© one of the amidines mentioned in an approximately equimolar amount.

Compounds of the formula (IV) in which Ηχ is hydrogen or C3-C4alkyl, Rg is a hydroxvprotecting group that cannot be removed under the conditions of the cyclisation process, R3 is phenyl, phenyl that is mono- to tri-sufostituted by Cj -C^,alkoxy, Cx-C4alkyl and/or by halogen, or is 4-nitrophenvl, R£ is an amino-protecting group and X is a nucleofugal leaving group, and the 2-carbon atom has the R-con.figuration and, if Ηχ is Cx~C4alkyl, the 3-carbon atom has the R- or the S-configuration, can be manufactured by reacting a carboxylic acid of the formula OH (VI’) , in which Rj, Rg and X have the meanings mentioned under formula IV? with an amine of the formula o R4NH-CH2-i-R3 (VII) in which R3 and R| have the meanings mentioned under formula V.

Compounds of the formula V can be manufactured, for example, by reacting a carboxylic acid of the formula OR’seH y (2s) ¢/ X0H (VI), in which Ηχ, R§ ’ and X have the meanings mentioned under formula V, with an amine of the formula ff R4NH-CH2-C~R3 (VII) in which R3 and R| have the meanings mentioned under formula V.

The reaction of amines of the formula VII with an acid of the formula VI is carried out in a manner known per se under acylating conditions, for example by condensing the two compounds with one another in the presence of a condensation agent, or by reacting a reactive functional derivative of a carboxylic acid of the formula VI with an amine of the formula VII.

Suitable condensation agents are, for example, diimides, such as diethyl or dicyclohexvl carbodiimide, or di-Nheterocyclyiearbonyl compounds, such as carbonyl18 diimidazole, or a 1,2-oxazolium compound, such as 2ethyl-5-phenyl-X,2-oxazolium 3-sulphonate or 2-tertbutyl-5-methyl-l,2-oxazolium perchlorate, which are used in the presence of an inert solvent at room temperature or slightly reduced or elevated temperature. Reactive functional derivatives of the carboxylic acid (VI) are especially anhydrides, especially mixed anhydrides, such as the corresponding carboxylic acid chloride or bromide, which react, where appropriate in the presence of a base, with the amine of the formula VII.

Compounds of the formula VI and VI5 in which X is halogen are known. They can be manufactured, for example, in a manner known oer se „ from L-serine or L-threonine or their D~isomers by diazotisation of the amino group with a nitrite salt, for example potassium nitrite, in the presence of a hydrohalic acid.

When using L-serine, according to the described processes it is possible, starting from compounds of the formula VI, to obtain compounds of the formula I in which the carbon atom in the 3-position of the azetidinone ring has the R-configuration.

When using L-threonine, compounds of the formula I are obtained in which the carbon atom in the 3-position ox the azetidinone ring has the R-conf iguration and the I5-carbon atom of the hydroxyethyl side chain has the Rconfiguration. If it is intended to manufacture compounds of the formula I in which the 3-carbon atom has the Rconfiguration and the 1’-carbon atom of the hvdroxyethyl side chain has the S-configuration, allothreonine is used as starting material. In all the reactions described, the configuration of the carbon atom that in compounds of the formula I corresponds to the Xs-carbon atom of the 3lower alkyl-CH-(OR2)- side chain remains unaltered.

In a manner analogous to that described for the manufacture of compounds of the formula V, compounds of the formula IV can be manufactured starting from com19 pounds of the formula VIII and compounds of the formula QR-ΐ H .X -f /\n (VI:) · Compounds of the formula VII are known or, if they are novel, can be manufactured in a manner known per ss.

The present invention also relates to those embodiments of the process in which a compound obtainable at any preliminary stage of the process is used as starting material and the subsequent process steps are carried out.

The invention also relates to a combination of the process stages starting from the compounds of the formulae VI, VI', VII and vm to form the compounds of the formula I.

The process according to the invention has the advantage that the compounds of the formula I can be manufactured stereospecifically in a high yield and in an economical manner.

The novel compounds and processes indicated in the Examples are preferred.

The following Examples serve to illustrate the invention. Temperatures are given in degrees Celsius and IR values in cm1. For tha 1H-NMR spectra, the chemical shifts (6) are given in ppm and tha coupling constants J 20 in Hertz (Hz). The specific rotation values [a] are [o]D values. For chromatographic separation in the case of preparative working up, columns filled with Merck silica gel 60 are used. Rf values apply to pre-coated plates for thin layer chromatography (Merck 60 F 254).

Abbreviations: m = medium strength absorption bands sh = sharp absorption bands s = singlet m = multiplet d = doublet m.p. = melting point b.p. - boiling point dd = doublet of doublets AB = signal group of type AB Example 1 : (2S,3R)-2-bromo-3-hydroxybutyric acid N-pmethoxyphenyl-N-phenacylamide .47 g of dicyclohexvl carbodiimide are added to a solution of 13,,73 g of (2S,3R)-2-bromo~3-hydroxybutyric acid and 18,.,08 g of phenacyl-p-anisidine in 70 ml of dry tetrahydrofuran and the whole is stirred under an argon atmosphere for 48 hours at room temperature. The dieyclohexylurea formed during the reaction is filtered off with suction and the filtrate is concentrated by evaporation under a water-jet vacuum. For purification purposes, the amorphous residue is chromatographed over SO times the amount by weight of silica gel using a toluene/ethyl acetate mixture (9s1). The resulting title compound, (NMR spectrum (CDCXj) signals at 1.23 (d) ,. 3 83 (s) , 3.88 (s) # 4.10 (m) , 4.18 (d)t 4.75/4.80/5.31/5.36 (AB) and 6.94 (dd))f can be used directly for the subsequent cyclisation.

Example 2: (2R,3R)-2 ,3-epoxybutyric acid N-p-methoxyphenyl-N’-phenacylamide Under argon at -10°, 165 pi (169 mgj 1.1 mmol) of 1,5-diasabicycloi5.4.0]undec-5-ene are added to a solution of 406 mg (1 mmol) of (2S,3R)-2-bromo-3hydroxybutyric acid N-p-methoxyphenyl-N-phenacylamide in 7 ml of absolute tetrahydrofuran and the resulting reaction mixture is stirred for 5 hours at 0° and for a further 3 hours at room temperature.

For working up# the reaction mixture is diluted with methylene chloride and washed in succession with water, 5% aqueous citric acid solution and 8% aqueous sodium bicarbonate solution. The aqueous portions, are then extracted with methylene chloride. The residue, obtained' by drying and concentrating the combined organic portions by evaporation in vacuo,» is chromatographed over silica gel plates in a toluene/ethyl acetate (1:1) mixture. The title compound is obtained in the form of a viscous oil, R^ (Merck silica gel pre-coated plates, toluene/ethyl acetate 1:1) 0 27; (IR CH^Clj) - inter alia bands at 1700, 1670, 1595, 1580, 1505, 1427, 1392, 1 365, 1348, 1300, 1243, 1221 , 1180, 1 170, 1 140, 1 103, 1028, 982,NMR (CDC13): signals at 1.50 (d) , 3.08 (m) , 3.36 (d) , 3.82 (s) , 4.86 (d) , 5.42 (d) , 6..91 (ra) , 7.34 (ra) , 7.46 (ra) , 7.57 (m) , 7.93 (m) .,.

Example 3_s (3S ,4S, 1 R) N-p-methoxyphenyl-3- (Ishydroxyethyl) -4-berizoylazetidin-2-one a) with lithium bis- (trimethylsilyl) -amide; While stirring under an argon atmosphere, 33 ral of a 0.5 molar solution of lithium bis-(triraethylsilyl)-amide in tetrahydrofuran are added to a solution, cooled to -20°, of 3.37 g of (2S,3R)-2-bromo-3-hydroxybutyric acid N-o-methoxyphenyl-N-phenacylaraide in 20 ral of tetrahvdrofuran and the whole is stirred for a further 1/2 hours while slowly heating to -10°. The reaction mixture is poured onto ice-water and extracted with methylene chloride. The organic phase is washed in succession with Ice-cold IN sulphuric acid, water, ice-cold saturated aqueous sodium bicarbonate solution and with water, dried and concentrated by evaporation in a rotary evaporator. The resulting crude product is chromatographed over silica gel. A toluene/ethyl acetate (9:1) mixture yields (3S,4S,1R)-N-p-methoxyphenyl-3- (1 ’-hydroxyethyl) -4-bensoylazetid'in-2-one which, after being dissolved and recrystallised from methylene chloride/ether, melts at 111-.113°. [c] = -95.1° (c = 1.121% In CHC13). b) with sodium hydroxides While adding 75 mg of benzyltriethylammonium chloride, a mixture of 950 rag of (2S , 3R)-2-bromo~3~hydroxybutyr ic acid N-jo-methoxyphenyl-N-phen.acyl amide in 25 ml of methylene chloride and 8 ml of 50% aqueous sodium hydroxide solution is vigorously stirred for 5 1/2 hours at room tempera5 ture» The sodium hydroxide solution is separated off from the reaction mixture and the organic phase is washed twice with water, dried and concentrated by evaporation under a water-jet vacuum. Subsequent chromatography over silica gel with a toluene/ethyl acetate (9:1) mixture followed by crystallisation of the homogeneous fractions yields the title compound in pure form,. c) with terrabutylammonium fluorides For dehydrating, activated molecular sieves (4 x 10"’ θχη) are added to a solution of 300 mg (0.95 mmol) of tetrabutylammonium fluoride trihydrate in 4 ml of tetrahydrofuran and the whole is left to stand under argon for 18 hours at 0°. ^Jhile stirring at 0°, a solution of 206' rag (0.63 mmol) of (2R,3R)2o 2,3-epoxybutyric acid N-g-methoxyphenyl-Nphenacylamide in 2 ml of absolute tetrahydrofuran is then added dropwise and the reaction mixture is stirred at 0° for a further 2 hours. The molecular sieves are filtered off and washing is carried out on the filter with tetrahydrofuran, the combined filtrates are concentrated by evaporation _in vacuo and the residue, dissolved in methylene chloride, is washed in succession with 1N HjSCh and water. The aqueous portions are then extracted with methylene chloride.

After being dried and concentrated by evaporation in vacuo, the combined organic portions yield a crude product which is chromatographed over silica gel plates with toluene/ethyl acetate (9:1). In this manner, the title compound is obtained having the data described above. d) with potassium carbonate: 55.2 rag of potassium carbonate are added to a solution of 13.0 g of (2Rt, 3R)2,3~epoxybutyric acid N-p-methoxyphenyl-N-phenacylamide in 74 ml of dimethyl sulphoxide and the whole is stirred under an argon atmosphere for β hours at from 21 to 24°„ The reaction mixture is poured onto 1.6 litres of ice-water and stirred for 2 hours. The precipitate is filtered off with suction, washed with water and taken up in methylene chloride. The organic phase is separated from the water, washed with saturated aqueous sodium chloride solution, dried and concentrated by evaporation. The resulting crude product is chromatographed on a silica gel column. Elution with a hexane/ethyl acetate (7s3} mixture yields a small amount of (35, 4R, 1 5R)-N-p-saethoxyphenyl-3- (1’-hydroxyethyl)-4-benzoylazetidin-2-one which xs homogeneous according to chromatography and which, after crystallisation from methylene chloride/diisopropyl ether, melts at 168-170°. Further elution with a hexane/ethyl acetate (Isl) mixture yields (35,45,1eR)-N-p-methoxyphenyi-3-(1’-hydroxyethyl) -4-benzoylazetidin-2-one which is homogeneous according to chromatography and which, after crystallisation from methylene chloride/diisopropyl ether, melts at 111-113°. e) with 1 ,5-diazabicyclo[5.4.0]undec-5-enes In a manner analogous to d), tha same compound is obtained if, under otherwise identical conditions, an equivalent amount of 1,5-diazabicyclo[5.4.OJ-undec-5-ene is used in place of potassium carbonate. f) by isomerising the cis-isomer with The (3S,4R)-xsomer of the title compound produced in small amounts as a by-product during the cyclisation of (2R,3R)-2,3-epoxybutyric acid N-p-methoxyphenyl-Nphenacylamide (Example 3d) can be isomerised to form the title, compound by stirring 3.9 g of this ciscorapound in 80 ml of dimethyl formamide with 6.6 g of potassium carbonate for 2.5 hours at 60° (bath temperature). The inorganic salt is filtered off, the filtrate is concentrated under reduced pressure? the residue is taken up in methylene chloride? the solution so obtained is washed with water and with aqueous sodium chloride solution? dried and concentrated in vacuo? and the residue is chromatographed over a silica gel column. With a hexane/ethyl acetate (2:1) mixture? first a small amount of the (3S?4R)-isomer is. eluted? followed? after elution with a hexane/ethyl acetate (1:1) mixture? by the pure title compound which? after crystallisation from methylene chloride/diisopropyi ether? melts at 111-113°. g) by isomerising the cis-isomer with NaOH; 3.9 g of (3Sr4Rr 1'R)"N"jo-methoxyphenyl-3-(1 hydroxyethyl)-4-benzoylazetidin-2-one (cis-isomer) are stirred for 2 hours at 21° in a two-phase mixture of equal volumes of methylene chloride and IN sodium hydroxide solution and in the presence of 60 mg of tetrabutyl ammonium bisulphate - The sodium hydroxide solution is separated off and the organic phase? after being washed with water? is dried and concentrated by evaporation in vacuo. The residue? containing a (7:3) mixture of the (3S?4S)- and (3S?4R)-compound? is separated into the pure isomers by chromatography over silica gel with toluene/ethyl acetate. After recrystallisation of the fractions that contain the (3S?4S)-compound and have been concentrated by evaporation? the pure title compound is obtained? m.p.111-113°.

Example 4 :, (3R#4R#1 *R)-N-p-methoxyphenyl-3-(1 hydroxyethyl) -4-benzoyloxyazetidin-2-one: 1.27 g of m-chloroperbensoic acid are added to a solution of 415 mg of (3Sf4S# 1 ’Rj-N-p-methoxyphenyl3-(1 5"hydroxyethyl)-4-benzoylasetidinone in 20 ml of methylene chloride and the whole is heated in a Carius tube for 72 hours at 45-50°,,, The reaction mixture is poured onto ice-water and diluted with methylene chloride. The organic phase is washed in succession with potassium iodide/sodium thiosulphate# ice-cold saturated sodium bicarbonate solution and water# dried and concentrated by evaporation in a rotary evaporator. Chromatography over silica gel (eluant: toluene/ethyl acetate 9:1 mixture) yields the pure (3R#4R#1’R)-N-pmethoxvphenyl-3-(1 -hydroxyethyl)-4-benzoyloxyazetidin2~one. IR,. : Bands# inter alia# at 3600# 1765# 1725, 1600, 1515# 1450# 1240# 1180# 1070 and 1025.

NMR.: Signals# inter alia# at 1.42 (d) # 3.38 (d) # 3.7 (ss) 4.30 (m) # 6.52/7.42 (AA'BB’)The same compound is also obtained under analogous conditions using p-nitroperbenzoic acid or with peracetic acid in acetic acid or ethyl acetate as solvent.

Example 5: (3R#4R#1'R)-3- (1,-hydroxyethyl)-4benzoyloxyaaetidin-2-one: A solution of 1.642 g of cerium (IV) ammonium nitrate In 15 ml of water Is added to a solution# cooled to 0°# of 325 mg of (3R#4R# 1 R)-N-£methoxyphenyl-3-(1 hydroxyethyl) -4-benzoyloxyazetidinone in 15 ml of acetonitrile and the whole is stirred for 30 minutes at from -5 to 0°. The reaction mixture is diluted with 200 ml of water and extracted three times with methylene chloride. The organic phases are washed in succession with dilute aqueous sodium bicarbonate solution, 10% sodium sulphite solution, sodium bicarbonate solution and water, dried and concentrated by evaporation. The resulting crude product yields, after filtration through 20 times the amount by weight of silica gel (eluantj toluene/ethyl acetate 8:2) and subsequent crystallisation from chloroform/petroleum ether of the fractions that are homogeneous according to thin-layer chromatography, the pure (3R,4R,1Ή)-3-(1 ’-hydroxyethyl) -4-bensoyloxyazetidin~2-one. M.p. 144.5-146°. (cl » 4-67.5 * 2.4° (c 0.414 %, CHClg) .

Example 6 s (35,4S , 1 *R)-3-(1'-hydroxyethyl)-4benzoylazeticiin-2-one a) A solution of 2.2 g of cerium (IV) ammonium nitrate In 5 ml of water is added to a solution, cooled to -18°, of 325 mg of (3S,4S,1’R)-N-o-methoxyphenyl-3(1 -hydroxyethyl)-4-benzoylazetidin-2-one in 10 ml of acetonitrile and the whole is stirred for 35 minutes at from -16 to -18°. The reaction mixture is poured onto ice-water and extracted three times with ethyl acetate. The organic phases are washed with ice-cold sodium bicarbonate solution, dried and concentrated by evaporation. After recrystallisation of the crude product from methylene chloride/ether, the pure (35,45,1"R)-3-(1'-hydroxyethyl) -4-benzoylasetidin-2-one melting at 132-134° is obtained. b) by isomerisation.of the cis-isomer with 1,5diazabicyelof5.4.0)undec-5-ene; 0.05 ml of 1,5-diasabicyclo[5 „ 4,., G]-undee-5-ene is added to a solution of 660 mg of (35,4R, 1 *R)-3-(1’-hydroxyethyl)-4-benzoylazetidin-2-one in 14 ml of chloroform and the whole is heated for 15 hours at 75°,., The reaction mixture is concentrated by evaporation in vacuo and the residue is chromatographed over a silica gel column. Using hexane/ethyl acetate (1:1)? first a small amount of the (3Se4R)-isomer is eluted followed by the (3S?4S}-isomer which Is crystallised from methylene chloride/diisopropyi ether. M.p. 131-135°.

The (3S? 4R? 19R)~ (1 ' - hydroxyethyl) -4-benzovlazetidin-2-one used as starting material can be manufactured as follows; A solution of 36.3 g of cerium(IV) ammonium nitrate in 150 ml of water is added to a suspension? cooled to -18°, of 9.7 g of (3S?4R?1’R)-N-£methoxyphenyl-3-(1 ’-hydroxyethyl)-4-benzoylazefcidin-2one (cis-isomer from Example 3d)) in 225 ml of acetonitrile and the whole is stirred for 30 minutes at from -15° to -5°. The reaction mixture is diluted with 800 ml of ice-water and extracted three times with 600 ml of ethyl acetate. The organic phases ace washed in succession with 1% sodium sulphite and sodium chloride solution? dried with sodium sulphate and concentrated by evaporation. The resulting crude product? after crystallisation from methylene chloride/diisopropyl ether? yields pure (3S,4R,1’R)-3~ (1'-hydroxyethyl)-4-benzoylazetidin-2-one having a melting point of 145-147°.

Example 7: (3R?4R?1 ' R)-3-(1-hydroxyethyl) -4benaoyloxyazetidin-2-one a) with m-chloroperbenzoic acid: 10.1 g of 85% m-chloroperbensoic acid are added to a solution of 1.9 g of (3S,4S?1'R)-3-(1 '-hydroxyethyl)-4-benzoylazetidinone in 172 ml of methylene chloride and the whole is stirred for 165 minutes at approximately room temperature. The reaction mixture is poured onto icewater and extracted twice with methylene chloride. The organic phases are washed in succession with aqueous potassium iodide/sodium thiosulphate solution and sodium bicarbonate solution and then with water, dried and concentrated by evaporation. Filtration of the resulting crude product in a toluene/ethyl acetate (8:2) mixture over 300 g of silica gel and subsequent crystallisation of the homogeneous fractions from methylene chlor5.de/ether yield pure (3R,4R, ι sR)-3-(1 hydroxyethyl)"4-bensoyloxyasetidin-2"One having a melting point of 145-147°«, The compound is identical with regard to IR and NMR spectra and optical rotation to the preparation described in Example 5. b) with peracetic acids The title compound can also be manufactured by adding 12.2 ml of a 30% peracetic acid solution in acetic acid to 4.27 g of (3S,4S,1’R)3-(1-hydroxyethyl)-4-benzoyl azetid in~2~one in SO ml of methylene chloride and heating the whole under reflux for S hours. The resulting reaction mixture is diluted with methylene chloride and washed in succession with 5% aqueous NaHSO^ solution, 8% aqueous NaHCOj solution and saturated aqueous sodium chloride 2o solution. The aqueous portions are then extracted with methylene chloride and the combined organic portions are dried over NagSO^and concentrated by evaporation. The crystalline crude product is recrystallised directly from methylene chloride/ether and yields the pure title compound having the data described above. c) with magnesium monoperphthalate hexahydrate: A solution of IS.5 g of magnesium monoperphthalate hexahydrate in SO nil of ethanol (96% strength) is added to a solution of 5 g of (3S,4S, 1 sR)-3-(1'-hydroxyethyl) -4-benzoylazetidin-2-one in 200 ml of ethyl acetate and the resulting reaction mixture is stirred for 5 hours at a bath temperature of 50°. A crystalline precipitate forms. Methylene chloride and % aqueous sodium sulphite solution are added to the suspension and the organic phase is then washed with 8% aqueous sodium bicarbonate solution. The aqueous portions are then extracted with methylene chloride, the organic extracts are combined and concentrated by evaporation and the residue is recrystallised from methylene chioride/pentane. The pure title compound having the properties mentioned above is obtained, d) with hydrogen peroxide and trichloroacetonitrilez The title compound can also be manufactured by reacting 11 g of (35,45,1’R)-3-(1 ’-hydroxyethyl)-4-benwylazetid in-2-one with 19 ml of 30 % hydrogen peroxide and 21 ml of trichloroacetonxtrIle in the presence of 10 g of potassium hydrogen phosphate in 200 ml of chloroform analogously to Example 13c).

Example 8 s (35,45,1 8R)-N-p-methoxyphenyl-3-(1 '-(2,2,2trichloroethoxycarbonyloxy)-ethyl] -4-benssoylazetidin-2one; 0.18 ml of triethylamine, 0.18 ml of chloroformic acid 2,2,2-trIchloroethyl ester and 130 mg of dimethylaminopyridine are added under argon to a solution, cooled to 0°, of 325 mg of (35,45,1 9R)-N-jo-mefchoxyphenyl-3- (1 -hydroxyethyl) -4-benzoylasetid in-2-one in 5 ml of methylene chloride and the whole is stirred for 7 hours at the same temperature. The reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed with 5 % aqueous citric acid solution and with ice-cold aqueous sodium bicarbonate solution, dried and concentrated by evaporation. Filtration of the residue over silica gel (toluene/ethyl acetate 9:1) yields the pure (3S, 45,1 eR)-N-j>-methoxyphenyl-3 - (1 ’-(2,2,2trichloroethoxycarbonyloxy)-ethyl)-4-bensoylasetid in-2one in the form of a colourless foam. IR: Bands, inter alia, at 1760, 1690, 1512, 1380, 1240 and 1183 csaj fc] = -9» 5° (c = 0. 980 chloroform), Example 9 s (3S ,4S ,1 R) -3- [1/- (2 ,2 ,2-trichloroethoxycarbonyloxy)-ethyl] -4-benzoylazetidin-2-ones A solution of 965 mg of ceriura(IV) ammonium nitrate in 5 ml of water is added to a solution, cooled to -18°, of 400 mg of (3S, Example 10s (3R,4R,1 9 R)-3-(1 81 - (2 ,2 ,2-trichloroechoxycarbonyloxy)-ethyl] -4-benzoyloxyazetidin-2-one: 683 mg of 85 % ra-chioroperbenzole acid are added to a solution of 230 mg of (3S, 4S, 1 R)-3-[1 (2,2, 2trichloroethoxycarbonyloxy)-ethyl]-4-benzoylazetidinone in 20 ml of methylene chloride and the whole is stirred at room temperature for 3 1/2 hours. The reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed in succession with aqueous potassium iodide/sodium thiosulphate solution, water, ice-cold aqueous sodium bicarbonate solution and water, dried and concentrated by evaporation. The crude product so obtained yields, after filtration over silica gel (toluene and toluene/ethyl acetate 8:2) and subsequent crystallisation of the homogeneous fractions from methylene chloride/ether/petroleum ether, pure (3R,4R, 1 'R)-3-[1 (2,2,2tr ichloroethoxycarbonvloxy) -ethyl] -4-bensoyloxyazetid in2-one having a melting point of 118-120°. ( Example 11 ; (3S,4Sr1'R)-N-p~methoxyphenyl-3-(1-allyloxycarbonyloxyethyl)~4-benzoylazetidin-2-one; 0.18 ml of triethylamine, 0.16 ml of chloroformic acid allyl ester and 130 mg of dimethyl aminopyridine are added under argon to a solution, cooled to 0°, of 325 mg of (3S,4Sf1iR)"N-p-methoxyphenyl-3-(1’" hydroxyethyl)-4-benzoyl azetid inone in 5 ml of methylene chloride and the whole is stirred at the same temperature for 1 hour. After renewed addition of the indicated amounts of triethylamine, chloroformic acid allyl ester and dimethyl aminopyridine, the whole is stirred for a further 17 hours at 0°, then a third portion of the same amounts of the three reagents is added and the whole is stirred for 24 hours at room temperature. The reaction mixture is poured onto icewater and extracted twice with methylene chloride. The organic phases are washed with 5 % aqueous citric acid solution and with ice-cold aqueous sodium bicarbonate solution, dried and concentrated by evaporation. Filtration of the residue over 40 g of silica gel (toluene/ethyl acetate 9s1) yields pure (3S,4S,1’R)-Njo-methoxyphenyl-3~ (1 '-allyloxycarbonyloxyethyl) -4benzoylazetidin-2-one. M.p. 78-80°.

Example 12: (3S,4S,1R)-3-(1 '-allyloxycarbonyloxyethyl)-4-benzoylazetidin-2-one: A solution of 800 mg of cerium(IV) ammonium nitrate in 5 ml of water is added to a solution, cooled to -18°, of 270 mg of (3S,4S,1'R)-N-p-mefchoxyphenyI~ 3- (ϊ '"allyloxycarbonyl oxye thyl) -4~benzoylazetidin-2one in Id ml of acetonitrile and while stirring the whole Is heated over a period of 3 hours to 0°. The reaction mixture is poured onto ice-water and extracted twice with ethyl acetate. The organic phases are washed twice with ice-cold aqueous sodium bicarbonate solution# dried and concentrated by evaporation. Filtration of the resulting crude product over 20 g of silica gel (toluene/ethyl acetate 8s 2) and subsequent crystallisation of the pure fractions from methylene chlorid e/ether/petr oleum ether yields pure (3S#4S#1’R)3 - (1 s - al 1 yl ox yea r bonyl ox ye thyl) -4-benzoyl a set id in-2 one# melting at 93-95°.

Example 13s (3R#4R#1 *R)-3-(1 *-ailyloxycarbonyloxyethyl)-4-benzoyloxyazetidin2~one a) with m-chloroperbenzoic acids 234 mg of 85 % m-chi o roper ben zoic acid are added to a solution of mg of (3S# 4S, 1SR)-3-(1 '-allyloxycarbonyloxyethyl) ~4~ benzoylazetidin-2-one in 5 ml of methylene chloride and the whole is stirred at room temperature for 3 1/2 hours. ‘Phe reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed in succession with aqueous potassium iodide/sod ium thiosulphate solution# water# ice-cold aqueous sodium bicarbonate solution and water# dried and concentrated by evaporation. The crude product so obtained yields, after filtration over silica gel (toluene and toluene/ethyl acetate 8:2) and subsequent crystallisation of the homogeneous fractions from methylene chloride/ether/petroleum ether# pure (3R# 4Rr 1 JR)"3~ (1 8"allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one having a melting point of 84-85°. b) with peracetic acid: The title compound can also be manufactured by adding in three portions a total of 0.4 ml of 30 % peracetic acid in acetic acid to a solution of 91 mg of (3S, 4S, 1 'R)-3-(1 '-allyloxvcarbonyloxyethyl)-4-benzoylasetidxn-2-one in 5 ml of methylene chloride and stirring the whole for 48 hours at room temperature. The resulting reaction mixture in methylene chloride is washed in succession with 5 % aqueous sodium sulphite solution,, 8 % aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The aqueous portions are then extracted with methylene chloride and the combined organic extracts, after being dried with NajSO^, are concentrated by evaporation. Chromatography of the resulting residue over silica gel plates with hexane/ethyl acetate (1:1) yields the pure title compound having the abovementioned properties. c) with hydrogen peroxide and trichloroacetonitrile: The title compound can also be manufactured by adding 0.3 ml of trichloroacetonitrile, 1,.2 sal of 30 % aqueous hydrogen peroxide and 138 mg of potassium hydrogen phosphate at room temperature to a solution of 152 mg of (3S,4S, (1 ’-allyloxycarbonyloxyethyl)-4benzoylazetic in-2-one in 3 ml of chloroform and stirring the resulting mixture for 21 hours at room temperature» After dilution with methylene chloride, the whole is washed in succession with 5 % aqueous sodium bisulphite solution, 8 % aqueous sodium bicarbonate solution and aqueous sodium chloride solution. The aqueous portions are then extracted with methylene chloride and the combined organic extracts, after being dried over Na9SO4f are concentrated by evaporation. Chromatography over silica gel plates in hexane/ethyl acetate (1:1) yields the pure title compound having the properties described above.

Example 14: (3S ,4R ,1 jR)-3- (1 ’’-allyloxycarbonyloxy35 ethyl)-4-M-allyloxycarbonylglycylfchxoazetidin-2-one: .75 g (75 mmol) of N--allyloxyca.rbonylthioglycine <3icyclohexylammonium salt are dissolved In 200 ml of water and 75 ml of IN NaOH and extracted three times with 100 ml of methylene chloride each time. The aqueous phase is cooled to 0° and adjusted, while monitoring the pH (glass electrode) , to pH 10.0 by adding IN NaOH. Under argon, while stirring vigorously, a solution of 8 g (25 mmol) of (3R,4S,1'R)-3-(1'allyloxycarbonyloxyethyl)-4-benzoyloxyasetidxn-2"One in 275 ml of acetone is added dropwise, the temperature being maintained below t°, After the addition has finished, stirring is continued for a further 15 minutes at 0-5° and the solution is concentrated to 300 ml in a rotary evaporator and extracted 4 times with 100 ml of methylene chloride each time.

The combined organic phases are washed a further twice with 100 ml of water each time and once with 100 ml of aqueous saturated sodium chloride solution, dried over Na-jSO^ and concentrated by evaporation. The resulting residue is chromatographed over 500 g of Merck silica gel in the flash process using CHCl^/acetone (9:1). The title compound Is obtained having an Rf value (Merck pre-coated plates CHClj/acetone 9:1) of 0.20.

Example 15: (5Rt»6S,1 R)-5-(1 8-allyloxycarbonyloxy·ethyl)-2-allyloxycarbonylaminomethyl-2-penem-3carboxylic acid allyl ester Nhxle stirring under an argon atmosphere at -15°, 557 mg (3,75 mmol; 1.5 equivalents) of oxalic acid allyl ester chloride and 0.64 ml (3.75 mmol) (1.5 equivalents) of Hunig base are added in succession to a solution of 930 mg (2.5 mmol) of (3S,4R,19R)~3~(1 8 allyloxycarbonyloxyethyl)-4-N-allyloxycarbonylglycyl36 thioaze tid in-2-one in 15 rol of rnethylene chloride (freshly Al oxite-filtered) and stirring is continued for 30 minutes at -15°. For working up, the reaction mixture is diluted with methylene chloride and vigorously and briefly shaken in succession with cold 0.1N HCl and (twice) with cold saturated NaHCOg solution (the last treatment removes the excess allyloxyoxalyl chloride) .., The aqueous portions are then extracted once with methylene chloride and the combined organic phases are dried with Na^SO^ and concentrated by evaporation in vacuo. The crude product is several times taken up in toluene, concentrated by evaporation and dried under a high vacuum. The resulting viscous residue, containing 2-[ (3S, 4R, 1 !R)-3-(1’-allyloxyc a ΐ bo ny 1 ox ye t hy 1) - 4 -N - al 1 yl ox yc a r bon yl g 1 yc yl th i o 2 - ox o1-azetidinyl]-2-oxoacetic acid allyl ester, is dissolved in 25 ml of absolute toluene for cyclising and, while stirring at room temperature (argon), 1.044 ml (6 mmol? 2.4 equivalents) of distilled triethyl phosphite are added and the reaction mixture is rapidly immersed In an oil bath previously heated to 100° and stirred under argon for 7 hours at the same temperature. The reaction mixture Is concentrated by evaporation in vacuo and the residue is chromatographed over 100 g of Merck silica gel (0.040.063 Him grain size) in the flash process. A preliminary fraction is taken initially from 500 ml of toluene/ethyl acetate (9:1) and a 150 mi fraction with toluene/ethyl acetate (4:1). The title compound is eluted in the following 25 ml fractions with toluene/ethyl acetate (4:1), it being possible for a small amount of a more mobile component (the corresponding cis-isomer) to be separated off in the first fractions. M.p. 58-59° (from ether/pentane) ,· (Merck pre-coated plates, toluene/ethyl acetate - 37 2:1) : 0.40; [«] = +127.7° (1.05 % in CH2C12)Example 15.:, (5R?5S ,1 eR) -2-aminomethvl-5- (1 - hydroxyethyl) -2-penem-3-earboxylic acid Argon is passed for 5 minutes through a solution of 100 rag (0.22 mmol) of (5R, 6S?ISR)-S-allyXoxycarbonylaminoroethyl-Q- (1 -allyloxycarbonyloxyethyl) -2-penem-3carboxylic acid allyl ester, 308 mg (2.2 nmol) of dimed one and 30 mg (0.11 mmol) of triphenylphosphine in 4 ml of tetrahvdrofuran. 22 mg (0.019 mmol) of tetrakis-triphenylphosphine-palladium are then added at room temperature. After 5 minutes a precipitate begins to form. The suspension is stirred under argon at room temperature for a total of 1 hour. The product that precipitates is filtered off? washed with tetrahydrofuran? ethyl acetate and hexane and dried under a high vacuum. R^ OPTI UPC, ™ 0.48. mg of crude (5R? 5S? 1 !R)-2-aminomethyl-6- (1 hydroxyefchyl) -2-penem-3-carboxyl ic acid is dissolved in 0.5 ml of twice-distilled water at 30°. The aqueous solution Is cooled to 5°? a small amount of activated carbon is added and the whole is stirred for 15 minutes and then filtered until clear. The clear filtrate is concentrated completely under a high vacuum and the residue is made into a slurry in 0.3 ml of ethanol (95 % strength). The suspension is stirred vigorously for 30 minutes at room temperature. The white crystals (needles) are filtered off and washed with ethanol &S % strength) . The product is dried at 20° under a high vacuum. M.p. 155° (decomposition).

Example 1 7: (2R?3R) -N-acetonyl-N-p-methoxyphenyl-2 ?3epoxybutyric acid amide While stirring (at --15 to -18°) . there are added dropwise in succession to a solution? cooled to -20°? of 73.2 g of M-acetonyl-p-anisidine hydrochloride in 1700 ml of toluene first, over a period of 15 minutes, 70.,2 g of N,N-dicyclohexyl carbodiimide dissolved in 170 ml of toluene and then, over a period of 60 minutes, 103 g of a solution of the dicyclohexylammonium salt of (?.Re 3R)-2,3-epoxvbutyric acid in 340 ml of dichioromethane. The reaction mixture is warmed up to 0° over a period of 45 minutes and stirring is carried out for a further 18 1/2 hours at 0-5°. The suspension is filtered with suction, the residue is washed thoroughly with toluene and the filtrate is washed twice with 1 litre of water each time, dried and concentrated under a water-jet vacuum. After cooling the red-brown oily crude product to approximately 4° crystals can be separated off. Flash chromatography of the mother liquor with a hexane/ethyl acetate 1:4 miscture yields as main product, in addition to regenerated N-acetonyljp-anisidine, (2R,3R)N-acetonyl-N-p-methoxyphenyl2,3-epoxybutyric acid amide in the form of a pale brown oil. The compound can be used directly for the cyclisation without being purified further. IR: Bands, inter alia, at 2840, 1735, 1670, 1510, 1240, 1220, 1170 and 840.

Example 18: (3S,4S,18 R)-N-p-methoxyphenyl-3-(1"25 hydroxyethyl) -4~acetylazetidin-2-one 19.1 g of potassium carbonate are added at 60° to a solution of 10.1 g of (2R,3R)-N~acetonyl~N-g-2,3epoxybutyric acid amide in (200 ml) dimethylformamide and the whole is stirred for 13 hours at the same 3q temperature. The undissolved potassium carbonate is filtered off from the cooled reaction mixture, 1 litre of methylene chloride is added and the whole is washed in succession five times with dilute aqueous sodium chloride solution, dried and concentrated by evapora39 tion. Flash chromatography with hexane/ethyl acetate (2s 3) over 700 g of silica gel yields as main product (3S, 4S, 1 ’R)"N-p-methoxyphenyl-3-(1 hydroxyethyl) 4-acetylazetie in-2-one which, after being recrystallised from methylene chloride/ether, melts at 91-92° ((el = -119.9° (c = 0.353 in chloroform)) and as by-product (approximately 10 %) (3S,4Rr1R)-Np-methoxvphenyl-3- (1 -hydroxyethyl) -<-acetylazetid in2-one (m.p. 165-1 68°).

Example 1 9 s (35,45,1 ' R)-N-p-raethoxyphenyl-3-(1 jte rt.-buty Id ime thylsilyloxye thyl)-4-ace ty laze t id intone 2.33 g of tert .-butyldimethylchlorosilane are added at room temperature to a solution of 3.39 g of (35,4.5, 1 'R)-N-p-methoxyphenyl-3-(1 ’-hydroxyethyl) -4acetylazetid in-2-one and 1.58 g of imidazole in 20 ml of dimethylformamide and the whole is stirred for 5 hours at room temperature. For working up, the reaction mixture is poured onto an ice/sodium bicarbonate solution, taken up in methylene chloride and the organic phase is washed in succession with sodium bicarbonate solution, 1 % citric acid solution and again with sodium bicarbonate solution. After drying over sodium sulphate and concentration by evaporation under reduced pressure, a crude product is obtained which is recrystallised from petroleum ether. The title compound is obtained in the form of colourless crystals, m.p. 82-84°. [©j - -116.3° (c — 0, 374 % in CHC13) .

Example 20g (35,45,1 R)-3-(1 81 -tert —butyldimethyΙέ ilyloxyethy 1)-4-ace tylazet id in-2-one Over a period of 15 minutes, 13.85 g of cerium ammonium nitrate dissolved in 70 ml of water are added dropwise at 0° to a solution# cooled to 0°,, of 4.34 g of. (3S # 4S 1 ’ R) -N-p~methoxyphenyl-3~ (1 e -tert ~ butyld imethyl silyl oxyethvl) -4-acetyl aset id in-2-one in 140 ml of acetonitrile. The reaction mixture is stirred at room temperature for 2 hours# poured onto ice-water and extracted with methylene chloride and the organic layer is washed twice with aqueous sodium bicarbonate solution and saturated sodium chloride solution# dried and concentrated by evaporation under a water-jet vacuum. Flash chromatography of the dark brown crude product in hexane/ethyl acetate (3:2) over silica gel and subsequent crystallisation of the homogeneous fractions from ether/petroleum ether yields pure (3S#4S#1R)-3-(1’-tert —butyldimethylsilyloxyethyl)-4~acetylazefcidin~2-onet m.p. 74-75°. (c] -14.6° (c - 0.397 %; CSC13).

Example 21 : (3R#4R# 1 R)-3-(1 1-tert—butyldimethylsilyloxy) -ethyl-4-acetoxyasetidin-2~one .75 g of 85 % m-chloroperbenzoic acid are added to a solution of 1.4 g of (3S#4S# 1 aR)-3-(1 '-tert—-butyldimethylsilyloxyethyl)-4-acetyXazetidin-2-one in 70 ml of methylene chloride and the whole is stirred at room temperature for 2 hours. The yellow reaction mixture is poured onto ice and extracted with methylene chloride and the organic phase is washed in succession with aqueous potassium iodide/sodium thiosulphate solution# water# aqueous sodium bicarbonate solution and water and concentrated by evaporation. Flash chromatography of the crude product in hexane/ethyl acetate (4:1) and subsequent crystallisation of the homogeneous fractions from low-boiling petroleum ether yields pure (3R#4R#1’R)-3-(1-tert—butyldimethylsilyloxyethyl)"4-acetoxyazetidin"2-one# m.p. 108-110°. («1 = +50.1° (c = 0.838 %# CHC13).

Example 22: (3St»4St,1 1R)-N-p-methoxyphenyl-3-[ 1 " (dimethyl-2,3-dimethylbut-2-ylsilyloxy)-ethyl]-4° benzoylazetidin-2-one 1,.,7 g of imidazole and 3.3 ml of dimethyl- (2,3dimethylbut-2-yl)-chlorosilane are added to a solution of 4.53 g of (3S, 4S „ 1 "R)-N~p~methoxyphenyl-3-(1 hydroxyethyl)-4-benzoylasetidin-2-one in 40 ml of dimethyl formamide and the whole is stirred for 23 hours at 25°. After the addition of a further 1.7 c of imidazole and 3.3 ml of dimethyl-(2,3~difflethylbut-2-yl) chlorosilane, the whole is stirred for a further 22 hours. The reaction mixture is poured into Ice-cold aqueous sodium bicarbonate solution and extracted with chloroform. The organic phase is washed in succession with aqueous sodium bicarbonate solution, 1 % aqueous citric acid, aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation in vacuo. The resulting crude product is subjected to " flash* chromatography in toluene/ethyl acetate (9s 1) over 521 g of silica gel. The combined homogeneous fractions are dissolved and recrystallised from ether/pefcroleum ether to yield pure (3S,4S, 1 yR)-Np-methoxyphenyl-3- [1 (dimethvl-2,3-dim ethyl but-2 ~ yl silyl oxy)-ethyl] -4-bensovlazetid in-2-one melting at 89-90°. [©] = -65.4° (c = 0.506 CHC13).

Example 23: (3S ,4S r1 R)-3-[1 '-(dimethyl-2,3-dimethylbut2-ylsilyloxy)-ethyl]-4-benzoylazetidin-2-one Over a period of 15 minutes, a solution of 95.4 g of cerium(IV) ammonium nitrate in 490 ml of water is added dropwise under argon to a solution, cooled to 0°, of 37.02 g of (3S,4S,1eR)-N-o~methoxyphenyl-3[1 (dimethyl-2,3-d imethylbut-2-yl silyl oxy)-ethyl] -4benzoylasetxdin-2-one in 980 ml of acetonitrile and the reaction mixture is stirred for 1 hour at 05°. The organic phase is then separated off and concentrated by evaporation at 30° in vacuo. The residue is combined, while adding ice, with the aqueous phase and the mixture is extracted with ethyl acetate. The extract is washed in succession twice with aqueous sodium bicarbonate solution and dilute aqueous sodium chloride solution, dried and concentrated by evaporation. The brownish residue is crystallised from methylene chloride/ether at 5°. The crystals, washed with 50 ml of a hexane/ether (3:2) mixture, are stirred with an additional 50 ml of this mixture at 20° and then at 0°, filtered with suction, washed with a little hexane/ether (3s2) mixture and dried at 50° under a high vacuum. The pure title compound melting at 165166° Is obtained. Flash chromatography of the mother liquor with hexane/ethyl acetate (80s 20) over 750 g of silica gel yields further amounts of the title compound. [c'j = -20,,4° (c ~ 0.499 %; CSClj) .

Example 24s (3R ,4R , 1 R) -3-(I 9 - (dimethyl-2 ,3-diniefhylbut-2-ylsilyloxy)-ethyl] -4-benso,yloxyazetidin-2-one 47.3 g of 85 % m-chloroperbensoic acid are added to a solution of 15.14 g of (3R, 4R, 1 ’R)-3= [1 (dimethyl2,3-din»ethylbut-2-yl silyl oxy)-ethyl] -4-benzoylazetid in2-one in 500 ml of methylene chloride and the whole is left to stand for 5 1/2 hours at room temperature. The reaction mixture is then poured onto ice-water and extracted with methylene chloride and the organic phase is washed in succession with aqueous potassium iod ide/sodium thiosulphate solution, water, aqueous sodium bicarbonate solution and water, dried and concentrated by evaporation™ On adding ether to the crude product, approximately 1.5 g of 3-chlorobenzoyl peroxide crystallises out. The crystals are filtered with suction andf after concentration, the crude product is crystallised from the filtrate using hexane. The slightly impure title compound so obtained is subjected to 83flash63 chromatography with hexane/ethyl acetate (90:10). The homogeneous fractions are dissolved and recrystallised from hexane, to yield pure (3R,4R,18R)-3-(1’-(dimethyl-2,3-dimethylbut-2-yIsilyloxy)-ethyl]-4-benzoyloxyasetidin~2-one melting at 8384°. ία] = +62.5° (c = 0.256%; CHClj) ..

Example 25: (3S ,4R, 1 * R)-3-[1'-(dimethyl-2 y3-dimethylbut-2-ylsilyloxy)-ethyl]-4-N-allyloxyearbonylglycylthioazetidin-2-one 2,.67 g (7.,5 mol) ox N-allyloxyearbonylthioglycine dicyclohexylammonium salt are dissolved in 7,5 ml of N NaOH and 20 ml of water. The resulting solution is extracted three times with methylene chlorxde^and 10 ml of acetone and then, while stirring at 0° under argon, a solution of 944 mg (2.5 mol) of (3R, 4R, 1 R)-3-[1 (dimethyl-2,3-dimethylbut-2-ylsilyloxy)-ethyl]-4-Nallyloxvcarbonylglycylthioasetidin-2-one in 20 ml of acetone are added to the aqueous portion. The reaction mixture is stirred at a pH of 10.5-10,7 for a further 5 hours while cooling. The acetone is distilled off under reduced pressure, the aqueous residue is extracted with methylene chloride, the organic phase, after being dried over NajSO^, is concentrated by evaporation, and the residue is chromatographed over silica gel plates in hexane/ethyl acetate (1:1). The title compound is obtained in the form of a colourless crystalline compound that is recrystallised from ether/hexane. M.p. 74-76°. [a] ~ -f-110.7 + 1.3° (c = 0.76 % in CHC13) .

Example 26; (5R,6S ?1 UR)-6-(1 8 -(dimethy1-2 ?3-dimethy1but-2-ylsilyloxy) -ethyl) -2-allyloxycarbonylaminomethyl 2-penem-3-carboxylic acid allyl ester 360 mg (approximately 2.41 mmol) of oxalic acid allyl ester chloride and 410 ml (approximately 2.41 mmol) of Hunig base are added in succession at -20° under argon to a solution of 692 mg (1.6 mmol) of (3S? 4R? 1 5R)~3-[1 (dimethyl-2? 3-dimethylbut-2ylsilyloxy) -ethyl] -4-N-allyloxycarbonylglycyl thioa set id in-2-one in 9 ml of methylene chloride and the resulting reaction mixture is stirred first for 2.5 hours at -10° and then for 80 minutes at 0°.

The mixture is diluted with methylene chloride and washed in succession with ice-cold 0.1N HC1 solution and 8 % aqueous NaHCOj solution. The organic portion is dried over and concentrated by evaporation. The resulting residue is dissolved in 3 ml of triethyl phosphite and the solution Is heated for 2 hours at 60° under argon. The volatile portions are removed first under reduced pressure then under a high vacuum? the residue is dissolved in 10 ml of absolute dioxan and the resulting solution is heated at 105° (bath temperature) under argon for 8 hours. The crude product obtained after concentration by evaporation from dioxan under reduced pressure is chromatographed on a silica gel column with hexane/ethyl acetate (9:1 and 4:1). The title compound is obtained in the form of a colourless oil.

Ic] « + 62 + 2.7° (c = 0.371 % in CHCI3) ? U.V. : ^max ~ 320 ran (ε = 6230; in ethanol) .

Example 27: (5R?6S?18R)-2-aminomethyl-6-[ 1 Mdimethyl2 ?3-dimethylbut-2-ylsilyloxy)-ethyl]-2-penem-3carboxylic acid 223 mg (1.59 mmol) of dimedone and 36 mg of tetrakis-triphenyl phosphine-palladium are added at room temperature to a solution of 367 mg (0.72 mmol) of (5R, 5S, 1 *R)-6- [1 ’’"dimethyl- (2,3-dimethylbut-2y 1 s x 1 yl ox y) - e t h yl ] - 2 - al 1 yl ox yc a r bon yl am in om e t h y 1 - 2 penem-3-carboxylic acid allyl ester in 7 ml of absolute tetrahydrofuran and the resulting solution is stirred at room temperature. The crystalline title compound soon begins to precipitate and after ϊ hour precipitation is virtually complete. The crystals are filtered off and washed on the filter with a small amount of tetrahydrofuran. The resulting title compound forms colourless crystals, m.p. 119°f· U.V.-. Xmax (EtOH): 309 ran, 268 nm.

Example 28: (3S ,4S ,1 !i'R)-N-p-methoxyphenyl-3-(1 8- (3 ,5dinitrobenzoyloxy)-ethyl] 4-benzoy_lazetidin-2-one Over a period of 10 minutes, 10.07 g of j>-toXuenesu!phonic acid chloride are added at room temperature to a solution of 6.16 g of 3, 5-dinitrobenzoic acid in 83 ml of pyridine. Stirring is then carried out for one hour. 9.01 g (27.7 mmol) of (3S, 4S, 1 BR)-N-omethoxyphenyl-3- (1 ’-hydroxyethyl) -4-benzo via set.Id in-2one are added to the reaction mixture, cooled to 05°, and the whole is stirred for 1 1/4 hours at the same temperature. The reaction mixture is poured into 500 ml of methylene chloride and extracted with 250 ml of ice-cold 4N hydrochloric acid. The organic phase is washed once with 100 ml of saturated aqueous sodium bicarbonate solution and once with 100 ml of saturated aqueous sodium chloride solution and dried over sodium sulphate. After concentration by evaporation, the red residue is purified over 250 g of silica gel with toluene/ethyl acetate (9s 1). The title compound is obtained in quantitative yield with the following physical data: IR (Ci^Clj): Bands, inter alia. at 3100, 1765, 1735, 1550, 1515, 1345, 1250; Rf (Merck silica gel pre-coated plates, ethyl acetate/toluene 1:1): 0.65.

Example 29; (35 ,45,1 ,JR) -3- [ 1 8 - (3 , 5-dinitrobenzoyloxy) ethyl]-4-benzoylazetidin-2-one Over a period of 15 minutes, a solution of 34.4 g (62.8 mmol) of cerium(IV) ammonium nitrate in 146 ml of 02° is added dropwise at 0° to a solution of 14.88 g (27.8 mmol) of (3S,4S, 1 'RJ-N-p-methoxyphenyl3- [1 (3,5-dinitrobenzovloxy) -ethyl] -4.-benzoylazetid in2-one in 290 ml of acetonitrile. After a further 30 minutes' reaction time at the above temperature, 500 ml of ethyl acetate are added and the organic phase is washed once with ice-cold aqueous sodium bicarbonate solution and twice with semi-saturated aqueous sodium chloride solution. After drying over sodium sulphate and concentration by evaporation, the crude product is crystallised from methylene chloride/ether and the title compound is obtained in pure form. Further amounts of the title compound are obtained from the mother liquor by concentration by evaporation and digestion in toluene. M.p. 156-160°; R.F value (Merck silica gel pre-coated plates, ethyl acetate/toluene 1:1): 0.42.

Example 30: (3R,4R,1R)-3-[18 - (3 ,5-dinitrobenzoyloxy)ethyl]-4-benzoyloxyazetidin-2-one 6.129 g (30 mmol) of m-chloroperbenzoic acid (85 % strength) are added to a solution of 8.30 g (20 mmol) of (38,45,1 R)-3-[1 (3,5-dinitrobenzoyloxy)-ethyl] -4foenzoylasetidin-2-one in 151 ml of methylene chloride and the whole is stirred first for one hour at room temperature and then for 2 1/2 hours at 30°c. For working up, 250 ml of methylene chloride are added and, at 0°, the whole is washed in succession with 100 ml of 10 % aqueous sodium bicarbonate solution# approximately 5 % aqueous sodium bisulphite solution and 100 ml of saturated aqueous sodium chloride solution. After drying and concentration# the crude product is crystallised from 50 ml of pentane. The title compound is obtained having a melting point of 165-169° (decomposition) (Merck silica gel pre-coated plates# ethyl acetate/toluene 1:1): 0.58.

Example 31 : (3S#4R#1 8 R)-3-(1 * - (3,5-dinitgobenzoyloxy)ethyl]-4-N-allyloxycarbonylglycylthio)-azetidin-2-one 3.77 g (10.6 mmol) of ^-allyloxycarbonylthioglycine dicyclohexylammonium salt are dissolved in 18.7 ml of H90 and 10.6 ml of aqueous IN MaOH and extracted three times with 5 ml of CH^Clg each time. The solution is adjusted to pH 7-8 with approximately 0.2 ml of 0.IN aqueous HCl and then added at 23° to a solution of 2.28 g (5.3 mmol) of (3R, 4R, 1 "R)3-(1 ·- (3,5-d in itr obenzoyl oxy) -ethyl] -4-benzoyl ox yazetidin-2-one In 50 ml of dioxan. Stirring is carried out for 1 1/2 hours at 23° and the whole is worked up with 100 ml of saturated aqueous NaHCO^ solution.

The organic phase is washed twice more with 20 ml of saturated aqueous sodium chloride solution each time# dried over sodium sulphate and freed from the solvent. The residue is purified by chromatography over 200 g of silica gel with methylene chloride/acetone (9:1)# yielding the title compound in the form of a foam.

Rf (Merck pre-coated plates# toluene/ethyl acetate 1:1): 0.38? [a] = +25° (c * 0.72? CHC13).

This product still contains approximately 5 % of the 3S# 4S-cis-isomer .

Example 32: (5R#6S#1 R) -6-[ 1 8 - (3 #5-dinit.robenzoyloxy) ~ ethyl] -2-al Ivloxycar bonylaminome thy 1-2-penem-3carboxylic acid allyl ester While stirring and with the exclusion of moisture, 84.5 ul (0.69 mmol) of oxalic acid allyl ester chloride and 124.2 ul (0.73 mmol) of Hunig base are added in succession at -20° to a solution of 241 mg (0 5 mmol) of (3S,4R,1 9R)-3-[1 '~(3,5-dinitrobenzoyloxy)-ethyl]-4-N~ allyl oxycarbonylglycyl thioase tid in-2-one in 3 ml of methylene chloride (freshly filtered over Aloxite) and the whole is stirred at -10° for a further 30 minutes. An IR sample shows the characteristic oxal iin id ecarbonyl absorption at 1820 For working up, the reaction mixture is diluted with 5 ml of CH2CI2 and the organic phase is washed in succession with ice-cold aqueous 0. IN HCl, 5 % NaHCO-j solution and saturated aqueous sodium chloride solution, dried over Na^SO#, and concentrated by evaporation _in vacuo. After drying under a high vacuum, (3S,4R,1 ’ R)-4-N-(allyloxycarbonylglycylthio)-3(1 (3,5-dinitrobenzoyXoxy) -ethyl] -azetidχη-2-οη- ί yloxalic acid allyl ester is obtained in the form of a beige foam. This is dissolved in 2.5 ml of dioxan (Merck, p.A.) and 312 ul (1.49 mmol) of triethyl phosphite are added at room temperature under an Nj atmosphere. The whole is stirred for 1 hour at room temperature and 2 hours at 40° bath temperature until an oxal Imide signal can no longer be detected in the IR spectrum (band at 1820 craT^). After concentration by evaporation, stirring is carried out three times with approximately 1.5 ml of decane and each time the whole is again concentrated by evaporation under a high vacuum. The resulting crude phosphorane is directly dissolved in 12.5 ml of dioxan (Merck, p.A.) for cyclisation and the whole is stirred for 17 hours at a bath temperature of 105°. The whole Is then concentrated in a rotary evaporator and the residue is chromatographed over 30 g of silica gel with toluene/ethyl acetate (4:1)., The title compound? which for its part contains approximately 5 % of 5S, 6S-cis-isomer as an impurity, is isolated from the middle fractions. Rg (Merck pre-coated plates? toluene/ethyl acetate 4:1): 0..48 (cis-product) and 0.38 (trans-product) .

Example 33: (5R?5S/I jR)~6~(1 e-hydroxyethyl)-2-allyloxycarbonylaminomefchyl-2~Penem-3-carboxylic acid allyl ester a) from (5R?6S?1 R)-6-[1 11 - (3 ^S-dinitrobenzoyloxv) ethyl] -2~allyloxycarbonylaminomethyl~2~penei»-3 carboxylic acid allyl ester: ml of saturated aqueous sodium bicarbonate solution are added at 0° to a solution of 1.28 g (2.27 mmol) of (5R, 6S? 1 (R)-6- Π (3? 5-dinitrobensoyloxy) -ethyl]-2-al1ylox yc arbonylam inora ethyl-2-penem-3 carboxylic acid allyl ester (trans:eis approximately 95:5) in Ϊ00 ml of methanol and 20 ml of water. After 20 minutes’ reaction time at 0°? the reaction mixture is poured into 300 ml of ethyl acetate and 50 ml of saturated aqueous sodium chloride solution? the organic phase is separated off and the aqueous phase is extracted again with 100 ml of ethyl acetate. The combined organic phases are dried over Na9SCb and concentrated in vacuo to a volume of approximately 30 ml. The whole is diluted with 150 ml of methylene chloride, dried again with and then concentrated completely by evaporation in a rotary evaporator. The residue is chromatographed over 80 g of silica gel with toluene/ethyl acetate 4:1 to 3:2? the title compound being obtained after crystallisation from efcher/hexane (3:7)? m.p. 141-141.5°. R.r (Merck pre-coated places? toluene/ethyl acetate 1:1): 0.20. b) from (5R,6S , 1 ’R)-6-[ 1 5 -(dimethyl-2,3-dimethylbut2-ylsiIyloxy) -ethyl] -2-allyloxycarbonylaminomethyl-2penem-3-carboxylic acid allyl ester: mg (approximately 30 mmol) of a 70 % HF/urea mixture are added to a solution of 50 mg of (5R,6S,1SR)6- 0 ’ " (dimethyl-2,3-d ime thyl but-2-yl silyl oxy) -ethyl] -2allyloxycarbonylaminomethyl-2-penem-3-carboxyl ic acid allyl ester in 1 ml of 2,6-lutidine and the whole is stirred for 2 hours at room temperature. A further 5 drops (approximately 100 mg - approximately 50 mmol) of HF/urea are added to the reaction solution. The viscous mixture is diluted with 1 ml of methylene chloride and stirred overnight at room temperature and 10 drops of HF/urea (approximately 100 mmol) are again added. After a further 24 hours’ reaction time at room temperature, the reaction mixture is diluted with water and extracted with ethyl acetate. The organic phase is then washed with 4N hydrochloric acid and with saturated aqueous sodium chloride solution, dried and concentrated In a rotary evaporator. Dissolving and recrystallising the resulting crude product from ether/hexane yields the pure title compound which is identical with the sample obtained under a) .

Example 34: (3S,4R,18R)-3-(1 ,-hydroxyethyl)-4-(Nallyloxycarbonylglycylthio) -2-azetidinone A solution of 14.2 g (40 mmol) of N-allyloxycarbonylthioglvcine dicyclohexyl ammonium salt in 60 ml of water and 40 ml of IN aqueous NaOH solution is extracted three times with 20 ml of methylene chloride each time and the pH Is adjusted to 7- 8 with approximately 1 ml of 0.1 N aqueous HCl.

The resulting aqueous thiolic acid solution is added at 30° within a period of 5 minutes to a solution of 4.70 g (20 mmol) of (3R, 4R, 1 ’R)-3-(1 -hydroxyethyl)-451 benzoyloxv-2·-azetidinone in 100 ml of acetonitrile. 2 ml of 0»IN aqueous NaOH solution are added at an internal temperature of 25° and the whole is stirred for a further 30 35 minutes at 25°. For working up, 250 ml of ethyl acetate and 30 g of NaCl are placed in a separating funnel and the reaction mixture is added thereto. After shaking well and separating off the aqueous phase, the organic phase is washed once again with 50 ml of 5% aqueous NaHCO^ solution and twice with 50 ml of brine and then dried over sodium sulphate. The solvent is removed in a rotary evaporator and the title compound is obtained in the form of an amorphous powder. The crude product can be purified by chromatography over silica gel (toluene/ethyl acetate 2:3). R^ value 0.23 (Merck pre-coated plates, toluene/ethyl acetate =· 1:4, ninhydrin as the developing reagent) .

Example 35: (5R,6S,1 BR)-(1’-hydroxyethyl)-2-allyloxycagbonylaminomethyl-2-penem-3-carboxylic acid allyl ester At — 10 to -15° while stirring and with the exclusion of moisture, 3.86 ml (31.5 mmol) of freshly distilled oxalic acid allyl ester chloride and 7.59 ml (44,8 mmol) of N-ethyldiisopropylamine are added in succession to a solution of 2,88 g (10.0 mmol) of (3S t4R,1aR)-3-(1 "-hydroxyethyl)-4-(N-allyloxycarbonylglycylthio)-2-azetidinone (crude product of process 34) in 80 ml of methylene chloride (freshly filtered over Aloxite) and the whole is stirred for a further 30 minutes at -10°. An IR sample shows the characteristic oxalimide-carbonyl absorption at 1820 cm’*.

For working up, the reaction mixture is diluted with 50 ml of CHjClj and washed three times with ice-cold water and once with ice-water and 5 ml of saturated aqueous NaHCO^ solution,, The aqueous portions are then extracted once with CI^CIq. The combined organic phases are dried with Na2SOzp concentrated by evaporation in vacuo and the crude product is dried under a high vacuum. The resulting viscous residue containing the (3S,4R, 1 R)-2-[4-(Nallyloxycarbonylglycyl thio) -3- (ί '-allyl ox alyl ox ye thyl) 2-oxo-l-azetidinyl]-2-oxoacefcie acid allyl ester Op 0 II II» I (IR(CB9C1?) 3440 (NHh '820 (N-C-Cfc 1 720-1 760 (C) ) , is dissolved in 30 ml of dioxan, and 7 ml (40.2 mmol) of triethyl phosphite are added at room temperature under an N9 atmosphere. After 15 hours at room temperature oxalimide can no longer be detected in the IR spectrum (band at 1820 cm"'1) . The reaction mixture is concentrated by evaporation in vacuo, 2 ml of toluene and 2 ml of decane are added to the residue three times and the eluants are drawn off again in each case under a high vacuum in order to remove excess phosphite/phosphate. For the purpose of cyclisation, the resulting crude phosphorane is dissolved in 250 ml of dioxan and stirred for 5 hours at 105-110°. The reaction mixture, containing the (5R,6S,1'R)~2-allyloxycarbonylami«omefchyl-6-[1 (allyl oxalyl oxy) -ethyl] -2-penem"3-carboxyl ic acid allyl ester (for analytical purposes a sample of the crude cyclisation product is purified over silica gel using toluene/ethyl acetate 4:1: OV (EtOH) 315 nm; I! (IR(CH2C12) 3440 (NH); 1790, 1770, 1 745, 1720 (C) ) is concentrated by evaporation in vacuo to approximately 15 ml, and, at 0°, 100 ml of methanol/H20 8:2 and 25 ml of saturated aqueous NaHCO^ solution are added thereto. After 20 minutes, the reaction mixture is poured onto 300 ml of ethyl acetate and 50 ml of H2O, the organic phase is separated off and the aqueous phase is then extracted again with 100 ml of ethyl acetate. The combined organic phases are dried over NajSO^ and concentrated in vacuo to a volume of approximately 50 ml. After diluting with 200 ml of methylene chloride, drying is carried out with Na2SO4 and the whole is completely concentrated by evaporation in. vacuo. The residue is chromatographed over 80 g of silica gel using toluene/ethyl acetate 3:2, the title compound being obtained after crystallisation from ether/hexane 3:7. M.p. 141 - 141.5°. R Example 36: (5R,6S,1 8R)-2-aminomethyl-6-(1 ’-hydroxyethyl) -2-penem-3-carboxylic acid .

A solution of 313 mg (0.85 mmol) of (5R,SS,ieR)" 2-allyloxycarbonyXaminomethyl-6-(18-hydroxyethyl)-2penem-3-carboxylic acid allyl ester and 174.6 mg (1.24 mmol) of dimedone in 7.5 ml of tetrahydrofuran is scavenged with argon for 5 minutes and then 27 mg (0.023 mmol) of tetrakis-trIphenylphosphine-palladium are added under an argon atmosphere at room temperature. After approximately 5 minutes a precipitate begins to form which, after stirring for a further 2 hours, is filtered off, washed with approximately 10 ml of tetrahydrofuran and then dissolved in 4 ml of H2O. A micro-spatula tip of activated carbon and 2 micro-spatula tips of tonsil are added to the beige solution, which is stirred well for 5 minutes and filtered over Hyflo until clear. Concentration is carried out under a high vacuum and 3 ml of cold ethanol are added to the resulting thick crystal mass and the whole is filtered with suction. The colourless crystals are washed with 2 ml of tetrahydrofuran and dried under a high vacuum. The title compound# having an Rf value of 0.50 (TLC: HjO# OPT! UPC12)? [a] 2° = +176° (c = 0»5# H90) is obtained.

Claims (22)

1. Patent Claims: 1- A f 4R1-3.4-trans-disubstituted azetidinone of the formula 5 in which Εχ is hydrogen or Cfo-C^aUcyl, R 2 is hydrogen or a hydroxy-protecting group R£, R 3 is phenyl, phenyl that is mono- to tri-substituted by Cj_-C 4 alkoxy , Ch CzjSlkyl and/or by halogen, or is 4-nitrophenyl and R 4 is hydrogen or an amino-protecting group . IQ 2. A compound of the formula I according to claim 1 in which R x is hydrogen or methyl, R 2 hydrogen, 2,2,2trichloroethoxycarbonyl, allyloxycarbonyl or 3,5-dinitrobenzoyl, R 3 is phenyl and R 4 is hydrogen or o-methoxyphenyl. 15 3. (3R, 4R, 1 'R) -N-p-methoxypheny 1-3 -(1'-hydroxyethyl )-4benzoyloxyazetidin-2-one according to claim 1. 4 - (3R, 4R, 1 e ’R) -3- (1 f -hydroxyethyl) -4-benzoyloxyazetidin2-one according to claim l. 5. (3R,4R ,1'R)-3-[1'- (2,2,2-trichloroethoxycarbonyloxv)ethyl]-4-benzoyloxyazetidin-2-one according to claim L·

2. o δ · (

3. R,

4. R,1 # R)-3-(1’-allyloxycarbonyloxyethyl)“4-benzovloxyazetidin-2-one according to claim 1. 7. (3R,4R,l‘R)-3-[1^-(dimethyl-2,3»dimsthylbut-2-ylsilyl56 oxy)-ethyl]-4-benzoyloxyazetidin-2“one according to claim 1. 8. (3R, 4R, 1R) -3- [ 1 f ' - (3 ,5-dinitrobenzoyloxy)-ethyl ]-4benzoyloxyazetidin-2-one according to claim 1.

5. 9. A process for the manufacture of a (4R)-3.4-transdisubstituted asetidinone of the formula in which r^ is hydrogen or C^-C^alkvl, R 2 is hydrogen or a hydroxy-protecting group R 2 , ^3 pheny1, phenyl that 1q is mono- to tri-substituted by Ch-C^alkoxy, C^-C&alkvl and/or by halogen, or is 4-nitropheny1 and R^ is hydrogen or an amino-protecting group R^, characterised in that a compound of the formula Ra- di), in which R·, , R 2 , R3 and R^ have the meanings mentioned under formula I, is subjected to a Bayer-Villiger reaction by treatment with a per acid, and, if desired, in an obtainable compound of the formula I in which R 2 is hydrogen the free hydroxy group is converted into a protected hydroxy group 0R£ and/or, if desired, in an obtainable compound of the formula I the hydroxy-protecting group R 2 and/or the amino-protecting group R^ are(is) removed.

6. 10, A process for the manufacture of a compound of the formula I according to claim 9, characterised in that there is used as starting material a compound of the formula II in which Ry is hydrogen or methyl, R 2 hydrogen or a hydroxy-protecting group R£, R 3 is phenyl and R 4 is hydrogen or an amino-protecting group R 4 .

7. 11. A compound of the formula in which R 3 is hydrogen or C^-C^alkyl, R 2 is hydrogen or a hydroxy-protecting group R£, R 3 is phenyl, phenyl that is mono- to tri-substituted by C 1 -C 4 alkoxy, C-i-C^alkyl and/or by halogen, or is 4-nitrophenyl and R 4 is hydrogen or an amino-protecting group R 4 .

8. 12. A compound of the formula II according to claim 11 in which Ri is hydrogen or methyl, R 2 is hydrogen or a hydroxy-protecting group R 2 , R 3 is phenyl and R 4 is hydrogen or an amino-protecting group RA

9. 13. A compound of the formula II according to claim 11 in which Rj is methyl, R 2 is hydrogen, 2,2,2-trichloroethoxycarbonyl , allyloxycarbonyl, tert-foutyldimethylsilyl, dimethyl-2,3-dimethylbut-2-ylsilyl or 3,5-dinitrobenzoyl, R 3 is phenyl and R 4 is hydrogen or o-methoxyphenyl.

10. 14. (3S,4S,1 -R)-N-p-methoxyphenyl-3-(l*-hydroxyethyl)-4benzoylasetidin-2-one according to claim 11.

11. 15. (3S,4S,l'R)-3(1 e “hydroxyethyl)--4-benzoylazetidin-2one, (3S,4S,1’R)-N-D-methoxyphenyl-3-[1 *-(2,2,2-trichloroethoxycarbonyloxy)-ethyl]-4-benzovla2etidin-2-one, (3S, 4S, lR) -3 — [ l ^ — (2,2,2-tr ichloroethoxycarbony loxy) ethyl]-4-benzoylazetidin-2-one, (3S,4S,1 ‘’R)-N-g-methoxyphenyl-3-(1 *-allyloxycarbonyloxyethyl)~4~henzoylazetidin2-one, and (3S f 4S f -l‘,R)-3-(I'-allyloxycarbonyloxyethyl)-4benzovlazetidin-2-one according to claim 11.

12. 16. (3S,4S,1 R)-N-o-methoxyphenyl-3-(1 ? -hydroxyethyl)-4benzoylazetidin-2-one, (3S,4S,1 ’’R) -N-n-me thoxy pheny 1-3[ 1' - (3,5-dinitrobenzoyloxy) -ethyl ] -4-benzoylazetidin-2“ one, and (3S f ,4S r l i ’R)-3-[l'-(3,5-dinitrobenzoyloxy)ethyl]-4-benzoylazetidin-2-one according to claim 11»

13. 17. (3S,4S,1*R)-N-©-methoxypheny1-3-[1-(dimethyl-2,3dimethylhut-2-ylsilyloxy)-ethyl]~4-foenzoylazetidin-2-one according to claim 11»

14. 18. ( 3S, 4S, 1 R) —3—[ V - (dimethyl-2,3-dimethylbut-2ylsilvloxy)-ethyl]~4~benzoylazetidin-2-one according to claim 11»

15. 19. A process for the manufacture of a compound of the formula (ID in which R^ is hydrogen or C 1 -C 4 alkyl f R 2 is hydrogen or a hydroxy-protecting group R^, R 3 is phenyl, phenyl that is mono- to tri-substituted by C^^-C^alkoxy, Ci-C 4 alkyl and/or by halogen, or is 4-nitrophenyl and R 4 is hydrogen or an amino-protecting group R|, characterised in that a) an c-carbanion of a compound of the formula Rx Η x : -Rx (HI) , in which R lr R 3 and have the meanings mentioned under formula II and the 2-carbon atom has the R-configuration and, if R 3 is C^-C^alkyl, the 3-carbon atom has the R- or 5 the S-configuration, or a compound of the formula in which Rj, R 3 and Rji have the meanings given under formula II, R^ is a hydroxy-protecting group that cannot be removed under the conditions of the cyclisation process and X is a nucleofugal leaving group, and the 2carbon atom has the R-configuration and, if R 3 is Cj-C^alkyl, the 3-carbon atom has the R- or the S~ configuration, is cyclised, or b) a cis-compound of the formula in which R 1# R 2 , R3 and R 4 have the meanings given under formula II, is isomerised, and, if desired? the aminoprotecting group R| is removed and replaced by hydrogen and/or, if desired, an obtainable compound of the formula

16. 20 II is converted into a different compound of the formula II. 20. A process according to claim 19 for the manufacture of a compound of the formula II in which Ri is hydrogen or methyl, R 2 is hydrogen or a hydroxy-protecting group R£, R 3 is phenyl and R 4 is hydrogen or an amino-protecting group R|, characterised in that a) an a-carbanion of a compound of the formula (III) in which R lr R 3 and R| have the meanings mentioned under formula II and the 2-carbon atom has the Reconfiguration and, if R^ is methyl, the 3-carbon atom has the R- or the S-configuration, or a compound of the formula H (IV) in which R^, R 3 and R 4 have the meanings mentioned under formula II, R^ is a hydroxy-protecting group that cannot be removed under the conditions of the cyclisation process and X is a nucleofugal leaving group, and the 2carbon atom has the Reconfiguration and, if Ri_ is methyl, the 3-carbon atom has the R- or the S-configuration, is cyclised and, if desired, the amino-protecting group R| .is removed and replaced by hydrogen and/or, if desired, an obtainable compound of the formula II is converted into a different compound of the formula II.

17. 21, A process for the manufacture of a (4R)-3,4-transdisubstituted azetidinone of the formula (I) in which R^ is hydrogen or Ci~C 4 alkyl, R 2 is hydrogen or a hydroxy-protecting group R£, R 3 is phenyl,, phenyl that is mono- to tri-substituted by C-j_-C 4 alkoxy Cj-C^alkyl 5 and/or by halogen, or is 4-nitrophenyl and R 4 is hydrogen or an amino-protecting group R 4 , characterised in that a compound of the formula (II), in which Πχ, R 2 , R 3 and R 4 have the meanings mentioned 1q under formula I, is subjected to a Bayer-Villiger reaction by treatment with a per acid, and, if desired, in an obtainable compound of the formula I in which R 2 is hydrogen, the free hydroxy group is converted into a protected hydroxy group 0R 2 and/or, if desired, in an 15 obtainable compound of the formula I the hydroxy-protecting group R 2 and/or the amino-protecting group R 4 are(is) removed, the process for the manufacture of a compound of the formula (ID , in which R^ is hydrogen or Cj-C^alkyl, R 2 s hydrogen or a hydroxy-protecting group Rg, R 3 is phenyl, phenyl that is mono- to tri-sutastituted by C^-C^alkoxy, C-i-C^alkyl and/or by halogen, or is 4-nitrophenyl and R 4 is hydrogen 5 or an amino-protecting group R£> being characterised in that a) an c-carbanion of a compound of the formula (HI), in which R^, R 3 and Rj. have the meanings mentioned under formula II and the 2-carbon atom has the R-configuration and, if R x is C^-C^alkyJ., the 3-carbon atom has the R- or the S-configuration, or a compound of the formula (IV), in which R^, R 3 and R| have the meanings mentioned under formula ΙΙ, Rg is a hydroxy-protecting group that cannot be removed under the conditions of the cyclisation process and X is a nucleofugal leaving group, and the 2carbon atom has the R-configuration and, if R^ is C^-C^·alkyl, the 3-carbon atom has the R- or the S~configuration, is cvclised or b) a cis-compound of the formula in which R 3 , R 2 , R 3 and R^ have the meanings indicated under formula II, is isomerised, and, if desired, the amino-protecting group R^ is removed and replaced by hydrogen and/or, if desired, an obtainable compound of the formula II is converted into a different compound of the formula II, the process for the manufacture of a compound of the formula Hz-E-Rj (III), in which Εχ is hydrogen or Ci-C^alkyl, R 3 is phenyl, phenyl that is mono- to tri-substituted by Cx-C^alkoxy, Cx“C 4 alkyl and/or by halogen, or is 4-nitrophenyl and R£ is an amino-protecting group, and the 2-carbon atom has the R-configuration and, if Ri is Cx-C 4 alkyl, the 3carbon atom has the R- or the S-configuration, being characterised in that a compound of the formula Ri-C (VIII) cr X 0H is reacted with an amine of the formula O It R£MH-CH 2 ~C~R 3 (VII) in which R 3 and R 4 have the meanings mentioned under formula V, or a compound of the formula III is manufactured, under carbanion-forming conditions and with a Walden inversion at the 2-carbon atom, from a compound of the formula Ri CH I . x :'(2S) (V) in which R lr R 3 , R^ and X have the meanings mentioned, RjV is hydrogen or a hydroxy-protecting group that can be removed under the conditions of the epoxide formation, and in which the 3-carbon atom has the R~ or the Sconfiguration if is Ci-C^alkvl, the process for the manufacture of a compound of the formula Rx.j CHR'z'O Rx (IV), -j q in which Ri is hydrogen or Ci-I^alkyl, R®J is a hydroxyprotecting group that cannot be removed under the conditions of the cyclisation process, R 3 is phenyl, phenyl that is mono- to tri-substituted by Ci-C 4 alkoxy, C^-C^alkyl and/or by halogen,, or is 4-nitrophenyl, R^ is -j5 an amino-protecting group and X is a nucleofugal leaving group, and the 2-carbon atom has the R-configuration and, if Rj is Cj-C^alkyl, the 3-carbon atom has the R- or the S-configuration, being characterised in that a carboxylic acid of the formula ^z x -y (VI'), in which Rj, R^ and X have the meanings mentioned under formula IV, is reacted with an amine of the formula R^NH-CH 2 “C-R 3 (VII) in which R 3 and R£ have the meanings mentioned under formula V, and the process for the manufacture of a compound of the formula Ri (3R) V .- x >H-y(2S) zO Η 2 Χϊ in which Rj is hydrogen or Cx“C 4 alkvl, Rg' is hydrogen or a hydroxy-protecting group that can be removed under the conditions of the epoxide formation, R 3 is phenyl, phenyl that is mono- to tri-substituted by Cx™C 4 alkoxy, Cx-C 4 alkyl and/or by halogen, or is 4-nitrophenyl, R 4 is an amino-protecting group and X is a nucleofugal leaving group and in which the 3-carbon atom has the Reconfiguration if Rx is Cx~C 4 alkyl, being characterised in that a carboxylic acid of the formula (VI) , in which Rx, Rg' and X have the meanings mentioned under formula V, is reacted with an amine of the formula O II R£MH-CH 2 -C-R 3 (VII) 20 in which R 3 and R 4 have the meanings mentioned under formula V. -6622. A compound of the formula (I) given and defined in claim 1, substantially as hereinbefore, described and exemplified. * '*

18. 23. A process for the manufacture of a compound of the formula (I) given and defined ip. claim 1, substantially as hereinbefore 5 described and exemplified. . \ \ . ·: * i

19. 24. A compound of the formula (X)/given and defined in claim 1, whenever manufactured by a pxW&ss claimed in any one of claims 9, 21 or 23.

20. 25. A compound of the formula (II) given and defined in claim 11, 10 substantially as hereinbefore described and exemplified.

21. 26. A process for the manufacture of a compound of the formula (II) given and defined in claitsa 11, substantially as hereinbefore described and exemplified.

22. 27. A compound of th® formula (II) given and defined in claim 11, 15 whenever manufactured by a process claimed in any one of claims 19, 20 or 26.