DD250532A5 - METHOD FOR THE PRODUCTION OF OPTICALLY ACTIVE ACYLOXYAZETIDINONES - Google Patents

Abstract

The invention relates to a process for the preparation of (4R) -3,4-trans-disubstituted azetidinones. A process for the preparation of optically active acyloxyazetidinones is provided which can be used as valuable intermediates for the preparation of optically active, antibiotically active penem and carbapenem compounds. The object of the invention is to find such new valuable intermediates. According to the invention, (4R) -3,4-trans-disubstituted azetidinones of the formula I in which the substituents have the meaning given in the description are prepared by reacting a compound of the formula II in which the substituents have the meanings given in the description, by treatment with a peracid of a Bayer-Villiger reaction, and if desired in a compound of formula I wherein R2 represents hydrogen, converting the free hydroxy group into the protected hydroxy group OR2 and / or, if desired, in a compound of formula I obtainable the hydroxy protecting group R 2 and / or the amino protecting group R 4 splits off. Formulas I and II

Description

Berlin, 23 · 12. 1985 65 955 12

Process for the preparation of optically active acyloxyazetidinones

Field of application of the invention

The invention relates to a process for the preparation of (4R) -3> 4-trans-disubstituted azetidinones, which are valuable intermediates for the preparation of penem and carbapenem compounds.

Characteristic of the known technical solutions

(4R) -3,4-trans-disubstituted acetone-dinones can be further processed in a manner known per se to antibiotically active penem or carbapenem compounds. · The further processing is analogous to that of known azetidinone compounds, eg. As described by G " Hayaschi et al., Chem. Pharm. Bull. 29, 3158, 1981, or in European Patent Application Nos. 42,026 (Peneme) or Nos. 78,026 (Carbapenems).

Object of the invention

A process for the preparation of (4R) -3> 4-transdisubstituted azetidinones is provided which can be used as valuable intermediates for the preparation of optically active, antibiotically active penem and carbapenem compounds.

Explanation of the essence of the invention

The object of the invention is to find valuable intermediates for the preparation of penem or carbapenem compounds.

α ο O λ -I

:> U j

The present invention relates to a process for the preparation of (4R) -3> 4-trans-disubstituted azetidinones of the formula

(D

wherein R is hydrogen or lower alkyl, R _{2 is} hydrogen or a hydroxy protecting group RA, R 1 is phenyl, substituted phenyl or lower alkyl and R, is hydrogen or an amino protecting group R! and the novel compounds of the formula I in which R-, R and R have the meanings indicated and R 1 is phenyl or substituted phenyl.

The general definitions used in the context of this invention preferably have the following meanings: The term used in connection with groups or radicals, for. B. lower alkyl, lower alkanoyl, lower alkanoyl, etc. used term "lower" means that the so-called groups or radicals, unless expressly otherwise defined, contain up to and including 7, preferably up to and including 4 carbon atoms.

Haloalkyl R- is preferably methyl, furthermore ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl.

R ₁ is preferably methyl or hydrogen.

" ² "? SO 5 3

R.2 is preferably hydrogen.

Hydroxy protecting groups Rj> and 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 Rj is, for example, the acyl group of a substituted carboxylic or sulfonic acid, e.g. lower alkanoyl substituted by halogen, such as fluorine or chlorine, e.g. 2,2-dichloro or 2,2,2-trifluoroacetyl, optionally substituted, e.g. by halogen, for. Chloro, phenyl or ρ -nitrophenyl substituted acyl group of a lower alkyl or lower alkenyl-carbonic monoester, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, optionally e.g. aroyl substituted by nitro, halo or lower alkoxy, such as benzoyl, e.g. 4-nitro, 3,5-dinitro, 4-chloro or 4-methoxybenzoyl, lower alkanesulfonyl such as methanesulfonyl, arylsulfonyl such as toluenesulfonyl, 2-oxa or 2-thiacycloalkyl having 5 to 7 ring atoms, e.g. 2-tetrahydrofuryl or 2-tetrahydropyranyl or a thia analogue thereof, 1-lower alkoxy-lower alkyl, e.g. Methoxymethyl or 1-ethoxyethyl, or a silyl group triply substituted by lower alkyl, aryl-lower alkyl and / or aryloxy.

Ra is preferably the substituted acyl group of a carbonic acid half ester, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, nitro, one to two times substituted benzoyl, e.g. 4-nitro- or 3,5-dinitrobenzoyl, or a silyl group substituted by said groups, e.g. Tri-lower alkylsilyl, such as trimethyl- or triethylsilyl, di-lower alkyl-tri-lower alkylmethylsilyl, e.g. Dimethyl or diethyl (2-ethyl-2-propyl) silyl, dimethyl (tert-butyl) silyl, or dimethyl (2,3-dimethylbut-2-yl) silyl, diaryl (lower alkyl) silyl, e.g. Diphenyl (tert-butyl) silyl, aryl (di-lower alkyl) silyl, e.g.

tert -butyl-methyl-phenylsilyl, and tri-lower-alkylaryloxy- (di-lower alkydsilyl, e.g., 2,4,6-tri (tert-butyl) phenoxy (dimethyl) silyl.

Particularly preferred protecting groups Rj are 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl and 3,5-dinitrobenzoyl for particularly easy cleavability.

Substituted phenyl R3 is, for example, mono- to tri-substituted by lower alkoxy, e.g. Methoxy, lower alkyl, e.g. Methyl, and / or halogen, e.g. Chlorine, substituted phenyl, e.g. 4-methoxy- or 4-nitrophenyl, 2-, 3- or 4-chlorophenyl or 4-tolyl. Lower alkyl R3 is, for example, Ci-Ci) -alkyl, such as ethyl, n-propyl, isopropyl, η-butyl, isobutyl or tert-butyl, and in particular methyl. R3 is preferably phenyl.

An amino protecting group Ri is preferably oxidatively cleavable arylmethyl or aryl, with aryl preferably being replaced by one or more, e.g. two, lower alkoxy groups, e.g. Methoxy, substituted phenyl, and in particular 4-methoxybenzyl or 2,4-dimethoxybenzyl or 4-methoxyphenyl or 3,4-dimethoxyphenyl.

The inventive method is characterized in that a compound of formula

(ID

wherein Ri, R2, R3 and Rij have the meanings given under formula I, by treatment with a peracid a Baeyer-Villiger reaction, and optionally in an available compound of formula I, wherein R2 is hydrogen, the free hydroxy group in the protected Converted hydroxy group OR2,

and / or, if desired, in a compound of the formula I obtainable, the hydroxy-protecting group R 1 and / or the amino-protecting group R 1 are split off.

In a starting material of the formula II, R 1 is preferably hydrogen or methyl, R 2 is hydrogen or one of the abovementioned hydroxyl-protecting groups R 1, such as 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, 3,5-dinitrobenzoyl, dimethyl-tert-butylsilyl or dimethyl-2,2 -dimethylbut-2-ylsilyl, R4 is hydrogen or an aryl group, especially p-methoxyphenyl, and R3 is phenyl or methyl.

In the reaction, organic, inorganic peracids or iminopercarboxylic acids or salts thereof, such as alkali metal or alkaline earth metal salts, e.g. Sodium, potassium or magnesium salts, e.g. optionally halogenated lower alkanecarboxylic acids, such as peracetic acid or trifluoroperacetic acid, optionally mono- or di-substituted by nitro and / or halo aromatic peracids, such as perbenzoic acid, p-nitroperbenzoic acid, m-chloroperbenzoic acid, 3,5-dinitroperbenzoic acid, monoperphthalic acid or a salt thereof, e.g. Magnesium monoperphthalate, peroxysulfuric acids, e.g. Peroxosulfuric acid, trihaloimino-peracetic acid, e.g. Trichloro- or trifluoriminoporacetic acid. Preference is given to peracetic acid, m-chloroperbenzoic acid and monoperphthalic acid.

The peracids may also be formed in situ, e.g. from the corresponding acid or an acid salt thereof and hydrogen peroxide. In particular, the iminopercarboxylic acids are usually prepared in situ, e.g. from the corresponding nitriles and hydrogen peroxide, preferably in the presence of a weakly acidic buffer, e.g. Potassium hydrogen phosphate. The reaction takes place in a conventional solvent, e.g. 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,

as a lower alkanol, for example ethanol, at temperatures between about 0 ° and about 100 ⁰ C, optionally in an inert gas atmosphere, and optionally under pressure, for example at about up to 10 bar instead.

The hydroxy-protecting group Rj can be introduced in a manner known per se, for example by reacting a compound of the formula I in which Rj is hydrogen and Ri _{1 is} preferably an amino-protecting group Ri, 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 anhydride, a mixed anhydride, for example an acid halide, for example 2,2-dichloroacetyl chloride, a mixed anhydride of a carbonic monoester, for example 2,2,2-trichloroethyl, allyl, phenyl or p-Nitrophenylchlorformiat, by reaction with 1,2-dihydrofuran or 1,2-dihydropyran in the presence of an acid, for example p-toluenesulfonic acid, or by reaction with a halosilane, for example a tri-lower alkylhalosilane, such as trimethylchloroethane or di-methyl-tert-butylchlorosilane.

In an available compound of the formula I, the removal of the protective group Rj takes place in a manner known per se, e.g. by solvolysis, e.g. Acidolysis, reduction or oxidation.

The acyl group Rj can be saponified under acidic or alkaline conditions, depending on the meaning of Rj, for example with acids such as formic or trifluoroacetic acid or with bases such as an alkali metal hydroxide or carbonate, e.g. Sodium bicarbonate, a bicyclic amidine such as 1, S-diazabicyclot S.A.Ojundec-S-ene, or an alkali metal halide. A 2-oxa or 2-thiacycloalkyl group is split off in the presence of acids.

Halo-lower alkoxycarbonyl and optionally nitro-substituted benzyloxycarbonyl Rj can be prepared by reduction, for example by catalytic hydrogenation with hydrogen in the presence of a suitable hydrogenation catalyst, e.g. Platinum oxide or

Palladium, or by treatment with chemical reducing agents, such as zinc in the presence of aqueous acetic acid, cleaved and replaced by hydrogen.

The silyl group Rj substituted as indicated may be neutral, acidic or alkaline in the presence of solvents containing hydroxyl groups, or in particular by treatment with a hydrofluoric acid salt yielding fluoride anions, such as with an alkali metal fluoride, e.g. Sodium fluoride optionally in the presence of a macrocyclic polyether ("crown ether") or with the fluoride of an organic quaternary base such as tetra-lower alkylammonium fluoride, e.g. Tetrabutylammonium fluoride, be cleaved.

The conversion of the Niederalkenyloxycarbonyloxy group -OR'2 in hydroxy, wherein lower alkenyl is in particular allyl, is preferably carried out with a lower alkenyl group acceptor in the presence of tetrakis-triphenylphosphine-palladium and optionally in the presence of triphenylphosphine. Suitable acceptors for lower alkenyl groups, especially the allyl group, are e.g. Amines, in particular sterically hindered amines, e.g. tert-butylamine, further tri-lower alkylamines, e.g. Triethylamine, morpholine or thiomorpholine, aliphatic or cycloaliphatic β-dicarbonyl compounds, e.g. Acetylacetone, ethyl acetoacetate or dimedone, and also lower alkanecarboxylic acids, e.g. Acetic or propionic acid. A preferred acceptor is dimedone. The reaction is carried out with 1.5 to 10 molar equivalents of the lower alkenyl group acceptor in the presence of 2 to 10 mol%, in particular 5 to 8 mol% (based on the starting compound of the formula I), tetrakis-triphenylphosphine palladium catalyst, if appropriate in the presence of up to 50 mole% of triphenylphosphine in an inert solvent such as an ether, eg Dioxane or, in particular, tetrahydrofuran, a halohydrocarbon, e.g. Methylene chloride, a lower alkanol, e.g. Ethanol, an ester, e.g. Ethyl acetate, or in a mixture thereof at room temperature or slightly elevated or

- ⁷ - 25053?

Rectified temperature, for example at about O ⁰ to about 40 ⁰ C, preferably at about 20 ° to about 25 ⁰ C, if necessary, in an inert gas atmosphere, as carried out in a nitrogen or argon atmosphere.

The arylmethyl group Ri, e.g. 4-methoxy- or 2,4-dimethoxybenzyl, e.g. oxidatively cleaved, e.g. by reaction with a strong oxidizing agent, e.g. an inorganic peroxy salt, e.g. Sodium or potassium peroxodisulfate, in the presence of an acidic salt, e.g. Dipotassium hydrogen phosphate, and optionally in the presence of a catalyst, e.g. a metal salt, e.g. an iron (II) and / or copper (II) salt, e.g. Iron (II) sulphate heptahydrate and / or cupric acetate hydrate, or in particular by reaction with a cerium (IV) salt, e.g. Cerium (IV) iodate, cerium (IV) nitrate (CeOH (NCh) 3). Cerium (IV) sulfate or, preferably, with diammonium cerium (IV) hexane nitrate, e.g. in aqueous-organic media, preferably in aqueous acetonitrile.

The aryl group Ri, e.g. 4-methoxyphenyl or 3,4-dimethoxyphenyl is preferably removed by oxidation, e.g. ozonolytic in ethyl acetate and subsequent decomposition of the formed ozonides by reduction with a reducing agent, e.g. Sodium thiosulfate, or by reaction with a cerium (IV) salt, e.g. Diammonium cerium (IV) hexanitrate.

R ^ can be cleaved either selectively or together with R'ζ, depending on the meaning of Rj.

The described cleavage reactions are carried out under conditions known per se, if necessary with cooling or heating and optionally in an inert gas, e.g. Nitrogen atmosphere.

The present invention preferably relates to a process for the preparation of compounds of formula I wherein R 1 is hydrogen or methyl, R 2 is hydrogen or a hydroxy-protecting group R 2, e.g. the substituted acyl group of a carbonic monoester, e.g. 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl,

η r '* r C J υ j

Benzyloxycarbonyl or p-nitrobenzyloxycarbonyl, 4-nitro- or 3,5-dinitrobenzoyl or tri-lower alkylsyl, for example trimethylsilyl, dimethyl-tert-butylsilyl, or dimethyl- (2,3-dimethylbut-2-yl) silyl, R3 is phenyl or methyl and Ri _{4 is} hydrogen or an amino protecting group R j, for example 4-methoxybenzyl, 2,4-dimethoxybenzyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl, and wherein the l-C atom of the side chain is the R or S configuration has, if Ri means lower alkyl ·

Compounds of formula I, especially those in which Rj is hydrogen or methyl, R2 is hydrogen or a hydroxy protecting group Ra, and Ri »is hydrogen, are valuable intermediates which can be further processed in known manner to antibiotically active penem or carbapenem compounds , Further processing is analogous to that of known azetidinone compounds of formula I wherein R 3 is methyl, e.g. as described by T. Hayashi et al., Chem. Pharm. Bull. 29, 3158, 1981 or in European Patent Application Nos. 42026 (to Peneme) or 78026 (to carbapenems).

The invention also relates to the starting compounds of the formula II, in particular those in which R 1, R 2, R 3 and R 4 have the preferred meanings, and to a process for their preparation.

The process for the preparation of compounds of the formula II is characterized in that a) an α-carbanion of a compound of the formula

3 y

Ri-CH-fi (2R) CH ₂ -OR ₃ (III)

VIi 1

wherein Ri, R3 and Ri have the meanings given under formula I, and the 2-C atom is the R- and, when Ri is lower alkyl, the 3-C atom has the R or the S configuration, or a compound the formula

OSO

U ^(iv) '

H ₂ -L ₃

wherein Ri, R3 and Ri have the meanings given under formula I, R "is a non-removable under the conditions of the ring closure hydroxy protecting group, and X represents a nucleofugic leaving group and the 2-C atom, the R- and, when Ri is lower alkyl, the 3-C-atom has the R- or the S-configuration, cyclized, or b) a cis-compound of the formula

² ΐ fs'

-,. MIIC-R;

^ yC-R ₃ (II ¹ )

wherein Ri, R2, R3 and R ^ have the meanings given under formula II, isomerized, and if desired, the amino-protecting group Ri is split off and replaced by hydrogen, and / or, if desired, an obtainable compound of formula II in another compound the formula II converts.

In a starting material of the formula IV, a hydroxy protecting group R "which can not be split off under the conditions of the ring-closing process is one of the acyl groups of a substituted carboxylic acid or sulfonic acid, for example 2,2,2-trifluoroacetyl, the substituted acyl group of a carbonic acid monoester, for example p-nitrobenzyloxycarbonyl , 2-tetrahydrofuryl or -pyranyl, or 1-lower alkoxy-lower alkyl, eg, methoxymethyl or 1-ethoxyethyl, or an optionally substituted aroyl, eg 4-nitrobenzoyl or 3,5-dinitrobenzoyl group, and a suitable nucleofuge leaving group X is, for example, halogen, eg Chlorine, bromine or iodine, lower alkanoyloxy, for example acetoxy, arylsulfonyloxy, for example phenylsulfonyloxy or tosyloxy, or lower alkylsulfonyloxy, for example mesyloxy.

2 S 0 5 3

By the α-carbanion of a compound of formula III or IV is meant an anion in which the negative charge on the carbon atom is in α-position to the -CO-R3 group, i. a corresponding compound with the partial formula -N-CH ~ -CO-R.3. Such carbanions are prepared in situ by treating a compound of formulas III or IV in a suitable solvent with a base which forms such carbanions. Such bases include, for example, alkali metal bases, such as hydroxides or carbonates of sodium, potassium or lithium, or organic alkali metal compounds, e.g. Lower alkyl lithium compounds such as η-butyl or tert-butyl lithium, alkali metal amides, e.g. Lithium diisopropylamide or di-tert-butylamide, and especially alkali metal amides wherein two hydrogen atoms are represented by silyl, e.g. Trimethylsilyl groups are replaced, e.g. Lithium, sodium or potassium bis (trimethylsilyl) amide.

Other bases are organic nitrogen bases, e.g. Amidines, such as 1,5-diazabicyclo [4.3.0] non-5-ene and 1,5-diazabicyclo [5.4.0] undec-5-ene, as well as reagents which provide fluoride ions in an aprotic, organic solvent and especially to Preparation of carbanions of the compounds of formula III are suitable.

A reagent which provides fluoride ions in an aprotic organic solvent is preferably a tetra-lower alkylammonium fluoride, especially tetra-n-butylammonium fluoride.

Suitable solvents for carbanion formation are, for example, hydrocarbons, such as benzene or toluene, halogenated hydrocarbons, such as methylene chloride or chloroform, ethers, such as dioxane, tetrahydrofuran or dimethoxyethane, amides, such as dimethylformamide or hexamethylphosphoric triamide, sulfoxides, such as dimethyl sulfoxide or nitriles, such as acetonitrile, or mixtures thereof , The reaction may also be carried out under phase transfer conditions, e.g. in the system consisting of methylene chloride and 50% sodium hydroxide in the presence of a phase transfer catalyst, such as Benzyltriethylaimnoniumchlorid or tetrabutyl

amtnoniumhydrogensulfat. The reaction temperature also depends on the base used and is between about -80 ⁰ C and 80 ⁰ C. It is preferably carried out under inert gas atmosphere, eg argon or nitrogen atmosphere.

In the process, an inversion of the configuration takes place at the 2-C atom of the starting material, so that a 3S compound of the formula II is formed from a 2R compound of the formulas III or IV. The configuration of the l'C atom (Ri "lower alkyl) in the side chain remains unchanged. For example, from R-glycidic amides of the formula (III) 3S-azetidinones of the formula II or from (2R, 3R) -2,3-epoxybutyric arraids of the formula III (3S-1'R) -3-hydroxyethylazetidinones of the formula II are obtained ,

The isomerization process b) takes place in a suitable solvent or solvent mixture in the presence of a base. Suitable solvents and bases as well as the reaction conditions are the same as those which can be used for the cyclization process a). Preference is given to using aprotic dipolar solvents, such as dimethylformamide, N-methylpyrrolidine, dimethyl sulfoxide or the like. Suitable bases are, in particular, potassium carbonate or 1,5-diazabicyclo [5.4.0] undec-5-ene, it also being possible to work under the phase transition conditions mentioned.

The cis compounds of the formula II 'can be formed as by-products in cyclization reaction a). They can be prepared in the usual way, e.g. by chromatography, be separated.

Compounds of the formula III can be prepared in a manner known per se by reacting compounds of the formula VII with epoxide acids of the formula

(VIII)

or their salts are prepared analogously as indicated below for the reaction of a carboxylic acid of the formula VI with an amine of the formula VII. The epoxy acids of the formula VIII are known or can be prepared in a manner known per se.

In a preferred embodiment of the process, starting materials of the formula III are prepared from compounds of the formula

wherein Ri, R3, Rl and X have the meanings given, R " ^{1 represents} hydrogen or a hydroxy protecting group which can be split off under the conditions of epoxide formation and in which the 3-C atom has the R or S configuration, if R ¹ denotes lower alkyl the said carbanion-forming conditions and under Walden reversal at the 2-carbon atom in situ .

In a compound of the formula V, a hydroxy protecting group which can be split off under the conditions of epoxide formation is R 2 '. a tri-lower alkylsilyl group, e.g. Dimethyl-tert-butylsilyl or trimethylsilyl. X is preferably halogen, e.g. Chlorine or bromine, lower alkanesulfonyloxy, e.g. Mesyloxy, or arylsulfonyloxy, e.g. Tosyloxy.

The cleavage of R "'- X, in which Rä' is hydrogen, takes place with one of said carbanion-forming bases, eg sodium or potassium hydroxide or sodium or potassium carbonate, preferably with an amidine, eg 1,5-diazabicyclo [5.4.0] undec-5-ene, or else with a tetra-lower alkylammonium fluoride, eg dehydrated tetra-n-butylammonium fluoride If R " ^{1 is} a tri-lower alkylsilyl group which can be split off under the conditions of the epoxide formation, a tetra-lower alkylammonium fluoride is preferably used.

_ ₁₃ - c. J - 'J - -

The conversion into an epoxy compound of the formula III is preferably carried out in an inert, preferably anhydrous, solvent or solvent mixture, for example in a carboxamide, for example dimethylformamide, a halogenated hydrocarbon, for example methylene chloride, chloroform, carbon tetrachloride or chlorobenzene, a ketone, for example acetone cyclic ethers, eg dioxan or tetrahydrofuran, an ester, for example ethyl acetate, or a nitrile, for example acetonitrile, or in mixtures thereof, optionally at reduced or elevated temperature, for example in a temperature range of about -4o ⁰ C to about +100 ⁰ C, preferably from about -10 ° C to about + 5O ⁰ C, and optionally under an inert gas, eg nitrogen atmosphere.

In the reaction according to this method, the configuration on the 2-C atom is reversed, while the configuration of the 3-C atom (Ri = lower alkyl) is retained. 2S-Halogen-3R-hydroxycarboxamides of the formula V give the (2R, 3R) compounds of the formula III. The same applies to the 2S-halogen-3S-hydroxycarboxamides of the formula III.

The epoxide of the formula III can also be isolated after its preparation by removal of R "'- X from a compound of the formula V.

The conversion of a compound of the formula V in which R " ^{1 is} hydrogen into the epoxy compound of the formula III and its isolation takes place in a manner known per se, for example under those from steroid chemistry, see C. Djerassi et al.," Steroid Reactions ", Holden Day, San Francisco 1963, pp. 606-613, in particular by means of one of the abovementioned amidines, such as 1, S-diazabicyclot S.A.Ojundec-S-en, if the compound of the formula III is to be isolated before it is further processed , It is preferable to use one of said amidines in about equimolar amount.

Compounds of the formulas IV and V and processes for their preparation are likewise provided by the present invention.

- ¹⁴ - 25053

Compounds of the formula V can be prepared, for example, by reacting a carboxylic acid of the formula

(VI)

c / \ h

wherein Ri, Rä 'and X have the meaning mentioned under formula V, with an amine of the formula

R 1 NH-CH ₂ -CR ₃ (VII),

wherein R3 and Ri have the meanings given under formula V, is reacted.

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 together in the presence of a condensing agent, or a reactive functional derivative of a carboxylic acid of the formula VI with a Reacting amine of formula VII. Suitable condensing agents are, for example, diimides, such as diethyl or dicyclohexylcarbodiimide, or di-N-heterocyclylcarbonyl compounds, such as carbonyldiimidazole, or a 1,2-oxazolium compound, such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulphonate or 2 tert-butyl 5-methyl-1,2-oxazolium perchlorate which are applied 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, in particular, anhydrides, in particular mixed anhydrides, such as the corresponding carboxylic acid chloride or bromide, which, if appropriate in the presence of a base, react with the amine of the formula VII.

Compounds of formula VI and VI ', wherein X is halogen, are known. These can be prepared, for example, in a manner known per se from L-serine or L-threonine or their D-isomers by diazotization of the amino group with a nitrite salt, e.g. Prepare potassium nitrite in the presence of a hydrohalic acid.

When L-serine is used, starting from compounds of the formula VI, compounds of the formula I in which the carbon in the 3-position of the azetidinone ring has the R configuration can be obtained by the processes described.

When L-threonine is used, compounds of the formula I are obtained in which the C atom in the 3-position of the azetidinone ring has the R configuration and the 1'-C atom of the hydroxyethyl side chain has the R configuration. When it is intended to prepare compounds of formula I in which the 3-C atom has the R configuration and the 1'-C atom of the hydroxyethyl side chain has the S configuration, allothreonine is used. In all the reactions described, the configuration of the C atom, which in compounds of the formula I corresponds to the 1'-C atom of the 3-lower-alkyl-CH- (OR 2> -side chain, remains unchanged.

In a manner analogous to the preparation of compounds of formula V, starting from compounds of formula VIII and the compounds of formula

HJC

(VI ')

produce the compounds of formula IV.

Compounds of the formula VII are known or, if they are new, can be prepared in a manner known per se.

- ie- 2 5 0-5 3 ί

The present invention also relates to such embodiments of the process starting from a compound obtainable on any precursor of the process and carrying out the subsequent process steps.

The invention also relates to the combination of the process steps starting from the compounds of the formulas VI, VI ¹ , VII and VIII up to the compounds of the formula I.

The process according to the invention has the advantage that the compounds of the formula I can be prepared stereospecifically in high yield and economically.

Preference is given to the novel compounds and processes specified in the examples.

The following examples serve to illustrate the invention. Temperatures are in degrees centigrade and IR values in centimeters. For the ¹ H NMR spectra, the chemical shifts (S) are given in ppm and coupling constants J in Hertz (Hz). The specific

20 see rotation values [α] are [ö] _n values. For the chromatographic separation during the preparative workup, columns filled with Merck Kieselgel 60 can be used. Rfr values apply to precast plates for thin-layer chromatography (Merck 60 F 254).

Abbreviations: m »medium absorption band

sh sharp absorption band

s singlet

m »multiplet

d = doublet

F. Melting point

Bp. = Boiling point

dd »doublet of doublets

AB »signal group of the AB type

9 5 O - *

Example 1; (2S, 3R) -2-bromo-3-hydroxybutyric acid-N-p-methoxyphenyl-N-phenacylamid

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 is added 15.47 g of dicyclohexylcarbodiimide and heated under argon atmosphere for 48 hours stirred at room temperature. The dicyclohexylurea formed during the reaction is filtered off with suction and the filtrate is evaporated in a water-jet vacuum. The amorphous residue is chromatographed on a 60-fold amount by weight of silica gel with a toluene / ethyl acetate (9: 1) mixture for purification. The title compound obtained (NMR spectrometry (CDCl ₃ ) signals at 1.23 (d), 3.83 (s), 3.88 (s), 4.10 (m), 4.18 (d), 4, 75 / 4.80 / -5.31 / 5.36 (AB) and 6.94 (dd)) can be used directly for subsequent cyclization.

Example 2: (2R, 3R) -2,3-epoxybutyric acid N-p-methoxyphenyl-N-phenacylamide

A solution of 406 mg (1 mmol) of (2S, 3R) -2-bromo-3-hydroxybutyric acid Np-methoxyphenyl-N-phenacylamide in 7 ml abs. Tetrahydrofuran is added under argon at -10 ° with 165 μΐ (169 mg, 1.1 mmol) of 1,5-diazabicyclo [5.4.0] undec-5-ene and the resulting reaction mixture for 5 hours at 0 ° and a further 3 hours Room temperature stirred. For workup, the reaction mixture is diluted with methylene chloride and washed successively with water, 5% aqueous citric acid solution and 8% aqueous sodium bicarbonate solution. The aqueous portions are back-extracted with methylene chloride. The residue obtained by drying and evaporation in vacuo of the combined organic fractions is chromatographed on silica gel plates in toluene / ethyl acetate (1: 1) mixture. The title compound is obtained as a viscous OeI, Rf (Merck silica gel prefabricated plates, toluene / ethyl acetate 1: 1): 0.27; (IR CH ₂ Cl ₂ ): et al. Bands at 1700, 1670, 1595, 1580, 1505, 1427, 1392, 1365, 1348, 1300, 1243, 1221, 1180, 1170, 1140, 1103, 1028, 982; NMR (CDCl ₃ ): signals at 1.50 (d), 3.08 (m), 3.36 (d), 3.82 (s), 4.86 (d), 5.42 (d), 6.91 (m), 7.34 (m), 7.46 (m), 7.57 (m), 7.93 (m).

Example 3: (3S, 4S, 1'R) -N-p-Methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one

a) with lithium bis (trimethylsilyl) araid: A solution of 3.37 g (2S, 3R) -2-bromo-3-hydroxybutyric acid Np-methoxyphenyl-u-phenacylamide, cooled to -20 °, in 20 ml of tetrahydrofuran With stirring in argon atmosphere with 33 ml of a 0.5 molar solution of lithium bis (trimethylsilyl) amide in tetrahydrofuran and stirred with slow warming to -10 ° for 1 1/2 hours. The reaction mixture is poured into ice-water and extracted with methylene chloride. The organic phase is washed successively with ice-cold 1N sulfuric acid, water, ice-cold, saturated, aqueous sodium bicarbonate solution and with water, dried and evaporated in a rotary evaporator. The resulting crude product is chromatographed on silica gel. With a toluene / ethyl acetate (9: 1) mixture to obtain the (3S, 4S, 1'R) -Np-methoxyphenyl-3- (l-hydroxyethyl) -4-benzoylazetidin-2-one, which after redissolution of Methylene chloride / ether at 111-113 °, melting [a] »-95.1 ° (c» 1.121% in CHCl ₃ ).

b) with sodium hydroxide: A mixture of 950 mg of (2S, 3R) -2-bromo-3-hydroxybutyric acid Np-methoxyphenyl-u-phenacylamide in 25 ml of methylene chloride and 8 ml of 50% aqueous sodium hydroxide solution is added Addition of 75 mg of benzyltriethylammonium chloride vigorously stirred for 5 1/2 hours at room temperature. From the reaction mixture, the sodium hydroxide solution is separated, the organic phase washed twice with water, dried and evaporated in a water jet vacuum. By subsequent chromatography on silica gel with toluene / ethyl acetate (9: 1) mixture followed by crystallization of the uniform fractions, the title compound is obtained pure.

c) with tetrabutylammonium fluoride:

A solution of 300 mg (0.95 mmol) tetrabutylammonium fluoride trihydrate in 4 ml of tetrahydrofuran is added to the dewatering with activated molecular sieves (4x10 m) and left under argon at 0 ° for 18 hours. Then, while stirring at 0 °, a solution of 206 mg (0.63 mmol) of (2R, 3R) -2,3-epoxybutyric acid N-p-methoxyphenyl-

, "Λ f 'λ, -';. η

- 19 - I 'JV : si /

N-phenacylamide in 2 ml abs. Dropped tetrahydrofuran and the reaction mixture was stirred at 0 ° for 2 hours. The molecular sieves are filtered off, washed at the filter with tetrahydrofuran, the combined filtrates evaporated in vacuo and the residue, dissolved in methylene chloride, washed successively with IN H2SO4 and water. The aqueous portions are back-extracted with methylene chloride. The combined organic fractions give, after drying and evaporation in vacuo, a crude product which is chromatographed on silica gel plates with toluene / ethyl acetate (9: 1). This gives the title compound with the data described above.

d) with potassium carbonate; A solution of 13.0 g (2R, 3R) -2,3-epoxybutyric acid-Np-methoxyphenyl-N-phenacylamide in 74 ml of dimethyl sulfoxide is treated with 55.2 mg of potassium carbonate and under argon atmosphere for 6 hours at 21 to 24 ° touched. The reaction mixture is poured onto 1.6 l 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 brine, dried and evaporated. The resulting crude product is chromatographed on a silica gel column. Elution with hexane / ethyl acetate (7: 3) mixture gives a small amount of chromatographically uniform (3S, 4R, 1'R) -Np-methoxyphenyl-3- (r-hydroxyethyl) -4-benzoylazetidin-2-one, which melts after crystallization from methylene chloride-diisopropyl ether at 168-170 °. Further elution with hexane / ethyl acetate (1: 1) mixture gives the chromatographically uniform (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one, which is determined by Crystallization from methylene chloride-diisopropyl ether at 111-113 ° melts.

e) with 1,5-diazabicyclo [5.4.0jundec-5-ene: analog d) the same compound is obtained if, under otherwise identical conditions, the equivalent amount of 1,5-diazabicyclo- [5.4.0] is used instead of potassium carbonate. undec-5-en.

f) by isomerization of the cis-isomer with K2CO3: The (3S, 4R) isomer of the title compound obtained by cyclization of (2R, 3R) -2,3-epoxybutyric acid-Np-methoxyphenyl-N-phenacylamide by-product in small amounts (Example 3d) can be isomerized to the title compound by stirring 3.9 g of this cis compound in 80 ml of dimethylformamide with 6.6 g of potassium carbonate for 2.5 hours at 60 ° (bath temperature). The inorganic salt is filtered off, the filtrate concentrated under reduced pressure, the residue taken up in methylene chloride, the resulting solution washed with water and with aqueous sodium chloride solution, dried, concentrated in vacuo, and the residue chromatographed on a silica gel column. Hexane-ethyl acetate (2: D mixture) is first eluted with a small amount of the (3S, 4R) isomer, followed by elution with hexane-ethyl acetate 1: 1 mixture, of the pure title compound which, after crystallization from methylene chloride / Diisopropyl ether at 111-113 ° melts.

g) by isomerization of the cis isomer with NaOH: In a two-phase mixture of equal volumes of methylene chloride and 1N sodium hydroxide solution and in the presence of 60 mg of tetrabutylammonium hydrogensulfate, 3.9 g of (3S, 4R, rR) -Np-methoxyphenyl-3- (1 ' -hydroxyethyl) -4-benzoylazetidin-2-one (cis isomer) for 2 hours at 21 °. The sodium hydroxide solution is separated off and the organic phase is dried after washing with water and evaporated in vacuo. The residue containing a (7: 3) mixture of the (3S, 4S) - and (3S, 4R) compound is separated by chromatography with toluene-ethyl acetate on silica gel in the pure isomers. After recrystallization of the (3S, 4S) compound containing and evaporated fractions gives the pure title compound, mp 111-113 °.

Example 4; (3R, 4R, 1'R) N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-

benzoyloxyazetidin-2-one:

A solution of 416 mg of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidinone in 20 ml of methylene chloride is added 1.27 g of m-chloroperbenzoic acid and placed in a bomb tube for 72 hours heated to 45-50 °. The reaction mixture is poured onto ice water and

2 5 O- 5 3

diluted with methylene chloride. The organic phase is washed successively with potassium iodide-sodium thiosulfate, ice-cold saturated sodium bicarbonate solution and water, dried and evaporated on a rotary evaporator. After chromatographing on silica gel (eluent: toluene / ethyl acetate 9: 1 mixture), the pure (3R, 4R, 1'R) -Np-methoxyphenyl-3- (I ¹ -hydroxyethyD-4-benzoyloxyazetidin-2-one is obtained. IR: bands at, inter alia, 3600, 1765, 1725, 1600, 1515, 1450, 1240, 1180, 1070 and 1025. NMR: signals among others at 1.42 (d), 3.38 (d), 3.7 ( s), 4.30 (m), 6.52 / 7.42 (AA'BB ¹ ).

The same compound is obtained under analogous conditions even when 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) -4-benzoyloxyazetidin-2-one:

A solution of 325 mg of (3R, 4R, l'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoyloxyazetidinone in 15 ml of acetonitrile, cooled to 0 °, is treated with a solution of 1.642 g of cerium (IV ) ammonium nitrate in 15 ml of water and stirred for 30 minutes at -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 successively with dilute, aqueous sodium bicarbonate, 10% sodium sulfite, sodium bicarbonate solution and water, dried and evaporated. The crude product obtained after filtration through the 20-fold amount by weight of silica gel (eluent: toluene / ethyl acetate 8: 2) and subsequent crystallization of thin-layer chromatographically uniform fractions from chloroform-petroleum ether, the pure (3R, 4R, 1'R) -3- ( 1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one. F. 144.5-146 °. [α] - +67.6 ± 2.4 ° (c.- 0.414%, CHCl _3).

Example 6: (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one a) A solution of 325 mg (3S, 4S, 1'R) cooled to -18 ° -Np-Methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidin-2-one in 10 ml of acetonitrile is treated with a solution of 2.2 g of cerium (IV) ammonium nitrate

in 5 ml of water and stirred for 35 minutes at -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 evaporated. After recrystallization of the crude product from methylene chloride / ether, the pure, melting at 132-134 ° (3S, 4S, 1'R) -3- (l'-hydroxyethyl) -4-benzoylazetidin-2-one is obtained.

b) by isomerization of the cis isomer with 1,5-diazabicyclo [5.4.0] undec-5-ene : A solution of 660 mg (3S, 4R, 1'R) -3- (1-hydroxyethyl) - 4-benzoylazetidin-2-one in 14 ml of chloroform is combined with 0.05 ml of 1,5-diazabicyclo [5.4.0] undec-5-ene and heated to 75 ° for 15 hours. The reaction mixture is evaporated in vacuo and the residue is chromatographed on a silica gel column. With hexane-ethyl acetate (1: 1), first a small amount of the (3S, 4R) -isomer is eluted, followed by the (3S, 4S) -isomer, which is crystallized from methylene chloride / diisopropyl ether. F. 131-135 °.

The (3S, 4R, 1 ¹ R) used as starting material - (I'-hydroxyethyl) -4-benzoylazetidinon-2-one can be prepared as follows:

A suspension of 9.7 g (3S, 4R, 1'R) -Np-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one (cis-isorner from Example 3d ) in 225 ml of acetonitrile is mixed with a solution of 36.3 g of cerium (IV) ammonium nitrate in 150 ml of water and stirred for 30 minutes at -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 are washed successively with 1% sodium sulfite and sodium chloride solution, dried with sodium sulfate and evaporated. The crude product obtained after crystallization from methylene chloride / diisopropyl ether gives the pure (3S, 4R, l'R) -3- (r-hydroxyethyl-4-benzoylazetidin-2-one, mp 145-147 °.

9c Λ tr

Example 7: (3R, 4R, rR) -3- (1-hydroxyethyl) -4-benzoyloxyazetidin-2-one

a) with m-chloroperbenzoic acid: A solution of 1.9 g of (3S, 4S, 1'R) -3- (1'-hydroxyethyl) -4-benzoylazetidinone in 172 ml of methylene chloride is mixed with 10.1 g of 85% iger m-chloroperbenzoic acid and stirred for 165 minutes at about room temperature. The reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous potassium iodide / sodium thiosulfate and sodium bicarbonate solution and then with water, dried and evaporated. After filtration of the resulting crude product in toluene / ethyl acetate (8: 2) mixture over 300 g of silica gel and subsequent crystallization of the uniform fractions from methylene chloride / ether, the pure (3R, 4R, 1'R) -3- (l-hydroxyethyl ) -4-benzoyloxyazetidin-2-one of melting point 145-147 °. The compound is identical to the preparation described in Example 5 in terms of IR and NMR spectrum and optical rotation.

b) with peracetic acid: The title compound can also be prepared by reacting 4,27. g (3S, 4S, 1'R) -3- (1-hydroxyethyl) -4-benzoylazetidin-2-one in 60 ml of methylene chloride with 12.2 ml of a 30% peracetic acid solution in acetic acid and 6 hours under Reflux heated. The resulting reaction mixture is diluted with methylene chloride and washed successively with 5% aqueous NaHSO3, 8% aqueous NaHCO3 and saturated aqueous sodium chloride solution. The aqueous portions are back-extracted with methylene chloride, the combined organic portions over Na2S0i »dried and evaporated. The crystalline crude product is recrystallized directly from methylene chloride / ether to yield the pure title compound having the data described above.

c) with magnesium monoperphthalate hexahydrate; A solution of 5 g of (3S, 4S, ^I l R) -3- ^(l> hydroxyethyl) -4-benzoylazetidin-2-one in 200 ml of ethyl acetate is added a solution of 16.5 g of magnesium monoperphthalate hexahydrate in 60 ml of ethanol (96% strength) and the resulting reaction mixture for 5 hours at 50 ° bath temperature

touched. This precipitates a crystalline precipitate. The suspension is mixed with methylene chloride and 5% aqueous sodium sulfite solution and the organic phase is subsequently washed with 8% aqueous sodium bicarbonate solution. The aqueous portions are back-extracted with methylene chloride, combined the organic extracts, evaporated and the residue recrystallized from methylene chloride / pentane. The pure title compound having the above-mentioned properties is obtained.

d) with hydrogen peroxide and trichlorofacetonitrile : The title compound can also be prepared by reaction of 11 g of (3S, 4S, l'R) -3- (i'-hydroxyethyl) -4-benzoylazetidin-2-one with 19 ml of 30% strength Hydrogen peroxide and 21 ml of trichloroacetonitrile in the presence of 10 g of potassium hydrogen phosphate in 200 ml of chloroform analogously to Example 13c).

Example 8: (3S, 4S, 1'R) -Np-Methoxyphenyl-3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] j-4-benzoylazetidin-2-one: A solution of 325 mg of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidin-2-one in 5 ml of methylene chloride is added under argon with 0.18 ml of triethylamine, 0.18 ml Chloroformic acid 2,2,2-trichloroethyl ester and 130 rag dimethylaminopyridine and 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 evaporated. Filtration of the residue over silica gel (toluene / ethyl acetate 9: 1) gives the pure (3S, 4S, 1'R) -Np-methoxyphenyl-3- [Γ- (2,2,2-trichloroethoxycarbonyloxy) -ethyl] 4-benzoylazetidin-2-one as a colorless foam. IR: bands among others at 1760, 1690, 1512, 1380, 1240 and 1183 cm; [α] = -9.5 ° (c = 0.980%, chloroform).

Example 9; (3S, 4S, ΓR) -3- [Γ- (2,2,2-trichloroethoxycarbonyloxy) -ethylj-4-benzoylazetidin-2-one:

A solution of 400 mg (3S, 4S, 1'R -) - Np-methoxyphenyl-3- [1 '- (2,2,2-trichloroethoxycarbonyl-oxy) ethyl] -4-benzoylazetidin-2-one, cooled to -18 ° in 10 ml of acetonitrile is added to a solution of 965 mg of cerium (IV) ammonium nitrate in 5 ml of water and within 2 1/2 hours with stirring to -5 ° .Heat. 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 evaporated. By crystallization of the resulting crude product from methylene chloride / ether / petroleum ether, the pure, at 106-108 ° melting (3S, 4S, 1'R) -3- [1 '- (2,2,2-Trichlorethoxycarbonyloxy) -ethyl] - 4-benzoylazetidin-2-one.

Example 10: (3R, 4R, 1'R) -3-f1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoyloxyazetidin-2-one:

A solution of 230 mg of (3S, 4S, 1 'R) -3- [r- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidinone in 20 ml of methylene chloride is admixed with 683 mg of 85% strength m-chloroperbenzoic acid and stirred for 3 1/2 hours at room temperature. The reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous potassium iodide / sodium thiosulfate solution, water, ice-cold, aqueous sodium bicarbonate solution and water, dried and evaporated. The crude product thus obtained gives, after filtration through silica gel (toluene and toluene / ethyl acetate-8: 2) and subsequent crystallization of the uniform fractions from methylene chloride / ether / petroleum ether, the pure (3R, 4R, ΓR) -3- [1 '- (2 , 2,2-Trichloroethoxycarbonyloxy) ethyl] -4-benzoyloxyazetidin-2-one of melting point 118-120 °. [α] - + 75 ° (c - 1.01%, chloroform).

Example 11: (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (1'-allyloxycarbonyl-

oxyethyl) -4-benzoylazetidin-2-one

A solution of 325 mg (3S.4S, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidinone, cooled to 0 °, in 5 ml of methylene

- 26 -. Oujo

Chloride is added under argon with 0.18 ml of triethylamine, .0.16 ml of allyl chloroformate and 130 mg of dimethylaminopyridine and stirred for 1 hour at the same temperature. After * re-addition of the indicated amounts of triethylamine, allyl chloroformate and dimethylaminopyridine is stirred for a further 17 hours at 0 °, then added a third portion of equal amounts of the three reagents and stirred for 24 hours at room 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 evaporated. After filtration of the residue over 40 g of silica gel (toluene / ethyl acetate-9: 1), the pure (3S, 4S, 1'R) -Np-methoxyphenyl-3- (l-allylbxycarbonyloxyethyl) -4-benzoylazetidin-2-one receive. F. 78-80 °.

Example 12: (3S, 4S, 1'R) -3- (Γ-Allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one:

A solution of 270 mg (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 10 ml of acetonitrile, cooled to -18 °, is treated with a solution of 800 Mg cerium (IV) ammonium nitrate in 5 ml of water and heated within 3 hours with stirring 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 evaporated. Filtration of the resulting crude product over 20 g of silica gel (toluene / ethyl acetate-8: 2) and subsequent crystallization of the pure fractions from methylene chloride / ether / petroleum ether, the pure, at 93-95 ° melting (3S, 4S, 1'R) - 3- (l-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one.

Example 13; (3R, 4R, 1'R) -3- (1'-Allyloxycarbonyloxyethyl) -4-benzoyl

oxyazetidin-2-one

a) with m-chloroperbenzoic acid: A solution of 60 mg (3S, 4S, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 5 ml

2 5 O s

Methylene chloride is treated with 234 mg of 85% strength m-chloroperbenzoic acid and stirred for 3 1/2 hours at room temperature. The reaction mixture is poured onto ice-water and extracted twice with methylene chloride. The organic phases are washed successively with aqueous Raliumjodid / sodium thiosulfate solution, water, ice-cold aqueous sodium bicarbonate solution and water, dried and evaporated. The crude product thus obtained gives, after filtration through silica gel (toluene and toluene / ethyl acetate-8: 2) and subsequent crystallization of the uniform fractions from methylene chloride / ether / petroleum ether, the pure (3R.4R, l'R) -3- (l' Allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one of melting point 84-85 °.

b) with peracetic acid: The title compound can also be prepared by dissolving a solution of 91 mg of (3S, 4S, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 5 ml of methylene chloride in three portions of a total of 0.4 ml of 30% peracetic acid in acetic acid and stirred for 48 hours at room temperature. The resulting reaction mixture is washed in methylene chloride successively with 5% aqueous sodium sulfite, 8% aqueous sodium bicarbonate and aqueous brine. The aqueous portions are back-extracted with methylene chloride, and the combined organic extracts, after drying with NaaSOi »evaporated. After chromatographing the residue obtained

ν silica gel plates with hexane / ethyl acetate (1: 1) gives the pure

Title compound having the above-mentioned properties.

c) with hydrogen peroxide and trichloroacetonitrile: The title compound can also be prepared by adding a solution of 152 mg of (3S, 4S, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one in 3 ml of chloroform Room temperature with 0.3 ml of trichloroacetonitrile, 1.2 ml of 30% aqueous hydrogen peroxide and 138 mg of potassium hydrogen phosphate and the resulting mixture is stirred for 21 hours at room temperature. After dilution methylene chloride is added successively with 5% aqueous sodium bisulfite, 8% aqueous sodium bicarbonate and aqueous

_ 28 - 2 5 0b-

washed salt solution. The aqueous portions are back-extracted with methylene chloride, and the combined organic extracts, after drying over NaaSOu, evaporated. Chromatography on silica gel plates in hexane / ethyl acetate (1: 1) gives the pure title compound having the properties described above.

Example 14: (3S, 4R, 1'R) -3- (1'-Allyloxycarbonyloxyethyl) -4-N-allyloxycarbonylglycylthioazetidin-2-one

26.75 g (75 mmol) of N-allyloxycarbonylthioglycine-dicyclohexylammonium salt are dissolved in 200 ml of water and 75 ml of 1N NaOH and extracted three times with 100 ml of methylene chloride each time. The aqueous phase is cooled to 0 ° and adjusted to pH 10.0 under pH control (glass electrode) by adding IN NaOH. With vigorous stirring under argon, a solution of 8 g (25 mmol) of (3R.4S, l'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one in 275 ml of acetone is added dropwise, the Temperature is kept below 4 °. After completion of the addition is stirred for a further 15 minutes at 0-5 °, the solution was concentrated in a rotary evaporator to 300 ml and extracted 4 times with 100 ml of methylene chloride. The combined organic phases are washed twice with 100 ml of water and once with 100 ml of aqueous, saturated sodium chloride solution, dried over NaaSOit and evaporated. The residue obtained is chromatographed on 500 g Merck silica gel in the flash method with CHCl3 / acetone (9: 1). The title compound is obtained from the Rf value (Merck Finished plates CHC1 ₃ / acetone 9: 1): 0.20.

Example 15: allyl (5R, 6S, 1'R) -6- (1'-Allyloxycarbonyloxyethyp-Z-allyloxycarbonyl-2-naphthyl-2-penem-3-carboxylate

A solution of 930 mg (2.5 mmol) (3S, 4R, l'R) -3- (1'-allyloxycarbonyloxyethyl) -4-N-allyloxycarbonylglycylthioazetidin-2-one in 15 ml of methylene chloride (fresh alox filtered) 557 mg (3.75 mmol, 1.5 equiv.), oxalic acid allyl ester chloride and 0.64 ml (3.75 mmol) (1.5 equiv.) of Hünig base are added under stirring in an argon atmosphere at -15 ° in succession, and 30 Stirred for a further 15 minutes at -15 °. For workup, the reaction mixture is diluted with methylene chloride and successively with cold 0.1 N HCl and (twice) with

shake cold, saturated NaHCO3 solution vigorously and briefly (the last treatment removes the excess allyloxyoxalyl chloride). The aqueous portions are extracted once with methylene chloride, and the combined organic phases are dried with Na ₂ SOu and evaporated in vacuo. The crude product is taken up several times in toluene, evaporated and dried under high vacuum. The resulting viscous residue containing 2- [(3S.4R, 1 * R) -3- (r-allyloxycarbonyloxyethyl) -4-N-allyloxycarbonylglycylthio-2-oxo, -lazetidinyl] -2-oxoacetic allyl ester becomes cyclization in 25 ml abs. Toluene, stirred at room temperature with stirring (argon) with 1.044 ml (6 mmol, 2.4 equiv.) Of triethyl phosphite distilled and the reaction mixture quickly immersed in an oil bath preheated to 100 ° and stirred under argon at the same temperature for 7 hours. The reaction mixture is evaporated in vacuo and the residue is chromatographed on 100 g of Merck silica gel (0.04-0.063 mm particle size) in a flash process. It is first a pre-fraction of 500 ml of toluene / ethyl acetate (9: 1) and a 150 ml fraction with toluene / ethyl acetate (4: 1) taken. The title compound is eluted in the following 25 ml fractions with toluene / ethyl acetate (4: 1), whereby a small amount of a more mobile component (the corresponding cis isomer) in the first fractions can be separated. F. 58-59 ° (from ether-pentane); Rf (Merck Finished Plates, toluene / ethyl acetate 2: 1): 0.40; [a] - + 127.7 ° (1.05% in CH ₂ Cl ₂ ).

Example 16: (5R, 6S, 1'R) -2-aminomethyl-6- (1-hydroxyethyl) -2-

penem-3-carboxylic acid

By a solution of 100 mg (0.22 mmol) of (5R, 6S, 1''R) -2-allyloxycarbonylaminomethyl-6- (1-allyloxycarbonyloxyethyl) -2-penem-3-carboxylic acid allyl ester, 308 mg (2, 2 mmol) of dimedone and 30 mg (0.11 mmol) of triphenylphosphine in 4 ml of tetrahydrofuran is bubbled with argon for 5 minutes. Then 22 mg (0.019 μmol) of tetrakis-triphenylphosphine-palladium are added at room temperature. After 5 minutes, a precipitate begins to precipitate. The suspension is stirred for a total of 1 hour at room temperature under argon. The

Os O ς 1 ο

precipitated product is filtered off, washed with tetrahydrofuran, ethyl acetate and hexane and dried under high vacuum. Rf (H ₂ O, OPTI UPC ₁₂ ): = 0.48.

50 mg of crude (5R, 6S, 1'R) -2-aminomethyl-6- (1-hydroxyethyl) -2-penem-3-carboxylic acid is dissolved in 0.5 ml of double distilled water at 30 °. The aqueous solution is cooled to 5 °, mixed with a little activated carbon, stirred for 15 minutes and then filtered clear. The clear filtrate is completely concentrated in a high vacuum and the residue slurried in 0.3 ml of ethanol (96% strength). The suspension is stirred vigorously at room temperature for 30 minutes. The white crystals (needles) are filtered off and washed with ethanol (96%). The product is dried at 20 ° in a high vacuum. F. 165 ° (decomp.).

Example 17: (2R, 3R) -N-acetonyl-N-p-methoxyphenyl-2,3-epoxybutyramide:

To a cooled to -20 ° C solution of 73.2 g of N-acetonyl panisidine hydrochloride in 1700 ml of toluene with stirring (at -15 to -18 °) successively within 15 minutes 70.2 g of Ν, Ν-dicyclohexylcarbodiimide, dissolved in 170 ml of toluene, and added dropwise within 60 minutes 103 g of a solution of the dicyclohexylammonium salt of (2R, 3R) -2,3-epoxybutyric acid in 340 ml dichloromethane. The reaction mixture is allowed to warm to 0 ° within 45 minutes and stirred for a further 18 1/2 hours at 0-5 °. The suspension is filtered off with suction, the residue washed thoroughly with toluene, the filtrate washed twice with 1 liter of water, dried and concentrated in a water-jet vacuum. From the red-brown, oily crude product, after cooling to about 4 ° crystals can be separated. Flash chromatography of the mother liquor with hexane / ethyl acetate 1: 4 mixture is, in addition to regenerated N-acetonyl-p-anisidine, as the main product in the form of a light brown OeIs (2R, 3R,) - N-acetonyl-Np-methoxyphenyl -2,3-epoxybutyramide obtained. The compound can be used directly for cyclization without further purification. IR: gangs and the like at 2840, 1735, 1670, 1510, 1240, 1220, 1170 and 840.

-31-. 25 0 5 3. ί

Example 18: (3S, AS, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-acetylazetidin-2-one:

A solution of 10.1 g (2R, 3R) -N-acetonyl-N-p-2,3-epoxybutyramide in (200 ml) dimethylformamide is added at 60 ° with 19.1 g of potassium carbonate and stirred for 13 hours at the same temperature. The cooled reaction mixture is filtered from undissolved potassium carbonate, treated with 1 liter of methylene chloride and washed successively five times with dilute aqueous sodium chloride solution, dried and evaporated. After flash chromatography with hexane / ethyl acetate (2: 3) of 700 g of silica gel 'is the main product after recrystallization from methylene chloride / ether at 91-92 ° melting (3S, 4S, 1'R) -N-pMethoxyphenyl-3 - (1'-hydroxyethyl-4-acetylazetidin-2-one ([α] »-119.9 ° (c» 0.853 in chloroform) and by-product (ca. 10%) the (3S, 4R, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-acetylazetidin-2-one (m.p. 165-168 °).

Example 19: (3S, 4S, 1'R) -Np-Methoxyphenyl-3- (1'-tert-butyldimethylsilyloxyethyl) -4-acetylazetidin-2-one A solution of 3.39 g (3S, -4S, 1 'R) -Np-methoxyphenyl-3- (l' -hydroxyethyl) -4-acetylazetidin-2-one and 1.58 g of imidazole in 20 ml of dimethylformamide is treated at room temperature with 2.33 g of tert-butyl-dimethylchlorosilane and stirred at room temperature for 5 hours. For workup, the reaction mixture is poured onto ice-Natriurahydrogencarbonat-solution, taken up in methylene chloride and the organic phase washed successively with sodium bicarbonate, 1% citric acid and again with sodium bicarbonate solution. After drying over sodium sulfate and evaporation under reduced pressure, a crude product is obtained, which is recrystallized from petroleum ether. The title compound is obtained as colorless crystals, mp 82-84 °. [et] - -116.3 ° (c = 0.374% in CHCl ₃ ).

Example 20: (3S, 4S, 1'R) -3- (1'-tert-butyldimethylsilyloxy)

ethyl) -4-acetylazetidin-2-one

To a cooled to 0 ° solution of 4.34 g (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (1'-tert-butyldimethylsilyloxyethyl) -4-acetyl

azetidin-2-one in 140 ml of acetonitrile are added dropwise within 15 minutes at 0 ° 13.85 g ceric ammonium nitrate dissolved in 70 ml of water. The reaction mixture is allowed to stir for 2 hours at room temperature, then poured into ice-water, extracted with methylene chloride, the organic layer is washed twice with aqueous sodium bicarbonate solution and saturated brine, dried and evaporated in a water-jet vacuum. By flash chromatography of the dark brown crude product in hexane / ethyl acetate (3: 2) on silica gel and subsequent crystallization of the uniform fractions from ether / petroleum ether, the pure (3S, 4S, 1'R) -3- (l'-tert-Butyldimethylsilyloxyethyl ) -4-acetylazetidin-2-one, m.p. 74-75 °, [α] - -14.6 ° (c - 0.397%, CHCl ₃ ).

Example 21: (3R, 4R, 1'R) -3- (1'-tert-butyl-dimethylsilyloxy) -ethy1-4-acetoxyazetidin-2-one

A solution of 1.4 g of (3S, 4S, l'R) -3- (r-tert-butyldimethylsilyloxyethyl) -4-acetylazetidin-2-one in 70 ml of methylene chloride is treated with 5.75 g of 85% m.p. Added perchloroperbenzoic acid and stirred for 2 hours at room temperature. The yellow reaction mixture is poured onto ice, extracted with methylene chloride, the organic phase washed successively with aqueous potassium iodide / sodium thiosulfate solution, water, aqueous sodium bicarbonate solution and water, and evaporated. Flash chromatography of the crude product in hexane / ethyl acetate (4: 1) and subsequent crystallization of the uniform fractions from low-boiling petroleum ether gives the pure (3R, 4R, 1'R) -3- (l '- (tert-butyl-dimethylsilyloxyethyl ) -4-acetoxyazetidin-2-one, m.p. 108-110 °. [Α] »+ 50.1 ° (c - 0.838%; CHCl ₃ ).

Example 22: (3S, 4S, 1'R) -Np-Methoxyphenyl-3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one A solution of 4 , 53 g of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidin-2-one in 40 ml of dimethylformamide is treated with 1.7 g of imidazole and 3.3 ml of dimethyl - (2,3-dimethylbut-2-yl) -chlorosilane and stirred for 23 hours at 25 °. After addition of a further 1.7 g of imidazole and 3.3 ml of dimethyl (2,3-dimethylbut-2-yl) chlorosilane

_ 33 -

£ D I / D

is stirred for another 22 hours. The reaction mixture is poured onto ice-cold, aqueous sodium bicarbonate solution and extracted with chloroform. The organic phase is washed successively with aqueous sodium bicarbonate solution, 1% aqueous citric acid, aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The resulting crude product is "flash" chromatographed in toluene / ethyl acetate (9: 1) on 521 g of silica gel. The combined, uniform fractions, after recrystallization from ether / petroleum ether, afford the pure (3S, 4S, 1'R) -Np-methoxyphenyl-3- [1 '- (dimethyl-2,3-dimethylbutene) melting at 89-90 °. 2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one. [α] - -65.4 ° (c - 0.506%; CHCl ₃ ).

Example 23: (3S, 4S, 1'R) -3- [1 '- (Dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one: To a solution cooled to 0 ° of 37.02 g of (3S, 4S, 1'R) -Np-methoxyphenyl-3- [Γ- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one in 980 ml Acetonitrile is added dropwise under argon within 15 minutes, a solution of 95.4 g of cerium (IV) ammonium nitrate in 490 ml of water and the Reaktionsgeraisch stirred for 1 hour at 0-5 °. The organic phase is separated thereon and evaporated in vacuo at 30 °. The residue is combined with the aqueous phase with the addition of ice, and the mixture is extracted with ethyl acetate. The extract is washed successively twice with aqueous sodium bicarbonate solution and dilute aqueous sodium chloride solution, dried and evaporated. The brownish residue is crystallized from methylene chloride / ether at 5 °. The crystals washed with 50 ml of hexane / ether (3: 2) mixture are stirred with an additional 50 ml of this mixture at 20 ° and then at 0 °, filtered off with suction, washed with a little hexane / ether (3: 2) mixture and at Dried at 50 ° in a high vacuum. The pure, at 165-166 ° melting title compound. Flash chromatography of the mother liquor with hexane / ethyl acetate (80:20) on 750 g of silica gel gives further quantities of the title compound, [ α ] --20.4 ° (c-0.499%, CHCl ₃ ).

- ³⁴ - 2 5Ci.

Example 24: (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoyloxyazetidin-2-one A solution of 15.14 g ( 3R, 4R, rR) -3- [l '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one in 500 ml of methylene chloride is mixed with 47.3 g of 85% strength M-Chlorperbenzoesa'ure added and left for 5 1/2 hours at room temperature. The reaction mixture is then poured into ice-water, extracted with methylene chloride, the organic phase is washed successively with aqueous potassium iodide / Natriurathiosulfat solution, water, aqueous sodium bicarbonate solution and water, dried and evaporated. Upon addition of the crude product with ether, about 1.5 g of 3-chlorobenzoyl peroxide crystallize out. The crystals are filtered off with suction and crystallized from the filtrate after concentration from hexane, the crude product. The resulting slightly contaminated title compound is "flash" chromatographed with hexane / ethyl acetate (90:10). The uniform fractions, after redissolution from hexane, afford pure (3R, 4R, l'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4 melting at 83-84 ° -benzoyloxyazetidin-2-one [α] - + 62.5 ° (c - 0.256%, CHCl ₃ ).

Example 25: (3S, 4R, l'R) -3- [l '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-N-allyloxycarbonylglycylthioazetidin-2-one 2.67 g (7 , 5 moles) of N-allyloxycarbonylthioglycine 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 chloride, the aqueous portion with 10 ml of acetone and at 0 ° with stirring under argon with a solution of 944 mg (2.5 mol) (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-N-allyloxycarbonylglycylthioazetidin-2-one in 20 ml of acetone. The reaction mixture is further stirred at a pH of 10.5-10.7 for 5 hours with cooling. The acetone is distilled off under reduced pressure, the aqueous residue extracted with methylene chloride, the organic phase after drying over NagSOi * evaporated and the residue on silica gel plates in hexane / ethyl acetate (1: 1) chromatographed. you

λ j υ

the title compound is obtained as a colorless, crystalline compound which is recrystallized from ether-hexane. F. 74-76 °. ία] - +110.7 ± 1.3 ° (c - 0.76% in CHCl ₃ ).

Example 26: (5R, 6S, 1'R) -6-f1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -2-allyloxycarbonyl-tninomethyl-2-penem-3-carboxylic acid allyl ester

A solution of 692 mg (1.6 mmol) (3S, 4R, 1'R) -3- [Γ- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-N-allyloxycarbonylglycylthioazetidine-2-one 360 ml (about 2.41 mmol) of oxalic acid allyl ester chloride and 410 ml (about 2.41 mmol) of Hünig base are added successively in 9 ml of methylene chloride at -20 ° under argon, and the resulting reaction mixture is first added for 2.5 hours -10 ° and then stirred for 80 minutes at 0 °. It is diluted with methylene chloride and washed successively with ice-cold 0.1N HCl and 8% aqueous NaHCO 3 solution. The organic portion is dried over Na 2 SO 4 and evaporated. The residue obtained is dissolved in 3 ml of triethyl phosphite and the solution is heated to 60 ° under argon for 2 hours. The volatiles are first under reduced pressure, then removed under high vacuum, the residue in 10 ml of abs. Dissolved dioxane and the resulting solution heated under argon for 8 hours at 105 ° (bath temperature). The crude product obtained after evaporation of dioxane under reduced pressure is chromatographed on a silica gel column with hexane / ethyl acetate (9: 1 and 4: 1). The title compound is obtained as a colorless oil, [α] »+62 + 2.7 ° (c» 0.371% in CHCl ₃ ), UV: λ = 320 nm (ε = 623Ο, in ethanol).

Max

Example 27: (5R, 6S, 1'R) -2-Aminomethyl-6- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -2-penem-3-carboxylic acid A solution of 367 mg (0.72 mmol) of (5R, 6S, l'R) -6- [1'-dimethyl- (2,3-dimethylbut-2-ylsilyloxy) ethyl] -2-allyloxycarbonylaminomethyl-ζ -penem-3-carboxylic acid allyl ester in 7 ml abs. Tetrahydrofuran is mixed at room temperature with 223 mg (1.59 mmol) of dimedone and 36 mg of tetrakis-triphenylphosphine-palladium and the resulting solution is stirred at room temperature. Soon, the precipitation of the crystalline title compound begins and is after 1 hour

Λ Γ Γ »! - ">

practically finished. The crystals are filtered off and washed on the filter with a little tetrahydrofuran. The title compound obtained forms colorless crystals, mp 119 °;

UV: λ (EtOH): 309 nm, 268 nm

 Max

Example 28: (3S, AS, 1'R) -N-p-methoxyphenyl-3- [Γ- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one

To a solution of 6.16 g of 3,5-dinitrobenzoic acid in 83 ml of pyridine 10.07 g of p-toluenesulfonyl chloride are added at room temperature within 10 minutes. Subsequently, one hour is stirred. To the reaction mixture, cooled to 0-5 °, are added 9.01 g (27.7 mmol) of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidin-2-one and 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 brine and dried over sodium sulfate. After evaporation, the red residue is purified on 250 g of silica gel with toluene / ethyl acetate (9: 1). The title compound with the following physical data is obtained in quantitative yield:

IR (CH ₂ Cl ₂ ): bands inter alia at 3100, 1765, 1735, 1550, 1515, 1345, 1250; Rf (Merck silica gel prefabricated plates, ethyl acetate / toluene 1: 1): 0.65.

Example 29: (3S, 4S, 1'R) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one

To a solution of 14.88 g (27.8 mmol) of (3S, 4S, 1'R) -Np-methoxyphenyl-3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidine-2-one. on in 290 ml of acetonitrile is added dropwise at 0 ° within 15 minutes, a solution of 34.4 g (62.8 mmol) of cerium (IV) ammonium nitrate in 146 ml of H2O. After a further 30 minutes of 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 semisaturated aqueous common salt solution. After drying over sodium sulfate and evaporation, the crude product from methylene

- 37 - 2 5 0 5 ·

chloride / ether crystallized to give the title compound in pure form. From the mother liquor, further amounts of the title compound are obtained by evaporation and trituration in toluene. F. 156-160 °; Rf value (Merck silica gel precoated plates, ethyl acetate / toluene 1: 1): 0.42.

Example 30; (3R, 4R, 1'R) -3- [1 '- (3,5-Dinitrobenzoyloxy) ethyl] -4-benzoyloxyazetidin-2-one

A solution of 8.30 g (20 mmol) of (3S, 4S, 1'R) -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one in 151 ml of methylene chloride is added 6.129 g (30 mmol) of m-chloroperbenzoic acid (85%) and stirred for one hour at room temperature, then 2 1/2 hours at 3O ⁰ C first. For working up, methylene chloride, 5% aqueous sodium bisulfite solution and 100 ml of saturated aqueous brine mixture is added with 250 ml and washed successively with 100 ml of 10% at 0 ⁰ C aqueous Natriumbicarbonatlb'eung, washed. After drying and concentration, the crude product is crystallized from 50 ml of pentane. The title compound of melting point 165-169 ° (dec.) Rf (Merck silica gel prefabricated plates, ethyl acetate / toluene 1: 1): 0.58.

Example 31: (3S, 4R, 1'R) -3- [l '- (3,5-dinitrobenzoyloxy) ethyl] -4-N-allyloxycanylphenylcyclothio) azetidin-2-one 3.77 g (10, 6 mmol) of N-allyloxycarbonylthioglycine-dicyclohexylammonium salt are dissolved in 18.7 ml of H 2 O and 10.6 ml of aqueous 1N NaOH and extracted three times with 5 ml of CH 2 Cl 2 each time. The solution is brought to pH 7-8 with about 0.2 ml of 0.1N aqueous HCl and then to a solution of 2.28 g (5.3 mmol) (3R, 4R, 1'R) -3- [ l '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoyloxyazetidin-2-one in 50 ml of dioxane at 23 °. The mixture is stirred for a further 1 1/2 hours at 23 ° and worked up with 100 ml of saturated, aqueous NaHCO 3 solution. The organic phase is washed twice with 20 ml of saturated, aqueous common salt solution, dried over sodium sulfate and freed from the solvent. The residue is chromatographed on 200 g of silica gel with methylene chloride / acetone (9: 1)

- ³⁸ - 2 5 0 5 3

to give the title compound as a foam. Rf (Merck Finished Plates, toluene / ethyl acetate 1: 1): 0.38; [α] * + 25 ° (c - 0.72, CHCl ₃ )

 This product still contains about 5% of the ßS ^ S-cis isomer.

Example 32: Allyl ester (5R, 6S, 1'R) -6- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -2-allyloxycarbonyl-inaniethyl-2-penem-3-carboxylate A solution of 241 mg (0.5 mmol) (3S, 4R, 1'R) -3- [l '- (3,5-Dinitrobenzoyloxy) ethyl] -4-N-allyloxycarbonylglycylthioazetidin-2-one in 3 ml of methylene chloride (filtered fresh over alox) with stirring and exclusion of moisture at -20 ° successively with 84.5 μΐ (0.69 mmol) Oxalsaureallylesterchlorid and 124.2 μΐ (0.73 mmol) Hünig base and stirred for 30 minutes at -10 °. An IR sample shows the characteristic oxalimide carbonyl absorption at 1820 cm. For work-up, the reaction mixture is diluted with 5 ml CH 2 Cl 2 and the organic phase is washed successively with ice-cold aqueous Ο, HCl, 5% NaHCO 3 solution and saturated, washed aqueous sodium chloride solution, dried over Na2SOif and evaporated in vacuo. After drying under high vacuum (3S, 4R, 1 ¹ R) -4-N ^ AlIyIoXycarbonylglycylthio) -3- [l '- (3,5-dinitrobenzoyloxy) ethyl] -azetidin-2-one-1-yloxalsäure allylester as add foam. This is dissolved in 2.5 ml of dioxane (Merck, pA) and treated at room temperature with 312 μΐ (1.49 mmol) of triethylphosphite under N 2 atomosphere. It is stirred for 1 hour at room temperature and 2 hours at 40 ° bath temperature until no more oxalimide signal can be detected in the IR (band at 1820 cm). After evaporation, it is stirred three times with about 1.5 ml of decane and again evaporated under high vacuum. The resulting crude phosphorane is dissolved directly in 12.5 ml of dioxane (Merck, pA) for cyclization and stirred for 17 hours at a bath temperature of 105 °. The mixture is then concentrated on a rotary evaporator and the residue is chromatographed on 30 g of silica gel with toluene / ethyl acetate (4: 1). From the middle fractions, the title compound is isolated, which in turn contains about 5% of 5S, 6S-cis isomer as an impurity. Rf (Merck precast plates, toluene / ethyl acetate 4: 1): 0.48 (cis product) and 0.38 (trans product).

I 3 υ j ο

Example 33: (5R, 6S, TR) -6- (1'-hydroxyethyl) -2-allyloxycarbonylaminomethyl-2-peneno-3-carboxylic acid allyl ester

a) From (5R.6S, TR) -O- [T- (3,5-dinitrobehzoyloxy) ethyl] -2-allyloxycaphenylamino-methyl-2-pentenone-3-carboxylic acid allyl :

To a solution of 1.28 g (2.27 mmol) of (5R, 6S, TR) -6- [T- (3,5-dinitrobenzoyloxy) ethyl] -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester (trans 95: 5) in 100 ml of methanol and 20 ml of water are added at 0 ° 5 ml of saturated aqueous sodium bicarbonate solution. After a reaction time of 20 minutes at 0 °, the reaction mixture is poured onto 300 ml of ethyl acetate and 50 ml of saturated, aqueous common salt solution, the organic phase is separated off and the aqueous phase is back-extracted with 100 ml of ethyl acetate. The combined organic phases are dried over Na 2 SO 4) and concentrated in vacuo to about 30 ml volume. It is diluted with 150 ml of methylene chloride, dried again with Na2SOij and then completely evaporated in a rotary evaporator. The residue is chromatographed on 80 g of silica gel with toluene / ethyl acetate 4: 1 to 3: 2 to give the title compound after crystallization from ether / hexane (3: 7), mp 141-141.5 °. Rf (Merck precast plates, toluene / ethyl acetate 1: 1): 0.20.

b) From (5R, 6S, TR) -6- [T- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) -ethyl) 3-allyloxycarbonylaminomethyl) -penem-S-carboxylic acid allyl ester :

A solution of 50 mg (5R, 6S, TR) -6- [T- (dimethyl-2,3-dimethylbut-2-ylsiyloxy) ethyl] -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester in 1 ml of 2, 6-Lutidine is mixed with 60 mg (about 3OmMoI) of a 70% HF-urea mixture and stirred for 2 hours at room temperature. Then another 5 drops (about 100 mg = about 50 mM) of HF urea are added to the reaction solution. The viscous mixture is diluted with 1 ml of methylene chloride, stirred overnight at room temperature and added again with 10 drops of HF urea (about 100 mM). After another 24 hours reaction time at

- 40 - 2 S 0 S 3 2

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. The pure title compound which is identical to the sample obtained under a) is obtained by recrystallization of the resulting crude product from ether / hexane.

Example 34: (3S, 4R, 1'R) -3- (1'-hydroxyethyl) -4- (N-allyloxycarbonylglycylthio) -2-azetidinone

A solution of 14.2 g (40 mmol) N-Allyloxycarbonylthioglycindicyclohexylammoniumsalz in 60 ml of water and 40 ml of 1 N aqueous NaOH solution is extracted three times with 20 ml of methylene chloride and with about 1 ml of 0.1 N aqueous HCl, the pH to 7 -8. The aqueous thiol acid solution obtained is added at 30 ° within 5 minutes to a solution of 4.70 g (20 mmol) of (3R, 4R, 1'R) -3- (1-hydroxyethyl) -4-benzoyloxy-2-azetidinone in Added 100 ml of acetonitrile. At an internal temperature of 25 °, 2 ml of 0.1 N aqueous NaOH solution are added and stirring is continued for 30-35 min at 25 °. For workup, 250 ml of ethyl acetate and 30 g of NaCl are placed in a separating funnel and the reaction mixture is added. After shaking well and separating the aqueous phase, the organic phase is washed once more with 50 ml of 5% aqueous NaHCO 3 solution and twice with 50 ml of brine and dried over sodium sulfate. The solvent is removed on a rotary evaporator and the title compound is obtained as an amorphous powder. The crude product can be purified by chromatography on silica gel (toluene / ethyl acetate 2: 3). Rf value 0.23 (Merck precast plates, toluene / ethyl acetate = * 1: 4, ninhydrin as developing agent).

Example 35: (5R, 6S, 1'R) - (1'-hydroxyethyl) -2-allyloxycarbonylaminomethyl-2-penem-3-carboxylic acid allyl ester

A solution of 2.88 g (10.0 mmol) of (3S, 4R, 1'R) -3- (1-hydroxyethyl) -4- (N-allyloxycarbonylglycylthio) -2-azetidinone (crude product of Method 34) in 80 ml of methylene chloride (fresh filtered through Alox) with stirring and exclusion of moisture at -10 to -15 °

2505

in succession with 3.86 ml (31.5 mmol) of freshly distilled oxalic acid allylesterchlorid and 7.69 ml (44.8 mmol) of N-ethyl-diisopropylamine and stirred for 30 min. At -10 °. An IR sample showed the characteristic oxalimide carbonyl absorption at 1820 cm

For work-up, the reaction mixture is diluted with 50 ml of CH 2 Cl 2, washed three times with ice-cold water and once with ice-water and 5 ml of saturated, aqueous NaHCO 3 solution. The aqueous portions are back-extracted once with CH 2 Cl 2. The combined organic phases are dried with Na ₂ SO 4, evaporated in vacuo and the crude product is dried under high vacuum. The resulting viscous residue containing the (3S, 4R, 1'R) -2- [4- (N-allyloxycarbonylglycylthio) -3- (1'-allyloxalyloxyethyl) -2-oxo-1-azetidinyl] -

2-oxoacetic allyl ester (IR (CH ₂ Cl ₂ ) 3440 (NH); 1820 (NCC);

1720-1760 (C)) is dissolved in 30 ml of dioxane and under N ₂ atmosphere at room temperature with 7 ml (40.2 mmol) of triethyl phosphite. After 15 hours at room temperature, no more oxaliride can be detected in the IR (band at 1820 cm). The reaction mixture is evaporated in vacuo, the residue is added three times with 2 ml of toluene and 2 ml of decane and the entraining agent is removed again to remove excess phosphite / phosphate under high vacuum. The resulting crude phosphorane is dissolved for cyclization in 250 ml of dioxane and stirred for 5 hours at 105-110 °. The reaction mixture containing the (5R, 6S, 1'R) -2-allyoxycarbonylaminomethyl-6- [1 '- (allyloxalyloxy) ethyl] -2-penem-3-carboxylic acid allyl ester (for analytical purposes, a sample of the crude cyclization product on silica gel purified with toluene / ethyl acetate 4: 1: UV (EtOH) 315 nm, IR (CH ₂ Cl ₂ ) 3440 (NH), 1790, 1770, 1745,

1720 (C)) is evaporated in vacuo to about 15 ml, with 100 ml of methanol / H20 8: 2 and treated with 25 ml of saturated aqueous NaHCO 3 solution at 0 °. After 20 minutes, the reaction mixture is poured onto 300 ml of ethyl acetate and 50 ml of H ₂ O, the organic phase is separated off and the aqueous phase is back-extracted with 100 ml of ethyl acetate. The combined organic phases

are dried over Na ₂ SOiJ and concentrated in vacuo to about 50 ml volume. After dilution with 200 ml of methylene chloride is dried with Na ₂ SO ₄ and completely evaporated in vacuo. The residue is chromatographed on 80 g of silica gel with toluene / ethyl acetate 3: 2, after crystallization from ether / hexane 3: 7, the title compound is obtained F. 141 - 141.5 °. Rf value 0.20 (Merck precast plates, toluene / ethyl acetate 1: 1).

Example 36: (5R, 6S, 1'R) -2-aminomethyl-6- (1'-hydroxyethyl) -2-penem-3-carboxylic acid

A solution of allyl 313 mg (0.85 mmol) of (5R, 6S, 1'R) -2-allyloxycarbonylaminomethyl-6- (1-hydroxyethyl) -2-penem-3-carboxylate and 174.6 mg (1.24 mmol) Dimedone in 7.5 ml of tetrahydrofuran is purged with argon for 5 minutes and treated under argon atmosphere at room temperature with 27 mg (0.023 mmol) Tetrakistriphenylphosphinpalladium. After about 5 minutes, a precipitate begins to precipitate, which is filtered off after stirring for a further 2 hours, washed with about 10 ml of tetrahydrofuran and then dissolved in 4 ml of H2O. To the beige solution, a micro spatula tip of activated charcoal and 2 micro spatula tips Tonsil be given, stirred well for 5 min and filtered through Hyflo clear. The mixture is concentrated under high vacuum and 3 ml of cold ethanol are added to the resulting thick crystal pulp and filtered off with suction. The colorless crystals are washed with 2 ml of tetrahydrofuran and dried under high vacuum. You get the title

of)

Compound of Rf = 0.50 (TLC: H ₂ O, OPTI UPCi ₂ ); MZT «+ 176 ° (c = 0.5, H ₂ O).

Claims (22)

claims: 1. A process for the preparation of (4R) -3,4-trans-disubstituted azetidinones of the formula -CR ₃ (I) wherein Ri is hydrogen or lower alkyl, R2 is hydrogen or a hydroxy protecting group Rj, R3 is phenyl, substituted phenyl or lower alkyl and Ri _{4 is} hydrogen or an amino protecting group Ri, characterized in that a compound of the formula , .., .J; M_D, fT-n , S) 3 i, (S) • V wherein Ri, R2, R3 and Ri »have the meanings given under formula I, by treatment with a peracid a Bayer-Villiger reaction, and if desired in an available compound of formula I, wherein R2 is hydrogen, the free hydroxy group in the protected hydroxy group ORj, and / or if desired, in an available compound of the formula I, the hydroxy protecting group Rj and / or the amino protecting group Rl splits off. Ό ζ P, C 2. A process for the preparation of compounds of formula I, according to item 1, characterized in starting from compounds of formula II wherein Ri is hydrogen or lower alkyl, R2 is hydrogen or a hydroxy protecting group R2, R3 is phenyl or substituted phenyl and Ri _{+ is} hydrogen or an amino protecting group Rj means. 3. The method according to item 1, characterized in that starting from compounds of formula II wherein Ri is hydrogen or methyl, R2 is hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl or 3,5-dinitrobenzoyl, R3 is phenyl or methyl and Ri *. Is hydrogen or p-methoxyphenyl. 4. A process for the preparation of (3R, 4R, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one according to item 1. 5. A process for the preparation of (3R, 4R, 1'R) -3- (1'-hydroxyethyl) -4-benzoyloxyazetidin-2-one according to item 1. 6. A process for the preparation of (3R, 4R, l'R) -3- [l '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoyloxyazetidin-2-one by period 7. Process for the preparation of (3R, 4R, 1'R) - [I '- (tert-butyldiraethylsilyloxy) ethyl] -4-acetoxyazetidin-2-one and (3R, 4R, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoyloxyazetidin-2-one according to item 1. 8. A process for the preparation of (3R, 4R, 1'R) -3- [r- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoyloxyazetidin-2-one according to item 1. 9. A process for the preparation of (3R, 4R, 1'R) -3- (1'-allyloxycarbonyloxyethyl) -4-benzoyloxyazetidin-2-one according to item 1. 10. The method according to item 1, characterized in that the compounds of the formula (II), 3 it I \ 2j wherein Ri is hydrogen or lower alkyl, R _{2 is} hydrogen or a hydroxy-protecting group R ₂ , R _{3 is} phenyl, substituted phenyl or lower alkyl and Ri * is hydrogen or an amino-protecting group Ri, by a) an a-carbanion of a compound of formula Ri-CH-O (2R) CH ₂ -CR ₃ (III), ⁰ JK wherein Ri, R ₃ and Ri have the meanings given under formula II, and the 2-C atom, the R- and, when Ri is lower alkyl, the 3-C atom has the R or the S configuration, or a Compound of the formula / -K Cf \ ' _k wherein Ri, R ₃ and Ri have the meanings given under formula II, R '* 2 is a non-releasable under the conditions of the ring closure hydroxy protective group, and X represents a nucleofugic leaving group and the 2-C atom, the R- and, if Ri is lower alkyl means that the 3-C atom has the R- or the S-configuration, cyclized or b) a cis-compound of the formula (II ¹ ), Γ
• - 2 5 O 5 wherein Ri, R2, Ra and Ri _{1 have} the meanings given under formula II, isonierisiert, and if desired, the amino-protecting group Ri cleaved and replaced by hydrogen and / or, if desired, an obtainable compound of formula II in another compound of formula II converts. 11. The method according to item 10 for the preparation of compounds of formula II, wherein Ri is hydrogen or lower alkyl, R2 is hydrogen or a hydroxy protecting group R2, R3 is phenyl or substituted phenyl and Ri> hydrogen or an amino protecting group Ri, characterized in that a) a a-carbanion of a compound of the formula 3? O R _{1 is} -CH-C (2R) CH ₂ -CR ₃ (III), VIl 1 wherein Ri, R3 and Ri have the meanings given under formula II, and the 2-C atom, the R- and, when Rj is lower alkyl, the 3-C atom has the R or the S configuration, or a compound the formula (IV), wherein Ri, R3 and Ri have the meanings given under formula II, R'2 represents a hydroxy protecting group which can not be split off under the conditions of the ring-closing process, and X represents a nucleofugic leaving group and the 2-C atom represents the R- and, when Ri denotes lower alkyl, the 3-C atom has the R or S configuration, cyclized and, if desired, the amino-protecting group Ri is split off and replaced by hydrogen and / or, if desired, an available compound of formula II is converted to another compound of formula II , 12. The method of item 10 for the preparation of compounds of formula II, wherein Ri is methyl, R _{2 is} hydrogen, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, tert-butyldimethylsilyl, dimethyl-2,3-dimethyl-but-2-ylsilyl, or 3,5-dinitrobenzoyl, R3 is phenyl or methyl and Ri _{4 is} hydrogen or p-methoxyphenyl. 13. A process for the preparation of (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-benzoylazetidin-2-one according to item 1. 14. Process for the preparation of (3S, 4S, 1'R) -3- (l'-hydroxyethyl) -4-benzoylazetidin-2-one, (3S, 4S, 1'R) -N-p-methoxyphenyl-3- [1 '- (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidin-2-one, (3S, 4S, 1 'R) -3- [1' - (2,2,2-trichloroethoxycarbonyloxy) ethyl] -4-benzoylazetidin-2-one, (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (1 '-allyloxycarbonyloxyethyl-4-benzoylazetidin-2-one and (3S, 4S, 1'R) - (1'-Allyloxycarbonyloxyethyl) -4-benzoylazetidin-2-one according to item 11. 15. Process for the preparation of (3S, 4S, 1'R) -Np-methoxyphenyl-3- (1-hydroxyethyl) -4-benzoylazetidin-2-one, (3S, 4S, 1'R) -Np-methoxyphenyly1 -3- [1 '- (3,5-dinitrobenzoyloxy) ethyl] -4-benzoylazetidin-2-one, (3S, 4S, 1'R) -3- [1 '.- (3,5-Dinitrobenzoyloxy) ethyl] -4-benzoylazetidin- (3S, 4S, 1'R) -N-p-methoxyphenyl-3- (1'-hydroxyethyl) -4-acetylazetidin- (3S, 4S, 1'R) -N- p -methoxyphenyl-3- [1 '- (tert-butyl-diraethylsilyloxy) ethyl] -4-acetylazetidin-2-one, (3S, 4S, 1'R) -3- [1 '- (tert-butyldimethylsilyloxy) ethyl] -4-acetylazetidin-2-one and (3S, 4S, 1'R) -N-p-Methoxyphenyl-3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy] ethyl] -4-benzoylazetidin-2-one from item 11. 2 S O η 3 ρ 16. A process for the preparation of (3S.4S, 1'R) -3- [1 '- (dimethyl-2,3-dimethylbut-2-ylsilyloxy) ethyl] -4-benzoylazetidin-2-one according to item 11. 17. The method according to item 1, characterized in that compounds of the formula 3? 0 ' Ri-CH-i (2R) CH ₂ -CR ₃ (III), 0 I _- II ι / Kii wherein R 1 is hydrogen or lower alkyl, R _{3 is} phenyl, substituted phenyl or lower alkyl and R 1 is an amino-protecting group, and the 2-C atom is R- and if R 1 is lower-alkyl, the 3-C-atom is R- or S- Configuration has established by connecting a formula (VIII) with an amine of the formula R 1 NH-CH ₂ -CR ₃ (VII), wherein R ₃ and R 'I _{4 have} the meanings given under formula (V), or of compounds of the formula wherein Ri, R3, Ri and X have the meanings mentioned, R'i 'is hydrogen or a cleavable under the conditions of the epoxide hydroxy protecting group and wherein the 3-C atom of the 5053 R or S configuration, when R 1 is lower alkyl, has been prepared under carbon ion-forming conditions and under Walden's reversal at the C 2 atom. , 18. The method according to item 1, characterized in that compounds of the formula ^Rl \ ³ i / S CH-Ct2R) CH ₂ -CR ₃
1 i wherein Ri is hydrogen or lower alkyl, R "is a hydroxy-protecting group not removable under the conditions of the ring-closing method, R3 is phenyl, substituted phenyl or lower alkyl, Ri is an amino-protecting group, and X is a nucleofuge leaving group and the 2-C atom is R- and, if Ri Lower alkyl means the 3-C atom has the R or S configuration prepared by reacting a carboxylic acid of the formula (VI ') c /' ^N OH wherein Ri, R ₂ and. X have the meanings mentioned under formula IV, with an amine of the formula R 1 NH-CH ₂ -CR ₃ (VII), wherein R ₃ and R'i * have the meanings given under formula (V). O ^Γ ·> Ο ^ ο C J U,! ν <* 19. The method according to item 1, characterized in that compounds of the formula (3R) / (2S) CH ₂ -OR ₃ C (2S) C j-ι wherein R 1 is hydrogen or lower alkyl, R "'2 is hydrogen or a hydroxy protecting group which can be split off under the conditions of epoxide formation, R 3 is phenyl, substituted phenyl or lower alkyl, R 1 is an amino-protecting group and X is a nucleofugic departure group and in which the 3-C atom is the R- When R 1 is lower alkyl, the configuration has been prepared by reacting a carboxylic acid of the formula "R"'2
.X (VI) wherein Ri R "'ζ and X have the meaning specified under formula (V) with an amine of the formula RUH-CH ₂ -CR ₃ (VII), wherein R3 and R \ have the meanings given under formula (V), implements. 20. A process for the preparation of compounds of formula V according to item 19, wherein Ri, R ₂ ¹ ", R'i» and X have the meanings given in item 19 and R3 is phenyl or substituted phenyl. 21. A process for the preparation of (2S, 3R) -2-bromo-3-hydroxybutyric acid N-p-methoxyphenyl-N-phenacylamide according to item 19. 22. The method of item 1 for the preparation of (4R) -3,4-trans disubstituted azetidinones of the formula (I) wherein Ri is hydrogen or lower alkyl, R2 is hydrogen or a hydroxy protecting group R2, R3 is phenyl, substituted phenyl or lower alkyl and Ri _{4 is} hydrogen or an amino protecting group Ri, characterized in that a compound of the formula (II) wherein Ri, R2, R3 and Ri _{1 have} the meanings given under formula I, by treating with a peracid a Bayer-Villiger reaction, and optionally in an available compound of formula I, wherein R 2 is hydrogen, the free hydroxy group in the protected hydroxy group OR2, and / or if desired in an available compound of the formula I, the hydroxy protecting group R2 and / or the amino- protecting group Rl splits off,
the process for the preparation of compounds of the formula (II) in which R 1 is hydrogen or lower alkyl, R 2 is hydrogen or a hydroxy-protecting group R 2, R 3 is phenyl, substituted phenyl or lower alkyl and R 1 ₊ hydrogen or an amino-protecting group R 1, characterized in that a) an α-carbanion of a compound of the formula - 6-α - 2 5 ζ η r · * < ft CH
O R ₁ -CH-O (2R) CH ₂ -OR ₃ (ill), wherein Ri, R3 and Ri have the meanings given under formula II, and the 2-C atom, the R- and, when Ri is lower alkyl, the 3-C atom has the R or the S configuration, or a compound the formula ^R VV * fl (IV) CH-CT2R) CH ₂ -CR ₃ ^{V J} ' RS (X 1 I wherein Ri, R3 and Rj have the meanings given under formula II, R "2 represents a hydroxy protecting group which can not be split off under the conditions of the ring-closing process, and X represents a nucleofugic leaving group and the 2-C atom represents the R- and, when Ri denotes lower alkyl, the 3-C atom has the R or S configuration, cyclized or b) a cis compound of the formula Ii _Kl _i-A, _j-yC-R, (H '), • Nm wherein Ri, R2, R3 and Ri _{1 have} the meanings given under formula II isomerizes, and if desired, the amino-protecting group R ^ split off and replaced by hydrogen and / or, if desired, an obtainable compound of formula II in another compound of Formula II converts the process for the preparation of compounds of the formula Ri-CH-i (2 R) CH ₂ -CR ₃ (III) ⁰ I - K </ NI 50522 wherein Ri is hydrogen or lower alkyl, R3 is phenyl, substituted phenyl or lower alkyl and Ri is an amino protecting group, and the 2-C atom is R- and if Ri is lower alkyl, the 3-C atom is R or S configuration has, characterized in that one is a compound of formula R ₁ -C 1 - b (VIII) Vl (/ ^X OH with an amine of the formula R 1 NH-CH ₂ -CR ₃ (VII), wherein R3 and K \ have the meanings mentioned under formula (V), or from compounds of the formula H ₂ -CR ₃ ^(V) ' wherein Ri, R ₃ , Ri and X have the meanings mentioned, R'2 ¹ 'is hydrogen or a hydroxy protecting group which can be split off under the conditions of the epoxide formation and wherein the 3-C atom has the R or S configuration, when R ^{1 is} lower alkyl means produced under carbon ion-forming conditions and under Walder's reversal at the 2-carbon atom,
the process for the preparation of compounds of the formula ^ CH ₂ -CR ₃ ^(IV) ' wherein R 1 is hydrogen or lower alkyl, R _{2 is} a hydroxy protecting group which can not be split off under the conditions of the ring-closing process, R _{3 is} phenyl, substituted phenyl or lower alkyl, -, - * $ i: η C ο η ~~ Oh ~ &'  · -^; - ·C Ri represents an amino-protecting group, and X represents a nucleofuge leaving group and the 2-C atom is R- and, when Ri is lower-alkyl, the 3-C-atom has the R or S configuration, characterized in that a Carboxylic acid of the formula R "HX -} (VI ¹ ) wherein Ri, R "and X have the meanings mentioned under formula IV, with an amine of the formula RiNH-CH ₂ -CR ₃ . (VII) wherein R3 and R'I _{1 have} the meanings mentioned under formula (V), and the process for the preparation of compounds of the formula CH 9 * (2S) H ₂ -CR ₃ R "' ₂ (y c / "V I » in which R 1 is hydrogen or lower alkyl, R "'2 is hydrogen or a hydroxy protecting group which can be split off under the conditions of epoxide formation, R 3 is phenyl, substituted phenyl or lower alkyl, R 1 is an amino-protecting group and X is a nucleofugic departure group and in which the 3-C atom is the R- When R 1 is lower alkyl, the configuration is characterized in that a carboxylic acid of the formula HX I · y (2s) (VI) - εS "- wherein Ri R "' ₂ and X have the meaning mentioned under formula (V), with an amine of the formula R 1 NH-CH ₂ -CR ₃ (VII), wherein R3 and R \ have the meanings given under formula (V), implements. FO 7.4 / KUN / sm *