CA2002045A1 - Process for the preparation of optically active acyloxyazetidinones - Google Patents
Process for the preparation of optically active acyloxyazetidinonesInfo
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- CA2002045A1 CA2002045A1 CA002002045A CA2002045A CA2002045A1 CA 2002045 A1 CA2002045 A1 CA 2002045A1 CA 002002045 A CA002002045 A CA 002002045A CA 2002045 A CA2002045 A CA 2002045A CA 2002045 A1 CA2002045 A1 CA 2002045A1
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- hydrogen
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
- C07D303/02—Compounds containing oxirane rings
- C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
4-17289/+
Process for the preparation of optically active acyloxyazetidinones Abstract Compounds of the formula
Process for the preparation of optically active acyloxyazetidinones Abstract Compounds of the formula
Description
Z[)(32045 , 4- 17289/-~
Process for the preparation of optically active acvloxvazetidinones The present invention relates to a process for the preparation of 3,4-trans-disubstituted azetidinones of the formula OR2 H H o (I) R~ ~o ll R3 H .~ N~l o in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group R~' and R3 is substituted or unsubstituted phenyl or lower alkyl.
The general definitions used within the scope of this invention preferably have the following meanings:
Groups or compounds marked "lower" preferably contain up to and including 7, preferably up to and including 4 carbon atoms.
As lower alkyl, Rl is preferably methyl and also ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Rl is primarily methyl and also hydrogen.
Hydroxyl protective groups R2~, including their introduction and removal, ale described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, and also in "Protective Gro~lps in Organic Chemistry", Wiley, New York 1974. A hydroxyl protective group is, for example, the acyl radical of a carboxylic acid, for example lower alkanoyl which is substituted by halogen, such as fluorine or chlorine, for example 2,2-dichloroacetyl or 2~2,2-trifluoroacetyl, or a benzoic acid which is unsub-stituted or substituted, for example, by nitro, halogen, such as chlorine, or lower alkoxy, such as methoxy, for example benzoyl or 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-chloro-~QC~4~
benzoyl or 4-methoxybellzoyl, and also the acyl radical of a carbonic acid lower alkyl or lower alkenyl half-ester which is unsubstituted or substituted, for example, by halogen, sllch as chlorine, or by phenyl which can contain substituents, suCIl as 4-nitrophenyl, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or 4-nitro-benzyloxycarbonyl, or the acyl radical of an organic sulfonic acid, for example lower alkanesulfonyl, such as methanesulfonyl, or arylsulfonyl, such as toluenesulfonyl.
Hydroxyl protective groups are also 2-oxacycloalkyl or 2-thiacycloalkyl having 5 or 6 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl, and also a thia analogue thereof, 1-lower alkyloxy-lower alkyl, for example methoxymethyl or 1-ethoxyethyl, or silyl which is trisubstituted, in particular, by lower alkyl, aryl-lower alkyl and/or aryloxy, for example tri-lower alkylsilyl, such as trimethylsilyl, triethylsilyl, dimethyl-(2-ethyl-2-propyl)-silyl, diethyl-(2-ethyl-2-propyl)-silyl, dimethyl-(tert-butyl)-silyl or dimethyl-(2,3-dimethyl-2-butyl)-silyl, diaryl-(lower alkyl)-silyl, for example diphenyl-(tert-butyl)-silyl, aryl-(di-lower alkyl)-silyl, for example tert-butylmethylphenylsilyl, and di-lower alkyl-(lower alkylphenoxy)-silyl, for example dimethyl-(2,4,6-tri-tert-butylphenoxy)-silyl. Pro-tective groups R2' which are particularly preferred because of their stability to bases and hydrolysis are trialkylsilyl, in particular trimethylsilyl, tert-butyldimethylsilyl or dimethyl-(2,3-dimethyl-2-butyl)-silyl.
As substituted phenyl, R3 is phenyl which is substituted, preferably monosubstituted to trisubstituted, for example by lower alkoxy, for example methoxy, lower alkyl, for example methyl and/or halogen, for example chlorine, for example 4-methoxyphenyl, 4-nitrophenyl, 2-, 3- or 4-chlorophenyl or 4-tolyl. As lower alkyl, R3 is, for example, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, especially methyl. R3 is preferably phenyl and methyl.
The process according to tlle invention comprises (a) treating a compound of the formula OR2 H H 0 ( R ~ ¦ (S) ~ (S) ¦¦ R
H .~N~
o C1~21r R4 ~o~
in which R4 is substituted or unsubstituted phenyl or lower allcyl with a peracid, or decarboxylating by acyloxylation a compound of the formula OR2 H H (IIb~
Rl~ - ~ COOH
H.~ N\
with the introduction of the radicals R3-C(=O)- or R4-C(=O)-, (b) replacing the radical of the formula R4-C(=O)- by hydrogen in a compound of the formula OR2 H H O (III) R1~---~o 1I R3 H.~ N\
o CH2--o ~r R4 obtainable as in (a), and (c) removing, in a compound of the forrnula OR2 H rl O (IV) Rl~- - ~O ~I R3 rl ~ N\
thus obtainable, the hydroxymethyl group in the 1-position, if appropriate after conversion into a forrnyl group, and, if desired, in a compound of the forrnula I thus obtainable in which R2 is a protective group R2', converting the protected hydroxyl group into the free hydroxyl group, andJor, if desired, in a compound of the for nula I thus obtainable in which R2 is hydrogen, converting the free hydroxyl group into a protected hydroxyl group.
Preferred starting materials are those of the formulae Ila or IIb in which Rl is hydrogen or methyl, R2 is hydrogen or a hydroxyl protective group R2', such as dimethyltert-butylsilyl or dimethyl-(2,2-dimethyl-2-butyl)-silyl, and R3 and R4, preferably both identical, are phenyl or methyl.
~o~zo~
The treatment of the starting material of the form-lla IIa with a peracid is preferably caTried out by the Baey~r-Villiger reaction, in which organic or inor~Tanic peracids or salts thereof, such as alkali metal or alkaline earth metal salts, for example sodium, potassiu}n or magnesium salts, can be employed. Organic peracids are, in particular, the corres-ponding percarboxylic acids, inter alia lower alkanepercarboxylic acids which are unsub-stituted or substiîuted, for example, by halogen, such as peracetic acid or trifluoroperacetic acid or trihalogenoiminoperacetic acid, for example trichloroiminoperacetic acid or tri-fluoroiminoperacetic acid, aromatic peracids which are unsubstituted or substituted, for example, by nitro and/or halogen, such as perbenzoic acid, 4-nitroperbenzoic acid, 3-chloroperbenzoic acid, 3,5-dinitroperbenzoic acid or monoperphthalic acid, or a salt thereof, for example magnesium monoperphthalate. Examples of inorganic peracids are peroxosulfuric acids, such as peroxosulfuric acid. Peracetic acid, 3-chloroperbenzoic acid and monperphthalic acid are preferred.
The peracids can also be formed in situ, for example from the corresponding acids or acid salts thereof and hydrogen peroxide. The iminopercarboxylic acids in particular are usually prepared in situ, for example from the corresponding nitriles and hydrogen peroxide, preferably in the presence of a weakly acid buffer, for example potassium hydrogen phosphate.
The reaction is usually carried out in a suitable solvent, such as a halogenated hydro-carbon, for example methylene chloride or chloroform, an ester, such as ethyl acetate, an acid, such as acetic acid, for example in the form of glacial acetic acid, or an alcohol, such as a lower alkanol, for example ethanol, at temperatures between about 0 and abowt 100C, if appropriate in an inert gas atmosphere and if appropriate under presswre, for example up to about 10 bar.
The acyloxylating decarboxylation whicll takes place with the introduction of thc acyl groups R3-C(=O)- or R4-C(=O)- of a compoun~l of the formwla llb is carried out in a manner known per se, for example by trcatment with lead(lV) acylates or by means of anodic oxidation in the presence of a carboxylic acid. The acyl radicals in this lead(lV) acylate correspond to the radicals R3-C(=O)- or R4-C(=O)-, and the carboxylic acid present in the anodic oxidation corresponds to the acids of the formula R3-C(=O)-OH or R4-C(=O)-OH; i.e in an intermediate product of the formula III which is prepared from a starting material of the formula lIb, the radicals R3 and R4 are identical.
Suitable lead(lV) acylates are the corresponding lower alkanoates wllich are unsubstituted or substitutcd, for examyle by halogen, such as fluorine, for example lead tetraacetate, lead tetrapropionate or lead tetra-(trifluoroacetate), or benzoates which are unsubstituted or substituted, for example, by lower alkyl, such as methyl, lower alkoxy, such as Methoxy, and/or halogen, such as fluorine or chlorine, for example lead tetrabenzoate.
These reagents are used in a customary manner, for example in the presence of a suitable solvent, such as an inert, polar solvent, for example tetrahydrofuran, dioxane, acetic acid, dimethylformamide, N-methylpyrTolidone or hexamethylphosphoric triamide, or a mixture of solvents, if necessary with the addition of an alkali metal acylate, for example sodium acetate or potassium acetate, and/or an amine, for example pyridine or lutidine, with cooling or heating, for example at temperatures from about 20C to about 80C and/or in an inert gas atmosphere, for example an argon atmosphere.
The anodic oxidation is usually carTied out in a mono-cell or in a divided cell having a mechanical diaphragm and being composed, for example, of porous clay, glass or polyvinyl chloride, or having an ion exchanger diaphragm, for example a diaphragm obtainable under the trade name Nafion~), and electrodes made of noble metal, such as platinum, titanium alloys, for example titanium-iridium or titanium-tantalum, and also nickel, lead dioxide, glassy carbon and/or graphite. The reaction is carried out in the presence of an acylate donor, such as an acetate donor, for example in acetic acid or in a mixture of acetic acid and an inert organic solvent, such as acetonitrile, dioxane or dimethylformamide, with the addition of an amine, such as a tri-lower alkylamine, for example triethylamine or tri-n-butylamine, or pyridine, and/or an alkali metal acylate, for example sodium acetate or potassium acetate, and, if desired, an additional so-called conductive salt which increases the conductivity, for example a lithium, sodium,potassium or tetraalkylammonium salt, for example the colTesponding tetrafluoborate.
Suitable curTent densities for tl-e electrolysis are betwcen about 10 alld about 400 mA/cm2, for example about 40 mA/cm2. Thc rcaction temperature is between about 0 and about 50C, preferably between room tempcr.ltllre and about 30C.
Both the reaction with a lead(IV) acyl.lte an(l the anodic oxidation in the presence of an acylate donor preferably result in a compound of the formula III in which the 1-hydroxyalkyl group at the C(3) ring carbon atom ~nd the acyloxy group at the C(4) ring carbon atom are arTanged in the trans-position to one another, i.e. result in a diastereomer having the (3R,4R) or the (3S,4S) configuration 2~2~4~
The selective removal of the acyl group R4-C(=O)- in an intermediate of the formula III
with the formation of the hydroxyl group is preferably carried out by means of enzymatic ester cleavage. Known esterases which are particularly suitable for cleaving esterified primary hydroxyl groups are used in this reaction. Thus, for example, for removing an acetyl group in an interrnediate of the formula III in which R4 is methyl, it is preferred to use the esterase from Nocardia mediterranei, an organism used for the preparation of rifamycin (Schar el al., Appl. Microbiol. Biotechnol. Volume 27, page 451 (1988)). A
benzoyloxy group in an intermediate of the formula III in which R4 is phenyl is cleaved, for example, by means of cholesterol esterase (Sigma C9530 from porcine pancreas, which is commercially available).
The reaction is carried out in a manner known per se, preferably under neutral conditions, for example in a suitable aqueous phosphate buffer solution, and at temperatures from about 10C to about 30C, usually at room temperature.
The removal of the hydroxymethyl group which is a substituent on the ring nitrogen atom can be effected in a manner known per se, for example by hydrolysis or by treatment with an acid reagent, preferably after prior oxidation of the hydroxymethyl group to the formyl group.
The latter reaction can be carried out, for example, by treating a compound of the formula IV with a suitable oxidizing metal compound, such as an appropriate chromiurn(VI) compound, for example chromium(VI) oxide, or an analogous oxidizing agent, preferably under the conditions of the Killiani oxidation, for example using an approximately 8 N
solution of chromium trioxide in aqueous sulfuric acid.
The removal of the N-hydroxymethyl or, in palticular, the N-formyl group can preferably be carried out under acid conditions, using primarily inorganic acids, such as mineral acids, for example hydrochloric acid or sulfuric acid, usually in the form of dilute, aqueous solutions, and also organic carboxylic or sulfonic acids, for example p-toluene-sulfonic acid. The N-formyl group, which can, for example, also be removed by treatment with an acid aluminium oxide, for example under the conditions of chromatography, can also be removed under mild basic conditions, for example in the presence of an alkali metal hydroxide, carbonate or bicarbonate or alkaline earth metal hydroxide, carbonate or bicarbonate, which is usually present in aqueous solution.
The hydrolytic removal of the N-hydroxymethyl or N-formyl group is usually carried out at room temperature or at a slightly elevated temperature, for example between about lS~C and about 50C, it being possible, in a given case, additionally to use organic solvents, such as suitable alcohols, for example water-soluble lower alkanols, or ether compounds.
In a compound of the formula I which can be obtained in accordance with the invention, and also in an intermediate at any stage of the process according to the invention, the removal of a protective group R2 can be effected in a manner known per se, for example by solvolysis, such as acidolysis, reduction or oxidation.
An acyl group R2 can be removed under acid or mild alkaline conditions, depending on the meaning of R2, for example by treatment with acids, such as formic or trifluoroacetic acid, or with bases, such as an alkali metal hydroxide, carbonate or bicarbonate, for example sodium bicarbonate, a bicyclic amidine, such as 1,5-diazabicyclo[5.4.0]undec-5-ene, or an alkali metal halide.
Certain acyl radicals of half-esters of carbonic acid, such as halogeno-lower alkoxy-carbonyl and benzyloxycarbonyl which is unsubstituted or substituted by nitro, can be re-moved and replaced by hydrogen by reduction, for example by means of catalytic hydro-genation in the presence of a suitable hydrogenation catalyst, for example platinum oxide or palladium, or by tretment with chemical reducing agents, such as zinc in the presence of aqueous acetic acid.
The removal of a lower alkenyloxycarbonyl group in which lower alkenyl is especially allyl can preferably be effected by treatment with a lower alkenyl group acceptor in the presence of a suitable catalyst, swch as a mctallic phosphine compound, for example tetrakistriphenylphosphine palladium, if appropriate in the presence of triphenylphosphine.
Examples of suitable acceptors for lower alkenyl groups, such as the allyl group, are amines, in particular sterically hindered amines, for example tert-butylamine, and also tri-lower alkylamines, for example triethylamine, morpholine or thiomorpholine, and also aliphatic or cycloaliphatic ~-dicarbonyl compounds, for example acetylacetone, ethyl acetoacetate or, preferably, dimedone, and also lower alkanecarboxylic acids, for example acetic acid or propionic acid. The reaction is usually carried out by treating the compound of the formula I having a suitably protected hydroxyl group with 1.5 to 10 molar Z~ 4S
equivalents of the lower alkenyl group acceptor in the presence of 2 to 10 mol %, in particulLIr S to 8 mol % (relative to the st~uting compound), of the catalyst, in particular tetrakistriphenylphosphine palladium catalyst, if appropriate in the presence of up to 50 mol % of triphenylphosphine, in an inert solvent, such as an ether, for example dioxane or especially tetrahydrofuran, a halogenated hydrocarbon, for example methylene chloride, a lower alkanol, for example ethanol, an ester, for example ethyl acetate, or a mixture of such solvents, at temperatures from about 0C to about 40C, preferably at about 2V to about 2~C, and, if necessary, in an inert gas atmosphere, such as an atmosphere of nitrogen or argon.
A 2-oxacycloalkyl or 2-thiacycloalkyl group R2 can be removed by treatment with an acid, such as a mineral acid, for example hydrochloric or sulfuric acid.
A silyl group R2 which is substituted as indicated can be removed in the presence of suitable, preferably polar, solvents, such as solvents containing hydroxyl groups, if appropriate under acid conditions or, in particular, by treatment with a salt of hydrofluoric acid which affords fluoride anions, such as an alkali metal fluoride, for example sodium fluoride, if appropriate in the presence of a macrocyclic polyether ("crown ether"), or with the fluoride of an organic quaternary base, such as a tetra-lower alkylammonium fluoride, for example tetrabutylammonium fluoride, if appropriate in the presence of an acid reagent.
In a compound of the formula I obtainLlble in accordLmce with the invention, and also in an intermediate at any stage of the process, in which R2 is hydrogen, the free hydroxyl group can be protected in a manner known per se, it being possible, if necessary, to protect temporarily an unsubstituted ring nitrogen atom. The protective group can be introduced, for example, by treatment with a suitable halogenosilane, for example a tri-lower alkyl halogeno silane, such as trimethylchlorosilane or dimethyltert-butylchlorosilane, or a suitable silazane compound, such as hexamethyl(lisilazane, or by treatment with a reactive derivative of an acid whose acyl radical acts as a hydroxyl protective group, for example by reaction with an anhydride, for example trifluoroacetic anhydride, a mixed anhydride, for example an acid halide, such as 2,2-dichloroacetyl chloride, or a mixed anhydride of a carbonic acid half-ester, for example 2,2,2-trichloroethyl, allyl, phenyl or p-nitrophenyl chloroformate, or by reaction with 1,2-dihydrofuran or 1,2-dihydropyran in the presence of an acid, for example p-toluenesulfonic acid.
2~ 5 The present invention preferably relates to a process for the preparation of compounds of the formula I in which Rl is hydrogen or, in particular, methyl, R2 is hydrogen or a hydroxyl protective group R2, such as the acyl radical of a carbonic acid half-ester, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitro-benzyloxycarbonyl, the acyl radical of a substituted or unsubstituted benzoic acid, for example 4-nitrobenzoyl or 3,5-dinitrobenzoyl, or, in particular, tri-lower alkylsilyl, for example trimethylsilyl, tert-butyldimethylsilyl, or dimethyl-(2,3-dimethyl-2-butyl)-silyl, and R3 is phenyl or methyl, and in which the 1'-C atom of the side chain can have the S
configuration or preferably the R configuration, if Rl is methyl.
The invention relates primarily to a process for the preparation of (3R,4R, l 'R)-4-acetoxy-3-( 1 '-hydroxyethyl)-azetidin-2-one or (3R,4R,l'R)-4-benzoyloxy-3-(1'-hydroxyethyl)-azetidin-2-one and their 1'-O-tri-lower alkylsilyl derivatives, such as 1'-O-tert-butyldimethylsilyl or 1'-O-dimethyl-(2,3-dimethyl-2-butyl)-silyl derivatives.
Compounds of the formula I, particularly those in which Rl is hydrogen or methyl, R2 is hydrogen or a hydroxyl protective group R2 and R3 is methyl or phenyl are valuable intermediates which can be processed further in a manner known per se to give penem or carbapenem compounds which have an antibiotic activity. Further processing is carried out analogously to that of known azetidinone compounds of the formula I in which R3 is methyl, for example as described by T. Hayashi et al., Chem. Pharm. Bull. 29, 3158, 1981, or in European Published Patent Applications No. 42,026 (for penems) or No. 78,026 (for carbapenems).
The starting materials and intermediates used in the process according to the invention are in part novel. They can be prepared in a manner known per se.
Thus, for example, compounds of the formul~ II (a and b) can be obtained by d) cyclizing the carbanion of a compound of the formula 2~ 45 H o (V) Rl--CH--C(R) C112--C--R3 0~ N
o in which R3' has the meaning of R3 or is etherified hydroxyl, and R4' has the meaning of R4 or is etherified hydroxyl, R3' and R4' either having the meanings of R3 and R4, respectively, or both being etherified hydroxyl, and in which, if Rl is lower alkyl, the 3-C
atom has the R configuration or the S configuration, or the carbanion of a compound of the formula \ 3 2 / (VI) ~ CH--C(R) CH2--C--R3 R20 l I l /~ N
in which R2 is a hydroxyl protective group which cannot be removed under the conditions of the cyclization process and X is a nucleofugic leaving group and, if Rl is lower alkyl, the 3-C atom has the R configuration or the S configuration, or e) by isomerizing a cis-compound of the formula loR2 11 o (VII) R~l Cllllll~llllll C-- R3 ¦ (S) (R) H
~ N~
C112--C--R~, o and, if desired, converting a compound of the formula II obtainable in accordance with the invention into another compound of the formula II.
3~
In a starting material of the formula VI a hydroxyl protective group R2 which cannot be removed under the conditions of the cyclization process is one of the acyl groups men-tioned under R~2 of a substituted carboxylic or sulfonic acid, for example 2,2,2-trifluoro-acetyl, and also the acyl radical of a carbonic acid half-ester, for example p-nitrobenzyl-oxycarbonyl, or 2-tetrahydrofuryl or 2-tetrahydropyranyl, and also 1-lower alkoxy-lower alkyl, for example methoxymethyl or 1-ethoxyethyl, or substituted or unsubstituted aroyl, for example 4-nitrobenzoyl or 3,5-dinitrobenzoyl. A suitable nucleofugic leaving group X
is preferably reactive esteri~led hydroxyl, for example halogen, for example chlorine, bromine or iodine, lower alkanoyloxy, such as acetoxy, arylsulfonyloxy, for example phenylsulfonyloxy or p-toluenesulfonyloxy, or lower alkylsulfonyloxy, for example methanesulfonyloxy.
An etherified hydroxyl group R3 or R4 is, in particular, a hydroxyl group which is etherified with an aliphatic, aromatic or araliphatic radical, such as lower alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy or primarily tert-butoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, for example benzyloxy.
In carbanions of compounds of the formula V or VI the negative charge on the carbon atom is located in the a-position relative to the ~roup of the formula -CO- R3; i.e. the corresponding compound has the partial formula ~N--C~ --CO--R3 . Carbanion com-pounds of this type are prepared in situ by treating a compound of the formula V or VI in a suitable solvent with a base which forms carbanions, in the course of which the cyclization of process d) takes place. Bases of this type are, inter alia, alkali metal bases, for example sodium hydroxide or carbonate, potassium hydroxide or carbonate or lithium hydroxide or carbonate, or organic alkali metal compounds, for example lower alkyllithium, such as n-butyllithium or tert-hutyllithium, alkali metal amides, for example lithium diisopropyl-amide or di-tert-butylamide, and especially alkali metal amides in which two hydrogell atoms have been replaced by org.lnic silyl grollps, for examplc trimethylsilyl ~roups, for example lithium bis-(trimethylsilyl)-amicle, sodium bis-(trimethylsilyl)-amide or potassium bis-(trimethylsilyl)-amide, inter alia lithium hexamethyldisihlzide, and also suitable organic nitrogen bases, such as cyclic amidines, for example 1,5-diazabicyclo-[4.3.0]non-5-ene or 1,5-diazabicycloLS.4.0]undec-5-ene, and also fluorine compounds which release fluoride ions in an aprotic, organic solvent and which are particularly suit-able for the preparation of carbanions of compounds of the formula V, preferably tetra-lower alkylammonium fluorides, especially tetra-n-butylamonium fluoride.
~Qlal2U4~
lf a suitable silyl reagellt, for example lithiurn hexamethyldisilazide, is used for the cyclization of a compound of the formula V or VI, under certain circumstances, for example if the reaction is carried out carefully, a compound of the formula Ila in which R2 is a silyl protective group, for example trimethylsilyl, can be obtained directly.
Examples of solvents suitable for the formation of carbanions are halogenated or non-halogenated hydrocarbons, such as benzene, toluene, methylene chloride or chloroform, ethers, such as dioxane, tetrahydrofuran or dimethoxyethane, amides, such as dimethyl-formamide or hexamethylphosphoric triamide, sulfoxides, such as dimethyl sulfoxide, or nitriles, such as acetonitrile, or mixtures thereof. The reaction can also be carried out under phase transfer conditions, for example in a system consisting of methylene chloride and 50 % aqueous sodium hydroxide solution in the presence of a phase transfer catalyst, such as benzyltriethylammonium chloride or tetrabutylammonium bisulfate. The reaction temperature, which depends, inter alia, on the choice of the base used, is between about -80C and about 80C, the reaction being preferably carried out under an inert gas atmosphere, for example an atmosphere of argon or nitrogen.
Under the conditions of the process, an inversion of the configuration at the 2-C atom of the starting material takes place, so that a 3S compound of the formula IIa is formed from a 2R compound of the formula V or VI; the configuration of the 1'-C atom in the side chain, if Rl is lower alkyl, remains unchanged. For example, 3S azetidinones of the for-mula IIa are obtained from R-glycidamides of the formula V, or (3S,l'R)-3-hydroxyethyl-azetidinones of the formula IIa are obtained from (2R,3R)-2,3-epoxybutyramides of the formula V.
The isomerization of a compound of the formula VII (process variant e) can be carried out in a suitable solvent or solvent mixture in the presence of a base. Suitable solvents and bases, and also the reaction conditions, are the sarne as those which can be used for the cyclization process d). It is preferred to employ aprotic dipoLu solvents, such as dirnethyl-formamide, N-methylpyrrolidone or dimethyl sulfoxide, and, as bases, in particular potassium carbonate or 1,5-diazabicyclo[5.4.0~undec-5-ene, and it is also possible to carry out the reaction under the phase transfer conditions described.
Starting materials of the formula Ilb can be obtained in a manner known per se, for example by solvolysis, from diesters of the formula IIb obtainable in accordance with the Q~
invention. The corresponding diester compounds can be converted into the free dicarboxylic acid compounds, for example by means of acid or basic hydrolysis, a di-tert-bu~yl ester ( R3 = R4~ = tert-butoxy) can, for example, be converted by treatment with dilute, for example 1 N, sodium hydroxide solution into a lower alkanol, for example methanol or ethanol, or with trifluoroacetic acid with the application of heat.
The cis-compounds of the formula VII can be formed as byp}oducts in the course of the cyclization reaction (d) and can be separated off from the products of the des*ed con-figuration in a customary manner, for example by means of chromatography.
Compounds of the forrnula V can be obtained in a manner known per se, for example by reacting an epoxy acid compound of the formula H (VIII) Rl--CH--C
\ o / C
// ~
0 0~1 or a suitable salt thereof with an amine compound of the formula (IX) Il ~ CH2--C-- R3 HN
o The reaction can be carried out under conditions which are analogolls to those of the process described in detail bclow for the preparation of compounds of the formula VIa.
The compounds of the formula VIII are known or c~m be prepared by processes known per se.
The starting materials of the formula V are preferably prepared in situ under the abovementioned carbanion-forming conditions and with a Walden inversion at the 2-C
atom from compounds of the formula Rl~ 3 H X O (VIa), ~ CH 2 C(S) CH2--C--R3 R20 D~ N
o CH2--C-- R4 o in which R~'is hydrogen or a hydroxyl protective gTOup which can be removed under the conditions of epoxide forrnation and in which, if Rl is lower alkyl, the 3-C atom has the R
configuration or the S configuration, the elements of a compound of the formula R~ -X
being removed.
In a compound of the formula VIa a hydroxyl protective gTOUp R~' which can be removed under the conditions of epoxide formation is a tri-lower alkylsilyl group, for example dimethyltert-butylsilyl or trimethylsilyl. X is preferably halogen, for example chlorine or bromine, lower alkanesulfonyloxy, for example methanesulfonyloxy, or arylsulfonyloxy, for example p-toluenesulfonyloxy.
The removal of R~'-xin which R~" iS hydrogen is effected in the course of the tTeatment with one of the carbanion-forming bases mentioned, for example sodium hydroxide or carbonate or potassium hydroxide or carbonate, preferably with an amidine, for example 1,5-diazabicyclo[5.4.0]undec-5-ene or with a tetra-lower alkylammonium fluoride, for example dehydrated tetra-ll-butylammonium fluoride, for example under the reaction conditions described by Djerassi et al., "Steroid Reactions", page 606 (Holden Day, San Francisco, 1963). If R~' iS, for example, a tri-lower alkylsilyl group which can be removed under the conditions of epoxide formation, it is preferred to use a tetra-lower alkylammonium fluoride.
The reaction of a compound of tlle formula VIa to give an epoxy compound of the formula V is preferably carried out in an inert solvent or solvent mixture, usually anhydrous, if necessary with cooling or heating, for example within a temperature range from about -40C to about +100C, preferably from about -10C to about +50C, and/or under an inert gas atmosphere, for example an atmosphere of nitrogen.
2[11~2 In the course of this process thc conf igur;ltion at the 2-C atom is inverted, whereas the configuration of the 3-C atom, if Rl is lower alkyl, is retained. Thus the (2R,3R) com-pounds of the formula V are formed from 2S-halogeno-3R-hydroxy compounds of the formula Vla and the (2R,3S) compounds of the formula V are formed from 2S-halogeno-3S-hydroxy compounds.
After ;t has been prepared, the epoxide of the formula V can, if desired, be isolated by the removal of R~'-x from a compound of the formula YIa by employing the amidine used as the reagent in approximately equimolar amounts.
The above compounds of the formula VIa can be prepared, for example, by reacting a compound of the formula OR2' H X (X) 21~
R ~--C--C(S) // \
O OH
or a reactive functional derivative thereof with an amine of the formula IX. This reaction can be carried out in a manner known per se, for example by subjecting the two reactants to a condensation reaction with one another in the presence of a condensing agent, and de-hydrating the free acid, for example in the presence of carbodiimides, such as diethyl-carbodiimide, diisopropylcarbodiimide or dicyclohexylcarbodiimide, or di-(N-hetero-cyclyl)-carbonyl compounds, such .IS carbonyl(liimid.lzole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, which are uscd in the prcsence of an inert solvent, such as di-methylformamide, if necessary at a slightly redllce(l or elevaled temperature. Reactive functional derivatives of Ll carboxylic acid of tlle formula X are primarily an}ly(lrides, in particular mixed anhydrides, such as the corresponding carboxylic acid chloride or bromide, which are preferably formed in situ by reacting a salt, for example the dicyclo-hexylamine salt of epoxy acids of the formula VIII with suitable halogenating agents, such as phosphorus oxychloride or thionyl chloride, in particular with oxalyl chloride, and which are, if appropriate, reacted with the amine of the formula IX in the presence of a base, for example N-methylmorpholine.
2~20~5 The comyounds of the formula VI can be prepared analogously, starting from compounds of the formula IX and from compounds of the formula OR2 H (Xa) -~x Rl--C C
H C
// \
O OH
Compounds of the formula X and Xa in which X is halogen are known. They can be prepared, for example, in a manner known per se from L-serine or L-threonine or the D-isomers thereof by diazotizing the amino group with a nitrite salt, for example potassium nitrite, in the presence of a hydrohalic acid.
If L-serine is used and compounds of the formula VI are the starting material, it is possible to obtain compounds of the formula I in which the carbon in the 3-position of the azetidinone ring has the R-configuration. If L-threonine is used, compounds of the formula I 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 (Rl is methyl) has the R-configuration. If it is intended to prepare compounds of the formula I in which the 3-C atom has the R-con-figuration and the 1'-C atom, for example, of a 1-hydroxyethyl side chain has the S-con-figuration, allothreonine is used as the starting material. 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 a 1-OR2-lower alkyl side chain having more than one carbon atom in the lower alkyl moiety remains unchanged.
Amines of the formula IX, in particular the amines having symmetrical substituents, are known or, if novel, can be prepared in a manner known per se. Thus, for example, a compound of the formula IX in which R3 and R4' are tert-butoxy can be prepared by the action of isobutylene on the corresponding acid, usually in dioxane in the presence of 95-98 % sulfuric acid at room temperature. A preferred process for the preparation of compounds of the formula IX in which Ri and R4' represent phenyl consists in reacting a phenacylamine hydrochloride with a phenacyl chloride or phenacyl bromide in the presence of a suitable base, for example triethylamine, and in methylene chloride.
2i~021~4~
The present invention also embraces embodiments of the process in which the starting material is a compound obtainable at any preliminary seage of the process and the sub-sequent process stages are carried out. It also embraces a combination of process steps, for example starting from one of the compounds of the formula VI to X to give a compound of the formula I or starting from one of the compounds of the formulae IX or X or Xa to give a compound of the formula VI or IVa, respectively.
The process according to the invention has the advantage that the compounds of the forrnula I can be prepared stereospecifically in a high yield and in an economical manner, and that it is possible to use the readily accessible and cheap symmetrically substituted amines of the formula IX, whose substituents serve on the one hand for the cyclization to give the ~-lactam compounds and on the other hand as a temporary N-protective group which can be removed under mild conclitions.
The following examples serve to illustrate the invention. Temperatures are in degrees centigrade. The specific angles of rotation are [ a ] 20 values. Columns packed with Merck silica gel 60 can be used for the separation by chromatography in preparative work-up.
Example 1 1.1. A solution of 0.866 g of (3S,4S,l'R)-4-benzoyl-3-(1'-hydroxyethyl)-1-phenacylazetidin- 2-one and 5.7 g of 3-chloroperbenzoic acid in 30 ml of methylene chloride is stirred for 8 hours at room temperature. The white suspension is diluted with methylene chloride and washed successively with a 5 % aqueous solution of sodium thio-sulfate/potassium iodide, water, aqueous sodium bicarbonate solution and water, dried and evaporated under a water pump vacuum. The crude product is purified by means of medium pressure chromatography (solvent: a 2:3 mixture of hexane and ethyl acetate).
After the main fraction has been recrystallized from methylene chloride/diethyl ether, (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-(1'-hydroxy-ethyl)-azetidin-2-one is obtained, melting point 136- 138.
1.2. 0.06 g of imidazole and 0.088 g of tert-butyldimethylchlorosilane are added to a solu-tion of 0.18 g of (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-(1'-hydroxyethyl)-azetidin-2-one in 1 ml of dimethylformamide and the mixture is stirred for 24 hours at room temperature. A further 0.015 g of imidazole and 0.022 g of tert-butyldimethylchloro-silane are added to the reaction mixture, which is stirred for a further 6 hours at room tem-perature and then discharged onto ice and a saturated aqueous solution of sodium bicarbo-nate, the product is taken up in diethyl ether, and the organic phase is washed once each with aqueous sodium bicarbonate solution, 1 % aqueous citric acid, water, aqueous sodium bicarbonate solution and water. The aqueous phases are washed again with diethyl ether; the combined organic extracts are dried with sodium sulfate and evaporated in a water pump vacuum. The crude product is dissolved in a 3:2 mixture of hexane and ethyl acetate and is filtered through silica gel 60. Recrystallization from methylene chloride/diethyl ether gives pure (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-[1'-(tert-butyl dimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 109- 110;
[ ] D = -14.1 (c = 0.545 % in chloroform).
1.3. 0.03 g (30 U) of cholesterol esterase (Sigma C 9530, from porcine pancreas) is dissolved in 33 ml of phosphate buffer pH 7 in a S0 ml round-bottomed flask controlled by thermostat at 30, and 0.05 g of (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-Ll'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, dissolved in 6 ml of acetone, is added in portions in the course of 10 hours. The reaction is followed by thin layer chromato-graphy (solvent: a 1: 1 mixture of ethyl acetate and hexane) and by high pressure liquid chromatography (solvent: an 85:15 mixture of acetonitrile and water). After 20 hours, the reaction mixture is extracted with six times 100 ml each of chloroform. The organic ex-tract gives a slightly yellow oil which, according to high pressure liquid chromatography, still contains about 10% of starting material. Chromatography over silica gel (mobile phase: a 4:1 mixture of methylene chloride and ethyl acetate) gives (3R,4R,l'R)-4-benzoyloxy- 1-hydroxy-methyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azeti~in-2-one, which, after recrystallization from methylene chloride/diethyl ether/hexane, melts at 83-85; [ a ] D = +68.5 (c = 0.672 % in chloroform).
1.4. 0.21 ml of 8 N chromosulfuric acid (Killiani mixture) is added to a solution of 0.16 g of (3R,4R,l'R)-4-benzoyloxy-1-hydroxymcthyl-3-[1'-(tert-blltyldimethylsilyloxy)-cthyll-azetidin-2-one in 10 ml of methylene chloride, and the mixture is stirred for S hours at room temperature. Excess oxidizing agent is destroyed by adding 1 ml of isopropanol, and the reaction mixture is applied directly to a columll of 80 g of aluminium oxide (Alox II, acid) and eluted with ethyl acetate. This gives virtually pure (3R,4R,l'R)-4-benzoyloxy-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 125- 126; [ a ] D =
71.1 (c = 0.85 % in chloroform), after recrystallization from diethyl ether/hexane.
Process for the preparation of optically active acvloxvazetidinones The present invention relates to a process for the preparation of 3,4-trans-disubstituted azetidinones of the formula OR2 H H o (I) R~ ~o ll R3 H .~ N~l o in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group R~' and R3 is substituted or unsubstituted phenyl or lower alkyl.
The general definitions used within the scope of this invention preferably have the following meanings:
Groups or compounds marked "lower" preferably contain up to and including 7, preferably up to and including 4 carbon atoms.
As lower alkyl, Rl is preferably methyl and also ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. Rl is primarily methyl and also hydrogen.
Hydroxyl protective groups R2~, including their introduction and removal, ale described, for example, in "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, and also in "Protective Gro~lps in Organic Chemistry", Wiley, New York 1974. A hydroxyl protective group is, for example, the acyl radical of a carboxylic acid, for example lower alkanoyl which is substituted by halogen, such as fluorine or chlorine, for example 2,2-dichloroacetyl or 2~2,2-trifluoroacetyl, or a benzoic acid which is unsub-stituted or substituted, for example, by nitro, halogen, such as chlorine, or lower alkoxy, such as methoxy, for example benzoyl or 4-nitrobenzoyl, 3,5-dinitrobenzoyl, 4-chloro-~QC~4~
benzoyl or 4-methoxybellzoyl, and also the acyl radical of a carbonic acid lower alkyl or lower alkenyl half-ester which is unsubstituted or substituted, for example, by halogen, sllch as chlorine, or by phenyl which can contain substituents, suCIl as 4-nitrophenyl, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or 4-nitro-benzyloxycarbonyl, or the acyl radical of an organic sulfonic acid, for example lower alkanesulfonyl, such as methanesulfonyl, or arylsulfonyl, such as toluenesulfonyl.
Hydroxyl protective groups are also 2-oxacycloalkyl or 2-thiacycloalkyl having 5 or 6 ring atoms, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl, and also a thia analogue thereof, 1-lower alkyloxy-lower alkyl, for example methoxymethyl or 1-ethoxyethyl, or silyl which is trisubstituted, in particular, by lower alkyl, aryl-lower alkyl and/or aryloxy, for example tri-lower alkylsilyl, such as trimethylsilyl, triethylsilyl, dimethyl-(2-ethyl-2-propyl)-silyl, diethyl-(2-ethyl-2-propyl)-silyl, dimethyl-(tert-butyl)-silyl or dimethyl-(2,3-dimethyl-2-butyl)-silyl, diaryl-(lower alkyl)-silyl, for example diphenyl-(tert-butyl)-silyl, aryl-(di-lower alkyl)-silyl, for example tert-butylmethylphenylsilyl, and di-lower alkyl-(lower alkylphenoxy)-silyl, for example dimethyl-(2,4,6-tri-tert-butylphenoxy)-silyl. Pro-tective groups R2' which are particularly preferred because of their stability to bases and hydrolysis are trialkylsilyl, in particular trimethylsilyl, tert-butyldimethylsilyl or dimethyl-(2,3-dimethyl-2-butyl)-silyl.
As substituted phenyl, R3 is phenyl which is substituted, preferably monosubstituted to trisubstituted, for example by lower alkoxy, for example methoxy, lower alkyl, for example methyl and/or halogen, for example chlorine, for example 4-methoxyphenyl, 4-nitrophenyl, 2-, 3- or 4-chlorophenyl or 4-tolyl. As lower alkyl, R3 is, for example, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, especially methyl. R3 is preferably phenyl and methyl.
The process according to tlle invention comprises (a) treating a compound of the formula OR2 H H 0 ( R ~ ¦ (S) ~ (S) ¦¦ R
H .~N~
o C1~21r R4 ~o~
in which R4 is substituted or unsubstituted phenyl or lower allcyl with a peracid, or decarboxylating by acyloxylation a compound of the formula OR2 H H (IIb~
Rl~ - ~ COOH
H.~ N\
with the introduction of the radicals R3-C(=O)- or R4-C(=O)-, (b) replacing the radical of the formula R4-C(=O)- by hydrogen in a compound of the formula OR2 H H O (III) R1~---~o 1I R3 H.~ N\
o CH2--o ~r R4 obtainable as in (a), and (c) removing, in a compound of the forrnula OR2 H rl O (IV) Rl~- - ~O ~I R3 rl ~ N\
thus obtainable, the hydroxymethyl group in the 1-position, if appropriate after conversion into a forrnyl group, and, if desired, in a compound of the forrnula I thus obtainable in which R2 is a protective group R2', converting the protected hydroxyl group into the free hydroxyl group, andJor, if desired, in a compound of the for nula I thus obtainable in which R2 is hydrogen, converting the free hydroxyl group into a protected hydroxyl group.
Preferred starting materials are those of the formulae Ila or IIb in which Rl is hydrogen or methyl, R2 is hydrogen or a hydroxyl protective group R2', such as dimethyltert-butylsilyl or dimethyl-(2,2-dimethyl-2-butyl)-silyl, and R3 and R4, preferably both identical, are phenyl or methyl.
~o~zo~
The treatment of the starting material of the form-lla IIa with a peracid is preferably caTried out by the Baey~r-Villiger reaction, in which organic or inor~Tanic peracids or salts thereof, such as alkali metal or alkaline earth metal salts, for example sodium, potassiu}n or magnesium salts, can be employed. Organic peracids are, in particular, the corres-ponding percarboxylic acids, inter alia lower alkanepercarboxylic acids which are unsub-stituted or substiîuted, for example, by halogen, such as peracetic acid or trifluoroperacetic acid or trihalogenoiminoperacetic acid, for example trichloroiminoperacetic acid or tri-fluoroiminoperacetic acid, aromatic peracids which are unsubstituted or substituted, for example, by nitro and/or halogen, such as perbenzoic acid, 4-nitroperbenzoic acid, 3-chloroperbenzoic acid, 3,5-dinitroperbenzoic acid or monoperphthalic acid, or a salt thereof, for example magnesium monoperphthalate. Examples of inorganic peracids are peroxosulfuric acids, such as peroxosulfuric acid. Peracetic acid, 3-chloroperbenzoic acid and monperphthalic acid are preferred.
The peracids can also be formed in situ, for example from the corresponding acids or acid salts thereof and hydrogen peroxide. The iminopercarboxylic acids in particular are usually prepared in situ, for example from the corresponding nitriles and hydrogen peroxide, preferably in the presence of a weakly acid buffer, for example potassium hydrogen phosphate.
The reaction is usually carried out in a suitable solvent, such as a halogenated hydro-carbon, for example methylene chloride or chloroform, an ester, such as ethyl acetate, an acid, such as acetic acid, for example in the form of glacial acetic acid, or an alcohol, such as a lower alkanol, for example ethanol, at temperatures between about 0 and abowt 100C, if appropriate in an inert gas atmosphere and if appropriate under presswre, for example up to about 10 bar.
The acyloxylating decarboxylation whicll takes place with the introduction of thc acyl groups R3-C(=O)- or R4-C(=O)- of a compoun~l of the formwla llb is carried out in a manner known per se, for example by trcatment with lead(lV) acylates or by means of anodic oxidation in the presence of a carboxylic acid. The acyl radicals in this lead(lV) acylate correspond to the radicals R3-C(=O)- or R4-C(=O)-, and the carboxylic acid present in the anodic oxidation corresponds to the acids of the formula R3-C(=O)-OH or R4-C(=O)-OH; i.e in an intermediate product of the formula III which is prepared from a starting material of the formula lIb, the radicals R3 and R4 are identical.
Suitable lead(lV) acylates are the corresponding lower alkanoates wllich are unsubstituted or substitutcd, for examyle by halogen, such as fluorine, for example lead tetraacetate, lead tetrapropionate or lead tetra-(trifluoroacetate), or benzoates which are unsubstituted or substituted, for example, by lower alkyl, such as methyl, lower alkoxy, such as Methoxy, and/or halogen, such as fluorine or chlorine, for example lead tetrabenzoate.
These reagents are used in a customary manner, for example in the presence of a suitable solvent, such as an inert, polar solvent, for example tetrahydrofuran, dioxane, acetic acid, dimethylformamide, N-methylpyrTolidone or hexamethylphosphoric triamide, or a mixture of solvents, if necessary with the addition of an alkali metal acylate, for example sodium acetate or potassium acetate, and/or an amine, for example pyridine or lutidine, with cooling or heating, for example at temperatures from about 20C to about 80C and/or in an inert gas atmosphere, for example an argon atmosphere.
The anodic oxidation is usually carTied out in a mono-cell or in a divided cell having a mechanical diaphragm and being composed, for example, of porous clay, glass or polyvinyl chloride, or having an ion exchanger diaphragm, for example a diaphragm obtainable under the trade name Nafion~), and electrodes made of noble metal, such as platinum, titanium alloys, for example titanium-iridium or titanium-tantalum, and also nickel, lead dioxide, glassy carbon and/or graphite. The reaction is carried out in the presence of an acylate donor, such as an acetate donor, for example in acetic acid or in a mixture of acetic acid and an inert organic solvent, such as acetonitrile, dioxane or dimethylformamide, with the addition of an amine, such as a tri-lower alkylamine, for example triethylamine or tri-n-butylamine, or pyridine, and/or an alkali metal acylate, for example sodium acetate or potassium acetate, and, if desired, an additional so-called conductive salt which increases the conductivity, for example a lithium, sodium,potassium or tetraalkylammonium salt, for example the colTesponding tetrafluoborate.
Suitable curTent densities for tl-e electrolysis are betwcen about 10 alld about 400 mA/cm2, for example about 40 mA/cm2. Thc rcaction temperature is between about 0 and about 50C, preferably between room tempcr.ltllre and about 30C.
Both the reaction with a lead(IV) acyl.lte an(l the anodic oxidation in the presence of an acylate donor preferably result in a compound of the formula III in which the 1-hydroxyalkyl group at the C(3) ring carbon atom ~nd the acyloxy group at the C(4) ring carbon atom are arTanged in the trans-position to one another, i.e. result in a diastereomer having the (3R,4R) or the (3S,4S) configuration 2~2~4~
The selective removal of the acyl group R4-C(=O)- in an intermediate of the formula III
with the formation of the hydroxyl group is preferably carried out by means of enzymatic ester cleavage. Known esterases which are particularly suitable for cleaving esterified primary hydroxyl groups are used in this reaction. Thus, for example, for removing an acetyl group in an interrnediate of the formula III in which R4 is methyl, it is preferred to use the esterase from Nocardia mediterranei, an organism used for the preparation of rifamycin (Schar el al., Appl. Microbiol. Biotechnol. Volume 27, page 451 (1988)). A
benzoyloxy group in an intermediate of the formula III in which R4 is phenyl is cleaved, for example, by means of cholesterol esterase (Sigma C9530 from porcine pancreas, which is commercially available).
The reaction is carried out in a manner known per se, preferably under neutral conditions, for example in a suitable aqueous phosphate buffer solution, and at temperatures from about 10C to about 30C, usually at room temperature.
The removal of the hydroxymethyl group which is a substituent on the ring nitrogen atom can be effected in a manner known per se, for example by hydrolysis or by treatment with an acid reagent, preferably after prior oxidation of the hydroxymethyl group to the formyl group.
The latter reaction can be carried out, for example, by treating a compound of the formula IV with a suitable oxidizing metal compound, such as an appropriate chromiurn(VI) compound, for example chromium(VI) oxide, or an analogous oxidizing agent, preferably under the conditions of the Killiani oxidation, for example using an approximately 8 N
solution of chromium trioxide in aqueous sulfuric acid.
The removal of the N-hydroxymethyl or, in palticular, the N-formyl group can preferably be carried out under acid conditions, using primarily inorganic acids, such as mineral acids, for example hydrochloric acid or sulfuric acid, usually in the form of dilute, aqueous solutions, and also organic carboxylic or sulfonic acids, for example p-toluene-sulfonic acid. The N-formyl group, which can, for example, also be removed by treatment with an acid aluminium oxide, for example under the conditions of chromatography, can also be removed under mild basic conditions, for example in the presence of an alkali metal hydroxide, carbonate or bicarbonate or alkaline earth metal hydroxide, carbonate or bicarbonate, which is usually present in aqueous solution.
The hydrolytic removal of the N-hydroxymethyl or N-formyl group is usually carried out at room temperature or at a slightly elevated temperature, for example between about lS~C and about 50C, it being possible, in a given case, additionally to use organic solvents, such as suitable alcohols, for example water-soluble lower alkanols, or ether compounds.
In a compound of the formula I which can be obtained in accordance with the invention, and also in an intermediate at any stage of the process according to the invention, the removal of a protective group R2 can be effected in a manner known per se, for example by solvolysis, such as acidolysis, reduction or oxidation.
An acyl group R2 can be removed under acid or mild alkaline conditions, depending on the meaning of R2, for example by treatment with acids, such as formic or trifluoroacetic acid, or with bases, such as an alkali metal hydroxide, carbonate or bicarbonate, for example sodium bicarbonate, a bicyclic amidine, such as 1,5-diazabicyclo[5.4.0]undec-5-ene, or an alkali metal halide.
Certain acyl radicals of half-esters of carbonic acid, such as halogeno-lower alkoxy-carbonyl and benzyloxycarbonyl which is unsubstituted or substituted by nitro, can be re-moved and replaced by hydrogen by reduction, for example by means of catalytic hydro-genation in the presence of a suitable hydrogenation catalyst, for example platinum oxide or palladium, or by tretment with chemical reducing agents, such as zinc in the presence of aqueous acetic acid.
The removal of a lower alkenyloxycarbonyl group in which lower alkenyl is especially allyl can preferably be effected by treatment with a lower alkenyl group acceptor in the presence of a suitable catalyst, swch as a mctallic phosphine compound, for example tetrakistriphenylphosphine palladium, if appropriate in the presence of triphenylphosphine.
Examples of suitable acceptors for lower alkenyl groups, such as the allyl group, are amines, in particular sterically hindered amines, for example tert-butylamine, and also tri-lower alkylamines, for example triethylamine, morpholine or thiomorpholine, and also aliphatic or cycloaliphatic ~-dicarbonyl compounds, for example acetylacetone, ethyl acetoacetate or, preferably, dimedone, and also lower alkanecarboxylic acids, for example acetic acid or propionic acid. The reaction is usually carried out by treating the compound of the formula I having a suitably protected hydroxyl group with 1.5 to 10 molar Z~ 4S
equivalents of the lower alkenyl group acceptor in the presence of 2 to 10 mol %, in particulLIr S to 8 mol % (relative to the st~uting compound), of the catalyst, in particular tetrakistriphenylphosphine palladium catalyst, if appropriate in the presence of up to 50 mol % of triphenylphosphine, in an inert solvent, such as an ether, for example dioxane or especially tetrahydrofuran, a halogenated hydrocarbon, for example methylene chloride, a lower alkanol, for example ethanol, an ester, for example ethyl acetate, or a mixture of such solvents, at temperatures from about 0C to about 40C, preferably at about 2V to about 2~C, and, if necessary, in an inert gas atmosphere, such as an atmosphere of nitrogen or argon.
A 2-oxacycloalkyl or 2-thiacycloalkyl group R2 can be removed by treatment with an acid, such as a mineral acid, for example hydrochloric or sulfuric acid.
A silyl group R2 which is substituted as indicated can be removed in the presence of suitable, preferably polar, solvents, such as solvents containing hydroxyl groups, if appropriate under acid conditions or, in particular, by treatment with a salt of hydrofluoric acid which affords fluoride anions, such as an alkali metal fluoride, for example sodium fluoride, if appropriate in the presence of a macrocyclic polyether ("crown ether"), or with the fluoride of an organic quaternary base, such as a tetra-lower alkylammonium fluoride, for example tetrabutylammonium fluoride, if appropriate in the presence of an acid reagent.
In a compound of the formula I obtainLlble in accordLmce with the invention, and also in an intermediate at any stage of the process, in which R2 is hydrogen, the free hydroxyl group can be protected in a manner known per se, it being possible, if necessary, to protect temporarily an unsubstituted ring nitrogen atom. The protective group can be introduced, for example, by treatment with a suitable halogenosilane, for example a tri-lower alkyl halogeno silane, such as trimethylchlorosilane or dimethyltert-butylchlorosilane, or a suitable silazane compound, such as hexamethyl(lisilazane, or by treatment with a reactive derivative of an acid whose acyl radical acts as a hydroxyl protective group, for example by reaction with an anhydride, for example trifluoroacetic anhydride, a mixed anhydride, for example an acid halide, such as 2,2-dichloroacetyl chloride, or a mixed anhydride of a carbonic acid half-ester, for example 2,2,2-trichloroethyl, allyl, phenyl or p-nitrophenyl chloroformate, or by reaction with 1,2-dihydrofuran or 1,2-dihydropyran in the presence of an acid, for example p-toluenesulfonic acid.
2~ 5 The present invention preferably relates to a process for the preparation of compounds of the formula I in which Rl is hydrogen or, in particular, methyl, R2 is hydrogen or a hydroxyl protective group R2, such as the acyl radical of a carbonic acid half-ester, for example 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl or p-nitro-benzyloxycarbonyl, the acyl radical of a substituted or unsubstituted benzoic acid, for example 4-nitrobenzoyl or 3,5-dinitrobenzoyl, or, in particular, tri-lower alkylsilyl, for example trimethylsilyl, tert-butyldimethylsilyl, or dimethyl-(2,3-dimethyl-2-butyl)-silyl, and R3 is phenyl or methyl, and in which the 1'-C atom of the side chain can have the S
configuration or preferably the R configuration, if Rl is methyl.
The invention relates primarily to a process for the preparation of (3R,4R, l 'R)-4-acetoxy-3-( 1 '-hydroxyethyl)-azetidin-2-one or (3R,4R,l'R)-4-benzoyloxy-3-(1'-hydroxyethyl)-azetidin-2-one and their 1'-O-tri-lower alkylsilyl derivatives, such as 1'-O-tert-butyldimethylsilyl or 1'-O-dimethyl-(2,3-dimethyl-2-butyl)-silyl derivatives.
Compounds of the formula I, particularly those in which Rl is hydrogen or methyl, R2 is hydrogen or a hydroxyl protective group R2 and R3 is methyl or phenyl are valuable intermediates which can be processed further in a manner known per se to give penem or carbapenem compounds which have an antibiotic activity. Further processing is carried out analogously to that of known azetidinone compounds of the formula I in which R3 is methyl, for example as described by T. Hayashi et al., Chem. Pharm. Bull. 29, 3158, 1981, or in European Published Patent Applications No. 42,026 (for penems) or No. 78,026 (for carbapenems).
The starting materials and intermediates used in the process according to the invention are in part novel. They can be prepared in a manner known per se.
Thus, for example, compounds of the formul~ II (a and b) can be obtained by d) cyclizing the carbanion of a compound of the formula 2~ 45 H o (V) Rl--CH--C(R) C112--C--R3 0~ N
o in which R3' has the meaning of R3 or is etherified hydroxyl, and R4' has the meaning of R4 or is etherified hydroxyl, R3' and R4' either having the meanings of R3 and R4, respectively, or both being etherified hydroxyl, and in which, if Rl is lower alkyl, the 3-C
atom has the R configuration or the S configuration, or the carbanion of a compound of the formula \ 3 2 / (VI) ~ CH--C(R) CH2--C--R3 R20 l I l /~ N
in which R2 is a hydroxyl protective group which cannot be removed under the conditions of the cyclization process and X is a nucleofugic leaving group and, if Rl is lower alkyl, the 3-C atom has the R configuration or the S configuration, or e) by isomerizing a cis-compound of the formula loR2 11 o (VII) R~l Cllllll~llllll C-- R3 ¦ (S) (R) H
~ N~
C112--C--R~, o and, if desired, converting a compound of the formula II obtainable in accordance with the invention into another compound of the formula II.
3~
In a starting material of the formula VI a hydroxyl protective group R2 which cannot be removed under the conditions of the cyclization process is one of the acyl groups men-tioned under R~2 of a substituted carboxylic or sulfonic acid, for example 2,2,2-trifluoro-acetyl, and also the acyl radical of a carbonic acid half-ester, for example p-nitrobenzyl-oxycarbonyl, or 2-tetrahydrofuryl or 2-tetrahydropyranyl, and also 1-lower alkoxy-lower alkyl, for example methoxymethyl or 1-ethoxyethyl, or substituted or unsubstituted aroyl, for example 4-nitrobenzoyl or 3,5-dinitrobenzoyl. A suitable nucleofugic leaving group X
is preferably reactive esteri~led hydroxyl, for example halogen, for example chlorine, bromine or iodine, lower alkanoyloxy, such as acetoxy, arylsulfonyloxy, for example phenylsulfonyloxy or p-toluenesulfonyloxy, or lower alkylsulfonyloxy, for example methanesulfonyloxy.
An etherified hydroxyl group R3 or R4 is, in particular, a hydroxyl group which is etherified with an aliphatic, aromatic or araliphatic radical, such as lower alkoxy, for example methoxy, ethoxy, n-propoxy, isopropoxy or primarily tert-butoxy, aryloxy, for example phenoxy, or aryl-lower alkoxy, for example benzyloxy.
In carbanions of compounds of the formula V or VI the negative charge on the carbon atom is located in the a-position relative to the ~roup of the formula -CO- R3; i.e. the corresponding compound has the partial formula ~N--C~ --CO--R3 . Carbanion com-pounds of this type are prepared in situ by treating a compound of the formula V or VI in a suitable solvent with a base which forms carbanions, in the course of which the cyclization of process d) takes place. Bases of this type are, inter alia, alkali metal bases, for example sodium hydroxide or carbonate, potassium hydroxide or carbonate or lithium hydroxide or carbonate, or organic alkali metal compounds, for example lower alkyllithium, such as n-butyllithium or tert-hutyllithium, alkali metal amides, for example lithium diisopropyl-amide or di-tert-butylamide, and especially alkali metal amides in which two hydrogell atoms have been replaced by org.lnic silyl grollps, for examplc trimethylsilyl ~roups, for example lithium bis-(trimethylsilyl)-amicle, sodium bis-(trimethylsilyl)-amide or potassium bis-(trimethylsilyl)-amide, inter alia lithium hexamethyldisihlzide, and also suitable organic nitrogen bases, such as cyclic amidines, for example 1,5-diazabicyclo-[4.3.0]non-5-ene or 1,5-diazabicycloLS.4.0]undec-5-ene, and also fluorine compounds which release fluoride ions in an aprotic, organic solvent and which are particularly suit-able for the preparation of carbanions of compounds of the formula V, preferably tetra-lower alkylammonium fluorides, especially tetra-n-butylamonium fluoride.
~Qlal2U4~
lf a suitable silyl reagellt, for example lithiurn hexamethyldisilazide, is used for the cyclization of a compound of the formula V or VI, under certain circumstances, for example if the reaction is carried out carefully, a compound of the formula Ila in which R2 is a silyl protective group, for example trimethylsilyl, can be obtained directly.
Examples of solvents suitable for the formation of carbanions are halogenated or non-halogenated hydrocarbons, such as benzene, toluene, methylene chloride or chloroform, ethers, such as dioxane, tetrahydrofuran or dimethoxyethane, amides, such as dimethyl-formamide or hexamethylphosphoric triamide, sulfoxides, such as dimethyl sulfoxide, or nitriles, such as acetonitrile, or mixtures thereof. The reaction can also be carried out under phase transfer conditions, for example in a system consisting of methylene chloride and 50 % aqueous sodium hydroxide solution in the presence of a phase transfer catalyst, such as benzyltriethylammonium chloride or tetrabutylammonium bisulfate. The reaction temperature, which depends, inter alia, on the choice of the base used, is between about -80C and about 80C, the reaction being preferably carried out under an inert gas atmosphere, for example an atmosphere of argon or nitrogen.
Under the conditions of the process, an inversion of the configuration at the 2-C atom of the starting material takes place, so that a 3S compound of the formula IIa is formed from a 2R compound of the formula V or VI; the configuration of the 1'-C atom in the side chain, if Rl is lower alkyl, remains unchanged. For example, 3S azetidinones of the for-mula IIa are obtained from R-glycidamides of the formula V, or (3S,l'R)-3-hydroxyethyl-azetidinones of the formula IIa are obtained from (2R,3R)-2,3-epoxybutyramides of the formula V.
The isomerization of a compound of the formula VII (process variant e) can be carried out in a suitable solvent or solvent mixture in the presence of a base. Suitable solvents and bases, and also the reaction conditions, are the sarne as those which can be used for the cyclization process d). It is preferred to employ aprotic dipoLu solvents, such as dirnethyl-formamide, N-methylpyrrolidone or dimethyl sulfoxide, and, as bases, in particular potassium carbonate or 1,5-diazabicyclo[5.4.0~undec-5-ene, and it is also possible to carry out the reaction under the phase transfer conditions described.
Starting materials of the formula Ilb can be obtained in a manner known per se, for example by solvolysis, from diesters of the formula IIb obtainable in accordance with the Q~
invention. The corresponding diester compounds can be converted into the free dicarboxylic acid compounds, for example by means of acid or basic hydrolysis, a di-tert-bu~yl ester ( R3 = R4~ = tert-butoxy) can, for example, be converted by treatment with dilute, for example 1 N, sodium hydroxide solution into a lower alkanol, for example methanol or ethanol, or with trifluoroacetic acid with the application of heat.
The cis-compounds of the formula VII can be formed as byp}oducts in the course of the cyclization reaction (d) and can be separated off from the products of the des*ed con-figuration in a customary manner, for example by means of chromatography.
Compounds of the forrnula V can be obtained in a manner known per se, for example by reacting an epoxy acid compound of the formula H (VIII) Rl--CH--C
\ o / C
// ~
0 0~1 or a suitable salt thereof with an amine compound of the formula (IX) Il ~ CH2--C-- R3 HN
o The reaction can be carried out under conditions which are analogolls to those of the process described in detail bclow for the preparation of compounds of the formula VIa.
The compounds of the formula VIII are known or c~m be prepared by processes known per se.
The starting materials of the formula V are preferably prepared in situ under the abovementioned carbanion-forming conditions and with a Walden inversion at the 2-C
atom from compounds of the formula Rl~ 3 H X O (VIa), ~ CH 2 C(S) CH2--C--R3 R20 D~ N
o CH2--C-- R4 o in which R~'is hydrogen or a hydroxyl protective gTOup which can be removed under the conditions of epoxide forrnation and in which, if Rl is lower alkyl, the 3-C atom has the R
configuration or the S configuration, the elements of a compound of the formula R~ -X
being removed.
In a compound of the formula VIa a hydroxyl protective gTOUp R~' which can be removed under the conditions of epoxide formation is a tri-lower alkylsilyl group, for example dimethyltert-butylsilyl or trimethylsilyl. X is preferably halogen, for example chlorine or bromine, lower alkanesulfonyloxy, for example methanesulfonyloxy, or arylsulfonyloxy, for example p-toluenesulfonyloxy.
The removal of R~'-xin which R~" iS hydrogen is effected in the course of the tTeatment with one of the carbanion-forming bases mentioned, for example sodium hydroxide or carbonate or potassium hydroxide or carbonate, preferably with an amidine, for example 1,5-diazabicyclo[5.4.0]undec-5-ene or with a tetra-lower alkylammonium fluoride, for example dehydrated tetra-ll-butylammonium fluoride, for example under the reaction conditions described by Djerassi et al., "Steroid Reactions", page 606 (Holden Day, San Francisco, 1963). If R~' iS, for example, a tri-lower alkylsilyl group which can be removed under the conditions of epoxide formation, it is preferred to use a tetra-lower alkylammonium fluoride.
The reaction of a compound of tlle formula VIa to give an epoxy compound of the formula V is preferably carried out in an inert solvent or solvent mixture, usually anhydrous, if necessary with cooling or heating, for example within a temperature range from about -40C to about +100C, preferably from about -10C to about +50C, and/or under an inert gas atmosphere, for example an atmosphere of nitrogen.
2[11~2 In the course of this process thc conf igur;ltion at the 2-C atom is inverted, whereas the configuration of the 3-C atom, if Rl is lower alkyl, is retained. Thus the (2R,3R) com-pounds of the formula V are formed from 2S-halogeno-3R-hydroxy compounds of the formula Vla and the (2R,3S) compounds of the formula V are formed from 2S-halogeno-3S-hydroxy compounds.
After ;t has been prepared, the epoxide of the formula V can, if desired, be isolated by the removal of R~'-x from a compound of the formula YIa by employing the amidine used as the reagent in approximately equimolar amounts.
The above compounds of the formula VIa can be prepared, for example, by reacting a compound of the formula OR2' H X (X) 21~
R ~--C--C(S) // \
O OH
or a reactive functional derivative thereof with an amine of the formula IX. This reaction can be carried out in a manner known per se, for example by subjecting the two reactants to a condensation reaction with one another in the presence of a condensing agent, and de-hydrating the free acid, for example in the presence of carbodiimides, such as diethyl-carbodiimide, diisopropylcarbodiimide or dicyclohexylcarbodiimide, or di-(N-hetero-cyclyl)-carbonyl compounds, such .IS carbonyl(liimid.lzole, or 1,2-oxazolium compounds, such as 2-ethyl-5-phenyl-1,2-oxazolium 3-sulfonate or 2-tert-butyl-5-methyl-1,2-oxazolium perchlorate, which are uscd in the prcsence of an inert solvent, such as di-methylformamide, if necessary at a slightly redllce(l or elevaled temperature. Reactive functional derivatives of Ll carboxylic acid of tlle formula X are primarily an}ly(lrides, in particular mixed anhydrides, such as the corresponding carboxylic acid chloride or bromide, which are preferably formed in situ by reacting a salt, for example the dicyclo-hexylamine salt of epoxy acids of the formula VIII with suitable halogenating agents, such as phosphorus oxychloride or thionyl chloride, in particular with oxalyl chloride, and which are, if appropriate, reacted with the amine of the formula IX in the presence of a base, for example N-methylmorpholine.
2~20~5 The comyounds of the formula VI can be prepared analogously, starting from compounds of the formula IX and from compounds of the formula OR2 H (Xa) -~x Rl--C C
H C
// \
O OH
Compounds of the formula X and Xa in which X is halogen are known. They can be prepared, for example, in a manner known per se from L-serine or L-threonine or the D-isomers thereof by diazotizing the amino group with a nitrite salt, for example potassium nitrite, in the presence of a hydrohalic acid.
If L-serine is used and compounds of the formula VI are the starting material, it is possible to obtain compounds of the formula I in which the carbon in the 3-position of the azetidinone ring has the R-configuration. If L-threonine is used, compounds of the formula I 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 (Rl is methyl) has the R-configuration. If it is intended to prepare compounds of the formula I in which the 3-C atom has the R-con-figuration and the 1'-C atom, for example, of a 1-hydroxyethyl side chain has the S-con-figuration, allothreonine is used as the starting material. 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 a 1-OR2-lower alkyl side chain having more than one carbon atom in the lower alkyl moiety remains unchanged.
Amines of the formula IX, in particular the amines having symmetrical substituents, are known or, if novel, can be prepared in a manner known per se. Thus, for example, a compound of the formula IX in which R3 and R4' are tert-butoxy can be prepared by the action of isobutylene on the corresponding acid, usually in dioxane in the presence of 95-98 % sulfuric acid at room temperature. A preferred process for the preparation of compounds of the formula IX in which Ri and R4' represent phenyl consists in reacting a phenacylamine hydrochloride with a phenacyl chloride or phenacyl bromide in the presence of a suitable base, for example triethylamine, and in methylene chloride.
2i~021~4~
The present invention also embraces embodiments of the process in which the starting material is a compound obtainable at any preliminary seage of the process and the sub-sequent process stages are carried out. It also embraces a combination of process steps, for example starting from one of the compounds of the formula VI to X to give a compound of the formula I or starting from one of the compounds of the formulae IX or X or Xa to give a compound of the formula VI or IVa, respectively.
The process according to the invention has the advantage that the compounds of the forrnula I can be prepared stereospecifically in a high yield and in an economical manner, and that it is possible to use the readily accessible and cheap symmetrically substituted amines of the formula IX, whose substituents serve on the one hand for the cyclization to give the ~-lactam compounds and on the other hand as a temporary N-protective group which can be removed under mild conclitions.
The following examples serve to illustrate the invention. Temperatures are in degrees centigrade. The specific angles of rotation are [ a ] 20 values. Columns packed with Merck silica gel 60 can be used for the separation by chromatography in preparative work-up.
Example 1 1.1. A solution of 0.866 g of (3S,4S,l'R)-4-benzoyl-3-(1'-hydroxyethyl)-1-phenacylazetidin- 2-one and 5.7 g of 3-chloroperbenzoic acid in 30 ml of methylene chloride is stirred for 8 hours at room temperature. The white suspension is diluted with methylene chloride and washed successively with a 5 % aqueous solution of sodium thio-sulfate/potassium iodide, water, aqueous sodium bicarbonate solution and water, dried and evaporated under a water pump vacuum. The crude product is purified by means of medium pressure chromatography (solvent: a 2:3 mixture of hexane and ethyl acetate).
After the main fraction has been recrystallized from methylene chloride/diethyl ether, (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-(1'-hydroxy-ethyl)-azetidin-2-one is obtained, melting point 136- 138.
1.2. 0.06 g of imidazole and 0.088 g of tert-butyldimethylchlorosilane are added to a solu-tion of 0.18 g of (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-(1'-hydroxyethyl)-azetidin-2-one in 1 ml of dimethylformamide and the mixture is stirred for 24 hours at room temperature. A further 0.015 g of imidazole and 0.022 g of tert-butyldimethylchloro-silane are added to the reaction mixture, which is stirred for a further 6 hours at room tem-perature and then discharged onto ice and a saturated aqueous solution of sodium bicarbo-nate, the product is taken up in diethyl ether, and the organic phase is washed once each with aqueous sodium bicarbonate solution, 1 % aqueous citric acid, water, aqueous sodium bicarbonate solution and water. The aqueous phases are washed again with diethyl ether; the combined organic extracts are dried with sodium sulfate and evaporated in a water pump vacuum. The crude product is dissolved in a 3:2 mixture of hexane and ethyl acetate and is filtered through silica gel 60. Recrystallization from methylene chloride/diethyl ether gives pure (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-[1'-(tert-butyl dimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 109- 110;
[ ] D = -14.1 (c = 0.545 % in chloroform).
1.3. 0.03 g (30 U) of cholesterol esterase (Sigma C 9530, from porcine pancreas) is dissolved in 33 ml of phosphate buffer pH 7 in a S0 ml round-bottomed flask controlled by thermostat at 30, and 0.05 g of (3R,4R,l'R)-4-benzoyloxy-1-benzoyloxymethyl-3-Ll'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, dissolved in 6 ml of acetone, is added in portions in the course of 10 hours. The reaction is followed by thin layer chromato-graphy (solvent: a 1: 1 mixture of ethyl acetate and hexane) and by high pressure liquid chromatography (solvent: an 85:15 mixture of acetonitrile and water). After 20 hours, the reaction mixture is extracted with six times 100 ml each of chloroform. The organic ex-tract gives a slightly yellow oil which, according to high pressure liquid chromatography, still contains about 10% of starting material. Chromatography over silica gel (mobile phase: a 4:1 mixture of methylene chloride and ethyl acetate) gives (3R,4R,l'R)-4-benzoyloxy- 1-hydroxy-methyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azeti~in-2-one, which, after recrystallization from methylene chloride/diethyl ether/hexane, melts at 83-85; [ a ] D = +68.5 (c = 0.672 % in chloroform).
1.4. 0.21 ml of 8 N chromosulfuric acid (Killiani mixture) is added to a solution of 0.16 g of (3R,4R,l'R)-4-benzoyloxy-1-hydroxymcthyl-3-[1'-(tert-blltyldimethylsilyloxy)-cthyll-azetidin-2-one in 10 ml of methylene chloride, and the mixture is stirred for S hours at room temperature. Excess oxidizing agent is destroyed by adding 1 ml of isopropanol, and the reaction mixture is applied directly to a columll of 80 g of aluminium oxide (Alox II, acid) and eluted with ethyl acetate. This gives virtually pure (3R,4R,l'R)-4-benzoyloxy-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 125- 126; [ a ] D =
71.1 (c = 0.85 % in chloroform), after recrystallization from diethyl ether/hexane.
4~
~3R,4R,l'R)-4-Benzoyloxy-3-(1'-hydroxyethyl)-azetidin-2-one, melting point 145-147 ~from methylene chloride/diethyl ether) can be obtained from the (3R,4R,l'R)-4-benzoyl-oxy-3-[1'-(tert-butylsimethylsilyloxy)-ethyl]-azetidin-2-one by treatment with tetrabutyl-ammonium fluoride trihydrate in tetrahydrofuran and acetic acid.
The starting material can be prepared as follows:
1.5. A solution of 2.7 ml of oxalyl chloride in 8.5 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture of 6.86 g of dimethylformamide and 40 ml of methylene chloride, cooled to -25. The white suspension is stirred for a further 20 minutes at -25, and a solution of 9.87 g of the dicyclohexylammonium salt of (2R,3R)-2,3-epoxybutyric acid in 40 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature and 8.7 ml of triethylamine are then added, followed, in portions, by 7.29 g of diphenacyl-amine hydrochloride. The cooling bath is removed and the reaction mixture is stirred for 21 hours at room temperature. The yellow suspension is then filtered through a sintered glass suction filter and the residue is washed exhaustively with methylene chloride. The filtrate is diluted with methylene chloride and washed successively with water,5 %
aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the com-bined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. The resulting crude product is purified by flash chromatography over 750 g of silica gel (Merck 9385; mobile ph.lse: a 2: l mixture of hexane and ethyl acetate), and (2R,3R)-2,3-epoxy-N,N-bis-phenacylbutyramide is obtained in the form of a yellowish oil.
1.6. A solution of 3.48 g of (2R,3R)-2,3-epoxy-N,N-bis-phenacylbutyramide in 100 ml of tetrahydrofuran is cooled with stirring to -15, and 20.6 ml of a 0.5-molar solution of lithium hexamethyldisil~zide in tetrallydrofuran is adde(l at a temperature between -10 and -15; the reaction is complete after stirring for about 4 hours within the same tempe-rature range. The dark red reaction mixture is poured onto 100 ml of an ice cold buffer solution (pH 6.0) and the product is extracted three times with methylene chloride. The organic extracts are washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated under a water pump vacuum. The crude product obtained is separated into three constituents by medium pressure chromatography over a 100-fold amount of a silica gel preparation [LiChroprep(~) ~i 60 made by Merck AG, Darmstadt s (West Gerrnany); particle size 25-40 ~-m; mobile phase: a 4:1 mixture of hexane and ethyl acetate]~ This gives~ as Ihe least polar *action, (3S,4S,1 'R)-4-benzoyl-3-(1 '-trimethylsilyl-oxyethyl)-1-phenacylazetidin-2-one, as the product of medium polarity, (3S,4R,l'R)-4-benzoyl-3-(1'-hydroxyethyl)-1-phenacylazetidin-2-one ("cis-compound") of melting point 128-129 (from methylene chloride/diethyl ether/hexane) and, finally, amorphous (3S,4S,1 'R)-4-benzoyl-3-(1 '-hydroxyethyl)-1-phenacylazetidin-2-one~
Example 2:
2.1. 8~95 g of lead tetraacetate are added under an argon atmosphere and with stirring at room temperature to a solution of 2~9 g of (3S,4S,l'R)-1-carboxymethyl-3-[1'-(tert-butyl-dimethylsilyloxy )-ethyl]-2-oxoazetidin-4-carboxylic acid in 90 ml of tetrahydrofuran and 13 ml of dimethylformamide~ After 75 minutes at 25, the excess lead tetraacetate is de-stroyed by adding 2 2 ml of ethylene glycol dropwise, the resulting white suspension is filtered through a silica gel preparation (Hyflo), the residue on the filter is subsequently washed thoroughly with tetrahydrofuran, and the filtrate is evaporated under a water pump vacuum~ The oily residwe is purified by flash chromatography over 250 ml of silica gel (silica gel 60; 0~040-0.63 mm; mobile phase: a 60:4 mixture of hexane and ethyl acetate)~
This gives (3R,4R,l'R)-4-acetoxy-1-acetoxymethyl-3-[1'-(tert-butyldi-methylsilyloxy)-ethyl]-azetidin-2-one in the form of an oil, [ ~ ] D = +9`4 (c = 0 287 % in chloroform).
(3R,4R,1 'R)-4-Acetoxy- 1 -acetoxymethyl-3-[1 '-(dimethyl-(2,3-dimethyl-2-butyl)-silyl-oxy)-ethyl]-azetidin-2-one is obtained analogously in amorphous form, [ ] D = +3~3 (c = 2.1 % in chloroform), starting from (3S,4S,l'R)-N-carboxymethyl-3-[1'-(dimethyl-(2,3-dimethyl-2-b utyl)-silyloxy)-ethyll-2-oxoazetidine-4-carboxylic acid~
2.2. 3 ml of a solution of acetyl esterase (aqlleous solution containing 723 U/ml) from Nocardia mediterranei [see: H.P~ Sch,ir, D~ Gygax, G~M~ Ramos Tombo and O~ Ghisalba, Appl. Microbiol. Biotechnol~, volume 27, page 451 (1988)l are added to 0~92 g of(3R,4R,1 'R)-4-acetoxy- 1 acetoxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in 70 ml of phosphate buffer of pH 7~ The solution is stirred for 24 hours at room temperature, then a further 2 ml of the above enzymc solution are added and after two further days the mixture is extracted with methylene chloride~ This gives a crude pro-duct which contains only small amounts of the starting materiah Purification by chromato-graphy (silica gel; mobile phase: a 96:4 mixture of methylene chloride and methanol) gives (3R,4R,1 'R)-4-acetoxy- 1 -hydroxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-2~45 azetidin-2-one, which crystalli~es spontaneously and melts at 51-53.
2.3. 2 ml of 8 N chromosulfuric acid (Killiani mixture) are added to a solution of 0.317 g (3R,4R,1 'R)-4-acetoxy-1-hydroxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-a~etidin-2-one in 2 ml of methylene chloride, and the mixture is stirred for 4 hours at room temperature. Stirring is continued for a further 24 hours after adding a further 0.25 ml of chromosulfuric acid. Excess oxidizing agent is destroyed by adding 1 ml of isopropanol, and the reaction mixture is applied directly to a column of 10 g of aluminium oxide (Alox II, acid) and eluted with a 1: 1 mixture of hexane and ethyl acetate. This gives (3R,4R,1 'R)-4-acetoxy-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 107-109 (from low-boiling petroleum ether).
2.4. 0.3 g of (3R,4R,l'R)-4-acetoxy-3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one is added with stirring to a solution of 0.63 g of tetrabutylammonium fluoride trihydrate in 10 ml of tetrahydrofuran and 0.8 ml of acetic acid, and the rnixture is stirred for 16 hours at room temperature. The reaction mixture is discharged onto ice water and extracted three times with methylene chloride. The combined organic extracts are washed successively with a saturated aqueous solution of sodium bicarbonate and a satu-rated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated under a water pump vacuum at a bath temperature of 35. The residue is recrystallized from methylene chloride/diethyl ether/hexane and affords (3R,4R,l'R)-4-acetoxy-3-(1-hydroxy-ethyl)-azetidin-2-one, melting point 110- 112.
The starting material can be obtained as follows:
2.5. A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added drop-wise, in the course of 15 minutes, to a mixture, coolcd to -25, of 20 g of dimethyl-formamide and 115 ml of methylcne chloride. The white suspension is stirred for a furthcr 20 minutes at -25, and a solution of 28.5 g of the dicyclohexylammonium salt of(2R,3R,)-2,3-epoxybutyric acid in l lS ml of methylene chloride is then added in the course of 10 minutes. I`he reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17 87 g of di-tert-butyl iminodiacetate in 90 ml of methyl-ene chloride and 9 22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of lS minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5 % aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9: 1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [ a ] D= +52 (c = 1.250 % in chloroform).
2.6. A solution of 13.18 g of (2R,3R)-N,N-bis-(tert-butoxycarbonylmethyl)-2,3-epoxy-butyramide in 100 ml of tetrahydrofuran is cooled with stirring to -15, and 100 ml of a 0.5-molar solution of lithium hexamethyldisilazide in tetrahydrofuran is added at tem-peratures between -15 and -10. The progress of the reaction is followed by thin layer chromatography (solvent: a 1:1 mixture of hexane and ethyl acetate); the reaction is com-plete after stirring for about 4 hours at the temperature indicated above. The reaction mix-ture is diluted with methylene chloride and poured onto ice, and the organic layer is washed successively with water, twice with 0. I N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. The wash water is extracted twice with methylene chloride, and the combined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. After flash chromatography over 750 g of silica gel 60 (0.040-0.063 mm, Merck; elution with a 6:4 mixture of hexane and ethyl acetate), the crude product obtained gives (3S ,4S,1 'R)-4-tert-butoxycarbonyl- 1 -tert-butoxycar-bonylmethyl-3-(1'-hydroxyethyl)-azetidin-2-one, which melts at 79-81;
[ ~ ] D -22.6 (c = 0.574 % in chloroform).
2.7. 2.45 g of imidazole and 3.61 g of tert-butyldimethylchlorosilane are added to a solution of 6.59 g of (3S,4S,l'R)-4-tert-butoxyc.llbonyl-1-tert-butoxycarbonylmethyl-3-(I'-hydroxyethyl)-azetidin-2-one in 25 ml of dimethylformamide, and the mixture is stirred for 6 hours at room temperature. The reaction mixture is discharged onto ice and a saturated aqueous solution of sodium bicarbon.lte and the product is taken up in diethyl ether. I he organic phase is washed once each with aqueous sodium bicarbonate solution, 1 % aqueous citric acid, water, aqueous sodium bicarbon.lte solution and water. The aqueous phases are extracted with diethyl ether, and the combined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. The crude product is dissolved in an 80:20 mixture of hexane and ethyl acetate, and the solution is filtered through 200 g of silica gel (silica gel 60) to give (3S,4S,l'R)-4-tert-butoyxcarbonyl-1-2~ 0~5 tert-butoxycarbonylmethyl-3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in the form of an oily product, [ a ] D = -14.6 (C = 0.553 % in chloroform).
(3S,3S,l'R)-4-tert-Butoxycarbonyl-l-tert-butoxycarbonylmethyl -3-[1'-(dimethyl-(2,3-dimethyl-2-butyl)-silyloxyethyl]-azetidin-2-one, [ a ] D = -16.8 (C = 2.5 in chloroforrn), is obtained analogously using dimethyl-(2,3-dimethyl-2-butyl)-chlorosilane.
2.8. 29.3 ml of 1 N aqueous sodium hydroxide solution are added dropwise, with ice cooling, to a solution, cooled to -5, of 5.4 g of (3S,4S,l'R)-4-tert-butoxycarbonyl-1-tert-butoxycarbonylmethyl -3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in 120 ml of ethanol. The reaction mixture is then stirred for 14 hours at 0 to 5, then concentrated to a volume of about 30 ml under a water pump vacuum on a rotary evaporator (bath tem-perature 30) and extracted twice with ethyl acetate. Ethyl acetate is added to the aqueous phase which has been separated off, and the mixture is again cooled to about 0 to 5 and adjusted to pH 2.0 by dropwise addition of orthophosphoric acid, with stirring and cooling in ice. The phases are separated, the aqueous layer is extracted three times with ethyl acetate, and the combined organic phases are dried with sodium sulfate and evaporated in a water pump vacuum. The crude product obtained is crystallized from ethyl acetate/hexane and gives (3S,4S,l'R)-1-carboxymethyl-3-[1'-(tert-butyldimethylsilyl-oxy)-ethyl]-2-oxoazetidine-4-carboxylic acid, which melts at 134-135;
[ (~ ] D = -32.9 (c = 1.058 % in chloroform).
Thecorresponding (3S,4S,l'R)-1-carboxymethyl-3-[1'-(dimethyl-(2,3-dimethyl-2-butyl)-silyloxy)-ethyl]-2-oxoazetidine-4-carboxylic acid is obtained analogously, starting from (3S,4S,1 'R)-4-tert-butoxycarbonyl-1-tert-butoxycarbonylmethy -3-[1 '-(dimethyl-(2,3-di-methyl-2-butyl)-silyloxv)-ethyl] -azetidin-2-one.
~3R,4R,l'R)-4-Benzoyloxy-3-(1'-hydroxyethyl)-azetidin-2-one, melting point 145-147 ~from methylene chloride/diethyl ether) can be obtained from the (3R,4R,l'R)-4-benzoyl-oxy-3-[1'-(tert-butylsimethylsilyloxy)-ethyl]-azetidin-2-one by treatment with tetrabutyl-ammonium fluoride trihydrate in tetrahydrofuran and acetic acid.
The starting material can be prepared as follows:
1.5. A solution of 2.7 ml of oxalyl chloride in 8.5 ml of methylene chloride is added dropwise, in the course of 15 minutes, to a mixture of 6.86 g of dimethylformamide and 40 ml of methylene chloride, cooled to -25. The white suspension is stirred for a further 20 minutes at -25, and a solution of 9.87 g of the dicyclohexylammonium salt of (2R,3R)-2,3-epoxybutyric acid in 40 ml of methylene chloride is then added in the course of 10 minutes. The reaction mixture is stirred for a further 20 minutes at the same temperature and 8.7 ml of triethylamine are then added, followed, in portions, by 7.29 g of diphenacyl-amine hydrochloride. The cooling bath is removed and the reaction mixture is stirred for 21 hours at room temperature. The yellow suspension is then filtered through a sintered glass suction filter and the residue is washed exhaustively with methylene chloride. The filtrate is diluted with methylene chloride and washed successively with water,5 %
aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the com-bined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. The resulting crude product is purified by flash chromatography over 750 g of silica gel (Merck 9385; mobile ph.lse: a 2: l mixture of hexane and ethyl acetate), and (2R,3R)-2,3-epoxy-N,N-bis-phenacylbutyramide is obtained in the form of a yellowish oil.
1.6. A solution of 3.48 g of (2R,3R)-2,3-epoxy-N,N-bis-phenacylbutyramide in 100 ml of tetrahydrofuran is cooled with stirring to -15, and 20.6 ml of a 0.5-molar solution of lithium hexamethyldisil~zide in tetrallydrofuran is adde(l at a temperature between -10 and -15; the reaction is complete after stirring for about 4 hours within the same tempe-rature range. The dark red reaction mixture is poured onto 100 ml of an ice cold buffer solution (pH 6.0) and the product is extracted three times with methylene chloride. The organic extracts are washed with saturated aqueous sodium chloride solution, dried with sodium sulfate and evaporated under a water pump vacuum. The crude product obtained is separated into three constituents by medium pressure chromatography over a 100-fold amount of a silica gel preparation [LiChroprep(~) ~i 60 made by Merck AG, Darmstadt s (West Gerrnany); particle size 25-40 ~-m; mobile phase: a 4:1 mixture of hexane and ethyl acetate]~ This gives~ as Ihe least polar *action, (3S,4S,1 'R)-4-benzoyl-3-(1 '-trimethylsilyl-oxyethyl)-1-phenacylazetidin-2-one, as the product of medium polarity, (3S,4R,l'R)-4-benzoyl-3-(1'-hydroxyethyl)-1-phenacylazetidin-2-one ("cis-compound") of melting point 128-129 (from methylene chloride/diethyl ether/hexane) and, finally, amorphous (3S,4S,1 'R)-4-benzoyl-3-(1 '-hydroxyethyl)-1-phenacylazetidin-2-one~
Example 2:
2.1. 8~95 g of lead tetraacetate are added under an argon atmosphere and with stirring at room temperature to a solution of 2~9 g of (3S,4S,l'R)-1-carboxymethyl-3-[1'-(tert-butyl-dimethylsilyloxy )-ethyl]-2-oxoazetidin-4-carboxylic acid in 90 ml of tetrahydrofuran and 13 ml of dimethylformamide~ After 75 minutes at 25, the excess lead tetraacetate is de-stroyed by adding 2 2 ml of ethylene glycol dropwise, the resulting white suspension is filtered through a silica gel preparation (Hyflo), the residue on the filter is subsequently washed thoroughly with tetrahydrofuran, and the filtrate is evaporated under a water pump vacuum~ The oily residwe is purified by flash chromatography over 250 ml of silica gel (silica gel 60; 0~040-0.63 mm; mobile phase: a 60:4 mixture of hexane and ethyl acetate)~
This gives (3R,4R,l'R)-4-acetoxy-1-acetoxymethyl-3-[1'-(tert-butyldi-methylsilyloxy)-ethyl]-azetidin-2-one in the form of an oil, [ ~ ] D = +9`4 (c = 0 287 % in chloroform).
(3R,4R,1 'R)-4-Acetoxy- 1 -acetoxymethyl-3-[1 '-(dimethyl-(2,3-dimethyl-2-butyl)-silyl-oxy)-ethyl]-azetidin-2-one is obtained analogously in amorphous form, [ ] D = +3~3 (c = 2.1 % in chloroform), starting from (3S,4S,l'R)-N-carboxymethyl-3-[1'-(dimethyl-(2,3-dimethyl-2-b utyl)-silyloxy)-ethyll-2-oxoazetidine-4-carboxylic acid~
2.2. 3 ml of a solution of acetyl esterase (aqlleous solution containing 723 U/ml) from Nocardia mediterranei [see: H.P~ Sch,ir, D~ Gygax, G~M~ Ramos Tombo and O~ Ghisalba, Appl. Microbiol. Biotechnol~, volume 27, page 451 (1988)l are added to 0~92 g of(3R,4R,1 'R)-4-acetoxy- 1 acetoxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in 70 ml of phosphate buffer of pH 7~ The solution is stirred for 24 hours at room temperature, then a further 2 ml of the above enzymc solution are added and after two further days the mixture is extracted with methylene chloride~ This gives a crude pro-duct which contains only small amounts of the starting materiah Purification by chromato-graphy (silica gel; mobile phase: a 96:4 mixture of methylene chloride and methanol) gives (3R,4R,1 'R)-4-acetoxy- 1 -hydroxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-2~45 azetidin-2-one, which crystalli~es spontaneously and melts at 51-53.
2.3. 2 ml of 8 N chromosulfuric acid (Killiani mixture) are added to a solution of 0.317 g (3R,4R,1 'R)-4-acetoxy-1-hydroxymethyl-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-a~etidin-2-one in 2 ml of methylene chloride, and the mixture is stirred for 4 hours at room temperature. Stirring is continued for a further 24 hours after adding a further 0.25 ml of chromosulfuric acid. Excess oxidizing agent is destroyed by adding 1 ml of isopropanol, and the reaction mixture is applied directly to a column of 10 g of aluminium oxide (Alox II, acid) and eluted with a 1: 1 mixture of hexane and ethyl acetate. This gives (3R,4R,1 'R)-4-acetoxy-3-[1 '-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one, melting point 107-109 (from low-boiling petroleum ether).
2.4. 0.3 g of (3R,4R,l'R)-4-acetoxy-3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one is added with stirring to a solution of 0.63 g of tetrabutylammonium fluoride trihydrate in 10 ml of tetrahydrofuran and 0.8 ml of acetic acid, and the rnixture is stirred for 16 hours at room temperature. The reaction mixture is discharged onto ice water and extracted three times with methylene chloride. The combined organic extracts are washed successively with a saturated aqueous solution of sodium bicarbonate and a satu-rated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated under a water pump vacuum at a bath temperature of 35. The residue is recrystallized from methylene chloride/diethyl ether/hexane and affords (3R,4R,l'R)-4-acetoxy-3-(1-hydroxy-ethyl)-azetidin-2-one, melting point 110- 112.
The starting material can be obtained as follows:
2.5. A solution of 11.6 g of oxalyl chloride in 25 ml of methylene chloride is added drop-wise, in the course of 15 minutes, to a mixture, coolcd to -25, of 20 g of dimethyl-formamide and 115 ml of methylcne chloride. The white suspension is stirred for a furthcr 20 minutes at -25, and a solution of 28.5 g of the dicyclohexylammonium salt of(2R,3R,)-2,3-epoxybutyric acid in l lS ml of methylene chloride is then added in the course of 10 minutes. I`he reaction mixture is stirred for a further 20 minutes at the same temperature, and a solution of 17 87 g of di-tert-butyl iminodiacetate in 90 ml of methyl-ene chloride and 9 22 ml of N-methylmorpholine are then added dropwise simultaneously in the course of lS minutes. The cooling bath is removed and the reaction mixture is stirred for 3 hours at room temperature. The white suspension is then filtered through a sintered glass suction filer, the residue is washed with methylene chloride, and the filtrate is diluted with methylene chloride and washed successively with water, 5 % aqueous citric acid, saturated aqueous sodium bicarbonate solution and water. The aqueous phases are subsequently extracted twice with methylene chloride, and the combined organic phases are dried and evaporated under a water pump vacuum. The yellow-brown crude product is purified by flash chromatography over silica gel (Merck 9385) using a 9: 1 mixture of methylene chloride and ethyl acetate as the mobile phase. (2R,3R)-N,N-Bis-(tert-butoxy-carbonylmethyl)-2,3-epoxybutyramide is obtained in the form of a pale yellow oil, [ a ] D= +52 (c = 1.250 % in chloroform).
2.6. A solution of 13.18 g of (2R,3R)-N,N-bis-(tert-butoxycarbonylmethyl)-2,3-epoxy-butyramide in 100 ml of tetrahydrofuran is cooled with stirring to -15, and 100 ml of a 0.5-molar solution of lithium hexamethyldisilazide in tetrahydrofuran is added at tem-peratures between -15 and -10. The progress of the reaction is followed by thin layer chromatography (solvent: a 1:1 mixture of hexane and ethyl acetate); the reaction is com-plete after stirring for about 4 hours at the temperature indicated above. The reaction mix-ture is diluted with methylene chloride and poured onto ice, and the organic layer is washed successively with water, twice with 0. I N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and water. The wash water is extracted twice with methylene chloride, and the combined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. After flash chromatography over 750 g of silica gel 60 (0.040-0.063 mm, Merck; elution with a 6:4 mixture of hexane and ethyl acetate), the crude product obtained gives (3S ,4S,1 'R)-4-tert-butoxycarbonyl- 1 -tert-butoxycar-bonylmethyl-3-(1'-hydroxyethyl)-azetidin-2-one, which melts at 79-81;
[ ~ ] D -22.6 (c = 0.574 % in chloroform).
2.7. 2.45 g of imidazole and 3.61 g of tert-butyldimethylchlorosilane are added to a solution of 6.59 g of (3S,4S,l'R)-4-tert-butoxyc.llbonyl-1-tert-butoxycarbonylmethyl-3-(I'-hydroxyethyl)-azetidin-2-one in 25 ml of dimethylformamide, and the mixture is stirred for 6 hours at room temperature. The reaction mixture is discharged onto ice and a saturated aqueous solution of sodium bicarbon.lte and the product is taken up in diethyl ether. I he organic phase is washed once each with aqueous sodium bicarbonate solution, 1 % aqueous citric acid, water, aqueous sodium bicarbon.lte solution and water. The aqueous phases are extracted with diethyl ether, and the combined organic phases are dried over sodium sulfate and evaporated under a water pump vacuum. The crude product is dissolved in an 80:20 mixture of hexane and ethyl acetate, and the solution is filtered through 200 g of silica gel (silica gel 60) to give (3S,4S,l'R)-4-tert-butoyxcarbonyl-1-2~ 0~5 tert-butoxycarbonylmethyl-3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in the form of an oily product, [ a ] D = -14.6 (C = 0.553 % in chloroform).
(3S,3S,l'R)-4-tert-Butoxycarbonyl-l-tert-butoxycarbonylmethyl -3-[1'-(dimethyl-(2,3-dimethyl-2-butyl)-silyloxyethyl]-azetidin-2-one, [ a ] D = -16.8 (C = 2.5 in chloroforrn), is obtained analogously using dimethyl-(2,3-dimethyl-2-butyl)-chlorosilane.
2.8. 29.3 ml of 1 N aqueous sodium hydroxide solution are added dropwise, with ice cooling, to a solution, cooled to -5, of 5.4 g of (3S,4S,l'R)-4-tert-butoxycarbonyl-1-tert-butoxycarbonylmethyl -3-[1'-(tert-butyldimethylsilyloxy)-ethyl]-azetidin-2-one in 120 ml of ethanol. The reaction mixture is then stirred for 14 hours at 0 to 5, then concentrated to a volume of about 30 ml under a water pump vacuum on a rotary evaporator (bath tem-perature 30) and extracted twice with ethyl acetate. Ethyl acetate is added to the aqueous phase which has been separated off, and the mixture is again cooled to about 0 to 5 and adjusted to pH 2.0 by dropwise addition of orthophosphoric acid, with stirring and cooling in ice. The phases are separated, the aqueous layer is extracted three times with ethyl acetate, and the combined organic phases are dried with sodium sulfate and evaporated in a water pump vacuum. The crude product obtained is crystallized from ethyl acetate/hexane and gives (3S,4S,l'R)-1-carboxymethyl-3-[1'-(tert-butyldimethylsilyl-oxy)-ethyl]-2-oxoazetidine-4-carboxylic acid, which melts at 134-135;
[ (~ ] D = -32.9 (c = 1.058 % in chloroform).
Thecorresponding (3S,4S,l'R)-1-carboxymethyl-3-[1'-(dimethyl-(2,3-dimethyl-2-butyl)-silyloxy)-ethyl]-2-oxoazetidine-4-carboxylic acid is obtained analogously, starting from (3S,4S,1 'R)-4-tert-butoxycarbonyl-1-tert-butoxycarbonylmethy -3-[1 '-(dimethyl-(2,3-di-methyl-2-butyl)-silyloxv)-ethyl] -azetidin-2-one.
Claims (13)
1. A process for the preparation of a compound of the formula (I), in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group R2' and R3 is substituted or unsubstituted phenyl or lower alkyl, which comprises (a) treating a compound of the formula (IIa), in which R4 is substituted or unsubstituted phenyl or lower alkyl with a peracid, or decarboxylating by acyloxylation a compound of the formula (IIb) with the introduction of the radicals R3-C(=O)- or R4-C(=O)-, (b) replacing the radical of the formula R4-C(=O)- by hydrogen in a compound of the formula (III) obtainable as in (a), and (c) removing, in a compound of the formula (IV) thus obtainable, the hydroxymethyl group in the 1-position, if appropriate after conversion into a formyl group, and, if desired, in a compound of the formula I thus obtainable in which R2 is a protective group R2', converting the protected hydroxyl group into the free hydroxyl group, and/or, if desired, in a compound of the formula I thus obtainable in which R2 is hydrogen, converting the free hydroxyl group into a protected hydroxyl group.
2. A process according to claim 1, wherein a starting material of the formula IIa is treated with an organic or inorganic peracid, such as an organic percarboxylic acid, for example peracetic, 3-chloroperbenzoic or monoperphthalic acid.
3. A process according to claim 1, wherein a starting material of the formula IIb is decarboxylated by acyloxylation by treatment with a lead(IV) acylate, such as lead tetraacetate.
4. A process according to claim 1, wherein the radical of the formula R4-C(=O)- in an intermediate of the formula III is removed and replaced by hydrogen by treatment with an esterase, for example an esterase from Nocardia mediterranei or cholesterol esterase.
5. A process according to claim 1, wherein the hydroxymethyl group in the 1-position of an intermediate of the formula IV is oxidized to a formyl group, for example by treatment with a chromium(VI) compound, such as chromium(VI) oxide, and the formyl group is removed under acid conditions.
6. A process according to claim 1, wherein compounds of the formula I in which R1 is hydrogen or especially methyl, R2 is hydrogen or a hydroxyl protective group, inparticular tri-lower alkylsilyl, and R3 is phenyl or methyl and in which the 1'-C atom of the side chain has the S-configuration or preferably the R-configuration, if R1 is methyl, are prepared.
7. A process according to claim 1, wherein (3R,4R,1'R)-4-benzoyloxy-3-(1'-hydroxyethyl)-azetidin-2-one or a 1'-O-tri-lower alkylsilyl derivative thereof is prepared.
8. A process according to claim 1, wherein (3S,4R,1'R)-4-acetoxy-3-(1'-hydroxyethyl)-azetidin-2-one or a 1'-O-tri-lower alkylsilyl derivative thereof is prepared.
9. A compound of the formula (IIa), in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group, R2', R3 is substituted or unsubstituted phenyl or lower alkyl and R4 is substituted or unsubstituted phenyl or lower alkyl.
10. A compound of the formula (IIb) in which R1 is hydrogen or lower alkyl and R2 is hydrogen or a hydroxyl protective group.
11. A compound of the formula (III) in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group, R3 is substituted or unsubstituted phenyl or lower alkyl and R4 is substituted or unsubstituted phenyl or lower alkyl.
12. A compound of the formula (IV) in which R1 is hydrogen or lower alkyl, R2 is hydrogen or a hydroxyl protective group and R3 is substituted or unsubstituted phenyl or lower alkyl.
13. A compound of the formula (V), in which R1 is hydrogen or lower alkyl, R3' has the meaning of R3 or is etherified hydroxyl, R4' has the meaning of R4 or is etherified hydroxyl and in which, if R1 is lower alkyl, the 3-C atom has the R-configuration or the S-configuration.
FO 7.4/WAR/ac*
FO 7.4/WAR/ac*
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4115/88-0 | 1988-11-04 | ||
| CH411588 | 1988-11-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2002045A1 true CA2002045A1 (en) | 1990-05-04 |
Family
ID=4270094
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002002045A Abandoned CA2002045A1 (en) | 1988-11-04 | 1989-11-02 | Process for the preparation of optically active acyloxyazetidinones |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0367722B1 (en) |
| JP (1) | JPH02172971A (en) |
| AT (1) | ATE89551T1 (en) |
| CA (1) | CA2002045A1 (en) |
| DE (1) | DE58904420D1 (en) |
| DK (1) | DK549789A (en) |
| ES (1) | ES2055155T3 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007004028A2 (en) * | 2005-06-30 | 2007-01-11 | Ranbaxy Laboratories Limited | Processes for the preparation of penems and its intermediate |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL129023C (en) * | 1965-04-26 | |||
| DE2046823A1 (en) * | 1970-09-23 | 1972-03-30 | Farbwerke Hoechst AG vormals Meister Lucius & Brüning, 6000 Frankfurt | New azetidinones (2) and processes for their preparation |
| CA1145347A (en) * | 1977-09-30 | 1983-04-26 | Akira Sato | 2-azetidinone derivatives |
| DE3587546D1 (en) * | 1984-10-01 | 1993-09-30 | Ciba Geigy | Process for the production of optically active acyloxyazetidinones. |
| US4882429A (en) * | 1986-03-03 | 1989-11-21 | Schering Corporation | Stereospecific preparation of (3S,4R,5R)-3-(1-hydroxyethyl)-4-benzoyloxy-azeridinones from L-(-)-theonine |
-
1989
- 1989-10-25 DE DE8989810804T patent/DE58904420D1/en not_active Expired - Fee Related
- 1989-10-25 AT AT89810804T patent/ATE89551T1/en not_active IP Right Cessation
- 1989-10-25 ES ES89810804T patent/ES2055155T3/en not_active Expired - Lifetime
- 1989-10-25 EP EP89810804A patent/EP0367722B1/en not_active Expired - Lifetime
- 1989-11-02 JP JP1285120A patent/JPH02172971A/en active Pending
- 1989-11-02 CA CA002002045A patent/CA2002045A1/en not_active Abandoned
- 1989-11-03 DK DK549789A patent/DK549789A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH02172971A (en) | 1990-07-04 |
| DK549789D0 (en) | 1989-11-03 |
| DE58904420D1 (en) | 1993-06-24 |
| ATE89551T1 (en) | 1993-06-15 |
| DK549789A (en) | 1990-05-05 |
| EP0367722A1 (en) | 1990-05-09 |
| ES2055155T3 (en) | 1994-08-16 |
| EP0367722B1 (en) | 1993-05-19 |
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