PROCESS FOR PREPARING OPTICALLY ACTIVE EPOXIDES

Abstract: The invention concerns a process for the production of optically active epoxides useful as pharmaceutical intermediates, particularly in the field of HIV protease inhibitors. The optically active epoxides are produced in commercially acceptable yields from an optically active alcohols by a Mitsunobu reaction and a cyclisation step, preferably comprising an intermediate recrystallisation step. The stereochemistry of the alcohol is inverted during the Mitsunobu reaction to produce the desired epoxide.

Description: PROCESS FOR PREPARING OPTICALLY ACTIVE EPOXIDES The present invention concerns a process for producing optically active epoxides, particularly those epoxides which are useful as pharmaceutical intermediates. There are a number of potential pharmaceutical products which contain the following optically active grouping: The enantiomer (2S, 3R) of this grouping may also be useful in pharmaceutical compounds. The grouping is derivable from the epoxide of equivalent stereochemistry, in the case ofthe (2R, 3S)-grouping, the (2R, 3S)-epoxide: SUBSTITUTE SHEET (RULE 2 where Boc is a butoxycarbonyl amine protecting group. EP-A-0885879 describes ' a process for producing optically active cyanohydrins, particularly an optically active N-(protected)-3-amino-2-hydroxy-4- phenylbutyronitrile which comprises treating a mixture of diastereomers of an N-(protected)-3-amino-2-hydroxy-4-phenylbutyromtrile in the presence of an amine and an organic solvent. The optically active compound is said to be an intermediate in the production of certain pharmaceutical compounds. EP-A-0934923 describes a method for producing optically active erythro-3- amino-2-hydroxybutyric esters comprising oxidising the hydroxyl group at the 2-position of an optically active (at the 3-position) 3-amino-2-hydroxybutyric ester and then reducing erythro-selectively the resulting product using aluminium alkoxide. The resulting optically active compound is said to be a pharmaceutical intermediate, specifically for HIV protease inhibitors. WO-A-99/38855 describes a process for producing optically active threo-3- amino-l,2-epoxy compounds comprising subjecting an optically active threo-3- amino-l,2-diol to alkylsulphonylation or arylsulphonylation in an organic solvent in the presence of a base to give the corresponding optically active threo-3-amino- 2-hydroxy-l-sulphonyloxy compound and subjecting the resulting compound to epoxidation in the presence of a base to give the corresponding optically active threo-3-amino-l,2-epoxy compound. WO-A-00/10986 describes a process for the preparation of (2R,3S)-3-amino-l,2- oxirane comprising treating a (2S,3S)-3-amino-l-halo-2-hydroxy-4-phenylbutane or a (2S,3S)-3-amino-4-phenylbutane-l,2-epoxide either with a quaternary ammonium carboxylate or with both a metal carboxylate and a quaternary ammonium salt to prepare a (2S,3S)-l-acyloxy-3-amino-2-hydroxy-4- phenylbutane, treating this compound with a sulphonyl halide in the presence of an organic base to prepare a (2S,3S)-l-acyloxy-3-amino-2-sulphonyloxy-4- phenylbutane and subjecting the compound thus obtained to treatment with an inorganic base. It is said that this process allows the production of intermediates for HIN protease inhibitors using L-phenylalanine as a raw material. US 5,936,104 describes a process for producing (2S,3S)- or (2R,3R)-l,2-epoxy-3- amino-4-phenylbutane derivatives comprising treating a l-halo-2-hydroxy-3- amino-4-phenylbutane derivative with a base in an aprotic polar organic solvent or a mixed solvent composed of an aprotic polar organic solvent and water and then causing the resulting epoxide to crystallise out from a mixed solvent composed of an aprotic polar organic solvent and water. The resulting compound is said to be useful as an intermediate in the production of various HIN protease inhibitors as described, for example, in Japanese Kokai Publication Hei-08-109131. O-A-95/08530 describes a process for producing 3-amino-2-hydroxy-l- propanol derivatives which are said to be useful as intermediates in the production of medicines. JP9323960 describes a method for obtaining 3-amino-l,2-oxirane by using a 3- amino-l,2-diol as a raw material. The process comprises reacting an N-(protected)-3-amino-l,2-diol with an orthoacetate or orthoformate in the presence of an acid catalyst to form an alkoxyalkylidene. The alkoxyalkylidene is reacted with a halogenating agent to form an alkoxy halide which is then treated with a base and converted to an epoxide, thus obtaining the 3-amino-l,2-oxirane. O-A-97/42180 describes a process for preparing oxiranemethanamine derivatives, which are said to be useful as intermediates for preparing aspartyl protease inhibitors, comprising the steps of activating an aminodiol, acylating the aminodiol and reacting the acylated aminodiol with a base to form an epoxy compound. The processes and methods described in these documents all suffer from one or more ofthe following disadvantages: they do not describe methods of synthesising 2R,3S-epoxides or their enantiomers; their stereochemistry is unclear; they use expensive or difficult to obtain reagents; they describe complex reaction procedures with numerous stages; they describe low product yields; the products described are insufficiently pure for use as pharmaceutical intermediates; they relate to laboratory scale processes and are of unproven or uncertain value on a commercial scale; or they are commercially unattractive for other reasons. The academic literature describes various methods of synthesising 2R,3S-epoxides but these also suffer from one or more ofthe aforesaid disadvantages or disclose mixtures of epoxides with other stereoisomers. Examples of such academic literature include Ojima et al, Tetrahedron Letters 39 (1998) 923-926; Barrish et al, J. Med.Chem. 1994, 37, 1758-1768; Romeo and Rich, Tetrahedron Letters, 35 (1994) 4939-4942; Luly et al, J.Org.Chem. 1987, 52, 1487-1492; Evans et al, J.Org.Chem. 1985, 50, 4615-4625 and Parkes et al, J.Org.Chem. 1994, 59, 3656-3664. Other attempts to find commercially acceptable routes to the 2S,3S- and 2R,3S- epoxides have been made recently by Malik, whose work in this respect was detailed at the 3rd International Conference "Organic Process Research and Development" organised by Scientific Update on 10-12 July 2000. However, the yields for individual steps described are poor (about 53%) and toxic and/or expensive chemicals, such as cesium acetate and 18-crown ether, are used. There remains a need in the art for an improved process for the production of optically active epoxide pharmaceutical intermediates. According to the present invention there is provided a process for producing an optically active (2R, 3S)-epoxide ofthe general formula (1): or its enantiomer wherein each of R, and R 2 is independently selected from hydrogen, optionally substituted alkyl, aryl, aralkyl or alkaryl groups, and amine- protecting groups and R 3 is selected from hydrogen and optionally suitably protected alkyl, cycloalky, aryl, aralkyl or alkaryl groups which comprises conducting a Mitsunobu reaction on an optically active (2S,3S)-alcohol of general formula (2): or its enantiomer wherein X is a leaving group and R„ R 2 and R 3 are the same as the corresponding R l5 R 2 and R 3 in formula (1) and cyclising the resulting Mitsunobu product. The Mitsunobu process has been known since 1967 (Mitsunobu and Yamada in M.Bull.Chem.SocJPN. 1967, 40, 2380-2382) and was later described in 1991, the general reference being Mitsunobu, Synthesis, 1981, 1-28. This document described intermolecular dehydration reactions between alcohols and acidic components on treatment with diethyl azodicarboxylate and triphenylphosphine in which virtually complete inversion ofthe configuration ofthe alcoholic hydroxy group takes place. The Mitsunobu process was reviewed by Hughes, Org.Reac. 1992, 42, 335. Mechanistic studies of Mitsunobu chemistry have been described by Camp and Jenkins in J.Org.Chem. 1989, 54, 3045-3049, Varasi et al in J.Org.Chem. 1987, 52, 4235-4238 and Hughes et al in J.Am.Chem.Soc 1988, 110, 6487-649. The effect ofthe acidic component in Mitsunobu chemistry has been described by Martin and Dodge in Tetrahedron Letters, 1991, Vol. 32 No. 26, pages 3017-3020, by Dodge et al in J.Org.Chem. 1994, 59, 234-236 and by Hughes and Reamer in J.Org.Chem. 1996, 61, 2967-2971. Examples of industrial processes utilising Mitsunobu chemistry are described by Thomas et al in Organic Process Research and Development 1997, 1, 294-299 and by Marzoni et al in Synthetic Communications, 25 (16), 2475-2482 (1995). Reference to the use of a Mitsunobu reaction for the synthesis of substituted piperazinones can be found in WO-A-00/01678. A preferred process according to the invention, comprises recrystallising the Mitsunobu reaction product prior to cyclising. R 3 is preferably a group selected from hydrogen and optionally substituted alkyl, cycloalkyl, aryl, aralkyl and alkaryl groups. The group is preferably protected where it contains free oxygen, nitrogen or sulphur, which may react with reagents used in the Mitsunobu reaction. The leaving group X is any suitable leaving group and is preferably selected from halogens, sulphonate esters and trialkyl ammonium groups. One reaction scheme according to the invention may be summarised as follows: Esterification Step The esterification step preferably comprises treating the compound of formula (2) with a phosphine and an azodicarboxylate under acid conditions to form an intermediate ester of formula (3): wherein X, R ]5 R 2 and R 3 are the same as the corresponding X, R ]5 R 2 and R 3 in formula (2) and R 4 is an optionally nitrogenated alkyl, aryl, aralkyl or alkaryl group. Suitable phosphines include trialkyl- and triaryl phosphines such as triphenylphosphine, tributylphosphine and methyldiphenylphosphine. Triphenylphosphine is preferred. Polymer bound triphenylphosphine as disclosed in J. Org. Chem, 1983, 48, 3598 may also be used, as may bis(diphenylphosphine)ethane disclosed in Tetrahedron Letters, 1998, 39, 7787. Suitable azodicarboxylates include diisopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD) and di-tert-butylazodicarboxylate (DTBA). DIAD is preferred. Suitable acids include carboxylic acids such as acetic acid, trifluoroacetic acid and para-nitrobenzoic acid (PNBA). PNBA is preferred. Suitable solvents for the esterification are aprotic solvents including benzene, toluene, chlorinated hydrocarbons, ethyl acetate and water miscible solvents including tetrahydrofuran, dimethoxyethane and dioxane. Toluene and tetrahydrofuran are preferred. Suitable solvents for crystallisation ofthe esterified product include low boiling alcohols, optionally in admixture with water. Ethanol/water mixtures are preferred. Recrystallisation Step The recrystallisation step is preferably effected from an ethanol/water mixture and is conducted to remove minor contaminants of triphenylphosphineoxide, DIAD- H2 and of 2S,3S-ester from the 2R,3S-ester (or 2R, 3R-ester from the 2S, 3R-ester in the enantiomerically equivalent process ofthe invention). Cyclisation Step The cyclisation step preferably comprises treating the recrystallised intermediate ester with an aqueous base. Suitable bases include alkali and alkaline earth metal hydroxides and quaternary ammonium or phosphonium compounds. The 2R,3S- ester intermediate can be saponified and cyclised by, for example, working up in ethanol and an aqueous base such as potassium hydroxide. Phase transfer conditions can also be employed using an aqeuous base, a water immiscible solvent, such as toluene or a chlorinated hydrocarbon, and a suitable catalyst, such as a quaternary ammonium or phosphonium salt. The alcohol of formula (2) may be obtained by known routes (e.g. J. Org. Chem. 1994, 59, 3656) from amino acids and synthetic amino acids. One preferred starting material for obtaining the 2R, 3S-epoxide is L-phenylalanine. A preferred starting material for obtaining the 2S, 3R-epoxide is D-phenylalanine. In the process ofthe invention, the alcohol is preferably a haloalcohol, even more preferably a chloroalcohol. The amine protecting group is preferably butoxycarbonyl or benzyloxycarbonyl. The invention will now be more particularly described with reference to the following examples. Example 1 A 3 (protected) amino-4-phenyl-l-chlorobutan-2-ol was esterified according to the following reaction scheme: Reagents Procedure A 2L flange necked flask was equipped with an overhead mechanical stirrer (paddle), thermometer, pressure equalised dropping funnel and nitrogen blanket. The flask was charged with 30. Og ofthe chloroalcohol of formula (2) and 1200ml of toluene to form a slurry. 30.6g of TPP and 20.2g of PNBA were then added and the mixture stirred at 18-20°C. 24.6g of DIAD was dripped into the flask over a 5min period, resulting in an exotherm to 25 °C. Once all the DIAD had been added, stirring was continued for 2hr to give a yellow solution. This solution was transferred to a rotary evaporator and the bulk ofthe toluene was distilled at approximately lOOmbar and 60 °C. The residual yellow oil was taken up in 450ml of ethanol and the solution was heated to 70 °C. 180ml of water were added in portions maintaining a temperature of >65°C. Care was taken, by means of gradual addition ofthe water over ten minutes, during water addition to prevent oiling ofthe product. The solution was cooled to 50 °C and seeded with product to induce crystallisation. The slurry was cooled to 10°C with the bulk ofthe product crystallising at 45-50 °C. The product was filtered through Whatman 54 paper and the cake was washed with 100ml of ethanol/water mixture at 0-5 °C and dried under vacuum at 200mbar, at 50-60°C for 18hr to furnish 31.0g (i.e. a 71% yield) of product as fine white needles. A second crop of crystals (1.2g, giving a total yield of 74%) was isolated from the mother liquors. The product was analysed by thin layer chromatography (one spot pure) and 'H nmr which showed essentially clean product with trace impurities of triphenylphosphine oxide and DIAD-H2 (both estimated at <0.5%). Example 2 The reaction scheme of Example 1 was followed but using a THF solvent instead of toluene. /> i > rs s o ι— r Procedure A IL flange necked flask was equipped with an overhead mechanical stirrer (paddle), thermometer, pressure equalized dropping funnel and nitrogen blanket. The flask was charged with 2S, 3S Boc-chloroalcohol (lOO.Og). THF (500ml) was added to form a slurry (KF 0.0805%). TPP (103.8g) and PNBA (66. Ig) were sequentially added to the slurry and the slurry was stirred at 18-25C. DIAD (83.4g) was dripped in via the dropping funnel over 20 min (4.2g/min) maintaining the exotherm at 18-20C. On full addition, stirring was continued at between 18-20C for 2 hr when the slurry had dissolved up to an olive coloured solution. The solution was quenched into ethanol (600ml) over 35 min (40g/min) with stirring at 18-20C resulting in crystallization of product. The slurry was then stirred for 60 min at 5-lOC. The slurry was filtered (54μ paper), 150 mm diameter, vacuum 700mbar, cake depth 40mm, filtration time 14m30s) and the cake washed with 1 :1 ethanohwater (2x500ml). The solid was dried on the filter overnight to give 119g of 14.5% KF solid, dry weight equivalent 102.3g. 99.0% area % HPLC, 69% molar yield. Example 3 The esterified product of Example 1 or Example 2 was recrystallised as follows. Reagents Procedure A IL flange necked flask was equipped with overhead mechanical stirrer (paddle) condenser, thermometer and nitrogen blanket. The flask was charged with 29.8g of ester and 300ml of ethanol and heated to 70-75°C until the ester was fully dissolved. Water was added in portions (causing turbidity) maintaining a temperature of >70°C. On full addition ofthe water the solution was heated for a further lOmin to give a pale yellow solution. The solution was cooled to 60 °C, seeded with the product to induce crystallisation and slowly cooled to 10°C over a period of lhr with the bulk ofthe product crystallising at 45-50°C. After stirring for 30min at 10°C the slurry was filtered through Whatman 54 paper and the cake was washed with 100ml of ethanol/water mixture at 0.5 °C and dried under vacuum at 50-60 °C, 200mbar for 18hr to give 28.8g (a 97% yield) of product as fine white needles. Thin layer chromatography analysis and ! H nmr demonstrated that the ester was uncontaminated with triphenylphosphineoxide and DIAD-H2 impurities. Example 4 The recrystallised, esterified product from Example 3 was cyclised according to the following reaction scheme: Reagents Procedure A 3L flange necked flask was equipped with an overhead mechanical stirrer (paddle), thermometer, pressure equalised dropping funnel and nitrogen blanket. The flask was charged with 30. Og of ester and 1020ml of ethanol to form a slurry. The slurry was cooled to 0-5 °C and 125ml of KOH solution were added over a 5min period maintaining the temperature at <5 °C. On full addition the reaction was monitored by HPLC and was complete after 3hr. The reaction was quenched with water (1000ml), stirred for 5min and extracted twice with MDC (once with 500ml of MDC and then once with 200ml of MDC). The combined organic extracts were washed with 300ml of 5% citric acid, 300ml of 5% NaHCO 3 and 300ml of water. The product solution was dried in the presence of anhydrous sodium sulphate, filtered and concentrated on a rotary evaporator at 50 °C from 50-85mbar to give 17.7g (i.e. >95% yield) of a clear oil that slowly solidified on refrigeration, having a melting point of 49 °C. The isolated product was >99% pure by area HPLC with no 2S,3S diastereomer observed. *H mnr of the product confirmed the structure. Examples 5 to 14 The following table shows summary procedures and results of further esterification reactions according to the invention. Unless otherwise specified, the procedures and conditions were similar to those mentioned above in Example 1. ϋ> ω H c -i m > o> rrs -s 5o e ι— r ϋ> w ω ■ H 3 a S l ω T —I r- m t Examples 15 to 17 The following table shows summary results of further examples ofthe recrystallisation step according to the invention. Unless otherwise specified, the procedures and conditions used are similar to those specified above in connection with Example 3. /24671 25 Examples 18 to 23 The following table shows in summary form further examples ofthe cyclisation step according to the invention. Unless otherwise specified, the procedures and conditions are similar to those specified above in connection with Example 4. Example Input Ester Scale Reagent charge Procedure Work-up Estimated Purity Yield 18 Recrystallised | 200mg Ethanol 25ml Add aqueous KOH to ethanol Neutralise with citric acid and >99% 79% ester KOH 30x slurry ofthe ester. Monitor reaction concentrate on RFE. Dissolve 2R.3S by LC. progress by LC. Complete after lhr in MDC, acid base wash, dry No 2S,3S isomer c at and concentrate to oil that observed. ED ω 0-2 °C solidifies on refrigeration Pure by nmr ■ 19 Recrystallised 5.0g Ethanol 200ml Add aqueous KOH to ethanol slurry Neutralise with citric acid and H 0.8% OPPh 3 88% a ester KOH 7x ofthe ester. Monitor reaction concentrate on RFE. Dissolve 98.9% 2R,3S progress by LC. Complete after in MDC, acid base wash, dry 0.2% alcohol ΪTl 3.5hr t 0-2°C and concentrate ω 20 Isolated ester 3.0g Isopropanol 120ml Add aqueous KOH to slurry ofthe Neutralise with citric acid and 7.6%imp 74% from Example 9 KOH 5.0x ester. Monitor reaction progress by concentrate on RFE. Dissolve 82.4% 2R,3S LC. Complete after 3.5hr at 0-2°C in MDC, acid base wash, dry 9.52%imp -4 and concentrate c 21 Recrystallised 3.0g Ethanol 120ml Add aqueous KOH to ethanol slurry Neutralise with citric acid and 99.8% 2R.3S 95% ester from KOH 7x ofthe ester, Monitor reaction concentrate on RFE. Dissolve r ™ 0.1% alcohol m Example 9 progress by LC. Complete after in MDC, acid base wash, dry 3.5hr at O-2"C and concentrate 03 22 Recrystallised 25.0g Ethanol 1000ml Add aqueous KOH to ethanol slurry Neutralise with citric acid and 0.4% 2S,3S or >95% ester from KOH 7x (105ml) of the ester. Monitor reaction concentrate on RFE to half OPPh 3 Example 1 progress by LC. Complete after 3hr volume. Dissolve in MDC, 99.6% 2R,3S at O-2°C acid base wash, dry and concentrate 23 Isolated ester 25.0g Ethanol 1000ml Add aqueous KOH to ethanol slurry Neutralise with citric acid and 1.0% 2S,3S or >95% from Example 10 KOH 7x (105ml) ofthe ester. Monitor reaction concentrate on RFE to half OPPh 3 progress by LC. Complete after hr volume. Dissolve in MDC, 99.6% 2R,3S at 0-2 "C acid base wash, dry and concentrate

Claims: CLAIMS 1. A process for producing an optically active (2R, 3S)-epoxide ofthe general formula (1): or its enantiomer wherein each of R, and R 2 is independently selected from hydrogen, optionally substituted alkyl, aryl, aralkyl or alkaryl groups, and amine- protecting groups and R 3 is selected from hydrogen and optionally suitably protected alkyl, cycloalkyl, aryl, aralkyl or alkaryl groups which comprises conducting a Mitsunobu reaction on an optically active (2S,3S)-alcohol of general formula (2): or its enantiomer wherein X is a leaving group and R b R 2 and R 3 are the same as the corresponding R l3 R 2 and R 3 in formula (1) and cyclising the resulting Mitsunobu product. 2. A process according to claim 1, comprising recrystallising the Mitsunobu reaction product prior to cyclising. 3. A process according to claim 1 or claim 2 wherein the Mitsunobu reaction comprises treating the compound of formula (2) with a phosphine and an azodicarboxylate under acid conditions to form an intermediate ester of formula (3): wherein X, R R 2 and R 3 are the same as the corresponding X, R,, R 2 and R 3 in formula (2) and R 4 is an optionally nitrogenated alkyl, aryl, aralkyl or alkaryl group. 4. A process according to claim 3, wherein the phosphine comprises triphenylphosphine . 5. A process according to claim 3 or claim 4, wherein the azodicarboxylate is diisopropylazodicarboxylate. 6. A process according to any one of claims 3 to 5, wherein the acid conditions are provided by a carboxylic acid. 7. A process according to claim 6, wherein the carboxylic acid is para- nitrobenzoic acid. 8. A process according to any one of claims 2 to 7, wherein the solvent for the esterification step comprises toluene or tetrahydrofuran. 9. A process according to any one of claims 2 to 8, wherein the recrystallisation step is carried out using a mixture of ethanol and water as the recrystallising solvent. 10. A process according to any one of claims 1 to 9, wherein the cyclisation step comprises treating the product ofthe recrystallisation step with a base. 11. A process according to claim 10 wherein the base is aqueous KOH and the cyclisation step is carried out in ethanol. 12. A process according to any one of claims 1 to 12, wherein the amine protecting group is butoxy/carbonyl. 13. A process according to any one of claims 1 to 12, wherein the alcohol is a haloalcohol.

Inventors: JUSTICE DAVID EDWARD, JUSTICE, DAVID, EDWARD
Applicants: JUSTICE DAVID EDWARD, PHOENIX CHEMICALS LTD, JUSTICE, DAVID, EDWARD, PHOENIX CHEMICALS LIMITED
Application year: 2001
Main classification: C07D303
IPC codes: C07B53, C07B61, C07C269, C07C271, C07D301, C07D303