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

[0001] The present invention concerns a process for producing optically active epoxides, particularly those epoxides which are useful as pharmaceutical intermediates.

[0002] There are a number of potential pharmaceutical products which contain the following optically active grouping: 1

[0003] 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 of the (2R, 3S)-grouping, the (2R, 3S)-epoxide: 2

[0004] where Boc is a butoxycarbonyl amine protecting group.

[0005] 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-phenylbutyronitrile 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.

[0006] 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.

[0007] WO-A-99/38855 describes aprocess for producing optically active threo-3-amino-1,2-epoxy compounds comprising subjecting an optically active threo-3-amino-1,2-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-1-sulphonyloxy compound and subjecting the resulting compound to epoxidation in the presence of a base to give the corresponding optically active threo-3-amino-1,2-epoxy compound.

[0008] WO-A-00/10986 describes a process for the preparation of (2R,3S)-3-amino-1,2-oxirane comprising treating a (2S,3S)-3-amino-1-halo-2-hydroxy-4-phenylbutane or a (2S,3S)-3-amino-4-phenylbutane-1,2-epoxide either with a quaternary ammonium carboxylate or with both a metal carboxylate and a quaternary ammonium salt to prepare a (2S,3S)-1-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)-1-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 HIV protease inhibitors using L-phenylalanine as a raw material.

[0009] U.S. Pat. No. 5,936,104 describes a process for producing (2S,3S)- or (2R,3R)-1,2-epoxy-3-amino-4-phenylbutane derivatives comprising treating a 1-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 HIV protease inhibitors as described, for example, in Japanese Kokai Publication Hei-08-109131.

[0010] WO-A-95/08530 describes a process for producing 3-amino-2-hydroxy-1-propanol derivatives which are said to be useful as intermediates in the production of medicines.

[0011] JP9323960 describes a method for obtaining 3-amino-1,2-oxirane by using a 3-amino-1,2-diol as a raw material. The process comprises reacting an N-(protected)-3-amino-1,2-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-1,2-oxirane.

[0012] WO-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.

[0013] The processes and methods described in these documents all suffer from one or more of the 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.

[0014] The academic literature describes various methods of synthesising 2R,3S-epoxides but these also suffer from one or more of the 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.

[0015] 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 Jul. 10-12, 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.

[0016] There remains a need in the art for an improved process for the production of optically active epoxide pharmaceutical intermediates.

[0017] According to the present invention there is provided a process for producing an optically active (2R, 3S)-epoxide of the general formula (1): 3

[0018] or its enantiomer wherein each of R1 and R2 is independently selected from hydrogen, optionally substituted alkyl, aryl, aralkyl or alkaryl groups, and amine-protecting groups and R3 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): 4

[0019] or its enantiomer wherein X is a leaving group and R1, R2 and R3 are the same as the corresponding R1, R2 and R3 in formula (1) and cyclising the resulting Mitsunobu product.

[0020] The Mitsunobu process has been known since 1967 (Mitsunobu and Yamada in M.Bull.Chem.Soc.JPN. 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 of the configuration of the 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 of the 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.

[0021] A preferred process according to the invention, comprises recrystallising the Mitsunobu reaction product prior to cyclising.

[0022] R3 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.

[0023] The leaving group X is any suitable leaving group and is preferably selected from halogens, sulphonate esters and trialkyl ammonium groups.

[0024] One reaction scheme according to the invention may be summarised as follows: 5

[0025] Esterification Step

[0026] 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): 6

[0027] wherein X, R1, R2 and R3 are the same as the corresponding X, R1, R2 and R3 in formula (2) and R4 is an optionally nitrogenated alkyl, aryl, aralkyl or alkaryl group.

[0028] 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.

[0029] Suitable azodicarboxylates include diisopropylazodicarboxylate (DIAD), diethylazodicarboxylate (DEAD) and di-tert-butylazodicarboxylate (DTBA). DIAD is preferred.

[0030] Suitable acids include carboxylic acids such as acetic acid, trifluoroacetic acid and para-nitrobenzoic acid (PNBA). PNBA is preferred.

[0031] 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 of the esterified product include low boiling alcohols, optionally in admixture with water. Ethanol/water mixtures are preferred.

[0032] Recrystallisation Step

[0033] 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 of the invention).

[0034] Cyclisation Step

[0035] 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.

[0036] 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 of the invention, the alcohol is preferably a haloalcohol, even more preferably a chloroalcohol.

[0037] The amine protecting group is preferably butoxycarbonyl or benzyloxycarbonyl.

[0038] The invention will now be more particularly described with reference to the following examples.

EXAMPLE 1

[0039] A 3 (protected) amino-4-phenyl-1-chlorobutan-2-ol was esterified according to the following reaction scheme: 7

Reagents
	100%
Reagents	Mass	Strength	Strength	MW	Moles	Eq.	Source
2S,3S chloroalcohol	30.0	g	96.9%	29.1	g	300	0.097	1.0x	Synthesised according
			2S,3S						to J. Org. Chem.
									1994, 59, 3656
DIAD	24.6	g	95%	23.4	g	202	0.116	1.2x	Aldrich
									PO 06304DR
Triphenylphosphine (TPP)	30.6	g	99%	30.3	g	262	0.116	1.2x	Aldrich
									60707009
p-Nitrobenzoic acid	20.2	g	98%	19.8	g	167	0.119	1.2x	Aldrich
(PNBA)									07117HU
Toluene	1200	ml	>99%	1200	ml	92	—	—	BDH 30454
Ethanol	450	ml	Absolute	450	ml	85	—	—	Hays DEB100
Water	180	ml	Towns	180	ml	18	—	—	Towns
Ethanol/Water	100	ml	Absolute/	1:1		—	—	—	Hays DEB 100 /
			Towns						Towns

[0040] Procedure

[0041] 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 30.0 g of the chloroalcohol of formula (2) and 1200 ml of toluene to form a slurry. 30.6 g of TPP and 20.2 g of PNBA were then added and the mixture stirred at 18-20° C. 24.6 g of DIAD was dripped into the flask over a 5 min period, resulting in an exotherm to 25° C. Once all the DIAD had been added, stirring was continued for 2 hr to give a yellow solution. This solution was transferred to a rotary evaporator and the bulk of the toluene was distilled at approximately 100 mbar and 60° C. The residual yellow oil was taken up in 450 ml of ethanol and the solution was heated to 70° C. 180 ml of water were added in portions maintaining a temperature of >65° C. Care was taken, by means of gradual addition of the water over ten minutes, during water addition to prevent oiling of the 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 of the product crystallising at 45-50° C. The product was filtered through Whatman 54 paper and the cake was washed with 100 ml of ethanol/water mixture at 0-5° C. and dried under vacuum at 200 mbar, at 50-60° C. for 18 hr to furnish 31.0 g (i.e. a 71% yield) of product as fine white needles. A second crop of crystals (1.2 g, giving a total yield of 74%) was isolated from the mother liquors. The product was analysed by thin layer chromatography (one spot pure) and 1H nmr which showed essentially clean product with trace impurities of triphenylphosphine oxide and DIAD-H2 (both estimated at <0.5%).

EXAMPLE 2

[0042] The reaction scheme of Example 1 was followed but using a THF solvent instead of toluene.

	Crude		100%
Chemical	Mass/Vol	Strength	Strength	MW	Moles	Molar Equiv	Source/Lot
2S,3S,	100.0	g	97.7% LC	98.0	g	300	0.327	1.0x	Synthesised
chloroalcohol									according to
									J. Org. Chem
									1994,
									59,3656
THF	500	ml	>99%	500	ml	72	—	—	Petrochem
									16/03 pre-
									sample
TPP	103.8	g	99%	103.8	g	262	0.392	1.2x	PCL 00722
PNBA	66.1	g	>99%	65.6	g	167	0.392	1.2x	PCL 00728
DIAD	83.4	g	95%	79.2	g	202	0.392	1.2x	Schwizerhall
									292-210-3288
Ethanol	600	ml	Absolute	600	ml	46	—	—	Shell 982437-
									18
Water	600	ml	Towns	600	ml	18	—	—	Towns
Ethanol:water	2 × 500	ml	1:1	84	ml	—	—	—	As above

[0043] Procedure

[0044] A 1L 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 (100.0 g). THF (500 ml) was added to form a slurry (KF 0.0805%). TPP (103.8 g) and PNBA (66.1 g) were sequentially added to the slurry and the slurry was stirred at 18-25 C. DIAD (83.4 g) was dripped in via the dropping funnel over 20 min (4.2 g/min) maintaining the exotherm at 18-20 C. On full addition, stirring was continued at between 18-20 C. for 2 hr when the slurry had dissolved up to an olive coloured solution. The solution was quenched into ethanol (600 ml) over 35 min (40 g/min) with stirring at 18-20 C. resulting in crystallization of product. The slurry was then stirred for 60 min at 5-10 C. The slurry was filtered (54μ paper), 150 mm diameter, vacuum 700 mbar, cake depth 40 mm, filtration time 14 m30 s) and the cake washed with 1:1 ethanol:water (2×500 ml). The solid was dried on the filter overnight to give 119 g of 14.5% KF solid, dry weight equivalent 102.3 g. 99.0% area % HPLC, 69% molar yield.

EXAMPLE 3

[0045] The esterified product of Example 1 or Example 2 was recrystallised as follows.

[0046] Reagents

	100%
Reagents	Mass	Strength	Strength	MW	Moles	Eq.	Source
2R,3S	29.8	g	99%	29.7	g	449	0.0663	1.0x	From Example 1
Nitro ester			(assumed)
Ethanol	300	ml	Absolute	300	ml	85	—	—	Hays DEB 100
Water	80	ml	Towns	80	ml	18	—	—	Towns
Ethanol/water	100	ml	Absolute /	1:1		—	—	—	Hays DEB 100 / Towns
			Towns

[0047] Procedure

[0048] A 1L flange necked flask was equipped with overhead mechanical stirrer (paddle) condenser, thermometer and nitrogen blanket The flask was charged with 29.8 g of ester and 300 ml 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 of the water the solution was heated for a further 10 min 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 1 hr with the bulk of the product crystallising at 45-50° C. After stirring for 30 min at 10° C. the slurry was filtered through Whatman 54 paper and the cake was washed with 100 ml of ethanol/water mixture at 0.5° C. and dried under vacuum at 50-60° C., 200 mbar for 18 hr to give 28.8 g (a 97% yield) of product as fine white needles. Thin layer chromatography analysis and 1H nmr demonstrated that the ester was uncontaminated with triphenylphosphineoxide and DIAD-H2 impurities.

EXAMPLE 4

[0049] The recrystallised, esterified product from Example 3 was cyclised according to the following reaction scheme:

Reagents
8
			100%
Reagents	Mass	Strength	Strength	MW	Moles	Eq.	Source
2R,3S Nitro ester	30.0	g	100% (assumed)	30.0	g	449	0.0668	1.0x	Example 2
Ethanol	1020	ml	Absolute	1020	ml	85	—	—	Hayman B100
KOH/water	125	ml	0.15 g/ml	18.8	g	40	0.47	7.0x	Aldrich MS09811ES
Water	1000	ml	Towns	1000	ml	18	—	—	Towns
MDC	700	ml	LC grade	700	ml	92	—	—	Baker 9930020017
Citric acid	300	ml	5%	15.0	g	192	0.078	—	Plant
NaHCO3	300	ml	5%	15.0	g	84	0.178	—	Aldrich 8116018
Water	300	ml	Towns	300	ml	18	—	—	Towns

[0050] Procedure

[0051] 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 30.0 g of ester and 1020 ml of ethanol to form a slurry.

[0052] The slurry was cooled to 0-5° C. and 125 ml of KOH solution were added over a 5 min period maintaining the temperature at <5° C. On full addition the reaction was monitored by HPLC and was complete after 3 hr. The reaction was quenched with water (1000 ml), stirred for 5 min and extracted twice with MDC (once with 500 ml of MDC and then once with 200 ml of MDC). The combined organic extracts were washed with 300 ml of 5% citric acid, 300 ml of 5% NaHCO3 and 300 ml 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 50-85 mbar to give 17.7 g (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. 1H nmr of the product confirmed the structure.

EXAMPLES 5 TO 14

[0053] 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.

	Input
Example	chloroalcohol	Scale	Reagent charge	Procedure	Work-up	Estimated Purity	Yield
5	98.3% 2S,3S	2.0	g	Toluene 70 ml	Add DEAD	Concentrate to oil then	98% (nmr)	78%
	0.7% 2R,3S			DEAD 1.2x	over 1 min then stir at	column chromatography
				PPh3 1.2x	20° C. for 2 hr
				PNBA 1.2x
6	96.3% 2S,3S	2.0	g	Toluene 100 ml	Add DIAD	Concentrate to oil then	98% (nmr)	82%
	2.2% 2R,3S			DIAD 1.2x	over 1 min then stir at	column chromatography
				PPh3 1.2x	20° C. for 2 hr
				PNBA 1.2x
7	98.3% 2S,3S	8.0	g	Toluene 250 ml	Add DEAD	Concentrate to oil, dissolve in	95% (nmr)	48%
	0.7% 2R,3S			DEAD 1.2x	over 1 min then stir at	ethanol (100 ml) then	Trace OPPh3
				PPh3 1.2x	20° C. for 2 hr	crystallise
				PNBA 1.2x
8	96.3% 2S,3S	10.0	g	Toluene 250 ml	Add DIAD	Concentrate to oil, dissolve in	95% (nmr)	67%
	2.2% 2R,3S			DIAD 1.2x	over 5 min then stir at	ethanol (100 ml) then	Trace OPPh3
				PPh3 1.2x	20° C. for 2 hr	crystallise (2 crops)
				PNBA 1.2x
9	96.3% 2S,3S	5.0	g	Toluene 200 ml	Add DIAD	Concentrate to oil, dissolve in	98% (nmr)	75%
	2.2% 2R,3S			DIAD 1.2x	over 5 min then stir at	ethanol (75 ml) then water	Trace OPPh3
				PPh3 1.2x	20° C. for 2 hr	added (300 ml) at 70-80° C.,	DIAD-H2
				PNBA 1.2x		cool and crystallise	contamination
10	96.9% 2S,3S	30.0	g	Toluene 1200 ml	Add DIAD over 5 min	Concentrate to oil, dissolve in	98% (nm)	67%
	0.8% 2R,3S			DIAD 1.2x	then stir at 20° C. for 2 hr	ethanol (450 ml) then water	Trace OPPh3
				PPh3 1.2x		added (200 ml) at 70-80° C.,	DIAD-H2
				PNBA 1.2x		cool and crystallise	contamination
11	98.8% 2S,3S	60.0	g	Toluene 2400 ml	Add DIAD over 10 min	Concentrate to oil, dissolve in	98% (nmr)	74%
	0.9% 2R,3S			DIAD 1.2x	then stir at 20° C. for 2 hr	ethanol (900 ml) then water	Trace OPPh3
				PPh3 1.2x		added (360 ml) at 70-80° C.,	DIAD-H2
				PNBA 1.2x		cool and crystallise	contamination
12	97.8% 2S,3S	25.0	g	Dimethoxyethane	Add DIAD over 10 min	Add reaction mixture to	98% (nmr) Trace	72%
	08.% 2R,3S			250 ml DIAD	Then 2 hr stir at 20° C.	ethanol (200 ml) and water	OPPh3 and
				1.4x, PPh3 1.4x,		(200 ml), filter resulting solid	DIAD-
				PNBA 1.4x			h2 contamination
13	97.7% 2S, 3S,	25.0	g	Tetrahydrofuran	Add DIAD over 20 min	Add reaction mixture to	90% (nmr)	68%
	1.0% 2R, 3S			125 ml DIAD	Then 2 hr stir at 20° C.	ethanol (220 ml) and water	Residual TPPO
				1.2x, PPh3 1.2x,		(300 ml), filter resulting solid
				PNBA 1.2x
14	97.7% 2S,3S 1.0%	100	g	Tetrahydrofuran	Add DIAD over 20 min	Add reaction mixture to	99.0% (HPLC)	69%
	2R,3S			500 ml DIAD	Then 2 hr stir at 20° C.	ethanol (600 ml) and water
				1.2x, PPh3 1.2x,		(600 ml), filter resulting solid
				PNBA 1.2x

EXAMPLES 15 TO 17

[0054] The following table shows summary results of further examples of the 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.

Example	Input Ester	Input Quality	Scale	Reagent Charge	Procedure	Estimated Purity	Yield
15	From Example 5	Trace OPPh3	2.3	g	23 ml ethanol	Heat to dissolve,	Free of impurities	74%
		and DEAD-H2				cool and filter.	by nmr
		contamination				Thick mixture	CHN fits
		by nmr
16	A blend	Trace OPPh3	14.7	g	147 ml ethanol	Heat to dissolve,	Free of impurities	78%
		and DEAD-H2				cool and filter.	by nmr
		contamination				Thick mixture
		by nmr
17	From Example 11	Trace OPPh3	65.7	g	600 ml ethanol	Heat ester in	Free of impurities	95%
		and DIAD-H2			160 ml water	ethanol to dissolve,	by nmr
		contamination				then add water at
		by nmr				70-75° C., cool and
						filter

EXAMPLES 18 TO 23

[0055] The following table shows in summary form further examples of the cyclisation step according to the invention. Unless otherwise specified, the procedures and conditions are similar to those specified above in connection with Example 4.

Exam-		Estimated
ple	Input Ester	Scale	Reagent charge	Procedure	Work-up	Purity	Yield
18	Recrystallised	200	mg	Ethanol 25 ml	Add aqueous KOH to ethanol	Neutralise with citric acid and	>99%	79%
	ester			KOH 30x	slurry of the ester. Monitor reaction	concentrate on RFE. Dissolve	2R,3S by
					progress by LC. Complete after 1 hr	in MDC, acid base wash, dry	LC. No
					at	and concentrate to oil that	2S,3S isomer
					0-2° C.	solidifies on refrigeration	observed.
							Pure by nmr
19	Recrystallised	5.0	g	Ethanol 200 ml	Add aqueous KOH to ethanol slurry	Neutralise with citric acid and	0.8% OPPh3	88%
	ester			KOH 7x	of the 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
					3.5 hr at 0-2° C.	and concentrate
20	Isolated ester	3.0	g	Isopropanol 120 ml	Add aqueous KOH to slurry of the	Neutralise with citric acid and	7.6% imp	74%
	from Example			KOH 5.0x	ester. Monitor reaction progress by	concentrate on RFE. Dissolve	82.4% 2R,3S
	9				LC. Complete after 3.5 hr at 0-2° C.	in MDC, acid base wash, dry	9.52% imp
						and concentrate
21	Recrystallised	3.0	g	Ethanol 120 ml	Add aqueous KOH to ethanol slurry	Neutralise with citric acid and	99.8% 2R,3S	95%
	ester from			KOH 7x	of the ester. Monitor reaction	concentrate on RFE. Dissolve	0.1% alcohol
	Example 9				progress by LC. Complete after	in MDC, acid base wash, dry
					3.5 hr at 0-2° C.	and concentrate
22	Recrystallised	25.0	g	Ethanol 1000 ml	Add aqueous KOH to ethanol slurry	Neutralise with citric acid and	0.4% 2S,3S	>95%
	ester from			KOH 7x (105 ml)	of the ester. Monitor reaction	concentrate on RFE to half	or OPPh3
	Example 17				progress by LC. Complete after 3 hr	volume. Dissolve in MDC,	99.6% 2R,3S
					at 0-2° C.	acid base wash, dry and
						concentrate
23	Isolated ester	25.0	g	Ethanol 1000 ml	Add aqueous KOH to ethanol slurry	Neutralise with citric acid and	1.0% 2S,3S	>95%
	from Example			KOH 7x (105 ml)	of the ester. Monitor reaction	concentrate on RFE to half	or OPPh3
	10				progress by LC. Complete after 3 hr	volume. Dissolve in MDC,	99.6% 2R,3S
					at 0-2° C.	acid base wash, dry and
						concentrate

Claims

1. A process for producing an optically active (2R, 3S)-epoxide of the general formula (1):

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):

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 of the 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.