Process for preparing optically active epoxides

Details Process for preparing optically active epoxides Process for preparing optically active epoxides

2003-01-10

2004-02-17

Owens, Amelia (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06693205

ABSTRACT:

This application is a 371 of PCT/GB01/04146 filed Sep. 18, 2001.
BACKGROUND OF THE INVENTION
Field of the Invention
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 of the (2R, 3S)-grouping, the (2R, 3S)-epoxide:
where Boc is a butoxycarbonyl amine protecting group.
SUMMARY OF THE INVENTION
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-bydroxy-4-Aphenylbutyronitrile 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 alubnum 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-1,2-epoxy compounds comprising subjecting an optically active threo-3-amino-1,2-diol to allkylsulphonylation 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.
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,3S3-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.
U.S. Pat. No. 5,936,104 describes a process for producing (2S,3S)- or (2R,3R)-1,2epoxy-3-amino-4phenylbutane 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.
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.
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.
WO-A-97/42180 describes a process for preparing oxiranemethanamine derivatives, which are said to be usefull 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 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.
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.
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 of the general formula (1):
or its enantiomer wherein each of R
1
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 alkal 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
1
, R
2
and R
3
are the same as the corresponding R
1
, R
2
and R
3
in formula (1) and cyclising the resulting Mitsunobu product
DESCRIPTION OF THE PREFERRED EMBODIMENTS
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

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