AU2001287871A1

AU2001287871A1 - Process for preparing optically active epoxides

Info

Publication number: AU2001287871A1
Application number: AU2001287871A
Authority: AU
Inventors: David Edward Justice
Original assignee: Phoenix Chemicals Ltd
Current assignee: Phoenix Chemicals Ltd
Priority date: 2000-09-18
Filing date: 2001-09-18
Publication date: 2002-04-02
Also published as: EP1318990A1; GB2369356B; ATE262514T1; US20030171603A1; GB2369356A; EP1318990B1; US6693205B2; DE60102483D1; GB0022772D0; WO2002024671A1; CA2400514A1; JP2004509879A

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 re-crystallisation 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 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):

or its enantiomer wherein X is a leaving group and R„ R₂ and R₃ are the same as

the corresponding R_l5 R₂ and R₃ 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. 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.

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 R₂ and R₃ are the same as the corresponding X, R_]5 R₂ and R₃ in

formula (2) and R₄ 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% NaHCO₃ 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% OPPh₃ 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 OPPh₃ 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 OPPh₃ 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

1. A process for producing an optically active (2R, 3S)-epoxide ofthe

general formula (1):

or its enantiomer wherein each of R, and R₂ is independently selected from

protecting groups and R₃ is selected from hydrogen and optionally suitably

protected alkyl, cycloalkyl, aryl, aralkyl or alkaryl groups which comprises

formula (2):

or its enantiomer wherein X is a leaving group and R_b R₂ and R₃ are the same as

the corresponding R_l3 R₂ and R₃ 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 R₂ and R₃ are the same as the corresponding X, R,, R₂ and R₃ in

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.