The present invention relates to an epoxide useful in stereoselective preparation of benzothiazepine type pharmaceuticals, to methods for preparation of such epoxides and to sulphinate ester intermediate to the epoxide.

Compounds of formula I

Ar-HC ACH-R

wherein :

Ar is selected from the groups consisting of aryl heteroaryl, substituted aryl, and substituted heteroaryl and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; are useful intermediates for preparation of biologically active compounds in which the stereochemistry of the final compound is controlled entirely or in part by the configuration of the chiral carbons (marked *). For example, Diltiazem, a benzothiazepine derivative which is well known as a vasodilator is one of four possible optical isomers. There is a wide variation in biological activity between Diltiazem and its three related optical isomers, Diltiazem being the isomer of commercial interest as a vasodilator. In a nonstereospecific synthesis of Diltiazem, the desired (2S,3S) isomer can be obtained in at most a 25% yield, and hence workers in the area have concentrated on stereoselective synthetic routes which require the intermediates such as the epoxide of formula I, to have a high optical purity.

We have now found that the compound of formula I may be prepared with high εtereoselectivity via formation of a sulphonate ester intermediate.

Accordingly we provide a stereoselective process for preparation of an epoxide of formula I

Ar-HC ACH-R

wherein :

Ar is selected from the group consisting of aryl, heteroaryl, substituted aryl and substituted heteroaryl, and R is a carboxylic acid group or ester or a group capable of being converted to a carboxylic acid group or ester; the process comprising reacting a diol of formula III with a sulfonating agent of formula IV to form a compound of formula V and eliminating the sulfonyloxy group from the compound of formula V to form the epoxide of formula I

τsL

V

In the compound of formula IV L is a leaving group such as halogen and preferably chlorine or bromine. In the compounds of formula IV and V, the group X, which may be different when there is more than one X, is preferably selected from the group consisting of C. to Q, alkyl and halogen, and preferably n is an integer from 1 to 5 and preferably 1 to 3.

In the compounds of formula I, III and V the group Ar is preferably selected from the group of formula VI

wherein A is independently selected from the group consisting of halogen, C. to C _g alkyl, C. to C _β alkoxy, C. to C _β alkylthio, and more preferably C. to C. alkyl and C. to C. alkoxy, and m is an integer of from 0 to 3 inclusive and preferably m is 0 or 1.

Most preferred Ar is p-(C, to C _g alkoxy)phenyl, for example p-methoxyphenyl;

Preferably R is selected from the group

0 II consisting of cyano, thiocarbomoyl, -C-G and CH-Z, wherein: G is chosen from the group consisting of: hydrogen, hydroxy, mercapto, C- to C. alkoxy, C. to C- _Q haloalkoxy, C~ to C. ₀ alkenyloxy, C ₃ to C.-. alkynyloxy, C, to C. _n alkynylthio, C, to C_ cycloalkoxy, C, to C_ cycloalkoxy substituted with one or two C. to C. alkyl groups, phenoxy, phenylthio, benzyloxy, benzylthio, the group C. to

C _fi alkoxy substituted with a substituent chosen from the group consisting of C 1_ to C _c b alkoxy, a ino, ammonic, cyano, N-(C 1. to Co _c alkyl)amino and N,N,N-tri(C. to C, alkyl)ammonio, the groups phenoxy, phenylthio, benzyloxy and benzylthio wherein in each group the phenyl ring is substituted with front I to 3 subεtituents chosen from the group consisting of halogen, nitro, cyano, C. to C _β alkyl, C. to C _fi haloalkyl and C. to C , alkoxy, the group -

— _> —

NHS0-. wherein R is chosen from C. to C _ιn alkyl and C, to C _fi haloalkyl, the group -NR 7R8 wherein R7 and R are independently chosen from the group consisting of hydrogen, C. to C, alkyl, phenyl and benzyl or R 7 and R8 heterocyclic ring, and the group R9 is a C. to

C. _n alkylidene group; Z is chosen from the group consisting of halogen, hydroxy, mercapto, C. to C, _Q alkoxy, C- to C- ₀ haloalkoxy, C. to C- _n alkylthio and the group -NR R wherein R and R are as hereinbefore defined.

0 II

Preferred R is cyano, the group -C-G wherein

G is selected from hydrogen, hydroxy, C. to C _fi alkyl, C. to C , alkoxy and the group CH ₂ Z wherein Z is hydroxy, chloro or C, to C _fi alkoxy.

0 II Particularly preferred R are the group -C-G where G is hydroxy or C. to C _β alkoxy (e.g. methoxy) . Specific examples of compounds of formula

I which may be prepared according to the present invention include the following:

0 / \

Ar - HC - CH - R

AR

0 //

(a) p-CH-OPh- -C0CH ₃

(b) p-CH-CH-OPh -CN

0

//

(c . p-CH ₃ Ph- -CH

0

(d) Ph- -C-OH

) p-CH-OPh- 0CH Ph

(Ph is phenyl J

Preferably the diol of formula III is reacted with the sulfonyl compound of formula IV in the presence of a suitable solvent. Examples of suitable solvents may include aromatic hydrocarbons aliphatic hydrocarbons, alcohols, ketones, esters and heteroaromatic compounds such as pyridine. Typically the sulfonyloxy group will be eliminated from the compound of formula V in the presence of a base catalyst and a solvent which is preferably a polar aprotic solvent such as THF, DMF or DMSO. Examples of suitable bases include sodium hydride and potasεium-t-butoxide. The process of the invention may be carried out at a range of temperatures, for example, a temperature in the range of from -10 to 150 . It is preferred that the sulfonation stage is carried out at a temperature in the range -10 to 40 C. Conveniently the sulfonyloxy group elimination from the compound V is carried out at a temperature of from -10 to 60 C. It is preferred that the composition of the diol of formula III is enriched in a one enantiomer and typically will comprise a high proportion, for example at least 80% (more preferably at least 90% w/w), of one enantiomer. Typically, by using such a composition the epoxide product will comprise at least 80% (preferably at least 90%) of one isomer.

Accordingly the invention further provides a composition comprising an epoxide of formula I wherein at least 80% (and preferably at least 90%) of said epoxide is in the form of one isomer.

For preparation of Diltiazem it is preferred to proceed via the cis-epoxide and to prepare the cis-epoxide it is preferred that the diol of formula I is enriched in the 2S, 3R enantiomer.

The enantiomerically enriched diol may be prepared by a variety of methods including classical resolution techniques however, as described in our copending International Patent Application No.PCT/AU88/00345 it is advantageous in most cases to prepare the diol in an enantioselective manner from the alkene of formula VII

Ar CH = CHR VII

In a further embodiment we provide a compound of formula V as hereinbefore defined. Preferably the composition of the compound of formula V will comprise at least 80% w/w and preferably at least

90% w/w of one enantiomer.

An enantiomerically enriched composition of the epoxide of formula I may be used in enantioselective preparation of the key intermediate to benzothiazepine compounds which intermediate has the formula VIII

OH Ar CH - CHR

wherein:

Y is oxygen or sulfur and G is chosen from nitro, C. to C _g alkyl, amino, C. to Cg alkyla ino, N,N-di(C. to C _g alkyl)amino, and N-(C.. to C _g alkyl)amino-substituted (C. to C _g alkylamino such as 2-diethylaminoethylamino. The compound of formula VIII may be prepared by reaction of the epoxide of formula I with a phenol/thiophenol of formula IX

preferably in the presence of a base. Generally the reaction is carried out in non-aqueous solution with a mild base such as sodium bicarbonate which is conveniently present in catalytic amounts. The invention will now be described by but is in no way limited to the following examples.

Example A

Preparation of 2,4,6 trichlorobenzenesulphonyl chloride Chlorosulphonic acid (20 ml) was added to

1,3,5-trichlorobenzene (10 g) via a dropping funnel over 15 min. with stirring at room temperature. The reaction mixture was then heated (oil bath) at 110°C for 2h. The resulting dark mixture was cooled to room temperature , poured into ice water (150 ml), the crude product collected by filtration and washed thoroughly with cold water (500 ml) giving beige coloured crystals (12.0 g, 80%). The crude was recrystallised from hexane resulting in pure sulphonyl chloride m.p. 47-49°C (lit ref. 90°C) . Ref: Farrer, W.V., J. Chem. Soc I960, 3063.

Example 1

(a) Preparation of methyl-2(S)-(2' .4' ,6 ' - trichlorobenzenesulphonyloxy)-3(R)-hydroxy -3-(4 '-methoxyphenyl)propionate

To a solution of (2S, 3R)-methyl 2,3-dihydroxy-3-(4-methoxyphenyl)propionate (0.2 g , 0.88 mol) in pyridine (2 ml) was added 2,4,6-trichlorobenzene sulphonyl

_T U _T TSHECT

chloride (0.27 g, 0.97 m ol), and the combined mixture was kept at 0-4°C for 18 h.

The resulting pale yellow solution was then poured into water (20 ml), extracted with ethyl acetate (3 x 20 ml) washed with 10% HCl

(20 ml ), water (20 ml) and finally dried

(Na2-SO4. ). The solvent was removed invacuo leaving a white solid residue (0.39. g, 96%) which analysed correctly for a C- monosubstituted sulphonate ester, m.p; 127-129°C (ethanol).

, Preparation of methyl (2R,3R) cis-3-(4- ethoxyphenyl)glycidate

To a solution of sulfonate ester of step (a) (0.30 g, 0.65 mmol) in THF (4 ml) was added

NaH (0.017 g, 1.1 mol equivalents), and the mixture was left to stir for 5 h. After this time TLC indicated completion of reaction. The reaction mixture was then poured into water (20 ml) and extracted with ethyl acetate (3 x 20 ml) washed with water (2 x 20 ml) and finally dried (Na ₂ SO.). The solvent was removed in vacuo giving a pale yellow oil (0.130 g, 97%). The oil was not purified further as it analysed correctly for the cis isomer of -3-(4-methoxyphenyl) glycidate.

Ref: Hashiyama, T., Inoue, H., et.al,

J. Chem.Soc. Perkin Trans.1, 1725, (1984).

(c) Addition of 2-nitrothiophenol to the cis σlvcidate

To a mixture of 2-nitrothiophenol (0.079 g, 0.52 mmol) and NaHCO-. (15 g - 20 mg) in dry 5 ethanol (5 ml) was added the cis glycidate prepared in step (b) CO.10 g 0.48 mmol). The reaction mixture was stirred at room temperature overnight. The resulting yellow suspension was then poured into water (20 0 ml), extracted with ethyl acetate (3 x 20 ml), washed with sat. NaHCO-. (20 ml) water (20 ml), brine (20 ml) and finally dried (NaHCO-). The solvent was removed in vacuo giving a yellow oil (0.15 g) . The crude was 5 purified by flash column chromatography (eluant CH-Cl-s ^Et 2° 20:1). Evaporation of the second eluant gave a yellow oil (0.10 g, 60%) which analysed correctly for 2R, 3S methyl-2-hydroxy-3- (2-nitrophenylthio)-3- (4-methoxyphenyl) propionate (threo thioether) Ref

Ref. Hashiyama T., Inoue, H. , et.al,

J. Chem Soc. Perkin Trans. 1, 1725, (1984).

A small portion of this yellow oil was 5 acetylated by heating with acetic anhydride and pyridine for 1.5 h on a water bath.

Excess anhydride, acetic acid and pyridine were removed under reduced pressure.

Analysis of the resulting oil by H n.m.r. 0 spectroscopy indicated a single isomer with the methyl signal for the OCOCH, group appearing at 2.10 ppm. This is correct for the threo isomer Ref

Ref. Hashiyama T., Inoue, H. , et.al, 5 J. Chem Soc. Perkin Trans. 1, 1725, (1984).