WO1994013828A1

WO1994013828A1 - Chiral arylpropionates and their use

Info

Publication number: WO1994013828A1
Application number: PCT/GB1993/002530
Authority: WO
Inventors: Raymond Mccague; Shouming Wang; Stephen John Clifford Taylor
Original assignee: Chiroscience Limited
Priority date: 1992-12-10
Filing date: 1993-12-10
Publication date: 1994-06-23
Also published as: AU5656994A

Abstract

Compounds having the formula: Ar-CHOR1-CHHal-COOR2 are useful as chiral synthons, for example in the synthesis of the anti-hypertensive agent diltiazem, and related calcium channel blocking agents. The synthons can be prepared in enantiomerically-purified form without wastage of the unwanted enantiomer.

Description

CHIRAL ARYLPROPIONATES AND THEIR USE

Field of the Invention

The present invention relates to compounds that are useful as chiral synthons, in particular in the synthesis of the anti-hypertensive agent diltiazem, and processes for making those synthons. Background of the Invention

Diltiazem is the compound of formula (I) , below. It is a calcium-channel blocking agent used for the treatment of hypertension. For this purpose, the compound is desirably in the form of a single enantiomer.

Diltiazem can be prepared from the intermediate (II) via the thiazepinone(VII; Ar = p-MeoPh) . Intermediate (II) can be made by reaction of o-aminobenzenethiol with the corresponding epoxide (V; see Scheme 1) . While the intermediate (II) can be resolved, such as by forming the R-α-methylbenzylamine salt, e.g. as described in EP-A- 0381570, such an approach suffers from the unwanted enantiomer, i.e. that is not a precursor of diltiazem, being unusable, thereby creating waste and requiring twice the amount of materials than is theoretically possible.

A better approach is to effect resolution of the epoxide intermediate (V) . This has been done, for example, classically on a potassium salt of the intermediate, when R = K, e.g. as described in JP-A-61145160. It has also been done enzymically on an ester of the intermediate, e.g. as described in EP-A-0343714. Either technique results in full utilisation of the o-aminobenzenethiol to form the desired enantiomer, thereby increasing process cost- effectiveness. However, again there is the problem of inutility of the unwanted enantiomer of the epoxide. In the case of the enzymic resolution, the unwanted enantiomer degrades to an aldehyde that is worthless, e.g. as described in WO-A-9004643. An alternative approach, which theoretically may be better still, is to effect an asymmetric synthesis of the epoxide, i.e. so that the unwanted enantiomer does not form. This has been done by employing a chiral auxiliary in the Darzens condensation used to form the epoxide (glycidate) intermediate, e.g. as described by A. Schwartz et al, J. Org. Chem. (1992) 57:851-6. However, here the process economy is determined by the efficiency of the synthesis and recovery of the auxiliary.

It would therefore be desirable to provide a process for preparing enantiomerically-pure intermediates of diltiazem, and also related calcium channel-blocking agents, that does not have the problems described above. Summary of the Invention

According to a first aspect of the present invention, a process for preparing an enantiomer of a compound having the formula III (see Scheme 1) , wherein R is H or acyl, R is H or an esterifying group, Ar is aryl and Hal is a halogen atom, in an excess of at least 50% with respect to the other enantiomer, comprises biotransformation of the corresponding racemate with a material having stereoselective esterase activity. The process provides a simple and efficient resolution technique, and allows the other, unwanted, enantiomer to be converted into a usable form, thereby reducing waste.

According to a second aspect of the present invention, a process for preparing a thiazepinone of formula (VII) in enantio eric form, comprises dehydrohalogenation of the corresponding enantiomer, described above, by reaction with alkoxide to form the epoxide, with subsequent addition of o-aminobenzenethiol and subsequent acid cyclisation, and proceeds without isolation of the intermediates from the enantiomer to the thiazepinone being necessary.

According to a third aspect of the present invention, a novel enantiomer (III) has Hal=Br. Description of the Invention

R can be H or acyl, and in some instances is preferably acyl for reasons described below. Suitable acyl groups include optionally-substituted (C_1-6 alkyl)carbonyl groups. R can be H or an esterifying group, suitable examples of which include optionally-substituted C₁.₆ alkyl groups.

Ar represents an aryl group, including heterocyclic aryl, e.g. optionally-substituted phenyl. The nature of Ar is not critical to the invention, but will be chosen according to the desired final product. For use in preparing diltiazem the most preferred aryl group is 4- methoxypheny1.

Hal represents a halogen atom, which with regard to the process economy is preferably chlorine or bromine, and is more preferably bromine, for reasons outlined below.

Scheme 1, below, outlines the processes of the invention and indicates how enantiomers of the invention may be prepared and used. In the first illustrated step, the starting material, a cinnamic acid ester, is reacted with halohydrin-forming reagents, e.g. N-bromosuccinimide for a bromohydrin, to give a halohydrin of formula (III) (R¹ = H) .

If desired, a halohydrin of formula (III) (R •= H) can be converted to the corresponding halohydrin ester (III: R = acyl) by acylation. Known procedures may be used.

The racemate (III) is then subjected to a biotransformation with a material having stereoselective esterase activity. Such a material is chosen so as to react with a single enantiomer only and in so doing convert it to a species that is separable from the unreacted enantiomer by a technique such as solvent partitioning. The biotransformation can be a hydrolysis reaction (as shown in Scheme 1) or an esterification reaction, depending upon the esterase and/or the reaction conditions chosen.

When R is acyl, it is generally that group that undergoes the hydrolytic biotransformation shown in Scheme

1. When R 1 is hydrogen, i.t is the ester group R2 that undergoes hydrolytic biotransformation. It is essential that R is not hydrogen in the substrate (III) , for hydrolytic biotransformation, since the reaction would not provide separable species. An esterification reaction, however, would provide such separable species.

When the biotransformation is a hydrolysis reaction, a process in which R is H as opposed to acyl is less preferred since although in principle the carboxylic acid that is then formed (R = H) can be recycled back to the race ate (III) , in practice this is difficult because of the instability of the carboxylic acid under the conditions preferred for the biotransformation. When the process proceeds via a bro ohydrin, that bro ohydrin, and therefore any subsequent ester thereof, is formed as a single diastereoisomer which can be resolved by biotransformation relatively easily to give an enantiomer having the correct configuration at C-2 for it to be a precursor of diltiazem. The formation of a single diastereisomer is likely to be due to the favoured bromonium ion intermediate which is described by, for example, Wilson and Woodgate, J. Chem. Soc. Perkin Trans. II (1976), 141-7. When the process proceeds via a chlorohydrin, however, a mixture of diastereoisomers is formed, which makes resolution by biotransformation more complex. As mentioned above, it is the configuration at C-2 in the biotransformation product that is important in the preparation of diltiazem. If the biotransformation is carried out on the terminal ester or acid group of the chlorohydrin compound, i.e. of which R is a part, satisfactory separation of enantio ers having different C-2 configurations can be achieved. The biocatalyst that carries out the biotransformation can be an enzyme such as a lipase, for example Mucor mieheii or Candida cylindracea lipase, or it can be a microorganism such as a bacterium, fungus or yeast that has the appropriate esterase activity. Biocatalysts that can act on either one of the enantiomers (III) can be simply selected by the skilled man. Following the biotrans ormation, the desired enantiomer, e.g. of [2(S),3(S)] stereochemistry as a diltiazem precursor, is recovered and is cyclised using alkoxide to the epoxide (V) which can then opened with o- aminobenzenethiol in a known procedure. Acid cyclisation gives the thiazepinone intermediate (VII) of correct configuration at its chiral centres for preparing diltiazem. These reactions can advantageously be carried out without isolation of any of the intermediates from the resolved halohydrin and the thiazepinone.

An acylation reaction can be carried out on the thiazepinone through its hydroxyl function, depending on the desired final product. Known procedures can be used. It is possible to carry out the acylation reaction immediately after the acid cyclisation described above, without isolation of the thiazepinone.

The unwanted enantiomer from the biotransformation can be cyclised to its corresponding epoxide, which is then inverted by acidic hydrolysis to the diol, followed by regioselective tosylation at C-2, as described by Rama Rao et aJ , J. Chem. Soc. Chem/Commun. (1992), 859-860, and then elimination using alkoxide to give epoxide (V) . The procedure may give a mixture of epi ers at C-3, but this does not affect the stereochemistry in any subsequently formed thiazepinone and/or diltiazem, as this is determined only by the configuration at C-2.

The following Examples illustrate the invention. Example 1 - Bromohydrin Diester Formation

Methyl 2-bromo-3-hydroxy-3- (4-methoxyphenyl) - propionate (33 g, 0.114 mol) , prepared in a similar manner to that described in Example 3, in diethyl ether (300 ml) , was cooled on ice with stirring. To this were added butyric anhydride (18.6 ml, 0.114 mol), triethylamine (16 ml, 0.114 mol) and 4-dimethylaminopyridine (1 g, 8 mol) , allowing the mixture to warm to room temperature. After stirring for 40 min. , the mixture was washed with water (4 x 350 rl ) , then the ether layers were dried over anhydrous magnesium sulphate and concentrated to give a pale yellow oil (34 g, 80% yield) of the butyrate ester. Example 2 - Biotransformation

The bromohydrin diester of Example 1 (30 g, 0.08 mol) was dissolved in toluene (200 ml) and 0.1M pH 7 Tris buffer (500 ml) . Candida cylindracea lipase (A ano MY; 6 g) was added. The mixture was stirred and maintained at pH 7 by addition of 1M NaOH, of which 40 ml (0.04 mol) had been added after 23 hours. Conversion was calculated at 25% from enantio eric excess (ee) measurements (see below) .

Stirring was discontinued, and the layers allowed to separate. The aqueous layer was discarded. The toluene layer was treated with Celite (registered Trade Mark) (20 g) and filtered. The filtrate consisted of two phases. The toluene layer was dried with magnesium sulphate and concentrated to give an oil which was partitioned between the phases of a mixture of cyclohexane (200 ml) , acetonitrile (200 ml), water (400 ml) and methanol (100 ml) . The lower phase was extracted with cyclohexane (4 x 200 ml) . The combined upper phases were dried with magnesium sulphate and concentrated to yield unconsumed diester (24 g) of enantiomeric excess 30%. The lower phase was extracted with ethyl acetate (200 ml) and the extract dried over magnesium sulphate and concentrated to give methyl [2S, 3S]-2-bromo-3-hydroxy-3- (4-methoxyphenyl) - propionate (6.1 g, 26% yield) of 94% ee. H NMR was consistent with the required structure. Enantiomeric Excess Determinations

The ee of the substrate diester was determined by HPLC (Daicel Chiracel-OJ column, 25 cm x 4 mm, eluent 10% 2- propanol in n-heptane, 1 ml/min, 254 n , retention times 16.7 and 19.7 in.). The ee of the product was determined by derivatisation to the epoxide, by reaction of a sample in methanol with 10% sodium methoxide. The mixture was neutralised by addition of silica, then assayed by HPLC (Chiracel-OD column, 25 cm x 4 mm, eluent 20% 2-propanol in n-heptane, 1 ml/min, 254 nm detection, retention times 11 and 14 min. ) .

Example 3 - Bromohydrin Formation

To a solution of ethyl p-methoxycinnamate (22.1 g, 0.11 mol) in acetone (225 ml) and water (60 ml) , N- bromosuccinimide (21.0 g, 0.12 mol) was added portionwise. The mixture was then stirred overnight (15 h) , followed by relux for a further 5 h. The solvent was removed under vacuum and the residue extracted with dichloro ethane. The organic phase was washed with brine, dried over anhydrous sodium sulphate and concentrated to give ethyl 2-bromo-3- hydroxy-3- (4-methoxyphenyl) propionate (32.4 g, 100%) as essentially a single diastereoiso er [2R , 3R ] . Example 4 - Preparation of Thiazepinone (VII) The product mixture from the biotransformation of ethyl [2R , 3R ] -2-bromo-3-hydroxy-3-(4-methoxyphenyl) - propionate (118 g) , prepared as described in Example 3, was separated into two layers. The toluene phase was filtered through Celite (registered Trade Mark) and dried over anhydrous magnesium sulphate, and then concentrated under vacuum to yield optically-active bromohydrin (76 g) . This was dissolved in methanol (950 ml) , cooled in ice and sodium methoxide (13.8 g) was added. After stirring the mixture for 20 min, the solution was neutralised with 1 M potassium dihydrogen phosphate, then the methanol was removed by evaporation in vacuo. The aqueous solution was then extracted with an equal volume of dichloromethane and the organic phase was dried over anhydrous magnesium sulphate and concentrated to yield 52 g crude epoxide as a yellow oil. This epoxide was heated to reflux in a solution of o-aminobenzenethiol (26 ml) in xylene (500 ml) and reflux was maintained for 4-^ h. After cooling, methanesulphonic acid (3.5 ml) was added, and the solution was then heated at reflux for a further 3 h. After cooling, crystallisation occured and the product benzothiazepinone (VII: Ar = 4-methoxyphenyl) was isolated by crystallisation, as a pale yellow solid (14 g, 61% ee as determined by HPLC on a Chiracel-OD column eluting with 20% isopropanol in heptane, flow 1 ml/ in, detection 254 nm) . Crystallisation of this product from ethyl acetate increased the enantiomeric excess to 96.6% ee (5 g) .

20

(ID

25

30

(VII) Scheme 1

Claims

1. A process for preparing an enantiomer of a compound having the formula

Ar-CHOR¹-CHHa1-COOR² wherein R is H or acyl, R is H or an esterifying group, Ar is aryl and Hal is a halogen atom, in an excess of at least 50% with respect to the other enantiomer, the process comprising biotransformation of the corresponding racemate with a material having stereoselective esterase activity.

2. A process according to claim 1, wherein Ar is 4-methoxypheny1.

3. A process according to claim 1 or claim 2, wherein R is H.

4. A process according to claim 3, wherein R is an esterifying group such as optionally substituted C ₆ alkyl.

5. A process according to any of the preceding claims, wherein the enantiomer has the formula

6. A process according to any of the preceding claims, wherein Hal is Br.

7. A mixture of an enantiomer having the formula defined in claim 4 with an opposite corresponding enantiomer in which R is H, each enantiomer being in an excess of at least 50% with respect to its other enantiomer.

8. A mixture of opposite enantiomers each having the formula defined in claim 1 or claim 2, wherein R is H in one enantiomer and acyl in the opposite enantiomer, and R is the same in each, and each enantiomer is in an excess of at least 50% with respect to its other enantiomer.

9. A mixture of opposite enantiomers each having the formula defined in claim 1 or claim 2, wherein R is H in one enantiomer and an esterifying group in the opposite enantiomer, and R is the same in each, and each enantiomer is in an excess of at least 50% with respect to its other enantiomer.

10. A process for preparing a thiazepinone of the formula

in enantiomeric form, which comprises subjecting an enantiomer having the formula defined in any of claims 1 to 6 and that is in an excess of at least 50% with respect to the other enantiomer, to dehydrohalogenation by reaction with alkoxide, reacting the resultant epoxide with o- aminobenzenethiol, and subjecting the product thereof to acid-catalysed cyclisation, wherein no intermediates from the enantiomer to the thiazepinone are isolated.

11. Use of an enantiomer having the formula defined in claim 5 or claim 6 as appendant on claim 5, and that is in an excess of at least 50% with respect to the other enantiomer, for the preparation of diltiazem.

12. An enantiomer having the formula defined in claim 6, in an excess of at least 50% with respect to the other enantiomer.