CS271143B1 - Method of optically pure erythro-(-)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl)propanoic acid production - Google Patents

Abstract

Erythro -(-)-3-(2-aminophenylthio) -2-hydroxy-3-(4-methoxyphenyl)propane acid is known and is an undesirable stereoisomer produced during the synthesis of diltiazem. It is used during the splitting of basic chiral substances. The merit of the solution concerns the fact that the raw abovementioned acid undergoes final treatment over its salt with (-)-ephedrine and is prepared by mixing of the raw acid with (-)-ephedrine in the medium of alcohol with 1 to 3 carbon atoms and crystallization of the product at the temperature of +6 to +40 degrees C.

Description

(57) Erythro - (-) - 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propanoic acid is known and is an undesirable stereoisomer resulting from the synthesis of diltiazem. It finds use in cleavage of chiral substances of basic nature. SUMMARY OF THE INVENTION The crude acid of the above-mentioned acid is purified via its β (-) - ephedrine salt prepared by mixing the crude acid with (-) - ephedrine in a C 1 -C 3 alcohol medium and crystallizing the product at + 6 to +40 OC.

CS 271143 Bl

The invention relates to a process for the preparation of optically pure erythro - (-) - 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propanoic acid of the formula

The acid of formula (I) is known and is an undesired stereoisomer, resulting in the synthesis of the diastereomer. It is used in the cleavage of chiral substances of basic nature.

The optically pure acid of the above formula is produced by resolution of racemic acid with basic resolving agents such as brucline (Helv. Chim. Acta 67, 916 (1984)); (-) - p-tolyl ethylamine (Japan kokai pat. 60243062); 1,2-diphenylethylamine (Japan Coca. Pat. 6169756); 1-phenylethylamine (Japan Kokai Pat. 57136581) or 1-naphthylethylamine (Japan Kokai Pat. 6133164). A common disadvantage of all processes is the necessity of using expensive resolving agents, which usually has to be produced first. Racemic acid resolution of the above formula can also be achieved by complexation with chiral macrocyclic polyethers (Japan Kokai Pat. 59144750, 59144751, 59110668). The process is not preferred because the chiral polyethers used are expensive and the implementation of the processes is in some cases expensive.

These disadvantages are overcome by the process according to the invention which is characterized in that the partially optically active crude acid of the above formula is crystallized with (-) - ephedrine in an amount of 1 equivalent in methanol, ethanol or 2-propanol over a temperature range of 4 *. 6 to +40 ° C and the obtained salt is further processed. Optionally, the optically active salt can also be prepared in the presence of up to 50 parts by volume of water or an inert organic solvent, for example acetone or ethyl acetate.

The process according to the invention utilizes a waste product which is optically and chemically purified by means of readily available (-) - ephedrine.

The process according to the invention is carried out by first liberating from (-) - ephedrine hydrochloride its base with an alkali metal hydroxide in an aqueous medium, which is extracted into an organic solvent which is recovered by distillation. Methanol, ethanol or 2-propanol, or mixtures thereof with 0 to 50 parts by volume of water or an inert organic solvent, for example acetone or ethyl acetate and the crude acid of the formula I, are added to the (-) - ephedrine residue, heated briefly to boiling and after filtration with activated carbon it is allowed to crystallize at a temperature of +6 to +40 ° C. The precipitated salt of (-) - ephedrine in the acid of formula I is separated and dissolved in dilute hydrochloric acid. The pH of the solution thus obtained is adjusted to 3.7 with an alkali metal hydroxide and the precipitated acid is filtered off, washed with water and dried. (-) - Ephedrine hydrochloride can be regenerated from the mother liquors.

The process of the present invention can be used to prepare erythro - (-) - 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propanoic acid useful, for example, as the racemic ephedrine optical resolution reagent of U.S. Pat. No. 271144.

CS 271143 Bl

The following examples illustrate but do not limit the method according to the invention.

Example 1

6.32 g of (-) - ephedrine hydrochloride are dissolved in distilled water with stirring, the ephedrine base is released with aqueous sodium hydroxide solution, extracted into chloroform and the solvent is distilled off under reduced pressure.

To the residue of (-) - ephedrine base are added 100 to 150 ml of ethanol and 10.0 g of crude erythro - (-) - 10 [.alpha.] D @ + = 370 to -410 DEG (c = 0.5; methanol). The mixture is heated briefly to boiling and filtered after brief stirring with 0.5 g of activated carbon. The clear solution was allowed to cool to 20 ° C and crystallized at this temperature for 15-20 hours. The precipitated (-) - ephedrine salt of erythro - (-) - I is filtered off, washed well with ethanol and dried. 12 to 13 * 5 g of product are obtained, which is dissolved in dilute hydrochloric acid with stirring. After alkalization with aqueous sodium hydroxide solution to pH 3 * 7, the precipitated pure erythro - (-) - 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propanoic acid is filtered off and washed well with distilled water. This is obtained

7.5-8.5 g of product, [.alpha.] D @ 54 = -454 DEG (c · 0.5; methanol).

Example 2

According to Example 1, erythro - (-) * 10 acid of / 546 ^and -451 ° (»0.5; methanol) was prepared except that crystallization of the optically active salt was performed in methanol at 40 ° C.

Example 3

According to Example 1, erythro - (-) - I? A? 546? -448 ° (c · 0.5; methanol) was prepared except that crystallization of the optically active salt was carried out in 2-propanol at +6. Deň: 32 ° C.

Example 4

According to Example 1, erythro - (-) - I Z Z / / 546 44 445 ° (c 0,5 0.5; methanol) was prepared except that crystallization of the optically active salt was carried out in methanol with 50 parts by volume of acetone with temperature +15 ° C.

Example 5

According to Example 1, erythro- (-) - X o ([.alpha.] D @ 20 = + 453 DEG (c 0.5, methanol) was prepared except that crystallization of the optically active salt was carried out in 20 volumes of ethanol. ethyl acetate at + 20 ° C.

Example 6

According to Example 1, erythro - (-) - I A of / 546 · 450 ° (c 0,5 0.5; methanol) was prepared except that the crystallization of the optically active salt was carried out in ethanol with 5 volumes of water at temperature +20 ° C.

Claims (2)

SUBJECT OF THE INVENTION 1 · Process for preparing optically pure erythro - (-) - 3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propanoic acid, characterized in that the partially optically active crude acid is crystallized with (-) - Ephedrine at 1 equivalent in methanol, ethanol or 2-propanol at temperatures of +6 to 4-40 ° C · 2 · The process according to claim 1, wherein the crystallization is carried out optionally in the presence of up to 50 parts by volume of water or an inert organic solvent, for example acetone or ethyl acetate.