CS265417B1 - Method for Cleavage of (±) -threo-2-hydroxy-3- (2'-aminophenylthio) -3- (4'-methoxyphenyl) -propanoic Acid to Optical Antipodes - Google Patents

Abstract

The racemic mixture of the acid of formula I is treated with (-)-ephedrine in a solution of aqueous ethanol with a concentration of 90-100% by weight at a temperature of 60 to 80 °C. After cooling to a temperature of 0 to 5 °C, crystals of the salt of one of the antipodes are precipitated, from which the (-)-enantiomer of the acid of formula I is released in an aqueous medium at 70 to 85 °C by the action of hydrochloric acid. From the mother liquor, after evaporation of the ethanol in an aqueous medium at 70 to 85 °C, crystals of the second (+)-enantiomer of the acid of formula I are precipitated by the action of hydrochloric acid. The dextrorotatory (2S,3S)- -enantiomer of the acid of formula I is an important intermediate in the synthesis of the drug with vasodilating effects of (+)-cis-dilthiazem of formula II.

Description

The invention relates to the resolution of (±) -threo-2-hydroxy-3- (2'-aminophenylthio) -3- (4'-methoxyphenyl) propanoic acid into optical antipodes. The dextrorotatory (2S, 3S) -enantiomer is an important intermediate in the synthesis of a drug with the vasodilating effects of (+) - cis-diltiazem of formula II.

A number of methods are described in the patent literature for the resolution of the racemic acid of formula I into the desired (2S, 3S) - (+) - enantiomer: (+) - alpha-phenylethylamine (AT Pat. 380,015 (1986); CA 106,

134 g) (Japan Kokai Pat. 57 136 581 (1982); CA 98, 89 404 (d), +) - alpha-p-tolylethylamine (Japan Kokai Pat. 60 243 062 (1985); CA 104, 168 151 q) ), (+) - (2 ^1-naphthyl) ethylamine (Japan Kokai Pat. 61,207,371 / 1986 /; CA 106, 119456), (-) - 1-amino-l, 2-diphenylethane (Japan Kokai Pat. 61 69 756 (1986); CA 105, 133 524 g), cinchonidine (Helv. Chim. Acta 67, 916 (1984)),

L-lysine (DOS 3,337,176 (1984); CA 101,110,549).

Several patents disclose separation of both acid antipodes by chromatography on a helical support (Japan Kokai Pat. 59,110,668 (1984); CA 101,191,353), (Japan Kokai Pat. 59,144,751 (1984);

CA 102, 61,943).

Recently, there have been several patents cleaving trans-2,3-epoxy-3- (4'-methoxyphenyl) propanoic acid, from which the hydroxy acid of formula I is readily accessible (Japan Kokai pat 60 13 775 (1985); CA 103, 71 180), (Japan Kokai Pat. 61,145,173 (1986); CA 106,332,811). A disadvantage of all these processes is the poor availability of amines suitable for cleavage.

This disadvantage is overcome by the process of resolution of racemic acid (±) -threo-2-hydroxy-3- (2'-aminophenylthio) -3- (4'-methoxyphenyl) propanoic acid according to the invention, which consists in with (-) - ephedrine in a solution of 90-100% by weight aqueous ethanol. at 60 to 80 ° C, after cooling to 0 to 5 ° C, salt crystals of one of the antipodes are precipitated from which the (-) - enantiomer of the acid of formula I is released in an aqueous medium at 70 to 85 ° C by treatment with hydrochloric acid, from the mother liquor, after evaporation of the ethanol in an aqueous medium at 70 to 85 ° C by hydrochloric acid, the crystals of the second (+) - enantiomer of the acid of formula (I) are separated due to the considerably different solubility of the two diastereoisomeric salts (-) and They can be easily separated by crystallization. Both salts yield the optically pure (+) and (-) - enantiomers of acid X after treatment with hydrochloric acid and subsequent crystallization.

The novelty of the invention is that it utilizes the available and readily regenerable (-) - ephedrine in comparison to the prior art methods of resolving the acid of formula I into optical antipodes and makes it possible to obtain both enantiomers of the acid of formula I in optically pure form.

The cleavage process is further illustrated in the exemplary embodiment.

Example

At 70 ° C, 3.2 g (10 mmol) of acid I and 1.65 g (10 mmol) of (-) - ephedrine were dissolved in 150 ml of ethanol. After standing at 0-5 ° C for 48 hours, the precipitated crystals (2.2 g) were aspirated and recrystallized three times from ethanol. Mp 122-122.5 ° C, α-β-310 ° (c 0.4, 50% aqueous methanol). The crystals were suspended in 50 ml of water 80 ° C warm and 1 ml of 5.2 N hydrochloric acid was added in several portions with vigorous stirring. After cooling, the crystals were aspirated. A total of 1.2 g of the (-) enantiomer of the acid of formula I was obtained at mp 133-135 ° C, α D ⁰ -317.2 ° (c 0.35, ethanol) (optical purity was 91.7%). After recrystallization from aqueous ethanol bylo.získáno 1.0 g crystals, mp 138-139 ° C, ^alpha-9 -343.2 ° (c 0.355, EtOH) (optical purity 99.2%). The mother liquor after sucking off the salt was evaporated to dryness, poured over 70 ml of water at 80 ° C warm and, with vigorous stirring, gradually acidified with 5.2 N hydrochloric acid (pH 4.0). The precipitated crystals (1.6 g) of the (+) - enantiomer of the acid of formula (I) melted at 127 DEG-130 DEG C., [.alpha.] D @ ²⁰ + 241.2 DEG (c 0.355, ethanol) (optical purity 69.7%). Repeated crystallization from aqueous ethanol yielded 0.85 g of white crystals, mp 135-136 ° C, α D 20 + 320.4 ° (optical purity 92.6%).

Claims (1)

Method for resolution of racemic (R) -threo-2-hydroxy-3- (2'-aminophenylthio) -3- (4'-methoxyphenyl) -propanoic acid of formula 1 to optical antipodes characterized in that the racemate is treated with (-) > -ephedrine in a solution of aqueous ethanol at a concentration of 90-100% by weight, at a temperature of 60 to 80 ° C, after cooling to a temperature of 0 to 5 ° C, salt crystals of one of the antipodes are precipitated from which 85 DEG C. by treatment with hydrochloric acid liberates the (-) enantiomer of the acid of formula X, crystals of the second (+) - enantiomer of the acid of formula I precipitate from the mother liquor after evaporation of the ethanol in an aqueous medium at 70 to 85 DEG C.