CS274214B1 - Method of /2s,3s/-3-hydroxy-2-/4-methoxyphenyl/-2,3-dihydro-1, 5-benzothiazepine-4/5h/-on production - Google Patents

Abstract

The solution concerns a method of production of (2S, 3S)-3-hydroxy-2-(4-methoxyphenyl)-2,3-dihydro-1,5-benzothiazepamine-4(5H)-one of formula I, an intermediate product of an important cardiovascular pharmaceutical diltiazem, which has an antihypertensive effect and acts as calcium antagonist. The complicated production method is simplified by using, as initial material, lysine salt of (2S, 3S)-3-(2-aminophenylthio)-2-hydroxy-3-(4-methoxyphenyl) propionic acid of formula II, obtained by optical resolution of racemic acid in the form of centrifuged and non-dried cake. All the L-lysine is returned back to the technological process.

Description

The present invention relates to a process for the preparation of (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one of formula I

The compound of formula I is an intermediate of an important cardiovascular drug diltiazem, which acts as an antihypertensive agent and as a calcium antagonist.

The compound of formula I is prepared according to known procedures by intramolecular cyclization of (2S, 3S) -3- (2-amino-phenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid III

boiling in xylene. Cyclization in xylene gives rise to colored ballast substances which must be removed from the product by purification at the expense of yield not exceeding 65% of theory. A relatively low yield is undesirable, in particular because an optically pure material is used in this step.

The compound of formula III is prepared by optical resolution of racemic (-) - threo-2-hydroxy-3- (2-aminophenylthio) -3- (4-methoxyphenyl) propionic acid. Optical resolution is effected by the action of a suitable optically active base such as R (+) - 1-phenylethylamine, (-) - 1-ephedrine or L-lysine. In all cases, the optically active bases form salts with both racemic acid antipodes, which are separated by different solubilities in the solvent used. The compound of formula III is obtained from the corresponding salt by the action of hydrochloric acid. The resulting hydrochloride of the optically active base passes to the waste water. Elution of the optically active base hydrochloride from the filter cake of compound III is time consuming and requires a disproportionately large amount of deionized water. Isolation of optically active base from waste water is laborious and demanding for other technological operations.

The above disadvantages are overcome by the process for the preparation of (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one according to the invention, characterized in that (2S, 3S) -3- (2-aminophenylthio) 2-hydroxy-3- (4-methoxyphenyl) propionic acid salt with L-lysine is reacted in a mixture of water and an organic solvent, for example toluene or xylene, suitably toluene in the presence of a mineral acid Suitably hydrochloric acid for 5 to 20 hours, during the reaction water is azeotropically distilled off from the reaction mixture, after completion of the reaction, the crystalline mass is separated and (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2, The 3-dihydro-1,5-benzothiazepin-4 (5H) -one is separated from L-lysine hydrochloride by extraction into an organic solvent such as chloroform or dichloromethane or 1,2-dichloroethane or acetone and is isolated as a crystalline solid from this solvent. . The amount of water and toluene or xylene for the reaction of the (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid lysine salt is 0.5 to 3 ml, preferably 1 to 2 ml. water per g of lysine salt and 1 to 6 ml, preferably 3 ml of toluene or xylene per g of lysine salt. The amount of hydrochloric acid is determined by the pH of the aqueous phase which is 2.5 to 5, preferably 3.4 to 3.5.

To separate (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepine-4- (5H) EN 274 214 B1

10 to 25 ml, preferably 16 to 18 ml, of an organic solvent, for example chloroform or dichloromethane or 1,2-dichloroethane or acetone, is used for the L-lysine hydrochloride.

An advantage of the process of producing (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one according to the invention is that it removes operations (centrifugation, washing) drying, coupled with the isolation of the intermediate, makes it possible to use (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid lysine salt as the starting material, obtained by optical resolution of racemic acid in the form of skimmed and undried cakes.

A further advantage of this process is that a simple process without the need for waste treatment yields all of the L-lysine initially contained in the lysine salt of the organic acid and returns as the hydrochloride to the process.

Example 1

The boiler was charged with 220 L of water, and 62.4 kg of (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) -propionic acid lysine salt was added. The mixture was heated to 60 ° C, 200 L toluene and 12.5 L concentrated hydrochloric acid were added. The water was removed by azeotropic distillation and heating was continued for 7 hours. 80-90 L of toluene is distilled off from the reaction mixture, the distillation residue is cooled to 65-60 ° C, 90 L of ethanol are added and the mixture is heated to boiling with stirring and then cooled to 30-25 ° C. The precipitated crystalline mass is filtered off and washed with 30 l of ethanol. The filter cake was transferred to 690 L of chloroform and refluxed for 1 hour. L-lysine hydrochloride is filtered off with suction. 520 L of chloroform was distilled off from the filtrate. The distillation residue was cooled to 20-15 ° C. The precipitated (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one was filtered off and dried.

The yield is 33-34 kg.

Content min. 98% (by high resolution liquid chromatography).

Specific rotation [.alpha.] = +66 DEG C. (c = 0.5, chloroform).

Example 2

300 liters of water and an undried (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid lysine salt filter cake from a racemic acid optical resolution containing an average of 62 , 4 kg of active ingredient and 120 kg of methanol. 200 kg of distillate of 120 kg of methanol and 80 kg of water are distilled off. To the distillation residue was added 200 L of toluene and 12.5 L of conc. hydrochloric acid. The yield of product is 33-34 kg.

Claims (4)

A process for the preparation of (2S, 3S) -3-hydroxy-2- (4-methoxyphenyl) -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one of formula I, (I) Characterized in that the salt of (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxyphenyl) propionic acid with L-lysine of formula II is reacted in a mixture of water and an organic a solvent such as toluene or xylene, suitably toluene in the presence of a mineral acid, preferably hydrochloric acid for 5 to 20 hours, during the reaction water is azeotropically distilled off from the reaction mixture, after completion of the reaction the crystalline mass is separated and -lysine hydrochloride by extraction into an organic solvent, for example chloroform or dichloromethane or 1,2-dichloroethane or acetone, from which the compound of formula I is isolated as a crystalline substance. 2. The process according to claim 1, wherein the amount of water and toluene or xylene for the reaction of the lysine salt of formula II is 0.5 to 3 ml, suitably 1 to 2 ml of water per g of lysine salt of formula II and 1 to 6 ml. 3 ml of toluene or xylene per g of lysine salt of the formula II. 3. The process according to claim 1, wherein the amount of hydrochloric acid is determined by the pH of the aqueous phase which is 2.5 to 5, preferably 3.4 to 3.5. 4. Process according to claim 1, characterized in that 10 to 25 ml, preferably 16 to 18 ml of an organic solvent, for example chloroform, dichloromethane, 1,2-dichloroethane, are used to separate the compound of the formula I from L-lysine hydrochloride. or acetone.