CS247590B1 - Process for preparing enantiomers of 3-fluoro-10- [4- (2-hydroxyethyl) piperazino] -8-isopropyl-10,11-dihydrodibenzo (b, f) thiepine - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is the preparation of enantiomers of neuroleptically and antipsychotically active 3-fluoro-10-/4-(2-hydroxyethyl)piperazino/- -8-isopropyl-10,11-dihydrodibenzo(b,f)- thiepine (I), whereby the levorotatory isomer is approximately twice as neuroleptically active as the racemate and 10 to 20 times more active than the dextrorotatory isomer. The preparation method according to the invention consists in neutralizing the racemic base I with both enantiomeric dibenzoyltartaric acids, whereby in both cases homogeneous diastereomeric salts result. In the case of dibenzoyl-(+)-tartaric acid, the salt of the levorotatory base I results, and in the case of dibenzoyl-(-)-tartaric acid, the salt of the dextrorotatory base I. By decomposition of both salts by alkalization, both enantiomeric bases I are obtained, which, upon neutralization with methanesulfonic acid, yield the corresponding monomethynesulfonates.

Description

The present invention relates to a process for the preparation of enantiomers of 3-fluoro-10- [4- (2-hydroxyethyl) piperazino] -8-isopropyl-10,11-dihydrodibenzo (b, f) thiepine of the formula I

i.e., resolution of the racemic compound I into optically active antipodes.

The racemic compound of formula I, known as isofloxythepin, is a highly and long-lasting neuroleptic which is particularly useful in the treatment of schizophrenic psychoses, especially in the form of monomethanesulfonate. In animal tests (mostly oral administration), the racemate exhibits the following properties: 1) In rats it inhibits apomorphine-induced stereotypes (Dtjg = 2.7 mg / kg) and also inhibits apomorphine-induced agitation (Dgg = 2.4 mg / kg). ) 0 rats act cataleptically; EDjjq = 2.1 mg / kg. 3) Suppresses amphetamine-induced hypermotility in mice (IDjg = 0.027 mg / kg).

4) In mice, it strongly inhibits spontaneous locomotor activity (D ^ g = 0.68 mg / kg). 5) In mice: acts incoordinating in the rotating rod test (ED? G = 1.0 mg / kg). 6) At a low dose, it raises the concentration of homovanilic acid to twice the control value in rat brain striatum (ED2QQ = less than 0.050 mg / kg at 3 h after administration and 0.70 mg / kg at 24 h).

The enantiomers of isofloxythepine of formula (I) prepared according to the invention exhibit stereoselectivity, with the levorotatory enantiomer being generally approximately twice as potent as the racemate and 10 to 20 times more potent than the dextrorotatory enantiomer. Stereoselectivity is not quite apparent in the central depressant effect (effect on locomotor activity of mice) and in the discoordination effect (rotating rod test in mice). Results of the tests referred to in the preceding paragraph for enantiomers of isofloxythepine: 1) Inhibition of apomorphine stereotypes in rats, D ₅₀ for (-) - I 1.2 mg / kg and for (+) - I 26.6 mg / kg; inhibition of agitation, D 5 _µl for (-) - I 1.1 mg / kg and for (+) - I 11.0 mg / kg. 2) Cataleptic effect in rats, ED ₅₀ for (-) - 1 mg / kg and for (+) - I 9.2 mg / kg. 3) Attenuation of amphetamine hypermotility in mice, It> ₅ g for (- (- 1 0.033 mg / kg and for (+) - I 0.360 mg / kg. 4) Inhibition of locomotor activity in mice, D ₅₀ for (-) - I 0.78 mg / kg and for (+) - I 0.94 mg / kg 5) Incoordinating effect on rotating rod in mice, EDjg for (- (- X 1.3 mg / kg and for (+) - I 1.5 mg / kg. 6) Increase the homovanillic acid level in the rat brain striatum ^{ed r} ° P 200 L ^{-) -1} .018 interval. 5 ha 0.31 at 24 h interval; for (+) -, 1 0.254 mg / kg at 3 h interval and more than 5.0 mg / kg at 24 h interval.

cleavage of the racemic isofloxythepin of formula I thus yields a substantially more potent (-) enantiomer, allowing it to be administered to patients at half doses (as compared to remate), resulting in a reduced incidence of side reactions.

The principle of the process for the preparation of the enantiomers of the compound of formula I according to the invention is the crystallization of salts of the base of formula I with both enantiomeric dibenzoyltartaric acids. Crystallization of the salt formed by neutralization of the racemic base of formula I with dibenzoyl - (+) - tartaric acid results in a homogeneous diastereomeric salt, the decomposition of which is alkalinized to give the levorotatory base of formula I and neutralization thereof with methanesulfonic acid. Conversely, crystallization of the salt formed by neutralization of the racemic base of formula I with dibenzoyl - (-) - tartaric acid results in a homogeneous diastereomer, the decomposition of which is alkalinized to give the dextrorotatory base of formula I and its neutralization with methanesulfonic acid.

Details of the process for preparing the enantiomers of the base of Formula I of the present invention are described in the Examples below. In addition to the indicated melting points and specific rotations, all reported compounds were analyzed (elemental analysis).

Example 1

Racemic base I (10.5 g) was dissolved together with 9.80 g of dibenzoyl - (+) - tartaric acid in boiling acetone (100 ml) and the solution was allowed to crystallize at room temperature for 12 h. rooms. There were obtained 4.95 g homogenous diastereomeric salts with acids and bases ratio of 1: 1, which melts at 174-175 ° C and exhibited a specific rotation [§ ² and + 52.7 ° (1% solution in methanol). Further crystallization from acetone does not change either the melting point or the specific rotation value. From 4.1 g of this salt, alkalization with aqueous ammonia and benzene extraction gave 2.36 g of a glassy base which crystallized from a mixture of gasoline and petroleum ether, melted at 93-94 ° C and showed a specific rotation of [α] ² β - 14.4 ° (1% solution in methanol). It is the levorotatory enantiomer of the base of formula I. Neutralization of 2.0 g of glassy (-) - base with 480 mg of methanesulfonic acid in acetone yields 1.8 g of the crystalline monomethanesulfonate of the levorotatory enantiomer of base I, mp 175-176 ° C, [α] ² ° - 14.0 ° (1% solution in methanol).

Example 2

The racemic base of formula I (20.0 g) was dissolved in 50 ml of methanol and the solution was neutralized with a solution of 18.8 g of dibenzoyl (-) - tartaric acid in 60 ml of methanol. After 15 hours of standing at room temperature, aspirated homogeneous 12.9 g of a diastereomeric salt of acid and base ratio of 2: 1, mp 177-178 ° C (methanol) L ^n] D ² '53 ° (1% solution in methanol) . 7.4 g of this salt were obtained. alkalization with aqueous ammonia and extraction with benzene gave 4.0 g of a glassy base, which crystallized from a mixture of benzene and petroleum ether, melting at 93-94 ° C and showing [α] ² g + 15.2 ° (1% solution in methanol). It dextrorotatory enantioijier Neutralization Base Formula I. 3.80 g of this base with 900 mg of methanesulfonic acid in an environment of 12 ml acetone to give 4.40 g of the crystalline base monomethanesulfonate salt of the dextrorotatory enantiomer of formula I, mp 173 DEG-174.5 DEG C. ^{[j 2} g + 13.5 ° (1% solution in methanol).

Claims (3)

object of the invention A process for the preparation of enantiomers of 3-fluoro-10- [4- (2-hydroxyethyl) piperazino] -8-isopropyl-10,11-dihydrodibenzo (b, f) thiepine of the formula I-NCH ₂ CH ₂ OH (I), characterized by neutralization of the racemic base of formula I with enantiomeric dibenzoyltartaric acids, crystallization of homogeneous diastereomeric salts, decomposition of these salts by alkalization on an optically active base of formula I and their neutralization with methanesulfonic acid to give methanesulfonates of optically active bases of formula I. 2. A process for the preparation of the (-) - enantiomer of the compound of formula (I) according to claim 1, characterized in that dibenzoyl - (+) - tartaric acid is used to neutralize the racemic base of formula (I). ³ 3. A process for the preparation of the (+) - enantiomer of the compound of formula I according to claim 1, characterized in that dibenzoyl - (-) - tartaric acid is used to neutralize the racemic base of formula I.