CS254743B1 - Process for preparing (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo / b, e / thiepin-11-ylidene) propylamine and its hydrogen maleate - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing antidepressant-active (E)-N,N-dimethyl-3-(6,11-dihydrodibenzo/b,e/thiepin-11-ylidene)propylamine and its hydrogen maleate, which consists in the reductive methylation of pure (E)-N-methyl-3-(6,11-dihydrodibenzo/b,e/thiepin-11-ylidene)propylamine with formaldehyde and formic acid in boiling water and in the subsequent neutralization of the obtained base with maleic acid, which results in crystalline hydrogen maleate, suitable for further purification of the product to a content of 99.6% of the desired (E)-compound

Description

The present invention relates to a process for the preparation of (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula I

CH ₂ N (CH ₃ ) ₂ and its hydrogen maleate. The compound of formula I is an antidepressant active trans-isomer of prothiadene, which is used in hydrochloride therapy (Rajšner M., Protiva M., Czech. Farm.

11, 404 (1962); Metyšová J. et al., Arzneim-Forsoh. 13, 1039 (1963); Vencovsky E. et al.,

Cesk. Psychiat. 60, 416 (1964). The maleate of the compound of formula I is very suitable for its purification and for the removal of the last cis-isomer residues by crystallization.

The preparation of the compound of formula I has so far been described in two ways. The first consists in repeated crystallization of the hydrochloride of a mixture of the predominant amount of (E) - and a minor amount of (Z) -isomer of N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine yields acid-catalyzed dehydration of 11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo [b, e] thiepin-11-ol (West German Laid-Open 1,199,278). Repeated and lossy crystallization is required to achieve the goal, which makes the process less efficient. According to a second method, the compound of formula I is prepared from the pure (E) -isomers of N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine by N-formylation with chloryl and subsequent reduction of the N-formyl derivative with hydride lithium aluminum in tetrahydrofuran (Rajner M. et al., Collect. Czech. Chem. Commun. 34, 1 963;

1969). In this case, the two-step transformation of the starting material to the desired compound of formula I is preparatively demanding and time consuming.

It has now been found that to convert pure (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] -

For a pure compound of formula I, a simple one-step process is entirely sufficient, consisting in the reductive methylation of a compound of formula II with formaldehyde and formic acid in boiling water. The base of formula (I) thus obtained is converted by neutralization with maleic acid to crystalline hydrogen maleate, the only crystallization from ethanol yielding a substance melting at 136 DEG-138 DEG C., which according to gas chromatography contains 99.6% of the (E) -isomers. The salt released from the salt is crystalline and melts at 52-54 ° C. Neutralization with hydrogen chloride in ethanol / ether gives the hydrochloride melting at 227-229 ° C.

The above novel process for the preparation of the compound of formula (I) is an object of the present invention, which also comprises the preparation of a hydrogen maleate not yet described. Details of carrying out the reductive methylation of a compound of Formula II to a compound of Formula I are given in the example, which is, of course, merely illustrative of the possibilities of the invention and does not exhaustively describe them. Preparing used default! compounds of formula II have been described (Rajšner M. et al., cited).

To a suspension of 58 g of (E) -N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine in 110 ml of water is added 53 ml of 85% formic acid and the mixture is heated until formation of a clear solution. 30 ml of a 35% aqueous formaldehyde solution are then added and the mixture is refluxed for 18 h. Dilute with 400 ml of water, basify with cooling with 40% sodium hydroxide solution while cooling, and extract the base with benzene.

Treatment of the extract yielded 57 g (94%) of homogeneous base I whose identity and configuration could be verified by NMR spectrum. Neutralization with a calculated amount of maleic acid in ethanol and addition of ether gives a crystalline hydrogen maleate, the melting point of which is constant after crystallization from ethanol (136 DEG-138 DEG C.) and which, according to gas chromatography, contains 99.6% of the desired trans-components. Decomposition of this salt with aqueous ammonia and extraction with dichloromethane gave a crystalline base I melting at 52-54 ° C. The literature (Rajšner M. et al., Cited) provides for a pure base I m.p. Mp 53-54 ° C. The hydrochloride prepared from this base melts at 227-229 ° C (ethanol-ether). The literature (Rajšner M. et al., Cited) discloses for completely pure base I hydrochloride m.p. Mp 226-227 ° C.

Claims (1)

object of the invention A process for the preparation of (E) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula I and its hydrogen maleate, characterized in that pure (E) -N- methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula II (II) is reductively methylated with formaldehyde and formic acid in boiling water, whereupon the base is optionally converted into maleic acid by neutralization with maleic acid, is purified by a single crystallization from ethanol.