CS254740B1 - Preparation of (Z) {cis) -N, N-dimathyl-3- (6,11-dihydrodibenzo / b, e-thiepin-11-ylidene) -propylamine - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing anti-. _ depressantly active (Z)(cis)-N,N-dimethyl- -3-(6,11-dihydrodibenzo/b,e/thiepin-ll- -ylidene)propy^-amine of formula I by the Wittig reaction of dibenzo/b,e/thiepin-ll(6H)-one with 3-dimethylaminopropylidenetriphenylphosphorane, in which the crude product is chromatographed on silica gel and the product strongly enriched in the cis-isomer is further purified by crystallization of the base and hydrogen maleate.

Description

This invention relates to the preparation of (Z) of (cis) -N, N-dimethyl-3- (6, ll-dihydro-dibenzo / b, e / thiepin. -11-ylidene) propylamine of formula I hr _{(CH2) 2} N ( CH ₃ ) ₂ (i)

This substance (I) is the cis-isomer of the known antidepressant drug of prothiadene (also referred to as dosulepin or dothiepine), which is the hydrochloride of the corresponding (Z) (trans) isomer (Protiva M. et al., Experientia LB, 326, 1962; Protiva M., Czech Republic LL, 404,

1962; Metyšová J. et al., Arzneim-Forsch. 13, 1039 (1963); Vencovsky E. et al., Cesk.

Psychiat. 60, 416 (1964); Rajsner M. et al., Collect.Czech.Chem. Commun. 34, 1963, 1969).

The compound of formula (I) is formed, together with its isomer, by the acid catalysed dehydration of 11- (3-dimethylaminopropyl) -6,11-dihydrodibenzo [b, e] thiepin-11-ol as a minor product (5-10%) and its preparation by separation of this mixture it was not preparatively performed (crystallization of the hydrochloride of the crude product leads to enrichment in the predominant (E) -isomers).

Separation of both isomers was achieved in the form of N-mono-methyl derivatives (Rajšner M. et al.

1969, cited): A mixture of the two geometric isomers of N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine was converted by reaction with ethyl chloroformate to a mixture of the corresponding carbamates, their alkaline hydrolysis being a mixture of geometric isomers of N-methyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine was obtained. By repeated crystallization of the hydrochloride prepared from this mixture, fractions heavily enriched in the (E) -isomers were obtained as the first crop, while the (Z) -isomeric hydrochloride was obtained from the mother liquors in a yield of 17%. Both pure isomers of N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine were prepared by methylation of both isomers, followed by chloral formylation followed by reduction with lithium aluminum hydride. Thus, this is the only way that the compound of formula I can be prepared in smaller quantities; this has already made it possible to ascertain that the compound of the formula I is practically equivalent to a counterheen in terms of its antidepressant activity and, therefore, if it is found to have a more robust synthetic process, it could become a substance practically used and technically significant.

In the case of the analogous N, N-dimethyl-3- (6,11-dihydrodibenz / b, e / c -epin-11-ylidene) propylamine, it was found that by the Wittig reaction of dibenz / b, e / oxepin-11 (6H) -one with 3-Dimethylaminopropylidentiphenylphosphorane yields a mixture of the desired products in which the (Z) -isomer (Dutch Patent Application 64/11 861) strongly predominates. A similar finding has been made more recently in the case of the analogous N, N-dimethyl-3- (4,9-dihydrothleno [2,3-c] -2-benzothiepin-4-ylidene) propylamine (Polívka Z. et al., Collect.Czech.Chem. Commun. 48, 623 (1983). It has now been found that the Wittig reaction can also advantageously be used to prepare a compound of formula I and this novel and abundant process for preparing a compound of formula I is an object of the present invention.

The starting materials are dibenzo [b, e] thiepin-11 (6H) -one (Rajsner®, Protiva®, cited) and 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide (Netherlands Pat. Appl. 64/11 861).

The latter salt is treated with n-butyllithium in tetrahydrofuran / hexane to liberate 3-dimethylaminopropylidentrifenylphosphorane, which reacts in situ with the ketone. Workup of the reaction mixture gave a crude base which was chromatographed on silica gel.

In this way, an almost homogeneous compound of formula I is obtained in a yield of approximately 50%. Subsequent purification by crystallization of the maleate yields a product consisting exclusively of the desired (Z) -isomers of formula I (100% by gas chromatography).

Decomposition of the maleate with aqueous ammonia gives a crystalline base of formula I which is converted to the hydrochloride. By working up the chromatography and mother liquors after crystallization of the maleate, the yield of the (Z) -isomers of formula I can be further increased. This method of preparation of Formula I opens the possibilities for its technical preparation and possible practical applicability in the therapy of mental depression.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE PREFERRED EMBODIMENT OF THE INVENTION The compounds of formula (I) of the present invention are shown in the following examples, which are merely illustrative of the possibilities of the invention and are not exhaustive.

A suspension of 357 g of 3-dimethylaminopropyltriphenylphosphonium bromide hydrobromide in tetrahydrofuran was prepared and cooled to 20 ° C under nitrogen. With stirring, a solution of 92.8 g of n-butyllithium in hexane (approximately 10% solution was used) was added dropwise at 20 to 28 ° C over 30 minutes. The mixture was then stirred for 30 min at 25 ° C, heated to 55 ° C for 15 min, cooled to 20 ° C, and then a solution of 132 g dibenzo / b, e / thiepin-11 (6H) -one was added dropwise over 30 min. in 300 mL of tetrahydrofuran; the temperature is maintained by external cooling at 23 to 28 ° C.

The mixture was stirred at room temperature for 10 h, then quenched with stirring by external cooling by slow addition of 150 mL of water, followed by 115% hydrochloric acid, diluted with 750 mL of water and washed with toluene. The acidic aqueous solution was basified by the slow addition of 1.25 L of concentrated ammonia and the liberated bases were extracted with dichloromethane. The filtrate was washed with water, 50 g of potassium carbonate and 25 g of activated carbon were added and left to stand overnight after stirring. The solids were then filtered off and the filtrate was evaporated. The residue (231 g) was dissolved in a 1: 3 mixture of chloroform and benzene and chromatographed on a 1.7 kg silica gel column. Elution with chloroform-benzene 1: 1, followed by chloroform with 20% benzene and finally chloroform with 2% methanol and 5% chloroform saturated with ammonia gave almost homogeneous (Z) -N, N-dimethyl-3- (6,11-dihydrodibenzo) / b, [(thiepin-11-ylidene) propylamine (I) which crystallized as a base from a mixture of 200 ml of benzene and 50 ml of heptane.

85 g (49%) of practically pure base of formula I are obtained, m.p. 87.5-92 ° C. For further purification, the base is converted to hydrogen maleate, the only crystallization of which results in a constant melting salt, m.p. 153-155 ° C. Decomposition of this salt with aqueous ammonia and extraction with ether gave pure base I, m.p. 91-92.5 ° C (literature cited 91-93 ° C), which according to gas chromatography contains 100% of the (Z) -isomer. The hydrochloride obtained from this base melts at 215-217 ° C (ethanol); literature (sieve) reports m.p. Mp 214-216 ° C. The identity of the product is further assured by base and salt analyzes, as well as the NMR spectrum of the base, which confirms its homogeneity and its cis-configuration.

Claims (1)

object of the invention Process for the preparation of (Z) (cis) -N, N-dimethyl-3- (6,11-dihydrodibenzo [b, e] thiepin-11-ylidene) propylamine of formula I Wittig reaction of dibenzo [b, e] thiepin-11 (6H) -one with 3-dimethylaminopropylidentiphenylphosphorane, characterized in that the crude product obtained is chromatographed on silica gel and the highly enriched cis-isomer is purified by crystallization of base and hydrogen maleate.