CS202332B1 - Method of preparing both geometrical isomers of novel 2-hydroxy-11-/3-dimethyl-aminopropylidene/-6,11-dihydrodibenzo/b,e/thiepine - Google Patents

Description

This invention relates to a process for the preparation of both geometric isomers of the novel 2-hydroxy-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine of formula I

(I) as well as their salts.

Compounds of formula I are preferred intermediates for the preparation of pharmacodynamically active compounds, especially those with antidepressant activity.

The process for the preparation of the compounds of the formula I according to the invention consists in the demethylation of the known 2-methoxy-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b.e) thiepine of the formula II.

HCH _t CH _and N (CH _A ) _A

This starting material, which has been described by Gadient et al. (Helv. Chim. Acta 45, 1860, 1962) in the form of the oxalate, mp 187-189 ° C, appears to be a mixture of geometric isomers (cis and trans) in which - similarly to analogous cases (M. Rajšner et al. Chem.Commun. 34, 1015, 1963, 1969) - the trans-form predominates strongly.

Depending on the demethylation of the substance, mixtures of geometric isomers of the compound of formula I of different compositions can be obtained, from which either the pure trans- or cis-isomer of formula I can be crystallized. Thus, with very gentle demethylation with boron tribromide in chloroform at room temperature. retained and the base of formula I obtained has a trans configuration on the double bond, as evidenced by the infrared spectra of the extra-plane vibrations of the CH bonds of the aromatic nuclei (solitary Ar-H band at 883 cm ¹ when measured in carbon disulfide solution). Demethylation of hydrobromic acid in acetic acid probably results in at least partial transient protonation of the starting material and, after deprotonation after dilution with water, a mixture of geometric isomers of the compound of formula I with a different isomer ratio to that of formula II is formed. This results in a difficult to divide mixture, but from this, however, the pure trans-isomer, identical to the material obtained by boron tribromide demethylation, is again isolated by crystallization. The most drastic demethylation method is by heating the compound of formula II with hydrobromic acid itself to boiling. Transient protonation is strongly applied, resulting in a violation of the double bond configuration. After dilution with water, the double bond is regenerated, but the mixture of geometric isomers has a completely different composition and its crystallization is successful in isolating the cis-isomer of the compound of formula I. Again, the configuration can be derived from the infrared spectrum (carbon disulfide). which corresponds to solitary Ar-H. Due to the interaction with the side chain, this band at 899 cm @ ¹ is strongly shifted to a higher frequency compared to the trans isomer.

The invention encompasses all of these demethylation methods and is thus a process for preparing both geometric isomers of the compound of Formula I. The trans-isomer base crystallizes from ethanol and melts at 198-200 ° C. . The cis-isomer base also crystallizes from ethanol and melts at 162-164 ° C.

Further details of the process for the preparation of the two geometric isomers of the compound I according to the invention are evident from the examples given below, which are merely illustrative of the possibilities of the invention and are not intended to fully describe these possibilities.

Examples

1. To a solution of 4.8 g of trans-2-methoxy-11- (3-dimethylaminopropyl) 6,11-dihydrodibenzo (b, e) thiepine crystalline base in 30 ml of absolute chloroform is added dropwise at 10 ° C over 10 minutes solution of 7.4 g of boron tribromide in 10 ml of chloroform and the mixture was stirred at room temperature for 2 hours. It is then decomposed by dropwise addition of a mixture of 70 ml of water and 15 ml of conc. aqueous ammonia. Stir until dissolved. The chloroform solution was then separated and shaken with excess 3% hydrochloric acid. The aqueous phase together with the precipitated oily hydrochloride was separated, basified with ammonia, and the precipitated phenolic base was re-extracted with chloroform. The extract was dried over potassium carbonate, filtered with charcoal and evaporated in vacuo. 2.8 g of crude product are obtained, which crystallizes rapidly on standing. Crystallization from ethanol yields pure trans-base I, which melts constantly at 198-200 ° C. Its characterization by infrared spectrum is described in the description. Neutralization with hydrogen chloride in a mixture of ethanol and ether affords crystalline hydrochloride with a melting point of 243-245 ° C (aqueous ethanol).

The starting crystalline base of formula 11 has not been described in the literature. It can be obtained by alkalization of the known oxalate (literature cited) and isolation by extraction with chloroform. It crystallizes from petroleum ether and melts at 53-55 ° C.

2. A mixture of 2.3 g of crude 2-methoxy-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (be) thiepine of formula II, 5 ml of acetic acid, 3 ml of 48% hydrobromic acid and 0.05 g of sodium hypophosphite was refluxed for 4 hours. After standing overnight, it was diluted with water, basified with aqueous ammonia and the base isolated by extraction with chloroform. The extract was dried over sodium sulfate and the chloroform evaporated. Yield 2.2 g (theoretical yield) of an oily mixture of the two geometric isomers of the compound of formula I. This mixture is chromatographed on a column of 100 g of neutral alumina, eluting with chloroform. After washing with 0.8 g of less polar portions containing the cis-isomer of the compound of formula I, it is eluted

1.2 g of base, which crystallizes from ethanol and melts at 195-197 ° C. It is a trans-base of formula I, identical to the product prepared according to example 1.

3. A mixture of 4.5 g of trans-2-methoxy-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (b, e) thiepine oxalate and 15 ml of 48% hydrobromic acid is refluxed for 3 hours in a bath. with a temperature of 120 ° C. After cooling, it was diluted with water, basified with ammonium hydroxide and extracted with chloroform. The extract was dried over sodium sulfate and evaporated. It is obtained

2.5 g of an amorphous base, in which a less polar substance predominates than the trans-base of formula I. The substance crystallizes from ethanol and melts constantly at 162-164 ° C after recrystallization. It is the cis-base of the compound of formula I, whose infrared characterization is described in the description.

Claims (4)

A process for the preparation of the two geometric isomers of the novel 2-hydroxy-11- (3-dimethylaminopropylidene) -6,11-dihydrodibenzo (be) thiepine of the formula I as well as their salts, characterized in that 2-methoxy-11- (3 -dimethylaminopropylidene) -6,1 l-dihydrodibenzo (b, phthiepine of formula II (I) 1 HCH ₂ CH _and N (GH 3) _t OCH, (II) demethylates and the bases of formula I obtained are optionally converted into salts by neutralization with inorganic or organic acids. 2. A process according to claim 1 wherein the trans-base of formula II is demethylated with boron tribromide in chloroform at room temperature and crystallization of the product yields pure transbase of formula I. 3. A process according to claim 1, wherein the crude base of formula II is demethylated by boiling with a mixture of 48% hydrobromic acid and acetic acid and chromatography and crystallization of the product yields pure trans-base of formula I. 4. A process according to claim 1, wherein the oxalate of the trans-base of formula II is demethylated by heating with 48% hydrobromic acid to 120 DEG C. and crystallizing the product to give pure cis-b ^ from formula I.