CS217881B1 - A process for preparing a novel amine derived from 2-chloro-11H-dibenz (b, f -1,4-oxathiepine) - Google Patents

Abstract

The invention relates to a method for preparing a new 2-chloro-11-(1-methyl-4-piperidylidene)-11H-dibenz(b,f)-1,4-oxathiepine and its salts. The named substance is both an intermediate in the preparation of neurotropically active drugs, and itself - especially in the form of salts - exhibits moderate neuroleptic activity: it has a distinct cataleptic activity, which is not accompanied by disturbing centrally suppressive activity. The method of preparation according to the invention consists in the dehydration of 2-chloro-11-(1-methyl-4-hydroxy-4-piperidyl)-11H-dibenzo(b,f)-1,4-oxathiepine, preferably carried out by the action of thionyl chloride in pyridine at temperatures of 80 to 100 °C.

Description

The present invention relates to a process for the preparation of a novel amine derived from 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine of formula I,

i.e. 2-chloro-11- (1-methyl-4-piperidylidene) -11H-dibenz (b, f) -1,4-oxathiepine and its salts.

The compound of formula I is an intermediate in the preparation of neurotrophically active drugs and in itself has a mild neuroleptic activity. Tested in rats in the form of hydrogen maleate show cataleptic activity; when administered orally, the median effective dose is 22 mg / kg.

At the same time, the substance does not have a centrally depressant effect because an oral dose of 25 mg / kg still does not induce ataxia in mice in the rotating rod test.

The process for the preparation of the compound (I) according to the invention consists in dehydrating 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine of the following formula II. For dehydration, treatment with thionyl chloride in pyridine at temperatures of 80-100 ° C is preferably used. The crystalline base I obtained is optionally converted by acid neutralization to salts, of which hydrogen maleate is particularly preferred.

Starting material of formula II

Cl

HO 'nch ₃ (II) is new and its method of preparation is described in the exemplary embodiment, which still contains further details on the preparation of Compound I.

Example

To a solution of 15 g of 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -1H-dibenz (b, f) -1,4-oxathiazine in 100 ml of pyridine, 5 ml of thionyl chloride is added dropwise with stirring. and the mixture was heated in a boiling water bath (100 ° C) for 8 h. It is then diluted with 800 ml of benzene, washed with water, dried over potassium carbonate and evaporated. 14 g of sulfuric oily 2-chloro-H- (1-methyl-4-piperidylidene-11H-benz (b, f) -1,4-oxathiepine) are obtained, which crystallizes from a mixture of benzene and cyclohexane and melts in the pure state at 125 DEG C. Neutralization with maleic acid in acetone and addition of ether yields crystalline hydrogen maleate, which is purified by recrystallization from said solvent mixture (acetone-ether) and melts in the pure state at 191-194 ° C.

The starting 2-chloro-11- (1-methyl-4-hydroxy-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine used is a novel substance: it is prepared, for example, by the following procedure:

To a solution of 120 g of 5-chloro-2-iodobenzoic acid (K. Pelz et al., Collect. Czech. Chem. Commun. 33, 1852, 1968) in 145 ml of tetrahydrofuran is added at 10-20 ° C with stirring over 45 minutes. C 16.1 g of sodium borohydride. The mixture was stirred at this temperature for 30 min and then a solution of 80.3 g (71.4 mL) of boron trifluoride etherate in 40 mL of tetrahydrofuran was added dropwise. Stirring is continued for 3 h and, under cooling with ice water, is decomposed at a maximum of 8 ° C by the dropwise addition of 50 ml of 5% hydrochloric acid. Dilute with water and extract with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. 110 g (96%) of dry 5-chloro-2-iodobenzyl alcohol are obtained, m.p. 115-117 ° C. An analytically pure material was obtained by crystallization from ethanol, m.p. 116-117 ° C.

A mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared under cooling, 108.3 g of 5-chloro-2-iodobenzyl alcohol are added dropwise with stirring at a maximum of 10 ° C, diluted. with 40 ml of benzene, stirred for 4 h at room temperature and 1 h at 50 ° C. After cooling, it is diluted with 120 ml of chloroform, washed with 25 ml of 5% hydrochloric acid, 5% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. 126 g (95%) of crude 5-chloro-2-iodobenzyl bromide melting at 75-79 ° C are obtained. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77-79 ° C.

To a mixture of 640 ml of dimethylformamide, 52.4 of potassium carbonate and 47.8 g of 2-hydroxythiophenol (R. Leuckart, J. Prakt. Chem. / 2 / 41. 192, 1890) was added a solution of 125.6 g of 5-chloro-2-hydroxy-. Of 2-iodobenzyl bromide in 500 ml of dimethylformamide, stirred for 1 h at room temperature, then 57 g of potassium carbonate and 4.5 g of copper are added and refluxed for 6 h. Dimethylformamide was distilled off under reduced pressure, the residue was diluted with water and shaken with benzene. After aspiration, the benzene layer was separated, washed with water, dried over potassium carbonate and evaporated. Distillation of the residue gave 42.5 g (45%) of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine, m.p. 148-168 ° C / 65 Pa, m.p. Mp 66-76 ° C. The pure product is obtained by crystallization from methanol and melting at 78-79 ° C.

To a solution of 9.9 g of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine in 130 ml of ether is added dropwise 30 ml of a 15% solution of n-butyllithium over 10 minutes at 10 ° C under nitrogen. in hexane. After stirring for 1 h, a solution of 7.2 g of 1-methyl-4-piperidone in 20 mL of ether was added dropwise over 10 min. The mixture was stirred at room temperature for 5 h, allowed to stand overnight, washed with water, dried over potassium carbonate and evaporated. The remaining crude oily base, i.e. 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine, was dissolved in ether and the solution was neutralized with 4.5 g of maleic acid in ethanol. 10.8 g of crystalline hydrogen maleate are obtained, which is recrystallized from ethanol and melts in the pure state at 195.5 to 197 ° C. Decomposition of the pure maleate with ammonium hydroxide and extraction with benzene gives the pure base which is used as the starting material for the process according to the invention.

Claims (1)

SUBJECT OF THE INVENTION Process for the preparation of a new amine derived from 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine of formula I, _o (I) ie 2-chloro-11- (1-methyl-4-piperidylidene) -11H -dibenz (b, f) -1,4-oxathiepine, and salts thereof, characterized in that 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -11H-dibenz (b) , f) -1,4-oxathiepino II _Λ JX (II) is subjected to dehydration, preferably by treatment with thionyl chloride in pyridine at temperatures of 80-100 ° C, whereupon the obtained crystalline base I or is converted by neutralization with inorganic or organic acids into salts.