CS217880B1 - Process for preparing a novel amino alcohol derived from 2-chloro-11Hdibenz (b, f) -1,4-oxathiepine - Google Patents

Abstract

The invention relates to a method for preparing a new 2-chloro-11-(1-methyl-4-hydroxy-4- -piperidyl)-11H-dibenz(b,f)-1,4-oxathiepine and its salts. The named substance and its salts are both intermediates in the preparation of neurotropically active drugs, and also exhibit moderate tranquilizing activity themselves. The method of preparation according to the invention consists in the reaction of 2-fluoro-11H-dibenz(b,f) -1,4-oxathiepine with butyllithium in ether and in the subsequent action of 1-methyl-4-piperidone

Description

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

(I) i.e. 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -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 tranquilizing activity. Tested in mice in the form of hydrogen maleate exhibits an incoordinating effect on the rotating rod; when administered orally, the mean effective dose of ^{ED is} 50 ~ ⁵⁶ mg / kg.

The process for the preparation of the compound (I) according to the invention consists in the reaction of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine of the formula II.

Cl (IX) with butyllithium in ether and subsequent treatment with 1-methyl-4-piperidone. The oily base I obtained is optionally converted by neutralization to crystalline salts, of which hydrogen maleate is particularly preferred. The starting material of formula (II) is novel and its preparation method is described in the exemplary embodiment, which contains still further details on the preparation of compound (I).

Example

To a solution of 9.9 g of 2-chloro-11H-dibenz (b, f) -oxathiepine in 130 ml of ether was added dropwise 30 ml of a 15% solution of n-butyllithium in hexane over 10 minutes at 10 ° C under nitrogen. 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 was dissolved in ether and the solution was neutralized with 4.5 g of maleic acid in ethanol. 10.8 g of crystalline 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine crystalline hydrogen maleate melts at 195 DEG C. in pure state. Mp 5-197 ° C (ethanol).

The starting 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine used is novo; prepared, for example, by the following procedure:

To a solution of 20 g of 5-chloro-2-iodobenzoic acid (K. Pelz et al .; Colleet. Czeeh.

Chem. Commun. (1968, 1968) in tetrahydrofuran (45 ml) was added sodium borohydride (16.1 g) at 10-20 ° C with stirring over 45 min. 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 ha under cooling with ice water decomposed at temperatures of up to 8 C ^U PRIK with ice cooling 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. 10 g (96 percent) of crude 5-chloro-2-iodobenzyl alcohol of m.p. 115 DEG-117 DEG C. are obtained. The analytically pure material was obtained by crystallization from ethanol, mp 1.6-1.7 ° C.

Under cooling, a mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared, while stirring at maximum 0 ° C, 108.3 g of 5-chloro-2-iodobenzyl alcohol are added dropwise over 1.5 h, Dilute with 40 ml of benzene, stir 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 potassium carbonate and 47.8 g of 2-hydroxythiophenol (F. Leuckart, J. Prakt. Chem. (2) 41, 192, 1890) is added a solution of 125.6 g of 5-chloro-2-hydroxy- thiophenol. 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-1H-dibenz (b, f) -1,4-oxathiepine having a m.p. of 148-168 ° C / 65 Pa and a melting point of 66-76 ° C. crystallized from methanol and melted at 78-79 ° C.

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of a new pin of formula I, an amino alcohol derived from 2-chloro-11H-dibenz (b, f) -1,4-oxathia (I) i. 2-chloro-11- (1-methyl-4-hydroxy-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine, as well as its salts, characterized in that 2-chloro- 11H-dibenz (b, f) -1,4-oxathiepine of formula II (II) Cl is reacted with butyllithium in ether and the resulting organometallic intermediate is reacted with 1-methyl-4-piperidone, whereupon the oily base I obtained is optionally neutralized with inorganic or organic acids to give salts.