CS217882B1 - Process for preparing 11- (aminoalkyl) derivatives of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide - Google Patents

Abstract

The invention relates to a method for the preparation of new 11-(aminoalkyl) derivatives of 2-chloro-11H-dibenz(b,f)-1,4-oxathiepin-10,10-dioxide, and their salts. These substances are both intermediates in the preparation of neurotropically active drugs, and themselves have a moderate tranquilizing and antidepressant effect. The method of preparation according to the invention consists in the metalation of 2-chloro-11H-dibenz(b,f)-1,4-oxathiepin-10,10-dioxide with sodium hydride in dimethylformamide and in the subsequent alkylation with aminoalkyl chlorides, specifically 2-dimethylaminoethyl chloride and 3-piperidinopropyl chloride.

Description

This invention relates to a process for the preparation of novel 11- (aminoalkyl) 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide derivatives of the general formula I,

Cl (I) (CH ₂ ) _n R wherein R is dimethylamino- or piperidino and _n is 2 or 3, and salts thereof.

The compounds of formula X are intermediates for the preparation of neurotrophic active drugs and in themselves have moderate tranquilizing and antidepressant activity. For example, 2-chloro-11- (2-dimethylaminoethyl-1H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide (I, R = dimethylamino, n = 2) in the form of hydro chloride shows slight incoordination efficacy in the rotating rod test in mice: an oral dose of 100 mg / kg induces ataxia in 60% of rats at 2 h after administration Also 2-chloro-11- (3-piperidinopropyl) -11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide (I, R = piperidino, n = 3) in the form of the hydrochloride showed an incoordination action in the same test a mean effective dose inducing ataxia of ED? _Q = 75 mg / kg after the oral dose; 00 mg / kg shows a slight antagonism to reserpine ptosis in the mouse, an effect typical of antidepressants.

The process for the preparation of the compounds of the formula I according to the invention consists in reacting 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide with sodium hydride in dimethylformamide and the subsequent treatment with aminoalkyl chlorides of the formula XI,

Cl (CH ₂ ) _n R where Ran denotes the same as in formula X. The oily bases X obtained are optionally converted by acid neutralization to salts, of which hydrochlorides in particular are preferred. The starting 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide is a novel substance and its preparation method is described in the Examples, which contain further details on the preparation of the compounds of formula I. of all mentioned products and intermediates was ensured by analyzes and spectra (UF,

IR (NMR, MS).

He added _φ

2-Chloro-11- (2-dimethylaminoethyl) -11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide

To a solution of 4.0 g of 2-chloro-11H-dibenzene (b, f) -1,4-oxathiepine-10,10-dioxide in 40 ml of dimethylformamide was added 0.63 g of sodium hydride and the mixture was stirred at 70 DEG for 30 min. Deň: 32 ° C. 1 ml of 2-dimethylaminoethyl chloride was then added and the mixture was stirred for an additional 3.5 h at 70 ° C. Then, 4 ml of ethanol are added dropwise, 500 ml of water are added and extracted with benzene. The base was extracted from the benzene solution with 100 ml of 3M hydrochloric acid, the acidic solution was separated and basified with aqueous ammonia. The liberated bases were extracted with chloroform, dried over potassium carbonate and evaporated. 2.65 g of an oily base are obtained. Neutralization with ethereal hydrogen chloride gives the hydrochloride, which crystallizes from ethanol and melts in the pure state at 235-237 ° C.

The starting material 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide is a novel substance which is prepared as follows:

To a solution of 120 g of 5-chloro-2-iodo-benzoic acid (K. Pelz et al., Collect, Czech. Chem. Commun, 33, 1852, 1968) in 45 ml of tetrahydrofuran is added under stirring at 45 ° C for 45 min. 20 ° 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 temperature 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. It is obtained

110 g (96%) of crude 5-chloro-2-iodobenzyl alcohol of m.p. The analytically pure material was obtained by crystallization from ethanol, m.p. 116-117 ° 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 10 ° C 108.3 g of 5-chloro-2-iodobenzyl alcohol are added dropwise over 1.5 h, 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-iodo-benzyl bromide are obtained, which melts at 75-79 ° C.

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 g of potassium carbonate and 47.8 g of 2-hydroxythiophenol (R. Leuckart, J. Prakt. Chem. / 2 / J92, 1890) was added a solution of 125.6 g of 5-chloro-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, mp 66-76 ° C. the pure product is obtained by crystallization from methanol and melts at 78-79 ° C.

To a solution of 10.0 g of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine in 100 ml of acetic acid was added dropwise with stirring 12 ml of 30% hydrogen peroxide and the mixture was refluxed for 30 min. After cooling, it is poured into 500 ml of water and extracted with chloroform. The extract was dried (MgSO4) and evaporated. 11.1 g (98%) of crude 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide melting at 159-166 ° C is obtained. Crystallization from ethanol gave the pure product, mp 166.5-167.5 ° C.

Example 2

2-Chloro-11- (3-piperidinopropyl) -11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide

To a solution of 4.18 g of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine-10,10-dioxide (see Example 1) in 40 ml of dimethylformamide was added 0.65 g of sodium hydride and the mixture was Stir 4.5 h at 70 ° C. Then 10 ml of 3-piperidinopropyl chloride was added and stirred for a further 3.5 h at 70 ° C. It is then quenched by the dropwise addition of 4 ml of ethanol, diluted with 700 ml of water and extracted with benzene. The base was extracted from the benzene solution with 100 ml of 3M hydrochloric acid. The separated acidic aqueous solution was basified with aqueous ammonia and the base was extracted with chloroform. The extract was dried over potassium carbonate and evaporated. The residue is chromatographed on a column of 400 g of neutral alumina (activity II). Benzene elutes less polar contaminants and elutes 4.37 g of homogeneous oil base with chloroform, which gives hydrochloride by neutralization with hydrogen chloride in ethanol / ether. Crystallization from ethanol / ether gave the pure product, m.p. 177-179 ° C.

Claims (1)

Process for the preparation of 11- (aminoalkyl) 2-chloro-11H-dibenz (b, f) -, 4-oxethiepine-10,10-dioxide derivatives of formula (I) (I) Cl '(CH ₂ ) n - wherein R is dimethylamino- or piperidino and n is 2 or 3, as well as salts thereof, characterized in that 2-chloro-11H-dibenz (b, f) -1,4- oxathiepine-10,10-dioxide is reacted with sodium hydride in dimethylformamide and subsequently treated with aminoalkyl chlorides of formula II, Cl (CH ₂ ) _n R (II) wherein Ran is the same as in Formula I, whereupon the oily base obtained is optionally converted into a salt by neutralization with inorganic or organic acids.