CS268486B1 - Method of 2-(phenylthio) benzylamines and their hydrogen maleates preparation - Google Patents

Abstract

The solution falls within the field of drug synthesis. It relates to a process for the preparation of 2- (phenylthio) benzylamines I and their crystalline hydrogen maltates. Base are intermediates preparing other pharmacodynamics effective substances while hydrogen maleate They are effective antlreserpline, potential antidepressants. Method of preparation substances consists in the reactions of 2- / phenylthio / benzylchloride with methylamine, diethylamine, pyrrolide, piperidine and morpholine used in 100-120 X excess in chloroform at 60 to 80 ° C ° C. Neutral1sac1 formed oily with malelic acid are obtained crystalline hydrogen maleate.

Description

This invention relates to the preparation of 2- / phenylthio / benzylamines of the formula I, SC ₆ H ₅ CH ₂ R / 1 / wherein R is the residue of dimethylamine, diethylamine, pyrrolidine, piperidine and morpholine, and hydrogen maleate.

The compounds of the formula I according to the invention are intermediates for the preparation of further pharmacodynamically active compounds. However, in the form of their hydrogen maleates, I reveal the pharmacodynamic effects which can be used on their own, primarily those which make them potential antidepressants.

A typical substance according to the invention is N, N-dimethyl-2- (phenylthio) benzylamine (1, R = N (CH 2) 3), whose hydrogen maleate has been tested for oral administration (except for in vitro tests). Its acute toxicity in LD50 mice is 211 mg / kg. In a test for new ulcers in rats, the substance has a significant inhibitory effect at a dose of 50 mg / kg. Also in the mouse reserpine ptosis test, the substance shows a significant antireserpine effect; the effect is significant at 12.5 mg / kg and the threshold effective dose is 3 mg / kg, which is similar to imipramine. The substance significantly inhibits the binding of 4 nM (1H) imipramine in the rat brain hypothalamus; IC-- 3 and u

13.54 nN. Similarly, it also inhibits 4 nM / H / desi pramin binding in the rat brain hypothalamus; IC _SO = 16.6 n «. '

Substances similar to the compounds of the invention are disclosed in U.S. Patent No. 4,018,830. However, this patent specifically discloses a single substance, i.e., N-methyl-2- (phenylthio) benzylamine (and its hydrogen maleate). It uses a fundamentally different method for its preparation than that which is the subject of the invention. In addition, substances which are specifically mentioned in the cited document / including the only named specific substance are referred to as anti-arrhythmics, which implies that the method of their use is completely different from the method of using the medicaments according to the invention. The substances according to the present invention are new from a scientific point of view, i.e. they have never been described and characterized in the literature before. Their identity is ensured by the usual analytical and spectral methods.

The compounds of formula I according to the invention are prepared by a substitution reaction of the known 2- (phenylthio) benzyl chloride [Jílek J. 0. et al., Monatsh. Chem. 96, 182 (1965); Jílek J. 0. et al., Collect. Czech. Chem. Commun. 32, 3186 (1967) with secondary amines of the general formula H-R, in which R is the same as in the formula I. The reaction can be carried out under various conditions, preferably in chloroform at temperatures of 60 to 80 ° C. The most preferred variant is the refluxing of a mixture of said chloride with a 100 to 120% excess of amine H-R in chloroform. If this does not allow the volatility of the amine used, the reaction is carried out in an autoclave. the bases obtained are converted by neutralization with maleic acid into the corresponding salts, i.e. hydrogen malonates. Further details of the process for the preparation of the compounds of the formula I according to the invention follow from the examples, which, of course, do not describe all the possibilities of the invention.

Example 1

N, N-D-methyl-2- (phenylthio) benzylamine

A solution of 11.7 g of 2- (phenylthio) benzyl chloride in 50 ml of chloroform was saturated with 9.0 g of dimethylamine and the mixture was heated in an autoclave at 75 ° C for 12 h. After cooling, chloroform was evaporated and the residue was partitioned between 150 ml of benzene and 150 ml of water with the addition of 10 ml of sodium hydroxide solution. The benzene layer was washed with water and the base was extracted into 15 ml of 1.5 N HCl. The aqueous solution together with the precipitated oily hydrochloride is basified with water2. CS268486 B1 ammonia and the base is extracted with benzene. Work-up of the extract gave 12.0 g of crude base, which was distilled in vacuo; 10.6 g (87%), m.p. 128-129 ° C (50 ° C). Neutralization with maleic acid in acetone gives crystalline hydrogen maleate, which crystallizes from acetone and melts in pure form at 144 ° C.

Example 2 ·

N, N-Blethyl-2- (phenylthio) benzylamine

A mixture of 11.7 g of 2- (phenylthio) benzyl chloride, 50 ml of chloroform and 14.6 g of diethylamine was refluxed for 8 hours and worked up as in the previous example. 10.8 g (80%) of an oily product boiling at 133 DEG-135 DEG C./50 Pa are obtained. It gives a crystalline hydrogen maleate melting at 68-69 ° C (acetyl ether). '

Example 3

N- [2- (Phenylthio) benzyl] pyrrolidine

A similar reaction of 11.7 g of 2-phenylthio / benzyl chloride and 14.2 g of pyrrolidine in 50 ml of boiling chloroform gives 10.2 g (76%) of an oily yellow base, m.p. 143-145 ° C / 50 Pa. It gives a crystalline hydrogen maleate melting at 93-94 ° C (acetone ether).

Example 4

N- [2- (Phenylthio) benzyl] piperidine

A similar reaction of 11.7 g of 2- (phenylthio) benzyl chloride and 17.0 g of piperidine in 50 ml of boiling chloroform gives 10.7 g (76%) of an oily yellow base boiling at 146-150 ° C / 60 Pa. The base gives crystalline hydrogen maleate, m.p. 102-103 ° C (acetone ether).

Example 5

N- [2- (Phenylthio) benzyl] morpholine

A similar reaction of 11.7 g of 2- (phenylthio) benzyl chloride and 17.4 g of morpholine in 50 ml of boiling chloroform gives 11.9 g (84%) of an oily base boiling at 159-161 ° C. Neutralization with malic acid gives crystalline hydrogen maleate, mp 118-119 ° C (acetone-ether).

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of 2- (phenylthio) benzylamine of general formula I, s _C6 h ₅ CH _of R (1) in which R is a residue of dimethylamine, diethylamine, pyrrolidine, piperidine or morpholine, and their hydrogen maleates, characterized in that 2- (phenylthio) benzyl chloride is reacted with a 100 to 120% excess of the secondary amine HR, wherein R is the same as in formula I, in chloroform at temperatures of 60 to 80 ° C, after which the bases of formula I obtained are converted into crystalline hydrogen maleatates by neutralization with malic acid.