GB837986A - New piperazine derivatives and process for the preparation thereof - Google Patents

Abstract

The invention comprises compounds of the general formula <FORM:0837986/IV (b)/1> (wherein R is a halogen atom or an alkyl radical, R1 is an alkyl, hydroxyalkyl, hydroxyalkoxyalkyl, aralkoxyalkyl or aralkyl radical, any carbocyclic ring of which may be substituted by an alkyl or alkoxy radical or a halogen atom, or R1 is an alkanoyl radical or an aroyl radical which may be halogen substituted, and n is an integer of from 2 to 6), and acid-addition salts thereof; and their preparation by the following methods: (1) reaction of a 1 - mono - [omega - (o - R - benzhydryloxy)-alkyl]-piperazine with an R1-halide, optionally in the presence of a hydrohalic acid acceptor, or with an aldehyde with subsequent reduction of the intermediate product with hydrogen in the presence of Raney nickel, or with an acid chloride to form an N-acyl piperazine which may then be reduced with lithium aluminium hydride to the corresponding N-alkyl- or aralkyl-piperazine; (2) reaction of an omega-(o - R - benzhydryloxy) - alkyl halide with a 1 - mono - R1 - piperazine, optionally in the presence of a hydrohalic acid acceptor; (3) reaction of an o-R-benzhydryl halide with a 1-(omega - hydroxyalkyl) - 4 - R1 - piperazine, optionally in the presence of a hydrohalic acid acceptor; (4) reaction of an o-R-benzhydrol with a 1 - (omega - halogen - alkyl) - 4 - R1-piperazine, optionally in the presence of a hydrohalic acid acceptor; or (5) by building up the R1 chain in several steps, for example by condensing the compound wherein R1 is -(CH2)2OH with ethylene chlorohydrin or ethylene oxide. Examples illustrate the above processes, in which R1 has the values hydroxy-ethoxyethyl, isopropyl, m - methyl - benzyl, acetyl, ethyl, methyl, 2-(p-t-butylbenzyloxy)-ethyl, isopropyl, n- and iso-butyl, 2-hydroxy-ethyl, 2 :3 - dihydroxypropyl, cyclohexyl, 3-methyl - cyclohexyl, benzyl, o - chlorobenzyl, o - methylbenzyl, p - t - butylbenzyl, o - methoxybenzyl, R has the values of chloro and methyl and n the values of 2,3,4- and 6. Hydrochlorides of the products are also described. 2 - (o - Chlorobenzhydryloxy) - ethyl chloride, 2 - (o - methylbenzhydryloxy) - ethyl chloride, 3-(o - chlorobenzhydryloxy) - propyl chloride, 4-(o - chlorobenzhydryloxy) - butyl chloride and 6 - (o - chlorobenzhydryloxy) - hexyl chloride are prepared from the appropriate benzhydrol and chloro-alkanol in presence of concentrated sulphuric acid and benzene. 1 - Mono - [2 - (o - chlorobenzhydryloxy)-ethyl] - piperazine (dihydrochloride also described), is prepared from 2-(o-chlorobenzhydryloxy)-ethyl chloride and piperazine, and 1 - mono - [2 - (o - methylbenzhydryloxy) - ethyl]-1 - [3 - (o - chlorobenzhydryloxy) - propyl] -, 1 - [4 - (o - chlorobenzhydryloxybutyl] - and 1 - [6 - o - chlorobenzhydryloxy) - hexyl] - piperazines are prepared similarly. 1 - Mono - cyclohexyl - piperazine is prepared from cyclohexyl bromide and piperazine, and 1 - (3 - methylcyclohexyl) - and 1 - mono - (o - methylbenzyl) - piperazines are prepared similarly. 1 - Mono - (2 : 3 - dihydroxypropyl - piperazine) is prepared from piperazine and epoxypropanol. 1 - (4 - Hydroxybutyl) - 4 - (m - methylbenzyl)-piperazine is prepared from 1-(m-methylbenzyl)-piperazine and 4-chlorobutanol, and 1-(3-hydroxypropyl) - 4 - (o - methylbenzyl) - piperazine is prepared similarly.