GB817231A - New derivatives of n-mono-benzhydryl-piperazine and process for the preparation thereof - Google Patents

Abstract

The invention comprises benzhydrylpiperazine derivatives of the general formula <FORM:0817231/IV (b)/1> and their acid addition and mono quaternary ammonium salts (wherein R and R1 each represent a hydrogen or halogen atom or an alkyl or alkoxy group and may be in an o-, m-, or p-position, and n is 1 or 2), together with their preparation by (1) reacting a 1-(R,R1-benz hydrylpiperazine) with a compound Hal-(CH2CH2O)n-CH2CH2OH (in which Hal is a halogen atom) in the presence of an acid-acceptor; (2) by converting a 1 - (R,R1 - benzhydryl) - 4 - (21 - hydroxyethyl)-piperazine into its chloro-derivative with thionyl chloride and reacting this with HO-(CH2CH2O)nM (wherein M is an alkali-metal atom); (3) by reacting a 1 - (R,R1 - benzhydryl) - 4 - (21 - hydroxyethyl) - piperazine, or its alkali - metal derivative, with Hal-(CH2CH2O)nH; (4) by reacting an R,R1-benzhydryl halide with a piperazine derivative of the formula <FORM:0817231/IV (b)/2> or (5) by reacting a 1-(R,R1-benzhydrylpiperazine) with ethylene oxide. Compounds of the formula I wherein n is 2 are also prepared by (6) converting a 1-(R,R1-benzhydryl)-4-[21 - (211 - hydroxyethoxy) - ethyl] - piperazine into the corresponding chloro-compound with thionyl chloride and reacting this with a monometallic derivative of glycol; or (7) by reacting a 1 - (R,R1 - benzhydryl) - 4 - [21 - (211 - hydroxyethoxy) - ethyl] - piperazine with a monohalohydrin of glycol. In examples, the preparation of the following compounds (together with some of their acid addition salts and quaternary ammonium compounds) is described, by the methods indicated in brackets: 1 - o - bromo -, 1 - m - bromo - and 1 - p - bromobenzhydryl - 4 - [21 - (211 - hydroxyethoxy) ethyl]-piperazine; (5), (2) and (1), respectively; 1 - m - methylbenzhydryl - 4 - [21 - (211 - hydroxyethoxy)ethyl]-piperazine, (3); 1-(p-methyl - p1 - methoxy) benzhydryl - 4 - [21-(211 - hydroxyethoxy)ethyl]-piperazine, (4); 1-p - bromo - and 1 - p - chlorobenzhydryl - 4 - {21 - [211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine, both (1); 1-o-chlorobenzhydryl-4-{21 - [211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine, (2); 1-o-bromo- and 1-m-bromobenzhydryl - 4 - {21 - [211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine, (3) and (6) respectively; 1 - m - n - butylbenzhydryl - 4 - {21 - [211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine, (7); 1-m-methoxybenzhydryl-4-{21-[211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine, (4); 1-(p-methoxy-p1-methyl)benzhydryl - 4 - {21 - [211 - (2111 - hydroxyethoxy) ethoxy]ethyl}-piperazine, (5). The following are also described, with physical constants: 1 - o - chloro -, 1 - m - chloro -, 1 - (p - chloro - p1 - chloro)-, 1-o-methyl-, 1-m-methoxy- and 1 - o - amyloxy - benzhydryl - 4 - [21 - (211-hydroxyethoxy)ethyl]-piperazine, and 1-benzhydryl-, 1 - p - chlorobenzhydryl - and 1 - m - methyl - benzhydryl - 4 - {21 - [211 - (2111 - hydroxyethoxy)ethoxy]ethyl}-piperazine. 1 - p - Bromobenzhydrylpiperazine is obtained by the action of p-bromobenzhydrylchloride on piperazine, and the following are also described (with boiling points): 1-o-chloro-, 1-m-chloro-, 1-o-bromo-, 1-m-bromo-, 1-p,p1-dichloro-, 1-o-methyl-, 1-m-methyl-, 1-m-methoxy-, 1-o-amyloxy- and 1 - (p - methyl - p1 - methoxy) - benzhydryl-piperazine. 1 - m - Bromobenzhydryl - 4 - (21 - hydroxyethyl)-piperazin is prepared by reacting m-bromobenzhydryl chloride with N-(2-hydroxyethyl) piperazine, and converted into the corresponding 21-chloro-compound; 1-m-methylbenzhydryl - 4 - (21 - hydroxyethyl) piperazine is prepared similarly. 1 - o - Chlorobenzhydryl - 4 - (21 - hydroxyethyl) piperazine is obtained by reacting o-chlorobenzhydryl chloride with 1-(21-hydroxyethyl) piperazine, and converted by the action of thionyl chloride into the corresponding 21 - chloro - derivative; o - bromobenzhydryl - 4 - (21\h - hydroxyethyl) piperazine is prepared similarly. 1 - m - Bromobenzhydryl - 4 - [21 - 211 - chlorethoxy)ethyl] - piperazine is prepared by the action of thionyl chloride on the corresponding hydroxy-compound. 1 - {21 - [211 - (2111 - Hydroxyethoxy)ethoxy]ethyl} - piperazine is obtained by reacting ethyleneglycol monochlorhydrin with piperazine. m - n - Butyl - benzhydrol, obtained by reacting benzaldehyde with a magnesium derivative of m-bromobutylbenzene, is converted into the corresponding chloride which in turn is reacted with piperazine to give 1-m-n-butylbenzhydryl-piperazine; the latter is condensed with 2-(21-chlorethoxy)ethanol to give 1-m-n-butyl - benzhydryl - 4 - [21 - (211 - hydroxyethoxy)-ethyl]-piperazine.