CS268400B1 - Process for the preparation of N - ((2-biphenylyloxy) alkyl) piperazines and their hydrochlorides - Google Patents

Abstract

The invention relates to the synthesis of drugs. Its subject is a method for preparing 1-(2-(2-biphonylyloxy)ethyl)- and 1-(3-(2-biphonylyloxy)propyl)-piperazines substituted in the 4-position by methyl, 2-hydroxyethyl or 3-hydroxypropyl, as well as their crystalline dihydrochlorides. The bases according to the invention are intermediates for the preparation of other pharmacodynamically active substances, the hydrochlorides themselves have anticonvulsant activity and are potential antiepileptics. The method of preparing the substances according to the invention consists in substitution reactions of 2-(2-bromoethoxy)biphenyl and 2-(3-bromopropoxy)biphenyl with 1-methylpiperazine, 2-(1-piperazinyl)ethanol or 3-(1-piperazinyl)propanol, which are carried out by heating the mixtures of the mentioned components to 130 to 140 °C. The obtained bases are neutralized with hydrogen chloride or hydrochloric acid and converted into hydrochlorides.

Description

Impact 1

1- (2- (2-Biphenylyloxy) -4-methylpiperazine

Stags 5.6 g of 2- (2-bromoethoxy) benzyl and 6.0 g of 1-methylphosphorus are stirred and heated at 130 DEG C. for 9 hours. Excess t-methylpiperazine is distilled off in vacuo, the residue ee dilute with water and extract ee with benzene. From the ee extract, the base is converted by shaking into excess 1: 1 dilute hydrochloric acid, the separated aqueous layer is basified with aqueous ammonia and the base is isolated by extraction with benzene. Work-up of the extract gave 5.3 C (88%) of crude oil, which was converted to the dihydrochloride by neutralization with ethereal hydrogen chloride. This crystallizes in 98% ethanol as the dihydrate and melts at 205 to 209 ° C.

The starting 2- (2-bromoethoxy) biphenyl used is prepared from commercial 2-hydroxybiphenyl as follows: A mixture of 9.2 g of 2-hydroxybiphenyl, 3.7 g of potassium hydroxide, 40 g of 1,2-dibromothane, 2 ml of water and 15 ml of tert-butyl alcohol is refluxed for 1 h. Then 20 g of 1,2-dibromoethane, 3.0 β of potassium hydroxide and 4 ml of water are added and the mixture is refluxed for a further 1 h. The volatiles were evaporated in vacuo, the residue was diluted with sodium hydroxide solution and extracted with benzene. Work-up of the extract gave 12.2 g (81%) of crude product, which crystallized on standing. It is purified by crystallization from ethanol and then melts at 65-67 ° C.

Example 2

1- (3- (2-Biphenylyloxy) propyl) -4-methylpiperazine

As in the previous example, a mixture of 5.8 g of 2- (3-bromopropoxy) -biphenyl and 6.0 g of 1-methylpiperazine was heated at 13 ° C for 16 h. Work-up gave 5.2 g (84%) of an oily base which was converted to the dihydrochloride, m.p. 198-202 ° C (ethanol).

Example 3

1- (2- (2-Biphenylyloxy) ethyl) -4- (2-hydroxyethyl) piperazine

As in the previous examples, a mixture of 6.9 g of 2- (2-bromoethoxy) biphenyl and 10.0 g of 2- (1-piperazinyl) ethanol is heated to 130 DEG C. for 10.5 h. Analogous work-up gave 7.7 g (95%) of an oily base which gave crystalline dihydrochloride, m.p. 188-192 ° C (methanol-ether),

Example 4

1- (3- (2-Biphenylyloxy) propyl) -4- (3-hydroxypropyl) piperazine

As in the previous example, a mixture of 5.8 g of 2- (3-bromopropoxy) -biphenyl and 8.6 g of 3- (1-piperazinyl) propanol is heated to 140 DEG C. for 12 hours. Analogous work-up gave 6.2 g (89%) of an oily base which gave crystalline dihydrochloride, m.p. 210-214 ° C (ethanol).

Example 5

1- (2- (2-Biphenylyloxy) ethyl) -4- (S-hydroxypropyl) piperazine

As in the previous examples, a mixture of 5.5 g of 2- (2-bromoethoxy) biphenyl and 8.6 g of 3- (1-piperazinyl) propanol is heated at 140 DEG C. for 12 hours. Analogous work-up gave 6.3 g (93%) of an oily bass, which was converted to crystalline dihydrochloride, m.p. 205 to 209 ° C (mothonol).

Claims (1)

BACKGROUND OF THE INVENTION A process for the preparation of an N - ((2-biphenylyloxy) alkyl) piperazine of formula I wherein n is 2 or 3 and R is hydrogen, CH 2 OH or C 1-6 Cl 2 OH, and is a hydrochloride, featuring! in that 2- (bromoalkoxy) biphenyls of the general formula II in which n denotes the same As in formula I, they heat up with the piperazinyl dorset of general formula III wherein R is the same as in Formula I, at 130 to 10 ° C, whereupon the oily base (s) obtained by the general formula (I) are converted to crystalline hydrochlorides by neutralization with hydrogen chloride or hydrochloric acid.