Patent GB-656588-A (GB)
Title: Improvements in or relating to substituted piperazines
IPC: C07D241/20
Filed: 1948-11-02
Abstract: 1-Substituted piperazines of the formula <FORM:0656588/IV (b)/1> where y1, y2, y3 and y4 are hydrogen methyl or ethyl and "Het" is the radical of a 5- or 6-membered nitrogen-containing mononuclear heterocyclic compound, attached via its <FORM:0656588/IV (b)/2> group, are obtained by reacting a piperazine <FORM:0656588/IV (b)/3> with a compound Het-Hal where "Hal" is chlorine, bromine or iodine. The reaction may be carried out in the presence of an acid-binding agent (e.g. alkali hydroxides and carbonates, piperazine, quinoline or pyridine) and a solvent (e.g. water, alcohol or organic bases). The products may be isolated by fractional crystallization or fractional distillation, or they may be converted into salts (e.g. hydrochloride, sulphate, citrate or lactate) from which the free bases may be regenerated.  In the examples the following "Het-Hal" compounds are used: 2-bromopyridine, 2-chloropyrimidine, 2 : 5-dichloropyrimidine, 2-chloropyrazine and 2-chlorothiazole.  1 : 4-Disubstituted piperazines of the formula <FORM:0656588/IV (b)/4> where y1, y2, y3, y4 and "Het" are as above, and R is alkyl or hydroxyalkyl of 1-6 carbon atoms, tertiary aminoalkyl, cycloalkyl, phenyl, tolyl, xylyl, naphthyl, halogen or hydroxy-substituted phenyl or naphthyl, aralkyl or "Het," are obtained (1) by treating 1-substituted piperazines as above with R-Hal, ethylene oxide or formaldehyde, or (2) by treating a piperazine of the formula <FORM:0656588/IV (b)/5> with Het-Hal; the mixture is heated to a temperature not above the boiling point at the operating pressure until reaction ceases. The reaction is preferably carried out in the presence of an acid-accepting agent at a temperature between 125 DEG and 200 DEG  C. with agitation.  The product may be separated by filtration or solvent extraction, followed by distillation or recrystallization. Alternatively, it may be converted into a salt such as a hydrochloride, hydrobromide, sulphate, citrate or quaternary methobromide or ethiodide.  The products are 1 : 4-derivatives of piperazine, or its mono-, di-, tri- and tetra-methyl- and ethyl-derivatives, e.g. 2-methyl-, 2-ethyl, 2 : 5- and 2 : 6-dimethyl- and diethyl-piperazines.  Specified radicals for R are methyl, ethyl, isopropyl, n-amyl, b -hydroxyethyl, b -dimethylaminoethyl, cyclohexyl, phenyl, p-chlorophenyl, p-hydroxyphenyl, p-tolyl, 2 : 4-xylyl, benzyl, p-methoxybenzyl and b -naphthyl.  "Het" may be pyridyl, pyrimidyl, 5-chloropyrimidyl, pyrazyl, thiazyl or pyridazyl.  Examples are given of both methods of obtaining the products, the reactants R-Hal in method (1) being ethylene oxide, b -dimethylaminoethyl chloride and formaldehyde. According to the Specification as open to inspection under Sect. 91, y1-4 may be any lower alkyl group; additional groups specified for R are n-propyl, n-butyl, isobutyl, isoamyl, hexyl, ethylcyclohexyl and phenylethyl.  It is also stated that both the 1- and 1 : 4-compounds may be prepared in an aqueous medium containing free hydroxyl groups, or in an alcoholic medium containing alkali or alkaline earth metal carbonates.  The 1 : 4-compounds may also be prepared in a basic organic solvent such as quinoline or pyridine.  This subject-matter does not appear in the Specification as accepted.