GB666420A - Improvements in or relating to the preparation of monocarbamyl substituted piperazines and hydrohalide salts thereof - Google Patents

Abstract

Monocarbamyl substituted piperazines of the general formula <FORM:0666420/IV (b)/1> (wherein R represents hydrogen or an alkyl radical of 1-4 carbon atoms and Alk represents an alkyl radical of 1-4 carbon atoms), and their hydrohalides, are manufactured by acylating an alkyl substituted piperazine of the formula <FORM:0666420/IV (b)/2> with a carbamyl halide <FORM:0666420/IV (b)/3> (wherein X represents halogen, e.g. bromine or especially chlorine), and, if desired, subsequently or simultaneously treating the resulting hydrohalide with a strong base to obtain the free monocarbamylpiperidine. The reaction is advantageously carried out at about 20-100 DEG C. in the presence of a solvent, e.g. at about 30-50 DEG C. in an aqueous alcoholic solvent such as aqueous ethanol, or at somewhat higher temperatures in non-aqueous solvents such as benzene, toluene, chloroform, carbon tetrachloride or dibutyl ether. The alkylpiperazine is preferably used in anhydrous form and in sufficient excess to provide an acceptor for the hydrohalic acid formed. In this case, when working in aqueous alcoholic solution, the excess alkylpiperazine may be precipitated with acid, leaving (when the starting material is unsubstituted on both nitrogen atoms) a solution of mono- and di-carbamylalkylpiperazines. The former may be caused to separate by concentrating the solution and removing the last traces of water by azeotropic distillation with benzene or toluene, and may, if desired, be further alkylated by treatment with an alkylating agent (e.g. an alkyl sulphate, sulphonate or halide, or formaldehyde in the presence of formic acid or of zinc and hydrochloric acid). The products are useful as veterinary filaricides. In examples: (1) 2 : 5-dimethylpiperazine is warmed with diethylcarbamyl chloride in benzene; (2) the product of (1) is reductively methylated by means of formaldehyde and formic acid. Additional starting materials specified are 2 : 6-dimethyl-and 1 : 2 : 5-, 1 : 2 : 6- or 1 : 3 : 5-trimethylpiperazine; methyl-, ethyl-, propyl-, dimethyl-, di-n- or iso-propyl- and methyl-ethylcarbamyl halides.