THE SYNTHESIS OF 2-METHYL-4-BIS-(2'-CHLOROETHYL)-AMINOMETHYL-THIAZOLE HYDROCHLORIDE

Ethyl cyanoacetate in ethyl alcohol (triethanolamine catalyst) was treated with hydrogen sulfide gas at 408—50° for 60 hours in order to get ethyl thiocarbamylacetate (Ⅰ). Treatment of the crude reaction mixture with 1, 3-dichloroacetone, however, gave 2-methyl-4-chloromethylthiazole hydrochloride (Ⅲ) instead of the expected ethyl 4-chloromethyl-2-thiazolylacetate (Ⅱ). It has been reported that ethyl thiocarbamylacetate (Ⅰ) reacted normally with α-halocarbonyl compounds to form thiazole derivatives. The method of preparation of Ⅰ in the literature cited consists of treatment of ethyl cyanoacetate in ether (triethylamine catalyst) with hydrogen sulfide at 65—70° for 2 hours. Probably our experimental condition was more strenuous so that Ⅰ suffered further decomposition giving thioacetamide as the result of hydrolysis and decarboxylation. The formation of Ⅲ from thioacetamide is straightforward. As part of a program on the study of physiologically active heterocycles, Ⅲ was treated with diethanolamine and then with thionyl chloride to give the nitrogen mustard, 2-methyl-4-bis-(2'-chloroethyl)-aminomethyl-thiazole hydrochloride (Ⅵ).