Structural Analogues of GABA. Synthesis of 5-Aminomethyl-3-isothiazolol (Thiomuscimol).

Abstract

The synthesis of 5-aminomethyl-3-isothiazolol zwitterion (12), a thio analogue of muscimol (5-aminomethyl-3-isoxazolol), is described. Reaction of the starting material aminofumaramide (1) with excess of H2S gives dithiodisuccinamide (2) which is oxidized by bromine to give 3-hydroxyisothiazole-5-carboxamide (3). Conversion of 3 into the O-methyl derivative 5 by treatment with diazomethane, followed by reduction with diborane gives 3-methoxy-5-aminomethylisothiazole, the hydrochloride 9 which is transformed into 5-aminomethyl-3-isothiazolol dihydrobromide (10). Treatment of 10 with ethanol gives the corresponding monohydrobromide 11 and conversion of 10 into 5-aminomethyl-3-isothiazolol zwitterion (12) is accomplished by treatment with triethylamine. The pKA values of 12 are determined to 6.06 .+-. 0.03 and 8.85 .+-. 0.04.