Scalable Process of Methimazole

Base hydrolysis of imidazole carboxylate was observed to be an efficient route for the scalable synthesis of the antithyroid drug methimazole. Ethyl 3-methyl-2-thioxo-2,3-dihydro-1H-imidazole-1-carboxylate (12) was produced as a key intermediate in the reaction of 1-methyl-1H-imidazole (4) with ethyl chloroformate (11) and sulfur. Compound 12 undergoes hydrolysis in two steps in the presence of a base to give methimazole (1) with an overall yield of 78%. The process was studied through the Quality by Design (QbD) concept and observed to be robust.