Synthesis and exchange reactions of 5-alkyl-2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acids

An improved preparation of 2-oxo-6-thioxo-1,2,3,6-hexahydropyrimidine-4-carboxylic acid 3, a potent inhibitor of dihydroorotase is presented. Trans-5-alkyl-2-oxo-6-thioxohexahydropyrimidine-4-carboxylic acids 12a-c were synthesised via the thiation of the p-methoxybenzyl esters of 5-alkyldihydroorotic acids with Lawesson's reagent followed by subsequent de-protection. The corresponding cisisomers were prepared by reduction of 5-alkyl-6-thioxoorotic acids with zinc in acetic acid. The stability and exchange reactions of 12a-c under physiological conditions were investigated by ultra-violet and ¹H nmr spectroscopy. The attempted synthesis of 16 , a fused cyclopentyl derivative of 3 is also presented.