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.