Development of a Practical Synthetic Route of a PDE V Inhibitor KF31327

An efficient route suitable for a large-scale preparation of KF31327 ( 1 ), a potent phosphodiesterase V inhibitor, has been developed. We selected 7-chloro-2,4(1 H,3 H )-quinazolinedione ( 15 ) as a starting material, which gave the desired 6-nitro compound with good selectivity. In the chlorination of 7-ethylamino-6-nitro-2,4(1 H,3 H )-quinazolinedione ( 17 ), reaction conditions were optimized to minimize the amount of phosphorus oxychloride, and 2,4-dichloro-7-ethylamino-6-nitroquinazoline ( 14 ) was obtained in excellent yield. After the selective substitution at C4 position, the chloro substituent at C2 position was successfully removed by hydrogenation concomitant with the reduction of nitro group. The construction of the imidazothione ring was achieved by using phenyl isothiocyanate as a thiocarbonyl donor instead of extremely flammable carbon disulfide. Multikilograms of drug substance have been successfully prepared by these procedures.