An improved route to urapidil from 1-(2-methoxyphenyl)piperazine and oxetane

Urapidil is an important drug for the treatment of essential hypertension and intravenously in hypertensive emergencies. Herein, an improved route to Urapidil was introduced. The new designed synthetic route starts with the addition reaction of 1-(2-methoxyphenyl)piperazine and oxetane catalyzed by Yb(OTf)3 in acetonitrile to form the key intermediate 3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-1-ol. Additionally, 3-(4-(2-methoxyphenyl)piperazin-1-yl)propan-1-ol was purified by recrystallization from the optimized solvents, which was beneficial to large scale production. Intermediate 3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl-4-methylbenzenesulfonate was cast directly for the subsequent reaction without further purification. The overall yield of this route is about 45%. The structure of the final product was well confirmed by 1H-NMR, 13C-NMR and HRMS.