The Synthesis Of Urapidil And Analyse Of Its Polymorphic Forms

Urapidil is a new antihypertensive drug, which can observably decline the blood pressure with a special mechanism. Urapidil was firstly synthesized and launched into the market in Germany in 1981. Now it has been widely selled in more than thirty countries, such as English and French. It also has been extensively applied in China since its prominent curative effect and high security.Three synthsis methods of urapidil have been reported in the literature. The bioavailability of pharmacologically active compounds is frequently dependent on their crystalline forms. By means of many experiment techniques, it was found that urapidil can exist in seven crystalline forms, anmely form I, form II, form III, methanol solvate, monohydrate, trihydrate and pentahydrate. Among them form II is the most suitable one for the industrial production since its high stability and bioavailability.In this paper, the reaction mechanism of urapidil was studied through theoretical analysis and experiments. The synthesis processes and reaction conditions of four intermediate materials for synthesis of urapidil, such as 6-amino-1,3-dimethyluracil, 1,3-dimethyl-4-(γ-hydroxypropylamino) uracil, 1,3-dimethyl-4-(γ-chloropropylamino) uracil and hydrates of urapidil, were investigated respectively. The synthesis routes were decided and the objective compound was synthesized through four steps. The total yield of urapidil was 85%.To investigate the effects of solvents on the crystal morphology of urapidil, urapidil crystals were grown from different solvents, such as methanol, isobutene, et al., and tested by the melting point method, differential scanning calorimetry and power X-ray diffraction. The best solvent for the industrial crystallization of urapidil of form II was selected. This work can supply data for industrial manufacture of urapidil with high quantity and good bioavailability.