Manidipine hydrochloride

89226-50-6

89226-75-5

Synthesis of 3-(2-(4-phenylpiperazin-1-yl)ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate from 3-(2-(4-phenylpiperazin-1-yl)ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5- Dicarboxylate dihydrochloride was prepared in the following general procedure: manidipine base (2.25 kg) was dissolved in a solvent mixture of dichloromethane (6.75 L) and methanol (4.5 L) and cooled to 0-10°C. Concentrated hydrochloric acid (1.07 L) was slowly added dropwise under stirring, and after completion of the dropwise addition, the reaction was continued with stirring for 1 hour by keeping the temperature at 0-10 °C. Subsequently, methyl tert-butyl ether (13.5 L) was added to the reaction system and stirring was continued for 1 h. A large amount of solid was observed to precipitate. Filtration was carried out and the filter cake was washed with a small amount of methyl tert-butyl ether. The filter cake was mixed with dichloromethane (22 L), refluxed and pulped for 1 hour, then cooled to room temperature and filtered again. The filter cake was washed with a small amount of methyl tert-butyl ether and finally dried at 40-50 °C in a blast to give a yellow solid product (2.05 kg). The yield of this step was 81.8% and the purity of the product was 99.8869% (see Figure 2 for HPLC analysis).