The general procedure for the synthesis of 4-(2,3-dichlorophenyl)-5-(methoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, using 3-(2-cyanoethyl) 5-methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3-dicarboxylate as a starting material, was as follows: in a three-necked flask equipped with a stirrer, add 400 g of Intermediate II and 2 L of isopropanol and stirred until completely dissolved. Subsequently, 30 g of potassium hydroxide and 10 g of triethylbenzyl ammonium bromide were added, heated to 80 °C and stirred at reflux for 5 to 6 hours. After completion of the reaction, it was cooled to room temperature and the reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure. To the dried residue, 2 L of dichloromethane and 2 L of water were added, stirred for 10 minutes and left to stratify. Dilute hydrochloric acid was slowly added dropwise to the aqueous phase under ice bath conditions to adjust the pH to 4.5 and stirring was continued for 1 hour. Subsequently, filtration was carried out and the filter cake was washed with pure water to pH=7. After drying, 260 g of product was obtained and the purity was 96.11% by HPLC.
In another reaction flask, 130 g of crude intermediate butyl clovedipine and 650 ml of ethyl acetate were added, stirred and heated to 40 °C, maintained for 10 min and then hot filtered. The filter cake was dried to give 122 g of pale yellow solid, the important intermediate clovidipine butyrate. The purity was 99.09% and the yield was 93% by HPLC. The total yield of the present synthesis method was 53%, which gave an important intermediate of clovidipine butyrate acid with high purity.
