Ivabradine hydrochloride

1086026-31-4

148849-67-6

1. 567 g of (S)-3-(3-(((3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl)methyl)(methyl)amino)propyl)-7,8-dimethoxy-1H-benzo[d]azepin-2(3H)-one was added to a reaction flask. 2. 2.55 L of glacial acetic acid and 141 g of palladium-carbon was added with thorough stirring and cooled to 20±5°C. 3. After evacuation, replace the nitrogen gas 3 times. 4. Control the temperature at 15~25°C and react under atmospheric pressure of hydrogen for 23 h. 5. Filter the reaction mixture through diatomaceous earth, and rinse the filter cake with glacial acetic acid. 6. Mix the filtrate with purified water and ethyl acetate, and mix thoroughly. 7. Adjust the pH to 9-10 with sodium hydroxide solution. 8. Separate the liquids, and the aqueous phase was extracted with ethyl acetate, and the organic phase was combined. 9. The organic phase was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution in turn. 10. The organic phase was dried overnight, filtered, and the filter cake was rinsed with ethyl acetate. 11. The filtrate was dried by rotary evaporation to give 403.9 g of ivabradine, with a yield of 70.9% and a purity of 96.3% by HPLC. 12. To a 10L reaction flask, 402 g of ivabradine and 6L of ethyl acetate were added and stirred. 13. 6L of ethyl acetate was added to a 10L reaction flask, stirred until complete dissolution, and cooled to 0~10°C. 13. 172.2g of 20wt% hydrogen chloride isopropanol solution was added, and a large amount of white solid precipitate was observed. 14. After stirring for 1 hour, it was filtered, and the filter cake was rinsed with ethyl acetate. 15. The solid was dried in vacuum for 15 hours, and 405.1g of white solid Ivabradine HCL was obtained, with the yields of 93.5% and HPLC purity of 99.3%. 16. HPLC purity was 99.8%.