The Synthesis Of Antianginal Drug Ivabradine Hydrochloride

Ivabradine hydrochloride, developed by Servier Company in France, is the first selective and specific If channal inhibitor with hate rate-lowering activity. It is the one of the most significant progress for treatment of cardiovascular disease in the past 20 years and is applied for the treatment of chronic stable angina pectoris.This article reports a synthetic route of racemic ivabradine hydrochloride based on the literature, which was designed to avoid patent protection and is economically feasible and suitable for industrial production. The target product was prepared via a 16-step reaction from the cheap available veratrum aldehyde and homoveratric acid. The overall yield of racemic ivabradine hydrochloride was 15.8% from homoveratric acid (8.7% reported in literature) in this thesis.During the preparation of 1-cyano-4,5-dimethoxybenzocyclobutene (2) from 3-(2-bromo-4, 5-dimethoxyphenyl)-propanenitrile (24), the use of LDA in THF instead of amino-sodium in liquid ammonia could improve the reaction yield and facilitate the reaction process.For the preparation of 7,8-dimethoxy-3-(3-chloropropyl)-1,3-dihydro-2H-benzazepin-2-one (7), the deprotonation of the lactam could be fulfilled by using inorganic base as NaOH or Na2CO3 while KOBu’had to be used in literatures. This reaction could be performed at room temperature in the case of NaOH.