A facile synthesis of epinastine HCl via dehydroepinastine intermediate

Abstract Epinastine is a second generation histamine H1 receptor antagonist used as a non-sedative antiallergic drug. When given orally, epinastine poorly penetrates blood-brain barrier (BBB) and appears to be free of cardiac toxicity as compared to other antihistamine drugs. A couple of synthetic approaches for epinastine HCl have been reported so far. They hold several problems such as explosive, highly toxic or expensive reagents. Moreover, they usually do not offer concise synthetic steps. In our synthesis shown here, a commonly used starting material, 6-(chloromethyl)-11H-dibenzo[b,e]azepine is treated with cyanamide to afford dehydroepinastine (14) in significantly high yield, which is subsequently reduced in the presence of aqueous HCl to give epinastine HCl in only two steps (75% overall yield for two steps). The problems associated with the reported processes such as using toxic and dangerous chemicals, lengthy synthetic steps or low overall product yields can be overcome by utilizing this new route. We believe our synthetic scheme might provide a breakthrough to reduce the cost of the production of epinastine HCl.