Synthetic Process Study Of Epinastine Hydrochloride

The incidence of allergic diseases is going to increase evey year, more and more people pay attention to public health problem around the world. Epinastine hydrochloride is an antihistamine developed by Nippon Boehringer Ingelheim and Sankyo Company jointly. And named Alesion go public in Japan since 1994, mainly for treatment of allergic rhinitis, dermatitis and other diseases. The drug has good features and other significant treatment effect and tolerability of anti-histamine in the competitive market. It is a considerable strength of the varieties and the market future is wide prospect.Designing of 2-amino benzophenone as the starting material on the basis of the literature, after reduction, acylation, cyclization, substitution, catalytic hydrogenation, hydrazinolysis, cyclization and sait-forming. Through detailed analysis of each reaction, this paper present made some optimization and improvement.2-benzyl-aniline is prepared with glycol monomethyl ether used as the solvent and hydrazine hydrate as the reducing agent, the optimal ratio of hydrazine hydrate is 1:4.5, and achieve recovery of the solvent, the yield increased from 40% to 94.5%, the purity is 97.5%. N-[2-(phenyl methyl)phenyl]-2-chloroacetamide is prepared with pyridine used as the acid-binding agent, the optimal ratio of chloroacetyl chloride was 1:1.1, the optimal reaction temperature is 0~5 ℃, the yield increased from 90% to 97.3%, the purity is 99.2%. 6-chloro-thiophene-methylmorpholine is prepared with phosphorus oxychloride and phosphorus pentoxide used as dehydrating agent, the optimal ratio of phosphorus oxychloride is 1:5.0, the reaction temperature is 90℃, reaction time was 5 h, the yield increased from 86% to 98.6%, the purity is 99.5%.6-phthalimide methyl pyridine alkyl thiophene is prepared with phthalimide potassium salt used as amino-protecting agent and acetonitrile replacing DMF as the solvent, and determine the optimal amount of acetonitrile, the yield and purity of the product are 98.6% and 99.5%, respectively. 6-(phthalimido-ylmethyl)-6,11-dihydro-5H-dibenzo-[b,e]azepine is prepared with Pd/C used as the catalyst by the methods of catalytic hydrogenation, palladium on carbon are activated by formic acid. the optimal amount of catalyst is 10%, the optimal hydrogen pressure is 600 kPa, the optimal reaction temperature is 60℃, the yield and purity of the product are 91.5% and 99.3%, respectively. 6-aminomethyl-6,11-dihydro-5H- dibenz [b, e] azepin is prepared with ethanol used as the solvent, the optimal ratio of hydrated hydrazine was 1:2.0, the yield increased from 70% to 77.5%, the purity is 99.5%.Epinastine hydrobromide is prepared with cyanogen bromide, the optimal ratio of cyanogen bromide is 1:1.4, the optimal reaction pH is 5, the optimal reaction temperature is 25℃, the yield increased from 64.5% to 86%, the purity is 99.3%.By this technology the recovery of epinastine hydrochloride is 48%, higher than 22.3% of the original technology. The structure and purity of the substances were confirmed by IR, 1HNMR and HPLC.