Improved Synthesis of Bepotastine Besilate

摘要

Bepotastine besilate (1, Figure 1, synonymous with bepotastine besylate), is a non-sedative highly selective histamine receptor antagonist, which has a stabilizing effect on mast cells. This antihistamine can also prevent eosinophils from migrating to inflammatory tissues and thus reduce allergic inflammation.This widely available commercial product works quickly and effectively. Methods for the synthesis of bepotastine besilate have been amply documented in the existing literature. Among them may be found the patented route of J. I. Kita and colleagues (Scheme 1). In this route, piperidine 2 was reacted with ethyl 4-bromobutyrate 3 to obtain compound 4. Then, butyric acid derivative 5 was prepared by hydrolysis, and bepotastine besilate 1 was finally obtained by salt formation with benzenesulfonic acid. This method has attracted our attention, and an improvement on it forms the subject of this communication. In particular, we have focused on the preparation of compound 4. According to the literature,8 2, 3 and potassium carbonate were loaded into acetone at room temperature and then heated to reflux for 7 hours. In our hands, we found that 2 could not react completely and the volume of solution was excessive. The reaction system was not uniform. If dimethylformamide (DMF) or an acetone-water system was used as solvent, the reaction could be complete, but the waste solvent was difficult to recover. The amount of waste liquid would of course be even larger upon scale-up. We thus made an analysis of the effects of solvent and particle size of the potassium carbonate, and the results are summarized in Table 1. The best results were obtained with crushed potassium carbonate and 5 volumes of acetone (Table 1, entry 5). In the post-treatment process, we only had to filter off the inorganic salts, and the filtrate could be concentrated under reduced pressure to get 4.