羟基依巴斯汀的合成方法研究

Study on synthetic process of hydroxyebastine

目的设计合成新型抗过敏药物依巴斯汀的人体活性代谢产物——羟基依巴斯汀。方法以苯甲酰氯为原料,经付克酰基化、还原和置换反应得到中间体二苯基溴甲烷(4);再以α,α-二甲基苯乙酸为原料,经过5步反应得到中间体9;中间体4和中间体9经缩合、水解反应得到目标产物。结果与结论目标化合物的总收率为21.0%,其结构经1H-NMR谱和M S谱确证,纯度经HPLC测定达99.6%。

A practical synthesis of hydroxyebastine,the primary active metabolite of a new antianaphylaxis drug ebastine,was fully described firstly.The successful synthesis of hydroxyebastine can facilitate the metabolism and bioavailability studies of ebastine.The crucial steps of this synthesis route were the Friedel-Crafts acylation of ethyl-2-methyl-2-phenyl propanoate with 4-chlorobutyryl chloride,followed by reaction with 4-hydroxypiperidine to form the key intermediate,ethyl-2-[4-（4-（4-hydroxy-1-piperidineyl）butyryl）phenyl]-2-methyl propanoate（9）.Bromodiphenylmethane（4）,another key intermediate,was prepared beforehand in three steps.After condensation between two key intermediates,followed by hydrolysis in alkaline solution,the target compound as a white solid was obtained.The total yield of the synthesis was 21.0% with 99.6% chemical purity by HPLC,and the structure of the target compound was confirmed by 1H-NMR and high-resolution MS.