盐酸西那卡塞合成工艺研究

Study on synthetic process of cinacalcet hydrochlorid

目的优化盐酸西那卡塞的合成工艺。方法以间三氟甲基苯丙醇为起始原料,经甲磺酸酯化后与(R)-1-萘乙胺发生亲核取代反应制备西那卡塞,再与盐酸成盐,在甲醇溶液中重结晶制得药用Ⅰ晶型盐酸西那卡塞。结果与结论目标化合物结构经1H-NMR谱确证,纯度在99.9%以上(HPLC法),总收率在65%以上。用甲基叔丁基醚代替甲苯,可以有效去除剩余反应物和二取代的副产物,不需乙酸乙酯重结晶过程。优化后的工艺操作步骤简便,反应收率提高,可得到高纯度的目标产物,更适合工业化生产。

Cinacalcet hydrochloride is a calcimimetic agent used to treat secondary hyperparathyroidism in dialysis patients.Although many synthetic routes of cinacalcet hydrochloride were described, but new routes of this important drug were still needed.In this paper the procedure for the preparation of cinacalcet hydrochloride was optimized.The target compound was synthesized from m-trifluoromethyl phenylpropanol via sulfonylation, nucleophilic substitution with(R)-1-naphthylethylamine and purification.The crystal form I of cinacalcet hydrochloride was obtained by recrystallization in methanol-water solvent system, which was confirmed by XDR experiment.The purity of the product was more than 99.9% by HPLC,and the total yield was above 65%.The study emphasized on optimizing the amount of(R)-1-naphthylethylamine in nucleophilic substitution reaction and using methyl-tert butyl ether as purification solvent instead of toluene and ethyl acetate mentioned in the literatures.It was not only simplified the operation process, but also effectively removd the excess of(R)-1-naphthylethylamine and the di-substituted byproduct generated during the reaction.Under optimized conditions, high-purity target product was obtained with a total yield of 65%.