盐酸吉西他滨的合成工艺研究

目的合成抗癌药盐酸吉西他滨并优化其合成工艺。方法以2-脱氧-2,2-二氟-D-赤式-呋喃戊糖-1-酮-3,5-二苯甲酸酯为起始原料,经还原、甲磺酰化、缩合、脱保护成盐、纯化得到目标化合物盐酸吉西他滨。结果与结论经四步反应和一步纯化过程制得盐酸吉西他滨,其结构经1H-NMR、13C-NMR、MS和IR谱确证。改进后的工艺操作简单,总收率达到7.36%,产品纯度达到99.91%,适合于工业化生产。

Study on synthetic process of gemcitabine hydrochloride

Gemcitabine hydrochloride, a nucleoside homologues, was developed by Eli Lilly and Company. It is the only one first-line drug to treat pancreatic cancer. In this paper, a new synthetic route has been estab lished based on the literatures. Using 2-deoxy-2,2-difluoro-D-erythropentofuranos-l-ulose-3,5-dibenzoate as the starting material, gemcitabine hydrochloride was synthesized through five steps, including reduction, mesylation, condensation, deprotection and purification. In the first step, 2-deoxy-2,2-difluoro-D-erythro-ri bofluranose-3,5-dibenzoate （3） was obtained by reduction of the starting material（2） in the presence of Li- A1 （OBu-t）3H in ethyl acetate which acted as both a reaction solvent and extraction solvent. The target com- pound, gemcitabine hydrochloride, was successfully obtained by deprotection of 2＇-deoxy-3＇, 5 ＇-di-O-benzo- yl-2＇ ,2＇-difluorocytidine（5） in the presence of tert-butylamine in methanol. The product was obtained by purified with a mixture solution of water and ethanol. The total yield of the procedure is 7.36% and the pu rity of the final product is 99. 91%. Its structure was confirmed by 1H-NMR, 13C-NMR,IR and MS spectra. The improved process has several advantages over these reported procedures, such as mild conditions and simple operations. Anyway it＇s more suitable for industrial production.