卡培他滨的合成工艺改进

Improvement of synthesis process of capecitabine

以D-核糖为起始原料经缩酮化、酯化、NaBH_4在DMSO与石油醚(1∶0.5∶1.5)还原、水解、无水醋酸钠催化酰化制备中间体(6a&6b)与5-氟胞嘧啶进行Silyl反应制备同一构型的5′-脱氧-2′,3′-二-O-乙酰基-5-氟胞苷(7),(7)再与氯甲酸正戊酯进行酰胺化,最后水解去除乙酰基得到卡培他滨,总收率42.17%。HPLC纯度为99.81%。该新合成方法原料廉价易购、反应条件温和、操作简单,适合工业化生产。

By using D-ribose as starting material,intermediates(6a,6b)were obtained by ketalization,esterification,NaBH 4 reduction in a mixed solvent of DMSO and petroleum ether(1∶0.5∶1.5),hydrolysis and acylation catalyzed by anhydrous sodium acetate,subsequent Silyl reaction with 5-fluorocytosine afforded 5′-deoxy-2′,3′-di-O-acetyl-5-Fluorocytidine(7),final amidation with n-amyl chloroformate and deacetylation afforded capecitabine with a purity of 99.81%and a total yield of 75.71%.The new synthetic process had the advantages of cheap,mild reaction conditions,simple and easy to operate and suitable for the industrial production.