索非布韦的合成工艺改进

Synthesis and process optimization of sofosbuvir

目的对索非布韦进行合成工艺改进以提高其收率。方法以(2'R)-N-苯甲酰基-2'-脱氧-2'-氟-2'-甲基胞苷-3',5'-二苯甲酸酯(6)为起始原料,于弱酸条件下选择性脱去氮上的保护基,碱性条件下脱去氧上的苯甲酰基,制得关键中间体(2'R)-2'-脱氧-2'-氟-2'-甲基脲苷(8);以L-丙氨酸异丙酯盐酸盐、二氯磷酸苯酯和五氟苯酚为原料合成稳定的磷酰胺试剂(5);磷酰胺试剂选择性对中间体8的5'位羟基进行亲核取代反应得终产物索非布韦。结果与讨论通过1H-NM R、13C-NM R、M S、IR及mp对索非布韦进行了结构确证,HPLC检测质量分数达99.6%,以原料6计算,总收率为14.97%。

Objective To improve the synthesis process of sofosbuvir for higher yield. Methods Using（ 2＇R）-N-benzoyl-2＇-deoxy-2＇-fluoro-2＇-methylcytidine 3＇,5＇-benzoate（ 6） as starting material,the key intermediate（ 2＇R）-2＇-deoxy-2＇-fluoro-2＇-methyluridine（ 8） was obtained by deprotecting of benzoyl under acetic acidand ammonia conditions. Stable phosphoramidatin greagent（ 5） was prepared by using L-alanine isopropyl ester hydrochloride,dichloro-phenyl phosphate and pentafluorophenol as materials of synthesis. Sofosbuvir could be obtained through selective nucleophilic displacement of 5＇-hydroxyl group of nucleosides（ 8）. Results and Conclusions Sofosbuvir was synthesizedwith total yield of 14. 97%（ based on the fed amount of compound 6 at the beginning） and with the purity of 99. 6%. The structure of sofosbuvir was confirmed by the using of techniques including1H-NMR,13C-NMR,MS,IR,and melting point determination.