N^6-苯甲酰基-2′-叔丁基二甲基硅氧基腺苷-3′-H-膦酸的合成工艺研究

Synthetic technology of N^6-benzoyl-2′-O-tert-butyldimethylsilyl-adenosine-3′-ylH-phosphonate

目的研究N^6-苯甲酰基-2′-叔丁基二甲基硅氧基腺苷-3′-H-膦酸的合成工艺。方法以腺苷为起始原料,先对腺苷的嘌呤氨基进行苯甲酰基保护,再分别向腺苷的5′位和2′位引入二甲氧基三苯甲基(DMT)和叔丁基二甲基硅基(TBDMS)保护基,制备得到关键中间体N^6-苯甲酰基-5′-二甲氧基三苯甲氧基-2′-叔丁基二甲基硅氧基腺苷(3)。中间体3与磷试剂2-氯-4H-1,3,2-苯并二氧磷杂环己烷-4-酮反应引入膦酸基团,最后使用二氯乙酸脱除DMT保护基得到目标产物。结果经过5步反应得到了目标化合物N^6-苯甲酰基-2′-叔丁基二甲基硅氧基腺苷-3′-H-膦酸,并利用~1H-NMR、^(31)P-NMR、质谱等方法确证了其结构。本合成工艺的总收率为35.7%,目标化合物的质量分数为98.5%。结论该合成工艺与原有方法相比步骤短,操作简单,具有良好的应用前景。

Objective To study the synthetic technology of N6-benzoyl-2′-O-tert-butyldimethylsilyl-adenosine-3′-yl-H-phosphonate. Methods Adenosine was used as the starting material. The N6 amino group of adenosine was protected by benzoyl, following with the introducing protecting groups of dimethoxytrityl （DMT） and tert-butyldimethylsilyl （TBDMS） to the 5′ and 2′ positions of adenosine respectively,obtaining the key intermediate of N6-benzoyl-5′-O-dimethoxytrityl-2′-O-tert-butyldimethylsilyl-adenosine （3）. The reagent of 2-chloro-4H-1,3,2-benzodioxaphosphorin-4-one was used to introduce phosphonate group to the 3′ position of intermediate 3. DMT group was deprotected by dichloroacetic acid and the target compound was obtained.Results The target compound of N6-benzoyl-2′-O-tert-butyldimethylsilyl- adenosine-3′-yl-H-phosphonate was achieved and characterized by 1H-NMR,31P-NMR, and MS. The total yield of this synthetic route was 35.7%. And the purity of target compound was 98.5%.Conclusion The synthetic process is superior to former with simple operations and simplified methods, which has a good application prospect.