从β-胸苷出发的司他夫定的合成工艺研究

首先β-胸苷与1.5mol的三苯基氯甲烷和1.5mol的吡啶在DMF中反应,生成5′-位羟基的醚化产物(2);化合物2再在三乙胺作用下与2mol的甲烷磺酰氯反应制成甲磺酸酯(3);然后,化合物3在乙醇中与等摩尔的氢氧化钠作用,制备成氧桥化合物(4);化合物4在DMSO中,在2mol的甲醇钠作用下,生成消除反应产物5;化合物3也可在DMSO中与4mol的甲醇钠作用,一步直接得到消除产物5;最后,化合物5脱保护制备得到司他夫定(d4T,1)。当合成采取“β-胸苷→2→3→4→5→1”路线时,五步反应总收率为74%。当合成采取“β-胸苷→2→3→5→1”路线时,四步反应总收率为70%。

A Practical Synthesis of Stavudine (d4T) from β-Thymidine

A practical synthesis of stavudine (d4T) was described. β-Thymidine was treated with 1.5 equiv of Ph3CCl in DMF in the presence of pyridine to form 5′-O-trityl thymidine (2) in 93% yield. The compound 2 then reacted with 2 equiv. of methylsulfonyl chloride and 3 equiv. of Et3N to produce 3′-O-methylsulfonyl-5′-O-trityl thymidine (3) in 98% yield. After the compound 3 was converted into 2,3′-anhydro-5′-O-trityl thymidine(4)in 95% yield by refluxing with equal equiv. of NaOH in ethanol, the compound 4 was then subjected to elimination with 2 equiv. of sodium methoxide in DMSO to obtain 5′-O-trityl -3′-deoxy-2′, 3′-didehydro-thymidine(5) in 96% yield. Finally, the removal of trityl group of 5 in 80% HOAc afforded(1)in 90% yield. The conversion from compound 3 to compound 5 can also be done in one step in 84% yield by treating(3)with 4 equiv. of sodium methoxide in DMSO.