索非布韦核苷中间体异构体的合成

Synthesis of the Intermediate Isomer of Sofosbuvir

以S-甘油醛缩丙酮为原料,经Wittig反应、高锰酸钾氧化、磺酰化、氟化、水解、内酯化得索非布韦关键中间体的异构体(3R,4R,5S)-3-氟-4-羟基-5-(羟基甲基)-3-甲基四氢呋喃-2-酮,优化反应条件:n(磺酰氯)/n(化合物3)=1.6/1.0,温度为-10℃,反应2 h;氟化试剂为TEAF(四乙基氟化铵),温度为100℃,反应3 h,制得5S-核苷的总收率为14.21%,化学纯度97.5%,ee值98.4%,经1HNMR,IR和MS(ESI)表征。

The key intermediates(3R,4R,5S)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyl-dihydrofuran-2(3H)-one for the impurity isomers of Sofosbuvir was synthesized via Wittig reaction,potassium permanganate oxidation,sulfonylation,fluorination,hydrolysis,lactonization from S-glyceraldehyde acetonide as raw material.Optimized reaction conditions:n(sulfonyl chloride)/n(compound 3)=1.6/1.0,reacting at-10℃for 2 h;the fluorination reagent was tetraethylammonium fluoride and reacting at 100℃for 3 h,the total yield of 5S-nucleoside was 14.21%,the purity and ee value were 97.5%and 98.4%,respectively.The structure was characterized by 1H NMR,IR and MS(ESI).