Study On Synthesis Of The Intermediate Of GS-7977

Hepatitis C was a serious viral infectious disease to human health founded in 1989. Currently, the rate of HCV infections was about 3% in the world. GS-7977 is a new type of nucleotide oral drug used in treating Hepatitis C. In 2013, FDA approved the drug listed in the USA, and it was expected to the sales of 50 billion dollars in 2018. The article focused on the synthesis of chiralintermediate-2’-deoxy-2’-fluoro-2’-C-methyluridine.D-Mannitol was selected as the starting material. By the acetone condensation protection, sodium periodate oxidation, D-glyceraldehyde acetonide was prepared, (2S,3R)-3-((R)-2,2-dimethyl-[1,3]dioxolan-4-y l)-2,3-dihydroxy-2-methy1-propionic acid ethyl ester was obtained from D-glyceraldehyde acetonide through Wittig reaction, sodium permanganate oxidation. The temperature of Wittig reaction was changed to -10℃ from -78℃ reported in literature and the workup was changed into distillation instead of column chromatography reported in literature. The operation was simplified and the yield of the reaction was improved.Then, the double band was oxidized by sodium permanganate, the glycol was prepared and then reacted with thionyl chloride, which was oxidized by sodium hypochlorite. Through fluorine substitution reaction by Et3N-HF, acetone protected group removed, intramolecular cyclization, hydroxyl groups were protected with benzoyl group through acylation and ((2R,3R,4R)-3-((4-Chlorobenzoyl)oxy)-4-fluoro-4-methyl-5-oxotetra-hydrofuran-2-yl)methyl 4-chlorobenzoate was synthesized.Through reduction of the carbonyl group of the heteroatom ring, reacted with methanesulfonyl chloride, nucleophilic substitution by N4-benzoylcytosine, protective group removed. Finally, the target product-(2’R)-2’-deoxy-2’-fluoro-2’-methyluridine was obtained. The hydroxyl group was substituted by N atom of the heteroatom through sulfonylation instead of halogenation in order to improve the yield.The total yield of the 14 reactions was 4.6%. The tittle compound-2’-deoxy-2’-fluoro-2’-C-methyluridine and other intermediates had been characterized by 13C-NMR,1H-NMR and IR. The optical purity was determined by polarimetric analysis.