The Synthesis Of Sofosbuvir

Sofosbuvir, first developed by Pharmasset company and then acquisition by Gilead to developed as the anti-HCV drugs, whose chemical name is N-[P-(S),2’R]-2’-deoxy-2’-fluoro-2’-methyl-P-phenyl--5’-uridine]-L-alanine isopropyl ester. It’s approved by the FDA in December 6th,2013. This drug has strong ability of anti-hepatitis C virus, which brings the gospel for the majority of HCV patients.This paper mainly completed the synthesis of sofosbuvir and optimized the major steps of this route, at the same time, a new synthesis method of the key intermediate is carried out.During the process of synthetic sofosbuvir, we mainly solve the following problems:the first one is the optimization of the double hydroxyl protection for 2-C-methyl-4,5-O-(1-methyl vinyl)-D-Arabia sugar acid ethyl ester, the sulfonyl chloride is used instead of thionyl chloride for the protection of the double hydroxyl, which can avoid the use of sodium hypochlorite as oxidant for further oxidation of sulfoxides, thus saving raw materials and the cost; the second one is the optimization of the synthetic method of 2-deoxy-2-fluoro-2-methyl-D-erythro pentofuranoses-3,5-dibenzoate-1-acetate, and HPLC measured the β/α ratio of the isolated compounds was 19.75:1, which is good for coupling reaction; the third one is the optimization of the coupling reaction of 2-deoxy-2-fluoro-2-methyl-D-erythro-pentofuranoses-3,5-dibenzoate-1-a cetate and N4-benzoyl cytosine, when using anhydrous chlorobenzene as solvent, stannic chloride as Lewis acid and the molar ratio of 2-deoxy-2-fluoro-2-methyl-D-erythro-pentofuranoses-3,5-dibenzoate-1-a cetate、N4-benzoyl cytosine、stannic chloride was 1:2:2, we get the β/α ratio of the isolated compounds was 5.37/1, with yield of 60.2%.In the innovational synthesis of the key intermediate of sofosbuvir, we synthesized erythro-pentofuranose sulfoether compounds and erythro-pentofuranose sulfoxide compounds, which can docking N4-benzoyl cytosine successfully and get the target compound:(2’R)-N--benzoyl-2’-deoxy-2’-fluoro-2’-methyl cytosine-3’,5’-dibenzoate, When use β-isomer of erythro-pentofuranose sulfoether compounds as raw material, the β/α ratio of the nucleoside was 1:3.4; When use β-isomer of erythro-pentofuranose sulfoxide compounds as raw material, the β/α ratio of the nucleoside was 1:2.3;...