Synthesis Of Sofosbuvir Derivatives And New Technology Research

Sofosbuvir approved by Food and Drug Administration is used for the treatment of chronic hepatitis C virus infection. Sofosbuvir was developed by Pharmasset company and the chemical name is N-[P-(S), 2’R]-2’-deoxy-2’-fluoro-2’-methyl-P-phenyl-5’-uridine]-L-alanine isopropyl ester. It is an effective and safety drug without interferon for the first.Our work included three parts. Firstly, we improved and optimized the synthetic process of Sofosbuvir. Secondly, we proposed a new method to synthesize Sofosbuvir. Finally, we designed two new synthetic routes and synthesized some new Sofosbuvir derivatives.During the research, we have solved the following problems:1.We optimized the coupling reaction of 2-deoxy-2-fluoro-2-methyl-D-erythro-ribofuranosyl-1-chloro-3,5-dibenzoate with N4-benzoylcytosine and improved the β/α ratio of the nucleoside by pressurization and controlling reaction temperature.2.During the synthesis of Sofosbuvir, we used 1,2,4-triazole as leaving group precursors instead of perfluorophenol, p-nitrophenol reported in literature. It will reduce cost and improve the product yield.3.We designed two new routes for the synthesis of 2-deoxy-2-fluoro-2-methyl-D-erythro-pentofuranoses-3,5-dibenzoate. We have obtained a number of new intermediates by using cis-2-butene-1,4-diol through epoxidation, cyanide, hydrolysis, esterification, methylation and fluride. We synthesized some Sofosbuvir derivatives with above intermediates.4. To avoid using sodium cyanide, we designed another new ronte from D-xylose and synthesized some new Sofosbuvir derivatives.After exploration and research, we optimized the original synthesis, designed two brand new routes and synthesized several derivatives of Sofosbuvir. The derivatives have been sent to Academy of Medical Sciences for the activity test. These work will contribute to the research for the activity of derivatives and the production of Sofosbuvir.