An Efficient and Diastereoselective Synthesis of PSI-6130: A Clinically Efficacious Inhibitor of HCV NS5B Polymerase

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• 作者：Peiyuan Wang ; Byoung-Kwon Chun ; Suguna Rachakonda ; Jinfa Du ; Noshena Khan ; Junxing Shi ; Wojciech Stec ; Darryl Cleary ; Bruce S. Ross ; Michael J. Sofia
• 刊名：Journal of Organic Chemistry
• 出版年：2009
• 出版时间：September 4, 2009
• 年：2009
• 卷：74
• 期：17
• 页码：6819-6824
• 全文大小：762K
• 年卷期：v.74,no.17(September 4, 2009)
• ISSN：1520-6904

文摘

R7128 is the prodrug of 2′-deoxy-2′-fluoro-2′-C-methylcytidine (PSI-6130), a potent and selective inhibitor of HCV NS5B polymerase. Currently, R7128 is in clinical trials for the treatment of HCV infection. To support clinical development efforts, we needed an efficient and scalable synthesis of PSI-6130. We describe an improved, diastereoselective synthetic route starting with protected d-glyceraldehyde. No chiral reagents or catalysts were used to produce the three new contiguous stereocenters. Introduction of fluorine at the C-2 tertiary carbon was accomplished in a highly regio- and stereoselective manner through nucleophilic substitution on a cyclic sulfate. Scale-limiting chromatographic purifications were eliminated through the use of crystalline intermediates.