Stereoselective Synthesis of PSI-352938: A 尾-d-2鈥?Deoxy-2鈥?伪-fluoro-2鈥?尾-C-methyl-3鈥?5鈥?cyclic Phosphate Nucleotide Prodrug for the Treatment of HCV

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• 作者：P. Ganapati Reddy ; Byoung-Kwon Chun ; Hai-Ren Zhang ; Suguna Rachakonda ; Bruce S. Ross ; Michael J. Sofia
• 刊名：Journal of Organic Chemistry
• 出版年：2011
• 出版时间：May 20, 2011
• 年：2011
• 卷：76
• 期：10
• 页码：3782-3790
• 全文大小：976K
• 年卷期：v.76,no.10(May 20, 2011)
• ISSN：1520-6904

文摘

PSI-352938 is a novel 2鈥?deoxy-2鈥?伪-fluoro-2鈥?尾-C-methyl 3鈥?5鈥?cyclic phosphate nucleotide prodrug currently under investigation for the treatment of hepatitis C virus (HCV) infection. PSI-352938 demonstrated superior characteristics in vitro that include broad genotype coverage, superior resistance profile, and high levels of active triphosphate in vivo in the liver compared to our first and second generation nucleoside inhibitors of this class. Consequently, PSI-352938 was selected for further development and an efficient and scalable synthesis was sought to support clinical development. We report an improved, diastereoselective synthesis of a key 1鈥?尾-nucleoside intermediate 13 via S_N2 displacement of 1-伪-bromo ribofuranose sugar 16 with the potassium salt of 6-chloro-2-amino purine and an efficient method to prepare cis-Rp cyclic phosphate (PSI-352938) in a highly stereoselective manner without any chromatographic purification. The 1-伪-bromo sugar 16 was stereospecifically prepared from the corresponding 1-尾-lactol in high yield under mild bromination conditions using CBr₄/PPh₃ (Appel reaction). The desired cis-Rp 3鈥?5鈥?cyclic phosphate construction was accomplished using isopropyl phosphorodichloridate readily obtained from POCl₃ and isopropyl alcohol. The base combination of Et₃N/NMI was identified as a key factor for producing PSI-352938 as the major (>95%) diastereomer (cis-Rp) in high yield after the final cyclization step. The current route described in this article was successfully used to produce PSI-352938 on multikilogram scale.