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Synthesis of Beclabuvir
The First Kilogram Synthesis of Beclabuvir, an HCV NS5B Polymerase Inhibitor.
Org. Process Res. Dev. 2018;
14 December 2018 (online)
Key wordsbeclabuvir - asymmetric cyclopropanation - arylation - Heck reaction - rhodium - palladium
Beclabuvir (Ximency®, BMS-791325) is a non-nucleoside, nonstructural protein 5B (NS5B) RNA polymerase inhibitor that was approved in Japan for use in combination with Asunaprevir and Daclatasvir for the treatment of hepatitis C virus infection.
Key steps in the large-scale synthesis depicted include (1) the rhodium-catalyzed asymmetric cyclopropanation of styrene C (94% yield, 83% ee) and (2) the construction of the seven-membered ring by an intramolecular Heck reaction. Beclabuvir was prepared in twelve linear steps with five isolations in 8% overall yield.