Synthesis of a Nucleoside Phosphoramidate Prodrug Inhibitor of HCV NS5B Polymerase: Phenylboronate as a Transient Protecting Group

A synthetic process for 2′-C-methylcytidine-5′-[2-[(3-hydroxy-2,2-dimethyl-1-oxopropyl)thio]ethyl-N-benzylphosphoramidate], a nucleotide prodrug inhibitor of hepatitis C virus NS5B polymerase, is described. The route developed was demonstrated on 100 g scale and featured the key application of phenylboronic acid as an effective transient means to protect the 2′,3′-hydroxyls of 2′-C-methylcytidine. This synthetic methodology resulted in a reduction in the number of isolations from five to two and an increase in the overall yield by 50% relative to the original unscalable discovery route. The synthesis and characterization of 2′-C-methylcytidine-2′,3′-O-phenylboronate is also provided.