Efficient Synthesis of Antiviral Agent Uprifosbuvir Enabled by New Synthetic Methods

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: 1) complexation-driven selective acyl migration/oxidation; 2) BSA-mediated cyclization to anhydrouridine; 3) hydrochlorination using FeCl3/TMDSO; 4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.