A Three-Pronged Approach to the Global Debenzylation of an Advanced Furanoside Intermediate <i>en Route</i> to Remdesivir

Herein are reported strategies to achieve the global deprotection of an advanced intermediate in the synthesis of remdesivir, the active pharmaceutical ingredient of Veklury and the first antiviral medication approved (October 2020) for the treatment of COVID-19. Three strategies to improve the efficiency of the BCl3-mediated debenzylation reaction were explored: 1) enhanced control over processing conditions via flow chemistry; 2) attenuation of the reactivity of the BCl3 with additive B(OMe)3; and 3) replacement of BCl3/CH2Cl2 with AlCl3/anisole. These three strategies were developed in parallel in pursuit of improved yield and process robustness to expedite the large-scale manufacturing of remdesivir during the COVID-19 outbreak.