7-Step flow synthesis of the anti-HBV nucleoside drug entecavir

Abstract

Entecavir, an important active pharmaceutical ingredient (API) for the treatment of hepatitis B virus (HBV), has been synthesized in continuous flow in 7 steps from commercially available (+)-Corey lactone diol. Leveraging a photocatalytic dehydrogenative decarboxyolefination as the key transformation, entecavir was obtained in 41% isolated overall yield with a total residence time of 111.5 minutes in sequential flow operations. This work provides a concise and sustainable route to carbocyclic nucleoside analogues and highlights the efficiency and sustainability of continuous flow synthesis in the preparation of complex APIs.