Continuous-flow synthesis and purification of atropine with sequential in-line separations of structurally similar impurities

Abstract

Flow chemistry has attracted significant interest in pharmaceutical development, where substantial efforts have been directed toward the design of continuous processes. Here, we report a total synthesis of atropine in flow that features an unusual hydroxymethylation and separation of several byproducts with high structural similarity to atropine. Using a combination of careful pH control in three sequential liquid-liquid extractions and a functionalized resin, atropine is delivered by the flow system with >98% purity.