Development and Scale-Up of a Regioselective Functionalization of 2-Cyano-3-Fluoropyridine in a Flow Reactor

A continuous-flow process was developed for the regioselective functionalization of 2-cyano-3-fluoropyridine using Corning® Advanced-Flow™ reactors. The flow set-up enabled the controlled generation of a pyridyllithium intermediate through deprotonation with lithium diisopropylamide (LDA) under noncryogenic conditions (-20 °C) with a short residence time of 6 s. Subsequent in-line trapping with electrophiles afforded the corresponding highly functionalized pyridine derivatives in high yields and excellent selectivity. The optimized process was seamlessly scaled up using a Corning® Advanced-Flow™ Reactor G1, maintaining high selectivity while achieving a throughput of 83 g.h-1.