Development andScale-Up of a Regioselective Functionalizationof 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 setup 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.