A Continuous Process for Buchwald–Hartwig Amination at Micro-, Lab-, and Mesoscale Using a Novel Reactor Concept

Abstract

A continuous Buchwald–Hartwig reaction using the bulky N-heterocyclic carbene (NHC) precatalyst [Pd(IPr*)(cin)Cl] 4 has been developed for the synthesis of a key pharmaceutical intermediate 2. Using microreactor technology, the reaction could be optimized under dilute conditions with low material burden and the kinetic parameters investigated. For larger lab-scale operation (gram scale), process-relevant concentrations could be employed and the conditions developed for continuous workup effectively demonstrated (batch methodology published concurrently). The stability of the NHC catalyst allowed for a continuous acidic extraction of the product and on-stream recycling of the catalyst in the organic phase. At this scale, sonication is employed to prevent clogging in the reactor unit. Finally, a bespoke continuous flow reactor has been developed for carrying out the reaction beyond lab scale. This novel reactor concept for running heterogeneous reactions in flow combines the flexibility of continuously stir...