To access unstable intermediates through exothermic pathways in a scalable fashion, the pharmaceutical industry has increasingly leveraged the use of plug flow reactors, in which a high surface-area-to-volume ratio allows for precise control of reaction time and temperature. In recent work towards the production of SHP2 inhibitor GDC-1971 (migoprotafib), efforts to improve the synthesis of upstream fragments included reworking the route to a key α-hydroxy ketone intermediate from 2-fluorobenzaldehyde and N-Boc-4-piperidone. A screen of nucleophilic acyl anion synthons identified several Katritzky benzotriazole hemiaminals, which were readily deprotonated by n-butyllithium at cryogenic temperatures to form highly unstable but potent nucleophiles towards the piperidone electrophile. In-situ FTIR experiments confirmed that these fleeting organolithium species were too unstable to study effectively in batch beyond flask-scale reactions using drop-wise reagent addition and extreme cryogenic temperatures (–78 °C). As such, reaction conditions such as time, temperature, reagent equivalence, and solvent composition were screened directly in a benchtop plug flow reactor, allowing for a smooth transition directly into a robust and scalable multikilogram manufacturing process under more moderate conditions. Considerations of rapid mixing and heat transfer in the context of reaction development in plug flow will be discussed.
