Development and Scale up of Cryogenic Lithiation in Continuous Flow Reactors

Organometallic reactions are one of most challenging reactions owing to the presence of highly reactive starting reagents, unstable energetic intermediates, high exothermicity, and are often run under cryogenic conditions. Continuous flow reactors offer several advantages over batch reactors in cases where maximizing heat removal and minimizing chemical inventory are critical for improving product quality and safety. The current case study of lithiation and borylation of indole involves cryogenic temperatures (-70 °C), pyrophoric starting reagents, highly reactive and unstable organolithium intermediate and exothermic quench, making it a particularly harder process to operate in batch mode.

The presentation describes the development of a continuous flow process for performing a sequence of four chemical reactions in series, all using tubular reactors. The process was scaled up in the pilot plant using a newly built continuous flow reactor system. Scale up challenges, startup learnings and potential for inline/online monitoring to address practical analytical constraints are also discussed.