(466b) Packed-Bed Hydrogenolysis: A Multi-Scale Study

In recent years, Eli Lilly chemical process development has devoted a great deal of focus on continuous-flow reaction and workup platforms for process intensification, increased safety, expanded range of reaction conditions, and improved plant space utilization. This talk will disclose our design and development of a continuous-flow packed catalyst bed system as applied to a two-step hydrogenolysis. The deprotection and ring-opening of an N-protected isoxazolidine substrate have been accomplished by use of a Pd/C catalyst in an aqueous alcohol solvent with hydrochloric acid, affording a hydrochloride salt solution. Numerous flow reaction studies have been performed to characterize the reactors and catalyst used for this purpose. The continuous-flow process resulted in a 60× reduction of residence time, improved impurity control strategy, and increased safety as compared to the batch process developed for this reaction. The process applied several in-line HPLC strategies for process analytical technology, providing real-time actionable process information and enabling rapid response to process departures and to changes in catalyst activity. Reaction scales from 10 to 600 g/hour of substrate and up to 10 kg of isolated product will be presented, demonstrating the utility and advantages of the non-cGMP reactor and equipment configuration versus batch, as well as the ability of continuous-flow technology to enable pilot-plant-scale or even manufacturing-scale production within laboratory-scale footprints.