Design and Scale Up of Fully Continuous Processes including Reaction, Workup, and Isolation

Several fully continuous processes have been run in Chemical Product Research and Development at Eli Lilly to enable scale up of chemistries that are not suitable for conventional batch equipment. Superheated thermal cyclization, high pressure hydroformylation (70 bar), high pressure asymmetric hydrogenation (70 bar), which were not feasible to scale up in existing in-house batch equipment, have been conducted safely in continuous reactors. Multi-stage counter-current extractive workup enabled higher product yield and better impurity rejection compared to batch. Continuous crystallization enabled higher ee upgrade compared to batch, seeding only once at the beginning of the campaign, and the quality assurance of steady state operation. Continuous distillation enabled difficult solvent exchanges with less solvent waste and less residence time in the evaporator compared to batch, and efficient separation of compounds with small relative volatility. Typical research scale throughputs are 1 to 10 g/h and pilot scale throughputs are 5 to 15 kg/day. Most continuous processes that were run at research and pilot scale in the development laboratories have solids in flow. Custom methods and devices for slurry mass transport are described. No mechanical pumps are used for slurry flow. Instead, automated sequenced block valves and pressure swing fluid transfer chambers are used for pumping and flow metering of slurries.