Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis

The design, development, and implementation of a pilot-scale continuous hydrogenolysis in a catalytic packed bed to generate a starting material is described. Control of a critical defluorination impurity under the reaction conditions has been achieved by reducing residence time inside the catalyst bed to 15–30 min. A reactor volume throughput of 206 kg/h·m3 was attained in a 3 L reactor (1.5 kg of 5% Pd/C catalyst) over a 9 h demonstration period, superior to the 1.3 kg/h·m3 volume throughput obtained in batch. The reaction was successfully scaled up from 9 g/h to 550 g/h in packed beds ranging from 20 to 1500 g catalyst, demonstrating heat/mass transfer sufficiency at all examined scales. The process was monitored by online HPLC, providing real-time reaction information, using an internally developed automation cart coupled to a standard HPLC. Significant technical and business drivers for running the process in continuous flow mode were proposed and examined during development, demonstrating superior c...