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

By Zaborenko, Nikolay; Linder, Ryan J.; Braden, Timothy M.; Campbell, Bradley M.; Hansen, Marvin M.; Johnson, Martin D.

Published on

Abstract

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 control of critical impurities and catalyst utilization with minimized risk to product and increased safety due to reduced handling of hydrogen and of palladium catalyst relative to equivalent substrate throughputs in a typical batch process.

Journal

Organic Process Research & Development. Volume 19, 2015, 1231–1243

DOI

10.1021/op5003177

Type of publication

Peer-reviewed journal

Affiliations

  • Eli Lilly and Company

Article Classification

Research Article

Classification Areas

  • Intermediate

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