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

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·m 3 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·m 3 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.

Continuous manufacturing – the Green Chemistry promise?

“…96 Heterogeneous catalysis can offer certain advantages; however, catalyst immobilization without significant leaching has proven challenging. 97,98 Biocatalysis is an alternative that is gaining considerable traction. It is a Greener catalytic solution as most enzymes are biodegradable and most often produced through fermentation of renewable feedstocks (G7, G9, G10).…”

Scalable thin-layer membrane reactor for heterogeneous and homogeneous catalytic gas–liquid reactions

“…13 The simplified fluid hydrodynamics in the thin-layer membrane reactor offers the opportunity for straightforward scale-up with a stackable design. The stackable design maintains a fixed heat and mass transfer distance (carbon cloth thickness) while increasing the reactor size laterally and in parallel, resulting in preserved heat and mass transfer advantages of the single-layer membrane reactor while meeting the required productivity.…”

“…Packed-bed reactors, a common type of gas-liquid reactor, despite their mature development in the petrochemical industry, have not been widely adopted in pharmaceutical manufacturing. 13 Zaborenko et al studied packed-bed reactors of small scale (20 g catalyst), medium scale (120 g catalyst), and pilot scale (1.5 kg catalyst) for successful development of continuous hydrogenation of a pharmaceutical intermediate. 13 Yang et al…”

“…13 Zaborenko et al studied packed-bed reactors of small scale (20 g catalyst), medium scale (120 g catalyst), and pilot scale (1.5 kg catalyst) for successful development of continuous hydrogenation of a pharmaceutical intermediate. 13 Yang et al…”

Flow chemistry—Microreaction technology comes of age

“…Packed bed reactors have attracted attention for hydrogenation and oxidation because of safety advantages and metal catalyst retention within the reaction system . Implementing these multiphase systems requires understanding of the complex flows in addition to the intrinsic catalyst performance .…”