Article pubs.acs.org/OPRD
Development of Pilot-Scale Continuous Production of an LY2886721 Starting Material by Packed-Bed Hydrogenolysis Nikolay Zaborenko,* Ryan J. Linder,* Timothy M. Braden, Bradley M. Campbell, Marvin M. Hansen, and Martin D. Johnson Small Molecule Design and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, United States S Supporting Information *
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.
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INTRODUCTION Continuous processing has enjoyed a recent surge of interest from the pharmaceutical industry,1 including from Eli Lilly and Company. Recent advances in process analytical technologies (PAT) have increased the potential to gain greater understanding and control of continuous-flow synthesis and workup operations as compared to traditional batch processing methods. Eli Lilly has made significant investments into the development of continuous processing to enable its use in the drug development and manufacture processes in order to apply its benefits and returns on investment in terms of safety, process intensification, nonstandard processing conditions, and quality. While these introductions are associated with capital expenditure, it is believed that once the core technology platforms2 are installed in pharmaceutical manufacturing plants and at material supply vendor sites, this mode of production will become commonplace and the cost for future implementation will drastically decline with equipment and infrastructure reuse. Recently, continuous-flow reaction and workup platforms have been demonstrated for their utility in pharmaceutical processes for rapid process development, robust production with reduced material risk, and enhanced safety profiles.3 Packed-bed reactors have shown a number of advantages for high-intensity chemical synthesis, coupling high temperatures and pressures with excellent gas−liquid−solid mass transfer to characterize and accelerate reactions4 as well as to enable novel syntheses.5 Trickle-bed reactors are especially widely used in petroleum, chemical, and waste-processing industries, processing over a billion tons of material per year.6 There has been a great deal of work in characterization of flow regimes required for trickle-bed operation7 as well as general reactor design and consideration.8 Additionally, demonstrations of scalability of © XXXX American Chemical Society
trickle-bed reactors from laboratory to industrial scale have been made.9 However, there is scarce literature on the advantages of packed-bed catalyst reactors for pharmaceutical manufacturing. This paper demonstrates the utility and scalability of packed-bed reactors, as well as the advantages afforded by real-time HPLC monitoring towards reaction characterization and optimization, for a pharmaceutical starting material synthesis via heterogeneously catalyzed hydrogenolysis. LY288672110 (Scheme 1) is a potent, selective inhibitor of beta-amyloid cleaving enzyme (BACE) and was in phase 2 Scheme 1. Structure of API and Key Starting Material (1)
clinical trials as a potential treatment for Alzheimer’s disease when clinical trials were terminated in 2013. Its asymmetric synthesis was developed via a key amino alcohol intermediate (1, Scheme 1) serving as a key starting material leading to the formation of the thiazine ring. The chemistry employed in the Received: October 9, 2014
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DOI: 10.1021/op5003177 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Article
Organic Process Research & Development
feasible, such a process may require a greatly reduced footprint due to small reactor sizes to achieve batch-equivalent throughput. Additionally, the potential for reduced amounts of hydrogen gas in the system at any given time may enable production-scale continuous-flow hydrogenation reactions to be performed outside of traditional hydrogenation bunkers, which may greatly expand the number of manufacturers capable of performing such a reaction. Previous batch development highlighted several process demands, which became the goals of the continuous packedbed investigation: 1. Better control of defluorination. The initially developed batch conditions produced the desF impurity 5 at approximately 0.04 area % per hour of additional reaction time past the end of the reaction. The rate of defluorination was even faster at lower H2 pressure (after venting), about 0.1% per hour. The target specification was
