Communication pubs.acs.org/OPRD
An Automated Intermittent Flow Approach to Continuous Suzuki Coupling Kevin P. Cole,*,† Bradley M. Campbell,† Mindy B. Forst,† Jennifer McClary Groh,† Molly Hess,† Martin D. Johnson,† Richard D. Miller,† David Mitchell,† Christopher S. Polster,† Brandon J. Reizman,† and Morgan Rosemeyer‡ †
Eli Lilly and Company, Indianapolis, Indiana 46285, United States D&M Continuous Solutions, LLC, Greenwood, Indiana 46143, United States
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S Supporting Information *
ABSTRACT: A fully automated fill/empty reactor system for liquid−liquid biphasic Suzuki couplings is described. The system was capable of charging reactant and catalyst solutions to a heated vessel, heating reagent solutions by flow heat exchanger on the way into the reactor, allowing the reaction to occur, monitoring reaction completion, discharge of the product solution, and initiation of another cycle in a repeating fashion. A unique noncontact colorimetric method was used to monitor reaction completion. The reactor system exhibits many of the characteristics of a fully continuous reactor such as (1) high productivity from a small process footprint, (2) a large number of volume turnovers each day, (3) higher heat transfer area per unit volume compared to batch because the reactor is 50× smaller, and (4) rapid heat up and cool down of process streams enabled by heat exchangers. Downstream unit operations that are intended for eventual integrated end-to-end continuous production included a batch metal removal step and a continuous antisolvent crystallization to isolate the product in high yield and purity.
Figure 1. Structure of merestinib and proposed Suzuki coupling to afford intermediate 2.
due to cytostatic/toxic APIs and/or genotoxic intermediates. The desire to better accommodate these low volume products as well as to address these containment requirements and embrace the potential of continuous processing has driven the foundation of a new manufacturing environment that has been termed small volume continuous (SVC) manufacturing. The concept of fume hood production has been previously described by us5 and others within industry and academia.6 In SVC, products meeting certain volume or containment requirements are produced for late stage development and commercial manufacturing in a flexible and dynamic environment located in walk in fume hoods and conducted in continuous flow mode at 3−10 kg/day throughput. The emphasis on flow is also intended to benefit quality and regulatory aspects of material production. Continuous processing is increasingly supported by the US FDA, which has encouraged the modernization of pharmaceutical manufacturing.7 The Suzuki coupling is a heavily utilized method for the formation of aryl−aryl bonds in pharmaceutical manufacturing.8 There have been numerous reports of continuous flow Suzuki couplings,9 but many suffer from certain fundamental limitations to their implementation at manufacturing scale.
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INTRODUCTION Merestinib (LY2801653, 1, Figure 1) is currently in Phase 2 clinical trials for the treatment of various solid tumors.1 Previous reports from our laboratories have described the preparation of 32 as well as downstream chemistry.3 We now wish to report the Suzuki coupling of bromide 3 with boronic ester 44 under continuous flow conditions. This is a step toward a completely continuous flow good manufacturing practices (GMP) sequence, ideally conducted in end-to-end continuous mode, where all unit operations of the registered sequence are run simultaneously in flow to maximize space-time yield, eliminate isolations, and improve safety, while reducing campaign duration and process footprint. Recent trends in the development pipeline at Eli Lilly and Company have shifted focus toward more selective compounds with smaller intended patient populations and lower peak demand in terms of material requirements (60 °C was observed to be 2.0−2.5 min. B
DOI: 10.1021/acs.oprd.6b00030 Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Organic Process Research & Development
Communication
Figure 4. Contour plot and graph of HPLC area % conversion results of a base and water loading study. Reactions conducted with 0.005 equiv of PdCl2[dtbpf], 5 mol % TBABr, 1.15 equiv of 4, water volumes with respect to 3 and THF (14 mL/g of 3) in vials placed in a pre-equilibrated heating block at 67 °C in a glovebox with magnetic stirring at 800 rpm. Heat-up time from 20 °C to >60 °C was observed to be 2.0−2.5 min.
Figure 5. Optimized reaction conditions and related substances observed from Suzuki cross coupling.
tailing and an elevated baseline between the two peaks. Additional complications included poor UV absorbance at >210 nm by both boronic species and the fact that they partitioned between both the organic and the aqueous layers. For these reasons, consumption of 4 was not monitored in this work. The biphasic nature of these reactions rendered flow-NMR16 characterization of this reaction system challenging. A number of minor (
