Manufacturing Process Development for the Biaryl Ether Fragment of Nemtabrutinib (MK-1026)

Deprez, Nicholas R.; Rose, Harrison B.; Peters, Byron K.; Diaz-Santana, Anthony; Liu, Zhuqing; Kuhl, Nadine; Chung, Cheol K.; Liu, Zhu; Newman, Justin A.; Corry, James; Guetschow, Erik D.; Hoyt, Erik; Jellett, Lisa; Kapil, Sunayana; Poirier, Marc; Shevlin, Michael; Sirota, Eric; Solovyov, Andrew; Sun, Alexandra C.; Thaisrivongs, David A.

doi:10.1021/acs.oprd.3c00218

Cited by 2 publications

(2 citation statements)

References 33 publications

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“…Nemtabrutinib is a reversible Bruton’s Tyrosine Kinase inhibitor developed for the investigational treatment of chronic lymphocytic leukemia . Development of the commercial route to nemtabrutinib through intermediate 5 has been reported, and is shown in Scheme . During the development of this process, it was found that 5 had a tendency to partition out of solution as an undesired oil phase during workup and crystallization.…”

Section: Resultsmentioning

confidence: 99%

Vision-Guided Automation Platform for Liquid–Liquid Extraction and Workup Development

Sun,

Jurica,

Rose

et al. 2023

Org. Process Res. Dev.

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Liquid–liquid extraction (LLE) screening can be a very labor-intensive exercise during commercial process development, particularly when workup challenges such as poor partitioning or emulsion formation arise. An automated platform for LLE has the potential to both accelerate process development and deliver a more optimized process, thereby reducing the burden on downstream purification requirements. To address this need, a fully automated liquid–liquid extraction workflow was designed and implemented to optimize extraction unit operations during process development. This workflow leverages commercially available hardware and software to perform extractions, identify phase boundaries, and prepare samples for analysis. A data visualization tool was also developed to streamline the processing of visual and quantitative data. Application of the automated LLE workflow on two case studies will be presented: one highlighting the development of an effective enzyme removal strategy for a biocatalytic cascade reaction and the other demonstrating the identification of operating parameters for workup of an intermediate with a tendency to partition into an oil layer.

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Section: Resultsmentioning

confidence: 99%

Vision-Guided Automation Platform for Liquid–Liquid Extraction and Workup Development

Sun,

Jurica,

Rose

et al. 2023

Org. Process Res. Dev.

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“…Finally, the reaction is quenched with aqueous acetic acid to arrive at the desired ketone ( 5 ). Additional processing steps outside the scope of this work are completed to arrive at the final active pharmaceutical ingredient, nemtabrutinib. − …”

Section: Introductionmentioning

confidence: 99%

Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib

Franklin,

Armiger,

Otte

et al. 2024

Org. Process Res. Dev.

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In one of the two penultimate steps in the commercial route to nemtabrutinib, a ketone intermediate is formed from 7-bromo-6-chloro-7-deazapurine and methyl 2-chloro-4-phenoxybenzoate in a series of reactions mediated by methyllithium and n-butyllithium. Flow chemistry was identified in development as a useful tool for safe and efficient scale-up for two of these reactions while minimizing the formation of unwanted impurities. Here, we present the first pilot-scale implementation of the process where a tubular flow reactor was employed to produce multiple kilograms of the ketone intermediate. Practical considerations for large-scale operations are discussed, including operation at low temperatures around −30 °C, stable and consistent control of flow rates, and planning for the prevention of and recovery from upset scenarios. Careful design and construction of equipment and procedures allowed for the successful execution of five pilot-scale batches with consistent yield and product quality to produce material needed for clinical development. Across the campaign, average isolated yield for the process was approximately 65%, with an average purity of 99.9% by weight. Also presented are the findings from a series of large-scale flow experiments, where temperature, residence time, and reaction stoichiometry were simultaneously varied to assess process robustness. In these experiments, n-butyllithium stoichiometry was found to have the greatest impact on reaction yield, as measured by product LC area percent. Additionally, the process impurities studied were each sensitive to a different combination of the varied parameters. Learnings from this pilot campaign were critical to guide future development efforts en route to a potential commercial supply of nemtabrutinib.

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Manufacturing Process Development for the Biaryl Ether Fragment of Nemtabrutinib (MK-1026)

Cited by 2 publications

References 33 publications

Vision-Guided Automation Platform for Liquid–Liquid Extraction and Workup Development

Vision-Guided Automation Platform for Liquid–Liquid Extraction and Workup Development

Pilot-Scale Operation and Characterization of an Organolithium-Mediated Coupling Reaction in Flow to Form a Ketone Intermediate on the Route to Nemtabrutinib

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