Integrating Process Development and Safety Analysis for Scale-Up of a Diborane-Generating Reduction Reaction

Seltorexant (1) is currently under clinical development as a selective orexin-2 antagonist for the treatment of major depressive disorder with insomnia symptoms. During the investigation of an improved synthesis route, a key (3 + 2) cycloaddition reaction was found to occur only at very high temperatures (>250 °C). An exploratory process development of such a challenging high-temperature cycloaddition was demonstrated in a continuous flow process. Together with the development of other steps, a proof of concept to the improved synthesis route to seltorexant was established.

Section: Resultsmentioning

confidence: 99%

Exploratory Process Development of a High-Temperature Thermal (3 + 2) Cycloaddition in Continuous Flow for the Synthesis of Seltorexant

Matcha,

Huygaerts,

Moens

et al. 2023

“…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

Self Cite

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.

“…The synthetic strategy for the manufacturing route of nemtabrutinib features the highly convergent route highlighted in Scheme . This strategy includes three key building blocks consisting of biaryl ether 4 , pyrrolopyrimidine 5 , and amino alcohol 6 . – These components are then assembled through metalation of pyrrolopyrimidine 5, followed by nucleophilic addition of the metalated intermediate into the ester of the biaryl ether 4 affording ketone 7 . Subsequent S N Ar of amino alcohol 6 with 7 provided nemtabrutinib 1 .…”

Section: Introductionmentioning

confidence: 99%

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

Deprez,

Rose,

Peters

et al. 2023

Self Cite

MK-1026, also known as nemtabrutinib (1), has been developed as a reversible Bruton's tyrosine kinase (BTK) inhibitor for the treatment of chronic lymphocytic leukemia. This article describes the two-step manufacturing synthesis and subsequent isolation of biaryl ether (4) en route to MK-1026. First, the esterification step employs unique conditions leveraging dimethyl carbonate as a dual-function reagent, acting as both the solvent and the desiccant to drive the reaction forward. Second, the heterogeneous etherification step requires water content control to achieve acceptable reaction rates and minimize undesired impurities. Finally, isolation from water was developed that addressed oiling issues while also affording effective drying, despite the low melting point (as low as 28 °C) of the biaryl ether.