Development of a Green and Sustainable Manufacturing Process for a Key Intermediate to Nemtabrutinib (MK-1026): Sequential Deprotonation–Lithiation as a Batch–Flow Process
Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C)...
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Published in | Organic process research & development Vol. 28; no. 5; pp. 1402 - 1410 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
American Chemical Society
17.05.2024
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Subjects | |
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Abstract | Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility. |
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AbstractList | Nemtabrutinib (MK-1026) is a novel oral Bruton’s tyrosine kinase (BTK) inhibitor for treatment of B-cell cancers. An initial synthetic supply route to generate ketone 3 relied on the generation of a highly reactive transient intermediate and the use of n-butyllithium. Cryogenic temperatures (−60 °C) were also required to achieve a modest 61% yield, with one major impurity, resulting from dehalogenation, accounting for the majority of the mass balance. An alternative process was developed to increase the yield and decrease the dependence on cryogenic temperatures, and this advancement was critical to the long-term robustness of the commercial process. Key advancements included performing the requisite deprotonation and metalation steps sequentially and performing the metalation and quench steps in flow. The final flow process was rapidly scaled from grams to tens of kilograms and has been successfully executed in a production facility. |
Author | Paulines, Mellie June Franklin, Robert D. Guetschow, Erik D. Jellett, Lisa Tan, Lushi Lévesque, François Corry, James Hall, Jackson R. Halsey, Holst M. Xiao, Kai-Jiong Patel, Pratiq A. Alwedi, Embarek Chen, Yonggang Ruccolo, Serge Armiger, Travis McMullen, Jonathan P. Ren, Hong Otte, Douglas A. L. Fier, Patrick S. Rodrigues, Vailankanni L. Chung, Cheol K. Kuhl, Nadine Thaisrivongs, David A. Larson, Reed T. Desmond, Richard Hartmanshenn, Clara |
AuthorAffiliation | Department of Analytical Research and Development Global Pharmaceutical Commercialization Development Merck & Co., Inc Department of Process Research and Development |
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Title | Development of a Green and Sustainable Manufacturing Process for a Key Intermediate to Nemtabrutinib (MK-1026): Sequential Deprotonation–Lithiation as a Batch–Flow Process |
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