Development of a Green and Sustainable Manufacturing Process for a Key Intermediate to Nemtabrutinib (MK-1026): Sequential Deprotonation–Lithiation as a Batch–Flow Process

• Published in: Organic process research & development Vol. 28; no. 5; pp. 1402 - 1410
• Main Authors: Otte, Douglas A. L., Larson, Reed T., Alwedi, Embarek, Armiger, Travis, Chen, Yonggang, Chung, Cheol K., Corry, James, Desmond, Richard, Fier, Patrick S., Franklin, Robert D., Guetschow, Erik D., Hall, Jackson R., Halsey, Holst M., Hartmanshenn, Clara, Jellett, Lisa, Kuhl, Nadine, Lévesque, François, McMullen, Jonathan P., Patel, Pratiq A., Paulines, Mellie June, Ren, Hong, Rodrigues, Vailankanni L., Ruccolo, Serge, Tan, Lushi, Thaisrivongs, David A., Xiao, Kai-Jiong
• Format: Journal Article
• Language: English
• Published: American Chemical Society 17.05.2024
• Subjects: CSTR; reactive intermediate; fluidics; continuously stirred; PFR; flow; plug flow

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)...