Leveraging Synergistic Solubility in the Development of a Direct Isolation Process for Nemtabrutinib

We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Signifi...

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Published inOrganic process research & development Vol. 27; no. 4; pp. 659 - 668
Main Authors Chen, Yonggang, Iuzzolino, Luca, Burgess, Samantha A., Chung, Cheol K., Corry, James, Crawford, Morgan, Desmond, Richard, Guetschow, Erik, Hartmanshenn, Clara, Kuhl, Nadine, Liu, Zhu, Luo, Hanlin, McQuilken, Alison C., Newman, Justin A., Ren, Hong, Thaisrivongs, David A., Wang, Zhixun, Sirota, Eric
Format Journal Article
LanguageEnglish
Published American Chemical Society 21.04.2023
Subjects
impurity crystallization kinetics
crystallization
SNAr
API
BTK inhibitor
synergistic solubility
polish filtration
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Summary:We report the process development for the active pharmaceutical ingredient (API) step of the commercial manufacturing route to nemtabrutinib (MK-1026), a reversible Bruton’s Tyrosine Kinase (BTK) inhibitor currently under investigation for the treatment of several hematological malignancies. Significant improvements on process efficiency were achieved by a direct isolation process leveraging optimal reaction conditions and synergistic API solubility in an ethanol/water system. In combination with additional robustness improvements on impurity control, an efficient, practical, and scalable synthesis of nemtabrutinib was developed.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.2c00391