Adagrasib’s Second-Generation Synthesis: Transitioning from Route Scouting to Optimization

Process optimization details are disclosed following the completion of process design for a second-generation manufacturing route of adagrasib. Key objectives for development included control of difficult-to-purge impurities in the key starting materials (KSMs), enhanced scalability of the KSM, impr...

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Bibliographic Details
Published inOrganic process research & development Vol. 28; no. 8; pp. 3128 - 3142
Main Authors Lu, Zhichao, Chen, Chengsheng, Paymode, Dinesh J., Gan, Yonghong, Scattolin, Thomas, Roshandel, Sahar, Dong, Weitong, Yu, Stanley, Lemeune, Stéphane, Snead, David R., Chen, Cheng-yi
Format Journal Article
LanguageEnglish
Published American Chemical Society 16.08.2024
Subjects
active pharmaceutical ingredient (API)
process chemistry
adagrasib
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Summary:Process optimization details are disclosed following the completion of process design for a second-generation manufacturing route of adagrasib. Key objectives for development included control of difficult-to-purge impurities in the key starting materials (KSMs), enhanced scalability of the KSM, improved pyrimidone formation of the core, increased robustness of oxidation, enhanced stability of the step 3 intermediate, removal of the halogenated solvent in the fourth step, and implementation of single crystallization of the final API. These improvements led to more efficient production of adagrasib and a further reduction in the cost of goods by approximately 50%.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.4c00024