Process Development and Manufacture of the Core Starting Material of Adagrasib (MRTX849)

β-Ketoester 1 is one of the critical starting materials used in the second-generation synthesis of adagrasib. Disclosed within is a new, streamlined, operationally simple, and more environmentally friendly three-step telescoped protocol which was demonstrated on a >100 kg batch with an overall yi...

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Bibliographic Details
Published inOrganic process research & development Vol. 28; no. 2; pp. 609 - 618
Main Authors Scattolin, Thomas, Paymode, Dinesh Jagannath, Snead, David Robinson, Lu, Zhichao, Yu, Stanley, Robert-Monpate, Maxime, Chao, Maria Noelia, Haas, Thomas Michael, Wang, Hanhui, Liang, Xuewei, Chen, Cheng-yi
Format Journal Article
LanguageEnglish
Published American Chemical Society 16.02.2024
Subjects
KRASG12C
MRTX849
Dieckmann condensation
adagrasib
β-ketoester
oncology
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Summary:β-Ketoester 1 is one of the critical starting materials used in the second-generation synthesis of adagrasib. Disclosed within is a new, streamlined, operationally simple, and more environmentally friendly three-step telescoped protocol which was demonstrated on a >100 kg batch with an overall yield of 70%. Identification of the shortcomings and the quality issues of the initial route are discussed. The process development work overcoming these challenges and leading to the new route of synthesis is described.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.3c00485