Development of a Scalable Alkylation via a Protection/Deprotection Sequence for BMT-773752: Key Intermediate in the Synthetic Route to Repotrectinib

The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purifi...

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Bibliographic Details
Published in:Organic process research & development 2024-07, Vol.28 (7), p.2659-2666
Main Authors: Zhang, Han, Li, Binfeng, Yang, Jin, Xu, Changchun, Carmona, Rafaela, Zhu, Jason, Hoblos, Bilal, Wisniewski, Steven
Format: Article
Language:English
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Summary:The development of a practical and scalable synthetic route to BMT-773752-02, a key starting material for repotrectinib, is described. The original sequence exhibited various limitations such as use of pyrophoric organolithium reagents, low yield, poor diastereoselectivity, and lengthy workup/purification procedures, which were overcome by development of a new route. A salt screening was conducted to improve the physical properties of the title compound. The scalability of the newly designed synthetic strategy has been demonstrated on multihundred-kilogram scale production to afford greater than a metric ton of this intermediate.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.4c00061