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Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036
Jie Xu1, Ngiap-Kie Lim1, Jacob C Timmerman1
1Department of Small Molecule Process Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, United States.
Organic Letters
|May 10, 2023
Summary
A novel, chromatography-free synthesis of GDC-6036 was developed using an atroposelective Negishi coupling. This efficient method yields high-purity GDC-6036, a crucial pharmaceutical compound.
Area of Science:
- Organic Chemistry
- Medicinal Chemistry
- Process Chemistry
Background:
- GDC-6036 is a critical pharmaceutical compound requiring efficient synthesis.
- Asymmetric synthesis is vital for producing enantiomerically pure active pharmaceutical ingredients.
- Chromatographic purification methods can be costly and time-consuming in large-scale synthesis.
Purpose of the Study:
- To develop a chromatography-free asymmetric synthesis of GDC-6036.
- To achieve high atroposelectivity in the key coupling step.
- To establish a scalable and efficient route to high-purity GDC-6036.
Main Methods:
- Atroposelective Negishi coupling of an aminopyridine and a quinazoline derivative using a palladium catalyst and a chiral ligand.
- Alkoxylation and global deprotection to form a key heterobiaryl intermediate.
- Stepwise acrylamide installation via acylation/sulfone elimination followed by salt formation and crystallization.
Main Results:
- Successful chromatography-free asymmetric synthesis of GDC-6036.
- High atroposelectivity achieved in the Negishi coupling step, yielding the desired (Ra)-enantiomer.
- Final product obtained in high purity through controlled acrylamide installation and crystallization.
Conclusions:
- The developed synthetic route is efficient and avoids chromatography.
- The method provides a scalable and cost-effective approach to GDC-6036.
- This strategy represents a significant advancement in the synthesis of complex heterobiaryl compounds.
