Asymmetric Synthesis of KRAS G12C Inhibitor MK-1084 via a Crystallization-Induced Diastereomer Transformation (CIDT)
Hongming Li1, Gao Shang1, Zhiguo J Song1
1Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
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MK-1084 is a potent KRAS G12 inhibitor characterized by a complex macrocyclic ring system incorporating two atropisomeric axes from a restricted rotation around both C-C and N-C bonds. Herein, we report an efficient synthetic approach to manufacture MK-1084 to enable clinical trials. By leveraging the in-depth understanding of the inherent properties of axial chirality, we discovered and developed a one-pot crystallization-induced diastereomer transformation (CIDT)/carbonylation process to establish the unique and challenging macrocyclic core with double axial chiral centers from a racemic advanced precursor and readily available raw materials.
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