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Experimental synthesis study demonstrates a one-pot diastereomer transformation to produce KRAS G12C inhibitor MK-1084, highlighting an efficient manufacturing route for clinical trials.
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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Li et al. (2026) studied this question.
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