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Synthesis of BMS-741672
Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.
ACS Med. Chem. Lett. 2019;
15 April 2019 (online)
Key wordsBMS-741672 - Hoffman rearrangement - Curtius rearrangement - iodolactamization - 1,2,4-triaminocyclohexanes
BMS-741672 is a chemotactic chemokine receptor 2 (CCR2) antagonist that is of interest for the treatment of inflammatory, cardiovascular, and metabolic diseases. The discovery synthesis depicted (>20 steps) is based on construction of the all-cis 1,2,4-triaminocyclohexane core using a Curtius rearrangement (A → B), an iodolactamization (D → E), and a Hoffman rearrangement (K → L).
The synthesis of lactam G was previously developed by Bristol-Myers Squibb (C. L. Campbell et al. J. Org. Chem. 2009, 74, 6368), and a shorter large-scale route to BMS-741672 was subsequently reported that delivered 50 kg of API for clinical evaluation (J. Deerberg et al. Org. Process Res. Dev. 2016, 20, 1949).