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Synfacts 2019; 15(05): 0465
DOI: 10.1055/s-0037-1612464
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of BMS-741672

Contributor(s):
Philip Kocienski
Carter PH. * et al. Bristol-Myers Squibb Company, Princeton, USA
Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672.

ACS Med. Chem. Lett. 2019;
10: 300-305
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Further Information

Publication History

Publication Date:
15 April 2019 (online)

 
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Key words

BMS-741672 - Hoffman rearrangement - Curtius rearrangement - iodolactamization - 1,2,4-triaminocyclohexanes

Significance

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).


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Comment

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).


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