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Synfacts 2015; 11(9): 0899
DOI: 10.1055/s-0034-1378765
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of JAK2 Inhibitor BMS-911543

Contributor(s):
Philip Kocienski
Eastgate MD * et al. Bristol-Myers Squibb, New Brunswick, USA
Ni-Catalyzed C–H Functionalization in the Formation of a Complex Heterocycle: Synthesis of the Potent JAK2 Inhibitor BMS-911543.

J. Org. Chem. 2015;
80: 6001-6011
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Further Information

Publication History

Publication Date:
18 August 2015 (online)

 
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Key words

BMS-911543 - JAK2 inhibitor - 1H-pyrrolo[2,3-b]-pyridines - C–H functionalization - nickel catalysis

Significance

BMS-911543 is a selective JAK2 kinase inhibitor that is of interest for the treatment of myeloproliferative disorders. The key step in the synthesis depicted is the nickel-mediated cyclization (B → F) that enabled the construction of the highly functionalized 1H-pyrrolo[2,3-b]pyridine core in just eight steps (29% overall yield) from ethyl 4-bromo-1H-pyrrole-2-carboxylate.


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Comment

The final amide bond formation was complex owing to the instability of dicyclopropylamine (DCPA). After screening a variety of more unusual conditions, 2-chloro-1,3-dimethylimidazolidinium chloride (J) cleanly and quantitatively formed the acid chloride of carboxylate I which smoothly coupled with DCPA.


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