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Synfacts 2009(11): 1190-1190  
DOI: 10.1055/s-0029-1218024
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of an Oral TACE Inhibitor

Contributor(s): Philip Kocienski
S. A. Savage*, R. E. Waltermire, S. Campagna, S. Bordawekar, J. D. R. Toma
Bristol-Myers Squibb, New Brunswick, USA
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Publication History

Publication Date:
22 October 2009 (online)

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Significance

BMS-561392 selectively inhibits TNF-α convertase enzyme (TACE) and is a lead for the treatment of rheumatoid arthritis. This large-scale synthesis features (1) an efficient C-alkylation of a phenolic α,α-disubstituted amino ester without protection of a phenol (B → C), (2) an enzymatic resolution of a quaternary amino ester C, and (3) synthesis of the final hydroxamic ester with undetectable amounts of mutagenic hydroxy-amine contamination.