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Synfacts 2016; 12(4): 0331
DOI: 10.1055/s-0035-1561765
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-8831

Contributor(s):
Philip Kocienski
Neelamkavil SF * et al. Merck Research Laboratories, Kenilworth, USA
Discovery of MK-8831, A Novel Spiro-Proline Macrocycle as a Pan-Genotypic HCV-NS3/4a Protease Inhibitor.

ACS Med. Chem. Lett. 2016;
7: 111-116
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Further Information

Publication History

Publication Date:
15 March 2016 (online)

 
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Key words

MK-8831 - HCV NS3/4a protease inhibitors - spirocycles - macrocycles

Significance

A Merck team has devised a route to HCV NS3/4a protease inhibitors containing a spirocyclic proline core. Optimization of the structure–activity relationships resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.


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Comment

Ketone F was cyclized with the previously reported macrocyclic prolinone G employing benzoic acid and pyrrolidine. Initial conditions gave very poor yields, but the optimized methods gave spirocycle H in 50% yield and high levels of diastereoselectivity (dr = 99:1).


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