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Synfacts 2012; 8(7): 0693
DOI: 10.1055/s-0031-1290413
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Vaniprevir

Contributor(s):
Philip Kocienski
Kong J, * Chen C.-y, * Balsells-Padros J, Cao Y, Dunn RF, Dolman SJ, Janey J, Li H, Zacuto MJ. Merck Research Laboratory, Rahway, USA
Synthesis of the HCV Protease Inhibitor Vaniprevir (MK-7009) Using Ring-Closing Metathesis Strategy.

J. Org. Chem. 2012;
77: 3820-3828
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Further Information

Publication History

Publication Date:
19 June 2012 (online)

 
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Key words

vaniprevir - MK-7009 - HCV protease inhibitors - ring-closing metathesis - macrocyclization

Significance

The key step in this synthesis of vaniprevir is the construction of the macrocycle (91% yield) via ring-closing metathesis (RCM). By using simultaneous slow addition of the substrate and the catalyst D (0.2 mol%), the RCM reaction could be conducted at high concentration (0.13 M) on a 100 g scale.


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Comment

2,6-Dichloro-1,4-benzoquinone was added to suppress isomerization of the allyl alkene in the isoindoline unit in C and consequent competing formation of a 19-membered ring by-product. An important contributor to the success of the RCM reaction was the high purity of crystalline B.


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