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Synfacts 2013; 9(3): 0239
DOI: 10.1055/s-0032-1318127
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of the Indole Core of MK-3281

Contributor(s):
Philip Kocienski
Alorati AD, * Gibb AD, * Mullens PR, Stewart GW. Merck Sharp & Dohme Ltd., Hoddesdon, UK
An Efficient Process for the Large-Scale Synthesis of a 2,3,6-Trisubstituted Indole.

Org. Process Res. Dev. 2012;
16: 1947-1952
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Further Information

Publication History

Publication Date:
15 February 2013 (online)

 
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Key words

MK-3281 - RNA polymerase NS5B inhibitor - indole ring synthesis - Truce–Smiles rearrangement

Significance

MK-3281 inhibits hepatitis C RNA polymerase NS5B. A synthesis starting from the indole fragment I was recently described: J. P. Scott et al. Org. Process Res. Dev. 2011, 15, 1116. In this paper a large scale synthesis of the MK-3281 fragment I is described that features a Truce–Smiles rearrangement.


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Comment

The highly telescoped synthesis of the indole fragment I depicted was accomplished on a >50 kg scale and delivered the target indole in 55% overall yield in five steps. All of the yields are assay yields. For the discovery synthesis of MK-3281, see: F. Narjes et al. J. Med. Chem. 2011, 54, 289.


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