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Synfacts 2013; 9(11): 1145
DOI: 10.1055/s-0033-1339864
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-5172

Contributor(s):
Philip Kocienski
Kuethe J, * Zhong Y.-L, * Yasuda N, * Beutner G, Linn K, Kim M, Marcune B, Dreher SD, Humphrey G, Pei T. Merck Research Laboratories, Rahway, USA
Development of a Practical, Asymmetric Synthesis of the Hepatitis C Virus Protease Inhibitor MK-5172.

Org. Lett. 2013;
15: 4174-4177
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Further Information

Publication History

Publication Date:
18 October 2013 (online)

 
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Key words

MK-5172 - hepatitis C virus protease inhibitor - macrolactamization - Sonogashira reaction

Significance

MK-5172 is a hepatitis C virus protease inhibitor. Key steps in the synthesis depicted are (1) the regioselective SNAr reaction of dichloroquinoxaline A with prolinol derivative B and (2) construction of the 18-membered macrocycle ­using a macrolactamization (F → G).


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Comment

The medicinal chemistry route to MK-5172 is based on a ring-closing metathesis strategy (S. Harper et al. ACS Med. Chem. Lett. 2012, 3, 332). The best regioselectivity (20:1) and minimization of double substitution in the SNAr reaction of A with B was achieved using 1,8-diaza­bicyclo[5.4.0]undec-7-ene (DBU) as the base in polar solvents such as DMSO, NMP, or DMAc.


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