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Synfacts 2013; 9(4): 0355
DOI: 10.1055/s-0032-1318322
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of MK-6096

Contributor(s):
Philip Kocienski
Girardin M, Ouellet SG, Gauvreau D, Moore JC, Hughes G, Devine PN, O’Shea PD, Campeau L.-C * Merck Frosst Center for Therapeutic Research, Kirkland, Canada and Merck Research Laboratories, Rahway, USA
Convergent Kilogram-Scale Synthesis of Dual Orexin Receptor Antagonist.

Org. Process Res. Dev. 2013;
17: 61-68
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Publication History

Publication Date:
15 March 2013 (online)

 
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Key words

MK-6096 - dual orexin receptor antagonist - biocatalytic transamination

Significance

The orexins are peptides that act as neurotransmitters in the central nervous system. MK-6096 is a dual orexin receptor antagonist that is a candidate for the treatment of insomnia. A noteworthy feature of the synthesis depicted is the biocatalytic transamination reaction on prochiral substrate A using a three-enzyme cocktail that delivers piperidinone B (>99% ee) on a multikilogram scale.


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Comment

The diastereoisomeric ratio of the α-hydroxymethyl lactam (dr = 1.7:1) was improved to >40:1 by reduction of the lactam followed by salt formation using d-(+)-camphorsulfonic acid [d-(+)-CSA]. For the development of transaminase ATA-117 in the manufacture of sitagliptin, see: C. K. Savile et al. Science 2010, 329, 305.


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