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Synfacts 2015; 11(2): 0113
DOI: 10.1055/s-0034-1379790
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Dual Orexin Receptor Antagonist MK-6096

Contributor(s):
Philip Kocienski
Chung JY. L, * Zhong Y.-L, * Maloney KM. * et al. Merck Research Laboratories and Merck Manufacturing Division, Rahway, USA
Unusual Pyrimidine Participation: Efficient Stereoselective Synthesis of Potent Dual Orexin Receptor Antagonist MK-6096.

Org. Lett. 2014;
16: 5890-5893
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Further Information

Publication History

Publication Date:
19 January 2015 (online)

 
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Key words

MK-6096 - orexin antagonists - amide bond formation - 1-propylphosphonic anhydride - enzymatic transamination - Mukaiyama directed aldol reaction

Significance

Orexins-A and -B are neuropeptides that regulate arousal and sleep–wake cycles by hypothalamic signaling through the orexin-1 and -2 receptors. MK-6096 is a dual orexin receptor antagonist that is of interest for the treatment of insomnia. In the asymmetric synthesis depicted (7 steps, 37% overall), the key stereogenic steps are (1) a biocatalytic transamination (A→B) and (2) a highly diastereoselective Mukaiyama directed aldol reaction (C→D, dr > 99:1).


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Comment

During a previous kg-scale synthesis of MK-6096 (M. Girardin et al. Org. Process Res. Dev. 2013, 17, 61) the challenging amidation of fragments I and J required 3.4 equivalents of expensive T3P (1-propylphosphonic anhydride). In the current route the same amidation was accomplished using only 0.05 equivalents of T3P together with stoichiometric amounts of pivaloyl choride as the dehydrating agent. A mechanism for this unusual transformation is presented that implicates participation by the pyrimidine ring.


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