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Synfacts 2016; 12(2): 0113
DOI: 10.1055/s-0035-1561111
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Omarigliptin

Contributor(s):
Philip Kocienski
Chung JY. L, * Scott JP. * et al. Merck and Co., Rahway, USA and Merck Sharp and Dohme, Hoddesdon, UK
Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.

Org. Process Res. Dev. 2015;
19: 1760-1768
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Publication History

Publication Date:
19 January 2016 (online)

 
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Synthesis of OmarigliptinSynfacts 2016; 12(04): 436-436
DOI: 10.1055/s-0035-1561959

Key words

omarigliptin - dipeptidyl dipeptidase-4 inhibitor - dynamic kinetic resolution - asymmetric transfer hydrogenation - ruthenium catalysis - cycloisomerization

Significance

Omarigliptin (MK-3102) is a dipeptidyl peptidase-4 (DPP-4) inhibitor that has received marketing authorization in Japan for the once-weekly treatment of type 2 diabetes. The synthesis of pyranone H depicted features three ruthenium-catalyzed reactions: (1) a DKR reduction of rac-α-aminoketone C to set the two contiguous stereogenic centers, (2) a cycloisomerization of alkyne E to dihydropyran F, and (3) a ruthenium-catalyzed oxidation of pyranol G to the desired pyranone H.


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Comment

The Takasago tethered ruthenium(II) catalyst D is a highly efficient asymmetric transfer hydrogenation catalyst. The catalyst loading was reduced to 0.1 mol% without sacrificing selectivity and reaction kinetics. It was critical to apply efficient N2 sparging during the reaction to remove CO2; otherwise, the reaction could stall if this was allowed to accumulate. For the discovery synthesis of omarigliptin, see: T. Biftu et al. J. Med. Chem. 2014, 57, 3205.


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