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
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.
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.
