Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP‑4 Inhibitor for the Treatment of Type 2 Diabetes

• Published in: Organic process research & development 2015-11, Vol.19 (11), p.1760-1768
• Main Authors: Chung, John Y. L, Scott, Jeremy P, Anderson, Camille, Bishop, Brian, Bremeyer, Nadine, Cao, Yang, Chen, Qinghao, Dunn, Robert, Kassim, Amude, Lieberman, David, Moment, Aaron J, Sheen, Faye, Zacuto, Michael
• Format: Article
• Language: English
• ISSN: 1083-6160; 1520-586X
• DOI: 10.1021/acs.oprd.5b00267

Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed reactions: (1) a DKR reduction of a rac-α-aminoketone to set the two contiguous stereogenic centers, (2) a cycloisomerization of a bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a pyranol to the desired pyranone. The regioselective synthesis of a N-Boc-1-mesyl pyrazole fragment was achieved via base-promoted mesyl group isomerization to afford 30:1 selectivity. A highlight of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.