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

Abstract

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. A regioselective synthesis of an N-Boc-1-mesyl pyrazole fragment was achieved via a base promoted mesyl group isomerisation 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 multi-kilogram deliveries, and improved the overall diastereoselectivity and efficiency of the route.

Synthesis of [14C]omarigliptin

“…The Medicinal Chemistry synthetic route for unlabeled MK‐3102 shown in Scheme served as the basis for the initial labeling approach …”

“…Although we gratified that our early work afforded the initial amount of [ 14 C]MK 3102, it was clear that additional improvements would be required, especially to address the lack of regiochemical control over the N‐sulfonation of the pyrazole moiety. To this end, we were inspired by progress on the parent development program whereby alcohol 12 was readily converted to sulfonylated pyrazole 8 through a two‐step sulfonation–isomerization sequence . Application of this approach with 14 C‐alcohol 12 in the synthesis of [ 14 C]MK 3102 is shown in Scheme .…”

“…The dipeptidyl peptidase 4 (DPP‐4) inhibitors, such as Merck's Sitagliptin, a once‐daily antidiabetic agent, have been widely used to treat T2DM. In an effort to identify other DPP‐4 inhibitors with long half‐lives and the potential for once‐weekly dosing, Merck teams developed Omarigliptin (MK‐3102) …”

Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

“…7 Starting from inexpensive glycine benzophenone imine ( 9 ), the current manufacturing route is a highly stereocontrolled synthesis and amenable to produce hundreds of kilograms of 1 with good overall yield. 8 While this synthesis is practical and efficient, we identified several specific opportunities for improvement.…”

Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives

“…Omarigliptin (MK‐3102) (approved in Japan in 2015) can be used as once‐weekly treatment and is generally well‐tolerated throughout the base and extension studies. Thus, the discovery of novel selective DPP‐4 inhibitors possessing antidiabetic activity is of great interest . Linagliptin (Fig.…”