- Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
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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.
- 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
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p. 1760 - 1768
(2015/12/01)
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- Omarigliptin (MK-3102): A novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes
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In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
- Biftu, Tesfaye,Sinha-Roy, Ranabir,Chen, Ping,Qian, Xiaoxia,Feng, Dennis,Kuethe, Jeffrey T.,Scapin, Giovanna,Gao, Ying Duo,Yan, Youwei,Krueger, Davida,Bak, Annette,Eiermann, George,He, Jiafang,Cox, Jason,Hicks, Jacqueline,Lyons, Kathy,He, Huaibing,Salituro, Gino,Tong, Sharon,Patel, Sangita,Doss, George,Petrov, Aleksandr,Wu, Joseph,Xu, Shiyao Sherrie,Sewall, Charles,Zhang, Xiaoping,Zhang, Bei,Thornberry, Nancy A.,Weber, Ann E.
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p. 3205 - 3212
(2014/05/20)
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- AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
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The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved
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Page/Page column 23
(2010/06/11)
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