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

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• 作者：John Y. L. Chung ; Jeremy P. Scott ; Camille Anderson ; Brian Bishop ; Nadine Bremeyer ; Yang Cao ; Qinghao Chen ; Robert Dunn ; Amude Kassim ; David Lieberman ; Aaron J. Moment ; Faye Sheen ; Michael Zacuto
• 刊名：Organic Process Research & Development
• 出版年：2015
• 出版时间：November 20, 2015
• 年：2015
• 卷：19
• 期：11
• 页码：1760-1768
• 全文大小：397K
• ISSN：1520-586X

文摘

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-伪-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.