Highly Efficient Asymmetric Synthesis of Sitagliptin

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• 作者：Karl B. Hansen ; Yi Hsiao ; Feng Xu ; Nelo Rivera ; Andrew Clausen ; Michele Kubryk ; Shane Krska ; Thorsten Rosner ; Bryon Simmons ; Jaume Balsells ; Nori Ikemoto ; Yongkui Sun ; Felix Spindler ; Christophe Malan
• 刊名：Journal of the American Chemical Society
• 出版年：2009
• 出版时间：July 1, 2009
• 年：2009
• 卷：131
• 期：25
• 页码：8798-8804
• 全文大小：278K
• 年卷期：v.131,no.25(July 1, 2009)
• ISSN：1520-5126

文摘

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/^tBu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, ‘green’ synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.