Highly Efficient Asymmetric Synthesis of Sitagliptin

被引：194

作者：

Hansen, Karl B. ^{[1
]}

Yi Hsiao ^{[1
]}

Xu, Feng ^{[1
]}

Rivera, Nelo ^{[1
]}

Clausen, Andrew ^{[1
]}

Kubryk, Michele ^{[1
]}

Krska, Shane ^{[1
]}

Rosner, Thorsten ^{[1
]}

Simmons, Bryon ^{[1
]}

Balsells, Jaume ^{[1
]}

Ikemoto, Nori ^{[1
]}

Sun, Yongkui ^{[1
]}

Spindler, Felix ^{[2
]}

Malan, Christophe ^{[2
]}

Grabowski, Edward J. J. ^{[1
]}

Armstrong, Joseph D., III ^{[1
]}

机构：

[1] Merck Res Lab, Dept Proc Res, Rahway, NJ 07065 USA

[2] Solvias AG, Basel, Switzerland

来源：

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY | 2009年 / 131卷 / 25期

关键词：

AMINO-ACID-DERIVATIVES; PEPTIDASE-IV INHIBITOR; MELDRUMS ACID; HYDROGENATION;

D O I：

10.1021/ja902462q

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

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)/Bu-1 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.

引用

页码：8798 / 8804

页数：7

共 25 条

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