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Cited by 314

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Highly Efficient Asymmetric Synthesis of Sitagliptin

Hansen, Karl B., Hsiao, Yi, Xu, Feng, Rivera, Nelo, Clausen, Andrew, Kubryk, Michele, Krska, Shane, Rosner, Thorsten, Simmons, Bryon, Balsells, Jaume, Ikemoto, Nori, Sun, Yongkui, Spindler, Felix, Malan, Christophe, Grabowski, Edward J. J., Armstrong, Joseph D.·2009·Journal of the American Chemical Society
DOI 10.1021/ja902462q
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Abstract

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)/(t)Bu 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.

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Research works printed but not linked: 24

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Metadata

Authors
Hansen, K. B., Hsiao, Y., Xu, F., Rivera, N., Clausen, A., Kubryk, M., Krska, S., Rosner, T., Simmons, B., Balsells, J., Ikemoto, N., Sun, Y., Spindler, F., Malan, C., Grabowski, E. J. J., & Armstrong, J. D.
Venue
Journal of the American Chemical Society
Publisher
American Chemical Society (ACS)
Published
2009-06-09
Volume
131
Issue
25
Pages
8798-8804
ISSN
  • 0002-7863 (ISSN-L)
  • 1520-5126
DOI
10.1021/ja902462q
OpenAlex
W1995075366
Cited by
314
References
0
FWCI
14.98
Type
journal article
Language
en
Open access
closed

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CoChat. (2026). Citation check: Highly Efficient Asymmetric Synthesis of Sitagliptin. https://app.cochat.ai/papers/10.1021/ja902462q
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Hansen, K. B., Hsiao, Y., Xu, F., Rivera, N., Clausen, A., Kubryk, M., Krska, S., Rosner, T., Simmons, B., Balsells, J., Ikemoto, N., Sun, Y., Spindler, F., Malan, C., Grabowski, E. J. J., & Armstrong, J. D. (2009). Highly Efficient Asymmetric Synthesis of Sitagliptin. Journal of the American Chemical Society. https://doi.org/10.1021/ja902462q

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