The DOI matches its Crossref record.
First Generation Process for the Preparation of the DPP-IV Inhibitor Sitagliptin
Abstract
A new synthesis of sitagliptin (MK-0431), a DPP-IV inhibitor and potential new treatment for type II diabetes, suitable for the preparation of multi-kilogram quantities is presented. The triazolopyrazine fragment of sitagliptin was prepared in 26% yield over four chemical steps using a synthetic strategy similar to the medicinal chemistry synthesis. Key process developments were made in the first step of this sequence, the addition of hydrazine to chloropyrazine, to ensure its safe operation on a large scale. The beta-amino acid fragment of sitagliptin was prepared by asymmetric reduction of the corresponding beta-ketoester followed by a two-step elaboration to an N -benzyloxy beta-lactam. Hydrolysis of the lactam followed by direct coupling to the triazolopiperazine afforded sitagliptin after cleavage of the N -benzyloxy group and salt formation. The overall yield was 52% over eight steps.
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Cited by
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Prescribed drugs containing nitrogen heterocycles: an overview
Heravi, M. M., & Zadsirjan, V. (2020) · RSC Advances · doi:10.1039/d0ra09198g · Cited by 1,194
Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals
Dunetz, J. R., Magano, J., & Weisenburger, G. A. (2016) · Organic Process Research & Development · doi:10.1021/op500305s · Cited by 819
Green Chemistry in the Synthesis of Pharmaceuticals
Kar, S., Sanderson, H., Roy, K., Benfenati, E., & Leszczynski, J. (2022) · Chemical Reviews · doi:10.1021/acs.chemrev.1c00631 · Cited by 566
Solvents and sustainable chemistry
Welton, T. (2015) · Proceedings of the Royal Society A: Mathematical, Physical and Engineering Sciences · doi:10.1098/rspa.2015.0502 · Cited by 412
Highly Efficient Asymmetric Synthesis of Sitagliptin
Hansen, K. B., Hsiao, Y., Xu, F., Rivera, N., Clausen, A., Kubryk, M., Krska, S., Rosner, T., Simmons, B., Balsells, J., et al. (2009) · Journal of the American Chemical Society · doi:10.1021/ja902462q · Cited by 314
Self-citationNext generation organofluorine containing blockbuster drugs
Han, J., Remete, A. M., Dobson, L. S., Kiss, L., Izawa, K., Moriwaki, H., Soloshonok, V. A., & O’Hagan, D. (2020) · Journal of Fluorine Chemistry · doi:10.1016/j.jfluchem.2020.109639 · Cited by 313
Metadata
- Authors
- Hansen, K. B., Balsells, J., Dreher, S., Hsiao, Y., Kubryk, M., Palucki, M., Rivera, N., Steinhuebel, D., Armstrong, J. D., Askin, D., & Grabowski, E. J. J.
- Venue
- Organic Process Research & Development
- Publisher
- American Chemical Society (ACS)
- Published
- 2005-08-31
- Volume
- 9
- Issue
- 5
- Pages
- 634-639
- ISSN
- 1083-6160 (ISSN-L)
- 1520-586X
- OpenAlex
- W1994890159
- Cited by
- 167
- References
- 0
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- closed
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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