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Synfacts 2011(8): 0811-0811  
DOI: 10.1055/s-0030-1260677
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of Carmegliptin

Contributor(s):Philip Kocienski
S. Abrecht, J.-M. Adam, U. Bromberger, R. Diodone, A. Fettes*, R. Fischer, V. Goeckel, S. Hildbrand, G. Moine, M. Weber
F. Hoffmann-La Roche Ltd., Basel, Switzerland
An Efficient Process for the Manufacture of Carmegliptin
Org. Process Res. Dev.  2011,  15:  503-514  
Crossref
Further Information

Publication History

Publication Date:
20 July 2011 (online)

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Key words

carmegliptin - DPP-4 inhibitors - Mannich reaction - crystallization-induced dynamic resolution - Hofmann rearrangement

Significance

Carmegliptin is a dipeptidyl di­peptidase-IV inhibitor under development for the treatment of type-2 diabetes. Over 1000 kg was synthesized by the route depicted featuring an efficient crystallization-induced dynamic resolution of rac-D and a large-scale Hofmann rearrangement of the amide F.

Comment

J.-M. Adam et al. (Org. Process Res. Dev. 2011, 15, 515) describe the synthesis of ­lactone H by asymmetric hydrogenation (10 kg scale), but a route starting from commercial (S)-tert-butyl glycidyl ether (derived from a Jacobsen hydrolytic kinetic resolution) delivered >500 kg of H.

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