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The Multistep Synthesis of Fexofenadine
Chem 213H: Organic Chemistry Lab
Department of Chemistry, Pennsylvania State University
Dr. Masters & Anthony Nocket
Christopher Mallis, Leon Lin, Kayla Shellhammer
Background
Fexofenadine is an anti-histamine drug used to treat allergy symptoms. It
works by blocking the H1 histamine receptor. Fexofenadine is the active
ingredient in Allegra. The objective for this project was to perform a
multistep synthesis of fexofenadine.
Reaction 1
Synthesis of gem-dimethyl ester 9 via successive bis-alkylation of 8
Reaction 4
Synthesis of alcohol 5 via Grignard addition of 6 to 7
Fexofenadine
www.sigmaaldrich.com
Retrosynthetic Scheme for Fexofenadine Synthesis
Scheme 1
Reaction 2
Synthesis of benzylic bromide 10 via Wohl-Ziegler Bromination of 9
Reaction 5
Synthesis of lactol 3a via acid-catalyzed transacetalization of 5
Scheme 2
Scheme 3
Sommelet
Oxidation
Synthetic Route
Scheme 4
Scheme 5
Scheme 6
Scheme 7
Wohl-Zeigler
bis -alkylation
Bromination
Reaction 3
Synthesis of ester aldehyde 7 via Sommelet Oxidation of 10
Conclusion
This synthetic pathway was successful until the Grignard addition. Starting
from 8, 9 was synthesized with a 52% yield. Using 9, 10 was synthesized with a
78% yield. Ester aldehyde 7 was synthesized with a 10% yield. A Grignard
addition was then performed on 7, but it did not yield a pure product. Overall, the
synthesis was fairly successful, and with more time Fexofenadine probably could
have been successfully synthesized.
Acknowledgements
The authors would like to acknowledge Penn State University for the use of
their lab and materials. The authors would also like to acknowledge Katherine
Masters and Anthony Nocket for their assistance in the lab.
References
1.
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Yougui, Z.; Guancho, Z. Res. Chem. Intermed. 2012. (c) Raghavendra, G. M.; Harsha, K. B.; Vinaya, K.;
Mantelingu, K.; Rangappa, K. S. Synth. Commun. 2011, 41, 2296-2303. Huang, J.; Wang, W.; Wang, L.-X. Org.
Proc. Res. Dev. 2010, 14, 1464-1468.
2.
(a) Fang, Q. K.; Senanayake, C. H.; Wilkinson, H. C.; Wald, S. A.; Li, H. Tetrahedron Lett. 1998, 39, 2701-2704.
(b) Yu, S.; Tang, L-H; Tao, L.; Qin, X-F. Chin. J. Pharm. 2006, 37, 439-440.
3.
Masters, K.M. Chem 213H Lab Guide, Spring 2013 Edition.