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. inter alia: (a) Kawai, S. H.; Hambalek, R. J.; Just, G. J. Org. Chem. 1994, 59, 2620-2622. (b) Ronggeng, W.; 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.