Reaction 1Synthesis of gem-dimethyl ester 9 via successive bis-alkylation of 8

Reaction 2Synthesis of benzylic bromide 10 via Wohl-Ziegler Bromination of 9

Reaction 3Synthesis of ester aldehyde 7 via Sommelet Oxidation of 10

The Multistep Synthesis of FexofenadineChem 213H: Organic Chemistry Lab

Department of Chemistry, Pennsylvania State UniversityDr. Masters & Anthony Nocket

Christopher Mallis, Leon Lin, Kayla Shellhammer

BackgroundFexofenadine 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.

Fexofenadine

www.sigmaaldrich.com

Retrosynthetic Scheme for Fexofenadine Synthesis

Scheme 1

Scheme 2

Scheme 3

Synthetic Route

Scheme 4

Scheme 5

Scheme 6

Scheme 7

bis -alkylationSommelet

Oxidation

Wohl-Zeigler

Bromination

1.999 3.0094.4562.7271.8571.980PPM6.86.46.05.65.24.84.44.03.63.22.82.42.01.61.20.80.40.0

SpinWorks 3: Mallis, Lin, ShellhammerWohl-Ziegler Starting Material03/21/2013

file: ...a\March21 - 100 - 1H - Ester 9\fid expt: <zg30>transmitter freq.: 400.132471 MHztime domain size: 65536 pointswidth: 8278.15 Hz = 20.6885 ppm = 0.126314 Hz/ptnumber of scans: 16freq. of 0 ppm: 400.130020 MHzprocessed size: 32768 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 122.661 ppm/cm: 0.30655

4.515 1.9992.624 6.171PPM7.26.86.46.05.65.24.84.44.03.63.22.82.42.01.61.20.80.40.0

SpinWorks 3: Kayla ShellhammerWohl-Ziegler

file: ...April2 - 260 - 1H - Bromide 10\fid expt: <zg30>transmitter freq.: 400.132471 MHztime domain size: 65536 pointswidth: 8278.15 Hz = 20.6885 ppm = 0.126314 Hz/ptnumber of scans: 16freq. of 0 ppm: 400.130010 MHzprocessed size: 32768 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 131.507 ppm/cm: 0.32866

1.000 2.0662.108 2.1222.974 5.196PPM9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0

SpinWorks 3: Ester aldehyde 7 - Kayla Shellhammer

file: ...April4 - 100 - 1H - Aldehyde 7\fid expt: <zg30>transmitter freq.: 400.132471 MHztime domain size: 65536 pointswidth: 8278.15 Hz = 20.6885 ppm = 0.126314 Hz/ptnumber of scans: 16freq. of 0 ppm: 400.130001 MHzprocessed size: 32768 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 166.300 ppm/cm: 0.41561

Reaction 4Synthesis of alcohol 5 via Grignard addition of 6 to 7

Reaction 5Synthesis of lactol 3a via acid-catalyzed transacetalization of 5

ConclusionThis 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.

AcknowledgementsThe 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.

References1. 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.

1.999 0.9690.9792.5412.3152.2471.0162.540 1.9582.1012.1702.6160.0000PPM6.86.46.05.65.24.84.44.03.63.22.82.42.01.61.20.80.40.0

SpinWorks 3: Alcohol 5 - Kayla Shellhammer

file: ...April16 - 150 - 1H - Alcohol 5\fid expt: <zg30>transmitter freq.: 400.132471 MHztime domain size: 65536 pointswidth: 8278.15 Hz = 20.6885 ppm = 0.126314 Hz/ptnumber of scans: 16freq. of 0 ppm: 400.129995 MHzprocessed size: 32768 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 124.430 ppm/cm: 0.31097

2.2152.239 5.9820.00003.984 3.2910.0000PPM6.86.46.05.65.24.84.44.03.63.22.82.42.01.61.20.80.40.0

SpinWorks 3: Alcohol 5 - Kayla Shellhammer

file: ...April16 - 150 - 1H - Alcohol 5\fid expt: <zg30>transmitter freq.: 400.132471 MHztime domain size: 65536 pointswidth: 8278.15 Hz = 20.6885 ppm = 0.126314 Hz/ptnumber of scans: 16freq. of 0 ppm: 400.129995 MHzprocessed size: 32768 complex pointsLB: 0.000 GF: 0.0000Hz/cm: 124.725 ppm/cm: 0.31171