An efficient and facile synthesis of racemic and optically active fexofenadine

Tetrahedron Letters

Volumn 39, Issue 18, 1998, Pages 2701-2704

  Fang, Qun K ^a   Senanayake, Chris H ^a   Wilkinson, H Scott ^a   Waid, Stephen A ^a   Li, Hui ^a  

^a DAINIPPON SUMITOMO PHARMA CO LTD   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

FEXOFENADINE;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; DRUG SYNTHESIS; RACEMIC MIXTURE; STEREOCHEMISTRY;

EID: 0032580381     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(98)00410-9     Document Type: Article

References (26)

1. 1. (a) Honig, P. K.; Woosley, R. L.; Zamani, K.; Conner, D. P.; Cantilena, L. R., Jr. Clin. Pharmacol. Ther. 1992, 52, 231.
2. (b) Honig, P. K. JAMA, 1993, 269, 1513.
3. (c) Woosley, L.; Young, J. W.; Chen, Y. US Patent 5375693.
4. 2. Carr, A. A.; Dolfini, J. E.; Wright, G. J. US patent 4254130 and Carr, A. A.; Dolfini, J. E.; Wright, G. J. US Patent 4285958.
5. 2. Carr, A. A.; Dolfini, J. E.; Wright, G. J. US patent 4254130 and Carr, A. A.; Dolfini, J. E.; Wright, G. J. US Patent 4285958.
6. 3. D'Ambra, T. E. US Patent 5581011 and US Patent 5578610.
7. 4. Kawai, S. H.; Hambalek, R. J.; Just, G. J. Org. Chem. 1994, 59, 2620
8. 5. Zhang, M. Q.; Ter Laak, A. M.; Timmerman, H. Bioorg. Med. Chem. Lett. 1991, 387.
9. 3).
10. (b) Chan, K. Y.; George, R. C.; Chen, T.; Okerhoan, R. A. J. Chromatogr. 1991, 571, 291 described the separation of the enantiomer by chiral column chromatography.
11. 7. Surapaneni, S.; Khalil, S. K. W. Chirality 1994, 6, 479.
12. 8. (a) Aldehyde 4a was prepared in large scale by bromination of ethyl α,α-dimethyl(4-methylphenyl)acetate (3) with NBS (75%), followed by Sommelet reaction (74%). 4a could also be prepared from ethyl α,α-dimethylphenyl acetate according to the procedure of Maillard, J.; Langlois, M.; Delaunay, P.; Tri, V. Chim. Ther. 1973 4, 487.
13. 4, followed by acid chloride formation (43%, not optimized). See, Larner, P. J. Chem. Soc. 1952, 680, 683. (equation presented)
14. 9. Buchi, G.; Wuest, H. J. Org. Chem. 1969, 34, 1122.
15. 3). δ 1.15-1.19 (t, J = 7.1 Hz, 3H), 1.55 (s, 6H), 1.65-1.90 (m, 4H), 2.92 (broad s, 1H), 3.75-3.88 (m, 2H), 3.90-3.97 (m, 2H), 4.06-4.13 (q, J = 7.0 Hz, 2H), 4.65-4.69 (m, 1H), 4.86-4.89 (m, 1H). 7.29 (s, 4H). Reaction by-products are identified as 14, 15, and 16. They are possibly formed by magnesium alkoxide-catalyzed Oppenauer oxidation. Their formation can be minimized to < 5% by adding 4a to Grignard 5 in THF at room temperature. (equation presented)
16. 2O), a complex mixture of products are formed (2 in 60%). See Greene, T. W.; Wuts, P. M in "Protective Groups in Organic Synthesis". John Wiley & Sons, Inc. New York, Sec. Ed. 1991, 190-192.
17. 1H NMR of the other isomer. δ: 1.18 (t, J -7.2 Hz, 3H). 1.56 (s, 6H), 1.65-2.44 (m, 4H) 2.58 (s, 1H), 3.65-3.85 (m, 4H), 4.12-4.16 (q, J = 7.3 Hz, 2H), 5.0 (m, 1H), 5.22 (m, 1H), 7.32 (s, 4H).
18. 3) δ 1.12-1.17 (t, J = 7.1 Hz), 1.53 (s, 6H), 1.40-1.80 (m, 611), 1.88-2.10 (m, 4H), 2.3-2.50 (m, 4H), 2.93-2.96 (d, J = 10 Hz, 1H), 3.11-3.15 (d, J = 11 Hz), 4.04-4.11 (q, J = 7.3 Hz, 2H), 4.56-4.59 (dd, J1 = 2.7. Hz, J2 = 8.4 Hz, 1H), 7.15-7.18 (m, 2H), 7.25-7.30 (m, 8H), 7.45-7.50 (m, 4H).
19. 14. (a) Corey, E. J.; Bakshi, R. K.; Shibita, S. J. J. Am. Chem. Soc. 1987, 109, 5551.
20. (b) Mathre, D. J.; Thompson, A. S.; Douglas, A. W.; Carrol, J. D.; Corley, E. G.; Grabowski, E. J. J. Org. Chem. 1993, 58, 2880.
21. (c). Hong, Y., Gao, Y.; Nie, X.; Zepp, C. M. Tetrahedron Lett. 1994, 35, 6631, and 5551.
22. 15. Asymmetric reductions utilizing (1R, 2S)-1-amino-2-tetrahydronaphathelenol see: Hett, R.; Senanayake, H. C.; Wald, A. S.; Tetrahedron Lett. 1998, 0000.
23. 3 catalyzed Grignard addition reaction see: Fiandanese, V.; Marchese. G.; Martina, V.; Ronzini, L. Tetrahedron Lett. 1984, 4805.
24. 17. With prolonged stirring of the reaction mixture (for example, reaction time is > 3h, ∼ 30% of alcohol was observed) an over-reduced by-product (ethyl ester of 6 to the corresponding alcohol) was detected.
25. 18. The ee of 6 was determined by HPLC analysis: Chiracel OD, 10 mm, 25 cm × 4.6 mm; UV 220 nm, mobile phase hexane/i-propanol (9:1), ambient temperature, flow rate 1.0 mL/min, retention times R (13.4 min), S (15.9 min).
26. 3 for S-1b).