Solid-phase synthesis of 4-aryl-1,4-dihydropyridines via the Hantzsch three component condensation

Tetrahedron Letters

Volumn 41, Issue 22, 2000, Pages 4311-4315

  Breitenbucher, J Guy ^a   Figliozzi, Gina ^a  

^a Axys Pharmaceuticals Inc   (United States)

Author keywords

Combinatorial chemistry; Hantzsch condensation; Solid phase synthesis

Indexed keywords

1,4 DIHYDROPYRIDINE DERIVATIVE;

ARTICLE; CARBON NUCLEAR MAGNETIC RESONANCE; CYCLIZATION; REACTION ANALYSIS; SYNTHESIS;

EID: 0034621975     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(00)00660-2     Document Type: Article

References (16)

1. For reviews, see: Dolle, R. E.; Nelson, K. H. J. Comb. Chem. 1999, 1, 235. Nuss, J. M.; Renhowe, P. A. Curr. Opin. Drug Disc. Dev. 1999, 2, 631.
2. For reviews, see: Dolle, R. E.; Nelson, K. H. J. Comb. Chem. 1999, 1, 235. Nuss, J. M.; Renhowe, P. A. Curr. Opin. Drug Disc. Dev. 1999, 2, 631.
3. Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6909.
4. Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997. DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R.; Pavia, M. R. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 6909.
5. For reviews, see: Gaudio, A. C.; Korolkovas, A.; Takahata, Y.; J. Pharm. Sci. 1994, 83, 1110. Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273.
6. For reviews, see: Gaudio, A. C.; Korolkovas, A.; Takahata, Y.; J. Pharm. Sci. 1994, 83, 1110. Mager, P. P.; Coburn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery 1992, 8, 273.
7. Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887.
8. Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924. Gordeev, M. F.; Patel, D. V.; England, B. P.; Supriya, J.; Combs, J. D.; Gordon, E. M. Bioorg. Med. Chem. Lett. 1998, 6, 883.
9. Gordeev, M. F.; Patel, D. V.; Gordon, E. M. J. Org. Chem. 1996, 61, 924. Gordeev, M. F.; Patel, D. V.; England, B. P.; Supriya, J.; Combs, J. D.; Gordon, E. M. Bioorg. Med. Chem. Lett. 1998, 6, 883.
10. Other groups have performed Hantzsch condensations on solid support. However, in these example the DHPs are oxidized during or after cleavage to afford 4-aryl pyridine products. See: Gordeev, M. F.; Patel, D. V.; Wu, J.; Gordon, E. M. Tetrahedron Lett. 1996, 37, 4643. Tadesse, S.; Bhandari, A.; Gallop, M. A. J. Comb. Chem. 1999, 1, 184.
11. Other groups have performed Hantzsch condensations on solid support. However, in these example the DHPs are oxidized during or after cleavage to afford 4-aryl pyridine products. See: Gordeev, M. F.; Patel, D. V.; Wu, J.; Gordon, E. M. Tetrahedron Lett. 1996, 37, 4643. Tadesse, S.; Bhandari, A.; Gallop, M. A. J. Comb. Chem. 1999, 1, 184.
12. Rishton, G. M. Drug Discovery Today 1997, 2, 382.
13. Breitenbucher, J. G.; Johnson, C. R.; Haight, M.; Phelan, J. C. Tetrahedron Lett. 1998, 39, 1295. Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager, K. M. Tetrahedron 1998, 54, 4097.
14. Breitenbucher, J. G.; Johnson, C. R.; Haight, M.; Phelan, J. C. Tetrahedron Lett. 1998, 39, 1295. Johnson, C. R.; Zhang, B.; Fantauzzi, P.; Hocker, M.; Yager, K. M. Tetrahedron 1998, 54, 4097.
15. Initially 4-aryl-pyridines were seen as by-products in this library. Oxidation to 4-aryl pyridines was minimized by diluting the products with 1:1 acetonitrile:toluene prior to concentration of the reaction mixture. This allowed for the maintenance of a low concentration of TFA during concentration.
16. 13C NMR, MS, and combustion analysis.