An efficient solid phase synthetic route to 1,3-disubstituted 2,4(1H,3H)-quinazolinediones suitable for combinatorial synthesis

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 13, 1996, Pages 1483-1486

  Smith, Adrian L ^a   Thomson, Christopher G ^a   Leeson, Paul D ^a  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTHRANILIC ACID DERIVATIVE; CHLOROFORMIC ACID ETHYL ESTER; QUINAZOLINE DERIVATIVE;

AMINO ACID SUBSTITUTION; ARTICLE; BLOOD BRAIN BARRIER; CYCLIZATION; DNA TEMPLATE; DRUG SYNTHESIS; LIGAND BINDING; NONHUMAN; SOLID PHASE EXTRACTION;

EID: 0030576328     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00253-3     Document Type: Article

References (28)

1. 1. (a) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251.
2. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1401.
3. 2. (a) DeWitt, S. H.; Kiely, J. S.; Stankovic, C. J.; Schroeder, M. C.; Cody, D. M. R; Pavia, M. R. Proc. Natl. Acad. Sci. USA 1993, 90, 6909-6913.
4. (b) Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997-10998.
5. (c) Bunin, B. A.; Plunkett, M. J.; Ellman, J. A. Proc. Natl. Acad. Sci. USA 1994, 91, 4708 -4712.
6. (d) Plunkett, M. J.; Ellman, J. A. J. Am. Chem. Soc. 1995, 117, 3306-3307.
7. (e) Gordon, D. W.; Steele, J. Bioorg. Med. Chem. Lett. 1995, 5, 47-50.
8. (f) Pátek, M.; Drake, B.; Lebl, M. Tetrahedron Lett. 1995, 36, 2227-2230.
9. (g) Boojamra, C. G.; Burow, K. M.; Ellman, J. A. J. Org. Chem. 1995, 60, 5742-5743.
10. (h) Goff, D. A.; Zuckermann, R. N. J. Org. Chem. 1995, 60, 5744-5745.
11. (i) Goff, D. A.; Zuckermann, R. N. J. Org. Chem. 1995, 60, 5748-5749.
12. (j) Wipf, P.; Cunningham, A. Tetrahedron Lett. 1995, 36, 7819-7822.
13. (k) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron Lett. 1996, 37, 937-940.
14. 3. Data obtained from the MDDR database, Molecular Designs Ltd, 2132 Farallon Drive, San Leandro, CA 94577.
15. 4. (a) Jacobs, R. L. J. Heterocycl. Chem. 1970, 7, 1337-1345.
16. (b) Gadekar, S. M.; Kotsen, A. M.; Cohen, E. J. Chem. Soc. 1964, 4666-4668.
17. (c) Taub, B.; Hino, J. B. J. Org. Chem. 1961, 26, 5238-5239.
18. (d) Cortez, R.; Rivero, I. A.; Aguirre, G.; Ramirez, F.; Hong, E.; Somanathan, R. Synthetic Commun. 1991, 21, 285-292.
19. 5. (a) Camps, E.; Cartells, J.; Pi, J. Anales de Quimica 1974, 70, 848-849.
20. (b) Plunkett, M. J.; Ellman, J. A. J. Org. Chem. 1995, 60, 6006-6007.
21. (c) Chenera, B.; Finkelstein, J. A.; Veber, D. F J. Am. Chem. Soc. 1995, 117, 11999-12000.
22. (d) Han, Y.; Walker, S. D.; Young, R. N. Tetrahedron Lett. 1996, 37, 2703-2706.
23. 2, 1 h, 20 °C. Loading was estimated gravimetrically after subsequent reaction, with the difference in loadings being attributed to cross-linking. The resulting resin has good solvation properties in the solvents used, whilst giving no PEG contamination in products unlike chloroformate-functionalized commercial PEG-grafted polystyrene resins. Reactions were typically carried out on 100 mg-5 g of resin.
24. 13C-NMR and MS analysis.
25. 8. All subunits are validated by single compound synthesis and analysis (yield / HPLC / MS) prior to library construction. Virtually all anthranilic acids (3) tested worked efficiently (∼80), as did a large proportion of the amines (5) (>400). The corresponding benzoxazinedione was never observed. Reactions were typically carried out on 10-100 mg of resin.
26. 9. Substantially reduced yields (∼0.02 mmol/g) were observed for secondary alkyl amines such as cyclohexylamine under the given cyclization conditions (125 °C, 16 h) due to incomplete reaction in the final step. This suggests that steric congestion is impeding the reaction in these cases.
27. 10. Brennan, S. T.; Colbry, N. L.; Leeds, R. L.; Leja, B.; Priebe, S. R.; Reily, M. D.; Showalter, H. D. H.; Uhlendorf, S. E.; Atwell, G. J.; Denny, W. A. J. Heterocyclic Chem. 1989, 26, 1469-1476.
28. 11. Furka, A.; Sebestyen, F.; Asgedom, M.; Dibo, G. Int. J. Pept. Protein Res. 1991, 37, 487-493.