A general and efficient solid phase synthesis of quinazoline-2,4-diones

Tetrahedron Letters

Volumn 38, Issue 10, 1997, Pages 1729-1732

  Gordeev, Mikhail F ^a   Hui, Hon C ^a   Gordon, Eric M ^a   Patel, Dinesh V ^a  

^a Versicor Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

QUINAZOLINE DERIVATIVE;

ARTICLE; CYCLIZATION; DRUG SYNTHESIS; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; REACTION ANALYSIS;

EID: 0031562439     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(97)00182-2     Document Type: Article

References (21)

1. 1. See, e.g., reviews: (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385;
2. (b) Gordon, E. M. Current Opinion in Biotechnology. 1995, 6, 624;
3. (c) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem. Res. 1996, 29; 144;
4. (d) Patel, D. V.; Gordon, E. M. Drug Discovery Today. 1996, 134;
5. (e) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996, 96, 555;
6. (f) Hermkens, P. P. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron. 1996, 52, 4527;
7. (g) Patel, D. V.; Gordon, E. M. Drug Discovery Today. 1996, I, 134;
8. (g) Gordeev, M. F.; Patel, D. V. In: Combinatorial Chemistry and Molecular Diversity in Drug Discovery. Eds. E. M. Gordon and J. F. Kerwin. 1996, in press.
9. 2. SPS offers unsurpassed advantages in comparison with traditional solution phase methodologies, such as high chemical efficiencies resulting from application of excess reagents, easy split-pool manipulations, and biological testing of nanomolar amounts of materials both in immobilized and solution phase formats.
10. 3. Recently, two different SPS of quinazoline-2,4-diones were reported: a) Smith, A. L.; Thomson, C. G.; Leeson, P. D. Bioorg. Med. Chem. Lett. 1996, 6, 1483;
11. b) Buckman, B. O.; Mohan, R. Tetrahedron Lett. 1996, 37, 4439. Both of these routes require immobilizations of anthranlic acids derivatives. The method in the first reference is limited to preparation of 7-hydroxyquinazoline-2,4-diones resulting from use of the phenolic group as a site of immobilization, whereas the second synthesis employs relatively harsh thermal conditions (125 °C, 16 h) potentially incompatible with labile building blocks and functional groups (such as dipeptides, hydroxamates, etc.), and does not allow for preparation of polymer bound QDs due to the heterocyclization mode involving cyclization at the linker ester group with simultaneous release of quinazoline-2,4-diones from the resin. No SPS of chiral qumazoline-2,4-dione amino acid derivatives has been previously reported.
12. 4. MDL Drug Data Registry database, by MDL Informations Systems, Inc., San Leandro, U.S.A.
13. 5. While immobilized isocyanates can be easily generated from tethered amino acids with triphosgene or phosgene in toluene in excess of base (2,6-lutidine, 0 °C to r.t., 2 h), amino acid-derived p-nitrophenyl carbamates are generally preferred reagents due to their relative hydrolytic stability and ease of handling in the air. For previous application of the tethered activated carbamates in SPS of ureas, see also Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35, 4055.
14. 6. Cannonne, P.; Akssira, M.; Dahdouh, A.; Kasmi, H.; Boumzebra, M. Heterocycles. 1993, 36, 1305.
15. 7. Polystyrene-based 2-methoxy-4-alkoxybenzyl alcohol resin: Mergler, M.; Tanner, R.; Gosteli, J.; Grogg, P. Terahedron Lett. 1988, 29, 4005.
16. 8. The SPS of QDs was conveniently performed using the CombiChem oven (by Stovall Life Sci., Inc).
17. 9. The SPS allows one to employ a large number of commercially available immobilized amino acids. Thus, the following side-chain protected amino acids pre-loaded on Sasrin resins were smoothly converted into respective QDs: Tyr(tBu), Lys(Boc), Trp(Boc), His(Trt), Glu(tBu), Asn(Trt), Gln(Trt).
18. 10. Bunin, B. A.; Ellman, J. A. J. Am. Chem. Soc. 1992, 114, 10997.
19. 3OD (δ, ppm): 1.43 (d, J = 7.2 Hz, 3 H), 3.48-3.60 (m, 2 H), 4.49 (m, 1 H), 5.83 (m, 1 H), 7.00-7.20 (m, 7 H), 7.58 (m, 1 H), 7.89 (dd, J = 8.1 and 1.5 Hz, 1 H).
20. 12. While this manuscript was in preparation, a similar solid phase approach to hydroxamates appeared in the literature: Floyd, C. D.; Lewis, C. N.; Patel, S. R.; Whittaker, M. Tetrahedron Lett. 1996, 37, 8045.
21. 3OD (δ, ppm): 3.72 (m, 2 H), 6.02 (m, 1 H), 7.20-7.38 (m, 7 H), 7.78 (dd, J = 8.1 and 3.9 Hz, 1 H), 8.04 (d, J= 8.1 Hz, 1 H).