A concise and efficient solid-phase synthesis of 2-amino-4(3H)-quinazolinones

Article abstract of DOI:10.1016/S0040-4039(00)01201-6

A concise and efficient solid-phase synthesis of 2-amino-4(3H)-quinazolinones is described. Reaction of polymer-bound isothiourea with isatoic anhydride provides 2-amino-4(3H)-quinazolinones with good yields and excellent purity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01201-6

Tetrahedron Letters 41 (2000) 7005±7008
A concise and ecient solid-phase synthesis of
2-amino-4(3H)-quinazolinones
Rui-Yang Yang* and Alan Kaplan
ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 17 June 2000; revised 7 July 2000; accepted 11 July 2000
Abstract
A concise and ecient solid-phase synthesis of 2-amino-4(3H)-quinazolinones is described. Reaction of
polymer-bound isothiourea with isatoic anhydride provides 2-amino-4(3H)-quinazolinones with good
yields and excellent purity. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: quinazolinones; thioformamidines; solid-phase synthesis.
The high-throughput syntheses of small organic molecules in both solution-phase and on solid
support has become a routine practice for lead discovery and lead optimization in pharmaceutical
research. As a result, the development of reaction conditions suitable for automated parallel
chemistry has attracted substantial attention in the past few years.1,2
4(3H)-Quinazolinone has been identi®ed as an important class of heterocyclic compounds in
medicinal chemistry, having anticonvulsant,3 antihypertensive,4 antidiabetic,5 and anti-tumor6
activity. Antimicrobial and antihistaminic activities have also been documented.7 A number of
syntheses of these types of compounds has previously been reported. Recently, Mayer and
co-workers8 disclosed a solid-phase synthesis approach to 2-alkyl substituted analogs. Villalgordo
and co-workers9 reported a solid-phase synthesis based on an aza Wittig-mediated annulation
strategy; however, a mixture of two isomers was formed. More recently, a paper by Gopalsamy10
disclosed a related solid-phase synthesis of 2-amino-4(3H)-quinazolinones. Our approach di€ers
from those previously reported in its eciency of chemical steps and feasibility of side-chain
functionality.
The general approach for the solid-phase synthesis of 2-amino-4(3H)-quinazolinones is shown
in Scheme 1. Thiourea 1 is eciently loaded to a chloromethylated polystyrene resin 2 (2% DVB
Merri®eld resin, 2.3 mmol/g) in DMF at 80ꢀC to form the polymer-bound isothiourea 3. The
results for the conversion of chloro resin 2 to isothiourea 3 are summarized in Table 1. All the
conversions are nearly quantitative, as determined by microanalysis of sulfur and nitrogen of
* Corresponding author. Tel: 1 781 994-0358; fax: 1 781 376-6019; e-mail: ruiyang@arqule.com
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01201-6

7006
Scheme 1.
Table 1
Conversion of resin 2 to polymer-bound isothiourea 3
polymer-bound 3. Reaction of 3 with isatoic anhydride 4 in DMF in the presence of
diisopropylethylamine at 80ꢀC a€orded 2-amino-4(3H)-quinazolinones 5. These products were
formed via acylation of the polymer-bound isothiourea 3 by isatoic anhydride 4, followed by
cleavage of the resulting product via an intramolecular cyclization. Results are summarized in
Table 2. Unlike most solid-phase chemistries that require a large excess of reagents to push the
reactions to completion, this reaction proceeds well with a stoichiometric amount of isatoic
anhydride 4. Reaction conditions are general with respect to both the thiourea and the isatoic
anhydride. All the desired products 5 were obtained in good to high yields with excellent purity.
The results are reported as isolated yields and calculated based on the amount of compound 4
used in the reaction. Purity was determined by HPLC analysis of crude product 5 by both UV
and ELSD. All of the products were also fully characterized by 1H NMR and mass spectrometric
techniques.11
In summary, we have disclosed a concise and ecient synthesis of 2-amino-4(3H)-quinazolinones
on solid support. This protocol only requires a two-step procedure and provides 2-amino-4(3H)-

7007
Table 2
Solid-phase synthesis of 2-amino-4(3H)-quinazolinones 5

7008
quinazolinones in good yield with excellent purity. Both building blocks mono-substituted
thioureas and isatoic anhydrides used in this chemistry are readily available from commercial
sources or can be easily synthesized.12,13 Unlike the method reported by Gopalsamy,10 which
involved the release of foul smelling methylthiol, the thiol generated in this method remains
attached to the solid support, thus providing a more environmentally benign and practical
synthesis of 2-amino-4(3H)-quinazolinones.
Acknowledgements
The authors thank the Analytical Department for the mass spectrometric analysis.
References
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1997, 97, 349. (b) Acc. Chem. Res. 1996, 29, No. 3. (c) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527. (d) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1997, 53, 5643.
(e) Booth, S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. Tetrahedron 1998, 54, 15385.
2. For solution phase synthesis, see: Gayo, L. M. Biotech. Bioeng. ( Combi. Chem.) 1998, 61, 95.
3. (a) Mannschreck, A.; Koller, H.; Stuhler, G.; Davies, M. A.; Traber, J. Eur. J. Med. Chem. 1984, 19, 381.
(b) Gupta, C. M.; Bhaduri, A. P.; Khanna, N. M. J. Med. Chem. 1968, 11, 392.
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6. (a) Baek, D.-J.; Park, Y.-K.; Heo, H. I.; Lee, M.; Yang, Z.; Choi, M. Bioorg. Med. Chem. Lett. 1998, 8, 3287.
(b) Webber, S. E.; Bleckman, T. M.; Attard, J.; Deal, J. G.; Kathardekar, V.; Welsh, K. M.; Webber, S.; Janson,
C. et al. J. Med. Chem. 1993, 36, 733.
7. Omar, A. M. M. E.; El-Din, S. A. S.; Labouta, I. M.; El-Tambary, A. A. Alexandria, J. Pharm. Sci. 1991, 5, 94.
8. Mayer, J. P.; Lewis, G. S.; Curtis, M. J.; Zhang, J. Tetrahedron Lett. 1997, 38, 8445.
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1
11. Compound 5a: H NMR (DMSO-d6) ꢀ 4.30 (s, 3H), 5.40 (d, 1H, J=11.0 Hz), 5.51 (d, 1H, J=18.0 Hz), 7.26 (br,
1H), 7.42 (t, 1H, J=8.5 Hz), 7.58 (d, 1H, J=8.5 Hz), 7.87 (t, 1H, J=8.5 Hz); MS (m/z): 202 (M+H+). Compound
5b: 1H NMR (DMSO-d6) ꢀ 2.60 (s, 3H), 4.30 (s, 3H), 5.40 (d, 1H, J=12.0 Hz), 5.52 (d, 1H, J=18.0 Hz), 6.18 (m,
1
1H), 7.53 (d, 1H, J=8.5 Hz), 7.72 (d, 1H, J=8.5 Hz), 7.99 (s, 1H); MS (m/z): 236 (M+H+). Compound 5c: H
NMR (DMSO-d6) ꢀ 4.25 (s, 3H), 5.37 (d, 1H, J=12.0 Hz), 5.48 (d, 1H, J=18.0 Hz), 6.17 (m, 1H), 7.10 (br, 1H),
1
7.55 (d, 1H, J=8.5 Hz), 7.82 (d, 1H, J=8.5 Hz), 8.07 (s, 1H); MS (m/z): 216 (M+H+). Compound 5d: H NMR
(DMSO-d6) ꢀ 4.05 (s, 3H), 4.07 (s, 3H), 4.16 (s, 3H), 4.23 (m, 2H), 5.36 (d, 1H, J=12.0 Hz), 5.48 (d, 1H, J=18.0
Hz), 6.64 (br, 1H), 7.42 (s, 1H); MS (m/z): 292 (M+H+). Compound 5e: 1H NMR (DMSO-d6) ꢀ 1.40 (t, 3H, J=6.5
Hz), 3.62 (q, 2H, J=6.5 Hz), 7.28 (br, 1H), 7.61 (d, 1H, J=8.5 Hz), 7.87 (d, 1H, J=8.5 Hz), 8.07 (s, 1H); MS (m/
z): 224 (M+H+). Compound 5f: 1H NMR (DMSO-d6) ꢀ 1.30±2.21 (m, 10H), 3.20 (m, 1H), 4.12 (br, 1H), 7.05 (br,
1
1H), 7.65 (d, 1H, J=8.5 Hz), 7.90 (d, 1H, J=8.5 Hz), 8.07 (s, 1H); MS (m/z): 278 (M+H+). Compound 5g: H
NMR (DMSO-d6) ꢀ 1.30±2.20 (m, 10H), 3.17 (m, 1H), 4.12 (br, 1H), 7.45 (t, 1H, J=7.8 Hz), 7.64 (d, 1H, J=8.5
Hz), 7.88 (t, 1H, J=7.2 Hz), 8.18 (t, 1H, J=7.2 Hz); MS (m/z): 244 (M+H+). Compound 5h: 1H NMR (DMSO-d6)
d 7.18±8.25 (m, 9H), 9.0 (s, 1H); MS (m/z): 238 (M+H+). Compound 5i: 1H NMR (DMSO-d6) ꢀ 1.50 (t, 3H, J=6.5
Hz), 3.61 (q, 2H, J=6.5 Hz), 4.05 (s, 3H), 4.08 (s, 3H), 4.17 (s, 3H), 6.42 (br, 1H), 7.40 (s, 1H); MS (m/z): 280
(M+H+). Compound 5j: 1H NMR (DMSO-d6) d 1.35±2.25 (m, 10H), 4.02 (s, 10H), 4.06 (s, 3H), 4.17 (s, 3H), 6.37
(br, 1H), 7.40 (s, 1H); MS (m/z): 334 (M+H+).
12. For the synthesis of mono-substituted thioureas, see: (a) Moore, M. L.; Crossley, F. S. Org. Synth. 1941, 21, 83.
(b) Poss, M. A.; Iwanowicz, E.; Reid, J. A.; Lin, J.; Gu, Z. Tetrahedron Lett. 1992, 33, 5933. (c) Patil, D. G.;
Chedekel, M. R. J. Org. Chem. 1984, 49, 997.
13. Coppola, G. M. Synthesis 1980, 505.