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Y. Zhang et al. / European Journal of Medicinal Chemistry 66 (2013) 335e344
247 ꢁC.1H NMR (CD3OD, 500 MHz):
d
2.24, 2.34 (2s, 6H, 2CH3), 3.94e
1H), 7.84 (d, 2H, J ¼ 8.6 Hz), 7.95 (d, 2H, J ¼ 8.6 Hz), 8.83 (s, 1H),
10.83 (s, 1H). 13C NMR (DMSO-d6, 500 MHz):
56.7, 56.8, 60.7, 91.6,
101.1, 123.6, 125.8, 126.6, 126.7, 135.8, 137.6, 142.5, 143.2, 151.1, 153.3,
4.20 (3s, 9H, 3OCH3), 7.02 (s, 1H), 7.15 (s, 1H), 7.39 (s, 1H), 8.16 (s, 1H).
13C NMR (CD3OD, 500 MHz):
17.7, 19.5, 56.2, 60.6, 62.2, 91.6, 96.4,
101.7, 121.7, 122.1, 130.4, 130.6, 138.1, 139.9, 141.7, 150.1, 150.7, 159.9,
d
d
159.6. IR (KBr) n: 810.6, 1149.6, 1280.3, 1475.2, 1625.3, 2935.6,
161.4. IR (KBr)
n
: 812.0, 1149.6, 1298.1, 1490.9, 1633.7, 2916.4, 2982.0,
2981.9, 3162.9, 3270.3, 3418.6 cmꢂ1. Anal. calcd. for C18H16F3N3O3
(%): C, 56.99; H, 4.25; N, 11.08. Found: C, 56.66; H, 4.09; N, 11.40.
3170.7, 3269.6, 3408.3 cmꢂ1. Anal. calcd. for C19H21BrClN3O3 (%): C,
50.18; H, 4.65; N, 9.24. Found: C, 50.30; H, 4.45; N, 9.11.
4.2.6.17. N-(3-Trifluoromethylphenyl)-5,6,7-trimethoxyquinazoline-
4-amine (6q). Yield: 85.1%; yellow solid; mp: 163e166 ꢁC. 1H NMR
4.2.6.11. N-(2-Chloro-4-bromophenyl)-5,6,7-trimethoxyquinazoline-
4-amine (6k). Yield: 81.0%; white needles; mp: 195e196 ꢁC. 1H
(CDCl3, 500 MHz):
1H, J ¼ 8.0 Hz), 7.47 (t, 1H, J ¼ 8.1 Hz), 7.58 (d, 1H, J ¼ 8.1 Hz), 7.83 (s,
1H), 8.78 (s, 1H), 10.69 (s, 1H). 13C NMR (CDCl3, 500 MHz):
57.4,
61.7, 63.2, 97.1, 102.6, 124.2, 125.2, 126.7, 130.9, 131.2, 133.4, 138.2,
138.8, 141.2, 150.1, 150.6, 159.2, 160.7. IR (KBr) : 809.5, 1157.1,
1295.4, 1496.2, 1635.7, 2889.3, 2956.8, 3009.6, 3254.4, 3420.2 cmꢂ1
d 3.85e4.18 (3s, 9H, 3OCH3), 7.31 (s, 1H), 7.35 (d,
NMR (DMSO-d6, 500 MHz): d 3.88e4.16 (3s, 9H, 3OCH3), 7.13 (s,1H),
7.62 (dd, 1H, J ¼ 9.2 Hz, 2.3 Hz), 7.85 (d, 1H J ¼ 2.3 Hz), 8.55 (s, 1H),
d
8.80 (d, 1H, J ¼ 9.2 Hz), 10.45 (s, 1H). 13C NMR (DMSO-d6, 500 MHz):
d
56.8, 61.5, 63.1, 104.2, 104.6, 115.2, 124.9, 125.0, 131.1, 131.8, 136.0,
n
140.9, 148.3, 148.7, 154.1, 156.7, 158.6. IR (KBr)
n
: 808.7, 1153.4,
.
1294.2, 1469.8, 1629.5, 2939.5, 2977.8, 3010.9, 3309.3, 3420.5 cmꢂ1
.
Anal. calcd. for C18H16F3N3O3 (%): C, 56.99; H, 4.25; N, 11.08. Found:
C, 56.78; H, 4.45; N, 11.26.
Anal. calcd. for C17H15BrClN3O3 (%): C, 48.08; H, 3.56; N, 9.89.
Found: C, 47.78; H, 3.83; N, 10.04.
4.2.6.18. N-(3-Chlorophenyl)-5,6,7-trimethoxyquinazoline-4-amine
4.2.6.12. N-(2-Bromo-5-fluorophenyl)-5,6,7-trimethoxyquinazoline-
4-amine (6l). Yield: 80.1%; pale yellow solid; mp: 158e161 ꢁC. 1H
hydrochloride (6r). Yield: 45.8% (only obtained under CH); yellow
solid; mp: 192e195 ꢁC. 1H NMR (DMSO-d6, 500 MHz):
d 3.88e4.14
NMR (DMSO-d6, 500 MHz):
d
3.91e4.26 (3s, 9H, 3OCH3), 7.22 (dt,
(3s, 9H, 3OCH3), 7.10 (s, 1H), 7.16 (dd,1H, J ¼ 8 Hz,1.2 Hz), 7.40 (t,1H,
1H, J ¼ 8.6 Hz, 2.9 Hz), 7.42 (s, 1H), 7.84 (dt, 1H, J ¼ 8.6 Hz, 2.9 Hz),
J ¼ 8.0 Hz), 7.72 (dd, 1H, J ¼ 8.0 Hz, 1.2 Hz), 8.21 (d, 1H, J ¼ 1.2 Hz),
8.06 (dd, 1H, J ¼ 10.3 Hz, 2.9 Hz), 8.87 (s, 1H), 10.90 (s, 1H). 13C NMR
8.53 (s, 1H), 10.01 (s, 1H). 13C NMR (DMSO-d6, 500 MHz):
d 56.3,
(DMSO-d6, 500 MHz):
d
57.4, 61.8, 63.5, 97.4, 102.6, 114.9, 115.2,
60.1, 62.3, 95.4, 101.7, 118.6, 121.0, 122.0, 124.1, 131.0, 133.7, 135.5,
115.7, 134.4, 137.6, 141.4, 149.9, 150.7, 159.2, 160.6, 161.0, 162.6. IR
141.5, 150.1, 152.9, 156.0, 158.7. IR (KBr) n: 803.6, 1147.6, 1278.5,
(KBr)
n
: 821.7, 1147.7, 1294.2, 1496.7, 1626.0, 2941.2, 2947.2, 3008.9,
1485.2, 1643.4, 2931.8, 2968.5, 3015.6, 3290.3, 3417.7 cmꢂ1. Anal.
calcd. for C17H17Cl2N3O3 (%): C, 53.42; H, 4.48; N, 10.99. Found: C,
53.30; H, 4.26; N, 10.70.
3240.3, 3410.5 cmꢂ1. Anal. calcd. for C17H15BrFN3O3 (%): C, 50.02; H,
3.70; N, 10.29. Found: C, 50.34; H, 3.43; N, 10.51.
4.2.6.13. N-(3-Fluorophenyl)-5,6,7-trimethoxyquinazoline-4-amine
4.2.6.19. N-(2-Bromo-5-trifluoromethylphenyl)-5,6,7-trimethoxyqui
nazoline-4-amine (6s). Yield: 83.6%; pale yellow solid; mp: 185e
(6m). Yield: 81.9% (only obtained under MW); white solid; mp:
158e161 ꢁC. 1H NMR (CDCl3, 500 MHz):
d
3.98e4.31 (3s, 9H,
188 ꢁC. 1H NMR (DMSO-d6, 500 MHz):
d 3.88e4.12 (3s, 9H, 3OCH3),
3OCH3), 7.04 (t, 1H, J ¼ 8.0 Hz), 7.36 (d, 1H, J ¼ 8.0 Hz), 7.45 (dd, 1H,
7.13 (s, 1H), 7.40 (dd, 1H, J ¼ 8.6 Hz, 2.3 Hz), 7.96 (d, 1H, J ¼ 8.1 Hz),
J ¼ 14.9 Hz, 8.6 Hz), 7.68 (d, 1H, J ¼ 10.0 Hz), 7.85 (s, 1H), 8.62 (s, 1H),
8.57 (s, 1H), 9.21 (s, 1H), 10.50 (s, 1H). 13C NMR (DMSO-d6,
10.68 (s, 1H). 13C NMR (CDCl3, 500 MHz):
d
57.4, 61.6, 62.9, 97.9,
500 MHz):
d 57.2, 61.3, 63.4, 92.5, 100.4, 123.5, 124.1, 124.6, 125.4,
102.0,110.8,113.9,118.5,130.5,137.4,142.0,148.9,149.0,158.6,161.2,
134.6, 135.9, 137.7, 141.4, 149.8, 150.6, 160.1, 160.5, 161.1. IR (KBr) n:
161.9, 163.9. IR (KBr)
n
: 801.7, 1159.2, 1292.3, 1487.1, 1631.8, 2856.8,
792.7, 1145.8, 1287.5, 1464.0, 1627.9, 2887.4, 2954.9, 3037.9, 3238.5,
3405.1 cmꢂ1. Anal. calcd. for C18H15BrF3N3O3 (%): C, 47.18; H, 3.30;
N, 9.17. Found: C, 47.36; H, 3.38; N, 9.07.
2983.9, 3012.5, 3271.3, 3451.2 cmꢂ1. Anal. calcd. for C17H16FN3O3
(%): C, 62.00; H, 4.90; N, 12.76. Found: C, 61.76; H, 5.01; N, 12.50.
4.2.6.14. N-(4-Bromophenyl)-5,6,7-trimethoxyquinazoline-4-amine
4.2.6.20. N-(4-Chlorophenyl)-5,6,7-trimethoxyquinazoline-4-amine
(6n). Yield: 82.4%; light yellow needles; mp: 143e145 ꢁC. 1H NMR
dihydrochloride (6t). Yield: 90.0%; light yellow needles; mp: 161e
(DMSO-d6, 500 MHz):
(d, 2H, J ¼ 9.2 Hz), 7.87 (d, 2H, J ¼ 8.6 Hz), 8.49 (s, 1H), 9.98 (s, 1H).
13C NMR (DMSO-d6, 500 MHz):
57.3, 61.7, 62.7, 103.9, 104.6, 115.6,
124.1, 131.9, 138.8, 140.8, 148.4, 148.6, 154.3, 156.9, 158.4. IR (KBr)
d
3.87e4.13 (3s, 9H, 3OCH3), 7.09 (s, 1H), 7.56
163 ꢁC. 1H NMR (CDCl3, 500 MHz):
d
3.97e4.30 (3s, 9H, 3OCH3);
7.44 (d, 2H, J ¼ 8.6 Hz), 7.65 (d, 2H, J ¼ 8.6 Hz), 7.80 (s, 1H), 8.59 (s,
1H), 10.59 (s, 1H). 13C NMR (CDCl3, 500 MHz):
54.3, 62.9, 63.5,
98.8, 102.3, 124.3, 129.5, 132.0, 134.9, 138.8, 141.9, 149.1, 149.8, 158.5,
d
d
n
:
817.8, 1139.9, 1298.1, 1467.8, 1608.6, 2947.2, 2990.6, 3003.2, 3294.6,
3411.7 cmꢂ1. Anal. calcd. for C17H16BrN3O3 (%): C, 52.32; H, 4.13; N,
10.77. Found: C, 52.05; H, 4.15; N, 10.87.
160.8. IR (KBr) n: 809.8, 1155.4, 1294.2, 1490.9, 1616.6, 2893.2,
2987.7, 3012.8, 3271.1, 3416.4 cmꢂ1. Anal. calcd. for C17H18Cl3N3O3
(%): C, 48.77; H, 4.33; N, 10.04. Found: C, 48.81; H, 4.60; N, 9.75.
4.2.6.15. N-((2-Fluoro-5-trifluoromethyl)phenyl)-5,6,7-trimethoxy
quinazoline-4-amine (6o). Yield: 80.7%; white solid; mp: 173e
4.2.6.21. N-(2-Fluoro-3-(trifluoromethyl)phenyl)-5,6,7-trimethoxyqu
inazolin-4-amine hydro-chloride (6u). Yield: 81.2%, yellow solid;
176 ꢁC. 1H NMR (DMSO-d6, 500 MHz):
d
3.90e4.22 (3s, 9H, 3OCH3),
7.39 (s, 1H), 7.67 (t, 1H, J ¼ 9.7 Hz), 7.79e7.81 (m, 1H), 8.36e8.37 (m,
1H), 8.85 (s, 1H), 10.80 (s, 1H). 13C NMR (DMSO-d6, 500 MHz):
57.3,
61.7, 63.1, 97.6, 102.6, 117.4, 117.6, 123.8, 125.1, 125.8, 126.9, 138.9,
141.3, 149.9, 151.0, 157.2, 159.4, 160.9. IR (KBr) : 810.1, 1161.0,
1292.3, 1489.0, 1627.9, 2941.4, 2970.4, 3030.2, 3277.2, 3430.9 cmꢂ1
mp: 152e154 ꢁC. 1H NMR (CDCl3, 500 MHz):
d 3.99e4.36 (3s, 9H,
3OCH3), 7.27 (s, 1H), 7.41 (t, 1H, J ¼ 8.0 Hz), 7.52 (t, 1H, J ¼ 7.5 Hz),
8.71 (s, 1H), 8.86 (t, 1H, J ¼ 7.5 Hz), 11.19 (s, 1H); 13C NMR (CDCl3,
500 MHz): 57.5, 61.7, 63.1, 98.2, 102.7, 121.1, 123.4, 124.8, 124.9,
126.5, 126.6, 127.8, 138.1, 142.2,149.0, 149.3, 158.6,161.5. Anal. calcd.
for C18H16ClF4N3O3: C, 49.84; H, 3.72; N, 9.69. Found C, 49.54; H,
4.01; N, 9.48.
d
n
.
Anal. calcd. for C18H15F4N3O3 (%): C, 54.41; H, 3.81; N, 10.58. Found:
C, 54.48; H, 4.10; N, 10.35.
4.2.6.22. N-(2-Bromo-4,6-difluorophenyl)-5,6,7-trimethoxyquinazolin-
4-amine (6v). Yield, 84.8%; yellow oil; 1H NMR (CDCl3, 500 MHz):
4.2.6.16. 5,6,7-Trimethoxy-N-(4-(trifluoromethyl)phenyl)quinazo-
line-4-amine (6p). Yield: 81.1%; yellow solid; mp: 143e145 ꢁC. 1H
d
3.97e4.20 (3s, 9H, 3OCH3), 6.97 (dt,1H, J ¼ 9.2 Hz, 2.9 Hz), 7.09 (s,1H),
NMR (DMSO-d6, 500 MHz):
d 3.90e4.23 (3s, 9H, 3OCH3), 7.38 (s,
7.26e7.29 (m,1H), 8.47 (s,1H), 9.07 (s,1H); 13C NMR (CDCl3, 500 MHz):