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Z. Wang et al. / European Journal of Medicinal Chemistry 53 (2012) 275e282
(m, 4H, NCHCHCH, ArH), 7.00 (t, J ¼ 8.4 Hz, 2H, ArH), 6.45
(d, J ¼ 8.7 Hz, 1H, ArH), 5.75 (s, 1H, ArNH), 5.64 (d, J ¼ 2.2 Hz, 1H,
NHCHN), 4.50e4.61 (m, 2H, ArCH2), 3.82 (s, 3H, OMe), 3.20 (s, 3H,
NMe); HRMS (ESI) calcd for C23H20FN4O3 (M ꢁ H)ꢁ: 419.1525,
found: 419.1528.
4.10.3. N-(4-fluorobenzyl)-2-(furan-2-yl)-5-methoxy-3-methyl-4-
oxo-3,4-dihydroquinazoline-6-carboxamide (10c)
White solid, 87% yield; mp: 131e132 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.47 (d, J ¼ 8.7 Hz, 1H, ArH), 8.34 (s, 1H, NH), 7.69 (s, 1H,
OCHCH), 7.59 (d, J ¼ 8.7 Hz, 1H, ArH), 7.35 (dd, J ¼ 8.3, 5.5 Hz, 2H,
ArH), 7.25 (s, 1H, CCHCH), 7.04 (t, J ¼ 8.6 Hz, 2H, ArH), 6.64
(dd, J ¼ 1.2, 2.8 Hz, 1H, CHCHCH), 4.65 (d, J ¼ 5.6 Hz, 2H, ArCH2),
3.84 (s, 3H, OMe), 3.77 (s, 3H, NMe); HRMS (ESI) calcd for
C22H17FN3O4 (M ꢁ H)ꢁ: 406.1209, found: 406.1207.
4.9.6. 2-Butyl-N-(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-
1,2,3,4-tetrahydroquinazoline-6-carboxamide (9f)
Colorless viscous liquid, 79% yield; 1H NMR (400 MHz, CDCl3):
d
8.29 (s, 1H, NH), 8.06 (d, J ¼ 8.6 Hz, 1H, ArH), 7.29 (dd, J ¼ 12.1,
6.4 Hz, 2H, ArH), 7.31 (t, J ¼ 8.5, 16.9 Hz, 2H, ArH), 6.49 (d, J ¼ 8.6 Hz,
1H, ArH), 5.22 (s, 1H, ArNH), 4.54e4.60 (m, 3H, ArCH2, NHCHN),
3.85 (s, 3H, OMe), 3.08 (s, 3H, NMe), 1.70e1.80 (m, 2H, CCH2CH2),
1.22e1.30 (m, 4H, CCH2CH2CH2), 0.86 (m, 3H, CH3CH2); HRMS (ESI)
calcd for C22H25FN3O3 (M ꢁ H)ꢁ: 398.1885, found: 398.1886.
4.10.4. N-(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-2-
(thiophen-2-yl)-3,4-dihydroquinazoline-6-carboxamide (10d)
White solid, 92% yield; mp: 172e174 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.48 (d, J ¼ 8.7 Hz, 1H, ArH), 8.34 (s, 1H, NH), 7.61
(d, J ¼ 5.1, 1H, ArH), 7.59 (s, 1H, SCH), 7.57 (d, J ¼ 4.0, 1H, SCCH), 7.36
(dd, J ¼ 5.5, 8.4 Hz, 2H, ArH), 7.19 (dd, J ¼ 3.9, 4.9 Hz, 1H, ArH), 7.05
(t, J ¼ 8.6 Hz, 2H, ArH), 4.65 (d, J ¼ 5.6 Hz, 2H, ArCH2), 3.90 (s, 3H,
OMe), 3.78 (s, 3H, NMe); HRMS (ESI) calcd for C22H17FN3O3S
(M ꢁ H)ꢁ: 422.0980, found: 422.0985.
4.9.7. N,2-bis(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-1,2,3,4-
tetrahydroquinazoline-6-carboxamide (9g)
White solid, 50% yield; mp: 231e233 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.11 (d, J ¼ 8.4 Hz, 1H, ArH), 7.64 (s, 1H, NH), 7.21e7.37
(m, 4H, ArH), 7.02 (t, J ¼ 5.1 Hz, 4H, ArH), 6.44 (d, J ¼ 8.7 Hz, 1H,
ArCH2), 4.76 (s, 1H, NHCHN), 4.68 (d, J ¼ 4.3 Hz, 2H, ArCH2), 4.60
(dd, J ¼ 6.4,11.0 Hz,1H, ArNH), 3.96 (s, 2H, ArCH2), 3.84 (s, 3H, OMe),
3.09 (s, 3H, NMe); HRMS (ESI) calcd for C25H22F2N3O3 (M ꢁ H)ꢁ:
450.1635, found: 450.1640.
4.10.5. N-(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-2-(pyridin-
2-yl)-3,4-dihydroquinazoline-6-carboxamide (10e)
White solid, 87% yield; mp: 214e216 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.73 (d, J ¼ 4.6 Hz, 1H, NCH), 8.50 (d, J ¼ 8.7 Hz, 1H, ArH),
8.36 (s, 1H, NH), 7.88e7.97 (m, 2H, NCCHCH), 7.61 (d, J ¼ 8.7 Hz, 1H,
ArH), 7.48 (dd, J ¼ 5.1, 6.1 Hz, 1H, NCHCH), 7.34 (dd, J ¼ 5.5, 8.5 Hz,
2H, ArH), 7.05 (t, J ¼ 8.6 Hz, 2H, ArH), 4.66 (d, J ¼ 5.6 Hz, 2H, ArCH2),
3.91 (s, 3H, OMe), 3.60 (s, 3H, NMe); HRMS (ESI) calcd for
C23H18FN4O3 (M ꢁ H)ꢁ: 4117.1368, found: 417.1369.
4.9.8. N-(4-fluorobenzyl)-5-methoxy-3-methyl-2-(4-nitrobenzyl)-
4-oxo-1,2,3,4-tetrahydroquinazoline-6-carboxamide (9h)
Yellow solid, 71% yield; mp: 195e196 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.12e8.21 (m, 4H, ArH, NH), 7.33 (dd, J ¼ 8.4, 5.5 Hz, 2H,
ArH), 7.25e7.27 (m, 2H, ArH), 7.03 (t, J ¼ 8.6 Hz, 2H, ArH), 6.49
(d, J ¼ 8.6 Hz, 1H, ArH), 4.94 (s, 1H, ArNH), 4.75e4.79 (m, 1H,
NHCHN), 4.55e4.65 (m, 2H, ArCH2NH), 3.85 (s, 3H, OMe), 3.10e3.20
(m, 2H, ArCH2CH), 3.10 (s, 3H, NMe); HRMS (ESI) calcd for
C25H23FN4NaO5 (M þ Na)þ: 501.1545, found: 501.1539.
4.10.6. 2-Butyl-N-(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-
3,4-dihydroquinazoline-6-carboxamide (10f)
White solid, 71% yield; mp: 109e110 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.44 (d, J ¼ 8.7 Hz, 1H, ArH), 8.34 (s, 1H, NH), 7.49
(d, J ¼ 8.7 Hz, 1H, ArH), 7.35 (dd, J ¼ 8.1, 5.7 Hz, 2H, ArH), 7.04
(t, J ¼ 8.6 Hz, 2H, ArH), 4.64 (d, J ¼ 5.6 Hz, 2H, ArCH2), 3.85 (s, 3H,
OMe), 3.60 (s, 3H, NMe), 2.81 (t, J ¼ 7.7 Hz, 2H, CCH2CH2), 1.79e1.86
(m, 2H, CCH2CH2CH2), 1.46e1.56 (m, 2H, CH2CH2CH3), 1.01
(t, J ¼ 7.3 Hz, 3H, CH3CH2); HRMS (ESI) calcd for C22H23FN3O3
(M ꢁ H)ꢁ: 396.1729, found: 396.1735.
4.10. General procedure for the preparation of compounds 10aeh
The solution of 9aeh (1.0 mmol) and I2 (3.0 mmol) in ethanol
(60 mL) was refluxed for 1 h, then cooled to room temperature and
stirred for 8 h, and then concentrated in vacuo. The residue was
taken into CH2Cl2 (100 mL), and washed with 10% Na2S2O4 solution
(3 ꢂ 50 mL), H2O (100 mL) and brine (100 mL), then dried with
anhydrous MgSO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel to afford
compounds 10aeh.
4.10.7. N,2-Bis(4-fluorobenzyl)-5-methoxy-3-methyl-4-oxo-3,4-
dihydroquinazoline-6-carboxamide (10g)
White solid, 41% yield; mp: 181e182 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.48 (d, J ¼ 8.7 Hz, 1H, ArH), 8.32 (s, 1H, NH), 7.55
(d, J ¼ 8.6 Hz, 1H, ArH), 7.24e7.38 (m, 4H, ArH), 7.04 (t, J ¼ 7.9 Hz,
4H, ArH), 4.65 (d, J ¼ 5.2 Hz, 2H, ArCH2), 4.20 (s, 2H, ArCH2), 3.84
(s, 3H, OMe), 3.48 (s, 3H, NMe); HRMS (ESI) calcd for C25H20F2N3O3
(M ꢁ H)ꢁ: 448.1478, found: 448.1469.
4.10.1. N-(4-fluorobenzyl)-2-(4-fluorophenyl)-5-methoxy-3-
methyl-4-oxo-3,4-dihydroquinazoline-6-carboxamide (10a)
White solid, 92% yield; mp: 219e221 ꢀC; 1H NMR (400 MHz,
CDCl3):
d
8.50 (d, J ¼ 8.7 Hz, 1H, ArH), 8.35 (s, 1H, NH), 7.58e7.64
4.10.8. N-(4-fluorobenzyl)-5-methoxy-3-methyl-2-(4-nitrobenzyl)-
4-oxo-3,4-dihydroquinazoline-6-carboxamide (10h)
(m, 2H, ArH), 7.36 (dd, J ¼ 8.2, 5.6 Hz, 2H, ArH), 7.22e7.27 (m, 3H,
ArH), 7.05 (t, J ¼ 8.6 Hz, 2H, ArH), 4.66 (d, J ¼ 5.6 Hz, 2H, ArCH2),
3.91 (s, 3H, OMe), 3.50 (s, 3H, NMe); HRMS (ESI) calcd for
C24H18F2N3O3 (M ꢁ H)ꢁ: 434.1322, found: 434.1329.
Slight yellow solid, 63% yield; mp: 234e236 ꢀC; 1H NMR
(400 MHz, CDCl3):
d
8.49 (d, J ¼ 8.7 Hz, 1H, ArH), 8.30 (s, 1H, NH),
8.24 (d, J ¼ 8.4 Hz, 2H, ArH), 7.50 (dd, J ¼ 15.3, 8.7 Hz, 3H, ArH),
7.35 (dd, J ¼ 5.7, 8.2 Hz, 2H, ArH), 7.04 (t, J ¼ 8.6 Hz, 2H, ArH), 4.65
(d, J ¼ 5.6 Hz, 2H, ArCH2), 4.32 (s, 2H, ArCH2), 3.50 (s, 3H, NMe);
HRMS (ESI) calcd for C22H20FN4O5 (M ꢁ H)ꢁ: 475.1423, found:
475.1422.
4.10.2. N-(4-fluorobenzyl)-5-methoxy-3-methyl-2-(4-nitrophenyl)-
4-oxo-3,4-dihydroquinazoline-6-carboxamide (10b)
Slight yellow solid, 87% yield; mp: 248e249 ꢀC; 1H NMR
(400 MHz, CDCl3):
d
8.53 (d, J ¼ 8.7 Hz, 1H, ArH), 8.43 (d, J ¼ 8.5 Hz,
2H, ArH), 8.33 (s, 1H, NH), 7.82 (d, J ¼ 8.5 Hz, 2H, ArH), 7.60
(d, J ¼ 8.7 Hz, 1H, ArH), 7.37 (dd, J ¼ 5.6, 8.2 Hz, 2H, ArH), 7.06
(t, J ¼ 8.6 Hz, 2H, ArH), 4.67 (d, J ¼ 5.5 Hz, 2H, ArCH2), 3.92 (s, 3H,
OMe), 3.49 (s, 3H, NMe); HRMS (ESI) calcd for C24H18FN4O5
(M ꢁ H)ꢁ: 461.1267, found: 461.1269.
4.11. General procedure for the preparation of compounds 11aeh
To a stirred solution of 10aeh (0.4 mmol) and AlCl3 (1.2 mmol)
in CH2Cl2 (60 mL) was added dropwise pyridine (4.8 mmol) at 30 ꢀC
under N2. The mixture was refluxed for 28 h, then cooled to room