M.R. Yadav et al. / European Journal of Medicinal Chemistry 48 (2012) 231e243
239
(1.00 g, 3.57 mmol) as starting materials, compound 6c was ob-
tained as a white solid (1.3 g, 70%): mp 183e185 ꢁC (dec.); IR (KBr):
NMR: 12.35 (b, 1H, NeH), 7.71e7.69 (d, 2H, AreH; J ¼ 8.7 Hz), 7.43
(s, 1H, AreH), 7.09 (s, 1H, AreH), 6.58e6.56 (d, 2H, AreH;
J ¼ 8.7 Hz), 6.06 (b, 1H, NeH), 5.06 (s, 2H, CH2), 3.87 (s, 3H,
OeCH3) and 3.86 (s, 3H, OeCH3); FAB-MS: m/z ¼ 356.3 (M þ Hþ).
Anal. Calcd. for C18H17N3O5: C, 60.84; H, 4.82; N, 11.82. Found C,
60.60; H, 4.72; N, 11.96%.
3470, 3224, 1660, 1619, 1525, 1386, 1271, 1085 and 1037 cmꢀ1 1H
;
NMR: 11.38 (s, 1H, NeH), 8.41 (s, 1H, AreH), 8.08e8.01 (m, 1H,
AreH), 7.88e7.83 (m, 2H, AreH), 7.55e7.45 (m, 4H, AreH), 6.83 (s,
1H, AreH), 5.62 (s, 2H, NeH), 4.19 (s, 2H, CH2), 3.92 (s, 3H, OeCH3)
and 3.68 (s, 3H, OeCH3); FAB-MS: m/z ¼ 365.4 (M þ Hþ).
4.1.23. 2-[(3-Methanesulfonylamidophenylamino)methyl]-6,7-
dimethoxyquinazolin-4(3H)-one (11b)
4.1.18. 2-(2-Chlorobenzyl)-6,7-dimethoxyquinazolin-4(3H)-one
(7a)
Following a procedure identical to the one as described for 11a,
Following a procedure identical to the one as described for 4e,
but using compound 6a (0.2 g, 0.57 mmol) as starting material,
compound 7a was obtained as a solid (0.18 g, 95%): 1H NMR: 11.50
(s, 1H, NeH), 7.56 (s, 1H, AreH), 7.41e7.39 (m, 1H, AreH), 7.31e7.29
(m, 1H, AreH), 7.26e7.23 (m, 2H, AreH), 7.06 (s, 1H, AreH), 4.15 (s,
2H, CH2), 4.00 (s, 3H, OeCH3) and 3.96 (s, 3H, OeCH3); FAB-MS: m/
z ¼ 331.8 (M þ Hþ). Anal. Calcd. for C17H15ClN2O3: C, 61.73; H, 4.57;
N, 8.47. Found C, 61.62; H, 4.71; N, 8.28%.
but
using
3-methanesulfonylamidoaniline
(10b)
(1.09 g,
5.89 mmol), compound 11b was obtained as a solid (0.43 g, 54%):
1H NMR: 12.26 (b, 1H, NeH), 7.40 (s, 1H, AreH), 7.02 (m, 2H, AreH),
5.80 (m, 2H, AreH), 5.59 (m, 1H, AreH), 5.06 (b, 1H, NeH), 4.00 (s,
1H, NeH), 3.85 (s, 3H, OeCH3) and 3.80 (s, 3H, OeCH3), 3.44 (m, 2H,
CH2), 2.82 (s, 3H, SO2eCH3); FAB-MS: m/z ¼ 405.4 (M þ Hþ). Anal.
Calcd. for C18H20N4O5S: C, 53.46; H, 4.98; N, 13.85. Found C, 53.42;
H, 5.01; N, 13.80%.
4.1.19. 2-(4-Chlorobenzyl)-6,7-dimethoxyquinazolin-4(3H)-one
(7b)
4.1.24. 2-[(4-Methanesulfonylamidophenylamino)methyl]-6,7-
dimethoxyquinazolin-4(3H)-one (11c)
Following a procedure identical to that of 4e, but using
compound 6b (0.2 g, 0.57 mmol) as starting material, compound 7b
was obtained as a solid (0.17 g, 89%): 1H NMR: 11.99 (s, 1H, NeH),
7.52 (s, 1H, AreH), 7.41e7.37 (m, 2H, AreH), 7.29e7.26 (m, 2H,
AreH), 7.09 (s, 1H, AreH), 3.98 (s, 3H, OeCH3), 3.96 (s, 3H, OeCH3)
and 3.94 (s, 2H, CH2); FAB-MS: m/z ¼ 331.8 (M þ Hþ). Anal. Calcd for
C17H15ClN2O3: C, 61.73; H, 4.57; N, 8.47. Found C, 61.80; H, 4.76; N,
8.60%.
Following a procedure identical to that of 11a, but using 4-
methanesulfonylamidoaniline
(10c)
(1.09 g,
5.89 mmol),
compound 11c was obtained as a solid (0.5 g, 63%): 1H NMR: 12.30
(b, 1H, NeH), 7.40 (s, 1H, AreH), 7.00 (s, 1H, AreH), 6.85 (d, 2H,
AreH; J ¼ 9.0 Hz), 6.33 (d, 2H, AreH; J ¼ 9.0 Hz), 6.06 (b, 1H, NeH),
5.06 (s, 2H, CH2), 3.87 (s, 3H, OeCH3) and 3.86 (s, 3H, OeCH3), 2.77
(s, 3H, SO2eCH3); FAB-MS: m/z ¼ 405.4 (M þ Hþ). Anal. Calcd. for
C18H20N4O5S: C, 53.46; H, 4.98; N, 13.85. Found C, 53.50; H, 5.06; N,
13.92%.
4.1.20. 6,7-Dimethoxy-2-[(naphthalen-1-yl)methyl]quinazolin-
4(3H)-one (7c)
4.1.25. 2-[(4-Methoxyphenylamino)methyl]-6,7-dimethoxyquina-
zolin-4(3H)-one (11d)
Following a procedure identical to that of 4e, but using
compound 6c (0.2 g, 0.55 mmol) as starting material, compound 7c
was obtained as a solid (0.17 g, 93%): 1H NMR: 11.57 (s, 1H, NeH),
8.23e8.21 (m, 1H, AreH), 7.88e7.86 (d, 1H, AreH; J ¼ 8.1 Hz),
7.81e7.79 (d,1H, AreH; J ¼ 8.0 Hz), 7.56e7.42 (m, 5H, AreH), 7.08 (s,
1H, AreH), 4.47 (s, 2H, CH2), 3.97 (s, 3H, OeCH3) and 3.95 (s, 3H,
OeCH3); FAB-MS: m/z ¼ 347.4 (M þ Hþ). Anal. Calcd. for
C21H18N2O3: C, 72.82; H, 5.24; N, 8.09. Found C, 72.70; H, 5.34; N,
8.26%.
Following a procedure identical to that of 11a, but using 4-
anisidine (10d) (0.72 g, 5.89 mmol), compound 11d was obtained
as a solid (0.42 g, 64%): 1H NMR: 12.30 (b, 1H, NeH), 7.48 (s, 1H,
AreH), 7.45e7.42 (m, 2H, AreH), 7.19 (s, 1H, AreH), 7.14e7.00 (m,
2H, AreH), 6.26 (b, 1H, NeH), 4.82 (s, 2H, CH2), 3.97 (s, 3H, OeCH3),
3.88 (s, 3H, OeCH3) and 3.87 (s, 3H, OeCH3); FAB-MS: m/z ¼ 342.4
(M þ Hþ). Anal. Calcd. for C18H19N3O4: C, 63.33; H, 5.61; N, 12.31.
Found C, 63.56; H, 5.76; N, 12.57%.
4.1.21. 2-Chloromethyl-6,7-dimethoxyquinazolin-4(3H)-one (9)
Chloroacetonitrile (1.17 mL, 18.96 mmol) was added to a satu-
rated solution of dry HCl in dioxane (10 mL). The mixture was
stirred at 0e5 ꢁC for 10 min under anhydrous conditions.
Compound 8 (2.0 g, 9.48 mmol) was added into the above solution
and the reaction mixture was stirred at rt for another 24 h. The
mixture was quenched in ice-cold water (150 mL) and neutralized
with aq ammonia. The precipitate formed was filtered, washed
with cold water and dried to afford compound 9 as a pale yellow
solid (1.8 g, 75%): mp 219e223 ꢁC; IR (KBr): 2931, 1670, 1608, 1498,
1438, 1377, 1240, 1078 and 1022 cmꢀ1; FAB-MS: m/z ¼ 255.7
(M þ Hþ).
4.1.26. N-n-Butyl-4,5-dimethoxy-2-nitrobenzamide (13)
A mixture of 4,5-dimethoxy-2-nitrobenzoic acid (12) (5.0 g,
22.0 mmol) and thionyl chloride (15 mL) was refluxed under
anhydrous conditions for 2 h. Excess of thionyl chloride was
recovered under reduced pressure and the residue was dissolved in
anhydrous THF (10 mL). This was then added to a solution of n-
butylamine (2.6 mL, 26.4 mmol) and triethylamine (TEA, 9.2 mL,
66.0 mmol) in THF (15 mL) at 0e5 ꢁC. The reaction mixture was
stirred for 2 h at rt and quenched in cold water. The precipitate so
formed was filtered, washed with cold water and dried. The solid
thus obtained was crystallized from methanol to obtain yellow
crystals (4.8 g, 77%): mp 130e132 ꢁC; IR (KBr): 3269, 1639, 1519,
1340, 1278, 1224, 1180 and 1026 cmꢀ1
.
4.1.22. 4-[(3,4-Dihydro-6,7-dimethoxy-4-oxoquinazolin-2-yl)
methylamino]benzoic acid (11a)
4.1.27. 2-Amino-N-n-butyl-4,5-dimethoxybenzamide (14)
4-Aminobenzoic acid (10a) (0.80 g, 5.89 mmol) and potassium
A solution of 2-nitro-N-n-butyl-4,5-dimethoxybenzamide (13)
(1.0 g, 3.5 mmol) in methanol (20 mL) was refluxed on a water
bath. Iron powder (1.6 g, 28.4 mmol) and a solution of ammo-
nium chloride (1.5 g, 28.3 mmol) in water (2 mL) were added
portion-wise (in 4 parts at an interval of 45 min) to the above
refluxing solution. Refluxing was continued for 7e8 h and the
solution was filtered through filtering aid and washed with hot
methanol (2 ꢂ 10 mL). The filtrate was concentrated under
carbonate (0.62 g, 5.89 mmol) were added to
a solution of
compound 9 (0.5 g, 1.96 mmol) in DMF (1 mL). The reaction
mixture was stirred at rt for 8 h, quenched into cold water and
neutralized (pH 4.5e5.0) with dilute hydrochloric acid. The
precipitate formed was filtered, washed with cold water and dried.
The solid thus obtained was recrystallized from a mixture of
chloroform and methanol to afford compound 11a (0.24 g, 35%): 1H