Z. Zhang et al. / European Journal of Medicinal Chemistry 69 (2013) 711e718
715
Fig. 2. (a) The resultant overlay of compound 1 (dark gray) on the Bim BH3 peptide (light gray) is displayed. (b) The resultant overlay of compound 6c (dark gray) on the Bim BH3
peptide (light gray) is displayed.
with benzoyl chloride (500
m
L). The mixture was stirred at 30 ꢁC for
3H, AreH), 7.84e7.86 (d, J ¼ 8.4 Hz, 2H, AreH), 7.59e7.61 (s,1H, Are
H), 7.17 (s, 1H, AreH), 5.37 (d, 2H, CH2), 4.01e4.03 (m, 12H, OCH3),
6 h and poured onto a mixture of ice and hydrochloric acid. The
obtained residue was washed with water, recrystallized from
ethanol as light pink solid. A suspension of this solid (573 mg) in
acetic anhydride (20 mL) was heated under reflux (4 h) and then
concentrated. The residue was crystallized from ethanol, giving
6,7,8-trimethoxy-2-phenyl-4H-benzo[d][1,3]oxazin-4-one
(450 mg, 78.6% overall) as dark yellow crystals, mp 170e171 ꢁC. 1H
NMR (400 MHz, DMSO-d6)
: 8.17e8.19 (d, J ¼ 8.4 H z, 2H, AreH),
7.59e7.67 (m, 3H, AreH), 7.39 (s, 1H, AreH), 3.93e4.09 (t, 9H,
3OCH3). 13C NMR (DMSO-d6)
: 159.44, 156.32, 151.53, 145.92,
2.37 (s, 3H, CH3). 13C NMR (DMSO-d6)
d: 165.64, 156.34, 153.76,
151.72, 146.85, 144.34, 138.52, 131.43, 130.57, 129.51, 129.08, 128.53,
128.23, 128.01, 127.75, 125.93, 121.43, 116.78, 115.32, 101.64, 61.92,
58.23, 56.78, 56.32, 39.87, 21.67. TOF MS (EIþ): C26H26N2O5, calcd
for 446.0243, found 446.0241.
(5)
d
5.1.8.3. 3-(5-isopropyl-2-methoxybenzyl)-6,7,8-trimethoxy-2-
phenylquinazolin-4(3H)-one (9d). Yield: 85 mg, 28.0%. 1H NMR
d
(400 MHz, DMSO-d6)
d
: 7.95e7.97 (d, J ¼ 8.4 Hz, 2H, AreH), 7.67e
145.23, 133.21, 131.02, 129.85, 128.83, 128.41, 128.12, 127.93, 110.53,
99.31, 60.82, 56.16, 55.76. TOF MS (EIþ): C17H15NO5, calcd for
313.0818, found 313.0816.
7.69 (m, 3H, AreH), 7.32e7.34 (d, J ¼ 8.4 Hz, 2H, AreH), 7.07e7.09
(s,1H, AreH), 6.79 (s, 1H, AreH), 5.39 (s, 2H, CH2), 4.24e4.28 (m,
12H, OCH3), 2.93 (m, 1H, CH), 1.76 (d, 6H, 2CH3). 13C NMR (DMSO-
d6) d: 161.62, 156.35, 153.67, 151.76, 149.43, 146.13, 143.97, 130.45,
5.1.7. 6,7,8-Trimethoxy-2-phenylquinazolin-4(3H)-one (8)
130.34, 129.34, 129.03, 128.75, 128.42, 128.12, 127.56, 126.15, 118.54,
115.12, 113.15,101.23, 62.13, 58.11, 57.34, 56.89, 39.34, 33.55, 23.56,
23.12. TOF MS (EIþ): C28H30N2O5, calcd for 474.0253, found
474.0256.
6,7,8-trimethoxy-2-phenyl-4H-benzo[d][1,3]oxazin-4-one (7)
(100 mg, 0.32 mmol) was stirred with ammonium acetate (2.5 g,
32 mmol) at 170 ꢁC for 1 h under nitrogen. After cooling to 50 ꢁC,
the solution was diluted with hot methanol (3 mL). The resultant
solution was stirred under reflux for 1 h, cooled to room temper-
ature. The resulting solid was filtered and rinsed with methanol
and dried. White solid was obtained yield 80%; mp 247e248 ꢁC. 1H
5.1.9. General procedure for the preparation of 10be10d
A stirred solution of 6,7,8-trimethoxy-2-phenyl-4H-benzo[d]
[1,3]oxazin-4-one (7) (90 mg, 0.287 mmol) in 5 mL of toluene was
added corresponding amine (0.733 mmol), and the reaction
mixture was heated under reflux for 4e5 h. After cooling down, the
residue was filtered, recrystallized from ethanol as the final
compound.
NMR (400 MHz, DMSO-d6)
7.88 (m, 3H, AreH), 7.28 (s,1H, AreH), 5.88 (s,1H, NH), 4.33e4.37 (t,
9H, OCH3). 13C NMR (DMSO-d6)
: 161.08, 152.32, 151.73, 146.67,
d: 8.36 (d, J ¼ 8.4 Hz, 2H, AreH), 7.86e
d
143.95, 132.52, 131.43, 130.45, 128.96, 128.32, 128.12, 127.54, 111.73,
101.52, 60.82, 57.34, 56.76. TOF MS (EIþ): C17H16N2O4, calcd for
312.0678, found 312.0679.
5.1.9.1. 2-Benzamido-N-butyl-3,4,5-trimethoxybenzamide
(10b).
Yield: 49 mg, 44.2%. 1H NMR (400 MHz, DMSO-d6)
d
: 8.26 (s, 1H,
5.1.8. General procedure for the preparation of 9be9d
NH), 8.11 (d, J ¼ 8.4 Hz, 2H, AreH), 7.96e7.98 (m, 3H, AreH), 7.43 (s,
1H, AreH), 5.58 (s, 1H, NH), 4.21e4.23 (t, 9H, OCH3), 3.89 (m, 2H,
CH2), 1.65e1.67 (m, 4H, CH2CH2), 1.12 (t, 3H, CH3). 13C NMR (DMSO-
A
stirred solution of 6,7,8-trimethoxy-2-phenylquinazolin-
4(3H)-one (8) (200 mg, 0.641 mmol) in 10 mL of DMF was added
sodium hydride (10 mmol) under nitrogen at room temperature.
After stirring for 1 h, corresponding benzyl bromide (3 mmol) and
iodomethane were added and the reaction mixture was further
stirred for 1e1.5 h under nitrogen. After pouring the mixture into
water slowly, standing for 1 h, the residue was filtered, recrystal-
lized from EtOH as the final compounds.
d6) d: 170.32, 164.76, 148.82, 142.87, 141.23, 134.25, 132.11, 128.76,
128.23, 127.53, 127.11, 120.32, 117.34, 105.35, 60.82, 60.24, 56.12,
39.42, 32.21, 19.86, 13.34. TOF MS (EIþ): C21H26N2O5, calcd for
386.0423, found 386.0426.
5.1.9.2. 2-Benzamido-N-benzyl-3,4,5-trimethoxybenzamide
(10c).
Yield: 55 mg, 45.6%. 1H NMR (400 MHz, DMSO-d6)
d
: 8.53 (s, 1H,
5.1.8.1. 3-Benzyl-6,7,8-trimethoxy-2-phenylquinazolin-4(3H)-one
NH), 8.11 (s, 1H, NH), 7.94e7.96 (d, J ¼ 8.4 Hz, 2H, AreH), 7.59e7.61
(m,3H, AreH), 7.37e7.39 (d, J ¼ 8.4 Hz, 2H, AreH), 7.09e7.11 (m,3H,
AreH), 6.89 (s,1H, AreH), 4.37 (d, 2H, CH2), 4.01e4.03 (t, 9H, OCH3).
(9b). Yield: 150 mg, 58.2%. 1H NMR (400 MHz, DMSO-d6)
d: 8.11 (d,
J ¼ 8.4 Hz, 2H, AreH), 7.96e7.98 (m, 3H, AreH), 7.63 (s, 1H, AreH),
7.37e7.39 (d, J ¼ 8.4 Hz, 2H, AreH), 7.09e7.11 (m, 3H, AreH), 5.61 (s,
13C NMR (DMSO-d6)
d: 167.86,164.71, 148.83, 142.92, 142.45, 137.96,
2H, CH2), 4.21e4.23 (t, 9H, OCH3). 13C NMR (DMSO-d6)
d
: 163.61,
134.26, 132.13, 128.92, 128.42, 128.11, 128.02, 127.68, 127.43, 126.97,
126.57, 126.01, 120.34, 117.23, 101.69, 60.91, 60.53, 56.15, 44.78. TOF
MS (EIþ): C24H24N2O5, calcd for 420.0243, found 420.0241.
156.25, 151.76, 147.34, 143.95, 136.57, 131.56, 130.47, 129.76, 129.01,
128.85, 128.67, 128.45, 128.21, 127.98, 127.75, 127.44, 127.03, 117.64,
101.23, 61.23, 57.82, 56.34, 46.12. TOF MS (EIþ): C24H22N2O4, calcd
for 402.0423, found 402.0426.
5.1.9.3. 2-Benzamido-3,4,5-trimethoxy-N-(3-phenylpropyl)benza-
mide (10d). Yield: 85 mg, 72.9%. 1H NMR (400 MHz, DMSO-d6)
d:
5.1.8.2. 6,7,8-Trimethoxy-3-(2-methoxy-5-methylbenzyl)-2-
8.23 (s, 1H, NH), 7.95e7.97 (d, J ¼ 8.4 Hz, 2H, AreH), 7.67e7.69
(m,3H, AreH), 7.32e7.34 (d, J ¼ 8.4 Hz, 2H, AreH), 7.07e7.09 (m,3H,
AreH), 6.79 (s, 1H, AreH), 6.07 (s, 1H, NH), 4.24e4.28 (t, 9H, OCH3),
phenylquinazolin-4(3H)-one (9c). Yield: 101 mg, 35.3%. 1H NMR
(400 MHz, DMSO-d6)
d
: 8.51 (d, J ¼ 8.4 Hz, 2H, AreH), 8.16e8.18 (m,