Organic & Biomolecular Chemistry
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s, Ar–H, H-2), 8.04 (1H, s, Ar–H, H-8), 7.87 (2H, d, J 8.7 Hz, ν = 1735, 1697 cm−1
.
1H NMR (400 MHz, DMSO-d6): δ 11.06
Ar–H, H-2′ + H-6′), 7.64 (2H, d, J 8.7 Hz, Ar–H, H-3′ + H-5′), (1H, s, NH), 10.24 (1H, s, NH), 8.80 (1H, s, Ar–H, H-2),
7.40 (1H, d, J 7.7 Hz, Ar–H, H-6″), 7.35–7.33 (2H, m, Ar–H, H-2″ 8.08 (1H, s, Ar–H, H-8), 7.87 (2H, d, J 8.5 Hz, Ar–H,
+ H-5″), 7.26 (1H, s, Ar–H, H-5), 6.99 (1H, dd, J = 8.0, 2.5 Hz, H-2′ + H-6′), 7.61 (2H, d, J 8.5 Hz, Ar–H, H-3′ + H-5′), 7.28 (1H,
Ar–H, H-4″), 3.99 (6H, s, 2 × OCH3). 13C NMR (125 MHz, s, Ar–H, H-5), 7.20–7.15 (3H, m, Ar–H), 6.81 (1H, app. d,
DMSO-d6): δ 166.0 (CvO), 158.5, 158.2, 157.8, 156.3, 150.4, J 8.0 Hz, Ar–H, H-4″), 4.00 (6H, s, 2 × OCH3). 13C NMR
150.3, 137.4, 136.8, 133.2, 129.9, 125.0, 120.9, 119.0, 118.6, (101 MHz, DMSO-d6): δ 166.8 (CvO), 158.5, 156.7, 150.6,
115.0, 107.9, 103.5, 102.1, 57.0, 56.8. LRMS [M + H+] 417.3. 149.6, 148.3, 138.1, 136.3, 132.5, 129.3, 125.5, 120.8, 118.0,
HRMS (ESI) m/z cald for C23H21N4O4 [M + H+]: 417.1557, found 116.0, 115.7, 114.0, 107.6, 103.8, 100.8, 57.1, 57.0. LRMS
417.1558.
N-(4-((6,7-Dimethoxyquinazolin-4-yl)amino)phenyl)-3-methoxy 416.1717, found 416.1717.
[M + H+] 416.3. HRMS (ESI) m/z cald for C23H22N5O3 [M + H+]:
benzamide (31). 4-Chloro-6,7-dimethoxyquinazoline 9 (72 mg,
3-(Cyanomethoxy)-N-(4-((6,7-dimethoxyquinazolin-4-yl)amino)-
0.32 mmol) was reacted with the corresponding 4-amino- phenyl)benzamide (34). Compound 30 (20 mg, 0.048 mmol),
carboxamide (78 mg, 0.32 mmol) in isopropanol (7.4 mL) accord- bromoacetonitrile (3.7 μL, 0.053 mmol) and cesium carbonate
ing to general procedure 1 to obtain compound 31 (90 mg, (39 mg, 0.12 mmol) in anhydrous acetonitrile (1 mL) was
65%) as a yellow solid after filtration and washing with diethyl heated at 80 °C for 1 h. The reaction was subsequently filtered
ether (2 × 10 mL). M.p. 187–190 °C (decomp.). IR (ATR): and the solvent was removed in vacuo to afford a crude residue
ν = 2952, 1674 cm−1 1H NMR (400 MHz, DMSO-d6): δ 11.11 that was purified by reverse phase HPLC (0 to 100% MeCN
.
(1H, s, NH), 10.36 (1H, s, NH), 8.78 (1H, s, Ar–H, H-2), 8.24 over 40 min) to afford compound 34 (TFA salt) as a yellow solid
(1H, s, Ar–H, H-8), 7.89 (2H, d, J = 8.4 Hz, Ar–H, H-2′ + H-6′), (12 mg, 55%). M.p. 141–144 °C. IR (ATR): ν = 2954, 2365,
7.67 (2H, d, J 8.4 Hz, Ar–H, H-3′ + H-5′), 7.57 (1H, app. d, 1672 cm−1. 1H NMR (500 MHz, DMSO-d6): δ 10.39 (1H, s, NH),
J 7.7 Hz, 1H, Ar–H, H-6″), 7.52 (1H, s, Ar–H, H-2″), 7.46 (1H, 8.76 (1H, s, Ar–H, H-2), 8.04 (1H, s, Ar–H, H-8), 7.89–7.87 (2H,
app. t, J 7.9 Hz, Ar–H, H-5″), 7.32 (1H, s, Ar–H, H-5), 7.17 (1H, m, Ar–H, H-2′ + H-6′), 7.71–7.63 (4H, m, Ar–H, H-3′ + H-5′, H-2″
dd, J = 8.0, 2.5 Hz, Ar–H, H-4″), 4.01 (3H, s, OCH3), 3.99 (3H, s, + H-6″), 7.56 (1H, t, J = 8.0 Hz, Ar–H, H-5″), 7.33 (1H, dd,
OCH3), 3.85 (3H, s, OCH3). 13C NMR (101 MHz, DMSO-d6): J = 8.2, 2.7 Hz, Ar–H, H-4″), 7.27 (1H, s, Ar–H, H-5), 5.28 (2H, s,
δ 165.7 (CvO), 159.7, 158.4 (×2), 156.6, 150.6, 149.5, 137.6, CH2), 3.99 (6H, 2 × OCH3). 13C NMR (126 MHz, DMSO-d6):
136.7, 133.0, 130.1, 125.4, 121.0, 120.4, 117.8, 113.5, 107.8, δ 165.2 (CvO), 158.5, 158.2, 156.8, 156.4, 150.4, 150.2, 137.3,
104.2, 100.9, 57.3, 56.9, 55.9. LRMS [M + H+] 417.3. HRMS 137.0, 133.3, 130.4, 125.1, 122.2, 121.0, 118.45, 116.9, 114.7,
(ESI) m/z cald for C23H21N4O4 [M + H+]: 417.1557, found 107.9, 103.6, 101.8, 57.0, 56.8, 54.2. LRMS [M + H+] 456.3.
417.1560.
N-(4-((6,7-Dimethoxyquinazolin-4-yl)amino)phenyl)-3-nitro- 456.1666.
HRMS (ESI) m/z cald for C25H22N5O4 [M + H+]: 456.1666, found
benzamide (32). 4-Chloro-6,7-dimethoxyquinazoline 9 (160 mg,
2-(3-((4-((6,7-Dimethoxyquinazolin-4-yl)amino)phenyl)carb-
0.69 mmol) was reacted with the corresponding 4-amino- amoyl)phenoxy)acetic acid (35). Compound 30 (60 mg,
carboxamide (177 mg, 0.69 mmol) in isopropanol (16 mL) accord- 0.14 mmol), tert-butyl bromoacetate (28 μL, 0.19 mmol) and
ing to general procedure 1 to obtain compound 32 (TFA salt) cesium carbonate (118 mg, 0.36 mmol) in anhydrous aceto-
as a yellow solid (300 mg, 98%) after filtration and washing nitrile (3 mL) was heated at 50 °C for 3 h. The reaction was
with diethyl ether (2 × 10 mL). M.p. 140–144 °C (decomp.). IR subsequently filtered and the solvent was removed in vacuo to
(ATR): ν = 1673, 1640 cm−1 1H NMR (500 MHz, DMSO-d6): afford a crude residue that was dissolved in a mixture of tri-
.
δ 10.69 (1H, s, NH), 8.79 (1H, t, J 2.0 Hz, Ar–H, H-2″), 8.71 (1H, fluoroacetic acid in dichloromethane (300 μL, 1 : 1 v/v). The
s, Ar–H, H-2), 8.44 (1H, dd, J 8.2, 2.0 Hz, Ar–H, H-4″), 8.43 (1H, reaction was stirred at room temperature for 16 h. The solvent
dd, J 8.0, 1.5 Hz, Ar–H, H-6″), 8.04 (1H, s, Ar–H, H-8), 7.88–7.84 was removed in vacuo to give a crude residue that was purified
(3H, m, Ar–H, H-2′ + H-6′ + H-5″), 7.68 (2H, d, J 9.0 Hz, Ar–H, by reverse phase HPLC (0 to 100% MeCN over 40 min) to
H-3′ + H-5′), 7.25 (1H, s, Ar–H, H-5), 3.98 (3H, s, OCH3), 3.97 afford compound 35 as a yellow solid (10 mg, 14% over 2
(3H, s, OCH3). 13C NMR (126 MHz, DMSO-d6): δ 164.1 (CvO), steps). M.p. 236–239 °C (decomp.). IR (ATR): ν = 3365, 1679,
158.4, 156.6, 150.6, 150.3, 148.4, 138.0, 136.9, 136.7, 134.7, 1631 cm−1. 1H NMR (500 MHz, DMSO-d6): δ 10.32 (1H, s, NH),
133.8, 130.9, 126.9, 125.3, 122.9, 121.5, 108.0, 103.6, 101.9, 8.61 (1H, s, Ar–H, H-2), 7.98 (1H, s, Ar–H, H-8). 7.83 (1H, d,
57.1, 57.0. LRMS [M + H+] 446.2. HRMS (ESI) m/z cald for J 8.5 Hz, Ar–H, H-3′ + H-5′), 7.70 (2H, d, J 8.5 Hz, H-2′ + H-6′),
C23H20N5O5 [M + H+]: 446.1459, found 446.1459.
7.59 (1H, app. d, J 8.0 Hz, Ar–H, H-6″), 7.51–7.50 (1H, m, Ar–H,
3-Amino-N-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenyl)- H-2″), 7.46–7.43 (1H, m, Ar–H, H-5″), 7.27 (1H, s, Ar–H, H-5),
benzamide (33). Compound 32 (61 mg, 0.13 mmol) in metha- 7.14 (1H, dd, J 8.5, 2.5 Hz, Ar–H, H-4″), 4.78 (2H, s, CH2), 3.97
nol (10 mL) was hydrogenated (1 atm) over 10% Pd/C (13 mg) (3H, s, OCH3), 3.95 (3H, s, OCH3). 13C NMR (126 MHz, DMSO-
for 24 h. The reaction mixture was subsequently filtered over d6): δ 170.5 (CvO), 165.4 (CvO), 158.8, 158.2, 157.7, 155.6,
Celite® and the filtrate concentrated in vacuo to afford a crude 151.4, 149.9, 136.6, 136.4, 134.3, 130.0, 124.3, 121.1, 120.8,
solid that was purified by reverse phase HPLC (gradient: 118.2, 114.1, 108.5, 104.2, 103.1, 65.1, 56.8, 56.6. LRMS
0–100% MeCN over 40 min) to afford compound 33 as a yellow [M + Na+] 496.9. HRMS (ESI) m/z cald for C25H23N4O6 [M + H+]:
solid (16 mg, 30%). M.p. 121–123 °C (decomp.). IR (ATR): 475.1612, found 475.1612.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem., 2013, 11, 8113–8126 | 8125