Molecules 2016, 21, 612
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3.1.6. General Procedure for the Preparation of
N1-(3-Fluoro-4-methoxyphenyl)-N3-(4-fluorophenyl)malonamide Derivatives Compound 13a–i
Compounds 12 were further reacted with compounds
the final products 13a–i as mentioned above.
5, 6, 7 in the presence of K2CO3 to obtain
Compound 13a: N1-{4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl}-N3-(4-fluorophenyl)-2,
2-dimethylmalonamide. White solid, yield 85%, m.p. 210–212 ˝C. 1H-NMR (400 MHz, CDCl3)
8.84
(s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 7.70 (m, 1H), 7.48 (s, 1H), 7.44–7.23 (m, 2H), 7.23–7.15 (m, 1H), 6.97
(t, J = 8.6 Hz, 1H), 3.99 (d, J = 4.3 Hz, 1H), 1.62 (s, 1H). 13C-NMR (100 MHz, CDCl3)
172.19, 171.92,
δ
δ
165.66, 162.17, 159.64, 156.11, 155.44, 153.27, 152.81, 150.33, 149.47, 136.40, 136.30, 136.20, 136.07, 133.02,
124.10, 122.59, 115.91, 110.17, 109.39, 109.15, 106.81, 100.93, 56.36, 50.76, 24.18. HRMS (m/z): calcd. for
523.1788 ([M + H]+), obsd.535.1791.
Compound 13b
cyclopropane-1,1-dicarboxamide. Yellow solid, yield 86%, m.p. 180–182 C. H-NMR (400 MHz,
CDCl3) 9.66 (s, 1H), 8.52 (s, 1H), 8.47 (s, 1H), 7.67 (d, J = 11.1 Hz, 1H), 7.48 (s, 1H), 7.38 (dd, J = 9.0, 4.8
Hz, 1H), 7.20 (d, J = 5.5 Hz, 1H), 6.98 (t, J = 8.6 Hz, 1H), 3.99 (d, J = 4.5 Hz, 3H), 1.66 (t, J = 6.1 Hz, 1H),
1.58–1.51 (m, 1H). 13C-NMR (100 MHz, CDCl3)
169.43, 168.43, 164.68, 156.04, 152.69, 150.36, 149.45,
:
N-{4-[(6,7-dimethoxyquinazolin-4-yl)oxy]-3-fluorophenyl}-N-(4-fluorophenyl)
˝
1
δ
δ
136.42, 136.03, 124.07, 122.95, 122.87, 116.10, 115.96, 115.73, 110.20, 109.63, 109.40, 106.78, 100.96, 56.37,
31.93, 29.70, 29.29, 22.69, 17.61, 14.12. HRMS (m/z): calcd. for 521.1631 ([M + H]+), obsd.521.1634.
Compound 13c
:
N-{4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-flu˝orophenyl}-N-(4-fluorophenyl)
cyclobutane-1,1-dicarboxamide. White solid, yield 80%, m.p. 250–252 C. 1H-NMR (400 MHz, CDCl3)
δ
8.58 (s, 1H), 8.53 (d, J = 7.2 Hz, 1H), 8.16 (d, J = 7.5 Hz, 1H), 7.80 (dd, J = 11.9, 2.1 Hz, 1H), 7.57–7.48
(m, 1H), 7.35–7.30 (m, 1H), 7.28 (d, J = 3.4 Hz, 1H), 7.03 (t, J = 8.5 Hz, 1H), 4.06 (d, J = 4.5 Hz, 1H),
2.06–1.90 (m, 1H), 1.28–1.23 (m, 1H). 13C-NMR (101 MHz, CDCl3)
170.54, 170.40, 164.67, 160.91,
δ
158.47, 156.02, 155.52, 153.05, 152.69, 150.34, 149.44, 136.64, 136.12, 133.38, 124.14, 122.02, 121.94, 115.88,
115.65, 110.16, 109.09, 108.86, 106.78, 100.93, 56.36, 56.02, 29.76, 15.67. HRMS (m/z): calcd. for 535.1788
([M + H]+), obsd.535.1793.
Compound 13d: N1-(4-fluorophenyl)-2,2-dimethyl-N3-{4-((2-(methylcarbamoyl)pyridin-4-yl)oxy]
phenyl}malonamide. Faint yellow solid, yield 82%, m.p. 113–115 ˝C. 1H-NMR (400 MHz, CDCl3)
δ
8.72 (s, 1H), 8.54 (s, 1H), 8.37 (d, J = 5.6 Hz, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.66 (d, J = 1.9 Hz, 1H), 7.60–7.50
(m, 3H), 7.09–6.99 (m, 4H), 6.94 (dd, J = 5.6, 2.5 Hz, 1H), 2.99 (d, J = 5.1 Hz, 3H), 1.70 (s, 6H). 13C-NMR
(100 MHz, CDCl3)
δ 171.71, 166.36, 164.46, 160.93, 158.50, 152.26, 150.23, 149.67, 135.10, 133.32, 122.47,
122.39, 122.32, 121.43, 115.81, 115.59, 114.10, 110.12, 50.69, 29.70, 26.15, 25.36, 24.24. HRMS (m/z): calcd.
for 451.1776 ([M + H]+), obsd.451.1779. Calcd. for 473.1596 ([M + Na]+), obsd.473.1602.
Compound 13e: N-(4-fluorophenyl)-N-{4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl}cyclopropane-1,
˝
1-dicarboxamide. White solid, yield 82%, m.p. 138–140 C. 1H-NMR (400 MHz, CDCl3)
δ 9.46 (s, 2H),
8.31 (d, J = 5.6 Hz, 1H), 7.99 (d, J = 4.9 Hz, 1H), 7.54–7.50 (m, 2H), 7.49 (s, 1H), 7.43–7.36 (m, 1H), 6.99
(s, 1H), 6.96 (d, J = 2.6 Hz, 1H), 6.94 (s, 1H), 6.91 (4, 1H), 4.03 (q, 1H), 2.88 (d, J = 5.1 Hz, 3H), 1.19
(t, 2H), 1.13 (d, J = 6.1 Hz, 2H). 13C-NMR (100 MHz, CDCl3)
δ 169.65, 169.34, 166.39, 164.64, 152.09,
150.24, 149.81, 135.18, 133.43, 123.21, 122.91, 121.42, 115.72, 115.50, 114.39, 109.72, 64.43, 60.43, 28.89,
26.18, 25.35, 21.05, 17.91, 14.19. HRMS (m/z): calcd. for 624.2087 ([M + H]+), obsd.449.1620. calcd. for
471.1439 ([M + Na]+), obsd.471.1464.
Compound 13f: N-(4-fluorophenyl)-N-{4-((2-(methylcarbamoyl)pyridin-4-yl)oxy)phenyl}cyclobutane-1,
˝
1-dicarboxamide. White solid, yield 77%, m.p. 192–194 C. 1H-NMR (400 MHz, CDCl3)
δ 8.29 (s, 1H),
8.27 (d, J = 5.1 Hz, 1H), 8.14 (s, 1H), 7.94 (d, J = 4.5 Hz, 1H), 7.60–7.56 (m, 1H), 7.54 (s, 1H), 7.49–7.38
(m, 1H), 6.96 (dd, J = 8.6, 4.5 Hz, 1H), 6.92 (s, 1H), 6.86 (dd, J = 5.5, 2.5 Hz, 1H), 2.92 (d, J = 5.1 Hz,
1H), 2.68 (t, J = 7.9 Hz, 1H), 2.01–1.88 (m, 1H). 13C-NMR (100 MHz, CDCl3)
δ
170.49, 170.45, 166.31,
164.53, 152.28, 150.10, 149.71, 135.33, 121.96, 121.88, 121.81, 121.43, 115.80, 115.57, 114.09, 110.09, 64.42,