NOVEL EGFR INHIBITORS
39
layers were washed with H2O (3 3 40 mL), 2 M J 5 7.8 Hz, 2H), 7.39 (d, J 5 8.0 Hz, 1H), 7.24 (s,
NaOH (3 3 40 mL), 2 M HCl (3 3 40 mL), and
brine (2 3 40 mL), dried over Na2SO4, and concen-
trated to give (2) (6.90 g, 95%) as a yellow solid,
which was used for the next step without further
purification.
1H), 6.91 (d, J 5 7.8 Hz, 2H), 6.89 (s, 1H), 4.18 (t,
J 5 4.2 Hz, 2H), 3.75–3.78 (m, 4H), 2.83 (t, J 5 4.2
Hz, 2H), 2.61 (s, 4H).
The title compounds (5b–5g) and (10b–10g)
were also prepared using the general procedure
described above.
4-(benzyloxy)-2-methoxybenzaldehyde (7) was
prepared using the same procedure described above.
2-(benzyloxy)-4-methoxybenzoic acid (3) [Miura
et al., 2006]. To a solution of (2) (7.27 g, 30 mmol)
in THF (100 mL) was added distilled H2O (40 mL)
and NaH2PO4 (2.16 g, 18 mmol). The mixture was
stirred at room temperature for 20 min. NaClO2
(8.96 g, 99 mmol) and 30% H2O2 (6.80 mL, 66
mmol) in distilled H2O (40 mL) were added. The
resultant mixture was stirred at room temperature for
3 h. THF was evaporated under vacuum and the res-
idue was extracted with EtOAc (3 3 70 mL). The
combined organic layers were washed with (3 3
30 mL) and the product was extracted with 2 M
NaOH (5 3 30 mL). The aqueous phase was acidi-
fied with concentrated HCl and the solid obtained
was collected by filtration and dried to give (3)
(7.210 g, 93%) as a white solid.
4-(benzyloxy)-2-methoxybenzoic acid (8) was
prepared using the same procedure described above.
2-(benzyloxy)-4-methoxy-N-(4-(2-morpholinoethoxy)
phenyl) benzamide (4a) [Nobuaki et al., 2009]. To a solu-
tion of compound (3) (1.29 g, 5 mmol) in anhydrous THF
(25 mL) were added EDCI (1.71 g, 8.92 mmol), HOBt
(1.20 g, 8.92 mmol), and triethylamine (2 mL). After stir-
ring at room temperature for 2 h, 4-(2-morpholinoethoxy)
aniline (1.78 g, 8mmol) in anhydrous THF (15 mL) was
added drop wise and the reaction continued for 48 h at
room temperature. Water (300 mL) was then added and
the mixture was stirred for 30 min. The water layer was
extracted with AcOEt (50 mL 3 3). The organic layer was
combined and washed with water and brine, and dried
over Na2SO4. The filtration and concentration in vacuo
afforded (4a) (0.78 g, 92%) are as white solid.
N-(4-(3-(dimethylamino) propoxy)-3-fluorophenyl)-
2-hydroxy-4-methoxybenzamide (5b). m.p.: 139–1408C.
EI-MS (m/z): 362.0 [M]1. 1H NMR (400 MHz, DMSO-
d6) d 7.44 (d, J5 8.0 Hz, 1H), 7.38 (d, J5 8.0 Hz, 1H),
7.35 (d, J5 8.0 Hz, 2H), 7.14 (d, J5 8.0 Hz, 1H), 7.07 (t,
J5 4.0 Hz, 1H), 6.93 (d, J5 8.0 Hz, 2H), 4.01 (t, J5 4.0
Hz, 2H), 3.78 (s, 6H), 3.09–3.15 (m, 2H), 2.48 (s, 2H).
N-(3-fluoro-4-(2-morpholinoethoxy)phenyl)-2-
hydroxy-4-methoxybenzamide (5c). m.p.: 172–1738C.
EI-MS (m/z): 390.2 [M]1. 1H NMR (400 MHz,
DMSO-d6) d 7.82 (dd, J 5 8.0 Hz, 1H), 7.49 (d,
J 5 8.0 Hz, 1H), 7.45 (dd, J 5 8.0 Hz, 1H), 7.38 (d,
J 5 8.0 Hz, 1H), 7.27 (t, J 5 4.0 Hz, 1H), 7.01 (d,
J 5 4.0 Hz, 1H), 4.42 (s, 2H), 3.83 (s, 4H), 3.61 (s,
4H), 3.39 (s, 2H).
N-(3-fluoro-4-(3-morpholinopropoxy)phenyl)-3-
hydroxy-4-methoxybenzamide (5d). m.p.: 169–1708C.
EI-MS (m/z): 404.3 [M]1. 1H NMR (400 MHz,
DMSO-d6) d 7.71 (dd, J 5 8.0 Hz, 1H), 7.50
(t, J 5 4.0 Hz, 2H), 7.38 (d, J 5 8.0 Hz, 1H), 7.12 (t,
J 5 4.0 Hz, 1H), 6.99 (d, J 5 8.0 Hz, 1H), 4.10 (t,
J 5 4.0 Hz, 2H), 3.65 (s, 4H), 2.51–2.57 (m, 3H),
1.95 (s, 1H).
N-(3-chloro-4-(2-morpholinoethoxy)phenyl)-3-
hydroxy-4-methoxybenzamide (5e). m.p.: 177–1788C.
EI-MS (m/z): 406.2 [M]1. 1H NMR (400 MHz,
DMSO-d6) d 7.69 (d, J 5 8.0 Hz, 2H), 7.45 (dd,
J 5 8.0 Hz, 1H), 7.39 (d, J 5 8.0 Hz, 1H), 6.99 (s,
1H), 6.95 (d, J 5 8.0 Hz, 2H), 4.35–4.41 (m, 2H),
3.79 (s, 4H), 3.51 (s, 4H), 3.40 (s, 2H).
N-(3-chloro-4-(2-morpholinoethoxy)phenyl)-3-
hydroxy-4-methoxybenzamide (5f). m.p.: 168–1698C.
EI-MS (m/z): 406.1 [M]1. 1H NMR (400 MHz,
DMSO-d6) d 7.75 (dd, J 5 8.0 Hz, 1H), 7.49 (d,
J 5 8.0 Hz, 1H), 7.42 (dd, J 5 8.0 Hz, 1H), 7.37 (d,
J 5 8.0 Hz, 1H), 7.18 (t, J 5 4.0 Hz, 1H), 6.97
(d, J 5 4.0 Hz, 1H), 4.37 (s, 2H), 3.90 (s, 4H), 3.68
(s, 4H), 3.40 (s, 2H).
4-(benzyloxy)-2-methoxy-N-(4-(2-morpholinoethoxy)
phenyl) benzamide (9a) was prepared using the same pro-
cedure described above.
2-hydroxy-4-methoxy-N-(4-(2-morpholinoethoxy)
phenyl) benzamide (5a) [Bazin et al., 2013]. To a
solution of compound (4a) (2.31 g, 5 mmol) in
50 mL of anhydrous MeOH was added Pd/C 10%
N-(3-chloro-4-(3-morpholinopropoxy)phenyl)-3-
hydroxy-4-methoxybenzamide (5g). m.p.: 156–1578C.
EI-MS (m/z): 420.0 [M]1. 1H NMR (400 MHz,
DMSO-d6) d 7.69 (dd, J 5 8.0 Hz, 1H), 7.48 (t,
J 5 4.0 Hz, 2H), 7.40 (d, J 5 8.0 Hz, 1H), 7.11
(t, J 5 4.0 Hz, 1H), 6.72 (d, J 5 8.0 Hz, 1H), 4.07 (t,
J 5 4.0 Hz, 2H), 3.70 (s, 4H), 2.57–2.63 (m, 3H),
(51 mg, 0.05 mmol). The suspension was refluxed for
R
5 h. Pd/C was filtered on CeliteV, and the filtrate was
concentrated in vacuo. The crude product was puri-
fied by silica gel chromatography using dichlorome-
thane as eluent to afford the title compound (5a)
(1.77 g, 95% yield). m.p.: 162–1638C. EI-MS (m/z):
1
372.2 [M]1. H NMR (400 MHz, CDCl3) d 7.51 (d, 1.99 (s, 1H).
Drug Dev. Res.