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T. Kuramochi et al. / Bioorg. Med. Chem. 13 (2005) 717–724
m), 8.27 (1H, dd, J = 8.8, 2.4Hz), 8.64 (1H, d,
J = 2.4Hz), 9.12 (1H, t, J = 5.8Hz); MS (FAB) m/z
447 (M+H)+. Anal. Calcd for C26H20N2O3F: C, 69.95;
H, 4.52; N, 6.27; F, 8.51. Found: C, 69.84; H, 4.54; N,
6.25; F, 8.66.
5.1.12. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(3-hydroxy-
benzyl)nicotinamide (7k). Compound 7k was prepared
from 6 by a procedure similar to that described for 7a.
Compound 7k was obtained as a white powder (36%):
1
mp 173–175°C; H NMR (400MHz, DMSO-d6) d 4.46
(2H, d, J = 5.8Hz), 5.15 (2H, s), 6.60–6.64 (1H, m),
6.70–6.74 (2H, m), 7.03–7.13 (6H, m), 7.14–7.20 (1H,
m), 7.28–7.33 (2H, m), 7.42–7.49 (1H, m), 8.27 (1H,
dd, J = 8.8, 2.4Hz), 8.64 (1H, d, J = 2.4Hz), 9.04
(1H, t, J = 5.9Hz), 9.31 (1H, s); MS (FAB) m/z 445
(M+H)+. Anal. Calcd for C26H21N2O4F: C, 70.26; H,
4.76; N, 6.30; F, 4.27. Found: C, 70.17; H, 4.85; N,
6.22; F, 4.44.
5.1.8.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(3-nitro-
benzyl)nicotinamide (7g). Compound 7g was prepared
from 6 by a procedure similar to that described for 7a.
Compound 7g was obtained as a white powder (93%):
mp 79–81°C; H NMR (400MHz, DMSO-d6) d 4.61
(2H, d, J = 5.9Hz), 5.15 (2H, s), 7.05–7.14 (5H, m),
7.14–7.20 (1H, m), 7.28–7.34 (2H, m), 7.42–7.49 (1H,
m), 7.64 (1H, t, J = 7.8Hz), 7.80 (1H, d, J = 7.8Hz),
8.10–8.14 (1H, m), 8.17–8.20 (1H, m), 8.28 (1H, dd,
J = 8.3, 2.5Hz), 8.65 (1H, d, J = 2.4Hz), 9.24 (1H, t,
J = 5.9Hz); MS (FAB) m/z 474 (M+H)+. Anal. Calcd
for C26H20N3O5F: C, 65.69; H, 4.26; N, 8.88; F, 4.01.
Found: C, 65.97; H, 4.21; N, 8.68; F, 4.10.
1
5.1.13. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(3-meth-
oxybenzyl)nicotinamide (7l). Compound 7l was prepared
from 6 by a procedure similar to that described for 7a.
Compound 7l was obtained as a white powder (81%):
1
mp 125–127°C; H NMR (400MHz, DMSO-d6) d 3.73
(3H, s), 4.45 (2H, d, J = 5.8Hz), 5.15 (2H, s), 6.79–
6.84 (1H, m), 6.86–6.90 (2H, m), 7.03–7.13 (5H, m),
7.14–7.21 (1H, m), 7.21–7.27 (1H, m), 7.28–7.34 (2H,
m), 7.42–7.49 (1H, m), 8.27 (1H, dd, J = 8.8, 2.5Hz),
8.63 (1H, d, J = 2.4Hz), 9.06 (1H, t, J = 5.8Hz); MS
(FAB) m/z 459 (M+H)+. Anal. Calcd for C27H23N2O4F:
C, 70.73; H, 5.06; N, 6.11; F, 4.14. Found: C, 69.82; H,
4.99; N, 6.06; F, 4.03.
5.1.9. N-(3-Cyanobenzyl)-6-{4-[(3-fluorobenzyl)oxy]phen-
oxy}nicotinamide hydrochloride (7h). Compound 7h was
prepared from 6 by a procedure similar to that described
for 7a. Compound 7h was obtained as white powder
(16%): mp 101–109°C; 1H NMR (400MHz, DMSO-
d6) d 4.53 (2H, d, J = 5.9Hz), 5.15 (2H, s), 7.04–7.13
(5H, m), 7.14–7.21 (1H, m), 7.28–7.33 (2H, m), 7.43–
7.49 (1H, m), 7.53–7.58 (1H, m), 7.65–7.69 (1H, m),
7.72–7.75 (1H, m), 7.71 (1H, s), 8.28 (1H, dd, J = 8.8,
2.5Hz), 8.65 (1H, d, J = 2.5Hz), 9.19 (1H, t,
J = 5.9Hz); MS (FAB) m/z 454 (M+H)+. Anal. Calcd
for C27H20N3O3FÆ0.5HClÆ0.1H2O: C, 68.49; H, 4.41;
N, 8.87; F, 4.01; Cl, 3.74. Found: C, 68.34; H, 4.38;
N, 8.88; F, 3.86; Cl, 3.55.
5.1.14. 6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-[3-(meth-
ylamino)benzyl]nicotinamide (7m). Compound 7m was
prepared from 6 by a procedure similar to that described
for 7a. Compound 7m was obtained as a white powder
(80%): mp 162–166°C; 1H NMR (400MHz, DMSO-
d6) d 2.92 (3H, s), 4.57 (2H, d, J = 5.3Hz), 5.15 (2H,
s), 7.05–7.13 (5H, m), 7.14–7.21 (1H, m), 7.28–7.40
(5H, m), 7.43–7.51 (2H, m), 8.29 (1H, dd, J = 8.8,
2.5Hz), 8.66 (1H, d, J = 2.5Hz), 9.21 (1H, t,
J = 5.9Hz); MS (FAB) m/z 458 (M+H)+. Anal. Calcd
for C27H24N3O3FÆ2HBrÆ0.2H2O: C, 52.06; H, 4.27; N,
6.75; F, 3.05; Br, 25.65. Found: C, 51.91; H, 4.16; N,
6.74; F, 2.96; Br, 25.62.
5.1.10.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-[3-(tri-
fluoromethyl)benzyl]nicotinamide hydrochloride (7i).
Compound 7i was prepared from 6 by a procedure simi-
lar to that described for 7a. Compound 7i was obtained
as a beige amorphous (26%): 1H NMR (400MHz,
DMSO-d6) d 4.57 (2H, d, J = 5.9Hz), 5.15 (2H, s),
7.04–7.13 (5H, m), 7.13–7.20 (1H, m), 7.28–7.33 (2H,
m), 7.43–7.49 (1H, m), 7.55–7.68 (4H, m), 8.27 (1H,
dd, J = 8.8, 2.4Hz), 8.64 (1H, d, J = 2.4Hz), 9.19 (1H,
t, J = 5.8Hz); MS (FAB) m/z 497 (M+H)+; HRMS:
(M+H)+Calcd for C27H21O3N2F4, 497.1488. Found:
497.1470.
5.1.15.
N-(3-Aminobenzyl)-6-{4-[(3-fluorobenzyl)oxy]-
phenoxy}nicotinamide hydrochloride (8). The mixture of
7g (450mg, 0.95mmol), EtOH (6mL), Fe powder
(265mg, 4.75mmol), and NH4Cl (153mg, 2.85mmol),
H2O (1mL) was stirred at 100°C for 90min. The mix-
ture was filtered through a Celite pad. The filtrate was
concentrated in vacuo. The residue was partitioned be-
tween CH3Cl and aqueous NaOH. The organic layer
was dried and concentrated. The residue was purified
by column chromatography on silica gel (CHCl3/
MeOH = 1:0–92:8) to give the free base of 8 as a pale
yellow solid. This material was converted to its hydro-
chloride salt by treating it with HCl/AcOEt in AcOEt–
MeOH. The mixture was concentrated in vacuo. The
residue was recrystallized from AcOEt–EtOH–hexane
to give 8 as a gray powder (237mg, 52%): mp 156–
5.1.11. Ethyl 3-({[(6-{4-[(3-fluorobenzyl)oxy]phenoxy}-
pyridin-3-yl)carbonyl]amino}methyl)benzoate hydrobro-
mide (7j). Compound 7j was prepared from 6 by a
procedure similar to that described for 7a. Compound
7j was obtained as a beige powder (83%): mp 150–
1
156°C; H NMR (400MHz, DMSO-d ) d 1.31 (3H, t,
6
J = 7.2Hz), 4.31 (2H, q, J = 7.3Hz), 4.54 (2H, d,
J = 5.8Hz), 5.15 (2H, s), 7.04–7.14 (5H, m), 7.14–7.21
(1H, m), 7.28–7.34 (2H, m), 7.43–7.51 (2H, m), 7.58–
7.62 (1H, m), 7.84 (1H, d, J = 8.8Hz), 7.92 (1H, s),
8.27 (1H, dd, J = 8.8, 2.5Hz), 8.64 (1H, d, J = 2.4Hz),
9.18 (1H, t, J = 6.9Hz); MS (FAB) m/z 501 (M+H)+.
Anal. Calcd for C29H25N2O5FÆHBr: C, 59.91; H, 4.51;
N, 4.82; F, 3.27; Br, 13.74. Found: C, 59.69; H, 4.56;
N, 4.77; F, 3.32; Br, 13.70.
1
158°C; H NMR (400MHz, DMSO-d6) d 4.50 (2H, d,
J =5.8Hz), 5.15 (2H, s), 7.03–7.13 (5H, m), 7.14–7.23
(2H, m), 7.24–7.34 (4H, m), 7.38–7.49 (2H, m), 8.30
(1H, dd, J = 8.8, 2.5Hz), 8.67 (1H, d, J = 2.5Hz), 9.28
(1H, t, J = 5.8Hz), 10.02 (2H, br s); MS (FAB) m/z