Journal of Medicinal Chemistry
Article
3-[3-tert-Butyl-4-methoxy-5-[(E)-2-(4-nitrophenyl)vinyl]-
phenyl]-2-methoxypyridine (31). To a slurry of NaH (0.17 g, 4.159
mmol, 60% in mineral oil) in THF (5 mL) containing 0.1 equiv of 15-
crown-5 cooled to 0 °C was added a solution of diethyl (4-
nitrophenyl)phosphonate (1.14 g, 4.16 mmol) in THF (5 mL). When
gas evolution ceased, a slurry of 30 (1.13 g, 3.78 mmol) was added and
stirred at room temperature for 18 h. An additional equivalent of NaH
was added to the partially reacted mixture, and stirring continued for 1 h.
The reaction mixture was partitioned between water and Et2O, and the
organic extract was sequentially washed with water and brine, dried
(Na2SO4), filtered, and evaporated. The crude product was purified over
SiO2 by chromatography (EtOAc/hexane, 50%) to afford 31 as a sole
geometric isomer. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 8.6 Hz, 2
H), 8.17 (d, J = 4.5 Hz, 1 H), 7.73−7.61 (m, 4 H), 7.57 (d, J = 16.2 Hz, 1
H), 7.53−7.47 (m, 1 H), 7.13 (d, J = 16.7 Hz, 1 H), 7.03−6.95 (m, 1 H),
4.01 (s, 3 H), 3.84 (s, 3 H), 1.45 (s, 9 H) ppm.
4-[2-[3-tert-Butyl-2-methoxy-5-(2-methoxy-3-pyridyl)-
phenyl]ethyl]aniline (32). To a solution of 31 (351 mg, 0.840 mmol)
in EtOAc (15 mL) and MeOH (15 mL) was added Pd(OH)2 (20% on
carbon, 166 mg, 0.237 mmol). H2 gas was bubbled into the solution for
15 min. The mixture was stirred under an atmosphere of H2 for 18 h.
The mixture was filtered, concentrated, and purified over SiO2 by
chromatography (EtOAc/hexane, 5−20%) to give 32 (106 mg, 32%) as
a colorless oil. LC/MS (ES/APCI): 391 (M + H)+.
concentrated. The crude residue was purified over SiO2 by
chromatography (EtOAc/hexane, 40%) to afford N-[4-[(E)-2-[3-tert-
butyl-2-methoxy-5-(2-methoxy-3-pyridyl)phenyl]vinyl]phenyl]-
1
methanesulfonamide (0.178 g, 96%) as a yellow foam. H NMR (400
MHz, CDCl3) δ 8.16 (dd, J = 4.5, 1.5 Hz, 1 H), 7.64 (d, J = 2.5 Hz, 2 H),
7.54 (d, J = 8.6 Hz, 2 H), 7.46 (d, J = 2.0 Hz, 1 H), 7.36 (d, J = 16.7 Hz, 1
H), 7.23 (d, J = 8.1 Hz, 2 H), 7.05 (s, 1 H), 7.02−6.95 (m, 1 H), 6.42 (s, 1
H), 4.00 (s, 3 H), 3.83 (s, 3 H), 3.04 (s, 3 H), 1.45 (s, 9 H) ppm.
A solution of N-[4-[(E)-2-[3-tert-butyl-2-methoxy-5-(2-methoxy-3-
pyridyl)phenyl]vinyl]phenyl]methanesulfonamide (0.14 g, 0.3 mmol),
AcOH (3 mL) and 48% HBr (0.105 mL) was heated at 60 °C for 18 h.
The reaction mixture was cooled to room temperature and diluted with
EtOAc and water to give a precipitate, which was filtered and washed
with water and ether to give 10 (115 mg, 67%) as an off-white solid. 1H
NMR (400 MHz, DMSO-d6) δ 7.84 (d, J = 1.5 Hz, 1 H), 7.67 (dd, J =
6.9, 2.0 Hz, 1 H), 7.58−7.51 (m, 3 H), 7.37 (dd, J = 6.3, 1.8 Hz, 1 H),
7.17 (d, J = 16.4 Hz, 1 H) 7.17−7.07 (m, 3 H), 6.29 (t, J = 6.6 Hz, 1 H),
3.75 (s, 3 H), 2.91 (s, 1 H), 1.39 (s, 9 H) ppm. LC/MS (ES/APCI): 453
(M + H)+.
3-(3-tert-Butyl-4-methoxy-5-nitrophenyl)-2-methoxypyri-
dine (35). A mixture of 5-bromo-1-tert-butyl-2-methoxy-3-nitro-
benzene (34) (0.48 g, 1.7 mmol), (2-methoxy-3-pyridyl)boronic acid
(0.28 g, 1.8 mmol), Pd(PPh3)4 (0.19 g, 0.17 mmol), and Na2CO3 (0.53
g, 5.0 mmol) in CH2Cl2/MeOH (3:1, 8 mL) was subjected to
microwave heating to 115 °C for 35 min. The reaction mixture was
filtered and the filtrate concentrated. The crude residue was purified
over SiO2 by chromatography (EtOAc/hexane, 0−20%) to afford 35
(0.44 g, 82%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.19 (dd,
J = 4.9, 1.5 Hz, 1 H), 7.87 (d, J = 2.3 Hz, 1 H), 7.72 (d, J = 1.9 Hz, 1 H),
7.61 (dd, J = 7.5, 1.9 Hz, 1 H), 7.00 (dd, J = 7.3, 5.1 Hz, 1 H), 3.99 (s, 3
H), 3.85 (s, 3 H), 1.44 (s, 9 H) ppm.
N-[4-[2-[3-tert-Butyl-2-methoxy-5-(2-oxo-1H-pyridin-3yl)-
phenyl]ethyl]phenyl]methanesulfonamide (4). To a solution of
32 (106 mg, 0.272 mmol) in pyridine (5 mL) at 0 °C was added
methanesulfonyl chloride (0.035 mL, 0.450 mmol). The mixture was
gradually warmed to room temperature and stirred for 1.5 h. The
solution was diluted with EtOAc, washed with saturated CuSO4 solution
and then 1 N HCl solution, and dried over Na2SO4. Purification over
SiO2 by chromatography (EtOAc/hexane, 10−25%) gave N-[4-[2-[3-
tert-butyl-2-methoxy-5-(2-methoxy-3-pyridyl)phenyl]ethyl]phenyl]-
3-tert-Butyl-2-methoxy-5-(2-methoxy-3-pyridyl)aniline (36).
To a solution of 35 (0.98 g, 3.1 mmol) in EtOAc/MeOH (2:1, 30 mL)
was added 10% Pd/C (0.10 g). A stream of H2 was bubbled through the
solution for 20 min, and then the solution was stirred at room
temperature for 16 h. The reaction mixture was filtered and
concentrated to afford 36. 1H NMR (300 MHz, CDCl3) δ 8.12 (dd, J
= 4.9, 1.9 Hz, 1 H), 7.59 (dd, J = 7.36, 1.7 Hz, 1 H), 7.02−6.84 (m, 3 H),
3.97 (s, 3 H), 3.84 (s, 3 H), 3.70 (br s, 2 H), 1.41 (s, 9 H) ppm.
N-[3-tert-Butyl-2-methoxy-5-(2-methoxy-3-pyridyl)phenyl]-
4-nitrobenzamide (37). To a solution of 36 (0.24 g, 0.85 mmol) and
Et3N (0.18 mL, 1.3 mmol) in CH2Cl2 (10 mL) at 0 °C was added 4-
nitrobenzoyl chloride (0.19 g, 1.0 mmol). The resulting mixture was
stirred at 0 °C for 3 h and then warmed to room temperature. The
mixture was then diluted with additional CH2Cl2, washed sequentially
with water and brine, dried (Na2SO4), filtered, and concentrated. The
crude residue was purified over SiO2 by chromatography to afford 37
1
methanesulfonamide (104 mg, 82%) as a colorless oil. H NMR (300
MHz, CDCl3) δ 8.13 (dd, J = 4.9, 1.5 Hz, 1 H), 7.57 (dd, J = 7.3, 1.7 Hz, 1
H), 7.43−7.27 (m, 2 H), 7.25−7.10 (m, 4 H), 6.96 (dd, J = 7.2, 5.3 Hz, 1
H), 6.39 (s, 1 H), 3.98 (s, 3 H), 3.83 (s, 3 H) 2.99 (s, 4 H), 2.97 (s, 3 H),
1.43 (s, 9 H) ppm.
A solution of N-[4-[2-[3-tert-butyl-2-methoxy-5-(2-methoxy-3-
pyridyl)phenyl]ethyl]phenyl]methanesulfonamide (104 mg, 0.222
mmol) and 48% HBr (0.1 mL, 0.87 mmol) in AcOH (3 mL) was
heated at 65 °C for 18 h in a sealed tube. The reaction mixture was
carefully poured into saturated aqueous NaHCO3 ice solution, extracted
with EtOAc, and dried over Na2SO4. Purification by SiO2 preparative
TLC (EtOAc/hexane, 1:1, followed by EtOAc/hexane, 2:1) gave 4 (51
mg, 51%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 11.68 (br s,
1 H), 9.59 (s, 1 H) 7.54 (dd, J = 6.9, 2.1 Hz, 1 H), 7.51 (d, J = 2.2 Hz, 1
H), 7.46 (d, J = 2.2 Hz, 1 H), 7.34 (dd, J = 6.4, 2.0 Hz, 1 H), 7.25 (d, J =
8.5 Hz, 2 H), 7.13 (d, J = 8.5 Hz, 2 H), 6.26 (t, J = 6.8 Hz, 1 H), 3.76 (s, 3
H), 2.93 (s, 3 H), 2.88 (s, 4 H), 1.36 (s, 9 H) ppm. LC/MS (ES/APCI):
455 (M + H)+.
4-[(E)-2-[3-tert-Butyl-2-methoxy-5-(2-methoxy-3-pyridyl)-
phenyl]vinyl]aniline (33). To a suspension of 31 (0.29 g, 0.693
mmol) in MeOH (5 mL) and water (5 mL) was added NH4Cl (0.37 g,
6.93 mmol) followed by Fe powder (0.19 g, 3.464 mmol). The solution
was heated at reflux for 1 h, cooled, and filtered. The filtrate was
concentrated in vacuo. The filtrate was taken up in EtOAc, washed with
brine, dried (Na2SO4), filtered, and evaporated. The crude product was
purified over SiO2 by chromatography (EtOAc/hexane, 30%) to afford
33 (0.26 g, 100%) as a yellow foam. 1H NMR (300 MHz, CDCl3) δ 8.15
(dd, J = 4.9, 1.9 Hz, 1 H), 7.63 (d, J = 2.3 Hz, 2 H), 7.44−7.33 (m, 3 H),
7.17 (d, J = 15.8 Hz, 1 H), 7.02−6.93 (m, 2 H), 6.69 (d, J = 8.3 Hz, 2 H),
4.00 (s, 3 H), 3.83 (s, 3 H), 3.81−3.69 (m, 2 H), 1.44 (s, 9 H) ppm.
N-[4-[(E)-2-[3-tert-Butyl-2-methoxy-5-(2-oxo-1H-pyridin-3-
yl)phenyl]vinyl]phenyl]methanesulfonamide (10). To a solution
of 33 (0.153 g, 0.394 mmol) in pyridine (4 mL) at 0 °C was added
methanesulfonyl chloride (0.037 mL, 0.055 g, 0.473 mmol). Stirring was
continued at 0 °C for 2 h and then at room temperature for an additional
2 h. The reaction mixture was diluted with EtOAc, washed sequentially
with aqueous CuSO4 and 2 N HCl, dried (Na2SO4), filtered, and
1
(0.36 g, 97%) as a light yellow solid. H NMR (400 MHz, CDCl3) δ
8.42−8.35 (m, 3 H), 8.27 (br s, 1 H), 8.16 (dd, J = 5.1, 1.5 Hz, 1 H), 8.10
(d, J = 8.56 Hz, 2 H), 7.66 (dd, J = 7.6, 1.5 Hz, 1 H), 7.40 (d, J = 2.0 Hz, 1
H), 6.98 (dd, J = 7.1, 5.0 Hz, 1 H), 4.00 (s, 3 H), 3.84 (s, 3 H), 1.45 (s, 9
H) ppm.
4-Amino-N-[3-tert-butyl-2-methoxy-5-(2-methoxy-3-
pyridyl)phenyl]benzamide (38). To a solution of 37 (0.36 g, 0.82
mmol) in EtOAc/MeOH (2:1, 15 mL) was added 10% Pd/C (0.035 g).
A stream of H2 gas was bubbled through the solution for 20 min, and the
white solid precipitate that formed was recovered by filtration to afford
38 (quantitative) which was carried onto the subsequent step without
further purification. 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 2.3 Hz, 1
H), 8.13 (d, J = 5.0 1.9 Hz, 1 H), 8.08 (br s, 1 H), 7.77 (d, J = 8.7 Hz, 2
H), 7.66 (dd, J = 7.3, 1.7 Hz, 1 H), 7.34 (d, J = 1.9 Hz, 1 H), 6.95 (dd, J =
7.2, 4.9 Hz, 1 H), 6.73 (d, J = 8.3 Hz, 2 H), 4.04 (br s, 2 H), 3.99 (s, 3 H),
3.83 (s, 3 H), 1.44 (s, 9 H) ppm.
N-[3-tert-Butyl-2-methoxy-5-(2-oxo-1H-pyridin-3-yl)phenyl]-
4-(methanesulfonamido)benzamide (5). To a solution of 38 (0.10
g, 0.25 mmol) in pyridine (2 mL) at 0 °C was added methanesulfonyl
chloride (0.034 g, 0.30 mmol). Stirring was continued at 0 °C for 2 h and
then at room temperature for an additional 2 h. The reaction mixture
was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2
N HCl, dried (Na2SO4), filtered, and concentrated. The crude residue
O
dx.doi.org/10.1021/jm401266k | J. Med. Chem. XXXX, XXX, XXX−XXX