4674 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 24
Shinkai et al.
7,8-H on quinoline), 8.66 (2H, br s, 4-NH2 on quinoline), 8.74
(1H, s, 5-H on quinoline), 10.86 (1H, s, NHCO), 13.93 (1H, br
s, HCl). Anal. (C26H25N3O2‚HCl‚H2O) C, H, N.
d, J ) 8.8 Hz), 7.99 (1H, d, J ) 9.2 Hz), 8.72 (2H, br s), 8.73
(1H, s), 10.87 (1H, s), 13.91 (1H, s). Anal. (C25H22ClN3O2‚HCl‚
0.2H2O) C, H, N.
N-(4-Am in o-2-m et h ylq u in olin -6-yl)-2-(4-m et h oxyp h e-
n oxym eth yl)ben za m id e h yd r och lor id e (12): mp 276 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.59 (3H, s), 3.65 (3H, s), 5.27
(2H, s), 6.60 (1H, s), 6.77-6.89 (4H, m), 7.48-7.68 (4H, m),
7.88-7.96 (2H, m), 8.70 (2H, br s), 8.74 (1H, s), 10.85 (1H, s),
13.78 (1H, s). Anal. (C25H23N3O3‚HCl) C, H, N.
N -(4-Am in o-2-p r op ylq u in olin -6-yl)-2-(4-ch lor op h e -
n oxym eth yl)ben za m id e h yd r och lor id e (25): mp 232-233
1
°C; H NMR (300 MHz, DMSO-d6) δ 0.96 (3H, t, J ) 7.4 Hz),
1.73-1.80 (2H, m), 2.85 (2H, t, J ) 7.4 Hz), 5.34 (2H, s), 6.65
(1H, s), 6.96 (2H, d, J ) 8.8 Hz), 7.26 (2H, d, J ) 8.8 Hz),
7.50-7.71 (4H, m), 7.94 (1H, d, J ) 9.2 Hz), 8.00 (1H, d, J )
9.2 Hz), 8.73 (2H, br s), 8.74 (1H, s), 10.87 (1H, s), 13.93 (1H,
s). Anal. (C26H24ClN3O2‚HCl‚0.3H2O) C, H, N.
N-(4-Am in o-2-m et h ylq u in olin -6-yl)-2-(4-h yd r oxyp h e-
n oxym eth yl)ben za m id e h yd r och lor id e (13): mp 183.0-
1
184.0 °C; H NMR (300 MHz, DMSO-d6) δ 2.58 (3H, s), 5.22
N-(2-Meth yl-4-m eth yla m in oqu in olin -6-yl)-2-(p h en oxy-
m eth yl)ben za m id e Hyd r och lor id e (22). A mixture of 32a
(4.32 g, 20 mmol) and phosphoryl chloride (9.32 mL, 100 mmol)
was heated at 100 °C for 30 min. After cooling to room
temperature, the mixture was poured into ice water (50 mL).
The aqueous solution was alkalinized with 28% ammonium
hydroxide. Then the precipitate was collected by filtration,
washed with ethyl ether (30 mL), and dried under a vacuum
to give 6-acetamide-4-chloro-2-methylquinoline 41 as a slightly
yellow solid (4.69 g, 100%). A solution of 41 (2.74 g, 11.7 mmol)
in N-methylformamide (5 mL) was heated at 170 °C for 3 h.
After cooling to room temperature, the reaction mixture was
diluted with chloroform (50 mL). The organic solution was
washed with saturated aqueous sodium bicarbonate (50 mL),
water (50 mL), and brine (50 mL), dried over sodium sulfate,
and concentrated. Then the crude product was chromato-
graphed on silica gel eluted with chlorofrom/methanol/am-
monium hydroxide (85:15:0.1) to give 6-acetamide-2-methyl-
4-methylaminoquinoline 42 as a slightly brown solid (255 mg,
9.4%). A solution of 42 (248 mg, 1.08 mmol) in 6 N hydrochloric
acid (10 mL) was refluxed for 2 h. After cooling to room
temperature, the mixture was alkalinized with 4 N aqueous
sodium hydroxide. The resulting precipitate was collected by
filtration and dried under a vacuum to give 6-amino-2-methyl-
4-methylaminoquinoline 43 as a slightly brown solid (202 mg,
100%). 2-(4-Chlorophenoxymethyl)benzoyl chloride (258 mg,
1.05 mmol) was added to a solution of 43 (187 mg, 1 mmol) in
pyridine (5 mL), after which the mixture was stirred at room
temperature for 12 h and concentrated under a vacuum. The
residue was dissolved in ethyl acetate (30 mL), which was
washed with saturated aqueous sodium bicarbonate (30 mL),
water (30 mL), and brine (30 mL), dried over sodium sulfate,
and concentrated. Next, a 4 N solution of hydrogen chloride
in ethyl acetate (0.5 mL) was added to a solution of the product
in ethyl acetate (10 mL). The precipitate was collected by
filtration and dried under a vacuum to give 22 as a slightly
(2H, s), 6.59 (1H, s), 6.61 (2H, d, J ) 9.6 Hz), 6.76 (2H, d, J )
9.6 Hz), 7.50-7.65 (4H, m), 7.89-7.99 (2H, m), 8.59 (2H, br
s), 8.74 (1H, s), 8.94 (1H, s), 10.83 (1H, s), 13.78 (1H, br s).
Anal. (C24H21N3O3‚HCl‚2H2O) C, H, N.
N -(4-Am in o-2-m e t h ylq u in olin -6-yl)-2-(4-a m in op h e -
n oxym eth yl)ben za m id e d ih yd r och lor id e (14): mp 237 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.60 (3H, s), 5.36 (2H, s), 6.61
(1H, s), 7.05 (2H, d, J ) 9.2 Hz), 7.28 (2H, d, J ) 9.2 Hz),
7.52-7.71 (4H, m), 7.96 (1H, s), 8.70 (2H, br s), 8.73 (1H, s),
10.24 (3H, br s), 10.89 (1H, s), 14.01 (1H, s). Anal. (C24H22N4O2‚
2HCl‚H2O) C, H, N.
N-(4-Am in o-2-m eth ylqu in olin -6-yl)-2-(4-tr iflu or om eth -
ylp h en oxym eth yl)ben za m id e d ih yd r och lor id e (15): mp
220 °C; 1H NMR (300 MHz, DMSO-d6) δ 2.60 (3H, s), 5.44 (2H,
s), 6.61 (1H, s), 7.13 (2H, d, J ) 8.7 Hz), 7.53-7.72 (6H, m),
7.95 (2H, s), 8.69 (2H, br s), 8.72 (1H, s). Anal. (C25H20F3N3O2‚
2HCl‚0.5H2O) C, H, N.
N-(4-Am in o-2-m eth ylqu in olin -6-yl)-2-(4-n itr op h en oxy-
m eth yl)ben za m id e h yd r och lor id e (16): mp 238 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.59 (3H, s), 5.50 (2H, s), 6.60
(1H, s), 7.16 (2H, d, J ) 9.15 Hz), 7.55-7.73 (4H, m), 7.93
(2H, s), 8.14 (2H, d, J ) 9.15 Hz), 8.69 (2H, br s), 8.71 (1H, s),
10.91 (1H, s), 13.95 (1H, s). Anal. (C24H20N4O4‚HCl‚H2O) C,
H, N.
N -(4-Am in o-2-m e t h ylq u in olin -6-yl)-2-(4-b r om op h e -
n oxym eth yl)ben za m id e h yd r och lor id e (17): mp 252 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.60 (3H, s), 5.34 (2H, s), 6.61
(1H, s), 6.91 (2H, d, J ) 8.9 Hz), 7.39 (2H, d, J ) 8.9 Hz),
7.52-7.70 (4H, m), 7.95 (2H, s), 8.66 (2H, br s), 8.72 (1H, s),
10.89 (1H, s), 14.01 (1H, s). Anal. (C24H20BrN3O2‚HCl‚1.5H2O)
C, H, N.
N -(4-Am in o-2-m e t h ylq u in olin -6-yl)-2-(4-ch lor op h e -
n oxym eth yl)ben za m id e h yd r och lor id e (18): mp 245 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.59 (3H, s), 5.33 (2H, s), 6.59
(3H, s), 6.95 (2H, d, J ) 8.9 Hz), 7.27 (2H, d, J ) 8.9 Hz),
7.49-7.70 (4H, m), 7.85-7.95 (2H, m), 8.67 (2H, br s), 8.73
(1H, s). Anal. (C24H20ClN3O2‚HCl‚0.7H2O) C, H, N.
N -(4-Am in o-2-m e t h ylq u in olin -6-yl)-2-(3-ch lor op h e -
n oxym eth yl)ben za m id e h yd r och lor id e (19): mp 147-149
°C; 1H NMR (300 MHz, DMSO-d6) δ 2.59 (3H, s), 5.36 (2H, s),
6.60 (1H, s), 6.90-6.99 (3H, m), 7.22-7.28 (1H, m), 7.50-7.71
(4H, m), 7.89-7.92 (2H, m), 8.61 (2H, br s), 8.73 (1H, s), 10.86
(1H, s), 13.85 (1H, br s). Anal. (C24H20Cl3O2‚HCl‚0.5H2O) C,
H, N.
1
yellow solid (216 mg, 50%): mp 284 °C; H NMR (300 MHz,
DMSO-d6) δ 2.66 (3H, s), 3.06 (3H, d, J ) 4.8 Hz), 5.34 (2H,
s), 6.65 (1H, s), 6.87-6.95 (3H, m), 7.21-7.26 (2H, m), 7.49-
7.70 (4H, m), 7.90 (2H, dd, J ) 9.2 and 1.8 Hz), 7.97 (1H, d, J
) 9.2 Hz), 8.83 (1H, s), 9.02 (1H, br s), 10.89 (1H, s), 14.15
(1H, s).. Anal. (C25H23N3O2‚HCl‚0.2H2O) C, H, N.
N-(4-Am in o-2-m eth ylqu in olin -6-yl)-N-m eth yl-2-(4-ch lo-
r op h en oxym eth yl)ben za m id e Hyd r och lor id e (26). 33a
(2.3 g, 10 mmol) was added to a suspension of sodium hydride
(440 mg, 11 mmol) in dimethylformamide (20 mL) at room
temperature, and the mixture was stirred for 30 min. Next,
iodomethane (747 µL, 12 mmol) was added dropwise to the
mixture, which was stirred for 2 h. The reaction mixture was
subsequently poured into water (100 mL), and the aqueous
solution was extracted with chloroform (100 mL). The organic
layer was washed with brine (50 mL), dried over sodium
sulfate, and concentrated under a vacuum. Then the residue
was chromatographed on silica gel eluted with chloroform to
give 4-methoxy-2-methyl-6-(N-methylacetamide)quinoline 44
as a pink solid (744 mg, 31%). A mixture of 44 (740 mg, 3.03
mmol) and ammonium acetate (3.5 g, 45.44 mmol) was heated
at 135 °C for 3.5 h. Water (3.5 mL) and 37% hydrochloric acid
(6 mL) were added to the mixture, which was heated at 90 °C
for 18 h. After cooling to room temperature, the mixture was
alkalinized with 4 N aqueous sodium hydroxide. The precipi-
tate was collected by filtration and washed with water to give
4-amino-2-methyl-6-methylaminoquinoline 45 as a slightly
N -(4-Am in o-2-m e t h ylq u in olin -6-yl)-2-(2-ch lor op h e -
n oxym eth yl)ben za m id e h yd r och lor id e (20): mp 165 °C;
1H NMR (300 MHz, DMSO-d6) δ 2.60 (3H, s), 5.44 (2H, s), 6.61
(1H, s), 6.93 (2H, d, J ) 8.9 Hz), 7.24-7.40 (3H, m), 7.54-
7.74 (4H, m), 7.96 (2H, s), 8.70 (2H, br s), 8.76 (1H, s), 10.90
(1H, s), 13.98 (1H, s). Anal. (C24H20ClN3O2‚HCl‚0.6H2O) C, H,
N.
N-(2-Met h ylq u in olin -6-yl)-2-(p h en oxym et h yl)b en za -
1
m id e h yd r och lor id e (21): mp 209 °C; H NMR (300 MHz,
DMSO-d6) δ 2.91 (3H, s), 5.33 (2H, s), 6.87-6.92 (3H, m), 7.18-
7.23 (2H, m), 7.52-7.68 (4H, m), 7.87 (1H, d, J ) 8.7 Hz),
8.18-8.25 (2H, m), 8.79 (1H, s), 8.92 (1H, d, J ) 8.7 Hz), 11.05
(1H, s). Anal. (C24H20N2O2‚HCl) C, H, N.
N-(4-Am in o-2-eth ylqu in olin -6-yl)-2-(4-ch lor op h en oxy-
m eth yl)ben za m id e h yd r och lor id e (24): mp 247-249 °C;
1H NMR (300 MHz, DMSO-d6) δ 1.32 (3H, t, J ) 7.7 Hz), 2.89
(2H, q, J ) 7.7 Hz), 5.34 (2H, s), 6.66 (1H, s), 6.96 (2H, d, J )
9.2 Hz), 7.26 (2H, d, J ) 8.8 Hz), 7.49-7.71 (4H, m), 7.95 (1H,