1H-Imidazo[4,5-c]quinolines That Induce Interferon
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 10 3489
and concentrated in vacuo to yield 17.7 g of unpurified product
as a tan solid. Recrystallization from tert-butyl methyl ether
gave 10.4 g (55%) of analytically pure product as tan crystals:
(50 mL) was added 25% methanolic sodium methoxide (11.5
g, 53.2 mmol), and the solution was refluxed for 4 h. The
solution was then concentrated in vacuo, and the residue was
mixed with water. The oily residue solidified rapidly and was
collected by vacuum filtration, washed with water, and par-
tially dried. The solid was dissolved in ether, dried over
magnesium sulfate, and filtered. The resulting ether solution
was diluted with hexanes, and the total volume was reduced
under vacuum until crystallization was initiated. After stand-
ing at ambient temperature for 15-30 min, the solid was
collected by vacuum filtration, washed with hexanes, and dried
to give 1.4 g (68%) of product as a light-yellow solid: mp 111-
114 °C; 1H NMR (300 MHz, CDCl3) δ 8.03-7.97 (m, 2 H), 7.81
(s, 1 H), 7.59 (t, J ) 8.4 Hz, 1 H), 7.46 (t, J ) 7.2 Hz, 1 H),
4.31 (d, J ) 7.4 Hz, 2 H), 4.26 (s, 3 H), 2.35 (m, 1 H), 1.03 (d,
J ) 6.7 Hz, 6 H). Anal. Calcd for C15H17N3O: C, 70.56; H, 6.71;
N, 16.46. Found: C, 70.37; H, 6.89; N, 16.51.
1
mp 108-111 °C; H NMR (300 MHz, CDCl3) δ 9.27 (s, 1 H),
8.25 (dd, J ) 1.6, 8.4 Hz, 1 H), 8.09 (dd, J ) 1.1, 7.9 Hz, 1 H),
7.63 (m, 2 H), 4.29 (d, J ) 7.6 Hz, 2 H), 2.85 (s, 3 H), 2.40 (m,
1 H), 1.04 (d, J ) 6.7 Hz, 6 H). Anal. Calcd for C15H17N3S: C,
66.39; H, 6.31; N, 15.48. Found: C, 65.83; H, 6.26; N. 15.25.
2-Methanesulfonyl-1-(2-methylpropyl)-1H-imidazo[4,5-
c]quinoline (19). A solution of KMnO4 (1.0 g, 6.3 mmol) in
H2O (35 mL) was added dropwise to a stirred solution of 18
(1.0 g, 3.7 mmol) in glacial acetic acid (15 mL) at ambient
temperature. A slight exotherm was observed, and the mixture
turned dark-brown. After the mixture was stirred at ambient
temperature for 3 h, TLC analysis (10% methanol/ethyl
acetate) showed no remaining starting material. To the dark
mixture was added solid NaHSO3 until the mixture was
decolorized. The mixture was diluted with water, and the
product was extracted into dichloromethane. The combined
extracts were washed successively with water and saturated
aqueous NaHCO3, dried over magnesium sulfate, filtered, and
concentrated in vacuo to give 0.9 g (80%) of unpurified product
as a colorless solid. Recrystallization from ether gave an
analytically pure sample of 19 as a colorless solid: mp 134-
136 °C; 1H NMR (300 MHz, CDCl3) δ 9.34 (s, 1 H), 8.33 (dd, J
) 1.2, 8.4 Hz, 1 H), 8.21 (dd, J ) 0.8, 8.1 Hz, 1 H), 7.79 (ddd,
J ) 1.4, 7.1, 8.3 Hz, 1 H), 7.72 (ddd, J ) 1.5, 7.0, 8.3 Hz, 1 H),
4.85 (d, J ) 7.7 Hz, 2 H), 3.63 (s, 3 H), 2.51 (m, 1 H), 1.05 (d,
J ) 6.7 Hz, 6 H). Anal. Calcd for C15H17N3O2S: C, 59.39; H,
5.65; N, 13.85. Found: C, 59.26; H, 5.57; N, 13.73.
1-(2-Methylpropyl)-2-phenoxy-1H-imidazo[4,5-c]quin-
oline (20). A solution of 19 (3.0 g, 9.9 mmol) and potassium
phenoxide (1.6 g, 12 mmol) in N,N-dimethylformamide (50 mL)
was refluxed for 1 h. The solution was cooled to ambient
temperature and diluted with a large volume of water to
precipitate the product. The solid was collected by filtration,
washed with water, and dried to yield 2.3 g (73%) of unpurified
product that was recrystallized from ether to yield an analyti-
cally pure sample as a colorless solid: mp 111-112 °C; 1H
NMR (300 MHz, CDCl3) δ 9.17 (s, 1 H), 8.24 (dd, J ) 2.2, 7.4
Hz, 1 H), 8.10 (dd, J ) 2.2, 7.4 Hz, 1 H), 7.69-7.59 (m, 4 H),
7.51-7.39 (m, 2 H), 7.31 (m, 1 H), 4.41 (d, J ) 7.6 Hz, 2 H),
2.46 (m, 1 H), 1.12 (d, J ) 6.7 Hz, 6 H). Anal. Calcd for
C20H19N3O: C, 75.69; H, 6.03; N, 13.24. Found: C, 75.40; H,
6.04; N, 13.16.
1-(2-Methylpropyl)-2-phenoxy-1H-imidazo[4,5-c]quin-
olin-4-amine (59). A solution of 20 (1.2 g, 3.8 mmol) in methyl
acetate (15 mL) was refluxed with peracetic acid (32% active
oxygen, 1.1 g, 4.5 mmol) for 1 h. Additional peracetic acid (330
mg, 1.4 mmol) was added, and heating was continued for an
additional 4 h. The mixture stood at ambient temperature
overnight. The resulting solid was collected by vacuum filtra-
tion to give 1.2 g (95%) of unpurified 21 as a white powder.
The unpurified N-oxide (1.2 g, 3.6 mmol) and concentrated
NH4OH (10 mL) were added to dichloromethane (20 mL), and
the mixture was stirred vigorously at ambient temperature.
p-Toluenesulfonyl chloride (0.76 g, 4.0 mmol) dissolved in
dichloromethane (10 mL) was added dropwise to the vigorously
stirred mixture at ambient temperature. An exotherm was
observed, and the mixture turned yellow. The mixture was
stirred at ambient temperature for 4 h and diluted with
dichloromethane (50 mL). The organic phase was separated,
washed with water, dried over magnesium sulfate, filtered,
and concentrated in vacuo to give 1.1 g (92%) of the unpurified
product that was recrystallized from toluene to give 0.9 g (75%)
of product. A second recrystallization from methanol provided
analytically pure material as pale-yellow crystals: mp 184-
186 °C; 1H NMR (300 MHz, CDCl3) δ 7.89 (dd, J ) 1.0, 8.2
Hz, 1 H), 7.81 (dd, J ) 0.9, 8.4 Hz, 1 H), 7.53-7.21 (m, 7 H),
5.27 (br s, 2 H), 4.31 (d, J ) 7.6 Hz, 2 H), 2.40 (m, 1 H), 1.07
(d, J ) 6.7 Hz, 6 H). Anal. Calcd for C20H20N4O: C, 72.27; H,
6.06; N, 16.85. Found: C, 72.45; H, 6.10; N, 16.90.
1,5-Dihydro-1-(2-methylpropyl)-4H-imidazo[4,5-c]quin-
olin-4-one (63). A solution of 7 (20.0 g, 77.0 mmol) in 6 N
HCl (200 mL) was refluxed for 1 h and cooled to ambient
temperature. A small amount of dark, gummy material
separated and was removed by vacuum filtration. The filtrate
was diluted with water (500 mL) and made basic with
concentrated aqueous NH4OH to precipitate the product. The
solid was collected by vacuum filtration, washed successively
with water, ethanol, and ethyl acetate, and dried to give 16.0
g of unpurified product as an off-white solid. Recrystallization
from methanol gave 13.3 g (72%) of analytically pure product:
1
mp >300 °C; H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1 H),
8.13 (s, 1 H), 7.96 (d, J ) 8.1 Hz, 1 H), 7.51-7.43 (m, 2 H),
7.29 (m, 1 H), 4.38 (d, J ) 7.5 Hz, 2 H), 2.13 (m, 1 H), 0.91 (d,
J ) 6.6 Hz, 6 H). Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27;
N, 17.41. Found: C, 69.70; H, 6.2; N, 17.4.
4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-
8-ol (72). A mixture of 71 (3.8 g, 14.1 mmol) and 48%
hydrobromic acid (50 mL) was refluxed for approximately 18
h. The cooled solution was diluted with water and neutralized
with concentrated ammonium hydroxide. The precipitated
product was collected by vacuum filtration, washed with water,
and dried. The solid was dissolved in dilute aqueous hydro-
chloric acid, and the resulting solution was treated with
charcoal and filtered through a filter aid pad. The filtrate was
treated with saturated aqueous sodium bicarbonate to pre-
cipitate a solid that was collected by vacuum filtration. The
solid was washed thoroughly with water and dried to yield
3.1 g (85%) of product as a colorless solid: mp 202-205 °C;
1H NMR (300 MHz, DMSO-d6) δ 9.48 (br s, 1 H), 8.03 (s, 1 H),
7.81 (d, J ) 8.8 Hz, 1 H), 6.96 (s, 1 H), 6.80 (d, J ) 8.8 Hz, 1
H), 6.43 (s, 2 H), 4.31 (d, J ) 7.4 Hz, 2 H), 2.15 (m, 1 H), 0.91
(d, J ) 6.6 Hz, 6 H). Anal. Calcd for C14H16N4O‚1.3H2O: C,
60.11; H, 6.70; N, 20.03. Found: C, 59.82; H, 6.72; N, 20.03.
8-Bromo-1-(2-methylpropyl)-1H-imidazo[4,5-c]quino-
lin-4-amine (74). Bromine (10.0 g, 62.4 mmol) was added in
a slow stream to a suspension of 26 (10.0 g, 41.6 mmol) in
acetic acid at ambient temperature, and the mixture was
stirred for 18 h. The resulting solid was collected by vacuum
filtration, pressed partially dry, and then suspended in a
saturated aqueous sodium bisulfite solution. The mixture was
made strongly basic with aqueous sodium hydroxide. The
resulting colorless solid was collected by vacuum filtration,
washed thoroughly with water, and dried. The solid was added
to methanol, and the mixture was stirred at ambient temper-
ature for 18-24 h and collected by vacuum filtration. The solid
was recrystallized from N,N-dimethylformamide to give 3.5 g
(26%) of analytically pure product: mp 221-223 °C; 1H NMR
(300 MHz, DMSO-d6) δ 8.24 (s, 1 H), 8.06 (s, 1 H), 7.56 (s, 1
H), 7.55 (s, 1 H), 6.81 (br s, 2 H), 4.41 (d, J ) 7.3 Hz, 2 H),
2.07-2.21 (m, 1 H), 0.94 (d, J ) 6.7 Hz, 6 H). Anal. Calcd for
C14H15BrN4: C, 52.68; H, 4.74; N, 17.55. Found: C, 52.78; H,
4.73; N, 18.08.
1-(2-Methylpropyl)-8-nitro-1H-imidazo[4,5-c]quinolin-
4-amine (75). A solution of 26 (24.0 g, 0.1 mol) in sulfuric
acid (150 mL) was prepared by gradual addition of 26 to the
sulfuric acid at 35 °C or less. To the solution was added
4-Methoxy-1-(2-methylpropyl)-1H-imidazo[4,5-c]quin-
oline (61). To a solution of 7 (2.1 g, 8.1 mmol) in methanol