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Y.-P. Li et al. / European Journal of Medicinal Chemistry 46 (2011) 1572e1581
5.1.2. 1-Azabenzanthrone (3a)
2.74 (q, 4H, J ¼ 7.1), 1.15 (t, 6H, J ¼ 7.1). 13C NMR (MeOD, 100 MHz)
To a mixture of anhydrous aluminum chloride (75 g, 0.56 mol)
and sodium chloride (15 g, 0.26 mol) was slowly added phenyl-
ethylphthalimide 1 (53 g, 0.2 mol) at 180 ꢀC for 30 min. The reaction
was allowed to continue at 220e230 ꢀC for 2 h. The product was
cooled, finely ground and poured slowly into concentrated sulfuric
acid (550 mL) at 90 ꢀC. The mixture was stirred and heated at
230e240 ꢀC for 2 h. After being cooled, the solution was poured
into ice. Sodium hydroxide was added until pH ¼ 3 was obtained,
and the resultant precipitate was filtered off and washed in turn
with dilute aqueous sodium hydroxide and water to give the crude
product 18g, which was extracted with acetic acid. The extract was
condensed under reduced pressure, and the resultant precipitate
was washed off, dried, and sublimed at 130e140 ꢀC at a pressure of
1 mm mercury to give the product 3a (15.3 g, 32%) as light-yellow
solid, mp 182e183 ꢀC (lit [27,28]. 181e183 ꢀC); 1H NMR (CDCl3,
d
184.7, 151.8, 141.8, 137.9, 135.1, 132.3, 131.1, 130.8, 130.4, 129.5,
129.4, 128.3, 128.1, 126.2, 125.6, 124.0, 68.4, 62.0, 52.4 (2C), 11.7 (2C).
m/z calcd for C22H22N2O2 346.17, ESI-MS m/z: 347.2 [M þ H]þ.
5.2.3. 3-(2-(Pyrrolidin-1-yl)ethoxy)-7H-dibenzo[de,h]quinolin-7-
one (5e)
Compound 5e was obtained with a yield of 36% (60 mg). Purity:
98.2% (by HPLC). 1H NMR (CDCl3, 300 MHz)
d
8.75 (d, 1H, J ¼ 7.7 Hz),
8.69 (d, 1H, J ¼ 7.2 Hz), 8.55 (d, 1H, J ¼ 7.9 Hz), 8.38 (d, 1H,
J ¼ 7.9 Hz), 8.32 (s, 1H), 7.89 (t, 1H, J ¼ 7.8 Hz), 7.77 (t, 1H, J ¼ 7.2 Hz),
7.57 (t, 1H, J ¼ 7.1 Hz), 4.50 (t, 2H, J ¼ 5.9 Hz), 3.13 (t, 2H, J ¼ 5.9 Hz),
2.77 (m, 4H), 1.87 (m, 4H). 13C NMR (DMSO-d6, 100 MHz)
d 182.5,
150.1, 140.4, 136.4, 134.2, 130.7, 130.2, 129.9, 129.4, 128.1, 127.9,
126.9, 126.6, 126.0, 124.2, 122.4, 68.5, 54.1 (2C), 47.5, 23.3 (2C). m/z
calcd for C22H20N2O2 344.15, ESI-MS m/z: 345.2[M þ H]þ.
300 MHz)
d
8.90 (d, 1H, J ¼ 7.9 Hz), 8.77 (d, 1H, J ¼ 5.6 Hz), 8.66 (d,
1H, J ¼ 7.2 Hz), 8.41 (d, 1H, J ¼ 7.8 Hz), 8.15 (d, 1H, J ¼ 8.2 Hz), 7.90 (t,
1H, J ¼ 7.3 Hz), 7.80 (t, 1H, J ¼ 7.3 Hz), 7.74 (d, 1H, J ¼ 5.8 Hz), 7.64 (t,
1H, J ¼ 7.7 Hz); m/z calcd for C16H9NO 231.07, ESI-MS m/z: 232.1
[M þ H]þ.
5.2.4. 3-(2-(Piperidin-1-yl)ethoxy)-7H-dibenzo[de,h]quinolin-7-
one (5f)
Compound 5f was obtained with a yield of 17% (30 mg). Purity:
99.5% (by HPLC). 1H NMR (CDCl3, 300 MHz)
d
8.76 (d, 1H, J ¼ 7.3 Hz),
8.69 (d,1H, J ¼ 7.3 Hz), 8.53 (d,1H, J ¼ 8.3 Hz), 8.38 (d,1H, J ¼ 7.8 Hz),
8.33 (s, 1H), 7.90 (t, 1H, J ¼ 7.8 Hz), 7.77 (t, 1H, J ¼ 7.3 Hz), 7.57 (t, 1H,
J ¼ 7.2 Hz), 4.51 (br, 2H, J ¼ 5.9 Hz), 3.03 (br, 2H, J ¼ 5.9 Hz), 2.66 (m,
4H), 1.68 (m, 4H), 1.50 (m, 4H). 13C NMR (DMSO-d6, 100 MHz)
5.1.3. 3-Bromo-7H-dibenzo[de,h]quinolin-7-one (4)
To a solution of bromine (1.8 mL) in nitrobenzene (33 mL) was
added compound 3a (1.1 g, 4.8 mmol) followed by one crystal of
iodine. The mixture was heated under reflux for 5 h. After cooling
and filtration, the pure compound 4 (1.35 g, 90%) was obtained [29].
d
182.5, 149.2, 140.6, 136.2, 134.4, 130.8, 130.5, 130.1, 129.7, 128.1,
128.0, 127.0, 126.5, 126.3, 124.3, 122.4, 62.4, 60.9 (2C), 47.7, 20.6, 19.4
1H NMR (CDCl3, 300 MHz)
d
8.76 (d, 1H, J ¼ 7.6 Hz), 8.69 (d, 1H,
(2C). m/z calcd for C23H22N2O2 358.17, ESI-MS m/z: 359.2 [M þ H]þ.
J ¼ 7.3 Hz), 8.57 (d, 1H, J ¼ 8.3 Hz), 8.38 (d, 1H, J ¼ 7.8 Hz), 8.30 (s,
1H), 7.90 (t, 1H, J ¼ 7.8 Hz), 7.77 (t, 1H, J ¼ 7.3 Hz), 7.57 (t, 1H,
J ¼ 7.8 Hz).
5.3. General procedure for preparation of quaternary methiodide
salts 6ce6f
5.2. General procedure for the synthesis of compounds 5ce5f
A mixture containing compound 5c (0.04 g), iodomethane
(0.5 mL), and chloroform (3 mL) was stirred at 25 ꢀC for 24 h. An
orange-yellow solid was collected after filtration and wash with
chloroform, and then dried in vacuum. The quaternary methiodide
salt 6c was obtained in a yield of 93% as an amorphous powder.
The target products 5ce5f were synthesized with the following
general procedure. A solution of compound 4 (0.5 mmol) in 2 mL
DMF, the corresponding alcohol ROH (1 mmol), 18-crown-6
(0.05 mmol), and finely ground potassium hydroxide (2 mmol)
were mixed, and the resulting mixture was stirred at 80 ꢀC for 6 h.
Then the reaction mixture was cooled to room temperature, and
poured into 5 mL of acidified water (pH 2). It was then extracted
with chloroform, and the organic phase was dried over anhydrous
Na2SO4 and evaporated to dryness under reduced pressure. The
residue was purified with flash column chromatography eluting
with CHCl3/CH3OH (100:3e100:5) to give a yellow solid.
Purity: 96% (by HPLC). 1H NMR (DMSO-d6, 300 MHz)
d 8.76 (d, 1H,
J ¼ 7.9 Hz), 8.65 (d, 1H, J ¼ 7.2 Hz), 8.63 (d, 1H, J ¼ 8.3 Hz), 8.60 (s,
1H), 8.28 (d, 1H, J ¼ 7.7 Hz), 8.12 (t, 1H, J ¼ 7.8 Hz), 7.91 (t, 1H,
J ¼ 7.6 Hz), 7.70 (t, 1H, J ¼ 7.9 Hz), 4.92 (br, 2H), 4.01 (br, 2H), 3.27 (s,
9H). 13C NMR (DMSO-d6, 125 MHz)
d 185.0, 151.0, 140.6, 138.1, 135.6,
131.7, 131.6, 131.4, 131.1, 130.1, 129.3, 128.6, 128.5, 126.8, 126.0, 124.5,
67.1, 65.0, 55.0 (3C). m/z calcd for C21H21N2O2 333.16, ESI-MS m/z:
333.2 [M]þ.
Compound 6d: Purity: 97.6% (by HPLC). 1H NMR (DMSO-d6,
5.2.1. 3-(2-(Dimethylamino)ethoxy)-7H-dibenzo[de,h]quinolin-7-
one (5c)
300 MHz)
d
8.75 (d, 1H, J ¼ 7.4 Hz), 8.64 (d, 1H, J ¼ 7.3 Hz), 8.60 (s,
1H), 8.58 (d, 1H, J ¼ 7.8 Hz), 8.28 (d, 1H, J ¼ 7.8 Hz), 8.13 (t, 1H,
J ¼ 7.8 Hz), 7.91 (t, 1H, J ¼ 7.4 Hz), 7.70 (t, 1H, J ¼ 7.9 Hz), 4.88 (t, 2H,
J ¼ 4.1 Hz), 3.96 (t, 2H, J ¼ 4.1 Hz), 3.53 (q, 4H, J ¼ 7.2 Hz), 3.15 (s,
Compound 5c was obtained with a yield of 26% (40 mg). Purity:
99.0% (by HPLC). 1H NMR (CDCl3, 300 MHz)
d
8.76 (d,1H, J ¼ 7.9 Hz,),
8.69 (d, 1H, J ¼ 7.3 Hz), 8.55 (d, 1H, J ¼ 8.3 Hz), 8.38 (d, 1H,
J ¼ 7.9 Hz), 8.33 (s, 1H), 7.89 (t, 1H, J ¼ 7.9 Hz), 7.77 (t, 1H, J ¼ 7.9 Hz),
7.57 (t, 1H, J ¼ 7.8 Hz), 4.45 (t, 2H, J ¼ 5.6 Hz), 2.96 (t, 2H, J ¼ 5.6 Hz),
3H), 1.34 (t, 6H, J ¼ 7.2 Hz). 13C NMR (100 MHz, DMSO-d6)
d 182.4,
149.2, 140.6, 136.2, 134.4, 130.8, 130.5, 130.1, 129.7, 128.0, 127.9,
127.0, 126.4, 126.3, 124.3,122.4, 62.6, 59.0, 56.5(2C), 47.3, 7.7(2C). m/
z calcd for C23H25N2O2 361.19, ESI-MS m/z: 361.2 [M]þ.
2.45 (s, 6H). 13C NMR (DMSO-d6, 100 MHz)
d 182.5, 150.1, 140.0,
136.4, 134.3, 130.7, 130.3, 130.0, 129.5, 128.2, 127.9, 127.0, 126.6,
126.1, 124.2, 122.4, 67.4, 57.6, 45.5 (2C). m/z calcd for C20H18N2O2
318.14, ESI-MS m/z: 319.1 [M þ H]þ.
Compound 6e: Purity: 97.7% (by HPLC). 1H NMR (DMSO-d6,
300 MHz)
d
8.75 (d, 1H, J ¼ 7.9 Hz), 8.66e8.60 (m, 3H), 8.28 (d, 1H,
J ¼ 7.8 Hz), 8.12 (t, 1H, J ¼ 7.8 Hz), 7.91 (t, 1H, J ¼ 7.6 Hz), 7.70 (t, 1H,
J ¼ 7.7 Hz), 4.92 (t, 2H, J ¼ 4.1 Hz), 4.06 (t, 2H, J ¼ 4.1 Hz), 3.72e3.65
(br, 4H), 3.21 (s, 3H), 2.12e2.21 (m, 4H). 13C NMR (100 MHz, MeOD)
5.2.2. 3-(2-(Diethylamino)ethoxy)-7H-dibenzo[de,h]quinolin-7-
one (5d)
d
184.9, 150.8, 143.2, 137.9, 135.4, 132.6, 131.6, 131.4, 130.9, 129.8,
Compound 5d was obtained with a yield of 27% (45 mg). Purity:
129.2, 128.3 (2C), 126.6, 125.8, 124.3, 66.7, 64.8, 64.3, 49.8 (2C), 22.6
(2C). m/z calcd for C23H23N2O2 359.18, ESI-MS m/z: 359.2 [M]þ.
Compound 6f: Purity: 96% (by HPLC). 1H NMR (DMSO-d6,
100% (by HPLC). 1H NMR (CDCl3, 300 MHz)
d
8.76 (d, 1H, J ¼ 7.9 Hz),
8.69 (d, 1H, J ¼ 7.3 Hz), 8.54 (d, 1H, J ¼ 8.3 Hz), 8.38 (d, 1H,
J ¼ 7.9 Hz), 8.33 (s, 1H), 7.90 (t, 1H, J ¼ 7.7 Hz), 7.77 (t, 1H, J ¼ 7.9 Hz),
7.57 (t, 1H, J ¼ 8.1 Hz), 4.42 (t, 2H, J ¼ 5.9 Hz), 3.09 (t, 2H, J ¼ 5.9 Hz),
300 MHz)
d
8.75 (d, 1H, J ¼ 7.8 Hz), 8.66e8.60 (m, 3H), 8.28 (d, 1H,
J ¼ 7.8 Hz), 8.12 (t, 1H, J ¼ 7.4 Hz), 7.91 (t, 1H, J ¼ 7.6 Hz), 7.70 (t, 1H,