Vol. 22, No. 9, 2011
Rojas and Kouznetsov
1779
agitation. Subsequently, 1.00 g (4.52 mmol) of quinoline
diamines (8a or 8b) in acetone were added dropwise to
the above solution and the reaction mass was stirred
for 7 h according to TLC analysis. Without any further
purification process, over the resulting mass, triethylamine
(3.00 g, 29.60 mmol) and then a solution of chloroacethyl
chloride in anhydrous acetone (1.10 g, 9.30 mmol) was
added during 30 min at 0 ºC. The reaction mass was
heated to room temperature and stirred over a 24 h period.
Resulting yellowish mass was neutralized with 30 mL
of sodium bicarbonate 10%, and extracted with ethyl
acetate (2 × 30 mL). The organic layer was dried over
Na2SO4 and concentrated under vacuum. Finally, hybrids
13, 14 were purified by flash column chromatography
using (20:1) ethyl acetate and methanol mixtures as
eluents. Physicochemical characteristics of the obtained
compounds are given in Table 2.
temperature was adjusted to 60 ºC and kept constant over
a 5 h period. Finally, the reaction mass was allowed to
cool and neutralized with sodium bicarbonate (1 mol L-1).
The coloured precipitate was filtered, washed with cold
water, and air dried. Hybrids 15-22 were finally purified by
flash column chromatography using (20:1) ethyl acetate-
methanol mixtures as mobile phase and TLC control (Rf).
Physicochemical characteristics of the obtained compounds
are given in Table 2.
1-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-1H-pyrrol-
2,5-dione (15): 1H NMR (400 MHz, DMSO-d6) d 8.42 (d,
1H, J 5.4 Hz, 2-H), 8.08 (d, 1H, J 9.0 Hz, 5-H), 7.79 (d,
1H, J 2.2 Hz, 8-H), 7.47 (m, 1H, NH), 7.44 (dd, 1H, J 9.0,
2.2 Hz, 6-H), 7.02 (s, 2H, 3’(4’)-H), 6.55 (d, 1H, J 5.5 Hz,
3-H), 3.65 (t, 2H, J 6.2 Hz, 2’-H), 3.48 (q, 2H, J 6.1 Hz,
13
1’-H); C NMR (100 MHz, DMSO-d6) d 170.5, 154.5,
152.7, 149.3, 134.9, 135.8, 129.4, 124.7, 121.6, 117.5,
99.2, 46.9, 50.5.
3-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-2-imino-
thiazolidin-4-one (13): H NMR (400 MHz, DMSO-d6)
1
d 8.42 (d, 1H, J 5.3 Hz, 2-H), 8.15 (d, 1H, J 9.0 Hz, 5-H),
7.79 (d, 1H, J 1.3 Hz, 8-H), 7.46 (d, 1H, J 8.9 Hz, 6-H),
6.58 (d, 1H, J 5.3 Hz, 3-H), 5.13 (d, 1H, J 10.9 Hz, C=NH),
4.37 (s, 2H, CH2), 3.61 (t, 2H, J 6.7 Hz, CH2), 3.48-3.43
(m, 2H, CH2), 7.45-7.49 (m, 1H, NH); 13C NMR (100 MHz,
DMSO-d6), d 171.8, 158.3, 154.5, 152.3, 149.3, 134.8,
129.2, 124.4, 121.7, 117.5, 99.2, 50.1, 46.5, 30.2.
1-(3-((7-Chloroquinolin-4-yl)amino)propyl)-
1H-pyrrol-2,5-dione (16): 1H NMR (400 MHz, DMSO-d6)
d 8.39 (d, 1H, J 5.4 Hz, 2-H), 7.98 (d, 1H, J 9.0 Hz, 5-H),
7.69 (d, 1H, J 2.1 Hz, 8-H), 7.46 (m, 1H, NH), 7.46 (dd,
1H, J 9.0, 2.1 Hz, 6-H), 7.11 (s, 2H, 4’(5’)-H), 6.55 (d,
1H, J 5.4 Hz, 3-H), 3.65 (t, 2H, J 6.2 Hz, 3’-H,), 3.48 (q,
13
2H, J 6.1 Hz, 1’-H), 2.03-1.99 (m, 2H, 2’-H); C NMR
(100 MHz, DMSO-d6) d 169.5, 155.3, 153.4, 148.7, 134.9,
3-(3-((7-Chloroquinolin-4-yl)amino)propyl)-2-imino-
thiazolidin-4-one (14): H NMR (400 MHz, DMSO-d6)
136.1, 130.1, 124.8, 121.5, 117.3, 99.0, 40.9, 39.0, 25.9.
1
d 8.42 (d, 1H, J 5.3 Hz, 2-H), 8.15 (d, 1H, J 9.0 Hz, 5-H),
7.79 (d, 1H, J 1.3 Hz, 8-H), 7.46 (d, 1H, J 8.9 Hz, 6-H), 6.58
(d, 1H, J 5.3 Hz, 3-H), 5.13 (d, 1H, J 10.9 Hz, C=NH), 4.37
(s, 2H, CH2), 3.61 (t, 2H, J 6.7 Hz, CH2), 3.48-3.43 (m, 2H,
CH2), 2.02 (m, 2H, CH2), 7.45-7.49 (m, 1H, NH); 13C NMR
(100 MHz, DMSO-d6) d 172.1, 158.5, 154.9, 152.7, 150.3,
135.1, 129.4, 124.8, 121.7, 118.0, 99.0, 40.9, 38.5, 26.2.
1-(2-((7-Chloroquinolin-4-yl)amino)ethyl)-3-methyl-
1H-pyrrol-2,5-dione (17): 1H NMR (400 MHz, DMSO-d6)
d 8.44 (d, 1H, J 5.4 Hz, 2-H), 8.06 (d, 1H, J 9.1 Hz, 5-H),
7.79 (d, 1H, J 2.3 Hz, 8-H), 7.45 (dd, 1H, J 2.2 and 9.0 Hz,
6-H), 7.36 (t, 1H, J 7.0 Hz, NH), 6.56 (d, 1H, J 5.5 Hz,
3-H), 5.76 (s, 1H, 3’-H,), 4.03 (q, 2H, J 7.1 Hz, 2’-H), 3.44
(m, 2H, 1’-H), 1.59 (s, 3H, CH3); 13C NMR (100 MHz,
DMSO-d6) d 173.9, 169.8, 154.5, 153.3, 150.1, 145.6,
135.1, 129.3, 128.6, 124.7, 121.5, 118.0, 98.91, 46.6,
51.1, 10.9.
General procedure for synthesis of chloroquine and
1H-pyrrol-2,5-dione hybrids (15-22)
1.0 g (4.24 mmol) of quinoline diamines (8a or 8b)
was dissolved in 5.0 mL of anhydrous dichloromethane
under vigorous agitation. Then, a solution of anhydride
(9-11) (0.7 g, 4.24 mmol) in dichloromethane was added
dropwise to the above solution for 30 min at 0 °C, stirring
the white precipitate formed for 2 h. Solvent excess
was distilled under reduced pressure, and the remaining
solid was filtered and washed with diethyl ether. Without
any further purification process, the obtained amic acid
15a-22a was mixed with 0.05 g (0.61 mmol) of sodium
acetate and dissolved in 1.0 mL acetic anhydride. Reaction
1-(3-((7-Chloroquinolin-4-yl)amino)propyl)-3-methyl-
1H-pyrrol-2,5-dione (18): 1H NMR (400 MHz, DMSO-d6)
d 8.39 (d, 1H, J 5.4 Hz, 2-H), 8.16 (d, 1H, J 9.1 Hz, 5-H),
7.79 (d, 1H, J 2.3 Hz, 8-H), 7.45 (dd, 1H, J 2.1 and 9.1 Hz,
6-H), 7.38 (t, 1H, J 7.0 Hz, NH), 6.59 (d, 1H, J 5.4 Hz, 3-H),
5.78 (s, 1H, 4’-H), 4.13 (q, 2H, J 7.1 Hz, 3’-H), 3.46 (m,
2H, 1’-H), 2.02 (m, 2H, 2’-H) 1.61 (s, 3H, CH3); 13C NMR
(100 MHz, DMSO-d6) d 174.0, 170.1, 154.5, 152.8, 149.3,
145.4, 134.7, 128.8, 127.8, 124.8, 121.6, 117.5, 99.1, 41.3,
39.4, 26.1, 10.9.