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Y. Zhang et al. / Bioorg. Med. Chem. 18 (2010) 2756–2766
was approximately 7. The white precipitate was formed, collected
by filtration, and dried under a vacuum for a 75% yield. 1H NMR
(400 MHz, DMSO) d 11.40 (s, 1H), 7.96 (d, J = 8.9, 1H), 7.42–7.35
(m, 2H), 7.13 (dd, J = 5.3, 27.9, 2H), 6.89 (dd, J = 2.4, 8.9, 1H), 6.23
(s, 1H), 6.13 (s, 2H), 3.85 (s, 3H). 13C NMR (101 MHz, DMSO) d
161.50, 148.77, 148.58, 147.79, 126.28, 121.36, 119.42, 112.82,
108.52, 107.32, 101.63, 55.30. MS (ESI) calculated for C17H13NO4
[M+H]+, 296.09; found, 296.07.
151.17, 148.32, 147.78, 134.11, 123.65, 122.56, 119.81, 116.79,
116.28, 109.14, 108.19, 107.51, 101.28, 62.83, 61.77, 55.67,
13.88. MS (ESI) calculated for C21H19NO6 [M+H]+, 382.13; found,
382.03.
5.14. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-4,5-
dimethoxyquinoline-3-carboxylate (24b)
The compound was prepared in a similar manner from 19b for a
77% yield. 1H NMR (400 MHz, CDCl3) d 7.70–7.57 (m, 2H), 7.18 (d,
J = 8.0, 1H), 6.84 (dd, J = 7.9, 16.0, 2H), 5.96 (s, 2H), 4.24 (q, J = 7.0,
2H), 3.98 (s, 3H), 3.96 (s, 3H), 1.17 (t, J = 7.1, 3H). 13C NMR
5.10. 2-(Benzo[d][1,3]dioxol-5-yl)-5-methoxyquinolin-4(1H)-
one (21b)
The compound was prepared in a manner similar to that of 21a
from 8 for an 80% yield. 1H NMR (400 MHz, DMSO) d 11.17 (br, 1H),
7.43 (dd, J = 25.9, 54.7, 4H), 7.09 (d, J = 8.2, 1H), 6.77 (s, 1H), 6.13
(s, 3H), 3.33 (s, 9H). 13C NMR (101 MHz, DMSO) d 177.95, 148.91,
147.81, 131.74, 121.50, 114.93, 108.54, 107.35, 104.28, 101.66,
55.73. MS (ESI) calculated for C17H13NO4 [M+H]+, 296.09; found,
295.97.
(101 MHz, CDCl3)
d 167.27, 162.79, 156.76, 155.77, 151.62,
148.56, 147.89, 133.46, 130.78, 122.76, 122.36, 121.82, 114.04,
109.17, 108.24, 106.17, 101.31, 64.15, 61.68, 56.33, 14.02. MS
(ESI) calculated for C21H19NO6 [M+H]+, 382.13; found, 382.03.
5.15. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-7-methoxy-4-
(methylamino)quinoline-3-carboxylate (25a)
5.11. 2-(Benzo[d][1,3]dioxol-5-yl)-7-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (22a)
The 4-chloro quinoline 19a (77 mg, 0.2 mmol) and 2 mL of
MeNH2 (2 M in THF) were refluxed at 85 °C for 30 min. After the
solution was cooled to rt, the solvent was evaporated. Then, to
the residue was added 2 mL of H2O. The precipitate was collected
by filtration. The compound was produced at a 63% yield. 1H
NMR (400 MHz, MeOD) d 8.09 (d, J = 9.2, 1H), 7.22 (s, 1H), 7.10
(d, J = 9.2, 1H), 6.91 (dd, J = 10.2, 20.3, 2H), 6.01 (s, 2H), 4.02 (q,
J = 7.1, 2H), 3.92 (s, 3H), 3.07 (s, 3H), 1.01 (t, J = 7.1, 3H). 13C NMR
Ethyl ester 7 (0.110 g, 0.3 mmol) underwent hydrolysis in 5 mL
of 1 N KOH at 75 °C overnight. The mixture was neutralized by
adding 1 N HCl (aqueous), followed by filtration to produce the
compound at a 55% yield. 1H NMR (400 MHz, DMSO) d 12.75 (s,
1H), 8.20 (d, J = 9.0, 1H), 7.24–6.99 (m, 5H), 6.13 (s, 2H), 3.89 (s,
3H). 13C NMR (101 MHz, DMSO) d 178.08, 165.30, 163.43, 156.61,
148.32, 146.59, 140.52, 128.70, 126.98, 122.51, 117.52, 116.15,
109.44, 107.79, 106.68, 101.44, 100.12, 55.78. MS (ESI) calculated
for C18H13NO6 [M+H]+, 340.08; found, 339.86.
(101 MHz, MeOD)
d 170.17, 161.59, 158.46, 150.74, 148.81,
147.82, 147.30, 134.96, 123.06, 121.76, 116.64, 112.40, 108.57,
107.27, 106.28, 105.58, 101.18, 60.97, 54.48, 30.94, 12.45. MS
(ESI) calculated for C21H20N2O5 [M+H]+, 381.15; found, 381.32.
5.12. 2-(Benzo[d][1,3]dioxol-5-yl)-7-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxamide (23a)
5.16. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-5-methoxy-4-
(methylamino)quinoline-3-carboxylate (25b)
N,N0-Carbonyldiimidazole (49 mg, 0.3 mmol) was added to the
corresponding carboxylic acid 22a (50 mg, 0.15 mmol) in 1 mL of
DMF. After being stirred at 65 °C for 2.5 h, the mixture was cooled
to rt and then poured into 5 mL of iced NH4OH. The solvent was
evaporated under a vacuum. To the residue was added 5 mL of
iced water, and precipitation was observed. The desired product
was collected by filtration at a 56% yield. 1H NMR (400 MHz,
DMSO) d 11.63 (s, 1H), 8.06 (d, J = 8.9, 1H), 7.12–6.89 (m, 6H),
6.12 (s, 2H), 3.85 (s, 3H). 13C NMR (101 MHz, DMSO) d 174.58,
167.18, 162.15, 149.85, 148.19, 146.80, 140.86, 128.99, 126.99,
122.45, 119.07, 116.10, 113.77, 108.92, 108.01, 101.46, 99.50,
55.44. MS (ESI) calculated for C18H14N2O5 [M+H]+, 339.10; found,
338.94.
The compound was prepared in a manner similar to that of 25a
from 19b for a 56% yield. 1H NMR (400 MHz, MeOD) d 7.55
(t, J = 8.2, 1H), 7.42 (d, J = 8.5, 1H), 6.94 (dd, J = 10.9, 28.2, 4H),
6.00 (d, J = 3.0, 2H), 4.07 (s, 3H), 4.01 (q, J = 7.2, 2H), 2.96 (s, 3H),
1.03 (t, J = 7.2, 2H). 13C NMR (101 MHz, MeOD) d 170.13, 158.15,
157.54, 152.34, 148.75, 147.78, 147.25, 134.45, 129.94, 121.61,
120.37, 109.65, 108.51, 107.24, 106.57, 104.97, 101.17, 61.12,
55.53, 30.48, 12.44. MS (ESI) calculated for C21H20N2O5 [M+H]+,
381.15; found, 380.98.
5.17. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-7-methoxyquinoline-
3-carboxylate (26a)
The corresponding 4-chloro quinoline 19a (93 mg, 0.24 mmol)
5.13. Ethyl 2-(benzo[d][1,3]dioxol-5-yl)-4,7-
in 5 mL of MeOH and 2 mL of THF was treated with H2 in the
dimethoxyquinoline-3-carboxylate (24a)
presence of Et3N (34 lL, 0.24 mmol) and 5 mol % of 5 wt % Pd/
C. After the mixture was stirred at rt overnight, the Pd/C was fil-
tered out though Celite. The filtrate was concentrated and then
purified by flash column chromatography to produce the com-
pound at a 65% yield. (SP1, 12S, SiO2, flow rate: 6 mL/min, gradi-
ent: 1–20% ethyl acetate in hexanes over 7 CV; 20% ethyl acetate
in hexanes over 10 CV). 1H NMR (400 MHz, CDCl3) d 8.55 (s, 1H),
7.76 (d, J = 9.0, 1H), 7.23–7.20 (m, 1H), 7.14 (d, J = 1.8, 1H), 7.06
(d, J = 8.0, 1H), 6.88 (d, J = 8.0, 1H), 6.00 (s, 2H), 4.23 (q, J = 7.2,
2H), 3.95 (s, 3H), 1.17 (t, J = 7.1, 3H). 13C NMR (101 MHz, CDCl3)
d 167.85, 162.77, 157.87, 148.25, 147.61, 139.21, 129.31, 123.01,
121.08, 120.81, 109.37, 108.15, 107.00, 106.71, 101.27, 61.48,
55.80, 13.96. MS (ESI) calculated for C20H17NO5 [M+H]+,
352.12; found, 352.02.
To fresh sodium methoxide solution, which was prepared
from Na (9 mg, 0.4 mmol) in 1 mL of MeOH, was added the cor-
responding 4-chloro quinoline 19a (77 mg, 0.2 mmol) in 0.5 mL
of dried tetrahydrofuran (THF). After the mixture was refluxed
at 85 °C for 30 min, the solvent was evaporated under a vacuum.
The obtained residue was purified by flash column chromatogra-
phy to produce the compound at a 44% yield (SP1, 12S, SiO2,
flow rate: 6 mL/min, gradient: 1–20% ethyl acetate in hexanes
over 7 CV; 20% ethyl acetate in hexanes over 10 CV). 1H NMR
(400 MHz, CDCl3) d 8.06 (d, J = 9.2, 1H), 7.49 (s, 1H), 7.20 (ddd,
J = 1.7, 8.2, 23.1, 3H), 6.91 (d, J = 8.0, 1H), 6.04 (s, 2H), 4.27 (q,
J = 7.2, 2H), 4.16 (s, 3H), 3.98 (s, 3H), 1.20 (t, J = 7.2, 3H). 13C
NMR (101 MHz, CDCl3)
d 167.60, 162.08, 161.98, 157.82,