180
C. Lu et al. / European Journal of Medicinal Chemistry 79 (2014) 173e183
were added. The reaction was stirred at reflux to completeness. The
warm mixture was filtered through a Celite patch and the
remaining solids were washed several times with warm EtOH. The
filtrates were combined and concentrated [33]. The residue was
purified by preparative thin layer chromatography on silica gel
(dichloromethane/methanol, 10/1) to give the product as a brown
solid (13 mg, 0.05 mmol, 36%), mp 190.3e192.0 ꢀC. 1H NMR
4.1.15. Ethyl 2-(4-ethoxybutyl)-6-nitro-4-oxo-1,4-
dihydroquinoline-3-carboxylate (20)
The title compound was prepared according to procedure B
from 34 (1.7 g, 7.87 mmol), sodium hydride (50e65% w/w, 360 mg,
7.50 mmol) and 6-nitro-1H-benzo[d][1,3]oxazine-2,4-dione (1.57 g,
7.55 mmol) After column chromatography on silica gel (n-hexane/
ethyl acetate, 1.2/1) and recrystallization from ethyl acetate the
product was isolated as a yellow solid (2.6 g, 7.18 mmol, 95%), mp
(500 MHz, MeOH-d4):
d
¼ 0.89 (t, J ¼ 7.0 Hz, 3H), 1.28e1.48 (m, 8H),
1.76 (quint, J ¼ 7.5 Hz, 2H), 2.83 (t, J ¼ 8.0 Hz, 2H), 7.27e7.30 (m,1H),
210.4e211.7 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 1.08 (t, J ¼ 7.0 Hz,
7.54 (d, J ¼ 3.5 Hz, 2H), 8.21 (d, J ¼ 8.5 Hz, 1H). 13C NMR (125 MHz,
3H), 1.28 (t, J ¼ 7.0 Hz, 3H), 1.56 (quint, J ¼ 7.0 Hz, 2H), 1.73 (quint,
J ¼ 7.0 Hz, 2H), 2.67 (t, J ¼ 7.5 Hz, 2H), 3.35e3.40 (m, 4H), 4.27 (q,
J ¼ 7.0 Hz, 2H), 7.75 (d, J ¼ 9.5 Hz, 1H), 8.45 (dd, J ¼ 2.5, 9.0 Hz, 1H),
8.79 (d, J ¼ 2.5 Hz, 1H), 12.30 (br, 1H). 13C NMR (125 MHz, DMSO-
MeOH-d4):
d
¼ 14.4, 23.7, 28.8, 30.2, 30.7, 31.3, 32.9, 118.8, 123.8,
125.6, 128.6, 131.3, 138.6, 139.5, 171.2. LC/MS: m/z 258.99 [MþH]þ,
99.9%.
d6):
d
¼ 14.0, 15.1, 25.8, 29.0, 31.9, 60.7, 65.2, 69.2, 116.2, 120.1, 121.5,
123.6, 126.5, 143.0, 143.1, 153.5, 165.9, 173.1. LC/MS: m/z 362.89
[MþH]þ, 97.9%.
4.1.12. 2-Heptyl-3-(hydroxymethyl)quinolin-4(1H)-one (15)
At 0 ꢀC LiAlH4 (120 mg, 3.16 mmol, 2.0 equiv) was added to a
stirred solution of 17 (500 mg, 1.59 mmol, 1.0 equiv) in dry THF
(30 mL). After stirring at room temperature for 2 h ethyl acetate
(10 mL) was added at 0 ꢀC and after filtration the solvent was
removed under reduced pressure [34]. The residue was purified by
column chromatography (dichloromethane/methanol, 40/1) to give
the product as a white solid (128 mg, 0.47 mmol, 30%), mp 297.2e
4.1.16. 2-Heptyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (21)
The title compound was prepared according to procedure B
from 17 (50 mg, 0.16 mmol). The product was isolated as a white
solid (32 mg, 0.11 mmol, 69%), mp 219.4e221.7 ꢀC. 1H NMR
(500 MHz, DMSO-d6):
d
¼ 0.86 (t, J ¼ 7.0 Hz, 3H), 1.26e1.41 (m, 8H),
1.66 (quint, J ¼ 7.5 Hz, 2H), 3.31 (t, J ¼ 7.5 Hz, 2H, covered by water
peak at 3.32), 7.56 (t, J ¼ 7.5 Hz, 1H), 7.77 (d, J ¼ 7.5 Hz, 1H), 7.87 (t,
J ¼ 7.5 Hz, 1H), 8.25 (d, J ¼ 7.5 Hz, 1H), 12.96 (br, 1H). 13C NMR
298.6 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 0.86 (t, J ¼ 7.0 Hz, 3H),
1.25e1.40 (m, 8H),1.67 (quint, J ¼ 7.5 Hz, 2H), 2.73 (t, J ¼ 8.0 Hz, 2H),
4.48 (d, J ¼ 5.5 Hz, 2H), 4.58 (t, J ¼ 5.5 Hz, 1H), 7.26 (td, J ¼ 1.0,
7.5 Hz, 1H), 7.52 (d, J ¼ 8.0 Hz, 1H), 7.60 (td, J ¼ 1.0, 8.0 Hz, 1H), 8.07
(dd, J ¼ 1.5, 8.0 Hz, 1H), 11.39 (s, 1H). 13C NMR (125 MHz, DMSO-d6):
(125 MHz, DMSO-d6):
d
¼ 13.9, 22.0, 28.3, 29.1, 29.2, 31.1, 33.3,105.7,
118.8, 122.9, 125.1, 125.8, 133.9, 138.2,162.4, 166.3, 179.0. LC/MS: m/z
287.92 [MþH]þ, 99.9%.
d
¼ 13.9, 22.0, 28.4, 29.0, 29.3, 31.1, 31.2, 54.1, 117.7, 118.0, 122.6,
123.9, 125.1, 131.3, 139.4, 152.3, 176.1. LC/MS: m/z 315.86 [MþH]þ,
4.1.17. 6-Nitro-4-oxo-2-(pentyloxymethyl)-1,4-dihydroquinoline-3-
carboxylic acid (23)
The title compound was prepared according to procedure B
from 19 (400 mg, 1.10 mmol). The product was isolated as a yellow
solid (262 mg, 0.78 mmol, 71%), mp 149.8e150.3 ꢀC. 1H NMR
98.9%.
4.1.13. Ethyl 2-heptyl-4-oxo-1,4-dihydroquinoline-3-carboxylate
(17)
(500 MHz, DMSO-d6):
d
¼ 0.89 (t, J ¼ 7.0 Hz, 3H), 1.29e1.37 (m, 4H),
1.70 (quint, J ¼ 7.0 Hz, 2H), 3.69 (t, J ¼ 7.0 Hz, 2H), 5.16 (s, 2H), 8.42
(d, J ¼ 9.0 Hz, 1H), 8.61 (dd, J ¼ 2.5, 9.0 Hz, 1H), 8.91 (d, J ¼ 2.5 Hz,
1H) 12.59 (br, 1H), 15.55 (br, 1H). 13C NMR (125 MHz, DMSO-d6):
The title compound was obtained according to procedure B from
32 (3.40 g, 16 mmol), sodium hydride (50e65% w/w, 0.72 g,
15 mmol) and isatoic anhydride (2.45 g, 15 mmol). After recrys-
tallization from ethyl acetate/methanol the product was isolated as
a white solid (2.68 g, 8.51 mmol, 57%), mp 151.1e153.0 ꢀC. 1H NMR
d
¼ 13.9, 21.9, 27.5, 28.3, 68.1, 71.4, 106.1, 121.1, 122.1, 123.1, 127.5,
141.5, 144.4, 160.6, 165.5, 178.1. LC/MS: m/z 334.95 [MþH]þ, 97.7%.
(500 MHz, DMSO-d6):
d
¼ 0.85 (t, J ¼ 7.0 Hz, 3H),1.25e1.34 (m,11H),
4.1.18. 2-(4-Ethoxybutyl)-6-nitro-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (24)
The title compound was obtained according to procedure B from
20 (0.7 g, 1.93 mmol). The product was isolated as a yellow solid
(192 mg, 0.57 mmol, 30%), mp 231.5e232.7 ꢀC. 1H NMR (500 MHz,
1.66 (quint, J ¼ 7.5 Hz, 2H), 2.63 (t, J ¼ 8.0 Hz, 2H), 4.23 (q, J ¼ 7.0 Hz,
2H), 7.34 (td, J ¼ 1.5, 7.5 Hz, 1H), 7.56 (d, J ¼ 8.0 Hz, 1H), 7.67 (td,
J ¼ 1.5, 7.5 Hz, 1H), 8.05 (dd, J ¼ 1.5, 7.5 Hz, 1H), 11.77 (br, 1H). 13
C
NMR (125 MHz, DMSO-d6):
d
¼ 13.9, 14,1, 22.0, 28.3, 28.7, 28.9, 31.0,
31.9, 60.3, 114.8, 118.1, 123.6, 124.4, 124.9, 132.2, 139.3, 152.1, 166.8,
DMSO-d6):
d
¼ 1.08 (t, J ¼ 7.0 Hz, 3H), 1.62 (quint, J ¼ 7.0 Hz, 2H),
173.6. LC/MS: m/z 315.86 [MþH]þ, 98.9%.
1.73 (quint, J ¼ 7.0 Hz, 2H), 3.29 (t, J ¼ 7.5 Hz, 2H. covered by water
peak at 3.33), 3.37e3.41 (m, 4H), 7.92 (d, J ¼ 9.0 Hz, 1H), 8.59 (dd,
J ¼ 2.5, 9.0 Hz, 1H), 8.92 (d, J ¼ 2.5 Hz, 1H), 13.24 (br, 1H), 15.67 (br,
4.1.14. Ethyl 6-nitro-4-oxo-2-(pentyloxymethyl)-1,4-
dihydroquinoline-3-carboxylate (19)
1H). 13C NMR (125 MHz, DMSO-d6):
d
¼ 15.1, 26.2, 29.3, 33.2, 66.2,
69.3, 107.7, 120.9, 121.5, 122.8, 127.7, 141.7, 144.2, 163.7, 165.5, 178.6.
The title compound was prepared according to procedure B
from 33 (234 mg, 1.08 mmol), sodium hydride (50e65% w/w,
58 mg, 1.21 mmol) and 6-nitro-1H-benzo[d][1,3]oxazine-2,4-dione
(200 mg, 0.96 mmol). After column chromatography on silica gel
(n-hexane/ethyl acetate, 1.2/1) and recrystallization from ethyl ac-
etate the product was isolated as a yellow solid (25 mg, 0.07 mmol,
LC/MS: m/z 334.95 [MþH]þ, 97.3%.
4.1.19. 2-Heptyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (25)
N,N0-Carbonyldiimidazole (62 mg, 0.38 mmol, 2.0 equiv) was
added to 21 (55 mg, 0.19 mmol, 1.0 equiv) in dry DMF (1 mL). After
stirring at 65 ꢀC for 5 h, the mixture was cooled to 0 ꢀC and iced
conc. NH3$H2O (5 mL) was added. After stirring overnight at room
temperature the solvent was evaporated under reduced pressure.
To the residue was added iced water (5 mL) and the precipitate was
isolated by filtration [35]. After purification by column chroma-
tography on silica gel (dichloromethane/methanol, 70/1) the
product was isolated as a gray solid (38 mg, 0.13 mmol, 68%), mp
7.3%), mp 207.6e209.0 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 0.85
(t, J ¼ 7.0 Hz, 3H), 1.27e1.29 (m, 7H), 1.55 (quint, J ¼ 7.5 Hz, 2H), 3.47
(t, J ¼ 7.0 Hz, 2H), 4.26 (q, J ¼ 7.0 Hz, 2H), 4.56 (s, 2H), 7.92 (d,
J ¼ 9.0 Hz, 1H), 8.47 (dd, J ¼ 2.5, 9.0 Hz, 1H), 8.81 (d, J ¼ 2.5 Hz, 1H),
12.32, (br, 1H). 13C NMR (125 MHz, DMSO-d6):
d
¼ 13.8, 14.0, 21.9,
27.5, 28.5, 60.7, 67.1, 70.7, 115.3, 120.6, 121.5, 124.2, 126.5, 142.9,
143.2, 150.1, 165.2, 173.1. LC/MS: m/z 362.76 [MþH]þ, 98.8%.
215.7e216.9 ꢀC. 1H NMR (500 MHz, DMSO-d6):
d
¼ 0.85 (t, J ¼ 7.0