Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 15 4877
palladium on carbon (500 mg). The mixture was hydrogenated
for 2 h at room temperature under atmospheric pressure. The
catalyst was filtered and washed with ethanol. The filtrate
combined was concentrated in vacuo to give 4-(2-methoxyben-
zyl)aniline (822 mg). This material was treated as described for
the synthesis of 5 to give 6-(2-methoxybenzyl)-4-oxo-1,4-dihy-
droquinoline-3-carboxylic acid ethyl ester. The title compound
was prepared from this ester as described for the synthesis of
3 (238 mg, 19%). Mp 243 °C. 1H NMR (DMSO-d6) δ 15.39 (1H,
br s), 13.37 (1H, br s), 8.84 (1H, d, J = 6.0 Hz), 8.06 (1H, s), 7.75
(2H, s), 7.27-7.18 (2H, m), 7.00 (1H, d, J =7.7 Hz), 6.93-6.87
(1H, m), 4.08 (2H, s), 3.77 (3H, s). MS (ESI) m/z 310 (M þ H)þ.
Anal. (C18H15NO4) C, H, N.
6-(2,3-Dichlorobenzyl)-4-oxo-1-propyl-1,4-dihydroquinoline-3-
carboxylic acid (19): 92% yield. Mp 220-221 °C. 1H NMR
(DMSO-d6) δ 15.19 (1H, br s), 9.02 (1H, s), 8.14 (1H, d, J =
1.9 Hz), 8.02 (1H, d, J=9.0 Hz), 7.83 (1H, dd, J = 8.9, 2.1 Hz),
7.58 (1H, dd, J = 7.9, 1.9 Hz), 7.46 (1H, dd, J = 7.7, 1.7 Hz),
7.41-7.36 (1H, m), 4.51 (2H, t, J=7.3 Hz), 4.36 (2H, s), 1.88-
1.76 (2H, m), 0.91 (3H, t, J = 7.3 Hz). MS (ESI) m/z 390 (M þ
H)þ. Anal. (C20H17Cl2NO3) C, H, N.
6-(2,3-Dichlorobenzyl)-1-(1-methylethyl)-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid (20): 55% yield. Mp 212-214 °C.
1H NMR (DMSO-d6) δ 8.86 (1H, s), 8.18-8.14 (2H, m), 7.85
(1H, dd, J=8.9, 2.1 Hz), 7.58 (1H, dd, J =7.8, 1.7 Hz), 7.47-
7.45 (1H, m), 7.41-7.36 (1H, m), 5.29-5.20 (1H, m), 4.37
(2H, s), 1.57 (6H, d, J=6.5 Hz). MS (ESI) m/z 390 (M þ H)þ.
Anal. (C20H17Cl2NO3) C, H, N.
4-Oxo-6-(2-trifluoromethylbenzyl)-1,4-dihydroquinoline-3-car-
boxylic Acid (13). The title compound was prepared from
2-bromotrifluoromethylbenzene and 4-methylnitrobenzene as
1-Butyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (21): 94% yield. Mp 213-214 °C. 1H NMR
(DMSO-d6) δ 15.19 (1H, br s), 9.02 (1H, s), 8.15 (1H, d, J =
1.9 Hz), 8.01 (1H, d, J=9.0 Hz), 7.84 (1H, dd, J = 8.9, 2.1 Hz),
7.58 (1H, dd, J = 7.9, 1.9 Hz), 7.46 (1H, dd, J = 7.5, 1.9 Hz),
7.41-7.36 (1H, m), 4.55 (2H, t, J=7.3 Hz), 4.37 (2H, s), 1.83-
1.71 (2H, m), 1.40-1.28 (2H, m), 0.90 (3H, t, J =7.3 Hz). MS
(ESI) m/z 404 (M þ H)þ. Anal. (C21H19Cl2NO3) C, H, N.
1-Carboxymethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroq-
uinoline-3-carboxylic acid (22): 67% yield. Mp 269 °C. 1H NMR
(DMSO-d6) δ 15.38 (1H, s), 8.85 (1H, s), 8.09 (1H, d,
J = 1.9 Hz), 7.77 (1H, dd, J = 8.9, 2.1 Hz), 7.70 (1H, d, J =
9.0 Hz), 7.57 (1H, dd, J = 7.5, 1.9 Hz), 7.43 (1H, dd, J = 7.5,
1.9 Hz), 7.40-7.35 (1H, m), 4.79 (2H, s), 4.34 (2H, s). MS (ESI)
m/z 406 (M þ H)þ. Anal. (C19H13Cl2NO5) C, H, N.
1
described for the synthesis of 12 (22% yield). Mp 245 °C. H
NMR (DMSO-d6) δ 15.26 (1H, br s), 13.38 (1H, br s), 8.85
(1H, s), 7.98 (1H, s), 7.80-7.76 (2H, m), 7.72-7.70 (1H, m),
7.67-7.63 (1H, m), 7.52-7.48 (1H, m), 7.43-7.41 (1H, m),
4.36 (2H, s). MS (ESI) m/z 348 (M þ H)þ. Anal. (C18H12F3NO3)
C, H, N.
6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroq-
uinoline-3-carboxylic Acid (27). Step 1. To a stirred mixture of
6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid ethyl ester (6.0 g, 16.0 mmol) and potassium carbonate (14.3 g,
103.5 mmol) in N,N-dimethylformamide (240 mL) was added 2-
bromoethyl acetate (6.0 mL, 24.2 mmol). The reaction mixture
was heated to 80 °C for 3.5 h, cooled, and diluted with water.
A precipitate was collected by filtration and then treated with
n-hexane/ethyl acetate (3/2 v/v). The resulting solid was collected
by filtration to give 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-
4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (6.0 g,
82%). 1H NMR (CDCl3) δ 8.59 (1H, s), 7.98 (1H, d, J=2.1 Hz),
7.83 (1H, d, J = 8.8 Hz), 7.68-7.65 (1H, m), 7.57 (1H, dd,
J=7.6, 1.9Hz), 7.43 (1H, dd, J=7.7, 2.0 Hz), 7.39-7.34 (1H, m),
4.63 (2H, t, J= 5.0 Hz), 4.37 (2H, t, J = 5.0 Hz), 4.29 (2H, s), 4.21
(2H, q, J=7.1 Hz), 1.90 (3H, s), 1.27 (3H, t, J=7.1 Hz).
Step 2. The title compound was prepared from the compo-
und of the previous step (6.0 g, 16.0 mmol) as described for
the synthesis of 3 (4.5 g, 72%). Mp 245-247 °C. 1H NMR
(DMSO-d6) δ 15.21 (1H, br s), 8.87 (1H, s), 8.15 (1H, d, J=2.3
Hz), 8.03 (1H, d, J=8.7 Hz), 7.82 (1H, dd, J= 9.0, 2.3 Hz), 7.58
(1H, dd, J = 7.7, 1.7 Hz), 7.46 (1H, dd, J =7.7, 1.7 Hz), 7.41-
7.36 (1H, m), 5.01 (1H, br s), 4.61 (2H, t, J = 4.9 Hz), 4.37
(2H, s), 3.80-3.71 (2H, m). MS (ESI) m/z 392 (MþH)þ. Anal.
(C19H15Cl2NO4) C, H, N.
1-Carbamoylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydro-
quinoline-3-carboxylic acid (24): 94% yield. Mp 276 °C. 1H NMR
(DMSO-d6) δ 15.09 (1H, br s), 9.02 (1H, s), 8.13 (1H,
d, J = 1.9 Hz), 7.90 (1H, br s), 7.85 (1H, dd, J = 8.8, 2.1 Hz),
7.64 (1H, d, J = 9.0 Hz), 7.58 (1H, dd, J = 7.9, 1.6 Hz), 7.54 (1H,
br s), 7.45 (1H, dd, J=7.8, 1.5 Hz), 7.40-7.36 (1H, m), 5.24
(2H, s), 4.35 (2H, s). MS (ESI) m/z 405 (M þ H)þ. Anal.
(C19H14Cl2N2O4 0.67H2O) C, H, N.
3
6-(2,3-Dichlorobenzyl)-1-(3-hydroxypropyl)-4-oxo-1,4-dihyd-
roquinoline-3-carboxylic acid (28): 21% yield. Mp 205-208 °C.
1H NMR (DMSO-d6) δ 15.16 (1H, br s), 8.96 (1H, s), 8.14
(1H, s), 8.00 (1H, d, J=6.7 Hz), 7.86-7.83 (1H, m), 7.57 (1H, d,
J = 5.9 Hz), 7.46-7.44 (1H, m), 7.40-7.36 (1H, m), 4.68 (1H,
br s), 4.61-4.58 (2H, m), 4.36 (2H, s), 3.47-3.44 (2H, m),
1.97-1.94 (2H, m). MS (ESI) m/z 406 (M þ H)þ. Anal.
(C20H17Cl2NO4) C, H, N.
6-(2-Chloro-3-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-di-
hydroquinoline-3-carboxylic acid (29): 87% yield. Mp 227-
The following compounds (4, 17-22, 24, 28-30, and 34-39)
were prepared using the above procedures.
1
228 °C. H NMR (DMSO-d6) δ 15.25 (1H, br s), 8.90 (1H, s),
6-Benzyl-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic
acid (4): 91% yield. Mp 233-235 °C. 1H NMR (CDCl3) δ 14.97
(1H, br s), 8.72 (1H, s), 8.41 (1H, d, J = 1.9 Hz), 7.68 (1H, dd,
J = 8.9, 2.1 Hz), 7.53 (1H, d, J = 8.7 Hz), 7.35-7.18
(5H, m), 4.17 (2H, s), 4.00 (3H, s). MS (ESI) m/z 294 (M þ
H)þ. Anal. (C18H15NO3) C, H, N.
6-(2,3-Dichlorobenzyl)-1-methyl-4-oxo-1,4-dihydroquinoline-
3-carboxylic acid (17): 84% yield. Mp 257 °C. 1H NMR
(DMSO-d6) δ 9.01 (1H, s), 8.12 (1H, s), 7.93 (1H, d, J = 8.9
Hz), 7.85 (1H, dd, J = 8.9, 2.0 Hz), 7.58 (1H, dd, J = 7.8, 1.7
Hz), 7.46 (1H, dd, J =7.6, 1.6 Hz), 7.40-7.35 (1H, m), 4.37
(2H, s), 4.09 (3H, s). MS (ESI) m/z 362 (M þ H)þ. Anal.
(C18H13Cl2NO3) C, H, N.
8.19 (1H, s), 8.08-8.05 (1H, m), 7.88-7.80 (1H, m), 7.45-7.29
(3H, m), 5.03 (1H, br s), 4.68-4.57 (2H, m), 4.39 (2H, s), 3.82-
3.73 (2H, m). MS (ESI) m/z 376 (M
(C19H15ClFNO4) C, H, N.
þ
H)þ. Anal.
6-(3-Chloro-2-fluorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-di-
hydroquinoline-3-carboxylic acid (30): 80% yield. Mp 225-
226 °C. 1H NMR (DMSO-d6) δ 8.87 (1H, s), 8.22 (1H, s),
8.04-8.01 (1H, m), 7.85-7.82 (1H, m), 7.51-7.46 (1H, m),
7.43-7.38 (1H, m), 7.24-7.19 (1H, m), 5.00 (1H, br s), 4.61 (2H,
t, J=5.1 Hz), 4.26 (2H, s), 3.80-3.71 (2H, m). MS (ESI) m/z 376
(M þ H)þ. Anal. (C19H15ClFNO4) C, H, N.
6-(2,3-Dichlorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (34): 85% yield. Mp 288 °C. 1H
NMR (DMSO-d6) δ 15.40 (1H, s), 8.80 (1H, s), 7.83 (1H, s), 7.59
(1H, dd, J=8.0, 1.5 Hz), 7.37-7.33 (2H, m), 7.25 (1H, dd, J=7.7,
1.4 Hz), 5.04 (1H, t, J=5.7 Hz), 4.65 (2H, t, J=4.8Hz),4.20(2H, s),
4.03 (3H, s), 3.81 (2H, dt, J=5.0, 2.5 Hz). MS (ESI) m/z 422
(M þ H)þ. Anal. (C20H17Cl2NO5) C, H, N.
6-(2,3-Dichlorobenzyl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-
carboxylic acid (18): 98% yield. Mp 222-223 °C. 1H NMR
(DMSO-d6) δ 15.20 (1H, br s), 9.04 (1H, s), 8.15 (1H, d, J =
1.9 Hz), 8.02 (1H, d, J= 8.7 Hz), 7.84 (1H, dd, J= 9.0, 2.3 Hz),
7.58 (1H, dd, J = 7.9, 1.9 Hz), 7.46 (1H, dd, J = 7.5, 1.9 Hz),
7.41-7.36 (1H, m), 4.59 (2H, q, J = 7.2 Hz), 4.37 (2H, s), 1.41
(3H, t, J = 7.2 Hz). MS (ESI) m/z 376 (M þ H)þ. Anal.
7-Chloro-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-
dihydroquinoline-3-carboxylic acid (35): 83% yield. Mp 282 °C.
(C19H15Cl2NO3 0.25H2O) C, H, N.
3