Journal of Medicinal Chemistry
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625 mg (77.6%) of white solid; mp 166−168 °C. 1H NMR (300 MHz,
DMSO-d6): δ 13.03 (bs, 1H), 11.58 (s, 1H), 7.69 (s, 1H), 7.39 (d, J =
8.8 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 2.99 (t, J = 7.4 Hz, 2H), 1.59 (h,
J = 7.4 Hz, 2H), 0.89 (t, J = 7.4 Hz, 3H). MS (EI) m/z = 237.0 (M+).
3-Butyl-5-chloro-1H-indole-2-carboxylic Acid (10b). The title
compound was prepared by hydrolysis of ethyl 5-chloro-3-butyl-1H-
indole-2-carboxylate 9b (1.28 g, 4.58 mmol) in ethanolic NaOH
solution according to the general procedure C to provide 1.03 g
product; mp 112−114 °C. 1H NMR (500 MHz, chloroform-d): δ 9.20
(s, 1H), 7.53 (s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz,
1H), 7.13 (d, J = 8.2 Hz, 2H), 6.73 (d, J = 8.2 Hz, 2H), 6.02 (s, 1H),
3.77 (q, J = 6.3 Hz, 2H), 2.93 (s, 6H), 2.87 (t, J = 6.3 Hz, 2H), 2.66 (t,
J = 7.5 Hz, 2H), 1.49 (h, J = 7.5 Hz, 2H), 0.83 (t, J = 7.2 Hz, 3H). MS
(EI) m/z = 384.5 (M+ + 1). Anal. Calcd for (C22H26ClN3O): C, 68.83;
H, 6.83; N, 10.95. Found: C, 68.56; H, 6.63; N, 10.68.
3-Butyl-5-chloro-N-(4-(dimethylamino)phenethyl)-1H-in-
dole-2-carboxamide (12e). The title compound was prepared from
3-butyl-5-chloro-1H-indole-2-carboxylic acid 10b (200 mg, 0.79
mmol) and 4-(2-aminoethyl)-N,N-dimethyl aniline 11b (156 mg,
0.95 mmol) according to the general procedure D. The crude product
was purified by Combiflash chromatography (30% ethyl acetate in
hexane), which provided 80 mg (25.0%) of white solid product; mp
198−200 °C. 1H NMR (500 MHz, chloroform-d): δ 9.19 (s, 1H), 7.52
(s, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.12 (d, J =
7.9 Hz, 2H), 6.72 (d, J = 8.2 Hz, 2H), 6.03 (s, 1H), 3.78 (q, J = 6.3 Hz,
2H), 2.93 (s, 6H), 2.87 (t, J = 6.3 Hz, 2H), 2.69 (t, J = 7.6 Hz, 2H),
1.43 (p, J = 7.5 Hz, 2H), 1.27−1.16 (m, 3H), 0.84 (t, J = 7.2 Hz, 3H).
MS (EI) m/z = 398.5 (M+ + 1). Anal. Calcd for (C23H28ClN3O): C,
69.42; H, 7.09; N, 10.56. Found: C, 69.38; H, 7.22; N, 10.28.
5-Chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-in-
dole-2-carboxamide (12f). The title compound was prepared from
5-chloro-3-hexyl-1H-indole-2-carboxylic acid 10c (200 mg, 0.71
mmol) and 4-(2-aminoethyl)-N,N-dimethyl aniline 11b (140 mg,
0.85 mmol) according to the general procedure D. The crude product
was purified by Combiflash chromatography (30% ethyl acetate in
hexane), which yielded 150 mg (49.6%) of white solid product; mp
158−160 °C. 1H NMR (500 MHz, chloroform-d): δ 9.14 (s, 1H), 7.52
(s, 1H), 7.29 (d, J = 8.7 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.12 (d, J =
8.2 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 6.02 (bs, 1H), 3.78 (q, J = 6.3
Hz, 2H), 2.93 (s, 6H), 2.86 (t, J = 6.6 Hz, 2H), 2.69 (t, J = 7.9 Hz,
2H), 1.50−1.40 (m, 2H), 1.33−1.13 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).
MS (EI) m/z = 426.6 (M+ + 1). Anal. Calcd for (C25H32ClN3O): C,
70.49; H, 7.57; N, 9.86. Found: C, 70.38; H, 7.63; N, 9.79.
1
(89.3%) of white solid product; mp 158−160 °C. H NMR (300
MHz, chloroform-d): δ 8.80 (s, 1H), 7.69 (s, 1H), 7.42−7.26 (m, 2H),
3.13 (t, J = 7.4 Hz, 2H), 1.69 (p, J = 7.4 Hz, 2H), 1.45 (h, J = 7.4 Hz,
2H), 0.98 (t, J = 7.4 Hz, 3H). MS (EI) m/z = 250.9 (M+).
5-Chloro-3-hexyl-1H-indole-2-carboxylic Acid (10c). The title
compound was prepared by hydrolysis of ethyl 5-chloro-3-hexyl-1H-
indole-2-carboxylate 9c (1.55 g, 5.04 mmol) in ethanolic NaOH
solution according to the general procedure C to provide 965 mg
1
(68.4%) of white solid product; mp 138−140 °C. H NMR (300
MHz, chloroform-d): δ 8.78 (s, 1H), 7.69 (s, 1H), 7.39−7.31 (m, 2H),
3.11 (t, J = 7.6 Hz, 2H), 1.70 (p, J = 7.2 Hz, 2H), 1.50−1.25 (m, 6H),
0.96−0.83 (m, 3H). MS (EI) m/z = 278.9 (M+).
5-Chloro-N-(4-(piperidin-1-yl)phenethyl)-3-propyl-1H-in-
dole-2-carboxamide (12a). The title compound was prepared from
5-chloro-3-propyl-1H-indole-2-carboxylic acid 10a (216 mg, 0.92
mmol) and 2-(4-piperidin-1-ylphenyl)-ethylamine 11a (224 mg, 1.1
mmol) according to the general procedure D. The crude product was
purified by Combiflash chromatography (30% ethyl acetate in hexane),
which yielded 142 mg (36.6%) of white solid product; mp 190−192
1
°C. H NMR (500 MHz, chloroform-d): δ 9.13 (bs, 1H), 7.53 (bs,
1H), 7.29 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.3
Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 6.00 (s, 1H), 3.78 (q, J = 6.2 Hz,
2H), 3.12 (t, J = 5.3 Hz, 4H), 2.87 (t, J = 6.2 Hz, 2H), 2.66 (t, J = 7.6
Hz, 2H), 1.79−1.65 (m, 4H), 1.59−1.45 (m, 2H), 1.37−1.20 (m, 2H),
0.87 (t, J = 6.9 Hz, 3H). MS (EI) m/z = 423.2 (M+). Anal. Calcd for
(C25H30ClN3O): C, 70.82; H, 7.13; N, 9.91. Found: C, 71.09; H, 7.24;
N, 9.64.
Methyl 2-Azidoacetate (14). Methylbromoacetate 13 (40 g,
263.0 mmol) was added dropwise to the suspension of sodium azide
(19.0 g, 292.3 mmol) in anhydrous DMF (72 mL) at room
temperature. The reaction mixture was stirred at room temperature
for 2 h. During the reaction, sodium bromide was formed which
precipitated out. Water was added until the NaBr solid was dissolved
and then the reaction mixture was extracted three times with diethyl
ether (3 × 50 mL). The combined organic layers were washed six
times with water (total 360 mL) and then separated and washed with
brine and dried over magnesium sulfate. Removal of the solvent in
5-Chloro-3-butyl-N-(4-piperidin-1-yl)phenethyl)-1H-indole-
2-carboxamide (12b). The title compound was prepared from 5-
chloro-3-butyl-1H-indole-2-carboxylic acid 10a (200 mg, 0.79 mmol)
and 2-(4-piperidin-1-ylphenyl)-ethylamine 11a (194 mg, 0.95 mmol)
according to the general procedure D. The crude product was purified
by Combiflash chromatography (30% ethyl acetate in hexane), which
provided 111 mg (31.9%) of white solid product; mp: 218−220 °C.
1H NMR (500 MHz, chloroform-d): δ 9.19 (bs, 1H), 7.53 (bs, 1H),
7.30 (d, J = 8.6 Hz, 1H), 7.20 (d, J = 8.6 Hz, 1H), 7.12 (d, J = 8.2 Hz,
2H), 6.91 (d, J = 8.2 Hz, 2H), 6.02 (bs, 1H), 3.78 (q, J = 6.3 Hz, 2H),
3.13 (t, J = 5.4 Hz, 4H), 2.87 (t, J = 6.3 Hz, 2H), 2.69 (t, J = 7.7 Hz,
2H), 1.75−1.66 (m, 2H), 1.60−1.53 (m, 6H), 0.86 (t, J = 7.7 Hz, 3H).
MS (EI) m/z = 437.2 (M+). Anal. Calcd for (C26H32ClN3O): C,
70.82; H, 7.13; N, 9.91. Found: C, 71.06; H, 7.42; N, 9.49.
5-Chloro-3-hexyl-N-(4-piperidin-1-yl)phenethyl)-1H-indole-
2-carboxamide (12c). The title compound was prepared from 5-
chloro-3-hexyl-1H-indole-2-carboxylic acid 10c (200 mg, 0.71 mmol)
and 2-(4-piperidin-1-ylphenyl)-ethylamine 11a (175 mg, 0.86 mmol)
according to the general procedure D. The crude product was purified
by Combiflash chromatography (0−30% ethyl acetate in hexane),
which provided 174 mg (52.6%) of white solid product; mp 160−162
°C. 1H NMR (500 MHz, chloroform-d): δ 9.14 (s, 1H), 7.52 (s, 1H),
7.29 (d, J = 8.7 Hz, 1H), 7.20 (dd, J = 8.7 Hz, 1.8 Hz, 1H), 7.12 (d, J =
8.1 Hz, 2H), 6.71 (d, J = 8.1 Hz, 2H), 6.02 (s, 1H), 3.78 (q, J = 6.3 Hz,
2H), 2.93 (s, 6H), 2.86 (t, J = 6.3 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H),
1.44 (q, J = 6.9 Hz, 2H), 1.33−1.13 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H).
MS (EI) m/z = 465.2 (M+). Anal. Calcd for (C28H36ClN3O): C,
72.16; H, 7.79; N, 9.02. Found: C, 72.24; H, 7.65; N, 9.01.
5-Chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-in-
dole-2-carboxamide (12d). The title compound was prepared from
5-chloro-3-propyl-1H-indole-2-carboxylic acid 10a (200 mg, 0.84
mmol) and 4-(2-aminoethyl)-N,N-dimethyl aniline 11b (166
mg,1.01 mmol) according to the general procedure D. The crude
product was purified by Combiflash chromatography (30% ethyl
acetate in hexane), which yielded 51 mg (15.8%) of white solid
1
vacuo yielded 25 g (83.3%) of colorless oil. H NMR (300 MHz,
chloroform-d): δ 3.90 (s, 2H), 3.81 (s, 3H). The NMR result is in
agreement with published data.41 Its purity matches with the
commercially available methyl-2-azidoacetate (Sigma-Aldrich), there-
fore 14 was used without further purification.
(Z)-Methyl 2-Azido-3-(4-chlorophenyl)acrylate (16a). To the
solution of freshly prepared sodium methoxide (480 mg, 8.89 mmol)
in anhydrous methanol (12 mL) cooled to −20 °C was added the
solution of 4-chlorobenzaldehyde (500 mg, 3.56 mmol) in anhydrous
methanol (2.5 mL) in one portion. The temperature was maintained at
−20 °C, and liquid methyl 2-azidoacetate (1.02 g, 8.89 mmol) was
added dropwise to the reaction mixture during 30 min. The mixture
was then allowed to warm to −5−0 °C and stirred at the same
temperature until reaction completion (7 h), which was monitored by
TLC. Then ice−water was added to the reaction mixture, which led to
the precipitation of a white solid, which was filtered off and then
washed with ice water and dried in vacuum oven to give 499 mg (59%)
of the product 16a. Alternatively, 16a can be prepared by
condensation of 4-chlorobenzaldehyde 15a (3 g, 21.34 mmol) and
methyl-2-azidoacetate 14 (24.6 g, 213.4 mmol) in similar conditions as
above to afford 4.72 g (93%) of white solid product; mp 35−37 °C. 1H
NMR (300 MHz, chloroform-d): δ 7.77 (d, J = 8.6 Hz, 2H), 7.37 (d, J
= 8.6 Hz, 2H), 6.78 (s, 1H), 3.93 (s, 3H). MS (EI) m/z = 237.1 (M+).
(Z)-Methyl 2-Azido-3-(4-fluorophenyl)acrylate (16b). To a
freshly prepared sodium methoxide (432 mg, 8.00 mmol) in
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dx.doi.org/10.1021/jm5000112 | J. Med. Chem. 2014, 57, 3040−3052