Du et al.
mixture was refluxed for 8 h, and the reaction mixture was
evaporated to dryness. The residue was dissolved in
EtOAc (100 mL), washed with H2O (50 mL), dried, and
evaporated to obtain the crude product, which was puri-
fied by flash chromatography (CH2Cl2/MeOH, 40:1) to
afford tert-butyl 4-(2-(cyclohexyl(phenyl)amino)-2- oxoethyl)
piperazine-1-carboxylate 9 as a yellow liquid (4.58 g, yield
2.2 Hz, 1H, Ar-H), 3.27 (s, 3H, CH3), 2.91 (s, 2H,
CH2CO), 2.70 (t, J = 7.5 Hz, 2H, CH2), 2.47–2.38 (m,
10H, CH2), 1.91–1.80 (m, 2H, CH2). 13C-NMR (100 MHz,
CDCl3) d 169.53, 158.81, 156.49, 143.55, 132.88, 129.70,
128.02, 127.92, 127.33, 123.09, 116.48, 116.43, 111.68,
111.58, 110.26, 109.99, 103.90, 103.67, 59.61, 58.16,
53.24, 53.02, 37.49, 27.13, 22.87. ESI-MS m/z 409.2
[M + H]+.
95.4%), (iii) To
a solution of compound 9 (3.0 g,
8.68 mmol) in CH2Cl2 (15 mL) was added trifluoroacetic
acid (15 mL). The mixture was stirred at room temperature
for 12 h, then concentrated, washed with PE and Et2O
separately to yield N-cyclohexyl-N-phenyl-2-(piperazin-1-yl)
acetamide10 as an off-white solid (2.68 g, yield 90%), (iv)
A solution of compound 10 (0.467 g, 1.17 mmol), com-
2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-
yl)-N-isopropyl-N-phenylacetamide (11d)
White solid (81 mg, yield 40.5%). 1H NMR (400 MHz,
CDCl3) d 8.04 (s, 1H), 7.41 (d, J = 6.1 Hz, 3H), 7.26–7.20
(m, 2H), 7.15–7.06 (m, 2H), 7.02 (s, 1H), 6.92 (td, J = 9.1,
2.4 Hz, 1H), 5.10–4.89 (m, 1H), 2.75 (s, 2H), 2.70 (t,
J = 7.5 Hz, 2H), 2.48–2.38 (m, 10H), 1.93–1.80 (m, 2H),
pound
3 (0.3 g, 1.17 mmol), and K2CO3 (0.324 g,
2.34 mmol) in acetonitrile (20 mL) was stirred at 80 °C for
12 h, then the reaction mixture was evaporated to dry-
ness, water added, and the mixture was extracted with
CH2Cl2 (3 9 30 mL), washed with brine, dried over anhy-
drous Na2SO4, and concentrated. The residue was puri-
fied with flash chromatography on silica gel (CH2Cl2/
MeOH, 40/1) to afford compound 11a as an off-white solid
(0.2 g, yield 35.7%) (17). 1H NMR (400 MHz, CDCl3) d
8.11 (s, 1H, NH), 7.40 (d, J = 5.1 Hz, 3H, Ar-H), 7.24 (dd,
J = 13.6, 8.6 Hz, 2H, Ar-H), 7.11–7.09 (m, 2H, Ar-H),
7.02 (s, 1H, Ar-H), 6.92 (t, J = 9.0 Hz, 1H, Ar-H), 4.59 (t,
J = 12.0 Hz, 1H, NCH), 2.75 (s, 2H, CH2CO), 2.70 (t,
J = 7.5 Hz, 2H, CH2), 2.44 (m, J = 22.1, 14.7 Hz, 10H,
CH2), 1.91–1.81 (m, 6H, CH2), 1.72 (d, J = 13.6 Hz, 3H),
1.57 (d, J = 12.6 Hz, 1H), 1.39 (dd, J = 26.0, 12.9 Hz,
2H), 0.98 (m, 4H).13C-NMR (100 MHz, CDCl3) d 170.38,
159.94, 157.63, 139.33, 134.79, 131.56, 130.45, 129.86,
129.10, 129.01, 124.99, 116.09, 116.04, 112.96, 112.87,
110.38, 110.12, 104.34, 103.81, 61.17, 59.27, 56.03,
53.73, 53.69, 32.62, 27.99, 26.92, 26.52, 23.88. ESI-MS
m/z 477.2 [M + H]+.
1.05 (d, J = 6.8 Hz, 6H). 13C-NMR (100 MHz, CDCl3)
d
168.72, 158.81, 156.49, 137.96, 132.88, 130.51, 129.16,
128.37, 128.01, 127.92, 123.10, 116.44, 116.40, 111.68,
111.58, 110.25, 109.99, 103.90, 103.67, 60.45, 58.17,
53.24, 53.26, 53.04, 46.16, 27.09, 22.86, 20.93. ESI-MS
m/z 437.2 [M + H]+.
N-cyclohexyl-2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)
piperazin-1-yl)-N-(2-methoxyphenyl)acetamide
(11e)
White solid (154 mg, yield 43.4%). White solid (160 mg,
yield 43.3%). 1H NMR (400 MHz, CD3OD) d7.41 (t,
J = 7.8 Hz, 1H), 7.25 (dd, J = 9.3, 4.7 Hz, 1H), 7.17–7.07
(m, 3H), 7.07(s, 1H), 7.01(t, J = 7.8 Hz, 1H), 6.82(td,
J = 9.0, 2.4 Hz, 1H), 4.42 (tt, J = 12.1, 3.5 Hz, 1H), 3.82
(s, 3H), 2.81–2.67 (m, 4H), 2.48–2.01 (m, 10H), 1.92–
1.1.74 (m, 5H), 1.67 (d, J = 11.4 Hz, 1H), 1.57 (d,
J = 12.9 Hz, 1H), 1.42–1.30(m, 2H), 0.96–0.80 (m, 3H).
13C-NMR (100 MHz, CDCl3) d 170.86, 159.84, 157.54,
157.47, 134.70, 132.28, 131.46, 129.01, 128.91, 127.89,
124.94, 121.86, 115.97, 115.92, 113.13, 112.90, 112.80,
110.31, 110.04, 103.98, 103.75, 60.64, 59.26, 56.68,
55.90, 53.73, 53.61, 33.10, 30.82, 27.96, 26.89, 26.86,
26.60, 23.84. ESI-MS m/z 507.4 [M + H]+.
2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-
yl)-N-phenylacetamide (11b)
White solid (150 mg, yield 40.5%). 1H NMR (400 MHz,
CDCl3) d 9.13 (s, 1H), 8.06 (s, 1H), 7.58–7.56 (m, 2H),
7.34 (t, J = 7.9 Hz, 2H), 7.27–7.23 (m, 2H), 7.11 (t,
J = 7.4 Hz, 1H), 7.03 (d, J = 1.8 Hz, 1H), 6.93 (td,
J = 9.1, 2.4 Hz, 1H), 3.14 (s, 2H), 2.75 (t, J = 7.5 Hz,
3H), 2.68 (s, 4H), 2.56 (s, 4H), 2.47 (t, J = 8.0 Hz, 2H),
1.94–1.87 (m, 2H). 13C-NMR (100 MHz, CDCl3) d 168.42,
158.86, 156.53, 137.64, 132.88, 129.05, 128.03, 127.94,
124.22, 123.06, 119.47, 116.51, 116.46, 111.69, 111.60,
110.37, 110.10, 103.93, 103.70, 61.97, 58.01, 53.52,
53.40, 27.24, 22.79. ESI-MS m/z 395.2 [M + H]+.
2-(4-(3-(5-chloro-1H-indol-3-yl)propyl)piperazin-1-
yl)-N-cyclohexyl-N-phenylacetamide (11f)
White solid (160 mg, yield 43.3%). 1H NMR (400 MHz,
CDCl3) d 8.50 (s, 1H), 7.41–7.40 (m, 3H), 7.27–7.24 (m,
2H), 7.12 (d, J = 7.9 Hz, 1H), 7.06–7.03 (m, 3H), 6.90 (td,
J = 9.0, 1.9 Hz, 1H), 4.53 (t, J = 12.1 Hz, 1H), 2.95–2.59
(m, 14H), 2.08–2.0 (m, 2H), 1.79 (d, J = 10.7 Hz, 2H),
1.71 (d, J = 13.1 Hz, 2H), 1.55 (d, J = 12.6 Hz, 1H),
1.41–1.31 (m, 2H), 1.06–0.84 (m, 3H). 13C-NMR
(100 MHz, CDCl3) d 167.94, 158.80, 156.47, 137.65,
132.83, 130.07, 129.49, 128.78, 127.47, 127.37, 123.55,
114.07, 112.00, 111.91, 110.47, 110.21, 103.42, 103.19,
59.38, 56.91, 54.47, 51.87, 50.61, 31.34, 29.68, 25.66,
25.23, 24.29, 22.13. ESI-MS m/z 477.2 [M + H]+.
2-(4-(3-(5-fluoro-1H-indol-3-yl)propyl)piperazin-1-
yl)-N-methyl-N-phenylacetamide (11c)
White solid (150 mg, yield 39.5%). 1H NMR (400 MHz,
CDCl3) d 8.06 (s, 1H, NH), 7.45–7.30 (m, 3H, Ar-H), 7.26–
7.17 (m, 1H, Ar-H), 7.00 (s, 1H, Ar-H), 6.91 (t, J = 9.0,
328
Chem Biol Drug Des 2013; 82: 326–335