C. Hocke et al.
MED
phenyl)piperazin-1-yl]butyl-1-amine (8b, 1 equiv) in dry CH2Cl2
(15 mL) under Ar atmosphere. The mixture was stirred at room
temperature overnight. After filtration of the precipitate, the re-
maining solution was washed with H2O (2ꢂ20 mL) and brine
(20 mL). The organic layer was separated, dried over Na2SO4, and
evaporated under reduced pressure to get a residue of crude prod-
uct. Subsequent column chromatography (CH2Cl2/MeOH; 9:1) gave
each compound 9a–d, 10a–d in yields of 43–79%.
J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 2H), 7.92–7.98 (m, 1H), 8.41 ppm
(d, J=2.5 Hz, 1H); 13C NMR (CDCl3) d=24.36, 27.41, 39.99, 49.98,
53.67, 58.03, 58.95, 109.51, 109.75, 116.93, 123.30, 124.56, 127.08,
127.83, 128.73, 134.62, 139.46, 139.70, 139.75, 145.85, 145.95,
146.45, 148.60, 162.59, 167.06 ppm; HRMS calcd for C27H30ClFN4O2
[M+]: 496.2041, found: 496.2042.
N-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl]-4-(6-bromopyridin-
2-yl)-benzamide (10a). Compound 10a was prepared from 4-[4-
(2-chlorophenyl)piperazin-1-yl]butyl-1-amine (8a) and 4-(6-bromo-
pyridin-2-yl)benzoic acid according to the general procedure. Yield:
N-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl]-4-(6-fluoropyridin-
2-yl)benzamide (9a). Compound 9a was prepared by coupling of
4-[4-(2-chlorophenyl)piperazin-1-yl]butyl-1-amine (8a) and 4-(6-flu-
oropyridin-2-yl)benzoic acid according to the general procedure.
Yield: 72%; 1H NMR (360 MHz, CDCl3): d=1.49–1.55 (m, 2H), 1.59
(td, J=13.7, 6.7 Hz, 2H), 2.27–2.37 (m, 2H), 2.49 (s, 4H), 2.85 (d, J=
57.53 Hz, 4H), 3.37 (dd, J=12.4, 6.7 Hz, 2H), 6.76 (dd, J=8.1,
2.7 Hz, 1H), 6.79–6.87 (m, 2H), 7.01–7.07 (m, 1H), 7.21 (dd, J=7.9,
1.5 Hz, 1H), 7.26 (q, J=5.6 Hz, 1H), 7.49 (dd, J=7.5, 2.1 Hz, 1H),
7.67–7.73 (m, 1H), 7.75–7.79 (m, 2H), 7.87–7.93 ppm (m, 2H);
13C NMR (CDCl3): d=24.24, 27.28, 39.86, 50.73, 53.08, 57.86, 108.09,
108.34, 117.49, 120.14, 123.47, 126.78, 127.35, 128.47, 130.38,
135.63, 139.76, 141.66, 141.71, 148.94, 154.70, 154.79, 162.37,
163.95, 167.13 ppm; HRMS calcd for C26H28ClFN4O [M+]: 466.1936,
found: 466.1936.
1
79%: H NMR (600 MHz, CDCl3): d=1.57–1.74 (m, 4H), 2.43 (t, J=
6.9 Hz, 2H), 2.60 (s, 4H), 3.01 (s, 4H), 3.40–3.52 (m, 2H), 6.89–6.97
(m, 2H), 7.12–7.19 (m, 1H), 7.29–7.35 (m, 2H), 7.37–7.42 (m, 1H),
7.52–7.58 (m, 1H), 7.63 (dd, J=7.7, 0.9 Hz, 1H), 7.82–7.88 (m, 2H),
7.95–8.01 ppm (m, 2H); 13C NMR (CDCl3): d=24.13, 27.22, 39.84,
50.74, 53.09, 57.79, 119.08, 120.13, 123.45, 126.73, 126.74, 127.38,
127.39, 128.42, 130.34, 135.58, 138.95, 139.78, 142.00, 148.87,
156.95, 167.15 ppm; HRMS calcd for C26H28BrClN4O [M+]: 526.1135,
found: 526.1135.
N-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl]-4-(6-nitropyridin-3-
yl)-benzamide (10b). Compound 10b was prepared from 4-[4-(2-
chlorophenyl)piperazin-1-yl]butyl-1-amine (8a) and 4-(6-nitropyri-
din-3-yl)benzoic acid according to the general procedure. Yield:
N-[4-[4-(2-Chlorophenyl)piperazin-1-yl]butyl]-4-(6-fluoropyridin-
3-yl)benzamide (9b). Compound 9b was prepared from 4-[4-(2-
chlorophenyl)piperazin-1-yl]butyl-1-amine (8a) and 4-(6-fluoropyri-
din-3-yl)benzoic acid according to the general procedure. Yield:
1
54%: H NMR (360 MHz, CDCl3): d=1.61–1.79 (m, 4H), 2.50 (t, J=
6.9 Hz, 2H), 2.65 (s, 4H), 3.04 (s, 4H), 3.46–3.58 (m, 2H), 6.91–6.99
(m, 2H), 7.07 (t, J=5.4 Hz, 1H), 7.13–7.21 (m, 1H), 7.28–7.36 (m,
1H), 7.66–7.72 (m, 2H), 7.93–7.99 (m, 2H), 8.16–8.22 (m, 1H), 8.33
(td, J=3.0, 1.5 Hz, 1H), 8.79–8.83 ppm (m, 1H); 13C NMR (CDCl3):
d=24.27, 27.34, 40.02, 50.86, 53.23, 57.89, 118.14, 120.12, 123.63,
127.45, 127.51, 128.12, 128.60, 130.53, 135.97, 137.82, 137.84,
141.18, 147.04, 148.96, 155.84, 166.62 ppm; HRMS calcd for
C26H28ClN5O4 [M+]: 493.1881, found: 493.1881.
1
47%; H NMR (360 MHz, CDCl3): d=1.67 (ddd, J=10.5, 9.2, 4.1 Hz,
2H), 1.70–1.76 (m, 2H), 2.48 (t, J=7.1 Hz, 2H), 2.64 (s, 4H), 3.03 (s,
4H), 3.51 (dd, J=12.3, 6.6 Hz, 2H), 6.95 (dd, J=3.0, 1.6 Hz, 1H),
6.96 (dd, J=3.6, 1.4 Hz, 1H), 7.01 (dd, J=8.5, 2.5 Hz, 1H), 7.17
(ddd, J=8.0, 7.4, 1.5 Hz, 2H), 7.31–7.34 (m, 1H), 7.54–7.58 (m, 2H),
7.88–7.92 (m, 2H), 7.95 (ddd, J=8.4, 7.6, 2.6 Hz, 1H), 8.39 ppm (d,
J=2.62 Hz, 1H); 13C NMR (CDCl3): d=24.28, 27.34, 39.94, 50.84,
53.19, 57.92, 109.42, 109.67, 120.12, 123.59, 126.92, 127.42, 127.82,
128.59, 130.49, 133.65, 134.57, 139.25, 139.61, 139.66, 145.72,
145.81, 148.95, 162.46, 164.06, 166.98 ppm; HRMS calcd for
C26H28ClFN4O [M+]: 466.1936, found: 466.1936.
N-[4-[4-(3-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl]-4-(6-
bromopyridin-2-yl)-benzamide (10c). Compound 10c was pre-
pared from 4-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]butyl-1-
amine (8b) and 4-(6-bromopyridin-2-yl)benzoic acid according to
1
the general procedure. Yield: 65%: H NMR (360 MHz, CDCl3): d=
1.58–1.77 (m, 4H), 2.45 (t, J=6.9 Hz, 2H), 2.59 (s, 4H), 3.08 (s, 4H),
3.40–3.54 (m, 2H), 3.84 (t sext., J=6.6, 5.0 Hz, 3H), 6.74 (dd, J=8.0,
1.6 Hz, 1H), 6.91 (t, J=8.0 Hz, 1H), 6.95–7.00 (m, 1H), 7.09 (t, J=
5.4 Hz, 1H), 7.43 (dd, J=7.7, 0.9 Hz, 1H), 7.59 (t, J=7.7 Hz, 1H),
7.67 (dd, J=7.7, 0.9 Hz, 1H), 7.81–7.89 (m, 2H), 7.98–8.05 ppm (m,
2H); 13C NMR (CDCl3): d=24.26, 27.32, 39.93, 49.91, 53.56, 57.94,
58.86, 116.97, 119.18, 123.12, 124.51, 126.87, 126.90, 127.42, 128.54,
135.71, 139.02, 139.99, 142.15, 146.39, 148.50, 157.12, 167.21 ppm;
HRMS calcd for C27H30BrClN4O2 [M+]: 556.1241, found: 556.1240.
N-[4-[4-(3-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl]-4-(6-
fluoropyridin-2-yl)benzamide (9c). Compound 9c was prepared
from 4-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]butyl-1-amine
(8b) and 4-(6-fluoropyridin-2-yl)benzoic acid according to the gen-
1
eral procedure. Yield: 69%; H NMR (360 MHz, CDCl3): d=1.62–1.68
(m, 2H), 1.69–1.74 (m, 2H), 2.45 (dd, J=16.3, 9.3 Hz, 2H), 2.58 (s,
4H), 3.08 (s, 4H), 3.50 (dd, J=12.3, 6.7 Hz, 2H), 3.82–3.86 (m, 3H),
6.70–6.76 (m, 1H), 6.87–6.93 (m, 2H), 6.97 (dt, J=8.0, 2.1 Hz, 1H),
7.03 (t, J=5.4 Hz, 1H), 7.62 (dd, J=7.5, 2.1 Hz, 1H), 7.83–7.87 (m,
3H), 8.02–8.03 (m, 1H), 8.03–8.05 ppm (m, 1H); 13C NMR (CDCl3):
d=24.41, 27.39, 40.00, 50.00, 53.64, 58.02, 58.89, 108.26, 108.51,
117.00, 117.59, 123.15, 124.53, 126.92, 127.44, 128.60, 135.75,
141.74, 141.79, 146.47, 148.55, 154.87, 154.96, 162.53, 164.11,
167.19 ppm; HRMS calcd for C27H30ClFN4O2 [M+]: 496.2041, found:
496.2041.
N-[4-[4-(3-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl]-4-(6-ni-
tropyridin-3-yl)-benzamide (10d). Compound 10d was prepared
from 4-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]butyl-1-amine
(8b) and 4-(6-nitropyridin-3-yl)benzoic acid according to the gener-
al procedure. Yield: 52%: 1H NMR (360 MHz, CDCl3): d=1.59–1.81
(m, 4H), 2.48 (t, J=6.8 Hz, 2H), 2.62 (s, 4H), 3.10 (s, 4H), 3.53 (q,
J=6.4 Hz, 2H), 3.84 (d, J=4.6 Hz, 3H), 6.74 (dd, J=8.0, 1.6 Hz, 1H),
6.87–7.02 (m, 3H), 7.65–7.73 (m, 2H), 7.90–7.98 (m, 2H), 8.18 (dd,
J=8.4, 2.4 Hz, 1H), 8.35 (dd, J=8.4, 0.7 Hz, 1H), 8.83 ppm (dd, J=
2.3, 0.7 Hz, 1H); 13C NMR (CDCl3): d=24.32, 27.36, 40.04, 49.98,
53.66, 57.97, 58.94, 116.88, 118.19, 123.29, 124.54, 127.60, 128.14,
128.72, 136.00, 137.90, 137.94, 141.24, 146.41, 147.12, 148.59,
155.93, 166.74 ppm; HRMS calcd for C27H30ClN5O4 [M+]: 523.1986,
found: 523.1986.
N-[4-[4-(3-Chloro-2-methoxyphenyl)piperazin-1-yl]butyl]-4-(6-
fluoropyridin-3-yl)benzamide (9d). Compound 9d was prepared
from 4-[4-(3-chloro-2-methoxyphenyl)piperazin-1-yl]butyl-1-amine
(8b) and 4-(6-fluoropyridin-3-yl)benzoic acid according to the gen-
1
eral procedure. Yield: 43%; H NMR (360 MHz, CDCl3) d=1.64–1.76
(m, 4H), 2.43–2.51 (m, 2H), 2.62 (s, 4H), 3.10 (s, 4H), 3.52 (dd, J=
12.2, 6.5 Hz, 2H), 3.83 (d, J=20.0 Hz, 3H), 6.74 (dd, J=8.1, 1.4 Hz,
1H), 6.87–6.94 (m, 2H), 7.01 (ddd, J=9.5, 8.3, 2.14 Hz, 2H), 7.58 (d,
946
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ChemMedChem 2010, 5, 941 – 948