M. Kimura et al. / Bioorg. Med. Chem. 11 (2003) 1621–1630
1627
1-[3,3-Bis(4-fluorophenyl)propyl]-4-[3-[(N-ethoxycarbo-
nyl-N-phenyl)amino]-2-hydroxypropyl]piperazine (5c).
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenyl-
.
amino)propyl]piperazine trihydrochloride (2 3HCl). This
compound was prepared from 2 according to the pro-
This compound was prepared as a pale yellow oil from
3 and 1-[3,3-bis(4-fluorophenyl)propyl]piperazine (4c)40
in 74% yield according to the procedure described for
.
cedure described for 7a 3HCl and recrystallized from
EtOꢂH to give white crystals in 92% yield. Mp 232–
233 C. IR (KBr) cmꢀ1: 3318, 1602, 1508, 1223. 1H
NMR (DMSO-d6) d 1.52–1.68 (2H, m), 2.03–2.09 (2H,
m), 2.24–2.94 (12H, m), 3.10–3.34 (2H, m), 4.02 (1H, t,
J=7.8 Hz), 4.21–4.33 (1H, m), 6.83 (2H, d, J=7.3 Hz),
7.10–7.33 (7H, m), 7.44–7.72(4H, m). Anal. calcd for
1
5a. IR (KBr) cmꢀ1: 3445, 1698, 1508, 1225. H NMR
(CDCl3) d 1.19 (3H, t, J=7.0 Hz), 2.14–2.55 (12H, m),
2.56–2.64 (2H, m), 3.65 (1H, dd, J=6.8, 14.3 Hz), 3.77
(1H, dd, J=3.8, 14.3 Hz), 3.92–4.08 (2H, m), 4.14 (2H,
q, J=7.0 Hz), 6.95 (3H, dt, J=1.9, 6.2Hz), 7.19–7.21
(3H, m), 7.35–7.53 (7H, m). HRFAB-MS calcd for
C31H38 F2N3O3 [M+H]+: 538.2881. Found: 538.2922.
.
C29H35F2N3O 3HCl: C, 59.14; H, 6.50; N, 7.13; Cl,
18.06. Found: C, 59.32; H, 6.47; N, 7.10; Cl, 17.98.
1-[3,3-Bis(4-fluorophenyl)propyl]-4-[2-hydroxy-3-(phenyl-
amino)propyl]piperazine (7c). This compound was pre-
pared as a pale yellow oil from 5c in 63% yield
according to the procedure described for 7a from 5a by
1-[5,5-Bis(4-fluorophenyl)pentyl]-4-[3-[(N-ethoxycarbo-
nyl-N-phenyl)amino]-2-hydroxypropyl]piperazine
(5e).
This compound was prepared as a pale yellow oil from
3 and 1-[5,5-bis(4-fluorophenyl)pentyl]piperazine (4e)40
in 60% yield according to the procedure described for
1
Route B. IR (KBr) cmꢀ1: 3389, 1603, 1507, 1222. H
1
NMR (CDCl3) d 2.13–2.56 (12H, m), 2.62–2.78 (2H, m),
3.24 (1H, dd, J=3.5, 12.4 Hz), 3.38 (1H, dd, J=5.9,
12.4 Hz), 3.93–4.02 (2H, m), 6.62 (2H, d, J=7.3 Hz),
6.70 (1H, t, J=7.3 Hz), 6.95 (3H, dt, J=2.4, 6.5 Hz),
5a. IR (KBr) cmꢀ1: 3399, 1752, 1600, 1508, 1223. H
NMR (CDCl3) d 1.19 (3H, t, J=7.6 Hz), 1.23–1.34 (2H,
m), 1.87–2.03 (2H, m), 2.24–2.49 (11H, m), 2.62–2.72 (2H,
m), 3.63 (1H, dd, J=7.3, 14.3 Hz), 3.74–4.05 (4H, m), 4.17
(2H, q, J=7.6 Hz), 6.95 (4H, t, J=7.3 Hz), 7.13–7.21 (4H,
m), 7.23–7.54 (5H, m). HRFAB-MS calcd for
C33H42F2N3O3 [M+H]+: 566.3194. Found: 566.3206.
7.13–7.27
(7H,
m).
HRFAB-MS
calcd
for
C28H34F2N3O [M+H]+: 466.2670. Found: 466.2713..
1-[3,3-Bis(4-fluorophenyl)propyl]-4-[2-hydroxy-3-(phenyl-
.
amino)propyl]piperazine trihydrochloride (7c 3HCl). This
compound was prepared from 7c according to the pro-
1-[5,5-Bis(4-fluorophenyl)pentyl]-4-[2-hydroxy-3-(phenyl-
amino)propyl]piperazine (7d). This compound was pre-
pared as a pale yellow oil from 5e in 53% yield
according to the procedure described for 7a from 5a by
.
cedure described for 7a 3HCl and recrystallized from
EtOH to give white crystals in 82% yield. Mp 241–
244 ꢂC. IR (KBr) cmꢀ1: 3320, 1603, 1508, 1226. 1H
NMR (DMSO-d6) d 2.52–2.63 (2H, m), 2.92–3.81 (14H,
m), 4.14 (1H, t, J=8.1 Hz), 4.23–4.38 (1H, m), 6.60 (2H,
t, J=6.5 Hz), 6.73 (1H, d, J=7.3 Hz), 7.16–7.23 (5H,
1
Route B. IR (KBr) cmꢀ1: 3389, 1603, 1223. H NMR
(CDCl3) d 1.23–1.32 (2H, m), 1.42–1.49 (2H, m), 1.93–
2.02 (2H, m), 2.24–2.83 (12H, m), 3.82–3.99 (1H, m),
4.04–4.15 (2H, m), 4.86–4.94 (1H, m), 6.93 (3H, t,
J=8.9 Hz), 7.16–7.23 (4H, m), 7.41–7.47 (3H, m), 7.48–
7.54 (3H, m). HRFAB-MS calcd for C30H38F2N3O
[M+H]+: 494.2983. Found: 494.2975.
m),
7.31–7.49
.
(5H,
m).
Anal.
calcd
for
C28H33F2N3O 3HCl: C, 58.49; H, 6.31; N, 7.31; Cl,
18.50. Found: C, 58.36; H, 6.52; N, 7.13; Cl, 18.22.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[3-[(N-ethoxycarbonyl-
N-phenyl)amino]-2-hydroxypropyl]piperazine (5d). This
compound was prepared as a pale yellow oil from 3 and
1-[4,4-bis(4-fluorophenyl)butyl]piperazine (4d)41,42 in
95% yield according to the procedure described for 5a.
IR (KBr) cmꢀ1: 3442, 1702, 1600, 1504, 1225. 1H NMR
(CDCl3) d 1.19 (3H, t, J=6.8 Hz), 1.42–1.57 (2H, m),
1.91–2.06 (2H, m), 2.33–2.54 (10H, m), 2.57–2.63 (2H,
m), 3.64 (1H, dd, J=7.3, 14.3 Hz), 3.83–3.96 (3H, m),
4.14 (2H, q, J=6.8 Hz), 6.88 (4H, t, J=4.6 Hz), 7.13–
7.24 (4H, m), 7.25-7.47 (5H, m). HRFAB-MS calcd for
C32H40F2N3O3 [M+H]+: 552.3038. Found: 552.2998.
1-[5,5-Bis(4-fluorophenyl)pentyl]-4-[2-hydroxy-3-(phenyl-
.
amino)propyl]piperazine trihydrochloride (7d 3HCl).
This compound was prepared from 7d according to the
.
procedure described for 7a 3HCl and recrystallized
from EtOH to give white crystals in 67% yield. Mp 236–
239 ꢂC. IR (KBr) cmꢀ1: 3402, 1603, 1223. 1H NMR
(DMSO-d6)d 1.13–1.24 (2H, m), 1.63–1.72 (2H, m),
2.01–2.14 (2H, m), 2.98–3.83 (14H, m), 4.00 (1H, t,
J=7.8 Hz), 4.21–4.33 (1H, brs), 6.96 (3H, t, J=7.8 Hz),
7.11 (4H, t, J=8.9 Hz), 7.23 (3H, t, J=7.3 Hz), 7.33–
.
7.44 (3H, m). Anal. calcd for C30H37F2N3O 3HCl: C,
59.76; H, 6.69; N, 6.97; Cl, 17.64. Found: C, 59.45; H,
6.57; N, 7.06; Cl, 17.42.
1-[4,4-Bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenyl-
amino)propyl]piperazine (2). This compound was pre-
pared from 5d according to the procedure described for
7a from 5a by Route B and recrystallized from EtOH to
give a white solid in 90% yield. Mp 99–100 ꢂC. IR (KBr)
1-[4,4-Bis(4-fluorophenyl)-3-butenyl]-4-[3-[(N-ethoxycar-
bonyl-N-phenyl)amino]-2-hydroxypropyl]piperazine (11).
This compound was prepared as a pale yellow oil from
3
and 1-[4,4-bis(4-fluorophenyl)-3-butenyl]piperazine
cmꢀ1: 3329, 1603, 1222. H NMR (CDCl3) d 1.53–1.68
(8)43 in 74% yield according to the procedure described
for 5a. IR (KBr) cmꢀ1: 3380, 1698, 1599, 1508, 1222. 1H
NMR (CDCl3) d 1.19 (3H, t, J=7.0 Hz), 2.24–2.53 (12H,
m), 2.61–2.73 (2H, m), 3.65 (1H, dd, J=7.3, 14.3 Hz), 3.79
(1H, dd, J=4.6, 14.3 Hz), 3.79–3.91 (1H, m), 4.14 (2H, q,
J=7.0 Hz), 5.98 (1H, t, J=7.0 Hz), 6.94 (2H, t, J=7.3
Hz), 7.02–7.48 (11H, m). FAB-MS m/z 550 [M+H]+.
1
(2H, m), 2.00–2.17 (2H, m), 2.33–2.65 (10H, m), 2.66–
2.74 (2H, m), 3.06 (1H, dd, J=5.9, 12.9 Hz), 3.25 (1H, dd,
J=4.1, 12.9 Hz), 3.86 (1H, t, J=7.8 Hz), 3.93–4.04 (1H,
m), 6.63 (2H, d, J=7.6 Hz), 6.91–7.01 (4H, m), 7.03 (1H,
t, J=7.6 Hz), 7.21–7.37 (6H, m). HRFAB-MS calcd for
C29H36F2N3O [M+H]+: 480.2826. Found: 480.2839.