160
H.D. Hansen et al. / European Journal of Medicinal Chemistry 79 (2014) 152e163
J ¼ 8.0 Hz), 8.41 (d, 1H, J ¼ 4.7 Hz), 8.76e8.78 (m, 1H). ESI-MS m/z
421 (M þ H)þ. ESI-MS/MS m/z 198 (100), 183 (15).
4.7.11. (R)-1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol ((R)-13)
Eluted with CHCl3/MeOH, 98:2. Pale yellow semisolid. 67% Yield.
1H NMR (CDCl3):
d 2.49e2.53 (m, 3H, 1H D2O exchanged), 2.56e
4.7.6. 1-(4-Methoxyphenoxy)-3-[4-[2-(3-pyridyl)-3-pyridyl]
piperazin-1-yl]-2-propanol (12)
2.60 (m, 2H), 2.64e2.69 (m, 2H), 2.88e2.97 (m, 4H), 3.76 (s, 3H),
3.93 (d, 2H, J ¼ 5.2 Hz), 4.02e4.10 (m, 1H), 6.80e6.87 (m, 4H), 7.26e
7.29 (m, 1H), 7.41 (dd, 1H, J ¼ 1.4 and 8.3 Hz), 7.92 (dd, 2H, J ¼ 1.7
and 4.7 Hz), 8.39 (dd,1H, J ¼ 1.4 and 4.4 Hz), 8.69 (dd, 2H, J ¼ 1.7 and
4.7 Hz). ESI-MS m/z 421 (M þ H)þ. ESI-MS/MS m/z 378 (100), 366
Eluted with CHCl3/MeOH, 98:2. 62% Yield. 1H NMR (CDCl3):
d
2.46e2.49 (m, 3H, 1H D2O exchanged), 2.54e2.57 (m, 2H), 2.64e
2.68 (m, 2H), 2.90e2.92 (m, 4H), 3.76 (s, 3H), 3.92 (d, 2H, J ¼ 4.7 Hz),
4.01e4.07 (m, 1H), 6.80e6.87 (m, 4H), 7.22e7.25 (m, 1H), 7.35e7.42
(m, 2H), 8.25 (d, 1H, J ¼ 8.0 Hz), 8.39 (d, 1H, J ¼ 4.7 Hz), 8.59 (d, 1H,
J ¼ 4.7 Hz), 9.27 (d, 1H, J ¼ 1.9 Hz). ESI-MS m/z 421 (M þ H)þ. ESI-
MS/MS m/z 366 (100), 238 (4). The hydrochloride salt melted at
173e175 ꢁC (from CH3OH/diethyl ether). Anal. (C24H28N4O3$3HCl)
C, H, N.
(73). [
a
]D: ꢂ3.5ꢁ (c ¼ 1.2, MeOH).
4.7.12. (S)-1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol ((S)-13)
Eluted with CHCl3/MeOH, 98:2. Pale yellow semisolid. 42% Yield.
1H NMR (CDCl3):
d 2.49e2.53 (m, 3H, 1H D2O exchanged), 2.56e
2.60 (m, 2H), 2.64e2.70 (m, 2H), 2.88e2.97 (m, 4H), 3.76 (s, 3H),
3.93 (d, 2H, J ¼ 4.9 Hz), 4.02e4.10 (m, 1H), 6.80e6.88 (m, 4H), 7.26e
7.29 (m, 2H), 7.41 (dd, 1H, J ¼ 1.4 and 8.3 Hz), 7.92 (dd, 2H, J ¼ 1.7
and 4.7 Hz), 8.38 (dd,1H, J ¼ 1.4 and 4.7 Hz), 8.68e8.70 (m, 2H). ESI-
MS m/z 421 (M þ H)þ. ESI-MS/MS m/z 378 (100), 366 (73).
4.7.7. 1-(4-Methoxyphenoxy)-3-[4-[2-(4-pyridyl)-3-pyridyl]
piperazin-1-yl]-2-propanol (13)
Eluted with CHCl3/MeOH, 98:2. 55% Yield. 1H NMR (CDCl3):
d
2.49e2.54 (m, 3H, 1H D2O exchanged), 2.56e2.59 (m, 2H), 2.64e
[a
]D: þ3.2ꢁ (c ¼ 1.5, MeOH).
2.69 (m, 2H), 2.92 (br s, 4H), 3.76 (s, 3H), 3.92 (d, 2H, J ¼ 4.9 Hz),
4.03e4.10 (m, 1H), 6.80e6.87 (m, 4H), 7.27e7.29 (m, 1H), 7.41 (dd,
1H, J ¼ 1.4 and 8.3 Hz), 7.91e7.93 (m, 2H), 8.39 (dd, 1H, J ¼ 1.4 and
4.7 Hz), 8.68e8.70 (m, 2H). 13C NMR (CD3OD): 53.1; 55.0; 59.0;
64.1; 70.6; 114.5; 115.5; 127.0; 127.4; 131.4; 142.5; 143.4; 144.2;
147.8; 152.8; 154.5; 154.6. ESI-MS m/z 421 (M þ H)þ. ESI-MS/MS
m/z 378 (100), 366 (57). The hydrochloride salt melted at 151e
154 ꢁC (from CH3OH/diethyl ether). Anal. (C24H28N4O3$3HCl)
C, H, N.
4.7.13. (R)-1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol ((R)-16)
Eluted with CHCl3/MeOH, 98:2. Pale yellow semisolid. 46% Yield.
1H NMR (CDCl3):
d 2.39e2.45 (m, 3H, 1H D2O exchanged), 2.48e
2.52 (m, 2H), 2.56e2.61 (m, 2H), 2.87 (br s, 4H), 3.85 (s, 3H), 4.06e
4.12 (m, 1H), 4.27 (dd, 1H, J ¼ 5.8 and 11.3 Hz), 4.38 (dd, 1H, J ¼ 3.6
and 11.3 Hz), 6.93 (d, 2H, J ¼ 8.8 Hz), 7.01e7.09 (m, 2H), 7.21e7.24
(m, 2H), 7.58 (d, 2H, J ¼ 8.8 Hz), 8.06 (dd,1H, J ¼ 1.4 and 2.7 Hz), 8.13
(d, 1H, J ¼ 3.0 Hz), 8.28 (d, 1H, J ¼ 1.4 Hz). 13C NMR (CD3OD): 50.6;
53.8; 61.0; 66.6; 69.0; 113.5; 118.1; 122.7; 127.8; 129.8; 131.0; 133.7;
134.9; 135.5; 136.2; 141.1; 150.2; 158.9; 160.7. ESI-MS m/z 421
4.7.8. 1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrimidinyloxy)-2-propanol (14)
Eluted with CHCl3/MeOH, 98:2. 30% Yield. 1H NMR (CDCl3):
(M þ H)þ. ESI-MS/MS m/z 325 (100), 281 (11), 224 (6). [
(c ¼ 1.1, MeOH).
a
]D: ꢂ7.5ꢁ
d
2.35e2.43 (m, 3H, 1H D2O exchanged), 2.53e2.59 (m, 4H), 2.83e
2.88 (m, 4H), 3.85 (s, 3H), 4.08e4.14 (m, 1H), 4.36e4.40 (m, 2H),
6.90e6.96 (m, 2H), 6.98e7.09 (m, 2H), 7.20e7.24 (m, 3H), 7.53e
7.58 (m, 2H), 8.51 (d, 2H, J ¼ 4.7 Hz). ESI-MS m/z 421 (M þ H)þ.
ESI-MS/MS m/z 325 (100), 281 (3). The hydrochloride salt melted
at 80 ꢁC dec (from CH3OH/diethyl ether). Anal. (C24H28N4O3$2HCl)
C, H, N.
4.7.14. (S)-1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol ((S)-16)
Eluted with CHCl3/MeOH, 98:2. Pale yellow semisolid. 60% Yield.
1H NMR (CDCl3):
d 2.39e2.44 (m, 3H, 1H D2O exchanged), 2.48e
2.53 (m, 2H), 2.57e2.63 (m, 2H), 2.83e2.93 (m, 4H), 3.85 (s, 3H),
4.05e4.12 (m, 1H), 4.26 (dd, 1H, J ¼ 5.8 and 11.3 Hz), 4.39 (dd, 1H,
J ¼ 3.8 and 11.3 Hz), 6.92e6.96 (m, 2H), 7.01e7.09 (m, 2H), 7.21e7.24
(m, 2H), 7.55e7.60 (m, 2H), 8.06 (dd, 1H, J ¼ 1.4 and 2.8 Hz), 8.13 (d,
1H, J ¼ 2.8 Hz), 8.28 (d, 1H, J ¼ 1.4 Hz). ESI-MS m/z 421 (M þ H)þ.
4.7.9. 1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(3-
pyridazinyloxy)-2-propanol (15)
Eluted with CHCl3/MeOH, 19:1. 40% Yield. 1H NMR (CDCl3):
d
2.38e2.46 (m, 3H, 1H D2O exchanged), 2.48e2.52 (m, 2H), 2.56e
ESI-MS/MS m/z 325 (100), 281 (9). [
a
]D: ꢂ7.8ꢁ (c ¼ 1.5, MeOH).
2.60 (m, 2H), 2.83e2.88 (m, 4H), 3.85 (s, 3H), 4.09e4.17 (m, 1H),
4.43 (dd, 1H, J ¼ 6.3 and 11.5 Hz), 4.64 (dd, 1H, J ¼ 3.0 and 11.3 Hz),
6.90e6.95 (m, 2H), 7.00e7.09 (m, 2H), 7.19e7.24 (m, 3H), 7.37 (dd,
1H, J ¼ 4.4 Hz), 7.53e7.59 (m, 2H), 8.83 (dd, 1H, J ¼ 1.1 and 4.1 Hz).
ESI-MS m/z 421 (M þ H)þ. ESI-MS/MS m/z 325 (100), 153 (96). The
tartrate salt melted at 115 ꢁC dec (from CH3OH/diethyl ether). Anal.
(C24H28N4O3$C4H6O6) C, H, N.
4.7.15. 1-[2-(4-Hydroxyphenyl)phenyl]piperazine (38)
A solution of 1-(4-methoxybiphenyl-2-yl)piperazine (0.16 g,
0.6 mmol) in 5 mL of 48% HBr was refluxed overnight. After cooling,
the reaction mixture was neutralized with conc. NH4OH and
extracted with AcOEt (3 ꢄ 20 mL). The organic layers were washed
with brine, dried over Na2SO4 and concentrated under reduced
pressure to yield pure compound as a brownish semisolid (0.10 g,
4.7.10. 1-[4-[2-(4-Methoxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol (16)
65% yield). 1H NMR (CDCl3):
d 1.71 (br s, 1H, D2O exchanged), 2.99
(br s, 8H), 6.86 (d, 2H, J ¼ 8.3 Hz), 6.99 (d, 1H, J ¼ 7.7 Hz), 7.07e7.10
(m, 1H), 7.12e7.22(m, 2H), 7.45 (d, 2H, J ¼ 8.5 Hz), 8.10 (br s, 1H, D2O
exchanged), 8.28 (d, 1H, J ¼ 1.4 Hz). GC/MS m/z 255 (Mþþ1, 9), 254
(Mþ, 56), 212 (100), 197 (44), 196 (55).
Eluted with CHCl3/MeOH, 98:2. 55% Yield. 1H NMR (CDCl3):
d
2.38e2.43 (m, 3H, 1H D2O exchanged), 2.47e2.52 (m, 2H), 2.56e
2.61 (m, 2H), 2.86e2.88 (m, 4H), 3.85 (s, 3H), 4.04e4.12 (m, 1H),
4.25e4.31 (m, 1H), 4.37e4.42 (m, 1H), 6.92e6.95 (m, 2H), 7.01e7.09
(m, 2H), 7.19e7.24 (m, 2H), 7.56e7.59 (m, 2H), 8.05 (dd, 1H, J ¼ 1.1
and 2.9 Hz), 8.13 (d, 1H, J ¼ 2.9 Hz), 8.28 (d, 1H, J ¼ 1.1 Hz). ESI-MS
m/z 421 (M þ H)þ. ESI-MS/MS m/z 325 (100), 281 (12). The hy-
drochloride salt melted at 208e210 ꢁC (from CH3OH/diethyl ether).
Anal. (C24H28N4O3$HCl) C, H, N.
4.8. (R)-1-[4-[2-(4-Hydroxyphenyl)phenyl]piperazin-1-yl]-3-(2-
pyrazinyloxy)-2-propanol ((R)-39)
The compound was prepared as reported for (R)-16 starting
from (R)-37 and piperazine 38. Eluted with CHCl3/MeOH, 98:2. Pale