4224
X. Che et al. / European Journal of Medicinal Chemistry 44 (2009) 4218–4226
6.1.5. Chemical synthesis of 3-(4-(3-(4-
benzamidophenoxy)propyl)piperazin-1-yl)-2-(2,4-difluorophenyl)-
1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12r)
C1–H), 3.97 (t, 2H, J ¼ 6.0 Hz, OCH2), 3.08 (d, 1H, J ¼ 13.5 Hz, C3–Ha),
2.69 (d, 1H, J ¼ 13.5 Hz, C3–Hb), 2.46 (t, 2H, J ¼ 7.3 Hz, piperazine–
CH2), 2.37 (br, 8H, piperazine–H), 2.18 (s, 3H, PhCH3), 2.00 (br, 2H,
CH2CH2CH2). MS (ESI) m/z: 472 (M þ 1). Anal. calcd. for
C25H31F2N5O2: C, 63.68; H, 6.63; N, 14.85. Found: C, 63.62; H, 6.64;
N, 14.87.
A solution of benzoyl chloride (0.007 g, 0.046 mmol) in 5 mL
methanol was added dropwise to the solution of 12o (0.02 g,
0.042 mmol), triethylamine (1 mL), and CH2Cl2 (5 mL) at 0 ꢀC. The
mixture was stirred at room temperature for 5 h. The solvent was
evaporated under reduced pressure. The residue was purified by
column chromatography (CH2Cl2:MeOH 100:2, v/v) to give 12r as
6.1.11. 3-(4-(3-(3-Bromophenoxy)propyl)piperazin-1-yl)-2-
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12d)
yellow oil, 0.02 g (90.9%). 1H NMR
d
(ppm): 8.31 (s,1H, TriazC3–H), 7.86
1H NMR
d (ppm): 8.13 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–
(s, 1H, TriazC5–H), 7.85 (s, 1H, NHCO), 6.80–7.79 (m, 13H, Ar–H), 4.54
(dd, 2H, J1 ¼3.8 Hz, J2 ¼14.3 Hz, C1–H), 4.00 (t, 2H, J ¼ 6.1 Hz, OCH2),
3.09 (d,1H, J ¼ 13.5 Hz, C3–Ha), 2.72 (d,1H, J ¼ 13.3 Hz, C3–Hb), 2.52 (br,
10H, piperazine–H, piperazine–CH2), 2.08 (br, 2H, CH2CH2CH2). MS
(ESI) m/z: 577 (M þ 1). Anal. calcd. for C31H34F2N6O3: C, 64.57; H, 5.94;
N, 14.57. Found: C, 64.51; H, 5.96; N, 14.62.
H), 6.78–7.26 (m, 7H, Ar–H), 5.29 (s, 1H, 2-OH), 4.51 (dd, 2H,
J1 ¼5.6 Hz, J2 ¼14.0 Hz, C1–H), 3.94 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.07
(d, 1H, J ¼ 13.5 Hz, C3–Ha), 2.67 (d, 1H, J ¼ 13.5 Hz, C3–Hb), 2.46
(t, 2H, J ¼ 7.4 Hz, piperazine–CH2), 2.39 (br, 8H, piperazine–H),
1.90 (br, 2H, CH2CH2CH2). 13C NMR
d (ppm): 162.43, 159.46,
158.61, 150.63, 144.36, 130.21, 129.05, 125.92, 123.37, 122.45,
117.43, 113.24, 111.22, 103.86, 71.70, 65.98, 62.02, 56.07, 54.44,
52.87, 26.22. MS (ESI) m/z: 537 (M þ 1). Anal. calcd. for
C24H28BrF2N5O2: C, 53.74; H, 5.26; N, 13.06. Found: C, 53.79; H,
5.24; N, 13.04.
The synthetic method for compound 12s was similar to the
synthesis of compound 12r.
6.1.6. 2-(2,4-Difluorophenyl)-3-(4-(3-phenoxypropyl)piperazin-1-
yl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (8a)
1H NMR
d
(ppm): 8.13 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.1.12. 2-(2,4-Difluorophenyl)-3-(4-(3-(4-fluorophenoxy)
6.77–7.55 (m, 8H, Ar–H), 5.30 (br, 1H, OH), 4.52 (dd, 2H, J1 ¼ 2.1 Hz,
J2 ¼14.7 Hz, C1–H), 3.96 (t, 2H, J ¼ 6.3 Hz, OCH2), 3.07 (d, 1H,
J ¼ 13.5 Hz, C3–Hb), 2.66 (d, 1H, J ¼ 13.5 Hz, C3–Ha), 2.47 (t, 2H,
J ¼ 7.8 Hz, piperazine–CH2), 2.37 (br, 8H, piperazine–H), 1.91 (br, 2H,
CH2CH2CH2). MS (ESI) m/z: 458 (M þ 1). Anal. calcd. for C26H33F2N5O2:
C, 63.00; H, 6.39; N, 15.31. Found: C, 62.95; H, 6.41; N, 15.30.
propyl)piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12e)
1H NMR
d (ppm): 8.14 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.78–7.55 (m, 7H, Ar–H), 4.51 (dd, 2H, J1 ¼7.3 Hz, J2 ¼ 14.2 Hz, C1–
H), 3.92 (t, 2H, J ¼ 6.3 Hz, OCH2), 3.06 (d, 1H, J ¼ 13.5 Hz, C3–Ha),
2.66 (d, 1H, J ¼ 13.6 Hz, C3–Hb), 2.44 (t, 2H, J ¼ 7.4 Hz, piperazine–
CH2), 2.35 (br, 8H, piperazine–H), 1.87 (br, 2H, CH2CH2CH2). 13C
NMR
d (ppm): 163.67, 161.69, 161.59, 156.13, 150.89, 144.55, 129.22,
6.1.7. 2-(2,4-Difluorophenyl)-3-(4-(4-phenoxybutyl)piperazin-1-yl)
126.16, 115.53, 111.44, 104.28, 71.84, 66.60, 52.17, 56.27, 54.76, 54.18,
53.05, 26.53. MS (ESI) m/z: 476 (M þ 1). Anal. calcd. for
C24H28F3N5O2: C, 60.62; H, 5.94; N, 14.73. Found: C, 60.67; H, 5.93;
N, 14.69.
-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (8b)
1H NMR
d (ppm): 8.15 (s, 1H, TriazC3–H), 7.79 (s, 1H, TriazC5–H),
6.78–7.53 (m, 8H, Ar–H), 5.30 (br, 1H, OH), 4.50 (dd, 2H, J1 ¼1.5 Hz,
J2 ¼ 12.2 Hz, C1–H), 3.96 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.06 (d, 1H,
J ¼ 13.8 Hz, C3–Ha), 2.62 (d, 1H, J ¼ 13.5 Hz, C3–Hb), 2.55 (t, 2H,
J ¼ 7.5 Hz, piperazine–CH2), 2.36 (br, 8H, piperazine–H), 1.74–7.77
(m, 2H, CH2CH2CH2CH2), 1.62 (br, 2H, CH2CH2CH2CH2). MS (ESI) m/
z: 472 (M þ 1). Anal. calcd. for C31H34F2N6O3: C, 63.68; H, 6.63; N,
14.85. Found: C, 63.62; H, 6.64; N, 14.87.
6.1.13. 3-(4-(3-(2-Chlorophenoxy)propyl)piperazin-1-yl)-2-
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12f)
1H NMR
d (ppm): 8.14 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.79–7.54 (m, 7H, Ar–H), 4.51 (dd, 2H, J1 ¼5.3 Hz, J2 ¼ 14.2 Hz, C1–
H), 4.04 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.06 (d, 1H, J ¼ 13.6 Hz, C3–Ha),
2.66 (d, 1H, J ¼ 13.6 Hz, C3–Hb), 2.51 (t, 2H, J ¼ 7.6 Hz, piperazine–
CH2), 2.37 (br, 8H, piperazine–H), 1.95 (br, 2H, CH2CH2CH2). MS
(ESI) m/z: 492 (M þ 1). Anal. calcd. for C24H28ClF2N5O2: C, 58.59; H,
5.74; N, 14.24. Found: C, 58.64; H, 5.73; N, 14.23.
6.1.8. 2-(2,4-Difluorophenyl)-3-(4-(5-phenoxypentyl)piperazin-1-yl)-
1-(1H-1,2,4-triazol-1-yl)propan-2-ol (8c)
1H NMR
d (ppm): 8.14 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.76–7.58 (m, 8H, Ar–H), 5.29 (br, 1H, OH), 4.47 (dd, 2H, J1 ¼4.8 Hz,
J2 ¼ 10.5 Hz, C1–H), 3.92 (t, 2H, J ¼ 6.4 Hz, OCH2), 3.06 (d, 1H,
J ¼ 13.5 Hz, C3–Ha), 2.65 (d, 1H, J ¼ 13.8 Hz, C3–Hb), 2.36 (br, 8H,
piperazine–H), 2.25 (t, 2H, J ¼ 7.6 Hz, piperazine–CH2), 1.74–1.78
(m, 2H, CH2CH2CH2CH2CH2), 1.45 (br, 4H, CH2CH2CH2CH2CH2). MS
(ESI) m/z: 486 (M þ 1). Anal. calcd. for C26H32F2N6O3: C, 64.31; H,
6.85; N, 14.42. Found: C, 64.28; H, 6.86; N, 14.42.
6.1.14. 3-(4-(3-(4-Bromophenoxy)propyl)piperazin-1-yl)-2-
(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12g)
1H NMR
d (ppm): 8.14 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.73–7.56 (m, H, Ar–H), 5.29 (s, 1H, 2-OH), 4.51 (dd, 2H, J1 ¼6.7 Hz,
J2 ¼ 14.2, C1–H), 3.92 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.06 (d, 1H, J ¼ 13.5 Hz,
C3–Ha), 2.66 (d, 1H, J ¼ 13.5 Hz, C3–Hb), 2.43 (t, 2H, J ¼ 7.1 Hz, piper-
azine–CH2), 2.35 (br, 8H, piperazine–H), 1.87 (br, 2H, CH2CH2CH2).
6.1.9. 2-(2,4-Difluorophenyl)-3-(4-(3-(m-tolyloxy)
13CNMR
d(ppm):163.23,161.29,157.73,150.53,144.29,131.79,129.00,
propyl)piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12b)
125.91, 115.96, 112.28, 111.20,103.86, 71.74, 65.95, 62.02, 56.00, 54.40,
53.97, 52.81, 26.19. MS (ESI) m/z: 537 (M þ 1). Anal. calcd. for
C24H28BrF2N5O2: C, 53.74; H, 5.26; N, 13.06. Found: C, 53.69; H, 5.27;
N, 13.09.
1H NMR
d (ppm): 8.13 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.66–7.55 (m, 7H, Ar–H), 4.51 (dd, 2H, J1 ¼5.4 Hz, J2 ¼ 14.0, C1–H),
3.94 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.06 (d,1H, J ¼ 13.5 Hz, C3–Ha), 2.66 (d,
1H, J ¼ 13.5 Hz, C3–Hb), 2.45 (t, 2H, J ¼ 7.4 Hz, piperazine–CH2), 2.37
(br, 8H, piperazine–H), 2.32 (s, 3H, PhCH3),1.89 (br, 2H, CH2CH2CH2).
MS (ESI) m/z: 472 (M þ 1). Anal. calcd. for C25H31F2N5O2: C, 63.68; H,
6.63; N, 14.85. Found: C, 63.63; H, 6.64; N, 14.88.
6.1.15. 2-(2,4-Difluorophenyl)-3-(4-(3-(4-
nitrophenoxy)propyl)piperazin-1-yl)-1-(1H-1,2,4-triazol-1-
yl)propan-2-ol (12h)
1H NMR
d (ppm): 8.14 (s, 1H, TriazC3–H), 7.78 (s, 1H, TriazC5–H),
6.1.10. 2-(2,4-Difluorophenyl)-3-(4-(3-(o-tolyloxy)
6.78–8.18 (m, 7H, Ar–H), 4.51 (dd, 2H, J1 ¼9.7 Hz, J2 ¼ 14.2, C1–H),
4.06 (t, 2H, J ¼ 6.2 Hz, OCH2), 3.07 (d, 1H, J ¼ 13.5 Hz, C3–Ha), 2.67
(d, 1H, J ¼ 13.5 Hz, C3–Hb), 2.46 (t, 2H, J ¼ 6.4 Hz, piperazine–CH2),
2.37 (br, 8H, piperazine–H), 1.94 (br, 2H, CH2CH2CH2). MS (ESI) m/z:
propyl)piperazin-1-yl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (12c)
1H NMR
d
(ppm): 8.15 (s, 1H, TriazC3–H), 7.80 (s, 1H, TriazC5–H),
6.76–7.53 (m, 7H, Ar–H), 4.53 (dd, 2H, J1 ¼3.2 Hz, J2 ¼ 14.1 Hz,