D. De Vita et al. / European Journal of Medicinal Chemistry 49 (2012) 334e342
339
injected by an Harvard pump using a flow-rate of 5e10
infused in the electrospray system.
Elemental analyses were obtained by a PE 2400 (PerkineElmer)
analyzer and the analytical results were within ꢀ0.4% of the
theoretical values for all compounds.
m
l minꢁ1
,
Methanol/dichloromethane (0.4 : 9.6) was used as eluent for the
chromatographic purification. 5a was obtained in 48% yield as
a white solid, mp 70e2 ꢂC (from ethylacetate).1H NMR (CDCl3):
d
8.14 (d, 2H, J ¼ 7.6 Hz), 7.72 (d, 2H, J ¼ 7.6 Hz), 7.38e7.32 (m, 6H),
7.00 (s,1H), 6.84 (s,1H), 6.22 (dd,1H, J ¼ 6.7 Hz, J ¼ 5.0 Hz), 4.44 (dd,
1H, J ¼ 14.1 Hz, J ¼ 6.3 Hz), 4.39 (dd, 1H, J ¼ 14.1 Hz, J ¼ 5.0 Hz). IR:
n
4.1.2. General procedure for the synthesis of 3aed, 5a and 6aec
4.1.2.1. Example: synthesis of (ꢀ)2-(1H-imidazol-1-yl)-1-phenylethyl-
3-(trifluoromethyl)benzoate (3a). To a stirred suspension of 2-(1H-
imidazol-1-yl)ethanol (2a) (0.53 mmol) in dry acetonitrile (5 mL)
was added sodium hydride (0.53 mmol). The reaction mixture was
stirred for 2 h at room temperature (rt) and then treated with 3-
(trifluoromethyl)benzoyl chloride (0.75 mmol). The reaction
mixture was stirred for 24 h at rt. The solvent was removed under
reduced pressure and the residue was dissolved in an adequate
volume of dichloromethane (5e25 mL) and washed with aqueous
saturated potassium carbonate.
1726 cmꢁ1. MS, m/z: 361 [M þ H]þ.
4.1.2.6. Synthesis of (ꢀ)2-(1H-imidazol-1-yl)-1-phenylethyl biphenyl-
4-carboxylate (6a). 6a was prepared as described above for 3d
using the alcohol 2a and biphenyl-4-carbonyl chloride. Methanol/
ethylacetate (0.25 : 9.75) was used as eluent for the chromato-
graphic purification. 6a was obtained in 40% yield as a white solid,
mp 110e2 ꢂC (from ethylacetate). 1H NMR (CDCl3):
d 8.15e8.08 (m,
2H), 7.55e7.68 (m, 2H), 7.69e7.60 (m, 2H), 7.50e7.29 (m, 9H), 7.02
(s, 1H), 6.84 (s, 1H), 6.24 (t, 1H, J ¼ 5.4 Hz), 4.49e4.40 (m, 2H). IR:
n
1718 cmꢁ1. MS, m/z: 369 [M þ H]þ.
The separated organic layer was dried over anhydrous sodium
sulphate and after filtration was evaporated under reduced pres-
sure. The obtained crude yellow oil was purified by column chro-
matography on silica gel using methanol/dichloromethane (1 : 9) as
eluent to give 80 mg of 3a as colorless oil (yield 58%).
4.1.2.7. Synthesis of (ꢀ)1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)
ethyl biphenyl-4-carboxylate (6b). 6b was prepared as described
above for 6a using the alcohol 2b. After addition of biphenyl-4-
carbonyl chloride the reaction mixture was refluxed for 3 h.
Methanol/ethylacetate (0.25 : 9.75) was used as eluent for the
chromatographic purification, and the more retained fraction was
furtherly purified by a column chromatography on alumina with
the same eluent. 6b was obtained in 75% yield as colorless waxy
solid.
1H NMR (CDCl3):
d
8.29 (s, 1H), 8.21 (d, 1H, J ¼ 7.8 Hz), 7.86 (dd,
1H, J ¼ 7.8 Hz, J ¼ 0.8 Hz), 7.63 (t, 1H, J ¼ 7.8 Hz), 7.41e7.38 (m, 4H),
7.34e7.30 (m, 2H), 7.04 (s, 1H), 6.86 (s, 1H), 6.21 (dd, 1H, J ¼ 6.6 Hz,
J ¼ 4.7 Hz), 4.49 (dd, 1H, J ¼ 6.6 Hz, J ¼ 16.6 Hz). 4.43 (dd, 1H,
J ¼ 4.7 Hz, J ¼ 16.6 Hz). IR:
n
1726 cmꢁ1. MS, m/z: 361 [M þ H]þ.
1H NMR (CDCl3):
d
8.13 (d, 2H, J ¼ 8.3 Hz), 7.71 (d, 2H, J ¼ 8.9 Hz),
4.1.2.2. Synthesis of (ꢀ)1-(4-fluorophenyl)-2-(1H-imidazol-1-yl)
ethyl 3-(trifluoromethyl)benzoate (3b). 3b was prepared as
described above for 3a using the alcohol 2b. Refluxing conditions
were used during 2 h period. Methanol/dichloromethane (0.4 : 9.6)
was used as eluent for the chromatographic purification. 3b was
7.69e7.61 (m, 2H), 7.55e7.46 (m, 3H), 7.44e7.40 (m, 1H), 7.33e7.25
(m, 2H), 7.09e7.01 (m, 3H), 6.88 (s, 1H), 6.25 (t, 1H, J ¼ 5.4 Hz), 4.46
(d, 2H, J ¼ 5.4 Hz). IR:
n
1713 cmꢁ1. MS, m/z: 387 [M þ H]þ.
4.1.2.8. Synthesis of (ꢀ)1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)
ethyl biphenyl-4-carboxylate (6c). 6c was prepared as described
above for 6a using the alcohol 2c. Methanol/ethylacetate (0.25 :
9.75) was used as eluent for the chromatographic purification. 6c
was obtained in 56% yield as a colorless waxy solid. 1H NMR
obtained in 54% yield as a colorless oil. 1H NMR (CDCl3):
d 8.30 (s,
1H), 8.23 (d, 1H, J ¼ 7.8 Hz), 7.87 (d, 1H, J ¼ 7.8 Hz), 7.63 (t, 1H,
J ¼ 7.8 Hz), 7.36 (s, 1H), 7.29e7.26 (m, 2H), 7.07e7.02 (m, 3H), 6.87
(s, 1H), 6.21 (t, 1H, J ¼ 6.6 Hz), 4.46 (dd, 1H, J ¼ 14.6 Hz, J ¼ 6.6 Hz),
4.40 (dd, 1H, J ¼ 14.6 Hz, J ¼ 4.8 Hz). IR:
n
1729 cmꢁ1. MS, m/z: 379
(CDCl3):
d
8.12 (d, 2H, J ¼ 8.4 Hz), 7.70 (d, 2H, J ¼ 8.4 Hz), 7.67e7.60
[M þ H]þ.
(m, 2H), 7.51e7.41 (m, 4H), 7.35 (d, 2H, J ¼ 8.4 Hz), 7.24 (d, 2H,
J ¼ 8.4 Hz), 7.04 (s, 1H), 6.86 (s, 1H), 6.22 (t, 1H, J ¼ 5.4 Hz), 4.43 (d,
4.1.2.3. Synthesis of (ꢀ)1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)
ethyl 3-(trifluoromethyl)benzoate (3c). 3c was prepared as
described above for 3a using the alcohol 2c. Methanol/dichloro-
methane (0.4 : 9.6) was used as eluent for the chromatographic
purification. 3c was obtained in 56% yield as a colorless oil. 1H NMR
2H, J ¼ 5.4 Hz). IR:
n
1718 cmꢁ1. MS, m/z: 403 [M þ H]þ.
4.1.3. Preparation of the hydrochlorides 4b, c
3b was dissolved in methanol and the solution was saturated
with gaseous HCl for 1 h and cooled at 0 ꢂC. The solvent was
removed under reduced pressure to give the hydrochloride 4b as
a white solid. The solid was washed with diethylether and crys-
tallized from methanol/diethylether. 4c was prepared using the
same procedure.
(CDCl3):
d
8.29 (s, 1H), 8.21 (d, 1H, J ¼ 7.8 Hz), 7.87 (d, 1H, J ¼ 7.8 Hz),
7.64 (t, 1H, J ¼ 7.8 Hz), 7.39e7.33 (m, 3H), 7.28e7.21 (m, 2H), 7.04 (s,
1H), 6.86 (s, 1H), 6.20 (t, 1H, J ¼ 5.3 Hz), 4.48e4.41 (m, 2H). IR:
n
1729 cmꢁ1. MS, m/z: 395 [M þ H]þ.
4b. Yield 100% as a white solid, mp 175e7 ꢂC 1H NMR (DMSO-
d6): 8.93 (s, 1H), 8.34 (d, 1H, J ¼ 7.7 Hz), 8.27 (s, 1H), 8.09 (d, 1H,
J ¼ 7.7 Hz), 7.80 (t, 1H, J ¼ 7.7 Hz), 7.76 (s, 1H), 7.61e7.53 (m, 3H),
7.29 (t, 2H, J ¼ 8.9 Hz), 6.36 (dd, 1H, J ¼ 8.9 Hz, J ¼ 3.3 Hz), 4.87 (dd,
4.1.2.4. Synthesis of (ꢀ)1-(4-trifluorophenyl)-2-(1H-imidazol-1-yl)
ethyl 3-(trifluoromethyl)benzoate (3d). 3d was prepared as
described above for 3a using the alcohol 2d. After addition of 3-
(trifluoromethyl)benzoyl chloride the reaction mixture was stirred
for 48 h. Methanol/dichloromethane (0.4 : 9.6) was used as eluent
for the chromatographic purification. 3d was obtained in 25% yield
1H, J ¼ 14.4 Hz, J ¼ 8.9 Hz), 4.73 (dd, 1H, J ¼ 14.4 Hz, J ¼ 3.3 Hz). IR:
n
1723 cmꢁ1
4c. Yield 100% as a white solid, mp 156e8 ꢂC (from methanol).
1H NMR (DMSO-d6):
.
as a colorless oil. 1H NMR (CDCl3):
d
8.30 (s, 1H), 8.22 (d, 1H,
d
9.08 (s, 1H), 8.34 (d, 1H, J ¼ 7.7 Hz), 8.27 (s,
J ¼ 7.8 Hz), 7.87 (d, 1H, J ¼ 7.8 Hz), 7.67e7.60 (m, 3H), 7.42 (d, 2H,
J ¼ 8.1 Hz), 7.37 (s, 1H), 7.04 (s, 1H), 6.86 (s, 1H), 6.27 (t, 1H,
J ¼ 5.5 Hz), 4.51 (dd, 1H, J ¼ 13,7 Hz, J ¼ 4.2 Hz), 4.46 (dd, 1H,
1H), 8.09 (d, 1H, J ¼ 7.7 Hz), 7.79e7.72 (m, 2H), 7.61 (s, 1H),
7.57e7.50 (m, 4H), 6.41, (dd, 1H, J ¼ 8.6 Hz, J ¼ 3.4 Hz), 4.88 (dd, 1H,
J ¼ 14.3 Hz, J ¼ 8.6 Hz), 4.77 (dd, 1H, J ¼ 14.3 Hz, J ¼ 3.4 Hz). IR:
n
J ¼ 13,7 Hz, J ¼ 2.9 Hz). IR:
n
1730 cmꢁ1. MS, m/z: 429 [M þ H]þ.
1727 cmꢁ1
.
4.1.2.5. Synthesis of (ꢀ)2-(1H-imidazol-1-yl)-1-phenylethyl 4-(tri-
fluoromethyl)benzoate (5a). 5a was prepared as described above for
3a using the alcohol 2a and 4-(trifluoromethyl)benzoyl chloride.
4.1.4. General procedure for the synthesis of 7b, c
4.1.4.1. Example: Synthesis of (ꢀ)1-(4-fluorophenyl)-2-(1H-imidazol-
1-yl)ethyl phenoxyacetate (7b). To a stirred suspension of 1-(4-