Pyrazole Derivatives as Anticancer Agents
layer was kept, washed with brine (3 9 15 mL), and dried
with anhydrous sodium sulfate. The solvent was removed,
the obtained solid was recrystallized by methanol to give a
white solid 7. Yield: 90%; M.P.: 112 ~ 114 °C [Ref (9): 113–
4-(4-Chlorobenzyl)-5-(4-chlorophenyl)-1H-pyrazole-
3-carboxylic acid (10)
Ethyl 4-(4-chlorobenzyl)-5-(4-chlorophenyl)-1H-pyrazole-3-
carboxylate 8 (200 mg, 0.53 mmol) was dissolved in a
mixture of ethanol-THF (1: 1, 10 mL), added with 10%
NaOH (5 mL). The reaction mixture was stirred at 60 °C
overnight and then the THF was removed under vacuum.
Water was added, and the residue was acidified with 1N
hydrochloric acid. The resulted solid was filtered, washed
by water, and dried to give a white solid 10. Yield: 92%;
115 °C].
1, 3-Bis (4-chlorophenyl) propan-2-one (6)
A
solution of 4-chlorophenylacetic acid (2.0 g,
14.7 mmol) in dry methylene chloride (80 mL) was
+
added slowly to a solution of DCC (2.8 g, 14.7 mmol)
and DMAP (0.45 g, 3.6 mmol) in dry methylene chloride.
After stirring at room temperature for 4 h, the solvent
was removed under vacuum; the residue was extracted
by ethyl estate and water; organic layer was taken,
washed with brine (3 9 15 mL), and dried with anhy-
drous sodium sulfate; the organic solvent was removed
to give a yellow solid 6. Yield: 75%; M.P.: 93 ~ 94 °C
M.P. 240 ~ 242 °C; MS (ESI): 346 [M] .
General procedure for synthesis of 11a-11e, 13a-
13e
9 or 10 (0.15 mM), DCC (62 mg, 0.30 mM), and HOBt
(21 mg, 0.15 mM) were dissolved in anhydrous methylene
chloride (10 mL). The reaction was protected under N2
and stirred at 0 °C for 30 min while added a solution of
corresponding secondary amine (22 mg, 0.30 mM) in
methylene chloride (10 mL). After 3 h, the solid was fil-
tered and the filtrate was washed with brine (3 9 10 mL)
and dried with anhydrous sodium sulfate. Purification of
the residue by flash chromatography (silica, petroleum
ether/ethyl estate/triethylamine = 3: 1: 0.01 ~ 1: 1: 0.01)
resulted in 11a-11e, 12a-12e.
[Re (10): 93 °C].
Ethyl 4, 5-bis (4-chlorophenyl)-1H-pyrazole-3-
carboxylate (7)
Compound 5 (260 mg, 2.28 mmol) and DBU (489 mg,
3.21 mmol) were slowly added to the solution of 2
(500 mg, 1.87 mmol) in acetonitrile (5 mL), protected by
N . The reaction was stirred at room temperature for 3 h.
2
The reaction solvent was removed under vacuum and
extracted by saturated sodium carbonate/methylene chlo-
ride (1: 1, 100 mL). The organic layer was kept, washed
with brine, and dried with anhydrous sodium sulfate. Purifi-
cation of the residue by flash chromatography (silica, ethyl
(4, 5-Bis (4-chlorophenyl)-1H-pyrazol-3-yl)
(pyrrolidin-1-yl) methanone (11a)
Yield: 83%; M.P.: 215 ~ 219 °C; H NMR (500 MHz,
1
CDCl ) d 7.34 (m, Ar-H, 6H), 7.23 (m, Ar-H, 2H), 3.57 (t,
3
estate/petroleum ether = 1:9 ~ 1: 1) resulted in a white oily
J = 7.0 Hz, CH
2H), 1.75 (m, CH
2
, 2H), 3.08 (m, CH
2 2
, 2H), 1.87 (m, CH ,
1
+
stuff 7. Yield: 50%; H NMR (500 MHz, CDCl
Ar-H, 4H), 7.25 (m, 4H), 4.22 (d, J = 7.1 Hz, CH
3
) d 7.35 (m,
, 2H),
2
, 2H); MS (ESI): 386 [M+H] .
2
+
3
1.17 (t, J = 7.1 Hz, CH , 3H); GC/MS (ESI): 360 [M] .
(
(
4, 5-Bis (4-chlorophenyl)-1H-pyrazol-3-yl)
piperidin-1-yl) methanone (11b)
1
Ethyl 4-(4-chlorobenzyl)-5-(4-chlorophenyl)-1H-
pyrazole-3-carboxylate (8)
Yield: 73%; M.P.: 191 ~ 195 °C; H NMR (500 MHz, CDCl )
3
d 7.28 (dt, J = 7.8, 6.0 Hz, Ar-H, 3H), 7.16 (d, J = 8.4 Hz,
Referring to above reaction, using 6 in replace of 5
Ar-H, 2H), 3.60 (m, CH
2
, 2H), 3.06 (m, CH
2
, 2H), 1.48 (m,
+
resulted to the white solid 8. Yield 80%; M.P.: 146 ~
CH 9 2, 4H), 1.02 (m, CH
2
2
, 2H); MS (ESI): 400 [M+H] .
1
1
7
1
47 °C; H NMR (500 MHz, CDCl
3
) d 7.81 (s, Ar-H, 2H),
.31 (m, Ar-H, 6H), 4.65 (s, CH , 2H), 4.15 (m, CH , 2H),
.28 (m, CH
2
2
+
3
, 3H); MS (ESI): 375 [M+H] .
(4, 5-Bis (4-chlorophenyl)-1H-pyrazol-3-yl)(4-
methylpiperazin-1-yl) methanone (11c)
Yield: 93%; M.P.: 225 ~ 230 °C; H NMR (500 MHz,
1
4
, 5-Bis (4-chlorophenyl)-1H-pyrazole-3-carboxylic
CDCl
CH 9 2, 4H), 1.87 (m, CH
MS (ESI): 415 [M+H] .
3
) d 7.34 (m, Ar-H, 6H), 7.23 (m, Ar-H, 2H), 3.57 (m,
acid (9)
2
2
+ CH , 5H), 1.75 (m, CH , 2H);
3
2
+
Ethyl 4, 5-bis (4-chlorophenyl)-1H-pyrazole-3-carboxylate
7
(200 mg, 0.56 mmol) was dissolved in a mixture of etha-
nol-THF (1: 1, 10 mL), added with 10% NaOH (5 mL). The
reaction mixture was stirred at 60 °C overnight, and then
the THF was removed under vacuum. Water was added,
and the residue was acidified with 1N hydrochloric acid.
The resulted solid was filtered, washed by water, and
4, 5-Bis (4-chlorophenyl)-N,N-diethyl-1H-pyrazole-
3-carboxamide (11d)
Yield: 82%; M.P.: 195 ~ 197 °C; H NMR (500 MHz,
1
CDCl ) d 7.43 (m Ar-H, 2H), 7.27 (m, Ar-H, 4H), 7.25 (m,
3
dried to give a white solid 9. Yield: 90%; M.P. 236 ~
Ar-H, 2H), 2.43 (q, J = 7.1 Hz, CH
2
9 2, 4H), 0.94 (t,
+
+
238 °C; MS (ESI): 332 [M] .
J = 7.1 Hz, CH 9 2, 6H); MS (ESI): 388 [M+H] .
3
Chem Biol Drug Des 2016; 87: 673–679
675