912 Letters in Drug Design & Discovery, 2011, Vol. 8, No. 10
Liu et al.
1
tube; uncorrected. IR spectra: Shimadzu FTIR-8400S
spectrophotometer. 1H-NMR spectra: Bruker ACF-300 Q
apparatus at 300 MHz (internal standard, TMS). Mass
spectrometry (MS): Hewlett–Packard 1100 LC/MSD
spectrometer; in m/z. Elemental analyses: CHN-O-Rapid
instrument.
1725, 1711, 1450, 832, 699; H-NMR (CDCl3, 300 MHz): ꢀ
1.30 (s, 6H, 2-CH3), 2.85 (s, 2H, -CH2-), 3.58 (s, 2H, -CH2-),
3.75 (s, 2H, -CH2-), 7.03-7.26 (m, 9H, Ar-H); Anal. calcd.
for C23H22ClNO2: C, 72.72; H, 5.84; N, 3.69%; Found C,
72.59; H, 5.98; N, 3.82%.
2-Chloro-1-(2-(4-chlorophenyl)-6,6-dimethyl-1-phenyl-6,7-
dihydro-5H-pyrrolizin-3-yl)ethanone (5)
6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-1H-
pyrrolizine (3)
The reactions were performed in a 100 mL three neck
round bottom flask fitted with a gas inlet port. The flask was
charged with 50 mL of absolute diethyl ether, 0.4 g (1.27
mmol) of 3, 0.25 mL of corresponding chloroacetyl chloride
and 3.72 mmol of Lewis acid (AlCl3 or BF3-Et2O). The
resulting solution was magnetically stirred at room
The 5-benzyl-3,3-dimethyl-3,4-dihydro-2H-pyrrole (2)
(10 g) was dissolved in absolute ethanol (130 mL). The
solution was cooled to 20 °C and 2-bromo-1-(4-
chlorophenyl)ethanone (13 g) was added. After stirring for
30 min, NaHCO3 (6 g) was added and the reaction was
continued at 20-25 °C with protection from light. After about
24 h, the yellowish suspension was then filtered under
suction and the solid was washed with a small amount of
cold ethanol. The dried product was suspended in water at
40-45 °C. After stirring for 30-35 min, the product was then
filtered under suction and dried in vacuo at 35-40 °C.
temperature and purged by nitrogen gas for
3 h.
Subsequently, the reaction mixture was hydrolyzed with 60
mL of water and the product was extracted with diethyl
ether. The organic layer was dried over Na2SO4 and the
solvent was distilled off to give the crude product, which
was then purified by flash column chromatography with
mixture eluent of petroleum ether and ethyl acetate (40:1) to
give a white solid.
Yield 25%; MS (ESI, m/z): [M+H]+ 322.2; IR (KBr, cm-
1
1): 2956, 2917, 2869, 1699, 1600, 832, 765, 699; H-NMR
(CDCl3, 300MHz): ꢀ 1.26 (s, 6H, 2-CH3), 2.79 (s, 2H, -CH2-
), 3.73 (s, 2H, -CH2-), 6.67 (s, 1H, =CH-); 7.03-7.26 (m, 9H,
Ar-H); Anal. calcd. for C21H20ClN: C, 78.37; H, 6.26; N,
4.35%; Found C, 78.56; H, 6.15; N, 4.31%.
Yield (40.1% (AlCl3) or 59.3 % (BF3-Et2O)); mp 157-
159 °C; MS (ESI, m/z): [M+H]+ 398.2, [M+Na]+ 420.2; IR
(KBr, cm-1): 2919, 2839, 1645, 1595, 1450, 1012, 748, 704;
1H-NMR (CDCl3, 300 MHz): ꢀ 1.31 (s, 6H, 2-CH3), 2.84 (s,
2H, -CH2-), 3.85 (s, 2H, -CH2-), 4.24 (s, 2H, -CH2-), 6.95-
7.38 (m, 9H, Ar-H). Anal. calcd. for C23H21Cl2NO: C, 69.35;
H, 5.31; N, 3.52%; Found C, 69.07; H, 5.41; N, 3.71%.
[2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-
pyrrolizin-5-yl]acetic acid (licofelone)
3 (4 g, 12.7mmol) was dissolved by stirring in dry THF.
The assembly was blanketed with N2 atmosphere. The
yellow colored solution was cooled to 10-15 °C and oxalyl
chloride (2.8 ml, 19.6 mmol) was slowly added below 15 °C
over a period of 30 min. The green colored solution was
further stirred at 18-25 °C for 20-30 min after complete
addition. The internal temperature did not exceed 20 °C, the
reaction mixture was then quenched carefully with ice (50
g). The reaction mixture was then stirred at 20-30 °C for 5-
10 min and was further diluted with diethylene glycol (32
ml) and hydrazine (6 ml, 120 mmol). The solvent THF was
distilled off during the process until the gradual rise in
internal temperature reaches 75-80 °C. The suspension was
then cooled to 50-55 °C and KOH (9.04 g, 161 mmol) was
added portion wise over a period of 30 min. The now
yellowish liquid was then heated to 95-110 °C gradually.
The temperature was then raised slowly to 140-145 °C and
during the process aqueous distillate was collected. The
batch was held at 130-145 °C for 2-3 h. The reaction
temperature was then cooled to 35-40 °C and water and
diethyl ether were added. The mixture was stirred vigorously
for 15-20 min and until the stirring switched off the layers
were allowed to settle. The aqueous phase was separated
cooled below 5 °C and acidified to pH 1 using a solution of
HCl maintaining temperature below 10 °C. The separated
solid was taken up in diethyl ether and the ethereal extract
was washed thoroughly with water. The ethereal extract was
charcoalized before being evaporated under vacuo below 20
°C. The solid was slurried in heptane and filtered under
suction and washed with heptane. The product was dried in
vacuum at 45-55 °C.
1-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-
1H-pyrrolizine-5-yl)-2-(1,2,4-triazole-1-yl)-ethanone (6)
The flask was charged with 10 mL of absolute acetone,
0.14 g (2 mmol) of 1H-1,2,4-triazole and 0.21 g (2 mmol) of
sodium carbonate, and 0.4 g (1.00 mmol) of 5. The resulting
solution was stirred at room temperature for over 24 h. Then
the solvent was distilled off to give the crude product, which
was then purified by flash column chromatography with
mixture eluent of petroleum ether and ethyl acetate (1:1) and
followed by recrystallization from acetone to give a white
solid.
Yield: 75.0%; mp: 121-122 °C; MS (ESI, m/z): [M+H]+
431, [M+Na]+ 453; IR (KBr, cm-1): 3113, 2969, 2854, 1640,
1
1490, 972, 883, 669; H-NMR (CDCl3, 300MHz): ꢀ 1.30 (s,
6H, 2-CH3), 2.85 (s, 2H, -CH2-), 4.19 (s, 2H, -CH2-), 4.69 (s,
2H, -CH2-), 6.97-7.42 (m, 9H, Ar-H), 7.92 (s, 1H, =CH-),
8.02 (s, 1H, =CH-); Anal. Calcd. for C25H23ClN4O: C, 69.68;
H, 5.38; N, 13.00%; Found C, 69.72; H, 5.31; N, 12.87%.
1-(6-(4-chlorophenyl)-2,2-dimethyl-7-phenyl-2,3-dihydro-
1H-pyrrolizine-5-yl)-2-methoxy-ethanone (7)
The flask was charged with 10 mL of absolute methanol,
0.1 g (2 mmol) of sodium methoxide and 0.4 g (1.00 mmol)
of 5. The resulting solution was stirred at room temperature
for over 24 h. Then the solvent was distilled off to give the
crude product, which was then purified by flash column
chromatography with mixture eluent of petroleum ether and
ethyl acetate (20:1) to give a white solid.
Yield: 72.5%; mp 128-130 °C; MS (ESI, m/z): [M+H]+
Yield 55.6%; mp 157 °C; MS (ESI, m/z): [M+H]+ 380,
394.2; IR (KBr, cm-1): 3437, 2959, 1650, 1515, 967, 923,
[M+Na]+ 402; IR (KBr, cm-1): 3402, 2958, 2917, 2900, 2849,