Candidate Cancer Drug for Use Against Chagas Disease
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 6 1645
hydroxylamine hydrochloride (97.54 g/mol). The solids were
suspended in 150 mL of anhydrous CH2Cl2 and stirred rapidly. Then
15.0 mL pyridine (186 mmol) was added slowly, and the mixture
was allowed to stir overnight. The crude mixture was partitioned
between CHCl3 and water. The organic phase was washed with
brine and dried with anhydrous MgSO4. Solvents were removed
under reduced pressure to produce a golden-colored oil which
crystallized upon standing. Product was triturated with hexanes,
filtered, and then used without further purification; 8.3 g lightly
6-Bromo-4-(3-chloro-2-methylphenyl)-2-methoxyquinoline (6g).
A flame dried 25 mL flask was fitted with a stir-bar and charged
with 500 mg (1.43 mmol) of 5g and 423 mg (2.86 mmol, 2 equiv)
BF4OMe3 and then sealed with a septum. The solids were suspended
in 5.5 mL of anhydrous CH2Cl2 and stirred for 20 h, at which time
5.5 mL of 1 M aqueous NaOH was added. The mixture was stirred
for about 3 h, then partitioned between CHCl3 and water, and the
organic was washed three times with brine and then dried with
MgSO4. Solvents were removed under reduced pressure to produce
a clear yellow oil, which crystallized upon standing. This was
purified on silica with 50:50 CH2Cl2:hexane to produce 329 mg of
6g as a flaky yellow-green solid, yield 63%. 1H NMR (300 MHz,
CDCl3, δ): 7.79 (d, J ) 9.0 Hz, 1H), 7.69 (dd, J ) 8.7 Hz, 2.3 Hz,
1H), 7.50 (dd, J ) 7.8 Hz, 1.2 Hz, 1H), 7.40 (d, J ) 2.1 Hz, 1H),
7.26 (m, 1H), 7.09 (dd, J ) 7.5 Hz, 1.2 Hz, 1H), 6.77 (s, 1H), 4.10
(s, 3H), 2.08 (s, 3H). ESI-MS m/z 362.3 (M + H+)+. MW: 362.65
g/mol.
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colored crystalline 12 was produced, 83% yield. H NMR (300
MHz, CDCl3, δ): 7.52 (d, J ) 2.4 Hz, 1H), 7.28 (dd, J ) 2.4 Hz,
8.1 Hz 1H), 6.61 (d, J ) 8.7 Hz, 1H), 4.69 (s (broad), 2H), 3.61
(s, 3H), 3.36 (s, 3H). ESI-MS m/z 283.1 (M + Na+)+. MW: 259.10
g/mol.
(2-Amino-5-bromophenyl)(3-chloro-2-methylphenyl)metha-
none (4g). A 250 mL flask was flame dried, charged with a stirbar,
and sealed with a new rubber septum. 2-Bromo-6-chlorotoluene
(6 mL, 45.9 mmol) was added to the flask and dissolved in 60 mL
of anhydrous THF under an atmosphere of dry nitrogen. The
solution was stirred for about 5 min and then cooled to -78 °C
with a dry ice acetone bath, and then stirred for about 10 min. Then
18 mL (45.9 mmol, 1 equiv) of n-butylithium (2.5 M in hexanes)
was added dropwise at a rate such that temperature of the reaction
remained close to -78 °C, as indicated by the slow sublimation of
CO2. The solution was allowed to stir for 20 min. A separate flask
was flame dried and fitted with a stir-bar and septum. 2-Amino-
5-bromo-N-methoxy-N-methylbenzamide 12 (5.95 g, 22.95 mmol,
0.5 equiv) was added and dissolved in 60 mL of anhydrous THF.
After stirring for about 5 min, this solution was transferred dropwise
by cannula to the flask containing the in situ generated aryllithium.
The solution was allowed to stir at this temperature for 2 h, at which
time the cooling bath was removed, allowing the flask to rise to
room temperature. Then 50 mL of 1 M aqueous HCl was added
and the biphasic mixture was allowed to stir for 30 min. Crude
product was partitioned between CHCl3 and water. The organic
phase was washed three times with saturated, aqueous NaHCO3,
and then separated and dried with MgSO4. Solvents were removed
under reduced pressure to produce an orange-brown colored oil.
This was purified on silica with 20% EtOAc/hexanes to produce
4-Chloro-N-methoxy-N-methylbenzamide (10c). 4-Chloroben-
zoic acid (20.0 g, 0.128 mols, 156.57 g/mol) was placed in a 500
mL round-bottomed flask. Thionyl chloride (120 mL) was added,
and the mixture was refluxed overnight. Thionyl chloride was
removed under reduced pressure to produce a red-colored oil.
Anhydrous toluene was added and then removed under reduced
pressure two times. The crude product was dissolved in 200 mL
anhydrous dichloromethane (DCM). Then 13.73 g (0.140 mols)
N,O-dimethylhydroxylamine·HCl (97.54 g/mol) was added, and
52 mL (0.640 mols) anhydrous pyridine was added over a period
of 10 min. The reaction was stirred under nitrogen at room
temperature overnight. Volatiles were removed under reduced
pressure. Solid was partitioned between CHCl3 and water. The
organic phase was washed with brine and then collected and dried
over anhydrous magnesium sulfate. The solvents were removed to
produce a red-colored oil, which was purified on silica with 5%
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MeOH/CH2Cl2 as eluent; 22.9 g produced, yield 90%. H NMR
(300 MHz, CDCl3, δ): 7.66 (d, J ) 8.4 Hz, 2H), 7.38 (d, J ) 8.4
Hz, 2H), 3.54 (s, 3H, -OMe), 3.36 (s, 3H, -NMe). ESI-MS m/z
200.4 (M + H+)+. MW: 199.63 g/mol.
(4-Chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (11c).
A flame-dried 125 mL round-bottomed flask was charged with a
stir bar and overpressurized with dry nitrogen gas and 3.0 mL (37.6
mmol) freshly distilled N-methylimidazole (82.11 g/mol, 1.035
g/mL). The flask was sealed with a new rubber septum, and 30
mL anhydrous THF was added. The solution was stirred for about
10 min, and then the temperature was lowered to -78 °C and stirred
for an additional 10 min. Then 16.2 mL (41.3 mmol) freshly titrated
n-butyl lithium (2.5 M in hexanes) was added dropwise through
the septum over a period of 10 min under an overpressure of dry
nitrogen. A slight color change to pale yellow was observed. This
was allowed to stir at this temperature for 45 min, and then 6.3
mL (37.6 mmol) 99% chlorotriethylsilane (Et3SiCl) was added
dropwise over 5 min. The reaction was allowed to stir for 1 h at
-78 °C, at which point 15.0 mL (37.6 mmol) freshly titrated n-butyl
lithium (2.5 M in hexanes) was added dropwise through the septum
over a period of 10 min and allowed to stir at -78 °C for an
additional 45 min. A separate flask was flame-dried and charged
with 5.0 g (25.1 mmol) Weinreb amide 10c (199.63 g/mol) and
sealed. Then 15 mL of anhydrous THF was added and the mixture
was stirred at room temperature for 10 min, and then at the
appropriate time, transferred via cannula to the flask containing
the in situ generated C-2 triethylsilyl protected N-methylimidazole
at a slow rate to maintain low temperature as indicated by the slow
sublimation of CO2. The mixture was left to stir overnight and
became a deep-red color. The reaction was quenched by the addition
of 1 M HCl until the pH of the aqueous phase was no longer basic,
as indicated by litmus paper, and then allowed to stir for one hour.
The pH of the aqueous phase was adjusted to above 8 with 1.5 M
NaOH, and the mixture was partitioned between CHCl3 and water.
The organic phase was washed with brine and dried with anhydrous
MgSO4. Solvents were removed under reduced pressure to produce
a reddish solid. Product was purified by recrystallization from
CH2Cl2 to produce 4.24 g of fluffy golden crystals, 76.6% yield.
1
6.3 g of yellow crystalline 4g, yield 85%. H NMR (300 MHz,
CDCl3, δ): 7.47 (d, J ) 7.8 Hz, 1H), 7.36 (dd, J ) 8.7 Hz, 2.1 Hz,
1H), 7.25 (d, J ) 2.1 Hz 1H), 7.21 (m, 2H), 7.11 (d, J ) 7.5 Hz
1H), 6.64 (d, J ) 8.7 Hz, 1H), 6.49 (s (broad), 2H), 2.27 (s, 3H).
ESI-MS m/z 324.3 (M + H+)+. MW: 324.60 g/mol.
6-Bromo-4-(3-chloro-2-methylphenyl)quinolin-2(1H)-one (5g). A
250 mL flask was fitted with a stir-bar and 11.9 g of 4g. A water
condenser was attached. Then 50 mL of anhydrous toluene was
added and 24.3 mL (257 mmol, 7 equiv) acetic anhydride was added
dropwise, rapidly. The solution was heated to reflux for 6 h, at
which time the volatiles were removed under reduced pressure.
Toluene was added and removed at reduced pressure two more
times. The crude product was set aside. A separate flask was fitted
with a stir-bar and a septum and loaded with 24.7 g (220 mmol, 6
equiv) of 95% tBuOK powder. This was suspended in 120 mL of
1,2-dimethoxyethane (DME) and stirred for about 10 min. The
temperature was lowered to 0 °C. The crude product set aside
previously was dissolved in 45 mL of 1,2-dimethoxyethane and
then transferred dropwise by cannula to the flask containing the
tBuOK suspension. The color of the solution changed to yellow,
and the mixture was allowed to stir under an inert atmosphere
overnight. DME solvent was removed at reduced pressure and the
resulting paste was suspended in approximately 300 mL water. The
solid was collected by filtration and used at the next step without
purification. 8.4 g (24.10 mmol) of 5g was produced as a fluffy,
1
white solid, yield 66%. H NMR (300 MHz, CDCl3, δ): 7.62 (dd,
J ) 8.7 Hz, 1.8 Hz, 1H), 7.53 (d, J ) 7.8 Hz, 1H), 7.39 (d, J )
8.7 Hz, 1H), 7.30 (m, 1H), 7.21 (d, J ) 1.8 Hz, 1H), 7.11 (d, J )
7.2 Hz, 1H), 6.62 (s, 1H), 2.17 (s, 3H). ESI-MS m/z 348.3 (M +
H+)+. MW: 348.62 g/mol.