dried (MgSO4, 10 g), and then filtered. The solution was
further diluted with ethyl acetate (150 mL), and dry HCl in
diethyl ether (20 mL, 0.072 mol) was added dropwise under
stirring. After 1 h the suspension was filtered. The crystals
were washed with 2-propanol (20 mL) and dried under
vacuum at 40 °C for 12 h to afford 20 g of 4‚HCl (67%
molar yield). This hydrochloride salt was resuspended in 95%
ethanol (500 mL) and refluxed under stirring for 2 h. After
cooling to room temperature, the suspension was stirred for
1.5 h and filtered. The filtrate was concentrated to dryness
and the residue taken up in acetone (250 mL) and heated at
reflux for 2 h. After cooling to room temperature, the
suspension was stirred for 1.5 h and filtered. The crystals
were washed with acetone (50 mL) and dried under vacuum
at 40 °C for 12 h to afford pure 4‚HCl (15 g, 50% molar
acetic acid (0.635 mL) were added with stirring, and the
mixture was extracted with CH2Cl2 (55 mL). The organic
layer was washed with water (3 × 50 mL), dried with MgSO4
(9 g), filtered, and concentrated under vacuum as an oil. The
oil was purified by chromatography on silica gel (80 g) using
toluene (500 mL), followed by a mixture toluene/ethyl
acetate/CH2Cl2 90/5/5 (600 mL) as eluent to afford 9 (375
1
mg, 29% molar yield). The HPLC retention time and H
NMR spectrum were identical to those of a reference sample.
(E)-δ-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-7-
(cyanomethoxy)-2,3-dihydro-1H-indole-1-pentanenitrile
14. To a solution of crude chloride 6 (15.7 g, approximately
85% purity, 0.03475 mol) in N-methylformamide (35 mL)
was added 7-cyanomethoxyindoline 13 (10.97 g, 0.063 mol),
and the resulting solution was heated at 50 °C under argon
for 48 h. Water (50 mL), saturated aqueous sodium bicar-
bonate (20 mL), and ethyl acetate (70 mL) were added, and
after vigorous stirring the organic layer was decanted off.
The aqueous layer was extracted with ethyl acetate (2 × 35
mL), and the combined organic layers were washed with
diluted sodium bicarbonate (50 mL) and water (50 mL), dried
over magnesium sulfate (10 g), filtered, and concentrated
under reduced pressure to give 26.35 g of crude material.
The crude mixture was purified by filtration on silica gel
(800 g, elution with toluene/ethyl acetate/CH2Cl2, 8/1/1). The
best chromatography fractions (11 g, 0.021 mol) were
dissolved in a mixture of ethyl acetate (62 mL) and
2-propanol (248 mL). These were then treated with a solution
of oxalic acid monohydrate (2.67 g, 0.021 mol) in 2-propanol
(62 mL). After 16 h, the crystals were filtered, washed with
2-propanol (2 × 25 mL), and dried in high vacuum to yield
14‚C2H2O4 (10 g, 82% molar yield) as yellow crystals. Calcd
For C32H27ClN4O‚C2H2O4: C, 67.04%; H, 4.80%; N, 9.20%;
Found: C, 66.77%; H, 4.75%; N, 9.29%.
1
yield over all). The HPLC retention time and H NMR
spectrum were identical to those of a reference sample.
(E)-δ-Chloro-3-[2-(7-chloro-2-quinolinyl)ethenyl-ben-
zenepentanenitrile 5. A suspension of 4‚HCl (20.05 g, 50.2
mmol) in CH2Cl2 (900 mL) was stirred under nitrogen at
room temperature. Thionyl chloride (7.28 mL, 100.4 mmol)
in CH2Cl2 (50 mL) was added over 30 min. The reaction
mixture was stirred for an additional 30 min with monitoring
by HPLC. The brown solution was cooled to 10 °C, and
aqueous saturated sodium bicarbonate solution (450 mL) was
added over 15 min. The heterogeneous mixture was stirred
vigorously for 1 h. After decanting, the organic layer was
washed with brine (100 mL), dried (MgSO4, 32 g), filtered,
and concentrated to afford 5 as brown oil (17.97 g, 93.8%
molar yield). The crude sample containing 15.5% w/w of
by-product 11 was used in the next step without further
purification. The HPLC retention time and 1H NMR spectrum
were identical to those of a reference sample.
7-Cyanomethoxyindole 8. Chloroacetonitrile (6.5 mL,
0.1 mol) was added to crude 7-hydroxyindole 6a (1.33 g,
0.01 mol) and potassium carbonate (1.38 g, 0.01 mol), and
the mixture was vigorously stirred for 24 h at room
temperature. The reaction mixture was diluted with water
(50 mL) and extracted with ethyl acetate (2 × 50 mL). The
combined organic layers were dried with anhydrous mag-
nesium sulfate (10 g) and concentrated under reduced
pressure to give 1.8 g of black oil. The crude material was
purified by filtration on a short path of silica gel (5 g, elution
with 100 mL of 1/1 CH2Cl2/n-hexane) to yield 1.3 g of a
white-to-yellow solid which was crystallized from diisopro-
pyl ether (6 mL) at 0 °C for 36 h to give 7-cyanomethoxy-
indole 8 (1.12 g, 65% molar yield); mp: 76-77 °C. The 1H
NMR spectrum was identical to that in the literature.
(E)-δ-[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-7-
(cyanomethoxy)-1H-indole-1-pentanenitrile 9. The indole
8 (655 mg, 3.75 mmol) and NaH (60% dispersion in oil;
153 mg, 3.75 mmol) were charged into a dry, 250-mL round-
bottom flask. The mixture was maintained at room temper-
ature, and DMSO (33 mL) was carefully added. After stirring
for 40 min the solution of the chloride 5 (969 mg, 2.5 mmol)
in DMSO (14 mL) was added over 10 min. The reaction
was monitored at different times (0, 0.5, 1, 2, 4, 6, 24 h) by
HPLC analysis of aliquots. After 24 h, water (50 mL) and
5-(3-Bromo-phenyl)-5-hydroxypentanenitrile 16. Prepa-
ration of iodo-(3-cyanopropyl)zinc: 2.75 g (42 mM) of zinc
dust in 4 mL of anhydrous THF was activated with 0.3 g
(1.6 mM) of 1,2-dibromoethane by heating 1 min at reflux
under nitrogen. After cooling, 0.16 mL (1.3 mM) of
trimethylsilyl chloride was added, and the suspension was
stirred for 15 min. A solution of 4-iodobutyronitrile (7.8 g,
40 mM) in 15 mL of anhydrous THF under nitrogen was
added over 15 min, and the temperature was maintained at
50 °C overnight.
The iodo-(3-cyanopropyl)zinc reagent (prepared as above)
was cooled to below 20 °C. Added to this successively were
a solution of 15 (4.25 g, 26.7 mM) in anhydrous THF (40
mL) and of 1 M TiCl4/CH2Cl2 (26.7 mL, 26.7 mM) over 15
min (T < 10 °C). After stirring 30 min at 0 °C and 5 h at 20
°C, 38 mL of water and 25 mL of saturated Na2CO3 were
added. Finally this mixture was diluted with 60 mL of CH2-
Cl2. After 30 min stirring, the salts were separated by
filtration and washed with 20 mL of water and 20 mL of
CH2Cl2. The organic layers were washed with 20 mL of
brine, dried with MgSO4, filtered, and evaporated to give 7
g of of crude oil. Purification by chromatography on silica
gel (hexane 70/EtOAc 30) and evaporation of the fractions
yielded pure 16 (5.08 g, 75% molar yield).
Vol. 10, No. 4, 2006 / Organic Process Research & Development
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