4588
Y.-Y. Ku et al./ Tetrahedron 62 (2006) 4584–4589
1.98 (t, JZ2.7 Hz, 1H), 2.15 (q, JZ8.8 Hz, 1H), 2.3–2.5 (m,
4H), 3.0 (m, 1H), 3.14 (td, JZ8.6, 2.8 Hz, 1H); 13C NMR
(400 MHz, CDCl3): d 18.7, 19.3, 21.9, 32.9, 52.9, 53.9,
59.7, 68.8, 83.0; GC–MS m/z 138 (MCC1).
methyl-pyrrolidin-1-yl)-ethyl]-benzofuran-5-yl}-benzoni-
trile 1. 2-Propanol (150 mL) and absolute EtOH 3A (60 mL)
were added. The resulting solution was heated to w60 8C,
and a solution of L-tartaric acid (7.5 g, 50.0 mmol) in
absolute ethanol 3A (90 mL) added slowly at 60 8C. The
resulting solution was seeded with w0.5 g of 1A, and
cooled very slowly to room temperature (approximately
w2 8C/h). The slurry was stirred at room temperature
overnight, it was then cooled to 0 8C for 2 h. The solid was
filtered and dried at 65 8C in a vacuum oven overnight to
give 19.6 g of 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-
benzofuran-5-yl}-benzonitrile L-tartrate 1A as a white
solid (81% recovery and 70% isolated overall yield). Mp
152–154 8C; 98% pure by HPLC (PA), eeZ98.2% by chiral
HPLC; Pd!10 ppm, Cu!10 ppm. Mp: 166–167 8C (lit.5
166–167 8C). The spectral data was consistent with those
reported.5
4.1.6. 40-Hydroxy-30-iodo-biphenyl-4-carbonitrile 3. To a
reaction vessel provided with a mechanical stirrer and
dropping funnel were charged 40-hydroxy-biphenyl-4-
carbonitrile 2 (215 g, 1.1 mol), glacial acetic acid (1.8 kg,
w1.7 L), and concentrated sulfuric acid (53.3 g, 0.54 mol).
N-Iodosuccinimide (240 g, 97%, 1.04 mol) was added
portion-wise at the internal temperature of w20 8C. The
suspension was agitated overnight (20 h) or until 2 was less
than 4% by HPLC. The reaction mixture was diluted with
water (3.4 kg, 3.4 L), and mixed at 20 8C for 1 h. The
product was collected by filtration, washed with water
(3.2 kg), and heptane (1.5 kg), dried at 55 8C under vacuum
with a nitrogen bleed for 48 h to give 327 g (93% yield) of 3
as an off-white solid. The product was used directly in the
next step without further purification. An analytical sample
was obtained by crystallizing from methanol; mp: 166–
1
References and notes
167 8C; H NMR (400 MHz, CDCl3): d 6.99 (3H, s), 7.62
(dd, JZ8.4, 2.3 Hz, 1H), 7.79 (d, JZ8.4 Hz, 2H), 7.85 (d,
JZ8.4 Hz, 2H), 8.05 (d, JZ2.3 Hz, 1H), 10.70 (s, br, 1H);
13C NMR (400 MHz, DMSO-d6), d 85.3, 108.8, 114.9,
118.5, 126.3, 127.9, 130.5, 132.2, 136.6, 142.5, 156.8;
CI-MS (NH3): m/z 339 (MCNHC4 ).
1. For reviews, see: Leurs, R.; Blandina, P.; Tedford, C.;
Timmerman, H. Trends Pharmacol. Sci. 1998, 19, 177. (b)
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4.1.7. 4-{2-[2-(2-Methylpyrrolidin-1-yl)-ethyl]-benzo-
furan-5-yl}-benzonitrile L-tartrate 1A. A solution
of 1-but-3-ynyl-2(R)-methyl-pyrrolidine
9
(12.0 g,
87.5 mmol) in CH3CN (200 mL) was purged with nitrogen.
To this solution were added 40-hydroxy-30-iodo-biphenyl-4-
carbonitrile
3 (18.7 g, 58.3 mmol), CuI (220 mg,
1.16 mmol), PdCl2–(Ph3P)2 (409 mg, 0.58 mmol), followed
by i-Pr2NH (35.0 g, 345 mmol) under N2. The resulting
mixture was stirred at room temperature overnight under
nitrogen or until all the starting material 40-hydroxy-30-
iodo-biphenyl-4-carbonitrile was consumed monitored by
HPLC. The reaction mixture was concentrated to about
100 mL volume, and toluene (400 mL) and 5% NaHCO3
aqueous solution were added. The mixture was stirred for
w10 min, and filtered through a layer of Celite to remove
some solid impurities. The filtrate was washed with 5%
NaHCO3 (2!400 mL). The organic layer was extracted
with mixture of solvents of CH3SO3H–NMP–H2O (10/20/
70 by volume) (300 and 100 mL), respectively. The
combined aqueous layer was washed with isopropyl acetate
(200 mL). Isopropyl acetate (400 mL) was added, and the
resulting mixture was cooled to w5 8C, and then basified to
pHw13 at the internal temperature ! 25 8C with 50%
NaOH. The upper organic phase was separated, and the
lower aqueous solution was extracted with IPAC (100 mL).
The combined organic solution was washed with 5%
NaHCO3 (2!400 mL), then 25% brine (200 mL). The
organic layer was assayed to contain 16 g of free base 1 by
HPLC. Activated carbon, Darco KB-B (1.5 g), and silica gel
(15.0 g) were added, and the mixture was stirred at room
temperature for 1 h and filtered through a layer of Celite.
The filtrate was concentrate to one-fourth of the original
volume, and isopropyl acetate (200 mL) was added. The
solution was filtered to remove inorganic salt, and
concentrated to dryness to give the free base 4-{2-[2-(2-
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