kg, 86.7%) as a colorless crystalline solid, mp 160-162 °C;
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J ) 8.5 Hz, 1H),
7.92 (s, 1H), 7.68 (d, J ) 8.5 Hz, 2H), 7.52-7.43(m, 4H),
7.38 (t, J ) 7.5 Hz, 1H), 7.31-7.22 (m, 2H), 6.71 (s, 1H),
3.80 (s, 3H), 2.34 (2, 1H), 1.64 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 193.52, 161.93, 150.47, 143.21, 139.12, 136.33,
135.54, 132.48, 132.29, 131.77, 131.47, 130.59, 130.57,
129.21, 129.19, 128.90, 128.49, 125.47, 123.91, 122.10,
119.66, 115.12, 95.99, 81.08, 65.36, 31.73, 30.11.
was allowed to cool and stirred at room temperature for 1 h.
The crystalline material was isolated by filtration, rinsed with
i-PrOH (1.9 L), and then dried under vacuum at 40-45 °C
to yield the tartrate salt 4 (358 g, 40%, 98.4% ee), mp 157
1
°C dec; H NMR (400 MHz, DMSO-d6) δ 7.67 (s, 1H),
7.63-7.55 (m, 2H), 7.46-7.40 (m, 2H), 7.36 (m, 4H), 7.18-
7.14 (m, 3H), 6.85 (s, 1H), 6.53 (s, 1H), 6.07 (s, 1H), 4.28
(s, 2H), 3.65 (s, 3H), 3.32 (s, 3H), 2.49 (s, 2H), 1.47 (s,
6H); 13C NMR (100 MHz, DMSO-d6) δ 174.05, 161.18,
149.92, 144.65, 140.99, 140.94, 139.90, 139.50, 137.25,
136.30, 132.71, 132.00, 130.69, 129.59, 129.11, 128.60,
125.43, 123.72, 121.58, 119.04, 115.85, 97.49, 80.61, 75.74,
72.89, 64.33, 33.90, 32.21.
(R,S)-6-[(4-Chlorophenyl)-hydroxy-(3-methyl-3H-im-
idazol-4-yl)-methyl]-4-(3-(3-hydroxy-3-methylbutyn-1-yl)-
phenyl)-1-methyl-1H-quinolin-2-one (8). To a stirred so-
lution of 13-mesylate (43.5 kg, 169 mol) in MTBE (160 L)
was added water (30 L) followed by aqueous NaOH (10.5
L, 50%). The mixture was stirred for 30 min, after which
the layers were separated. The aqueous phase was extracted
with MTBE (83 L), and the combined organic phases were
washed with water (17 L), followed by aqueous sodium
chloride (5.35 kg in 15 L of water). The organic solution
was dried over MgSO4 (14 kg), filtered, and rinsed with
MTBE (19 L). The filtrate was stirred in the presence of
molecular sieves (4Å, 20 kg) for 24 h. The sieves were
removed by filtration and rinsed with MTBE (19 L). The
solution was concentrated under vacuum to an oil, then
diluted with THF (22.7 L, 276 mol) and dichloromethane
(625 L). A solution of 1 M EtMgBr/MTBE (116 kg, 138
mol) was slowly added over 1 h, and the resulting solution
was stirred for an additional 7 h. A solution of 9 (15.8 kg,
35 mol) in dichloromethane (265 L) was added to the
Grignard mixture over 30 min. The reaction mixture was
heated to reflux for 8 h and then allowed to cool to room
temperature and was quenched with aqueous NH4Cl solution
(80.2 kg in 590 L of water). The biphasic mixture was stirred
for 30 min, allowed to settle, and then the layers were
separated. The organic solution was washed with water (590
L) and then atmospherically distilled to 75 L. The resulting
slurry was allowed to cool to ambient temperature and further
stirred for 2 h. The crystalline material was isolated by
filtration, rinsed with dichloromethane (38 L), and dried
under vacuum at 40-45 °C to yield the title compound (16.4
kg, 88%) as a colorless crystalline solid, mp 175 °C dec; 1H
NMR (400 MHz, DMSO-d6) δ 7.63-7.55 (m, 3H), 7.46-
7.40 (m, 2H), 7.36-7.27 (m, 4H), 7.18-7.14 (m, 3H), 6.83
(s, 1H), 6.53 (s, 1H), 6.04 (s, 1H), 5.74 (s, 1H), 3.65 (s,
3H), 3.34 (s, 3H), 1.47 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 161.15, 149.90, 144.96, 141.27, 139.87, 139.71, 137.29,
136.02, 132.55, 132.00, 130.96, 130.30, 129.64, 129.15,
128.56, 125.38, 123.67, 121.58, 118.98, 115.87, 97.52, 80.58,
75.77, 64.30, 33.58, 32.25, 29.93.
(R)-6-[(4-Chlorophenyl)-hydroxy-(3-methyl-3H-imida-
zol-4-yl)-methyl]-4-(3-ethynylphenyl)-1-methyl-1H-quino-
lin-2-one (1). A solution of 4 (5.8 kg, 8.4 mol) in 2-Me-
THF (116 L) was stirred in the presence of aqueous sodium
hydroxide (58 L, 1 M) for 30 min. The layers were separated,
and the organic phase was successively washed with 1 N
NaOH (58 L), water (58 L), and saturated brine (58 L). The
organic solution was concentrated by distillation to 50 L,
diluted with THF (46.4 L), and further distilled to 50 L. The
residual material was allowed to cool to room temperature
and then was diluted with THF (46.4 L). To the resulting
solution was added KOtBu (208 g, 1.85 mol), and the
reaction mixture was atmospherically distilled while adding
fresh THF to maintain constant reaction volume until 186 L
THF had been distilled. The solution was then further
concentrated in a vacuum to 14 L. The residual material was
dissolved in DCM (58 L) and stirred in the presence of water
(58 L) and saturated brine (11.6 L). The layers were separated
after 30 min, and the aqueous phase was extracted with DCM
(58 L). The combined organics were successively washed
with water (58 L) and saturated brine (11.6 L). The organic
solution was atmospherically concentrated to 12L, diluted
with EtOAc (17.4 L), further distilled to 12 L, diluted with
EtOAc (17.4 L) and reconcentrated 23 L. The resulting
suspension was cooled to 0 °C, and stirred for 1 h. The
crystalline material was isolated by filtration, rinsed with ice-
cold EtOAc (5.8 L), and then dried under vacuum at 40-45
°C to yield the title compound (3.12 g, 77%) as a white
1
crystalline solid, mp 232 °C dec; H NMR (400 MHz,
CDCl3) δ 7.68-7.62 (m, 2H), 7.49 (d, J ) 8.0 Hz, 1H),
7.36 (d, J ) 9.0 Hz, 1H), 7.30-7.23 (m, 5H), 7.19 (d, J )
9.0 Hz, 2H), 7.05 (d, J ) 8.0 Hz, 1H), 6.51 (s, 1H), 6.20 (s,
1H), 3.65 (s, 3H), 3.41 (s, 3H), 3.15 (s, 1H); 13C NMR (100
MHz, CDCl3) δ 161.86, 149.96, 143.06, 139.72, 139.25,
136.62, 136.41, 133.72, 132.61, 132.36, 130.48, 129.26,
128.90, 128.50, 125.97, 122.77, 121.48, 119.25, 114.66,
83.00, 78.77, 75.93, 33.97, 29.86.
(R)-6-[(4-Chloro-phenyl)-hydroxy-(3-methyl-3H-imida-
zol-4-yl)-methyl]-4-(3-ethynylphenyl-1-methyl)-1H-quino-
lin-2-one D-Tartaric Acid Salt (2). To a solution of 1 (7.6
kg, 16 mol) in THF (120 L) and water (3 L) was added a
solution of D-tartaric acid (3.09 kg, 21 mol) in water (5.7
L). The resulting slurry was stirred for 12 h at room
temperature and then diluted with EtOAc (152 L). The
resulting solution was distilled while adding fresh EtOAc
(R)-6-[(4-Chlorophenyl)-hydroxy-(3-methyl-3H-imida-
zol-4-yl)-methyl]-4-(3-(3-hydroxy-3-methylbutyn-1-yl)-
phenyl)-1-methyl-1H-quinolin-2-one L-Tartaric Acid Salt
(4). A solution of 8 (700 g, 1.3 mol) and L-tartaric acid (195
g, 1.3 mol) in i-PrOH (16.1 L) and water (116 mL) was
heated to 80 °C, allowed to cool slowly to room temperature,
and then stirred for 12 h. The crystalline material was isolated
by filtration and rinsed with I i-PrOH (3.5 L). The wet cake
was stirred in i-PrOH (3.8 L) at 50 °C for 1 h. The suspension
648
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Vol. 8, No. 4, 2004 / Organic Process Research & Development