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N. K. Yee et al. / Tetrahedron: Asymmetry 14 (2003) 3495–3501
(50 L) was added to the mixture for extraction. The
layers were separated, the organic layer was washed
with water (40 L), and concentrated under reduced
pressure. After collecting ꢀ30 L of distillate, the mix-
ture became a slurry. Toluene (20 L) was added to
dissolve the slurry and the solution was then transferred
into a container with aid of 12 L of toluene. The total
weight of this solution was 75.45 kg and this material
was used for next step directly. The crude alkylated
product 9 was estimated to be 17.50 kg (96%). Analyti-
cally pure sample was obtained by flash chromatogra-
phy. Mp 164°C; [h]2D0=+89.8 (c 1.01, CH2Cl2); 1H
NMR (CDCl3, 400 MHz) two rotamers l 7.23–7.29 (m,
3H), 6.93 (s, 1H), 6.76–6.79 (m, 3H), 5.66 (s, 0.4H),
5.40 (s, 0.6H), 3.72 (d, J=14 Hz, 0.6H), 3.26 (d, J=14
Hz, 0.4H), 3.08 (t, J=15 Hz, 1H), 1.96 (s, 0.6H), 1.93
(s, 0.4H), 0.86 (s, 6.4H), 0.73 (s, 3.6H). Anal. calcd for
C23H22BrCl2F3N2O2: C, 48.79; H, 3.92; N, 4.95. Found:
C, 49.02; H, 3.95; N, 4.88.
dichloromethane (72 L) was concentrated under
reduced pressure to remove dichloromethane, which
was replaced with THF. The resulting solution of 2 in
THF (40 L) was cooled to 10°C and triethylamine (4.32
kg, 42.7 mol) was slowly added. The internal tempera-
ture was then adjusted to 0°C and methyl chlorofor-
mate (3.054 kg, 32.3 mol) was added at a rate to keep
the internal temperature below 10°C. The temperature
was then increased and the mixture was stirred at reflux
(68°C) for 14 h and quenched with water (3.5 L). The
mixture was then concentrated under reduced pressure
keeping the jacket temperature at 57–60°C until
approximately 43 L of distillate was collected. Water
(28 L) was added and the internal temperature was
adjusted to 20–23°C. The product was extracted with
dichloromethane (2×19 L), the combined organic por-
tions were washed with water (14 L) and concentrated
under reduced pressure. Methanol (30 L) was added
and the mixture was again concentrated under reduced
pressure keeping the jacket temperature at 60–65°C
until 43 L of distillate was collected. Afterwards, tri-
ethylamine (4.34 kg, 42.9 mol) and methanol (19 L)
were added and the mixture was stirred and heated at
reflux for 14 h. The mixture was concentrated under
reduced pressure keeping the jacket temperature at
60°C. After 39 L of distillate were collected, the distilla-
tion was stopped and mixture was cooled to 20°C. The
total weight of the crude 10 solution was 20.05 kg and
used for next step directly. An analytically pure sample
was obtained by flash chromatography. foam; [h]2D0=
−120.0 (c 1.02, CH2Cl2); 1H NMR (CDCl3, 400 MHz) l
7.46 (d, J=8.3 Hz, 2H), 7.34 (s, 1H), 7.06 (d, J=8.3
Hz, 2H), 6.98 (s, 2H), 6.84 (br. s, 1H), 3.13 (d, J=13
Hz, 1H), 2.91 (d, J=13 Hz, 1H), 1.60 (s, 3H); 13C
NMR (CDCl3, 100 MHz) l 174.1, 154.7, 135.2, 132.8,
132.7, 131.7, 128.5, 124.5, 122.0, 62.7, 43.5, 23.3. Anal.
calcd for C17H13BrCl2N2O2: C, 50.46; H, 5.44; N, 8.41.
Found: C, 50.40; H, 5.42; N, 8.27.
4.6. (2R)-2-Amino-3-(4-bromophenyl)-N-(3,5-dichloro-
phenyl)-2-methyl-propionamide 2
A solution of 9 in toluene (75.45 kg, max. 32.07 mol)
from last step was transferred into a 50-gallon reactor
with aid of 15 L of toluene. The solution was subjected
to vacuum distillation (jacket temp. <65°C) to collect
ꢀ80 L of distillate. At this point, 1,4-dioxane (80 L)
was added and distillation continued to collect ꢀ16 L
of distillate. At 20°C, an aqueous 40% (w/w)
BnMe3NOH (20.15 kg, 48.2 mol) was added to the
reaction mixture followed by 50% NaOH (5.13 kg, 64
mol). The reaction mixture was then heated to 40°C
and vigorously agitated at this temperature for 12 h. An
HCl solution (prepared by mixing 19.40 kg of conc.
HCl and 10 L of water) was added to the reaction
mixture. The reaction mixture was then heated to 50°C
and stirred for 4 h. The reaction mixture was subjected
to vacuum distillation (jacket temp. <65°C). After ꢀ65
L of distillate was collected, toluene (50 L) was added
and the mixture was cooled to ꢀ10°C. A 50% NaOH
solution was added at a rate to keep the internal
temperature below 20°C until the pH of aqueous layer
reached 13–14 (ꢀ10.5 kg of 50% NaOH was used). The
layers were separated, the organic layer was washed
with water (2×40 L) and concentrated under reduced
pressure to give 13.33 kg of crude 2 which contained
7% by weight of residual toluene. The yield of 2 was
12.4 kg (96%). Analytically pure sample was obtained
by flash chromatography. Mp 81°C; [h]2D0=+176.6 (c
4.8. (5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-1,5-
dimethyl-imidazolidine-2,4-dione 1
The above solution containing crude hydantoin 10
(20.05 kg, max. 19.65 mol) was concentrated under
reduced pressure to remove methanol. Toluene (60 L)
was added and distilled to remove the residual
methanol. DMF (25 L) was added and the internal
temperature was adjusted to 7.5 2.5°C as lithium
bis(trimethylsilyl)amide (21.03 kg, 1.0 M in THF, 20.4
mol) was slowly added. The internal temperature was
adjusted to 15 2°C and a solution of iodomethane
(3.82 kg, 29.9 mol) in DMF (5.0 L) was slowly added at
a rate to keep the internal temperature at 15–20°C. The
mixture was then stirred at 20°C for 3 h. The reaction
was then quenched with water (105 L) at 25°C. The
product was extracted from the above aqueous mixture
with ethyl acetate (3×15 L) and the combined organic
layers were then washed with water (60 L). The result-
ing solution was filtered to remove any solid particle
The resulting solution was concentrated under reduced
pressure with a jacket temperature at 55-60°C until 32
L of distillate was collected. Crystallization was carried
1
1.07, CH2Cl2); H NMR (CDCl3, 400 MHz) l 9.74 (br.
s, 1H), 7.52 (d, J=1.9 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H),
7.08 (t, J=1.9 Hz, 1H), 7.05 (d, J=8.3 Hz, 2H), 3.47
(d, J=13 Hz, 1H), 2.61 (d, J=13 Hz, 1H), 1.45 (s, 3H);
13C NMR (CDCl3, 100 MHz) l 174.7, 139.4, 135.3,
135.1, 131.8, 131.6, 123.9, 121.2, 117.5, 58.8, 45.6, 28.0.
Anal. calcd for C16H15BrCl2N2O: C, 47.79; H, 3.76; N,
6.97. Found: C, 47.89; H, 3.81; N, 6.75.
4.7. (5R)-5-(4-Bromobenzyl)-3-(3,5-dichlorophenyl)-5-
methyl-imidazolidine-2,4-dione 10
A solution of intermediate 2 (7.90 kg, 19.65 mol) in