stirred suspension was cooled in an ice bath to 10 °C, and
TFA (99+%, 684.0 g, 6.0 mol) was added dropwise over a
30-min period. After the addition, the reaction was gently
heated to reflux at 40 °C for 16 h, and the progress of
racemization was determined by chiral HPLC (Method B)
until complete racemization of 8/9 (free base) was observed.
The solution was cooled to 20 °C and vigorously agitated
while a 7% NaOH solution (4.3 L, 7.5 mol) was added over
a 20-min period. The organic phase was separated, washed
with brine (2.0 L), and concentrated to dryness. The resulting
material was placed in a vacuum oven under house vacuum
at 60 °C for 16 h. There was recovered 912.3 g (93% yield)
of racemized product (8/9, 48%/52%).
Step 4. 3-(R)-2-Benzyl-3-(2,3-dihydrobenzofuran-5-yl)-
1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one (12).9 A
5-L RBF was charged with DMF (1.5 L) and potassium
superoxide (96%, 255.6 g, 3.6 mol) with agitation under
nitrogen followed by Aliquat 175 (methyltributylammonium
chloride, 75 wt % in H2O, 39.1 mL, 0.12 mol). The mixture
was warmed to 40 °C for 20 min, and then a solution of
1-(R)-2-benzyl-â-carboline 10 (228.0 g, 0.60 mol) in DMF
(0.5 L) was added over a 30-min period while the reaction
temperature was maintained between 40 and 60 °C. After
the addition was complete, the heating mantle was replaced
with a water bath, and the reaction was agitated at 40-60
°C for 4 h (see Note below). The reaction was cooled to 20
°C using an ice-water bath, and the resulting orange slurry
was slowly transferred to a 22-L RBF that contained H2O
(3.6 L) and ice (3.6 kg) with rapid agitation. The yellowish
slurry was stirred for 30 min and acidified with 3 N HCl
solution (0.7 L) to pH ) 8-9. The solid was isolated by
filtration, washed with H2O (0.5 L × 2), and dried by air
suction. This crude material was placed in a vacuum oven
under house vacuum at 60 °C for 16 h. There was obtained
145.0 g (61% yield) of crude compound 12. Recrystallization
of the crude material in refluxing CH3OH (650 mL) afforded
99.8 g (42% yield) of 1-(R)-2-benzylpyrrolidinequinolinone
12 as pale-yellowish solid (97.2% ee; Method B), which was
This mixture was resolved with recovered N-acetyl-D-
leucine 7 (from step 2A) to give an additional 26% yield of
the desired 1-(R)-â-carboline salt 8 with high chiral purity
(98.0% ee, Method B).
Step 3. 1-(R)-1-(2,3-Dihydrobenzofuran-5-yl)-2-benzyl-
2,3,4,9-tetrahydro-1H-â-carboline (10). A 22-L RBF was
charged with N-acetyl-D-leucine salt 8 (1368 g, 2.95 mol)
and CH2Cl2 (12.0 L) with stirring under nitrogen. Solid K2-
CO3 (98+%, 913.5 g, 6.49 mol) was added over a 3-min
period. After stirring for 10 min at 20 °C, benzyl bromide
(98%, 520.0 g, 2.98 mol) was added over a 20-min period
and the suspension was agitated at 20 °C for 30 min. The
reaction was then gently heated to 38 ( 2 °C and stirred for
10 h. The reaction was cooled to 20 °C, and the white solid
was isolated by filtration. The filter cake was washed with
CH2Cl2 (2.0 L × 2) and saved for step 3A. The combined
organic phase was condensed in vacuo, and the resulting off-
white yellowish solid was dried in a vacuum oven under
house vacuum at 60 °C for 16 h. There was obtained 1054.0
g (94% yield) of 1-(R)-2-benzyl-â-carboline 10 with 98%
chemical purity (Method A) and 99% ee (Method B). The
2-benzyl compound 10 was used in the next step without
further purification. 1H NMR (300 MHz, DMSO-d6) δ 2.53-
2.61 (m, 1 H), 2.67-2.80 (m, 2 H), 2.98-3.06 (m, 1 H),
3.13 (t, J ) 8.4 Hz, 2 H), 3.44 (d, J ) 11.8 Hz, 1 H), 3.76
(d, J ) 12.2 Hz, 1 H), 4.48 (t, J ) 8.2 Hz, 2 H), 4.64 (s,
1H), 6.72 (d, J ) 7.8 Hz, 1 H), 6.81-7.03 (m, 2 H), 7.08
(dd, J ) 1.1, 7.6 Hz, 1 H), 7.14-7.28 (m, 3 H), 7.29-7.36
(m, 4 H), 7.40 (d, J ) 7.5 Hz, 1 H), 10.24 (s, 1H). MS 381
(MH+), 403 (MNa+), 276, 262.
Step 3A. Recovery of N-Acetyl-D-leucine (7). A 12-L
RBF was charged with potassium N-acetyl-D-leucine salt 11
from step 3 and H2O (3.5 L). The solution was cooled to 4
°C in an ice bath, and then a 37% HCl solution (1.5 L) was
carefully added over a 30-min period. The agitation was
continued for an additional 30 min. The white solid was
isolated by filtration and washed with cold H2O (1 L × 2),
and the cake was dried as described in step 2A. There was
obtained 410.0 g (80% yield) of recovered N-acetyl-D-leucine
7 as an off-white solid, of which the spectroscopic and optical
properties were identical to compound 7 made from step 1A.
This material was combined with that from step 2A and
used in the resolution of racemate 6 without further purifica-
tion.
1
used in the next step without further purification. H NMR
(300 MHz, DMSO-d6) δ 3.05-3.22 (m, 2 H), 3.52 (dd, J )
1.4, 9.8 Hz, 1 H), 3.61 (d, J ) 12.4 Hz, 1 H), 3.82 (d, J )
12.1 Hz, 1 H), 3.92 (dd, J ) 1.1, 9.6 Hz, 1 H), 3.98-4.16
(br s, 1 H), 4.54 (t, J ) 8.6 Hz, 2 H), 5.05 (s, 1H), 6.82 (d,
J ) 7.9 Hz, 1 H), 7.13 (d, J ) 7.2 Hz, 1 H), 7.13-7.38 (m,
6 H), 7.48-7.63 (m, 2 H), 8.08 (d, J ) 7.8 Hz, 1 H), 11.40
(s, 1H). MS 395 (MH+), 417 (MNa+), 811 (2MNa+).
Note: An ARC bomb determination showed that
exothermic decomposition starts at 39 °C with increased
decomposition at 60 °C and significant pressure buildup
at 60-70 °C. Therefore, careful control of the internal
reaction temperature below 60 °C is very important.
Step 5. 3-(R)-3-(2,3-Dihydrobenzofuran-5-yl)-1,2,3,4-
tetrahydropyrrolo[3,4-b]quinolin-9-one Hydrogen Chlo-
ride Salt (1).3 A 6-L Parr pressure reactor was charged with
12 (319.2 g, 0.81 mol) and CH3OH (1.8 L) with stirring under
nitrogen. To this mixture was added a 6 N HCl solution
(0.136 L) over a 3-min period followed by the addition of
5% Pd/C (115.2 g, 6.6% mol of Pd). The system was closed
and purged with nitrogen (× 2) followed by hydrogen (×
2). The reaction was carried out at 23-28 °C under H2
pressure (50 psi) with moderate agitation (400 rpm) for 4 h.
The progress of the reaction was determined by HPLC
(Method A). After the completion of the reaction, the catalyst
was removed by filtration through a Celite 545 short cartridge
and the filter cake was washed with CH3OH (0.2 L × 4).
The filtrate was condensed in vacuo, and the resulting
material was placed in a vacuum oven under high vacuum
(∼10 mmHg) at 60 °C for 24 h. There was obtained 275.4
g of 3-(R)-quinolinopyrrolidine HCl salt 1 as a greenish solid
in excellent yield (99.8%) and optical purity (98.1% ee,
Method B). 1H NMR (300 MHz, CD3OD) δ 3.24 (t, J ) 8.1
644
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Vol. 9, No. 5, 2005 / Organic Process Research & Development