AcOH (2.62 kg, 43.6 mol) and pyrrolidine (3.11 kg, 43.6 mol)
were then added, and the batch was aged at 85 °C for 4 h.
Water (130.9 kg) was charged at 85 °C, and the batch was
mixed for 10 min prior to settling. The lower aqueous was cut
away, and the organic was washed with further water (130.9
kg). The aqueous was cut, and the organics were distilled to a
volume of ca. 57 L at 45 °C. On cooling to 39 °C, the batch
crystallised, and after formation of a seedbed, heptane (58.5
kg) was added over 20 min. After aging a minimum of 1 h,
filtration, washing with heptane (14.9 kg), and drying in vacuo
L (8 mL/g) by concentrating to around 40 L and then charging
IPA (76.9 kg). Further distillation was performed to reach the
target volume of 56 L. This isopropanol solution was heated at
80 °C for 15 h to effect cyclisation. A volume of 7 L of IPA (3
mL/g) was removed by distillation (giving a 35 L/5 mL/g
solution), and the solution was cooled to 45 °C and seeded
(0.1–0.2 wt %). After a seedbed had formed, water (70 L) was
added dropwise over 1 h. The slurry was allowed to cool to
ambient, aged for 1 h, and filtered, washing with 5% IPA/water
(21 L) and water (14 kg). Drying in vacuo at 50 °C under a
at 45 °C for 16 h afforded 13.83 kg of 9 as a tan solid in 85%
nitrogen stream for 16 h afforded 4.53 kg of 23 as a pink solid
1
yield with 52% ee. H NMR (400 MHz, CDCl
3
) δ 7.45 (1H,
1
in 91% yield and 97.5% ee. H NMR (400 MHz, d
0.90 (1H, s), 7.53 (1H, d, J ) 8.4 Hz), 6.97 (1H, d, J ) 8.4
Hz), 6.03 (1H, s), 3.18–3.02 (2H, m), 2.82–2.78 (1H, m),
6
-DMSO) δ
d, J ) 8.4 Hz), 7.30–7.21 (2H, m), 6.95–6.83 (2H, m),
.80–6.76 (2H, m), 6.21 (1H, s), 4.03–3.91 (5H, m), 3.39–3.35
1H, d, J ) 17.2 Hz), 2.83–2.68 (2H, m), 2.53 (1H, dd, J )14.8,
.8 Hz), 2.40 (1H, dd, J ) 3.2, 13.2 Hz), 2.21–1.98 (3H, m);
1
6
(
4
2
1
1
5
2
.26–2.15 (1H, m), 1.98–1.85 (3H, m), 1.72–1.63 (1H, m),
13
.50–1.40 (1H, m); C NMR (100 MHz, d -DMSO) δ 202.4,
6
13
C NMR (100 MHz, CDCl ) δ 198.7, 171.2, 158.3, 157.9,
3
73.9, 157.0, 148.9, 128.6, 123.7, 117.2, 116.9, 112.8, 52.7,
1
6
4
46.7, 131.5, 129.4, 122.1, 120.9, 119.6, 116.7, 114.2, 111.6,
0.9, 43.2, 39.4, 36.8, 26.1; mp 216–217 °C; Chiralpak OJ-H
4.6, 56.6, 46.0, 43.0, 36.6, 34.0, 32.5; Chiralpak AD 250 ×
-1
50 × 4.6 mm, 1.5 mL min , 35 °C, 10% EtOH/hexane
-1
.6 mm, 1.5 mL min , 35 °C, 10% EtOH/heptane isocratic
isocratic elution, t
R
) 15.2 min (desired), t
R
) 17.0 min
elution, t
S-10), t
R
) 8.9 min (S-9), t
) 12.1 min (R-10); HRMS (ES) calcd for C22H22ClO
R
) 10.8 min (R-9), t
R
) 15.5 min
+
(
undesired); HRMS (ES) calcd for C15
found 261.0694.
7ꢀ-9aꢀ)-1,4-Dichloro-2-hydroxygibba-1(10a),2,4,4b-tet-
raen-6-one (1). A suspension of 23 (4.1 kg, 13.9 mol) in MeCN
29.0 kg) was heated to 71–75 °C. NCS (2.23 kg, 14.7 mol)
H
14ClO
2
(MH ) 261.0682,
(
R
3
+
(MH ) 369.1257, found 369.1274.
(
Enantiopurity Upgrade for (9aS)-8-Chloro-7-methoxy-
a-(2-phenoxyethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (9).
9
(
Tetrahydrofluorenone (9) (27.4 kg, 74.3 mol, 52% ee) was
suspended in IPAc (358.0 kg), and the mixture was degassed
and placed under nitrogen. The mixture was heated to 76 °C to
dissolve the batch, then cooled to 20 °C over >1 h, and aged
at 20 °C for at least 1 h. The crystallised racemic material was
then filtered off, and the solid was washed with cold (4 °C)
IPAc (23.9 kg). HPLC assay of the combined filtrates gave
was dissolved in MeCN (14.9 kg) and added over 20 min. The
batch was aged at 71–75 °C for 1.5 h and then cooled to 20
°C, and water (92.0 kg) was added over 1.5 h to crystallise the
batch. After aging 12–16 h, the batch was filtered, and the solids
were washed with 2:1 water/MeCN (16.4 L) and dried at 40
°
C in vacuo for 22 h. A total of 4.08 kg of crude 1 was obtained
1
as a brown/green solid in 87% yield and 99.4% ee. H NMR
400 MHz, d -DMSO) δ 11.20 (1H, s), 8.04 (1H, d, J ) 8.4
Hz), 7.06 (1H, d, J ) 8.4 Hz), 3.24 (1H, d, J ) 18.0 Hz),
96.3% ee, 14.7 kg. The filtrates were distilled under vacuum
(
6
to a volume of 4.5 mL/g based on the previous assay (ca. 222
mg/mL) and then heated to 65 °C to redissolve the crystallised
solids. The batch was allowed to cool to 60 °C, and then seed
was added (1 wt %) based on assay. After formation of a
seedbed, the batch was allowed to cool to ambient and then
cooled to -5 e T e 0 °C, aging for >1 h. Filtration and
washing with cold (4 °C) IPAc and drying in vacuo at 45 °C
for 16 h afforded 12.84 kg of 9 in 47% yield and 97% ee; mp
3
.12–3.04 (2H, m), 2.30–2.21 (1H, m), 2.05–1.90 (3H, m),
13
1.80–1.69 (1H, m), 1.55–1.45 (1H, m); C NMR (100 MHz,
6
d -DMSO) δ 195.0, 166.2, 157.4, 150.3, 127.6, 127.4, 118.3,
1
17.3, 116.7, 55.6, 50.7, 42.7, 39.8, 36.8, 25.9; mp 231–232
-1
°
C; Chiralpak OJ-H 250 × 4.6 mm, 1.5 mL min , 35 °C, 10%
EtOH/hexane isocratic elution, t ) 15.3 min (desired), t
7.5 min (undesired); HRMS (ES) calcd for C15
R
R
)
1
2 2
H13Cl O
1
15–116 °C.
7ꢀ-9aꢀ)-1-Chloro-2-hydroxygibba-1(10a),2,4,4b-tetraen-
-one (23). Boron tribromide (1 M in dichloromethane, 97.4
+
(MH ) 295.0293, found 295.0291.
(
Color/Purity Upgrade for (7ꢀ-9aꢀ)-1,4-Dichloro-2-hy-
6
droxygibba-1(10a),2,4,4b-tetraen-6-one (1). Crude 1 (8.14 kg)
and Darco G60 (1.63 kg) were slurried in MeOH (48.3 kg)
and MeCN (144.0 kg) and stirred at 20 °C for 2 h. The batch
was filtered through a 1 µm cartridge filter and 0.1 µm cartridge
filter followed by a rinse with MeOH (4.8 kg) and MeCN (14.4
kg). The batch was distilled under vacuum to a volume of 40
L, then IPAc (71.1 kg) was added, and distillation repeated to
achieve a batch volume of 40 L (internal batch temperature
<40 °C). Futher IPAc (71.1 kg) was added, and the distillation
was repeated to a volume of 40 L. The batch was cooled to 20
°C, heptane (27.8 kg) was added over 70 min, and then the
batch was aged for 9 h. The batch was filtered, and the solids
were washed with heptane (15 kg) mixed with IPAc (7.0 kg).
kg, 66.4 mol) was cooled to 1 °C. A solution of 9 (7.0 kg, 19.0
mol, 97% ee) in dichloromethane (31.0 kg) was added over 10
min such that T < 15 °C. The solution was aged at 12–14 °C
for 22 h. The solution was cooled to 1 °C, and methanol (8.51
kg.) was added over 1 h, T < 15 °C. After a 1 h age, water (21
kg) was added, followed by dichloromethane (23.2 kg), and
the slurry was stirred for 20 min at ambient. The batch was
then filtered, and the solid was washed with dichloromethane
(2 × 18.6 kg). The filtrate and washes were combined, and
further water (28 kg) added. The batch was agitated for 10 min
and left to settle, and the layers were cut. The organic layer
was washed with 5 wt % sodium bicarbonate (47.25 L, prepared
from 45.0 kg water and 2.36 kg sodium hydrogen carbonate).
The organic layer was switched to IPA at a final volume of 56
2
Drying in vacuo at 40 °C under a N sweep for 21 h afforded
Vol. 12, No. 4, 2008 / Organic Process Research & Development
•
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