pressure (20-40 °C) to remove the solvents (Me-THF and
methanol). Toluene (104.1 kg) was added, followed by hexane
(49.3 kg). The mixture was stirred overnight at 15 °C and then
at 11 °C for 2 h. The mixture was filtered through a Nutsche
filter, and the solid was washed with a mixture of toluene (6.6
kg) and hexane (4.9 kg). The white solid was dried at 60 °C
overnight under reduced pressure to give the near racemic 15
(3.22 kg, 7% ee, 100% HPLC purity). The filtrate (97% ee)
was extracted with two portions of saturated aqueous NaHCO3
(160.7 kg then 81.3 kg). The combined aqueous layer was
acidified with conc. HCl (32.0 kg, pH ) 0.7), and the mixture
was extracted with toluene (245.7 kg). The organic extract was
washed with brine (180 kg) and concentrated under reduced
pressure (35-65 °C, jacket temperature). THF (59.3 kg) was
added to the residue (15, 97% ee, 100% HPLC purity), and the
solution (75 kg) was used to the next step without further
purification. 1H NMR (300 MHz, CDCl3) δ 2.53-2.87 (m, 4
H), 3.54-3.71 (m, 1 H), 3.59 (s, 3 H), 6.91-7.07 (m, 2 H),
7.12-7.25 (m, 2 H).
(R)-3-(4-Fluorophenyl)-2-formylpentanedioic Acid 1-M-
ethyl Ester (16). To a solution of diisopropylamine (12.1 kg,
120 mol) in THF (62.3 kg) at -10 to 8 °C was added n-BuLi
(33.7 kg, 2.5 M in hexane, 122 mol) over 45 min. The resulting
LDA solution was kept at 0 °C overnight, and then cooled to
-55 °C. To this LDA solution was added cooled (∼ 0 °C)
crude 15 in THF (∼75 kg) over 3.5 h at < -45 °C. After 60
min at -45 to -55 °C, methyl formate (7.91 kg, 132 mol)
was added over 5 min at < -35 °C. The mixture was warmed
to -20 °C over 1 h and then stirred at -20 °C for 1 h. The
mixture was quenched with 3 N HCl (107.9 kg) at e20 °C.
The mixture was extracted with EtOAc (91.7 kg). The organic
layer was separated and washed with brine (128 kg). The
solution was concentrated to 97 kg under reduced pressure to
give 16 as an ethyl acetate solution.
1508, 1473, 1440, 1351, 1304, 1222, 1204, 1176, 1099, 839
cm-1; 1H NMR (300 MHz, CDCl3) δ 2.71 (d, J ) 16.58 Hz,
1 H) 3.00 (dd, J ) 16.58, 8.29 Hz, 1 H) 3.71 (s, 3 H) 4.18 (d,
J ) 7.16 Hz, 1 H) 6.90-7.05 (m, 2 H) 7.13-7.24 (m, 2 H)
7.48 (d, J ) 5.65 Hz, 1 H) 7.93 (br s, 1 H); 13C NMR (75.4
MHz, CDCl3) δ 35.8, 38.1, 51.8, 111.0, 115.6, 115.9, 128.2,
128.3, 135.4, 137.1, 137.2, 160.3, 163.6, 166.3, 170.5; Anal.
Calcd for C13H12FNO3: C, 62.65; H, 4.85; N, 5.62. Found: C,
62.78; H, 4.77; N, 5.64.
(S)-4-(4-Fluorophenyl)-1-methyl-6-oxo-1,4,5,6-tetrahy-
dropyridine-3-Carboxylic Acid Methyl Ester (4). The sol-
vents in a solution of 16 (23.3 kg from the 97 kg batch described
above, ∼13.8 mol) were removed under reduced pressure.
Acetic acid (8.58 kg, 143 mol) and methylamine in water (3.21
kg, 40 wt %, 41.3 mol) were added successively to the residue
with cooling (0-30 °C) over 15 min, and the mixture was
warmed to 65 °C over 1 h. After 3 h at 65 °C, the mixture was
cooled to 20 °C. Ethyl acetate (32.4 kg) and MTBE (26.2 kg)
were added, and the mixture was washed with water (50 kg),
saturated aqueous sodium carbonate (two times, 61 kg, then
55 kg), water (50 kg), and brine (40 kg). Solvent was removed
under reduced pressure (30-125 Torr) at 40 °C. MTBE (4.4
kg) was added to the residue, and the mixture was heated to
reflux (65 °C jacket temperature) until homogeneous. The
mixture was slowly cooled to 0 °C over 4 h and aged at 0 °C
for 1 h. The mixture was then filtered and washed with cooled
MTBE (1.0 kg, 0 °C) to give a white solid, which was dried
under reduced pressure (30-50 Torr) at 50 °C to give 4 (2.0
kg, 44% yield from 13, 100% ee): mp 100-102 °C; [R]20
)
D
108.0 (MeOH); HPLC assay >99%; IR (KBr): ν 3410, 3064,
2952, 1712, 1684, 1640, 1603, 1507, 1434, 1361, 1300, 1249,
1223, 1199, 1161, 1115, 1028, 960, 844, 806, 673 cm-1; H
1
NMR (300 MHz, CDCl3) δ 2.74 (dd, J ) 16.58, 1.88 Hz, 1
H), 2.96 (dd, J ) 16.58, 8.29 Hz, 1 H), 3.19 (s, 3 H), 3.68 (s,
3 H), 4.12 (dd, J ) 8.29, 1.51 Hz, 1 H), 6.86-7.01 (m, 2 H),
7.06-7.19 (m, 2 H), 7.45 (s, 1 H); 13C NMR (75.4 MHz,
CDCl3) δ 34.6, 35.8, 38.4, 51.6, 110.8, 115.4, 115.7, 128.0,
128.1, 137.0.4, 137.1, 140.9, 160.1, 163.4, 166.2, 168.7; Anal.
Calcd for C13H12FNO3: C, 63.87; H, 5.36; N, 5.32. Found: C,
63.50; H, 5.29; N, 5.25.
(S)-4-(4-Fluorophenyl)-6-oxo-1,4,5,6-tetrahydropyridine-
3-carboxylic Acid Methyl Ester (3). The solvents from a
solution of 16 (73.2 kg from the 97 kg batch, ∼43.3 mol) were
removed under reduced pressure. Acetic acid (32.3 kg, 716 mol)
and ammonium acetate (8.3 g, 143 mol) were added to the
residue, and the mixture was warmed to 80 °C. After being
left overnight at 80 °C, the mixture was cooled to 25 °C, and
water (92.0 kg) was added over 3 h. The mixture was agitated
over 3 days at 25 °C, then cooled to 0 °C over 10 h, and stirred
for another 10 h. The cooled mixture was filtered and washed
with water (16 kg) and cold toluene (29.6 kg, 0 °C). The solid
was dried at 70 °C under reduced pressure (30-50 Torr) for
20 h to give product 3 (5.75 kg, 43% yield from 13, 97% ee)
Acknowledgment
We thank Drs. Pankaj Rege and Hanbiao Yang for helpful
suggestions, and Frida Dobrouskin and Tim Lane for analytical
support.
Received for review February 10, 2010.
OP1000447
as a white solid: mp 176-178 °C; [R]20 ) 182.6 (MeOH);
D
HPLC assay >99%; IR (KBr): ν 3274, 2954, 1688, 1648, 1602,
616
•
Vol. 14, No. 3, 2010 / Organic Process Research & Development