Organic Process Research & Development
Article
complete conversion to tetrahydrooxazole 8 (>90.0% con-
version). The mixture was cooled to below 25 °C, and THF
(140 kg) and acetic acid (69.3 kg, 1155 mol, 3.0 equiv) were
added. Zinc dust (75.4 kg, 1155 mol, 3.0 equiv) was added
while maintaining the internal temperature below 45 °C. The
resulting mixture was stirred between 35 and 45 °C for 1 h,
and the reaction was monitored for complete conversion to
amino alcohol 9 (>98.0% conversion). The mixture was cooled
to 15−20 °C, and dichloromethane (205 kg) was added.
Aqueous ammonium hydroxide (25%, 107 kg) was added until
the pH reached 10−12. The resulting mixture was stirred for
15 min, and 40 kg of Celite was added. After 30 min of stirring,
the suspension was filtered in two equal portions by means of a
centrifuge. Each portion was washed with 20 kg of dichloro-
methane. The combined filtrates were transferred to a reactor,
and the layers were separated. The upper aqueous layer was
extracted twice with dichloromethane (230 kg each). The
combined organic layers were washed with 65 kg of deionized
water, treated with 7 kg of sodium sulfate, and filtered through
a bag filter. The resulting organic layer was concentrated under
reduced pressure (jacket T < 35 °C); meanwhile, solvent
exchange was performed with 235 kg of absolute ethanol. After
solvent exchange, 236.5 kg of concentrate containing amino
alcohol 9 (75.2 kg, 80.3 area % purity, 334 mol, 86.9% yield)
was obtained. 1H NMR (500 MHz, DMSO) δ 7.63 (td, J = 8.6,
1.7 Hz, 1H), 7.32−7.24 (m, 1H), 7.20−7.08 (m, 2H), 4.43 (s,
1H), 4.07 (dd, J = 8.7, 1.3 Hz, 1H), 4.02 (dq, J = 8.5, 6.1 Hz,
1H), 3.68−3.57 (m, 2H), 3.55−3.46 (m, 1H), 2.23 (dd, J =
14.4, 6.7 Hz, 1H), 1.24 (d, J = 6.1 Hz, 3H); 13C NMR (125
Chiral HPLC Parameters. Column: Chiralcel OD-H, 4.6 ×
250 mm, 5 μm, mobile phase (isocratic):n-heptane/2-
propanol/triethylamine = 98/2/0.05, flow rate 1.0 mL/min,
injection volume 20 μL, temperature 40 °C, detection 262 nm,
total running time 80 min, dilution solvent 2-propanol, relative
retention time (RRT) of (ent)-9 = 0.90, RRT of 9 = 1.00
N-((3S,4R,5R)-3-(2-Fluorophenyl)-4-(hydroxymethyl)-
5-methyltetrahydrofuran-3-ylcarbamothioyl)-
benzamide (10). A reactor was charged with 9-DBT (30.0
kg, 48.5 mol) and ethyl acetate (81 kg). The mixture was
cooled to 0−10 °C. A 1.00 M aqueous NaOH (120 L, 120
mol, 2.47 equiv) solution was added. Benzoyl isothiocyanate
(9.42 kg, 56.5 mol, 1.16 equiv) was added with vigorous
stirring while maintaining the internal temperature between 0
and 10 °C. After complete addition, stirring was continued at
0−5 °C over 2 h and the reaction was monitored for complete
consumption of 9-DBT (target >98.0% conversion). The
reaction mixture was filtered, and the filter cake was rinsed
with (1) deionized water (60 kg) and (2) a mixture of heptane
(27 kg) and ethyl acetate (36 kg). The solid was dried under
reduced pressure (T < 40 °C) to give 10 (17.0 kg, 93.5 wt %
purity, 40.9 mol, 84.3% yield). 1H NMR (500 MHz, CDCl3) δ
11.78 (s, 1H), 8.88 (s, 1H), 7.88−7.82 (m, 2H), 7.67 (td, J =
8.1, 1.6 Hz, 1H), 7.65−7.59 (m, 1H), 7.50 (dd, J = 10.8, 4.8
Hz, 2H), 7.30−7.23 (m, 1H), 7.15 (td, J = 7.8, 1.2 Hz, 1H),
7.01 (ddd, J = 12.3, 8.2, 1.1 Hz, 1H), 4.73 (d, J = 10.1 Hz,
1H), 4.42 (dd, J = 10.1, 1.7 Hz, 1H), 4.10−4.03 (m, 1H),
4.03−3.91 (m, 2H), 2.80 (t, J = 5.3 Hz, 1H), 2.63−2.52 (m,
1H), 1.35 (d, J = 6.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
179.42, 166.60, 160.35 (d, JCF = 247.4 Hz), 133.60, 131.81,
129.27 (d, JCF = 8.9 Hz), 129.20 (d, JCF = 3.7 Hz), 129.15,
127.55, 127.39 (d, JCF = 10.0 Hz), 123.96 (d, JCF = 3.3 Hz),
116.18 (d, JCF = 23.0 Hz), 76.90 (d, JCF = 2.8 Hz), 76.27,
69.26, 59.49, 58.03, 20.04.
MHz, DMSO) δ 160.69 (d, JCF = 244.7 Hz), 133.57 (d, JCF
=
11.3 Hz), 128.95 (d, JCF = 8.8 Hz), 128.81 (d, JCF = 4.8 Hz),
124.33 (d, JCF = 3.2 Hz), 116.32 (d, JCF = 23.5 Hz), 79.58 (d,
JCF = 4.9 Hz), 78.52, 63.99 (d, JCF = 3.5 Hz), 59.39, 56.91 (d,
JCF = 2.2 Hz), 21.37.
((2R,3R,4S)-4-Amino-4-(2-fluorophenyl)-2-methylte-
trahydrofuran-3-yl)methanol (2S,3S)-2,3-Bis-
(benzoyloxy)succinate (9-DBT). A reactor was charged
with 236 kg of an ethanol solution containing amino alcohol 9
(75.2 kg, 334 mol) and ethanol (253 kg). The mixture was
heated to an internal temperature of 65−70 °C. To the mixture
was added a solution of dibenzoyl-D-tartaric acid (125 kg, 332
mol, 1.0 equiv) in ethanol (148 kg) and deionized water (12.8
kg) in 5−10 min while maintaining the internal temperature
above 60 °C. After being stirred for 60 min at 60−70 °C, the
mixture was cooled to 50 °C at a rate 3 °C/h, while crystal
seeds were added in every hour. After being stirred for 1 h at
50 °C, the mixture was cooled to 10 °C (at 10 °C/h) and
stirred for at least 2 h at 5−10 °C. The crystals were then
filtered, rinsed with prechilled ethanol (15 kg), and dried
under vacuum at 50 °C to a constant weight. A 74.0 kg amount
of 9-DBT (98.7 area % purity, 95.5 ee %, water 5.6%, 120 mol,
(4aS,5R,7aS)-7a-(2-Fluorophenyl)-5-methyl-4a,5,7,7a-
tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (12). A
reactor was charged with isothiourea 10 (17.0 kg, 40.8 mol),
pyridine (49 kg) and toluene (44 kg). The resulting mixture
was cooled to below −15 °C. Trifluoromethanesulfonic
anhydride (12.7 kg, 45.0 mol, 1.10 equiv) was added while
maintaining the internal temperature below 0 °C. Upon
complete addition, stirring between −5−0 °C was continued
for 1.5 h and the reaction was monitored for complete
conversion of 10 (≥97.0%). Toluene (88 kg) and 20 wt %
aqueous ammonium chloride solution (71 kg) were added.
The resulting biphasic mixture was warmed to 15−25 °C,
stirred for at least 15 min and then allowed to partition. The
lower aqueous layer was separated, and the upper organic
phase was collected. The aqueous layer was extracted with
toluene (44 kg). The combined organic layers were washed
with deionized water (34 kg) and concentrated under reduced
pressure to give crude 11 as a thick brown oil. 2-propanol (41
kg) and 3.0 M aqueous sodium hydroxide (60 kg, 51 L) were
added, and the resulting reaction mixture was heated to 80 °C
for 6 h and monitored for complete conversion of 11
(>99.0%). n-Heptane (24 kg) and deionized water (17 kg)
were added while keeping the internal temperature above 60
°C. The resulting mixture was cooled to 0−5 °C, maintained at
this temperature for at least 2 h, and then filtered. The reactor
and filter cake were rinsed with a mixture of deionized water
(31 kg) and 2-propanol (2.7 kg), and then a mixture of
heptane (20 kg) and ethyl acetate (3.1 kg). The solids were
dried to give isothiourea 12 (9.45 kg, 96.7 wt % purity, 34.3
1
35.9% yield) was obtained as a white powder. H NMR (500
MHz, CD3OD) δ 8.14−8.10 (m, 4H), 7.60 (t, J = 7.4 Hz, 2H),
7.55 (td, J = 8.1, 1.3 Hz, 1H), 7.47 (t, J = 7.8 Hz, 4H), 7.46−
7.42 (m, 1H), 7.30−7.19 (m, 2H), 5.90 (s, 2H), 4.39−4.26
(m, 2H), 4.15 (dd, J = 10.4, 2.4 Hz, 1H), 3.93 (dd, J = 11.7,
4.4 Hz, 1H), 3.87 (dd, J = 11.7, 5.4 Hz, 1H), 2.52 (dt, J = 8.4,
5.0 Hz, 1H), 1.31 (d, J = 6.1 Hz, 3H); 13C NMR (125 MHz,
CD3OD) δ 171.37, 167.32, 161.76 (d, J = 245.5 Hz), 134.36,
132.46 (d, JCF = 9.8 Hz), 131.16, 130.98, 129.47, 128.98 (d, JCF
= 2.9 Hz), 126.23 (d, JCF = 3.9 Hz), 125.65 (d, JCF = 10.8 Hz),
117.84 (d, JCF = 23.5 Hz), 77.75, 75.73 (d, JCF = 4.9 Hz),
74.91, 67.01 (d, JCF = 2.0 Hz), 58.84, 56.28, 20.40.
H
Org. Process Res. Dev. XXXX, XXX, XXX−XXX