to attain the following levels of volatiles: ethyl acetate (<5 A
%), heptane (<1 A %), THF (<1 A %), bromodifluorobenzene
(<2 A %), and KF < 0.5%. After 4 h, the final ethyl acetate
content by GC was 0.004%. This produced 122.7 kg of solution
(56.7 wt % 7, 81.1% yield, 98.0% ee). An analytical sample
was prepared by silica gel chromatography using ethyl acetate/
heptane. HRMS calcd M + H: 271.1146; obsd. M + H:
271.1145. 1H NMR (CDCl3, 500 MHz) mixture of diastereo-
mers, 7.85-7.92 (m, 1H), 6.96 (dd, J ) 8.6, 7.8 Hz; 1H),
6.79-6.90 (m, 1H), 5.08 (q, J ) 7.1, 2.4 Hz; S diast. of THP),
4.86 (qd, J ) 6.8, 1.2 Hz; R diast; 1H if combined with previous
signal), 4.75 (t, J ) 3.6 Hz; R diast.), 4.65 (t, J ) 3.6 Hz; S
diast.; 1H if combined with previous signal), 3.82-3.91 (m),
3.66-3.75 (m, 1H if combined with previous signal), 3.45-3.54
(m), 3.28-3.36 (m, 1H if combined with precious signal),
1.30-1.90 (m, 6H), 1.47 (dd, J ) 6.8, 1.2 Hz; S diast.), 1.42
(dd, J ) 6.8, 1.2 Hz; R diast.; 3H if combined with previous
signal). 13C NMR (CDCl3, 100 MHz) mixture of diastereomers,
198.2 (S diast.), 197.9 (R diast.), 165.9 (dd, J ) 258, 12 Hz; S
diast.), 165.7 (dd, J ) 257, 12 Hz; R diast.), 163.0 (dd, J )
257, 13 Hz; S diast.), 162.0 (dd, J ) 257, 13 Hz; R diast.),
133.1 (dd, J ) 11, 10.8 Hz; S diast.), 133.0 (dd, J ) 11, 10.8
Hz; R diast.), 121.4 (dd, J ) 42.1, 14.0 Hz; R diast.), 121.2
(dd, J ) 42.1, 14 Hz; S diast.), 112.5 (dd, J ) 21.6, 3.4 Hz; R
diast.), 112.3 (dd, J ) 21.6, 3.4 Hz; S diast.), 104.8 (dd, J )
27.8, 25.4 Hz; R diast.), 104.7 (dd, J ) 27.8, 25.4 Hz; S diast.),
98.7 (R diast.), 98.3 (S diast.), 77.4 (R diast.), 76.7 (S diast.),
62.8 (S diast.), 62.6 (R diast.), 30.7 (assign. uncer.), 30.6 (assign.
uncer.), 25.6 (R diast.), 25.4 (S diast.), 19.5, 18.4 (S diast.), 17.5
(R diast.). Anal. Calcd for C14H16F2O3: C, 62.21; H, 5.96. Found:
C, 62.37; H, 5.81. See ref 7 for a laboratory scale preparation
and further spectral data.
Methanesulfonate 1-[(2R,3R)-2-(2,4-difluoro-phenyl)-2,3-
dihydroxy-butyl]-1H-[1,2,4]triazol-4-ium (11). A solution of
30 wt % sodium tert-butoxide in THF (197.3 kg, 615.9 mol)
was added to a solution of trimethylsulfoxonium iodide (70.8
kg, 321.7 mol), 1,2,4-triazole (22.2 kg, 321.4 mol), and DMF
(498 kg) at <35 °C. The addition line was rinsed with DMF (5
kg), and the reaction mixture was stirred at 20-25 °C for 30
min. A solution of 53.1 wt % 7 in DMF (142.4 kg, 279.8 mol)
was added at <30 °C followed by a DMF (26 kg) rinse. The
reaction mixture was stirred for 30 min at which point an HPLC
sample determined complete reaction (<0.1 HPLC area % of 7
relative to 8; target was <5%). The mixture was heated to
85-90 °C for 12 h at which point an HPLC sample determined
a complete reaction (2.9 HPLC area % 8 relative to 9; target
was <5%). The mixture was cooled to 20 °C and quenched
with water (381 kg). The solution was extracted with isopropyl
acetate (2 × 393 kg), and the combined extracts were washed
first with 12 wt % NaCl solution (378 kg) followed by water
(2 × 378 kg). The organic solution was distilled to 150 L at
0.08 bar at 55 °C. Isopropyl acetate (298 kg) was added and
again distilled to achieve the end points of <0.3% water and of
isopropyl acetate at e15 relative GC area % versus all other
solvents. The solution was concentrated to 150 L and cooled
to 25 °C, and MSA (34.9 kg, 363.1 mol) was added at <35 °C.
The mixture was stirred at 20-25 °C for 30 min during which
time 11 started to crystallize. Sampling indicated complete
reaction (1.1 HPLC area % 9 relative to 10; target <5%). The
slurry was stirred for an additional 12 h at 20-25 °C, cooled
to 0-5 °C, and stirred for 3 h. The solids were collected by
filtration and washed sequentially with isopropyl acetate (2 ×
90 kg) and n-heptane (77 kg). The cake was dried under vacuum
at 45-50 °C to yield 11 (52.48 kg, 143.6 mol) in 51.3% yield
as an off-white crystalline solid (mp ) 173.5-174.5 °C).
HRMS calcd M + H for C12H14F2N3O2: 270.1054; found M
+ H: 270.1054. 1H NMR (DMSO-d6, 400 MHz) 8.92 (s, 1H),
8.09 (s, 1H), 7.25-7.19 (m, 1H), 7.18-7.11 (m, 1H), 6.87 (td,
J ) 8.46, 2.53 Hz, 1H), 4.80 (d, J ) 14.40 Hz, 1H), 4.72 (d,
J ) 14.40 Hz, 1H), 4.19 (qd, J ) 6.31, 2.78 Hz, 1H), 2.40 (s,
3H), 0.80 (d, J ) 6.31 Hz, 3H); exchangeable protons not
detected. 13C NMR (DMSO-d6, 126 MHz) 161.70 (dd, JC-F
)
246.05, 12.62 Hz), 158.56 (dd, JC-F ) 246.83, 11.83 Hz),
146.45, 143.45, 129.79 (t, JC-F ) 8.68 Hz), 124.01 (dd, JC-F
) 12.62, 3.15 Hz), 110.94 (dm, JC-F ) 20.50 Hz), 103.81 (t,
JC-F ) 27.61 Hz), 76.73 (d, JC-F ) 6.31 Hz), 68.14 (d, JC-F
)
4.73 Hz), 56.20 (d, JC-F ) 4.73 Hz), 39.68, 17.45. Anal. Calcd
for C13H17F2N3O5S: C, 42.73; H, 4.69; F, 10.40; N, 11.50; S,
8.77. Found: C, 42.63; H, 4.55; F, 10.47; N, 11.51; S, 9.16.
See ref 7 for a laboratory scale preparation of the free base and
spectral data.
2-((R)-1-((R)-2-(2,4-Difluorophenyl)oxiran-2-yl)ethoxy)tet-
rahydro-2H-pyran (8). An analytical sample was prepared by
flash chromatography on silica gel using ethyl acetate/heptane
to produce a colorless oil. HRMS calcd M + H for C15H19F2O3:
1
285.1302; found M + H: 285.1302. H NMR (CDCl3, 400
MHz) mixture of diastereomers, 7.54-7.48 (m, 1H), 7.40-7.35
(m, 1H), 6.89-6.83 (m, 2H), 6.81-6.75 (m, 2H), 4.92-4.90
(m, 1H), 4.75-4.74 (m, 1H), 4.07-4.00 (m, 1H), 3.99-3.93
(m, 1H), 3.89-3.79 (m, 2H), 3.53-3.46 (m, 2H), 3.31 (d, J )
5.31 Hz, 1H), 3.03 (d, J ) 5.06 Hz, 1H), 2.84-2.80 (m, 2H),
1.86-1.46 (m, 12H), 1.21 (dd, J ) 6.82, 1.51 Hz, 3H), 1.12
(dd, J ) 6.44, 1.14 Hz, 3H). 13C NMR (CDCl3, 126 MHz)
mixture of diastereomers, 162.76 (dd, JC-F ) 249.20, 4.73 Hz),
162.66 (dd, JC-F ) 249.20, 4.73 Hz), 160.56 (dd, JC-F
)
249.20, 3.15 Hz), 160.46 (dd, JC-F ) 249.20, 3.15 Hz), 131.70
(t, JC-F ) 4.73 Hz), 131.58 (dd, JC-F ) 9.47, 6.31 Hz), 121.40
(dd, JC-F ) 14.99, 3.95 Hz), 120.76 (dd, JC-F ) 14.99, 3.95
Hz), 111.16 (dd, JC-F ) 20.51, 3.16 Hz), 111.11 (dd, JC-F
)
22.08, 3.15 Hz), 103.54 (t, JC-F ) 26.03 Hz), 103.41 (t, JC-F
) 26.03 Hz), 98.61, 94.59, 74.45, 71.08, 62.58, 61.60, 59.77,
59.73, 51.18, 50.77, 30.59, 30.49, 25.41, 19.74, 19.48, 19.00,
17.48, 14.55. Anal. Calcd for C15H18F2O3: C, 63.37; H, 6.25;
F, 13.36. Found: C, 63.29; H, 6.25; F, 13.40. See ref 7 for a
laboratory scale preparation and further spectral data.
(3R)-2-(2,4-Difluoro-phenyl)-3-(tetrahydro-pyran-2-yloxy)-
1-[1,2,4]triazol-1-yl-butan-2-ol (9). An analytical sample was
prepared by flash chromatography on silica gel using ethyl
acetate/heptane to isolate 9 as a colorless oil. HRMS calcd M
+ H for C17H22F2N3O3: 354.1629; found: 354.1629. 1H NMR
(CDCl3, 400 MHz) mixture of diastereomers, 7.94 (s, 1H), 7.91
(s, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.43-7.37 (m, 2H),
6.75-6.68 (m, 4H), 4.90-4.79 (m, 3H), 4.69-4.67 (m, 1H),
4.65-4.57 (m, 2H), 4.40-4.34 (m, 1H), 4.34-4.29 (m, 1H),
3.99-3.93 (m, 1H), 3.92-3.86 (m, 1H), 3.56-3.49 (m, 2H),
1.89-1.70 (m, 4H), 1.65-1.48 (m, 8H), 1.09 (d, J ) 6.32 Hz,
726
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Vol. 13, No. 4, 2009 / Organic Process Research & Development