by filtration. The filter cake was washed with isopropanol (7
kg) followed by drying at 60 °C under vacuum in a tray drier
to yield 12.5 kg of 6 (88%). 1H NMR (DMSO-d6) δ 3.26 (s, 3
H), 4.33 (s, 2 H), 7.81 (s, 1 H) 8.14 (d, 1 H, J ) 9.54), 8.28 (d,
1H, J ) 9.54). 13C NMR (DMSO-d6) δ 166.49, 158.61, 156.08,
131.18, 121.17, 113.54, 113.28, 42.90, 37.57. Anal. Calcd for
C9H8ClFN2O3: C, 43.83; H, 3.27; N, 11.36; F, 7.70. Found: C,
43.78; H, 3.32; N, 11.12; F, 7.62. MS m/z 247 (M+).
(R)-[3-(7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-
ylamino)-2-hydroxy-propyl]carbamic Acid Methyl Ester
(11). A glass-lined reactor was charged with 8 (2.7 kg, 15 mol)
and solid lithium triflate (2.4 kg, 15.4 mol) followed by the
addition of ethanol (18.7 kg). The (S)-epoxide 10 (2.1 kg, 16
mol) was added, and the reaction mixture was allowed to stir
at 35 °C for 168 h. Additional charges of 10 (0.4 kg, 3 mol)
were made at 120 and 144 h, respectively. The reactor was
charged with methyl tert-butyl ether (7.9 kg). The resulting fine
slurry was cooled to 0 °C and held for 1 h followed by filtering
and washing with additional methyl tert-butyl ether (1.7 kg).
The solids were dried under vacuum at 50 °C to give 3.2 kg
(68%) of 11. 1H NMR (DMSO-d6) δ 2.45 (m, 1 H), 3.00 (m,
3 H), 3.15 (d, 3 H, J ) 2.5), 3.43 (s, 2 H), 3.47(s, 3 H), 3.60
(m, 1 H), 4.87 (d, 1 H, J ) 5.1), 5.47 (t, 1 H, J ) 5.8), 6.27 (d,
1H, J ) 14.4), 6.39 (s, 1 H), 7.02 (t, 1 H). Anal. Calcd for
C14H18FN3O4: C, 54.01; H, 5.83; N, 13.50; F, 6.10. Found: C,
53.90; H, 5.62; N, 13.31; F, 6.16.
7-Fluoro-1-methyl-5-nitro-1,3-dihydroindol-2-one (5). A
Hastelloy reactor was charged with 6 (6.7 kg, 27.2 mol)
followed by trifluorotoluene (60.7 kg) and triethylamine (2.8
kg, 27.7 mol). The stirring reaction was heated to 30 °C and
then degassed three times with vacuum followed by nitrogen
inertion. Palladium acetate (0.18 kg, 0.82 mol) and 2-(di-tert-
butylphosphino)biphenyl (0.49 kg, 1.6 mol) were added, and
the mixture was degassed an additional two times. The mixture
was heated to an internal temperature of 55 °C for 6 h. The
mixture was vacuum distilled to ∼20 L followed by the addition
of isopropanol (39 kg) and again concentrated to ∼20 L.
Cooling to 5 °C was followed by filtering and then washing
with isopropanol (8 kg) and with water (22 kg). The resulting
tan solid was dried at 50 °C under vacuum to afford 4.94 kg
(87% yield) of 5. 1H NMR (DMSO, d6) δ 3.3 (s, 2 H), 3.74 (s,
3 H), 8.1 (s, 1 H), 8.13 (d, 1 H, J ) 1.2). 13C NMR (DMSO-
d6) δ 175.16, 147.01, 144.58, 142.29, 129.21, 116.91, 113.47,
113.23, 36.08, 28.9. Anal. Calcd for C9H7FN2O3: C, 51.43; H,
3.36; N, 13.33; F, 9.04. Found: C, 51.36; H, 3.38; N, 12.85; F,
9.03. MS m/z 209 (M-).
5-Amino-7-fluoro-1-methyl-1,3-dihydro-indol-2-one (8).
A reactor was charged with 5% Pd/C (0.5 kg) followed by 5
(4.94 kg, 23.5 mol) and THF (68 kg). After several nitrogen
purges and several hydrogen purges the contents of the reactor
were heated to 40 °C at 65 PSIG for 20 h. After several nitrogen
purges the catalyst was removed by filtration under nitrogen
followed by washing with additional THF (37 kg). The solu-
tion of 8 was condensed to ∼45 L by atmospheric distillation
followed by cooling to 30 °C and holding until crystallization
occurred. Heptane (16 kg) was added followed by cooling to 5
°C followed by filtering and rinsing with 1:1 THF/heptane (6
kg). The product was dried at 40 °C under vacuum to give 2.7
kg of 8 as a tan solid (65%). 1H NMR (DMSO-d6) δ 3.15 (s,
3 H), 3.43 (s, 2H), 5.05 (s broad, 2 H), 6.27 (d, 1 H, J ) 13.9)
and 6.34 (s, 1 H). 13C NMR (DMSO-d6) δ 173.81, 149.06,
146.70, 146.04, 129.02, 120.80, 107.91, 100.32, 100.10, 36.38,
28.68. Anal. Calcd for C9H9FN2O: C, 59.99; H, 5.03; N, 15.55;
F, 10.54. Found: C, 59.84; H, 4.76; N, 15.36; F, 10.15. MS
m/z 181 (M+).
(S)-[3-(7-Fluoro-1-methyl-2-oxo-2,3-dihydro-1H-indol-5-
yl)-2-oxo-oxazolidin-5-ylmethyl]carbamic Acid Methyl Ester
(1). A glass-lined reactor was charged with 11 (3.2 kg, 10.3
mol) followed by CDI (2.1 kg, 13 mol) and acetonitrile (31
kg). The contents of the reactor were heated to 30 °C and stirred
for 3 h at which point the reaction was complete. The contents
were heated to 65 °C and held for 1 h followed by the addition
of water (4.4 kg) and a hot filtration. The contents of the reactor
were cooled to -5 °C and isolated by filtration. The resulting
filter cake was recrystallized from acetonitrile (21.5 kg) and
water (2.7 kg), cooled to -5 °C, and filtered. Upon drying at
ambient temperature and vacuum filtering, 2.97 kg of 1 was
1
isolated as an off-white solid (77%). H NMR (DMSO-d6) δ
3.22 (d, 3 H, J ) 2.5), 3.22 (t, 2 H, J ) 5.8), 3.52 (s, 3 H),
3.57 (s, 2 H), 3.70 (m, 1 H), 4.03 (m, 1 H), 4.64 (m, 1 H), 7.30
(s, 2 H), 7.52 (broad t, 1 H, J ) 5.8);13C NMR (DMSO-d6) δ
174.40, 157.88, 154.74, 147.83, 145.45, 134.29, 134.20, 128.86,
128.81, 127.65, 127.57, 111.58, 106.25, 105.10, 72.08, 52.24,
48.09, 43.94, 40.71, 40.50, 36.38, 28.68, 28.63. Anal. Calcd
for C15H16FN3O5: C, 53.41; H, 4.78; N, 12.46; F, 5.63. Found:
C, 53.24; H, 4.43; N, 12.35; F, 5.53; MS m/z 338 (M+).
Acknowledgment
We thank Brian Moon, Nathan Jenkins, Paul Angell,
William Perrault, and J. Vara Prasad for helpful discussions.
Received for review May 20, 2008.
OP8001195
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