Experimental Section
160 mol, 75% yield). Spectroscopic analysis was in agreement
with the reported data.1
General. Starting materials, reagents, and solvents were
obtained from commercial suppliers and used without further
purification. IR spectra were recorded using a Thermo Electron
Avatar FT-IR instrument. Melting points were obtained with a
Mettler Toledo DSC822e instrument. NMR spectra were
obtained using Bruker DPX 400, DRX 500, and Avance 600
2-Amino-4,6-difluorobenzoic Acid (17). A solution of
sodium hydroxide (102.1 kg, 2553 mol) in water (113 L) was
added to a suspension of 16 (35.35 kg, 193 mol) in water (210
L) at ambient temperature over 1 h. A water (55 L) line wash
was applied. The mixture was heated to 63 °C before adding
hydrogen peroxide (67.5 L of a 30% solution in water, 595
mol) over 2.5 h, maintaining the temperature at 63-67 °C.
Water (17 L) was added as a line wash and the mixture stirred
for 1 h before cooling to 3 °C. Hydrochloric acid (188 L of a
36% w/w solution, 1856 mol) was added over 4 h followed by
a water (18 L) line wash. Acetic acid (20 L, 349 mol) was
charged over 1 h to adjust the pH to 3 (desired range 2-4),
and a water (18 L) line wash was applied. The mixture was
heated to 20 °C before extracting three times with MTBE (720
kg, 239 kg and 236 kg). The combined organics were washed
with a solution of sodium sulphite (3.55 kg, 28.2 mol) in water
(176 L) for 15 min and the organics tested for the presence of
peroxide with test strips. The organics were washed twice with
a solution of potassium carbonate (3.50 kg in 176 L water in
two equal aliquots) and water (170 L). The organic phase was
concentrated by distillation (55 °C, 636 L of distillate, ∼160 L
remaining) before adding MTBE (136 kg) and redistilling (55
°C, 177 L distillate, 160 L remaining). The solution was cooled
to ambient temperature and used directly in the next step. 17
(119 kg, 18.9% w/w, 130 mol, 67% yield). Spectroscopic
analysis of a sample evaporated to dryness was in agreement
with the reported data.1
2-Amino-4,6-difluorobenzoic Acid (17), Alternative Pro-
cedure. To a solution of sodium hydroxide (11.5 kg, 287 mol)
in water (59 L) at ambient temperature was added 16 (4.6 kg,
26.6 mol) in aliquots over 40 min, maintaining the temperature
at 25 °C. Hydrogen peroxide (4.3 L of a 30% solution in water,
38 mol) was added over 2.5 h, maintaining the temperature at
20-25 °C. Water (2 L) was added as a line wash and the
mixture stirred for 4 h before adding water (23 L). Hydrochloric
acid (∼10 kg of a 36% w/w solution, mol) was added over
1 h, maintaining the temperature below 15 °C to adjust the pH
to 2 (caution, frothing). A water (1 L) line wash was applied.
The mixture was stirred for 30 min before filtering, washing
the cake with water (2 × 10 L), and drying under reduced
pressure (50-60 °C) to give 17 (3.5 kg, 92% w/w, 18.6 mol,
70% yield). Spectroscopic analysis of a sample evaporated to
dryness was in agreement with the reported data.1
1
instruments; H spectra were measured with reference to an
internal standard of tetramethylsilane at 0 ppm, and 13C spectra
were measured with reference to the DMSO signal at 39.5 ppm.
LC-MS and HRMS data were obtained using Waters Micro-
mass ZMD4000 and Waters Micromass LCT Classic instru-
ments, respectively. HPLC analyses were performed with an
Agilent 1100 instrument.
(2Z)-N-(3,5-Difluorophenyl)-2-(hydroxyimino)aceta-
mide (15). Sodium sulphate (29.0 kg, 204.2 mol) was dissolved
in water (75 L) at 45-50 °C. Chloral (17.3 kg, 117.4 mol) was
added over 1 h, maintaining the temperature between 45-50
°C. A water (13 L) line wash was applied and the reaction
mixture stirred for 20 min at 45 °C. A solution of 3,5-
difluoroaniline (11.0 kg, 85.9 mol), and hydrochloric acid (9.2
kg of a 36% solution, 90.8 mol) in water (43.5 L), preheated
to 60 °C, was added to the reaction mixture over 20 min. (The
solution of 14 must be kept above 50 °C to prevent precipita-
tion.) A water (11 L) line wash was applied before adding
toluene (19 kg). The reaction mixture was heated to 55 °C
before a solution of hydroxylamine hydrochloride (19.0 kg,
273.4 mol) in water (41 L) was added to the reaction mixture
over 1 h, maintaining the temperature at 55 °C. A water (11 L)
line wash at 41 °C was applied and the reaction held at 55 °C
for 7 h. The reaction mixture was cooled to 10 °C over 4 h and
held for 1 h. The product was filtered and washed with chilled
water (3 × 44 L, 5-10 °C) and dried under reduced pressure
at 50 °C to give 15 (11.6 kg at 94% w/w, 54.5 mol, 63% yield).
1H NMR (300 MHz, 300 K, DMSO-d6) δ 12.32 (1H, s), 10.56
(1H, s), 7.64 (1H, s), 7.51-7.43 (2H, m), 6.95 (1H, tt, J ) 9.3,
2.4); 13C NMR (100 MHz, 300 K, DMSO-d6) δ 162.3 (dd, JCF
) 243, 15), 160.9, 143.7, 140.9 (t, JCF ) 14), 102.6 (dd, JCF
21, 9), 98.9 (t, JCF ) 26); HRMS (ES accurate mass) calcd for
C8H7F2N2O2 201.0470, found 201.0501.
)
4,6-Difluoro-1H-indole-2,3-dione (16). Sulphuric acid (28
kg of 50% w/w, 143 mol) was cooled to 5 °C before adding
sulphuric acid (316.3 kg, 3225 mol), maintaining the temper-
ature at 5 °C.11 The solution was heated to 60 °C before adding
15 (42.81 kg, 214 mol) in 10 equal portions over 5 h,
maintaining the temperature between 58-62 °C. The reaction
was stirred for a further 1.5 h before cooling to 10 °C and adding
to water (800 L) precooled to 5 °C followed by a water (170
L) line wash. After 2 h the mixture was filtered and the cake
washed with water (3 × 210 L at 0-6 °C) before drying under
reduced pressure at 45 °C to give 16 (35.35 kg at 83% w/w,
Methyl 2-Amino-4,6-difluorobenzoate (18). To a solution
of 17 in MTBE (119 kg of a 18.9% w/w solution, 130 mol)
was added NMP (119 kg). The mixture was distilled under
reduced pressure to remove the MTBE (40 °C, 135 L distillate,
113 L remaining). The resulting solution was added to a mixture
of potassium carbonate (44.64 kg, 323 mol) in NMP (42 kg) at
3 °C over 1 h. (Caution gas eVolution!) Dimethyl sulphate (18.2
kg, 144 mol) was added to the mixture at 2 °C over 1 h before
stirring further for an hour. Analysis showed that the reaction
was not complete, so additional potassium carbonate (2.25 kg,
16 mol) and dimethyl sulphate (0.9 kg, 7 mol) were charged,
and the resulting mixture was stirred further for 35 min. The
mixture was warmed to ambient temperature before adding
(11) The use of concentrated sulphuric acid in lab experiments frequently
resulted in ejection of the reaction mixture from the vessel, presumably
due to the heat generated by the interaction of sulphuric acid with the
water released by the reaction. By using sulphuric acid which already
contained a small amount of water, this could be prevented.
(12) Ford, J. G.; O’Kearney-McMullan, A.; Pointon, S. M.; Powell, L.;
Siedlecki, P. S.; Purdie, M.; Withnall, J.; O’Keefe, P.; Wood, F., Org.
Process. Res. DeV., 2010, 14, DOI: 10.1021/op100163m.
1084
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Vol. 14, No. 5, 2010 / Organic Process Research & Development