Organic Process Research & Development
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7.03 (d, J = 8.4 Hz, 1H), 2.38 (s, 3H), 2.31 (d, J = 2.0 Hz, 3H);
13C NMR (400 MHz, MeOD-d4) 161.8 (d, J = 241.0 Hz),
143.3, 141.9, 138.7 (d, J = 3.0 Hz), 133.1 (d, J = 5.0 Hz), 129.9,
126.9, 121.9 (d, J = 23.0 Hz), 121.7 (d, J = 14.0 Hz), 81.9 (d,
J = 27.0 Hz), 21.4, 10.0 (d, J = 4.0 Hz); HRMS calculated for
C7H7FIN [M + H]+: 251.9685, Found: 251.9675.
2-Fluoro-3-methyl-4-(acetyl)aminobenzoic Acid (9a).
Compound 9a was prepared in 62% yield according to the
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procedure for 18a: mp 228−229 °C; H NMR (400 MHz,
MeOD-d4) 7.76 (t, J = 8.0 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H),
2.21 (s, 3H), 2.20 (s, 3H); 13C NMR (400 MHz, MeOD-d4)
172.2, 167.4 (d, J = 4.0 Hz), 161.9 (d, J = 255.0 Hz), 143.1 (d,
J = 7.0 Hz), 130.2 (d, J = 3.0 Hz), 121.5 (d, J = 19.0 Hz), 121.0,
116.9 (d, J = 11.0 Hz), 23.3, 9.8 (d, J = 6.0 Hz); HRMS calcd
for C10H10FNO3 [M + H]+: 212.0717, Found: 212.0726.
Compound 9b was isolated in 34% yield: mp 114−116 °C; 1H
NMR (400 MHz, MeOD-d4) 7.17 (m, 2H), 6.95 (m, 1H), 2.17
(s, 3H), 2.15 (d, J = 5.0 Hz, 3H); 13C NMR (400 MHz,
MeOD-d4) 172.3, 162.8 (d, J = 241.0 Hz), 138.8 (d, J =
6.0 Hz), 127.7 (d, J = 10.0 Hz), 122.7 (d, J = 3.0 Hz), 121.8 (d,
J = 18.0 Hz), 113.7 (d, J = 23.0 Hz), 23.0, 9.8 (d, J = 5.0 Hz);
HRMS calcd for C9H10FNO [M + H]+: 168.0819, Found:
168.0827.
A small amount of 22 was isolated by flash chromatography
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on silica gel: mp 89−91 °C; H NMR (600 MHz, DMSO-d6)
7.45 (dd, J = 8.0, 8.4 Hz, 1H), 6.30 (t, J = 8.4 Hz, 1H), 2.09 (d,
J = 2.0 Hz, 3H); 13C NMR (600 MHz, DMSO-d6) 161.0 (d, J =
237.8 Hz), 147.6 (d, J = 7.5 Hz), 136.0 (d, J = 10.2 Hz), 108.5
(d, J = 19.7 Hz), 105.1 (d, J = 24.5 Hz), 77.2 (d, J = 2.0 Hz),
9.7 (d, J = 5.6 Hz); HRMS calculated for C7H7FIN [M + H]+:
251.9685, Found: 251.9685.
A small amount of 23 was isolated by flash chromatography
on silica gel: mp 92−94 °C; 1H NMR (400 MHz, CDCl3) 7.81
(dd, J = 0.4, 6.4 Hz, 1H), 2.15 (m, 3H); 13C NMR (400 MHz,
CDCl3) 160.0 (d, J = 239.0 Hz), 146.7 (d, J = 6.0 Hz), 143.4
(d, J = 3.0 Hz), 109.9 (d, J = 22.0 Hz), 78.2 (d, J = 3.0 Hz),
66.7 (d, J = 29.0 Hz), 10.7 (d, J = 5.0 Hz); HRMS calcd for
C7H6FI2N [M + H]+: 377.8652, Found: 377.8652.
4-{2-[4-Chloro-2-(3-fluoro-5-trifluoromethylbenzoyl)-
phenoxy]acetylamino}-2-fluoro-3-methylbenzoic Acid
(1). To a mixture of 15 (920 g, 2.44 mol) and DMF
(3.0 mL, 39 mmol) in acetonitrile (6.75 L) was added oxalyl
chloride (358 g, 2.76 mol). The resulting mixture was stirred at
30 °C for 3 h and concentrated to ∼2.5 L. This solution of acid
chloride 8 was used directly without isolation. This solution
was added to a suspension of 3 (393 g, 2.33 mol) and K3PO4
(1000 g, 4.57 mol) in acetonitrile (4.3 L) at 0−5 °C over
30 min. After being stirred at room temperature for 10 h, the
mixture was quenched by addition of 6% HCl (5.5 L) over 1 h.
The resulting slurry was filtered, and the cake was washed
with water to give 1 as an off-white solid after drying in an
2-Fluoro-3-methyl-4-aminobenzoic Acid (3). To a
solution of 18 (655 g, 2.04 mol) in THF (2500 mL) was
added 1.0 M p-tolylmagnesium bromide (2090 g, 2.20 mol) in
THF at −10 to 0 °C over 30 min. Isopropylmagnesium
chloride (2.0 M, 1070 g, 2.20 mol) in THF was then added
over 20 min at the same temperature. After 10 min, gas CO2
(300 g, 6.82 mol) was bubbled into the reaction mixture for
20 min at −10 to 15 °C. The reaction mixture was then
quenched with 2 N HCl (2300 mL) and extracted with toluene
(1500 mL). The organic phase was washed with water
(2500 mL) and extracted with 2 N NaOH (2000 mL × 2).
The combined extracts were heated to 80 °C with the addition
of NaOH (400 g, 10.0 mol) for 8 h and cooled to 0−5 °C. To
the mixture was added concentrated HCl (1130 mL) over 1 h.
The slurry was filtered, and the filter cake was washed with
water to give 3 (294 g, 85%) as a white solid. mp 196−198 °C;
1H NMR (500 MHz, DMSO-d6) 7.48 (t, J = 8.0 Hz, 1H), 6.46
(d, J = 9.0 Hz, 1H), 1.97 (s, 3H); 13C NMR (500 MHz,
DMSO-d6) 165.5 (d, J = 3.6 Hz), 161.1 (d, J = 251.4 Hz), 153.1
(d, J = 8.5 Hz), 130.1 (d, J = 3.4 Hz), 108.7 (d, J = 1.6 Hz), 106.9
(d, J = 19.1 Hz), 105.0 (d, J = 11.4 Hz), 8.2 (d, J = 7.4 Hz); HRMS
calcd for C8H8FNO2 [M + H]+: 170.0611, Found: 170.0617.
A small amount of 18a was isolated by crystallization from a
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oven (1080 g, 86%). mp >200 °C (decomposed); H NMR
(500 MHz, DMSO-d6) 9.54 (s, 1H), 7.96 (d, J = 7.0 Hz, 1H),
7.88 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.65 (m, 2H), 7.54 (s,
1H), 7.41 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 8.5 Hz, 1H), 4.81 (s,
2H), 2.02 (s, 3H); 13C NMR (500 MHz, DMSO-d6) 191.6,
165.9, 164.9, 164.8, 161.9 (d, J = 247.5 Hz), 159.6 (d, J = 253.4
Hz), 154.3, 140.8 (d, J = 6.8 Hz), 139.9 (d, J = 6.8 Hz), 132.7,
131.3 (dq, J = 7.9, 33.0 Hz), 129.3, 128.7 (d, J = 2.4 Hz), 128.1,
125.3, 122.8 (q, J = 270.1 Hz), 121.7 (m), 120.3 (d, J = 22.1
Hz), 118.9 (m), 117.4 (m), 115.4 (d, J = 11.6 Hz), 115.3, 67.1,
9.3 (d, J = 6.3 Hz); HRMS calcd for C24H15ClF5NO5 [M + H]+:
528.0631, Found: 528.0642.
A small amount of 25 was isolated by prep HPLC: 1H NMR
(500 MHz, MeOD-d4) 7.80 (t, J = 8.0 Hz, 1H), 7.70 (s, 1H),
7.59 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.47 (d, J =
8.0 Hz, 1H), 7.43 (dd, J = 2.0, 8.5 Hz, 1H), 7.17 (d, J = 8.5 Hz,
1H), 7.03 (d, J = 2.0 Hz, 1H), 5.29 (s, 1H), 2.27 (d, J = 2.0 Hz,
3H); 13C NMR (400 MHz, MeOD-d4) 167.4, 167.1, 163.9 (d,
J = 245.5 Hz), 161.9 (d, J = 254.9 Hz), 159.4, 148.7 (d, J = 7.3
Hz), 142.0 (d, J = 6.8 Hz), 134.6 (dq, J = 8.0, 33.0 Hz), 132.2,
130.4 (d, J = 2.0 Hz), 128.4, 125.8, 124.8 (q, J = 270 Hz), 122.6
(d, J = 19.0 Hz), 121.6 (d, J = 4.0 Hz), 121.4 (d, J = 4.0 Hz),
120.7 (d, J = 4.0 Hz), 119.0 (d, J = 23.0 Hz), 117.6 (d, J = 11.0 Hz),
113.7, 113.2 (dd, J = 4.0, 25.0 Hz), 94.1, 83.7, 9.9 (d, J = 7.0 Hz);
HRMS calcd for C24H13F5ClNO4 [M + H2O + NH4]+: 545.0897,
Found: 545.0916.
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mixture of IPA/water: mp >200 °C (decomposed); H NMR
(400 MHz, DMSO-d6) 9.52 (s, 1H), 7.66 (t, J = 8.4 Hz, 1H),
7.41 (d, J = 8.8 Hz, 1H), 2.72 (m, 1H), 2.11 (d, J = 2.4 Hz,
3H), 1.12 (d, J = 6.8 Hz, 6H); 13C NMR (400 MHz, DMSO-
d6) 175.6, 165.0 (d, J = 3.0 Hz), 159.6 (d, J = 253.0 Hz), 142.1
(d, J = 7.0 Hz), 128.6 (d, J = 2.0 Hz), 119.7 (d, J = 3 0.0 Hz),
119.4 (d, J = 18.0 Hz), 115.0 (d, J = 2.0 Hz), 34.4, 19.4, 9.6 (d,
J = 6.0 Hz); HRMS calcd for C12H14FNO3 [M + H]+:
240.1030, Found: 240.1033. A small amount of 18b was iso-
lated by flash chromatography on silica gel: mp 129−130 °C;
1H NMR (400 MHz, MeOD-d4) 7.17 (m, 1H), 7.11 (d, J =
8.0 Hz, 1H), 6.96 (t, J = 8.4 Hz, 1H), 2.71 (m, 1H), 2.14 (d, J =
2.0 Hz, 3H), 1.24 (d, J = 6.8 Hz, 6H); 13C NMR (400 MHz,
MeOD-d4) 179.1, 162.8 (d, J = 241.0 Hz), 138.8 (d, J = 6.0
Hz), 127.7 (d, J = 10.0 Hz), 123.0 (d, J = 3 0.0 Hz), 122.3 (d,
J = 18.0 Hz), 113.8 (d, J = 13.0 Hz), 36.5, 20.0, 9.9 (d, J =
5.0 Hz); HRMS calcd for C11H14FNO [M + H]+: 196.1132,
Found: 196.1140.
A small amount of 26 was isolated by prep HPLC: 1H NMR
(500 MHz, DMSO-d6) 8.51 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H),
7.67 (dd, J = 2.0, 8.5 Hz, 1H), 7.56 (d, J = 2.0 Hz, 1H), 7.56−
7.50 (m, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.45 (s, 1H), 7.35 (d,
J = 8.5 Hz, 1H), 6.68 (d, J = 8.5 Hz, 1H), 1.74 (s, 3H); 13C
NMR (500 MHz, DMSO-d6) 193.0, 164.9 (d, J = 3.1 Hz),
161.5 (d, J = 247.4 Hz), 160.2 (d, J = 246.0 Hz), 147.0
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dx.doi.org/10.1021/op200301h | Org. Process Res. Dev. 2012, 16, 561−566