Organic Process Research & Development
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was cooled to 0−10 °C, stirred for 1 h, and then filtered. The
wet cake was washed with H2O (3 × 30 L) and dried in vacuo at
40 °C to afford 21 as a yellow solid (10.8 kg, 94%). HPLC
purity: 99.9 area % (HPLC condition A); Mp 109−112 °C; 1H
for 1 h, and then filtered. The wet cake was washed with
diisopropyl ether (20 mL) and dried in vacuo at 50 °C to afford
13 as a white solid (11.9 g, 76%). HPLC purity: 98.3 area %,
residual 26b: 1.0 area % (HPLC condition B). An analytical
sample was prepared by recrystallization from EtOAc/n-
4
NMR (300 MHz, DMSO-d6) δ 7.59 (d, JHF = 7.0 Hz, 1H),
3
7.70 (d, JHF = 11.0 Hz, 1H), 11.1 (br s, 1H); 13C NMR (75
1
heptane (1:2). Mp 96−97 °C; H NMR (300 MHz, DMSO-
MHz, DMSO-d6) δ 111.9 (dd, 3JCF = 2.5 Hz), 119.8 (dd, 2JCF
=
d6) δ 5.48 (br s, 2H), 6.33 (ddd, 4JHF = 6.5 Hz, J = 8.7, 2.9 Hz,
3
2
1H), 6.57 (dd, 4JHF = 7.6 Hz, J = 2.9 Hz, 1H), 7.09 (dd, 3JHF
=
25.5 Hz), 127.4 (sd, JCF = 9.3 Hz), 135.4 (sd, JCF = 8.4 Hz),
1
4
147.7 (sd, JCF = 256.2 Hz), 150.1 (sd, JCF = 2.8 Hz); IR
(ATR) 3376, 3116, 3062, 1616, 1591, 1524, 1487, 1420, 1359,
1349, 1334, 1293, 1232, 1198, 1184, 1099, 1022, 1004, 901,
865, 844, 799, 756, 705, 637, 599, 556, 494, 468, 455, 433, 417
cm−1; MS (ESI): m/z 192 [M + H]+; Anal. Calcd for
C6H3ClFNO3: C, 37.62; H, 1.58; Cl, 18.51; F, 9.92; N, 7.31.
Found: C, 37.51; H, 1.76; Cl, 18.54; F, 9.87; N, 7.39.
11.2 Hz, J = 8.7 Hz, 1H), 7.58 (dd, J = 9.0, 2.9 Hz, 1H), 8.32
(d, J = 9.0 Hz, 1H), 8.38 (d, J = 2.9 Hz, 1H); 13C NMR (75
MHz, DMSO-d6) δ 106.6 (dd, 3JCF = 7.1 Hz), 107.3 (dd, 3JCF
=
5.2 Hz), 116.2 (dd, 2JCF = 20.4 Hz), 120.6 (d), 126.2 (d), 138.3
2
1
(d), 138.6 (sd, JCF = 14.9 Hz), 148.2 (sd, JCF = 235.1 Hz),
150.6 (sd, 4JCF = 2.0 Hz), 150.9 (s), 159.0 (s); IR (ATR) 3499,
3402, 1635, 1567, 1513, 1453, 1396, 1352, 1286, 1235, 1198,
1150, 1140, 1111, 972, 911, 873, 853, 841, 810, 767, 747, 710,
690, 627, 607, 472, 451, 416, 406 cm−1; Anal. Calcd for
C11H8FN3O3: C, 53.02; H, 3.24; N, 16.86. Found: C, 52.99; H,
3.26; N, 16.60.
3-Amino-4-fluorophenol (2). A 300 L GL vessel was
charged with MeOH (108 L), 21 (5.40 kg, 28.2 mol), and
NaOAc (2.54 kg, 30.6 mol). After the reaction vessel was
evacuated and backfilled with nitrogen, 10% Pd/C (PE type,
52.7% H2O wet, 1.32 kg, 0.587 mol as Pd) was quickly added to
the solution. The reaction vessel was evacuated and backfilled
with nitrogen and then evacuated and backfilled with hydrogen
three times. The reaction mixture was stirred at 15−25 °C for 4
h while maintaining hydrogen pressure at 0.1 MPa. The
hydrogen was vented, and the reaction vessel was evacuated
and backfilled with nitrogen. The reaction mixture was filtered,
and the cake was washed with MeOH (32 L). The combined
filtrate was concentrated under reduced pressure. EtOAc (22 L)
was added to the residue and concentrated under reduced
pressure again. Then EtOAc (54 L) and H2O (27 L) were
added, and the layers were separated. After washing with 5%
aqueous NaCl (27 L), the organic layer was concentrated to
10.8 L under reduced pressure. EtOAc (43 L) was added, and
the solution was concentrated to 10.8 L under reduced pressure
again. To this solution was slowly added n-heptane (43 L), and
the resulting slurry was stirred at 15−25 °C for 30 min. After
cooling to 0−10 °C, the slurry was stirred for 2 h and then
filtered. The wet cake was washed with EtOAc/n-heptane (1:4,
10.8 L) and dried in vacuo at 50 °C to afford 2 as a pale-brown
solid (2.85 kg, 80%). HPLC purity: 94.5 area % (HPLC
N-(2-Fluoro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyra-
zole-5-carboxamide (4).17 4 was synthesized according to
the reported procedure. HPLC purity: 98.9 area % (HPLC
condition A); 1H NMR (300 MHz, DMSO-d6) δ 2.21 (s, 3H),
4
4.21 (s, 3H), 6.64 (ddd, JHF = 7.0 Hz, J = 8.9, 3.8 Hz, 1H),
4
6.85 (br s, 1H), 7.06 (dd, JHF = 6.2 Hz, J = 3.8 Hz, 1H), 7.07
(dd, 3JHF = 10.1 Hz, J = 8.9 Hz, 1H), 9.48 (br s, 1H), 9.85 (br s,
1H); 13C NMR (75 MHz, DMSO-d6) δ 13.3 (q), 38.8 (q),
3
3
107.7 (d), 113.1 (dd, JCF = 4.0 Hz), 113.2 (dd, JCF = <4.0
2
2
Hz), 116.1 (dd, JCF = 21.3 Hz), 125.3 (sd, JCF = 13.7 Hz),
135.5 (s), 145.8 (s), 149.7 (sd, 1JCF = 237.1 Hz), 153.6 (sd, 4JCF
= 1.8 Hz), 158.3 (s).
N-{2-Fluoro-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1,3-di-
methyl-1H-pyrazole-5-carboxamide (6). Preparation via
Route A. A flask was charged with 1,3-dimethyl-1H-pyrazole-5-
carboxylic acid 27 (1.18 g, 8.43 mmol) and DMAC (9 mL). To
the mixture was slowly added SOCl2 (1.18 g, 9.93 mmol) at 0−
15 °C. The mixture was stirred at 10 °C for 1 h, and then 13
(2.00 g, 8.03 mmol) was added portionwise, followed by
addition of DMAC (3 mL). The reaction mixture was stirred at
room temperature for 1 h, and H2O (20 mL), 8 M NaOH (2.2
mL), and EtOAc (40 mL) were added in this sequence. After
phase separation, the organic layer was washed with H2O (10
mL) and concentrated under reduced pressure. The crude
product was suspended in EtOAc (10 mL), followed by slow
addition of n-heptane (30 mL). The resulting slurry was stirred
at room temperature for 1 h and then filtered. The wet cake
was washed with n-heptane (10 mL) and dried in vacuo at 50
°C to afford 6 as a pale-yellow solid (2.60 g, 87%). HPLC
purity: 99.4 area % (HPLC condition B); Mp 132−133 °C; 1H
NMR (300 MHz, DMSO-d6) δ 2.20 (s, 3H), 3.99 (s, 3H), 6.88
(s, 1H), 7.20 (ddd, J = 6.9, 3.2, 3.2 Hz, 1H), 7.47 (t like, J = 9.1
Hz, 1H), 7.59 (dd, J = 6.3, 3.0 Hz, 1H), 7.66 (dd, J = 9.0, 2.9
Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 8.44 (d, J = 2.7 Hz, 1H),
10.2 (br s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 13.2 (q),
1
condition A); Mp 143−145 °C; H NMR (300 MHz, DMSO-
d6) δ 4.91 (br s, 2H, NH2), 5.86 (ddd, 4JHF = 6.4 Hz, J = 8.6, 3.1
4
Hz, 1H), 6.18 (dd, JHF = 7.9 Hz, J = 3.1 Hz, 1H), 6.69 (dd,
3JHF = 11.4 Hz, J = 8.6 Hz, 1H), 9.10 (br s, 1H, OH); 13C NMR
3
(75 MHz, DMSO-d6) δ 102.4 (dd, JCF = 6.6 Hz), 103.0 (dd,
2
2
3JCF = 3.7 Hz), 115.0 (dd, JCF = 19.5 Hz), 137.0 (sd, JCF
=
1
14.3 Hz), 145.1 (sd, JCF = 226.6 Hz), 154.1 (s); IR (ATR)
3387, 3295, 3045, 2953, 2832, 2723, 2362, 1631, 1605, 1509,
1360, 1317, 1208, 1159, 1132, 1080, 966, 837, 770, 726, 696,
616, 597, 595, 442 cm−1; MS (ESI): m/z 128 [M+H]+; Anal.
Calcd for C6H6FNO: C, 56.69; H, 4.76; F, 14.95; N, 11.02.
Found: C, 56.67; H, 4.84; F, 14.91; N, 10.99.
2-Fluoro-5-[(6-nitropyridin-3-yl)oxy]aniline (13). A
flask was charged with H2O (50 mL), DMSO (50 mL), 5-
chloro-2-nitropyridine 5b (10.0 g, 63.1 mmol), 2 (9.62 g, 75.7
mmol), and K3PO4 (25.4 g, 120 mmol). The mixture was
heated to 75−80 °C and stirred for 9 h. After the mixture was
cooled to room temperature, toluene (200 mL) and 1 M
NaOH (100 mL) were added, and then layers were separated.
The organic layer was washed with H2O (100 mL) and
concentrated under reduced pressure. The residue was
suspended in diisopropyl ether (50 mL) and stirred at 50 °C
for 1 h. The slurry was cooled to room temperature and stirred
2
38.8 (q), 108.0 (d), 117.7 (dd, JCF = 22.2 Hz), 118.3 (d),
118.5 (dd, 3JCF = 8.2 Hz), 120.7 (d), 126.7 (d), 126.8 (sd, 2JCF
= 14.0 Hz), 135.0 (s), 138.5 (d), 145.7 (s), 149.8 (sd, 4JCF = 2.6
1
Hz), 151.2 (s), 152.8 (sd, JCF = 252.8 Hz), 158.3 (s), 158.6
(s); IR (ATR) 1686, 1624, 1573, 1541, 1523, 1433, 1348, 1242,
1190, 1167, 1111, 1014, 972, 877, 865, 855, 825, 813, 759, 745,
692, 667, 646, 610, 592, 507 cm−1; MS (ESI): m/z 372 [M +
H]+; Anal. Calcd for C17H14FN5O4: C, 54.99; H, 3.80; N,
18.86. Found: C, 55.00; H, 3.82; N, 18.73.
J
dx.doi.org/10.1021/op4002824 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX