240 JOURNAL OF CHEMICAL RESEARCH 2017
filtered to recover the catalyst. The solvent was removed under reduced
pressure to afford 7: grey solid; yield 9.4 g, 96%; m.p. 179–181 °C; IR
(νmax/cm–1) KBr: 3516, 3450, 3348, 2948, 1681, 1469, 1270, 1003, 709;
1H NMR (300 MHz, DMSO-d6) δ 8.42 (br s, D2O exchangeable, 2H),
3.79 (s, 6 H); 13C NMR (75 MHz, DMSO-d6) δ 166.9 (s), 154.02–153.6
(q, JC–F = 24.2 Hz), 150.7–150.3 (q, JC–F = 21.1 Hz), 141.8–141.6 (t, JC–F
= 6.0 Hz), 130.5–130.3 (t, JC–F = 11.3 Hz), 126.0–125.6 (t, JC–F = 17.4
Hz), 97.8 (d, JC–F = 12.8 Hz), 62.3 (s), 60.8 (d, JC–F = 3.0 Hz); HRMS
(ESI) calcd for C9H9F2NO4 [M – H]–: 232.0421; found: 232.0425.
6-nitro-2,3,4,5-tetrafluorobenzoic acid (4). Because of the
electron-withdrawing effects of the F and COOH groups in
compound 3, the nitration reaction of 3 was less efficient and
required a high reaction temperature. The yield of compound
4 was 77%. Compound 4 was reacted with sodium methoxide
to generate 3,5-dimethoxy-6-nitro-2,4-difluorobenzoic acid (5)
in 75% yield. Hydrogenation of 5 catalysed by Pd/C afforded
3,5-dimethoxy-6-amino-2,4-difluorobenzoic acid (6) in excellent
yield (96%). After hydrogenation, compound 6 was converted
to the target compound 2 by diazotisation and reduction with
H3PO2/HCl in one step.
3,5-Dimethoxy-2,4-difluorobenzoic acid (2)
A mixture of compound 6 (9.0 g, 38.6 mmol) and water (100 mL) was
cooled to 0 °C and concentrated hydrochloric acid (29.7 g) was added
dropwise the temperature was kept below 5 °C, and a white solid
precipitated in the process. The mixture was stirred for 30 minutes.
A solution of NaNO2 (4.0 g, 57.9 mmol) in water (25 mL) was added
dropwise to this cold emulsion. Stirring was continued for another
30 minutes, the reaction mixture turned to clear solution. Then a
solution of hypophosphorous acid (14 mL) and water (30 mL) was
added dropwise below 5 °C for nearly 1 h. The mixture was stirred
for a further 1 h. The reaction was monitored by TLC (25% EtOAc,
5% AcOH in hexane). The reaction mixture was extracted with
dichloromethane (2 × 300 mL) and the combined organic phases
were decolourised with activated charcoal and dried over anhydrous
Na2SO4. The solvent was removed under reduced pressure to afford a
white solid. The crude product was washed with a mixture of hexane
and EtOAc (12 mL, 5:1), and dried between 50 and 55 °C for 5 h to
obtain 2: White solid; yield 6.1 g, 72%; m.p. 161–163 °C; IR (νmax/cm–1)
KBr: 2967, 1703, 1610, 1482, 1140, 922; 1H NMR (300 MHz, CDCl3) δ
10.85 (br s, 1H, D2O exchangeable), 7.31 (q, J = 6.72 Hz, 1H), 4.05 (s,
1H), 3.94 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 169.1 (s), 153.1–149.6
(q, JC–F = 258.9 Hz), 151.5–148.0 (q, JC–F = 258.1 Hz), 144.5–144.6 (d,
JC–F = 9.8 Hz), 138.3–138.0 (t, JC–F = 11.3, 15.8 Hz), 112.6–112.5 (t,
JC–F = 3.8, 4.5 Hz), 108.3 (d, JC–F = 2.3 Hz), 62.1 (s), 56.6 (s); HRMS
(ESI) calcd for C9H8F2O4 [M – H]–: 217.0312; found: 217.0316.
Experimental
All reactions were monitored by TLC. Melting points were determined
by the capillary method without correction. IR spectra were recorded
1
on Agilent Technologies Cary 630 FTIR instrument. H NMR and
HRMS (ESI) spectra were recorded on a Bruker Avance 300 NMR
spectrometer and an Agilent 6530 Accurate-Mass Q-TOF LC/MS
spectrometer respectively.
6-Nitro-2,3,4,5-tetrafluorobenzoic acid (4)
A solution of 2,3,4,5-tetrafluorobenzoic acid (3) (15.0 g, 77.3 mmol) in
concentrated H2SO4 (98%, 84.0 g) was added dropwise to a solution
of concentrated HNO3 (65%, 10.5 g) and H2SO4 (98%, 15 g) in an ice-
bath, the temperature was kept below 50 °C in the addition process.
Then the mixture was allowed to stir for another 12 h at 100 °C
until TLC (50% EtOAc in hexane) showed that the starting material
had disappeared. After the reaction finished, the reaction mixture
was cooled to 0 °C and poured into ice-water (150 g) and stirred for
another 2 h at 0 °C, filtered and washed with water to afford a white
solid (18.3 g). The crude product was purified by recrystallisation from
hexane to afford 4: White solid; yield 14.2 g, 77%; m.p. 138–139 °C;
IR (νmax/cm–1): 3056, 2907, 1739, 1565, 1487, 1079, 770; 1H NMR
(300 MHz, DMSO-d6) δ 14.54 (br s, D2O exchangeable, 1H); 13C NMR
(75 MHz, DMSO-d6) δ 160.2 (s), 146.3 (d, JC–F = 12.1 Hz), 145.0–141.2
(q, JC–F = 256.6 Hz), 143.8–139.7 (q, JC–F = 257.4 Hz), 133.1 (s), 114.6
(d, JC–F = 18.9 Hz), 109.6 (d, JC–F = 23.4 Hz); HRMS (ESI) calcd for
C7HF4NO4 [M – COOH]–: 193.9864; found: 193.9869.
Electronic Supplementary Information
The ESI {HRMS (ESI) spectra} is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
3,5-Dimethoxy-6-nitro-2,4-difluorobenzoic acid (5)
A solution of compound 4 (14.0 g, 58.6 mmol) and methanol (250 mL)
was stirred in an ice-bath, sodium methoxide (7.5 g) was added in
portions, after the addition was complete, the mixture was warmed
to room temperature and stirred for 3 h when TLC (25% EtOAc, 5%
AcOH in hexane) showed that the starting material had disappeared.
The solution was adjusted to neutral pH with acetic acid. The solvent
was removed under reduced pressure to afford a yellow solid, which
was recrystallised from EtOAc to afford 5: Light yellow solid; yield
11.5 g, 75%; m.p. 127–129 °C; IR (νmax/cm–1) KBr: 3147, 2961, 2361,
1602, 1540, 1372, 1023, 853; 1H NMR (300 MHz, DMSO-d6) δ
3.9 (s, 3H), 4.0 (s, 3 H); 13C NMR (75 MHz, DMSO-d6): δ 161.2
(s), 148.7–145.2 (q, JC–F = 248.3 Hz), 137.3 (s), 139.4–136.7 (q,
JC–F = 162.3 Hz), 123.1 (d, JC–F = 24.2 Hz), 112.3 (d, JC–F =18.9 Hz),
108.6 (d, JC–F = 24.9 Hz), 63.1 (d, JC–F = 4.5 Hz), 62.1 (s); HRMS (ESI)
calcd for C9H7F2NO6 [M – COOH]–: 218.0265; found: 218.0268.
Received 5 February 2017; accepted 9 March 2017
Paper 1704582
Published online: 5 April 2017
References
1
European Pharmacopoeia Commission, European Pharmacopoeia 8.0,
European Directorate for the Quality of Medicines & Health Care, 2013,
pp. 2803–2804.
2
3
4
5
6
7
W.Y. Zhou, S.T. Yu, Z.J. Xia, M.G. Zhang, S. Lin and Z.X. Chen, J. Chem.
W.Y. Zhou, X.H. Feng, S.T. Yu, Z.J. Xia, Y. Chen and Z.X. Chen, J. Chem.
T. Wang, P. Rabe, C.A. Citron and J.S. Dickschat, Beilstein J. Org. Chem.,
2013, 9, 2767.
L. Testaferri, M. Tiecco, M. Tingoli, D. Chianelli and M. Montanucci,
Tetrahedron, 1983, 39, 193.
W.C. Sun, K.R. Gee, D.H. Klaubert and R.P. Haugland, J. Org. Chem.,
1997, 62, 6469.
3,5-Dimethoxy-6-amino-2,4-difluorobenzoic acid (6)
Compound 5 (11.0 g, 41.8 mmol), Pd/C (10%, 1.1 g), and methanol
(120 mL) were placed in an autoclave (250 mL). H2 was purged into
the autoclave three times to remove air, and the reaction mixture was
stirred at 30 °C for 7 h under a pressure between 2.0 and 2.2 MPa.
After the reaction, the resultant mixture was transferred into a tube and