An efficient synthesis of 2,4-difluoro-3,5-dichlorobenzoic acid

Article abstract of DOI:10.3184/174751915X14295255352061

2,4-Difluoro-3,5-dichlorobenzoic acid, as a key intermediate for preparing quinolone-3-carboxylic acids, was synthesised from the commercially available 2,4-difluoro-3-chlorobenzoic acid in excellent yield by a reaction sequence involving nitration, selec

Full text of DOI:10.3184/174751915X14295255352061

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 MAY, 277–278
RESEARCH PAPER 277
An efficient synthesis of 2,4-difluoro-3,5-dichlorobenzoic acid
Weiyou Zhou , Shuitao Yu , Zhengjun Xia , Mingguang Zhang , Song Lin and Zaixin Chen
a,b
a,c
a,c
a,c
a,c
a,c*
a
Yabang Medical Research Institute, Changzhou 213145, P.R. China
Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou 213164, P.R. China
Jiangsu Novel Quinolone Antibacterial Drugs Engineering Research Center, Changzhou 213145, P.R. China
b
c
2
,4-Difluoro-3,5-dichlorobenzoic acid, as a key intermediate for preparing quinolone-3-carboxylic acids, was synthesised from the
commercially available 2,4-difluoro-3-chlorobenzoic acid in excellent yield by a reaction sequence involving nitration, selective reduction,
diazotisation and chlorination.
Keywords: quinolone-3-carboxylic acids derivatives , 2,4-difluoro-3,5-dichlorobenzoic acid, synthesis
Since its discovery in 2006, quinolone-3-carboxylic acid
derivatives, which are believed to be antibacterial agents,
have attracted a great deal of attention due to their high
activity and favourable pharmacokinetic properties.
Experimental
All reactions were monitored by TLC. Melting points were determined
by the capillary method and are uncorrected. IR spectra were recorded
on a NICOLET Impact 410FT-IR instrument. NMR and HRESIMS
spectra were recorded on a Bruker Avance 300 NMR spectrometer
and an Agilent 6530 Accurate-Mass Q-TOF LC/MS spectrometer,
respectively.
2
,3,4,5-Tetrahalogenated benzoic acid derivatives are
1,2
valuable intermediates in the synthesis of these compounds.
,4-Difluoro-3,5-dichlorobenzoic acid (1) is the key
2
3
intermediate for the synthesis of 2 and 3, which are potential
antibacterial agents. However, there has been only one method
for the preparation of the title compound 1 (Scheme 1). Heating
tetrachlorobenzoyl chloride (4) with potassium fluoride in
sulfolane at elevated temperature can give the compound 5, and
the title compound could then be obtained through hydrolysis
of 5. However, the yield of 5 was very low, because 5-chloro-
5-Nitro-2,4-difluoro-3-chlorobenzoic acid (7): A stirred solution
of 2,4-difluoro-3-chlorobenzoic acid (6) (15 g, 77.9 mmol) in
concentrated H SO (98%, 49.5 g) was treated dropwise with the
2
4
mixture of concentrated HNO (65%, 9.0 g) and H SO (98%,
3
2
4
9.3 g) for 1h at 90 ℃. The reaction progress was monitored by TLC
(30% ethyl acetate in hexane). After completion of the reaction, the
reaction mixture was cooled to room temperature and ice (12 g) was
added. The precipitate was separated by centrifugation and dried
between 40–45 ℃ for 18 h. The crude product was purified by column
chromatography using 20% ethylacetate:hexane as eluent. The solvent
was removed under reduced pressure to afford a yellow solid 7 (17.5 g)
2
,3,4-trifluorobenzoyl fluoride was also formed as a co-product
3,4
in the process. To avoid the problem, we have developed a
simple and efficient route for the synthesis of 2,4-difluoro-3,5-
dichlorobenzoic acid 1 as shown in Scheme 1.
–
1
in 94.6% yield. m.p. 123–124 ℃. IR ν (cm ): 3267, 3053, 1689, 1529,
In the preferred route, 2,4-difluoro-3-chlorobenzoic acid (6)
was chosen as the precusor. Treatment of 6 with concentrated
nitric acid provided 7 in a high yield (94.6%) when the water
produced in the process was removed by distillation. Compound
1
1
319, 891. H NMR (300 MHz, DMSO-d ): δ 13.9 (br s, 1H), 8.57(t,
6
13
J= 8.19 Hz, 1H), 8.57 (t, J= 7.83 Hz, 1H, D O exchangeable). C NMR
2
(
(
300 MHz, DMSO-d ): δ 161.9–162.0 (d, J = 13.1 Hz), 158.5–162.2
6
C
-
F
q, JC-F = 267.8 Hz), 152.6.–156.2 (q, JC-F = 268.5 Hz), 133.8–134.0 (q,
7
was reducted by H catalysed by Pd/C to generate 2,4-difluoro-
2
JC-F = 7.1 Hz), 127.4 (d, JC-F = 1.5 Hz), 116.7–116.9 (q, JC-F = 12.0 Hz),
12.9–113.4 (q, J = 22.5 Hz).HRESIMS calcd for C H ClF NO [M-
3
-chloro-5-aminobenzoic acid (8) in moderate yield (87.0%)
1
C-F
7
2
2
4
5
in an environmentally friendly method. No reduction of the
carboxylic acid group to aldehyde nor alcohol was observed.
After completion of reduction, compound 8 was converted to
the objective compound by diazotisation and chlorination by
–
H] 235.9562; found 235.9566.
2,4-Difluoro-3-chloro-5-aminobenzoic acid (8): Compound
7
(17.1 g, 72.0 mmol), Pd/C (10%, 1.71 g), and methanol (180 mL) were
placed in a autoclave (250 mL). The autoclave was purged with H2
three times to remove air, and the reaction mixture was stirred with
6
CuCl/HCl in the final step.
O
C
O
C
O
C
O
C
O
C
Cl
Cl
Cl
F
H
2
N
O
N
2
Cl
a
F
OH
OH
c
OH
d
Cl
F
F
F
F
F
F
F
b
e
Cl
Cl
Cl
Cl
Cl
O
C
4
5
8
7
6
Cl
F
OH
F
Cl
1
O
N
O
O
N
O
Cl
N
Cl
OH
OH
HN
N
N
,
Cl
Cl
2
3
Scheme 1 Reagents and conditions: (a) KF, sulfolane; (b) hydrolysis; (c) HNO (65%), H SO (98%); (d) H , Pd/C; (e) HCl/NaNO , CuCl.
3
2
4
2
2
*
Correspondent. E-mail: zaixin-chen@163.com

278 JOURNAL OF CHEMICAL RESEARCH 2015
a balloon of H at room temperature for 6.5 h under a pressure of 0.6
(6 mL) and ethyl acetate (3 mL), and then dried between 50 and 55 ℃
2
MPa. After the reaction, the resultant mixture was transferred into a
tube and the solid was separated by centrifugation. The solvent was
removed under reduced pressure to afford a white solid 8 (13.0 g) in
for 7.5 h. The compound was obtained as a white solid (3.8 g, 12.9%).
m.p. 155–156 ℃. IR ν (cm ): 3295, 3061, 1659, 852. H NMR (300
–1
1
MHz, DMSO-d ): δ 13.9 (br s, 1 H), 7.98–8.03 (t, J= 7.71 Hz, 1H),
6
–1
13
8
7.0% yield. m.p. 156–157 ℃. IR ν (cm ): 3473, 3128, 3279, 3041,
7.95–8.00 (t, J= 7.71 Hz, 1H, D O exchangeable). C NMR (300
2
1
1673, 1348, 883. H NMR (300 MHz, DMSO-d ): 13.1(1H, s), 7.31 (1H,
MHz, DMSO-d ): δ =162.4–162.5 (d, J = 3.8 Hz), 154.6–158.1 (q,
6
6
C-F
13
br s, CH), 6.51(2H, s). C NMR (500 MHz, DMSO-d ): δ 167.2, (d, J
JC-F = 264.0 Hz), 154.4–157.8 (q, JC-F = 252.8 Hz), 131.2 (d, JC-F = 2.3
Hz), 117.4–117.6 (q, JC-F = 11.6 Hz) , 116.3–116.6 (q, JC-F = 18.0 Hz),
111.4–111.9 (q, J = 20.3 Hz). HRESIMS calcd for C H Cl F O [M-
6
C-F
=
3.8 Hz), 151.0–153.0 (d, JC-F = 250.0 Hz), 150.6–152.6 (d, JC-F = 250.0
Hz), 135.1–135.2 (q, JC-F = 12.5 Hz), 117.9 (d, JC-F = 6.3 Hz), 117.5–117.6
C-F
7
2
2
2
2
–
(
q, JC-F = 10.0 Hz), 112.1–112.5 (q, J = 18.8 Hz). HRESIMS calcd for
H] 224.9322; found 224.9326.
C-F
–
C H ClF NO [M-H] 205.9820; found 205.9825.
7
2
2
4
2
,4-Difluoro-3,5-dichlorobenzoic acid (1): A mixture of compound
Received 1 March 2015; accepted 8 April 2015
8
(12.0 g, 57.8 mmol), concentrated hydrochloric acid (72.0 g), water
Paper 1503223 doi: 10.3184/174751915X14295255352061
Published: 08 May 2015
(72.0 g), CuCl (21.3 g, 215.2 mmol) and dichloromethane (174.0
g) was stirred at 0 ℃. To this emulsion a solution of NaNO (5.1
2
g, 73.9 mmol) in water (72.0 mL) was added dropwise to the cooled
reaction mixture. The reaction mixture was stirred for another 4
hours at room temperature. The reaction progress was monitored by
TLC (30% ethyl acetate in hexane). The reaction mixture extracted
with dichloromethane (2 × 30 mL) and the combined organic phases
were washed with Na S O solution (10%, 2 × 24 mL), HCl solution
References
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2
4
(5%, 2 × 24 mL), decolourised with activated carbon and dried over
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2
4
white solid. The crude product was washed with a mixture of hexane

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