An efficient synthesis of 5-chloro-2, 3, 4-trifluorobenzoic acid

Article abstract of DOI:10.3184/174751915X14322269913981

5-Chloro-2, 3, 4-trifluorobenzoic acid, a key intermediate for preparing quinolone-3-carboxylic acid derivatives, was synthesised from the commercially available 2, 3, 4, 5-trifluorobenzoic acid in excellent yield by a reaction sequence involving nitration, selective reduction, diazotisation and chlorination.

Full text of DOI:10.3184/174751915X14322269913981

326 RESEARCH PAPER
VOL. 39 JUNE, 326–327
JOURNAL OF CHEMICAL RESEARCH 2015
An efficient synthesis of 5-chloro-2, 3, 4-trifluorobenzoic acid
Shuitao Yua,c, Weiyou Zhoua,b, Zhengjun Xiaa,c, Song Lina,c and Zaixin Chena,c*
aYabang Medical Research Institute, Changzhou 213145, P.R. China
bJiangsu Key Laboratory of Advanced Catalytic Materials and Technology, Changzhou University, Changzhou 213164, P.R. China
cJiangsu Novel Quinolone Antibacterial Drugs Engineering Research Center, Changzhou 213145, P.R. China
5-Chloro-2, 3, 4-trifluorobenzoic acid, a key intermediate for preparing quinolone-3-carboxylic acid derivatives, was synthesised from the
commercially available 2, 3, 4, 5-trifluorobenzoic acid in excellent yield by a reaction sequence involving nitration, selective reduction,
diazotisation and chlorination.
Keywords: quinolone-3-carboxylic acids derivatives, 5-chloro-2, 3, 4-trifluorobenzoic acid
5-Nitro-2,3,4-trifluorobenzoic acid (6): A stirred solution of 2, 3,
4-trifluorobenzoic acid (5) (10 g, 56.8 mmol) in concentrated H2SO4
(98%, 33.0 g) was treated dropwise with the mixture of concentrated
HNO3 (65%, 6.0g) and H2SO4 (98%, 6.3g) for 3.5 h between 90 and
95 °C. 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-water (50g) was
added. The precipitation was separated by centrifugation and dried
between 50 and 55 °C for 8 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 white solid 6
(12.2 g) in 97.1% yield; m.p. 125–126 ℃. IR (KBr) /cm–1: 3258, 3047,
1681, 1479, 1238, 887. 1H NMR (300 MHz, DMSO-d6): δ 13.9 (br s,
1H), 8.39–8.44 (q, J= 7.29 Hz, 1 H), 8.42 (s, 1H, D2O exchangeable).
13C NMR(DMSO-d6, 300 MHz): δ 162.0 (s), 151.9–155.6 (m, JC-F
= 268.9 Hz), 146.0–149.9 (m, JC-F = 269.6 Hz), 139.0–142.8 (m, JC-F
Quinolone-3-carboxylic acids derivatives have recently
attracted attention due to their high activity and favourable
pharmacokinetic properties as antibacterial agents. 5-Chloro-2,
3, 4-trifluorobenzoic acid derivatives are valuable intermediates
for the synthesis of these compounds1,2 such as compound 1.3
However, there is only one method for the preparation of the title
compound 2 (Scheme 1) using tetrachlorobenzoyl chloride (3)
as the starting matierial. Heating compound 3 with potassium
fluoride in sulfolane at elevated temperature resulted in the
product but the yield was low, because 2, 4-difluoro-3, 5-dichloro
benzoyl fluoride was also formed as a byproduct.3 This is
unattractive for the large-scale synthesis of 2 due to the low yield.
Consequently, we have developed a simple and efficient route
for the preparation of 5-chloro-2, 3, 4-trifluorobenzoic acid. The
synthetic route is shown in Scheme 1.
2, 3, 4-Trifluorobenzoic acid (5) was treated with concentrated
nitric acid and sulfuric acid to give 6 in a high yield (97.1%)
when the water produced in the process was removed by
distillation. Compound 6 was reduced with H2 catalysed by
Pd/C to generate 2, 3, 4-trifluoro-5-aminobenzoic acid (7) in
high yield (98.2%) and in an environmentally friendly method.4
No reduction of the carboxylic acid group to an aldehyde
or alcohol was observed. After completion of the reduction,
compound 7 was converted to the required compound (2) by
diazotisation and chlorination with CuCl/HCl in the final step.5
= 251.6 Hz), 133.5 (s) , 116.6–116.8 (q, JC-F = 9.0 Hz), 112.9 (d, JC-F
=
2.3 Hz). HRESIMS calcd for C7HF3NO4 [M–H]– 219.9858; found
219.9863.
5-Amino-2,3,4-trifluorobenzoic acid (7): Compound 6 (12.0 g,
54.3 mmol), Pd/C (10%, 1.2g), and methanol (120 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 a balloon of H2 at
room temperature for 6.0 h under a pressure between 1.0 and 1.2 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 7 (10.2 g) in 98.2% yield;
m.p. 157–158 ℃. IR (KBr) /cm–1: 3465, 3117, 3265, 3031, 1685, 1335,
872. 1H NMR (300 MHz, DMSO-d6): δ 8.89 (br s, 2H), 7.15–7.21 (m,
J= 8.01 Hz, 1 H). 13C NMR(DMSO-d6, 300 MHz): δ 164.0–164.1 (t,
JC-F = 3.0 Hz), 140.1–143.5 (m, JC-F = 246.8 Hz), 140.0–143.4 (m, JC-F
Experimental
All reactions were monitored by TLC. Melting points were determined
by the capillary method without correction. IR spectra were recorded
on NICOLET Impact 410FT-IR instrument. NMR and HRESIMS
spectra were recorded on a Bruker Avance 300 NMR spectrometer
and a Agilent 6530 Accurate-Mass Q-TOF LC/MS spectrometer,
respectively.
= 234.0 Hz), 138.4–142.0 (m, JC-F = 243.4 Hz), 132.9–133.0 (d, JC-F
=
9.8 Hz) , 115.7–115.9 (q, JC-F = 7.9 Hz), 111.6–111.7 (q, JC-F = 5.3 Hz).
HRESIMS calcd for C7H3F3NO2 [M–H]– 190.0116; found 190.0121.
O
N
O
C
O
C
O
C
O
C
l
C
l
C
l
C
l
C
H
O
l
C
a
F
H
O
b
R1
R2
l
C
l
C
N
F
F
F
F
,
F
l
C
F
F
2
3
4
1
R1
R2
HN
N
HN
N
N
N
O
C
O
C
O
C
:
,
N
O2
H2N
F
,
H
O
c
H
O
H
O
d
F
F
F
F
F
HN
N
N
N
H
H
N
2C 2C
,
F
F
F
,
H
O
5
7
6
Scheme 1 Reagents and conditions: (a) KF, sulfolane; (b) hydrolysis; (c) HNO3 (65%), H2SO4 (98%); (d) H2, Pd/C; (e) HCl/NaNO2, CuCl.
* Correspondent. E-mail: zaixin-chen@163.com

JOURNAL OF CHEMICAL RESEARCH 2015 327
5-Chloro-2,3,4-trifluorobenzoic acid (2): A mixture of compound
7 (10.0 g, 52.3 mmol), concentrated hydrochloric acid (47.6 g),
water (119.0 g), CuCl (27.5 g, 277.8 mmol) and dichloromethane
(107 mL) was stirred at 0 ℃. To this emulsion a solution of NaNO2
(4.8 g, 69.6 mmol) in water (56.0 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 × 20 mL) and the combined organic phases
were washed with Na2S2O4 solution (10%, 2 × 20 mL), HCl solution
(5%, 2 × 20 mL), decolourised with activated charcoal and dried over
Na2SO4. The solvent was removed under reduced pressure to afford a
white solid. The crude product was washed with a mixture of hexane
(5 mL) and ethyl acetate (2 mL), and then dried between 50 and 55 ℃
for 5 h. The product (2) was obtained as a white solid (7.1 g, 64.5%);
8.01–8.08 (t, J= 7.8 Hz, 1H, D2O exchangeable). 13C NMR (DMSO-d6,
300 MHz): δ 162.5 (s), 148.3–150.5 (m, JC-F = 261.3 Hz), 148.2–150.3
(m, JC-F = 275.6 Hz), 139.4–141.6 (m, JC-F = 275.0 Hz), 126.2 (d, JC-F
= 2.5 Hz) , 116.3–116.4 (m, JC-F = 14.9 Hz), 112.7 (t, JC-F = 30.0 Hz).
HRESIMS calcd for C7HClF3O2 [M–H]– 208.9617; found 208.9623.
Received 3 May 2015; accepted 19 May 2015
Paper 1503341 doi: 10.3184/174751915X14322269913981
Published online : 4 June 2015
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1
m.p. 155–156 ℃. IR (KBr) /cm–1: 3297, 3085, 1660, 873. H NMR
(300 MHz, DMSO-d6): δ 13.4 (br s, 1H), 7.87–8.07 (t, J= 7.8 Hz, 1H),