Preparation of 2,3,4,5-tetrafluorobenzoic acid

Article abstract of DOI:10.5012/jkcs.2010.54.6.744

2,3,4,5-Tetrafluorobenzoic acid, an important intermediates of fluoroquinolone antibiotics, was synthesized from tetrachloride phthalic anhydride through imidation, fluorination, hydrolysis and decarboxylation. The effects of phase transfer catalyst on imidation and fluorination reaction and the effects of surfactants on the hydrolysis reaction were studied, respectively. Experimental results showed that the imidation reaction time was greatly reduced in the presence of a phase transfer catalyst, hexadecyltrimethyl, resulting in imidation yield as high as 98.2%. The fluorination yield reached 81.3% when tetrabutylammonium bromide was chosen as a phase transfer catalyst. The hydrolysis reaction time was also decreased by adding hexadecyltrimethyl while increasing the yield to 88.6%. In the post-processing, the sublimation method was used to purify the product, and ideal effect was obtained. In the decarboxylation reaction, tetrafluoride phthalic acid was obtained by decarboxylation in the solvent of tri-n-butyl amine and decarboxylation yield reached 81.6%. Compared with the literature method, the overall reaction time of the improved method decreased from 53 h to 20.5 h and the total yield increased from 47.3% to 57.4%.

Full text of DOI:10.5012/jkcs.2010.54.6.744

Journal of the Korean Chemical Society
2010, Vol. 54, No. 6
Printed in the Republic of Korea
DOI 10.5012/jkcs.2010.54.6.744
2,3,4,5-Tetrafluorobenzoic Acid의 합성
Hua Li*, Hongkai Wang, Ruiju Zhao†, Juan Liu, Zhengui Zhao, Guoqin Hu, and Zhengyong Liang
School of Chemical and Energy Engineering, Zhengzhou University, Zhengzhou, 450001, P. R. China
†Researching Institute of Henan Electric Power Test, Zhengzhou, 4500052, P. R. China
(접수 2010. 4. 16; 수정 2010. 5. 27; 게재확정 2010. 6. 13)
Preparation of 2,3,4,5-Tetrafluorobenzoic Acid
Hua Li*, Hongkai Wang, Ruiju Zhao†, Juan Liu, Zhengui Zhao, Guoqin Hu, and Zhengyong Liang
School of Chemical and Energy Engineering, Zhengzhou University, Zhengzhou, 450001, P. R. China
†Researching Institute of Henan Electric Power Test, Zhengzhou, 4500052, P. R. China
*E-mail: Lihua@zzu.edu.cn
(Received April 16, 2010; Revised May 27, 2010; Accepted June 13, 2010)
요약. Fluoroquinolone 항생제의 중요한 중간체인 2,3,4,5-tetrafluorobenzoic acid를 tetrachloride phthalic anhydride에서 출발
하여 imidation, fluorination, hydrolysis과 decarboxylation단계를 거쳐서 합성하였다. Imdation 단계에서는 상전이 촉매를 이
용하여 98.2%의 수율로 합성하였으며, fluorination 단계에서는 81.3%, 가수분해 단계에서는 88.6%, 마지막으로 decar-
boxylation단계에서는 81.6%의 수율로 합성하였다.
주제어: Tetrafluorobenzoic acid, Tetrachloride phthalic anhydride, Imidation, Fluorinaon, 가수분해, Decarboxylatio
ABSTRACT. 2,3,4,5-Tetrafluorobenzoic acid, an important intermediates of fluoroquinolone antibiotics, was synthesized from
tetrachloride phthalic anhydride through imidation, fluorination, hydrolysis and decarboxylation. The effects of phase transfer
catalyst on imidation and fluorination reaction and the effects of surfactants on the hydrolysis reaction were studied, respectively.
Experimental results showed that the imidation reaction time was greatly reduced in the presence of a phase transfer catalyst,
hexadecyltrimethyl, resulting in imidation yield as high as 98.2%. The fluorination yield reached 81.3% when tetrabutylammonium
bromide was chosen as a phase transfer catalyst. The hydrolysis reaction time was also decreased by adding hexadecyltrimethyl
while increasing the yield to 88.6%. In the post-processing, the sublimation method was used to purify the product, and ideal
effect was obtained. In the decarboxylation reaction, tetrafluoride phthalic acid was obtained by decarboxylation in the solvent
of tri-n-butyl amine and decarboxylation yield reached 81.6%. Compared with the literature method, the overall reaction time of
the improved method decreased from 53 h to 20.5 h and the total yield increased from 47.3% to 57.4%.
Keywords: Tetrafluorobenzoic acid, Tetrachloride phthalic anhydride, Imidization, Fluorinaon, Hydrolysis
and economic forecast. In the field of medicines for anti-
biotic therapy, the global market focus is transferring from
cephalosporin to fluoroquinolones. Therefore, it is meaning-
ful to study a suitable industrial routine for the synthesis of
2,3,4,5-tetrafluorobenzoic acid.
The synthetic methods of 2,3,4,5-tetrafluorobenzoic acid
can be summarized according to the different raw materials.
① 1,2,3,4-tetrachloro-phthalicanhydride,1,2,3 ② O-phtha-
lodinitrile,4 ③N-phenyltetrachlorophthalimidine, ④Otach-
loro-naphthalene,5 ⑤1,2,3,4-tetrafluorobenzene,6 ⑥2,3,4,5-
tetrafluoro-benhydrol etc. therein: ①the process with starting
1,2,3,4-tetrachlorophthalicanhydride and aniline through
imidization reaction,7,8,9 fluoridization reaction, hydrolysis
reaction and decarboxylation reaction is described, this pro-
INTRODUCTION
2,3,4,5-Tetrafluorobenzoic acid is an important pharma-
ceutical intermediate, commonly used in preparation of anti-
bacterial agents of quinolone, such as lomefloxacin, spar-
floxacin, fleroxacin, ofloxacin, levofloxacin and rufloxacin
etc. which is characterized by broad-spectrum antimicrobial
activity, high-effective and low cytotoxicity to human. Qui-
nolone drug is clinically recognized to be a powerful and
safe weapon for the treatment of various bacterial infec-
tions and has become a blockbuster drug, with annual sales
of around 3 billion dollars worldwide. Quinolone drug is
synthesized from 2,3,4,5-tetrafluorobenzoic acid, so the de-
velopment of 2,3,4,5-tetrafluorobenzoic acid has good social
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2,3,4,5-Tetrafluorobenzoic Acid의 합성
745
cess is characterized with plenty raw material source, simple
process and mild reaction condition, therefore it is suitable
for commercial production. Based on traditional technology,
the improved process is researched in the presence of a
phase transfer catalyst, the overall reaction time of the im-
proved method decrease from 53 h to 20.5 h and the total
yield increase from 47.3% to 57.4%.
moles; dried 48 hours at 300 oC, 1 mm Hg), 0.3 g tributyl-
hexadecylphosphonium bromide ( dried 16 hours at 150 oC,
0.5 mm Hg) and 100 mL dried DMF in a 3-neck round-
bottom flask fitted with a cold-water condenser, overhead
stirrer and thermometer. The reaction was run under a po-
sitive pressure of N2 at 140 oC for 8 hours. The hot mixture
was filtered and the filter cake was washed with acetone.
Acetone was flash evaporated from the distillate. The product
was separated from the DMF. The solid was filtered, dried
and recystallized, 9.97 g white crystalline solid was ob-
tained and the yield was 81.3%, the melting point was 203 -
204 oC, the literature data was 204 - 205 oC.10 The product
was identified by HPLC and IR.
EXPERIMENTAL
Materials
Potassium fluoride was industrial grade; other reagents
were all of AR grade and were obtained from Shanghai Che-
mical Reagent Co. with purities of 0.995 in mass fraction.
Dimethylformamide (DMF), DMSO, TMSO2 (Sulfolane)
were dried and dewatered. Melting point was tested by
RD.II digital melting point meter (from Tianjin Instruments
Company); Water was determined with DL 18 Karl Fisher
titrator; Waters2487 high-performance liquid chromato-
graphy was used to HPLC (600 pumps, 600 controllers). IR
spectrum was tested by Shimadzu IR2408.
The reaction equation was as follows:
DMF
TBAB
Hydrolysis
10.0 g N-phenyl phthalimide were put into a 3-neck
round-bottom flask, followed by a mixture that 0.05 g
hexadecyltrimethyl ammino bromide dissolved in 80 mL
80 % sulfuric acid, and this combination was allowed to
reflux (110 oC) for 8 hours. The reaction equation was as
follows:
The imidization of Tetrachlorophthalic anhydride
A mixture of 100 mL acetic acid and 25.00 g (0.087 mol)
pretreated tetrachlorophthalic anhydride was stirred in a
3-neck round bottom flask equipped with a overhead stirrer,
a thermometer, a dropping funnel and a 14-in glass helices-
packed column having a variable reflux ratio still-head.
8.55 g (0.092 mol) aniline was added through the dropping
funnel at a suitable stirred rate. The reaction temperature
was kept at 120 oC and 0.5 g cetyltrimethylammonium bro-
mide was added. External cooling was applied when nece-
ssary and the mixture was violently agitated and reacted for
0.5 h then the product was cooled.
H2SO4
The post-processing method: The reaction mixture was
adjusted to weakly acidic solution, whose pH was 5, with
sodium solution of 20%, and being extracted with 80 mL
dichloromethane, then being extracted with dichloromethane
(50 mL × 2) for two more times. The combined filtrate was
dried by 10 g sodium sulphate anhydrous and filtered to re-
move sodium sulphate and dichloromethane was evapo-
rated and recycled using a rotary evaporator. 7.15 g white
powder was obtained, it’s melting point was 145 - 148 oC,
literature value was 150 - 151 oC,10 and the yield was 88.6%.
The reaction equation was as follows:
CTAB
Acetic acid
The post-processing method: The mixture was separated
and distilled, the obtained product was 30.80 g and the
yield was 98.2%, the melting point was 274 - 275 oC, the
literature data was 275.3 oC - 275.8 oC.10
Purifying tetrafluorophthalic acid by sublimation
According to the determination of melting point and
HPLC, the purity of the product obtained from above 1.4
was not high enough, thus, the purification of tetrafluoro-
Fluorination11
Tetrachloro-N-phenylphthalimide (15 g, 0.042 moles) was
combined in a nitrogen atmosphere with 19.5 g KF (0.34
2010, Vol. 54, No. 6

746
Hua Li, Hongkai Wang, Ruiju Zhao, Juan Liu, Zhengui Zhao, Guoqin Hu, and Zhengyong Liang
phthalic acid was essential. In this step, sublimation method
was used to purify tetrafluorophthalic acid, tetrafluoroph-
thalic acid was increased to 130 - 140 oC and cooled, the
white crystalline in high purity with the melting point 150 -
151 oC was obtained.
Table 1. The effects of phase transfer catalyst on fluorination
No.
catalysts
Reaction Time (h)
yield (%)
1
2
3
TBAB
CTAB
PEG-6000
8
8
8
81.3
76.4
73.8
The effects of solvent on the fluorination reaction13
The synthesis of tetrafluorobenzoic acid
Tri-n-butyl amine 35 mL together with 4 g tetrafluoro-
phthalic acid were added into a 3-neck round-bottom flask,
and this combination was allowed to heated to 130 oC and
reacted for 4 h and cooled to room temperature. Tetrafluo-
rophthalic acid was treated with Tri-n-butyl amine by de-
carboxylation to give tetrafluorobenzoic acid. The reaction
equation was as follows:
was determined at 254 nm in the condition that mobile
phase anhydrous methanol:water = 4:1 (v:v) and the solvent
was DMF, with a flow rate of 1100 mL/min). It could be
found from Table 1 that the best catalyst was tetrabutylam-
monium bromide of quaternary ammonium salts, and the by-
product was not found by HPLC.
The Halogen-exchange of tetrachloro-N-phenyl-phtha-
limide was liquid-solid reaction. Despite the great thermo-
dynamics strength of C-F bond, fluorine was easily replaced
by strong nucleophiles, such as hydroxyl, amine etc., because
the electronegativity of the element fluorine can make the
transition state of reaction steady. Consequently, fluorination
should be reacted in anhydrous non-proton polarity solvent
to avoid the occurrence of side reaction of fluorine hydro-
lysis.
The concentration of fluoride in solvents can also influ-
ence the rate of fluorination, therefore the solvents must
have some solubility to alkali metal salt. The alkali metal
salt of fluoride, that was, fluoride, had relatively large solu-
bility in polar solvents,14,15 such as tetrahydrofuran, DMF.
The increase in solubility of fluoride in polar solvents would
increase the reaction rate; hence, non-proton polarity orga-
nic solvents with high boiling points were an ideal solvent
for the fluorination reaction.
Tri-n-butyl amine
The post-processing method: In view of the price of tri-
n-butyl amine was higher, tri-n-butyl amine needed to be
recycled. 20% NaOH was added to extract tetrafluorobenzoic
acid, then the organic phase was the recycled tri-n-butyl
amine and the aqueous phase was treated with concentrated
hydrochloric acid, with the mass fraction of about 38%, to
adjust the pH to 1, followed by the appearance of gray white
precipitate which was obtained by filtering the solution; the
solution was extracted with methylene chloride, 10 g anhy-
drous sodium sulfate was added into the organic phase, gray
white solid was given by a rotary evaporator; The gray white
solid obtained twice which weighed 2.66 g were the product,
melting point was 89 - 91 oC, literature value was 85 - 87 oC,10
and the yield was 81.6%; In this way, the tri-n-butyl amine
was used as solvent replacing of poisonous methylbenzene,
therefore the environment pollution can be avoided and the
harm to the health of human beings can be decreased.
TMSO2 and DMF were important solvents in industrial
fluorination of halogen exchange. But the price of TMSO2
was 5 times as much as DMF and the boiling point of TMSO2
was much higher than DMF, so in the consideration of the
cost and energy -saving as well as solvent recovery, DMF
of lower price was selected to be the solvent in the fluo-
rination in this experiment.
RESULTS AND DISCUSSION
The effects of reaction time on the fluorination reaction
Reaction time was another important factor that influenced
the reaction. The reaction was investigated by TLC with
the mixture of cyclohexane and ethyl acetate (v:v = 3:1) as
developing solvent. The conditions of the reaction were ob-
served and tested by thin-layer chromatography when the
reaction time was 3 h, 5 h, 6 h, 7 h, 8 h and 12 h respec-
tively. The effects of different reaction time on fluorination
were showed in Table 2.
The effects of phase transfercatalyst on fluorination12
As the fluoridation of fluoride salt was a solid-liquid
reaction, the addition of phase-transfer catalysts could de-
crease reaction temperature, shorten reaction time and in-
crease yield. Therefore the effects of different phase-transfer
catalysts on transformation activity of tetrafluoro products
were showed in Table 1. (The reaction temperature was
150 oC and the reaction time was 8 h, then the wavelength
Journal of the Korean Chemical Society

2,3,4,5-Tetrafluorobenzoic Acid의 합성
747
energy. Reaction temperature influenced greatly not only
the yield of end product, but also the degree of fluorination.
In order to determine the influences of reaction temperature
on the fluorination reaction, reaction temperatures of 120 oC,
130 oC, 140 oC, 150 oC, 160 oC and 170 oC were experiment-
ed respectively. The experimental results were showed in
Table 3.
It was found from Table 3 that the appropriate reaction
temperature was in the range 140 to 150 oC, if the reaction
temperature was too high, coking phenomenon was serious
in aqueous reaction; otherwise, if the reaction temperature
was too low, reaction time would be increased greatly and
the reactant did not react completely.
Table 2. The effect of reaction time on the fluorination reaction
Reaction
Time (h)
Reaction
NO.
TLC
Temperature (oC)
1
2
3
4
5
6
3
5
6
7
8
140
140
140
140
140
140
3 points
3 points
2 points
2 points
1 point
12
multiple points
Table 3. The effects of reaction temperature on the fluorination
reaction
Reaction
Reaction
Time (h)
No.
Yield (%)
Temperature (oC)
The effects of surfactants on hydrolysis
1
2
3
4
5
6
7
120
130
140
150
150
160
170
8
8
8
8
12
8
50.3
64.6
80.2
81.5
75.1
73.4
59.8
The effects of different surfactants on the hydrolysis
were showed in Table 4.
The conventional hydrolysis required 19 h, and the reac-
tants were easy to agglomerate and was not easy to disperse
due to their strong hydrophobicity, therefore the addition
of surfactant can change the surface of the powder reactants
from hydrophobicity to hydrophilcity, which can ensure
good dispersion of reactants in the aqueous phase, the reac-
tion time shortened to 8 h. Compare with different surfactants,
it was found that cetyl trimethyl ammonium bromide played
a very good dispersion effect, the reaction time was 8 h in
88.6% yield. Surfactants with high molecular weight (such
as PEG-6000) had a little bad dispersing effect, this may be
due to the bridge and flocculation of the large molecules of
PEG-6000 between particles. If without surfactant, the yield
could only reach 24.6%
8
Table 4. The effects of different surfactants on the hydrolysis
Surfactants
Reaction Time (h)
Yield (%)
CTAB
8
8
8
88.6
76.2
24.6
PEG-6000
without surfactants
Table 5. The effects of different solvents on the synthesis of tetra-
fluorobenzoic acid
Solvents
Reaction Time (h)
Yield (%)
The effects of sublimationonthe purity of of tetrafluoro-
phthalic acid
The high pure white tetrafluorophthalic acid was obtained
by sublimation. The melting point was 150 - 151 oC.
N,N-dimethylformamide
Dimethyl sulfoxide
Tri-n-butyl amine
4
4
4
70.5
72.8
81.6
The effects of differentsolvents onthe synthesis of tetra-
fluorobenzoic acid
The effects of N,N-dimethyl formamide, dimethyl sulfo-
xide, and tributylamine acid on the synthesis of tetrafluoro-
benzoic acid were studied and the experimental results were
showed in Table 5:
It was found from Table 2 that the appropriate reaction
time was 8 h; if the reaction time was shorter, the reaction
was incomplete, and some intermediate products of two
fluoride and trifluoride were formed. On the contrary, if the
reaction time was longer, some side reactions would be
occurred.
The yield of tri-n-butyl amine as solvent was 81.6% in
Table 5, tri-n-butyl amine played three roles in the reaction:
(1) the alkaline structure of tri-n-butyl amine can react with
hydrogen of the carboxyl group to prompte the decarboxyla-
tion reaction; (2) the alkaline structure of tri-n-butyl amine
can combine with generated carbon dioxide and promote the
The effects of reaction temperature on the fluorination
reaction
Reaction temperature was very important factor for the
reaction. Higher reaction temperature was usually required
in nucleophilic fluorination reaction to obtain activation
2010, Vol. 54, No. 6

748
Hua Li, Hongkai Wang, Ruiju Zhao, Juan Liu, Zhengui Zhao, Guoqin Hu, and Zhengyong Liang
reaction movement towards positive reaction direction; (3)
as solvent, tri-n-butyl amine, in the boiling point range 210
to 215 oC, can meet the temperature requirement of decar-
boxylation reaction in the synthesis of tetrafluorophthalic
acid.
poisonous methylbenzene, and the tri-n-butyl amine can be
recycled. Compared with the literature method, the overall
reaction time of the improved method decreased from 53 h
to 20.5 h and the total yield increased from 47.3% to 57.4%;
(5) The addition of phase transfer catalyst can accelerate
the reaction and the amounts of catalyst is 4% (based on the
mass of N-phenyl-Tetrachloro-phthalimide);
CONCLUSION
(6) Potassium fluoride need to be pretreated before reac-
tion, the fineness and water content of potassium fluoride
directly influenced the yield of fluorination;
(7) Considering the effect of the reaction temperature of
140 - 150 oC and the recovery of the solvent etc., it was eco-
nomical and feasible with DMF as the solvent.
2,3,4,5-Tetrafluorobenzoic acid was synthesized from
1,2,3,4-tetrachlorophthalic anhydride and aniline through
imidization, fluorination, hydrolysis and decarboxylation
with tetrabutylammonium bromide as phase transfer catalyst.
The experimental results showed that:
(1) In the imidation reaction, N-phenyl-Tetrachloro-phtha-
limide was synthesized from tetrachloro-phthalic anhydride
and aniline as raw materials, the proportion of which was
1.1:1, using acetic acid as solvent and hexadecyltrimethyl
ammino bromide as catalyst, reflux for 0.5 h and the 98.2%
yield can be obtained;
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(2) In the fluorination reaction, N-phenyl phthalimide was
synthesized from N-phenyl-Tetrachloro-phthalimide and
potassium fluoride as the raw materials, the ratio of N-
phenyl-Tetrachloro-phthalimide to potassium fluoride was
8:1, potassium fluoride as fluoride and DMF as solvent,
tetrabutylammonium bromide as catalyst, reaction for 8 h.
N-phenyl phthalimide was obtained in 81.3% yield.
(3) In the hydrolysis reaction. Tetrafluorophthalic acid
was synthesized from N-phenyl tetrafluoride phthalimide
as the raw material, using 80% of sulfuric acid as the sol-
vent, reaction for 8 h at 110 oC,with a yield of 88.6%. In the
presence of CTAB, hydrolysis reaction time decreased
obviously from 40 h to 8 h and the concentration of the acid
increased from 50% to 80%; ether was replaced by dichloro-
methane in the product treatment; tetrafluorophthalic acid
was purified by sublimation;
(4) In the decarboxylation reaction, tetrafluorobenzoic
acid was prepared from tetrafluorophthalic acid as raw ma-
terials, with tri-n-butyl amine as solvent kept at 130 oC for 4 h
and the yield reached 81.6%. An improved method was
provided with the tri-n-butyl amine as solvent replacing of
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Journal of the Korean Chemical Society