Preparation of 2,4,5-trifluorobenzoic acid by decarboxylation of 3,4,6-trifluorophthalic acid

3,4,6-Trifluorophthalic acid may be decarboxylated in a controlled manner to form 2,4,5-trifluorobenzoic acid by heating the phthalic acid in a dipolar aprotic solvent in the absence of any catalyst.

BACKGROUND OF THE INVENTION 
This invention relates to a method for the preparation of 
2,4,5-trifluorobenzoic acid by the decarboxylation of 
3,4,6-trifluorophthalic acid. 2,4,5-trifluorobenzoic acid is a useful 
intermediate in the manufacture of quinolone antibacterial drugs. 
Heretofore, 2,4,5-trifluorobenzoic acid has been difficult to synthesize. 
One known method of synthesis involves the cyanation of 
2,4,5-trifluorobromobenzene using copper cyanide in dimethyl formamide, 
followed by hydrolysis of the product nitrile with sulfuric acid [Sanchez, 
J. P. et al J. Med. Chem. (1988), 31, 983]. This synthetic method is 
difficult to use, and expensive. 
We have now discovered that 2,4,5-trifluorobenzoic acid may be prepared by 
the decarboxylation of 3,4,6-trifluorophthalic acid. The reaction may be 
conducted in dipolar aprotic solvents, without the use of a catalyst. 
Surprisingly, only one of the two carboxyl groups is removed, and 
2,4,5-trifluorobenzoic acid is produced in good yield. 
3,4,6-Trifluorophthalic acid may be conveniently prepared from 
3,4,6-trichlorophthalic acid. The acid is reacted with aniline to form 
3,4,6-N-phenylphthalimide. The phthalimide is then treated with potassium 
fluoride in sulfolane using tributylhexadecylphosphonium bromide as a 
phase transfer catalyst. The method is disclosed in copending patent 
application Ser. No. 07/315,746, which is hereby specifically incorporated 
by reference. 
Many examples of decarboxylation reactions have been reported. Basic 
substances have been used to catalyze such reactions. For example, it is 
disclosed in D. S. Tarbell, et al Org. Syn., III coll. vol. (1955) 267, 
that 3,5-dichloro-4-hydroxybenzoic acid may be decarboxylated by vigorous 
heating in N,N-dimethylaniline. It is disclosed in A. Singer and S. M. 
McElvane, Org. Syn., coll. vol. II (1943) 214, that 
3,5-dicarboxy-2,6-dimethylpyridine di-potassium salt may be completely 
decarboxylated by heating the salt in the presence of calcium hydroxide. 
Copper and copper salts have been used to catalyze decarboxylation 
reactions. For example, H. R. Snyder et al, Org. Syn., coll. vol. III 
(1955) 471 disclose the use of copper oxide catalyst for the 
decarboxylation of imidazole-4,5-dicarboxylic acid. 
Some compounds may be decarboxylated without catalysts. For example, C. 
Wang, Bul. Inst. Kim. Acad. Sinica, no. 2156 (1972), as abstracted in CA79 
(15):91729, discloses that tetrachloro or tetrabromophthalic acids, or 
their anhydrides, may be decarboxylated to the corresponding benzoic acids 
when refluxed in dimethyl formamide. 3-nitrophthalic acid underwent a 
similar reaction. Under similar conditions 1,8-naphthalene dicarboxylic 
acid, and its 3-nitro derivative merely formed the corresponding 
anhydride. 
Decarboxylation is not always a predictable reaction. For example, A. S. 
Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 
41:6223(e) discloses that salicylic acid may be decarboxylated by 
autoclaving the acid in the presence of copper bronze and benzene at 
170.degree. C. The acid alone decarboxylates at 205.degree. C., while in 
the presence of aniline decarboxylation begins at 170.degree. C. In the 
case of salicylic acid, aniline and copper bronze seem to be equal in 
catalytic ability. On the other hand, when phthalic acid is heated in 
aniline at 180.degree. C., decarboxylation does not occur and instead 
phthalic anhydride is produced. Heating phthalic anhydride with copper 
bronze in chloroform at 180.degree. C. gave a 22% yield of benzoic acid. 
Phthalic acid was found to decarboxylate to yield benzoic acid merely by 
heating in water at 235.degree. C. 
Decarboxylations of certain fluorophthalic acids have been reported. 
3,4,5,6-tetrafluorophthalic acid decarboxylates under certain conditions 
to yield 2,3,4,5-tetrafluorobenzoic acid. For example, Japanese Patent JP 
61/85349 A2[86/85349]as abstracted in CA105:152719r discloses that the 
reaction may be conducted in an aqueous medium at 150.degree. to 
230.degree. C. The reaction may be carried out at lower temperature 
(100.degree. to 250.degree. C.) in the presence of copper, zinc, cadmium, 
iron, cobalt, nickel, other oxides, hydroxides and/or carbonates. Japanese 
Patent Application 86/103,317 as abstracted in CA105 (22):193368u 
discloses that the above reaction may be conducted in an aqueous medium at 
a pH of 0.7-2.2 at a temperature of 100.degree.-200.degree. C. The pH of 
the medium is adjusted by acidifying with sulfuric acid and partial 
neutralization with calcium hydroxide. Japanese Patent 63/295529m 
A2[88/295529](as abstracted in Chem. Abstracts CA 111 (3): 23221X) 
discloses that the reaction may be conducted at 130.degree. in 
tri-butylamine. 
Small changes in structure of molecule, or conditions can result in major 
changes in the product produced when fluorinated phthalic acids are 
decarboxylated. For example, Yacobsen, O. J. discloses in Zh. Obsch. Khim. 
36 (1966) page 139 (as appearing in Journal of General Chemistry of the 
U.S.S.R., translated from Russian, 36 (1966) page 144), that 
3,4,5,6-tetrafluorophthalic acid may be decarboxylated to yield 44% 
2,3,4,5-tetrafluorobenzoic acid by heating for one hour at 145.degree. C. 
in dimethyl formamide. An unspecified amount of tetrafluorobenzene was 
found but it was not clear whether or not the amount of tetrafluorobenzene 
found accounts for the remainder of the starting material. 
Under slightly more vigorous conditions, Japanese Patent Application 
61/43130 A2[86/43130]as abstracted in CA106 (1):4629S and Derwent, 
accession number 86-097893/15, discloses that 3,4,5,6-tetrafluorophthalic 
acid may be completely decarboxylated to 1,2,3,4-tetrafluorobenzene in an 
aqueous medium from 210.degree. to 300.degree. C. In the presence of a 
catalyst, such as powdered metallic copper, zinc, cadmium, iron, cobalt or 
nickel or acids, hydroxides or carbonates of those metals the complete 
decarboxylation proceeds at temperatures as low as 100.degree. C. and 
preferably from 160.degree.-240.degree. C. 
U.S. Pat. No. 4,782,180 discloses that 3,4,5,6-tetrafluoropthalic acid may 
be decarboxylated to form tetrafluorobenzoic acid. The reaction may be 
carried out in polar aprotic solvents and requires the presence of a base 
catalyst. Although organic amines are preferred, inorganic bases such as 
sodium bicarbonate, potassium carbonate, and sodium hydroxide may also be 
used. Potassium carbonate as a catalyst apparently leads to 
monodecarboxylation, whereas the carbonate of copper, zinc, cadmium, iron, 
cobalt, or nickel would lead to total decarboxylation, as reported in 
Japanese Patent application 61/43130 A2 (86/43130). 
U.K. Patent 2,122,190 discloses that tetrafluoroterphthalic acid, in which 
the carboxyl groups are para to one another, readily decarboxylates in 
polar aprotic solvents to form 1,2,4,5-tetrafluorobenzene. The process may 
be conducted at temperatures as low as 100.degree. C. No catalyst is 
required, although a copper oxide catalyst may be used if desired. 
Japanese Patent Application 86/290399 as abstracted in CA109 (19) 170038e 
discloses that 3,5,6-trifluoro-4-hydroxyphthalic acid may be 
decarboxylated by heating the compound for three hours, in water, under 
nitrogen atmosphere, at 140.degree. C. (in a sealed tube) to yield 
2,4,5-trifluoro-3-hydroxybenzoic acid. 
Aroskar et al (J. Chem. Soc. (1964) 2975) discloses a method for preparing 
3,4,6-trifluorophthalic acid. They found that upon slowly heating a 
mixture of the acid and soda lime to 300.degree. C., they obtained a low 
yield of the fully decarboxylated 1,2,4-trifluorobenzene. 
Japanese Patent JP 01/52737 discloses the preparation of 
2,4,5-trifluorobenzoic acid by the decarboxylation of 
3,4,6-trifluorophthalic acid in a liquid medium at a temperature of 
80.degree.-250.degree. C. The liquid media disclosed include water, DMSO, 
tetramethyl sulfone, DMF, dimethylacetamide, N-methylpyrrolidone, 
acetonitrile, nitrobenzene, diethylene glycol, dimethyl ether, 
tetraethylene glycol, dimethyl ether, and tertiary amines such as tributyl 
amine, and dimethyl aniline. The patent further discloses that a catalyst 
such as the ammonium or alkaline earth metal salts of hydroxide, 
carbonate, bicarbonate, sulfate or fluoride may be used. 
In U.S. Pat. No. 4,935,541, the present inventors have disclosed a process 
for the preparation of 2,4,5-trifluorobenzoic acid by decarboxylation of 
3,4,6-trifluorophthalic anhydride at elevated temperatures in apolar, 
aprotic solvent, preferably in the presence of a copper catalyst. 
SUMMARY OF THE INVENTION 
Surprisingly, we have now found that 3,4,6-trifluorophthalic acid may be 
decarboxylated in a controlled manner to form 2,4,5-trifluorobenzoic acid 
by heating the phthalic acid in a dipolar aprotic solvent in the absence 
of any catalyst.

DETAILED DESCRIPTION OF THE INVENTION 
##STR1## 
According to the present invention, 2,4,5-trifluorobenzoic acid may be 
prepared in good yield by the decarboxylation of 3,4,6-trifluorophthalic 
acid. The decarboxylation process is not complex. The acid is dissolved in 
the appropriate solvent and the mixture is heated along with stirring, 
until the desired percentage of starting material has been converted to 
products. At any point in the reaction, the degree of conversion of 
starting materials to products can readily be judged by gas 
chromatographic analysis. However, the reaction is reproducible and once 
convenient conditions within the scope of this invention have been 
established for conducting the reaction, the gas chromatographic analysis 
need not be conducted routinely. 
The desired product of this reaction is 2,4,5-trifluorobenzoic acid. 
However, it can readily be seen that the two carboxyl groups in the 
3,4,6-trifluorophthalic acid molecule are not equivalent to each other. 
The removal of the carboxyl at position 2 leads to the desired product, 
while the removal of the carboxyl at position one leads to 
2,3,5-trifluorobenzoic acid. The 2,3,5-product is not desired and the 
methods of this invention minimize its formation. 
In the present process it has been found that a dipolar aprotic solvent 
such as dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, and 
N-methylpyrrolidone is appropriate. The foregoing list of dipolar aprotic 
solvents is not exclusive and other such solvents may be used in 
practicing this invention. The preferred solvents are dimethyl sulfoxide, 
dimethyl acetamide and N-methylpyrrolidone, the most preferred solvent is 
N-methylpyrrolidone. It has been found that the reaction may be conducted 
in a temperature range from about 125.degree.-190.degree. C. The preferred 
temperature is approximately 150.degree. C. 
Surprisingly, copper catalysts, which are well known for use in 
decarboxylation reactions, are not useful for the preparation of 
2,4,5-trifluorobenzoic acid (2,4,5-TiFBA) from 3,4,6-trifluorophthalic 
acid. reaction. As can be seen from the table below, the copper catalysts 
increase the rate of the reaction, but produce high percentage of the 
undesired 2,3,5-trifluorobenzoic acid (2,3,5-TiFBA). 
______________________________________ 
3,4,6-trifluorophthalic Acid 
Decarboxylation Catalyst Study 
150.degree. C. in Dimethyl Acetamide 
Gas Chromatography Area % 
Catalyst 
Period 2,4,5-TiFBA 2,3,5-TiFBA 
Ratio 
______________________________________ 
none 4 hr. 81% 5% 16.2 
Cu 0.5 hr. 65% 27% 2.4 
Cu.sub.2 O 
0.5 hr. 62% 31% 2.0 
CuO 1.5 hr. 77% 18% 4.3 
CuI 1.5 hr. 59% 21% 2.8 
______________________________________ 
Similarly, the use of basic catalysts such as organic amines or inorganic 
bases is not necessary. Furthermore, the presence of a catalyst introduces 
an unnecessary and undesirable impurity to be removed form the final 
product. Accordingly, the process is conducted in the absence of any 
catalyst. 
The 2,4,5-trifluorobenzoic acid produced by this process contains some 
impurities of 2,3,5-trifluorobenzoic acid as well as other minor 
impurities. If a higher purity product is desired, the reaction product 
may be readily purified by known methods such as chromatography on silica 
gel and recrystallization. 
The following specific examples are provided to further illustrate this 
invention and the manner in which it may be carried out. It will be 
understood, however, that the specific details given in the examples have 
been chosen for purposes of illustration and are not to be construed as a 
limitation on the invention. In the examples, unless otherwise indicated, 
all parts and percentages are by weight and al temperatures are in degrees 
Celsius. 
EXAMPLE 1 Perforation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in N-Methylpyrrolidone (NMP) 
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of 
NMP. The reaction mixture was then heated with stirring for 18 hr. at a 
bath temperature of 140.degree. C., followed by 55 hr. at a bath 
temperature of 150.degree. C. The flask was then allowed to cool to room 
temperature and the contents were poured into 500 mL of water, and 
extracted with 4.times.200 mL of ethyl acetate. The combined organic 
extracts were washed with water (2.times.200 mL), dried over magnesium 
sulfate, filtered, and the solvent removed on a rotary evaporator followed 
by drying at the pump overnight. The crude product (24.25 g) was then 
dissolved in 25 mL of ethyl acetate and introduced at the top of a silica 
column (4.5 cm ID.times.56 cm, flushed with hexane). The product was then 
eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, 
and the fractions (500 mL each) were monitored by gas chromatography. The 
fractions containing the product were combined, the solvent removed on a 
rotary evaporator, and then dried at the pump overnight to give 
2,4,5-trifluorobenzoic acid as a light yellow solid (21.06 g, 98.97% 
pure, 87.8% yield). Recrystallization of the product from toluene (50 mL, 
ca. 60.degree. C.) gave a white product (71.1% overall yield) mp 
101.degree.-102.degree. C. 
EXAMPLE 2 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in Dimethyl sulfoxide(DMSO) 
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of 
dimethyl sulfoxide. The reaction mixture was then heated with stirring for 
27.5 hr. at a bath temperature of 149.degree. C. The flask was then 
allowed to cool to room temperature and the contents were poured into 500 
mL of water, and extracted with 4.times.200 mL of ethyl acetate. The 
combined organic extracts were washed with water (2.times.200 mL), dried 
over magnesium sulfate, filtered, and the solvent removed on a rotary 
evaporator followed by drying at the pump overnight. The crude product was 
then dissolved in 25 mL of ethyl acetate and introduced at the top of a 
silica column (4.5 cm ID.times.56 cm, flushed with hexane). The product 
was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen 
pressure, and the fractions (500 mL each) were monitored by gas 
chromatography. The fractions containing the product were combined, the 
solvent removed on a rotary evaporator, and then dried at the pump 
overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. 
Recrystallization of the product from toluene (50 mL, ca. 60.degree. C.) 
gave a white product (66.9% overall yield). 
EXAMPLE 3 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in Dimethyl Acetamide (DMAc) 
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of 
dimethyl acetamide. The reaction mixture was then heated with stirring for 
29.2 hr. at a bath temperature of 127.degree. C. The flask was then 
allowed to cool to room temperature and the contents were poured into 500 
mL of water, and extracted with 4.times.200 mL of ethyl acetate. The 
combined organic extracts were washed with water (2.times.200 mL), dried 
over magnesium sulfate, filtered, and the solvent removed on a rotary 
evaporator followed by drying at the pump overnight. The crude product was 
then dissolved in 25 mL of ethyl acetate and introduced at the top of a 
silica column (4.5 cm ID.times.56 cm, flushed with hexane). The product 
was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen 
pressure, and the fractions (500 mL each) were monitored by gas 
chromatography. The fractions containing the product were combined, the 
solvent removed on a rotary evaporator, and then dried at the pump 
overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid. 
Recrystallization of the product from toluene (50 mL, ca. 60.degree. C.) 
gave a white product (65.0% overall yield). 
EXAMPLE 4 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in Dimethyl Acetamide(DMAc) 
A 10 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 0.2 g of 3,4,6-trifluorophthalic acid, and 200 mL of 
dimethyl acetamide. The reaction mixture was then heated with stirring for 
22 hr. at a bath temperature of 125.degree. C. followed by 2 hr. at a bath 
temperature of 150.degree. C. The flask was then allowed to cool to room 
temperature and the contents were analyzed by gas chromatography. The 
percentage of the total peak area corresponding to 2,4,5-trifluorobenzoic 
acid was 86%. 
EXAMPLE 5 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in Dimethyl Sulfoxide (DMSO) 
A 10 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 0.2 g of 3,4,6-trifluorophthalic acid, and 200 mL of 
dimethyl sulfoxide. The reaction mixture was then heated with stirring for 
22 hr. at a bath temperature of 125.degree. C. followed by 11 hr. at a 
bath temperature of 150.degree. C. The flask was then allowed to cool to 
room temperature and the contents were analyzed by gas chromatography. The 
percentage of the total peak area corresponding to 2,4,5-trifluorobenzoic 
acid was 96%. 
EXAMPLE 6 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in N-Methylpyrrolidone (NMP) 
A 10 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 0.2 g of 3,4,6-trifluorophthalic acid, and 2 mL of 
N-methylpyrrolidone. The reaction mixture was then heated with stirring 
for 4.4 hr. at a bath temperature of 125.degree. C. followed by 4.7 hr. at 
a bath temperature of 150.degree. C. The flask was then allowed to cool to 
room temperature and the contents were analyzed by gas chromatography. The 
percentage of the total peak area corresponding to 2,4,5-trifluorobenzoic 
acid was 97%. 
EXAMPLE 7 Preparation of 2,4,5-Trifluorobenzoic Acid by the Decarboxylation 
of 3,4,6-Trifluorophthalic Acid in Dimethyl Formamide (DMF) 
A 10 mL single-neck flask equipped with a condenser and a magnetic stirrer 
was charged with 0.2 g of 3,4,6-trifluorophthalic acid, and 2 mL of 
dimethyl formamide. The reaction mixture was then heated with stirring for 
22 hr. at a bath temperature of 125.degree. C. The flask was then allowed 
to cool to room temperature and the contents were analyzed by gas 
chromatography. The percentage of the total peak area corresponding to 
2,4,5-trifluorobenzoic acid was 63%.