JPH0780815B2 - Nuclear fluorinated aromatic carboxylic acid esters and method for producing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention relates to a nuclear fluoroaromatic carboxylic acid ester useful as an intermediate for medicines and agricultural chemicals, particularly an antibacterial agent, and a method for producing the same.

[Prior Art] Generally, when a halogen bonded to a benzene ring is replaced with fluorine by a reaction with a fluorinating agent such as an alkali metal fluoride, the presence of an electron-withdrawing group at the ortho or para position with respect to the halogen. is necessary. Conventionally, (such as JP 53-111020 JP) nitro group (-NO ₂₎ as an electron-withdrawing group, a cyano group (-CN) (JP 58-189151 Laid etc.), chloroformyl group (-COCl ) (JP-A-61-1667). However, there is no known example in which an alkoxycarbonyl group (-COOR) or an aryloxycarbonyl group (-COOR) is used as an electron-withdrawing group.

Further, it is presumed that it is possible to obtain a nuclear fluorinated aromatic carboxylic acid ester by a combination of conventional techniques. For example, taking the nuclear fluorinated benzoate as an example, the following method can be considered.

That is, a method in which a halogenated benzonitrile compound is fluorinated with KF (JP-A-58-189151, etc.), hydrolysis and esterification are carried out (1), and the halogenated benzoic acid compound is converted into a benzoyl chloride compound, Fluorination (JP-A-61-1667), followed by reaction with alcohols or phenols to obtain a nuclear fluorinated benzoic acid ester (2), fluorination of halogenated phthalic anhydride with KF, ( J. Chem. Soc., 1964, 1194 (1964), a method of undergoing hydrolysis, decarboxylation and esterification (3).

[Problems to be Solved by the Invention] In the method (1) using a halogenated benzonitrile compound as a starting material, the starting material is relatively expensive, and it may be difficult to obtain it depending on the compound.

Method using halogenated benzoic acid compound as a starting material (2)
However, three steps are required, and it is necessary to use a dehydrated and dried benzoic acid compound because the acid chloride reaction is a water-free reaction. In addition, when thionyl chloride is used as a reaction reagent in this reaction, a large amount of harmful sulfurous acid gas (SO ₂ ) is produced as a by-product. Moreover, the obtained benzoyl chloride compound is unstable with respect to water, and thus requires careful handling. In addition to that,
When the benzoyl chloride compound is fluorinated, it is necessary to sufficiently dehydrate the solvent and the fluorinating agent. Therefore, this method is not preferable because it has many complicated points.

The method (3) using halogenated phthalic anhydride as a starting material requires multiple steps, and a compound such as 2,6-difluorobenzoic acid ester cannot be obtained, and the compound that can be produced is also limited. I will end up. In addition, if tetrachlorophthalic anhydride is fluorinated with KF, the target tetrafluorophthalic anhydride will not be obtained and it will become octafluoroanthraquinone.

The present invention [SUMMARY OF] are those shortens the multistage reaction had prior art, and has been made for improving the complicated point in the process, with respect to ¹ group -COOR Represented by the following general formula (2) by nuclear fluorinating an aromatic carboxylic acid ester represented by the following general formula (1) having chlorine or bromine at the ortho and / or para positions with a fluorinating agent. The present invention relates to a method for producing a nuclear fluorinated aromatic carboxylic acid ester, which comprises obtaining a nuclear fluorinated aromatic carboxylic acid ester.

(In the formula, R ¹ represents an alkyl group, an aryl group, or a fluoroalkyl group. A and B are hydrogen, halogen, an alkyl group,
At least one selected from an aryl group and a fluoroalkyl group is shown. m and n are integers, m + n = 6, and m is 1 or 2. However, at least one of chlorine or bromine in the ortho position and / or the para position with respect to the —COOR ¹ group is activated chlorine or bromine, and B corresponding to the activated chlorine or bromine is Fluorine and other B are the same as A. Also, m is 2 and A
Are all chlorine or bromine, at least one of the chlorines or bromines in the ortho and / or para positions relative to the —COOR ¹ group and all chlorines or bromines in the meta position are activated. B or chlorine corresponding to the activated chlorine or bromine is fluorine, and other B is the same as A. This method is characterized in that a nuclear fluorinated aromatic carboxylic acid ester is obtained by reacting an inexpensive and easily available halogenated aromatic carboxylic acid ester with a fluorinating agent such as an alkali metal fluoride. The raw material ester may be obtained by esterifying an inexpensive halogenated aromatic carboxylic acid. According to this method, a nuclear fluorinated aromatic carboxylic acid ester can be produced inexpensively and in good yield. Further, it is rational without a complicated process such as a solid dehydration process which is required in the combination of the conventional techniques.

The alkyl group or fluoroalkyl group in the above general formulas (1) and (2) (wherein part or all of the hydrogen of the alkyl group is substituted with a fluorine atom, and a part of the fluorine atom is a chlorine or bromine atom) The number of carbon atoms of (optionally) may be 1 to 20, and the aryl group may have a substituent such as a halogen or an alkyl group. The halogen for A or B is selected from chlorine, fluorine, bromine and the like. At least one of the chlorine or bromine in the ortho and / or para position to the —COOR ¹ group is activated chlorine or bromine, and B corresponding to the activated chlorine or bromine is fluorine. Yes, other B are the same as A. At least one chlorine or bromine in the ortho and / or para to ¹ group -COOR is activated by -COOR ¹ in the formula. By changing the type of R ¹ , it is possible to activate only the ortho-position, the para-position, or the ortho-position and the para-position chlorine or bromine, and the activated chlorine or bromine is fluorine-substituted by nuclear fluorination. It On the other hand, when m is 2 in the formula and all of A are chlorine or bromine, at least one chlorine or bromine in the ortho position and / or the para position with respect to the —COOR ¹ group, and meta. All chlorines or bromines in the position are activated chlorines or bromines, the B corresponding to the activated chlorines or bromines is fluorine and the other Bs are the same as A.

Specific examples of the aromatic carboxylic acid ester represented by the general formula (1) include 2,2,2-trifluoroethyl 2-chlorobenzoate, ethyl 4-chlorobenzoate, isopropyl 4-chlorobenzoate, 2,4-Dichlorobenzoic acid-
2,2,2-trifluoroethyl, 2,4-dichloro-5-fluorobenzoic acid-2,2,2-trifluoroethyl, methyl 2,4-dichlorobenzoate, isopropyl 2,4-dichlorobenzoate, 2,6-Dichlorobenzoic acid-2,2,2-trifluoroethyl, ethyl 2,6-dichlorobenzoate, isopropyl 2,6-dichlorobenzoate, methyl 2,6,6-trichlorobenzoate, 2,4 -Methyl dichloro-5-fluorobenzoate, 2,4
-Ethyl dichloro-5-fluorobenzoate, n-propyl 2,4-dichloro-5-fluorobenzoate, isopropyl 2,4-dichloro-5-fluorobenzoate, butyl 2,4-dichloro-5-fluorobenzoate , 2,4-dichloro-
Isobutyl 5-fluorobenzoate, 2,4-dichloro-5
-Cyclohexyl fluorobenzoate, 2,4-dichloro-
Phenyl 5-fluorobenzoate, 2,4-dichloro-5-
Fluorobenzoic acid-2,2,2-trifluoroethyl, tetrachlorophthalic acid dimethyl, tetrachlorophthalic acid bis (2,2,2-trifluoroethyl) ester, or some or all of the chlorine in these compounds Is a compound that is changed to bromine.

The reaction of substituting chlorine or bromine in the benzene nucleus of the aromatic carboxylic acid ester with fluorine may be carried out by reacting with a fluorinating agent in a solvent-free or aprotic solvent. As the fluorinating agent, alkali metal fluorides such as NaF, KF, RbF, and CsF are preferable, and spray-dried fluorpotassium is particularly preferable. Use mol. During the fluorination, a phase transfer catalyst may be added as a reaction accelerator. Examples of such a phase transfer catalyst include tetramethylammonium chloride, quaternary ammonium salts such as tetrabutylammonium bromide, or tetrabutylphosphonium bromide,
Examples thereof include quaternary phosphonium salts such as tetraphenylphosphonium bromide.

As the aprotic solvent, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, dimethylsulfone, sulfolane, hexamethylphosphortriamide, N-methyl-2-pyrrolidone, acetonitrile, benzonitrile, dioxane, diglyme. ,
Tetraglyme and the like can be used, but sulfolane and N, N-dimethylformamide are preferable. The amount used is from 1 to 10 times the weight of the raw material, preferably from 2 to 5 times. The reaction is carried out at atmospheric pressure or under pressure of 50 to
Suitably it is carried out at a reaction temperature of 250 ° C, preferably 100-230 ° C.

Preferred examples of the compounds represented by the general formulas (1) and (2) are 2,4-represented by the following general formula (3), respectively.
They are dichloro-5-fluorobenzoic acid ester and 2-chloro-4,5-difluorobenzoic acid ester represented by the general formula (4). The compound represented by the general formula (3) in which R ¹ is a branched alkyl group or a fluoroalkyl group, and the compound represented by the general formula (4) are novel substances.

(In the formula, R ¹ represents an alkyl group, an aryl group, or a fluoroalkyl group.) Specifically, isopropyl 2,4-dichloro-5-fluorobenzoate, n-, 2,4-dichloro-5-fluorobenzoate
Propyl, butyl 2,4-dichloro-5-fluorobenzoate, isobutyl 2,4-dichloro-5-fluorobenzoate, cyclohexyl 2,4-dichloro-5-fluorobenzoate, 2,4-dichloro-5-fluoro Benzoic acid-2,2,2-
Trifluoroethyl or methyl 2-chloro-4,5-difluorobenzoate, ethyl 2-chloro-4,5-difluorobenzoate, n-propyl 2-chloro-4,5-difluorobenzoate, 2-chloro- Isopropyl 4,5-difluorobenzoate, butyl 2-chloro-4,5-difluorobenzoate, isobutyl 2-chloro-4,5-difluorobenzoate, 2-chloro-4,5-difluorobenzoic acid-2,2 , 2
-Trifluoroethyl etc. can be mentioned.

The compound represented by the general formula (3) can be easily produced by the following reaction formula.

(In the formula, X represents a halogen atom, preferably a chlorine atom, and R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) That is, the compound 2,4-dichloro-5 represented by the formula (5) −
Fluoro-α, α, α-trihalogenoacetophenone may be reacted with alcohols or phenols. This reaction is preferably carried out in the presence of a base, and as the base, an inorganic base such as potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium carbonate or sodium acetate, or an organic base such as pyridine, triethylamine or ethylamine is used. However, the present invention is not limited to these. The amount of the base used is 0.01 to 2 times mol, preferably 0.1 to 1 times mol, of the raw material. The amount of alcohol or phenol used is 1 to 3 times mol, preferably 1 to 1.5 times mol, of the raw material. The reaction temperature is 0 ° C to 100 ° C, preferably 50 ° C to 90 ° C.
Is.

These fluorine-containing benzoates can also be synthesized, for example, by the following reaction.

That is, 1,4-dichloro-5-fluoroacetophenone
A haloform reaction is performed in a 2% aqueous solution of sodium hypochlorite to give 2,4-dichloro-5-fluorobenzoic acid.
Next, by reacting this benzoic acid with alcohols or phenols in the presence of an acid catalyst, the above-mentioned fluorine-containing benzoic acid esters can be obtained.

Further, these benzoic acid esters can be converted into the corresponding benzoic acid by, for example, the following reaction, and can be further converted into a quinolonecarboxylic acid useful as a synthetic antibacterial agent by a known reaction in several steps.

(In the formula, R ² is R ³ is Is preferred. ) The 2,4-dichloro-5-fluoro-α, α, α-trihalogenone represented by the general formula (5) is a novel substance, and specifically represents the following compound. α,
α, α, 2,4-Pentachloro-5-fluoroacetophenone (X = C1) α, α, α-tribromo-2,4-dichloro-5-fluoroacetophenone (X = Br) 2,4-dichloro-5- Fluoro-α, α, α-triiodoacetophenone (X = I) The compound represented by the general formula (5) can be easily produced by the following reaction formula.

(In the formula, X is a halogen atom) That is, the compound 2,4-dichloro-5 represented by the formula (6)
-The fluoroacetophenone may simply be reacted with the halogenating agent. As the halogenating agent, chlorine gas, bromine,
Iodine is preferred, and the amount used is 1.5 to 10 times, preferably 3 to 6 times the mol of the raw material. Reaction temperature is 50 ℃ ~
The temperature is 250 ° C, preferably 100 ° C to 220 ° C.

The 2-chloro-4,5-difluorobenzoic acid ester represented by the following general formula (4) is obtained by reacting 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) with a halogenating agent, It is represented by the following general formula (5). 2,4-Dichloro-5-fluoro-α, α, α-trihalogenoacetophenone is obtained, and then reacted with alcohols or phenols to give 2,4-dichloro represented by the following general formula (3). It can be obtained by obtaining -5-fluorobenzoic acid ester and then subjecting this to nuclear fluorination with a fluorinating agent.

(In the formula, X represents a halogen atom, R ¹ is an alkyl group,
An aryl group or a fluoroalkyl group is shown. In addition, 2,4-dichloro-5-fluoro-α, α, α represented by the general formula (5) using the general formula (5) as a starting material
Represented by the above general formula (3) by reacting trihalogenoacetophenone with alcohols or phenols
2,4-dichloro-5-fluorobenzoic acid ester is obtained,
Then, this is subjected to nuclear fluorination with a fluorinating agent to give 2-chloro-4,5 represented by the general formula (4).
A difluorobenzoic acid ester can be obtained.

On the other hand, 2,4-dichloro-represented by the above general formula (3)
The 5-fluorobenzoic acid ester is obtained by reacting 2,4-dichloro-5-fluoroacetophenone represented by the general formula (6) with a halogenating agent to form the 2,4-dichloro-ester represented by the general formula (5). It can be obtained by obtaining 5-fluoro-α, α, α-trihalogenoacetophenone, which is then reacted with alcohols or phenols.

Hereinafter, examples of the present invention will be described more specifically.

Example 1 Isopropyl 2,4-dichloro-5-fluorobenzoate α, α, α, 2,4-pentachloro-5-fluoroacetophenone 310.5 g (1 mol) and 2-propanol 90 g (1.5 mol)
l) and 13.8 g (0.1 mol) of potassium carbonate were added, and the mixture was added at 85 ° C for 6
Reacted for hours. After cooling, the inorganic salt was filtered off and distilled under reduced pressure to obtain 218 g (yield 87%) of isopropyl 2,4-dichloro-5-fluorobenzoate. The analytical values for this compound were as follows:

・ Boiling point 94 ℃ / 3mmHg ・ Melting point 35 ℃ ・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -117.1ppm (d, d, J _FH = 6.5Hz, J _FH = 9.0Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.39 (6H, d, J = 6.3Hz) δ 5.26 (1H, m) δ 7.50 (1H, d, J _HF = 6.5Hz) δ 7.61 (1H, d, J _HF = 9.0Hz) IR analysis 1738 cm ^-1 (C = 0) Example 2 Propyl 2,4-dichloro-5-fluorobenzoate 1-Propanol 90.0 g (1.5 mol) was used and Example 1
2,4-by reacting at 85 ℃ for 4 hours
215.9 g (yield 86%) of propyl dichloro-5-fluorobenzoate was obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -117.0ppm (d, d, J _FH = 6.4Hz, J _FH = 9.0Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.04 (3H, t, J = 7.4Hz) δ 1.76 (2H, m) δ 4.30 (2H, t, J = 6.6Hz) δ 7.46 (1H, d, J _HF = 6.4Hz) δ 7.63 (1H, d, J _HF = 9.0 Hz) · IR analysis 1738 cm ⁻¹ (C = 0) Example 3 Butyl 2,4-dichloro-5-fluorobenzoate 1-Propanol Example 1 was used with 111.2 g (1.5 mol).
Similarly, by reacting at 98 ℃ for 4 hours, 2,4-
235,9 g of butyl dichloro-5-fluorobenzoate (yield
89%) obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ −117.2ppm (d, d, J _FH = 6.5Hz, J _FH = 9.0Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.24ppm (3H , t, J = 6.7Hz) δ 1.28 to 1.92ppm (4H, m) δ 4.61ppm (2H, t, J = 6.2Hz) δ 7.77ppm (1H, d, J _FH = 6.5Hz) δ 7.91ppm (1H , d, J _FH = 9.0 Hz) ・ IR analysis 1739 cm ^-1 (C = 0) Example 4 Using 111.2 g (1.5 mol) of 2,4-dichloro-5-fluorobenzoic acid (2-butyl) 2-butanol Then, by reacting at 98 ° C. for 4 hours in the same manner as in Example 1, 233.2 g of 2,4-dichloro-5-fluorobenzoic acid (2-butyl) was obtained.
(88% yield) was obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ −117.1ppm (d, d, J _FH = 6.4Hz, J _FH = 9.0Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.28ppm (3H , t, J = 7.4Hz) δ 1.65ppm (3H, d, J = 6.3Hz) δ 1.98ppm (2H, m) δ 5.40ppm (1H, m) δ 7.75ppm (1H, d, J _FH = 6.4Hz ) 7.91 ppm (1H, d, J _FH = 9.0 Hz) -IR analysis 1739 cm ^-1 (C = 0) Example 5 2,4-Dichloro-5-fluorobenzoic acid cyclohexyl cyclohexanol 150.2 g (1.5 mol) Then, by reacting at 100 ° C. for 6 hours in the same manner as in Example 1, 2,4
25-cyclohexyl dichloro-5-fluorobenzoate
6.2 g (yield 88%) was obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -117.3ppm (d, d, J _FH = 6.5Hz, J _FH = 9.0Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.31 to 2.09ppm (10H, m) δ 5.04 (1H, m) δ 7.51 (1H, d, J _HF = 6.5Hz) δ 7.64 (1H, d, J _HF = 9.0Hz) ・ IR analysis 1738cm ^-1 (C = 0) Example 6 2,4-dichloro-5-fluorobenzoic acid-2,2,2-trifluoroethyl 2,2,2-trifluoroethanol 150.0 g (1.5 mol) was used in the same manner as in Example 1 at 75 ° C. 2,4-dichloro-5-fluorobenzoic acid-2,2,2
-253.1 g (yield 87%) of trifluoroethyl was obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ-116.2ppm (1F, d, d, J _FH = 6.5Hz, J _FH = 8.9Hz) δ-74.1ppm (3F, t, J _FH = 8.3 Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 4.73ppm (2H, q, J _HF = 8.3Hz) δ 7.54ppm (1H, d, J _HF = 6.5Hz) δ 7.71 (1H, d, J _HF ＝ 8.9 Hz) ・ IR analysis 1740 cm ^-1 (C = 0) Example 7 Isopropyl 2-chloro-4,5-difluorobenzoate 2,4-dichloro-in one glass reaction vessel with cooling tube
251.0 g (1 mol) of isopropyl 5-fluorobenzoate,
87 g (1.5 mol) of spray-dried potassium fluoride, 25.1 g of tetramethylammonium chloride and 500 g of sulfolane were charged and reacted at 150 ° C. for 9 hours with vigorous stirring.
After cooling, the inorganic salt was filtered off and further distilled under reduced pressure to obtain 199.8 g (yield 85.2%) of isopropyl 2-chloro-4,5-difluorobenzoate. The analytical values for this compound were as follows:

・ Boiling point 84 ℃ / 5mmHg ・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -130.3ppm (d, d, d, J _FF = 20.6Hz J _FH = 10.3Hz, J
_FH = 8.5Hz) δ-138.9ppm (d, d, d, J _FF = 22.2Hz J _FH = 8.4Hz, J
_FH = 6.2Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.38ppm (6H, d, J = 6.3Hz) δ 5.26ppm (1H, m) δ 7.28ppm (1H, d, d, J _HF = 8.4 Hz, J _HF = 6.2Hz) δ 7.70ppm (1H, d, d, J _HF = 10.3Hz, J _HF = 8.5Hz ・ IR analysis 1742cm ^-1 (C = 0) Example 8 Same as Example 7 , Methyl 2,4-dichloro-5-fluorobenzoate 223 g (1 mol) was used for the reaction, and
99.1 g (yield 48.0%) of methyl 2-chloro-4,5-difluorobenzoate was obtained at 0 ° C for 8 hours. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -129.6ppm (d, d, d, J _FF = 20.6Hz, J _FH = 10.3Hz, J
_FH = 8.5Hz) δ-138.6ppm (d, d, d, J _FF = 22.0Hz, J _FH = 8.4Hz, J
_FH = 6.2Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 3.93ppm (3H, s) δ 7.30ppm (1H, d, d, J _HF = 8.4Hz, J _HF = 6.2Hz) δ 7.74ppm (1H , d, d, J _HF = 10.3 Hz, J _HF = 8.5 Hz IR analysis 1742 cm ^-1 (C = 0) Example 9 In the same manner as in Example 7, ethyl 2,4-dichloro-5-fluorobenzoate 237 g (1 mol) was used to react, 150
111.8 g (yield 50.7%) of ethyl 2-chloro-4,5-difluorobenzoate was obtained at 9 ° C for 9 hours. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -130.0ppm (d, d, d, J _FF = 20.6Hz, J _FH = 10.4Hz, J
_FH = 8.2Hz) δ-138.8ppm (d, d, d, J _FF = 21.8Hz, J _FH = 8.4Hz, J
_FH = 6.4Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.41ppm (3H, t, J = 7.1Hz) δ 4.40ppm (2H, q, J = 7.1Hz)) δ 7.29ppm (1H, d, d, J _HF = 8.4Hz, J _HF = 6.4Hz) δ 7.73ppm (1H, d, d, J _HF = 10.4Hz, J _HF = 8.2Hz) ・ IR analysis 1742cm ^-1 (C = 0) Example 10 In the same manner as in Example 7, 251 g (1 mol) of propyl 2,4-dichloro-5-fluorobenzoate was used for the reaction,
199.8 g (yield 85.2%) of propyl 2-chloro-4,5-difluorobenzoate was obtained at 150 ° C for 9 hours. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -130.0ppm (d, d, d, J _FF = 20.6Hz, J _FH = 10.4Hz, J
_FH = 8.3Hz) δ -138.7ppm (d, d, d, J _FF = 22.0Hz, J _FH = 8.4Hz, J
_FH = 6.4Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 1.04ppm (3H, t, J = 6.9Hz) δ 1.80ppm (2H, m) δ 4.30ppm (2H, t, J = 6.6Hz) δ 7.30ppm (1H, d, d, J _HF = 8.4Hz, J _HF = 6.4Hz) δ 7.74ppm (1H, d, d, J _HF = 10.4Hz, J _HF = 8.3Hz) ・ IR analysis 1742cm ^-1 ( C = 0) Example 11 In the same manner as in Example 7, 265 g (1 mol) of butyl 2,4-dichloro-5-fluorobenzoate was used to carry out the reaction.
179.9 g (yield 72.4%) of butyl 2-chloro-4,5-difluorobenzoate was obtained at 0 ° C for 3 hours. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -130.0ppm (d, d, d, J _FF = 20.6Hz, J _FH = 10.5Hz, J
_FH = 8.4Hz) δ -138.7ppm (d, d, d, J _FF = 21.8Hz, J _FH = 8.4Hz, J
_FH = 6.2Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 0.98ppm (3H, t, J = 6.5Hz) δ 1.28 ~ 1.93ppm (4H, m) δ 4.34ppm (2H, t, J = 6.4Hz) ) δ 7.29ppm (1H, d, d, J HF = 8.4Hz, J HF = 6.2Hz) δ 7.73ppm (1H, d, d, J HF = 10.5Hz, J HF = 8.4Hz) · IR analysis 1742 cm ^{- 1} (C = 0) Example 12 In the same manner as in Example 7, 265 g (1 mol) of isobutyl 2,4-dichloro-5-fluorobenzoate was used to carry out the reaction, and the reaction was carried out at 150 ° C. for 3 hours with 2-chloro. 194.8 g (yield 78.4%) of isobutyl -4,5-difluorobenzoate was obtained. The analytical values for this compound were as follows:

・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -130.3ppm (d, d, d, J _FF = 20.8, J _FH = 10.4Hz, J _FH
＝ 8.4Hz) δ −138.8ppm (d, d, d, J _FF ＝ 21.8, J _FH ＝ 8.4Hz, J _FH
= 6.4Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 0.99ppm (3H, t, J = 7.0Hz) δ 1.35ppm (3H, d, J = 6.3Hz) δ 1.87ppm (2H, m) δ 5.11 ppm (1H, m) δ 7.28ppm (1H, d, d, J _HF = 8.4Hz, J _HF = 6.4Hz) δ 7.71ppm (1H, d, d, J _HF = 10.4Hz, J _HF = 8.4Hz) IR analysis 1742 cm ^-1 (C = 0) Example 13 In the same manner as in Example 7, 291 g (1 mol) of 2,4-dichloro-5-fluorobenzoic acid-2,2,2-trifluoroethyl was obtained.
Was carried out at 150 ° C. for 4 hours to obtain 256.2 g (yield 83.3%) of 2-chloro-4,5-difluorobenzoic acid-2,2,2-trifluoroethyl.

・ Boiling point 106 ℃ / 16mmHg ・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -127.6ppm (1F, d, d, d, J _FF = 20.6Hz J _FH = 10.2H
z, J _FH = 8.2Hz) δ-137.7ppm (1F, d, d, d, J _FF = 21.8Hz J _FH = 8.4H
z, J _FH = 6.2Hz) δ-74.1ppm (3F, t, J _FH = 8.3Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 4.71ppm (2H, q, J _HF = 8.3Hz) δ 7.35ppm (1H, d, d, J _HF = 8.4Hz, J _HF = 6.2Hz) δ 7.70ppm (1H, d, J _HF = 10.2Hz, J _HF = 8.2Hz) ・ IR analysis 1740cm ^-1 (C = 0) Example 14 α, α, α, 2,4-pentachloro-5-fluoroacetophenone 2,4-dichloro-5-fluoroacetophenone 207 in a 500 ml glass reactor equipped with cooling and gas blowing tubes.
g (1 mol) was charged, and while increasing the reaction temperature from 120 ° C. to 200 ° C., chlorine gas was blown in at 426 g (6 mol) for 20 hours under normal pressure. After cooling, washing with water, washing with 5% potassium hydrogen carbonate aqueous solution, washing with water, drying and vacuum distillation to obtain 298 g (yield 96%) of α, α, α, 2,4-pentachloro-5-fluoroacetophenone. It was

The analytical values for this compound were as follows:

・ Boiling point 110 ℃ / 2.5mmHg ・ NMR analysis < ¹⁹ Fnmr> δppm from CFCl ₃ in CDCl ₃ δ -115.6ppm (d, d, J _FH = 6.6Hz, J _FH = 8.2Hz) < ¹ Hnmr> δppm from TMS in CDCl ₃ δ 7.58 (1H, d, J _HF = 6.6Hz) δ 7.62 (1H, d, H, J _HF = 8.2Hz) ・ IR analysis 1740cm ^-1 (C = 0) Example 15 2-chloro-4, 5-difluorobenzoic acid-2,2,2-trifluoroethyl 2,4-dichloro-in one reaction vessel made of glass with cooling tube
2-fluorobenzoic acid-2,2,2-trifluoroethyl was added to 2
91g (1mol), spray dried potassium fluoride 87g (1.5mo
l), 500 g of sulfolane were charged, and 180 with vigorous stirring
The reaction was carried out at 9 ° C for 9 hours. After cooling, the inorganic salt was separated by filtration and further distilled under reduced pressure to obtain 239.4 g (yield 87.2%) of 2,2,2-trifluoroethyl 2-chloro-4,5-difluorobenzoate.

Example 16 2,4,5-trifluorobenzoic acid-2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoic acid-2,2,2-trifluoroethyl 291 g (1 mol) Using 2,8-2,2,2-trifluoroethyl 2,4,5-trifluorobenzoate 158.7 by reacting for 32 hours at 180 ℃ in the same manner as in Example 15.
g (yield 61.5%) was obtained.

Example 17-2,2,2-trifluoroethyl 2-fluorobenzoic acid-2,2,2-trifluoroethyl 2-chlorobenzoic acid
Using 8.5 g (1 mol), in the same manner as in Example 15 at 180 ° C.
By reacting for 2 hours, 2-fluorobenzoic acid-2,
2,2-trifluoroethyl (yield 80.7%) was obtained.

Example 18-2,2,2-Trifluoroethyl 4-fluorobenzoic acid-2,2,2-trifluoroethyl 4-chlorobenzoic acid
Using 8.5 g (1 mol), the same as in Example 15 at 180 ° C.
By reacting for 4 hours, 4-fluorobenzoic acid-2,
183.2 g (yield 82.5%) of 2,2-trifluoroethyl was obtained.

Example 19 2,4-difluorobenzoic acid-2,2,2-trifluoroethyl 2,4-difluorobenzoic acid-2,2,2-trifluoroethyl 273.5 g (1 mol) was used in Example 15 By reacting at 180 ° C for 15 hours in the same manner as described above, 191.5 g of 2,4-difluorobenzoic acid-2,2,2-trifluoroethyl (yield 79.8
%)Obtained.

Example 20 2,6-Difluorobenzoic acid-2,2,2-trifluoroethyl 2,6-difluorobenzoic acid-2,2,2-trifluoroethyl 273.5 g (1 mol) in Example 15 By reacting at 180 ° C for 20 hours in the same manner as described above, 175.9 g of 2,6-difluorobenzoic acid-2,2,2-trifluoroethyl (yield 73.3
%)Obtained.

Example 21 2-Chloro-4,5-difluorobenzoic acid-1-trifluoromethyl-2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoic acid-1-trifluoromethyl-2, 359.0g of 2,2-trifluoroethyl (1mo
l-) was reacted at 180 ° C. for 8 hours in the same manner as in Example 15 to give 2-chloro-4,5-difluorobenzoic acid-1-trifluoromethyl-2,2,2-trifluoroethyl. 290.4 g (yield 84.8%) was obtained.

Example 22 2-Chloro-4,5-difluorobenzoic acid-2,2,3,3,3-pentafluoropropyl 2,4-dichloro-5-fluorobenzoic acid-2,2,3,3,3- 341.0 g (1 mol) of pentafluoropropyl was reacted at 180 ° C. for 8 hours in the same manner as in Example 15 to give 2
276.1 g (yield 85.1%) of -chloro-4,5-difluorobenzoic acid-2,2,3,3,3-pentafluoropropyl were obtained.

Example 23 In a glass reaction vessel equipped with a cooling tube, 238.5 g (1 mol) of 2,2,2-trifluoroethyl 2-chlorobenzoate, 87 g (1.5 mol) of spray-dried potassium fluoride, tetrabutylphosphonium bromide 23.9 g and 480 g of sulfolane were charged and reacted at 180 ° C. for 20 hours with vigorous stirring. After cooling, the inorganic salt was filtered off and further distilled under reduced pressure to obtain 2
-Fluorobenzoic acid-2,2,2-trifluoroethyl 13
4.3 g (yield 60.5%) was obtained.

Example 24 In the same manner as in Example 23, a reaction was carried out using 198.5 g (1 mol) of isopropyl 4-chlorobenzoate and 19.9 g of tetramethylammonium chloride, and at 4 hours at 150 ° C. for 15 hours.
147.8 g (81.7%) of isopropyl fluorobenzoate was obtained.

Example 25 In the same manner as in Example 24, a reaction was carried out using 233 g (1 mol) of isopropyl 2,4-dichlorobenzoate at 150 ° C. for 14 hours to obtain 173.4 g of isopropyl 2-chloro-4-fluorobenzoate ( Yield 80.1%) was obtained.

Example 26 In the same manner as in Example 23, 2,4-dichlorobenzoic acid-2,2,2
-The reaction was carried out using 273 g (1 mol) of trifluoroethyl, and 2,4-difluorobenzoic acid-2,2,2,2-
139.8 g (yield 58.3%) of 2-trifluoroethyl was obtained.

Example 27 In the same manner as in Example 23, 2,6-dichlorobenzoic acid-2,2,2
-The reaction was carried out using 273 g (1 mol) of trifluoroethyl, and 2,6-difluorobenzoic acid-2,2,2 was obtained at 200 ° C for 30 hours.
138.2 g (yield 57.6%) of trifluoroethyl was obtained.

Example 28 In the same manner as in Example 24, a reaction was carried out using 223 g (1 mol) of methyl 2,4-dichloro-5-fluorobenzoate, and
99.1 g (yield 48.0%) of methyl 2-chloro-4,5-difluorobenzoate was obtained at 0 ° C for 8 hours.

Example 29 A reaction was carried out in the same manner as in Example 24 using 237 g (1 mol) of ethyl 2,4-dichloro-5-fluorobenzoate, and
111.1 g (yield 50.7%) of methyl 2-chloro-4,5-difluorobenzoate was obtained at 0 ° C for 9 hours.

Example 30 In the same manner as in Example 24, a reaction was carried out using 251 g (1 mol) of isopropyl 2,4-dichloro-5-fluorobenzoate, and 2-chloro-4,5-difluoro was carried out at 150 ° C for 9 hours. 199.8 g (yield 85.2%) of isopropyl benzoate was obtained.

Example 31 In the same manner as in Example 24, a reaction was carried out using 285 g (1 mol) of phenyl 2,4-dichloro-5-fluorobenzoate,
194.5 g (yield 72.4%) of phenyl 2-chloro-4,5-difluorobenzoate was obtained at 150 ° C for 3 hours.

Example 32 In the same manner as in Example 23, 291 g (1 mol) of 2,4-dichloro-5-fluorobenzoic acid-2,2,2-trifluoroethyl was added.
The reaction was carried out using 200 ° C. for 30 hours to obtain 2,4,5-trifluorobenzoic acid-2,2,2-trifluoroethyl 126.2 g.
(Yield 48.2%) was obtained.

Example 33 In the same manner as in Example 23, tetrachlorophthalic acid bis (2,
The reaction was carried out using 234 g (0.5 mol) of 2,2-trifluoroethyl) ester, and 104.5 g (yield of tetrafluorophthalic acid bis (2,2,2-trifluoroethyl) ester was obtained at 200 ° C. for 30 hours. 52.0%) was obtained.

[Effects of the Invention] In the present invention, the target nuclear fluorinated aromatic carboxylic acid ester can be industrially produced at low cost and in high yield from the readily available aromatic carboxylic acid ester.

In addition, by changing the alkyl (aryl) portion of the alkoxycarbonyl (aryloxycarbonyl) group of the aromatic carboxylic acid ester that is the raw material, only the halogen in the para position to the alkoxycarbonyl (aryloxycarbonyl) group is fluorine-substituted. Or ortho position,
Both halogens at the para position can be substituted with fluorine, which is highly useful.

Claims (11)

[Claims] 1. Nuclear fluorination of an aromatic carboxylic acid ester represented by the following general formula (1) having chlorine or bromine in the ortho position and / or para position with respect to the -COOR ¹ group using a fluorinating agent. Thus, a method for producing a nuclear fluorinated aromatic carboxylic acid ester represented by the following general formula (2) is obtained. (In the formula, R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group. A and B represent at least one selected from hydrogen, halogen, an alkyl group, an aryl group and a fluoroalkyl group. M and n are M + n = 6, m is 1 or 2. However, at least one of chlorine or bromine in the ortho position and / or para position with respect to the -COOR ¹ group is activated chlorine or bromine. And B corresponding to the activated chlorine or bromine is fluorine, and the other B are the same as A. Further, m is 2, and A is
Are all chlorine or bromine, at least one of the chlorines or bromines in the ortho and / or para positions relative to the —COOR ¹ group and all chlorines or bromines in the meta position are activated. B or chlorine corresponding to the activated chlorine or bromine is fluorine, and other B is the same as A. ) 2. The activated chlorine or bromine is --COOR ¹
A chlorine or bromine para position to the group.
The manufacturing method described in. 3. A compound represented by the following general formula (4) by fluorinating 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3) with a fluorinating agent. A method for producing 2-chloro-4,5-difluorobenzoic acid ester, which comprises obtaining -chloro-4,5-difluorobenzoic acid ester. (In the formula, R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 4. The following general formula (3) is obtained by reacting 2,4-dichloro-5-fluoro-α, α, α-trihalogenoacetophenone represented by the following general formula (5) with alcohols or phenols. 2.) A method for producing a 2,4-dichloro-5-fluorobenzoic acid ester, which comprises obtaining a 2,4-dichloro-5-fluorobenzoic acid ester represented by (In the formula, X represents a halogen atom, and R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 5. Reacting 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) with a halogenating agent,
A method for producing 2,4-dichloro-5-fluoro-α, α, α-trihalogenoacetophenone, which comprises obtaining 4-dichloro-5-fluoro-α, α, α-trihalogenoacetophenone. (In the formula, X represents a halogen atom.) 6. A 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) is reacted with a halogenating agent to give a 2,4-dichloro-5- represented by the following general formula (5). Fluoro-α, α, α-trihalogenoacetophenone is obtained and then reacted with an alcohol or a phenol to give a 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3). Obtained and then subjected to nuclear fluorination with a fluorinating agent to give 2-chloro-4 represented by the following general formula (4):
A method for producing 2-chloro-4,5-difluorobenzoic acid ester, which comprises obtaining 5-difluorobenzoic acid ester. (In the formula, X represents a halogen atom, and R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 7. A 2,4-dichloro-5-fluoro-α, α, α-trihalogenoacetophenone represented by the following general formula (5) is reacted with an alcohol or a phenol to give the following general formula (3): 2,4-dichloro-5 represented by
-A fluorobenzoic acid ester is obtained, which is then subjected to nuclear fluorination using a fluorinating agent to obtain a 2-chloro-4,5-difluorobenzoic acid ester represented by the following general formula (4). 2-chloro-4,5
-Method for producing difluorobenzoic acid ester. (In the formula, X represents a halogen atom, and R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 8. A 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) is reacted with a halogenating agent to give a 2,4-dichloro-5- represented by the following general formula (5). Fluoro-α, α, α-trihalogenoacetophenone is obtained and then reacted with an alcohol or a phenol to give a 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3). A method for producing 2,4-dichloro-5-fluorobenzoic acid ester, which is characterized by obtaining the same. (In the formula, X represents a halogen atom, and R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 9. A 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3). (In the formula, R ¹ represents a branched alkyl group or a fluoroalkyl group.) 10. A 2-chloro-4,5-difluorobenzoic acid ester represented by the following general formula (4). (In the formula, R ¹ represents an alkyl group, an aryl group or a fluoroalkyl group.) 11. A 2,4-dichloro-5-fluoro-α, α, α-trihalogenoacetophenone represented by the following general formula (5). (In the formula, X represents a halogen atom.)