JPH02191239A - Nuclear fluorinated aromatic carboxylic acid esters and production thereof - Google Patents

Abstract

PURPOSE:To industrially obtain partially new nuclear fluorinated aromatic carboxylic acid esters from readily available raw materials in a short process in high yield at a low cost by carrying out nuclear fluorination of partially new aromatic dicarboxylic acid esters with a fluorinating agent. CONSTITUTION:Aromatic carboxylic acid esters expressed by formula I are subjected to nuclear fluorination using a fluorinating agent (especially preferably an alkali metal fluoride) to afford nuclear fluorinated aromatic carboxylic acid esters expressed by formula II (R<1> is alkyl, aryl or fluoroalkyl; A and B are H, halogen, alkyl, aryl or fluoroalkyl; m+n=6 and m is 1 or 2, provided that at least one A is activated chlorine or bromine and B corresponding to the activated chlorine or bromine is fluorine). An especially new compound expressed by formula III is reacted with alcohols or phenols to provide a new 2,4-dichloro-5-fluorobenzoic acid ester expressed by formula IV, which is then subjected to nuclear fluorination to afford a new 2-chloro-4,5-difluorobenzoic acid ester expressed by formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to nuclear fluorine aromatic carboxylic acid esters useful as intermediates for medicines and agrochemicals, particularly antibacterial agents, and a method for producing the same.

[Prior art] Generally, when a halogen bonded to a benzene ring is replaced with fluorine by reaction with a fluorinating agent such as an alkali metal fluoride, the presence of an electron-withdrawing group at the ortho or para position relative to the halogen is is necessary. Conventionally, nitro group (-NO□) (JP-A-53-111020, etc.) and cyano group (-CN) (JP-A-58-18) have been used as electron-withdrawing groups.
9151, etc.), chloroformyl group (-COCI
) (Japanese Unexamined Patent Publication No. 61-1667) is known. However, there is no known example in which an alkoxycarbonyl group (-COOR) or an aryloxycarbonyl group (-GOOR) is used as an electron-withdrawing group.

Furthermore, it is estimated that it is possible to obtain a nuclear fluorinated aromatic carbonaceous ester by a combination of conventional techniques. For example, taking nuclear fluorinated benzoin ester as an example, the following method can be considered.

□□□ α)OH α-R (X=C1, Br) (X=C1, Br) In other words, a halogenated benzonitrile compound is fluorinated with KF (Japanese Unexamined Patent Application Publication No. 189151/1980, etc.)
, a method (1) that involves hydrolysis and esterification, after converting a halogenated benzoic acid compound to a benzoyl chloride compound,
A method (2) in which fluorination is carried out (Japanese Patent Application Laid-Open No. 1667/1983) and then reacted with alcohols or phenols to obtain a nuclear fluorinated benzoic acid ester, fluorination of halogenated phthalic anhydride with KF ( J. Chem.
Soc.

1964, 1194 (1964)), and method (3) which involves hydrolysis, decarboxylation, and esterification.

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

Method using a halogenated benzoic acid compound as a starting material (2)
This method requires three steps, and since the acid chloridation reaction is a water-restricted reaction, it is necessary to use a dehydrated and dried benzoin compound. Furthermore, when thionyl chloride is used as a reaction reagent in this reaction, a large amount of harmful sulfur dioxide gas (SO,) is produced as a by-product. In addition, the obtained benzoyl chloride compound is unstable in water and must be handled with care. In addition, when fluorinating the benzoyl chloride compound, it is necessary to sufficiently dehydrate the solvent and the fluorinating agent. Therefore, this method is not preferable because it is complicated.

Method (3) using halogenated phthalic anhydride as a starting material requires multiple steps, and compounds such as 2,6-difluorobenzoate cannot be obtained, and the compounds that can be produced are limited. Put it away. In addition, when tetrachlorophthalic anhydride is fluorinated using KF, the desired tetrafluorophthalic anhydride is not obtained, but octafluoroanthraquinone is obtained.

[Means for Solving the Problems] The present invention has been made to shorten the multi-step reaction that the prior art had and to improve the complicated points in the process. A nuclear fluorinated aromatic compound characterized in that a nuclear fluorinated aromatic carboxylic acid ester represented by the following general formula (2) is obtained by nuclear fluorinating the aromatic carboxylic acid ester represented by the formula (2) using a fluorinating agent. The present invention relates to a method for producing group carboxylic acid esters.

(In the formula, R1 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, and m and n are integers. So, m+n=6, m
represents 1 or 2, provided that at least one of A is activated chlorine or bromine, and B corresponding to the activated chlorine or bromine is fluorine. ) Mizudrop is characterized by obtaining a nuclear fluorinated aromatic carboxylic acid ester 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. Due to its nature, nuclear fluorinated aromatic carboxylic acid esters can be produced at low cost and with good yield. In addition, there is no complicated process such as a solid dehydration process that was required in the combination of conventional techniques (it is reasonable).

Alkyl groups and fluoroalkyl groups in the above general formulas (1) and (2) (part or all of the hydrogen atoms of the alkyl group are substituted with fluorine atoms, and some of the fluorine atoms are chlorine or bromine atoms) The carbon number of A) is suitably 1 to 20, and the aryl group may have a substituent such as a halogen or an alkyl group.
Alternatively, the halogen of B is selected from chlorine, fluorine, bromine, etc., and at least one of A is activated chlorine or bromine.

B corresponding to this activated chlorine or bromine is fluorine.

The chlorine or bromine in A is activated by -COOR' in the formula, and the chlorine or bromine at the ortho or para position to -GOOR' is particularly activated. By changing the type of R1, it is possible to activate only the ortho and para positions or chlorine or bromine at the ortho and para positions, and this activated chlorine or bromine is substituted with fluorine by nuclear fluorination. . On the other hand, when m=2 in the formula and all the remaining A's are chlorine or bromine, the chlorine or bromine at the meta position relative to -COOR' is also activated, and this chlorine or bromine is replaced with fluorine by nuclear fluorination. Ru.

Specific examples of the aromatic carboxylic acid ester represented by the general formula (1) include 2-chlorobenzoic acid-2,2,2
-) Lifluoroethyl, ethyl 4-chlorobenzoate, 4
-isopropyl chlorobenzoate, 2,4-dichlorobenzoate-2,2,2-trifluoroethyl, 2,4-dichloro-5-fluorobenzoate-2,2,2-trifluoroethyl, 2.4- Methyl dichlorobenzoate, 2,4-
Isopropyl dichlorobenzoate, 2,2,2-)lifluoroethyl 2,6-dichlorobenzoate, ethyl 2,6-dichlorobenzoate, isopropyl 2,6-dichlorobenzoate, 2,4,6-trichlorobenzoate methyl acid, 2,
Methyl 4-dichloro-5-fluorobenzoate, 2,4-
Ethyl dichloro-5-fluorobenzoate, isopropyl 2,4-dichloro-5-fluorobenzoate, isopropyl 2,4-dichloro-5-fluorobenzoate, 2.4-
Butyl dichloro-5-fluorobenzoate, isobutyl 2,4-dichloro-5-fluorobenzoate, cyclohexyl 2,4-dichloro-5-fluorobenzoate, 2,4-
Dichloro-5-fluorobenzoic acid phenyl, 2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoate, dimethyl tetrachlorophthalate, bis(2,2,2-trichlorophthalate) fluoroethyl)
These include esters, or compounds in which part or all of the chlorine in these compounds has been changed to bromine.

The reaction of substituting chlorine or bromine in the benzene nucleus of an aromatic carboxylic acid ester with fluorine may be carried out with a fluorinating agent without a solvent or in an aprotic solvent. Fluorinating agents include NaF and KF.

Alkali metal fluorides such as RbF and CsF are preferred, and spray-dried fluorium is particularly preferred, preferably 1 to 5 times the mole relative to the halogen atom to be replaced, preferably 1
~2 times the molar amount is used. During fluorination, a phase transfer catalyst may be added as a reaction promoter. Examples of such phase transfer catalysts include quaternary ammonium salts such as tetramethylammonium chloride and tetrabutylammonium bromide;
Alternatively, quaternary phosphonium salts such as tetrabutylphosphonium bromide and tetraphenylphosphonium bromide may be mentioned.

Aprotic solvents include N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dimethylphorphone, sulfolane, hexamethylphosphorotriamide, N-methyl-2-pyrrolidone, acetonitrile, benzonitrile, dioxane, Diglyme, tetraglyme, etc. can be used, but sulfolane and N,N-dimethylformamide are preferable.

The amount used is from the same weight to the lθθ type weight, preferably 2 to 5 times the weight of the raw material. The reaction is suitably carried out at a reaction temperature of 50 to 250°C, preferably 100 to 230°C, under normal pressure or increased pressure.

Preferred examples of the compounds represented by the general formulas (1) and (2) are 2 and 4 represented by the following general formula (3), respectively.
-dichloro-5-fluorobenzoic acid ester and 2-chloro-4,5-difluorobenzoic acid ester represented by general formula (4). These are all new substances.

(In the formula, R' 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 2,2,2-trifluoroethyl benzoate or methyl 2-chloro-4,5-difluorobenzoate, ethyl 2-chloro-4,5-difluorobenzoate, 2-chloro-4
, 5-difluorobenzoic acid n-propyl, 2-chloro-
Isopropyl 4,5-difluorobenzoate, butyl 2-chloro-4,5-difluorobenzoate, 2-chloro-4
, 5-difluorobenzoic acid isobutyl, 2-chloro-4
, 2,2,2-trifluoroethyl 5-difluorobenzoate, and the like.

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 R1 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 examples of the base include potassium hydrogen carbonate, hydrogen carbonate, etc. Inorganic bases such as sodium, potassium carbonate, sodium carbonate, and sodium acetate, and organic bases such as pyridine, triethylamine, and ethylamine can be used, but are not limited to these.

The amount of the base used is 0.01 to 2 moles, preferably 0.1 to 1 mole, based on the raw material. The amount of alcohol or phenol used is 1 to 3 times the mole, preferably 1 to 1.5 times the mole of the raw materials.The reaction temperature is 0°C to
The temperature is 100°C, preferably 50°C to 90°C.

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

That is, 2,4-dichloro-5-fluoroacetophenone is subjected to a haloform reaction in a 12% aqueous sodium hypochlorite solution to form 2,4-dichloro-5-fluorobenzoic acid, and then in the presence of an acid catalyst, By reacting this benzoic acid with alcohols or phenols, the above-mentioned fluorine-containing benzoic acid esters can be obtained.

Moreover, these benzoic acid esters can be converted into the corresponding benzoic acids, for example, by the following reaction, and further can be derived into quinolone carboxylic acids useful as synthetic antibacterial agents by several known reaction steps.

) 2,4-dichloro-5- represented by the general formula (5)
Fluoro-α,α,α-trihalotrihalo is a new substance, and specifically represents the following compounds. α,
α,α 2,4-pentachloro-5-fluoroacetophenone (X=C1) α,α,α-tribromo2,4-dichloro-5-fluoroacetophenone (X=Br)2,4-dichloro-5
-fluoroα,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 represented by the formula (6) 2.4-dichloro-
5-fluoroacetophenone may simply be reacted with a halogenating agent. As the halogenating agent, chlorine gas, bromine, and iodine are preferable, and the amount used is 1.5 to 1
0 times the molar amount, preferably 3 to 6 times the molar amount. The reaction temperature is 50°C to 250°C, preferably 100°C to 220°C.

2-chloro-4゜5-difluorobenzoic acid ester represented by the following general formula (4) is prepared by reacting 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) with a halogenating agent. By obtaining 2,4-dichloro-5-fluoro-α,α,α-trihalogenoacetophenone represented by the following general formula (5) and then reacting it with alcohols or phenols, the following general formula (3) is obtained. ) can be obtained by obtaining 2,4-dichloro-5-fluorobenzoic acid ester represented by the following formula and then nuclear fluorinating this using a fluorinating agent.

(In the formula, X represents a halogen atom, and R1 represents an alkyl group, an aryl group, or a fluoroalkyl group.) Also, represented by the general formula (5) using the above general formula (5) as a starting material 2.4- Dichloro-5-fluoro-α,α
, α-trihalogenoacetophenone is reacted with alcohols or phenols to obtain 2,4-dichloro-5-fluorobenzoic acid ester represented by the general formula (3), and then this is reacted with a fluorinating agent. By nuclear fluorination, 2-chloro-4,5-difluorobenzoic acid ester represented by the above general formula (4) can be obtained.

On the other hand, 2,4-dichloro-5-fluorobenzoic acid ester represented by the general formula (3) is produced by reacting 2,4-dichloro-5-fluoroacetophenone represented by the general formula (6) with a halogenating agent. 2,4-dichloro-5-fluoro-α, α, represented by the general formula (5)
By obtaining α-trihalogenoacetophenone and then reacting it with alcohols or phenols,
Obtainable.

Examples of the present invention will be described in more detail below.

[Example] Example 1 2-Propatool 90g (1, 5mol) Potassium carbonate 13.8g
(0.1 mol) was added and reacted at 85°C for 6 hours.

After cooling, inorganic salts are filtered off and distilled under reduced pressure to obtain 2.
Isopropyl 4-dichloro-5-fluorobenzoate 2
18 g (yield: 87%) was obtained. The analytical values for this compound were as follows.

・Boiling point 94℃/3auaHg ・Melting point 35℃ ・NMR analysis <"Fntar> δppra from CFC1
* in CDC1xδ −117,1ppa+ (d
,d,Jr-o=6.5)1z, ,b-H”9,0
Hz) <'Hnmr> δppa+ from TM
S in CDCl5δ 1.39 (6H, d,
J:6.3Hz) δ 5.26 (IH, m) δ 7.50 (IH, d, Jn-r”6.58
Z) δ 7.61 (IH, d, Jn-r=9.
0Hz)・IR analysis 1738cm+-' (C=0) Example 2 Propyl 2.4-dichloro-5-fluorobenzoate 1-
Using 90.0 g (1,5 o1) of propatool, the reaction was carried out at 85°C for 4 hours in the same manner as in Example 1, thereby producing 215.9 g (215.9 g) of propyl 2,4-dichloro-5-fluorobenzoate. Yield: 86%). The analytical values for this compound were as follows.

・NMR analysis <“Fnmr> δppm from CFCla
in CDCl5δ −117,0ppa+ (d,
d, JF-11"6.4H2, JF-11"9, 0H
z) <'Hna+r> δppm fr
om+ TMS in CDCl5δ 1.04
(3H, t, J=7.4H2)61.76 (
2H, m) 64.30 (2H, t, J=6.6Hz) δ
7.46 (IH, d, Jn-r”6.4H2)6
7.63 (IH, d, JH-r=9.0Hz)
・IR analysis 1738 cm-' (C=0) Example 3 111.2 g (1.5 mol) of butyl 2.4-dichloro-5-fluorobenzoate was heated to 98°C in the same manner as in Example 1. By reacting for 4 hours,
2.Butyl 4-dichloro-5-fluorobenzoate 23
5.9 g (yield: 89%) was obtained. The analytical values for this compound were as follows.

・NMR analysis <“Fna+r> δppm from CFCI
s in CDCl5δ -117,2ppm+
(d, d, J, -n"6.5H2, tJF-11"9
, 0Hz) <'Hnmr> δppm from TMS
in CDCl5δ 1.24ppm (3H,t,
J=6.7)1z)61.28~1.92ppm (
4H, m)64.61ppa (2)1. t,
J=6.2Hz)67.77ppm (IH,d,
JP-11=6.5H2)67.91ppm (
IH. By reacting at 98° C. for 4 hours in the same manner as in Example 1, 233.2 g (yield: 88%) of isobutyl 2,4-dichloro-5-fluorobenzoate was obtained. Analysis of this compound The values were as follows.

・NMR analysis <“Fnmr> δppa+ from CFCI
s in CDCl5δ -117,lppm (
d, d, Jr-w=6.4H2, JF-H"9, 0H
z) <'Hna+r> δppm froo+T
MS in CDCl5δ 1.28ppm (3H,
t, J=7.4Hz) δ 1.65ppm (3H,
d, J=6.3Hz) δ 1.98ppm (2H
,s) 65.40ppm (IH,a+) 67.75ppm (IH,d, Jr-,"6.
4)+2)67.91ppa+ (IH, d, J
r-n"9.0H2)・IR analysis 1739 cm-' (C=0) Example 5 Using 150.2 g (1.5 mol) of 2.4-dichloro-5-fluorobenzoic acid cyclohexylcyclohexanol, Example By reacting at 100° C. for 6 hours in the same manner as in 1, 256.2 g (yield: 88%) of cyclohexyl 2,4-dichloro-5-fluorobenzoate was obtained.

The analytical values for this compound were as follows.

・NMR analysis <“Fnmr> δppm from CFCIs
in CDCl5δ -11? , 3ppa+ (d,
d, Jr-o”6.5Hz, , b-o”9.0Hz
) <'Hnmr> δppm from TMS
in CDCII61.31 ~2.09ppm
(1ON, m) 65.04 (IH, m) 67.51 <l) I, d, JH-r: 6.
5Hz) 67.64 (1H, d, J, 1-F=
9.0H2)・IR analysis 1738cm-' (C:0) Example 6 2.4-dichloro-5-fluorobenzoic M-2,2,2
-Trifluoroethyl 2.2.2- Trifluoroethanol 150.0g (
2.4-dichloro-5-
2,2,2-trifluoroethyl fluorobenzoate in 2s3. tg (yield 87%) was obtained. The analytical values for this compound were as follows.

・NMR analysis <I″Fnmr> δppm froIICFCl,
in CDCl5δ -116,2ppm (IF
, d, d, Jy-s”6.5Hz.

Jr-n=8.9H2) δ -74, lppm (3F, t, Jr-n=8
．． 3Hz) <'Hnrar> δppm
from MS in CDCIgδ 4
．． 73ppm (2H, q, J#1-r118.
3Hz) 67.54ppm (IH, d, JN-
n=6.5Hz) δ 7.71ppm (1B,
d, Js-n=8.9Hz)-IR analysis 174
0 cm-' (C=0) Example 7 Isopropyl 2-chloro-4,5-difluorobenzoate 251.0 g of isopropyl 2,4-dichloro-5-fluorobenzoate was placed in a glass 1F2 reaction vessel equipped with a cooling tube.
(1 mol), spray-dried potassium fluoride 87 g (1
, 5 mol), tetramethylammonium chloride 25
．． 1 g of sulfolane and 500 g of sulfolane were charged, and the mixture was reacted at 150° C. for 9 hours with vigorous stirring. After cooling, the inorganic salts are filtered off and further distilled under reduced pressure.
Isopropyl 4,5-difluorobenzoate 199.8
g (yield: 85.2%). The analytical values for this compound were as follows.

・Boiling point 84℃75mmHg ・NMR analysis <"Fnmr> δppm from CFClm
in CDCl5δ -130,3ppm (d,
d, d, Jr-r”20.6H2Jr-o”l00
3HL Jr-n=8.51(z)δ-138,9
ppm (d, d, d, J,, = 22.2HzJ
F-H”8.4H2, JF-H”6.2H2) <'H
nmr > δppm from TMS in C
DCl561.38ppm (6H, d, J=6
．． 3Hz) 65.26ppm (IH, m) 67.28ppm (LH, d, d, JH-F=
8.4H2, Jll-F=6.2Hz) 67.70ppm (IH, d, d, JH-r:
10.3) 1z.

JH-F"8.5H2 ・IR analysis 1742 cm-' (C=0) Example 8 A reaction was carried out in the same manner as in Example 7 using 223 g (1a+ol) of methyl 2.4-dichloro-5-fluorobenzoate. 2-chloro-4,5-
Methyl difluorobenzoate at 99. tg (yield 48.
0%) obtained. The analytical values for this compound were as follows.

・NMR analysis <“Fnmr> δppm from CFClm
in CDCl5δ -129,6ppm (d, d
,d, ,br”20.6Hz+JF-11J0.3
Hz, JF-14"8.5H2) δ -138,6p
pm (d, d, d, J, -n=22.0Hz.

Jt-n=8.4Hz, Jr-H”6.2)1z)
<')Inmr> δppm from TMS
in CDCl5δ 3.93ppn+ (3H,s
) δ 7.30ppa+ (1)1. d, d, J
n-, =8.4Hz, JH-n=6°2Hz) 67.74ppm (1)1. d, d, Jll-
F=10.3H2゜J□, =8.5Hz ・IR analysis 1742cm-' (C:0) Example 9 In the same manner as in Example 7, 237g (1 mol) of ethyl 2,4-dichloro-5-fluorobenzoate was added. The reaction was carried out using ttt, gg (yield 5o, 7%) of ethyl 2-chloro-4,5-difluorobenzoate at 150°C for 9 hours.
)Obtained. The analytical values for this compound were as follows.

・NMR analysis <"Fna+r> 6ppm floor+ CFC
Is in CDCl5δ -130, (lppm (
d, d, d, Jv-120,6Hz.

JF-14N0.4H2, Jr-o”C21(Z)δ
-138,8ppm (d, d, d, Jt-r-21
,8Hz.

Jv-H”8.4H2, Jr-++”6.4)12)<
') Inmr > δppn+ from TM
S in CDC1°δ 1.41ppm (3)!
, t, J=7.1Hz)64.40ppm (2
H, q, J=7.1Hz))67.29ppm (
IH, d, d, JH-v=8.4Hz, JH-
F=6.4Hz) 67.73ppm (IH, d, d, +14-r"
10.4Hz.

JH-F"8.2)+2) ・IR analysis 1742c"' (C=0) Example 10 In the same manner as in Example 7, 251 g of propyl 2,4-dichloro-5-fluorobenzoate (la+ol) was used. The reaction was carried out at 150°C for 9 hours to form 2-chloro-4,5
-199.8g (yield: 85.2%) of propyl difluorobenzoate was obtained. The analytical values for this compound were as follows.

・NMR analysis <“Fna+r> δppm from CFCl
a in CDCl5δ -130,0ppra (d
, d, d, Jr-r=20.6Hz.

Jr-*t”IO, 4H2, Jr-s”8°3Hz) δ
-138,7ppm (d, d, d, Jr-r”2
2.0Hz.

Jr-H118, 4H2, Jr-s”6.4Hz)<
'Hnmr > δppm from
TMS in CDCl5δ 1. O4ppm
(3H, t, J=6.9Hz) δ 1.80ppra
(2H,m)δ 4.30ppm (2H,t,
J=6.6Hz)67.30ppm (IH,d,
d, Jn-r”8.4Hz, JH-r=6.4Hz
) 67.74ppm (IH, d, d, JH-r=1
0.4H2゜JN-F"8.3H2) ・IR analysis 1742 cm-' (C=O) Example 11 In the same manner as in Example 7, butyl 2,4-dichloro-5-fluorobenzoate 265 g (1 mol) 179.9 g of butyl 2-chloro-4,5-difluorobenzoate (yield 72.4
%)Obtained. The analytical values for this compound were as follows.

・NMR analysis <“Fnmr> δppm from CFCIs
in CDCl5δ -130,0ppm (d, d
, d, Jr-r”20.6Hz.

JF-HJo, 5H2, JP-H”8.4H2) δ −
138.7ppm (d, d, d, Jr-r"21.
8Hz.

JF-14=8.4H2, Jr-o”6.2H2)<
') Inmr > δppo+ from TMS
in CDCl5δ 0.98ppm (3H,t
, J=6.5Hz) 61.28-1.93ppm
(4H, m)64.34ppm (2)1. t,
J=6.4Hz) δ 7.29ppa+ (IH, d
, d, JH-v4.4Hz, JN-F=6.2)1
z) δ 7.73ppn+ (IH, d, d, JH-
r"10,5H2゜J,,=J1.4Hz) ・IR analysis 1742 cm"' (c=o) Example 12 In the same manner as in Example 7, 265 g of isobutyl 2,4-dichloro-5-fluorobenzoate ( The reaction was carried out using 1 mol of 2-chloro-4,
194.8 g (yield 78.4%) of isobutyl 5-difluorobenzoate was obtained. The analytical values for this compound were as follows.

・NMR analysis <“Fna+r> δppm from CFCl
a in CDC1aδ -130,3ppm (d,
d, d, , b-rx20.8゜JF-NJo, 4Hz
, JF-H"8.4H2) δ -138,8ppm
(d, d, d, Jr-r”21.8°Jy-s=8.
4Hz, Jr-w"6.4H2) <'Hnmr>
δppm from TMS in CDC1aδ
0.99ppm+ (3)1. t, Jx7. O
Hz) δ 1.35ppm (3H, d, J=6
．． 3Hz) δ 1.87ppm (2H, m) 65, llppm (IH, m) 67.28ppm (LH, d, d, JH-r”
8.4Hz+ J, -v=6.4)1z) 67.71ppm (l)l, d, d, Jll-
F=10.4H2゜JH-r! 8.4 Hz) -IR analysis 1742 cm-' (C=0) Example 13 In the same manner as in Example 7, 2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoate was added to 291
2-chloro-4,5-difluorobenzoic #-2,2 was reacted at 150°C for 4 hours using
, 256.2 g of 2-trifluoroethyl (yield: 83.
3%) obtained.

・Boiling point 106℃/16mmHg ・NMR analysis <"Fnmr> δppm from CFCI
s in CDCl5δ -127,6ppa+ (
IF, d, d, d, Jr-y=20.68zJP-
11"10.2Hz, JF-H"8.2H2) δ
-137.7ppm (IF, d, d, d,
j, -r"21.8H2JF-)l"8.4H2,JF
-14"6.2H2) δ -74,lppm+ (3
F, t, Jr-h=8.3Hz) <'Hna
+r > δppm from TMS in CD
Cl5δ 4.719pffl (2H,Q, J
H-F”8.3H2)67.35ppm (IH,d
, d, JH-r”Jl, 4Hz.

JH-, =6.2)12) δF, 70ppm (1)1. d, JH-
r"lo, 2H2゜Jll-F"8.2H2) ・IR analysis 1740c+a-'(C;0) Example 14 α, α, α, 2,4-pentachloro-5-fluoroacetophenone cooling tube and gas blowing tube Glass 500ai with
207 g (1 mol) of 2,4-dichloro-5-fluoroacetophenone was charged into a 12-liter reactor, and the reaction temperature was set to 12
While raising the temperature from 0°C to 200°C, 426 g (6 mol) of chlorine gas was blown in under normal pressure over 20 hours. After cooling, washing with water, washing with a 5% potassium bicarbonate aqueous solution, washing with water, drying, and reduced pressure. By distilling α, α, α, 2.
29 4-pentachloro-5-fluoroacetophenone
8 g (yield 96%) was obtained.

The analytical values for this compound were as follows.

・Boiling point 110℃/2.5mmHg ・NMR analysis <"Fnmr>δri p11 floor+ CFCIs
in CDCl5δ −115,6 ppm (d, d
, Jr-14"6.6Hz, Jr-o"8, 2Hz
) <'Hnmr> δppm from
TMS in CDC1g67.58 (IH,
d, Jh-r=6.6Hz) δ 7.62 (IH
, d, JH-r"8.2H2)・IR analysis 1740ca+-' (C=o) Example 15 2-chloro-4,5-difluorobenzoic acid-2,2,2
- Trifluoroethyl In a glass 1°C reaction vessel equipped with a cooling tube, 291 g (1 mol) of 2,4-dichloro-5-fluorobenzoic acid (2,2,2-) 1j fluoroethyl and 87 g of spray-dried potassium fluoride ( 1.5 mol), Sulfolane 500
g was charged and reacted at 180° C. for 9 hours with vigorous stirring. After cooling, inorganic salts are filtered off and further distilled under reduced pressure to obtain 2-chloro-4,5-difluorobenzoic acid.
239.4 g (yield: 87.2%) of 2,2,2-trifluoroethyl was obtained.

Example 16 2,2,2-trifluoroethyl 2,4.5-)lifluorobenzoate.

2.4-dichloro-5-fluorobenzoic acid-2,2,2
- By using 291 g (1 mol) of trifluoroethyl and reacting at 180°C for 32 hours in the same manner as in Example 15, 2.4.5-trifluorobenzoyane-2
, 158.7 g of 2,2-trifluoroethyl (yield: 6
1.5%) was obtained.

Example 17 Using 238.5 g (1 mol) of 2-fluorobenzoic acid-2,2,2-trifluoroethyl 2-chlorobenzoic acid-2,2,2-)-trifluoroethyl, Example 15 and Similarly, by reacting at 180°C for 18 hours, 2
179.2 g (yield: 80.7%) of 2,2,2-trifluoroethyl-fluorobenzoate was obtained.

Example 18 Using 238.5 g (1 mol) of 4-fluorobenzoic acid-2,2,2-)lifluoroethyl 4-chlorobenzoate-2,2,2-), Example 15 and Similarly, by reacting at 180°C for 10 hours, 4-
183.2 g (yield: 82.5%) of 2,2,2-1-lifluoroethyl fluorobenzoate was obtained.

Example 19 Example 19 Using 273.5 g (1 mol) of 2,2,2-trifluoroethyl 2.4-difluorobenzoate 2,2,2-trifluoroethyl 2.4-dichlorobenzoate 1
By reacting at 180° C. for 15 hours in the same manner as in Example 5, t9t, sg of 2,2,2-trifluoroethyl 2,4-difluorobenzoate (yield 79.8%) was obtained.

Example 20 Example using 273.5 g (1 mol) of 2,2,2-trifluoroethyl 2.6-dichlorobenzoate-2,2,2-trifluoroethyl 2.6-dichlorobenzoate. 1
By reacting at 180° C. for 20 hours in the same manner as in Example 5, 9 g (yield 73.3%) of 2,2,2-trifluoroethyl 2,6-difluorobenzoate was obtained at 7s.

Example 21 3-chloro-4,5-difluorobenzoic acid-2,2,2
-Trifluoroethyl 3. By reacting 307.5 g (1 mol) of 4.5-trichlorobenzoate-2,2,2-trifluoroethyl at 180°C for 10 hours in the same manner as in Example 15. 3-chloro-4,5-difluorobenzoic acid-2,
179.5 g of 2,2-trifluoroethyl (yield 65
．． 4%) was obtained.

Example 22 3,4.5-) 2,2,2-trifluoroethyl trifluorobenzoate 3.4.307.5 g (1 mol) of 2,2,2-trifluoroethyl 5-trichlorobenzoate make use of,
By reacting at 180°C for 30 hours in the same manner as in Example 15, 3,4.5-)lifluorobenzoic acid-2,2,
97.7g of 2-trifluoroethyl (yield 35.6%)
)Obtained.

Example 23 2-Chloro-4,5-difluorobenzoic acid-1-trifluoromethyl-2,2,2-trifluoroethyl 2.4
-dichloro-5-fluorobenzoic acid-1-)lifluoromethyl-2,2,2-trifluoroethyl 359,0
g (1 mol) at 180°C in the same manner as in Example 15.
2-chloro-4,5-
1-trifluoromethyl-2,2 difluorobenzoate
, 290.4 g of 2-trifluoroethyl (yield: 84.
8%).

Example 24 2-chloro-4,5-difluorobenzoic acid-2,2,3
゜3.3-Pentafluoropropyl 2,4-dichloro-5-fluorobenzoic acid-2,2,3
゜3.3-pentafluoropropyl 341.0g (1
8 mol) at 180°C in the same manner as in Example 15.
By reacting for hours, 76.1 g (yield: 85.1%) of 2,2,3,3,3-pentafluoropropyl 2-chloro-4,5-difluorobenzoate was obtained.

Example 25 238.5 g of 2,2,2-trifluoroethyl 2-chlorobenzoate (
1 mol)-, spray-dried potassium fluoride 87 g (1
, 5 mol), tetrabutylphosphonium bromide 2
3.9g of sulfolane and 480g 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-trifluorobenzoic acid. Fluoroethyl 134.3
g (yield 60.5%) was obtained.

Example 26 In the same manner as in Example 25, a reaction was carried out using 198.5 g (1 mol) of isopropyl 4-chlorobenzoate and 19.9 g of tetramethylammonium chloride, and 1
147.8g (81.7%) of isopropyl 4-fluorobenzoate was obtained at 50°C for 15 hours.

Example 27 In the same manner as in Example 26, a reaction was carried out using 233 g (1'mol) of isopropyl 2,4-dichlorobenzoate at 150°C for 14 hours to convert 173 g of isopropyl 2-chloro-4-fluorobenzoate. .4g (yield 80.1%)
Obtained.

Example 28 In the same manner as in Example 25, 2,4-dichlorobenzoic acid-
2,2,2-trifluoroethyl 273g (1mol
) at 200°C for 20 hours.
139.8g (yield 58.3%) of 2,2,2-trifluoroethyl-difluorobenzoate was obtained.

Example 29 In the same manner as in Example 25, 2,6-dichlorobenzoic acid-
2,2,2-1-lifluoroethyl 273g (1mol
) at 200°C for 30 hours.
138.2 g (yield 57.6%) of 2,2,2-trifluoroethyl-difluorobenzoate was obtained.

Example 30 In the same manner as in Example 26, a reaction was carried out using 223 g (1 mol) of methyl 2,4-dichloro-5-fluorobenzoate, and 2-chloro-4,5-
99.1 g of methyl difluorobenzoate (yield 48.0
%)Obtained.

Example 31 In the same manner as in Example 26, a reaction was carried out using 237 g (1 mol) of ethyl 2,4-dichloro-5-fluorobenzoate, and 2-di-4-4,5-
111.1 g of methyl difluorobenzoate (yield: 50.
7%) obtained.

Example 32 In the same manner as in Example 26, a reaction was carried out using 251 g (1 mol) of isopropyl 2,4-dichloro-5-fluorobenzoate, and 2-chloro-4 was reacted at 150°C for 9 hours.
, 199.8g of isopropyl 5-difluorobenzoate
(yield 85.2%).

Example 33 In the same manner as in Example 26, a reaction was carried out using 285 g (1 mol) of phenyl 2.4-dichloro-5-fluorobenzoate, and 4.5
194.5g of phenyl difluorobenzoate (yield: 7
2.4%) was obtained.

Example 34 In the same manner as in Example 25, 2,2,2-trifluoroethyl 2,4-dichloro-5-fluorobenzoate was added to 29
The reaction was carried out using 1 g (1 mol) at 200°C, 3
2.4.5-trifluorobenzoic acid-2,2, at 0 hours
126.2g of 2-trifluoroethyl (yield 48.
2%) was obtained.

Example 35 In the same manner as in Example 25, tetrachlorophthalate (
2,2,2-trifluoroethyl) ester 234g (
0.5 mol) at 200°C13
104.5 g of tetrafluorophthalic acid bis(2,2,2-trifluoroethyl) ester (yield 52
．． 0%) obtained.

[Effects of the Invention] According to the present invention, the desired nuclear fluorinated aromatic carboxylic acid ester can be obtained industrially at low cost and in high yield from an aromatic carboxylic acid ester that is easy to use.

In addition, by variously converting the alkyl (aryl) moiety of the alkoxycarbonyl (aryloxycarbonyl) group of the raw material aromatic carboxylic acid ester, only the halogen at the para position to the alkoxycarbonyl (aryloxycarbonyl) group is replaced with fluorine. Or, ortho rank,
Both halogens at the para position can be substituted with fluorine, which is highly useful.

Claims (1)

[Scope of Claims] (1) By nuclearly fluorinating an aromatic carboxylic acid ester represented by the following general formula (1) using a fluorinating agent, a nuclear fluorinated aromatic acid represented by the following general formula (2) is produced. A method for producing a nuclear fluorinated aromatic carboxylic acid ester, the method comprising obtaining a group carboxylic acid ester. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (1) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (2) (In the formula, R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group. A and B are Represents at least one selected from hydrogen, halogen, alkyl group, aryl group, and fluoroalkyl group. m and n are integers, m + n = 6, m represents 1 or 2. However, at least one of A is active (2) The activated chlorine or bromine is -COOR^1, and B corresponding to the activated chlorine or bromine is fluorine.)
The manufacturing method according to claim 1, wherein chlorine or bromine is at the ortho or para position relative to the group. (3) The manufacturing method according to claim 1, wherein the fluorinating agent is an alkali metal fluoride. (4) By nuclear fluorinating the 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3) using a fluorinating agent, the 2-chloro-5-fluorobenzoic acid ester represented by the following general formula (4) is A method for producing 2-chloro-4,5-difluorobenzoic acid ester, which comprises obtaining -4,5-difluorobenzoic acid ester. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(3) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(4) (In the formula, R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group.) (5) The manufacturing method according to claim 4, wherein the fluorinating agent is an alkali metal fluoride. (6) By reacting 2,4-dichloro-5-fluoro-α,α,α-trihalogenoacetophenone represented by the following general formula (5) with alcohols or phenols, the following general formula (3) can be obtained. A method for producing 2,4-dichloro-5-fluorobenzoic acid ester, characterized by obtaining 2,4-dichloro-5-fluorobenzoic acid ester represented by the following formula. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(5)▲There are mathematical formulas, chemical formulas, tables, etc.▼(3) (In the formula, X represents a halogen atom, and R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group. ) (7) The manufacturing method according to claim 6, wherein in the general formula, X is a chlorine atom. (8) By reacting 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) with a halogenating agent, 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (5)
A method for producing 2,4-dichloro-5-fluoro-α,α,α-trihalogenoacetophenone, which comprises obtaining -dichloro-5-fluoro-α,α,α-trihalogenoacetophenone. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(6)▲There are mathematical formulas, chemical formulas, tables, etc.▼(5) (In the formula, X represents a halogen atom.) (9) In the general formula, X is a chlorine atom. The manufacturing method according to claim 8. (10) The manufacturing method according to claim 8, wherein the halogenating agent is chlorine gas. (11) 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) is reacted with a halogenating agent to produce a 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (5). By obtaining α,α,α-trihalogenoacetophenone and then reacting it with alcohols or phenols, a 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3) is obtained, 2-chloro-4,5-difluorobenzoic acid ester represented by the following general formula (4) is then obtained by nuclear fluorination using a fluorinating agent. Method for producing 5-difluorobenzoic acid ester. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(6)▲There are mathematical formulas, chemical formulas, tables, etc.▼(5)▲There are mathematical formulas, chemical formulas, tables, etc.▼(3)▲There are mathematical formulas, chemical formulas, tables, etc.▼( 4
) (In the formula, X represents a halogen atom, and R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group.) (12) 2,4-dichloro-5-fluoro represented by the following general formula (5) - Reacting α, α, α-trihalogenoacetophenone with alcohols or phenols,
2,4-dichloro-5- represented by the following general formula (3)
A 2-chloro-4,5-difluorobenzoic acid ester represented by the following general formula (4) is obtained by obtaining a fluorobenzoic acid ester and then nuclear fluorinating this using a fluorinating agent. 2-chloro-4
, 5-difluorobenzoic acid ester manufacturing method. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (4) (In the formula, X represents a halogen atom, (R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group.) (13) 2,4-dichloro-5-fluoroacetophenone represented by the following general formula (6) is reacted with a halogenating agent to form the following general By obtaining 2,4-dichloro-5-fluoro-α,α,α-trihalogenoacetophenone represented by formula (5) and then reacting it with alcohols or phenols, the following general formula (3) is obtained. A method for producing 2,4-dichloro-5-fluorobenzoic acid ester, characterized by obtaining 2,4-dichloro-5-fluorobenzoic acid ester represented by the following formula. ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (6) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (5) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (3) (In the formula, X represents a halogen atom, (R^1 represents an alkyl group, an aryl group, or a fluoroalkyl group.) (14) 2,4-dichloro-5-fluorobenzoic acid ester represented by the following general formula (3). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (3) (In the formula, R^1 represents an alkyl group, aryl group, or fluoroalkyl group.) (15) In the general formula, R^1 is isopropyl, propyl, butyl, 2, 4 according to claim 14, which is one selected from isobutyl, cyclohexyl, and tetrafluoroethyl.
-dichloro-5-fluorobenzoic acid ester. (16) 2-chloro-4 represented by the following general formula (4)
, 5-difluorobenzoic acid ester. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (4) (In the formula, R^1 represents an alkyl group, aryl group, or fluoroalkyl group.) (17) In the general formula, R^1 is methyl, ethyl, propyl,
17. The 2-chloro-4,5-difluorobenzoic acid ester according to claim 16, which is one selected from isopropyl, butyl, isobutyl, and trifluoroethyl. (18) 2,4-dichloro-5-fluoro-α,α,α-trihalogenoacetophenone represented by the following general formula (5). ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (5) (In the formula, X represents a halogen atom.) (19) 2,4-dichloro-5 according to claim 18, wherein X in the general formula is a chlorine atom. -Fluoro-α,α,α-trihalogenoacetophenone.