JP2008031028A - Potassium fluoride dispersion solution and process for production of fluorine-containing organic compound using the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a potassium fluoride dispersion solution having high activity as a fluorinating agent. <P>SOLUTION: The potassium fluoride dispersion solution is substantially comprised of potassium fluoride and an aprotic organic solvent having a boiling point higher than that of methanol, which is prepared by mixing a mixture of potassium fluoride and methanol in an amount of 5 to 50-fold greater by weight than that of potassium fluoride with the aprotic organic solvent, and then condensing the resulting mixture. Also, a process for the production of a fluorine-containing organic compound, comprises the step of contacting the potassium fluoride dispersion solution with an organic compound having at least one group which can be substituted by a fluorine atom in a nucleophilic manner. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a potassium fluoride dispersion and a method for producing a fluorine-containing organic compound using the same.

  Potassium fluoride is useful as a fluorinating agent for organic compounds. Since the fluorination reaction of an organic compound using potassium fluoride is usually carried out in a non-uniform state in which an inorganic salt is precipitated, the reactivity may be lowered depending on the shape of potassium fluoride. Moreover, although potassium fluoride has a hygroscopic property, the fluorination reaction is a nucleophilic substitution reaction, and the reactivity may be lowered by moisture. Therefore, a methanol solution of potassium fluoride was prepared using 0.5 to 0.6 ml of methanol per 1 g of potassium fluoride, and 40 to 60 ml of an aromatic compound and 2 to 3 g of an aprotic polar solvent were added thereto. Thus, a method of using a potassium fluoride dispersion obtained by distillation for the reaction has been proposed (see Patent Document 1). However, since the potassium fluoride dispersion obtained by such a method is not yet sufficiently reactive as a fluorinating agent, it is necessary to carry out the reaction using an expensive phase transfer catalyst. In order to achieve this, further improvement in reactivity has been demanded.

JP-T 63-502181

  Under such circumstances, the present inventors have conducted extensive studies to develop a more reactive fluorinating agent. As a result, a mixture comprising potassium fluoride and methanol of 5 to 50 times its weight is obtained. And an aprotic organic solvent, and a potassium fluoride dispersion substantially comprising potassium fluoride and an aprotic organic solvent obtained by concentrating the resulting mixture is industrially satisfactory fluorine It has been found that the fluorination reaction of an organic compound can proceed efficiently without using a phase transfer catalyst if the potassium fluoride dispersion is used, and has led to the present invention. .

  That is, the present invention can be obtained by mixing a mixture comprising potassium fluoride and methanol 5 to 50 times its weight with an aprotic organic solvent having a boiling point higher than that of methanol, and concentrating the resulting mixture. A potassium fluoride dispersion substantially comprising potassium fluoride and an aprotic organic solvent, a method for producing a fluorine-containing organic compound using the same, and the like are provided.

  According to the present invention, it is possible to easily obtain a potassium fluoride dispersion having high reactivity with respect to a fluorination reaction of an organic compound. By using this potassium fluoride dispersion, it is possible to efficiently produce fluorine-containing organic compounds important as various chemical products such as medical pesticides and electronic materials, and synthetic intermediates without using an expensive phase transfer catalyst. Industrially advantageous.

  Hereinafter, the present invention will be described in detail.

  As potassium fluoride, a commercially available product can be used, or potassium hydroxide and hydrogen fluoride can be reacted as described later. When using a commercially available product, its properties are not particularly limited. For example, both dried products and hydrates can be used.

  Commercially available methanol can be used. Not only anhydrous products but also water containing up to about 5% by weight can be used. The amount of methanol used is in the range of 5 to 50 times the weight of potassium fluoride. The resulting mixture is preferably a solution in which potassium fluoride is completely dissolved in methanol. The amount of methanol used to prepare such a solution varies depending on conditions such as dissolution and temperature during use and water content, but it is more preferably 8 times by weight or more with respect to potassium fluoride.

  Preparation of a mixture comprising potassium fluoride and 5 to 50 times its methanol is, for example, a method of mixing potassium fluoride and methanol, or mixing potassium hydroxide and hydrogen fluoride in methanol. Methods and the like. In the former case, the mixing order of potassium fluoride and methanol is not particularly limited. Usually, mixing is performed under normal pressure conditions, but may be performed under reduced pressure conditions or pressurized conditions. Mixing temperature is 0-100 degreeC normally, Preferably it is the range of 20-70 degreeC.

  A method of mixing potassium hydroxide and hydrogen fluoride in methanol is preferable from the viewpoint of cost.

  As the potassium hydroxide, a commercially available product can be used as it is, or it can be used after drying. Moreover, what was manufactured by arbitrary methods can also be used. The shape is not particularly limited, and may be, for example, a piece, a tablet, or a rod, an aqueous solution, or an alcohol solution. It is preferable that the water content is small. When an alcohol solution is used, a methanol solution is preferable.

  Commercially available hydrogen fluoride can be used, and its properties are not particularly limited. Hydrogen fluoride gas or hydrofluoric acid can be used, and hydrofluoric acid is preferably used from the viewpoint of operability and availability. Commercially available hydrogen fluoride may be used as it is, or it may be used as a mixture with methanol or water. When hydrogen fluoride gas is used, it may be mixed with a gas inert to the reaction. When hydrofluoric acid is used, the concentration is preferably higher. The usage-amount of hydrogen fluoride is 0.9-1.1 mol times normally with respect to potassium hydroxide, Preferably it is the range of 0.99-1.01 mol times.

  The order of mixing potassium hydroxide, hydrogen fluoride, and methanol is not particularly limited, but it is usually preferable to add hydrogen fluoride gas or hydrofluoric acid to a mixture of potassium hydroxide and methanol. Usually, mixing is performed under normal pressure conditions, but may be performed under reduced pressure conditions or pressurized conditions. Mixing temperature is 0-100 degreeC normally, Preferably it is the range of 20-70 degreeC.

  The solvent used in the production of the potassium fluoride dispersion of the present invention is an aprotic organic solvent, and is particularly limited as long as it has a boiling point higher than that of methanol under pressure conditions at the time of methanol distillation removal described later. However, a nonpolar solvent may be used, but it is preferable to use an aprotic polar solvent in that it can be used as it is as a fluorination reaction solvent described later. Such a solvent may be used alone or as a mixed solvent of two or more. Examples of the aprotic polar solvent include ether solvents such as diisopropyl ether, dibutyl ether, dioxane, diethylene glycol dimethyl ether, and triethylene glycol dimethyl ether; sulfone solvents such as sulfolane, dimethyl sulfone, and methyl ethyl sulfone; dimethyl sulfoxide, diethyl sulfoxide, tetra Sulfoxide solvents such as methylene sulfoxide; alkylamide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methyl-2-pyrrolidone; nitrile solvents such as butyronitrile and adiponitrile; A sulfone solvent, a sulfoxide solvent or an alkylamide solvent is preferred. Moreover, when using a nonpolar solvent, C6-C8 aliphatic hydrocarbon solvents, such as hexane, heptane, octane, and cyclohexane; Aromatic hydrocarbon solvents, such as benzene, toluene, xylene; .

  If the amount of the aprotic organic solvent having a boiling point higher than that of the methanol is usually 1 times by weight or more with respect to potassium fluoride, the object of the present invention can be achieved and there is no upper limit, but it is too much. And the productivity is reduced, so that it is practically 20 weight times or less.

The potassium fluoride dispersion of the present invention is produced, for example, by the operation method shown in the following (a) to (c).
(A) A method of mixing a mixture comprising potassium fluoride and 5 to 50 times by weight of methanol with an aprotic polar solvent and concentrating the resulting mixture (b) Potassium fluoride and 5- A method comprising mixing a mixture comprising 50 times by weight of methanol and a nonpolar solvent, concentrating the resulting mixture, adding an aprotic polar solvent, and concentrating the resulting mixture (c) A method of concentrating while adding a mixture comprising potassium fluoride and methanol 5 to 50 times its weight in an aprotic polar solvent under a temperature condition higher than the boiling point Among the above (a) to (c), the reaction A preferred embodiment in terms of activity is the method (c).

  For the purpose of substantially not leaving methanol or water in the potassium fluoride dispersion, the dispersion may be concentrated using a solvent azeotroped with methanol or water. Examples of the solvent azeotropic with methanol and water include aromatic hydrocarbon solvents such as benzene, toluene and xylene; aliphatic hydrocarbon solvents such as hexane and cyclohexane;

  The operating pressure during concentration is usually in the range of 0.7 to 200 kPa, and the operating temperature is usually in the range of 20 to 200 ° C.

  The potassium fluoride dispersion thus obtained is a mixture substantially composed of potassium fluoride and the above aprotic organic solvent, in which fine powder of potassium fluoride is dispersed in the aprotic organic solvent. The content of potassium fluoride in the potassium fluoride dispersion is usually in the range of 5 to 70% by weight.

  In particular, potassium fluoride in a potassium fluoride dispersion prepared using a solution in which potassium fluoride is completely dissolved in methanol usually has a primary particle diameter of 0.1 to 5 μm, Part or all of them aggregate to form particles having a volume-converted average particle diameter of 5 to 25 μm.

  The potassium fluoride dispersion of the present invention has utility as a composition for fluorination reaction. Hereinafter, a method for fluorinating an organic compound in which the organic compound having at least one group that can be nucleophilically substituted with a fluorine atom and the potassium fluoride dispersion of the present invention are brought into contact (in the present specification, simply referred to as “fluorination”). "Reaction" may be described in detail.).

Examples of the organic compound having at least one group that can be nucleophilically substituted with a fluorine atom include:
An organic compound in which at least one hydrogen atom on the optionally substituted aliphatic hydrocarbon compound is substituted with a group capable of nucleophilic substitution with a fluorine atom;
An organic compound in which at least one hydrogen atom on the optionally substituted aromatic hydrocarbon compound is substituted with a group capable of nucleophilic substitution with a fluorine atom;
An organic compound in which at least one hydrogen atom on the optionally substituted heteroaromatic compound is substituted with a group capable of nucleophilic substitution with a fluorine atom;
Etc., corresponding to the respective fluorination reactions,
An organic compound in which at least one hydrogen atom on the optionally substituted aliphatic hydrocarbon compound is substituted with a fluorine atom;
An organic compound in which at least one hydrogen atom on the optionally substituted aromatic hydrocarbon compound is substituted with a fluorine atom;
An organic compound in which at least one hydrogen atom on the optionally substituted heteroaromatic compound is substituted with a fluorine atom;
give.

  Examples of the aliphatic hydrocarbon compound include linear, branched or cyclic such as methane, ethane, propane, butane, isobutane, pentane, decane, cyclopropane, 2,2-dimethylcyclopropane, cyclopentane, and cyclohexane. The C1-C20 alkane of these is mentioned. Examples of the group which may be substituted on the aliphatic hydrocarbon compound include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, and a 3-phenoxyphenyl group. 2,3,5,6-tetrafluorophenyl group, 2,3,5,6-tetrafluoro-4-methylphenyl group, 2,3,5,6-tetrafluoro-4-methoxyphenyl group, 2, An optionally substituted aryl group having 5 to 20 carbon atoms such as 3,5,6-tetrafluoro-4-methoxymethylphenyl group, 2-pyridyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, An optionally substituted alkoxy group having 1 to 20 carbon atoms such as a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, or a trifluoromethoxy group; An aryloxy group having 6 to 20 carbon atoms, such as an enoxy group, 2-methylphenoxy group, 4-methylphenoxy group, 4-methoxyphenoxy group, 3-phenoxyphenoxy group; benzyloxy group, 4- Methylbenzyloxy group, 4-methoxybenzyloxy group, 3-phenoxybenzyloxy group, 2,3,5,6-tetrafluorobenzyloxy group, 2,3,5,6-tetrafluoro-4-methylbenzyloxy group , 2,3,5,6-tetrafluoro-4-methoxybenzyloxy group, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyloxy group, etc. Good aralkyloxy group; fluorine atom; optionally substituted alkyl having 2 to 20 carbon atoms such as acetyl group and ethylcarbonyl group An arylcarbonyl group having 7 to 20 carbon atoms such as benzoyl group, 2-methylbenzoyl group, 4-methylbenzoyl group, 4-methoxybenzoyl group; benzylcarbonyl group, 4-methylbenzylcarbonyl Groups that do not participate in the fluorination reaction, such as a group, an optionally substituted aralkylcarbonyl group having 8 to 20 carbon atoms such as a 4-methoxybenzylcarbonyl group; a carboxy group; and the like. Examples of the aliphatic hydrocarbon compound substituted with such a group include fluoromethane, trifluoromethane, methoxymethane, ethoxymethane, methoxyethane, toluene, 4-methoxytoluene, 3-phenoxytoluene, 2,3,5,6- Tetrafluorotoluene, 2,3,5,6-tetrafluoro-paraxylene, 2,3,5,6-tetrafluoro-4-methoxytoluene, 2,3,5,6-tetrafluoro-4-methoxymethyltoluene , 2-propylnaphthalene, methyl isobutyl ketone, acetophenone, 4-methylacetophenone, phenylacetone and the like.

  As an aromatic hydrocarbon compound, C6-C20 aromatic hydrocarbon compounds, such as benzene and naphthalene, are mentioned, for example. Examples of the group which may be substituted on the aromatic hydrocarbon compound include a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, and a 3-phenoxyphenyl group. 2,3,5,6-tetrafluorophenyl group, 2,3,5,6-tetrafluoro-4-methylphenyl group, 2,3,5,6-tetrafluoro-4-methoxyphenyl group, 2, An optionally substituted aryl group having 5 to 20 carbon atoms such as 3,5,6-tetrafluoro-4-methoxymethylphenyl group, 2-pyridyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, An optionally substituted alkoxy group having 1 to 20 carbon atoms such as a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, or a trifluoromethoxy group; An aryloxy group having 6 to 20 carbon atoms, such as an enoxy group, 2-methylphenoxy group, 4-methylphenoxy group, 4-methoxyphenoxy group, 3-phenoxyphenoxy group; benzyloxy group, 4- Methylbenzyloxy group, 4-methoxybenzyloxy group, 3-phenoxybenzyloxy group, 2,3,5,6-tetrafluorobenzyloxy group, 2,3,5,6-tetrafluoro-4-methylbenzyloxy group , 2,3,5,6-tetrafluoro-4-methoxybenzyloxy group, 2,3,5,6-tetrafluoro-4-methoxymethylbenzyloxy group, etc. A good aralkyloxy group; an optionally substituted alkylcarbonyl group having 2 to 20 carbon atoms such as an acetyl group and an ethylcarbonyl group; 7-C20 optionally substituted arylcarbonyl group such as benzoyl group, 2-methylbenzoyl group, 4-methylbenzoyl group, 4-methoxybenzoyl group; benzylcarbonyl group, 4-methylbenzylcarbonyl group, 4 -Aralkylcarbonyl group having 8 to 20 carbon atoms, such as methoxybenzylcarbonyl group, which may be substituted; carboxy group; sulfonamide group; cyano group; amide group; fluorine atom; It is done. Further, among these groups, two adjacent groups may be bonded to each other to form a ring together with the bonded carbon atoms. Examples of the aromatic hydrocarbon compound substituted with such a group include cyanobenzene, terephthalonitrile, isophthalonitrile, orthophthalonitrile, fluorobenzene, 1,4-difluorobenzene, benzenesulfonamide, biphenyl, and 2-phenylnaphthalene. , Diphenyl ether, benzophenone, 1,2-diphenylethanone and the like.

  Examples of the heteroaromatic compound include C5-C20 heteroaromatic compounds such as pyridine, quinoline, and pyrimidine. Examples of the group which may be substituted on the heteroaromatic compound include groups which are not involved in the fluorination reaction exemplified as the group which may be substituted on the above-described aromatic hydrocarbon compound. Examples of the heteroaromatic compound substituted with such a group include 3-methylpyridine and 4-phenylpyridine.

  Examples of the group that can be nucleophilically substituted with a fluorine atom include a chlorine atom, a bromine atom, an iodine atom, a nitro group, a sulfo group, an optionally substituted alkylsulfonyloxy group, and an optionally substituted arylsulfonyloxy group. Group, an optionally substituted alkylcarbonyloxy group or an optionally substituted arylcarbonyloxy group. When two or more such groups are present, they may be the same as or different from each other.

  Examples of the optionally substituted alkylsulfonyloxy group include a methanesulfonyloxy group, an ethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the like. Examples of the optionally substituted arylsulfonyloxy group include a paratoluenesulfonyloxy group, a benzenesulfonyloxy group, and a 1-naphthalenesulfonyloxy group. Examples of the optionally substituted alkylcarbooxy group include a trifluoroacetoxy group and a pentafluoroethylcarbonyloxy group. Examples of the optionally substituted arylcarbonyloxy group include a tetrafluorobenzoyloxy group and a benzoyloxy group.

  Examples of the organic compound having at least one group that can be nucleophilically substituted with a fluorine atom include 1-chlorobutane, 1-bromobutane, 1-iodobutane, 1-chlorocyclobutane, 1-chloropentane, 1-bromopentane, 1 -Chlorocyclopentane, 1-chloro-4-bromobutane, 1-chlorohexane, 1-bromohexane, 1,6-dibromohexane, 1-chloroheptane, 1-bromoheptane, 2-chloroheptane, 2-bromoheptane 1-chlorooctane, 1-bromooctane, 2-chlorooctane, 2-bromooctane, benzyl chloride, benzyl bromide, (1-chloroethyl) benzene, (1-bromoethyl) benzene, 4-methoxybenzyl chloride, 4-methyl Benzyl bromide, 3,4,5-trifluoro Benzyl bromide, n-butyl p-toluenesulfonate, n-butyl methanesulfonate, n-pentyl p-toluenesulfonate, n-pentyl methanesulfonate, n-hexyl p-toluenesulfonate, n-hexyl methanesulfonate, p-toluene N-heptyl sulfonate, n-heptyl methanesulfonate, n-octyl p-toluenesulfonate, n-octyl methanesulfonate, n-butyl trifluoroacetate, n-butyl tetrafluorobenzoate, n-octyl trifluoroacetate, 4-chloronitrobenzene, 4-bromonitrobenzene, 2-chloronitrobenzene, 2-bromonitrobenzene, 2,4-dichloronitrobenzene, 2,6-dichloronitrobenzene, 3,5-dichloronitrobenzene, 4-cyanochlorobenzene, -Cyanobromobenzene, 1-chloro-2,4-dinitrobenzene, tetrachloroterephthalonitrile, tetrachloroisophthalonitrile, tetrachloroorthophthalonitrile, 1,3-dichloro-4,6-dinitrobenzene, 2-chloro Examples include quinoline, 2-chloro-5-nitropyridine, 2-chloro-5-trifluoromethylpyridine, 4,5,6-trichloropyrimidine and the like.

  A fluorine-containing organic compound is obtained by bringing the organic compound having at least one group that can be nucleophilically substituted with a fluorine atom into contact with the potassium fluoride dispersion of the present invention. Here, when using an organic compound having two or more groups that can be nucleophilically substituted with fluorine atoms, they may be different substituents, and usually exhibit the following reactivity, Only a highly reactive group may be substituted with a fluorine atom, or depending on the reaction conditions, two or more identical or different groups may be substituted with a fluorine atom.

  In the case of an organic compound in which at least one hydrogen atom on an optionally substituted aromatic hydrocarbon compound is substituted with a group that can be nucleophilically substituted with a fluorine atom, usually an electron is attracted to the para or ortho position. Groups that have a sexual group and can be substituted nucleophilically with fluorine atoms are preferentially substituted with fluorine atoms. For example, in the reaction of 4-chloronitrobenzene, both a chlorine atom and a nitro group are groups that can be nucleophilically substituted with a fluorine atom, but a chlorine atom having a higher electron-withdrawing nitro group in the para position is preferential. In general, 4-fluoronitrobenzene is selectively produced. Of course, for example, if the reaction conditions are appropriately selected, such as using a large excess of the potassium fluoride dispersion of the present invention, the nitro group can also be substituted with a fluorine atom to obtain paradifluorobenzene.

  In the case of an organic compound in which at least one hydrogen atom on the optionally substituted heteroaromatic compound is substituted with a group that can be nucleophilically substituted with a fluorine atom, usually, the heteroaromatic ring constituting the heteroaromatic ring is formed. A group that can be nucleophilically substituted with a fluorine atom at the 2-position, 4-position or 6-position is preferentially substituted with a fluorine atom. For example, in 2-chloro-3-nitropyridine, the 2-position chloro group is usually substituted to produce 2-fluoro-3-nitropyridine. Of course, for example, if the reaction conditions are appropriately selected, such as using a large excess of the potassium fluoride dispersion of the present invention, the nitro group can also be substituted with a fluorine atom, and 2,3-difluoropyridine can be obtained.

  The amount of the potassium fluoride dispersion of the present invention used is usually 1 for potassium fluoride with respect to a group for which a fluorination reaction is desired on an organic compound having at least one group that can be nucleophilically substituted with a fluorine atom. What is necessary is just the quantity which contains more than mol times. The upper limit is not particularly limited, but when it has only one group that can be nucleophilically substituted with a fluorine atom, it is preferably 1.5 to 5 moles from the viewpoint of reaction efficiency. In addition, when there are two or more groups that can be nucleophilically substituted with fluorine atoms, based on the above-mentioned priority of reactivity, the amount to be used is within a range in which a group desired for fluorine reaction is preferentially substituted with fluorine atoms. What is necessary is just to set suitably.

  The fluorination reaction is carried out in the presence of a solvent. As the solvent, usually, the solvent contained in the potassium fluoride dispersion of the present invention can be used as it is, but in the fluorination reaction, the same or different solvent may be additionally used. Examples of such a solvent include the same solvents as those described above for the aprotic polar solvent.

  When the contact temperature is too low, the fluorination reaction is difficult to proceed, and when the contact temperature is too high, side reactions such as decomposition of raw materials and products may proceed. Therefore, the practical contact temperature is usually 20 to 250 ° C. Range.

  The fluorination reaction is carried out by contacting an organic compound having at least one group that can be nucleophilically substituted with a fluorine atom and the potassium fluoride dispersion of the present invention, and the mixing order thereof is not particularly limited. . For example, the potassium fluoride dispersion of the present invention may be added to an organic compound having at least one group that can be nucleophilically substituted with a fluorine atom under reaction temperature conditions, or vice versa. Moreover, you may adjust reaction temperature, after mixing both reagents simultaneously.

  The fluorination reaction may be carried out under normal pressure conditions or under pressurized conditions. In addition, the progress of the reaction can be confirmed by ordinary analysis means such as gas chromatography, high performance liquid chromatography, thin layer chromatography, NMR, IR and the like.

  After completion of the fluorination reaction, the resulting reaction mixture is subjected to crystallization treatment, distillation treatment, or the like, or extracted with water and / or an organic solvent immiscible with water, if necessary, to the resulting organic layer. The fluorine-containing organic compound can be isolated by performing a concentration treatment. The isolated fluorine-containing organic compound may be further purified by ordinary purification means such as distillation and column chromatography.

  Here, examples of the organic solvent immiscible with water include aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as pentane, hexane and heptane; halogenated carbonization such as dichloromethane, dichloroethane and chloroform. Hydrogen solvents; ether solvents such as diethyl ether, methyl tert-butyl ether and tetrahydrofuran; ester solvents such as ethyl acetate;

  Examples of the fluorine-containing organic compound thus obtained include 1-fluorobutane, 1-fluorocyclobutane, 1-fluoropentane, 1-fluorocyclopentane, 1,4-difluorobutane, 1-chloro-4-fluorobutane, 1-fluorobutane, Fluorohexane, 1,6-difluorohexane, 1-fluoroheptane, 2-fluoroheptane, 1-fluorooctane, 2-fluorooctane, benzyl fluoride, (1-fluoroethyl) benzene, 4-methoxybenzyl fluoride, 4-methylbenzyl fluoride, 3,4,5-trifluorobenzyl fluoride, 4-fluoronitrobenzene, 2-fluoronitrobenzene, 2,4-difluoronitrobenzene, 2,6-dichlorofluorobenzene, 3,5-difluoronitrobenzene , -Cyanofluorobenzene, 1-fluoro-2,4-dinitrobenzene, tetrafluoroterephthalonitrile, tetrafluoroisophthalonitrile, tetrafluoroorthophthalonitrile, 1,3-difluoro-4,6-dinitrobenzene, 2-fluoro Examples include quinoline, 2-fluoro-5-nitropyridine, 2-fluoro-5-trifluoromethylpyridine, 4,6-difluoro-5-chloro-pyrimidine, 4,5,6-trifluoropyrimidine and the like.

  Hereinafter, as a specific example of the fluorination method of the present invention, a method for producing tetrafluoroterephthalic acid difluoride will be further described, but the present invention is not limited thereto.

  When tetrachloroterephthalic acid dichloride is brought into contact with the potassium fluoride dispersion of the present invention, tetrafluoroterephthalic acid difluoride is usually obtained. The product is a useful compound that can be used as a raw material for medicines and agrochemicals (see, for example, Chinese Patent Publication No. 1458137 and Japanese Patent No. 2606892).

  Tetrachloroterephthalic acid dichloride can be produced, for example, by a known method described in Japanese Patent Publication No. 2-11571.

  The amount of use of the potassium fluoride dispersion of the present invention is usually an amount that contains 6 mol times or more of potassium fluoride with respect to tetrachloroterephthalic acid dichloride, and there is no particular upper limit. To preferably 10 mol times or less.

  The normal contact temperature is as described above, but is preferably in the range of 120 to 200 ° C.

  After completion of the fluorination reaction, tetrafluoroterephthalic acid difluoride can be isolated by a normal isolation operation such as distillation under reduced pressure. The obtained tetrafluoroterephthalic acid difluoride may be further purified by an ordinary purification method such as rectification.

  Moreover, tetrafluoroterephthalic acid diester can also be produced by reacting the obtained tetrafluoroterephthalic acid difluoride with alcohol. Hereinafter, this reaction may be described as an esterification reaction.

  Tetrafluoroterephthalic acid difluoride may be used after being isolated from the mixture obtained by the fluorination reaction, or the mixture obtained by the fluorination reaction may be used as it is.

  Examples of the alcohol include alcohols having 1 to 6 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, and cyclohexanol.

（式中、Ｒ’は上記と同一の意味を表す。）
で示されるテトラフルオロテレフタル酸ジエステルが得られる。 As alcohol, for example, formula (1)
R'OH (1)
(In the formula, R ′ represents an alkyl group having 1 to 6 carbon atoms.)
When the alcohol represented by formula (2) is used,

(In the formula, R ′ represents the same meaning as described above.)
A tetrafluoroterephthalic acid diester represented by the following formula is obtained.

  Examples of the alkyl group having 1 to 6 carbon atoms represented by R include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n- Examples include a linear, branched or cyclic alkyl group such as a pentyl group, a cyclopentyl group, and a cyclohexyl group.

  The amount of alcohol used is not particularly limited, and an excess amount may be used also as a solvent, but it is usually in the range of 2 to 50 mol times with respect to tetrafluoroterephthalic acid difluoride.

  When the mixture after fluorination reaction is used as it is as tetrafluoroterephthalic acid difluoride, it can be carried out without newly using an organic solvent, but when an isolated one is used, it can be used in the presence of the organic solvent. It is preferable to carry out. Examples of the organic solvent include aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as pentane, hexane and heptane; halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform; diethyl ether, And ether solvents such as methyl tert-butyl ether; ester solvents such as ethyl acetate; The amount of the organic solvent used is not particularly limited.

  The esterification reaction is carried out by mixing tetrafluoroterephthalic acid difluoride and alcohol, if necessary, in the presence of an organic solvent, and the mixing order is not particularly limited.

  The temperature of esterification reaction is not specifically limited, Usually, it is the range of 0-100 degreeC.

  The esterification reaction is usually performed under normal pressure conditions, but may be performed under pressurized conditions. The progress of the reaction can be confirmed by ordinary analytical means such as gas chromatography or liquid chromatography.

  After completion of the esterification reaction, tetrafluoroterephthalic acid diester can be isolated by subjecting the reaction mixture to the isolation means exemplified below. In addition, since inorganic salts, such as potassium chloride, usually precipitate in the reaction mixture, it can be subjected to an isolation treatment after removing the inorganic salt by performing a filtration treatment if necessary.

<Example of isolation means 1>
For example, tetrafluoroterephthalic acid diester can be precipitated as crystals by concentrating the reaction mixture and mixing the resulting residue with water. If such crystals are collected by filtration, tetrafluoroterephthalic acid diester can be isolated.

<Isolation Example 2>
For example, the tetrafluoroterephthalic acid diester can be taken out as an organic layer by mixing the reaction mixture and water in the presence of an organic solvent immiscible with water, if necessary, and performing a liquid separation treatment. If the organic layer is concentrated, tetrafluoroterephthalic acid diester can be isolated. Here, examples of the organic solvent immiscible with water include aromatic hydrocarbon solvents such as toluene, xylene and chlorobenzene; aliphatic hydrocarbon solvents such as pentane, hexane and heptane; halogenated carbonization such as dichloromethane, dichloroethane and chloroform. Examples thereof include hydrogen solvents; ether solvents such as diethyl ether and methyl tert-butyl ether; ester solvents such as ethyl acetate; and the amount used is not particularly limited.

  The isolated tetrafluoroterephthalic acid diester may be further purified by ordinary purification means such as crystallization and column chromatography.

  Examples of the tetrafluoroterephthalic acid diester thus obtained include dimethyl 2,3,5,6-tetrafluoroterephthalate, diethyl 2,3,5,6-tetrafluoroterephthalate, and 2,3,5,6-tetrafluoro. Di (n-propyl) terephthalate, diisopropyl 2,3,5,6-tetrafluoroterephthalate, di (n-butyl) 2,3,5,6-tetrafluoroterephthalate, 2,3,5,6- And tetrafluoroterephthalic acid di (tert-butyl).

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited by these Examples.

Example 1
A 500 ml flask equipped with a reflux condenser was charged with 30 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) and 400 g of methanol, and heated to reflux for 30 minutes. The potassium fluoride was completely dissolved. 100 g of toluene was added to the solution, and 200 g of a methanol / toluene mixture was distilled off at 90 to 100 ° C. under normal pressure. Further, 100 g of toluene was added to the flask, and 200 g of a methanol / toluene mixture was distilled off. Next, 110 g of sulfolane was added to the flask, the temperature was raised to 130 ° C., and the methanol / toluene mixture was distilled off. After the temperature was raised to 140 ° C. and almost no distillate was discharged, the pressure was reduced to 6 kPa at the same temperature, and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 22 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 145 ° C., and incubated and stirred for 3 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. When a part of the toluene solution was sampled and analyzed using a gas chromatograph mass spectrometer, 2,3,5,6-tetrafluoroterephthalic acid difluoride was obtained as the main product, and the raw material had disappeared. confirmed. To the reaction solution, 15 g of methanol was added dropwise, and the mixture was stirred at room temperature for 12 hours while removing hydrogen fluoride gas by-produced using nitrogen gas to the outside of the flask. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and the washing solution were combined, and after adding 100 g of water, 300 mg of potassium carbonate was added to adjust the pH of the aqueous layer to 7. The organic layer obtained by separating the mixture was analyzed by gas chromatography internal standard method to determine the yield.
Yield of dimethyl 2,3,5,6-tetrafluoroterephthalate: 88%
Yield of dimethyl 2,3,5-trifluoro-6-chloroterephthalate: 8%
Yield of difluoro and dimethyl dichloroterephthalate (total of three isomers): 5%

Example 2
A 200 ml flask equipped with a reflux condenser was charged with 110 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 30 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 350 g of methanol. After the whole amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled off, 50 g of toluene was added, and the methanol / toluene mixture was distilled off. After almost no distillate came out, the pressure was reduced to 6 kPa at the same temperature, and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 22 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 145 ° C., and incubated and stirred for 3.5 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. 15 g of methanol was added dropwise, and the mixture was stirred at room temperature for 12 hours while removing by-product hydrogen fluoride gas from the flask. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and the washing solution were combined, and after adding 100 g of water, 400 mg of potassium carbonate was added to adjust the pH of the aqueous layer to 7. The mixture was separated, and the obtained organic layer was concentrated by an evaporator (decompression degree: 10 to 100 kPa, water bath: 30 to 50 ° C.) to obtain an oily residue. When the residue and 110 g of water were mixed, crystals were precipitated from the mixture. Toluene contained in the residue was removed azeotropically by distilling off about 5 g of water from the mixture using an evaporator (decompression degree: 10-100 kPa, water bath: 30-50 ° C.). After cooling to room temperature, the crystals were filtered and dried to obtain 17.2 g of light yellow crystals. When the crystals were analyzed by a gas chromatography area percentage method, the purity of dimethyl 2,3,5,6-tetrafluoroterephthalate was 93%.
Isolated yield: 93%.

Example 3
A 200 ml flask equipped with a reflux condenser was charged with 110 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 30 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 350 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 22 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 145 ° C., and incubated and stirred for 3.5 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. 15 g of methanol was added dropwise, and the mixture was stirred at room temperature for 12 hours while removing by-product hydrogen fluoride gas from the flask. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and the washing solution were combined, 100 g of water was added, 600 mg of potassium carbonate was added, and the pH of the aqueous layer was adjusted to 7. The mixture was separated, and the obtained organic layer was concentrated by an evaporator (decompression degree: 10 to 100 kPa, water bath: 30 to 50 ° C.) to obtain an oily residue. When the residue and 110 g of water were mixed, crystals were precipitated from the mixture. Toluene contained in the residue was removed azeotropically by distilling off about 5 g of water from the mixture using an evaporator (decompression degree: 10-100 kPa, water bath: 30-50 ° C.). After cooling to room temperature, the crystals were filtered and dried to obtain 17.4 g of light yellow crystals. When the crystals were analyzed by gas chromatography area percentage method, the purity of dimethyl 2,3,5,6-tetrafluoroterephthalate was 92%.
Isolated yield: 93%.

Example 4
A 50 ml flask equipped with a reflux condenser was charged with 480 mg of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) and 5 g of methanol and heated to reflux for 30 minutes. The potassium fluoride was completely dissolved. To the solution, 5 g of toluene was added, and the methanol / toluene mixture was distilled off at 90 to 100 ° C. under normal pressure. After almost no methanol was distilled, 1.7 g of dimethyl sulfone was added, the temperature was raised to 140 ° C., and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 340 mg of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 145 ° C., and kept warm and stirred for 2 hours while stirring at the same temperature. After the reaction, the reaction mixture was cooled to room temperature, 10 g of methanol was added, and the precipitated crystals were pulverized, followed by stirring at room temperature for 1 hour. 10 g of ethyl acetate was added and analyzed by gas chromatography internal standard method to determine the yield.
Yield of dimethyl 2,3,5,6-tetrafluoroterephthalate: 75%
Yield of dimethyl 2,3,5-trifluoro-6-chloroterephthalate: 12%
Yield of difluoro and dimethyl dichloroterephthalate (total of three isomers): 11%

Comparative Example 1
To a 50 ml flask equipped with a reflux condenser, 960 mg of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) and 2 g of methanol were added and refluxed for 30 minutes, but potassium fluoride was not completely dissolved. . 3 g of sulfolane and 3 g of toluene were added to the resulting mixture, and the methanol / toluene mixture was distilled off at 130 ° C. under normal pressure. After almost no methanol was distilled, the temperature was raised to 140 ° C. and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 680 mg of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 150 ° C., and kept warm and stirred for 4 hours while stirring at the same temperature. After the reaction, the mixture was cooled to room temperature, 5 g of methanol was added, and the mixture was stirred at room temperature for 1 hour. 10 g of ethyl acetate was added and analyzed by gas chromatography internal standard method to determine the yield.
Yield of dimethyl 2,3,5,6-tetrafluoroterephthalate: 0%
Yield of dimethyl 2,3,5-trifluoro-6-chloroterephthalate: 0%
Yield of dimethyl difluoro-dichloroterephthalate (total of three isomers): 0%
Yield of dimethyl 2-fluoro-3,5,6-trichloroterephthalate: 1%
Yield of dimethyl 2,3,5,6-tetrachloroterephthalate: 98%

Example 5
A 50 ml flask equipped with a reflux condenser was charged with 25 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 4.5 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 60 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, 10 g of toluene was added, and the methanol / toluene mixture was distilled off. After the distillate almost did not come out at normal pressure, the pressure was reduced to 6 kPa at the same temperature, and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5 g of 2,4-dichloronitrobenzene. The resulting mixture was heated to 180 ° C., and kept warm and stirred for 10 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Yield of 2,4-difluoronitrobenzene: 92%
Yield of fluoro and chloronitrobenzene (total of two isomers): 8%

Example 6
A 50 ml flask equipped with a reflux condenser was charged with 25 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 4.5 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 60 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion. When the residual amount of methanol in the potassium fluoride dispersion was analyzed by a gas chromatography area comparison method, it was 0.02% by weight or less based on sulfolane.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5 g of 2,4-dichloronitrobenzene. The resulting mixture was heated to 180 ° C., and kept warm and stirred for 8 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Yield of 2,4-difluoronitrobenzene: 90%
Yield of fluoro and chloronitrobenzene (total of two isomers): 10%

Example 7
A 50 ml flask equipped with a reflux condenser was charged with 25 g of dimethyl sulfoxide and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 2.8 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 40 g of methanol. After all the potassium fluoride / methanol solution was charged and almost no methanol was distilled off, the pressure was reduced to 6 kPa at the same temperature to further distill off the methanol and 10 g of dimethyl sulfoxide to disperse the potassium fluoride. A liquid was obtained.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5 g of 4-chloronitrobenzene. The resulting mixture was heated to 185 ° C., and kept warm and stirred for 4 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
4-Fluoronitrobenzene yield: 97%
Recovery rate of 4-chloronitrobenzene: 3%

Example 8
A 50 ml flask equipped with a reflux condenser was charged with 25 g of N-methyl-2-pyrrolidone and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 2.8 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 40 g of methanol. After all the potassium fluoride / methanol solution was charged and methanol was hardly distilled off, the pressure was reduced to 6 kPa at the same temperature to further distill off methanol and 10 g of N-methyl-2-pyrrolidone. A potassium fluoride dispersion was obtained.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5.5 g of benzyl bromide. The resulting mixture was heated to 120 ° C., and kept warm and stirred for 4 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Benzyl fluoride yield: 93%
Benzyl bromide recovery: 3%

Example 9
A 500 ml flask was charged with 350 g of methanol and 29.0 g of potassium hydroxide and dissolved by stirring at room temperature. To this solution, 22.0 g of 47% by weight hydrofluoric acid was added dropwise with stirring while maintaining the internal temperature at 30 ° C. or lower. The resulting mixture was a homogeneous solution.
A 200 ml flask equipped with a reflux condenser was charged with 110 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol and water were distilled off while dropping the above potassium fluoride / methanol solution. After all the potassium fluoride / methanol solution was charged and methanol and water were hardly distilled, 10 g of toluene was added, and the methanol / water / toluene mixture was distilled off. After the distillate almost disappeared, the pressure was reduced to 6 kPa at the same temperature, and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 22 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to 145 ° C., and kept warm and stirred for 4 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. 15 g of methanol was added dropwise, and the mixture was stirred at room temperature for 12 hours while removing by-product hydrogen fluoride gas from the flask. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and the washing solution were combined, 100 g of water was added, 600 mg of potassium carbonate was added, and the pH of the aqueous layer was adjusted to 7. The mixture was separated, and the obtained organic layer was concentrated by an evaporator (decompression degree: 10 to 100 kPa, water bath: 30 to 50 ° C.) to obtain an oily residue. When the residue and 110 g of water were mixed, crystals were precipitated from the mixture. Toluene contained in the residue was removed azeotropically by distilling off about 5 g of water from the mixture using an evaporator (decompression degree: 10-100 kPa, water bath: 30-50 ° C.). After cooling to room temperature, the crystals were filtered and dried to obtain 17.6 g of light yellow crystals. When the crystals were analyzed by gas chromatography area percentage method, the purity of dimethyl 2,3,5,6-tetrafluoroterephthalate was 87%.
Isolated yield: 89%.

Example 10
A 200 ml flask was charged with 53 g of methanol and 4.4 g of potassium hydroxide, and stirred and dissolved at room temperature. To this solution, 3.3 g of 47% by weight hydrofluoric acid was added dropwise with stirring while maintaining the internal temperature at 30 ° C. or lower. The resulting mixture was a homogeneous solution.
A 50 ml flask equipped with a reflux condenser was charged with 25 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol and water were distilled off while dropping the above potassium fluoride / methanol solution. After the potassium fluoride / methanol solution was completely charged and methanol and water almost ceased to distill, methanol and water were further distilled off at 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion. .
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5.0 g of 2,4-dichloronitrobenzene. The resulting mixture was heated to 180 ° C., and kept warm and stirred for 10 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Yield of 2,4-difluoronitrobenzene: 89%
Yield of fluoro and chloronitrobenzene (total of two isomers): 9%

Example 11
A 200 ml flask was charged with 35 g of methanol and 2.7 g of potassium hydroxide and dissolved by stirring at room temperature. To this solution, 2.0 g of 47% by weight hydrofluoric acid was added dropwise with stirring while maintaining the internal temperature at 30 ° C. or lower. The resulting mixture was a homogeneous solution.
A 50 ml flask equipped with a reflux condenser was charged with 25 g of N-methyl-2-pyrrolidone and heated to an internal temperature of 140 ° C. Methanol and water were distilled off while dropping the above potassium fluoride / methanol solution. After the entire amount of potassium fluoride / methanol solution was charged and methanol and water almost distilled, the pressure was reduced to 6 kPa at the same temperature, and methanol and water were further distilled off, and 10 g of N-methyl-2-pyrrolidone was distilled. By leaving, a potassium fluoride dispersion was obtained.
The potassium fluoride dispersion was cooled to 100 ° C. and mixed with 5.5 g of benzyl bromide. The resulting mixture was heated to 120 ° C., and kept warm and stirred for 4 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 100 g of toluene was added, and then cooled to room temperature. The precipitated crystals were separated by filtration, and the crystals were washed with 10 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Benzyl fluoride yield: 94%
Benzyl bromide recovery: 3%

Example 12
A 500 ml flask equipped with a reflux condenser was charged with 75 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 17.8 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 209 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion.
A 120 ml autoclave reactor was charged with 10.3 g of 4,5,6-trichloropyrimidine, and the above potassium fluoride dispersion was added and sealed. After adjusting the internal pressure to 0.5 MPa at room temperature using nitrogen, the mixture was heated to an internal temperature of 220 ° C. and reacted at the same temperature for 10 hours. The internal pressure after the reaction was 0.82 MPa at 220 ° C. The reaction mixture was cooled to room temperature, and the supernatant was analyzed by gas chromatography internal standard method to determine the yield.
Yield of 4,5,6-trifluoropyrimidine: 50%
Yield of 4,6-difluoro-5-chloro-pyrimidine: 26%

Example 13
A 200 ml flask equipped with a reflux condenser was charged with 70 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 13.6 g of potassium fluoride (purchased from Aldrich; spray dried product; product code 307599) and 1.0 g of water in 180 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 140 ° C. and mixed with 10 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to an internal temperature of 145 ° C., and kept warm and stirred for 3 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 20 g of toluene was added, and then cooled to room temperature. Methanol 9.4g was dripped at the reaction liquid, and it stirred at room temperature for 1 hour, removing the hydrogen fluoride gas byproduced using nitrogen gas out of a flask. The precipitated crystals were filtered off and washed with 50 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Yield of dimethyl 2,3,5,6-tetrafluoroterephthalate: 82%
Yield of dimethyl 2,3,5-trifluoro-6-chloroterephthalate: 7%
Yield of dimethyl difluoro-dichloroterephthalate (total of three isomers): 5%

Comparative Example 2
To a 200 ml flask equipped with a reflux condenser, 13.6 g of potassium fluoride (purchased from Aldrich; spray-dried product; product code 307599) and 1.0 g of water were added, and 20 g of methanol was further added and refluxed for 30 minutes. Potassium fluoride did not dissolve completely. To the resulting mixture, 70 g of sulfolane and 22 g of toluene were added, and the methanol / toluene mixture was distilled off at 130 ° C. under normal pressure. After almost no methanol was distilled, the temperature was raised to 140 ° C. and toluene was distilled off to obtain a potassium fluoride dispersion.
The potassium fluoride dispersion was cooled to 140 ° C. and mixed with 10 g of tetrachloroterephthalic acid dichloride. The resulting mixture was heated to an internal temperature of 145 ° C., and kept warm and stirred for 3 hours while stirring at the same temperature. After the reaction, the mixture was cooled to 100 ° C., 20 g of toluene was added, and then cooled to room temperature. Methanol 9.4g was dripped at the reaction liquid, and it stirred at room temperature for 1 hour, removing the hydrogen fluoride gas byproduced using nitrogen gas out of a flask. The precipitated crystals were filtered off and washed with 50 g of toluene. The filtrate and washing solution were combined, and the resulting solution was analyzed by gas chromatography internal standard method to determine the yield.
Yield of dimethyl 2,3,5,6-tetrafluoroterephthalate: 1%
Yield of dimethyl 2,3,5-trifluoro-6-chloroterephthalate: 10%
Yield of dimethyl difluoro-dichloroterephthalate (total of three isomers): 48%
Yield of dimethyl 2-fluoro-3,5,6-trichloroterephthalate: 10%
Yield of dimethyl 2,3,5,6-tetrachloroterephthalate: 4%

Example 14
A 500 ml flask equipped with a reflux condenser was charged with 300 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 58 g of potassium fluoride (purchased from Aldrich; spray dried product; product code 307599) and 3 g of water in 772 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion.
The number of particles of potassium fluoride in the obtained potassium fluoride dispersion and the volume-converted particle size distribution were measured using an inline particle size distribution / particle number change measurement system (FBRM) “D600L” manufactured by Laser Sensor Technology. The particle size distribution data was acquired using the data processing system attached to “D600L”. The obtained particle size distribution data is shown in FIG. The volume conversion average particle size was 19.7 μm.
After the measurement, the potassium fluoride dispersion was filtered, and the obtained potassium fluoride particles were washed with 100 g of ethyl acetate and dried under the conditions of 80 ° C. and 1.3 kPa. The dried potassium fluoride particles were pretreated by a Pt—Pd vapor deposition method, using a field emission scanning electron microscope (FE-SEM) “S-800” manufactured by Hitachi, Ltd., under the condition of an acceleration voltage of 10 kV, When form observation was performed, the particle diameter of primary particles of potassium fluoride in the potassium fluoride dispersion was 0.1 to 5 μm. The results are shown in FIG. 5 and FIG. FIG. 5 is an SEM image with an imaging magnification of 2000 times, and FIG. 6 is an SEM image with an imaging magnification of 5000 times.

Comparative Example 3
To a 500 ml flask equipped with a reflux condenser, 83 g of potassium fluoride (purchased from Aldrich; spray-dried product; product code 307599) and 5 g of water were added, and 119 g of methanol was further added and refluxed for 30 minutes. It did not dissolve completely. To the resulting mixture, 300 g of sulfolane and 130 g of toluene were added, and the methanol / toluene mixture was distilled off at 130 ° C. under normal pressure. After almost no methanol was distilled, the temperature was raised to 140 ° C. and toluene was distilled off to obtain a potassium fluoride dispersion.
The number of particles of potassium fluoride in the obtained potassium fluoride dispersion and the volume-converted particle size distribution were measured using an inline particle size distribution / particle number change measurement system (FBRM) “D600L” manufactured by Laser Sensor Technology. The particle size distribution data was acquired using the data processing system attached to “D600L”. The obtained particle size distribution data is shown in FIG. The average particle diameter in terms of volume was 29.7 μm.
After the measurement, the potassium fluoride dispersion was filtered, and the obtained potassium fluoride particles were washed with 150 g of ethyl acetate and dried under the conditions of 80 ° C. and 1.3 kPa. The dried potassium fluoride particles were pretreated by a Pt—Pd vapor deposition method, using a field emission scanning electron microscope (FE-SEM) “S-800” manufactured by Hitachi, Ltd., under the condition of an acceleration voltage of 10 kV, Morphological observation was performed. The results are shown in FIG. FIG. 7 is an SEM image with an imaging magnification of 2000 times.

Comparative Example 4
Potassium fluoride (purchased from Aldrich; spray-dried product; product code 307599) was dispersed in sulfolane to prepare a potassium fluoride dispersion.
The number of particles of potassium fluoride in the obtained potassium fluoride dispersion and the volume-converted particle size distribution were measured using an inline particle size distribution / particle number change measurement system (FBRM) “D600L” manufactured by Laser Sensor Technology. The particle size distribution data was acquired using the data processing system attached to “D600L”. The obtained particle size distribution data is shown in FIG. The volume conversion average particle diameter was 127.2 μm.
After the measurement, the potassium fluoride dispersion was filtered, and the obtained potassium fluoride particles were washed with 150 g of ethyl acetate and dried under the conditions of 80 ° C. and 1.3 kPa. The dried potassium fluoride particles were pretreated by a Pt—Pd vapor deposition method, using a field emission scanning electron microscope (FE-SEM) “S-800” manufactured by Hitachi, Ltd., under the condition of an acceleration voltage of 10 kV, Morphological observation was performed. The results are shown in FIG. FIG. 8 is an SEM image with a photographing magnification of 1000 times.

Example 15
A 500 ml flask equipped with a reflux condenser was charged with 300 g of sulfolane and heated to an internal temperature of 140 ° C. Methanol was distilled off while dropwise adding a solution prepared by dissolving 58 g of potassium fluoride (purchased from Nacalai Tesque; product code 28611-95) in 772 g of methanol. After the entire amount of potassium fluoride / methanol solution was charged and methanol was hardly distilled, methanol was further distilled off under the condition of 160 ° C./2.7 kPa to obtain a potassium fluoride dispersion.
The number of particles of potassium fluoride in the obtained potassium fluoride dispersion and the volume-converted particle size distribution were measured using an inline particle size distribution / particle number change measurement system (FBRM) “D600L” manufactured by Laser Sensor Technology. The particle size distribution data was acquired using the data processing system attached to “D600L”. The obtained particle size distribution data is shown in FIG. The volume conversion average particle diameter was 20.2 μm.
After the measurement, the potassium fluoride dispersion was filtered, and the obtained potassium fluoride particles were washed with 150 g of ethyl acetate and dried under the conditions of 80 ° C. and 1.3 kPa. The dried potassium fluoride particles were pretreated by a Pt—Pd vapor deposition method, using a field emission scanning electron microscope (FE-SEM) “S-800” manufactured by Hitachi, Ltd., under the condition of an acceleration voltage of 10 kV, When form observation was performed, the particle diameter of primary particles of potassium fluoride in the potassium fluoride dispersion was 0.1 to 5 μm. The results are shown in FIG. 9 and FIG. FIG. 9 is an SEM image with an imaging magnification of 2000 times, and FIG. 10 is an SEM image with an imaging magnification of 5000 times.

It is a figure which shows the volume conversion particle size distribution of the potassium fluoride dispersion liquid obtained in Example 14. It is a figure which shows the volume conversion particle size distribution of the potassium fluoride dispersion liquid obtained by the comparative example 3. It is a figure which shows the volume conversion particle size distribution of the potassium fluoride dispersion liquid obtained by the comparative example 4. It is a figure which shows the volume conversion particle size distribution of the potassium fluoride dispersion liquid obtained in Example 15. It is a FE-SEM image (photographing magnification 2000 times) of the potassium fluoride particle in the potassium fluoride dispersion liquid obtained in Example 14. It is a FE-SEM image (photographing magnification 5000 times) of the potassium fluoride particle in the potassium fluoride dispersion liquid obtained in Example 14. It is a FE-SEM image (photographing magnification 2000 times) of the potassium fluoride particle in the potassium fluoride dispersion liquid obtained by the comparative example 3. 6 is an FE-SEM image (photographing magnification: 1000 times) of potassium fluoride particles in a potassium fluoride dispersion obtained in Comparative Example 4. FIG. 2 is an FE-SEM image (photographing magnification: 2000 times) of potassium fluoride particles in the potassium fluoride dispersion obtained in Example 15. FIG. 2 is an FE-SEM image (photographing magnification: 5000 times) of potassium fluoride particles in a potassium fluoride dispersion obtained in Example 15. FIG.

Claims (24)

A mixture comprising potassium fluoride and 5 to 50 times by weight of methanol is mixed with an aprotic organic solvent having a boiling point higher than that of methanol, and the resulting mixture is substantially fluorinated. A potassium fluoride dispersion composed of potassium and an aprotic organic solvent. The potassium fluoride dispersion according to claim 1, wherein the mixture comprising potassium fluoride and 5 to 50 times by weight of methanol is a solution in which potassium fluoride is completely dissolved in methanol. Potassium fluoride in the potassium fluoride dispersion has a primary particle size of 0.1 to 5 μm, and a part or all of the particles aggregate to form particles with a volume-converted average particle size of 5 to 25 μm. The potassium fluoride dispersion according to claim 2, which is potassium fluoride. A mixture comprising potassium fluoride and 5 to 50 times by weight of methanol is mixed with an aprotic organic solvent having a boiling point higher than that of methanol, and the resulting mixture is concentrated. A method for producing a potassium fluoride dispersion comprising potassium fluoride and an aprotic organic solvent. And a step of concentrating the mixture in a non-protic organic solvent having a boiling point higher than that of methanol while adding a mixture comprising potassium fluoride and 5 to 50 times its methanol by weight. 4. The production method according to 4. Potassium fluoride in the potassium fluoride dispersion has a primary particle size of 0.1 to 5 μm, and a part or all of the particles aggregate to form particles with a volume-converted average particle size of 5 to 25 μm. The production method according to claim 5, which is potassium fluoride. The production method according to any one of claims 4 to 6, wherein the mixture comprising potassium fluoride and methanol of 5 to 50 times by weight thereof is a solution in which potassium fluoride is completely dissolved in methanol. The production method according to claim 4, wherein the aprotic organic solvent having a boiling point higher than that of methanol is an aprotic polar solvent. The production method according to claim 8, wherein the aprotic polar solvent is a sulfone solvent or a sulfoxide solvent. The production according to any one of claims 4 to 9, wherein the mixture comprising potassium fluoride and 5 to 50 times by weight of methanol is a mixture obtained by mixing potassium hydroxide and hydrogen fluoride in methanol. Method. The method according to claim 10, wherein the hydrogen fluoride is hydrofluoric acid. Production of a fluorine-containing organic compound comprising contacting an organic compound having at least one group that can be nucleophilically substituted with a fluorine atom with the potassium fluoride dispersion according to any one of claims 1 to 3. Method. An organic compound having at least one group that can be nucleophilically substituted with a fluorine atom,
The production method according to claim 12, which is an organic compound in which at least one hydrogen atom on the optionally substituted aliphatic hydrocarbon compound is substituted with a group capable of nucleophilic substitution with a fluorine atom. An organic compound having at least one group that can be nucleophilically substituted with a fluorine atom,
The production method according to claim 12, which is an organic compound in which at least one hydrogen atom on the optionally substituted aromatic hydrocarbon compound is substituted with a group capable of nucleophilic substitution with a fluorine atom. An organic compound having at least one group that can be nucleophilically substituted with a fluorine atom,
The production method according to claim 12, which is an organic compound in which at least one hydrogen atom on the optionally substituted heteroaromatic compound is nucleophilically substituted with a group capable of being substituted with a fluorine atom. A group that can be nucleophilically substituted with a fluorine atom is a chlorine atom, a bromine atom, an iodine atom, a nitro group, a sulfo group, an optionally substituted alkylsulfonyloxy group, an optionally substituted arylsulfonyloxy group, The production method according to claim 12, which is an optionally substituted alkylcarbonyloxy group or an optionally substituted arylcarbonyloxy group. A method for producing tetrafluoroterephthalic acid difluoride, comprising bringing tetrachloroterephthalic acid dichloride into contact with the potassium fluoride dispersion according to any one of claims 1 to 3. The manufacturing method of the tetrafluoro terephthalic-acid diester which makes the tetrafluoro terephthalic-acid difluoride obtained by the manufacturing method of Claim 17 react with alcohol. A method for producing 4,5,6-trifluoropyrimidine, comprising contacting 4,5,6-trichloropyrimidine with the potassium fluoride dispersion according to any one of claims 1 to 3. Use of the potassium fluoride dispersion according to any one of claims 1 to 3 for fluorinating an organic compound. Use of the potassium fluoride dispersion obtained by the production method according to any one of claims 4 to 11 for fluorinating an organic compound. A method for fluorinating an organic compound, comprising contacting an organic compound having at least one group that can be nucleophilically substituted with a fluorine atom with the potassium fluoride dispersion according to any one of claims 1 to 3. . An organic compound having at least one group that can be nucleophilically substituted with a fluorine atom is brought into contact with a potassium fluoride dispersion obtained by the production method according to any one of claims 4 to 11. Fluorination method for organic compounds. A mixture comprising potassium fluoride and 5 to 50 times by weight of methanol is mixed with an aprotic organic solvent having a boiling point higher than that of methanol, and the resulting mixture is substantially fluorinated. A composition for fluorination reaction comprising potassium and an aprotic organic solvent.

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