Method for producing fluorine-containing compound

Abstract

To provide a method for producing fluorine-containing compounds using a nucleophilic substitution fluorination reaction that can accelerate reactions without substantially using organic solvents, is applicable to a wide variety of substrates, and enables reactions to proceed with high yields, and to provide a method for producing fluorine-containing compounds using a nucleophilic substitution fluorination reaction that can accelerate reactions without substantially using organic solvents, is applicable to a wide variety of substrates, and enables reactions to proceed with high yields without requiring difficult-to-handle or expensive reagents, and to provide a method for producing fluorine-containing compounds using a nucleophilic substitution fluorination reaction that can proceed even when at least one, preferably two or more of starting materials are solids without substantially using organic solvents, can accelerate the reaction, is applicable to a wide variety of substrates, and enables reaction to proceed with high yields.SOLUTION: There is provided a method for producing fluorine-containing compounds, wherein a substrate containing a compound represented by formula (I); A1-Xm...(I), wherein A1 represents any one of an m-valent aromatic hydrocarbon group which may have substituents, an m-valent aromatic heterocyclic group which may have substituents, an m-valent heterocyclic group which may have substituents, an m-valent aliphatic hydrocarbon group which may have substituents, or an m-valent unsaturated aliphatic hydrocarbon group which may have substituents; X represents the leaving group in a nucleophilic substitution reaction, and when there are multiple X's, they may be the same or different; and m is an integer of 1 or greater, and a fluorinating agent are reacted by a mechanochemical method under conditions where the amount of solvent used is 0.8 mL or less per 1 mmol of the total amount of the substrate and fluorinating agent.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a method for producing a fluorine-containing compound. [Background technology]

[0002] Fluorine-containing compounds, especially aromatic fluorine compounds, play an important role in the development of functional materials such as pharmaceuticals, agricultural chemicals, liquid crystal compounds, organic electroluminescent compounds, organic thin-film solar cells, polymer compounds, oligomers, electrolytes, coloring materials, energy ray absorbing materials, information recording materials, wavelength conversion materials, indicator materials, sensor materials, organic light-emitting diodes (OLEDs), and organic semiconductor materials.

[0003] As a method for producing fluorine-containing compounds, a method using various organic compounds as raw materials and hydrogen fluoride or the like as a fluorinating agent has been used. In recent years, a method for introducing fluorine atoms into an organic compound using a nucleophilic substitution reaction, for example, an aromatic nucleophilic substitution reaction, has been known. Among these, the aromatic nucleophilic substitution fluorination reaction using a fluorine anion as a nucleophile is an important synthetic reaction as a method for fluorinating electron-deficient aromatic compounds. In general, the aromatic nucleophilic substitution fluorination reaction uses a reagent (fluorinating agent) having a fluorine anion and dissolves the reactants in a highly polar and high-boiling organic solvent to carry out the reaction.

[0004] Non-Patent Document 1 discloses that an aromatic nucleophilic substitution fluorination reaction is carried out using anhydrous tetramethylammonium fluoride obtained by reacting potassium fluoride with tetramethylammonium chloride as a fluorinating agent. Non-Patent Document 2 discloses that potassium fluoride is used in combination with an additive promoter such as tributylmethylammonium or tetraphenylphosphonium chloride to carry out a nucleophilic substitution fluorination reaction of tri- and penta-substituted picolinic acid ester substrates in dimethyl sulfoxide under heating. Non-Patent Document 3 describes that an aromatic nucleophilic substitution fluorination reaction is carried out in dimethylformamide at room temperature using anhydrous tetramethylammonium fluoride as a fluorinating agent. Patent Document 1 discloses a method for substituting chlorine or bromine in an aromatic halide with fluorine, in which dimethylacetamide is used as a solvent under high temperature and high pressure conditions and an alkali fluoride is reacted therewith. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] YYSee, et al, Acc. Chem. Res.,2020,Vol.53,No.10, 2372-2383. [Non-patent document 2] LJAllen, et al, Org. Process.Res. Dev. 2014, Vol.18, No.8,1045-1054. [Non-patent document 3] SDSchimler, et al, J. Org. Chem.2015, Vol.80, No.24, 12137-12145. [Patent documents]

[0006] [Patent Document 1] Special Publication No. 55-10573 Summary of the Invention [Problem to be solved by the invention]

[0007] In the production method of a fluorine-containing compound, when a fluorinating agent having toxicity or corrosive properties such as hydrogen fluoride is used, special equipment and techniques are required, which poses the problem of poor handling. Furthermore, when an ammonium fluoride salt is used as a fluorinating agent in a method for producing a fluorine-containing compound, the reaction must be carried out at high temperature for a long time under solution reaction conditions using a highly polar, high-boiling organic solvent, leaving room for improvement in terms of production efficiency, production cost, burden on the working environment, burden on the global environment, treatment of the organic solvent after use, separation of the highly polar, high-boiling organic solvent, decrease in purity of the reaction product, purification efficiency, etc. Furthermore, there is also room for improvement in terms of handleability and practicality, such as the need for strict dehydration conditions when using a fluorinating agent.

[0008] Organic synthesis methods in which reactant materials are directly contacted without using organic solvents have attracted attention as environmentally friendly synthesis methods that do not use organic solvents, and are of interest both academically and industrially. However, there have been no reports to date of methods for producing fluorine-containing compounds by nucleophilic substitution fluorination reactions without substantially using organic solvents.

[0009] One of the problems to be solved by the present invention is to provide a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which method is capable of increasing the reaction rate without substantially using an organic solvent, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield. One of the problems to be solved by the present invention is to provide a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which can accelerate the reaction substantially without using an organic solvent, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield without using reagents that are difficult to handle or expensive. One of the problems to be solved by the present invention is to provide a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which method is capable of proceeding with the reaction substantially without using an organic solvent even when at least one, preferably two or more, of the starting materials are solids, is capable of accelerating the reaction, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield. [Means for solving the problem]

[0010] As a result of extensive investigations, the present inventors have found that the above-mentioned problems can be solved by carrying out an aromatic nucleophilic substitution fluorination reaction by a mechanochemical method under specific conditions, and have thus completed the present invention. That is, the present invention relates to the following method for producing a fluorine-containing compound. [Term 1] Formula (I); A 1 -X m (I) In formula (I), A 1 represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted m-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different, and m is an integer of 1 or greater. A method for producing a fluorinated compound, comprising reacting a substrate containing a compound represented by the formula (I) with a fluorinating agent by a mechanochemical method under conditions in which the amount of solvent used is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent. [Item 2] The method for producing a fluorine-containing compound according to Item 1, wherein the reaction is carried out in the presence of a quaternary ammonium salt. [Item 3] The method for producing a fluorine-containing compound according to Item 1 or 2, wherein the fluorinating agent comprises one or more alkali metal fluorides and / or one or more alkaline earth metal fluorides. [Section 4] The fluorine-containing compound has the formula (II); X m-n -A 1 -F n (II) In formula (II), A 1represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted n-valent aliphatic hydrocarbon group, and an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different; m is an integer of 1 or more; n is the number of F and is an integer of 1 or more; and mn is 0 or a number of 1 or more. [Effects of the Invention]

[0011] The present invention provides a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which can accelerate the reaction substantially without using an organic solvent, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield. The present invention provides a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which can accelerate the reaction substantially without using an organic solvent, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield without using reagents that are difficult to handle or expensive. The present invention provides a method for producing a fluorine-containing compound using a nucleophilic substitution fluorination reaction, which is capable of proceeding with the reaction substantially without using an organic solvent even when at least one, preferably two or more, of the starting materials is solid, is capable of accelerating the reaction, is applicable to a wide variety of substrates, and allows the reaction to proceed in high yield.

[0012] In the method for producing a fluorine-containing compound of the present invention, even when an inexpensive reagent such as potassium fluoride is used, the reaction can be accelerated, the reaction can be completed in a short time, and the reaction can proceed in a high yield. Furthermore, the method for producing a fluorine-containing compound of the present invention can substantially eliminate the use of organic solvents, does not require high-temperature heating during the reaction, can avoid the use of dangerous raw materials that are toxic, corrosive, etc., can facilitate the desolvation process during the production of the reaction product without using strict dehydration conditions, and can suppress a decrease in the purity of the reaction product, thereby being advantageous in terms of cost, risk associated with the reaction, and the environment. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 2 shows the results of solid-state NMR measurement of the mechanochemical reaction product of a fluorinating agent and a quaternary ammonium compound in Reference Example 1. [Figure 2] FIG. 2 shows the results of powder X-ray diffraction measurement of the mechanochemical reaction product of a fluorinating agent and a quaternary ammonium compound in Reference Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0014] The method for producing a fluorine-containing compound of the present invention comprises reacting a compound represented by formula (I); A 1 -X m (I) In formula (I), A 1 represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted m-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different, and m is an integer of 1 or greater. This is a method for producing a fluorinated compound, comprising reacting a substrate containing a compound represented by the formula (I) with a fluorinating agent by a mechanochemical method under conditions in which the amount of solvent used is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent. The method for producing a fluorine-containing compound of the present invention can be a method for producing a fluorine-containing compound in which the reaction is carried out in the presence of a quaternary ammonium salt. The method for producing a fluorine-containing compound of the present invention can be a method for producing a fluorine-containing compound using a fluorinating agent containing one or more alkali metal fluorides and / or one or more alkaline earth metal fluorides.

[0015] In the method for producing a fluorine-containing compound of the present invention, the fluorine-containing compound is a compound represented by the formula (II); X m-n -A 1 -F n (II) In formula (I), A 1 represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted n-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different; m is an integer of 1 or more; n is the number of F and is an integer of 1 or more; and mn is 0 or a number of 1 or more. The method for producing a fluorine-containing compound of the present invention will be described in detail below.

[0016] [Substrate] In the method for producing a fluorine-containing compound of the present invention, a compound represented by the formula (I); A 1 -X m (I) In formula (I), A 1represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted m-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different, and m is an integer of 1 or more. A substrate is used that contains a compound in which

[0017] In the compound represented by formula (I) contained in the substrate used in the method for producing a fluorine-containing compound of the present invention, the number of leaving groups in a nucleophilic substitution reaction can be m as X. When the number of leaving groups, m, is an integer of 2 or more, A in formula (I) 1 The valence of A corresponds to the number of leaving groups. For example, when m=2, A 1 is divalent, and when m=4, A 1 becomes tetravalent.

[0018] In the method for producing a fluorine-containing compound of the present invention, a substrate containing one or more compounds represented by formula (I) can be used. In the method for producing a fluorine-containing compound of the present invention, a commercially available product can be used as the substrate containing the compound represented by formula (I) either as is or after purification.

[0019] <A in formula (I) 1 Base> A 1 The number of carbon atoms in the m-valent aromatic hydrocarbon group, which may have a substituent, in the group is not particularly limited and is, for example, 6 to 60, preferably 6 to 40, and more preferably 6 to 30. In the m-valent aromatic hydrocarbon group, m is an integer of 1 or more, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 4. A 1In the m-valent aromatic hydrocarbon group which may have a substituent in the group, examples of the monovalent aromatic hydrocarbon group where m=1 include a phenyl group, a naphthyl group, an anthracenyl group (or anthracene group), a phenanthrenyl group (or phenanthrene group), a biphenyl group, a terphenyl group, a pyrenyl group (or pyrene group), a perylenyl group (or perylene group), a triphenylenyl group (or triphenylene group), a fluorenyl group, and a spirobifluorenyl group. Also, A 1 In the m-valent aromatic hydrocarbon group which may have a substituent in the group, examples of the m-valent aromatic hydrocarbon group where m is an integer of 2 or more include those in which m-1 hydrogen atoms have been removed from the aromatic ring in the above-mentioned monovalent aromatic hydrocarbon group.

[0020] A 1 The number of carbon atoms in the m-valent aromatic heterocyclic group which may have a substituent in the group is not particularly limited, and is, for example, 4 to 60, preferably 4 to 40, and more preferably 4 to 30. A 1 In the m-valent aromatic heterocyclic group in the group, m is an integer of 1 or more, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 4. A 1In the m-valent aromatic heterocyclic group optionally having a substituent in the group, examples of the monovalent aromatic heterocyclic group where m=1 include sulfur-containing heteroaryl groups such as a thiophenyl group (thiophene group or thienyl group), a benzothienyl group (benzothiophene group), and a dibenzothienyl group (dibenzothiophene group); oxygen-containing heteroaryl groups such as a furanyl group (or furan group), a benzofuranyl group (benzofuran group), a dibenzofuranyl group (dibenzofuran group), a phenyldibenzofuranyl group, and a dibenzofuranylphenyl group; a pyridyl group (or pyridine group), a pyrimidinyl group (or pyrimidine group), a pyrazyl group, nitrogen-containing heteroaryl groups such as a group (or pyrazine group), a quinolyl group (or quinoline group), an isoquinolyl group (or isoquinoline group), a carbazolyl group (or carbazole group), a 9-phenylcarbazolyl group, an acridinyl group (or acridine group), a quinazolyl group (or quinazoline group), a quinoxalyl group (or quinoxaline group), a 1,6-naphthyridinyl group, a 1,8-naphthyridinyl group, and a porphyrin group (or porphyrin ring); and heteroaryl groups containing two or more types of heteroatoms (for example, nitrogen and sulfur), such as a benzothiazolyl group (or benzothiazole group) and a benzothiadiazole group.Further, a pyrrole group, a silole group, a borole group, a phosphole group, a selenophene group, a germole group, an indole group, an indene group, a benzosilole group, a benzoborole group, a benzophosphole group, a benzoselenophene group, a benzogermole group, a dibenzosilole group, a dibenzoborole group, a dibenzophosphole group, a dibenzoselenophene group, a dibenzogermole group, a dibenzothiophene 5-oxide group, a 9H-fluoren-9-one group, a dibenzothiophene 5,5-dioxide group, an azabenzothiophene group, an azabenzofuran group, an azaindole group, an azaindene group, an azabenzosilole group, an azabenzoborole group, an azabenzophosphole group, an azabenzoselenophene group, an azabenzogermole group, an azadibenzothiophene group, an azadibenzofuran group, Examples thereof include an azacarbazole group, an azafluorene group, an azadibenzosilole group, an azadibenzoborole group, an azadibenzophosphole group, an azadibenzoselenophene group, an azadibenzogermole group, an azadibenzothiophene 5-oxide group, an aza-9H-fluoren-9-one group, an azadibenzothiophene 5,5-dioxide group, a pyridazine group, a triazine group, a phenanthroline group, a pyrazole group, an imidazole group, a triazole group, an oxazole group, an isoxazole group, a thiazole group, an isothiazole group, an oxadiazole group, a thiadiazole group, a benzopyrazole group, a benzimidazole group, a benzoxazole group, a benzoxadiazole group, a 5,6,7,8-tetrahydroisoquinoline group, and a 5,6,7,8-tetrahydroquinoline group. Also, A 1 In the m-valent aromatic heterocyclic group optionally having a substituent in the group, examples of the m-valent aromatic heterocyclic group where m is an integer of 2 or more include those in which m-1 hydrogen atoms have been removed from the aromatic ring in the above-mentioned monovalent aromatic heterocyclic group. Other examples include a benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole skeleton (benzobisthiadiazole group), a thienylenyl group (or a thiophenediyl group), a phenyldibenzothienylenyl group, a dibenzothienylenylphenyl group, and a pyridylenyl group (or a pyridinediyl group).

[0021] A 1The number of carbon atoms in the m-valent aliphatic hydrocarbon group which may have a substituent in the group is not particularly limited, and is, for example, 2 to 60, preferably 3 to 40, and more preferably 5 to 30. A 1 In the m-valent aliphatic hydrocarbon group in the group, m is an integer of 1 or more, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 4. A 1 In the m-valent aliphatic hydrocarbon group which may have a substituent in the group, examples of the monovalent aliphatic hydrocarbon group where m=1 include saturated aliphatic hydrocarbon groups such as alkyl groups and cycloolefin groups. Also, A 1 In the m-valent aliphatic hydrocarbon group which may have a substituent in the group, examples of the m-valent aliphatic hydrocarbon group where m is an integer of 2 or greater include those in which m-1 hydrogen atoms have been removed from the above-mentioned monovalent aliphatic hydrocarbon group. A 1 The m-valent aliphatic hydrocarbon group, which may have a substituent in the group, may contain a heteroatom (e.g., nitrogen, oxygen, phosphorus, sulfur, etc.) in the main chain or in the substituent. Examples of the substituent containing a heteroatom include the above-mentioned aromatic heterocyclic groups such as the thiophenyl group, furanyl group, and pyrrole group, and saturated heterocyclic groups such as the tetrahydrothienyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperazyl group, and morpholyl group.

[0022] A 1 The number of carbon atoms in the m-valent unsaturated aliphatic hydrocarbon group which may have a substituent in the group is not particularly limited, and is, for example, 2 to 60, preferably 3 to 40, and more preferably 5 to 30. A 1 In the m-valent unsaturated aliphatic hydrocarbon group in the group, m is an integer of 1 or more, for example, 1 to 10, preferably 1 to 6, and more preferably 1 to 4. A 1 In the m-valent unsaturated aliphatic hydrocarbon group which may have a substituent in the group, examples of the monovalent aromatic hydrocarbon group where m=1 include an alkenyl group and an alkynyl group. Also, A 1In the m-valent unsaturated aliphatic hydrocarbon group which may have a substituent in the group, examples of the m-valent unsaturated aliphatic hydrocarbon group where m is an integer of 2 or more include those in which m-1 hydrogen atoms have been removed from the above-mentioned monovalent unsaturated aliphatic hydrocarbon group. A 1 The m-valent unsaturated aliphatic hydrocarbon group, which may have a substituent in the group, may contain a heteroatom (e.g., nitrogen, oxygen, phosphorus, sulfur, etc.) in the main chain or in the substituent. Examples of the substituent containing a heteroatom include the above-mentioned aromatic heterocyclic groups such as the thiophenyl group, furanyl group, and pyrrole group, and saturated heterocyclic groups such as the tetrahydrothienyl group, tetrahydrofuranyl group, pyrrolidinyl group, piperazyl group, and morpholyl group.

[0023] In the compound represented by formula (I), A in formula (I) 1 Examples of the group include the following groups. phenyl groups, alkyl (e.g., methyl)phenyl groups, dialkyl (e.g., dimethyl)phenyl groups, alkoxy (e.g., methoxy)phenyl groups, dialkylamino (e.g., dimethylamino)phenyl groups, diaryl (e.g., diphenyl)aminophenyl groups, perfluoroalkyl (e.g., trifluoromethyl)phenyl groups, alkyl (e.g., ethyl)oxycarbonylphenyl groups, alkanoyl (e.g., acyl)phenyl groups, alkylene groups, phenyl groups bridged with a linking group such as an ether group or an ester group; naphthyl groups such as naphthyl groups, aryl (e.g., phenyl, etc.) naphthyl groups, naphthyl groups having alkylene (e.g., ethylene, etc.) bridges, and naphthyl groups having arylene (e.g., phenylene, etc.) bridges; phenanthrenyl group; anthracenyl groups such as an anthracenyl group, an aryl (e.g., phenyl, etc.) anthracenyl group, a diaryl (e.g., dinaphthyl, etc.) anthracenyl group, and a diarylboryl (e.g., bis(trialkylphenyl)boryl, etc.) anthracenyl group; pyrenyl groups such as pyrenyl groups and alkyl (e.g., tert-butyl, etc.) pyrenyl groups; biphenyl groups, such as biphenyl groups, biphenyl groups having alkylene (e.g., propylene, isopropylene, etc.) bridges; terphenyl groups such as terphenyl groups, tetraaryl (e.g., tetraphenyl, etc.) terphenyl groups; Triphenylenyl group; Fluorenyl group, spirobifluorenyl group; 2-aryl (e.g., phenyl, etc.) ethenylphenyl group, 1,2,2-triaryl (e.g., triphenyl, etc.) ethenylphenyl group, 2-aryl (e.g., phenyl, etc.) ethenylphenyl group; aryl (e.g., phenyl, etc.) substituted carbazolyl groups; anthracene-9.10-dione group; Aryl (e.g., phenyl, etc.)-substituted thienyl groups, thiophene groups, benzothiadiazole groups; Groups having a valence of 2 or more, such as a phenylene group, an aryl (for example, bis(3,5-methylphenyl)) porphyrin ring, a pyrene-tetrayl group, and a benzo[1,2-c:4,5-c']bis[1,2,5]thiadiazole skeleton (benzobisthiadiazole group). sulfur-containing heteroaryl groups such as a thiophenyl group (thiophene group or thienyl group), a thienylenyl group (or thiophenediyl group), a benzothienyl group, a dibenzothienyl group, a phenyldibenzothienylenyl group, and a dibenzothienylphenyl group; oxygen-containing heteroaryl groups such as furanyl (or furan) group, benzofuranyl group, dibenzofuranyl group, phenyldibenzofuranyl group, and dibenzofuranylphenyl group; nitrogen-containing heteroaryl groups such as a pyridyl group (or pyridine group), a pyridylenyl group (or pyridinediyl group), a pyrimidinyl group (or pyrimidine group), a pyrazyl group (or pyrazine group), a quinolyl group (or quinoline group), an isoquinolyl group (or isoquinoline group), a carbazolyl group (or carbazole group), a 9-phenylcarbazolyl group, an acridinyl group (or acridine group), a quinazolyl group (or quinazoline group), a quinoxalyl group (or quinoxaline group), a 1,6-naphthyridinyl group, a 1,8-naphthyridinyl group, and a porphyrin group (or porphyrin ring); Heteroaryl groups containing two or more heteroatoms (for example, nitrogen and sulfur), such as benzothiazolyl groups (or benzothiazole groups).

[0024] A 1 The substituent that the m-valent aromatic hydrocarbon group optionally having a substituent, the m-valent aromatic heterocyclic group optionally having a substituent, the m-valent aliphatic hydrocarbon group optionally having a substituent, or the m-valent unsaturated aliphatic hydrocarbon group optionally having a substituent in the group is not particularly limited, as long as it does not interfere with the nucleophilic substitution fluorination reaction in the production method for a fluorinated compound of the present invention.

[0025] Examples of the substituent include alkyl groups having 1 to 24, for example, 1 to 18, for example, 1 to 12, or for example, 1 to 8 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, and octyl groups); alkoxy groups having 1 to 24, for example, 1 to 18, for example, 1 to 12, or for example, 1 to 8 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and octyl groups); cycloalkyl groups having, for example, 3 to 24 carbon atoms, for example, 3 to 18, for example, 3 to 12, for example, 3 to 8 carbon atoms (for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.); alkenyl groups having, for example, 1 to 24 carbon atoms, for example, 1 to 18, for example, 1 to 12, for example, 1 to 8 carbon atoms (for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, etc.); alkynyl groups having, for example, 1 to 24 carbon atoms, for example, 1 to 18, for example, 1 to 12, for example, 1 to 8 carbon atoms (for example, ethynyl, propenyl, an aryl group having, for example, 5 to 24, for example, 5 to 18, for example, 5 to 12, for example, 5 to 8 carbon atoms (for example, a phenyl group, a naphthyl group, a biphenyl group, etc.); an arylalkyl group having, for example, 7 to 24, for example, 7 to 19, for example, 7 to 13, for example, 7 to 9 carbon atoms (for example, a monophenylmethyl group, a monophenylpropyl group, a triphenylmethyl group, etc.); an aryloxy group having, for example, 5 to 24, for example, 5 to 18, for example, 5 to 12, for example, 5 to 8 carbon atoms (for example, a phenoxy group, a naphthyloxy group, etc. , biphenyloxy group, etc.); heteroaryl groups having, for example, 4 to 24, for example, 4 to 18, for example, 4 to 12, for example, 4 to 8 carbon atoms (for example, a thiophenyl group, a furanyl group, a carbazole group, a benzothiophenyl group, a benzofuranyl group, an indolyl group, a pyrrolyl group, a pyridyl group, etc.); acyl groups having, for example, 1 to 24, for example, 1 to 18, for example, 1 to 12, for example, 1 to 8 carbon atoms (for example, an acetyl group, a propionyl group, a butanoyl group, a pentanoyl group, a heptanoyl group, and groups in which the carbonyl group contained in the acyl group is substituted with an ester group or an amide group, etc.);Examples include one or more selected from the group consisting of an amino group having 1 to 24 carbon atoms, for example, 1 to 18, for example, 1 to 12, for example, 1 to 8 carbon atoms (for example, a diphenylamino group, a dimethylamino group, etc.); fluorine, a fluorine-containing group such as a fluorine-containing hydrocarbon group having 1 to 30 carbon atoms, for example, 1 to 12 carbon atoms; a cyano group, a nitro group, etc.; The substituents may be crosslinked to each other, or the substituents may together form a cyclic structure (aromatic group). The substituent may further have a substituent.

[0026] <X group in formula (I)> The X group represents any one of chlorine, bromine, and iodine, and when there are a plurality of X's, they may be the same or different. Appropriate groups can be used depending on reactivity and the like. X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple X's, they may be the same or different. X's are, for example, groups selected from chlorine, bromine, and iodine. The number m of X groups in formula (I) is not particularly limited as long as it is an integer of 1 or more and is within a range in which a nucleophilic substitution fluorination reaction can be carried out, and can be, for example, 10 or less, preferably 8 or less, more preferably 6 or less, and even more preferably 4 or less.

[0027] [Fluorinating agent] The fluorinating agent used in the method for producing a fluorine-containing compound of the present invention is not particularly limited as long as it can carry out fluorination by nucleophilic substitution fluorination reaction, preferably aromatic nucleophilic substitution reaction.For example, metal fluoride, ammonium fluoride salt, hydrofluoride salt, dialkylamino sulfur fluoride, etc. can be mentioned.Among these, it is preferable to use metal fluoride from the viewpoint of easy availability, handling, etc.The fluorinating agent may be a commercially available product or may be synthesized when used.

[0028] Examples of metal fluorides include one or more selected from the group consisting of alkali metal fluorides, alkaline earth metal fluorides, transition metal fluorides, etc. Among these, one or more selected from the group consisting of sodium fluoride, potassium fluoride, cesium fluoride, magnesium fluoride, calcium fluoride, strontium fluoride, barium fluoride, etc.

[0029] In the method for producing a fluorine-containing compound of the present invention, the amount of the fluorinating agent used is not particularly limited as long as it is an amount that allows fluorination by nucleophilic substitution fluorination reaction, preferably aromatic nucleophilic substitution reaction, to be carried out. For example, the amount can be 0.1 equivalents or more, 0.2 equivalents or more, 1 / 3 equivalents or more, 0.5 equivalents or more, 0.75 equivalents or more, or 1 equivalent or more relative to 1 equivalent of the substrate, and can be, for example, 10 equivalents or less, 5 equivalents or less, 3 equivalents or less, or 2 equivalents or less. The range of the amount of the fluorinating agent used is, for example, 0.1 equivalents or more and 10 equivalents or less, 0.2 equivalents or more and 10 equivalents or less, 1 / 3 equivalents or more and 10 equivalents or less, 0.5 equivalents or more and 10 equivalents or less, 0.75 equivalents or more and 10 equivalents or less, 1 equivalent or more and 10 equivalents or less, 0.1 equivalents or more and 5 equivalents or less, 0.2 equivalents or more and 5 equivalents or less, 1 / 3 equivalents or more and 5 equivalents or less, 0.5 equivalents or more and 5 equivalents or less, 0.75 equivalents or more and 5 equivalents or less, 1 equivalent or more The amount can be any of 5 equivalents or less, 0.1 to 3 equivalents, 0.2 to 3 equivalents, 1 / 3 to 3 equivalents, 0.5 to 3 equivalents, 0.75 to 3 equivalents, 1 to 3 equivalents, 0.1 to 2 equivalents, 0.2 to 2 equivalents, 1 / 3 to 2 equivalents, 0.5 to 2 equivalents, 0.75 to 2 equivalents, and 1 to 2 equivalents.

[0030] [solvent] In the method for producing a fluorinated compound of the present invention, the amount of solvent used satisfies the condition that it is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent. Such conditions can be said to be conditions under which no solvent is used substantially. In the present invention, "conditions under which no solvent is used substantially" refers to any of an embodiment in which no solvent is used at all, an embodiment in which no solvent is actively used, and an embodiment in which a solvent is used but in such a small amount that the solvent effect is not exerted.

[0031] In the method for producing a fluorine-containing compound of the present invention, the solvent used under conditions of 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent is not particularly limited. The solvent is liquid at room temperature (25°C ± 5°C) and does not react with the substrate including the compound represented by formula (I) and the fluorinating agent. Examples of the solvent include solvents used in homocoupling reactions carried out in a solution system. Examples include methanol, ethanol, n-propanol, isopropanol, 1-butanol, 1,1-dimethylethanol, tert-butanol, 2-methoxyethanol, ethylene glycol, polyethylene glycol, polypropylene glycol, diethyl ether, diisopropyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, tetrahydropyran, cyclopentyl methyl ether, dimethoxyethane, 1,4-dioxane, anisole, acetoxy-2-ethoxyethane, propylene glycol monomethyl ether acetate, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, Examples of suitable solvents include oxygen-containing organic solvents such as diethyl ether, 1-methoxy-1,1,2,2-tetrafluoroethane, 1-ethoxy-1,1,2,2-tetrafluoroethane, acetone, methyl ethyl ketone, ethyl acetate, butyl acetate, and acetic acid; aromatic solvents such as benzene, toluene, xylene, mesitylenedurene, and decalin; aliphatic organic solvents such as hexane, pentane, and heptane; halogenated hydrocarbon organic solvents such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, and 1,2-dichlorobenzene; nitrogen-containing organic solvents such as acetonitrile, N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methyl-2-pyrrolidone, and pyridine; sulfur-containing organic solvents such as dimethyl sulfoxide, and water. The solvent preferably has a melting point of 30°C or less, and more preferably has a melting point of 30°C or less.

[0032] In the method for producing a fluorine-containing compound of the present invention, when reacting by a mechanochemical method, a solvent can be used as a liquid grinding aid (Liquid Assisted Grinding: LAG). As the liquid grinding aid, among the above-mentioned solvents, for example, at least one selected from the group consisting of oxygen-containing organic solvents such as 2-methoxyethanol, ethylene glycol, diethyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, propylene glycol monomethyl ether acetate, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, diethyl ether, dibutyl ether, tetrahydrofuran, ethylene glycol, polypropylene glycol, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether; nitrogen-containing organic solvents such as N,N'-dimethylformamide, N,N'-dimethylacetamide, N-methyl-2-pyrrolidone, pyridine; sulfur-containing organic solvents such as dimethyl sulfoxide; and the like are preferred. Particularly preferably, one or more selected from the group consisting of 2-methoxyethanol, ethylene glycol, diethyl ether, dibutyl ether, t-butyl methyl ether, tetrahydrofuran, N',N'-dimethylformamide, N,N'-dimethylacetamide, N-methyl-2-pyrrolidone, pyridine, and dimethyl sulfoxide can be used.

[0033] In the method for producing a fluorinated compound of the present invention, the amount of solvent used is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent. The amount of solvent used can be 0.5 mL or less, 0.1 mL or less, 0.05 mL or less, 0.02 mL or less, 0.01 mL or less, or 0 mL (no solvent used) per 1 mmol of the total of the substrate and the fluorinating agent. Generally, in a nucleophilic substitution fluorination reaction carried out in a solution system, an organic solvent is used in an amount of 1 mL or more, for example, 1 to 2 mL, per 1 mmol of the total of the reaction raw materials. In the present invention, the amount of solvent, particularly the organic solvent, used is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent, so the amount of solvent used is clearly small. In the method for producing a fluorine-containing compound of the present invention, the reaction components such as the substrate and the fluorinating agent usually react in a state where at least a part of them is not dissolved in the solvent, etc., at the start of the reaction, and in some cases where they are not dissolved at all in the solvent, etc., and exist in a solid state.

[0034] [Quaternary ammonium salts] In the method for producing a fluorine-containing compound of the present invention, a quaternary ammonium salt can also be used. The quaternary ammonium salt is represented by the formula (III); [NR 1 R 2 R 3 R 4 ] + X - (III) In formula (III), R 1 ~R 4 are each independently hydrogen, an optionally substituted alkyl group, an optionally substituted aryl group, R 1 ~R 4 Any two or more of the following may be bonded together, and X - is a compound that represents any one of a chlorine anion, a bromine anion, an iodo anion, a trifluoromethanesulfonate anion, and a hydroxy anion.

[0035] Examples of the alkyl group which may have a substituent include one or more selected from the group consisting of a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, etc. Furthermore, two alkyl groups may be bonded together, and R 1 -R 2 and / or R 3 -R 4Examples of the alkyl group include one or more selected from the group consisting of an ethylene group, a 1,1,2,2-tetramethylethylene group, a 2,2-dimethylpropylene group, a hexylene group (or a 1,1,3-trimethylpropylene group), and the like. The aryl group which may have a substituent is selected from, for example, a phenyl group, a naphthyl group, a biphenyl group, etc. Furthermore, R 1 ~R 4 Two or more of these may form a ring structure, for example, an aromatic group, and specific examples thereof include a 1,2-phenylene group.

[0036] Examples of the substituent that the alkyl group and aryl group may have include one or more selected from the group consisting of a halogen group, an alkyl group, an aryl group, an alkoxy group, an aryloxy group, etc. When there are two or more substituents, they may be the same or different and may be crosslinked to each other. The substituent may have a further substituent.

[0037] Examples of quaternary ammonium salts include those containing one or more selected from the group consisting of tetramethylammonium chloride, tetraethylammonium chloride, tetrapropylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraphenylammonium chloride, etc. Commercially available quaternary ammonium salts may be used, or they may be obtained by chemical synthesis.

[0038] In the present invention, the quaternary ammonium salt that can be used is solid at room temperature (25° C.±5° C.). Furthermore, the quaternary ammonium salt can be used without dissolving in a solvent.

[0039] The equivalent of the quaternary ammonium salt is not particularly limited as long as it is an amount that can cause the aromatic nucleophilic substitution fluorination reaction to proceed. For example, it can be any of 0.5 equivalents or more, 0.8 equivalents or more, 1.0 equivalents or more, 1.2 equivalents or more, or 1.4 equivalents or more relative to 1 equivalent of the substrate, and can be any of 10.0 equivalents or less, 5.0 equivalents or less, 4.0 equivalents or less, or 3.0 equivalents or less. In the present invention, for example, the amount of the quaternary ammonium salt relative to 1 equivalent of the substrate is 0.5 equivalents or more to 10.0 equivalents or less, 0.8 equivalents or more to 10.0 equivalents or less, 1.0 equivalents or more to 10.0 equivalents or less, 1.2 equivalents or more to 10.0 equivalents or less, 1.4 equivalents or more to 10.0 equivalents or less, 0.5 equivalents or more to 5.0 equivalents or less, 0.8 equivalents or more to 5.0 equivalents or less, 1.0 equivalents or more to 5.0 equivalents or less, 1.2 equivalents or more to 5.0 equivalents or less, 1.4 equivalents or more to 5.0 equivalents or less. equivalents or less, 0.5 or more and 4.0 or less, 0.8 or more and 4.0 or less, 1.0 or more and 4.0 or less, 1.2 or more and 4.0 or less, 1.4 or more and 4.0 or less, 0.5 or more and 3.0 or less, 0.8 or more and 3.0 or less, 1.0 or more and 3.0 or less, 1.2 or more and 3.0 or less, or 1.4 or more and 3.0 or less.

[0040] The method for producing a fluorine-containing compound of the present invention does not require the use of a quaternary ammonium salt. In the method for producing a fluorine-containing compound of the present invention, the reactivity can be improved by using a quaternary ammonium salt. Furthermore, in the method for producing a fluorine-containing compound of the present invention, a quaternary ammonium salt that is solid at room temperature can be used even under conditions in which substantially no solvent is used. Usually, when a reaction is carried out using solid components without a solvent, it is expected that the diffusion of each reaction component is inefficient and the reaction does not proceed easily. However, contrary to expectations, in the method for producing a fluorine-containing compound of the present invention, the reaction can be carried out substantially without a solvent.

[0041] [Other ingredients] In the method for producing a homocoupling reaction product of the present invention, other components may be used in addition to the substrate containing the compound represented by formula (I), the fluorinating agent, the quaternary ammonium salt, and the solvent as a liquid assisted grinding aid (LAG). Examples of other components that may be used include one or more promoters for the nucleophilic substitution fluorination reaction. Examples of promoters for the nucleophilic substitution fluorination reaction include crown ethers. The amount of the other components used is not particularly limited as long as it is within a range that does not inhibit the progress of the nucleophilic substitution fluorination reaction.

[0042] [Mechanochemical method] The mechanochemical method used in the method for producing a fluorinated compound of the present invention is a method in which mechanical energy is applied to a substrate containing the compound represented by formula (I) as a reaction component, a fluorinating agent, and the like, to cause a reaction. Mechanical energy can be generated mechanically by means of grinding, shearing, impact, compression, and the like. By applying such mechanical energy to the substrate or the fluorinating agent, they can be activated and reacted. The mechanochemical method is an organic synthesis reaction method in which the components contained in the reaction system are directly contacted and mixed to cause a reaction, eliminating the need for organic solvents, and is highly reactive while having a low environmental impact. The reaction apparatus and reaction conditions in the mechanochemical method used in the method for producing a fluorine-containing compound of the present invention can be, for example, as follows.

[0043] <Reaction apparatus> The reaction apparatus used in the method for producing a fluorine-containing compound of the present invention is not particularly limited as long as it is an apparatus that can apply mechanical energy to the components participating in the reaction and thereby carry out a nucleophilic substitution fluorination reaction. For example, it can be an apparatus that can carry out one or more operations selected from the group consisting of shaking, rubbing, pressing, dispersing, kneading, crushing, etc.

[0044] Such devices include, for example: Grinding machines such as ball mills, rod mills, jet mills, SAG mills, etc.; Twin-screw mixers, single-screw mixers, mixers, roll mills and other mixers; Rotary mills, grinders, and other grinding machines; Horizontal cylindrical, V-type, double cone type, square cube type, S-type and continuous V-type (horizontal axis rotation) container rotating type mixers; Horizontal cylindrical, V-shaped, double cone-shaped and ball mill-shaped (with baffle blades) container-rotating mixers; (Rotary vibration) container-rotating mixers such as rocking and cross-rotary types; Fixed vessel mixers (horizontal axis rotation) such as ribbon, paddle, single-shaft rotor and bag mill types; Ribbon type, screw type, planetary type, turbine type, high-speed flow type, rotating disk type and Mahler type (vertical axis rotating) stationary vessel type mixers; (vibrating) stationary vessel type mixing equipment such as vibrating mills and sieves; (Fluidization) fluid movement type mixers such as heterogeneous fluidized beds, swirling fluidized beds, types with risers and jot pump types; (gravity) fluid motion type mixing devices such as gravity type and static mixers; and the like.

[0045] In the method for producing a homocoupling reaction product of the present invention, preferably, one or more selected from the group consisting of a pulverizer such as a ball mill, a grinder, a mixer, a kneader, etc. are used, and particularly preferably, a mixer is used. Examples of the mixer include the powder mixers described in Table 5 and Figure 9 of Sakashita, "Powder Mixing Process Technology," Color Materials, 77(2), 75-85 (2004). Specifically, a ball mill, a twin-screw kneader, a planetary ball mill, a SPEX mixer mill, a twin-screw ball mill, etc. can be used.

[0046] The apparatus used for the reaction by the mechanochemical method may be equipped with one or more means selected from the group consisting of a measuring means, a decompression or pressure means, an atmosphere adjustment means (gas introduction or discharge means), a means for introducing various components, a means for discharging various components and reaction products, a purification means, an analysis means, a reaction monitoring means, and the like.

[0047] <Reaction vessel> In the method for producing a fluorine-containing compound of the present invention, the reaction vessel used in the reaction by the mechanochemical method is not particularly limited as long as it is a reaction vessel that can carry out a nucleophilic substitution fluorination reaction, taking into consideration the physical properties, reactivity, and abundance of components present in the reaction system, such as the substrate and fluorinating agent, as well as the reaction conditions by the mechanochemical method, etc. For example, when a device that performs a mechanical mixing treatment (e.g., a ball mill, etc.) is used, a ball mill jar or the like can be used as the reaction vessel.

[0048] In the method for producing a fluorine-containing compound of the present invention, the reaction vessel may be equipped with a means for stirring the components involved in the reaction in the reaction vessel. The means for stirring the components involved in the reaction in the reaction vessel is not particularly limited as long as it is any of various stirring means that can be equipped in the reaction apparatus. The means using a device that performs mechanical mixing treatment described above (Reaction apparatus) can be used. For example, a ball mill is preferably used as the device that performs mechanical mixing treatment.

[0049] <Mechanochemical reaction conditions> In the method for producing a fluorine-containing compound of the present invention, the reaction conditions for the reaction by the mechanochemical method are not particularly limited, as long as the reaction conditions allow for the nucleophilic substitution fluorination reaction to be carried out, taking into consideration the physical properties, reactivity, and amounts of components present in the reaction system, such as the substrate and the fluorinating agent, as well as the reaction conditions by the mechanochemical method.

[0050] <Added mechanical energy> In the method for producing a fluorine-containing compound of the present invention, the mechanical energy applied during the reaction by the mechanochemical method is not particularly limited as long as it is mechanical energy capable of carrying out a fluorination reaction by a nucleophilic substitution reaction, preferably a fluorination ring reaction by an aromatic nucleophilic substitution reaction. It can be appropriately determined taking into consideration the types and amounts of the reaction raw materials, the reaction temperature, etc. For example, when a mixer is used as the device used for the reaction by the mechanochemical method, the mixing speed is not particularly limited. It can be appropriately determined taking into consideration the physical properties, reactivity, and amounts of the substrate, organohalogen compound, nickel catalyst, and other components present in the reaction system, as well as the reaction conditions for the mechanochemical method. For example, when a ball mill is used, shaking can be performed at 5 Hz or higher, preferably 10 Hz or higher, and more preferably 20 Hz or higher.

[0051] (Reaction temperature) In the method for producing a fluorine-containing compound of the present invention, the reaction temperature (temperature inside the reaction vessel during mixing) is not particularly limited. A temperature that allows for the nucleophilic substitution fluorination reaction can be selected, taking into consideration the physical properties, reactivity, and amounts of components present in the reaction system, such as the substrate and fluorinating agent, as well as the reaction conditions for the mechanochemical method. For example, the temperature is −50° C. or higher, preferably 0° C. or higher, more preferably 20° C. or higher, even more preferably 50° C. or higher, and most preferably 60° C. or higher, and is, for example, 500° C. or lower, preferably 300° C. or lower, and more preferably 250° C. or lower. In the present invention, the nucleophilic substitution fluorination reaction can be carried out at room temperature (25° C.±5° C.) without heating. Alternatively, the reaction vessel (reaction system) can be heated to the desired temperature by using a heating device such as a heat gun. The method for controlling the reaction temperature is not particularly limited. Temperature control methods used in chemical reactions can be used. For example, a method for controlling the temperature inside the reaction vessel by immersing the reaction vessel in a coolant such as liquid nitrogen, a method for controlling the temperature inside the reaction vessel by using hot air, a method for controlling the temperature inside the reaction vessel by covering the reaction vessel with a heat medium at a predetermined temperature, a method for controlling the temperature inside the reaction vessel by providing a heating element, etc. can be mentioned. In the present invention, a method of controlling the temperature inside the reaction vessel by applying hot air generated by a heat gun to the reaction vessel is preferred from the viewpoints of safety and ease of temperature control operation.

[0052] (pressure) In the method for producing a fluorine-containing compound of the present invention, the reaction pressure (pressure inside the reaction vessel during mixing) when reacting by the mechanochemical method is not particularly limited. Taking into consideration the physical properties, reactivity, and abundance of components present in the reaction system, such as the substrate and fluorinating agent, as well as the reaction conditions for the mechanochemical method, the pressure can be set to a pressure that allows for the nucleophilic substitution fluorination reaction to be carried out. If necessary, the reaction pressure can be controlled using a pressure reducing device or a pressure increasing device, and the reaction can be carried out without pressurizing or depressurizing. Of these, carrying out the reaction without pressurizing or depressurizing (carrying out the reaction at atmospheric pressure) is preferred from the viewpoints of reaction operation, reaction equipment, etc.

[0053] (reaction atmosphere) In the method for producing a fluorine-containing compound of the present invention, the reaction atmosphere (the atmosphere in the reaction vessel during mixing) is not particularly limited. The reaction atmosphere can be selected so as to allow for the nucleophilic substitution fluorination reaction, taking into consideration the physical properties, reactivity, and amounts of components present in the reaction system, such as the substrate and fluorinating agent, as well as the reaction conditions for the mechanochemical method. For example, the reaction can be carried out in an air atmosphere without any particular atmospheric adjustment. Alternatively, the reaction can be carried out in an inert gas atmosphere such as nitrogen, helium, neon, argon, etc., as necessary. In the method for producing a fluorine-containing compound of the present invention, the reaction can be carried out without adjusting the atmosphere in a reaction vessel.

[0054] (Reaction time) In the method for producing a fluorine-containing compound of the present invention, the reaction time (mixing time; time for performing treatment by mechanical means) is not particularly limited. It can be appropriately determined taking into consideration the physical properties, reactivity, and amounts of components present in the reaction system, such as the substrate and fluorinating agent, as well as the reaction conditions for the mechanochemical method. For example, it can be 1 minute or more, 5 minutes or more, 10 minutes or more, 15 minutes or more, 30 minutes or more, 45 minutes or more, or 60 minutes or more. The upper limit of the reaction time is not particularly limited, but can be, for example, 10 hours or less, 5 hours or less, 3 hours or less, or 2 hours or less.

[0055] (Order of adding reaction components, post-reaction treatment, etc.) In the method for producing a fluorine-containing compound of the present invention, when reacting by a mechanochemical method, the order in which the reaction components are charged into a reaction vessel is not particularly limited, and the means for charging them is also not particularly limited. After the reaction is completed, the resulting reaction product may be purified as needed. The purification method is not particularly limited, and methods such as filtration, distillation, recrystallization, column chromatography, washing with a solvent, etc. may be used.

[0056] [Reaction products in the production process of fluorine-containing compounds] The reaction product produced by the method for producing a fluorine-containing compound of the present invention is a compound represented by the formula (II); X m-n -A 1 -F n (II) In formula (II), A 1 represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted n-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different; m is an integer of 1 or greater; n is the number of F and is an integer of 1 or greater; and mn is 0 or an integer of 1 or greater. The reaction product produced by the method for producing a fluorine-containing compound of the present invention may include reaction products having a variety of structures in addition to the reaction product represented by the formula (II).

[0057] A in the reaction product represented by formula (II) 1 is A in the compound represented by formula (I) contained in the substrate in the method for producing a fluorine-containing compound of the present invention. 1 can be a group similar to the following: X in the reaction product represented by formula (II) can be the same group as X in the compound represented by formula (I) contained in the substrate in the method for producing a fluorine-containing compound of the present invention.

[0058] In the reaction product represented by formula (II), n represents the number of fluorine atoms introduced by the nucleophilic substitution fluorination reaction in the method for producing a fluorinated compound of the present invention, and is an integer of 1 or more, preferably 1 or more, and for example, 6 or less, preferably 4 or less. In the reaction product represented by formula (II), mn is the number of leaving groups that remain in the nucleophilic substitution reaction among the leaving groups that the substrate had in the nucleophilic substitution fluorination reaction and that have not been replaced with fluorine in the nucleophilic substitution fluorination reaction, and is a number of 0 or 1 or more. For example, it can be 0, 5.0 or less, 4.0 or less, 3.0 or less, or 1.5 or less. mn represents the apparent number of introduced fluorine atoms in the reaction mixture that did not become leaving groups in the nucleophilic substitution reaction, and is an integer of 1 or more. It is preferably 1 or more, for example, 6 or less, preferably 4 or less.

[0059] The reaction products in the method for producing a fluorine-containing compound of the present invention can be used as components of functional materials such as pharmaceuticals, agricultural chemicals, liquid crystal compounds, organic electroluminescent compounds, organic thin-film solar cells, polymer compounds, oligomers, electrolytes, coloring materials, energy ray absorbing materials, information recording materials, wavelength converting materials, indicator materials, sensor materials, organic light-emitting diodes (OLEDs), and organic semiconductor materials. [Example]

[0060] The present invention will be specifically and in detail explained below with reference to examples and comparative examples. These examples are merely one embodiment of the present invention, and the present invention is not limited by these examples in any way.

[0061] In the examples and comparative examples, when reactions were carried out using a ball mill, each reagent was placed in a stainless steel ball mill jar, and a ball mill MM400 manufactured by Verder Scientific Co., Ltd. (formerly Retsch) was used. When carrying out the reaction using a ball mill, heating was performed by heating the outside of the ball mill jar to a specified temperature with a heat gun (Takagi, HG-1450B). The internal temperature of the ball mill jar (temperature of the reaction system) was measured by checking the internal temperature of the ball mill jar using a thermographic image after the reaction.

[0062] Unless otherwise specified, the compounds used in the examples and comparative examples were commercially available products and were used as they were without further purification.

[0063] The substrates (1a) to (1aa) used in the examples and comparative examples are as follows: [ka]

[0064] [ka]

[0065] The target reaction products (2a) to (2aa) produced in the examples and comparative examples are as follows: [ka]

[0066] [ka]

[0067] [Example 1] A 1.5 mL stainless steel ball mill jar containing a 5 mm diameter stainless steel ball was charged with 31.8 mg (0.5 mmol, 1.0 equiv.) of 2-chloroquinoline (1a) as the substrate, 151.9 mg (1.0 mmol, 2.0 equiv.) of cesium fluoride as the fluorinating agent, and dimethyl sulfoxide as the liquid grinding aid (LIQUID Assisted Grinding: LAG) at a concentration of 0.2 μL / mg of 2-chloroquinoline under air. The ball mill jar was then closed with its lid and attached to the ball mill. The jar was heated with a heat gun and shaken and stirred at an internal temperature of 120 °C and a frequency of 30 Hz for 60 minutes. After the reaction was complete, the reaction mixture was passed through a short silica gel column chromatography using ethyl acetate and dichloromethane to remove inorganic salts. The ethyl acetate and dichloromethane were removed using an evaporator. 19 The yield of the desired reaction product (2-fluoroquinoline (2a)) by F NMR was 36%.

[0068] [Example 2] A 5.0 mL stainless steel ball mill jar containing a 10 mm diameter stainless steel ball was charged with 88.8 mg (0.5 mmol, 1.0 equiv.) of 2-chloro-3-methylquinoline (1b) as the substrate, 58.1 mg (1.0 mmol, 2.0 equiv.) of potassium fluoride as the fluorinating agent, and 124.3 mg (0.75 mmol, 1.5 equiv.) of tetraethylammonium chloride as the quaternary ammonium salt under air. The ball mill jar was then closed with its lid and attached to the ball mill. The mixture was heated with a heat gun to an internal temperature of 130 °C and shaken and stirred at a frequency of 30 Hz for 60 minutes. After completion of the reaction, the reaction mixture was passed through a short silica gel column chromatography using ethyl acetate and dichloromethane to remove inorganic salts. The ethyl acetate and dichloromethane were removed using an evaporator. 19The yield of the desired reaction product (2-fluoro-3-methylquinoline (2b)) by F NMR was over 95%. The reaction mixture was purified by silica gel column chromatography, and 68.8 mg of the desired reaction product (2-fluoro-3-methylquinoline (2b)) was isolated (0.427 mmol, 85% isolated yield).

[0069] [Example 3] The fluorination reaction was carried out in the same manner as in Example 2, except that 208.4 mg (0.75 mmol, 1.5 equivalents) of tetra-n-butylammonium chloride was added as a quaternary ammonium salt, to obtain the target reaction product (2-fluoro-3-methylquinoline (2b)). The NMR yield was 88%.

[0070] [Example 4] The fluorination reaction was carried out in the same manner as in Example 3, except that dimethyl sulfoxide was added as a liquid grinding aid (LAG) in an amount of 0.2 μL / mg relative to 2-chloro-3-methylquinoline, to obtain the target reaction product (2-fluoro-3-methylquinoline (2b)). The NMR yield was 72%.

[0071] [Example 5] The fluorination reaction was carried out in the same manner as in Example 2, except that 166.4 mg (0.75 mmol, 1.5 equivalents) of tetra-n-propylammonium chloride was added as a quaternary ammonium salt, to obtain the target reaction product (2-fluoro-3-methylquinoline (2b)). The NMR yield was 89%.

[0072] [Examples 6 to 21] The fluorination reaction was carried out in the same manner as in Example 2, except that 0.5 mmol (1.0 equivalent) of each of the compounds shown in Table 1 was used instead of 2-chloro-3-methylquinoline (1b), to obtain the target reaction products (2a to 2q). The NMR yields and isolation yields are also shown in Table 1.

[0073] [Example 22] The fluorination reaction was carried out in the same manner as in Example 2, except that 74.0 mg (0.5 mmol, 1.0 equivalent) of 2,6-dichloropyridine (1r) was used instead of 2-chloro-3-methylquinoline (1b), 116.2 mg (2.0 mmol, 4.0 equivalents) of potassium fluoride was used as the fluorinating agent, and 248.6 mg (1.5 mmol, 3.0 equivalents) of tetraethylammonium chloride was used as the quaternary ammonium salt, to obtain the target reaction product (2r). The NMR yield and isolation yield are also shown in Table 1.

[0074] [Table 1] In Table 1, "-" indicates that no measurement was performed.

[0075] [Example 23] A 1.5 mL stainless steel ball mill jar containing a 5 mm diameter stainless steel ball was charged with 69.3 mg (0.5 mmol, 1.0 equiv.) of 2-chloro-5-cyanopyridine (1s) as the substrate, 58.1 mg (1.0 mmol, 2.0 equiv.) of potassium fluoride as the fluorinating agent, and 124.3 mg (0.75 mmol, 1.5 equiv.) of tetraethylammonium chloride as the quaternary ammonium salt under air. The ball mill jar was then closed with its lid and attached to the ball mill. The mixture was heated with a heat gun to an internal temperature of 130°C and shaken and stirred at a frequency of 30 Hz for 60 minutes. After completion of the reaction, the reaction mixture was passed through a short silica gel column chromatography using ethyl acetate and dichloromethane to remove inorganic salts. The ethyl acetate and dichloromethane were removed using an evaporator. 19 The yield of the desired reaction product (2-fluoro-5-cyanopyridine (2s)) by F NMR was over 95%. Furthermore, when the reaction mixture was purified and isolated by silica gel column chromatography, the isolated yield of the desired reaction product was 55%.

[0076] [Examples 24 to 31] The fluorination reaction was carried out in the same manner as in Example 24, except that 0.5 mmol (1.0 equivalent) of each of the compounds (1t to 1aa) shown in Table 2 was used instead of 2-chloro-5-cyanopyridine (1s), to obtain the target reaction products (2t to 2aa). The NMR yields and isolation yields are also shown in Table 2.

[0077] [Table 2] In Table 2, "-" indicates that no measurement was performed.

[0078] [Example 32] <Gram-scale reaction> A 10.0 mL stainless steel ball mill jar containing three 10 mm diameter stainless steel balls was charged with 1.07 g (6.0 mmol, 1.0 equivalent) of 2-chloro-3-methylquinoline (1b) as the substrate, 2.0 equivalents of potassium fluoride as the fluorinating agent, and 1.5 equivalents of tetraethylammonium chloride as the quaternary ammonium salt under air. The ball mill jar was then closed and attached to the ball mill. The mixture was heated to 135 °C with a heat gun set to 250 °C and shaken and stirred at a frequency of 30 Hz for 60 minutes. After the reaction was complete, the reaction mixture was passed through a short silica gel column with ethyl acetate and dichloromethane to remove inorganic salts. The ethyl acetate and dichloromethane were removed using an evaporator. 19 The yield of the target reaction product (2-fluoro-3-methylquinoline (2b)) by F NMR was over 95%. Furthermore, when the reaction mixture was purified and isolated by silica gel column chromatography, the isolated yield of the target reaction product was 89%.

[0079] [Comparative Example 1] To a reaction vessel, 88.8 mg (0.5 mmol, 1.0 equivalent) of 2-chloro-3-methylquinoline (1a) as the substrate, 58.1 mg (1.0 mmol, 2.0 equivalents) of potassium fluoride, 124.3 mg (0.75 mmol, 1.5 equivalents) of tetraethylammonium chloride, and 2.2 g of dimethyl sulfoxide (DMSO) were added, and the mixture was stirred at 130°C for 60 minutes to react. After the reaction was completed, the reaction mixture was passed through a short silica gel column chromatography using ethyl acetate and dichloromethane to remove inorganic salts. The ethyl acetate and dichloromethane were then removed using an evaporator. 19 The yield of the desired reaction product (2-fluoro-3-methylquinoline (2b)) by F NMR was 28%.

[0080] [Reference example 1] A 5.0 mL stainless steel ball mill jar containing a 10 mm diameter stainless steel ball was charged with 124.3 mg (0.75 mmol) of tetraethylammonium chloride (quaternary ammonium salt) and 1.3 equivalents of potassium fluoride under air. The ball mill jar was then closed and attached to the ball mill. The jar was heated with a heat gun and shaken and stirred at an internal temperature of 130°C for 60 minutes at a frequency of 30 Hz. After the reaction was complete, the mixture containing only the fluorinating agent and the quaternary ammonium salt was observed using solid-state NMR and powder X-ray diffraction (PXRD). The results are shown in Figures 1 and 2.

[0081] [Examples, Comparative Examples, and Reference Examples] As shown in Examples 1 to 31, the method for producing a fluorine-containing compound according to the present invention is a method that can carry out a nucleophilic substitution fluorination reaction under mild reaction conditions and with a simple reaction procedure without using an organic solvent, and can give a reaction product in high yield in a short time. As shown in Example 32, the method for producing a fluorine-containing compound according to the present invention is a method which enables the reaction to be carried out under mild reaction conditions and with simple reaction operations, even when the reaction is carried out on a gram scale, and which enables the production of a reaction product in high yield in a short period of time. As shown in Examples 1 to 32, the method for producing a fluorine-containing compound according to the present invention is a method in which the reaction can be carried out under mild reaction conditions and with simple reaction procedures without using an organic solvent, and the reaction product can be obtained in high yield in a short time, and further it is found that a wide range of substrates can be used. From this, it can be seen that the present invention is extremely useful industrially.

[0082] 1 and 2 obtained in Reference Example 1, no significant salt exchange reaction was observed. This suggests that in the method for producing a fluorine-containing compound of the present invention, the quaternary ammonium salt exhibits appropriate fluidity in the reaction system, and the substrate reacts with the small amount of ammonium fluoride produced in the fluidized bed. The present inventors presume that this is why the method for producing a fluorine-containing compound of the present invention exhibits excellent effects, but this presumption does not limit the present invention in any way.

Claims

1. Formula (I); A １ -X ｍ (I) In formula (I), A １ represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted m-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different, and m is an integer of 1 or greater. A method for producing a fluorinated compound, comprising reacting a substrate containing a compound represented by the formula (I) with a fluorinating agent by a mechanochemical method under conditions in which the amount of solvent used is 0.8 mL or less per 1 mmol of the total of the substrate and the fluorinating agent.

2. The method for producing a fluorine-containing compound according to claim 1, wherein the reaction is carried out in the presence of a quaternary ammonium salt.

3. 3. The method for producing a fluorine-containing compound according to claim 1, wherein the fluorinating agent comprises one or more alkali metal fluorides and / or one or more alkaline earth metal fluorides.

4. The fluorine-containing compound is represented by formula (II); X ｍ－ｎ -A １ -F ｎ (II) In formula (II), A １ represents any one of an optionally substituted m-valent aromatic hydrocarbon group, an optionally substituted m-valent aromatic heterocyclic group, an optionally substituted m-valent heterocyclic group, an optionally substituted n-valent aliphatic hydrocarbon group, or an optionally substituted m-valent unsaturated aliphatic hydrocarbon group; X represents a leaving group in a nucleophilic substitution reaction, and when there are multiple Xs, they may be the same or different; m is an integer of 1 or more; n is the number of F and is an integer of 1 or more; and m-n is 0 or a number of 1 or more.

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