WO2016052353A1

WO2016052353A1 - Method for producing geminal difluoro compound

Info

Publication number: WO2016052353A1
Application number: PCT/JP2015/077175
Authority: WO
Inventors: 昭裕長屋; 章一近藤; 準武岡; 智中野
Original assignee: 日産化学工業株式会社
Priority date: 2014-09-29
Filing date: 2015-09-25
Publication date: 2016-04-07
Also published as: CN106687431A; JPWO2016052353A1; KR20170066310A

Abstract

　Provided is a novel method for producing a geminal difluoro compound. A novel production method for obtaining a geminal difluoro compound represented by formula (2) at a high yield by reacting a compound represented by formula (1) with a fluorinating agent in the presence of an N-chloroimide compound. (In the formula, R¹ indicates a C_1-4 alkyl, X indicates a halogen atom.)　

Description

Method for producing geminal difluoro compound

The present invention relates to a novel method for producing a geminal difluoro compound using an oxime compound as a starting material.

A geminal difluoro compound having, as a partial structure, a group in which two fluorine atoms are substituted on one carbon atom is a compound useful as a pharmaceutical or agricultural chemical, or an intermediate thereof (Patent Document 1), and a method for producing these compounds As many reactions have been developed. A typical example is a difluorination reaction of an oxime compound (Non-Patent Documents 1 to 3).
As a difluorination reaction using an oxime compound as a starting material, a method using iodine monofluoride (Non-patent Document 2) has been reported. However, the iodine monofluoride used can only exist at a low temperature, and in the reaction, in order to generate iodine monofluoride in the system, pulverized iodine is added to the reaction solution, and fluorine / An operation for blowing nitrogen gas is required. Therefore, the use of iodine monofluoride has a problem of using special reaction conditions and a reaction apparatus (Non-Patent Documents 2 and 4).

A method using nitrosyltetrafluoroborate and a hydrogen fluoride-pyridine complex (Non-patent Document 3) has also been reported. However, in the example applied to the synthesis of a 1-phenyl-1,1-difluoroethane derivative, the target compound is obtained only in a low yield (Patent Document 2). Since nitrosyltetrafluoroborate has a strong hygroscopic property, it is necessary to handle it under a dry inert gas when performing a difluorination reaction, and there is a problem that it is expensive (non-patent document). 5, 6).
Therefore, a novel method for producing a geminal difluoro compound that is useful as an industrial production method with high yield without using these reagents has been desired.

International Publication No. 2011/154298 International Publication No. 2012/139775

An object of the present invention is to provide a method for producing a geminal difluoro compound with high yield, which does not require a special reaction apparatus or reaction conditions.

As a result of intensive studies, the present inventors have found a novel production method for producing a geminal difluoro compound in high yield by reacting a fluorinating agent with an oxime compound in the presence of an N-chloroimide compound, The present invention has been completed. That is, the present invention is characterized by the following.

[1] Production of geminal difluoro compound represented by formula (2), wherein oxime compound represented by formula (1) is reacted with a fluorinating agent in the presence of an N-chloroimide compound Method.

[Wherein R ¹ represents C _1-4 alkyl, and X represents a halogen atom. ]

[Wherein, R ¹ and X represent the same meaning as described above. ]
[2] The above-mentioned [1], wherein the N-chloroimide compound is N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or trichloroisocyanuric acid A method for producing a geminal difluoro compound.
[3] The method for producing a geminal difluoro compound according to the above [2], wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid.
[4] The amount of the N-chloroimide compound is 0.1 to 100 equivalents per 1 equivalent of the oxime compound of the formula (1), according to any one of [1] to [3] above. A method for producing a geminal difluoro compound.
[5] Geminal difluoro according to any one of [1] to [4] above, wherein the amount of the fluorinating agent used is 2 to 1000 equivalents relative to 1 equivalent of the oxime compound of formula (1). Compound production method.
[6] The geminal difluoro according to any one of the above [1] to [5], wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or poly [4-vinylpyridinium poly (hydrogen fluoride)]. Compound production method.
[7] The method for producing a geminal difluoro compound according to the above [6], wherein the fluorinating agent is a hydrogen fluoride-pyridine complex.
[8] The method for producing a geminal difluoro compound according to the above [7], wherein the weight ratio of hydrogen fluoride to pyridine in the hydrogen fluoride-pyridine complex is 70:30 to 20:80.
[9] The method for producing a geminal difluoro compound according to any one of [1] to [5], wherein the fluorinating agent is hydrogen fluoride.
[10] The method for producing a geminal difluoro compound according to any one of [1] to [9], wherein R ¹ is methyl.
[11] The method for producing a geminal difluoro compound according to any one of [1] to [10], wherein X is a chlorine atom or a bromine atom.
[12] The method for producing a geminal difluoro compound according to the above [11], wherein X is a bromine atom.
[13] The method for producing a geminal difluoro compound according to any one of [1] to [12], wherein the reaction is performed in the presence of a solvent.
[14] The method for producing a geminal difluoro compound according to the above [13], wherein the solvent is a halogen-containing hydrocarbon.

According to the present invention, a novel production method is provided in which geminal difluoro compounds useful as intermediates for medical and agricultural chemicals can be obtained in high yield.

Hereinafter, the present invention will be described in detail.
In the present specification, “n-” means normal, “s-” means secondary, and “t-” means tertiary.
In addition, “(E)” means E-form and “(Z)” means Z-form, which are used for describing chemical structures.

“C _1-4 alkyl” means a linear or branched alkyl having 1 to 4 carbon atoms. Specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl or t-butyl is meant.
“Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

(Method for producing geminal difluoro compound)

The geminal difluoro compound (compound) represented by formula (2) is reacted with the oxime compound (compound (1)) represented by formula (1) in the presence of an N-chloroimide compound. (2)) can be manufactured.

In the present specification, the N-chloroimide compound means an imide compound in which a nitrogen atom is chlorinated. Examples of the N-chloroimide compound used in the present invention include N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate, trichloroisocyanuric acid and the like. A preferred N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid, and a more preferred N-chloroimide compound is trichloroisocyanuric acid.

These N-chloroimide compounds may be used alone or in combination of two or more.

Among the N-chloroimide compounds used in the present invention, trichloroisocyanuric acid is known to be used as a pool disinfectant, deodorant and the like. Furthermore, trichloroisocyanuric acid is known to be a highly stable and inexpensive reagent (Organic Process Research and Development, 2002, Vol. 6, pages 384-393).

The amount of the N-chloroimide compound used is preferably 0.1 equivalents to 100 equivalents, more preferably 0.5 equivalents to 30 equivalents, still more preferably 1 equivalents to 15 equivalents, relative to compound (1). It is.

Examples of the fluorinating agent used in the present invention include hydrogen fluoride-pyridine complex, poly [4-vinylpyridinium poly (hydrogen fluoride)], and the like. A preferred fluorinating agent is a hydrogen fluoride-pyridine complex.

As the fluorinating agent, hydrogen fluoride can also be used.

A compound having a hydrogen fluoride-pyridine complex weight ratio of hydrogen fluoride: pyridine = 70: 30 is known as Olah reagent (Encyclopedia of Reagents for Organic Synthesis, 1995, Vol. 6, 4373-4375). Olah reagent is known to act as hydrogen fluoride which is stabilized and has low volatility, and is suitable for industrial use.

Poly [4-vinylpyridinium poly (hydrogen fluoride)] is a compound composed of a polymer of a pyridine derivative and hydrogen fluoride (Synlett, 1990, pp. 267-269).

For the hydrogen fluoride-pyridine complex used in the present invention, an oral reagent having a weight ratio of hydrogen fluoride: pyridine = 70: 30 can be obtained from, for example, Aldrich, Fluorochem, and the like. Moreover, the thing of the composition whose weight ratio is hydrogen fluoride: pyridine = 60: 40, 50:50, 40:60, and 20:80 is available from Manchester Organics, for example, and hydrogen fluoride: pyridine = A 55:45 composition is available, for example, from Apollo Scientific.

The weight ratio of the hydrogen fluoride-pyridine complex used in the present invention is preferably hydrogen fluoride: pyridine = 70: 30 to 20:80. A more preferred weight ratio is hydrogen fluoride: pyridine = 70: 30 to 50:50, and a more preferred weight ratio is hydrogen fluoride: pyridine = 68: 32 to 63:37.

The amount of the fluorinating agent used in the present invention can be 2 to 1000 equivalents relative to 1 equivalent of the oxime compound represented by the formula (1). The equivalent amount is more preferably 5 to 200 equivalents.

The compound (1) used in the present invention means any one of the oxime compounds represented by the formula (1a) or the formula (1b), or a mixture of the formula (1a) and the formula (1b).

According to the ranking rule, the oxime compound represented by the formula (1a) has the stereochemical structure of (E), and the oxime compound represented by the formula (1b) has the stereochemical structure of (Z).
The compound which is the stereochemistry of (E) and the compound which is the stereochemistry of (Z) are geometric isomers of each other and in many cases they can be isolated. In order to obtain one of the isomers, isomerization to a thermodynamically stable isomer can be performed by fractional recrystallization, hydrochloric acid treatment or the like. In the present invention, it is possible to use only one isomer of the oxime compound, and it is also possible to use a mixture of the oxime compounds of (E) and (Z).

As a general method for producing an oxime compound, for example, a condensation reaction of a carbonyl compound and hydroxylamine can be mentioned, and an oxime compound can be produced according to a method described in known literature (Comprehensive Organic Functional Group Transformations II, 2005, volume 3, pages 451-467).

The solvent used in the present invention is not particularly limited as long as the reaction is not hindered, and examples thereof include the following. Alcohol solvents (eg, methanol, ethanol, 2-propanol), halogen-containing hydrocarbon solvents (eg, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene), aromatic Group halogenated hydrocarbon solvents (eg, chlorobenzene, dichlorobenzene), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene), aliphatic hydrocarbon solvents (eg, hexane, heptane), amine solvents (eg, Triethylamine, N, N-dibutylbutan-1-amine, 2-methyl-N, N-bis (2-methylbutyl) -1-butanamine, N, N-dimethylaniline), pyridine solvents (eg pyridine, picoline) Ether solvents (e.g. dimethyl ether Ether, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, cyclopentylmethyl ether, 1-methoxy-2- (2-methoxyethoxy) ethane) and the like.
Preferred are halogen-containing hydrocarbon solvents, amine solvents, pyridine solvents or ether solvents, more preferred are halogen-containing hydrocarbon solvents, and more preferred are dichloromethane and chloroform.
These solvents may be used alone or in combination of two or more.

The amount of the solvent that can be used in the production method of the present invention is preferably 0 to 1000 times, more preferably 1 to 100 times the oxime compound represented by the formula (1). More preferably, it is 5 to 50 times by weight.

The reaction temperature is not particularly limited but is preferably from −78 ° C. to the reflux temperature of the reaction mixture, more preferably from −60 ° C. to 50 ° C., still more preferably from −40 ° C. to 30 ° C. In another embodiment of the preferred reaction, the temperature is 0 ° C. until about 7 hours from the start of the reaction, and thereafter, at 20 ° C.-30 ° C. for 3-21 hours.
The total reaction time is within about 28 hours, preferably 3 to 21 hours. When hydrogen fluoride is used as the fluorinating agent, it is within about 20 hours, preferably 1 to 5 hours.

The reference synthesis examples and synthesis examples are shown below to describe the present invention in more detail, but the present invention is not limited to these examples.

Proton nuclear magnetic resonance ( ¹ H NMR) in Examples (Synthesis Examples) is carried out in deuterated chloroform using JNM-ECP300 manufactured by JEOL or JNM-ECX300 manufactured by JEOL. The chemical shift was represented by a δ value (ppm) when tetramethylsilane was used as an internal standard (0.0 ppm).
The fluorine nuclear magnetic resonance ( ¹⁹ F NMR) of the example was measured in deuterated chloroform solvent using JNM-ECX300 manufactured by JEOL, and the chemical shift was determined using hexafluorobenzene as an internal standard (-162.2 ppm). ) Value (ppm).

In describing NMR spectra, “s” is singlet, “d” is doublet, “t” is triplet, “q” is quartet, “m” is multiplet, “br” is broad, “J” is coupling constant “Hz” means Hertz and “CDCl ₃ ” means deuterated chloroform.

Synthesis example 1
Production of 1- (1,1-difluoroethyl) -4-bromobenzene

After replacing the inside of a reaction vessel made of a resin of tetrafluoroethylene / perfluoroalkyl vinyl ether copolymer (abbreviated as PFA) with nitrogen gas, hydrogen fluoride-pyridine complex (10.0 g, [63.8% Hydrogen fluoride): 36.2% (pyridine)], 318.8 mmol as hydrogen fluoride, manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, in a reaction vessel, a solution of trichloroisocyanuric acid (2.70 g, 11.62 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) in dichloromethane (30.0 g) was added. Sequentially added, the reaction mixture was stirred at 0 ° C. for 7 h. Furthermore, after raising the reaction temperature to 20 ° C., the mixture was stirred at the same temperature for 3 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the target compound (0.93 g, yield 90%) as a colorless liquid.
¹ H NMR (CDCl ₃ ): δ 7.56 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 1.90 (t, J = 18.3 Hz, 3H).
¹⁹ F NMR (CDCl ₃ ): δ-88.3 (2F, q, J = 18.3 Hz).

Synthesis example 2
Production of 1- (1,1-difluoroethyl) -4-bromobenzene After replacing the inside of a reaction vessel made of PFA resin with nitrogen gas, hydrogen fluoride-pyridine complex (10.0 g, [63.8% (Hydrogen fluoride): 36.2% (pyridine) weight ratio, 318.8 mmol as hydrogen fluoride, manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, a dichloromethane (30.0 g) solution of N-chlorosuccinimide (5.01 g, 37.52 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) was added to the reaction vessel. Were added sequentially and the reaction mixture was stirred at 0 ° C. for 3 h. Further, after raising the reaction temperature to 25 ° C. to 30 ° C., the mixture was stirred at the same temperature for 21 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the target compound (0.94 g, yield 88%) as a colorless liquid.
¹ H NMR (CDCl ₃ ): δ 7.55 (d, J = 8.7 Hz, 1H), 7.37 (d, J = 8.7 Hz, 1H), 1.90 (t, J = 18.2 Hz, 3H).

Synthesis example 3
Production of 1- (1,1-difluoroethyl) -4-bromobenzene After replacing the inside of a reaction vessel made of PFA resin with nitrogen gas, hydrogen fluoride-pyridine complex (10.0 g, [63.8% (Hydrogen fluoride): 36.2% (pyridine) weight ratio, 318.8 mmol as hydrogen fluoride, manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, the reaction vessel was charged with 1,3-dichloro-5,5-dimethylhydantoin (4.60 g, 23.35 mmol) and 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol). Of dichloromethane (30.0 g) was added sequentially and the reaction mixture was stirred at 0 ° C. for 7 h. Furthermore, after raising the reaction temperature to 20 ° C., the mixture was stirred at the same temperature for 3 hours. The reaction was then stopped by adding water to the reaction mixture. Next, chloroform was added to the reaction mixture, and the organic layer was separated. The obtained organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel chromatography (eluent: n-hexane) to obtain the target compound (0.96 g, yield 93%) as a colorless liquid.
¹ H NMR (CDCl ₃ ): δ 7.55 (d, J = 8.6 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 1.90 (t, J = 18.1 Hz, 3H).

In the following Synthesis Examples 4 to 6, ultra-high-speed liquids using 1- (1,1-difluoroethyl) -4-bromobenzene isolated and purified as a standard substance and methyl 4-hydroxybenzoate as an internal standard substance The reaction yield was calculated by a quantitative analysis method using chromatography.
Ultra-high performance liquid chromatography: Waters ACQUITY UPLC H-Class
Column: Waters Acquity UPLC BEH C18 (1.7μm, 2.1x50mm) column
Column oven temperature: 40 ° C
Eluent: Acetonitrile: 10 mM ammonium acetate aqueous solution / acetonitrile = 100/5 (v / v), 30:70 (0-1 min), 30: 70-95: 5 (1-3 min), 95: 5 (3-5 min ), (v / v)
Eluent speed: 0.5 mL / min
Detection wavelength: 230 nm

Synthesis example 4
Production of 1- (1,1-difluoroethyl) -4-bromobenzene After the inside of a reaction vessel made of PFA resin was replaced with nitrogen gas, hydrogen fluoride-pyridine complex (1.00 g, [63.8% (Hydrogen fluoride): 36.2% (pyridine) weight ratio, 31.9 mmol as hydrogen fluoride] (manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, trichloroisocyanuric acid (0.24 g, 1.03 mmol) was added to the reaction vessel, and then 1- (4-bromophenyl) ethanone oxime (103.5 mg, 0.484 mmol) in chloroform (2. 01 g) The solution was added and the reaction mixture was stirred at 0 ° C. for 3 h. Next, the reaction was stopped by adding chloroform and water to the reaction mixture, and after separation, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. When the obtained organic layer was quantified, the quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 97%.

Synthesis example 5
Production of 1- (1,1-difluoroethyl) -4-bromobenzene After the inside of a reaction vessel made of PFA resin was replaced with nitrogen gas, hydrogen fluoride-pyridine complex (1.00 g, [63.8% (Hydrogen fluoride): 36.2% (pyridine) weight ratio, 31.9 mmol as hydrogen fluoride] (manufactured by Aldrich) was added to the reaction vessel and cooled to 0 ° C. Subsequently, trichloroisocyanuric acid (0.23 g, 0.99 mmol) was added to the reaction vessel, and then 1- (4-bromophenyl) ethanone oxime (104.3 mg, 0.487 mmol) was added to react. The mixture was stirred at 0 ° C. for 3 hours 30 minutes. Next, the reaction was stopped by adding chloroform and water to the reaction mixture, and after separation, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. When the obtained organic layer was quantified, the quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 94%.

Synthesis Example 6
In a reaction vessel made of a resin of ethylene trifluoride chloride copolymer, 1- (4-bromophenyl) ethanone oxime (1.00 g, 4.67 mmol) and trichloroisocyanuric acid (2.40 g, 10.33 mmol) Were added sequentially. Next, the reaction vessel was cooled with a dry ice-methanol bath, and hydrogen fluoride (11 mL, 551 mmol) was introduced under reduced pressure. Next, the external temperature of the reaction vessel was kept at −38 to −35 ° C. and stirred for 3 hours. Subsequently, the reaction vessel was cooled with a dry ice-methanol-water bath, and hydrogen fluoride was distilled off under reduced pressure. Next, chloroform and water were added to the reaction vessel and the mixture was stirred and separated, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution. When the obtained organic layer was quantified, the quantitative yield of 1- (1,1-difluoroethyl) -4-bromobenzene (target compound) was 51%.

Reference synthesis example 1
Production of 1- (4-bromophenyl) ethanone oxime

After replacing the inside of the glass reaction vessel with nitrogen gas, 4′-bromoacetophenone (50.0 g, 251.31 mmol), ethanol (100 g), and hydroxyamine hydrochloride (19.6 g, 282.05 mmol) were placed in the reaction vessel. In addition, the reaction mixture was heated to 72 ° C. The reaction mixture was then stirred at 72 ° -80 ° C. for 3 hours. Subsequently, the reaction was stopped by cooling the reaction mixture to 5 ° C. Next, water (100 g) was added to the reaction mixture to precipitate a solid, and after filtration, the obtained solid was washed with a mixed solution of ethanol (50 g) and water (100 g). Furthermore, the obtained solid and ethanol (100 g) were added to the reaction vessel, and the mixture was heated to 65 ° C., and then the reaction mixture was cooled to 4 ° C., and the solid was precipitated again and filtered. The obtained solid was washed with ethanol (50 g) cooled to 0 ° C. and dried under reduced pressure at 50 ° C. for 3 hours to obtain the target compound (26.15 g, yield 49%) as a white solid.
¹ H NMR (CDCl ₃ ): δ 8.59 (s, 1H), 7.50 (s, 4H), 2.27 (s, 3H).

The geminal difluoro compound obtained by the present invention is used in a wide range of fields as a production intermediate for medical and agricultural chemicals.
The entire contents of the specification, claims, and abstract of Japanese Patent Application No. 2014-199055 filed on September 29, 2014 are incorporated herein as the disclosure of the specification of the present invention. Is.

Claims

A method for producing a geminal difluoro compound represented by formula (2), wherein the oxime compound represented by formula (1) is reacted with a fluorinating agent in the presence of an N-chloroimide compound.

[Wherein R 1 represents C 1-4 alkyl, and X represents a halogen atom. ]

[Wherein, R 1 and X represent the same meaning as described above. ]
The geminal difluoro compound according to claim 1, wherein the N-chloroimide compound is N-chlorosuccinimide, N-chlorophthalimide, 1,3-dichloro-5,5-dimethylhydantoin, sodium dichloroisocyanurate or trichloroisocyanuric acid. Manufacturing method.
The method for producing a geminal difluoro compound according to claim 2, wherein the N-chloroimide compound is N-chlorosuccinimide, 1,3-dichloro-5,5-dimethylhydantoin or trichloroisocyanuric acid.
The geminal difluoro compound according to any one of claims 1 to 3, wherein the abundance of the N-chloroimide compound is 0.1 to 100 equivalents relative to 1 equivalent of the oxime compound of the formula (1). Production method.
The method for producing a geminal difluoro compound according to any one of claims 1 to 4, wherein the amount of the fluorinating agent used is 2 to 1000 equivalents relative to 1 equivalent of the oxime compound of the formula (1).
The method for producing a geminal difluoro compound according to any one of claims 1 to 5, wherein the fluorinating agent is a hydrogen fluoride-pyridine complex or poly [4-vinylpyridinium poly (hydrogen fluoride)].
The method for producing a geminal difluoro compound according to claim 6, wherein the fluorinating agent is a hydrogen fluoride-pyridine complex.
The method for producing a geminal difluoro compound according to claim 7, wherein the weight ratio of hydrogen fluoride to pyridine in the hydrogen fluoride-pyridine complex is 70:30 to 20:80.
The method for producing a geminal difluoro compound according to any one of claims 1 to 5, wherein the fluorinating agent is hydrogen fluoride.
The method for producing a geminal difluoro compound according to any one of claims 1 to 9, wherein R 1 is methyl.
The method for producing a geminal difluoro compound according to any one of claims 1 to 10, wherein X is a chlorine atom or a bromine atom.
The method for producing a geminal difluoro compound according to claim 11, wherein X is a bromine atom.
The method for producing a geminal difluoro compound according to any one of claims 1 to 12, wherein the reaction is carried out in the presence of a solvent.
The method for producing a geminal difluoro compound according to claim 13, wherein the solvent is a halogen-containing hydrocarbon.