JP2013216605A - Method of producing 3-difluoroalkyl pyrazole compound - Google Patents

Abstract

【選択図】なしThe present invention provides a method for efficiently producing a 3-difluoroalkylpyrazole compound useful as an intermediate for producing pharmaceuticals and agricultural chemicals.
A pyrazole compound represented by the following general formula (1) and a compound represented by the general formula (2) are reacted in the presence of a reaction initiator, a base and an inert solvent. (3) The method to manufacture the compound represented.
[Chemical 1]

[Selection figure] None

Description

  The present invention relates to a method for producing a 3-difluoroalkylpyrazole compound useful as an intermediate for producing pharmaceuticals and agricultural chemicals.

  The 3-difluoroalkylpyrazole compound obtained by the present invention is very useful as an intermediate for producing the following 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, which is a component of pharmaceuticals and agricultural chemicals.

  Until now, as a method for obtaining 3-difluoroalkylpyrazole compounds, starting from a difluoroacetic acid derivative such as ethyl difluoroacetate, this is reacted with ethyl acetate, further reacted with an alkoxy compound, and further reacted with methylhydrazine. A method of synthesizing through a plurality of steps is known (see Patent Document 1). In addition, a method of obtaining a 3-difluoroalkylpyrazole compound by synthesizing a ketoester from chlorodifluoromethyl acid chloride and ketene and then cyclizing is also known (see Patent Document 2).

Special table 2010-528071 gazette International Publication No. 2012/010692

However, in the method described in Patent Document 1, three reaction steps are required to obtain a 3-difluoroalkylpyrazole compound from a difluoroacetic acid derivative. Therefore, not only the operation and work in the production of the target product become complicated, but also the reaction takes a long time. In addition, the starting difluoroacetic acid derivative is expensive.
On the other hand, the method described in Patent Document 2 requires a complicated technique (use of ketene).
Therefore, it has been desired to develop a method for producing a 3-difluoroalkylpyrazole compound, which is simpler in operation and work and advantageous in terms of process time than the conventional technology.

  In view of the situation as described above, the present inventor conducted extensive research on a method for producing a 3-difluoroalkylpyrazole compound, and as a result, by reacting the pyrazole compound with a halogenated difluoromethane, the 3-difluoroalkylpyrazole compound. Has been found to be synthesized in a single step, and the present invention has been completed.

That is, the present invention relates to the following <1> to <3>.
<1> A pyrazole compound represented by the following general formula (1) and a compound represented by the general formula (2) are reacted in the presence of a reaction initiator, a base and an inert solvent. A method for producing the compound represented by 3).

(Where
R ¹ may have a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or a substituent. Good phenyl group, optionally substituted naphthyl group, optionally substituted heteroaryl group, cyano group, —C (═O) —OR ^1a , —C (═O) —NR ^1b R ^1c , -C (= O) -SR ^1d or -C (= S) -SR ^1e .
R ² represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkoxy group having 3 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, The alkylthio group having 1 to 8 carbon atoms, the cycloalkylthio group having 3 to 8 carbon atoms, the alkenylthio group having 2 to 8 carbon atoms, or —NR ^1b R ^{1c, in} which a hydrogen atom may be substituted with a halogen atom.
R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1a , R ^1d and R ^1e are each independently an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. C 1-4 alkyl group having an alkoxy group, C 1-4 alkyl group having a C 3-8 cycloalkyl group, C 1-4 having a C 3-8 cycloalkoxy group An alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, and Y represents a chlorine atom, a bromine atom or an iodine atom. )
<2> A pyrazole compound represented by the following general formula (1) and a compound represented by the general formula (4) are reacted in the presence of a reaction initiator, a base and an inert solvent, and the following general formula ( A method for producing a compound represented by the following general formula (6), wherein the compound represented by 5) is obtained and the compound represented by the general formula (5) is reduced.

(Where
R ¹ may have a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or a substituent. Good phenyl group, optionally substituted naphthyl group, optionally substituted heteroaryl group, cyano group, —C (═O) —OR ^1a , —C (═O) —NR ^1b R ^1c , -C (= O) -SR ^1d or -C (= S) -SR ^1e .
R ² represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkoxy group having 3 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, The alkylthio group having 1 to 8 carbon atoms, the cycloalkylthio group having 3 to 8 carbon atoms, the alkenylthio group having 2 to 8 carbon atoms, or —NR ^1b R ^{1c, in} which a hydrogen atom may be substituted with a halogen atom.
R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1a , R ^1d and R ^1e are each independently an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. C 1-4 alkyl group having an alkoxy group, C 1-4 alkyl group having a C 3-8 cycloalkyl group, C 1-4 having a C 3-8 cycloalkoxy group An alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X ′ represents a chlorine atom, a bromine atom or an iodine atom.
Y represents a chlorine atom, a bromine atom or an iodine atom. )
<3> A compound represented by the following general formula (7).

(Where
R ¹ ′ represents —C (═O) —OR ^1a . R ² ′ represents a hydrogen atom, a halogen atom or —NR ^1b R ^1c . R ³ ′ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
R ^1a is a C 1-4 alkyl having a C 1-8 alkyl group, a C 3-8 cycloalkyl group, or a C 1-4 alkoxy group in which a hydrogen atom may be substituted with a halogen atom. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkoxy group having 3 to 8 carbon atoms, It represents an alkenyl group, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X ′ represents a chlorine atom, a bromine atom or an iodine atom. )

  According to the present invention, the 3-difluoroalkylpyrazole compound represented by the general formula (3) can be produced from the pyrazole compound represented by the general formula (1) in a single step. Since the method for producing a 3-difluoroalkylpyrazole compound according to the present invention is a single step, it is easy to operate and work, and is advantageous for production on an industrial scale in terms of process time. This is extremely useful as a production method.

Hereinafter, the present invention will be described in detail.
The “compound represented by the general formula (X)” is also referred to as “compound (X)”.

  In the production method of the present invention, a pyrazole compound represented by the following general formula (1) and a halogenated difluoromethane represented by the general formula (2) are present in the presence of a reaction initiator, a base and an inert solvent. React. Thereby, a difluoroalkyl group can be directly introduced into the 3-position of the pyrazole ring, and a 3-difluoroalkylpyrazole compound represented by the following general formula (3) can be obtained in a single step.

<Compound represented by the general formula (1)>
The definitions of R ^{1 to} R ³ in the general formula (1) are as follows.
R ¹ may have a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or a substituent. Good phenyl group, optionally substituted naphthyl group, optionally substituted heteroaryl group, cyano group, —C (═O) —OR ^1a , —C (═O) —NR ^1b R ^1c , -C (= O) -SR ^1d or -C (= S) -SR ^1e .

Examples of the substituent that the phenyl group, naphthyl group, and heteroaryl group may have include a halogen atom, a cyano group, a nitro group, and a C 1-4 alkyl group in which a hydrogen atom may be substituted with a halogen atom. , An alkoxy group having 1 to 4 carbon atoms which may have a halogen atom, an alkylthio group having 1 to 4 carbon atoms which may have a halogen atom, -C (= O) -OR ^1f , -C (= O ) —NR ^1g R ^1h , —S (═O) —R ¹ⁱ and —S (═O) ₂ —R ^1j . The phenyl group, naphthyl group and heteroaryl group may have 1 to 3 substituents independently selected from the above.

Here, R ^1a , R ^1d , R ^1e and R ^1f are each independently an alkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. An alkyl group having 1 to 4 carbon atoms having an alkoxy group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, and a cycloalkoxy group having 3 to 8 carbon atoms. It represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
Here, the substituent that the benzyl group and the phenyl group may have includes a halogen atom, a cyano group, a nitro group, an alkyl group having 1 to 4 carbon atoms that may have a halogen atom, and a halogen atom. Examples thereof may include an alkoxy group having 1 to 4 carbon atoms. The benzyl group and the phenyl group may have 1 to 3 substituents independently selected from the above.

R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
Here, examples of the substituent that the benzyl group, the phenyl group, and the biphenyl group may have include a halogen atom, a cyano group, a nitro group, and an alkyl having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. Group, a C 1-4 alkoxy group in which a hydrogen atom may be substituted with a halogen atom. The benzyl group, phenyl group and biphenyl group may have 1 to 3 substituents independently selected from the above.

R ^1c , R ^1g and R ^1h each independently represent a hydrogen atom, a C 1-8 alkyl group in which the hydrogen atom may be substituted with a halogen atom, a C 3-8 cycloalkyl group, a carbon number C1-C4 alkyl group having 1-4 alkoxy groups, C1-C4 alkyl groups having C3-C8 cycloalkyl groups, C2-C8 alkenyl groups, and substituents Represents a phenyl group which may have a benzyl group or a substituent which may be substituted.
Here, as the substituent that the benzyl group and the phenyl group may have, a halogen atom, a cyano group, a nitro group, a C1-C4 alkyl group in which a hydrogen atom may be substituted with a halogen atom, hydrogen Examples thereof include an alkoxy group having 1 to 4 carbon atoms in which an atom may be substituted with a halogen atom. The benzyl group and the phenyl group may have 1 to 3 substituents independently selected from the above.

R ¹ⁱ and R ^1j are each independently an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom or a carbon atom having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. An alkoxy group;

R ¹ is preferably —C (═O) —OR ^1a or —C (═O) —NR ^1b R ^1c from the viewpoint of the synthesis method.
As R ^1a , R ^1b , and R ^1c , any of a hydrogen atom, a methyl group, and an ethyl group is preferable independently from the viewpoint of the synthesis method.

R ² represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkoxy group having 3 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, The alkylthio group having 1 to 8 carbon atoms, the cycloalkylthio group having 3 to 8 carbon atoms, the alkenylthio group having 2 to 8 carbon atoms, or —NR ^1b R ^{1c, in} which a hydrogen atom may be substituted with a halogen atom. R ^1b, meaning of ^{R 1c} is the same as ^{R 1b, R 1c} described in the above ^{R 1.}

R ² is preferably a hydrogen atom, a halogen atom, a C 1-8 alkoxy group in which the hydrogen atom may be substituted with a halogen atom, or —NR ^1b R ^1c from the viewpoint of the synthesis method.
R ^1b and R ^1c are each independently preferably a hydrogen atom, a methyl group or an ethyl group.

R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.

  Here, as the substituent that the benzyl group and the phenyl group may have, a halogen atom, a cyano group, a nitro group, a C1-C4 alkyl group in which a hydrogen atom may be substituted with a halogen atom, hydrogen Examples thereof include an alkoxy group having 1 to 4 carbon atoms in which an atom may be substituted with a halogen atom. The benzyl group and the phenyl group may have 1 to 3 substituents independently selected from the above.

R ³ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

<Compound represented by formula (2)>
In the general formula (2) CF ₂ XY, X represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, and Y represents a chlorine atom, a bromine atom or an iodine atom.
Among these, from the viewpoint of handling, X is preferably a hydrogen atom, bromine atom or iodine atom, and Y is preferably a bromine atom or iodine atom.
If X is a hydrogen atom, the target compound 3-difluoromethylpyrazole (general formula (6) described later) can be directly synthesized from the starting pyrazole compound (1), and therefore the reduction reaction step described later can be omitted.
When X is other than a hydrogen atom, X and Y may be the same or different, and it is preferable that X and Y are both bromine atoms or iodine atoms.

  As the pyrazole compound of the general formula (1) and the difluoromethane compound of the general formula (2), known substances can be used.

<Reaction initiator>
As the reaction initiator, a reducing agent, a radical initiator, light irradiation, or the like can be used.
As the reducing agent, for example, dithionite such as sodium dithionite and potassium dithionite or zinc-sulfite aqueous solution can be used, and the amount used is not particularly limited, but usually a reaction raw material (pyrazole compound (1) 1) About 1/100 to 10 equivalents, preferably 1/10 to 2 equivalents.
As radical initiators, 2,2′-azobisisobutyronitrile, 2,2′-azobis (2,4-dimethylvaleronitrile), 2,2′-azobis (2-butyronitrile), dimethyl-2, Azo compounds such as 2′-azobisisobutyrate and 1,1′-azobis (cyclohexane-1-carbonitrile); benzoyl peroxide, lauryl peroxide, octanoyl peroxide, acetyl peroxide, di-t-butyl Peroxides such as peroxide, t-butylcumyl peroxide, dicumyl peroxide, t-butylperoxyacetate, t-butylperoxybenzoate, t-butylperoxyneodecanoate; and tetraethylthiuram disulfide Dithiocarbamate; and the like can be used.
The light source used for the light irradiation is not particularly limited as long as it has sufficient energy for starting the reaction. For example, a high-pressure mercury lamp can be used. The reducing agent, radical initiator or light irradiation as the reaction initiator may be used alone or in combination.

<Base>
As the base, an inorganic base or an organic base can be used. Examples of the inorganic base include alkali metal carbonates such as sodium bicarbonate, sodium carbonate and potassium carbonate; inorganic bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; and organic bases such as triethylamine, Organic bases such as 4-dimethylaminopyridine can be used.

<Phase transfer catalyst>
In the reaction of the pyrazole compound (1) and the difluoromethane compound (2), it is preferable to use a phase transfer catalyst. Examples of the phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and tetrabutylammonium hydrogen sulfate, organophosphorus compounds such as tetrabutylphosphonium bromide, and alkyl polyether alkyls such as tris (methoxyethoxyethyl) amine. Amine compounds can be used. Although a phase transfer catalyst is not always necessary, it may give better results. The amount of the phase transfer catalyst used is not limited, but is usually about 1/500 to 2 equivalents, preferably about 1/50 to 1 equivalent, relative to the reaction raw material (pyrazole compound (1)) 1.

<Inert solvent>
The inert solvent is not particularly limited as long as it does not significantly inhibit the progress of the reaction. For example, an ether solvent such as diethyl ether, tetrahydrofuran, dioxane, or t-butyl methyl ether, a halogen solvent such as dichloroethane, or an inert solvent such as nitrobenzene. Benzene solvents, ketone solvents such as acetone and cyclohexanone, ester solvents such as ethyl acetate, nitrile solvents such as acetonitrile and pivalonitrile, amide solvents such as N, N-dimethylformamide, water, etc. can be used. These inert solvents can be used alone or in admixture of two or more.

  Moreover, when using a phase transfer catalyst, it can also react by a two-phase system combining water and other inert solvents other than water as an inert solvent. Other inert solvents can be appropriately selected from the above inert solvents. Good results are obtained by using a two-phase system of water and other inert solvents.

<Reaction temperature>
The reaction can be carried out at a temperature close to the boiling point of the solvent used under the conditions from −20 ° C. It is advantageous in industrial production to carry out at a temperature of preferably about 0 to 50 ° C.

<Reaction time>
While the reaction time varies depending on the reaction conditions, it is usually from several minutes to several tens of hours, preferably from about 30 minutes to 24 hours.
In this reaction, the target compound represented by the following general formula (3) can be produced by isolating the target product from the reaction system by a conventional method after completion of the reaction and purifying it as necessary.

<Compound represented by formula (3)>
The meanings of R ^{1 to} R ³ and X in the 3-difluoroalkylpyrazole compound represented by the following general formula (3) are the same as the meanings in the above general formulas (1) and (2).

When R ¹ is other than —C (═O) —OH, it can be converted to —C (═O) —OH by post-treatment such as hydrolysis. For example, when R ¹ is —C (═O) —OR ^1a , it can be converted to —C (═O) —OH by hydrolysis using sodium hydroxide or the like.

When R ² is a hydrogen atom, a regioisomer of pyrazole may also be formed. However, by carrying out separation by purification or the like, the target compound having a difluoroalkyl group at the 3-position can be obtained. Further, the positional isomer of pyrazole can be converted into a compound having a difluoroalkyl group at the 3-position by isomerization (see International Publication No. 2012/019950). Therefore, even if a regioisomer of pyrazole is produced, the substantially desired product can be obtained.

When R ² is other than a hydrogen atom, R ² can be converted to a hydrogen atom by performing a reductive treatment. For example, when R ² is —NH ₂ , it can be reductively converted to a hydrogen atom via a diazonium salt. When the substituent on the nitrogen atom is a protective group, the substituent on the nitrogen atom can be converted to a hydrogen atom by performing a deprotection reaction usually used in an organic synthesis reaction.

  As a compound represented by Formula (3), the compound represented by following General formula (7) is preferable.

(In the formula, R ¹ ′ represents —C (═O) —OR ^1a . R ² ′ represents a hydrogen atom, a halogen atom or —NR ^1b R ^1c . R ³ ′ represents a hydrogen atom or a carbon number of 1 to 4. X ′ represents a chlorine atom, a bromine atom or an iodine atom.
R ^1a , R ^1b and R ^1c have the same meaning as described above. )

The method for isolating the target compound (3) after the synthesis is not particularly limited, but the target compound is slightly dissolved not only in the organic layer after the reaction but also in the aqueous layer. It is preferable to extract using an organic solvent. It is more preferable to perform the extraction three times or more.
The original organic layer and the organic layer extracted from the aqueous layer are combined and desolvated and filtered, and then the solvent is distilled off. A commonly used solvent removal agent may be used, but sodium sulfate is preferably used. Moreover, atmospheric distillation or vacuum distillation is preferably used for distilling off the organic solvent.
The residue after distilling off the organic solvent can be purified to obtain the target compound. The purification method is not particularly limited, and examples thereof include recrystallization and silica column chromatography.

  In addition, since the method for producing a 3-difluoroalkylpyrazole compound according to the present invention is a single step, the residue after completion of the synthesis reaction is reused, and the yield of the target compound is obtained through the same synthesis process. Can be substantially increased.

<Reduction reaction>
In the present invention, when the halogenated difluoromethane CF ₂ X′Y represented by the general formula (4) is used, the compound (5) obtained by the reaction described above is represented by the following general formulas (5-1) to (5-3). It is either of the compounds represented by these.

  By reducing the compounds represented by these general formulas (5-1) to (5-3), a compound represented by the following general formula (6) can be synthesized.

As the reduction reaction, a reduction reaction using a metal catalyst or a light irradiation reaction can be used.
As the metal catalyst, a transition metal catalyst such as nickel, palladium, platinum, rhodium, iridium, iron, ruthenium can be used, and the reaction can be performed in a hydrogen atmosphere.
The light source used for the light irradiation is not particularly limited as long as it has sufficient energy for starting the reaction. For example, a high pressure mercury lamp can be used, and hydrogen or hydrogen such as isopropyl alcohol can be used. The reaction can be carried out in the presence of a source.

  EXAMPLES The present invention will be specifically described below with reference to examples. However, the present invention is not limited to these examples.

Example 1: Synthesis of ethyl 5-amino-3-bromodifluoromethyl-1-methylpyrazole-4-carboxylate
Ethyl 5-amino-1-methylpyrazole-4-carboxylate (10 g), dibromodifluoromethane (manufactured by Aldrich, 24.8 g), sodium dithionite (Tokyo Kasei Co., Ltd.) synthesized by a known method in a 200 mL autoclave 20.6 g), sodium hydrogen carbonate (manufactured by Kanto Chemical Co., Ltd., 9.9 g) and tetrabutylammonium bromide (manufactured by Junsei Chemical Co., Ltd., 1.9 g) in acetonitrile (35.5 mL) and water (41.4 mL). It melt | dissolved in the mixed solvent and stirred at room temperature for 20 hours. After completion of the reaction, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted three times with diethyl ether (100 mL). The organic layer and the layer extracted with diethyl ether were combined, dried over sodium sulfate, filtered, and the organic solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography to obtain the labeled compound as a pale yellow solid (yield 3.3 g, yield 20%).

The obtained compound (a) was identified by ¹ H-NMR and ¹⁹ F-NMR. The results of the NMR chart are shown below.
¹ H-NMR (300 MHz, deuterated chloroform): δ = 1.38 (t, 3H), 3.66 (s, 3H), 4.31 (q, 2H), 5.42 (brs, 2H)
¹⁹ F-NMR (300 MHz, deuterated chloroform)): δ = −47.1 (s, 2F)

<Example 2: Synthesis of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate>
The reaction was carried out under the same conditions as in Example 1, except that ethyl 1-methylpyrazole-4-carboxylate instead of ethyl 5-amino-1-methylpyrazole-4-carboxylate and difluoroiodomethane instead of dibromodifluoromethane were used. And a mixture of the labeled compound and its isomer was obtained.

  According to the present invention, a 3-difluoroalkylpyrazole compound useful as a production intermediate for pharmaceuticals, agricultural chemicals, and the like can be obtained by a single process, and therefore, pharmaceuticals and agricultural chemicals themselves are advantageous in terms of convenience and process time. Production is expected.

Claims (3)

In the following general formula (3), a pyrazole compound represented by the following general formula (1) and a compound represented by the general formula (2) are reacted in the presence of a reaction initiator, a base and an inert solvent. A method for producing the represented compound.

(Where
R ¹ may have a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or a substituent. Good phenyl group, optionally substituted naphthyl group, optionally substituted heteroaryl group, cyano group, —C (═O) —OR ^1a , —C (═O) —NR ^1b R ^1c , -C (= O) -SR ^1d or -C (= S) -SR ^1e .
R ² represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkoxy group having 3 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, The alkylthio group having 1 to 8 carbon atoms, the cycloalkylthio group having 3 to 8 carbon atoms, the alkenylthio group having 2 to 8 carbon atoms, or —NR ^1b R ^{1c, in} which a hydrogen atom may be substituted with a halogen atom.
R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1a , R ^1d and R ^1e are each independently an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. C 1-4 alkyl group having an alkoxy group, C 1-4 alkyl group having a C 3-8 cycloalkyl group, C 1-4 having a C 3-8 cycloalkoxy group An alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X represents a hydrogen atom, a chlorine atom, a bromine atom or an iodine atom, and Y represents a chlorine atom, a bromine atom or an iodine atom. ) A pyrazole compound represented by the following general formula (1) and a compound represented by the general formula (4) are reacted in the presence of a reaction initiator, a base and an inert solvent, and the following general formula (5) The method to manufacture the compound represented by the following general formula (6) which obtains the compound represented and reduces the compound represented by the said General formula (5).

(Where
R ¹ may have a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or a substituent. Good phenyl group, optionally substituted naphthyl group, optionally substituted heteroaryl group, cyano group, —C (═O) —OR ^1a , —C (═O) —NR ^1b R ^1c , -C (= O) -SR ^1d or -C (= S) -SR ^1e .
R ² represents a hydrogen atom, a halogen atom, an alkoxy group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkoxy group having 3 to 8 carbon atoms, an alkenyloxy group having 2 to 8 carbon atoms, The alkylthio group having 1 to 8 carbon atoms, the cycloalkylthio group having 3 to 8 carbon atoms, the alkenylthio group having 2 to 8 carbon atoms, or —NR ^1b R ^{1c, in} which a hydrogen atom may be substituted with a halogen atom.
R ³ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1a , R ^1d and R ^1e are each independently an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, or an alkyl group having 1 to 4 carbon atoms in which a hydrogen atom may be substituted with a halogen atom. C 1-4 alkyl group having an alkoxy group, C 1-4 alkyl group having a C 3-8 cycloalkyl group, C 1-4 having a C 3-8 cycloalkoxy group An alkyl group having 2 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X ′ represents a chlorine atom, a bromine atom or an iodine atom.
Y represents a chlorine atom, a bromine atom or an iodine atom. ) A compound represented by the following general formula (7).

(Where
R ¹ ′ represents —C (═O) —OR ^1a . R ² ′ represents a hydrogen atom, a halogen atom or —NR ^1b R ^1c . R ³ ′ represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
R ^1a is a C 1-4 alkyl having a C 1-8 alkyl group, a C 3-8 cycloalkyl group, or a C 1-4 alkoxy group in which a hydrogen atom may be substituted with a halogen atom. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkoxy group having 3 to 8 carbon atoms, It represents an alkenyl group, an optionally substituted benzyl group or an optionally substituted phenyl group.
R ^1b is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, a benzyl group that may have a substituent, a substituent The phenyl group which may have a group, or the biphenyl group which may have a substituent is represented.
R ^1c is a carbon atom having a hydrogen atom, an alkyl group having 1 to 8 carbon atoms in which the hydrogen atom may be substituted with a halogen atom, a cycloalkyl group having 3 to 8 carbon atoms, or an alkoxy group having 1 to 4 carbon atoms. An alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms having a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an optionally substituted benzyl group or a substituent. The phenyl group which may have is represented.
X ′ represents a chlorine atom, a bromine atom or an iodine atom. )