JP2018083758A - Method for producing pyrazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel method for producing a 3-substituted-4-trifluoromethyl pyrazole derivative and a 3-substituted-pyrazole-4-carboxylic acid derivative, useful as intermediates of medicines and agrochemicals, and a novel intermediate compound in the method.SOLUTION: A method for producing a pyrazole derivative (5) includes reacting a compound (1) with a compound (2) to obtain a compound (3), and then reacting the compound (3) with a compound (4), and a method for producing a pyrazole-4-carboxylic acid derivative includes hydrolyzing the pyrazole derivative (5).SELECTED DRAWING: None

Description

  The present invention relates to a novel process for producing 3-substituted-4-trifluoromethylpyrazole derivatives and 3-substituted-pyrazole-4-carboxylic acid derivatives that are useful as intermediates for pharmaceuticals and agricultural chemicals, and novel intermediates in the above methods It relates to compounds.

  3-Substituted-4-trifluoromethylpyrazole derivatives and 3-substituted-pyrazole-4-carboxylic acid derivatives are useful as intermediates for pharmaceuticals and agricultural chemicals, and some production methods have been reported so far. For example, as an intermediate of a pyrazole compound useful for the treatment of inflammation, ethyl 4,4,4-trifluoro-butyrate and trimethylsilyldiazomethane are reacted to give ethyl 4-trifluoromethylpyrazole-3-carboxylate A production method has been reported (for example, see Patent Document 1). In addition, a process for producing ethyl 1-methyl-4-trifluoromethyl-1H-pyrazole-3-carboxylate by reacting ethyl 4,4,4-trifluoro-butyrate with 3-methylcydnone has been reported. (For example, refer to Patent Document 2).

International Publication No. 2007/045868 International Publication No. 2007/071900

  However, ethyl 4,4,4-trifluoro-butyrate, which is one of the raw materials of these production methods, is expensive, and trimethylsilyldiazomethane and 3-methyl sydnone, which are the other raw materials, are unstable and difficult to handle. The production method is not industrially suitable. An object of the present invention is to provide an easier, more economical and practical production method for producing 3-substituted-4-trifluoromethylpyrazole derivatives and 3-substituted-pyrazole-4-carboxylic acid derivatives. It is.

［ただし、
Ｒ^１は、Ｃ１〜８のアルキル基、Ｃ１〜８のハロアルキル基、Ｃ３〜８のシクロアルキル基、置換基を有するＣ３〜８のシクロアルキル基、アリール基、置換基を有するアリール基、ヘテロアリール基、置換基を有するヘテロアリール基又はエステル基。
Ｒ^２は、水素原子又はＣ１〜８のアルキル基。
Ｒ^Ａは、ＯＲ^３又はＮＲ^４Ｒ^５（ただし、Ｒ^３は、Ｃ１〜８のアルキル基、アリール基又は置換基を有するアリール基。Ｒ^４及びＲ^５は、互いに独立して、水素原子、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^４及びＲ^５は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。）。
Ｘは、ハロゲン原子。
Ｙ^１は、酸素原子又はＮ^＋Ｒ^６Ｒ^７・Ａ⁻（ただし、Ｒ^６及びＲ^７は、互いに独立して、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^６及びＲ^７は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。Ａ⁻は、カウンターアニオン。）。
また、式（３）における波線は、Ｒ^Ａの結合位置がＥであってもＺであってもよいことを示す。］。 As a result of intensive studies in view of the above problems, the present inventors have completed the present invention.
The present invention is as follows:
[1] A compound represented by the following formula (3) is obtained by reacting a compound represented by the following formula (1) with a compound represented by the following formula (2): A method for producing a pyrazole derivative, comprising: reacting a compound represented by the following formula (4) with a compound represented by the following formula (4) to obtain a pyrazole derivative represented by the following formula (5):

[However,
R ¹ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, an aryl group having a substituent, heteroaryl Group, a heteroaryl group or an ester group having a substituent.
R ² is a hydrogen atom or a C1-8 alkyl group.
R ^A is OR ³ or NR ⁴ R ⁵ (wherein R ³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ⁴ and R ⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
X is a halogen atom.
Y ¹ represents an oxygen atom or N ⁺ R ⁶ R ⁷ • A ⁻ (where R ⁶ and R ⁷ are each independently a C 1-8 alkyl group, aryl group or aryl group having a substituent, or R ⁶ and R ⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3) shows that the coupling | bonding position of ^RA may be E or Z. ].

［ただし、
Ｒ^１は、Ｃ１〜８のアルキル基、Ｃ１〜８のハロアルキル基、Ｃ３〜８のシクロアルキル基、置換基を有するＣ３〜８のシクロアルキル基、アリール基、置換基を有するアリール基、ヘテロアリール基、置換基を有するヘテロアリール基又はエステル基。
Ｒ^２は、水素原子又はＣ１〜８のアルキル基。
Ｒ^Ａは、ＯＲ^３又はＮＲ^４Ｒ^５（ただし、Ｒ^３は、Ｃ１〜８のアルキル基、アリール基又は置換基を有するアリール基。Ｒ^４及びＲ^５は、互いに独立して、水素原子、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^４及びＲ^５は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。）。
Ｙ^１は、酸素原子又はＮ^＋Ｒ^６Ｒ^７・Ａ⁻（ただし、Ｒ^６及びＲ^７は、互いに独立して、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^６及びＲ^７は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。Ａ⁻は、カウンターアニオン。）。
また、式（３）における波線は、Ｒ^Ａの結合位置がＥであってもＺであってもよいことを示す。］。 [2] A pyrazole derivative obtained by reacting a compound represented by the following formula (3) with a compound represented by the following formula (4) to obtain a pyrazole derivative represented by the following formula (5) Manufacturing method.

[However,
R ¹ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, an aryl group having a substituent, heteroaryl Group, a heteroaryl group or an ester group having a substituent.
R ² is a hydrogen atom or a C1-8 alkyl group.
R ^A is OR ³ or NR ⁴ R ⁵ (wherein R ³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ⁴ and R ⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
Y ¹ represents an oxygen atom or N ⁺ R ⁶ R ⁷ • A ⁻ (where R ⁶ and R ⁷ are each independently a C 1-8 alkyl group, aryl group or aryl group having a substituent, or R ⁶ and R ⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3) shows that the coupling | bonding position of ^RA may be E or Z. ].

[3] The method for producing a pyrazole derivative according to the above [1] or [2], wherein R ¹ is a difluoromethyl group.

（ただし、
Ｒ^１１は、Ｃ１〜８のアルキル基、Ｃ１〜８のハロアルキル基（ただし、トリハロメチル基を除く）、Ｃ３〜８のシクロアルキル基、置換基を有するＣ３〜８のシクロアルキル基、アリール基、置換基を有するアリール基、ヘテロアリール基又は置換基を有するヘテロアリール基。
Ｒ^２は、水素原子又はＣ１〜８のアルキル基。） [4] A method for producing a pyrazole-4-carboxylic acid derivative represented by the following formula (6), wherein the compound represented by the following formula (5a) is hydrolyzed.

(However,
R ¹¹ is a C1-8 alkyl group, a C1-8 haloalkyl group (excluding a trihalomethyl group), a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, An aryl group having a substituent, a heteroaryl group, or a heteroaryl group having a substituent;
R ² is a hydrogen atom or a C1-8 alkyl group. )

[5] The method for producing a pyrazole-4-carboxylic acid derivative according to the above [4], wherein R ¹¹ is a difluoromethyl group.

[6] The method for producing a pyrazole-4-carboxylic acid derivative according to the above [4] or [5], wherein the hydrolysis is performed in the presence of an acid.

[7] The method for producing a pyrazole-4-carboxylic acid derivative according to the above [6], wherein the acid is fuming sulfuric acid.

[8] The pyrazole-4-carboxylic acid derivative according to any one of [4] to [7] above, wherein the compound represented by the formula (5a) is obtained by the production method according to [1] or [2]. Manufacturing method.

[9] The method for producing a pyrazole-4-carboxylic acid derivative according to any one of the above [4] to [8], wherein R ¹ is a difluoromethyl group.

［ただし、
Ｒ^Ａ１は、ＯＲ^１３又はＮＲ^１４Ｒ^１５（ただし、Ｒ^１３は、Ｃ１〜８のアルキル基、アリール基又は置換基を有するアリール基。Ｒ^１４及びＲ^１５は、互いに独立して、水素原子、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^１４及びＲ^１５は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。）。
Ｙ^１１は、酸素原子又はＮ^＋Ｒ^１６Ｒ^１７・Ａ⁻（ただし、Ｒ^１６及びＲ^１７は、互いに独立して、Ｃ１〜８のアルキル基、アリール基もしくは置換基を有するアリール基。又はＲ^１６及びＲ^１７は、互いに結合して、それらが結合している窒素原子と一緒になって５〜６員のヘテロ環基を形成してもよい。Ａ⁻は、カウンターアニオン。）。
また、式（３ｃ）における波線は、Ｒ^Ａ１の結合位置がＥであってもＺであってもよいことを示す。］。 [10] A compound represented by the following formula (3c).

[However,
R ^A1 is OR ¹³ or NR ¹⁴ R ¹⁵ (where R ¹³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ¹⁴ and R ¹⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
Y ¹¹ represents an oxygen atom or N ⁺ R ¹⁶ R ¹⁷ · A ⁻ (where R ¹⁶ and R ¹⁷ are each independently a C1-8 alkyl group, aryl group or aryl group having a substituent, or R ¹⁶ and R ¹⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3c) shows that the coupling ^| bonding position of RA1 may be E or Z. ].

（ただし、
Ｒ^１２は、水素原子又はＣ１〜８のアルキル基。）。 [11] A compound represented by the following formula (5b).

(However,
R ¹² represents a hydrogen atom or a C1-8 alkyl group. ).

  According to the production method of the present invention, 3-substituted-4-trifluoromethylpyrazole derivatives and 3-substituted-pyrazole-4-carboxylic acid derivatives useful as intermediates for pharmaceuticals and agricultural chemicals can be easily produced. Also provided are novel compounds useful in the production. Further, the production method of the present invention is an industrially and economically excellent method because it does not use expensive raw materials and has high selectivity and yield.

Hereinafter, embodiments of the present invention will be described in detail.
[Definition of terms]
In the present specification, a numerical range indicated using “to” indicates a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively. C1 indicates that the number of carbon atoms is 1, and the same applies to other expressions.

  In the present invention, the “C1-8 alkyl group” means a linear or branched alkyl group having 1 to 8 carbon atoms, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl. Group, s-butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group and the like.

  The “C1-8 haloalkyl group” means a group in which one or more hydrogen atoms of the alkyl group are substituted with a halogen atom. Examples of the halogen atom include a bromine atom, an iodine atom, a fluorine atom, and a chlorine atom. Examples of the C1-8 haloalkyl group include bromomethyl group, 2-bromoethyl group, 3-bromopropyl group, 4-bromobutyl group, 5-bromopentyl group, 6-bromohexyl group, iodomethyl group, 2-iodoethyl group, 3 -Iodopropyl group, 4-iodobutyl group, 5-iodopentyl group, 6-iodohexyl group, fluoromethyl group, 2-fluoroethyl group, 3-fluoropropyl group, 4-fluorobutyl group, 5-fluoropentyl group, Examples include 6-fluorohexyl group, tribromomethyl group, trichloromethyl group, trifluoromethyl group and the like.

  The “C3-8 cycloalkyl group” means a cycloalkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cyclooctyl group.

  The “C 3-8 cycloalkyl group having a substituent” means a group in which one or more hydrogen atoms of the cycloalkyl group are substituted with a substituent. The substituent is selected from groups not involved in the reaction in the production method of the present invention, and includes a C1-8 alkyl group, a C1-8 alkoxy group, an aryl group, and the like. The carbon number of the C3-8 cycloalkyl group having a substituent is 3-8 including the carbon number of the substituent. Examples of the C3-8 cycloalkyl group having a substituent include a 2-methylcyclopropyl group, a 1-methylcyclopentyl group, and a 4-methylcyclohexyl group.

  “C1-8 alkoxy group” means a group RO— (wherein R is a C1-8 alkyl group), and is a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a butoxy group, an isobutyloxy group. Group, s-butyloxy group, t-butyloxy group, hexyloxy group and the like.

  “C3-8 cycloalkoxy group” means a group R′O— (wherein R ′ is a C3-8 cycloalkyl group), cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, A cyclohexyloxy group etc. can be illustrated.

  The “aryl group” means an aromatic hydrocarbon group having 6 to 18 carbon atoms, and examples thereof include a phenyl group, a naphthyl group, and an anthryl group.

  The “aryl group having a substituent” means a group in which one or more hydrogen atoms of the aryl group are substituted with a substituent. The substituent is selected from groups not involved in the reaction in the production method of the present invention, and is a C1-8 alkyl group, a C1-8 alkoxy group, a C3-8 cycloalkyl group, or a C3-8 cycloalkoxy group. And halogen atoms. Examples of the aryl group having a substituent include 2-methylphenyl group (o-tolyl group), 3-methylphenyl group (m-tolyl group), 4-methylphenyl group (p-tolyl group), 2,4- Examples thereof include a di-t-butylphenyl group, a 4-methoxyphenyl group, and a 4-chlorophenyl group.

  “Heteroaryl group” means a 3- to 10-membered monovalent aromatic heterocyclic group containing at least one heteroatom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom. Is furyl, benzofuranyl, dibenzofuranyl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, carbazolyl, imidazolyl, benzoimidazolyl, pyrazolyl, oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, furazanyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl , Pyridazinyl, triazinyl, azepinyl, quinolyl, indolizinyl, cinnolinyl, purinyl, carbonylyl, phenanthrolinyl, imidazopyrimidinyl and the like.

  The “heteroaryl group having a substituent” refers to a group in which one or more hydrogen atoms of the heteroaryl group are substituted with a substituent. The substituent is selected from groups not involved in the reaction in the production method of the present invention, and is a C1-8 alkyl group, a C1-8 alkoxy group, a C3-8 cycloalkyl group, or a C3-8 cycloalkoxy group. , Halogen atom, aryl group and the like.

  “Ester group” means a group —COOR ″ (where R ″ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group or an aryl group), and cyclopropyl. Examples thereof include an oxy group, a cyclobutyloxy group, a cyclopentyloxy group, and a cyclohexyloxy group.

R ⁴ and R ⁵ , and R ⁶ and R ⁷ are bonded to each other and a 5- to 6-membered heterocyclic group that may be formed together with the nitrogen atom to which they are bonded. 5 to 6-membered monovalent saturated or unsaturated containing at least one nitrogen atom and optionally containing at least one additional heteroatom selected from the group consisting of nitrogen, oxygen and sulfur atoms A heterocyclic group of Examples of 5- to 6-membered heterocyclic groups include pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, thiazolylyl, thiazolyl, , Isothiazolinyl, isothiazolidinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl, isoxazolinyl, isoxazolidinyl, morpholinyl and the like.

  A halogen atom means an iodine atom, a bromine atom, a chlorine atom or a fluorine atom.

The counter anion is an anion selected from the group consisting of a halide ion, a fluorohydrogenate anion ((HF) _n F ⁻ , where n represents an integer), a halogen oxoacid ion, an inorganic acid ion, and an organic acid ion. Is preferred. Examples of halide ions include fluoride ions (F ⁻ ), chloride ions (Cl ⁻ ), bromide ions (Br ⁻ ), and iodide ions (I ⁻ ). Examples of halogen oxoacid ions include hypochlorite ion (ClO ⁻ ), chlorite ion (ClO ₂ ⁻ ), chlorate ion (ClO ₃ ⁻ ), perchlorate ion (ClO ₄ ⁻ ), hypobromite Acid ion (BrO ⁻ ), bromate ion (BrO ₂ ⁻ ), bromate ion (BrO ₃ ⁻ ), perbromate ion (BrO ₄ ⁻ ), hypoiodite ion (IO ⁻ ), iodate ion (IO ₂ ⁻ ), iodate ion (IO ₃ ⁻ ), periodate ion (IO ₄ ⁻ ) and the like can be mentioned. Examples of inorganic acid ions include hydroxide ions, carbonate ions, sulfate ions, hydrogen sulfate ions, phosphate ions, hydrogen phosphate ions, dihydrogen phosphate ions, nitrate ions, borate ions, or tetrafluoroborate ions. Can be mentioned. Examples of organic acid ions include acetate ions, trifluoroacetate ions, trifluoromethanesulfonate ions, tetraphenylborate ions, and the like.

[Production route of the present invention]
The following scheme 1 shows an outline of the production route of the present invention. Hereinafter, embodiments of the present invention will be described in detail for each step of Scheme 1. However, in the embodiment of the present invention, each step may be performed independently, or a part or all of them may be performed continuously. May be. “Compound (n)” means a compound represented by the formula (n).

However, the symbols in the formula have the following meanings.
R ¹ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, an aryl group having a substituent, heteroaryl Group, a heteroaryl group or an ester group having a substituent.
R ² is a hydrogen atom or a C1-8 alkyl group.
R ^A is OR ³ or NR ⁴ R ⁵ (wherein R ³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ⁴ and R ⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
X is a halogen atom.
Y ¹ represents an oxygen atom or N ⁺ R ⁶ R ⁷ • A ⁻ (where R ⁶ and R ⁷ are each independently a C 1-8 alkyl group, aryl group or aryl group having a substituent, or R ⁶ and R ⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
R ¹¹ is a C1-8 alkyl group, a C1-8 haloalkyl group (excluding a trihalomethyl group), a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, An aryl group having a substituent, a heteroaryl group, or a heteroaryl group having a substituent;
Moreover, the wavy line in Formula (3) shows that the coupling | bonding position of ^RA may be E or Z.

[Production Process of Compound (3) (Process 1)]
Compound (3) can be produced by reacting a compound represented by the following formula (1) with a compound represented by the following formula (2). Hereinafter, the step of producing compound (3) from compound (1) is referred to as step 1.

In the compound (1), R ^A is OR ³ or NR ⁴ R ⁵ . The compound (1) in which R ^A is OR ³ is a compound represented by the following formula (1a). The compound (1) in which R ^A is NR ⁴ R ⁵ is a compound represented by the following formula (1b).

R ³ has the same meaning as described above, and is preferably a methyl group, an ethyl group, or a phenyl group.
R ⁴ and R ⁵ are as defined above, preferably, a methyl group, an ethyl group or a phenyl group, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded. To form pyrrolidinyl, piperidinyl or morpholinyl.
Compound (1) is a known method from compounds such as 1-chloro-3,3,3-trifluoropropene and the corresponding alcohol (R ³ OH) or amine (NHR ⁴ R ⁵ ) that are easily available as commercial products. (Alcohol can be produced according to, for example, Journal of Fluorine Chemistry 129 (2008) 35-39, and amine can be produced according to, for example, JP-A-2006-124283).

^{Y 1} of compound in Step 1 (2) represents an oxygen atom or ^{N + R 6 R 7 · A} - is. The compound (2) in which Y ¹ is an oxygen atom is an acyl halide compound represented by the following formula (2a). The compound (2) in which Y ¹ is N ⁺ R ⁶ R ⁷ · A ⁻ is an iminium salt compound represented by the following formula (2b).

R ¹ is as defined above, and is preferably a C1-8 haloalkyl group.
X is as defined above, preferably a fluorine atom or a chlorine atom.
R ⁶ and R ⁷ are as defined above, preferably a methyl group, an ethyl group or a phenyl group, or bonded to each other and together with the nitrogen atom to which they are bonded, pyrrolidinyl, piperidinyl Alternatively, morpholinyl is formed.
A ⁻ has the same meaning as described above, and is preferably a halide ion such as a fluoride ion or a chloride ion, or a tetrafluoroborate anion (BF ₄ ⁻ ).

Compound (2a) is commercially available. For example, 2,2-difluoroacetic acid chloride can be easily obtained as a commercial product. The known methods from the corresponding carboxylic acid (R ¹ COOH) and the like are commercially available (e.g., Journal of Fluorine Chemistry 23 (1983 ) 383-388) can be produced according to.
Compound (2b) is produced from a corresponding amine (R ¹ CX ₂ NR ⁶ R ⁷ ), which is a commercially available product, and an acid that can serve as a counter anion source according to a known method (for example, International Publication No. 2008-022777). it can.

The reaction in the step 1 is a reaction of the compound (2) having a group —C (═Y ¹ ) X with respect to the compound (1) in which CF ₃ is bonded to a double bond. There are no reports. According to the reaction of the present invention, R ¹ —C (═Y ¹ ) — structure is introduced into a double bond using various compounds (2) having different structures of R ¹ —C (═Y ¹ ) — moieties. The desired R ¹ group can be introduced into the pyrazole ring by obtaining the compound (3) obtained and cyclizing the compound (3).
There is no restriction | limiting in particular in the addition order of the compound (1) in a process 1, and a compound (2). The usage-amount of a compound (2) is not specifically limited, From an economical viewpoint, 0.8-3.0 mol is preferable with respect to 1 mol of compound (1), and 0.9-2.0 mol is preferable. More preferably, 1.0-1.8 mol is still more preferable.

  You may perform reaction of a compound (1) and a compound (2) in presence of a solvent. The solvent is preferably selected from solvents that are inert to the reaction, and is appropriately selected according to the reaction temperature, the solubility of the substrate, and the like. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran and dioxane, ketone solvents such as acetone, methyl ethyl ketone and methyl isobutyl ketone, carboxylic acid solvents such as acetic acid and propionic acid, methyl acetate, ethyl acetate and butyl acetate. , Ester solvents such as ethyl propionate, aromatic hydrocarbon solvents such as benzene, toluene, xylene and mesitylene, aromatic halogen solvents such as monochlorobenzene and dichlorobenzene, aliphatic such as hexane, heptane, octane and cyclohexane Examples thereof include hydrocarbon solvents, aliphatic halogen solvents such as methylene chloride, chloroform and ethylene dichloride, and nitrile solvents such as acetonitrile, propionitrile and benzonitrile. Only one type of solvent may be used, or two or more types of mixed solvents may be used. From the viewpoint of reaction rate, the solvent is preferably an aromatic hydrocarbon solvent or a nitrile solvent, and more preferably toluene or acetonitrile.

  There is no restriction | limiting in particular in the usage-amount of a solvent, 1-50 times amount (weight basis) is preferable with respect to a compound (1), and 2-10 times amount (weight basis) is more preferable.

You may implement reaction of a compound (1) and a compound (2) in presence of a base. Bases include metal hydrides such as sodium hydride, potassium hydride, calcium hydride; imidazole, pyridine, 2,6-lutidine, s-collidine, N-methylpyrrolidine, N-methylpiperidine, ethyldiisopropylamine, triethylamine And organic amines such as tri (C1-4 alkyl) amine including tributylamine; inorganic salts such as sodium hydroxide, potassium hydroxide and potassium carbonate. As the base, an organic amine is preferable because the yield is improved, and pyridine or triethylamine is more preferable.
The amount of the base used is preferably 0.8 to 3.0 mol, more preferably 0.9 to 2.0 mol, and 1.0 to 1.8 mol with respect to 1 mol of the compound (1). Is more preferable.

  The reaction temperature in step 1 is preferably adjusted to the lower limit of about −70 ° C., and the upper limit is suitably adjusted as the boiling point of the solvent. From the viewpoint of reaction rate and reaction efficiency, −40 ° C. to 150 ° C. is preferable, and −20 ° C. 100 degreeC is more preferable and -20 degreeC-60 degreeC is still more preferable. The reaction time is appropriately set according to the amount and type of the substrate and solvent, the reaction temperature, and the like, and from the viewpoint of reaction rate and reaction efficiency, 5 minutes to 24 hours are preferable, 10 minutes to 6 hours are more preferable, 30 Minutes to 2 hours are more preferable. The reaction pressure is appropriately set as necessary, and may be any of pressurization, reduced pressure, and atmospheric pressure, and atmospheric pressure is preferable. The reaction atmosphere is preferably in air or an inert gas atmosphere such as nitrogen or argon.

  The reaction crude product produced by the reaction of compound (1) and compound (2) may be used as it is in the next reaction, but in the usual case, the compound (3) is purified from the reaction crude product. It is preferred to isolate. As a purification method, a method known or known to those skilled in the art can be employed, and examples thereof include solvent extraction, distillation, silica gel column chromatography, preparative thin layer chromatography, preparative liquid chromatography and the like.

[Production Process of Compound (5) (Process 2)]
Compound (5) can be produced by reacting a compound represented by the following formula (3) with a compound represented by the following formula (4). Hereinafter, the step of producing compound (5) from compound (3) is referred to as step 2. A cyclization reaction occurs by reacting compound (3) with compound (4). The cyclization reaction can produce regioisomers having different substitution positions of the substituents (R ¹ , R ² , CF ₃ ) of the pyrazole ring together with the target compound (5). The production of the compound is extremely small, and the compound (5) can be obtained in a high yield. In addition, it is very advantageous in industrial practice that regioisomers having chemical properties similar to those of compound (5) can be easily separated.

In the compound (3) of step 2, the definitions and preferred embodiments of R ¹ , R ^A and Y ¹ are as defined above.

In the hydrazine compound (4) of Step 2, R ² is a hydrogen atom or a C1-8 alkyl group, hydrazine (a compound in which R ² is a hydrogen atom), methyl hydrazine (a compound in which R ² is a methyl group) And ethylhydrazine (a compound in which R ² is an ethyl group). These are easily available as commercial products. The hydrazine compound (4) may be a hydrate or an aqueous solution. For example, hydrazine monohydrate or 40% aqueous solution of methyl hydrazine can be used.

  There is no restriction | limiting in particular in the addition order of the compound (3) in a process 1, and a compound (4). The usage-amount of a compound (4) is not specifically limited, From an economical viewpoint, 0.8-3.0 mol is preferable with respect to 1 mol of compound (3), and 0.9-2.0 mol is preferable. More preferably, 1.0-1.8 mol is still more preferable, and 1.1-1.5 mol is especially preferable.

  The reaction of compound (3) and compound (4) may be carried out in the presence of a solvent. The solvent is preferably selected from solvents that are inert to the reaction, and is appropriately selected according to the reaction temperature, the solubility of the substrate, and the like. Examples of the solvent include ether solvents such as diethyl ether, tetrahydrofuran and dioxane, carboxylic acid solvents such as acetic acid and propionic acid, ester solvents such as methyl acetate, ethyl acetate, butyl acetate and ethyl propionate, benzene and toluene. , Aromatic hydrocarbon solvents such as xylene and mesitylene, aromatic halogen solvents such as monochlorobenzene and dichlorobenzene, aliphatic hydrocarbon solvents such as hexane, heptane, octane and cyclohexane, methylene chloride, chloroform, ethylene dichloride, etc. However, it is not limited to these, and the aliphatic halogen solvents, nitrile solvents such as acetonitrile, propionitrile, and benzonitrile, or a mixed solvent thereof with water can be used. These solvents may be used alone or in combination of two or more. From the viewpoint of reaction rate, the solvent is preferably an aliphatic halogen solvent or a nitrile solvent, and more preferably methylene chloride or acetonitrile.

  There is no restriction | limiting in particular in the usage-amount of a solvent, 1-50 times amount (weight basis) is preferable with respect to a compound (3), and 2-10 times amount (weight basis) is more preferable.

  The reaction temperature in step 2 is preferably adjusted to the lower limit of about −50 ° C. and the upper limit of the boiling point of the solvent as appropriate. From the viewpoint of reaction rate and reaction efficiency, −40 ° C. to 100 ° C. is preferable, More preferred is room temperature (about 25 ° C.). The reaction time is appropriately set according to conditions such as the amount and type of the substrate and solvent, and the reaction temperature, and is preferably 5 minutes to 24 hours, more preferably 10 minutes to 8 hours, from the viewpoint of reaction rate and reaction efficiency. 30 minutes to 4 hours is more preferable. The reaction pressure is appropriately set as necessary, and may be any of pressurization, reduced pressure, and atmospheric pressure, and atmospheric pressure is preferable. The reaction atmosphere is preferably in air or an inert gas atmosphere such as nitrogen or argon.

  The reaction crude product produced by the reaction between the compound (3) and the compound (4) may be used as it is in the next reaction, but in the usual case, the compound (5) is purified from the reaction crude product. It is preferred to isolate. As a purification method, a method known or known to those skilled in the art can be employed, and examples thereof include solvent extraction, distillation, silica gel column chromatography, preparative thin layer chromatography, preparative liquid chromatography and the like.

[Production Process of Compound (6) (Process 3)]
Compound (6) can be produced by hydrolyzing the compound represented by the following formula (5a). Hereinafter, the step of producing compound (6) from compound (5a) is referred to as step 3.

The definitions and preferred embodiments of R ¹¹ and R ² are as defined above.
For the hydrolysis reaction in Step 3, a known or well-known technique can be applied, a method of reacting compound (5a) in the presence of an acid or base and water, and a reaction of compound (5a) in the presence of an acid or base. Thereafter, it is preferably carried out by a method of contacting with water, and a method of contacting with water after reacting compound (5a) in the presence of an acid is preferred. Examples of the acid include sulfuric acid, phosphoric acid, trifluoromethanesulfonic acid, fuming sulfuric acid and the like, and fuming sulfuric acid is preferable. As for the quantity of an acid, 1 equivalent or more is preferable with respect to a compound (5a), and 1-150 equivalent is further more preferable. The amount of water is preferably 2 equivalents or more, particularly preferably 10 to 50 equivalents, relative to compound (5a).

  In step 3, the reaction between the compound (5a) and the acid can be carried out in the presence or absence of a solvent. The solvent is preferably selected from solvents that are inert to the reaction, and is appropriately selected according to the reaction temperature, the solubility of the substrate, and the like. Step 3 is preferably performed in the absence of a solvent.

  In the reaction between the compound (5a) and the acid, the lower limit is preferably about 0 ° C., and the upper limit is preferably adjusted appropriately as the boiling point of the solvent or acid. From the viewpoint of reaction rate and reaction efficiency, room temperature (about 25 ° C.) to 160 ° C is preferred, and room temperature to 100 ° C is more preferred. The reaction time is appropriately set according to conditions such as the amount and type of the substrate and acid, and the reaction temperature, and is preferably 5 minutes to 24 hours, more preferably 10 minutes to 8 hours, from the viewpoint of reaction rate and reaction efficiency. 30 minutes to 4 hours is more preferable. The reaction pressure is appropriately set as necessary, and may be any of pressurization, reduced pressure, and atmospheric pressure, and atmospheric pressure is preferable. The reaction atmosphere is preferably in air or an inert gas atmosphere such as nitrogen or argon.

  It is preferable to purify and isolate the compound (6) from the reaction crude product containing the compound (6) obtained by reacting the compound (5a) with an acid. As a purification method, a method known or known to those skilled in the art can be employed, and examples thereof include solvent extraction, distillation, silica gel column chromatography, preparative thin layer chromatography, preparative liquid chromatography and the like.

[Intermediate compound]
Of the compounds produced by the reaction between the compound (1) and the compound (2), the compound represented by the following formula (3c) is a novel and useful compound. That is, the present invention provides a novel compound represented by the following formula (3c).

R ^A1 is OR ¹³ or NR ¹⁴ R ¹⁵ .
R ¹³ is a C1-8 alkyl group, an aryl group, or an aryl group having a substituent, and is preferably a methyl group, an ethyl group, or a phenyl group.
R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, a C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ¹⁴ and R ¹⁵ are bonded to each other, and You may form the 5-6 membered heterocyclic group with the nitrogen atom which has couple | bonded. R ¹⁴ and R ¹⁵ are preferably a methyl group, an ethyl group or a phenyl group, or R ¹⁴ and R ¹⁵ are preferably bonded together and together with the nitrogen atom to which they are bonded. Form pyrrolidinyl, piperidinyl or morpholinyl.
Y ¹¹ is an oxygen atom or N ⁺ R ¹⁶ R ¹⁷ · A ⁻ .
R ¹⁶ and R ¹⁷ are each independently a C1-8 alkyl group, aryl group or aryl group having a substituent, or R ¹⁶ and R ¹⁷ are bonded to each other, and A 5-6 membered heterocyclic group may be formed together with the nitrogen atom. R ¹⁶ and R ¹⁷ are preferably a methyl group, an ethyl group or a phenyl group, or R ¹⁶ and R ¹⁷ are bonded to each other and together with the nitrogen atom to which they are bonded, pyrrolidinyl, Forms piperidinyl or morpholinyl.
In the compound (3c), A ⁻ is a counter anion. A ⁻ is preferably a halide ion such as fluoride ion or chloride ion, or tetrafluoroborate ion (BF ₄ ⁻ ).
Moreover, the wavy line in Formula (3c) shows that the coupling ^| bonding position of RA1 may be E or Z.

Specific examples of the compound (3c) include the following compounds.

Of the compound (5) produced by the reaction of the compound (3) and the compound (4), the compound represented by the following formula (5b) is a novel compound. That is, the present invention provides a novel compound represented by the following formula (5b).

R ¹² is a hydrogen atom or a C1-8 alkyl group, preferably a hydrogen atom, a methyl group or an ethyl group.
Specific examples of the compound represented by the compound (5b) include the following compounds.

Compound (3c) and compound (5b) are intermediate compounds useful in the production method of the present invention. Compound (5) and compound (6) produced via these intermediates are useful as intermediates for pharmaceuticals and agricultural chemicals.
According to the present invention, compound (3c) and compound (5b), which are novel and useful intermediates, can be produced from inexpensive raw materials under reaction conditions advantageous for industrial implementation.
Since the compound (3) and the compound (5) used in the production method of the present invention are chemically stable and easy to handle, the production method of the present invention via these intermediates and the production of the present invention A method for producing a pharmaceutical or an agricultural chemical using these compounds obtained by the method as starting materials is a method more suitable for industrial implementation than the conventional methods.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to these examples. In the following, “compound n” means a compound represented by the formula (n). The structure of the product obtained in each example was determined by NMR (JNM-ECP400 manufactured by JEOL Ltd.). The unit of yield obtained from NMR is mol%.

[Example 1]
Synthesis of 2-difluoroacetyl-3,3,3-trifluoro-1-propen-1-ylpiperazine

Under a nitrogen atmosphere, 1.9 g (18.6 mmol) of triethylamine and 2.6 g (14.3 mmol) of 3,3,3-trifluoropropenylpiperidine were dissolved in 20 ml of toluene and cooled to −20 ° C. Thereto was slowly added 2.1 g (18.6 mmol) of difluoroacetic acid chloride, and the mixture was warmed to room temperature and stirred for 1 hour. Water and toluene were added for liquid separation, and the organic layer was washed with saturated NaHCO ₃ water and saturated NaCl water, and then concentrated with an evaporator to give 94% of 2-difluoroacetyl-3,3,3-trifluoropropenylpiperazine. Obtained in yield.

¹ H NMR (CDCl ₃ ) δ = 1.75 (m, 6H), 3.50 (m, 4H), 6.14 (t, 1H), 7.66 (br, 1H)
¹⁹ F NMR (CDCl ₃ ) δ = -124.5 (br, 2F), -51.7 (br, 3F)

[Example 2]
Synthesis of 1-methyl-3-difluoromethyl-4-trifluoromethylpyrazole

Under a nitrogen atmosphere, 0.6 g (5.0 mmol) of 40% aqueous methylhydrazine solution (40% MMH) was added to 5 ml of methylene chloride and cooled to -20 ° C. Subsequently, 1.1 g (4.2 mmol) of 2-difluoroacetyl-3,3,3-trifluoropropenylpiperazine was dissolved in 3 ml of methylene chloride and slowly added. After stirring at −20 ° C. for 1 hour, the mixture was warmed to room temperature and stirred for 1 hour. Water was added for liquid separation, and the organic layer was dried over Na ₂ SO ₄ and concentrated by an evaporator to obtain 1-methyl-3-difluoromethyl-4-trifluoromethylpyrazole in a yield of 80%.

¹ H NMR (CDCl ₃ ) δ = 3.94 (s, 3H), 6.72 (t, 1H), 7.72 (s, 1H)
¹⁹ F NMR (CDCl ₃ ) δ = -113.3 (d, 2F), -56.2 (t, 3F)

[Example 3]
Synthesis of 1H-3-difluoromethyl-4-trifluoromethylpyrazole

Under a nitrogen atmosphere, 0.4 g (7.5 mmol) of hydrazine monohydrate was added to 5 ml of methylene chloride and ice-cooled. Then, 1.6 g (6.2 mmol) of 2-difluoroacetyl-3,3,3-trifluoropropenylpiperazine was dissolved in 3 ml of methylene chloride and slowly added. After stirring at 0 ° C. for 1 hour, the mixture was warmed to room temperature and stirred for 1 hour. Water was added for liquid separation, and the organic layer was dried over Na ₂ SO ₄ and then concentrated by an evaporator to obtain 1H-3-difluoromethyl-4-trifluoromethylpyrazole in a yield of 44%.

¹ H NMR (CDCl ₃ ) δ = 6.82 (t, 1H), 7.95 (s, 1H)
¹⁹ F NMR (CDCl ₃ ) δ = -113.9 (d, 2F), -56.2 (s, 3F)

[Example 4]
Synthesis of N- (1,1-difluoro-4- (piperidin-1-yl) -3- (trifluoromethyl) -but-3-en-2-ylidene) -N-methylmethanaminium tetrafluoroborate

In a nitrogen atmosphere, 9.5 g (30.7 mmol) of a 19% BF ₃ -acetonitrile solution and 10 ml of acetonitrile were ice-cooled, and then 4.5 g (30.7 mmol) of N-1,1,2,2-tetrafluoroethyldimethylamine. ) Was added slowly. After stirring for 30 minutes under ice cooling, 3.2 g (17.7 mmol) of 3,3,3-trifluoropropenylpiperidine was slowly added. Then, it heated up at 60 degreeC and stirred for 2 hours. Acetonitrile was concentrated by an evaporator to give N- (1,1-difluoro-4- (piperidin-1-yl) -3- (trifluoromethyl) -but-3-en-2-ylidene) -N-methylmethanamine. Nitrotetrafluoroborate was obtained in 82% yield.

¹⁹ F NMR (acetonitrile) δ = -122.2 (d, 2F), -51.9 (s, 3F)

[Example 5]
Synthesis of 1-methyl-3-difluoromethyl-4-trifluoromethylpyrazole

In a nitrogen atmosphere, 1.9 g (6.1 mmol) of 19% BF ₃ -acetonitrile solution and 5 ml of acetonitrile were ice-cooled, and then 0.9 g (6.1 mmol) of N-1,1,2,2-tetrafluoroethyldimethylamine was cooled. ) Was added slowly. After stirring for 30 minutes under ice cooling, 1.0 g (5.5 mmol) of 3,3,3-trifluoropropenylpiperidine was slowly added, the temperature was raised to 60 ° C., and the mixture was stirred for 2 hours. Thereafter, the reaction solution was cooled to −40 ° C., 0.3 g (6.7 mmol) of 98% methyl hydrazine was slowly added, stirred at −40 ° C. for 1 hour, and then warmed to room temperature. After concentrating acetonitrile with an evaporator, the solution was separated with water and methylene chloride, and the organic layer was dried over sodium sulfate. Concentration with an evaporator gave 1-methyl-3-difluoromethyl-4-trifluoromethylpyrazole in 32% yield.

[Example 6]
Synthesis of 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid

  Under a nitrogen atmosphere, 0.5 g (2.5 mmol) of 1-methyl-3-difluoromethyl-4-trifluoromethylpyrazole was added to 10 ml of 60% fuming sulfuric acid and heated at 150 ° C. for 5 hours. Thereafter, the reaction solution was added to ice water and extracted with isopropyl acetate. The organic layer was concentrated with an evaporator to obtain 1-methyl-3-difluoromethylpyrazole-4-carboxylic acid in a yield of 60%.

¹ H NMR (acetone-d ₆ ) δ = 4.00 (s, 3H), 7.18 (t, 1H), 8.23 (s, 1H)
¹⁹ F NMR (acetone-d ₆ ) δ = -113.6 (d, 2F)

[Example 7]
Synthesis of 1H-3-difluoromethylpyrazole-4-carboxylic acid

  Under a nitrogen atmosphere, 0.1 g (0.5 mmol) of 1H-3-difluoromethyl-4-trifluoromethylpyrazole was added to 5 ml of 60% fuming sulfuric acid and heated at 50 ° C. for 3 hours. Thereafter, the reaction solution was added to ice water and extracted with isopropyl acetate. The organic layer was concentrated with an evaporator to obtain 1H-3-difluoromethylpyrazole-4-carboxylic acid in a yield of 19%.

¹ H NMR (acetone-d ₆ ) δ = 7.19 (t, 1H), 8.23 (s, 1H)
¹⁹ F NMR (acetone-d ₆ ) δ = -113.6 (d, 2F)

Claims (11)

A compound represented by the following formula (3) is obtained by reacting a compound represented by the following formula (1) with a compound represented by the following formula (2), and then represented by the formula (3). And a compound represented by the following formula (4) are reacted to obtain a pyrazole derivative represented by the following formula (5):

[However,
R ¹ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, an aryl group having a substituent, heteroaryl Group, a heteroaryl group or an ester group having a substituent.
R ² is a hydrogen atom or a C1-8 alkyl group.
R ^A is OR ³ or NR ⁴ R ⁵ (wherein R ³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ⁴ and R ⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
X is a halogen atom.
Y ¹ represents an oxygen atom or N ⁺ R ⁶ R ⁷ • A ⁻ (where R ⁶ and R ⁷ are each independently a C 1-8 alkyl group, aryl group or aryl group having a substituent, or R ⁶ and R ⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3) shows that the coupling | bonding position of ^RA may be E or Z. ]. A method for producing a pyrazole derivative, wherein a compound represented by the following formula (3) and a compound represented by the following formula (4) are reacted to obtain a pyrazole derivative represented by the following formula (5): .

[However,
R ¹ is a C1-8 alkyl group, a C1-8 haloalkyl group, a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, an aryl group having a substituent, heteroaryl Group, a heteroaryl group or an ester group having a substituent.
R ² is a hydrogen atom or a C1-8 alkyl group.
R ^A is OR ³ or NR ⁴ R ⁵ (wherein R ³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ⁴ and R ⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group, or an aryl group having a substituent, or R ⁴ and R ⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5-6 membered hetero A cyclic group may be formed.)
Y ¹ represents an oxygen atom or N ⁺ R ⁶ R ⁷ • A ⁻ (where R ⁶ and R ⁷ are each independently a C 1-8 alkyl group, aryl group or aryl group having a substituent, or R ⁶ and R ⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3) shows that the coupling | bonding position of ^RA may be E or Z. ]. The method for producing a pyrazole derivative according to claim 1 or 2, wherein R ¹ is a difluoromethyl group. A method for producing a pyrazole-4-carboxylic acid derivative represented by the following formula (6), wherein the compound represented by the following formula (5a) is hydrolyzed.

(However,
R ¹¹ is a C1-8 alkyl group, a C1-8 haloalkyl group (excluding a trihalomethyl group), a C3-8 cycloalkyl group, a C3-8 cycloalkyl group having a substituent, an aryl group, An aryl group having a substituent, a heteroaryl group, or a heteroaryl group having a substituent;
R ² is a hydrogen atom or a C1-8 alkyl group. ) The method for producing a pyrazole-4-carboxylic acid derivative according to claim 4, wherein R ¹ is a difluoromethyl group.   The method for producing a pyrazole-4-carboxylic acid derivative according to claim 4 or 5, wherein the hydrolysis is carried out in the presence of an acid.   The method for producing a pyrazole-4-carboxylic acid derivative according to claim 6, wherein the acid is fuming sulfuric acid.   The manufacturing method of the pyrazole-4-carboxylic acid derivative in any one of Claims 4-7 which obtains the compound represented by Formula (5a) by the manufacturing method of Claim 1 or 2. The method for producing a pyrazole-4-carboxylic acid derivative according to any one of claims 4 to 8, wherein R ¹ is a difluoromethyl group. A compound represented by the following formula (3c).

[However,
R ^A1 is OR ¹³ or NR ¹⁴ R ¹⁵ (where R ¹³ is a C1-8 alkyl group, aryl group or aryl group having a substituent. R ¹⁴ and R ¹⁵ are each independently a hydrogen atom, A C1-8 alkyl group, an aryl group or an aryl group having a substituent, or R ¹⁴ and R ¹⁵ are bonded to each other and together with the nitrogen atom to which they are bonded, a 5- to 6-membered heterocycle Group may be formed).
Y ¹¹ represents an oxygen atom or N ⁺ R ¹⁶ R ¹⁷ · A ⁻ (where R ¹⁶ and R ¹⁷ are each independently a C1-8 alkyl group, aryl group or aryl group having a substituent, or R ¹⁶ and R ¹⁷ may be bonded together to form a 5- to 6-membered heterocyclic group together with the nitrogen atom to which they are bonded, A ⁻ is a counter anion.).
Moreover, the wavy line in Formula (3c) shows that the coupling ^| bonding position of RA1 may be E or Z. ]. A compound represented by the following formula (5b).

(However,
R ¹² represents a hydrogen atom or a C1-8 alkyl group. ).