JP5500582B2 - Pyrazole-4-carboxamide derivatives, methods for producing them, and fungicides containing them as active ingredients - Google Patents

Description

  The present invention relates to a pyrazol-4-carboxamide derivative effective for controlling harmful pathogens in agricultural and horticultural scenes and a method for producing them.

  Conventionally, in the field of agriculture and horticulture, many bactericides for the purpose of controlling various diseases have been developed and put into practical use, but they are not always satisfactory in terms of effects, spectrum, or residual effect. Moreover, it cannot be said that the social request, such as the number of times of application and the amount of applied medicine, is sufficiently satisfied.

  In addition, the emergence of disease-causing bacteria that have acquired resistance to conventionally used disinfectants is also a problem. Some pesticides have not yet acquired resistance, but these are generally unfavorable from the viewpoint of environmental pollution and the like due to the large amount of applied medicine and the number of times of application. Therefore, there is an urgent need to develop a novel fungicide that exhibits a sufficient control effect at low doses against various diseases that have acquired resistance to conventional fungicides and that has little adverse effect on the environment.

  Furthermore, improving the productivity of important crops is indispensable for eliminating the food crisis accompanying the expected increase in the world population in the near future. In order to provide a stable food supply, it is necessary to economically and efficiently control pathogens that hinder the cultivation of crops, and the development of new fungicides as a solution is increasingly important.

  Until now, many pyrazol-4-carboxamide derivatives having bactericidal activity have been known and used, for example, as agricultural and horticultural fungicides (see, for example, Patent Documents 1 and 2). However, no fungicides have been put to practical use among the pyrazol-4-carboxamide derivatives of the present invention having a pyrazol-4-yl group on the amide nitrogen atom.

  In addition, some compounds having a structure similar to the pyrazol-4-carboxamide derivative having a pyrazol-4-yl group on the amide nitrogen atom of the present invention are also known. However, these compounds are completely different from the pyrazol-4-carboxamide derivatives of the present invention in that the 1-position of the pyrazol ring of the pyrazol-4-yl group is an alkyl group. On the other hand, N- (3,5-dimethyl-1-phenylpyrazol-4-yl) -1-methylpyrazole having an unsubstituted phenyl group at the 1-position of the pyrazol ring of the pyrazol-4-yl group 4-Carboxamide (CAS Registry Number 1060984-13-5) is the only known, but no method for synthesizing or biological activity of these pyrazol-4-carboxamide derivatives including this compound has been reported.

JP-A-2-131481 JP 2001-151770 A

  The problem of the present invention is that it has a high control effect and a broad bactericidal spectrum not only against various pathogens that are harmful to the cultivation of crops, but also against pathogens that are resistant to conventional agricultural and horticultural fungicides, and The object of the present invention is to provide a new fungicide having both high safety for crops and excellent environmental conservation.

  As a result of intensive studies to solve the above problems, the present inventors have found that the pyrazol-4-carboxamide derivative represented by the general formula (1) is a compound having excellent bactericidal activity that can solve the above problems. As a result, the present invention has been completed.

  That is, the present invention relates to the general formula (1)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; An alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; Substituted with alkyl group having 1 to 6 carbon atoms, acyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, benzenesulfonyl group or p-tolylsulfonyl group And n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different.) Pyrazol-4-carboxamide derivative About.

  The present invention also provides a general formula (2)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. Y represents a leaving group), and a pyrazol-4-carboxylic acid derivative represented by formula (3):

(Wherein R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group of 6; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; A halogen atom; an alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkoxy group having 1 to 6 carbon atoms; A nitro group; or an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or a benzenesulfonyl group Or an amino group which may be substituted with a p-tolylsulfonyl group, n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different. A 4-aminopyrazole derivative having the general formula (1)

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and n represent the same meaning as described above), and a method for producing a pyrazol-4-carboxamide derivative represented by the formula:

  Furthermore, the present invention relates to a general formula (1)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; An alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; Substituted with alkyl group having 1 to 6 carbon atoms, acyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, benzenesulfonyl group or p-tolylsulfonyl group And n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different.) Pyrazol-4-carboxamide derivative It is related with the disinfectant which uses as an active ingredient.

  The pyrazol-4-carboxamide derivative of the present invention has excellent bactericidal activity, and can effectively control harmful disease-causing bacteria without causing harm to cultivated crops in agricultural and horticultural scenes.

  The present invention is described in further detail below.

[About R ¹ , R ² , R ³ , R ⁴ , X, Y, n]
(About R ¹ and R ² )
R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms.
The alkyl group having 1 to 6 carbon atoms represented by R ¹ and R ² may be linear, branched or cyclic, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclo group. Propyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, cyclopropylmethyl group, cycloptyl group, pentyl group, isopentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2-methylbutyl group And cyclopentyl group, hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group and the like. R ¹ is preferably an alkyl group having 1 to 4 carbon atoms, and more preferably a methyl group, because of its high effect as a bactericidal agent.

The haloalkyl group having 1 to 6 carbon atoms represented by R ² may be linear, branched or cyclic, and includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and 2-fluoro Ethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, Examples include chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group and the like. R ² is preferably a fluorine-substituted alkyl group having 1 to 4 carbon atoms, and more preferably a difluoromethyl group or a trifluoromethyl group, from the viewpoint that the effect as a bactericidal agent is high.

Further, the combination of R ¹ and R ² is preferably a combination of R ¹ is an alkyl group having 1 to 4 carbon atoms and R ² is a fluorine-substituted alkyl group having 1 to 4 carbon atoms in terms of high effect as a bactericidal agent. Furthermore, R ¹ is preferably a methyl group and R ² is preferably a difluoromethyl group or a trifluoromethyl group.

(For ^{R 3)}
R ³ represents a hydrogen atom or a halogen atom.
Examples of the halogen atom represented by R ³ include a fluorine atom, a chlorine atom and a bromine atom. R ³ is preferably a hydrogen atom, a fluorine atom, or a chlorine atom because it has a high effect as a disinfectant.

(For ^{R 4)}
R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms A formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (alkoxy having 1 to 6 carbons) iminomethyl group; or (acyloxy having 1 to 6 carbons) iminomethyl group.

Examples of the halogen atom represented by R ⁴ include a fluorine atom, a chlorine atom, and a bromine atom.

The alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms represented by R ⁴ may be linear, branched or cyclic, and methyl. Group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, cyclopropylmethyl group, cycloptyl group, pentyl group, isopentyl group, neopentyl group, 2- Pentyl group, 3-pentyl group, 2-methylbutyl group, cyclopentyl group, hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropyloxymethyl Group, butoxymethyl group, isobutyloxymethyl group, s-butyloxymethyl group, t-butyloxymethyl group, Nethyloxymethyl group, isopentyloxymethyl group, neopentyloxymethyl group, 2-pentyloxymethyl group, 3-pentyloxymethyl group, 2-methylbutyloxymethyl group, hexyloxymethyl group, isohexyloxymethyl group 2-ethylbutyloxymethyl group, 1,3-dimethylbutyloxymethyl group, dimethoxymethyl group, diethoxymethyl group, -methoxyethyl group, ethoxyethyl group, propoxyethyl group, isopropyloxyethyl group, butoxyethyl group, Isobutyloxyethyl group, s-butyloxyethyl group, t-butyloxyethyl group, pentyloxyethyl group, isopentyloxyethyl group, neopentyloxyethyl group, 2-pentyloxyethyl group, 3-pentyloxyethyl group, 2-methylbutyloxyethyl group, f Sill oxyethyl group, iso-hexyloxy ethyl group, 2-ethyl-butyloxyethyl group, can be exemplified 1,3-dimethylbutyl oxyethyl group.

The haloalkyl group having 1 to 6 carbon atoms represented by R ⁴ may be linear, branched or cyclic, and includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and 2-fluoro Ethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, Examples include chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group and the like. Among them, R ⁴ is preferably a haloalkyl group having 1 to 4 carbon atoms, and more preferably a trifluoromethyl group, from the viewpoint that the effect as a fungicide is high.

The alkoxy group having 1 to 6 carbon atoms represented by R ⁴ may be linear, branched or cyclic, and includes a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, a cyclopropyl group. Examples thereof include a methyloxy group, a butyloxy group, an isobutyloxy group, a s-butyloxy group, a pentyloxy group, a cyclopentyloxy group, and a hexyloxy group.

Examples of the iminomethyl group represented by R ⁴ (alkoxy having 1 to 6 carbon atoms) include methoxyiminomethyl group, ethoxyiminomethyl group, propyloxyiminomethyl group, isopropyloxyiminomethyl group, cyclopentylmethyloxyiminomethyl group, butyl Examples thereof include oxyiminomethyl group, s-butyloxyiminomethyl group, t-butyloxyiminomethyl group, pentyloxyiminomethyl group, cyclopentyloxyiminomethyl group, hexyloxyiminomethyl group and the like.

Examples of the iminomethyl group represented by R ⁴ (acyloxy having 1 to 6 carbon atoms) include formyloxyiminomethyl group, acetoxyiminomethyl group, propionyloxyiminomethyl group, isobutyryloxyiminomethyl group, valeryloxyiminomethyl group Group, isovaleryloxyiminomethyl group, pivaloyloxyiminomethyl group and the like.

R ² and R ⁴ are preferably each independently a haloalkyl group having 1 to 6 carbon atoms in terms of high effect as a fungicide.

(About X)
X is a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; A haloalkoxy group; a cyano group; a nitro group; or an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a benzenesulfonyl group, or a p-tolylsulfonyl group. An amino group which may be substituted is represented.

  Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. A fluorine atom, a chlorine atom, and a bromine atom are preferable at the point with the high effect as a disinfectant.

  The alkyl group having 1 to 6 carbon atoms represented by X may be linear, branched or cyclic, and is methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl Group, isobutyl group, s-butyl group, t-butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2-methylbutyl group, cyclopentyl group, Examples include a hexyl group, an isohexyl group, a 2-ethylbutyl group, a 1,3-dimethylbutyl group, a 2-cyclopropylcyclopropyl group, and the like. A methyl group, an ethyl group, an isopropyl group, an isobutyl group, a s-butyl group, and a 1,3-dimethylbutyl group are preferable in that the effect as a bactericidal agent is high.

  The haloalkyl group having 1 to 6 carbon atoms represented by X may be linear, branched or cyclic, and is a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group. Group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, chloro Examples thereof include a methyl group, a 2-chloroethyl group, a bromomethyl group, a 2-bromoethyl group, and a bromodifluoromethyl group. A trifluoromethyl group is preferred because it is highly effective as a bactericidal agent.

  The alkenyl group having 2 to 6 carbon atoms represented by X may be either linear or branched, and examples thereof include a vinyl group, a 1-propenyl group, an isopropenyl group, and a 1-hexenyl group. can do. These alkenyl groups may be substituted with a trimethylsilyl group, an acetoxy group, a phenyl group, or the like. A vinyl group and an isopropenyl group are preferable in that the effect as a bactericidal agent is high.

  The alkoxy group having 1 to 6 carbon atoms represented by X may be linear, branched or cyclic, and is a methoxy group, ethoxy group, propoxy group, isopropyloxy group, cyclopropylmethyloxy Group, butoxy group, isobutyloxy group, s-butyloxy group, t-butyloxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methylbutyloxy Group, cyclopentyloxy group, hexyloxy group, isohexyloxy group, 2-ethylbutyloxy group, 1,3-dimethylbutyloxy group and the like. A methoxy group, an ethoxy group, an isopropyloxy group, an isobutyloxy group, a s-butyloxy group, and an isopentyloxy group are preferable in that the effect as a fungicide is high.

  Examples of the haloalkoxy group having 1 to 6 carbon atoms represented by X include a trifluoromethoxy group, a difluoromethoxy group, a bromodifluoromethoxy group, and a 2,2,2-trifluoroethoxy group. A trifluoromethoxy group is preferred because of its high effect as a bactericide.

  May be substituted with an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, a benzenesulfonyl group or a p-tolylsulfonyl group represented by X As amino group, amino group, methylamino group, dimethylamino group, isopropylamino group, hexylamino group, formylamino group, acetamino group, propionylamino group, isobutyrylamino group, valerylamino group, isovalerylamino group, Pivaloylamino group, benzoylamino group, 4-fluorobenzoylamino group, methylsulfonylamino group, ethylsulfonylamino group, benzenesulfonylamino group, p-tolylsulfonylamino group and the like can be exemplified.

(About Y)
Examples of the leaving group represented by Y include halogen atoms such as chlorine atom and bromine atom, hydroxyl group, pivaloyloxy group, ethoxycarbonyloxy group and the like. A chlorine atom and an ethoxycarbonyloxy group are preferable because they can be easily prepared.

(About n)
n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different.

[Production method of pyrazol-4-carboxamide derivative (1)]
Next, the production method of the pyrazol-4-carboxamide derivative of the present invention will be described in detail.
The pyrazol-4-carboxamide derivative (1) of the present invention can be produced by the method shown in the following reaction formula.

(In the formula, R ¹ , R ² , R ³ , R ⁴ , X, Y and n represent the same meaning as described above.)

  That is, the production method (step-1) of the present invention comprises reacting a pyrazol-4-carboxylic acid derivative (2) with a 4-aminopyrazole derivative (3) to produce the pyrazol-4-carboxamide of the present invention. This is a method for producing the derivative (1).

When the leaving group Y is a halogen atom, step-1 is preferably carried out in the presence of a base as a hydrogen halide scavenger. As the base, an inorganic base such as an alkali metal base or an alkaline earth metal base, an alkali metal carboxylate, or an organic base can be used. More specifically, inorganic bases such as alkali metal bases and alkaline earth metal bases include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, Examples thereof include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, and potassium bicarbonate. Examples of the alkali metal carboxylate include sodium acetate and potassium acetate. Examples of the organic base include tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine, and pyridine.
Of these, inorganic bases such as sodium carbonate and potassium carbonate, and tertiary amines such as triethylamine and tributylamine are preferred in that the yield of the target product is good and inexpensive.
Although there is no restriction | limiting in particular in the usage-amount of a base, A target object can be obtained with a sufficient yield by using 1-5 equivalent with respect to a reaction substrate, Preferably it is 1-2 equivalent.

  When the leaving group Y is a hydroxyl group, the step-1 is preferably performed in the presence of a dehydrating agent. Examples of the dehydrating agent include dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide and the like. There is no restriction | limiting in particular in the usage-amount of a dehydrating agent, A target object can be obtained with a sufficient yield by using 1-3 equivalent with respect to the reaction substrate, Preferably it uses 1-1.5 equivalent. In this reaction, the reaction may be carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine depending on circumstances.

  When the leaving group Y is an active ester such as a pivaloyloxy group or an ethoxycarbonyloxy group, a base is not particularly required, but the reaction can be performed in the presence of a base. Examples of the base include those listed above.

The reaction in step-1 is preferably carried out in a solvent. Solvents that can be used vary depending on the reaction conditions, but can be used as long as they do not harm the reaction. For example, aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene, diethyl ether, etc. -Ether solvents such as ter, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, nitriles such as acetonitrile, propionitrile, ethyl acetate, ethyl propionate , Esters such as ethyl butanoate, dimethyl carbonate, diethyl carbonate, amides such as N, N-dimethylformamide (DMF), N-methylpyrrolidone, dimethyl sulfoxide (DMSO), or a mixed solvent thereof. it can.
Among these, toluene, dichloromethane, chloroform, ethyl acetate, or a mixed solvent thereof is preferable in that the yield and selectivity of the target product are good and inexpensive. There is no restriction | limiting in particular in the usage-amount of a reaction solvent.

  In addition, the target product can be obtained in high yield by carrying out the reaction in Step-1 at a reaction temperature appropriately selected from 0 to 150 ° C., preferably from 20 to 100 ° C. There is no particular limitation on the reaction time.

  After completion of the reaction, the pyrazol-4-carboxamide derivative (1) of the present invention can be obtained by ordinary operations. If necessary, it can be purified by recrystallization, column chromatography or the like.

In the substituent R ⁴ in the pyrazol-4-carboxamide derivative (1) of the present invention, for example, when R ⁴ is a diethoxymethyl group, it is hydrolyzed to formyl group, and this formyl group is further reduced. Then, it can be converted into a hydroxymethyl group. In addition, the formyl group can be converted into a hydroxyiminomethyl group by reacting hydroxylamines, and further, for example, alkylated or acylated to form an alkyloxyiminomethyl group or an acyloxyiminomethyl group. Can be converted. The present invention also includes compounds having these substituents.

  Further, in the substituent X on the benzene ring at the 1-position of the pyrazole ring in the pyrazol-4-carboxamide derivative (1) of the present invention, for example, when X is a hydrogen atom, that is, the 1-position of the pyrazole ring is absent. In the case of a substituted phenyl group, this compound is nitrated to reduce the compound (1) of the present invention in which X is a nitro group. If the nitro group is reduced, the compound (1) of the present invention in which X is an amino group Further, when a substituent is introduced onto the amino group, the compound (1) of the present invention wherein X is a substituted amino group can be produced, and the present invention also includes these compounds.

(About the manufacturing method of pyrazole 4-carboxylic acid derivative (2))
The pyrazol-4-carboxylic acid derivative (2) used as a raw material for the production method (step-1) of the present invention is disclosed in International Patent Publication WO06-090778, J. MoI. Heterocyclic Chem, 27, 243-245 (1990) or Aust. J. et al. Chem, 36, 135-147 (1983) and the like can be easily synthesized.

(Regarding Method for Producing 4-Aminopyrazole Derivative (3)) In addition, the other raw material, 4-aminopyrazol derivative (3), is a part of a known compound. Although it can be synthesized according to the method described in Heterocyclic Chem, 25, 555-558 (1988), it can also be produced by the method exemplified below. That is, hydrolyzing pyrazol-4-carboxylic acid ester (4) which can be produced from 2-alkoxymethylene-β-ketoester or 2- (dimethylamino) methylene-β-ketoester and substituted phenylhydrazines or hydrochloride thereof. The resulting carboxylic acid (5) was condensed with sodium azide to give acyl azide (6). This is reacted with Curtius in the presence of alcohol to give a carbamate (7), and then decarboxylated simultaneously with the hydrolysis of the ester to produce the 4-aminopyrazole derivative (3). (See the reference example below). The 4-aminopyrazole derivative (3) can also be produced directly by the Curtius reaction of acyl azide (6).

(Wherein R ⁴ , X and n represent the same meaning as described above, R ⁵ represents an alkoxy group having 1 to 4 carbon atoms or a dimethylamino group, R ⁶ represents an alkyl group having 1 to 4 carbon atoms, R ⁷ Represents t-butyl group, 2,2,2-trichloroethyl group, 2-trimethylsilylethyl group or benzyl group.)

[About the bactericidal action of pyrazol-4-carboxamide derivative (1)]
Next, the bactericidal action of the pyrazol-4-carboxamide derivative of the present invention will be described in detail.
The pyrazol-4-carboxamide derivative (1) of the present invention can be controlled at low doses against diseases harmful to agricultural and horticultural crops, and is useful as a fungicidal composition for agricultural and horticultural use.

  When the pyrazol-4-carboxamide derivative (1) of the present invention is used as a bactericidal composition for agricultural and horticultural use, various crops such as powdery mildew fungi (Ascomycetes), various crops Basidiomycetes such as rust fungus and rice blight fungus, downy mildew of various crops, oomycetes such as plague of various crops, non-parasitic in various crops such as blast fungus and gray fungus In addition to complete fungi (Deuteromycetes), it has a high control effect against a wide range of phytopathogenic fungi such as Nemophila (Plasmodiophoromycetes) and is useful as a fungicide for agriculture and horticulture.

  More specific examples of plant diseases that can be controlled according to the present invention include, for example, rice blast (Piculararia grisea), sesame leaf blight (Cochliobolus miyabeanus), leaf blight (Thanatephorus cucumeris), Gibberella fujikuroi), seedling blight (Fusarium, Rhizopus, Pythium, Trichoderuma viride), rice mildew (Clavicumumumumus) Snow rot (Pythium, Typhula, M nographella nivalis, Myriosclerotinia borealis), loose smut (Ustilago nuda), fishy smell smut (Tilletia controversa), Memonbyo (Pseudocercosporella herpotrichoides), leaf blight (Septoria tritici), glume blotch (Phaeosphaeria nodorum), black spot of citrus Disease (Diaporthe citri), small sunspot disease (Diaporthe medusa, Alternaria citri), common scab (Elsinoe fawcetii), brown rot (Phytophthora citrophthra), green mold pitum Blue mold (Penicillium italicum), apple Monilia disease (Monilinia mali), black scab (Venturia inaequalis), spotted leaf disease (Alternaria maria), black spot (Mycosphaerella pomi), spot disease (spot) Zygophyla jamaicensis), Ringworm disease (Diplocarpon mary), Blast disease (Diplocarpon madarie), Red rot (Gymnosporanium yamadae), Rot disease (Valenceur spleen) iaticum), ringworm disease (Botryosphaeria berengeriana), blight disease (Phomopsis fukushii), peach leaf disease (Taphrina deformums), ash star disease (Moniliniafructicola) Phomopsis, sweet scab (Monilinia fructicola), larvae (Monilinia kusanoi), ume black scab (Cladosporium carpophilum), grape rust trichum acutatum, Glomerella cingulata, brown spot disease (Pseudocercospora vitis), vine split disease (Phomopsis viticola), oyster spot leaf spot disease (Cercospora kaki), leafy leaf disease (well) longiseta, Pestaliopsis theae, brown circle star disease (Pseudocercospora ocellate, Cercospora chaae), rice blast (Exobasidium vexans), net blast (Exobasidium bacterium), Exobasidium reticulium disease Fusarium oxysporum, black scab (Cladosporium cucumerinum), brown spot (Corynespora cassiicola), tomato leaf mold (Fulvia fulva), ring rot (Alternaria solmonis vs) , Japanese mildew (Mycovelosiella natrassii), white rust of cruciferous vegetables (Albugo macrospora), white spot (Cercosporella brassicae), rot of strawberry diseases ae), potato summer blight (Alternaria solani), soybean stem blight (Phytophthora sojae), purpura (Cercospora kikuchii), azuki bean stem blight (Phytophthora vignae), brown leaf boiled pea Spot disease (Cercospora beticola), leaf rot (Thanatephorus cucumeris), buckwheat cultivar leaf blight (Curvularia fungus), dala-spot disease (Sclerotinia homoeocarpa), Helmintosporidium rose blight (Cochloboli olus boli) Black spot disease (Diplocarpon rosae), chrysanthemum white rust disease (Pucci) ia horiana), and various crop downy mildews (Peronospora, Pseudoperonospora, Plasmopara, Bremia), plagues (Phytophthora, Blaeria) Uncinula, Oidiopsis), Rust (Puccinia, Uromyces, Physopella), Anthrax (Glomerella, Colletotrichum, Gloeosporium), Black spot (Alternaria), Gray Nuclear disease (Sclerotinia scleroti) rum), white rot (Rosellinia necatrix), purple rot (Helicobasidium mompa), white rot (Sclerotium rolfsii), various other soil diseases (Fusarium, Rhizotium, Phythium phytium, Phythium phytium, Diseases such as bacteria, Plasmophora brassicae, etc.). But the plant pathogen used as the control object of this invention is not limited to what was illustrated above.

  When the pyrazol-4-carboxamide derivative (1) of the present invention is used as an active ingredient of an agricultural and horticultural fungicide, it may be used alone, but is produced using a general agricultural chemical auxiliary. It is desirable to use it in the form of a composition. The dosage form of the bactericide of the present invention is not particularly limited. For example, emulsion, suspension, wettable powder, aqueous solvent, liquid, sol (flowable), granule wettable powder, powder, fine granule, granule It is preferable to use dosage forms such as tablets, oils, sprays, fumes, aerosols and pastes. In addition, one or more of the pyrazol-4-carboxamide derivatives (1) of the present invention can be blended as an active ingredient, and in addition to the agricultural chemical auxiliary, other fungicidal ingredients are included as active ingredients. May be.

  The content of the pyrazol-4-carboxamide derivative (1) in the agricultural and horticultural fungicide of the present invention can be appropriately selected depending on the dosage form and method of use of the preparation. It is arbitrarily selected from the range of 0.1 to 90 parts by weight with respect to the total amount of the preparation.

  Ingredients as an agrochemical adjuvant used for producing an agricultural and horticultural fungicide containing the pyrazol-4-carboxamide derivative (1) of the present invention as an active ingredient include carriers, surfactants and other agrochemical supplements. Agents.

The carrier contained in the agricultural and horticultural fungicide of the present invention may be either a liquid carrier or a solid carrier as long as it can be used for agricultural and horticultural purposes, and is not limited to a specific one.
Liquid carriers include water, alcohols such as isopropyl alcohol and ethylene glycol, ketones such as cyclohexanone and methyl ethyl ketone, ethers such as propylene glycol monomethyl ether and diethylene glycol mono-n-butyl ether. -Aliphatic hydrocarbons such as tellurium, kerosene, light oil, aromatic hydrocarbons such as xylene, trimethylbenzene, tetramethylbenzene, methylnaphthalene, solvent naphtha, amides such as N-methyl-2-pyrrolidone, fatty acids And other vegetable oils such as soybean oil and rapeseed oil.
Solid carriers include starch, activated carbon, soybean flour, wheat flour, wood flour, fish flour, powdered milk and other animal and vegetable powders, talc, kaolin, bentonite, zeolite, diatomaceous earth, white carbon, clay, alumina, calcium carbonate, and chloride. Mineral powders such as potassium and ammonium sulfate can be used. Two or more of these carriers can be used in combination.

Examples of the surfactant contained in the agricultural and horticultural fungicide of the present invention include nonionic surfactants, anionic surfactants, cationic surfactants, and amphoteric surfactants. The following are listed.
Nonionic surfactants include, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan alkylate. -Polyoxyethylene phenyl ether polymer, polyoxyethylene alkylene aryl phenyl ether, polyoxyethylene alkylene glycol, polyoxyethylene polyoxypropylene block polymer, and the like.
Examples of the anionic surfactant include lignin sulfonate, alkyl aryl sulfonate, dialkyl sulfosuccinate, polyoxyethylene alkyl aryl ether tersulfate, alkyl naphthalene sulfonate, polyoxy And ethylene styryl phenyl ether sulfate.
Examples of the cationic surfactant include alkylamine salts.
Examples of amphoteric surfactants include quaternary ammonium salt alkylbetaines and amine oxides.
The surfactant that can be used for formulation is not limited to these. Two or more surfactants can be used in combination.

  Other agricultural chemical adjuvants contained in the agricultural and horticultural fungicides of the present invention include binders, thickeners, sticking agents, antiseptic fungicides, solvents, stabilizers for agricultural chemical active ingredients, antioxidants, ultraviolet rays Examples thereof include, but are not limited to, inhibitors, crystal precipitation inhibitors, antifoaming agents, physical property improvers, and colorants.

  The binder, thickener, and sticking agent are not particularly limited. For example, starch, dextrin, cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose. , Hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl starch, pullulan, sodium alginate, ammonium alginate, propylene glycol alginate, guar gum, locust bean gum, gum arabic, xanthan gum, gelatin, casein , Polyvinyl alcohol, polyethylene oxide, polyethylene glycol, ethylene / propylene block polymer, sodium polyacrylate, polyvinyl pyrrolidone and the like.

  The agricultural and horticultural fungicide of the present invention should be produced according to a general formulation method according to the intended dosage form, except that the pyrazol-4-carboxamide derivative (1) of the present invention is blended. Can do.

  The agricultural and horticultural fungicides of the present invention include other fungicides (fungicides, bactericides, antiviral agents, plant resistance inducers), insecticides, acaricides, nematicides, insect growth regulators. , Insect attractant, herbicide, plant growth regulator, synergist, safener, bird repellent, fertilizer, soil improver, etc. In addition, the pyrazol-4-carboxamide derivative (1) of the present invention and these active ingredients can be mixed and used at the time of formulation.

  Representative examples that can be used by mixing and mixing with the agricultural and horticultural fungicide of the present invention are shown below, but are not necessarily limited thereto.

[Fungicide]: amisulbrom (cyamifamid), dimethomorph (cymoxanil), fluopicolide (fluopicolide) acibenzalar, isothianil, thiadinyl, probenazole, carpropamide, diclocymet, fenoxanil, olcyclyl-zol roquilon, phthalide, azoxystrobin, oryzatrobin, cresoxime-methyl, trifloxystrobin, tropoxystrobin (pixoxystrobin) pyraclostrobin, famoxadone, methominostrobin, thiophanate-methyl, diethofencarb (thiabendazol), thiabendazol, ole), imibenconazole, oxpoconazol-ol-ol-tetra-zole, diphenoconazole, teproconazole, cyproconazole, cyproconazole. (Tetraconazole), triadimefone, triflumizole, triforine, bittertanol, fenarimol, prozolco, fenbuconazol opiconazole, hexaconazole, pefurazoate, microbutanil, metconazole, epoxiconazole, epoxiconazole, epoxiconazol bifafene, furametopyr, flutolanil, penthiopyrad, boscalid, mepronil, isoprothiolane, ferrimone (d), felimone (d) edine), pencyclon, iprodione, procymidone, cyprodinil, mepanipyrim, lumethanil, hexhexamin, f Cyflufenamide, metraphenone, quinoxyfen, iminoctadate acetate, iminoctaden arbesylate, propamate salt Salt (propacarbcarb hydrochloride), chlorothalonil (TPN), captan, fluorimide, holpet, dithianon, quinoxaline (chinodiflutine), quinoxaline (chinodiflutine) Fosetyl-alummium, ambam, ziram, thiadiazine, thyram, polycarbamate, manczeb, manneb, sulf de), hydroxyisoxazole (hymexazole), echromezol (etridiazole), iprobenfos (IBP), edifenphos (EDDP), tolclofos-methyl (tolclofos-methyl) ), Validamycin, blastcidin-S, polyoxins, polyoxin zinc salt (polyoximine), kasugamycin, oxytetracycline oxycline, retinocycline oxycline, retinoic acid (Oxolinic acid), teclophthalam (t cloftalam, sulfur, sodium hydrogen carbonate, potassium hydrogen carbonate, metallic silver, basic copper chloride, copper sulfate, copper hydroxide, anhydrous copper sulfate , Copper nonylphenol sulfonate, 8-hydroxyquinoline copper, DBEDC, and the like.

[Insecticides, acaricides] Acephate, isoxathion, ethylthiodemethon, cadusafos, chlorpyrifos, chlorpyrifosmethyl, chloropyrifosmethyl Diclofenthion (ECP), dimethoate (dimethoate), dichlorvos (DDVP), diazinon (diazinon), trichlorfon (TRIP), piramlothio (ph) (Fenitothion, MEP), fenthion (MPP), phentoate (PAP), prothiofos (profiofos), profenophos (fosenolone), fosalone (fostiazate), thion Methidathion (DMTP), EPN, alanic carb, isoprocarb (isoprocarb, MIPC), ethiofencarb (ethiofencarb), oxamyl (oxamyl), carbaryl (NC), carbosulf (c) Fracioca Furathiocarb, benfuracarb, methomyl, fenobucarb, BPMC, XMC, acrinathrin, allethrin, etofenprox (etofroproline, etofenprox) cyhalothrin), cyfluthrin, cypermethrin, silafluofen, tefluthrin, tralomethrin, bifenthrein, bifenthretriate Fenpropatorin, flucitrinate, fluvalinate, permethrin, fenvalerate, cartap, thiocyclamate, thiocyclam , Imidacloprid, clothianidin, dinotefuran, thiacloprid, thiamethoxam, nitenpyram, chlorfluron ), Diflubenzuron (diflubenzuron), teflubenzuron (teflubenzuron), novaluron (novaluron), flufenoxuron (flufenoxuron), lufenuron (lufenuron), chromafenozide (chromafenozide), tebufenozide (tebfenozide), buprofezin (buprofenzin), methoxyfenozide (methoxyfenozide), cyromazine (Cyromazine), benzopiene (endosulfan), ethiprole (fipronil), indoxacarb MP (indoxacarb), chlorfenapyr, diafenthiuron (dia) fenthiuron, tolfenpyrad, pymetrozine, pyridalyl, flubenamide, chlorantaniprole, flavantamide, florantamide benzoate, spinosad, milbemectin, lepimectin, pyrethrins, starch, fatty acid glycerides, propylene glycol monofatty acid ester, machine oil (petrolium oil), olein Sodium (sodium oleate), BT, acequinosyl (acequinocyl), amitraz, etoxazol (etoxazole), clofentezine (spirodiclofen), spirodiclofen (i), spiromethifro (i) spirotetramat, tebufenpyrad, bifenazate, pyridaben, pyrimidifene, fenothiocarb, fenpyroxito-x ) Fluacrypyrim (fluacrypyrim), hexythiazox (hexythiazox), such as.

  In addition, it described more concretely about the manufacturing method of the agricultural and horticultural fungicide of this invention to the formulation example as described in the below-mentioned Example. Of course, the fungicide of the present invention is not limited to these formulation examples, and other various additives can be mixed in any ratio, and other fungicides can be mixed in any ratio. Can also be formulated.

  In addition, the application method of the agricultural and horticultural fungicide of the present invention (including a diluted product thereof) is not particularly limited, and spraying (for example, spraying, misting, atomizing, dusting, dusting, water surface application, Box application, etc.), soil application (eg, mixing, irrigation, etc.), surface application (eg, application, powder coating, coating, etc.), immersion, etc.

  The application amount of the agricultural and horticultural fungicide of the present invention is not particularly limited, the concentration of the active ingredient in the fungicide, the dosage form of the preparation, the target disease or crop type, the degree of damage caused by the disease, the application location, the application method, It is appropriately selected from a wide range according to various conditions such as application time, types and amounts of drugs and fertilizers to be used in combination, and weather. Usually, the amount of the active ingredient compound of the present invention is about 1 to 100,000 g, preferably about 10 to 10,000 g per hectare.

  In addition, when the agricultural and horticultural fungicide of the present invention is used by diluting with water, such as a liquid agent, an emulsion, a wettable powder, a sol (flowable agent) or a granular wettable powder, its application concentration is 0.1 to Although used at about 10,000 ppm by mass, preferably about 1 to 500 ppm by mass, it is not limited to these.

  EXAMPLES Hereinafter, although an Example, a reference example, a formulation example, and a test example are given and this invention is demonstrated further in detail, this invention is not limited to these.

[Examples of Synthesis of Pyrazol-4-carboxamide Derivative (1), Pyrazol-4-carboxylic Acid Derivative (2), 4-Aminopyrazole Derivative (3)]
Examples 1 to 99 are examples of pyrazol-4-carboxamide derivative (1), Reference Examples 1 to 9 are examples of pyrazol-4-carboxylic acid derivative (2), and Reference Examples 10 to 14 are 4-aminopyrazo. This is an example of a -le derivative (3).

Reference example-1

Anhydrous DMF (19 mL, 245 mmol) was cooled in a salt bath, and phosphorus oxychloride (48 mL, 515 mmol) was added dropwise with care so that the temperature of the reaction solution did not exceed 10 ° C. To this was added 5-hydroxy-1,3-dimethylpyrazole (13.1 g, 117 mmol), and the temperature was gradually raised to reflux. After further refluxing for 18 hours, the reaction solution cooled to room temperature was poured into ice. The resulting solution was stirred for 4 hours taking care that the temperature did not exceed 20 ° C., and the precipitated solid was collected by filtration to give a gray solid of 5-chloro-1,3-dimethylpyrazole-4- Carbaldehyde (2.10 g, yield: 11%) was obtained. Further, the filtrate was extracted with toluene (200 mL × 2), and the combined organic layer was washed with water (100 mL). Then, after drying over anhydrous magnesium sulfate, concentration under reduced pressure gave 5-chloro-1,3-dimethylpyrazole-4-carbaldehyde pale yellow solid (12.6 g, yield: 68%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.45 (3H, s), 3.82 (3H, s), 9.85 (1H, s).

5-chloro-1,3-dimethylpyrazole-4-carbaldehyde (3.17 g, 20.0 mmol), potassium hydroxide (300 mg), potassium permanganate (3.16 g, 20.0 mmol) and water (40 mL) ) Was stirred at 60 ° C. for 1 hour. The reaction solution was returned to room temperature, insoluble solids were filtered off, and concentrated hydrochloric acid was added to the filtrate to make it acidic. The precipitated solid was then collected by filtration, suspended in ethanol and then refluxed for 15 minutes. The insoluble solid was again removed by filtration, and the filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a colorless solid of 5-chloro-1,3-dimethylpyrazole-4-carboxylic acid (2.84 g, yield: 81%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.47 (3H, s), 3.83 (3H, s).

A mixture of 5-chloro-1,3-dimethylpyrazole-4-carboxylic acid (568 mg, 3.25 mmol), 10% palladium carbon (100 mg) and 5% aqueous sodium carbonate solution (20 mL) was added at room temperature under a hydrogen atmosphere at room temperature. Stir for days. The catalyst was removed by filtration, and the filtrate was acidified with concentrated hydrochloric acid and extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 1,3-dimethylpyrazole-4-carboxylic acid colorless solid (36 mg, yield: 7.9%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.48 (3H, s), 3.88 (3H, s), 7.87 (1H, s).

Example-1

A mixture of 1,3-dimethylpyrazole-4-carboxylic acid (128 mg, 0.913 mmol), anhydrous toluene (5.0 mL) and thionyl chloride (0.50 mL) was refluxed for 1 hour and then concentrated under reduced pressure to obtain 1, 3-Dimethylpyrazole-4-carboxylic acid chloride was obtained. This was dissolved in anhydrous dichloromethane (1.0 mL), triethylamine (200 mg, 1.98 mmol) was added, and the mixture was cooled with ice, and then 4-amino-5-trifluoromethyl-1- (2,4,6-trimethyl). Fluorophenyl) pyrazole (200 mg, 0.711 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 1,3-dimethyl -N- [5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl] pyrazol-4-carboxamide as a pale yellow solid (146 mg, yield: 51% ) Mp: 145-148 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.54 (3H, s), 3.89 (3H, s), 6.82 to 6.91 (2H, m), 7.58 (1H, brs) , 7.82 (1H, s), 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −101.8 (1F, t, J = 7.1 Hz), −59.0 (3F, t, J = 5) .9 Hz).

Example-2

A mixture of 5-chloro-1,3-dimethylpyrazole-4-carboxylic acid (230 mg, 1.32 mmol), anhydrous toluene (3.0 mL) and a catalytic amount of anhydrous DMF was ice-cooled, and oxalyl chloride (0.22 mL) was added. , 2.60 mmol). The reaction solution was stirred at room temperature for 19 hours and then concentrated under reduced pressure to obtain 5-chloro-1,3-dimethylpyrazole-4-carboxylic acid chloride. This was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (200 mg, 1.98 mmol) was added and ice-cooled, and then 4-amino-5-trifluoromethyl-1- (2,4,6-trimethyl) was added. Fluorophenyl) pyrazole (280 mg, 1.00 mmol) was added. The reaction mixture was stirred at room temperature for 2 days, saturated aqueous sodium hydrogen carbonate solution (40 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5-chloro-1 , 3-Dimethyl-N- [5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl] pyrazol-4-carboxamide (313 mg, yield) Rate: 72%). Mp: 168-172 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.54 (3H, s), 3.86 (3H, s), 6.82 to 6.91 (2H, m), 8.20 (1H, brs) , 8.71 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −101.9 (1F, t, J = 7.1 Hz), −58.9 (3F, t, J = 3) .1 Hz).

Reference example-2

Ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate (77.2 g, 378 mmol) was dissolved in ethanol (200 mL), 10% aqueous sodium hydroxide solution (200 mL) was added, and the mixture was refluxed for 1 hour. . The reaction solution was returned to room temperature and acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration to give a brown solid of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (55.6 g, yield: 84%). ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.91 (3H, s), 7.20 (1 H, t, J _HF = 53.8 Hz), 8.34 (1 H, s), 12.83 (1H, brs). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-114.9 (2F, s).

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (1.94 g, 11.0 mmol), anhydrous toluene (10 mL) and thionyl chloride (5.0 mL) was refluxed for 30 minutes, followed by Dean-Stark. Was used to remove toluene and excess thionyl chloride. Further, the solvent was completely removed successively using an evaporator and a vacuum pump to quantitatively obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (2.14 g). . This was used in the next reaction without purification. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 6.92 (1H, t, J _HF = 53.5 Hz), 8.08 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-117.1 (2F, s).

Example-3

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) was dissolved in anhydrous dichloromethane (2.5 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-methyl-1- (2,4,6-trifluorophenyl) pyrazole (340 mg, 1.50 mmol) was added. The reaction mixture was stirred at room temperature for 4 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give 3-difluoromethyl- N- [5-Methyl-1- (2,4,6-trifluorophenyl) -5-methylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide colorless solid (555 mg, yield: 96%). Mp: 72-74 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.14 (3H, s), 3.96 (3H, s), 6.82 to 6.92 (2H, m), 6.88 (1H, t, _{J HF = 54.3Hz), 7.81 (} 1H, brs), 8.05 (1H, s), 8.15 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.0 (2F, d, J = 7.1 Hz), −107.8 (2F, s), −104.3 (1F, t, J = 7) .1 Hz).

Example-4

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-ethyl-1- (2,4,6-trifluorophenyl) pyrazole (370 mg, 1.53 mmol) was added. The reaction mixture was stirred at room temperature for 28 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give 3-difluoromethyl- A brown solid (711 mg) of N- {5-ethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide was obtained quantitatively. . Mp: 63-68 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.07 (3H, t, J = 7.5 Hz), 2.54 (2H, q, J = 7.5 Hz), 3.96 (3H, s), _{6.81~6.92 (2H, m), 6.88} (1H, t, J HF = 54.3Hz), 7.87 (1H, brs), 8.06 (1H, s), 8.18 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 7.1 Hz), −107.8 (2F, s), −103.9 (1F, t, J = 7) .1 Hz).

Example-5

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-propyl-1- (2,4,6-trifluorophenyl) pyrazole (390 mg, 1.53 mmol) was added. The reaction mixture was stirred at room temperature for 28 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give 3-difluoromethyl- A yellow solid (733 mg) of 1-methyl-N- {5-propyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide was obtained quantitatively. It was. Mp: 54-58 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.84 (3H, t, J = 7.4 Hz), 1.38 to 1.53 (2H, m), 2.46 to 2.52 (2H, m ), 3.96 (3H, s), 6.81 to 6.91 (2H, m), 6.87 (1H, t, J _HF = 54.1 Hz), 7.85 (1H, brs), 8 .07 (1H, s), 8.24 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 7.1 Hz), -107.6 (2F, brs), -104.0 (1F, brs).

Example-6

After 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (350 mg, 1.80 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added and the mixture was ice-cooled. 4-Amino-1- (4-ethoxy-2,6-difluorophenyl) -5-propylpyrazole (423 mg, 1.50 mmol) was added. The reaction mixture was stirred at room temperature for 28 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give 3-difluoromethyl- N- {1- (4-Ethoxy-2,6-difluorophenyl) -5-propylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide as a yellow solid (488 mg, yield: 74%) Got. Mp: 149-152 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.83 (3H, t, J = 7.4 Hz), 1.37 to 1.52 (2H, m), 1.45 (3H, t, J = 7) .0Hz), 2.46 to 2.52 (2H, m), 3.95 (3H, s), 4.06 (2H, q, J = 7.0 Hz), 6.54 to 6.62 (2H) M), 6.88 (1H, t, J _HF = 54.3 Hz), 7.88 (1H, brs), 8.05 (1H, s), 8.20 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-117.9 (2F, s), -107.9 (2F, s).

Example-7

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (280 mg, 1.44 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-isopropyl-1- (2,4,6-trifluorophenyl) pyrazole (310 mg, 1.21 mmol) was added. After stirring the reaction solution at room temperature for 27 hours, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/7) to give 3-difluoromethyl- N- {5-Isopropyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide yellow solid (380 mg, yield: 76%) Got. Mp: 149-151 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.25 (6H, d, J = 7.3 Hz), 2.80 (1H, septet, J = 7.3 Hz), 3.96 (3H, s), _{6.80~6.90 (2H, m), 6.88} (1H, t, J HF = 54.1Hz), 7.79 (1H, brs), 8.07 (1H, s), 8.15 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.6 (2F, d, J = 7.1 Hz), −107.5 (2F, s), −103.9 (1F, t, J = 7) .1 Hz).

Example-8

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-butyl-1- (2,4,6-trifluorophenyl) pyrazole (410 mg, 1.52 mmol) was added. The reaction mixture was stirred at room temperature for 29 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give N- {5- A brown oily substance (754 mg) of butyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide was quantitatively obtained. It was. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.80 (3H, t, J = 7.3 Hz), 1.16 to 1.46 (4H, m), 2.48 to 2.54 (2H, m ), 3.96 (3H, s), 6.81 to 6.92 (2H, m), 6.87 (1H, t, J _HF = 54.3 Hz), 7.86 (1H, brs), 8 .07 (1H, s), 8.22 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 7.1 Hz), −107.6 (2F, s), −103.9 (1F, t, J = 7) .1 Hz).

Example-9

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (280 mg, 1.44 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-tert-butyl-1- (2,4,6-trifluorophenyl) pyrazole (330 mg, 1.23 mmol) was added. After stirring the reaction solution at room temperature for 27 hours, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/7) to give N- {5- A pale yellow solid of t-butyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (380 mg, yield: 76%). Mp: 180-184 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.26 (9H, s), 3.95 (3H, s), 6.78 to 6.87 (2H, m), 6.89 (1H, t, _{J HF = 54.3Hz), 7.70 (} 1H, brs), 7.91 (1H, s), 8.04 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.6 (2F, d, J = 7.1 Hz), −108.0 (2F, s), −103.9 (1F, t, J = 7) .1 Hz).

Example-10

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (780 mg, 4.01 mmol), triethylamine (600 mg, 5.93 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4-amino After adding a solution of -5-difluoromethyl-1-phenylpyrazole (360 mg, 1.72 mmol) in anhydrous dichloromethane (2.0 mL), the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), and dried over anhydrous magnesium sulfate. The crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give 3-difluoromethyl-N- (3-difluoromethyl-1-methylpyrazole-4. A yellow solid (375 mg, yield: 42%) of -yl) carbonyl-N- (5-difluoromethyl-1-phenylpyrazol-4-yl) -1-methylpyrazol-4-carboxamide was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.88 (6H, s), 6.66 (1 H, t, J _HF = 52.8 Hz), 6.98 (2 H, t, J _HF = 54.1 Hz) ), 7.46-7.57 (5H, m), 7.57 (2H, s), 7.73 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.6 (4F, s), -114.2 (2F, s).

3-Difluoromethyl-N- (3-difluoromethyl-1-methylpyrazol-4-yl) carbonyl-N- (5-difluoromethyl-1-phenylpyrazol-4-yl) -1-methylpyrazol- A mixture of 4-carboxamide (355 mg, 0.676 mmol), dioxane (5.0 mL) and 2N hydrochloric acid (5.0 mL) was refluxed for 3 hours. The reaction solution was returned to room temperature, 10% aqueous sodium hydroxide solution (30 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate (20 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow solid obtained by silica gel column chromatography (hexane / ethyl acetate = 2/3). ) To give 3-difluoromethyl-N- (5-difluoromethyl-1-phenylpyrazol-4-yl) -1-methylpyrazol-4-carboxamide as a yellow solid (114 mg, yield: 46%) ) Mp: 176-177 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.71 (1 H, t, J _HF = 52.9 Hz), 6.88 (1 H, t, J _HF = 54.1 Hz) ), 7.43-7.57 (5H, m), 8.05 (1H, s), 8.42 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-112.4 (2F, t, J = 7.1 Hz), −109.1 (2F, t, J = 7.1 Hz).

Example-11

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (553 mg, 2.84 mmol) was dissolved in anhydrous dichloromethane (4.0 mL), triethylamine (575 mg, 5.68 mmol) was added, and the mixture was ice-cooled. Furthermore, 4-amino-1-phenyl-5-trifluoromethylpyrazole (645 mg, 2.84 mmol) dissolved in anhydrous dichloromethane (1.5 mL) was added dropwise, and the mixture was stirred at room temperature for 19 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with chloroform (3 × 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1), and further purified from ethanol. Crystallized white solid 3-difluoromethyl-1-methyl-N- {1-phenyl-5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide (471 mg, yield: 43 %). Mp: 172-174 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.85 (1 H, t, J _HF = 54 Hz), 7.48 (5 H, m), 8.07 (1 H, s ), 8.34 (1H, brs), 8.54 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-56.0 (3F, q, J = 8.4 Hz), −108.6 (2F, q, J = 7.5 Hz).

Example-12

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (468 mg, 2.41 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (305 mg, 3.01 mmol) was added, and the mixture was cooled with ice. 4-Amino-1- (2-fluorophenyl) -5-trifluoromethylpyrazole (488 mg, 1.99 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 3-difluoromethyl-N- {1- (2-fluorophenyl) -5-trifluoromethyl. A pale yellow solid (320 mg, yield: 40%) of pyrazol-4-yl} -1-methylpyrazol-4-carboxamide was obtained. Mp: 154-155 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.21 to 7.30 (2H, m), 7 .42-7.53 (2H, m), 8.08 (1H, s), 8.34 (1H, brs), 8.60 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-122.1 (1F, q, J = 4.7 Hz), −108.5 (2F, q, J = 7.1 Hz), −58.0 (3F) , M).

Example-13

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- A solution of (2-chlorophenyl) -5-trifluoromethylpyrazole (523 mg, 2.00 mmol) in anhydrous dichloromethane (1.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (2-chlorophenyl) -5-trifluoromethylpyrazole- as a colorless solid. 4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (650 mg, yield: 78%) was obtained. Mp: 161-162 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1H, t, J _HF = 54.1 Hz), 7.36-7.57 (4H, m), 8 .08 (1H, s), 8.35 (1H, brs), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, m), -57.8 (3F, t, J = 6.3 Hz).

Example-14

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (470 mg, 2.42 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (308 mg, 3.04 mmol) was added, and the mixture was cooled with ice. 4-Amino-1- (2-bromophenyl) -5-trifluoromethylpyrazole (612 mg, 2.00 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1), and N- {1- (2-bromophenyl) -5-trifluoromethylpyrazole- A pale yellow solid (322 mg, yield: 35%) of 4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide was obtained. Mp: 160-162 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.37-7.47 (3H, m), 7 .70-7.75 (1H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, q, J = 7.1 Hz), −57.6 (3F, t, J = 7.1 Hz).

Example-15

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (387 mg, 1.99 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- (2-Methylphenyl) -5-trifluoromethylpyrazole (480 mg, 1.99 mmol) was added under ice cooling, followed by stirring at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl-1-methyl-N- {1- (2-methylphenyl) as a pale yellow solid. -5-Trifluoromethylpyrazol-4-yl} pyrazole-4-carboxamide (632 mg, yield: 80%) was obtained. Mp: 168 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.06 (3H, s), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.28-7 .45 (4H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.56 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 6.6 Hz), −57.5 (3F, t, J = 6.6 Hz).

Example-16

After 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (472 mg, 2.43 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (304 mg, 3.00 mmol) was added and ice-cooled. 4-Amino-1- (2-ethylphenyl) -5-trifluoromethylpyrazole (510 mg, 2.00 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2), and 3-difluoromethyl-N- {1- (2-ethylphenyl) -5-trifluoromethyl. A brown solid (405 mg, yield: 49%) of pyrazol-4-yl} -1-methylpyrazol-4-carboxamide was obtained. Mp: 142 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.14 (3H, t, J = 7.5 Hz), 2.35 (2H, q, J = 7.5 Hz), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.25 to 7.50 (4H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, m), −57.1 (3F, t, J = 7.1 Hz).

Example-17

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (460 mg, 2.36 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (350 mg, 3.46 mmol) was added, and the mixture was cooled with ice. 4-Amino-5-trifluoromethyl-1- (2-trifluoromethylphenyl) pyrazole (583 mg, 1.98 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1), and 3-difluoromethyl-1-methyl-N- {5-trifluoromethyl-1- (2 A colorless solid (349 mg, yield: 39%) of -trifluoromethylphenyl) pyrazol-4-yl} pyrazol-4-carboxamide was obtained. Mp: 89-91 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J _HF = 54.0 Hz), 7.44 to 7.47 (1 H, m), 7 .65 to 7.73 (2H, m), 7.82 to 7.86 (1H, m), 8.08 (1H, s), 8.33 (1H, brs), 8.60 (1H, s) ). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, m), −60.7 (3F, q, J = 2.4 Hz), −57.1 (3F, m).

Example-18

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (5.04 g, 25.9 mmol), triethylamine (1.56 g, 15.4 mmol) and anhydrous dichloromethane (50 mL) was ice-cooled, and 4 -Amino-1- (2-methoxyphenyl) -5-trifluoromethylpyrazole (2.47 g, 10.3 mmol) was added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3). A brown solid of 3-difluoromethyl-N- {1- (2-methoxyphenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide (3. 23 g, yield: 76%). Mp: 174-179 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.78 (3H, s), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.01 to 7 .08 (2H, m), 7.35 (1H, dd, J ₁ = 6.3 Hz, J ₂ = 1.5 Hz), 7.44-7.51 (1H, m), 8.07 (1H, s), 8.32 (1H, brs), 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 7.1 Hz), −58.4 (3F, t, J = 7.1 Hz).

Example-19

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- A solution of (3-chlorophenyl) -5-trifluoromethylpyrazole (523 mg, 2.00 mmol) in anhydrous dichloromethane (1.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give N- {1- (3-chlorophenyl) -5-trifluoromethylpyrazole- as a colorless solid. 4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (288 mg, yield: 34%) was obtained. Mp: 175-177 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1, t, J _HF = 54.1 Hz), 7.35 to 7.50 (4H, m), 8 .08 (1H, s), 8.35 (1H, brs), 8.57 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 6.7 Hz), −55.9 (3F, t, J = 6.7 Hz).

Example-20

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (465 mg, 2.39 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (305 mg, 3.01 mmol) was added, and the mixture was cooled with ice. 4-Amino-1- (3-bromophenyl) -5-trifluoromethylpyrazole (607 mg, 1.98 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (3-bromophenyl) -5-trifluoromethylpyrazo as a colorless solid. -L-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (397 mg, yield: 43%) was obtained. Mp: 176-178 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.33 to 7.44 (2H, m), 7 60 to 7.66 (2H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.57 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 7.1 Hz), −55.8 (3F, t, J = 7.1 Hz).

Example-21

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (387 mg, 1.99 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- (3-Methylphenyl) -5-trifluoromethylpyrazole (486 mg, 2.01 mmol) was added under ice cooling, followed by stirring at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl-1-methyl-N- {1- (3-methylphenyl) as a pale yellow solid. -5-Trifluoromethylpyrazol-4-yl} pyrazole-4-carboxamide (555 mg, yield: 70%) was obtained. Mp: 126-128 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.42 (3H, s), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.1 Hz), 7.23-7 .39 (4H, m), 8.07 (1H, s), 8.34 (1H, brs), 8.53 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 6.5 Hz), −56.0 (3F, t, J = 6.5 Hz).

Example-22

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (484 mg, 2.49 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (4-fluorophenyl) -5-trifluoromethylpyrazole (610 mg, 2.49 mmol) in anhydrous dichloromethane (3.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a colorless solid. ^{From 1} H-NMR, it was found that this contained 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give a colorless solid pure 3-difluoromethyl-N- {1- (4-fluorophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazo- Ru-4-carboxamide (620 mg, yield: 62%) was obtained. Mp: 166-167 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.1 Hz), 7.18 (2H, dd, J ₁ = 8.8 Hz) , J ₂ = 8.3 Hz), 7.44 (2H, dd, J ₁ = 8.8 Hz, J ₂ = 4.8 Hz), 8.08 (1H, s), 8.34 (1H, brs), 8.54 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.3 (1F, s), −108.6 (2F, q, J = 6.6 Hz), −56.0 (3F, t, J = 6) .6 Hz).

Example-23

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- (4-Chlorophenyl) -5-trifluoromethylpyrazole (523 mg, 2.00 mmol) was added under ice cooling, followed by stirring at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give N- {1- (4-chlorophenyl) -5-trifluoromethylpyrazole- as a colorless solid. 4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (714 mg, yield: 85%) was obtained. Mp: 163 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.84 (1 H, t, J _HF = 54.1 Hz), 7.40 (2 H, d, J = 8.9 Hz) 7.47 (2H, d, J = 8.9 Hz), 8.07 (1H, s), 8.34 (1H, brs), 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 6.6 Hz), −55.9 (3F, t, J = 6.6 Hz).

Example-24

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (2.20 g, 11.3 mmol), triethylamine (1.50 g, 14.8 mmol) and anhydrous dichloromethane (15 mL) was ice-cooled, and 4 A solution of 2-amino-1- (4-bromophenyl) -5-trifluoromethylpyrazole (3.75 g, 12.3 mmol) in anhydrous dichloromethane (3.5 mL) was added, Stir for hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (50 mL) and extracted with ethyl acetate (50 mL × 1, 15 mL × 1). The organic layers were combined, dried over anhydrous magnesium sulfate, and the brown solid obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (4 -Bromophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide as a pale yellow solid (4.04 g, yield: 77%) Obtained. Mp: 179-183 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.84 (1H, t, J _HF = 54.1 Hz), 7.35 (2H, d, J = 8.8 Hz) 7.62 (2H, d, J = 8.8 Hz), 8.07 (1H, s), 8.34 (1H, brs), 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, q, J = 7.1 Hz), −55.9 (3F, t, J = 7.1 Hz).

Example-25

N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (419 mg, 1.05 mmol) synthesized separately ) Was dissolved in concentrated sulfuric acid (6.0 mL) and added to a mixture of ice (4.0 g) and acetonitrile (8 mL). To this solution, an aqueous solution in which sodium nitrite (77.5 mg, 1.14 mmol) was dissolved in water (0.20 mL) was added over 10 minutes, taking care not to increase the liquid temperature to 5 ° C. or higher. Stir for 20 minutes. Next, an aqueous solution in which potassium iodide (174 mg, 1.05 mmol) was dissolved in water (0.17 mL) was added little by little, followed by stirring at room temperature for 2 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give a yellow solid 3- Difluoromethyl-N- {1- (4-iodophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide (207 mg, yield: 39%) Obtained. Mp: 204-208 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.21 (2H, d, J = 8.6 Hz) 7.82 (2H, d, J = 8.6 Hz), 8.07 (1H, s) 8.34 (1H, brs), 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 7.1 Hz), −55.8 (3F, t, J = 7.1 Hz).

Example-26

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (387 mg, 1.99 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino-1- (4-Methylphenyl) -5-trifluoromethylpyrazole (480 mg, 1.99 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl-1-methyl-N- {1- (4-methylphenyl) as a pale yellow solid. -5-Trifluoromethylpyrazol-4-yl} pyrazole-4-carboxamide (652 mg, yield: 82%) was obtained. Mp: 154-157 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.43 (3H, s), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.27 (2H , D, J = 8.3 Hz), 7.33 (2H, d, J = 8.3 Hz), 8.07 (1H, s), 8.33 (1H, brs), 8.52 (1H, s) ). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 6.5 Hz), −56.0 (3F, t, J = 6.5 Hz).

Example-27

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (4-t-butylphenyl) -5-trifluoromethylpyrazole (566 mg, 2.00 mmol) in anhydrous dichloromethane (4.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 15 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give N- {1- (4-t-butylphenyl) -5-trifluoromethylpyra as a pale yellow solid. Zol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (639 mg, yield: 70%) was obtained. Mp: 169-171 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.36 (9H, s), 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.37 (2H , D, J = 8.6 Hz), 7.49 (2H, d, J = 8.6 Hz), 8.07 (1H, s), 8.33 (1H, brs), 8.52 (1H, s) ). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 6.5 Hz), −56.0 (3F, t, J = 6.5 Hz).

Example-28

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 -Amino-5-trifluoromethyl-1- (4-trifluoromethylphenyl) pyrazole (370 mg, 1.25 mmol) dissolved in anhydrous dichloromethane (3.0 mL) was added, and then at room temperature for 2 days Stir. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give 3-difluoromethyl-1- A pale yellow solid (305 mg, yield: 65%) of methyl-N- {5-trifluoromethyl-1- (4-trifluoromethylphenyl) pyrazol-4-yl} pyrazol-4-carboxamide was obtained. Obtained. Mp: 194-195 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.1 Hz), 7.62 (2 H, d, J = 8.5 Hz) , 7.77 (2H, d, J = 8.5 Hz), 8.09 (1H, s), 8.37 (1H, brs), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.4 (2F, q, J = 7.1 Hz), −63.0 (3F, s), −55.7 (3F, t, J = 7) .1 Hz).

Example-29

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (10.0 g, 51.4 mmol), triethylamine (3.00 g, 29.7 mmol) and anhydrous dichloromethane (100 mL) was ice-cooled, and 4 -Amino-1- (4-methoxyphenyl) -5-trifluoromethylpyrazole (4.82 g, 20.0 mmol) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1). 3-Difluoromethyl-N- {1- (4-methoxyphenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide as a brown solid (7. 62 g, yield: 92%). Mp: 134-135 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.87 (3H, s), 3.97 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 6.97 (2H , D, J = 9.0 Hz), 7.36 (2H, d, J = 9.0 Hz), 8.07 (1H, s), 8.32 (1H, brs), 8.51 (1H, s) ). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, q, J = 7.1 Hz), −56.2 (3F, t, J = 7.1 Hz).

Example-30

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (468 mg, 2.41 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (344 mg, 3.40 mmol) was added, and the mixture was ice-cooled. 4-Amino-1- (4-trifluoromethoxyphenyl) -5-trifluoromethylpyrazole (622 mg, 2.00 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2) and 3-difluoromethyl-1-methyl-N- {1- (4-trifluoromethoxyphenyl). A pale yellow solid (353 mg, yield: 38%) of -5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide was obtained. Mp: 155 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.0 Hz), 7.34 (2 H, d, J = 9.0 Hz) 7.51 (2H, d, J = 9.0 Hz), 8.08 (1H, s), 8.36 (1H, brs), 8.57 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 7.1 Hz), −58.2 (3F, s), −55.9 (3F, t, J = 7) .1 Hz).

Example-31

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol), triethylamine (300 mg, 2.96 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4-amino A solution of -1- (4-cyanophenyl) -5-trifluoromethylpyrazole (500 mg, 1.98 mmol) dissolved in anhydrous dichloromethane (7.0 mL) was added, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was poured into 2N hydrochloric acid (30 mL) and extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined and washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow solid obtained by silica gel column chromatography (hexane / ethyl acetate = 1/2 ) To give N- {1- (4-cyanophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide as pale yellow A solid (166 mg, yield: 20%) was obtained. Mp: 218-222 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.98 (3H, s), 7.31 (1 H, t, J _HF = 54.0 Hz), 7.77 (2H, d, J = 8. 6 Hz), 8.10 (2H, d, J = 8.6 Hz), 8.13 (1 H, s), 8.47 (1 H, s), 10.12 (1 H, s). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-114.6 (2F, s), -56.0 (3F, s).

Example-32

Concentrated nitric acid (2.0 mL) was ice-cooled, and concentrated sulfuric acid (2.0 mL) was slowly added. To this was separately synthesized 3-difluoromethyl-1-methyl-N- (1-phenyl-5-trifluoromethylpyrazol-4-yl) pyrazol-4-carboxamide (530 mg, 1.38 mmol). ) Was slowly added to concentrated sulfuric acid (5.0 mL), followed by stirring at 0 ° C. for 1 hour. The reaction solution was poured into ice water (150 mL), and the precipitated solid was collected by filtration. This was washed with water and hexane to give 3-difluoromethyl-1-methyl-N- {1- (4-nitrophenyl) -5-trifluoromethylpyrazol-4-yl} pyrazol-4 -A light yellow solid (556 mg, yield: 94%) of carboxamide was obtained. Mp: 199-201 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.1 Hz), 7.70 (2 H, d, J = 9.0 Hz) , 8.09 (1H, s), 8.38 (2H, d, J = 9.0 Hz), 8.38 (1H, brs), 8.65 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.3 (2F, q, J = 7.1 Hz), −55.5 (3F, t, J = 7.1 Hz).

Example-33

Separately synthesized 3-difluoromethyl-1-methyl-N- {1- (4-nitrophenyl) -5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide (8.67 g, 20.2 mmol) was dissolved in acetic acid (870 mL), platinum dioxide hydrate (401 mg) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. After completion of the reaction, the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazo- A brown solid (7.90 g, yield: 98%) of ru-4-carboxamide was obtained. Mp: 204-208 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.97 (3H, s), 5.55 (2H, brs), 6.64 (2H, d, J = 8.5 Hz), 7.10 ( _{2H, d, J = 8.5Hz)} , 7.31 (1H, t, J HF = 54.0Hz), 7.88 (1H, s), 8.45 (1H, s), 9.89 (1H , Brs). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-114.5 (2F, s), -56.6 (3F, s).

Example-34

N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (401 mg, 1.00 mmol) synthesized separately ), Triethylamine (153 mg, 1.51 mmol) and anhydrous dichloromethane (5.0 mL) were ice-cooled, and acetic anhydride (0.10 mL, 1.75 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, 2N hydrochloric acid (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/9), and N- {1- ( 4-Acetaminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide as a brown solid (287 mg, yield: 65%) Obtained. Mp: 239-242 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 2.10 (3H, s), 3.98 (3H, s), 7.31 (1 H, t, J _HF = 55.0 Hz), 7.44 (2H, d, J = 10.0 Hz), 7.76 (2H, d, J = 10.0 Hz), 7.98 (1 H, s), 8.46 (1 H, s), 9.97 (1 H , S), 10.24 (1H, s). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-114.5 (2F, s), -56.4 (3F, s).

Example-35

N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (400 mg, 1.00 mmol) synthesized separately , A mixture of triethylamine (164 mg, 1.62 mmol) and anhydrous dichloromethane (5.0 mL) was ice-cooled, and 4-fluorobenzoyl chloride (0.13 mL, 1.10 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, 2N hydrochloric acid (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/3) to give colorless solid 3-difluoro. Methyl-N- [1- {4- (4-fluorobenzoylamino) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide (344 mg, yield: 66%). Mp: 242-245 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.98 (3H, s), 7.32 (1H, t, J _HF = 55.0 Hz), 7.37-7.45 (2H, m) 7.52 (2H, d, J = 9.0 Hz), 7.97 (2H, d, J = 9.0 Hz), 8.01 (1H, s), 8.04 to 8.11 (2H, m), 8.47 (1H, s), 9.99 (1H, s), 10.55 (1H, s). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-114.5 (2F, s), -108.7 (1F, s), -56.3 (3F, s).

Example-36

N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (404 mg, 1.01 mmol) synthesized separately , Anhydrous pyridine (0.12 mL, 1.48 mmol) and anhydrous dichloromethane (5.0 mL) were ice-cooled, and p-tolylsulfonyl chloride (211 mg, 1.11 mmol) was added. The reaction mixture was stirred at room temperature for 15 hours, 2N hydrochloric acid (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 3-difluoromethyl- 1-methyl-1- {4- (p-tolylsulfamino) phenyl} -N- [5-trifluoromethylpyrazol-4-yl] pyrazol-4-carboxamide brown solid (450 mg, Yield: 81%) was obtained. Mp: 103-104 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.39 (3H, s), 3.97 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.13 (1H , S), 7.18 (2H, d, J = 8.8 Hz), 7.25 (2H, d, J = 8.8 Hz), 7.32 (2H, d, J = 8.8 Hz), 7 .68 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.32 (1H, brs), 8.50 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, q, J = 7.0 Hz), −56.0 (3F, t, J = 7.0 Hz).

Example-37

N- {1- (4-aminophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (997 mg, 2.49 mmol) synthesized separately Was dissolved in ethanol (100 mL), an aqueous formaldehyde solution (37%, 7.5 mL, 92.4 mmol) and 10% palladium carbon (50.0 mg) were added, and the mixture was stirred at room temperature for 5 days in a hydrogen gas atmosphere. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure, and the resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 3-difluoromethyl-N- [1-{( A colorless solid (285 mg, yield: 27%) of 4-dimethylamino) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide was obtained. Mp: 162-163 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.02 (6H, s), 3.97 (3H, s), 6.71 (2H, d, J = 9.0 Hz), 6.85 (1H, t, J _HF = 54.0 Hz), 7.27 (2H, d, J = 9.0 Hz), 8.06 (1H, s), 8.31 (1H, brs), 8.47 (1H, s ). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.9 (2F, q, J = 7.1 Hz), −56.3 (3F, t, J = 7.1 Hz).

Example-38

4-amino-1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole (200 mg, 0.59 mmol), triethylamine (0.087 mg, 0.86 mmol), anhydrous dichloromethane ( 2.0 mL) was cooled on ice, and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (112 mg, 0.58 mmol) dissolved in anhydrous dichloromethane (1.0 mL) was added. Stir at room temperature for 2 days. The reaction was poured into saturated aqueous sodium bicarbonate (10 mL) and extracted with chloroform (3 × 25 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give N- [ 1- (2-Bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide (158 mg, yield: 55%). Mp: 144-146 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.86 (1H, t, J = 54.1 Hz), 7.01 (1H, td, J = 8.2, 2) .6 Hz), 7.30 (1 H, dt, J = 7.7, 2.3 Hz), 8.09 (1 H, s), 8.38 (1 H, brs), 8.69 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.9 (1F, m), −108.7 (2F, q, J = 4.7 Hz), −103.6 (1F, d, J = 7) .1 Hz), -59.2 (3F, m).

Example-39

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (360 mg, 1.85 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (2,3-dichlorophenyl) -5-trifluoromethylpyrazole (540 mg, 1.82 mmol) in anhydrous dichloromethane (1.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a yellow solid. ^{From 1} H-NMR, it was found that this contained 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give pure N- {1- (2,3-dichlorophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1- Methylpyrazole-4-carboxamide (356 mg, yield: 42%) was obtained. Mp: 183-184 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1H, t, J _HF = 54.1 Hz), 7.31 to 7.41 (2H, m), 7 .65 (1H, dd, J ₁ = 7.1 Hz, J ₂ = 2.6 Hz), 8.09 (1H, s), 8.36 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 6.6 Hz), −57.8 (3F, t, J = 6.6 Hz).

Example-40

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (2,4-difluorophenyl) -5-trifluoromethylpyrazole (526 mg, 2.00 mmol) in anhydrous dichloromethane (2.5 mL) was added under ice-cooling, followed by stirring at room temperature for 15 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a pale yellow solid. ^{From 1} H-NMR, it was found that this contained 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give pure 3-difluoromethyl-N- {1- (2,4-difluorophenyl) -5-trifluoromethylpyrazol-4-yl} -1 as a pale yellow solid. -Methylpyrazole-4-carboxamide (484 mg, yield: 56%) was obtained. Mp: 165-166 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 6.97 to 7.05 (2H, m), 7 .44 (1H, ddd, J ₁ = 8.1 Hz, J ₂ = 8.1 Hz, J ₃ = 5.9 Hz), 8.08 (1H, s), 8.34 (1H, brs), 8.60 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.7 (1F, dq, J ₁ = 9.4 Hz, J ₂ = 4.5 Hz), −108.5 (2F, q, J = 6.4 Hz) ), −105.3 (1F, d, J = 9.4 Hz), −58.0 (3F, td, J ₁ = 6.4 Hz, J ₂ = 4.5 Hz).

Example-41

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (2,4-dichlorophenyl) -5-trifluoromethylpyrazole (590 mg, 1.99 mmol) in anhydrous dichloromethane (2.5 mL) was added under ice-cooling, followed by stirring at room temperature for 1 hour. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (2,4-dichlorophenyl) -5-trifluoromethylpyrazo- as a yellow solid. Lu-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (695 mg, yield: 74%) was obtained. Mp: 120-125 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.37 to 7.39 (2H, m), 7 .57 (1H, dd, J ₁ = 1.1 Hz, J ₂ = 1.1 Hz), 8.08 (1H, s), 8.35 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, m), -57.7 (3F, t, J = 6.6 Hz).

Example-42

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 -Amino-1- (2,5-dichlorophenyl) -5-trifluoromethylpyrazole (370 mg, 1.25 mmol) dissolved in anhydrous dichloromethane (2.5 mL) was added, and then at room temperature for 2 days Stir. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting yellow solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (2 , 5-Dichlorophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (363 mg, yield: 78%) was obtained. It was. Mp: 213-215 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.45 to 7.52 (3H, m), 8 .09 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.4 (2F, q, J = 7.1 Hz), −57.8 (3F, t, J = 7.1 Hz).

Example-43

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice. 4-Amino-1- (2,6-difluorophenyl) -5-trifluoromethylpyrazole (400 mg, 1.52 mmol) was added. The reaction mixture was stirred at room temperature for 29 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 3-difluoromethyl- Pale yellow solid of N- {1- (2,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide (523 mg, yield: 82% ) Mp: 157-158 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.85 (1H, t, J _HF = 54.0 Hz), 7.04 to 7.13 (2H, m), 7 .45 to 7.57 (1H, m), 8.08 (1H, s), 8.37 (1H, brs), 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-118.6 (2F, q, J = 2.4 Hz), −108.6 (2Fq, J = 7.1 Hz), −59.3 (3F, m ).

Example-44

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (2,6-dichlorophenyl) -5-trifluoromethylpyrazole (590 mg, 1.99 mmol) in anhydrous dichloromethane (4.0 mL) was added under ice-cooling, followed by stirring at room temperature for 1.5 hours. . 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a yellow solid. ^{From 1} H-NMR, it was found that this contained 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pure N- {1- (2,6-dichlorophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1- Methylpyrazole-4-carboxamide (420 mg, yield: 45%) was obtained. Mp: 184-186 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1H, t, J _HF = 54.1 Hz), 7.38-7.50 (3H, m), 8 .09 (1H, s), 8.37 (1H, brs), 8.70 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 6.5 Hz), −59.3 (3F, t, J = 6.5 Hz).

Example-45

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (3,4-dichlorophenyl) -5-trifluoromethylpyrazole (590 mg, 1.99 mmol) in anhydrous dichloromethane (3.5 mL) was added under ice-cooling, followed by stirring at room temperature for 1.5 hours. . 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to obtain a yellow solid. ^{From 1} H-NMR, it was found that this contained 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain pure N- {1- (3,4-dichlorophenyl) -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1- Methylpyrazole-4-carboxamide (540 mg, yield: 58%) was obtained. Mp: 144-147 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.1 Hz), 7.33 ( ₁ H, dd, J ₁ = 8.5 Hz) , J ₂ = 2.5 Hz), 7.57 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 2.5 Hz), 8.08 (1H, s), 8. 35 (1H, brs), 8.57 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.4 (2F, q, J = 6.7 Hz), −55.8 (3F, t, J = 6.7 Hz).

Example-46

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (400 mg, 2.06 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (2.0 mL) and 4-amino-1- A solution of (3,5-dichlorophenyl) -5-trifluoromethylpyrazole (590 mg, 1.99 mmol) in anhydrous dichloromethane (4.5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give N- {1- (3,5-dichlorophenyl) -5-trifluoromethylpyrazo as a pale yellow solid. -L-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (577 mg, yield: 62%) was obtained. Mp: 219-222 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.0 Hz), 7.41 (2 H, d, J = 1.8 Hz) 7.48 (1H, t, J = 1.8 Hz), 8.08 (1H, s), 8.36 (1H, brs), 8.59 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.4 (2F, q, J = 6.7 Hz), −55.8 (3F, t, J = 6.7 Hz).

Example-47

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 A solution of 2-amino-1- {3,5-bis (trifluoromethyl) phenyl} -5-trifluoromethylpyrazole (450 mg, 1.24 mmol) in anhydrous dichloromethane (3.5 mL) was added. Thereafter, the mixture was stirred at room temperature for 2 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and the brown solid obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [1- {3 , 5-Bis (trifluoromethyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide (409 mg, yield) : 76%). Mp: 163-165 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.99 (3H, s), 6.84 (1 H, t, J _HF = 54.0 Hz), 7.9 (3H, s) , 8.09 (1H, s), 8.40 (1H, brs), 8.66 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.2 (2F, q, J = 7.1 Hz), −63.3 (6F, s), −55.6 (3F, t, J = 7) .1 Hz).

Example-48

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 After adding a solution of 2-amino-5-trifluoromethyl-1- (2,3,4-trifluorophenyl) pyrazole (350 mg, 1.24 mmol) in anhydrous dichloromethane (2.5 mL), room temperature For 2 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give 3-difluoromethyl-1- Methyl-N- {5-trifluoromethyl-1- (2,3,4-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide pale yellow solid (333 mg, yield: 74 %). Mp: 142-145 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J _HF = 54.0 Hz), 7.06 to 7.29 (2H, m), 8 .09 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-156.6 (1F, dd, J ₁ = 21.1 Hz, J ₂ = 21.1 Hz), −139.5 (1F, m), −129.2 (1F, dd, J ₁ = 21.2 Hz, J ₂ = 9.4 Hz), −108.4 (2F, q, J = 6.5 Hz), −57.9 (3F, td, J ₁ = 6. 5 Hz, J ₂ = 4.4 Hz).

Example-49

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 After adding a solution of 2-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (350 mg, 1.24 mmol) in anhydrous dichloromethane (3.5 mL), room temperature For 2 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown solid was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 3-difluoromethyl-1- Methyl-N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide pale yellow solid (330 mg, yield: 73 %). Mp: 128-130 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.82 to 6.91 (2H, m), 6.84 (1H, t, J _HF = 54.1 Hz), 8 .09 (1H, s), 8.37 (1H, brs), 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −108.4 (2F, q, J = 7.1 Hz), −101.9 (1F, t, J = 8) .2 Hz), -59.3 (3F, m).

Example-50

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (5.0 mL) and 4-amino-1- (2,4,6-Trichlorophenyl) -5-trifluoromethylpyrazole (670 mg, 2.03 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 3-difluoromethyl-1-methyl-N- {1- (2,4,6) as a pale yellow solid. -Trichlorophenyl) -5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide (557 mg, yield: 57%) was obtained. Mp: 168-169 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1H, t, J _HF = 54.1 Hz), 7.50 (2H, s), 8.09 (1H , S), 8.38 (1H, brs), 8.70 (1H, s). ¹⁹ H-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, q, J = 6.3 Hz), −59.3 (3F, t, J = 6.3 Hz).

Example-51

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled, and 4 A solution of 2-amino-1- (2,6-dichloro-4-trifluoromethylphenyl) -5-trifluoromethylpyrazole (456 mg, 1.25 mmol) in anhydrous dichloromethane (2.0 mL) was added. After that, the mixture was stirred at room temperature for 2 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- ( 2,6-Dichloro-4-trifluoromethyl) phenyl-5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide as a pale yellow solid (296 mg, Yield: 55%) was obtained. Mp: 154-157 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J _HF = 54.0 Hz), 7.75 (2 H, q, J _HF = 0.5 Hz) ), 8.10 (1H, s), 8.40 (1H, brs), 8.74 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.3 (2F, q, J = 7.1 Hz), −63.5 (3F, s), −59.3 (3F, t, J = 7) .1 Hz).

Example-52

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (200 mg, 1.03 mmol), triethylamine (0.20 mL, 1.43 mmol) and anhydrous dichloromethane (2.0 mL) was ice-cooled. A solution of 2-amino-1- (2,3,5,6-tetrafluorophenyl) -5-trifluoromethylpyrazole (370 mg, 1.24 mmol) in anhydrous dichloromethane (3.0 mL) was added. Thereafter, the mixture was stirred at room temperature for 2 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (30 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the brown oil obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 3-difluoromethyl-1 -Methyl-N- {1- (2,3,5,6-tetrafluorophenyl) -5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide pale yellow solid (335 mg, Yield: 71%) was obtained. Mp: 148-150 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J _HF = 54.0 Hz), 7.33 ( ₁ H, tt, J ₁ = 9.8 Hz) , J ₂ = 7.3 Hz), 8.10 (1H, s), 8.39 (1H, brs), 8.74 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-145.5 (2F, m), −137.4 (2F, m), −108.2 (2F, q, J = 7.1 Hz), −59 .1 (3F, m).

Example-53

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (467 mg, 2.40 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), and triethylamine (300 mg, 2.97 mmol) was added and ice-cooled. 4-Amino-1- (2,3,4,5,6-pentafluorophenyl) -5-trifluoromethylpyrazole (631 mg, 1.99 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2) and 3-difluoromethyl-1-methyl-N- {1- (2,3,4,5). , 6-Pentafluorophenyl) -5-trifluoromethylpyrazol-4-yl} pyrazol-4-carboxamide was obtained as a pale yellow solid (215 mg, yield: 23%). Mp: 164-166 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.83 (1H, t, J _HF = 54.0 Hz), 8.10 (1H, s), 8.39 (1H , Brs), 8.73 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-160.5 (2F, m), -149.5 (1F, m), -144.8 (2F, m), -108.2 (2F, q , J = 7.1 Hz), -59.2 (3F, m).

Example-54

3-Difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (469 mg, 2.41 mmol) was dissolved in anhydrous dichloromethane (3.0 mL), triethylamine (310 mg, 3.06 mmol) was added, and the mixture was cooled with ice. 4-Amino-1- (3-ethoxy-2,5,6-trifluoro-4-trifluoromethylphenyl) -5-trifluoromethylpyrazole (786 mg, 2.00 mmol) was added. After stirring at room temperature for 3 days, the reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2), and 3-difluoromethyl-N- {1- (3-ethoxy-2,5,6-tri-). Fluoro-4-trifluoromethylphenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide was obtained as a pale yellow solid (176 mg, yield: 16%). . Mp: 38-40 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.43 (3H, t, J = 7.0 Hz), 3.98 (3H, s), 4.18 to 4.29 (2H, m), 6. _{84 (1H, t, J HF} = 54.0Hz), 8.10 (1H, s), 8.39 (1H, brs), 8.74 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-145.5 (1F, m), −139.7 (1F, m), −137.1 (1F, m), −108.3 (2F, q) , J = 7.0 Hz), -59.2 (3F, m), -56.8 (3F, d, J = 28.2 Hz).

Example-55

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (2.00 g, 10.3 mmol), triethylamine (1.50 g, 14.8 mmol) and anhydrous dichloromethane (10 mL) was ice-cooled, and 4 -Amino-1- (4-ethoxy-2,3,5,6-tetrafluorophenyl) -5-trifluoromethylpyrazole (3.80 g, 11.1 mmol) in anhydrous dichloromethane (7.0 mL) After the dissolved solution was added, the mixture was stirred at room temperature for 14 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (50 mL), the organic layer was collected, and the aqueous layer was extracted with chloroform (15 mL). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the brown oil obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl-N -{1- (4-Ethoxy-2,3,5,6-tetrafluorophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide as a light brown solid (2.30 g, yield: 45%) was obtained. Mp: 103-105 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.47 (3H, t, J = 7.0 Hz), 3.98 (3H, s), 4.43 (2H, m), 6.84 (1H, t, J _HF = 54.0 Hz), 8.09 (1H, s), 8.38 (1H, brs), 8.70 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-156.8 (2F, m), −147.4 (2F, m), −108.4 (2F, q, J = 7.1 Hz), −59 .2 (3F, m).

Example-56

Separately synthesized 3-difluoromethyl-N- {5-formyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide (3.74 g) , 9.37 mmol) was dissolved in methanol (400 mL), and sodium borohydride (1.40 g, 37.0 mmol) was added little by little under ice cooling. After further stirring at the same temperature for 1 hour, the reaction solution was acidified with 2N hydrochloric acid, and then neutralized with a saturated aqueous sodium hydrogen carbonate solution. This was concentrated under reduced pressure, water (150 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4 to ethyl acetate only). A pale yellow solid of 3-difluoromethyl-N- {5-hydroxymethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide ( 1.55 g, yield: 41%). Further, insoluble matters present in the aqueous layer at the time of extraction were collected by filtration, and 3-difluoromethyl-N- {5-hydroxymethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl. } -1-Methylpyrazol-4-carboxamide was obtained as a colorless solid (2.00 g, yield: 53%). Mp: 230-232 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.97 (3H, s), 4.40 (2H, d, J = 5.5 Hz), 5.10 (1H, t, J = 5.5 Hz) ), 7.34 (1H, t, J _HF = 54.0 Hz), 7.46-7.56 (2H, m), 7.94 (1H, s), 8.45 (1H, s), 9 .73 (1H, s). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-116.7 (2F, d, J = 7.1 Hz), −114.4 (2F, s), −105.1 (1F, t, J = 7.1 Hz).

Example-57

A mixture of 4-amino-1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole (4.84 g, 14.7 mmol) and triethylamine (2.20 g, 21.7 mmol) was added to anhydrous dichloromethane (20 mL). And a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (3.50 g, 18.0 mmol) in anhydrous dichloromethane (5.0 mL) was added dropwise under ice cooling. . The reaction solution was stirred at room temperature for 23 hours and then subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1, 1% triethylamine added) to give N- {1- (2,4-dichlorophenyl) -5-di A brown solid (979 mg, yield: 14%) of ethoxymethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide was obtained. Mp: 149-154 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.16 (6H, br.t, J = 6.8 Hz), 3.57 (4H, brs), 3.98 (3H, s), 5.55 ( 1H, s), 6.97 (1H, t, J _HF = 54.0 Hz), 7.32 (1H, d, J = 8.5 Hz), 7.38 (1H, dd, J ₁ = 8.5 Hz) , J ₂ = 2.0 Hz), 7.55 (1H, d, J = 2.0 Hz), 7.91 (1H, s), 8.57 (1H, s), 8.98 (1H, brs) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-110.0 (2F, d, J = 14.1 Hz).
Simultaneously, a yellow solid of N- {1- (2,4-dichlorophenyl) -5-formylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide (4.25 g, yield) : 70%) was obtained. Mp: 174-176 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 7.09 (1 H, t, J _HF = 54.0 Hz), 7.47 ( ₁ H, dd, J ₁ = 8.5 Hz) , J ₂ = 2.0 Hz), 7.52 (1H, d, J = 8.5 Hz), 7.62 (1H, d, J = 2.0 Hz), 7.98 (1H, s), 8. 68 (1H, s), 9.61 (1H, m), 9.81 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-112.5 (2F, s).

Example-58

Separately synthesized 3-difluoromethyl-N- {5-formyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide (3.11 g , 7.79 mmol), a mixture of hydroxylamine hydrochloride (550 mg, 7.91 mmol) and ethanol (30 mL) was refluxed for 3 hours. After the reaction solution returned to room temperature was concentrated under reduced pressure, the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give 3-difluoromethyl-N- {5-hydroxyimino. A pale yellow solid (2.78 g, yield: 86%) of methyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide was obtained. It was. Mp: 214-216 ° C. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.98 (3H, s), 7.33 (1H, t, J _HF = 53.8 Hz), 7.47 to 7.56 (2H, m) , 8.19 (1H, s), 8.25 (1H, s), 8.47 (1H, s), 9.92 (1H, s), 11.56 (1H, s). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-117.3 (2F, d, J = 7.1 Hz), −114.4 (2F, s), −105.2 (1F, t, J = 7.1 Hz).

Example-59

Separately synthesized 3-difluoromethyl-N- {5-hydroxyiminomethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide (300 mg , 0.724 mmol) and acetic anhydride (3.0 mL) was refluxed for 30 minutes. The reaction solution returned to room temperature was poured into ice water (30 mL) and extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined and washed with water (10 mL), and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/3) to give N- {5-acetoxyiminomethyl- A pale yellow solid (270 mg, yield: 82%) of 1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazol-4-carboxamide was obtained. Obtained. Mp: 74-76 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.24 (3H, s), 4.03 (3H, s), 6.89 to 6.97 (2H, m), 7.35 (1H, t, _{J HF = 54.0Hz), 8.16 (} 1H, s), 8.48 (1H, s), 8.71 (1H, s), 9.93 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (2F, s), −114.9 (2F, d, J = 7.1 Hz), −102.1 (1F, t, J = 7) .1 Hz).

Example-60

After 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (350 mg, 1.80 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added and the mixture was ice-cooled. 4-Amino-1- (2-ethylphenyl) -5- (1,1,2,2,2-pentafluoroethyl) pyrazole (460 mg, 1.51 mmol) was added. The reaction mixture was stirred at room temperature for 29 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl- N- {1- (2-ethylphenyl) -5- (1,1,2,2,2-pentafluoroethyl) pyrazol-4-yl} -1-methylpyrazol-4-carboxamide as a yellow solid (444 mg, yield: 64%) was obtained. Mp: 110-112 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.15 (3H, t, J = 7.5 Hz), 2.15 to 2.38 (2H, m), 3.97 (3H, s), 6. 83 (1H, t, J _HF = 54.0 Hz), 7.25 to 7.49 (4H, m), 8.08 (1H, s), 8.30 (1H, brs), 8.62 (1H , S). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.3 to -113.0 (1F, m), -110.1 to -108.7 (3F, m), -84.9 (3F, m ).

Example-61

After 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (350 mg, 1.80 mmol) was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (300 mg, 2.96 mmol) was added and the mixture was ice-cooled. 4-Amino-5- (1,1,2,2,2-pentafluoroethyl) -1- (2,4,6-trifluorophenyl) pyrazole (500 mg, 1.51 mmol) was added. The reaction mixture was stirred at room temperature for 29 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 3-difluoromethyl- 1-methyl-N- {5- (1,1,2,2,2-pentafluoroethyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol- A colorless solid of 4-carboxamide (198 mg, yield: 27%) was obtained. Mp: 148 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.79 to 6.88 (2H, m), 6.82 (1H, t, J _HF = 54.0 Hz), 8 .09 (1H, s), 8.35 (1H, brs), 8.75 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.4 (2F, m), -114.2 (2F, m), -108.4 (2F, m), -102.2 (1H, t , J = 7.1 Hz), −85.6 (3F, m).

Example-62

4-Amino-5-diethoxymethyl-1- (2,4,6-trifluorophenyl) pyrazole (7.67 g, 24.3 mmol) and triethylamine (5.00 g, 49.4 mmol) were added to anhydrous dichloromethane ( 25 mL), and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (34.1 mmol) in anhydrous dichloromethane (5.0 mL) was added dropwise under ice cooling. After the reaction solution was stirred at room temperature for 2 hours, the formed precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. This was dissolved in acetone (100 mL), 2N hydrochloric acid (30 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (200 mL) was added, and the mixture was extracted with ethyl acetate (300 mL × 1, 100 mL × 3). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product obtained by silica gel column chromatography (hexane / ethyl acetate = 3 / 2-1 / 2) to give 3-difluoromethyl-N- {5-formyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazole A yellow solid (7.15 g, yield: 74%) of -4-carboxamide was obtained. Mp: 208-210 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 6.90 to 6.99 (2H, m), 7.07 (1H, t, J _HF = 54.0 Hz), 7 .99 (1H, s), 8.75 (1H, s), 9.68 (1H, s), 9.79 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (2F, d, J = 7.1 Hz), −112.2 (2F, s), −101.8 (1F, t, J = 7) .1 Hz).

Reference example-3

Potassium hydroxide (4.68 g, 83.4 mmol) was dissolved in water (200 mL), methylhydrazine (3.84 g, 83.4 mmol) was added, and the mixture was ice-cooled. To this was added ethyl 2-ethoxymethylenetrifluoroacetoacetate (20.0 g, 83.3 mmol) dropwise. After completion of dropping, the precipitated yellow solid was collected. Ethanol (40 mL) and 5% aqueous sodium hydroxide solution (40 mL) were added thereto, and the mixture was stirred at room temperature for 14 hours. After adding water (200 mL) to the reaction solution, the solution was acidified with concentrated hydrochloric acid, and the precipitated solid was collected to give a colorless solid of 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (6 .88 g, yield: 43%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.00 (3H, s), 8.02 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-62.5 (3F, s).

A mixture of 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (780 mg, 4.02 mmol), anhydrous toluene (10 mL) and thionyl chloride (5.0 mL) was refluxed for 1 hour, and then Dean- Toluene and excess thionyl chloride were removed using Stark. Further, the solvent was completely removed successively using an evaporator and a vacuum pump to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (812 mg, yield: 95%) as a brown oil. ) This was used in the next reaction without purification. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.03 (3H, s), 8.16 (1H, s).

Example-63

A mixture of 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (780 mg, 4.02 mmol), thionyl chloride (3.0 mL) and anhydrous toluene (10 mL) was refluxed for 30 minutes. Toluene and excess thionyl chloride were distilled off using Dean-Stark and then dried with a vacuum pump. Triethylamine (600 mg, 5.93 mmol) and anhydrous dichloromethane (2.0 mL) were added thereto, and the mixture was ice-cooled. 4-Amino-5-difluoromethyl-1-phenylpyrazole (360 mg, 1.72 mmol) was added to anhydrous dichloromethane ( (2.0 mL) was added, followed by stirring at room temperature for 18 hours. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated aqueous sodium hydrogen carbonate solution (20 mL), and dried over anhydrous magnesium sulfate. The brown solid obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2) to give a yellow solid. This was dissolved in dioxane (10 mL), 2N hydrochloric acid (10 mL) was added, and the mixture was refluxed for 3 hours. The reaction solution was returned to room temperature, saturated aqueous sodium hydrogen carbonate solution (40 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with a saturated aqueous solution of sodium hydrogencarbonate (20 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow solid obtained by silica gel column chromatography (hexane / ethyl acetate = 2/3). N- (5-difluoromethyl-1-phenylpyrazol-4-yl) -1-methyl-3-trifluoromethylpyrazol-4-carboxamide as an orange solid (285 mg, yield) : 43%). Mp: 124-129 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 6.71 (1H, t, J _HF = 53.0 Hz), 7.44 to 7.66 (5H, m), 8 .06 (1H, s), 8.13 (1H, brs), 8.51 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-112.5 (2F, q, J = 4.5 Hz), −60.2 (3F, t, J = 4.5 Hz).

Example-64

To 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (1.00 g, 5.15 mmol) was added anhydrous toluene (10 mL) and a catalytic amount of anhydrous DMF, and the mixture was ice-cooled. Oxalyl chloride (1.30 g, 10.3 mmol) was added dropwise thereto, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and chloroform (10 mL) and triethylamine (1.43 g, 10.3 mmol) were added to the residue. Further, 4-amino-1-phenyl-5-trifluoromethylpyrazole (1.64 g, 7.71 mmol) dissolved in chloroform (1.0 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. did. After adding 2N hydrochloric acid (30 mL) to the reaction solution, the organic layer was recovered, and the aqueous layer was extracted with chloroform (2 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1), and further purified from ethanol. Crystallization gave colorless solid 1-methyl-N- (1-phenyl-5-trifluoromethylpyrazol-4-yl) -3-trifluoromethylpyrazol-4-carboxamide (646 mg, yield). Rate: 31%). Mp: 155-157 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.02 (3H, s), 7.48 (5H, m), 8.00 (1H, brs), 8.08 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-56.0 (3F, q, J = 3.9 Hz), −60.2 (3F, q, J = 3.8 Hz).

Example-65

1-Methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (430 mg, 2.02 mmol) and triethylamine (350 mg, 3.46 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) and 4-amino A solution of -1- (2-chlorophenyl) -5-trifluoromethylpyrazole (520 mg, 1.99 mmol) in anhydrous dichloromethane (3.0 mL) was added under ice cooling, followed by stirring at room temperature for 1.5 hours. did. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to obtain a pale yellow solid. ^{From 1} H-NMR, it was found that this contained 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give pure N- {1- (2-chlorophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methyl-3-trifluoromethyl as a pale yellow solid. Pyrazol-4-carboxamide (392 mg, yield: 44%) was obtained. Mp: 128-130 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.02 (3H, s), 7.37-7.58 (4H, m), 8.02 (1H, brs), 8.10 (1H, s) , 8.60 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-60.1 (3F, q, J = 3.8 Hz), −57.9 (3F, q, J = 3.8 Hz).

Example-66

1-Methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (383 mg, 1.80 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL) to give 4-amino A solution of -1- (3-chlorophenyl) -5-trifluoromethylpyrazole (470 mg, 1.80 mmol) in anhydrous dichloromethane (1.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to obtain a yellow solid. ^{From 1} H-NMR, it was found that this contained 3-trifluoromethyl-1-methylpyrazole-4-carboxylic acid as an impurity. Therefore, it was dissolved again in ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL × 2), and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give pure N- {1- (3-chlorophenyl) -5-trifluoromethylpyrazol-4-yl} -1-methyl-3-trifluoromethyl as a pale yellow solid. Pyrazol-4-carboxamide (414 mg, yield: 53%) was obtained. Mp: 159-160 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.02 (3H, s), 7.35 to 7.50 (4H, m), 8.01 (1H, brs), 8.09 (1H, s) 8.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-60.1 (3F, q, J = 3.8 Hz), −55.9 (3F, q, J = 3.8 Hz).

Example-67

1-Methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (400 mg, 1.88 mmol) and triethylamine (300 mg, 2.96 mmol) were dissolved in anhydrous dichloromethane (3.0 mL). A solution of -1- (4-chlorophenyl) -5-trifluoromethylpyrazole (491 mg, 1.88 mmol) in anhydrous dichloromethane (2.0 mL) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- {1- (4-chlorophenyl) -5-trifluoromethylpyrazole as a pale yellow solid. -4-yl} -1-methyl-3-trifluoromethylpyrazol-4-carboxamide (328 mg, yield: 40%) was obtained. Mp: 152-157 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.02 (3H, s), 7.40 (2H, d, J = 8.8 Hz), 7.48 (2H, d, J = 8.8 Hz), 7.99 (1H, brs), 8.09 (1H, s), 8.54 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-60.1 (3F, q, J = 3.8 Hz), −56.0 (3F, q, J = 3.8 Hz).

Reference example-4

Methylhydrazine (7.50 g, 163 mmol) was dissolved in ethanol (100 mL), and ethyl trifluoroacetoacetate (30.0 g, 163 mmol) was added dropwise under ice cooling, and then gradually returned to room temperature for 16 hours. Stir. The reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with hexane to obtain 5-hydroxy-2-methyl-5-trifluoromethylpyrazolidine-3-one as a pale yellow solid. This was suspended in toluene (75 mL), and refluxed for 13 hours while removing water using Dean-Stark. The reaction mixture was allowed to cool to room temperature, and the precipitated solid was collected by filtration to give 5-hydroxy-1-methyl-3-trifluoromethylpyrazole as a pale yellow solid (19.9 g, yield: 73%). It was. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ3.59 (3H, s), 5.72 (1H, s), 11.71 (1H, brs). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-61.7 (3F, s).

Anhydrous DMF (19 mL, 245 mmol) was cooled in a salt bath, and phosphorus oxychloride (66 mL, 708 mmol) was added dropwise with care so that the temperature of the reaction solution did not exceed 10 ° C. To this was added 5-hydroxy-1-methyl-3-trifluoromethylpyrazole (17.1 g, 103 mmol), and the temperature was gradually raised to reflux. After further refluxing for 18 hours, the reaction solution cooled to room temperature was poured into ice. The resulting solution was stirred for 4 hours taking care that the temperature did not exceed 20 ° C., and then extracted with toluene (200 mL × 3). The organic layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1). As a result, yellow solid 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carbaldehyde (16.2 g, yield: 74%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.96 (3H, s), 9.96 (1 H, q, J = 0.8 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-61.9 (3F, s).

5-Chloro-1-methyl-3-trifluoromethylpyrazole-4-carbaldehyde (4.25 g, 20.0 mmol), potassium hydroxide (290 mg), potassium permanganate (3.16 g, 20. 0 mmol) and water (40 mL) were stirred at 60 ° C. for 1 h. The reaction solution was returned to room temperature, insoluble solids were filtered off, and concentrated hydrochloric acid was added to the filtrate to make it acidic. Next, the precipitated solid was collected by filtration, suspended in ethyl acetate, and then refluxed for 15 minutes. The insoluble solid was again removed by filtration, and the filtrate was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give colorless solid 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (3 .40 g, yield: 74%). ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.92 (3H, s), 13.43 (1H, brs). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-61.6 (3F, s).

Example-68

A mixture of 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (300 mg, 1.31 mmol), anhydrous toluene (5.0 mL) and a catalytic amount of anhydrous DMF was ice-cooled, Oxalyl chloride (0.22 mL, 2.60 mmol) was added. The reaction solution was stirred at room temperature for 19 hours and then concentrated under reduced pressure to obtain 5-chloro-1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride. This was dissolved in anhydrous dichloromethane (5.0 mL), triethylamine (200 mg, 1.98 mmol) was added and ice-cooled, and then 4-amino-5-trifluoromethyl-1- (2,4,6-trimethyl) was added. Fluorophenyl) pyrazole (280 mg, 1.00 mmol) was added. The reaction mixture was stirred at room temperature for 2 days, saturated aqueous sodium hydrogen carbonate solution (40 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 5-chloro-1 Light yellow solid of 2-methyl-3-trifluoromethyl-N- [5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl] pyrazol-4-carboxamide (169 mg, yield: 34%) was obtained. Mp: 121-122 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.99 (3H, s), 6.82 to 6.91 (2H, m), 8.03 (1H, brs), 8.71 (1H, s) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −101.6 (1F, t, J = 7.1 Hz), −62.0 (3F, s), −59 .2 (3F, m).

Reference Example-5

Ethyl 4,4,5,5,5-pentafluoro-3-oxopentanoate (10.5 g, 44.8 mmol), triethyl orthoformate (12.5 g, 84.3 mmol) and acetic anhydride (8.60 g, 84 .2 mmol) was gradually heated from 140 ° C. to 160 ° C. over 5 hours while distilling off the low-boiling compounds. The reaction solution returned to room temperature was concentrated under reduced pressure, and the resulting crude product was purified by distillation under reduced pressure to give 2-ethoxymethylene-4,4,5,5,5-pentafluoro-3-oxopentane as a yellow oil. Ethyl acid (10.1 g, yield: 77%) was obtained. Bp: 90-103 ° C./6 mmHg. ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.25 to 1.47 (6H, m), 4.20 to 4.36 (4H, m), 7.71 (0.3H, s), 7. 74 (0.7H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-120.9 (1.4 F, s), −117.3 (0.6 F, s), −81.72 (2.1 F, s), −81 .67 (0.9F, s).

A mixture of methyl hydrazine (500 mg, 10.9 mmol), 10% aqueous sodium hydroxide (5.0 mL) and toluene (5.0 mL) was ice-cooled, and 2-ethoxymethylene-4, 4, 5, 5, 5- After dropwise addition of ethyl pentafluoro-3-oxopentanoate (2.91 g, 10.0 mmol), the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid and extracted with toluene (10 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1-methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylic acid as a yellow solid. Ethyl (2.64 g, yield: 97%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.34 (3H, t, J = 7.1 Hz), 3.98 (3H, s), 4.31 (2H, q, J = 7.1 Hz), 7.9 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-109.9 (2F, q, J = 2.2 Hz), −83.1 (3F, t, J = 2.2 Hz).

1-Methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylate (2.60 g, 9.55 mmol), ethanol (15 mL) and 10% water A mixture of aqueous sodium oxide (15 mL) was stirred at room temperature for 3 hours. Concentrated hydrochloric acid is added to the reaction solution to make it acidic, and the extracted solid is collected by filtration, and 1-methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylic acid is collected. A pale yellow solid (1.18 g, yield: 51%) was obtained. Furthermore, the organic layer was collected from the filtrate, and the aqueous layer was extracted with ethyl acetate (40 mL × 2). The organic layers are combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a yellow solid of 1-methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylic acid. (1.00 g, yield: 43%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 8.06 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-110.2 (2F, q, J = 1.9 Hz), −83.1 (3F, t, J = 1.9 Hz).

Example-69

1-methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylic acid (370 mg, 1.52 mmol), anhydrous toluene (5.0 mL) and thionyl chloride (1. (0 mL) was refluxed for 2 hours and then concentrated under reduced pressure to obtain 1-methyl-3- (1,1,2,2,2-pentafluoroethyl) pyrazole-4-carboxylic acid chloride. This was dissolved in anhydrous dichloromethane (2.5 mL), triethylamine (300 mg, 2.96 mmol) was added, and the mixture was cooled with ice, and then 4-amino-5-trifluoromethyl-1- (2,4,6-trimethyl). Fluorophenyl) pyrazole (290 mg, 1.03 mmol) was added. The reaction mixture was stirred at room temperature for 5 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1 to 3/2). -Methyl-3- (2,2,3,3,3-pentafluoroethyl) -N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl } A yellow solid (168 mg, yield: 32%) of pyrazol-4-carboxamide was obtained. Mp: 109-111 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.03 (3H, s), 6.82 to 6.92 (2H, m), 8.08 (1H, brs), 8.12 (1H, s) , 8.66 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.9 (2F, m), −107.3 (2F, m), −101.7 (1F, t, J = 7.1 Hz), −83 .2 (3F, brs), -59.4 (3F, brs).

Reference Example-6

A mixture of ethyl hydrazine (1.22 g, 20.1 mmol), 10% aqueous sodium hydroxide (10 mL) and toluene (10 mL) was ice-cooled, and ethyl ethoxymethylenedifluoroacetoacetate (4.46 g, 20.1 mmol) was added. Then, the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid (30 mL) and extracted with toluene (10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 3-difluoromethyl-1 A brown solid (2.56 g, yield: 58%) of ethyl -ethylpyrazole-4-carboxylate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.36 (3H, t, J = 7.3 Hz), 1.53 (3H, t, J = 7.3 Hz), 4.23 (2H, q, J = 7.3Hz), 4.32 (2H, q, J = 7.3Hz), 7.10 (1H, t, J HF = 54.0Hz), 7.93 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (2F, s).

Ethyl 3-difluoromethyl-1-ethylpyrazole-4-carboxylate (2.56 g, 11.7 mmol) is dissolved in ethanol (20 mL), 10% aqueous sodium hydroxide solution (20 mL) is added at room temperature. Stir for 17 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was washed with toluene (10 mL × 2). Next, concentrated hydrochloric acid was added to make it acidic, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-difluoromethyl-1-ethylpyrazole-4-carboxylic acid brown solid (1.37 g, yield: 62%). . ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.56 (3H, t, J = 7.3 Hz), 4.26 (2H, q, J = 7.3 Hz), 7.11 (1H, t, J _HF = 53.8 Hz), 8.01 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.4 (2F, s).

Example-70

A mixture of 3-difluoromethyl-1-ethylpyrazole-4-carboxylic acid (380 mg, 2.00 mmol), thionyl chloride (1.0 mL) and anhydrous toluene (5.0 mL) was refluxed for 30 minutes and then concentrated under reduced pressure. Thus, 3-difluoromethyl-1-ethylpyrazole-4-carboxylic acid chloride was obtained. This was dissolved in 4-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (427 mg, 1.52 mmol), triethylamine (306 mg, 3.02 mmol) and anhydrous dichloromethane ( (3.0 mL), and the mixture was stirred at room temperature for 2 days. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 3-difluoromethyl- 1-ethyl-N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide brown solid (475 mg, yield: 52%). Mp: 121-123 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.55 (3H, t, J = 7.5 Hz), 4.23 (2H, q, J = 7.5 Hz), 6.82 to 6.91 (2H M), 6.84 (1H, t, J _HF = 54.0 Hz), 8.12 (1H, s), 8.38 (1H, brs), 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −108.2 (2F, q, J = 7.1 Hz), −102.0 (1F, t, J = 7) .1 Hz), -59.3 (3F, m).

Reference Example-7

A mixture of propylhydrazine (1.48 g, 20.0 mmol), 10% aqueous sodium hydroxide (10 mL) and toluene (10 mL) was ice-cooled, and ethyl ethoxymethylenedifluoroacetoacetate (4.44 g, 20.0 mmol) was added. Then, the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid (30 mL) and extracted with toluene (10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 3-difluoromethyl-1 A brown oily substance (2.54 g, yield: 55%) of ethyl 4-propylpyrazole-4-carboxylate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.94 (3H, t, J = 7.5 Hz), 1.36 (3H, t, J = 7.0 Hz), 1.86 to 2.01 (2H M), 4.13 (2H, t, J = 7.0 Hz), 4.32 (2H, q, J = 7.0 Hz), 7.10 (1H, t, J _HF = 54.0 Hz), 7.91 (1H, t, J = 1.0 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (2F, s).

Ethyl 3-difluoromethyl-1-propylpyrazole-4-carboxylate (2.54 g, 10.9 mmol) is dissolved in ethanol (20 mL), 10% aqueous sodium hydroxide solution (20 mL) is added at room temperature. Stir for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was washed with toluene (10 mL × 2). Next, concentrated hydrochloric acid was added to make it acidic, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-difluoromethyl-1-propylpyrazole-4-carboxylic acid as a yellow solid (2.02 g, yield: 91%). . ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.95 (3H, t, J = 7.3 Hz), 1.88 to 2.02 (2H, m), 4.16 (2H, t, J = 7) .3 Hz), 7.11 (1 H, t, J _HF = 53.8 Hz), 7.99 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.4 (2F, s).

Example-71

A mixture of 3-difluoromethyl-1-propylpyrazole-4-carboxylic acid (419 mg, 2.05 mmol), thionyl chloride (1.0 mL) and anhydrous toluene (5.0 mL) was refluxed for 30 minutes and then concentrated under reduced pressure. Thus, 3-difluoromethyl-1-propylpyrazole-4-carboxylic acid chloride was obtained. This was dissolved in 4-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (426 mg, 1.49 mmol), triethylamine (303 mg, 2.99 mmol) and anhydrous dichloromethane ( (3.0 mL), and the mixture was stirred at room temperature for 2 days. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 3-difluoromethyl- 1-propyl-N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide yellow solid (546 mg, yield: 60%). Mp: 88-92 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.96 (3H, t, J = 7.1 Hz), 1.87 to 2.02 (2H, m), 4.13 (2H, t, J = 6) .8 Hz), 6.81 to 6.91 (2 H, m), 6.84 (1 H, t, J _HF = 54.1 Hz), 8.10 (1 H, s), 8.39 (1 H, brs) , 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −108.2 (2F, q, J = 7.1 Hz), −102.0 (1F, t, J = 7) .1 Hz), -59.3 (3F, m).

Reference Example-8

A mixture of isopropyl hydrazine (1.49 g, 20.1 mmol), 10% aqueous sodium hydroxide (10 mL) and toluene (10 mL) was ice-cooled, and ethyl ethoxymethylenedifluoroacetoacetate (4.45 g, 20.0 mmol) was added. Then, the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid (30 mL) and extracted with toluene (10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 3-difluoromethyl-1 A brown oily substance (1.87 g, yield: 40%) of ethyl -isopropylpyrazole-4-carboxylate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.36 (3H, t, J = 7.0 Hz), 1.54 (6H, d, J = 6.8 Hz), 4.32 (2H, q, J = 7.0 Hz), 4.56 (1 H, septet, J = 6.8 Hz), 7.09 (1 H, t, J _HF = 54.0 Hz), 7.96 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.1 (2F, s).

Ethyl 3-difluoromethyl-1-isopropylpyrazole-4-carboxylate (1.87 g, 8.06 mmol) was dissolved in ethanol (20 mL), and 10% aqueous sodium hydroxide solution (20 mL) was added. Stir at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was washed with toluene (10 mL × 2). Next, concentrated hydrochloric acid was added to make it acidic, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 3-difluoromethyl-1-isopropylpyrazole-4-carboxylic acid as a yellow solid (1.23 g, yield: 75%). Obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.56 (6H, d, J = 6.5 Hz), 4.59 (1H, septet, J = 6.5 Hz), 7.11 (1H, t, J _HF = 53.8 Hz), 8.03 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.3 (2F, s).

Example-72

After refluxing a mixture of 3-difluoromethyl-1-isopropylpyrazole-4-carboxylic acid (1.23 g, 6.04 mmol), thionyl chloride (1.0 mL) and anhydrous toluene (5.0 mL) for 30 minutes. After concentration under reduced pressure, 3-difluoromethyl-1-isopropylpyrazole-4-carboxylic acid chloride was obtained. This was dissolved in 4-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (427 mg, 1.49 mmol), triethylamine (310 mg, 3.06 mmol) and anhydrous dichloromethane ( 3.0 mL), and the mixture was stirred at room temperature for 1 day. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give 3-difluoromethyl- 1-Isopropyl-N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide yellow solid (576 mg, yield: 82%). Mp: 98-102 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.57 (6H, d, J = 6.4 Hz), 4.53 (1H, septet, J = 6.4 Hz), 6.82 to 6.91 (2H M), 6.84 (1H, t, J _HF = 50.8 Hz), 8.16 (1H, s), 8.40 (1H, brs), 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −108.0 (2F, q, J = 7.1 Hz), −102.0 (1F, t, J = 7) .1 Hz), -59.3 (3F, m).

Reference Example-9

A mixture of isobutylhydrazine (1.77 g, 20.1 mmol), 10% aqueous sodium hydroxide (10 mL) and toluene (10 mL) was ice-cooled, and ethyl ethoxymethylenedifluoroacetoacetate (4.46 g, 20.1 mmol) was added. Then, the mixture was stirred at the same temperature for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid (30 mL) and extracted with toluene (10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give 3-difluoromethyl-1 A brown oily substance (2.41 g, yield: 49%) of ethyl -isobutylpyrazole-4-carboxylate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.93 (6H, d, J = 6.8 Hz), 1.36 (3H, t, J = 7.0 Hz), 2.18 to 2.34 (1H M), 3.95 (2H, d, J = 7.3 Hz), 4.32 (2H, q, J = 7.0 Hz), 7.10 (1H, t, J _HF = 54.0 Hz), 7.88 (1H, t, J = 1.0 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (2F, s).

Ethyl 3-difluoromethyl-1-isobutylpyrazole-4-carboxylate (2.41 g, 9.80 mmol) was dissolved in ethanol (20 mL), and 10% aqueous sodium hydroxide solution (20 mL) was added. Stir at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was washed with toluene (10 mL × 2). Next, concentrated hydrochloric acid was added to make it acidic, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give 3-difluoromethyl-1-isobutylpyrazole-4-carboxylic acid as a pale yellow solid (1.85 g, yield: 86%). Got. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.94 (6H, d, J = 6.8 Hz), 2.16 to 2.38 (1H, m), 3.99 (2H, d, J = 7) .3 Hz), 7.11 (1 H, t, J _HF = 53.8 Hz), 7.96 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.4 (2F, s).

Example-73

After refluxing a mixture of 3-difluoromethyl-1-isobutylpyrazole-4-carboxylic acid (1.85 g, 8.47 mmol), thionyl chloride (1.0 mL) and anhydrous toluene (5.0 mL) for 30 minutes. After concentration under reduced pressure, 3-difluoromethyl-1-isobutylpyrazole-4-carboxylic acid chloride was obtained. This was dissolved in 4-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (422 mg, 1.48 mmol), triethylamine (305 mg, 3.01 mmol) and anhydrous dichloromethane ( 3.0 mL), and the mixture was stirred at room temperature for 1 day. The reaction solution was washed with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with ethyl acetate (10 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 3-difluoromethyl- 1-Isobutyl-N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazol-4-carboxamide pale yellow solid (477 mg, yield) : 66%). Mp: 106-109 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.95 (6H, d, J = 6.5 Hz), 2.16 to 2.33 (1H, m), 3.96 (2H, d, J = 7) .3 Hz), 6.82 to 6.91 (2 H, m), 6.84 (1 H, t, J _HF = 54.0 Hz), 8.08 (1 H, s), 8.39 (1 H, brs) , 8.68 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −108.1 (2F, q, J = 7.1 Hz), −102.0 (1F, t, J = 7) .1 Hz), -59.3 (3F, m).

Reference Example-10

A suspension of 2,4,6-trifluorophenylhydrazine (5.08 g, 31.3 mmol) in toluene (25 mL) was ice-cooled, 5% aqueous sodium hydroxide solution (25 mL) was added, and 2-ethoxymethylene was added. Ethyl trifluoroacetoacetate (7.53 g, 31.4 mmol) was added dropwise. The mixture was further stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a black oily product of ethyl 5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate. (9.62 g, yield: 91%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.39 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 6.88 (2H, m), 8.22 (1H, q, J _HF = 0.5 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.7 (2F, m), −101.8 (1F, t, J = 7.1 Hz), −58.8 (3F, t, J = 1) .4 Hz).

Ethyl 5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (9.60 g, 28.4 mmol), ethanol (20 mL) and 10% sodium hydroxide A mixture of aqueous solution (20 mL) was stirred at room temperature for 40 minutes. The reaction mixture was acidified with concentrated hydrochloric acid, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 1, 30 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a black solid of 8-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (8 .77 g) was obtained quantitatively. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 7.67 (2H, ddd, J ₁ = 11.9 Hz, J ₂ = 8.7 Hz, J ₃ = 3.1 Hz), 8.45 (1H, q , J _HF = 0.5 Hz). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-118.0 (2F, m), −101.6 (1F, t, J = 8.2 Hz), −58.0 (3F, s).

5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (8.75 g, 28.2 mmol), triethylamine (4.30 g, 42.5 mmol) and acetone ( 100 mL) was ice-cooled and ethyl chloroformate (3.0 mL, 31.4 mmol) was added slowly. After stirring at the same temperature for 20 minutes, a solution of sodium azide (3.60 g, 55.4 mmol) dissolved in water (10 mL) was slowly added. After further stirring for 40 minutes at the same temperature, water (300 mL) was added to the reaction solution, and the mixture was extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure while paying attention to the extent that no solid precipitated, and this was then added dropwise to a mixture of t-butyl alcohol (10.0 g, 135 mmol) and toluene (10 mL) in reflux. After further refluxing for 30 minutes, the reaction solution returned to room temperature was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazo- A brown oily substance (6.41 g, yield: 60%) of t-4-butyl carbamate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.52 (1H, brs), 6.79 to 6.89 (2H, m), 8.37 (1H, brs) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.9 (2F, s), −102.2 (1F, t, J = 7.1 Hz), −59.1 (3F, s).

N- {5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} carbamate t-butyl (6.38 g, 16.7 mmol), dioxane (10 mL) and A mixture of 2N hydrochloric acid (10 mL) was refluxed for 2 hours. The reaction solution was returned to room temperature, 5% aqueous sodium hydroxide solution (40 mL) was added, and the mixture was extracted with chloroform (15 mL × 3). The organic layers were combined, washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-amino-5-trifluoromethyl-1- (2,4,6-trifluoro). A brown solid of phenyl) pyrazole (4.36 g, yield: 93%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.53 (2H, brs), 6.77 to 6.87 (2H, m), 7.43 (1H, q, J _HF = 0.5 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (2F, s), -102.9 (1F, t, J = 7.1 Hz), -59.2 (3F, t, J = 2) .9 Hz).

Reference Example-11

A mixture of methyl 4,4-dimethyl-3-oxopentanoate (5.00 g, 31.6 mmol) and N, N-dimethylformamide dimethylacetate (10 mL, 75.3 mmol) was refluxed for 14 hours. The reaction solution was returned to room temperature and concentrated under reduced pressure to obtain a yellow solid methyl 2-dimethylaminomethylene-4,4-dimethyl-3-oxopentanoate. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.22 (9H, s), 2.89 (6H, brs), 3.69 (3H, s), 7.35 (1H, s).

This was dissolved in butanol (50 mL), 2,4,6-trifluorophenylhydrazine (5.12 g, 31.6 mmol) was added, and the mixture was refluxed for 7 hours. The reaction solution returned to room temperature was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to give 5-t-butyl-1- (2 , 4,6-trifluorophenyl) pyrazol-4-carboxylate (3.83 g, yield: 39%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.35 (9H, s), 3.85 (3H, s), 6.78 to 6.88 (2H, m), 8.10 (1H, s) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.3 (2F, d, J = 7.1 Hz), −103.5 (1F, t, J = 7.1 Hz).

5-t-butyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate methyl (3.80 g, 12.2 mmol), ethanol (60 mL) and 10% sodium hydroxide A mixture of aqueous solutions (40 mL) was stirred at room temperature for 3 hours. Concentrated hydrochloric acid is added to the reaction solution to make it acidic, and the extracted solid is collected by filtration to give colorless solid 5-tert-butyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid. (1.71 g, yield: 47%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.38 (9H, s), 6.79 to 6.89 (2H, m), 8.21 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.4 (2F, d, J = 7.1 Hz), −103.3 (1F, t, J = 7.1 Hz).

5-t-butyl-1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (1.68 g, 5.63 mmol), triethylamine (850 mg, 8.40 mmol) and acetone (30 mL) The mixture was ice-cooled, ethyl chloroformate (0.65 mL, 6.80 mmol) was added dropwise, and the mixture was stirred at the same temperature for 10 min. An aqueous solution in which sodium azide (730 mg, 11.2 mmol) was dissolved in water (3.0 mL) was added dropwise thereto, and the mixture was further stirred at the same temperature for 10 minutes. Water (100 mL) was added to the reaction solution, and extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and part of the solvent was distilled off under reduced pressure while paying sufficient attention so that no solid precipitated. The obtained acyl azide solution was added dropwise to a refluxing mixture of 2,2,2-trichloroethanol (920 mg, 6.16 mmol) and toluene (10 mL), and the mixture was further refluxed for 15 hours. The reaction liquid was returned to room temperature, and the brown oil obtained by concentration under reduced pressure was dissolved in xylene (30 mL). To this solution was added potassium carbonate (1.00 g), and the mixture was refluxed for 1.5 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give N- {5-t-butyl-1 as a yellow solid. -(2,4,6-trifluorophenyl) pyrazol-4-yl} carbamate 2,2,2-trichloroethyl (1.34 g, yield: 52%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.27 (9H, s), 4.84 (2H, brs), 6.27 (1H, brs), 6.78 to 6.87 (2H, m) , 7.76 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.4 (2F, d, J = 7.1 Hz), −103.6 (1F, t, J = 7.1 Hz).

N- {5-t-butyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl} carbamate 2,2,2-trichloroethyl (1.32 g, 2.88 mmol) The mixture was dissolved in a mixed solvent of acetic acid (45 mL) and water (5.0 mL), zinc (4.00 g) was added, and the mixture was stirred at room temperature for 30 minutes. After removing zinc by filtration, the filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1, 1% triethylamine added) to give 4-amino acid as a yellow solid. -5-t-butyl-1- (2,4,6-trifluorophenyl) pyrazole (666 mg, yield: 86%) was obtained. Mp: 97-104 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.27 (9H, s), 2.91 (2H, brs), 6.74 to 6.84 (2H, m), 7.36 (1H, s) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.1 Hz), −104.8 (1F, t, J = 7.1 Hz).

Reference Example-12

A mixture of ethyl 2-ethoxymethylenetrifluoroacetoacetate (6.70 g, 27.9 mmol), toluene (25 mL) and 4-methylphenylhydrazine hydrochloride (4.43 g, 27.9 mmol) was ice-cooled, 10% water A sodium oxide aqueous solution (25 mL) was added dropwise, followed by stirring at the same temperature for 30 minutes. Concentrated hydrochloric acid was added to the reaction solution to make it acidic, the organic layer was collected, and the aqueous layer was extracted with toluene (20 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 1- (4-methylphenyl) -5-trifluoromethylpyrazole-4-carboxylate (8.61 g) as a black brown oil. Was obtained quantitatively. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.38 (3H, t, J = 7.1 Hz), 2.44 (3H, s), 4.37 (2H, q, J = 7.1 Hz), 7.29 (4H, s), 8.10 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-55.7 (3F, s).

Ethyl 1- (4-methylphenyl) -5-trifluoromethylpyrazole-4-carboxylate (8.60 g, 27.9 mmol) was dissolved in ethanol (25 mL), and 10% aqueous sodium hydroxide solution was dissolved. (25 mL) was added and stirred at room temperature for 20 hours. The reaction solution was acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. This was washed successively with water and hexane, dried by toluene azeotrope, and dried as a brown solid 1- (4-methylphenyl) -5-trifluoromethylpyrazole-4-carboxylic acid (5.65 g, yield). : 75%). ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 2.41 (3H, s), 7.37 (2H, d, J = 9.0 Hz), 7.41 (2H, d, J = 9.0 Hz) ), 8.22 (1H, s), 13.33 (1H, brs). ¹⁹ F-NMR (235 MHz, DMSO-d ₆ ): δ-54.8 (3F, s).

A solution of 1- (4-methylphenyl) -5-trifluoromethylpyrazole-4-carboxylic acid (5.63 g, 20.8 mmol) and triethylamine (3.20 g, 31.6 mmol) in acetone (30 mL) was added. The mixture was ice-cooled, and ethyl chloroformate (2.2 mL, 23.0 mmol) was added dropwise. After stirring at the same temperature for 15 minutes, an aqueous solution in which sodium azide (2.70 g, 41.5 mmol) was dissolved in water (15 mL) was added dropwise. After further stirring at 0 ° C. for 20 minutes, water (100 mL) was added, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, taking care not to exhaust the solvent. The obtained solution was added dropwise to a refluxing benzyl alcohol (2.25 g, 20.8 mmol) solution in anhydrous toluene (10 mL), and the mixture was further refluxed for 3.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by recrystallization (hexane / ethyl acetate or isopropyl alcohol) to give N- {1- (4-methylphenyl) -5-trimethyl as a colorless solid. Benzyl fluoromethylpyrazol-4-yl} carbamate (4.90 g, yield: 63%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.42 (3H, s), 5.24 (2H, s), 6.73 (1H, brs), 7.26 (2H, d, J = 8. 6 Hz), 7.31 (2H, d, J = 8.6 Hz), 7.36-7.44 (5 H, m), 8.25 (1 H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-55.9 (3F, s).

N- {1- (4-Methylphenyl) -5-trifluoromethylpyrazol-4-yl} carbamate benzyl (4.86 g, 12.9 mmol), 10% palladium on carbon (150 mg) and ethanol (150 mL) was stirred for 12 hours at room temperature under 1 atmosphere of hydrogen. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to quantitatively obtain 4-amino-1- (4-methylphenyl) -5-trifluoromethylpyrazole (3.10 g) as a black solid. . Mp: 59-62 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.40 (3H, s), 3.47 (2H, brs), 7.23 (2H, d, J = 8.4 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.31 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-55.8 (3F, s).

Reference Example-13

A mixture of ethyl diethoxyacetate (100 g, 568 mmol) and ethyl acetate (75 mL, 768 mmol) was heated to 80 ° C., and sodium (13.1 g, 570 mmol) was added little by little under a stream of argon. Stir for hours. To this was added ethyl acetate (75 mL, 768 mmol), followed by sodium (13.1 g, 570 mmol) in small portions. After completion of sodium addition, the mixture was stirred at 80 ° C. for 5 hours. Next, ethanol (40 mL) was added in four portions to completely dissolve excess sodium. The reaction solution returned to room temperature was poured into ice water (500 mL) and extracted with ethyl acetate (200 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by distillation under reduced pressure to obtain yellow oily ethyl 4,4-diethoxyacetoacetate (85.1 g, yield: 69%). ^{From 1} H-NMR, the keto body and the enol body were present at a ratio of 80/20 in the CDCl ₃ solution. Bp: 101-108 ° C./8 mmHg. ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.22 to 1.33 (9H, m), 3.52 to 3.77 (4H, m), 3.60 (1.6H, s), 4. 15 to 4.26 (2H, m), 4.68 (0.8 H, s), 4.92 (0.2 H, d, J = 0.5 Hz), 5.45 (0.2 H, d, J) = 0.5 Hz), 11.89 (0.2 H, s).

A mixture of ethyl 4,4-diethoxyacetoacetate (21.2 g, 97.1 mmol), triethyl orthoformate (14.4 g, 97.2 mmol) and acetic anhydride (19.8 g, 194 mmol) was added to the low-boiling compound. The mixture was stirred at 135 ° C. for 2 hours. The reaction solution was returned to room temperature and then concentrated under reduced pressure using an evaporator. The resulting residue was purified by distillation under reduced pressure to obtain yellow oily ethyl 4,4-diethoxy-2-ethoxymethyleneacetoacetate (17.3 g, yield: 65%). ^{From 1} H-NMR, the product was a mixture of two geometric isomers (mixing ratio: 56/44). Bp: 160-168 ° C./8 mmHg. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.13 to 1.41 (12H, m), 3.50 to 3.78 (4H, m), 4.15 to 4.32 (4H, m), 5.16 (0.56H, s), 5.25 (0.44H, s), 7.59 (0.44H, s), 7.79 (0.56H, s).

Ethyl 4,4-diethoxy-2-ethoxymethyleneacetoacetate (8.23 g, 30.0 mmol), 2,4-dichlorophenylhydrazine hydrochloride (6.40 g, 30.0 mmol), ethanol (80 mL) and triethylamine ( (6.00 g, 59.3 mmol) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure to give 1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole as a brown oil. Ethyl 4-carboxylate (12.8 g) was obtained quantitatively. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.09 (6H, br.t, J = 6.1 Hz), 1.39 (3H, t, J = 7.1 Hz), 3.44 to 3.68 (4H, m), 4.34 (2H, q, J = 7.1 Hz), 6.20 (1H, s), 7.30 (1H, dd, J ₁ = 8.5 Hz, J ₂ = 2. 3 Hz), 7.44 (1 H, d, J = 8.5 Hz), 7.50 (1 H, d, J = 2.3 Hz), 8.05 (1 H, s).

Ethyl 1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole-4-carboxylate (12.8 g, 30.0 mmol) was dissolved in ethanol (60 mL) and 10% sodium hydroxide was dissolved. Aqueous solution (60 mL) was added and stirred at room temperature for 4 hours. The reaction mixture was ice-cooled, acidified with 2N hydrochloric acid, water (200 mL) was further added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic layers were dried over anhydrous potassium carbonate and concentrated under reduced pressure to give a brown solid (11.7 g) of 1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole-4-carboxylic acid. Obtained quantitatively. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.90 (6H, br.t, J = 6.8 Hz), 3.27 to 3.45 (4H, m), 6.07 (1H, s), 7.19 (1H, dd, J ₁ = 8.5 Hz, J ₂ = 2.3 Hz), 7.32 (1H, d, J = 8.5 Hz), 7.42 (1H, d, J = 2. 3 Hz), 7.90 (1 H, s).

A mixture of 1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole-4-carboxylic acid (11.7 g, 30.0 mmol) and triethylamine (4.50 g, 44.5 mmol) was added to acetone (100 mL). And ethyl chloroformate (3.4 mL, 35.6 mmol) was added dropwise under ice cooling. The reaction solution was further stirred at the same temperature for 10 minutes, and then an aqueous solution in which sodium azide (4.00 g, 61.5 mmol) was dissolved in water (12 mL) was added dropwise. After completion of the dropwise addition, the mixture was further stirred for 1 hour at the same temperature, and then the reaction solution was poured into water (250 mL) and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous potassium carbonate, and then a part of the solvent was distilled off under reduced pressure while paying attention so as not to precipitate the crude product solid. . The obtained solution was added dropwise to a refluxing mixed solution of 2- (trimethylsilyl) ethanol (4.20 g, 35.5 mmol) and toluene (10 mL), and the mixture was further refluxed for 1 hour. The reaction mixture was returned to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1, 1% triethylamine added) to give N- {1- 2-Trimethylsilylethyl (8.51 g, yield: 60%) of (2,4-dichlorophenyl) -5-diethoxymethylpyrazol-4-yl} carbamate was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.07 (9H, s), 1.06 (2H, br.t, J = 8.0 Hz), 1.16 (6H, br.t, J = 7) .0 Hz), 3.50 (4H, br.q, J = 7.0 Hz), 4.28 (2H, br.t, J = 8.0 Hz), 5.52 (1H, s), 7.30 (1H, d, J = 8.5 Hz), 7.36 (1H, dd, J ₁ = 8.5 Hz, J ₂ = 2.0 Hz), 7.40 (1H, d, J = 2.0 Hz), 7.63 (1H, brs), 8.28 (1H, brs).

N- {1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazol-4-yl} carbamate 2-trimethylsilylethyl (160 mg, 0.337 mmol) was added to 1.0 M tetrabutylammonium fluoride ( (TBAF) / tetrahydrofuran solution (0.35 mL) and stirred at room temperature for 3 days. The reaction mixture was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/2, 1% triethylamine added) to give a brown oil Of 4-amino-1- (2,4-dichlorophenyl) -5-diethoxymethylpyrazole (98 mg, yield: 88%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.15 (6H, t, J = 7.0 Hz), 3.38 to 3.63 (6H, m), 5.46 (1H, s), 7. 29 (1H, dd, J ₁ = 8.5 Hz, J ₂ = 0.5 Hz), 7.34 (1 H, s), 7.34 ( ₁ H, dd, J ₁ = 8.5 Hz, J ₂ = 2. 0 Hz), 7.51 (1H, br.d, J = 2.0 Hz).

Reference Example-14

A solution of sodium nitrite (8.64 g, 125 mmol) in sulfuric acid (60.0 mL) was added to a solution of 2-bromo-4,6-difluoroaniline (20.9 g, 101 mmol) in acetic acid (100 mL) that had been ice-cooled in advance. It added under ice-cooling so that the temperature of a liquid might not become 50 degreeC or more. Next, a solution of tin chloride (76.2 g, 402 mmol) in hydrochloric acid (60.0 mL) was added so that the temperature of the reaction solution did not exceed 10 ° C., and then the reaction solution was poured onto ice (600 g). To this was added sodium hydroxide little by little to make it alkaline, diluted with water (200 mL), and extracted with chloroform (300 mL × 2). The organic layers were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-bromo-4,6-difluorophenylhydrazine (20.9 g, yield) as a brown solid. : 93%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.87 (2H, brs), 5.21 (1H, s), 6.80 to 6.89 (1H, m), 7.05 to 7.10 ( 1H, m). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-121.3 (1F, d, J = 2.4 Hz), −117.7 (1F, d, J = 2.4 Hz).

2-Bromo-4,6-difluorophenylhydrazine (6.43 g, 28.8 mmol), ethyl 2-ethoxymethylenetrifluoroacetoacetate (6.92 g, 28.8 mmol), triethylamine (3.00 g, 29.6 mmol) And ethanol (60 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to give 1- (2-bromo-4,6-difluorophenyl) as a brown oil. Ethyl-5-trifluoromethylpyrazole-4-carboxylate (5.89 g, yield: 51%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.39 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 7.03 (1H, ddd, J ₁ = 9.0 Hz, J ₂ = 8.0 Hz, J ₃ = 2.8 Hz), 7.32 (1H, ddd, J ₁ = 7.8 Hz, J ₂ = 2.8 Hz, J ₃ = 2.3 Hz) , 8.24 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), −103.5 (1F, d, J = 9.4 Hz), −58.6 (3F, d, J = 0) .9 Hz).

Ethyl 1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylate (5.86 g, 14.7 mmol), ethanol (15 mL) and 10% water A mixture of aqueous sodium oxide (15 mL) was stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, acidified with concentrated hydrochloric acid, and the precipitated solid is collected by filtration to give 1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazo- as a yellow solid. Lu-4-carboxylic acid (4.11 g, yield: 75%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 7.00 to 7.08 (1H, m), 7.31 to 7.36 (1H, m), 8.32 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), -103.1 (1F, d, J = 9.4 Hz), -58.7 (3F, s).

1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylic acid (11.5 g, 31.0 mmol), triethylamine (4.70 g, 46.4 mmol) and A mixture of acetone (150 mL) was ice-cooled, and ethyl chloroformate (3.5 mL, 36.6 mmol) was added dropwise, followed by stirring at the same temperature for 10 minutes to obtain a mixed acid anhydride. Next, a solution of sodium azide (4.00 g, 61.5 mmol) in water (12 mL) was added dropwise thereto, and the mixture was further stirred for 10 minutes under ice cooling. Water (400 mL) was added to the reaction solution, and extracted with toluene (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and part of the solvent was distilled off under reduced pressure while paying sufficient attention so that no solid precipitated. The obtained acyl azide solution was dropped into a mixture of t-butyl alcohol (20 mL) and toluene (20 mL) in a reflux state, and the mixture was further refluxed for 2 hours. The reaction mixture was returned to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give N- {1- (2-bromo- 4,6-Difluorophenyl) -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (10.2 g, yield: 75%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.53 (1H, brs), 6.95 to 7.03 (1H, m), 7.26 to 7.31 ( 1H, m), 8.40 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.9 (1F, m), -103.8 (1F, d, J = 7.1 Hz), -59.0 (3F, s).

1,4-Dioxane to t-butyl N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate (534 mg, 1.20 mmol) (3 mL) and 4N hydrochloric acid-methanol solution (2 mL) were added, and the mixture was stirred at 60 ° C. for 1 hour. After completion of the reaction, 1N aqueous sodium hydroxide solution (10 mL) was added, and the product was extracted with chloroform (5 mL × 3). The organic phase was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 4-amino-1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole white solid ( Quantitative). Mp: 58-59 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ) d 3.55 (2H, brs), 6.97 (1H, m), 7.27 (1H, m), 7.43 (1H, s). ¹⁹ F-NMR (235 Hz, CDCl ₃ ) d-112.2 (1F, m), −104.5 (1F, d, J = 7.1 Hz), −59.0 (3F, d, J = 4. 7 Hz).

Example-74

4-Amino-5-methoxymethyl-1- (2,4,6-trifluorophenyl) pyrazole (310 mg, 1.21 mmol) was dissolved in anhydrous dichloromethane (2.0 mL) and triethylamine (300 mg, 2. 96 mmol) was added and the mixture was ice-cooled. Further, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (280 mg, 1.44 mmol) dissolved in anhydrous dichloromethane (2.0 mL) was added. The reaction mixture was stirred at room temperature for 27 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4). The obtained yellow solid (474 mg) was recrystallized from ethyl acetate / hexane to give 3-difluoromethyl-N- (3-difluoromethyl-1-methylpyrazol-4-yl) carbonyl-N- [5- (5- ( A colorless solid (106 mg, yield: 15%) of 2-methoxymethyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazol-4-carboxamide was obtained. Obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.12 (3H, s), 3.89 (6H, s), 4.19 (2H, s), 6.83 to 6.93 (2H, m) , 6.99 (2H, t, J = 54.4 Hz), 7.45 (2H, s), 7.71 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.0 (4F, s), −115.9 (2F, d, J = 7.1 Hz), −102.5 (1F, t, J = 7) .1 Hz).

Further, the recrystallized filtrate was concentrated under reduced pressure, dissolved in dioxane (5.0 mL), 2N hydrochloric acid (5.0 mL) was added, and the mixture was refluxed for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (30 mL) was added to the reaction solution returned to room temperature, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give a yellow solid 3- Difluoromethyl-N- [5- (2-methoxymethyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazol-4-carboxamide (203 mg, yield) 40%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.32 (3H, s), 3.96 (3H, s), 4.41 (2H, s), 6.81 to 6.91 (2H, m) 6.88 (1H, t, J = 54.1 Hz), 8.03 (1H, s), 8.44 (1H, brs), 8.45 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (2F, d, J = 7.1 Hz), −109.1 (2F, s), −103.8 (1F, t, J = 7) .1 Hz).

Example-75

4-Amino-5- (2-methoxyethyl) -1- (2,4,6-trifluorophenyl) pyrazole (330 mg, 1.22 mmol) was dissolved in anhydrous dichloromethane (2.0 mL) and triethylamine ( (300 mg, 2.96 mmol) was added and the mixture was ice-cooled. Further, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (300 mg, 1.54 mmol) dissolved in anhydrous dichloromethane (2.0 mL) was added. The reaction mixture was stirred at room temperature for 28 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give a pale yellow solid (482 mg). ) This was recrystallized from ethyl acetate to give colorless solid 3-difluoromethyl-N- [5- (2-methoxyethyl) -1- (2,4,6-trifluorophenyl) pyrazol-4- Yl] -1-methylpyrazol-4-carboxamide (244 mg, yield: 47%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.76 (2H, t, J = 5.5 Hz), 3.35 (3H, s), 3.54 (2H, t, J = 5.5 Hz), 3.99 (3H, s), 6.81 to 6.91 (2H, m), 7.10 (1H, t, J = 54.0 Hz), 7.85 (1H, s), 8.36 ( 1H, s), 8.72 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 7.1 Hz), −112.1 (2F, s), −103.8 (1F, t, J = 7) .1 Hz).

Example-76

4-Amino-5-isopropyl-1- (2,4-difluoro-6-dimethylaminophenyl) pyrazole (340 mg, 1.21 mmol) was dissolved in anhydrous dichloromethane (2.0 mL) and triethylamine (300 mg, 2 .96 mmol) was added and ice-cooled. Further, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (280 mg, 1.44 mmol) dissolved in anhydrous dichloromethane (2.0 mL) was added. The reaction mixture was stirred at room temperature for 27 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (3 × 10 mL). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) to give a yellow solid (527 mg). Got. This was recrystallized from ethyl acetate to give 3-difluoromethyl-N- [1- (2,4-difluoro-6-dimethylaminophenyl) -5-isopropylpyrazol-4-yl as a pale yellow solid. ] -1-methylpyrazol-4-carboxamide (157 mg, yield: 30%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.20 (3H, d, J = 7.1 Hz), 2.59 (6H, s), 2.66 to 2.80 (1H, m), 3. 96 (3H, s), 6.36 to 6.44 (2H, m), 6.86 (1H, t, J = 54.3 Hz), 7.74 (1H, brs), 8.06 (1H, s), 8.12 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.7 (1F, d, J = 9.4 Hz), −107.7 (1F, d, J = 9.4 Hz), −107.4 (2F) , S).

Example-77

A mixture of 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid (250 mg, 1.29 mmol), anhydrous toluene (5.0 mL) and thionyl chloride (1.0 mL) was refluxed for 30 minutes. Toluene and excess thionyl chloride were distilled off using a Dean-Stark, and then the crude product returned to room temperature was dried with an evaporator and then with a vacuum pump. The obtained 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride was dissolved in anhydrous dichloromethane (2.0 mL), triethylamine (370 mg, 1.32 mmol) was added, and the mixture was ice-cooled. 4-amino-5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazole (370 mg, 1.32 mmol) was added to the resulting mixture, and the mixture was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give 1-methyl-3-trifluoromethyl-N- [ 5-trifluoromethyl-1- (2,4,6-trifluorophenyl) pyrazol-4-yl] pyrazol-4-carboxamide (250 mg, yield: 42%) was obtained. Mp: 150-152 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.02 (3H, s), 6.82 to 6.92 (2H, m), 8.01 (1H, brs), 8.09 (1H, s) , 8.66 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, m), −101.7 (1F, t, J = 7.1 Hz), −60.1 (3F, m), −59 .4 (3F, m).

Example-78

Mixture of 4-amino-1- (2-nitrophenyl) -5-trifluoromethylpyrazole (1.53 g, 5.62 mmol), triethylamine (1.00 g, 9.88 mmol) and anhydrous dichloromethane (10 mL) After cooling with ice, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (1.20 g, 6.17 mmol) dissolved in anhydrous dichloromethane (10 mL) was added dropwise, and the mixture was stirred at room temperature for 2 days. 2N Hydrochloric acid (75 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed successively with saturated brine (40 mL) and saturated aqueous sodium hydrogen carbonate solution (40 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product obtained by silica gel column chromatography. Purified with (hexane / ethyl acetate = 1/1). The obtained yellow solid (2.79 g) was dissolved in dioxane (30 mL), 2N hydrochloric acid (15 mL) was added, and the mixture was refluxed for 4 hr. The reaction solution returned to room temperature was poured into a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 × 50 mL). The organic layers were combined, washed with a saturated aqueous sodium hydrogen carbonate solution (2 × 50 mL), dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and a pale yellow solid of 3-difluoromethyl-1-methyl-N- [ 1- (2-Nitrophenyl) -5-trifluoromethylpyrazol-4-yl] pyrazol-4-carboxamide (2.09 g, yield: 87%) was obtained. Mp: 218-220 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 6.85 (1H, t, J = 54.1 Hz), 7.58 to 7.61 (1H, m), 7.68 to 7.82 (2H, m ), 8.08 (1H, dd, J = 7.8, 1.8 Hz), 8.36 (1H, brs), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.6 (2F, q, J = 6.6 Hz), −57.2 (3F, t, J = 6.6 Hz).

Example-79

A mixture of 4-amino-1- (2,4,6-trifluorophenyl) pyrazole (440 mg, 2.06 mmol), triethylamine (300 mg, 2.96 mmol) and anhydrous dichloromethane (2.5 mL) was ice-cooled. . Further, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (460 mg, 2.36 mmol) dissolved in anhydrous dichloromethane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed successively with saturated brine (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product obtained by silica gel column chromatography. Purified with (hexane / ethyl acetate = 1/4). The resulting pale yellow solid (725 mg) was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 × 15 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 3-difluoromethyl-1-methyl-N- [1- (2,4,6-trifluorophenyl) pyrazole-4 as a pale yellow solid. -Il] pyrazole-4-carboxamide (681 mg, yield: 89%) was obtained. Mp: 155-157 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.80 to 6.91 (2H, m), 6.91 (1H, t, J = 54.1 Hz), 7. 80 (1H, s), 8.01 (1H, s), 8.19 (1H, brs), 8.24 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.6 (2F, d, J = 7.1 Hz), −108.7 (2F, s), −105.5 (1F, t, J = 7) .1 Hz).

Example-80

Mixture of 4-amino-5-bromo-1- (2,4,6-trifluorophenyl) pyrazole (630 mg, 2.16 mmol), triethylamine (300 mg, 2.96 mmol) and anhydrous dichloromethane (4.0 mL) The mixture was ice-cooled, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (460 mg, 2.36 mmol) was added dropwise, and the mixture was stirred at room temperature for 2 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed successively with saturated brine (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product obtained by silica gel column chromatography. Purified with (hexane / ethyl acetate = 1/1). The obtained pale yellow solid (743 mg) was recrystallized from ethyl acetate to give N- [5-bromo-1- (2,4,6-trifluorophenyl) pyrazol-4-yl]-as a colorless solid. 3-Difluoromethyl-1-methylpyrazole-4-carboxamide (333 mg, yield: 34%). Mp: 165-167 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.84 to 6.93 (2H, m), 6.87 (1H, t, J = 54.1 Hz), 8. 02 (1H, brs), 8.07 (1H, s), 8.50 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.1 (2F, d, J = 7.1 Hz), −107.5 (2F, s), −102.9 (1F, t, J = 7) .1 Hz).

Example-81

Mixture of 4-amino-5-methoxy-1- (2,4,6-trifluorophenyl) pyrazole (200 mg, 0.822 mmol), triethylamine (200 mg, 1.98 mmol) and anhydrous dichloromethane (2.5 mL) Was ice-cooled. Further, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (170 mg, 0.874 mmol) dissolved in anhydrous dichloromethane (2.5 mL) was added dropwise, and the mixture was stirred at room temperature for 2 days. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed successively with saturated brine (20 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product obtained by silica gel column chromatography. Purified with (hexane / ethyl acetate = 1/4). The resulting pale yellow solid (321 mg) was dissolved in ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (2 × 15 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give 3-difluoromethyl-N- [5-methoxy-1- (2,4,6-trifluorophenyl) pyrazole-4 as a pale yellow solid. -Il] -1-methylpyrazol-4-carboxamide (300 mg, yield: 91%) was obtained. Mp: 75-80 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 3.96 (3H, s), 6.79 to 6.89 (2H, m), 6.87 (1H, t, J = 54.1 Hz), 7.67 (1H, brs), 7.95 (1H, s), 8.06 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 7.1 Hz), −107.9 (2F, s), −104.6 (1F, t, J = 7) .1 Hz).

Hereinafter, the compound name; shape; yield; melting point; ¹ H-NMR and ¹⁹ F-NMR spectra of the compounds of the present invention synthesized by the methods exemplified in the above Examples and Reference Examples are shown.

Example-82

N- [1- (2-Cyano-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; white solid (Yield: 43%); Mp: 159-161 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J = 54.1 Hz), 7.26-7.41 (2H, m), 8.10 (1 H, s), 8.39 (1 H, brs), 8.76 (1 H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ) : Δ-111.3 (2F, m), -108.4 (2F, s), -101.2 (1F, d, J = 11.8 Hz), -58.6 (3F, m).

Example-83

N- [1- (4-Bromo-2-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; Mp: 167 to 169 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.83 (1 H, t, J = 54.1 Hz), 7. 29-7.68 (3H, m), 8.08 (1H, s), 8.34 (1H, brs), 8.61 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ -118.8 (1F, m), -108.4 (2F, m), -58.0 (3F, m).

Example-84

N- [1- (5-Bromo-2-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; white solid (yield) Mp: 163-165 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J = 54.1 Hz), 7. 15 (1H, t, J = 9.4 Hz), 7.60-7.65 (2H, m), 8.08 (1H, s), 8.34 (1H, brs), 8.62 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.4 (1F, m), -108.4 (2F, m), -58.0 (3F, m).

Example-85

N- [1- (2-Bromo-4-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; white solid (yield) Rate: 52%); Mp: 186-189 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J = 54.1 Hz), 7. 12-7.20 (1H, m), 7.41-7.49 (2H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.61 (1H, s) ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.2 (2F, m), -107.5 (1F, s), -57.6 (3F, m).

Example-86

N- [1- (4-Cyano-2-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; pale yellow solid ( Yp: 216-220 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.83 (1 H, t, J = 54.1 Hz), 7 .56-7.62 (3H, m), 8.09 (1H, s), 8.37 (1H, brs), 8.67 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-117.8 (1F, m), -108.2 (2F, s), -57.9 (3F, m).

Example-87

N- [1- (5-Cyano-2-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; Rate: 57%); Mp: 191-193 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J = 54.1 Hz), 7. 40 (1H, t, J = 8.6 Hz), 7.80 to 7.87 (2H, m), 8.09 (1H, s), 8.36 (1H, brs), 8.66 (1H, ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.2 (1F, m), −108.3 (2F, m), −58.0 (3F, m).

Example-88

N- [1- (4-Bromo-2,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; white solid (Yield: 63%); Mp: 165-167 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.83 (1 H, t, J = 54.1 Hz), 7.29 (2H, d, J = 6.5 Hz), 8.08 (1 H, s), 8.36 (1 H, brs), 8.68 (1 H, s); ¹⁹ F-NMR (376 MHz, CDCl) ₃ ): δ-116.2 (2F, m), -108.1 (2F, m), -58.9 (3F, m).

Example-89

N- [1- (4-Cyano-2,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; white solid (Yield: 30%); Mp: 199 to 202 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.83 (1 H, t, J = 54.1 Hz), 7.43 (2H, d, J = 6.1 Hz), 8.09 (1H, s), 8.38 (1H, brs), 8.73 (1H, s); ¹⁹ F-NMR (376 MHz, CDCl) ₃ ): δ-113.3 (2F, m), -107.9 (2F, m), -58.9 (3F, m).

Example-90

N- [1- (2-Bromo-6-fluoro-4-methoxyphenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; White solid (yield: 64%); Mp: 166-168 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.87 (3H, s), 3.97 (3H, s), 6.74 ( 1H, dd, J = 10.7, 2.6 Hz), 6.85 (1H, t, J = 54.1 Hz), 7.04 to 7.05 (1H, m), 8.08 (1H, s ), 8.36 (1H, brs), 8.66 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (1F, m), −108.6 (2F, m) ), -59.2 (3F, m).

Example-91

N- [1- (2-Bromo-4-fluoro-6-methoxyphenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; Colorless oil (yield: 51%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.78 (3H, s), 3.97 (3H, s), 6.72 (1H, dd, J = 10.0, 2.6 Hz), 6.85 (1 H, t, J = 54.1 Hz), 7.04 (1 H, dd, J = 7.8, 2.6 Hz), 8.08 (1 H, s ), 8.35 (1H, brs), 8.64 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, m), -105.4 (1F, s) ), -59.5 (3F, m).

Example-92

N- [1- (2-Bromo-6-ethoxy-4-fluorophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide; White solid (yield: 69%); Mp: 174-176 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.27 (3H, t, J = 7.0 Hz), 4.01 (2H, q , J = 3.8 Hz), 3.97 (3H, s), 6.70 (1H, dd, J = 10.1, 2.6 Hz), 6.85 (1H, t, J = 54.1 Hz) , 7.02 (1H, dd, J = 8.0, 2.6 Hz), 8.07 (1H, s), 8.34 (1H, brs), 8.64 (1H, s); ¹⁹ F- _{NMR (235MHz, CDCl 3):} δ-108.7 (2F, d, J = 4.7Hz), - 105.8 (1F, s), - 59. (3F, t, J = 5.9Hz).

Example-93

N- [1- (2-Bromo-4-fluoro-6-isopropoxyphenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazol-4-carboxamide Colorless oil (yield: 72%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.22 (3H, d, J = 2.5 Hz), 1.24 (3H, d, J = 2. 5 Hz), 4.47 (3 H, m), 6.69 (1 H, dd, J = 10.4, 2.5 Hz), 6.85 (1 H, t, J = 54.1 Hz), 6.99 ( 1 H, dd, J = 7.8, 2.6 Hz), 8.07 (1 H, s), 8.33 (1 H, brs), 8.62 (1 H, s); ¹⁹ F-NMR (235 MHz, CDCl) _{3): δ-108.7 (2F} , m), - 106.2 (1F, s), - 59.3 (3F, t, J = 14.1Hz)

Example-94

3-difluoromethyl-N- [1- (2,4-difluoro-6-vinylphenyl) -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide; white solid (Yield: 77%); Mp: 126-128 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 5.41 (1 H, d, J = 10.9 Hz), 5.77 (1H, d, J = 17.4 Hz), 6.12 (1H, ddd, J = 17.4, 11.0, 1.0 Hz), 6.84 (1H, t, J = 54. 1 Hz), 6.90 (1 H, ddd, J = 8.6, 8.6, 2.7 Hz), 8.08 (1 H, s), 8.37 (1 H, brs), 8.66 (1 H, ^{s); 19 F-NMR (} 235MHz, CDCl 3): δ-116.7 (1F, m), - 108.5 (2F, q, J = .7Hz), - 105.5 (1F, d, J = 9.4Hz), - 58.9 (3F, m).

Example-95

3-difluoromethyl-N- [1- (2,4-difluoro-6-isopropenylphenyl) -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide; colorless Oily substance (yield: 79%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.83 (3H, s), 3.95 (3H, s), 4.92 (1H, s), 5. 09 (1H, t, J = 1.5 Hz), 6.87 (1H, t, J = 54.0 Hz), 6.86-6.97 (2H, m), 8.08 (1H, s), 8.34 (1H, brs), 8.60 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.4 (1F, m), -108.9 (2F, q, J = 8.2 Hz), -106.0 (1F, d, J = 9.4 Hz), -58.8 (3F, m).

Example-96

3-Difluoromethyl-N- {1- [2,4-difluoro-6- (1-pentenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4- Carboxamide; pale yellow oil (yield: 85%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.87 (3H, t, J = 7.4 Hz), 1.41 (2H, m), 2 .10 (2H, qd, J = 5.4, 1.1 Hz), 3.98 (3H, s), 5.76 (1H, dd, J = 15.8, 1.3 Hz), 6.26 ( 1H, dt, J = 15.8, 7.1 Hz), 6.78 to 6.82 (1H, m), 6.85 (1H, t, J = 54.0 Hz), 7.10 to 7.16 (1H, m), 8.08 (1H, s), 8.38 (1H, brs), 8.67 (1H, s); ¹⁹ F-NMR (235 MHz, CDC) l ₃ ): δ-117.2 (1F, m), −108.6 (2F, q, J = 4.7 Hz), −106.2 (1F, d, J = 9.4 Hz), −59. 0 (3F, m).

Example-97

3-Difluoromethyl-N- [1- (2,4-difluoro-6-vinylphenyl) -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazol-4-carboxamide (152 mg, 0.33 mmol) was dissolved in tetrahydrofuran (5 mL), platinum (IV) oxide hydrate (7.5 mg, 0.033 mmol) was added, and the mixture was stirred under a hydrogen atmosphere for 4 hours. After completion of the reaction, insoluble matter was removed through Celite pad, the solvent was distilled off, and white solid 3-difluoromethyl-N- {1- [2-ethyl-4,6-difluorophenyl] -5-trifluoro was obtained. Methylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide (145 mg, yield: 95%) was obtained. Mp: 132-134 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.16 (3H, t, J = 7.6 Hz), 2.35 (2H, q, J = 7.6 Hz), 3.98 (3H, s), 6.84 (1H, t, J = 54.1 Hz), 6.78 to 6.94 (2H, m), 8.08 (1H, s), 8.36 (1H, brs), 8.64 ( 1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.9 (1F, m), −108.6 (2F, m), −105.9 (1F, d, J = 9.4 Hz), −59 .0 (3F, m).

Hereafter, the compound name; shape; yield; melting point; ¹ H-NMR and ¹⁹ F-NMR spectra of the compound of the present invention synthesized by the same operation as in the above Examples are shown.

Example-98

3-difluoromethyl-N- {1- [2,4-difluoro-6-isopropylphenyl] -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide; white solid (Yield: 97%); Mp: 94 to 96 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.14 to 1.19 (6H, m), 2.40 to 2.52 (1 H, m ), 3.97 (3H, s), 6.81 (1H, ddd, J = 9.2, 8.2, 2.8 Hz), 6.86 (1H, t, J = 54.1 Hz), 6 .94 (1H, ddd, J = 9.6,2.5,1.8Hz), 8.09 (1H, s), 8.37 (1H, brs), 8.63 (1H, s); 19 F-NMR (235 MHz, CDCl ₃ ): δ-108.7 (2F, s), -105.4 (1F, d, J = 7.1 Hz), −58 .9 (3F, m).

Example-99

3-difluoromethyl-N- {1- [2,4-difluoro-6-pentylphenyl] -5-trifluoromethylpyrazol-4-yl} -1-methylpyrazol-4-carboxamide; white solid (quantitative). Mp: 118 to 119 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 0.85 (3H, t, J = 6.8 Hz), 1.15 to 1.35 (4H, m), 1.40 1.66 (2H, m), 2.17 to 2.41 (2H, m), 3.98 (3H, s), 6.77 to 6.94 (2H, m), 6.85 (1H, t, J = 54.1 Hz), 8.08 (1H, s), 8.37 (1H, brs), 8.64 (1H, s); ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116 .8 (1F, m), -108.6 (2F, q, J = 6.5 Hz), -106.2 (1F, d, J = 9.4 Hz), -59.0 (3F, m).

  The pyrazol-4-carboxamide derivatives (1) of the present invention that can be produced by the methods exemplified in Examples and Reference Examples are shown in Table-1 to Table-9. However, the present invention is not limited to these examples.

[Evaluation of bactericidal action of pyrazol-4-carboxamide derivative (1)]
Next, specific examples of the method for formulating the pyrazol-4-carboxamide derivative (1) of the present invention as an agricultural and horticultural fungicide are shown in Formulation Examples-1 to 4. “Parts” in formulation examples represents parts by weight.
Additives and addition ratios of formulation examples shown below are not limited to these formulation examples, and can be changed in a wide range.

(Formulation example)
Formulation Example-1 [wettable powder]
The compounds of the present invention corresponding to the compound numbers shown in Tables 12 to 17 below (20 parts by weight), sodium alkylbenzenesulfonate (3 parts by weight), polyoxyethylene nonylphenyl ether (5 parts by weight) and clay ( 72 parts by weight) of the mixture was uniformly mixed and pulverized to obtain a wettable powder containing 20% by weight of the active ingredient. Furthermore, a wettable powder can be obtained by the same method using each compound shown in Tables 1 to 9.

Formulation Example-2 [Emulsion]
The compound of the present invention (30 parts by weight), methyl ethyl ketone (40 parts by weight) and polyoxyethylene nonylphenyl ether (30 parts by weight) corresponding to the compound numbers shown in Tables 12 to 17 below are mixed and dissolved. To give an emulsion containing 30% by weight of the active ingredient. Furthermore, an emulsion can be obtained by the same method using each compound shown in Tables 1 to 9.

Formulation Example-3 [Flowable Agent]
Compounds of the present invention corresponding to the compound numbers shown in Tables 12 to 17 below (25 parts by weight), polyoxyethylene alkyl ether (1 part by weight), sodium alkylnaphthalene sulfonate (1 part by weight), carboxymethyl A flowable agent containing 25% by weight of the active ingredient was obtained by uniformly mixing a mixture of cellulose (1 part by weight) and water (72 parts by weight). Furthermore, each flowable agent can be obtained by the same method using each compound shown in Tables 1 to 9.

Formulation Example-4 [Granule]
The compounds of the present invention (5 parts by weight) corresponding to the compound numbers listed in Tables 12 to 17 below, sodium lauryl sulfate (1 part by weight), calcium lignin sulfonate (5 parts by weight), bentonite (30 parts by weight) and Water (15 parts by weight) is further added to a mixture of clay (59 parts by weight), kneaded with a kneader, granulated with a granulator, and dried with a fluid dryer to obtain 5% by weight of the active ingredient. The contained granule was obtained. Furthermore, each granule can be obtained by the same method using each compound described in Tables 1 to 9.

(Test example)
Next, the usefulness of the agricultural and horticultural fungicide containing the pyrazol-4-carboxamide derivative (1) of the present invention as an active ingredient will be clarified with reference to the following Test Examples-1 to 6. However, the utility of the present invention is not limited to the utility revealed by these test examples.

Test Example-1 [Test of control effect by spraying foliage against cucumber gray mold]
One pot of dilute liquid (100 ppm) prepared in Formulation Example-1 is added to 1.5-leaf seedlings of cucumber (variety: Sagamihanjiro) grown in a plastic pot with a diameter of 6 cm in a greenhouse. 10 mL was sprayed (stem and leaf spraying). The day after the drug treatment, inoculated onto the first leaf of the cucumber treated with cucumber gray fungus (Botrytis cinerea) agar-containing agar pieces (diameter 5 mm) in advance and inoculated at 20 ° C It was placed in a box (RH = 100%) to promote onset. Four days after the inoculation, the lesion diameter (cm) was measured, and the control value (%) was calculated by the following formula-1. And according to Table-10, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained. In addition, the degree of phytotoxicity to crops was investigated according to the criteria in Table-11. These results are shown in Table-12. The conversion standard for the control value and the survey index for the degree of chemical damage were also applied in Test Examples-2 to 6.

      Formula-1: Control value (%) = [1− (spot diameter in the spray area / spot diameter in the non-spread area)] × 100

Test Example-2 [Control effect test by spraying foliage against wheat red rust]
10 ml per emulsion of diluted emulsion (100 ppm) prepared in Formulation Example-2 to 1.5-leaf seedlings of wheat (variety: Norin 61) grown in a plastic pot with a diameter of 6 cm in a greenhouse Sprayed (stem and leaf spraying). The day after the chemical treatment, per spore suspension of a spore suspension of wheat rust (Puccinia recondita) formed in advance on another wheat leaf (spore concentration 5 × 10 ⁵ cells / mL) per pot After inoculating 5 mL of spray and allowing to stand in an inoculation box at 20 ° C. (RH = 100%) for 24 hours, the disease was promoted in an artificial weather chamber at 20 ° C. Ten days after the inoculation, the number of lesions (pieces) on the first leaf was examined, and the control value (%) was calculated by the following formula-2. And according to Table-10, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained. These results are shown in Table 13 below.

    Formula-2: Control value (%) = [1− (number of lesions in sprayed area / number of lesions in non-sprayed area)] × 100

Test Example-3 [Pesticide effect test by spraying foliage against rice blight]
10 ml per pot of dilute liquid (100 ppm) prepared in Formulation Example-3 to 7-leaf seedlings (pots) of paddy rice (variety: Asahi) grown in a plastic pot with a diameter of 6 cm in a greenhouse Sprayed (stem and leaf spray). The day after the chemical treatment, inoculated into the plant stock of the pot sprayed with the rice sheath blight fungus (Thanatephorus cucumeris) previously cultured in the rice straw medium, in an artificial climate room at 24 ° C. (RH = 100%), The disease was promoted. Seven days after the inoculation, the lesion height of rice blight (height from the strain (cm)) was examined, and the control value (%) was calculated by the following formula-3. And according to Table-10, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained. These results are shown in Table 14 below.

    Formula-3: Control value (%) = [1- (spot height in the sprayed area / health height in the non-sprayed area)] × 100

Test Example-4 [Testing of control effect by spraying foliage against rice blast]
A diluted liquid (100 ppm) of the flowable agent prepared in Formulation Example-3 was added to the three leaf seedlings (5 seedlings / pot) of paddy rice (variety: Asahi) grown in a plastic pot with a diameter of 6 cm in a greenhouse. 10 mL was sprayed (stem and leaf spraying) per pot. The day after the chemical treatment, per spore suspension of a rice blast fungus (Pyricularia grisea) conidial spore (spore concentration 2 × 10 ⁶ cells / mL) previously formed on another rice leaf After inoculating 5 mL of spray and allowing to stand in an inoculation box at 24 ° C. (RH = 100%) for 24 hours, the disease was promoted in an artificial weather room at 24 ° C. Seven days after the inoculation, the number of lesions (number) of the 3rd rice blast was investigated, and the control value (%) was calculated by the following formula-4. And according to Table-10, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained. These results are shown in Table 15 below.

    Formula-4: Control value (%) = [1- (number of lesions in the sprayed area / number of lesions in the non-sprayed area)] × 100

Test Example-5 [Test of control effect by water application against rice blight disease]
Prepared in Formulation Example-4 on 8-leaf seedlings (1 strain / pot) of paddy rice (variety: Asahi) cultivated in a pot (1/10000 al size) filled with paddy soil (brown water) in a greenhouse 4 kg of granule was sprayed into Ta surface water per 10 alarms. Seven days after the chemical treatment, inoculated into the plant stock of the pot sprayed with the rice sheath blight fungus (Thanatephorus cucumeris) previously cultured in the rice straw medium, and in an artificial climate room at 24 ° C. (RH = 100%) Urged the disease. Seven days after the inoculation, the height of spotted rice blight (height from the strain (cm)) was examined, and the control value (%) was calculated by the following formula-5. And according to Table-10, the control value was converted into the evaluation value. This test was carried out in a triple regime of 1 pot and 1 pot per 1 drug treatment amount. The average evaluation value of the control effect was obtained. These results are shown in Table-16.

    Formula-5: Control value (%) = [1− (health height of sprayed area / health height of non-sprayed area)] × 100

Test Example 6 [Control Effect Test by Irrigation Treatment for Rice Blight Disease]
The flowable preparation prepared in Formulation Example-3 was applied to 2.5-leaf seedlings of paddy rice (variety: Asahi) grown in a greenhouse using a seedling box (1/10 size of standard nursery box: 12 cm x 15 cm x 4 cm in height). The diluted solution (20000 ppm) was irrigated with 50 mL. This was immediately transplanted at 5 seedlings / pot into a pot (1/10000 alarm size) filled with paddy soil (brown water). After incubating in a greenhouse for 4 weeks, inoculate the plant stock of a pot sprayed with rice leaf blight fungus (Thanatephorus cucumeris) previously cultured in a rice straw medium, and artificial climate at 24 ° C. (RH = 100%) In the room, illness was promoted. Seven days after the inoculation, the lesion height of rice blight (height from the strain (cm)) was investigated, and the control value (%) was calculated by the following formula-6. And according to Table-10, the control value was converted into the evaluation value. This test was conducted in a triple system of 1 pot per 1 chemical solution concentration. The average evaluation value of the control effect was obtained. These results are shown in Table 17 below.

    Formula-6: Control value (%) = [1− (health height in irrigated area / health height in non-irrigated area)] × 100

  The pyrazol-4-carboxamide derivative of the present invention can be used as a fungicide for agriculture and horticulture.

Claims (4)

General formula (1)
(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; An alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; Substituted with alkyl group having 1 to 6 carbon atoms, acyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, benzenesulfonyl group or p-tolylsulfonyl group And n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different.) Pyrazol-4-carboxamide derivative . The pyrazol-4-carboxamide derivative according to claim 1, wherein R ² and R ⁴ are each independently a haloalkyl group having 1 to 6 carbon atoms. General formula (2)
(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. Y represents a leaving group), and a pyrazol-4-carboxylic acid derivative represented by formula (3):
(Wherein R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group of 6; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; A halogen atom; an alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkoxy group having 1 to 6 carbon atoms; A nitro group; or an alkyl group having 1 to 6 carbon atoms, an acyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, or a benzenesulfonyl group Or an amino group which may be substituted with a p-tolylsulfonyl group, n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different. A 4-aminopyrazole derivative having the general formula (1)
(Wherein R ¹ , R ² , R ³ , R ⁴ , X and n represent the same meaning as described above), a method for producing a pyrazol-4-carboxamide derivative. General formula (1)
(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms that may be substituted with an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; An alkoxy group; a formyl group; a hydroxymethyl group; a hydroxyiminomethyl group; (an alkoxy having 1 to 6 carbon atoms) an iminomethyl group; or (an acyloxy having 1 to 6 carbon atoms) an iminomethyl group, wherein X is a hydrogen atom; An alkyl group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; an alkenyl group having 2 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl having 1 to 6 carbon atoms; Substituted with alkyl group having 1 to 6 carbon atoms, acyl group having 1 to 6 carbon atoms, alkylsulfonyl group having 1 to 6 carbon atoms, benzenesulfonyl group or p-tolylsulfonyl group And n represents an integer of 1 to 5. When n is 2 or more, X may be the same or different.) Pyrazol-4-carboxamide derivative A bactericidal agent containing as an active ingredient.