JP2012056944A - Pyrazole-4-carboxamide derivative, method for producing the same, and horticultural fungicide having the pyrazole-4-carboxamide derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new fungicide exhibiting a high controlling effect to various harmful bacteria which do damage to cultivation of crops, and having both of high safety to crops and outstanding environmental maintainability.SOLUTION: A pyrazole-4-carboxamide derivative (1) useful as an active ingredient of the fungicide is obtained by condensing a pyrazole-4-carboxylic acid derivative (2) and a 4-amino pyrazole derivative (3) with each other.

Description

  The present invention relates to a pyrazole-4-carboxamide derivative that is effective in controlling harmful pathogens in agricultural and horticultural settings and a method for producing the same.

  Conventionally, in the field of agriculture and horticulture, many agricultural and horticultural fungicides for the purpose of controlling various diseases have been developed and put to practical use. However, they are not necessarily satisfactory in terms of effect, spectrum, or residual effect. Absent. 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 agricultural and horticultural fungicides that have been widely used in the past 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, development of a novel agricultural and horticultural fungicide that shows a sufficient control effect at low doses and has little adverse effect on the environment against various diseases that have acquired resistance to conventional fungicides is eagerly desired. .

  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 agricultural and horticultural fungicides that will be the solution has become increasingly important. Yes.

  So far, many pyrazole-4-carboxamide derivatives having bactericidal activity have been known. For example, compounds described in Patent Document 1, Patent Document 2, and the like have been used as agricultural and horticultural fungicides. However, no fungicides have been put to practical use in the pyrazole-4-carboxamide derivatives having a pyrazol-4-yl group on the amide nitrogen atom of the present invention.

  In addition, some compounds having a structure similar to the pyrazole-4-carboxamide derivative having a pyrazol-4-yl group on the amide nitrogen atom of the present invention are also known. However, synthesis examples and biological activities of compounds having a phenyl group which may be substituted at the 5-position of the pyrazole ring of the pyrazol-4-yl group have not been reported so far as far as the inventors investigated. .

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

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

  As a result of intensive studies to solve the above problems, the present inventors have found that the pyrazole-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 halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; X represents a hydrogen atom; halogen atom; alkyl group having 1 to 6 carbon atoms; alkoxy group having 1 to 6 carbon atoms; haloalkyl group having 1 to 6 carbon atoms; alkylthio group having 1 to 6 carbon atoms Or X represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted by an adjacent alkyl group having 1 to 3 carbon atoms; 1 to 3 A methylenedioxy group optionally substituted with an alkyl group, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, where n represents an integer of 1 to 5. When it is 2 or more, X may be the same or different from each other.) Relates to a pyrazole-4-carboxamide derivative represented by:

The present invention also relates to a pyrazole-4-carboxamide derivative in which R ² is a haloalkyl group having 1 to 6 carbon atoms in the general formula (1). The present invention further relates to a pyrazole-4-carboxamide derivative in which R ² is a difluoromethyl group or a trifluoromethyl group in the general formula (1).

  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 pyrazole-4-carboxylic acid derivative represented by the general formula (3):

(Wherein R ⁴ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; or Represents an alkyl group having 1 to 6. X represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; Or represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted with two adjacent X groups together with an alkyl group having 1 to 3 carbon atoms; A methylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, n is an integer of 1 to 5 The table When n is 2 or more, X may be the same or different.) A 4-aminopyrazole derivative represented by the general formula (1) is condensed.

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and n represent the same meanings as described above).

  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 halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; X represents a hydrogen atom; halogen atom; alkyl group having 1 to 6 carbon atoms; alkoxy group having 1 to 6 carbon atoms; haloalkyl group having 1 to 6 carbon atoms; alkylthio group having 1 to 6 carbon atoms Or X represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted by an adjacent alkyl group having 1 to 3 carbon atoms; 1 to 3 A methylenedioxy group optionally substituted with an alkyl group, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, where n represents an integer of 1 to 5. When it is 2 or more, X may be the same or different.) The present invention relates to an agricultural and horticultural fungicide containing a pyrazole-4-carboxamide derivative represented by

  The present invention is described in further detail below.

The alkyl group having 1 to 6 carbon atoms represented by R ¹ and R ⁴ 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, cyclobutyl 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 strong activity as a fungicide. R ⁴ is preferably a methyl group or a t-butyl group.

The alkyl group having 1 to 6 carbon atoms represented by R ² may be linear, branched or cyclic, and may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, Butyl, isobutyl, s-butyl, t-butyl, cyclopropylmethyl, cyclobutyl, pentyl, isopentyl, neopentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, cyclopentyl Hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group and the like. The haloalkyl group having 1 to 6 carbon atoms represented by R ² may be linear, branched or cyclic, and is a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2-fluoro Ethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, chloromethyl Group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group and the like can be exemplified. R ² is preferably an alkyl group having 1 to 4 carbon atoms or a haloalkyl group, and more preferably a methyl group, a difluoromethyl group, or a trifluoromethyl group, because of its high effect as a bactericidal agent.

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, and more preferably a hydrogen atom, from the viewpoint of a high effect as a disinfectant.

Examples of the optionally substituted phenyl group represented by R ⁴ include a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms. A phenyl group which may be substituted, and examples of the halogen atom include a fluorine atom, a chlorine atom and a bromine atom. The alkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic, and is a methyl group, an ethyl group, a propyl group, an isopropyl group, a cyclopropyl group, a butyl group, or an isobutyl group. , S-butyl group, t-butyl group, cyclopropylmethyl group, cyclobutyl 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 and the like can be exemplified. Examples of the alkoxy group having 1 to 6 carbon atoms include methoxy group, ethoxy group, propyloxy group, isopropyloxy group, butyloxy group, isobutyloxy group, s-butyloxy group, cyclopropylmethyloxy group, pentyloxy group, and isopentyl group. Oxy group, 2-pentyloxy group, 3-pentyloxy group, 2-methylbutyloxy group, cyclopentyloxy group, hexyloxy group, isohexyloxy group, 2-ethylbutyloxy group, 1,3-dimethylbutyloxy group Etc. can be illustrated. The haloalkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic, and is a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2, 2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, chloromethyl group, 2-chloroethyl Group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group and the like can be exemplified.

From the viewpoint of high effect as a bactericidal agent, the optionally substituted phenyl group represented by R ⁴ is preferably a phenyl group substituted with a halogen atom, such as 2-fluorophenyl group, 4-fluorophenyl group, 2 -Chlorophenyl group, 4-chlorophenyl group, 2,4-difluorophenyl group, 2,4-dichlorophenyl group, 4-chloro-2-fluorophenyl group, 2-chloro-4-fluorophenyl group, 2,4,6- Examples thereof include a trifluorophenyl group, 2,4,6-trichlorophenyl group, 6-bromo-2,4-difluorophenyl group, 4-bromo-2,6-difluorophenyl group and the like. , 6-trifluorophenyl group, 6-bromo-2,4-difluorophenyl group or 4-bromo-2,6-difluorophenyl group is preferred.

  Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, and a bromine atom. A fluorine atom or a chlorine atom is preferable in that the effect as a disinfectant is high.

  The alkyl group having 1 to 6 carbon atoms represented by X may be any of linear, branched or cyclic, methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl Group, isobutyl group, s-butyl group, t-butyl group, cyclopropylmethyl group, cyclobutyl group, pentyl group, isopentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2-methylbutyl group, cyclopentyl group, Examples thereof include a hexyl group, an isohexyl group, a 2-ethylbutyl group, and a 1,3-dimethylbutyl group.

  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, propyloxy group, isopropyloxy group, cyclopropyloxy group. Group, butyloxy group, isobutyloxy group, s-butyloxy group, t-butyloxy group, cyclopropylmethyloxy group, cyclobutyloxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, 2-pentyloxy group, Examples include 3-pentyloxy group, 2-methylbutyloxy group, cyclopentyloxy group, hexyloxy group, isohexyloxy group, 2-ethylbutyloxy group, 1,3-dimethylbutyloxy group, and the like.

  The haloalkyl group having 1 to 6 carbon atoms represented by X may be linear, branched or cyclic, and includes a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and 2-fluoroethyl. Group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, chloromethyl group , 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group and the like.

  The alkylthio group having 1 to 6 carbon atoms represented by X may be any of linear, branched or cyclic, methylthio group, ethylthio group, propylthio group, isopropylthio group, cyclopropylthio group , Butylthio group, isobutylthio group, s-butylthio group, t-butylthio group, cyclopropylmethylthio group, cyclobutylthio group, pentylthio group, isopentylthio group, neopentylthio group, 2-pentylthio group, 3-pentylthio group 2-methylbutylthio group, cyclopentylthio group, hexylthio group, isohexylthio group, cyclohexylthio group, 2-ethylbutylthio group, 1,3-dimethylbutylthio group, and the like. An isopentylthio group, a 2-methylbutylthio group, or a cyclohexylthio group is preferable because of its high effect as a bactericidal agent.

  X is preferably a halogen atom or a haloalkyl group having 1 to 4 carbon atoms, and more preferably a fluorine atom, a chlorine atom, or a trifluoromethyl group, because of its high effect as a fungicide.

  Examples of the polymethylene chain having 3 to 5 carbon atoms formed by uniting two adjacent Xs together include a trimethylene group, a tetramethylene group, and a pentamethylene group. These polymethylene chains may be substituted with an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, or an isopropyl group. Further, the methylenedioxy group or ethylenedioxy group formed by uniting two adjacent X's together is substituted with an alkyl group having 1 to 3 carbon atoms such as a methyl group, an ethyl group, or an isopropyl group. Also good.

  Next, the manufacturing method of the pyrazole-4-carboxamide derivative of this invention is demonstrated in detail.

  The pyrazole-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, in the production method of the present invention (Step-1), the pyrazole-4-carboxylic acid derivative (2) is condensed with the 4-aminopyrazole derivative (3) to produce the pyrazole-4-carboxamide derivative (1) of the present invention. It is a method of manufacturing.

  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 alkali metals and alkalis such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, and barium hydroxide. Examples include earth metal hydroxides, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, and the like. 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.

  The amount of the base used is not particularly limited, but the target product can be obtained in good yield by using 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to the reaction substrate.

  When the leaving group Y is a hydroxyl group, 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 to 3 equivalent with respect to the reaction substrate, Preferably it uses 1 to 1.5 equivalent. In this reaction, in some cases, the reaction can be carried out in the presence of a base such as triethylamine or 4-dimethylaminopyridine.

  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 tellurium, 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 may be used. 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 the range of 0 to 150 ° C., preferably 20 to 100 ° C. There is no particular limitation on the reaction time.

  After completion of the reaction, the pyrazole-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.

  Further, the pyrazole-4-carboxamide derivative 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 and n represent the same meaning as described above. R ⁵ represents an alkyl group having 1 to 6 carbon atoms or a benzyl group, and Z represents an oxygen atom or sulfur. Represents an atom.)
That is, the production method of the present invention (step-2) is carried out by converting the pyrazole-4-carboxamide derivative (1a) of the present invention into the general formula R ⁵ ZH (wherein R ⁵ is an alkyl group having 1 to 6 carbon atoms or benzyl In the method for producing the pyrazole-4-carboxamide derivative (1b) of the present invention by subjecting to a substitution reaction with alcohols or thiols represented by the following formula: Z represents an oxygen atom or a sulfur atom. is there.

The alkyl group having 1 to 6 carbon atoms represented by R ⁵ may be linear, branched or cyclic, and is a 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 and the like.

  The reaction of step-2 is preferably carried out in the presence of a base. As the base, tertiary amine base such as triethylamine, tetramethylethylenediamine, 1,4-diazabicyclo [2.2.2] octane, N, N-diisopropylethylamine, or sodium carbonate, potassium carbonate, potassium phosphate, Inorganic bases such as cesium carbonate, sodium-t-butoxide, potassium-t-butoxide, sodium hydride and potassium hydride can be used, and bulky N, N-diisopropylethylamine, potassium carbonate and the like are preferable. 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 substrate.

  It is essential to carry out the reaction of Step-2 in the presence of a palladium catalyst and a phosphine ligand. Examples of the palladium catalyst include bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium chloride and the like, and bis (dibenzylideneacetone) palladium and tris in terms of good yield. Zero-valent palladium complexes such as (dibenzylideneacetone) dipalladium are preferred. As the phosphine ligand, 4,5-bis (di-t-butylphosphino) -9,9-dimethylxanthene, 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene, bis [2 -(Diphenylphosphino) phenyl] ether, tricyclohexylphosphine, tri-t-butylphosphine, TolBINAP and the like can be exemplified, and 4,5-bis (diphenylphosphino) -9,9 in terms of good yield. -Dimethylxanthene, TolBINAP, etc. are preferable. There is no restriction | limiting in particular in the usage-amount of a palladium catalyst and a phosphine ligand, What is necessary is just to use 1 to 10 mol%.

  The reaction of step-2 can be carried out in an organic solvent, and any organic solvent that does not harm the reaction can be used. Examples of the organic solvent include ether solvents such as diisopropyl ether, cyclopentyl methyl ether, dimethoxyethane, and dioxane. By carrying out the reaction at a temperature appropriately selected from the range of room temperature to the solvent reflux temperature, the desired product can be obtained in good yield. There is no particular limitation on the reaction time.

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

  The pyrazole-4-carboxylic acid derivative (2) used as a raw material for the production method (step-1) of the present invention is disclosed in International 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.

  The 4-aminopyrazole derivative (3), which is the other raw material, is partly a known compound. For example, US Patent Application Publication US2006 / 014700, International Publication WO99 / 64415, Farmoco, Editione Scientifica, 23 (10), 919-914 (1968), J. Am. Med. Chem. , 40 (9), 1347-1365 (1997), J. MoI. Chem. Inform. Compt. Sci. , 41 (6), 1553-1560 (2001), Bioorg. Med. Chem. Lett. , 12 (3), 267-270 (2002), J. Am. Heterocyclic Chem, 25, 555-558 (1988) and the like. The 4-aminopyrazole derivative (3) that can be used as a raw material of the present invention can be synthesized using the methods described in these reported examples, but can also be produced by the methods exemplified below. That is, an alkoxymethylene group was introduced into the methylene moiety of a benzoyl acetate ester that can be derived from substituted acetophenones. A 5-substituted phenylpyrazole-4-carboxylic acid ester (5) was synthesized by a condensation reaction between this benzoylacetic acid derivative (4) and hydrazines having a desired substituent. The carboxylic acid (6) obtained by hydrolyzing the ester moiety was converted to an acid halide or mixed acid anhydride (7), and then condensed with sodium azide to give an acyl azide (8). This is converted to a carbamate ester (9) by subjecting it to a Curtius rearrangement reaction in the presence of an alcohol such as t-butyl alcohol, and then decarboxylated simultaneously with the hydrolysis of the ester to give a 4-aminopyrazole derivative. (3) It can be manufactured (see the following reference example). The 4-aminopyrazole derivative (3) can also be produced directly by the Curtius rearrangement of acyl azide (8).

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

  The pyrazole-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 and useful organisms in agricultural and horticultural scenes. .

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.
Example-1

Triethylamine (300 mg, 2.96 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (490 mg, 2.52 mmol) in dichloromethane (2 mL), and the mixture was ice-cooled. -A solution of methyl-5-phenylpyrazole (436 mg, 2.52 mmol) in dichloromethane (2 mL) was added, and the mixture was stirred at room temperature for 23 hours. After completion of the reaction, the reaction solution was poured into 2N hydrochloric acid (30 mL) and extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The combined organic layers were washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL) and then dried over anhydrous magnesium sulfate. The light yellow solid obtained by concentrating the organic layer under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/9) to give 3-difluoromethyl-1-methyl-N- (1 -Methyl-5-phenylpyrazol-4-yl) pyrazole-4-carboxamide (600 mg, yield: 72%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.80 (3H, s), 3.91 (3H, s), 6.68 (1H, t, J = 54.1 Hz), 7.36-7. 39 (2H, m), 7.43-7.56 (3H, m), 7.79 (1H, brs), 7.96 (1H, s), 8.19 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.5 (2F, s).
Example-2

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.139 g, 0.79 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was connected. Used to remove toluene and excess thionyl chloride. Further, the solvent was distilled off from the reaction solution using an evaporator and then a vacuum pump to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride as a brown oily substance. This was used in the next reaction without purification. A solution of 4-amino-5- (2-fluorophenyl) -1-methylpyrazole (0.150 g, 0.79 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.119 g, 1.18 mmol) and 3 -A solution of difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (2-Fluorophenyl) -1-methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (273 mg, yield: quantitative) was obtained. Mp: 127.9-129.4 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.78 (3H, d, J = 0.8 Hz), 3.91 (3H, s), 6.67 (1H, t, J = 54.2 Hz), 7.22-7.27 (1 H, m), 7.30 (1 H, td, J = 7.5 and 1.1 Hz), 7.34 (1 H, td, J = 7.4 and 1.8 Hz), 7.46 -7.52 (1H, m), 7.73 (1H, brs), 7.97 (1H, s), 8.18 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.5 (1F, m), -108.4 (2F, m).
Example-3

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.139 g, 0.79 mmol) in toluene (3 mL) was added thionyl chloride (1 mL), and the mixture was refluxed for 30 minutes. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (4-fluorophenyl) -1-methylpyrazole (0.150 g, 0.79 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.119 g, 1.18 mmol) and 3 -A solution of difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (ethyl acetate) to give colorless oil 3-difluoromethyl-N- [5- (4-Fluorophenyl) -1-methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (267 mg, yield: 98%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.78 (3H, s), 3.91 (3H, s), 6.67 (1H, t, J = 54.2 Hz), 7.19-7. 25 (2H, m), 7.34-7.38 (2H, m), 7.73 (1H, brs), 7.98 (1H, s), 8.16 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.3 (1F, s), -107.8 (2F, s).
Example-4

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.128 g, 0.73 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (2-chlorophenyl) -1-methylpyrazole (0.150 g, 0.72 mmol) in dichloromethane (1 mL) was ice-cooled, triethylamine (0.110 g, 1.08 mmol) and 3-difluoro were added. A solution of methyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (ethyl acetate) to give N- [5- (2-chlorophenyl) as a white solid. -1-Methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (238 mg, yield: 90%) was obtained. Mp: 150.8-152.9 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.71 (3H, s), 3.90 (3H, s), 6.63 (1H, t, J = 54.0 Hz), 7.36 (1H, dd, J = 7.4 and 1.8 Hz), 7.41 (1 H, td, J = 7.4 and 1.5 Hz), 7.46 (1 H, td, J = 7.6 and 1.8 Hz), 7.57 (1 H , Dd, J = 7.9 and 1.3 Hz), 7.61 (1H, brs), 7.95 (1H, s), 8.18 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.6 (2F, m).
Example-5

Triethylamine (200 mg, 1.98 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (260 mg, 1.34 mmol) in dichloromethane (2 mL) and the mixture was ice-cooled, and then 4-amino-5. A solution of-(4-chlorophenyl) -1-methylpyrazole (139 mg, 0.67 mmol) in dichloromethane (2.5 mL) was added. The solution was stirred at room temperature for 22 hours, diluted with ethyl acetate (30 mL), washed with a saturated aqueous sodium hydrogen carbonate solution (10 mL), and dried over anhydrous magnesium sulfate. The yellow solid obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/9) to give N- [5- (4-chlorophenyl) -1-methylpyrazole-4 as a pale yellow solid. -Yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (319 mg, yield: quantitative) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.79 (3H, s), 3.92 (3H, s), 6.70 (1H, t, J = 54.1 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.50 (2H, d, J = 8.5 Hz), 7.75 (1H, brs), 7.97 (1H, s), 8.14 (1H, s) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.0 (2F, s).
Example-6

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.127 g, 0.72 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (3,5-difluorophenyl) -1-methylpyrazole (0.150 g, 0.72 mmol) in dichloromethane (1 mL) was ice-cooled and then triethylamine (0.109 g, 1.1 mmol). And a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (ethyl acetate) to give colorless oil 3-difluoromethyl-N- [5- (3,5-Difluorophenyl) -1-methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (251 mg, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.83 (3H, s), 3.92 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 6.91-6. 95 (3H, m), 7.78 (1H, brs), 8.00 (1H, s), 8.15 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.7 (2F, s), -107.6 (2F, s).
Example-7

Triethylamine (200 mg, 1.98 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (260 mg, 1.34 mmol) in dichloromethane (2 mL) and the mixture was cooled with ice, and then 4-amino-5 was added. A solution of-(3,4-dichlorophenyl) -1-methylpyrazole (300 mg, 1.24 mmol) in dichloromethane (2.5 mL) was added. The solution was stirred at room temperature for 22 hours, then diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by medium pressure column chromatography to obtain N- [5- (3,4-dichlorophenyl) -1- Methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (321 mg, yield: 65%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.80 (3H, s), 3.92 (3H, s), 6.70 (1H, t, J = 54.3 Hz), 7.23 (1H, dd, J = 8.3 and 2.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 7.59 (1H, d, J = 8.3 Hz), 7.75 (1H, brs), 7.9 (1H, s), 8.13 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-107.8 (2F, s).
Example-8

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.110 g, 0.63 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-methyl-5- (4-trifluoromethylphenyl) pyrazole (0.150 g, 0.62 mmol) in dichloromethane (1 mL) was ice-cooled and then triethylamine (0.094 g, 0.93 mmol). And a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (ethyl acetate) to give colorless oil 3-difluoromethyl-1-methyl-N. -[1-Methyl-5- (4-trifluoromethylphenyl) pyrazol-4-yl] pyrazole-4-carboxamide (248 mg, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.82 (3H, s), 3.92 (3H, s), 6.68 (1H, t, J = 54.2 Hz), 7.53 (2H, d, J = 8.0 Hz), 7.75 (1H, brs), 7.78 (2H, d, J = 8.0 Hz), 7.98 (1H, s), 8.15 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.6 (2F, s), -62.8 (3F, s).
Example-9

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.086 g, 0.49 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1-methylpyrazole (0.150 g, 0.49 mmol) in dichloromethane (1 mL) was ice-cooled and then triethylamine (0.074 g). , 0.73 mmol) and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL). The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (ethyl acetate) to give a white solid N- [5- {3,5- Bis (trifluoromethyl) phenyl} -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (205 mg, yield: 90%) was obtained. Mp: 193.3-196.9 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.82 (3H, s), 3.92 (3H, s), 6.65 (1H, t, J = 54.2 Hz), 7.73 (1H, brs), 7.87 (2H, s), 7.98 (1H, s), 8.00 (1H, s), 8.13 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.0 (6F, s), -107.3 (2F, s).
Example-10

Triethylamine (200 mg, 1.98 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (260 mg, 1.34 mmol) in dichloromethane (2 mL), and the mixture was ice-cooled. A solution of -t-butyl-5-phenylpyrazole (270 mg, 1.25 mmol) in dichloromethane (4 mL) was added. The solution was stirred at room temperature for 22 hours, then diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (10 mL). The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by medium pressure column chromatography to obtain a light yellow solid N- (1-t-butyl-5-phenylpyrazole- 4-yl) -3-difluoromethyl-1-methylpyrazole-4-carboxamide (320 mg, yield: 69%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.87 (3H, s), 6.49 (1H, t, J = 54.1 Hz), 7.33-7. 50 (6H, m), 7.91 (1H, s), 8.19 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-109.3 (2F, s).
Example-11

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.113 g, 0.64 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-t-butyl-5- (2-fluorophenyl) pyrazole (0.150 g, 0.64 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.130 g, 0.18 mL). And a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid N- [1 -T-Butyl-5- (2-fluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (207 mg, yield: 82%) was obtained. Mp: 156.8-158.9 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.48 (9H, s), 3.88 (3H, s), 6.50 (1H, t, J = 54.2 Hz), 7.20 (1H, t, J = 8.8 Hz), 7.24-7.28 (1 H, m), 7.33 (1 H, td, J = 7.4 and 1.8 Hz), 7.41 (1 H, brs), 7. 47-7.52 (1H, m), 7.94 (1H, s), 8.21 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.1 (1F, s), -108.8 (2F, s).
Example-12

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.113 g, 0.64 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-t-butyl-5- (4-fluorophenyl) pyrazole (0.150 g, 0.64 mmol) in dichloromethane (2 mL) was ice-cooled and then triethylamine (0.130 g, 1.11 mmol). And a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give N- [1- t-Butyl-5- (4-fluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.246 g, yield: 98%) was obtained. Mp: 189.6-191.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.88 (3H, s), 6.51 (1H, t, J = 54.2 Hz), 7.17 (2H, t, J = 8.6 Hz), 7.34 (2H, dd, J = 8.7 and 5.4 Hz), 7.41 (1H, brs), 7.94 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.5 (1F, s), -108.6 (2F, s).
Example-13

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.077 g, 0.44 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-t-butyl-3- (3,5-difluorophenyl) pyrazole (0.110 g, 0.44 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.066 g,. 65 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (ethyl acetate) to give N- [1-t-butyl-5 as a white solid. -(3,5-Difluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (163 mg, yield: 91%) was obtained. Mp: 183.8-184.9 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 3.89 (3H, s), 6.54 (1H, t, J = 54.2 Hz), 6.90-6. 98 (3H, m), 7.42 (1H, brs), 7.96 (1H, s), 8.16 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.43 (2F, s), −108.37 (2F, s).
Example-14

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (93.0 mg, 0.53 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-t-butyl-3- (3,4-dichlorophenyl) pyrazole (0.150 g, 0.53 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.080 g, 0.79 mmol). ) And 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) were added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (ethyl acetate) to give N- [1-t-butyl-5 as a white solid. -(3,4-Dichlorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (216 mg, yield: 92%) was obtained. Mp: 228.5-230.4 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.89 (3H, s), 6.55 (1H, t, J = 54.2 Hz), 7.21 (1H, dd, J = 8.2 and 2.0 Hz), 7.40 (1H, brs), 7.48 (1H, d, J = 2.0 Hz), 7.56 (1H, d, J = 8.2 Hz), 7.95 (1H, s), 8.14 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.4 (2F, s).
Example-15

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.094 g, 0.53 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole (0.150 g, 0.53 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0.080 g,. 79 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 1 day, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give N- [1- t-Butyl-5- (4-trifluoromethylphenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (203 mg, yield: 87%) was obtained. Mp: 200.9-202.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.88 (3H, s), 6.48 (1H, t, J = 54.2 Hz), 7.35 (1H, brs), 7.51 (2H, d, J = 7.9 Hz), 7.74 (2H, d, J = 8.0 Hz), 7.94 (1H, s), 8.16 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.5 (2F, s), -62.9 (3F, s).
Example-16

After thionyl chloride (1 mL) was added to a toluene (3 mL) solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.075 g, 0.43 mmol) and refluxed for 30 minutes, a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole (0.150 g, 0.43 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine (0 0.065 g, 0.64 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) were added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the brown oil obtained was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid N- [5 -{3,5-bis (trifluoromethyl) phenyl} -1-t-butylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (194 mg, yield: 89%). Obtained. Mp: 152.9-154.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.88 (3H, s), 6.45 (1H, t, J = 54.2 Hz), 7.34 (1H, brs), 7.86 (2H, s), 7.96 (1H, s), 8.01 (1H, s), 8.16 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.1 (6F, s), -108.3 (2F, s).
Example-17

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) in dichloromethane (2 mL) was added triethylamine (300 mg, 2.96 mmol), and the mixture was ice-cooled, and then 4-amino-1 , 5-Diphenylpyrazole (470 mg, 2.00 mmol) in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 23 hours, poured into 2N hydrochloric acid (30 mL), and extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The combined organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (20 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a pale yellow solid obtained by silica gel column chromatography (hexane / ethyl acetate = 1/4). ) To give 3-difluoromethyl-N- (1,5-diphenylpyrazol-4-yl) -1-methylpyrazole-4-carboxamide (725 mg, yield: 92%) as a pale yellow solid. . ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.93 (3H, s), 6.71 (1 H, t, J = 54.1 Hz), 7.21-7.42 (10 H, m), 7. 94 (1H, brs), 8.00 (1H, s), 8.46 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-108.3 (2F, s).
Example-18

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.086 g, 0.49 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.150 g, 0.49 mmol) in dichloromethane (1 mL) was ice-cooled, and triethylamine ( 0.074 g, 0.73 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) were added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give colorless oily 3-difluoromethyl. -N- [5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (182 mg, yield: 80%) Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93 (3H, s), 6.68-6.74 (2H, m), 6.70 (1H, t, J = 54.1 Hz), 7. 10-7.25 (3H, m), 7.37-7.43 (1H, m), 7.90 (1H, brs), 8.02 (1H, s), 8.56 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.7 (2F, s), -113.2 (1F, m), -108.2 (2F, s), -104.1 (1F, m ).
Example-19

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.086 g, 0.49 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (4-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.150 g, 0.49 mmol) in dichloromethane (1 mL) was ice-cooled, and then triethylamine ( 0.074 g, 0.73 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) were added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give colorless oily 3-difluoromethyl. -N- [5- (4-Fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (219 mg, yield: 96%) Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 6.69-6.75 (2H, m), 7. 08 (2H, t, J = 8.6 Hz), 7.23-7.25 (2H, m), 7.92 (1H, brs), 8.03 (1H, s), 8.54 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.8 Hz), -110.6 (1F, s), −107.4 (2F, s), −103 .6 (1F, t, J = 6.8 Hz).
Example-20

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.088 g, 0.50 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.163 g, 0.50 mmol) in dichloromethane (1 mL) was ice-cooled, A solution of triethylamine (0.076 g, 0.75 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give colorless oily 3-difluoromethyl. -N- [5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (227 mg, yield: 94 %). Mp: 170.9-172.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.72 (1H, t, J = 54.1 Hz), 6.74-6.87 (5H, m), 7. 97 (1H, brs), 8.05 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, d, J = 6.9 Hz), −107.5 (2F, s), −107.3 (2F, s), −103 .0 (1F, t, J = 6.4 Hz).
Example-21

Triethylamine (300 mg, 2.96 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) in dichloromethane (10 mL), and the mixture was ice-cooled, and then 4-amino-5. A solution of-(3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (540 mg, 1.51 mmol) in dichloromethane (5 mL) was added. After stirring this solution at room temperature for 3 hours, a saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 1, 10 mL × 2). The combined organic layers were 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 a colorless solid N- [ 5- (3,4-Dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (586 mg, yield: 75 %). Mp: 88 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.72 (1H, t, J = 54.1 Hz), 6.72-6.80 (2H, m), 7. 07 (1H, dd, J = 8.3 and 2.0 Hz), 7.39 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.3 Hz), 7.94 (1H , Brs), 8.04 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 7.1 Hz), −107.4 (2F, s), −103.3 (1F, t, J = 7) .1 Hz).
Example-22

Triethylamine (300 mg, 2.96 mmol) was added to a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (390 mg, 2.00 mmol) in dichloromethane (2.5 mL), and the mixture was ice-cooled. A solution of -5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole (500 mg, 1.50 mmol) in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate solution (30 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were 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 = 2/3) to give a colorless solid N- [ 5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (538 mg, yield: 73%) was obtained. . Mp: 82-87 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.05 (3H, t, J = 7.5 Hz), 2.35 (2H, q, J = 7.5 Hz), 3.95 (3H, s), 6.75 (1H, t, J = 54.3 Hz), 6.96 (1H, dd, J = 8.0 and 2.0 Hz), 7.10-7.39 (6H, m), 7.95 (1H , Brs), 8.05 (1H, s), 8.40 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-107.5 (2F, s).
Example-23

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.088 g, 0.50 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.179 g, 0.50 mmol) in dichloromethane (1 mL) was ice-cooled, A solution of triethylamine (0.076 g, 0.75 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give colorless oily 3-difluoromethyl. -1-methyl-N- [5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] pyrazole-4-carboxamide (245 mg, yield: 95 %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.70 (1H, t, J = 54.2 Hz), 6.70-6.77 (2H, m), 7. 39 (2H, d, J = 8.1 Hz), 7.65 (2H, d, J = 8.1 Hz), 7.95 (1H, brs), 8.04 (1H, s), 8.55 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, d, J = 6.9 Hz), −107.2 (2F, s), −103.2 (1F, t, J = 7) .0Hz), -62.9 (3F, s).
Example-24

To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.088 g, 0.50 mmol) in toluene (3 mL) was added thionyl chloride (1 mL) and refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was distilled off from the reaction solution under reduced pressure to obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. A solution of 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1- (2,4,6-trifluorophenyl) pyrazole (0.213 g, 0.50 mmol) in dichloromethane (1 mL) was added. After ice cooling, a solution of triethylamine (0.076 g, 0.75 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (25 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give colorless oil N- [ 5- {3,5-bis (trifluoromethyl) phenyl} -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide ( 238 mg, yield: 82%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.67 (1H, t, J = 54.3 Hz), 6.74-6.80 (2H, m), 7. 73 (2H, s), 7.89 (1H, s), 7.95 (1H, brs), 8.06 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.9 Hz), −106.9 (2F, s), −102.3 (1F, s), −63 .2 (6F, s).
Example-25

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.181 g, 1.03 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. A mixed solution of 4-amino-1-methyl-5- (3-trifluoromethylphenyl) pyrazole (0.250 g, 1.03 mmol), triethylamine (0.156 g, 1.54 mmol) and dichloromethane (2 mL) was ice-cooled. After that, a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oily substance obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-1-methyl-N- [1-methyl-5- (3- (Trifluoromethylphenyl) pyrazol-4-yl] pyrazole-4-carboxamide (0.139 g, yield: 34%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.81 (3H, s), 3.91 (3H, s), 6.65 (1H, t, J = 54.2 Hz), 7.58-7. 75 (5H, m), 7.99 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.7 (2F, s), -62.9 (3F, s).
Example-26

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.216 g, 1.23 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. After cooling a mixed solution of 4-amino-5- (3-methoxyphenyl) -1-methylpyrazole (0.250 g, 1.23 mmol), triethylamine (0.187 g, 1.85 mmol) and dichloromethane (2 mL) with ice. A solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3-methoxyphenyl) -1-methylpyrazole as a white solid. -4-yl] -1-methylpyrazole-4-carboxamide (0.315 g, yield: 71%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.80 (3H, s), 3.84 (3H, s), 3.91 (3H, s), 6.69 (1H, t, J = 54. 2 Hz), 6.89 (1 H, brs), 6.95 (1 H, d, J = 7.5 Hz), 7.01 (1 H, ddd, J = 8.4, 2.6 and 0.9 Hz), 7. 43 (1H, dd, J = 8.4 and 7.5 Hz), 7.78 (1H, brs), 7.96 (1H, s), 8.19 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.2 (2F, s).
Example-27

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.462 g, 2.62 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. After cooling a mixed solution of 4-amino-5- (3-fluorophenyl) -1-methylpyrazole (0.502 g, 2.63 mmol), triethylamine (0.399 g, 3.94 mmol) and dichloromethane (2 mL) with ice. A solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3-fluorophenyl) -1-methylpyrazole-4- Yl] -1-methylpyrazole-4-carboxamide (0.504 g, yield: 56%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.81 (3H, s), 3.92 (3H, s), 6.68 (1H, t, J = 54.2 Hz), 7.09-7. 20 (3H, m), 7.47-7.52 (1H, m), 7.79 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.3 (1F, s), -107.9 (2F, s).
Example-28

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.127 g, 0.721 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. A mixed solution of 4-amino-5- (3,4-difluorophenyl) -1-methylpyrazole (0.150 g, 0.717 mmol), triethylamine (0.109 g, 1.08 mmol) and dichloromethane (2 mL) was ice-cooled. After that, a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oily substance obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3,4-difluorophenyl) -1- Methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.264 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.79 (3H, s), 3.92 (3H, s), 6.68 (1H, t, J = 54.2 Hz), 7.11-7. 15 (1H, m), 7.20-7.25 (1 H, m), 7.32 (1 H, dt, J = 10.0 and 8.4 Hz), 7.74 (1 H, brs), 7.9 ( 1H, s), 8.13 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-135.7 (1F, d, J = 21.3 Hz), −135.5 (1F, d, J = 21.3 Hz), −107.5 (2F) , S).
Example-29

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.096 g, 0.545 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. Mixture of 4-amino-5- (4-chloro-3-trifluoromethylphenyl) -1-methylpyrazole (0.150 g, 0.544 mmol), triethylamine (0.083 g, 0.82 mmol) and dichloromethane (2 mL) The solution was ice-cooled, and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give N- [5- (4-chloro-3-trifluoromethylphenyl) -1-methyl as a white solid. Pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.229 g, yield: 97%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.80 (3H, s), 3.92 (3H, s), 6.67 (1H, t, J = 54.2 Hz), 7.51 (1H, dd, J = 8.2 and 1.8 Hz), 7.67 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 1.8 Hz), 7.73 (1H, brs), 7.9 (1H, s), 8.13 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.3 (2F, s), -63.0 (3F, s).
Example-30

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.528 g, 3.00 mmol), toluene (15 mL) and thionyl chloride (2.0 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. After cooling a mixed solution of 4-amino-5- (3-bromophenyl) -1-methylpyrazole (0.756 g, 3.00 mmol), triethylamine (0.455 g, 4.50 mmol) and dichloromethane (8 mL) with ice. A solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (8 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give N- [5- (3-bromophenyl) -1-methylpyrazol-4-yl] as a white solid. -3-Difluoromethyl-1-methylpyrazole-4-carboxamide (1.209 g, yield: 98%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.80 (3H, s), 3.92 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.39 (1H, t, J = 8.0 Hz), 7.54 (1H, s), 7.61 (1H, d, J = 8.0 Hz), 7. 77 (1H, brs), 7.98 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.8 (2F, s).
Example-31

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.528 g, 3.00 mmol), toluene (15 mL) and thionyl chloride (2.0 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. After cooling a mixed solution of 4-amino-5- (4-bromophenyl) -1-methylpyrazole (0.756 g, 3.00 mmol), triethylamine (0.455 g, 4.50 mmol) and dichloromethane (8 mL) with ice. A solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (8 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give N- [5- (4-bromophenyl) -1-methylpyrazol-4-yl] as a white solid. -3-Difluoromethyl-1-methylpyrazole-4-carboxamide (1.224 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.79 (3H, s), 3.92 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 7.25 (2H, d, J = 8.5 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.74 (1H, brs), 7.97 (1H, s), 8.14 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.7 (2F, s).
Example-32

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.124 g, 0.70 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. Mixture of 4-amino-5- (2,3-dihydroinden-5-yl) -1-methylpyrazole (0.15 g, 0.70 mmol), triethylamine (0.106 g, 1.05 mmol) and dichloromethane (2 mL) The solution was ice-cooled, and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (2,3-dihydroinden-5-yl as a white solid]. ) -1-Methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.252 g, yield: 97%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.14 (2H, quintet, J = 7.5 Hz), 2.98 (4H, dt, J = 7.5 and 4.2 Hz), 3.80 (3H, s ), 3.91 (3H, s), 6.70 (1H.t, J = 54.2 Hz), 7.11 (1H, d, J = 7.6 Hz), 7.21 (1H, s), 7.35 (1H, d, J = 7.6 Hz), 7.78 (1H, brs), 7.95 (1H, s), 8.19 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.5 (2F, s).
Example-33

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.117 g, 0.66 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. A mixed solution of 4-amino-5- (3,4-ethylenedioxyphenyl) -1-methylpyrazole (0.153 g, 0.66 mmol), triethylamine (0.100 g, 0.99 mmol) and dichloromethane (2 mL) was added. After cooling with ice, a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oily substance obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3,4-ethylenedioxyphenyl)- 1-methylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.257 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.78 (3H, s), 3.91 (3H, s), 4.29-4.34 (4H, m), 6.72 (1H, t, J = 54.2 Hz), 6.83 (1H, dd, J = 8.2 and 2.0 Hz), 6.88 (1H, d, J = 2.0 Hz), 6.99 (1H, d, J = 8) .2 Hz), 7.76 (1H, brs), 7.95 (1H, s), 8.15 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.5 (2F, s).
Example-34

N- [5- (3-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was purged with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%) and cyclohexanethiol (0.078 g 0.67 mmol) were added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give N- [5- (3-cyclohexylthiophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl- as a white solid. 1-methylpyrazole-4-carboxamide (0.254 g, yield: 93%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.22-1.63 (6H, m), 1.75-1.79 (2H, m), 1.97-2.02 (2H, m), 3.13-3.20 (1H, m), 3.79 (3H, s), 3.91 (3H, s), 6.68 (1H, t, J = 54.2 Hz), 7.20 ( 1H, d, J = 7.5 Hz), 7.36 (1H, s), 7.40 (1H, t, J = 7.5 Hz), 7.47 (2H, dt, J = 8.0 and 1.6 Hz) ), 7.74 (1H, brs), 7.96 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.2 (2F, s).
Example-35

N- [5- (3-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was degassed with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), α-toluenethiol (0.083 g 0.67 mmol) was added. . This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography (ethyl acetate) to give N- [5- (3-benzylthiophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl as a yellow-orange solid. -1-Methylpyrazole-4-carboxamide (0.184 g, yield: 66%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.66 (3H, s), 3.91 (3H, s), 4.15 (2H, s), 6.68 (1H, t, J = 54. 1 Hz), 7.16-7.31 (7H, m), 7.37-7.42 (2H, m), 7.73 (1H, brs), 7.95 (1H, s), 8.15 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.0 (2F, s).
Example-36

N- [5- (3-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was purged with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), 2-methyl-1-butanethiol (0.070 g, 0 .67 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-1-methyl-N- {1-methyl-5- [3- (2-methylbutylthio) as a tan oil. ) Phenyl] pyrazol-4-yl} pyrazole-4-carboxamide (0.242 g, yield: 92%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.89 (3H, t, J = 7.4 Hz), 1.02 (3H, d, J = 6.6 Hz), 1.22-1.33 (1H , M), 1.48-1.58 (1H, m), 1.64-1.74 (1H, m), 2.78 (1, dd, J = 12.4 and 7.5 Hz), 2.96. (1H, dd, J = 12.4 and 5.9 Hz), 3.79 (3H, s), 3.91 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 7.11 -7.16 (1H, m), 7.27 (1H, s), 7.38-7.43 (1H, m), 7.76 (1H, brs), 7.96 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.2 (2F, s).
Example-37

N- [5- (3-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was degassed with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), 3-methyl-1-butanethiol (0.070 g, 0 .67 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3-isopentylthiophenyl) -1-methylpyrazol-4-yl as a tan oil. ] -1-methylpyrazole-4-carboxamide (0.250 g, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.91 (6H, d, J = 6.6 Hz), 1.52-1.58 (2H, m), 1.72 (1H, m), 2. 93-2.97 (2H, m), 3.79 (3H, s), 3.91 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 7.15 (1H, dt, J = 6.8 and 1.7 Hz), 7.27 (1H, s), 7.37-7.44 (2H, m), 7.76 (1H, brs), 7.96 (1H, s) , 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.1 (2F, s).
Example-38

N- [5- (4-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was purged with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%) and cyclohexanethiol (0.078 g, 0.67 mmol) were added. . This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give N- [5- (4-cyclohexylthiophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl- as a white solid. 1-methylpyrazole-4-carboxamide (0.246 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.27-1.67 (6H, m), 1.79-1.82 (2H, m), 2.03 to 2.06 (2H, m), 3.18-3.26 (1H, m), 3.80 (3H, s), 3.91 (3H, s), 6.67 (1H, t, J = 54.2 Hz), 7.27 ( 2H, d, J = 8.4 Hz), 7.49 (2H, d, J = 8.4 Hz), 7.75 (1H, brs), 7.97 (1H, s), 8.17 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.0 (2F, s).
Example-39

N- [5- (4-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was degassed with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), α-toluenethiol (0.083 g, 0.67 mmol). added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give N- [5- (4-benzylthiophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl as a yellow-orange solid. -1-methylpyrazole-4-carboxamide (0.187 g, yield: 68%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.77 (3H, s), 3.92 (3H, s), 4.19 (2H, s), 6.67 (1H, t, J = 54. 2 Hz), 7.24-7.36 (7 H, m), 7.41 (2 H, d, J = 8.4 Hz), 7.74 (1 H, brs), 7.96 (1 H, s), 8 .16 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.9 (2F, s).
Example-40

N- [5- (4-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was degassed with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), 2-methyl-1-butanethiol (0.070 g, 0 .67 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-1-methyl-N- {1-methyl-5- [4- (2-methylbutylthio) as a tan oil. ) Phenyl] pyrazol-4-yl} pyrazole-4-carboxamide (0.239 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.93 (3H, t, J = 7.4 Hz), 1.05 (3H, d, J = 6.7 Hz), 1.26 to 1.36 (1H , M), 1.52-1.62 (1H, m), 1.66-1.78 (1H, m), 2.81 (1, dd, J = 12.5 and 7.5 Hz), 3.01 (1H, dd, J = 12.5 and 5.8 Hz), 3.79 (3H, s), 3.91 (3H, s), 6.70 (1H, t, J = 54.2 Hz), 7.26 (2H, d, J = 8.4 Hz), 7.41 (2H, d.J = 8.4 Hz), 7.75 (1H, brs), 7.96 (1H, s), 8.16 (1H , S). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.1 (2F, s).
Example-41

N- [5- (4-Bromophenyl) -1-methylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.609 mmol), N, N-diisopropyl A mixed solution of ethylamine (0.158 g, 1.22 mmol) and 1,4-dioxane (2 mL) was purged with argon, and then tris (dibenzylideneacetone) dipalladium (0) (0.014 g, 0.015 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.018 g, 0.031 mmol, 5 mol%), 3-methyl-1-butanethiol (0.070 g, 0 .67 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (4-isopentylthiophenyl) -1-methylpyrazol-4-yl as a tan oil. ] -1-methylpyrazole-4-carboxamide (0.234 g, yield: 89%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.95 (6H, d, J = 6.6 Hz), 1.56-1.62 (2H, m), 1.77 (1H, m), 2. 97-3.01 (2H, m), 3.79 (3H, s), 3.92 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 7.27 (2H, d, J = 8.4 Hz), 7.41 (2H, d, J = 8.4 Hz), 7.75 (1H, brs), 7.96 (1H, s), 8.17 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.0 (2F, s).
Example-42

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.176 g, 1.00 mmol), toluene (3 mL), and thionyl chloride (1.0 mL) was refluxed for 30 minutes, and then an excess was obtained under reduced pressure. The thionyl chloride and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.357 g, 1.00 mmol), triethylamine (0.152 g, 1.50 mmol), A mixed solution of dichloromethane (2 mL) was ice-cooled, and a dichloromethane solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was added, followed by stirring at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give 3-difluoromethyl-1-methyl-N- {5- (3-tri Fluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazole-4-carboxamide (0.110 g, yield: 22%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93 (3H, s), 6.67 (1H, t, J = 54.2 Hz), 6.74 (2H, dd, J = 8.4 and 7.4 Hz) ), 7.44 (1H, d, J = 7.8 Hz), 7.50-7.54 (2H, m), 7.65 (1H, d, J = 7.8 Hz), 7.96 (1H , Brs), 8.04 (1H, s), 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 7.0 Hz), −107.4 (2F, s), −103.2 (1F, t, J = 7) .0Hz), -63.1 (3F, s).
Example-43

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.135 g, 0.767 mmol), toluene (3 mL), and thionyl chloride (1.0 mL) was refluxed for 30 minutes, and then an excess was obtained under reduced pressure. The thionyl chloride and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.250 g, 0.769 mmol), triethylamine (0.117 g, 1.16 mmol), A mixed solution of dichloromethane (1 mL) was ice-cooled, and a dichloromethane solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with chloroform (25 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid 3 -Difluoromethyl-N- {5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -1-methylpyrazole-4-carboxamide (0.351 g Yield: 95%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.70 (1H, t, J = 54.2 Hz), 6.75 (2H, m), 6.98-7. 02 (1H, m), 7.11 (1H, ddd, J = 10.0, 7.4 and 2.0 Hz), 7.19 (1 H, dt, J = 10.0 and 8.3 Hz), 7.92 (1 H , Brs), 8.04 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-135.4 (1F, d, J = 21.3 Hz), -135.0 (1F, d, J = 21.3 Hz), -114.5 (2F , D, J = 7.0 Hz), −107.2 (2F, s), −103.2 (1F, t, J = 7.0 Hz).
Example-44

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.113 g, 0.642 mmol), toluene (3 mL), and thionyl chloride (1.0 mL) was refluxed for 30 minutes, and then an excess was obtained under reduced pressure. The thionyl chloride and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.250 g, 0.638 mmol), triethylamine (0.097 g, 0 969 mmol) and dichloromethane (1 mL) were ice-cooled, and a dichloromethane solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with chloroform (25 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid N -{5- (4-Chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.335 g, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.69 (1H, t, J = 54.2 Hz), 6.76 (2H, m), 7.34 (1H, dd, J = 8.3 and 2.0 Hz), 7.52 (1H, d, J = 8.3 Hz), 7.63 (1H, d, J = 2.0 Hz), 7.92 (1H, brs), 8.05 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.9 Hz), −106.9 (2F, s), −102.7 (1F, t, J = 6) .9 Hz), -63.2 (3F, s).
Example-45

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.479 g, 2.72 mmol), toluene (5 mL), and thionyl chloride (1.0 mL) was refluxed for 30 minutes, and then an excess was obtained under reduced pressure. The thionyl chloride and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (1.00 g, 2.72 mmol), triethylamine (0.413 g, 4.07 mmol), dichloromethane ( 4 mL) was ice-cooled, and a dichloromethane solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with chloroform (25 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid N -{5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (1.429 g, yield) Rate: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.71 (1H, t, J = 54.2 Hz), 6.74 (2H, m), 7.17 (1H, d, J = 7.7 Hz), 7.25 (1H, d, J = 7.7 Hz), 7.43 (1H, m), 7.52 (1H, ddd, J = 8.0, 1.9and1) .1 Hz), 7.95 (1H, brs), 8.03 (1H, s), 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 7.0 Hz), −107.4 (2F, s), −103.4 (1F, t, J = 7) .0Hz).
Example-46

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.479 g, 2.72 mmol), toluene (5 mL), and thionyl chloride (1.0 mL) was refluxed for 30 minutes, and then an excess was obtained under reduced pressure. The thionyl chloride and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (1.00 g, 2.72 mmol), triethylamine (0.413 g, 4.07 mmol), dichloromethane ( 4 mL) was ice-cooled, and a dichloromethane solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was added, followed by stirring at room temperature for 24 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL) and extracted with chloroform (25 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting brown oil was purified by silica gel chromatography (hexane / ethyl acetate = 1/2) to give a white solid N -{5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (1.429 g, yield) Rate: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.71 (1H, t, J = 54.1 Hz), 6.73 (2H, m), 7.12 (2H, d, J = 8.4 Hz), 7.52 (2H, d, J = 8.4 Hz), 7.93 (1H, brs), 8.02 (1H, s), 8.53 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.8 Hz), −107.3 (2F, s), −103.5 (1F, t, J = 6) .8 Hz).
Example-47

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.107 g, 0.61 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. 4-amino-5- (2,3-dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazole (0.20 g, 0.61 mmol), triethylamine (0.093 g, 0 .92 mmol) and dichloromethane (2 mL) were cooled with ice, and then a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oil obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (2,3-dihydroinden-5-yl as a white solid]. ) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.201 g, yield: 68%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.07 (2H, quintet, J = 7.5 Hz), 2.89 (4H, dt, J = 10.8 and 7.5 Hz), 3.93 (3H, s ), 6.71 (2H, dd, J = 8.4 and 7.2 Hz), 6.72 (1H.t, J = 54.2 Hz), 6.95 (1H, d, J = 7.5 Hz), 7 .12 (1H, s), 6.18 (1H, d, J = 7.5 Hz), 7.96 (1H, brs), 8.00 (1H, s), 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.7 Hz), −108.2 (2F, s), −104.4 (1F, t, J = 6) .7 Hz).
Example-48

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (0.102 g, 0.58 mmol), toluene (3 mL) and thionyl chloride (0.5 mL) was refluxed for 30 minutes, and then the solvent was removed under reduced pressure. By completely distilling off, 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride was obtained. This was used in the next reaction without purification. 4-amino-5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.20 g, 0.58 mmol), triethylamine (0.088 g, 0.87 mmol) ) And dichloromethane (2 mL) were cooled with ice, and then a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added. The mixed solution was stirred at room temperature for 24 hours. The brown oily substance obtained by concentrating the reaction solution under reduced pressure was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3,4-ethylenedioxyphenyl)- 1-methylpyrazol-4-yl] -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxamide (0.284 g, yield: 98%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.93 (3H, s), 4.23-4.28 (4H, m), 6.73 (1H, t, J = 54.1 Hz), 6. 70-6.76 (4H, m), 6.85 (1H, d, J = 8.3 Hz), 7.93 (1H, brs), 8.00 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.6 Hz), −108.1 (2F, s), −104.2 (1F, t, J = 6) .6 Hz).
Example-49

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (98 mg, 0.56 mmol), toluene (3 mL), and thionyl chloride (0.5 mL) was refluxed for 30 minutes, followed by excess chloride under reduced pressure. Thionyl and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-chloro-2,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.20 g, 0.56 mmol), triethylamine (0.085 g, 0 .83 mmol) and dichloromethane (2 mL) were ice-cooled, and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added, followed by stirring at room temperature for 24 hours. After completion of the reaction, the brown oil obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give N- {5- (4-chloro-2,5- Difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.256 g, yield: 89%) was obtained. It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.72 (1H, t, J = 54.1 Hz), 6.73-6.78 (2H, m), 7. 05 (1H, dd, J = 8.6 and 6.0 Hz), 7.21 (1 H, dd, J = 8.6 and 6.0 Hz), 7.88 (1 H, brs), 8.04 (1 H, s), 8.52 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-118.9 (1F, d, J = 15.2 Hz), -116.3 (1F, m), -114.8 (2F, s), −107 .6 (2F, s), -103.2 (1F, t, J = 6.8 Hz).
Example-50

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (69 mg, 0.39 mmol), toluene (3 mL), and thionyl chloride (0.5 mL) was refluxed for 30 minutes, followed by excess chloride under reduced pressure. Thionyl and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazole (0.15 g, 0.39 mmol), triethylamine (0.059 g, 0.58 mmol) and dichloromethane (2 mL) were ice-cooled, and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added, followed by stirring at room temperature for 24 hours. After completion of the reaction, the brown oil obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give N- {5- (4-chloro-2,5- Difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.198 g, yield: 94%) Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.42 (3H, t, J = 7.0 Hz), 3.93 (3H, s), 4.00 (2H, q, J = 7.0 Hz), 6.47 (1H, d, J = 9.4 Hz), 6.72 (1H, t, J = 54.1 Hz), 7.03 (1H, dd, J = 8.6 and 6.1 Hz), 7.20 (1H, dd, J = 8.6 and 6.1 Hz), 7.87 (1H, brs), 8.02 (1H, s), 8.47 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-119.3 (1F, d, J = 15.1 Hz), -118.0 (2F, s), -116.2 (1F, m), −107 .8 (2F, s).
Example-51

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (69 mg, 0.39 mmol), toluene (3 mL), and thionyl chloride (0.5 mL) was refluxed for 30 minutes, followed by excess chloride under reduced pressure. Thionyl and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.15 g, 0.39 mmol), triethylamine (0.059 g , 0.58 mmol) and dichloromethane (2 mL) were ice-cooled, a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added, and the mixture was stirred at room temperature for 24 hours. . After completion of the reaction, the brown oil obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give N- {5- (4-chloro-2-ethoxy- 5-Fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.205 g, yield: 97%) Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24 (3H, t, J = 7.0 Hz), 3.83-4.03 (2H, m), 3.94 (3H, s), 6. 58-6.95 (5H, m), 7.96 (1H, brs), 8.00 (1H, s), 8.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.7 (1F, s), -114.5 (2F, m), -108.5 (2F, m), -104.2 (1F, t , J = 6.7 Hz).
Example-52

A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (28 mg, 0.16 mmol), toluene (2 mL), and thionyl chloride (0.5 mL) was refluxed for 30 minutes, followed by excess chloride under reduced pressure. Thionyl and the solvent were completely distilled off to obtain 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride. This was used in the next reaction without purification. 4-amino-5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazole (643 mg, 0.16 mmol), triethylamine (0.024 g, 0.24 mmol) and dichloromethane (2 mL) were ice-cooled, and a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride in dichloromethane (2 mL) was added, followed by stirring at room temperature for 24 hours. After completion of the reaction, the brown oil obtained by concentration under reduced pressure was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give N- {5- (4-chloro-2-ethoxy- 5-fluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (76 mg, yield: 86%). Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 7.0 Hz), 3.94 (3H, s), 3.99 (4H, q, J = 7.0 Hz), 6.44 (2H, brs), 6.74 (1H, t, J = 54.1 Hz), 6.90 (1H, d, J = 9) .0Hz), 6.94 (1H, d, J = 6.2 Hz), 7.97 (1H, brs), 7.98 (1H, s), 8.49 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.8 (1F, s), -117.6 (2F, s), -108.9 (2F, m).
Example-53

N- [5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), cyclohexanethiol (0 0.061 g, 0.525 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give white solid N- [5- (3-cyclohexylthiophenyl) -1- (2,4,6-trifluorophenyl) pyrazole- 4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.263 g, yield: 99%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21-1.61 (6H, m), 1.70-1.84 (4H, m), 2.93-3.00 (1H, m), 3.93 (3H, s), 6.57-6.84 (3H, m), 7.16 (1H, d, J = 7.6 Hz), 7.19 (1H, s), 7.31 ( 1H, t, J = 7.6 Hz), 7.39 (1H, ddd, J = 7.8, 1.7 and 1.3 Hz), 7.93 (1H, brs), 8.01 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 6.8 Hz), −107.8 (2F, s), −103.8 (1F, t, J = 6) .8 Hz).
Example-54

N- [5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), α-toluenethiol (0.065 g, 0.523 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give yellow-orange solid N- [5- (3-benzylthiophenyl) -1- (2,4,6-trifluorophenyl) pyrazole. -4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.253 g, yield: 93%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.93 (3H, s), 4.03 (2H, s), 6.57-6.84 (3H, m), 7.05-7.27 ( 9H, m), 7.92 (1H, brs), 8.01 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 6.7 Hz), −107.7 (2F, s), −103.7 (1F, t, J = 6) .7 Hz).
Example-55

N- [5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), 2-methyl- 1-Butanethiol (0.054 g, 0.518 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-1-methyl-N- {5- [3- (2-methylbutylthio) phenyl]- 1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazole-4-carboxamide (0.255 g, yield: 98%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.86 (3H, t, J = 7.4 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.16-1.27 (1H , M), 1.42-1.60 (2H, m), 2.64 (1, dd, J = 12.4 and 7.3 Hz), 2.81 (1H, dd, J = 12.4 and 5.6 Hz) , 3.93 (3H, s), 6.58-6.85 (3H, m), 7.05 (1H, d, J = 7.1 Hz), 7.13 (1H, s), 7.26 -7.33 (2H, m), 7.95 (1H, brs), 8.01 (1H, s), 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.7 Hz), −107.8 (2F, s), −103.8 (1F, t, J = 6) .7 Hz).
Example-56

N- [5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol), 1,4-dioxane (2 mL) was degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), 3-methyl- 1-Butanethiol (0.054 g, 0.518 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (3-isopentylthiophenyl) -1- (2, 4, 6 -Trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.249 g, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.88 (6H, d, J = 6.6 Hz), 1.42-1.48 (2H, m), 1.67 (1H, m), 2. 80-2.84 (2H, m), 3.93 (3H, s), 6.57-6.84 (3H, m), 7.04-7.06 (1H, m), 7.14 ( 1H, s), 7.28-7.32 (2H, m), 7.95 (1H, brs), 8.01 (1H, s), 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.8 Hz), −107.8 (2F, s), −103.7 (1F, t, J = 6) .8 Hz).
Example-57

N- [5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol), 1,4-dioxane (2 mL) was degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), cyclohexanethiol (0 0.061 g, 0.525 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate), and white solid N- [5- (4-cyclohexylthiophenyl) -1- (2,4,6-trifluorophenyl) pyrazole- 4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.244 g, yield: 91%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25-1.65 (6H, m), 1.75-1.80 (2H, m), 1.97-2.00 (2H, m), 3.14-3.20 (1H, m), 3.93 (3H, s), 6.56-6.83 (3H, m), 7.14 (2H, d, J = 8.2 Hz), 7.33 (2H, d, J = 8.2 Hz), 7.92 (1H, brs), 8.02 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.7 Hz), −107.6 (2F, s), −103.9 (1F, t, J = 6) .7 Hz).
Example-58

N- [5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), α-toluenethiol (0.065 g, 0.523 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give N- [5- (4-benzylthiophenyl) -1- (2,4,6-trifluorophenyl) pyrazole as a yellow-orange solid. -4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.247 g, yield: 91%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.94 (3H, s), 4.13 (2H, s), 6.55-6.82 (3H, m), 7.11 (2H, d, J = 8.3 Hz), 7.24-7.29 (7H, m), 7.92 (1H, brs), 8.01 (1H, s), 8.54 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.8 Hz), −107.5 (2F, s), −103.9 (1F, t, J = 6) .8 Hz).
Example-59

N- [5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), 2-methyl- 1-Butanethiol (0.054 g, 0.518 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-1-methyl-N- {5- [4- (2-methylbutylthio) phenyl]- 1- (2,4,6-trifluorophenyl) pyrazol-4-yl} pyrazole-4-carboxamide (0.246 g, yield: 94%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.90 (3H, t, J = 7.4 Hz), 1.02 (3H, d, J = 6.6 Hz), 1.22-1.33 (1H M), 1.48-1.53 (1H, m), 1.63-1.71 (1, m), 2.76 (1H, dd, J = 12.4 and 7.5 Hz), 2.95. (1H, dd, J = 12.4 and 5.8 Hz), 3.93 (3H, s), 6.57-6.84 (3H, m), 7.12 (2H, d, J = 8.3 Hz) 7.26 (2H, d, J = 8.3 Hz), 7.93 (1H, brs), 8.01 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.8 Hz), −107.7 (2F, s), −104.0 (1F, t, J = 6) .8 Hz).
Example-60

N- [5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (0.250 g, 0.475 mmol), N, N-diisopropylethylamine (0.123 g, 0.952 mmol) and 1,4-dioxane (2 mL) were degassed with argon, and tris (dibenzylideneacetone) dipalladium (0 ) (0.011 g, 0.012 mmol, 2.5 mol%), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.014 g, 0.024 mmol, 5 mol%), 3-methyl- 1-Butanethiol (0.054 g, 0.518 mmol) was added. This mixed solution was refluxed for 15 hours. After completion of the reaction, the mixture was cooled to room temperature, insolubles were filtered off, and concentrated under reduced pressure. The obtained crude product was purified by silica gel chromatography (ethyl acetate) to give 3-difluoromethyl-N- [5- (4-isopentylthiophenyl) -1- (2, 4, 6 -Trifluorophenyl) pyrazol-4-yl] -1-methylpyrazole-4-carboxamide (0.235 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.92 (6H, d, J = 6.6 Hz), 1.51-1.57 (2H, m), 1.72 (1H, m), 2. 91-2.95 (2H, m), 3.93 (3H, s), 6.57-6.84 (3H, m), 7.14 (2H, d, J = 8.3 Hz), 7. 26 (2H, d, J = 8.3 Hz), 7.93 (1H, brs), 8.01 (1H, s), 8.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 6.8 Hz), −107.6 (2F, s), −104.0 (1F, t, J = 6) .8 Hz).
Reference Example-1

To a solution of ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate (77.2 g, 378 mmol) in ethanol (200 mL) was added 10% aqueous sodium hydroxide (200 mL), and the mixture was refluxed for 1 hr. 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 = 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).
To a solution of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (1.94 g, 11.0 mmol) in toluene (10 mL) was added thionyl chloride (5 mL), refluxed for 30 minutes, and then using a Dean-Stark tube. Toluene and excess thionyl chloride were removed. Further, the solvent was completely removed from the reaction solution under reduced pressure 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 = 53.5 Hz), 8.08 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-117.1 (2F, s).
Reference example-2

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. Water (200 mL) was added to the reaction solution, 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), toluene (10 mL) and thionyl chloride (5 mL) was refluxed for 1 hour, and then toluene was used using a Dean-Stark tube. And excess thionyl chloride was removed. Further, the solvent was completely removed from the reaction solution under reduced pressure to obtain brown oily 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (812 mg, yield: 95%). 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).
Reference example-3

  A mixture of ethyl benzoyl acetate (25.0 g, 130 mmol), triethyl orthoformate (38.6 g, 261 mmol) and acetic anhydride (25 mL, 265 mmol) was stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C. over 5 hours. The solution returned to room temperature was purified by distillation under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylenebenzoyl acetate (23.0 g, yield: 71%).

  A solution of ethyl 2-ethoxymethylenebenzoyl acetate (25.0 g, 101 mmol) in ethanol (25 mL) was added dropwise while refluxing a mixed solution of 35% aqueous methylhydrazine (20.0 g, 152 mmol) and ethanol (25 mL). Stir for another 5 minutes. The solution was returned to room temperature, 2N hydrochloric acid (200 mL) was added, acidified with further addition of concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL × 1, 50 mL × 2). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting yellow oil was purified by silica gel column chromatography (hexane / ethyl acetate = 4 / 1-1 / 1) to give a yellow oil. Ethyl 1-methyl-3-phenylpyrazole-4-carboxylate (17.5 g, yield: 75%) and ethyl 1-methyl-5-phenylpyrazole-4-carboxylate (3.02 g, yield) Rate: 13%).

1-methyl-3-phenylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.27 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.24 (2H, q, J = 7.1 Hz), 7.33-7.49 (3H, m), 7.74-7.78 (2H, m), 7.96 (1H, s).
1-methyl-5-phenylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.17 (3H, t, J = 7.1 Hz), 3.73 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 7.33-7.49 (5H, m), 7.99 (1H, s).
To a solution of ethyl 1-methyl-5-phenylpyrazole-4-carboxylate (3.00 g, 13.0 mmol) in ethanol (15 mL) was added 10% aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature for 1.5 hours. Thereafter, the mixture was refluxed for 1 hour. Concentrated hydrochloric acid was added to the reaction solution returned to room temperature to make it acidic, water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 1, 50 mL × 2). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then dried under reduced pressure to give colorless solid 1-methyl-5-phenylpyrazole-4-carboxylic acid (2.43 g, Yield: 92%) was obtained. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.65 (3H, s), 7.43-7.51 (5H, m), 7.89 (1H, s).
Reference example-4

Thionyl chloride (5 mL) was added to a toluene (20 mL) solution of 1-methyl-5-phenylpyrazole-4-carboxylic acid (2.40 g, 11.9 mmol), and the mixture was refluxed for 30 minutes. Then, using a Dean-Stark tube. Toluene and excess thionyl chloride were distilled off. Furthermore, the brown solid was obtained by removing a solvent etc. under reduced pressure. This was dissolved in acetone (20 mL) and ice-cooled, and then a solution of sodium azide (1.50 g, 23.1 mmol) in water (5 mL) was slowly added. Furthermore, after stirring for 10 minutes at the same temperature, water (100 mL) was added and extracted with toluene (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure while paying attention to the extent that no solid precipitated. This solution was added dropwise to a toluene (10 mL) solution of 2,2,2-trichloroethanol (1.90 g, 12.7 mmol) in a reflux state. After further refluxing for 5 hours, the reaction solution returned to room temperature was concentrated under reduced pressure to obtain a brown oil. This was dissolved in toluene (100 mL) and extracted with 10% aqueous sodium hydroxide / ethanol (4/1, 50 mL × 3). The aqueous layers were combined and extracted again with toluene (50 mL × 2), and the organic layers were combined and washed with saturated brine (50 mL). This was dried over anhydrous magnesium sulfate and dried under reduced pressure to give 2,2,2-trichloroethyl N- (1-methyl-5-phenylpyrazol-4-yl) carbamate (2.70 g, yield) as a yellow solid. : 65%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.78 (3H, s), 4.78 (2H, s), 6.35 (1H, brs), 7.34-7.38 (2H, m) 7.47-7.53 (3H, m), 7.83 (1H, brs).
To a solution of 2,2,2-trichloroethyl N- (1-methyl-5-phenylpyrazol-4-yl) carbamate (2.68 g, 7.69 mmol) in acetic acid (90 mL) was added water (10 mL) and zinc ( 6.0 g) was added and stirred at room temperature for 30 minutes. Zinc was removed by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting black oil was purified by silica gel column chromatography (ethyl acetate, 1% triethylamine added) to give 4-amino-1 as a brown oil. -Methyl-5-phenylpyrazole (785 mg, yield: 59%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ2.73 (2H, brs), 3.76 (3H, s), 7.24 (1H, s), 7.35-7.53 (5H, m) .
Reference Example-5

  While stirring a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144 mmol) at 60 ° C., a solution of 2-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) was added dropwise. The mixture was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (220 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 2-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 2-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (2-fluorobenzoyl) acetate (12.7 g, yield: 66%).

A solution of ethyl 2-ethoxymethylene-2- (2-fluorobenzoyl) acetate (4.0 g, 15.0 mmol) in ethanol (12 mL) was added to a 25% aqueous ammonia solution (2.25 mL) so that the reaction temperature did not exceed 30 ° C. 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.875 mL, 15.0 mmol) was added dropwise while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature, the solution was neutralized, extracted with ethyl acetate (50 mL × 2), washed with saturated brine, and dried over anhydrous magnesium sulfate. . The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (2-fluorophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (3.18 g, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.16 (3H, t, J = 7.1 Hz), 3.74 (3H, d, J = 0.8 Hz), 4.16 (2H, q, J = 7.1 Hz), 7.18-7.22 (1 H, m), 7.27 (1 H, td, J = 7.5 and 1.0 Hz), 7.35 (1 H, td, J = 7.4 and 1. 9 Hz), 7.46-7.52 (1 H, m), 8.02 (1 H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.5 (1F, s).
A mixture of ethyl 5- (2-fluorophenyl) -1-methylpyrazole-4-carboxylate (2.0 g, 8.06 mmol), ethanol (25 mL) and 10% aqueous sodium hydroxide (8 mL) at 60 ° C. Stir for hours. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane and then dried under reduced pressure to obtain white solid 5- (2-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.56 g, yield: 88%). It was. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.73 (3H, d, J = 0.7 Hz), 7.18-7.23 (1H, m), 7.24-7.28 (1H, m ), 7.35 (1H, td, J = 7.3 and 1.8 Hz), 7.46-7.52 (1H, m), 8.05 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.5 (1F, s).
Reference Example-6

A mixture of 5- (2-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.0 g, 4.54 mmol), triethylamine (0.689 g, 6.81 mmol) and acetone (15 mL) was ice-cooled, Ethyl chloroformate (0.542 g, 4.99 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.590 g, 9.08 mmol) in water (1.5 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and hexane was added to remove a precipitate formed by filtration. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (2-fluorophenyl) -1- Methylpyrazol-4-yl] t-butyl carbamate (0.66 g, yield: 50%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.45 (9H, s), 3.73 (3H, d, J = 0.9 Hz), 5.91 (1H, brs), 7.21-7. 36 (3H, m), 7.45-7.51 (1H, m), 7.88 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.6 (1F, s).
T-butyl N- [5- (2-fluorophenyl) -1-methylpyrazol-4-yl] carbamate (0.40 g, 1.37 mmol), 1,4-dioxane (10 mL) and 2N hydrochloric acid (7 mL) Was stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a yellow color. Oily 4-amino-5- (2-fluorophenyl) -1-methylpyrazole (229 mg, yield: 87%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.90 (2H, brs), 3.72 (3H, d, J = 1.0 Hz), 7.20-7.25 (1H, m), 7. 25 (1H, s), 7.28 (1H, dd, J = 7.4 and 1.1 Hz), 7.35 (1 H, td, J = 7.5 and 1.9 Hz), 7.40-7.46 (1H , M). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.8 (1F, s).
Reference Example-7

  A solution of 4-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) with stirring at 60 ° C. to a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144.4 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (220 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 4-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl ethyl 2-ethoxymethylene-2- (4-fluorobenzoyl) acetate (14.6 g, yield: 76%).

To a solution of ethyl 2-ethoxymethylene-2- (4-fluorobenzoyl) acetate (4.0 g, 15.0 mmol) in ethanol (12 mL) was added 25% aqueous ammonia solution (2.25 mL) so that the reaction temperature did not exceed 30 ° C. 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.875 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, followed by stirring at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (4-fluorophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (3.43 g, yield: 92%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (3H, t, J = 7.1 Hz), 3.73 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.15-7.21 (2H, m), 7.34-7.39 (2H, m), 7.98 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.3 (1F, s).
A mixture of ethyl 5- (4-fluorophenyl) -1-methylpyrazole-4-carboxylate (2.0 g, 8.06 mmol), ethanol (25 mL) and 10% aqueous sodium hydroxide (8 mL) Stir for hours. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane, and then dried under reduced pressure to give 5- (4-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.60 g, yield: 90%) as a white solid. Obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.73 (3H, s), 7.15-7.21 (2H, m), 7.33-7.39 (2H, m), 8.02 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.8 (1F, s).
Reference Example-8

Triethylamine (0.689 g, 6.81 mmol) was added to a solution of 5- (4-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.0 g, 4.54 mmol) in acetone (15 mL), and the mixture was ice-cooled. Ethyl chloroformate (0.542 g, 4.99 mmol) was added slowly. The reaction solution was stirred at the same temperature for 20 minutes, and then a solution of sodium azide (0.590 g, 9.08 mmol) in water (1.5 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and hexane was added to remove a precipitate formed by filtration. The crude product obtained by concentrating the solution again under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (4-fluorophenyl) -1 as a colorless oil. -Methylpyrazol-4-yl] t-butyl carbamate (0.617 g, yield: 47%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.73 (3H, s), 5.86 (1H, brs), 7.21 (2H, t, J = 8. 7 Hz), 7.34 (2H, dd, J = 8.7 and 5.3 Hz), 7.82 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.5 (1F, s).
To a solution of t-butyl N- [5- (4-fluorophenyl) -1-methylpyrazol-4-yl] carbamate (0.45 g, 1.54 mmol) in 1,4-dioxane (10 mL) was added 2N hydrochloric acid (8 mL). ) And stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a yellow color. Oily 4-amino-5- (4-fluorophenyl) -1-methylpyrazole (251 mg, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.88 (2H, brs), 3.73 (3H, s), 7.19 (2H, t, J = 8.7 Hz), 7.22 (1H, s), 7.35 (2H, dd, J = 10.3 and 5.3 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.7 (1F, s).
Reference Example-9

  While stirring at 60 ° C., a solution of 2-chloroacetophenone (15.0 g, 97.0 mmol) in diethyl carbonate (20 mL) was added dropwise to a mixture of diethyl carbonate (150 mL) and potassium t-butoxide (21.8 g, 194 mmol). did. The reaction solution was stirred at the same temperature for 3 hours and then cooled to room temperature. To this solution was added 2N hydrochloric acid (220 mL), and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was distilled off from this solution under reduced pressure to obtain brown oily ethyl 2-chlorobenzoyl acetate (yield: quantitative).

  A mixture of ethyl 2-chlorobenzoyl acetate (97.0 mmol), triethyl orthoformate (28.8 g, 194 mmol) and acetic anhydride (19.8 g, 194 mmol) was heated and stirred at 135 ° C. for 2 hours, and then heated to 160 ° C. The low boiling point compound was distilled off over 3.5 hours. The solution was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (2-chlorobenzoyl) -2-ethoxymethylene acetate (21.2 g, yield: 77%) as a yellow oil.

To a solution of ethyl 2- (2-chlorobenzoyl) -2-ethoxymethyleneacetate (5.0 g, 17.7 mmol) in ethanol (15 mL) was added 25% aqueous ammonia solution (2.65 mL) so that the reaction temperature did not exceed 30 ° C. 35.4 mmol) was added dropwise. Next, 98% methylhydrazine (1.03 mL, 17.7 mmol) was added dropwise while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining this temperature, and the solution was neutralized, followed by extraction with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give ethyl 5- (2-chlorophenyl) -1-methylpyrazole-4-carboxylate. (3.63 g, yield: 78%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.12 (3H, t, J = 7.1 Hz), 3.68 (3H, s), 4.13 (2H, qd, J = 7.1 and 1.0 Hz) ), 7.32 (1H, dd, J = 7.6 and 1.7 Hz), 7.38 (1 H, td, J = 6.7 and 1.4 Hz), 7.45 (1 H, td, J = 7.4 and 1. 8 Hz), 7.52 (1H, dd, J = 8.0 and 1.3 Hz), 8.01 (1H, s).
A mixture of ethyl 5- (2-chlorophenyl) -1-methylpyrazole-4-carboxylate (2.0 g, 7.56 mmol), ethanol (25 mL) and 10% aqueous sodium hydroxide (8 mL) at 60 ° C. for 2 hours. Stir. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane and then dried under reduced pressure to obtain white solid 5- (2-chlorophenyl) -1-methylpyrazole-4-carboxylic acid (1.70 g, yield: 95%). . ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.66 (3H, s), 7.30 (1H, dd, J = 7.6 and 1.7 Hz), 7.37 (1H, td, J = 7.5 and 1) .4 Hz), 7.44 (1 H, td, J = 7.4 and 1.8 Hz), 7.52 (1 H, dd, J = 8.0 and 1.2 Hz), 8.03 (1 H, s).
Reference Example-10

After adding triethylamine (0.641 g, 6.33 mmol) to an acetone (15 mL) solution of 5- (2-chlorophenyl) -1-methylpyrazole-4-carboxylic acid (1.0 g, 4.23 mmol) and cooling with ice. Ethyl chloroformate (0.504 g, 4.64 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.549 g, 8.44 mmol) in water (1.4 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and hexane was added to remove a precipitate formed by filtration. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (2-chlorophenyl) -1-methyl as a white solid. Pyrazol-4-yl] carbamate t-butyl (0.53 g, yield: 41%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.66 (3H, s), 5.82 (1H, brs), 7.34 (1H, d, J = 6. 8 Hz), 7.40 (1 H, td, J = 7.4 and 1.4 Hz), 7.44 (1 H, td, J = 7.4 and 1.9 Hz), 7.56 (1 H, dd, J = 7.9 and 1) .4 Hz), 7.88 (1H, brs).
To a solution of t-butyl N- [5- (2-chlorophenyl) -1-methylpyrazol-4-yl] carbamate (0.40 g, 1.30 mmol) in 1,4-dioxane (10 mL) was added 2N hydrochloric acid (6. 5 mL) was added and stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a yellow oil. Of 4-amino-5- (2-chlorophenyl) -1-methylpyrazole (0.25 g, yield: 93%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.83 (2H, brs), 3.64 (3H, s), 7.24 (1H, s), 7.32-7.43 (3H, m) 7.52-7.57 (1H, m).
Reference Example-11

  A mixture of potassium t-butoxide (37.0 g, 330 mmol) and diethyl carbonate (280 mL) was heated to 60 ° C., and a solution of 4-chloroacetophenone (25.0 g, 162 mmol) in diethyl carbonate (60 mL) was added dropwise. The solution was stirred at 60 ° C. for 3 hours, then returned to room temperature, 2N hydrochloric acid (400 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 1, 50 mL × 1). The combined organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain brown oily ethyl 4-chlorobenzoyl acetate (37.5 g, yield: quantitative). This was directly used in the next reaction.

  After stirring a mixture of crude 4-chlorobenzoyl ethyl acetate (37.5 g, 162 mmol), triethyl orthoacetate (47.9 g, 323 mmol) and acetic anhydride (31 mL, 328 mmol) at 135 ° C. for 2 hours, While distilling off the compound, the temperature was gradually raised to 160 ° C. over 5 hours. The reaction solution returned to room temperature was purified by distillation under reduced pressure to obtain ethyl 2- (4-chlorobenzoyl) -2-ethoxymethylene acetate (31.4 g, yield: 69%) as a pale yellow oil.

  Ethanol of ethyl 2- (4-chlorobenzoyl) -2-ethoxymethylene acetate (30.2 g, 107 mmol) in a mixture of 35% aqueous methylhydrazine solution (20.0 g, 152 mmol) and ethanol (40 mL) at reflux. (25 mL) The solution was added dropwise and stirred for 5 minutes. The solution was returned to room temperature, 2N hydrochloric acid (200 mL) was added, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (100 mL × 1, 50 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting yellow solid was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give a pale yellow solid 3- ( Ethyl 4-chlorophenyl) -1-methylpyrazole-4-carboxylate (18.9 g, yield: 67%) and ethyl 5- (4-chlorophenyl) -1-methylpyrazole-4-carboxylate ( 4.35 g, yield: 15%) were obtained.

Ethyl 3- (4-chlorophenyl) -1-methylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.29 (3H, t, J = 7.1 Hz), 3.95 (3H , S), 4.24 (2H, q, J = 7.1 Hz), 7.37 (2H, d, J = 8.6 Hz), 7.74 (2H, d, J = 8.6 Hz), 7 .95 (1H, s).
Ethyl 5- (4-chlorophenyl) -1-methylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 3.73 (3H , S), 4.17 (2H, q, J = 7.1 Hz), 7.32 (2H, d, J = 8.6 Hz), 7.47 (2H, d, J = 8.6 Hz), 7 .98 (1H, s).
To a solution of ethyl 5- (4-chlorophenyl) -1-methylpyrazole-4-carboxylate (4.33 g, 16.4 mmol) in ethanol (15 mL) was added 10% aqueous sodium hydroxide solution (15 mL) and refluxed for 1 hour. Then, it returned to room temperature and 2N hydrochloric acid (30 mL) was added. The precipitated solid was collected by filtration and washed with water and hexane to give colorless solid 5- (4-chlorophenyl) -1-methylpyrazole-4-carboxylic acid (3.17 g, yield: 82%). It was. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.67 (3H, s), 7.49 (2H, d, J = 8.8 Hz), 7.57 (2H, d, J = 8.8 Hz) ), 7.89 (1H, s), 12.18 (1H, brs).
Reference Example-12

Thionyl chloride (5 mL) was added to a toluene (20 mL) solution of 5- (4-chlorophenyl) -1-methylpyrazole-4-carboxylic acid (3.15 g, 13.3 mmol), and the mixture was refluxed for 2.5 hours. -Toluene and excess thionyl chloride were distilled off using a Stark tube. Furthermore, a light yellow solid was obtained by removing the solvent and the like from the reaction solution under reduced pressure. This was dissolved in acetone (20 mL), triethylamine (2.10 g, 20.8 mmol) was added, and then a solution of sodium azide (1.80 g, 27.7 mmol) in water (5 mL) was slowly added under ice cooling. added. The reaction solution was stirred at the same temperature for 1 hour, water (100 mL) was added, and the mixture was extracted with toluene (30 mL × 2). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, and then refluxed 2,2,2-trichloroethanol (2.30 g, 15.4 mmol) and toluene (20 mL). ). The reaction mixture was refluxed for 12 hours and then returned to room temperature and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give a colorless solid N- [ 5- (4-Chlorophenyl) -1-methylpyrazol-4-yl] carbamate 2,2,2-trichloroethyl (4.19 g, yield: 82%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.77 (3H, s), 4.78 (2H, s), 6.28 (1H, brs), 7.31 (2H, d, J = 8. 4 Hz), 7.50 (2H, d, J = 8.4 Hz), 7.78 (1 H, brs).
To a solution of N- [5- (4-chlorophenyl) -1-methylpyrazol-4-yl] carbamate 2,2,2-trichloroethyl (4.16 g, 10.9 mmol) in acetic acid (90 mL) was added water (10 mL). ) And zinc (8.0 g) were added and stirred at room temperature for 3 hours. Zinc was removed by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting brown oil was purified by silica gel column chromatography (ethyl acetate, 1% triethylamine added) to give 4-amino acid as a pale yellow oil. -5- (4-Chlorophenyl) -1-methylpyrazole (139 mg, yield: 6%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.89 (2H, brs), 3.74 (3H, s), 7.22 (1H, s), 7.32 (2H, d, J = 8. 5 Hz), 7.48 (2H, d, J = 8.5 Hz).
Reference Example-13

  To a mixture of diethyl carbonate (55 mL) and potassium t-butoxide (7.19 g, 64.1 mmol) with stirring at 60 ° C., 3,5-difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl carbonate (10 mL) ) The solution was added dropwise and stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, 2N hydrochloric acid (110 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily ethyl 3,5-difluorobenzoyl acetate (yield: quantitative). It was.

  A mixture of ethyl 3,5-difluorobenzoyl acetate (14.6 g, 64.0 mmol), triethyl orthoformate (19.0 g, 128 mmol) and acetic anhydride (13.1 g, 128 mmol) was heated and stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,5-difluorobenzoyl) -2-ethoxymethylene acetate (12.2 g, yield: 67%) as a yellow oil.

To a solution of ethyl 2- (3,5-difluorobenzoyl) -2-ethoxymethyleneacetate (1.95 g, 6.84 mmol) in ethanol (5 mL), a 25% aqueous ammonia solution (1 0.02 mL, 13.6 mmol) was added dropwise. Next, 98% methyl hydrazine (0.399 mL, 6.85 mmol) was added dropwise to the reaction solution while maintaining the reaction temperature at 5 ° C. or lower, followed by stirring at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (3,5-difluorophenyl) -1-methylpyrazole-4. -Ethyl carboxylate (1.41 g, yield: 77%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 3.75 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 6.90-6.97 (3H, m), 7.98 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.8 (2F, s).
To a solution of ethyl 5- (3,5-difluorophenyl) -1-methylpyrazole-4-carboxylate (1.30 g, 4.88 mmol) in ethanol (15 mL) was added 10% aqueous sodium hydroxide solution (5 mL) to give 60. Stir at 0 ° C. for 2 hours. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, and water (50 mL) was added. The deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane and then dried under reduced pressure to give white solid 5- (3,5-difluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.14 g, yield: 98%). Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.75 (3H, s), 6.90-6.98 (3H, m), 8.03 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.5 (2F, s).
Reference Example-14

Triethylamine (0.637 g, 6.30 mmol) was added to a solution of 5- (3,5-difluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.0 g, 4.20 mmol) in acetone (15 mL) and iced. After cooling, ethyl chloroformate (0.501 g, 4.62 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.546 g, 8.40 mmol) in water (1.4 mL) was slowly added and stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a portion 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The solution was cooled to room temperature, concentrated under reduced pressure, and hexane was added to remove the precipitate formed by filtration. The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (3,5-difluorophenyl)-as a white solid. 1-methylpyrazol-4-yl] t-butyl carbamate (0.84 g, yield: 65%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.79 (3H, s), 5.88 (1H, brs), 6.88-6.94 (3H, m) , 7.80 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-107.7 (2F, s).
T-butyl N- [5- (3,5-difluorophenyl) -1-methylpyrazol-4-yl] carbamate (0.40 g, 1.29 mmol), 1,4-dioxane (10 mL) and 2N hydrochloric acid ( (6.5 mL) was stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/2). To give 4-amino-5- (3,5-difluorophenyl) -1-methylpyrazole (227 mg, yield: 84%) as a white oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.96 (2H, brs), 3.78 (3H, s), 6.82-6.88 (1H, m), 6.90-6.96 ( 2H, m), 7.22 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.3 (2F, s).
Reference Example-15

  A solution of 3,4-dichloroacetophenone (15.0 g, 79.3 mmol) in diethyl carbonate (20 mL) was stirred at 60 ° C. in a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (17.8 g, 159 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,4-dichlorobenzoyl acetate (yield: quantitative). .

A mixture of crude 3,4-chlorobenzoyl acetate (79.3 mmol), triethyl orthoformate (23.5 g, 159 mmol) and acetic anhydride (16.2 g, 159 mmol) was stirred with heating at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethylene acetate (16.6 g, yield: 66%) as a yellow oil.
(Synthesis Example-1)
To a solution of ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethyleneacetate (5.0 g, 15.8 mmol) in ethanol (15 mL), a 25% aqueous ammonia solution (2 .36 mL, 31.5 mmol) was added dropwise. Next, 98% methylhydrazine (0.918 mL, 15.8 mol) was added dropwise to the reaction solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl acid (3.89 g, yield: 83%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (3H, t, J = 7.1 Hz), 3.75 (3H, s), 4.18 (2H, q, J = 7.1 Hz), 7.23 (1H, dd, J = 8.3 and 2.0 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.2 Hz), 7.98 (1H, s).
(Synthesis Example-2)
In a mixture of 35% aqueous methylhydrazine (18.0 g, 137 mmol) and ethanol (40 mL) at reflux, ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethylene acetate (28.1 g, 88.88). 6 mmol) in ethanol (25 mL) was added dropwise, and the mixture was further stirred for 5 minutes. The reaction solution was returned to room temperature, and the precipitated light yellow solid (17.3 g, yield: 65%) of ethyl 3- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylate was collected by filtration. Washed with water and hexane. The organic layer was collected from the filtrate, and the aqueous layer was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting brown oil was recrystallized (hexane / ethyl acetate = 3/1) and silica gel column chromatography (hexane / ethyl acetate = 4 / 1) to give a pale yellow solid of ethyl 3- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylate (2.10 g, yield: 8%) and 5- ( Ethyl 3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylate (4.75 g, yield: 18%) was obtained.

Ethyl 3- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.30 (3H, t, J = 7.1 Hz), 3.95 (3H, s), 4.26 (2H, q, J = 7.1 Hz), 7.47 (1H, d, J = 8.5 Hz), 7.69 (1H, dd, J = 8.5and2. 0 Hz), 7.95 (1 H, d, J = 2.0 Hz), 7.96 (1 H, s).
To a solution of ethyl 5- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylate (4.73 g, 15.8 mmol) in ethanol (15 mL) was added 10% aqueous sodium hydroxide (15 mL) for 1 hour. Refluxed. The solution was returned to room temperature, 2N hydrochloric acid (100 mL) was added, and the precipitated solid was collected by filtration. This was washed with water and hexane, and dried under reduced pressure to obtain 5- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylic acid (3.81 g, yield: 89%) as a colorless solid. . ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 3.69 (3H, s), 7.48 (1H, dd, J = 8.3 and 2.0 Hz), 7.77 (1H, d, J = 8) .3 Hz), 7.81 (1H, d, J = 2.0 Hz), 7.90 (1H, s).
Reference Example-16

After thionyl chloride (5 mL) was added to a toluene (20 mL) solution of 5- (3,4-dichlorophenyl) -1-methylpyrazole-4-carboxylic acid (3.80 g, 14.0 mmol) and refluxed for 3 hours, Dean. -Toluene and excess thionyl chloride were distilled off using a Stark tube. Further, a light yellow solid was obtained by removing the solvent and the like from the reaction solution under reduced pressure. This was dissolved in acetone (20 mL), triethylamine (2.10 g, 20.8 mmol) was added, and then a solution of sodium azide (1.80 g, 27.7 mmol) in water (5 mL) was slowly added under ice cooling. added. The mixture was stirred at the same temperature for 1 hour, water (100 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 2). The organic layers were combined, washed with saturated brine (30 mL), and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was added dropwise to a refluxing mixture of 2,2,2-trichloroethanol (2.30 g, 15.4 mmol) and toluene (20 mL). After the reaction solution was refluxed for 12 hours, the reaction solution returned to room temperature was concentrated under reduced pressure, and the resulting brown oil was purified by silica gel column chromatography (hexane / ethyl acetate = 3/2) to give a pale yellow solid. N- [5- (3,4-dichlorophenyl) -1-methylpyrazol-4-yl] carbamate 2,2,2-trichloroethyl (4.53 g, yield: 77%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ3.78 (3H, s), 4.78 (2H, s), 6.33 (1H, brs), 7.22 (1H, d, J = 8. 3 and 2.0 Hz), 7.48 (1 H, d, J = 2.0 Hz), 7.59 (1 H, d, J = 8.3 Hz), 7.74 (1 H, brs).
To a solution of N- [5- (3,4-dichlorophenyl) -1-methylpyrazol-4-yl] carbamate 2,2,2-trichloroethyl (4.50 g, 10.8 mmol) in acetic acid (90 mL) was added water. (10 mL) and zinc (8.0 g) were added and stirred at room temperature for 3 hours. Zinc was removed by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). 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 (ethyl acetate, 1% triethylamine added) to give 4-amino acid as a pale yellow solid. -5- (3,4-dichlorophenyl) -1-methylpyrazole (1.01 g, yield: 39%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.91 (2H, brs), 3.75 (3H, s), 7.22 (1H, s), 7.23 (1H, dd, J = 8. 5 and 2.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 7.57 (1H, d, J = 8.5 Hz).
Reference Example-17

  A solution of 4-trifluoromethylacetophenone (10.0 g, 53.1 mmol) in diethyl carbonate (20 mL) with stirring at 60 ° C. in a mixture of diethyl carbonate (120 mL) and potassium t-butoxide (11.9 g, 106 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-trifluoromethylbenzoyl acetate (yield: quantitative). .

  A mixture of ethyl 4-trifluoromethylbenzoyl acetate (13.8 g, 53.1 mmol) and triethyl orthoformate (15.7 g, 106 mmol) and acetic anhydride (10.8 g, 106 mmol) was heated and stirred at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain light yellow solid ethyl 2-ethoxymethylene-2- (4-trifluoromethylbenzoyl) acetate (13.1 g, yield: 78%).

To a solution of ethyl 2-ethoxymethylene-2- (4-trifluoromethylbenzoyl) acetate (2.90 g, 9.17 mmol) in ethanol (10 mL) was added 25% aqueous ammonia solution (1) so that the reaction temperature did not exceed 30 ° C. 37 mL, 18.3 mmol) was added dropwise. Next, 98% methyl hydrazine (0.534 mL, 9.17 mmol) was added dropwise to the reaction solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added dropwise while maintaining the temperature, the solution was neutralized, and extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 1-methyl-5- (4-trifluoromethylphenyl) pyrazole-4. -Ethyl carboxylate (2.36 g, yield: 86%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (3H, t, J = 7.1 Hz), 3.75 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.52 (2H, dd, J = 8.5 and 0.6 Hz), 7.76 (2H, d, J = 8.0 Hz), 8.00 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (3F, s).
To a solution of ethyl 1-methyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylate (2.0 g, 6.71 mmol) in ethanol (25 mL) was added a 10% aqueous sodium hydroxide solution (8 mL) and added 60. Stir at 0 ° C. for 2 hours. The solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane and then dried under reduced pressure to give 1-methyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid as a white solid (1.77 g, yield: 97%). Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.74 (3H, s), 7.51 (2H, d, J = 8.0 Hz), 7.75 (2H, d, J = 8.1 Hz), 8.04 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (3F, s).
Reference Example-18

To a solution of 1-methyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid (1.0 g, 3.70 mmol) in acetone (15 mL) was added triethylamine (0.562 g, 5.55 mmol) and iced. After cooling, ethyl chloroformate (0.442 g, 4.07 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.481 g, 7.40 mmol) in water (1.2 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10.0 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction mixture was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [1-methyl-5- ( 4-Trifluoromethylphenyl) pyrazol-4-yl] carbamate t-butyl (794 mg, yield: 63%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.78 (3H, s), 5.89 (1H, brs), 7.50 (2H, d, J = 8. 0 Hz), 7.78 (2H, d, J = 8.1 Hz), 7.84 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, s).
T-butyl N- [1-methyl-5- (4-trifluoromethylphenyl) pyrazol-4-yl] carbamate (0.40 g, 1.17 mmol), 1,4-dioxane (10 mL) and 2N hydrochloric acid ( 6 mL) of the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), 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 = 1/2). Purification gave yellow oil 4-amino-1-methyl-5- (4-trifluoromethylphenyl) pyrazole (251 mg, yield: 89%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.94 (2H, brs), 3.78 (3H, s), 7.24 (1H, s), 7.53 (2H, d, J = 8. 2 Hz), 7.76 (2H, d, J = 8.0 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
Reference Example-19

  To a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (13.1 g, 117 mmol) with stirring at 60 ° C., 3,5-bis (trifluoromethyl) acetophenone (15 g, 58.6 mmol) of diethyl carbonate ( 20 mL) solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (yield: quantitative). Obtained).

  A mixture of ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (19.2 g, 58.6 mmol), triethyl orthoformate (17.4 g, 117 mmol) and acetic anhydride (12.0 g, 118 mmol) was added at 135 ° C. After heating and stirring for 2 hours, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature, and distilled under reduced pressure to give ethyl 2-ethoxymethylene-2- [3,5-bis (trifluoromethyl) benzoyl] acetate (14.9 g, yield: 66%) as a pale yellow solid. Obtained.

In a solution of ethyl 2-ethoxymethylene-2- [3,5-bis (trifluoromethyl) benzoyl] acetate (4.0 g, 10.4 mmol) in ethanol (15 mL), the reaction temperature was adjusted to 25 ° C. so that the reaction temperature did not exceed 30 ° C. % Aqueous ammonia (1.56 mL, 20.8 mmol) was added dropwise. Next, 98% methyl hydrazine (0.606 mL, 10.4 mmol) was added dropwise to the reaction solution while maintaining the reaction temperature at 5 ° C. or lower, followed by stirring at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added dropwise while maintaining the temperature to neutralize the solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- [3,5-bis (trifluoromethyl) phenyl] -1- Ethyl methylpyrazole-4-carboxylate (2.81 g, yield: 74%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.15 (3H, t, J = 7.1 Hz), 3.78 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.87 (2H, s), 8.01 (1H, s), 8.04 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (6F, s).
To a solution of ethyl 5- [3,5-bis (trifluoromethyl) phenyl] -1-methylpyrazole-4-carboxylate (2.0 g, 5.46 mmol) in ethanol (25 mL) was added 10% aqueous sodium hydroxide (8 mL). ) And stirred at 60 ° C. for 2 hours. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the deposited precipitate was collected by filtration. The obtained solid was washed with water and hexane and then dried under reduced pressure to give white solid 5- [3,5-bis (trifluoromethyl) phenyl] -1-methylpyrazole-4-carboxylic acid (1.60 g, yield). Rate: 87%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.79 (3H, s), 7.86 (2H, s), 8.01 (1H, s), 8.06 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.0 (6F, s).
Reference Example-20

Triethylamine (0.449 g, 4.43 mmol) was added to a solution of 5- [3,5-bis (trifluoromethyl) phenyl] -1-methylpyrazole-4-carboxylic acid (1.0 g, 2.96 mmol) in acetone (10 mL). ) And ice-cooled, and then ethyl chloroformate (0.353 g, 3.26 mmol) was slowly added. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.384 g, 5.91 mmol) in water (1 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, and then water (50 mL) was added, followed by extraction with toluene (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. 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 = 1/1) to give a white solid N- [5- {3,5- Bis (trifluoromethyl) phenyl} -1-methylpyrazol-4-yl] t-butyl carbamate (916 mg, yield: 76%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.44 (9H, s), 3.80 (3H, s), 5.77 (1H, brs), 7.69 (1H, brs), 7.88 (2H, s), 7.96 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, s).
T-butyl N- [5- {3,5-bis (trifluoromethyl) phenyl} -1-methylpyrazol-4-yl] carbamate (0.40 g, 0.98 mmol), 1,4-dioxane (10 mL ) And 2N hydrochloric acid (5 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), 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 = 1/2). Purification gave white solid 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1-methylpyrazole (271 mg, yield: 90%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.95 (2H, brs), 3.79 (3H, s), 7.26 (1H, s), 7.87 (2H, s), 7.90 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, s).
Reference Example-21

  A mixture of ethyl benzoyl acetate (25.0 g, 130 mmol), triethyl orthoformate (38.6 g, 261 mmol) and acetic anhydride (25 mL, 265 mmol) was stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C. over 5 hours. The reaction solution returned to room temperature was purified by distillation under reduced pressure to obtain ethyl 2-benzoyl-2-ethoxymethylene acetate (23.0 g, yield: 71%) as a yellow oil.

To a solution of t-butylhydrazine hydrochloride (2.80 g, 22.5 mmol) in toluene (20 mL) was added 10% aqueous sodium hydroxide solution (20 mL), cooled to 0 ° C., and then 2-benzoyl-2-ethoxymethyleneacetic acid. Ethyl (5.00 g, 20.1 mmol) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, 2N hydrochloric acid (20 mL) was added, the organic layer was separated, and the aqueous layer was extracted with toluene (20 mL). The combined organic layer was 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 = 9/1) to give a pale yellow solid (3 .61 g, yield: 66%). ^{From 1} H-NMR, this is a 70/30 mixture of ethyl 1-t-butyl-5-phenylpyrazole-4-carboxylate and ethyl 1-t-butyl-3-phenylpyrazole-4-carboxylate. It became clear.

1-t-butyl-5-phenylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.04 (3H, t, J = 7.3 Hz), 1.45 (9H, s ), 4.04 (2H, q, J = 7.3 Hz), 7.28-7.46 (5H, m), 7.94 (1H, s).
1-t-butyl-3-phenylpyrazole-4-carboxylate: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.28 (3H, t, J = 7.3 Hz), 1.64 (9H, s ), 4.24 (2H, q, J = 7.3 Hz), 7.28-7.46 (3H, m), 7.79 (2H, m), 8.08 (1H, s).
Mixture of ethyl 1-t-butyl-5-phenylpyrazole-4-carboxylate and ethyl 1-t-butyl-3-phenylpyrazole-4-carboxylate (3.59 g, 13.2 mmol, mixing ratio: 70/30 ) In ethanol (40 mL) was added 10% aqueous sodium hydroxide (40 mL) and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. This was washed with water and hexane and dried by toluene azeotropy to obtain a colorless solid (2.92 g, yield: 91%). ^{According to 1} H-NMR, this is a 75/25 mixture of 1-t-butyl-5-phenylpyrazole-4-carboxylic acid and 1-t-butyl-3-phenylpyrazole-4-carboxylic acid. It became clear.

1-t-butyl-5-phenylpyrazole-4-carboxylic acid: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.42 (9H, s), 7.26-7.45 (5H, m), 7 97 (1H, s).
1-t-butyl-3-phenylpyrazole-4-carboxylic acid: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.63 (9H, s), 7.26-7.45 (3H, m), 7 .78 (2H, m), 8.12 (1H, s).
Reference Example-22

  To a solution of 1-t-butyl-5-phenylpyrazole-4-carboxylic acid and 1-t-butyl-3-phenylpyrazole-4-carboxylic acid (10.4 g, 42.6 mmol) in acetone (400 mL), Triethylamine (6.50 g, 64.2 mmol) was added. To this was slowly added ethyl chloroformate (4.5 mL, 47.1 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 min. A solution of sodium azide (5.50 g, 84.6 mmol) in water (20 mL) was slowly added to the reaction solution, and the mixture was stirred at 0 ° C. for 10 minutes. The reaction solution was poured into water (1 L) and extracted with toluene (250 mL × 3). The organic layers were combined, washed with saturated brine (200 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 mixed with 2,2,2-trichloroethanol (6.60 g, 44.2 mmol) and toluene (20 mL) in reflux. It was dripped at the liquid. After the mixture was refluxed for 12 hours, the reaction solution which had been returned to room temperature was concentrated under reduced pressure to obtain a brown oil. This was purified by silica gel column chromatography (hexane / ethyl acetate = 9/1) to give a pale yellow solid of N- (1-tert-butyl-5-phenylpyrazol-4-yl) carbamic acid 2,2,2 -Trichloroethyl (6.02 g, yield: 36%) and yellow solid 2,2,2-trichloroethyl N- (1-t-butyl-3-phenylpyrazol-4-yl) carbamate (3.05 g) , Yield: 18%).

N- (1-t-butyl-5-phenylpyrazol-4-yl) carbamate 2,2,2-trichloroethyl: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.43 (9H, s), 4 .73 (2H, s), 5.97 (1H, brs), 7.32-7.35 (2H, m), 7.42-7.51 (3H, m), 7.83 (1H, brs) ).
N- (1-t-butyl-3-phenylpyrazol-4-yl) carbamate 2,2,2-trichloroethyl: ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.62 (9H, s), 4 .83 (2H, s), 6.67 (1H, brs), 7.33-7.49 (3H, m), 7.61-7.65 (2H, m), 7.94 (1H, brs) ).
To a solution of N- (1-tert-butyl-5-phenylpyrazol-4-yl) carbamate 2,2,2-trichloroethyl (6.00 g, 15.4 mmol) in acetic acid (270 mL), water (30 mL) and Zinc (15.0 g) was added and stirred at room temperature for 30 minutes. Zinc was removed by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (200 mL) was added, and the mixture was extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting yellow solid was subjected to silica gel column chromatography (hexane / ethyl acetate = 1 / 9,1). % Triethylamine added) to obtain 4-amino-1-t-butyl-5-phenylpyrazole (2.74 g, yield: 83%) as a yellow solid. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.42 (9H, s), 2.51 (2H, brs), 7.21 (1H, s), 7.30-7.50 (5H, m) .
Reference Example-23

  While stirring a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144 mmol) at 60 ° C., a solution of 2-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) was added dropwise. The mixture was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (220 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 2-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 2-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (2-fluorobenzoyl) acetate (12.7 g, yield: 66%).

To a solution of t-butylhydrazine hydrochloride (1.742 g, 13.6 mmol) in toluene (20 mL) was added 5% aqueous sodium hydroxide solution (20 mL) under ice cooling, and then 2-ethoxymethylene-2- ( A solution of ethyl 2-fluorobenzoyl) acetate (3.0 g, 11.3 mmol) in toluene (10 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (20 mL) and triethylamine (1.59 mL) were added to this, and the mixture was refluxed at 100 ° C. for 2 days. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-tert-butyl-5- (2-fluorophenyl) pyrazole-4 as a yellow solid. -A mixture of ethyl carboxylate and ethyl 1-t-butyl-3- (2-fluorophenyl) pyrazole-4-carboxylate was obtained. Reprecipitation from hexane gave ethyl 1-t-butyl-5- (2-fluorophenyl) pyrazole-4-carboxylate (1.90 g, yield: 58%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05 (3H, t, J = 7.1 Hz), 1.48 (9H, s), 4.06 (2H, qd, J = 7.1 and 0.8 Hz) ), 7.12-7.17 (1H, m), 7.21 (1H, td, J = 7.4 and 1.1 Hz), 7.27 (1H, td, J = 7.5 and 1.8 Hz), 7 .43-7.49 (1H, m), 7.98 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.0 (1F, s).
To a solution of ethyl 1-t-butyl-5- (2-fluorophenyl) pyrazole-4-carboxylate (1.9 g, 6.54 mmol) in ethanol (50 mL) was added 10% aqueous sodium hydroxide solution (10 mL). The mixture was stirred at room temperature for 10 hours and at 60 ° C. for 1 hour. The reaction solution was returned to room temperature, acidified with concentrated hydrochloric acid, water (50 mL) was added, and the mixture was extracted with chloroform (50 mL × 1, 30 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate and dried under reduced pressure to give 1-tert-butyl-5- (2-fluorophenyl) pyrazole-4-carboxylic acid (1.62 g, yield: white solid). 94%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 7.10-7.15 (1H, m), 7.19 (1H, td, J = 7.3 and 1.0 Hz), 7.25 (1H, td, J = 7.0 and 1.8 Hz), 7.42-7.48 (1H, m), 7.99 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.0 (1F, s).
Reference Example-24

Triethylamine (0.579 g, 5.72 mmol) was added to a solution of 1-t-butyl-5- (2-fluorophenyl) pyrazole-4-carboxylic acid (1.0 g, 3.81 mmol) in acetone (15 mL) and iced. After cooling, ethyl chloroformate (0.455 g, 4.19 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.496 g, 7.63 mmol) in water (1.3 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution 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) to give N- [1-t-butyl-5 as a white solid. -(2-Fluorophenyl) pyrazol-4-yl] carbamate t-butyl (597 mg, yield: 47%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (18H, s), 5.54 (1H, brs), 7.19 (1H, t, J = 8.9 Hz), 7.23-7. 34 (2H, m), 7.46-7.52 (1H, m), 7.88 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-109.7 (1F, s).
To a solution of t-butyl N- [1-t-butyl-5- (2-fluorophenyl) pyrazol-4-yl] carbamate (0.80 g, 2.40 mmol) in 1,4-dioxane (12 mL) was added 2N hydrochloric acid. (12 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a brown color. Solid 4-amino-1-t-butyl-5- (2-fluorophenyl) pyrazole (0.227 g, yield: 41%) was obtained. Mp: 123.3-123.7 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (9H, s), 2.60 (2H, brs), 7.15-7.20 (1H, m), 7.22-7.26 ( 1H, m), 7.25 (1 H, s), 7.32 (1 H, td, J = 7.4 and 1.9 Hz), 7.42-7.48 (1 H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.4 (1F, s).
Reference Example-25

  To a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144 mmol), a solution of 4-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) was added dropwise with stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (220 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 4-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl ethyl 2-ethoxymethylene-2- (4-fluorobenzoyl) acetate (14.6 g, yield: 76%).

  To a solution of t-butylhydrazine hydrochloride (2.41 g, 18.8 mmol) in toluene (20 mL) was added 5% aqueous sodium hydroxide solution (35 mL) at 0 ° C., and then 2-ethoxymethylene-2- (4- A solution of fluorobenzoyl) ethyl acetate (5.0 g, 18.8 mmol) in toluene (15 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The combined organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Ethanol (20 mL) and triethylamine (3.93 mL) were added to this and refluxed overnight. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-tert-butyl-5- (4-fluorophenyl) pyrazole-4 as a white solid. -A 71/29 mixture (4.01 g, yield: 74%) of ethyl carboxylate and ethyl 1-t-butyl-3- (4-fluorophenyl) pyrazole-4-carboxylate was obtained.

1-t-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.09 (3H, t, J = 7.1 Hz), 1. 45 (9H, s), 4.06 (2H, q, J = 7.1 Hz), 7.08-7.15 (2H, m), 7.26-7.28 (1H, m), 7. 78-7.82 (1H, m), 7.93 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.3 (1F, s).
1-t-butyl-3- (4-fluorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.29 (3H, t, J = 7.1 Hz), 1. 64 (9H, s), 4.24 (2H, q, J = 7.1 Hz), 7.08-7.15 (2H, m), 7.26-7.28 (1H, m), 7. 78-7.82 (1H, m), 8.07 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.1 (1F, s).
A mixture of ethyl 1-t-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylate and ethyl 1-t-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylate (1.0 g, To a solution of 3.44 mmol) in ethanol (25 mL) was added 10% aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at room temperature for 24 hours. The reaction solution was acidified with concentrated hydrochloric acid, water (50 mL) was added, and the mixture was extracted with chloroform (50 mL × 1, 30 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 1-tert-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylic acid and 1-tert-butyl-3 as yellow solids. A 72/28 mixture (0.891 g, yield: 99%) of-(4-fluorophenyl) pyrazole-4-carboxylic acid was obtained.

1-t-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (9H, s), 7.06-7.13 (2H M), 7.24-7.28 (1H, m), 7.78-7.81 (1H, m), 7.97 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.9 (1F, s).
1-t-butyl-3- (4-fluorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.63 (9H, s), 7.06-7.13 (2H M), 7.24-7.28 (1H, m), 7.78-7.81 (1H, m), 8.12 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-113.7 (1F, s).
Reference Example-26

  A mixture of 1-t-butyl-5- (4-fluorophenyl) pyrazole-4-carboxylic acid and 1-t-butyl-3- (4-fluorophenyl) pyrazole-4-carboxylic acid (1.5 g, 5. 72 mmol) in acetone (20 mL) was added triethylamine (0.868 g, 8.61 mmol), ethyl chloroformate (0.683 g, 6.30 mmol) was slowly added under ice-cooling, and the mixture was stirred for 20 minutes. Next, a solution of sodium azide (0.744 g, 11.4 mmol) in water (2 mL) was slowly added to the reaction solution, and the mixture was further stirred at the same temperature for 40 minutes. Water (30 mL) was added to the reaction solution, and extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution 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) to give N- [1-t-butyl-5 as a white solid. -(4-Fluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.750 g, yield: 39%) and N- [1-tert-butyl-3- (4-fluorophenyl) as a yellow oil Pyrazol-4-yl] carbamate t-butyl (0.324 g, yield: 17%) was obtained.

T-butyl N- [1-t-butyl-5- (4-fluorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.41 (18H, s), 5 .51 (1H, brs), 7.16 (2H, t, J = 8.7 Hz), 7.29-7.32 (2H, m), 7.82 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.6 (1F, s).
T-butyl N- [1-t-butyl-3- (4-fluorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 1 .60 (9H, s), 6.20 (1H, brs), 7.13 (2H, t, J = 8.7 Hz), 7.56-7.60 (2H, m), 7.93 (1H) , Brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (1F, s).
To a solution of t-butyl N- [1-t-butyl-5- (4-fluorophenyl) pyrazol-4-yl] carbamate (0.80 g, 2.40 mmol) in 1,4-dioxane (12 mL) was added 2N hydrochloric acid. (12 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, 10% aqueous sodium hydroxide solution (9.6 mL) was added, and the mixture was extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a brown solid. Of 4-amino-1-t-butyl-5- (4-fluorophenyl) pyrazole (184 mg, yield: 33%) was obtained. Mp: 135.0-136.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.41 (9H, s), 2.58 (2H, brs), 7.15 (2H, t, J = 8.7 Hz), 7.20 (1H, s), 7.29-7.33 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.5 (1F, s).
Reference Example-27

  To a mixture of diethyl carbonate (55 mL) and potassium t-butoxide (7.19 g, 64.1 mmol) with stirring at 60 ° C., 3,5-difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl carbonate (10 mL) ) The solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (110 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily ethyl 3,5-difluorobenzoyl acetate (yield: quantitative). It was.

  A mixture of ethyl 3,5-difluorobenzoyl acetate (14.6 g, 64.0 mmol), triethyl orthoformate (19.0 g, 128 mmol) and acetic anhydride (13.1 g, 128 mmol) was heated and stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,5-difluorobenzoyl) -2-ethoxymethylene acetate (12.2 g, yield: 67%) as a yellow oil.

  To a toluene (20 mL) solution of t-butylhydrazine hydrochloride (2.26 g, 17.6 mmol) was added 5% aqueous sodium hydroxide solution (20 mL) under ice-cooling, and then 2- (3,5-difluorobenzoyl ) A solution of ethyl 2-ethoxymethylene acetate (5.0 g, 17.6 mmol) in toluene (10 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The combined organic layer was dried over anhydrous magnesium sulfate, and then the solvent was concentrated under reduced pressure and purified by column chromatography (hexane / ethyl acetate = 4/1) to give a white solid 1-t-butyl-5- Mixture of ethyl (3,5-difluorophenyl) pyrazole-4-carboxylate and ethyl 1-t-butyl-3- (3,5-difluorophenyl) pyrazole-4-carboxylate (4.35 g, yield: 80 %, Production ratio: 72/28).

1-t-butyl-5- (3,5-difluorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.11 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 4.08 (2H, q, J = 7.1 Hz), 6.84-6.95 (3H, m), 7.93 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-109.6 (2F, s).
1-t-butyl-3- (3,5-difluorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.31 (3H, t, J = 7.1 Hz), 1.64 (9H, s), 4.27 (2H, q, J = 7.1 Hz), 6.77-6.83 (1H, m), 7.44-7.47 (2H, m), 8.08 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.1 (2F, s).
A mixture of ethyl 1-t-butyl-5- (3,5-difluorophenyl) pyrazole-4-carboxylate and ethyl 1-t-butyl-3- (3,5-difluorophenyl) pyrazole-4-carboxylate ( To a solution of 4.00 g, 13.0 mmol) in ethanol (50 mL) was added 10% aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature for 24 hours, and further heated at 60 ° C. for 1 hour. After cooling to room temperature, the reaction mixture was acidified with concentrated hydrochloric acid, water (50 mL) was added, and the mixture was extracted with chloroform (50 mL × 1, 30 mL × 2). The combined organic layers were dried over anhydrous magnesium sulfate and evaporated to dryness to give white solids 1-t-butyl-5- (3,5-difluorophenyl) pyrazole-4-carboxylic acid and 1-t-butyl- A mixture of 3- (3,5-difluorophenyl) pyrazole-4-carboxylic acid (3.51 g, yield: 97%, production ratio: 70/30) was obtained.

1-t-butyl-5- (3,5-difluorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 6.84-6.95 (3H, m), 7.98 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-109.3 (2F, s).
1-t-butyl-3- (3,5-difluorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.64 (9H, s), 6.78-6.83 (1H, m), 7.42-7.48 (2H, m), 8.15 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-110.8 (2F, s).
Reference Example-28

  A mixture of 1-t-butyl-5- (3,5-difluorophenyl) pyrazole-4-carboxylic acid and 1-t-butyl-3- (3,5-difluorophenyl) pyrazole-4-carboxylic acid (2. To a solution of 80 g, 10.0 mmol) in acetone (35 mL) was added triethylamine (1.52 g, 15.0 mmol), and then ethyl chloroformate (1.19 g, 6.30 mmol) was slowly added under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (1.30 g, 20.0 mmol) in water (2 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (30 mL) was added, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution 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) to give N- [1-t-butyl-5 as a white solid. -(3,5-difluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.36 g, yield: 39%) and yellow solid N- [1-t-butyl-3- (3,5 -Difluorophenyl) pyrazol-4-yl] t-butyl carbamate (0.662 g, yield: 19%) was obtained.

T-butyl N- [1-t-butyl-3- (3,5-difluorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.44 (18H, s) 5.52 (1H, brs), 6.88-6.96 (3H, m), 7.80 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.4 (2F, s).
T-butyl N- [1-t-butyl-5- (3,5-difluorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s) 1.60 (9H, s), 6.17 (1H, brs), 6.76 (1H, tt, J = 9.0 and 2.4 Hz), 7.19 (2H, d, J = 6.4 Hz) , 7.91 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-109.5 (2F, s).
To a solution of t-butyl N- [1-t-butyl-5- (3,5-difluorophenyl) pyrazol-4-yl] carbamate (1.00 g, 2.85 mmol) in 1,4-dioxane (15 mL) 2N hydrochloric acid (15 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate) to give a white product. Solid 4-amino-1-tert-butyl-5- (3,5-difluorophenyl) pyrazole (0.132 g, yield: 19%) was obtained. Mp: 129.3-131.2 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.44 (9H, s), 2.63 (2H, brs), 6.86-6.93 (3H, m), 7.19 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-108.8 (2F, s).
Reference Example-29

  A solution of 3,4-dichloroacetophenone (15.0 g, 79.3 mmol) in diethyl carbonate (20 mL) was stirred at 60 ° C. in a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (17.8 g, 159 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,4-dichlorobenzoyl acetate (yield: quantitative). .

  A mixture of crude 3,4-chlorobenzoyl acetate (79.3 mmol), triethyl orthoformate (23.5 g, 159 mmol) and acetic anhydride (16.2 g, 159 mmol) was stirred with heating at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethylene acetate (16.6 g, yield: 66%) as a yellow oil.

  To a solution of t-butylhydrazine hydrochloride (2.43 g, 18.9 mmol) in toluene (35 mL) was added 5% aqueous sodium hydroxide solution (35 mL) under ice-cooling, and then 2- (3,4-dichlorobenzoyl). ) A solution of ethyl 2-ethoxymethylene acetate (5.0 g, 15.8 mmol) in toluene (15 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (20 mL) and triethylamine (2.20 mL) were added to this and refluxed at 100 ° C. overnight. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give pink solid 1-tert-butyl-5- (3,4-dichlorophenyl) pyrazole- A mixture of ethyl 4-carboxylate and ethyl 1-t-butyl-3- (3,4-dichlorophenyl) pyrazole-4-carboxylate (4.78 g, yield: 89%, production ratio: 73/27) was obtained. It was.

1-t-butyl-5- (3,4-dichlorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.11 (3H, t, J = 7.1 Hz), 1 .47 (9H, s), 4.04-4.11 (2H, m), 7.16 (1H, dd, J = 8.2 and 2.0 Hz), 7.42 (1H, d, J = 2. 0 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.93 (1H, s).
1-t-butyl-3- (3,4-dichlorophenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.31 (3H, t, J = 7.1 Hz), 1 .64 (9H, s), 4.26 (2H, q, J = 7.1 Hz), 7.46 (1H, d, J = 8.4 Hz), 7.72 (1H, dd, J = 8. 4 and 2.0 Hz), 7.97 (1H, d, J = 2.0 Hz), 8.08 (1H, s).
A mixture of ethyl 1-t-butyl-5- (3,4-dichlorophenyl) pyrazole-4-carboxylate and ethyl 1-t-butyl-3- (3,4-dichlorophenyl) pyrazole-4-carboxylate (4. 00 g, 11.7 mmol) in ethanol (50 mL) was added 10% aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at room temperature overnight and at 60 ° C. for 6 hours. After cooling to room temperature, the reaction mixture was acidified with concentrated hydrochloric acid, water (50 mL) was added, and the solvent was evaporated. The produced precipitate was collected by filtration and washed with water to give 1-tert-butyl-5- (3,4-dichlorophenyl) pyrazole-4-carboxylic acid and 1-tert-butyl-3- (3) as white solids. , 4-dichlorophenyl) pyrazole-4-carboxylic acid (3.22 g, yield: 88%, production ratio: 67/33) was obtained.

1-t-butyl-5- (3,4-dichlorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 7.16 (1H, dd, J = 8.2 and 2.0 Hz), 7.41 (1H, d, J = 2.0 Hz), 7.51 (1H, d, J = 8.2 Hz), 7.97 (1H, s).
1-t-butyl-3- (3,4-dichlorophenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.63 (9H, s), 7.46 (1H, d, J = 8.1 Hz), 7.72 (1H, dd, J = 8.4 and 2.0 Hz), 7.95 (1H, d, J = 2.0 Hz), 8.14 (1H, s).
Reference Example-30

  A mixture of 1-t-butyl-5- (3,4-dichlorophenyl) pyrazole-4-carboxylic acid and 1-t-butyl-3- (3,4-dichlorophenyl) pyrazole-4-carboxylic acid (2.00 g, To a solution of 6.39 mmol) in acetone (20 mL), triethylamine (0.97 g, 9.58 mmol) and then ethyl chloroformate (0.76 g, 7.02 mmol) were slowly added under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.83 g, 12.8 mmol) in water (2 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (30 mL) was added to the reaction solution, and extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution 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) to give N- [1-t-butyl-5 as a white solid. -(3,4-Dichlorophenyl) pyrazol-4-yl] carbamate t-butyl (0.92 g, yield: 38%) and yellow solid N- [1-tert-butyl-3- (3,4- Dichlorophenyl) pyrazol-4-yl] t-butyl carbamate (0.51 g, yield: 21%) was obtained.

T-butyl N- [1-t-butyl-5- (3,4-dichlorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (18H, s), 5.50 (1H, brs), 7.18 (1H, d, J = 7.1 Hz), 7.44 (1H, d, J = 1.1 Hz), 7.55 (1H, d, J = 8) .2 Hz), 7.79 (1H, brs).
T-butyl N- [1-t-butyl-3- (3,4-dichlorophenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s), 1.60 (9H, s), 6.13 (1H, brs), 7.46-7.51 (2H, m), 7.76 (1H, s), 7.89 (1H, brs).
To a solution of t-butyl N- [1-t-butyl-5- (3,4-dichlorophenyl) pyrazol-4-yl] carbamate (0.881 g, 2.29 mmol) in 1,4-dioxane (15 mL) was added 2N. Hydrochloric acid (15 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/2). To give gray solid 4-amino-1-tert-butyl-5- (3,4-dichlorophenyl) pyrazole (0.31 g, yield: 48%). Mp: 144.2-145.2 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.42 (9H, s), 2.60 (2H, brs), 7.18-7.20 (2H, m), 7.45 (1H, d, J = 2.0 Hz), 7.54 (1H, d, J = 8.2 Hz).
Reference Example-31

  To a mixture of diethyl carbonate (120 mL) and potassium t-butoxide (11.9 g, 106 mmol), a solution of 4-trifluoromethylacetophenone (10 g, 53.1 mmol) in diethyl carbonate (20 mL) was added dropwise with stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-trifluoromethylbenzoyl acetate (yield: quantitative). .

  A mixture of ethyl 4-trifluoromethylbenzoyl acetate (13.8 g, 53.1 mmol), triethyl orthoformate (15.7 g, 106 mmol) and acetic anhydride (10.8 g, 106 mmol) was heated and stirred at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain light yellow solid ethyl 2-ethoxymethylene-2- (4-trifluoromethylbenzoyl) acetate (13.1 g, yield: 78%).

  To a toluene (30 mL) solution of t-butylhydrazine hydrochloride (4.06 g, 31.6 mmol) was added 5% aqueous sodium hydroxide solution (30 mL) under ice-cooling, and then 2-ethoxymethylene-2- (4 -A solution of ethyl trifluoromethylbenzoyl) acetate (5.0 g, 15.8 mmol) in toluene (15 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (20 mL) and triethylamine (1.81 mL) were added to this, and the mixture was refluxed at 100 ° C. overnight. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 1-tert-butyl-5- (4-trifluoromethylphenyl) pyrazole-4- A mixture of ethyl carboxylate and ethyl 1-t-butyl-3- (4-trifluoromethylphenyl) pyrazole-4-carboxylate (5.06 g, yield: 94%, production ratio: 70/30) was obtained. .

1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.04 (3H, t, J = 7.1 Hz), 1.45 (9H, s), 4.04 (2H, q, J = 7.1 Hz), 7.46 (2H, dd, J = 8.5 and 0.6 Hz), 7.70 (2H, d, J = 8.0 Hz), 7.96 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
1-t-butyl-3- (4-trifluoromethylphenyl) pyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.30 (3H, t, J = 7.1 Hz), 1.65 (9H, s), 4.26 (2H, q, J = 7.1 Hz), 7.65 (2H, d, J = 8.0 Hz), 7.95 (2H, d, J = 8) .0Hz), 8.10 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.6 (3F, s).
A mixture of ethyl 1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylate and ethyl 1-t-butyl-3- (4-trifluoromethylphenyl) pyrazole-4-carboxylate ( To a solution of 5.00 g, 14.7 mmol) in ethanol (50 mL) was added 10% aqueous sodium hydroxide solution (15 mL), and the mixture was stirred at 80 ° C. overnight. After cooling to room temperature, the reaction mixture was acidified with concentrated hydrochloric acid, water (50 mL) was added, and the solvent was evaporated. The produced precipitate was collected by filtration and washed with water, whereby 1-tert-butyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid and 1-tert-butyl-3- ( 4-Trifluoromethylphenyl) pyrazole-4-carboxylic acid (4.58 g, yield: quantitative, production ratio: 69/31) was obtained.

1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (9H, s), 7.44 (2H, d , J = 8.0 Hz), 7.68 (2H, d, J = 8.0 Hz), 7.99 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
1-t-butyl-3- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.64 (9H, s), 7.64 (2H, d , J = 8.2 Hz), 7.93 (2H, d, J = 8.0 Hz), 8.15 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.6 (3F, s).
Reference Example-32

  A mixture of 1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid and 1-t-butyl-3- (4-trifluoromethylphenyl) pyrazole-4-carboxylic acid (2. To a mixture of 50 g, 8.01 mmol), triethylamine (1.22 g, 12.0 mmol) and acetone (30 mL), ethyl chloroformate (0.956 g, 8.81 mmol) was slowly added under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (1.04 g, 16.0 mmol) in water (3 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution 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) to give N- [1-t-butyl-5 as a white solid. -(4-Trifluoromethylphenyl) pyrazol-4-yl] carbamate t-butyl (1.12 g, yield: 37%) and yellow oil N- [1-t-butyl-3- (4-tri Fluoromethylphenyl) pyrazol-4-yl] t-butyl carbamate (0.56 g, yield: 18%) was obtained.

T-butyl N- [1-t-butyl-5- (4-trifluoromethylphenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.43 (18H, s) , 5.48 (1H, brs), 7.48 (2H, d, J = 7.9 Hz), 7.73 (2H, d, J = 8.0 Hz), 7.82 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, s).
T-Butyl N- [1-t-butyl-3- (4-trifluoromethylphenyl) pyrazol-4-yl] carbamate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s) , 1.61 (9H, s), 6.24 (1H, brs), 7.69 (2H, d, J = 8.2 Hz), 7.76 (2H, d, J = 8.1 Hz), 7 .95 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.5 (3F, s).
To a solution of t-butyl N- [1-t-butyl-5- (4-trifluoromethylphenyl) pyrazol-4-yl] carbamate (0.80 g, 2.09 mmol) in 1,4-dioxane (10 mL) 2N hydrochloric acid (10 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/2). To give 4-amino-1-t-butyl-5- (4-trifluoromethylphenyl) pyrazole (0.17 g, yield: 29%) as a white solid. Mp: 144.4-146.3 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.42 (9H, s), 2.59 (2H, brs), 7.22 (1H, s), 7.48 (2H, d, J = 7. 8 Hz), 7.73 (2H, d, J = 7.9 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
Reference Example-33

  To a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (13.1 g, 117 mmol) with stirring at 60 ° C., 3,5-bis (trifluoromethyl) acetophenone (15 g, 58.6 mmol) of diethyl carbonate ( 20 mL) solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (yield: quantitative). Obtained).

  A mixture of ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (58.6 mmol), triethyl orthoformate (17.4 g, 117 mmol) and acetic anhydride (12.0 g, 118 mmol) was heated and stirred at 135 ° C. for 2 hours. Then, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give ethyl 2- [3,5-bis (trifluoromethyl) benzoyl] -2-ethoxymethylene acetate (14.9 g, yield: 66%) as a pale yellow solid. Obtained.

  To a solution of t-butylhydrazine hydrochloride (3.34 g, 26.0 mmol) in toluene (25 mL) was added 5% aqueous sodium hydroxide solution (25 mL) under ice-cooling, and then 2- [3,5-bis ( A solution of (trifluoromethyl) benzoyl] -2-ethoxymethylene ethyl acetate (5.0 g, 13.0 mmol) in toluene (15 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethanol (20 mL) and triethylamine (1.81 mL) were added to this, and the mixture was refluxed at 100 ° C. overnight. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 5- [3,5-bis (trifluoromethyl) phenyl] -1-t- A mixture of ethyl butylpyrazole-4-carboxylate and ethyl 3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylate (4.85 g, yield: 91%, Production ratio: 72/28).

Ethyl 5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 0.98 (3H, t, J = 7.1 Hz), 1.45 (9 H, s), 4.02 (2 H, q, J = 7.1 Hz), 7.80 (2 H, s), 7.99 (1 H, s), 8.34 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, s).
Ethyl 3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylate: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.28 (3H, t, J = 7.1 Hz), 1.66 (9 H, s), 4.27 (2 H, q, J = 7.1 Hz), 7.86 (1 H, s), 7.99 (2 H, s), 8.14 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (6F, s).
Ethyl 5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylate and 3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butyl To a solution of ethyl pyrazole-4-carboxylate (4.08 g, 10.0 mmol) in ethanol (50 mL) was added 10% aqueous sodium hydroxide solution (10 mL), and the mixture was stirred for 2 hours at room temperature and 6 hours at 60 ° C. did. After cooling to room temperature, the reaction mixture was acidified with concentrated hydrochloric acid, water (50 mL) was added, and the solvent was evaporated. The produced precipitate was collected by filtration and washed with water to give 5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylic acid and 3- [3 , 5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylic acid (3.64 g, yield: 96%, production ratio: 70/30) was obtained.

5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.44 (9H, s), 7. 77 (2H, s), 7.97 (1H, s), 8.33 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.0 (6F, s).
3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylic acid: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.65 (9H, s), 7. 86 (1H, s), 8.00 (2H, s), 8.18 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, s).
Reference Example-34

5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole-4-carboxylic acid and 3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole To a mixture of -4-carboxylic acid (2.50 g, 6.57 mmol), triethylamine (0.998 g, 9.86 mmol) and acetone (20 mL), ethyl chloroformate (0.784 g, 7.22 mmol) was added to ice. Slowly added under cold. After stirring at the same temperature for 20 minutes, a solution of sodium azide (0.855 g, 13.2 mmol) in water (2 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (30 mL) was added to the reaction solution, and extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction solution was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- [5- {3,5- Bis (trifluoromethyl) phenyl} -1-t-butylpyrazol-4-yl] carbamate t-butyl and N- [3- {3,5-bis (trifluoromethyl) phenyl} -1-t-butyl A mixture of t-butyl pyrazol-4-yl] carbamate (2.10 g, yield: 71%, production ratio: 70/30) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.38-1.62 (18H, s), 5.48 (0.66H, brs), 6.01 (0.28H, brs), 7.69- 8.15 (4H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, m).
N- [5- {3,5-bis (trifluoromethyl) phenyl} -1-t-butylpyrazol-4-yl] carbamate t-butyl and N- [3- {3,5-bis (trifluoro) 2N Hydrochloric acid (15 mL) was added to a solution of t-butyl (methyl) phenyl} -1-t-butylpyrazol-4-yl] carbamate (1.50 g, 3.32 mmol) in 1,4-dioxane (30 mL). And heated at 80 ° C. for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1). To give a yellow solid of 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1-tert-butylpyrazole (0.62 g, yield: 53%) and 4 of a yellow oil. -Amino-3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole (0.23 g, yield: 19%) was obtained.

4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole: Mp: 95.2-96.1 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.40 (9H, s), 2.55 (2H, brs), 7.23 (1H, s), 7.83 (2H, m), 7.96 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.9 (6F, s).
4-amino-3- [3,5-bis (trifluoromethyl) phenyl] -1-t-butylpyrazole: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.59 (9H, s), 3.03 (2H, brs), 7.25 (1H, s), 7.74 (1H, s), 8.34 (2H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (6F, s).
Reference Example-35

  A mixture of ethyl benzoyl acetate (25.0 g, 130 mmol), triethyl orthoformate (38.6 g, 261 mmol) and acetic anhydride (25 mL, 265 mmol) was stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C. over 5 hours. The solution returned to room temperature was purified by distillation under reduced pressure to obtain yellow oily ethyl 2-benzoyl-2-ethoxymethylene acetate (23.0 g, yield: 71%).

To a solution of phenylhydrazine (2.40 g, 22.2 mmol) in toluene (20 mL) was added 5% aqueous sodium hydroxide solution (20 mL), and ethyl 2-ethoxymethylenebenzoyl acetate (5.00 g, 20.1 mmol) was added at 0 ° C. And then stirred at the same temperature for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with toluene (20 mL × 2). The combined organic layer was washed with saturated brine (20 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 = 9 / 1-5). / 1) to obtain ethyl 1,5-diphenylpyrazole-4-carboxylate (2.96 g, yield: 50%) as a yellow solid. ¹ H-NMR (250 MHz, CDCl ₃ ) δ 1.22 (3H, t, J = 7.2 Hz), 4.21 (2H, q, J = 7.2 Hz), 7.18-7.38 (10H, m), 8.19 (1H, s). Further, a tan solid ethyl 1,3-diphenylpyrazole-4-carboxylate (572 mg, yield: 10%) was obtained as a by-product. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.31 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 7.26-7.97 (10H , M), 8.51 (1H, s).
To a solution of ethyl 1,5-diphenylpyrazole-4-carboxylate (2.94 g, 10.1 mmol) in ethanol (30 mL) was added 10% aqueous sodium hydroxide (30 mL), and the mixture was stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration. This was washed with water and hexane, and dried by toluene azeotropy to obtain 1,5-diphenylpyrazole-4-carboxylic acid (2.63 g, yield: 99%) as a pale yellow solid. ¹ H-NMR (250 MHz, DMSO-d ₆ ): δ 7.18-7.22 (2H, m), 7.26-7.37 (8H, m), 8.14 (1H, s), 12. 34 (1H, brs).
Reference Example-36

To a solution of 1,5-diphenylpyrazole-4-carboxylic acid (2.62 g, 9.91 mmol) in toluene (15 mL) was added thionyl chloride (5 mL), refluxed for 2 hours, and then toluene and excess thionyl chloride were added to Dean. -Removed using Stark tube. Furthermore, after removing the solvent from the reaction solution under reduced pressure, acetone (20 mL) and triethylamine (1.50 g, 14.8 mmol) were added and ice-cooled. A solution of sodium azide (1.30 g, 20.0 mmol) in water (5 mL) was slowly added thereto, and the mixture was stirred at the same temperature for 10 minutes. Water (100 mL) was added to the reaction solution, and the mixture was extracted with toluene (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL) and dried over anhydrous magnesium sulfate. Next, a solution obtained by distilling off a part of the solvent under reduced pressure while paying sufficient attention not to precipitate a solid was added to 2,2,2-trichloroethanol (4.45 g, 29.8 mmol) in a reflux state. ) In toluene (10 mL) and then refluxed for another 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give N- (1,5-diphenylpyrazol-4-yl as a light brown solid. ) 2,2,2-trichloroethyl carbamate (2.88 g, yield: 71%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.82 (2H, s), 6.49 (1H, brs), 7.20-7.41 (10H, m), 8.11 (1H, brs) .
To a solution of 2,2,2-trichloroethyl N- (1,5-diphenylpyrazol-4-yl) carbamate (2.87 g, 6.99 mmol) in acetic acid (90 mL), water (10 mL) and zinc (6. 0 g) was added and stirred at room temperature for 20 minutes. Zinc was removed by filtration, and the filtrate was concentrated under reduced pressure. A 10% aqueous sodium hydroxide solution (50 mL) was added to the obtained crude product, and the mixture was extracted with ethyl acetate (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. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 3 / 2− Then, 4-amino-1,5-diphenylpyrazole (1.38 g, yield: 84%) was obtained as a light brown solid. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.09 (2H, brs), 7.17-7.40 (10H, m), 7.47 (1H, s).
Reference Example-37

  To a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144 mmol), a solution of 2-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) was added dropwise with stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (220 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 2-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 2-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, 160 The temperature was raised to 0 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (2-fluorobenzoyl) acetate (12.7 g, yield: 66%).

To a solution of 2,4,6-trifluorophenylhydrazine (1.83 g, 11.3 mmol) in toluene (10 mL) was added 5% aqueous sodium hydroxide solution (9 mL) under ice cooling, and then 2-ethoxymethylene- A solution of ethyl 2- (2-fluorobenzoyl) acetate (3.0 g, 11.3 mmol) in toluene (10 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown oil. Ethanol (20 mL) and triethylamine (1.59 mL) were added to this and refluxed for 1 hour. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give white solid 5- (2-fluorophenyl) -1- (2, 4, 6 -Trifluorophenyl) pyrazole-4-carboxylate (1.37 g, yield: 33%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 4.22 (2H, q, J = 7.1 Hz), 6.71 (2H, t, J = 7.9 Hz), 7.03-7.08 (1H, m), 7.13 (1 H, td, J = 7.6 and 1.1 Hz), 7.25-7.29 (1 H, m), 7 .36-7.41 (1H, m), 8.28 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, m), −112.4 (1F, m), −102.9 (1F, m).
To a solution of ethyl 5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (1.37 g, 3.76 mmol) in ethanol (10 mL) was added 10% hydroxide. Aqueous sodium solution (3 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with concentrated hydrochloric acid, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layers are combined, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give yellow solid 5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (1.20 g, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.71 (2H, t, J = 8.1 Hz), 7.03-7.15 (2H, m), 7.25-7.29 (1H, m ), 7.37-7.42 (1H, m), 8.33 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, m), −112.3 (1F, m), −102.6 (1F, m).
Reference Example-38

To a solution of 5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (1.20 g, 3.57 mmol) in acetone (15 mL) was added triethylamine (0.54 g). , 5.35 mmol), and then ethyl chloroformate (0.43 g, 3.93 mmol) was added slowly under ice cooling. The reaction solution was stirred at the same temperature for 20 minutes, and then a solution of sodium azide (0.464 g, 7.14 mmol) in water (1.2 mL) was slowly added. The reaction mixture was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution 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) to give N- [5- (2-fluorophenyl) as a yellow solid. ) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.937 g, yield: 64%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 6.11 (1H, brs), 6.66-6.72 (2H, m), 7.10-7.20 ( 3H, m), 7.35-7.41 (1H, m), 8.29 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (2F, s), -113.4 (1F, s), -104.3 (1F, s).
1,4-N- [5- (2-Fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.611 g, 1.50 mmol) 2N hydrochloric acid (7.5 mL) was added to the dioxane (10 mL) solution, and the mixture was refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give red-brown solid 4-amino-5- (2-fluorophenyl) -1- (2,4,6-trifluorophenyl). Pyrazole (0.317 g, yield: 69%) was obtained. Mp: 99.6-101.5 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.11 (2H, brs), 6.67-6.71 (2H, m), 7.07-7.19 (3H, m), 7.30- 7.36 (1H, m), 7.57 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.2 (2F, m), -113.6 (1F, m), -105.1 (1F, t, J = 6.4 Hz).
Reference Example-39

  To a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144 mmol), a solution of 4-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (20 mL) was added dropwise with stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (220 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-fluorobenzoyl acetate (yield: quantitative).

  After stirring a mixture of ethyl 4-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (14.8 g, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl ethyl 2-ethoxymethylene-2- (4-fluorobenzoyl) acetate (14.6 g, yield: 76%).

To a solution of 2,4,6-trifluorophenylhydrazine (1.83 g, 11.3 mmol) in toluene (10 mL) was added 5% aqueous sodium hydroxide solution (9 mL) under ice cooling, and then 2-ethoxymethylene- A solution of ethyl 2- (4-fluorobenzoyl) acetate (3.0 g, 11.3 mmol) in toluene (10 mL) was added dropwise. The reaction solution was stirred at the same temperature for 10 minutes, acidified with concentrated hydrochloric acid, and extracted with ethyl acetate (30 mL × 1, 20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a brown oil. Ethanol (20 mL) and triethylamine (1.59 mL) were added to this and refluxed for 1 hour. After completion of the reaction, the residue concentrated under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (4-fluorophenyl) -1- (2,4,6) as a yellow oil. -Trifluorophenyl) pyrazole-4-carboxylate (1.07 g, yield: 26%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24 (3H, t, J = 7.1 Hz), 4.22 (2H, q, J = 7.1 Hz), 6.69-6.75 (2H M), 7.03 (2H, t, J = 8.7 Hz), 7.27-7.31 (2H, m), 8.25 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, m), -110.5 (1F, s), -102.6 (1F, m).
To a solution of ethyl 5- (4-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (1.04 g, 2.85 mmol) in ethanol (10 mL) was added 10% sodium hydroxide. Aqueous solution (2 mL) was added and stirred at room temperature for 2 hours. The reaction mixture was acidified with concentrated hydrochloric acid, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layers are combined, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give yellow solid 5- (4-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (0.888 g, yield: 93%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.70-6.74 (2H, m), 7.03 (2H, t, J = 8.7 Hz), 7.27-7.30 (2H, m ), 8.28 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, d, J = 6.9 Hz), -110.0 (1F, s), −102.2 (1F, t, J = 7) .2 Hz).
Reference Example-40

To a solution of 5- (4-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (0.885 g, 2.63 mmol) in acetone (15 mL) was added triethylamine (0.40 g). , 3.95 mmol), and then ethyl chloroformate (0.31 g, 2.89 mmol) was added slowly under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.342 g, 5.26 mmol) in water (1 mL) was slowly added. The reaction mixture was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 30 minutes. 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) to give N- [5- (4-fluorophenyl) as a yellow oil. ) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.608 g, yield: 57%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.04 (1H, brs), 6.68-6.73 (2H, m), 7.07 (2H, t, J = 8.6 Hz), 7. 19-7.23 (2H, m), 8.24 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, s), -110.8 (1F, s), -103.8 (1F, s).
1,4-N- [5- (4-Fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.608 g, 1.49 mmol) To a dioxane (10 mL) solution, 2N hydrochloric acid (7 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-5- (4-fluorophenyl) -1- (2,4,6-trifluorophenyl) as a yellow solid. Pyrazole (0.381 g, yield: 83%) was obtained. Mp: 86.6-88.0 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.06 (2H, brs), 6.69-6.73 (2H, m), 7.05 (2H, t, J = 8.7 Hz), 7. 19-7.23 (2H, m), 7.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.0 Hz), -112.2 (1F, s), -104.5 (1F, t, J = 6) .7 Hz).
Reference Example-41

  To a mixture of diethyl carbonate (55 mL) and potassium t-butoxide (7.19 g, 64.1 mmol) with stirring at 60 ° C., 3,5-difluoroacetophenone (5.0 g, 32.0 mmol) in diethyl carbonate (10 mL). ) The solution was added dropwise. The reaction mixture was stirred at the same temperature for 3 hours, cooled to room temperature, 2N hydrochloric acid (110 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a brown oily ethyl 3,5-difluorobenzoyl acetate (yield: quantitative). It was.

  A mixture of ethyl 3,5-difluorobenzoyl acetate (14.6 g, 64.0 mmol), triethyl orthoformate (19.0 g, 128 mmol) and acetic anhydride (13.1 g, 128 mmol) was heated and stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,5-difluorobenzoyl) -2-ethoxymethylene acetate (12.2 g, yield: 67%) as a yellow oil.

To a solution of 2,4,6-trifluorophenylhydrazine (2.85 g, 17.6 mmol) in ethanol (10 mL) was added triethylamine (1.78 g, 17.6 mmol) under ice cooling, and then 2- (3 , 5-Difluorobenzoyl) -2-ethoxymethylene ethyl acetate (5.0 g, 17.6 mmol) in ethanol (10 mL) was added dropwise. After the reaction solution was stirred at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (3,5-difluorophenyl) -5- (2,4,6-trifluorophenyl) as a yellow solid. Ethyl pyrazole-4-carboxylate (5.50 g, yield: 82%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25 (3H, t, J = 7.1 Hz), 4.24 (2H, q, J = 7.1 Hz), 6.73-6.79 (2H M), 6.81-6.87 (3H, m), 8.25 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 7.8 Hz), −108.9 (2F, s), −101.9 (1F, t, J = 7) .4 Hz).
To a solution of ethyl 5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (5.50 g, 14.4 mmol) in ethanol (20 mL) was added 10% Aqueous sodium hydroxide solution (12 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4- Carboxylic acid (4.80 g, yield: 94%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.74-6.79 (2H, m), 6.83-6.88 (3H, m), 8.29 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.9 Hz), −108.5 (2F, s), −101.5 (1F, t, J = 7) .4 Hz).
Reference Example-42

To a solution of 5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (2.13 g, 6.0 mmol) in acetone (20 mL) was added triethylamine (0 .915 g, 9.0 mmol) was added, and then ethyl chloroformate (0.716 g, 6.6 mmol) was slowly added under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.780 g, 12.0 mmol) in water (2 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction mixture was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- [5- (3,5- Difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.79 g, yield: 70%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s), 6.06 (1H, brs), 6.73-6.85 (5H, m), 8.23 (1H, brs) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, s), −107.4 (2F, s), −103.2 (1F, s).
N- [5- (3,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.80 g, 1.88 mmol) 1, To a solution of 4-dioxane (15 mL), 2N hydrochloric acid (9.4 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (3,5-difluorophenyl) -1- (2,4,6-trifluoro) as a yellow solid. Phenyl) pyrazole (0.550 g, yield: 90%) was obtained. Mp: 132.7-134.3 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.16 (2H, brs), 6.73-6.79 (5H, m), 7.55 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.0 (2F, d, J = 6.8 Hz), −108.1 (2F, s), −104.0 (1F, t, J = 6) .8 Hz).
Reference Example-43

  A solution of 3,4-dichloroacetophenone (15.0 g, 79.3 mmol) in diethyl carbonate (20 mL) was stirred at 60 ° C. into a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (17.8 g, 159 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,4-dichlorobenzoyl acetate (yield: quantitative). .

  A mixture of crude 3,4-chlorobenzoyl acetate (79.3 mmol), triethyl orthoformate (23.5 g, 159 mmol) and acetic anhydride (16.2 g, 159 mmol) was stirred with heating at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethylene acetate (16.6 g, yield: 66%) as a yellow oil.

2- (3,4-dichlorobenzoyl) -2-ethoxymethylene ethyl acetate (1.59 g, 5.01 mmol), 2,4,6-trifluorophenylhydrazine (815 mg, 5.03 mmol) and triethylamine (510 mg, 5 (.04 mmol) in ethanol (10 mL) was stirred at room temperature for 14 hours. The reaction solution was distilled off under reduced pressure to obtain ethyl 5- (3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate as black oil. ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.25 (3H, t, J = 7.0 Hz), 4.24 (2H, q, J = 7.0 Hz), 6.70-6.81 (2H M), 7.12 (1H, dd, J = 8.3 and 2.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 7.44 (1H, d, J = 2.0 Hz) , 8.25 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.6 (2F, d, J = 7.1 Hz), −102.2 (1F, t, J = 7.1 Hz).
To a solution of the crude product (5.01 mmol) of ethyl 5- (3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate in ethanol (15 mL) was added 10% water. An aqueous sodium oxide solution (15 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 2N hydrochloric acid, and the precipitated solid was collected by filtration to give a brown solid of 5- (3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxyl. An acid (1.77 g, yield: 91%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 6.73-6.79 (2H, m), 7.13 (1H, dd, J = 8.3 and 1.8 Hz), 7.41-7.44 (2H , M), 8.29 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.5 (2F, d, J = 7.1 Hz), −101.8 (1F, t, J = 7.1 Hz).
Reference Example-44

To a solution of 5- (3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (1.75 g, 4.52 mmol) in acetone (25 mL), triethylamine (670 mg, 6.62 mmol) was added, and then ethyl chloroformate (0.47 mL, 4.92 mmol) was added dropwise under ice cooling, followed by stirring at the same temperature for 10 minutes. A solution of sodium azide (580 mg, 8.92 mmol) in water (2 mL) was added dropwise thereto, and the mixture was further stirred at the same temperature for 10 minutes. Water (80 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 (680 mg, 4.55 mmol) and toluene (10 mL), and the mixture was further refluxed for 3 hours. The reaction solution 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) to give N- [5- (3,4- Dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate 2,2,2-trichloroethyl (1.80 g, yield: 75%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.83 (2H, s), 6.43 (1H, brs), 6.71-6.81 (2H, m), 7.05 (1H, dd, J = 8.3 and 2.0 Hz), 7.37 (1H, d, J = 2.0 Hz), 7.46 (1H, d, J = 8.3 Hz), 8.16 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 7.1 Hz), −102.9 (1F, t, J = 7.1 Hz).
N- [5- (3,4-Dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate 2,2,2-trichloroethyl (1.77 g, 3.32 mmol) Water (7 mL) and zinc (3.0 g) were added to an acetic acid (49 mL) solution, and the mixture was stirred at room temperature for 45 minutes. Insoluble solids were removed from the reaction solution by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with toluene (40 mL × 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/2). 1-aminoethyl triethylamine was added) to give 4-amino-5- (3,4-dichlorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole (1.07 g, yield: 90) as a yellow solid. %). Mp: 169-174 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.07 (2H, brs), 6.69-6.80 (2H, m), 7.02 (1H, dd, J = 8.3 and 2.0 Hz), 7.38 (1H, d, J = 2.0 Hz), 7.41 (1H, d, J = 8.3 Hz), 7.55 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (2F, d, J = 7.1 Hz), −104.2 (1F, t, J = 7.1 Hz).
Reference Example-45

  A solution of 3,4-dichloroacetophenone (15.0 g, 79.3 mmol) in diethyl carbonate (20 mL) was stirred at 60 ° C. in a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (17.8 g, 159 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,4-dichlorobenzoyl acetate (yield: quantitative). .

  A mixture of a crude product of ethyl 2-chlorobenzoyl acetate (79.3 mmol), triethyl orthoformate (23.5 g, 159 mmol) and acetic anhydride (16.2 g, 159 mmol) was heated and stirred at 135 ° C. for 2 hours. The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain ethyl 2- (3,4-dichlorobenzoyl) -2-ethoxymethylene acetate (16.6 g, yield: 66%) as a yellow oil.

2- (3,4-Dichlorobenzoyl) -2-ethoxymethylene ethyl acetate (1.59 g, 5.01 mmol), 2-ethylphenylhydrazine hydrochloride (870 mg, 5.04 mmol) and triethylamine (1.02 g, 10. 1 mmol) in ethanol (10 mL) was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure and then suspended in ethyl acetate. The insoluble solid was then filtered off, and the filtrate was concentrated under reduced pressure to give a brown oily ethyl 5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole-4-carboxylate (2.10 g, Yield: quantitative). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.07 (3H, t, J = 7.5 Hz), 1.28 (3H, t, J = 7.0 Hz), 2.30 (2H, q, J = 7.5 Hz), 4.25 (2H, q, J = 7.0 Hz), 7.04 (1H, dd, J = 8.3 and 2.0 Hz), 7.09 (1H, d, J = 7. 8, 1.3 Hz), 7.16-7.23 (1 H, m), 7.26-7.36 (3 H, m), 7.39 (1 H, d, J = 2.0 Hz), 8. 19 (1H, s).
To a solution of a crude product of ethyl 5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole-4-carboxylate (5.01 mmol) in ethanol (15 mL), 10% aqueous sodium hydroxide solution (15 mL) And stirred at room temperature for 1 hour. The reaction mixture was acidified with 2N hydrochloric acid, and the precipitated solid was collected by filtration to give a brown solid of 5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole-4-carboxylic acid (1. 63 g, yield: 90%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.07 (3H, t, J = 7.5 Hz), 2.30 (2H, q, J = 7.5 Hz), 7.04-7.11 (2H M), 7.17-7.40 (5H, m), 8.25 (1H, s).
Reference Example-46

Add triethylamine (670 mg, 6.62 mmol) to a solution of 5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole-4-carboxylic acid (1.60 g, 4.43 mmol) in acetone (25 mL). Then, ethyl chloroformate (0.47 mL, 4.92 mmol) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. A solution of sodium azide (580 mg, 8.92 mmol) in water (2 mL) was added dropwise thereto, and the mixture was further stirred at the same temperature for 10 minutes. Water (80 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 (680 mg, 4.55 mmol) and toluene (10 mL), and the mixture was further refluxed for 3 hours. The reaction mixture was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give N- [5- (3,4- Dichlorophenyl) -1- (2-ethylphenyl) pyrazol-4-yl] carbamate 2,2,2-trichloroethyl (1.53 g, yield: 68%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.04 (3H, t, J = 7.5 Hz), 2.33 (2H, q, J = 7.5 Hz), 4.84 (2H, s), 6.44 (1H, brs), 6.94 (1H, dd, J = 8.3 and 2.0 Hz), 7.11-7.40 (6H, m), 8.02 (1H, brs).
N- [5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazol-4-yl] carbamate 2,2,2-trichloroethyl (1.50 g, 2.95 mmol) in acetic acid (49 mL) ) Water (7 mL) and zinc (3.0 g) were added to the solution and stirred at room temperature for 50 minutes. Insoluble solids were removed from the reaction solution by filtration, the filtrate was concentrated under reduced pressure, 10% aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with toluene (40 mL × 3). The organic layers were combined, washed with saturated brine (40 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting crude product was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1, Purification with 1% triethylamine was added to give orange solid 4-amino-5- (3,4-dichlorophenyl) -1- (2-ethylphenyl) pyrazole (786 mg, yield: 80%). Mp: 109-118 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.02 (3H, t, J = 7.5 Hz), 2.34 (2H, q, J = 7.5 Hz), 3.10 (2H, brs), 6.91 (1H, dd, J = 8.3 and 2.0 Hz), 7.10-7.37 (6H, m), 7.45 (1H, s).
Reference Example-47

  To a mixture of diethyl carbonate (120 mL) and potassium t-butoxide (11.9 g, 106 mmol), a solution of 4-trifluoromethylacetophenone (10 g, 53.1 mmol) in diethyl carbonate (20 mL) was added dropwise with stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give brown oily ethyl 4-trifluoromethylbenzoyl acetate (yield: quantitative). .

  A mixture of ethyl 4- (trifluoromethyl) benzoyl acetate (13.8 g, 53.1 mmol), triethyl orthoformate (15.7 g, 106 mmol) and acetic anhydride (10.8 g, 106 mmol) was heated at 135 ° C. for 2 hours. After stirring, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain light yellow solid ethyl 2-ethoxymethylene-2- (4-trifluoromethylbenzoyl) acetate (13.1 g, yield: 78%).

A solution of 2,4,6-trifluorophenylhydrazine (2.56 g, 15.8 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (1.60 g, 15.8 mmol) was added, and 2-ethoxymethylene- A solution of ethyl 2- (4-trifluoromethylbenzoyl) acetate (5.0 g, 15.8 mmol) in ethanol (10 mL) was added dropwise. After the reaction solution was stirred at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give yellow solid 5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) Ethyl pyrazole-4-carboxylate (4.97 g, yield: 76%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.23 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 6.70-6.76 (2H M), 7.44 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8.1 Hz), 8.27 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 6.9 Hz), −102.0 (1 F, t, J = 7.3 Hz), −63.0 (3F) , S).
To a solution of ethyl 5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (4.97 g, 12.0 mmol) in ethanol (20 mL) was added 10% Aqueous sodium hydroxide (10 mL) was added and stirred at room temperature for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic layers were combined, dried over anhydrous magnesium sulfate, and dried under reduced pressure to give 5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4- Carboxylic acid (4.38 g, yield: 95%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.71-6.75 (2H, m), 7.43 (2H, d, J = 8.1 Hz), 7.60 (2H, d, J = 8) .1 Hz), 8.31 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.1 Hz), −101.7 (1F, t, J = 7.4 Hz), −63.0 (3F) , S).
Reference Example-48

To a solution of 5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (2.32 g, 6.0 mmol) in acetone (20 mL) was added triethylamine (0 .915 g, 9.0 mmol) was added, and then ethyl chloroformate (0.716 g, 6.6 mmol) was slowly added under ice cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.780 g, 12.0 mmol) in water (2 mL) was slowly added. The reaction was stirred at the same temperature for an additional 40 minutes. Water (50 mL) was added to the reaction solution, and the mixture was extracted with toluene (50 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- [5- (4-trifluoro) as a yellow solid. Methylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.84 g, yield: 67%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 6.07 (1H, brs), 6.71-6.75 (2H, m), 7.36 (2H, d, J = 8.0 Hz), 7.65 (2H, d, J = 8.1 Hz), 8.26 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, s), -103.3 (1F, s), -62.9 (3F, s).
N- [5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.80 g, 1.75 mmol) 1, To a 4-dioxane (15 mL) solution, 2N hydrochloric acid (8.7 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-trifluoromethylphenyl) -1- (2,4,6-trifluoro) as a yellow solid. Phenyl) pyrazole (570 mg, yield: 91%) was obtained. Mp: 120.0-120.8 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.14 (2H, brs), 6.70-6.76 (2H, m), 7.35 (2H, d, J = 8.0 Hz), 7. 57 (1H, s), 7.61 (2H, d, J = 8.1 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.0 (2F, d, J = 6.8 Hz), −104.1 (1F, t, J = 6.7 Hz), −62.8 (3F) , S).
Reference Example-49

  To a mixture of diethyl carbonate (130 mL) and potassium t-butoxide (13.1 g, 117 mmol) with stirring at 60 ° C., 3,5-bis (trifluoromethyl) acetophenone (15 g, 58.6 mmol) of diethyl carbonate ( 20 mL) solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, 2N hydrochloric acid (270 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give a brown oily ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (yield: quantitative). Obtained).

  A mixture of ethyl 3,5-bis (trifluoromethyl) benzoyl acetate (19.2 g. 58.6 mmol), triethyl orthoformate (17.4 g, 117 mmol) and acetic anhydride (12.0 g, 117 mmol) was added at 135 ° C. After heating and stirring for 2 hours, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give ethyl 2- [3,5-bis (trifluoromethyl) benzoyl] -2-ethoxymethylene acetate (14.9 g, yield: 66%) as a pale yellow solid. Obtained.

A solution of 2,4,6-trifluorophenylhydrazine (2.11 g, 13.0 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (1.32 g, 13.0 mmol) was added, and then 2- [3, A solution of ethyl 5-bis (trifluoromethyl) benzoyl] -2-ethoxymethylene acetate (5.0 g, 13.0 mmol) in ethanol (10 mL) was added dropwise. After the reaction solution was stirred at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 1- [3,5-bis (trifluoromethyl) phenyl] -5- (2,4,6- Ethyl trifluorophenyl) pyrazole-4-carboxylate (4.87 g, yield: 78%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 6.76 (2H, t, J = 8.1 Hz), 7.78 (2H, s), 7.89 (1H, s), 8.31 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 7.5 Hz), −101.2 (1F, t, J = 7.4 Hz), −63.1 (6F) , S).
Ethyl 5- [3,5-bis (trifluoromethyl) phenyl] -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (4.87 g, 10.1 mmol) in ethanol (20 mL) To the solution was added 10% aqueous sodium hydroxide solution (8 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was acidified with concentrated hydrochloric acid, water (20 mL) was added, and the mixture 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 5- [3,5-bis (trifluoromethyl) phenyl] -1- (2,4,6-trifluorophenyl) as a yellow solid. Pyrazole-4-carboxylic acid (4.14 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.75-6.79 (2H, m), 7.77 (2H, s), 7.90 (1H, s), 8.34 (1H, s) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 7.9 Hz), −100.8 (1F, t, J = 7.5 Hz), −63.2 (6F) , S).
Reference Example-50

A solution of 5- [3,5-bis (trifluoromethyl) phenyl] -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (2.73 g, 6.0 mmol) in acetone (20 mL) Was added triethylamine (0.915 g, 9.0 mmol), and then ethyl chloroformate (0.716 g, 6.6 mmol) was slowly added under ice-cooling. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.780 g, 12.0 mmol) in water (2 mL) was slowly added. The reaction solution was further stirred at the same temperature for 40 minutes, water (50 mL) was added, and the mixture was extracted with toluene (50 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and a 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 (10 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction solution was returned to room temperature, and the crude product obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- [5- {3,5- Bis (trifluoromethyl) phenyl} -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (2.13 g, yield: 67%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 6.01 (1H, brs), 6.73-6.79 (2H, m), 7.71 (2H, s) , 7.86 (1H, s), 8.10 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -102.4 (1F, s), -63.1 (6F, s).
N- [5- {3,5-bis (trifluoromethyl) phenyl} -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.80 g, 1. To a solution of 52 mmol) in 1,4-dioxane (15 mL), 2N hydrochloric acid (7.6 mL) was added and refluxed for 1 hour. The reaction solution was returned to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- [3,5-bis (trifluoromethyl) phenyl] -1- (2,4 , 6-trifluorophenyl) pyrazole (0.619 g, yield: 96%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.18 (2H, brs), 6.73-6.79 (2H, m), 7.59 (1H, s), 7.69 (2H, s) , 7.80 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.8 Hz), −103.2 (1F, t, J = 6.8 Hz), −63.2 (6F) , S).
Reference Example-51

A solution of 3-trifluoromethylacetophenone (10.8 g, 57.4 mmol) in diethyl carbonate (22 mL) with stirring at 60 ° C. in a mixture of diethyl carbonate (135 mL) and potassium t-butoxide (12.8 g, 114 mmol). Was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (235 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give ethyl 3-trifluoromethylbenzoyl acetate (yield: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.23-1.31 (3H, m), 4.05, 5.72 and 12.65 (total 2H), 4.19-4.30 (2H, m) 7.54-8.21 (4H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.1 (3F, m).
A mixture of ethyl 3-trifluoromethylbenzoyl acetate (15.0 g, 57.6 mmol), triethyl orthoformate (17.1 g, 115 mmol) and acetic anhydride (10.9 mL, 115 mmol) was heated and stirred at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (3-trifluoromethylbenzoyl) acetate (11.6 g, yield: 64%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.03-1.46 (6H, m), 4.11-4.34 (4H, m), 7.59-8.14 (5H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-63.0 (3F, m).
To a solution of ethyl 2-ethoxymethylene-2- (3-trifluoromethylbenzoyl) acetate (4.74 g, 15.0 mmol) in ethanol (15 mL), add a 25% aqueous ammonia solution (2) so that the reaction temperature does not exceed 30 ° C. 24 mL, 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.81 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 1-methyl-5- (3-trifluoromethylphenyl) pyrazole-4- Ethyl carboxylate (3.84 g, yield: 86%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.15 (3H, t, J = 7.1 Hz), 3.75 (3H, s), 4.15 (2H, q, J = 7.1 Hz), 7.57-7.66 (3H, m), 7.75 (1H, d, J = 7.6 Hz), 8.02 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
A mixed solution of ethyl 1-methyl-5- (3-trifluoromethylphenyl) pyrazole-4-carboxylate (3.58 g, 12.0 mmol), ethanol (12 mL), 10% aqueous sodium hydroxide (10 mL) was added at room temperature. For 30 minutes. After completion of the reaction, the reaction mixture was neutralized with concentrated hydrochloric acid, poured into water (50 mL), and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. This solution was dried under reduced pressure to obtain 1-methyl-5- (3-trifluoromethylphenyl) pyrazole-4-carboxylic acid (2.57 g, yield: 72%) as a white solid. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.75 (3H, s), 7.57-7.65 (3H, m), 7.75 (1H, d, J = 7.6 Hz), 8. 04 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
Reference Example-52

Triethylamine (0.911 g, 9.00 mmol) was added to a solution of 1-methyl-5- (3-trifluoromethylphenyl) pyrazole-4-carboxylic acid (1.62 g, 6.00 mmol) in acetone (30 mL) and iced. After cooling, ethyl chloroformate (0.629 mL, 6.60 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.780 g, 12.0 mmol) in water (2 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (6.2 g) and toluene (30 mL) in reflux, and further refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give colorless oil N- [1-methyl-5- T-Butyl (3-trifluoromethylphenyl) pyrazol-4-yl] carbamate (1.14 g, yield: 56%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.45 (9H, s), 3.77 (3H, s), 5.82 (1H, brs), 7.55-7.73 (4H, m) 7.79 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
To a solution of t-butyl N- [1-methyl-5- (3-trifluoromethylphenyl) pyrazol-4-yl] carbamate (1.00 g, 2.92 mmol) in 1,4-dioxane (15 mL) was added 2N hydrochloric acid. (15 mL) was added and stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then dried under reduced pressure to give 4-amino-1-methyl-5- (3-trifluoromethylphenyl). Pyrazole (0.626 g, yield: 89%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.92 (2H, brs), 3.76 (3H, s), 7.25 (1H, s), 7.57-7.68 (4H, m) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
Reference Example-53

While stirring at 60 ° C., a solution of 3-methoxyacetophenone (10.0 g, 66.6 mmol) in diethyl carbonate (20 mL) was added dropwise to a mixture of diethyl carbonate (150 mL) and potassium t-butoxide (15.0 g, 134 mmol). And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (275 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain ethyl 3-methoxybenzoyl acetate (yield: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.22-1.29 (3H, m), 3.81 (3H, s), 3.96, 5.65 and 12.62 (total 2H), 4.16 -4.27 (2H, m), 6.96-7.50 (4H, m).
After stirring a mixture of ethyl 3-methoxybenzoyl acetate (14.8 g, 66.6 mmol), triethyl orthoformate (22.2 mL, 133 mmol) and acetic anhydride (12.6 mL, 133 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (3-methoxybenzoyl) acetate (11.4 g, yield: 62%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05-1.40 (6H, m), 3.81 (3H, s), 4.04-4.25 (4H, m), 7.02- 7.71 (5H, m).
To a solution of ethyl 2-ethoxymethylene-2- (3-methoxybenzoyl) acetate (4.17 g, 15.0 mmol) in ethanol (15 mL) was added 25% aqueous ammonia solution (2.24 mL) so that the reaction temperature did not exceed 30 ° C. 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.81 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (3-methoxyphenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (2.10 g, yield: 53%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (3H, t, J = 7.1 Hz), 3.74 (3H, s), 3.84 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 6.90 (1H, dd, J = 2.6 and 1.5 Hz), 6.94 (1H, ddd, J = 7.5, 1.5 and 0.9 Hz), 7.01 (1H, ddd, J = 8.3, 2.6 and 0.9 Hz), 7.39 (1 H, dd, J = 8.3 and 7.5 Hz), 7.98 (1 H, s).
A mixed solution of ethyl 5- (3-methoxyphenyl) -1-methylpyrazole-4-carboxylate (1.82 g, 7.00 mmol), ethanol (7 mL), 10% aqueous sodium hydroxide solution (6 mL) at 60 ° C. Stir for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with concentrated hydrochloric acid, poured into water (50 mL), and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. This solution was dried under reduced pressure to obtain white solid 5- (3-methoxyphenyl) -1-methylpyrazole-4-carboxylic acid (1.09 g, yield: 67%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.73 (3H, s), 3.83 (3H, s), 6.89 (1H, dd, J = 2.6 and 1.5 Hz), 6.94 ( 1H, ddd, J = 7.5, 1.5 and 0.9 Hz), 7.02 (1 H, ddd, J = 8.4, 2.6 and 0.9 Hz), 7.39 (1H, dd, J = 8. 4 and 7.5 Hz), 8.02 (1H, s).
Reference Example-54

Triethylamine (0.84 mL, 6.0 mmol) was added to a solution of 5- (3-methoxyphenyl) -1-methylpyrazole-4-carboxylic acid (0.93 g, 4.00 mmol) in acetone (20 mL), and the mixture was ice-cooled. Later, ethyl chloroformate (0.42 mL, 4.4 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.52 g, 8.0 mmol) in water (2 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (5 mL) and toluene (30 mL) in a reflux state, and further refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give colorless oil N- [5- (3-methoxy Phenyl) -1-methylpyrazol-4-yl] carbamate t-butyl (0.73 g, yield: 60%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.76 (3H, s), 3.85 (3H, s), 5.97 (1H, brs), 6.87 (1H, s), 6.92 (1H, d, J = 7.5 Hz), 6.99 (1H, ddd, J = 8.4, 2.6 and 0.8 Hz), 7.42 (1H, dd, J = 8.4 and 7.5 Hz), 7.87 (1H, brs).
To a solution of t-butyl N- [5- (3-methoxyphenyl) -1-methylpyrazol-4-yl] carbamate (0.70 g, 2.3 mmol) in 1,4-dioxane (12 mL) was added 2N hydrochloric acid (12 mL). ) And stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to give 4-amino-5- (3-methoxyphenyl) -1-methyl. Pyrazole (0.32 g, yield: 69%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.94 (2H, brs), 3.76 (3H, s), 3.85 (3H, s), 6.90-6.96 (3H, m) , 7.23 (1H, s), 7.41 (1H, dd, J = 8.4 and 7.5 Hz).
Reference Example-55

While stirring at 60 ° C., a solution of 3-fluoroacetophenone (10.0 g, 72.4 mmol) in diethyl carbonate (27 mL) was added dropwise to a mixture of diethyl carbonate (170 mL) and potassium t-butoxide (16.3 g, 145 mmol). And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (300 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give ethyl 3-fluorobenzoyl acetate (yield: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.23-1.30 (3H, m), 3.98, 5.66 and 12.60 (total 2H), 4.18-4.28 (2H, m) , 7.11-7.73 (4H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.5and-111.6 (total 1F).
After stirring a mixture of ethyl 3-fluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (24.1 mL, 145 mmol) and acetic anhydride (15.0 mL, 145 mmol) at 135 ° C. for 2 hours, The temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (3-fluorobenzoyl) acetate (13.0 g, yield: 67%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.04-1.44 (6H, m), 4.09-4.30 (4H, m), 7.17-7.74 (5H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.7 and 112.4 (total 1F).
To a solution of ethyl 2-ethoxymethylene-2- (3-fluorobenzoyl) acetate (4.00 g, 15.0 mmol) in ethanol (15 mL), add a 25% aqueous ammonia solution (2.24 mL) so that the reaction temperature does not exceed 30 ° C. 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.81 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 5- (3-fluorophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (3.72 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (3H, t, J = 7.1 Hz), 3.74 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.09-7.21 (3H, m), 7.43-7.49 (1H, m), 7.99 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.4 (1F, s).
A mixed solution of ethyl 5- (3-fluorophenyl) -1-methylpyrazole-4-carboxylate (2.60 g, 10.5 mmol), ethanol (10 mL), 10% aqueous sodium hydroxide (8 mL) at 60 ° C. Stir for 3 hours. The mixture was cooled to room temperature, neutralized with concentrated hydrochloric acid, and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtered. This solution was dried under reduced pressure to obtain 5- (3-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (2.13 g, yield: 92%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.74 (3H, s), 7.08-7.22 (3H, m), 7.43-7.49 (1H, m), 8.03 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-112.1 (1F, s).
Reference Example-56

Triethylamine (2.09 mL, 15.0 mmol) was added to a solution of 5- (3-fluorophenyl) -1-methylpyrazole-4-carboxylic acid (2.20 g, 10.0 mmol) in acetone (50 mL), and the mixture was cooled with ice. Later, ethyl chloroformate (1.05 mL, 11.0 mmol) was added slowly. After the reaction solution was stirred at the same temperature for 20 minutes, a solution of sodium azide (1.30 g, 20.0 mmol) in water (4 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (13 mL) and toluene (13 mL) in a reflux state, and further refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give colorless oil N- [5- (3-fluoro Phenyl) -1-methylpyrazol-4-yl] carbamate t-butyl (0.95 g, yield: 33%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.77 (3H, s), 5.90 (1H, brs), 7.07-7.10 (1H, m) 7.13-7.19 (2H, m), 7.46-7.52 (1H, m), 7.85 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-11. 12 (1F, s).
To a solution of t-butyl N- [5- (3-fluorophenyl) -1-methylpyrazol-4-yl] carbamate (1.11 g, 3.8 mmol) in 1,4-dioxane (19 mL) was added 2N hydrochloric acid (19 mL). ) And stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure. The resulting crude product was purified by column chromatography to obtain 4-amino-5- (3-fluorophenyl) -1-methylpyrazole (0.50 g, yield: 69%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.05 (2H, brs), 3.74 (3H, s), 7.05-7.10 (2H, m), 7.14-7.17 ( 1H, m), 7.18 (1H, s), 7.42-7.48 (1H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-111.7 (1F, s).
Reference Example-57

To a mixture of diethyl carbonate (125 mL) and potassium t-butoxide (16.2 g, 144.4 mmol) with stirring at 60 ° C., 3,4-difluoroacetophenone (11.3 g, 72.4 mmol) in diethyl carbonate (20 mL). ) The solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (220 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to obtain reddish brown oily ethyl 3,4-difluorobenzoyl acetate (16.5 g, yield: Quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24-1.33 (3H, m), 3.93, 5.58 and 12.6 (total 2H, m), 4.18-4.29 (2H, m), 6.97-7.83 (3H, m).
A mixture of ethyl 3,4-difluorobenzoyl acetate (15.2 g, 72.4 mmol), triethyl orthoformate (21.5 g, 145 mmol) and acetic anhydride (13.7 mL, 145 mmol) was stirred with heating at 135 ° C. for 2 hours. Thereafter, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to obtain yellow oily ethyl 2-ethoxymethylene-2- (3,4-difluorobenzoyl) acetate (9.38 g, yield: 50%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.07-1.51 (6H, m), 4.08-4.30 (4H, m), 6.94-7.75 (4H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.7 (1F, m), -130.5 (1F, m).
To a solution of ethyl 2-ethoxymethylene-2- (3,4-difluorobenzoyl) acetate (4.26 g, 15.0 mmol) in ethanol (12 mL), a 25% aqueous ammonia solution (2) so that the reaction temperature does not exceed 30 ° C. 25 mL, 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.875 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, followed by stirring at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (3,4-difluorophenyl) -1-methylpyrazole-4- Ethyl carboxylate (2.36 g, yield: 59%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (3H, t, J = 7.1 Hz), 3.74 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 7.12 (1H, dddd, J = 8.4, 4.3, 2.0 and 1.6 Hz), 7.24 (1 H, ddd, J = 10.5, 7.5 and 2.1 Hz), 7.29 ( 1H, dt, J = 10.0 and 8.3 Hz), 7.98 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.7 (1F, d, J = 20.6 Hz), −135.7 (1F, d, J = 21.5 Hz).
A mixture of ethyl 5- (3,4-difluorophenyl) -1-methylpyrazole-4-carboxylate (2.00 g, 7.51 mmol), acetic acid (15.0 mL) and concentrated hydrochloric acid (7.5 mL) for 16 hours. Refluxed. The reaction solution cooled to room temperature was poured into water (200 mL), and the precipitated solid was collected by filtration and then dried under reduced pressure to give white solid 5- (3,4-difluorophenyl) -1-methylpyrazole-4-carboxylic acid. The acid (1.62 g, yield: 91%) was obtained. ¹ H-NMR (400 MHz, DMSO-d6): δ 3.78 (3H, s), 7.32-7.36 (1 H, m), 7.57 (1 H, dt, J = 10.8 and 8.5 Hz) , 7.65 (1H, ddd, J = 11.5, 7.8 and 2.1 Hz), 7.89 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-138.8 (1F, d, J = 22.1 Hz), -137.7 (1F, d, J = 22.9 Hz).
Reference Example-58

Triethylamine (0.759 g, 7.50 mmol) was added to a solution of 5- (3,4-difluorophenyl) -1-methylpyrazole-4-carboxylic acid (1.191 g, 5.00 mmol) in acetone (15 mL) and iced. After cooling, ethyl chloroformate (0.524 mL, 5.50 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.650 g, 10.0 mmol) in water (1.7 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give colorless oil N- [5- (3,4 -Difluorophenyl) -1-methylpyrazol-4-yl] t-butyl carbamate (0.59 g, yield: 38%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.75 (3H, s), 5.88 (1H, brs), 7.08-7.13 (1H, m) , 7.22 (1H, ddd, J = 10.0, 7.5 and 2.0 Hz), 7.31 (1 H, dt, J = 10.0 and 8.3 Hz), 7.78 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.1 (1F, d, J = 20.4 Hz), −135.6 (1 F, d, J = 20.4 Hz).
To a solution of t-butyl N- [5- (3,4-difluorophenyl) -1-methylpyrazol-4-yl] carbamate (0.40 g, 1.29 mmol) in 1,4-dioxane (10 mL) was added 2N hydrochloric acid. (6.5 mL) was added and stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then dried under reduced pressure to give 4-amino- [5- (3,4-difluorophenyl) as a tan solid. )]-1-methylpyrazole (0.27 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.89 (2H, brs), 3.74 (3H, s), 7.10-7.14 (1H, m), 7.19-7.24 ( 2H, m), 7.30 (1H, dt, J = 10.1 and 8.4 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-137.3 (1F, d, J = 21.7 Hz), −136.0 (1F, d, J = 21.7 Hz).
Reference Example 59

To a mixture of diethyl carbonate (80 mL) and potassium t-butoxide (10.1 g, 90.0 mmol) with stirring at 60 ° C., 4-chloro-3-trifluoromethylacetophenone (10.02 g, 45.0 mmol) was added. A solution of diethyl carbonate (10 mL) was added dropwise, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (140 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give a yellow brown oily ethyl 4-chloro-3-trifluoromethylbenzoyl acetate (13.2 g). Yield: quantitative). ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25-1.33 (3H, m), 3.97, 5.69 and 12.6 (total 2H, m), 4.20-4.32 (2H, m), 7.56-8.28 (3H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, m).
Ethyl 4-chloro-3-trifluoromethylbenzoyl acetate (13.26 g, 45.0 mmol), triethyl orthoformate (15.0 mL, 13.4 g, 90.0 mmol) and acetic anhydride (8.5 mL, 9.20 g, 90.0 mmol) was heated and stirred at 135 ° C. for 2 hours, and then heated to 160 ° C. to distill off the low-boiling compounds over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give ethyl 2- (4-chloro-3-trifluoromethylbenzoyl) -2-ethoxymethylene acetate (13.0 g, yield: 82%) as a yellow oil. . ^{1 H-NMR (400MHz, CDCl} 3): δ1.06-1.49 (6H, m), 4.11-4.35 (4H, m), 7.56-8.17 (4H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, m).
To a solution of ethyl 2- (4-chloro-3-trifluoromethylbenzoyl) -2-ethoxymethylene acetate (5.26 g, 15.0 mmol) in ethanol (12 mL) was added 25% so that the reaction temperature did not exceed 30 ° C. Aqueous ammonia solution (2.25 mL, 30.1 mmol) was added dropwise. Next, 98% methyl hydrazine (0.875 mL, 15.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, followed by stirring at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (4-chloro-3-trifluoromethylphenyl) -1-methyl. Ethyl pyrazole-4-carboxylate (4.36 g, yield: 87%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.19 (3H, t, J = 7.1 Hz), 3.76 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 7.52 (1H, dd, J = 8.3 and 1.9 Hz), 7.64 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 2.1 Hz), 8.01 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.7 (3F, s).
Of ethyl 5- (4-chloro-3-trifluoromethylphenyl) -1-methylpyrazole-4-carboxylate (4.00 g, 12.0 mmol), acetic acid (24.0 mL) and concentrated hydrochloric acid (12.0 mL). The mixture was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (200 mL), and the precipitated solid was collected by filtration and then dried under reduced pressure to give white solid 5- (4-chloro-3-trifluoromethyl) -1-methylpyrazole- 4-carboxylic acid (2.84 g, yield: 78%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.76 (3H, s), 7.52 (1H, dd, J = 8.0 and 1.9 Hz), 7.64 (1H, d, J = 8.2 Hz) ), 7.71 (1H, d, 2.0 Hz), 8.04 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, s).
Reference Example-60

Triethylamine (0.759 g, 7.50 mmol) was added to a solution of 5- (4-chloro-3-trifluoromethylphenyl) -1-methylpyrazole-4-carboxylic acid (1.523 g, 5.00 mmol) in acetone (15 mL). After adding ice and cooling with ice, ethyl chloroformate (0.524 mL, 5.50 mmol) was slowly added. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (0.650 g, 10.0 mmol) in water (1.7 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with toluene (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (20 mL) in a reflux state, and further refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give colorless oil N- [5- (4-chloro -3-Trifluoromethylphenyl) -1-methylpyrazol-4-yl] t-butyl carbamate (1.13 g, yield: 60%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.45 (9H, s), 3.77 (3H, s), 5.80 (1H, brs), 7.50 (1H, dd, J = 8. 2 and 1.9 Hz), 7.67 (1 H, d, J = 8.2 Hz), 7.72 (1 H, s), 7.74 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, s).
1,4-Dioxane (10 mL) of t-butyl N- [5- (4-chloro-3-trifluoromethylphenyl) -1-methylpyrazol-4-yl] carbamate (0.40 g, 1.06 mmol) 2N hydrochloric acid (6.5 mL) was added to the solution, and the mixture was stirred at 80 ° C. for 1 hr. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then dried under reduced pressure to give a tan solid 4-amino- [5- (4-chloro-3- Trifluoromethylphenyl)]-1-methylpyrazole (0.27 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.91 (2H, brs), 3.76 (3H, s), 7.24 (1H, s), 7.51 (1H, dd, J = 8. 2 and 2.0 Hz), 7.64 (1H, d, J = 8.2 Hz), 7.72 (1H, d, J = 2.0 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-62.8 (3F, s).
Reference Example-61

To a mixture of diethyl carbonate (215 mL) and potassium t-butoxide (28.2 g, 251 mmol), a solution of 3-bromoacetophenone (25.0 g, 126 mmol) in diethyl carbonate (35 mL) was added dropwise with stirring at 60 ° C. Stir at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (400 mL) was added. Ethyl acetate (100 mL × 3) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain red-brown oily ethyl 3-bromobenzoyl acetate (yield: quantitative). . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.25-1.35 (3H, m), 3.96, 5.65 and 12.54 (total 2H, m), 4.17-4.30 (2H, m), 7.26-8.08 (4H, m).
A mixture of ethyl 3-bromobenzoyl acetate (34.1 g, 126 mmol), triethyl orthoformate (37.2 g, 251 mmol) and acetic anhydride (23.7 mL, 251 mmol) was stirred with heating at 135 ° C. for 2 hours, then 160 ° C. The low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give ethyl 2- (3-bromobenzoyl) -2-ethoxymethylene acetate (31.4 g, yield: 76%) as a yellow oil. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.04-1.46 (6H, m), 4.09-4.31 (4H, m), 7.28-8.00 (5H, m).
To a solution of ethyl 2- (3-bromobenzoyl) -2-ethoxymethyleneacetate (9.815 g, 30.0 mmol) in ethanol (25 mL) was added 25% aqueous ammonia solution (4.50 mL) so that the reaction temperature did not exceed 30 ° C. , 60.0 mmol) was added dropwise. Next, 98% methyl hydrazine (1.75 mL, 30.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (3-bromophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (8.65 g, yield: 93%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.18 (3H, t, J = 7.1 Hz), 3.74 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.31 (1H, dt, J = 7.7 and 1.4 Hz), 7.36 (1 H, td, J = 7.7 and 0.3 Hz), 7.54 (1 H, t, J = 1.7 Hz), 7 .62 (1H, ddd, J = 7.8, 1.9 and 1.4 Hz), 7.99 (1H, s).
To a solution of ethyl 5- (3-bromophenyl) -1-methylpyrazole-4-carboxylate (7.73 g, 25.0 mmol) in ethanol (25 mL) was added 10% aqueous sodium hydroxide solution (25 mL), and For 2 hours. The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid, and water (50 mL) was added. The deposited precipitate was collected by filtration, washed with water, and dried under reduced pressure to give white solid 5- (3-bromophenyl) -1-methylpyrazole-4-carboxylic acid (6.84 g, yield: 97%). Got. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 3.67 (3H, s), 7.46-7.49 (2H, m), 7.68-7.71 (2H, m), 7. 89 (1H, s).
Reference Example-62

Triethylamine (2.43 g, 24.0 mmol) was added to a solution of 5- (3-bromophenyl) -1-methylpyrazole-4-carboxylic acid (4.50 g, 16.0 mmol) in acetone (50 mL), and the mixture was ice-cooled. Later, ethyl chloroformate (1.68 mL, 17.6 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (2.08 g, 32.0 mmol) in water (5.5 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (80 mL) was added to the reaction solution, and extracted with toluene (100 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (5.0 mL) and toluene (50 mL) in a reflux state, and further refluxed overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (3- Bromophenyl) -1-methylpyrazol-4-yl] carbamate t-butyl (2.89 g, yield: 51%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.76 (3H, s), 5.88 (1H, brs), 7.29 (1H, dt, J = 7. 7 and 1.2 Hz), 7.39 (1 H, t, J = 7.8 Hz), 7.52 (1 H, brs), 7.59 (1 H, ddd, J = 8.0, 2.0 and 1.2 Hz), 7.81 (1H, brs).
To a solution of t-butyl N- [5- (3-bromophenyl) -1-methylpyrazol-4-yl] carbamate (1.50 g, 4.26 mmol) in 1,4-dioxane (25 mL) was added 2N hydrochloric acid (21 0.5 mL) was added and stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then dried under reduced pressure to give a tan solid 4-amino- [5- (3-bromophenyl)]. −1-methylpyrazole (1.08 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.92 (2H, brs), 3.75 (3H, s), 7.22 (1H, s), 7.31 (1H, dt, J = 8. 0 and 1.4 Hz), 7.37 (1 H, t, J = 8.0 Hz), 7.52 to 7.55 (2 H, m).
Reference Example-63

While stirring at 60 ° C., a solution of 4-bromoacetophenone (25.0 g, 126 mmol) in diethyl carbonate (35 mL) was added dropwise to a mixture of diethyl carbonate (215 mL) and potassium t-butoxide (28.2 g, 251 mmol). Stir at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (400 mL) was added. Ethyl acetate (100 mL × 3) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was distilled off under reduced pressure to obtain red brown oily ethyl 4-bromobenzoyl acetate (yield: quantitative). . ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24-1.33 (3H, m), 3.95, 5.64 and 12.56 (total 2H), 4.18-4.30 (2H, m) 7.54-7.83 (4H, m).
A mixture of ethyl 4-bromobenzoyl acetate (34.1 g, 126 mmol), triethyl orthoformate (37.2 g, 251 mmol) and acetic anhydride (23.7 mL, 251 mmol) was stirred with heating at 135 ° C. for 2 hours, then 160 ° C. The low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give yellow oily 2- (4-bromobenzoyl) -2-ethoxymethylene-2- (4-bromobenzoyl) ethyl acetate (33.5 g, yield: 82%) Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.05-1.45 (6H, m), 4.08-4.30 (4H, m), 7.46-7.77 (5H, m).
To a solution of ethyl 2- (4-bromobenzoyl) -2-ethoxymethyleneacetate (9.815 g, 30.0 mmol) in ethanol (25 mL) was added 25% aqueous ammonia solution (4.50 mL) so that the reaction temperature did not exceed 30 ° C. , 60.0 mmol) was added dropwise. Next, 98% methyl hydrazine (1.75 mL, 30.0 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (4-bromophenyl) -1-methylpyrazole-4-carboxylic acid. Ethyl (8.37 g, yield: 90%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 3.73 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.26 (2H, d, J = 8.5 Hz), 7.62 (2H, d, J = 8.5 Hz), 7.98 (1H, s).
To a solution of ethyl 5- (4-bromophenyl) -1-methylpyrazole-4-carboxylate (7.73 g, 25.0 mmol) in ethanol (25 mL) was added 10% aqueous sodium hydroxide solution (25 mL), and For 2 hours. The reaction mixture was cooled to room temperature, acidified with concentrated hydrochloric acid, and water (50 mL) was added. The precipitated precipitate was collected by filtration, washed with water, and dried under reduced pressure to give white solid 5- (4-bromophenyl) -1-methylpyrazole-4-carboxylic acid (7.02 g, yield: quantitative). Got. ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 3.66 (3H, s), 7.42 (2H, d, J = 8.5 Hz), 7.70 (2H, d, J = 8.6 Hz) ), 7.89 (1H, s).
Reference Example-64

Triethylamine (2.43 g, 24.0 mmol) was added to a solution of 5- (4-bromophenyl) -1-methylpyrazole-4-carboxylic acid (4.50 g, 16.0 mmol) in acetone (50 mL), and the mixture was ice-cooled. Later, ethyl chloroformate (1.68 mL, 17.6 mmol) was added slowly. After stirring the reaction solution at the same temperature for 20 minutes, a solution of sodium azide (2.08 g, 32.0 mmol) in water (5.5 mL) was slowly added, and the mixture was further stirred at the same temperature for 40 minutes. Water (80 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), dried over anhydrous magnesium sulfate and filtered, and then 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 (5.0 mL) and toluene (50 mL) in a reflux state, and further refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (4-bromo Phenyl) -1-methylpyrazol-4-yl] carbamate t-butyl (2.72 g, yield: 48%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.46 (9H, s), 3.75 (3H, s), 5.87 (1H, brs), 7.23 (2H, d, J = 8. 4 Hz), 7.65 (2H, d, J = 8.5 Hz), 7.82 (1 H, brs).
To a solution of t-butyl N- [5- (4-bromophenyl) -1-methylpyrazol-4-yl] carbamate (1.50 g, 4.26 mmol) in 1,4-dioxane (25 mL) was added 2N hydrochloric acid (21 0.5 mL) was added and stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then dried under reduced pressure to give a tan solid 4-amino- [5- (4-bromophenyl)]. −1-methylpyrazole (1.07 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.89 (2H, brs), 3.74 (3H, s), 7.22 (1H, s), 7.26 (2H, d, J = 8. 5 Hz), 7.63 (2H, d, J = 8.5 Hz).
Reference Example-65

A solution of 5-acetylindane (10.0 g, 62.4 mmol) in diethyl carbonate (30 mL) was added dropwise to a mixture of diethyl carbonate (100 mL) and potassium t-butoxide (14.0 g, 125 mmol) while stirring at 60 ° C. And stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (200 mL) was added. Ethyl acetate (100 mL × 3) was added to the solution and the layers were separated. The organic layers are combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure to give 3- (2,3-dihydroinden-5-yl) -3-oxopropane. Ethyl acid (yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.24-1.32 (3H, m), 2.12 (2H, quintet, J = 7.5 Hz), 2.88-3.00 (4H, m ), 3.96, 5.63 and 12.59 (total 2H), 4.18-4.28 (2H, m), 7.24-7.80 (3H, m).
Ethyl 3- (2,3-dihydroinden-5-yl) -3-oxopropanoate (14.5 g, 62.4 mmol), triethyl orthoformate (20.8 mL, 125 mmol) and acetic anhydride (11.8 mL, 125 mmol) The mixture was heated and stirred at 135 ° C. for 2 hours, then heated to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give a yellow oily ethyl 3- (2,3-dihydroinden-5-yl) -2-ethoxymethylene-3-oxopropanoate (11.5 g, yield: 62). %). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.07-1.44 (6H, m), 2.11 (2H, quintet, J = 7.4 Hz), 2.92-2.96 (4H, m ), 4.06-4.26 (4H, m), 7.22-7.80 (4H, m).
To a solution of ethyl 3- (2,3-dihydroinden-5-yl) -2-ethoxymethylene-3-oxopropanoate (5.00 g, 17.3 mmol) in ethanol (20 mL), the reaction temperature exceeded 30 ° C. A 25% aqueous ammonia solution (2.60 mL, 34.7 mmol) was added dropwise so that there was not. Next, 98% methyl hydrazine (0.94 mL, 17.4 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (2,3-dihydroinden-5-yl) -1-methyl. Ethyl pyrazole-4-carboxylate (4.00 g, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 2.13 (2H, quintet, J = 7.4 Hz), 2.97 (4H, t, J = 7.4 Hz), 3.73 (3H, s), 4.16 (2H, q, J = 7.1 Hz), 7.12 (1, dd, J = 7.7 and 1.5 Hz), 7.21 (1H, d, J = 1.5 Hz), 7.31 (1H, d, J = 7.7 Hz), 7.97 (1H, s).
To a solution of ethyl 5- (2,3-dihydroinden-5-yl) -1-methylpyrazole-4-carboxylate (4.00 g, 14.8 mmol) in ethanol (20 mL), 10% aqueous sodium hydroxide solution (12 mL) And stirred at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, acidified with concentrated hydrochloric acid, extracted with chloroform (50 mL × 2), washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated to dryness to give 5- (2,3-dihydroinden-5-yl) -1-methylpyrazole-4-carboxylic acid (3.35 g, yield: 94%). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 2.06 (2H, quintet, J = 7.4 Hz), 2.89-2.95 (4H, m), 3.63 (3H, s), 7.16 (1H, dd, J = 7.7 and 1.5 Hz), 7.27 (1H, brs), 7.33 (1H, d, J = 7.7 Hz), 7.86 (1H, s), 12.00 (1H, brs).
Reference Example-66

Triethylamine (0.607 g, 6.00 mmol) in a solution of 5- (2,3-dihydroinden-5-yl) -1-methylpyrazole-4-carboxylic acid (0.969 g, 4.00 mmol) in acetone (20 mL) After adding ice and cooling with ice, ethyl chloroformate (0.42 mL, 4.4 mmol) was slowly added. After stirring the reaction solution at the same temperature for 30 minutes, a solution of sodium azide (0.52 g, 8.0 mmol) in water (3 mL) was slowly added, and the mixture was further stirred at the same temperature for 1 hour. Water (20 mL) was added to the reaction solution, and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then part of the solvent was distilled off under reduced pressure while paying sufficient attention so that no solid precipitated. The resulting acyl azide solution was added dropwise to a refluxing mixture of t-butyl alcohol (1.5 mL) and toluene (10 mL) and further refluxed overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (2,3-dihydroindene). -5-yl) -1-methylpyrazol-4-yl] carbamate t-butyl (0.278 g, yield: 22%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 2.14 (2H, quintet, J = 7.4 Hz), 2.97 (4H, t, J = 7.4 Hz), 3.74 (3H, s), 5.98 (1H, brs), 7.09 (1H, d, J = 7.6 Hz), 7.18 (1H, s), 7.35 (1H, d, J = 7.6 Hz), 7.87 (1H, brs).
1,4-Dioxane (10 mL) of t-butyl N- [5- (2,3-dihydroinden-5-yl) -1-methylpyrazol-4-yl] carbamate (0.272 g, 0.88 mmol) 2N hydrochloric acid (4 mL) was added to the solution and stirred at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (20 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to give 4-amino-5- (2,3-dihydroindene-5 Yl) -1-methylpyrazole (0.150 g, yield: 81%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.13 (2H. Quintet, J = 7.4 Hz), 2.82 (2H, brs), 2.97 (4H, t, J = 7.4 Hz), 3.74 (3H, s), 7.12 (1H, dd, J = 7.7 and 1.6 Hz), 7.21 (1H, brs), 7.22 (1H, s), 7.34 (1H, d, J = 7.7 Hz).
Reference Example-67

To a mixture of diethyl carbonate (100 mL) and potassium t-butoxide (12.6 g, 112 mmol) with stirring at 60 ° C., 6-acetyl-1,4-benzodioxane (10.0 g, 56.1 mmol) in diethyl carbonate (20 mL) The suspension was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (200 mL) was added. Ethyl acetate (100 mL × 3) was added to the solution and the layers were separated. The organic layers were combined and washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure to give ethyl 3- (3,4-ethylenedioxyphenyl) -3-oxopropanoate. (Yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24-1.33 (3H, m), 3.91, 5.55 and 12.58 (total 2H), 4.16-4.33 (6H, m) , 6.87-7.52 (3H, m).
Of ethyl 3- (3,4-ethylenedioxyphenyl) -3-oxopropanoate (14.0 g, 56.1 mmol), triethyl orthoformate (18.7 mL, 112 mmol) and acetic anhydride (10.6 mL, 112 mmol) After the mixture was heated and stirred at 135 ° C. for 2 hours, the temperature was raised to 160 ° C., and the low boiling point compound was distilled off over 3.5 hours. The residue was cooled to room temperature and distilled under reduced pressure to give a yellow oily ethyl 2-ethoxymethylene-3- (3,4-ethylenedioxyphenyl) -3-oxopropanoate (10.1 g, yield: 59%). Got. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.11-1.43 (6H, m), 4.06-4.26 (4H, m), 4.26-4.33 (4H, m), 6.85-7.64 (4H, m).
In a solution of ethyl 2-ethoxymethylene-3- (3,4-ethylenedioxyphenyl) -3-oxopropanoate (5.00 g, 16.3 mmol) in ethanol (20 mL), the reaction temperature should not exceed 30 ° C. A 25% aqueous ammonia solution (2.50 mL, 33.4 mmol) was added dropwise. Next, 98% methylhydrazine (0.88 mL, 16.3 mmol) was added dropwise to this solution while maintaining the reaction temperature at 5 ° C. or lower, and the mixture was stirred at 60 ° C. for 4 hours. Next, the reaction solution was cooled to 20 ° C. or lower, concentrated hydrochloric acid was added while maintaining the temperature to neutralize the solution, followed by extraction with ethyl acetate (50 mL × 2), washing with saturated brine, and anhydrous magnesium sulfate. And dried and filtered. The solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 5- (3,4-ethylenedioxyphenyl) -1-methylpyrazole- Ethyl 4-carboxylate (4.13 g, yield: 88%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.22 (3H, t, J = 7.1 Hz), 3.74 (3H, s), 4.17 (2H, q, J = 7.1 Hz), 4.28-4.33 (4H, m), 6.84 (1H, dd, J = 8.3 and 2.0 Hz), 6.89 (1H, d, J = 2.0 Hz), 6.95 (1H , D, J = 8.3 Hz), 7.95 (1H, s).
To a solution of ethyl 5- (3,4-ethylenedioxyphenyl) -1-methylpyrazole-4-carboxylate (4.13 g, 14.3 mmol) in ethanol (20 mL) was added 10% aqueous sodium hydroxide solution (12 mL). And stirred at 50 ° C. for 1 hour. The reaction solution was cooled to room temperature, acidified with concentrated hydrochloric acid, extracted with chloroform (50 mL × 2), washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. This solvent was dried under reduced pressure to obtain 5- (3,4-ethylenedioxyphenyl) -1-methylpyrazole-4-carboxylic acid (3.71 g, yield: quantitative). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 3.65 (3H, s), 4.28-4.32 (4H, m), 6.88 (1H, dd, J = 8.3 and 2.0 Hz) ), 6.95 (1H, d, J = 8.3 Hz), 6.96 (1H, d, J = 2.0 Hz), 7.84 (1H, s), 12.03 (1H, brs).
Reference Example-68

Triethylamine (1.21 g, 12.0 mmol) was added to a solution of 5- (3,4-ethylenedioxyphenyl) -1-methylpyrazole-4-carboxylic acid (2.082 g, 8.00 mmol) in acetone (30 mL). After cooling with ice, ethyl chloroformate (0.84 mL, 8.8 mmol) was slowly added. After stirring the reaction solution at the same temperature for 30 minutes, a solution of sodium azide (1.04 g, 16.0 mmol) in water (3 mL) was slowly added, and the mixture was further stirred at the same temperature for 1 hour. Water (50 mL) was added to the reaction solution, and extracted with toluene (100 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.5 mL) and toluene (20 mL) in a reflux state, and further refluxed for 2 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [5- (3,4-ethylenediene). Oxyphenyl) -1-methylpyrazol-4-yl] carbamate t-butyl (0.409 g, yield: 15%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 3.73 (3H, s), 4.31 (4H, s), 5.97 (1H, brs), 6.80 (1H, dd, J = 8.2 and 1.9 Hz), 6.84 (1H, d, J = 1.9 Hz), 6.98 (1H, d, J = 8.2 Hz), 7.85 (1H, brs).
To a solution of t-butyl N- [5- (3,4-ethylenedioxyphenyl) -1-methylpyrazol-4-yl] carbamate (0.250 g, 0.75 mmol) in 1,4-dioxane (10 mL) 2N hydrochloric acid (4 mL) was added and stirred at 80 ° C. for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (20 mL × 3). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to give 4-amino-5- (3,4-ethylenedioxyphenyl). −1-methylpyrazole (0.153 g, yield: 97%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.83 (2H, brs), 3.73 (3H, s), 4.31 (4H, s), 6.83 (1H, dd, J = 8. 2 and 2.0 Hz), 6.87 (1 H, d, J = 2.0 Hz), 6.97 (1 H, d, J = 8.2 Hz), 7.20 (1 H, s).
Reference Example-69

A solution of 2,4,6-trifluorophenylhydrazine (2.43 g, 15.0 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (1.52 g) was added, and then 2-ethoxymethylene-2- (3 -A solution of ethyl (trifluoromethylbenzoyl) acetate (4.74 g, 15.0 mmol) in ethanol (15 mL) was added dropwise. After stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4 -Ethyl carboxylate (3.48 g, yield: 56%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.20 (3H, t, J = 7.1 Hz), 4.22 (2H, q, J = 7.1 Hz), 6.73 (2H, dd, J = 8.4 and 7.3 Hz), 7.45-7.52 (2H, m), 7.59 (1 H, s), 7.63-7.65 (1 H, m), 8.28 (1 H, s) ). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 7.0 Hz), −102.1 (1F, t, J = 7.0 Hz), −62.9 (2F) , S).
Ethyl 5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (3.48 g, 8.40 mmol), ethanol (10 mL) and 10% hydroxylation A mixture of aqueous sodium (7 mL) was stirred at 60 ° C. for 5 hours. The reaction solution was cooled to room temperature, poured into water (50 mL), and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness under reduced pressure to give 5- (3-trifluoromethylphenyl) -1- (2,4,4). 6-trifluorophenyl) pyrazole-4-carboxylic acid (1.70 g, yield: 53%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.73 (2H, dd, J = 8.2 and 7.5 Hz), 7.46-7.66 (4H, m), 8.31 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.6 Hz), −101.8 (1 F, t, J = 7.6 Hz), −63.0 (3F) , S).
Reference Example-70

5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (1,70 g, 4.4 mmol), triethylamine (0.67 g, 6.6 mmol) A mixture of acetone and acetone (22 mL) was ice-cooled, and ethyl chloroformate (0.46 mL, 4.8 mmol) was slowly added. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (0.57 g, 8.8 mmol) was dissolved in water (1.5 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (50 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), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (15 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (3- Trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.97 g, yield: 48%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 6.01 (1H, brs), 6.72 (2H, dd, J = 8.4 and 7.4 Hz), 7.42 ( 1H, d, J = 7.7 Hz), 7.50-7.54 (2H, m), 7.63 (1H, d, J = 7.7 Hz), 8.21 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -103.3 (1F, s), -63.0 (3F, s).
T-butyl N- [5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate (0.97 g, 2.1 mmol), 1, A mixture of 4-dioxane (10 mL) and 2N hydrochloric acid (10 mL) was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole (0.69 g, yield: 91%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.12 (2H, brs), 6.72 (2H, dd, J = 8.4 and 7.4 Hz), 7.41 (1H, d, J = 7.8 Hz) ), 7.46-7.50 (2H, m), 7.56 (1H, d, J = 7.8 Hz), 7.57 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.8 Hz), −104.1 (1F, t, J = 6.8 Hz), −63.0 (3F) , S).
Reference Example-71

A solution of 2,4,6-trifluorophenylhydrazine (2.96 g, 18.2 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (1.84 g) was added, and then 2- (3,4-difluorobenzoyl) was added. ) A solution of ethyl 2-ethoxymethylene acetate (5.00 g, 18.2 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give tan oily 5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl). ) Ethyl pyrazole-4-carboxylate (4.42 g, yield: 66%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25 (3H, t, J = 7.1 Hz), 4.24 (2H, q, J = 7.1 Hz), 6.75 (2H, m), 7.00-7.04 (1H, m), 7.09-7.21 (2H, m), 8.24 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.7 (1F, d, J = 21.2 Hz), −134.9 (1F, d, J = 21.2 Hz), −114.4 (2F) , D, J = 7.2 Hz), −102.1 (1F, t, J = 7.2 Hz).
Ethyl 5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (4.42 g, 11.6 mmol), acetic acid (20 mL) and concentrated hydrochloric acid (12 mL ) Was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain a pale yellow solid. This crude product was washed with water and then dried under reduced pressure to give white solid 5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid ( 3.60 g, yield: 88%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.75 (2H, m), 7.00-7.04 (1H, m), 7.10-7.17 (2H, m), 8.29 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.3 (1F, d, J = 20.9 Hz), −134.3 (1 F, d, J = 20.9 Hz), −114.3 (2F) , D, J = 7.8 Hz), −101.7 (1F, t, J = 7.8 Hz).
Reference Example-72

5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (2.125 g, 6.00 mmol), triethylamine (0.915 g, 9.04 mmol) And a mixture of acetone (20 mL) was ice-cooled, and ethyl chloroformate (0.63 mL, 6.6 mmol) was slowly added. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (0.780 g, 12.0 mmol) was dissolved in water (2 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (50 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), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (3, 4-Difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.49 g, yield: 58%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 6.01 (1H, brs), 6.73 (2H, m), 6.96 (1H, dt, J = 8. 5 and 2.0 Hz), 7.09 (1H, dd, J = 10.6 and 2.0 Hz), 7.18 (1 H, q, J = 8.9 Hz), 8.21 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-135.3 (2F, s), -114.6 (2F, s), -103.3 (1H, s).
T-butyl N- [5- (3,4-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate (1.00 g, 2.35 mmol), 1, A mixture of 4-dioxane (15.0 mL) and 2N hydrochloric acid (12.0 mL) was refluxed for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (3,4-difluorophenyl) -1- (2,4,6-trifluoro) as a white solid. Phenyl) pyrazole (0.53 g, yield: 69%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.08 (2H, brs), 6.73 (2H, m), 6.93-6.97 (1H, m), 7.08 (1H, ddd, J = 10.8, 7.5 and 2.1 Hz), 7.15 (1 H, dt, J = 10.1 and 8.4 Hz), 7.54 (1 H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-136.7 (1F, d, J = 21.7 Hz), −135.9 (1F, d, J = 21.7 Hz), −115.0 (2F) , D, J = 6.7 Hz), −104.1 (1H, t, J = 6.7 Hz).
Reference Example-73

A solution of 2,4,6-trifluorophenylhydrazine (2.31 g, 14.3 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (1.45 g) was added, and 2- (4-chloro-3- A solution of ethyl trifluoromethylbenzoyl) -2-ethoxymethylene acetate (5.00 g, 14.3 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give tan solid 5- (4-chloro-3-trifluoromethylphenyl) -1- (2,4,6 -Trifluorophenyl) pyrazole-4-carboxylate (5.46 g, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24 (3H, t, J = 7.1 Hz), 4.24 (2H, q, J = 7.1 Hz), 6.76 (2H, m), 7.42 (1H, dd, J = 8.3 and 1.9 Hz), 7.49 (1H, d, J = 8.3 Hz), 7.66 (1H, d, J = 1.9 Hz) 8.27 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.4 (2F, d, J = 7.2 Hz), −101.6 (1F, t, J = 7.2 Hz), −62.9 (3F) , S).
Ethyl 5- (4-chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (4.96 g, 11.1 mmol), acetic acid (20 mL) and A mixture of concentrated hydrochloric acid (12 mL) was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain a pale yellow solid. The crude product was washed with water and then dried under reduced pressure to give 5- (4-chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4 as a white solid. -Carboxylic acid (4.81 g, yield: quantitative) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.77 (2H, m), 7.43 (1H, dd, J = 8.3 and 1.9 Hz), 7.50 (1H, d, J = 8.3 Hz) ), 7.63 (1H, d, J = 1.9 Hz), 8.31 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 8.0 Hz), −101.2 (1F, t, J = 8.0 Hz), −63.0 (3F) , S).
Reference Example-74

5- (4-Chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (2.52 g, 6.00 mmol), triethylamine (0.915 g, (9.04 mmol) and acetone (20 mL) were ice-cooled, and ethyl chloroformate (0.63 mL, 6.6 mmol) was slowly added. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (0.780 g, 12.0 mmol) was dissolved in water (2 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (50 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), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (4- Chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.12 g, yield: 38%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 5.96 (1H, brs), 6.75 (2H, m), 7.33 (1H, dd, J = 8. 3 and 1.8 Hz), 7.52 (1 H, d, J = 8.3 Hz), 7.59 (1 H, s), 8.16 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -102.8 (1F, s), -63.0 (3F, s).
N- [5- (4-Chloro-3-trifluoromethylphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.80 g, 1.63 mmol) ), 1,4-dioxane (10.0 mL), and 2N hydrochloric acid (8.0 mL) were refluxed for 1 hour. The reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-chloro-3-trifluoromethylphenyl) -1- (2, 4, 6-trifluorophenyl) pyrazole (0.49 g, yield 77%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.11 (2H, brs), 6.75 (2H, m), 7.32 (1H, dd, J = 8.3 and 2.0 Hz), 7.49 ( 1H, d, J = 8.3 Hz), 7.56 (1H, s), 7.59 (1H, d, J = 2.0 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.8 Hz), −103.6 (1 F, t, J = 6.8 Hz), −62.9 (3F) , S).
Reference Example-75

A solution of 2,4,6-trifluorophenylhydrazine (3.24 g, 20.0 mmol) in ethanol (20 mL) was ice-cooled, triethylamine (2.02 g) was added, and then 2- (3-bromobenzoyl)- A solution of ethyl 2-ethoxymethylene acetate (6.54 g, 20.0 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give brown oily 5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole- Ethyl 4-carboxylate (7.23 g, yield: 85%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.23 (3H, t, J = 7.1 Hz), 4.22 (2H, q, J = 7.1 Hz), 6.73 (2H, m), 7.19-7.21 (2H, m), 7.49-7.52 (2H, m), 8.25 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.7 Hz), −102.3 (1F, t, J = 7.7 Hz).
Of ethyl 5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (7.23 g, 17.0 mmol), acetic acid (30 mL) and concentrated hydrochloric acid (17 mL) The mixture was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain a pale yellow solid. The crude product was washed with water and then dried under reduced pressure to give white solid 5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (5. 34 g, yield: 79%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.74 (2H, m), 7.19-7.24 (2H, m), 7.45 (1H, m), 7.50-7.53 ( 1H, m), 8.29 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, d, J = 7.6 Hz), −102.0 (1F, t, J = 7.6 Hz).
Reference Example-76

5- (3-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (3.97 g, 10.0 mmol), triethylamine (1.52 g, 15.0 mmol) and acetone (30 mL) was ice-cooled and ethyl chloroformate (1.05 mL, 11.0 mmol) was added slowly. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (1.30 g, 20.0 mmol) was dissolved in water (3 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (100 mL) was added to the reaction solution, and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (3.0 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (3- Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] t-butyl carbamate (3.47 g, yield: 74%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 6.06 (1H, brs), 6.72 (2H, m), 7.12-7.14 (1H, m) , 7.23 (1H, d, J = 8.0 Hz), 7.40 (1H, m), 7.50 (1H, ddd, J = 8.0, 2.0 and 1.1 Hz), 8.23 ( 1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -103.6 (1F, s).
T-Butyl N- [5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate (2.50 g, 5.34 mmol), 1,4- A mixture of dioxane (25.0 mL) and 2N hydrochloric acid (15.0 mL) was refluxed for 1 hour. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (3-bromophenyl) -1- (2,4,6-trifluorophenyl) as a white solid. Pyrazole (1.69 g, yield: 86%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.12 (2H, brs), 6.73 (2H, m), 7.10-7.23 (2H, m), 7.42-7.45 ( 2H, m), 7.54 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.7 Hz), −104.4 (1F, t, J = 6.7 Hz).
Reference Example-77

A solution of 2,4,6-trifluorophenylhydrazine (3.24 g, 20.0 mmol) in ethanol (20 mL) was ice-cooled, triethylamine (2.02 g) was added, and then 2- (4-bromobenzoyl)- A solution of ethyl 2-ethoxymethylene acetate (6.54 g, 20.0 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 14 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give brown oily 5- (4-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole Ethyl-4-carboxylate (7.09 g, yield: 83%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.25 (3H, t, J = 7.1 Hz), 4.23 (2H, q, J = 7.1 Hz), 6.73 (2H, m), 7.17 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5 Hz), 8.24 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.0 Hz), −102.4 (1F, t, J = 7.0 Hz).
Of ethyl 5- (4-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (7.09 g, 16.7 mmol), acetic acid (30 mL) and concentrated hydrochloric acid (17 mL) The mixture was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate, filtered and dried under reduced pressure to obtain a pale yellow solid. The crude product was washed with water and then dried under reduced pressure to give white solid 5- (4-bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (6. 24 g, yield: 94%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 6.73 (2H, m), 7.16 (2H, d, J = 8.5 Hz), 7.47 (2H, d, J = 8.5 Hz), 8.29 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.3 (2F, d, J = 7.1 Hz), −102.0 (1F, t, J = 7.1 Hz).
Reference Example 78

5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (3.97 g, 10.0 mmol), triethylamine (1.52 g, 15.0 mmol) and acetone (30 mL) was ice-cooled and ethyl chloroformate (1.05 mL, 11.0 mmol) was added slowly. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (1.30 g, 20.0 mmol) was dissolved in water (3 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (100 mL) was added to the reaction solution, and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (3.0 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (4- Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] t-butyl carbamate (2.76 g, yield: 59%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 6.04 (1H, brs), 6.72 (2H, m), 7.09 (2H, d, J = 8. 5 Hz), 7.52 (2H, d, J = 8.5 Hz), 8.24 (1 H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (2F, s), -103.7 (1F, s).
N- [5- (4-Bromophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (2.00 g, 4.27 mmol), 1,4- A mixture of dioxane (20.0 mL) and 2N hydrochloric acid (10.0 mL) was refluxed for 1 hour. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-bromophenyl) -1- (2,4,6-trifluorophenyl) as a white solid. Pyrazole (1.06 g, yield: 68%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.08 (2H, brs), 6.72 (2H, m), 7.10 (2H, d, J = 8.5 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.54 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.7 Hz), −104.4 (1F, t, J = 6.7 Hz).
Reference Example-79

A solution of 2,4,6-trifluorophenylhydrazine (2.80 g, 17.3 mmol) in ethanol (30 mL) was ice-cooled, triethylamine (1.82 g, 18.0 mmol) was added, and 3- (2, A solution of ethyl 3-dihydroinden-5-yl) -2-ethoxymethylene-3-oxopropanoate (5.00 g, 17.3 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give brown oily 5- (2,3-dihydroinden-5-yl) -1- (2,4,6- Ethyl trifluorophenyl) pyrazole-4-carboxylate (6.64 g, yield: 99%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.24 (3H, t, J = 7.1 Hz), 2.05 (2H, quintet, J = 7.4 Hz), 2.84-2.90 (4H) M), 4.22 (2H, q, J = 7.1 Hz), 6.70 (2H, dd, J = 8.4 and 7.3 Hz), 7.02 (1H, dd, J = 8.1 and 0. 9 Hz), 7.13-7.15 (2H, m), 8.23 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, d, J = 6.9 Hz), −103.3 (1F, t, J = 6.9 Hz).
Ethyl 5- (2,3-dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (6.64 g, 17.2 mmol), acetic acid (35 mL) and A mixture of concentrated hydrochloric acid (17 mL) was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. This solution was dried under reduced pressure to give 5- (2,3-dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (5.46 g) as a pale yellow solid. Yield: 89%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.06 (2H, quintet, J = 7.4 Hz), 2.84-2.91 (4H, m), 6.70 (2H, dd, J = 8) .4 and 7.3 Hz), 7.02 (1 H, d, J = 8.2 Hz), 7.12-7.15 (2 H, m), 8.27 (1 H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.1 (2F, d, J = 7.2 Hz), −103.0 (1F, t, J = 7.2 Hz).
Reference Example-80

5- (2,3-dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (3.00 g, 8.37 mmol), triethylamine (1.27 g, A mixture of 12.6 mmol) and acetone (30 mL) was ice-cooled, and ethyl chloroformate (0.88 mL, 9.2 mmol) was slowly added. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (1.09 g, 16.8 mmol) was dissolved in water (3 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (100 mL) was added to the reaction solution, and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.5 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (2, 3-Dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (2.39 g, yield: 66%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 2.07 (2H, quintet, J = 7.4 Hz), 2.85-2.91 (4H, m), 6. 12 (1H, brs), 6.69 (2H, dd, J = 8.5 and 7.2 Hz), 6.94 (1H, d, J = 7.5 Hz), 7.06 (1H, s), 7. 20 (1H, d, J = 7.5 Hz), 8.26 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -104.6 (1F, s).
N- [5- (2,3-dihydroinden-5-yl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.00 g, 2.33 mmol) ), 1,4-dioxane (20.0 mL), and 2N hydrochloric acid (12.0 mL) were refluxed for 2 hours. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (2,3-dihydroinden-5-yl) -1- (2,4,6-tri Fluorophenyl) pyrazole (0.663 g, yield: 87%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.06 (2H, quintet, J = 7.4 Hz), 2.84-2.90 (4H, m), 3.00 (2H, brs), 6. 66-6.73 (2H, m), 6.94 (1H, d, J = 7.8 Hz), 7.10 (1H, s), 7.17 (1H, d, J = 7.8 Hz), 7.54 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (2F, d, J = 6.3 Hz), −105.2 (1F, t, J = 6.3 Hz).
Reference Example-81

A solution of 2,4,6-trifluorophenylhydrazine (2.64 g, 16.3 mmol) in ethanol (30 mL) was ice-cooled, triethylamine (1.67 g, 16.5 mmol) was added, and then 2-ethoxymethylene- A solution of ethyl 3- (3,4-ethylenedioxyphenyl) -3-oxopropanoate (5.00 g, 16.3 mmol) in ethanol (10 mL) was added dropwise. After stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazole Ethyl-4-carboxylate (5.83 g, yield: 88%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (3H, t, J = 7.1 Hz), 4.21-4.26 (6H, m), 6.70-6.80 (4H, m ), 6.85 (1H, d, J = 1.9 Hz), 8.21 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.2 (2F, d, J = 7.0 Hz), −103.2 (1F, t, J = 7.0 Hz).
Ethyl 5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (5.83 g, 14.4 mmol), acetic acid (30 mL) and concentrated hydrochloric acid (14 mL) was refluxed for 16 hours. The reaction solution cooled to room temperature was poured into water (100 mL) and extracted with chloroform (50 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate and filtered. The solution was dried under reduced pressure to give a pale yellow solid of 5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (4.89 g, yield). Rate: 90%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 4.23-4.27 (4H, m), 6.70-6.76 (5H, m), 8.26 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.1 (2F, d, J = 6.9 Hz), −102.9 (1F, t, J = 6.9 Hz).
Reference Example-82

5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid (3.00 g, 7.97 mmol), triethylamine (1.21 g, 12. 0 mmol) and acetone (30 mL) were ice-cooled and ethyl chloroformate (0.85 mL, 8.9 mmol) was added slowly. After stirring at the same temperature for 1 hour, an aqueous solution in which sodium azide (1.04 g, 16.0 mmol) was dissolved in water (3 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (100 mL) was added to the reaction solution, and extracted with toluene (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.5 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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 a pale yellow solid N- [5- (3, 4-Ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.75 g, yield: 49%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 4.23-4.28 (4H, m), 6.12 (1H, brs), 6.64-6.74 ( 4H, m), 6.84 (1H, d, J = 8.3 Hz), 8.25 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.5 (2F, s), -104.4 (1F, s).
N- [5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (1.00 g, 2.11 mmol), A mixture of 1,4-dioxane (20.0 mL) and 2N hydrochloric acid (12.0 mL) was refluxed for 2 hours. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (3,4-ethylenedioxyphenyl) -1- (2,4,6-trifluorophenyl). ) Pyrazole (0.749 g, yield: 96%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.97 (2H, brs), 4.22-4.26 (4H, m), 6.65-6.76 (4H, m), 6.81 ( 1H, d, J = 8.3 Hz), 7.52 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.9 (2F, d, J = 6.3 Hz), −105.0 (1F, t, J = 6.3 Hz).
Reference Example-83

  To a mixture of diethyl carbonate (100 mL) and potassium t-butoxide (11.8 g, 105 mmol) with stirring at 60 ° C., 4-chloro-2,5-difluoroacetophenone (10.0 g, 52.5 mmol) in diethyl carbonate (10 mL) The solution was added dropwise and stirred at the same temperature for 3 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and 2N hydrochloric acid (200 mL) was added. Ethyl acetate (100 mL × 2) was added to the solution and the layers were separated. The organic layers are combined, washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent is distilled off under reduced pressure to obtain reddish brown oily ethyl 4-chloro-2,5-difluorobenzoyl acetate and 4-chloro. A mixture of ethyl 2-ethoxy-5-fluorobenzoyl acetate was obtained. Triethyl orthoformate (17.5 mL, 105 mmol) and acetic anhydride (9.9 mL, 105 mmol) were added to this mixture, and the mixture was heated and stirred at 135 ° C. for 2 hours. Distilled off over time. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 1/1) to give ethyl 2- (4-chloro-2,5-difluorobenzoyl) -2-ethoxymethylene acetate (2.25 g, yield: 14). %) And 2- (4-chloro-2-ethoxy-5-fluorobenzoyl) -2-ethoxymethylene acetate (1.40 g, yield: 8%).

2- (4-Chloro-2,5-difluorobenzoyl) -2-ethoxymethylene acetate; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.10-1.48 (6H, m), 4.09- 4.37 (4H, m), 7.13-7.73 (3H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-120.3, −120.2, −116.0 and −115.6 (total 2F).
1- (4-chloro-2-ethoxy-5-fluorobenzoyl) -2-ethoxymethylene acetate; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.02-1.11 (3H, m), 1. 32-1.45 (6H, m), 3.94-4.19 (6H, m), 6.85-7.61 (3H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-126.2 and 126.1 (total 1F).
Reference Example-84

A solution of 2,4,6-trifluorophenylhydrazine (1.15 g, 7.07 mmol) in ethanol (10 mL) was ice-cooled, triethylamine (0.716 g, 7.08 mmol) was added, and then 2- (4- A solution of chloro-2,5-difluorobenzoyl) -2-ethoxymethylene ethyl acetate (2.25 g, 7.06 mmol) in ethanol (5 mL) was added dropwise. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (4-chloro-2,5-difluorophenyl) -1- (2,4,6-trifluorophenyl). ) Ethyl pyrazole-4-carboxylate (2.49 g, yield: 84%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.26 (3H, t, J = 7.1 Hz), 4.25 (2H, q, J = 7.1 Hz), 6.73-6.79 (2H M), 7.10-7.16 (2H, m), 8.27 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-120.1 (1F, d, J = 15.0 Hz), -115.6 (1F, m), -114.5 (2F, m), −102 .0 (1F, t, J = 7.3 Hz).
Ethyl 5- (4-chloro-2,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (2.49 g, 5.97 mmol), ethanol (20 mL) and A mixture of 10% aqueous sodium hydroxide (5 mL) was stirred at 50 ° C. for 2 hours. The reaction solution cooled to room temperature was neutralized with concentrated hydrochloric acid and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate and filtered, and this solution was dried under reduced pressure to give 5- (4-chloro-2,5-difluorophenyl) -1 -(2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid and 5- (4-chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazole- A 4-carboxylic acid mixture (2.22 g) was obtained.
To this mixture, triethylamine (0.864 g, 8.54 mmol) and acetone (20 mL) were added and ice-cooled, and ethyl chloroformate (0.60 mL, 6.3 mmol) was slowly added. After stirring at the same temperature for 30 minutes, an aqueous solution in which sodium azide (0.742 g, 11.4 mmol) was dissolved in water (2 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (30 mL) was added to the reaction solution, and extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (2.0 mL) and toluene (20 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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- (4-chloro-2, 5-Difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] t-butyl carbamate (1.14 g, yield: 41%) and N- [5- (4- Chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.52 g, yield: 18%) was obtained.

N- [5- (4-chloro-2,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.49 (9H, s), 6.02 (1H, brs), 6.71-6.77 (2H, m), 7.03 (1H, dd, J = 8.5 and 6.1 Hz) ), 7.21 (1H, dd, J = 8.7 and 6.0 Hz), 8.23 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-118.8 (1F, d, J = 15.4 Hz), -116.6 (1F, s), -114.9 (2F, s), − 103.4 (1F, s).
^1- H-NMR (400 MHz) N- [5- (4-chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] carbamate; , CDCl ₃ ): δ 1.41 (3H, t, J = 7.0 Hz), 1.49 (9H, s), 3.99 (2H, q, J = 7.0 Hz), 6.01 (1H, brs), 6.38-6.53 (2H, m), 7.01 (1H, dd, J = 8.6 and 6.1 Hz), 7.20 (1 H, dd, J = 8.7 and 6.0 Hz), 8.19 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-119.2 (1F, d, J = 15.5 Hz), -118.0 (2F, s), -116.6 (1F, s).
Reference Example-85

N- [5- (4-Chloro-2,5-difluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.700 g, 1.52 mmol) ), 1,4-dioxane (10 mL), and 2N hydrochloric acid (8 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-chloro-2,5-difluorophenyl) -1- (2,4,6-tri Fluorophenyl) pyrazole (0.501 g, yield: 92%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.12 (2H, brs), 6.73 (2H, dd, J = 8.4 and 7.5 Hz), 6.99 (1H, dd, J = 8.8 and 6) .2 Hz), 7.18 (1 H, dd, J = 8.9 and 6.1 Hz), 7.56 (1 H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-119.5 (1F, d, J = 15.4 Hz), -116.8 (1F, m), -115.3 (2F, m), −104 .2 (1F, t, J = 6.5 Hz).
Reference Example-86

T-butyl N- [5- (4-chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] carbamate (0.520 g, 1. 07 mmol), 1,4-dioxane (10 mL), and 2N hydrochloric acid (5 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, and the solution diluted with water (50 mL) was neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-chloro-2,5-difluorophenyl) -1- (4-ethoxy-2,6 -Difluorophenyl) pyrazole (0.339 g, yield: 82%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.41 (3H, t, J = 7.0 Hz), 3.99 (2H, q, J = 7.0 Hz), 3.09 (2H, brs), 6.44-6.48 (2H, m), 6.97 (1H, dd, J = 8.9 and 6.2 Hz), 7.18 (1H, dd, J = 8.8 and 6.1 Hz), 7.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-119.9 (1F, d, J = 15.0 Hz), -118.4 (2F, d, J = 2.5 Hz), -116.8 (1F , Dt, J = 15.0 and 2.5 Hz).
Reference Example-87

A solution of 2,4,6-trifluorophenylhydrazine (0.658 g, 4.06 mmol) in ethanol (7 mL) was ice-cooled, triethylamine (0.414 g, 4.09 mmol) was added, and then 2- (4- A solution of ethyl chloro-2-ethoxy-5-fluorobenzoyl) -2-ethoxymethylene acetate (1.40 g, 4.06 mmol) in ethanol (3 mL) was added dropwise. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give 5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6-trimethyl). Ethyl fluorophenyl) pyrazole-4-carboxylate (1.51 g, yield: 84%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.21 (3H, t, J = 7.0 Hz), 1.24 (3H, t, J = 7.1 Hz), 3.74-3.89 (2H M), 4.18-4.25 (2H, m), 6.65-6.78 (2H, m), 6.81 (1H, d, J = 6.0 Hz), 7.10 (1H , D, J = 8.8 Hz), 8.24 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-126.0 (1F, s), -114.7 (1F, d, J = 6.5 Hz), -112.8 (1F, d, J = 6) .5 Hz), -103.3 (1F, t, J = 6.9 Hz).
Ethyl 5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylate (1.51 g, 3.42 mmol), ethanol (15 mL ) And 10% aqueous sodium hydroxide (3 mL) was stirred at 50 ° C. for 2 hours. The reaction solution cooled to room temperature was neutralized with concentrated hydrochloric acid and extracted with chloroform (30 mL × 3). The combined organic layer was washed with saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate and filtered, and this solution was dried under reduced pressure to give 5- (4-chloro-2-ethoxy-5-fluorophenyl). -1- (2,4,6-trifluorophenyl) pyrazole-4-carboxylic acid and 5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2,6-difluoro Phenyl) pyrazole-4-carboxylic acid mixture (1.29 g) was obtained.

  To this mixture, triethylamine (0.472 g, 4.66 mmol) and acetone (10 mL) were added and ice-cooled, and ethyl chloroformate (0.33 mL, 3.5 mmol) was slowly added. After stirring at the same temperature for 30 minutes, an aqueous solution in which sodium azide (0.40 g, 6.2 mmol) was dissolved in water (1 mL) was slowly added. The mixture was further stirred for 1 hour at the same temperature. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate and filtered, and then 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 (1.0 mL) and toluene (10 mL) under reflux conditions, and the mixture was further refluxed for 2 hours. The reaction mixture was cooled 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- (4-chloro-2- Ethoxy-5-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.51 g, yield: 31%) and N- [5- ( 4-chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] t-butyl carbamate (0.13 g, yield: 8%) Got.

N- [5- (4-Chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl; ¹ H-NMR ( 400 MHz, CDCl ₃ ): δ 1.34 (3H, t, J = 7.0 Hz), 1.50 (9H, s), 3.98 (2H, q, J = 7.0 Hz), 6.39 (1H , Brs), 6.72 (2H, t, J = 8.1 Hz), 6.84 (1H, d, J = 9.0 Hz), 6.96 (1H, d, J = 6.2 Hz), 8 .72 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.3 (1F, s), -114.6 (2F, s), -104.4 (1F, s).
^1- H-NMR N- [5- (4-Chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] carbamate; (400 MHz, CDCl ₃ ): δ 1.35 (3H, t, J = 7.0 Hz), 1.41 (3H, t, J = 7.0 Hz), 1.50 (9H, s), 3.95− 4.02 (4H, m), 6.39-6.50 (2H, m), 6.72 (1 H, brs), 6.84 (1 H, d, J = 9.1 Hz), 6.97 ( 1H, d, J = 6.1 Hz), 8.23 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.5 (1F, s), -117.7 (2F, s).
Reference Example-88

N- [5- (4-Chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6-trifluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.509 g, 1 .05 mmol), 1,4-dioxane (10 mL), and 2N hydrochloric acid (5 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized with a 10% aqueous sodium hydroxide solution, and extracted with chloroform (50 mL × 3) from a solution diluted with water (50 mL). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (2,4,6 -Trifluorophenyl) pyrazole (0.34 g, yield: 84%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.30 (3H, t, J = 7.0 Hz), 3.14 (2H, brs), 3.93 (2H, q, J = 7.0 Hz), 6.67-6.73 (2H, m), 6.89 (1H, d, J = 9.1 Hz), 6.92 (1H, d, J = 6.2 Hz), 7.53 (1H, s ). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-125.0 (1F, s), -115.0 (2F, s), -105.2 (1F, t, J = 6.5 Hz).
Reference Example-89

N- [5- (4-Chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2,6-difluorophenyl) pyrazol-4-yl] carbamate t-butyl (0.133 g, 0.26 mmol), 1,4-dioxane (5 mL), and 2N hydrochloric acid (1.5 mL) were stirred at 80 ° C. for 1 hour. The reaction solution was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide solution, and extracted with chloroform (30 mL × 3) from a solution diluted with water (20 mL). The organic layers were combined, washed with saturated brine (30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 4-amino-5- (4-chloro-2-ethoxy-5-fluorophenyl) -1- (4-ethoxy-2 , 6-Difluorophenyl) pyrazole (64 mg, yield: 60%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.31 (3H, t, J = 7.1 Hz), 1.39 (3H, t, J = 7.1 Hz), 3.10 (2H, brs), 3.90-4.12 (4H, m), 6.40-6.98 (4H, m), 7.53 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.5 (1F, s), -117.9 (2F, s).
The pyrazole-4-carboxamide derivative (1) of the present invention that can be produced by the methods exemplified in Examples and Reference Examples is exemplified in Table-1. However, the present invention is not limited to these examples.

  The pyrazole-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 pyrazole-4-carboxamide derivative (1) of the present invention is used as an agricultural and horticultural fungicidal composition, Ascomycetes such as powdery mildew of various crops, rust fungus of various crops Infectious fungi parasitic on various crops such as basidiomycetes such as rice mold blight fungi, downy mildews of various crops, oomycetes such as plagues of various crops, blast fungus, gray mold fungus, etc. In addition to (Deuteromycetes), it has a high control effect against a wide range of phytopathogenic fungi such as Plasmophorophycetes 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 citrus (Pentum citrus) 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) Zygophila jamaicensis, Ringworm disease (Diplocarpon mary), Blast disease (Diplocarpon mali), Red rot (Gymnosporangium 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 caribaria leaf blight (Curvularia fungus), dollar spot disease (Sclerotinia homoeocarpa), Helmintosporum leaf blight (us) (Diplocarpon rosae), chrysanthemum rust (Pucc) inia horiana), and various crop downy mildews (Peronospora bacteria, Pseudoperonospora bacteria, Plasmopara bacteria, Bremia bacteria), plagues (Phytophthora bacteria), powdery mildew (Erysiphe bacteria, Blumeria bacteria, Blumeria bacteria, Blumeria bacteria) Uncinula, Oidiopsis), Rust (Puccinia, Uromyces, Physopella), Anthrax (Glomerella, Colletotrichum, Gloeosporium), Black spot (Alternaria), Gray Nuclear Disease (Sclerotinia sclerot orum), white leaf blight (Rosellinia necatrix), purple coat blight (Helicobasidium mompa), white silkworm (Sclerotium rolfsii), other various soil diseases (Fusarium fungi, Rhizoctomia fungi, Phythium vulgaris, Phythium vulgari, 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 pyrazole-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 a composition produced using a general agricultural chemical auxiliary. It is desirable to use this form. The form of the disinfectant of the present invention is not particularly limited, but for example, emulsion, suspension, wettable powder, aqueous solvent, liquid, sol (flowable), granular wettable powder, powder, fine granule, granule, It is preferable to use tablets, oils, sprays, fumes, aerosols, pastes and the like. Moreover, 1 type, or 2 or more types of the pyrazole-4-carboxamide derivative (1) of this invention can be mix | blended as an active ingredient, and other bactericidal components may be included as an active ingredient besides an adjuvant. .

  The content of the pyrazole-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 amount.

  Examples of the component as an agricultural chemical auxiliary used for producing an agricultural and horticultural fungicide containing the pyrazole-4-carboxamide derivative (1) of the present invention as an active ingredient include carriers, surfactants and other auxiliary agents. It is done.

  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.

  Examples of 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, and aliphatic hydrocarbons such as kerosene and light oil. , Aromatic hydrocarbons such as xylene, trimethylbenzene, tetramethylbenzene, methylnaphthalene and solvent naphtha, amides such as N-methyl-2-pyrrolidone, esters such as glycerin esters of fatty acids, soybean oil, rapeseed oil And vegetable oils. 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, potassium chloride. Mineral powders such as 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.

  Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkyl aryl ether, polyoxyethylene styryl phenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan alkylate, and 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, alkylaryl sulfonate, dialkyl sulfosuccinate, polyoxyethylene alkyl aryl ether sulfate, alkyl naphthalene sulfonate, polyoxyethylene styryl phenyl ether sulfate, and the like. Can be mentioned.

  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 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, and UV protection. Agents, crystal precipitation inhibitors, antifoaming agents, physical property improvers, colorants and the like, but are not limited thereto.

  The binder, thickener, and sticking agent are not particularly limited. For example, starch, dextrin, cellulose, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylstarch , 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 Examples include pyrrolidone.

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

  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 pyrazole-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, cyazofamid, dimethomorph, cymoxanil, fluorpicolide, bentavaliculbylp acibenzalar, isotianil, thiadinil, probenazole, carpropamide, diclocymet, phenoxanil, tricyclazole tricolazole pyroquilon, phthalide, azoxystrobin, oryzatrobin, cresoxime-methyl, trifloxystrobin, picoxystrobin pyraclostrobin, famoxadone, metminostrobin, thiophanate-methyl, diethofencarb, thiabendazoleole, benabazolezole ipconazole), imibenconazole, oxpoconazole fumarate (dipoconazole), difenoconazole, cyproconazole, cyproconazole. Triadimefon, triflumizole, triforine, bittertanol, fenarimol, fenbuconazole, prochloraz (proloraz) z), propiconazole, hexaconazole, pefurazoate, microbutanil, metconazole, epoxiconazole, epoxiconazole, epoxiconazole, epoxiconazole, epoxiconazole. , Bixafen, furamethpyr, flutolanil, penthiopyrad, boscalid, mepronil, isoprothizone, iprothizone ne), dichromedine, pencyclone, iprodione, procymidone, cyprodinil, mepaniprimimine, pyrimethanyl (pyrimethanil) Fludioxonil, cyflufenamide, metrafenone, quinoxyphene, iminoctadine triacetate, iminoctadine albecate iniminate silate, propamocarb hydrochloride, chlorothalonil, TPN, captan, fluorimid, fluoretine, dithianon, dithianon, dithianon Anilazine, fosetyl-aluminium, ambam, ziram, thiadiazine, tiram, polycarbamate, mancob, mancob Flusulfamide (flusulfamide), hydroxyisoxazole (hymexazole, hymezazole), eclomezole (etridiazole, etridiazole), iprobenfos (iprobenfos, IBP), edifenphos (edifenphos, EDDP), toltrofosmethyl (tolyfolofosmethyl) , Blasticidin-S, polyoxins, polyoxin zinc salt (polyoxim), kasugamycin, oxytetracycline, streptomycinic acid (streptoxylinic acid) olic acid, teclophthalam, sulfur, sodium hydrogen carbonate, potassium hydrogen carbonate, metallic silver, basic copper chloride, copper sulfate, cupric hydroxide (copper) hydroxide, anhydrous copper sulfate, copper nonylphenol sulfonate, 8-hydroxyquinoline copper, DBEDC, and the like.
[Insecticides, acaricides] Acephate, isoxathion, ethylthiomethetone, cadusafos, chlorpyrifos, chlorpyrifos-thio, chlorpyrifos-thio-C, dichlorfention, ECP), dimethoate, dichlorvos, DDVP, diazinon, trichlorfon, DEP, pyracrofos, pyrimiphosmethyl, pirimimiphos Thione (fentrothion, MEP), fenthion (fenthion, MPP), fentoate (phenhoate, PAP), prothiofos (profiofos), profenophos (fosalone), fothiazate (fostiazate), thion, thion DMTP), EPN, alaniccarb, isoprocarb, MIPC, etiofencarb, oxamyl, carbaryl, NAC, carbosulfan, iodocarb Thiocarb (furathiocarb), benfuracarb (benfuracarb), mesomil (methomyl), fenobucarb (fenobucarb, BPMC), XMC, acrinathrin (arthrin), halothrin (etropro), ethenproline (c) cyhalothrin, cyfluthrin, cypermethrin, silafluofen, tefluthrin, tralomethrin, bifenthraterin, bifenthrate. te), fenpropatrin, flucitrinate, fluvalinate, permethrin, fenvalerate, cartap, thiocyclampirapitarin (Acetampirid), imidacloprid, clothianidin, dinotefuran, thiacloprid, thiamethoxam, nitenpyram (nitrogen) azuron), diflubenzuron (diflubenzuron), teflubenzuron (teflubenzuron), novaluron (novaluron), flufenoxuron (flufenoxuron), lufenuron (lufenuron), chromafenozide (chromafenozide), tebufenozide (tebfenozide), buprofezin (buprofenzin), methoxyfenozide (methoxyfenozide), Cyromazine, benzopiene, etiprole, fipronil, indoxacarb MP (indoxacarb), chlorfenapyr, diaphene Uron (diafenthiuron), tolfenpyrad (pymetrozine), pyridalyl, flubenamide (flabendiamide), chlorantaniprole (phloradimicin) emamectin benzoate, spinosad, milbemectin, repimectin, pyrethrins, starch, fatty acid glycerides, propylene glycol monofatty acid ester, machine oil (petroleum oil), Neoil oil, sodium oleate, BT, acequinocyl, amitraz, etoxazole, clofentezine, spirodiclofen, spirodiclofen, spiromechrofen Tetramat, tebufenpyrad, bifenazate, pyridaben, pyrimidifene, fenothiocarb, fenpyroxene atin oxide), fluacrypyrim (fluacrypyrim), hexythiazox (hexythiazox), such as.

  In addition, it described more concretely about the manufacturing method of the agricultural / horticultural fungicide of this invention to the below-mentioned formulation 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 form of the preparation, the target disease or crop type, the degree of damage caused by the disease, the application location, the application method, the application It is appropriately selected from a wide range according to various conditions such as timing, types and amounts of drugs and fertilizers to be used together, weather, and the like. 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 after being diluted with water, such as a liquid agent, an emulsion, a wettable powder, a sol (flowable) or a granular wettable powder, the application concentration is from 0.1. It is used at about 10,000 ppm by mass, preferably about 1 to 500 ppm by mass, but is not limited thereto.

  Next, specific examples of methods for formulating the pyrazole-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 1 [hydrating agent]
By uniformly mixing and grinding a mixture of the compound of the present invention (20 parts by weight), sodium alkylbenzenesulfonate (3 parts by weight), polyoxyethylene nonylphenyl ether (5 parts by weight) and clay (72 parts by weight) A wettable powder containing 20% by weight of the active ingredient can be obtained. Furthermore, a wettable powder can be obtained by the same method using each compound described in Table-1.
Formulation Example-2 [Emulsion]
By mixing and dissolving 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), an emulsion containing 30% by weight of the active ingredient can be obtained. . Furthermore, an emulsion can be obtained by the same method using each compound described in Table-1.
Formulation Example-3 [Flowable Agent]
Uniform mixture of compound of the present invention (25 parts by weight), polyoxyethylene alkyl ether (1 part by weight), sodium alkylnaphthalene sulfonate (1 part by weight), carboxymethylcellulose (1 part by weight) and water (72 parts by weight) To obtain a sol containing 25% by weight of the active ingredient. Furthermore, each flowable agent can be obtained by the same method using each compound described in Table-1.
Formulation Example-4 [Granule]
To a mixture of the compound of the present invention (5 parts by weight), sodium lauryl sulfate (1 part by weight), calcium lignin sulfonate (5 parts by weight), bentonite (30 parts by weight) and clay (59 parts by weight), water (15 Parts by weight) and kneaded with a kneader, granulated with a granulator, and dried with a fluid dryer to obtain a granule containing 5% by weight of the active ingredient. Furthermore, each granule can be obtained by the same method using each compound described in Table-1.

Next, the usefulness of the agricultural and horticultural fungicide containing the pyrazole-4-carboxamide derivative (1) of the present invention as an active ingredient will be clarified with reference to Test Examples 1 to 5 below. However, the utility of the present invention is not limited to the utility revealed by these test examples.
Test Example 1 [Pesticide effect test by spraying foliage against cucumber gray mold]
To a 1.5 leaf seedling of cucumber (variety: Sagamihanjiro) cultivated in a plastic pot with a diameter of 6 cm in a greenhouse, a dilute solution (100 ppm) of a wettable powder prepared according to Preparation Example-1 10 mL was sprayed per pot (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-2, 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-3. These results are shown in Table-4. In addition, the evaluation value of the control effect and the survey index of the degree of chemical damage were also applied to Test Examples 2 to 5.

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 Leaf and Leaf against Wheat Red Rust]
1 pot of diluted emulsion (100 ppm) prepared according to 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 10 mL was 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 on the first leaf was examined, and the control value (%) was calculated by the following formula-2. And according to Table-2, 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 5 below.

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

Test Example 3 [Test for controlling effect by spraying foliage against rice blight]
A 7-leaf seedling (pot) of paddy rice (variety: Asahi) cultivated in a plastic pot with a diameter of 6 cm in a greenhouse is filled with a flowable diluent (100 ppm) prepared according to Formulation Example 3 per pot. 10 mL was sprayed (foliage 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 (height from the strain) of rice blight was investigated, and the control value (%) was calculated by the following formula-3. And according to Table-2, 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 6 below.

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

Test Example 4 [Pesticide effect test by spraying foliage against rice blast]
A flowable diluted solution (100 ppm) prepared according to Formulation Example 3 was applied 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 spray) per pot. On the day after the chemical treatment, per spore suspension of conidia of rice blast fungus (Pyricularia grisea) formed on another rice leaf in advance (spore concentration 2 × 10 ⁶ cells / mL) per pot. 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 of rice blast of the third leaf was examined, and the control value (%) was calculated by the following formula-4. And according to Table-2, 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 7 below.

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

Test Example-5 [Testing for controlling effect of tomato ring disease by foliage spray]
1 pot of diluted emulsion solution (100 ppm) prepared according to Formulation Example-2 to 2.0-leaf seedlings of tomato (variety: Toko K) 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, ⁵ mL per pot is sprayed onto a pot sprayed with a fractional spore suspension (Spore concentration 1 × 10 ⁵ / mL) of tomato ring-shaped mold (Alternaria solani) previously formed on PDA medium. After inoculation and standing in a 24 ° C. inoculation box (RH = 100%) for 24 hours, the disease was promoted in an artificial climate room at 24 ° C. Four days after the inoculation, the number of lesions per pot was examined, and the control value (%) was calculated by the following formula-5. And according to Table-2, 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 8 below.

Formula-5: Control value (%) = [1− (number of lesions in sprayed area / number of spots in non-sprayed area)] × 100

Claims (5)

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 halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; X represents a hydrogen atom; halogen atom; alkyl group having 1 to 6 carbon atoms; alkoxy group having 1 to 6 carbon atoms; haloalkyl group having 1 to 6 carbon atoms; alkylthio group having 1 to 6 carbon atoms Or X represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted by an adjacent alkyl group having 1 to 3 carbon atoms; 1 to 3 A methylenedioxy group optionally substituted with an alkyl group, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, where n represents an integer of 1 to 5. When two or more, X may be the same or different.). The pyrazole-4-carboxamide derivative according to claim 1, wherein R ² is a haloalkyl group having 1 to 6 carbon atoms. The pyrazole-4-carboxamide derivative according to claim 1, wherein R ² is a difluoromethyl group or a trifluoromethyl group. 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 pyrazole-4-carboxylic acid derivative represented by the general formula (3):

(Wherein R ⁴ is a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; or Represents an alkyl group having 1 to 6. X represents a hydrogen atom; a halogen atom; an alkyl group having 1 to 6 carbon atoms; an alkoxy group having 1 to 6 carbon atoms; a haloalkyl group having 1 to 6 carbon atoms; Or represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted with two adjacent X groups together with an alkyl group having 1 to 3 carbon atoms; A methylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, n is an integer of 1 to 5 The table When n is 2 or more, X may be the same or different.) A 4-aminopyrazole derivative represented by the general formula (1) is condensed.

(Wherein R ¹ , R ² , R ³ , R ⁴ , X and n represent the same meaning as described above), a method for producing a pyrazole-4-carboxamide derivative represented by: 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 halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; X represents a hydrogen atom; halogen atom; alkyl group having 1 to 6 carbon atoms; alkoxy group having 1 to 6 carbon atoms; haloalkyl group having 1 to 6 carbon atoms; alkylthio group having 1 to 6 carbon atoms Or X represents a benzylthio group, and X represents a polymethylene chain having 3 to 5 carbon atoms which may be substituted by an adjacent alkyl group having 1 to 3 carbon atoms; 1 to 3 A methylenedioxy group optionally substituted with an alkyl group, or an ethylenedioxy group optionally substituted with an alkyl group having 1 to 3 carbon atoms, where n represents an integer of 1 to 5. When it is 2 or more, the fungicides for agricultural and horticultural use comprising as an active ingredient a pyrazole-4-carboxamide derivative represented by the following formula: