JP2012056945A - 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 situations 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, these compounds are completely different from the pyrazole-4-carboxamide derivatives of the present invention in that the 1-position of the pyrazole ring of the pyrazol-4-yl group is an alkyl group. On the other hand, N- (3,5-dimethyl-1-phenylpyrazol-4-yl) -1-methylpyrazole-4-carboxamide having an unsubstituted phenyl group at the 1-position of the pyrazole ring of the pyrazol-4-yl group (CAS registration) No. 1060984-13-5) is known only, but there is no report about the synthesis method or biological activity of these pyrazole-4-carboxamide derivatives including this compound.

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 hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 to carbon atoms. A phenyl group optionally substituted by an alkoxy group having 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 to 6 carbon atoms An alkyl group, an alkoxy group having 1 to 6 carbon atoms or a pyridyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; a halogen atom or an alkyl group having 1 to 6 carbon atoms A thienyl group which may be substituted; or a furyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a carbon number of 1; To n, and n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different, and a pyrazole-4-carboxamide derivative represented by: .

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

The present invention also relates to a pyrazole-4-carboxamide derivative in which, in the general formula (1), Ar is a phenyl group which may be substituted with a halogen atom, and X is a halogen atom. Further, the present invention provides the compound represented by the general formula (1), wherein R ² and R ⁴ are each independently a haloalkyl group having 1 to 4 carbon atoms, Ar is a phenyl group optionally substituted with a halogen atom, and X is The present invention relates to a pyrazole-4-carboxamide derivative which is a halogen atom. Furthermore, in the general formula (1), the present invention relates to a phenyl group in which R ² is a difluoromethyl group or a trifluoromethyl group, R ⁴ is a trifluoromethyl group, and Ar is optionally substituted with a halogen atom. And X relates to a pyrazole-4-carboxamide derivative wherein X is a halogen atom.

  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):

(In the formula, R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms. Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a carbon number. A phenyl group optionally substituted by an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 carbon atom A pyridyl group optionally substituted by 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; may be substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms Or a furyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms. Or a haloalkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different. General formula (1), characterized by condensation

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

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

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 to carbon atoms. A phenyl group optionally substituted by an alkoxy group having 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 to 6 carbon atoms An alkyl group, an alkoxy group having 1 to 6 carbon atoms or a pyridyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; a halogen atom or an alkyl group having 1 to 6 carbon atoms A thienyl group which may be substituted; or a furyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a carbon number of 1; To 6 in which n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different, and a pyrazole-4-carboxamide derivative represented by It relates to the agricultural and horticultural fungicide.

  The present invention is described in further detail below.

The alkyl group having 1 to 6 carbon atoms represented by R ¹ 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. 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.

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 a haloalkyl group having 1 to 4 carbon atoms, more preferably a difluoromethyl group or a trifluoromethyl group, and even more preferably a hydrogen atom in terms of 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 because it has a high effect as a disinfectant.

Examples of the halogen atom represented by R ⁴ include a fluorine atom, a chlorine atom, and a bromine atom. The alkyl group having 1 to 6 carbon atoms represented by R ⁴ 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 ⁴ 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 ⁴ is preferably a haloalkyl group having 1 to 4 carbon atoms, and more preferably a trifluoromethyl group, from the viewpoint of high effect as a bactericidal agent.

  The optionally substituted phenyl group represented by Ar includes 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, and 1 to carbon atoms. 6 represents a haloalkoxy group having 6 or a phenyl group optionally substituted by an alkylthio group having 1 to 6 carbon atoms, and the halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, etc .; the alkyl having 1 to 6 carbon atoms The group may be linear, branched or cyclic, and may be a methyl group, ethyl group, propyl group, isopropyl group, cyclopropyl group, butyl group, isobutyl group, s-butyl group, t- Butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, neopentyl, 2-pentyl, 3-pentyl, 2-methylbutyl, cycl A pentyl group, a hexyl group, an isohexyl group, a 2-ethylbutyl group, a 1,3-dimethylbutyl group, a 2-cyclopropylcyclopropyl group, and the like; It may be in the form of a ring or a ring, and is a methoxy group, ethoxy group, propyloxy group, isopropyloxy group, cyclopropylmethyloxy group, butyloxy group, isobutyloxy group, s-butyloxy group, pentyloxy group, cyclopentyloxy group The haloalkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic, and may be a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, 2 -Fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, penta A trifluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropentyl group, perfluorohexyl group, chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, bromodifluoromethyl group, etc .; The haloalkoxy group represented by the formula 1 to 6 may be linear, branched or cyclic, and may be a difluoromethyloxy group, a bromodifluoromethyloxy group, a trifluoromethyloxy group, 2, 2, 2 -Trifluoroethyloxy group, pentafluoroethyloxy group, 3-fluoropropyloxy group, 3,3,3-trifluoropropyloxy group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group, etc .; The alkylthio group of formula 1 to 6 may be linear, branched or cyclic , Methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group, and the like. Ar is preferably a phenyl group substituted with a halogen atom or a haloalkyl group having 1 to 4 carbon atoms because it is highly effective as a fungicide.

  Examples of the pyridyl group represented by Ar include a 2-pyridyl group, a 3-pyridyl group, and a 4-pyridyl group. These pyridyl groups may be substituted with 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. The alkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic, and includes a methyl group, an ethyl group, a propyl group, an isopropyl group, Cyclopropyl group, butyl group, isobutyl group, s-butyl group, t-butyl group, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2-methylbutyl Group, cyclopentyl group, hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-cyclopropylcyclopropyl A pill group or the like; the alkoxy group having 1 to 6 carbon atoms may be linear, branched or cyclic, and includes a methoxy group, an ethoxy group, a propyloxy group, an isopropyloxy group, and a cyclopropyl group. A methyloxy group, a butyloxy group, an isobutyloxy group, an s-butyloxy group, a pentyloxy group, a cyclopentyloxy group, a hexyloxy group and the like; the haloalkyl group having 1 to 6 carbon atoms is linear, branched or It may be any of cyclic, 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 It can be exemplified 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, a bromodifluoromethyl group. Ar is preferably a pyridyl group substituted with a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a haloalkyl group having 1 to 4 carbon atoms in terms of high effect as a fungicide.

  Examples of the thienyl group represented by Ar include a 2-thienyl group or a 3-thienyl group. These thienyl groups may be substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms, such as a fluorine atom, a chlorine atom, a bromine atom, etc .; the alkyl group having 1 to 6 carbon atoms 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 Group, cyclobutyl group, cyclopropylmethyl 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, Examples thereof include 3-dimethylbutyl group and 2-cyclopropylcyclopropyl group. Ar is preferably a thienyl group substituted with a halogen atom because it is highly effective as a fungicide.

  As the furyl group represented by Ar, a 2-furyl group or a 3-furyl group can be exemplified. These furyl groups may be substituted with an alkyl group having 1 to 6 carbon atoms, and the alkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic, Methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, s-butyl, t-butyl, cyclobutyl, cyclopropylmethyl, pentyl, isopentyl, neopentyl, 2 Examples include -pentyl group, 3-pentyl group, 2-methylbutyl group, cyclopentyl group, hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-cyclopropylcyclopropyl group, and the like. .

  The substitution position of the phenyl group, pyridyl group, thienyl group and furyl group represented by Ar on the benzene ring at the 1-position of the pyrazole ring is not particularly limited, and the substitution is performed at any position of the ortho-position, meta-position or para-position. However, the ortho position is preferable in that it provides excellent bactericidal activity.

  Specific examples of the optionally substituted phenyl group represented by Ar include a phenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-fluorophenyl group, and a 3-fluoro group. Phenyl group, 4-fluorophenyl group, 3-iodophenyl group, 2-chloro-4-fluorophenyl group, 2-chloro-5-fluorophenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3 -Fluorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 3,4-dichlorophenyl group, 3,5-dichlorophenyl group, 2,3-difluorophenyl group, 2, 4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4-difluoro Phenyl group, 3,5-difluorophenyl group, 2,3,4-trifluorophenyl group, 2,4,5-trifluorophenyl group, 2,4,6-trifluorophenyl group, 3,4,5- Trifluorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-chloro-4-methylphenyl group, 2-chloro-5-methylphenyl group, 3-chloro-4-methyl Phenyl group, 4-chloro-3-methylphenyl group, 2-fluoro-4-methylphenyl group, 2-fluoro-5-methylphenyl group, 3-fluoro-4-methylphenyl group, 4-fluoro-2-methyl Phenyl group, 4-fluoro-3-methylphenyl group, 5-fluoro-2-methylphenyl group, 2,3-dimethylphenyl group, 2,4-dimethylphenyl group, 2, -Dimethylphenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-isopropyl Phenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 3-t-butylphenyl group, 4-t-butylphenyl group, 4-pentylphenyl group, 4-isobutylphenyl group, 2- (1,3- Dimethylbutyl) phenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-chloro-4-trifluoromethylphenyl group, 2-chloro-5-trifluoro Methylphenyl group, 4-chloro-2-trifluoromethylphenyl group, 4-chloro-3-trifluoro Romethylphenyl group, 2-fluoro-4-trifluoromethylphenyl group, 2-fluoro-5-trifluoromethylphenyl group, 4-fluoro-2-trifluoromethylphenyl group, 4-fluoro-3-trifluoromethyl Phenyl group, 2,4-bis (trifluoromethyl) phenyl group, 3,5-bis (trifluoromethyl) phenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-fluoro -3-methoxyphenyl group, 2-fluoro-6-methoxyphenyl group, 3-fluoro-4-methoxyphenyl group, 5-fluoro-2-methoxyphenyl group, 3-fluoro-4-ethoxyphenyl group, 2-ethoxy Phenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 4-isopropyloxypheny Group, 2-trifluoromethoxyphenyl group, 3-trifluoromethoxyphenyl group, 4-trifluoromethoxyphenyl group, 2-fluoro-4-trifluoromethoxyphenyl group, 3-fluoro-4-trifluoromethoxyphenyl group, Examples include 2-methylthiophenyl group, 3-methylthiophenyl group, 4-methylthiophenyl group, 3-ethylthiophenyl group, 3-isopropylthiophenyl group, 3-fluoro-4-methylthiophenyl group, and the like.

  Specific examples of the optionally substituted pyridyl group represented by Ar include a 2-pyridyl group, a 3-chloro-2-pyridyl group, a 3-bromo-2-pyridyl group, 3,5- Dichloro-2-pyridyl group, 3,5-difluoro-2-pyridyl group, 3,5,6-trifluoro-2-pyridyl group, 3-chloro-5-trifluoromethyl-2-pyridyl group, 4-methyl 2-pyridyl group, 5-methyl-2-pyridyl group, 6-methyl-2-pyridyl group, 6-methoxy-2-pyridyl group, 3-pyridyl group, 2-chloro-3-pyridyl group, 6-chloro -3-pyridyl group, 2-fluoro-3-pyridyl group, 6-fluoro-3-pyridyl group, 2-methoxy-3-pyridyl group, 4-methoxy-3-pyridyl group, 5-methoxy-3-pyridyl group 6-methoxy-3-pi Zyl group, 2,4-dichloro-3-pyridyl group, 2,6-dimethoxy-3-pyridyl group, 4-pyridyl group, 2-chloro-4-pyridyl group, 3-chloro-4-pyridyl group, 3- Examples include fluoro-4-pyridyl group, 3-methoxy-4-pyridyl group, 2,3-dichloro-4-pyridyl group, 3,5-dichloro-4-pyridyl group and the like.

  Specific examples of the optionally substituted thienyl group represented by Ar include a 2-thienyl group, a 3-thienyl group, a 5-chloro-2-thienyl group, a 5-bromo-2-thienyl group, Examples include 3-methyl-2-thienyl group, 4-methyl-2-thienyl group, 5-methyl-2-thienyl group, 3-thienyl group, 4-methyl-3-thienyl group and the like.

  More specific examples of the optionally substituted furyl group represented by Ar include a 2-furyl group, a 5-methyl-2-furyl group, a 3-furyl group, and the like.

  Examples of the halogen atom represented by X include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. 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, cyclobutyl group, cyclopropylmethyl group, pentyl group, isopentyl group, neopentyl group, 2-pentyl group, 3-pentyl group, 2-methylbutyl group, cyclopentyl group, Examples include hexyl group, isohexyl group, 2-ethylbutyl group, 1,3-dimethylbutyl group, 2-cyclopropylcyclopropyl 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. X is preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms or a haloalkyl group having 1 to 4 carbon atoms in view of high effect as a bactericidal agent.

  Examples of the leaving group represented by Y include halogen atoms such as chlorine atom and bromine atom; hydroxyl groups; substituted oxy groups such as pivaloyloxy group and ethoxycarbonyloxy group. A chlorine atom is preferable because it can be easily produced.

  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.

(Wherein R ¹ , R ² , R ³ , R ⁴ , Ar, 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), whereby the pyrazole-4-carboxamide derivative of the present invention ( 1).

  When the leaving group Y is a halogen atom, step-1 is preferably performed in the presence of a base. The halogen atom is preferably a chlorine atom that can be easily produced. As the base, an inorganic base such as an alkali metal base or an alkaline earth metal base, an alkali metal carboxylate, or an organic base can be used. More specifically, inorganic bases such as alkali metal bases and alkaline earth metal bases include hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, Examples thereof include carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, and potassium bicarbonate. Examples of the alkali metal carboxylate include sodium acetate and potassium acetate. Examples of the organic base include tertiary amines such as trimethylamine, triethylamine, tributylamine, N-methylpyrrolidine, N-methylpiperazine, N-methylmorpholine, and pyridine. Of these, inorganic bases such as sodium carbonate and potassium carbonate, and tertiary amines such as triethylamine and tributylamine are preferred in that the yield of the target product is good and inexpensive.

  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 a substituted oxy group such as a pivaloyloxy group or an ethoxycarbonyloxy group, the reaction proceeds without using a base, but the reaction can also be performed in the presence of a base. Examples of the base include the above bases.

  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.

  Further, the reaction of Step-1 can be carried out at a reaction temperature appropriately selected from 0 to 150 ° C., preferably from 20 to 100 ° C., whereby the target product can be obtained with good yield. 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.

  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 other raw material, 4-aminopyrazole derivative (3) is, for example, J.P. Heterocyclic Chem, 25, 555-558 (1988) can be used for the synthesis, but it can be produced by the method exemplified below.

That is, pyrazole-4-carboxylic acid ester (4) that can be produced from 2-alkoxymethylene-β-ketoester or 2- (dimethylamino) methylene-β-ketoester and a substituted phenylhydrazine having a bromine atom or its hydrochloride. The resulting carboxylic acid (5) obtained by hydrolysis was converted to acid chloride or active ester (6), and then condensed with sodium azide to give acyl azide (7). This was derived into the carbamate (8) by, for example, Curtius rearrangement in the presence of alcohols such as t-butyl alcohol. In the presence of a palladium catalyst such as tetrakistriphenylphosphine palladium and a base such as sodium carbonate, Ar—B (OH) ₂ or Ar—B (Pin) (wherein Ar represents the same meaning as described above). .Pin represents a pinacolato group.) Carbamate ester in which a desired aromatic group (Ar) is introduced into the substituted position of the bromine atom on the 1-position phenyl group of the pyrazole ring by coupling with a boron reagent such as (9) was obtained. Then, the desired 4-aminopyrazole derivative (3) can be produced by simultaneously carrying out hydrolysis and decarboxylation of the carbamic acid ester (see the following reference example).

(Wherein R ⁴ , Ar, X, Y and n represent the same meaning as described above, R ⁵ represents an alkoxy group having 1 to 4 carbon atoms or a dimethylamino group, and R ⁶ represents an alkyl group having 1 to 4 carbon atoms. Represents.)
Pyrazole-4 which can be produced by cyclocondensation of phenylhydrazines substituted with a desired aromatic group (Ar) in advance and 2-alkoxymethylene-β-ketoester or 2- (dimethylamino) methylene-β-ketoester -Hydrolysis of the carboxylic acid ester (4 ') and conversion of the resulting carboxylic acid (5') to acid chloride or active ester (6 '), followed by condensation with sodium azide to give acyl azide (7') did. This product is converted to a carbamate ester (8 ′) by carrying out a Curtius rearrangement in the presence of an alcohol such as t-butyl alcohol, and then hydrolysis and decarboxylation of the ester are carried out simultaneously to achieve the desired 4- An aminopyrazole derivative (3) can be produced. The 4-aminopyrazole derivative (3) can also be produced directly by the Curtius rearrangement of acyl azide (6).

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

Dichloromethane (1 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-fluorophenyl) phenyl] -5-trifluoromethylpyrazole (200 mg, 0.56 mmol), and the mixture was ice-cooled. A solution of triethylamine (85 mg, 0.84 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (109 mg, 0.56 mmol) in dichloromethane (1 mL) was added. The mixed solution was stirred at room temperature for 2 days, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (20 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 = 1/1) to give a white solid N- [ 1- {2,4-difluoro-6- (3-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (159 mg, yield) : 57%). Mp: 195.3-198.5 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.96 (3H, s), 6.79 (1H, t, J = 54.1 Hz), 6.93-7.06 (5H, m), 7. 23-7.28 (1H, m), 8.04 (1H, s), 8.21 (1H, brs), 8.60 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.0 (1F, m), −112.3 (1F, m), −108.4 (2F, m), −104.6 (1F, d) , J = 9.5 Hz), -58.5 (3F, m).
Example-2

Dichloromethane (1 mL) was added to 4-amino-1- [2- (3-chlorophenyl) -4,6-difluorophenyl] -5-trifluoromethylpyrazole (170 mg, 0.45 mmol), and the mixture was ice-cooled, followed by triethylamine. A solution of (69 mg, 0.68 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (105 mg, 0.54 mmol) in dichloromethane (1 mL) was added. After this mixed solution was stirred at room temperature for 24 hours, a saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a colorless oily N- [ 1- {2- (3-chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (140 mg, yield: 58%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.80 (1H, t, J = 54.1 Hz), 6.98-7.32 (6H, m), 8. 03 (1H, s), 8.20 (1H, brs), 8.60 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (1F, m), −108.7 (2F, q, J = 7.0 Hz), −104.8 (1F, d, J = 9) .4 Hz), -58.7 (3F, m).
Example-3

N- [1- (4-Bromophenyl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (350 mg, 0.75 mmol), phenylboric acid (100 mg, 0.82 mmol), sodium carbonate (240 mg, 2.26 mmol), water (1 mL) and tetrakis (triphenylphosphine) palladium (45 mg, 0.039 mmol) in dioxane (4 mL) were stirred at 100 ° C. for 1 hour. Water (30 mL) was added to the reaction solution cooled to room temperature, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layer was 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 = 2/3) to give a pale yellow solid N- [ 1- (biphenyl-4-yl) -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide (263 mg, yield: 76%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ) δ 3.98 (3H, s), 6.85 (1H, t, J = 54.0 Hz), 7.36-7.51 (3H, m), 7.53 (2H, d, J = 8.6 Hz), 7.60-7.65 (2H, m), 7.70 (2H, d, J = 8.6 Hz), 8.08 (1H, s), 8 .36 (1H, brs), 8.57 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ) δ-108.6 (2F, q, J = 7.1 Hz), −55.8 (3F, t, J = 7.1 Hz).
Example-4-28
Hereinafter, the reaction formula, name of product, property (yield), melting point, and NMR spectrum of the pyrazole-4-carboxamide derivative of the present invention synthesized by the same method are shown.
Example-4

3-difluoromethyl-N- [1- {2-fluoro-4- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white solid ( Yp: 486.4); Mp: 166.4-167.8 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J = 54. 1 Hz), 7.14 (2H, t, J = 8.7 Hz), 7.31 (1, t, J = 8.9 Hz), 7.49-7.53 (2H, m), 7.60 ( 1H, dd, J = 6.9 and 2.2 Hz), 7.63-7.67 (1H, m), 8.08 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.3 (1F, m), -114.4 (1F, s), -108.2 (2F, m), -57.6 (3F, m).
Example-5

N- [1- {5- (2-chlorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: colorless oil ( Yield: 53%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.96 (3H, s), 6.86 (1H, t, J = 54.1 Hz), 7.27-7.57 ( 7H, m), 8.08 (1H, s), 8.37 (1H, brs), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.6 (1F, m), −108.8 (2F, s), −57.9 (3F, m).
Example-6

N- [1- {5- (3-chlorophenyl) -2-fluorophenyl] -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white solid (yield) Rate: 61%); Mp: 146-148 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J = 54.1 Hz), 7. 29-7.71 (7H, m), 8.09 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.5 (1F, m), -108.5 (2F, s), -57.9 (3F, m).
Example-7

N- [1- {5- (4-chlorophenyl) -2-fluorophenyl] -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white solid (yield) Rate: 62%); Mp: 183-185 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1 H, t, J = 54.1 Hz), 7. 28-7.67 (7H, m), 8.08 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.0 (1F, m), −108.5 (2F, m), −57.9 (3F, m).
Example-8

3-difluoromethyl-N- [1- {2-fluoro-5- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white oil (Yield: 42%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J = 54.1 Hz), 7.18 (2H, t , J = 8.7 Hz), 7.40-7.45 (2H, m), 7.48-7.52 (1H, m), 7.56-7.60 (2H, m), 8.08. (1H, s), 8.36 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-121.2 (1F, m), -113.4 (1F, s), -108.2 (2F, m), -57.6 (3F, m).
Example-9

N- [1- {2,4-difluoro-6- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white Solid (Yield: 65%); Mp: 108.6-112.7 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.79 (1H, t, J = 54.1 Hz), 6.96-7.04 (4H, m), 7.19-7.23 (2H, m), 8.04 (1H, s), 8.20 (1H, brs), 8 .59 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.2 (1F, m), −112.6 (1F, m), −108.4 (2F, m), −104.8 (1F, d, J = 9.4 Hz), -58.5 (3F, m).
Example-10

N- [1- {2- (2-chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: colorless oil Product (yield: 58%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.93 (3H, s), 6.80 (1 H, t, J = 54.1 Hz), 6.99-7. 27 (4H, m), 7.40 (1H, d, J = 7.9 Hz), 8.01 (1H, s), 8.18 (1H, brs), 8.47 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.9 (1F, brs), −108.8 (2F, s), −106.0 (1F, d, J = 9.4 Hz), − 58.6 (3F, brs).
Example-11

N- [1- {2- (4-chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white solid (Yield: 59%); Mp: 157-158 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.94 (3H, s), 6.81 (1 H, t, J = 54.1 Hz), 6.97-7.04 (2H, m), 7.17 (2H, d, J = 8.6 Hz), 7.27 (2H, d, J = 8.6 Hz), 8.03 (1H, s ), 8.20 (1H, brs), 8.59 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.4 (1F, m), −108.8 (2F, q, J = 7.0 Hz), −104.9 (1F, d, J = 9.4 Hz), -58.8 (3F, td, J = 10.1 and 3.3 Hz).
Example-12

N- [1- {2,4-difluoro-6- (4-methylphenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: yellow Solid (Yield: 75%); Mp: 150-153 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.31 (3H, s), 3.95 (3H, s), 6.79 (1H , T, J = 54.1 Hz), 6.92-7.06 (2H, m), 7.10 (4H, s), 8.03 (1H, s), 8.19 (1H, brs), 8.59 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.0 (1F, m), −108.8 (2F, q, J = 7.1 Hz), −105.6 (1F, d, J = 9.4 Hz), -58.7 (3F, td, J = 9.4 and 4.7 Hz).
Example-13

N- [1- {2- (4-tert-butylphenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide : Colorless oil (yield: 75%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.28 (9H, s), 3.95 (3H, s), 6.79 (1H, t, J = 54.1 Hz), 6.92-7.00 (1H, m), 7.05 (1H, ddd, J = 9.1, 1.9 and 1.8 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.30 (2H, d, J = 8.5 Hz), 8.03 (1 H, s), 8.21 (1 H, brs), 8.60 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (1F, m), −108.8 (2F, q, J = 9.4 Hz), −105.7 (1F, d, J = 7.1 Hz), -58.9 (3F, td, J = 11.8 and 3.5 Hz).
Example-14

N- [1- {2,4-difluoro-6- (4-methoxyphenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white Solid (Yield: 87%); Mp: 122-123 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.77 (3H, s), 3.94 (3H, s), 6.81 (1H , T, J = 54.1 Hz), 6.81 (2H, d, J = 8.8 Hz), 6.90-7.05 (2H, m), 7.15 (2H, d, J = 8. 8Hz), 8.03 (1H, s), 8.20 (1H, brs), 8.60 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.1 (1F, m), −108.9 (2F, m), −105.7 (1F, d, J = 9.2 Hz), − 58.9 (3F, td, J = 11.8 and 3.5 Hz).
Example-15

N- [1- {2,6-difluoro-4- (3-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white Solid (Yield: 39%); Mp: 178.3-180.5 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J = 54.1 Hz), 7.15-7.18 (1H, m), 7.26-7.31 (3H, m), 7.36-7.39 (1H, m) 7.45-7.52. (3H, m), 8.09 (1H, s), 8.38 (1H, brs), 8.70 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.5 (2F, m), −111.7 (1F, s), −108.1 (2F, m), −58.9 (3F, m).
Example-16

N- [1- {2,6-difluoro-4- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white Solid (Yield: 48%); Mp: 179.5-182.5 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.84 (1H, t, J = 54.1 Hz), 7.17-7.26 (4H, m), 7.55-7.59 (2H, m), 8.09 (1H, s), 8.38 (1H, brs), 8 .70 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.8 (2F, m), -112.2 (1F, m), -108.2 (2F, m), -58.9 (3F, m).
Example-17

3-difluoromethyl-N- [1- {2,4-difluoro-6- (3-pyridyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: colorless oil Product (yield: 33%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.80 (1 H, t, J = 54.1 Hz), 7.02-7. 26 (3H, m), 7.54-7.57 (1H, m), 8.04 (1H, s), 8.22 (1H, brs), 8.51-8.59 (3H, m) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (1F, m), −108.8 (2F, m), −104.3 (1 F, d, J = 9.4 Hz), − 58.8 (3F, m).
Example-18

3-Difluoromethyl-N- [1- {2,4-difluoro-6- (4-pyridyl) phenyl] -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: yellow solid (Yield: 46%); Mp: 199-201 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.80 (1 H, t, J = 54.1 Hz), 7.0-4.20 (4H, m), 8.05 (1H, s), 8.23 (1H, brs), 8.56 (2H, d, 6.1 Hz), 8.61 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.6 (1F, m), −108.6 (2F, m), −104.0 (1 F, d, J = 9.4 Hz), − 58.7 (3F, m).
Example-19

3-difluoromethyl-N- [1- {2-fluoro-5- (2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white solid (yield) Mp: 143-145 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J = 54.1 Hz), 7. 09 (1H, dd, J = 5.1 and 3.7 Hz), 7.26-7.33 (3H, m), 7.65-7.70 (2H, m), 8.08 (1H, s), 8.36 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.9 (1F, m), -108.5 (2F, m), -57.9 (3F, m).
Example-20

3-Difluoromethyl-N- [1- {2-fluoro-5- (3-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white solid (yield) Rate: 53%); Mp: 154-156 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.85 (1 H, t, J = 54.1 Hz), 7. 24-7.69 (6H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.63 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.6 (1F, m), −108.5 (2F, m), −57.9 (3F, m).
Example-21

3-difluoromethyl-N- [1- {2,4-difluoro-6- (2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white solid (Yield: 61%); Mp: 133-135 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.96 (3H, s), 6.84 (1H, t, J = 54.1 Hz), 6.83-6.97 (3H, m), 7.26 (1H, ddd, J = 9.3, 2.7 and 1.9 Hz), 7.33 (1H, dd, J = 5.1 and 1.1 Hz) , 8.07 (1H, s), 8.33 (1H, brs), 8.70 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.2 (1F, m), −108.7 (2F, m), −105.0 (1 F, d, J = 9.4 Hz), − 59.2 (3F, m).
Example-22

3-Difluoromethyl-N- [1- {2,4-difluoro-6- (3-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: white solid (Yield: 64%); Mp: 69-72 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.82 (1 H, t, J = 54.1 Hz), 6.90 (1H, dd, J = 5.1 and 1.3 Hz), 6.95 (1 H, ddd, J = 8.7, 8.1 and 2.8 Hz), 7.05 (1H, dd, J = 3. 0 and 1.3 Hz), 7.15 (1 H, ddd, J = 9.1, 2.7 and 1.9 Hz), 8.06 (1 H, s), 8.27 (1 H, brs), 8.67 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.7 (1F, m), −108.8 (2F, m), −105.3 (1F, d, J = 9.4 Hz), − 59.1 (3F, m).
Example-23

3-Difluoromethyl-N- [1- {2,4-difluoro-6- (5-methyl-2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4- Carboxamide: white solid (yield: 61%); Mp: 129-132 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.43 (3H, s), 3.97 (3H, s), 6. 83 (1H, t, J = 53.9 Hz), 6.60-6.91 (4H, m), 7.20 (1H, ddd, J = 9.5, 2.6 and 1.9 Hz), 8.07 (1H, s), 8.34 (1H, brs), 8.71 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.6 (1F, m), −108.7 (2F, m), −105.3 (1 F, d, J = 9.4 Hz), − 59.2 (3F, m).
Example-24

3-difluoromethyl-N- [1- {2-fluoro-5- (2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: yellow oil ( ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.48 (1H, dd, J = 3.4 and 1.8 Hz), 6.65 (1H, d, J = 3.4 Hz), 6.85 (1H, t, J = 54.1 Hz), 7.22-7.30 (1H, m), 7.48 (1H, d, J = 1.4 Hz) ), 7.72-7.81 (2H, m), 8.08 (1H, s), 8.35 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.8 (1F, m), −108.5 (2F, m), −58.0 (3F, m).
Example-25

3-difluoromethyl-N- [1- {2-fluoro-5- (3-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4-carboxamide: yellow solid (yield) Rate: 60%); Mp: 107-109 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.98 (3H, s), 6.65 (1 H, dd, J = 1.8 and 0.9 Hz), 6.85 (1H, t, J = 54.1 Hz), 7.25 (1H, t, J = 8.9 Hz), 7.48-7.62 (3H, m), 7.72 (1H, s ), 8.08 (1H, s), 8.35 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.6 (1F, m), -108.5 (2F, m), -58.0 (3F, m).
Example-26

N- [1- {2,4-difluoro-6- (2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: pale yellow Solid (Yield: 57%); Mp: 152-153 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 5.40 (1 H, d, J = 3.4 Hz) 6.35 (1 H, dd, J = 3.6 and 1.8 Hz), 6.85 (1 H, t, J = 54.1 Hz), 6.86-6.95 (1 H, m), 7.44 ( 1H, d, J = 1.5 Hz), 7.43-7.51 (1H, m), 8.09 (1H, s), 8.60 (1H, brs), 8.74 (1H, s) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.3 (1F, m), −108.7 (2F, q, J = 4.7 Hz), −104.6 (1F, d, J = 9.4 Hz), -59.5 (3F, m).
Example-27

N- [1- {2,4-difluoro-6- (3-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -3-difluoromethyl-1-methylpyrazole-4-carboxamide: white solid (Yield: 67%); Mp: 164-166 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.97 (3H, s), 6.25 (1 H, dd, J = 1.9 and 0.9 Hz) ), 6.84 (1H, t, J = 54.1 Hz), 6.88-6.97 (2H, m), 7.12 (1H, ddd, J = 9.2, 2.7 and 1.9 Hz) 7.37 (1 H, t, J = 1.7 Hz), 8.08 (1 H, s), 8.35 (1 H, brs), 8.70 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.7 (1F, m), −108.7 (2F, m), −105.2 (1F, d, J = 9.4 Hz), − 59.3 (3F, m).
Example-28

3-Difluoromethyl-N- [1- {2,4-difluoro-6- (5-methyl-2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] -1-methylpyrazole-4- Carboxamide: yellow solid (yield: 70%); Mp: 125-127 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.29 (3H, s), 3.98 (3H, s), 5. 30 (1 H, d, J = 3.4 Hz), 5.95 (1 H, dd, J = 3.4 and 0.9 Hz), 6.83 (1 H, ddd, J = 9.1, 9.0 and 2.8 Hz) 6.84 (1H, t, J = 54.1 Hz), 7.43 (1H, ddd, J = 9.8, 2.6 and 2.0 Hz), 8.09 (1H, s), 8.38 ( 1H, brs), 8.72 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.6 (1F, m), −108.5 (2F, m), −105.1 (1F, d, J = 9.4 Hz), − 59.5 (3F, m).
Example-29

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazole (250 mg, 0.65 mmol). After ice cooling, a solution of triethylamine (98 mg, 0.97 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (126 mg, 0.65 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (20 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a white solid N- { 1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide ( 155 mg, yield: 44%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.87 (3H, s), 3.96 (3H, s), 6.80 (1H, t, J = 54.1 Hz), 6.86 (1H, t, J = 8.5 Hz), 6.92-7.03 (4H, m), 8.04 (1H, s), 8.21 (1H, brs), 8.62 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-134.5 (1F, s), −115.2 (1F, m), −108.4 (2F, m), −104.9 (1F, d) , J = 9.3 Hz), −58.5 (3F, td, J = 6.2 and 2.4 Hz).
Example-30

Add dichloromethane (2.0 mL) to 4-amino-1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) phenyl] -5-trifluoromethylpyrazole (250 mg, 0.67 mmol). After cooling with ice, a solution of triethylamine (102 mg, 1.01 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (0.67 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (20 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a white solid N- { 1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide ( 182 mg, yield: 51%). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.21 (3H, d, J = 1.8 Hz), 3.95 (3H, s), 6.80 (1H, t, J = 54.1 Hz), 6.90 (1H, t, J = 8.9 Hz), 6.95-7.03 (3H, m), 7.07 (1H, dd, J = 7.2 and 2.1 Hz), 8.03 (1H , S), 8.20 (1H, brs), 8.58 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.0 (1F, s), −115.4 (1F, m), −108.4 (2F, m), −105.1 (1F, d) , J = 9.4 Hz), -58.5 (3F, td, J = 6.7 and 2.6 Hz).
Example-31

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-trifluoromethoxyphenyl) phenyl] -5-trifluoromethylpyrazole (250 mg, 0.59 mmol) and iced. After cooling, a solution of triethylamine (90 mg, 0.88 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (0.59 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours. After completion of the reaction, 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- [2,4-difluoro-6 as a white solid. -(3-Trifluoromethoxyphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (186 mg, yield: 54%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.95 (3H, s), 6.79 (1H, t, J = 54.1 Hz), 7.01-7.07 (2H, m), 7. 10 (1H, brs), 7.15-7.19 (2H, m), 7.33 (1H, t, J = 8.0 Hz), 8.03 (1H, s), 8.19 (1H, brs), 8.58 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (1F, m), −108.4 (2F, m), −104.4 (1F, d, J = 9.5 Hz), −58 .5 (3F, m), -58.0 (3F, s).
Example-32

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-methylthiophenyl) phenyl] -5-trifluoromethylpyrazole (250 mg, 0.65 mmol) and cooled with ice. Thereafter, a solution of triethylamine (98 mg, 0.97 mmol) and 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (0.65 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours. After completion of the reaction, 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- [2,4-difluoro-6 as a white solid. -(3-Methylthiophenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -3-difluoromethyl-1-methylpyrazole-4-carboxamide (214 mg, yield: 61%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.40 (3H, s), 3.95 (3H, s), 6.79 (1H, t, J = 54.1 Hz), 6.97-7. 07 (3H, m), 7.08-7.09 (1H, m), 7.19-7.21 (2H, m), 8.03 (1H, s), 8.20 (1H, brs) 8.56 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (1F, m), −108.4 (2F, m), −104.9 (1F, d, J = 8.8 Hz), −58 .4 (3F, m).
Example-33

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazole (150 mg, 0.39 mmol). After ice cooling, a solution of triethylamine (59 mg, 0.58 mmol) and 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (0.39 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (20 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a white solid N- { 1- [2,4-Difluoro-6- (3-fluoro-4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -1-methyl-3-trifluoromethylpyrazole-4-carboxamide (33 mg, yield: 15%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.87 (3H, s), 4.00 (3H, s), 6.84-7.04 (5H, m), 7.87 (1H, brs) , 8.05 (1H, s), 8.60 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-134.5 (1F, s), −115.2 (1F, m), −104.6 (1F, d, J = 9.4 Hz), −59 .9 (3F, m), -58.6 (3F, m).
Example-34

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) phenyl] -5-trifluoromethylpyrazole (150 mg, 0.40 mmol). After cooling with ice, a solution of triethylamine (61 mg, 0.60 mmol) and 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (0.40 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours, poured into a saturated aqueous sodium hydrogen carbonate solution (10 mL), and extracted with chloroform (20 mL × 3). The combined organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give a white solid N- { 1- [2,4-Difluoro-6- (4-fluoro-3-methylphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -1-methyl-3-trifluoromethylpyrazole-4-carboxamide (151 mg, yield: 68%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.21 (3H, d, J = 1.8 Hz), 4.00 (3H, s), 6.88-7.08 (5H, m), 7. 84 (1H, brs), 8.04 (1H, s), 8.57 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.0 (1F, s), −115.4 (1F, m), −104.9 (1F, d, J = 9.3 Hz), −59 .9 (3F, m), -58.6 (3F, m).
Example-35

Dichloromethane (2.0 mL) was added to 4-amino-1- [2,4-difluoro-6- (3-methylthiophenyl) phenyl] -5-trifluoromethylpyrazole (150 mg, 0.39 mmol) and cooled with ice. Thereafter, a solution of triethylamine (59 mg, 0.58 mmol) and 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid chloride (0.39 mmol) in dichloromethane (2.0 mL) was added. The mixed solution was stirred at room temperature for 24 hours. After completion of the reaction, 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- [2,4-difluoro-6 as a colorless oil. -(3-Methylthiophenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} -1-methyl-3-trifluoromethylpyrazole-4-carboxamide (44 mg, yield: 20%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.40 (3H, s), 3.99 (3H, s), 6.78-7.04 (4H, m), 7.19-7.21 ( 2H, m), 7.84 (1H, brs), 8.04 (1H, s), 8.57 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (1F, m), −104.6 (1F, d, J = 9.4 Hz), −59.9 (3F, m), −58 .5 (3F, m).
Reference Example-1

Ethyl 3-difluoromethyl-1-methylpyrazole-4-carboxylate (77.2 g, 378 mmol) was dissolved in ethanol (200 mL), 10% aqueous sodium hydroxide solution (200 mL) was added, and the mixture was refluxed for 1 hr. The reaction mixture was cooled 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).
A mixture of 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid (1.94 g, 11.0 mmol), anhydrous toluene (10 mL) and thionyl chloride (5 mL) was refluxed for 30 minutes, and then a Dean-Stark tube was used. Toluene and excess thionyl chloride were removed. Further, the solvent was completely removed sequentially using an evaporator and a vacuum pump to quantitatively obtain brown oily 3-difluoromethyl-1-methylpyrazole-4-carboxylic acid chloride (2.14 g). This was used in the next reaction without purification. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 4.01 (3H, s), 6.92 (1H, t, J = 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), anhydrous toluene (10 mL) and thionyl chloride (5 mL) was refluxed for 1 hour and then used with a Dean-Stark tube. Toluene and excess thionyl chloride were removed. Further, the solvent was completely removed sequentially using an evaporator and a vacuum pump 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 solution of sodium nitrite (8.64 g, 125 mmol) in sulfuric acid (60 mL) was added to a solution of 2-bromo-4,6-difluoroaniline (20.9 g, 101 mmol) in acetic acid (100 mL) that had been ice-cooled in advance. It added under ice-cooling so that temperature might not become 50 degreeC or more. Next, a solution of tin chloride (76.2 g, 402 mmol) in hydrochloric acid (60 mL) was added so that the temperature of the reaction solution did not exceed 10 ° C., and then the reaction solution was poured into ice (600 g). To this was added sodium hydroxide little by little to make it alkaline, diluted with water (200 mL), and extracted with chloroform (300 mL × 2). The organic layers were combined, washed with saturated brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 2-bromo-4,6-difluorophenylhydrazine (20.9 g, yield) as a brown solid. : 93%). ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.87 (2H, brs), 5.21 (1H, s), 6.80-6.89 (1H, m), 7.05-7.10 ( 1H, m). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-121.3 (1F, d, J = 2.4 Hz), −117.7 (1F, d, J = 2.4 Hz).
2-bromo-4,6-difluorophenylhydrazine (6.43 g, 28.8 mmol), ethyl 2-ethoxymethylenetrifluoroacetoacetate (6.92 g, 28.8 mmol), triethylamine (3.00 g, 29.6 mmol) And ethanol (60 mL) was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 20/1) to give 1- (2-bromo-4,6-difluorophenyl) as a brown oil. Ethyl 5-trifluoromethylpyrazole-4-carboxylate (5.89 g, yield: 51%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.39 (3H, t, J = 7.1 Hz), 4.39 (2H, q, J = 7.1 Hz), 7.03 (1H, ddd, J = 9.0, 8.0 and 2.8 Hz), 7.32 (1 H, ddd, J = 7.8, 2.8 and 2.3 Hz), 8.24 (1 H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), −103.5 (1F, d, J = 9.4 Hz), −58.6 (3F, d, J = 0) .9 Hz).
Ethyl 1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylate (5.86 g, 14.7 mmol), ethanol (15 mL) and 10% aqueous sodium hydroxide (15 mL) ) Was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, acidified with concentrated hydrochloric acid, and the precipitated solid was collected by filtration to give 1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4 as a yellow solid. -Carboxylic acid (4.11 g, yield: 75%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 7.00-7.08 (1H, m), 7.31-7.36 (1H, m), 8.32 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), -103.1 (1F, d, J = 9.4 Hz), -58.7 (3F, s).
1- (2-Bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylic acid (11.5 g, 31.0 mmol), triethylamine (4.70 g, 46.4 mmol) and acetone (150 mL) ) Was ice-cooled and ethyl chloroformate (3.5 mL, 36.6 mmol) was added dropwise, followed by stirring at the same temperature for 10 minutes to obtain a mixed acid anhydride. Next, a solution of sodium azide (4.00 g, 61.5 mmol) in water (12 mL) was added dropwise thereto, and the mixture was further stirred for 10 minutes under ice cooling. Water (400 mL) was added to the reaction solution, and extracted with toluene (100 mL × 3). The organic layers were combined, washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and part of the solvent was distilled off under reduced pressure while paying sufficient attention so that no solid precipitated. The obtained acyl azide solution was dropped into a mixture of t-butyl alcohol (20 mL) and toluene (20 mL) in a reflux state, and 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 = 9/1) to give N- [1- (2-bromo -4,6-Difluorophenyl) -5-trifluoromethylpyrazol-4-yl] t-butyl carbamate (10.2 g, yield: 75%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.53 (1H, brs), 6.95-7.03 (1H, m), 7.26-7.31 ( 1H, m), 8.40 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.9 (1F, m), -103.8 (1F, d, J = 7.1 Hz), -59.0 (3F, s).
Reference example-4

Under argon atmosphere, N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol), bis (dibenzyl Denacetone) palladium (58 mg, 0.10 mmol), 2- (dicyclohexylphosphino) biphenyl (35 mg, 0.10 mmol), 3-fluorophenylboronic acid (0.840 g, 6.0 mmol) and potassium phosphate (2. (55 g, 12.0 mmol) in DMF (10 mL) was stirred with heating at 100 ° C. (oil bath temperature) for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give N- [1- {2,4-difluoro-6- (3-fluorophenyl) phenyl} -5--5 as white solid. T-butyl (trifluoromethylpyrazol-4-yl) carbamate (532 mg, yield: 58%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s), 6.40 (1H, brs), 6.99-7.05 (5H, m), 7.23-7.28 ( 1H, m), 8.31 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.0 (1F, s), −112.4 (1F, s), −104.7 (1F, s), −58.2 (3F, s) ).
1,4 of t-butyl N- [1- {2,4-difluoro-6- (3-fluorophenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate (532 mg, 1.16 mmol) -2N hydrochloric acid (6 mL) was added to the dioxane (10 mL) solution, and it stirred at 80 degreeC for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (3-fluorophenyl) phenyl] -5-5 as white solid. Trifluoromethylpyrazole (261 mg, yield: 63%) was obtained. Mp: 89.8-93.3 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.38 (2H, brs), 6.93-7.03 (5H, m), 7.22-7.28 (1H, m), 7.32 ( 1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (1F, m), −112.7 (1F, s), −105.4 (1F, m), −58.4 (3F, d) , J = 2.7 Hz).
Reference Example-5

Under an argon atmosphere, tetrakistriphenylphosphine palladium (116 mg, 0.10 mmol), 3-chlorophenylboronic acid (0.938 g, 6.0 mmol), N- [1- (2-bromo-4,6-difluorophenyl)- 5-Trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol) and sodium carbonate (1.27 g, 12.0 mmol) in DMF (1 mL) at 100 ° C. (oil bath temperature) And stirred for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). After drying the organic layer with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 10-4 / 1) to give N- [1- {2- (3-chlorophenyl) -4,6-difluorophenyl} as a colorless oil. -5-Trifluoromethylpyrazol-4-yl] carbamate t-butyl (427 mg, yield: 45%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.51 (9H, s), 6.38 (1H, brs), 6.92-7.31 (6H, m), 8.29 (1H, brs) . ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.3 (1F, m), −104.9 (1F, d, J = 9.4 Hz), −58.5 (3F, s).
1,4-N- [1- {2- (3-Chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (427 mg, 0.90 mmol) A 12N hydrochloric acid-methanol solution (1 / 3.5, 5 mL) was added to a dioxane (5.0 mL) solution, and the mixture was stirred at 60 ° C. for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform (15 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2- (3-chlorophenyl) -4,6-difluorophenyl] -5-trimethyl as a white solid. Fluoromethylpyrazole (222 mg, yield: 66%) was obtained. Mp: 60-62 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.37 (2H, brs), 6.96-7.04 (2H, m), 7.07-7.11 (1H, m), 7.18- 7.30 (3H, m), 7.33 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.5 (1F, m), −105.6 (1F, d, J = 9.4 Hz), −58.6 (3F, t, J = 2) .4).
Reference Example-6

Under an argon atmosphere, tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol), 2-chlorophenylboronic acid (0.235 g, 1.50 mmol), N- [1- (2-bromo-4,6-difluorophenyl)- A solution of t-butyl 5-trifluoromethylpyrazol-4-yl] carbamate (221 mg, 0.50 mmol) and sodium carbonate (0.318 g, 3.0 mmol) in DMF (2 mL) at 100 ° C. (oil bath temperature) And stirred for 24 hours. The reaction mixture was cooled to room temperature, water (2 mL) was added, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100 / 10-4 / 1) to give N- [1- {2- (2-chlorophenyl) -4,6-difluorophenyl} as a colorless oil. -5-Trifluoromethylpyrazol-4-yl] carbamate t-butyl (121 mg, yield: 51%) was obtained. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.48 (9H, s), 6.41 (1H, brs), 6.97-7.27 (6H, m), 7.37-7.40 ( 1H, m), 8.19 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.9 (1F, brs), -106.1 (1F, d, J = 9.4 Hz), -58.5 (3F, brs).
1,4- of t-butyl N- [1- {2- (2-chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate (121 mg, 0.26 mmol) A 4N hydrochloric acid-methanol solution (2 mL) was added to the dioxane (2 mL) solution, and the mixture was stirred at 60 ° C. for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform (5 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2- (2-chlorophenyl) -4,6-difluorophenyl] -5-trimethyl as a white solid. Fluoromethylpyrazole (82 mg, yield: 86%) was obtained. Mp: 64-67 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.31 (2H, brs), 6.96-7.26 (6H, m), 7.41 (1H, m). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.1 (1F, brs), −106.8 (1F, d, J = 7.1 Hz), −58.6 (3F, brs).
Reference Example-7

Under an argon atmosphere, tetrakistriphenylphosphine palladium (58 mg, 0.05 mmol), 4-methylphenylboronic acid (408 mg, 3.0 mmol), N- [1- (2-bromo-4,6-difluorophenyl) -5 -Trifluoromethylpyrazol-4-yl] t-butyl carbamate (442 mg, 1.0 mmol) and sodium carbonate (0.636 g, 6.0 mmol) in DMF (10 mL) at 100 ° C. (oil bath temperature). The mixture was heated and stirred for 24 hours. The reaction mixture was cooled to room temperature, water (15 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. 1,4-Dioxane (5 mL) and 12N hydrochloric acid-methanol solution (1/3, 5 mL) were added to the resulting residue, and the mixture was stirred at 60 ° C. for 1 hour. After completion of the reaction, the reaction mixture was neutralized with 10% aqueous sodium hydroxide solution and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (4-tolyl) phenyl] -5-trimethyl as a yellow solid. Fluoromethylpyrazole (333 mg, yield: 94%) was obtained. Mp: 83-85 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.27 (3H, s), 3.37 (2H, brs), 6.88 (1H, ddd, J = 9.0, 8.0 and 3.0 Hz), 6.99 (1H, ddd, J = 9.0, 3.0 and 2.0 Hz), 7.04-7.12 (4H, m), 7.26 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.3 (1F, m), −106.3 (1F, d, J = 9.4 Hz), −58.6 (3F, t, J = 5) .9 Hz).
Reference Example-8

Under an argon atmosphere, tetrakistriphenylphosphine palladium (231 mg, 0.20 mmol), 2-furylboronic acid (448 mg, 4.0 mmol), N- [1- (2-bromo-4,6-difluorophenyl) -5-tri A solution of t-butyl fluoromethylpyrazol-4-yl] carbamate (0.884 g, 2.0 mmol) and sodium carbonate (0.848 g, 8.0 mmol) in DMF (5 mL) at 100 ° C. (oil bath temperature). And stirred for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- [1- {2,4-difluoro-6- (2-furyl) phenyl} -5-trimethyl as a white solid. Fluoromethylpyrazol-4-yl] t-butyl carbamate (0.38 g, yield: 44%) was obtained. Mp: 135-140 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.56 (9H, s), 5.35 (1H, dd, J = 5.0 and 1.3 Hz), 6.34 (1H, dd, J = 3.8 and 2) .5Hz), 6.56 (1H, brs), 6.83-6.88 (1H, m), 7.44-7.50 (2H, m), 8.45 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.3 (1F, d, J = 7.1 Hz), −104.8 (1F, d, J = 9.4 Hz), −59.3 (3F) , S).
N- [1- {2,4-difluoro-6- (2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (303 mg, 0.71 mmol), 1,4- A mixture of dioxane (3 mL) and 2N hydrochloric acid (2 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 (20 mL × 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4-amino-1- [2,4-difluoro-6- 6 as a pale yellow solid. (2-Furyl) phenyl] -5-trifluoromethylpyrazole (0.23 g, yield: quantitative) was obtained. Mp: 112-115 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ3.54 (2H, brs), 5.37 (1H, d, J = 3.5 Hz), 6.34 (1H, dd, J = 3.6 and 1.8 Hz) ), 6.85 (1H, ddd, J = 9.1, 8.0 and 2.8 Hz), 7.44-7.49 (3H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-116.5 (1F, m), -105.4 (1F, d, J = 9.4 Hz), -59.3 (3F, m).
Reference Example-9

Under an argon atmosphere, bis (dibenzylideneacetone) palladium (72 mg, 0.13 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (119 mg, 0.25 mmol), pyridine-3-boronic acid (500 mg) , 4.07 mmol), t-butyl N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate (1.10 g, 2.5 mmol) and A solution of potassium phosphate (1.06 g, 5.0 mmol) in DMF (5 mL) was stirred with heating at 100 ° C. (oil bath temperature) for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1) to give N- [1- {2,4-difluoro-6- (3-pyridyl) phenyl} -5-trifluoromethylpyrazole. A yellow solid (0.91 g, yield: 83%) of t-butyl carbamate was obtained. Mp: 130-132 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.50 (9H, s), 6.39 (1H, brs), 7.02-7.07 (2H, m), 7.23 (1H, dd, J = 8.0 and 5.0 Hz), 7.51-7.56 (1H, m), 8.48 (1H, brs), 8.49 (1H, d, J = 2.1 Hz), 8.56 ( 1H, dd, J = 4.8 and 1.6 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.8 (1F, s), −104.4 (1F, d, J = 9.4 Hz), −58.5 (3F, s).
T-butyl N- [1- {2,4-difluoro-6- (3-pyridyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate (0.91 g, 2.07 mmol), 1, A mixture of 4-dioxane (12 mL) and 2N hydrochloric acid (10 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, and concentrated under reduced pressure to give 4-amino-1- [2,4-difluoro-6- (3-pyridyl). ) Phenyl] -5-trifluoromethylpyrazole yellow solid (0.49 g, yield: 90%) was obtained. Mp: 73-75 ° C. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.38 (2H, brs), 7.00-7.06 (2H, m), 7.23 (1H, ddd, J = 8.0, 4.9 and 0 .8 Hz), 7.32 (1 H, d, J = 0.7 Hz), 7.52-7.55 (1 H, m), 8.49 (1 H, d, J = 1.9 Hz), 8.52 (1H, dd, J = 4.9 and 1.6 Hz). ¹⁹ F-NMR (376 Hz, CDCl ₃ ): δ-114.8 (1F, m), -104.8 (1F, m), -58.3 (3F, m).
Reference Example-10-31
Hereinafter, the reaction formula of 4-aminopyrazole derivative synthesized by the same method as in the above Reference Example, product name, property (yield), melting point, and NMR spectrum are shown.
Reference Example-10

T-butyl N- [1- {2-fluoro-4- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 75%); Mp: ^{101.3-107.8 ℃; 1 H-NMR (} 400MHz, CDCl 3): δ1.54 (9H, s), 6.59 (1H, brs), 7.15 (2H, t, J = 8. 7Hz), 7.37-7.41 (2H, m), 7.44-7.48 (1H, m), 7.54-7.57 (2H, m), 8.33 (1H, brs) . ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-121.3 (1F, s), -113.4 (1F, s), -57.5 (3F, s).
4-amino-1- {2-fluoro-4- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazole: white solid (yield: 81%); Mp: 90.0-91.8 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.50 (2H, brs), 7.17 (2H, t, J = 8.7 Hz), 7.37-7.48 (4H, m), 7. 55-7.59 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-121.5 (1F, m), -113.6 (1F, s), -57.5 (3F, m).
Reference Example-11

^1- H- [1- {5- (2-chlorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 64%); NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.52 (1H, brs), 7.29-7.34 (4H, m), 7.45-7.56 (3H, m ), 8.32 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.6 (1F, d, J = 4.7 Hz), −57.7 (3F, m).
4-amino-1- [5- (2-chlorophenyl) -2-fluorophenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 88%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.37 (2H, brs), 7.24-7.52 (8H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-123.8 (1F, d, J = 2.4 Hz), −57.7 (3F, m).
Reference Example-12

^1- H- [1- {5- (3-chlorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 61%); NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.53 (1H, brs), 7.26-7.65 (7H, m), 8.33 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.5 (1F, m), -57.7 (3F, m).
4-amino-1- [5- (3-chlorophenyl) -2-fluorophenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 71%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.40 (2H, brs), 7.29-7.66 (8H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-123.7 (1F, m), -57.7 (3F, m).
Reference Example-13

T-butyl N- [1- {5- (4-chlorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 60%); Mp: 102 ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.51 (1H, brs), 7.30-7.34 (1H, m), 7.40- 7.49 (4H, m), 7.57-7.68 (2H, m), 8.32 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.0 (1F, d, J = 4.7 Hz), −57.7 (3F, d, J = 4.7 Hz).
4-amino-1- [5- (4-chlorophenyl) -2-fluorophenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 87%); ¹ H-NMR (250 MHz CDCl ₃ ): δ3. 40 (2H, brs), 7.21-7.60 (8H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-124.2 (1F, d, J = 4.7 Hz), −57.7 (3F, d, J = 4.7 Hz).
Reference Example-14

^1- H- [1- {2-fluoro-5- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 85%); _{-NMR (400MHz, CDCl 3):} δ1.55 (9H, s), 6.53 (1H, brs), 7.13 (2H, t, J = 8.7Hz), 7.29 (1H, t, J = 9.0 Hz), 7.47-7.52 (2H, m), 7.56-7.52 (1 H, m), 7.61-7.65 (1 H, m), 8.34 ( 1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.4 (1F, s), -114.4 (1F, s), -57.5 (3F, s).
4-amino-1- [2-fluoro-5- (4-fluorophenyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 98%); Mp: 97.1-100.6 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.51 (2H, brs), 7.13 (2H, t, J = 8.7 Hz), 7.28 (1H, t, J = 9.0 Hz), 7.41 (1H, s), 7.48-7.52 (2H, m), 7.55-7.62 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.6 (1F, m), -114.6 (1F, s), -57.4 (3F, m).
Reference Example-15

T-butyl N- [1- {2,4-difluoro-6- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 59%); Mp: 112.1-114.9 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.51 (9H, s), 6.39 (1H, brs), 6.96-7.00 (4H, m), 7.17-7.20 (2H, m), 8.30 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (1F, s), −112.7 (1F, s), −105.0 (1F, m), −58.3 (3F, s).
4-Amino-1- [2,4-difluoro-6- (4-fluorophenyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 93%); Mp: 162.8-164.8 ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.37 (2H, brs), 6.95-7.00 (4H, m), 7.18-7.21 (2H, m), 7. 32 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (1F, m), -113.1 (1F, s), -105.6 (1F, m), -58.4 (3F, d, J = 2.6 Hz).
Reference Example-16

N- [1- {2- (4- chlorophenyl) -4,6-difluorophenyl} -5-trifluoromethyl-4-yl] carbamate t- butyl: white solid (yield: ^{59%); 1} H-NMR (250 MHz, CDCl ₃ ): δ 1.50 (9H, s), 6.44 (1H, brs), 6.94-7.07 (2H, m), 7.12-7.20 (2H) M), 7.2-3.30 (2H, m), 8.31 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.4 (1F, d, J = 7.1 Hz), −105.0 (1F, d, J = 9.4 Hz), −59.6 ( 3F, s).
4-amino-1- [2- (4-chlorophenyl) -4,6-difluorophenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 82%); Mp: 122-125 ° C .; ¹ H- NMR (250 MHz, CDCl ₃ ): δ 3.38 (2H, brs), 7.01-6.93 (2H, m), 7.17-7.13 (2H, m), 7.28-7.24 (2H, m), 7.32 (1H, d, J = 2.5 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.6 (1F, dq, J = 9.4 and 3.5 Hz), −105.7 (1F, d, J = 9.4 Hz), −58. 6 (3H, d, J = 3.5 Hz).
Reference Example-17

T-butyl N- [1- {2,4-difluoro-6- (4-methylphenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: yellow solid (yield: 36%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.50 (9H, s), 2.31 (3H, s), 6.40 (1H, brs), 6.89-7.05 (2H, m) , 7.08 (4H, s), 8.29 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.1 (1F, m), −105.7 (1F, d, J = 9.4 Hz), −58.6 (3F, s).
Reference Example-18

N- [1- {2- (4-t-butylphenyl) -4,6-difluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl: white solid (yield: 36% ); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.29 (9H, s), 1.51 (9H, s), 6.41 (1H, brs), 6.93 (1H, ddd, J = 9.0, 8.0 and 3.0 Hz), 7.03 (1H, ddd, J = 9.0, 9.0 and 1.5 Hz), 7.12 (2H, d, J = 8.0 Hz), 7.29 (2H, d, 9.0 Hz), 8.30 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.2 (1F, d, J = 4.7 Hz), −105.8 (1F, d, J = 9.4 Hz), −58.6 ( 3F, s).
4-amino-1- [2- (4-t-butylphenyl) -4,6-difluorophenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 71%); Mp: 107-108 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.29 (9H, s), 3.36 (2H, brs), 6.92 (1H, ddd, J = 9.1, 8.2 and 2.8 Hz), 7.02 (1H, ddd, J = 9.2, 2.8 and 1.7 Hz), 7.13 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.6 Hz) , 7.33 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.4 (1F, m), −106.5 (1F, d, J = 9.4 Hz), −58.7 (3F, t, J = 2.4 Hz).
Reference Example-19

T-butyl N- [1- {2,4-difluoro-6- (4-methoxyphenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 41%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.51 (9H, s), 3.78 (3H, s), 6.40 (1H, brs), 6.80 (2H, d, J = 9. 0 Hz), 6.93 (1H, ddd, J = 9.0, 8.0 and 3.0 Hz), 7.01 (1 H, ddd, J = 9.0, 9.0 and 1.8 Hz), 7.12 (2H , D, J = 9.0 Hz), 8.31 (1H, brs). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-116.1 (1F, d, J = 7.1 Hz), −105.8 (1F, d, J = 9.4 Hz), −58.7 ( 3F, s).
4-amino-1- [2,4-difluoro-6- (4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 42%); Mp: 76-78 ° C .; ¹ H -NMR (250 MHz, CDCl ₃ ): δ 3.36 (2H, brs), 3.78 (3H, s), 6.80 (2H, d, J = 9.0 Hz), 7.01-6.88 ( 2H, m), 7.14 (2H, d, J = 8.0 Hz), 7.32 (1H, brs). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-116.3 (1F, dq, J = 9.4 and 4.7 Hz), −106.4 (1F, d, J = 9.4 Hz), −58. 7 (3F, d, J = 4.7 Hz).
Reference Example-20

T-butyl N- [1- {2,6-difluoro-4- (3-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 71%); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.55 (1H, brs), 7.12-7.17 (1H, m), 7.25-7.30 ( 3H, m), 7.35-7.38 (1H, m) 7.41-7.49 (1H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.5 (2F, s), -111.8 (1F, s), -58.7 (3F, s).
4-Amino-1- [2,6-difluoro-4- (3-fluorophenyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 46%); Mp: 127.2-132.4 ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.53 (2H, brs), 7.11-7.17 (1H, m), 7.23-7.30 (3H, m), 7. 35-7.38 (1H, m) 7.43-7.49 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.8 (2F, m), −111.9 (1F, s), −58.8 (3F, m).
Reference Example-21

T-butyl N- [1- {2,6-difluoro-4- (4-fluorophenyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: yellow solid (yield: 50%); Mp: 131.1-134.1 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ1.55 (9H, s), 6.55 (1H, brs), 7.18 (2H, t, J = 8.6 Hz), 7.23 (2H, d, J = 8.2 Hz), 7.54-7.58 (2H, m), 8.41 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.8 (2F, s), -112.2 (1F, s), -58.7 (3F, s).
4-Amino-1- [2,6-difluoro-4- (4-fluorophenyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 80%); Mp: 104.30-11.54 ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.53 (2H, brs), 7.18 (2H, t, J = 8.7 Hz), 7.22 (2H, d, J = 8.2 Hz) ), 7.46 (1H, s), 7.54-7.57 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-118.1 (2F, m), -112.5 (1F, s), -58.8 (3F, m).
Reference Example-22

T-butyl N- [1- {2,4-difluoro-6- (4-pyridyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: yellow solid (yield: 52%); Mp ^{: 146-147 ℃; 1 H-NMR} (250MHz, CDCl 3): δ1.51 (9H, s), 6.41 (1H, brs), 7.05 (2H, d, J = 8.3Hz), 7.13 (2H, d, J = 6.1 Hz), 8.31 (1H, brs), 8.56 (2H, d, J = 6.1 Hz). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-114.7 (1F, s), −104.1 (1F, d, J = 9.4 Hz), −58.5 (3F, s).
4-amino-1- [2,4-difluoro-6- (4-pyridyl) phenyl] -5-trifluoromethylpyrazole: white solid (yield: 87%); Mp: 150-151 ° C .; ¹ H- NMR (400 MHz, CDCl ₃ ): δ 3.40 (2H, brs), 7.04 (2H, d, J = 3.5 Hz), 7.13 (2H, d, J = 3.6 Hz), 7.32 (1H, d, J = 2.8 Hz), 8.55 (2H, d, J = Hz). ¹⁹ F-NMR (376 Hz, CDCl ₃ ): δ-114.6 (1F, m), -104.6 (1F, m), -58.2 (3F, m).
Reference Example-23

T-butyl N- [1- {2-fluoro-5- (2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 89%); ¹ H- NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.52 (1H, brs), 7.08 (1H, dd, J = 5.1, 3.7 Hz), 7.20-7 .33 (3H, m), 7.62-7.66 (2H, m), 8.33 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.0 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
4-amino-1- [2-fluoro-5- (2-thienyl) phenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 73%); Mp: 78-79 ° C .; ¹ H-NMR ( 250 MHz, CDCl ₃ ): δ 3.70 (2H, brs), 7.08 (1H, dd, J = 5.1 and 3.7 Hz), 7.19-7.31 (2H, m), 7.41 (1H) , D, J = 0.5 Hz), 7.62-7.69 (2H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-124.1 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
Reference Example-24

T-butyl N- [1- {2-fluoro-5- (3-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 85%); Mp: 81 ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.55 (9 H, s), 6.52 (1 H, brs), 7.25 (1 H, t, J = 9.0 Hz), −83 ° C. 32 (1H, dd, J = 5.0 and 1.5 Hz), 7.39-7.44 (2H, m), 7.61-7.64 (2H, m), 8.32 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.6 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
4-amino-1- [2-fluoro-5- (3-thienyl) phenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 81%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.45 (2H, brs), 7.24 (1H, t, J = 8.8 Hz), 7.33 (1H, dd, J = 5.0 and 1.4 Hz), 7.38-7.43 (3H , M), 7.59-7.69 (2H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-124.8 (1F, m), -57.7 (3F, d, J = 4.7 Hz).
Reference Example-25

T-butyl N- [1- {2,4-difluoro-6- (2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 51%); Mp ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.51 (1H, brs), 6.82 (1H, m), 6.88-6. 98 (2H, m), 7.23-7.34 (2H, m), 8.41 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.3 (1F, s), −105.2 (1F, d, J = 9.4 Hz), −59.0 (3F, s).
4-amino-1- [2,4-difluoro-6- (2-thienyl) phenyl] -5-trifluoromethylpyrazole: pale yellow oil (yield: quantitative); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.48 (2H, brs), 6.85 (1H, dd, J = 3.7 and 1.2 Hz), 6.90 (1 H, ddd, J = 9.0, 8.0 and 2.8 Hz), 6.97 (1H, dd, J = 5.1 and 3.7 Hz), 7.22-7.26 (1H, m), 7.33 (1H, dd, J = 5.1 and 1.2 Hz), 7.44 (1H, d, J = 0.7 Hz). ¹⁹ F-NMR (376 Hz, CDCl ₃ ): δ-115.2 (1F, m), −105.5 (1F, d, J = 9.5 Hz), −58.8 (3F, m).
Reference Example-26

T-butyl N- [1- {2,4-difluoro-6- (3-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 49%); Mp : 123-125 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.53 (9H, s), 6.45 (1H, brs), 6.88 (1H, dd, J = 5.1 and 1.4 Hz) ), 6.93 (1H, ddd, J = 9.0, 8.1 and 2.8 Hz), 7.02 (1H, dd, J = 3.0 and 1.3 Hz), 7.14 (1H, ddd, J = 9.2, 2.8 and 1.8 Hz), 7.25-7.27 (1H, m), 8.39 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.5 (1F, s), -105.2 (1F, d, J = 8.1 Hz), -58.6 (3F, s).
4-amino-1- [2,4-difluoro-6- (3-thienyl) phenyl] -5-trifluoromethylpyrazole: pale yellow oil (yield: quantitative); ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.43 (2H, brs), 6.89-6.94 (2H, m), 7.03 (1H, dd, J = 3.0 and 1.3 Hz), 7.13 (1H, ddd, J = 9.2, 2.8 and 1.8 Hz), 7.24-7.26 (1 H, m), 7.40 (1 H, d, J = 0.7 Hz). ¹⁹ F-NMR (376 Hz, CDCl ₃ ): δ-115.7 (1F, m), -105.8 (1F, m), -58.7 (3F, s).
Reference Example-27

T-butyl N- [1- {2,4-difluoro-6- (5-methyl-2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: pale yellow solid (yield: Mp: 144-146 ° C .; ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.54 (9H, s), 2.43 (3H, s), 6.40 (1H, brs), 6 .57-6.62 (2H, m), 6.83-6.88 (1H, m), 7.17-7.20 (1H, m), 8.41 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.3 (1F, s), −105.2 (1F, d, J = 8.4 Hz), −58.7 (3F, s).
4-amino-1- [2,4-difluoro-6- (5-methyl-2-thienyl) phenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 88%); Mp: 106-108 ° C. ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.43 (3H, s), 3.47 (2H, brs), 6.61 (2H, s), 6.84 (1H, ddd, J = 8); .9, 8.1 and 2.8 Hz), 7.18 (1 H, ddd, J = 9.6, 2.6 and 2.0 Hz), 7.44 (1 H, s). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-115.9 (1F, m), −106.1 (1F, d, J = 9.4 Hz), −59.0 (3F, d, J = 7.1 Hz).
Reference Example-28

^1- H- [1- {2-fluoro-5- (2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 71%); NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.48 (1H, dd, J = 3.4, 1.8 Hz), 6.53 (1H, brs), 6.64 (1H , D, J = 3.4 Hz), 7.24 (1H, t, J = 9.0 Hz), 7.47 (1H, d, J = 1.1 Hz), 7.69-7.79 (2H, m), 8.32 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.9 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
4-amino-1- [2-fluoro-5- (2-furyl) phenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 80%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ3.51 (2H, brs), 6.47 (1H, dd, J = 3.4 and 1.8 Hz), 6.63 (1H, d, J = 3.4 Hz), 7.23 (1H, t, J = 8.9 Hz), 7.46 (1 H, s), 7.46 (1 H, d, J = 1.4 Hz), 7.68-7.77 (2 H, m). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-124.0 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
Reference Example-29

T-butyl N- [1- {2-fluoro-5- (3-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 68%); ¹ H- NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 6.53 (1H, brs), 6.64-6.67 (1H, m), 7.23 (1H, t, J = 8 .9 Hz), 7.48-7.60 (3H, m), 7.70 (1H, s), 8.32 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.6 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
4-amino-1- [2-fluoro-5- (3-furyl) phenyl] -5-trifluoromethylpyrazole: yellow oil (yield: 70%); ¹ H-NMR (250 MHz, CDCl ₃ ): δ 3.44 (2H, brs), 6.64 (1H, d, J = 0.9 Hz), 7.21 (1H, t, J = 8.9 Hz), 7.40 (1H, s), 7. 47-7.58 (3H, m), 7.70 (1H, s). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-124.8 (1F, d, J = 4.7 Hz), −57.8 (3F, d, J = 4.7 Hz).
Reference Example-30

T-butyl N- [1- {2,4-difluoro-6- (3-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: brown solid (yield: 40%); Mp : 104-106 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.24-6.25 (1H, m), 6.53 (1H, brs), 6. 87-7.13 (3H, m), 7.36-7.38 (1H, m), 8.41 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.7 (1F, d, J = 7.1 Hz), −105.4 (1F, d, J = 9.4 Hz), −59.0 ( 3F, s).
4-amino-1- [2,4-difluoro-6- (3-furyl) phenyl] -5-trifluoromethylpyrazole: pale yellow solid (yield: 98%); Mp: 88-90 ° C .; ¹ H NMR (400 MHz, CDCl ₃ ): δ 3.50 (2H, brs), 6.27 (1H, dd, J = 1.9 and 0.9 Hz), 6.85-6.91 (2H, m), 7. 10 (1H, ddd, J = 9.3, 2.8 and 1.8 Hz), 7.37 (1H, t, J = 1.7 Hz), 7.44 (1H, s). ¹⁹ F-NMR (376 Hz, CDCl ₃ ): δ-115.6 (1F, m), -105.7 (1F, s), -5.8.8 (3F, m).
Reference Example-31

T-butyl N- [1- {2,4-difluoro-6- (5-methyl-2-furyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 32 ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.55 (9H, s), 2.30 (3H, s), 5.23 (1H, d, J = 3.4 Hz), 5.93. (1H, dd, J = 3.4 and 0.6 Hz), 6.56 (1H, brs), 6.77-6.85 (1H, m), 7.40-7.45 (1H, m), 8 .43 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.7 (1F, d, J = 4.7 Hz), −105.2 (1F, d, J = 9.4 Hz), −59.3 ( 3F, s).
4-amino-1- [2,4-difluoro-6- (5-methyl-2-furyl) phenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 75%); Mp: 110-113 ° C ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.31 (3H, s), 3.52 (2H, brs), 5.23 (1H, d, J = 3.4 Hz), 5.93 (1H) , Dd, J = 3.4 and 0.6 Hz), 6.80 (1H, ddd, J = 8.6, 8.1 and 2.8 Hz), 7.42 (1 H, dt, J = 9.8 and 2.6 Hz), 7.47 (1H, s). ¹⁹ F-NMR (235 Hz, CDCl ₃ ): δ-116.8 (1F, m), -105.8 (1F, d, J = 11.8 Hz), -59.4 (3F, d, J = 4.7 Hz).
Reference Example-32

Under an argon atmosphere, N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol), bis (dibenzylidene) Acetone) palladium (58 mg, 0.10 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (48 mg, 0.10 mmol), 3-fluoro-4-methoxyphenylboronic acid (1. 02 g, 6.0 mmol) and potassium phosphate (2.55 g, 12.0 mmol) in 1,2-dimethoxyethane (10 mL) were heated and stirred at 85 ° C. (oil bath temperature) for 12 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- {1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) as a tan oil. Phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (597 mg, yield: 61%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s), 3.88 (3H, s), 6.42 (1H, brs), 6.84-7.01 (5H, m) , 8.32 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-134.7 (1F, s), −115.3 (1F, s), −105.0 (1F, d, J = 7.7 Hz), −58 .3 (3F, s).
N- {1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (0.597 g, 1. 2N hydrochloric acid (6 mL) was added to a solution of 22 mmol) in 1,4-dioxane (6 mL), and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide, and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (3-fluoro-4-methoxyphenyl) as a tan oil. Phenyl] -5-trifluoromethylpyrazole (406 mg, yield: 86%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.38 (2H, brs), 3.88 (3H, s), 6.86 (1H, t, J = 8.6 Hz), 6.92-7. 01 (4H, m), 7.34-7.36 (1H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-134.9 (1F, s), −115.5 (1F, m), −105.6 (1F, d, J = 9.3 Hz), −58 .4 (3F, d, J = 2.7 Hz).
Reference Example-33

Under an argon atmosphere, N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol), bis (dibenzylidene) Acetone) palladium (58 mg, 0.10 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (48 mg, 0.10 mmol), 4-fluoro-3-methylphenylboronic acid (0. A solution of 924 g, 6.0 mmol) and potassium phosphate (2.55 g, 12.0 mmol) in 1,2-dimethoxyethane (10 mL) was heated and stirred at 85 ° C. (oil bath temperature) for 12 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- {1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) as a tan oil. Phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (537 mg, yield: 57%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.51 (9H, s), 2.21 (3H, s), 6.39 (1H, brs), 6.86-7.10 (5H, m) , 8.30 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.2 (1F, s), −115.5 (1F, s), −105.2 (1F, d, J = 7.1 Hz), −58 .3 (3F, s).
N- {1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (0.537 g, 1. 2N hydrochloric acid (6 mL) was added to a solution of 14 mmol) in 1,4-dioxane (6 mL), and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide, and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (4-fluoro-3-methylphenyl) as a tan oil. Phenyl] -5-trifluoromethylpyrazole (367 mg, yield: 87%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.21 (3H, d, J = 1.9 Hz), 3.36 (2H, brs), 6.89 (1H, t, J = 8.9 Hz), 6.92-7.00 (3H, m), 7.06 (1H, dd, J = 7.3 and 2.0 Hz), 7.31-7.32 (1H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-117.5 (1F, s), -115.7 (1F, m), −105.8 (1F, d, J = 9.5 Hz), −58 .4 (3F, d, J = 2.9 Hz).
Reference Example-34

Under an argon atmosphere, N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol), bis (dibenzylidene) Acetone) palladium (58 mg, 0.10 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (48 mg, 0.10 mmol), 3-trifluoromethoxyphenylboronic acid (1.236 g, A solution of 6.0 mmol) and potassium phosphate (2.55 g, 12.0 mmol) in 1,2-dimethoxyethane (10 mL) was heated and stirred at 85 ° C. (oil bath temperature) for 12 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- {1- [2,4-difluoro-6- (3-trifluoromethoxyphenyl) phenyl] as a tan oil. Tert-Butyl -5-trifluoromethylpyrazol-4-yl} carbamate (656 mg, yield: 63%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 6.37 (1H, brs), 7.00-7.04 (2H, m), 7.08 (1H, brs) 7.15-7.18 (2H, m), 7.33 (1H, t, J = 8.0 Hz), 8.29 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (1F, s), −104.5 (1F, d, J = 7.5 Hz), −58.3 (3F, s), −57 .9 (3F, s).
N- {1- [2,4-difluoro-6- (3-trifluoromethoxyphenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate t-butyl (0.656 g, 1.25 mmol) 2N hydrochloric acid (6 mL) was added to a 1,4-dioxane (6 mL) solution, and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide, and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (3-trifluoromethoxyphenyl) phenyl] as a tan oil. -5-trifluoromethylpyrazole (385 mg, yield: 73%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.37 (2H, brs), 6.97-7.04 (2H, m), 7.10 (1H, brs), 7.14-7.19 ( 2H, m), 7.31 (1H, s), 7.33 (1H, t, J = 8.0 Hz). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.1 (1F, m), −105.2 (1F, d, J = 9.4 Hz), −58.4 (3F, d, J = 2) .8 Hz), -57.9 (3F, s).
Reference Example-35

Under an argon atmosphere, N- [1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazol-4-yl] carbamate t-butyl (884 mg, 2.0 mmol), bis (dibenzylidene) Acetone) palladium (58 mg, 0.10 mmol), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (48 mg, 0.10 mmol), 3-methylthiophenylboronic acid (1.01 g, 6. 0 mmol) and potassium phosphate (2.55 g, 12.0 mmol) in 1,2-dimethoxyethane (10 mL) were heated and stirred at 85 ° C. (oil bath temperature) for 12 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) to give N- {1- [2,4-difluoro-6- (3-methylthiophenyl) phenyl] -5 as a tan oil. -Trifluoromethylpyrazol-4-yl} t-butyl carbamate (698 mg, yield: 72%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.50 (9H, s), 2.40 (3H, s), 6.39 (1H, brs), 6.96-7.05 (3H, m) 7.07 (1H, brs), 7.19-7.20 (2H, m), 8.30 (1H, brs). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.4 (1F, s), −105.0 (1F, d, J = 8.5 Hz), −58.2 (3F, s).
1 of t-butyl N- {1- [2,4-difluoro-6- (3-methylthiophenyl) phenyl] -5-trifluoromethylpyrazol-4-yl} carbamate (0.698 g, 1.44 mmol) 2, N-dioxane (7 mL) was added with 2N hydrochloric acid (7 mL), and the mixture was stirred at 80 ° C. for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature, neutralized with 10% aqueous sodium hydroxide, and extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 4-amino-1- [2,4-difluoro-6- (3-methylthiophenyl) phenyl] -5 as a tan oil. -Trifluoromethylpyrazole (490 mg, yield: 94%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.41 (3H, s), 3.37 (2H, brs), 6.94-7.04 (3H, m), 7.07-7.08 ( 1H, m), 7.19-7.20 (2H, m), 7.31 (1H, s). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (1F, m), −105.6 (1F, d, J = 9.4 Hz), −58.3 (3F, d, J = 2) .7 Hz).
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 [wettable powder]
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 4 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 phytotoxicity were also applied to Test Examples-2 to 4.

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 tomato ring disease]
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-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

Claims (6)

General formula (1)

(In the formula, R ¹ represents an alkyl group having 1 to 6 carbon atoms. R ² represents an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms. R ³ represents a hydrogen atom or a halogen atom. R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 to carbon atoms. A phenyl group optionally substituted by an alkoxy group having 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 to 6 carbon atoms An alkyl group, an alkoxy group having 1 to 6 carbon atoms or a pyridyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; a halogen atom or an alkyl group having 1 to 6 carbon atoms A thienyl group which may be substituted; or a furyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a carbon number of 1; To 6 in which n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different, and a pyrazole-4-carboxamide derivative. The pyrazole-4-carboxamide derivative according to claim 1, wherein R ² and R ⁴ are each independently a haloalkyl group having 1 to 4 carbon atoms. The pyrazole-4-carboxamide derivative according to claim 1, wherein R ² is a difluoromethyl group or a trifluoromethyl group, and R ⁴ is a trifluoromethyl group.   The pyrazole-4-carboxamide derivative according to any one of claims 1 to 3, wherein Ar is a phenyl group which may be substituted with a halogen atom, and X is a halogen atom. 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):

(In the formula, R ⁴ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms. Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a carbon number. A phenyl group optionally substituted by an alkoxy group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 carbon atom A pyridyl group optionally substituted by 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; may be substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms Or a furyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, or an alkyl group having 1 to 6 carbon atoms. Or a haloalkyl group having 1 to 6 carbon atoms, n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different. General formula (1), characterized by condensation

(Wherein R ¹ , R ² , R ³ , R ⁴ , Ar, 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 hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 to carbon atoms. A phenyl group optionally substituted by an alkoxy group having 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, a haloalkoxy group having 1 to 6 carbon atoms, or an alkylthio group having 1 to 6 carbon atoms; a halogen atom, 1 to 6 carbon atoms An alkyl group, an alkoxy group having 1 to 6 carbon atoms or a pyridyl group optionally substituted by a haloalkyl group having 1 to 6 carbon atoms; a halogen atom or an alkyl group having 1 to 6 carbon atoms A thienyl group which may be substituted; or a furyl group which may be substituted with an alkyl group having 1 to 6 carbon atoms, X is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a carbon number of 1; To 6 in which n represents an integer of 1 to 4. When n is 2 or more, X may be the same or different, and a pyrazole-4-carboxamide derivative represented by Agricultural / horticultural fungicide.