JP2012036137A - 1-substituted phenyl-4-aminopyrazole derivative, production intermediate thereof, and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a 1-substituted phenyl-4-aminopyrazole derivative which is useful as a production intermediate of an N-(1-substituted phenylpyrazole-4-yl)pyrazole-4-carboxamide derivative having high controlling effect to various pathogenic bacteria causing damage to crop cultivation, and to provide a production method thereof.SOLUTION: A 1-substituted phenyl-4-aminopyrazole derivative (1b) which is useful as a production intermediate of a fungicide can be produced easily by hydrolyzing a 1-substituted phenyl-4-aminopyrazole derivative (1a) obtained by coupling of carbamic acid ester (2) and a boric acid compound (3).

Description

  The present invention relates to 1-substituted phenyl-4-amino which can be used as an intermediate for producing N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives useful as active ingredients of agricultural and horticultural fungicides. The present invention relates to pyrazole derivatives and methods for producing them.

  4-Aminopyrazole derivatives are useful as medical pesticides or their production intermediates, and many compounds are known. The 1-substituted phenyl-4-aminopyrazole derivative of the present invention is characterized by having an aromatic group such as an optionally substituted phenyl group, pyridyl group or thienyl group on the substituted phenyl group at the 1-position of the pyrazole ring. It is. As a pyrazole derivative having a structure similar to the 1-substituted phenyl-4-aminopyrazole derivative of the present invention, Patent Document 1 and Non-Patent Documents 1 and 2 have a phenyl group or a substituted phenyl group at the 1-position of the pyrazole ring. -Aminopyrazole derivatives are described, but the present invention is not limited in that an aromatic group is not substituted on the phenyl group at the 1-position of the pyrazole ring and a phenyl group or a substituted phenyl group is also present at the 5-position of the pyrazole ring. Different from compound. Further, 4-amino-5-cyano-1-phenylpyrazole described in Non-Patent Document 3 and 4-amino-5-methyl-1-described in Patent Documents 2 and 3 and Non-Patent Document 4 Phenylpyrazole differs from the compound of the present invention in that the phenyl group is unsubstituted. Further, 4-aminopyrazole derivatives included in Patent Document 4 and 4-amino-1- (4-chlorophenyl) -5-trifluoromethylpyrazole described in Patent Document 5 are phenyl groups at the 1-position of the pyrazole ring. Differs from the compounds of the present invention in that is not substituted with an aromatic group.

International Patent Publication WO99-094415 European Patent No. 239191 International Patent Publication WO04-098528 European Patent No. 202169 International Patent Publication WO 03-037274

Farmo, Editione Scientific, 23 (10), 919-944. J. et al. Med. Chem, 40 (9), 1347-1365 (1997) J. et al. Heterocyclic Chem, 25 (2), 555-558 (1988) J. et al. Chem. Soc, 3259-3263 (1958)

  The problem of the present invention is that it can be used as an intermediate for producing an N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivative that is useful as an active ingredient of agricultural and horticultural fungicides. The object is to provide 1-substituted phenyl-4-aminopyrazole derivatives having a phenyl group substituted with a group at the 1-position of the pyrazole ring, intermediates for producing them, and methods for producing them.

  As a result of intensive studies to solve the above problems, the present inventors have found that the 1-substituted phenyl-4-aminopyrazole derivative represented by the general formula (1) is a compound that can solve the above problems, The present invention has been completed.

  That is, the present invention provides the general formula (1)

(In the formula, R ¹ represents 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 6 carbon atoms. Or a phenyl group which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkyl having 1 to 6 carbon atoms A pyridyl group optionally substituted by a group; a thienyl group optionally substituted by a halogen atom or an alkyl group having 1 to 6 carbon atoms; or a furyl group optionally substituted by an alkyl group having 1 to 6 carbon atoms X 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, n represents an integer of 1 to 4. When n is 2 or more, X represents May be the same or different from each other, Q represents a hydrogen atom or a t-butyloxycarbonyl group.) Relates to a 1-substituted phenyl-4-aminopyrazole derivative represented by:

  The present invention also provides a compound represented by the general formula (1a)

(In the formula, R ¹ represents 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 6 carbon atoms. Or a phenyl group which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkyl having 1 to 6 carbon atoms A pyridyl group optionally substituted by a group; a thienyl group optionally substituted by a halogen atom or an alkyl group having 1 to 6 carbon atoms; or a furyl group optionally substituted by an alkyl group having 1 to 6 carbon atoms X 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, n represents an integer of 1 to 4. When n is 2 or more, X represents May be the same or different from each other. 1-substituted phenyl-4-aminopyrazole derivative represented by the general formula (1b)

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

  The present invention also provides a general formula (2)

(Wherein R ¹ represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms. X represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 carbon atom. To 6 in which n represents an integer of 1 to 4. When n is 2 or more, Xs may be the same or different, and the carbamic acid ester represented by In the presence of general formula (3)

(In the formula, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; halogen atom, carbon A pyridyl group which may be substituted with 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; substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms A thienyl group which may be substituted; or a furyl group optionally substituted with an alkyl group having 1 to 6 carbon atoms.), Which can be produced by reacting with a boric acid compound represented by the general formula (1a)

(Wherein R ¹ , Ar, X and n represent the same meaning as described above) 1-substituted phenyl-4-aminopyrazole derivative represented by the general formula (1b)

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

  Furthermore, the present invention provides a method for producing a 1-substituted phenyl-4-aminopyrazole derivative (1a) by reacting a carbamic acid ester (2) with a boric acid compound (3) in the presence of a palladium catalyst and a base. 1-Substituted phenyl-4-aminopyrazole derivative (1a), characterized in that a palladium catalyst comprising tetrakis (triphenylphosphine) palladium or bis (dibenzylideneacetone) palladium and a tertiary phosphine ligand is used as the palladium catalyst. And a method for producing a 1-substituted phenyl-4-aminopyrazole derivative (1a), wherein sodium carbonate, potassium carbonate, potassium phosphate or sodium phosphate is used as a base.

  The present invention is described in further detail below.

Examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom and a bromine atom. The alkyl group having 1 to 6 carbon atoms represented by R ¹ may be linear, branched or cyclic, and is a methyl group, ethyl group, propyl group, isopropyl group, 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 ¹ may be linear, branched or cyclic, and is a fluoromethyl group, difluoromethyl group, 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. The bactericidal effect of N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced using the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention as a raw material is high. In this respect, R ¹ is preferably a haloalkyl group having 1 to 4 carbon atoms, and more preferably a trifluoromethyl group.

  The optionally substituted phenyl group represented by Ar is 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 halogen atom may be a fluorine atom, a chlorine atom, a bromine atom or the like; and the alkyl group having 1 to 6 carbon atoms may be linear, branched or cyclic Well, 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, hexyl group, isohexyl group, 2-ethylbutyl group, 1,3- A methylbutyl group, a 2-cyclopropylcyclopropyl group, etc .; the alkoxy group having 1 to 6 carbon atoms may be linear, branched or cyclic, and includes a methoxy group, an ethoxy group, and a propyloxy group. Group, isopropyloxy group, cyclopropylmethyloxy group, butyloxy group, isobutyloxy group, s-butyloxy group, pentyloxy group, cyclopentyloxy group, hexyloxy group, etc .; It may be linear, branched or cyclic, and is a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2- Trifluoroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group, perfluoropen Group, perfluorohexyl group, chloromethyl group, 2-chloroethyl group, bromomethyl group, 2-bromoethyl group, can be exemplified bromodifluoromethyl group. The bactericidal effect of N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced using the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention as a raw material is high. In this regard, Ar is preferably a halogen atom or a phenyl group substituted with a haloalkyl group having 1 to 4 carbon atoms.

  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. The bactericidal effect of N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced using the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention as a raw material is high. In this respect, Ar is preferably a halogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, or a pyridyl group substituted with a haloalkyl group having 1 to 4 carbon atoms.

  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. The bactericidal effect of N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced using the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention as a raw material is high. In this respect, Ar is preferably a thienyl group substituted with a halogen atom.

  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. It may be.

  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, can be exemplified 4-trifluoromethoxyphenyl group.

  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. The bactericidal effect of N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced using the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention as a raw material is high. In this respect, 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.

  Next, the production method of the 1-substituted phenyl-4-aminopyrazole derivative (1) of the present invention will be described in detail.

  The 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention can be produced by the method shown in the following reaction formula.

(In the formula, R ¹ , Ar, X and n have the same meaning as described above.)
That is, the production method of the present invention (Step-1) deprotects the t-butyloxycarbonyl group on the nitrogen atom of the 1-substituted phenyl-4-aminopyrazole derivative (1a), This is a method for producing a -4-aminopyrazole derivative (1b).

  The deprotection of the t-butyloxycarbonyl group in step-1 can be carried out under acidic conditions, and an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or p-toluenesulfonic acid can be used as the acid. There is no restriction | limiting in particular in the usage-amount of an acid.

  The reaction of step-1 can be carried out in a solvent that does not adversely affect the reaction. Examples of the solvent include alcohol solvents such as methanol, ethanol and t-butyl alcohol, ether solvents such as dimethoxyethane, 1,4-dioxane, tetrahydrofuran and cyclopentyl methyl ether, aromatic solvents such as benzene and toluene, dichloromethane, Examples thereof include halogen solvents such as chloroform, amide solvents such as N, N-dimethylformamide and N, N-dimethylacetamide, and sulfoxide solvents such as dimethyl sulfoxide. Furthermore, a mixed solvent in which these solvents are appropriately combined can be used.

  The reaction in Step-1 can be carried out at a temperature appropriately selected from the temperature from room temperature to the boiling point of the solvent used, but it is preferably carried out at a temperature of 50 to 100 ° C.

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

  The 1-substituted phenyl-4-aminopyrazole derivative (1a) of the present invention, which is a raw material for producing the 1-substituted phenyl-4-aminopyrazole derivative (1b) of the present invention, is obtained by the method shown in the following reaction formula. Can be manufactured.

(In the formula, R ¹ , Ar, X and n have the same meaning as described above.)
That is, in the production method of the present invention (step-2), the carbamate ester (2) having a bromine atom on the benzene ring is reacted with the boric acid compound (3) in the presence of a palladium catalyst and a base. This is a method for producing the 1-substituted phenyl-4-aminopyrazole derivative (1a) of the present invention.

It is essential to carry out the reaction of Step-2 in the presence of a palladium catalyst. As a palladium catalyst,
Dichlorobis (triphenylphosphine) palladium, dichlorobis (tricyclohexylphosphine) palladium, dichlorobis (tri-o-tolylphosphine) palladium, dichlorobis (triethylphosphine) palladium, tetrakis (triphenylphosphine) palladium, dichloro [1,2-bis ( Diphenylphosphino) ethane] palladium, dichloro [1,3-bis (diphenylphosphino) propane] palladium, dichloro [1,4-bis (diphenylphosphino) butane] palladium, dichloro [1,1′-bis (diphenyl) Illustrative of palladium complexes coordinated by tertiary phosphine ligands such as phosphino) ferrocene] palladium, dichloro [1,1′-bis (di-t-butylphosphino) ferrocene] palladium. Kill. From the viewpoint of good yield, tetrakis (triphenylphosphine) palladium is preferable.

  Palladium catalysts include palladium chloride, palladium acetate, π-allyl palladium chloride dimer, bis (acetylacetonato) palladium, dichlorobis (acetonitrile) palladium, dichlorobis (benzonitrile) palladium, bis (dibenzylideneacetone) palladium, tris (Dibenzylideneacetone) A palladium complex such as dipalladium and a tertiary phosphine ligand may be used in combination. Tertiary phosphine ligands include triphenylphosphine, triethylphosphine, tributylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine, methyldiphenylphosphine, dimethylphenylphosphine, bis (diphenylphosphino) methane, 1,2 -Bis (diphenylphosphino) ethane, 1,3-bis (diphenylphosphino) propane, 1,4-bis (diphenylphosphino) butane, 1,1'-bis (diphenylphosphino) ferrocene, 2,2 ' -Bis (diphenylphosphino) -1,1'-binaphthyl, bis [2- (diphenylphosphino) phenyl] ether, 1,1'-bis (di-tert-butylphosphino) ferrocene, 2- (dicyclohexylphos Fino) biphenyl, 2- Cyclohexylphosphino-2 '-(dimethylamino) biphenyl, 2- (di-tert-butylphosphino) biphenyl, 2- (dicyclohexylphosphino) biphenyl, 2-dicyclohexylphosphino-2', 4 ', 6'- A triisopropyl biphenyl etc. can be illustrated. A combination of bis (dibenzylideneacetone) palladium and triphenylphosphine or 2-dicyclohexylphosphino-2 ', 4', 6'-triisopropylbiphenyl is preferable in terms of a good yield. Although there is no restriction | limiting in particular in the compounding ratio of a palladium complex and a tertiary phosphine ligand, It is preferable at a point with a sufficient yield to use a 1 to 4 equivalent tertiary phosphine ligand with respect to a palladium complex.

  There is no restriction | limiting in particular in the addition amount of a palladium catalyst, even if it is what is called a catalyst amount, reaction will fully advance and the target object can be obtained with a sufficient yield.

  It is essential to carry out the reaction of step-2 in the presence of a base. Examples of the base include tertiary amines such as triethylamine, tributylamine, N-methylmorpholine, pyridine, sodium carbonate, potassium carbonate, sodium phosphate, potassium phosphate, sodium-tert-butoxide, potassium-tert-butoxide, etc. An alkali metal base can be illustrated. An alkali metal base is preferable in terms of a good yield, and sodium carbonate, potassium carbonate, sodium phosphate, and potassium phosphate are more preferable. There is no restriction | limiting in particular in the usage-amount of a base, A target object can be obtained with a sufficient yield by using 1 equivalent or more with respect to a boric-acid compound (3).

  The reaction of step-2 can be carried out in an organic solvent, and any organic solvent that does not cause harm to the reaction can be used. As the organic solvent, tetrahydrofuran, diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, methyl-tert-butyl ether, ether solvents such as 1,2-dimethoxyethane, hydrocarbon solvents such as hexane and octane, benzene, Aromatic solvents such as toluene, xylene and chlorobenzene, amide solvents such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, nitrile solvents such as acetonitrile and propionitrile, dimethyl sulfoxide, Examples thereof include sulfoxide solvents such as diethyl sulfoxide, alcohol solvents such as methanol, ethanol, propanol, isopropyl alcohol, and butanol. Moreover, the mixed solvent which mixed these solvents suitably can be used. From the viewpoint of good yield, ether solvents and aromatic solvents are preferable, and N, N-dimethylformamide, 1,4-dioxane and toluene are more preferable.

  The reaction of step-2 can be carried out at a temperature appropriately selected from room temperature to 150 ° C. From the viewpoint of good yield, 20 ° C to 100 ° C is preferable.

  A part of the boric acid compound (3) used in the reaction of Step-2 is commercially available and can be easily obtained, but Boronic Acid, WILEY-VCH, D.M. G. Hall, Chapter-1 or Chem. Rev, 1995, 95, 2457-2483, etc., and can be produced according to a general method described in the literature.

  The carbamate ester (2) having a bromine atom on the benzene ring, which is a raw material for the production method of the present invention (step-2), can be produced by the method shown in the following reaction formula.

(Wherein R ¹ , Ar, X and n represent the same meaning as described above. R ¹ represents an alkyl group having 1 to 4 carbon atoms. Y represents a halogen atom or an alkoxycarbonyloxy group having 1 to 4 carbon atoms. To express.)
That is, 1-substituted phenylpyrazole-4-carboxylic acid ester (4) obtained by condensation reaction (step-3) of 2-alkoxymethylene-β-ketocarboxylic acid ester and a substituted phenylhydrazine having a bromine atom is hydrolyzed. (Step-4) and converting the obtained 1-substituted phenylpyrazole-4-carboxylic acid (5) into an acid halide or active ester (6) (Step-5), and then reacting with sodium azide (Step- 6) to obtain an acyl azide derivative (7). The carbamate ester (2) can then be produced by subjecting this to a Curtius rearrangement in the presence of t-butyl alcohol. Hereinafter, each step will be described in detail.

  In Step-3, 1-substituted phenylpyrazole-4-carboxylic acid ester (4) is produced by a condensation reaction of 2-alkoxymethylene-β-ketocarboxylic acid ester and a substituted phenylhydrazine having a bromine atom (Step-3). It is a process to do. The reaction can be carried out in a solvent, and any solvent can be used as long as it does not harm the reaction. Alcohol solvents such as methanol and ethanol, aromatic solvents such as benzene and toluene And ether solvents such as tetrahydrofuran and dimethoxyethane. The reaction may be carried out in the presence of a base. Examples of the base include tertiary amines such as triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, and alkali metal bases such as sodium carbonate and potassium carbonate. These bases can also be used as an aqueous solution. The reaction can be carried out at a temperature appropriately selected from room temperature to 100 ° C., and the reaction proceeds sufficiently even at room temperature. After completion of the reaction, it can be purified by a method such as column chromatography after usual post-treatment, but can also be subjected to the next step-4 as a crude product.

  Step-4 is a step of producing 1-substituted phenylpyrazole-4-carboxylic acid (5) by hydrolyzing 1-substituted phenylpyrazole-4-carboxylic acid ester (4). General ester hydrolysis conditions can be applied to the reaction, and the hydrolysis reaction easily proceeds when carried out in an aqueous solution of sodium hydroxide or potassium hydroxide. The reaction can be carried out in the presence of a solvent that is uniformly mixed with water. Examples of such solvents include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran, and nitrile solvents such as acetonitrile. The reaction can be carried out at a temperature appropriately selected from room temperature to 100 ° C., and the reaction proceeds sufficiently even at room temperature. After completion of the reaction, free carboxylic acid can be isolated by treatment with acid.

  Step-5 is a step of converting 1-substituted phenylpyrazole-4-carboxylic acid (5) into acid halide or active ester (6).

  1-substituted phenylpyrazole-4-carboxylic acid halide (6) in which Y is a halogen atom is treated with a halogenating agent such as thionyl chloride, for example. Thus, it can be easily manufactured. The reaction is preferably carried out in an aromatic solvent such as toluene at the reflux temperature of the reaction solution. After completion of the reaction, the solvent and the halogenating agent can be removed and subjected to the next step-6 without purification.

  A 1-substituted phenylpyrazole-4-carboxylic acid derivative (6) in which Y is an alkoxycarbonyloxy group is obtained by reacting 1-substituted phenylpyrazole-4-carboxylic acid (5) with, for example, ethyl chloroformate in the presence of a base. It can manufacture easily by processing with chloroformic acid esters, such as. It is essential to carry out the reaction in the presence of a base. Examples of the base include tertiary amines such as triethylamine, N-methylmorpholine, pyridine and 4-dimethylaminopyridine, and alkali metal bases such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide. it can. There is no restriction | limiting in particular in the usage-amount of a base, A target object can be obtained with a sufficient yield by using 1 equivalent or more with respect to carboxylic acid (5) of a raw material. The reaction can be carried out in an organic solvent that does not adversely affect the reaction. As the solvent, a ketone solvent such as acetone, a nitrile solvent such as acetonitrile, an aromatic solvent such as toluene, or the like is used. be able to. In consideration of the reaction in the next step-6, polar solvents such as acetone and acetonitrile are preferred. The reaction is preferably carried out at a low temperature, and can be carried out at a temperature appropriately selected from 0 to 50 ° C. After completion of the reaction, it can be subjected to the next step-6 without purification.

  Step-6 is a step of producing an acyl azide derivative (7) by reacting an acid halide or active ester (6) with sodium azide.

  When Y is a halogen atom such as a chlorine atom, the reaction is preferably performed in the presence of a base. Examples of the base include tertiary amines such as triethylamine, N-methylmorpholine and pyridine, and alkali metal bases such as potassium carbonate and sodium carbonate. Usually, by using a general-purpose amine such as triethylamine, the target product can be obtained in good yield. Although there is no restriction | limiting in particular in the usage-amount of a base, The target object can be obtained with a sufficient yield by using 1 equivalent or more with respect to the reaction substrate, Preferably 1-2 equivalent is used. When Y is an alkoxycarbonyloxy group, the reaction can be carried out in the presence of a base. Examples of the base include tertiary amines such as triethylamine, N-methylmorpholine, and pyridine. Usually, by using a general-purpose amine such as triethylamine, the target product can be obtained in good yield. Although there is no restriction | limiting in particular in the usage-amount of a base, The target object can be obtained with a sufficient yield by using 0.1-2 equivalent with respect to the reaction substrate, Preferably 0.1-0.5 equivalent is used.

  The reaction in step-6 is preferably carried out in a solvent. Solvents include aromatic solvents such as benzene, toluene, xylene and chlorobenzene, ether solvents such as tetrahydrofuran, dioxane and dimethoxyethane, halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, acetone and 2-butanone. Ketone solvents such as acetonitrile, nitriles such as acetonitrile and propionitrile, ester solvents such as ethyl acetate, ethyl propionate, ethyl butanoate, dimethyl carbonate and diethyl carbonate, N, N-dimethylformamide, N-methylpyrrolidone and the like These amide solvents, dimethyl sulfoxide, or a mixed solvent thereof can be used. A polar solvent such as tetrahydrofuran, acetone or acetonitrile is preferred in view of the yield of the target product.

  By carrying out the reaction of Step-6 at a temperature appropriately selected from -20 to 100 ° C, preferably from 0 to 50 ° C, the desired product can be obtained in good yield. After completion of the reaction, the desired product can be obtained by ordinary operations. After extracting the desired product from the reaction mixture and drying, the resulting solution of the acyl azide derivative (7) is directly used in the next step-7. Can be used.

  In the reaction of Step-6, the amount of sodium azide used is not particularly limited, and is 1 to 3 equivalents, preferably 1 to 1.5 equivalents based on the pyrazole-4-carboxylic derivative (6). The target product can be obtained with good yield.

  Step-7 is a step of producing the carbamic acid ester (2) which is a raw material of the production method of the present invention by heating the acyl azide derivative (7) in t-butyl alcohol to cause the Curtius rearrangement. In this reaction, the acyl azide derivative (7) undergoes Curtius rearrangement by heat to produce an isocyanate derivative (8), and t-butyl alcohol is added to the isocyanato group to give the desired product.

(In the formula, R ¹ , X and n represent the same meaning as described above.)
It is essential to carry out the reaction in Step-7 under heating. By carrying out the reaction at a reaction temperature appropriately selected from 60 to 200 ° C., preferably from 80 to 150 ° C., the target product can be obtained with good yield. Can do.

  There is no restriction | limiting in particular in the usage-amount of t-butyl alcohol, A target object can be obtained with a sufficient yield by using 1-30 equivalent with respect to an acyl azide derivative (7), Preferably 1-3 equivalent. The reaction can also be performed in the presence of another organic solvent. As the organic solvent, any solvent that does not harm the reaction can be used. Examples of the solvent include aromatic solvents such as benzene, toluene, xylene, and chlorobenzene, and ethers such as tetrahydrofuran, dioxane, and dimethoxyethane. Solvent, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ketone solvents such as acetone and 2-butanone, nitriles such as acetonitrile and propionitrile, ethyl acetate, ethyl propionate, ethyl butanoate, Ester solvents such as dimethyl carbonate and diethyl carbonate, amide solvents such as N, N-dimethylformamide and N-methylpyrrolidone, dimethyl sulfoxide, or a mixed solvent thereof can be used. Aromatic solvents such as toluene, xylene and chlorobenzene are preferred in that the yield of the target product is good.

  After completion of the reaction, the carbamate (2) can be obtained by ordinary post-treatment. If necessary, it is purified by recrystallization or column chromatography and used as a raw material for the production method of the present invention.

  According to the present invention, a 4-aminopyrazole derivative which is a production intermediate of a pyrazole-4-carboxamide derivative useful as an active ingredient of an agricultural and horticultural fungicide can be easily produced.

EXAMPLES Hereinafter, although an Example and a reference example are given and this invention is demonstrated further in detail, this invention is not limited to these.
Example-1

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) 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 N, N-dimethylformamide (10 mL) was heated and stirred 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 to 7.05 (5H, m), 7.23 to 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 to 7.03 (5H, m), 7.22 to 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).
Example-2

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)- A solution of t-butyl 5-trifluoromethylpyrazol-4-yl] carbamate (884 mg, 2.0 mmol) and sodium carbonate (1.27 g, 12.0 mmol) in N, N-dimethylformamide (15 mL) was added at 100 ° C. The mixture was heated and stirred at (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 (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 to 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 to 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 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 to 7.04 (2H, m), 7.07 to 7.11 (1H, m), 7.18 to 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).
Example-3

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 N, N-dimethylformamide (2 mL) was added at 100 ° C. The mixture was heated and stirred at (oil bath temperature) 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 to 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).
Example-4

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 N, N-dimethylformamide (10 mL) at 100 <0> C ( The mixture was heated and stirred for 24 hours at an oil bath temperature. 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, 3.0 Hz) ), 6.99 (1H, ddd, J = 9.0, 3.0, 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).
Example-5

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 N, N-dimethylformamide (5 mL) at 100 ° C. ( The mixture was heated and stirred for 24 hours at an oil bath temperature. 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, 1.3 Hz), 6.34 (1H, dd, J = 3) .8, 2.5 Hz), 6.56 (1H, brs), 6.83 to 6.88 (1H, m), 7.44 to 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 ): δ 3.54 (brs, 2H), 5.37 (d, J = 3.5 Hz, 1H), 6.34 (dd, J = 3.6, 1.8 Hz) , 1H), 6.85 (ddd, J = 9.1, 8.0, 2.8 Hz, 1H), 7.44-7.49 (m, 3H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.5 (m, 1F), −105.4 (d, J = 9.4 Hz, 1F), −59.3 (m, 3F).
Example-6

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-boron 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 potassium phosphate (1.06 g, 5.0 mmol) in N, N-dimethylformamide (5 mL) were heated and stirred 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 to 7.07 (2H, m), 7.23 (1H, dd, J = 8.0, 5.0 Hz), 7.51 to 7.56 (1H, m), 8.48 (1H, brs), 8.49 (1H, d, J = 2.1 Hz), 8. 56 (1H, dd, J = 4.8, 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 (brs, 2H), 7.00 to 7.06 (m, 2H), 7.23 (ddd, J = 8.0, 4.9, 0 .8 Hz, 1H), 7.32 (d, J = 0.7 Hz, 1H), 7.52 to 7.55 (m, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8 .52 (dd, J = 4.9, 1.6 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.8 (m, 1F), −104.8 (m, 1F), −58.3 (m, 3F).
Examples-7-28
Hereinafter, the reaction formula, name of product, property (yield), melting point, and NMR spectrum of 1-substituted phenyl-4-aminopyrazole derivative synthesized by the same method as in the above Examples are shown.
Example-7

T-butyl N- [1- {4- (4-fluorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 75%); Mp: ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.54 (9H, s), 6.59 (1H, brs), 7.15 (2H, t, J = 8. 7 Hz), 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- {4- (4-fluorophenyl) -2-fluorophenyl} -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).
Example-8

^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 to 7.34 (4H, m), 7.45 to 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 (brs, 2H), 7.24 to 7.52 (m, 8H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.8 (d, J = 2.4 Hz, 1F), −57.7 (m, 3F).
Example-9

^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 (brs, 2H), 7.29-7.66 (m, 8H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-123.7 (m, 1F), -57.7 (m, 3F).
Example-10

T-butyl N- [1- {5- (4-chlorophenyl) -2-fluorophenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 60%); Mp: 102 ˜104 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ1.55 (9H, s), 6.51 (1H, brs), 7.30 to 7.34 (1H, m), 7.40 to 7.49 (4H, m), 7.57 to 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 (brs, 2H), 7.21 to 7.60 (m, 8H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.2 (d, J = 4.7 Hz, 1F), −57.7 (d, J = 4.7 Hz, 3F).
Example-11

^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 to 7.52 (2H, m), 7.56 to 7.52 (1H, m), 7.61 to 7.65 (1H, 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 to 7.52 (2H, m), 7.55 to 7.62 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-124.6 (1F, m), -114.6 (1F, s), -57.4 (3F, m).
Example-12

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 to 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 to 7.00 (4H, m), 7.18 to 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).
Example-13

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 to 7.07 (2H, m), 7.12 to 7.20 (2H) , M), 7.23-7.30 (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 to 6.93 (2H, m), 7.17 to 7.13 (2H, m), 7.28 to 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, 3.5 Hz), −105.7 (1F, d, J = 9.4 Hz), − 58.6 (3H, d, J = 3.5 Hz).
Example-14

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 to 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).
Example-15

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, 3.0 Hz), 7.03 (1H, ddd, J = 9.0, 9.0, 1.5 Hz), 7.12 (2H, d, J = 8.0 Hz) 7.29 (2H, d, 9.0 Hz), 8.30 (1 H, 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, 2.8 Hz) ), 7.02 (1H, ddd, J = 9.2, 2.8, 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).
Example-16

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, 3.0 Hz), 7.01 (1H, ddd, J = 9.0, 9.0, 1.8 Hz), 7 .12 (2H, d, J = 9.0 Hz), 8.31 (1H, brs). ¹⁹ F-NMR (235 MHz, 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 (brs, 2H), 3.78 (s, 3H), 6.80 (d, J = 9.0 Hz, 2H), 7.01 to 6.88 ( m, 2H), 7.14 (d, J = 8.0 Hz, 2H), 7.32 (brs, 1H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.3 (1F, dq, J = 9.4, 4.7 Hz), −106.4 (1F, d, J = 9.4 Hz), − 58.7 (3F, d, J = 4.7 Hz).
Example-17

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 to 7.17 (1H, m), 7.25 to 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 to 7.17 (1H, m), 7.23 to 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).
Example-18

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 to 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 to 110.54 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 to 7.57 (2H, m). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-118.1 (2F, m), -112.5 (1F, s), -58.8 (3F, m).
Example-19

T-butyl N- [1- {2,4-difluoro-6- (4-pyridyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: yellow solid (yield: 52%); Mp 1146-147 ° C .; ¹ H-NMR (250 MHz, CDCl ₃ ): δ 1.51 (9H, s), 6.41 (1H, brs), 7.05 (2H, d, J = 8.3 Hz), 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 (brs, 2H), 7.04 (d, J = 3.5 Hz, 2H), 7.13 (d, J = 3.6 Hz, 2H), 7.32 (D, J = 2.8 Hz, 1H), 8.55 (d, J = Hz, 2H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-114.6 (m, 1F), −104.6 (m, 1F), −58.2 (m, 3F).
Example-20

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 (brs, 2H), 7.08 (dd, J = 5.1, 3.7 Hz, 1H), 7.19 to 7.31 (m, 2H), 7.41 (D, J = 0.5 Hz, 1H), 7.62-7.69 (m, 2H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.1 (d, J = 4.7 Hz, 1F), −57.8 (d, J = 4.7 Hz, 3F).
Example-21

T-butyl N- [1- {2-fluoro-5- (3-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 85%); Mp: 81 ^{~83 ℃; 1 H-NMR (} 250MHz, CDCl 3): δ1.55 (9H, s), 6.52 (1H, brs), 7.25 (1H, t, J = 9.0Hz), 7. 32 (1H, dd, J = 5.0, 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 (brs, 2H), 7.24 (t, J = 8.8 Hz, 1H), 7.33 (dd, J = 5.0, 1.4 Hz, 1H), 7.38-7.43 (M, 3H), 7.59-7.69 (m, 2H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.8 (m, 1F), −57.7 (d, J = 4.7 Hz, 3F).
Example-22

T-butyl N- [1- {2,4-difluoro-6- (2-thienyl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 51%); Mp ^{: 129~131 ℃; 1 H-NMR} (250MHz, CDCl 3): δ1.54 (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 (brs, 2H), 6.85 (dd, J = 3.7, 1.2 Hz, 1H), 6.90 (ddd, J = 9.0, 8.0, 2.8 Hz) , 1H), 6.97 (dd, J = 5.1, 3.7 Hz, 1H), 7.22 to 7.26 (m, 1H), 7.33 (dd, J = 5.1, 1.. 2 Hz, 1H), 7.44 (d, J = 0.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.2 (m, 1F), −105.5 (d, J = 9.5 Hz, 1F), −58.8 (m, 3F).
Example-23

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, 1) .4 Hz), 6.93 (1H, ddd, J = 9.0, 8.1, 2.8 Hz), 7.02 (1H, dd, J = 3.0, 1.3 Hz), 7.14 ( 1H, ddd, J = 9.2, 2.8, 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 (brs, 2H), 6.89 to 6.94 (m, 2H), 7.03 (dd, J = 3.0, 1.3 Hz, 1H), 7.13 (ddd, J = 9.2, 2.8, 1.8 Hz, 1H), 7.24-7.26 (m, 1H), 7.40 (d, J = 0.7 Hz, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.7 (m, 1F), −105.8 (m, 1F), −58.7 (s, 3F).
Example-24

T-butyl N- [1- {2,4-difluoro-6- (5-methylthiophen-2-yl) 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-methylthiophen-2-yl) phenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 88%); Mp: 106-108 ¹ H-NMR (250 MHz, CDCl ₃ ): δ 2.43 (s, 3H), 3.47 (brs, 2H), 6.61 (s, 2H), 6.84 (ddd, J = 8. 9, 8.1, 2.8 Hz, 1H), 7.18 (ddd, J = 9.6, 2.6, 2.0 Hz, 1H), 7.44 (s, 1H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-115.9 (m, 1F), −106.1 (d, J = 9.4 Hz, 1F), −59.0 (d, J = 7. 1 Hz, 3F).
Example-25

N- [1- {2- fluoro-5- (furan-2-yl) phenyl} -5-trifluoromethyl-4-yl] carbamate t- butyl: white solid (yield: ^{71%); 1} 1 H-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 (brs, 2H), 6.47 (dd, J = 3.4, 1.8 Hz, 1H), 6.63 (d, J = 3.4 Hz, 1H), 7.23 (t, J = 8.9 Hz, 1H), 7.46 (s, 1H), 7.46 (d, J = 1.4 Hz, 1H), 7.68-7.77 (m, 2H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.0 (d, J = 4.7 Hz, 1F), −57.8 (d, J = 4.7 Hz, 3F).
Example-26

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 to 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 (brs, 2H), 6.64 (d, J = 0.9 Hz, 1H), 7.21 (t, J = 8.9 Hz, 1H), 7.40 (s, 1H), 7. 47-7.58 (m, 3H), 7.70 (s, 1H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-124.8 (d, J = 4.7 Hz, 1F), −57.8 (d, J = 4.7 Hz, 3F).
Example-27

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 (brs, 2H), 6.27 (dd, J = 1.9, 0.9 Hz, 1H), 6.85 to 6.91 (m, 2H), 7.10 (ddd, J = 9.3, 2.8, 1.8 Hz, 1H), 7.37 (t, J = 1.7 Hz, 1H), 7.44 (s, 1H). ¹⁹ F-NMR (376 MHz, CDCl ₃ ): δ-115.6 (m, 1F), -105.7 (s, 1F), -5.8.8 (m, 3F).
Example-28

T-butyl N- [1- {2,4-difluoro-6- (5-methylfuran-2-yl) phenyl} -5-trifluoromethylpyrazol-4-yl] carbamate: white solid (yield: 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, 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-methylfuran-2-yl) phenyl] -5-trifluoromethylpyrazole: yellow solid (yield: 75%); Mp: 110-113 ¹ H-NMR (250 MHz, CDCl ₃ ) δ 2.31 (s, 3H), 3.52 (brs, 2H), 5.23 (d, J = 3.4 Hz, 1H), 5.93 (dd , J = 3.4, 0.6 Hz, 1H), 6.80 (ddd, J = 8.6, 8.1, 2.8 Hz, 1H), 7.42 (dt, J = 9.8, 2 .6 Hz, 1H), 7.47 (s, 1H). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-116.8 (m, 1F), −105.8 (d, J = 11.8 Hz, 1F), −59.4 (d, J = 4. 7Hz, 3F).
Reference Example-1

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 to 6.89 (1H, m), 7.05 to 7.10 ( 1H, m). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-121.3 (1F, d, J = 2.4 Hz), −117.7 (1F, d, J = 2.4 Hz).
2-bromo-4,6-difluorophenylhydrazine (6.43 g, 28.8 mmol), ethyl 2-ethoxymethylenetrifluoroacetoacetate (6.92 g, 28.8 mmol), triethylamine (3.00 g, 29.6 mmol) And ethanol (60 mL) was stirred at room temperature for 3 hours. The reaction 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 ₁ = 9.0 Hz, J ₂ = 8.0 Hz, J ₃ = 2.8 Hz), 7.32 (1H, ddd, J ₁ = 7.8 Hz, J ₂ = 2.8 Hz, J ₃ = 2.3 Hz) , 8.24 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), −103.5 (1F, d, J = 9.4 Hz), −58.6 (3F, d, J = 0) .9 Hz).
Ethyl 1- (2-bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylate (5.86 g, 14.7 mmol), ethanol (15 mL) and 10% 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 to 7.08 (1H, m), 7.31 to 7.36 (1H, m), 8.32 (1H, s). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-113.0 (1F, m), -103.1 (1F, d, J = 9.4 Hz), -58.7 (3F, s).
1- (2-Bromo-4,6-difluorophenyl) -5-trifluoromethylpyrazole-4-carboxylic acid (11.5 g, 31.0 mmol), triethylamine (4.70 g, 46.4 mmol) and 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 to 7.03 (1H, m), 7.26 to 7.31 ( 1H, m), 8.40 (1H, brs). ¹⁹ F-NMR (235 MHz, CDCl ₃ ): δ-111.9 (1F, m), -103.8 (1F, d, J = 7.1 Hz), -59.0 (3F, s).
Reference example-2

Dichloromethane (1 mL) was added to 4-amino-1- [2,4-difluorophenyl-6- (3-fluorophenyl)]-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 to 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 to 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).
Reference example-3

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 to 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).
The N- (1-substituted phenylpyrazol-4-yl) pyrazole-4-carboxamide derivatives that can be produced from the 1-substituted phenyl-4-aminopyrazole derivatives of the present invention are harmful in the cultivation scene of agricultural and horticultural crops. It is useful as an active ingredient of fungicides for disease-causing bacteria. For example, the compounds exemplified in Reference Examples-2 and 3 exhibit strong bactericidal activity against gray mold disease, ring disease, red rust disease and the like.

Claims (5)

General formula (1)

(In the formula, R ¹ represents 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 6 carbon atoms. Or a phenyl group which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkyl having 1 to 6 carbon atoms A pyridyl group optionally substituted by a group; a thienyl group optionally substituted by a halogen atom or an alkyl group having 1 to 6 carbon atoms; or a furyl group optionally substituted by an alkyl group having 1 to 6 carbon atoms X 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, n represents an integer of 1 to 4. When n is 2 or more, X represents 1 may be the same or different, and Q represents a hydrogen atom or a t-butyloxycarbonyl group. General formula (1a)

(In the formula, R ¹ represents 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 6 carbon atoms. Or a phenyl group which may be substituted with an alkoxy group having 1 to 6 carbon atoms; a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms or a haloalkyl having 1 to 6 carbon atoms A pyridyl group optionally substituted by a group; a thienyl group optionally substituted by a halogen atom or an alkyl group having 1 to 6 carbon atoms; or a furyl group optionally substituted by an alkyl group having 1 to 6 carbon atoms X 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, n represents an integer of 1 to 4. When n is 2 or more, X represents May be the same or different from each other. 1-substituted phenyl-4-aminopyrazole derivative represented by the general formula (1b)

(Wherein R ¹ , Ar, X and n represent the same meaning as described above), a method for producing a 1-substituted phenyl-4-aminopyrazole derivative represented by: The 1-substituted phenyl-4-aminopyrazole derivative represented by the general formula (1a) according to claim 2 is represented by the general formula (2).

(Wherein R ¹ represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, or a haloalkyl group having 1 to 6 carbon atoms. X represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, or 1 carbon atom. To 6 in which n represents an integer of 1 to 4. When n is 2 or more, Xs may be the same or different, and the carbamic acid ester represented by In the presence of general formula (3)

(In the formula, Ar represents a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, or a phenyl group optionally substituted with a haloalkyl group having 1 to 6 carbon atoms; halogen atom, carbon A pyridyl group which may be substituted with 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; substituted with a halogen atom or an alkyl group having 1 to 6 carbon atoms Or 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). .   The production method according to claim 3, wherein the palladium catalyst is a catalyst comprising tetrakis (triphenylphosphine) palladium or bis (dibenzylideneacetone) palladium and a tertiary phosphine ligand. The production method according to claim 3 or 4, wherein the base is sodium carbonate, potassium carbonate, potassium phosphate or sodium phosphate.