JP2009215194A - Method for producing fluorine-containing pyrazolecarbonitrile derivative, and method for producing fluorine-containing pyrazolecarboxylic acid derivative by utilizing the fluorine-containing pyrazolecarbonitrile derivative - Google Patents

Abstract

（１）
（式中、Ｒｆは少なくとも１つのフッ素原子で置換されている炭素数１〜６のアルキル基を表し、Ｒ１は水素原子、炭素数１〜６のアルキル基等を表す。）で表される含フッ素ピラゾールカルボニトリル誘導体を製造する。該含フッ素ピラゾールカルボニトリル誘導体は、アルキル化、続く、加水分解を行なうことにより、含フッ素ピラゾールカルボン酸誘導体に変換できる。
【選択図】なし【Task】
PROBLEM TO BE SOLVED: To provide a method for producing a fluorinated pyrazole carbonitrile derivative and a method for producing a fluorinated pyrazole carboxylic acid derivative using the fluorinated pyrazole carbonitrile derivative as a simple and industrially feasible method. And
[Solution]
A fluorine-containing acylacetonitrile derivative is prepared from a fluorine-containing acyl derivative and an aminoacrylonitrile derivative and then reacted with hydrazine to give a general formula (1)

(1)
In the formula, Rf represents a C 1-6 alkyl group substituted with at least one fluorine atom, and R 1 represents a hydrogen atom, a C 1-6 alkyl group, or the like. Fluorine pyrazole carbonitrile derivative is produced. The fluorinated pyrazole carbonitrile derivative can be converted to a fluorinated pyrazole carboxylic acid derivative by alkylation followed by hydrolysis.
[Selection figure] None

Description

  The present invention relates to a method for producing a fluorine-containing pyrazole carbonitrile derivative and a method for producing a fluorine-containing pyrazole carboxylic acid derivative using the fluorine-containing pyrazole carbonitrile derivative.

  It is known that a compound group containing a fluorine-containing pyrazole carbonitrile derivative can be an effective physiologically active substance in the fields of medicine and agricultural chemicals. Furthermore, since the cyano group can be converted into various functional groups such as carboxylic acid, aminomethyl group, aminocarbonyl group, and alkoxyimidoyl group, the fluorine-containing pyrazole carbonitrile derivative is also a useful production intermediate in the field. Can be. Therefore, it is important to provide a novel fluorine-containing pyrazole carbonitrile derivative and a method for producing the same, and various technological developments have been performed.

A typical prior art example is shown below.
(1) A method of introducing a cyano group with copper cyanide after iodination of a trifluoromethylpyrazole derivative using [bis (trifluoroacetoxy) iodo] benzene and iodine (for example, see Patent Document 1).
(2) A method for synthesizing a pyrazole carbonitrile derivative by introducing a formyl group into a trifluoromethylpyrazole derivative with a Vilsmeier reagent and then reacting with hydroxylamine and subsequent phosphorus oxychloride (see, for example, Patent Document 2).
International Publication No. 05/056015 Pamphlet JP-A-8-208620

  However, with regard to the method (1), reagents such as [bis (trifluoroacetoxy) iodo] benzene and copper cyanide are not preferable for safety, and transition metals such as copper have a problem in disposal. In addition, the number of steps from the trifluoromethyl source is large and is not suitable for industrial production. (2) has the same problem. Hydroxylamine is used as a reagent that causes safety problems, phosphorus oxychloride is used as a reagent that causes disposal problems, and the number of processes is large. Furthermore, purification by silica gel column chromatography that is unsuitable for mass synthesis is required.

  The present invention provides a method for producing a fluorinated pyrazole carbonitrile derivative, and a method for producing a fluorinated pyrazole carboxylic acid derivative using the fluorinated pyrazole carbonitrile derivative, as those that can be carried out simply and on an industrial scale. The task is to do.

  As a result of intensive studies to solve the above-mentioned problems, it was found that a fluorine-containing pyrazolecarbonitrile derivative can be produced by preparing a fluorine-containing acylacetonitrile derivative from a fluorine-containing acyl derivative and an aminoacrylonitrile derivative and then reacting with hydrazine. It was. Subsequently, the fluorine-containing pyrazole carbonitrile derivative can be converted into an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative by reacting with the alkylating agent. Furthermore, the alkyl-substituted fluorinated pyrazole carbonitrile derivative can be converted to a fluorinated pyrazole carboxylic acid derivative by hydrolysis. This fluorine-containing pyrazole carboxylic acid derivative can be an important raw material for agricultural and horticultural fungicides including 1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid. Such a method is simple and can be a production method capable of mass production. Thus, the present invention has been completed.

That is, the present invention is as follows.
[1] The following general formula (1)

(1)
Wherein Rf represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, and X represents a halogen atom, a hydroxyl group, or a carbonyloxy group; Formula (2)

(2)
(Wherein R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group which may be substituted, or an arylalkyl group which may be substituted; Each R3 is independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group that may be substituted, an arylalkyl group that may be substituted, or 1 carbon atom. -6 represents an optionally substituted acyl group, or an atomic group necessary to form a 5- to 6-membered ring containing 0 to 1 heteroatom and a nitrogen atom to which R2 and R3 are bonded. Is reacted with a compound represented by the general formula (3)

(3)
(Wherein Rf, R1, R2 and R3 have the same meanings as described above), and further comprising reacting the compound represented by the general formula (3) with hydrazine. General formula (4)

(4)
(Wherein Rf and R1 have the same meanings as described above), and a method for producing a fluorine-containing pyrazole carbonitrile derivative.
[2] R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom to which R2 and R3 are bonded. And the method for producing a fluorinated pyrazole carbonitrile derivative according to [1], which represents an atomic group necessary for forming a 5- to 6-membered ring containing 0 to 1 heteroatom.
[3] The process for producing a fluorinated pyrazole carbonitrile derivative according to [2], wherein Rf represents a trifluoromethyl group, and R2 and R3 both represent a methyl group.
[4] The method further comprises a step of reacting the compound represented by the general formula (4) obtained in [1] with an alkylating agent.

(5)
(In the formula, Rf and R1 have the same meanings as those described in [1], and R4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an arylalkyl group which may be substituted. The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative represented by:
[5] R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom to which R2 and R3 are bonded. The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative according to [4], which represents an atomic group necessary for forming a 5- to 6-membered ring containing 0 to 1 heteroatoms.
[6] Rf represents a trifluoromethyl group, R2 and R3 both represent a methyl group, R4 represents an alkyl group having 1 to 6 carbon atoms, and the alkyl-substituted fluorine-containing pyrazolecarbonitrile derivative according to [5]. Production method.
[7] The method further comprises a step of reacting the compound represented by the general formula (5) obtained in [4] with water.

(6)
(Wherein Rf, R1 and R4 have the same meanings as described in [4]).
[8] R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom to which R2 and R3 are bonded. The method for producing a fluorinated pyrazole carboxylic acid derivative according to [7], which represents an atomic group necessary for forming a 5- to 6-membered ring containing 0 to 1 heteroatoms.
[9] The method for producing a fluorinated pyrazole carboxylic acid derivative according to [8], wherein Rf represents a trifluoromethyl group, R2 and R3 both represent a methyl group, and R4 represents an alkyl group having 1 to 6 carbon atoms. .
[10] The following general formula (3)

(3)
(In the formula, Rf represents a C1-C6 alkyl group substituted with at least one fluorine atom, and R1 represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl. Group, an aryl group which may be substituted, or an arylalkyl group which may be substituted, R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclohexane having 3 to 6 carbon atoms. An alkyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group, an optionally substituted acyl group having 1 to 6 carbon atoms, or a nitrogen atom and a hetero atom 0 to which R2 and R3 are bonded; Which represents a group of atoms necessary to form a 5- to 6-membered ring containing 1 to 5), and a step of reacting hydrazine with the compound represented by the general formula (4)

(4)
(Wherein Rf and R1 have the same meanings as described above), and a method for producing a fluorine-containing pyrazole carbonitrile derivative.
[11] R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom to which R2 and R3 are bonded. The method for producing a fluorinated pyrazole carbonitrile derivative according to [10], which represents an atomic group necessary for forming a 5- to 6-membered ring containing 0 to 1 heteroatoms.
[12] The process for producing a fluorinated pyrazole carbonitrile derivative according to [11], wherein Rf represents a trifluoromethyl group, and R2 and R3 both represent a methyl group.
[13] The following general formula (4)

(4)
(In the formula, Rf represents a C1-C6 alkyl group substituted with at least one fluorine atom, and R1 represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl. Group, an aryl group that may be substituted, or an arylalkyl group that may be substituted) and a step of reacting a compound represented by general formula (5)

(5)
(Wherein Rf and R1 are as defined above, and R4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and an arylalkyl group which may be substituted). A process for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative.
[14] The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative according to [13], wherein R1 is a hydrogen atom.
[15] The process for producing an alkyl-substituted fluorinated pyrazole carbonitrile derivative according to [14], wherein Rf represents a trifluoromethyl group.

  According to the present invention, a method for producing a fluorine-containing pyrazole carbonitrile derivative and a method for producing a fluorine-containing pyrazole carboxylic acid derivative using the fluorine-containing pyrazole carbonitrile derivative can be produced simply and on an industrial scale. Can be offered at.

The present invention will be described in detail below.

The method for producing the fluorine-containing acylacetonitrile derivative represented by the general formula (3) includes an acylation reaction in which the compound represented by the general formula (1) and the compound represented by the general formula (2) are reacted. . This reaction can further include a post-treatment step and a purification step, if necessary, in addition to the production step.
Hereinafter, the general formula (1) will be described.

  The alkyl group having 1 to 6 carbon atoms in Rf in the general formula (1) may be a linear alkyl group or a branched alkyl group. Specifically, linear groups such as methyl group, ethyl group, propyl group, butyl group, pentyl group, hexyl group, isopropyl group, isobutyl group, sec-butyl group, 1-methylbutyl group, 2-methylbutyl group Group, 3-methylbutyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4 -Methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethyl It represents a branched one such as a butyl group.

  Rf in the general formula (1) is sufficient if the alkyl group having 1 to 6 carbon atoms is substituted with at least one fluorine atom. Specifically, even if it is a perfluoroalkyl group such as a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, a heptafluoroisopropyl group or a nonafluorobutyl group, a hydrogen such as a monofluoromethyl group or a difluoromethyl group Even a fluoroalkyl group having an atom may be a fluoroalkyl group having a fluorine atom and other halogen atoms such as a chlorodifluoromethyl group and a bromodifluoromethyl group.

  In the present invention, Rf is preferably a fluoroalkyl group selected from a trifluoromethyl group, a difluoromethyl group, a chlorodifluoromethyl group, a pentafluoroethyl group, and a heptafluoropropyl group, and a trifluoromethyl group and a difluoromethyl group It is more preferable that

  The halogen atom in X in the general formula (1) represents fluorine, chlorine, bromine and iodine.

  The carbonyloxy group in X in the general formula (1) is the general formula (7).

(7)
(Wherein R5 represents an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom) or a general formula (8)

(8)
(Wherein R5 is the same as defined above).

  The halogen atom in R5 in General formula (7) and General formula (8) is synonymous with the halogen atom in X in General formula (1).

  The C1-C6 alkyl group in R5 in General formula (7) and General formula (8) is synonymous with the C1-C6 alkyl group in Rf in General formula (1). Further, these alkyl groups may be substituted with halogen atoms at one or more positions, and are not particularly limited as long as the target acyl group is introduced. When substituting halogen atoms at two or more positions, they may be substituted with the same or two or more types of halogen atoms, and there is no particular limitation as long as the target acyl group is introduced.

  The usage-amount of the compound represented by General formula (1) will not be specifically limited if it is 1 equivalent or more with respect to the compound represented by General formula (2). However, from an economic viewpoint, 1 equivalent or more and 3 equivalents or less are preferable.

Examples of the compound represented by the general formula (1) include trifluoroacetic acid, trifluoroacetic anhydride, trifluoroacetyl chloride, difluoroacetic acid, chlorodifluoroacetic acid, pentafluoropropionic acid, heptafluorobutyric acid and the like. it can. These can use a commercial item, and can also use what was manufactured by the well-known method.
Hereinafter, the compound represented by the general formula (2) will be described.

  The C1-C6 alkyl group in R1 in General formula (2) is synonymous with the C1-C6 alkyl group in Rf in General formula (1).

  The cycloalkyl group having 3 to 6 carbon atoms in R1 in the general formula (2) represents a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like.

The substituent used for the optionally substituted aryl group or the optionally substituted arylalkyl group in R1 in the general formula (2) is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, Alkyl groups such as isobutyl group, sec-butyl group, tert-butyl group; cycloalkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group; trifluoromethyl group, pentafluoroethyl group, hexafluoropropyl group, A halogen-substituted alkyl group such as a hexafluoroisopropyl group, a trifluoroethyl group, a difluoromethyl group, a chlorodifluoromethyl group, a bromodifluoromethyl group and a monofluoromethyl group; an aryl group such as a phenyl group; an arylalkyl group such as a benzyl group; Methoxy group, ethoxy group, pro Alkoxy groups such as xoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group; cycloalkoxy groups such as cyclopropoxy group, cyclobutoxy group, cyclopentyloxy group, cyclohexyloxy group; trifluoro Halogen-substituted alkoxy groups such as methoxy group, difluoromethoxy group, trifluoroethoxy group, and trichloroethoxy group; aryloxy groups such as phenoxy group; arylalkyloxy groups such as benzyloxy group; methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl An alkoxycarbonyl group such as a group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group; Cycloalkoxycarbonyl groups such as sicarbonyl group, cyclobutoxycarbonyl group, cyclopentyloxycarbonyl group, cyclohexyloxycarbonyl group; halogen substitution such as trifluoromethoxycarbonyl group, difluoromethoxycarbonyl group, trifluoroethoxycarbonyl group, trichloroethoxycarbonyl group Alkoxycarbonyl group; aryloxycarbonyl group such as phenoxycarbonyl group; arylalkyloxycarbonyl group such as benzyloxycarbonyl group; alkylthio group such as methylthio group, ethylthio group, propylthio group, butylthio group; cyclopropylthio group, cyclobutylthio Group, cycloalkylthio group such as cyclopentylthio group, cyclohexylthio group; trifluoromethylthio group, difluoromethylthio group Groups, halogen-substituted alkylthio groups such as trifluoroethylthio groups; arylthio groups such as phenylthio groups; arylalkylthio groups such as benzylthio groups; alkylsulfinyl groups such as methanesulfinyl groups, ethanesulfinyl groups, propanesulfinyl groups, butanesulfinyl groups; Cycloalkylsulfinyl groups such as cyclopropanesulfinyl group, cyclobutanesulfinyl group, cyclopentanesulfinyl group, cyclohexanesulfinyl group; halogen-substituted alkylsulfinyl groups such as trifluoromethanesulfinyl group, difluoromethanesulfinyl group, trifluoroethanesulfinyl group; phenylsulfinyl group Arylsulfinyl groups such as benzylsulfinyl groups; arylalkylsulfinyl groups such as benzylsulfinyl groups; Alkylsulfonyl groups such as ethanesulfonyl group, propanesulfonyl group, butanesulfonyl group; cycloalkylsulfonyl groups such as cyclopropanesulfonyl group, cyclobutanesulfonyl group, cyclopentanesulfonyl group, cyclohexanesulfonyl group; trifluoromethanesulfonyl group, difluoromethanesulfonyl group Halogen substituted alkylsulfonyl groups such as trifluoroethanesulfonyl group; arylsulfonyl groups such as phenylsulfonyl group; arylalkylsulfonyl groups such as benzylsulfonyl group; methylcarbonyl group, ethylcarbonyl group, propylcarbonyl group, isopropylcarbonyl group, butyl Alkylcarbonyl such as carbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group Groups: cycloalkylcarbonyl groups such as cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopropylcarbonyl group, cyclopentylcarbonyl group, cyclohexylcarbonyl group; halogen-substituted alkyls such as trifluoromethanecarbonyl group, difluoromethanecarbonyl group, trichloromethanecarbonyl group Carbonyl group; arylcarbonyl group such as benzoyl group; methylcarbonyloxy group, ethylcarbonyloxy group, propylcarbonyloxy group, isopropylcarbonyloxy group, butylcarbonyloxy group, isobutylcarbonyloxy group, sec-butylcarbonyloxy group, tert -Alkylcarbonyloxy groups such as butylcarbonyloxy group; cyclopropylcarbonyloxy group, cyclobutylcarbonyloxy group Cycloalkylcarbonyloxy groups such as xy group, cyclopropylcarbonyloxy group, cyclopentylcarbonyloxy group, cyclohexylcarbonyloxy group; arylcarbonyloxy groups such as benzoyloxy group; methylcarbonylamino group, ethylcarbonylamino group, propylcarbonylamino group Alkylcarbonylamino groups such as isopropylcarbonylamino group, butylcarbonylamino group, isobutylcarbonylamino group, sec-butylcarbonylamino group, tert-butylcarbonylamino group; cyclopropylcarbonylamino group, cyclobutylcarbonylamino group, cyclopropyl Cycloalkylcarbonylamino groups such as carbonylamino group, cyclopentylcarbonylamino group, and cyclohexylcarbonylamino group Arylcarbonylamino group such as benzoylamino group; methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, sec-butoxycarbonylamino group, tert -Butoxycarbonylamino group, methoxycarbonyl (methyl) amino group, ethoxycarbonyl (methyl) amino group, propoxycarbonyl (methyl) amino group, isopropoxycarbonyl (methyl) amino group, butoxycarbonyl (methyl) amino group, isobutoxycarbonyl (Methyl) amino group, sec-butoxycarbonyl (methyl) amino group, tert-butoxycarbonyl (methyl) amino group, methoxycarbonyl (ethyl Amino group, ethoxycarbonyl (ethyl) amino group, propoxycarbonyl (ethyl) amino group, isopropoxycarbonyl (ethyl) amino group, butoxycarbonyl (ethyl) amino group, isobutoxycarbonyl (ethyl) amino group, sec-butoxycarbonyl ( Alkoxy) amino group such as ethyl) amino group, tert-butoxycarbonyl (ethyl) amino group; cyclopropoxycarbonylamino group, cyclobutoxycarbonylamino group, cyclopentyloxycarbonylamino group, cyclohexyloxycarbonylamino group, cyclopropoxycarbonyl (methyl) ) Amino group, cyclobutoxycarbonyl (methyl) amino group, cyclopentyloxycarbonyl (methyl) amino group, cyclohexyloxycarbonyl (methyl) ) Cycloalkoxycarbonylamino groups such as amino group, cyclopropoxycarbonyl (ethyl) amino group, cyclobutoxycarbonyl (ethyl) amino group, cyclopentyloxycarbonyl (ethyl) amino group, cyclohexyloxycarbonyl (ethyl) amino group; trifluoromethoxy Carbonylamino group, difluoromethoxycarbonylamino group, trifluoroethoxycarbonylamino group, trichloroethoxycarbonylamino group, trifluoromethoxycarbonyl (methyl) amino group, difluoromethoxycarbonyl (methyl) amino group, trifluoroethoxycarbonyl (methyl) amino Group, trichloroethoxycarbonyl (methyl) amino group, trifluoromethoxycarbonyl (ethyl) amino group, difluoromethoxycarbo Halogen-substituted alkoxycarbonylamino groups such as ru (ethyl) amino group, trifluoroethoxycarbonyl (ethyl) amino group, trichloroethoxycarbonyl (ethyl) amino group; phenoxycarbonylamino group, phenoxycarbonyl (methyl) amino group, phenoxycarbonyl ( An aryloxycarbonylamino group such as an ethyl) amino group; an arylalkyloxycarbonylamino group such as a benzyloxycarbonylamino group, a benzyloxycarbonyl (methyl) amino group, or a benzyloxycarbonyl (ethyl) amino group; a methylaminocarbonyloxy group; Ethylaminocarbonyloxy group, propylaminocarbonyloxy group, isopropylaminocarbonyloxy group, butylaminocarbonyloxy group, isobutylaminocarbonyl Nyloxy, sec-butylaminocarbonyloxy, tert-butylaminocarbonyloxy, dimethylaminocarbonyloxy, {ethyl (methyl) amino} carbonyloxy, {propyl (methyl) amino} carbonyloxy, {isopropyl ( Methyl) amino} carbonyloxy group, {butyl (methyl) amino} carbonyloxy group, {isobutyl (methyl) amino} carbonyloxy group, {sec-butyl (methyl) amino} carbonyloxy group, {tert-butyl (methyl) Amino} carbonyloxy group, {methyl (ethyl) amino} carbonyloxy group, diethylaminocarbonyloxy group, {propyl (ethyl) amino} carbonyloxy group, {isopropyl (ethyl) amino} carbonyloxy group, {butyl (ethyl) amino } Carbo Alkylaminocarbonyloxy groups such as ruoxy group, {isobutyl (ethyl) amino} carbonyloxy group, {sec-butyl (ethyl) amino} carbonyloxy group, {tert-butyl (ethyl) amino} carbonyloxy group; cyclopropylamino Carbonyloxy group, cyclobutylaminocarbonyloxy group, cyclopentylaminocarbonyloxy group, cyclohexylaminocarbonyloxy group, {cyclopropyl (methyl) amino} carbonyloxy group, {cyclobutyl (methyl) amino} carbonyloxy group, {cyclopentyl (methyl ) Amino} carbonyloxy group, {cyclohexyl (methyl) amino} carbonyloxy group, {cyclopropyl (ethyl) amino} carbonyloxy group, {cyclobutyl (ethyl) amino} carbonyloxy group, Cycloalkylaminocarbonyloxy groups such as lopentyl (ethyl) amino} carbonyloxy group, {cyclohexyl (ethyl) amino} carbonyloxy group; trifluoromethylaminocarbonyloxy group, difluoromethylaminocarbonyloxy group, trifluoroethylaminocarbonyloxy group Group, trichloroethylaminocarbonyloxy group, {trifluoromethyl (methyl) amino} carbonyloxy group, {difluoromethyl (methyl) amino} carbonyloxy group, {trifluoroethyl (methyl) amino} carbonyloxy group, {trichloroethyl (Methyl) amino} carbonyloxy group, {trifluoromethyl (ethyl) amino} carbonyloxy group, {difluoromethyl (ethyl) amino} carbonyloxy group, {trifluoroethyl (ethyl Halogen-substituted alkylaminocarbonyloxy groups such as amino} carbonyloxy group, {trichloroethyl (ethyl) amino} carbonyloxy group; phenylaminocarbonyloxy group, {phenyl (methyl) amino} carbonyloxy group, {phenyl (ethyl) amino } Arylaminocarbonyloxy group such as carbonyloxy group; arylalkylaminocarbonyloxy group such as benzylaminocarbonyloxy group, {benzyl (methyl) amino} carbonyloxy group, {benzyl (ethyl) amino} carbonyloxy group; pyrrolidino Cyclic aminocarbonyloxy group such as carbonyloxy group, piperidinocarbonyloxy group, morpholinocarbonyloxy group; methylaminocarbonylamino group, ethylaminocarbonylamino group, propylaminocarboni Ruamino, isopropylaminocarbonylamino, butylaminocarbonylamino, isobutylaminocarbonylamino, sec-butylaminocarbonylamino, tert-butylaminocarbonylamino, dimethylamino

Rubonylamino group, {ethyl (methyl) amino} carbonylamino group, {propyl (methyl) amino} carbonylamino group, {isopropyl (methyl) amino} carbonylmethyl group, {butyl (methyl) amino} carbonylamino group, {isobutyl (Methyl) amino} carbonylamino group, {sec-butyl (methyl) amino} carbonylamino group, {tert-butyl (methyl) amino} carbonylamino group, {methyl (ethyl) amino} carbonylamino group, diethylaminocarbonylamino group {Propyl (ethyl) amino} carbonylamino group, {isopropyl (ethyl) amino} carbonylamino group, {butyl (ethyl) amino} carbonylamino group, {isobutyl (ethyl) amino} carbonylamino group, {sec-butyl ( Ethyl) amino} carbonylamino group, { ert-butyl (ethyl) amino} carbonylamino group, methylaminocarbonyl (methyl) amino group, ethylaminocarbonyl (methyl) amino group, propylaminocarbonyl (methyl) amino group, isopropylaminocarbonyl (methyl) amino group, butylamino Carbonyl (methyl) amino group, isobutylaminocarbonyl (methyl) amino group, sec-butylaminocarbonyl (methyl) amino group, tert-butylaminocarbonyl (methyl) amino group, methylaminocarbonyl (ethyl) amino group, ethylaminocarbonyl (Ethyl) amino group, propylaminocarbonyl (ethyl) amino group, isopropylaminocarbonyl (ethyl) amino group, butylaminocarbonyl (ethyl) amino group, isobutylaminocarbonyl (e L) amino group, sec-butylaminocarbonyl (ethyl) amino group, tert-butylaminocarbonyl (ethyl) amino group, dimethylaminocarbonyl (methyl) amino group, {ethyl (methyl) amino} carbonyl (methyl) amino group, {Propyl (methyl) amino} carbonyl (methyl) amino group, {isopropyl (methyl) amino} carbonyl (methyl) amino group, {butyl (methyl) amino} carbonyl (methyl) amino group, {isobutyl (methyl) amino} carbonyl (Methyl) amino group, {sec-butyl (methyl) amino} carbonyl (methyl) amino group, {tert-butyl (methyl) amino} carbonyl (methyl) amino group, dimethylaminocarbonyl (ethyl) amino group, {ethyl ( Methyl) amino} carbonyl (ethyl) amino group, {pro Pyr (methyl) amino} carbonyl (ethyl) amino group, {isopropyl (methyl) amino} carbonyl (ethyl) amino group, {butyl (methyl) amino} carbonyl (ethyl) amino group, {isobutyl (methyl) amino} carbonyl ( Ethyl) amino group, {sec-butyl (methyl) amino} carbonyl (ethyl) amino group, {tert-butyl (methyl) amino} carbonyl (ethyl) amino group, diethylaminocarbonyl (methyl) amino group, {ethyl (propyl) Amino} carbonyl (methyl) amino group, {ethyl (isopropyl) amino} carbonyl (methyl) amino group, {butyl (ethyl) amino} carbonyl (methyl) amino group, {ethyl (isobutyl) amino} carbonyl (methyl) amino group , {Sec-butyl (ethyl) amino} carbonyl (methyl) Mino group, {tert-butyl (ethyl) amino} carbonyl (methyl) amino group, diethylaminocarbonyl (ethyl) amino group, {ethyl (propyl) amino} carbonyl (ethyl) amino group, {ethyl (isopropyl) amino} carbonyl ( Ethyl) amino group, {ethyl (butyl) amino} carbonyl (ethyl) amino group, {ethyl (isobutyl) amino} carbonyl (ethyl) amino group, {sec-butyl (ethyl) amino} carbonyl (ethyl) amino group, { tert-butyl (ethyl) amino} carbonyl (ethyl) amino group and other alkylaminocarbonylamino groups; cyclopropylaminocarbonylamino group, cyclobutylaminocarbonylamino group, cyclopentylaminocarbonylamino group, cyclohexylaminocarbonylamino group, {cycline Propyl (methyl) amino} carbonylamino group, {cyclobutyl (methyl) amino} carbonylamino group, {cyclopentyl (methyl) amino} carbonylamino group, {cyclohexyl (methyl) amino} carbonylamino group, {cyclopropyl (ethyl) amino } Carbonylamino group, {Cyclobutyl (ethyl) amino} carbonylamino group, {Cyclopentyl (ethyl) amino} carbonylamino group, {Cyclohexyl (ethyl) amino} carbonylamino group, Cyclopropylaminocarbonyl (methyl) amino group, Cyclobutyl Aminocarbonyl (methyl) amino group, cyclopentylaminocarbonyl (methyl) amino group, cyclohexylaminocarbonyl (methyl) amino group, cyclopropylaminocarbonyl (ethyl) amino group, cyclobutylamino Carbonyl (ethyl) amino group, cyclopentylaminocarbonyl (ethyl) amino group, cyclohexylaminocarbonyl (ethyl) amino group, {cyclopropyl (methyl) amino} carbonyl (methyl) amino group, {cyclobutyl (methyl) amino} carbonyl (methyl ) Amino group, {cyclopentyl (methyl) amino} carbonyl (methyl) amino group, {cyclohexyl (methyl) amino} carbonyl (methyl) amino group, {cyclopropyl (methyl) amino} carbonyl (ethyl) amino group, {cyclobutyl ( Methyl) amino} carbonyl (ethyl) amino group, {cyclopentyl (methyl) amino} carbonyl (ethyl) amino group, {cyclohexyl (methyl) amino} carbonyl (ethyl) amino group, {cyclopropyl (ethyl) amino} carbonyl (methyl Amino group, {cyclobutyl (ethyl) amino} carbonyl (methyl) amino group, {cyclopentyl (ethyl) amino} carbonyl (methyl) amino group, {cyclohexyl (ethyl) amino} carbonyl (methyl) amino group, {cyclopropyl (ethyl) ) Amino} carbonyl (ethyl) amino group, {cyclobutyl (ethyl) amino} carbonyl (ethyl) amino group, {cyclopentyl (ethyl) amino} carbonyl (ethyl) amino group, {cyclohexyl (ethyl) amino} carbonyl (ethyl) amino A cycloalkylaminocarbonylamino group such as a group; trifluoromethylaminocarbonylamino group, difluoromethylaminocarbonylamino group, trifluoroethylaminocarbonylamino group, trichloroethylaminocarbonylamino group, {trifluorome Ru (methyl) amino} carbonylamino group, {difluoromethyl (methyl) amino} carbonylamino group, {trifluoroethyl (methyl) amino} carbonylamino group, {trichloroethyl (methyl) amino} carbonylamino group, {trifluoro Methyl (ethyl) amino} carbonylamino group, {difluoromethyl (ethyl) amino} carbonylamino group, {trifluoroethyl (ethyl) amino} carbonylamino group, {trichloroethyl (ethyl) amino} carbonylamino group, trifluoromethyl Aminocarbonyl (methyl) amino group, difluoromethylaminocarbonyl (methyl) amino group, trifluoroethylaminocarbonyl (methyl) amino group, trichloroethylaminocarbonyl (methyl) amino group, trifluoromethylaminocarbonyl ( Ethyl) amino group, difluoromethylaminocarbonyl (ethyl) amino group, trifluoroethylaminocarbonyl (ethyl) amino group, trichloroethylaminocarbonyl (ethyl) amino group,
{Trifluoromethyl (methyl) amino} carbonyl (methyl) amino group, {difluoromethyl (methyl) amino} carbonyl (methyl) amino group, {trifluoroethyl (methyl) amino} carbonyl (methyl) amino group, {trichloroethyl (Methyl) amino} carbonyl (methyl) amino group, {trifluoromethyl (methyl) amino} carbonyl (ethyl) amino group, {difluoromethyl (methyl) amino} carbonyl (ethyl) amino group, {trifluoroethyl (methyl) Amino} carbonyl (ethyl) amino group, {trichloroethyl (methyl) amino} carbonyl (ethyl) amino group, {trifluoromethyl (ethyl) amino} carbonyl (methyl) amino group, {difluoromethyl (ethyl) amino} carbonyl ( Methyl) amino group, {trifluoroethyl (d L) amino} carbonyl (methyl) amino group, {trichloroethyl (ethyl) amino} carbonyl (methyl) amino group, {trifluoromethyl (ethyl) amino} carbonyl (ethyl) amino group, {difluoromethyl (ethyl) amino} Halogen-substituted alkylaminocarbonylamino groups such as carbonyl (ethyl) amino group, {trifluoroethyl (ethyl) amino} carbonyl (ethyl) amino group, {trichloroethyl (ethyl) amino} carbonyl (ethyl) amino group; phenylaminocarbonyl Amino group, {phenyl (methyl) amino} carbonylamino group, {phenyl (ethyl) amino} carbonylamino group, phenylaminocarbonyl (methyl) amino group, phenylaminocarbonyl (ethyl) amino group, {methyl (phenyl) amino} Carbonyl (methyl ) Amino group, {methyl (phenyl) amino} carbonyl (ethyl) amino group, {ethyl (phenyl) amino} carbonyl (methyl) amino group, {ethyl (phenyl) amino} carbonyl (ethyl) amino group, etc. arylaminocarbonyl Amino group; benzylaminocarbonylamino group, {benzyl (methyl) amino} carbonylamino group, {benzyl (ethyl) amino} carbonylamino group, benzylaminocarbonyl (methyl) amino group, benzylaminocarbonyl (ethyl) amino group, { Methyl (benzyl) amino} carbonyl (methyl) amino group, {methyl (benzyl) amino} carbonyl (ethyl) amino group, {ethyl (benzyl) amino} carbonyl (methyl) amino group, {ethyl (benzyl) amino} carbonyl ( Aryl) arylalkyl such as amino group Aminocarbonylamino group; pyrrolidinocarbonylamino group, piperidinocarbonylamino group, morpholinocarbonylamino group, pyrrolidinocarbonyl (methyl) amino group, piperidinocarbonyl (methyl) amino group, morpholinocarbonyl (methyl) amino group, Cyclic aminocarbonyloxy groups such as pyrrolidinocarbonyl (ethyl) amino group, piperidinocarbonyl (ethyl) amino group, morpholinocarbonyl (ethyl) amino group; methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropyl Aminocarbonyl group, butylaminocarbonyl group, isobutylaminocarbonyl group, sec-butylaminocarbonyl group, tert-butylaminocarbonyl group, dimethylaminocarbonyl group, {ethyl (methyl L) amino} carbonyl group, {methyl (propyl) amino} carbonyl group, {isopropyl (methyl) amino} carbonyl group, {butyl (methyl) amino} carbonyl group, {isobutyl (methyl) amino} carbonyl group, {sec- Butyl (methyl) amino} carbonyl group, {tert-butyl (methyl) amino} carbonyl group, {ethyl (methyl) amino} carbonyl group, {ethyl (propyl) amino} carbonyl group, {ethyl (isopropyl) amino} carbonyl group , {Butyl (ethyl) amino} carbonyl group, {isobutyl (ethyl) amino} carbonyl group, {sec-butyl (ethyl) amino} carbonyl group, {tert-butyl (ethyl) amino} carbonyl group, etc. alkylaminocarbonyl groups A cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, Clopentylaminocarbonyl group, cyclohexylaminocarbonyl group, {cyclopropyl (methyl) amino} carbonyl group, {cyclobutyl (methyl) amino} carbonyl group, {cyclopentyl (methyl) amino} carbonyl group, {cyclohexyl (methyl) amino} carbonyl A cycloalkylaminocarbonyl group such as a group, {cyclopropyl (ethyl) amino} carbonyl group, {cyclobutyl (ethyl) amino} carbonyl group, {cyclopentyl (ethyl) amino} carbonyl group, {cyclohexyl (ethyl) amino} carbonyl group; Trifluoromethylaminocarbonyl group, difluoromethylaminocarbonyl group, trifluoroethylaminocarbonyl group, trichloroethylaminocarbonyl group, {trifluoromethyl (methyl) amino} carbonyl group, {diflu Romethyl (methyl) amino} carbonyl group, {trifluoroethyl (methyl) amino} carbonyl group, {trichloroethyl (methyl) amino} carbonyl group, {trifluoromethyl (ethyl) amino} carbonyl group, {difluoromethyl (ethyl) Amino} carbonyl group, {trifluoroethyl (ethyl) amino} carbonyl group, halogen-substituted alkylaminocarbonyl group such as {trichloroethyl (ethyl) amino} carbonyl group; phenylaminocarbonyl group, {phenyl (methyl) amino} carbonyl group , {Arylaminocarbonyl groups such as phenyl (ethyl) amino} carbonyl group; arylalkylaminocarbonyl groups such as benzylaminocarbonyl group, {benzyl (methyl) amino} carbonyl group, {benzyl (ethyl) amino} carbonyl group; pyrrolidinoca Cyclic aminocarbonyl groups such as bonyl group, piperidinocarbonyl group, morpholinocarbonyl group; methoxycarbonyloxy group, ethoxycarbonyloxy group, propoxycarbonyloxy group, isopropoxycarbonyloxy group, butoxycarbonyloxy group, isobutoxycarbonyl Alkoxycarbonyloxy groups such as oxy group, sec-butoxycarbonyloxy group, tert-butoxycarbonyloxy group; cycloalkoxy such as cyclopropoxycarbonyloxy group, cyclobutoxycarbonyloxy group, cyclopentyloxycarbonyloxy group, cyclohexyloxycarbonyloxy group, etc. Carbonyloxy group; trifluoromethoxycarbonyloxy group, difluoromethoxycarbonyloxy group, trifluoroethoxycarbonyl A halogen-substituted alkoxycarbonyloxy group such as a ruoxy group or a trichloroethoxycarbonyloxy group; an aryloxycarbonyloxy group such as a phenoxycarbonyloxy group; an arylalkyloxycarbonyloxy group such as a benzyloxycarbonyloxy group; a methylamino group or an ethylamino group Alkylamino groups such as propylamino group, isopropylamino group, dimethylamino group, diethylamino group, dipropylamino group and diisopropylamino group; cyclic amino groups such as pyrrolidino group, piperidino group and morpholino group; tert-butyldimethylsilyloxy Groups, silyloxy groups such as tert-butyldiphenylsilyloxy group, dimethylphenylsilyloxy group; halogen atoms such as chlorine, fluorine, bromine, iodine; nitro group; cyano group It is shown.

  The substitution position of the substituent may be on the aryl group constituting the arylalkyl group or an alkyl moiety, but is preferably on the aryl group. Further, the number of substituents on the aryl group is not limited. When substituted with two or more substituents, they may be composed of the same or two or more kinds of substituents, and are not particularly limited.

  The aryl group in R1 in the general formula (2) represents a phenyl group, a naphthyl group, an anthranyl group, a phenanthryl group, or the like.

  The aryl group of the arylalkyl group in R1 in the general formula (2) has the same meaning as the aryl group.

The alkyl part of the arylalkyl group in R1 and R2 in the general formula (2) represents an alkylene group having 1 to 4 carbon atoms.
R2 and R3 in the general formula (2) are independent of each other.

  The C1-C6 alkyl group in R2 or R3 in General formula (2) is synonymous with the C1-C6 alkyl group in Rf in General formula (1).

  The cycloalkyl group having 3 to 6 carbon atoms in R2 or R3 in the general formula (2) has the same meaning as the cycloalkyl group having 3 to 6 carbon atoms in R1 in the general formula (2).

  The aryl group which may be substituted in R2 or R3 in the general formula (2) has the same meaning as the aryl group which may be substituted in R1 in the general formula (2).

  The arylalkyl group which may be substituted in R2 or R3 in the general formula (2) has the same meaning as the arylalkyl group which may be substituted in R1 in the general formula (2).

  The substituent of the acyl group having 1 to 6 carbon atoms which may be substituted in R2 or R3 in the general formula (2) is an aryl group which may be substituted in R1 in the general formula (2) or a substituted group. It is synonymous with the substituent used in the arylalkyl group which may be.

  The acyl group in the acyl group having 1 to 6 carbon atoms which may be substituted in R2 or R3 in the general formula (2) is a formyl group, a methylcarbonyl group, an ethylcarbonyl group, a propylcarbonyl group, an isopropylcarbonyl group, Butylcarbonyl group, isobutylcarbonyl group, sec-butylcarbonyl group, tert-butylcarbonyl group, pentylcarbonyl group, isoamylcarbonyl group, 3-methyl-2-butylcarbonyl group, tert-pentylcarbonyl group, neo-pentylcarbonyl group, 2-pentylcarbonyl group, 3-pentylcarbonyl group and the like are represented.

  R2 and R3 in the general formula (2) may be an atomic group necessary for forming a 5- to 6-membered ring structure containing 0 to 1 heteroatoms. Specific examples of the 5-6 membered ring structure include pyrrolidino group, piperidino group, morpholino group and the like.

  The compound represented by the general formula (2) may be a compound having a structure of either a trans isomer or a cis isomer, or a compound in which a trans isomer and a cis isomer are mixed at an arbitrary ratio, and the structure is limited. There is nothing.

  As the compound represented by the general formula (2), a commercially available product can be used, or a compound produced by referring to JP-A-55-130950, US Pat. No. 3,966,791, etc. It can also be used.

As a compound represented by the general formula (2), R1 is hydrogen, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or R2 What represents an atomic group required in order to form a 5-6 membered ring containing the nitrogen atom which R3 and R3 couple | bond, and 0-1 heteroatoms is used preferably. More preferred is a compound wherein R1 is hydrogen and R2 and R3 are both methyl groups.
Hereinafter, the compound represented by the general formula (3) will be described.

Rf in the general formula (3) has the same meaning as Rf in the general formula (1).
R1 in the general formula (3) has the same meaning as R1 in the general formula (2).
R2 or R3 in the general formula (3) has the same meaning as R2 or R3 in the general formula (2).

The compound represented by the general formula (3) may be a compound having a structure of either a trans isomer or a cis isomer, or a compound in which a trans isomer and a cis isomer are mixed in an arbitrary ratio, and the structure is limited. There is nothing.
Hereinafter, this acylation reaction will be described.
Hereinafter, the reaction in which X in the general formula (1) is a halogen atom will be described.

When reacting the compound represented by the general formula (1) and the compound represented by the general formula (2), it is preferable to use a base.
The base used is an organic base or an inorganic base.

  Specific examples of the organic base include triethylamine, tributylamine, trioctylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, and the like. And aromatic amines such as pyridine, collidine, lutidine, 4-dimethylaminopyridine, and the like. Specific examples of the inorganic base include sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, carbonic acid. Examples include potassium and cesium carbonate. These bases can be used alone, or two or more kinds can be mixed at an arbitrary ratio.

  If the equivalent of the base to be used is 1 equivalent or more with respect to General formula (2), it will not be specifically limited. From an economical viewpoint, 1 equivalent or more and 5 equivalent or less are preferable.

  A solvent can be used for the reaction. The solvent used for the reaction is not particularly limited as long as it does not react with the compound represented by the general formula (1).

  Specific examples of the solvent include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, hydrocarbon solvents such as hexane, heptane and cyclohexane, ethyl acetate, Ester solvents such as butyl acetate and isopropyl acetate, ether solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, nitrile solvents such as acetonitrile and propionitrile, and methyl isobutyl ketone Examples include aprotic solvents such as ketone solvents. These solvents can be used alone or in admixture of two or more at any ratio.

  Although the usage-amount of a solvent is not specifically limited, Usually the weight of 3 times or more and 40 times or less is preferable with respect to the weight of General formula (2).

The reaction temperature is not particularly limited as long as each compound is not decomposed, but it can usually be set to −30 ° C. or higher and 150 ° C. or lower or the boiling point of the solvent or lower.
When X of the compound represented by the general formula (1) is a halogen atom, a compound in which Rf in the general formula (1) is an alkyl group having 1 to 3 carbon atoms substituted with at least one fluorine atom is preferable. It can be adapted to the present invention. More preferably, the compound represented by the general formula (1) is trifluoroacetyl chloride or trifluoroacetyl fluoride.
Hereinafter, the reaction when X in the general formula (1) is a hydroxyl group will be described.

  When X in the general formula (1) is a hydroxyl group, it is preferable to use a halogenating agent or an imidazoling agent.

  What is necessary is just to select the reagent which can substitute the hydroxyl group of the compound represented by General formula (1) with a halogen as a halogenating agent, and as long as reaction advances, there will be no restriction | limiting in particular.

Specific examples of the halogenating agent include sulfur-containing halogenating agents such as sulfuryl chloride, thionyl chloride and thionyl bromide, carbonyl-containing halogenating agents such as oxalyl chloride, oxalyl bromide and phosgene, phosphorus oxychloride, phosphorus trichloride, Examples thereof include phosphorus-containing halogenating agents such as phosphorus bromide and phosphorus pentachloride The amount of the halogenating agent used is not particularly limited as long as it is 1 equivalent or more with respect to the general formula (1), but is economical. From the viewpoint, it is usually 1 equivalent or more and 3 equivalents or less.

  As the halogenating agent, a formamide derivative such as dimethylformamide may be added and converted into a Vilsmeier reagent for use.

  Vilsmeier reagent is the general formula (9)

(9)
(Wherein R6 and R7 are each independently a C1-6 alkyl group, and Y represents a halogen atom).

  The C1-C6 alkyl group in R6 and R7 in General formula (9) is synonymous with the C1-C6 alkyl group in Rf in General formula (1).

  The halogen atom in General formula (9) is synonymous with the halogen atom in General formula (1).

  A specific example of the imidazoling agent is N, N′-carbonyldiimidazole.

  The amount of the imidazole agent used is not particularly limited as long as it is 1 equivalent or more with respect to the compound represented by the general formula (1), but is usually 1 equivalent or more and 3 equivalents or less from an economic viewpoint. .

  When reacting the compound represented by the general formula (1) and the compound represented by the general formula (2), it is preferable to use a base.

  The base used is an organic base or an inorganic base.

  Specific examples of the organic base include triethylamine, tributylamine, trioctylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, and the like. And aromatic amines such as pyridine, collidine, lutidine, 4-dimethylaminopyridine, and the like. Specific examples of the inorganic base include sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, carbonic acid. Examples include potassium and cesium carbonate. These bases can be used alone, or two or more kinds can be mixed at an arbitrary ratio.

  The equivalent of the base to be used is not particularly limited as long as it is 2 equivalents or more with respect to the general formula (2). From an economical viewpoint, 2 to 5 equivalents are preferable.

  A solvent can be used for the reaction. The solvent used for the reaction is not particularly limited as long as it does not react with the compound represented by the general formula (1).

  Specific examples of the solvent include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, hydrocarbon solvents such as hexane and heptane, ethyl acetate and butyl acetate. , Ester solvents such as isopropyl acetate, ether solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, nitrile solvents such as acetonitrile and propionitrile, and ketone systems such as methyl isobutyl ketone Examples include aprotic solvents such as solvents.

  Although the usage-amount of a solvent is not specifically limited, The weight of 3 times or more and 40 times or less is preferable normally with respect to the weight of the compound represented by General formula (2).

The reaction temperature is not particularly limited as long as it is set so that each compound does not decompose, but it is usually from −30 ° C. to 150 ° C. or the boiling point of the solvent.
With regard to the method of charging the reagent, it is preferable to charge the halogenating agent last with respect to the solvent represented by the compound represented by the general formula (1), the compound represented by the general formula (2) and the base. . Moreover, you may add a formamide derivative to the solvent containing the compound represented by General formula (1), the compound represented by General formula (2), and a base as needed. By this charging method, the yield of the compound represented by the general formula (3) is remarkably improved.

When X of the compound represented by the general formula (1) is a hydroxyl group, an alkyl group having 1 to 3 carbon atoms in which Rf in the general formula (1) is substituted with at least one fluorine atom is preferable and conforms to the present invention. it can. Alternatively, the compound represented by the general formula (1) can be preferably adapted to trifluoroacetic acid, difluoroacetic acid, chlorodifluoroacetic acid, pentafluoropropionic acid, and heptafluorobutyric acid. More preferred are trifluoroacetic acid and difluoroacetic acid.
Hereinafter, the reaction in which X in the general formula (1) is a carbonyloxy group will be described.

In reacting the compound represented by the general formula (1) and the compound represented by the general formula (2), a base can be used, but it is not essential.
When a base is used, it is an organic base or an inorganic base.

Specific examples of the organic base include triethylamine, tributylamine, trioctylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] -7-undecene, and the like. And aromatic amines such as pyridine, collidine, lutidine, 4-dimethylaminopyridine, and the like. Specific examples of the inorganic base include sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, carbonic acid. Examples include potassium and cesium carbonate. These bases can be used alone, or two or more kinds can be mixed at an arbitrary ratio.
The equivalent of the base used is not particularly limited. From an economical viewpoint, it is 5 equivalents or less.

  A solvent can be used for the reaction. The solvent used for the reaction is not particularly limited as long as it does not react with the compound represented by the general formula (1).

  Specific examples of the solvent include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, hydrocarbon solvents such as hexane and heptane, ethyl acetate and butyl acetate. , Ester solvents such as isopropyl acetate, ether solvents such as diethyl ether, diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, nitrile solvents such as acetonitrile and propionitrile, and ketone systems such as methyl isobutyl ketone Examples include aprotic solvents such as solvents.

  Although the usage-amount of a solvent is not specifically limited, The weight of 3 times or more and 40 times or less is preferable normally with respect to the weight of the compound represented by General formula (2).

  The reaction temperature is not particularly limited as long as each compound is not decomposed, but it can usually be set to −30 ° C. or higher and 150 ° C. or lower or the boiling point of the solvent or lower.

When X of the compound represented by the general formula (1) is a carbonyloxy group, X is a substituent represented by the general formula (7), and R5 in the general formula (7) is Rf. A compound (denoted -O (C = O) Rf) is compatible with the present invention. More preferably, the compound represented by the general formula (1) is trifluoroacetic anhydride.
Hereinafter, the post-processing process will be described. These post-treatments are common in each reaction when X is a halogen atom, a hydroxyl group or a carbonyloxy group.

  The reaction mixture containing the compound represented by the general formula (3) obtained by reacting the compound represented by the general formula (1) with the compound represented by the general formula (2) is water, an alkaline aqueous solution, an acidic solution. It can be washed with an aqueous solution or saline.

The alkaline aqueous solution and acidic aqueous solution used for washing are not particularly limited as long as the compound represented by the general formula (3) is not decomposed, and are usually sodium hydrogen carbonate aqueous solution, sodium carbonate aqueous solution, sodium hydroxide aqueous solution, Examples include alkaline aqueous solutions such as potassium hydrogen carbonate aqueous solution, potassium carbonate aqueous solution and potassium hydroxide aqueous solution, and acidic aqueous solutions such as hydrochloric acid aqueous solution and sulfuric acid aqueous solution.
The number of times of washing the reaction mixture is not particularly limited.

  The reaction mixture containing the compound represented by the general formula (3) washed with water, an aqueous alkaline solution, or an acidic aqueous solution can be dehydrated with sodium sulfate, magnesium sulfate, or the like.

  The reaction mixture containing the compound represented by the general formula (3) washed with water, an alkaline aqueous solution, an acidic aqueous solution, or a saline solution, or a reaction mixture after dehydration with sodium sulfate, magnesium sulfate, or the like is subjected to pyrazolation in the next step as it is. Can be used for Moreover, you may use for the following process, after distilling a solvent off. Further, after purification by recrystallization, reprecipitation, solvent washing, distillation or the like, it may be used in the next step.

  The solvent used in performing recrystallization, reprecipitation, and solvent washing is not particularly limited as long as the compound represented by the general formula (3) is not decomposed.

  Specific examples of solvents used for recrystallization, reprecipitation, and solvent washing include water, halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene, and anisole, and diethyl ether. , Ether solvents such as diisopropyl ether, 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol, isopropyl alcohol, hydrocarbon solvents such as heptane, hexane, cyclohexane, ethyl acetate, isopropyl acetate, butyl acetate, etc. Examples thereof include ester solvents, nitrile solvents such as acetonitrile and propionitrile, and ketone solvents such as methyl isobutyl ketone. It can be used alone or in admixture of two or more at any ratio.

  The amount of the solvent used is not particularly limited as long as it is set according to the intended yield and purity. Usually, the weight is 1 to 40 times the weight of the compound represented by the general formula (3).

In this acylation reaction, R1 is hydrogen, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or R2 and R3 are bonded to each other. It can be preferably adapted to a compound group representing an atomic group necessary to form a 5- to 6-membered ring containing a nitrogen atom and 0 to 1 heteroatom. More preferably, Rf represents a trifluoromethyl group and a difluoromethyl group, R1 is hydrogen, and R2 and R3 can be preferably adapted to a group of compounds each representing a methyl group.
The method for producing the fluorine-containing pyrazole carbonitrile derivative represented by the general formula (4) includes a cyclization reaction in which the compound represented by the general formula (3) is reacted with hydrazine. This reaction can further include a post-treatment step and a purification step, if necessary, in addition to the production step.
Hereinafter, hydrazine will be described.

Hydrazine can use a commercial item.
Hydrazine may be either an anhydride or a hydrate, and the form is not limited.
Although the usage-amount of hydrazine will not be specifically limited if it is 1 equivalent or more with respect to the compound represented by General formula (3), It is 1 equivalent or more and 5 equivalent or less from an economical viewpoint.

Hereinafter, the general formula (4) will be described.
Rf in the general formula (4) has the same meaning as Rf in the general formula (1).
R1 in the general formula (4) has the same meaning as R1 in the general formula (2).
Hereinafter, this cyclization reaction will be described.

  The reaction between the compound represented by the general formula (3) and hydrazine can be carried out by charging the compound represented by the general formula (3) into hydrazine or by converting the hydrazine into a compound represented by the general formula (3). Any of the charging methods may be used. At this time, the general formula (3) or hydrazine can be used by dissolving or suspending in an appropriate solvent.

  A solvent can be used for this reaction. The solvent to be used is not particularly limited as long as the reaction proceeds. Specific examples of the solvent to be used include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, diethyl ether, diisopropyl ether, 1,2-dimethoxyethane and tetrahydrofuran. , Ether solvents such as dioxane, hydrocarbon solvents such as heptane, hexane and cyclohexane, ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N Amide solvents such as 1, N-dimethylacetamide, urea solvents such as 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone Sulfonyl oxides such as dimethyl sulfoxide Solvents include ketone solvents such as methyl isobutyl ketone, and water and the like. These solvents can be used alone or in admixture of two or more at any ratio.

The amount of the solvent used is not particularly limited, but usually it is preferably 3 to 40 times the weight of the compound represented by the general formula (3). Although there is no particular limitation as long as the reaction proceeds, it can usually be set to −40 ° C. or higher and 150 ° C. or lower, or below the boiling point of the solvent.

  The post-treatment of the reaction mixture containing the compound of the general formula (4) can be carried out without any particular limitation as long as the compound of the general formula (4) is not decomposed. A specific example of the post-processing method will be described below.

  Regarding a reaction mixture in which a two-layer solvent composed of an organic solvent incompatible with water and water is a reaction solvent, an organic layer containing a compound represented by the general formula (4) is obtained by liquid separation. Can do.

  Regarding a reaction mixture in which a homogeneous solvent composed of an organic solvent compatible with water and water is the reaction solvent, the organic solvent is distilled off under reduced pressure, and then the organic solvent separated from water is represented by the general formula (4). The compounds represented can be extracted.

  Regarding the reaction mixture in which the organic solvent incompatible with water is the reaction solvent, the solvent can be distilled off under reduced pressure as it is to obtain the compound represented by the general formula (4). Or you may implement the liquid separation operation mentioned later before solvent distillation.

  Regarding the reaction mixture in which the organic solvent compatible with water is the reaction solvent, the solvent can be distilled off under reduced pressure as it is to obtain the compound represented by the general formula (4). After distilling off the solvent, an organic solvent that separates from water and water may be added, and the following liquid separation operation may be performed.

  Regarding the reaction mixture in which water is the reaction solvent, the precipitate may be collected by filtration when the compound represented by the general formula (4) is precipitated. If the compound does not precipitate, it can be extracted by adding an organic solvent that separates from water.

  The organic layer containing the compound represented by the general formula (4) can be washed with water, an acidic aqueous solution, an alkaline aqueous solution, or a saline solution. The number of washings, washing order, etc. are not particularly limited as long as the compound is not decomposed.

  The acidic aqueous solution and alkaline aqueous solution used for washing are not particularly limited as long as the compound represented by the general formula (4) is not decomposed. Usually, acidic aqueous solutions, such as hydrochloric acid aqueous solution and sulfuric acid aqueous solution, and alkaline aqueous solutions, such as sodium hydrogen carbonate aqueous solution, sodium carbonate aqueous solution, sodium hydroxide aqueous solution, potassium hydrogen carbonate aqueous solution, potassium carbonate aqueous solution, potassium hydroxide aqueous solution, are illustrated.

  The organic layer containing the compound represented by the general formula (4) can be dehydrated with sodium sulfate, magnesium sulfate or the like.

  The organic layer containing the compound represented by the general formula (4) can be used as it is in the next alkylation step. It is also possible to alkylate the compound after distilling off the solvent under reduced pressure.

  In order to increase the purity of the compound represented by the general formula (4), distillation, recrystallization, reprecipitation, solvent washing and the like can be performed.

  The solvent used for recrystallization, reprecipitation, and solvent washing is not particularly limited as long as the compound represented by the general formula (4) is not decomposed.

  Specific examples of solvents used for recrystallization, reprecipitation, and solvent washing include halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene, and anisole, diethyl ether, and diisopropyl. Ether solvents such as ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohol solvents such as methanol, ethanol and isopropyl alcohol, hydrocarbon solvents such as heptane, hexane and cyclohexane, ethyl acetate, isopropyl acetate and butyl acetate Ester solvents such as acetonitrile, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl isobutyl ketone, and water. These solvents can be used alone or in admixture of two or more at any ratio.

  The amount of the solvent used may be set according to the target yield and purity, and is not particularly limited. Usually, the weight is 1 to 40 times the weight of the compound represented by the general formula (4).

As described above, in this pyrazole cyclization reaction, R1 is hydrogen, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or R2 and R3, Can be preferably adapted to a group of compounds representing an atomic group necessary to form a 5- to 6-membered ring containing a nitrogen atom to which is bonded and 0 to 1 heteroatoms. More preferably, Rf represents a trifluoromethyl group and a difluoromethyl group, R1 is hydrogen, and R2 and R3 can be preferably adapted to a group of compounds each representing a methyl group.
The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative represented by the general formula (5) includes an alkylation reaction in which the compound represented by the general formula (4) is reacted with an alkylating agent. This reaction can further include a post-treatment step and a purification step, if necessary, in addition to the production step.

Hereinafter, the alkylating agent will be described.
The alkylating agent is not particularly limited as long as it can alkylate the nitrogen atom at the 1-position in the pyrazole derivative represented by the general formula (4).

  Specific examples of the alkylating agent include dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dipropyl sulfate, diisopropyl sulfate, and dibutyl sulfate; methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, propyl chloride, odor Propyl iodide, Propyl iodide, Isopropyl chloride, Isopropyl bromide, Isopropyl iodide, Butyl chloride, Butyl bromide, Butyl iodide, Isobutyl chloride, Isobutyl bromide, Isobutyl iodide, sec-butyl chloride, sec-butyl bromide , Sec-butyl iodide, pentyl chloride, pentyl bromide, pentyl iodide, isopentyl chloride, isopentyl bromide, isopentyl iodide, 2-bromopentyl, 3-bromopentyl, 1-chloro-2-methylbutane, 1-iodo 2-methylbutane, 1-chloro-2,2-dimethyl Propane, 1-bromo-2,2-dimethylpropane, hexyl chloride, hexyl bromide, hexyl iodide, 2-chlorohexane, 2-bromohexane, 3-chlorohexane, 3-bromohexane, 1-bromo- Halogenated alkyl such as 4-methylpentane; Halogenated cycloalkyl such as cyclopropyl bromide, cyclobutyl chloride, cyclobutyl bromide, cyclopentyl chloride, cyclopentyl bromide, cyclohexyl chloride, cyclohexyl bromide, cyclohexyl iodide; benzyl chloride, odor Arylalkyl halides such as benzyl chloride, phenethyl chloride, phenethyl bromide, phenethyl iodide, 3-phenylpropyl chloride, 3-phenylpropyl bromide, 4-phenylbutyl chloride, 4-phenylbutyl bromide; dimethyl carbonate, diethyl carbonate, etc. of And dialkyl carbonate.

The amount of the alkylating agent used is not particularly limited as long as it is 1 equivalent or more with respect to the compound represented by the general formula (4), and can be used as a solvent.
Hereinafter, the compound represented by Formula (5) will be described.

Rf in the general formula (5) has the same meaning as Rf in the general formula (1).
R1 in the general formula (5) has the same meaning as R1 in the general formula (2).
The C1-C6 alkyl group in R4 in General formula (5) is synonymous with the C1-C6 alkyl group in Rf in General formula (1).

  The C3-C6 cycloalkyl group in R4 in General formula (5) is synonymous with the C3-C6 cycloalkyl group in R1 in General formula (2).

The arylalkyl group which may be substituted in R4 in the general formula (5) has the same meaning as the arylalkyl group which may be substituted in R1 in the general formula (2).
Hereinafter, this alkylation reaction will be described.
A base can be used for this reaction. The base is an organic base or an inorganic base, but is not particularly limited as long as the reaction proceeds.

  Specific examples of the organic base include metal alkoxides such as sodium methoxide and sodium ethoxide, secondary amines such as diisopropylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2. ], Tertiary amines such as octane and 1,8-diazabicyclo [5.4.0] -7-undecene, and aromatic amines such as pyridine, collidine, lutidine, and 4-dimethylaminopyridine.

  Specific examples of the inorganic base include sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.

These bases can be used alone, or two or more kinds can be mixed at an arbitrary ratio.
The amount of the base used is not particularly limited as long as the target reaction proceeds, but is usually 1 equivalent or more and 10 equivalents or less.

  In this reaction, a solvent can be used. The solvent to be used is not particularly limited as long as the reaction proceeds. Specific examples of the solvent to be used include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, diethyl ether, diisopropyl ether, 1,2-dimethoxyethane and tetrahydrofuran. , Ether solvents such as dioxane, hydrocarbon solvents such as heptane, hexane and cyclohexane, ester solvents such as ethyl acetate, isopropyl acetate and butyl acetate, N-methyl-2-pyrrolidone, N, N-dimethylformamide, N Amide solvents such as 1, N-dimethylacetamide, urea solvents such as 1,3-dimethyl-2-imidazolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone Sulfonyl oxides such as dimethyl sulfoxide Solvents include ketone solvents such as methyl isobutyl ketone. These solvents can be used alone or in admixture of two or more at any ratio.

The amount of the solvent used is not particularly limited, but usually it is preferably 3 to 40 times the weight of the compound represented by the general formula (4). Although there is no particular limitation as long as the reaction proceeds, it can usually be set to −40 ° C. or higher and 150 ° C. or lower, or below the boiling point of the solvent.

  For a reaction mixture in which an organic solvent incompatible with water is a reaction solvent, the solvent can be distilled off under reduced pressure as it is to obtain a compound represented by the general formula (5). Or you may implement the liquid separation operation mentioned later before solvent distillation.

  Regarding the reaction mixture in which the organic solvent compatible with water is the reaction solvent, the solvent can be distilled off under reduced pressure as it is to obtain the compound represented by the general formula (5). After distilling off the solvent, an organic solvent that separates from water and water may be added and a liquid separation operation described later may be performed.

  The organic layer containing the compound represented by the general formula (5) can be washed with water, an acidic aqueous solution, an alkaline aqueous solution, or a saline solution. The number of washings, washing order, etc. are not particularly limited as long as the compound is not decomposed.

  The acidic aqueous solution and alkaline aqueous solution used for washing are not particularly limited as long as the compound represented by the general formula (5) is not decomposed. Usually, acidic aqueous solutions, such as hydrochloric acid aqueous solution and sulfuric acid aqueous solution, and alkaline aqueous solutions, such as sodium hydrogen carbonate aqueous solution, sodium carbonate aqueous solution, sodium hydroxide aqueous solution, potassium hydrogen carbonate aqueous solution, potassium carbonate aqueous solution, potassium hydroxide aqueous solution, are illustrated.

  The organic layer containing the compound represented by the general formula (5) can be dehydrated with sodium sulfate, magnesium sulfate or the like.

  The organic layer containing the compound represented by the general formula (5) can be used as it is in the subsequent hydrolysis step. It is also possible to hydrolyze the compound after distilling off the solvent under reduced pressure.

In order to increase the purity of the compound represented by the general formula (5), distillation, recrystallization, reprecipitation, solvent washing and the like can be performed.
The solvent used for recrystallization, reprecipitation, and solvent washing is not particularly limited as long as the compound represented by the general formula (5) is not decomposed.

  Specific examples of solvents used for recrystallization, reprecipitation, and solvent washing include halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene, and anisole, diethyl ether, and diisopropyl. Ether solvents such as ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohol solvents such as methanol, ethanol and isopropyl alcohol, hydrocarbon solvents such as heptane, hexane and cyclohexane, ethyl acetate, isopropyl acetate and butyl acetate Ester solvents such as acetonitrile, nitrile solvents such as acetonitrile and propionitrile, ketone solvents such as methyl isobutyl ketone, and water. These solvents can be used alone or in admixture of two or more at any ratio.

  The amount of the solvent used may be set according to the target yield and purity, and is not particularly limited. Usually, the weight is 1 to 40 times the weight of the compound represented by the general formula (5).

This alkylation reaction can be preferably applied to a group of compounds in which R1 is hydrogen and those in which the alkylating agent is a dialkylsulfuric acid and a dialkyl carbonate. More preferably, it can be preferably applied to a group of compounds in which Rf is a trifluoromethyl group and a difluoromethyl group, R1 is hydrogen, and those in which the alkylating agent is dimethyl sulfate, diethyl sulfate, dimethyl carbonate, or diethyl carbonate.
The method for producing the fluorine-containing pyrazole carboxylic acid derivative represented by the general formula (6) includes a hydrolysis reaction in which the compound represented by the general formula (5) is reacted with water. This reaction can further include a post-treatment step and a purification step, if necessary, in addition to the production step.
Hereinafter, the compound represented by the general formula (6) will be described.

Rf in the general formula (6) has the same meaning as Rf in the general formula (1).
R1 in the general formula (6) has the same meaning as R1 in the general formula (2).
R4 in the general formula (6) has the same meaning as R4 in the general formula (5).
Hereinafter, this hydrolysis reaction will be described.

In order to advance the hydrolysis reaction, it is preferable to use an acid or a base.
First, a hydrolysis reaction in which a compound represented by the general formula (5) is reacted with water under acidic conditions to convert it into a compound represented by the general formula (6) will be described.

  If the usage-amount of water is 2 equivalent or more with respect to the compound represented by General formula (5), it will not specifically limit. Water can also be used as a solvent. The amount used as a solvent is not particularly limited as long as the number of equivalents is satisfied. Usually, the upper limit can be 40 times or less with respect to the compound represented by General formula (5).

The acid to be used is not particularly limited as long as the reaction proceeds, and is an organic acid or an inorganic acid.
Specific examples of the organic acid include sulfonic acids such as methanesulfonic acid and toluenesulfonic acid, and carboxylic acids such as trichloroacetic acid and trifluoroacetic acid.
Specific examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid and the like.

  The amount of acid used is not particularly limited as long as the target reaction proceeds. Usually, it should just be 0.1 equivalent or more with respect to the compound represented by General formula (5).

  In the present invention, a solvent can be used. Examples of the solvent to be used include carboxylic acid solvents such as acetic acid, alcohol solvents such as methanol, ethanol, propanol, isopropyl alcohol and butanol, ether solvents such as tetrahydrofuran and dioxane, and water. These solvents can be used alone, but two or more kinds can be mixed at an arbitrary ratio.

  Although the usage-amount of a solvent is not specifically limited, The weight of 3 times or more and 40 times or less is preferable normally with respect to the weight of the compound represented by General formula (5).

  The reaction temperature is not particularly limited as long as the intended reaction proceeds, but it can usually be 0 ° C. or higher and 150 ° C. or lower or the boiling point of the solvent or lower.

  Regarding the post-treatment method of the reaction mixture containing the compound represented by the general formula (6) obtained under acidic conditions, there is a particular limitation as long as the compound represented by the general formula (6) as the target product is not decomposed. Not provided. Hereinafter, a specific example of the post-processing method will be described.

  When the compound represented by the general formula (6) is precipitated from the reaction mixture or the reaction mixture obtained by distilling off the solvent, the precipitate may be collected by filtration.

  Separation can be performed on the reaction mixture or the reaction mixture obtained by distilling off the solvent. At that time, if necessary, water or an organic solvent can be added. The water used for liquid separation may contain a salt such as sodium chloride. Further, the number of times of liquid separation is not particularly limited.

  The organic solvent used for liquid separation is not particularly limited as long as the compound represented by the general formula (6) is not decomposed.

  Specific examples of organic solvents include halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene and anisole, ether solvents such as diethyl ether and diisopropyl ether, heptane and hexane. And hydrocarbon solvents such as cyclohexane, and ester solvents such as ethyl acetate, isopropyl acetate, and butyl acetate. These solvents can be used alone or in admixture of two or more at any ratio.

The amount of the organic solvent used is not particularly limited, but usually a weight of 1 to 40 times the weight of the compound represented by the general formula (6) is preferable. The organic layer containing the compound represented by (6) can be dehydrated with sodium sulfate, magnesium sulfate or the like.

  The organic layer containing the compound represented by the general formula (6) obtained by liquid separation or the organic layer after dehydration with sodium sulfate, magnesium sulfate, or the like is obtained by distilling off the solvent under reduced pressure. Can do. Depending on the required purity, the obtained compound can be purified by recrystallization, reprecipitation, solvent washing, distillation or the like.

The solvent used when performing recrystallization, reprecipitation, and solvent washing is not particularly limited as long as the compound represented by the general formula (6) is not decomposed.
Specific examples of solvents used for recrystallization, reprecipitation, and solvent washing include halogen solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene, and anisole, diethyl ether, and diisopropyl. Ether solvents such as ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohol solvents such as methanol, ethanol and isopropyl alcohol, hydrocarbon solvents such as heptane, hexane and cyclohexane, ethyl acetate, isopropyl acetate and butyl acetate And ester solvents such as acetonitrile, nitrile solvents such as acetonitrile and propionitrile, and water. These solvents can be used alone or in admixture of two or more at any ratio.

The amount of the solvent used may be set according to the target yield and purity, and is not particularly limited. Usually, the weight is 1 to 40 times the weight of the compound represented by the general formula (6).

Next, the hydrolysis reaction in which the compound represented by the general formula (5) is reacted with water under basic conditions to convert it into the compound represented by the general formula (6) will be described.

  If the usage-amount of water is 2 equivalent or more with respect to the compound represented by General formula (5), it will not specifically limit. At this time, water can also be used as a solvent. The amount used as a solvent is not particularly limited as long as the number of equivalents is satisfied. Usually, the upper limit is 40 times or less the weight of the compound represented by the general formula (5).

  The base to be used is not particularly limited as long as the reaction proceeds, and is an organic base or an inorganic base.

  Specific examples of the organic base include metal alkoxides such as sodium methoxide and sodium ethoxide, secondary amines such as diisopropylamine, triethylamine, tributylamine, trioctylamine, diisopropylethylamine, 1,4-diazabicyclo [2.2.2. ], Tertiary amines such as octane and 1,8-diazabicyclo [5.4.0] -7-undecene, and aromatic amines such as pyridine, collidine, lutidine, and 4-dimethylaminopyridine.

  Specific examples of the inorganic base include lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate and the like.

  These bases can be used alone, or two or more kinds can be mixed at an arbitrary ratio.

  The amount of the base used is not particularly limited as long as the target reaction proceeds. Usually, it is 0.1 equivalent or more and 20 equivalent or less with respect to the compound represented by General formula (5).

  A solvent can be used for the reaction. Examples of the solvent to be used include alcohol solvents such as methanol, ethanol, propanol, isopropyl alcohol and butanol, ether solvents such as tetrahydrofuran and dioxane, and water. These solvents can be used alone, but two or more kinds can be mixed at an arbitrary ratio.

  The amount of solvent used is not particularly limited. Usually, a weight of 3 to 40 times the weight of the compound represented by the general formula (5) is preferable.

  The reaction temperature is not particularly limited as long as the intended reaction proceeds, but it can usually be 0 ° C. or higher and 150 ° C. or lower or the boiling point of the solvent or lower.

  The method of post-treating the reaction mixture containing the compound represented by the general formula (6) obtained under basic conditions is not particularly limited as long as the compound represented by the general formula (6) as the target product is not decomposed. It will not be done. Hereinafter, a specific example of the post-processing method will be described.

  The compound represented by the general formula (6) obtained by reacting the compound represented by the general formula (5) with water under basic conditions exists in a salt state in the reaction mixture. When the salt precipitates in the reaction mixture, the precipitate may be collected by filtration. On the other hand, when the salt does not precipitate, it is possible to remove impurities by adding an organic solvent separable from water and separating the solution. Prior to the liquid separation operation, the solvent can be distilled off under reduced pressure, or water or an organic solvent can be added.

  It is represented by the general formula (6) by adding an acid to the salt obtained by filtration, the salt contained in the separation-purified reaction mixture, or the salt contained in the untreated reaction mixture. Can be converted to compounds.

  Examples of the acid to be added include organic acids such as methanesulfonic acid and sulfonic acid, and inorganic acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid.

  The amount of the acid used is not particularly limited as long as it is 1 equivalent to the total number of moles of the base used in the reaction and the generated ammonia.

  Regarding the method for taking out the compound represented by the general formula (6) prepared by acid addition, when the compound is precipitated from the reaction mixture, the precipitate may be collected by filtration. Moreover, this compound can also be extracted with an organic solvent irrespective of precipitation. The compound is obtained by distilling off the solvent of the extracted organic layer under reduced pressure. Before depressurizing distillation, dehydration can be performed with sodium sulfate, magnesium sulfate or the like. The compound thus obtained can be purified by recrystallization, reprecipitation, solvent washing, distillation or the like according to the required purity.

  The solvent used when performing recrystallization, reprecipitation, and solvent washing is not particularly limited as long as the compound represented by the general formula (6) is not decomposed.

  Specific examples of solvents used for recrystallization, reprecipitation, and solvent washing include water, halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane, aromatic solvents such as benzene, toluene, xylene, and anisole, and diethyl ether. , Ether solvents such as diisopropyl ether, 1,2-dimethoxyethane, tetrahydrofuran and dioxane, alcohol solvents such as methanol, ethanol and isopropyl alcohol, hydrocarbon solvents such as heptane, hexane and cyclohexane, ethyl acetate, isopropyl acetate, Examples thereof include ester solvents such as butyl acetate, and nitrile solvents such as acetonitrile and propionitrile. These solvents can be used alone or in admixture of two or more at any ratio.

  The amount of the solvent used may be set according to the target yield and purity, and is not particularly limited. Usually, the weight is 1 to 40 times the weight of the compound represented by the general formula (6).

  This hydrolysis reaction can be preferably adapted to a group of compounds in which R1 represents hydrogen. More preferably, Rf is a trifluoromethyl group or a difluoromethyl group, R1 is hydrogen, and R4 is preferably compatible with a group of compounds having 1 to 6 carbon atoms.

By the methods described above, it has become possible to provide a method for producing a fluorinated pyrazole carbonitrile derivative and a method for producing a fluorinated pyrazole carboxylic acid derivative using the fluorinated pyrazole carbonitrile derivative.

  The present invention will be illustrated in more detail by the following examples, but the present invention is not limited thereto.

Hereinafter, 3-dimethylamino-acrylonitrile is compound (I), 3- (dimethylamino) -2-trifluoroacetylacrylonitrile is compound (II), 3-trifluoromethyl-1H-pyrazole-4-carbonitrile is compound ( III), 1-methyl-3-trifluoromethyl-1H-pyrazole-4-carbonitrile as compound (IV), 1-methyl-3- (trifluoromethyl) -1H-pyrazole-4-carboxylic acid as compound ( V) High performance liquid chromatography is referred to as HPLC.
Example 1 Synthesis of Compound (II) with Trifluoroacetic Acid and Phosgene

Under a nitrogen atmosphere, 5.24 g of trifluoroacetic acid was added dropwise to 80 ml of toluene containing 4.65 g of 95% by weight of Compound (I) and 9.30 g of triethylamine under ice cooling. Next, 40 ml of toluene containing 5.00 g of phosgene was added dropwise. After completion of dropping, the temperature was raised to room temperature and stirred for 2 hours. Nitrogen was bubbled through the reaction solution for 1 hour, and then the reaction yield was observed by HPLC. Compound (II) was quantitatively produced. Next, 120 ml of water was added for liquid separation, and the organic layer was washed with 120 ml of saturated aqueous sodium hydrogen carbonate and dried over sodium sulfate. After removing sodium sulfate, the solvent was distilled off under reduced pressure, and isopropyl ether was added to the residue and stirred. The precipitate was collected by filtration, and the resulting light brown solid was 7.32 g (yield 83%) of compound (II).
Substance data of compound (II)
¹ H NMR (CDCl ₃ ) δ 3.38 (1H, s), 3.58 (1H, s), 7.96 (1H, s).
¹³ C NMR (CDCl ₃ ) δ 39.45, 48.89, 75.08, 116.03, 116.69 (q, J = 290.4 Hz), 159.61, 176.25 (q, J = 34. 3 Hz).
IR (cm ^<-1 >) 1140, 1186, 1624, 2210.
Melting point 68.4-69.3 ° C

[Example 2] Synthesis of compound (III)

Under ice cooling, 60 ml of ethanol containing 5.0 g of the compound (II) obtained in the same manner as in Example 1 was added dropwise to 20 ml of ethanol containing 1.60 g of 98% by weight hydrazine monohydrate. After stirring at room temperature for 5 hours, concentration was performed under reduced pressure. Ethyl acetate and water were added to the residue for liquid separation, and magnesium sulfate was added to the separated organic layer. The desiccant was filtered off and concentrated under reduced pressure. Hexane and diisopropyl ether were added to the residue and stirred, and the precipitate was collected by filtration. The pale yellow solid obtained was 3.59 g of the title compound (III).

Substance data of compound (III)
¹ H NMR (DMSO-d ₆ ) δ 8.90 (1H, s).
¹³ C NMR (CDCl ₃ ) δ 89.13, 111.50, 120.31 (q, J = 269.6 Hz), 138.40, 142.2 (q, J = 38.0 Hz).

Example 3 Synthesis of Compound (IV) 1

1.88 g of dimethyl sulfate was added dropwise to 20 ml of DMF containing 2.0 g of compound (III) and 2.06 g of potassium carbonate, followed by stirring at 80 ° C. for 2 hours. After cooling to room temperature and observing the reaction mixture by HPLC, compound (IV) was produced in a yield of 79%. Then, the precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure, and then water and ethyl acetate were added to the residue for liquid separation. The separated organic layer was further washed with water and then dried by adding magnesium sulfate. The desiccant was removed and dried under reduced pressure to give 1.90 g of the title compound (IV) as a yellow oil with a purity of 85.9%. Yield 75%.

Material data (IV)
¹ H NMR (CDCl ₃ ) δ 4.03 (3H, s), 7.91 (1H, s).

Example 4 Synthesis of Compound (V)

1.87 g of compound (IV) obtained in Example 3 (1.61 g in terms of purity) was added to 15 ml of water containing 2.36 g of sodium hydroxide, and the mixture was stirred at an ambient temperature of 100 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was acidified with concentrated hydrochloric acid. The precipitate was filtered to obtain 1.73 g of the title compound (V) as a pale yellow solid. Yield 97%.

[Example 5] Synthesis of Compound (IV) 2
5 ml of dimethyl carbonate containing 0.5 g of compound (III) and 0.51 g of potassium carbonate was reacted at 90 ° C. for 7.5 hours. After cooling to room temperature, the reaction mixture was observed by HPLC. Compound (IV) was produced in a yield of 76%.

Example 6 Synthesis of Compound (IV) 3
5 ml of DMF containing 0.5 g of compound (III) and 0.27 g of lithium carbonate was added and stirred at 80 ° C. for 30 minutes. After cooling to room temperature, 352 μl of dimethyl sulfuric acid was added dropwise and reacted at 80 ° C. for 3 hours. After cooling to room temperature, the reaction mixture was observed by HPLC. Compound (IV) was formed at 65%.

Example 7 Synthesis of Compound (IV) 4
The reaction was carried out in the same manner as in Example 6 except that lithium carbonate was changed to sodium carbonate. When the reaction mixture was observed by HPLC, compound (IV) was produced at 83%.

Example 8 Synthesis of Compound (IV) 4
The reaction was carried out in the same manner as in Example 6 except that lithium carbonate was changed to cesium carbonate. When the reaction mixture was observed by HPLC, compound (IV) was produced at 80%.

  According to the present invention, it has become possible to produce a fluorinated pyrazole carbonitrile derivative and a fluorinated pyrazole carboxylic acid derivative using the fluorinated pyrazole carbonitrile derivative. This method is suitable as an industrial production method because it does not use a reagent that causes problems in mass production and is easy to operate. In addition, a fluorinated pyrazole carboxylic acid derivative that can be derived from a fluorinated pyrazole carbonitrile derivative can be an important raw material for agricultural and horticultural fungicides. From the above, in the fields of medicine and agricultural chemicals, the usefulness of the present invention is very high and the industrial applicability is high.

Claims (15)

General formula (1)

(1)
Wherein Rf represents an alkyl group having 1 to 6 carbon atoms substituted with at least one fluorine atom, and X represents a halogen atom, a hydroxyl group, or a carbonyloxy group; Formula (2)

(2)
(Wherein R1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group which may be substituted, or an arylalkyl group which may be substituted; Each R3 is independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, an aryl group that may be substituted, an arylalkyl group that may be substituted, or 1 carbon atom. -6 represents an optionally substituted acyl group, or an atomic group necessary to form a 5- to 6-membered ring containing 0 to 1 heteroatom and a nitrogen atom to which R2 and R3 are bonded. Obtained by reacting a compound represented by the general formula (3)

(3)
(Wherein Rf, R1, R2 and R3 have the same meanings as described above) and a step of reacting hydrazine with the compound represented by the general formula (4)

(4)
(Wherein Rf and R1 have the same meanings as described above), and a method for producing a fluorine-containing pyrazole carbonitrile derivative.   R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom and a hetero atom to which R2 and R3 are bonded. The manufacturing method of the fluorine-containing pyrazole carbonitrile derivative | guide_body of Claim 1 showing the atomic group required in order to form the 5-6 membered ring containing 0-1 piece.   The method for producing a fluorinated pyrazole carbonitrile derivative according to claim 2, wherein Rf represents a trifluoromethyl group, and R2 and R3 both represent a methyl group. The method further comprises a step of reacting the compound represented by the general formula (4) obtained in claim 1 with an alkylating agent.

(5)
Wherein Rf and R1 are as defined in claim 1, and R4 is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or an arylalkyl group which may be substituted. The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative represented by:   R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom and a hetero atom 0 to which R2 and R3 are bonded. The manufacturing method of the alkyl substituted fluorine-containing pyrazole carbonitrile derivative | guide_body of Claim 4 showing the atomic group required in order to form the 5-6 membered ring containing -1.   The method for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative according to claim 5, wherein Rf represents a trifluoromethyl group, R2 and R3 both represent a methyl group, and R4 represents an alkyl group having 1 to 6 carbon atoms. The method further comprises a step of reacting the compound represented by the general formula (5) obtained in claim 4 with water.

(6)
(Wherein, Rf, R1, and R4 have the same meanings as described in claim 4).   R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom and a hetero atom 0 to which R2 and R3 are bonded. The manufacturing method of the fluorine-containing pyrazole carboxylic acid derivative of Claim 7 showing the atomic group required in order to form the 5-6 membered ring containing -1.   The method for producing a fluorinated pyrazole carboxylic acid derivative according to claim 8, wherein Rf represents a trifluoromethyl group, R2 and R3 both represent a methyl group, and R4 represents an alkyl group having 1 to 6 carbon atoms. General formula (3)

(3)
(In the formula, Rf represents a C1-C6 alkyl group substituted with at least one fluorine atom, and R1 represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl. Group, an aryl group which may be substituted, or an arylalkyl group which may be substituted, R2 and R3 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a cyclohexane having 3 to 6 carbon atoms. An alkyl group, an optionally substituted aryl group, an optionally substituted arylalkyl group, an optionally substituted acyl group having 1 to 6 carbon atoms, or a nitrogen atom and a hetero atom 0 to which R2 and R3 are bonded; Which represents a group of atoms necessary to form a 5- to 6-membered ring containing 1 to 5), and a step of reacting hydrazine with the compound represented by the general formula (4)

(4)
(Wherein Rf and R1 have the same meanings as described above), and a method for producing a fluorine-containing pyrazole carbonitrile derivative.   R1 is a hydrogen atom, and R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a nitrogen atom and a hetero atom 0 to which R2 and R3 are bonded. The manufacturing method of the fluorine-containing pyrazole carbonitrile derivative | guide_body of Claim 10 showing the atomic group required in order to form the 5-6 membered ring containing -1.   The method for producing a fluorinated pyrazole carbonitrile derivative according to claim 11, wherein Rf represents a trifluoromethyl group, and R2 and R3 both represent a methyl group. General formula (4)

(4)
(In the formula, Rf represents a C1-C6 alkyl group substituted with at least one fluorine atom, and R1 represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl. Group, an aryl group that may be substituted, or an arylalkyl group that may be substituted) and a step of reacting a compound represented by general formula (5)

(5)
(Wherein Rf and R1 are as defined above, and R4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, and an arylalkyl group which may be substituted). A process for producing an alkyl-substituted fluorine-containing pyrazole carbonitrile derivative.   The method for producing an alkyl-substituted fluorinated pyrazole carbonitrile derivative according to claim 13, wherein R1 is a hydrogen atom.   The method for producing an alkyl-substituted fluorinated pyrazole carbonitrile derivative according to claim 14, wherein Rf represents a trifluoromethyl group.