JP2007326784A - Method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester useful as a synthetic intermediate of a medicine, an agrochemical and a functional material simply by a safe operation in a high yield and highly selectively. <P>SOLUTION: This method for producing the 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester expressed by general formula (4) [wherein, R<SP>1</SP>is H or a halogen atom; R<SP>2</SP>is H, a 1-12C alkyl which may be substituted by a chlorine atom or fluorine atom; R<SP>3</SP>is a 1-6C alkyl; and R<SP>4</SP>is a 1-6C alkyl which may be substituted or phenyl which may be substituted] is provided by reacting 2-hydroxymethylenefluoroacyl acetic acid ester with an alkali metal base in an aqueous solvent or a mixed solvent of water with an organic solvent to make 2-(alkali metal oxymethylene)fluoroacyl acetic acid ester and then reacting with hydrazines. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester represented by the following general formula (4), which is useful as a synthetic intermediate for medicines and agricultural chemicals and functional materials.

(Wherein R ¹ represents a hydrogen atom or a halogen atom, R ² represents a hydrogen atom, a fluorine atom, a chlorine atom or an alkyl group having 1 to 12 carbon atoms which may be substituted with a fluorine atom. R ³ represents (C 1-6 represents an alkyl group, and R ⁴ represents an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group.)

  In general, in the reaction between 2-alkoxymethylene acylacetate and substituted hydrazines, the reaction selectivity is inferior due to the presence of a plurality of reaction sites on each reaction substrate, and 1,3-disubstituted pyrazole- It is known that 4-carboxylic acid esters and 1,5-disubstituted pyrazole-4-carboxylic acid esters are produced together. Therefore, in order to obtain the target pyrazole derivative, a purification step such as silica gel column chromatography, which is difficult to implement industrially, is usually required. JP 2000-128763 A (Patent Document 1) discloses 1,3- and 1,5-disubstituted pyrazole-4-carboxylic acid esters obtained as a mixture by hydrolysis, Although it is described that 3-disubstituted pyrazole-4-carboxylic acid is obtained, it is necessary to crystallize under strict pH control in order to obtain a high-purity target product, which is complicated industrially. It requires operation. Furthermore, Patent Document 1 does not describe a method for obtaining a 1,5-disubstituted pyrazole-4-carboxylic acid ester or a carboxylic acid thereof according to the present invention.

JP-A-1-113371 (Patent Document 2) describes a process for producing 1,3-disubstituted pyrazole-4-carboxylic acid esters by reacting 2-ethoxymethyleneacyl acetates with substituted hydrazines. However, there is no detailed description of the yield and selectivity of 1-substituted-5-trifluoromethylpyrazole-4-carboxylic acid ester according to the present invention.
The present inventors conducted a reaction between ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate and methyl hydrazine using the method described in Patent Document 2, and found that 1-methyl-3-trimethyl The production ratio of ethyl fluoromethylpyrazole-4-carboxylate and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate according to the present invention is 76:24, and this production method is a method with good selectivity. It is hard to say (see Comparative Example 2 below).

  In Example 1 of JP-A-6-199803 (Patent Document 3), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate and methylhydrazine are reacted in ethanol at a predetermined temperature. A process for producing ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate according to the present invention, It is specified that the production ratio of ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate according to the invention is 15%. Furthermore, the method described in this publication needs to prepare the reaction at a low temperature of −40 to −35 ° C., and is not economical economically.

  JP 2000-212166 (Patent Document 4) discloses 1-substituted-3-trifluoromethylpyrazole using 2-ethoxymethylene-4,4,4-trifluoroacetoacetate and substituted hydrazine. A process for the preparation of 4-carboxylic acid esters is described. According to this method (Examples 2 to 4), it is described that 1-substituted-3-trifluoromethylpyrazole-4-carboxylic acid ester is obtained in a yield of about 85%. On the other hand, although there is no description regarding the formation of 1-substituted-5-trifluoromethylpyrazole-4-carboxylic acid ester according to the present invention, 2-ethoxymethylene acylacetates and alkylhydrazines are not included in the specification. When reacted at 10 ° C. in an ester, 1,3-dialkylpyrazole-4-carboxylic acid esters (yield 80-85%) and 1,5-dialkylpyrazole-4-carboxylic acid esters according to the present invention It is specified that a mixture with (yield 10-15%) is obtained. In the method described in this publication, usable solvents are limited, and it is essential to perform the reaction in an ester solvent (for example, ethyl acetate or dimethyl carbonate). Furthermore, it is necessary to carry out the reaction at a low temperature of 5 to 10 ° C. at the start of the reaction and thereafter at the solvent reflux temperature, which is not necessarily an industrially advantageous production method.

  Furthermore, in the production methods described in JP-A-1-113371 (Patent Document 2), JP-A-6-1998803 (Patent Document 3) and JP-A 2000-212166 (Patent Document 4), Although anhydrous hydrazines are used as a raw material, as is well known, anhydrous hydrazines are highly explosive and are extremely dangerous when used in large quantities on an industrial scale. Therefore, if the target 1,5-disubstituted pyrazole-4-carboxylic acid ester can be produced with high yield and high selectivity using hydrazine hydrates having low explosive properties or an aqueous hydrazine solution, Although it is considered that it can be an extremely excellent method as an industrial production method, in any of the above Patent Documents 2 to 4, when water coexists in the reaction system, 1,5-disubstituted pyrazole-4-carboxylic acid There is no mention of the effect of water on the yield and selectivity of the ester. However, as a result of actually carrying out this reaction in the presence of water, it became clear that the selectivity was greatly reduced. By simply carrying out the reaction in the presence of water, the desired 1,5- It has been found that disubstituted pyrazole-4-carboxylic acid esters cannot be obtained. (See Comparative Examples 1, 3, 4, and 5 below)

  In JP-T-2003-518110 (Example 30) (Patent Document 5), 2-hydroxymethylene trifluoroacetoacetic acid ethyl and 4-nitrophenylhydrazine are reacted in a 50% ethanol solution of pyridine. Although it is described that ethyl (4-nitrophenyl) -5-trifluoromethylpyrazole-4-carboxylate is obtained, there is no description of detailed experiments, and 1- (4-nitrophenyl) which is an isomer. No mention is made of the production ratio with ethyl -3-trifluoromethylpyrazole-4-carboxylate.

The present inventors filed as Japanese Patent Application No. 2005-052004 and Japanese Patent Application No. 2005-052006 regarding a method for selectively obtaining 1-substituted-3-fluoroalkylpyrazole-4-carboxylic acid ester, and priority is given to these. I have filed a PCT application (PCT / JP2006 / 303269).
JP 2000-128763 A JP-A-1-113371 Japanese Patent Laid-Open No. 6-199803 (DE4231517A1) JP 2000-212166 A Special table 2003-518110 gazette

  The present invention provides a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester useful as an intermediate for pharmaceutical agriculture or functional materials by reacting 2-hydroxymethylenefluoroacyl acetate with hydrazines. The present invention provides a new method which can be produced with high yield and high selectivity by a safe and safe operation.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that in the above reaction, the 2-hydroxymethylenefluoroacylacetic acid ester represented by the general formula (1) is in an aqueous solvent or a mixed solvent of water and an organic solvent. And then, by reacting with an alkali metal base and then reacting with hydrazines, it was found that the desired 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester can be produced selectively and in high yield, The present invention has been completed.

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

(Wherein R ¹ , R ² and R ³ represent the same meaning as described above), an alkali metal base in an aqueous solvent or a mixed solvent of water and an organic solvent. With general formula (2)

(In general formula (2), R ¹ , R ² and R ³ represent the same meaning as described above. M represents an alkali metal.) 2- (alkali metal oxymethylene) fluoroacyl acetate ester, General formula (3)

(In General Formula (3), R ⁴ represents an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group), and is reacted with hydrazines represented by The general formula (4)

(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above), and relates to a method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester.

Here, R ² in the above general formula is preferably a linear alkyl group having 1 to 4 carbon atoms.
The alkali metal base is preferably sodium hydroxide or potassium hydroxide.
Furthermore, the amount of the alkali metal base used is preferably 0.01 equivalents or more with respect to the 2-hydroxymethylenefluoroacyl acetate represented by the general formula (1) as the reaction substrate.
Furthermore, the organic solvent is preferably at least one selected from the group consisting of aromatic hydrocarbon solvents, aliphatic hydrocarbon solvents, alcohol solvents, ester solvents and halogen solvents.
Furthermore, it is preferable that reaction temperature is -30-60 degreeC.
Further, 2- (alkali metal oxymethylene) fluoroacyl acetate represented by the general formula (2) is represented by the general formula (5).

(Wherein R ¹ , R ² and R ³ represent the same meaning as described above), and obtained by reacting 2-alkoxymethylenefluoroacylacetic acid ester with an alkali metal base in an aqueous solution. Is preferred.

  According to the method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester of the present invention, the conventional problems can be overcome and high-yield and high-selectivity can be achieved with a simple and safe operation. Can be manufactured. The 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester that can be produced by the production method of the present invention is particularly useful as an intermediate for medical and agricultural chemicals or functional materials, and the present invention is an industrially very useful production method. Is to provide.

The production method of the present invention will be described in detail below.
A part of 2-hydroxymethylenefluoroacylacetic acid ester (general formula (1)) used as a raw material in the production method of the present invention is a known compound (Japanese Patent Laid-Open No. 11-119373, Japanese Patent Publication No. 2003-518110). It can be easily produced by ordinary organic synthesis techniques. For example, it can also be produced by hydrolyzing the alkoxy group of 2-alkoxymethylenefluoroacylacetic acid ester (general formula (5)) in an alkaline aqueous solution, but can also be produced by a hydrolysis reaction using copper acetate. can do. (See Synthesis Example 1 below)

Here, in the present invention, examples of substituents represented by R ¹ , R ² , R ³ and R ⁴ in the general formulas (1) to (5) are shown below.

Examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom or a bromine atom.

Examples of the alkyl group having 1 to 12 carbon atoms which may be substituted with a chlorine atom or a fluorine atom represented by R ² include a trifluoromethyl group, a difluoromethyl group, a chlorodifluoromethyl group, a pentafluoroethyl group, and perfluoropropyl. Group, perfluoropentyl group, 1,1,2,2,3,3,4,4,5,5-decafluoropentyl group, perfluorohexyl group, perfluorononyl group, perfluorodecyl group, perfluorododecyl group, etc. be able to.
Among these, R ² is preferably a linear alkyl group having 1 to 4 carbon atoms such as a trifluoromethyl group, a difluoromethyl group, a chlorodifluoromethyl group, a pentafluoroethyl group, or a perfluoropropyl group.

Examples of the alkyl group having 1 to 6 carbon atoms represented by R ³ in the general formula (1) include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, and a tert-butyl group. , A pentyl group, a hexyl group, and the like.

Examples of the optionally substituted alkyl group represented by R ⁴ in the hydrazines represented by the general formula (3) include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropylmethyl group. Butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group and the like. Further, one or more of these alkyl groups may be substituted with a halogen atom or the like, specifically, 2-chloroethyl group, 2-bromoethyl group, 2-hydroxyethyl group, 2,2,2-trifluoroethyl. Group, 3-chloropropyl group and the like.
Examples of the optionally substituted phenyl group represented by R ⁴ include a halogen atom, a lower alkyl group, a lower alkyloxy group, a lower haloalkyl group, a lower haloalkyloxy group, a lower alkyloxycarbonyl group, a cyano group on the benzene ring. Examples thereof include a phenyl group which may be substituted with a group, a nitro group, a substituted sulfonyl group and the like.

  Some of the hydrazines that are raw materials in this production method are readily available, and can be easily produced by existing methods. In addition, these hydrazines can be used in the form of salts such as hydrochlorides and sulfates, anhydrides, hydrates or aqueous solutions.

In the production method of the present invention, the reaction is preferably carried out at a relatively low temperature in the presence of an alkali metal base and water in view of good yield and selectivity.
As the alkali metal base, lithium hydroxide, sodium hydroxide, potassium hydroxide or the like can be used. Among them, sodium hydroxide or potassium hydroxide is preferable because the yield and selectivity of the target product are good and inexpensive.

  The alkali metal base is not particularly limited in the amount used or the concentration of the aqueous solution, and 0.01 equivalents or more, preferably 0.05 equivalents or more based on the 2-alkoxymethylenefluoroacylacetic acid ester as a reaction substrate. The target product can be obtained with good yield and selectivity.

  Moreover, M in the said General formula (2) shows an alkali metal, and lithium, sodium, and potassium are mentioned.

  The amount of water used is not particularly limited, but since this reaction is carried out in an aqueous alkali metal base solution, depending on the reaction conditions, hydrolysis reaction of the raw material and the ester site of the product occurs. Therefore, it is preferable to carry out the reaction by controlling the amount of water added. The amount of water used is that the polymerization ratio of 2-alkoxymethylenefluoroacyl acetate (1) and water is 1 / 0.25 to 1/100, preferably 1/1 to 1/50. It is preferable in terms of good rate and selectivity.

  Moreover, in the manufacturing method of this invention, reaction can also be implemented in coexistence of an organic solvent. Examples of the organic solvent include aromatic hydrocarbon solvents such as benzene, toluene, xylene, chlorobenzene and dichlorobenzene, aliphatic hydrocarbon solvents such as pentane, hexane and octane, dichloromethane, chloroform, carbon tetrachloride, 1,2- Halogen solvents such as dichloroethane, ester solvents such as ethyl acetate, butyl acetate, dimethyl carbonate, alcohol solvents such as methanol, ethanol, propyl alcohol, isopropyl alcohol, butyl alcohol, tert-butyl alcohol, diethyl ether, diisopropyl ether, Examples thereof include ether solvents such as cyclopentyl methyl ether, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, preferably aromatic hydrocarbon solvents, fats Hydrocarbon solvents, alcohol solvents, halogen-based solvents or ester solvents. There is no restriction | limiting in particular in the usage-amount of an organic solvent.

  Moreover, since this manufacturing method reacts in alkali metal base aqueous solution, the hydrolysis reaction of the ester site | part of a raw material or a product occurs depending on reaction conditions. In particular, when the reaction temperature is high, ester hydrolysis is likely to occur. Therefore, the reaction is carried out at a reaction temperature appropriately selected from −30 to 60 ° C., preferably from −20 to 50 ° C., thereby improving the yield and selectivity. The object can be obtained. However, in the reaction in an aqueous solvent, it is preferable to carry out the reaction at a temperature at which water does not solidify.

  In the present invention, the 2- (alkali metal oxymethylene) fluoroacyl acetate represented by the general formula (2) is represented by the general formula (5).

(Wherein R ¹ , R ² and R ³ represent the same meaning as described above) and obtained by reacting 2-alkoxymethylenefluoroacylacetic acid ester with an alkali metal base in an aqueous solution. Also good.

  EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated still in detail, this invention is not limited to a following example.

Example 1
The target ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

Ethyl 2-hydroxymethylene-4,4,4-trifluoroacetoacetate (163 mg, 0.77 mmol) was cooled on ice water, water (0.8 mL), 1N aqueous sodium hydroxide solution (0.08 mL, 0.08 mmol). ) Was added and stirred. Methylhydrazine (67 mg, 1.45 mmol) was added thereto, and the mixture was stirred at this temperature for 10 minutes. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (10 mL × 3). Furthermore, 2N hydrochloric acid (1 mL) was added to the separated aqueous layer, followed by extraction with chloroform (10 mL × 3). After all the organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A yellow oil (92 mg, yield 54%) consisting of ethyl acetate and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 19:81.
1-methyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.1 Hz, 3H), 3.97 (s , 3H), 4.32 (q, J = 7.1 Hz, 2H), 7.96 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.3.
1-methyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.36 (t, J = 7.2 Hz, 3H), 4.08 (q , J = 1.8 Hz, 3H), 4.33 (q, J = 7.2 Hz, 2H), 7.91 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-57.4.

Example 2
The target ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.98 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Methylhydrazine (1.43 g, 31.0 mmol) was added dropwise to this solution, and then stirred for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (4.01 g, yield 87%) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 33:67.

Example 3
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.98 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 20 minutes. Methylhydrazine (1.43 g, 31.0 mmol) was added dropwise to this solution, and then stirred for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (3.93 g, yield 85%) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 21:79.

Example 4
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.98 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 30 minutes. Methylhydrazine (1.43 g, 31.0 mmol) was added dropwise to this solution, and then stirred for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (4.11 g, 89% yield) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 21:79.

Example 5
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.95 g, 20.6 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) previously cooled on ice water was added to this solution, and methyl hydrazine (1.43 g, 31.0 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (3.64 g, yield 80%) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 23:77.

Example 6
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.98 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 20 minutes. Chloroform (25 mL) previously cooled on ice water was added to this solution, and methyl hydrazine (1.43 g, 31.0 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (4.21 g, yield 92%) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 26:74.

Example 7
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.98 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. To this solution was added toluene (25 mL) cooled in advance on ice water, and methyl hydrazine (1.43 g, 31.0 mmol) was added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-methyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (3.43 g, yield 75%) consisting of ethyl and ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 21:79.

Example 8
The target ethyl 1-ethyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Ethyl hydrazine (1.87 g, 31.1 mmol) was added dropwise to this solution, and then stirred for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the aqueous layer was extracted with chloroform (20 mL × 3). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-ethyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (4.42 g, yield 90%) consisting of ethyl and ethyl 1-ethyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 34:66.
_{^{1-ethyl-3-trifluoromethylpyrazole-4-carboxylate; 1 H-NMR (CDCl 3}} , TMS, ppm): δ1.35 (t, J = 7.2Hz, 3H), 1.54 (t , J = 7.4 Hz, 3H), 4.23 (q, J = 7.4 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 8.00 (q, J = 0.0). 8Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.3.
1-ethyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.1 Hz, 3H), 1.49 (t , J = 7.3 Hz, 3H), 4.33 (q, J = 7.1 Hz, 2H), 4.40 (qq, J ₁ = 7.3 Hz, J ₂ = 0.8 Hz, 2H), 7. 94 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-57.4.

Example 9
To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.96 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) previously cooled on ice water was added to this solution, and ethyl hydrazine (1.87 g, 31.1 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-ethyl-3-trifluoromethylpyrazole-4-carboxylic acid. A light brown oily substance (4.02 g, yield 82%) consisting of ethyl and ethyl 1-ethyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 20:80.

Example 10
The target ethyl 1-n-propyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) cooled in advance on ice water was added to this solution, and n-propylhydrazine (2.30 g, 31.0 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-n-propyl-3-trifluoromethylpyrazole-4- A pale brown oily substance (4.04 g, yield 78%) consisting of ethyl carboxylate and ethyl 1-n-propyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 36:64.
1-n-propyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.95 (t, J = 7.3 Hz, 3H), 1.35 (T, J = 7.1 Hz, 3H), 1.93 (sextet, J = 7.3 Hz, 2H), 4.13 (t, J = 7.3 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.97 (q, J = 0.8 Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.3.
1-n-propyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.94 (t, J = 7.5 Hz, 3H), 1.35 (T, J = 7.1 Hz, 3H), 1.90 (sextet, J = 7.5 Hz, 2H), 4.30 (tq, J ₁ = 7.5 Hz, J ₂ = 0.5 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7.93 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-57.0.

Example 11
The target ethyl 1-isopropyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) cooled in advance on ice water was added to this solution, and isopropylhydrazine (2.30 g, 31.0 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-isopropyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (3.79 g, 73% yield) consisting of ethyl and ethyl 1-isopropyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 16:84.
1-isopropyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.1 Hz, 3H), 1.55 (d , J = 6.8 Hz, 6H), 4.32 (q, J = 7.1 Hz, 2H), 4.56 (septet, J = 6.8 Hz, 1H) 8.02 (q, J = 0.8 Hz) , 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.3.
1-isopropyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.1 Hz, 3H), 1.54 (d , J = 6.5 Hz, 6H), 4.32 (q, J = 7.1 Hz, 2H), 4.80 (septet, J = 6.5 Hz, 1H) 7.94 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-56.8.

Example 12
The target ethyl 1-isobutyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) cooled in advance on ice water was added to this solution, and isobutylhydrazine (2.71 g, 31.7 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers are combined and dried over anhydrous magnesium sulfate, the desiccant is filtered off, and the solvent is distilled off from the filtrate under reduced pressure to give 1-isobutyl-3-trifluoromethylpyrazole-4-carboxylic acid. A brown oil (4.30 g, yield 79%) consisting of ethyl and ethyl 1-isobutyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 44:56.
1-isobutyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.94 (d, J = 6.8 Hz, 6H), 1.36 (t , J = 7.1 Hz, 3H), 2.25 (m, 1H), 3.95 (d, J = 7.3 Hz, 2H), 4.32 (q, J = 7.1 Hz, 2H), 7 .95 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.2.
1-isobutyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 0.92 (d, J = 6.5 Hz, 6H), 1.36 (t , J = 7.1 Hz, 3H), 2.25 (m, 1H), 4.14 (dq, J ₁ = 7.5 Hz, J ₂ = 0.8 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 7.94 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-56.6.

Example 13
The target ethyl 1-tert-butyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. To this solution, chloroform (25 mL) previously cooled on ice water was added, and tert-butylhydrazine hydrochloride (3.89 g, 31.2 mmol) was added to an 8N aqueous sodium hydroxide solution (4.0 mL, 32.0 mmol) and A solution dissolved in a mixed solution of chloroform (4.0 mL) was added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (20 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-tert-butyl-3-trifluoromethylpyrazole-4- A brown oil (4.46 g, yield 82%) consisting of ethyl carboxylate and ethyl 1-tert-butyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 8:92.
1-tert-butyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.1 Hz, 3H), 1.69 (S, 9H), 4.32 (q, J = 7.1 Hz, 2H), 8.10 (q, J = 0.9 Hz, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.2.
1-tert-butyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.35 (t, J = 7.2 Hz, 3H), 1.69 (S, 9H), 4.32 (q, J = 7.2 Hz, 2H), 7.79 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-52.8.

Example 14
The target ethyl 1-phenyl-5-trifluoromethylpyrazole-4-carboxylate was produced according to the following reaction formula.

To a 1N aqueous sodium hydroxide solution (23.0 mL, 23.0 mmol), ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (4.97 g, 20.7 mmol) was added dropwise with ice cooling, and the same temperature. For 10 minutes. Chloroform (25 mL) previously cooled on ice water was added to this solution, and phenylhydrazine (3.40 g, 31.4 mmol) was further added dropwise, followed by stirring for 10 minutes. 2N Hydrochloric acid (30 mL) was added to the reaction mixture, and the organic layer was collected. The aqueous layer was extracted with chloroform (20 mL × 2). The organic layers were combined and dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was removed from the filtrate under reduced pressure to give 1-phenyl-3-trifluoromethylpyrazole-4-carboxylic acid. A dark brown oil (5.48 g, yield 93%) consisting of ethyl and ethyl 1-phenyl-5-trifluoromethylpyrazole-4-carboxylate was obtained. ^{From 19} F-NMR analysis, it was found that the production ratio of the former and the latter was 15:85.
1-phenyl-3-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.39 (t, J = 7.1 Hz, 3H), 4.37 (q , J = 7.1 Hz, 2H), 7.42 (m, 1H), 7.52 (m, 2H), 7.72 (m, 2H) 8.48 (q, J = 1.0 Hz, 1H) . ¹⁹ F-NMR (CDCl ₃ , ppm): δ-62.5.
1-phenyl-5-trifluoromethylpyrazole-4-carboxylate; ¹ H-NMR (CDCl ₃ , TMS, ppm): δ 1.39 (t, J = 7.1 Hz, 3H), 4.38 (q , J = 7.1 Hz, 2H), 7.43 (m, 2H), 7.51 (m, 3H), 8.12 (s, 1H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-55.6.

Synthesis Example 1 (Method for producing ethyl 2-hydroxymethylene-4,4,4-trifluoroacetoacetate)
Reaction was performed according to the following method.

Anhydrous copper acetate second (7.00 g, 38.5 mmol) was added to water (100 mL) to give a suspension solution. To this was slowly added ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (19.9 g, 82.9 mmol) at room temperature, followed by stirring for 3 hours and 20 minutes. The precipitated solid was collected by filtration and washed with diethyl ether (100 mL) cooled to about 5 ° C. The obtained green solid (5.84 g) was suspended in diethyl ether (40 mL), and 2N sulfuric acid (18 mL) was added dropwise at room temperature. After stirring for another 20 minutes, the organic layer was recovered. The aqueous layer was extracted with diethyl ether (10 mL × 2), and then the organic layers were combined and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off from the filtrate under reduced pressure to obtain a green oil (3.61 g). This was purified by distillation under reduced pressure, and a fraction of 40-60 ° C./10 mmHg was collected to obtain a colorless oily product of ethyl 2-hydroxymethylene-4,4,4-trifluoroacetoacetate (266 mg, yield 1.5). %).
¹ H-NMR (CDCl ₃ , ppm): δ. 1.34 (t, J = 7.1 Hz, 0.6H), 1.39 (t, J = 7.1 Hz, 2.4H), 4.31 (q, J = 7.1 Hz, 0.4H) , 4.40 (q, J = 7.1 Hz, 1.6H), 8.37 (s, 0.8H), 8.69 (s, 0.2H), 14.1 (br.s, 0. 8H), 14.5 (br.s, 0.2H). ¹⁹ F-NMR (CDCl ₃ , ppm): δ-72.9, -73.9.

Reference Example 1 (Example 1 of PCT / JP2006 / 303269)
Reaction was performed according to the following method.

A 35 wt% aqueous solution of methyl hydrazine (0.197 mL, 1.5 mmol) was added to a solution of potassium hydroxide (28 mg, 0.5 mmol) in water (5.0 mL) and stirred. To this solution, ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (0.097 mL, 120 mg, 0.5 mmol) was added dropwise under ice cooling, and the mixture was stirred at this temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid, saturated aqueous sodium chloride solution (20 mL) was added, and the mixture was extracted with chloroform (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was dried under reduced pressure to give ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5. A white solid (90 mg, yield 81%) consisting of ethyl trifluoromethylpyrazole-4-carboxylate was obtained. From the gas chromatography (GC) analysis, it was found that the production ratio of the former and the latter was 93: 7.
In the above method, the yield of ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate is not the target of the present invention, but ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate. There were many.

Reference Example 2 (Example 1 of PCT / JP2006 / 303269)
Reaction was performed according to the following method.
To a solution of sodium hydroxide (20 mg, 0.5 mmol) in water (5.0 mL) was added 35 wt% aqueous methylhydrazine solution (0.197 mL, 2.3 mmol), and the mixture was stirred. To this solution, ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (0.097 mL, 120 mg, 0.5 mmol) was added dropwise under ice cooling, and the mixture was stirred at this temperature for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid, saturated aqueous sodium chloride solution (20 mL) was added, and the mixture was extracted with chloroform (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was dried under reduced pressure to give ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5. A white solid (96 mg, yield 86%) consisting of ethyl trifluoromethylpyrazole-4-carboxylate was obtained. From the GC analysis, it was found that the production ratio of the former and the latter was 98: 2.
In the above method, the yield of ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate is not the target of the present invention, but ethyl 1-methyl-5-trifluoromethylpyrazole-4-carboxylate. There were many.

Comparative Example 1
A 35 wt% aqueous solution of methyl hydrazine (0.197 mL, 2.3 mmol) was added to water (5.0 mL) and stirred. To this solution, ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (0.097 mL, 120 mg, 0.5 mmol) was added dropwise under ice cooling, and the mixture was stirred at this temperature for 1 hour. A saturated aqueous sodium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was dried under reduced pressure to give ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5. A white solid (101 mg, yield 91%) consisting of ethyl trifluoromethylpyrazole-4-carboxylate was obtained. From the GC analysis, it was found that the production ratio of the former and the latter was 66:34.

Comparative Example 2 (Method described in Cited Document 2)
Methylhydrazine (69 mg, 1.5 mmol) was added to ethanol (5.0 mL) and stirred. To this solution, ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (0.097 mL, 120 mg, 0.5 mmol) was added dropwise under ice cooling, and the mixture was stirred at this temperature for 1 hour. A saturated aqueous sodium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was dried under reduced pressure to give ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5. A white solid (103 mg, yield 93%) consisting of ethyl trifluoromethylpyrazole-4-carboxylate was obtained. From the GC analysis, it was found that the production ratio of the former and the latter was 76:24.

Comparative Example 3
Methylhydrazine (69 mg, 1.5 mmol) was added to a mixed solution of ethyl acetate (5.0 mL) and water (5.0 mL) and stirred. To this solution, ethyl 2-ethoxymethylene-4,4,4-trifluoroacetoacetate (0.097 mL, 120 mg, 0.5 mmol) was added dropwise at room temperature and stirred for 1 hour. A saturated aqueous sodium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous sodium sulfate, the desiccant was filtered off, and the filtrate was dried under reduced pressure to give ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5. A white solid (103 mg, yield 93%) consisting of ethyl trifluoromethylpyrazole-4-carboxylate was obtained. From the GC analysis, it was found that the production ratio of the former and the latter was 79:21.

Comparative Example 4
To a solution of methyl hydrazine (0.19 mL, 3.61 mmol) in water (5.0 mL), a solution of ethyl 2-ethoxymethylenetrifluoroacetoacetate (1.0 g, 4.16 mmol) in toluene (5.0 mL) was ice-cooled. The solution was added dropwise over 10 minutes and stirred at the same temperature for 10 minutes. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 3). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off from the filtrate under reduced pressure to obtain ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5-trifluoromethylpyrazole- A mixture consisting of ethyl 4-carboxylate was obtained almost quantitatively. From the GC analysis, it was found that the production ratio of the former and the latter was 81:19.

Comparative Example 5
A solution of methyl hydrazine (0.19 mL, 3.61 mmol) in water (5.0 mL) and a solution of ethyl 2-ethoxymethylenetrifluoroacetoacetate (1.0 g, 4.16 mmol) in toluene (5.0 mL) at 50 ° C. And stirred at the same temperature for 10 minutes. 1N Hydrochloric acid (10 mL) was added to the reaction mixture, and the mixture was extracted with toluene (30 mL × 3). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was distilled off from the filtrate under reduced pressure to obtain ethyl 1-methyl-3-trifluoromethylpyrazole-4-carboxylate and 1-methyl-5-trifluoromethylpyrazole- A mixture consisting of ethyl 4-carboxylate was obtained almost quantitatively. From the GC analysis, it was found that the production ratio of the former and the latter was 74:26.

The 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester that can be produced by the production method of the present invention is particularly useful as a synthetic intermediate for pharmaceuticals, agricultural chemicals, and functional materials, and the present invention is an industrially very useful production. A method is provided.

Claims (7)

General formula (1)
(In the formula, R ¹ represents a hydrogen atom or a halogen atom, and R ² represents a hydrogen atom, a fluorine atom, a chlorine atom, or an alkyl group having 1 to 12 carbon atoms which may be substituted with a fluorine atom. R ³ Represents an alkyl group having 1 to 6 carbon atoms) and is reacted with an alkali metal base in an aqueous solvent or a mixed solvent of water and an organic solvent, and the general formula (2)
(Wherein R ¹ , R ² and R ³ have the same meaning as described above. M represents an alkali metal), 2- (alkali metal oxymethylene) fluoroacyl acetate ester, and then the general formula (3 )
(Wherein R ⁴ represents an optionally substituted alkyl group having 1 to 6 carbon atoms or an optionally substituted phenyl group) and is reacted with a hydrazine represented by the general formula: (4)
(Wherein R ¹ , R ² , R ³ and R ⁴ represent the same meaning as described above), a method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester. The method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester according to claim 1, wherein R ² is a linear alkyl group having 1 to 4 carbon atoms.   The method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester according to claim 1, wherein the alkali metal base is sodium hydroxide or potassium hydroxide.   The usage-amount of an alkali metal base is 0.01 equivalent or more with respect to 2-hydroxymethylene fluoroacyl acetate shown by the said General formula (1) which is a reaction substrate. A method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester.   The organic solvent is at least one selected from the group of an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent, an alcohol solvent, an ester solvent, and a halogen solvent, according to any one of claims 1 to 4. A method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester.   The method for producing 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester according to any one of claims 1 to 5, wherein the reaction temperature is -30 to 60 ° C. General formula (2)
(Wherein R ¹ represents a hydrogen atom or a halogen atom, R ² represents a hydrogen atom, a fluorine atom, a chlorine atom or an alkyl group having 1 to 12 carbon atoms which may be substituted with a fluorine atom. R ³ represents 2- (alkali metal oxymethylene) fluoroacyl acetate represented by the alkyl group having 1 to 6 carbon atoms, wherein M represents an alkali metal.
(Wherein R ¹ , R ² and R ³ represent the same meaning as described above), and obtained by reacting 2-alkoxymethylenefluoroacyl acetate ester with an alkali metal base in an aqueous solution. 6. A method for producing a 1-substituted-5-fluoroalkylpyrazole-4-carboxylic acid ester according to any one of 6 above.