JPH06306053A - Production of 3-azole-carboxylic acid derivative and intermediate thereof - Google Patents

Abstract

PURPOSE:To obtain the compound which is useful as a synthetic intermediate for medicines and agrochemicals from an inexpensive starting substance by condensation reaction of beta,gamma-unsaturated-alpha-ketocarboxylic acid derivative with an amine derivative followed by oxidative cyclization. CONSTITUTION:The reaction of a compound of formula I (R<1>, R<2> are H, alkyl, cycloalkyl, aryl or R<1> and R<2> are incorporated with carbon atoms to form a ring; R<3> is H, alkyl, aralkyl) with a compound of the formula: H2N-XH (X is O, N-Y; Y is aryl) is carried out in a solvent such as methanol at -20 to +200 deg.C to give beta,gamma-unsaturated-alpha-ketocarboxylic acid derivative of formula II. Then, the product is allowed to react with iodine in a two-layer system of water and an organic solvent in the presence of a base and an alkali metal iodide at 0 to 150 deg.C to obtain a compound of formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION The compounds which can be produced by the production method of the present invention are disclosed in JP-A-1-156964 and JP-A-2-156964.
62876, pyrazole derivatives having insecticidal activity and acaricidal activity or intermediates for producing the same, European Patent 0459244A1 and German Patent 402975.
3A1. Production intermediates for herbicide sulfonamide derivatives described in JP 3A1 and further European Patent 0477049A.
It can be a synthetic intermediate of the drug described in JP-A-1.

[0002]

2. Description of the Related Art The production of 3-pyrazolecarboxylic acid derivatives is carried out by (a) reaction of α, γ-diketocarboxylic acid esters with hydrazines (Ann. Chem., 536 , 97 (193)
8)), a method by a 1,3-dipolar cyclization reaction using a reaction between (b) phenylsydnone and acetylenes (German Patent No. 1261125), (c) N-phenyl-C-alkoxycarbonyl -It has been reported that it can be produced by a method of reacting a nitrilimine with norbornadiene (Japanese Patent Laid-Open No. 64-83070) and a reaction of (d) N-phenyl-C-alkoxycarbonyl-nitrileimine with an enamine.

On the other hand, as a method for producing a 3-isoxazolecarboxylic acid derivative, (e) a method of reacting an α, γ-diketocarboxylic acid ester with hydroxylamine, and (f) a nitrile oxide and 1,3 of acetylenes
-A method using a dipolar cyclization reaction and the like can be mentioned.

[0004]

In the above production method, in the methods (a), (b), (e) and (f), the azolecarboxylic acid derivative is obtained as a mixture of positional isomers of carboxylic acid. . Therefore, it is necessary to separate the isomers in order to obtain the desired 3-azolecarboxylic acid derivative.
Further, in the methods (a) and (e), it is difficult to synthesize various derivatives because the raw material α, γ-diketocarboxylic acid ester is limited. Furthermore, the methods of (c) and (d) can selectively produce a 3-pyrazolecarboxylic acid derivative, but in (c), it is impossible to introduce a substituent into the 3- and 4-positions of the pyrazole ring. In (d), enamines are limited, so that it is difficult to synthesize various derivatives. As described above, as a method for producing a 3-azolecarboxylic acid derivative that can be an important production intermediate for agricultural chemicals and pharmaceuticals, there is no method with high generality until now, and various derivatives can be easily produced from inexpensive raw materials. Method development is desired.

[0005]

Means for Solving the Problems As a result of extensive studies on the excellent method for producing a 3-azolecarboxylic acid derivative, the present inventors have used a β, γ-unsaturated-α-ketocarboxylic acid derivative as a raw material, and The present invention has been completed by finding that the desired 3-azolecarboxylic acid derivative can be easily obtained by reacting with hydroxylamine or hydrazines.

That is, the present invention is based on the general formula (1)

[0007]

[Chemical 10]

(In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are carbon atoms bonded to each other. good .R ³ may form a ring together is indicated by.) represents a hydrogen atom, an alkyl group or an aralkyl group, beta, and γ- unsaturated -α- ketocarboxylic acid derivatives of the general formula (2)

[0009]

[Chemical 11]

(In the formula, X represents an oxygen atom or N--Y,
Y represents an aryl group. ) By the reaction with an amine derivative represented by the general formula (3)

[0011]

[Chemical 12]

(In the formula, X represents an oxygen atom or N—Y, and Y represents an aryl group. R ¹ and R ² are each independently a hydrogen atom, a linear or branched alkyl group, or a cycloalkyl group. Or an aryl group, R ¹ and R ² may form a ring together with the carbon to which they are bonded, and R ³ represents a hydrogen atom, an alkyl group or an aralkyl group. , γ-unsaturated-α-iminocarboxylic acid derivative,
Then, by reacting this with iodine in the presence of a base and an alkali metal iodide, a compound of the general formula (4)

[0013]

[Chemical 13]

(In the formula, X represents an oxygen atom or N—Y, and Y represents an aryl group. R ¹ and R ² are each independently a hydrogen atom, a linear or branched alkyl group, or a cycloalkyl group. Or an aryl group, R ¹ and R ² may together with the carbon to which they are bonded to form a ring, and R ³ represents a hydrogen atom, an alkyl group or an aralkyl group. -Method for producing azolecarboxylic acid derivative and general formula (1)

[0015]

[Chemical 14]

A β, γ-unsaturated-α-ketocarboxylic acid derivative represented by the formula (wherein R ¹ , R ² and R ³ have the same meanings as described above);

[0017]

[Chemical 15]

(Wherein R ⁴ represents a lower alkyl group, a substituted or unsubstituted phenyl group or a lower perfluoroalkyl group), and a hydrazine derivative represented by the general formula (6)

[0019]

[Chemical 16]

A β, γ-unsaturated-α-iminocarboxylic acid derivative represented by the formula (wherein R ¹ , R ² and R ³ have the same meanings as described above) is obtained. General formula (7) by processing

[0021]

[Chemical 17]

The present invention relates to a method for producing a 3-pyrazolecarboxylic acid derivative represented by the formula (wherein R ¹ , R ² and R ³ have the same meanings as described above).

Further, the present invention is represented by the general formula (8), which is an important intermediate in the above-mentioned production method.

[0024]

[Chemical 18]

(In the formula, R ¹ , R ² and R ³ have the same meanings as described above. X ′ represents an oxygen atom or N—Y ′,
Y 'represents a group represented by the aryl group or -SO ₂ R ^4,
R ⁴ represents a lower alkyl group, a substituted or unsubstituted phenyl group or a lower perfluoroalkyl group. ) Related to the β, γ-unsaturated-α-iminocarboxylic acid derivative.

The production method of the present invention will be described in more detail by the following process formulas. That is, the 3-azolecarboxylic acid derivative represented by the general formula (4) has a β, γ-unsaturation-α
By producing a β, γ-unsaturated-α-iminocarboxylic acid derivative (3) by a condensation reaction between a ketocarboxylic acid derivative (1) and an amine derivative (2), and then oxidatively cyclizing this product. It can be manufactured.

[0027]

[Chemical 19]

(In the formula, R ¹ , R ² , R ³ and X have the same meanings as described above.)

Further, the 3-azolecarboxylic acid derivative represented by the general formula (7) can be obtained by the condensation reaction of the β, γ-unsaturated-α-ketocarboxylic acid derivative (1) and the hydrazine derivative (5). It can be prepared by obtaining an -unsaturated-α-iminocarboxylic acid derivative (6), which is then cyclized and simultaneously desulfonated.

[0030]

[Chemical 20]

(In the formula, R ¹ , R ² , R ³ and R ³ have the same meanings as described above.) Step-1 is a β, γ-unsaturated-α-ketocarvone represented by the general formula (1). This is a step of producing a β, γ-unsaturated-α-iminocarboxylic acid derivative represented by the general formula (3) by reacting an acid derivative with an amine derivative represented by the general formula (2).

In this step, the reaction can be carried out in a solvent. As the solvent, any solvent which does not harm the reaction can be used, such as methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, acetonitrile, N, N-dimethylformamide, Examples thereof include N, N-dimethylacetamide, acetic acid, propionic acid, water and mixed solvents thereof.

The reaction temperature is selected from the range of -20 to 200 ° C, but it is preferably carried out at 0 to 100 ° C from the viewpoint of good yield.

Hydrochlorides or hydrazines represented by the general formula (2) can be used in the reaction with their hydrochlorides or sulfates, but in this case, the reaction is preferably carried out in the presence of a base. Examples of the base to be used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, lithium hydride and sodium hydride,
Examples thereof include alkali metals such as potassium hydride and alkali metal alkoxides such as sodium methoxide and sodium ethoxide. The amount of the base used is the minimum amount necessary to neutralize the salt.

After completion of the reaction, the desired product can be obtained by a usual extraction operation, and if necessary, it can be purified by column chromatography.

The step-2 comprises β, represented by the general formula (3),
By reacting the γ-unsaturated-α-iminocarboxylic acid derivative with iodine in the presence of a base and an alkali metal iodide in a bilayer solvent of water and an organic solvent, the compound represented by the general formula (4) This is a step of producing an azolecarboxylic acid derivative.

As the organic solvent, any solvent which does not influence the reaction can be used. For example, tetrahydrofuran, diethyl ether, dioxane, dimethoxyethane, benzene, toluene, xylene, chloroform,
Examples include methylene chloride, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide and the like.

The reaction can be carried out at a reaction temperature in the range of 0 to 150 ° C., but it is preferably carried out at room temperature to 100 ° C. in terms of good yield.

Examples of the base used include alkali metal hydrogen carbonates such as sodium hydrogen carbonate and potassium hydrogen carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkali metals such as sodium carbonate and potassium carbonate. A metal carbonate etc. can be illustrated.
The amount of base used is 1.0 to 8.0 with respect to the reaction substrate.
It can be carried out using an equivalent amount, preferably 3.0 to 4.0 equivalents.

The amount of iodine used is preferably equivalent to or more than the reaction substrate in terms of good yield. Also, the amount of alkali metal iodide used is 0.1 with respect to the reaction substrate.
It is preferable to use 5 to 5 equivalents, preferably 3 to 4 equivalents in terms of good yield. Examples of alkali metal iodides include iodides such as potassium iodide and sodium iodide.

After completion of the reaction, the desired product can be obtained by a usual extraction operation, and if necessary, it can be purified by column chromatography.

In step-3, the β, γ-unsaturated-α-ketocarboxylic acid derivative (1) is reacted with the hydrazine derivative (5) to give a β, γ-unsaturated-α-iminocarboxylic acid derivative (6). Is a process of manufacturing.

The reaction can be carried out in a solvent. Any solvent can be used as long as it does not harm the reaction, and methanol, ethanol, isopropyl alcohol, butanol, ethylene glycol, tetrahydrofuran, dioxane, diethyl ether, dimethoxyethane, acetonitrile, N, N-dimethylformamide,
N, N-dimethylacetamide, acetic acid, propionic acid,
Water or a mixed solvent thereof can be exemplified.

The reaction temperature can be carried out in the range of -20 to 200 ° C, but it is preferably carried out at 0 to 100 ° C because the reaction operation is simple.

As the hydrazine derivative (5), its hydrochloride or sulfate can be used in the reaction. In that case, the reaction is preferably carried out in the presence of a base. Examples of the base used include alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, alkali metal carbonates such as sodium carbonate and potassium carbonate, alkalis such as lithium hydride, sodium hydride and potassium hydride. Examples of the metal include alkali metal alkoxides such as sodium methoxide and sodium ethoxide. The amount of the base used is the minimum amount necessary to neutralize the salt.

After completion of the reaction, the desired product can be obtained by a usual extraction operation, and if necessary, it can be purified by column chromatography.

Step-4 is a step of producing a 3-pyrazolecarboxylic acid derivative (7) by reacting the β, γ-unsaturated-α-iminocarboxylic acid derivative (6) with a base in an organic solvent. .

As the organic solvent, any solvent which does not affect the reaction can be used. For example, methanol,
Ethanol, isopropanol, butanol, acetonitrile, tetrahydrofuran, ether, dioxane,
Examples thereof include benzene, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide and the like.

It is essential to use a base in this reaction,
Examples of the base used include alkali metal alkoxides such as sodium ethoxide and sodium methoxide, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, and alkali metal carbonates such as sodium carbonate and potassium carbonate. From the viewpoint of good yield, it is preferable to use an equivalent amount or more with respect to the reaction substrate.

The reaction can be carried out at a temperature in the range of 0 to 150 ° C, and is preferably room temperature to 100 ° C in terms of good yield.

After completion of the reaction, the desired product can be produced by an ordinary extraction operation, and if necessary, it can be purified by column chromatography.

3-which can be manufactured in this way
The azole carboxylic acid ester derivative can be easily converted into a free carboxylic acid by an ordinary hydrolysis treatment.

[Beta], [gamma] -unsaturated- [alpha] -iminocarboxylic acid derivatives represented by the above general formulas (3), (4), (6) and (7), which can be produced by the processes of steps 1-4. Alternatively, in the 3-azolecarboxylic acid derivative, the alkyl group represented by R ¹ and R ² includes a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a hexyl group, an octyl group, and dodecanyl. Examples thereof include a group and an octadodecanyl group.
Examples of the aryl group represented by R ¹ and R ² include a phenyl group, a naphthyl group, an anthranyl group and the like. When a ring is formed integrally with the carbon atom to which R ¹ and R ² are bonded, the ring forming group consisting of R ¹ and R ² is
Examples thereof include trimethylene group, tetramethylene group, pentamethylene group and hexamethylene group. Further, these alkyl group, aryl group and ring forming group may be substituted with a halogen atom, an alkyl group, an alkoxy group, a carboxy group, an alkoxycarbonyl group and / or a nitro group. Examples of the alkyl group represented by R ³ include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group. The aralkyl group may be a benzyl group.

X represents an oxygen atom or N--Y, and Y
Represents an aryl group. The aryl group represented by Y includes a phenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2,3-dichlorophenyl group, a 2,4-dichlorophenyl group, a 2,5-dichlorophenyl group, and a 2 group. , 6-dichlorophenyl group, 3,4
-Dichlorophenyl group, 3,5-dichlorophenyl group,
2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2,4-dibromophenyl group, 2,5
-Dibromophenyl group, 2,6-dibromophenyl group,
2-fluorophenyl group, 3-fluorophenyl group, 4
-Fluorophenyl group, 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4
-Difluorophenyl group, 3,5-difluorophenyl group, 2-chloro-4-fluorophenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-2-fluorophenyl group, 4-chloro-2-fluoro Phenyl group-5
-Methoxyphenyl group, 4-chloro-2-fluoro-5
-Ethoxyphenyl group, 4-chloro-2-fluoro-5
-Isopropyloxyphenyl group, 4-chloro-2-fluoro-5-propargyloxyphenyl group, 4-chloro-5-cyclopentyloxy-2-fluorophenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group Group, 4-trifluoromethylphenyl group, 2-methylphenyl group, 3-methylphenyl group,
4-methylphenyl group, 2-methoxyphenyl group, 3-
Methoxyphenyl group, 4-methoxyphenyl group, 2-phenoxyphenyl group, 3-phenoxyphenyl group, 4-
Phenoxyphenyl group, 3-benzyloxyphenyl group, 4-benzyloxyphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group,
Examples thereof include a 2-nitrophenyl group, a 3-nitrophenyl group and a 4-nitrophenyl group.

Further, in the above general formulas (5) and (6) of the present invention, the substituent represented by R ⁴ is a lower alkyl group such as a methyl group, an ethyl group, or a substituted or unsubstituted phenyl group. , Phenyl group, tolyl group,
Furthermore, examples of the perfluoroalkyl group include a trifluoromethyl group, a pentafluoroethyl group, and the like.

Therefore, in the β, γ-unsaturated-α-iminocarboxylic acid derivative which is the compound of the present invention represented by the general formula (8), R ¹ , R ² and R ³ are represented by the general formula (3),
The same substituents as the β, γ-unsaturated-α-iminocarboxylic acid derivative or the 3-azolecarboxylic acid derivative represented by (4) and (7) can be exemplified. X'represents an oxygen atom or N-Y ', Y'is an aryl group or -SO.
₂ represents a group represented by R ⁴ . The aryl group includes β, γ-unsaturated-containing groups represented by the general formulas (3) and (4).
The same substituents as the α-iminocarboxylic acid derivative or the 3-azolecarboxylic acid derivative can be exemplified, and R ⁴
As the substituent represented by, a lower alkyl group is a methyl group, an ethyl group, a substituted or unsubstituted phenyl group is a phenyl group, a tolyl group, and a perfluoroalkyl group is a trifluoromethyl group, a pentafluoro group. An ethyl group etc. can be illustrated.

The β, γ-unsaturated-α-ketocarboxylic acid derivative represented by the general formula (1), which is the starting material of the present invention, can be produced, for example, by the method described in Japanese Patent Application No. 3-325022.

[0058]

The present invention will be described in more detail with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example-1

[0060]

[Chemical 21]

A solution of methyl 2-oxo-3-methyl-3-pentenoate (1.36 g, 9.57 mmol) in methanol (30 ml) was added with hydroxylamine hydrochloride (731 mg, 10.5 mmol) and potassium carbonate (727 mg, 5.26 mmol). Was added and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was treated with 1N-hydrochloric acid (20 m
l) was added, and the mixture was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the desired product, methyl 2-hydroxylimino-3-methyl-3-pentenoate (1.15 g, yield 7
An oily substance (6.5%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.82 (d, J = 7.47Hz, 1H),
1.84 (s, 3H), 3.89 (s, 3H), 5.74 (q, J = 7.47Hz, 1H), 8.12 (br
s, 1H).

Example-2

[0063]

[Chemical formula 22]

To a solution of ethyl 2-oxo-3-methyl-3-pentenoate (859 mg, 5.5 mmol) in ethanol (20 ml), hydroxylamine hydrochloride (459 mg, 6.6 mmol) and potassium carbonate (418 mg, 3.03 mmol) were added. The mixture was stirred at room temperature for 2 days. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was treated with 1N-hydrochloric acid (20 m
l) was added, and the mixture was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 2-hydroxylimino-3-methyl-3-pentenoate (3.00 g, yield 8).
5.8%) of white solid was obtained. MP: 80.0-82.0 ° C ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.50 (t, J = 7.50Hz, 3H),
1.99 (d, J = 7.00Hz, 3H), 2.03 (s, 3H), 4.81 (q, J = 7.50Hz, 2
H), 5.74 (q, J = 7.47Hz, 1H), 8.12 (br s, 1H) .IR (KBr disk, cm-1): 3500 ~ 2700,1745,1640,1440,1320,
1220,1110,1075,1010,960,900,855,750.

Example-3

[0066]

[Chemical formula 23]

A solution of methyl 2-oxo-3-methyl-3-heptenate (1.92 g, 11.3 mmol) in methanol (30 ml) was charged with hydroxylamine hydrochloride (862 mg, 12.4 mmol) and potassium carbonate (3.12 g, 22.6 mmol). ) Was added and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was treated with 1N-hydrochloric acid (30 m
l) was added, and the mixture was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. Column chromatography of this product (ethyl acetate / hexane = 1/4)
After purification and separation by filtration, methyl 2-hydroxylimino-3-methyl-3-heptenoate (200 m
g, yield 9.57%) was obtained as an oil. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ0.92 (d, J = 7.04Hz, 3H),
1.30 (sep, J = 7.04Hz, 2H), 1.83 (d, J = 1.32Hz, 3H), 2.18 (q, J
= 7.04Hz, 2H), 3.90 (s, 3H), 5.64 (q, J = 7.47Hz, 1H), 7.99 (br
s, 1H).

Example-4

[0069]

[Chemical formula 24]

A solution of ethyl 2-oxo-3-ethyl-3-pentenoate (1.65 g, 9.64 mmol) in ethanol (20 ml) was charged with hydroxylamine hydrochloride (0.74 g, 10.6 mmol) and potassium carbonate (0.73 g, 5.30). mmol) was added and the mixture was stirred at room temperature overnight. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was 1N hydrochloric acid (20 ml).
Was added and extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to give the desired product ethyl 2-hydroxylimino-3-ethyl-3-pentenoate (801 mg, yield 44.
9%) of oil was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.30 (t, J = 7.03Hz, 3H),
1.36 (t, J = 7.03Hz, 3H), 1.82 (d, J = 6.81Hz, 3H), 2.38 (q, J =
7.03Hz, 2H), 4.39 (q, J = 7.03Hz, 2H), 5.75 (q, J = 6.81Hz, 1
H), 8.10 (brs, 1).

Example-5

[0072]

[Chemical 25]

A solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (3.08 g, 16.9 mmol) in ethanol (60 ml) was charged with hydroxylamine hydrochloride (1.41 g, 20.3 mmol) and potassium carbonate (1.28 g, 9.30 mmol) was added and the mixture was stirred at room temperature for 2 days. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was 1N.
-Hydrochloric acid (30 ml) was added, and the mixture was extracted with ether (30 ml x 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is concentrated under reduced pressure to give the desired product. 2
A white solid of ethyl -hydroxyimino-2- (1-cyclohexenyl) acetate (3.17 g, yield 95.0%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.00Hz, 3H),
1.4 ~ 2.0 (m, 4H), 2.0 ~ 2.4 (m, 4H), 4.39 (q, J = 7.00Hz, 2H),
6.00 (brs, 1H), 8.07 (brs, 1H).

Example-6

[0075]

[Chemical formula 26]

A solution of methyl 2-oxo-3-phenyl-3-pentenoate (1.80 g, 8.81 mmol) in methanol (30 ml) was added,
Hydroxylamine hydrochloride (674 mg, 9.70 mmol) and potassium carbonate (670 g, 4.85 mmol) were added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was diluted with 1N-hydrochloric acid (2
0 ml) was added, and the mixture was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to give the desired product, methyl 2-hydroxylimino-3-phenyl-3-pentenoate (1.33 g,
An oily substance with a yield of 68.9% was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.66 (d, J = 7.03Hz, 3H),
3.91 (s, 3H), 6.00 (q, J = 7.03Hz, 1H), 7.1〜7.7 (m, 5H).

Example-7

[0078]

[Chemical 27]

2-hydroxyimino-3-methyl-3
-THF (10 ml) of methyl pentenoate (500 mg, 3.18 mmol)-
Sodium hydrogen carbonate (1.07g, 12.7m) in a mixed solution of water (20ml)
mol), potassium iodide (2.32g, 14.0mmol), iodine (969m
g, 3.82 mmol) was added. The reaction mixture is protected from light by 50 to 6
The mixture was heated and stirred at 0 ° C. After 6 hours, the reaction solution was cooled to room temperature, sodium thiosulfate (10 ml) was added thereto, and ether (3
It was extracted with 0 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, an oily product of methyl 4,5-dimethylisoxazole-3-carboxylate (370 mg, yield 74.9%). Got ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 2.38 (s, 3 H), 2.13 (s, 3
H), 3.96 (s, 3H).

Example-8

[0081]

[Chemical 28]

2-hydroxyimino-3-methyl-3
-THF (80 ml) of ethyl pentenoate (3.00 g, 17.5 mmol)-
Sodium hydrogen carbonate (5.89g, 70.1m) in a mixed solution of water (80ml).
mol), potassium iodide (12.8 g, 77.0 mmol), iodine (5.34
g, 21.0 mmol) was added. The reaction mixture is protected from light by 60 to 7
The mixture was heated and stirred at 0 ° C for 4 hours. After completion of the reaction, the reaction solution was cooled to room temperature, sodium thiosulfate (40 ml) was added thereto, and the mixture was extracted with ether (50 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, an oil of ethyl 4,5-dimethylisoxazole-3-carboxylate (1.32 g, yield 44.6%). I got a thing. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.41 (t, J = 7.00Hz, 3H),
2.38 (s, 3H), 2.13 (s, 3H), 4.45 (q, J = 7.00Hz, 2H) .IR (KBr disk, cm ^-1 ): 3000,2950,1730,1450,1290,1210,1
180,1080.

Example-9

[0084]

[Chemical 29]

2-Hydroxylimino-3-methyl-3
-Methyl heptenoate (200 mg, 1.08 mmol) in THF (4 ml)-
Sodium hydrogen carbonate (363 mg, 4.32 m) was added to the mixed solution of water (8 ml).
mol), potassium iodide (789mg, 4.75mmol), iodine (329m
g, 1.30 mmol) was added. The reaction mixture is protected from light by 50 to 6
The mixture was heated and stirred at 0 ° C for 7 hours. After completion of the reaction, the reaction solution was cooled to room temperature, sodium thiosulfate (10 ml) was added thereto, and the mixture was extracted with ether (10 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, methyl 4-methyl-5-propylisoxazole-3-carboxylate (50 mg, yield 25.3).
%) Oily matter was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ0.96 (t, J = 7.03Hz, 3H),
1.64 (t, J = 7.03Hz, 2H), 2.72 (t, J = 7.03Hz, 2H), 3.95 (s, 3
H).

Example-10

[0087]

[Chemical 30]

2-Hydroxylimino-3-ethyl-3
-THF (20 ml) of ethyl heptenoate (801 mg, 4.32 mmol)-
Sodium hydrogen carbonate (1.45 g, 17.3 g) was added to a mixed solution of water (20 ml).
mmol), potassium iodide (3.12 g, 19.0 mmol), iodine (1.32
g, 5.18 mmol) was added. The reaction mixture was heated and stirred at 70 ° C. for 2 hours while protected from light. After completion of the reaction, the reaction solution was cooled to room temperature, sodium thiosulfate (20 ml) was added thereto, and ether was added.
It was extracted with (20 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, ethyl 4-ethyl-5-methylisoxazole-3-carboxylate (291 mg, yield 36.7%). An oil was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.13 (t, J = 7.50Hz, 3H),
1.42 (t, J = 7.50Hz, 3H), 2.40 (s, 3H), 2.62 (q, J = 7.50Hz, 2
H), 4.45 (q, J = 7.50Hz, 2H).

Example-11

[0090]

[Chemical 31]

Ethyl 2-hydroxyimino-2- (1-cyclohexenyl) acetate (3.02 g, 16.2 mmol) in THF (1
5 ml) -water (15 ml) in a mixed solution of sodium hydrogen carbonate (5.45
g, 64.9 mmol), potassium iodide (11.9 g, 71.4 mmol) and iodine (4.94 g, 19.5 mmol) were added. The reaction mixture was heated and stirred at 70 ° C. for 6 hours while protected from light. After completion of the reaction, the reaction solution was cooled to room temperature, sodium thiosulfate (20 ml) was added thereto, and the mixture was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. By purifying and separating this by column chromatography (ethyl acetate / hexane = 1/4), ethyl 4,5,6,7-tetrahydrobenz [d] isoxazole-3-carboxylate (1.83 g) was obtained as a target product. A pale yellow solid with a yield of 57.9% was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.43 (t, J = 7.25Hz, 3H),
1.7 ~ 2.0 (m, 4H), 2.5 ~ 2.9 (m, 4H), 4.47 (q, J = 7.25Hz, 2H).

Example-12

[0093]

[Chemical 32]

2-hydroxyimino-3-phenyl-
Methyl 3-pentenoate (1.33 g, 6.07 mmol) in THF (25 ml)
− Sodium hydrogen carbonate (2.04 g, 2
4.3 mmol), potassium iodide (4.43 g, 26.7 mmol), iodine
(1.85g, 7.28mmol) was added. The reaction mixture is protected from light by 70
The mixture was heated and stirred at 0 ° C for 2 hours. After completion of the reaction, the reaction solution was cooled to room temperature, sodium thiosulfate (30 ml) was added thereto, and the mixture was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (40 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure to obtain a crude product. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, methyl 4-phenyl-5-methylisoxazole-3-carboxylate (370 mg, yield 28.1).
%) Oily matter was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.44 (s, 3H), 3.87 (s, 3
H), 7.2 ~ 7.6 (m, 5H).

Example-13

[0096]

[Chemical 33]

Phenylhydrazine (1.07 g, 9.91 mmol) was added to a solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.63 g, 10.4 mmol) in ethanol (30 ml) at room temperature. Two
After stirring for an hour, the solvent was distilled off under reduced pressure, saturated aqueous ammonium chloride solution (30 ml) was added to the residue, and this was added with ether (2
It was extracted with 0 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/20) to give the desired product, 2-phenylhydrazono-3.
A pale yellow oily substance was obtained-ethyl methyl-3-pentenoate (628 mg, yield 24.4%). ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.03Hz, 3),
1.79 (d, J = 6.81Hz, 3H), 1.94 (s, 3H), 4.32 (q, J = 7.03Hz, 2
H), 5.87 (q, J = 6.81Hz, 1H), 7.1〜7.5 (m, 5H), 11.34 (brs, 1
H).

Example-14

[0099]

[Chemical 34]

Phenylhydrazine (1.08 g, 10.0 mmol) was added to a solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (1.82 g, 10.0 mmol) in ethanol (40 ml) at room temperature. After stirring overnight, the solvent was evaporated under reduced pressure, saturated aqueous ammonium chloride solution (40 ml) was added to the residue, and this was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/20) to give the desired product, ethyl 2-phenylhydrazono-2- (1-cyclohexenyl) acetate (1.30 g, yield 47.8). %) Was obtained as a pale yellow oily substance. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.04Hz, 3H),
1.5 to 1.9 (m, 4H), 2.1 to 2.5 (m, 4H), 4.33 (q, J = 7.04Hz, 2H),
6.1 ~ 6.3 (m, 1H), 6.8 ~ 7.5 (m, 5H), 11.23 (brs, 1H).

Example-15

[0102]

[Chemical 35]

2-Fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine (2.47 g) was added to a solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (1.84 g, 10.1 mmol) in ethanol (40 ml). , 10.1 mmol) was added at room temperature. After stirring for 2 hours, the precipitated solid was filtered to obtain the desired product, 2- (2-fluoro-4-chloro-5-cyclopentyloxyphenylhydrazono)-.
Ethyl 2- (1-cyclohexenyl) acetate (2.41 g, yield
58.9%) of a light brown solid was obtained. mp 92.0-93.5 ° C ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.39 (t, J = 7.04Hz, 4H),
1.6 to 2.1 (m, 12H), 2.1 to 2.5 (m, 4H), 4.37 (q, J = 7.04Hz, 2
H), 4.7 ~ 4.9 (m, 1H), 6.1 ~ 6.4 (m, 1H) 7.06 (d, JHF = 11.0Hz,
1H), 7.16 (d, JHF = 7.91Hz, 1H), 10.93 (brs, 1H) .IR (KBr disk, cm-1): 2950, 1685,1620,1540,1445,1290,
1190.

Example-16

[0105]

[Chemical 36]

A solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.58 g, 10.1 mmol) in ethanol (30 ml) was added with 4-.
Chlorophenylhydrazine hydrochloride (1.81 g, 10.1 mmol) and potassium carbonate (768 mg, 5.56 mmol) were added at room temperature. After stirring for 19 hours, the solvent was evaporated under reduced pressure, 1N-hydrochloric acid (30 ml) was added to the residue, and this was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/20) to give the desired product, 2- (4-chlorophenyl) hydrazono-3.
A pale yellow oily substance was obtained-ethyl methyl-3-pentenoate (1.51 g, yield 53.2%). ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.04Hz, 3H),
1.79 (t, J = 7.03Hz, 3H), 1.93 (s, 3H), 4.32 (q, J = 7.03Hz, 2
H), 5.87 (q, J = 7.03Hz, 1H), 7.09 (d, J = 7.75Hz, 2H), 7.26 (d,
J = 7.75Hz, 2H), 11.32 (brs, 1H).

Example-17

[0108]

[Chemical 37]

A solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.50 g, 9.6 mmol) in ethanol (40 ml) was treated with 2-
Fluoro-4-chloro-5-cyclopentyloxyphenylhydrazine (2.35g, 9.6mmol) was added at room temperature. Three
After stirring for an hour, the solvent was distilled off under reduced pressure, and the residue was 1N-
Hydrochloric acid (30 ml) was added, and this was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/20) to give the desired product, 2- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) hydrazono-3-methyl-.
A pale yellow oily product of ethyl 3-pentenoate (2.17 g, yield 59.0%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.03Hz, 3H),
1.6 to 2.1 (m, 14H), 4.35 (q, J = 7.03Hz, 2H), 4.7 to 5.0 (m, 1
H), 5.93 (q, J = 6.82Hz, 1H), 7.06 (d, JHF = 10.6Hz, 1H), 7.18
(d, JHF = 7.47Hz, 1H).

Example-18

[0111]

[Chemical 38]

4-Chlorophenylhydrazine hydrochloride (983 mg, 5.49 m) was added to a solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (1.00 g, 5.49 mmol) in ethanol (30 ml).
mol) and potassium carbonate (417 mg, 3.02 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure and the residue was 1
N-hydrochloric acid (30 ml) was added and this was extracted with ether (20 ml x 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtered solution is distilled off under reduced pressure to obtain the target product. 2
A pale yellow oily product of ethyl-(4-chlorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (1.71 g, yield 101%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.03Hz, 3H),
1.5 to 1.9 (m, 4H), 2.0 to 2.5 (m, 4H), 4.33 (q, J = 7.03Hz, 2H),
6.1 to 6.3 (m, 1H), 7.07 (d, J = 9.01Hz, 2H), 7.24 (d, J = 9.01H
z, 2H), 11.2 (brs, 1H).

Example-19

[0114]

[Chemical Formula 39]

2-oxo-2- (cyclohexene-1-
) Ethyl acetate (1.94 g, 10.7 mmol) in ethanol (40 ml)
3-trifluoromethylphenylhydrazine (1.8
7 g, 10.7 mmol) was added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid (40 ml) was added to the residue, and this was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (40 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain the desired product, ethyl 2- (3-trifluoromethylphenyl) hydrazono-2- (1-cyclohexenyl) acetate (2.85 g, yield). 78.2%) of a pale yellow oily substance was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.38 (t, J = 7.03Hz, 3H),
1.6 to 1.9 (m, 4H), 2.1 to 2.6 (m, 4H), 4.35 (q, J = 7.03Hz, 2H),
6.1 ~ 6.4 (m, 1H), 7.1 ~ 7.5 (m, 4H), 11.2 (brs, 1H).

Example 20

[0117]

[Chemical 40]

To a solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.58 g, 10.1 mmol) in ethanol (40 ml) was added 2.
4-dichlorophenylhydrazine hydrochloride (2.16g, 10.1mmo
l) and potassium carbonate (768 mg, 5.56 mmol) were added at room temperature.
After stirring for 19 hours, the solvent was distilled off under reduced pressure, and the residue was 1
N-hydrochloric acid (30 ml) was added and this was extracted with ether (20 ml x 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain the desired product, ethyl 2- (2,4-dichlorophenyl) hydrazono-3-methyl-3-pentenoate (3.06 g, yield 96.0%). ) Was obtained as a pale yellow oil. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.38 (t, J = 7.03Hz, 3H),
1.80 (d, J = 6.82Hz, 3H), 1.94 (s, 3H), 4.37 (q, J = 7.03Hz, 2
H), 5.93 (q, J = 6.82Hz, 1H), 7.1〜7.4 (m, 1H), 7.32 (d, J = 8.5
7Hz, 1H), 11.34 (brs, 1H).

Example-21

[0120]

[Chemical 41]

A solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.45g, 9.29mmol) in ethanol (40ml) was added with 4-.
Fluorophenylhydrazine hydrochloride (1.51 g, 9.29 mmol) and potassium carbonate (706 mg, 5.11 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, and 1N-hydrochloric acid was added to the residue.
(30 ml) was added and this was extracted with ether (20 ml x 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtered solution is distilled off under reduced pressure to obtain the target product. 2
-(4-Fluorophenyl) hydrazono-3-methyl-
A pale yellow oily product of ethyl 3-pentenoate (2.38 g, yield 96.9%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.03Hz, 3H),
1.78 (d, J = 6.81Hz, 3H), 1.93 (s, 3H), 4.31 (q, J = 7.03Hz, 2
H), 5.88 (q, J = 6.81Hz, 1H), 6.8〜7.3 (m, 4H).

Example-22

[0123]

[Chemical 42]

A solution of ethyl 2-oxo-3-methyl-3-pentenoate (1.56 g, 10.0 mmol) in ethanol (30 ml) was treated with 2-
Chlorophenylhydrazine sulfate (1.92 g, 5.00 mmol) and potassium carbonate (760 mg, 5.50 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, and the residue was diluted with 1N-hydrochloric acid (3
0 ml) was added and this was extracted with ether (20 ml x 3 times).
The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration, and the filtrate is distilled off under reduced pressure to obtain the desired product 2- (2-
A pale yellow oily product of ethyl dichlorophenyl) hydrazono-3-methyl-3-pentenoate (2.46 g, yield 87.7%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.50Hz, 3H),
1.82 (d, J = 7.50Hz, 3H), 1.97 (s, 3H), 4.43 (q, J = 7.50Hz, 2
H), 5.96 (q, J = 7.50Hz, 1H), 7.2〜7.7 (m, 4H), 11.3 (br s, 1
H).

Example-23

[0126]

[Chemical 43]

A solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (0.86 g, 4.72 mmol) in ethanol (15 ml) was treated with 4-fluorophenylhydrazine hydrochloride (0.77 g, 4.72 mmol).
2 mmol) and potassium carbonate (0.36 g, 2.60 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure and the residue was 1
N-hydrochloric acid (20 ml) was added and this was extracted with ether (20 ml x 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to give the desired product, 2- (4-fluorophenyl) hydrazono-2- (1-
A pale yellow oily product of ethyl cyclohexenyl) acetate (1.38 g, yield 100%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.25Hz, 3H),
1.5 to 1.9 (m, 4H), 2.0 to 2.6 (m, 4H), 4.34 (q, J = 7.25Hz, 2H),
6.1 ~ 6.4 (m, 1H), 6.8 ~ 7.3 (m, 4H), 11.3 (br s, 1H).

Example-24

[0129]

[Chemical 44]

To a solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (0.81 g, 4.43 mmol) in ethanol (15 ml) was added 2,4-dichlorophenylhydrazine hydrochloride (0.95 g,
4.43 mmol) and potassium carbonate (0.34 g, 2.44 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid (20 ml) was added to the residue, and this was added with ether (20 ml × 3).
Times). The organic layers were combined and then saturated brine (20
ml) and dried over anhydrous magnesium sulfate. The desiccant is separated by filtration, and the filtrate is distilled off under reduced pressure to give the desired product, 2- (2,4-dichlorophenyl) hydrazono-.
Ethyl 2- (1-cyclohexenyl) acetate (1.08 g, yield 7
1.1%) of a pale yellow oil was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.25Hz, 3H),
1.5 to 1.9 (m, 4H), 2.1 to 2.6 (m, 4H), 4.39 (q, J = 7.25Hz, 2H),
6.1 to 6.4 (m, 1H), 7.0 to 7.4 (m, 2H), 7.52 (d, J = 7.75Hz, 1H),
11.3 (br s, 1H).

Example-25

[0132]

[Chemical formula 45]

A solution of ethyl 2-oxo-4-phenyl-3-butenoate (233 mg, 1.14 mmol) in ethanol (8 ml) was treated with 2-
Chlorophenylhydrazine sulfate (219 mg, 0.57 mmol) and potassium carbonate (87 mg, 0.63 mmol) were added at room temperature. After stirring for 20 hours, the solvent was evaporated under reduced pressure, 1N-hydrochloric acid (10 ml) was added to the residue, and this was extracted with ether (8 ml × 3 times). The organic layers were combined, then washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a tan oil. By purifying and separating this by column chromatography (ethyl acetate / hexane = 1/10),
The desired product, 2- (2-chlorophenyl) hydrazono-
Ethyl 4-phenyl-3-butenoate (234 mg, yield 62.4%)
A pale yellow oily substance was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.42 (t, J = 7.25Hz, 3H),
4.39 (q, J = 7.25Hz, 2H), 6.94 (d, J = 8.57Hz, 1H), 7.1〜7.6
(m, 9H), 7.77 (d, J = 8.57Hz, 1H).

Example-26

[0135]

[Chemical formula 46]

A solution of ethyl 2-oxo-3-methyl-3-pentenoate (7.65 g, 49.0 mmol) in ethanol (200 ml) was added with benzenesulfonyl hydrazide (8.44 g, 49.0 mmol) and acetic acid 8: 1.
Drops were added at room temperature. After stirring for 20 hours, the solvent was evaporated under reduced pressure, 1N-hydrochloric acid (100 ml) was added to the residue, and this was extracted with ether (100 ml × 3 times). The organic layers were combined, then washed with saturated brine (100 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. By purifying and separating this by column chromatography (ethyl acetate / hexane = 1/4), ethyl 2-benzenesulfonylhydrazono-3-methyl-3-pentenoate (10.3
A pale yellow oily matter (g, yield 67.5%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.34 (t, J = 7.25Hz, 3H),
1.74 (t, J = 6.81Hz, 3H), 1.79 (s, 3H), 4.33 (q, J = 7.25Hz, 2
H), 5.86 (q, J = 6.81Hz, 1H), 7.4〜7.7 (m, 3H), 7.9〜8.1 (m, 2
H), 9.55 (br s, 1H).

Example-27

[0138]

[Chemical 47]

Ethyl 2-oxo-2- (1-cyclohexenyl) acetate (5.67 g, 30.0 mmol) in ethanol (100 ml)
Benzenesulfonyl hydrazide (8.44g, 49.0mmol) in the solution
And 4 drops of acetic acid were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid (60 ml) was added to the residue, and this was extracted with ethyl acetate (50 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtered solution was distilled off under reduced pressure to obtain a crude product. By recrystallizing this, ethyl 2-benzenesulfonylhydrazono-2- (1-cyclohexenyl) acetate (6.95
A pale yellow solid (g, yield 73.4%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.25Hz, 3H),
1.4 to 1.9 (m, 4H), 1.9 to 2.5 (m, 4H), 4.37 (q, J = 7.25Hz, 2H),
6.1 ~ 6.4 (m, 1H), 7.4 ~ 7.8 (m, 3H), 7.8 ~ 8.1 (m, 2H), 9.53
(br s, 1).

Example-28

[0141]

[Chemical 48]

2-Phenylhydrazono-3-methyl-3
-THF (20 ml) of ethyl pentenoate (628 mg, 2.54 mmol)-
To a mixed solution of water (20 ml), sodium hydrogencarbonate (854 mg, 1
0.2 mmol), potassium iodide (1.86 g, 11.2 mmol), iodine (7
(11 mg, 2.80 mmol) was added, and the mixture was heated with stirring at 70 ° C. for 2 hours while protected from light. After completion of the reaction, sodium thiosulfate (20 ml) was added to the reaction solution, and this was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1-phenyl-4,5-dimethylpyrazole-
A tan solid of ethyl 3-carboxylate (264 mg, 42.5% yield) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
2.22 (s, 3H), 2.29 (s, 3H), 4.42 (q, J = 7.03Hz, 2H), 7.44 (s, 5
H).

Example-29

[0144]

[Chemical 49]

Ethyl 2-phenylhydrazono-2- (1-cyclohexenyl) acetate (1.30 g, 4.78 mmol) in THF (3
(0 ml) -water (30 ml) in a mixed solution of sodium hydrogen carbonate (1.61
g, 19.1 mmol), potassium iodide (3.49 g, 21.0 mmol), iodine
(1.33g, 5.26mmol) was added and the mixture was protected from light at 70 ° C.
The mixture was heated and stirred for 2 hours. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was then added with ether (30 ml x 3 times).
It was extracted with. The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. By recrystallizing this product, the desired product 1-
Phenyl-4,5,6,7-tetrahydroindazole-
A tan solid of ethyl 3-carboxylate (783 mg, 60.6% yield) was obtained. MP: 102.0 to 104.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
1.7 to 1.9 (m, 4H), 2.6 to 3.0 (m, 4H), 4.42 (q, J = 7.03Hz, 2H),
7.3 ~ 7.6 (m, 5H) .IR (KBr disk, cm ^-1 ): 2950,1715,1600,1500,1440,1375,12
45,1140,770.

Example-30

[0147]

[Chemical 50]

2- (2-Fluoro-4-chloro-5-cyclopentyloxyphenyl) hydrazono-2- (1-
Cyclohexenyl) ethyl acetate (1.76g, 4.29mmol) TH
To a mixed solution of F (30 ml) -water (30 ml), sodium hydrogen carbonate
(1.44g, 17.2mmol), potassium iodide (3.14g, 18.9mmol),
Iodine (1.31 g, 5.15 mmol) was added, and the mixture was heated and stirred at 70 ° C. for 2 hours while protected from light. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was added with ether (30 ml).
(× 3 times). Combine the organic layers, then saturated saline
It was washed with (30 ml) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (2-fluoro-4-chloro-5).
-Cyclopentyloxyphenyl) -ethyl 4,5,6,7-tetrahydroindazole-3-carboxylate (1.53
g, yield 87.4%) was obtained as a tan solid. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
1.5 ~ 2.1 (m, 12H), 2.3 ~ 2.6 (m, 2H), 2.7 ~ 3.0 (m, 2H), 4.41
(q, J = 7.03Hz, 2H), 4.7〜4.9 (m, 1H), 7.02 (d, J _HF = 6.81Hz, 1
H), 7.25 (d, J _HF = 9.45Hz, 1H).

Example-31

[0150]

[Chemical 51]

2- (4-chlorophenyl) hydrazono-
To a mixed solution of ethyl 3-methyl-3-pentenoate (1.51 g, 5.37 mmol) in THF (30 ml) -water (30 ml), sodium hydrogen carbonate (1.80 g, 21.5 mmol) and potassium iodide (3.92 g, 23.6 mmo) were added.
l) and iodine (1.64 g, 6.44 mmol) were added, and the mixture was heated and stirred at 70 ° C. for 2 hours while protected from light. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was added with ether (3 ml).
It was extracted with 0 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (4-chlorophenyl)-.
Ethyl 4,5-dimethylpyrazole-3-carboxylate (1.
(05 g, 70.2% yield) was obtained as a tan solid. MP: 88.0-89.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
2.22 (s, 3H), 2.28 (s, 3H), 4.41 (q, J = 7.03Hz, 2H), 7.41 (s, 4
H) .IR (KBr disk, cm ^-1 ): 3000,2950,1730,1500,1440,1380,12
75,1160,1090,835.

Example-32

[0153]

[Chemical 52]

Ethyl 2- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) hydrazono-3-methyl-3-pentenoate (2.0 g, 5.22 mmol) in THF (30 m
l) -water (30 ml) in a mixed solution of sodium hydrogen carbonate (1.75 g, 2
0.9 mmol), potassium iodide (3.82 g, 23.0 mmol), iodine
(1.59g, 6.26mmol) was added and the mixture was protected from light at 70 ° C.
The mixture was heated and stirred for 2 hours. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was then added with ether (30 ml x 3 times)
It was extracted with. Combine the organic layers, then saturated brine (30 ml)
It was washed with and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4,5-dimethyl. A yellow-brown oily substance of ethyl pyrazole-3-carboxylate (1.65 g, yield 82.9%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
1.6 ~ 2.0 (m, 8H), 2.12 (s, 3H), 2.28 (s, 3H), 4.42 (q, J = 7.03
Hz, 2H), 4.6 ~ 5.0 (m, 1H) 6.99 (d, J _HF = 6.59Hz, 1H), 7.26 (d,
J _HF = 9.23Hz, 1H).

Example-33

[0156]

[Chemical 53]

2- (4-chlorophenyl) hydrazono-
Ethyl 2- (1-cyclohexenyl) acetate (1.71g, 5.56m
mol (THF) (30 ml) -water (30 ml) in a mixed solution of sodium hydrogen carbonate (1.87 g, 22.2 mmol) and potassium iodide (4.06 g, 24.
5 mmol) and iodine (1.69 g, 6.67 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 2 hours under light shielding. After completion of the reaction, sodium thiosulfate (20 ml) was added to the reaction solution, and this was extracted with ethyl acetate (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (4-chlorophenyl) -4,5,6,7-tetrahydroindazole-3-.
A tan solid of ethyl carboxylate (655 mg, 42.3% yield) was obtained. MP: 143.0-145.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
1.7 to 2.0 (m, 4H), 2.5 to 3.0 (m, 4H), 4.41 (q, J = 7.03Hz, 2H),
7.44 (s, 4H) .IR (KBr disk, cm ^-1 ): 2950,1730,1505,1450,1385,1255,11
55,1090,835.

Example-34

[0159]

[Chemical 54]

2- (3-trifluoromethylphenyl)
Ethyl hydrazono-2- (1-cyclohexenyl) acetate
THF (60 ml) of (2.84 g, 8.33 mmol) -water (60 ml) in a mixed solution of sodium hydrogen carbonate (2.80 g, 33.3 mmol), potassium iodide (6.08 g, 36.7 mmol), iodine (2.54 g, 10.0 mmol). ),
This mixture was heated and stirred at 70 ° C. for 2 hours while protected from light. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution,
This was extracted with ether (30 ml x 3). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (3-trifluoromethylphenyl) -4,5,6,7-tetrahydroindazole-3. -Ethyl carboxylate (2.29 g, yield 81.
4%) of a tan solid was obtained. MP: 77.5-78.5 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.41 (t, J = 7.03Hz, 3H),
1.6 ~ 2.0 (m, 4H), 2.6 ~ 3.0 (m, 4H), 4.42 (q, J = 7.03Hz, 2H),
7.4 ~ 8.0 (m, 4H) .IR (KBr disk, cm ^-1 ): 3000,2960,1725,1490,1445,1430,13
80,1335,1255,1155,1120,890,805,700.

Example-35

[0162]

[Chemical 55]

Ethyl 2- (2,4-dichlorophenyl) hydrazono-3-methyl-3-pentenoate (3.06 g, 9.70 m
THF (70 ml) -water (70 ml) mixed solution of sodium hydrogen carbonate (3.26 g, 38.8 mmol), potassium iodide (7.08 g, 42.
7 mmol) and iodine (2.95 g, 11.6 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 3 hours under light shielding. After completion of the reaction, sodium thiosulfate (20 ml) was added to the reaction solution, and this was extracted with ether (40 ml × 3 times). The organic layers were combined, washed with saturated brine (40 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. By recrystallizing this product, the desired product, 1- (2,4-dichlorophenyl) -4,5
-Ethyl dimethylpyrazole-3-carboxylate (1.79 g,
A tan solid with a yield of 58.8% was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz, 3H),
2.07 (s, 3H), 2.29 (s, 3H), 4.41 (q, J = 7.03Hz, 2H), 7.36 (d, J
= 1.32Hz, 2H), 7.53 (d, J = 1.32Hz, 1H).

Example-36

[0165]

[Chemical 56]

Ethyl 2- (4-fluorophenyl) hydrazono-3-methyl-3-pentenoate (2.38 g, 9.00 mmol)
In THF (65 ml) -water (65 ml) mixed solution with sodium hydrogen carbonate (3.02 g, 36.0 mmol) and potassium iodide (6.57 g, 39.6 mmo).
l) and iodine (2.74 g, 10.8 mmol) were added, and the mixture was heated and stirred at 70 ° C. for 3 hours in the dark. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was added with ether (4 ml).
It was extracted with 0 ml × 3 times). The organic layers were combined, washed with saturated brine (40 ml), and dried over anhydrous magnesium sulfate.
The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (4-fluorophenyl)-.
Ethyl 4,5-dimethylpyrazole-3-carboxylate (1.
32 g, yield 55.8%) was obtained as a tan solid. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.40 (t, J = 7.03Hz3), 2.
20 (s, 3H), 2.29 (s, 3H), 4.41 (q, J = 7.03Hz, 2H), 7.15 (dd, J =
8.79Hz, J _HF = 8.79Hz, 2H), 7.42 (dd, J = 8.79Hz, J _HF = 5.05Hz,
2H).

Example-37

[0168]

[Chemical 57]

Ethyl 2- (4-fluorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (1.38 g, 4.7
7 mmol of THF (20 ml) -water (20 ml) in a mixed solution of sodium hydrogen carbonate (1.60 g, 19.1 mmol) and potassium iodide (3.48 g, 2
1.0 mmol) and iodine (1.45 g, 5.72 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 4 hours under light shielding. After the reaction,
Sodium thiosulfate (10 ml) was added to the reaction solution, and this was extracted with ether (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (4-fluorophenyl) -4,5,6,7-tetrahydroindazole-3-.
A yellow-brown solid of ethyl carboxylate (0.59 g, yield 43.0%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.38 (t, J = 7.25Hz, 3H),
1.6 ~ 2.0 (m, 4H), 2.4 ~ 3.0 (m, 4H), 4.43 (q, J = 7.25Hz, 2H),
7.0 to 7.6 (m, 4H).

Example-38

[0171]

[Chemical 58]

Ethyl 2- (2,4-dichlorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (1.08
g, 3.16 mmol) in THF (15 ml) -water (15 ml) in a mixed solution of sodium hydrogen carbonate (1.06 g, 12.7 mmol) and potassium iodide.
(2.31 g, 13.9 mmol) and iodine (0.96 g, 3.80 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 4 hours under light shielding. After completion of the reaction, sodium thiosulfate (10 ml) was added to the reaction solution, and this was extracted with ether (20 ml × 3 times). Combine the organic layers,
Then, it was washed with saturated saline (20 ml) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (2,4-dichlorophenyl) -4,5,6,7-tetrahydroindazole-3-. A yellow-brown solid of ethyl carboxylate (0.99 g, yield 91.1%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.39 (t, J = 7.25Hz, 3H),
1.5 ~ 2.0 (m, 4H), 2.2 ~ 2.6 (m, 4H), 2.7 ~ 3.1 (m, 2H), 4.43
(q, J = 7.25Hz, 2H), 7.1〜7.8 (m, 3H).

Example-39

[0174]

[Chemical 59]

2- (2-chlorophenyl) hydrazono-
Ethyl 3-methyl-3-pentenoate (2.26g, 8.76mmol) in a mixed solution of THF (30ml) -water (30ml) sodium hydrogen carbonate (2.94g, 35.0mmol), potassium iodide (6.39g, 38.5mmo)
l) and iodine (2.67 g, 10.5 mmol) were added, and the mixture was heated and stirred at 70 ° C. for 4 hours in the dark. After the reaction was completed, sodium thiosulfate (20 ml) was added to the reaction solution, which was added with ether (3 ml).
It was extracted with 0 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (2-chlorophenyl)-.
Ethyl 4,5-dimethylpyrazole-3-carboxylate (1.
06 g, yield 43.6%) was obtained as a tan solid. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.39 (t, J = 7.25Hz, 3H),
2.07 (s, 3H), 2.30 (s, 3H), 4.43 (q, J = 7.25Hz, 2H), 7.2〜7.6
(m, 4H).

Example-40

[0177]

[Chemical 60]

2- (2-chlorophenyl) hydrazono-
Sodium hydrogen carbonate was added to a mixed solution of ethyl 4-phenyl-3-butenoate (234 mg, 0.71 mmol) in THF (5 ml) -water (5 ml).
(239 mg, 2.84 mmol), potassium iodide (520 mg, 3.13 mmol),
Iodine (216 mg, 0.85 mmol) was added, and the mixture was heated with stirring at 70 ° C. for 2 hours while protected from light. After the reaction was completed, sodium thiosulfate (10 ml) was added to the reaction solution, which was added with ether (10 ml).
(× 3 times). The organic layers were combined and then saturated brine (2
It was washed with 0 ml) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, ethyl 1- (2-chlorophenyl) -5-phenylpyrazole-3-carboxylate (139 mg, yield). Five
A pale yellow oil (9.9%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.42 (t, J = 7.25Hz, 3H),
4.43 (q, J = 7.25Hz, 2H), 7.09 (s, 1H), 7.2〜7.6 (m, 9H).

Example-41

[0180]

[Chemical formula 61]

2-Benzenesulfonylhydrazono-3-
Ethyl methyl-3-pentenoate (6.76 g, 21.8 mmol) in ethanol (100 ml) was added with sodium ethoxide (2.32 g, 32.7 g).
mmol) was added and the mixture was heated under reflux for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and this was mixed with ethyl acetate (4
It was extracted with 0 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure to give a pale yellow solid. This was washed with hexane and collected by filtration to obtain the desired product, 4,5-dimethylpyrazole-
Ethyl 3-carboxylate (2.03 g, yield 55.4%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.25Hz, 3H),
2.21 (s, 3H), 2.24 (s, 3H), 4.37 (q, J = 7.25Hz, 2H), 10.5 ~ 1
2.0 (br s, 1H) .IR (KBr disk, cm ^-1 ): 3250,1700,1440,1285,1170.

Example-42

[0183]

[Chemical formula 62]

2-Benzenesulfonylhydrazono-2-
Ethyl (1-cyclohexenyl) acetate (6.95g, 22.8mmol)
Solution of sodium ethoxide (1.55
g, 22.8 mmol) was added and the mixture was heated with stirring at 60 ° C. for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and this was extracted with ethyl acetate (50 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure to give a pale yellow solid. This was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, ethyl 4,5,6,7-tetrahydroindazole-3-carboxylate (2.26).
A white solid (g, yield 51.0%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.36 (t, J = 7.25Hz, 3H),
1.5 ~ 2.0 (m, 3H), 2.4 ~ 3.1 (m, 3H), 4.38 (q, J = 7.25Hz, 2H),
8.30 (br s, 1H) .IR (KBr disk, cm ^-1 ): 3200,2950,1730,1440,1260,1140.

Example-43

[0186]

[Chemical formula 63]

4,5-Dimethylisoxazole-3-
To a solution of ethyl carboxylate (0.48 g, 2.82 mmol) in 1,4-dioxane (10 ml), 1N-sodium hydroxide aqueous solution (3.1 m
l, 3.10 mmol) was added. After stirring at room temperature for 1 hour, 1N-hydrochloric acid was added to the reaction solution to adjust the pH to 1. This solution was extracted with ethyl acetate (10 ml × 3 times), the obtained organic layer was washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a white solid (0.39 g, yield 98.0%) of the desired product, 4,5-dimethylisoxazole-3-carboxylic acid. MP: 149.0-154.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.16 (s, 3H), 2.41 (s, 3
H), 7.24 (br s, 1H) .IR (KBr disk, cm ^-1 ): 3600 ~ 2400,1730,1625,1460,1270,
1200,1180,1085,760.

Example-44

[0189]

[Chemical 64]

4,5,6,7-Tetrahydrobenz [d]
Ethyl isoxazole-3-carboxylate (1.83g, 9.40m
To a 1,4-dioxane (30 ml) solution of (mol) was added 1N-sodium hydroxide aqueous solution (10.3 ml, 10.3 mmol). After stirring at room temperature for 1 hour, 1N-hydrochloric acid was added to the reaction solution to adjust the pH to 1
Adjusted to. This solution was extracted with ethyl acetate (20 ml x 3 times), and the obtained organic layer was washed with saturated brine (30 ml),
It was dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtered solution is distilled off under reduced pressure to obtain the desired product 4,5,
6,7-Tetrahydrobenz [d] isoxazole-
A white solid of 3-carboxylic acid (1.44 g, yield 91.9%) was obtained. MP: 129.5 to 131.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.7 to 2.0 (m, 4H), 2.5
~ 2.9 (m, 4H), 8.90 (br s, 1H) .IR (KBr disk, cm ^-1 ): 3500,2950,1710,1465,1280,1250,12
20,1180,775.

Example-45

[0192]

[Chemical 65]

Ethyl 1-phenyl-4,5-dimethylpyrazole-3-carboxylate (264 mg, 1.08 mmol) in 1,4-
1N-Sodium hydroxide aqueous solution (1.19 ml, 1.19 mmol) was added to the dioxane (8 ml) solution at room temperature. After stirring overnight, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (10 ml × 3 times). The organic layers were combined, then washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure to obtain the desired product, 1-phenyl-4,5-dimethylpyrazole-3-carboxylic acid (223 mg, yield 95.5%). ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.25 (s, 3H), 2.31 (s, 3
H), 7.46 (s, 5H).

Example-46

[0195]

[Chemical formula 66]

Ethyl 1-phenyl-4,5,6,7-tetrahydroindazole-3-carboxylate (200 mg, 0.74 mmo
1N-Sodium hydroxide aqueous solution (0.89 ml, 0.89 mmol) was added to a 1,4-dioxane (5 ml) solution of l) at room temperature. After stirring overnight, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (10 ml × 3 times). The organic layers were combined, then washed with saturated brine (10 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain the desired product, 1-phenyl-4,5,
6,7-Tetrahydroindazole-3-carboxylic acid (18
2 mg, yield 100%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.6 ~ 2.0 (m, 4H), 2.5 ~
3.0 (m, 4H), 7.3 ~ 7.8 (m, 5H), 9.1 (br s, 1H).

Example-47

[0198]

[Chemical formula 67]

Ethyl 1- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4,5,6,7-tetrahydroindazole-3-carboxylate (1.53 g, 3.7
5 mmol) in 1,4-dioxane (10 ml) at room temperature, 1N
-Sodium hydroxide aqueous solution (4.12 ml, 4.12 mmol) was added. After stirring for 1 day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (15 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is evaporated under reduced pressure to give the desired product, 1- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl).
-4,5,6,7-Tetrahydroindazole-3-carboxylic acid (1.35 g, yield 95.1%) was obtained. MP: 167.0 to 169.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.5 to 2.2 (m, 12H), 2.4
~ 2.7 (m, 2H), 2.7 ~ 3.1 (m, 2H), 4.7 ~ 5.0 (m, 1H), 7.35 (d, J
_HF = 6.81Hz, 1H), 7.31 (d, J _HF = 9.45Hz, 1H) .IR (KBr disk, cm ^-1 ): 2950,1700,1500,1470,1420,1260,12
00,1165.

Example-49

[0201]

[Chemical 68]

Ethyl 1- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4,5-dimethylpyrazole-3-carboxylate (1.65 g, 4.33 mmol)
To a solution of 4-dioxane (10 ml) at room temperature, 1N-aqueous sodium hydroxide solution (4.76 ml, 4.76 mmol) was added. After stirring for 1 day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (15 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is evaporated under reduced pressure to give the desired product, 1- (2-fluoro-4-chloro-5-cyclopentyloxyphenyl) -4,5-dimethylpyrazole-3-carboxylic acid. (1.53 g, yield 100%) was obtained. MP: 170.0 to 173.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.5 to 2.1 (m, 8H), 2.15
(d, J = 1.75Hz, 3H), 2.30 (s, 3H), 4.7〜5.0 (m, 1H), 6.98 (d, J
_HF = 6.81Hz, 1H), 7.29 (d, J _HF = 9.45Hz, 1H) .IR (KBr disk, cm ^-1 ): 3300 ~ 2500,1700,1505,1460,1420,1
270,1200,1175.

Example-50

[0204]

[Chemical 69]

Ethyl 1- (4-chlorophenyl) -4,5-dimethylpyrazole-3-carboxylate (0.50 g, 1.79 m)
mol) in 1,4-dioxane (10 ml) at room temperature, 1N-
Aqueous sodium hydroxide solution (1.97 ml, 1.97 mmol) was added.
After stirring for 1 day, adjust the pH to 1 by adding 1N hydrochloric acid,
This was extracted with ethyl acetate (15 ml x 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is evaporated under reduced pressure to give the desired product, 1- (4-chlorophenyl) -4,5-dimethylpyrazole-3-carboxylic acid.
(448 mg, yield 100%) was obtained. MP: 176.0-184.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.24 (s, 3H), 2.29 (s, 3
H), 7.43 (s, 4H) .IR (KBr disk, cm ^-1 ): 3300 ~ 2500,1690,1500,1455,1375,1
260,1165,1090,840.

Example-51

[0207]

[Chemical 70]

1- (3-trifluoromethylphenyl)
-Ethyl 4,5,6,7-tetrahydroindazole-3-carboxylate (1.70g, 5.02mmol) in 1,4-dioxane (5m
l) solution at room temperature, 1N-sodium hydroxide aqueous solution (5.02m
l, 5.02 mmol) was added. After stirring for 1 day, adjust the pH to 1 by adding 1N-hydrochloric acid, and add ethyl acetate (20 ml x 3 times).
It was extracted with. Combine the organic layers, then saturated brine (20 ml)
It was washed with and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain the desired product, 1- (3-trifluoromethylphenyl) -4,5 ,.
6,7-Tetrahydroindazole-3-carboxylic acid (1.
45 g, yield 92.8%) was obtained. MP: 77.5 to 78.5 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 1.7 to 2.0 (m, 4H), 2.6 to
3.0 (m, 4H), 7.5 ~ 7.9 (m, 4H) .IR (KBr disk, cm ^-1 ): 3300 ~ 2500,1690,1505,1455,1440,1
380,1330,1280,1160,1130,950,835,810,700.

Example-52

[0210]

[Chemical 71]

1- (2,4-dichlorophenyl) -4,
Ethyl 5-dimethylpyrazole-3-carboxylate (1.40
g, 4.48 mmol) in 1,4-dioxane (15 ml) at room temperature,
1N-Sodium hydroxide aqueous solution (4.93 ml, 4.93 mmol) was added. After stirring for one day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product, 1- (2,4-).
Dichlorophenyl) -4,5-dimethylpyrazole-3
-Carboxylic acid (1.24 g, yield 94.2%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.07 (s, 3H), 2.29 (s, 3
H), 7.3 to 7.6 (m, 3H) .IR (KBr disk, cm ^-1 ): 3300 to 2400,1700,1500,1450,1305,1
275,1180,840,790.

Example-53

[0213]

[Chemical 72]

1- (4-fluorophenyl) -4,5-
Ethyl dimethylpyrazole-3-carboxylate (1.32g, 5.0
2 mmol) in 1,4-dioxane (10 ml) at room temperature, 1N
-Sodium hydroxide aqueous solution (5.52 ml, 5.52 mmol) was added. After stirring for one day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain the desired product, 1- (4-fluorophenyl) -4,5-dimethylpyrazole-3-carboxylic acid (1.14 g, yield 96.6%). Got MP: 191.5-192.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.23 (s, 3H), 2.31 (s, 3
H), 7.18 (d, d, J = 9.01Hz, J _HF = 9.01Hz, 2H), 7.43 (d, d, J = 9.0
1Hz, J _HF = 4.84Hz, 2H) .IR (KBr disk, cm ^-1 ): 3300 ~ 2400,1690,1515,1455,1225,1
170,840.

Example-54

[0216]

[Chemical formula 73]

Ethyl 1- (2-chlorophenyl) -5-phenylpyrazole-3-carboxylate (139 mg, 0.43 mmo
1N-Sodium hydroxide aqueous solution (0.47 ml, 0.47 mmol) was added to a 1,4-dioxane (1 ml) solution of l) at room temperature. After stirring for one day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (20 ml × 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure to give the desired product, 1- (2-chlorophenyl) -5-phenylpyrazole-3-carboxylic acid (1.1
A pale yellow solid (4 g, yield 96.6%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ 7.1 to 7.6 (m, ¹⁰ H).

Example-55

[0219]

[Chemical 74]

Ethyl 1- (2-chlorophenyl) -4,5-dimethylpyrazole-3-carboxylate (1.06 g, 3.82 m
mol) in 1,4-dioxane (15 ml) at room temperature, 1N-
Aqueous sodium hydroxide solution (4.20 ml, 4.20 mmol) was added.
After stirring for 1 day, adjust the pH to 1 by adding 1N hydrochloric acid,
It was extracted with ethyl acetate (20 ml x 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product, 1- (2-chlorophenyl) -4,5-dimethylpyrazole-3-carboxylic acid.
(0.96 g, yield 100%) was obtained. MP: 237.0-239.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ2.09 (s, 3H), 2.32 (s, 3
H), 7.3 ~ 7.5 (m, 4H) .IR (KBr disk, cm ^-1 ): 3300 ~ 2400,1700,1500,1455,1300,1
275,1180,760.

Example-56

[0222]

[Chemical 75]

1- (4-fluorophenyl) -4,5,
To a solution of ethyl 6,7-tetrahydroindazole-3-carboxylate (0.59 g, 2.05 mmol) in 1,4-dioxane (10 ml) at room temperature, 1N-sodium hydroxide aqueous solution (2.25 ml, 2.25
mmol) was added. After stirring for 1 day, add 1N hydrochloric acid and add
The H was adjusted to 1 and this was extracted with ethyl acetate (20 ml x 3 times). The organic layers were combined, washed with saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product 1.
-(4-Fluorophenyl) -4,5,6,7-tetrahydroindazole-3-carboxylic acid (0.32 g, yield 60.0%)
To give a pale yellow solid. MP: 207.0 to 211.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): 1.5 to 2.1 (m, 4H), 2.4 to 3.
0 (m, 4H), 6.9 ~ 7.7 (m, 4H), 8.8 ~ 9.8 (br s, 1H) .IR (KBr disk, cm ^-1 ): 3200 ~ 2200,1690,1515,1460,1380,1
280,1225,1170,845.

Example-57

[0225]

[Chemical 76]

1- (2,4-dichlorophenyl) -4,
To a solution of ethyl 5,6,7-tetrahydroindazole-3-carboxylate (0.99 g, 2.91 mmol) in 1,4-dioxane (15 ml) at room temperature, 1N-sodium hydroxide aqueous solution (3.20 ml, 3.
20 mmol) was added. After stirring for 1 day, 1N-hydrochloric acid was added to adjust the pH to 1, and this was extracted with ethyl acetate (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product 1.
-(2,4-Dichlorophenyl) -4,5,6,7-tetrahydroindazole-3-carboxylic acid (0.79 g, yield 86.8
%) White solid was obtained. MP: 248.0 to 249.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.6 to 2.1 (m, 4H), 2.3 to
2.7 (m, 2H), 2.7 to 3.1 (m, 2H), 7.3 to 7.7 (m, 3H) .IR (KBr disk, cm ^-1 ): 3300 to 2400,1695,1500,1450,1270,1
165,820.

Example-58

[0228]

[Chemical 77]

A solution of ethyl 2-oxo-2- (1-cyclohexenyl) acetate (2.99 g, 16.4 mmol) in ethanol (85 ml) was added with 3,5-dichlorophenylhydrazine hydrochloride (3.50).
g, 16.4 mmol) and potassium carbonate (1.25 g, 9.02 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid (40 ml) was added to the residue, and this was mixed with ethyl acetate (30 ml).
(× 3 times). Combine the organic layers, then saturated saline
It was washed with (30 ml) and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was evaporated under reduced pressure to give the desired product, ethyl 2- (3,5-dichlorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (5.69 g, yield 101%). ) Was obtained as a light brown oily substance. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.38 (t, J = 7.25H
z, 3H), 1.5 to 1.9 (m, 4H), 2.1 to 2.5 (m, 4H), 4.34 (q, J = 7.25H
z, 2H), 6.1 ~ 6.3 (m, 1H), 6.87 (t, J = 1.75Hz, 1H), 7.0 ~ 7.2
(m, 2H), 11.1 (brs, 1H).

Example-59

[0231]

[Chemical 78]

To a solution of ethyl 2-oxo- (1-cyclohexenyl) acetate (2.92 g, 16.0 mmol) in ethanol (80 ml) was added 2 parts.
-Fluorophenylhydrazine hydrochloride (2.68 g, 16.0 mmol)
And potassium carbonate (1.22 g, 8.8 mmol) were added at room temperature. After stirring overnight, the solvent was distilled off under reduced pressure, 1N-hydrochloric acid (40 ml) was added to the residue, and this was extracted with ether (30 ml × 3 times). The organic layers were combined, washed with saturated brine (30 ml), and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the target compound.
A light brown oily substance of ethyl-(2-fluorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (4.13 g, yield 89%) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.37 (t, J = 7.25H
z, 3H), 1.5 to 2.0 (m, 4H), 2.0 to 2.6 (m, 4H), 4.36 (q, J = 7.25H
z, 2H), 6.1 ~ 6.3 (m, 1H), 6.7 ~ 7.3 (m, 3H), 7.5 (t, J = 7.50H
z, 1H), 11.0 (brs, 1H).

Example-60

[0234]

[Chemical 79]

Ethyl 2- (3,5-dichlorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (5.69
g, 16.7 mmol) in THF (100 ml) -water (100 ml) in a mixed solution of sodium hydrogen carbonate (5.60 g, 66.7 mmol) and potassium iodide.
(12.2 g, 73.4 mmol) and iodine (5.08 g, 20.0 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 2 hours under light shielding. After completion of the reaction, sodium thiosulfate (50 ml) was added to the reaction solution, and this was extracted with ether (50 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give 1- (3,5-
Dichlorophenyl) -4,5,6,7-tetrahydroindazole-3-carboxylate ethyl (2.37 g, yield 41.8%)
To give a tan solid. MP: 117.0-118.0 ° C. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.41 (t, J = 7.03H
z, 3H), 1.7 to 2.0 (m, 4H), 2.6 to 3.0 (m, 4H), 4.42 (q, J = 7.03H
z, 2H), 7.35 (t, J = 1.75Hz, 1H), 7.49 (d, J = 1.76Hz, 2H) .IR (KBr disk, cm ^-1 ): 1710,1585,1430,1420,1230,1155 , 85
0,805.

Example-61

[0237]

[Chemical 80]

Ethyl 2- (2-fluorophenyl) hydrazono-2- (1-cyclohexenyl) acetate (4.62 g, 16.
To a mixed solution of THF (100 ml) -water (100 ml) of 0 mmol) sodium hydrogen carbonate (5.38 g, 64.0 mmol), potassium iodide (11.7
g, 70.4 mmol) and iodine (4.87 g, 19.2 mmol) were added, and this mixture was heated with stirring at 70 ° C. for 4 hours under light shielding. After completion of the reaction, sodium thiosulfate (50 ml) was added to the reaction solution, and this was extracted with ether (50 ml × 3 times). The organic layers were combined, then washed with saturated brine (50 ml), and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the filtrate was distilled off under reduced pressure to obtain a crude product. This product was purified and separated by column chromatography (ethyl acetate / hexane = 1/4) to give the desired product, 1- (2-fluorophenyl) -4,5,6,7-tetrahydroindazole-3-carboxylic acid. A tan solid of ethyl acidate (3.12 g, 67.8% yield) was obtained. ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.39 (t, J = 7.25H
z, 3H), 1.7 ~ 1.9 (m, 4H), 2.3 ~ 2.7 (m, 2H), 2.6 ~ 3.0 (m, 2
H), 4.43 (q, J = 7.25Hz, 2H), 7.1〜7.7 (m, 4H).

Example-62

[0240]

[Chemical 81]

1- (3,5-dichlorophenyl) -4,
Ethyl 5,6,7-tetrahydroindazole-3-carboxylate (2.37 g, 6.99 mmol) in 1,4-dioxane (30 ml)
To the solution, 1N-sodium hydroxide aqueous solution (7.69 ml, 7.69 mm
ol) was added. After stirring overnight at room temperature, 1N-
Hydrochloric acid was added to adjust the pH to 1. This solution was extracted with ethyl acetate (20 ml x 3 times), and the obtained organic layer was saturated brine.
It was washed with (20 ml) and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product, 1- (3,5-dichlorophenyl) -4,5,5.
6,7-Tetrahydroindazole-3-carboxylic acid
A pale yellow solid (2.01 g, yield 92.5%) was obtained. MP: 213.0-217.0 ° C ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.6-2.1 (m, 4H),
2.6〜3.0 (m, 4H), 7.38 (t, J = 1.76Hz, 1H), 7.50 (d, J = 1.76H
z (2H) .IR (KBr disk, cm ^-1 ): 3200 ~ 2400,1685,1585,1430,1275,1
250,1155,1135,805.

Example-63

[0243]

[Chemical formula 82]

1- (2-fluorophenyl) -4,5,
To a solution of ethyl 6,7-tetrahydroindazole-3-carboxylate (3.11 g, 10.8 mmol) in 1,4-dioxane (50 ml), 1N-sodium hydroxide aqueous solution (12.0 ml, 12.0 mmol) was added.
Was added. After stirring at room temperature overnight, 1N-hydrochloric acid was added to the reaction solution to adjust the pH to 1. This solution was added to ethyl acetate (2
The organic layer obtained was extracted with saturated saline (20 m).
It was washed with l) and dried over anhydrous magnesium sulfate. The desiccant is filtered off, and the filtrate is distilled off under reduced pressure to obtain the desired product, 1- (2-fluorophenyl) -4,5,6,7-.
A light yellow solid of tetrahydroindazole-3-carboxylic acid (2.51 g, yield 96.4%) was obtained. MP: 202.0-203.0 ° C ¹ H-NMR spectrum (CDCl ₃ , TMS, ppm): δ1.7-2.0 (m, 4H),
2.4-2.7 (m, 2H), 2.7-3.0 (m, 2H), 7.1-7.7 (m, 4H) .IR (KBr disk, cm ^-1 ): 3200-2400,1690,1510,1450,1270,1
170,760.

[0245]

By using the method and intermediate of the present invention, the above-mentioned 3-azolecarboxylic acid derivative having various substituents can be easily obtained from an inexpensive raw material.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location C07D 231/54 261/18 261/20

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are integrated with the carbon to which they are bonded. R ³ represents a hydrogen atom, an alkyl group or an aralkyl group) and a β, γ-unsaturated-α-ketocarboxylic acid derivative represented by the general formula (2) (In the formula, X represents an oxygen atom or N—Y, and Y represents an aryl group.)
General formula (3) (In the formula, X represents an oxygen atom or N—Y, and Y represents an aryl group. R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² may combine with the carbon to which they are bonded to form a ring, and R ³ represents a hydrogen atom, an alkyl group or an aralkyl group. A saturated -α-iminocarboxylic acid derivative is obtained, which is then reacted with iodine in the presence of a base and an alkali metal iodide; (In the formula, X represents an oxygen atom or N—Y, and Y represents an aryl group. R ¹ and R ² are each independently a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² may combine with the carbon to which they are bonded to form a ring, and R ³ represents a hydrogen atom, an alkyl group or an aralkyl group. Method for producing acid derivative. 2. A compound represented by the general formula (1): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are integrated with the carbon to which they are bonded. R ³ represents a hydrogen atom, an alkyl group or an aralkyl group), and a β, γ-unsaturated-α-ketocarboxylic acid derivative represented by the general formula (5): ] (In the formula, R ⁴ represents a lower alkyl group, a substituted or unsubstituted phenyl group or a lower perfluoroalkyl group.)
By reacting with a hydrazine derivative represented by the general formula (6) (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are integrated with the carbon to which they are bonded. R ³ represents a hydrogen atom, an alkyl group or an aralkyl group, and R ⁴ represents a lower alkyl group, a substituted or unsubstituted phenyl group or a lower perfluoroalkyl group. , γ-Unsaturated-α-iminocarboxylic acid derivative is obtained, and then this is reacted with a base, which is represented by the general formula (7): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are integrated with the carbon to which they are bonded. may form a ring Te .R ³ the method of manufacturing a hydrogen atom, 3-pyrazole carboxylic acid derivative represented by an alkyl group or an aralkyl group.). 3. The general formula (8): (In the formula, R ¹ and R ² each independently represent a hydrogen atom, a linear or branched alkyl group, a cycloalkyl group or an aryl group. Further, R ¹ and R ² are integrated with the carbon to which they are bonded. may form a ring Te .R ³ is .X 'is oxygen atom represents a hydrogen atom, an alkyl group or an aralkyl group or an N-,
'Represent, Y' Y represents a group represented by the aryl group or -SO ₂ R ^4, R ⁴ represents a lower alkyl group, a substituted or unsubstituted phenyl group or a lower perfluoroalkyl group. ), The β, γ-unsaturated-α-iminocarboxylic acid derivative.