JP2006206473A - Method for producing 3-hydroxypyrazole-1-carboxamide derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for the industrial production of a 3-hydroxypyrazole-1-carboxamide derivative (2) useful as an important production intermediate for a 3-(substituted aryloxy)pyrazole-1-carboxamide derivative useful as an active component of herbicides and provide the important production intermediate. <P>SOLUTION: The 3-hydroxy-5-methylpyrazole-1-carboxamide derivative expressed by general formula (2) is produced by reacting a compound of general formula (1) with diketene. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 3-hydroxypyrazole-1-carboxamide derivative, which is a production intermediate of a herbicide, and a production intermediate thereof.

The method for producing a 3-hydroxy-5-methylpyrazole-1-carboxamide derivative by the reaction of a 4N-substituted semicarbazide derivative with diketene, which is the present invention, is a novel method, and no examples have been reported so far. The 3-hydroxypyrazole-1-carboxamide derivative that can be produced according to the present invention is a compound useful as an important production intermediate of a 3- (substituted aryloxy) pyrazole-1-carboxamide derivative useful as an active ingredient of a herbicide. Yes (see Patent Document 1). Patent Document 1 discloses that a 3-hydroxypyrazole-1-carboxamide derivative can be produced by reacting 3-hydroxypyrazole and an isocyanate in the presence of a base in some cases. In addition to the 3-hydroxypyrazole-1-carboxamide derivative, 5-hydroxypyrazole-1-carboxamide derivative, which is a positional isomer, is by-produced, and it is not necessarily an industrially preferable production method.
International Publication No. 02/066439 Pamphlet

  The object of the present invention is to industrially produce 3-hydroxypyrazole-1-carboxamide derivative (2), which is an important production intermediate of 3- (substituted aryloxy) pyrazole-1-carboxamide derivatives useful as active ingredients of herbicides. It is to provide a production method and to provide an important production intermediate.

  As a result of intensive studies to solve the above problems, the present inventors have reacted the 4N-substituted semicarbazide derivative (1) with diketene to give the desired 3-hydroxypyrazole-1-carboxamide derivative (2). Was able to be produced with good selectivity and yield, and the present invention was completed.

That is, the present invention relates to the general formula (1)
(Wherein R represents an optionally substituted alkyl group having 1 to 12 carbon atoms) and a diketene is optionally reacted in the presence of an acid catalyst. General formula (2)
(Wherein, R represents the same meaning as described above) relates to a method for producing a 3-hydroxypyrazole-1-carboxamide derivative.

Furthermore, the present invention provides a general formula (1)
(Wherein R represents the same meaning as described above), and a diketene is reacted with a 4K-substituted semicarbazide derivative represented by the general formula (3) of the present invention.
(Wherein R represents the same meaning as described above) is produced by cyclization of the 1N, 4N-disubstituted semicarbazide derivative represented by the following formula in the presence of an acid catalyst. (2)
(Wherein, R represents the same meaning as described above) relates to a method for producing a 3-hydroxypyrazole-1-carboxamide derivative.

  The present invention provides a simple yield of 3-hydroxypyrazole-1-carboxamide derivative (2), which is an important production intermediate of 3- (substituted aryloxy) pyrazole-1-carboxamide derivatives useful as active ingredients of herbicides. The present invention provides an industrially extremely useful production method that can be produced well.

  In the present invention, the alkyl group having 1 to 12 carbon atoms which may be substituted represented by R may be any of linear, branched or cyclic, methyl group, ethyl group, propyl Group, isopropyl group, cyclopropyl group, cyclopropylmethyl group, butyl group, isobutyl group, tert-butyl group, sec-butyl group, pentyl group, tert-pentyl group, 2-pentyl group, 3-pentyl group, cyclopentyl group Exemplify 1-methylcyclopentyl group, hexyl group, 2-hexyl group, 3-hexyl group, cyclohexyl group, heptyl group, octyl group, 2-ethylhexyl group, nonyl group, decyl group, undecyl group, dodecyl group, etc. Can do. Further, one or more of these alkyl groups may be substituted with a halogen atom, an alkyloxycarbonyl group, a cyano group, a heterocyclic ring, etc., specifically, a 2-chloroethyl group, a 2-bromoethyl group, a 3-chloropropyl group. Methoxycarbonylmethyl group, ethoxycarbonylethyl group, furfuryl group, tetrahydrofurfuryl group and the like.

  Hereinafter, the production method of the present invention will be described in more detail. According to the present invention, 3-hydroxypyrazole-1-carboxamide derivative (2) can be produced by the following production method-1 and production method-2.

Production method-1 (Step-1) is a method of reacting 4N-substituted semicarbazide derivative (1) with diketene to produce 3-hydroxypyrazole-1-carboxamide derivative (2) in one step.
(Wherein R represents the same meaning as described above.)
Although this reaction can be carried out without a solvent, it can also be carried out in a solvent that does not adversely influence the reaction. Such solvents include hydrocarbon solvents such as hexane, heptane, octane, ligroin, petroleum ether, aromatic solvents such as toluene, xylene, chlorobenzene, dichlorobenzene, ethyl acetate, propyl acetate, methyl propionate, etc. Ester solvents, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxyethane (DME), ether solvents such as cyclopentyl methyl ether (CPME), acetonitrile, propionitrile, iso Nitrile solvents such as butyronitrile, halogen solvents such as chloroform, dichloromethane, carbon tetrachloride, acid amides such as formamide, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone solvent Dimethyl sulfoxide (DMSO), sulfur-based solvents such as sulfolane, water, and further can be exemplified a mixture of these solvents. Of these, DMSO or water is preferred because of its good yield.

  This reaction is preferably carried out at a reaction temperature appropriately selected from −30 to 180 ° C. in that the desired product can be obtained in high yield. However, the initial stage of the reaction in which the 4N-substituted semicarbazide derivative (1) is added to the diketene is carried out at a low temperature of about -30 to 60 ° C., so that the selectivity of the reaction is excellent and the formation of by-products is suppressed. This is preferable in that it can be performed.

  In addition, the stage in which the adduct 1N, 4N-disubstituted semicarbazide derivative (3) is cyclized is carried out at a reaction temperature selected from a temperature of 60 ° C. or higher. It is preferable in terms of good yield. Furthermore, this reaction can be completed in a shorter time by carrying out in the presence of an acid catalyst. As the acid, either a protonic acid or a Lewis acid can be used. Protic acids include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, carboxylic acids such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -Toluenesulfonic acid, camphorsulfonic acid, sulfonic acid such as Nafion, phosphoric acid such as phosphoric acid, polyphosphoric acid, etc., Lewis acid includes zinc chloride, tin dichloride, aluminum trichloride, boron trifluoride ether complex, Examples thereof include iron trichloride, titanium tetrachloride, nickel chloride, and palladium chloride. Protonic acids such as hydrochloric acid, sulfuric acid, and acetic acid that are inexpensive and easy to handle are preferable.

The amount of acid used may be a so-called catalytic amount, and by using 0.0001 to 0.5 equivalents of the reaction substrate, the target product can be obtained in good yield. An organic acid such as acetic acid can also be used as a solvent.
After completion of the reaction, the desired product can be obtained by ordinary post-treatment, and the obtained crude product can be used for the next reaction without purification.If necessary, it can be purified by recrystallization or the like. You can also.

In production method-2, the 4N-substituted semicarbazide derivative (1) is reacted with diketene, preferably at a low temperature, to obtain an intermediate 1N, 4N-disubstituted semicarbazide derivative (3) (step-2). This is a method (Step 3) for producing a pyrazole-1-carboxamide derivative (2) by cyclizing a product under heating.
(Wherein R represents the same meaning as described above.)

  The reaction in Step-2 is preferably performed at a low temperature of about −30 to 60 ° C. in order to obtain the target compound (3) with good yield. However, even at this reaction temperature, a part of the cyclization reaction of the next step-3 proceeds, and the 3-hydroxypyrazole-1-carboxamide derivative (2) is by-produced together with the target 1N, 4N-disubstituted semicarbazide derivative. . However, since the cyclized 3-hydroxypyrazole-1-carboxamide derivative (2) is a product of the next step-3, it does not harm the reaction and does not need to be separated.

  Although this reaction can be carried out without solvent, it can also be carried out in a solvent that does not harm the reaction. Examples of such organic solvents include hydrocarbon solvents such as hexane, heptane, octane, ligroin, petroleum ether, aromatic solvents such as toluene, xylene, chlorobenzene, and dichlorobenzene, ethyl acetate, propyl acetate, and methyl propionate. Ester solvents such as diethyl ether, diisopropyl ether, THF, 1,4-dioxane, DME, CPME, etc., nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, chloroform, dichloromethane, Illustrative examples include halogen solvents such as carbon chloride, acid amide solvents such as formamide, DMF, N, N-dimethylacetamide and N-methylpyrrolidone, sulfur solvents such as DMSO and sulfolane, water, and mixed solvents thereof. be able to. Of these, DMSO or water is preferred because of its good yield.

In the 1N, 4N-disubstituted semicarbazide derivative (3) obtained in this step, for example, the presence of several tautomers (3a, 3b) as shown below can be considered. It includes tautomers. Here, for the sake of convenience, it will be displayed in a diket (3).
(Wherein R represents the same meaning as described above.)

Step-3 is a step of cyclizing the 1N, 4N-disubstituted semicarbazide derivative (3) to convert it to a pyrazole-1-carboxamide derivative (2).
Although this reaction can be carried out without a solvent, it can also be carried out in a solvent that does not adversely influence the reaction. Such organic solvents include hexane, heptane, octane, ligroin, petroleum ether and other hydrocarbon solvents, toluene, xylene, chlorobenzene, dichlorobenzene and other aromatic solvents, ethyl acetate, propyl acetate, methyl propionate, etc. Ester solvents, diethyl ether, diisopropyl ether, THF, ether solvents such as 1,4-dioxane, DME, CPME, nitrile solvents such as acetonitrile, propionitrile, isobutyronitrile, chloroform, dichloromethane, tetrachloride Halogen solvents such as carbon, acid amide solvents such as formamide, DMF, N, N-dimethylacetamide and N-methylpyrrolidone, sulfur solvents such as DMSO and sulfolane, ketones such as acetone, ethyl methyl ketone and cyclohexanone. Down solvents, water, and further can be exemplified a mixture of these solvents. Of these, DMSO or water is preferred because of its good yield.

  By carrying out this reaction in the presence of an acid catalyst, the reaction can be completed in a shorter time. As the acid, either a protonic acid or a Lewis acid can be used. Protic acids include mineral acids such as hydrochloric acid, sulfuric acid and nitric acid, acetic acid, propionic acid, butyric acid, valeric acid, benzoic acid, carboxylic acids such as trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -Toluenesulfonic acid, camphorsulfonic acid, sulfonic acid such as Nafion, phosphoric acid such as phosphoric acid, polyphosphoric acid, etc., Lewis acid includes zinc chloride, tin dichloride, aluminum trichloride, boron trifluoride ether complex, Examples thereof include iron trichloride, titanium tetrachloride, nickel chloride, and palladium chloride. Protonic acids such as hydrochloric acid, sulfuric acid, and acetic acid that are inexpensive and easy to handle are preferable.

The amount of acid used may be a so-called catalytic amount, and by using 0.0001 to 0.5 equivalents of the reaction substrate, the target product can be obtained in good yield. An organic acid such as acetic acid can also be used as a solvent.
After completion of the reaction, the desired product can be obtained by ordinary post-treatment, and the obtained crude product can be used for the next reaction without purification.If necessary, it can be purified by recrystallization or the like. You can also.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these. Further, the 3-hydroxypyrazole-1-carboxamide derivative obtained by the present invention is derived into a 3- (substituted aryloxy) pyrazole-1-carboxamide derivative useful as an active ingredient of a herbicide by the method described in Patent Document 1. Some examples are given in the following reference examples.

Example-1
To a solution of diketene (1.65 mL, 21.3 mmol) in DMSO (4 mL) was slowly added a solution of ethyl semicarbazide (2.00 g, 19.4 mmol) in DMSO (16 mL) at 0 ° C. over 1 hour, and then at room temperature, 0.5 mL. Stir for hours. Next, sulfuric acid (0.02 mL, 0.35 mmol) was added to the reaction solution, and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate (30 mL × 5). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/1) to give a white solid of N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide. (2.52 g, 77%) was obtained. Melting point: 107-109 ° C; 500 MHz ¹ H-NMR (CDCl ₃ ): δ 8.40 (1H, br s), 6.50 (1H, br t, J = 5.8 Hz), 5.63 (1H, s), 3.39 (2H , dq, J = 5.8 and 7.3 Hz), 2.55 (3H, s), 1.24 (3H, t, J = 7.3 Hz).

Example-2
To a solution of diketene (8.23 mL, 107 mmol) in DMSO (20 mL) was slowly added a solution of ethyl semicarbazide (10 g, 97.0 mmol) in DMSO (80 mL) at 0 ° C. over 1 hour, and then at room temperature, 0.5 mL. Stir for hours. Next, sulfuric acid (0.11 mL, 1.94 mmol) was added to the reaction solution, and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, water (50 mL) and saturated aqueous sodium hydrogen carbonate solution (20 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (300 mL × 6). The organic layer was washed with a saturated aqueous sodium chloride solution (200 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/1) to give a white solid (14.2 g, N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide). 86%). The NMR spectrum was consistent with the product obtained in Example-1.

Example-3
To a solution of diketene (1.65 mL, 21.3 mmol) in water (4 mL) was slowly added a solution of ethyl semicarbazide (2.0 g, 19.4 mmol) in water (16 mL) at 0 ° C. over 1 hour, and then at room temperature, 0.5 mL. Stir for hours. Next, sulfuric acid (0.02 mL, 0.35 mmol) was added to the reaction solution, and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, the reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 5). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/1) to give a white solid of N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide. (2.11 g, 64%) was obtained. The NMR spectrum was consistent with the product obtained in Example-1.

Example-4
To a solution of diketene (1.50 mL, 19.4 mmol) in DMSO (4 mL) was slowly added a solution of ethyl semicarbazide (2.04 g, 19.4 mmol) in DMSO (16 mL) at 0 ° C. over 1 hour, and then at room temperature, 0.5 mL. Stir for hours. Next, it heated at 100 degreeC for 1 hour. After completion of the reaction, the reaction mixture was washed with water (20
mL) and extracted with ethyl acetate (30 mL × 5). The organic layer was washed with a saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/1) to give a white solid of N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide. (0.99 g, 30%) was obtained. The NMR spectrum was consistent with the product obtained in Example-1.

Example-5
To a solution of diketene (1.34 mL, 17.4 mmol) in DMSO (4 mL) was slowly added a solution of ethyl semicarbazide (1.80 g, 17.4 mmol) in DMSO (14 mL) at 0 ° C. over 1 hour, and then at room temperature, 0.5 mL. Stir for hours. Ethyl acetate (100 mL) and hexane (400 mL) were added to the reaction mixture and stirred. The precipitated white precipitate was collected by filtration and washed with ethyl acetate to obtain a white solid (1.05 g, 32%) of 1N-1,3-dioxobutyl-4N-ethylsemicarbazide. Melting point: 130.5-132 ° C; 500 MHz ¹ H-NMR (DMSO): δ 9.65 (1H, d, J = 1.2 Hz), 7.82 (1H, d, J = 1.2 Hz), 6.35 (1H, t, J = 5.0 Hz), 3.34 (2H, s), 3.04 (2H, dq, J = 5.0 and 7.2Hz), 2.18 (3H, s), 1.00 (3H, t, J = 7.2 Hz).

Example-6
A solution of diketene (1.65 mL, 21.4 mmol) in DMF (4 mL) at 0 ° C. with ethyl semicarbazide (2.0
g, 19.4 mmol) in DMF (16 mL) was slowly added over 1 hour and then stirred at room temperature for 0.5 hour. Ethyl acetate (100 mL) and hexane (400 mL) were added to the reaction mixture and stirred. The precipitated white precipitate was collected by filtration and washed with ethyl acetate to obtain a white solid (1.20 g, 33%) of 1N-1,3-dioxobutyl-4N-ethylsemicarbazide. The NMR spectrum was consistent with the product obtained in Example-5.

Example-7
To a solution of 1N-1,3-dioxobutyl-4N-ethylsemicarbazide (200 mg, 1.07 mmol) in DMSO (2 mL) was added sulfuric acid (1.1 μL, 0.02 mmol), and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, the organic layer was extracted with ethyl acetate (30 mL × 3), and saturated aqueous sodium chloride solution (10 mL). After washing with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 1/1) to give a white solid of N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide. (143 mg, 79%) was obtained. The NMR spectrum was consistent with the product obtained in Example-1.

Example-8
1N-1,3-dioxobutyl-4N-ethylsemicarbazide (200 mg, 1.07 mmol) in water (2
mL) To the solution was added sulfuric acid (1.1 μL, 0.02 mmol), and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (30 mL), saturated aqueous sodium hydrogen carbonate solution (10 mL) was added, the organic layer was extracted with ethyl acetate (30 mL × 3), and saturated aqueous sodium chloride solution (10 mL). After washing with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/4 to 1/1) to give a white solid of N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide. (154 mg, 85%) was obtained. The NMR spectrum was consistent with the product obtained in Example-1.

Example-9
To a solution of diketene (0.4 mL, 5.03 mmol) in DMSO (1 mL), a solution of N-tert-butylsemicarbazide (0.6 g, 4.57 mmol) in DMSO (3.6 mL) at 0 ° C. was slowly added over 0.5 hours. Thereafter, the mixture was stirred at room temperature for 0.5 hour. Next, sulfuric acid (5.0 μL, 0.091 mmol) was added to the reaction solution, and the mixture was stirred at 100 ° C. for 10 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate (30 mL × 5). The organic layer was washed with a saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/4) to give N-tert-butyl-3-hydroxy-5-methylpyrazole-1-carboxamide. A pale yellow oil (0.43 g, 47%) was obtained. 500 MHz ¹ H-NMR (CDCl ₃ ): δ 9.27 (1H, br s), 6.43 (1H, s), 5.60 (1H, s), 2.54 (3H, s), 1.44 (9H, s).

Reference Example-1
To a solution of 3-chloro-4,5-difluorobenzotrifluoride (25.6 g, 118.2 mmol) in DMSO (300 mL) was added N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide (10 g, 59.1 mmol). ) And potassium carbonate (8.2 g, 59.1 mmol) were added, followed by stirring at 28 ° C. for 5 hours. After completion of the reaction, 1N-hydrochloric acid (50 mL) was added while cooling the reaction solution to 0 ° C., and extracted with ethyl acetate (200 mL × 5). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/4) to give N-ethyl-3- (2-chloro-6-fluoro-4-trifluoro). A white solid (16.3 g, 75%) of methylphenyloxy) -5-methylpyrazole-1-carboxamide was obtained. Melting point: 84-86 ° C; 500 MHz ¹ H-NMR (Acetone-d ₆ , Acetone, ppm): δ7.82 (1H, m), 1.10 (3H, t, J = 7.2 Hz), 7.75 (1H, ddq, J = 2.1 and J _HF = 9.7 and 0.7Hz), 7.39-7.48 (1H, m), 5.98 (1H, q, J = 0.9Hz), 3.26 (2H, dq, J = 6.1 and 7.2Hz), 2.55 ( (3H, d, J = 0.9Hz).

Reference example-2
To a solution of 3,5-dichloro-4-fluorobenzotrifluoride (1.16 g, 5.0 mmol) in DMF (5 mL) was added N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide (0.85 g, 5.0 mmol). ) And potassium carbonate (0.35 g, 2.5 mmol) were added, followed by stirring at 60 ° C. for 6 hours. After completion of the reaction, 1N-hydrochloric acid (10 mL) was added while cooling the reaction solution to 0 ° C., and extracted with ethyl acetate (10 mL × 3). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/5) to give N-ethyl-3- (2,6-dichloro-4-trifluoromethylphenyloxy) -5. A white solid (0.93 g, 49%) of -methylpyrazole-1-carboxamide was obtained. Melting point: 80-82 ° C; 500 MHz ¹ H-NMR (Acetone-d ₆ , Acetone, ppm): δ 7.67 (2H, q, J _HF = 0.7 Hz), 7.37-7.48 (1H, m), 5.71 (1H , q, J = 0.8Hz), 3.25 (2H, dq, J = 6.1 and 7.2Hz), 2.55 (3H, d, J = 0.8Hz), 1.10 (3H, t, J = 7.2Hz).

Reference example-3
To a solution of 3-chloro-4,5-difluorobenzotrifluoride (767 mg, 3.54 mmol) in DMSO (9 mL) was added N-ethyl-3-hydroxy-5-methylpyrazole-1-carboxamide (300 mg,
1.77 mmol) and potassium carbonate (245 mg, 1.77 mmol) were added, followed by stirring at 28 ° C. for 4 hours. Subsequently, ethyl isocyanate (0.28 mL, 3.54 mmol) was added to the reaction solution, followed by stirring at 28 ° C. for 1 hour. After completion of the reaction, 1N hydrochloric acid (10 mL) was added while cooling the reaction solution to 0 ° C., and the mixture was extracted with ethyl acetate (40 mL × 4). The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained crude product was purified by silica gel column chromatography (ethyl acetate / hexane = 1/9 to 1/4) to give N-ethyl-3- (2-chloro-6-fluoro-4-trifluoro). A white solid (525 mg, 81%) of methylphenyloxy) -5-methylpyrazole-1-carboxamide was obtained. The NMR spectrum was consistent with the product obtained in Reference Example-1.

Claims (6)

General formula (1)

(Wherein R represents an optionally substituted alkyl group having 1 to 12 carbon atoms), and a diketene is optionally reacted in the presence of an acid catalyst. The general formula (2)

(Wherein R represents the same meaning as described above), a method for producing a 3-hydroxypyrazole-1-carboxamide derivative. The production method according to claim 1, wherein the acid catalyst is a protonic acid. General formula (1)

(Wherein R represents the same meaning as described above) and a diketene is reacted with a 4N-substituted semicarbazide derivative represented by the general formula (3)

(Wherein R represents the same meaning as described above), and a method for producing a 1N, 4N-disubstituted semicarbazide derivative represented by: General formula (3)

(Wherein R represents the same meaning as described above) 1N, 4N-disubstituted semicarbazide derivative. General formula (3)

(Wherein R represents the same meaning as described above), wherein the 1N, 4N-disubstituted semicarbazide derivative represented by the general formula (2) is optionally cyclized in the presence of an acid catalyst.

(Wherein R represents the same meaning as described above), a method for producing a 3-hydroxypyrazole-1-carboxamide derivative. The production method according to claim 5, wherein the acid catalyst is a protonic acid.