Process for producing 1-alkyl-5-hydroxypyrazole

Abstract

To provide a novel industrial production method of 1-alkyl-5-hydroxypyrazole obtained easily, with high yield and with high purity by using a raw material acquired easier than in conventional methods.SOLUTION: The invention relates to a production method with which 1-alkyl-5-hydroxypyrazole can be easily obtained by making a dialkylaminoacrylic acid ester and an alkyl hydrazine react with each other as shown by the reaction equation A (in the equation, each of R1, R2 and R3 is mutually independently a 1-6C alkyl group, R4 is a hydrogen atom, a 1-6C alkyl group, a 2-6C alkenyl group, a 3-6C cycloalkyl group or an aryl group, and these groups may be substituted with a halogen, a hydroxy group, an alkoxy group or a 1-6C alkyl group).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing hydroxypyrazoles, and more particularly to a novel method for producing 1-alkyl-5-hydroxypyrazole.

Background Art

[0002] 1-Alkyl-5-hydroxypyrazole is used as an intermediate for producing crop protection agents mainly for pharmaceuticals and herbicides. For example, in pharmaceuticals, it is disclosed as an anti-inflammatory agent by VR1 receptor antagonism, an asthma drug by 5-LO inhibitory effect, and a therapeutic drug for mental disorders, and in pesticides, it is disclosed as an intermediate for a plurality of field-acting herbicides. 5-Hydroxypyrazoles have been of interest in their production methods as useful compounds. So far, the following synthetic methods have been known as the main production methods of hydroxypyrazoles. 1) A production method in which dialkyl alkoxymethylenemalonate and alkylhydrazine are cyclized to synthesize alkyl 1-alkyl-5-hydroxypyrazole-4-carboxylate, and then the reaction product is simultaneously hydrolyzed and decarboxylated to obtain 1-alkyl-5-hydroxypyrazoles (Patent Document 1) 2) A production method in which 3-hydrazinopropionate formed by the addition of hydrazine to acrylic acid ester is subjected to a dehydration condensation reaction with an aldehyde to produce the corresponding hydrazone, and then cyclized to obtain 1-alkyl-5-hydroxypyrazoles (Patent Document 2) 3) A production method in which 3-alkoxyacrylic acid ester is reacted with alkylhydrazine to directly obtain 1-alkyl-5-hydroxypyrazoles (Patent Documents 3 and 4)

[0003] The above first manufacturing method requires many steps. After obtaining dialkyl alkoxymethylenemalonate as the raw material, it is cyclized with alkylhydrazine to synthesize alkyl 1-alkyl-5-hydroxypyrazole-4-carboxylate, and finally, through hydrolysis reaction and decarboxylation reaction, the target 1-alkyl-5-hydroxypyrazole is obtained. Furthermore, the obtained reaction product contains, in addition to 1-alkyl-5-hydroxypyrazole, the simultaneously generated positional isomer 1-alkyl-3-hydroxypyrazole, and a complicated procedure is required to separate them from the target compound. Therefore, the yield of this synthesis method is low.

[0004] The second manufacturing method also requires many steps and is complicated. 3-Hydrazinopropionate formed by the addition reaction of hydrazine to acrylic acid ester is subjected to a dehydration condensation reaction with an aldehyde to produce the corresponding hydrazone, and then cyclized to finally obtain 1-alkyl-5-hydroxypyrazole. Many by-products are generated from this complicated method, and only a low yield can be obtained.

[0005] The third manufacturing method can obtain 1-alkyl-5-hydroxypyrazole in one step using 3-alkoxyacrylic acid ester, but 3-alkoxyacrylic acid ester is difficult to manufacture and is expensive.

[0006] The following method is known for the manufacture of 3-alkoxyacrylic acid ester used as the raw material here. (1) Reaction of methanol with expensive propiolate esters; (2) Reaction of expensive and difficult-to-synthesize α,α-dichlorodiethyl ether with also expensive bromoacetate esters; (3) Reaction of expensive bromoacetate esters with trialkyl formates; (4) Elimination of methanol from 3,3-dialkoxypropionate esters obtained by reaction of expensive methyl propiolate with methanol; (5) Reaction of 3-(N-acetyl-N-alkyl)amino-3-methoxypropionate esters with methanol; (6) Reaction of acrylate esters with alkylamines and acetic anhydride; (7) Reaction of difficult-to-handle ketene with trialkyl orthoformate; (8) Catalytic reaction of acrylate esters with methanol using palladium and copper; (9) Reaction of trichloroacetyl chloride with vinyl alkyl ethers; (10) Reaction of α,α,α-trichloro-β-methoxybuten-2-one with methanol; and (11) Reaction of the sodium salt of 3-hydroxyacrylate esters with alcohols. Thus, since 3-alkoxyacrylate esters cannot be easily produced, they are expensive, and thus the third synthesis method is an uneconomical method.

[0007] As a result, these synthetic routes are not satisfactory as an economical and efficient production method for 1-alkyl-5-hydroxypyrazoles.

Prior Art Documents

Patent Documents

[0008]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0009] The present invention aims to solve the problems associated with the prior art as described above, and provides a new method for producing 1-alkyl-5-hydroxypyrazole, which is useful as an intermediate for agricultural chemicals, particularly herbicides. The method can obtain the product simply, in high yield and high purity, using raw materials that are more readily available compared to conventional methods, and is an industrial production method.

Means for Solving the Problems

[0010] The inventor of the present invention focused on dialkylaminoacrylic acid esters as raw materials that are easy to react and readily available. As shown in the following Reaction Scheme A, by reacting dialkylaminoacrylic acid esters with alkylhydrazines, 1-alkyl-5-hydroxypyrazole can be easily obtained. The inventor found this and completed the present invention. This reaction produces few by-products of positional isomers and can provide an industrial production method capable of obtaining high-purity 1-alkyl-5-hydroxypyrazole in high yield. (Reaction Scheme A)

Chemical Formula

Effects of the Invention

[0011] According to the method for producing 1-alkyl-5-hydroxypyrazole according to the present invention, 1-alkyl-5-hydroxypyrazole, which is useful for producing agricultural herbicides and the like, can be obtained simply, in high yield and high purity, in a short process and by simple operations from readily available dialkylaminoacrylic acid esters, compared to conventional methods. A production method that can be used as an industrial production method is provided.

Embodiments for Carrying Out the Invention

[0012] The method for producing 1-alkyl-5-hydroxypyrazole according to the present invention is to react a dialkylaminoacrylate represented by the general formula (1) with an alkylhydrazine represented by the general formula (2) as shown in the above reaction formula A, thereby producing 1-alkyl-5-hydroxypyrazole represented by the general formula (3). Hereinafter, the method for producing 1-alkyl-5-hydroxypyrazole according to the present invention will be specifically described in terms of the starting compounds, target compounds, and production methods including reaction methods.

[0013] (Dialkylaminoacrylate) The dialkylaminoacrylate as the starting material is represented by the following general formula (1). General formula (1): [Chemical formula] In the formula, R1, R2, and R3 are each independently an alkyl group having 1 to 6 carbon atoms, that is, a C1-C6 alkyl group. The alkyl group includes both a straight-chain alkyl group and a branched-chain alkyl group. Among these alkyl groups, as R1 and R2, a methyl group and an ethyl group are preferable from the viewpoints of ease of removal and economy, and a methyl group is particularly preferable. As R3, a methyl group and an ethyl group are preferable from the viewpoints of ease of removal and economy, and an ethyl group is particularly preferable.

[0014] Such a dialkylaminoacrylate represented by the formula (1) is in increasing demand as a raw material for fluoroquinolone synthetic antibacterial drugs such as ciprofloxacin, talibut, clavibit, and norfloxacin, the demand for which has increased significantly in recent years.

[0015] In addition, the dialkylamino acrylate represented by such formula (1) can be easily synthesized by reacting an acetate ester and sodium alkoxide with carbon monoxide or a formate ester and then reacting with a dialkylamine or its mineral acid salt. For example, it is also available as a commercial product from Tokyo Chemical Industry Co., Ltd., Fujifilm Wako Pure Chemical Corporation, and the like.

[0016] (Alkylhydrazine) In addition, the alkylhydrazine that reacts with the above dialkylamino acrylate is a compound represented by the general formula (2). [Chemical formula] R4 in the formula is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, that is, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C3-C6 cycloalkyl group, or an aryl group, and these groups may be substituted with a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.

[0017] Here, the main object of the present invention is to obtain 1-alkyl-5-hydroxypyrazole, and the case of 1-alkyl-5-hydroxypyrazole will be described. However, when R4 is a hydrogen atom, an alkenyl group, or an aryl group, the products are 5-hydroxypyrazole, 1-alkenyl-5-hydroxypyrazole, and 1-aryl-5-hydroxypyrazole, respectively, which are different substituents from the alkyl group. Even in this case, it can be synthesized in the same manner as in the case of synthesizing 1-alkyl-5-hydroxypyrazole using the alkylhydrazine described in the present invention. Therefore, as derivatives of hydrazine used in the reaction, including those that are not alkyl groups, although strictly speaking they cannot be called "alkyl", compounds represented by the general formula (2) are collectively referred to as "alkylhydrazine" including cases other than alkyl groups. Note that this also applies to compounds represented by the general formula (3) which are reaction products obtained using alkylhydrazine, and they are collectively referred to as "1-alkyl-5-hydroxypyrazole" including cases where the group is not an alkyl group.

[0018] As for the alkyl group with 1 to 6 carbon atoms, that is, C1 - C6, used in the reaction, it includes both straight-chain alkyl groups and alkyl groups with branched chains. Among these alkyl groups, a methyl group and an ethyl group are preferable from the perspective of economy, and a methyl group is particularly preferable.

[0019] Also, as for the alkenyl group with 2 to 6 carbon atoms, that is, C2 - C6, it may be either straight-chain or branched-chain, and the position of the double bond may be at any position, whether at the end or in the middle. Among such alkenyl groups, an allyl group is preferable from the perspectives of physiological activity and applicability of further modification reactions.

[0020] Also, as for the cycloalkyl group with 3 to 6 carbon atoms, that is, C3 - C6, it includes cases where an alkyl group is substituted on the cycloalkyl group or the cycloalkyl group is bonded via an alkylene group. Note that in the case of a cycloalkyl group, the carbon number means the number of carbon atoms constituting the ring, and the carbon number of the alkyl group or alkylene group bonded to the ring is not included in those with the above carbon number of 3 to 6. Among these cycloalkyl groups, a cyclopropyl group is preferable from the perspective of physiological activity.

[0021] These groups may also be substituted with a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group. However, since the reactivity of R4 in the formula decreases as the number of carbon atoms increases, the upper limit of the number of carbon atoms is preferably C18. In the case of a C1-C6 alkyl group or a C2-C6 alkenyl group as R4, even if it is considered that the above C1-C6 alkyl group is substituted on these groups, the number of carbon atoms of the alkyl group and the alkynyl group must both be within 6, and there is no need to consider the case where the C1-C6 alkyl group is substituted.

[0022] When these substituents R4 are used as intermediate raw materials for pharmaceuticals, agricultural chemicals, etc., those compatible with intermediate raw materials for pharmaceuticals and agricultural chemicals are selected. Generally, they are often an alkyl group or an aryl group.

[0023] The above alkylhydrazine can be synthesized by alkylation of hydrazine. However, it can also be obtained as a commercial product from, for example, Tokyo Chemical Industry Co., Ltd. and Fujifilm Wako Pure Chemical Corporation. Such alkylhydrazine is also commercially available as an aqueous solution. Although the concentration varies depending on the type of alkylhydrazine, it is generally about 30-50%. In the production method of the present invention, either alkylhydrazine itself or an aqueous solution as commercially available can be used.

[0024] (1-alkyl-5-hydroxypyrazole) The product obtained by reacting the dialkylaminoacrylate of the above formula (1) with the alkylhydrazine of formula (2) is 1-alkyl-5-hydroxypyrazole represented by general formula (3). General formula (3) [Chemical formula] In the formula, R4 is the same substituent as R4 of the alkylhydrazine represented by formula (2). Considering that the resulting compound represented by formula (3) is an intermediate raw material for agricultural chemicals and pharmaceuticals, R4 is preferably an alkyl group or an aryl group, and these groups may be substituted with a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.

[0025] By the way, in the synthesis of 1-alkyl-5-hydroxypyrazole by the reaction of 3-substituted (for example, 3-alkoxy group)-acrylate ester and alkylhydrazine, since the product 1-alkyl-5-hydroxypyrazole shows acidity, it forms a salt with alkylhydrazine. Therefore, in order to terminate the reaction, it was necessary to use an excessive amount of alkylhydrazine or add a base component that forms a salt with 1-alkyl-5-hydroxypyrazole. On the other hand, in the production method of the present invention, 1-alkyl-5-hydroxypyrazole is obtained by reacting a dialkylaminoacrylate ester of formula (1) with an alkylhydrazine of formula (2). At this time, since a dialkylamine is by-produced and the product 1-alkyl-5-hydroxypyrazole and the dialkylamine form a salt, the reaction can be terminated without adding an excessive base component, so that the target product can be obtained simply, in high yield, and with high purity.

[0026] To produce the 1-alkyl-5-hydroxypyrazole of the present invention, as shown in Reaction Scheme A, a dialkylaminoacrylate ester of formula (1) and an alkylhydrazine of formula (2) are reacted in the absence of a solvent or in the presence of a solvent. After removing the by-produced dialkylamine, crystallization is carried out to easily obtain the target compound, 1-alkyl-5-hydroxypyrazole of formula (3).

[0027] In the present invention, the charged amounts of the dialkylaminoacrylate represented by formula (1) and the alkylhydrazine represented by formula (2) in the reaction are such that the alkylhydrazine is in the range of 0.5 to 2.0 equivalents, preferably in the range of 0.8 to 1.2 equivalents, and more preferably 1.0 equivalent, relative to 1.0 equivalent of the dialkylaminoacrylate. When the dialkylaminoacrylate is charged in excess, the yield decreases due to a side reaction between the target compound 1-alkyl-5-hydroxypyrazole and the dialkylaminoacrylate. When the alkylhydrazine is charged in excess, the alkylhydrazine tends to remain in the crystallization step, increasing the loss of the target compound 1-alkyl-5-hydroxypyrazole to the mother liquor and decreasing the yield.

[0028] In the present invention, as described above, the alkylhydrazine represented by formula (2) can, of course, react with the alkylhydrazine itself, i.e., high-purity alkylhydrazine, but can also react with an alkylhydrazine containing water or other solvents. For example, commercially available alkyl (e.g., methyl) hydrazine containing water can be used as it is in the state of an aqueous solution containing water without removing the water, and substantially the same results as when using alkyl (methyl) hydrazine as it is can be obtained. Alkylhydrazine generally has a low flash point and is prone to ignition by oxidation, but the presence of water may be preferable in that it lowers the flash point of the alkylhydrazine and makes it easier to handle.

[0029] In the present invention, the reaction can be carried out without a solvent, but a solvent may be used to remove the heat of reaction. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropanol, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petroleum ether, aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether and diisopropyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, and nitriles such as acetonitrile and propionitrile. Among these solvents, alcohols and nitriles are preferred, and alcohols are particularly preferred. These solvents can be used alone or in combination of two or more, and the mixing ratio can be any ratio. The amount of the solvent used is in the range of 0.01 to 5.0 parts by weight, preferably 0.1 to 1.0 parts by weight, based on 1.0 part by weight of the dialkylaminoacrylate represented by the formula (1).

[0030] The reaction may be carried out by reacting the dialkylaminoacrylate of the formula (1) with the alkylhydrazine of the formula (2). The dialkylaminoacrylate of the formula (1) and the alkylhydrazine of the formula (2) may be simultaneously added to a reaction vessel, mixed, and reacted, or one of the compounds, i.e., the dialkylaminoacrylate of the formula (1) or the alkylhydrazine of the formula (2), may be reacted while adding the other compound thereto. Since this reaction is exothermic, it is desirable to carry out the reaction by dropping either the dialkylaminoacrylate represented by the formula (1) or the alkylhydrazine represented by the formula (2), or by simultaneously dropping the dialkylaminoacrylate represented by the formula (1) and the alkylhydrazine represented by the formula (2). However, since the unreacted dialkylaminoacrylate decomposes at high temperatures, it is more desirable to drop the dialkylaminoacrylate represented by the formula (1).

[0031] When the reaction is carried out by dropping the alkylhydrazine represented by the formula (2), or when the reaction is carried out by dropping the dialkylaminoacrylate represented by the formula (1) and the alkylhydrazine represented by the formula (2) simultaneously, a low temperature is desirable. The temperature range for dropping the raw materials is -20°C to 60°C, preferably 0°C to 40°C. The temperature range for the reaction after dropping the raw materials is 0°C to 80°C, preferably 0°C to 60°C. When the reaction is carried out by dropping the dialkylaminoacrylate represented by the formula (1), the temperature range for dropping the raw materials and the temperature range for the reaction after dropping the raw materials are 0°C to 80°C, preferably 0°C to 60°C. Since the reaction rate decreases as the reaction proceeds, it is preferable to increase the reaction temperature in the latter half of the reaction. In the present invention, the dropping time of the raw materials is in the range of 1 to 20 hours, preferably in the range of 2 to 10 hours. The reaction time after dropping the raw materials is in the range of 1 to 30 hours, preferably in the range of 2 to 20 hours.

[0032] Within these ranges of reaction temperature and reaction time, the formation of positional isomers is less, and the final reaction product can be obtained with high purity and high yield. When the reaction temperature is higher than the above range and when the reaction time is longer than the above range, side reactions occur, resulting in a decrease in yield and purity. Therefore, it is preferable to carry out the reaction within the above temperature range and time range. Also, the dropping temperature during dropping of the raw materials is preferably low in order to avoid excessive reaction during dropping. However, within the above range of dropping temperature and dropping time, it will not affect the reaction after dropping and is preferable.

[0033] In the present invention, the crystals of 1-alkyl-5-hydroxypyrazole represented by the formula (3) can be easily obtained by crystallization. For crystallization, it is preferable to remove the dialkylamine by-produced in the reaction before crystallization. The dialkylamine can be removed by concentration, distillation, neutralization, filtration, or liquid separation operations, but the removal method is not particularly limited, and the methods may be combined.

[0034] When removing the by-produced dialkylamine by concentration or distillation, it can be distilled off under normal pressure or reduced pressure. Although it depends on the type of the by-produced dialkylamine, generally, the concentration or distillation temperature is in the range of 30 to 150 °C, preferably in the range of 50 to 120 °C. The degree of reduced pressure can be carried out in the range from normal pressure to vacuum.

[0035] The by-produced dialkylamine can be removed by neutralizing it by adding an acid to form a dialkylamine salt and then filtering, washing, or liquid-separating the produced dialkylamine salt. Examples of the acid include mineral acids such as hydrogen chloride, hydrogen bromide, nitric acid, and sulfuric acid; carboxylic acids such as formic acid, acetic acid, citric acid, oxalic acid, and benzoic acid; organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid; solid acids such as acidic ion exchange resins and zeolites.

[0036] In the present invention, crystals of 1-alkyl-5-hydroxypyrazole represented by the formula (3) are obtained by recrystallization. It is important to remove the by-produced dialkylamine before crystallization, and it is preferable to remove 90% or more. Preferred crystallization solvents include alcohols such as methanol, ethanol, and isopropanol; aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petroleum ether; aromatic hydrocarbons such as toluene and xylene; ethers such as diethyl ether and diisopropyl ether; halogenated hydrocarbons such as methylene chloride and chloroform; nitriles such as acetonitrile and propionitrile; and esters such as ethyl acetate and butyl acetate. Particularly, acetonitrile and ethyl acetate are preferred.

[0037] By filtering and drying after recrystallization, high-purity 1-alkyl-5-hydroxypyrazole represented by the general formula (3) can be obtained. In this case, a simple production method is provided without any need for purification steps such as distillation or column chromatography.

Examples

[0038] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited by these examples.

[0039] Example 1 Into a 2 L four-necked flask equipped with a refrigerant-cooled reflux tube, 572.8 g (4.0 mol) of ethyl dimethylaminoacrylate and 256.3 g of methanol were added. While maintaining the temperature at 5°C or lower, 184.3 g (4.0 mol) of methylhydrazine was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 5°C for 20 hours. When the reaction solution was analyzed by liquid chromatography, the yield of 1-methyl-5-hydroxypyrazole was 95.3%, and the yield of 1-methyl-3-hydroxypyrazole, which is a positional isomer, was 0.5%.

[0040] After completion of the reaction, 253.3 g of the reaction solution was concentrated under reduced pressure to remove dimethylamine by-produced together with the solvent. The temperature of the concentrated solution at the end of concentration was 100°C, and the degree of reduced pressure was 5 mmHg. Analysis of dimethylamine in the concentrated solution showed 1.8 g, and 96% of the by-produced amount was removed. After concentration, 110.0 g of acetonitrile was added, dissolved at 60°C, and then cooled to 0°C to precipitate crystals. The precipitated crystals were filtered, and the collected crystals were dried to obtain 71.7 g (0.73 mol) of 1-methyl-5-hydroxypyrazole. The yield was 73.1%, and the purity was 99.9%. 1-Methyl-3-hydroxypyrazole, which is an isomer, was not detected.

[0041] Example 2 Into a 300 mL four-necked flask equipped with a refrigerant-cooled reflux tube, 143.2 g (1.0 mol) of ethyl dimethylaminoacrylate and 51.3 g of methanol were added. While maintaining the temperature at 5°C or lower, 131.6 g (1.0 mol) of 35% methylhydrazine was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 5°C for 30 hours. When the reaction solution was analyzed by liquid chromatography, the yield of 1-methyl-5-hydroxypyrazole was 91.0%, and the yield of 1-methyl-3-hydroxypyrazole, which is a positional isomer, was 1.5%.

[0042] After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent and by-produced dimethylamine. The temperature of the concentrated solution at the end of concentration was 100 °C, and the degree of reduced pressure was 5 mmHg. Analysis of dimethylamine in the concentrated solution showed it to be 2.7 g, and 94% of the by-produced amount was removed. After concentration, 110.0 g of acetonitrile was added, dissolved at 60 °C, and then cooled to 0 °C to precipitate crystals. The precipitated crystals were filtered, and the collected crystals were dried to obtain 60.6 g (0.62 mol) of 1-methyl-5-hydroxypyrazole. The yield was 61.8%, and the purity was 99.9%. The isomer 1-methyl-3-hydroxypyrazole was not detected.

[0043] Example 3 253.3 g of the reaction solution obtained under the same conditions as in Example 1 was concentrated under reduced pressure to a degree of reduced pressure of 15 mmHg to remove the solvent and by-produced dimethylamine. The concentration was terminated at a temperature of 100 °C for the concentrated solution. Analysis of dimethylamine in the concentrated solution showed it to be 6.1 g, and 13.5% of the by-produced amount remained. 110.0 g of acetonitrile was added to the concentrated solution and dissolved at 70 °C. 35 g of strongly acidic ion exchange resin (trade name, Amberlyst 15DRY, manufactured by Organo Corporation) was added, and after stirring for 10 minutes, the ion exchange resin was filtered off by hot filtration. Dimethylamine was not detected in the filtered solution. The solution was cooled to 0 °C to precipitate crystals. The precipitated crystals were filtered, and the collected crystals were dried to obtain 75.8 g (0.77 mol) of 1-methyl-5-hydroxypyrazole. The yield was 77.3%, and the purity was 99.9%. The isomer 1-methyl-3-hydroxypyrazole was not detected.

[0044] Example 4 253.3 g of the reaction solution obtained under the same conditions as in Example 1 was concentrated under reduced pressure to remove the solvent and by-produced dimethylamine. The temperature of the concentrated solution at the end of concentration was 100 °C, and the degree of reduced pressure was 20 mmHg. Analysis of dimethylamine in the concentrated solution showed that it was 4.7 g, and 10.5% of the by-production amount (89.5% of the by-production amount was removed) remained. 110.0 g of acetonitrile was added to the concentrated solution, dissolved at 60 °C, and then cooled to 0 °C to precipitate crystals. The precipitated crystals were filtered, and the collected crystals were dried to obtain 45.9 g (0.47 mol) of 1-methyl-5-hydroxypyrazole. The yield was 46.8%, and the purity was 99.9%. The isomer 1-methyl-3-hydroxypyrazole was not detected.

[0045] Example 5 11.6 g (0.25 mol) of methylhydrazine and 16.1 g of methanol were added to a 100 mL four-necked flask equipped with a refrigerant cooling reflux tube. While maintaining the temperature at 30 °C, 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 60 °C for 2 hours. When the reaction solution was analyzed by liquid chromatography, the yield of 1-methyl-5-hydroxypyrazole was 92.0%, and the yield of the positional isomer 1-methyl-3-hydroxypyrazole was 0.3%.

[0046] Example 6 16.1 g of methanol was added to a 100 mL four-necked flask equipped with a refrigerant cooling reflux tube. While maintaining the temperature at 30 °C, 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate and 11.6 g (0.25 mol) of methylhydrazine were added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 60 °C for 2 hours. When the reaction solution was analyzed by liquid chromatography, the yield of 1-methyl-5-hydroxypyrazole was 85.0%, and the yield of the positional isomer 1-methyl-3-hydroxypyrazole was 0.1%.

[0047] Example 7 In a 100 mL four-necked flask equipped with a refrigerant-cooled reflux tube, 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate and 16.1 g of methanol were added. While maintaining the temperature at 5°C or lower, 12.5 g (0.25 mol) of hydrazine hydrate was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 30°C for 2 hours. When the reaction solution was analyzed by liquid chromatography, the yield of 5-hydroxypyrazole was 98.5%.

[0048] Comparative Example 1 In a 300 mL four-necked flask equipped with a refrigerant-cooled reflux tube, 116.4 g (1.0 mol) of methyl 3-methoxyacrylate and 64.1 g of methanol were added. While maintaining the temperature at 25°C or lower, 46.1 g (1.0 mol) of methylhydrazine was added dropwise over 2 hours. After completion of the dropwise addition, the mixture was stirred at 25°C for 20 hours. When the reaction solution was analyzed by liquid chromatography, the reaction conversion rates of methyl 3-methoxyacrylate and methylhydrazine were 89.1% and 88.7% respectively, the yield of 1-methyl-5-hydroxypyrazole was 77.6%, and the yield of the positional isomer 1-methyl-3-hydroxypyrazole was 1.8%.

Industrial Applicability

[0049] The production method of the present invention can obtain 1-alkyl-5-hydroxypyrazole, which is useful as a herbicide for agricultural chemicals, from an easily available dialkylaminoacrylate simply, in high yield and high purity, and is useful as an industrial production method.

Claims

1. General formula (1): 【Chemical 1】 (wherein R １ , R ２ , and R ３ each independently represent an alkyl group having 1 to 6 carbon atoms.) The dialkylaminoacrylate represented by the formula, and the general formula (2) 【Chemical 2】 (In the formula, R ４ is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C3-C6 cycloalkyl group, or an aryl group, and these groups may be substituted with a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.) The alkylhydrazine represented by the formula, and reacting them, characterized in that the general formula (3) [Chemical 3] (wherein, R ４ is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C3-C6 cycloalkyl group, or an aryl group, and these groups may be substituted with a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.) A method for producing 1-alkyl-5-hydroxypyrazole represented by the formula.

2. The reaction is carried out by a method of dropping the alkylhydrazine represented by the general formula (2) or the dialkylaminoacrylate represented by the general formula (1), or a method of simultaneously dropping the alkylhydrazine represented by the general formula (2) and the dialkylaminoacrylate represented by the general formula (1). The production method according to claim 1.

3. The production method according to claim 1 or 2, wherein the alkylhydrazine represented by the general formula (2) is an aqueous solution.

4. Removing the by-produced dialkylamine and obtaining crystals of 1-alkyl-5-hydroxypyrazole represented by the general formula (3) by crystallization. The production method according to any one of claims 1 to 3.

5. Removing 90% or more of the by-produced dialkylamine. The production method according to claim 4.

6. Removing the by-produced dialkylamine by vacuum concentration. The production method according to claim 5.

7. Removing the by-produced dialkylamine with an ion exchange resin. The production method according to claim 5.

8. R in general formulas (2) and (3) ４ The production method according to any one of claims 1 to 7, wherein R is a methyl group or an ethyl group.

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