Method for producing 1-alkyl-5-hydroxypyrazole

Abstract

The present invention is a method for producing a 1-alkyl-5-hydroxypyrazole, which is represented by the following reaction formula (A), and which can easily obtain a 1-alkyl-5-hydroxypyrazole by reacting a dialkylamino acrylate with an alkylhydrazine. (In the formula, R1, R2, and R3 are each independently a C1-C6 alkyl group, R4 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 by a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group. > # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method for producing hydroxy pyrazoles, and more particularly to a new method for producing 1-alkyl-5-hydroxy pyrazoles. Background Art

[0002] 1-alkyl-5-hydroxy pyrazoles are used as intermediates for the production of pharmaceuticals and crop protection agents centered on herbicides. For example, in pharmaceuticals, they are disclosed as intermediates for anti-inflammatory agents based on VR1 receptor antagonism, asthma drugs based on 5-LO inhibitory effects, and psychotropic drugs. In pesticides, they are disclosed as intermediates for various field herbicides. As useful compounds, 5-hydroxy pyrazoles have attracted attention for their production methods. So far, the following methods are known as the main production methods for hydroxy pyrazoles.

[0003] 1) A method for producing 1-alkyl-5-hydroxy pyrazoles by cyclizing dialkyl alkoxymethylenemalonates and alkyl hydrazines to synthesize alkyl 1-alkyl-5-hydroxy pyrazole-4-carboxylates, and then simultaneously hydrolyzing and decarboxylating the reaction product (Patent Document 1)

[0004] 2) A method for producing 1-alkyl-5-hydroxy pyrazoles by subjecting 3-hydrazinopropionate formed by adding hydrazine to acrylate to a dehydration condensation reaction with an aldehyde to produce the corresponding hydrazone, and then cyclizing (Patent Document 2)

[0005] 3) A method for directly obtaining 1-alkyl-5-hydroxy pyrazoles by reacting 3-alkoxyacrylates with alkyl hydrazines (Patent Documents 3 and 4)

[0006] Prior Art Documents

[0007] Patent Documents

[0008] Patent Document 1: Japanese Patent Application Laid-Open No. 61-257974

[0009] Patent Document 2: Japanese Patent Publication No. 7-30031

[0010] Patent Document 3: US Patent No. 6,392,058

[0011] Patent Document 4: International Publication No. 2017 / 004674 Summary of the Invention

[0012] Problems to be Solved by the Invention

[0013] The manufacturing method of 1) above requires many processes. After obtaining dialkyl alkoxymethylenemalonate as a raw material, it is cyclized with alkylhydrazine to synthesize alkyl 1-alkyl-5-hydroxypyrazole-4-carboxylate, and then through hydrolysis reaction and decarboxylation reaction, finally the target 1-alkyl-5-hydroxypyrazole is obtained. In addition, in the resulting reaction product, in addition to 1-alkyl-5-hydroxypyrazole, the simultaneously generated positional isomer 1-alkyl-3-hydroxypyrazole is also contained, and in order to separate them from the target compound, a complex procedure is required. Therefore, the yield of this synthesis method is low.

[0014] The manufacturing method of 2) above also requires many processes and is very complex. The corresponding hydrazone is produced by subjecting 3-hydrazinopropionate formed by the reaction of hydrazine addition to acrylate to dehydration condensation reaction with an aldehyde, and then cyclization is carried out, and finally 1-alkyl-5-hydroxypyrazole is obtained. Many by-products are generated by this complex method, and only a low yield can be obtained.

[0015] Although the manufacturing method of 3) above can obtain 1-alkyl-5-hydroxypyrazole in one step using 3-alkoxyacrylate, 3-alkoxyacrylate is difficult to manufacture and is expensive.

[0016] Here, the following methods are known for the manufacture of 3-alkoxyacrylate used as a raw material in the manufacturing method of 3) above.

[0017] It is carried out by (1) the reaction of methanol with an expensive propionate, (2) the reaction of α,α-dichloroethyl ether, which is expensive and difficult to synthesize, with an equally expensive bromoacetate, (3) the reaction of an expensive bromoacetate with a trialkyl formate, (4) elimination of methanol from 3,3-dialkoxypropionate obtained from the reaction of expensive methyl propionate with methanol, (5) the reaction of 3-(N-acetyl-N-alkyl)amino-3-methoxypropionate with methanol, (6) the reaction of acrylate with an alkylamine and acetic anhydride, (7) the reaction of a difficult-to-treat ketene with a trialkyl orthoformate, (8) the catalytic reaction of acrylate with methanol using palladium and copper, (9) the reaction of trichloroacetyl chloride with vinyl alkyl ether, (10) the reaction of α,α,α-trichloro-β-methoxybuten-2-one with methanol, and (11) the reaction of the sodium salt of 3-hydroxyacrylate with an alcohol.

[0018] Thus, since 3-alkoxyacrylate cannot be easily manufactured and becomes expensive, the preparation method of 3) above is an uneconomical method.

[0019] As a result, these synthetic routes are not satisfactory as economical and effective manufacturing methods for 1-alkyl-5-hydroxypyrazoles.

[0020] The object of the present invention is to solve the problems associated with the prior art as described above. The problem to be solved by the present invention is to provide an industrial manufacturing method of 1-alkyl-5-hydroxypyrazole which uses easily accessible raw materials compared to conventional methods and can be obtained simply, in high yield, and with high purity.

[0021] Means for Solving the Problem

[0022] As a raw material that is easily reactive and easily accessible, the present inventors focused on dialkyl aminoacrylate and found that, as shown in the following reaction formula A, by reacting dialkyl aminoacrylate with alkyl hydrazine, 1-alkyl-5-hydroxypyrazole can be obtained simply, thus completing the present invention. According to this reaction, there are few by-produced positional isomers, and 1-alkyl-5-hydroxypyrazole with high purity can be obtained in high yield.

[0023] (Reaction formula A)

[0024]

[0025] (In the formula, R1, R2, and R3 are each independently a C1-C6 alkyl group, R4 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 by a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.)

[0026] Effects of the Invention

[0027] According to the manufacturing method of 1-alkyl-5-hydroxypyrazole according to the present invention, provided is a manufacturing method that can obtain 1-alkyl-5-hydroxypyrazole useful in the manufacture of agricultural herbicides, etc. simply, in high yield, and with high purity from easily accessible dialkyl aminoacrylate through a short process and simple operation, and can be used as an industrial manufacturing method. Detailed Description of the Invention

[0028] The manufacturing method of 1-alkyl-5-hydroxypyrazole according to the present invention is as shown in the above reaction formula A, and 1-alkyl-5-hydroxypyrazole represented by the general formula (3) is manufactured by reacting a dialkyl aminoacrylate represented by the general formula (1) with an alkyl hydrazine represented by the general formula (2).

[0029] Hereinafter, for the manufacturing method of 1-alkyl-5-hydroxypyrazole according to the present invention, the starting material compounds, target compounds, and manufacturing methods including reaction methods, etc. will be specifically described.

[0030] (Dialkyl Aminoacrylate)

[0031] The dialkyl aminoacrylate as the starting material is represented by the following general formula (1).

[0032] General formula (1):

[0033]

[0034] In the formula, R1, R2 and R3 are each independently an alkyl group having 1 to 6 carbon atoms, i.e., a C1-C6 alkyl group. This alkyl group includes either a straight-chain alkyl group or a branched-chain alkyl group. Among these alkyl groups, as R1 and R2, from the viewpoints of easy removal and economy, methyl and ethyl are preferred, and methyl is particularly preferred. In addition, as R3, from the viewpoints of easy removal and economy, methyl and ethyl are preferred, and ethyl is particularly preferred.

[0035] The dialkylaminoacrylate represented by such formula (1) is in increasing demand as a raw material for fluoroquinolone synthetic antibacterial drugs such as ciprofloxacin ( ciproxan ), tarivid, cravit, norfloxacin, etc.

[0036] In addition, the dialkylaminoacrylate represented by such formula (1) can be easily synthesized by reacting carbon monoxide or a formate with an acetate and sodium alkoxide and then reacting with a dialkylamine or its inorganic acid salt. It can also be obtained as a commercially available product from, for example, Tokyo Chemical Industry Co., Ltd. or Fujifilm Wako Pure Chemical Corporation, etc.

[0037] (alkyl hydrazine)

[0038] In addition, the alkyl hydrazine that reacts with the above dialkylaminoacrylate is a compound represented by the general formula (2).

[0039]

[0040] In the formula, R4 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, i.e., 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 by a halogen, a hydroxyl group, an alkoxy group or a C1-C6 alkyl group.

[0041] 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. 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, and the substituents are different from the alkyl group. However, even in this case, it can be synthesized in the same manner as the case of synthesizing 1-alkyl-5-hydroxypyrazole using alkyl hydrazine described in the present invention.

[0042] Therefore, as derivatives of hydrazine used in the reaction, non-alkyl derivatives are also included. As a result, strictly speaking, they cannot be called "alkyl", but in this specification, for the compounds represented by the general formula (2), including cases other than alkyl, they are collectively referred to as "alkyl hydrazine". For the reaction products obtained using alkyl hydrazine, that is, the compounds represented by the general formula (3), including cases other than alkyl, they are also collectively referred to as "1-alkyl-5-hydroxy pyrazole".

[0043] As the alkyl group having 1 to 6 carbon atoms, that is, C1-C6, used in the reaction, either a straight-chain alkyl group or a branched-chain alkyl group is included. Among these alkyl groups, from the viewpoint of economy, methyl and ethyl are preferred, and methyl is particularly preferred.

[0044] In addition, as the alkenyl group having 2 to 6 carbon atoms, that is, C2-C6, it can be a straight-chain or branched-chain alkenyl group. The position of the double bond can be at any position, either at the end or in the middle. As such an alkenyl group, from the viewpoints of physiological activity or applicability to further modification reactions, allyl is preferred.

[0045] In addition, as the cycloalkyl group having 3 to 6 carbon atoms, that is, C3-C6, cases where the cycloalkyl group is substituted by an alkyl group or cases where the cycloalkyl group is bonded via an alkylene group are also included. It should be noted that in the case of a cycloalkyl group, as the number of carbon atoms, it refers to the number of carbons constituting the ring, and the number of carbon atoms of the alkyl group or alkylene group bonded to the ring is not included in the above-mentioned cycloalkyl group having 3 to 6 carbon atoms. Among these cycloalkyl groups, from the viewpoint of physiological activity, cyclopropyl is preferred.

[0046] In addition, these groups can be substituted by halogen, hydroxyl, alkoxy, or C1-C6 alkyl, but if the number of carbon atoms of R4 in the formula increases, the reactivity decreases. Therefore, the upper limit of the number of carbon atoms is preferably C18. It should be noted that in the case of C1-C6 alkyl and C2-C6 alkenyl as R4, even if these groups are substituted by the above-mentioned C1-C6 alkyl, the number of carbon atoms of both this alkyl and the alkynyl group must be within 6, so the case of C1-C6 alkyl substitution does not need to be considered.

[0047] It should be noted that when used as an intermediate raw material for drugs, pesticides, etc., groups suitable as intermediate raw materials for drugs and pesticides are selected for these substituents R4, but usually they are mostly alkyl groups and aryl groups.

[0048] The above-mentioned alkyl hydrazine can be synthesized by alkylation of hydrazine. It can also be obtained as a commercially available product from, for example, Tokyo Chemical Industry Co., Ltd. or Fujifilm Wako Pure Chemical Corporation, etc. In addition, such alkyl hydrazine is also sold on the market as an aqueous solution, and its concentration varies depending on the type of alkyl hydrazine, but it is generally about 30-50%. In the preparation method of the present invention, alkyl hydrazine itself can be used, or an aqueous solution like the commercially available one can be used.

[0049] (1-alkyl-5-hydroxypyrazole)

[0050] The product obtained by reacting the dialkylaminoacrylate of the above formula (1) with an alkylhydrazine of formula (2) is 1-alkyl-5-hydroxypyrazole represented by the general formula (3).

[0051] General formula (3)

[0052]

[0053] 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 pesticides or drugs, R4 is preferably an alkyl group or an aryl group, and these groups may be substituted by a halogen, a hydroxyl group, an alkoxy group, or a C1-C6 alkyl group.

[0054] When synthesizing 1-alkyl-5-hydroxypyrazole by reacting a 3-substituted (e.g., 3-alkoxy)-acrylate with an alkylhydrazine, since the resulting 1-alkyl-5-hydroxypyrazole shows acidity and forms a salt with the alkylhydrazine. Therefore, in order to terminate the reaction, it is necessary to use an excessive amount of alkylhydrazine or add a basic component that forms a salt with 1-alkyl-5-hydroxypyrazole.

[0055] In contrast, in the production method of the present invention, 1-alkyl-5-hydroxypyrazole is obtained by reacting the dialkylaminoacrylate of formula (1) with the alkylhydrazine of formula (2). At this time, dialkylamine is by-produced, and the resulting 1-alkyl-5-hydroxypyrazole forms a salt with the dialkylamine. Therefore, the reaction can be terminated without adding an excessive amount of basic component, and thus the target product can be obtained simply, in high yield, and with high purity.

[0056] To produce the 1-alkyl-5-hydroxypyrazole of the present invention, as shown in Reaction Scheme A, the dialkylaminoacrylate of formula (1) is reacted with the alkylhydrazine of formula (2) in the absence of a solvent or in the presence of a solvent, the by-produced dialkylamine is removed, and then crystallization is carried out, whereby the 1-alkyl-5-hydroxypyrazole of formula (3) as the target compound can be easily obtained.

[0057] In the present invention, regarding the feeding amounts of the dialkyl aminoacrylate represented by the formula (1) and the alkyl hydrazine represented by the formula (2) in the reaction, relative to 1.0 equivalent of the dialkyl aminoacrylate, the alkyl hydrazine is preferably in the range of 0.5 to 2.0 equivalents, more preferably in the range of 0.8 to 1.2 equivalents, and still more preferably 1.0 equivalent. If the dialkyl aminoacrylate is fed in excess, the yield is reduced due to the side reaction between the 1-alkyl-5-hydroxypyrazole as the target compound and the dialkyl aminoacrylate. If the alkyl hydrazine is fed in excess, the alkyl hydrazine easily remains in the crystallization step, the loss of the 1-alkyl-5-hydroxypyrazole as the target compound in the mother liquor increases, and the yield is reduced.

[0058] In the present invention, the alkyl hydrazine represented by the formula (2), as described above, can of course be reacted with the alkyl hydrazine itself, that is, high-purity alkyl hydrazine, but even alkyl hydrazine containing water or other solvents can be reacted. For example, commercially available alkyl (e.g., methyl) hydrazine containing water can be directly used in the state of an aqueous solution containing water without removing the water, and substantially the same results as when directly using alkyl (methyl) hydrazine can be obtained. Alkyl hydrazine generally has a low flash point and is prone to ignition due to oxidation, but the presence of water lowers the flash point of alkyl hydrazine, which is also preferable in terms of facilitating the operation.

[0059] In the present invention, the reaction can be carried out without a solvent, but a solvent can also be used to remove the reaction heat. Examples of the solvent include water, alcohols such as methanol, ethanol, and isopropyl alcohol, aliphatic hydrocarbons such as pentane, hexane, cyclohexane, and petroleum ether, aromatic hydrocarbons such as toluene and xylene, ethers such as diethyl ether and isopropyl ether, halogenated hydrocarbons such as dichloromethane 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. Relative to 1.0 part by weight of the dialkyl aminoacrylate represented by the formula (1), the amount of the solvent used is preferably in the range of 0.01 to 5.0 parts by weight, more preferably in the range of 0.1 to 1.0 part by weight.

[0060] For the reaction, it is only necessary to react a dialkyl aminoacrylate of formula (1) with an alkyl hydrazine of formula (2). The dialkyl aminoacrylate of formula (1) and the alkyl hydrazine of formula (2) can be added and mixed simultaneously in a reaction vessel to carry out the reaction, or the reaction can be carried out while adding one compound to the other compound in either the dialkyl aminoacrylate of formula (1) or the alkyl hydrazine of formula (2). Since this reaction is exothermic, it is preferably carried out by dropwise adding either the dialkyl aminoacrylate represented by formula (1) or the alkyl hydrazine represented by formula (2), or by simultaneously dropwise adding the dialkyl aminoacrylate represented by formula (1) and the alkyl hydrazine represented by formula (2). If the temperature is high, the unreacted dialkyl aminoacrylate will decompose, so it is more preferred to dropwise add the dialkyl aminoacrylate represented by formula (1).

[0061] When the reaction is carried out by dropwise adding the alkyl hydrazine represented by formula (2), or when the reaction is carried out by simultaneously dropwise adding the dialkyl aminoacrylate represented by formula (1) and the alkyl hydrazine represented by formula (2), the dropping temperature of the raw materials is preferably low. The temperature range for dropping the raw materials is preferably from -20°C to 60°C, more preferably from 0°C to 40°C. The reaction temperature range after dropping the raw materials is preferably from 0°C to 80°C, more preferably from 0°C to 60°C. When the reaction is carried out by dropwise adding the dialkyl aminoacrylate represented by formula (1), the dropping temperature of the raw materials and the reaction temperature range after dropping the raw materials are preferably from 0°C to 80°C, more preferably from 0°C to 60°C. Since the reaction rate decreases as the reaction proceeds, it is preferred to increase the reaction temperature in the latter half of the reaction. In the present invention, the dropping time of the raw materials is preferably in the range of 1 to 20 hours, more preferably in the range of 2 to 10 hours. The reaction time after dropping the raw materials is preferably in the range of 1 to 30 hours, more preferably in the range of 2 to 20 hours.

[0062] If it is within these reaction temperature ranges and reaction time ranges, the formation of positional isomers is less, and the final reactant can be obtained with high purity and high yield. It should be noted that when the reaction temperature is higher than the above range and when the reaction time is longer than the above range, side reactions will occur, and it is found that the yield or purity decreases. Therefore, it is preferred to carry out the reaction within the above temperature range and time range.

[0063] In addition, in order to avoid excessive reaction during dropping, the dropping temperature during dropping of the raw materials is preferably low. If it is within the above dropping temperature and dropping time ranges, it will not affect the reaction after dropping, so it is preferred.

[0064] In the present invention, the crystals of 1-alkyl-5-hydroxypyrazole represented by formula (3) can be easily obtained by crystallization. For crystallization, it is preferred to remove the by-produced dialkylamine in the reaction before crystallization. The dialkylamine can be removed by concentration or distillation, neutralization, filtration, and liquid separation operations. The removal method is not particularly limited, and combinations can also be used.

[0065] In the case of removing the by-produced dialkylamine by concentration or distillation, it can be distilled off under normal pressure or reduced pressure. Although it also depends on the type of the by-produced dialkylamine, the concentration or distillation temperature is generally in the range of 30 to 150 °C, preferably in the range of 50 - 120 °C. Regarding the degree of reduced pressure, it can be carried out in the range from normal pressure to vacuum.

[0066] For the by-produced dialkylamine, it can be neutralized by adding an acid. After forming the dialkylamine salt, the generated dialkylamine salt can be removed by filtration or washing / liquid separation. Examples of the acid include inorganic 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.

[0067] In the present invention, 1-alkyl-5-hydroxypyrazole represented by formula (3) is obtained in the form of crystals by recrystallization. Before crystallization, it is important to remove the by-produced dialkylamine, and preferably more than 90% is removed. As the crystallization solvent, 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 isopropyl ether; halogenated hydrocarbons such as dichloromethane and chloroform; nitriles such as acetonitrile and propionitrile; esters such as ethyl acetate and butyl acetate are preferred, and acetonitrile or ethyl acetate is particularly preferred.

[0068] After recrystallization, high-purity 1-alkyl-5-hydroxypyrazole represented by the general formula (3) can be obtained by filtration and drying. In this case, a simple manufacturing method that completely eliminates purification processes such as distillation or column chromatography is provided.

[0069] Examples

[0070] Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited by these examples.

[0071] Example 1

[0072] To 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 below 5 °C, 184.3 g (4.0 mol) of methylhydrazine was added dropwise over 2 hours. After the addition was completed, the mixture was stirred at 5 °C for 20 hours. The reaction solution was analyzed by liquid chromatography, and the yield of 1-methyl-5-hydroxypyrazole was found to be 95.3%, and the yield of 1-methyl-3-hydroxypyrazole as a positional isomer was 0.5%.

[0073] After the reaction was completed, 253.3 g of the reaction solution was concentrated under reduced pressure to remove by-produced dimethylamine together with the solvent. The temperature of the concentrated solution at the end of concentration was 100 °C, and the reduced pressure was 5 mmHg. The dimethylamine in the concentrated solution was analyzed, and the result was 1.8 g, and 96% of the by-production 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, and as a result, 71.7 g (0.73 mol) of 1-methyl-5-hydroxypyrazole was obtained. The yield was 73.1% and the purity was 99.9%. 1-Methyl-3-hydroxypyrazole as an isomer was not detected.

[0074] Example 2

[0075] To 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 below 5 °C, 131.6 g (1.0 mol) of 35% methylhydrazine was added dropwise over 2 hours. After the addition was completed, the mixture was stirred at 5 °C for 30 hours. The reaction solution was analyzed by liquid chromatography, and the yield of 1-methyl-5-hydroxypyrazole was found to be 91.0%, and the yield of 1-methyl-3-hydroxypyrazole as a positional isomer was 1.5%.

[0076] After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove by-produced dimethylamine together with the solvent. The temperature of the concentrated solution at the end of concentration was 100 °C, and the reduced pressure was 5 mmHg. The dimethylamine in the concentrated solution was analyzed, and the result was 2.7 g, and 94% of the by-production 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, and as a result, 60.6 g (0.62 mol) of 1-methyl-5-hydroxypyrazole was obtained. The yield was 61.8% and the purity was 99.9%. 1-Methyl-3-hydroxypyrazole as an isomer was not detected.

[0077] Example 3

[0078] 253.3 g of the reaction solution obtained under the same conditions as in Example 1 was concentrated under reduced pressure to a reduced pressure of 15 mmHg, and by-produced dimethylamine and the solvent were removed together. The concentration was terminated at a temperature of 100 °C of the concentrated solution. The dimethylamine in the concentrated solution was analyzed, and as a result, it was 6.1 g, and 13.5% of the by-production amount remained. 110.0 g of acetonitrile was added to the concentrated solution and dissolved at 70 °C. 35 g of a 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 separated by hot filtration. Dimethylamine was not detected in the solution separated by filtration. The solution was cooled to 0 °C to precipitate crystals. The precipitated crystals were filtered, and the collected crystals were dried. As a result, 75.8 g (0.77 mol) of 1-methyl-5-hydroxypyrazole was obtained. The yield was 77.3%, and the purity was 99.9%. 1-Methyl-3-hydroxypyrazole as an isomer was not detected.

[0079] Example 4

[0080] The by-produced dimethylamine and the solvent were removed together from 253.3 g of the reaction solution obtained under the same conditions as in Example 1 by concentration under reduced pressure. The temperature of the concentrated solution at the end of concentration was 100 °C, and the reduced pressure was 20 mmHg. The dimethylamine in the concentrated solution was analyzed, and as a result, it was 4.7 g, and 10.5% of the by-production amount remained (89.5% of the by-production amount was removed). 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. As a result, 45.9 g (0.47 mol) of 1-methyl-5-hydroxypyrazole was obtained. The yield was 46.8%, and the purity was 99.9%. 1-Methyl-3-hydroxypyrazole as an isomer was not detected.

[0081] Example 5

[0082] 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-cooled reflux tube, and while maintaining the temperature at 30 °C, 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours. After the dropwise addition was completed, the mixture was stirred at 60 °C for 2 hours. The reaction solution was analyzed by liquid chromatography, and as a result, the yield of 1-methyl-5-hydroxypyrazole was found to be 92.0%, and the yield of 1-methyl-3-hydroxypyrazole as a positional isomer was 0.3%.

[0083] Example 6

[0084] 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 the addition was completed, the mixture was stirred at 60 °C for 2 hours. The reaction solution was analyzed by liquid chromatography, and the yield of 1-methyl-5-hydroxypyrazole was found to be 85.0%, and the yield of 1-methyl-3-hydroxypyrazole as a positional isomer was 0.1%.

[0085] Example 7

[0086] 35.8 g (0.25 mol) of ethyl dimethylaminoacrylate 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 below 5 °C, 12.5 g (0.25 mol) of hydrazine hydrate was added dropwise over 2 hours. After the addition was completed, the mixture was stirred at 30 °C for 2 hours. The reaction solution was analyzed by liquid chromatography, and the yield of 5-hydroxypyrazole was found to be 98.5%.

[0087] Comparative Example 1

[0088] 116.4 g (1.0 mol) of methyl 3-methoxyacrylate and 64.1 g of methanol were added to a 300 mL four-necked flask equipped with a refrigerant cooling reflux tube. While maintaining the temperature below 25 °C, 46.1 g (1.0 mol) of methylhydrazine was added dropwise over 2 hours. After the addition was completed, the mixture was stirred at 25 °C for 20 hours. The reaction solution was analyzed by liquid chromatography, and the reaction conversion rates of methyl 3-methoxyacrylate and methylhydrazine were found to be 89.1% and 88.7% respectively, the yield of 1-methyl-5-hydroxypyrazole was 77.6%, and the yield of 1-methyl-3-hydroxypyrazole as a positional isomer was 1.8%.

[0089] Industrial Applicability

[0090] The production method of the present invention can easily and highly efficiently obtain 1-alkyl-5-hydroxypyrazole, which can be used as a herbicide for pesticides, from easily accessible dialkylaminoacrylates with high purity, and can be used as an industrial production method.

Claims

1. Process for producing 1-alkyl-5-hydroxypyrazole represented by the general formula (3), wherein R4 is a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or aryl, and these groups may be substituted by halogen, hydroxy, alkoxy or C1-C6 alkyl, It is characterized in that, reacting a dialkylaminoacrylate represented by the general formula (1) with an alkylhydrazine represented by the general formula (2): wherein R1, R2 and R3 each independently represent C1-C6 alkyl; wherein R4 is a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl or aryl, and these groups may be substituted by halogen, hydroxy, alkoxy or C1-C6 alkyl.

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

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

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

5. The manufacturing method according to claim 4, wherein, Removing more than 90% of the by-produced dialkylamine.

6. The manufacturing method according to claim 5, wherein Removing the by-produced dialkylamine by concentration under reduced pressure.

7. The manufacturing method according to claim 5, wherein Removing the by-produced dialkylamine by an ion exchange resin.

8. The manufacturing method according to any one of claims 1 to 7, wherein, R4 in the general formulas (2) and (3) is methyl or ethyl.

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