Method for producing 1-alkyl-5-hydroxypyrazole

Abstract

To provide a new industrial production method that yields crystals of 1-alkyl-5-hydroxy pyrazole, using more readily available materials compared to conventional approaches, with simplicity, high yield, and high purity.SOLUTION: According to this production method, as illustrated in the reaction formula A, dialkylamino acrylate ester is reacted with alkylhydrazine, to synthesize 1-alkyl-5-hydroxy pyrazole, and organic acid is then added during crystallization, which can readily yield the crystals of 1-alkyl-5-hydroxy pyrazole. (Reaction formula A) (R1, R2, and R3 independently represent a C1-C6 alkyl group, R4 represents a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C3-C6 cycloalkyl group, or an aryl group, where these groups are optionally substituted with halogen, a hydroxy group, an alkoxy group, or a C1-C6 alkyl group).SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to a method for producing hydroxypyrazoles, and more particularly, to an industrial production method of 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 agricultural chemicals, it is disclosed as an intermediate for a plurality of field-acting herbicides. 5-Hydroxypyrazoles have attracted 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 decarbonated 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 first manufacturing method described above requires many steps. After obtaining the starting material, dialkyl alkoxymethylenemalonate, it is cyclized with alkylhydrazine to synthesize alkyl 1-alkyl-5-hydroxypyrazole-4-carboxylate. Further hydrolysis and decarboxylation reactions are then performed to finally obtain the desired 1-alkyl-5-hydroxypyrazole. Furthermore, the resulting reaction product contains not only 1-alkyl-5-hydroxypyrazole but also the simultaneously produced positional isomer 1-alkyl-3-hydroxypyrazole, and separating these from the target compound requires a complex procedure. Therefore, this synthesis method has a low yield.

[0004] The second manufacturing method is also complex and requires many steps. It involves the addition reaction of hydrazine to an acrylic acid ester to form 3-hydrazinopropionic acid ester, which is then subjected to a dehydration condensation reaction with an aldehyde to produce the corresponding hydrazone. Subsequently, cyclization yields 1-alkyl-5-hydroxypyrazole. This complex method generates many by-products and yields only low yields.

[0005] A third manufacturing method allows for the production of 1-alkyl-5-hydroxypyrazole in one step using 3-alkoxyacrylate esters, but 3-alkoxyacrylate esters are difficult to produce and expensive.

[0006] As a result, these three synthetic routes make it difficult to isolate 1-alkyl-5-hydroxypyrazole and are not satisfactory as economical and efficient industrial production methods for 1-alkyl-5-hydroxypyrazoles. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Application Publication No. 61-257974 [Patent Document 2] Special Publication No. 7-30031 [Patent Document 3] U.S. Patent No. 6,392,058 [Patent Document 4] International Publication No. 2017 / 004674 [Overview of the project] [Problems that the invention aims to solve]

[0008] The present invention aims to solve the problems associated with the prior art described above, and provides an efficient method for producing 1-alkyl-5-hydroxypyrazole, which is useful as an intermediate for pesticides, particularly herbicides, and offers an industrial production method that is simple, yields high yields, and produces high purity. [Means for solving the problem]

[0009] The inventors have discovered that when synthesizing 1-alkyl-5-hydroxypyrazole by reacting a dialkylaminoacrylate ester with alkylhydrazine, as shown in reaction formula A below, adding an organic acid that forms a salt with the by-product dialkylamine suppresses the increase in the solubility of 1-alkyl-5-hydroxypyrazole in the crystallization solvent due to the dialkylamine. The resulting dialkylamine salt dissolves in the crystallization solvent, and 1-alkyl-5-hydroxypyrazole can be obtained as crystals in high yield by crystallization. This discovery has led to the completion of the present invention. This manufacturing method suppresses the sublimation and decomposition of 1-alkyl-5-hydroxypyrazole, providing an industrial manufacturing method that can be expected to achieve high yield and cost reduction. (Reaction equation A) [ka] (In the formula, R1, R2, and R3 are each independently C1-C6 alkyl groups, and 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 with halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups.)

[0010] In other words, the present invention is a manufacturing method characterized by synthesizing 1-alkyl-5-hydroxypyrazole according to the above reaction formula A, then adding an organic acid to crystallize it and obtain crystals of 1-alkyl-5-hydroxypyrazole. [Effects of the Invention]

[0011] The present invention provides a method for producing 1-alkyl-5-hydroxypyrazole, which is useful for producing agricultural herbicides and the like, from readily available dialkylaminoacrylic acid esters in a short number of steps and simple operations. This method is simpler, yields higher yields and has higher purity compared to conventional methods, and can be used as an industrial production method. [Modes for carrying out the invention]

[0012] The applicant previously proposed a method for producing 1-alkyl-5-hydroxypyrazole represented by general formula (3) by reacting a dialkylaminoacrylate ester represented by general formula (1) with an alkylhydrazine represented by general formula (2) (Japanese Patent Application No. 2021-92213). This reaction method is an excellent method that allows for the simple production of 1-alkyl-5-hydroxypyrazole in one step using readily available dialkylaminoacrylate esters compared to conventional reaction methods, and a production method using this reaction method has been provided.

[0013] However, further investigation revealed that in this manufacturing method, if the by-product dialkylamine is included during crystallization, the solubility of 1-alkyl-5-hydroxypyrazole in the crystallization solvent increases, significantly reducing the crystal yield. While the dialkylamine can be removed by concentration along with the by-product alcohol and the solvent used in the reaction, 1-alkyl-5-hydroxypyrazole forms a salt with the dialkylamine, hindering its removal by distillation. Therefore, reducing the amount of dialkylamine requires high-temperature and high-pressure concentration, but since 1-alkyl-5-hydroxypyrazole decomposes and sublimes at high temperatures and high pressure, blockage of the vacuum line due to decomposition and sublimation during concentration becomes a problem. In addition, dialkylamine, with its low boiling point, is an odor-causing substance, and the amount of gas generated increases as the scale-up increases during high-temperature and high-pressure concentration. Depending on the capacity of the vacuum and decontamination equipment, it is practically difficult to remove dialkylamine in a short time while suppressing thermal decomposition during mass production. Thus, it was found that this synthesis method is extremely difficult to implement as an industrial manufacturing method in terms of equipment requirements. In contrast, the present invention solves the above problem by obtaining crystals of 1-alkyl-5-hydroxypyrazole represented by general formula (3) by adding an organic acid and performing crystallization.

[0014] In other words, the method for producing 1-alkyl-5-hydroxypyrazole according to the present invention is a method for producing 1-alkyl-5-hydroxypyrazole represented by general formula (3) by reacting a dialkylaminoacrylate ester represented by general formula (1) with an alkylhydrazine represented by general formula (2), as shown in the above reaction formula A, and further comprising adding an organic acid and crystallizing to obtain crystals of 1-alkyl-5-hydroxypyrazole represented by general formula (3). The following describes in detail the method for producing 1-alkyl-5-hydroxypyrazole according to the present invention, including the starting materials, the target compound, and the production method, such as the reaction method and crystallization method.

[0015] (Dialkylaminoacrylate) The dialkylaminoacrylate used 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.

[0016] The dialkylaminoacrylate represented by such formula (1) is in increasing demand as a raw material for fluoroquinolone synthetic antibacterial drugs such as ciprofloxacin, talibut, clavibet, and norfloxacin, for which demand has increased significantly in recent years.

[0017] In addition, the dialkylaminoacrylate represented by such formula (1) can be easily synthesized by reacting acetic ester and sodium alkoxide with carbon monoxide or formic ester and then reacting with a dialkylamine or its mineral acid salt. For example, it is also available as a commercial product from companies such as Tokyo Chemical Industry Co., Ltd. and Fujifilm Wako Pure Chemical Corporation.

[0018] (Alkylhydrazine) Moreover, the alkylhydrazine that reacts with the above dialkylaminoacrylate is a compound represented by the general formula (2). General formula (2) [Chemical formula] In the formula, R4 is preferably 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 halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups.

[0019] Here, the main objective 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. Although these substituents are different from alkyl groups, even in this case, the synthesis can be carried out in the same manner as when 1-alkyl-5-hydroxypyrazole is synthesized using alkylhydrazine as described in the present invention. Therefore, although the hydrazine derivatives used in the reaction include those that are not alkyl groups, and thus cannot be strictly called "alkyl," the compounds represented by general formula (2), including those that are not alkyl groups, are collectively referred to as "alkylhydrazines." Similarly, the compounds represented by general formula (3), which are reaction products obtained using alkylhydrazines, are also collectively referred to as "1-alkyl-5-hydroxypyrazoles," including those that are not alkyl groups.

[0020] The alkyl groups with 1 to 6 carbon atoms used in the reaction, i.e., C1 to C6, include both linear and branched alkyl groups. Of these alkyl groups, methyl and ethyl groups are preferred from an economic standpoint, with methyl groups being particularly preferred.

[0021] Furthermore, the alkenyl group having 2 to 6 carbon atoms, i.e., C2 to C6, may be linear or branched, and the position of the double bond may be terminal or intermediate. Among such alkenyl groups, the allyl group is preferred from the viewpoint of physiological activity and applicability to further modification reactions.

[0022] Furthermore, cycloalkyl groups with 3 to 6 carbon atoms, i.e., C3 to C6, also include cases where an alkyl group is substituted on the cycloalkyl group or where the cycloalkyl group is bonded via an alkylene group. Note that in the case of cycloalkyl groups, the number of carbon atoms refers to the number of carbon atoms 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 C3 to C6 groups. Among these cycloalkyl groups, the cyclopropyl group is preferred from the viewpoint of physiological activity.

[0023] Furthermore, these groups may be substituted with halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups. However, since the reactivity of R4 decreases as the number of carbon atoms increases, the upper limit of the number of carbon atoms is preferably C18. Note that in the case of C1-C6 alkyl groups and C2-C6 alkenyl groups as R4, even if these groups are considered to be substituted with the above-mentioned C1-C6 alkyl groups, the number of carbon atoms in the alkyl group and alkynyl group must all be 6 or less, and it is not necessary to consider the case where C1-C6 alkyl groups are substituted.

[0024] Furthermore, when these substituents R4 are used as intermediate raw materials for pharmaceuticals, agrochemicals, etc., those suitable for use as intermediate raw materials for pharmaceuticals and agrochemicals are selected, but generally, they are often alkyl groups or aryl groups.

[0025] The alkylhydrazines mentioned above can be synthesized by alkylating hydrazine, but they can also be obtained commercially from companies such as Tokyo Chemical Industries, Ltd. and Fujifilm Wako Pure Chemical Industries, Ltd. Such alkylhydrazines are also commercially available as aqueous solutions, and their concentrations vary depending on the type of alkylhydrazine, but are generally around 30-50%. In the manufacturing method of the present invention, either the alkylhydrazine itself or commercially available aqueous solutions can be used.

[0026] (1-alkyl-5-hydroxypyrazole) The product obtained by reacting the dialkylaminoacrylate ester of formula (1) with the alkylhydrazine of formula (2) is 1-alkyl-5-hydroxypyrazole, which is represented by general formula (3). General formula (3) [ka] In the formula, R4 is the same substituent as R4 in the alkylhydrazine represented by formula (2). Considering that the resulting compound represented by formula (3) is an intermediate raw material for pesticides and pharmaceuticals, R4 is preferably an alkyl group or an aryl group, and these groups may be substituted with halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups.

[0027] Incidentally, in the synthesis of 1-alkyl-5-hydroxypyrazole by reaction of a 3-substituted (e.g., 3-alkoxy group) acrylic acid ester with alkylhydrazine, the product 1-alkyl-5-hydroxypyrazole is acidic and forms a salt with alkylhydrazine. Therefore, in order to terminate the reaction, it was necessary to use an excess of alkylhydrazine or to add a basic component that forms a salt with 1-alkyl-5-hydroxypyrazole. In contrast, in the production method of the present invention, 1-alkyl-5-hydroxypyrazole is obtained by reacting a dialkylaminoacrylic acid ester of formula (1) with alkylhydrazine of formula (2). In this process, a dialkylamine is produced as a by-product, and the product 1-alkyl-5-hydroxypyrazole and the dialkylamine form a salt. Therefore, the reaction can be terminated without adding an excess basic component, making it possible to obtain the target product simply, in high yield, and with high purity.

[0028] To produce the 1-alkyl-5-hydroxypyrazole of the present invention, the dialkylaminoacrylate ester of formula (1) and alkylhydrazine of formula (2) are reacted in the absence of a solvent or in the presence of a solvent, as shown in reaction formula A, and the target compound, 1-alkyl-5-hydroxypyrazole of formula (3), is obtained by adding an organic acid and crystallizing.

[0029] In the present invention, the amounts of dialkylaminoacrylate represented by formula (1) and alkylhydrazine represented by formula (2) charged in the reaction are in the range of 0.5 to 2.0 equivalents of alkylhydrazine per 1.0 equivalent of dialkylaminoacrylate, preferably in the range of 0.8 to 1.2 equivalents, and more preferably in the range of 1.0 equivalent. If dialkylaminoacrylate is charged in excess, the yield will decrease due to a side reaction between the target compound, 1-alkyl-5-hydroxypyrazole, and the dialkylaminoacrylate. If alkylhydrazine is charged in excess, alkylhydrazine is likely 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.

[0030] In this invention, the alkylhydrazine represented by formula (2) can, as described above, be reacted with alkylhydrazine itself, i.e., high-purity alkylhydrazine, but it can also be reacted with alkylhydrazine containing water or other solvents. For example, commercially available alkyl(e.g., methyl)hydrazine containing water can be used as is in an aqueous solution containing water without removing the water, and results almost equivalent to those obtained when alkyl(methyl)hydrazine is used as is can be obtained. Alkylhydrazines generally have a low flash point and are easily flammable upon oxidation, but the presence of water can be preferable in that it lowers the flash point of the alkylhydrazine and makes it easier to handle.

[0031] In this invention, the reaction can be carried out without a solvent, but a solvent may be used to remove the heat of reaction. Examples of solvents 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. Of these solvents, alcohols and nitriles are preferred, and alcohols are particularly preferred. These solvents can be used individually or as a mixture of two or more, and the mixing ratio can be any ratio. The amount of solvent used is in the range of 0.01 to 5.0 parts by mass per 1.0 part by mass of the dialkylaminoacrylic acid ester represented by formula (1), and preferably in the range of 0.1 to 1.0 parts by mass.

[0032] The reaction involves reacting the dialkylaminoacrylate of formula (1) with the alkylhydrazine of formula (2). The dialkylaminoacrylate of formula (1) and the alkylhydrazine of formula (2) may be added simultaneously to the reaction vessel and mixed before the reaction, or one of the compounds, the dialkylaminoacrylate of formula (1) or the alkylhydrazine of formula (2), may be added to the other compound while the reaction is occurring. Since this reaction is exothermic, it is desirable to add either the dialkylaminoacrylate of formula (1) or the alkylhydrazine of formula (2) dropwise, or to add the dialkylaminoacrylate of formula (1) and the alkylhydrazine of formula (2) simultaneously dropwise. However, since the unreacted dialkylaminoacrylate decomposes at high temperatures, it is more desirable to add the dialkylaminoacrylate of formula (1) dropwise.

[0033] When reacting by adding alkylhydrazine represented by formula (2), or when reacting by simultaneously adding dialkylaminoacrylate ester represented by formula (1) and alkylhydrazine represented by formula (2), a low temperature is desirable for the dropping temperature of the raw materials. The temperature range for dropping the raw materials is -20°C to 60°C, with 0°C to 40°C being preferred. The reaction temperature range after dropping the raw materials is 0°C to 80°C, with 0°C to 60°C being preferred. When reacting by adding dialkylaminoacrylate ester represented by formula (1), the temperature range for dropping the raw materials and the reaction temperature after dropping the raw materials is 0°C to 80°C, with 0°C to 60°C being preferred. Since the reaction rate decreases as the reaction progresses, it is preferable to raise the reaction temperature in the latter half of the reaction. In this invention, the dropping time for 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.

[0034] Within these reaction temperature and time ranges, the formation of positional isomers is minimal, and the final reaction product can be obtained with high purity and high yield. If the reaction temperature is higher than the above range, or if the reaction time is longer than the above range, side reactions will occur, resulting in a decrease in yield and purity. Therefore, it is preferable to carry out the reaction within the above temperature and time ranges. Furthermore, while a lower temperature is preferable when adding the raw materials to avoid excessive reactions during the addition process, the above-mentioned range of adding temperature and time is preferable as it does not affect the reaction after addition.

[0035] In this invention, crystals of 1-alkyl-5-hydroxypyrazole represented by formula (3) are obtained by crystallization. However, if dialkylamine remains as a by-product, it greatly increases the solubility of 1-alkyl-5-hydroxypyrazole in the crystallization solvent, so it is desirable to remove it before crystallization. Dialkylamine can be removed by concentration, but 1-alkyl-5-hydroxypyrazole is thermally unstable and decomposes during concentration. In particular, when scaling up, the treatment of dialkylamine, which has a low boiling point and is an malodorous substance, takes time, and the yield decreases due to thermal decomposition. Also, if the removal rate of dialkylamine increases, sublimation of 1-alkyl-5-hydroxypyrazole occurs, causing blockage of condensers and vacuum lines. For these reasons, it is practically difficult to remove all of the dialkylamine by concentration, so it is desirable to remove only a portion. Concentration is carried out at atmospheric pressure or under reduced pressure, and the degree of reduced pressure can be in the range from atmospheric pressure to vacuum. Although it depends on the solvent used and the type of alcohol or amine produced as a by-product, the concentration temperature is generally in the range of 30 to 120°C, preferably in the range of 50 to 100°C. Furthermore, by adding an inert gas such as nitrogen or a volatile organic solvent dropwise during concentration, the dialkylamine distills off together with the gas and solvent, increasing the removal effect and shortening the concentration time.

[0036] Dialkylamines that remain after concentration inhibit the crystallization of 1-alkyl-5-hydroxypyrazole during crystallization. Depending on the crystallization solvent, the solubility of 1-alkyl-5-hydroxypyrazole in the crystallization solvent increases by several times the equivalent amount of the remaining dialkylamine. In contrast, by adding an organic acid that forms a dialkylamine salt and a salt that dissolves in the crystallization solvent, the solubility of 1-alkyl-5-hydroxypyrazole in the crystallization solvent decreases to an equivalent amount significantly lower than the equivalent amount of the remaining dialkylamine. Depending on the crystallization conditions, adding an organic acid during crystallization when dialkylamine remains reduces the solubility of 1-alkyl-5-hydroxypyrazole, which is caused by the dialkylamine, to about 1 / 10. When the equivalent amount of added organic acid is small, an increase in the solubility of 1-alkyl-5-hydroxypyrazole is observed due to the dialkylamine that does not form a salt. Furthermore, even in excess, the solubility of 1-alkyl-5-hydroxypyrazole increases. Therefore, the amount of basic component contained during crystallization should be in the range of 0.8 to 1.2 equivalents, preferably 1.0 equivalent.

[0037] If the amount of dialkylamine salt formed exceeds the solubility of the crystallization solvent, the dialkylamine salt will be mixed into the 1-alkyl-5-hydroxypyrazole crystals when crystallization is performed to obtain 1-alkyl-5-hydroxypyrazole crystals. Therefore, it is desirable to add as little organic acid as possible. More than 50% of the by-product dialkylamine is removed by the concentration of the by-product alcohol and solvent, but the higher the concentration of the dialkylamine, the more the decomposition of 1-alkyl-5-hydroxypyrazole progresses. For this reason, it is desirable to add organic acid in an amount of 50% equivalent or less of the by-product dialkylamine.

[0038] The organic acid to be added must be such that the salt formed with the dialkylamine is soluble in the crystallization solvent. Furthermore, since 1-alkyl-5-hydroxypyrazole forms a salt with the dialkylamine, an acid stronger than 1-alkyl-5-hydroxypyrazole, i.e., an organic acid with a pKa of 3 or less, is used. The type of acid is not particularly limited, but organic sulfonic acids and carboxylic acids are preferred, and specifically, methanesulfonic acid and p-toluenesulfonic acid are used.

[0039] In the present invention, crystals of 1-alkyl-5-hydroxypyrazole represented by formula (3) are obtained by recrystallization. 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, with acetonitrile and ethyl acetate being particularly preferred.

[0040] As described above, the crystallization step after the reaction in the present invention preferably involves first removing the by-product dialkylamine from the reaction liquor, preferably by 50% equivalent or more, and then adding a specific organic acid to perform crystallization. In this case, a crystallization solvent may be used as needed. Here, the by-product dialkylamine can be removed, for example, by concentrating the reaction liquor under atmospheric pressure and / or reduced pressure, but it is also possible by other methods that can remove amines, such as treatment with ion exchange resin or adsorbent. Subsequently, depending on the amount of remaining dialkylamine, an organic acid is added and crystallization is performed by conventional methods to obtain crystals of the target product.

[0041] The 1-alkyl-5-hydroxypyrazole separated by crystallization is preferably washed with the crystallization solvent to remove the dialkylamine salt dissolved in the crystallization solvent. By washing with the crystallization solvent, the content of the dialkylamine salt in the obtained 1-alkyl-5-hydroxypyrazole crystals can be reduced to 0.1% or less. After recrystallization, filtration and drying can be performed to obtain high-purity 1-alkyl-5-hydroxypyrazole represented by general formula (3). In this case, a simple manufacturing method is provided that does not require any purification steps such as distillation or column chromatography. [Examples]

[0042] The present invention will be described in more detail below based on examples, but the present invention is not limited by these examples.

[0043] Example 1 In a 1000 mL four-necked flask equipped with a refrigerant reflux condenser, 115.7 g (2.5 mol) of monomethylhydrazine and 160.7 g of methanol were added, and 71.9 g (0.5 mol) of ethyl dimethylaminoacrylate was added dropwise over 30 minutes while maintaining the temperature below 20°C. The mixture was then stirred at 20°C for 1 hour. After stirring, 287.7 g (2.0 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours, followed by stirring at 60°C for 2 hours. After the reaction was complete, the reaction mixture was analyzed by liquid chromatography, and the yield of 1-methyl-5-hydroxypyrazole was 95.8%, while the yield of its positional isomer, 1-methyl-3-hydroxypyrazole, was 0.6%.

[0044] After the reaction was complete, 636.0 g of the reaction solution was concentrated under reduced pressure to remove the by-product dimethylamine along with the solvent. The temperature of the concentrate at the end of concentration was 80°C, and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrate revealed 34.3 g, indicating that 70% of the by-product was removed. After concentration, 275.0 g of acetonitrile and 143.3 g (0.75 mol) of p-toluenesulfonic acid monohydrate were 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 167.0 g (1.70 mol) of 1-methyl-5-hydroxypyrazole. The yield was 67.8%, and the purity was 99.9%. The p-toluenesulfonic acid-dimethylamine salt in the crystals was less than 0.1%, and the isomer 1-methyl-3-hydroxypyrazole was not detected.

[0045] Example 2 393.5 g (8.5 mol) of monomethylhydrazine and 546.3 g of methanol were added to a 3000 mL four-necked flask equipped with a refrigerant reflux tube. 245 g (1.7 mol) of ethyl dimethylaminoacrylate was added dropwise over 30 minutes while maintaining the temperature below 20°C. The mixture was then stirred at 20°C for 1 hour. After stirring, 978.2 g (6.8 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours, followed by stirring at 60°C for 2 hours. After the reaction was complete, the reaction mixture was analyzed by liquid chromatography. The yield of 1-methyl-5-hydroxypyrazole was 95.8%, and the yield of its positional isomer, 1-methyl-3-hydroxypyrazole, was 0.6%.

[0046] After the reaction was complete, 2163 g of the reaction solution was concentrated under reduced pressure by bubbling 291.8 g of methanol into the solution to remove the by-product dimethylamine along with the solvent. At the end of concentration, the temperature of the concentrate was 80°C and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrate revealed 48.5 g, indicating that 87.3% of the by-product was removed. After concentration, 935.0 g of acetonitrile and 204.7 g (1.08 mol) of p-toluenesulfonic acid monohydrate were added, dissolved at 60°C, and then cooled to 0°C to precipitate crystals. The precipitated crystals were separated by centrifugation, and the collected crystals were dried to obtain 604.0 g (6.15 mol) of 1-methyl-5-hydroxypyrazole. The yield was 72.3%, and the purity was 99.9%. The p-toluenesulfonic acid-dimethylamine salt in the crystals was less than 0.1%, and the isomer 1-methyl-3-hydroxypyrazole was not detected.

[0047] Example 3 In a 1000 mL four-necked flask equipped with a refrigerant reflux condenser, 115.7 g (2.5 mol) of monomethylhydrazine and 160.7 g of methanol were added, and 72 g (0.5 mol) of ethyl dimethylaminoacrylate was added dropwise over 30 minutes while maintaining the temperature below 20°C. The mixture was then stirred at 20°C for 1 hour. After stirring, 287.7 g (2.0 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours, followed by stirring at 60°C for 2 hours. After the reaction was complete, the reaction mixture was analyzed by liquid chromatography, and the yield of 1-methyl-5-hydroxypyrazole was 95.7%, while the yield of its positional isomer, 1-methyl-3-hydroxypyrazole, was 0.6%.

[0048] Of the 636.1 g of reaction solution obtained, 100.1 g was concentrated under reduced pressure while bubbling nitrogen into the solution to remove the by-product dimethylamine along with the solvent. At the end of concentration, the temperature of the concentrate was 80°C and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrate revealed 3.9 g, indicating that 11.6% of the by-product amount remained (88.4% of the by-product amount was removed). 82.5 g of acetonitrile and 16.6 g (0.09 mol) of p-toluenesulfonic acid monohydrate were added to the concentrate, 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 56.9 g (0.58 mol) of 1-methyl-5-hydroxypyrazole. The yield was 77.3%, and the purity was 99.9%. The p-toluenesulfonic acid dimethylamine salt in the crystals was less than 0.1%, and its isomer, 1-methyl-3-hydroxypyrazole, was not detected.

[0049] Example 4 50.9 g (1.1 mol) of monomethylhydrazine and 70.7 g of methanol were added to a 500 mL four-necked flask equipped with a refrigerant reflux tube. 31.7 g (0.2 mol) of ethyl dimethylaminoacrylate was added dropwise over 30 minutes while maintaining the temperature below 20°C. The mixture was then stirred at 20°C for 1 hour. After stirring, 126.6 g (0.9 mol) of ethyl dimethylaminoacrylate was added dropwise over 2 hours, followed by stirring at 60°C for 2 hours. After the reaction was complete, the reaction mixture was analyzed by liquid chromatography. The yield of 1-methyl-5-hydroxypyrazole was 94.8%, and the yield of its positional isomer, 1-methyl-3-hydroxypyrazole, was 0.6%.

[0050] After the reaction was complete, 278.9 g of the reaction solution was concentrated under reduced pressure while blowing nitrogen into the solution to remove the by-product dimethylamine along with the solvent. At the end of concentration, the temperature of the concentrate was 90°C and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrate revealed 4.3 g, indicating that 91.4% of the by-product was removed. After concentration, 101.3 g of 121.0 g of acetonitrile solution was added to 222.8 g of acetonitrile solution, to which 4.1 g (0.04 mol) of methanesulfonic acid was added. The solution was 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 33.5 g (0.33 mol) of 1-methyl-5-hydroxypyrazole. The yield was 66.7%, and the purity was 99.9%. The methanesulfonic acid-dimethylamine salt in the crystals was less than 0.1%, and the isomer 1-methyl-3-hydroxypyrazole was not detected.

[0051] Example 5 636.1 g of the reaction solution obtained in the same manner as in Example 3 was concentrated under reduced pressure to remove the dimethylamine produced as a by-product along with the solvent. The temperature of the concentrated solution at the end of concentration was 80°C, and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrated solution revealed 24.5 g, indicating that 78.7% of the by-product amount was removed. After concentration, 112.4 g of 112.4 g of acetonitrile solution (561.8 g of which 275.5 g of acetonitrile was added) was mixed with 16.3 g (0.11 mol) of trifluoromethanesulfonic acid. The solution was 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 34.9 g (0.36 mol) of 1-methyl-5-hydroxypyrazole. The yield was 69.8%, and the purity was 99.9%. The trifluoromethanesulfonic acid-dimethylamine salt in the crystals was less than 0.1%, and the isomer 1-methyl-3-hydroxypyrazole was not detected.

[0052] Example 6 Of the 561.8 g of acetonitrile solution obtained in Example 5, 112.4 g was mixed with 5.0 g (0.11 mol) of formic acid. The mixture was 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 22.6 g (0.23 mol) of 1-methyl-5-hydroxypyrazole. The yield was 45.1%, and the purity was 99.9%. The formic acid-dimethylamine salt in the crystals was less than 0.1%, and the isomer 1-methyl-3-hydroxypyrazole was not detected.

[0053] Comparative Example 1 Of the 636.1 g of reaction solution obtained in Example 3, 100.1 g was concentrated under reduced pressure while blowing nitrogen into the solution to remove the by-product dimethylamine along with the solvent. At the end of concentration, the temperature of the concentrated solution was 80°C and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrated solution revealed 4.0 g, indicating that 11.8% of the by-product amount remained (88.2% of the by-product amount was removed). 82.5 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 30.2 g (0.31 mol) of 1-methyl-5-hydroxypyrazole. The yield was 41.0%, and the purity was 99.9%. The isomer 1-methyl-3-hydroxypyrazole was not detected.

[0054] Comparative Example 2 Of the 561.8 g of acetonitrile solution obtained in Example 5, 220.3 g was 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 13.4 g (0.14 mol) of 1-methyl-5-hydroxypyrazole. The yield was 13.7%, and the purity was 99.9%. The isomer 1-methyl-3-hydroxypyrazole was not detected.

[0055] Comparative Example 3 278.9 g of the reaction solution obtained in the same manner as in Example 4 was concentrated under reduced pressure while blowing nitrogen into the solution to remove the by-product dimethylamine along with the solvent. The temperature of the concentrated solution at the end of concentration was 90°C and the degree of reduced pressure was 50 mmHg. Analysis of the dimethylamine in the concentrated solution revealed 5.7 g, indicating that 88.6% of the by-product amount was removed. After concentration, 121.0 g of acetonitrile was added to obtain 224.2 g of acetonitrile solution. 101.9 g of this solution was mixed with 2.9 g (0.03 mol) of sulfuric acid, 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 36.6 g (0.33 mol) of 1-methyl-5-hydroxypyrazole. The yield was 65.5%, and the purity was 87.8%. The sulfuric acid-dimethylamine salt in the crystals was 12.2%, and the isomer 1-methyl-3-hydroxypyrazole was not detected. [Industrial applicability]

[0056] The manufacturing method of the present invention allows for the simple, high-yield, and high-purity production of 1-alkyl-5-hydroxypyrazole, which is useful as an agricultural herbicide, from readily available dialkylaminoacrylate esters, making it a useful industrial manufacturing method.

Claims

1. General formula (1): 【Chemistry 1】 (In the formula, R １ , R ２ , and R ３ Each of these independently represents a C1-C6 alkyl group. Dialkylaminoacrylate esters represented by general formula (2) 【Chemistry 2】 (In the formula, R ４ (These groups are 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 halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups.) By reacting an alkylhydrazine represented by with , we obtain general formula (3) 【Transformation 3】 (In the formula, R ４ (These groups are 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 halogens, hydroxyl groups, alkoxy groups, or C1-C6 alkyl groups.) A method for producing 1-alkyl-5-hydroxypyrazole represented by the formula (3), wherein crystals of 1-alkyl-5-hydroxypyrazole represented by the general formula (3) are obtained by adding an organic acid and crystallizing.

2. The manufacturing method according to claim 1, wherein 50% equivalent or more of the by-product dialkylamine is removed, and then an organic acid is added to crystallize it.

3. The manufacturing method according to claim 1, comprising adding an organic acid equivalent to 0.8 to 1.2 equivalents of the basic component contained during crystallization.

4. The production method according to claim 1, wherein the organic acid added is an organic sulfonic acid or a carboxylic acid.

5. The manufacturing method according to claim 1, wherein the organic acid added is an organic sulfonic acid.

6. The method for producing the product according to claim 1, wherein the organic acid added is p-toluenesulfonic acid, methanesulfonic acid, or trifluoromethanesulfonic acid.

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