A method for preparing 5-hydroxy-1-methylpyrazole

Abstract

The present application provides a method for preparing 5-hydroxy-1-methylpyrazole, which comprises the following steps: S1: subjecting N,N-dimethylamino alkyl acrylate and methylhydrazine to a Michael addition reaction in a two-phase solvent system consisting of water and a non-polar organic solvent in the presence of a phase transfer catalyst and a polymerization inhibitor to obtain a β-hydrazino ester intermediate; S2: subjecting the β-hydrazino ester intermediate to an internal cyclization reaction, and removing dimethylamine and low-carbon alcohol byproducts to obtain 5-hydroxy-1-methylpyrazole. This method can effectively improve the site selectivity of 5-hydroxy-1-methylpyrazole, significantly inhibit the formation of structural isomers, and particularly avoid the common 3-hydroxy-1-methylpyrazole byproduct in the prior art, thereby improving the purity and yield of the main product and having good reaction stability and scale-up adaptability.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular to a method for preparing 5-hydroxy-1-methylpyrazole. Background Art

[0002] 5-Hydroxy-1-methylpyrazole is an important pesticide intermediate, widely used in the synthesis of benzoylpyrazole compounds, particularly playing a key role in the synthesis of highly effective herbicides such as fenpyrazone. Benzoylpyrazole compounds, as hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors, possess advantages such as high efficiency, high selectivity, and low toxicity. Therefore, high purity and yield of these intermediates are required.

[0003] The existing synthesis methods of 5-hydroxy-1-methylpyrazole mainly include the following two routes:

[0004] The first type uses methyl 3-methoxyacrylate and methylhydrazine as raw materials, producing the target product through addition and cyclization reactions. For example, patent CN109320457A discloses the use of continuous flow technology to achieve this reaction, improving synthesis efficiency; CN1330639A discloses a method for synthesizing 3-alkoxyacryloyl chloride from phosgene and esterifying it to obtain methyl 3-methoxyacrylate, which is then reacted with methylhydrazine. However, this route has the following problems: First, phosgene is a highly toxic substance, posing a safety hazard; second, pH control during the addition-cyclization process is difficult, which can easily lead to the formation of structural isomers such as 3-hydroxy-1-methylpyrazole, affecting the purity of the target product.

[0005] The second type uses a 1,3-dielectrophilic compound (such as diethyl ethoxymethylenemalonate) as a starting material. It first reacts with an amide source (such as tetrahydropyrrole or diethylamine), then condenses with methylhydrazine and undergoes cyclization to form an ester intermediate. This intermediate is then hydrolyzed and decarboxylated under acidic conditions to yield 5-hydroxy-1-methylpyrazole. This method effectively controls the selectivity of the hydroxyl group at the 5-position, but it often suffers from harsh reaction conditions, numerous steps, complex post-processing, poor intermediate stability, and difficulty in separation.

[0006] Given the difficulty in separating 5-hydroxy-1-methylpyrazole from its isomer, 3-hydroxy-1-methylpyrazole, and the relatively high cost of methyl 3-methoxyacrylate used in existing methods, current research has primarily focused on the second route. For example, patents IN201611027903, CN112480008A, and CN119684212A all employ this route, but it suffers from common issues such as complex reaction steps, unstable intermediates, severe decarboxylation side reactions, low yields, and difficulty in scale-up.

[0007] Therefore, there is an urgent need to provide a new method for synthesizing 5-hydroxy-1-methylpyrazole with higher site selectivity, which can effectively avoid the formation of isomers and has a stable and controllable process, so as to solve the problems existing in the prior art. Summary of the Invention

[0008] The present application provides a method for preparing 5-hydroxy-1-methylpyrazole, aiming to overcome the problems of isomer formation, poor site selectivity, complex steps and difficulty in process scale-up existing in the prior art.

[0009] In a first aspect, the present application provides a method for preparing 5-hydroxy-1-methylpyrazole, comprising the following steps:

[0010] S1: N,N-dimethylamino alkyl acrylate and methyl hydrazine undergo Michael addition reaction in a two-phase solvent system consisting of water and a non-polar organic solvent in the presence of a phase transfer catalyst and a polymerization inhibitor to obtain a β-hydrazino ester intermediate;

[0011] S2: subjecting the β-hydrazino ester intermediate to an internal cyclization reaction and removing dimethylamine and lower alcohol by-products to obtain 5-hydroxy-1-methylpyrazole.

[0012] According to the present application, this method can effectively improve the site selectivity of 5-hydroxy-1-methylpyrazole, significantly inhibit the formation of structural isomers, especially avoid the common 3-hydroxy-1-methylpyrazole by-product in the prior art, improve the purity and yield of the main product, and have good reaction stability and scale-up adaptability.

[0013] Specifically, compared to the 3-methoxyacrylate raw material widely used in the prior art, the N,N-dimethylaminoalkyl acrylate is structurally more reaction-oriented: its β-position dimethylamino group has excellent leaving properties, and after addition, it can spontaneously deaminize under mild conditions to form a pyrazole ring, effectively locking the hydroxyl group at the 5-position and avoiding the isomerization reaction path induced by the double bond conjugated system. However, the cyclization process after the addition of 3-methoxyacrylate requires precise pH control to control the reaction path, and its methoxy group has relatively poor leaving properties, which can easily lead to non-selective cyclization of the addition intermediate between the α / β positions, thereby generating a 3-hydroxy structural isomer, increasing the proportion of by-products, reducing purity, and increasing the difficulty of separation.

[0014] Furthermore, the byproduct dimethylamine, formed by the deamination of N,N-dimethylamino alkyl esters after addition, is highly volatile and has a low boiling point. However, in traditional alcoholic single-phase solvent systems (including water, which is miscible with alcoholic solvents), its boiling point is close to that of the alcoholic solvent, making it difficult to separate and easily retained in the reaction system. This can inhibit the internal cyclization reaction of the β-hydrazino ester intermediate or lead to reversible equilibrium side reactions, thereby reducing the conversion rate and structural purity of the target product. Especially under industrial scale-up conditions, the residual presence of this byproduct can easily cause process fluctuations and purification difficulties.

[0015] In view of this, the present application adopts a two-phase reaction system consisting of water and a non-polar organic solvent. A phase transfer catalyst is used to guide the selective Michael addition reaction between nucleophiles and electrophiles at the interface, allowing the addition intermediates to rapidly migrate to the aqueous phase and complete the spontaneous deamination cyclization reaction under mild conditions. This circumvents the problems of unclear intermediate conversion pathways, significant byproduct interference, and difficult separation in traditional single-phase systems. Furthermore, the introduction of a polymerization inhibitor effectively suppresses the polymerization side reaction of N,N-dimethylamino alkyl acrylate in the organic phase, ensuring the single-path operation of the reaction and the structural specificity of the target product.

[0016] In summary, the present application has formed an efficient, stable, and structurally selective 5-hydroxy-1-methylpyrazole synthesis route by selecting raw materials with clearer structure guidance, combining a two-phase migration synergistic system with a side reaction inhibition strategy. Compared with the system based on 3-methoxyacrylate in the prior art, the intermediate of the present application can spontaneously deamine and close the ring without relying on fine pH adjustment, effectively avoiding the risk of isomer formation and simplifying the operation process. At the same time, the overall synthesis system provided by the present invention is not a replacement for a single component, but achieves the target effect through the collaborative conception of "raw material structure-phase boundary migration-side reaction inhibition", constructing an efficient synthesis process that can operate stably under mild conditions and has high selectivity and yield advantages.

[0017] In some embodiments, in step S1, the molar ratio of the N,N-dimethylamino alkyl acrylate to the methylhydrazine is 1:(1.01-1.2); the volume ratio of the water to the non-polar organic solvent is (1-3):10, and the non-polar organic solvent includes at least one of cyclohexane, ethyl acetate, and n-heptane.

[0018] In some of the above embodiments, an appropriate excess of methylhydrazine helps ensure the complete nucleophilic addition reaction, reduces the residual N,N-dimethylamino alkyl acrylate, and prevents polymerization or other side reactions in the reaction system, thereby improving the production efficiency of the β-hydrazine ester intermediate and the overall yield of the target product. The volume ratio of water to non-polar organic solvent is controlled at (1-3):10, which helps to establish a stable liquid-liquid interface environment, improves the mass transfer efficiency of the phase transfer catalyst between the two phases, and allows the nucleophile (methylhydrazine) and the electrophile (N,N-dimethylamino alkyl acrylate) to be enriched at the interface and quickly undergo Michael addition reaction; at the same time, the generated β-hydrazine ester intermediate quickly migrates to the aqueous phase after the reaction, which is conducive to spontaneous cyclization and by-product release under mild conditions. It is preferred to use a low-polarity, moderately boiling point non-polar organic solvent such as cyclohexane, ethyl acetate or n-heptane, which not only facilitates the stable dispersion of the electrophile in the organic phase, but also facilitates the migration of by-products and solvent post-processing. Compared with the traditional single-phase alcohol-soluble system, the proportion design of the above two-phase system shows better comprehensive effects in improving interfacial reaction efficiency, reaction path controllability and subsequent separation convenience, significantly improving the stability of the overall process and product purity.

[0019] In some embodiments, step S1 includes: dissolving a phase transfer catalyst and an inhibitor in a non-polar organic solvent, then adding N,N-dimethylamino alkyl acrylate and methyl hydrazine aqueous solution to the solution at -10~0°C, reacting at -10~0°C for 6~10 hours, standing and separating after the reaction, and collecting the aqueous phase including the β-hydrazino ester intermediate.

[0020] In some of the aforementioned embodiments, by pre-dissolving the phase transfer catalyst and polymerization inhibitor in a non-polar organic solvent, their full dispersion in the reaction system is ensured, allowing for a stable and efficient reaction environment to be formed at the organic-aqueous phase interface during the initial stages of the reaction. The phase transfer catalyst facilitates the efficient migration of the highly nucleophilic methylhydrazine from the aqueous phase to the organic phase interface, prompting a rapid Michael addition reaction with the electrophilic N,N-dimethylamino alkyl acrylate. The polymerization inhibitor effectively suppresses the free radical polymerization side reaction of the unsaturated ester monomer in the reaction system, ensuring the selectivity and smooth progress of the primary reaction pathway.

[0021] Furthermore, the entire reaction is controlled within a low-temperature range of -10°C to 0°C, which helps reduce side reactions of the active intermediate and prolongs its stable existence in the reaction system, thereby facilitating the complete conversion of the intermediate and creating favorable conditions for subsequent layering operations. Low temperatures also help control the initial release of dimethylamine, preventing it from interfering with the system pH or reaction pathway. After the reaction is completed and the layers are allowed to separate, the resulting aqueous phase is enriched with the β-hydrazino ester intermediate, which not only facilitates the subsequent cyclization step but also simplifies the solid-liquid separation and solvent recovery processes, further enhancing the process's scalability.

[0022] In some embodiments, in step S1, adding N,N-dimethylaminoacrylate alkyl ester and methylhydrazine aqueous solution to the solution comprises: adding N,N-dimethylaminoacrylate alkyl ester and methylhydrazine aqueous solution to the solution at the same time.

[0023] In some of the aforementioned embodiments, the "simultaneous metered addition" approach can avoid instantaneous concentration differences between the reactants, preventing excessive concentrations of methylhydrazine or unsaturated ester monomers in localized areas, which could trigger side reactions or drastic pH fluctuations in the system. Furthermore, a stable mass transfer layer is formed at the interface between the two phases, facilitating the synchronous migration of reactants to the interface at equimolar rates, ensuring that the Michael addition reaction proceeds smoothly along the ideal path. In particular, for the aqueous-organic biphasic system and phase transfer catalysis employed in this application, controlling the rate and synchronization of reactant addition can effectively improve interfacial reaction efficiency and reduce the risk of intermediate structural heterogeneity or competitive reactions caused by uneven reactions.

[0024] In addition, by metering and controlling the flow rate and concentration of each reactant, it is also possible to combine it with the automation control requirements of the production process to provide operational stability and repeatability guarantees for subsequent process scale-up.

[0025] In some embodiments, step S2 includes: adding an inorganic salt to the aqueous phase including the β-hydrazino ester intermediate until saturated, reacting at 20-30° C. for 8-12 hours, and removing dimethylamine and low-carbon alcohol by-products by vacuum decompression to obtain an aqueous solution of 5-hydroxy-1-methylpyrazole.

[0026] In some of the above embodiments, adding an inorganic salt (such as sodium chloride) to the aqueous phase until saturated can significantly increase the ionic strength of the solution. On the one hand, it effectively reduces the solubility of the product in water and promotes the migration or precipitation of the target product generated after internal cyclization to the organic phase, which is beneficial to subsequent extraction and separation; on the other hand, the salting-out effect can drive the low-boiling point by-products (such as dimethylamine, methanol or ethanol) generated in the system to transfer to the gas phase, thereby improving the removal efficiency of the vacuum distillation and avoiding the purity reduction or alkaline interference caused by the retention of by-products in the aqueous phase.

[0027] Controlling the reaction temperature between 20 and 30°C helps maintain the stability of the intermediate and promotes smooth deamination and cyclization under mild conditions, reducing side reactions or product decomposition induced by excessively high temperatures. Combined with appropriate decompression, volatile byproducts can be efficiently removed, providing a good foundation for subsequent purification of the target product. Compared to direct extraction without the use of inorganic salts or under insufficient decompression, the above-mentioned embodiment can further improve the conversion efficiency, structural selectivity, and post-processing convenience of the target product.

[0028] In some embodiments, the method further comprises: step S3: adjusting the pH of the 5-hydroxy-1-methylpyrazole aqueous solution to 6.5-7 at 0-5° C., performing extraction treatment with butanol, and collecting the organic phase including 5-hydroxy-1-methylpyrazole.

[0029] In some of the above embodiments, by cooling the aqueous phase after the reaction to 0~5°C, the solubility of the product in the aqueous phase can be reduced, its loss with the aqueous phase can be inhibited, and the subsequent extraction efficiency can be improved; at the same time, this temperature condition helps to maintain the stability of the product structure and avoid the occurrence of heat-sensitive degradation or side reactions. Adjusting the pH to a near-neutral range of 6.5~7 can ensure the stability of the target product structure, which is conducive to maintaining the dissociation state of the hydroxyl group in the pyrazole ring system and avoiding hydrolysis, isomerization or other side reactions under strong acidic or alkaline conditions; using butanol as an extractant, which has both good affinity and extraction selectivity for the target product, can efficiently enrich 5-hydroxy-1-methylpyrazole to the organic phase under the above conditions and achieve preliminary separation from residual by-products in the aqueous phase. Compared with directly drying the aqueous phase or using a more polar extractant, this embodiment can significantly improve the extraction purity, simplify the subsequent processing flow, and lay the foundation for further purification of the product.

[0030] In some embodiments, the method further comprises: step S4: using a cation exchange resin to adsorb residual dimethylamine in the organic phase of the 5-hydroxy-1-methylpyrazole, distilling off butanol under reduced pressure, and washing with petroleum ether to obtain a crude 5-hydroxy-1-methylpyrazole product.

[0031] In some of the aforementioned embodiments, dimethylamine released during the addition-cyclization process has a certain affinity for organic phases and may partially remain in the butanol extraction layer. If not promptly removed, this may adversely affect subsequent recrystallization and purification. Treatment with a cation exchange resin selectively adsorbs free amines, particularly low-molecular-weight alkaline impurities such as dimethylamine, thereby improving the purity of the target product in the organic phase and preventing discoloration, degradation, or uneven crystal formation caused by alkaline impurities during subsequent solvent evaporation or crystal formation.

[0032] Subsequently, butanol is distilled off under reduced pressure to effectively remove residual solvent from the organic phase and further enrich the target product. Washing the distilled residue with petroleum ether helps remove small amounts of non-polar impurities and oily byproducts while preventing redispersion or loss of the target product in the polar solvent. This yields a relatively uniform crude 5-hydroxy-1-methylpyrazole product, providing a favorable prerequisite for final purification.

[0033] Compared with the process without adsorption treatment or direct concentration followed by crystallization, the above embodiment can further improve the yield and purity of the product, and is particularly suitable for the production scenario of pesticide intermediates with high requirements for the purity of the final product.

[0034] The specific type of cation exchange resin can be selected according to actual needs. As an example, 732 cation exchange resin is used in one embodiment of the present application.

[0035] In some embodiments, the method further comprises: step S5: heating the crude 5-hydroxy-1-methylpyrazole product under reflux and dissolving it in ethanol, decolorizing it with activated carbon, filtering it while hot and then cooling and crystallizing it, filtering and drying it to obtain high-purity 5-hydroxy-1-methylpyrazole.

[0036] In some of the above-mentioned embodiments, ethanol is used to completely dissolve the crude product under reflux conditions, which facilitates the release and dispersion of impurities, paving the way for subsequent decolorization and purification. As a moderately polar solvent, ethanol fully dissolves the target product while minimizing swelling or colloidation of impurities, making it a preferred solvent for this system, balancing solubility and process safety.

[0037] Activated carbon decolorization effectively removes pigment impurities, amine oxidation byproducts, and organic residues from the system, thereby improving product color and chemical purity. The treatment time is preferably 0.5-3 hours to balance decolorization efficiency and product stability. Hot filtration prevents impurities from being embedded in crystals during solution cooling, thereby improving crystal purity.

[0038] Cooling to 0-5°C induces crystallization, which helps the target product form a complete, dense crystal structure, further improving physical purity and controllable drying efficiency. Finally, filtering and drying yield a light-colored, highly crystalline, and high-purity 5-hydroxy-1-methylpyrazole product, meeting subsequent application requirements in pesticide synthesis and other fields.

[0039] In some embodiments, the N,N-dimethylamino alkyl acrylate includes at least one of methyl N,N-dimethylamino acrylate and ethyl N,N-dimethylamino acrylate.

[0040] Based on the above embodiment, different ester chain lengths have a regulatory effect on the electrophilicity of the addition reaction and the stability of the generated intermediates. Among them, N,N-dimethylaminoacrylate ethyl ester has better dispersibility and reactivity, which is beneficial to improving the reaction rate and subsequent cyclization conversion efficiency; while N,N-dimethylaminoacrylate methyl ester helps to control the reaction process under mild conditions, reduce the risk of side reactions, and facilitate industrial scale-up.

[0041] In some embodiments, the phase transfer catalyst includes at least one of tetrabutylammonium bromide and benzyltriethylammonium bromide; the amount of the phase transfer catalyst is 1 wt % to 3 wt % of the amount of the N,N-dimethylamino alkyl acrylate.

[0042] Based on the above implementation method, the quaternary ammonium salt phase transfer catalyst can significantly enhance the interfacial transport efficiency of electrophiles in the organic phase, so that the nucleophilic addition reaction can be carried out efficiently at the liquid-liquid interface, shortening the reaction time and increasing the main product generation rate; controlling the catalyst dosage within an appropriate range helps to avoid side reactions caused by the catalyst itself or the difficulty of subsequent removal, thereby improving the system stability and cost control capabilities.

[0043] In some embodiments, the polymerization inhibitor includes at least one of hydroquinone and ferric chloride; the amount of the polymerization inhibitor is 0.1 wt% to 0.5 wt% of the amount of the N,N-dimethylamino alkyl acrylate.

[0044] Based on the above embodiment, the addition of a polymerization inhibitor can effectively inhibit the polymerization reaction of N,N-dimethylamino alkyl acrylate caused by high concentration or local active sites during the addition reaction, especially in a two-phase system, where the control of interfacial reaction activity is particularly critical; an appropriate amount of polymerization inhibitor not only ensures the singleness of the main reaction path, but also avoids the residue of polymerization by-products during the post-processing process, thereby improving product purity.

[0045] In some embodiments, the inorganic salt includes at least one of sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate.

[0046] Based on the above implementation methods, different types of inorganic salts can provide diverse ionic strength adjustment pathways, which can not only promote the migration of target products from the aqueous phase to the organic phase through the "salting-out effect", but also drive the release and migration of low-boiling-point by-products, thereby enhancing post-processing efficiency. Among them, sodium chloride and sodium sulfate are preferred salts for industrial operations due to their wide availability, low cost, and high operational stability.

[0047] In some embodiments, the method comprises the following steps:

[0048] S1: dissolving a phase transfer catalyst and a polymerization inhibitor in a non-polar organic solvent, and then simultaneously adding N,N-dimethylamino alkyl acrylate and a methylhydrazine aqueous solution to the solution at -10-0°C, reacting at -10-0°C for 6-10 hours, allowing the mixture to stand for separation, and collecting the aqueous phase containing the β-hydrazino ester intermediate;

[0049] S2: adding an inorganic salt to the aqueous phase including the β-hydrazino ester intermediate until saturated, reacting at 20-30° C. for 8-12 hours, and removing dimethylamine and lower alcohol by-products under reduced pressure at -0.08-0.09 MPa to obtain an aqueous solution of 5-hydroxy-1-methylpyrazole;

[0050] S3: adjusting the pH of the 5-hydroxy-1-methylpyrazole aqueous solution to 6.5-7 using hydrochloric acid at 0-5° C., extracting with butanol, and collecting the organic phase containing 5-hydroxy-1-methylpyrazole;

[0051] S4: using a cation exchange resin to adsorb the residual dimethylamine in the organic phase of the 5-hydroxy-1-methylpyrazole, distilling off butanol under reduced pressure and washing with petroleum ether to obtain a crude 5-hydroxy-1-methylpyrazole product;

[0052] S5: The crude 5-hydroxy-1-methylpyrazole product was dissolved in ethanol under heating reflux at 60-70°C, decolorized with activated carbon for 0.5-3h, filtered while hot, and cooled at 0-5°C for crystallization, filtered and dried to obtain high-purity 5-hydroxy-1-methylpyrazole.

[0053] In the above embodiment, the method is carried out in sequence according to steps S1 to S5, constructing a three-stage reaction system of "Michael addition-internal cyclization deamination-refining and purification", which overall achieves high selectivity, high purity and high yield preparation of 5-hydroxy-1-methylpyrazole.

[0054] This method uses N,N-dimethylaminoalkyl acrylate as the starting material. In the presence of a phase transfer catalyst and a polymerization inhibitor, a Michael addition reaction with methylhydrazine occurs in a two-phase system consisting of water and a non-polar organic solvent, leading to the formation of a well-defined β-hydrazino ester intermediate. Unlike the prior art, which employs isomerization pathways for 3-methoxyacrylate, this method leverages the favorable leaving properties of dimethylamine to induce spontaneous cyclization of the intermediate under mild conditions, effectively targeting the 5-hydroxy structure of the target product and significantly suppressing the formation of the 3-hydroxy isomer.

[0055] Subsequently, dimethylamine and lower alcohol byproducts were removed through synergistic removal of inorganic salt saturation precipitation and reduced-pressure volatilization, creating an aqueous phase system conducive to product precipitation and separation. A further purification process, combining pH adjustment with butanol extraction, resin adsorption, and recrystallization, not only achieved efficient removal of byproducts and impurities, but also ensured the purity and color of the target product.

[0056] The overall process flow has good reaction path control capabilities and separation convenience, avoiding problems such as acid-catalyzed dehydroxylation or pH-adjusted cyclization that are prone to loss of control in traditional methods, significantly improving process safety, selectivity and industrial scale-up adaptability, and is suitable for the efficient large-scale synthesis of high-purity 5-hydroxy-1-methylpyrazole.

[0057] Compared with the prior art, the present invention has the following advantages:

[0058] 1. The N,N-dimethylamino alkyl acrylate raw material structure has excellent reaction orientation. After addition, the intermediate can spontaneously cyclize and remove dimethylamine under mild conditions, significantly improving the site selectivity of 5-hydroxy-1-methylpyrazole and reducing the problem of generating 3-hydroxy isomers in the prior art.

[0059] 2. By constructing a two-phase synergistic system of water and non-polar organic solvent, combined with the coordinated regulation of phase transfer catalysts and polymerization inhibitors, not only the efficiency of the addition reaction is effectively improved, but also the side polymerization reaction of the ester monomer is suppressed, thereby improving the specificity of the main reaction and the stability of the reaction system;

[0060] 3. The introduction of inorganic salts promotes product precipitation and drives the volatilization of low-boiling point by-products, achieving coordinated control of cyclization-deamination-separation and avoiding alkaline environment and impurity interference caused by residual by-products;

[0061] 4. Combined with subsequent pH adjustment, extraction, resin adsorption and crystallization purification measures, a complete set of high-purity product preparation processes suitable for industrial scale-up is formed, which improves the overall product yield and quality, simplifies the operation process, and reduces safety and environmental risks. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the present application and, together with the description, serve to explain the principles of the present application.

[0063] Figure 1 This is a chemical reaction formula for preparing 5-hydroxy-1-methylpyrazole in one embodiment of the present application.

[0064] Figure 2 This is the HPLC spectrum of 5-hydroxy-1-methylpyrazole standard.

[0065] Figure 3 This is the HPLC spectrum of the pure 5-hydroxy-1-methylpyrazole prepared in Example 1 of the present application. DETAILED DESCRIPTION

[0066] The various embodiments or implementation schemes in this specification are described in a progressive manner, and each embodiment focuses on the differences from other embodiments.

[0067] Throughout this specification, reference to terms such as "one embodiment," "some embodiments," "illustrative embodiments," "examples," "specific examples," or "some examples" means that a specific feature, structure, material, or characteristic described in conjunction with an embodiment or example is included in at least one embodiment or example of the present application. In this specification, illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples.

[0068] Furthermore, the terms "first" and "second" are used for descriptive purposes only and should not be construed as indicating or implying relative importance or implicitly specifying the number of the technical features being referred to. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one of such features. Throughout the description of this application, "plurality" means at least two, for example, two, three, etc., unless otherwise specifically defined.

[0069] In the description of this specification, unless otherwise specified, "parts" refer to "parts by mass".

[0070] Below, the embodiment of the present application is described. The embodiment described below is exemplary and is only used to explain the present application, and is not to be construed as limiting the present application. Where specific techniques or conditions are not specified in the embodiments, the techniques or conditions described in the literature in this area or the product specifications are used. Reagents or instruments used that do not specify the manufacturer are conventional products that can be obtained commercially.

[0071] Example 1

[0072] Add 200 mL of cyclohexane to a 1 L three-necked flask, and then add 1.2 g of tetrabutylammonium bromide (phase transfer catalyst, accounting for 2 wt% of the mass of N,N-dimethylaminoethyl acrylate) and 0.24 g of hydroquinone (polymerization inhibitor, accounting for 0.4 wt% of the mass of N,N-dimethylaminoethyl acrylate) in that order. Stir to dissolve, and then cool to -5°C in an ice-water bath.

[0073] Dissolve 60 g (approximately 0.42 mol) of ethyl N,N-dimethylaminoacrylate in 100 mL of cyclohexane to obtain an ethyl N,N-dimethylaminoacrylate solution. Add 60 mL of an aqueous solution containing 20.3 g (approximately 0.441 mol) of methylhydrazine to the cyclohexane dropwise over 40 minutes at -5 to 0°C using a dropping funnel. After the addition is complete, stir at low temperature for 8 hours. The mixture is then allowed to stand and separate into layers. The lower aqueous phase is collected to obtain an aqueous solution of the β-hydrazino ester intermediate.

[0074] Sodium chloride was slowly added to the aqueous phase until it was close to saturation. The reaction temperature was controlled at 25°C and the reaction was stirred for 10 hours. At the same time, the low-boiling point by-products (dimethylamine and ethanol) in the aqueous phase were slowly evaporated under a vacuum of -0.08 MPa to obtain a light yellow clear aqueous solution of 5-hydroxy-1-methylpyrazole.

[0075] The resulting aqueous solution was cooled to 0-5°C, and the pH was adjusted to 6.8 using 30 wt% hydrochloric acid. Then, an equal volume of butanol was added three times for extraction. The butanol phases were combined and allowed to stand to remove water for later use.

[0076] The butanol phase was mixed with 15 g of 732 cation exchange resin and adsorbed with stirring at room temperature for 2 hours. The organic phase was then filtered through a filter cloth and recovered. The butanol was evaporated to dryness under reduced pressure, and the residual solid was washed three times with petroleum ether and filtered to obtain approximately 39.8 g of a pale yellow crude product, 5-hydroxy-1-methylpyrazole.

[0077] Dissolve the crude product in 200 mL of anhydrous ethanol and heat under reflux at 65°C for 30 minutes. Add 2.5 g of activated carbon while hot, stir, and decolorize for 1 hour. Filter while hot. Cool the filtrate naturally to 0-5°C and let stand for 12 hours to crystallize. Filter and vacuum dry to obtain approximately 36.0 g of pure 5-hydroxy-1-methylpyrazole as colorless crystals.

[0078] Based on N,N-dimethylamino ethyl acrylate, the yield is 36.0 / (98.1×0.42)×100%=87.3%;

[0079] The pure product of 5-hydroxy-1-methylpyrazole was subjected to HPLC liquid phase detection. The HPLC liquid phase detection conditions were as follows:

[0080] Chromatographic column: C18 150×4.6mm, 5μm;

[0081] Mobile phase: acetonitrile / 0.1wt% phosphoric acid water = 70 / 30 (volume ratio);

[0082] Detection wavelength: 254nm;

[0083] Flow rate: 1 mL / min;

[0084] Column temperature: 40°C.

[0085] The reaction equation of the above embodiment is as follows Figure 1 As shown, N,N-dimethylaminoethyl acrylate is added to methylhydrazine and then cyclized to remove dimethylamine and ethanol to obtain 5-hydroxy-1-methylpyrazole.

[0086] The HPLC spectra of 5-hydroxy-1-methylpyrazole standard product and the pure 5-hydroxy-1-methylpyrazole obtained in the above example are respectively Figure 2 and Figure 3 According to the spectrum, the HPLC purity of the pure 5-hydroxy-1-methylpyrazole obtained in the above example is 98.9%.

[0087] Comparative Example 1

[0088] Add 200 mL of methanol to a 1 L three-necked flask, and then add 1.2 g of tetrabutylammonium bromide (phase transfer catalyst, accounting for 2 wt% of the mass of N,N-dimethylaminoethyl acrylate) and 0.24 g of hydroquinone (polymerization inhibitor, accounting for 0.4 wt% of the mass of N,N-dimethylaminoethyl acrylate) in that order. Stir to dissolve, and then cool to -5°C in an ice-water bath.

[0089] Dissolve 60 g (approximately 0.42 mol) of ethyl N,N-dimethylaminoacrylate in 100 mL of methanol to obtain an ethyl N,N-dimethylaminoacrylate solution. Add 60 mL of an aqueous solution containing 20.3 g (approximately 0.441 mol) of methylhydrazine to the methanol dropwise over 40 minutes at -5 to 0°C using a dropping funnel. After the addition is complete, maintain the reaction at low temperature with stirring for 8 hours.

[0090] After the reaction, the reaction mixture was concentrated under reduced pressure. After removing the solvent, the product was dissolved in 200 mL of ethyl acetate. The organic phase was washed three times with water, and 15 g of 732 cation exchange resin was added. The mixture was stirred and adsorbed at room temperature for 2 hours. The organic phase was filtered through a filter cloth and recovered. The ethyl acetate was evaporated to dryness under reduced pressure, and the residual solid was washed three times with petroleum ether and filtered to obtain a brownish-yellow crude product, 5-hydroxy-1-methylpyrazole.

[0091] Dissolve the crude product in 200 mL of anhydrous ethanol and heat under reflux at 65°C for 30 minutes. Add 2.5 g of activated carbon while hot, stir, and decolorize for 1 hour. Filter while hot. Cool the filtrate naturally to 0-5°C and let stand for 12 hours to crystallize. Filter and vacuum dry to obtain approximately 32.5 g of pure 5-hydroxy-1-methylpyrazole as light yellow crystals.

[0092] Based on N,N-dimethylamino ethyl acrylate, the yield is 32.5 / (98.1×0.42)×100%=78.4%;

[0093] The test was carried out under the same liquid phase conditions as in Example 1. The HPLC purity was about 91.2%, with a large number of impurity peaks.

[0094] According to the experimental results of Example 1 and Comparative Example 1, the method for synthesizing 5-hydroxy-1-methylpyrazole using ethyl N,N-dimethylaminoacrylate and methylhydrazine in this application must be carried out in a phase-separated system consisting of water and an organic solvent in order to effectively control the reaction path and improve the product yield and purity. The product obtained in Example 1 has a purity of up to 98.9% and a yield of 85.7%. However, in Comparative Example 1, under the same feed ratio and temperature control, using a traditional single-phase methanol reaction system, only a product with a purity of 91.2% and a yield of 78.4% was obtained, showing a significant performance difference.

[0095] This may be because the dimethylamino group in the structure of N,N-dimethylaminoalkyl acrylate is an excellent leaving group, but it also easily releases dimethylamine, a volatile, strongly alkaline byproduct, during the reaction. If the reaction is carried out in a single-phase polar solvent, the dimethylamine is difficult to effectively remove. This not only increases the alkalinity of the system and destabilizes the target product, but also may react with unreacted electrophilic intermediates to form stable complexes or polymer byproducts, seriously interfering with reaction selectivity and yield.

[0096] This application utilizes a three-in-one strategy of phase separation, salting out, and vacuum removal to precisely control the selective cyclization of the intermediate in the aqueous phase. This strategy then drives the migration of dimethylamine to the gas phase through inorganic salt saturation, synergizing with vacuum decompression to achieve efficient removal of byproducts. This system design is specifically designed to address the challenges of byproduct interference, difficult selectivity control, and product purification challenges faced by N,N-dimethylamino alkyl acrylate systems in industrial reactions.

[0097] In contrast, existing systems that react methyl 3-methoxyacrylate with methylhydrazine do not involve a by-product removal step. The methoxy group is a weak leaving group, and cyclization occurs slowly under mild conditions, eliminating the need for extensive control of by-product migration. Therefore, the reaction can be completed in a single methanol solvent. However, due to its slow cyclization rate and weak site-directed nature, both 5- and 3-hydroxy structural isomers are easily generated, resulting in a complex product structure, reduced purity, and difficult separation.

[0098] In summary, the present application uses N,N-dimethylamino alkyl acrylate as a raw material, and at the same time constructs a dedicated reaction environment and step design for the N,N-dimethylamino alkyl acrylate system, which fully solves the problems of heavy by-product interference and many side reactions in the industrial synthesis of this type of raw material, and can obtain high-purity 5-hydroxy-1-methylpyrazole; and the cost of N,N-dimethylamino alkyl acrylate is lower than that of methyl 3-methoxyacrylate, which can effectively reduce the production cost of 5-hydroxy-1-methylpyrazole.

[0099] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that they can still modify the technical solutions described in the aforementioned embodiments, or make equivalent replacements for some or all of the technical features therein. These modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for preparing 5-hydroxy-1-methylpyrazole, characterized in that: The following steps are involved: S1: dissolving a phase transfer catalyst and a polymerization inhibitor in a non-polar organic solvent, then adding N,N-dimethylamino alkyl acrylate and a methylhydrazine aqueous solution to the solution at -10-0°C, reacting at -10-0°C for 6-10 hours, allowing the mixture to stand for separation, and collecting the aqueous phase containing the β-hydrazino ester intermediate; S2: adding an inorganic salt to the aqueous phase including the β-hydrazino ester intermediate until saturated, reacting at 20-30° C. for 8-12 hours, and removing dimethylamine and lower alcohol by-products by vacuum decompression to obtain an aqueous solution of 5-hydroxy-1-methylpyrazole.

2. The method according to claim 1, characterized in that In the step S1, The molar ratio of the N,N-dimethylamino alkyl acrylate to the methyl hydrazine is 1:(1.01-1.2); The volume ratio of the water to the non-polar organic solvent is (1-3):10, and the non-polar organic solvent includes at least one of cyclohexane and n-heptane.

3. The method according to claim 2, characterized in that In the step S1, the step of adding N,N-dimethylamino alkyl acrylate and methylhydrazine aqueous solution into the solution comprises: Alkyl N,N-dimethylaminoacrylate and aqueous methylhydrazine solution are metered simultaneously into the solution.

4. The method according to claim 1, wherein The method further comprises: Step S3: adjusting the pH of the 5-hydroxy-1-methylpyrazole aqueous solution to 6.5-7 at 0-5° C., performing extraction treatment with butanol, and collecting the organic phase containing 5-hydroxy-1-methylpyrazole.

5. The method according to claim 4, characterized in that The method further comprises: Step S4: using a cation exchange resin to adsorb the residual dimethylamine in the organic phase of the 5-hydroxy-1-methylpyrazole, distilling off butanol under reduced pressure, and washing with petroleum ether to obtain a crude 5-hydroxy-1-methylpyrazole product.

6. The method according to claim 5, characterized in that The method further comprises: Step S5: The crude 5-hydroxy-1-methylpyrazole product is heated under reflux and dissolved in ethanol, decolorized with activated carbon, filtered while hot, cooled and crystallized, and filtered and dried to obtain high-purity 5-hydroxy-1-methylpyrazole.

7. The method according to any one of claims 1 to 6, characterized in that The method satisfies at least one of the following conditions: 1) The N,N-dimethylamino alkyl acrylate includes at least one of N,N-dimethylamino methyl acrylate and N,N-dimethylamino ethyl acrylate; 2) The phase transfer catalyst comprises at least one of tetrabutylammonium bromide and benzyltriethylammonium bromide; the amount of the phase transfer catalyst used is 1 wt% to 3 wt% of the amount of the N,N-dimethylamino alkyl acrylate; 3) The polymerization inhibitor comprises at least one of hydroquinone and ferric chloride; the amount of the polymerization inhibitor is 0.1 wt% to 0.5 wt% of the amount of the N,N-dimethylamino alkyl acrylate; 4) The inorganic salt includes at least one of sodium chloride, potassium chloride, sodium sulfate, and potassium sulfate.

8. The method according to claim 7, characterized in that The following steps are involved: S1: dissolving a phase transfer catalyst and a polymerization inhibitor in a non-polar organic solvent, and then simultaneously adding N,N-dimethylamino alkyl acrylate and a methylhydrazine aqueous solution to the solution at -10-0°C, reacting at -10-0°C for 6-10 hours, allowing the mixture to stand for separation, and collecting the aqueous phase containing the β-hydrazino ester intermediate; S2: adding an inorganic salt to the aqueous phase including the β-hydrazino ester intermediate until saturated, reacting at 20-30° C. for 8-12 hours, and removing dimethylamine and lower alcohol by-products under reduced pressure at -0.08-0.09 MPa to obtain an aqueous solution of 5-hydroxy-1-methylpyrazole; S3: adjusting the pH of the 5-hydroxy-1-methylpyrazole aqueous solution to 6.5-7 using hydrochloric acid at 0-5° C., extracting with butanol, and collecting the organic phase containing 5-hydroxy-1-methylpyrazole; S4: using a cation exchange resin to adsorb the residual dimethylamine in the organic phase of the 5-hydroxy-1-methylpyrazole, distilling off butanol under reduced pressure and washing with petroleum ether to obtain a crude 5-hydroxy-1-methylpyrazole product; S5: The crude 5-hydroxy-1-methylpyrazole product was dissolved in ethanol under heating reflux at 60-70°C, decolorized with activated carbon for 0.5-3h, filtered while hot, and cooled at 0-5°C for crystallization, filtered and dried to obtain high-purity 5-hydroxy-1-methylpyrazole.

Images