Preparation method of 5, 5-dimethyl isoxazolidine-3-thioketone and intermediate

Abstract

The invention provides a preparation method of 5, 5-dimethyl isoxazolidine-3-thioketone and an intermediate thereof, and relates to the technical field of chemical synthesis. The preparation method comprises the following steps: mixing hydroxylamine hydrochloride, isopentenal, sulfide and a first alkali substance, and carrying out a reaction, so as to obtain the 5, 5-dimethyl isoxazolidine-3-thioketone. The hydroxylamine hydrochloride, the isopentenal, the sulfide and the first alkali substance directly react, and a simple and low-cost preparation route is constructed. In the process, a tedious halogenation step is omitted, highly toxic, stink and high-pollution dangerous reagents are completely abandoned, and emission of ammonia-nitrogen wastewater and stink gas is eliminated from the source. The system is mild and stable, and high-efficiency output of high-quality products is realized while extremely high safety and environmental friendliness are ensured.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and more specifically, to a method for preparing 5,5-dimethylisoxazolidine-3-thione and its intermediates. Background Technology

[0002] Pyroxasulfone is a highly effective pre-emergence soil treatment agent that exerts its herbicidal activity primarily by inhibiting the synthesis of very long-chain fatty acids in plants. Due to its extremely high herbicidal activity, excellent crop safety, and very low risk of resistance, it has been widely used in weed control in various crops such as corn, wheat, and soybeans, and is currently an important agent for controlling annual grass weeds and some small broadleaf weeds.

[0003] In the synthesis of sulfonylpyrazine, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole and its core precursor 5,5-dimethylisoxazolidine-3-thione are indispensable key intermediates. The synthesis efficiency and process performance of these two intermediates directly determine the smoothness of the final preparation of sulfonylpyrazine. Existing literature reports various synthetic routes for the above intermediates. For example, in the existing process for synthesizing 5,5-dimethylisoxazolidine-3-thione, 3-halo-5,5-dimethyl-4,5-dihydroisoxazole is usually used as the starting material and reacted with phosphorus pentasulfide or sodium hydrosulfide, respectively; or 3-substituted-5,5-dimethyl-4,5-dihydroisoxazole is used as the starting material and reacted with thiourea; in addition, there are also reports of processes that directly react 5,5-dimethyl-4,5-dihydroisoxazole with sulfur powder.

[0004] However, the existing preparation processes described above have many obvious technical defects in practical applications. First, the process using phosphorus pentasulfide as the reaction reagent uses highly toxic chemicals, and the reaction process is accompanied by the generation of a large amount of waste, posing extremely high safety hazards and environmental pressures. Second, the process using sodium hydrosulfide results in poor raw material stability, and the wastewater produced contains a large amount of sodium hydrosulfide, emitting a strong odor, and creating an extremely harsh operating environment. Furthermore, if thiourea is used for the reaction, not only is the atom utilization rate of the reaction low, but it also leads to extremely high ammonia nitrogen content in the subsequent wastewater discharge, increasing the difficulty of wastewater degradation and treatment.

[0005] In general, existing synthetic processes for key intermediates of sulfonylpyrazine face technical challenges such as long synthetic routes, expensive and unstable starting materials, and cumbersome operating procedures. More critically, existing processes rely excessively on highly toxic, irritating, or potentially hazardous materials that cause high concentrations of ammonia nitrogen pollution in key steps such as sulfidation, leading to extremely serious environmental pressures and safety risks. These inherent technical bottlenecks severely restrict the efficient, green, and safe preparation of such core intermediates.

[0006] In view of this, the present invention is hereby proposed. Summary of the Invention

[0007] The primary objective of this invention is to provide a method for preparing 5,5-dimethylisoxazolidine-3-thione and sulfopyrazol intermediates. This method provides a simplified, efficient, safe, and environmentally friendly new preparation route by directly mixing and reacting four specific basic raw materials, thus completely solving the problems of high risk, high pollution, and waste treatment caused by the use of highly toxic and malodorous reagents in existing processes.

[0008] In order to achieve the above-mentioned objectives of the present invention, the following technical solution is adopted: In a first aspect, the present invention provides a method for preparing 5,5-dimethylisoxazolidine-3-thione, comprising: mixing hydroxylamine hydrochloride, isopentenal, sulfide and a first base substance and reacting them to obtain the 5,5-dimethylisoxazolidine-3-thione.

[0009] In an optional embodiment, the method for preparing 5-dimethylisoxazolidine-3-thione includes a sulfide comprising at least one of a polysulfide, sulfur, sodium hydrosulfide, and hydrogen sulfide; preferably, the sulfide comprises at least one of a polysulfide, sulfur, and hydrogen sulfide; more preferably, the sulfide comprises at least one of a polysulfide and sulfur; and / or, The first alkali substance includes at least one selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, potassium phosphate, potassium hydrogen phosphate, and triethylamine; and / or, The mixing reaction is carried out in a first solvent or under solvent-free conditions; preferably, the first solvent includes at least one of water, dichloromethane, dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile.

[0010] In an optional embodiment, the preparation method of 5-dimethylisoxazolidine-3-thione involves reacting at a temperature controlled between 90°C and 100°C; and / or, The reaction time is at least 24 hours.

[0011] In an optional embodiment, the method for preparing 5-dimethylisoxazolidine-3-thione involves a molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first base substance of 1:(1.0~1.5):(1.5~5.0):(0.5~2.0). Preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:(1.1~1.3):(2.5~3.5):(0.8~1.2); Preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide and the first alkali is 1:1.2:3:1.

[0012] In an optional embodiment, the method for preparing 5-dimethylisoxazolidine-3-thione involves generating isopentenal from isopentenol via an oxidation reaction. Preferably, after isopentenol is oxidized to isopentenal, it is either separated or not, and then subjected to a mixed reaction.

[0013] In an optional embodiment, the method for preparing 5-dimethylisoxazolidine-3-thionone involves cooling the mixture after the reaction is complete, adding methyl tert-butyl ether for extraction, separating the aqueous phase, and then distilling the organic phase to obtain the 5,5-dimethylisoxazolidine-3-thionone.

[0014] In a second aspect, the present invention provides a method for preparing a sulfonylpyrazol intermediate, wherein the sulfonylpyrazol intermediate is 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, or 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole; The preparation method includes: The 5,5-dimethylisoxazolidine-3-thione prepared according to any of the foregoing embodiments is reacted with a pyrazole compound and a second base in a second solvent to obtain the sulfopyrazol intermediate.

[0015] In an optional embodiment, the pyrazole compound is any one of the following: A. 5-Difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole; B, 5-Difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole; C, 5-hydroxy-4-hydroxymethyl-1-methyl-3-trifluoromethyl-1Hpyrazole; D, 5-hydroxy-1-methyl-3-trifluoromethyl-1Hpyrazole; E, 5-hydroxy-4-chloromethyl-1-methyl-3-trifluoromethyl-1Hpyrazole; When the pyrazole compound is 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, an aqueous formaldehyde solution is also added to the reaction system; and / or, The second type of alkali includes at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide; and / or, The second solvent includes dichloromethane; and / or, The molar ratio of the 5,5-dimethylisoxazolidine-3-thione to the pyrazole compound is 1:(1~1.5).

[0016] In an optional embodiment, the reaction steps include: mixing the 5,5-dimethylisoxazolidine-3-thione, the second solvent, and the second base substance at 25°C to 30°C, adding the pyrazole compound, and then raising the temperature to 65°C to continue the reaction; Preferably, the reaction time is at least 5 hours.

[0017] In an optional embodiment, after the reaction is completed, water is added to quench the reaction; When the sulfonylpyrazol intermediate is 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, the quenching reaction further includes a step of adding hydrochloric acid for neutralization.

[0018] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention provides a method for preparing 5,5-dimethylisoxazolidine-3-thione, which directly constructs the target product by reacting a mixture of hydroxylamine hydrochloride, isopentenal, a sulfide, and a first-base substance. This preparation process breaks free from the lengthy constraints of traditional synthetic routes, eliminating the need for complex intermediate steps such as halogenation, thus significantly simplifying the process. This one-step reaction design not only makes the actual operation simpler but also significantly reduces dependence on expensive raw materials, effectively controlling the overall preparation cost.

[0019] Meanwhile, this preparation system completely avoids the use of highly toxic reagents such as phosphorus pentasulfide, as well as hazardous materials such as sodium hydrosulfide and thiourea, which are prone to causing serious pollution and foul odors. This change fundamentally eliminates the volatilization of highly irritating and malodorous gases, greatly reduces the emission of pollutants such as high-concentration ammonia nitrogen in wastewater and the overall generation of "three wastes," significantly improves the safety factor of production operations, and effectively relieves the environmental treatment pressure in the preparation process.

[0020] Furthermore, the combination of the aforementioned specific reactants exhibits excellent system stability, overcoming the drawback of easily deteriorating starting materials in existing preparation processes. The reaction process is mild and efficient, ensuring high stability in the yield and quality indicators of the target product, laying a solid material foundation for the high-purity synthesis of core components for subsequent herbicides, and possessing extremely high value for green industrial applications. Attached Figure Description

[0021] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0022] Figure 1 This is a schematic diagram of the chemical equations for the oxidation of isopentenol to isopentenaldehyde and the subsequent series of reactions in the embodiments of this application. Figure 2 This is a schematic diagram of the chemical structure of four pyrazole compounds with different substituents in the embodiments of this application; Figure 3 This is a schematic diagram of the synthetic route equation for preparing 5,5-dimethylisoxazolidine-3-thione in Example 1 of this application; Figure 4 This is a schematic diagram of the synthetic route equation for preparing 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole in Example 2 of this application; Figure 5 This is a schematic diagram of the synthetic route equation for preparing 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole in Example 3 of this application; Figure 6 A schematic diagram of a derivatization synthetic route equation provided in this application, which involves coupling followed by difluoromethylation. Detailed Implementation

[0023] The embodiments of the present invention will be described in detail below with reference to examples. However, those skilled in the art will understand that the following examples are for illustrative purposes only and should not be considered as limiting the scope of the invention. Unless otherwise specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0024] This application provides a method for preparing 5,5-dimethylisoxazolidine-3-thione, comprising: mixing hydroxylamine hydrochloride, isopentenal, sulfide and a first base substance and reacting them to obtain the 5,5-dimethylisoxazolidine-3-thione.

[0025] In this invention, the synthetic route for 5,5-dimethylisoxazolidine-3-thione references and improves upon the Willgerodt-Kindler reaction mechanism. Under the catalysis of a first base, the oxime intermediate formed in situ from isopentenal and hydroxylamine hydrochloride undergoes a highly efficient oxidative cyclization reaction with the sulfide, achieving simultaneous completion of the isoxazolium ring construction and thiolation reaction in a one-pot process. The introduction of this specific reaction mechanism allows this process to successfully bypass the halogenation intermediate step required in traditional techniques, significantly improving atom economy.

[0026] In one specific embodiment of this application, a method for preparing 5,5-dimethylisoxazolidine-3-thione is provided, the core process steps of which include: mixing hydroxylamine hydrochloride, isopentenal, sulfide and a first base substance and allowing them to undergo a series of reactions.

[0027] In the specific reaction mechanism, the above mixing and reaction process is a one-pot synthesis process. First, the first base substance neutralizes with hydroxylamine hydrochloride in the mixed system, releasing highly reactive free hydroxylamine in situ. Subsequently, in the same reaction system, the free hydroxylamine, isopentenal, and sulfide simultaneously complete the sulfidation of the carbon skeleton and the intramolecular condensation ring-closing reaction under the suitable alkaline catalytic environment provided by the first base substance.

[0028] To achieve thorough mixing and efficient reaction, the four raw materials can be stirred and mixed in a first solvent (e.g., water or an organic solvent), or directly mixed in a solvent-free state at a specific ratio. The reaction system is typically stirred continuously under certain heating conditions (preferably controlled at 90°C to 100°C) for a set time to ensure complete conversion of the raw materials.

[0029] After the reaction process, to obtain high-purity 5,5-dimethylisoxazolidine-3-thione, this method also includes conventional product separation and purification steps. Specifically, the reaction solution can be cooled to room temperature, an organic solvent can be added for extraction and separation to remove the aqueous phase containing inorganic salt impurities, and the organic phase can be distilled under normal or reduced pressure to recover the solvent. Finally, the target product is collected in high yield. This method avoids the halogenation intermediate step in traditional processes, eliminates the need for highly toxic and malodorous sulfurizing agents, and features a simple and continuous operation process, making it extremely suitable for large-scale green industrial production.

[0030] In summary, this embodiment presents a novel and simplified route for the preparation of 5,5-dimethylisoxazolidine-3-thione by directly mixing and reacting hydroxylamine hydrochloride, isopentenal, sulfides, and a primary base. This process eliminates the need for cumbersome intermediate steps such as halogenation, making it extremely simple to operate and effectively reducing raw material costs. More importantly, this method completely eliminates highly toxic phosphorus pentasulfide, odorous sodium hydrosulfide, and thiourea, which easily generates ammonia nitrogen wastewater, thus eliminating odorous environments and environmental hazards at the source and significantly reducing the discharge of waste gas, wastewater, and solid waste. The reaction system is mild and stable, greatly improving production safety and environmental friendliness, while also ensuring efficient product conversion and stable quality, demonstrating significant industrial applicability.

[0031] In some embodiments, the method for preparing 5-dimethylisoxazolidine-3-thione includes a sulfide comprising at least one of a polysulfide, sulfur, sodium hydrosulfide, and hydrogen sulfide; preferably, the sulfide comprises at least one of a polysulfide, sulfur, and hydrogen sulfide; more preferably, the sulfide comprises at least one of a polysulfide and sulfur; and / or, the first alkali comprises at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, potassium phosphate, potassium hydrogen phosphate, and triethylamine; and / or, the mixing reaction is carried out in a first solvent or under solvent-free conditions; preferably, the first solvent comprises at least one of water, dichloromethane, dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile.

[0032] In the preferred embodiments described above in this application, the basic materials participating in the reaction have been optimized in order to balance production costs, operational safety, and reaction efficiency.

[0033] Specifically, the sulfide preferably includes at least one selected from polysulfides, sulfur, sodium hydrosulfide, and hydrogen sulfide. Furthermore, in a preferred embodiment, the sulfide may include at least one selected from polysulfides, sulfur, and hydrogen sulfide; in a further preferred embodiment, the sulfide may include at least one selected from polysulfides and sulfur. In practical industrial applications, sulfur is particularly recommended as the sulfur source reagent; sulfur is not only inexpensive and chemically stable, but also exhibits excellent thiolation activity when combined with specific alkaline substances, fundamentally replacing the highly toxic and polluting sulfiding agents in traditional processes, and greatly improving the operating environment.

[0034] In conjunction with the aforementioned sulfidation process, the first alkali substance preferably includes at least one selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, potassium phosphate, potassium hydrogen phosphate, and triethylamine. The aforementioned alkali substances are diverse, encompassing both inorganic salts and organic bases. Their mild alkalinity not only allows for the smooth release of hydroxylamine required for the reaction but also effectively suppresses potential side reactions such as carbon chain polymerization in the reaction system, ensuring extremely high atom economy and product purity.

[0035] Furthermore, this reaction system exhibits exceptional operational adaptability. The mixing and reaction processes can be carried out in the first solvent to achieve excellent thermodynamic and kinetic control, or directly under solvent-free conditions to achieve maximum production efficiency. When using a solvent system, the first solvent is preferably at least one of water, dichloromethane, dichloroethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), and acetonitrile. For example, using water as the reaction solvent enables the construction of an absolutely green all-aqueous phase synthesis process; while using polar organic solvents or halogenated hydrocarbons allows for in-situ separation and promotion of reactants and products based on differences in solubility, meeting the engineering requirements of different batches or continuous production.

[0036] In some embodiments, the method for preparing 5-dimethylisoxazolidine-3-thione involves a reaction temperature controlled at 90°C to 100°C; and / or a reaction time of at least 24 hours.

[0037] In the preferred embodiments described above in this application, in order to ensure the efficient execution of the multi-component cascade cyclization reaction and maximize the yield of the target product, the thermodynamic and kinetic process parameters for the synthesis of 5,5-dimethylisoxazolidine-3-thione were precisely controlled.

[0038] Specifically, the reaction temperature is preferably controlled between 90°C and 100°C. For example, it can be 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, etc.

[0039] Since this reaction involves multiple stages, including the condensation of free hydroxylamine, nucleophilic attack of active sulfur, and intramolecular cyclization, the set temperature range provides sufficient activation energy for the system. Especially when the system contains a solid sulfur source (such as sulfur), this temperature range effectively promotes mass transfer between the solid and liquid phases and the activation of sulfur atoms. Simultaneously, limiting the maximum temperature to around 100℃ effectively avoids side reactions such as polymerization and carbonization of the reactants (such as isopentenal) under excessive thermal stress, ensuring the color and purity of the product.

[0040] Regarding kinetic control, the reaction time is preferably at least 24 hours. Given the complexity of the reaction system in this one-pot direct cyclization process, maintaining continuous stirring for at least 24 hours ensures the reaction proceeds thoroughly towards the formation of the thermodynamically most stable target product. Sufficient reaction time allows for the complete consumption of various transition intermediates, significantly reducing the impurity content in the final reaction solution and ensuring a stable, high yield of 5,5-dimethylisoxazolidine-3-thione. In practical engineering operations, routine central-control sampling analysis (such as chromatographic monitoring) can be used to assist in confirming that the reaction has achieved complete conversion.

[0041] In some embodiments, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:(1.0~1.5):(1.5~5.0):(0.5~2.0); preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:(1.1~1.3):(2.5~3.5):(0.8~1.2); preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:1.2:3:1.

[0042] In the preparation method of 5,5-dimethylisoxazolidine-3-thione provided in the above embodiments of this application, in order to ensure efficient conversion of the reaction and suppress the occurrence of side reactions, the feed ratio of each raw material in the reaction system has specific requirements. Specifically, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide and the first base substance is 1:(1.0~1.5):(1.5~5.0):(0.5~2.0).

[0043] The molar ratio of hydroxylamine hydrochloride to isopentenal ranges from 1.0 to 1.5. For example, the molar ratio can be 1.0, 1.05, 1.1, 1.15, 1.2, 1.25, 1.3, 1.35, 1.4, 1.5, etc. The molar ratio of the sulfide to isopentenal ranges from 1.5 to 5.0. For example, the molar ratio can be 1.5, 1.8, 2.0, 2.5, 3.0, 3.2, 3.5, 4.0, 4.5, 5.0, etc. The molar ratio of the first alkali to isopentenal ranges from 0.5 to 2.0. For example, the molar ratio can be 0.5, 0.6, 0.8, 1.0, 1.2, 1.4, 1.5, 1.6, 1.8, 2.0, etc.

[0044] The principle and beneficial effects of controlling the above molar ratio are as follows: using isopentenal as the reaction reference substrate and hydroxylamine hydrochloride as the nitrogen source for the reaction, maintaining their molar ratio in a slightly excess state of 1.0~1.5 can effectively ensure the complete conversion of isopentenal and improve atom utilization; the main role of the first base is to neutralize the acidic components in the hydroxylamine hydrochloride dissociation system and maintain the alkaline environment required for the cyclization reaction. Controlling its ratio at 0.5~2.0 can effectively release free hydroxylamine and provide suitable catalytic conditions, avoiding side reactions caused by excessive base; the reaction process of this application is accompanied by the construction of sulfur-containing heterocycles. Sulfides not only act as sulfiding reagents but also participate in the redox process in the system. Therefore, controlling the molar ratio of sulfides in a relatively excess range of 1.5~5.0 can significantly promote the forward reaction and improve the yield of the final cyclized product.

[0045] To further optimize the reaction process, reduce reaction costs, and decrease the pressure of impurity removal during post-reaction processing, preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is controlled as 1:(1.1~1.3):(2.5~3.5):(0.8~1.2).

[0046] In a preferred embodiment of this application, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:1.2:3:1. Under this optimal ratio, the synergistic effect between the materials is best, enabling the production of high-purity 5,5-dimethylisoxazoline-3-thione with a yield of up to 96%, while significantly reducing waste emissions.

[0047] In some embodiments, the method for preparing 5-dimethylisoxazolidine-3-thione involves the isopentenal being generated from isopentenol via an oxidation reaction.

[0048] Preferably, after isopentenol is oxidized to isopentenal, it is either separated or not, and then subjected to a mixed reaction.

[0049] In the preferred embodiment described above, the isopentenal, which is the main reactant, can be generated from isopentenol through an oxidation reaction, as described above. Figure 1 Isoprene alcohol, as an readily available basic chemical raw material, can be efficiently converted into the desired isopentenyl aldehyde through conventional selective oxidation methods for alcohols in the art (such as, but not limited to, manganese dioxide oxidation, TEMPO catalytic oxidation, or air catalytic oxidation). Using isopentenyl alcohol as a starting material further broadens the range of raw material options for the process in this application, helping to control production costs from the source.

[0050] More preferably, after the isopentenol is oxidized to isopentenal, it can be purified by conventional separation methods such as extraction and distillation before subsequent mixing reactions, or it can be directly mixed without separation. When using a continuous series process without separation (i.e., one-pot method), not only is the purification step of the intermediate isopentenal eliminated, greatly simplifying the operation process and shortening the production cycle, but the use of organic solvents and the generation of industrial waste are also significantly reduced during the purification process. At the same time, the in-situ reaction without separation effectively avoids the volatilization loss or self-polymerization deterioration that may occur during the purification and storage of isopentenal, thereby improving the overall atomic utilization rate of the process and the overall yield of the final 5,5-dimethylisoxazolidine-3-thione.

[0051] In a preferred embodiment provided in this application, the product separation and purification (i.e. post-processing) step after the main reaction is completed includes: cooling, adding methyl tert-butyl ether for extraction, separating the aqueous phase, and distilling the organic phase to obtain the 5,5-dimethylisoxazolidine-3-thione.

[0052] The aforementioned specific post-processing steps have significant synergistic benefits. First, cooling after the reaction (preferably to 20°C~30°C, for example, 25°C) can effectively quench the thermodynamically active reaction system, prevent the target product from undergoing side reactions or degradation at high temperatures, and also provide a safe temperature environment for the subsequent addition of the extractant.

[0053] Secondly, this application innovatively selects methyl tert-butyl ether as the extraction solvent. The target product, 5,5-dimethylisoxazolidine-3-thione, exhibits excellent solubility in methyl tert-butyl ether, while residual inorganic bases, hydroxylamine hydrochloride, and other water-soluble byproducts are highly concentrated in the aqueous phase. By allowing the mixture to stand and separate into layers, and then removing the aqueous phase, the target product can be completely separated from inorganic impurities with an extremely high partition coefficient. Compared to traditional halogenated hydrocarbons (such as dichloromethane) or explosive ethers (such as diethyl ether), the use of methyl tert-butyl ether not only offers high extraction efficiency and less emulsification, but also exhibits low toxicity and good safety, greatly improving the operating environment and meeting the demands of green and environmentally friendly industrialization.

[0054] Finally, the obtained organic phase is distilled. Since methyl tert-butyl ether has a low boiling point, it can be easily volatilized and recovered using atmospheric or vacuum distillation, achieving a closed-loop solvent cycle. After distillation until no liquid remains, high-purity 5,5-dimethylisoxazolidine-3-thione can be directly collected in high yield. This post-processing method eliminates the need for complex column chromatography or recrystallization steps, is streamlined, easy for continuous industrial production, and yields products with stable quality indicators.

[0055] In this application embodiment, a method for preparing a sulfonylpyrazol intermediate is provided, wherein the sulfonylpyrazol intermediate is 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, or 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole; The preparation method includes: The 5,5-dimethylisoxazolidine-3-thione prepared according to any of the foregoing embodiments is reacted with a pyrazole compound and a second base in a second solvent to obtain the sulfopyrazol intermediate.

[0056] In a method for preparing sulfonylpyrazol intermediate provided in this application, 5,5-dimethylisoxazolidine-3-thione, which is newly prepared by the method provided in the foregoing embodiments, is used as a key intermediate. It is reacted with a pyrazole compound and a second base in a second solvent to obtain 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole or its hydroxy derivative in high yield.

[0057] The reaction mechanism and synergistic advantage of this method lie in the fact that the reaction is an intermolecular nucleophilic substitution coupling process. 5,5-Dimethylisoxazolidine-3-thione undergoes deprotonation and tautomerism under the action of a second base, generating in situ a highly nucleophilic thioanion (thiol salt). This highly reactive intermediate then attacks the alkyl carbon atom of a pyrazole compound with a leaving group (or activating group), successfully constructing a thioether bond backbone connecting two key heterocycles.

[0058] Compared to existing synthetic routes for sulfonylpyrazine intermediates, the preparation method described in this application represents a significant improvement: First, it completely eliminates the highly toxic and hazardous phosphorus pentasulfide reagent used in traditional processes, greatly enhancing the inherent safety of the process; second, it eliminates the need for sodium hydrosulfide or thiourea, fundamentally eliminating the foul odor and high-concentration ammonia nitrogen wastewater discharge during production, making it extremely environmentally friendly; third, it cleverly utilizes 5,5-dimethylisoxazolidine-3-thione prepared by a novel upstream method, saving the complex intermediate steps of multiple halogenation and substitution reactions in traditional processes, resulting in a shorter route and higher atom economy. Simultaneously, the second base not only catalyzes tautomerization but also effectively neutralizes the acidic byproducts generated by the substitution reaction, driving the reaction forward at a very high conversion rate (e.g., a stable yield of over 90%). This method is simple to operate, uses readily available raw materials, and operates under mild reaction conditions, providing a low-cost and highly competitive new green synthetic route for the large-scale industrial production of sulfonylpyrazine.

[0059] In some embodiments, in a method for preparing a sulfonylpyrazol intermediate provided in this application, a highly flexible range of substrates is provided for pyrazole compounds that undergo coupling reactions with 5,5-dimethylisoxazoline-3-thione. The pyrazole compounds are any of the following: A. 5-Difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole; B, 5-Difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole; C, 5-hydroxy-4-hydroxymethyl-1-methyl-3-trifluoromethyl-1Hpyrazole; D. 5-hydroxy-1-methyl-3-trifluoromethyl-1H pyrazole; when the pyrazole compound is 5-hydroxy-1-methyl-3-trifluoromethyl-1H pyrazole, an aqueous formaldehyde solution is also added to the reaction system.

[0060] For details, please refer to... Figure 2 .

[0061] This diverse substrate selection endows the synthetic process with extremely high economic adaptability. When pyrazole compounds with chloromethyl or hydroxymethyl substituents are selected, they can directly undergo a substitution reaction with the highly nucleophilic thiolate anions generated in situ from thion under alkaline conditions, removing water or hydrogen chloride and efficiently constructing intermolecular thioether bonds. To promote the generation of thioanions and promptly neutralize acidic byproducts generated in the system, potassium carbonate, sodium hydroxide, sodium alkoxide, etc., are selected as second bases; and dichloromethane, etc., with excellent dissolving properties, is used as a second solvent to provide a good mass transfer environment.

[0062] Of particular note is the ingenious one-pot tandem strategy employed in this application when using 5-hydroxy-1-methyl-3-trifluoromethyl-1H pyrazole, a more fundamental and lower-cost raw material. This involves adding an aqueous formaldehyde solution to the reaction system, using formaldehyde to first perform in-situ hydroxymethylation at the 4-position of the pyrazole ring. Subsequently, without separation, the resulting intermediate directly undergoes nucleophilic substitution coupling with thion. This synergistic process eliminates the complex purification steps of the precursor intermediates, significantly shortening the process route and reducing waste emissions. Furthermore, the yield of the final target product still reaches approximately 93%, demonstrating excellent atom economy.

[0063] Furthermore, this application also provides a highly flexible derivatization synthetic route (see reference). Figure 6When 5-hydroxy-4-chloromethyl-1-methyl-3-trifluoromethyl-1H-pyrazole (compound E) is selected as the substrate, it can first undergo nucleophilic substitution coupling with the aforementioned 5,5-dimethylisoxazolidine-3-thionone to obtain an intermediate containing a free hydroxyl group in high yield. Subsequently, this free hydroxyl group can be derivatized with conventional difluoromethylating agents (such as difluorochloromethane) to ultimately obtain 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazole-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. This route demonstrates that the method provided in this application is applicable to both fluorination-before-coupling and coupling-before-fluorination strategies, greatly enriching the options for industrial preparation.

[0064] In some embodiments, the second alkali substance includes at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide.

[0065] In some embodiments, the second solvent includes dichloromethane.

[0066] In some embodiments, the molar ratio of the 5,5-dimethylisoxazolidine-3-thione to the pyrazole compound is 1:(1~1.5). For example, the molar ratio can specifically be: 1:1.0, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.5, etc.

[0067] Furthermore, to ensure the most complete conversion of the high-value-added 5,5-dimethylisoxazolidine-3-thione in the reaction system, this process precisely controls the molar ratio of 5,5-dimethylisoxazolidine-3-thione to pyrazole compounds within the range of 1:(1~1.5). By maintaining the relatively readily available pyrazole substrate in an equivalence or slight excess state, the chemical equilibrium is effectively shifted to the right, ensuring high yield and high purity of the final product.

[0068] In some embodiments, the reaction steps include: mixing the 5,5-dimethylisoxazolidine-3-thione, the second solvent, and the second base substance at 25°C to 30°C, adding the pyrazole compound, and then heating to 65°C to continue the reaction; preferably, the reaction time is at least 5 hours.

[0069] In a preferred embodiment provided in this application, the coupling reaction for preparing the sulfonylpyrazol intermediate employs a two-stage temperature-controlled program. The specific steps include: first, at 25°C to 30°C, thoroughly mixing or dissolving the 5,5-dimethylisoxazolidine-3-thione, the second solvent, and the second base; under these mild conditions, slowly adding (preferably by dropwise addition) the pyrazole compound; after the addition is complete, raising the temperature to 65°C and continuing the reaction.

[0070] This application employs a process combining stepwise feeding and programmed temperature control, which has a profound chemical mechanism basis and significant synergistic technical effects. In the first stage (25℃~30℃), 5,5-dimethylisoxazolidine-3-thione undergoes stable deprotonation and tautomerism in an alkaline environment, safely generating highly active thiolate anions in situ. By controlling this activation stage under mild conditions close to room temperature, and in conjunction with the slow introduction of pyrazole compounds, not only can the risk of material overflow caused by excessively high local substrate concentrations or violent exothermic reactions be effectively avoided, but the self-condensation of pyrazole precursors and the formation of other heat-sensitive byproducts can also be suppressed to the greatest extent, ensuring the inherent safety of the process.

[0071] In the second stage, the system is heated to 65°C. This specific temperature provides just the right thermodynamic driving force for the subsequent nucleophilic substitution reaction, enabling the molecule to acquire sufficient activation energy to overcome steric hindrance and complete the construction of the thioether bond, without compromising the stability of the heterocyclic skeleton due to excessive temperature.

[0072] Preferably, the isothermal reaction time at 65°C is at least 5 hours. This sufficient 'heat preservation and aging' time follows the laws of reaction kinetics, providing ample time for the complete conversion of residual substrate in the system, thereby achieving an extremely high substrate conversion rate. Relying on the above-mentioned scientifically rigorous process parameter control, this invention ultimately obtains the target sulfonylpyrazol intermediate with extremely high purity and a yield that can be consistently maintained above 90%, with extremely simple operation and stable batch quality.

[0073] In some embodiments, after the reaction is completed, water is added to quench the reaction; When the sulfonylpyrazol intermediate is 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, the quenching reaction further includes a step of adding hydrochloric acid for neutralization.

[0074] In the preferred embodiments provided in this application, a simple and highly targeted separation and purification strategy is designed for the post-processing steps after the coupling reaction. Specifically, when the reaction is determined to be complete, water is first added to the reaction system to quench the reaction. Adding water not only rapidly dilutes and dissolves the inorganic base and byproduct salts in the system, disrupting the catalytic environment and thus precisely terminating the reaction process, but also promotes the natural separation of the reaction liquid into an organic phase and an aqueous phase, achieving preliminary macroscopic separation of the target product from water-soluble impurities. The operation is extremely simple and cost-effective.

[0075] It is particularly noteworthy that this application ingeniously designs differentiated pH adjustment steps for target products with different substituent structures. When the prepared sulfonylpyrazol intermediate is 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole with a free hydroxyl group, the hydroxyl group on the pyrazol ring is weakly acidic and readily deprotonates under the alkaline environment of the reaction to form a water-soluble salt compound. If liquid-liquid separation is performed directly, a large amount of the target product will be lost into the aqueous phase.

[0076] Therefore, this application specifically introduces a neutralization step by adding hydrochloric acid after water quenching. By adding hydrochloric acid (e.g., commonly used 36% concentrated hydrochloric acid) to adjust the pH of the system, the target product hydrolyzed into a salt can be reprotonated and restored to an electrically neutral free molecular form. The solubility of the target molecule in the aqueous phase is significantly reduced after restoring neutrality, thus allowing for efficient back-extraction and high enrichment in the organic phase (e.g., the dichloromethane layer). This precise post-processing strategy based on the molecular acid-base properties fundamentally eliminates product loss during water washing and complements the efficient preceding coupling reaction, jointly ensuring an excellent yield of over 90% for this hydroxyl-substituted intermediate.

[0077] The present invention will be further illustrated below with specific embodiments. However, it should be understood that these embodiments are merely for the purpose of more detailed illustration and should not be construed as limiting the present invention in any way.

[0078] Example 1 In this embodiment, a key intermediate, 5,5-dimethylisoxazolidine-3-thione, was prepared. The method uses commercially available isopentenal and hydroxylamine hydrochloride as raw materials to efficiently synthesize a sulfur-containing heterocyclic skeleton via a one-pot process.

[0079] Experimental Method: 41.7 g (0.6 mol) of hydroxylamine hydrochloride, 42.0 g (0.5 mol) of isopentenal, 48.0 g (1.5 mol) of sulfur, 69.0 g (0.5 mol) of potassium carbonate, and 300 mL of water were added to a reaction flask. Stirring was started to ensure uniform mixing. The reaction temperature was then raised to 90℃~100℃ and maintained at this temperature for 24 hours. After the reaction was complete, the system was cooled to 25℃, and methyl tert-butyl ether was added for liquid-liquid extraction. After separation by settling, the lower aqueous phase was removed, and the product-rich organic phase was collected. This organic phase was subjected to atmospheric distillation to recover the extraction solvent, followed by vacuum distillation until no liquid distilled off. (Reference Synthetic Route) Figure 3 .

[0080] Experimental results: 62.8 g of compound 5,5-dimethylisoxazolidine-3-thione was finally collected.

[0081] NMR data (300 MHz, CDCl3): 1.42 (s, 6H); 2.56 (s, 2H).

[0082] Mass spectrometry results: ESI: m / z 132.0 [M+H] + Theoretical molecular weight: 131.0.

[0083] Calculations show that the molar yield of isopentenal in this embodiment is as high as 96%. This synthetic route is highly efficient, requires no traditional chlorination reaction steps, and is extremely simple to operate.

[0084] It is particularly important to note (comparative analysis): if the traditional process using 3-halo-5,5-dimethyl-4,5-dihydroisoxazole as a raw material to react with sodium hydrosulfide is adopted, a strong odor of hydrogen sulfide will permeate the operating environment; if the traditional process using thiourea is adopted, extremely high concentrations of ammonia nitrogen (which is usually difficult to biodegrade) will remain in the wastewater after the reaction. However, this embodiment uses a novel one-pot aqueous system of isopentenal, hydroxylamine hydrochloride, sulfur, and potassium carbonate. No irritating odorous gases are emitted throughout the reaction, and the aqueous phase produced after separation is completely free of ammonia nitrogen. This invention significantly shortens the process route, stabilizes the yield at over 95%, and fundamentally solves the environmental and occupational health problems of traditional processes.

[0085] Example 2 This embodiment provides a method for preparing the sulfonylpyrazol intermediate 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. This embodiment examines a process for nucleophilic substitution coupling of a pyrazol derivative containing "chloromethyl" with a self-prepared thionone intermediate.

[0086] Experimental Method: 62.8 g of 5,5-dimethylisoxazolidine-3-thione (prepared in Example 1), 500 g of dichloromethane, and 138.0 g (1.0 mol) of potassium carbonate were added to a reaction flask. Stirring was started to ensure homogeneous mixing, and the system temperature was controlled at 25℃~30℃. Subsequently, 132.0 g (0.5 mol) of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole was slowly added dropwise over approximately 1 hour. After the addition was complete, the temperature was raised to 65℃ and the reaction was maintained at this temperature for 5 hours. The temperature was then lowered to 25℃, and stirring was started. After the reaction was confirmed to be complete by central monitoring, water was added to quench the reaction. The mixture was allowed to stand and separate into layers; the aqueous phase was separated, and the organic phase was collected. The organic phase was distilled to recover the dichloromethane solvent. (Reference Synthetic Route) Figure 4 .

[0087] Experimental results: 165.3 g of the target product 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole was finally collected.

[0088] NMR data (300 MHz, CDCl3): 1.42 (s, 6H); 2.79 (s, 2H); 3.84 (s, 3H); 4.20 (s, 2H); 6.73 (t, 1H).

[0089] Mass spectrometry results: ESI: m / z 360.0 [M+H] + Theoretical molecular weight: 359.0.

[0090] Results analysis: The molar yield of this reaction step was calculated to be 92%. The experiment shows that the chloromethyl group in the substrate is an excellent leaving group that can efficiently couple with the thioanion generated in situ from thion, achieving excellent yields under mild conditions.

[0091] If extraction and separation are performed directly without the aforementioned hydrochloric acid neutralization (comparative simulation), most of the product will be lost with the aqueous phase due to the formation of water-soluble phenolate / enolate salts by the hydroxyl-containing sulfonylpyrazine intermediate under strongly alkaline conditions, leading to a sharp decrease in the actual yield in the organic phase. Therefore, the specific acid quenching and neutralization step in this embodiment, combined with the one-pot coupling reaction, forms an excellent technical synergy and is an indispensable key step in ensuring a high yield of 93% for this specific structural intermediate.

[0092] Example 3 This embodiment provides a method for preparing the hydroxyl-derived sulfonylpyrazol intermediate 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. This embodiment focuses on the process of in-situ one-pot tandem hydroxymethylation and coupling reactions using formaldehyde when the substrate lacks a linked methylene group, and also examines the acid quenching post-treatment strategy.

[0093] Experimental Method: 62.8 g of 5,5-dimethylisoxazolidine-3-thione, 500 g of dichloromethane, and 138.0 g (1.0 mol) of potassium carbonate were added to a reaction flask. The mixture was stirred until homogeneous, and the system temperature was maintained at 25℃~30℃. 93.8 g of formaldehyde aqueous solution was slowly added dropwise to the system, and the reaction was stirred for 1 hour. Subsequently, 83.0 g (0.5 mol) of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole was slowly added dropwise over approximately 1 hour. After the addition was complete, the system temperature was raised to 65℃, and the reaction was maintained at this temperature for 5 hours. After the reaction was complete, the temperature was lowered to 25℃, the stirring was turned on, and the reaction was monitored to ensure completion. Water was added to quench the reaction. At this point, 36% hydrochloric acid was added to the system for neutralization and pH adjustment. The mixture was then allowed to stand and separate into layers. The aqueous phase was separated, and the organic phase was collected. The solvent was recovered by distillation of the organic phase. (Reference Synthetic Route) Figure 5 .

[0094] Experimental results: 137.9 g of the target product 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole was finally collected.

[0095] NMR data (300 MHz, CDCl3): 1.42 (s, 6H); 2.81 (s, 2H); 3.54 (s, 3H); 3.89 (s, 2H) 10.23 (s, 1H).

[0096] Results analysis: The molar yield of this reaction step was 93%. The experiment shows that the introduction of formaldehyde aqueous solution can efficiently construct the connecting bridge in situ, eliminating the need for substrate purification; at the same time, the addition of hydrochloric acid for neutralization in the post-treatment successfully overcomes the risk of hydroxyl products being lost through salt formation in the alkaline aqueous phase, ensuring an extremely high product yield.

[0097] Example 4 In this embodiment, the same target product as in Example 2 was prepared, and the feasibility and reaction effect of using a pyrazole derivative containing "hydroxymethyl" as a coupling substrate were mainly investigated.

[0098] Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 2. The difference was that 5-difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole was used as the coupling substrate, in place of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole in Example 2, in an equimolar amount. All other reagent volumes, temperatures, times, and post-treatment procedures such as quenching with water and separation were consistent with those in Example 2.

[0099] Experimental results: The target product was collected.

[0100] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 90%. The results indicate that even using hydroxymethyl substrates with relatively weak leaving ability, the optimized solvent and base catalytic system of this application still enables highly efficient dehydration sulfide coupling, broadening the range of feedstock options.

[0101] Example 5 In this embodiment, the same target product as in Example 3 was prepared, and the process of directly using a hydroxypyrazole derivative containing a "hydroxymethyl" substituent for coupling reaction was mainly investigated.

[0102] Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 3. The difference was that 5-hydroxy-4-hydroxymethyl-1-methyl-3-trifluoromethyl-1H-pyrazole was used as the coupling substrate, replacing the 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole in Example 3 in an equimolar amount (since the substrate already has a hydroxymethyl linker, the in-situ reaction process was adjusted accordingly). The remaining reagent amounts, reaction temperatures, times, and post-treatment procedures such as neutralization with hydrochloric acid were consistent with those in Example 3.

[0103] Experimental results: The target product was collected.

[0104] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 89%. The results confirm the effectiveness of this direct coupling route and provide another high-yield alternative route for the synthesis of sulfonylpyrazol intermediates containing free hydroxyl groups.

[0105] Example 6 In this embodiment, the same target product as in Example 1 was prepared, mainly by changing the amount of sulfur to 1.5 times, while the rest remained unchanged; Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 1. The difference was that the amount of sulfur used was 72.0 g (2.25 mol). The amounts of other reagents, temperatures, times, and post-treatment procedures such as quenching with water and separating the liquid were consistent with those in Example 1.

[0106] Experimental results: The target product was collected.

[0107] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 97%. The results indicate that increasing the amount of sulfur slightly improved the yield, thus expanding the range of acceptable raw material amounts.

[0108] Example 7 In this embodiment, the same target product as in Example 1 was prepared, mainly by changing the potassium carbonate to twice the amount, while the rest remained unchanged; Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 1. The difference was that the amount of potassium carbonate used was 138.0 g (1 mol). The amounts of other reagents, temperatures, times, and post-treatment procedures such as quenching with water and separating the solution were consistent with those in Example 1.

[0109] Experimental results: The target product was collected.

[0110] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 92%. The results indicate that increasing the amount of potassium carbonate slightly decreased the yield. This expands the range of possible raw material dosages.

[0111] Example 8 In this embodiment, the same target product as in Example 1 was prepared, mainly by replacing potassium carbonate with triethylamine, while the rest remained unchanged; Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 1. The difference was that the amount of triethylamine used was 101.0 g (1 mol). The amounts of other reagents, temperatures, times, and post-treatment procedures such as quenching with water and separation were consistent with those in Example 1.

[0112] Experimental results: The target product was collected.

[0113] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 88%. The results indicate that changing the inorganic base to triethylamine slightly decreased the yield, but increased the range of organic bases that could be selected.

[0114] Example 9 In this embodiment, the same target product as in Example 1 was prepared, mainly by changing the solvent to NMP (N-methylpyrrolidone), while the rest remained unchanged; Experimental Methods: The same compound was prepared according to the experimental methods and procedures in Example 1. The difference was that the amount of NMP used was 300 mL. The amounts of other reagents, temperatures, times, and post-treatment procedures such as quenching with water and separating the solution were all consistent with those in Example 1.

[0115] Experimental results: The target product was collected.

[0116] Results Analysis: Calculations showed that the molar yield of the target product in this embodiment was 95%. The results indicate that using NMP instead of water as a solvent also yields the product, thus expanding the range of solvent options.

[0117] Comparative Example 1: 500.0g methanol and 76.0g thiourea were used, and the mixture was stirred and heated to 66°C. o C. Add 133.0 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole and 80.0 g of sodium hydroxide. After the reaction is complete, concentrate the solution. Quench with 500.0 g of water, neutralize with hydrochloric acid, extract twice with dichloromethane, and obtain 5,5-dimethylisoxazolidine-3-thione under reduced pressure. Yield: 82%. Ammonia nitrogen content in the wastewater: 2020 mg / L.

[0118] Comparative Example 2: 11.2 g of sodium hydrosulfide (0.2 mol) was added to 100 g of water, along with 13.3 g of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole and 50.0 g of toluene. The reaction temperature was controlled between -5 and 0 °C. o C. Adjust the pH to alkalinity with sodium hydroxide and separate the toluene layer; adjust the pH to acidity, extract twice with dichloromethane, and obtain 5,5-dimethylisoxazolidine-3-thione under reduced pressure. Yield: 45%. Ammonia nitrogen content in the wastewater: 20 mg / L.

[0119] Example 10 This embodiment provides another method for preparing a sulfonylpyrazine intermediate, specifically: The same compound was prepared according to the method in Example 2, except that 5-hydroxy-4-chloromethyl-1-methyl-3-trifluoromethyl-1H pyrazole (i.e., compound E) was used instead of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole for the reaction.

[0120] Experimental results: The target product was collected. Calculations showed that the molar yield of the target product in this embodiment was 89%.

[0121] Example 11 This embodiment examines a process involving coupling followed by fluorination using a chloromethylpyrazole derivative containing a free hydroxyl group (corresponding to...). Figure 6 route).

[0122] Step 1 (Coupling Reaction): The experimental method and procedures were followed as in Example 2, except that the coupling substrate was replaced with 5-hydroxy-4-chloromethyl-1-methyl-3-trifluoromethyl-1H pyrazole (108.3 g, 0.5 mol) instead of 5-difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole in Example 2. After the reaction was completed, the mixture was quenched with water, neutralized with hydrochloric acid, back-extracted, and then distilled to obtain 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazole-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole intermediate, with a calculated yield of 91%.

[0123] Step 2 (Difluoromethylation): The intermediate obtained above was subjected to difluoromethylation under alkaline conditions by passing difluorochloromethane gas through it. After the reaction was completed, post-processing was performed to obtain the final target product 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole. The overall yield of the two steps was 81%.

[0124] Example 1 was compared with Comparative Examples 1 and 2 in terms of yield, ammonia nitrogen content, and odor level, as detailed below: Table 1. Comparison of the effects of the examples and comparative examples

[0125] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A process for the preparation of 5,5-dimethylisoxazolidine-3-thione, characterized in that, include: Hydroxylamine hydrochloride, isopentenal, sulfide and a first base are mixed and reacted to obtain the 5,5-dimethylisoxazolidine-3-thione.

2. The process for the preparation of 5,5-dimethylisoxazolidine-3-thione according to claim 1, characterized in that, The sulfide includes at least one selected from polysulfides, sulfur, sodium hydrosulfide, and hydrogen sulfide; preferably, the sulfide includes at least one selected from polysulfides, sulfur, and hydrogen sulfide; more preferably, the sulfide includes at least one selected from polysulfides and sulfur; and / or, The first alkali substance includes at least one selected from potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, potassium phosphate, potassium hydrogen phosphate, and triethylamine; and / or, The mixing reaction is carried out in a first solvent or under solvent-free conditions; preferably, the first solvent includes at least one of water, dichloromethane, dichloroethane, N,N-dimethylformamide, N-methylpyrrolidone, and acetonitrile.

3. The method for preparing 5,5-dimethylisoxazolidine-3-thione as described in claim 1, characterized in that, The reaction temperature is controlled at 90℃~100℃; and / or, The reaction time is at least 24 hours.

4. The method for preparing 5,5-dimethylisoxazolidine-3-thione as described in claim 1, characterized in that, The molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:(1.0~1.5):(1.5~5.0):(0.5~2.0); Preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide, and the first alkali is 1:(1.1~1.3):(2.5~3.5):(0.8~1.2); Preferably, the molar ratio of isopentenal, hydroxylamine hydrochloride, sulfide and the first alkali is 1:1.2:3:

1.

5. The method for preparing 5,5-dimethylisoxazolidine-3-thione according to claim 1, characterized in that, The isopentenaldehyde is generated from isopentenol through an oxidation reaction; Preferably, after isopentenol is oxidized to isopentenal, it is either separated or not, and then subjected to a mixed reaction.

6. The method for preparing 5,5-dimethylisoxazolidine-3-thione as described in claim 1, characterized in that, After the reaction was completed, the temperature was lowered, methyl tert-butyl ether was added for extraction, the aqueous phase was separated, and the organic phase was distilled to obtain the 5,5-dimethylisoxazolidine-3-thione.

7. A method for preparing a sulfonylpyrazole intermediate, characterized in that, The sulfonylpyrazol intermediate is 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, or 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole; The preparation method includes: The 5,5-dimethylisoxazolidine-3-thione prepared according to any one of claims 1-6 is reacted with a pyrazole compound and a second base in a second solvent to obtain the sulfonylpyrazol intermediate.

8. The method for preparing the sulfonylpyrazol intermediate as described in claim 7, characterized in that, The pyrazole compound is any one of the following: A. 5-Difluoromethoxy-4-chloromethyl-1-methyl-3-trifluoromethylpyrazole; B, 5-Difluoromethoxy-4-hydroxymethyl-1-methyl-3-trifluoromethylpyrazole; C, 5-hydroxy-4-hydroxymethyl-1-methyl-3-trifluoromethyl-1Hpyrazole; D, 5-hydroxy-1-methyl-3-trifluoromethyl-1Hpyrazole; E, 5-hydroxy-4-chloromethyl-1-methyl-3-trifluoromethyl-1Hpyrazole; When the pyrazole compound is 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole, an aqueous formaldehyde solution is also added to the reaction system; and / or, The second type of alkali includes at least one of potassium carbonate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium methoxide, sodium ethoxide, and potassium tert-butoxide; and / or, The second solvent includes dichloromethane; and / or, The molar ratio of the 5,5-dimethylisoxazolidine-3-thione to the pyrazole compound is 1:(1~1.5).

9. The method for preparing the sulfonylpyrazol intermediate as described in claim 8, characterized in that, The reaction steps include: mixing the 5,5-dimethylisoxazolidine-3-thionone, the second solvent and the second base substance at 25℃~30℃, adding the pyrazole compound, and then raising the temperature to 65℃ to continue the reaction; Preferably, the reaction time is at least 5 hours.

10. The method for preparing the sulfonylpyrazol intermediate as described in claim 8, characterized in that, After the reaction is completed, water is added to quench the reaction. When the sulfonylpyrazol intermediate is 3-[(5-hydroxy-1-methyl-3-trifluoromethylpyrazol-4-yl)-methylthio]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, the quenching reaction further includes a step of adding hydrochloric acid for neutralization.

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