Pyroxasulfone intermediate synthesis optimization process

Abstract

The invention relates to a pyroxasulfone intermediate synthesis optimization process, and relates to the technical field of organic synthesis, and the pyroxasulfone intermediate synthesis optimization process comprises the following steps: adding ethyl trifluoroacetoacetate into a solvent, adding methylhydrazine hydrochloride, adding a sodium hydroxide solution, heating, refluxing, stirring, reacting, cooling, crystallizing, carrying out suction filtration, washing a filter cake, and drying to obtain the pyroxasulfone intermediate. Drying to obtain an intermediate I; mixing the intermediate I, paraformaldehyde and zinc chloride into a solvent, adding acetic acid, heating, stirring, reacting, cooling, separating liquid, extracting to obtain an organic phase, washing, drying and concentrating the organic phase to obtain an intermediate II; and dissolving the solid in a solvent, adding a phase transfer catalyst, carrying out a stirring reaction, introducing monochlorodifluoromethane, carrying out a stirring reaction, carrying out a quenching reaction, and carrying out extraction, washing, concentration and recrystallization to obtain the pyroxasulfone intermediate. The method has the effect of improving the environmental protection property of the process, and the product has high yield and purity.

Description

Technical Field

[0001] This application relates to the field of organic synthesis technology, and in particular to an optimized process for the synthesis of sulfopyrazole intermediates. Background Technology

[0002] In the field of pesticide technology, herbicide research and development has always been an important research direction. With the continuous development of agriculture, the performance requirements for herbicides are becoming increasingly stringent, such as high efficiency, broad spectrum, and safety. The development of new herbicides can not only improve crop yield and quality but also reduce labor costs and promote the modernization of agriculture. The emergence of new herbicides like sulfadiazine provides agricultural production with more effective weed control methods, which can be widely applied to a variety of major crops, meeting the needs of different planting environments and occupying an important position in the pesticide market.

[0003] Early synthesis of sulfonylpyrazole typically involved first synthesizing intermediates of a dihydroisoxazole ring and an N-methylpyrazole ring, followed by substitution, difluoromethylation, and oxidation to obtain sulfonylpyrazole. This process used relatively hazardous reagents such as liquid bromine, chlorine, or isobutylene, and the reaction conditions were quite harsh. In recent years, several research institutions have optimized the preparation process of sulfonylpyrazole. Most methods first synthesize two intermediates, a pyrazole ring and an oxazole ring, and then perform substitution, oxidation, and other operations on these intermediates to finally obtain the target product, sulfonylpyrazole. In these synthetic methods, the synthesis of N-methyl-3-trifluoromethyl-4-hydroxymethyl-5-difluoromethoxypyrazole is the key step in the synthesis of the pyrazole ring.

[0004] Existing technologies for the synthesis of sulfonylpyrazine have significant drawbacks. Early synthesis methods used hazardous reagents such as liquid bromine, chlorine, or isobutylene, posing safety threats to operators. Furthermore, the demanding reaction conditions increased operational difficulty and cost. In addition, both early and recent optimized methods generate large amounts of waste during post-processing, which adversely affects the environment and does not meet modern environmental protection requirements. Therefore, improvements are needed. Summary of the Invention

[0005] To improve the environmental friendliness of the synthesis process of sulfonylpyrazole intermediates, this application provides an optimized synthesis process for sulfonylpyrazole intermediates.

[0006] The optimized synthesis process for a sulfopyrazine intermediate provided in this application adopts the following technical solution: An optimized process for the synthesis of sulfonylpyrazole intermediates includes the following steps: S1. Add ethyl trifluoroacetoacetate to the solvent, add methylhydrazine hydrochloride and sodium hydroxide solution under a protective atmosphere. After the addition is complete, heat and reflux the mixture and stir to react. After cooling, crystallize, filter, wash the filter cake, and dry to obtain intermediate I. S2. Intermediate I, paraformaldehyde and zinc chloride are mixed in a solvent, acetic acid is added, and the mixture is heated and stirred under a protective atmosphere. After cooling, the mixture is separated and extracted to obtain an organic phase. The organic phase is washed, dried and concentrated to obtain intermediate II. S3. Under a protective atmosphere, the solid is dissolved in a solvent, a phase transfer catalyst is added, the reaction is stirred, difluorochloromethane is introduced, the reaction is stirred and then quenched, and the product is extracted, washed, concentrated and recrystallized to obtain sulfopyrazole intermediate.

[0007] The optimized synthesis process for sulfonylpyrazine intermediates improves safety, environmental friendliness, and reaction efficiency through key reagent substitution and reaction pathway reconstruction. The process replaces the highly toxic and flammable liquid methylhydrazine aqueous solution used in traditional processes with solid methylhydrazine hydrochloride, reducing the risks associated with raw material transportation and handling. Halogen-free hydroxymethylation is achieved through a reaction system of paraformaldehyde, zinc chloride, and acetic acid, eliminating the need for hazardous reagents such as liquid bromine, chlorine, or thionyl chloride required in traditional processes, thus reducing the generation of halogen-containing waste gas and toxic byproducts. A phase-transfer catalyst is used to promote the difluoromethoxylation reaction, replacing the high-pressure fluorination process and reducing equipment requirements and energy consumption. The optimized low-temperature crystallization purification technology replaces high-vacuum distillation, simplifying post-processing steps and reducing the use of organic solvents. These improvements not only significantly reduce emissions of waste gas, wastewater, and solid waste, solving the environmental pressure problem of traditional processes, but also suppress side reactions through process optimization, improving intermediate purity and yield, and providing a reliable path for the green industrial production of sulfonylpyrazine.

[0008] Preferably, the molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride and sodium hydroxide in step S1 is (0.92-0.98):1:1.1.

[0009] Preparing intermediate I according to the above mass ratio can enable efficient reaction and improve the yield and purity of the product.

[0010] Preferably, in step S1, methylhydrazine hydrochloride is added at 0-5°C, and after the addition is complete, sodium hydroxide solution is added. The addition is completed within 1-2 hours, and the temperature is controlled to be less than 10°C during the addition. The temperature is then raised to 45-55°C and stirred and refluxed at a speed of 200-300 rpm for 3.5-4.5 hours. The temperature is then lowered to below 5°C for crystallization.

[0011] Low-temperature feeding inhibited intermolecular condensation of methylhydrazine hydrochloride, reducing the formation of byproducts such as dimethylhydrazine. Controlling the slow addition of alkali and strictly limiting the upper temperature limit reduced the risk of hydrolysis of ethyl trifluoroacetoacetate under strong alkaline conditions, while ensuring sufficient dissociation of the hydrazine salt to promote nucleophilic attack. The intermediate-temperature reflux reaction balanced the ring-closing rate with the thermal stability of the pyrazole ring, making the cyclization reaction close to complete conversion. Cooling crystallization utilized solubility differences to efficiently separate the target product, effectively retaining unreacted raw materials and water-soluble salt impurities. The coupling of these parameters not only reduced side reactions at the source, but also improved the solid purity of the intermediate through crystallization kinetic optimization, providing high-quality raw materials for subsequent hydroxymethylation and difluoromethoxylation, thereby improving the yield and purity of the product.

[0012] Preferably, the molar ratio of intermediate I, paraformaldehyde, zinc chloride and acetic acid in step S2 is 1:1.1:(0.08-0.12):0.5.

[0013] Reacting according to the above mass ratio can effectively improve the yield and purity of the product.

[0014] Preferably, in step S2, the reaction is carried out at a constant temperature of 40-45°C for 6-8 hours.

[0015] Within the intermediate temperature reaction window, the Lewis acidity of zinc chloride is fully activated, promoting the dissociation of paraformaldehyde into active formaldehyde monomers and their targeted attack on the pyrazole ring. At the same time, this temperature range effectively inhibits the hydroxymethyl crosslinking side reaction caused by excessive aggregation of zinc ions. The appropriate reaction time ensures that the hydroxymethylation conversion is close to complete, reducing the possibility of unreacted formaldehyde resinifying and forming tar-like polymers during the later concentration process. The synergistic optimization of temperature and time not only ensures the structural stability and reaction yield of intermediate II, but also maintains the integrity of the hydroxymethyl group in the product molecule by suppressing the risks of high-temperature decomposition or low-temperature residue, providing a key precursor with high purity and high reactivity for the subsequent difluoromethoxylation step.

[0016] Preferably, step S2 further includes the addition of tetrabutylammonium bromide.

[0017] Tetrabutylammonium bromide, with its unique amphiphilic structure, can efficiently shuttle between the organic and aqueous phases, migrating the dissociated active formaldehyde monomer from the aqueous phase to the organic phase, thus increasing the nucleophilic substitution rate. Tetrabutylammonium bromide forms a synergistic catalytic mechanism with zinc chloride, activating the formaldehyde monomer through electrostatic interaction and inhibiting the ineffective resinification of paraformaldehyde or the excessive cross-linking of hydroxymethyl side reactions, ensuring the structural stability of intermediate II. This improvement not only avoids the problems of incomplete reaction and increased by-products caused by limited mass transfer in traditional processes, but also shortens the high-temperature maintenance time due to the improved reaction efficiency, reducing the decomposition risk of zinc ion catalysts. This reduces tar-like polymers and metal residues at the source, providing a higher purity precursor for the subsequent difluoromethoxylation step, and enhancing the economic efficiency and greenness of the process.

[0018] Preferably, the molar ratio of zinc chloride to tetrabutylammonium bromide in step S2 is 1:(0.05-0.15).

[0019] The combination of catalysts according to the above ratio can effectively increase the reaction rate, reduce the formation of by-products, and improve the yield and purity of the products.

[0020] Preferably, the phase transfer catalyst in step S3 comprises triethylbenzylammonium chloride and potassium carbonate.

[0021] Triethylbenzylammonium chloride, with its amphiphilic structure, migrates efficiently at the organic-aqueous interface, encapsulating and transporting nucleophilic anions dissociated from potassium carbonate dissolved in the aqueous phase to the organic phase. This directionally activates intermediate II, which then undergoes a nucleophilic substitution reaction with difluorochloromethane diffused in the gas phase. Simultaneously, potassium carbonate, as a mild alkali source, avoids the side reactions of pyrazole ring opening or hydroxymethyl hydrolysis caused by strong bases, ensuring the stability of the intermediate structure. This synergistic mechanism not only significantly improves the atom utilization rate of Freon and reduces the residue of unreacted raw materials, but also reduces the high-pressure requirement due to the increased reaction efficiency. It achieves efficient difluoromethoxylation under normal pressure conditions, avoiding the safety risks and energy consumption burden of high-pressure equipment from the source, while inhibiting the formation of chloromethyl crosslinking byproducts. This provides a key precursor with high purity and high reactivity for the subsequent synthesis of sulfopyrazine.

[0022] Preferably, the molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate and difluorochloromethane in step S3 is 1:0.3:2:(1.9-2.1).

[0023] Reaction according to the above ratio can efficiently generate products and improve product yield and purity.

[0024] Preferably, in step S3, after stirring at 100-200 rpm for 20-40 min, the temperature is raised to 25-30°C, the difluorochloromethane is introduced at a rate of 25-35 mL / min, and the reaction is stirred at 200-300 rpm for 8-12 h.

[0025] Under the action of phase transfer catalyst, an appropriate stirring rate can ensure uniform dispersion of catalyst and reactants, avoiding side reactions caused by local concentration differences; a gentle increase in temperature to a suitable range can activate the catalytic system and increase the reaction rate, while avoiding the destruction of the pyrazole ring structure caused by high temperature; the introduction of difluorochloromethane at a moderate rate can balance gas solubility and reaction activation energy, preventing waste of raw materials or violent reaction caused by gas escape; controlling the reaction time can ensure the conversion rate of hydroxyl fluorination while reducing the generation of impurities caused by over-reaction; this optimization enables the reaction to have both high selectivity and economy under mild conditions, and achieves the unity of efficient synthesis and green production through kinetic regulation.

[0026] In summary, this application includes at least one of the following beneficial technical effects: 1. The optimized synthesis process of sulfonylpyrazine intermediates improves the safety, environmental friendliness, and reaction efficiency of the synthesis process through key reagent substitution and reaction pathway reconstruction. The process replaces the highly toxic and flammable liquid methylhydrazine aqueous solution used in traditional processes with solid methylhydrazine hydrochloride, reducing the risks associated with raw material transportation and operation. Halogen-free hydroxymethylation is achieved through a reaction system of paraformaldehyde, zinc chloride, and acetic acid, eliminating the need for hazardous reagents such as liquid bromine, chlorine, or thionyl chloride required in traditional processes, thus reducing the generation of halogen-containing waste gas and toxic byproducts. A phase-transfer catalyst is used to promote the difluoromethoxylation reaction, replacing the high-pressure fluorination process, reducing equipment requirements and energy consumption. The optimized low-temperature crystallization purification technology replaces high-vacuum distillation, simplifying post-processing steps and reducing the use of organic solvents. These improvements not only significantly reduce the emission of waste gas, wastewater, and solid waste, solving the environmental pressure problem of traditional processes, but also suppress side reactions through process optimization, improving the purity and yield of intermediates, and providing a reliable path for the green industrial production of sulfonylpyrazine.

[0027] 2. Tetrabutylammonium bromide, with its unique amphiphilic structure, can efficiently shuttle between the organic and aqueous phases, migrating the dissociated active formaldehyde monomer from the aqueous phase to the organic phase, thereby increasing the nucleophilic substitution rate. Tetrabutylammonium bromide forms a synergistic catalytic mechanism with zinc chloride, activating the formaldehyde monomer through electrostatic interaction and inhibiting the ineffective resinification of paraformaldehyde or the excessive cross-linking of hydroxymethyl side reactions, ensuring the structural stability of intermediate II. This improvement not only avoids the problems of incomplete reaction and increased by-products caused by limited mass transfer in traditional processes, but also shortens the high-temperature maintenance time due to the improved reaction efficiency, reducing the risk of zinc ion catalyst decomposition. This reduces tar-like polymers and metal residues at the source, providing a higher purity precursor for the subsequent difluoromethoxylation step, and enhancing the economic efficiency and greenness of the process.

[0028] 3. Triethylbenzylammonium chloride has an amphiphilic structure, which allows for efficient migration at the organic-aqueous interface. It encapsulates and transports the nucleophilic anions dissociated from potassium carbonate dissolved in the aqueous phase to the organic phase, directionally activating intermediate II. This intermediate then undergoes a nucleophilic substitution reaction with difluorochloromethane diffused in the gas phase. Simultaneously, potassium carbonate, as a mild alkali source, avoids the side reactions of pyrazole ring opening or hydroxymethyl hydrolysis caused by strong alkali, ensuring the stability of the intermediate structure. This synergistic mechanism not only significantly improves the atom utilization rate of Freon and reduces the residue of unreacted raw materials, but also reduces the high-pressure requirement due to the improved reaction efficiency. It achieves efficient difluoromethoxylation under normal pressure conditions, avoiding the safety risks and energy consumption burden of high-pressure equipment from the source. At the same time, it inhibits the formation of chloromethyl crosslinking byproducts, providing a high-purity and highly reactive key precursor for the subsequent synthesis of sulfopyrazine. Attached Figure Description

[0029] Figure 1 This is the reaction structure formula in Example 1 of this application. Detailed Implementation

[0030] This application discloses an optimized process for the synthesis of sulfonylpyrazole intermediates. Unless otherwise specified, all raw materials used in this application are commercially available. The following detailed description, in conjunction with embodiments, further illustrates this application: Raw material description: Ethyl trifluoroacetoacetate (CAS No.: 372-31-6), methylhydrazine hydrochloride (CAS No.: 7339-53-9), paraformaldehyde (CAS No.: 30525-89-4), acetic acid (CAS No.: 64-19-7), disodium ethylenediaminetetraacetate (CAS No.: 139-33-3), triethylbenzylammonium chloride (CAS No.: 56-37-1), difluorochloromethane (CAS No.: 75-43-4), n-heptane (CAS No.: 142-82-5), ethyl acetate (CAS No.: 141-78-6), N,N-dimethylformamide (CAS No.: 68-12-2), tetrabutylammonium bromide (CAS No.: 1643-19-2).

[0031] Example 1 S1. Ethyl trifluoroacetoacetate was added to a solvent (a mixture of ethanol and water in a volume ratio of 3:1), with a solvent volume of 5 mL / g of ethyl trifluoroacetoacetate. Under nitrogen protection, methylhydrazine hydrochloride was added in portions at 0°C at a rate of 5 g / min, with stirring at 200 rpm. A 1 mol / L sodium hydroxide aqueous solution was added over 1 hour, with the temperature controlled below 10°C during addition. The molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was 0.92:1:1.1. After the addition was complete, the temperature was raised to 45°C and refluxed with stirring at 200 rpm for 4.5 hours. The mixture was then cooled to 0°C for crystallization. The crystals were filtered, and the filter cake was washed with an ethanol-water aqueous solution (ethanol and water in a volume ratio of 4:1, 0-5°C). After vacuum drying at 60°C, intermediate I was obtained. S2. Intermediate I, paraformaldehyde, and zinc chloride were mixed in a solvent (dichloroethane) and stirred at 200 rpm for 10 min. Acetic acid was added. The molar ratio of intermediate I, paraformaldehyde, zinc chloride, and acetic acid was 1:1.1:0.08:0.5. Nitrogen gas was introduced for protection, and the reaction was carried out at a constant temperature of 40 °C for 8 h. After cooling to 25 °C, the mixture was separated and extracted to obtain the organic phase. The organic phase was washed twice with a 5% (w / w) aqueous solution of disodium ethylenediaminetetraacetate (pH 6). The washed organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and concentrated under reduced pressure to obtain intermediate II. S3. Under a protective atmosphere, intermediate II was dissolved in a solvent (anhydrous N,N-dimethylformamide), and triethylbenzylammonium chloride and potassium carbonate were added. The mixture was stirred at 100 rpm for 40 min, then heated to 25 °C, and difluorochloromethane was introduced. The molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate, and difluorochloromethane was 1:0.3:2:1.9, and the difluorochloromethane was introduced at a rate of 25 mL / min. The mixture was stirred at 200 rpm for 12 h, and the reaction was quenched with ice water (ice to water volume ratio of 1:5). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the product. The product was recrystallized in a mixture of n-heptane and ethyl acetate (n-heptane to ethyl acetate volume ratio of 4:1) and dried under vacuum at 60 °C to obtain sulfopyrazol intermediate.

[0032] Example 2 S1. Ethyl trifluoroacetoacetate was added to a solvent (a mixture of ethanol and water in a volume ratio of 3:1), with a solvent volume of 5 mL / g of ethyl trifluoroacetoacetate. Under nitrogen protection, methylhydrazine hydrochloride was added in portions at a rate of 5 g / min at 5 °C, with stirring at 200 rpm. A 1 mol / L sodium hydroxide aqueous solution was added over 2 hours, with the temperature controlled below 10 °C during addition. The molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was 0.98:1:1.1. After the addition was complete, the temperature was raised to 55 °C and refluxed with stirring at 300 rpm for 3.5 hours. The mixture was then cooled to 0 °C for crystallization. The mixture was filtered, and the filter cake was washed with an ethanol-water aqueous solution (ethanol and water in a volume ratio of 4:1, 0-5 °C). After vacuum drying at 60 °C, intermediate I was obtained. S2. Intermediate I, paraformaldehyde, and zinc chloride were mixed in a solvent (dichloroethane) and stirred at 200 rpm for 10 min. Acetic acid was added. The molar ratio of intermediate I, paraformaldehyde, zinc chloride, and acetic acid was 1:1.1:0.12:0.5. Nitrogen gas was introduced for protection, and the reaction was carried out at a constant temperature of 45°C for 6 h. After cooling to 25°C, the mixture was separated and extracted to obtain the organic phase. The organic phase was washed twice with a 5% (w / w) aqueous solution of disodium ethylenediaminetetraacetate (pH 6). The washed organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and concentrated under reduced pressure to obtain intermediate II. S3. Under a protective atmosphere, intermediate II was dissolved in a solvent (anhydrous N,N-dimethylformamide), and triethylbenzylammonium chloride and potassium carbonate were added. The mixture was stirred at 200 rpm for 20 min, then heated to 30 °C, and difluorochloromethane was introduced. The molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate, and difluorochloromethane was 1:0.3:2:2.1, and the difluorochloromethane was introduced at a rate of 35 mL / min. The mixture was stirred at 300 rpm for 8 h, and the reaction was quenched with ice water (ice to water volume ratio of 1:5). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the product. The product was recrystallized in a mixture of n-heptane and ethyl acetate (n-heptane to ethyl acetate volume ratio of 4:1) and dried under vacuum at 60 °C to obtain sulfopyrazol intermediate.

[0033] Example 3 S1. Ethyl trifluoroacetoacetate was added to a solvent (a mixture of ethanol and water in a volume ratio of 3:1), with a solvent volume of 5 mL / g of ethyl trifluoroacetoacetate. Under nitrogen protection, methylhydrazine hydrochloride was added in portions at a rate of 5 g / min at 2.5 °C, with stirring at 200 rpm. A 1 mol / L sodium hydroxide aqueous solution was added over 1.5 h, with the temperature controlled below 10 °C during addition. The molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was 0.95:1:1.1. After the addition was complete, the temperature was raised to 50 °C and refluxed with stirring at 250 rpm for 4 h. The mixture was then cooled to 0 °C for crystallization. The crystals were filtered, and the filter cake was washed with an ethanol-water aqueous solution (ethanol and water in a volume ratio of 4:1, 0-5 °C). After vacuum drying at 60 °C, intermediate I was obtained. S2. Intermediate I, paraformaldehyde, and zinc chloride were mixed in a solvent (dichloroethane) and stirred at 200 rpm for 10 min. Acetic acid was added. The molar ratio of intermediate I, paraformaldehyde, zinc chloride, and acetic acid was 1:1.1:0.1:0.5. Nitrogen gas was introduced for protection, and the reaction was carried out at a constant temperature of 42.5℃ for 7 h. After cooling to 25℃, the mixture was separated and extracted to obtain the organic phase. The organic phase was washed twice with a 5% (w / w) aqueous solution of disodium ethylenediaminetetraacetate (pH 6). The washed organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and concentrated under reduced pressure to obtain intermediate II. S3. Under a protective atmosphere, intermediate II was dissolved in a solvent (anhydrous N,N-dimethylformamide), and triethylbenzylammonium chloride and potassium carbonate were added. The mixture was stirred at 150 rpm for 30 min, then heated to 27.5 °C, and difluorochloromethane was introduced. The molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate, and difluorochloromethane was 1:0.3:2:2, and the difluorochloromethane was introduced at a rate of 30 mL / min. The mixture was stirred at 250 rpm for 10 h, and the reaction was quenched with ice water (ice to water volume ratio of 1:5). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the product. The product was recrystallized in a mixture of n-heptane and ethyl acetate (n-heptane to ethyl acetate volume ratio of 4:1) and dried under vacuum at 60 °C to obtain sulfopyrazol intermediate.

[0034] Example 4 Example 4 is based on Example 3. The only difference between Example 4 and Example 3 is that in Example 4, the molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride and sodium hydroxide in step S1 is 0.85:1:1.1.

[0035] Example 5 Example 5 is based on Example 3. The only difference between Example 5 and Example 3 is that in step S1 of Example 5, the molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride and sodium hydroxide is 1.05:1:1.1.

[0036] Example 6 Example 6 is based on Example 3. The only difference between Example 6 and Example 3 is that in Example 6, in step S1, methylhydrazine hydrochloride is added at 2.5°C. After the addition is complete, sodium hydroxide solution is added and the addition is completed within 0.5 hours. The temperature is controlled to be less than 10°C during the addition. The temperature is raised to 35°C and stirred and refluxed at 250 rpm for 5.5 hours. The temperature is then lowered to below 5°C for crystallization.

[0037] Example 7 Example 7 is based on Example 3. The only difference between Example 7 and Example 3 is that in Example 7, in step S1, methylhydrazine hydrochloride is added at 2.5°C. After the addition is complete, sodium hydroxide solution is added and the addition is completed within 2.5 hours. The temperature is controlled to be less than 10°C during the addition. The temperature is raised to 65°C and stirred and refluxed at 250 rpm for 2.5 hours. The temperature is then lowered to below 5°C for crystallization.

[0038] Example 8 Example 8 is based on Example 3. The only difference between Example 8 and Example 3 is that in Example 8, the molar ratio of intermediate I, paraformaldehyde, zinc chloride and acetic acid in step S2 is 1:1.1:0.05:0.5.

[0039] Example 9 Example 9 is based on Example 3. The only difference between Example 9 and Example 3 is that in Example 9, the molar ratio of intermediate I, paraformaldehyde, zinc chloride and acetic acid in step S2 is 1:1.1:0.15:0.5.

[0040] Example 10 Example 10 is based on Example 3. The only difference between Example 10 and Example 3 is that in step S2 of Example 10, the reaction is carried out at a constant temperature of 30°C for 10 hours.

[0041] Example 11 Example 11 is based on Example 3. The only difference between Example 11 and Example 3 is that in step S2 of Example 11, the reaction is carried out at a constant temperature of 55°C for 4 hours.

[0042] Example 12 Example 12 is based on Example 3. The only difference between Example 12 and Example 3 is that in Example 12, tetrabutylammonium bromide is added in step S2, and the molar ratio of zinc chloride to tetrabutylammonium bromide is 1:0.05.

[0043] S1. Ethyl trifluoroacetoacetate was added to a solvent (a mixture of ethanol and water in a volume ratio of 3:1), with a solvent volume of 5 mL / g of ethyl trifluoroacetoacetate. Under nitrogen protection, methylhydrazine hydrochloride was added in portions at a rate of 5 g / min at 2.5 °C, with stirring at 200 rpm. A 1 mol / L sodium hydroxide aqueous solution was added over 1.5 h, with the temperature controlled below 10 °C during addition. The molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was 0.95:1:1.1. After the addition was complete, the temperature was raised to 50 °C and refluxed with stirring at 250 rpm for 4 h. The mixture was then cooled to 0 °C for crystallization. The crystals were filtered, and the filter cake was washed with an ethanol-water aqueous solution (ethanol and water in a volume ratio of 4:1, 0-5 °C). After vacuum drying at 60 °C, intermediate I was obtained. S2. Intermediate I, paraformaldehyde, zinc chloride, and tetrabutylammonium bromide were mixed in a solvent (dichloroethane) and stirred at 200 rpm for 10 min. Acetic acid was added. The molar ratio of intermediate I, paraformaldehyde, zinc chloride, tetrabutylammonium bromide, and acetic acid was 1:1.1:0.1:0.005:0.5. Nitrogen gas was introduced for protection, and the reaction was carried out at a constant temperature of 42.5℃ for 7 h. After cooling to 25℃, the mixture was separated and extracted to obtain the organic phase. The organic phase was washed twice with a 5% (w / w) aqueous solution of disodium ethylenediaminetetraacetate (pH 6). The washed organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and concentrated under reduced pressure to obtain intermediate II. S3. Under a protective atmosphere, intermediate II was dissolved in a solvent (anhydrous N,N-dimethylformamide), and triethylbenzylammonium chloride and potassium carbonate were added. The mixture was stirred at 150 rpm for 30 min, then heated to 27.5 °C, and difluorochloromethane was introduced. The molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate, and difluorochloromethane was 1:0.3:2:2, and the difluorochloromethane was introduced at a rate of 30 mL / min. The mixture was stirred at 250 rpm for 10 h, and the reaction was quenched with ice water (ice to water volume ratio of 1:5). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, and concentrated under reduced pressure to obtain the product. The product was recrystallized in a mixture of n-heptane and ethyl acetate (n-heptane to ethyl acetate volume ratio of 4:1) and dried under vacuum at 60 °C to obtain sulfopyrazol intermediate.

[0044] Example 13 Example 13 is based on Example 12. The only difference between Example 13 and Example 12 is that the molar ratio of zinc chloride and tetrabutylammonium bromide in Example 13 is 1:0.15.

[0045] Example 14 Example 14 is based on Example 12. The only difference between Example 14 and Example 12 is that the molar ratio of zinc chloride and tetrabutylammonium bromide in Example 14 is 1:0.1.

[0046] Example 15 Example 15 is based on Example 12. The only difference between Example 15 and Example 12 is that the molar ratio of zinc chloride and tetrabutylammonium bromide in Example 15 is 1:0.02.

[0047] Example 16 Example 16 is based on Example 12. The only difference between Example 16 and Example 12 is that the molar ratio of zinc chloride and tetrabutylammonium bromide in Example 16 is 1:0.2.

[0048] Example 17 Example 17 is based on Example 3. The only difference between Example 17 and Example 3 is that in Example 17, the molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate and difluorochloromethane in step S3 is 1:0.3:2:1.7.

[0049] Example 18 Example 18 is based on Example 3. The only difference between Example 18 and Example 3 is that in Example 18, the molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate and difluorochloromethane in step S3 is 1:0.3:2:2.3.

[0050] Example 19 Example 19 is based on Example 3. The only difference between Example 19 and Example 3 is that in Example 19, after stirring at 150 rpm for 30 min in step S3, the temperature is raised to 27.5 °C, the difluorochloromethane is introduced at a rate of 15 mL / min, and the reaction is stirred at 250 rpm for 15 h.

[0051] Example 20 Example 20 is based on Example 3. The only difference between Example 20 and Example 3 is that in Example 20, after stirring at 150 rpm for 30 min, the temperature is raised to 27.5 °C, difluorochloromethane is introduced at a rate of 50 mL / min, and the reaction is stirred at 250 rpm for 5 h.

[0052] Comparative Example 1 Comparative Example 1 replaced the phase transfer catalyst in step S3 with sodium hydride.

[0053] S1. Ethyl trifluoroacetoacetate was added to a solvent (a mixture of ethanol and water in a volume ratio of 3:1), with a solvent volume of 5 mL / g of ethyl trifluoroacetoacetate. Under nitrogen protection, methylhydrazine hydrochloride was added in portions at a rate of 5 g / min at 2.5 °C, with stirring at 200 rpm. A 1 mol / L sodium hydroxide aqueous solution was added over 1.5 h, with the temperature controlled below 10 °C during addition. The molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was 0.95:1:1.1. After the addition was complete, the temperature was raised to 50 °C and refluxed with stirring at 250 rpm for 4 h. The mixture was then cooled to 0 °C for crystallization. The crystals were filtered, and the filter cake was washed with an ethanol-water aqueous solution (ethanol and water in a volume ratio of 4:1, 0-5 °C). After vacuum drying at 60 °C, intermediate I was obtained. S2. Intermediate I, paraformaldehyde, and zinc chloride were mixed in a solvent (dichloroethane) and stirred at 200 rpm for 10 min. Acetic acid was added. The molar ratio of intermediate I, paraformaldehyde, zinc chloride, and acetic acid was 1:1.1:0.1:0.5. Nitrogen gas was introduced for protection, and the reaction was carried out at a constant temperature of 42.5℃ for 7 h. After cooling to 25℃, the mixture was separated and extracted to obtain the organic phase. The organic phase was washed twice with a 5% (w / w) aqueous solution of disodium ethylenediaminetetraacetate (pH 6). The washed organic phase was dried with anhydrous magnesium sulfate, decolorized with activated carbon, and concentrated under reduced pressure to obtain intermediate II. S3. Under a protective atmosphere, intermediate II was dissolved in a solvent (anhydrous N,N-dimethylformamide), and sodium hydride was added in three batches, with the temperature controlled below 10°C. After the addition was complete, the temperature was raised to 25°C, and difluorochloromethane was introduced. The molar ratio of intermediate II, sodium hydride, and difluorochloromethane was 1:1.3:2, and the difluorochloromethane was introduced at a rate of 30 mL / min. The mixture was stirred at 250 rpm for 10 h, and the reaction was quenched with ice water (ice to water volume ratio of 1:5). The mixture was extracted with ethyl acetate, washed with saturated sodium chloride aqueous solution, concentrated under reduced pressure, and the product was obtained. The product was recrystallized in a mixture of n-heptane and ethyl acetate (n-heptane to ethyl acetate volume ratio of 4:1) and dried under vacuum at 60°C to obtain sulfopyrazol intermediate.

[0054] Performance testing The yield and purity of the sulfonylpyrazine intermediate were determined and calculated, and the results are recorded in Table 1.

[0055] Table 1. Results of yield and purity determination of sulfonylpyrazine intermediate. As shown in Table 1, the yields of Examples 1-3 are greater than 66.4% and the purity is greater than 97.9%, which demonstrates that the optimized process of this application can effectively improve the efficient synthesis of sulfopyrazole intermediates and enhance its greenness and environmental friendliness.

[0056] As shown in Table 1, the only difference between Examples 4 and 5 and Example 3 is that the molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide was disrupted in Examples 4 and 5. Compared with Example 3, the performance of Examples 4 and 5 decreased. This is because too much or too little dosage will disrupt the reaction equilibrium, increase side reactions, and thus affect the yield and purity.

[0057] As shown in Table 1, the only difference between Examples 6 and 7 and Example 3 is that the defined reaction condition range was disrupted in Examples 6 and 7. Compared with Example 3, the performance of Examples 6 and 7 decreased. This is because temperature and time affect the occurrence of the main reaction and side reactions. Disrupting the reaction conditions will affect the yield and purity.

[0058] As shown in Table 1, the only difference between Examples 8 and 9 and Example 3 is that the molar ratio of intermediate I, paraformaldehyde, zinc chloride, and acetic acid was disrupted in Examples 8 and 9. Compared with Example 3, the performance of Examples 8 and 9 decreased. This is because too much or too little zinc chloride will affect the balance of the reaction and side reactions, thereby affecting the yield and purity.

[0059] As shown in Table 1, the only difference between Examples 10 and 11 and Example 3 is that the temperature and time constraints were disrupted in Examples 10 and 11, and the performance of Examples 10 and 11 decreased compared with Example 3. This is because disrupting the balance of temperature and time will affect the reaction performance and process, and the by-products will reduce the activity of subsequent reactions and the purity of the products, thereby affecting the yield.

[0060] As shown in Table 1, the only difference between Examples 12-16 and Example 3 is that tetrabutylammonium bromide was added in Examples 12-16, and the performance of Examples 12-14 improved because tetrabutylammonium bromide and zinc chloride catalyze synergistically, which improves the reaction performance; Examples 15 and 16 disrupted the optimal ratio, and the performance improvement effect decreased.

[0061] As shown in Table 1, the only difference between Examples 17 and 18 and Example 3 is that Examples 17 and 18 disrupted the molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate, and difluorochloromethane. Compared with Example 3, the performance of Examples 17 and 18 decreased. This is because disrupting the reaction ratio will break the equilibrium of the reaction, thus resulting in a decrease in performance.

[0062] As shown in Table 1, the only difference between Examples 19 and 20 and Example 3 is that the reaction conditions were not limited in Examples 19 and 20. Compared with Example 3, the performance of Examples 19 and 20 decreased because the reaction equilibrium was broken, the probability of side reactions increased, and the yield and purity of the product were affected.

[0063] As shown in Table 1, the only difference between Comparative Example 1 and Example 3 is that the phase transfer catalyst in step S3 of Comparative Example 1 was replaced with sodium hydride. Compared with Example 3, the performance of Comparative Example 1 was significantly reduced. This is because the strong alkalinity of sodium hydride will increase the probability of side reactions, affecting the yield and purity of the product.

[0064] This specific embodiment is merely an explanation of this application and is not intended to limit it. Based on the above description, those skilled in the art can make various changes and modifications without departing from the technical concept of this application. The technical scope of this application is not limited to the contents of the specification but must be determined according to the scope of the claims.

Claims

1. An optimized process for the synthesis of sulfonylpyrazine intermediates, characterized in that: Includes the following steps: S1. Add ethyl trifluoroacetoacetate to the solvent, add methylhydrazine hydrochloride and sodium hydroxide solution under a protective atmosphere. After the addition is complete, heat and reflux the mixture and stir to react. After cooling, crystallize, filter, wash the filter cake, and dry to obtain intermediate I. S2. Intermediate I, paraformaldehyde and zinc chloride are mixed in a solvent, acetic acid is added, and the mixture is heated and stirred under a protective atmosphere. After cooling, the mixture is separated and extracted to obtain an organic phase. The organic phase is washed, dried and concentrated to obtain intermediate II. S3. Under a protective atmosphere, the solid is dissolved in a solvent, a phase transfer catalyst is added, the reaction is stirred, difluorochloromethane is introduced, the reaction is stirred and then quenched, and the product is extracted, washed, concentrated and recrystallized to obtain sulfopyrazole intermediate.

2. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 1, characterized in that: In step S1, the molar ratio of ethyl trifluoroacetoacetate, methylhydrazine hydrochloride, and sodium hydroxide is (0.92-0.98):1:1.

1.

3. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 2, characterized in that: In step S1, methylhydrazine hydrochloride is added at 0-5℃. After the addition is complete, sodium hydroxide solution is added and the addition is completed within 1-2 hours. The temperature is controlled to be less than 10℃ during the addition. The temperature is then raised to 45-55℃ and stirred and refluxed at 200-300 rpm for 3.5-4.5 hours. The temperature is then lowered to below 5℃ for crystallization.

4. The optimized synthesis process of sulfonylpyrazine intermediate according to claim 1, characterized in that: The molar ratio of intermediate I, paraformaldehyde, zinc chloride and acetic acid in step S2 is 1:1.1:(0.08-0.12):0.

5.

5. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 4, characterized in that: In step S2, the reaction is carried out at a constant temperature of 40-45℃ for 6-8 hours.

6. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 5, characterized in that: Step S2 also involves adding tetrabutylammonium bromide.

7. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 6, characterized in that: In step S2, the molar ratio of zinc chloride to tetrabutylammonium bromide is 1:(0.05-0.15).

8. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 1, characterized in that: The phase transfer catalyst in step S3 includes triethylbenzylammonium chloride and potassium carbonate.

9. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 8, characterized in that: The molar ratio of intermediate II, triethylbenzylammonium chloride, potassium carbonate and difluorochloromethane in step S3 is 1:0.3:2:(1.9-2.1).

10. The optimized synthesis process for sulfonylpyrazol intermediate according to claim 9, characterized in that: In step S3, after stirring at 100-200 rpm for 20-40 min, the temperature is raised to 25-30℃, the difluorochloromethane is introduced at a rate of 25-35 mL / min, and the reaction is stirred at 200-300 rpm for 8-12 h.

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