A process for the production of pyroxasulfone and intermediates thereof

Abstract

This invention provides a method for producing sulfonylpyrazole and its intermediates. The method uses ethyl trifluoroacetoacetate as a raw material and synthesizes sulfonylpyrazole through steps including cyclization, O-difluoromethylation, chloromethylation, isothioureation, isothiourea hydrolysis, condensation, and oxidation. The product purity is ≥99.5%, content is >99%, and the overall yield exceeds 45%. The process of this invention eliminates column chromatography and crystallization purification, simplifying operations and shortening the production cycle. It solves the problems of high production cost, low product quality, and significant environmental impact associated with existing sulfonylpyrazole technologies. The technical solution of this invention improves product quality and yield, reduces costs, and increases production efficiency, providing technical support for the industrial production of sulfonylpyrazole.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically a method for producing sulfonylpyrazine and its intermediates. Background Technology

[0002] Pyroxasulfone is an isoxazole broad-spectrum herbicide developed and marketed by Japan Combinatorial Chemicals Co., Ltd. It is mainly used to control annual grasses and some broadleaf weeds. Belonging to the sulfonamide class of herbicides, it inhibits the synthesis of branched-chain amino acids in weeds by suppressing acetolactate synthase (ALS), thus hindering weed growth and ultimately causing their death. Pyroxasulfone is mainly used for field weed control in the following crops: (1) Corn: controlling annual grasses and some broadleaf weeds; (2) Wheat: used for pre-emergence or early post-emergence weed control; (3) Soybeans: used before sowing or before emergence to control various weeds; (4) Other crops: such as cotton, sugarcane, etc. Pyroxasulfone is an important herbicide variety due to its high efficiency, broad spectrum, long-lasting effect, low toxicity, environmental friendliness, and flexible application.

[0003] Most of the currently disclosed methods for preparing sulfonylpyrazine involve long reaction routes and complex operations, with few efficient and continuous preparation methods.

[0004] The original research was reported by Anhara Chemical Co., Ltd. of Japan in patent CN101384556B, which describes the preparation method of 5-alkoxy-4-hydroxymethylpyrazole (compound 3), an intermediate of sulfonylpyrazole, as follows: .

[0005] The route uses ethyl trifluoroacetoacetate as a raw material, which undergoes cyclization, hydroxymethylation, and O-difluoromethylation to obtain the pyrazolium intermediate 5-alkoxy-4-hydroxymethylpyrazole (compound 3). This route has the following problems: Compound 2 requires alkaline conditions for hydroxymethylation, but under alkaline conditions, Compound 2 is unstable and produces many impurities that are difficult to process. Studies have found that during the synthesis of Compound 3, introducing dichlorodifluoromethane at atmospheric pressure produces impurities with incomplete O-difluoromethyl substitution, and requires vacuum distillation for purification, resulting in low production efficiency.

[0006] The original research company, Japan Combinatorial Chemicals Co., Ltd., reported the preparation method of sulfonylpyrazole in patent CN112969697A as follows: .

[0007] The route uses compound 4 as a starting material, which is condensed with compound 5 and oxidized with sodium tungstate and hydrogen peroxide to obtain sulfopyrazine. This route has the following problems: (1) A large amount of thionyl chloride is required to prepare compound 4 in compound 3. A large amount of sulfur dioxide and hydrogen chloride are produced during the reaction, which brings huge environmental pressure to industrialization. (2) When compounds 4 and 5 react to form compound 6, high-purity compound 5 is required. Currently, obtaining high-purity compound 5 is difficult, requiring multiple recrystallizations to remove free thiourea, resulting in high industrial manufacturing costs. If compound 5 contains excess free thiourea, the free thiourea will react with compound 4 to produce impurity A. Impurity A will introduce impurity B into sulfopyrazine during subsequent oxidation reactions. This impurity is extremely difficult to remove, severely affecting product yield and quality. If an equimolar amount of thiourea is added, a high-temperature reaction is required. Compound 5 is unstable at high temperatures and easily degrades. (3) In the synthesis of sulfonylpyrazole, acetonitrile or butyl acetate is used as the reaction solvent to control sulfoxide impurities. However, after the reaction is complete, extraction, evaporation of the organic solvent, and addition of alcohol for crystallization are required to obtain the product. The process is cumbersome and the manufacturing cost is high. The patent implementation case also mentions the use of alcohols as solvents, which allows the product to precipitate directly from the system, simplifying the operation steps. However, it is difficult to completely oxidize with alcohols as solvents, resulting in excessive sulfoxide impurities. For example, in Examples 2-6, the oxidation of sulfonylpyrazole using n-butanol as the reaction solvent produces 2.2% sulfoxide impurity C. In Patent Examples 2-7-12, the oxidation reaction is promoted by adding tetrabutylammonium hydrogen sulfate and phenyl phosphate to the system, and the impurity can only be controlled at about 0.4% to 1.8%. Since the structure of sulfoxide impurity C is very similar to that of sulfonylpyrazole, it will accumulate during crystallization and is difficult to remove from the product. If sulfoxide impurity C is not separated, it will lead to a decrease in the quality of the sulfonylpyrazole formulation and cause phytotoxicity to crops. Furthermore, failure to control sulfoxide impurity C may also lead to regulatory issues.

[0008] Patent CN1678588 provides the following synthetic scheme for compound 4: .

[0009] The starting materials for this scheme are scarce, and the chlorination yields using sulfonyl chloride and chlorine are low, resulting in poor product purity and significant environmental pressure. In the implementation case, the purity of the product using sulfonyl chloride as a chlorination reagent was only 30%, and the yield using chlorine was only 62%.

[0010] The synthesis method of sulfonylpyrazine key formula disclosed in patent CN101213181A: .

[0011] This route prepares sulfonylpyrazine via a nucleophilic substitution reaction of compounds 7 and 8 under alkaline conditions. The crude product obtained requires column chromatography purification, which is difficult to scale up industrially.

[0012] Patent CN 115836067 A discloses another method for synthesizing the key formula of sulfonylpyrazine: .

[0013] This route uses compound 9 as the starting material, undergoes bromination and thiolation, and then undergoes a nucleophilic substitution reaction to obtain the sulfonylpyrazol intermediate, with a yield of only 15.3% and a purity of 44%.

[0014] Patent WO2024209278 reports another method for synthesizing sulfonylpyrazine key compound 4: .

[0015] This route uses ethyl trifluoroacetoacetate as a starting material, and through cyclization, O-difluoromethylation, and chloromethylation, yields the key compound 4 of sulfopyrazine. Studies have revealed that in this route: ①When compound 1 reacts with Freon, the reaction is incomplete, and a large amount of compound 1 remains. ② During the synthesis of compound 4, when hydrochloric acid aqueous solution and paraformaldehyde were used for chloromethylation, the actual yield of compound 4 was very low, and a large amount of hydrolysis products were generated. ③ In Case 6 of this literature, in step 5 of preparing intermediate, although the molar ratio of thiourea and intermediate 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole was controlled at 1:1, a large amount of thiourea remained in the actual product. ④ In the preparation of sulfonylpyrazine from intermediate 6, sodium tungstate or tungstic acid was used as a catalyst, hydrogen peroxide as an oxidant, and methanol as a solvent. Verification showed that a large amount of sulfoxide impurities were generated, resulting in poor product purity. The literature also suggested using chloroacetic acid or a mixture of chloroacetic acid (dichloroacetic acid) and acetic acid as the reaction solvent. However, chloroacetic acid and dichloroacetic acid are highly toxic and detrimental to production management.

[0016] Therefore, there is a need for a production method of sulfopyrazole that is mild in reaction conditions, easy to operate, has a high yield, controllable cost, and is environmentally friendly. Summary of the Invention

[0017] The main objective of this invention is to provide a method for producing sulfonylpyrazole and its intermediates, so as to improve product yield and purity, simplify operation, increase efficiency, and reduce mass production costs.

[0018] To meet the needs of industrial production, this invention provides a sulfonylpyrazine production technology solution.

[0019] In view of the problems of low purity, high cost, low yield and great environmental pressure of the sulfonylpyrazine intermediate formula 3 in the existing technology, the present invention also provides an optimized process for intermediate formula 3.

[0020] In addition, in order to control impurities B and C in the final product, we optimized the production of intermediate formula 6 and the final product in the subsequent steps, thereby obtaining a production scheme with simple operation and controllable cost.

[0021] The main contents of this invention are as follows: A method for producing sulfonylpyrazole, following the route shown in the diagram, produces sulfonylpyrazole without column chromatography or crystallization purification of intermediates. .

[0022] One method for producing the sulfonylpyrazol intermediate of formula 3 involves reacting the compound of formula 1 with dichlorofluoromethane under pressure in the presence of a strong base and a phase transfer catalyst to generate the compound of formula 2. Further, under anhydrous conditions, formaldehyde polymer, Lewis acid, and hydrogen chloride are added to obtain the compound of formula 3.

[0023] The solvent used in the reaction of the compounds of Formula 1 to Formula 3 is selected from one or more of acetonitrile, dichloroethane, dichloromethane, and chloroform.

[0024] The phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, or triethylbenzylammonium chloride.

[0025] The pressurization conditions are 0.01~1 MPa higher than the standard atmospheric pressure.

[0026] One method for producing sulfonylpyrazine intermediate Formula 6 involves reacting an alcoholic solution of compound Formula 3 with thiourea to obtain compound Formula 4; further addition of a strong base to the system to obtain compound Formula 5; and further addition of a phase transfer catalyst and compound 15 to obtain compound Formula 6.

[0027] The alcohol solution is selected from one or a mixture of methanol, ethanol, isopropanol, and n-butanol.

[0028] The strong base mentioned is an alkali metal hydroxide or an alkali metal hydride.

[0029] A method for producing sulfonylpyrazole involves adding an organic phase containing a compound of formula 6 to an alcoholic solution, acetic acid, hydrogen peroxide, and sodium tungstate, and reacting to obtain sulfonylpyrazole.

[0030] Compared with the prior art, the beneficial effects of the present invention are as follows: (1) This production process reduces crystallization and purification, avoids column chromatography and other operation steps, and shortens the overall reaction route and production cycle; (2) By controlling the pressure of monochlorodifluoromethane and adding a phase transfer catalyst, the difficulty of incomplete O-difluoromethyl substitution in the key step was overcome, the reaction cycle was shortened, and Freon was saved; (3) Formula 3 is synthesized by adding zinc chloride to achieve one-step synthesis of hydroxymethyl and chlorinated compounds; thus avoiding the use of thionyl chloride; (4) It solves the problem of instability of thiourea in the prior art, thereby improving the purity and yield of intermediate formula 6; (5) In the synthesis of sulfonepyrazole, alcohols are used as solvents and acetic acid is added at the same time to solve the problem of large sulfoxide impurity C produced by incomplete oxidation, which is difficult to remove. The resulting product has high purity and crystallizes directly from the reaction system. The proportion of impurity C is less than 0.1%, which reduces raw material costs and improves product yield and production efficiency. Detailed Implementation

[0031] The present invention will be further described below with reference to specific embodiments, so that those skilled in the art can better understand the present invention, but this does not limit the present invention. Example 1

[0032] Add 200 g of ethyl trifluoroacetoacetate and 1.3 g of glacial acetic acid to the reaction flask, keep the temperature below 90 °C, add 138 g of 40% methylhydrazine aqueous solution dropwise, and keep the reaction at 85-90 °C for 2 h. After the reaction is completed, cool down to 40-50 °C, add 600 g of purified water, continue to cool down to 0-10 °C, stir for 2 h, filter, and directly add the obtained wet product to the next step (after drying, 164.2 g of formula 1 is obtained, the yield of this step is 91%).

[0033] Add the wet product from step 1 (after purification), 600 g of dichloroethane, 495 g of 20% sodium hydroxide aqueous solution, and 6.4 g of tetrabutylammonium bromide to a high-pressure reactor. Control the temperature at 20-30 ℃, introduce dichlorofluoromethane, control the pressure at 0.01-0.05 MPa, and maintain the temperature at 20-30 ℃ for 5 h. Stop the reaction, allow it to stand and separate the liquids. Extract the aqueous phase with 150 g of dichloroethane, combine the organic phases and directly add them to the next step. (The content obtained by external standard analysis was 186 g, and the yield of this step was 87.1%).

[0034] Add the organic phase of formula 2 from the previous step, 232.4 g of oligooxymethylene, and 351.8 g of anhydrous zinc chloride to the reaction flask. Control the temperature at 5-10 ℃, introduce hydrogen chloride gas, and maintain the temperature at 60-65 ℃ for 5 h. Pour the reaction solution into 200 g of purified water, separate the liquids, concentrate the organic phase to obtain formula 3, and directly add it to the next step. (The content was measured by external standard, yielding 203 g, with a yield of 89.1% for this step).

[0035] Add the concentrated solution from step 3, 800 ml of methanol, and 61.3 g of thiourea to the reaction flask. Reflux for 2 h, cool to 50 °C, add 753 g of 20% potassium hydroxide aqueous solution dropwise, and maintain the temperature at 50 °C for 2 h. After concentration, add 600 g of dichloroethane for extraction and separation to obtain the organic phase of formula 5, which is directly added to the next step. (The content obtained by external standard was 186 g, and the yield of this step was 85.3%).

[0036] Add the organic phase of formula 5, compound 15 (105 g), and tetrabutylammonium bromide (5.9 g) to the reaction flask. Maintain the temperature below 15 °C, then add 578 g of 30% sodium carbonate aqueous solution dropwise. Insulate the temperature at 10-15 °C for 4 h, maintain the temperature at 10-20 °C, separate the liquids, and concentrate the organic phase to obtain formula 6, which is then directly added to the next step. (The yield of this step is 93.5%, based on external standard analysis, resulting in 220 g of the product).

[0037] Add the concentrated solution of Formula 6, 880 ml of ethanol, 1.3 g of sodium tungstate, and 220 ml of acetic acid to the reaction flask. Control the temperature at 70-75℃, add 312 g of 30% hydrogen peroxide dropwise, and maintain the reaction temperature at 75-85℃ for 10 h. Cool down to 5-10℃, stir and crystallize for 2 h, filter, wash the filter cake with a mixture of 50 g of ethanol and water (1:1), and dry it at 60℃ to obtain 208 g of sulfonylpyrazine white solid. The yield of this step is 86.8%, the yield of the six-step continuous addition is 48.9%, the HPLC purity is 99.9%, the content is 99.4%, the impurity C (sulfoxide) impurity ratio is 0.03%, and impurities A and B are not detected. Example 2

[0038] Add 200 g of ethyl trifluoroacetoacetate and 2 g of 36% hydrochloric acid to the reaction flask, keep the temperature below 90 °C, add 138 g of 40% methylhydrazine aqueous solution dropwise, and keep the reaction at 85-90 °C for 2 h. After the reaction is completed, cool down to 40-50 °C, add 600 g of purified water, continue to cool down to 0-10 °C, stir for 2 h, filter, and directly add the obtained wet product to the next step (after drying, 1160 g is obtained, the yield of this step is 88.7%).

[0039] Add the wet product from step 1 (after purification), 600 g of chloroform, 482 g of 20% sodium hydroxide aqueous solution, and 9.32 g of tetrabutylammonium chloride to a high-pressure reactor. Control the temperature at 20-30 ℃, introduce monochlorodifluoromethane, control the pressure at 0.04-0.06 MPa, and maintain the temperature at 20-30 ℃ for 5 h. Stop the reaction, allow it to stand and separate the liquids. Extract the aqueous phase with 150 g of chloroform, combine the organic phases and directly add them to the next step. (The yield was 182 g after external standard analysis, with a yield of 87.4%).

[0040] Add the organic phase of formula 2 from the previous step, 230 g of paraformaldehyde, and 336 g of anhydrous aluminum chloride to the reaction flask. Control the temperature at 5-10℃, introduce hydrogen chloride gas, and maintain the temperature at 60-65℃ for 5 h. Pour the reaction solution into 200 g of purified water, separate the liquids, concentrate the organic phase to obtain formula 3, and directly add it to the next step. (The content was 190 g after external standard analysis, and the yield of this step was 85.2%).

[0041] Add the concentrated solution from step 3, 800 ml of methanol, and 57.4 g of thiourea to the reaction flask. Reflux for 4 h, cool to 50 °C, add 300 g of 20% lithium hydroxide aqueous solution dropwise, and maintain the temperature at 50 °C for 2 h. After concentration, add 600 g of dichloroethane for extraction and separation to obtain the organic phase of formula 5, which is directly added to the next step. (The content obtained by external standard was 177 g, and the yield of this step was 86.7%).

[0042] Add the organic phase of formula 5, compound 15 (99 g), and triethylbenzylammonium chloride (6 g) to the reaction flask. Maintain the temperature below 15 °C, then add 550 g of 30% sodium carbonate aqueous solution dropwise. Insulate the temperature at 10-15 °C for 4 h, maintaining the temperature at 10-20 °C. Separate the liquid and concentrate the organic phase to obtain formula 6, which is then directly added to the next step. (The yield of this step is 89.3%, based on external standard analysis, resulting in 200 g of the compound).

[0043] Add the concentrated solution of Formula 6, 800 ml of isopropanol, 1.3 g of sodium tungstate, and 600 ml of acetic acid to the reaction flask. Control the temperature at 70-75℃, add 284 g of 30% hydrogen peroxide dropwise, and maintain the temperature at 75-85℃ for 10 h. Cool down to 5-10℃, stir and crystallize for 2 h, filter, wash the filter cake with a mixture of 50 g of isopropanol and water (1:1), and dry it at 60℃ to obtain 198 g of sulfonylpyrazol white solid. The yield of this step is 90.9%, the yield of the six-step continuous addition is 46.4%, the HPLC purity is 99.8%, the content is 99.6%, the impurity C (sulfoxide) impurity ratio is 0.01%, and impurities A and B are not detected. Example 3

[0044] Add 1 kg of ethyl trifluoroacetoacetate and 15 g of concentrated sulfuric acid to the reaction flask, keep the temperature below 90 °C, add 689 g of 40% methylhydrazine aqueous solution dropwise, and keep the reaction at 85 ~ 90 °C for 2 h. After the reaction is completed, cool down to 40 ~ 50 °C, add 3 kg of purified water, continue to cool down to 0 ~ 10 °C, stir for 2 h, filter, and directly add the obtained wet product to the next step (after drying, 1810 g is obtained, the yield of this step is 89.8%).

[0045] Add the wet product from step 1 (after purification), 3 kg of acetonitrile, 1.22 kg of 40% sodium hydroxide aqueous solution, and 30 g of triethylbenzylammonium chloride to a high-pressure reactor. Control the temperature at 20-30 ℃, introduce dichlorofluoromethane, control the pressure at 0.06-1 MPa, and maintain the temperature at 20-30 ℃ for 7 h. Stop the reaction, allow it to stand and separate the liquids. The organic phase is directly added to the next step. (The yield was 893 g after external standard analysis, with a yield of 84.7% for this step).

[0046] Add the organic phase of formula 2 from the previous step, 1.16 kg of oligooxymethylene, and 1.7 kg of anhydrous zinc chloride to the reaction flask. Maintain the temperature at 5-10℃, introduce hydrogen chloride gas, and react at 60-65℃ for 5 h. Pour the reaction solution into 1 kg of purified water, separate the liquids, concentrate the organic phase to obtain formula 3, and directly add it to the next step. (The content was measured by external standard, yielding 969 g, with a yield of 88.6% for this step).

[0047] Add the concentrated solution from step 3, 4 L of methanol, and 293 g of thiourea to the reaction flask. Reflux for 2 h, cool to 50 °C, add 1.28 kg of 40% sodium hydroxide aqueous solution dropwise, maintain the temperature at 50 °C for 2 h, concentrate, and extract with 3 kg of dichloromethane to obtain the organic phase of formula 5, which is directly added to the next step. (The content obtained by external standard analysis was 870 g, and the yield of this step was 83.9%).

[0048] Add the organic phase of formula 5, compound 15 (490 g), and tetrabutylammonium bromide (35 g) to the reaction flask. Maintain the temperature below 15 °C, add 2.7 kg of 30% sodium carbonate aqueous solution dropwise, and maintain the temperature at 10-15 °C for 4 h. Maintain the temperature at 10-20 °C, separate the liquids, and concentrate the organic phase to obtain formula 6, which is then directly added to the next step. (The yield of this step is 990 g, obtained by external standard analysis; yield is 90.0%).

[0049] Add the concentrated solution of Formula 6, 4 L of methanol, 10 g of sodium tungstate, and 1 L of acetic acid to the reaction flask. Control the temperature at 70-75℃, add 1.41 kg of 30% hydrogen peroxide dropwise, and maintain the reaction temperature at 75-85℃ for 10 h. Cool down to 5-10℃, stir and crystallize for 2 h, filter, wash the filter cake with a mixture of 500 g of methanol and water (1:1), and dry it in a forced-air oven at 60℃ to obtain 970 g of sulfonylpyrazol white solid. The yield of this step is 90.0%, the yield of the six-step continuous addition is 45.7%, the HPLC purity is 99.7%, the content is 99.5%, and impurities A, B, and C are not detected.

[0050] Example 4 (Pilot-scale)

[0051] Add 200 kg of ethyl trifluoroacetoacetate and 2 kg of glacial acetic acid to the reaction vessel, keep the temperature below 90 °C, add 138 kg of 40% methylhydrazine aqueous solution dropwise, and keep the reaction at 85-90 °C for 2 h. After the reaction is completed, cool down to 40-50 °C, add 600 kg of purified water, continue to cool down to 0-10 °C, stir for 2 h, filter, and directly feed the obtained wet product into the next step (after drying, 1162 kg of formula 1 is obtained, the yield of this step is 89.8%).

[0052] Add the wet product from step 1 (after purification), 600 kg of dichloroethane, 487 kg of 20% sodium hydroxide aqueous solution, and 9 kg of tetrabutylammonium chloride to a high-pressure reactor. Maintain the temperature at 20-30 °C, introduce dichlorofluoromethane, and control the pressure at 0.01-0.02 MPa. Maintain the temperature at 20-30 °C for 5 hours. Stop the reaction, allow the mixture to stand, and separate the liquids. Extract the aqueous phase with 150 kg of dichloroethane. Combine the organic phases and directly add them to the next step. (The yield was 181.8 kg after external standard analysis, with a yield of 86.2% for this step.)

[0053] Add the organic phase of formula 2 from the previous step, 240 kg of oligooxymethylene, and 344 kg of anhydrous aluminum chloride to the reaction flask. Control the temperature at 5-10℃, introduce hydrogen chloride gas, and maintain the temperature at 60-65℃ for 5 hours. Pour the reaction solution into 200 kg of purified water, separate the liquids, concentrate the organic phase to obtain formula 3, and directly add it to the next step. (The yield of this step is 85.2%, based on external standard content of 188 kg).

[0054] Add the concentrated solution from step 3, 800 L of methanol, and 57 kg of thiourea to the reaction flask. Reflux for 4 h, cool to 50 °C, add 500 kg of 20% sodium hydroxide aqueous solution dropwise, and maintain the temperature at 50 °C for 2 h. After concentration, add 600 kg of dichloroethane for extraction and separation to obtain the organic phase of formula 5, which is directly added to the next step. (The yield of this step is 86.7%, based on external standard analysis, is 175 kg).

[0055] Add the organic phase of Formula 5, 98.7 kg of compound 15, and 6 kg of triethylbenzylammonium chloride to the reaction flask. Maintain the temperature below 15 °C, then add 544 kg of 30% sodium carbonate aqueous solution dropwise. Insulate the temperature at 10-15 °C for 4 h, maintain the temperature at 10-20 °C, separate the liquids, and concentrate the organic phase to obtain Formula 6, which is then directly added to the next step. (The yield of this step is 90.8%, based on external standard analysis, is 201 kg).

[0056] Add the concentrated solution of Formula 6, 800 L of ethanol, 1.5 kg of sodium tungstate, and 600 L of glacial acetic acid to the reaction flask. Control the temperature at 70-75℃, add 286 kg of 30% hydrogen peroxide dropwise, and maintain the temperature at 75-85℃ for 15 h. Cool down to 5-10℃, stir and crystallize for 2 h, filter, wash the filter cake with a mixture of 50 kg of ethanol and water (1:1), and dry it at 60℃ to obtain 200 kg of sulfonylpyrazol white solid. The yield of this step is 91.4%, the yield of the six-step continuous addition is 47.4%, the HPLC purity is 99.9%, the content is 99.5%, the impurity C (sulfoxide) impurity ratio is 0.01%, and impurities A and B are not detected.

[0057] The 1H NMR spectrum is as follows: 1H NMR (400 MHz, Chloroform) δ 6.649-7.267 (t, J = 114.6 Hz, 1H), 4.598 (s, 2H), 3.875 (s, 3H), 3.102 (s, 2H), 1.200-1.596 (s, 6H). Comparative Example 1

[0058] Reference to original patent CN 112969697 A Under nitrogen atmosphere, Formula 6 (3.05 g), methanol (6.7 g), water (0.9 ml), sodium tungstate dihydrate (0.084 g), and sulfuric acid (0.087 g) were added to a reaction flask. The mixture was heated to 65°C–70°C. A 35% aqueous hydrogen peroxide solution (4.13 g) was added dropwise over 1 hour at 65°C–70°C, and the mixture was aged for 6 hours while maintaining the temperature at 65°C–70°C. Impurity C accounted for 14%.

[0059] Table 1: Comparison of the present invention with existing technologies reaction solvent alcohols, acetic acid Methanol, sulfuric acid Oxidizing agent hydrogen peroxide hydrogen peroxide catalyst Sodium tungstate Sodium tungstate reaction temperature 75℃ ~ 85℃ 65℃ ~ 70℃ impurity C percentage Less than 0.1% 14% According to Table 1, the technical solution of the present invention can largely remove impurity C and improve the purity of sulfonylpyrazine product.

Claims

1. A method for producing sulfonylpyrazole, characterized in that... The following route is used to produce sulfopyrazine without column chromatography or crystallization purification of intermediates. ， The production method includes the preparation of sulfonylpyrazol intermediate Formula 3, specifically: the compound of Formula 1 reacts with monochlorodifluoromethane under pressure in the presence of a strong base and a phase transfer catalyst to generate compound of Formula 2, and further, under anhydrous conditions, formaldehyde polymer, Lewis acid and hydrogen chloride are added to obtain compound of Formula 3. The production method includes the preparation of sulfonylpyrazol intermediate Formula 6, specifically: reacting an alcoholic solution of compound Formula 3 with thiourea to obtain compound Formula 4; further adding a strong base to the system to obtain compound Formula 5; and further adding a phase transfer catalyst and compound 15 to obtain compound Formula 6. The production method includes the preparation of sulfonylpyrazole, specifically: adding an organic phase containing a compound of formula 6 to an alcohol solution, acetic acid, hydrogen peroxide, and sodium tungstate, and reacting to obtain sulfonylpyrazole.

2. The production method according to claim 1, characterized in that, In the preparation of intermediate formula 3, the solvent used in the reaction of compounds of formula 1 to formula 3 is selected from one or more of acetonitrile, dichloroethane, dichloromethane, and chloroform.

3. The production method according to claim 1, characterized in that, In the preparation of intermediate formula 3, the phase transfer catalyst is selected from one or more of tetrabutylammonium bromide, tetrabutylammonium chloride, or triethylbenzylammonium chloride.

4. The production method according to claim 1, characterized in that, The pressure conditions during the preparation of intermediate formula 3 are 0.01~1 MPa higher than the standard atmospheric pressure.

5. The production method according to claim 1, characterized in that, In the preparation of intermediate formula 6, the alcohol solution is selected from one or a mixture of methanol, ethanol, isopropanol, and n-butanol.

6. The production method according to claim 1, characterized in that, In the preparation of intermediate formula 6, the strong base is an alkali metal hydroxide or an alkali metal hydride.

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