Synthesis method and application of pyroxasulfone intermediate

Abstract

The invention relates to the technical field of synthesis of pyroxasulfone intermediates, in particular to a synthesis method and application of a pyroxasulfone intermediate. Comprising the following preparation steps: (1) adding a reaction solvent into sodium formaldehyde sulfoxylate, adding 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole, heating, and completely reacting to obtain sodium hydroxypyrazole methyl sulfinate; and (2) cooling the reaction liquid, adding acetonitrile and alkali liquor, introducing monochlorodifluoromethane gas, after the reaction is completed, concentrating, removing acetonitrile and water, adding methanol, stirring, filtering, and concentrating the filtrate to obtain the pyroxasulfone intermediate difluoromethoxy pyrazole methyl sodium sulfinate. The specific reaction process is as follows. According to the method, the sodium formaldehyde sulfoxylate which is low in cost and easy to obtain is used, synthesis of a 5, 5-dimethyl-4, 5-dihydroisoxazole thioether compound is avoided when pyroxasulfone is prepared from the intermediate obtained in the invention, three wastes and production cost are reduced, industrial production is easy to realize, and the method has relatively high practical value.

Description

Technical Field

[0001] This invention relates to the field of sulfonylpyrazole intermediate synthesis technology, specifically to a method for synthesizing and applying a sulfonylpyrazole intermediate. Background Technology

[0002] Sulfonylpyrazole is a novel, broad-spectrum, highly active pre-emergence soil treatment agent. It belongs to the isoxazole class of herbicides and can be used as a pre-emergence soil treatment agent in most crop fields. After application, it is absorbed by the young roots and shoots of weeds, inhibiting early seedling growth and destroying meristems and coleoptiles. It is a serious potential inhibitor in the biosynthesis of VLCFAs (very long side chain fatty acids) in plants.

[0003] Currently, there are few reports on the synthesis process of sulfonylpyrazole. Chinese invention patent application CN117263925A discloses a method for synthesizing sulfonylpyrazole. This method uses 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole as a raw material, which undergoes a hydroxymethylation reaction with formaldehyde under alkaline conditions to obtain hydroxypyrazole methanol. Subsequently, it reacts with sodium bisulfite to obtain sodium hydroxypyrazole methanesulfonate, then undergoes an etherification reaction with difluorochloromethane under alkaline conditions to obtain sodium difluoromethoxypyrazole methanesulfonate. Finally, it undergoes a Minisci reaction with 5,5-dimethyl-4,5-dihydroisoxazole to obtain sulfonylpyrazole. However, this method still has shortcomings in optimizing reaction conditions, and further research and optimization of reaction conditions are needed to improve the yield and efficiency of the reaction. Chinese invention patent application CN117327016A discloses a method for preparing a sulfonylpyrazol intermediate. This method involves hydroxymethylating 1-methyl-3-trifluoromethyl-1H-pyrazole-5-ol and formaldehyde under alkaline conditions to obtain the intermediate hydroxypyrazole methanol. The intermediate hydroxypyrazole methanol then undergoes an etherification reaction with sodium difluorochloroacetate to obtain 5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-methanol. However, this method still needs improvement in optimizing the etherification reaction conditions; further optimization of the reaction conditions is required to improve the reaction yield and product purity.

[0004] Therefore, there is an urgent need to develop a low-cost, simple, high-yield, and high-purity synthetic method and application for sulfopyrazole intermediates. Summary of the Invention

[0005] To address the shortcomings of existing technologies, this invention provides a method for synthesizing and applying a sulfonylpyrazine intermediate. The method for synthesizing the sulfonylpyrazine intermediate provided by this invention uses 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole as a raw material, reacting it with sodium formaldehyde sulfoxylate to obtain sodium hydroxypyrazole methyl sulfinate; then, under alkaline conditions, it undergoes an etherification reaction with dichlorofluoromethane to obtain the sulfonylpyrazine intermediate sodium difluoromethoxypyrazole methyl sulfinate. Sodium formaldehyde sulfoxylate is inexpensive and readily available. The reaction process avoids the synthesis of 5,5-dimethyl-4,5-dihydroisoxazole sulfide compounds, reducing waste and production costs, and is easily scalable for industrial production, thus possessing high practical value.

[0006] This invention is achieved through the following technical solutions: The first aspect of this invention relates to a method for synthesizing a sulfonylpyrazole intermediate, the method comprising the following preparation steps: (1) Add reaction solvent to sodium formaldehyde sulfoxylate, add 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole, heat up, and the reaction is complete to obtain sodium hydroxypyrazole methyl sulfinate. (2) Cool the reaction solution, add acetonitrile and alkaline solution, pass in dichlorofluoromethane gas, and after the reaction is complete, concentrate, remove acetonitrile and water, add methanol, stir, filter, concentrate the filtrate to obtain sodium difluoromethoxypyrazole methyl sulfinate, the intermediate of sulfonylpyrazole. The specific reaction process is as follows: .

[0007] Preferably, the molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to sodium formaldehyde sulfoxylate in step (1) is 1:1.0-3.0.

[0008] Preferably, the reaction solvent in step (1) is selected from methanol or water, the temperature is raised to 60-100℃, and the reaction time is 1-2h.

[0009] Preferably, the alkaline solution in step (2) is selected from sodium hydroxide or potassium hydroxide solution, with a mass concentration of 20-50%, and the molar ratio of the amount of alkaline solution added to 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 1.0-5.0:1.

[0010] Preferably, the molar ratio of the amount of monochlorodifluoromethane gas added in step (2) to 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 1.0-5.0:1.

[0011] More preferably, the reactions described in steps (1) and (2) are completely monitored by HPLC.

[0012] The second aspect of the present invention relates to the use of the sulfonylpyrazole intermediate prepared by the above-described synthetic method in the preparation of sulfonylpyrazole.

[0013] Preferably, the preparation process of sulfonylpyrazole is as follows: 5,5-dimethyl-4,5-dihydroisoxazole, trifluoroethanol, CuCl2, and K2S2O8 are added to sodium difluoromethoxypyrazole methyl sulfinate, the temperature is raised to 80°C, and the mixture is stirred for 8-10 hours. After the reaction is complete, the mixture is cooled to room temperature, filtered, the filter cake is recrystallized, and dried to obtain sulfonylpyrazole. The reaction process is as follows: .

[0014] Preferably, the mass ratio of sodium difluoromethoxypyrazole methyl sulfinate to 5,5-dimethyl-4,5-dihydroisoxazole is 1:1.2-1.5; more preferably 1:1.2.

[0015] The beneficial effects of this invention are: this invention uses inexpensive and readily available sodium formaldehyde sulfoxylate as raw material, and prepares the target product through simple reaction conditions, avoiding complex intermediate synthesis steps, significantly reducing production costs and improving economic benefits. Detailed Implementation

[0016] The present invention will be further described below with reference to specific embodiments, and the advantages and features of the present invention will become clearer as a result. However, these embodiments are merely exemplary and do not constitute any limitation on the scope of the present invention. Those skilled in the art should understand that modifications or substitutions can be made to the details and form of the technical solutions of the present invention without departing from the spirit and scope of the present invention, but all such modifications and substitutions fall within the protection scope of the present invention.

[0017] Example 1: Add 17.1g of sodium formaldehyde sulfoxylate and 100mL of water to a 500mL four-necked flask, stir to dissolve, then add 20.0g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole, reflux at 100℃, and after reacting for 2 hours, monitor the reaction of the starting material by HPLC to ensure complete reaction, and obtain sodium hydroxypyrazole methyl sulfinate. No purification is required, and proceed directly to the next step of the reaction. After the above reaction solution cooled to room temperature, 100 mL of acetonitrile was added, followed by dropwise addition of 32.1 g of 30% sodium hydroxide solution. After the addition was complete, 31.2 g of dichlorofluoromethane gas was introduced into the reaction solution. The reaction was allowed to proceed for 2 hours at room temperature, and HPLC monitoring was used to ensure complete reaction of the starting materials. After the reaction was complete, the solution was concentrated under vacuum to remove water and acetonitrile. 100 mL of methanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated to obtain 41.6 g of a white solid, sodium difluoromethoxypyrazole methanesulfinate, with a yield of 88.5% and a purity of 81.0%.

[0018] Example 2: 17.1g of sodium formaldehyde sulfoxylate and 100mL of methanol were added to a 500mL four-necked flask to form a suspension. Then 20.0g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole was added, and the mixture was refluxed. After reacting for 2 hours, the reaction was monitored by HPLC to ensure that the starting material was completely reacted, and sodium hydroxypyrazole methyl sulfinate was obtained. The solvent was evaporated to obtain a viscous substance. 100 mL of acetonitrile was added to the above viscous substance, followed by the dropwise addition of 32.1 g of 30% sodium hydroxide solution. After the addition was complete, 31.2 g of dichlorofluoromethane gas was introduced into the reaction solution. The reaction was carried out at room temperature for 2 hours, and the reaction was monitored by HPLC to ensure complete reaction of the starting materials. After the reaction was complete, the solution was concentrated under vacuum to remove water and acetonitrile. 100 mL of methanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated to obtain 39.5 g of white solid sodium difluoromethoxypyrazole methanesulfinate, with a yield of 86.9% and a purity of 83.8%.

[0019] Example 3: Add 17.1g of sodium formaldehyde sulfoxylate and 100mL of water to a 500mL four-necked flask, stir to dissolve, then add 20.0g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole, heat to 60℃, and monitor the reaction of the starting material by HPLC to obtain sodium hydroxypyrazole methyl sulfinate. No purification is required, and the next reaction can be carried out directly. After the above reaction solution cooled to room temperature, 100 mL of acetonitrile was added, followed by dropwise addition of 32.1 g of 30% sodium hydroxide solution. After the addition was complete, 31.2 g of dichlorofluoromethane gas was introduced into the reaction solution. The reaction was carried out at room temperature for 2 hours, and HPLC monitoring was performed to ensure the reaction was complete. After the reaction was complete, the solution was concentrated under vacuum to remove water and acetonitrile. 100 mL of methanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated to obtain 28.4 g of a white solid, sodium difluoromethoxypyrazole methanesulfinate, with a yield of 60.2% and a purity of 80.6%.

[0020] Comparative Example 1: 17.1g of sodium formaldehyde sulfoxylate and 100mL of water were added to a 500mL four-necked flask and stirred to dissolve. Then 20.0g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole was added, and the mixture was refluxed at 100℃. After reacting for 2 hours, the reaction of the starting material was monitored by HPLC to ensure that the reaction was complete, and sodium hydroxypyrazole methyl sulfinate was obtained. After the above reaction solution cooled to room temperature, 100 mL of acetonitrile was added, followed by dropwise addition of 25.5 g of 30% sodium carbonate solution. After the addition was complete, 31.2 g of dichlorofluoromethane gas was introduced into the reaction solution. The reaction was allowed to proceed for 2 hours at room temperature, and HPLC monitoring was used to ensure complete reaction of the starting materials. After the reaction was complete, the solution was concentrated under vacuum to remove water and acetonitrile. 100 mL of methanol was added, and the mixture was stirred at room temperature for 2 hours. The mixture was then filtered, and the filtrate was concentrated to obtain a white solid, sodium difluoromethoxypyrazole methanesulfinate.

[0021] The difference from Example 1 is that the alkaline conditions for the reaction of sodium hydroxypyrazole methyl sulfinate with dichlorofluoromethane are different, and the 32.1g of 30% sodium hydroxide solution is replaced with 127.7g of 20% sodium carbonate solution. The rest is the same as in Example 1.

[0022] Results: 5.6 g of the intermediate sodium difluoromethoxypyrazole methyl sulfinate was obtained with a yield of 3.2% and a purity of 22.1%.

[0023] Comparative Example 2: The difference from Example 1 is that the molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to sodium formaldehyde sulfoxylate is different. In this comparative example, the amount of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 20g and the amount of sodium formaldehyde sulfoxylate is 71.1g.

[0024] Results: 81.3 g of the intermediate sodium difluoromethoxypyrazole methyl sulfinate was obtained, with a yield of 64.5% and a purity of 30.2%.

[0025] Comparative Example 3: The difference from Example 1 is that the molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to sodium formaldehyde sulfoxylate is different. In this comparative example, the amount of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 20g and the amount of sodium formaldehyde sulfoxylate is 11.4g.

[0026] Results: 21.5 g of the intermediate sodium difluoromethoxypyrazole methyl sulfinate was obtained with a yield of 44.6% and a purity of 78.9%.

[0027] Application example: Synthesis of sulfonylpyrazine In a 500 mL four-necked flask, 20 g of sodium difluoromethoxypyrazole methanesulfinate (purity: 83.8%), 6.4 g of 5,5-dimethyl-4,5-dihydroisoxazole, 100 mL of trifluoroethanol, 10 mol% CuCl2, and 3 eq of K2S2O8 were added sequentially. The mixture was heated to 80 °C and stirred for 8–10 hours. The reaction was monitored by HPLC until the reactants were fully reacted. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filter cake was recrystallized and dried to obtain 18.0 g of a white solid sulfonylpyrazol. Yield: 85.2%, purity: 98%.

[0028] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing a sulfonylpyrazole intermediate, characterized in that, The synthesis method includes the following preparation steps: (1) Add reaction solvent to sodium formaldehyde sulfoxylate, add 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole, heat up, and the reaction is complete to obtain sodium hydroxypyrazole methyl sulfinate. (2) Cool the reaction solution, add acetonitrile and alkaline solution, pass in dichlorofluoromethane gas, and after the reaction is complete, concentrate, remove acetonitrile and water, add methanol, stir, filter, concentrate the filtrate to obtain sodium difluoromethoxypyrazole methyl sulfinate, the intermediate of sulfonylpyrazole. The specific reaction process is as follows: 。 2. The synthesis method according to claim 1, characterized in that, The molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to sodium formaldehyde sulfoxylate in step (1) is 1:1.0-3.

0.

3. The synthesis method according to claim 1, characterized in that, The reaction solvent in step (1) is selected from methanol or water, the temperature is 60-100℃, and the reaction time is 1-2h.

4. The synthesis method according to claim 1, characterized in that, The alkaline solution mentioned in step (2) is selected from sodium hydroxide or potassium hydroxide solution, with a mass concentration of 20-50%, and the molar ratio of the amount of alkaline solution added to 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 1.0-5.0:

1.

5. The synthesis method according to claim 1, characterized in that, The molar ratio of the amount of monochlorodifluoromethane gas added in step (2) to that of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole is 1.0-5.0:

1.

6. The synthesis method according to any one of claims 1-5, characterized in that, The reactions described in steps (1) and (2) were completely monitored by HPLC.

7. The use of the sulfonylpyrazole intermediate prepared by the synthesis method according to any one of claims 1-6 in the preparation of sulfonylpyrazole.

8. The application according to claim 7, characterized in that, The preparation process of sulfonylpyrazole is as follows: 5,5-dimethyl-4,5-dihydroisoxazole, trifluoroethanol, CuCl2, and K2S2O8 are added to sodium difluoromethoxypyrazole methyl sulfinate. The mixture is heated to 80°C and stirred for 8-10 hours. After the reaction is complete, the mixture is cooled to room temperature, filtered, and the filter cake is recrystallized and dried to obtain sulfonylpyrazole. The reaction process is as follows: 。 9. The application according to claim 7, characterized in that, The molar ratio of sodium difluoromethoxypyrazole methyl sulfinate to 5,5-dimethyl-4,5-dihydroisoxazole is 1:1.2-1.5.

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