A method for synthesizing sulfonylpyrazole

Abstract

This invention discloses a method for synthesizing sulfonylpyrazole, using 1-methyl-3-trifluoromethyl-5-hydroxy-1 H Using pyrazole as a raw material, under alkaline conditions, it undergoes a hydroxymethylation reaction with formaldehyde to obtain hydroxypyrazole methanol; hydroxypyrazole methanol reacts with sodium bisulfite to obtain sodium hydroxypyrazole methanesulfonate; then, under alkaline conditions, it undergoes an etherification reaction with difluorochloromethane to obtain sodium difluoromethoxypyrazole methanesulfonate; after chlorination, it obtains difluoromethoxypyrazole methanesulfonyl chloride, which then reacts with sodium sulfite to obtain sodium difluoromethoxypyrazole methyl sulfinate; finally, it undergoes a Minisci reaction with 5,5-dimethyl-4,5-dihydroisoxazole to obtain sulfonylpyrazole. This invention uses inexpensive and readily available sulfite as a sulfur source, avoiding the synthesis of 5,5-dimethyl-4,5-dihydroisoxazole sulfide compounds, reducing waste and production costs, and is easy to industrialize, thus having high practical value.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, and in particular to a method for synthesizing sulfonylpyrazine. Background Technology

[0002] Pyroxasulfone, also known as sulfonylpyrazole, is a novel, broad-spectrum, highly active pre-emergence soil treatment agent developed by Japan's Combinatorial Chemicals Co., Ltd. It belongs to the isoxazole class of herbicides. Its chemical name is 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isooxazole, CAS number: 447399-55-5, molecular formula: C 12 H 14 F5N3O4S, molecular weight: 391.31, chemical structure:

[0003]

[0004] Sulfonazole, as an excellent pre-emergence soil treatment agent, has the same mechanism of action as classic soil treatment agents such as acetochlor and S-metolachlor, but requires only about 1 / 10 of their dosage. Furthermore, this product has a broad spectrum of control and can be safely used on crops such as corn, cotton, peanuts, wheat, and sunflowers; it effectively controls grasses such as *Setaria*, *Digitaria*, and *Echinochloa*, as well as broadleaf weeds such as *Amaranthus*, *Datura*, *Solanum*, and *Abutilon*. In countries like Australia, sulfonazole is considered the best agent for controlling herbicide-resistant weeds such as straight ryegrass, and it is expected to potentially replace chloroacetamide herbicides in the future, becoming a new benchmark for soil treatment agents, thus possessing excellent market development prospects.

[0005] The reported methods for synthesizing sulfonylpyrazole can be summarized as follows:

[0006]

[0007] Currently, there are two common routes. One route involves the substitution and docking of a halogenated pyrazole intermediate with a dihydroisoxazole sulfide compound, followed by oxidation and other steps to obtain sulfopyrazol. The other route involves the substitution reaction of a pyrazole thiol intermediate with a chlorodihydroisoxazole to obtain a sulfide intermediate, which is then oxidized to yield the product. Both routes require the preparation of the key intermediate, halodihydroisoxazole (dihydroisoxazole sulfide is obtained by substituting halodihydroisoxazole with a small molecule sulfide or thiol compound). The preparation of halodihydroisoxazole usually requires excess bromine or chlorine, making the process cumbersome, inconvenient, and yielding low results. Furthermore, the substitution and docking process between the sulfide and the halogenated compound generates disulfides, which require further purification and removal, increasing production costs. Summary of the Invention

[0008] This invention provides a method for synthesizing sulfonylpyrazole to solve the problems of low yield and high cost in existing sulfonylpyrazole synthesis routes.

[0009] To achieve the above objectives, the technical solution of the present invention is as follows:

[0010] A method for synthesizing sulfonylpyrazole, the reaction formula is as follows:

[0011]

[0012] Using 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole as a raw material, in the presence of solvent and alkaline solution, it undergoes a hydroxymethylation reaction with formaldehyde to obtain hydroxypyrazole methanol; hydroxypyrazole methanol reacts with sodium bisulfite to obtain sodium hydroxypyrazole methanesulfonate; then undergoes an etherification reaction with difluorochloromethane to obtain sodium difluoromethoxypyrazole methanesulfonate; after chlorination, it obtains difluoromethoxypyrazole methanesulfonyl chloride, which then reacts with sodium sulfite to obtain sodium difluoromethoxypyrazole methyl sulfinate; finally, it undergoes a Minisci reaction with 5,5-dimethyl-4,5-dihydroisoxazole to obtain sulfopyrazole.

[0013] A method for synthesizing sulfonylpyrazole includes the following steps:

[0014] S1: Add 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole and 10% to 30% alkaline solution to the solvent, stir, and react at 0 to 35°C. Then add formaldehyde solution dropwise, keeping the temperature constant until the 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole has reacted completely to obtain hydroxypyrazole methanol.

[0015] S2: Add water and sodium bisulfite to step S1, heat to 80-110°C, and react in the presence of air or an oxidant to obtain sodium hydroxypyrazole methanesulfonate.

[0016] S3: Cool the reaction solution in step S2 to room temperature, add alkaline solution, and pass difluorochloromethane gas through until the sodium hydroxypyrazole methanesulfonate has reacted completely to obtain sodium difluoromethoxypyrazole methanesulfonate.

[0017] S4: Chlorinate the sodium difluoromethoxypyrazole methanesulfonate obtained in step S3 under the action of a chlorinating reagent to obtain difluoromethoxypyrazole methanesulfonyl chloride.

[0018] S5: Add the difluoromethoxypyrazole methanesulfonyl chloride obtained in step S4 to the solvent, and react it with sodium sulfite under the action of alkali to obtain sodium difluoromethoxypyrazole methyl sulfinate.

[0019] S6: Sodium difluoromethoxypyrazole methyl sulfinate and 5,5-dimethyl-4,5-dihydroisoxazole obtained in step S4 are added to the solvent. The Minisci reaction occurs under the action of an oxidant. After the reaction is completed, the mixture is quenched, filtered, and washed with water to obtain sulfopyrazole.

[0020] Furthermore, in step S1, the molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to the base is 1:1 to 5; and the molar ratio of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole to formaldehyde is 1:1 to 3.

[0021] Furthermore, in step S1, the solvent is one or more of water, alcohols (C1-C4 alcohol solutions), and nitrile compounds (selected from acetonitrile); the alkaline solution is one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, and potassium carbonate solution. The solvent is used to dissolve the intermediate and facilitate the reaction in solution.

[0022] Furthermore, the oxidant in step S2 is one of potassium persulfate, sodium persulfate, ammonium persulfate, oxygen, or air, with air being the most preferred; the molar ratio of hydroxypyrazole methanol to sodium bisulfite is 1:1 to 2.

[0023] Furthermore, in step S3, the alkali is one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate solution, and potassium carbonate solution; the molar ratio of sodium hydroxypyrazole methanesulfonate to the alkali is 1:1 to 3; and the molar ratio of sodium hydroxypyrazole methanesulfonate to difluorochloromethane is 1:1 to 5.

[0024] Furthermore, in step S4, the chlorinating agent is one of phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, and chlorine; the molar ratio of sodium difluoromethoxypyrazole methanesulfonate to the chlorinating agent is 1:1 to 5.

[0025] Furthermore, in step S5, the solvent is one or more of water, alcohols (C1-C4 alcohols), nitriles (mainly acetonitrile), and amides (mainly DMF and formamide); the base is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate; the molar ratio of difluoromethoxypyrazole methanesulfonyl chloride to the base is 1:1 to 3; the molar ratio of difluoromethoxypyrazole methanesulfonyl chloride to sodium sulfite is 1:1 to 3. The solvent is used to dissolve the intermediate and facilitate the reaction in solution.

[0026] Furthermore, in step S6, the solvent is one or more of water, alcohols (C1-C4 alcohols), nitriles (mainly acetonitrile), and amides (mainly DMF and formamide). The solvent is used to dissolve the intermediate and facilitate the reaction in solution. The oxidant is one of potassium persulfate, sodium persulfate, and ammonium persulfate; the molar ratio of sodium difluoromethoxypyrazole methyl sulfinate to 5,5-dimethyl-4,5-dihydroisoxazole is 1:1 to 3; and the molar ratio of sodium difluoromethoxypyrazole methyl sulfinate to the oxidant is 1:1 to 5.

[0027] This invention presents a method for synthesizing sulfonylpyrazole. Using 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole as a raw material, a hydroxymethylation reaction is carried out with formaldehyde in the presence of solvent and alkaline solution to obtain hydroxypyrazole methanol. Then, sodium bisulfite is added to the system to react and obtain sodium hydroxypyrazole methanesulfonate. Next, difluorochloromethane gas is introduced into the system to induce an etherification reaction, followed by treatment to obtain sodium difluoromethoxypyrazole methanesulfonate. This is then chlorinated to obtain difluoromethoxypyrazole methanesulfonyl chloride, which reacts with sodium sulfite to obtain sodium difluoromethoxypyrazole methylsulfinate. Finally, a Minisci reaction is carried out with 5,5-dimethyl-4,5-dihydroisoxazole to obtain sulfonylpyrazole. The technical route of sulfonylpyrazole designed in this invention differs from existing processes, eliminating the need to synthesize thioether compounds. It features shorter reaction steps, higher yield, lower cost, and the hydroxymethylation, sulfonation, and etherification reactions can be carried out directly in the same reaction flask in a one-pot reaction, making it more suitable for industrial production. Detailed Implementation

[0028] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are described clearly and completely. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1

[0030] Add 64 g of 15% sodium hydroxide solution (0.24 mol, 1.2 eq.) to a 1000 ml four-necked flask. While maintaining the system temperature at 5–10 °C, add 33.2 g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole (0.2 mol, 1.0 eq.) in portions with stirring. Continue stirring for 0.5 h, keeping the temperature constant. Then, add 19.5 g of 37% formaldehyde aqueous solution (0.24 mol, 1.2 eq.) dropwise over approximately 0.5 h. After the addition is complete, gradually raise the temperature to room temperature and allow the reaction to proceed for 5 h. Monitor the reaction using HPLC. Once the starting material has reacted completely, hydroxypyrazole methanol is obtained.

[0031] When there is no 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole remaining in the four-necked flask, add 200 mL of water to the system, and then add 20.8 g (0.2 mol, 1.0 eq.) of sodium bisulfite. The system is then refluxed at 100 °C in air for 8 h. The reaction is monitored by HPLC until the hydroxypyrazole methanol reaction is complete, yielding sodium hydroxypyrazole methanesulfonate (no purification required, directly added to the next step) (refer to reference J. Am. Chem. Soc. 1966, 88, 13, 3084–3087).

[0032] After the hydroxypyrazole-methanol reaction was complete, the mixture was cooled to room temperature, and 32 g (0.24 mol, 1.2 eq.) of 30% sodium hydroxide solution was added. Then, difluorochloromethane was bubbled into the reaction solution, and HPLC monitoring was performed until the sodium hydroxypyrazole methanesulfonate reaction was complete. After the reaction was complete, the water was evaporated, and the resulting white solid was extracted five times with ethanol. The ethanol was combined and distilled to obtain 60.5 g of the white solid sodium difluoromethoxypyrazole methanesulfinate, with a yield of 91% and a purity of 92%.

[0033] Under nitrogen protection, 33.2 g (0.1 mol, 1.0 eq.) of sodium difluoromethoxypyrazole methyl sulfinate and 46 g (0.3 mol, 3.0 eq.) of phosphorus oxychloride were added to a 250 mL three-necked flask. The mixture was stirred at room temperature for 5 h. After the sodium difluoromethoxypyrazole methyl sulfinate was completely consumed by HPLC, phosphorus oxychloride was evaporated under reduced pressure. The remaining residue was dissolved in 200 mL of dichloromethane, washed twice with water, dried, and the dichloromethane was evaporated to obtain 30.6 g of difluoromethoxypyrazole methanesulfonyl chloride, with a yield of 93% and a purity of 90%.

[0034] Under nitrogen protection, 16.4 g (50 mmol, 1.0 eq.) of difluoromethoxypyrazole methanesulfonyl chloride, 50 mL of water, 12.6 g (100 mmol, 2.0 eq.) of sodium sulfite, and 8.4 g (100 mmol, 2.0 eq.) of sodium bicarbonate were added sequentially to a 100 mL three-necked flask. The mixture was heated to 80 °C and reacted for 5 h. After the reaction was completed, the water was removed by vacuum distillation. The resulting solid was extracted with ethanol, the ethanol was combined, and the mixture was evaporated to dryness to obtain 12.6 g of sodium difluoromethoxypyrazole methanesulfonate as a white solid, with a yield of 80% and a purity of 94%.

[0035] In a 100 mL three-necked flask, 6.3 g (20 mmol, 1.0 eq.) of sodium difluoromethoxypyrazole methyl sulfinate, 30 mL of water, 20 mL of acetonitrile, 3.0 g (30 mmol, 1.5 eq.) of 5,5-dimethyl-4,5-dihydroisoxazole, and 10.8 g (40 mmol, 2.0 eq.) of potassium persulfate were added sequentially. The mixture was heated to 80 °C and reacted for 5 h. The acetonitrile was evaporated, filtered, and washed with water to obtain 7.35 g of white solid sulfonylpyrazole with a purity of 98.5% and a yield of 94%.

[0036] Example 2

[0037] Add 64 g of 15% sodium hydroxide solution (0.24 mol, 1.2 eq.) to a 1000 ml four-necked flask. While maintaining the system temperature at 5–10 °C, add 33.2 g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole (0.2 mol, 1.0 eq.) in portions with stirring. Continue stirring for 0.5 h, keeping the temperature constant. Then, add 19.5 g of 37% formaldehyde aqueous solution (0.24 mol, 1.2 eq.) dropwise over approximately 0.5 h. After the addition is complete, gradually raise the temperature to room temperature and allow the reaction to proceed for 5 h. Monitor the reaction using HPLC. Once the starting material has reacted completely, hydroxypyrazole methanol is obtained.

[0038] When there was no 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole remaining in the four-necked flask, 200 mL of water was added to the system, followed by 20.8 g (0.2 mol, 1.0 eq.) of sodium bisulfite. The mixture was then refluxed at 100 °C for 8 h under nitrogen protection. HPLC monitoring showed no formation of sodium hydroxypyrazole methanesulfonate.

[0039] Example 3

[0040] Add 64 g of 15% sodium hydroxide solution (0.24 mol, 1.2 eq.) to a 1000 ml four-necked flask. While maintaining the system temperature at 5–10 °C, add 33.2 g of 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole (0.2 mol, 1.0 eq.) in portions with stirring. Continue stirring for 0.5 h, keeping the temperature constant. Then, add 19.5 g of 37% formaldehyde aqueous solution (0.24 mol, 1.2 eq.) dropwise over approximately 0.5 h. After the addition is complete, gradually raise the temperature to room temperature and allow the reaction to proceed for 5 h. Monitor the reaction using HPLC. Once the starting material has reacted completely, hydroxypyrazole methanol is obtained.

[0041] When there is no 1-methyl-3-trifluoromethyl-5-hydroxy-1H-pyrazole remaining in the four-necked flask, add 200 mL of water to the system, and then add 20.8 g (0.2 mol, 1.0 eq.) of sodium bisulfite. The system is then refluxed at 100 °C for 8 h under an oxygen atmosphere. The reaction is monitored by HPLC until the hydroxypyrazole methanol reaction is complete, yielding sodium hydroxypyrazole methanesulfonate (no purification required, directly added to the next step) (refer to reference J. Am. Chem. Soc. 1966, 88, 13, 3084–3087).

[0042] After the hydroxypyrazole-methanol reaction was complete, the mixture was cooled to room temperature, and 32 g (0.24 mol, 1.2 eq.) of 30% sodium hydroxide solution was added. Then, difluorochloromethane was bubbled into the reaction solution, and HPLC monitoring was performed until the sodium hydroxypyrazole methanesulfonate reaction was complete. After the reaction was complete, the water was evaporated, and the resulting white solid was extracted five times with ethanol. The ethanol was combined and distilled to obtain 57.8 g of the white solid sodium difluoromethoxypyrazole methanesulfinate, with a yield of 87% and a purity of 90%.

[0043] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing sulfonylpyrazole, characterized in that, Includes the following steps: (1) Dissolve pyrazole intermediate 1 in an alkaline aqueous solution, add formaldehyde aqueous solution dropwise, and carry out hydroxymethylation reaction to generate hydroxypyrazole methanol intermediate 2; (2) Hydroxypyrazole methanol intermediate 2 and sodium bisulfite reacted in an aqueous phase under heating in the presence of an oxidant to obtain hydroxypyrazole methanesulfonate intermediate 3. (3) Sodium hydroxypyrazole methanesulfonate intermediate 3 undergoes an etherification reaction with difluorochloromethane in a solvent under alkaline conditions to obtain sodium difluoromethoxypyrazole methanesulfonate intermediate 4; (4) Sodium difluoromethoxypyrazole methanesulfonate intermediate 4 was chlorinated to obtain difluoromethoxypyrazole methanesulfonyl chloride intermediate 5; (5) Difluoromethoxypyrazole methanesulfonyl chloride intermediate 5 reacts with sodium sulfite in water under the action of alkali to give sodium difluoromethoxypyrazole methyl sulfinate intermediate 6. (6) Sodium difluoromethoxypyrazole methyl sulfinate intermediate 6 reacts with 5,5-dimethyl-4,5-dihydroisoxazole in a solvent under the action of an oxidant to give sulfopyrazole; The reaction formula is as follows: 。 2. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (1), the alkaline aqueous solution is a NaOH solution or other alkali metal hydroxide solution, and the molar ratio of intermediate 1 to alkali and formaldehyde is 1:(1-5):(1-3). The solvent is one or more of water, C1-C4 alcohols, and acetonitrile.

3. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (2), the molar ratio of hydroxypyrazole methanol intermediate 2 to sodium bisulfite is 1:(1-2), the solvent used is water, and the reaction temperature is 25-100℃.

4. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (2), the oxidant is one or more of potassium persulfate, sodium persulfate, ammonium persulfate, air, and oxygen.

5. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (3), the molar ratio of sodium hydroxypyrazole methanesulfonate intermediate 3, alkali, and difluorochloromethane is 1:(1-3):(1-5).

6. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (3), the solvent is one or more of water, acetonitrile, and tetrahydrofuran; the base is one or more of NaOH, KOH, Na2CO3, and K2CO3.

7. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (4), the chlorination reagent used in the sodium difluoromethoxypyrazole methanesulfonate intermediate 4 is one of SOCl2, POCl3, and PCl5; the molar ratio of sodium difluoromethoxypyrazole methanesulfonate intermediate 4 to the chlorination reagent is 1:(1-5).

8. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (5), the molar ratio of difluoromethoxypyrazole methanesulfonyl chloride intermediate 5 to sodium sulfite is 1:(1.5-3); The alkali is one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate. The molar ratio of difluoromethoxypyrazole methanesulfonyl chloride, alkali, and sodium sulfite is 1:1~3:1~3.

9. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (6), The solvent is one or more of water, C1-C4 alcohols, acetonitrile, and DMF; The oxidizing agent is one or more of potassium persulfate, sodium persulfate, and ammonium persulfate.

10. The method for preparing sulfonylpyrazole according to claim 1, characterized in that, In step (6), The molar ratio of sodium difluoromethoxypyrazole methyl sulfinate intermediate 6, 5,5-dimethyl-4,5-dihydroisoxazole, and oxidant is 1:(1-3):(1-5).

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