A method for preparing an oxasulfuron intermediate and its application

Abstract

The present invention relates to the field of pesticide preparation, and discloses a method for preparing a sulfentrazone intermediate and its application. The structure of the sulfentrazone intermediate is shown in Formula 1. The method includes: mixing a chloro-isoxazole, a metal sulfide and a thiosulfate for reaction to obtain the sulfentrazone intermediate. By using the thiosulfate and the metal sulfide to react with the chloro-isoxazole, the method effectively inhibits the generation of by-products, and at the same time greatly improves the product yield of sulfentrazone, having greater industrial application prospects.

Description

Technical Field

[0001] The present invention relates to the field of pesticide preparation, and specifically relates to a method for preparing an intermediate of pyroxasulfone and its application. Background Art

[0002] Pyroxasulfone, with the chemical name of 3 - [5 - (difluoromethoxy) - 1 - methyl - 3 - (trifluoromethoxy)pyrazol - 4 - ylmethylsulfonyl] - 4,5 - dihydro - 5,5 - dimethyl - 1,2 - isoxazole, and the molecular formula C 12 H 14 F5N3O4S, with a relative molecular mass of 391.32, is a novel broad - spectrum and highly active pre - emergence soil treatment agent developed by the Japanese company Kumi Chemical Co., Ltd. It is widely used for weed control in crops such as corn, cotton, beans, peanuts, potatoes, rice, sunflowers, and castor, with obvious effects and environmental safety.

[0003] At present, there are few reports on the synthesis method of pyroxasulfone. The more common method is to couple the Mannich adduct of 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 5 - ol and formaldehyde with sodium salt of S - (5,5 - dimethyl - 4,5 - dihydroisoxazol - 3 - yl) to obtain an intermediate, then protect the hydroxyl group with difluoromethyl, and finally oxidize it with hydrogen peroxide to obtain pyroxasulfone. However, in this method, the yield of the intermediate of pyroxasulfone is too low, and there are many by - products in the reaction process, which is not conducive to large - scale industrial production.

[0004] Chinese Patent Application CN 114716428A discloses a method for preparing an intermediate of pyroxasulfone. This method uses sodium thiocyanate with relatively high toxicity for preparation, and the preparation process is relatively cumbersome, which poses a great harm to the health of process operators. Finally, the yield of the obtained intermediate 4 - ((((5,5 - dimethyl - 4,5 - dihydroisoxazol - 3 - yl)thio)methyl) - 1 - methyl - 3 - (trifluoromethyl) - 1H - pyrazol - 5 - ol (INT 1) is not high, and there are also problems such as a relatively high content of by - products in the preparation process.

[0005] 5,5 - Dimethyl - 4,5 - dihydroisoxazole - 3 - thiol is a common and important intermediate for synthesizing pyroxasulfone. However, there are not many reports on the synthesis process of such intermediates at present, and usually, toxic phosphorus pentasulfide is required for the reaction. A large amount of toxic and harmful by - products are easily generated in the synthesis route, which hinders its industrialization process. Summary of the Invention

[0006] The object of the present invention is to overcome the problems existing in the prior art that the preparation process of the sulfentrazone intermediate is cumbersome, with many by-products, a long process production route, great production difficulty and a low yield of the final product. A method for preparing the sulfentrazone intermediate and its application are provided. By using thiosulfate and metal sulfide to react with chloro-isoxazole, the generation of by-products is effectively inhibited, and at the same time, the product yield of sulfentrazone is greatly improved, having greater industrial application prospects.

[0007] To achieve the above object, on the one hand, the present invention provides a method for preparing sulfentrazone. The structure of the sulfentrazone intermediate is shown in Formula 1. The method includes: mixing chloro-isoxazole, metal sulfide and thiosulfate for reaction to obtain the sulfentrazone intermediate;

[0008]

[0009] Preferably, the preparation method of the chloro-isoxazole includes the following steps:

[0010] (1) Mixing hydroxylamine hydrochloride and glyoxylic acid for reaction;

[0011] (2) Mixing the material obtained in step (1), an acid-binding agent, hydrochloric acid and hypochlorite for reaction to obtain dichloroformaldoxime;

[0012] (3) Mixing the dichloroformaldoxime, an acid-binding agent and isobutene for reaction.

[0013] Preferably, the reaction conditions include: temperature is 30 - 100 °C, and time is 0.5 - 10 h.

[0014] Preferably, the molar ratio of the amounts of metal sulfide, chloro-isoxazole and thiosulfate is 1 - 2:1:0.01 - 1;

[0015] and / or, the metal sulfide is selected from sodium sulfide and / or potassium sulfide;

[0016] and / or, the thiosulfate is selected from sodium thiosulfate and / or potassium thiosulfate.

[0017] Preferably, the molar ratio of the amounts of glyoxylic acid, hydroxylamine hydrochloride and hypochlorite is 1:1.1 - 4:2.1 - 4.

[0018] and / or, the molar ratio of the amounts of dichloroformaldoxime and isobutene is 1:1.1 - 4.

[0019] Preferably, the acid-binding agent is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate and sodium carbonate;

[0020] and / or, the molar ratio of the amounts of glyoxylic acid and the acid-binding agent is 1:1.1 - 4.

[0021] Preferably, in step (2), the reaction conditions include: temperature is 30 - 50 °C, and time is 1 - 10 h.

[0022] Preferably, in step (3), the reaction conditions include: temperature is 30 - 100 °C, and time is 1 - 10 h.

[0023] Preferably, in step (1), the reaction conditions include: temperature is 20 - 30 °C, and time is 1 - 10 h.

[0024] The second aspect of the present invention provides an application of the above - mentioned method for preparing the sulfentrazone intermediate in the preparation of sulfentrazone.

[0025] The method of the present invention uses chloro - isoxazole to react with thiosulfate and metal sulfide to prepare the sulfentrazone intermediate 5,5 - dimethyl - 4,5 - dihydroisoxazole - 3 - thiol. By selecting safer and more easily accessible compounds as raw materials, it greatly reduces the difficulty of obtaining raw materials in the preparation process of the sulfentrazone intermediate. And the method of the present invention can obtain the product through one - step reaction, shortening the reaction time, greatly reducing the production difficulty of the sulfentrazone intermediate, simplifying the preparation process route, reducing the generation of three wastes, reducing the environmental protection pressure on enterprises, and being suitable for large - scale industrial production.

[0026] In addition, in the method of the present invention, by using thiosulfate and metal sulfide as reaction raw materials, it can significantly inhibit the production of by - products, improve the yield of the product, enhance the utilization rate of raw materials, and create greater economic value. Detailed Description of the Invention

[0027] The following provides a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only for the purpose of illustrating and explaining the present invention, and are not used to limit the present invention.

[0028] In the ranges disclosed herein, the endpoints and any value are not limited to the exact range or value. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0029] The present invention provides a method for preparing a sulfentrazone intermediate. The structural formula of the sulfentrazone intermediate is shown in Formula 1. The method includes: mixing chloro - isoxazole, metal sulfide and thiosulfate for reaction to obtain the sulfentrazone intermediate;

[0030]

[0031] In the method of the present invention, the scientific name of the oxasulfuron intermediate is 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol.

[0032] In the method of the present invention, the thiosulfate used participates in the actual reaction process and is used for the reaction with chloro-isoxazole and metal sulfide. It can inhibit the generation of disulfide bonds due to its strong reducibility, thereby inhibiting the generation of by-products, reducing the content of by-products in the reaction process, and increasing the purity of the target product in the product.

[0033] In the method of the present invention, the reaction raw material metal sulfide is simple and easy to obtain. And the oxasulfuron intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol can be directly obtained in one step by the reaction of metal sulfide and chloro-isoxazole, which greatly simplifies the production process. Moreover, the raw materials are non-toxic, harmless, simple and easy to obtain, and at the same time, the preparation cost of the oxasulfuron intermediate is reduced.

[0034] The method of the present invention prepares the oxasulfuron intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thiol by reacting metal sulfide and thiosulfate with chloro-isoxazole. The raw materials used in the method are all simple and easy to obtain and relatively inexpensive, further saving the preparation cost. At the same time, the method of the present invention can greatly inhibit the generation of by-products and increase the final yield of the product.

[0035] In a specific embodiment, an organic solvent is also required to be added during the reaction process to dissolve the raw materials, and the organic solvent can be N,N-dimethylformamide (DMF).

[0036] In the method of the present invention, the structure of the chloro-isoxazole is shown in Formula 2. In the method of the present invention, the source of the chloro-isoxazole in the raw materials is not limited and can be a conventional commercially available product or prepared according to common methods in the art.

[0037]

[0038] In a preferred embodiment, in order to further increase the yield of the final product, the reaction conditions need to be limited. The reaction conditions include: the temperature is 30-100 °C, preferably 50-85 °C; the time is 0.5-10 h, preferably 2-5 h. Specifically, the reaction temperature is 30 °C, 40 °C, 50 °C, 60 °C, 80 °C or 100 °C; the reaction time is 0.5 h, 2 h, 4 h, 6 h, 8 h or 10 h.

[0039] In a preferred embodiment, the molar ratio of the amounts of the metal sulfide, chloro isoxazole and thiosulfate is 1-2:1:0.01-1, preferably 1-2:1:0.1-1. Specifically, the molar ratio of the amounts of the metal sulfide, chloro isoxazole and thiosulfate can be 1:1:0.01, 1.5:1:0.01, 2:1:0.01, 1:1:0.5, 1:1:1, 1.5:1:0.5, 1.5:1:0.01, 2:1:0.01 or 2:1:1.

[0040] In a preferred embodiment, the metal sulfide is selected from sodium sulfide and / or potassium sulfide.

[0041] In a preferred embodiment, the thiosulfate is selected from sodium thiosulfate and / or potassium thiosulfate.

[0042] In a preferred embodiment, in order to further improve the yield of the pyroxasulfone intermediate, the preparation method of the chloro isoxazole comprises the following steps:

[0043] (1) Mix hydroxylamine hydrochloride and glyoxylic acid for reaction;

[0044] (2) Mix the material obtained in step (1), an acid-binding agent, hydrochloric acid and hypochlorite for reaction to obtain dichloroglyoxime;

[0045] (3) Mix the dichloroglyoxime, an acid-binding agent and isobutene for reaction.

[0046] In the method of the present invention, in step (1), when hydroxylamine hydrochloride and glyoxylic acid are mixed for reaction, the reaction that occurs is a condensation reaction, and the product obtained is acetaldoxime formic acid.

[0047] In a preferred embodiment, in step (1), the reaction conditions include: the temperature is 20-30 °C and the time is 1-10 h. Specifically, the reaction temperature can be 20 °C, 25 °C or 30 °C; the reaction time can be 1 h, 5 h, 8 h or 10 h.

[0048] In the method of the present invention, in step (2), the material obtained in step (1), an acid-binding agent, hydrochloric acid and hypochlorite are mixed for chlorination reaction to obtain dichloroglyoxime.

[0049] In a specific embodiment, the material obtained after the reaction in step (2) will be layered, and the lower layer material is dichloroglyoxime. After collecting the lower layer material, it can be directly used for the reaction in step (3).

[0050] In a specific embodiment, in step (2), the acid-binding agent is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate and sodium carbonate.

[0051] In a specific embodiment, in step (2), in order to facilitate the full mixing of raw materials, an organic solvent can be added to the reaction system to promote the full dissolution and mixing of the raw materials. The organic solvent can be a common organic solvent in the art, such as dichloromethane, xylene, toluene, chlorobenzene or ethyl acetate.

[0052] In the method of the present invention, in step (2), the material obtained in step (1) can be first mixed with an organic solvent and an acid-binding agent, and then hydrochloric acid and hypochlorite are sequentially added to the reaction system and mixed before reacting.

[0053] In a preferred embodiment, in order to facilitate the progress of the reaction, the hypochlorite can be added to the reaction system by a dropping method. Additionally, before dropping, the temperature of the reaction system can be first raised to the reaction temperature.

[0054] In a preferred embodiment, in step (2), the reaction conditions include: a temperature of 30 - 50 °C and a time of 1 - 10 h. Specifically, the reaction temperature can be 30 °C, 40 °C or 50 °C; the reaction time can be 1 h, 3 h, 5 h, 8 h or 10 h.

[0055] In the method of the present invention, in step (3), dichloroformaldoxime reacts with isobutene gas to prepare chloro - isoxazole.

[0056] In a specific embodiment, in step (3), dichloroformaldoxime can be first mixed with an acid - binding agent, and then the temperature of the reaction system is raised to the reaction temperature and isobutene is introduced for reaction.

[0057] In a preferred embodiment, in step (3), the reaction conditions include: a temperature of 30 - 100 °C and a time of 1 - 10 h. Specifically, the reaction temperature can be 30 °C, 50 °C, 80 °C or 100 °C; the reaction time can be 1 h, 3 h, 5 h, 8 h or 10 h.

[0058] In a preferred embodiment, the flow rate of introducing the isobutene gas into the reaction system is 3 - 8 g / min.

[0059] In the method of the present invention, in order to increase the yield of chloro - isoxazole, the molar ratio of the amounts of glyoxylic acid, hydroxylamine hydrochloride and hypochlorite is limited to 1:1.1 - 4:2.1 - 4, preferably 1:1.1 - 2:2.1 - 3. Specifically, the molar ratio of the amounts of glyoxylic acid, hydroxylamine hydrochloride and hypochlorite can be 1:1.1:2.1, 1:2:2.5, 1:2:3, 1:2:4, 1:2.5:2.1, 1:2.5:3, 1:3:2.1, 1:3.5:3, 1:4:2.1 or 1:4:4.

[0060] In a preferred embodiment, the molar ratio of the amount of dichloroformaldoxime to isobutene is 1:1.1 - 4, preferably 1:1.15 - 2. Specifically, the molar ratio of the amount of dichloroformaldoxime to isobutene can be 1:1.1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0061] In a preferred embodiment, the molar ratio of the amount of glyoxylic acid to the acid-binding agent is 1:1.1 - 4, preferably 1:2 - 3. Specifically, the molar ratio of the amount of dichloroformaldoxime to isobutene can be 1:1.1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5 or 1:4.

[0062] The present invention further provides an application of the above method for preparing the sulfentrazone intermediate in the preparation of sulfentrazone.

[0063] In the present invention, the yield of the sulfentrazone intermediate prepared by the method of the present invention is higher, and in the prior art, when using the sulfentrazone intermediate of the present invention to prepare sulfentrazone, the method is simpler and the process flow is more convenient.

[0064] The present invention will be described in detail below through examples, but the protection scope of the present invention is not limited thereto.

[0065] In the following examples, the experimental methods, unless otherwise specified, are all conventional methods in the art. The experimental materials used in the following examples, unless otherwise specified, can all be obtained commercially.

[0066] In the following examples and comparative examples, the content of the products involved was tested by liquid chromatography (Agilent HPLC1260);

[0067] The yield of the product was obtained according to the formula: (the molar amount of the raw material input - the molar amount of the raw material remaining in the product) ÷ the molar amount of the raw material input × 100%.

[0068] The chloro - isoxazole used in the following examples and comparative examples was prepared by the following method:

[0069] (1) Prepare an aqueous solution of glyoxylic acid with a concentration of 50% (the amount of substance of glyoxylic acid is 1.01 mol), then add 50 mL of water and stir. During stirring, add 1.19 mol of hydroxylamine hydrochloride for reaction. The reaction temperature is 25°C and the reaction time is 4 h;

[0070] (2) Add 200 g of dichloroethane and 80 g of sodium bicarbonate solution (mass concentration: 30%) to the reaction materials obtained in step (1). Then add 2.2 mol of hydrochloric acid (volume concentration: 30%). Next, control the reaction temperature at 40 °C and dropwise add a 10% sodium hypochlorite solution (the amount of substance of sodium hypochlorite is 2.2 mol) to the system. Then continue the reaction for 2 h. After the reaction ends, let the obtained materials stand for layering, and collect the lower organic phase to obtain dichloroformaldoxime;

[0071] (3) Transfer the collected dichloroformaldoxime (amount of substance: 1.26 mol) into a 500 ml round-bottom flask, add 165 g of sodium bicarbonate, then heat up to 80 °C and introduce isobutene gas (amount of substance: 1.569 mol) at a flow rate of 5 g / min for reaction for 5 h; After the reaction ends, filter and concentrate the obtained materials in sequence to obtain the product. The purity of chloro-isoxazole in the product is 94.5%, and the yield is 81%.

[0072] Example 1

[0073] Add 0.1 mol of chloro-isoxazole, 0.2 mol of sodium sulfide, 0.01 mol of sodium thiosulfate, and 100 g of DMF to a 100 mL four-necked flask for reaction. The reaction temperature is 60 °C, and the reaction time is 3 h. After the reaction ends, filter. Then, carry out vacuum recovery of the solvent DMF for the obtained filtrate to obtain the crude product. Then, crystallize the crude product with ethanol to obtain the final product.

[0074] Example 2

[0075] Add 0.1 mol of chloro-isoxazole, 0.15 mol of sodium sulfide, 0.01 mol of sodium thiosulfate, and 100 g of DMF to a 100 mL four-necked flask for reaction. The reaction temperature is 65 °C, and the reaction time is 3.5 h. After the reaction ends, filter. Then, carry out vacuum recovery of the solvent DMF for the obtained filtrate to obtain the crude product. Then, crystallize the crude product with ethanol to obtain the final product.

[0076] Example 3

[0077] Add 0.1 mol of chloro-isoxazole, 0.2 mol of sodium sulfide, 0.1 mol of sodium thiosulfate, and 100 g of DMF to a 100 mL four-necked flask for reaction. The reaction temperature is 70 °C, and the reaction time is 3 h. After the reaction ends, filter. Then, carry out vacuum recovery of the solvent DMF for the obtained filtrate to obtain the crude product. Then, crystallize the crude product with ethanol to obtain the final product.

[0078] Example 4

[0079] Carry out the implementation according to the method of Example 1, the difference is that the dosage of sodium thiosulfate is 0.0008 mol.

[0080] Example 5

[0081] It was carried out according to the method of Example 1, except that the reaction temperature was 120 °C.

[0082] Comparative Example 1

[0083] It was carried out according to the method of Example 1, except that sodium thiosulfate was not added during the preparation.

[0084] Test Example

[0085] The yields of the products finally obtained in Test Examples 1-5 and Comparative Example 1 and the contents of the target products in the final products were tested, and the results are shown in Table 1.

[0086] Table 1

[0087] Example number Yield of oxasulfuron intermediate % Content of oxasulfuron intermediate in the final product % Example 1 90％ 96％ Example 2 88％ 96％ Example 3 92％ 96％ Example 4 90％ 65％ Example 5 82％ 70％ Comparative Example 1 40％ 50％

[0088] It can be seen from the results in Table 1 that by using the method described in the present invention, the yield of the oxasulfuron intermediate can be significantly improved, and the content of by-products during the reaction can also be inhibited. Moreover, the overall production process is simple, the raw materials are environmentally friendly, safe and inexpensive, and it has great industrial application prospects.

[0089] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. A method for preparing an oxasulfuron intermediate, the structure of the oxasulfuron intermediate is shown in Formula 1, characterized in that, The method includes: mixing a chloro - isoxazole, a metal sulfide, and a thiosulfate for reaction to obtain an oxadiargyl intermediate; Among them, the structure of the chloro - isoxazole is shown in Formula 2; 2. The method for preparing the intermediate of oxasulfuron according to claim 1, characterized in that, The preparation method of the chloro - isoxazole includes the following steps: (1) Mixing hydroxylamine hydrochloride and glyoxylic acid for reaction; (2) Mixing the material obtained in step (1), an acid - binding agent, hydrochloric acid, and a hypochlorite for reaction to obtain dichloroformaldoxime; (3) Mixing the dichloroformaldoxime, an acid - binding agent, and isobutene for reaction.

3. The method for preparing the oxasulfuron intermediate according to claim 1, characterized in that, The conditions of the reaction include: temperature is 30 - 100 °C, and time is 0.5 - 10 h.

4. The method for preparing the oxasulfuron intermediate according to claim 1, characterized in that, The molar ratio of the amounts of the metal sulfide, chloro - isoxazole, and thiosulfate used is 1 - 2:1:0.01 - 1; and / or, the metal sulfide is selected from sodium sulfide and / or potassium sulfide; and / or, the thiosulfate is selected from sodium thiosulfate and / or potassium thiosulfate.

5. The method for preparing the intermediate of oxasulfuron according to claim 2, wherein The molar ratio of the amounts of glyoxylic acid, hydroxylamine hydrochloride, and hypochlorite used is 1:1.1 - 4:2.1 - 4; and / or, the molar ratio of the amounts of dichloroformaldoxime and isobutene used is 1:1.1 - 4.

6. The method for preparing the sulfentrazone intermediate according to claim 2, characterized in that, The acid - binding agent is selected from one or more of sodium bicarbonate, potassium bicarbonate, potassium carbonate, and sodium carbonate; and / or, the molar ratio of the amounts of glyoxylic acid and the acid - binding agent used is 1:1.1 - 4.

7. The method for preparing the sulfentrazone intermediate according to claim 2, wherein, In step (2), the conditions of the reaction include: temperature is 30 - 50 °C, and time is 1 - 10 h.

8. The method for preparing the intermediate of oxasulfuron according to claim 2, characterized in that, In step (3), the conditions of the reaction include: temperature is 30 - 100 °C, and time is 1 - 10 h.

9. The method for preparing the oxasulfuron intermediate according to claim 2, wherein In step (1), the conditions of the reaction include: temperature is 20 - 30 °C, and time is 1 - 10 h.

10. Use of the method for preparing an oxadiargyl intermediate according to any one of claims 1 - 9 in the preparation of oxadiargyl.

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