Synthesis method of pyroxasulfone key intermediate

Abstract

The invention relates to the technical field of chemical synthesis, and particularly discloses a synthesis method of a pyroxasulfone key intermediate. According to the synthesis process of the pyroxasulfone key intermediate, provided by the invention, 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole with high yield and high purity is prepared by taking an acidic material as a catalyst and taking cheap dichloroethane as a reaction solvent, the content of condensation impurities is controlled to be 0.5%-1%, and the yield is controlled to be 0.5%-1%. The product yield can reach 96%-98%, raw materials are easy to obtain, operation steps are simple, process conditions are mild, product aftertreatment is simple, and the method is suitable for large-scale industrial production and has very important significance on sustainable development of pyroxasulfone pesticides.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a synthesis method of a key intermediate of pyroxasulfone. BACKGROUND

[0002] Pyroxasulfone is an isoxazole herbicide, and its chemical name is 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl-4,5-dihydro-5,5-dimethyl-1,2-isoxazole (CAS No. 447399-55-5). The herbicide is developed by K-I Chemical Research Institute of Japan, and is industrialized by Japan Synergy and Anpo Chemical Company. Its structural formula is as follows. Pyroxasulfone is a pre-emergence soil closing herbicide, which has high activity, wide herbicidal spectrum, low unit area dosage, and is 8-10 times lower than isopropylamine and ethylamine. It has a long effective period, is safe to the environment, and is safe to the next crop and the next crop. Pyroxasulfone can expand the application range of crops by compounding with classic herbicides, and will become a popular variety to replace ethylamine, (precise) isopropylamine, and other products, and the market demand will further increase.

[0003] 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, whose structural formula is as follows, is a key intermediate for synthesizing pyroxasulfone, and the quality and preparation process thereof directly affect the large-scale production of pyroxasulfone. At present, there are mainly two routes for synthesizing the compound.

[0004]

[0005] Route 1 uses 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as a raw material, and 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is prepared by chlorination in an organic solvent. The reaction equation is as follows. The yield of the product of the process is relatively large, the yield in the dichloroethane system is relatively low, and the yield in the acetonitrile system is relatively high, with a yield deviation of 10 percentage points. However, the reaction in acetonitrile as a solvent will cause the cost of raw materials to be relatively high, and the appearance of the product is poor, which is not conducive to the industrialization of large-scale production.

[0006]

[0007] Route 2 takes 4-methyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole as raw material, and the target compound is synthesized by radical reaction with chlorinating reagent, and the reaction equation is as follows. The process needs to be reacted under ultraviolet light, the yield of the product is low, the product is difficult to purify, and the economic cost is high. Therefore, developing a synthesis method of the intermediate with high yield, simple process, good product quality and more suitable for scale-up production is an urgent problem to be solved in the field of mefenpyr-diethyl.

[0008] SUMMARY

[0009] In view of the problems of low product yield and purity and high production cost in the synthesis method of the key intermediate of mefenpyr-diethyl in the prior art, the present application provides a synthesis method of the key intermediate of mefenpyr-diethyl.

[0010] To solve the above technical problems, the technical scheme provided by the present application is: A synthesis method of a key intermediate of mefenpyr-diethyl, comprising the following steps: Under the condition of an organic solvent, 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is used as raw material, an acidic substance is used as catalyst, and chlorination reaction is carried out with chlorinating reagent to obtain 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole. The reaction equation is as follows:

[0011] It should be noted that the key intermediate of mefenpyr-diethyl in the present application refers to 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

[0012] The inventors found that during the chlorination reaction of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, the hydroxymethyl group on the carbon at position 4 has more affinity due to its structure, causing the raw material and the product to easily undergo self-condensation reaction to generate condensation impurities, and the reaction mechanism is as follows. The inventors separated and purified 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole synthesized by the conventional chlorination process by column chromatography, and obtained the condensation impurities shown in the structure, and the content of the impurities in the 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole product can reach about 3% to 4%, which will affect the quality and yield of the downstream product and mefenpyr-diethyl.

[0013] Structural characterization data of condensation impurities: Liquid mass M+1: 475.07.

[0014] NMR data:1 H NMR (300MHz, DMSO) δ: 3.48 (3H,s,CH3), 4.80 (2H,s,CH2), 7.36-7.7 (1H,t,CH).

[0015]

[0016] To address the aforementioned problems, the present invention provides a method for synthesizing key intermediates of sulfonylpyrazole. This method incorporates an acidic substance as a catalyst during the chlorination reaction, effectively improving the selectivity of the chlorination reaction. The product yield can reach 96%–98%, the content of condensation impurities is controlled between 0.5% and 1%, and the product purity reaches 96%–98%. Furthermore, no special reaction conditions are required; the chlorination reaction can be carried out efficiently at room temperature, which is more conducive to large-scale industrial production and application, and is of great significance to the development of sulfonylpyrazole pesticides.

[0017] Furthermore, the acidic substance is one or more of hydrogen chloride, a strong acidic cation exchange resin, phosphoric acid, a solid superacid, or aluminum trichloride.

[0018] Preferably, the acidic substance is one or more of hydrogen chloride, phosphoric acid, or aluminum trichloride. More preferably, it is hydrogen chloride.

[0019] Furthermore, the molar ratio of the acidic substance to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 0.25:1 to 0.75:1.

[0020] Preferably, the molar ratio of the acidic substance to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 0.3:1 to 0.5:1.

[0021] The preferred catalyst of this invention can reduce the probability of the hydroxymethyl group on the carbon at the 4-position of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole undergoing a self-condensation reaction with the product, thereby significantly reducing the content of condensation impurities and improving the yield and purity of the product.

[0022] Furthermore, the organic solvent is dichloroethane.

[0023] Furthermore, the mass ratio of the organic solvent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1:1 to 3:1.

[0024] Preferably, the mass ratio of the organic solvent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1.5:1 to 2:1.

[0025] This invention uses inexpensive dichloroethane as a solvent and, under specific acidic catalytic conditions, can improve the selectivity of the chlorination reaction, reduce the generation of condensation impurities, and effectively reduce production costs. Moreover, it does not require special reaction conditions, providing a new approach for the synthesis of sulfopyrazine.

[0026] Furthermore, the chlorinating agent is one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride. Thrionyl chloride is preferred.

[0027] Furthermore, the molar ratio of the chlorinating agent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1.1:1 to 1.5:1.

[0028] Preferably, the molar ratio of the chlorinating agent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1.1:1 to 1.2:1.

[0029] Furthermore, the chlorination reaction is carried out at a temperature of 20°C to 40°C for a duration of 2 hours to 4 hours.

[0030] Preferably, the chlorination reaction is carried out at a temperature of 25°C to 35°C.

[0031] The synthesis method for the key intermediate of sulfonylpyrazine provided by this invention has mild reaction conditions, can achieve efficient chlorination reaction at room temperature, and the raw materials are readily available, which is more conducive to scale-up production.

[0032] As a specific embodiment of the present invention, the method for synthesizing the key intermediate of sulfonylpyrazole specifically includes the following steps: 4-Hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was added to an organic solvent, mixed thoroughly, cooled to -10℃ to 5℃, and then an acidic substance and a chlorination reagent were added. The temperature was then raised to 20℃ to 40℃ and maintained for chlorination. After the reaction was completed, the organic solvent was removed, and the mixture was distilled to obtain 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

[0033] Furthermore, the solvent removal is performed under vacuum, with a vacuum level below 0.095 MPa and the reactor temperature controlled at 80°C.

[0034] Furthermore, the vacuum degree of the distillation is ≤200Pa and the pot temperature is ≤120℃.

[0035] The post-processing of the synthesis method of this invention is simple, requiring only simple solvent removal and vacuum distillation to obtain high-purity 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole. Furthermore, the recovered solvent can be recycled, reducing the generation of waste and material costs.

[0036] It should be noted that when the recovered solvent is recycled, the total amount of chlorinating reagent added and the total amount of chlorinating reagent in the recovered solvent should meet the following condition: the molar ratio of chlorinating reagent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1.1:1 to 1.2:1.

[0037] The synthesis process of the key intermediate of sulfonylpyrazole provided by this invention uses an acidic substance as a catalyst and inexpensive dichloroethane as a reaction solvent to prepare 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole with high yield and high purity. The content of condensation impurities is controlled between 0.5% and 1%. The raw materials are readily available, the operation steps are simple, the process conditions are mild, and the product post-processing is simple. It is suitable for large-scale industrial production and is of great significance to the sustainable development of sulfonylpyrazole pesticides. Detailed Implementation

[0038] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0039] To better illustrate the present invention, further examples are provided below.

[0040] In the following examples and comparative examples of the present invention, 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was obtained through commercial purchase or could be prepared by methods described in the prior art.

[0041] In the following examples and comparative examples, the contents of products and condensation impurities were determined by high-performance liquid chromatography (HPLC, Agilent) using the external standard method. The specific detection conditions for the HPLC method are as follows: Chromatographic column: C18, 250mm*4.6mm, 5μm; Mobile phase A: 0.1% aqueous phosphoric acid solution; Mobile phase B: 95% acetonitrile aqueous solution; Detection wavelength: 220nm; Flow rate: 1.0 mL / min; Column temperature: 35℃; Injection volume: 5 μL; Gradient elution sequence:

[0042] Example 1 This embodiment provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 100.0 g of dichloroethane solution. Start stirring and cool to -10℃ to -5℃. Install a venting device and introduce 3.45 g (99%, 0.094 mol) of hydrogen chloride gas. Add 22.56 g (99%, 0.188 mol) of thionyl chloride dropwise over 30 min. After the addition is complete, raise the temperature to 20℃. The reaction was carried out at a constant temperature for 3 hours. After the reaction was completed, the temperature of the vessel was controlled at 80℃ and the vacuum degree was below 0.095MPa to remove dichloroethane and unreacted thionyl chloride. The remaining material in the vessel was then subjected to vacuum distillation to a level below 200Pa and the temperature of the vessel was controlled at a level below 120℃. The fraction was collected and 32.42g of a pale yellow-green oily substance was obtained, which was the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 96%, a purity of 98.0%, and a condensation impurity content of 0.68%.

[0043] Example 2 This embodiment provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 35.0 g of dichloroethane solution. Start stirring and cool to -10℃ to -5℃. Install a venting device and introduce 1.15 g (99%, 0.032 mol) of hydrogen chloride gas. Add 16.54 g (99%, 0.137 mol) of thionyl chloride dropwise over 30 min. After the addition is complete, raise the temperature to 30℃ and maintain the temperature. The reaction was carried out for 2 hours. After the reaction was completed, the temperature of the reactor was controlled at 80℃ and the vacuum degree was below 0.095MPa to remove dichloroethane and unreacted thionyl chloride. The remaining reactor material was then subjected to vacuum distillation to a level below 200Pa and the temperature of the reactor was controlled at a level below 120℃. The fraction was collected to obtain 33.79g of a pale yellow-green oily substance, which is the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 98.6%, a purity of 96.5%, and a condensation impurity content of 0.96%.

[0044] Example 3 This embodiment provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 70.0 g of dichloroethane solution. Start stirring and cool to -5℃~5℃. Add 3.60 g (85%, 0.0313 mol) of concentrated phosphoric acid and 19.09 g (99%, 0.137 mol) of phosphorus trichloride dropwise over 30 min. After the addition is complete, raise the temperature to 30℃ and maintain the reaction temperature for 2 h. After the reaction was completed, the reactor temperature was controlled at 80℃ and the vacuum degree was below 0.095MPa to remove dichloroethane and unreacted phosphorus trichloride. For the remaining reactor material, the vacuum degree was further increased to below 200Pa, and the reactor temperature was controlled at below 120℃. The mixture was then distilled under reduced pressure, and the fraction was collected to obtain 33.82g of a pale yellow-green oily substance, which was the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 98.6%, a purity of 96.4%, and a condensation impurity content of 0.92%.

[0045] Example 4 This embodiment provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 100.0 g of dichloroethane solution. Start stirring and cool to -5℃~0℃. Add 4.22 g (99%, 0.032 mol) of anhydrous aluminum trichloride and dropwise add 19.55 g (99%, 0.163 mol) of thionyl chloride over 30 min. After the addition is complete, raise the temperature to 40℃ and maintain the reaction temperature for 4 h. After the reaction was completed, the reactor temperature was controlled at 80℃ and the vacuum degree was below 0.095MPa to remove dichloroethane and unreacted thionyl chloride. For the remaining reactor material, the vacuum degree was further increased to below 200Pa, and the reactor temperature was controlled at below 120℃. The mixture was then distilled under reduced pressure, and the fraction was collected to obtain 33.54g of a pale yellow-green oily substance, which was the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 98.6%, a purity of 97.2%, and a condensation impurity content of 0.76%.

[0046] Example 5 This embodiment provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 100.0 g of recovered dichloroethane thionyl chloride solution (thionyl chloride content 2.50%). Start stirring and cool to -10℃ to -5℃. Install a venting device and introduce 1.25 g (99%, 0.034 mol) of hydrogen chloride gas. Add 15.32 g (99%, 0.129 mol) of thionyl chloride dropwise over 30 min. After the reaction was completed, the temperature was raised to 30℃ and the reaction was maintained for 2 hours. Once the reaction was complete, the temperature of the vessel was controlled at 80℃ and the vacuum degree was below 0.095 MPa to remove dichloroethane and unreacted thionyl chloride. For the remaining material in the vessel, the vacuum degree was further increased to below 200 Pa and the temperature of the vessel was controlled at below 120℃. The vessel was then distilled under reduced pressure, and the fraction was collected to obtain 32.83 g of a pale yellow-green oily substance, which is the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 97.6%, a purity of 98.3%, and a condensation impurity content of 0.56%.

[0047] Comparative Example 1 This comparative example provides a production process for a key intermediate of sulfonylpyrazole, which differs from Example 2 only in that hydrogen chloride is not added as a catalyst, and the chlorination reaction time is extended to 5 hours. The specific steps are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 35.0 g of dichloroethane solution. Start stirring and cool to -10℃ to -5℃. Add 16.54 g (99%, 0.137 mol) of thionyl chloride dropwise over 30 min. After the addition is complete, raise the temperature to 30℃ and maintain the reaction temperature for 5 h. After the reaction is complete, control the reactor temperature at 80℃. At ℃ and a vacuum degree below 0.095 MPa, dichloroethane and unreacted thionyl chloride were removed. The remaining material was then subjected to vacuum distillation to a pressure below 200 Pa, with the reactor temperature controlled below 120℃. The fraction was collected to obtain 31.20 g of a pale yellow-green oily substance, which was the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole, with a yield of 84.6%, a purity of 89.7%, and a condensation impurity content of 3.75%.

[0048] Comparative Example 2 This comparative example provides a production process for a key intermediate of sulfonylpyrazole, the specific steps of which are as follows: Weigh 35.0 g (88%, 0.125 mol) of 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole and place it in 35.0 g of dichloroethane solution. Turn on the stirrer and cool the solution to -10℃ to -5℃. Install a venting device and introduce 3.55 g (99%, 0.096 mol) of hydrogen chloride gas. Raise the temperature to 30℃ and maintain the reaction for 3 h. At this time, solid precipitates from the liquid. Take a sample for control and do not detect the target product 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

[0049] In summary, the embodiments of the present invention use a specific acidic substance as a catalyst and inexpensive dichloroethane as a reaction solvent to prepare 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole with a yield of over 96% and a purity of over 96%. The yield and purity are superior to those of traditional chlorination reactions. Furthermore, the process conditions are mild, the post-processing is simple, the reaction solvent can be recycled, and the amount of waste generated is low. The process economy and environmental friendliness are significantly improved, and it has high practical value.

[0050] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a key intermediate of sulfonylpyrazine, characterized in that, Includes the following steps: Under organic solvent conditions, 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was used as a raw material and an acidic substance was used as a catalyst to carry out a chlorination reaction with a chlorinating agent to obtain 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

2. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1, characterized in that, The acidic substance is one or more of hydrogen chloride, strong acidic cation exchange resin, phosphoric acid, solid superacid, or aluminum trichloride.

3. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1 or 2, characterized in that, The molar ratio of the acidic substance to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 0.25:1 to 0.75:

1.

4. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1, characterized in that, The organic solvent is dichloroethane.

5. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1 or 4, characterized in that, The mass ratio of the organic solvent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1:1 to 3:

1.

6. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1, characterized in that, The chlorinating agent is one or more of thionyl chloride, phosphorus trichloride, phosphorus pentachloride, or phosphorus oxychloride.

7. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1 or 6, characterized in that, The molar ratio of the chlorinating agent to 4-hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole is 1.1:1 to 1.5:

1.

8. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1, characterized in that, The chlorination reaction is carried out at a temperature of 20℃ to 40℃ for 2 hours to 4 hours.

9. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 1, characterized in that, Specifically, the steps include the following: 4-Hydroxymethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was added to an organic solvent, mixed thoroughly, cooled to -10℃ to 5℃, and then an acidic substance and a chlorination reagent were added. The temperature was then raised to 20℃ to 40℃ and maintained for chlorination. After the reaction was completed, the organic solvent was removed, and the mixture was distilled to obtain 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

10. The method for synthesizing the key intermediate of sulfonylpyrazine as described in claim 9, characterized in that, The vacuum degree of the distillation is ≤200Pa, and the pot temperature is ≤120℃.

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