Process for the preparation of a mesotrione intermediate
By optimizing the synthesis process of cyclosulfonone intermediates, replacing acetylation with formylation, and controlling the reaction conditions, the problems of multiple synthesis steps, low yield, and low purity in existing technologies have been solved, achieving efficient and safe preparation of intermediates.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-08-11
- Publication Date
- 2026-03-31
AI Technical Summary
Existing methods for synthesizing cyclosulfonone intermediates involve multiple steps, resulting in insufficient yield and purity, and complex post-processing, especially the use of aluminum reagents which increases the difficulty.
The more reactive formylation reaction was used instead of acetylation. By controlling the reaction temperature and reagent ratio, the synthesis steps were simplified and the reaction efficiency was improved. The ratio of formylation reagent, catalyst and substrate was (2.8-3.2):(1-1.1):(0.95-1.1), the reaction temperature was 45-55℃, the reaction time was 8-12h, and the hydrogen peroxide ratio was 1:(2.3-2.6) and controlled at 45℃ to avoid the generation of byproducts.
It improved the yield and purity of cyclosulfonone intermediates, simplified the synthesis steps, reduced the generation of byproducts, and improved reaction safety and efficiency.
Smart Images
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical technology, particularly to the field of IPC C07C315, and more specifically, to a method for preparing a cyclic sulfonone intermediate. Background Technology
[0002] Cyclosulfonone was independently developed by Bayer in 2007. Cyclosulfonone has higher activity than mesotrione, is safe for crops, and is mainly used for weed control in corn fields. It has a broad spectrum of weed control. 2-Chloro-3-methyl-4-methylsulfonylbenzoic acid is a key intermediate in the synthesis of cyclosulfonone, but the existing technology involves many steps in the synthesis of this intermediate, and the yield and purity are not high enough.
[0003] CN 115232039 B discloses a method for preparing methyl 3-methyl-2-chloro-4-methylsulfonylbenzoate, an intermediate for the synthesis of benzoylcyclohexanediones. The method includes the following steps: (1) using sulfuric acid as an acid catalyst, and slowly adding concentrated nitric acid to the raw material 3-methyl-2-chloro-4-methylthioacetophenone at a temperature of 40-80°C to carry out an oxidation reaction to generate 3-methyl-2-chloro-4-methylsulfinylbenzoic acid; (2) adding anhydrous methanol to carry out an esterification reaction to generate methyl 3-methyl-2-chloro-4-methylsulfinylbenzoate; (3) adding an oxidant to carry out an oxidation reaction to generate methyl 3-methyl-2-chloro-4-methylsulfonylbenzoate. However, this invention involves acetylation, which requires two oxidation steps to obtain the product, increasing the reaction steps. It also involves adding aluminum to adjust the pH, and the subsequent quenching of aluminum also increases the difficulty of post-processing. Summary of the Invention
[0004] This invention provides a method for preparing a cyclic sulfonone intermediate, comprising the following steps:
[0005] S1, 3-chloro-2-methylaniline, hydrochloric acid and purified water are placed in a reaction vessel, stirred and cooled, and NaNO2 solution is added dropwise. After the addition is complete, the temperature is kept warm and the reaction continues. CH3SNa aqueous solution is added under controlled temperature. After the addition is complete, the temperature is raised and the reaction continues for 6-10 hours. After the reaction is completed, 1-chloro-2-methylanisole is obtained by extraction, washing with water and distillation.
[0006] S2, under a nitrogen atmosphere, at 0-10℃, the formylation reagent is added to the reaction vessel, the catalyst is added dropwise and stirred, then 1-chloro-2-methylbenzyl sulfide is added dropwise, the temperature is raised to carry out the reaction, and after post-treatment, 2-chloro-3-methyl-4-methylthiobenzaldehyde is obtained.
[0007] S3, under a nitrogen atmosphere, methanol, 2-chloro-3-methyl-4-methyl sulfide benzaldehyde, and sodium tungstate dihydrate were added to a reaction vessel, hydrogen peroxide was added dropwise, the reaction temperature was controlled, the reaction was carried out, and after washing with water, stirring, and filtering, the filter cake was obtained.
[0008] Existing technologies often employ acetylation, which, due to its low reactivity, requires two oxidation steps, increasing the synthesis process. Furthermore, the post-processing, involving the use of aluminum reagents to adjust the pH, is difficult to quench, further complicating the process. This invention utilizes more reactive formylation, enabling one-step oxidation of the product. However, this higher reactivity also makes it more susceptible to affecting reaction byproducts, purity, and yield. The applicant's research has found that a reaction temperature of 45-55℃ and a reaction time of 8-12 hours in S2 can improve reaction efficiency while avoiding the generation of byproducts. Further research has revealed that the weight ratio of formylation reagent, catalyst, and 1-chloro-2-methylbenzyl sulfide in S2 is (2.8-3.2):(1-1.1):(0.95-1.1), which reduces byproducts while improving catalytic effect, thereby increasing product yield.
[0009] The applicant's research found that in S3, when the weight ratio of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde to hydrogen peroxide is 1:(2.3-2.6), and the reaction temperature is controlled at 45°C, the reaction efficiency and safety can be improved, and the amount of hydrogen peroxide used can be reduced. When the reaction temperature increases by 10°C, the amount of hydrogen peroxide used increases by 20%. At the same time, the higher temperature and the amount of hydrogen peroxide used increase the degree of danger of the reaction.
[0010] Preferably, the formylation agent includes one of Vilsmeier reagent (chloroimine salt) and N,N-disubstituted formamide.
[0011] Preferably, the catalyst comprises one of phosphorus oxychloride, thionyl chloride, and oxalyl chloride.
[0012] More preferably, the catalyst comprises phosphorus oxychloride, and the formylation agent comprises N,N-dimethylformamide.
[0013] Preferably, the post-treatment in S2 includes: after cooling, adding water and dichloroethane in sequence, stirring for 20-40 minutes, allowing it to stand, separating the organic phase, and performing vacuum distillation.
[0014] Preferably, the weight ratio of water to dichloroethane is 1:(0.8-1.2).
[0015] More preferably, the weight ratio of water to dichloroethane is 1:1.
[0016] Preferably, the weight ratio of the formylation reagent, catalyst, and 1-chloro-2-methylbenzyl sulfide in S2 is (2.8-3.2):(1-1.1):(0.95-1.1).
[0017] More preferably, the weight ratio of the formylation reagent, the catalyst, and 1-chloro-2-methylbenzyl sulfide in S2 is 180:65:61.
[0018] The reaction temperature in S2 is 45-55℃, and the reaction time is 8-12h.
[0019] Preferably, the reaction temperature in S2 is 50°C and the reaction time is 10 hours.
[0020] The dropping rate of 1-chloro-2-methylbenzyl sulfide in S2 is 10-2000 g / min.
[0021] The weight ratio of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde and hydrogen peroxide in S3 is 1:(2.3-2.6).
[0022] Preferably, the weight ratio of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde and hydrogen peroxide in S3 is 1:2.5.
[0023] The reaction temperature in S3 is 40-50℃.
[0024] Preferably, the reaction temperature in S3 is 45°C.
[0025] Beneficial effects
[0026] 1. The reaction temperature in S2 is 45-55℃ and the reaction time is 8-12h, which can improve the reaction efficiency and avoid the generation of by-products.
[0027] 2. The weight ratio of the formylation reagent, catalyst, and 1-chloro-2-methylbenzyl sulfide in S2 is (2.8-3.2):(1-1.1):(0.95-1.1), which can reduce the number of synthesis steps, reduce by-products, improve the catalytic effect, reduce the amount of catalyst used, and thus increase the yield of the product.
[0028] 3. When the weight ratio of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde to hydrogen peroxide in S3 is 1:(2.3-2.6), and the reaction temperature is controlled at 45℃, the reaction efficiency can be improved, the reaction safety can be improved, and the amount of hydrogen peroxide used can be reduced. Attached Figure Description
[0029] Figure 1 This is the reaction formula for S1 in Example 1.
[0030] Figure 2 This is the reaction formula for S2 in Example 1.
[0031] Figure 3 This is the reaction formula for S3 in Example 1.
[0032] Figure 4 This is the HPLC spectrum of the product of reaction S1 in Example 1.
[0033] Figure 5 The image shows the HPLC spectrum of the S2 reaction product in Example 1.
[0034] Figure 6 The image shows the HPLC spectrum of the S2 reaction product in Comparative Example 1.
[0035] Figure 7 The image shows the HPLC spectrum of the S2 reaction product in Comparative Example 1.
[0036] Figure 8 The image shows the HPLC spectrum of the S2 reaction product in Comparative Example 1.
[0037] Figure 9 The image shows the HPLC spectrum of the product of reaction S3 in Example 1. Detailed Implementation
[0038] Example 1
[0039] A method for preparing a cyclic sulfonone intermediate includes the following steps:
[0040] S1, as Figure 1 As shown, 70 kg of 3-chloro-2-methylaniline, 120 kg of 35 wt% HCl, and 150 kg of purified water were placed in a 500 L reactor and stirred. The mixture was cooled to 0 °C, and 120 kg of 30% NaNO₂ solution was slowly added dropwise (the addition was completed in 1 hour). After the addition was complete, the reaction was continued at 0 °C for 3 hours. Then, 200 kg of 20% CH₃SNa aqueous solution was added. After the addition was complete, the temperature was raised to 25 °C and the reaction continued for 8 hours. After the reaction was completed, the mixture was extracted with 3 × 80 L of toluene, and the organic phase was washed with 3 × 50 L of water. The product was then distilled under reduced pressure to obtain 70 kg of 1-chloro-2-methylanisole. Figure 4 The figure shows the purity obtained from the corresponding HPLC test.
[0041] S2, as Figure 2 As shown, under nitrogen protection and at 0°C, 1800 kg of DMF (N,N-dimethylformamide) was added to a reaction vessel, followed by the dropwise addition of 650 kg of phosphorus oxychloride over 3 hours with stirring for 20 minutes. Then, 610 kg of 1-chloro-2-methylbenzyl sulfide was added dropwise over 2 hours. After the addition was complete, the reaction temperature was raised to 50°C and the reaction continued for 10 hours. After the reaction was complete, the reaction temperature was lowered to 0°C, and then 1000 kg of water and 1000 kg of dichloroethane were added sequentially, stirred for 30 minutes, and allowed to stand. The organic phase was then separated and distilled under reduced pressure to obtain 720 kg of 2-chloro-3-methyl-4-methylthiobenzaldehyde. Figure 5 The figure shows the purity obtained from the corresponding HPLC test.
[0042] S3, as Figure 3 As shown, under nitrogen protection, 1200 L of methanol, 720 kg of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde, and 10 kg of sodium tungstate dihydrate were added to a reaction vessel. Then, 1800 kg of hydrogen peroxide (concentration: 30%) was added dropwise to the reaction. The reaction temperature was controlled at 45℃. After 6 hours of reaction, 1000 L of water was added to the reaction mixture, stirred, and filtered. The filter cake was 800 kg of 2-chloro-3-methyl-4-methylsulfonylbenzoic acid. Figure 9 The figure shows the purity obtained from the corresponding HPLC test.
[0043] Comparative Example 1
[0044] The specific implementation method is the same as in Example 1; the difference is that the reaction temperature in S2 in Comparative Example 1 is 70°C. Figure 6 The figure shows the purity obtained from the corresponding HPLC test.
[0045] Comparative Example 2
[0046] The specific implementation method is the same as in Example 1; the difference is that the reaction temperature in S2 in Comparative Example 2 is 90°C. Figure 7 The figure shows the purity obtained from the corresponding HPLC test.
[0047] Comparative Example 3
[0048] The specific implementation method is the same as in Example 1; the difference is that the amount of phosphorus oxychloride used in Comparative Example 3 is 845 kg. Figure 8 The figure shows the purity obtained from the corresponding HPLC test.
[0049] Comparative Example 4
[0050] The specific implementation method is the same as in Example 1; the difference is that, in S3 of Comparative Example 4, under nitrogen protection, 1200L of methanol, 720kg of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde, and 10kg of sodium tungstate dihydrate were added to the reaction vessel, and then 2160kg of hydrogen peroxide (concentration: 30%) was added dropwise to the reaction. The reaction temperature was controlled at 60℃. After reacting for 5 hours, 1000L of water was added to the reaction, stirred, and filtered. The filter cake was 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.
[0051] Comparative Example 5
[0052] The specific implementation method is the same as in Example 1; the difference is that, in S3 of Comparative Example 5, under nitrogen protection, 1200L of methanol, 720kg of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde, and 10kg of sodium tungstate dihydrate were added to the reaction vessel, and then 1980kg of hydrogen peroxide (concentration: 30%) was added dropwise to the reaction. The reaction temperature was controlled at 60℃. After reacting for 5 hours, 1000L of water was added to the reaction, stirred, and filtered. The filter cake was 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.
[0053] Comparative Example 6
[0054] The specific implementation method is the same as in Example 1; the difference is that, in S3 of Comparative Example 6, under nitrogen protection, 1200L of methanol, 720kg of 2-chloro-3-methyl-4-methyl sulfide benzaldehyde, and 10kg of sodium tungstate dihydrate were added to the reaction vessel, and then 2340kg of hydrogen peroxide (concentration: 30%) was added dropwise to the reaction. The reaction temperature was controlled at 60℃. After reacting for 5 hours, 1000L of water was added to the reaction, stirred, and filtered. The filter cake was 2-chloro-3-methyl-4-methylsulfonylbenzoic acid.
[0055] Performance testing methods
[0056] Performance tests were conducted on the examples and comparative examples, and the test data are listed in Table 1.
[0057] Table 2 is... Figure 4 Data analysis; Table 3 shows Figure 5 Data analysis; Table 4 is Figure 6 Data analysis; Table 5 shows... Figure 7 Data analysis; Table 6 is Figure 8 Data analysis; Table 7 shows... Figure 9 Data analysis.
[0058] Performance test data
[0059] Table 1
[0060]
[0061]
[0062] Table 2
[0063]
[0064] Table 3
[0065]
[0066] Table 4
[0067]
[0068] Table 5
[0069]
[0070] Table 6
[0071]
[0072] Table 7
[0073]
Claims
1. A process for the preparation of an intermediate of tembotrione characterized in that, The method comprises the following steps: S1, 3-chloro-2-methyl aniline, hydrochloric acid and pure water are placed in a reaction kettle, stirred, cooled, and NaNO2 solution is added dropwise, after dropwise addition is completed, the reaction is continued, CH3SNa aqueous solution is added under temperature control, after dropwise addition is completed, the temperature is increased, and the reaction is continued for 6-10 h; after the reaction is completed, extraction, water washing and distillation are sequentially performed to obtain 1-chloro-2-methyl benzyl sulfide; S2, under a nitrogen atmosphere, formylation reagent is added to a reaction kettle, a catalyst is added dropwise and stirred, 1-chloro-2-methyl benzyl sulfide is added dropwise, the temperature is increased, and the reaction is performed; after treatment, 2-chloro-3-methyl-4-methylthio benzaldehyde is obtained; S3, under a nitrogen atmosphere, methanol, 2-chloro-3-methyl-4-methylthio benzaldehyde, and sodium tungstate dihydrate are added to a reaction kettle, hydrogen peroxide is added dropwise, the reaction temperature is controlled, and the reaction is performed; after water washing and stirring, filtration is performed, and the filter cake is obtained; The weight ratio of the formylation reagent, the catalyst and 1-chloro-2-methyl benzyl sulfide in S2 is (2.8-3.2):(1-1.1):(0.95-1.1); the reaction temperature in S2 is 45-55 DEG C, and the reaction time is 8-12 h; the weight ratio of 2-chloro-3-methyl-4-methylthio benzaldehyde and hydrogen peroxide in S3 is 1:(2.3-2.6); the reaction temperature in S3 is 40-50 DEG C; The formylation reagent comprises N,N-disubstituted formamide. The catalyst comprises phosphorus oxychloride.
2. A process for the preparation of a mesotrione intermediate according to claim 1, characterized by, The formylation reagent comprises N,N-dimethylformamide.
3. The method for preparing a cyclic sulfonone intermediate according to claim 1, characterized in that, The post-treatment in S2 comprises the following steps: after cooling, water and dichloroethane are sequentially added, stirring is performed for 20-40 min, after standing, the organic phase is separated, and vacuum distillation is performed.
4. The method for preparing a cyclic sulfonone intermediate according to claim 1, characterized in that, The dropwise addition speed of 1-chloro-2-methyl benzyl sulfide in S2 is 10-2000 g / min.
Citation Information
Patent Citations
Preparation method of tembotrione
CN117126084A