Green synthesis process of pyraclostrobin
By replacing dimethyl sulfate with N,N-dimethylformamide dimethyl acetal and organic amine catalysts, the safety and environmental protection issues in the synthesis of pyraclostrobin have been solved, achieving high yield and high purity of pyraclostrobin, which is suitable for industrial application.
Patent Information
- Application Number
- CN202510948820.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-07-10
- Publication Date
- 2025-10-31
AI Technical Summary
Existing methods for synthesizing pyraclostrobin use highly toxic dimethyl sulfate, which poses problems such as poor safety, high hazardous waste treatment costs, and impacts product quality.
Pyrazosulfuron was prepared by replacing dimethyl sulfate with N,N-dimethylformamide dimethyl acetal as a raw material and using organic amine compounds as catalysts for etherification reaction.
It improves process safety and environmental friendliness, reduces wastewater treatment costs, and significantly increases product yield and purity, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pesticide preparation technology, and in particular to a green synthesis process for pyraclostrobin. Background Technology
[0002] Pyraclostrobin, chemically known as N-[2-[[1-(4-chlorophenyl)pyrazol-3-yl]oxymethyl]phenyl]-N-methoxycarbamate, is a methoxyacrylate fungicide containing a pyrazole structure. Its mechanism of action involves inhibiting electron transfer between cytochrome b and C1 in mitochondrial respiration of pathogenic cells, preventing mitochondria from providing the energy needed for cellular metabolism, thereby achieving a fungicidal effect. Furthermore, pyraclostrobin is also a hormone-type fungicide, inducing physiological changes in crops, especially grains. For example, it can enhance the activity of nitrate reductase, increase nitrogen absorption, reduce ethylene biosynthesis, and delay crop senescence. When crops are attacked by viruses, it can also accelerate the formation of resistance proteins and promote crop growth. Pyraclostrobin has systemic properties and is both protective and curative for its target organisms. It can control plant diseases caused by various types of fungal pathogens, including Ascomycota, Basidiomycetes, Deuteromycetes, and Oomycetes. It is widely used for the prevention and control of diseases in fruit trees, vegetables, and grains. It is a fungicide with a wide range of applications, high efficiency, low toxicity, and safe action.
[0003] Currently, the industrial production method of pyraclostrobin mainly involves the etherification reaction of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound (II)) and dimethyl sulfate in an alkaline system. This method uses the highly toxic reagent dimethyl sulfate, which places high demands on process operation and wastewater treatment. Furthermore, the residual dimethyl sulfate in the product poses a certain degree of environmental hazard. Therefore, developing a green synthesis process for pyraclostrobin that uses environmentally friendly raw materials, operates under mild reaction conditions, and boasts high atom economy is of significant practical importance and meets market demand.
[0004] Summary of the Invention
[0005] To address the problems of poor safety, high hazardous waste treatment costs, and negative impacts on product quality associated with existing methods for synthesizing pyraclostrobin, this invention provides a green synthesis process for pyraclostrobin. This invention replaces highly toxic dimethyl sulfate with N,N-dimethylformamide dimethyl acetal, improving process safety, reducing environmental pollution, and achieving high product yield and purity, making it suitable for industrial production applications.
[0006] To solve the above-mentioned technical problems, the technical solution provided by the present invention is as follows:
[0007] This invention provides a green synthesis process for pyraclostrobin, comprising the following steps:
[0008] Using N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and N,N-dimethylformamide dimethyl acetal as raw materials, and organic amine compounds as catalysts, pyrazolamide was obtained through an etherification reaction.
[0009] Specifically, the green synthesis process of pyraclostrobin includes the following steps:
[0010] N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and organic amine compounds were added to the reaction solvent and mixed thoroughly. N,N-dimethylformamide dimethyl acetal was then added dropwise. After the addition was complete, the temperature was raised to react and pyrazosulfuron was obtained.
[0011] Existing traditional methods for synthesizing pyraclostrobin use highly toxic dimethyl sulfate as a raw material, which not only poses a potential threat to the health of operators, but also easily causes leakage and residue during the production process, polluting the environment. Furthermore, wastewater treatment is difficult, and the process is neither economical nor environmentally friendly.
[0012] Compared with existing technologies, the synthesis process of pyraclostrobin provided by this invention uses low-toxicity N,N-dimethylformamide dimethyl acetal instead of highly toxic dimethyl sulfate, thereby improving the safety and environmental friendliness of the process from the source. Simultaneously, the use of organic amines as catalysts effectively promotes the etherification reaction, making the reaction more complete and significantly improving the yield and purity of the pyraclostrobin product. Furthermore, the etherification process is mild, greatly reducing energy consumption and equipment wear. The wastewater generated by the process is low-toxicity and easy to treat, significantly reducing wastewater treatment costs and environmental risks. It is suitable for industrial production, possessing high economic and environmental benefits, and has extremely high application value.
[0013] The reaction equation of this invention is as follows:
[0014]
[0015] Furthermore, the organic amine compound is at least one of N-methylmorpholine, 1,4-dimethylpiperazine, or triethylenediamine.
[0016] The preferred organic amine catalysts have high catalytic activity and selectivity, which can promote the etherification reaction to proceed fully and improve atom economy. At the same time, they can also effectively activate reactant molecules, enabling the etherification reaction to proceed efficiently under mild conditions, thereby increasing the reaction rate and reducing reaction energy consumption.
[0017] More preferably, the organic amine compound is 1,4-dimethylpiperazine.
[0018] Furthermore, the reaction solvent is a chlorinated hydrocarbon or an aromatic hydrocarbon.
[0019] More preferably, the chlorinated hydrocarbon is at least one of dichloromethane, 1,2-dichloroethane, trichloromethane, or carbon tetrachloride; and the aromatic hydrocarbon is at least one of benzene, toluene, xylene, or chlorobenzene.
[0020] More preferably, the chlorinated hydrocarbon is 1,2-dichloroethane, and the aromatic hydrocarbon is toluene.
[0021] The preferred reaction solvent can promote the full progress of the etherification reaction, improve the reaction selectivity, and reduce the generation of impurities.
[0022] Further, the molar ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to N,N-dimethylformamide dimethyl acetal is 1:(1-1.5).
[0023] Further, the mass ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to the organic amine compound is 1:(0.01-0.05).
[0024] Furthermore, the mass-to-volume ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to the reaction solvent is 1 g:(5-10) mL.
[0025] Furthermore, the temperature of the heating reaction is 30℃~80℃, and the reaction time is 2h~6h.
[0026] Optimized reaction conditions are beneficial for improving the yield and purity of pyraclostrobin.
[0027] It should be noted that the reaction process includes the following post-processing steps: cooling the reaction solution, adding water to dissolve it, concentrating the organic phase under reduced pressure to obtain a concentrate; adding a polar solvent to the concentrate, mixing it evenly, cooling it to crystallize, filtering it, and drying it to obtain the pyraclostrobin product.
[0028] Furthermore, the polar solvent is at least one of methanol, anhydrous ethanol, isopropanol, or acetone.
[0029] Furthermore, the temperature for the cooling crystallization is -5℃ to 25℃.
[0030] The pyraclostrobin synthesis process provided by this invention has high reaction selectivity. After the reaction is completed, only simple separation and crystallization are needed to obtain pyraclostrobin products with a content of more than 99%, which effectively simplifies the post-processing steps.
[0031] In summary, the synthesis process of pyraclostrobin provided by this invention uses the low-toxicity reagent N,N-dimethylformamide dimethyl acetal instead of the highly toxic reagent dimethyl sulfate, reducing process safety risks and the generation of saline wastewater. The solvent can be directly reused during the reaction, making it environmentally friendly. Moreover, the prepared pyraclostrobin product has high yield and purity, with a yield of over 96.5% and a purity of over 99%. It is a green production route suitable for industrialization and has broad application prospects. Detailed Implementation
[0032] 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.
[0033] This invention provides a synthesis process for pyraclostrobin, specifically including the following steps:
[0034] N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and organic amine compounds were added to the reaction solvent and mixed thoroughly. N,N-dimethylformamide dimethyl acetal was then added dropwise. After the addition was complete, the temperature was raised to react the mixture. After post-treatment, pyrazosulfuron was obtained.
[0035] Furthermore, the organic amine compound is at least one of N-methylmorpholine, 1,4-dimethylpiperazine, or triethylenediamine.
[0036] To address the problems of poor environmental friendliness, high hazardous waste treatment costs, and negative impacts on product quality associated with existing pyraclostrobin synthesis processes, this invention innovatively proposes a novel pyraclostrobin synthesis route. This route uses N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and N,N-dimethylformamide dimethyl acetal as raw materials, and organic amine compounds as catalysts, to produce pyraclostrobin via an etherification reaction. Compared to traditional processes, the pyraclostrobin synthesis route provided by this invention has significant advantages:
[0037] In terms of environmental friendliness, this invention uses low-toxic raw materials instead of the highly toxic reagent dimethyl sulfate, and the organic amine catalyst is low in toxicity and easily degraded in the environment, significantly reducing damage to the ecological environment and the cost of hazardous waste treatment, while improving process safety. Regarding product quality improvement, the organic amine catalyst selected in this invention has high catalytic selectivity, which can promote the full progress of the etherification reaction and significantly reduce the occurrence of side reactions. Furthermore, enterprises do not need to invest large sums of money in hazardous waste treatment, further reducing overall production costs, improving production efficiency, and achieving a win-win situation for both environmental and economic benefits.
[0038] To better illustrate the present invention, further examples are provided below.
[0039] Example 1
[0040] This embodiment provides a synthesis process for pyraclostrobin, including the following steps:
[0041] 74.8 g (0.2 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 500 mL of dichloromethane, followed by 1.8 g of N-methylmorpholine. The mixture was stirred until homogeneous, and then 28.6 g (0.24 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise at 25–30 °C. After the addition was complete, the mixture was heated to 40 °C and reacted for 4 h. Under controlled temperature (C), the reaction was completed. The mixture was cooled to 25°C, and 250 mL of water was added to wash the material. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a light yellow transparent oily substance. 180 mL of acetone was added, and the mixture was stirred to dissolve it into a homogeneous liquid. The mixture was slowly cooled to 25°C and stirred to crystallize. The mixture was filtered at 0°C and dried under vacuum at 30–35°C to obtain compound (Ⅰ), namely pyraclostrobin, a light yellow crystalline powder, weighing 75.72 g. The HPLC external standard content was 99.17%, and the yield was 96.82%.
[0042] 1 H NMR(400MHz, CDCl3)δ:7.65-7.69(m,2H),7.61-7.55(m,2H),7.35-7.40(m,4H) ),7.34(s,1H),5.92(d,J=2.4Hz,1H),5.34(s,2H),3.79(s,3H),3.76(s,3H).
[0043] LC-MS[M+H] + 388.81.
[0044]
[0045] Example 2
[0046] This embodiment provides a synthesis process for pyraclostrobin, including the following steps:
[0047] 74.8 g (0.2 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 600 mL of toluene, followed by 2.0 g of triethylenediamine. The mixture was stirred until homogeneous, and 31 g (0.26 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise at 25–30 °C. After the addition was complete, the mixture was heated to 50 °C and reacted for 5 h. The reaction was detected by HPLC and found to be complete. The mixture was then cooled to 25 °C, and 300 mL of water was added to wash the mixture. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a light yellow transparent oily substance. 250 mL of anhydrous ethanol was added, and the mixture was stirred to dissolve it into a homogeneous liquid. The mixture was slowly cooled to 15 °C and stirred to crystallize. The mixture was filtered at 0–5 °C and dried under vacuum at 30–35 °C to obtain 75.67 g of compound of formula (I), namely pyrazoloxyfen, a light yellow crystalline powder. The HPLC external standard content was 99.04%, and the yield was 96.63%.
[0048]
[0049] Example 3
[0050] This embodiment provides a synthesis process for pyraclostrobin, including the following steps:
[0051] 74.8 g (0.2 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 380 mL 1.5 g of 1,4-dimethylpiperazine was added to 1,2-dichloroethane and stirred until homogeneous. 26.2 g (0.22 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise at 25–30 °C. After the addition was complete, the mixture was heated to 45 °C and reacted for 4 h. The reaction was detected by HPLC and found to be complete. The mixture was then cooled to 25 °C, and 200 mL of water was added to wash the mixture. The liquid was separated, and the organic phase was concentrated under reduced pressure to obtain a light yellow, transparent oily substance. 250 mL of methanol was added, and the mixture was stirred to dissolve it into a homogeneous liquid. The mixture was slowly cooled to 20 °C and stirred to crystallize. The crystals were filtered at 0–5 °C and dried under vacuum at 30–35 °C to obtain 75.73 g of compound (I), namely pyraclostrobin, a light yellow crystalline powder. The HPLC external standard content was 99.28%, and the yield was 96.94%.
[0052]
[0053] Example 4
[0054] This embodiment provides a synthesis process for pyraclostrobin, including the following steps:
[0055] 74.8 g (0.2 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 525 mL of carbon tetrachloride, followed by 0.8 g of N-methylmorpholine. The mixture was stirred and stirred until homogeneous. 33.4 g (0.28 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise at 25–30 °C. After the addition was complete, the mixture was heated to 35 °C and reacted for 6 h. The reaction was detected by HPLC and found to be complete. The mixture was cooled to 25 °C, and 250 mL of water was added to wash the mixture. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a light yellow transparent oily substance. 180 mL of acetone was added, and the mixture was stirred to dissolve it into a homogeneous liquid. The mixture was slowly cooled to 0 °C and stirred to crystallize. The mixture was filtered at 0 °C and dried under vacuum at 30–35 °C to obtain 75.64 g of compound of formula (I), namely pyrazolyl ether, as a light yellow crystalline powder. The HPLC external standard content was 99.18%, and the yield was 96.72%.
[0056]
[0057] Example 5
[0058] This embodiment provides a synthesis process for pyraclostrobin, including the following steps:
[0059] 74.8 g (0.2 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 700 mL of benzene, followed by 3.74 g of 1,4-dimethylpiperazine. The mixture was stirred until homogeneous, and then 35.7 g (0.3 mol) of N,N-dimethylformamide dimethyl acetal (DMF-DMA) was added dropwise at 25–30 °C. After the addition was complete, the mixture was heated to 80 °C and reacted for 2 h. Under controlled temperature (C), the reaction was completed. The mixture was cooled to 25°C, and 250 mL of water was added to wash the material. The mixture was separated, and the organic phase was concentrated under reduced pressure to obtain a light yellow transparent oily substance. 250 mL of isopropanol was added, and the mixture was stirred to dissolve it into a homogeneous liquid. The mixture was slowly cooled to 10°C and stirred to crystallize. The mixture was filtered at 0°C and dried under vacuum at 30–35°C to obtain compound (Ⅰ), namely pyraclostrobin, a light yellow crystalline powder, weighing 75.61 g. The HPLC external standard content was 99.06%, and the yield was 96.57%.
[0060]
[0061] Comparative Example 1
[0062] This comparative example provides a synthesis process for pyraclostrobin, which differs from Example 1 only in that N-methylmorpholine is not added; otherwise, the process is identical. HPLC control detection confirmed that no pyraclostrobin was generated.
[0063] Comparative Example 2
[0064] This comparative example provides a synthesis process for pyraclostrobin, the specific steps of which are as follows:
[0065] 74.8 g (0.20 mol) of N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate (compound of formula (II)) was added to 525 mL of xylene, followed by 0.75 g of tetrabutylammonium bromide. The mixture was stirred until homogeneous, heated to 65 °C, and then 27.7 g (0.22 mol) of dimethyl sulfate was added. 96 g (0.24 mol) of a 10% NaOH aqueous solution was then added dropwise. After the addition was complete, the reaction was maintained at this temperature for 5 h. The reaction was monitored by PLC and found to be complete. 150 mL of water was added to wash the material, and the mixture was separated. The organic phase was concentrated under reduced pressure to obtain a brownish-yellow oily substance. 150 mL of methanol was added, and the mixture was stirred to dissolve. The temperature was slowly lowered to 22°C, and the mixture was stirred to crystallize. A large amount of white solid precipitated out, which was difficult to stir. The mixture was filtered at 8°C and dried under vacuum at 30-35°C to obtain compound (Ⅰ), namely pyraclostrobin, a white powder solid of 75.09 g. The HPLC external standard content was 97.84%, and the yield was 94.72%.
[0066] The above Examples 1-3, using other raw material ratios and solvent addition amounts as defined in this invention, as well as other types of reaction solvents and organic amine compounds, can achieve technical effects that are basically equivalent to those in Examples 1-3.
[0067] 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 green synthesis process for pyraclostrobin, characterized in that, Using N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and N,N-dimethylformamide dimethyl acetal as raw materials, and organic amine compounds as catalysts, pyrazolamide was obtained through an etherification reaction.
2. The green synthesis process of pyraclostrobin as described in claim 1, characterized in that, Specifically, the following steps are included: N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate and organic amine compounds were added to the reaction solvent and mixed thoroughly. N,N-dimethylformamide dimethyl acetal was then added dropwise. After the addition was complete, the temperature was raised to react and pyrazosulfuron was obtained.
3. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, The organic amine compound is at least one of N-methylmorpholine, 1,4-dimethylpiperazine, or triethylenediamine; and / or The reaction solvent is a chlorinated hydrocarbon or an aromatic hydrocarbon.
4. The green synthesis process of pyraclostrobin as described in claim 3, characterized in that, The organic amine compound is 1,4-dimethylpiperazine; and / or The chlorinated hydrocarbon is at least one of dichloromethane, 1,2-dichloroethane, trichloromethane, or carbon tetrachloride; the aromatic hydrocarbon is at least one of benzene, toluene, xylene, or chlorobenzene.
5. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, The molar ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to N,N-dimethylformamide dimethyl acetal is 1:(1-1.5).
6. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, The mass ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to the organic amine compound is 1:(0.01-0.05).
7. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, The mass-to-volume ratio of the N-hydroxy-N-2-[(N-p-chlorophenyl)-3-pyrazoloxymethyl]phenylcarbamate to the reaction solvent is 1 g:(5-10) mL.
8. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, The temperature of the heating reaction is 30℃~80℃, and the reaction time is 2h~6h.
9. The green synthesis process of pyraclostrobin as described in claim 2, characterized in that, After the reaction is complete, the following post-processing steps are also included: cooling the reaction solution, adding water to dissolve it, concentrating the organic phase under reduced pressure to obtain a concentrate; adding a polar solvent to the concentrate, mixing it evenly, cooling it to crystallize, filtering it, and drying it to obtain the pyraclostrobin product.
10. The green synthesis process of pyraclostrobin as described in claim 9, characterized in that, The polar solvent is at least one of methanol, anhydrous ethanol, isopropanol, or acetone; and / or The cooling crystallization temperature is -5℃ to 25℃.