Synthesis method for azoxystrobin

Abstract

Provided is a synthesis method for azoxystrobin, comprising: in a water-oil system of an organic solvent and an aqueous solution of trimethylamine, a compound represented by formula I reacts with 2-cyanophenol to obtain azoxystrobin, wherein the molar ratio of the compound represented by formula I to trimethylamine is 1:(0.96-2). The synthesis method has high reaction efficiency, does not produce CO2, avoids the risks of entrainment and overflow, reduces the generation of side reactions and solid waste emissions and is environmentally friendly. In addition, the method does not require the use of solid sodium carbonate or potassium carbonate, and the material reaction system is an oil-water reaction system, so that the reaction efficiency is greatly improved, and the yield can also be maintained at 95% or more, thereby taking both the efficiency (timeliness) and the yield into account and easily achieving continuous reaction, and thus providing technical support for intelligent and unmanned production. Moreover, since trimethylamine can be recycled, the use of one raw material is reduced, and further there is no need for complicated treatment for mixed salts and waste water thereof, thereby significantly reducing the energy consumption.

Description

A method for synthesizing pyraclostrobin

[0001] Cross-references

[0002] This application claims priority to Chinese Patent Application No. 202411979270.1, filed on December 31, 2024, entitled "A Method for Synthesizing Azoxystrobin", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to the field of pesticide technology, and in particular to a method for synthesizing pyraclostrobin. Background Technology

[0004] (E)-2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate is a highly effective, broad-spectrum agricultural fungicide with multiple functions including systemic action, prevention, protection, and treatment. It exhibits good control efficacy against powdery mildew, rust, glume blight, downy mildew, and rice blast. Currently reported synthetic processes involve the preparation of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate (compound I) with 2-cyanophenol and solid carbonate in a near-anhydrous organic solvent and in the presence of a catalyst, or with (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate and an alkali metal salt of 2-cyanophenol. However, current reaction routes still have a series of problems:

[0005] For example, patents WO9208703 and EP0382375 both use a mixture of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate and o-hydroxybenzonitrile, with potassium carbonate added as an acid-binding agent, cuprous chloride as a catalyst, and DMF as a solvent, reacting at 120°C. However, this route is difficult to process and crystallize (crystallization at room temperature takes 3 weeks), making it unsuitable for large-scale industrial production. The process route is as follows:

[0006] For example, patent CN101163682B discloses the reaction of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate and 2-cyanophenol in DMF slurry in the presence of an acid acceptor (potassium carbonate or sodium carbonate) using DABCO as a catalyst to obtain azoxystrobin, as in step c) of Example 1. The reaction liquid in slurry state removes DMF under vacuum distillation. The resulting distillation residue has a high solid content, requiring high power for the stirring equipment. The reaction process will emit CO2 products. 160 mL of toluene and 265 mL of water (total amount of reaction raw materials 167 g) are added to the distillation residue at 60 °C. The mixture of the two phases is then heated to 70-80 °C and stirred for 40 minutes. The mixture is then allowed to settle, and the lower aqueous phase is separated. The post-processing involves a large amount of solvent and water. The added water is used to dissolve excess acid acceptors (potassium carbonate or sodium carbonate) and the resulting potassium chloride, potassium bicarbonate, or sodium chloride and sodium bicarbonate. It is evident that the post-processing of the target product is cumbersome and time-consuming. The generated mixed salts also require the addition of hydrochloric acid to form a single salt. A large amount of CO2 is emitted during the process. The brine needs to be heated, distilled, and separated. The process involves many equipment, is not easy to be continuous, consumes a lot of energy, and involves many steps. It is difficult to achieve intelligent and continuous industrial production, requires a large number of operators, and has high costs.

[0007] For example, patent CN109721548B discloses a reaction of 2-cyanophenol or its salt with (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl)phenyl]-3-methoxyacrylate in the presence of an acid acceptor (potassium carbonate or sodium carbonate) using trimethylamine as a catalyst to obtain azoxystrobin. The amount of trimethylamine used is 0.5-15 mol% of (E)-2-[2-(6-chloropyrimidin-4-yloxy)phenyl)phenyl]-3-methoxyacrylate, the acid acceptor is potassium carbonate and / or sodium carbonate, the reaction is carried out at 50-120℃, and usually takes 5-20 hours to complete. In Example 1, after the reaction was completed, 100g of water was added. The total amount of raw materials fed at the beginning of the reaction was 145.5g. It can be seen that the water was added to dissolve the excess acid acceptor (potassium carbonate or sodium carbonate) and by-product salt. The oil phase and water phase were obtained by separation. Although the treatment technology of the water phase was not described, according to the knowledge of those skilled in the art, the treatment method has the same unresolved technical problem as patent CN101163682B.

[0008] In the above-mentioned technical solutions, the reaction system materials are often 2-cyanophenol or its salt and (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxymethyl acrylate as raw materials, and potassium carbonate and sodium carbonate as acid binders (or acid acceptors). Although this technical solution can achieve a relatively high yield of azoxystrobin, the reaction process is a solid-liquid mixture system, mainly a batch reaction. It not only requires a solid feeding device, but also has problems such as the emission of CO2 by-products during the reaction, long reaction time, low production efficiency and high energy consumption. If continuous operation is carried out, not only will the required equipment be complex, but the investment cost of the corresponding mass transfer equipment will also be higher, increasing costs and making it unsuitable for industrial production. Many technicians have also tried to improve its production efficiency to better carry out industrial production, and have tried in many aspects such as catalysts and reaction raw materials, but have not yet found a way to solve the above problems, that is, it is difficult to simultaneously achieve both yield and timeliness.

[0009] Since the synthesis of azoxystrobin is generally carried out in the organic phase, the carbonate used as an acid-binding agent has low solubility in organic solvents such as toluene and DMF, and exists basically in the solid state, forming a solid-liquid heterogeneous slurry reaction system. The reaction rate with 2-cyanophenol is slow. Even if 2-cyanophenol is fed directly as a potassium or sodium salt, the solubility of the potassium or sodium salt of 2-cyanophenol in organic solvents is also reduced, still resulting in a solid-liquid heterogeneous slurry reaction system. The condensation reaction with (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate is slow, which reduces the reaction efficiency. Existing literature and patents indicate that when sodium carbonate or potassium carbonate are used as acid-binding agents, the presence of a large amount of water creates alkaline conditions. During the high-temperature heating process, (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate methyl ester readily undergoes hydrolysis, producing byproducts and thus reducing the reaction yield. Therefore, anhydrous or low-aqueous organic solvent reaction systems are generally used. Although a series of problems exist in solid-liquid mixed reactions, using sodium carbonate or potassium carbonate as acid-binding agents remains the recognized choice for obtaining azoxystrobin in high yields. Therefore, many researchers hope to improve the production efficiency through catalyst selection.

[0010] However, the above technical solutions still have the following problems: Production requires costly mass transfer equipment; the reaction process releases a large amount of greenhouse gas CO2, necessitating an additional tail gas treatment system; and CO2 overflow is prone to risks such as solvent entrainment, foaming, and spillage. Furthermore, 2-cyanophenol is prone to cyano polymerization at high temperatures during the reaction, especially under alkaline conditions, where excessively high temperatures and prolonged reaction times can lead to varying degrees of polymerization. As temperature and time increase, the degree of polymerization increases, resulting in more byproducts and reduced yield or purity. When the reaction time is too long, the raw material (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate will undergo hydrolysis or alcoholysis. The post-treatment slurry reaction solution requires the addition of a large amount of water for dissolution before separation, resulting in a mixed salt problem of chlorides, acid carbonates, and carbonate solids in the aqueous phase. Converting this mixed salt to a single chloride salt requires the addition of a large amount of hydrochloric acid, leading to high post-treatment costs and increased carbon emissions. Summary of the Invention

[0011] Purpose of the invention

[0012] To overcome the above shortcomings, the present invention aims to provide a highly efficient, resource-saving, low-solid-waste, low-capital-investment, and highly automated continuous, low-carbon, and high-efficiency method for synthesizing azoxystrobin. The inventors have discovered that by using trimethylamine aqueous solution as an acid-binding agent, the material reaction system becomes an oil-water reaction system, significantly improving reaction efficiency. Furthermore, the use of solid potassium carbonate / sodium carbonate is eliminated, and the reaction process generates and emits no CO2 gas, avoiding the risk of gas carrying liquid out of the reaction system. The oil-water reaction system equipment is more suitable for continuous production, supporting the digital, intelligent, and green transformation of industrial production, enhancing competitiveness, and achieving higher operational efficiency. Trimethylamine can be recycled, avoiding the cumbersome post-processing of mixed salts. Moreover, separation can be achieved without adding additional water to dissolve the generated chlorides, bicarbonates, and unreacted potassium carbonate / sodium carbonate, reducing water consumption, avoiding the treatment of large amounts of mixed salt wastewater, further reducing industrial energy consumption, and lowering industrial production costs.

[0013] Solution

[0014] To achieve the purpose of this application, the technical solution adopted in this application is as follows:

[0015] In a first aspect, the present invention provides a method for synthesizing azoxystrobin, comprising: reacting the compound of Formula I with 2-cyanophenol in an oil-water system of an organic solvent and an aqueous trimethylamine solution to obtain azoxystrobin;

[0016] The molar ratio of the compound shown in Formula I to trimethylamine is 1:(0.96~2).

[0017] Further, the molar ratio of the compound shown in Formula I to trimethylamine is 1:(1-2), optionally 1:(1.06-2), optionally 1:(1.1-2), optionally 1:(1.06-1.8), optionally 1:(1.1-1.8).

[0018] Further, the molar ratio of the compound shown in Formula I to 2-cyanophenol is 1:(1 to 5), optionally 1:(1 to 1.5), or optionally 1:(1 to 1.2).

[0019] Furthermore, the mass fraction of trimethylamine in the aqueous trimethylamine solution is 20%–40%, optionally 25%–40%, optionally 20%–30%, optionally 25%–30%, optionally 30%–40%.

[0020] And / or, the molar ratio of the compound shown in Formula I to water is 1:4.728 to 23.64, optionally 1:4.925 to 23.64, optionally 1:5.2205 to 23.64, optionally 1:5.66 to 23.64, optionally 1:7.65 to 23.64, optionally 1:5.66 to 15.29, optionally 1:7.65 to 15.29.

[0021] And / or, the molar percentage of water in the water-oil system is 30–60 mol%, optionally 31–60 mol%, optionally 31–54 mol%, optionally 31–53 mol%, optionally 35–53 mol%.

[0022] Furthermore, no additional sodium carbonate or potassium carbonate needs to be added, or only a very small amount needs to be added; (it should be noted that "no additional addition" means that the present invention does not require the addition of sodium carbonate or potassium carbonate as an acid-binding agent. However, it should be understood that even if a very small amount of sodium carbonate or potassium carbonate is added to the reaction system, it will have little impact on the effect of the present invention and can still solve the technical problem to be solved by the present invention, which is equivalent to substitution).

[0023] Furthermore, the amount of organic solvent added is at least the amount used to dissolve the compound shown in Formula I with 2-cyanophenol.

[0024] Further, the weight ratio of the compound shown in Formula I to the organic solvent is 1:(2-8), optionally 1:(2-5.7), optionally 1:(2-4), optionally 1:(2.3-5.7), optionally 1:(2.3-4).

[0025] Furthermore, the organic solvent includes toluene.

[0026] Optionally, the reaction is carried out in an oil-water system consisting of an organic solvent and an aqueous solution of trimethylamine.

[0027] Further, the reaction temperature is 50–170°C, optionally 88–170°C, optionally 97–170°C, optionally 110–170°C, optionally 140–170°C, optionally 140–160°C, optionally 80–150°C, optionally 80°C to reflux temperature. Optionally, it is 50°C, 80°C, 88°C, 97°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, or any range between two of these.

[0028] Furthermore, the reaction pressure is greater than atmospheric pressure, and can be optionally 0.12–1.2 MPa, optionally 0.29–1.2 MPa, optionally 0.5–1.2 MPa, or optionally 0.55–1.1 MPa.

[0029] Furthermore, the reaction time is 5 min to 360 min, optionally 15 min to 360 min, optionally 30 min to 360 min, optionally 5 min to 60 min, optionally 30 min to 60 min, and optionally 5 min to 30 min.

[0030] Furthermore, the reaction is carried out in a continuous pipeline reaction apparatus, with a pipeline temperature of 110–170°C, optionally 110–150°C, optionally 140–170°C, optionally 140–160°C, or optionally 140–150°C; and optionally a reaction pressure of 0.55–1.1 MPa, optionally 0.5–0.7 MPa.

[0031] Furthermore, a batch reaction or a continuous reaction in a kettle is adopted, with a reaction temperature of 85–150℃, optionally 85–110℃, optionally 85–97℃, or optionally 85–95℃. Optionally, the temperature can be 50℃, 80℃, 88℃, 97℃, 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, or any range between two of these. Optionally, the reaction pressure can be atmospheric pressure to 1.1 MPa, optionally greater than atmospheric pressure but ≤1.1 MPa, or optionally 0.12–1.1 MPa.

[0032] The reaction system of the present invention can significantly accelerate the reaction rate by increasing the temperature under pressure, and will not produce excessive by-products due to increasing the temperature or pressure.

[0033] Furthermore, the pipeline continuous reaction equipment includes a feed pump, a pressure relief safety valve, a static mixer, a delay pipeline, a back pressure valve, a receiving device, and a heat exchanger.

[0034] In the continuous reaction in the pipeline, the compound shown in Formula I, 2-cyanophenol and organic solvent are used as material A, and trimethylamine aqueous solution is used as material B. The mass ratio of material A to material B is 4 to 7:1, so that the molar ratio of the compound shown in Formula I to trimethylamine in the system is maintained at 1: (1 to 2), optionally 1: (1.06 to 1.8), optionally 1: (1.1 to 1.8).

[0035] Further, after the reaction is completed, post-processing is performed to obtain the azoxystrobin product; optional post-processing includes: direct separation of the material after the reaction (direct separation means without adding additional water), desolventizing the oil phase, and purification.

[0036] Optionally, purification includes redissolution (which may be done with methanol), crystallization, filtration, washing, and drying.

[0037] Furthermore, the aqueous phase after separation is subjected to trimethylamine recovery and reuse; optional recovery methods include: adjusting the pH of the aqueous phase to 2-8, concentrating it, adding alkali (optionally alkali is used to release trimethylamine), and recovering to obtain a solution containing trimethylamine.

[0038] Furthermore, in the recycling and reuse of trimethylamine, the amount of alkali added is 0.95 to 1.2 times the molar amount of the compound shown in Formula I, and optionally 1 to 1.2 times;

[0039] And / or, in the recycling and reuse of trimethylamine, the alkali is an alkali metal hydroxide, which may be sodium or an alkali (such as NaOH or KOH), or other alkalis. Beneficial effects

[0040] The synthesis method of this invention is highly efficient, resource-saving, produces very little solid waste, and has low carbon emissions. It offers high comprehensive engineering benefits, reduces capital investment, enables continuous reaction, improves reaction efficiency, provides technical support for continuous and intelligent production, achieves inherent safety design, and significantly reduces the number of employees required for industrial production. This invention uses trimethylamine aqueous solution as an acid-binding agent, eliminating the need for solid potassium carbonate or sodium carbonate, and the conversion of 2-cyanophenol to 2-cyanophenol salt. The material reaction system is an oil-water reaction system, with no CO2 emissions during the reaction process. Furthermore, trimethylamine can be recycled, reducing the use of one raw material and eliminating the need for cumbersome treatment of mixed salts and wastewater. This innovative technical solution features low energy consumption from the reaction source design. It also achieves liquid-liquid separation without the need for additional water, avoiding water waste. The oil-water reaction system used in this invention has higher mass and heat transfer efficiency than the solid-liquid slurry reaction system, resulting in shorter reaction time and reduced equipment wear. This invention does not use potassium carbonate or sodium carbonate, thus avoiding the problems of large amounts of greenhouse gas CO2 and the risk of material spillage that existing technologies generate (large amounts of greenhouse gas CO2 are not conducive to green and low-carbon transformation, requiring additional tail gas treatment systems, and the emissions may carry solvents and reaction liquids, which can easily cause spillage). It reduces the use of one raw material from the design stage, and innovatively achieves carbon emission reduction and inherent process safety through technological reform. The synthesis method of this invention can reduce the problem of cyanopolymerization of 2-cyanophenol at high temperatures, and the reaction time is greatly shortened, which can also reduce the hydrolysis or alcoholysis of compound I, thereby improving yield and purity. Attached Figure Description

[0041] One or more embodiments are illustrated by way of example with reference to the accompanying drawings, and these illustrative examples are not intended to limit the embodiments. The term "illustrative" as used herein means "serving as an example, embodiment, or illustration." Any embodiment illustrated herein as "illustrative" is not necessarily to be construed as superior to or better than other embodiments.

[0042] Figure 1 shows the changes in the material state before and after the reaction in Comparative Example 2 and Example 3 of the present invention. A represents the material state before heating in Comparative Example 2; C represents the material state during heating in Comparative Example 2; E represents the material state during the heat preservation stage in Comparative Example 2; G represents the material state after the reaction in Comparative Example 2 is complete; B represents the material state before heating in Example 3; D represents the material state during heating in Example 3; F represents the material state during the heat preservation stage in Example 3; and H represents the material state after the reaction in Example 3 is complete.

[0043] Figure 2 shows the HPLC spectrum of the organic phase after the reaction of Comparative Example 2 and the detection results. Among them, 11.528 min is the peak of azoxystrobin, 14 min is the solvent peak, and the others are impurity peaks.

[0044] Figure 3 shows the HPLC spectrum of the organic phase after the reaction in Example 3 and the detection results. Among them, 11.558 min is the peak of azoxystrobin, 14 min is the solvent peak, and the others are impurity peaks. Detailed Implementation

[0045] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this application, not all embodiments. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this application.

[0046] Furthermore, to better illustrate this application, numerous specific details are provided in the following detailed embodiments. Those skilled in the art should understand that this application can be implemented without certain specific details. In some embodiments, materials, methods, techniques, etc., well-known to those skilled in the art, are not described in detail in order to highlight the main points of this application.

[0047] Unless otherwise expressly stated, throughout the specification and claims, the term "comprising" or its variations such as "including" or "comprises" shall be understood to include the stated elements or components without excluding other elements or other components.

[0048] The (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate, 2-cyanophenol, trimethylamine, and other reagents used in the following examples are commercially available; unless otherwise specified, the reaction process and results were detected by high performance liquid chromatography (HPLC), and the content was determined by external standard method.

[0049] The compound of Formula I ((E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate) and 2-cyanophenol (the compound of Formula II) are dissolved in an organic solvent and reacted with an aqueous trimethylamine solution to generate azoxystrobin (the compound of Formula III). The reaction route is as follows:

[0050] In the following examples, the compound represented by Formula I refers to (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate.

[0051] In the following examples, the reference for the detection of byproducts is: Chen Haiyan, Tao Wenbo, Ding Kehong. Analysis of side reactions in the synthesis of azoxystrobin by liquid chromatography-mass spectrometry [J]. Pesticides, 2016, 55(10): 725-728. The structures of impurities 1 and 4 of P727 are...

[0052] In the following embodiments, system pressure refers to gauge pressure (because industrial production records are usually recorded using gauge pressure, i.e., by directly reading the gauge pressure of a pressure gauge to simplify the operation and production record-keeping of industrial workers), rather than absolute pressure (absolute pressure = gauge pressure + atmospheric pressure). For example, in embodiment 6, the pressure relief valve is set to 0.55 MPa (i.e., gauge pressure), and some embodiments are described as system pressure (e.g., the system pressure in embodiment 14 is 0.02 MPa, and the absolute pressure (reaction pressure) is 0.12 MPa).

[0053] The HPLC chromatogram conditions for the organic phase after the reaction in Example 3 and Comparative Example 2 were as follows: Agilent 1260, column: ODS-3 4.6*250mm 5μm, column temperature oven 30℃, mobile phase: acetonitrile:water:trifluoroacetic acid = 600:400:2, detection wavelength 254nm, flow rate: 1.0ml / min.

[0054] Through continuous research, the inventors discovered that using trimethylamine aqueous solution as an acid-binding agent not only transforms the material reaction system into an oil-water reaction system, significantly improving reaction efficiency, but also maintaining a yield of over 95%. This approach simultaneously balances efficiency (timeliness) and yield, and facilitates continuous reaction, making it suitable for industrial production. Further research revealed that other tertiary amines, such as triethylamine or NaOH aqueous solution, cannot achieve similar reaction effects when using trimethylamine as an acid-binding agent. Specific examples are as follows:

[0055] Example 1

[0056] A solution was prepared by adding 131 g (0.40 mol) of the compound shown in Formula I and 51.5 g (0.424 mol) of 2-cyanophenol to 301 g of toluene. Then, 83.4 g of trimethylamine aqueous solution (30% concentration, 0.424 mol) was added, and the solution was refluxed at normal pressure for 4.5 h. During the reflux process, the color of the solution gradually lightened. After the reflux was completed, the solution was cooled to 30 °C and allowed to stand directly, resulting in a clear oil and water phase. The phases were separated, and the reddish-brown oil phase was washed and then distilled under reduced pressure to remove toluene. The solution was cooled to 60–65 °C, methanol was added, and the solution was refluxed to dissolve the toluene. The solution was then cooled to approximately 0 °C and allowed to crystallize for 2 h. The crystals were then filtered, washed, and the filter cake was dried to obtain 157.6 g of azoxystrobin product with a purity of 98.7% and a yield of 96.4%.

[0057] Example 2

[0058] 131 g (0.40 mol) of the compound shown in Formula I and 55.8 g (0.46 mol) of 2-cyanophenol were added to 747 g of toluene to prepare a solution. 110.1 g (30% concentration, 0.56 mol) of trimethylamine aqueous solution was then added. During the heat treatment process, the color of the solution gradually lightened. The solution was then refluxed at normal pressure for 5 hours. After the heat treatment was completed, the temperature was lowered to 30°C and allowed to stand directly, resulting in a clear oil and water two-phase mixture. The phases were separated, and the reddish-brown oil phase was washed and then distilled under reduced pressure to remove toluene. The solution was then cooled to 60–65°C, methanol was added, and the mixture was refluxed to dissolve the toluene. The solution was then cooled to approximately -5°C and allowed to crystallize for 2 hours. The crystals were filtered, washed, and the filter cake was dried to obtain 159.2 g of azoxystrobin product with a purity of 98.1% and a yield of 96.8%.

[0059] Example 3

[0060] 131 g (0.40 mol) of the compound shown in Formula I and 55.8 g (98% purity, 0.46 mol) of 2-cyanophenol were added to 400 g of toluene to prepare a solution. Then, 78.7 g (30% purity, 0.40 mol) of trimethylamine aqueous solution was added. The solution was refluxed at normal pressure for 6 hours, during which the color of the solution gradually lightened. After reflux, the solution was cooled to 30°C and allowed to stand directly, resulting in a clear oil and water phase. The phases were separated, and the reddish-brown oil phase was washed and then distilled under reduced pressure to remove toluene. The solution was cooled to 60–65°C, methanol was added, and the solution was refluxed to dissolve it. The solution was then cooled to approximately -5°C and allowed to crystallize for 2 hours. The crystals were filtered, washed, and the filter cake was dried to obtain 157.7 g of azoxystrobin product with a purity of 97.9% and a yield of 95.7%.

[0061] Example 4

[0062] 131 g (0.40 mol) of the compound shown in Formula I, 53.4 g (0.44 mol) of 2-cyanophenol, and 500 g of toluene were added to a closed reactor to prepare a solution. After stirring evenly, 102.3 g (30% concentration, 0.52 mol) of trimethylamine aqueous solution was added. The reactor was closed, and the temperature was raised to 150℃ and maintained for 0.5 h. The system pressure was 0.55 MPa. After the reaction was completed, the temperature was lowered to about 30℃ and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The temperature was lowered to 60-65℃, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The temperature was lowered to about -5℃ and crystallized for 2 h. The mixture was filtered, washed, and the filter cake was dried to obtain 158.4 g of azoxystrobin product with a purity of 98.2% and a yield of 96.4%.

[0063] Example 5

[0064] 131 g (0.40 mol) of the compound shown in Formula I, 58.3 g (0.48 mol) of 2-cyanophenol, and 500 g of toluene were added to a closed reactor to prepare a solution. After stirring evenly, 118 g of trimethylamine aqueous solution (30% content, 0.60 mol) was added. The reactor was closed, and the temperature was raised to 160℃ and maintained for 0.25 h until the reaction was completed. The system pressure was 0.77 MPa. After the reaction was completed, the temperature was lowered to about 30℃ and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The temperature was lowered to 60-65℃, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The temperature was lowered to about -5℃ and crystallized for 2 h. The mixture was filtered, washed, and the filter cake was dried to obtain 158.2 g of azoxystrobin product with a content of 98.0% and a yield of 96.1%.

[0065] Example 6

[0066] Add 1310g (4.00mol) of the compound shown in Formula I and 544g (4.48mol) of 2-cyanophenol to 5246g of toluene, stir until dissolved, and set aside (denoted as Material A); weigh 1023g of trimethylamine aqueous solution (30% content, 5.20mol), and set aside (denoted as Material B); connect Material A and Material B to a static mixer preheated to 150℃ via metering pumps, respectively. Connect the outlet of the static mixer to a sealed reaction vessel, close the pressure relief valve at the outlet of the reaction vessel and set the pressure to 0.55MPa. The outlet of the feed pipe is located at the bottom of the reaction vessel. The discharge pipe is located above the liquid surface. The feed mass ratio of material A to material B is 6.94:1. Adjust the appropriate feed flow rate and control the residence time of the materials in the reactor to 0.5 hours. After stable operation, continuously collect material from the discharge port, cool it down, and let it stand directly to obtain clear oil and water phases. Separate the phases. After washing, remove toluene by vacuum distillation of the oil phase, cool it to 60-65°C, add methanol, heat it up and reflux to dissolve it, cool it down to about -5°C, crystallize for 2 hours, filter, wash, and dry the filter cake to obtain 1585.6g of azoxystrobin product with a content of 98.3% and a yield of 96.6%.

[0067] Example 7

[0068] Add 1310g (4.00mol) of the compound shown in Formula I and 544g (4.48mol) of 2-cyanophenol to 5240g of toluene, stir until dissolved, and set aside (denoted as Material A); weigh 1180g of trimethylamine aqueous solution (content 30%, 6.00mol), and set aside (denoted as Material B); connect Material A and Material B to a static mixer preheated to 150℃ via a metering pump, respectively. Connect the outlet of the static mixer to a sealed reaction vessel. Close the pressure relief valve at the outlet of the reaction vessel and set the pressure to 0.55MPa. The feed pipe outlet is located at the bottom of the reaction vessel, and the discharge pipe is located above the liquid surface. The feed mass ratio of material A to material B was 6.02:1. The feed flow rate was adjusted appropriately, and the residence time of the materials in the reactor was controlled to be 0.4 hours. After stable operation, materials were continuously collected from the outlet, cooled, and allowed to stand directly to obtain clear oil and water phases. The phases were separated, and the oil phase was washed and then subjected to vacuum distillation to remove toluene. The mixture was cooled to 60–65°C, and 550 g of methanol was added. The mixture was then heated to reflux to dissolve the toluene, cooled to approximately -5°C, and allowed to crystallize for 3 hours. After filtration, washing, and drying of the filter cake, 1595.4 g of azoxystrobin product was obtained, with a content of 98.2% and a yield of 97.1%.

[0069] Example 8

[0070] Add 1310g (4.00mol) of the compound shown in Formula I and 544g (4.48mol) of 2-cyanophenol to 5240g of toluene, stir until dissolved, and set aside (denoted as Material A); weigh 1416g of trimethylamine (content 30%, 7.20mol), set aside, and denoted as Material B; connect Materials A and B to the inlet of a static mixer via pipelines according to the feed mass ratio using metering pumps A and B respectively. A safety relief valve is connected between metering pump A and the static mixer. The static mixer is preheated to 150℃. The outlet of the static mixer is connected to a delay pipeline, and the temperature of the delay pipeline is controlled at 170℃. The outlet of the delay pipeline is connected in sequence to a cooling coil and a back pressure valve, and a receiving bottle. The back pressure valve is set to a pressure of 0.95MPa. Adjust the length of the delay pipeline so that the residence time of the material in the delay pipeline is 12min. The feed rate ratio of material A to material B was set at 5:1. After the operation stabilized, the effluent was collected, cooled, and allowed to stand directly to obtain clear oil and water phases. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. Methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to about -5°C and allowed to crystallize for 3 hours. After filtration, washing, and drying of the filter cake, 1583.9 g of azoxystrobin product was obtained, with a content of 98.0% and a yield of 96.2%.

[0071] Example 9

[0072] Add 1310g (4.00mol) of the compound shown in Formula I and 544g (4.48mol) of 2-cyanophenol to 5240g of toluene, stir until dissolved, and set aside (denoted as Material A); weigh 1573g of trimethylamine (content 30%, 8.00mol), set aside, and denoted as Material B; connect Materials A and B to the inlet of a static mixer via pipelines according to the feed mass ratio using metering pumps A and B, respectively. A safety relief valve is connected between metering pump A and the static mixer. The static mixer is preheated to a reaction temperature of 160℃. The outlet of the static mixer is connected to a delay pipeline, and the temperature of the delay pipeline is controlled at 160℃. The outlet of the delay pipeline is connected in sequence to a cooling coil and a back pressure valve, and a receiving bottle. The back pressure valve is set to a pressure of 1.1MPa. Adjust the length of the delay pipeline so that the residence time of the material in the delay pipeline is 10min. The feed rate ratio of material A to material B was set at 4.51:1. After the operation stabilized, the effluent was collected, cooled, and allowed to stand directly to obtain clear oil and water phases. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The temperature was lowered to 60-65℃, methanol was added, and the mixture was heated to reflux to dissolve. The temperature was then lowered to about -5℃, and crystallization was allowed to occur for 1 hour. The mixture was then filtered, washed, and the filter cake was dried to obtain 1573.8g of azoxystrobin product with a content of 97.5% and a yield of 95.1%.

[0073] Example 10

[0074] Trimethylamine initial recovery and reuse: The pH of the aqueous phase obtained in Example 4 was adjusted to 2-3 by adding hydrochloric acid, followed by the addition of 0.2% activated carbon by weight. The temperature was raised to 60°C for adsorption and impurity removal for 0.5 h. The filtrate was concentrated to 130°C under normal pressure and pretreated with 53.4 g of NaOH solution (30% content, 0.40 mol). 4.1 g of trimethylamine aqueous solution (30% content, 0.021 mol) was added and transferred to the reactor. Toluene, 131 g (0.40 mol) of the compound shown in Formula I, and 51.5 g (0.42 mol) of 2-cyanophenol were added to the reactor. The reactor was closed and the temperature was raised to 150°C (system pressure 0.55 MPa). The reaction was maintained at this temperature for 0.5 h. The mixture was cooled to about 30°C and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The mixture was cooled to 60-65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to about -5°C and allowed to crystallize for 2 hours. The crystals were then filtered, washed, and the filter cake was dried to obtain 158.1g of azoxystrobin product with a content of 98.5% and a yield of 96.5%.

[0075] Example 11

[0076] The aqueous phase obtained in Example 10 was adjusted to pH 2-3 with hydrochloric acid, and 0.2% activated carbon by weight of the aqueous phase was added. The temperature was raised to about 60°C, and the mixture was stirred for adsorption and impurity removal for 0.5 h. The filtrate was concentrated to 130°C under normal pressure, cooled to 50°C, filtered to remove salt, and a small amount of water was added to wash the salt. The washing liquid and filtrate were combined, and 53.5 g of NaOH solution (30% content, 0.40 mol) was added for treatment. 4.1 g of trimethylamine aqueous solution (30% content, 0.021 mol) was added and transferred to the reaction vessel. 500 g of toluene, 131 g (0.40 mol) of the compound shown in Formula I, and 51.5 g (0.42 mol) of 2-cyanophenol were added to the reaction vessel. The reaction vessel was closed and the temperature was raised to 150°C (system pressure 0.55 MPa). The reaction was maintained at this temperature for 0.5 h to end. The mixture was cooled to about 30°C and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The mixture was cooled to 60-65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to about -5°C and allowed to crystallize for 2 hours. The crystals were then filtered, washed, and the filter cake was dried to obtain 157.8g of azoxystrobin product with a content of 98.5% and a yield of 96.3%.

[0077] Example 12

[0078] The aqueous phase obtained in Example 11 was adjusted to pH 2-3 with hydrochloric acid, and 0.2% (by weight) of activated carbon was added. The temperature was raised to about 60°C, and the mixture was stirred for adsorption and impurity removal for 0.5 h. The filtrate was concentrated to 130°C under normal pressure, cooled to 50°C, and filtered to remove salt. A small amount of water was added to wash the salt, and the washing liquid was combined with the filtrate. 4.1 g of trimethylamine aqueous solution (30% content, 0.021 mol) was added, along with 50.7 g of NaOH solution (30% content, 0.38 mol). The mixture was then transferred to a reaction vessel, and 600 g of toluene, 131 g (0.40 mol) of the compound shown in Formula I, and 51.5 g (0.42 mol) of 2-cyanophenol were added to the reaction vessel. The reaction vessel was closed and the temperature was raised to 150°C (system pressure 0.55 MPa). The reaction was maintained at this temperature for 0.5 h. The mixture was cooled to about 30°C and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The mixture was cooled to 60-65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to about -5°C and allowed to crystallize for 2 hours. The crystals were then filtered, washed, and the filter cake was dried to obtain 158.3g of azoxystrobin product with a content of 98.4% and a yield of 96.5%.

[0079] Example 13

[0080] The aqueous phase obtained in Example 12 was adjusted to pH 2-3 with hydrochloric acid, and 0.2% activated carbon by weight of the aqueous phase was added. The temperature was raised to about 60°C, and the mixture was stirred for adsorption and impurity removal for 0.5 h. The filtrate was concentrated to 130°C under normal pressure, cooled to 50°C, filtered to remove salt, and a small amount of water was added to wash the salt. The washing liquid and filtrate were combined, and 56.0 g of KOH solution (48% content, 0.48 mol) was added for treatment. The mixture was then transferred to a reaction vessel, and toluene, 131 g (0.40 mol) of the compound shown in Formula I, and 51.5 g (0.42 mol) of 2-cyanophenol were added to the reaction vessel. The reaction vessel was closed and the temperature was raised to 150°C (system pressure 0.55 MPa). The reaction was maintained at this temperature for 0.5 h to complete the reaction. The mixture was cooled to about 30°C and allowed to stand directly to obtain a clear oil and water two-phase mixture. The phases were separated, and the oil phase was washed and then distilled under reduced pressure to remove toluene. The mixture was cooled to 60-65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to about -5°C and allowed to crystallize for 2 hours. The crystals were then filtered, washed, and the filter cake was dried to obtain 159.0g of azoxystrobin product with a content of 98.1% and a yield of 96.7%.

[0081] The results of Examples 11-13 show that the aqueous post-treatment of the present invention is relatively simple, including: adding a small amount of hydrochloric acid (to adjust the pH to 2-3) to fix free trimethylamine (trimethylamine hydrochloride has high solubility), decolorizing with activated carbon, and desalting by vacuum concentration (no desalting is required for the first application, and only a single salt is removed after the second application (NaCl in Examples 11 and 12, and KCl in Example 13). The types of salts are relatively simple, and the recovered salts can be used as recycled resources). The filtrate is then alkali-added to release trimethylamine, which can be directly reused without separation.

[0082] Example 14

[0083] 131 g (0.40 mol) of the compound shown in Formula I, 53.4 g (0.44 mol) of 2-cyanophenol, and 350 g of toluene were added to a sealed reactor. After stirring evenly, 129.8 g (20% concentration, 0.44 mol) of trimethylamine aqueous solution was added. The reactor was closed, and the mixture was stirred and heated to 88°C at a system pressure of 0.02 MPa. During the heat preservation process, the color of the liquid gradually lightened. The reaction was maintained at this temperature for 4 hours, and the reaction was considered complete. The mixture was then cooled to 30°C, allowed to stand, and separated to obtain clear oil and water phases. The phases were separated. The reddish-brown oil phase was washed and distilled under reduced pressure to remove toluene. The mixture was cooled to 60–65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to approximately 0°C and allowed to crystallize for 2 hours. The crystals were filtered, washed, and the filter cake was dried to obtain 158.75 g of azoxystrobin product with a purity of 98.3% and a yield of 96.7%.

[0084] Example 15

[0085] 131 g (0.40 mol) of the compound shown in Formula I, 52.21 g (0.43 mol) of 2-cyanophenol, and 350 g of toluene were added to a sealed reactor. After stirring evenly, 67.97 g (40% concentration, 0.46 mol) of trimethylamine aqueous solution was added. The reactor was closed, and the mixture was stirred and heated to 97°C at a system pressure of 0.08 MPa. During the heat preservation process, the color of the liquid gradually lightened. The reaction was maintained at this temperature for 3.5 h, and the reaction was completed under controlled conditions. The mixture was then cooled to 35°C, allowed to stand, and separated to obtain clear oil and water phases. The phases were separated. The reddish-brown oil phase was washed and distilled under reduced pressure to remove toluene. The mixture was cooled to 60–65°C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to approximately -5°C and allowed to crystallize for 1.5 h. The crystals were then filtered, washed, and the filter cake was dried to obtain 159.22 g of azoxystrobin product with a purity of 98.2% and a yield of 96.9%.

[0086] Example 16

[0087] 131 g (0.40 mol) of the compound shown in Formula I, 55.91 g (0.46 mol) of 2-cyanophenol, and 398 g of toluene were added to a sealed reactor. After stirring evenly, 102.45 g (30% concentration, 0.52 mol) of trimethylamine aqueous solution was added. The reactor was closed, and the mixture was stirred and heated to 120 °C at a system pressure of 0.19 MPa. During the heat preservation process, the color of the liquid gradually lightened. The reaction was maintained at this temperature for 1.3 h, and the reaction was completed under controlled conditions. The mixture was then cooled to 35 °C, allowed to stand, and separated to obtain clear oil and water phases. The phases were separated. The reddish-brown oil phase was washed and distilled under reduced pressure to remove toluene. The mixture was cooled to 60–65 °C, methanol was added, and the mixture was heated to reflux to dissolve the toluene. The mixture was then cooled to approximately 0 °C and allowed to crystallize for 2 h. The crystals were filtered, washed, and the filter cake was dried to obtain 158.56 g of azoxystrobin product with a purity of 98.0% and a yield of 96.3%.

[0088] Comparative Example 1: Using liquid alkali as an acid-binding agent

[0089] Add 450g of toluene, 120g (0.370mol, 99%) of the compound shown in Formula I, 49g (0.408mol, 99%) of 2-cyanophenol, 5.31g (0.0297mol, 33%) of trimethylamine aqueous solution, and 53.55g (0.428mol, 32%) of liquid alkali to a 1000ml four-necked flask. Slowly raise the temperature to 80℃. During the heat preservation process, the color of the liquid deepens. After 10 hours, the reaction is complete. Separate the phases to obtain 597.2g of dark red toluene solution. The content of the external standard pyraclostrobin is 22.73%, and the conversion rate is 90.7%.

[0090] This Comparative Example 1 illustrates that when liquid alkali is used as an acid-binding agent, the conversion rate of the product decreases. The inventors speculate that this may be because the liquid alkali is too alkaline, leading to the generation of byproducts. The large amount of alkali present at high temperatures causes the ester group hydrolysis of compound 1 and pyraclostrobin, as well as the chlorine of compound 1 being replaced by hydroxyl groups.

[0091] Comparative Example 2: Using potassium carbonate as an acid-binding agent

[0092] Add 300g of toluene, 162g (0.500mol, 99%) of compound I ((E)-2-[2-[6-chloropyrimidin-4-yloxy]phenyl]-3-methoxyacrylate), 66.15g (0.550mol, 99%) of 2-cyanophenol, and 55.8g (0.4mol, 99%) of potassium carbonate to a 1000mL reaction flask. The high solids content of the material made stirring difficult; adding 150g of toluene improved stirring. Then, add 7.15g (0.04mol, 33%) of trimethylamine aqueous solution. Stirring under normal pressure and heating to 80℃ resulted in the release of alkaline gas from the condenser, foaming of the reaction liquid, and volume expansion. The solution was kept at this temperature for 10 hours. After the reaction was complete, 200g of water was added, and the mixture was separated into layers to obtain 650.03g of azoxystrobin in toluene, with a purity of 29.85% and a conversion rate of 96.2%.

[0093] In Comparative Example 2, the trimethylamine in the aqueous phase can be recovered and reused. However, because the aqueous phase also contains chlorides, acid carbonates, and mixed carbonate salts, the post-treatment of the aqueous phase is relatively cumbersome. This includes: nitrogen stripping of the trimethylamine followed by absorption with water (or methanol) (trimethylamine has high solubility in water, 20g / 100g (30℃), requiring a large amount of N2 to ensure trimethylamine recovery). The brine after trimethylamine recovery needs to be treated with acid (usually hydrochloric acid) to remove excess carbonates and bicarbonates, followed by decolorization and concentration of the filtrate for desalination. In Comparative Example 2, the reaction solution needs to be dissolved in water until clear before separation, and the separated aqueous phase requires the addition of a large amount of hydrochloric acid to treat it into chlorides, significantly increasing post-treatment costs. The recovery of trimethylamine also requires a significant amount of water. In short, this comparative example requires a large amount of water resources, leading to water waste.

[0094] In Comparative Example 2, solid potassium carbonate is added, which is complicated to operate and requires a long reaction time (10h). Industrial production requires opening manholes or setting up solid feed silos. Theoretically, 1t of product will produce 54.6kg of CO2 emissions as a byproduct. The reaction materials have high requirements for stirring devices, the system should not be sealed, and the reaction should be carried out at atmospheric pressure.

[0095] Comparative Example 3: Triethylamine as an acid-binding agent

[0096] 230 g of toluene, 81 g (0.25 mol, 99%) of compound I ((E)-2-[2-[6-chloropyrimidin-4-yloxy]phenyl]-3-methoxyacrylate), 33.06 g (0.275 mol, 99%) of 2-cyanophenol, and 20.44 g (0.2 mol, 99%) of triethylamine were added sequentially to a 500 mL reaction flask. The mixture was stirred and heated to 90 °C, and the solution was kept at this temperature for 10 h. 100 g of water was then added, and the mixture was separated into layers to obtain 356.78 g of toluene solution of azoxystrobin, with a purity of 6.47% and a yield of 22.89%.

[0097] In Comparative Example 3, triethylamine was used as an acid-binding agent. Although it has a similar structure to trimethylamine, it cannot make the reaction proceed effectively, resulting in a low conversion rate.

[0098] Comparative Example 4: Using trimethylamine-methanol solution as an acid-binding agent

[0099] To a 500 mL reaction flask, 230 g of toluene, 81 g (0.25 mol, 99%) of the compound shown in Formula I ((E)-2-[2-[6-chloropyrimidin-4-yloxy]phenyl]-3-methoxyacrylate), 33.06 g (0.275 mol, 99%) of 2-cyanophenol, and 49.2 g (0.275 mol, 33%) of trimethylamine-methanol solution were added sequentially. The mixture was stirred and heated, during which a large amount of alkaline gas was released. The mixture was refluxed for 10 h, after which the raw materials ceased to convert. 200 g of water was added, and the mixture was stirred and allowed to stand for phase separation. 335.1 g of oil phase with a purity of 23.56% and a conversion rate of 78.29% were obtained.

[0100] In Comparative Example 4, a trimethylamine-methanol solution was used as an acid-binding agent. Although the reaction system also contained trimethylamine, the reaction conversion efficiency was low.

[0101] Comparative Example 5: Using potassium carbonate aqueous solution as an acid-binding agent

[0102] Add 450g of toluene, 162g (0.500mol, 99%) of compound I ((E)-2-[2-[6-chloropyrimidin-4-yloxy]phenyl]-3-methoxyacrylate), 66.15g (0.550mol, 99%) of 2-cyanophenol, 55.8g (0.4mol, 99%) of potassium carbonate, 7.15g (0.04mol, 33%) of trimethylamine aqueous solution, and 55g of water to a 1000mL reaction flask to form a water-oil system. Stir and heat to 80℃ under normal pressure. Alkaline gas is discharged from the condenser, the reaction solution foams, and a large amount of salt slowly precipitates. Keep the solution at this temperature for 9 hours. After the reaction is complete, add 150g of water to dissolve the salt. After separation, 649.87g of toluene solution of azoxystrobin is obtained, with a purity of 28.83% and a conversion rate of 92.89%.

[0103] Compared with Comparative Example 2, adding a certain amount of water to dissolve potassium carbonate in the early stage of the reaction will reduce the reaction conversion rate. In addition, as the reaction proceeds, potassium chloride and potassium bicarbonate byproducts precipitate out, reforming the gas-liquid-solid three-phase system. After the reaction is completed, water still needs to be added to dissolve the salt. The final weight of the brine is about 260g, which is nearly 68% higher than the weight of the batch of trimethylamine aqueous solution (taking Example 2 as an example, the weight of the brine is about 124g).

[0104] In addition, this Comparative Example 4 is the same as Comparative Example 2, both of which require the addition of solid potassium carbonate, making the operation complex and the reaction time long. Industrial production requires opening manholes or setting up solid feed silos. Theoretically, 1 ton of product yields 54.6 kg of CO2 as a byproduct. The reaction materials have high requirements for the stirring device, the system should not be sealed, and the reaction should be carried out at atmospheric pressure.

[0105] Comparative Examples 1-5 show that Comparative Example 2, using potassium carbonate as an acid-binding agent and trimethylamine as a catalyst, has a relatively high product yield, but it also has several problems: Comparative Example 2 (traditional process) is a solid-liquid heterogeneous reaction, and the material after stirring and dissolving darkens to a blackish-brown color, producing certain colored impurity byproducts (see Figure 1, A). Due to the heterogeneity during heating or holding, the material easily adheres to the reactor walls during stirring (see Figure 1, C, E). In actual industrial production, the solid phase material can also easily wear down the reactor, increasing maintenance costs. After the reaction is complete, a large amount of inorganic salts are deposited at the bottom (see Figure 1, G), requiring the addition of water for separation. The organic phase after the reaction is complete is still dark in color (see Figure 1, G). After adding water and separating the layers, HPLC analysis of the organic phase is shown in Figure 2. The results indicate that three types of impurities with high content were produced (impurity peaks at 2.959 min, 9.196 min, and 10.652 min, respectively), accounting for nearly 8.4%. More stringent crystallization procedures are needed to avoid impurity entrainment affecting quality and increasing costs.

[0106] In this invention, trimethylamine is used as an acid-binding agent, especially in the synthesis of azoxystrobin via aqueous solution. This eliminates the need for additional acid acceptors or conversion of 2-cyanophenol to 2-cyanophenol salt, and also eliminates the need for solid potassium carbonate or sodium carbonate. Taking Example 3 as an example, the reaction system is an oil-water system, and the organic phase is reddish-brown (significantly lighter than the color in Figure 1A), indicating fewer colored impurities and byproducts (see Figure 1B). This facilitates stirring during the heating and holding process (see Figure 1D and F). After the reaction, simple settling yields a clear oil and water phase. The phase color did not deepen, indicating that fewer colored impurities were generated during the reaction (see H in Figure 1). The organic phase was analyzed by HPLC, and the results are shown in Figure 3. The results show that there are only two types of impurities with high peak proportions (impurity peaks at 9.222 min and 10.674 min, respectively), with an impurity proportion of only 5.1% (significantly less than the impurity proportion of Comparative Example 2). The effective component proportion is 93.4%, which is higher than the effective component content. This reduces the post-processing cost, allows for direct separation without the need for water addition, greatly improves efficiency, and avoids the waste of water resources and the post-processing of large amounts of mixed salt in traditional technologies.

[0107] The present invention uses trimethylamine aqueous solution, which can effectively reduce the generation of colored impurities, improve the reaction yield, reduce purification cost and difficulty, and avoid the problem that (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate is prone to hydrolysis in the presence of a large amount of water in the sodium carbonate / potassium carbonate system.

[0108] Furthermore, the inventors of this invention have discovered that when 2-cyanophenol salt is used, trimethylamine will overflow in large quantities, which not only affects the environment but also increases the difficulty of treatment.

[0109] The inventors of this invention also studied the stability of 2-cyanophenol, finding that it gradually polymerizes above 110°C. After holding at this temperature for 0.5 hours, the clear solution of 2-cyanophenol became significantly turbid, and the degree of polymerization increased with increasing temperature and time, solidifying upon cooling. Therefore, improving the reaction efficiency can effectively reduce the formation of polymerization byproducts of 2-cyanophenol.

[0110] The reaction temperature of this invention is 50-170℃, the reaction pressure is atmospheric pressure to 1.1 MPa, and the reaction time is 5 min to 360 min. The reaction conditions are mild, efficient, and short. This invention is based on a method for synthesizing azoxystrobin under atmospheric or slightly positive pressure using trimethylamine as an acid-binding agent. The reaction can be batch or continuous.

[0111] In batch or continuous reaction in a reactor, the reaction endpoint can be reached when the reaction temperature is 150℃, the pressure is 0.55MPa, and the reaction is held at this temperature for 30 minutes.

[0112] In a batch reactor, the reaction endpoint is reached when the reaction temperature is 85–90°C, the pressure is atmospheric pressure, and the temperature is maintained for 4–5 hours.

[0113] The reaction time at atmospheric pressure reflux temperature (e.g., Examples 1-3) is slightly longer, about 4-5 hours. However, even when using trimethylamine as an acid-binding agent and not using solid sodium carbonate or potassium carbonate, a high reaction yield and purity can still be obtained.

[0114] The reaction of the present invention can be a batch reaction in a kettle, a continuous reaction in a kettle, or a continuous reaction in a pipeline. In the continuous reaction in a pipeline, efficient synthesis can be achieved in a very short time, thereby improving production efficiency.

[0115] When using a continuous pipeline reaction, at a reaction temperature of 150℃, the reaction reaches its endpoint after approximately 10 minutes. The continuous pipeline reaction equipment consists of a feed pump, a pressure relief safety valve, a static mixer, a delay pipeline, a back pressure valve, a receiving device, and a heat exchanger.

[0116] The post-treatment procedures for the above-mentioned batch reactor, continuous reactor at atmospheric pressure, and continuous pipeline reactor are the same. After the reaction is complete, the phases are separated. The pH of the aqueous phase is adjusted to 2-8, concentrated, and then an alkaline substance is added. The alkaline substance is NaOH or KOH, and the amount of alkaline substance added is 0.95-1.2 times the molar amount of (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate. After treatment, it is reused for the next batch. When continuously reused, NaCl (or KCl) is separated by filtration after concentration. The brine after separating NaCl (or KCl) is alkali-added and reused. The oil phase is washed, desolventized, purified, separated, and dried.

[0117] This invention uses trimethylamine as an acid-binding agent, which effectively prevents the cyano polymerization of 2-cyanophenol. Furthermore, increasing the amount of trimethylamine significantly accelerates the reaction rate, avoiding the hydrolysis or alcoholysis of the raw material (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate and the occurrence of side reactions during the heating reaction of 2-cyanophenol. It solves the problems of foaming and overflow in existing processes, and also reduces the difficulty of post-treatment of the aqueous phase (traditional processes use sodium carbonate, which leads to the formation of chlorides, acid carbonates, and mixed carbonate salts, requiring dissolution, separation, and large-scale acid neutralization to chlorides, increasing costs, carbon emissions, and environmental pollution). It also avoids the wear and tear on the reactor caused by solid materials. This invention uses trimethylamine aqueous solution as an acid-binding agent, eliminating the need to add sodium carbonate or potassium carbonate, or to convert 2-cyanophenol into 2-cyanophenol salt. The material reaction system is an oil-water reaction system, which is conducive to molecular or ion diffusion, improves reaction efficiency, and trimethylamine can be recycled, avoiding the cumbersome post-processing of mixed salts. Furthermore, separation can be achieved without adding extra water, avoiding waste of water resources; the reaction is highly efficient and the reaction time is shortened.

[0118] This invention requires no catalyst, resulting in a simpler reaction system. The acid-binding agent used in this invention is recyclable, avoiding the industrial waste salts and greenhouse gas CO2 generated by traditional technologies using sodium carbonate or potassium carbonate, making it cleaner and less costly. The reaction solution contains no solids, making operation convenient and allowing for continuous production using conventional equipment, improving production efficiency, reducing labor and equipment investment, and lowering costs. This invention solves the problems of solid-liquid heterogeneous reaction systems, achieving efficient mass and heat transfer during the reaction process, resulting in higher production efficiency and cleaner operation. Furthermore, the absence of gas generation fundamentally avoids the risk of spillage, ensuring inherent safety in the production process.

[0119] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention. Industrial applicability

[0120] This application discloses a method for synthesizing azoxystrobin, comprising: reacting the compound of Formula I with 2-cyanophenol in an oil-water system of an organic solvent and an aqueous solution of trimethylamine to obtain azoxystrobin; wherein the molar ratio of the compound of Formula I to trimethylamine is 1:(0.96-2). The synthesis method of this invention has higher reaction efficiency, does not generate CO2, avoids the risk of spillage, reduces side reactions, reduces solid waste emissions, and is environmentally friendly. This invention does not require the use of solid sodium carbonate or potassium carbonate; the material reaction system is an oil-water reaction system, which significantly improves reaction efficiency and maintains a yield of over 95%. It simultaneously considers efficiency (timeliness) and yield, and easily achieves continuous reaction, providing technical support for intelligent and unmanned production. Furthermore, trimethylamine can be recycled, reducing the use of one raw material, thus eliminating the need for cumbersome treatment of mixed salts and wastewater, and significantly reducing energy consumption.

Claims

1. A method for synthesizing azoxystrobin, characterized in that, It includes: In an oil-water system of organic solvent and trimethylamine aqueous solution, the compound shown in Formula I reacts with 2-cyanophenol to give pyraclostrobin; The molar ratio of the compound shown in Formula I to trimethylamine is 1:(0.96~2).

2. The synthesis method according to claim 1, characterized in that, The molar ratio of the compound shown in Formula I to trimethylamine is 1:(1-2), optionally 1:(1.06-2), optionally 1:(1.1-2), optionally 1:(1.06-1.8), optionally 1:(1.1-1.8); And / or, the molar ratio of the compound shown in Formula I to 2-cyanophenol is 1:(1 to 5), optionally 1:(1 to 1.5), optionally 1:(1 to 1.2); And / or, the mass fraction of trimethylamine in the aqueous trimethylamine solution is 20% to 40%, optionally 25% to 40%, optionally 20% to 30%, optionally 25% to 30%, optionally 30% to 40%; And / or, the molar ratio of the compound shown in Formula I to water is 1:4.728–23.64, optionally 1:4.925–23.64, optionally 1:5.2205–23.64, optionally 1: 5.66~23.64, with option 1: 7.65~23.64, with an optional ratio of 1:5.66~15.29, with an optional ratio of 1:7.65~15.29; And / or, the molar percentage of water in the water-oil system is 30–60 mol%, optionally 31–60 mol%, optionally 31–54 mol%, optionally 31–53 mol%, optionally 35–53 mol%. And / or, no additional sodium carbonate or potassium carbonate needs to be added.

3. The synthesis method according to claim 1, characterized in that, The amount of organic solvent added is at least the amount needed to dissolve the compound shown in Formula I and 2-cyanophenol; And / or, the weight ratio of the compound shown in Formula I to the organic solvent is 1:(2-8), optionally 1:(2-5.7), optionally 1:(2-4), optionally 1:(2.3-5.7), optionally 1:(2.3-4); And / or, the organic solvent includes toluene; And / or, the reaction is carried out in an oil-water system consisting of an organic solvent and an aqueous solution of trimethylamine.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature is 50–170℃, optionally 88–170℃, optionally 110–170℃, optionally 140–170℃, optionally 140–160℃, optionally 80–150℃, optionally 80℃ to reflux temperature; And / or, the reaction pressure is greater than atmospheric pressure, optionally 0.12–1.2 MPa, optionally 0.29–1.2 MPa, optionally 0.5–1.2 MPa, optionally 0.55–1.1 MPa; And / or, the reaction time is 5 min to 360 min, optionally 15 min to 360 min, optionally 30 min to 360 min, optionally 5 min to 60 min, optionally 30 min to 60 min, optionally 5 min to 30 min.

5. The synthesis method according to claim 1, characterized in that, The reaction is carried out in a continuous pipeline reaction unit, with a pipeline temperature of 110–170°C, optionally 140–160°C; and an optional reaction pressure of 0.55–1.1 MPa, optionally 0.5–0.7 MPa. Optionally, in the continuous reaction in the pipeline, the compound shown in Formula I, 2-cyanophenol and organic solvent are used as material A, and the trimethylamine aqueous solution is used as material B. The mass ratio of material A to material B is 4 to 7:1, so that the molar ratio of the compound shown in Formula I to trimethylamine in the system is maintained at 1:(1 to 2), optionally 1:(1.06 to 1.8), optionally 1:(1.1 to 1.8); Alternatively, a batch reaction or a continuous reaction can be carried out in a kettle, with a reaction temperature of 85–150°C, optionally 85–95°C; optionally, the reaction pressure is atmospheric pressure to 1.1 MPa, optionally, the reaction pressure is greater than atmospheric pressure but ≤1.1 MPa, optionally, the reaction pressure is 0.12–1.1 MPa.

6. The synthesis method according to claim 5, characterized in that, The continuous reaction equipment in the pipeline includes a feed pump, a pressure relief safety valve, a static mixer, a delay pipeline, a back pressure valve, a receiving device, and a heat exchanger.

7. The synthesis method according to any one of claims 1 to 6, characterized in that, After the reaction is complete, post-processing is performed to obtain the azoxystrobin product. Post-processing includes: direct separation of the reaction material, desolventization of the oil phase, and purification.

8. The synthesis method according to claim 7, characterized in that, Purification includes redissolution, crystallization, filtration, washing, and drying; alternatively, redissolution may be performed using methanol.

9. The synthesis method according to claim 7, characterized in that, The aqueous phase after separation is subjected to trimethylamine recovery and reuse; the recovery method includes: adjusting the pH of the aqueous phase to 2-8, concentrating it, adding alkali, and recovering to obtain a solution containing trimethylamine.

10. The synthesis method according to claim 9, characterized in that, In the recycling and reuse of trimethylamine, the amount of alkali added is 0.95 to 1.2 times or 1 to 1.2 times the molar amount of the compound shown in Formula I; And / or, in the recycling and reuse of trimethylamine, the alkali is an alkali metal hydroxide; And / or, bases are used to release trimethylamine.

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