Synthesis method of azoxystrobin

Abstract

The invention relates to a divisional application with the application number of 202411979270.1, and discloses a synthesis method of azoxystrobin, which comprises the following steps: in a water-oil system of an organic solvent and a trimethylamine aqueous solution, reacting a compound as shown in a formula I with 2-cyanophenol to obtain azoxystrobin, wherein the molar ratio of the compound as shown in the formula I to the trimethylamine is 1: (0.96-2); the addition amount of the organic solvent is at least used for dissolving the compound shown in the formula I and 2-cyanophenol. The synthesis method has the advantages of higher reaction efficiency, no generation of CO2, avoidance of the risk of entrainment of flash materials, reduction of side reactions, reduction of solid waste discharge, greenness and environmental protection, no need of adopting solid sodium carbonate or potassium carbonate, realization of an oil-water reaction system, great improvement of the reaction efficiency, and maintenance of the yield of 95% or more, and is suitable for industrial production. The efficiency and the yield can be considered at the same time, and continuous reaction is easy to realize; and the trimethylamine can be recycled, so that the use of one raw material is reduced, and the energy consumption is obviously reduced.

Description

[0001] This invention is a divisional application of a Chinese application with an application date of December 31, 2024, an application number of 202411979270.1, and an invention title of "A method for synthesizing azoxystrobin". Technical Field

[0002] This invention relates to the field of pesticides, and particularly to a method for synthesizing azoxystrobin. Background Art

[0003] (E)-Methyl 2-[2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl]-3-methoxyacrylate is a highly efficient and broad-spectrum agricultural fungicide, with multiple functions such as systemic conduction, prevention, protection and treatment, and has good control effects on powdery mildew, rust, glume blotch, downy mildew and rice blast of plants. Currently reported synthesis processes are all prepared from (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate (compound of formula I) with 2-cyanophenol and solid carbonate in the presence of an aprotic organic solvent and a catalyst, or prepared from (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate with an alkali metal salt of 2-cyanophenol. However, the current reaction routes still have a series of problems:

[0004] For example, patents WO9208703 and EP0382375 both use a mixture of (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate and o-hydroxybenzonitrile, add potassium carbonate as an acid-binding agent, use copper(I) chloride as a catalyst, and DMF as a solvent, and react at 120 °C. However, the post-treatment of this route is difficult and crystallization is difficult (crystallization at room temperature for 3 weeks), which is not suitable for industrial large-scale production. The process route is as follows:

[0005]

[0006] For another example, Patent CN101163682B discloses that methyl (E)-2-(2-[6-chloropyrimidin-4-yloxy]phenyl)-3-methoxyacrylate and 2-cyanophenol are reacted in a 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 feed liquid in the slurry state removes DMF under vacuum distillation, and the obtained distillation residue has a high solid content, requires a large power for stirring equipment, and 160 mL of toluene and 265 mL of water (the total feed amount of reaction raw materials is 167 g) are added to the distillation residue at 60 °C. Then, the two-phase mixture is heated to 70 - 80 °C, the mixture is stirred for 40 minutes, then settled, and the lower aqueous phase is separated. During the post-treatment process, the amount of solvent and water added is very large. The added water is used to dissolve the excessive acid acceptor (potassium carbonate or sodium carbonate) raw materials and the formed potassium chloride, potassium bicarbonate or sodium chloride, sodium bicarbonate. It can be seen that the post-treatment of the target product is cumbersome and time-consuming, and the formed mixed salts also need to be heated to evaporate water and separated. There are many devices, it is not easy to be continuous, the energy consumption is large, the steps are long, and it is not easy to realize intelligent and continuous industrial production. A large number of operator personnel are required, and the cost is high.

[0007] For another example, Patent CN109721548B discloses that 2-cyanophenol or its salt reacts with methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)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 methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)3-methoxyacrylate, and the acid acceptor is potassium carbonate and / or sodium carbonate. The reaction is carried out at 50 - 120 °C and usually takes 5 - 20 h to complete. In Example 1, after the reaction is completed, 100 g of water is added. The total feed amount of raw materials at the initial stage of the reaction is 145.5 g. It can be seen that the added water is used to dissolve the excessive acid acceptor (potassium carbonate or sodium carbonate) and by-product salts. The oil phase and the aqueous phase are obtained by liquid separation. Although the treatment technical solution of the aqueous phase is not described, according to the cognition of those skilled in the art, the treatment method has the same technical problems not solved as Patent CN101163682B.

[0008] In the above technical solution, the reaction system materials often use 2-cyanophenol or its salt and methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate as raw materials, and potassium carbonate and sodium carbonate are used as acid-binding agents (or acid acceptors). Although this technical solution can obtain a relatively high yield of azoxystrobin, the reaction process is a solid-liquid mixed system, mainly intermittent reaction. It not only requires a solid feeding device, but also has problems such as long reaction time, low production efficiency and high energy consumption. If continuous operation is carried out, not only the required equipment is complex, but also the investment cost of the corresponding mass transfer equipment is higher, increasing the cost and not being suitable for industrial production; many technicians have also tried to improve its production efficiency for better industrial production, and have made attempts from multiple aspects such as catalysts and reaction raw materials, but have never found a solution to the above problems, that is, it is difficult to balance the yield and timeliness at the same time.

[0009] In addition, the problems existing in the above technical solution are as follows: In production, mass transfer equipment with a relatively high cost is required. A large amount of greenhouse gas CO2 will be released during the reaction process, and an additional tail gas treatment system needs to be added. Moreover, there are risks such as solvent entrainment, foaming and overflow during CO2 overflow; in addition, 2-cyanophenol is prone to cyanide polymerization at high temperatures during the reaction process, especially at too high temperatures and for too long under alkaline conditions, different degrees of polymerization will occur, and as the temperature rises and the time prolongs, the degree of polymerization increases, increasing by-products and resulting in a decrease in yield or purity; when the reaction time is too long, the raw material methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate will undergo hydrolysis or alcoholysis; for the post-treatment slurry reaction liquid, a large amount of water needs to be added to dissolve it before normal liquid separation. There are problems of chlorides, bicarbonates and carbonate solids in the aqueous phase, and a large amount of hydrochloric acid needs to be added to convert the mixed salts into a single salt, greatly increasing the post-treatment cost, not only increasing the cost, but also increasing carbon emissions and polluting the environment. Summary of the Invention

[0010] Object of the Invention

[0011] To overcome the above deficiencies, the object of the present invention is to provide a method for synthesizing azoxystrobin with high efficiency, resource conservation, extremely low solid waste, low capital investment and high automation degree, which can be continuous, low-carbon and highly profitable. The inventors of the present invention found that when an aqueous solution of trimethylamine is used as an acid-binding agent, the material reaction system will become an oil-water reaction system, and the reaction efficiency is greatly improved; moreover, it is no longer necessary to use solid potassium carbonate / sodium carbonate, and the oil-water reaction system equipment is more convenient to use a continuous production device, providing support for the digital and intelligent transformation of industrial production, enhancing competitiveness and achieving higher operating efficiency; and trimethylamine can be recycled, avoiding problems such as cumbersome post-treatment of mixed salts; and it is not necessary to add extra water to dissolve potassium carbonate / sodium carbonate to achieve liquid separation, reducing the water consumption, avoiding the treatment of a large amount of mixed salt wastewater, further reducing the energy consumption in industrial production and reducing the industrial production cost.

[0012] Solution

[0013] To achieve the object of the present invention, the technical solution adopted by the present invention is as follows:

[0014] In the first aspect, the present invention provides a method for synthesizing azoxystrobin, which includes: in a water-oil system of an organic solvent and an aqueous solution of trimethylamine, the compound shown in formula I reacts with 2-cyanophenol to obtain azoxystrobin;

[0015]

[0016] Among them, the molar ratio of the compound shown in formula I to trimethylamine is 1:(0.96 - 2);

[0017] The addition amount of the organic solvent is at least the amount for dissolving the compound shown in formula I and 2-cyanophenol.

[0018] Optionally, the reaction is carried out in a water-oil system composed of an organic solvent and an aqueous solution of trimethylamine.

[0019] 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).

[0020] Further, the molar ratio of the compound shown in formula I to 2-cyanophenol is 1:(1 - 5), optionally 1:(1 - 1.5), optionally 1:(1 - 1.2).

[0021] Further, the mass fraction of trimethylamine in the aqueous solution of trimethylamine is 20% - 40%, optionally 25% - 40%, optionally 20% - 30%, optionally 25% - 30%, optionally 30% - 40%.

[0022] Further, no additional sodium carbonate or potassium carbonate is required or only a very small amount of sodium carbonate or potassium carbonate is added; (it should be noted that no additional addition means that the present invention does not require additional addition of sodium carbonate or potassium carbonate as an acid-binding agent, but it should be understood that even if a very small amount of sodium carbonate or potassium carbonate is added to the reaction system, the effect on the present invention is very small and can also solve the technical problems to be solved by the present invention, which belongs to equivalent substitution).

[0023] Further, the amount of the organic solvent added is at least an amount sufficient to dissolve the compound shown in Formula I and 2-cyanophenol or its salt.

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

[0025] (2 - 5.7), optionally 1:(2 - 4), optionally 1:(2.3 - 5.7), optionally 1:(2.3 - 4).

[0026] Further, the organic solvent includes toluene.

[0027] Further, the reaction temperature is 50 - 170°C, optionally 110 - 170°C, optionally 140 - 170°C, optionally 140 - 160°C, optionally 80 - 150°C, optionally 80°C to the reflux temperature.

[0028] Further, the reaction pressure is greater than atmospheric pressure, optionally the reaction pressure is greater than atmospheric pressure and ≤1.2 MPa; optionally it is 0.5 - 1.2 MPa, optionally 0.55 - 1.1 MPa.

[0029] Further, the reaction time is 5 min - 360 min, optionally 15 min - 360 min, optionally 30 min - 360 min, optionally 5 min - 60 min, optionally 30 min - 60 min, optionally 5 min - 30 min.

[0030] Further, the reaction is carried out in a continuous flow reactor, the temperature of the pipeline is 110 - 170°C, optionally 110 - 150°C, optionally 140 - 170°C, optionally 140 - 160°C, optionally 140 - 150°C; optionally the reaction pressure is greater than atmospheric pressure, optionally 0.55 - 1.1 MPa, optionally 0.5 - 0.7 MPa, optionally the pressure is 0.5 - 0.6 MPa, optionally the pressure is 0.55 - 0.6 MPa.

[0031] Further, batch or continuous kettle reactions are employed, with the reaction temperature being 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 and ≤ 1.1 MPa.

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

[0033] Further, the continuous pipeline 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 pipeline reaction, the compound shown in formula I, 2-cyanophenol, and a solvent are used as material A, and an aqueous solution of trimethylamine is used as material B. The mass ratio of material A to material B is 4 - 7:1, and the molar ratio of the compound shown in formula I to trimethylamine in the system is maintained at 1:(1 - 2), optionally 1:(1.06 - 1.8), optionally 1:(1.1 - 1.8).

[0035] Further, after the reaction is completed, the azoxystrobin product is obtained through post-treatment; optionally the post-treatment includes: directly separating the liquid of the material after the reaction is completed (directly separating the liquid means no additional water is required), removing the solvent from the oil phase, and purification.

[0036] Optionally, the purification includes re-dissolution (re-dissolution can use methanol), crystallization, suction filtration, washing, and drying.

[0037] Further, the aqueous phase after liquid separation is subjected to trimethylamine recovery and reuse; optionally the recovery method includes: adjusting the pH of the aqueous phase to 2 - 8, concentrating and then adding an alkali (the alkali is used to liberate trimethylamine), and recovering to obtain a solution containing trimethylamine.

[0038] Further, in the trimethylamine recovery and reuse, the addition amount of the alkali is 0.95 - 1.2 times the molar amount of the compound shown in formula I, optionally 1 - 1.2 times;

[0039] And / or, in the trimethylamine recovery and reuse, the alkali uses an alkali metal hydroxide, optionally the alkali metal is sodium or an alkali (it can be NaOH or KOH), and it can also be other alkalis.

[0040] Beneficial effects

[0041] The synthesis method of the present invention is highly efficient, resource-saving, with extremely low solid waste, low-carbon, and high efficiency. It reduces capital investment, enables continuous reaction, improves reaction efficiency, provides technical support for intelligent and unmanned production, realizes intrinsic safety design, and significantly reduces the number of employees required for industrial production. The present invention uses aqueous trimethylamine solution as an acid-binding agent, does not require the use of solid potassium carbonate or sodium carbonate, nor does it require the conversion of 2-cyanophenol into 2-cyanophenolate. The material reaction system is an oil-water reaction system, and trimethylamine can be recycled, reducing the use of one raw material. Furthermore, there is no need to deal with problems such as mixed salts in a cumbersome manner, nor is it necessary to treat mixed salt wastewater. The innovative technical solution has low energy consumption designed from the source of the reaction; and liquid separation can be achieved without additional water addition, avoiding waste of water resources. The oil-water reaction system adopted by the present invention has higher mass transfer and heat transfer efficiency than the solid-liquid slurry reaction system, with a shorter reaction time and less equipment wear. The present invention does not use potassium carbonate or sodium carbonate, which can avoid the problems of generating a large amount of greenhouse gas CO2 and the risk of material overflow in the prior art (a large amount of greenhouse gas CO2 is not conducive to the green and low-carbon transformation, and an additional tail gas treatment system is required. In addition, the emissions will entrain solvents and the reaction liquid is prone to overflow risk), reducing the use of one raw material, achieving low-carbon emissions and the intrinsic safety of the process from the scheme design stage; the synthesis method of the present invention can reduce the problem that 2-cyanophenol is prone to cyanide polymerization at high temperatures, and the greatly shortened reaction time can also reduce the hydrolysis or alcoholysis of the compound of formula I, improving the yield and purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] One or more embodiments are illustrated by way of example in the accompanying drawings, and these exemplary illustrations do not constitute a limitation on the embodiments. The special term "exemplary" herein means "serving as an example, embodiment, or illustrative". Any embodiment illustrated as "exemplary" herein need not be construed as superior to or better than other embodiments.

[0043] Figure 1 This shows the change in the material state before and after the reaction of Comparative Example 2 and Example 3 of the present invention. Among them, A is the material state of Comparative Example 2 before heating; C is the material state of Comparative Example 2 during heating; E is the material state of Comparative Example 2 during the heat preservation stage; G is the material state of Comparative Example 2 after the reaction is completed; B is the material state of Example 3 before heating; D is the material state of Example 3 during heating; F is the material state of Example 3 during the heat preservation stage; H is the material state of Example 3 after the reaction is completed. DETAILED DESCRIPTION OF THE INVENTION

[0044] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Apparently, the described embodiments are some, but not all, of the embodiments of the present invention. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0045] In addition, for a better illustration of the present invention, numerous specific details are given in the following specific implementation manners. Those skilled in the art should understand that the present invention can also be implemented without some specific details. In some embodiments, raw materials, schemes, methods, means, etc. well-known to those skilled in the art are not described in detail to highlight the gist of the present invention.

[0046] Unless otherwise clearly stated, in the whole specification and claims, the term "comprising" or its variations such as "including" or "having" etc. will be understood to include the stated elements or components, without excluding other elements or other components.

[0047] In the following embodiments, methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate, 2-cyanophenol, trimethylamine, and other reagents are commercially available; if not otherwise specified, the reaction process and results are detected by high performance liquid chromatography (HPLC), and the content detection uses the external standard method.

[0048] The compound shown in Formula I of the present invention (methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate) and 2-cyanophenol (the compound shown in Formula II) are dissolved in an organic solvent and react under the action of an aqueous solution of trimethylamine to form azoxystrobin (the compound shown in Formula III), and the reaction route is as follows:

[0049]

[0050] In the following embodiments, the compound shown in Formula I refers to methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate.

[0051] In the following embodiments, the reference for the detection of by-products 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 impurity structures 1 and 4 on P727 are

[0052]

[0053] Through continuous research, the inventor found that when using aqueous trimethylamine solution as an acid-binding agent, not only the material reaction system becomes an oil-water reaction system, but also the reaction efficiency is greatly improved, and the yield can be maintained above 95%. It can take into account both efficiency (timeliness) and yield, and is easy to achieve continuous reaction, being suitable for industrial production. In further research, it was found that other tertiary amines such as triethylamine or aqueous NaOH solution cannot achieve a reaction effect similar to that of trimethylamine as an acid-binding agent. Specifically, some examples are as follows:

[0054] Example 1

[0055] 131 g (0.40 mol) of the compound shown in Formula I and 51.5 g (0.424 mol) of 2-cyanophenol were added to 301 g of toluene to form a solution. 83.4 g (content 30%, 0.424 mol) of aqueous trimethylamine solution was added, and the mixture was refluxed under atmospheric pressure and kept warm for 4.5 h. During the warming process, the color of the liquid material gradually became lighter. After the warming was completed, the temperature was lowered to 30 °C, and it was directly left to stand to obtain clear oil and water phases. After phase separation, the reddish-brown oil phase was washed and then toluene was removed by vacuum distillation. The temperature was lowered to 60 - 65 °C, methanol was added, and the mixture was heated to reflux for dissolution. Then the temperature was lowered to about 0 °C, crystallization was carried out for 2 h, filtration, washing were carried out, and the filter cake was dried to obtain 157.6 g of azoxystrobin product with a content of 98.7% and a yield of 96.4%.

[0056] Example 2

[0057] 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 form a solution. 110.1 g (content 30%, 0.56 mol) of aqueous trimethylamine solution was added, and during the warming process, the color of the liquid material gradually became lighter. The reflux under atmospheric pressure and keeping warm ended after 5 h. During the warming process, the color of the liquid material gradually became lighter. After the warming was completed, the temperature was lowered to 30 °C, and it was directly left to stand to obtain clear oil and water phases. After phase separation, the reddish-brown oil phase was washed and then toluene was removed by vacuum distillation. The temperature was lowered to 60 - 65 °C, methanol was added, and the mixture was heated to reflux for dissolution. Then the temperature was lowered to about -5 °C, crystallization was carried out for 2 h, filtration, washing were carried out, and the filter cake was dried to obtain 159.2 g of azoxystrobin product with a content of 98.1% and a yield of 96.8%.

[0058] Example 3

[0059] 131 g (0.40 mol) of the compound shown in Formula I and 55.8 g (98% content, 0.46 mol) of 2-cyanophenol were added to 400 g of toluene to form a solution. 78.7 g (30% content, 0.40 mol) of aqueous trimethylamine solution was added, and the mixture was refluxed under atmospheric pressure and kept warm for 6 h to complete the reaction. During the warming process, the color of the material solution gradually became lighter. After the warming was completed, the temperature was lowered to 30 °C, and it was directly allowed to stand still to obtain clear oil and water phases. The phases were separated. The reddish-brown oil phase was washed and then toluene was removed by distillation under reduced pressure. The temperature was lowered to 60 - 65 °C, methanol was added, and the mixture was heated to reflux to dissolve. The temperature was lowered to about -5 °C, crystallization was carried out for 2 h, filtration was carried out, and the filter cake was washed and dried to obtain 157.7 g of azoxystrobin product with a content of 97.9% and a yield of 95.7%.

[0060] Example 4

[0061] 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 reaction kettle to form a solution. After stirring evenly, 102.3 g (30% content, 0.52 mol) of aqueous trimethylamine solution was added. The reaction kettle was closed, and the temperature was raised to 150 °C and kept warm for 0.5 h to complete the reaction. The system pressure was 0.55 MPa. After the reaction was completed, the temperature was lowered to about 30 °C, and it was directly allowed to stand still to obtain clear oil and water phases. The phases were separated. The oil phase was washed and then toluene was removed by distillation under reduced pressure. The temperature was lowered to 60 - 65 °C, methanol was added, and the mixture was heated to reflux to dissolve. The temperature was lowered to about -5 °C, crystallization was carried out for 2 h, filtration was carried out, and the filter cake was washed and dried to obtain 158.4 g of azoxystrobin product with a content of 98.2% and a yield of 96.4%.

[0062] Example 5

[0063] 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 reaction kettle to form a solution. After stirring evenly, 118 g (30% content, 0.60 mol) of aqueous trimethylamine solution was added. The reaction kettle was closed, and the temperature was raised to 160 °C and kept warm for 0.25 h to complete the reaction. The system pressure was 0.77 MPa. After the reaction was completed, the temperature was lowered to about 30 °C, and it was directly allowed to stand still to obtain clear oil and water phases. The phases were separated. The oil phase was washed and then toluene was removed by distillation under reduced pressure. The temperature was lowered to 60 - 65 °C, methanol was added, and the mixture was heated to reflux to dissolve. The temperature was lowered to about -5 °C, crystallization was carried out for 2 h, filtration was carried out, and the filter cake was washed and dried to obtain 158.2 g of azoxystrobin product with a content of 98.0% and a yield of 96.1%.

[0064] Example 6

[0065] Add 1310 g (4.00 mol) of the compound shown in Formula I and 544 g (4.48 mol) of 2-cyanophenol to 5246 g of toluene, stir until dissolved and clear, and set aside (recorded as Material A); weigh 1023 g of aqueous trimethylamine solution (content 30%, 5.20 mol), and set aside (recorded as Material B); connect Material A and Material B to a static mixer preheated to 150 °C through metering pumps via pipelines respectively. The outlet of the static mixer is connected to a closed reaction kettle. The pressure of the pressure relief valve at the outlet of the closed reaction kettle is set to 0.55 MPa. The outlet of the feed pipeline is set at the bottom of the reaction kettle, and the outlet pipeline of the discharge port is set above the liquid level. The feed mass ratio of Material A and Material B is 6.94:1. Adjust the appropriate feed flow rate, control the residence time of the materials in the reaction kettle to be 0.5 h. After stable operation, continuously take samples at the discharge port, cool down, directly let it stand still, obtain clear oil and water two phases, separate the phases. The oil phase is washed and then the toluene is removed by vacuum distillation. Cool down to 60 - 65 °C, add methanol, heat up to reflux for dissolution, cool down to about -5 °C, crystallize for 2 h, filter by suction and wash. The filter cake is dried to obtain 1585.6 g of azoxystrobin product, with a content of 98.3% and a yield of 96.6%.

[0066] Example 7

[0067] Add 1310 g (4.00 mol) of the compound shown in Formula I and 544 g (4.48 mol) of 2-cyanophenol to 5240 g of toluene, stir until dissolved and clear, and set aside (recorded as Material A); weigh 118 g of aqueous trimethylamine solution (content 30%, 6.00 mol), and set aside (recorded as Material B); connect Material A and Material B to a static mixer preheated to 150 °C through metering pumps via pipelines respectively. The outlet of the static mixer is connected to a closed reaction kettle. The pressure of the pressure relief valve at the outlet of the closed reaction kettle is set to 0.55 MPa. The outlet of the feed pipeline is set at the bottom of the reaction kettle, and the outlet pipeline of the discharge port is set above the liquid level. The feed mass ratio of Material A and Material B is 6.02:1. Adjust the appropriate feed flow rate, control the residence time of the materials in the reaction kettle to be 0.4 h. After stable operation, continuously take samples at the discharge port, cool down, directly let it stand still, obtain clear oil and water two phases, separate the phases. The oil phase is washed and then the toluene is removed by vacuum distillation. Cool down to 60 - 65 °C, add 550 g of methanol, heat up to reflux for dissolution, cool down to about -5 °C, crystallize for 3 h, filter by suction and wash. The filter cake is dried to obtain 1595.4 g of azoxystrobin product, with a content of 98.2% and a yield of 97.1%.

[0068] Example 8

[0069] Add 1310 g (4.00 mol) of the compound shown in Formula I and 544 g (4.48 mol) of 2-cyanophenol to 5240 g of toluene, stir until dissolved and clear, and set aside (recorded as Material A); weigh 1416 g of trimethylamine (content 30%, 7.20 mol), set aside, and record as Material B; connect the inlets of Material A and Material B to the static mixer through pipelines by metering pumps A and B according to the feeding mass ratio. A safety relief valve is connected between metering pump A and the static mixer. The static mixer is preheated to 150 °C for the reaction. The outlet of the static mixer is connected to a delay pipeline, and the temperature of the delay pipeline is controlled at 170 °C. The outlet of the delay pipeline is successively connected to a cooling coil, a back pressure valve, and a receiving bottle. The back pressure valve is set at a pressure of 0.95 MPa. Adjust the length of the delay pipeline so that the residence time of the material in the delay pipeline is 12 min. Set the feeding speed ratio of Material A to Material B as 5:1. After stable operation, receive the effluent, cool down, directly let it stand, obtain clear oil and water phases, separate the phases, wash the oil phase, then distill off toluene under reduced pressure, add methanol, heat to reflux for dissolution, cool down to about -5 °C, crystallize for 3 h, filter by suction, wash, and dry the filter cake to obtain 1583.9 g of azoxystrobin product with a content of 98.0% and a yield of 96.2%.

[0070] Example 9

[0071] Add 1310 g (4.00 mol) of the compound shown in Formula I and 544 g (4.48 mol) of 2-cyanophenol to 5240 g of toluene, stir until dissolved and clear, and set aside (recorded as Material A); weigh 1573 g of trimethylamine (content 30%, 8.00 mol), set aside, and record as Material B; connect the inlets of Material A and Material B to the static mixer through pipelines by metering pumps A and B according to the feeding mass ratio. A safety relief valve is connected between metering pump A and the static mixer. The static mixer is preheated to 160 °C for the reaction. The outlet of the static mixer is connected to a delay pipeline, and the temperature of the delay pipeline is controlled at 160 °C. The outlet of the delay pipeline is successively connected to a cooling coil, a back pressure valve, and a receiving bottle. The back pressure valve is set at a pressure of 1.1 MPa. Adjust the length of the delay pipeline so that the residence time of the material in the delay pipeline is 10 min. Set the feeding speed ratio of Material A to Material B as 4.51:1. After stable operation, receive the effluent, cool down, directly let it stand, obtain clear oil and water phases, separate the phases, wash the oil phase, then distill off toluene under reduced pressure, cool down to 60 - 65 °C, add methanol, heat to reflux for dissolution, cool down to about -5 °C, crystallize for 1 h, filter by suction, wash, and dry the filter cake to obtain 1573.8 g of azoxystrobin product with a content of 97.5% and a yield of 95.1%.

[0072] Example 10

[0073] First recovery and reuse of trimethylamine: Hydrochloric acid was added to the aqueous phase obtained in Example 4 to adjust the pH to 2-3, and then 0.2% (by weight) of activated carbon was added. The temperature was raised to 60 °C for 0.5 h of adsorption and impurity removal. The filtrate was concentrated at atmospheric pressure to 130 °C, pretreated with 53.4 g of NaOH solution (content 30%, 0.40 mol), and 4.1 g of aqueous trimethylamine solution (content 30%, 0.021 mol) was added and transferred to the reaction kettle. 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 kettle. The reaction kettle was closed and the temperature was raised to 150 °C (system pressure 0.55 MPa), and the reaction was kept for 0.5 h to end. The temperature was lowered to about 30 °C and directly allowed to stand to obtain clear oil and water phases. After phase separation, the oil phase was washed and then distilled under reduced pressure to remove toluene. The temperature was lowered to 60-65 °C, methanol was added, and the mixture was heated to reflux for dissolution. The temperature was lowered to about -5 °C and crystallization was carried out for 2 h. Filtration, washing, and drying of the filter cake gave 158.1 g of azoxystrobin product with a content of 98.5% and a yield of 96.5%.

[0074] Example 11

[0075] The aqueous phase obtained in Example 10 was adjusted to pH 2-3 with hydrochloric acid, 0.2% (by weight of the aqueous phase) of activated carbon was added, the temperature was raised to about 60 °C, and stirring was carried out for 0.5 h for adsorption and impurity removal. The filtrate was concentrated at atmospheric pressure to 130 °C, cooled to 50 °C for salt filtration, washed with a small amount of water, and the washing liquid was combined with the filtrate. 53.5 g of NaOH solution (content 30%, 0.40 mol) was added for treatment, and 4.1 g of aqueous trimethylamine solution (content 30%, 0.021 mol) was added and transferred to the reaction kettle. 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 kettle. The reaction kettle was closed and the temperature was raised to 150 °C (system pressure 0.55 MPa), and the reaction was kept for 0.5 h to end. The temperature was lowered to about 30 °C and directly allowed to stand to obtain clear oil and water phases. After phase separation, the oil phase was washed and then distilled under reduced pressure to remove toluene. The temperature was lowered to 60-65 °C, methanol was added, and the mixture was heated to reflux for dissolution. The temperature was lowered to about -5 °C and crystallization was carried out for 2 h. Filtration, washing, and drying of the filter cake gave 157.8 g of azoxystrobin product with a content of 98.5% and a yield of 96.3%.

[0076] Example 12

[0077] The aqueous phase obtained in Example 11 was adjusted to pH 2 - 3 with hydrochloric acid, activated carbon accounting for 0.2% of the weight of the aqueous phase was added, the temperature was raised to about 60 °C, and stirring was carried out for 0.5 h for adsorption and impurity removal. The filtrate was concentrated at atmospheric pressure to 130 °C, cooled to 50 °C for salt filtration, a small amount of water was added to wash the salt, the washing liquid was combined with the filtrate, 4.1 g of trimethylamine aqueous solution (content 30%, 0.021 mol) was added, and 50.7 g of NaOH solution (content 30%, 0.38 mol) was added for treatment. It was transferred to a reaction kettle, 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 kettle. The reaction kettle was closed and the temperature was raised to 150 °C (system pressure 0.55 MPa), and the heat preservation reaction was ended after 0.5 h. It was cooled to about 30 °C and directly allowed to stand, obtaining clear oil and water phases. After phase separation, the oil phase was washed and then toluene was removed by vacuum distillation. The temperature was cooled to 60 - 65 °C, methanol was added, the temperature was raised for reflux dissolution, cooled to about - 5 °C, crystallization was carried out for 2 h, suction filtration and washing were carried out, and the filter cake was dried to obtain 158.3 g of azoxystrobin product with a content of 98.4% and a yield of 96.5%.

[0078] Example 13

[0079] The aqueous phase obtained in Example 12 was adjusted to pH 2 - 3 with hydrochloric acid, activated carbon accounting for 0.2% of the weight of the aqueous phase was added, the temperature was raised to about 60 °C, and stirring was carried out for 0.5 h for adsorption and impurity removal. The filtrate was concentrated at atmospheric pressure to 130 °C, cooled to 50 °C for salt filtration, a small amount of water was added to wash the salt, the washing liquid was combined with the filtrate, and 56.0 g of KOH solution (content 48%, 0.48 mol) was added for treatment. It was transferred to a reaction kettle, 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 kettle. The reaction kettle was closed and the temperature was raised to 150 °C (system pressure 0.55 MPa), and the heat preservation reaction was ended after 0.5 h. It was cooled to about 30 °C and directly allowed to stand, obtaining clear oil and water phases. After phase separation, the oil phase was washed and then toluene was removed by vacuum distillation. The temperature was cooled to 60 - 65 °C, methanol was added, the temperature was raised for reflux dissolution, cooled to about - 5 °C, crystallization was carried out for 2 h, suction filtration and washing were carried out, and the filter cake was dried to obtain 159.0 g of azoxystrobin product with a content of 98.1% and a yield of 96.7%.

[0080] The results of Examples 11 - 13 show that the post - treatment of the aqueous phase of the present invention is relatively simple, including: adding a small amount of hydrochloric acid (adjusting pH 2 - 3) to fix free trimethylamine (solubility of trimethylamine hydrochloride), decolorization with activated carbon, concentration under reduced pressure to remove salt (no salt removal is required for the first application, and a single salt is removed after the second application (NaCl in Examples 11 and 12, KCl in Example 13), the types of salts are relatively single, and the recovered salts can be used as recovered resources), adding alkali to the filtrate to liberate trimethylamine, and it can be directly applied without separation.

[0081] Comparative Example 1: Using liquid alkali as an acid - binding agent

[0082] Add 450 g of toluene, 120 g (0.370 mol, 99% content) of the compound shown in Formula I, 49 g (0.408 mol, 99% content) of 2-cyanophenol, 5.31 g (0.0297 mol, 33% content) of aqueous trimethylamine solution, and 53.55 g (0.428 mol, 32% content) of liquid caustic soda into a 1000 mL four-necked flask. Slowly heat up to 80 °C. During the heat preservation process, the color of the liquid material deepens. Keep warm for 10 h. After the reaction ends, separate the phases to obtain 597.2 g of dark red toluene solution. The content of azoxystrobin determined by external standard is 22.73%, and the conversion rate is 90.7%.

[0083] This Comparative Example 1 shows that when liquid caustic soda is used as an acid-binding agent, the conversion rate of the product will decrease. The inventor speculates that it may be because the alkalinity of liquid caustic soda is too strong, resulting in the generation of by-products. A large amount of alkali at high temperature causes the hydrolysis of the ester group of the compound of Formula 1 and azoxystrobin, and the substitution of chlorine in the compound of Formula 1 by hydroxyl group.

[0084] Comparative Example 2: Using potassium carbonate as an acid-binding agent

[0085] Add 300 g of toluene, 162 g (0.500 mol, 99%) of the compound shown in Formula I ((E)-2-[2-[6-chloropyrimidin-4-yloxy]phenyl]-3-methoxyacrylate methyl ester), 66.15 g (0.550 mol, 99%) of 2-cyanophenol, and 55.8 g (0.4 mol, 99%) of potassium carbonate into a 1000 mL reaction flask in sequence. The solid content of the material is high and it is difficult to stir. Add 150 g of toluene to make the stirring smoother. Then add 7.15 g (0.04 mol, 33% concentration) of aqueous trimethylamine solution. Stir and heat up to 80 °C at normal pressure. Alkaline gas is discharged at the condenser, and the reaction liquid foams and the volume expands. Keep the liquid material warm for 10 h. After the reaction ends, add 200 g of water. Separate the layers to obtain 650.03 g of toluene solution of azoxystrobin, with a content of 29.85% and a conversion rate of 96.2%.

[0086] In this Comparative Example 2, trimethylamine in the aqueous phase can be recycled and reused. However, since the aqueous phase also contains chloride, acid carbonate, and carbonate mixed salts, the post-treatment of the aqueous phase is relatively cumbersome, including: it is necessary to blow off trimethylamine with nitrogen and absorb it with water (or methanol) (trimethylamine has a large solubility in water, 20 g / 100 g (30 °C), and a large amount of N2 is required to ensure the recovery rate of trimethylamine). The brine after recovering trimethylamine needs to be treated with acid (usually hydrochloric acid) to remove excessive carbonate and bicarbonate, and then decolorized, and the filtrate is concentrated to remove salts. In this Comparative Example 2, the reaction liquid needs to be dissolved with water until the salt is clear before liquid separation, and a large amount of hydrochloric acid needs to be added to the separated aqueous phase to treat it into chloride, which greatly increases the post-treatment cost. Recycling trimethylamine also requires a large amount of water. That is, this Comparative Example requires a large amount of water resources, resulting in waste of water resources.

[0087] In Comparative Example 2, solid potassium carbonate was added, with complex operations, requiring a long reaction time (10 h). In industrial production, it is necessary to open the manhole or set up a solid feeding bin. For every 1 t of product, 54.6 kg of CO2 is theoretically by-produced and discharged; the reaction materials have relatively high requirements for the stirring device, the system is not suitable for being airtight, and the reaction needs to be carried out under normal pressure.

[0088] Comparative Example 3: Triethylamine was used as the acid-binding agent

[0089] Into 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 methyl ester), 33.06 g (0.275 mol, 99%) of 2-cyanophenol, and 20.44 g (0.2 mol, 99%) of triethylamine were successively added. The mixture was stirred and heated to 90 °C, and the liquid material was kept at this temperature for 10 h. Then 100 g of water was added, and after liquid separation, 356.78 g of toluene solution of azoxystrobin with a content of 6.47% was obtained, with a yield of 22.89%.

[0090] In this Comparative Example 3, although triethylamine has a similar structure to trimethylamine, it was used as the acid-binding agent, but it could not make the reaction proceed effectively, and the conversion rate was relatively low.

[0091] Comparative Example 4: Trimethylamine-methanol solution was used as the acid-binding agent

[0092] Into 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 methyl ester), 33.06 g (0.275 mol, 99%) of 2-cyanophenol, and 49.2 g (0.275 mol, with a content of 33%) of trimethylamine-methanol solution were successively added. The mixture was stirred and heated. During the heating process, a large amount of alkaline gas overflowed (the inventor speculated that the solubility of trimethylamine in methanol is 30 - 47%, resulting in its easy volatilization). The mixture was refluxed for 10 h, 200 g of water was added, and after stirring and standing for phase separation, 335.1 g of the oil phase with a content of 23.56% and a conversion rate of 78.29% was obtained.

[0093] In this Comparative Example 4, although trimethylamine was also contained in the reaction system when trimethylamine-methanol solution was used as the acid-binding agent, the reaction conversion efficiency was relatively low.

[0094] Comparative Examples 1 - 4 show that in Comparative Example 2, potassium carbonate was used as the acid-binding agent and trimethylamine was used as the catalyst, and the product yield was relatively high, but there were many problems: Comparative Example 2 (traditional process) was a solid-liquid heterogeneous reaction (see Figure 1 A in Figure 1In C and E), in actual industrial production, solid-phase materials can also easily wear the reactor, increasing the maintenance cost. After the reaction is completed, a large amount of inorganic salts are deposited at the bottom (see Figure 1 in G), and water needs to be added for liquid separation.

[0095] In the present invention, trimethylamine is used as an acid-binding agent. Especially when using an aqueous solution for the synthesis of azoxystrobin, there is no need to additionally add an acid acceptor or convert 2-cyanophenol into 2-cyanophenolate, nor is it necessary to use solid potassium carbonate or sodium carbonate. Taking Example 3 as an example, the material reaction system is an oil-water reaction system (see Figure 1 in B), and it is easy to stir during the stirring process of heating and maintaining the temperature (see Figure 1 in D and F). After the reaction is completed, a simple static settlement can obtain clear oil and water phases (see Figure 1 in H), and liquid separation can be directly carried out without adding water, greatly improving the efficiency and avoiding the waste of water resources and the post-treatment of a large amount of mixed salts in the traditional technology.

[0096] In addition, the inventors of the present invention also found that when 2-cyanophenolate is used, a large amount of trimethylamine will overflow, which not only affects the environment but also increases the treatment difficulty.

[0097] The inventors of the present invention also studied the stability of 2-cyanophenol and found that it will gradually polymerize when the temperature is above 110 °C. After maintaining the temperature for 0.5 h, the clear solution of 2-cyanophenol has become significantly turbid, and with the increase of temperature and time, the degree of polymerization increases and solidifies after cooling. Therefore, improving the reaction efficiency can effectively reduce the generation of polymerization by-products of 2-cyanophenol.

[0098] The reaction temperature of the present invention is 50-170 °C, the reaction pressure is normal pressure to 1.1 Mpa, and the reaction time is 5 min to 360 min. The reaction conditions are mild, with high efficiency and short reaction time. The method for synthesizing azoxystrobin based on trimethylamine as an acid-binding agent under normal pressure or slightly positive pressure in the present invention can be intermittent or continuous.

[0099] In a batch or continuous reaction in a kettle, when the reaction temperature is 150 °C and the pressure is 0.55 MPa, the reaction can reach the end point after maintaining the temperature for 30 min.

[0100] In a batch reaction in a kettle, when the reaction temperature is 85-90 °C and the pressure is normal pressure, the reaction reaches the end point after maintaining the temperature for 4-5 h.

[0101] The reaction time at the normal pressure reflux temperature (such as in Examples 1-3) is slightly longer, about 4-5 h, but when using trimethylamine as an acid-binding agent and not using solid sodium carbonate or potassium carbonate, a relatively high reaction yield and purity can still be obtained.

[0102] 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. Among them, in the continuous reaction in a pipeline, high-efficiency synthesis can be achieved in an extremely short time, improving production efficiency.

[0103] When a continuous reaction in a pipeline is adopted and the reaction temperature is 150 °C, the reaction reaches the end point after staying for about 10 minutes. 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.

[0104] The post-treatment schemes for the above batch reaction in a kettle, continuous reaction at normal pressure in a kettle, and continuous reaction in a pipeline are the same. After the reaction is completed, phase separation is carried out. The pH of the aqueous phase is adjusted to 2-8, and after concentration, an alkaline substance is added. The alkaline substance is NaOH or KOH, and the amount of the alkaline substance added is 0.95-1.2 times the molar amount of methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate. After treatment, it is recycled for the next batch; when continuously recycled, NaCl (or KCl) is filtered and separated after concentration, and the brine after separating NaCl (or KCl) is added with alkali and continues to be recycled. The oil phase is washed, desolvated, refined, separated, and dried.

[0105] The present invention uses trimethylamine as an acid-binding agent, which can effectively avoid the cyanide polymerization of 2-cyanophenol; and by increasing the amount of trimethylamine used, the reaction rate can be significantly accelerated, avoiding the hydrolysis or alcoholysis of the raw material methyl (E)-2-(2-((6-chloropyrimidin-4-yl)oxy)phenyl)-3-methoxyacrylate and the occurrence of side reactions of 2-cyanophenol during the heating reaction. It solves the problems of easy foaming and overflowing during the reaction process in the prior art, and also reduces the difficulty of post-treatment of the aqueous phase (the problem of forming a mixed salt of chloride, acid carbonate, and carbonate after using sodium carbonate in the traditional process, which requires a large amount of acid to be added for neutralization to chloride after dissolution and liquid separation, not only increasing costs but also increasing carbon emissions and polluting the environment), and also avoids the problem of wear of the reactor by solid materials. The present invention uses an aqueous solution of trimethylamine as an acid-binding agent, does not need to add sodium carbonate or potassium carbonate, and does not need to convert 2-cyanophenol into 2-cyanophenolate. The material reaction system is an oil-water reaction system, which is conducive to the diffusion of molecules or ions, improves the reaction efficiency, and trimethylamine can be recycled, avoiding problems such as cumbersome post-treatment of mixed salts; and liquid separation can be achieved without additional water, avoiding waste of water resources; the high-efficiency reaction time is shortened.

[0106] The present invention does not require a catalyst, and the reaction system is simpler; the acid-binding agent used in the present invention can be recycled, avoiding the generation of solid waste and greenhouse gas CO2 produced by using sodium carbonate or potassium carbonate in traditional technologies, being cleaner and having lower costs; the present invention does not involve solid materials, is convenient to operate, can achieve continuous production with conventional equipment, improves production efficiency, reduces manpower and equipment investment, and has low costs; the present invention solves the problems of the solid-liquid heterogeneous reaction system, realizes efficient mass transfer and heat transfer during the reaction process, has higher production efficiency and is cleaner; the present invention does not generate gas, fundamentally avoids the risk of overflow, and realizes the inherent safety of the production process.

[0107] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features; and these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the various embodiments of the present invention.

Claims

1. A method for synthesizing azoxystrobin, characterized in that, It includes: In a water-oil system of an organic solvent and an aqueous solution of trimethylamine, the compound shown in Formula I reacts with 2-cyanophenol to obtain azoxystrobin; Among them, the molar ratio of the compound shown in Formula I to trimethylamine is 1:(0.96 - 2); The addition amount of the organic solvent is at least the amount for dissolving the compound shown in Formula I and 2-cyanophenol.

2. The synthesis method according to claim 1, wherein 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 - 5), optionally 1: (1 - 1.5), optionally 1:(1 - 1.2); And / or, the mass fraction of trimethylamine in the aqueous solution of trimethylamine is 20% - 40%, optionally 25% - 40%, optionally 20% - 30%, optionally 25% - 30%, optionally 30% - 40%; 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 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 a water-oil system composed 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°C, optionally 110 - 170°C, optionally 140 - 170°C, optionally 140 - 160°C, optionally 80 - 150°C, optionally 80°C - reflux temperature; And / or, the reaction pressure is greater than atmospheric pressure, optionally the reaction pressure is greater than atmospheric pressure and ≤1.2 MPa; optionally 0.5 - 1.2 MPa, optionally 0.55 - 1.1 MPa; And / or, the reaction time is 5 min - 360 min, optionally 15 min - 360 min, optionally 30 min - 360 min, optionally 5 min - 60 min, optionally 30 min - 60 min, optionally 5 min - 30 min.

5. The synthesis method according to claim 1, wherein The reaction is carried out in a pipeline continuous reaction device, the pipeline temperature is 110 - 170°C, optionally 140 - 160°C; optionally the reaction pressure is greater than atmospheric pressure, optionally 0.55 - 1.1 MPa, optionally 0.5 - 0.7 MPa, optionally 0.5 - 0.6 MPa, optionally 0.55 - 0.6 MPa; Or, a batch reaction in a kettle or a continuous reaction in a kettle is adopted, optionally the reaction temperature is 85 - 150°C, optionally the reaction temperature is 85 - 95°C; optionally the reaction pressure is atmospheric pressure - 1.1 MPa, optionally the reaction pressure is greater than atmospheric pressure, ≤1.1 MPa.

6. The synthesis method according to claim 5, characterized in that, The pipeline continuous reaction device 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. According to the synthesis method described in any one of claims 1 to 6, characterized in that, After the reaction is completed, post-treatment is carried out to obtain azoxystrobin products; the post-treatment includes: directly separating the liquid of the material after the reaction is completed, removing the solvent from the oil phase, and purification.

8. The synthesis method according to claim 7, wherein Purification includes re-dissolution, crystallization, suction filtration, washing and drying. Optionally, methanol is used for re-dissolution.

9. The synthesis method according to claim 7, characterized in that, Trimethylamine is recovered and recycled from the aqueous phase after liquid separation; the recovery method includes: adjusting the pH of the aqueous phase to 2-8, adding an alkali after concentration, and recovering to obtain a solution containing trimethylamine.

10. The synthesis method according to claim 9, wherein, In the recovery and recycling of trimethylamine, the addition amount of the alkali is 0.95-1.2 times or 1-1.2 times the molar amount of the compound shown in formula I; and / or, in the recovery and recycling of trimethylamine, the alkali used is an alkali metal hydroxide; and / or, the alkali is used to liberate trimethylamine.

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