Method for synthesizing thiamethoxam

Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a method for synthesizing thiamethoxam, which comprises the following steps: (1) preparing 2-chloro-5-chloromethylthiazole; (2) preparing thiazole hydrazone; (3) preparing an oxadiazine ring intermediate; and (4) carrying out nitration reaction on the oxadiazine ring intermediate, and finally carrying out post-treatment and purification to obtain thiamethoxam. According to the scheme, a brand-new integrated quality and process control strategy from high-purity preparation of initial raw materials, key intermediate generation and in-situ purification to final product ring construction, functional group conversion and crystallization purification is constructed, so that the whole process can be efficiently operated under mild and stable conditions; and finally, a thiamethoxam product with high purity and high yield is obtained.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical technology, and more specifically, relates to a method for synthesizing thiamethoxam. Background Technology

[0002] This invention belongs to the field of agricultural chemical synthesis technology, specifically relating to a highly efficient and high-purity synthesis method for a neonicotinoid insecticide—thiamethoxam. Thiamethoxam, as a representative of second-generation neonicotinoid insecticides, plays a crucial role in global agricultural production due to its excellent systemic conductivity, broad-spectrum insecticidal activity, low toxicity to mammals, and relatively environmentally friendly characteristics. It is widely used to control piercing-sucking pests on various crops such as rice, corn, and cotton. With the increasing demands for agricultural product safety and environmental protection in modern agriculture, developing a more economical, efficient, green, and easily industrialized thiamethoxam synthesis process has become a core research topic of continuous focus in this field.

[0003] In existing thiamethoxam synthesis routes, the core step is typically the condensation reaction of 2-chloro-5-chloromethylthiazole and 3-methyl-4-nitroimino-1,3,5-oxadiazine. Extensive research has been conducted on this process. For example, Chinese patent CN103880832B discloses a preparation method using C2-C5 fatty alcohols as the reaction solvent and an inorganic base as an acid-binding agent, conducting the reaction at a pressure of 0.1-0.5 MPa and a relatively high temperature of 80-150°C. This technical solution, during a specific historical period, effectively improved the reaction rate and conversion efficiency by employing pressurized and high-temperature reaction conditions, achieving a high yield and providing a feasible path for the industrial production of thiamethoxam. The design concept of this method lies in overcoming the reaction energy barrier by strengthening external reaction conditions, i.e., using high pressure and high temperature, forcibly driving the reaction towards the product, thereby achieving high production efficiency on a macroscopic scale. However, with the continuous development of chemical engineering and process control technologies, and the market's increasingly stringent requirements for production costs, operational safety, and product quality, the limitations of the aforementioned process routes, which rely on high pressure and high temperature conditions, are becoming increasingly apparent due to their inherent characteristics at the principle level. This is because this reaction method, while increasing the main reaction rate, inevitably accelerates a series of side reactions. The formation of these byproducts not only consumes raw materials and increases production costs, but also, because their physicochemical properties are similar to the target product thiamethoxam, subsequent separation and purification processes are difficult, ultimately affecting the purity and stability of the target product. Furthermore, the high investment and maintenance costs of high-pressure reactors, along with the higher standards required for operator skills and safety management, limit the versatility and economic viability of this process to some extent.

[0004] To avoid the drawbacks of high temperature and high pressure, researchers have begun to focus on controlling the activity of reactants. For example, the method disclosed in Chinese patent CN115974866B first reacts 3-methyl-4-nitroimino-1,3,5-oxadiazine with a strong organic base to pre-prepare an oxadiazine salt with higher reactivity. This salt is then reacted with 2-chloro-5-chloromethylthiazole under relatively mild atmospheric pressure (50–60°C). This pre-activation process of the substrate is relatively mild, reducing equipment requirements and energy consumption, avoiding inorganic salt byproducts introduced by inorganic bases, and simplifying the post-processing. However, this process still has problems. The preparation of the oxadiazine salt is extremely sensitive to pH changes; even small changes can lead to salt decomposition or incomplete formation, directly affecting the yield and selectivity of subsequent condensation reactions. Furthermore, the above-mentioned technological improvements primarily focus on the final condensation step, lacking a holistic consideration of the quality control of starting materials and key intermediates throughout the entire synthetic route. Trace amounts of impurities or moisture introduced in any early step of the synthetic route may be amplified in subsequent reactions, becoming the fundamental limiting factor that ultimately affects the selection of reaction conditions and product quality.

[0005] Therefore, how to construct an integrated quality control strategy from the preparation of starting materials, the generation and purification of key intermediates, to the final condensation, nitration and crystallization, and achieve efficient operation under mild and stable conditions, has become a technical problem that urgently needs to be solved by those skilled in the art. Summary of the Invention

[0006] To address the aforementioned issues, this invention provides a method for synthesizing thiamethoxam. By constructing a novel integrated quality and process control strategy that encompasses the preparation of high-purity starting materials, the generation and in-situ purification of key intermediates, and the final product ring construction, functional group transformation, and crystallization purification, the entire process can operate efficiently under mild and stable conditions, ultimately yielding a high-purity, high-yield thiamethoxam product. Furthermore, this method possesses excellent inherent process safety and stability, and is highly compatible with continuous production models.

[0007] A method for synthesizing thiamethoxam includes the following steps: Includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: Thiourea and ethyl 2-chloroacetoacetate are used as raw materials, wherein the molar ratio of thiourea to ethyl 2-chloroacetoacetate is 1:1.0-1.1. After cyclization reaction, acetic acid is used as the catalyst, and the amount of the catalyst is 5%-10% of the total mass of the raw materials. The temperature is 80-90℃ and the reaction time is 2-4 hours. Then, sodium hypochlorite solution with a mass fraction of 10%-15% is used as the chlorination reagent for chlorination reaction. The amount of sodium hypochlorite is 1.05-1.15 times the molar amount of ethyl 2-chloroacetoacetate. The temperature is 60-70℃ and the reaction time is 1-2 hours to obtain 2-chloro-5-chloromethylthiazole. Step (2) Preparation of thiazolylhydrazone: The 2-chloro-5-chloromethylthiazolium and hydrazine are reacted with each other in an anhydrous organic solvent under acidic conditions to generate thiazolylhydrazone. The reaction temperature is controlled at 0-10℃ and the reaction time is 2-4 hours. After the reaction is completed, the generated water is removed by azeotropic dehydration. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium is 1-1.2:1. Step (3) Preparation of the oxadiazine ring intermediate: The thiazolylhydrazone is reacted with paraformaldehyde under acidic conditions. The catalyst is p-toluenesulfonic acid, and the amount of catalyst is 1.5 mol%-3.5 mol% of the molar amount of thiazolylhydrazone. Toluene is used as the solvent, and the reaction temperature is 60-70℃. Water is removed through a water separator until the amount of water removed is ≥ 1.0-1.2 times the theoretical amount. Then, 3Å molecular sieve is added, with the amount corresponding to the reaction liquid volume being 4-6 g / L. The mixture is heated to 80-90℃ and refluxed for 1.5-3.5 hours at a gauge pressure of -0.04 to -0.06 MPa, with a stirring rate of 200-300 rpm to generate the oxadiazine ring intermediate. The amount of paraformaldehyde is 1.1-1.3 times the molar amount of thiazolylhydrazone. After the first use, the 3Å molecular sieve is recovered by vacuum drying at 120℃ for 2 hours. Before reuse, it needs to be activated again at 350-450℃ for 1-2 hours. After 24 hours (shortening activation time and reducing energy consumption), and after being reused 3 times, its dehydration efficiency still remains above 90% of the initial efficiency.

[0008] Step (4) Nitration reaction of the oxadiazine ring intermediate: The oxadiazine ring intermediate is mixed with the nitrifying reagent at a molar ratio of 1:1-1.2 and reacted at 0-10℃ for 1-2 hours. After the reaction is completed, excess nitrifying reagent is captured with urea. After post-treatment and purification, the thiamethoxam is obtained. The nitrifying reagent is urea nitrate. The amount of urea used is 1.1-1.3 times the molar amount of the nitrifying reagent.

[0009] Preferably, in step (2), the anhydrous organic solvent is toluene; under acidic conditions, acetic acid with a mass fraction ≥98% is used, and the amount of acetic acid is 0.5%-1.0% of the mass of 2-chloro-5-chloromethylthiazolium; the azeotropic dehydration time is 2-3 hours. Choosing acetic acid with a mass fraction ≥98% avoids the introduction of additional moisture by low-concentration acetic acid, ensuring an anhydrous environment in the reaction system, thereby improving the purity of thiazolium hydrazone.

[0010] Preferably, in step (3), before the thiazolyl hydrazone reacts with paraformaldehyde under acidic conditions, the paraformaldehyde is depolymerized at 80-90°C under nitrogen protection; the 3Å molecular sieve is activated at 350-450°C for 3-5 hours under nitrogen atmosphere before use, and can be reused ≥3 times.

[0011] Preferably, in step (3), the acidic condition is acetic acid with a mass fraction of 20%-30%, and the amount of acetic acid used is 0.5%-1.0% of the mass of thiazolylhydrazone.

[0012] Preferably, in step (4), when the nitrating agent is urea nitrate, the molar ratio of urea nitrate to the oxadiazine ring intermediate is 1:1.

[0013] Preferably, in step (4), the capture reaction temperature for capturing excess nitrifying reagent with urea is 0-5℃ and the time is 0.5-1 hour.

[0014] Preferably, the post-treatment and purification process specifically involves: washing the nitration product with sodium carbonate solution, washing with water, drying with anhydrous sodium sulfate, removing the solvent by vacuum distillation, purifying by recrystallization, and cooling to obtain thiamethoxam with a purity ≥98%.

[0015] Preferably, during the recrystallization purification, the recrystallization solvent is a mixture of ethanol and water.

[0016] Preferably, the volume ratio of ethanol to water is 1:3 to 1:4.

[0017] Preferably, during the recrystallization purification, the crystallization temperature is -5 to 5°C and the crystallization time is 1 to 2 hours.

[0018] Preferably, the sodium carbonate solution has a mass fraction of 10%.

[0019] In this invention, by effectively controlling the ratio of thiourea to ethyl 2-chloroacetoacetate and rationally regulating the temperature and time of the cyclization and chlorination reactions, 2-chloro-5-chloromethylthiazole with a purity ≥97% can be obtained. Using it as the starting material for subsequent reactions can reduce the introduction of potential impurities at the source.

[0020] In the process of preparing high-purity thiazolyl hydrazone intermediates, azeotropic dehydration technology is used to completely remove the trace amounts of water generated in the reaction, ensuring that thiazolyl hydrazone is generated in an anhydrous environment, which facilitates the efficient execution of subsequent water-sensitive cyclization reactions.

[0021] In the preparation of the oxadiazine ring intermediate, the reaction conditions are relatively mild, and the reaction is highly efficient and selective. First, a condensation reaction and preliminary dehydration are performed. To the anhydrous toluene solution of the thiazolylhydrazone obtained above, p-toluenesulfonic acid is added as a weakly acidic catalyst. Then, under nitrogen protection, the system temperature is raised to 80-90℃. At this temperature, paraformaldehyde is depolymerized, and the depolymerized formaldehyde monomer undergoes a condensation reaction with the thiazolylhydrazone. During the reaction, the system temperature is maintained at 60-70℃, and the water generated in the reaction is continuously removed using the same azeotropic water separator as in the previous step. Heating is stopped when the amount of water separated in the water separator reaches 1.0-1.2 times the theoretical amount of water generated, indicating that the condensation reaction is essentially complete.

[0022] Following this, a deep dehydration and ring-closure reaction using molecular sieves was performed. After the reaction solution, having undergone initial dehydration, was cooled to room temperature, pre-activated 3Å molecular sieves were added to the reactor. The molecular sieves irreversibly adsorbed trace amounts of residual water in the system, while the negative pressure lowered the solvent's boiling point. This process facilitated a forward shift in the equilibrium of the dehydration and ring-closure reaction, ensuring the complete formation of the oxadiazine ring. After the reaction, the molecular sieves were removed by filtration, and the resulting filtrate was a toluene solution of the oxadiazine ring intermediate, which could be directly used in the subsequent nitration reaction.

[0023] In the selective nitration step of the oxadiazine ring intermediate, a mild nitration system is employed, the reaction process is precisely controlled at low temperatures, and an excess nitrifying agent capture mechanism is incorporated to ensure high selectivity and operational safety. When urea nitrate is used as the nitrifying agent, urea nitrate, as a solid nitrifying agent, exhibits mild reactivity and can slowly release nitrating active species into the organic phase, effectively avoiding violent exothermic reactions and side reactions. After the reaction, to completely quench any remaining excess nitrifying agent in the system, urea powder is added to the reactor. Urea reacts with the residual nitrating active substances to generate harmless nitrogen, carbon dioxide, and water, thereby completely eliminating safety hazards in the post-processing.

[0024] Then, through a systematic washing, drying, and cooling recrystallization process, the target product thiamethoxam is efficiently separated and purified, ultimately yielding a product with good crystal form and extremely high purity.

[0025] Compared with the prior art, the present invention has the following advantages: 1. This invention breaks through the dependence on single reagents in existing technologies in component selection. It achieves fundamental blocking of impurity accumulation through a synergistic strategy of source purification, intermediate stabilization, and precise product modification. The starting material is high-purity 2-chloro-5-chloromethylthiazole, prepared by precise proportioning of thiourea and ethyl 2-chloroacetoacetate and chlorination with sodium hypochlorite, avoiding the generation of perchlorinated impurities associated with traditional chlorine chlorination. The key intermediate, thiazolylhydrazone, is generated using anhydrous toluene as a solvent, combined with the weak acid catalysis of acetic acid. This suppresses the self-condensation side reaction of hydrazine and efficiently removes water through a toluene-water azeotrope, solving the ring-opening problem caused by water in existing technologies. In the oxadiazine ring construction stage, the weak acidity of p-toluenesulfonic acid and the physical adsorption of 3Å molecular sieves work synergistically to replace strong acid-base catalysis, avoiding side reactions. Nitration uses mild reagents such as urea nitrate, combined with a urea quenching system, solving the problems of over-nitration and corrosion associated with traditional mixed acid nitration. Recrystallization uses a mixed solvent of ethanol and water, achieving efficient separation of impurities and products through polarity matching. Compared to the high-pressure solvents with strong driving force or the sensitive control of oxadiazine salts in the prior art, the component selection of the present invention forms chemical compatibility from raw materials to products, fundamentally eliminating impurity transport pathways. Detailed Implementation

[0026] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0027] Example 1 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.05, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 7% of the total mass of the raw materials, the temperature is 85℃, and the reaction time is 3 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.08 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 65℃, and the reaction time is 1.5 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.2%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 5°C, the reaction time was 3 hours, and the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.3%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 99% acetic acid, with a dosage of 0.7% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.5 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone and paraformaldehyde were reacted under acidic conditions with p-toluenesulfonic acid as the catalyst. The amount of p-toluenesulfonic acid was 2.5 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent. The reaction temperature was 65℃. Water was removed by a water separator until the amount of water removed was ≥ 1.1 times the theoretical amount. Then, 3 Å molecular sieves were added at a dosage of 5 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 85℃ and refluxed for 2.5 hours at a gauge pressure of -0.05 MPa with a stirring rate of 250 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used is 1.2 times the molar amount of thiazolylhydrazone, the depolymerization temperature is 85℃, and the process is carried out under nitrogen protection; the 3Å molecular sieve is activated at 400℃ for 4 hours under nitrogen atmosphere before use, and can be reused 4 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with a nitrifying agent at 5°C for 1.5 hours. The nitrifying agent was urea nitrate. After the reaction, excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrifying agent was urea nitrate, and the molar ratio of urea nitrate to oxadiazine ring intermediate was 1:1. The amount of urea used was 1.2 times the molar amount of nitrifying agent. The capture reaction temperature was 3°C and the time was 0.8 hours. Post-processing and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.5%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.5, the crystallization temperature was 0℃, and the crystallization time was 1.5 hours.

[0028] Example 2 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.0, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 8% of the total mass of the raw materials, the temperature is 80℃, and the reaction time is 4 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.05 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 60℃, and the reaction time is 2 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.1%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 0℃, the reaction time was 4 hours, and the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.0%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.2:1. The acidic conditions were 98% acetic acid, and the dosage was 0.5% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone and paraformaldehyde were reacted under acidic conditions with p-toluenesulfonic acid as the catalyst. The amount of p-toluenesulfonic acid was 1.5 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent. The reaction temperature was 60℃. Water was removed through a water separator until the amount of water removed was ≥ 1.0 times the theoretical amount. Then, 3Å molecular sieve was added at a dosage of 4 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 80℃ and refluxed for 1.5 hours at a gauge pressure of -0.04 MPa with a stirring rate of 200 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used is 1.1 times the molar amount of thiazolylhydrazone, the depolymerization temperature is 80℃, and the process is carried out under nitrogen protection; the 3Å molecular sieve is activated at 350℃ for 5 hours under nitrogen atmosphere before use, and can be reused 3 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 0°C for 2 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrating agent was urea nitrate at 1 molar amount of the oxadiazine ring intermediate; the amount of urea was 1.1 times the molar amount of the nitrating agent; the capture reaction temperature was 0℃; and the reaction time was 1 hour. Post-processing and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.0%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3, the crystallization temperature was -5℃, and the crystallization time was 2 hours.

[0029] Example 3 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.1, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 5% of the total mass of the raw materials, the temperature is 90℃, and the reaction time is 2 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.15 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 70℃, and the reaction time is 1 hour, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.5%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 10℃, the reaction time was 2 hours, and the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.6%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.0:1. The acidic conditions were 99% acetic acid, with a dosage of 1.0% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 3 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone and paraformaldehyde were reacted under acidic conditions with p-toluenesulfonic acid as the catalyst. The amount of p-toluenesulfonic acid was 3.5 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent. The reaction temperature was 70°C. Water was removed by a water separator until the amount of water removed was ≥ 1.2 times the theoretical amount. Then, 3 Å molecular sieves were added at a volume corresponding to the reaction liquid volume of 6 g / L. The mixture was heated to 90°C and refluxed for 3.5 hours at a gauge pressure of -0.06 MPa with a stirring rate of 300 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used is 1.3 times the molar amount of thiazolylhydrazone, the depolymerization temperature is 90℃, and the process is carried out under nitrogen protection; the 3Å molecular sieve is activated at 450℃ for 3 hours under nitrogen atmosphere before use, and can be reused 5 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate is reacted with a nitrifying agent at 10°C for 1 hour. The nitrifying agent is urea nitrate. After the reaction is completed, excess nitrifying agent is captured with urea. After post-treatment and purification, thiamethoxam is obtained. The nitrifying reagent was in a 1:1 molar ratio of nitrate to urea; the amount of urea used was 1.3 times the molar amount of the nitrifying reagent; the capture reaction temperature was 5℃; and the reaction time was 0.5 hours. Post-processing and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.6%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:4, the crystallization temperature was 5℃, and the crystallization time was 1 hour.

[0030] Example 4 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.02, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 6% of the total mass of the raw materials, the temperature is 82℃, and the reaction time is 3.5 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.06 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 62℃, and the reaction time is 1.2 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.8%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 2℃, and the reaction time was 3.5 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.4%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 98.5% acetic acid, with a dosage of 0.6% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.2 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazolhydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, which was used at 1.8 mol% of the molar amount of thiazohydrazone. Toluene was used as the solvent. The reaction temperature was 62℃. Water was removed through a water separator until the amount of water removed was ≥ 1.05 times the theoretical amount. Then, 3Å molecular sieve was added at a volume corresponding to the reaction liquid volume of 4.5 g / L. The mixture was heated to 82℃ and refluxed for 2 hours at a gauge pressure of -0.042 MPa with a stirring rate of 220 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.15 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 82℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 380℃ for 4.5 hours under nitrogen atmosphere before use, and could be reused 4 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 2°C for 1.8 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrating agent was urea nitrate at a molar ratio of 1 molar amount of the oxadiazine ring intermediate; the amount of urea was 1.15 times the molar amount of the nitrating agent; the capture reaction temperature was 1℃; and the reaction time was 0.9 hours. Post-processing and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.4%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.2, the crystallization temperature was -3℃, and the crystallization time was 1.8 hours.

[0031] Example 5 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.08, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 9% of the total mass of the raw materials, the temperature is 88℃, and the reaction time is 2.5 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.12 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 68℃, and the reaction time is 1.3 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.3%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 8°C, and the reaction time was 2.2 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.1%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 99% acetic acid, with a dosage of 0.9% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.8 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 3.0 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 68℃. Water was removed through a water separator until the amount of water removed was ≥ 1.15 times the theoretical amount. Then, 3Å molecular sieve was added, and the amount corresponding to the reaction liquid volume was 5.5 g / L. The mixture was heated to 88℃ and refluxed for 3 hours at a gauge pressure of -0.058 MPa and a stirring rate of 280 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.25 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 88℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 420℃ for 3.5 hours under nitrogen atmosphere before use, and could be reused 4 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with a nitrifying agent at 8°C for 1.2 hours. The nitrifying agent was urea nitrate. After the reaction was completed, excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrifying reagent was nitrate-urea in a molar ratio of 1:1; the amount of urea used was 1.25 times the molar amount of the nitrifying reagent; the capture reaction temperature was 4℃; and the reaction time was 0.6 hours. Post-treatment and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.1%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.8, the crystallization temperature was 3℃, and the crystallization time was 1.2 hours.

[0032] Example 6 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.03, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 5.5% of the total mass of the raw materials, the temperature is 83℃, and the reaction time is 3.2 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.07 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 63℃, and the reaction time is 1.1 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.9%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 3℃, and the reaction time was 3.8 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.7%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 98% acetic acid, with a dosage of 0.55% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.1 hours. The hydrazone reaction was carried out using a microchannel made of Hastelloy C276 with an inner diameter of 1.3 mm, a flow rate of 0.15 mL / min, and a residence time of 28 minutes. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 2.0 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 63℃. Water was removed through a water separator until the amount of water removed was ≥ 1.02 times the theoretical amount. Then, 3Å molecular sieve was added, and the amount of water added was 4.2 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 83℃ and refluxed for 1.8 hours at a gauge pressure of -0.045 MPa and a stirring rate of 210 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.12 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 83℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 370℃ for 4.8 hours under nitrogen atmosphere before use, and could be reused 3 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 3°C ​​for 1.7 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrating agent was urea nitrate at a molar ratio of 1 molar amount of the oxadiazine ring intermediate; the amount of urea was 1.12 times the molar amount of the nitrating agent; the capture reaction temperature was 2℃; and the reaction time was 0.85 hours. Post-treatment and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.7%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.1, the crystallization temperature was -4℃, and the crystallization time was 1.7 hours.

[0033] Example 7 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.09, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 8.5% of the total mass of the raw materials, the temperature is 87℃, and the reaction time is 2.2 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating agent, the amount of which is 1.13 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 67℃, and the reaction time is 1.4 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.4%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 9°C, and the reaction time was 2.3 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.2%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 98% acetic acid, with a dosage of 0.95% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.9 hours. The hydrazone reaction was carried out using a microchannel made of Hastelloy C276 with an inner diameter of 1.9 mm, a flow rate of 0.45 mL / min, and a residence time of 11 minutes. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 3.2 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 67°C. Water was removed through a water separator until the amount of water removed was ≥ 1.18 times the theoretical amount. Then, 3 Å molecular sieve was added, and the amount of water added was 5.8 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 87°C and refluxed for 3.2 hours at a gauge pressure of -0.059 MPa with a stirring rate of 290 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.28 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 87℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 430℃ for 3.2 hours under nitrogen atmosphere before use, and could be reused 5 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with a nitrifying agent at 9°C for 1.1 hours. The nitrifying agent was urea nitrate. After the reaction, excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrifying agent was urea nitrate in a molar ratio of 1:1. The amount of urea used was 1.28 times the molar amount of the nitrifying agent. The capture reaction temperature was 4.5°C and the time was 0.55 hours. Post-treatment and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.2%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.9, the crystallization temperature was 4℃, and the crystallization time was 1.1 hours.

[0034] Example 8 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.04, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 7.5% of the total mass of the raw materials, the temperature is 84℃, and the reaction time is 2.8 hours; the chlorination reaction uses 10% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.09 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 64℃, and the reaction time is 1.6 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.6%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 4℃, and the reaction time was 3.3 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.8%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 98.5% acetic acid, with a dosage of 0.65% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.4 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 2.2 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 64℃. Water was removed through a water separator until the amount of water removed was ≥ 1.08 times the theoretical amount. Then, 3Å molecular sieve was added, and the amount of water added was 4.8 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 84℃ and refluxed for 2.2 hours at a gauge pressure of -0.048 MPa and a stirring rate of 230 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.18 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 84℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 390℃ for 4.2 hours under nitrogen atmosphere before use, and could be reused 4 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 4°C for 1.4 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrating agent was urea nitrate at a molar ratio of 1 molar amount of the oxadiazine ring intermediate; the amount of urea was 1.18 times the molar amount of the nitrating agent; the capture reaction temperature was 2.5℃ and the time was 0.75 hours; post-treatment and purification: the nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. After purification by recrystallization, the recrystallization solvent was a mixed solvent of ethanol and water, and the temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.8%; The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.3, the crystallization temperature was -2℃, and the crystallization time was 1.4 hours.

[0035] Example 9 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.06, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 9.5% of the total mass of the raw materials, the temperature is 86℃, and the reaction time is 2.6 hours; the chlorination reaction uses 15% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.11 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 66℃, and the reaction time is 1.7 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.0%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 6℃, and the reaction time was 2.7 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.3%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 99% acetic acid, with a dosage of 0.85% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.6 hours. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 2.8 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 66℃. Water was removed through a water separator until the amount of water removed was ≥ 1.12 times the theoretical amount. Then, 3Å molecular sieve was added, and the amount of water added was 5.2 g / L corresponding to the volume of the reaction liquid. The mixture was heated to 86℃ and refluxed for 2.8 hours at a gauge pressure of -0.055 MPa and a stirring rate of 260 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.22 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 86℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 410℃ for 3.8 hours under nitrogen atmosphere before use, and could be reused 4 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 7°C for 1.3 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrifying reagent was nitrate-urea in a molar ratio of 1:1; the amount of urea used was 1.22 times the molar amount of the nitrifying reagent; the capture reaction temperature was 3.5℃; the reaction time was 0.65 hours; post-treatment and purification: the nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.3%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.6, the crystallization temperature was 2℃, and the crystallization time was 1.3 hours.

[0036] Example 10 A method for synthesizing thiamethoxam includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: The preparation method of 2-chloro-5-chloromethylthiazole is as follows: using thiourea and ethyl 2-chloroacetoacetate as raw materials, with a molar ratio of 1:1.07, a cyclization reaction is carried out, with acetic acid as the catalyst, the amount of which is 6.5% of the total mass of the raw materials, the temperature is 89℃, and the reaction time is 2.4 hours; the chlorination reaction uses 12% sodium hypochlorite solution as the chlorinating reagent, the amount of which is 1.14 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 69℃, and the reaction time is 1.8 hours, to obtain 2-chloro-5-chloromethylthiazole with a purity of 97.7%; Step (2) Preparation of thiazohydrazone: 2-chloro-5-chloromethylthiazolium was used as the starting material and reacted with hydrazine under acidic conditions to generate thiazohydrazone. The generation of thiazohydrazone used an anhydrous organic solvent as the reaction medium, toluene, the reaction temperature was controlled at 7°C, and the reaction time was 3.6 hours. After the reaction, the generated water was removed by azeotropic dehydration. The azeotropic solvent was toluene-water azeotrope. The water was removed until the solvent was clear to obtain thiazohydrazone with a purity of 98.9%. The molar ratio of hydrazine to 2-chloro-5-chloromethylthiazolium was 1.1:1. The acidic conditions were 98% acetic acid, with a dosage of 0.75% of the mass of 2-chloro-5-chloromethylthiazole; the azeotropic dehydration time was 2.7 hours. The hydrazone reaction was carried out using a microchannel made of Hastelloy C276 with an inner diameter of 1.7 mm, a flow rate of 0.38 mL / min, and a residence time of 14 minutes. Step (3) Preparation of the oxadiazine ring intermediate: Thiazol hydrazone was reacted with paraformaldehyde under acidic conditions. The catalyst was p-toluenesulfonic acid, and the amount of p-toluenesulfonic acid was 3.3 mol% of the molar amount of thiazolyl hydrazone. Toluene was used as the solvent, and the reaction temperature was 69°C. Water was removed through a water separator until the amount of water removed was ≥ 1.19 times the theoretical amount. Then, 3 Å molecular sieve was added, and the amount corresponding to the reaction liquid volume was 5.9 g / L. The mixture was heated to 89°C and refluxed for 3.3 hours at a gauge pressure of -0.057 MPa with a stirring rate of 275 rpm to generate the oxadiazine ring intermediate. The acidic conditions are 25% acetic acid, and the dosage is 0.7% of the mass of thiazolyl hydrazone. The amount of paraformaldehyde used was 1.27 times the molar amount of thiazolylhydrazone, the depolymerization temperature was 89℃, and the process was carried out under nitrogen protection; the 3Å molecular sieve was activated at 440℃ for 3.0 hours under nitrogen atmosphere before use, and could be reused 5 times. Step (4) Nitration reaction of oxadiazine ring intermediate: The oxadiazine ring intermediate was reacted with the nitrifying agent at 6°C for 1.6 hours. The nitrifying agent was urea nitrate. After the reaction was completed, the excess nitrifying agent was captured with urea. After post-treatment and purification, thiamethoxam was obtained. The nitrating agent was urea nitrate at a molar ratio of 1 molar amount of the oxadiazine ring intermediate; the amount of urea was 1.27 times the molar amount of the nitrating agent; the capture reaction temperature was 4.8℃; and the reaction time was 0.58 hours. Post-treatment and purification: The nitration product was washed with 10% sodium carbonate solution, washed with water, dried with anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. Then, it was purified by recrystallization. The recrystallization solvent was a mixture of ethanol and water. The temperature was lowered from 40℃ to 0℃ at a rate of 2℃ / min to obtain thiamethoxam with a purity of 98.9%. The recrystallization solvent was a mixture of ethanol and water in a volume ratio of 1:3.7, the crystallization temperature was -1℃, and the crystallization time was 1.6 hours.

[0037] Comparative Example 1 The difference from Example 1 is that the chlorination reaction temperature in step (1) is 75°C.

[0038] Comparative Example 2 The difference from Example 1 is that the anhydrous organic solvent used in step (2) to prepare thiazolylhydrazone is ethanol.

[0039] Comparative Example 3 The difference from Example 1 is that in step (3) when preparing the oxadiazine ring intermediate, the amount of p-toluenesulfonic acid used is 5.0 mol of the molar amount of thiazolylhydrazone.

[0040] Comparative Example 4 The difference from Example 1 is that in step (4) nitration reaction, the molar ratio of urea nitrate to the oxadiazine ring intermediate is 1:0.8.

[0041] Comparative Example 5 The difference from Example 1 is that the recrystallization solvent in step (4) is a mixed solvent of ethanol and water in a volume ratio of 1:1.

[0042] Comparative Example 6 The difference from Example 1 is that in step (3) when preparing the oxadiazine ring intermediate, the amount of 3Å molecular sieve used is 2 g / L of the corresponding reaction liquid volume.

[0043] Comparative Example 7 The difference from Example 1 is that in step (3) when preparing the oxadiazine ring intermediate, the amount of paraformaldehyde used is 0.9 times the molar amount of thiazolylhydrazone.

[0044] Comparative Example 8 The difference from Example 1 is that the reaction temperature in step (2) for preparing thiazolylhydrazone is 25°C.

[0045] Comparative Example 9 The difference from Example 1 is that the cooling rate during recrystallization in step (5) is 5°C / min.

[0046] Comparative Example 10 The difference from Example 1 is that the depolymerization temperature of paraformaldehyde is 95°C when preparing the oxadiazine ring intermediate in step (3).

[0047] Comparative Example 11 The difference from Example 1 is that the recrystallization temperature in step (5) is 10°C.

[0048] Comparative Example 12 This comparative example employs a synthetic route that simulates a relatively crude control method that may exist in existing technologies.

[0049] Step 1 (Chlorination): After the cyclization reaction, the system was cooled to 30°C, and chlorine gas was introduced for photochlorination instead of using sodium hypochlorite. After the reaction, various perchlorinated and cyclic chlorinated byproducts were detected. The purity of the obtained 2-chloro-5-chloromethylthiazole intermediate was only 89.5% after preliminary purification.

[0050] Step 2 (hydrazone conversion): 85% hydrazine hydrate was added dropwise directly to the intermediate solution without the addition of glacial acetic acid catalyst. After the reaction was completed, only a portion of the water and solvent was removed by simple vacuum distillation; azeotropic dehydration was not employed.

[0051] Step 3 (cyclization): The aqueous crude product obtained in the previous step is directly heated in toluene to 110°C and refluxed for 6 hours to carry out one-step dehydration and cyclization.

[0052] Step 4 (Nitrification): A traditional mixed acid (concentrated nitric acid / concentrated sulfuric acid volume ratio 1:2) is used as the nitrating agent, and nitration is carried out at a temperature of 10-15℃. The reaction is highly exothermic, requiring the immediate addition of a large amount of crushed ice to control the reaction.

[0053] Step 5 (Crystallization): Dissolve the crude product after nitration and simple neutralization in hot ethanol, and then pour it directly into an ice-water bath for rapid quenching and crystallization.

[0054] Finally, using an equimolar amount of 2-chloro-5-chloromethylthiazole (1.0 kmol) as the starting material, and following the comparative method described above, 105.7 kg of solid product was obtained. HPLC analysis showed a purity of 92.5% and an overall yield of 63.8%. Impurity profile analysis revealed several significant impurity peaks exceeding 0.5%, including unreacted intermediates, ring-opening products, and polymers with unknown structures.

[0055] Detection: Purity of products at each stage: Organic phase purity detection (HPLC method) is shown in Table 1.

[0056] Table 1. Methods for testing the purity of process materials and final products.

[0057] Yield: Yield (%) = (Actual yield / Theoretical yield) × 100%, where the theoretical yield is calculated from the molar ratio and molar mass of the raw materials in the reaction formula; Catalyst residue detection: The 3Å molecular sieve contains metal elements, and the metal ion content can be detected by inductively coupled plasma optical emission spectrometry (ICP-OES); the characteristic anions of ionic liquids (ILs) can be detected by gas chromatography-mass spectrometry (GC-MS). The target catalyst residue is ≤0.1%, as shown in Table 2. Before detection, molecular sieve sample: take 10g of reaction solution → add 10mL of nitric acid → microwave digestion (200℃ / 30min) → make up to 50mL with ultrapure water; organic acid residue: take 0.5g of product → dissolve in acetonitrile and make up to 25mL → filter with 0.22μm filter membrane.

[0058] Table 2. Methods for detecting catalyst residues

[0059] Mandatory testing items are listed in Table 3: Table 3 Mandatory Testing Items

[0060] The test results are shown in Table 4.

[0061] Table 4. Test results for examples and comparative examples.

[0062] The technical advantage of this embodiment stems from the component-process synergistic control strategy. Through precise component selection and process parameter coordination, a closed loop of quality transfer from raw materials to products is formed at each stage, ultimately achieving a thiamethoxam purity of ≥98% and a yield of 88%-91%, demonstrating a deep synergy between component selection and process control.

[0063] Comparative Example 1: In the preparation of the starting materials, the chlorination reaction temperature was increased to 75°C, exceeding the optimized range of 60-70°C in Example 1. This resulted in a decrease in the reaction selectivity of sodium hypochlorite, leading to a reduction in the purity of 2-chloro-5-chloromethylthiazole compared to the Example, falling below 97.2% of Example 1. The lower purity of the starting materials allowed impurities to participate in subsequent reactions, including hydrazone formation, cyclization, and nitration, disrupting the coordination of components and processes in each step. Consequently, the product purity decreased to 95.8%, significantly lower than 98.5% of Example 1.

[0064] Comparative Example 2: Ethanol was used instead of toluene as the reaction medium in the hydrazone reaction. Ethanol has strong hydrophilicity and cannot construct a strictly anhydrous environment as in the anhydrous organic solvent in Example 1. This resulted in the purity of the oxadiazine ring intermediate dropping to 90.8% and the purity of the final product being only 93.7%, which destroyed the component-process synergy system from hydrazone to cyclization to the final product.

[0065] Comparative Example 3: In the oxadiazine cyclocondensation and cyclization reaction, the amount of p-toluenesulfonic acid was increased to 5.0 mol%, far exceeding the range of 1.5-3.5 mol% in Example 1. Excessive catalyst led to increased side reactions, affecting the selectivity of the condensation reaction and reducing the purity of the oxadiazine ring intermediate to 93.2%, with the final product purity at 96.2%. This disrupted the coordination between catalyst dosage, reaction temperature, and subsequent purification processes.

[0066] Comparative Example 4: In the nitration reaction, the molar ratio of the nitrating agent urea nitrate to the oxadiazine ring intermediate decreased to 1:0.8, lower than the 1:1 ratio in Example 1. Insufficient nitrating agent resulted in incomplete nitration. At the reaction temperature of 0-10°C, some of the oxadiazine ring intermediate was not nitrated. The remaining intermediate was difficult to completely separate from the target product in subsequent processing, leading to an increase in impurity content in the product and a decrease in purity to 94.5%. This disrupted the coordination between the amount of reagent used, the reaction temperature, and the post-processing in the nitration reaction.

[0067] Comparative Example 5: In the post-treatment and purification, the volume ratio of recrystallization solvent ethanol to water changed to 1:1, which differed from the 1:3-1:4 ratio in Example 1. Under this ratio, the polarity of the mixed solvent changed, adversely affecting the solubility and crystallization properties of thiamethoxam, thus impacting the product purification effect.

[0068] Comparative Example 6: In the oxadiazine cyclocondensation and cyclization reaction, the amount of 3Å molecular sieve was reduced to 2 g / L, lower than the 4-6 g / L in Example 1. When the reaction was refluxed at 85°C under a gauge pressure of -0.05 MPa, the smaller amount of molecular sieve could not fully adsorb the trace moisture in the system, and could not effectively promote the forward shift of the equilibrium of the dehydration and ring-closure reaction, resulting in a final product purity of only 93.2%.

[0069] Comparative Example 7: In the cyclocondensation and cyclization reaction of oxadiazine, the amount of paraformaldehyde used was only 0.9 times the molar amount of thiazolylhydrazone, which was lower than 1.1-1.3 times that of Example 1. The insufficient amount of paraformaldehyde could not fully react with thiazolylhydrazone, resulting in an incomplete condensation reaction, which ultimately affected the purity of the product, reducing it to 91.5%.

[0070] Comparative Example 8: The hydrazone reaction temperature was increased to 25°C, exceeding the 0-10°C range of Example 1. At this temperature, the activity of hydrazine increased, the rate of side reactions accelerated, and the higher temperature also affected the stability of the acetic acid catalyst, reducing catalytic efficiency.

[0071] Comparative Example 9: In the post-processing and purification, the recrystallization cooling rate was increased to 5°C / min, which is faster than the 2°C / min in Example 1. The rapid cooling caused the thiamethoxam crystals to precipitate quickly. During the crystal growth process, there was not enough time for them to arrange themselves in an orderly manner, and impurities could not be effectively removed. They were encapsulated in the crystals, resulting in a product purity of 96.8%.

[0072] Comparative Example 10: In the oxadiazine cyclocondensation and cyclization reaction, the depolymerization temperature of paraformaldehyde increased to 95°C, higher than the 80-90°C range in Example 1. The excessively high depolymerization temperature caused the paraformaldehyde to depolymerize too quickly, potentially leading to excessively high local formaldehyde concentrations and triggering side reactions, such as formaldehyde self-polymerization or unnecessary side reactions with thiazolylhydrazone. During the condensation at 65°C and cyclization at 85°C under a gauge pressure of -0.05 MPa, the side reaction products affected the catalytic effect of p-toluenesulfonic acid and the dehydration effect of the 3Å molecular sieve, resulting in a decrease in the purity of the oxadiazine cyclointermediate to 88.2%, and the final product purity to only 88.6%, thus disrupting the coordination between the depolymerization temperature and subsequent reaction processes.

[0073] Comparative Example 11: In the post-processing and purification, the recrystallization temperature was increased to 10°C, which is higher than the -5 to -5°C range of Example 1. The higher crystallization temperature increased the solubility of thiamethoxam in the solvent, making it difficult to effectively remove impurities during crystallization. These impurities were trapped inside the crystals, resulting in a decrease in product purity to 94.3% and affecting the recrystallization purification effect.

[0074] Comparative Example 12: Using a traditional, extensive synthetic route, the chlorination reaction employed photochlorination with chlorine gas instead of sodium hypochlorite, resulting in a large amount of perchlorinated and cyclic chlorinated byproducts, with the purity of 2-chloro-5-chloromethylthiazole being only 89.5%. The hydrazone reaction lacked an acetic acid catalyst and azeotropic dehydration, leading to incomplete reaction and high water content in the system. The one-step dehydration process in the cyclization reaction involved excessively high temperatures (110°C) and excessively long times (6 hours), resulting in increased side reactions. Nitration used mixed acids (concentrated nitric acid / concentrated sulfuric acid), which caused violent exothermic reactions and triggered side reactions. Rapid quenching during crystallization resulted in severe impurity encapsulation. The entire process exhibited severe mismatch between the components and the process, failing to form a synergistic control system, resulting in a product purity of only 92.5% and a yield of 63.8%, far lower than Example 1.

Claims

1. A method for synthesizing thiamethoxam, characterized in that, Includes the following steps: Step (1) Preparation of 2-chloro-5-chloromethylthiazole: Thiourea and ethyl 2-chloroacetoacetate are used as raw materials, the molar ratio of thiourea to ethyl 2-chloroacetoacetate is 1:1.0-1.1, and a cyclization reaction is carried out. Acetic acid is used as the catalyst, the amount of the catalyst is 5%-10% of the total mass of the raw materials, the temperature is 80-90℃, and the reaction time is 2-4 hours. Then, sodium hypochlorite is used as the chlorinating agent to carry out the chlorination reaction. The amount of sodium hypochlorite is 1.05-1.15 times the molar amount of ethyl 2-chloroacetoacetate, the temperature is 60-70℃, and the reaction time is 1-2 hours to obtain 2-chloro-5-chloromethylthiazole; Step (2) Preparation of thiazolylhydrazone: The 2-chloro-5-chloromethylthiazolium and hydrazine are reacted with each other in an anhydrous organic solvent at a molar ratio of 1:1-1.2 under acidic conditions to generate thiazolylhydrazone. The reaction temperature is controlled at 0-10℃ and the reaction time is 2-4 hours. After the reaction is completed, the generated water is removed by azeotropic dehydration. Step (3) Preparation of the oxadiazine ring intermediate: The thiazolylhydrazone is reacted with paraformaldehyde under acidic conditions. The catalyst is p-toluenesulfonic acid, and the amount of catalyst is 1.5 mol%-3.5 mol% of the molar amount of thiazolylhydrazone. Toluene is used as the solvent, and the reaction temperature is 60-70℃. Water is removed through a water separator until the amount of water removed is ≥ 1.0-1.2 times the theoretical amount. Then, 3Å molecular sieve is added, and the amount corresponding to the reaction liquid volume is 4-6 g / L. The mixture is heated to 80-90℃ and refluxed for 1.5-3.5 hours at a gauge pressure of -0.04 to -0.06 MPa, with a stirring rate of 200-300 rpm to generate the oxadiazine ring intermediate. The amount of paraformaldehyde is 1.1-1.3 times the molar amount of thiazolylhydrazone. Step (4) Nitration reaction of the oxadiazine ring intermediate: The oxadiazine ring intermediate is mixed with the nitrifying reagent at a molar ratio of 1:1-1.2 and reacted at 0-10℃ for 1-2 hours. After the reaction is completed, excess nitrifying reagent is captured with urea. After post-treatment and purification, the thiamethoxam is obtained. The nitrifying reagent is urea nitrate. The amount of urea used is 1.1-1.3 times the molar amount of the nitrifying reagent.

2. The method for synthesizing thiamethoxam according to claim 1, characterized in that, In step (2), the anhydrous organic solvent is toluene.

3. The method for synthesizing thiamethoxam according to claim 1, characterized in that, In step (2), under acidic conditions, acetic acid with a mass fraction ≥98% is used, and the amount of acetic acid used is 0.5%-1.0% of the mass of 2-chloro-5-chloromethylthiazole; The azeotropic dehydration process takes 2-3 hours.

4. The method for synthesizing thiamethoxam according to claim 1, characterized in that, In step (3), before the thiazolyl hydrazone reacts with paraformaldehyde under acidic conditions, the paraformaldehyde is depolymerized at 80-90℃ under nitrogen protection; the 3Å molecular sieve is activated at 350-450℃ for 3-5 hours under nitrogen atmosphere before use, and can be reused ≥3 times.

5. The method for synthesizing thiamethoxam according to claim 1, characterized in that, When the nitrifying agent in step (4) is urea nitrate, the molar ratio of urea nitrate to the oxadiazine ring intermediate is 1:

1.

6. The method for synthesizing thiamethoxam according to claim 1, characterized in that, In step (4), the capture reaction temperature for capturing excess nitrifying reagent with urea is 0-5℃ and the time is 0.5-1 hour.

7. The method for synthesizing thiamethoxam according to claim 1, characterized in that, The post-processing and purification process specifically involves: washing the nitration product with sodium carbonate solution, washing with water, drying with anhydrous sodium sulfate, removing the solvent by vacuum distillation, purifying by recrystallization, and cooling to obtain thiamethoxam with a purity ≥98%.

8. The method for synthesizing thiamethoxam according to claim 7, characterized in that, During the recrystallization purification, the recrystallization solvent is a mixture of ethanol and water.

9. A method for synthesizing thiamethoxam according to claim 8, characterized in that, The volume ratio of ethanol to water is 1:3 to 1:

4.

10. A method for synthesizing thiamethoxam according to claim 7, characterized in that, During the recrystallization purification, the crystallization temperature is -5 to 5°C and the crystallization time is 1 to 2 hours.

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