A process for the preparation of fluopyram

Abstract

The application discloses a preparation method of fluopyram, which comprises the following steps: step 1: in the presence of solvent 1 and a base, dimethyl malonate and 2,3-dichloro-5-trifluoromethyl pyridine are added to react, a salt reaction is carried out by adjusting pH, and 2-[3-chloro-5-(trifluoromethyl) pyridyl] dimethyl malonate potassium salt, namely intermediate 1, is obtained; step 2: o-trifluoromethyl benzoyl chloride, an organic base and chloromethylamine are added to react, and intermediate 2 is obtained; step 3: solvent 3, intermediate 1 and intermediate 2 are added to react, and intermediate 3 is obtained; step 4: water, a base, solvent 4 and intermediate 3 are added, pH is adjusted after reaction, and continuous reaction is carried out, and fluopyram is obtained. By adopting the preparation method, the yield of fluopyram is high, the purity is high, the reaction time is short, the reaction condition is mild, and the method is suitable for mass production.

Description

Technical Field

[0001] This invention relates to a method for preparing fluopyram, belonging to the field of organic chemistry technology. Background Technology

[0002] Fluopyram is a benzamide fungicide discovered and developed by Bayer, and is a succinate dehydrogenase inhibitor (SDHI). Its chemical name is: N-{2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethyl}-2-(trifluoromethyl)benzamide; molecular formula: C16H11ClF6N2O; relative molecular mass: 396.76; CAS Registry Number: 658066-35-4. Fluopyram is an excellent fungicide and nematicide, currently registered and marketed in over 60 countries and regions worldwide, and used on more than 70 crops. This product is highly effective in controlling many diseases, such as gray mold, powdery mildew, sclerotinia rot, and soybean sudden death syndrome. It can also control many nematodes, such as root-knot nematodes, root-rot nematodes, borer nematodes, hairy nematodes, and stinging nematodes. It is the first SDHI fungicide to provide nematicidal activity. Fluopyram has low toxicity, requires low dosage, and is environmentally friendly.

[0003] Bayer CropScience AG of Germany applied for a compound invention patent in China on August 8, 2003 (patent number: 038194716). On November 5, 2012, it obtained pesticide registration in China for 96% fluopyram technical grade (registration certificate number PD20121673).

[0004] Currently, the actual production of fluopyram faces problems such as long production routes, difficulty in cost control, low yield, poor product quality, and low purity and content. To improve market competitiveness, it is necessary to find a preparation process route that is short, low-cost, high-yield, and produces products with high purity and content. The main process routes for fluopyram are as follows:

[0005] Route 1: Patent EP1674455 discloses a method using 2,3-dichloro-5-trifluoromethylpyridine and ethyl cyanoacetate as raw materials, followed by nucleophilic substitution, hydrolytic decarboxylation, catalytic hydrogenation, and hydrolysis to obtain 3-chloro-5-(trifluoromethyl)-2-(2-aminoethyl)pyridine A4, which is then reacted with the intermediate o-trifluoromethylbenzoyl chloride to obtain fluopyram. This route has a low overall yield of approximately 44%. Furthermore, it requires the use of palladium as a catalyst for hydrogenation reduction, significantly increasing costs. Additionally, this hydrogenation step is prone to dechlorination side reactions, generating difficult-to-remove impurities, which is detrimental to industrial-scale production.

[0006]

[0007] Route 2: Patent WO2018 / 114484 discloses a process using o-trifluoromethylbenzoic acid as a raw material, which involves acylation, amination, hydroxymethylation, and esterification to produce intermediate B5; 2,3-dichloro-5-trifluoromethylpyridine and diethyl malonate are then condensed to produce intermediate B1; intermediate B5 and intermediate B1 are then condensed together to produce intermediate B6; finally, hydrolysis and decarboxylation yield fluopyram. This process involves as many as seven steps, and the condensation reaction conditions between intermediates B5 and B1 are quite harsh, with a low overall yield of approximately 49%. The operation is complex and cumbersome, increasing costs and hindering industrial-scale production.

[0008]

[0009] Route 3: Patent CN113620867A uses 2,3-dichlorotrifluorotoluene to obtain intermediate C6 through fluorination, cyano substitution, hydrolysis, hydroxymethylation, and esterification; 2,3-dichloro-5-trifluoromethylpyridine is reacted with malonate diester to obtain intermediate C1; intermediate C6 and intermediate C1 are condensed, then hydrolyzed, decarboxylated, and finally hydrogenated and dechlorinated to obtain fluopyram. This route is long and has many side reactions. In particular, this route requires the use of palladium as a catalyst for hydrogenation reduction, which greatly increases the cost. At the same time, it is difficult to control the reaction conditions for selective dechlorination in this hydrogenation step, which easily generates impurities that are difficult to remove, which is not conducive to industrial production. In addition, the overall yield of the product is low, only 50.3%.

[0010]

[0011] For the reasons mentioned above, there is an urgent need for a method to prepare fluopyram to solve the problems of long production routes, difficulty in cost control, low yield, poor product quality, and low purity and content, thereby improving market competitiveness. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to provide a method for preparing fluopyram with high yield, high purity and low cost.

[0013] The present invention solves the above-mentioned technical problems through the following technical solutions:

[0014] This invention provides a method for preparing fluopyram, comprising the following steps:

[0015] Step 1: In the presence of solvent 1 and alkali, dimethyl malonate and 2,3-dichloro-5-trifluoromethylpyridine are added to react and the pH is adjusted to 4-6 to obtain a crude product. The crude product is then added to an alcoholic solvent containing potassium alkoxide to carry out a salting reaction to obtain potassium salt of 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, i.e., intermediate 1.

[0016] Step 2: In the presence of solvent 2, o-trifluoromethylbenzoyl chloride, organic base and chloromethylamine are added to the reaction vessel to carry out the reaction. After the reaction is completed, N-(chloromethyl)-2-trifluoromethylbenzamide, i.e. intermediate 2, is obtained.

[0017] Step 3: In the presence of solvent 3, intermediate 1 and intermediate 2 are added to the reaction vessel to carry out the reaction. After the reaction is completed, intermediate 3 is obtained.

[0018] Step 4: Add water, alkali, solvent 4, and intermediate 3 to the reaction vessel. After the reaction, remove the solvent, adjust the pH, and continue the reaction. After the reaction is completed, the product fluopyram is obtained.

[0019]

[0020] Preferably, in step 1, solvent 1 is selected from N,N-dimethylacetamide and / or N,N-dimethylformamide; the solvent used to adjust the pH is selected from hydrochloric acid; the base is selected from potassium hydroxide; the alcohol solvent is selected from at least one of tert-butanol, methanol, and isopropanol; the potassium alkoxide is selected from potassium tert-butoxide and / or potassium methoxide; the mass ratio of 2,3-dichloro-5-trifluoromethylpyridine to solvent 1 is 1:3.0-7.0; the mass ratio of 2,3-dichloro-5-trifluoromethylpyridine to alcohol solvent is 1:2.0. -8.0; the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to base is 1:1.0-1.2; the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to dimethyl malonate is 1:1.0-1.2; the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to potassium alkoxide is 1:1.1-2.0; the temperature at which it is added is 25-40℃; the reaction temperature is 25-50℃, and the reaction time is 2-5 hours; the salt formation temperature is 10-40℃, and the salt formation reaction time is 0.5-3 hours.

[0021] More preferably, step 1, after adjusting the pH, further includes a post-processing step: extraction, merging the organic phases, and concentration under reduced pressure; the mass ratio of 2,3-dichloro-5-trifluoromethylpyridine to the extraction solvent is 1:3.0-8.0, and the extraction solvent is methyl tert-butyl ether.

[0022] More preferably, after the reaction in step 1 is completed, a post-processing step is further included: filtration, the mother liquor can be reused, the filter cake is washed with an alcohol solvent and then dried, wherein the alcohol solvent is selected from at least one of tert-butanol, methanol and isopropanol.

[0023] Preferably, in step 2, solvent 2 is selected from 1,2-dichloroethane and / or dichloromethane; the mass ratio of o-trifluoromethylbenzoyl chloride to solvent 2 is 1:3.0-8.0; the organic base is selected from triethylamine and / or diisopropylethylamine; the molar ratio of o-trifluoromethylbenzoyl chloride to organic base is 1:1.0-1.3; the molar ratio of o-trifluoromethylbenzoyl chloride to chloromethylamine is 1:1.0-1.4; the reaction temperature is -5-20℃, and the reaction time is 3-6 hours.

[0024] More preferably, after the reaction in step 2 is completed, a post-processing step is also included: vacuum concentration.

[0025] Preferably, in step 3, solvent 3 is N,N-dimethylacetamide and / or dimethyl sulfoxide; the molar ratio of intermediate 1 to intermediate 2 is 1:1.0-1.2; the addition temperature is 40-60℃; the reaction temperature is 45-65℃; and the reaction time is 2-4 hours.

[0026] More preferably, after the reaction in step 3 is completed, a post-processing step is further included: solvent recovery under reduced pressure, adding organic solvent and water to the residue, extraction and separation, washing the organic phase with water, concentration under reduced pressure to obtain crude product; recrystallization, wherein the organic solvent is selected from methyl tert-butyl ether and / or 1,2-dichloroethane, and the solvent used for recrystallization is selected from at least one of methanol, ethanol and water.

[0027] Preferably, in step 4, solvent 4 is methanol; the mass ratio of intermediate 3 to water is 1:1.0-3.0; the mass ratio of intermediate 3 to solvent 4 is 1:1.0-3.0; the alkali is potassium hydroxide; the reaction temperature is 25-45℃; the reaction time is 3-6 hours; the reaction temperature for continued reaction is 40-60℃, and the reaction time for continued reaction is 2-5 hours.

[0028] More preferably, after the reaction in step 4 is completed, a post-processing step is also included: filtration, washing, drying, and recrystallization. The solvent used for recrystallization is preferably methanol and / or water, and the mass ratio of intermediate 3 to the solvent is 1:2.0-6.0.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] 1. In step 1 of this invention, 2,3-dichloro-5-trifluoromethylpyridine is used as raw material. By controlling process conditions such as temperature, potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonic acid is obtained in high yield through condensation reaction and salt formation. At the same time, the alcoholic solution of the potassium alkoxide used for salt formation can be reused for the next batch of salt formation, resulting in high raw material utilization and reduced environmental pollution. The separation efficiency is high, the yield is high, the purity is high, the reaction time is short, and the reaction conditions are mild, making it suitable for large-scale production.

[0031] 2. In step 2 of this invention, through numerous experiments, it was found that using chloromethylamine can synthesize N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, in high yield. This preparation process can synthesize intermediate 2 in one step, and the post-processing process is simple. The product does not need to be purified and can be used for the next reaction. The raw material utilization rate is high. This method can greatly improve the synthesis efficiency of intermediate 2. The obtained intermediate 2 has high purity and stable quality, which is conducive to improving the yield of intermediate 3 in subsequent steps and simplifying the purification process.

[0032] 3. In step 3 of this invention, the reaction time is short, the reaction conditions are mild, and intermediate 3 can be obtained in high yield. The selectivity of the reaction is improved, the generation of impurities is suppressed, and high-purity intermediate 3 can be obtained by simple recrystallization. Meanwhile, in step 4 of this invention, by controlling the amount of water and alkali and the reaction temperature, the hydrolysis and decarboxylation reactions can be carried out in a one-pot process, significantly reducing the amount of waste, production time, and post-processing. High-purity fluopyram can be obtained in high yield by simple recrystallization. The fluopyram product obtained by this method has a purity ≥98.5%, a mass content ≥98.0%, and a total yield of ≥66.9% across the four steps. Detailed Implementation

[0033] To make the present invention more apparent and understandable, preferred embodiments are described in detail below:

[0034] Unless otherwise specified, percentages in this invention refer to mass concentration or mass percentage.

[0035] In all embodiments of this invention, purity determination was performed using high performance liquid chromatography.

[0036] In this embodiment of the invention, the 2,3-dichloro-5-trifluoromethylpyridine and o-trifluoromethylbenzoyl chloride used were purchased from commercially available industrial products with a purity of ≥99.0%. All other reagents were commercially available products with a purity of ≥99.0%.

[0037] Example 1

[0038] Step 1: In a reaction vessel, add solvent N,N-dimethylacetamide (108.00 g) and potassium hydroxide (90%, 6.23 g, 0.11 mol). Stir at 25-35°C for 2 hours, controlling the dropping temperature at 31-35°C. Add dimethyl malonate (15.20 g, 0.115 mol). After the addition is complete, continue stirring for 2 hours, controlling the dropping temperature at 33-36°C. Add 2,3-dichloro-5-trifluoromethylpyridine (21.60 g, 0.10 mol). After the addition is complete, raise the temperature to the reaction temperature of 45°C and continue stirring for 4 hours until the conversion is satisfactory. After the reaction is complete, add water to the reaction solution, adjust the pH to 4-6 with hydrochloric acid, and extract with methyl tert-butyl ether (86.40 g). After separation, back-extract the aqueous phase with methyl tert-butyl ether (43.20 g), combine the organic phases, and concentrate under reduced pressure to obtain the crude product. The crude product was added to a solution prepared with potassium tert-butoxide (16.83 g, 0.15 mol) and isopropanol (64.80 g). The salt-forming temperature was controlled at 21-25 °C. After stirring for 3 hours, a large amount of solid precipitated. The solid was filtered, and the mother liquor could be reused for the next batch of salt formation. The filter cake was washed with isopropanol and dried to obtain potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, i.e., intermediate 1, with a mass of 32.87 g. The yield of intermediate 1 in this step was calculated to be 94.0%, and the purity of the product was 98.0%.

[0039] Step 2: Add 1,2-dichloroethane (83.44 g), o-trifluoromethylbenzoyl chloride (20.86 g, 0.10 mol), and triethylamine (12.14 g, 0.12 mol) to the reaction vessel. Under stirring at 0°C, add chloromethylamine (7.21 g, 0.11 mol) dropwise. After the addition is complete, continue the reaction for 4 hours. After the conversion is qualified under control, concentrate the reaction solution under reduced pressure to obtain N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, with a mass of 22.81 g. The yield of intermediate 2 in this step is calculated to be 96.0%, and the purity of the product is 94.0%. This intermediate does not require purification and can be used directly in the next step.

[0040] Step 3: Add N,N-dimethylacetamide (69.94 g) to the reaction vessel. At room temperature, add intermediate 1 (34.97 g, 0.1 mol), stir and heat to 41-45°C. Add intermediate 2 (28.51 g, 0.12 mol) dropwise. After the addition is complete, heat to 52°C and react for 3 hours. After the conversion is successful under controlled pressure, recover the solvent under reduced pressure. Add methyl tert-butyl ether (69.94 g) and water (114.04 g) to the residue, extract and separate the liquid. Wash the organic phase with water and concentrate under reduced pressure to obtain the crude product. Recrystallize the crude product from methanol (containing 10% water, 104.91 g) to obtain intermediate 3 with a mass of 44.10 g. The yield of intermediate 3 in this step is calculated to be 86.0%, and the product purity is 97.5%.

[0041] Step 4: Add water (51.28 g) to the reactor, then add a certain amount of potassium hydroxide (90%, 15.59 g, 0.25 mol), stir to dissolve, then add methanol (51.28 g) and intermediate 3 (25.64 g, 0.05 mol), stir and heat to 30°C. After reacting for 4 hours, once the conversion is qualified, evaporate the methanol, cool to room temperature, adjust the pH to 1.5-2.5 with 36% hydrochloric acid aqueous solution, then stir and heat to the reaction temperature of 50°C, react for 3 hours, filter while hot, wash the solid with water, filter again, and dry to obtain the crude product. Recrystallize the crude product with methanol (containing 30% water, 64.1 g), filter, and dry to obtain the product fluopyram, with a mass of 18.25 g. The yield of fluopyram in this step is calculated to be 92.0%. The purity of the fluopyram product from this method is 98.5%, and the mass content is 98.2%. The overall yield of the four steps is calculated to be 71.4%.

[0042] Example 2

[0043] Step 1: In a reaction vessel, add solvent N,N-dimethylacetamide (108.00 g) and potassium hydroxide (90%, 6.23 g, 0.11 mol). Stir at 25-35°C for 2 hours, controlling the dropping temperature at 35-37°C. Add dimethyl malonate (15.86 g, 0.12 mol). After the addition is complete, continue stirring for 2 hours, controlling the dropping temperature at 33-36°C. Add 2,3-dichloro-5-trifluoromethylpyridine (21.60 g, 0.10 mol). After the addition is complete, raise the temperature to the reaction temperature of 47°C and continue stirring for 5 hours until the conversion is satisfactory. After the reaction is complete, add water to the reaction solution, adjust the pH to 4-6 with hydrochloric acid, and extract with methyl tert-butyl ether (86.40 g). After separation, back-extract the aqueous phase with methyl tert-butyl ether (43.20 g), combine the organic phases, and concentrate under reduced pressure to obtain the crude product. The crude product was added to a solution prepared with potassium tert-butoxide (15.71 g, 0.14 mol) and tert-butanol (64.80 g). The salt-forming temperature was controlled at 25-30 °C. After stirring for 3 hours, a large amount of solid precipitated. The solid was filtered, and the mother liquor could be reused for the next batch of salt formation. The filter cake was washed with tert-butanol and dried to obtain potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, with a mass of 32.52 g. The yield of intermediate 1 in this step was calculated to be 93.0%, and the product purity was 97.7%.

[0044] Step 2: Dichloromethane (83.44 g), o-trifluoromethylbenzoyl chloride (20.86 g, 0.10 mol), and triethylamine (12.14 g, 0.12 mol) were added to the reaction vessel. Chloromethylamine (7.89 g, 0.12 mol) was added dropwise with stirring at 0°C. After the addition was complete, the reaction continued for 4 hours. After the conversion was deemed successful under control, the reaction solution was concentrated under reduced pressure to obtain N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, with a mass of 22.69 g. The yield of intermediate 2 in this step was calculated to be 95.5%, and the purity of the product was 93.2%. This intermediate can be used directly in the next step without further purification.

[0045] Step 3: Add N,N-dimethylacetamide (69.94 g) to the reaction vessel. At room temperature, add intermediate 1 (34.97 g, 0.1 mol), stir and heat to 45-50°C. Add intermediate 2 (26.13 g, 0.11 mol) dropwise. After the addition is complete, heat to 60°C and react for 3 hours. After the conversion is successful under controlled pressure, recover the solvent under reduced pressure. Add methyl tert-butyl ether (69.94 g) and water (114.04 g) to the residue, extract and separate the liquid. Wash the organic phase with water and concentrate under reduced pressure to obtain the crude product. Recrystallize the crude product from ethanol (containing 10% water, 104.91 g) to obtain intermediate 3 with a mass of 43.33 g. The yield of intermediate 3 in this step is calculated to be 84.5%, and the product purity is 97.4%.

[0046] Step 4: Add water (64.10 g) to the reactor, then add a certain amount of potassium hydroxide (90%, 16.84 g, 0.27 mol), stir to dissolve, then add methanol (51.28 g) and intermediate 3 (25.64 g, 0.05 mol), stir and heat to 35°C. After reacting for 4 hours, once the conversion is qualified, evaporate the methanol, cool to room temperature, adjust the pH to 1.5-2.5 with 36% hydrochloric acid aqueous solution, then stir and heat to the reaction temperature of 55°C, react for 3 hours, filter while hot, wash the solid with water, filter again, and dry to obtain the crude product. Recrystallize the crude product with methanol (containing 35% water, 76.92 g), filter, and dry to obtain the product fluopyram, with a mass of 18.07 g. The yield of fluopyram in this step is calculated to be 91.1%. The purity of the fluopyram product from this method is 98.4%, and the mass content is 98.0%. The overall yield of the four steps is calculated to be 68.37%.

[0047] Example 3

[0048] Step 1: In a reaction vessel, add solvent N,N-dimethylformamide (108.00 g) and potassium hydroxide (90%, 6.23 g, 0.11 mol). Stir at 25-35°C for 2 hours, controlling the dropping temperature at 35-37°C. Add dimethyl malonate (15.86 g, 0.12 mol). After the addition is complete, continue stirring for 2 hours, controlling the dropping temperature at 30-35°C. Add 2,3-dichloro-5-trifluoromethylpyridine (21.60 g, 0.10 mol). After the addition is complete, raise the temperature to the reaction temperature of 45°C and continue stirring for 5 hours until the conversion is satisfactory. After the reaction is complete, add water to the reaction solution, adjust the pH to 4-6 with hydrochloric acid, and extract with methyl tert-butyl ether (86.40 g). After separation, back-extract the aqueous phase with methyl tert-butyl ether (43.20 g), combine the organic phases, and concentrate under reduced pressure to obtain the crude product. The crude product was added to a solution prepared from potassium methoxide (10.52 g, 0.15 mol) and methanol (64.80 g). The salt-forming temperature was controlled at 15-20 °C. After stirring for 3 hours, a large amount of solid precipitated. The solid was filtered, and the mother liquor could be reused for the next batch of salt formation. The filter cake was washed with methanol and dried to obtain potassium 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonic acid dimethyl ester, with a mass of 31.89 g. The yield of intermediate 1 in this step was calculated to be 91.2%, and the product purity was 97.9%.

[0049] Step 2: Add 1,2-dichloroethane (62.58 g), o-trifluoromethylbenzoyl chloride (20.86 g, 0.10 mol), and diisopropylethylamine (15.51 g, 0.12 mol) to the reaction vessel. While stirring, add chloromethylamine (7.89 g, 0.12 mol) dropwise at 2°C. After the addition is complete, continue the reaction for 5 hours. After the conversion is successful, concentrate the reaction solution under reduced pressure to obtain N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, with a mass of 22.93 g. The yield of intermediate 2 in this step is calculated to be 96.5%, and the purity is 93.5%. This intermediate does not require purification and can be used directly in the next step.

[0050] Step 3: Add dimethyl sulfoxide (69.94 g) to the reaction vessel. At room temperature, add intermediate 1 (34.97 g, 0.1 mol), stir and heat to 50-55°C. Add intermediate 2 (26.13 g, 0.11 mol) dropwise. After the addition is complete, heat to 65°C and react for 3 hours. After the conversion is successful under controlled conditions, recover the solvent under reduced pressure. Add 1,2-dichloroethane (69.94 g) and water (114.04 g) to the residue, extract and separate the liquid. Wash the organic phase with water and concentrate under reduced pressure to obtain the crude product. Recrystallize the crude product from methanol (containing 10% water, 87.43 g) to obtain intermediate 3 with a mass of 43.12 g. The yield of intermediate 3 in this step is calculated to be 84.1%, and the product purity is 97.1%.

[0051] Step 4: Add water (38.36 g) to the reactor, then add a certain amount of potassium hydroxide (90%, 16.84 g, 0.27 mol), stir to dissolve, then add methanol (51.28 g) and intermediate 3 (25.64 g, 0.05 mol), stir and heat to 30°C. After reacting for 5 hours, once the conversion is qualified, evaporate the methanol, cool to room temperature, adjust the pH to 1.5-2.5 with 36% hydrochloric acid aqueous solution, then stir and heat to the reaction temperature of 50°C, react for 4 hours, filter while hot, wash the solid with water, filter again, and dry to obtain the crude product. Recrystallize the crude product from methanol (containing 35% water, 64.1 g), filter, and dry to obtain the product fluopyram, with a mass of 17.93 g. The yield of fluopyram in this step is calculated to be 90.4%. The purity of the fluopyram product from this method is 98.6%, and the mass content is 98.1%. The overall yield of the four steps is calculated to be 66.91%.

Claims

1. A method for preparing fluopyram, characterized in that, Includes the following steps: Step 1: In the presence of solvent 1 and alkali, dimethyl malonate and 2,3-dichloro-5-trifluoromethylpyridine are added to react and the pH is adjusted to 4-6 to obtain a crude product. The crude product is then added to an alcoholic solvent containing potassium alkoxide to carry out a salting reaction to obtain potassium salt of 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, i.e., intermediate 1. Step 2: In the presence of solvent 2, o-trifluoromethylbenzoyl chloride, organic base and chloromethylamine are added to the reaction vessel to carry out the reaction. After the reaction is completed, N-(chloromethyl)-2-trifluoromethylbenzamide, i.e. intermediate 2, is obtained. Step 3: Add solvent 3, intermediate 1, and intermediate 2 to the reaction vessel and react. After the reaction is complete, intermediate 3 is obtained. Step 4: Add water, alkali, solvent 4, and intermediate 3 to the reaction vessel. After the reaction, remove the solvent, adjust the pH, and continue the reaction to obtain the product fluopyram. In step 1, solvent 1 is N,N-dimethylacetamide and / or N,N-dimethylformamide, and the solvent used to adjust the pH is hydrochloric acid; the base is potassium hydroxide; the alcohol solvent is at least one of tert-butanol, methanol, and isopropanol; and the potassium alkoxide is potassium tert-butoxide and / or potassium methoxide. In step 1, the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to the base is 1:1.0-1.2; the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to dimethyl malonate is 1:1.0-1.2; and the molar ratio of 2,3-dichloro-5-trifluoromethylpyridine to potassium alkoxide is 1:1.1-2.

0. In step 1, the temperature at which the substance is added is 25-40℃; the reaction temperature is 25-50℃; the reaction time is 2-5 hours; the salt formation temperature is 10-40℃; and the salt formation reaction time is 0.5-3 hours. In step 3, solvent 3 is N,N-dimethylacetamide and / or dimethyl sulfoxide; the molar ratio of intermediate 1 to intermediate 2 is 1:1.0-1.2; the addition temperature is 40-60℃; the reaction temperature is 45-65℃; and the reaction time is 2-4 hours.

2. The preparation method according to claim 1, characterized in that, In step 2, solvent 2 is 1,2-dichloroethane and / or dichloromethane; organic base is triethylamine and / or diisopropylethylamine; the molar ratio of o-trifluoromethylbenzoyl chloride to organic base is 1:1.0-1.3; and the molar ratio of o-trifluoromethylbenzoyl chloride to chloromethylamine is 1:1.0-1.

4.

3. The preparation method according to claim 1, characterized in that, In step 2, the reaction temperature is -5 to 20°C, and the reaction time is 3 to 6 hours.

4. The preparation method according to claim 1, characterized in that, In step 4, solvent 4 is methanol; the molar ratio of intermediate 3 to alkali is 1:3.5-6.0; and alkali is potassium hydroxide.

5. The preparation method according to claim 1, characterized in that, In step 4, the reaction temperature is 25-45℃; the reaction time is 3-6 hours; the reaction temperature for continued reaction is 40-60℃, and the reaction time for continued reaction is 2-5 hours.

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