Process method for preparing fluopyram

Abstract

Disclosed in the present invention is a process method for preparing fluopyram. The process method comprises the following steps: in the presence of a solvent 1, the compound potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]malonate reacting with a compound 1-D in a reaction vessel to obtain an intermediate compound, then distilling, and recovering the solvent 1, wherein the intermediate compound does not need to be purified; then adding water, a base, and a solvent 2 to the reaction vessel for reaction; after the reaction is finished, adjusting the pH, and continuing reaction; and after the reaction is finished, performing work-up to obtain the product fluopyram. The solvent 1 is selected from acetate solvents having a boiling point ranging from 40ºC to 110ºC at room temperature and atmospheric pressure. The process method of the present invention is simple, has high overall yield, and low cost, the quality of the product is stable and meets standards, and fluopyram is prepared in one pot, thereby facilitating reduction of the number of production devices, reducing investment, reducing costs, and increasing efficiency, and facilitating large-scale commercial production.

Description

A process for preparing fluopyram Technical Field

[0001] This invention relates to a process for preparing fluopyram, belonging to the field of pesticide chemical 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: C 16 H 11 ClF6N2O; 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. Fluopyram has low toxicity and is environmentally friendly.

[0003] Currently, the actual production of fluopyram faces problems such as cumbersome processes, low overall yield, difficulty in controlling production costs, and unstable quality. To improve market competitiveness, it is necessary to find a simple, high-yield, low-cost, and stable preparation process. The main processing methods for fluopyram include the following:

[0004] 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, 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. The process is cumbersome and not conducive to industrial-scale production.

[0005] Route 2: Patent CN108822024 discloses a fluopyram and its synthesis method. The fluopyram comprises the following raw materials: trifluoromethylbenzoic acid, thionyl chloride, ammonia, water, potassium carbonate, paraformaldehyde, formamide, acetic anhydride, dimethyl 5-trifluoromethyl-2-malonate-3-chloropyridine, sodium chloride, and hydrochloric acid. The obtained fluopyram has a purity of over 98% and a total yield of over 63%. In this route, the total yield of steps 4, 5, and 6, calculated based on the hydroxymethylated product, is approximately 79.3%. Steps 4 and 5 use formamide as a solvent, and step 6 requires activated carbon decolorization, purification, and multiple drying operations to achieve acceptable quality. The process is cumbersome and not conducive to industrial production.

[0006] Route 3: Patent WO2018114484 discloses a process using o-trifluoromethylbenzoic acid as a raw material, which involves acylation, amination, hydroxymethylation, and esterification to prepare intermediate B5; 2,3-dichloro-5-trifluoromethylpyridine and diethyl malonate are condensed to prepare intermediate B1; then intermediate B5 and intermediate B1 are condensed to prepare intermediate B6, and finally hydrolyzed and decarboxylated to obtain fluopyram. In this process, intermediate B5 and intermediate B1 undergo a condensation reaction at 80°C, using N,N-dimethylacetamide and acetic acid as solvents. However, in actual scale-up reactions, the distillation recovery of N,N-dimethylacetamide is subject to harsh conditions, and the mixed solvents are difficult to separate and recover, which is not conducive to large-scale production. After diluting the intermediate B6 mixture with water, it is extracted with methyl tert-butyl ether (MTBE), and subsequent distillation is required to remove MTBE. Intermediate B6 requires extraction and purification, making the process quite cumbersome. The yield of the last four steps is approximately 86.5%, and the overall yield is low, approximately 49%.

[0007] Route 4: 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%.

[0008] Route 5: Patent CN117003691A discloses a method for preparing fluopyram. This patent uses potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate, i.e., intermediate 1, and N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, in the presence of solvent 3. After separation, intermediate 3 is obtained. Then, intermediate 3 is reacted with water and alkali in solvent 4 to continue the reaction. Finally, the product fluopyram is obtained by separation. This route is relatively long. After the reaction in step 3, it also includes post-processing steps: 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 the crude product, recrystallization, etc., to obtain intermediate 3. Meanwhile, solvent 3 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (above 150°C), resulting in long recovery time and high recovery cost. The total yield of the two steps in steps 4 and 5 (the last two steps) is about 76.1-79.2%, and its overall yield is about 66.9-71.4%.

[0009] Route Six: Patent CN116854629A discloses a method for preparing fluopyram. Potassium salt of 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate (intermediate 1) and N-(chloromethyl)-2-trifluoromethylbenzamide (intermediate 3) are reacted in the presence of solvent 4. After separation, intermediate 4 is obtained. Then, intermediate 4 is reacted with water and alkali in solvent 5, and finally, the product fluopyram is obtained.

[0010] This route is relatively long. After the reaction in step 4, it also includes post-processing steps: 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 the crude product, recrystallization, etc., to obtain intermediate 4. Meanwhile, solvent 4 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (above 150°C), resulting in long recovery time and high recovery cost. At the same time, the total yield of the two steps (steps 4 and 5, the last two steps) is about 80.5-80.9%, and the overall yield of the route is about 68.2-70.9%.

[0011] In summary, there is an urgent need for a process for preparing fluopyram to address the problems of cumbersome processes, low overall yield, difficulty in controlling production costs, and unstable quality, thereby improving market competitiveness. Summary of the Invention

[0012] The purpose of this invention is to provide a simple, high-yield, low-cost, and stable process for preparing fluopyram.

[0013] To achieve the above objectives, the present invention provides a process for preparing fluopyram, the reaction equation of which is shown below, and includes the following steps:

[0014] In the presence of solvent 1, compound 1-F (potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate) and compound 1-D were reacted in a reaction vessel to obtain intermediate compound 1-G. After distillation to recover solvent 1, intermediate compound 1-G did not require purification. Then, water, alkali, and solvent 2 were added to the same reaction vessel, and the reaction was continued. After the reaction, the pH was adjusted, and the reaction was continued. After the reaction was completed, post-treatment was performed to obtain the product fluopyram.

[0015] Wherein, compound 1-D is selected from compound 1-D-1: N-(acetoxymethyl)-2-trifluoromethylbenzamide and / or compound 1-D-2: N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., formula); solvent 1 is selected from acetate solvents with a boiling point range of 40-110℃ at room temperature and pressure.

[0016] In the process method described in this invention, all reaction steps before the product undergoes post-processing are carried out in the same reaction vessel using a one-pot method.

[0017] Preferably, solvent 1 is selected from one or more combinations of methyl acetate, ethyl acetate, and isopropyl acetate.

[0018] Preferably, the alkali is sodium hydroxide; the solvent 2 is methanol; and the acid used to adjust the pH is selected from hydrochloric acid.

[0019] Preferably, in the reaction for preparing intermediate compound 1-G: the molar ratio of compound 1-F to compound 1-D is 1:0.95-1.10; the mass ratio of compound 1-F to solvent 1 is 1:5.0-11.0; the feeding temperature is 40-55℃; the reaction temperature is 40-65℃; and the reaction time is 3-6 hours.

[0020] Preferably, the distillation temperature in the distillation recovery solvent 1 is 40-100℃, and the vacuum degree of distillation is -0.070 to -0.098 MPa.

[0021] Preferably, in the reaction for preparing the product from intermediate compound 1-G: the amount of water added is 1:2.0-5.0 by mass ratio of compound 1-F to water; the amount of solvent 2 added is 1:1.0-5.0 by mass ratio of compound 1-F to solvent 2; the amount of alkali added is 1:2.0-4.0 by molar ratio of compound 1-F to sodium hydroxide; the reaction temperature is 25-45℃, and the time is 3-6 hours; the temperature for further reaction is 40-60℃, and the time is 2-6 hours.

[0022] Preferably, the purity of compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, is ≥97.0%, and the mass content is ≥93.0%. In this invention, compound 1-F can be prepared by methods described in the literature (e.g., the method described in patent CN116854629A, but not limited to this method), or commercially available products can be used.

[0023] In this invention, compounds 1-D-1 and 1-D-2 can be prepared using methods described in the literature (e.g., the method described in patent CN116854629A, but not limited to this method).

[0024] Preferably, after distillation to recover solvent 1, the purity of intermediate compound 1-G is ≥95.8%, and no purification treatment is required.

[0025] Preferably, the post-processing includes sequentially performing filtration, water pulping and washing, filtration, and drying.

[0026] When preparing fluopyram using a process route similar to that of this invention, three related impurities, as shown in the structural formula below, are typically generated. In this invention, these are named impurities MW440, MW454, and MW401. Impurities MW440 and MW401 are particularly easy to generate; MW440 has a molecular weight of 440.73, and MW401 has a molecular weight of 401.13, and they are relatively easy to detect using conventional analytical methods such as liquid chromatography-mass spectrometry (LC-MS). Typically, impurity MW440 appears as a bar graph in MS mass spectrometry, similar to that shown in Figure 2 of this invention. Similarly, impurity MW401 typically appears as a bar graph in MS mass spectrometry, similar to that shown in Figure 3 of this invention. When using the process for preparing fluopyram provided by this invention, the content of impurities MW440 and MW454 in the product is very low. Typically, impurity MW454 is undetectable, while the content of impurity MW440 is ≤0.3%, and the content of impurity MW401 is ≤0.3%.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] 1. This invention provides a one-pot process for preparing fluopyram using compound 1-F (potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate) and compound 1-D as raw materials in a suitable acetate solvent. This process employs a one-pot method, where condensation, hydrolysis, and decarboxylation reactions are carried out continuously in the same reactor. The resulting intermediate compound 1-G has a high purity (≥95.8%) and requires no further purification. The process is simple; after each reaction step, no post-treatment is required, or only distillation is performed, and the crude product is directly used for the next reaction. Purification is concentrated in the final post-treatment stage, improving production efficiency, reducing waste generation, lowering equipment requirements, and significantly reducing initial investment and production costs. This method has excellent application prospects.

[0029] 2. In this invention, acetate solvents with a boiling point range of 40-110℃ under normal temperature and pressure, such as methyl acetate, ethyl acetate, and isopropyl acetate, are used. These acetate solvents are more suitable for this process than other solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, formamide, and acetic acid. Using these acetate solvents in this process has at least the following advantages: First, the resulting reaction intermediate has high purity and few impurities; second, these acetate solvents are easy and simple to recover under mild conditions, with a high solvent recovery rate, and virtually no new impurities are generated during the solvent recovery process; at the same time, the small amount of these acetate solvents remaining in the intermediate compound of formula 1-G will not affect the subsequent hydrolysis and decarboxylation reactions, thus realizing the one-pot preparation of fluoropyridine. Fluopyram is produced using a process that features a short production route and simple operation, along with high overall yield and stable quality. The molar yield of fluopyram obtained by this process is ≥88.2%, with a maximum of 92.5% (calculated based on potassium 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate), and the mass content of the fluopyram is ≥96.4%, with a maximum of 98.8%. The fluopyram obtained by this process is of acceptable quality (content ≥96.0%, moisture ≤0.5%, pH = 5.0–8.0, acetone insoluble matter ≤0.5%, single related impurities ≤0.3%). The increased overall yield helps reduce raw material costs. Therefore, the high overall yield, low cost, and stable quality are conducive to large-scale commercial production.

[0030] 3. Compound 1-F, namely the potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, generally exhibits good solubility in highly polar solvents. In the prior art, solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, formamide, and acetic acid are usually preferred. However, through extensive experimentation, this invention has found that acetate ester solvents with a boiling point range of 40-110℃ at room temperature and pressure, such as methyl acetate, ethyl acetate, and isopropyl acetate, exhibit good solubility for compound 1-F. Furthermore, it is suitable for the reaction of compound 1-F with either compound 1-D-1 or compound 1-D-2, demonstrating good versatility, scalability, and promising application prospects. Attached Figure Description

[0031] Figure 1 shows the reaction equation of the present invention;

[0032] Figure 2 shows the LCMS mass spectrum bar chart of impurity MW440;

[0033] Figure 3 shows the LCMS bar chart of impurity MW401. Detailed Implementation

[0034] To make the present invention more apparent and understandable, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0035] Unless otherwise specified, percentages in this invention refer to mass concentration or mass percentage.

[0036] In the embodiments of this invention, the purity or content was determined by high performance liquid chromatography.

[0037] In this embodiment of the invention, the product fluopyram is considered to be of acceptable quality if its various test indicators meet the following requirements: content ≥ 96.0%, moisture ≤ 0.5%, pH = 5.0–8.0, acetone insoluble matter ≤ 0.5%, and single related impurity ≤ 0.3%. If any of the above test indicators fails to meet the requirements, the fluopyram is considered to be of unacceptable quality.

[0038] The process method in this embodiment of the invention, and its reaction equation are shown in Figure 1. The compound used, formula 1-F, i.e., potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, is prepared according to the method in patent CN116854629A, with a purity ≥97.0% and a mass content ≥93.0%. The N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-1) is prepared according to the method in patent CN116854629A, with a mass content ≥97.0%. The N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-2) is prepared according to the method in patent CN116854629A, with a mass content ≥97.0%. All other reagents are commercially available products with a purity ≥99.0%.

[0039] Example 1

[0040] In a reaction vessel, solvent 1 (2232.6 g) and compound 1-F, namely potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate (purity 98%, mass content 94%, 372.1 g, 1.0 mol), were added. The temperature was controlled at 48–53 °C, and the mixture was stirred for 3–4 hours until compound 1-F was mostly dissolved. The dropping temperature was controlled at 48–53 °C, and a solution prepared from N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-1) (mass content 97%, 274.7 g, 1.02 mol) and solvent 1 (372.1 g) was added dropwise to the reaction vessel. After the addition was complete, the temperature was raised to 50–55 °C, and the reaction was continued with stirring for 4 hours until the conversion was satisfactory. A sample was taken at point 1; at this point, the purity of the intermediate compound 1-G was 97.9%. The distillation temperature was controlled at 40-100℃, and the vacuum degree was -0.080~-0.098Mpa. Solvent 1 was recovered by distillation until almost no solvent 1 was distilled off. The recovered solvent 1 was 2364.4g, and the recovery rate of solvent 1 was 94.3%. At sampling point 2, the purity of intermediate compound formula 1-G was 97.8%, and the residual amount of solvent 1 in intermediate compound formula 1-G was 1.5%. Then, solvent 2 (632.6g) was added to the reaction vessel, and the mixture was refluxed and stirred for about 0.5-1.0 hours. After the material was basically dissolved, the temperature was lowered to 35-40℃, and the prepared sodium hydroxide aqueous solution (121g sodium hydroxide, 3.0 mol; 930.3g water) was added. The temperature was maintained at 35-40℃, pH=14, and the reaction was carried out for 3-6 hours until the conversion was qualified. At sampling point 3, the purity of intermediate compound formula 1-G was ≤0.5%. Hydrochloric acid was added dropwise to the reaction vessel to adjust the pH to 2-3. The temperature was controlled at 55-60℃, and the reaction was continued for 2-4 hours until the conversion was successful. A sample was taken at point 4, at which point the purity of the product fluopyram was 94.9%. After the reaction was complete, a small amount of sodium hydroxide aqueous solution was added to the reaction vessel to adjust the pH to 6.5-7.5. The temperature was lowered to 15-25℃, and the mixture was filtered. The solid was washed with water, filtered again, and dried to obtain 371.4 g of the product fluopyram, with a molar yield of 92.5% (calculated as potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate). The product fluopyram had a purity of 99.0%, a mass content of 98.8%, a moisture content of 0.4%, a pH of 6.5, acetone-insoluble matter of 0.4%, and a single related impurity ≤0.3%.

[0041] In this Example 1, solvent 1 is ethyl acetate and solvent 2 is methanol.

[0042] Example 2

[0043] In a 50-liter reaction vessel, solvent 1 (21564 g) and compound 1-F, namely potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate (98% purity, 94% mass content, 3535 g, 9.5 mol), were added. The temperature was controlled at 48–54 °C, and the mixture was stirred for 3–4 hours until compound 1-F was mostly dissolved. The dropping temperature was controlled at 48–54 °C, and a solution prepared from N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-1) (97% mass content, 2609 g, 9.69 mol) and solvent 1 (3535 g) was added dropwise to the reaction vessel. After the addition was complete, the temperature was raised to the reaction temperature of 50–55 °C, and the reaction was continued with stirring for 4 hours until the conversion was satisfactory. A sample was taken at point 1; at this point, the purity of intermediate compound 1-G was 97.6%. The distillation temperature was controlled at 40-100℃, and the vacuum degree was -0.080~-0.098Mpa. Solvent 1 was recovered by distillation until almost no solvent 1 was distilled off. The recovered solvent 1 was 23718g, and the recovery rate of solvent 1 was 94.5%. At sampling point 2, the purity of intermediate compound formula 1-G was 97.4%, and the residual amount of solvent 1 in intermediate compound formula 1-G was 1.3%. Then, solvent 2 (8660g) was added to the reaction vessel, and the mixture was refluxed and stirred for about 0.5-1.0 hours. After the material was basically dissolved, the temperature was lowered to 35-40℃, and the prepared sodium hydroxide aqueous solution (1150g sodium hydroxide, 28.5 mol; 8838g water) was added. The temperature was maintained at 35-40℃, pH=14, and the reaction was carried out for 3-6 hours until the conversion was qualified. At sampling point 3, the purity of intermediate compound formula 1-G was ≤0.5%. Hydrochloric acid was added dropwise to the reaction vessel to adjust the pH to 2-3. The temperature was controlled at 55-60℃, and the reaction was continued for 2-4 hours until the conversion was successful. A sample was taken at point 4, at which point the purity of the product fluopyram was 94.4%. After the reaction was complete, a small amount of sodium hydroxide aqueous solution was added to the reaction vessel to adjust the pH to 6.5-7.5. The temperature was lowered to 15-25℃, and the mixture was filtered. The solid was washed with water, filtered again, and dried to obtain 3519 g of the product fluopyram, with a molar yield of 91.7% (calculated as potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate). The product fluopyram had a purity of 98.6%, a mass content of 98.2%, a moisture content of 0.4%, a pH of 6.7, acetone-insoluble matter of 0.3%, and a single related impurity ≤0.3%.

[0044] In this Example 2, solvent 1 is ethyl acetate and solvent 2 is methanol.

[0045] Examples 3-8

[0046] A process for preparing fluopyram differs from Example 1 in that the process parameters are different. For example, the only difference between Example 3 and Example 1 is the reaction substrate (named compound 1-D). In Example 3, the reaction substrate is compound 1-D-2, while in Example 1, the reaction substrate is compound 1-D-1. All other conditions are the same. Specific differences in other examples are shown in Table 1.

[0047] Table 1. Preparation method parameters for Examples 3-8

[0048] The samples from each sampling point obtained in Examples 3 to 8, as well as the products, were subjected to high performance liquid chromatography (HPLC) for purity and mass content detection and molar yield calculation. The results are shown in Table 2.

[0049] Table 2. Sample purity, product mass content, and molar yield at each sampling point in Examples 3-8

[0050] Based on the data from Examples 1-8 and Tables 1 and 2, ethyl acetate, methyl acetate, and isopropyl acetate are all suitable for the process method of this invention. The one-pot process using these acetate solvents yields intermediate compound 1-G with high purity, ≥95.8%.

[0051] Based on the data from Examples 1-8 and Tables 1 and 2, the process method of this application yields reaction intermediate compound 1-G with high purity and few impurities. Furthermore, the recovery of these acetate solvents is convenient and simple, the conditions are mild, the solvent recovery rate is high, and virtually no new impurities are generated during the solvent recovery process. Simultaneously, the small amount of these acetate solvents remaining in intermediate compound 1-G does not affect subsequent hydrolysis and decarboxylation reactions, thus achieving a one-pot preparation of fluopyram. This process method also features high overall yield and stable quality. The molar yield of fluopyram obtained by this process is ≥88.2%, reaching a maximum of 92.5% (calculated based on potassium 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate), and the mass content of the fluopyram is ≥96.4%, reaching a maximum of 98.8%. The product fluopyram obtained by this process is of qualified quality (content ≥96.0%, moisture ≤0.5%, pH=5.0~8.0, acetone insoluble matter ≤0.5%, single related impurity ≤0.3%).

[0052] Comparative Examples 1-6

[0053] A process for preparing fluopyram is described, and Comparative Examples 1-6 differ from Example 3 only in the process parameters; all other conditions are the same. Specific differences are shown in Table 3.

[0054] Table 3. Preparation process parameters for Comparative Examples 1–6

[0055] The purity and mass content of the samples obtained from each sampling point of Comparative Examples 1 to 6, as well as the products, were determined by high performance liquid chromatography (HPLC), and the molar yield was calculated. The results are shown in Table 4.

[0056] Table 4. Sample purity, product mass content, and molar yield at each sampling point of Comparative Examples 1–6

[0057] Based on the data from Examples 1-8, Comparative Examples 1-6, and Tables 1, 2, 3, and 4, it can be seen that solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, formamide, and acetic acid have relatively poor effects in this process. For example, when using N,N-dimethylacetamide, N-methylpyrrolidone, and formamide as solvents, the condensation reaction effect is acceptable at the beginning, but the purity of intermediates and products is significantly lower during subsequent distillation and subsequent reactions. Using the process method of the present invention, comparing the reaction effects of different solvents, the reaction effect is significantly better when using the preferred acetate solvents of the present invention than when using solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, formamide, and acetic acid. Using the process method of the present invention, the reaction effect of the preferred acetate solvents of the present invention is also better than other ester solvents such as n-butyl acetate.

[0058] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any form or substance. It should be noted that those skilled in the art can make several improvements and additions without departing from the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A process for preparing fluopyram, characterized in that, Includes the following steps: In the presence of solvent 1, compound 1-F, namely potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, and compound 1-D were reacted in a reaction vessel to obtain intermediate compound 1-G. After distillation to recover solvent 1, intermediate compound 1-G did not require purification. Then, water, alkali, and solvent 2 were added to the reaction vessel, and the reaction was carried out. After the reaction, the pH was adjusted, and the reaction continued. After the reaction was completed, the product fluopyram was obtained after post-treatment. Wherein, compound 1-D is selected from compound 1-D-1: N-(acetoxymethyl)-2-trifluoromethylbenzamide and / or compound 1-D-2: N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., formula); solvent 1 is selected from acetate solvents with a boiling point range of 40-110℃ at room temperature and pressure.

2. The process method as described in claim 1, characterized in that, The solvent 1 is selected from one or more combinations of methyl acetate, ethyl acetate and isopropyl acetate.

3. The process method as described in claim 1, characterized in that, The alkali is sodium hydroxide; the solvent 2 is methanol; and the acid used to adjust the pH is selected from hydrochloric acid.

4. The process method as described in claim 1, characterized in that, In the reaction for preparing intermediate compound 1-G: the molar ratio of compound 1-F to compound 1-D is 1:0.95-1.10; the mass ratio of compound 1-F to solvent 1 is 1:5.0-11.0; the feeding temperature is 40-55℃; the reaction temperature is 40-65℃; and the reaction time is 3-6 hours.

5. The process method as described in claim 1, characterized in that, The distillation temperature in the solvent recovery process 1 is 40-100℃, and the vacuum degree of distillation is -0.070 to -0.098 MPa.

6. The process method as described in claim 1, characterized in that, In the reaction for preparing the product from intermediate compound 1-G: the amount of water added is 1:2.0-5.0 by mass ratio of compound 1-F to water; the amount of solvent 2 added is 1:1.0-5.0 by mass ratio of compound 1-F to solvent 2; the amount of alkali added is 1:2.0-4.0 by molar ratio of compound 1-F to sodium hydroxide; the reaction temperature is 25-45℃, and the time is 3-6 hours; the reaction continues at 40-60℃ for 2-6 hours.

7. The process method as described in claim 1, characterized in that, The purity of compound 1-F, namely potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, is ≥97.0%, and its mass content is ≥93.0%.

8. The process method as described in claim 1, characterized in that, After distillation to recover solvent 1, the purity of intermediate compound 1-G is ≥95.8%, requiring no further purification.

9. The process method as described in claim 1, characterized in that, The post-processing includes sequentially performing filtration, water pulping and washing, filtration, and drying.

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