Process method for preparing fluopyram

Abstract

The invention discloses a process method for preparing fluopyram. The process method comprises the following steps: in the presence of a solvent 1, reacting a compound 2-[3-chloro-5-(trifluoromethyl) pyridyl] dimethyl malonate potassium salt with a compound 1-D in a reaction container to obtain an intermediate compound, and distilling to recover the solvent 1 without purification treatment of the intermediate compound; adding water, alkali and a solvent 2 into the reaction container for reaction; adjusting the pH value after the reaction, and continuing the reaction; and after the reaction is finished, carrying out post-treatment to obtain the product fluopyram. Wherein the solvent 1 is selected from acetic ester solvents with the boiling point range of 40-110 DEG C at normal temperature and normal pressure. The process method is simple, convenient, high in total yield, low in cost and stable and qualified in product quality, fluopyram is prepared through a one-pot method, production equipment is reduced, investment is reduced, cost is reduced, efficiency is improved, and commercialized mass production is facilitated.

Description

Technical Field

[0001] The invention relates to a process for preparing fluopyram, and belongs to the technical field of pesticide chemical industry. Background Art

[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 CIF 6 N 2 O; relative molecular mass: 396.76; CAS registration number: 658066-35-4. Fluopyram is an excellent fungicide and nematicide, used in more than 70 crops. Fluopyram has low toxicity and is environmentally friendly.

[0003] At present, in actual production, fluopyram has problems such as complicated process, low total yield, difficult production cost control, unstable quality, etc. In order to improve market competitiveness, it is necessary to find a preparation process with simple process, high total yield, low cost and stable quality. The main process methods of fluopyram are as follows:

[0004] Route 1: Patent EP1674455 discloses that 2,3-dichloro-5-trifluoromethylpyridine and ethyl cyanoacetate are used as raw materials, and 3-chloro-5-(trifluoromethyl)-2-(2-aminoethyl)pyridine is obtained through nucleophilic substitution, hydrolysis decarboxylation, catalytic hydrogenation, and hydrolysis, and finally reacted with the intermediate o-trifluoromethylbenzoyl chloride to obtain fluopyram. The total yield of this route is about 44% low. In addition, the route requires the use of precious metal palladium to catalyze hydrogenation reduction, which greatly increases the cost. At the same time, the hydrogenation step is more likely to produce a dechlorination side reaction, generating impurities that are difficult to remove. The process method is cumbersome and is not conducive to industrial production.

[0005] Route 2: Patent CN108822024 discloses a fluopyram and a method for synthesizing the same, wherein the fluopyram comprises the following raw materials: trifluoromethylbenzoic acid, thionyl chloride, ammonia, water, potassium carbonate, paraformaldehyde, formamide, acetic anhydride, 5-trifluoromethyl-2-dimethyl malonate-3-chloropyridine, sodium chloride and hydrochloric acid. The fluopyram content obtained is more than 98%, and the total yield is more than 63%. The total yield of the three-step reaction of step 4, step 5 and step 6 in the route is about 79.3% calculated by the hydroxymethylation product. In step 4 and step 5, formamide is used as a solvent. In step 6, activated carbon decolorization, purification, and multiple drying operations are required to meet the quality requirements. The process method is cumbersome and is not conducive to industrial production.

[0006] Route 3: Patent WO2018114484 discloses that o-trifluoromethylbenzoic acid is used as a raw material, and intermediate B5 is prepared by acylation, amination, hydroxymethylation, and esterification; 2,3-dichloro-5-trifluoromethylpyridine and diethyl malonate are used as raw materials for condensation to prepare intermediate B1, and then intermediate B5 and intermediate B1 are condensed to prepare intermediate B6, and finally hydrolyzed and decarboxylated to obtain fluopyram. In this process route, intermediate B5 and intermediate B1 are condensed at 80°C, and N,N-dimethylacetamide and acetic acid are used as solvents. The conditions for distillation and recovery of N,N-dimethylacetamide are relatively harsh during the actual amplification reaction, and the mixed solvent is also difficult to separate and recover, which is not conducive to large-scale production. After the intermediate B6 mixture is diluted with water, methyl tert-butyl ether (MTBE) is used for extraction, and MTBE needs to be distilled to remove MTBE later. Intermediate B6 needs to be extracted and purified, and the process is relatively cumbersome. The yield of the last four steps is about 86.5%, and the total yield is low, about 49%.

[0007]

[0008] 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 is condensed with intermediate C1, and then hydrolyzed and decarboxylated, and finally hydrogenated and dechlorinated to obtain fluopyram. This route is long and has many side reactions. In particular, the route requires the use of precious metal palladium to catalyze hydrogenation reduction, which greatly increases the cost. At the same time, the hydrogenation step is difficult to control the reaction conditions of selective dechlorination, and it is easy to generate impurities that are difficult to remove, which is not conducive to industrial production. At the same time, the total yield of the product is low, only 50.3%.

[0009]

[0010] Route 5: Patent CN117003691A discloses a method for preparing fluopyram. The patent uses 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate dimethyl potassium salt, i.e., intermediate 1, and N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, to react in the presence of solvent 3, and obtain intermediate 3 after separation; then intermediate 3 is neutralized with water in solvent 4, and the base continues to react, and finally the product fluopyram is separated. This route is relatively long, and after the reaction of step 3 is completed, a post-treatment step is also included: recovering the solvent under reduced pressure, adding an organic solvent and water to the residue, separating the liquids after extraction, washing the organic phase with water, concentrating under reduced pressure to obtain a crude product, and recrystallizing to obtain intermediate 3; at the same time, solvent 3 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (over 150°C), a long recovery time, and a high recovery cost; the total yield of the two-step reaction of step 4 and step 5 (the last two steps) is about 76.1-79.2%, and the total yield thereof is about 66.9-71.4%.

[0011]

[0012] Route 6: Patent CN116854629A discloses a method for preparing fluopyram. 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate dimethyl potassium salt, i.e., intermediate 1, and N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 3, are reacted in the presence of solvent 4, and intermediate 4 is obtained after separation; then intermediate 4 is neutralized with water in solvent 5, and the alkali is further reacted, and finally the product fluopyram is separated.

[0013] This route is relatively long, and after the reaction of step 4 is completed, a post-treatment step is also included: recovering the solvent under reduced pressure, adding an organic solvent and water to the residue, separating the liquids after extraction, washing the organic phase with water, concentrating under reduced pressure to obtain a crude product, and recrystallizing to obtain intermediate 4; at the same time, solvent 4 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (over 150°C), a long recovery time, and a high recovery cost; at the same time, the total yield of the two-step reaction of step 4 and step 5 (the last two steps) is about 80.5-80.9%, and the total yield of the route is about 68.2-70.9%.

[0014]

[0015] In summary, there is an urgent need for a process for preparing fluopyram, so as to solve the problems of fluopyram, such as complicated process, low total yield, difficult production cost control, unstable quality, etc., and improve market competitiveness. Summary of the invention

[0016] The purpose of the present invention is to provide a process for preparing fluopyram with simple process, high total yield, low cost and stable quality.

[0017] In order to achieve the above object, the present invention provides a process for preparing fluopyram, the reaction equation is as follows, which comprises the following steps:

[0018] In the presence of solvent 1, compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate, and compound 1-D are reacted in a reaction vessel to obtain an intermediate compound 1-G, and after distilling and recovering solvent 1, the intermediate compound 1-G does not need to be purified; water, a base and solvent 2 are added to the reaction vessel to react; after the reaction, the pH is adjusted and the reaction is continued; after the reaction is completed, the product fluopyram is obtained through post-treatment;

[0019]

[0020] Wherein, the 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); the solvent 1 is selected from an acetate solvent having a boiling point range of 40-110°C at normal temperature and pressure.

[0021] In the process of the present invention, all reaction steps before the product is post-treated are carried out in the same reaction vessel by a one-pot process.

[0022] Preferably, the solvent 1 is selected from a combination of one or more of methyl acetate, ethyl acetate and isopropyl acetate.

[0023] Preferably, the base is sodium hydroxide; the solvent 2 is methanol; and the acid used to adjust the pH is selected from hydrochloric acid.

[0024] Preferably, in the reaction for preparing the intermediate compound 1-G: the molar ratio of the compound 1-F to the compound 1-D is 1:0.95-1.10; the mass ratio of the compound 1-F to the solvent 1 is 1:5.0-11.0; the feeding temperature is 40-55°C; the reaction temperature is 40-65°C, and the reaction time is 3-6 hours.

[0025] Preferably, the distillation temperature in the distillation recovery solvent 1 is 40-100° C., and the vacuum degree of distillation is -0.070 to -0.098 Mpa.

[0026] Preferably, in the reaction of preparing the product from the intermediate compound 1-G: the water is added in an amount according to a mass ratio of compound 1-F to water of 1:2.0-5.0; the solvent 2 is added in an amount according to a mass ratio of compound 1-F to solvent 2 of 1:1.0-5.0; the base is added in an amount according to a molar ratio of compound 1-F to sodium hydroxide of 1:2.0-4.0; the reaction temperature is 25-45°C, and the time is 3-6 hours; the temperature of the continued reaction is 40-60°C, and the time is 2-6 hours.

[0027] Preferably, the compound 1-F, i.e., 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate dimethyl ester potassium salt, has a purity of ≥97.0% and a mass content of ≥93.0%. In the present invention, the compound 1-F can be prepared by a literature method (e.g., the method described in patent CN116854629A but not limited to this method), or a commercially available product can be selected.

[0028] In the present invention, the compounds 1-D-1 and 1-D-2 can be prepared by using literature methods (such as the method described in patent CN116854629A but not limited to this method).

[0029] Preferably, after the solvent 1 is recovered by distillation, the purity of the intermediate compound 1-G is ≥95.8%, and no purification treatment is required.

[0030] Preferably, the post-treatment comprises filtering, water slurry washing, filtering and drying in sequence.

[0031] When fluopyram is prepared by a process similar to the present invention, three related impurities shown in the following structural formula are usually produced, which are named as impurity MW440, impurity MW454 and impurity MW401 in the present invention. In particular, impurity MW440 and impurity MW401 are usually easy to produce. The molecular weight of impurity MW440 is 440.73, and the molecular weight of impurity MW401 is 401.13, and they are easy to detect by conventional analytical means such as liquid chromatography-mass spectrometry (LCMS). Typically, impurity MW440 appears in the MS mass spectrum as shown in the attached figure of the present invention. Figure 2 Typically, impurity MW401 appears in the MS mass spectrum as shown in the attached figure of the present invention. Figure 3 When the process for preparing fluopyram provided by the present invention is adopted, the contents of impurity MW440 and impurity MW454 in the product are both small. Typically, impurity MW454 cannot be detected, and the content of impurity MW440 is ≤0.3%, and the content of impurity MW401 is ≤0.3%.

[0032]

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] 1. The present invention provides a process for preparing fluopyram by a one-pot method in a suitable acetate solvent using compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate and compound 1-D as raw materials; the process adopts a one-pot method, and condensation, hydrolysis, and decarboxylation reactions are continuously carried out in the same reactor; the purity of the intermediate compound 1-G generated is as high as ≥95.8%, and no purification is required; the process is simple, and after each step of the reaction is completed, no post-treatment is performed or only distillation treatment is performed, and the crude product is directly used for the next step of reaction; in the final post-treatment stage, concentrated purification treatment is performed, which improves production efficiency, reduces the amount of three wastes generated, reduces the demand for production equipment, greatly reduces the initial investment cost and the cost of the production process, and has a good application prospect;

[0035] 2. In the present invention, acetate solvents such as methyl acetate, ethyl acetate, isopropyl acetate, etc. with a boiling point range of 40-110° C. at normal temperature and pressure are used. These acetate solvents are more suitable for the process method than other solvents such as N,N-dimethylacetamide, N-methylpyrrolidone, 1,2-dichloroethane, formamide, acetic acid, etc.; the use of these acetate solvents in the process method has at least the following advantages: first, the obtained reaction intermediate has high purity and few impurities; secondly, these acetate solvents are easy to recycle, the conditions are mild, the solvent recovery rate is high, and basically no new impurities are generated during the solvent recovery process; at the same time, a small amount of these acetate solvents remain in the intermediate compound formula 1-G, and will not affect the subsequent hydrolysis and decarboxylation reactions, thereby realizing the one-pot preparation of fluoropyrrolidone The process method has the characteristics of short production route and simple process, high total yield and stable quality. The molar yield of the product fluopyram obtained by the process method is ≥88.2%, and can reach up to 92.5% (calculated as 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate dimethyl ester potassium salt). The mass content of the product fluopyram is ≥96.4%, and can reach up to 98.8%. The product fluopyram obtained by the process method has qualified quality (content ≥96.0%, moisture ≤0.5%, pH=5.0-8.0, acetone insoluble matter ≤0.5%, single related impurity ≤0.3%). The improvement of the total yield is conducive to the reduction of raw material costs. Therefore, the total yield is high, the cost is low, the quality is stable, and it is conducive to large-scale commercial production.

[0036] 3. Compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate, generally has good solubility in highly polar solvents. In the prior art, preferred solvents include N,N-dimethylacetamide, N-methylpyrrolidone, formamide, acetic acid, etc.; however, the present invention has found through numerous attempts that the use of acetate solvents such as methyl acetate, ethyl acetate, isopropyl acetate, etc., having a boiling point range of 40-110° C. at room temperature and pressure, has good solubility for compound 1-F and is also suitable for the reaction of compound 1-F and compound 1-D-1 or compound 1-D-2, has good universality, can be scaled up, and has application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 Is the reaction equation of the present invention;

[0038] Figure 2 is the mass spectrum bar graph of LCMS of impurity MW440;

[0039] Figure 3 It is the mass spectrum bar chart of LCMS of impurity MW401. DETAILED DESCRIPTION

[0040] In order to make the present invention more clearly understood, preferred embodiments are described in detail below with reference to the accompanying drawings.

[0041] The percentages not otherwise specified in the present invention refer to mass concentration or mass percentage.

[0042] The purity or content determination in the examples of the present invention is carried out by high performance liquid chromatography.

[0043] In the embodiment of the present invention, the quality of the product fluopyram is qualified, which means that each test index of fluopyram meets the following requirements: content ≥96.0%, moisture ≤0.5%, pH=5.0-8.0, acetone insoluble matter ≤0.5%, single related impurity ≤0.3%. If one of the above test indicators is unqualified, the quality of fluopyram is unqualified.

[0044] The process method in the embodiment of the present invention has a reaction equation as follows: Figure 1As shown, the compound formula 1-F, i.e., 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonic acid dimethyl ester potassium salt, is prepared by referring to the method in patent CN116854629A, with a purity of ≥97.0% and a mass content of ≥93.0%; the N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-1) is prepared by referring to the method in patent CN116854629A, with a mass content of ≥97.0%; the N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-2) is prepared by referring to the method in patent CN116854629A, with a mass content of ≥97.0%. The remaining reagents are all commercially available products with a purity of ≥99.0%.

[0045] Example 1

[0046] In a reaction vessel, add solvent 1 (2232.6 g) and compound formula 1-F, i.e., 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonic acid dimethyl ester potassium salt (purity 98%, mass content 94%, 372.1 g, 1.0 mole), control the temperature at 48-53°C, stir for 3-4 hours, until most of compound 1-F is dissolved. Control the dropping temperature at 48-53°C, drop N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-1) (mass content 97%, 274.7 g, 1.02 mole) and solvent 1 (372.1 g) into the reaction vessel, after the dropping is complete, heat to 50-55°C, continue stirring and react, react for 4 hours, until the conversion is qualified, take a sample at point 1, at which time the purity of the intermediate compound formula 1-G is 97.9%. The distillation temperature is controlled to be 40-100°C, the vacuum degree is -0.080~-0.098Mpa, and the solvent 1 is distilled and recovered until there is basically no solvent 1 distilled out. The recovered solvent 1 is 2364.4 grams, and the recovery rate of solvent 1 is 94.3%. The sampling point 2, at this time, the purity of the intermediate compound formula 1-G is 97.8%, and the residual amount of solvent 1 in the intermediate compound formula 1-G is 1.5%. Solvent 2 (632.6 grams) is added to the reaction container, refluxed and stirred for about 0.5-1.0 hours, and after the material is basically dissolved, the temperature is lowered to 35-40°C, and the prepared sodium hydroxide aqueous solution (including 121 grams of sodium hydroxide, 3.0 moles; 930.3 grams of water) is added, the temperature is maintained at 35-40°C, PH=14, and the reaction is carried out for 3-6 hours until the conversion is qualified, and the sampling point 3 is taken. At this time, the purity of the intermediate compound formula 1-G is ≤0.5%. Hydrochloric acid was added dropwise to the reaction vessel, pH was adjusted to 2-3, the temperature was controlled at 55-60°C, and the reaction was continued for 2-4 hours until the conversion was qualified, and the sample point 4 was taken. At this time, the purity of the product fluopyram was 94.9%. After the reaction was completed, a small amount of sodium hydroxide aqueous solution was added to the reaction vessel, pH was adjusted to 6.5-7.5, and the temperature was lowered to 15-25°C, and then filtered. The solid was washed with water for pulping, filtered, and dried to obtain 371.4 grams of product fluopyram, with a molar yield of 92.5% (calculated as 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonic acid dimethyl ester potassium salt). After testing, 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, an acetone insoluble matter of 0.4%, and a single related impurity of ≤0.3%.

[0047] In this Example 1, solvent 1 is ethyl acetate and solvent 2 is methanol.

[0048] Example 2

[0049] In a 50-liter reaction vessel, add solvent 1 (21564 g) and compound formula 1-F, i.e., 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonic acid dimethyl ester potassium salt (purity 98%, mass content 94%, 3535 g, 9.5 moles), control the temperature at 48-54°C, stir for 3-4 hours until most of compound 1-F is dissolved. Control the dropping temperature at 48-54°C, drop N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound formula 1-D-1) (mass content 97%, 2609 g, 9.69 moles) and solvent 1 (3535 g) into the reaction vessel, after the dropping is complete, heat to the reaction temperature of 50-55°C, continue stirring the reaction, react for 4 hours, until the conversion is qualified, take a sample at point 1, at which time the purity of the intermediate compound formula 1-G is 97.6%. The distillation temperature is controlled to be 40-100°C, the vacuum degree is -0.080~-0.098Mpa, and the solvent 1 is distilled and recovered until there is basically no solvent 1 distilled out. The recovered solvent 1 is 23718 grams, and the recovery rate of solvent 1 is 94.5%. The sampling point 2, at this time, the purity of the intermediate compound formula 1-G is 97.4%, and the residual amount of solvent 1 in the intermediate compound formula 1-G is 1.3%. Solvent 2 (8660 grams) is added to the reaction container, refluxed and stirred for about 0.5-1.0 hours, and after the material is basically dissolved, the temperature is lowered to 35-40°C, and the prepared sodium hydroxide aqueous solution (including 1150 grams of sodium hydroxide, 28.5 moles; 8838 grams of water) is added, the temperature is maintained at 35-40°C, PH=14, and the reaction is carried out for 3-6 hours until the conversion is qualified, and the sampling point 3 is taken. At this time, the purity of the intermediate compound formula 1-G is ≤0.5%. Hydrochloric acid was added dropwise to the reaction vessel, pH was adjusted to 2-3, the temperature was controlled at 55-60°C, and the reaction was continued for 2-4 hours until the conversion was qualified, and the sample point 4 was taken. At this time, the purity of the product fluopyram was 94.4%. After the reaction was completed, a small amount of sodium hydroxide aqueous solution was added to the reaction vessel, pH was adjusted to 6.5-7.5, and the temperature was lowered to 15-25°C, and then filtered. The solid was washed with water, filtered, and dried to obtain 3519 grams of product fluopyram, with a molar yield of 91.7% (calculated as 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonic acid dimethyl ester potassium salt). After testing, 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, an acetone insoluble matter of 0.3%, and a single related impurity of ≤0.3%.

[0050] In this Example 2, solvent 1 is ethyl acetate and solvent 2 is methanol.

[0051] Embodiments 3 to 8

[0052] A process for preparing fluopyram, which differs from Example 1 in that the process parameters of the process are different, for example, the difference between Example 3 and Example 1 is only that the reaction substrate (named as compound 1-D) is different, the reaction substrate in Example 3 is compound formula 1-D-2, and the reaction substrate in Example 1 is compound formula 1-D-1, and other conditions are the same. The specific differences of other embodiments are shown in Table 1.

[0053] Table 1. Preparation method parameters of Examples 3 to 8

[0054]

[0055] The samples at each sampling point obtained in Examples 3 to 8 and the products were subjected to high performance liquid chromatography (HPLC) purity and mass content detection and molar yield calculation. The results are shown in Table 2.

[0056] Table 2. Sample purity, product mass content, and molar yield of each sampling point in Examples 3 to 8

[0057]

[0058]

[0059] Combining the data of Examples 1 to 8 and Tables 1 and 2, it can be seen that ethyl acetate, methyl acetate, and isopropyl acetate are all suitable for the process of the present invention. The intermediate compound 1-G prepared by the one-pot process using these acetate solvents has a high purity of ≥95.8%.

[0060] Combined with the data of Examples 1 to 8 and Tables 1 and 2, it can be seen that in the process method of the present application, the reaction intermediate compound formula 1-G obtained has high purity and few impurities; secondly, these acetate solvents are easy to recover, the conditions are mild, the solvent recovery rate is high, and basically no new impurities are generated during the solvent recovery process; at the same time, a small amount of these acetate solvents remain in the intermediate compound formula 1-G, and the subsequent hydrolysis and decarboxylation reactions will not be affected, and a one-pot method for preparing fluopyram is achieved. At the same time, the process method has the characteristics of high total yield and stable quality. The product fluopyram obtained by the process method has a molar yield of ≥88.2%, up to 92.5% (calculated as 2-[3-chloro-5-(trifluoromethyl)pyridinyl] dimethyl malonate potassium salt), and the product fluopyram mass content is ≥96.4%, up to 98.8%. The product fluopyram obtained by the 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%).

[0061] Comparative Examples 1 to 6

[0062] A process for preparing fluopyram, wherein comparative examples 1 to 6 differ from example 3 only in the process parameters of the process, and other conditions are the same. The specific differences are shown in Table 3.

[0063] Table 3. Preparation process parameters of comparative examples 1 to 6

[0064]

[0065]

[0066] The samples at each sampling point obtained in Comparative Examples 1 to 6 and the products were subjected to high performance liquid chromatography (HPLC) purity and mass content detection and molar yield calculation, and the results are shown in Table 4.

[0067] Table 4. Sample purity, product mass content, and molar yield of each sampling point of Comparative Examples 1 to 6

[0068]

[0069] In combination with the data of Examples 1 to 8, Comparative Examples 1 to 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 the process method. For example, when N,N-dimethylacetamide, N-methylpyrrolidone and formamide are used as solvents, the condensation reaction effect is acceptable at the beginning, but during the subsequent distillation and subsequent reactions, the purity of the intermediate and the product will be significantly low; using the process method of the present invention, comparing the reaction effects of different solvents, when the preferred acetate solvent of the present invention is selected, the reaction effect is significantly better than using 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 solvent of the present invention is also better than other ester solvents such as n-butyl acetate.

[0070] The above description is only a preferred embodiment of the present invention and is not any formal or substantial limitation of the present invention. It should be pointed out that a person skilled in the art can make several improvements and supplements without departing from the present invention, and these improvements and supplements should also be regarded as the protection scope of the present invention.

Claims

1. A process for preparing fluopyram, characterized in that: The following steps are involved: In the presence of solvent 1, compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate, and compound 1-D are reacted in a reaction vessel to obtain an intermediate compound 1-G, and after distilling and recovering solvent 1, the intermediate compound 1-G does not need to be purified; water, alkali and solvent 2 are then added to the reaction vessel to react; after the reaction, the pH is adjusted and the reaction is continued; after the reaction is completed, the product fluopyram is obtained through post-treatment. Wherein, the 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); the solvent 1 is selected from an acetate solvent having a boiling point range of 40-110°C at normal temperature and pressure.

2. The process according to 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 according to claim 1, characterized in that: The base is sodium hydroxide; the solvent 2 is methanol; and the acid used to adjust the pH is selected from hydrochloric acid.

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

5. The process according to claim 1, characterized in that: The distillation temperature in the distillation recovery solvent 1 is 40-100° C., and the vacuum degree of the distillation is -0.070 to -0.098 MPa.

6. The process according to claim 1, characterized in that: In the reaction of preparing the product from the intermediate compound 1-G: the water is added in an amount according to a mass ratio of compound 1-F to water of 1:2.0-5.0; the solvent 2 is added in an amount according to a mass ratio of compound 1-F to solvent 2 of 1:1.0-5.0; the base is added in an amount according to a molar ratio of compound 1-F to sodium hydroxide of 1:2.0-4.0; the reaction temperature is 25-45°C, and the time is 3-6 hours; the temperature of the continued reaction is 40-60°C, and the time is 2-6 hours.

7. The process according to claim 1, characterized in that: The compound 1-F, ie, 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate dimethyl ester potassium salt, has a purity of ≥97.0% and a mass content of ≥93.0%.

8. The process according to claim 1, characterized in that: After the solvent 1 is recovered by distillation, the purity of the intermediate compound 1-G is ≥95.8%, and no purification treatment is required.

9. The process according to claim 1, characterized in that: The post-treatment comprises filtering, water slurry washing, filtering and drying in sequence.

Images