Process for preparing key intermediate of fluopyram

Abstract

Disclosed in the present invention is a process for preparing a key intermediate of fluopyram. The key intermediate is dimethyl [3-chloro-5-(trifluoromethyl)pyridin-2-yl]({[2-(trifluoromethyl)benzoyl]amino}methyl)malonate. The process comprises the following steps: in the presence of a solvent 1, reacting the compound potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate with the compound 1-D in a reaction container, and recovering the solvent 1 by means of distillation, so as to obtain the intermediate compound, wherein the solvent 1 is selected from acetic ester solvents having a boiling point range of 40-110°C at a normal temperature and a normal pressure. The process of the present invention is simple and convenient, the total yield is high, the solvent is easy to recover, and the product purity is high; the intermediate does not require any post-purification treatment, and can be directly used for the synthesis of fluopyram; and the process can be amplified, and is beneficial for cost reduction, efficiency improvement and commercial mass production.

Description

A process for preparing key intermediates of fluopyram Technical Field

[0001] This invention relates to a process for preparing a key intermediate of fluopyram, specifically a process for preparing dimethyl [3-chloro-5-(trifluoromethyl)pyridin-2-yl]({[2-(trifluoroformyl)benzoyl]amino}methyl)malonate, 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] [3-Chloro-5-(trifluoromethyl)pyridin-2-yl]({[2-(trifluoroformyl)benzoyl]amino}methyl)dimethyl malonate, molecular formula: C 20 H 15 ClF6N2O5; relative molecular mass: 512.79; CAS Registry Number: 895525-76-5, is a key intermediate in the synthesis of fluopyram, abbreviated as intermediate compound 1-G, and its chemical structural formula is as follows:

[0004] Currently, in actual production, the preparation of the key intermediate [3-chloro-5-(trifluoromethyl)pyridin-2-yl]({[2-(trifluoromethyl)benzoyl]amino}methyl)dimethyl malonate (intermediate compound 1-G) suffers from problems such as cumbersome processes, low yields, difficult solvent recovery, and low product purity. To improve market competitiveness, it is necessary to find a preparation process that is simple, has a high overall yield, is easy to recover solvents, and produces high product purity. Currently, the main processes for preparing this intermediate compound 1-G are as follows:

[0005] Route 1: Patent CN108822024 discloses a method for synthesizing intermediate compound 1-G, including: Step 4, adding formamide as a solvent to a hydroxymethylated white solid, heating, adding acetic anhydride dropwise, continuing the reaction after the addition, cooling to 25°C to obtain an esterified product; Step 5, adding dimethyl 5-trifluoromethyl-2-malonate-3-chloropyridine to the esterified product, heating and maintaining the reaction for 6 hours, cooling to 25°C to obtain a condensation product, which is intermediate compound 1-G. The overall yield of steps 4, 5, and 6 in this route, calculated based on the hydroxymethylated product, is approximately 79.3%. In steps 4 and 5, formamide is used as a solvent, which is difficult to recover. The purity of intermediate compound 1-G is not reported in this patent.

[0006] Route 2: 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 then condensed to prepare intermediate B1. Intermediate B5 and intermediate B1 are then condensed together to prepare intermediate B6, which is intermediate compound 1-G. Finally, hydrolysis and decarboxylation yield fluopyram. In this process, intermediates B5 and 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 stringent conditions, and the mixed solvents are difficult to separate and recover, hindering large-scale production. The intermediate B6 mixture is diluted with water and extracted with methyl tert-butyl ether (MTBE), requiring further distillation to remove MTBE. Intermediate B6 requires extraction and purification, making the process complex, with the yield of the last four steps approximately 86.5%.

[0007] Route 3: Patent CN117003691A, patent name: A method for preparing fluopyram. Potassium salt of 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, i.e., intermediate 1, is reacted with N-(chloromethyl)-2-trifluoromethylbenzamide, i.e., intermediate 2, in the presence of solvent 3. After separation, intermediate 3, i.e., intermediate compound 1-G, is obtained. Then, intermediate 3 is reacted with water and alkali in solvent 4 to continue the reaction, and finally, the product fluopyram is obtained by separation. The 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 the intermediate compound 1-G. The process is quite complicated. At the same time, solvent 3 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (above 150°C), making it difficult to recover and resulting in high recovery costs. The total yield of the two steps in steps 4 and 5 (the last two steps) is about 76.1-79.2%, and the overall yield of the route is about 66.9-71.4%.

[0008] Route 4: Patent CN116854629A, Patent Name: A Method for Preparing Fluopyram. Potassium salt of 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate (intermediate 1) and N-(chloromethyl)-2-trifluoromethylbenzamide (intermediate 3) are reacted in the presence of solvent 4. After separation, intermediate 4, which is intermediate compound 1-G, is obtained. Then, intermediate 4 is reacted with water and alkali in solvent 5 to continue the reaction, and finally, the product fluopyram is obtained. The process is quite lengthy. After step 4, the reaction still requires post-processing steps: solvent recovery under reduced pressure, addition of organic solvent and water to the residue, extraction and separation, washing of the organic phase with water, concentration under reduced pressure to obtain the crude product, recrystallization, etc., to obtain the intermediate compound 1-G. The process is rather complicated. In addition, solvent 4 is N,N-dimethylacetamide and / or dimethyl sulfoxide, which has a high boiling point (above 150°C), making it difficult to recover and resulting in high recovery costs. Furthermore, the total yield of the two steps (steps 4 and 5, the last two steps) is approximately 80.5-80.9%, while the overall yield of the route is approximately 68.2-70.9%.

[0009] For the reasons mentioned above, there is an urgent need for a process to prepare the key intermediate [3-chloro-5-(trifluoromethyl)pyridin-2-yl]({[2-(trifluoromethyl)benzoyl]amino}methyl)dimethyl malonate (intermediate compound 1-G), in order to solve the problems of cumbersome process, low yield, difficult solvent recovery, and low product purity in the preparation of this intermediate compound, and improve market competitiveness. Summary of the Invention

[0010] The purpose of this invention is to address the shortcomings of existing technologies by providing a simple, high-yield, solvent-recoverable, and high-purity preparation process for a key intermediate of fluopyram (intermediate compound 1-G).

[0011] To achieve the above objectives, this invention provides a process for preparing a key intermediate of fluopyram, comprising the following steps: In the presence of solvent 1, compound 1-F (potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate) and compound 1-D are reacted in a reaction vessel; after the reaction is complete, solvent 1 is recovered by distillation to obtain intermediate compound 1-G; the reaction equation is shown below:

[0012] Wherein, compound 1-D is selected from N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-1) and / or N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-2); solvent 1 is selected from acetate solvents with a boiling point range of 40-110℃ at room temperature and pressure.

[0013] Preferably, solvent 1 is selected from one or more combinations of methyl acetate, ethyl acetate, and isopropyl acetate.

[0014] Preferably, the molar ratio of compound 1-F to compound 1-D is 1:0.95-1.10; and the mass ratio of compound 1-F to solvent 1 is 1:5.0-11.0.

[0015] Preferably, in the above steps, the feeding temperature is 40-55℃; the reaction temperature is 40-65℃; and the reaction time is 3-6 hours.

[0016] 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.

[0017] 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.

[0018] Preferably, in the above steps, after distillation and recovery of solvent 1, the residual amount of solvent 1 is ≤3%, and the purity of intermediate compound 1-G is ≥95.8%.

[0019] The present invention also experimentally verified that the intermediate compound 1-G obtained by this process has a high purity of ≥95.8%. The small amount of byproducts and solvent 1 can be used directly without purification, with little impact on subsequent reactions. After further reaction, it can be converted into a bactericide such as fluopyram.

[0020] Compared with the prior art, the present invention has the following beneficial effects:

[0021] 1. This invention provides a process for preparing intermediate compound 1-G from compound 1-F (potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate) and compound 1-D in a suitable acetate solvent. The intermediate compound 1-G prepared by this process has high purity, ≥95.8%, and can reach up to 97.8%, and requires no additional purification steps. The process is simple and suitable for large-scale production.

[0022] 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 obtained intermediate compound 1-G has high purity and few impurities; second, these acetate solvents are easy and simple to recover under mild conditions, have a high solvent recovery rate, and basically do not generate new impurities during the solvent recovery process; this process... In addition to its simple process, this method also features a high overall yield. The molar yield of intermediate compound 1-G obtained by this method is ≥95.5%, and can reach up to 97.7% (calculated based on potassium 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate). The crude intermediate compound 1-G obtained by this method, along with a small amount of byproducts and solvent 1, can be used directly without purification, having little impact on subsequent reactions. The simplified production process helps reduce manufacturing costs, and the increased overall yield helps reduce raw material costs, thus promoting cost reduction and efficiency improvement, and facilitating large-scale commercial production.

[0023] 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. Preferred solvents for its reaction include N,N-dimethylacetamide, N-methylpyrrolidone, formamide, and acetic acid. Through extensive experimentation, this invention unexpectedly discovered that acetate ester solvents with boiling points in the range of 40-110℃ at room temperature and pressure, such as methyl acetate, ethyl acetate, and isopropyl acetate, provide good solubility for compound 1-F. Furthermore, these solvents are 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. Detailed Implementation

[0024] To make the present invention more apparent and understandable, preferred embodiments are described in detail below.

[0025] Unless otherwise specified, percentages in this invention refer to mass concentration or mass percentage.

[0026] In the embodiments of this invention, the purity or content was determined by high performance liquid chromatography.

[0027] In this embodiment of the invention, compound 1-F, i.e., potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate, was prepared according to the method of patent CN116854629A, with a purity ≥97.0% and a mass content ≥93.0%; N-(acetoxymethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-1) was prepared according to patent CN116854629A, with a mass content ≥97.0%; N-(chloromethyl)-2-trifluoromethylbenzamide (i.e., compound 1-D-2) was prepared according to patent CN116854629A, with a mass content ≥97.0%. All other reagents were commercially available products with a purity ≥99.0%.

[0028] Example 1

[0029] 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 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 97.9%. 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 2364.4 g, and the recovery rate of solvent 1 was 94.3%. Sampling point 2 was taken. At this point, the purity of intermediate compound 1-G was 97.8%, and the residual amount of solvent 1 in intermediate compound 1-G was 1.5%. 624.8 g of intermediate compound 1-G was obtained. The product mass content was determined, and the molar yield was calculated to be 97.7% (calculated based on potassium 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate).

[0030] In this Example 1, solvent 1 is ethyl acetate.

[0031] Example 2

[0032] In a 50-liter reaction vessel, solvent 1 (21564 g) and compound 1-F, namely potassium salt of 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%. Sampling point 2 was taken. At this point, the purity of intermediate compound 1-G was 97.4%, and the residual amount of solvent 1 in intermediate compound 1-G was 1.3%. 5944g of intermediate compound 1-G was obtained. The product mass content was determined, and the molar yield was calculated to be 97.2% (calculated based on potassium salt of dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridinyl]malonate).

[0033] In this Example 2, solvent 1 is ethyl acetate.

[0034] Examples 3-8

[0035] A process for preparing a key intermediate of fluopyram is disclosed, differing from Example 1 in the process parameters. For instance, the only difference between Example 3 and Example 1 is the reaction substrate compound 1-D. In Example 3, compound 1-D is selected from formula 1-D-2, i.e., N-(chloromethyl)-2-trifluoromethylbenzamide, while in Example 1, compound 1-D is selected from formula 1-D-1, i.e., N-(acetoxymethyl)-2-trifluoromethylbenzamide. All other conditions remain the same. Specific differences in other examples are shown in Table 1.

[0036] Table 1. Preparation method parameters for Examples 3-8

[0037] The purity and molar yield of the samples and products obtained from each sampling point in Examples 3 to 8 were calculated by high performance liquid chromatography (HPLC), and the results are shown in Table 2.

[0038] Table 2. Sample purity and molar yield at each sampling point in Examples 3-8

[0039] 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. Using these acetate solvents, the intermediate compound 1-G prepared has a purity of ≥95.8%, and can reach up to 97.8%.

[0040] 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 organic 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, this process method features a high overall yield. The molar yield of intermediate compound 1-G obtained by this process method is ≥95.5%, and can reach a maximum of 97.7% (calculated as potassium 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate).

[0041] Example 9

[0042] 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 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 97.9%. 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 1-G was 97.8%, and the residual amount of solvent 1 in intermediate compound 1-G was 1.5%. Methanol (632.6g) was then 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 this time, the purity of intermediate compound 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 satisfactory. At this point, 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 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, and dried to obtain 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, and 0.4% acetone-insoluble matter.

[0043] In this Example 9, solvent 1 is ethyl acetate.

[0044] Comparative Examples 1-6

[0045] A process for preparing a key intermediate of fluopyram is disclosed. 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.

[0046] Table 3. Preparation method parameters for Comparative Examples 1–6

[0047] The purity and molar yield of the samples from each sampling point obtained from Comparative Examples 1 to 6, as well as the products, were calculated by high performance liquid chromatography (HPLC), and the results are shown in Table 4.

[0048] Table 4. Sample purity and molar yield at each sampling point in Comparative Examples 1–6

[0049] Based on Examples 1-8 and comparing the data from 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 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 the purity of the intermediate 1-G compound is significantly lower during distillation. 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.

[0050] 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 a key intermediate of fluopyram, characterized in that, The reaction includes the following steps: In the presence of solvent 1, compound 1-F (potassium dimethyl 2-[3-chloro-5-(trifluoromethyl)pyridyl]malonate) and compound 1-D are reacted in a reaction vessel. After the reaction is complete, solvent 1 is recovered by distillation to obtain intermediate compound 1-G. The reaction equation is shown below: Wherein, compound 1-D is selected from N-(acetoxymethyl)-2-trifluoromethylbenzamide and / or N-(chloromethyl)-2-trifluoromethylbenzamide; 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 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.

4. The process method as described in claim 1, characterized in that, In the steps described, 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, 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%.

7. The process method as described in claim 1, characterized in that, In the steps described, after distillation and recovery of solvent 1, the residual amount of solvent 1 is ≤3%, and the purity of intermediate compound 1-G is ≥95.8%.

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