Preparation method of 2, 4-bis [2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl] dimethyl glutarate

Abstract

The invention discloses a preparation method of 2, 4-bis [2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl] dimethyl glutarate. The 2, 4-bis [2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl] dimethyl glutarate is used as a raw material. 2, 4-bis [2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl] dimethyl glutarate is taken as an associated impurity in the synthesis process of picoxystrobin, and the prepared high-purity impurity standard sample has important significance on registration of picoxystrobin at home and abroad and qualitative and quantitative impurity and process optimization in the research and development process. At present, the compound 2, 4-bis [2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl] dimethyl glutarate is not reported in literatures, and a preparation method of the compound is not provided. According to the method, a picoxystrobin key intermediate 2-(6-trifluoromethylpyridine-2-oxymethyl) phenyl methyl acetate is taken as a raw material and reacts with paraformaldehyde under the action of strong base to generate a crude product, and finally, a pure product of the compound is obtained through column chromatography.

Description

Technical Field

[0001] The invention relates to a preparation method of 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutaric acid dimethyl ester, belonging to the technical field of organic synthesis. Technical Background

[0002] Picoxystrobin is a strobilurin fungicide, mainly used to prevent and treat foliar diseases of wheat such as leaf blight, leaf rust, glumen blight, brown spot, powdery mildew, etc. Compared with other existing strobilurin fungicides, it has a stronger therapeutic effect on wheat leaf blight, net spot and moire. It has no cross-resistance with other fungicides currently used in the domestic market, and can be quickly degraded in plants, soil and water. It has the characteristics of protection, treatment, eradication, penetration, no carcinogenicity and mutagenicity, and is another type of pesticide with great development potential in the world pesticide industry after triazole fungicides.

[0003] Dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate is an impurity produced during the synthesis of picoxystrobin, and its structural formula is as follows:

[0004]

[0005] As an impurity in the synthesis of picoxystrobin, the preparation of high-content pure 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate plays an important guiding role in the quantitative and qualitative characterization of impurities in the registration of picoxystrobin products, the tracking of impurities during process research and development, and the production process.

[0006] However, the compound and its preparation method have not been reported in the literature, so it is necessary to develop a method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate. Summary of the invention

[0007] The invention provides a method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate.

[0008] The invention aims to prepare high-purity 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate dimethyl ester as a picoxystrobin impurity standard sample for the registration of picoxystrobin, and at the same time plays an important guiding role in the qualitative and quantitative analysis of impurities in the development process of picoxystrobin and in the later production tracking.

[0009] The invention provides a method for preparing 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]pentanedioic acid dimethyl ester. The method comprises the following steps: taking 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester and paraformaldehyde as raw materials, reacting in a non-polar solvent under the action of a strong base, and obtaining 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]pentanedioic acid dimethyl ester.

[0010] The preparation method of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate of the present invention is expressed by the following chemical reaction equation:

[0011]

[0012] Furthermore, in the above technical solution, the specific steps of the preparation method are as follows:

[0013] (1) Condensation reaction: methyl 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetate is dissolved in a non-polar solvent, and a strong base and paraformaldehyde are added at room temperature to react to obtain a crude product of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate;

[0014] (2) Separation and purification: The crude product of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate is separated by column chromatography to obtain high-purity dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate.

[0015] Furthermore, in the above technical solution, the non-polar solvent is selected from xylene, toluene or ethylene dichloride.

[0016] Furthermore, in the above technical solution, the reaction temperature is 0-80°C, preferably 20-25°C.

[0017] Furthermore, in the above technical solution, the strong base is selected from at least one of sodium hydrogen, sodium methoxide, sodium hydroxide and potassium hydroxide. Preferably, the strong base is sodium hydrogen.

[0018] Furthermore, in the above technical solution, the molar ratio of methyl 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetate, paraformaldehyde and strong base is 1:1-1.2:1-2.5.

[0019] Furthermore, in the above technical solution, the solvent used for column chromatography in the purification step is n-heptane and ethyl acetate in a ratio of 5-30:1. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1This is the HNMR spectrum of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate obtained in Example 5. DETAILED DESCRIPTION

[0021] The present invention provides a method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate. The preparation method of the present invention is further illustrated by examples below.

[0022] Example 1 Synthesis of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate

[0023] In a 250mL four-necked bottle equipped with mechanical stirring, add 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester 33.43g (0.1mol, 1.0eq, 97.3%) and toluene 60g, stir and dissolve at room temperature. At room temperature, add sodium hydroxide 8.3g (0.2mol, 2.0eq, 96%) to the system, control the temperature at 20-25°C, add paraformaldehyde 3.13g (0.1mol, 1.0eq, 96%), heat to 75-80°C after addition and react for 5h, cool to room temperature after reaction, add 60g water dropwise, maintain the temperature at 20-25°C, stir for 0.5h after dropwise addition, stand and separate, wash the organic phase with 60g water once, desolventize and evaporate the organic phase to obtain 27g crude product, with a target product normalized content of 56%. The crude product was separated by column chromatography (n-heptane / ethyl acetate = 30:1) to obtain 12.1 g (98.8%) of pure product.

[0024] Example 2 Synthesis of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate

[0025] In a 250mL four-necked bottle equipped with mechanical stirring, add 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester 33.43g (0.1mol, 1.0eq, 97.3%) and toluene 60g, stir and dissolve at room temperature. Add sodium methoxide 13.64g (0.25mol, 2.5eq, 99%) to the system at room temperature, control the temperature at 20-25°C, add paraformaldehyde 3.13g (0.1mol, 1.0eq, 96%), heat to 50°C and react for 3h after adding, cool the system to 20-25°C after the reaction, add 60g water dropwise, maintain the temperature at 20-25°C, stir for 0.5h after dropping, stand and separate, wash the organic phase with 60g water once, desolventize the organic phase and evaporate to dryness to obtain 28g crude product, with a target product normalized content of about 71%. The crude product was separated by column chromatography (n-heptane / ethyl acetate = 20:1) to obtain 15.3 g (99.0%) of pure product.

[0026] Example 3 Synthesis of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate

[0027] In a 250mL four-necked bottle equipped with a mechanical stirrer, 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester 33.43g (0.1mol, 1.0eq, 97.3%) and dichloroethane 60g were added, and stirred and dissolved at room temperature. Sodium methoxide 13.64g (0.25mol, 2.5eq, 99%) was added to the system at room temperature, the temperature was controlled at 20-25°C, and paraformaldehyde 3.13g (0.1mol, 1.0eq, 96%) was added, and the reaction was carried out at room temperature for 4h. After the reaction, 60g of water was added dropwise, and the temperature was maintained at 20-25°C. After the addition, stirring was continued for 0.5h, and the liquid was separated. The organic phase was washed once with 60g of water, and the organic phase was desolventized and evaporated to obtain 27.6g of crude product, and the normalized content of the target product was about 72.2%. The crude product was separated by column chromatography (n-heptane / ethyl acetate = 15:1) to obtain 15.9 g (98.9%) of pure product.

[0028] Example 4 Synthesis of dimethyl 2,4-bis[2-(6-trifluoromethylpyridinium-2-oxymethyl)phenyl]glutarate

[0029] In a 250mL four-necked bottle equipped with mechanical stirring, add 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester 33.43g (0.1mol, 1.0eq, 97.3%) and xylene 60g, stir and dissolve at room temperature. Add sodium hydride 4.4g (0.11mol, 1.1eq, 60%) to the system at room temperature, control the temperature at 20-25°C, add paraformaldehyde 3.13g (0.1mol, 1.0eq, 96%), cool to 0-5°C after addition and react for 5h, add 60g water dropwise after the reaction is completed, maintain the temperature at 20-25°C, stir for 0.5h after dropwise addition, stand and separate, wash the organic phase with 60g water once, desolventize and evaporate the organic phase to obtain 28.3g crude product, with a target product normalized content of about 73%. The crude product was separated by column chromatography (n-heptane / ethyl acetate = 10:1) to obtain 16 g (99.1%) of pure product.

[0030] Example 5 Synthesis of dimethyl 2,4-bis[2-(6-trifluoromethylpyridinium-2-oxymethyl)phenyl]glutarate

[0031] In a 250mL four-necked bottle equipped with mechanical stirring, add 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester 33.43g (0.1mol, 1.0eq, 97.3%) and toluene 60g, stir and dissolve at room temperature. Add sodium hydride 4.4g (0.11mol, 1.1eq, 60%) to the system at room temperature, control the temperature at 20-25°C, add paraformaldehyde 3.13g (0.1mol, 1.0eq, 96%), react at 20-25°C for 3h, add 60g water dropwise after the reaction is completed, maintain the temperature at 20-25°C, stir for 0.5h after the dropwise addition, stand and separate, wash the organic phase with 60g water once, desolventize and evaporate the organic phase to obtain 29g crude product, with a target product normalized content of about 80%. The crude product was separated by column chromatography (n-heptane / ethyl acetate v / v=15:1) to obtain 18 g (99.2%) of pure product.

[0032] 1 HNMR (400MHz, CDCl3): 2.59 (t, 2H, J = 7.6Hz), 3.54 (s, 6H), 4.04 (t, 2H, J = 7.6Hz), 5.17-5.25 (m, 4H), 6.94 (d, 2H,J=8.4Hz),7.23-7.27(m,4H),7.29-7.34(m,2H),7.37-7.39(m,2H),7.47-7.49(m,2H),7.66-7.70(m,2H).

[0033] The above description of the embodiments is to facilitate the understanding and use of the invention by those skilled in the art. It is obvious that those skilled in the art can easily make various modifications to these embodiments and apply the general principles described herein to other embodiments without creative work. Therefore, the present invention is not limited to the above embodiments, and improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the present invention should be within the scope of protection of the present invention.

Claims

1. A method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate, characterized in that: The method comprises the following steps: using 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester and polyformaldehyde as raw materials, reacting in a non-polar solvent under the action of a strong base to obtain 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutaric acid dimethyl ester.

2. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 1, characterized in that: The specific steps are as follows: (1) Condensation reaction: methyl 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetate is dissolved in a non-polar solvent, and a strong base and paraformaldehyde are added at room temperature to react to obtain a crude product of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate; (2) Separation and purification: The crude product of dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate is separated by column chromatography to obtain high-purity dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate.

3. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 1 or 2, characterized in that: The non-polar solvent is selected from xylene, toluene or ethylene dichloride.

4. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 1 or 2, characterized in that: The reaction temperature is 0-80°C.

5. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 4, characterized in that: The reaction temperature is 20-25°C.

6. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 1 or 2, characterized in that: The strong base is selected from at least one of sodium hydroxide, sodium methoxide, sodium hydroxide and potassium hydroxide.

7. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 6, characterized in that: The strong base is sodium hydrogen.

8. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 1 or 2, characterized in that: The molar ratio of 2-(6-trifluoromethylpyridine-2-oxymethyl)phenylacetic acid methyl ester, paraformaldehyde and strong base is 1:1-1.2:1-2.

5.

9. The method for preparing dimethyl 2,4-bis[2-(6-trifluoromethylpyridine-2-oxymethyl)phenyl]glutarate according to claim 2, characterized in that: The solvent used for column chromatography in the purification step is n-heptane and ethyl acetate in a ratio of 5-30:1.

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