Preparation method of fluazinam

Abstract

The invention discloses a preparation method of fluazinam, which comprises the following specific steps: by taking anhydrous alkyl substituted aromatic hydrocarbon as a solvent, adding 2, 4-dichloro-3, 5-dinitro-trifluorotoluene and 2-amino-3-chloro-5-trifluoromethylpyridine to prepare a mixed solution; and preparing anhydrous alkyl substituted aromatic hydrocarbon containing an acid-binding agent, stirring for bottoming, and dropwise adding the mixed solution into the anhydrous alkyl substituted aromatic hydrocarbon to prepare fluazinam. According to the method, no water is generated in the reaction process, generation of by-products caused by hydrolysis of nitride raw materials is effectively prevented, post-treatment is convenient, the product does not need to be purified, the content can reach 99% or above, the yield can reach 99% or above, and industrial production of fluazinam is better facilitated.

Description

Technical Field

[0001] The invention belongs to the field of organic chemical synthesis, and specifically relates to a preparation method of fluazinam. Background Art

[0002] Fluazinam, chemical name is 3-chloro-N-(3-chloro-5-trifluoromethyl-2-pyridyl)-A,A,A-trifluoro-2,6-dinitro-p-toluidine, and its structural formula is as follows:

[0003]

[0004] This pesticide is a pyridinamine derivative and belongs to the dinitroaniline fungicide. It has no therapeutic effect and systemic activity, but is a high-efficiency protective fungicide with a wide spectrum. Fluazinam is very effective against Alternaria, Phytophthora, Monoparacephala, Sclerotinia and Venturia. It also has a good effect on Botrytis cinerea, which is resistant to benzimidazole and dicarboximide fungicides, and rice damping-off disease caused by Rhizopus. This product is extremely resistant to rain erosion and has a long residual effect. In addition, it also has the function of controlling phytophagous mites.

[0005] At present, the synthesis of fluazinam is mainly based on the condensation of intermediate I: 2-amino-3-chloro-5-trifluoromethylpyridine and intermediate II: 2,4-dichloro-3,5-dinitro-trifluorotoluene. In addition to producing fluazinam, this process often produces impurities with the following structure; this impurity is usually generated by the hydrolysis of intermediate II under alkaline conditions, so in order to control this impurity, it is necessary to control the water content in the system during the reaction process.

[0006]

[0007] Patent CN103626695A discloses the synthesis of fluazinam using a mixed solvent as a reaction solvent, but the disadvantages are that: 3 times the equivalent of potassium hydroxide needs to be used, and the amount of waste salt and waste water after neutralization is large; the use of potassium hydroxide in the reaction will generate water, and the solvent methyl isobutyl ketone is prone to aldol condensation reaction under strong alkaline and water conditions; there are two strong electron-withdrawing groups, trifluoromethyl and nitro, on the benzene ring of the intermediate II 2,4-dichloro-3,5-dinitro-trifluorotoluene. Because water is generated in the reaction, the para-chlorine of the trifluoromethyl group is particularly easy to hydrolyze to produce dinitrophenol impurities. The distillation decomposition temperature of the impurity is very low, and it is easy to cause explosion danger; the base needs to be added more than thirty times, and the operation is very complicated.

[0008] Patent CN110143916A discloses the synthesis of fluazinam using ether solvents as reaction solvents, but the disadvantages are: using 2.2 to 5 times the amount of alkali, the amount of waste salt and waste water after neutralization is large; using tetrahydrofuran as solvent requires water control, and the recovery of the solvent containing salt and waste water after post-treatment of neutralization is difficult and costly; and dinitrophenol impurities are also easily generated.

[0009] Patent CN109988103A discloses the synthesis of fluazinam using anisole as a reaction solvent, but the disadvantage is that the density of anisole is 0.953 g / cm 3 , close to water, post-treatment and water removal and recovery are difficult; 2 to 2.5 times the amount of alkali is used, and the amount of waste salt and wastewater after neutralization is large; it needs to be refined, and the crystal seeding and crystallization operation is relatively complicated.

[0010] In addition, the methods disclosed in patents EP0031257A2 and WO2009017241A2 have the problem of too low yield or content, and are not suitable for the industrial preparation of fluazinam.

[0011] Therefore, how to develop a preparation method that is free of water and by-products, has high yield and purity, and is green and safe is the key to achieving industrial production of fluazinam. Summary of the invention

[0012] In order to overcome the above-mentioned deficiencies of the prior art, the present invention aims at a method for preparing fluazinam.

[0013] The technical solution of the present invention to solve the above technical problems is as follows:

[0014] The present invention discloses a method for preparing fluazinam, which is characterized by comprising the following steps:

[0015] (1) using anhydrous alkyl substituted aromatic hydrocarbon as a solvent, adding 2,4-dichloro-3,5-dinitro-trifluorotoluene and 2-amino-3-chloro-5-trifluoromethylpyridine to prepare a mixed solution;

[0016] (2) preparing an anhydrous alkyl-substituted aromatic hydrocarbon containing an acid-binding agent as a base, and adding the mixed solution dropwise therein to prepare fluazinam;

[0017] Furthermore, in step (1), the molar ratio of 2,4-dichloro-3,5-dinitro-trifluorotoluene to 2-amino-3-chloro-5-trifluoromethylpyridine is 1 to 1.1:1, preferably 1:1;

[0018] Further, the anhydrous alkyl-substituted aromatic hydrocarbon is selected from one or more of toluene, o-xylene, m-xylene or p-xylene, preferably toluene;

[0019] Furthermore, the water content of the anhydrous alkyl-substituted aromatic hydrocarbon is less than 0.05%;

[0020] Furthermore, in step (2), the acid-binding agent is selected from sodium hydride, potassium hydride or calcium hydride, preferably sodium hydride;

[0021] Further, the molar ratio of the acid binding agent to 2,4-dichloro-3,5-dinitro-trifluorotoluene is 1 to 1.2:1, preferably 1.15:1;

[0022] Furthermore, the dropping temperature in step (2) is 20 to 30° C., preferably 20 to 25° C.; the dropping time is 2 to 4 hours, preferably 2 to 3 hours;

[0023] Furthermore, the present invention also includes the steps of adding methanol to the reaction system, washing with water, adjusting the pH, layering or concentrating after the reaction is completed;

[0024] Furthermore, the methanol is added at a temperature of 20 to 40°C, preferably 20 to 30°C;

[0025] Furthermore, the pH is adjusted to 4-5.

[0026] If there is a conflict between the Chinese name and the structural formula of the compound in the present invention, the structural formula shall prevail, unless there is an obvious error in the structural formula.

[0027] The beneficial effects of the present invention are:

[0028] 1. The solvent used in the preparation of fluazinam in the present invention is an alkyl-substituted aromatic hydrocarbon, which is easier to recover and has a lower water content than the currently reported tetrahydrofuran, MIBK, etc., wherein the water content of the recovered solvent can be controlled at <0.05%;

[0029] 2. The present invention uses sodium hydride as an acid-binding agent to prepare fluazinam, ensuring that no water is generated during the reaction process, thereby preventing the generation of side reactions at the source, and the content can reach more than 99% without post-processing purification, and the yield can reach more than 99%;

[0030] 3. The preparation of fluazinam by the present invention can realize the one-time addition of sodium hydride for reaction, without the need to adopt the method of adding in batches to prevent hydrolysis caused by strong alkalinity, thus simplifying the operation method;

[0031] 4. The preparation of fluazinam by the present invention greatly reduces the amount of acid-binding agent, reduces the amount of waste salt and the amount of hydrochloric acid used for neutralization, is more environmentally friendly and efficient, and is conducive to the industrial production of fluazinam. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 : Hydrogen spectrum of fluazinam prepared in Example 1. DETAILED DESCRIPTION

[0033] The present invention is described below with reference to examples, but the present invention is not limited thereto. In the art, simple replacement or improvement made by technicians in the field to the present invention belongs to the technical solution protected by the present invention.

[0034] Embodiment 1:

[0035] Add 504 g of fresh anhydrous toluene (water content <0.05%) into a 1L four-necked bottle, and add 2-amino-3-chloro-5-trifluoromethylpyridine (98.74 g, 0.5 mol, 196.56) and 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27 g, 0.5 mol, 304.99) respectively under stirring. Stir for 15 minutes to prepare a solution for use.

[0036] Add 200g of fresh anhydrous toluene to a 2L four-necked bottle, add sodium hydride (23g, 0.575mol, 24) (washed with normal hexane) under nitrogen protection and stirring, drip the above-mentioned mixed solution prepared at 20-25 ℃ of temperature control, drip off in about 2-3 hours, drip off and keep warm at this temperature for 1 hour, HPLC detects that the raw material 2-amino-3-chloro-5-trifluoromethylpyridine reacts completely and stops the reaction. Temperature control 20-30 ℃ drips 10g of methanol into the reaction system and stirs for 1 hour to destroy sodium hydride, then adds 120g of water and drips a small amount of hydrochloric acid to adjust the system pH value to 4-5, standing for stratification, washing the toluene organic phase with water, concentrating to obtain a yellow fluazinam product: 233.18g (465.09), content: 99.2%, yield: 99.47%, no dinitro raw material hydrolysis impurities are detected in the product. Toluene washing, reflux and azeotropy with water jacket, control the water content <0.05%, control the methanol content <0.02%.

[0037] 1 H NMR (CDCl 3 )δ7.94(S.1H),8.25(S,1H),8.6(S,1H),8.93(S,1H).

[0038] Embodiment 2:

[0039] To a 1L four-necked bottle, add 504g of recovered toluene (water content <0.05%, methanol: 0.015%), and add 2-amino-3-chloro-5-trifluoromethylpyridine (98.74g, 0.5mol, 196.5) and 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27g, 0.5mol, 304.99) respectively under stirring. After adding, stir for 15 minutes to prepare a solution for use.

[0040] Add 200g of fresh anhydrous toluene (water content <0.05%, methanol: 0.015%) to a 2L four-necked bottle, add sodium hydride (23g, 0.575mol, 24) (washed with n-hexane) under nitrogen protection and stirring, drip the above-prepared mixed solution at 20-25°C, drip it in about 2-3 hours, keep it warm at this temperature for 1 hour, and stop the reaction when the raw material 2-amino-3-chloro-5-trifluoromethylpyridine reacts completely by HPLC detection. Control the temperature at 20-30°C, drip 10g of methanol into the reaction system, stir for 1 hour to destroy the sodium hydride, then add 120g of water, drip a small amount of hydrochloric acid to adjust the system pH value to 4-5, let stand for stratification, wash the toluene organic phase with water, and concentrate to obtain a yellow fluazinam product: 232.27g (465.09), content: 99.3%, yield: 99.18%. No dinitro raw material hydrolysis impurities were detected in the product.

[0041] Embodiment 3:

[0042] Add 510 g of fresh anhydrous xylene (water content <0.05%) into a 1L four-necked bottle, and add 2-amino-3-chloro-5-trifluoromethylpyridine (98.74 g, 0.5 mol, 196.5) and 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27 g, 0.5 mol, 304.99) respectively under stirring. Stir for 15 minutes to prepare a solution for use.

[0043] Add 200g of fresh anhydrous xylene to a 2L four-necked bottle, add sodium hydride (23g, 0.575mol, 24) (washed with normal hexane) under nitrogen protection and stirring, and drip the above-configured mixed solution at 20-25°C, drip it in about 2-3 hours, and keep it warm at this temperature for 1 hour. HPLC detects that the raw material 2-amino-3-chloro-5-trifluoromethylpyridine reacts completely and stops the reaction. Control the temperature at 20-30°C, drip 10g of methanol into the reaction system, stir for 1 hour to destroy the sodium hydride, then add 120g of water, drip a small amount of hydrochloric acid to adjust the system pH value to 4-5, stand for stratification, wash the toluene organic phase with water, and concentrate to obtain a yellow fluazinam product: 231.8g (465.09), content: 99.4%, yield: 99.08%. No dinitro raw material hydrolysis impurities were detected in the product.

[0044] Embodiment 4:

[0045] Add 504 g of fresh anhydrous toluene (water content <0.05%) into a 1L four-necked bottle, and add 2-amino-3-chloro-5-trifluoromethylpyridine (98.74 g, 0.5 mol, 196.5) and 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27 g, 0.5 mol, 304.99) respectively under stirring. Stir for 15 minutes to prepare a solution for use.

[0046] Add 200 g of fresh anhydrous toluene to a 2L four-necked bottle, add potassium hydroxide (88.42 g, 1.5 mol, 56.1) under nitrogen protection and stirring, and add the prepared mixed solution dropwise at a temperature of 20-25°C for about 2-3 hours. After the addition, keep warm at this temperature for 2 hours. HPLC detection shows that 10.5% of the raw material 2-amino-3-chloro-5-trifluoromethylpyridine remains unreacted, and the dinitro hydrolysis impurity content is detected to be 11.2%. 365 g of 10% hydrochloric acid was slowly added dropwise under temperature control to adjust the pH value of the system to 4-5, and the mixture was allowed to stand for stratification. 148 g of methanol was added to the toluene organic phase, and the temperature was refluxed for 0.5 hour to dissolve the solid completely. Then 58 g of methanol was distilled off, and the mixture was cooled to 20°C and 0.4 g of fluazinam seed was added. The mixture was then cooled to 0-5°C for crystallization and kept warm for 1.5 hours. The mixture was filtered and the filter cake was rinsed with 50 g of cold methanol and dried to obtain a primary fluazinam product: 181.66 g (465.09), with a content of 96.2%, a yield of 75.15%, and a primary product of dinitrohydrolysis impurities content of 2.5%; the methanol mother liquor was concentrated into 55 g of methanol for a secondary time, cooled, crystallized, filtered, and dried to obtain a secondary crystalline fluazinam product: 10.7 g (465.09), with a content of 89.5%, a yield of 4.12%, and a secondary product of dinitrohydrolysis impurities content of 5.4%, and a total yield of 79.27%.

[0047] Embodiment 5:

[0048] To a 1L four-necked bottle, add 504g of methyl isobutyl ketone (water content <0.05%), and add 2-amino-3-chloro-5-trifluoromethylpyridine (98.74g, 0.5mol, 196.5) and 153.27g of 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27g, 0.5mol, 304.99) respectively under stirring. After adding, stir for 15 minutes until a solution is prepared for use.

[0049] To a 2L four-necked bottle, 200 g of methyl isobutyl ketone (water content <0.05%) was added, potassium hydroxide (88.42 g, 1.5 mol, 56.1) was added under nitrogen protection and stirring, and the mixed solution prepared above was added dropwise at a temperature of 20-25° C. The mixture was added dropwise for about 2-3 hours, and the mixture was kept at this temperature for 2 hours. HPLC detected that 2.5% of the raw material 2-amino-3-chloro-5-trifluoromethylpyridine remained unreacted, and the dinitro hydrolysis impurity content was detected to be 2.7%. The temperature was controlled and 365 g of 10% hydrochloric acid was slowly added dropwise to adjust the pH value of the system to 4-5, and the methyl isobutyl ketone organic phase was washed with water and concentrated to recover 0.2% impurities in the methyl isobutyl ketone solvent (due to condensation between the solvent molecules under strong alkaline conditions); 148 g of methanol was added to the concentrated crude product and the temperature was refluxed for 0.5 hours to dissolve the solid completely, and then 58 g of methanol was evaporated, cooled to 20°C, 0.4 g of fluazinam seed crystals were added, and then the temperature was lowered to 0-5°C for crystallization and kept warm for 1.5 hours, filtered, and the filter cake was washed with 50 g cold methanol was eluted and dried to obtain a primary fluazinam product: 206.11 g (465.09), content: 97.2%, yield: 86.15%, primary product dinitrohydrolysis impurity content: 1.7%; methanol mother liquor was secondary concentrated to 55 g methanol, cooled, crystallized, filtered, and dried to obtain a secondary crystalline fluazinam product: 10.23 g (465.09), content: 95.5%, yield: 4.2%, secondary fluazinam product dinitrohydrolysis impurity content: 2.4%, total yield: 90.35%.

[0050] Embodiment 6:

[0051] Add 404 g of fresh tetrahydrofuran into a 1 L four-necked bottle, add 2,4-dichloro-3,5-dinitro-trifluorotoluene (153.27 g, 0.5 mol, 304.99) under stirring, stir for 15 minutes after the addition to prepare a solution for use.

[0052] Under nitrogen protection and stirring, add 300g of fresh tetrahydrofuran, potassium hydroxide (88.42g, 1.5mol, 56.1), and 2-amino-3-chloro-5-trifluoromethylpyridine (98.7g, 0.5mol, 196.5) into a 2L four-necked bottle; control the temperature at 20-25°C and add the prepared mixed solution dropwise for about 2 to 3 hours. After the addition, keep the mixture at this temperature for 2 hours. HPLC detection shows that 1.7% of the raw material 2-amino-3-chloro-5-trifluoromethylpyridine remains unreacted, and the dinitro hydrolysis impurity content is 1.9%. 365 g of 10% hydrochloric acid was slowly added dropwise under temperature control to adjust the pH value of the system to 4-5, distilled, filtered, washed with water, 148 g of methanol was added to the crude product and the temperature was refluxed for 0.5 hour to dissolve the solid completely, then 58 g of methanol was distilled off, cooled to 20 ° C, 0.4 g of fluazinam seed was added, the temperature was lowered to 0-5 ° C for crystallization and kept warm for 1.5 hours, filtered, the filter cake was rinsed with 50 g of cold methanol, and the primary fluazinam product after drying was 213.96 g (465.09), content: 98.2%, yield: 90.35%, primary fluazinam product dinitro hydrolysis impurity content: 0.9%; methanol mother liquor was concentrated into 55 g of methanol for the second time, cooled, crystallized, filtered, and dried to obtain a secondary fluazinam product: 10.84 g (465.09), content: 96.5%, yield: 4.5%, secondary product dinitro hydrolysis impurity content: 1.8%, total yield: 94.85%.

[0053] The above is only a preferred embodiment of the present invention. It should be pointed out that a person skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A method for preparing fluazinam, It is characterized in that The steps include: (1) using anhydrous alkyl substituted aromatic hydrocarbon as a solvent, adding 2,4-dichloro-3,5-dinitro-trifluorotoluene and 2-amino-3-chloro-5-trifluoromethylpyridine to prepare a mixed solution; (2) preparing an anhydrous alkyl-substituted aromatic hydrocarbon containing an acid-binding agent as a base, and adding the above mixed solution dropwise therein to prepare fluazinam.

2. The method for preparing fluazinam according to claim 1, It is characterized in that In the step (1), the molar ratio of 2,4-dichloro-3,5-dinitro-trifluorotoluene to 2-amino-3-chloro-5-trifluoromethylpyridine is 1 to 1.1:

1.

3. The method for preparing fluazinam according to claim 1, It is characterized in that The anhydrous alkyl-substituted aromatic hydrocarbon is selected from one or more of toluene, o-xylene, m-xylene or p-xylene.

4. The method for preparing fluazinam according to claim 1, It is characterized in that The water content of the anhydrous alkyl-substituted aromatic hydrocarbon is less than 0.05%.

5. The method for preparing fluazinam according to claim 1, It is characterized in that In the step (2), the acid binding agent is selected from sodium hydride, potassium hydride or calcium hydride.

6. The method for preparing fluazinam according to claim 1, It is characterized in that The molar ratio of the acid binding agent to 2,4-dichloro-3,5-dinitro-trifluorotoluene is 1-1.2:

1.

7. The method for preparing fluazinam according to claim 1, It is characterized in that The dropping temperature in step (2) is 20-30° C., and the dropping time is 2-4 hours.

8. The method for preparing fluazinam according to claim 1, It is characterized in that The method also includes the steps of adding methanol dropwise to the reaction system, washing with water, adjusting the pH, layering or concentrating after the reaction is completed.

9. The method for preparing fluazinam according to claim 8, It is characterized in that The dropping temperature of the methanol is 20-40°C.

10. The method for preparing fluazinam according to claim 8, It is characterized in that The pH is adjusted to 4-5.

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