A method for preparing fluoxastrobin

Abstract

The application discloses a preparation method of fluoxapyroxad, which comprises the following steps: mixing 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, a catalyst and a first organic solvent and heating to 83 DEG C-140 DEG C, then adding a mixed solution composed of 3', 4', 5'-trifluoro-2-aminobiphenyl and a second organic solvent, keeping warm after adding, continuously releasing hydrogen chloride during the reaction, adding an aqueous solution of inorganic base after the reaction is completed, stirring and standing, separating the water layer, cooling and crystallizing the organic phase, filtering and drying to obtain the fluoxapyroxad product. The preparation method does not need to add an acid-binding agent, has the advantages of high yield, less waste, low cost, simple operation and good safety.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic chemical industry, and particularly relates to a preparation method of fluoxapyroxad. BACKGROUND

[0002] Fluoxapyroxad is a succinate dehydrogenase inhibitor (SDHI) fungicide developed by BASF, with the trade name Xemium, and the ISO common name Fluxapyroxad obtained in April 2015. The chemical name is 3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide. Fluoxapyroxad is one of the products that BASF focuses on, and the company plans to introduce it into more than 70 countries in the world for more than 100 crops. In 2011, fluoxapyroxad was first registered in the United Kingdom, and was put on the market in 2012. The product has been registered and put on the market in most major markets in the world, including the United States, Canada, the United Kingdom, Australia, the European Union 25 countries, Brazil, China, Japan, India, Argentina, etc.

[0003] Since fluoxapyroxad was put on the market, its sales have been rising, and in 2015, it successfully surpassed boscalid to become the first product in the SDHI fungicide market, and has maintained this market position ever since. In 2019, the global sales of fluoxapyroxad were 491 million US dollars, with a year-on-year growth of 4.5%, and the compound annual growth rate from 2012 to 2019 was 26.4%, showing a rapid growth trend. According to the forecast of BASF, the peak annual sales of fluoxapyroxad will reach 600 million euros.

[0004] There are many synthesis methods of fluoxapyroxad, mainly using 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 3',4',5'-trifluoro-2-aminobiphenyl to synthesize fluoxapyroxad (1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route), and some other synthesis methods are sporadically reported (other methods).

[0005] 1, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route

[0006]

[0007] Liu et al. [Synthesis of new fungicide fluazinam and bixafen [J]. Modern Pesticides, 2016, 15(1): 16-18] used triethylamine as an acid-binding agent, and reacted 3', 4', 5'-trifluoro-2-aminobiphenyl with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride in toluene under reflux for 5 h to obtain fluazinam with a normalized content of 95.2% and a yield of 82.3%. Wang et al. [Synthesis and biological activity of fluazinam [J]. Modern Pesticides, 2017, 16(4): 12-15] used triethylamine as an acid-binding agent, and reacted 3', 4', 5'-trifluoro-2-aminobiphenyl with excess 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride in dichloromethane at room temperature to obtain fluazinam with a normalized content of 95.2% and a yield of 41.7%. Jasch H et al. [Journal of Organic Chemistry, 2012, 77(23): 10699-10706] used pyridine as an acid-binding agent, heated a toluene solution of 3', 4', 5'-trifluoro-2-aminobiphenyl and excess pyridine to 55°C, added an equimolar amount of a toluene solution of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride dropwise, raised the temperature to 70°C after the reaction was completed, and then sequentially washed with hydrochloric acid, saturated sodium bicarbonate solution, and water. After drying with anhydrous sodium sulfate, fluazinam was obtained by column chromatography with a yield of 92%. Yin et al. [New synthesis process of new fungicide fluazinam [J]. World Pesticides, 2020, 42(10): 42-45] heated a toluene solution of 3', 4', 5'-trifluoro-2-aminobiphenyl to 45°C, added 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride dropwise, raised the temperature to 70°C after the addition was completed, and then sequentially washed with 5% hydrochloric acid, 10% sodium bicarbonate solution, and water after the reaction was completed. Fluazinam was obtained by post-treatment with a yield of 90.5%.

[0008] 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route synthesis of fluazinam usually requires the use of excess pyridine, triethylamine and other acid binding agents, and the generated pyridine hydrochloride, triethylamine hydrochloride and other materials need to be neutralized with a large amount of liquid alkali, resulting in a large amount of wastewater; then the recovery of anhydrous pyridine and anhydrous triethylamine requires a large amount of energy consumption. The use of acid binding agents by Yin Kai et al. [New synthetic process of novel fungicide fluazinam [J]. World Pesticides, 2020, 42(10): 42-45] will cause the generated hydrogen chloride to be difficult to discharge from the reaction system, and the hydrogen chloride and 3', 4', 5'-trifluoro-2-aminobiphenyl will generate a large amount of hydrochloride, thereby causing the stirring to fail. The stirring failure on the industrial production device is prone to cause safety accidents to occur, and at the same time, due to the stirring failure, the reaction of 3', 4', 5'-trifluoro-2-aminobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is insufficient, and a large amount of acid and base need to be used for washing the unreacted 3', 4', 5'-trifluoro-2-aminobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, resulting in a large amount of wastewater and serious pollution.

[0009] 2. Other methods

[0010] T. Zieg et al. [Process for the production of N-substituted (3-dihalomethyl-1- methylpyrazol-4-yl)carboxamides. CN101679282 B, 2012-11-28] used Pd(PhCN)2Cl2 as catalyst, 2,2-dimethyl-1,3-bis(diphenylphosphino)propane as ligand, diazabicycloundecane as acid binding agent, 3-difluoromethyl-1-methyl-4-bromopyrazole, 3', 4', 5'-trifluoro-2-aminobiphenyl and CO were reacted in DMF for 20 h (150℃, 1 MPa), and the yield of fluazinam was 81%.

[0011]

[0012] The method uses 3-difluoromethyl-1-methyl-4-bromopyrazole, which is simpler to synthesize than 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, and only needs to use difluoroacetyl chloride as raw material to obtain through 3 steps. However, in the process of synthesizing fluazinam from 3-difluoromethyl-1-methyl-4-bromopyrazole, the reaction time is long, the amount of palladium catalyst used is large, the production cost is high, and it is difficult to industrialize production.

[0013] Cheng Yanli [a method for synthesizing fluazinam based on Suzuki reaction. CN113402464A[P]. 2021-09-17] and others take 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as raw material, under the action of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and other condensing agents, condense with 2-iodoaniline to obtain 3-difluoromethyl-N-(2-iodophenyl)-1-methyl-1-pyrazole-4-amide, then under the action of palladium metal catalyst such as tetrakis(triphenylphosphine)palladium, it is coupled with 3,4,5-trifluorobenzenboronic acid by Suzuki coupling reaction to generate fluazinam, and the total yield is 74.5%.

[0014]

[0015] This method uses 2-iodoaniline with high price, large amount of palladium catalyst, high cost of raw materials, and intermediates and products need to be purified by column chromatography, which is difficult to industrialize.

[0016] J·Yaoenzai [a method for manufacturing pyrazole compounds. CN111587242A[P]. 2020-08-25] and others take 1,1,3,3-tetramethyl guanidine as organic base catalyst, 2,2,2-trichloro-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-yl) ethan-1-one reacts with 3',4',5'-trifluoro-2-aminobiphenyl in toluene to obtain fluazinam.

[0017]

[0018] This method avoids the use of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, 2,2,2-trichloro-1-(3-difluoromethyl-1-methyl-1H-pyrazole-4-yl) ethan-1-one can be obtained from 1,1,1-trichloro-4-ethoxybut-3-en-2-one as raw material, through 4-step reaction. Since 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is an intermediate of various fungicides, it has scale advantage and lower cost. This method does not have advantage.

[0019] As the expiration date of the original patent of fluazinam is approaching, the effective production capacity of fluazinam will gradually be released, and the environmental protection requirements will continue to improve, it is necessary to develop a new synthesis process of fluazinam, improve the reaction yield, reduce the production of "three wastes", and achieve the goal of improving the economic and social benefits of enterprises. SUMMARY

[0020] The technical problem to be solved by the present application is to overcome the shortcomings of the prior art, and to provide a preparation method of fluazinam which does not need to add acid-binding agent, has high reaction yield, less waste, low cost, simple operation and good safety.

[0021] To solve the above technical problems, the present application adopts the following technical solutions.

[0022] A preparation method of fluazinam, comprising the following steps: firstly, mixing 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride, a catalyst and a first organic solvent and heating to 83-140 DEG C, then adding a mixed solution composed of 3', 4', 5'-trifluoro-2-aminobiphenyl and a second organic solvent, keeping warm and reacting, continuously releasing hydrogen chloride during the reaction, after the reaction, adding an aqueous solution of inorganic base, stirring and then standing, separating the water layer, washing the organic phase with water, cooling and crystallizing, filtering and drying to obtain fluazinam product.

[0023] The chemical reaction formula of the present application is as follows:

[0024]

[0025] The preparation method of fluazinam described above, preferably, the adding time of the mixed solution composed of 3', 4', 5'-trifluoro-2-aminobiphenyl and the organic solvent is 0.5-2 h.

[0026] The preparation method of fluazinam described above, preferably, the catalyst is one or more of acetylacetone iron, acetylacetone cobalt and acetylacetone nickel.

[0027] The preparation method of fluazinam described above, preferably, the mass of the catalyst is 0.05-0.5% of the mass of 3', 4', 5'-trifluoro-2-aminobiphenyl.

[0028] The preparation method of fluazinam described above, preferably, the molar ratio of 3', 4', 5'-trifluoro-2-aminobiphenyl to 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride is 1:1-1.03.

[0029] The preparation method of fluazinam described above, preferably, the mass ratio of the first organic solvent to 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride is 0.9-2:1, and the mass ratio of the second organic solvent to 3', 4', 5'-trifluoro-2-aminobiphenyl is 0.8-2.5:1.

[0030] The preparation method of fluazinam described above, preferably, the first organic solvent and the second organic solvent are the same, and the first organic solvent and the second organic solvent are one of 1, 2-dichloroethane, toluene, chlorobenzene and dimethylbenzene.

[0031] The preparation method of the above flumetover, preferably, the aqueous solution of the inorganic base is one of aqueous solution of sodium hydroxide, aqueous solution of potassium hydroxide, aqueous solution of sodium carbonate and aqueous solution of potassium carbonate, the mass of the aqueous solution of the inorganic base is 20%-60% of the mass of the 3', 4', 5'-trifluoro-2-aminobiphenyl, and the mass fraction of the inorganic base in the aqueous solution of the inorganic base is 5%-20%.

[0032] The preparation method of the above flumetover, preferably, the time of the heat preservation reaction is 0.5h-2h.

[0033] The preparation method of the above flumetover, preferably, the content of the flumetover product is greater than or equal to 98%, and the yield is greater than or equal to 98%.

[0034] The main innovation of the present application is that:

[0035] In the prior art, 3', 4', 5'-trifluoro-2-aminobiphenyl reacts with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride to form fluazinam, and triethylamine, pyridine and other acid binding agents are usually added, on the one hand, to combine the acid binding agent with hydrogen chloride, promote the reaction to move in the positive direction, and on the other hand, to prevent hydrogen chloride from combining with 3', 4', 5'-trifluoro-2-aminobiphenyl to form hydrochloride (3', 4', 5'-trifluoro-2-aminobiphenyl hydrochloride has special properties: it is easy to disperse into paste in organic solvents, resulting in stirring failure). Fluazinam can also react with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride to form impurity 3-(difluoromethyl)-N-(3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbonyl)-1-methyl-N-(3', 4', 5'-trifluoro-[1, 1'-biphenyl]-2-yl)-1H-pyrazine-4-carboxamide (molecular weight 539.41, hereinafter referred to as M539) under the action of the acid binding agent, so the yield reported in the existing literature is 41.7%-92%. The applicant found that at a relatively high temperature, the organic solution of 3', 4', 5'-trifluoro-2-aminobiphenyl is added dropwise into the organic solution of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, which continuously releases hydrogen chloride, making the reaction system acidic, forming an acidic system, and in the acidic system, the amount of impurity M539 formed by the reaction of fluazinam with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is extremely small, and through the addition of a catalyst, the reaction rate of 3', 4', 5'-trifluoro-2-aminobiphenyl with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride can be targetedly improved, thereby improving the conversion rate and reaction selectivity of 3', 4', 5'-trifluoro-2-aminobiphenyl. At the same time, at a relatively high temperature in the acidic system, the use of an acid binding agent does not cause the hydrogen chloride produced in the reaction to be difficult to discharge from the reaction system, avoiding the stirring failure caused by the generation of a large amount of hydrochloride of 3', 4', 5'-trifluoro-2-aminobiphenyl and hydrogen chloride, and improving the safety of the reaction. In addition, the applicant found that impurity M539 can be decomposed to obtain fluazinam in the presence of an inorganic alkali aqueous solution, and fluazinam is stable in the presence of an inorganic alkali aqueous solution, so after the reaction is completed, the reaction solution is treated with an inorganic alkali aqueous solution, and the content of the fluazinam product obtained is ≥98%, and the yield is ≥98%, achieving efficient and clean synthesis of fluazinam.

[0036] Compared with the prior art, the present application has the following advantages:

[0037] The application adopts an acidic synthesis system (without adding an acid binding agent) and adds a catalyst, and the reaction rate of 3', 4', 5'-trifluoro-2-aminobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is improved, thereby improving the conversion rate and reaction selectivity of 3', 4', 5'-trifluoro-2-aminobiphenyl.

[0038] The application does not cause the generated hydrogen chloride to be difficult to discharge from the reaction system at a higher temperature and in an acidic system without using an acid binding agent, avoids the generation of a large amount of hydrochloride salt by the reaction of hydrogen chloride and 3', 4', 5'-trifluoro-2-aminobiphenyl, and improves the safety of the reaction.

[0039] In the application, the reaction solution is treated with an aqueous inorganic base after the reaction is completed, a small amount of generated impurity M539 can be decomposed, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and the catalyst are washed away, the content of the obtained fluazinam product is ≥98%, the yield is ≥98%, the clean production of the fluazinam synthesis step is realized, the production cost is reduced, and the goal of improving the economic and social benefits of enterprises is achieved. DETAILED DESCRIPTION

[0040] The application will be further described below in combination with specific preferred embodiments, but the protection scope of the application is not limited by this. The materials and instruments used in the following embodiments are commercially available, wherein 3', 4', 5'-trifluoro-2-aminobiphenyl is purchased from Henan Yingchuang Biological Technology Co., Ltd., and the main content is 98.5% as determined by liquid chromatography external standard method.

[0041] 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride can be self-made or purchased, and the synthesis method of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is as follows, but is not limited thereto: 71.2g (99%, 0.4mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, 142.4g toluene and 0.7g DMF are placed in a 1000ml four-necked flask, heated to 70℃, and a solution formed by 48g (99%, 0.16mol) triphosgene and 144g toluene is added dropwise. After the dropwise addition is completed, the reaction is controlled by liquid chromatography, and the normalized content of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is 0.2% or less, which indicates that the reaction is complete. After the reaction is completed, the temperature is cooled to about 30℃, filtered, and the filtrate is evaporated under reduced pressure to remove phosgene and toluene, thereby obtaining 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride. The main content is 98.8% as determined by gas chromatography internal standard method.

[0042] Example 1

[0043] A preparation method of fluazinam according to the application, comprising the following steps:

[0044] Into a 1000 mL four-necked flask, 78.77 g (98.8%, 0.4 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.25 g of iron acetyl acetonate and 150 g of 1,2-dichloroethane were added, and heated to 83°C. A mixed solution of 90.64 g (98.5%, 0.4 mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 200 g of 1,2-dichloroethane was added dropwise within 2 h (the reaction solution was clear, and no solid was generated), and after the dropwise addition was completed, the reaction was continued for 2 h. During the reaction, hydrogen chloride was continuously released, and after the reaction was completed, 18.13 g of 20% sodium hydroxide aqueous solution was added, stirred, and then allowed to stand, and the water layer was separated. The organic phase was washed with water again, and then water was separated, and cooled to crystallize, filtered, and dried to obtain 151.81 g of fl uoxastrobin product, with a content of 98.5% and a yield of 98.04%. It was tested that the melting point of the fl uoxastrobin product was 136.3-137.1°C. 1 H NMR (400 MHz, CDCl3) δ: 3.92 (s, 3H), 6.62 (t, 1H), 6.95-7.06 (m, 2H), 7.22-7.26 (m, 2H), 7.41-7.48 (m, 1H), 7.80 (bs, 1H), 7.95 (s, 1H), 8.22 (d, 1H).

[0045] Example 2

[0046] A method for preparing fl uoxastrobin according to the present application, comprising the following steps:

[0047] Into a 1000 mL four-necked flask, 78.77 g (98.8%, 0.4 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.25 g of iron acetyl acetonate and 150 g of 1,2-dichloroethane were added, and heated to 83°C. A mixed solution of 90.64 g (98.5%, 0.4 mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 200 g of 1,2-dichloroethane was added dropwise within 2 h (the reaction solution was clear, and no solid was generated), and after the dropwise addition was completed, the reaction was continued for 2 h. During the reaction, hydrogen chloride was continuously released, and after the reaction was completed, 18.13 g of 20% sodium hydroxide aqueous solution was added, stirred, and then allowed to stand, and the water layer was separated. The organic phase was washed with water again, and then water was separated, and cooled to crystallize, filtered, and dried to obtain 151.81 g of fl uoxastrobin product, with a content of 98.5% and a yield of 98.04%. It was tested that the melting point of the fl uoxastrobin product was 136.3-137.1°C.

[0048] Example 3

[0049] A method for preparing fl uoxastrobin according to the present application, comprising the following steps:

[0050] Into a 1000ml four-necked flask, 79.56g (98.8%, 0.404mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.15g cobalt acetylacetonate and 100g toluene were added, and the temperature was raised to 110°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3', 4', 5'-trifluoro-2-aminobiphenyl and 171.92g toluene was added dropwise within 1.5h (the reaction solution was clear and no solid was formed), and the reaction was continued for 1h after the dropwise addition was completed. Hydrogen chloride was continuously released during the reaction, and after the reaction was completed, 27.19g of 15% potassium hydroxide aqueous solution was added. After stirring, the water layer was separated, the organic phase was washed with water, and then water was separated, cooled and crystallized, filtered, and dried to obtain 152.2g of fl uoxastrobin product with a content of 98.51% and a yield of 98.3%.

[0051] Example 4

[0052] A method for preparing fl uoxastrobin according to the present application, comprising the following steps:

[0053] Into a 1000ml four-necked flask, 79.56g (98.8%, 0.404mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.15g cobalt acetylacetonate and 100g toluene were added, and the temperature was raised to 110°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3', 4', 5'-trifluoro-2-aminobiphenyl and 171.92g toluene was added dropwise within 1.5h (the reaction solution was clear and no solid was formed), and the reaction was continued for 1h after the dropwise addition was completed. Hydrogen chloride was continuously released during the reaction, and after the reaction was completed, 27.19g of 15% potassium hydroxide aqueous solution was added. After stirring, the water layer was separated, the organic phase was washed with water, and then water was separated, cooled and crystallized, filtered, and dried to obtain 152.2g of fl uoxastrobin product with a content of 98.51% and a yield of 98.3%.

[0054] Example 5

[0055] A method for preparing fl uoxastrobin according to the present application, comprising the following steps:

[0056] Into a 1000ml four-necked flask, 80.35g (98.8%, 0.408mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.05g nickel acetyl acetonate and 100g chlorobenzene were added, and the temperature was raised to 130°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3',4',5'-trifluoro-2-aminobiphenyl and 100g chlorobenzene was added dropwise within 1h (the reaction solution was clear and no solid was formed), and after the dropwise addition was completed, the reaction was continued for 1h. During the reaction, hydrogen chloride was continuously released, and after the reaction was completed, 30g of a 15% by mass aqueous potassium carbonate solution was added, and after stirring, the water layer was separated, the organic phase was washed with water, and after the water was separated, crystallization was carried out, filtration was carried out, and drying was carried out, to obtain 153.57g of fluazinam product, with a content of 98.16% and a yield of 98.83%.

[0057] Example 6

[0058] A method for preparing fluazinam according to the present application, comprising the steps of:

[0059] Into a 1000ml four-necked flask, 80.35g (98.8%, 0.408mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.05g nickel acetyl acetonate and 100g chlorobenzene were added, and the temperature was raised to 130°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3',4',5'-trifluoro-2-aminobiphenyl and 100g chlorobenzene was added dropwise within 1h (the reaction solution was clear and no solid was formed), and after the dropwise addition was completed, the reaction was continued for 1h. During the reaction, hydrogen chloride was continuously released, and after the reaction was completed, 30g of a 15% by mass aqueous potassium carbonate solution was added, and after stirring, the water layer was separated, the organic phase was washed with water, and after the water was separated, crystallization was carried out, filtration was carried out, and drying was carried out, to obtain 153.57g of fluazinam product, with a content of 98.16% and a yield of 98.83%.

[0060] Example 7

[0061] A method for preparing fluazinam according to the present application, comprising the steps of:

[0062] Into a 1000 mL four-necked flask, 81.14 g (98.8%, 0.412 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.05 g of nickel acetylacetonate and 80 g of xylene were added, and the temperature was raised to 140°C. A mixed solution consisting of 90.64 g (98.5%, 0.4 mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 101.28 g of xylene was added dropwise within 0.5 h (the reaction solution was clear, and no solid was generated). After the dropwise addition was completed, the reaction was continued for 1 h. During the reaction, hydrogen chloride was continuously released. After the reaction was completed, 54.38 g of 5% sodium hydroxide aqueous solution was added, and after stirring, the water layer was separated. The organic phase was washed with water, and after the water was separated, it was cooled to crystallize, filtered, and dried to obtain 153.82 g of fluoxastrobin product, with a content of 98.03% and a yield of 98.86%.

[0063] Comparative Example 1

[0064] A method for preparing fluoxastrobin, which is different from Example 3 only in that no cobalt acetylacetonate is used, comprises the following steps:

[0065] Into a 1000 mL four-necked flask, 79.56 g (98.8%, 0.404 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 100 g of toluene were added, and the temperature was raised to 110°C. A mixed solution consisting of 90.64 g (98.5%, 0.4 mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 171.92 g of toluene was added dropwise within 1.5 h (the reaction solution was clear, and no solid was generated). After the dropwise addition was completed, the reaction was continued for 1 h. During the reaction, hydrogen chloride was continuously released. After the reaction was completed, 27.19 g of 15% potassium hydroxide aqueous solution was added, and after stirring, the water layer was separated. The organic phase was washed with water, and after the water was separated, it was cooled to crystallize, filtered, and dried to obtain 143.06 g of fluoxastrobin product, with a content of 97.85% and a yield of 91.78%.

[0066] Comparative Example 2

[0067] Into a 1000 mL four-necked flask, 79.56 g (98.8%, 0.404 mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 90.64 g (98.5%, 0.4 mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 271.92 g of toluene were added, and heated. When the temperature was raised to 35°C, solid began to appear, and the reaction system became turbid. When the temperature was raised to 50°C, the reaction system became solid, and stirring was disabled.

[0068] Comparative Example 3

[0069] A method for preparing fluoxastrobin, which comprises the following steps:

[0070] 1000 mL four-mouth flask was added a mixed solution of 90.64 g (98.5%, 0.4 mol) 3', 4', 5'-trifluoro-2-aminobiphenyl and 100 g toluene, and the temperature was raised to 110°C. A mixed solution of 79.56 g (98.8%, 0.404 mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 171.92 g toluene was added dropwise within 1.5 h. After about 30 g was added, the reaction liquid became viscous and stirring was disabled. The dropping was continued and the heating was continued, and after 2 h of stirring disability, the solid matter gradually decreased and the stirring was enabled. After about 0.5 h, the reaction liquid became clear, and the reaction was continued for 0.5 h. After the reaction was completed, 27.19 g of 15% potassium hydroxide aqueous solution was added, and after stirring, the water layer was separated, the organic phase was washed with water, and then water was separated, cooled and crystallized, filtered, and dried to obtain 141.66 g of fluoxastrobin product, with a content of 97.96% and a yield of 90.98%.

[0071] The above description is only the preferred embodiment of the present application, and does not limit the present application in any form. Although the present application has been disclosed as above with the preferred embodiment, it is not intended to limit the present application. Any person skilled in the art can make many possible changes and modifications to the technical solutions of the present application, or modify equivalent embodiments with the above disclosed methods and technical contents, without departing from the spirit and technical solutions of the present application. Therefore, any simple modification, equivalent replacement, equivalent change and modification of the above embodiments according to the technical essence of the present application, which does not depart from the content of the technical solutions of the present application, still belongs to the protection scope of the technical solutions of the present application.

Claims

1. A method for preparing fluopyram, characterized in that, The steps include: first, 1-methyl-3-difluoromethyl-1 H Pyrazole-4-formyl chloride, a catalyst, and a first organic solvent are mixed and heated to 83°C–140°C. Then, a mixed solution of 3',4',5'-trifluoro-2-aminobiphenyl and a second organic solvent is added, and the mixture is kept at this temperature. Hydrogen chloride is continuously released during the reaction. After the reaction is complete, an aqueous solution of an inorganic base is added, stirred, allowed to stand, and the aqueous layer is separated. The organic phase is washed with water, cooled to crystallize, filtered, and dried to obtain the fluopyram product. The catalyst is one or more of acetylacetonate iron, acetylacetonate cobalt, and acetylacetonate nickel.

2. The method for preparing fluopyram according to claim 1, characterized in that, The mixed solution composed of 3',4',5'-trifluoro-2-aminobiphenyl and organic solvent is added at a time of 0.5 h to 2 h.

3. The method for preparing fluopyram according to claim 1, characterized in that, The mass of the catalyst is 0.05% to 0.5% of the mass of the 3',4',5'-trifluoro-2-aminobiphenyl.

4. The method for preparing fluopyram according to claim 1, characterized in that, The 3',4',5'-trifluoro-2-aminobiphenyl and the 1-methyl-3-difluoromethyl-1 H The molar ratio of pyrazole-4-carboxyl chloride is 1:1 to 1.

03.

5. The method for preparing fluopyram according to claim 1, characterized in that, The first organic solvent and the 1-methyl-3-difluoromethyl-1 H The mass ratio of pyrazole-4-formyl chloride is 0.9 to 2:1, and the mass ratio of the second organic solvent to the 3',4',5'-trifluoro-2-aminobiphenyl is 0.8 to 2.5:

1.

6. The method for preparing fluopyram according to any one of claims 1 to 5, characterized in that, The first organic solvent is the same as the second organic solvent, and the first organic solvent and the second organic solvent are one of 1,2-dichloroethane, toluene, chlorobenzene and xylene.

7. The method for preparing fluopyram according to any one of claims 1 to 5, characterized in that, The aqueous solution of the inorganic base is one of sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution, and potassium carbonate aqueous solution. The mass of the aqueous solution of the inorganic base is 20% to 60% of the mass of 3',4',5'-trifluoro-2-aminobiphenyl, and the mass fraction of the inorganic base in the aqueous solution of the inorganic base is 5% to 20%.

8. The method for preparing fluopyram according to any one of claims 1 to 5, characterized in that, The heat preservation reaction time is 0.5h to 2h.

9. The method for preparing fluopyram according to any one of claims 1 to 5, characterized in that, The content of the fluopyram product is ≥98%, and the yield is ≥98%.

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