Preparation method of fluxapyroxad

Abstract

The invention discloses a fluxapyroxad preparation method, which comprises: mixing 1-methyl-3-difluoromethyl-1H-pyrazole-4-formyl chloride, a catalyst and a first organic solvent, heating to a temperature of 83-140 DEG C, adding a mixed solution composed of 3 ', 4', 5 '-trifluoro-2-aminobiphenyl and a second organic solvent, carrying out a thermal insulation reaction after the addition is completed, cooling to a room temperature, filtering, washing, and drying to obtain the fluxapyroxad. Continuously releasing hydrogen chloride in the reaction process, after the reaction is finished, adding an aqueous solution of inorganic alkali, stirring, standing, separating out a water layer, washing an organic phase with water, cooling, crystallizing, filtering and drying to obtain a fluxapyroxad product. The preparation method disclosed by the invention does not need to add an acid-binding agent, and has the advantages of high yield, less three wastes, low cost, simplicity and convenience in operation, good safety and the like.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical industry, and particularly relates to a method for preparing fluopyraclostrobin. Background Art

[0002] Fluoxapyroxad is a succinate dehydrogenase inhibitor (SDHI) fungicide developed by BASF. Its trade name is Xemium. In April 2015, it obtained the ISO pesticide common name Fluxapyroxad. Its 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 BASF's key products. The company plans to introduce it to more than 70 countries in the world for use in more than 100 crops. In 2011, Fluoxapyroxad was first registered in the UK and was launched in 2012. The product has now been registered and launched in most major markets around the world, including the United States, Canada, the United Kingdom, Australia, 25 EU countries, Brazil, China, Japan, India, Argentina, etc.

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

[0004] There are many methods for synthesizing fluopyram, mainly using 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 3',4',5'-trifluoro-2-aminobiphenyl to synthesize fluopyram (1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route), and there are sporadic reports on some other synthetic methods (other methods).

[0005] 1. 1-Methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route

[0006]

[0007] Liu Anchang et al. [Study on the synthesis of new fungicides fluopyram and bixafen [J]. Modern Pesticides, 2016, 15(1): 16-18] used triethylamine as an acid-binding agent, and refluxed unrefined 3',4',5'-trifluoro-2-aminobiphenyl with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride in toluene for 5 hours to obtain fluopyram with a normalized content of 95.2% and a yield of 82.3%. Wang Gang et al. [Synthesis and biological activity of fluopyram [J]. Modern Pesticides, 2017, 16(4): 12-15] used triethylamine as an acid-binding agent, and stirred 3',4',5'-trifluoro-2-aminobiphenyl obtained by column chromatography with an excess of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride in dichloromethane at room temperature to obtain fluopyram 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 an excess of pyridine to 55°C, added an equimolar toluene solution of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, heated the temperature to 70°C after the reaction, washed with hydrochloric acid, saturated sodium bicarbonate solution and water in sequence, dried over anhydrous sodium sulfate and purified by column chromatography to obtain fluopyraclostrobin with a yield of 92%. Yin Kai et al. [New process for the synthesis of new fungicide fluopyram [J]. World Pesticides, 2020, 42(10): 42-45] Heat the toluene solution of 3',4',5'-trifluoro-2-aminobiphenyl to 45°C, add 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride dropwise, and heat to 70°C for reaction. After the reaction, wash with 5% hydrochloric acid, 10% sodium bicarbonate solution and water in turn, and obtain fluopyram after post-treatment with a yield of 90.5%.

[0008] The synthesis of fluopyraclostrobin via the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride route usually requires the use of excessive amounts of acid-binding agents such as pyridine and triethylamine. The resulting pyridine hydrochloride, triethylamine hydrochloride and other materials require a large amount of liquid alkali to neutralize, resulting in a large amount of wastewater. The subsequent distillation to recover anhydrous pyridine and anhydrous triethylamine requires a large amount of energy consumption. Yin Kai et al. [New process for the synthesis of new fungicide flupyraclostrobin [J]. World Pesticides, 2020, 42(10): 42-45]. Failure to use an acid binder will make it difficult to discharge the hydrogen chloride produced by the reaction from the reaction system. Hydrogen chloride and 3',4',5'-trifluoro-2-aminobiphenyl will generate a large amount of hydrochloride, which will cause the stirring to fail. Stirring failure in industrial production equipment can easily lead to safety accidents. At the same time, due to stirring failure, 3',4',5'-trifluoro-2-aminobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride do not react fully. Post-treatment requires the use of a large amount of acid and alkali to wash the unreacted 3',4',5'-trifluoro-2-aminobiphenyl and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, respectively, resulting in a large amount of wastewater and serious pollution.

[0009] 2. Other methods

[0010] T. Qi Ke et al. [Method for producing N-substituted (3-dihalomethyl-1-methylpyrazol-4-yl) carboxamide. CN101679282 B, 2012-11-28] Pd(PhCN) 2 Cl 2 The reaction was carried out in DMF at 150°C, 1 MPa for 20 h with 2,2-dimethyl-1,3-bis(diphenylphosphino)propane as catalyst, diazabicycloundecene as ligand, 3-difluoromethyl-1-methyl-4-bromopyrazole, 3',4',5'-trifluoro-2-aminobiphenyl and CO as acid-binding agent, and the yield of fluopyram was 81%.

[0011]

[0012] The 3-difluoromethyl-1-methyl-4-bromopyrazole used in this method has a simpler synthesis process than 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid, and only needs difluoroacetyl chloride as a raw material and is obtained through three steps of reaction. However, in the process of synthesizing fluopyraclostrobin 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 Yanni [A method for synthesizing fluopyram based on Suzuki reaction. CN113402464A[P]. 2021-09-17] et al. used 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid as raw material, and condensed it with 2-iodoaniline under the action of condensation agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride to obtain 3-difluoromethyl-N-(2-iodophenyl)-1-methyl-1-pyrazole-4-amide, and then reacted it with 3,4,5-trifluorophenylboric acid under the action of palladium metal catalysts such as tetrakis(triphenylphosphine)palladium to generate fluopyram through Suzuki coupling reaction, with a total yield of 74.5%.

[0014]

[0015] This method uses high-priced 2-iodoaniline, a large amount of palladium catalyst, high raw material costs, and both the intermediates and products need to be purified by column chromatography, making industrial production difficult.

[0016] J. Yaoenzeus [Method for producing pyrazole compounds. CN111587242A[P]. 2020-08-25] et al. used 1,1,3,3-tetramethylguanidine as an organic base catalyst, and 2,2,2-trichloro-1-(3-difluoromethyl-1-methyl-1H-pyrazol-4-yl)ethan-1-one and 3',4',5'-trifluoro-2-aminobiphenyl in toluene to obtain fluopyraclostrobin.

[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-pyrazol-4-yl)ethan-1-one can be obtained from 1,1,1-trichloro-4-ethoxybut-3-en-2-one as a raw material through 4 steps of reaction. Since 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is an intermediate of many fungicides, it has scale advantages and lower costs, which does not have advantages in this method.

[0019] As the expiration date of the patent for the original drug of fluopyrab is approaching, the effective production capacity of fluopyrab will be gradually released, and the environmental protection requirements are constantly increasing. It is necessary to develop a new fluopyrab synthesis process to improve the reaction yield, reduce the production of "three wastes", and achieve the goal of improving the economic and social benefits of the enterprise. Summary of the invention

[0020] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a preparation method of fluopyram which does not require the addition of an acid binding agent, has a high reaction yield, reduces the three wastes, has a low cost, is easy to operate and has good safety.

[0021] In order to solve the above technical problems, the present invention adopts the following technical solutions.

[0022] A preparation method of fluopyram comprises the following steps: firstly, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, a catalyst and a first organic solvent are mixed and heated to 83°C to 140°C, then a mixed solution consisting of 3',4',5'-trifluoro-2-aminobiphenyl and a second organic solvent is added, the mixture is kept warm for reaction, hydrogen chloride is continuously released during the reaction, after the reaction is completed, an aqueous solution of an inorganic base is added, the mixture is stirred and then allowed to stand, a water layer is separated, an organic phase is washed with water, cooled for crystallization, filtered and dried to obtain a fluopyram product.

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

[0024]

[0025] In the above-mentioned method for preparing fluopyraclostrobin, preferably, the mixed solution consisting of 3',4',5'-trifluoro-2-aminobiphenyl and the organic solvent is added for 0.5h to 2h.

[0026] In the above-mentioned method for preparing fluopyraclostrobin, preferably, the catalyst is one or more of iron acetylacetonate, cobalt acetylacetonate and nickel acetylacetonate.

[0027] In the above-mentioned method for preparing fluopyraclostrobin, preferably, the mass of the catalyst is 0.05% to 0.5% of the mass of the 3',4',5'-trifluoro-2-aminobiphenyl.

[0028] In the above-mentioned method for preparing fluopyrabamide, preferably, the molar ratio of the 3',4',5'-trifluoro-2-aminobiphenyl to the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is 1:1 to 1.03.

[0029] In the above-mentioned method for preparing fluopyrabamide, preferably, the mass ratio of the first organic solvent to the 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is 0.9-2:1, and the mass ratio of the second organic solvent to the 3',4',5'-trifluoro-2-aminobiphenyl is 0.8-2.5:1.

[0030] In the above-mentioned method for preparing fluopyraclostrobin, preferably, 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.

[0031] In the above-mentioned method for preparing flupyraclostrobin, preferably, the aqueous solution of the inorganic base is one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution, an aqueous sodium carbonate solution and an aqueous potassium carbonate solution, the mass of the aqueous solution of the inorganic base is 20% to 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% to 20%.

[0032] In the above-mentioned method for preparing fluopyraclostrobin, preferably, the insulation reaction time is 0.5h to 2h.

[0033] In the above-mentioned method for preparing fluopyrabamide, preferably, the content of the fluopyrabamide product is ≥ 98%, and the yield is ≥ 98%.

[0034] The main innovations of the present invention are:

[0035] In the prior art, 3',4',5'-trifluoro-2-aminobiphenyl reacts with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride to generate fluopyraclostrobin, and an acid-binding agent such as triethylamine or pyridine is usually added. On the one hand, the acid-binding agent is combined with hydrogen chloride to promote the reaction to move in the positive direction, and on the other hand, hydrogen chloride is prevented from combining with 3',4',5'-trifluoro-2-aminobiphenyl to generate hydrochloride (3',4',5'-trifluoro-2-aminobiphenyl hydrochloride has a special physical property: it is easily dispersed into a paste in an organic solvent, resulting in stirring failure). Fluopyrabamide can also react with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride under the action of an acid-binding agent to generate an 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). Therefore, the yield reported in existing literature is 41.7%-92%. The applicant has found that: at a relatively high temperature, when an organic solution of 3',4',5'-trifluoro-2-aminobiphenyl is added dropwise to an organic solution of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, hydrogen chloride is continuously released, making the reaction system acidic to form an acidic system. In the acidic system, the amount of impurity M539 generated by the reaction of flupyraclostrobin with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is extremely small. By adding a catalyst, the reaction rate of 3',4',5'-trifluoro-2-aminobiphenyl with 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride can be specifically increased, thereby improving the conversion rate and reaction selectivity of 3',4',5'-trifluoro-2-aminobiphenyl. At the same time, at relatively high temperatures and in an acidic system, the absence of an acid-binding agent will not cause the hydrogen chloride produced by the reaction to be difficult to discharge from the reaction system, thereby avoiding the generation of a large amount of hydrochloride by hydrogen chloride and 3',4',5'-trifluoro-2-aminobiphenyl, which will render stirring ineffective, thereby improving the safety of the reaction. In addition, the applicant has found that impurity M539 can be decomposed to obtain fluopyrabamide in the presence of an inorganic alkali aqueous solution, and fluopyrabamide is stable in the presence of an inorganic alkali aqueous solution. Therefore, after the reaction is completed, the reaction solution is treated with an inorganic alkali aqueous solution, and the content of the obtained fluopyrabamide product is ≥98%, and the yield is ≥98%, thereby achieving efficient and clean synthesis of fluopyrabamide.

[0036] Compared with the prior art, the advantages of the present invention are:

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

[0038] The present invention does not use an acid-binding agent at a relatively high temperature in an acidic system and will not cause the hydrogen chloride generated by the reaction to be difficult to discharge from the reaction system, thereby avoiding the generation of a large amount of hydrochloride by hydrogen chloride and 3',4',5'-trifluoro-2-aminobiphenyl to render stirring ineffective, thereby improving the safety of the reaction.

[0039] In the present invention, after the reaction is completed, the reaction liquid is treated with an aqueous solution of an inorganic alkali to decompose a small amount of impurity M539 generated, and 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and a catalyst are washed away. The content of the obtained fluopyrabamide product is ≥98%, and the yield is ≥98%, thereby realizing clean production of the fluopyrabamide synthesis step, reducing the production cost, and achieving the goal of improving the economic and social benefits of the enterprise. DETAILED DESCRIPTION

[0040] The present invention is further described below in conjunction with specific preferred embodiments, but the protection scope of the present invention is not limited thereby. The materials and instruments used in the following embodiments are all commercially available, among which 3',4',5'-trifluoro-2-aminobiphenyl was purchased from Henan Yingchuang Biotechnology Co., Ltd., and the main content was 98.5% as determined by liquid chromatography external standard method.

[0041] 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride can be prepared by yourself or purchased from the market. The synthesis method of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride is as follows, but not limited thereto: 71.2g (99%, 0.4mol) of 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°C, and a solution formed by 48g (99%, 0.16mol) of triphosgene and 144g toluene is added dropwise. After the addition is complete, the reaction is controlled in a liquid chromatography, and the reaction is complete when the normalized content of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carboxylic acid is less than 0.2%. After the reaction is completed, the temperature is cooled to about 30°C, filtered, and the filtrate is decompressed to remove phosgene and toluene to obtain 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride. The main content was determined by gas chromatography internal standard method and was 98.8%.

[0042] Example 1

[0043] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

[0044] 78.77g (98.8%, 0.4mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.25g ferric acetylacetonate and 150g 1,2-dichloroethane were added to a 1000mL four-necked flask and heated to 83°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3',4',5'-trifluoro-2-aminobiphenyl and 200g 1,2-dichloroethane was added dropwise within 2h (the reaction solution was clear and no solid was generated). After the addition was completed, the reaction was continued at the temperature for 2h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 18.13 g of a 20% sodium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 151.81 g of a fluopyrabamide product with a content of 98.5% and a yield of 98.04%. After testing, the melting point of the fluopyrabamide product was 136.3-137.1°C. 1 H NMR (400 MHz, CDCl 3 )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 fluopyraclostrobin of the present invention comprises the following steps:

[0047] 78.77g (98.8%, 0.4mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.45g ferric acetylacetonate and 150g 1,2-dichloroethane were added to a 1000mL four-necked flask and heated to 83°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3',4',5'-trifluoro-2-aminobiphenyl and 212.56g 1,2-dichloroethane was added dropwise within 2h (the reaction solution was clear and no solid was generated). After the addition was completed, the reaction was continued at room temperature for 1.5h. Hydrogen chloride was continuously released during the reaction. After the reaction, 18.13 g of a 20% sodium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 151.31 g of a fluopicolide product with a content of 98.86% and a yield of 98.07%.

[0048] Example 3

[0049] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

[0050] 79.56g (98.8%, 0.404mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.15g acetylacetonate cobalt and 100g toluene were added to a 1000mL four-necked flask and heated 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 generated). After the addition was completed, the reaction was continued to be kept warm for 1h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 27.19g of a 15% potassium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 152.2g of flupyraclostrobin product with a content of 98.51% and a yield of 98.3%.

[0051] Example 4

[0052] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

[0053] 79.56g (98.8%, 0.404mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.35g cobalt acetylacetonate and 100g toluene were added to a 1000mL four-necked flask and heated to 110°C. A mixed solution consisting of 90.64g (98.5%, 0.4mol) 3',4',5'-trifluoro-2-aminobiphenyl and 150g toluene was added dropwise within 1h (the reaction solution was clear and no solid was generated). After the addition was completed, the reaction was continued to be kept warm for 1h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 30g of a 15% potassium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 152.85g of flupyraclostrobin product with a content of 98.28% and a yield of 98.49%.

[0054] Example 5

[0055] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

[0056] 80.35g (98.8%, 0.408mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.25g nickel acetylacetonate and 100g chlorobenzene were added to a 1000mL four-necked flask and heated 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 generated). After the addition was completed, the reaction was continued to be kept warm for 0.5h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 45g of a 10% sodium carbonate aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 152.03g of flupyraclostrobin product with a content of 98.52% and a yield of 98.2%.

[0057] Example 6

[0058] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

[0059] 80.35g (98.8%, 0.408mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, 0.05g nickel acetylacetonate and 100g chlorobenzene were added to a 1000mL four-necked flask and heated 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 generated). After the addition was completed, the reaction was continued to be kept warm for 1h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 30g of a 15% potassium carbonate aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 153.57g of flupyraclostrobin product with a content of 98.16% and a yield of 98.83%.

[0060] Example 7

[0061] A method for preparing fluopyraclostrobin of the present invention comprises the following steps:

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

[0063] Comparative Example 1

[0064] A method for preparing fluopyraclostrobin, which differs from Example 3 only in that cobalt acetylacetonate is not used, comprises the following steps:

[0065] 79.56g (98.8%, 0.404mol) 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 100g toluene were added to a 1000mL four-necked flask and heated 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 generated). After the addition was completed, the reaction was continued to be kept warm for 1h. Hydrogen chloride was continuously released during the reaction. After the reaction was completed, 27.19g of a 15% potassium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 143.06g of flupyraclostrobin product with a content of 97.85% and a yield of 91.78%.

[0066] Comparative Example 2

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

[0068] Comparative Example 3

[0069] A method for preparing fluopyraclostrobin comprises the following steps:

[0070] Add 90.64g (98.5%, 0.4mol) of 3',4',5'-trifluoro-2-aminobiphenyl and 100g of toluene mixed solution into a 1000mL four-necked flask and heat to 110℃. Add 79.56g (98.8%, 0.404mol) of 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride and 171.92g of toluene mixed solution dropwise within 1.5h. After about 30g was added dropwise, the reaction liquid became viscous and stirring failed. Continue to add dropwise and continue heating. After 2h of stirring failure, the solid matter gradually decreased and could be stirred. After about 0.5h, the reaction liquid became clear and the reaction was kept warm for 0.5h. After the reaction, 27.19 g of a 15% potassium hydroxide aqueous solution was added, stirred and allowed to stand, the water layer was separated, the organic phase was washed with water, separated, cooled and crystallized, filtered, and dried to obtain 141.66 g of a fluopicolide product with a content of 97.96% and a yield of 90.98%.

[0071] The above is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as above in the preferred embodiment, it is not used to limit the present invention. Any technician familiar with the art can make many possible changes and modifications to the technical solution of the present invention by using the methods and technical contents disclosed above without departing from the spirit and technical solution of the present invention, or modify it into an equivalent embodiment of equivalent changes. Therefore, any simple modification, equivalent replacement, equivalent change and modification made to the above embodiments according to the technical essence of the present invention without departing from the content of the technical solution of the present invention, still fall within the scope of protection of the technical solution of the present invention.

Claims

1. A method for preparing fluopyraclostrobin, characterized in that: The method comprises the following steps: firstly, 1-methyl-3-difluoromethyl-1H-pyrazole-4-carbonyl chloride, a catalyst and a first organic solvent are mixed and heated to 83°C to 140°C, then a mixed solution consisting of 3',4',5'-trifluoro-2-aminobiphenyl and a second organic solvent is added, the mixture is kept warm for reaction, hydrogen chloride is continuously released during the reaction, after the reaction is finished, an aqueous solution of an inorganic base is added, the mixture is stirred and allowed to stand, a water layer is separated, the organic phase is washed with water, cooled for crystallization, filtered and dried to obtain a fluopyraclostrobin product.

2. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: The adding time of the mixed solution consisting of 3',4',5'-trifluoro-2-aminobiphenyl and the organic solvent is 0.5h to 2h.

3. The method for preparing fluopyraclostrobin according to claim 1, characterized in that: The catalyst is one or more of iron acetylacetonate, cobalt acetylacetonate and nickel acetylacetonate.

4. The method for preparing fluopyraclostrobin 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.

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

03.

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

1.

7. The method for preparing fluopyrabendazim according to any one of claims 1 to 6, 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.

8. The method for preparing fluopyrabendazim according to any one of claims 1 to 6, characterized in that: The aqueous solution of the inorganic base is one of a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a sodium carbonate aqueous solution and a potassium carbonate aqueous solution. The mass of the aqueous solution of the inorganic base is 20% to 60% of the mass of the 3',4',5'-trifluoro-2-aminobiphenyl. The mass fraction of the inorganic base in the aqueous solution of the inorganic base is 5% to 20%.

9. The method for preparing fluopyrabendazim according to any one of claims 1 to 6, characterized in that: The insulation reaction time is 0.5h to 2h.

10. The method for preparing fluopyrabamide according to any one of claims 1 to 6, characterized in that: The content of the flupyraclostrobin product is ≥98%, and the yield is ≥98%.

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