A process for the preparation of a myclobutanil intermediate, 1-(2,4,6-trichlorophenyl)-propan-2-one

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one of fluopyram. The method involves reacting 1,2,3,5-tetrachlorobenzene with acetylacetone-like raw materials, followed by acidification and decarboxylation to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one. This method employs a two-step one-pot process of aryl nucleophilic substitution and decarboxylation. The synthesis route is short, with high atom utilization, mild reaction conditions, simple process, low cost, high yield, minimal waste, no scale-up effect, high intrinsic safety, high production efficiency, and is environmentally friendly, making it suitable for large-scale industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one of fluopyram. Background Technology

[0002] Fluopyram, a pyrazole amide fungicide discovered, developed, and manufactured by Syngenta, is one of the most valuable products among succinate dehydrogenase inhibitors (SDHI) fungicides. It features a novel molecular structure, high fungicidal activity, and broad spectrum. Fluopyram's key properties lie in its activity against leaf spot and powdery mildew. The structure of fluopyram is as follows:

[0003]

[0004] The main process for the synthesis of fluopyram involves the synthesis of the intermediate O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine. The preceding intermediate, 1-(2,4,6-trichlorophenyl)-propyl-2-one, can be prepared via different routes. The structure of 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows:

[0005]

[0006] Method 1: Patents WO2013127764 and WO2013127441 use 2,4,6-trichloroaniline as the starting material, reacting it with isopropyl acetate in the presence of tert-butyl nitrite to yield l-(2,4,6-trichlorophenyl)-propyl-2-one. The raw materials used in this route, isopropyl acetate and tert-butyl nitrite, are relatively expensive. Essentially, this is a diazotization coupling reaction of tert-butyl nitrite with aromatic amines, which is one of the key regulated hazardous chemical processes. Furthermore, the reaction yields are only 48% and 58% respectively, posing safety risks, resulting in low yields and generating numerous byproducts and waste, making it unsuitable for industrial production. The reaction route is as follows:

[0007]

[0008] Method 2: Patent WO2010063700 uses 2,4,6-trichlorobenzaldehyde as the starting material. In acetic acid solution, it reacts with nitrobenzene to obtain 1,3,5-trichloro-2-((E)-2-nitro-propenyl)benzene, which is then reduced with iron powder in hydrochloric acid to obtain l-(2,4,6-trichlorophenyl)-propyl-2-one. This route uses 2,4,6-trichlorobenzaldehyde. The synthesis of 2,4,6-trichlorobenzaldehyde requires the reaction of butyllithium, diisopropylamine, and N,N-dimethylformamide at a low temperature of -78°C, which is relatively dangerous and costly. Furthermore, nitrobenzene is a potentially explosive hazardous chemical, subject to strict regulation in its production and use, resulting in high equipment maintenance and safety costs. The exothermic reaction during hydrochloric acid and iron powder reduction is difficult to control and generates a large amount of solid waste, making industrialization difficult. The reaction route is as follows:

[0009]

[0010] Method 3: Patent CN108610290A uses p-chloroaniline as a starting material. It reacts with isopropyl acetate in the presence of tert-butyl nitrite to obtain 4-chlorophenylacetone. The 4-chlorophenylacetone is then reacted with chlorine gas in carbon tetrachloride solvent under ferric chloride catalysis to yield l-(2,4,6-trichlorophenyl)-propyl-2-one. While this route can reduce raw material costs, the raw materials isopropyl acetate and tert-butyl nitrite are relatively expensive. It also involves a dangerous diazotization reaction, and the chlorination reaction is one of the key regulated hazardous chemical processes. Both steps involve safety issues, resulting in extremely high production costs, equipment investment, and safety risks, making it unsuitable for industrialization. The reaction route is as follows:

[0011]

[0012] Method 4: Chinese patent CN113004131A prepares 2,4,6-trichlorophenylbenzyl chloride in an organic solvent at a certain temperature using 2,4,6-trichlorotoluene and a chlorinating agent. Then, it is coupled with acetylenyl magnesium halide under a metal catalyst, followed by acid-catalyzed addition with water to finally obtain the product 2,4,6-trichlorophenyl-substituted acetone. This route has several drawbacks: the raw material 2,4,6-trichlorotoluene is expensive and difficult to obtain; the Grignard reagent for acetylenyl magnesium halide is costly; the self-synthesis of acetylenyl magnesium halide requires acetylene and n-butylmagnesium chloride; acetylene is a hazardous chemical with stringent storage and usage conditions, posing a high risk; and the preparation of the Grignard reagent also requires n-butylmagnesium chloride. Grignard reagents are highly sensitive to water, requiring anhydrous and oxygen-free conditions for the solvents and reaction equipment; the metal-catalyzed coupling is exothermic, necessitating strict temperature control and heat exchange requirements for the equipment, making it unsuitable for industrial production. The reaction route is as follows:

[0013]

[0014] In summary, the methods for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one have problems such as high cost, complex synthesis process, and high risk. There is an urgent need for a method that is simple to synthesize, easy to operate, has a high safety factor, low cost, and can be used for industrial production of 1-(2,4,6-trichlorophenyl)-propyl-2-one. Summary of the Invention

[0015] To address the shortcomings of existing synthetic techniques for 1-(2,4,6-trichlorophenyl)-propyl-2-one, this invention proposes a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one from fluopyram. This method is simple to synthesize, has a short reaction route, uses inexpensive and readily available raw materials, has high atom utilization, does not use expensive reagents or special equipment requiring pressure resistance or corrosion resistance, has mild reaction conditions, a simple synthetic process that is easy to control industrially, does not use hazardous chemical processes under key supervision, and is inherently safe and suitable for industrial production.

[0016] The technical solution of the present invention is as follows:

[0017] A method for preparing the fluoxetine intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one, using 1,2,3,5-tetrachlorobenzene and acetylacetone-like substances as raw materials, is disclosed. The reaction route is as follows:

[0018]

[0019] As a preferred option, the acetylacetone-like substance is one of acetylacetone, ethyl acetoacetate, methyl acetoacetate, tert-butyl acetoacetate, and phenolic acetoacetate.

[0020] As a preferred embodiment, the solvent is one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, and the mass-to-volume ratio of 1,2,3,5-tetrachlorobenzene (g) to the solvent (mL) is 1:5 to 1:10.

[0021] As a preferred option, the alkali is one of potassium carbonate, sodium bicarbonate, cesium carbonate, sodium ethoxide, and sodium methoxide.

[0022] As a preferred option, the inorganic acid is an aqueous solution of sulfuric acid with a mass fraction of 50%-60%.

[0023] As a preferred option, the mass ratio of 1,2,3,5-tetrachlorobenzene to acetic acid is 1:8 to 1:13; the mass ratio of 1,2,3,5-tetrachlorobenzene to inorganic acid is 1:2.0 to 1:11. Acetic acid and sulfuric acid aqueous solution are chosen because sulfuric acid aqueous solution plays a major role in decarboxylation, while acetic acid is used to increase the solubility of the undecarboxylated substance in sulfuric acid aqueous solution.

[0024] As a preferred option, the molar ratio of 1,2,3,5-tetrachlorobenzene to acetylacetone is 1:1.05 to 1:1.5.

[0025] As a preferred option, the molar ratio of 1,2,3,5-tetrachlorobenzene to the alkali substance is 1:2.1 to 1:2.3.

[0026] Preferably, the reaction temperature of 1,2,3,5-tetrachlorobenzene with acetylacetone is between room temperature and 100°C.

[0027] As a preferred embodiment, the preparation method of the fluoxetine intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one comprises the following steps: 1,2,3,5-tetrachlorobenzene, acetylacetone, and an alkali are dissolved in a solvent, and the mixture is stirred at room temperature to 100°C for 24-75 hours to obtain a reaction mixture. After extraction, washing, drying, and vacuum distillation, acetic acid and an inorganic acid are added. The mixture is heated while stirring and reacted at reflux temperature for 2.5-4 hours. The reactants are cooled to room temperature, and some water and acetic acid are removed by distillation. After extraction, washing, drying, vacuum distillation, and recrystallization, the product is obtained.

[0028] This invention proposes a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one of fluopyram. The method involves reacting inexpensive and readily available 1,2,3,5-tetrachlorobenzene with acetylacetone-like raw materials, followed by acidification and decarboxylation to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one. This method employs a two-step, one-pot process involving aryl nucleophilic substitution and decarboxylation. The synthesis route is short, with high atom utilization, mild reaction conditions, simple process, low cost, high yield, minimal waste, no scale-up effect, high intrinsic safety, high production efficiency, and is environmentally friendly, making it suitable for large-scale industrial production. This method eliminates the outdated and dangerous process of preparing 2,4,6-trichlorophenylacetic acid by reacting arylbenzyl chloride with highly toxic sodium cyanide or potassium cyanide in a polar solvent (such as DMF, DMSO, NMP) in an SN2 reaction to generate arylphenylacetonitrile, followed by hydrolysis with sodium hydroxide aqueous solution. This process generates a lot of waste and requires the use of highly toxic raw materials. This method does not require the use of the dangerous process of diazotization of tert-butyl nitrate, and also avoids the use of precious metals for dangerous carbonylation reactions.

[0029] This invention provides a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one of fluopyram. This method is simple to synthesize, has a short synthetic reaction route, uses inexpensive and readily available raw materials, has high atom utilization, does not use expensive reagents, does not use special equipment such as pressure-resistant and corrosion-resistant equipment, has mild reaction conditions, and has a simple synthetic process that is easy to control in industrial applications. It does not use hazardous chemical processes that are subject to key supervision, and is inherently safe and suitable for industrial production. Detailed Implementation

[0030] The present invention is further illustrated by the following embodiments, but these embodiments should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and variations to the present invention without departing from its technical scope should be included within the technical scope of the present invention. The technical solution of this patent will be further described in detail below with reference to specific embodiments.

[0031] The technical solution of this patent will be further described in detail below with reference to specific embodiments.

[0032] Example 1

[0033] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0034]

[0035] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 mL dimethyl sulfoxide, 12.62 g acetylacetone (0.126 mol, 1.1 eq) was added, followed by 34.83 g potassium carbonate (0.252 mol, 2.2 eq). After stirring at room temperature for 48 hours, 750 mL toluene was added to the reaction mixture and stirred. Then, 150 mL of water was added, and the toluene layer was separated and extracted. 100 mL of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 mL of water, then washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 320 g acetic acid and 256 g dimethyl sulfoxide were added. A 50% sulfuric acid aqueous solution was used to heat the mixture in a controlled-temperature oil bath with stirring, increasing the temperature at 10℃ / 10min until reflux was reached. The reaction mixture was then reacted at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The resulting toluene phases were combined, washed three times with 300 ml of water, and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 21.30 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 78%. ¹H NMR (400 MHz, Chloroform-d) δ: 7.33 (s, 2H, ArH), 4.05 (s, 2H, CH₂), 2.21 (s, 3H, CH₃) ppm.

[0036] Example 2

[0037] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one

[0038]

[0039] 34.83 g of potassium carbonate (0.252 mol, 2.2 eq) powder was added in one go to a solution of 25 g of 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) dissolved in 125 ml of N,N-dimethylformamide to form a suspension. The suspension was heated to 40 °C, and then 12.62 g of acetylacetone (0.126 mol, 1.1 eq) was slowly added. The reaction mixture was heated to 80-85 °C and stirred under a nitrogen atmosphere for 24 hours. Then, 750 ml of toluene was added to the reaction mixture and stirred. Next, it was added to 150 ml of cold water (10 °C), and the toluene layer was separated and extracted. Then, 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 ml of water, then washed with 100 ml of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 320 g of acetic acid and 256 g of... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 5°C / 10min until reflux), and finally reacted at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off, and 200 ml of toluene and 400 ml of water were added. The toluene phase was separated, and the aqueous phase was extracted twice with 50 ml of toluene. The obtained toluene phases were combined, washed three times with 300 ml of water, washed once with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 23.21 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 85%.

[0040] Example 3

[0041] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0042]

[0043] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 ml N-methylpyrrolidone, 12.62 g acetylacetone (0.126 mol, 1.1 eq) was added, followed by 10.08 g sodium hydride (60%) (commercially available sodium hydride content 60%) (0.252 mol, 2.2 eq). After stirring at room temperature for 36 hours, 750 ml toluene was added to the reaction mixture and stirred. Then, it was added to 150 °C cold water (10 °C) to separate and extract the toluene layer. 100 ml toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 ml water, then washed with 100 ml saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 320 g acetic acid and 256 g N-methylpyrrolidone were added. A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 6°C / 10min until reflux). The reaction mixture was then reacted at reflux for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The combined toluene phases were washed three times with 300 ml of water and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 24.30 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 89%.

[0044] Example 4

[0045] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0046]

[0047] 34.83 g of potassium carbonate (0.252 mol, 2.2 eq) powder was added in one go to a solution of 25 g of 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) dissolved in 125 mL of N,N-dimethylformamide to form a suspension. The suspension was heated to 50 °C, and then 16.40 g of ethyl acetoacetate (0.126 mol, 1.1 eq) was slowly added. The mixture was then stirred at 50-55 °C for 19 hours under a nitrogen atmosphere and cooled to 22 °C. 750 mL of toluene was added to the reaction mixture and stirred. This mixture was then added to 200 mL of cold water (10 °C), and the toluene layer was separated and extracted. 100 mL of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, and 150 mL of the solution was added to the aqueous phase. The aqueous phase was extracted twice with a 5% sodium hydroxide aqueous solution. The resulting aqueous phase was then adjusted to pH 3 with 30% hydrochloric acid, followed by two extractions with 150 mL of toluene. The toluene solution was then removed by vacuum distillation. 220 g of acetic acid and 60 g of 50% sulfuric acid aqueous solution were added. The mixture was stirred and slowly heated (increasing the temperature by 8°C / 10 min until reflux), and finally reacted at reflux temperature for 3 h. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 mL of toluene and 400 mL of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 mL of toluene. The combined toluene phases were washed three times with 300 mL of water and once with 100 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 20.75 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 76%.

[0048] Example 5

[0049] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0050]

[0051] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 225 ml N,N-dimethylformamide, 16.40 g ethyl acetoacetate (0.126 mol, 1.1 eq) was added, followed by 82.10 g cesium carbonate (0.252 mol, 2.2 eq) powder. The mixture was stirred at 35-40 °C for 65 hours. Then, 750 ml toluene was added to the reaction mixture and stirred. This mixture was then added to 200 ml of cold water (10 °C) to separate and extract the toluene layer. 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, and 150 mL of 5% sodium hydroxide aqueous solution was added to extract the aqueous phase twice. The pH of the resulting aqueous phase was adjusted to 3 with 30% hydrochloric acid, and 150 mL of toluene was used for two extractions. The toluene solution was then purified by vacuum distillation to remove toluene. 220 g acetic acid and 60 g... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 6°C / 10min until reflux), and finally reacted at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, the toluene phase was separated, and the aqueous phase was extracted twice with 50 ml of toluene. The resulting toluene phases were combined, washed three times with 300 ml of water, washed once with 100 ml of saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 22.12 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 81%.

[0052] Example 6

[0053] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0054]

[0055] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 ml N,N-dimethylformamide, 16.40 g ethyl acetoacetate (0.126 mol, 1.1 eq) was added, followed by 17.14 g sodium ethoxide (60%) (0.252 mol, 2.2 eq). After stirring at room temperature for 48 hours, 750 ml toluene was added to the reaction mixture and stirred. This mixture was then added to 150 ml of cold water (10°C), and the toluene layer was separated and extracted. Then, 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, and 150 ml of 5% sodium hydroxide aqueous solution was added to extract the aqueous phase twice. The pH of the resulting aqueous phase was adjusted to 3 with 30% hydrochloric acid, and 150 ml of toluene was used for two extractions. The resulting toluene solution was purified by vacuum distillation to remove toluene. 220 g acetic acid and 60 g... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 7°C / 10min until reflux), and finally reacted at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The combined toluene phases were washed three times with 300 ml of water and once with 100 ml of saturated brine. After drying with anhydrous sodium sulfate and removing the solvent under reduced pressure, the resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 21.57 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 79%.

[0056] Example 7

[0057] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0058]

[0059] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 ml N,N-dimethylformamide, 19.93 g tert-butyl acetoacetate (0.126 mol, 1.1 eq) was added, followed by 34.83 g potassium carbonate powder (0.252 mol, 2.2 eq). The mixture was stirred at 35-40 °C for 65 hours. Then, 750 ml toluene was added to the reaction mixture and stirred. This mixture was then added to 200 ml of cold water (10 °C) to separate and extract the toluene layer. 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 mL of water, then washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 220 g acetic acid and 60 g... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 5°C / 10min until reflux). The reaction was then carried out at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The resulting toluene phases were combined, washed three times with 300 ml of water, and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 22.39 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 82%.

[0060] Example 8

[0061] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0062]

[0063] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 ml N,N-dimethylformamide, 14.61 g methyl acetoacetate (0.126 mol, 1.1 eq) was added, followed by 34.83 g potassium carbonate powder (0.252 mol, 2.2 eq). The mixture was stirred at 40-45 °C for 68 hours. Then, 750 ml toluene was added to the reaction mixture and stirred. This mixture was then added to 200 ml of cold water (10 °C) to separate and extract the toluene layer. 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 mL of water, then washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 220 g acetic acid and 60 g... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 5-10℃ / 10min until reflux). The reaction was then carried out at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The resulting toluene phases were combined, washed three times with 300 ml of water, and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 20.75 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 76%.

[0064] Example 9

[0065] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0066]

[0067] 34.83 g of potassium carbonate powder (0.252 mol, 2.2 eq) was added in one go to a solution of 25 g of 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) dissolved in 125 mL of N,N-dimethylformamide to form a suspension. The suspension was heated to 40 °C, and then 22.45 g of phenyl acetoacetate (0.126 mol, 1.1 eq) was slowly added. The reaction mixture was heated to 80-85 °C and stirred under a nitrogen atmosphere for 24 hours. Then, 750 mL of toluene was added to the reaction mixture and stirred. This mixture was then added to 150 mL of cold water (10 °C), and the toluene layer was separated and extracted. Then, 100 mL of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 mL of water, then washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 320 g of acetic acid and 256 g of... A 50% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 5-10℃ / 10min until reflux). The reaction was then carried out at reflux temperature for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The resulting toluene phases were combined, washed three times with 300 ml of water, and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 21.85 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 80%.

[0068] Example 10

[0069] Preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0070]

[0071] In a mixed solution of 25 g 1,2,3,5-tetrachlorobenzene (0.115 mol, 1.0 eq) and 125 ml N,N-dimethylformamide, 14.61 g methyl acetoacetate (0.126 mol, 1.1 eq) was added, followed by 34.83 g potassium carbonate powder (0.252 mol, 2.2 eq). The mixture was stirred at 40-45 °C for 68 hours. Then, 750 ml toluene was added to the reaction mixture and stirred. This mixture was then added to 200 ml of cold water (10 °C) to separate and extract the toluene layer. 100 ml of toluene was added to the aqueous phase, and the extraction was repeated twice. The resulting toluene phases were combined, washed three times with 150 mL of water, then washed with 100 mL of saturated brine, and dried over anhydrous sodium sulfate. After filtration, toluene was removed by vacuum distillation. 220 g acetic acid and 60 g... A 60% sulfuric acid aqueous solution was used to slowly heat the mixture while stirring (increasing the temperature by 7°C / 10min until reflux). The reaction mixture was then reacted at reflux for 3 hours. After cooling the reaction mixture to room temperature, some water and acetic acid were distilled off. 200 ml of toluene and 400 ml of water were added, and the toluene phase was separated. The aqueous phase was extracted twice with 50 ml of toluene. The combined toluene phases were washed three times with 300 ml of water and once with 100 ml of saturated brine. The mixture was dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The resulting solid was recrystallized twice with 100 g of 50% methanol aqueous solution to give 21.30 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 78%.

[0072] This invention provides a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, an intermediate of fluopyram, using inexpensive and readily available organic synthetic intermediates. The method involves reacting 1,2,3,5-tetrachlorobenzene with acetylacetone-like raw materials, followed by acidification and decarboxylation to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one. The method employs a two-step one-pot process of aryl nucleophilic substitution and decarboxylation. This method is simple to synthesize, has a short reaction route, uses inexpensive and readily available raw materials, has high atom utilization, does not use expensive reagents or special equipment requiring pressure resistance or corrosion resistance, has mild reaction conditions, and a simple synthetic process that is easy to control industrially. It does not use hazardous chemical processes under strict supervision, and is inherently safe and suitable for industrial production.

Claims

1. A method for preparing the fluopyram intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one, characterized in that, 1-(2,4,6-trichlorophenyl)-propyl-2-one was prepared from 1,2,3,5-tetrachlorobenzene and acetylacetone-like substances via the following reaction route: ； The acetylacetone-like substance is one of acetylacetone, ethyl acetoacetate, methyl acetoacetate, tert-butyl acetoacetate, and phenolic acetoacetate. The solvent is one of N,N-dimethylformamide, dimethyl sulfoxide, and N-methylpyrrolidone, and the mass-volume ratio of 1,2,3,5-tetrachlorobenzene to the solvent is 1:5-1:

10. The inorganic acid is an aqueous solution of sulfuric acid with a mass fraction of 50%-60%. The mass ratio of 1,2,3,5-tetrachlorobenzene to acetic acid is 1:8 to 1:13; the mass ratio of 1,2,3,5-tetrachlorobenzene to inorganic acid is 1:2.0 to 1:

11. The reaction temperature of the 1,2,3,5-tetrachlorobenzene with acetylacetone is between room temperature and 100°C.

2. The method for preparing the fluopyram intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one according to claim 1, characterized in that, The alkali is one of potassium carbonate, sodium bicarbonate, cesium carbonate, sodium ethoxide, and sodium methoxide.

3. The method for preparing the fluopyram intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one according to claim 1, characterized in that, The molar ratio of 1,2,3,5-tetrachlorobenzene to acetylacetone is 1:1.05 to 1:1.

5.

4. The method for preparing the fluopyram intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one according to claim 1, characterized in that, The molar ratio of 1,2,3,5-tetrachlorobenzene to the alkali substance is 1:2.1 to 1:2.

3.

5. The method for preparing the fluopyram intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one according to claim 1, characterized in that, The specific steps are as follows: 1,2,3,5-Tetrachlorobenzene, acetylacetone, and alkali are dissolved in a solvent and stirred for 24-75 hours to obtain a reaction mixture. After extraction, washing, drying, and vacuum distillation, acetic acid and inorganic acid are added. The mixture is stirred and heated at reflux temperature for 2.5-4 hours. The reactants are cooled to room temperature, and some water and acetic acid are removed by distillation. After extraction, washing, drying, vacuum distillation, and recrystallization, the product is obtained.

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