A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one

Abstract

This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one. Starting from 1,3,5-trichlorobenzene, 1-(2,4,6-trichlorophenyl)-propyl-2-one is prepared through chloromethylation, carbonylation, and Dakin-West reaction. This method is simple to synthesize, easy to operate, has a high safety factor, low cost, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one. 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 1-(2,4,6-trichlorophenyl)-propyl-2-one. This method is simple to synthesize, easy to operate, has a high safety factor, low cost, and is suitable for industrial production.

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

[0017] A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, starting from 1,3,5-trichlorobenzene, involves chloromethylation, carbonylation, and Dakin-West reaction to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one. The reaction route is as follows:

[0018]

[0019] Preferably, the specific steps are as follows:

[0020] (1) 1,3,5-trichlorobenzene was used as the starting material and chloromethylation reaction was carried out to obtain 1,3,5-trichloro-2-(chloromethyl)benzene;

[0021] (2) 2,4,6-trichlorophenylacetic acid was obtained by carbonylation reaction with 1,3,5-trichloro-2-(chloromethyl)benzene;

[0022] (3) 2,4,6-trichlorophenylacetic acid was reacted with Dakin-West to give 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0023] More preferably, the chloromethylation reaction involves using 1,3,5-trichlorobenzene and formaldehyde or / and paraformaldehyde as raw materials, and benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-chlorobenzenesulfonyl chloride, p-trifluoromethylbenzenesulfonyl chloride, iso-benzenedisulfonyl chloride, p-benzenedisulfonyl chloride, and diphenyl chlorophosphate as chlorine atom donors. Under the condition of adding a catalyst, the chloromethylation reaction yields the chloromethylated product 2,4,6-trichlorobenzyl chloride. This reaction can be carried out according to the reaction conditions of existing technology, specifically according to the preparation method disclosed in CN202010323817.8.

[0024] More preferably, the carbonylation catalyst is one of palladium chloride and palladium acetate, the carbonyl group is derived from one of carbon monoxide and formic acid, the solvent used in the carbonylation reaction is one of N-methylpyrrolidone (NMP), N,N-dimethylformamide (DMF), and acetonitrile, the inorganic base used in the carbonylation reaction is one of sodium carbonate, sodium phosphate, potassium carbonate, cesium carbonate, cesium fluoride, and potassium phosphate, the ligand used in the carbonylation reaction is one of triphenylphosphine and bis(diphenylphosphine)ferrocene (DPPF), and the dehydrating agent used in the carbonylation reaction is N,N-dicyclohexylcarbodiimide. Even more preferably, the carbonylation catalyst is palladium acetate, the solvent is acetonitrile, the carbonyl group is derived from formic acid, and the ligand is triphenylphosphine.

[0025] Preferably, the molar ratio of the catalyst to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.015–0.02:1, the molar ratio of the ligand to 1,3,5-trichloro-2-(chloromethyl)benzene is 0–0.04:1, the molar ratio of the inorganic base to 1,3,5-trichloro-2-(chloromethyl)benzene is 0–2.0:1, the molar ratio of the carbonyl source to 1,3,5-trichloro-2-(chloromethyl)benzene is 1.1–7.0:1, and the molar ratio of the dehydrating agent to 1,3,5-trichloro-2-(chloromethyl)benzene is 0–2:1.

[0026] More preferably, the molar ratio of the catalyst to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.02:1, the molar ratio of the ligand to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.04:1, the molar ratio of the inorganic base to 1,3,5-trichloro-2-(chloromethyl)benzene is 2.0:1, the molar ratio of the carbonyl source to 1,3,5-trichloro-2-(chloromethyl)benzene is 7.0:1, and the molar ratio of the dehydrating agent to 1,3,5-trichloro-2-(chloromethyl)benzene is 2:1.

[0027] More preferably, the carbonyl insertion reaction temperature is between 65°C and 200°C, and even more preferably between 65°C and 75°C.

[0028] More preferably, in step (3), the catalyst is an organic base and the reaction solvent is acetic anhydride.

[0029] More preferably, the organic base is one of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine (DMAP), 1-methylimidazole, and 4-methylimidazole; more preferably, the organic base is 4-methylimidazole.

[0030] More preferably, the molar ratio of the organic base to 2,4,6-trichlorophenylacetic acid is 0.25 to 2:1, more preferably 1:1, and the molar ratio of the reaction solvent to 2,4,6-trichlorophenylacetic acid is 5 to 10:1, more preferably 10:1.

[0031] More preferably, the Dakin-West reaction temperature is from an ice bath to room temperature.

[0032] More preferably, the Dakin-West reaction time is 6 to 24 hours.

[0033] To address the technical problems in the current preparation of 1-(2,4,6-trichlorophenyl)-propyl-2-one, the present invention proposes a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one. This method provides a method for preparing the intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one, which is obtained from the inexpensive and readily available organic synthetic intermediate 1,3,5-trichlorobenzene via chloromethylation to obtain 1,3,5-trichloro-2-(chloromethyl)benzene, followed by a carbonylation reaction to obtain 2,4,6-trichlorophenylacetic acid, and then by a Dakin-West reaction to obtain the fluopyram-hydroxylamine intermediate 1-(2,4,6-trichlorophenyl)-propyl-2-one. This method eliminates the need for the outdated and dangerous traditional process of preparing 2,4,6-trichlorophenylacetic acid from arylbenzyl chloride via an SN2 reaction with highly toxic sodium cyanide or potassium cyanide in a polar solvent (such as DMF, DMSO, or NMP) to generate arylphenylacetonitrile, followed by hydrolysis with sodium hydroxide aqueous solution. This process generates significant waste and requires highly toxic raw materials. Furthermore, it avoids the use of the hazardous diazotization reaction of tert-butyl nitrate. This invention offers undemanding reaction conditions, a 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.

[0034] The present invention provides a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, which does not require the use of hazardous chemicals, uses inexpensive and readily available raw materials, is simple to synthesize, easy to operate, has a high safety factor, low cost, and high yield with stable and reliable production, achieving unexpected results and is suitable for industrial production. Detailed Implementation

[0035] 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 the technical scope described herein should be included within the technical scope of the present invention.

[0036] The technical solution of this patent will be further described in detail below with reference to specific embodiments.

[0037] Example 1

[0038] Synthesis of 1,3,5-trichloro-2-(chloromethyl)benzene:

[0039]

[0040] 300g of 1,3,5-trichlorobenzene and 100g of paraformaldehyde (purchased from TCI (Shanghai) Chemical Industry Development Co., Ltd.) were added to a 1L three-necked flask. 5g of lanthanum trifluoromethanesulfonate catalyst was added, and a mechanical stirrer was attached. An air condenser with a balloon at the top and a constant-pressure dropping funnel containing 160ml of p-phenylenesulfonyl chloride were connected to the flask. The reaction was carried out in an ice-water bath at 0℃. P-phenylenesulfonyl chloride was slowly added dropwise while stirring. After the addition was completed in 2 hours, the temperature was raised to 60℃ and the reaction was carried out for 24 hours. After the reaction was complete, saturated sodium carbonate solution was added to completely neutralize the unreacted acid. Then, the product was extracted with dichloromethane. After separation, the mixed solution was washed twice with saturated sodium chloride solution. The resulting organic layer solution was dried with anhydrous sodium sulfate to remove water. After the organic solvent was evaporated, the solution was distilled under reduced pressure using an oil pump. The main fraction was the unreacted raw material and product. After the raw material was separated, it was quickly condensed into a solid. The distillation temperature was further increased, and 307.9 g of an oily, colorless, transparent liquid with a pungent odor was collected at 180°C, with a yield of 81%. 1 HNMR (400MHz, Chloroform-d) δ: 7.37 (s, 2H, ArH), 4.82 (s, 2H, CH2) ppm.

[0041] Example 2

[0042] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0043]

[0044] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation device. 43g of water (2.38mol, 1.096eq), 498.90g of 1,3,5-trichloro-2-(chloromethyl)benzene (2.17mol, 1.0eq) and 3.85g of palladium chloride (21.7mmol, 0.01eq) prepared in Example 1 were added to the reactor and dissolved in 750g of N-methylpyrrolidone. Carbon monoxide gas was introduced into the reactor to maintain a pressure of 5MPa. The stirrer was turned on, and the reactor was heated to maintain a temperature of 110℃-115℃ for 8 hours. After the reaction was completed, the reactor was cooled to ambient temperature and depressurized. The reactor was opened, and 500ml of water and 500ml x 2 of methyl tert-butyl ether were added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 415.73g of 2,4,6-trichlorophenylacetic acid, yield: 80%. 1 HNMR (400MHz, DMSO-d6) δ: 12.81 (brs, 1H, COOH) 7.73 (s, 2H, Ar), 3.85 (s, 2H, CH2).

[0045] Example 3

[0046] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0047]

[0048] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation device. 600.06 g of 1,3,5-trichloro-2-(chloromethyl)benzene (2.61 mol, 1.0 eq), 5.86 g of palladium acetate (26.1 mmol, 0.01 eq), 132.15 g of formic acid (2.87 mol, 1.1 eq), and 850 g of DMF prepared in Example 1 were added to the reactor and stirred until dissolved. The reactor was sealed and heated to maintain a temperature of 115°C-120°C for 9 hours. After the reaction was complete, the reactor was cooled to ambient temperature, opened, and 520 ml of water and methyl tert-butyl ether (650 ml x 2) were added for extraction twice. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 531.28 g of 2,4,6-trichlorophenylacetic acid, yield: 85%.

[0049] The palladium chloride and carbon monoxide used in Example 2, and the palladium acetate and formic acid used in Example 3, resulted in a significantly higher yield in Example 3 than in Example 2.

[0050] Example 4

[0051] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0052]

[0053] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation device. 6.73g palladium acetate (30mmol, 0.02eq), 318g sodium carbonate (3.0mol, 2.0eq), 344.86g 1,3,5-trichloro-2-(chloromethyl)benzene (1.5mol, 1.0eq) prepared in Example 1, 483.31g formic acid (10.5mol, 7.0eq), and 1750g acetonitrile were added to the reactor and stirred until dissolved. The reactor was sealed and heated to 65℃-70℃ for 20 hours. After the reaction was complete, the reactor was cooled to ambient temperature. The reactor was then opened, and the reaction mixture was washed sequentially with water (1L), NaOH solution (0.3mol / L, 1L), and the pH was adjusted to 1 with (0.5mol / L) HCl solution. Methyl tert-butyl ether (550ml) was added. x2) Extracted twice, the organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 316.11 g of 2,4,6-trichlorophenylacetic acid, yield: 88%.

[0054] Example 5

[0055] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0056]

[0057] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation device. 6.73g palladium acetate (30mmol, 0.02eq), 15.74g triphenylphosphine (60mmol, 0.04eq), 318g sodium carbonate (3.0mol, 2.0eq), 344.86g 1,3,5-trichloro-2-(chloromethyl)benzene (1.5mol, 1.0eq) prepared in Example 1, 483.31g formic acid (10.5mol, 7.0eq), and 1750g acetonitrile were added to the reactor and stirred until dissolved. The reactor was sealed and heated to 65℃-70℃ for 20 hours. After the reaction was complete, the reactor was cooled to ambient temperature. The reactor was then opened, and the reaction mixture was washed sequentially with water (1L), NaOH solution (0.3mol / L, 1L), and the pH was adjusted to 1 with (0.5mol / L) HCl solution. Methyl tert-butyl ether (550ml) was added. x2) Extracted twice, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 330.48 g of 2,4,6-trichlorophenylacetic acid, yield: 92%.

[0058] Example 5 added a ligand, triphenylphosphine, compared to Example 4. The yield of Example 4 was only 88%, while the yield of Example 5 reached 92%. Example 5, with the addition of the ligand, achieved significant progress.

[0059] Example 6

[0060] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0061]

[0062] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation. 6.73 g of palladium acetate (30 mmol, 0.02 eq) and 33.26 g of... 1,1'-bis(diphenylphosphine)ferrocene (DPPF) (60 mmol, 0.04 eq), 318 g sodium carbonate (3.0 mol, 2.0 eq), 344.86 g 1,3,5-trichloro-2-(chloromethyl)benzene (1.5 mol, 1.0 eq) prepared in Example 1, 483.31 g formic acid (10.5 mol, 7.0 eq), and 1750 g acetonitrile were stirred and dissolved. The reactor was sealed and heated to 65°C-70°C for 20 hours. After the reaction was completed, the reactor was cooled to ambient temperature. The reactor was opened, and the reaction mixture was washed successively with water (1 L) and NaOH solution (0.3 mol / L, 1 L). The pH was adjusted to 1 with (0.5 mol / L) HCl solution. The mixture was extracted twice with methyl tert-butyl ether (550 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 323.30 g 2,4,6-trichlorophenylacetic acid, yield: 90%.

[0063] Example 6 uses a different ligand than Example 5. Obviously, the yield of the final product prepared by choosing ligand DPPF is not as high as that obtained by choosing ligand triphenylphosphine.

[0064] Example 7

[0065] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0066]

[0067] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation. The following ingredients were added to the reactor: 6.73 g palladium acetate (30 mmol, 0.02 eq), 15.74 g triphenylphosphine (60 mmol, 0.04 eq), 318 g sodium carbonate (3.0 mol, 2.0 eq), 619.0 g N,N-dicyclohexylcarbodiimide (DCC) (3.0 mol, 2.0 eq), and 344.86 g of the solution prepared in Example 1. 1,3,5-Trichloro-2-(chloromethyl)benzene (1.5 mol, 1.0 eq), 483.31 g formic acid (10.5 mol, 7.0 eq), and 1750 g acetonitrile were dissolved by stirring. The reactor was sealed and heated to 65℃-75℃ for 20 hours. After the reaction was completed, the reactor was cooled to ambient temperature. The reactor was then opened, and the reaction mixture was washed successively with water (1 L) and NaOH solution (0.3 mol / L, 1 L). The pH was adjusted to 1 with (0.5 mol / L) HCl solution. The mixture was extracted twice with methyl tert-butyl ether (550 ml x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 348.43 g of 2,4,6-trichlorophenylacetic acid, yield: 97%.

[0068] Compared to Example 5, Example 7 added a dehydrating agent, and the yield of Example 7 increased by 5% compared to Example 5, achieving unexpected technical effects and making great progress.

[0069] Example 8

[0070] Synthesis of 2,4,6-trichlorophenylacetic acid:

[0071]

[0072] The reaction was carried out in a 5L Hastelloy pressure reactor equipped with a magnetic stirrer, automatic temperature control, and pressure regulation. The following ingredients were added to the reactor: 6.73 g palladium acetate (30 mmol, 0.02 eq), 15.74 g triphenylphosphine (60 mmol, 0.04 eq), 636.8 g potassium phosphate (3.0 mol, 2.0 eq), 619.0 g N,N-dicyclohexylcarbodiimide (DCC) (3.0 mol, 2.0 eq), and 344.86 g of the solution prepared in Example 1. 1,3,5-Trichloro-2-(chloromethyl)benzene (1.5 mol, 1.0 eq), 483.31 g formic acid (10.5 mol, 7.0 eq), and 1750 g acetonitrile were dissolved by stirring. The reactor was sealed and heated to 65-70°C for 20 hours. After the reaction was complete, the reactor was cooled to ambient temperature. The reactor was then opened, and the reaction mixture was washed successively with water (1 L), NaOH solution (0.3 mol / L, 1 L), and the pH was adjusted to 1 with (0.5 mol / L) HCl solution. Methyl tert-butyl ether (550 ml x 2) was added. The mixture was extracted twice, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 340.54 g of 2,4,6-trichlorophenylacetic acid, yield: 94.8%.

[0073] Compared to Example 7, Example 8 uses a different inorganic base. Obviously, the process of using sodium carbonate has a higher yield than that of using potassium phosphate.

[0074] Example 9

[0075] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0076]

[0077] 11.97 g of 2,4,6-trichlorophenylacetic acid (0.05 mol, 1.0 eq) prepared in Example 7 was dissolved in 25.52 g of acetic anhydride (0.25 mol, 5.0 eq). The mixture was stirred at room temperature and the air was purged with nitrogen (to remove air from the reactor). 2.53 g of triethylamine (0.025 mol, 0.05 eq) was added as a catalyst. The reaction was carried out at room temperature for 12 hours until the reactants were completely converted (TLC monitoring). 10 ml of water was added to the reaction flask, and the mixture was stirred at room temperature for another 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 25 g of 50% methanol aqueous solution to obtain 8.90 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 75%. 1HNMR (400MHz, Chloroform-d) δ: 7.33 (s, 2H, ArH), 4.05 (s, 2H, CH2), 2.21 (s, 3H, CH3) ppm.

[0078] Example 10

[0079] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0080]

[0081] 11.97 g of 2,4,6-trichlorophenylacetic acid (0.05 mol, 1.0 eq) prepared in Example 7 was dissolved in 25.52 g of acetic anhydride (0.25 mol, 5.0 eq). The mixture was stirred at room temperature and the air was replaced with nitrogen (to purge the air from the reactor). 1.98 g of pyridine (0.025 mol, 0.05 eq) was added as a catalyst. The reaction was carried out at room temperature for 24 hours until the reactants were completely converted. Water (10 ml) was added to the reaction flask and the mixture was stirred at room temperature for another 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 25 g of 50% methanol aqueous solution to obtain 8.31 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 70%.

[0082] In the synthesis method of Example 9, triethylamine was selected as the catalyst, while in Example 10, pyridine was selected as the catalyst. The synthesis method using triethylamine as the catalyst had a higher yield than the synthesis method using pyridine as the catalyst, and the reaction time was shortened by 12 hours when triethylamine was used as the catalyst.

[0083] Example 11

[0084] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0085]

[0086] 11.97 g of 2,4,6-trichlorophenylacetic acid (0.05 mol, 1.0 eq) prepared in Example 7 was dissolved in 25.52 g of acetic anhydride (0.25 mol, 5.0 eq). The mixture was stirred at room temperature and the air was replaced with nitrogen (to purge the air from the reactor). 3.05 g of DMAP catalyst (0.025 mol, 0.05 eq) was added, and the reaction was carried out at room temperature for 10 hours. TLC monitoring showed complete conversion of the reactants. Water (10 ml) was added to the reaction flask, and the mixture was stirred at room temperature for another 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 25 g of 50% methanol aqueous solution to obtain 10.10 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 85%.

[0087] Compared to Example 10, Example 11 uses a different catalyst. DMAP was selected as the catalyst in Example 11, and the yield of the final product was increased by 15% compared to Example 10, while the reaction time was shortened by 14 hours.

[0088] Example 12

[0089] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0090]

[0091] 11.97 g of 2,4,6-trichlorophenylacetic acid (0.05 mol, 1.0 eq) prepared in Example 7 was dissolved in 25.52 g of acetic anhydride (0.25 mol, 5.0 eq). The mixture was stirred at room temperature and the air was replaced with nitrogen (to purge the air from the reactor). 2.05 g of 1-methylimidazole catalyst (0.025 mol, 0.05 eq) was added, and the reaction was carried out at room temperature for 10 hours until the reactants were completely converted. Water (10 ml) was added to the reaction flask, and the mixture was stirred at room temperature for another 24 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 25 g of 50% methanol aqueous solution to obtain 10.10 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 85%.

[0092] Example 13

[0093] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0094]

[0095] 11.97 g of 2,4,6-trichlorophenylacetic acid (0.05 mol, 1.0 eq) prepared in Example 7 was dissolved in 25.52 g of acetic anhydride (0.25 mol, 5.0 eq). The mixture was stirred at room temperature and the air was replaced with nitrogen (to purge the air from the reactor). 2.05 g of 4-methylimidazole catalyst (0.025 mol, 0.05 eq) was added, and the reaction was carried out at room temperature for 8 hours. TLC monitoring showed complete conversion of the reactants. Water (10 ml) was added to the reaction flask, and the mixture was stirred at room temperature for another 24 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 25 g of 50% methanol aqueous solution to obtain 10.56 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 89%.

[0096] Compared to Example 10, Example 13 used 4-methylimidazole as a catalyst. The yield of Example 13 was 19% higher than that of Example 10, and the reaction time differed by 16 hours. Example 13 achieved a very significant improvement over Example 10.

[0097] Example 14

[0098] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0099]

[0100] At room temperature, nitrogen gas was bubbled through 51.05 g of acetic anhydride (0.5 mol, 5.0 eq) to degas it (this not only purged the air in the reactor but also removed the air dissolved in the acetic anhydride). 23.79 g of 2,4,6-trichlorophenylacetic acid (0.1 mol, 1.0 eq) prepared in Example 7 was dissolved in the acetic anhydride, cooled and stirred in an ice bath, and 4.10 g of catalyst was added. 4-Methylimidazole (0.05 mol, 0.5 eq) was used to slowly raise the mixture, which was cooled in an ice-water bath, to room temperature and maintain this temperature for 12 hours until the reactants were completely converted. The reaction mixture was then concentrated under vacuum. The resulting brown oil was added to a stirred ice / water mixture (500 g), which was then raised to room temperature and maintained for 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 50 g of a 50% methanol aqueous solution to give 21.65 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 91%.

[0101] Compared to Example 13, Example 14 removes all the air from the acetic anhydride, resulting in a higher yield of the final product.

[0102] Example 15: Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0103]

[0104] Nitrogen gas was bubbled through 102.09 g of acetic anhydride (1.0 mol, 10.0 eq) at room temperature to degas it; 23.79 g of 2,4,6-trichlorophenylacetic acid (0.1 mol, 1.0 eq) prepared in Example 7 was dissolved in acetic anhydride, cooled and stirred in an ice bath, and 4.10 g of catalyst was added. 4-Methylimidazole (0.05 mol, 0.5 eq) was used to slowly raise the mixture, which was cooled in an ice-water bath, to room temperature and maintain this temperature for 10 hours until the reactants were completely converted. The reaction mixture was then concentrated under vacuum, and the resulting brown oil was added to a stirred ice / water mixture (500 g). The mixture was then raised to room temperature and maintained for 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate and concentrated. The resulting solid was recrystallized twice from 50 g of a 50% (w / w) methanol aqueous solution to give 22.08 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, with a yield of 93%.

[0105] Compared to Example 14, Example 15 increased the amount of acetic anhydride used as the reaction solvent, with a molar ratio of acetic anhydride to 2,4,6-trichlorophenylacetic acid of 10:1. As a result, the yield of the product in Example 15 was increased compared to that in Example 14.

[0106] Example 16

[0107] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0108]

[0109] Nitrogen gas was bubbled through 102.09 g of acetic anhydride (1.0 mol, 10.0 eq) at room temperature to degas it. 23.79 g of 2,4,6-trichlorophenylacetic acid (0.1 mol, 1.0 eq) prepared in Example 7 was dissolved in the acetic anhydride, cooled and stirred in an ice bath, and 8.21 g of catalyst was added. 4-Methylimidazole (0.1 mol, 1.0 eq) was used to slowly raise the mixture, which was cooled in an ice-water bath, to room temperature and maintained for 6 hours until the reactants were completely converted. The reaction mixture was concentrated under vacuum, and the resulting brown oil was added to a stirred ice / water mixture (500 g), which was then raised to room temperature and maintained for 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 50 g of 50% methanol aqueous solution to give 22.82 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 96.1%.

[0110] Compared to Example 15, Example 16 adjusted the use of catalyst so that the molar ratio of catalyst to 2,4,6-trichlorophenylacetic acid was 1:1. Under this specific ratio, the product yield of Example 16 differed from that of Example 15 by 3.1%, which is a significant improvement.

[0111] Example 17

[0112] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0113]

[0114] Nitrogen gas was bubbled through 102.09 g of acetic anhydride (1.0 mol, 10.0 eq) at room temperature to degas it. 23.79 g of 2,4,6-trichlorophenylacetic acid (0.1 mol, 1.0 eq) prepared in Example 7 was dissolved in acetic anhydride, cooled and stirred in an ice bath, and 2.05 g of 4-methylimidazole (0.025 mol, 0.25 eq) was added as a catalyst. The mixture cooled in an ice-water bath was slowly raised to room temperature and maintained for 14 hours until the reactants were completely converted. The reaction mixture was concentrated under vacuum, and the resulting brown oil was added to the stirred ice / water mixture (500 g), raised to room temperature, and maintained for 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 50 g of 50% methanol aqueous solution to obtain 21.85 g of brownish-yellow solid 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 92%.

[0115] Example 18

[0116] Synthesis of 1-(2,4,6-trichlorophenyl)-propyl-2-one:

[0117]

[0118] Nitrogen gas was bubbled through 102.09 g of acetic anhydride (1.0 mol, 10.0 eq) at room temperature to degas it. 23.79 g of 2,4,6-trichlorophenylacetic acid (0.1 mol, 1.0 eq) was dissolved in acetic anhydride, cooled and stirred in an ice bath, and 16.42 g of 4-methylimidazole (0.2 mol, 2.0 eq) was added as a catalyst. The mixture, cooled in an ice-water bath, was slowly brought to room temperature and maintained for 14 hours until the reactants were completely converted. The reaction mixture was concentrated under vacuum, and the resulting brown oil was added to a stirred ice / water mixture (500 g), brought to room temperature, and maintained for 18 hours. The aqueous phase was extracted with methyl tert-butyl ether, and the mixed organic phase was washed with water, saturated sodium bicarbonate, and 1 mol / L hydrochloric acid. The mixture was dried over anhydrous sodium sulfate, concentrated, and the resulting solid was recrystallized twice from 50 g of 50% methanol aqueous solution to give 22.27 g of a brownish-yellow solid, 1-(2,4,6-trichlorophenyl)-propyl-2-one, yield: 93.8%.

[0119] In Examples 17 and 18, the amount of catalyst used was slightly lower than in Example 16. Although the yield of the final synthesized product was a significant improvement over the prior art, the yield was still significantly lower than that of the synthesis method using the catalyst specified in Example 16.

[0120] The present invention provides a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, which does not require the use of hazardous chemicals, uses inexpensive and readily available raw materials, is simple to synthesize, easy to operate, has a high safety factor, low cost, and high yield with stable and reliable production, achieving unexpected results and is suitable for industrial production.

Claims

1. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one, characterized in that, 1-(2,4,6-trichlorophenyl)-propan-2-one is prepared by chloromethylation, carbonyl insertion and Dakin-West reaction using 1,3,5-trichlorobenzene as starting material, and the reaction route is as follows: ； The specific steps are as follows: (1) 1,3,5-trichloro-2-(chloromethyl)benzene is prepared by chloromethylation using 1,3,5-trichlorobenzene as starting material; (2) 2,4,6-trichlorophenylacetic acid is prepared by carbonyl insertion using 1,3,5-trichloro-2-(chloromethyl)benzene; (3) 1-(2,4,6-trichlorophenyl)-propan-2-one is prepared by Dakin-West reaction using 2,4,6-trichlorophenylacetic acid.

2. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, In step (2), the catalyst for the carbonyl insertion is one of palladium chloride and palladium acetate; the source of the carbonyl group for the carbonyl insertion is one of carbon monoxide and formic acid; the solvent used for the carbonyl insertion is one of N-methylpyrrolidone, N,N-dimethylformamide and acetonitrile; the inorganic base used for the carbonyl insertion is one of sodium carbonate, sodium phosphate, potassium carbonate, cesium carbonate, cesium fluoride and potassium phosphate; the ligand used for the carbonyl insertion is one of triphenylphosphine and bis(diphenylphosphino)ferrocene; and the dehydrating agent used for the carbonyl insertion is N,N-dicyclohexylcarbodiimide.

3. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 2, characterized in that, The molar ratio of the catalyst to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.015-0.02:1, the molar ratio of the ligand to 1,3,5-trichloro-2-(chloromethyl)benzene is 0-0.04:1, the molar ratio of the inorganic base to 1,3,5-trichloro-2-(chloromethyl)benzene is 0-2.0:1, the molar ratio of the source of the carbonyl group to 1,3,5-trichloro-2-(chloromethyl)benzene is 1.1-7.0:1, and the molar ratio of the dehydrating agent to 1,3,5-trichloro-2-(chloromethyl)benzene is 0-2:

1.

4. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 3, characterized in that, In step (2), the molar ratio of the catalyst to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.02:1, the molar ratio of the ligand to 1,3,5-trichloro-2-(chloromethyl)benzene is 0.04:1, the molar ratio of the inorganic base to 1,3,5-trichloro-2-(chloromethyl)benzene is 2.0:1, the molar ratio of the source of the carbonyl group to 1,3,5-trichloro-2-(chloromethyl)benzene is 7.0:1, and the molar ratio of the dehydrating agent to 1,3,5-trichloro-2-(chloromethyl)benzene is 2:

1. The temperature for the carbonyl insertion is 65-200℃. In step (3), the catalyst is an organic base, and the reaction solvent is acetic anhydride. The organic base is one of triethylamine, diisopropylethylamine, pyridine, DMAP, 1-methylimidazole and 4-methylimidazole.

5. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, The molar ratio of the catalyst to 2,4,6-trichlorophenylacetic acid is 0.25-2:1, and the molar ratio of the reaction solvent to 2,4,6-trichlorophenylacetic acid is 5-10:

1.

6. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, The temperature for the Dakin-West reaction is between ice water bath and room temperature, and the time for the Dakin-West reaction is 6-24 hours.

7. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 6, characterized in that, ​ 8. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 6, characterized in that, ​ 9. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, ​

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