Preparation method of 1-(2, 4, 6-trichlorophenyl)-propyl-2-ketone

Abstract

The invention relates to the technical field of pesticide preparation, and particularly discloses a novel preparation method of a key intermediate 1-(2, 4, 6-trichlorophenyl)-propyl-2-ketone of a bactericide pydiflumetofen. The method comprises the following steps: by taking 3, 5-dichloro-4-fluoronitrobenzene as a starting raw material, sequentially carrying out four-step unit reactions: reacting with ethyl acetoacetate under an alkaline condition to prepare 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutyric acid ethyl ester, and reacting with ethyl acetoacetate under an alkaline condition to prepare 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutyric acid ethyl ester; carrying out degreasing under an acidic condition, so as to obtain 1-(2, 6-dichloro-4-nitrophenyl)-propyl-2-ketone; reducing the nitro group to obtain 1-(4-amino-2, 6-dichlorophenyl)-propyl-2-ketone; and performing Sandmeyer reaction to obtain a target product. The preparation method is novel in synthetic route, few in side reaction and high in total yield, the content of a target product is larger than 99%, the preparation method is suitable for industrial production, and a key support is provided for industrialization of pydiflumetofen.

Description

Technical Field

[0001] This invention relates to the field of pesticide preparation technology, and in particular to a novel method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, a key intermediate in the fungicide fluopyram. Background Technology

[0002] Pydiflumetofen is a pyrazolamide succinate dehydrogenase inhibitor (SDHI) fungicide developed by Syngenta. Due to its high activity, broad spectrum, low toxicity, and low residue, it is widely used in agricultural disease control. This fungicide exhibits excellent control efficacy against various pathogens, including wheat rust, powdery mildew, cucumber downy mildew, and tomato gray mold. Furthermore, it shows no cross-resistance with triazole and methoxyacrylate fungicides, effectively addressing the challenge of controlling resistant diseases, and possesses extremely high market potential and application value.

[0003] 1-(2,4,6-trichlorophenyl)-propyl-2-one is a core intermediate in the synthesis of fluopyram, and the rationality, economics, and industrial feasibility of its synthesis process directly determine the production cost and market competitiveness of fluopyram. Therefore, developing an efficient, low-cost, and large-scale production process for 1-(2,4,6-trichlorophenyl)-propyl-2-one has become a crucial step in the industrialization of fluopyram.

[0004] Currently, the synthetic routes for 1-(2,4,6-trichlorophenyl)-propyl-2-one disclosed in domestic and international literature and patents have many defects, as follows: Route 1 (patents WO2013127764, WO2013127441): Starting with 2,4,6-trichloroaniline, a Millwell reaction is carried out with tert-butyl nitrite and excess isopropyl acetate under the catalysis of copper salt or potassium carbonate. This route requires more than 10 equivalents of isopropyl acetate, resulting in high raw material consumption, severe side reactions, numerous impurities, and a product that is often a brownish-black oily substance. Separation and purification are extremely difficult, with a pure yield of only 48%-58%, making it economically unfeasible.

[0005]

[0006] Route 2 (Patent WO2010063700): Using 2,4,6-trichlorobenzaldehyde as a raw material, it is condensed with nitrobenzene in an ammonium acetate / acetic acid system to produce 1,3,5-trichloro-2-((E)-2-nitro-propenyl)benzene (yield 61%), which is then reduced with iron powder to obtain the target product (yield 83%). This route has two major bottlenecks: first, the starting material 2,4,6-trichlorobenzaldehyde is scarce and expensive in the market; second, nitrobenzene is a potentially explosive and hazardous chemical, with strict production regulations, and post-processing requires column chromatography purification, making industrial scale-up impossible.

[0007]

[0008] Route 3 (Patent CN108610290A): Using p-chloroaniline as a raw material, 4-chlorophenylacetone is first synthesized, and then the target product is obtained by catalytic chlorination with ferric chloride in carbon tetrachloride. This route uses highly toxic chlorine gas as a chlorinating agent, posing significant safety hazards in the production process; moreover, the chlorination reaction has poor selectivity, is prone to over-chlorination of methyl and methylene groups, produces many byproducts, and makes it difficult to control the purity of the product.

[0009]

[0010] Route 4 (Patent CN113004131A): Using 2,4,6-trichlorotoluene as a starting material, the target product is obtained through a multi-step reaction (preparation of benzyl chloride, coupling with ethynyl magnesium halide, and acid-catalyzed addition). This route relies on expensive and unstable ethynyl magnesium halide, while the starting material 2,4,6-trichlorotoluene is not readily available, resulting in high production costs.

[0011]

[0012] Routes 5 and 6 (patents CN117326921A and CN117603033A): use 1,3,5-trichlorobenzene and 1,2,3,5-tetrachlorobenzene as starting materials, respectively. They require expensive reagents or catalysts such as terephthaloyl chloride, palladium acetate, and triphenylphosphine, and have problems such as many chloromethylation side reactions and poor alkylation selectivity. The economics and feasibility of industrial production are extremely low.

[0013]

[0014]

[0015] In summary, existing synthetic routes generally suffer from problems such as expensive and scarce raw materials, highly toxic reagents, numerous side reactions, complex post-processing, and significant safety hazards, failing to meet the demands of large-scale industrial production. Therefore, developing a new process for the preparation of 1-(2,4,6-trichlorophenyl)-propyl-2-one that features readily available raw materials, high reaction selectivity, simple post-processing, and is safe and economical has significant practical implications and industrial value. Summary of the Invention

[0016] To address the problems existing in the prior art, this invention provides a method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, a novel process for synthesizing 1-(2,4,6-trichlorophenyl)-propyl-2-one, namely, using 3,5-dichloro-4-fluoronitrobenzene as the starting material, and synthesizing 1-(2,4,6-trichlorophenyl)-propyl-2-one through substitution reaction, hydrolysis deesterification, reduction reaction and Sandmeier reaction.

[0017] To achieve the above-mentioned objectives, the present invention adopts the following technical solution: A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one, the synthetic route of which is as follows:

[0018] The preparation method includes the following steps: S1. 3,5-Dichloro-4-fluoronitrobenzene is added to a reaction system containing ethyl acetoacetate, an alkaline substance, and a solvent to carry out a substitution reaction, thereby preparing ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate. S2. The reaction system containing ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate was hydrolyzed under acidic conditions. After the reaction was complete, 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was obtained by extraction, washing, drying and concentration. S3. The obtained 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one undergoes a nitro reduction reaction. After the reaction is complete, the product is subjected to post-treatment including filtration, acid washing, extraction, acid-base adjustment, extraction, drying and concentration to obtain 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one. S4. The obtained 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one reacts with tert-butyl nitrite in the presence of copper chloride in a Sandmeier reaction. After the reaction is complete, the product is subjected to post-treatment including filtration, acid washing, extraction, drying, decolorization and concentration to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0019] Further, in step S1, the molar ratio of 3,5-dichloro-4-fluoronitrobenzene, ethyl acetoacetate, basic substance, and solvent is 1:1~2.5:1~3:15~20; the basic substance is selected from at least one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, or potassium carbonate; the solvent is selected from at least one of dimethyl sulfoxide or N-methylpyrrolidone, a polar aprotic solvent that can promote nucleophilic substitution reactions.

[0020] Further, in step S1, the substitution reaction process is as follows: first, ethyl acetoacetate, an alkaline substance, and a solvent are mixed and stirred at 30~60℃ for 0.8-1.2 hours, then 3,5-dichloro-4-fluoronitrobenzene is added in batches. After the 3,5-dichloro-4-fluoronitrobenzene has reacted completely, a reaction system containing ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate is directly obtained without the need to separate intermediates.

[0021] Further, in step S2, the acidic conditions are provided by concentrated hydrochloric acid; the molar ratio of ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate to concentrated hydrochloric acid is 1:5~10; and the temperature of the hydrolysis reaction is 90~110℃.

[0022] Further, in step S2, the post-treatment step after the hydrolysis reaction is as follows: water is added to the reaction system, and the mixture is extracted multiple times with toluene, and the organic layers are combined; the organic layers are washed multiple times with a 4% sodium hydroxide aqueous solution, then dried, and concentrated under reduced pressure to obtain 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one. Preferably, the toluene extraction is performed three times, with a volume of 50 mL each time; the sodium hydroxide aqueous solution is used for washing twice, with a volume of 50 mL each time.

[0023] Further, in step S3, the nitro reduction reaction uses acetic acid as the reaction solvent and reduced iron powder as the reducing agent; the molar ratio of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one, reduced iron powder and acetic acid is 1:3:15~20; the temperature of the nitro reduction reaction is 30~50℃.

[0024] Further, in step S3, the post-processing steps after the nitro reduction reaction are as follows: filter the reaction system, wash the filter cake multiple times with acetic acid, and combine the filtrate and washing liquid; add water to the combined liquid, extract multiple times with dichloromethane, and collect the organic layer; extract the organic layer multiple times with a 10% hydrochloric acid solution to obtain a hydrochloric acid layer; adjust the pH of the hydrochloric acid layer to 10 with a 50% sodium hydroxide aqueous solution, and then extract multiple times with dichloromethane, combining the organic layers; dry the organic layer, filter, and concentrate under reduced pressure to obtain 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one. Preferably, the filter cake is washed with acetic acid three times, with a volume of 20 mL each time; the dichloromethane extraction is performed three times, with a volume of 100 mL each time; and the hydrochloric acid extraction is performed three times, with a volume of 100 mL each time.

[0025] Further, in step S4, the Sandmeier reaction uses acetonitrile as the reaction solvent; the molar ratio of 1-(4-amino-2,6-dichloro-phenyl)-propyl-2-one, tert-butyl nitrite, copper chloride and acetonitrile is 1:1~2:1~2:15~20; the temperature of the Sandmeier reaction is 50~80℃.

[0026] Further, in step S4, the post-processing steps after the Sandmeier reaction are as follows: filter the reaction system, add 5% hydrochloric acid to the filtrate, extract multiple times with methyl tert-butyl ether, and collect the organic layer; wash the organic layer multiple times with 5% hydrochloric acid, then add petroleum ether, anhydrous magnesium sulfate, and activated carbon to the organic layer, and stir for 1 hour; filter to remove solid impurities, and concentrate the filtrate under reduced pressure to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one. Preferably, the methyl tert-butyl ether extraction is performed 3 times, with each extraction using 100 mL; the hydrochloric acid washing is performed 3 times, with each washing using 50 mL; and the amount of petroleum ether added is 300 mL.

[0027] Furthermore, the reaction progress of the raw materials is monitored by liquid chromatography during the reaction process of the present invention.

[0028] Compared with the prior art, the present invention uses 3,5-dichloro-4-fluoronitrobenzene and ethyl acetoacetate as initial raw materials to generate ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate via a substitution reaction; this intermediate does not need to be separated and is directly hydrolyzed under acidic conditions to give 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one; subsequently, the nitro group is converted to an amino group via a nitro reduction reaction to give 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one; finally, a third chlorine atom is introduced via a Sandmeier chlorination reaction to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-one.

[0029] This invention has the following significant advantages: Excellent raw material economy: The starting material 3,5-dichloro-4-fluoronitrobenzene is an important intermediate for pesticides, pharmaceuticals and dyes. It is in ample domestic supply and inexpensive, which greatly reduces production costs. High reaction selectivity: In the substitution reaction, the fluorine atom (activated by a strong electron-withdrawing group) of 3,5-dichloro-4-fluoronitrobenzene is easily replaced by the active methylene nucleophilic group of ethyl acetoacetate, resulting in fewer side reactions; Sandmeier chlorination reaction adopts a one-step method catalyzed by copper chloride, avoiding the traditional two-step method with complex operation; High process efficiency: The substitution products in step S1 do not need to be separated and can directly enter the hydrolysis in step S2, realizing a "one-pot" operation, shortening the process cycle and improving production efficiency. The post-processing is simple: each post-processing step adopts conventional operations such as "extraction-washing-concentration", without the need for complex purification methods such as column chromatography, which is suitable for industrial scale-up; High safety: Avoids the use of highly toxic or explosive reagents such as chlorine and nitrosane; reaction conditions are mild (maximum temperature 110℃); production process is safe and controllable. Detailed Implementation

[0030] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0031] To better illustrate the preparation method of 1-(2,4,6-trichlorophenyl)-propyl-2-one provided in the embodiments of the present invention, further examples are given below.

[0032] Example 1 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 15.6 g (0.12 mol) ethyl acetoacetate, 117 g (1.5 mol) dimethyl sulfoxide and 15.8 g (0.24 mol) 85% potassium hydroxide were mixed and stirred at 60 °C for 1 hour. Then, 21.1 g (0.1 mol) 3,5-dichloro-4-fluoronitrobenzene was added in batches to react. After the reaction of the raw materials was completed by liquid chromatography, a solution of ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate was obtained.

[0033] 50.7 g (0.5 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 100 °C. After the starting material reacted completely, 100 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 68 g of yellow crystals of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one, with a yield of 82%.

[0034] 1 H NMR (400MHz, CDCl3): δ2.34(s,3H,CH3),4.21(s,2H,CH2),8.20(s,2H, Ar-H) 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 120 g (2 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 30 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 19.3 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 88.0%.

[0035] 1 H NMR (400MHz, CD4O): δ2.30(s,3H,CH3),4.22(s,2H,CH2),7.36(s,2H, Ar-H) 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one was mixed with 61.5 g (1.5 mol) of acetonitrile and 16.1 g (0.12 mol) of copper chloride. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 60 °C to initiate the reaction. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for 1 hour, filtered, and concentrated under reduced pressure to obtain 20.5 g of a white solid powder of 1-(2,4,6-trichlorophenyl)-propyl-2-one, with a yield of 86.3%.

[0036] 1H NMR (400MHz, CDCl3): δ2.37(s,3H,CH3),4.24(s,2H,CH2),8.24(s,2H, Ar-H) Example 2 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 19.5 g (0.15 mol) of ethyl acetoacetate, 117 g (1.5 mol) of dimethyl sulfoxide and 41.4 g (0.3 mol) of potassium carbonate were mixed and stirred at 60 °C for 1 hour. Then, 21.1 g (0.1 mol) of 3,5-dichloro-4-fluoronitrobenzene was added in batches to react with the raw materials. After the reaction was complete, a solution of ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate was prepared.

[0037] 81.1 g (0.8 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 100 °C. After the starting material reacted completely, 100 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 27.8 g of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one yellow solid, with a yield of 74.8%.

[0038] 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 120 g (2 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 40 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 17.4 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 79.6%.

[0039] 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one was reacted with 61.5 g (1.5 mol) of acetonitrile and 20.1 g (0.15 mol) of copper chloride. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 60 °C. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for one hour, filtered, and concentrated under reduced pressure to obtain 21.3 g of a white solid of 1-(2,4,6-trichlorophenyl)-propyl-2-one, with a yield of 89.7%.

[0040] Example 3 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 19.5 g (0.15 mol) of ethyl acetoacetate, 140 g (1.8 mol) of DMF and 41.4 g (0.3 mol) of potassium carbonate were mixed and stirred at 50 °C for 1 hour. Then, 21.1 g (0.1 mol) of 3,5-dichloro-4-fluoronitrobenzene was added in batches to react with the raw materials. After the reaction was complete, ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution was obtained.

[0041] 81.1 g (0.8 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 110 °C. After the starting material reacted completely, 150 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 28.6 g of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one yellow solid, with a yield of 76.9%.

[0042] 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 120 g (2 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 50 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 17.6 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 80.6%.

[0043] 61.5 g (1.5 mol) of acetonitrile and 20.1 g (0.15 mol) of copper chloride were added to 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 50 °C to initiate the reaction. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for one hour, filtered, and concentrated under reduced pressure to obtain 20.7 g of a white solid of 1-(2,4,6-trichlorophenyl)-propyl-2-one, with a yield of 87.3%.

[0044] Example 4 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 26 g (0.2 mol) of ethyl acetoacetate, 178 g (1.8 mol) of N-methylpyrrolidone and 26.4 g (0.4 mol) of 85% potassium hydroxide were mixed and stirred at 50 °C for 1 hour. Then, 21.1 g (0.1 mol) of 3,5-dichloro-4-fluoronitrobenzene was added in batches to react with the raw materials. After the reaction was complete, a solution of ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate was obtained.

[0045] 81.1 g (0.8 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 110 °C. After the starting material reacted completely, 150 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 40.3 g of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one yellow solid, with a yield of 82.5%.

[0046] 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 150 g (2.5 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 30 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 17.7 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 81.1%.

[0047] 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one was reacted with 61.5 g (1.5 mol) of acetonitrile and 24.1 g (0.18 mol) of copper chloride. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 70 °C. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for one hour, filtered, and concentrated under reduced pressure to obtain 20.9 g of a pale yellow solid of 1-(2,4,6-trichlorophenyl)-propyl-2-one, with a yield of 88.2%.

[0048] Example 5 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 26 g (0.2 mol) ethyl acetoacetate, 117 g (1.5 mol) dimethyl sulfoxide and 16 g (0.4 mol) sodium hydroxide were mixed and stirred at 60 °C for 1 hour. Then, 21.1 g (0.1 mol) 3,5-dichloro-4-fluoronitrobenzene was added in batches to react with the raw materials. After the reaction was complete, ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution was obtained.

[0049] 50.7 g (0.5 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 110 °C. After the starting material reacted completely, 100 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 40.3 g of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one yellow solid, with a yield of 81.2%.

[0050] 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 150 g (2.5 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 40 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 17.5 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 80.3%.

[0051] 73.8 g (1.8 mol) of acetonitrile and 20.1 g (0.15 mol) of copper chloride were added to 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 70 °C to initiate the reaction. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for one hour, filtered, and concentrated under reduced pressure to obtain 21 g of 1-(2,4,6-trichlorophenyl)-propyl-2-one as a white solid, with a yield of 88.6%.

[0052] Example 6 A method for preparing 1-(2,4,6-trichlorophenyl)-propyl-2-one is as follows: 32.5 g (0.25 mol) ethyl acetoacetate, 117 g (1.5 mol) dimethyl sulfoxide and 32.9 g (0.5 mol) 85% potassium hydroxide were mixed and stirred at 60 °C for 1 hour. Then, 21.1 g (0.1 mol) 3,5-dichloro-4-fluoronitrobenzene was added in batches to react with the raw materials. After the reaction was complete, ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution was obtained.

[0053] 101.4 g (1 mol) of 36% concentrated hydrochloric acid was added to the ethyl 2-(2,6-dichloro-4-nitrophenyl)-3-oxobutyrate solution obtained in the previous step, and the reaction was carried out at 110 °C. After the starting material reacted completely, 100 mL of water was added, and the mixture was extracted with 50 mL × 3 toluene. The organic layer was washed with 4% sodium hydroxide aqueous solution (50 mL × 2), dried, and concentrated under reduced pressure to obtain 51.7 g of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one yellow solid, with a yield of 83.4%.

[0054] 24.7 g (0.1 mol) of 1-(2,6-dichloro-4-nitrophenyl)-propyl-2-one was added to 150 g (2.5 mol) of acetic acid. 16.8 g (0.3 mol) of reduced iron powder was added in portions at 30 °C to carry out the reaction. After the reaction was complete, the mixture was filtered. The filter cake was washed with 20 mL × 3 acetic acid solutions. The filtrate was added to 600 mL of water and extracted with 100 mL × 3 dichloromethane solutions. The organic layer was extracted with 10% hydrochloric acid (100 mL × 3 solutions). The hydrochloric acid layer was adjusted to pH 10 with 50% sodium hydroxide aqueous solution and then extracted with 100 mL × 3 dichloromethane solutions. The mixture was dried, filtered, and concentrated under reduced pressure to obtain 17.9 g of a yellow oily substance of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one, with a yield of 81.9%.

[0055] 21.8 g (0.1 mol) of 1-(4-amino-2,6-dichlorophenyl)-propyl-2-one was reacted with 61.5 g (1.5 mol) of acetonitrile and 20.1 g (0.15 mol) of copper chloride. 15.5 g (0.15 mol) of tert-butyl nitrite was added dropwise at 80 °C. After the reaction was complete, the mixture was filtered. 80 mL of 5% hydrochloric acid was added to the filtrate, and the mixture was extracted with 100 mL × 3 methyl tert-butyl ether. The organic layer was washed with 5% hydrochloric acid (50 mL × 3). Then, 300 mL of petroleum ether, anhydrous magnesium sulfate, and activated carbon were added to the organic layer. The mixture was stirred for one hour, filtered, and concentrated under reduced pressure to obtain 21.2 g of 1-(2,4,6-trichlorophenyl)-propyl-2-one as a white solid, with a yield of 89.3%.

[0056] The above embodiments show that the preparation method of the present invention is stable and reproducible, with considerable yields (74.8%~89.7%) in each step and a target product content ≥99%, fully meeting the requirements of industrial production for efficiency, cost and product quality.

[0057] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions or improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one, characterized in that, The method comprises the following steps: S1, 3, 5-dichloro-4-fluoro nitrobenzene is added to a reaction system containing ethyl acetoacetate, a basic substance and a solvent to perform a substitution reaction to prepare ethyl 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutanoate; S2, the reaction system containing ethyl 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutanoate is subjected to a hydrolysis reaction under acidic conditions, after the reaction is completed, the product is treated by extraction, washing, drying and concentration to prepare 1-(2, 6-dichloro-4-nitrophenyl)-propyl-2-ketone; S3, the obtained 1-(2, 6-dichloro-4-nitrophenyl)-propyl-2-ketone is subjected to a nitro reduction reaction, after the reaction is completed, the product is treated by filtration, acid washing, extraction, acid-base adjustment, extraction, drying and concentration to prepare 1-(4-amino-2, 6-dichlorophenyl)-propyl-2-ketone; S4, the obtained 1-(4-amino-2, 6-dichlorophenyl)-propyl-2-ketone is subjected to a Sandmeyer reaction with tert-butyl nitrite under the action of copper chloride, after the reaction is completed, the product is treated by filtration, acid washing, extraction, drying, decolorization and concentration to prepare 1-(2, 4, 6-trichlorophenyl)-propyl-2-ketone.

2. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, In step S1, the molar ratio of 3, 5-dichloro-4-fluoro nitrobenzene, ethyl acetoacetate, the basic substance and the solvent is 1:1-2.5:1-3:15-20; the basic substance is at least one selected from sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate or potassium carbonate; and the solvent is at least one selected from dimethyl sulfoxide or N-methyl pyrrolidone.

3. Process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1 or 2, characterized in that, In step S1, the substitution reaction is performed by first mixing ethyl acetoacetate, the basic substance and the solvent, stirring at 30-60℃ for 0.8-1.2 hours, then adding 3, 5-dichloro-4-fluoro nitrobenzene in batches, and directly obtaining a reaction system containing ethyl 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutanoate after the reaction of 3, 5-dichloro-4-fluoro nitrobenzene is completed.

4. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, In step S2, the acidic condition is provided by concentrated hydrochloric acid; the molar ratio of ethyl 2-(2, 6-dichloro-4-nitrophenyl)-3-oxobutanoate to concentrated hydrochloric acid is 1:5-10; and the temperature of the hydrolysis reaction is 90-110℃.

5. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1 or 4, characterized in that, In step S2, the post-treatment steps after the completion of the hydrolysis reaction are adding water to the reaction system, performing multiple extractions with toluene to combine the organic layers, washing the organic layers with 4% sodium hydroxide aqueous solution multiple times, then drying the organic layers, and concentrating under reduced pressure to obtain 1-(2, 6-dichloro-4-nitrophenyl)-propyl-2-ketone.

6. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, In step S3, the nitro reduction reaction uses acetic acid as the reaction solvent and uses reduced iron powder as the reducing agent; the molar ratio of 1-(2, 6-dichloro-4-nitrophenyl)-propyl-2-ketone, reduced iron powder and acetic acid is 1:3:15-20; and the temperature of the nitro reduction reaction is 30-50℃.

7. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1 or 6, characterized in that, In step S3, the post-treatment step after the nitro reduction reaction is completed: filtering the reaction system, washing the filter cake with acetic acid multiple times, and combining the filtrate and the washing liquid; adding water to the combined liquid, extracting with dichloromethane multiple times, and collecting the organic layer; extracting the organic layer with a 10% mass fraction hydrochloric acid solution multiple times to obtain a hydrochloric acid layer; adjusting the pH of the hydrochloric acid layer to 10 with a 50% mass fraction sodium hydroxide aqueous solution, and extracting with dichloromethane multiple times to combine the organic layers; drying the organic layer, filtering, and concentrating under reduced pressure to obtain 1-(4-amino-2,6-dichlorophenyl)-propyl-2-ketone.

8. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, In step S4, the Sandmeyer reaction uses acetonitrile as the reaction solvent; the molar ratio of 1-(4-amino-2,6-dichloro-phenyl)-propyl-2-ketone, tert-butyl nitrite, and copper chloride to acetonitrile is 1:1-2:1-2:15-20; and the temperature of the Sandmeyer reaction is 50-80°C.

9. Process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1 or 8, characterized in that, In step S4, the post-treatment step after the Sandmeyer reaction is completed is: filtering the reaction system, adding a 5% mass fraction hydrochloric acid to the filtrate, extracting with methyl tert-butyl ether multiple times, and collecting the organic layer; washing the organic layer with a 5% mass fraction hydrochloric acid multiple times, then adding petroleum ether, anhydrous magnesium sulfate, and activated carbon to the organic layer, and stirring for 1 hour; filtering to remove solid impurities, and concentrating the filtrate under reduced pressure to obtain 1-(2,4,6-trichlorophenyl)-propyl-2-ketone.

10. The process for the preparation of l-(2,4,6-trichlorophenyl)-propan-2-one according to claim 1, characterized in that, During the reaction, the progress of the raw materials is monitored by liquid chromatography.

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