Preparation method of topramezone intermediate and preparation method of topramezone

Abstract

The invention discloses a preparation method of a topramezone intermediate and a preparation method of topramezone, and belongs to the technical field of organic synthesis. The preparation method of the topramezone intermediate has the advantages of easily available initial raw materials, simple reaction route, high total yield of the product, mild reaction conditions, high reliability, high repeatability and high safety, and is more suitable for large-scale industrial production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and in particular to a preparation method of an intermediate of pyrazogeton and a preparation method of pyrazogeton. Background Art

[0002] Pyrazogeton is the first benzyl pyrazolone herbicide developed by BASF. It is widely used for controlling annual gramineous and broad-leaved weeds in corn fields. At present, its application scope has gradually expanded to crops such as rice and sugarcane, and its market share has been rapidly increased. Pyrazogeton has excellent efficacy and broad market prospects, but its extremely difficult synthesis process makes its price high, thus limiting its wide use. Therefore, it is urgent to explore new synthesis methods and industrialization plans for pyrazogeton.

[0003] Currently, pyrazogeton is mainly prepared by coupling the key intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid with N-methyl-5-hydroxypyrazole. Its synthesis route is usually as follows: 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (Compound 1) is converted into an acyl chloride, and then directly acylated with pyrazole to prepare pyrazogeton. This step is suitable for industrial production and has a relatively high yield (the reported value in the literature is 92%).

[0004]

[0005] Preparation of pyrazogeton from Compound 1

[0006] It can be seen that the key to the synthesis of pyrazogeton is to prepare the intermediate 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid. This intermediate is a tetrasubstituted benzene compound, and its four substituents are different and arranged adjacent to each other in sequence, so its synthesis is extremely difficult. In the existing process methods, the methyl group in Compound 1 is generally carried by the raw material; the methylsulfonyl group is generally obtained by oxidizing methyl sulfide; Isoxazole The five-membered ring is generally prepared by first oxidizing methyl to an oxime with n-butyl nitrite, then chlorinating and cyclizing with ethylene; the carboxylic acid is usually introduced subsequently. Generally speaking, the synthesis route of Compound 1 is usually long. Currently, the more classic synthesis routes include the following four:

[0007] Route 1: Starting from 2,3-dimethylbenzyl methyl sulfide (this raw material cannot be directly purchased and still needs to be prepared by oneself), through acylation, oxidation with hydrogen peroxide, oxidation with hypochlorous acid, esterification, chlorination with NBS, oxidation with nitrogen oxides to aldehyde, condensation with hydroxylamine to oxime, cyclization, and hydrolysis to obtain Compound 1. The route has a total of 9 steps (excluding the self-preparation step of the starting material), and the total yield is about 16%.

[0008]

[0009] Routes 2 and 3: Routes 2 and 3 were designed and developed by Li Lin et al. (CN110183392A). Starting from commercially available 2-methyl-6-nitrobenzonitrile, the product was obtained through the following 7-step reactions. The first three steps of the two routes are the same. Using sodium methanethiolate as the raw material, the key intermediate 4-carboxy-3-methyl-2-cyanobenzenemethanethiol was prepared through nitro substitution reaction, bromination, and Grignard reaction. Then, Route 2 first underwent oximation, chlorination, and cyclization to form an isoxazole five-membered ring, and then was oxidized by peroxide to obtain intermediate compound 1. While Route 3 first oxidized methanethiol to methylsulfonyl, then formed an oxime, chlorinated, and cyclized to obtain intermediate compound 1. The two routes only differ in the reaction sequence, and the overall yields are not very different, with the total yield between 20% and 24%. The disadvantage of these two synthetic routes is that the selectivity of the bromination reaction is poor, and a Grignard reaction is required to introduce a carboxylic acid substituent.

[0010]

[0011] Routes 2 and 3

[0012] Route 4: Using 2,3-dimethylbenzenemethanethiol as the starting material (this raw material cannot be directly purchased and still needs to be prepared), it was chlorinated with thionyl chloride, oxidized with hydrogen peroxide, oximated with n-butyl nitrite, and then chlorinated with NSC, cyclized, cyanide-substituted, and hydrolyzed to obtain intermediate compound 1. However, this route requires the use of dangerous sulfonyl chloride and aluminum trichloride for the chlorination reaction, and highly toxic cuprous cyanide or sodium cyanide is also required to introduce a carboxyl group and react at 100 °C for 24 h, with relatively large industrial conversion limitations.

[0013]

[0014] Route 4

[0015] The above 4 synthetic routes show that the synthetic route of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid is relatively long, all requiring about 10 steps of reaction, and the starting materials such as 2,3-dimethylbenzenemethanethiol and 2-methyl-6-nitrobenzonitrile are not easily commercially available and are expensive. In addition, in order to introduce a carboxyl group on the aromatic ring, the route often contains various dangerous reactions or reagents such as Grignard reaction, copper cyanide, and sodium hypochlorite oxidation, which is not conducive to industrial conversion.

[0016] Therefore, the research and development of a new preparation method for the key intermediate of benzobicyclon, 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid (Compound 1), is of great significance for the wide application of benzobicyclon. Summary of the Invention

[0017] In view of this, the technical problem to be solved by the present invention is to provide a preparation method of a benzobicyclon intermediate and a preparation method of benzobicyclon. The starting materials of the preparation method are easily available, the reaction conditions are mild, and the reliability, repeatability and safety are relatively high, which is suitable for large-scale industrial production.

[0018] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0019] The present invention provides a preparation method of a benzobicyclon intermediate, comprising the following steps:

[0020] (1) Under an alkaline environment, reacting 4-chloro-3-fluorotoluene with a soluble methyl mercaptide to prepare 4-chloro-3-methylthiotoluene;

[0021] (2) Performing a Friedel-Crafts alkylation reaction on 4-chloro-3-methylthiotoluene and carbon tetrachloride under the action of a catalyst to prepare 4-chloro-3-methylthio-6-trichloromethyltoluene;

[0022] (3) Reacting an acylating reagent obtained by mixing DMF and POCl 3 with 4-chloro-3-methylthio-6-trichloromethyltoluene to prepare 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde;

[0023] (4) Reacting 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde with hydroxylamine hydrochloride to form an intermediate oxime, and then successively performing a chlorination reaction and a cyclization reaction with ethylene to obtain an intermediate, namely 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole;

[0024] (5) Sequentially oxidizing and photocatalytically dechlorinating the intermediate obtained in step (4) to obtain 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, and then performing acid hydrolysis to obtain a benzobicyclon intermediate, namely 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid.

[0025] In the above preparation method, the 4-chloro-3-fluorotoluene in step (1) is prepared by chlorinating m-fluorotoluene.

[0026] The alkaline environment in step (1) is provided by one or more of, including but not limited to, potassium carbonate, potassium carbonate, etc.

[0027] The reaction temperature in step (1) is preferably 35°C - 45°C.

[0028] Preferably, the soluble methyl mercaptide in step (1) is selected from sodium methyl mercaptide or potassium methyl mercaptide.

[0029] Preferably, the catalyst in the step (2) is selected from the mixture of Lewis acid and strongly acidic ion exchange resin;

[0030] Preferably, the mass ratio of the Lewis acid to the strongly acidic ion exchange resin is 1:(0.3 - 1.5); more preferably 1:1.

[0031] Preferably, the strongly acidic ion exchange resin contains sulfonic acid group and also contains styryl or acrylate group. Specifically, it includes but is not limited to D001H strongly acidic hydrogen - type sulfonic acid - based cation exchange resin or 01 - type styryl - based strongly acidic ion exchange resin, etc.

[0032] Preferably, the Lewis acid in the present invention is selected from one or more of AlCl 3 , boron trifluoride etherate, zinc chloride.

[0033] Preferably, the molar ratio of 4 - chloro - 3 - (methylthio)toluene to carbon tetrachloride in the step (2) is 1:(15 - 30).

[0034] Preferably, the temperature of the Friedel - Crafts alkylation reaction in the step (2) is 50°C - 70°C. Preferably, in the present invention, the molar ratio of DMF to POCl 3 in the acylation reagent mixed in the step (3) is 1:(1 - 3); more preferably 1:1. 3 Preferably, the molar ratio of 4 - chloro - 3 - (methylthio)-6 - (trichloromethyl)toluene to POCl

[0035] in the step (3) is 1:(18 - 22); more preferably 0.1:2. 3 Preferably, the temperature of the reaction in the step (3) is 75°C - 85°C; more preferably 80°C.

[0036] More preferably, in the present invention, the chlorination reaction in the step (4) is specifically:

[0037] Carry out the chlorination reaction on the intermediate oxime with the mixed solution of CH

[0038] Cl 2 and H 2 O, and aqueous NaClO solution. 2 Preferably, the oxidant in the step (5) is selected from hydrogen peroxide and / or sodium tungstate; more preferably hydrogen peroxide and sodium tungstate.

[0039] Preferably, the solvent in the step (5) is selected from glacial acetic acid.

[0040]

[0041] ​Preferably, the catalyst for photocatalytic dechlorination in step (5) is selected from potassium tert-butoxide or sodium tert-butoxide;

[0042] Preferably, the temperature for photocatalytic dechlorination in step (5) is 30°C - 40°C. In some specific embodiments of the present invention, it is 35°C.

[0043] The light for photocatalytic dechlorination in step (5) can be obtained by irradiating with blue LED, and the wavelength of the light is 200 - 550 nm.

[0044] Preferably, the acidifying reagent for acid hydrolysis in step (5) is selected from concentrated hydrochloric acid;

[0045] Preferably, the catalyst for acid hydrolysis is selected from ferric chloride or zinc chloride. In some specific embodiments of the present invention, the catalyst for acid hydrolysis is ferric chloride.

[0046] Preferably, the temperature for acid hydrolysis is 30°C - 40°C. In some specific embodiments of the present invention, it is 35°C.

[0047] In the above preparation method, in step (5), the intermediate 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole (i.e., intermediate 7) obtained in step (4) is oxidized to obtain 3-(3-chloro-6-methyl-2-(methylsulfonyl)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole (i.e., intermediate 8).

[0048] Then, the intermediate 8 is subjected to a photocatalytic dechlorination reaction to obtain 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole (i.e., intermediate 9).

[0049] Finally, the intermediate 9 is subjected to acid hydrolysis to obtain the intermediate of benzobicyclon.

[0050] The present invention also provides a preparation method of benzobicyclon, comprising the following steps:

[0051] (1) The intermediate of benzobicyclon is prepared by using the above preparation method of the intermediate of benzobicyclon;

[0052] (2) The intermediate of benzobicyclon obtained in step (1) is subjected to a coupling reaction with N-methyl-5-hydroxypyrazole to prepare benzobicyclon.

[0053] By adopting the above preparation method of the intermediate of benzobicyclon, the yield of the total synthesis route for preparing benzobicyclon is increased, and no other dangerous reagents are used, and the requirements for the process equipment for preparing benzobicyclon are also significantly reduced.

[0054] Compared with the prior art, the preparation method of the topramezone intermediate provided by the present invention comprises the following steps: (1) reacting 4-chloro-3-fluorotoluene with soluble methyl mercaptide in an alkaline environment to prepare 4-chloro-3-methylthiotoluene; (2) carrying out a Friedel-Crafts alkylation reaction on 4-chloro-3-methylthiotoluene and carbon tetrachloride under the action of a catalyst to prepare 4-chloro-3-methylthio-6-trichloromethyltoluene; (3) reacting a mixed acylating reagent of DMF and POCl 3 with 4-chloro-3-methylthio-6-trichloromethyltoluene to prepare 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde; (4) reacting 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde with hydroxylamine hydrochloride to form an intermediate oxime, and then successively carrying out a chlorination reaction and a cyclization reaction with ethylene to obtain an intermediate, namely 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole; (5) successively oxidizing and photocatalytically dechlorinating the intermediate obtained in step (4) to obtain 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, and then carrying out acid hydrolysis to obtain a topramezone intermediate, namely 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid. The preparation method of the topramezone intermediate has easily available starting materials, a simple reaction route, a relatively high overall yield of the product, mild reaction conditions, high reliability, repeatability and safety, and is more suitable for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 1H NMR spectrum of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid prepared in Example 1;

[0056] Figure 2 Mass spectrum of 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid prepared in Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0057] To further illustrate the present invention, the preparation method of the topramezone intermediate and the preparation method of topramezone provided by the present invention will be described in detail below with reference to examples.

[0058] The sources of the following reaction raw materials are not particularly limited and are all ordinary commercially available products.

[0059] Example 1

[0060] (1) Add m-fluorotoluene (0.1 mol) and L-type molecular sieve (1.5 g) into the reaction flask, introduce chlorine gas (5 at), react at 110 °C for 3 h. When the gas phase detection shows that the m-fluorotoluene has completely reacted, stop the reaction. Filter and recover the molecular sieve, and directly input the filtrate (containing 4-chloro-3-fluorotoluene) into the next reaction step.

[0061] (2) Dissolve the filtrate (containing 4-chloro-3-fluorotoluene) obtained in the previous step in DMA (15 mL), add sodium methyl mercaptide (0.3 mol) and potassium carbonate (0.1 mol), and keep stirring and reacting at 40 °C for 12 h. Then add 30 mL of water and 30 mL of dichloromethane to the reaction solution, separate the layers, and collect the organic phase. Wash the separated organic layer with saturated sodium chloride aqueous solution, and dry with Na 2 SO 4 Filter and concentrate to obtain a milky yellow intermediate 3, which is 4-chloro-3-(methylthio)toluene, with a yield of 92%.

[0062] (3) Add AlCl 3 (15 g), D001H strongly acidic hydrogen sulfonic acid group cation exchange resin (15 g), zeolite (15 g) and 200 mL of CCl 4 into a 500 mL reaction flask, heat to 60 °C, and stir to obtain a slurry; dissolve the above intermediate 3 (0.1 mol) in 30 mL of CCl 4 , and then drop it into the aforementioned reaction flask. The dropping is completed in about 1 h, and then keep reacting for 1 h. Cool to room temperature, slowly drop 300 mL of ice water into the reaction solution to quench the reaction, and extract the organic phase with dichloromethane. Wash the separated organic layer with saturated sodium chloride aqueous solution, and dry with Na 2 SO 4 Filter, quickly filter and wash the filtrate with 300-mesh silica gel, concentrate under reduced pressure to about 10 mL, let it stand for crystallization to obtain a white solid intermediate 4, which is 4-chloro-3-(methylthio)-6-(trichloromethyl)toluene, with a yield of 86%.

[0063] (4) Drop POCl 3 (2.0 mol) into DMF (2.0 mol) under ice-water bath conditions, stir for 1 h, then dissolve the above intermediate 4 (0.1 mol) in 50 mL of DMF solution, and drop the obtained solution into the aforementioned POCl 3 solution. After dropping, stir and react the reaction solution overnight under an 80 °C oil bath condition. Cool the reaction solution, prepare 3 L of sodium hydroxide aqueous solution (2 mol / L), add it to the above reaction system under ice-water bath, neutralize the solution to pH 6 - 8 (universal test paper), and carry out hydrolysis reaction for 2 h under ice-water bath. Extract the organic phase of the reaction solution with dichloromethane (300 mL * 3), wash the separated organic layer with saturated sodium chloride aqueous solution, and dry with Na2 SO 4 Dry, filter, concentrate, and quickly filter and wash the residue with 300-mesh silica gel to obtain Intermediate 5, which is 2-methyl-3-trichloromethyl-5-chloro-6-methylthio benzaldehyde, with a yield of 85%.

[0064] (5) Dissolve the above Intermediate 5 (0.1 mol) in 200 mL of a methanol / water mixture (1:1, v / v), then add sodium carbonate (0.1 mol) and hydroxylamine hydrochloride (0.1 mol), and stir the reaction at room temperature for 12 h. Distill off methanol under reduced pressure, cool to room temperature, precipitate will form, filter to obtain oxime Intermediate 6. Add oxime Intermediate 6 to a high-pressure reactor containing a CH 2 Cl 2 / H 2 O (200 mL / 200 mL) mixed solution, add an aqueous solution of NaClO (0.13 mol), displace the air in the reactor with ethylene, stabilize the pressure at 2.0 MPa, and stir the reaction at room temperature for 24 h. Stop the reaction, extract the reaction solution with CH 2 Cl 2 (300 mL * 3), combine the organic layers and dry with anhydrous Na 2 SO 4 Dry, filter, and concentrate to obtain a yellow oily substance, Intermediate 7, which is 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 85%.

[0065] (6) Dissolve the above Intermediate 7 (0.1 mol) in glacial acetic acid (40 mL) and add sodium tungstate (0.7 g, 0.02 mol), heat to 100 °C and reflux, and add H 2 O 2 (0.3 mol) dropwise over 1 h, react for half an hour. After monitoring the reaction to completion by gas chromatography-mass spectrometry, pour the reaction solution into ice water (100.0 mL), precipitate will form, filter to obtain a yellow Intermediate 8, which is 3-(3-chloro-6-methyl-2-(methylsulfonyl)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 95%.

[0066] (7) Dissolve the above Intermediate 8 (0.1 mol) in anhydrous DMF (100 mL), and add t BuOK (0.25 mol), heat to 35 °C, and keep the reaction at this temperature under the irradiation of a blue LED (405 nm, 27 W) and under nitrogen protection for 10 h. Stop the reaction, pour the reaction solution into ice water (250 mL), precipitate will form, filter to obtain a yellow Intermediate 9, which is 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 90%.

[0067] (8) Dissolve the above intermediate 9 (0.1 mol) in acetonitrile (100 mL), add 30 mL of concentrated hydrochloric acid and a catalytic amount of ferric chloride, heat to 35 °C, and keep the reaction at this temperature for 3 h. Stop the reaction, remove acetonitrile under reduced pressure, and extract the residue with CH 2 Cl 2 (300 mL * 3). The organic layer is dried over anhydrous Na 2 SO 4 , filtered, and concentrated to obtain product 10, which is 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, with a yield of 86%. ESI-MS: m / z [M + H] + = 284.05420. 1 H NMR (400 MHz, DMSO) δ 13.64 (br, 1H), 7.61 - 7.96 (m, 2H), 4.44 (t, J = 7.2 Hz, 2H), 3.37 (t, J = 7.2 Hz, 2H), 3.23 (s, 3H), 2.35 (s, 3H).

[0068]

[0069] Example 2

[0070] (1) Add m-fluorotoluene (0.1 mol) and L-type molecular sieve (1.5 g) to a reaction flask, introduce chlorine gas (5 at), and react at 110 °C for 1 h. Stop the reaction when gas-phase detection shows that m-fluorotoluene has completely reacted. Filter and recover the molecular sieve, and directly use the filtrate (containing 4-chloro-3-fluorotoluene) in the next step of the reaction.

[0071] (2) Dissolve the filtrate obtained in the previous step (containing 4-chloro-3-fluorotoluene) in DMA (15 mL), add sodium methyl mercaptide (0.3 mol) and potassium hydroxide (0.1 mol), and keep stirring and reacting at 90 °C for 5 h. Cool the reaction solution, then add 30 mL of water and 30 mL of dichloromethane to the reaction solution, separate the layers, and collect the organic phase. Wash the separated organic layer with saturated sodium chloride aqueous solution, and dry it over Na 2 SO 4 , filter, and concentrate to obtain a milky yellow intermediate 3, which is 4-chloro-3-(methylthio)toluene, with a yield of 96%.

[0072] (3) Add boron trifluoride-ether (15 g), 01 type styrene-based strongly acidic ion exchange resin (15 g), and 200 mL of CCl 4 to a 500 mL reaction flask, heat to 60 °C, and stir to obtain a slurry; dissolve the above intermediate 3 (0.1 mol) in 30 mL of CCl 4Then, it was added dropwise to the aforementioned reaction flask, and the addition was completed in about 1 h. Then, the reaction was carried out under heat preservation for 1 h. After cooling to room temperature, 300 mL of ice water was slowly added dropwise to the reaction solution to quench the reaction, and the organic phase was extracted with dichloromethane. The separated organic layer was washed with saturated sodium chloride aqueous solution, Na 2 SO 4 dried, filtered, and the filtrate was quickly filtered through 300-mesh silica gel and concentrated under reduced pressure to about 10 mL. It was allowed to stand for crystallization, and a white solid intermediate 4, namely 4-chloro-3-methylthio-6-trichloromethyltoluene, was obtained with a yield of 93%.

[0073] (4) POCl 3 (3.0 mol) was added dropwise to DMF (3.0 mol) under an ice-water bath condition and stirred for 1 h. Then, the above intermediate 4 (0.1 mol) was dissolved in 50 mL of DMF solution, and the obtained solution was added dropwise to the aforementioned POCl 3 solution. After the addition was completed, the reaction solution was stirred and reacted overnight under an 80 °C oil bath condition. The reaction solution was cooled, and 3 L of sodium hydroxide aqueous solution (2 mol / L) was prepared and added to the above reaction system under an ice-water bath. The solution was neutralized to pH 6 - 8 (universal test paper), and a hydrolysis reaction was carried out for 2 h under an ice-water bath. The reaction solution was extracted with dichloromethane for the organic phase (300 mL * 3), and the separated organic layer was washed with saturated sodium chloride aqueous solution, Na 2 SO 4 dried, filtered, concentrated, and the residue was quickly filtered through 300-mesh silica gel to obtain intermediate 5, namely 2-methyl-3-trichloromethyl-5-chloro-6-methylthio benzaldehyde, with a yield of 88%.

[0074] (5) The above intermediate 5 (0.1 mol) was dissolved in 200 mL of methanol / water mixed solution (1:1, v / v), then sodium hydroxide (0.1 mol) and hydroxylamine hydrochloride (0.1 mol) were added, and the reaction was stirred at room temperature for 12 h. Methanol was distilled off under reduced pressure, and after cooling to room temperature, a precipitate was formed. It was filtered to obtain oxime intermediate 6. The oxime intermediate 6 was added to a high-pressure autoclave containing a CH 2 Cl 2 / H 2 O (200 mL / 200 mL) mixed solution, and an aqueous sodium hypochlorite solution (0.13 mol) was added. The air in the autoclave was displaced with ethylene, the pressure was stabilized at 2.0 MPa, and the reaction was stirred at room temperature for 24 h. The reaction was stopped, and the reaction solution was extracted with CH 2 Cl 2 (300 mL * 3), the organic layers were combined and dried with anhydrous Na 2 SO 4It was dried, filtered, and concentrated to obtain a yellow oily intermediate 7, which was 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 85%.

[0075] (6) Using the intermediate 7 obtained in the previous step as the raw material, and the other operations were the same as those in step (6) of Example 1. The yellow intermediate 8 was obtained, which was 3-(3-chloro-6-methyl-2-(methylsulfonyl)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 95%.

[0076] (7) Dissolve the above intermediate 8 (0.1 mol) in anhydrous DMF (100 mL), and add t BuOK (0.25 mol), heat to 35 °C, and keep the reaction under the irradiation of a blue LED (200 nm, 27 W) and under nitrogen protection for 10 h. Stop the reaction, pour the reaction solution into ice water (250 mL), and a solid precipitated. Filter to obtain the yellow intermediate 9, which was 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, with a yield of 94%.

[0077] (8) Using the intermediate 9 obtained in the previous step as the raw material, and the other operations were the same as those in step (8) of Example 1. The product 10 was obtained, which was 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid, with a yield of 86%.

[0078] The description of the above examples is only used to help understand the method of the present invention and its core idea. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing a fenpyroxetine intermediate, characterized in that: The following steps are involved: (1) Under alkaline conditions, 4-chloro-3-fluorotoluene is reacted with soluble methyl mercaptan salt to prepare 4-chloro-3-methylthiotoluene; (2) subjecting 4-chloro-3-methylthiotoluene to a Friedel-Crafts alkylation reaction with carbon tetrachloride in the presence of a catalyst to prepare 4-chloro-3-methylthio-6-trichloromethyltoluene; (3) reacting an acylating agent mixed with DMF and POCl3 with 4-chloro-3-methylthio-6-trichloromethyltoluene to prepare 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde; (4) reacting 2-methyl-3-trichloromethyl-5-chloro-6-methylthiobenzaldehyde with hydroxylamine hydrochloride to form an intermediate oxime, and then sequentially subjecting the reaction to a chlorination reaction and a cyclization reaction with ethylene to obtain an intermediate, namely 3-(3-chloro-6-methyl-2-(methylthio)-5-(trichloromethyl)phenyl)-4,5-dihydroisoxazole; (5) The intermediate obtained in step (4) is subjected to oxidation and photocatalytic dechlorination in sequence to obtain 3-(2-methyl-6-(methylsulfonyl)-3-(trichloromethyl)phenyl)-4,5-dihydroisoxazole, and then acidified and hydrolyzed to obtain the fenpyroxene intermediate, namely 3-(4,5-dihydro-3-isoxazolyl)-2-methyl-4-(methylsulfonyl)benzoic acid.

2. The preparation method according to claim 1, characterized in that: The soluble methyl mercaptan salt in step (1) is selected from sodium methyl mercaptan or potassium methyl mercaptan; The catalyst in step (2) is selected from a mixture of Lewis acid and strongly acidic ion resin; The mass ratio of the Lewis acid to the strong acid ion resin is 1:(0.3-1.5); The strong acid ion resin contains a sulfonic acid group and also contains a styrene group or an acrylate group.

3. The preparation method according to claim 2, characterized in that: The Lewis acid is selected from one or more of AlCl3, boron trifluoride etherate, and zinc chloride.

4. The preparation method according to any one of claims 1 to 3, characterized in that In the step (2), the molar ratio of 4-chloro-3-methylthiotoluene to carbon tetrachloride is 1:(15-30); The temperature of the Friedel-Crafts alkylation reaction in step (2) is 50°C-70°C.

5. The preparation method according to claim 1, characterized in that: The molar ratio of DMF to POCl3 in the acylating agent mixed with DMF and POCl3 in step (3) is 1:(1-3); In the step (3), the molar ratio of 4-chloro-3-methylthio-6-trichloromethyltoluene to POCl3 is 1:(18-22); The reaction temperature of step (3) is 75°C-85°C.

6. The preparation method according to claim 1, characterized in that: The chlorination reaction in step (4) is specifically: A mixed solution of CH2Cl2 and H2O, an aqueous solution of NaClO and the intermediate oxime are subjected to chlorination reaction.

7. The preparation method according to claim 1, characterized in that: The oxidant in step (5) is selected from hydrogen peroxide and / or sodium tungstate; The solvent in step (5) is selected from glacial acetic acid.

8. The preparation method according to claim 1, characterized in that: The catalyst for photocatalytic dechlorination in step (5) is selected from potassium tert-butoxide or sodium tert-butoxide; The temperature of the photocatalytic dechlorination in step (6) is 30°C-40°C.

9. The preparation method according to claim 1, characterized in that: The acidifying agent for acidification and hydrolysis in step (5) is selected from concentrated hydrochloric acid; The catalyst for the acidification hydrolysis is selected from ferric chloride or zinc chloride; The temperature of the acidification hydrolysis is 30°C-40°C.

10. A method for preparing fenpyrazone, characterized in that: The following steps are involved: (1) preparing a fenpyrazone intermediate by the method for preparing a fenpyrazone intermediate according to claim 1; (2) coupling the fenpyrazone intermediate obtained in step (1) with N-methyl-5-hydroxypyrazole to prepare fenpyrazone.

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