5,5-dimethyl-4,5-dihydroisoxazole-3-thione and a synthesis method, application thereof

Abstract

The application relates to 5,5-dimethyl-4,5-dihydroisoxazole-3-thione and a synthesis method and application thereof, and belongs to the technical field of pesticide intermediate preparation. 5,5-dimethyl-4,5-dihydroisoxazole-3-thione is prepared by reacting 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole with sulfur powder under copper catalysis, then the intermediate is used to prepare 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole by reacting with 5-difluoromethoxy-1-methyl-3-trifluoromethyl-4-chloromethylpyrazole in an alkaline environment. The method provided by the application simplifies the synthesis process, has fast reaction speed, mild reaction condition, relatively simple synthesis and post-treatment process, low impurity content, high product yield and the like.

Description

Technical Field

[0001] The present invention relates to a sulfonepyrazoline intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione and a synthesis method and application thereof, and particularly to a synthesis method of a new sulfonepyrazoline intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione and 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole, belonging to the technical field of pesticide intermediate preparation. Background Art

[0002] Pyroxasulfone is an isoxazole herbicide developed by Kumihiko Chemical Co., Ltd. of Japan. Its chemical name is 3-[5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl]-4,5-dihydro-5,5-dimethyl-1,2-isoxazole, and its molecular formula is C 12 H 14 F5N3O4S, with a molecular weight of 391.32 and a CAS registration number of 447399-55-5. Sulfonepyraclostrobin has attracted widespread attention due to its broad spectrum of weed control, high activity, low dosage, and good safety. Sulfonepyraclostrobin can be used as a pre-emergence soil treatment agent in most crop fields. As a very-long-chain fatty acid elongase synthase inhibitor herbicide, it exerts its efficacy by inhibiting very-long-chain fatty acid elongase synthase (VLCFAE). It inhibits the biosynthetic pathway of VLCFAE in plants, converting stearic acid to arachidic acid, arachidic acid to behenic acid, behenic acid to tetracosanoic acid, tetracosanoic acid to ceric acid, and ceric acid to montanic acid, ultimately inhibiting the synthesis of myristic acid. Its structure is as follows:

[0003]

[0004] Currently, there are few reports on the synthesis of sulfonepyrazoline. Patent CN102666502 discloses the following process: Under alkaline conditions, 1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-ol, aqueous formaldehyde solution, and 5,5-dimethyl-4,5-dihydroisoxazolesulfonamidine hydrochloride are condensed in water to produce intermediate A. Intermediate A is then alkylated with difluorochloromethane to produce intermediate B. Intermediate B is oxidized with hydrogen peroxide to produce sulfonepyrazoline. The reaction formula is as follows:

[0005]

[0006] The above process route uses 5,5-dimethyl-4,5-dihydroisoxazolesulfonamidine hydrochloride as an intermediate. During the reaction of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-ol, formaldehyde aqueous solution and 5,5-dimethyl-4,5-dihydroisoxazolesulfonamidine hydrochloride, a large amount of ammonia nitrogen wastewater will be generated, which will damage the ecological environment, cause eutrophication of water bodies and loss of water balance, and even have toxic effects on people and organisms.

[0007] Patent CN115335375A discloses a method for synthesizing a sulfonepyrazoline intermediate, wherein an isoxazole of formula (II) is reacted with a sulfurizing agent to produce an S-substituted thioisoxazole of formula (III). Finally, the thioisoxazole is combined with a pyrazole of formula (IV) to obtain a sulfonepyrazoline intermediate of formula (I). The reaction scheme is as follows:

[0008]

[0009] The sulfiding reagents used in the synthesis of S-substituted thioisoxazoles of formula (III) in the above-mentioned route include dimethylthioformamide, thiosulfate, dithiooxamide, alkyl xanthate, thiobenzamide, N-substituted thiourea and thioacetate, etc., which are expensive and need to be completed under nitrogen protection. The reaction operation is complicated, the synthesized thioisoxazole is not easy to store, and has low industrial practical value. Summary of the Invention

[0010] Aiming at the shortcomings of the intermediates used in the synthesis of sulfonepyraclostrobin in the existing process, the present invention provides a novel sulfonepyraclostrobin intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione.

[0011] The present invention also provides a method for synthesizing the above-mentioned sulfonepyraclostrobin intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione. The method uses a simple sulfur source, has a high atomic utilization rate, avoids a large amount of ammonia nitrogen wastewater or other organic waste, is good for the environment, and the conditions of the entire reaction route are moderate, the post-processing method is simple, and the operability is strong, and the method has good industrial practical value.

[0012] Another object of the present invention is to provide a method for preparing 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole using 5,5-dimethyl-4,5-dihydroisoxazole-3-thione.

[0013] The technical solution adopted by the present invention to achieve the above-mentioned purpose is: (Claims)

[0014] The present invention provides a 5,5-dimethyl-4,5-dihydroisoxazole-3-thione having the structural formula shown in formula (2):

[0015] .

[0016] The present application also provides a synthesis method of the above-mentioned 5,5-dimethyl-4,5-dihydroisoxazole-3-thione, which comprises the following steps: i) reacting 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole of formula (1) with sulfur powder under alkaline conditions in the presence of a catalyst to obtain 5,5-dimethyl-4,5-dihydroisoxazole-3-thione; and ii) acidifying the 5,5-dimethyl-4,5-dihydroisoxazole-3-thione obtained in step i).

[0017] The specific reaction formula is as follows:

[0018] .

[0019] Further, in the formula (1) of step i), X is chlorine or bromine.

[0020] The raw material compound of formula (1) used in the present application can be prepared according to the method disclosed in the literature: Journal of Agricultural and Food Chemistry (2008), 56(22), 10805-10810, patent CN101389625A.

[0021] Further, the catalyst of step i) is a copper-based metal catalyst; and the copper-based metal catalyst is cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide.

[0022] Further, in step i), the base used in the alkaline condition is sodium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; preferably, the concentration of the tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide used is 40%wt.

[0023] Further, in step i), the acid used in the acidification is hydrochloric acid; preferably, the concentration of the hydrochloric acid is 5-7%wt.

[0024] Further, in step i), the molar ratio of the 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole to sulfur powder is 1.0:2.0-4.0; the molar ratio of the 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole to the catalyst is 1.0:0.05-0.15; and the molar ratio of the 3-halogenated-5,5-dimethyl-4,5-dihydroisoxazole to the base is 1.0:2.1-2.5.

[0025] Further, in step i), the temperature of the catalytic reaction is 60-80°C.

[0026] Further, the catalytic reaction is carried out in a solvent.

[0027] The solvent is a nitrile solvent or an amide solvent; preferably, the solvent is acetonitrile, DMF or DMAC; most preferably, the solvent is acetonitrile.

[0028] Further, in the process i, the acid used in the acidification process is adjusted to the reaction end point pH = 6 ~ 8 shown in process i.

[0029] The present application also provides a method for preparing 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl) methylthio]-4,5-dihydro-5,5-dimethylisoxazole using the above-mentioned sulfentrazone intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione; the 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl) methylthio]-4,5-dihydro-5,5-dimethylisoxazole has a structural formula as shown in formula (4):

[0030] .

[0031] The present application also provides a synthesis method of the above-mentioned 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl) methylthio]-4,5-dihydro-5,5-dimethylisoxazole, which is obtained by reacting 5,5-dimethyl-4,5-dihydroisoxazole-3-thione shown in formula (2) with a compound shown in formula (3) under basic conditions, as shown in process ii, and the reaction formula is as follows:

[0032]

[0033] Further, the compound shown in formula (3) in the above-mentioned process ii can be prepared according to the method disclosed in patents WO2007 / 094225A1 and CN112969697A.

[0034] Further, in the process ii, the base used in the basic condition is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine or DBU.

[0035] Further, in the process ii, the molar ratio of the compound 5,5-dimethyl-4,5-dihydroisoxazole-3-thione shown in formula (2) to the compound shown in formula (3) is 1.01 ~ 1.0: 1.0, preferably the molar ratio is 1.07: 1.0; the molar ratio of formula (2) to the base shown in process ii is 1.0: 1.3 ~ 1.8.

[0036] Further, in the process ii, the temperature for the reaction of the compound 5,5-dimethyl-4,5-dihydroisoxazole-3-thione shown in formula (2) with the compound shown in formula (3) is 40 ~ 50℃.

[0037] Furthermore, step ii is carried out in a solvent; preferably, the solvent is an amide solvent or a nitrile solvent; most preferably, the solvent is DMF, DMAC or acetonitrile.

[0038] The novel intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione of the present invention and the specific route for synthesizing 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole using the intermediate are as follows:

[0039] .

[0040] Compared with the prior art, the present invention has the following advantages:

[0041] (1) The present invention provides a new intermediate of sulfonepyraclostrobin, 5,5-dimethyl-4,5-dihydroisoxazole-3-thione. The synthesis method provided by the present invention uses a simple sulfur source, has high atom utilization, avoids a large amount of organic waste, is good for the environment, has moderate conditions for the entire reaction route, and has a simple post-processing method with strong operability, and has good industrial practical value.

[0042] (2) The novel intermediate provided by the present invention is further used to prepare 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole. This method has the advantages of simplified synthesis process, fast reaction speed, mild reaction conditions, relatively simple synthesis and post-treatment processes, low impurity content, and high product yield. The novel intermediate 5,5-dimethyl-4,5-dihydroisoxazole-3-thione (2) provided by the present invention is used as a precursor for the synthesis of sulfonepyrazoline intermediate (4), avoiding many shortcomings of the 5,5-dimethyl-4,5-dihydroisoxazole sulfamidine hydrochloride intermediate. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 5,5-dimethyl-4,5-dihydroisoxazole-3-thione 1 H NMR spectrum;

[0044] Figure 2 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole 1 H NMR spectrum. DETAILED DESCRIPTION

[0045] The application will be further described in connection with the specific embodiments. The following description is only exemplary and does not limit the scope of protection. Other embodiments obtained by those skilled in the art without creative efforts based on the inventive concept of the application are within the scope of protection.

[0046] In the following examples, the raw materials used are commercially available products, unless otherwise specified.

[0047] In the following examples, the concentrations are mass percentages, unless otherwise specified.

[0048] In the following examples, the yield = actual mass of product x purity / theoretical mass of product.

[0049] Example 1

[0050] In a four-necked flask, 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole 16.69 g (0.1 mol, 80% purity), cuprous oxide 2.15 g (0.015 mol) and 30 g of acetonitrile were added at room temperature, stirred for 10 min, then placed at 0°C, and sodium hydroxide 8.7 g (0.21 mol) was added in portions, then warmed to 80°C and refluxed, sulfur powder 9.62 g (0.3 mol) was added in portions, and the reaction was carried out for 48 h. HPLC detection showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >60% (HPLC area %). After the reaction was completed, the reaction liquid was cooled to room temperature, filtered, 7% wt hydrochloric acid was added dropwise to adjust pH = 8, separated, and the organic phase was removed under reduced pressure to obtain a dark yellow solid 5.48 g, purity 75.5%, yield 31.53%. After recrystallization with ethyl acetate / methanol (v / v = 5:1), the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was obtained in a purity of 99%, a white-like solid, and the hydrogen spectrum is shown in Figure 1 1 H NMR (400 MHz, CDCl3): δ ppm 2.50 (s, 2H), 1.37 (s, 6H).

[0051] Example 2

[0052] ​At room temperature, 16.69 g (0.1 mol, 80% purity) of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, 1.43 g (0.01 mol) of cuprous bromide, and 30 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min and placing the mixture at 0°C, 162.16 g (0.25 mol) of 40% wt tetrabutylammonium hydroxide was slowly added dropwise. The temperature was then raised to 80°C, and 9.62 g (0.3 mol) of sulfur powder was added in batches. The reaction was continued for 30 h. HPLC analysis showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >65% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 8. The liquid was separated to obtain 7.56 g of dark yellow solid with a purity of 78.3% and a yield of 45.12%.

[0053] Example 3

[0054] At room temperature, 22.25 g (0.1 mol, 80% purity) of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole of formula (1) shown in step i, 1.43 g (0.01 mol) of cuprous bromide and 30 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min and placing at 0°C, 162.16 g (0.25 mol) of 40% wt tetrabutylammonium hydroxide was slowly added dropwise. The temperature was then raised to 80°C, and 9.62 g (0.3 mol) of sulfur powder was added in batches. The reaction was continued for 26 h. HPLC analysis showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >78% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 8. The liquids were separated and the organic phase was evaporated under reduced pressure to obtain 8.21 g of a dark yellow solid with a purity of 78.1% and a yield of 48.87%.

[0055] Example 4

[0056] At room temperature, 22.25 g (0.1 mol, 80% purity) of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, 1.33 g (0.007 mol) of cuprous iodide, and 30 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min and placing the mixture at 0°C, 162.16 g (0.25 mol) of 40% wt tetrabutylammonium hydroxide was slowly added dropwise. The temperature was then raised to 60°C, and 9.62 g (0.3 mol) of sulfur powder was added in batches. The reaction was continued for 18 h. HPLC analysis showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >93% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 8. The liquids were separated and the organic phase was evaporated under reduced pressure to obtain 12.31 g of a light yellowish-white solid with a purity of 95.1% and a yield of 89.23%.

[0057] Example 5

[0058] At room temperature, 22.25 g (0.1 mol, 80% purity) of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, 1.33 g (0.007 mol) of cuprous iodide, and 30 g of DMF were added to a four-necked reaction flask. After stirring for 10 min and placing the mixture at 0°C, 162.16 g (0.25 mol) of 40% wt tetrabutylammonium hydroxide was slowly added dropwise. The temperature was then raised to 60°C, and 9.62 g (0.3 mol) of sulfur powder was added in batches. The reaction was continued for 10 h. HPLC analysis showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >83% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature and filtered. 7% wt hydrochloric acid was added dropwise to the filtrate to adjust the pH to 8, and the solution was filtered. After 120 g of water was added to the filtrate, a white solid precipitated, which was filtered and dried to obtain 7.21 g of a light yellowish-white solid with a purity of 97.1% and a yield of 53.36%.

[0059] Example 6

[0060] At room temperature, 22.25 g (0.1 mol, 80% purity) of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, 1.33 g (0.007 mol) of cuprous iodide, and 30 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min and placing the mixture at 0°C, 56.96 g (0.25 mol) of 40% wt tetramethylammonium hydroxide was slowly added dropwise. The temperature was then raised to 60°C, and 9.62 g (0.3 mol) of sulfur powder was added in batches. The reaction was continued for 25 h. HPLC analysis showed that the raw material 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was <1% (HPLC area %), and the product 5,5-dimethyl-4,5-dihydroisoxazole-3-thione was >91% (HPLC area %). After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and 7% wt hydrochloric acid was added dropwise to adjust the pH to 8. The liquids were separated and the organic phase was evaporated under reduced pressure to obtain 10.05 g of a yellow solid with a purity of 94.8% and a yield of 72.62%.

[0061] Example 7

[0062] At room temperature, 20.85 g (0.067 mol, 85% purity) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole of formula (3) shown in step ii and 20 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min, 11.61 g (0.11 mol) of sodium carbonate was added. The temperature was lowered to 5°C, and a mixed solution of 5,5-dimethyl-4,5-dihydroisoxazole-3-thione in acetonitrile (33.2% wt, 5,5-dimethyl-4,5-dihydroisoxazole-3-thione 9.94 g, 0.072 mol, 95% purity, 20 g of acetonitrile) was added dropwise. The temperature was raised to 50°C, and the reaction was carried out for 5 h. The raw material 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was detected by HPLC to be <1% (HPLC area %). The product 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole>70% (HPLC area %). After the reaction, the reaction solution was cooled to room temperature, filtered, 30% wt hydrochloric acid was added dropwise to adjust the pH to neutral, the liquid was separated, and the organic phase was evaporated under reduced pressure to obtain 18.79 g of a dark red oily liquid with a purity of 79.4% and a yield of 61.97%. After purification using HPLC preparative liquid chromatography, a white solid was obtained with a purity of 99%. The hydrogen spectrum is as shown below. Figure 2 As shown: 1 H NMR (400MHz, CDCl3): δ ppm 6.75 (t, J = 91.9Hz, 1H), 4.19 (s, 2H), 3.82 (s, 3H), 2.79 (s, 2H), 1.42 (s, 6H).

[0063] Example 8

[0064] At room temperature, 20.85 g (0.067 mol, 85% purity) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole of formula (3) shown in step ii and 20 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min, 12.14 g (0.12 mol) of triethylamine was added. The temperature was lowered to 5°C, and a mixed solution of 5,5-dimethyl-4,5-dihydroisoxazole-3-thione in acetonitrile (33.2% wt, 9.94 g of 5,5-dihydroisoxazole-3-thione, 0.072 mol, 95% purity, and 20 g of acetonitrile was added dropwise. The temperature was raised to 50°C, and the reaction was carried out for 5 h. The raw material 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was detected by HPLC to be <1% (HPLC area %). The product, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole, was obtained in an amount greater than 85% (HPLC area %). After the reaction, the reaction solution was cooled to room temperature, filtered, and the pH was adjusted to neutral by adding 30% wt hydrochloric acid dropwise. The layers were separated, and the organic phase was evaporated under reduced pressure to yield 19.97 g of a dark red oily liquid with a purity of 81.1% and a yield of 67.27%.

[0065] Example 9

[0066] At room temperature, 20.85 g (0.067 mol, 85% purity) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole of formula (3) shown in step ii and 20 g of acetonitrile were added to a four-necked reaction flask. After stirring for 10 min, 18.27 g (0.12 mol) of DBU was added. The temperature was lowered to 5°C, and a mixed solution of 5,5-dimethyl-4,5-dihydroisoxazole-3-thione in acetonitrile (33.2% wt, 9.94 g of 5,5-dihydroisoxazole-3-thione, 0.072 mol, 95% purity, and 20 g of acetonitrile was added dropwise. The temperature was raised to 50°C, and the reaction was carried out for 6 h. The raw material 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was detected by HPLC to be <1% (HPLC area %). The product, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole, was found to be >93% (HPLC area %). After the reaction, the reaction solution was cooled to room temperature, filtered, and the pH was adjusted to neutral by adding 30% wt hydrochloric acid dropwise. The layers were separated, and the organic phase was evaporated under reduced pressure to obtain 23.64 g of yellow crystalline solid with a purity of 87.6% and a yield of 86.02%.

[0067] Example 10

[0068] At room temperature, 20.85 g (0.067 mol, 85% purity) of 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole of formula (3) shown in step ii and 20 g of DMF were added to a four-necked reaction flask. After stirring for 10 min, 16.58 g (0.12 mol) of potassium carbonate was added. The temperature was lowered to 5°C, and a DMF mixed solution of 5,5-dimethyl-4,5-dihydroisoxazole-3-thione (33.2% wt, 5,5-dimethyl-4,5-dihydroisoxazole-3-thione 9.94 g, 0.072 mol, 95% purity, DMF 20 g) was added dropwise. The temperature was raised to 50°C, and the reaction was carried out for 6 h. The raw material 4-chloromethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole was detected by HPLC to be <1% (HPLC area %). The product, 3-[(5-difluoromethoxy-1-methyl-3-trifluoromethylpyrazol-4-yl)methylthio]-4,5-dihydro-5,5-dimethylisoxazole, was obtained in >91% (HPLC area %). After the reaction, the reaction solution was cooled to room temperature, filtered, and the pH was adjusted to neutral by adding 30% wt hydrochloric acid dropwise. The mixture was separated, and the organic phase was washed with water two to three times to obtain 20.98 g of dark red crystalline solid with a purity of 87.8% and a yield of 76.51%.

Claims

1. A method for synthesizing 5,5-dimethyl-4,5-dihydroisoxazole-3-thione, characterized in that: The compound 3-halogeno-5,5-dimethyl-4,5-dihydroisoxazole represented by formula (1) is first catalyzed by a catalyst and then acidified to obtain formula (2); ； The catalyst is cuprous oxide, cuprous chloride, cuprous bromide or cuprous iodide.

2. The synthesis method according to claim 1, wherein In formula (1), X is chlorine or bromine.

3. The synthesis method according to claim 1, wherein Under alkaline conditions, the base used is sodium hydroxide, tetramethylammonium hydroxide, tetraethylammonium hydroxide or tetrabutylammonium hydroxide; during the acidification process, the acid used is hydrochloric acid with a concentration of 5-7%wt; the acidification uses acid to adjust the pH to 6-8.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the 3-halogenated 5,5-dimethyl-4,5-dihydroisoxazole to sulfur powder is 1.0:2.0-4.0; the molar ratio of the 3-halogenated 5,5-dimethyl-4,5-dihydroisoxazole to the catalyst is 1.0:0.05-0.15; and the molar ratio of the 3-halogenated 5,5-dimethyl-4,5-dihydroisoxazole to the base is 1.0:2.1-2.

5.

5. The synthesis method according to any one of claims 1 to 4, characterized in that The temperature of the catalytic reaction is 60-80° C.; the catalytic reaction is carried out in a solvent, which is acetonitrile, DMF or DMAC.

6. The synthesis method according to claim 5, characterized in that The solvent is acetonitrile.

7. A method for preparing a compound of formula (4) by using 5,5-dimethyl-4,5-dihydroisoxazole-3-thione prepared by the synthesis method according to any one of claims 1 to 6, characterized in that: The compound 5,5-dimethyl-4,5-dihydroisoxazole-3-thione represented by formula (2) is reacted with the compound represented by formula (3) under alkaline conditions to obtain; 。 8. The method according to claim 7, characterized in that In step ii, under alkaline conditions, the base used is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine or DBU.

9. The method according to claim 7, characterized in that In step ii, the molar ratio of the 5,5-dimethyl-4,5-dihydroisoxazole-3-thione to the compound represented by formula (3) is 1.01-1.10:1.0; the molar ratio of the 5,5-dimethyl-4,5-dihydroisoxazole-3-thione to the base is 1.0:1.3-1.

8.

10. The method according to claim 9, characterized in that In step ii, the molar ratio of the 5,5-dimethyl-4,5-dihydroisoxazole-3-thione to the compound represented by formula (3) is 1.07:1.

0.

11. The method according to claim 7, characterized in that The reaction temperature of step ii is 40-50° C.; the reaction is carried out in a solvent; the solvent is DMF, DMAC or acetonitrile.

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