Preparation method of 3-(3-bromo-2-methyl-6-methylsulfonyl phenyl)-4, 5-dihydroisoxazole

Abstract

The invention provides a preparation method of 3-(3-bromine-2-methyl-6-methylsulfonyl phenyl)-4, 5-dihydroisoxazole, and the preparation method comprises the following steps: (1) reacting 2, 3-dimethyl-4-methylsulfonyl bromobenzene with an oximation reagent to obtain a 3-bromine-2-methyl-6-methylsulfonyl benzaldoxime reaction solution; (2) mixing the 3-bromine-2-methyl-6-methylsulfonyl benzaldoxime reaction solution obtained in the step (1) with a chlorination reagent to react, so as to obtain a 3-bromine-2-methyl-6-methylsulfonyl benzaldoxime acyl chloride reaction solution; and (3) carrying out a ring closing reaction on the 3-bromo-2-methyl-6-methylsulfonyl benzoxime acyl chloride reaction solution obtained in the step (2) and ethylene, so as to obtain the 3-(3-bromo-2-methyl-6-methylsulfonyl phenyl)-4, 5-dihydroisoxazole. The preparation method is simple in operation steps, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of chemical synthesis and relates to a method for preparing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole. Background Art

[0002] Topramezon is the first benzoyl pyrazolone herbicide developed by BASF. It is the safest of all cornfield herbicides currently used. 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole is an important intermediate in the preparation of Topramezon.

[0003] BASF's WO9958509 application discloses a method for preparing this intermediate, using 2,3-dimethylaniline as a raw material to synthesize 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole through thioetherification, bromination, oxidation, oximation, chlorination and cyclization. The reaction route is as follows:

[0004]

[0005] The three steps of oximation, chlorination and cyclization in this method have the following disadvantages: 1. Post-oximation treatment includes neutralization, extraction, washing, solvent removal and drying, which is cumbersome; 2. After oximation and chlorination, the reaction solution is poured into a large amount of water, generating a large amount of wastewater (about 100 tons of wastewater / ton of product), and the solvent is difficult to recycle; 3. The two-step yield of chlorination to obtain 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride and cyclization to obtain 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole is only 57%, and the total yield of the three steps is 42%, which is low; 4. A variety of organic solvents are used in the extraction and purification process, and the pressure of energy consumption for recovery is relatively large.

[0006] Therefore, developing a process for synthesizing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole with high yield and simple operation has great social value. Summary of the invention

[0007] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, and in particular to provide a method for preparing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole with high yield and suitable for industrial production. The preparation method of the present invention has simple operation steps, high yield, and is suitable for industrial production.

[0008] To achieve this object, the present invention adopts the following technical solutions:

[0009] In one aspect, the present invention provides a method for preparing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, the method comprising the following steps:

[0010] (1) reacting 2,3-dimethyl-4-methylsulfonyl bromobenzene with an oximation reagent to obtain a 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime reaction solution;

[0011] (2) mixing the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime reaction solution obtained in step (1) with a chlorination reagent to obtain the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime chloride reaction solution;

[0012] (3) The 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride reaction solution obtained in step (2) is subjected to a cyclization reaction with ethylene to obtain 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole.

[0013] In the present invention, the product is obtained through oximation reaction, followed by chlorination and then cyclization, which is simple to operate and has a high yield. After the oximation reaction and the chlorination reaction are completed, the next step of reaction is directly carried out without treatment, avoiding operations such as quenching, extraction, desolventization, and purification. The process is greatly simplified and the amount of wastewater is small.

[0014] Preferably, the oximation reagent in step (1) is an alkyl nitrite, preferably n-butyl nitrite.

[0015] Preferably, the molar ratio of the oximation reagent to 2,3-dimethyl-4-methylsulfonyl bromobenzene in step (1) is (1.0-3.0):1.0, such as 1.0:1.0, 1.5:1.0, 2.0:1.0, 2.5:1.0 or 3.0:1.0, preferably (1.5-2.0):1.0.

[0016] Preferably, the reaction in step (1) is carried out in the presence of an alkaline substance.

[0017] Preferably, the alkaline substance is selected from any one of potassium methoxide, sodium methoxide or potassium tert-butoxide, or a combination of at least two thereof, preferably sodium methoxide.

[0018] Preferably, the molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromobenzene to the alkaline substance is 1:(2.0-4.0), for example, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, preferably 1:(2.5-3.0).

[0019] Preferably, in step (1), the alkaline substance is added to the reaction system at -50 to -10°C (can be -50°C, -40°C, -30°C, -20°C or -10°C), and the alkaline substance is added to the reaction system within 3-10 hours (for example, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 10 hours).

[0020] Preferably, the solvent for the reaction in step (1) is any one of N,N-dialkylformamide, N,N-dialkylacetamide or N-methylpyrrolidone (NMP) or a combination of at least two thereof, preferably N,N-dimethylformamide (DMF) or N-methylpyrrolidone (NMP).

[0021] Preferably, the reaction temperature in step (1) is -50 to -10°C, and may be -50°C, -40°C, -30°C, -20°C or -10°C, preferably -40 to -20°C.

[0022] Preferably, the time for adding the base in the reaction of step (1) is 2-10 h, for example 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, preferably 2-6 h.

[0023] Preferably, the chlorination agent in step (2) is chlorine gas.

[0024] Preferably, the molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromobenzene to the chlorination reagent in step (2) is 1:(1.0-3.0), for example 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2.0, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.0, preferably 1:(2.0-2.5).

[0025] Preferably, the reaction temperature in step (2) is -40 to 60°C, and may be -40°C, -30°C, -20°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, preferably 0-30°C.

[0026] Preferably, the reaction time of step (2) is 1-12 h, for example, 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h or 12 h, preferably 2-6 h.

[0027] Preferably, the cyclization reaction in step (3) is carried out in the presence of an alkaline substance.

[0028] Preferably, the alkaline substance in step (3) is any one of an organic base, an alkali metal bicarbonate or an alkali metal hydroxide, or a combination of at least two thereof.

[0029] Preferably, the organic base is selected from triethylamine and / or pyridine.

[0030] Preferably, the alkali metal carbonate is selected from sodium carbonate and / or potassium carbonate.

[0031] Preferably, the alkali metal bicarbonate is selected from sodium bicarbonate and / or potassium bicarbonate.

[0032] Preferably, the alkali metal hydroxide is selected from sodium hydroxide and / or potassium hydroxide.

[0033] Preferably, the alkaline substance is selected from any one of triethylamine, sodium carbonate, sodium bicarbonate or sodium hydroxide, or a combination of at least two thereof.

[0034] Preferably, the molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromobenzene to the alkaline substance in step (3) is 1:(0.5-4.0), for example, 1:0.5, 1:1.0, 1:1.5, 1:2.0, 1:2.5, 1:3.0, 1:3.5, 1:4.0, preferably 1:(1.0-2.5).

[0035] Preferably, the amount of ethylene used in step (3) is such that the system pressure reaches 0.1 MPa-2 MPa, for example, the system pressure is 0.1 MPa, 0.5 MPa, 0.8 MPa, 1 MPa, 1.3 MPa, 1.5 MPa, 1.8 MPa or 2 MPa.

[0036] Preferably, in the ring-closing reaction of step (3), nitrogen is used to replace the air in the system before adding ethylene.

[0037] Preferably, the temperature of the ring-closing reaction in step (3) is 0 to 100°C, for example, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C or 100°C, preferably 0 to 30°C.

[0038] Preferably, the ring-closing reaction time in step (3) is 2 to 8 h, for example 2 h, 2.5 h 3 h, 3.5 h, 4 h, 4.5 h, 5 h, 5.5 h, 6 h, 6.5 h, 7 h, 7.5 h, or 8 h, preferably 4 to 6 h.

[0039] Preferably, the solvent for the reactions in step (2) and step (3) is the same as the solvent for the reaction in step (1).

[0040] Preferably, the ring closing in step (3) is followed by purification, and the solvent used for the purification is methanol and / or ethanol, preferably ethanol.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The preparation method of the present invention is easy to operate. After the reaction of step (1) oximation reaction and step (2) chlorination reaction is completed, the next step reaction is directly carried out without treatment. The solvent is single and the recovery is convenient. At the same time, the extraction, desolventization, drying and other operations are avoided, the process is greatly simplified, and the energy consumption is greatly reduced. After the oximation reaction of step (1) and the chlorination reaction of step (2) are completed, there is no need to add a large amount of water for post-treatment. The amount of wastewater is at most 5% of the document (CN1300284A), and even no wastewater is generated, and the environmental pressure is small. In the oximation reaction of step (1), alkali is slowly added at low temperature, and the side reaction is relatively small. The reaction yield is about 85%, and the yield of the oximation reaction in the document (CN1300284A) is 75%. After the product of the oximation reaction of step (1), it is not separated. In the same solvent system, chlorine is used to replace N-chlorosuccinimide to carry out the chlorination reaction of step (2), and the reaction yield is almost 100%. After the chlorination reaction in step (2) is completed, the ring-closing reaction in step (3) is continued in the same solvent system, and the reaction yield is almost 100%. There is basically no loss of materials during the chlorination and ring-closing reaction. Ethanol is selected as the refining solvent after the ring-closing (the document CN1300284A uses isopropanol, and the refining loss is 24%), and the refining loss is only about 5%. The total yield of the three steps is as high as 70%-81%, which is greatly improved than that of the document CN1300284A (the three-step yield of the document is only 42%). DETAILED DESCRIPTION

[0043] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0044] The yields or contents described in the examples and the specification are all mass yields or contents.

[0045] In the following examples, the content is detected by high performance liquid chromatography external standard method, and the chromatographic column specification is Shimadzu Shim-pack GIST C18 (5 μm), 4.6 ID×150 mm stainless steel column.

[0046] In the present invention, the raw material 2,3-dimethyl-4-methylsulfonyl bromobenzene is purchased.

[0047] Example 1

[0048] In this embodiment, a method for synthesizing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole is provided, which specifically comprises the following steps:

[0049] (1) 960 g of N,N-dimethylformamide (purity 99%), 2,3-dimethyl-4-methylsulfonyl bromobenzene (221.5 g, content 95.0%, 0.80 mol), and n-butyl nitrite (156.1 g, 1.44 mol, content 95%) were added to a 2000 mL three-necked flask. After stirring to dissolve, the temperature was lowered to -40°C, and sodium methoxide (111.4 g, 2.0 mol, content 97%) was added dropwise. After the addition was completed in 4 hours, the mixture was kept at -40°C and stirred for 4 hours. The reaction solution weighed 1449.0 g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime in the reaction solution was 13.7%, with a yield of 85%.

[0050] (2) The temperature of the reaction liquid obtained in step (1) was controlled to be 30°C, and 129 g (1.8 mol) of chlorine gas was introduced within 2 hours. After the introduction, the next step of reaction was carried out. The reaction liquid weighed 1578.0 g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzoyloxime chloride in the reaction liquid was 14.0%, and the yield was 100%;

[0051] (3) The reaction solution obtained in step (2) was transferred to a 2L autoclave, the autoclave was closed, stirring was started, 0.3Mpa nitrogen was used to replace the system three times, and then ethylene was introduced to a pressure of 0.5Mpa, and then 204.4g (2mol, 99%) of triethylamine was continuously pumped into the autoclave by a high-pressure input pump at about 30°C for 4 hours. After the pumping was completed, the reaction was stirred at 30°C and a pressure of 0.5Mpa for another 4 hours. The autoclave was depressurized and discharged, and the reaction solution weighed 1809.8g, and the content of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole in the reaction solution was 11.8%, and the yield was 99%. After the reaction solution was desolventized, 321 g of ethanol was added, and the mixture was heated to reflux. After the solution became clear, the mixture was cooled to 0°C for crystallization, and 202.6 g (content 99.2%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole was obtained after filtration and drying. The total yield of the three steps was 79%. Melting point: 138.8-139.2°C.

[0052] In this embodiment, no water is involved in the post-treatment, so no wastewater is generated.

[0053] Structural detection: Mass spectrometry LC / MS: [M+H] + =317.9797;

[0054] 1 H NMR (400 MHz, DMSO-d6) data are as follows (δ [ppm]): 8.06–8.03 (d, 1H), 7.81–7.79 (d, 1H), 4.51–4.46 (t, 2H), 3.35–3.29 (m, 2H), 3.24 (s, 3H), 2.36 (s, 3H).

[0055] Example 2

[0056] In this example, the reaction temperature in step (1) was adjusted to -50°C, and the other operations were the same as in Example 1 to obtain 195.1 g (content 99.1%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, with a total yield of 76% in three steps.

[0057] Example 3

[0058] In this example, the solvent used in step (1) was replaced with N-methylpyrrolidone (NMP), the reaction temperature was -20°C, and the other operations were the same as in Example 1 to obtain 181.7 g (content 99.2%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, with a total yield of 71% in three steps.

[0059] Example 4

[0060] In this example, the solvent used in step (1) was replaced with N,N-dialkylacetamide, the reaction temperature was -20°C, and the other operations were the same as in Example 1 to obtain 189.6 g (content 99.3%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, with a total yield of 74% in three steps.

[0061] Example 5

[0062] In this embodiment, a method for synthesizing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole is provided, which specifically comprises the following steps:

[0063] (1) 984 g of N,N-dimethylformamide (purity 99%) was added to a 2000 mL three-necked flask, and then a mixed solution of 2,3-dimethyl-4-methylsulfonyl bromobenzene (227.0 g, content 95%, 0.82 mol) and n-butyl nitrite (160.7 g, 1.48 mol, content 95%) was added, cooled to -45°C, and sodium methoxide (131.5 g, 2.34 mol, content 97%) was added dropwise. After 6 hours of addition, the mixture was stirred for 4 hours at the same temperature. The reaction solution weighed 1503.2 g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime in the reaction solution was 13.9%, with a yield of 87%.

[0064] (2) Chlorine gas was introduced into the reaction solution obtained in step (1), the temperature was maintained at 20° C., and the aeration was continued for 4 h. A total of 142.7 g (1.99 mol) of chlorine gas was introduced. After the aeration was completed, the next step of reaction was carried out; the reaction solution weighed 1645.9 g, the content of 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride in the reaction solution was 14.2%, and the yield was 100%.

[0065] (3) The reaction solution obtained in step (2) was transferred to a 2L autoclave, the autoclave was closed, stirring was started, 0.3Mpa nitrogen was used to replace the system three times, and then ethylene was introduced to a pressure of 0.5Mpa, and then 364.8g (0.52mol, content 15%) of sodium carbonate aqueous solution was continuously pumped into the autoclave at about 30°C for 4 hours through a high-pressure input pump. After the pumping was completed, the reaction was stirred at 30°C and 0.5Mpa for another 4 hours. The reaction solution was depressurized, discharged, filtered, and the filter cake was washed with 220g of DMF. The filtrate weighed 2016.8g. The content of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole in the reaction solution was 11.2%, and the yield was 100%. After the filtrate was desolvated under reduced pressure, 329 g of ethanol was added, and after reflux, the solution was cleared and then cooled to 0°C for crystallization, filtration and drying to obtain 213.3 g (content 99.0%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole. The total yield of the three steps was 81%.

[0066] Example 6

[0067] In this example, the base in step (3) was replaced with 30% sodium hydroxide (138.7 g, 1.04 mol) and the other operations were the same as in Example 5 to obtain 200.0 g (content 99.1%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, with a total yield of 76% in three steps.

[0068] Example 7

[0069] In this example, the base in step (3) was replaced with 8% sodium bicarbonate (1155 g, 1.1 mol), and the other operations were the same as in Example 5 to obtain 205.0 g (content 99.2%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, with a total yield of 78% in three steps.

[0070] Example 8

[0071] (1) Add 960g N,N-dimethylformamide (purity 99%), 2,3-dimethyl-4-methylsulfonyl bromobenzene (221.5g, content 95.0%, 0.80mol), and n-butyl nitrite (86.7g, 0.8mol, content 95%) to a 2000mL three-necked flask, stir until dissolved, then cool to -40°C, add sodium methoxide (111.4g, 2.0mol, content 97%) dropwise, keep stirring at -40°C for 4 hours, and add concentrated hydrochloric acid (197.3g, 2.0mol) dropwise at -40°C. The reaction solution weighs 1576.9g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime in the reaction solution is 11.1%, with a yield of 75%.

[0072] (2) The temperature of the reaction solution obtained in step (1) was controlled to be 30° C., 57.4 g (0.8 mol) of chlorine gas was introduced within 1 hour, and after the ventilation was completed, the next step of reaction was carried out; the reaction solution weighed 1634.3 g, the content of 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride in the reaction solution was 12.0%, and the yield was 100%.

[0073] (3) The reaction solution obtained in step (2) was transferred to a 2L autoclave, the autoclave was closed, stirring was started, 0.3Mpa nitrogen was used to replace the system three times, and then ethylene was introduced to a pressure of 0.5Mpa, and then 364.8g (0.52mol, content 15%) of sodium carbonate aqueous solution was continuously pumped into the autoclave at about 30°C for 4 hours through a high-pressure input pump. After the pumping was completed, the reaction was stirred at 30°C and 0.5Mpa for another 4 hours. The autoclave was depressurized and discharged, filtered, and the filter cake was washed with 220g of DMF. The filtrate weighed 2007.2g. The content of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole in the reaction solution was 9.5%, and the yield was 100%. The filtrate was desolvated under reduced pressure, 320 g of ethanol was added, and after reflux, the solution was cleared, and the temperature was lowered to 0°C for crystallization and desolvation under reduced pressure. After purification with ethanol, filtration and drying, 179.9 g (content 99.0%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole was obtained, and the total yield of the three steps was 70%.

[0074] Example 9

[0075] (1) Add 960 g of N,N-dimethylformamide (purity 99%), 2,3-dimethyl-4-methylsulfonyl bromobenzene (221.5 g, content 95.0%, 0.80 mol), and n-butyl nitrite (260.2 g, 2.4 mol, content 95%) to a 3000 mL three-necked flask, stir until dissolved, then cool to -40°C, and add sodium methoxide (178.1 g, 3.2 mol, content 97%) dropwise. After the addition is complete over 10 hours, stir at -40°C for 4 hours, and then add concentrated hydrochloric acid (315.7 g, 3.2 mol) dropwise at -20°C. The reaction solution weighs 1935.5 g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime in the reaction solution is 10.1%, with a yield of 84%.

[0076] (2) The temperature of the reaction solution obtained in step (1) was controlled to be 60° C., 172.1 g (2.4 mol) of chlorine gas was introduced within 12 hours, and after the ventilation was completed, the next step of reaction was carried out; the reaction solution weighed 2107.6 g, the content of 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride in the reaction solution was 10.3%, and the yield was 99%.

[0077] (3) The reaction solution obtained in step (2) was transferred to an autoclave, the autoclave was closed, stirring was started, 0.3 MPa nitrogen was used to replace the system three times, and then ethylene was introduced to a pressure of 0.5 MPa, and then 326.5 g (3.2 mol, content 99%) of triethylamine was continuously pumped into the autoclave by a high-pressure input pump at about 30° C. within 4 hours. After the pumping was completed, the reaction was stirred at 30° C. and 0.5 MPa for another 8 hours. The autoclave was depressurized, the material was discharged, filtered, and the filter cake was washed with 220 g of DMF. The filtrate weighed 2446.1 g. The content of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole in the reaction solution was 8.6%, and the yield was 99%. The filtrate was desolvated under reduced pressure, and then 321 g of ethanol was added for purification. After filtering and drying, 200.2 g (content 99.1%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole was obtained. The total yield of the three steps was 78%.

[0078] Example 10

[0079] (1) Add 960 g of N,N-dimethylformamide (purity 99%), 2,3-dimethyl-4-methylsulfonyl bromobenzene (221.5 g, content 95.0%, 0.80 mol), and n-butyl nitrite (173.5 g, 1.6 mol, content 95%) to a 2000 mL three-necked flask, stir until dissolved, then cool to -40°C, add sodium methoxide (111.4 g, 2.0 mol, content 97%) dropwise, keep stirring at -40°C for 4 hours, and then add concentrated hydrochloric acid (197.3 g, 2.0 mol) dropwise at -40°C. The reaction solution weighs 1663.7 g, and the content of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime in the reaction solution is 11.9%, with a yield of 85%.

[0080] (2) The temperature of the reaction solution obtained in step (1) was controlled to be 20° C., 114.7 g (1.6 mol) of chlorine gas was introduced within 4 hours, and after the ventilation was completed, the next step of reaction was carried out; the reaction solution weighed 1778.4 g, the content of 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride in the reaction solution was 12.5%, and the yield was 100%.

[0081] (3) The reaction solution obtained in step (2) was transferred to a 2L autoclave, the autoclave was closed, stirring was started, 0.3Mpa nitrogen was used to replace the system three times, and then ethylene was introduced to a pressure of 0.5Mpa, and then 204g (2.0mol, content 99%) of triethylamine was continuously pumped into the autoclave by a high-pressure input pump at about 30°C for 4 hours. After the pumping was completed, the reaction was stirred at 30°C and 0.5Mpa for another 4 hours. The autoclave was depressurized and discharged, filtered, and the filter cake was washed with 160g of DMF. The filtrate weighed 1990.2g, and the content of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole in the reaction solution was 10.8%, and the yield was 99%. The filtrate was desolvated under reduced pressure, and 321 g of ethanol was added for purification. After filtering and drying, 202.8 g (content 99.2%) of 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole was obtained. The total yield of the three steps was 79%.

[0082] The applicant declares that the present invention illustrates the preparation method of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole, characterized in that: The preparation method comprises the following steps: (1) reacting 2,3-dimethyl-4-methylsulfonyl bromobenzene with an oximation reagent to obtain a 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime reaction solution; (2) mixing the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime reaction solution obtained in step (1) with a chlorination reagent to obtain the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime chloride reaction solution; (3) The 3-bromo-2-methyl-6-methylsulfonylbenzoxime chloride reaction solution obtained in step (2) is subjected to a cyclization reaction with ethylene to obtain 3-(3-bromo-2-methyl-6-methylsulfonylphenyl)-4,5-dihydroisoxazole.

2. The preparation method according to claim 1, characterized in that: The oximation reagent in step (1) is an alkyl nitrite, preferably n-butyl nitrite.

3. The preparation method according to claim 1 or 2, characterized in that: The molar ratio of the oximation reagent to 2,3-dimethyl-4-methylsulfonyl bromobenzene in step (1) is (1.0-3.0):1.0, preferably (1.5-2.0):1.

0.

4. The preparation method according to any one of claims 1 to 3, characterized in that The reaction in step (1) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from any one of potassium methoxide, sodium methoxide or potassium tert-butoxide, or a combination of at least two thereof, preferably sodium methoxide.

5. The preparation method according to any one of claims 1 to 4, characterized in that: The molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromobenzene to the alkaline substance is 1:(2.0-4.0), preferably 1:(2.5-3.0); Preferably, in step (1), the alkaline substance is added to the reaction system at -50 to -10°C, and the alkaline substance is added to the reaction system within 3 to 10 hours.

6. The preparation method according to any one of claims 1 to 5, characterized in that: The solvent for the reaction in step (1) is any one of N,N-dialkylformamide, N,N-dialkylacetamide or N-methylpyrrolidone or a combination of at least two thereof; preferably N,N-dimethylformamide or N-methylpyrrolidone. Preferably, the reaction temperature in step (1) is -50 to -10°C, preferably -40 to -20°C.

7. The preparation method according to any one of claims 1 to 6, characterized in that: The chlorination reagent in step (2) is chlorine gas.

8. The preparation method according to any one of claims 1 to 7, characterized in that: The molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromide benzene to the chlorination reagent in step (2) is 1:(1.0-3.0), preferably 1:(2.0-2.5); Preferably, the reaction temperature in step (2) is -40 to 60°C, preferably 0 to 30°C; Preferably, the reaction time in step (2) is 1-12 h, preferably 2-6 h.

9. The preparation method according to any one of claims 1 to 8, characterized in that: The ring-closing reaction in step (3) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance in step (3) is any one of an organic base, an alkali metal bicarbonate or an alkali metal hydroxide, or a combination of at least two thereof; Preferably, the organic base is selected from triethylamine and / or pyridine; Preferably, the alkali metal carbonate is selected from sodium carbonate and / or potassium carbonate; Preferably, the alkali metal bicarbonate is selected from sodium bicarbonate and / or potassium bicarbonate; Preferably, the alkali metal hydroxide is selected from sodium hydroxide and / or potassium hydroxide; Preferably, the alkaline substance is selected from any one of triethylamine, sodium carbonate, sodium bicarbonate or sodium hydroxide, or a combination of at least two thereof.

10. The preparation method according to any one of claims 1 to 9, characterized in that: The molar ratio of the 2,3-dimethyl-4-methylsulfonyl bromide to the alkaline substance in step (3) is 1:(0.5-4.0), preferably 1:(1.0-2.5); Preferably, the amount of ethylene used in step (3) is such that the system pressure reaches 0.1 MPa-2 MPa; Preferably, in the ring-closing reaction of step (3), nitrogen is used to replace the air in the system before adding ethylene; Preferably, the temperature of the ring-closing reaction in step (3) is 0 to 100° C., preferably 0 to 30° C.; Preferably, the ring-closing reaction time in step (3) is 2 to 8 hours, preferably 4 to 6 hours; Preferably, the solvent for the reaction of step (2) and step (3) is the same as the solvent for the reaction of step (1); Preferably, the ring closing in step (3) is followed by purification, and the solvent used in the purification is methanol and / or ethanol, preferably ethanol.

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