A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole

Abstract

The present invention is used in the technical field of preparation of fenpyroxene, and discloses a method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, using 4-methylsulfonyl-2,3-dimethylbromobenzene as raw material, reacting with a strong alkaline catalyst in a fixed bed reactor, and then after post-treatment, the intermediate obtained is 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime, and then the intermediate is reacted with chlorine and ethylene in a "one-pot method", and the obtained product is 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole. The method is simple to operate, mild reaction conditions, high degree of automation, high safety factor, and can realize continuous production; the utilization rate of raw and auxiliary materials is high, the product yield is high, and the equipment occupies a small area and saves space; there are few industrial wastes, it is environmentally friendly, and it is conducive to industrialization; the total yield of the method is not less than 80%, and the purity is greater than 99%.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of fenpyroxetine, and specifically to a method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole. Background Art

[0002] Topramezone is a new type of pyrazolone post-emergence foliar treatment herbicide developed by BASF Europe. This herbicide is a highly efficient and low-toxic benzoyl ester pyrazolone, a 4-hydroxyphenylpyruvate dioxidase (4-HPPD) inhibitor, and has a good control effect on weeds resistant to glyphosate, triazines, acetolactate synthase (ALS) preparations and acetyl-CoA carboxylase (ACCase) inhibitors. It is mainly used to control weeds in corn fields, such as broadleaf weeds and grass weeds. Topramezone has the characteristics of high safety, excellent selectivity, broad-spectrum herbicidal activity, long duration and strong compatibility. It is the safest corn herbicide and one of the least toxic to animals, and has a good market prospect.

[0003] In the method for synthesizing fenpyroxil, the intermediate 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole is one of the key raw materials. Currently, there are many synthesis routes, but most of the synthesis methods are similar. In fact, the methods for synthesizing the intermediate 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole are mainly the following:

[0004] 1. U.S. Patent No. 20030216580 describes the process of diazotizing 2,3-dimethylaniline to obtain methylthio group to obtain 2,3-dimethylanisyl sulfide, brominating to obtain 4-bromo-2,3-dimethylanisyl sulfide, oxidizing to obtain 2,3-dimethyl 4-methylsulfonyl bromobenzene, oximating to obtain 3-bromo-2-methyl-6-(methylsulfonyl)benzaldehyde oxime, and cyclizing to obtain 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole;

[0005] 2. Chinese patent CN103788083A describes the use of 3-nitro-o-phenylenediol as a raw material, DMF as a solvent, and n-butyl nitrite to obtain 2-methyl-6-nitrobenzaldehyde oxime. After ring formation, the nitro group is reduced by hydrogen to obtain 2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline. The amino group is diazotized with a diazotizing agent, replaced with a methylthio group, and then brominated to obtain 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole, and finally the intermediate 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole;

[0006] 3. Chinese patent CN107652246B describes the use of 2-methylbenzaldehyde as a substrate, through bromination, NH2OH·HCl condensation, chlorination cyclization, and then adding a sulfonylating agent for mesylation, and finally secondary bromination to obtain the target product 3-[3-bromo-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0007] The above methods all have certain defects, such as low reaction yield, complicated operation, the oximation reaction needs to be carried out at ultra-low temperature and the reaction cannot be carried out continuously, there are many side reactions, and separation is difficult, which makes industrial production difficult and costly. Summary of the invention

[0008] The object of the present invention is to provide a method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, so as to solve the problems of low reaction yield and complicated operation proposed in the above background technology.

[0009] To achieve the above object, the present invention provides the following technical solution: a method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the method comprising the following steps:

[0010] Step 1: Arrange fixed bed reactor:

[0011] At least four fixed bed reactors are used, the fixed bed reactor is provided with a jacket on its outer shell, and a heat-insulating layer is provided on the jacket, a feed port, a discharge port, a nitrogen port, and a reserved port are reserved on the fixed bed reactor, a freezing liquid inlet and a freezing liquid outlet are provided on the jacket, an inner bypass pipe is provided inside the fixed bed reactor, and a freezing liquid inlet and a freezing liquid outlet are provided at both ends of the inner bypass pipe, respectively, a multi-layer reaction bed plate is provided inside the fixed bed reactor, the reaction bed plate is detachable, and a plurality of small holes are provided on the reaction bed plate only for the solution to flow out;

[0012] Step 2: Prepare and load the catalyst:

[0013] In a dry environment, the catalyst and the solid dispersant are fully mixed, the catalyst is loaded onto the reaction bed plate of each fixed bed reactor, and the catalyst is evenly distributed on the reaction bed plate;

[0014] Step 3: Assemble and precool the fixed bed reactor:

[0015] The discharge port of the first-stage fixed bed reactor is connected to the feed port of the next-stage fixed bed reactor, and then each fixed bed reactor is pre-cooled to a temperature of -30 to -10°C;

[0016] Step 4: Prepare a mixed solution of 4-methylsulfonyl-2,3-dimethylbromobenzene:

[0017] Mix and dissolve 4-methylsulfonyl-2,3-dimethylbromobenzene, n-butyl nitrite and an aprotic solvent according to a certain proportion;

[0018] Step 5: Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime:

[0019] The first-stage fixed bed reactor pumps the mixed solution of the fourth step into the reactor from its feed port, so that the mixed solution is fully in contact with the catalyst, and then reacts the material at the reaction temperature for a preset time, and then the mixed solution material flows out through the small holes on the reaction bed plate, and then is fed into the next-stage fixed bed reactor through its discharge port. The reaction mixture of the last-stage fixed bed reactor is evenly mixed with the pumped acetic acid and dichloroethane solution through its discharge port, and separated by a solid-liquid separator, the solid is the by-product sodium acetate, and the liquid is the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed liquid;

[0020] Step 6: Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method":

[0021] The 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed liquid synthesized in the fifth step is transferred to a pressure autoclave, and chlorine is introduced for chlorination. After the chlorination is completed, the pH is adjusted to 8-9 with a weak base, nitrogen is replaced, ethylene gas is introduced, the temperature is controlled at 5-30°C, the pressure is 0.3-1Mpa, and the reaction is carried out for 4-10 hours. After the reaction is completed, the liquid is separated, washed with water, and the solvent is removed under reduced pressure. Methanol is added for purification, crystallization and filtration are performed, and the filter cake is dried to obtain the product 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0022] Preferably, the catalyst is one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, and sodium hydride.

[0023] Preferably, the solid dispersant is one or a combination of porous activated carbon, molecular sieve, activated silica, and porous ceramics.

[0024] Preferably, the weight ratio of the catalyst to the solid dispersant is (1-10):1.

[0025] Preferably, the aprotic solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0026] Preferably, the weight ratio of n-butyl nitrite, 4-methylsulfonyl-2,3-dimethylbromobenzene and aprotic solvent is (0.5-1):1:(2-10).

[0027] Preferably, the reaction temperatures of the first stage fixed bed reactor and each intermediate stage fixed bed reactor are respectively -30 to -5°C, and the reaction temperature of the last stage fixed bed reactor is -10 to -5°C.

[0028] Preferably, in the fifth step, the rate of pumping materials into each fixed bed reactor is 1-100 ml / min.

[0029] Preferably, the weak base is one or a combination of sodium carbonate, potassium carbonate, triethylamine, sodium phosphate, and sodium hydrogen phosphate.

[0030] Compared with the prior art, the invention has the following beneficial effects: the method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole:

[0031] 1. Simple operation, mild reaction conditions, high safety factor, controllable risks, high degree of automation, and continuous production can be achieved;

[0032] 2. After the catalyst and solid dispersant are fully mixed, they are evenly distributed on the reaction bed, which increases the contact surface area of ​​the catalyst and makes full use of it. At the same time, the contact time of the material under strong alkali is reduced, which effectively reduces the side reactions in the reaction. The final yield is relatively high; the total yield is not less than 80%, and the purity is greater than 99%;

[0033] 3. The fixed bed reactor occupies a small area, which can make full use of space and save land resources;

[0034] 4. Solid dispersants can be reused, produce very little industrial waste, are environmentally friendly, and can achieve green industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 Schematic diagram of the synthesis mechanism of the present invention;

[0036] Figure 2 This is a structural diagram of a fixed bed reactor of the present invention;

[0037] Figure 3 It is the reaction flow chart of the present invention;

[0038] Figure 4 It is a schematic diagram of the series assembly of fixed bed reactors in various embodiments of the present invention;

[0039] Figure 5 Schematic diagram of HPLC purity of the product in Example 1 of the present invention.

[0040] In the figure: 1. Jacket; 2. Nitrogen inlet; 3. Reserved port; 4. Catalyst; 5. Feed inlet; 6. Reaction bed; 7. Refrigerant outlet 2; 8. Refrigerant outlet 1; 9. Small hole; 10. Inner bypass pipe; 11. Insulation layer; 12. Discharge port; 13. Refrigerant inlet 2; 14. Refrigerant inlet 1. DETAILED DESCRIPTION

[0041] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0042] See also Figure 1-Figure 5 The present invention provides a technical solution: a method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, the method comprising the following steps:

[0043] Step 1: Arrange fixed bed reactor:

[0044] At least four fixed bed reactors are used, the outer shell of the fixed bed reactor is provided with a jacket 1, and the jacket 1 is provided with an insulation layer 11, the fixed bed reactor is provided with a feed port 5, a discharge port 12, a nitrogen port 2, and a reserved port 3, the jacket 1 is provided with a refrigerant inlet 14 and a refrigerant outlet 8, an inner bypass pipe 10 is provided in the fixed bed reactor, and the two ends of the inner bypass pipe 10 are respectively provided with a refrigerant inlet 13 and a refrigerant outlet 7, a multi-layer reaction bed plate 6 is provided inside the fixed bed reactor, the reaction bed plate 6 is detachable, and the reaction bed plate 6 is provided with a plurality of small holes 9 only for the solution to flow out.

[0045] Step 2: Preparation and loading of catalyst 4:

[0046] In a dry environment, the catalyst 4 is fully mixed with the solid dispersant, and the catalyst 4 is respectively loaded onto the reaction bed plate 6 of each fixed bed reactor, and the catalyst 4 is evenly distributed on the reaction bed plate 6; the catalyst 4 is one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, and sodium hydride; the solid dispersant is one or a combination of porous activated carbon, molecular sieve, activated silica, and porous ceramics; the weight ratio of the catalyst 4 to the solid dispersant is (1-10):1.

[0047] Step 3: Assemble and precool the fixed bed reactor:

[0048] The discharge port 12 of the first-stage fixed bed reactor is connected to the feed port 5 of the next-stage fixed bed reactor, and then each fixed bed reactor is pre-cooled to a temperature of -30 to -10°C.

[0049] Step 4: Prepare a mixed solution of 4-methylsulfonyl-2,3-dimethylbromobenzene:

[0050] 4-methylsulfonyl-2,3-dimethylbromobenzene, n-butyl nitrite and aprotic solvent are mixed and dissolved in proportion; the aprotic solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; the weight ratio of n-butyl nitrite, 4-methylsulfonyl-2,3-dimethylbromobenzene and aprotic solvent is (0.5-1):1:(2-10).

[0051] Step 5: Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime:

[0052] The first-stage fixed-bed reactor pumps the fourth-step mixed solution into the reactor from its feed port 5, so that the mixed solution is fully in contact with the catalyst 4, and then the material is reacted at the reaction temperature for a preset time, and then the mixed solution material flows out through the small holes 9 on the reaction bed plate 6, and then is sent to the next-stage fixed-bed reactor through its discharge port 12. The reaction mixture of the last-stage fixed-bed reactor is uniformly mixed with the pumped acetic acid and dichloroethane solution through its discharge port 12, and separated by a solid-liquid separator. The solid is the by-product sodium acetate, and the liquid is the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed liquid; the reaction temperatures of the first-stage fixed-bed reactor and each intermediate-stage fixed-bed reactor are -30 to -5°C, respectively, and the reaction temperature of the last-stage fixed-bed reactor is -10 to -5°C; the rate of pumping materials into each fixed-bed reactor is 1 to 100 ml / min, respectively.

[0053] Step 6: Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method":

[0054] The 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed liquid synthesized in the fifth step is transferred to a pressure autoclave, and chlorine is introduced for chlorination. After the chlorination is completed, the pH is adjusted to 8-9 with a weak base, nitrogen is replaced, ethylene gas is introduced, the temperature is controlled at 5-30°C, the pressure is 0.3-1Mpa, and the reaction is carried out for 4-10 hours. After the reaction is completed, the liquid is separated, washed with water, the solvent is removed under reduced pressure, methanol is added for refining, crystallization is filtered, and the filter cake is dried to obtain the product 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole; the weak base is one or a combination of sodium carbonate, potassium carbonate, triethylamine, sodium phosphate, and sodium hydrogen phosphate.

[0055] Each intermediate fixed bed reactor pumps the material into the reactor from its feed port 5, and then reacts the material at the reaction temperature for a preset time, and then feeds the reaction mixture into the next fixed bed reactor through its discharge port 12. After running for a period of time, when no product is generated by liquid phase HPLC at the discharge port 12 of the first fixed bed reactor, the feeding is suspended, and after nitrogen purging, the original second fixed bed reactor is switched to the first stage, the original third stage is switched to the second stage, and the original fourth stage is switched to the third stage, and a group of fixed bed reactors is added as the fourth stage, and so on. After a cycle, the products are combined, weighed, tested, and the product yield is calculated. For the replaced fixed bed reactor, the solid dispersion is taken out, the catalyst is re-prepared and loaded, and it is incorporated into the fixed bed reactor system again.

[0056] Example 1: This example is a specific implementation example of preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0057] Some specific details of this embodiment are as follows:

[0058] Arrangement of fixed bed reactors: Four fixed bed reactors are used and arranged in series in sequence.

[0059] Preparation and loading of catalyst 4: Under dry conditions, 200 g of sodium methoxide and 40 g of porous activated carbon were fully stirred and loaded into a fixed bed reactor, and nitrogen was introduced for purging to evenly distribute the dehydrating agent on the reaction bed.

[0060] Cooling treatment of fixed bed reactor: introducing freezing liquid for cooling, the temperature of the first stage fixed bed reactor is -30~-20℃, the temperature of the second stage fixed bed reactor is -30~-20℃, the temperature of the third stage fixed bed reactor is -20~-15℃, and the temperature of the fourth stage fixed bed reactor is -15~-10℃.

[0061] Prepare a mixed solution of 4-methylsulfonyl-2,3-dimethylbromobenzene: put 50 g of 4-methylsulfonyl-2,3-dimethylbromobenzene, 30 g of n-butyl nitrite and 150 g of DMF into a flask, stir until dissolved and clear, and set aside.

[0062] Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime: The material was pumped into each fixed-bed reactor at a rate of 2 ml / min, and the feeding was completed in about 120 min. The material of the last stage fixed-bed reaction was pumped into a flask containing 200 g of dichloroethane and 56 g of acetic acid. After the pumping was completed, it was stirred at 5-10 ° C for 30 min, and the solid material was filtered out to obtain a 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution containing 50.1 g of the intermediate with a yield of 90.27% (theoretical weight 55.5 g).

[0063] Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method": the above 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution was transferred to a pressure autoclave, chlorine gas was introduced at 5-10°C for chlorination, and after the chlorination was completed, the pH was adjusted to 8-9 with a saturated sodium carbonate solution, ethylene was introduced at 10-15°C, the pressure of the reactor was controlled to be 0.4-0.5 MPa, and the reaction was kept warm for 6 hours. The reaction solution was separated and washed with water, the solvent was removed under reduced pressure, and 150g of methanol was added for purification to obtain 48.6g of the product 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole with a purity of 99.27% ​​and a yield of 89.01% (theoretical weight 54.6g). The total yield of the two steps was 80.33% (theoretical weight 60.5g).

[0064] Example 2: This example is a specific implementation example of preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0065] Some specific details of this embodiment are as follows:

[0066] Arrangement of fixed bed reactors: Four fixed bed reactors are used and arranged in series in sequence.

[0067] Preparation and loading of catalyst 4: Under dry conditions, 200 g of sodium methoxide and 60 g of porous activated carbon were fully stirred and loaded into a fixed bed reactor, and nitrogen was introduced for purging to evenly distribute the dehydrating agent on the reaction bed.

[0068] Cooling treatment of fixed bed reactor: introduce freezing liquid for cooling, the temperature of the first stage fixed bed reactor is -30~-20℃, the temperature of the second stage fixed bed reactor is -25~-20℃, the temperature of the third stage fixed bed reactor is -25~-20℃, and the temperature of the fourth stage fixed bed reactor is -15~-10℃.

[0069] Preparation of 4-methylsulfonyl-2,3-dimethylbromobenzene mixed solution: Add 50 g of 4-methylsulfonyl-2,3-dimethylbromobenzene, 50 g of n-butyl nitrite and 250 g of DMF into a flask, stir until dissolved and clear, and set aside.

[0070] Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime: The material was pumped into each fixed-bed reactor at a rate of 4 ml / min, and the feeding was completed in about 90 minutes. The material of the last stage fixed-bed reaction was pumped into a flask containing 300 g of dichloroethane and 56 g of acetic acid. After the pumping was completed, it was stirred at 5-10°C for 30 minutes, and the solid material was filtered out to obtain a 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution containing 50.8 g of the intermediate, with a yield of 91.53% (theoretical weight 55.5 g).

[0071] Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method": The above 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution was transferred to a pressure autoclave, chlorine gas was introduced at 10-15°C for chlorination, and after the chlorination was completed, the pH was adjusted to 8-9 with a saturated sodium carbonate solution, ethylene was introduced at 10-15°C, and the pressure of the reactor was controlled to be 0.5-0.6 MPa. The reaction was kept warm for 4 hours, the reaction solution was layered and washed with water, the solvent was removed under reduced pressure, and 150g of methanol was added for purification to obtain 49.2g of the product 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole with a purity of 99.14% and a yield of 88.97% (theoretical weight 55.3g). The total yield of the two steps was 81.32% (theoretical weight 60.5g).

[0072] Example 3: This example is a specific implementation example of preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

[0073] Some specific details of this embodiment are as follows:

[0074] Arrangement of fixed bed reactors: Four fixed bed reactors are used and arranged in series in sequence.

[0075] Preparation and loading of catalyst 4: Under dry conditions, 250 g of sodium methoxide and 50 g of porous activated carbon were fully stirred and loaded into a fixed bed reactor, and nitrogen was introduced for purging to evenly distribute the dehydrating agent on the reaction bed.

[0076] Cooling treatment of fixed bed reactor: introducing freezing liquid for cooling, the temperature of the first stage fixed bed reactor is -30~-25℃, the temperature of the second stage fixed bed reactor is -15~-10℃, the temperature of the third stage fixed bed reactor is -20~-15℃, and the temperature of the fourth stage fixed bed reactor is -15~-10℃.

[0077] Prepare a mixed solution of 4-methylsulfonyl-2,3-dimethylbromobenzene: put 50 g of 4-methylsulfonyl-2,3-dimethylbromobenzene, 40 g of n-butyl nitrite and 300 g of DMF into a flask, stir until dissolved and clear, and set aside.

[0078] Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime: The material was pumped into each fixed bed reactor at a rate of 5 ml / min, and the feeding was completed in about 80 minutes. The material of the last fixed bed reaction was pumped into a flask containing 250 g of dichloroethane and 60 g of acetic acid. After the pumping was completed, it was stirred at 5-10°C for 30 minutes, and the solid material was filtered out to obtain a 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution containing 51 g of the intermediate with a yield of 91.89% (theoretical weight 55.5 g).

[0079] Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method": the above 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime solution was transferred to a pressure autoclave, chlorine gas was introduced at 5-10°C for chlorination, and after the chlorination was completed, the pH was adjusted to 8-9 with a saturated sodium carbonate solution, ethylene was introduced at 10-15°C, the pressure of the reactor was controlled to be 0.4-0.5 MPa, and the reaction was kept warm for 6 hours. The reaction solution was separated and washed with water, and the solvent was removed under reduced pressure. 150g of methanol was added for purification to obtain 49.7g of the product 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole with a purity of 99.07% and a yield of 89.55% (theoretical weight 55.5g). The total yield of the two steps was 82.15% (theoretical weight 60.5g).

[0080] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole, characterized in that: The method comprises the following steps: Step 1: Arrange fixed bed reactor: At least four fixed bed reactors are used, wherein the outer shell of the fixed bed reactor is provided with a jacket (1), and the jacket (1) is provided with an insulation layer (11); the fixed bed reactor is provided with a feed port (5), a discharge port (12), a nitrogen port (2), and a reserved port (3); the jacket (1) is provided with a first freezing liquid inlet (14) and a first freezing liquid outlet (8); an inner bypass pipe (10) is provided inside the fixed bed reactor, and two ends of the inner bypass pipe (10) are provided with a second freezing liquid inlet (13) and a second freezing liquid outlet (7), respectively; a multi-layer reaction bed plate (6) is provided inside the fixed bed reactor, and the reaction bed plate (6) is detachable, and a plurality of small holes (9) are provided on the reaction bed plate (6) for only solution outflow; Step 2: Prepare and load the catalyst (4): In a dry environment, the catalyst (4) and the solid dispersant are fully mixed, the catalyst (4) is respectively loaded onto the reaction bed plate (6) of each fixed bed reactor, and the catalyst (4) is evenly distributed on the reaction bed plate (6); the catalyst is one or a combination of sodium methoxide, potassium methoxide, sodium ethoxide, and sodium hydride; the solid dispersant is one or a combination of porous activated carbon, molecular sieve, activated silicon dioxide, and porous ceramics; Step 3: Assemble and precool the fixed bed reactor: The discharge port (12) of the first-stage fixed bed reactor is connected to the feed port (5) of the next-stage fixed bed reactor, and then each fixed bed reactor is pre-cooled to a temperature of -30 to -10°C; Step 4: Prepare a mixed solution of 4-methylsulfonyl-2,3-dimethylbromobenzene: Mix and dissolve 4-methylsulfonyl-2,3-dimethylbromobenzene, n-butyl nitrite and an aprotic solvent according to a certain proportion; Step 5: Preparation of 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime: The first stage fixed bed reactor pumps the mixed solution of the fourth step into the reactor from its feed port (5) so that the mixed solution is fully in contact with the catalyst (4). Then, the material is reacted at the reaction temperature for a preset time, and then the mixed solution material flows out through the small holes (9) on the reaction bed plate (6) and is then fed into the next stage fixed bed reactor through its discharge port (12). The reaction mixture of the last stage fixed bed reactor is mixed evenly with the pumped acetic acid and dichloroethane solution through its discharge port (12), and separated by a solid-liquid separator. The solid is the by-product sodium acetate, and the liquid is the 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed material liquid. The reaction temperatures of the first stage fixed bed reactor and each intermediate stage fixed bed reactor are -30 to -5°C, respectively, and the reaction temperature of the last stage fixed bed reactor is -10 to -5°C. Step 6: Preparation of 3-(3-bromo-2-methyl-6-methylthiophenyl)-4,5-dihydroisoxazole by "one-pot method": The 3-bromo-2-methyl-6-methylsulfonylbenzaldehyde oxime mixed liquid synthesized in the fifth step is transferred to a pressure autoclave, and chlorine is introduced for chlorination. After the chlorination is completed, the pH is adjusted to 8-9 with a weak base, nitrogen is replaced, ethylene gas is introduced, the temperature is controlled at 5-30°C, the pressure is 0.3-1Mpa, and the reaction is carried out for 4-10 hours. After the reaction is completed, the liquid is separated, washed with water, and the solvent is removed under reduced pressure. Methanol is added for purification, crystallization and filtration are performed, and the filter cake is dried to obtain the product 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole.

2. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole according to claim 1, characterized in that: The weight ratio of the catalyst to the solid dispersant is (1-10):

1.

3. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole according to claim 2, characterized in that: The aprotic solvent is one or a combination of N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

4. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole according to claim 3, characterized in that: The weight ratio of n-butyl nitrite, 4-methylsulfonyl-2,3-dimethylbromobenzene and aprotic solvent is (0.5-1):1:(2-10).

5. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole according to claim 4, characterized in that: In the fifth step, the rate of pumping materials into each fixed bed reactor is 1-100 ml / min.

6. A method for preparing 3-[3-bromo-2-methyl-6-(methylsulfonyl)phenyl]-4,5-dihydroisoxazole according to claim 1, characterized in that: The weak base is one or a combination of sodium carbonate, potassium carbonate, triethylamine, sodium phosphate, and sodium hydrogen phosphate.

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