A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole

Abstract

The present invention provides a preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, the preparation method comprising: dibromoformaldehyde oxime is mixed with isobutylene in a closed reaction device to obtain a mixture; an acid binding agent is added to the mixture, and the reaction is performed to obtain the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole; the pressure of the reaction is 0.1-5.0 MPa. The raw materials of the preparation method are easy to obtain, the process step is simple, the reaction conditions are mild, the preparation process is controllable, no catalyst is required, and there are few side reactions, and the raw material conversion rate is high, and high-purity, high-yield 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole can be obtained; meanwhile, the safety of the preparation method is good, green and environmentally friendly, and the escape of isobutylene or the potential safety hazard of the discharge are effectively avoided, and it is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic compound preparation, and specifically relates to a method for preparing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole. Background Art

[0002] Pyroxasulfone is an isoxazole herbicide developed by Kumizu Chemical Industries, Ltd. Its chemical name is 3-(5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)pyrazol-4-ylmethylsulfonyl)-4,5-dihydro-5,5-dimethyl-1,2-isoxazole (CAS: 447399-55-5), and its molecular formula is C 12 H 14 F 5 N 3 O 4 S, the structural formula is as follows: Sulfonepyraclostrobin can be used as a pre-emergence soil treatment agent in most crop fields. After application, it is absorbed by the young roots and shoots of weeds, which can inhibit the early growth of seedlings, destroy meristems and coleoptiles, and is a serious potential inhibitor of VLCFA (very long side-chain fatty acids, C20-C30) biosynthesis in plants.

[0003] 3-halogen-5,5-dimethyl-4,5-dihydroisoxazole ( Wherein, X represents halogen, usually Cl or Br) is a key intermediate for the synthesis of sulfonepyraclostrobin, and its product quality and preparation process will directly affect the large-scale production of sulfonepyraclostrobin. WO2007096576A1 discloses a hydroxyurea route, and the specific synthesis route is as follows:

[0004]

[0005] In this synthetic route, hydroxyurea and ethyl dimethacrylate are condensed and cyclized under the action of sodium methoxide to obtain 5,5-dimethyl-isoxazolidin-3-one (yield 49%), and then chlorinated to obtain 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole (yield 69%). The reaction cycle for preparing 5,5-dimethyl-isoxazolidin-3-one by this method is long, requiring more than 15 hours; the total yield of the route is about 33.8%, which is low and not suitable for industrialization.

[0006] BASF (WO2011063842A1, WO2011063843A1) discloses an acetone oxime route: X is Cl or Br. Acetone oxime reacts with 3-methyl-2-butenal in the presence of N-methylaniline trifluoroacetate to prepare 5,5-dimethyl-4,5-dihydroisoxazole (yield 76%), which is then halogenated with a halogenating agent to obtain 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole or 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole (yield 70%), with a total yield of about 53.2%. The raw material 3-methyl-2-butenal in this route can be prepared by oxidation of methylbutynol under high temperature conditions. The reaction conditions are harsh, and there are many impurities in the halogenation process, which is not easy to purify.

[0007] WO2007096576A1, WO2004014138A1, WO20080275249A1 and the like reported the dichloroformaldehyde oxime method: It uses glyoxylic acid as a raw material, and prepares 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole through oximation, chlorination, and cyclization. The main problems of this method are that dichloroformaldehyde is highly toxic, has poor thermal stability and is easily decomposed, and its activity is also poor. When it is cyclized with isobutylene, there are more impurities, and the total yield is low, only 33.19%.

[0008] The current mainstream synthesis method is the dibromoformaldehyde oxime method disclosed in WO2006038657A1, which uses glyoxylic acid as a raw material, and is prepared by oximation, bromination, and cyclization to obtain 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole. It is safe to use, has good activity, and has a high yield. The route is as follows:

[0009]

[0010] The scheme still has shortcomings in the cyclization step. First, a quaternary ammonium salt, a quaternary phosphonium salt or a crown ether is used as a phase transfer catalyst, or a polyalkylene glycol surfactant is used as a catalyst in the cyclization reaction to obtain a higher yield. However, the yield of the catalyst is 78-94%, the yield fluctuates greatly, is not stable enough, and the cost is increased. The catalyst eventually enters the water phase, which increases the difficulty of wastewater treatment. Second, the cyclization reaction is carried out under normal pressure, and gaseous isobutylene will inevitably escape partially. In order to reduce the escape, isobutylene is slowly introduced into the system four times, which is cumbersome to operate and difficult to control. Moreover, the amount of isobutylene used in the cyclization reaction needs to reach 3-6 equivalents, which shows that isobutylene is bound to escape, and isobutylene is a flammable and explosive toxic gas. The escape of isobutylene not only increases the cost of raw materials, but also has a huge impact on the environment, posing a safety hazard.

[0011] Therefore, it is an urgent problem to be solved in the art to develop a method for synthesizing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole with high yield, easy availability of raw materials, simple process, good safety and green environmental protection. Summary of the invention

[0012] In view of the deficiencies in the prior art, the object of the present invention is to provide a method for preparing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole. The raw materials of the preparation method are easily available, the process is simple, and high-yield and high-purity 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole can be obtained without using a catalyst. Moreover, the process is highly safe and environmentally friendly, and the potential safety hazards caused by isobutylene escape are effectively avoided.

[0013] To achieve this object, the present invention adopts the following technical solutions:

[0014] The invention provides a method for preparing 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole. The method comprises: mixing dibromoformaldehyde oxime with isobutylene in a closed reaction device to obtain a mixture; adding an acid binding agent to the mixture, reacting to obtain the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole; and the reaction pressure is 0.1-5.0 MPa.

[0015] In the present invention, the "reaction pressure" means the pressure gauge pressure (gauge pressure) of the reaction system, that is, normal pressure is 0 MPa; the reaction pressure is 0.1-5.0 MPa, for example, it can be 0.2 MPa, 0.3 MPa, 0.5 MPa, 0.7 MPa, 0.9 MPa, 1 MPa, 1.1 MPa, 1.3 MPa, 1.5 MPa, 1.8 MPa, 2 MPa, 2.5 MPa, 3 MPa, 3.5 MPa, 4 MPa or 4.5 MPa, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0016] The reaction formula of the preparation method provided by the present invention is as follows: The whole process is carried out in a closed reaction device, and a certain pressure (0.1-5.0 MPa) is applied, which promotes the full reaction of isobutylene and dibromoformaldehyde oxime, avoids the escape of isobutylene, and obtains 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole at an extremely high yield level without using a catalyst (without using a phase transfer catalyst or a surfactant); and the preparation method first mixes dibromoformaldehyde oxime with isobutylene, and then adds an acid binding agent to the mixed system, effectively inhibits the decomposition of dibromoformaldehyde oxime and other side reactions, improves the conversion rate of raw materials, and improves the yield and purity of the product, so that the yield of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole is ≥96.5%, and the purity is ≥96.8%. The process route of the preparation method is simple, green and environmentally friendly, and has high safety. No catalyst is required, and no complicated post-processing steps are required. The yield and purity of the obtained target product are high, and it is suitable for large-scale production.

[0017] Preferably, the molar ratio of dibromoformaldehyde oxime to isobutylene is 1:(1.1-2.5), for example, it can be 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 or 1:2.4, and more preferably 1:(1.1-1.5).

[0018] Preferably, the mixing temperature is -10 to 50°C, for example, it can be -8°C, -5°C, -2°C, 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range, and it is further preferably 0 to 20°C.

[0019] Preferably, the mixing method comprises: introducing isobutylene into the dibromoformaldehyde oxime solution, and mixing to obtain the mixture.

[0020] Preferably, the solvent of the solution includes any one of ester solvents, halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, alkane solvents or ketone solvents, or a combination of at least two of them; further preferably, it is any one of ester solvents, halogenated hydrocarbon solvents or ether solvents, or a combination of at least two of them.

[0021] Preferably, the solvent of the solution includes any one of ethyl acetate, butyl acetate, dimethyl carbonate, ethylene dichloride, chloroform, isopropyl ether, methyl tert-ether, toluene, xylene or methyl isobutyl ketone or a combination of at least two thereof, and more preferably any one of dimethyl carbonate, ethylene dichloride, isopropyl ether or methyl tert-ether or a combination of at least two thereof.

[0022] Preferably, the amount of the solvent in the solution is 400-2500 g, based on 1 mol of dibromoformaldehyde oxime, for example, 500 g, 800 g, 1000 g, 1200 g, 1500 g, 1800 g, 2000 g, 2200 g or 2400 g, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range.

[0023] Preferably, the molar ratio of the dibromoformaldehyde oxime to the acid binding agent is 1:(0.5-3.0), for example, it can be 1:0.6, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:2.2, 1:2.5 or 1:2.8, etc.

[0024] Preferably, the acid binding agent includes any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium sulfate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof.

[0025] Preferably, the acid binding agent is selected from any one of sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof, and the molar ratio of the acid binding agent to dibromoformaldehyde oxime is (1.1-3.0):1, for example, it can be 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.8:1, 2:1, 2.2:1, 2.5:1 or 2.8:1, etc., and is further preferably (1.2-1.5):1.

[0026] Preferably, the acid binding agent is selected from any one of sodium carbonate, potassium carbonate or sodium sulfate, or a combination of at least two thereof, and the molar ratio of the acid binding agent to dibromoformaldehyde oxime is (0.55-1.5):1, for example, it can be 0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or 1.4:1, etc.

[0027] Preferably, the acid binding agent is added to the mixture in the form of an aqueous solution thereof.

[0028] Preferably, the aqueous solution is a saturated aqueous solution, more preferably a saturated aqueous solution at 10°C.

[0029] Preferably, the acid binding agent is added at a temperature of -10 to 50°C, for example, -8°C, -5°C, -2°C, 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, as well as specific values ​​between the above values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific values ​​included in the range, and is further preferably 0 to 20°C.

[0030] Preferably, the addition time of the acid binding agent is 1 to 10 hours, for example, it can be 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours or 9 hours, as well as specific values ​​between the above points. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific points included in the range, and it is further preferably 2 to 5 hours.

[0031] Preferably, the reaction temperature is -10 to 50°C, for example, -8°C, -5°C, -2°C, 0°C, 2°C, 5°C, 8°C, 10°C, 12°C, 15°C, 18°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively enumerates the specific point values ​​included in the range, and it is further preferably 0 to 20°C.

[0032] As a preferred technical solution of the present invention, the system temperature in the preparation method (including the temperature of mixing dibromoformaldehyde oxime and isobutylene, the temperature of adding the acid binding agent, and the temperature of the reaction) is -10 to 50°C, and more preferably 0 to 20°C, which can not only effectively inhibit the decomposition of dibromoformaldehyde oxime, but also ensure the sufficient reaction of dibromoformaldehyde oxime and isobutylene.

[0033] Preferably, the reaction time is 1 to 6 h, for example, it can be 1.25 h, 1.5 h, 1.75 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 4.5 h, 5 h or 5.5 h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of simplicity, the present invention no longer exhaustively lists the specific point values ​​included in the range, and it is further preferably 1 to 2 h.

[0034] Preferably, the reaction pressure is 0.2-1.5 MPa.

[0035] Preferably, the closed reaction device is an autoclave.

[0036] Preferably, the preparation method further comprises the step of introducing an auxiliary gas.

[0037] The auxiliary gas is a gas that does not participate in the reaction (such as an inert gas); preferably, the auxiliary gas includes any one or a combination of two of air, nitrogen, carbon dioxide or helium, and more preferably nitrogen and / or carbon dioxide.

[0038] Preferably, the auxiliary gas is introduced into the reaction system before the acid binding agent is added.

[0039] In the present invention, the pressure (gauge pressure) of the reaction is 0.1 to 5.0 MPa, preferably 0.2 to 1.5 MPa, which can effectively inhibit the escape of isobutylene and promote the full reaction of dibromoformaldehyde oxime and isobutylene. The source of the pressure of the reaction includes auxiliary gas and / or acid binding agent (for example, any one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or a combination of at least two thereof).

[0040] In a preferred embodiment, the acid binding agent is selected from any one of sodium hydroxide, potassium hydroxide, sodium sulfate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof, and the source of the reaction pressure is an auxiliary gas.

[0041] In another preferred embodiment, the acid binding agent is selected from any one of sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, or a combination of at least two thereof. The acid binding agent can generate gas, so no auxiliary gas needs to be added to the reaction system.

[0042] Preferably, the reaction further comprises post-treatment of the product after completion.

[0043] Preferably, the post-treatment method includes delamination and desolvation.

[0044] Preferably, the preparation method comprises: in a closed reaction device, introducing isobutylene into a solution of dibromoformaldehyde oxime, mixing to obtain a mixture; adding an acid binding agent to the mixture, reacting for 1 to 6 hours under the conditions of 0.2 to 1.5 MPa and 0 to 20° C., to obtain the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole; the temperatures for introducing isobutylene and adding the acid binding agent are each independently 0 to 20° C.; the acid binding agent is added to the mixture in the form of an aqueous solution thereof, and the addition time is 2 to 5 hours; the molar ratio of the dibromoformaldehyde oxime, isobutylene and the acid binding agent is 1:(1.1 to 2.5):(0.5 to 3.0).

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] The preparation method provided by the present invention obtains the target product through the cyclization reaction of dibromoformaldehyde oxime and isobutylene, and the raw materials are easily available, the steps are simple, the process conditions are mild, the preparation process is controllable, no catalyst is required, and there are few side reactions and a high raw material conversion rate. The yield of the obtained 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole is ≥96.5% and the purity is 96.8-98%. At the same time, the preparation method has good safety, is green and environmentally friendly, effectively avoids the potential safety hazards of isobutylene escape or emission, and is suitable for industrial production. DETAILED DESCRIPTION

[0047] 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.

[0048] In the following examples and comparative examples of the present invention, dibromoformaldehyde oxime can be purchased from the market or prepared by methods described in the prior art, such as the method described in WO2006038657A1; the pressures mentioned in the examples and comparative examples are all gauge pressures (gauge pressures).

[0049] In the following examples and comparative examples of the present invention, the quantitative content (purity) of the product was measured by high performance liquid chromatography (HPLC, LC-20AT, Shimadzu, Japan) external standard method.

[0050] Example 1

[0051] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 100g of tertiary methyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 10°C, then introducing 17.0g of isobutylene (purity 99%, 0.3mol), at which time the system pressure is about 0.1MPa, and after the isobutylene is introduced, controlling the system temperature at 10-15°C, pumping in 137.8g of sodium carbonate solution (sodium carbonate is 0.13mol, and a 10% aqueous solution of sodium carbonate concentration is pumped in) within 3h, with the addition of an acid binding agent (sodium carbonate), the system produces carbon dioxide as a by-product, and the system pressure increases to 0.7MPa; after the acid binding agent is pumped in, the system is kept at 10-15°C for reaction for 1h, and the reaction is stopped. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and desolventization, 35.2 g of a yellow oily product, namely the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained, with a quantitative content of 97.7% and a yield of 97.1%.

[0052] Structural testing:

[0053] Ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) (m / z, ESI + ): 177.98617 (M+H) + ; Theoretical value: 177.98620 (positive ion).

[0054] 1 H-NMR (CDCl 3 , 400MHz): δ1.519 (s, 6H, CH 3 ), 3.105(s, 2H, CH 2 ).

[0055] Example 2

[0056] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 150g of dimethyl carbonate into an autoclave, sealing the system, starting stirring, lowering the system temperature to 15°C, then introducing 13.6g of isobutylene (purity 99%, 0.24mol), at which time the system pressure is about 0.05MPa, and after the isobutylene is introduced, controlling the system temperature at 15-20°C, pumping in 129.7g of potassium carbonate solution (0.14mol of potassium carbonate, and a 15% aqueous solution of potassium carbonate concentration) within 5h, with the addition of an acid binding agent (potassium carbonate), the system produces carbon dioxide as a by-product, and the system pressure rises to 0.7MPa, and after the acid binding agent is pumped in, keeping the temperature at 15-20°C for 2h for reaction, and then stopping the reaction. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and solvent removal, 35.2 g of a yellow oily product was obtained, which was the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, with a quantitative content of 97.9% and a yield of 97.3%.

[0057] Example 3

[0058] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 300g of isopropyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 5°C, then introducing 14.7g of isobutylene (purity 99%, 0.26mol), then introducing nitrogen until the system pressure reaches 1.0MPa, and after the gas is introduced, controlling the system temperature at 5-10°C, pumping in 32.0g of sodium hydroxide solution (0.24mol of sodium hydroxide, and a 30% aqueous solution of sodium hydroxide concentration) within 3h, then keeping the temperature at 5-10°C for reaction for 2h, and then stopping the reaction. After the autoclave was depressurized, the reaction solution was poured out, and 29.5 g of a yellow oily product, namely 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained by layering and desolvation, with a quantitative content of 91.7% and a yield of 76.4%. The acid binding agent in this embodiment is sodium hydroxide, which has a strong alkalinity, and the raw material dibromoformaldehyde oxime is decomposed more, resulting in a decrease in yield.

[0059] Example 4

[0060] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 500g of dichloroethane into an autoclave, sealing the system, starting stirring, lowering the system temperature to 0°C, then introducing 13.6g of isobutylene (purity 99%, 0.24mol), at which time the system pressure is about 0.05MPa, and after the isobutylene is introduced, controlling the system temperature at 0-5°C, pumping in 2h of 224.0g of sodium bicarbonate solution (sodium bicarbonate is 0.24mol, and a 9% aqueous solution of sodium bicarbonate concentration is pumped in), with the addition of an acid binding agent (sodium bicarbonate), the system produces carbon dioxide as a by-product, the system pressure rises to 0.6MPa, and the reaction is stopped after being kept at 0-5°C for 2h. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and desolventization, 35.4 g of a yellow oily product was obtained, namely the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, with a quantitative content of 96.8% and a yield of 96.8%.

[0061] Example 5

[0062] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 120g of tertiary methyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 5°C, then introducing 12.5g of isobutylene (purity 99%, 0.22mol), at which time the system pressure is about 0.05MPa, and after the isobutylene is introduced, controlling the system temperature at 10-15°C, pumping in 300.0g of potassium bicarbonate solution (0.3mol of potassium bicarbonate, and a 10% aqueous solution of potassium bicarbonate concentration) within 3h, and as an acid binding agent (potassium bicarbonate) is added, the system produces carbon dioxide as a by-product, the system pressure rises to 0.7MPa, and the reaction is stopped after being kept at 10-15°C for 1h. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and desolventization, 35.2 g of a yellow oily product, namely the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained, with a quantitative content of 97.8% and a yield of 97.2%.

[0063] Example 6

[0064] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 120g of isopropyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 5°C, then introducing 14.7g of isobutylene (purity 99%, 0.26mol), then introducing nitrogen until the system pressure reaches 0.5MPa, after the gas is introduced, controlling the system temperature at 10-15°C, pumping 224.0g of sodium bicarbonate solution (sodium bicarbonate is 0.24mol, and a 9% aqueous solution of sodium bicarbonate concentration is pumped in) within 3h, with the addition of an acid binding agent (sodium bicarbonate), the system produces carbon dioxide as a by-product, the system pressure rises to 1.2MPa, then keeping the temperature at 10-15°C for reaction for 1h, and then stopping the reaction. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and desolventization, 35.3 g of a yellow oily product, namely the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained, with a quantitative content of 97.6% and a yield of 97.3%.

[0065] Example 7

[0066] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 150g of tertiary methyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 0°C, then introducing 13.6g of isobutylene (purity 99%, 0.24mol), at which time the system pressure is about 0.05MPa, and after the isobutylene is introduced, controlling the system temperature at 0-5°C, pumping in 205.3g of sodium bicarbonate solution (sodium bicarbonate is 0.22mol, and a 9% aqueous solution of sodium bicarbonate concentration is pumped in) within 4h, with the addition of an acid binding agent (sodium bicarbonate), the system produces carbon dioxide as a by-product, and the system pressure increases to 0.4MPa; after the acid binding agent is pumped in, keeping the temperature at 0-5°C for 2h for reaction, and stopping the reaction. After the pressure in the autoclave was released, the reaction liquid was poured out, and after layering and desolventization, 35.1 g of a yellow oily product, namely the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained, with a quantitative content of 97.3% and a yield of 96.5%.

[0067] Example 8

[0068] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 100g of tertiary methyl ether into an autoclave, sealing the system, starting stirring, and introducing 17.0g of isobutylene (purity 99%, 0.3mol) at room temperature (about 25°C), at which the system pressure is about 0.1MPa. After the introduction of isobutylene, the system temperature is controlled at 30-35°C, 137.8g of sodium carbonate solution (sodium carbonate is 0.13mol, and a 10% aqueous solution of sodium carbonate concentration is introduced) is pumped in within 3h, and as an acid binding agent (sodium carbonate) is added, the system produces carbon dioxide as a by-product, and the system pressure increases to 0.7MPa; after the acid binding agent is pumped in, the system is kept at 30-35°C for reaction for 2h, and the reaction is stopped. After the autoclave was depressurized, the reaction solution was poured out, and 30.6 g of yellow oily product, i.e., the target product 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, was obtained by layering and desolvation, with a quantitative content of 93.2% and a yield of 80.6%. The reaction temperature in this embodiment was high, resulting in the decomposition of the raw material dibromoformaldehyde oxime, and the yield was significantly reduced.

[0069] Comparative Example 1

[0070] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 100g of tertiary methyl ether into an autoclave, sealing the system, starting stirring, lowering the system temperature to 5-10°C, and pumping in 137.8g of sodium carbonate solution (sodium carbonate is 0.13mol, and an aqueous solution with a sodium carbonate concentration of 10%) within 3h; then controlling the temperature to 5-10°C, introducing 17.0g of isobutylene (purity 99%, 0.3mol) into the system, and keeping the temperature at 5-10°C for 2h before stopping the reaction. After the autoclave is depressurized, the reaction liquid is poured out, and 31.5g of a yellow oily product is obtained through layering and desolventizing. The yellow oily product is quantitatively analyzed, and the content of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole is 42.1%, and the yield is 37.5%. In this comparative example, the order of feeding was changed, resulting in the decomposition of dibromoformaldehyde oxime under the action of sodium carbonate, and an intermolecular reaction also occurred, generating a large amount of impurity 3,6-dibromo-1,4,2,5-dioxadiazine, resulting in a significant decrease in yield.

[0071] Comparative Example 2

[0072] A preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole comprises the following specific steps: adding 41.8g of dibromoformaldehyde oxime (purity 96%, 0.2mol) and 100g of tertiary methyl ether into a four-necked bottle, starting stirring, adding 137.8g of sodium carbonate solution (sodium carbonate is 0.13mol, and an aqueous solution with a sodium carbonate concentration of 10%) at room temperature (about 25°C); then controlling the temperature at 40°C and introducing 17.0g of isobutylene (purity 99%, 0.3mol) into the system for cyclization reaction; after the introduction, filtering and desolventizing to obtain 26.4g of a yellow oily product, wherein the yellow oily product has a 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole content of 12.5% ​​and a yield of 9.3% through quantitative analysis. In this comparative example, the order of feeding was changed and the reaction temperature was increased, which intensified the decomposition of dibromoformaldehyde oxime under the action of sodium carbonate. At the same time, intermolecular reactions occurred to generate a large amount of impurity 3,6-dibromo-1,4,2,5-dioxadiazine, resulting in a significant decrease in yield.

[0073] The applicant declares that the present invention illustrates the preparation method of 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole 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-bromo-5,5-dimethyl-4,5-dihydroisoxazole, characterized in that: The preparation method comprises: mixing dibromoformaldehyde oxime and isobutylene in a closed reaction device to obtain a mixture; adding an acid binding agent to the mixture for reaction to obtain the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole; the reaction pressure is 0.2-1.5 MPa; the reaction temperature is 0-20° C.; the molar ratio of the dibromoformaldehyde oxime to the isobutylene is 1:(1.1-2.5); the acid binding agent comprises any one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium sulfate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof.

2. The preparation method according to claim 1, characterized in that: The molar ratio of the dibromoformaldehyde oxime to isobutylene is 1:(1.1-1.5).

3. The preparation method according to claim 1, characterized in that: The mixing temperature is -10 to 50°C.

4. The preparation method according to claim 3, characterized in that: The mixing temperature is 0-20°C.

5. The preparation method according to claim 1, characterized in that: The mixing method comprises: introducing isobutylene into the dibromoformaldehyde oxime solution, and mixing to obtain the mixture.

6. The preparation method according to claim 5, characterized in that: The solvent of the solution includes any one of ester solvents, halogenated hydrocarbon solvents, ether solvents, aromatic hydrocarbon solvents, alkane solvents or ketone solvents, or a combination of at least two thereof.

7. The preparation method according to claim 6, characterized in that: The solvent of the solution is any one of an ester solvent, a halogenated hydrocarbon solvent or an ether solvent, or a combination of at least two of them.

8. The preparation method according to claim 6, characterized in that: The solvent of the solution includes any one of ethyl acetate, butyl acetate, dimethyl carbonate, ethylene dichloride, chloroform, isopropyl ether, methyl tert-ether, toluene, xylene or methyl isobutyl ketone, or a combination of at least two thereof.

9. The preparation method according to claim 8, characterized in that: The solvent of the solution is any one of dimethyl carbonate, ethylene dichloride, isopropyl ether or methyl tert-ether, or a combination of at least two thereof.

10. The preparation method according to claim 5, characterized in that: In the solution, based on the usage of dibromoformaldehyde oxime as 1 mol, the usage of the solvent is 400-2500 g.

11. The preparation method according to claim 1, characterized in that: The molar ratio of the dibromoformaldehyde oxime to the acid binding agent is 1:(0.5-3.0).

12. The preparation method according to claim 1, characterized in that: The acid binding agent is selected from any one of sodium bicarbonate, potassium bicarbonate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof, and the molar ratio of the acid binding agent to dibromoformaldehyde oxime is (1.1-3.0):

1.

13. The preparation method according to claim 1, characterized in that: The acid binding agent is selected from any one of sodium carbonate, potassium carbonate or sodium sulfate or a combination of at least two thereof, and the molar ratio of the acid binding agent to dibromoformaldehyde oxime is (0.55-1.5):

1.

14. The preparation method according to claim 1, characterized in that: The acid binding agent is added to the mixture in the form of an aqueous solution thereof.

15. The preparation method according to claim 14, characterized in that: The aqueous solution is a saturated aqueous solution.

16. The preparation method according to claim 1, characterized in that: The acid binding agent is added at a temperature of -10 to 50°C.

17. The preparation method according to claim 16, characterized in that: The acid binding agent is added at a temperature of 0 to 20°C.

18. The preparation method according to claim 1, characterized in that: The acid binding agent is added for 1 to 10 hours.

19. The preparation method according to claim 18, characterized in that: The acid binding agent is added for 2 to 5 hours.

20. The preparation method according to claim 1, characterized in that: The reaction time is 1 to 6 hours.

21. The preparation method according to claim 20, characterized in that: The reaction time is 1 to 2 hours.

22. The preparation method according to claim 1, characterized in that: The closed reaction device is an autoclave.

23. The preparation method according to claim 1, characterized in that: The preparation method also includes the step of introducing auxiliary gas.

24. The preparation method according to claim 23, characterized in that: The auxiliary gas includes any one of air, nitrogen, carbon dioxide or helium, or a combination of two of them.

25. The preparation method according to claim 24, characterized in that: The auxiliary gas is nitrogen and / or carbon dioxide.

26. The preparation method according to claim 23, characterized in that: The auxiliary gas is introduced into the reaction system before the acid binding agent is added.

27. The preparation method according to claim 1, characterized in that: After the reaction is completed, the product may be post-processed.

28. The preparation method according to claim 27, characterized in that: The post-treatment method includes delamination and desolvation.

29. The preparation method according to claim 1, characterized in that: The preparation method comprises: in a closed reaction device, introducing isobutylene into a solution of dibromoformaldehyde oxime, mixing to obtain a mixture; adding an acid binding agent into the mixture, reacting for 1 to 6 hours under the conditions of 0.2 to 1.5 MPa and 0 to 20° C., to obtain the 3-bromo-5,5-dimethyl-4,5-dihydroisoxazole; the temperatures for introducing isobutylene and adding the acid binding agent are independently 0 to 20° C.; the acid binding agent is added into the mixture in the form of its aqueous solution, and the adding time is 2 to 5 hours; the molar ratio of the dibromoformaldehyde oxime, isobutylene and the acid binding agent is 1:(1.1 to 2.5):(0.5 to 3.0); the acid binding agent comprises any one of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium sulfate, sodium bisulfate, sodium methoxide or sodium ethoxide, or a combination of at least two thereof.

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