A process for the preparation of 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole

Abstract

The present application relates to the technical field of organic synthesis, and provides a preparation method of 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole.The present application uses 3-amino-o-xylene as a starting material, and through diazotization, bromination, oxidation, oximation, chlorination and 1,3-dipole addition reaction, 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole is obtained;in the diazotization reaction, the present application uses a magnesium oxide supported titanium polyalkyl copper supported catalyst, which can significantly improve the selectivity and yield of the reaction, and the catalyst can be recycled and reused, thereby reducing the generation of solid waste;the present application combines the three reactions of oximation, chlorination and 1,3-dipole addition into a continuous one-step reaction, thereby eliminating the intermediate treatment process of the oximation and chlorination reactions, simplifying the synthesis steps, reducing the difficulty of the synthesis process of the key intermediate, and greatly improving the selectivity and yield of the product.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole. Background Technology

[0002] The chemical structure of 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole is as follows:

[0003]

[0004] 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole is a key intermediate for benzoxazine; this intermediate only requires a one-step carbonylation reaction with 5-hydroxy-1-methylpyrazole to synthesize benzoxazine technical. Benzoxazine is a novel hydroxyphenyl pyruvate dioxygenase inhibitor (4-HPPD) recently developed and marketed by BASF in Germany. It is a post-emergence herbicide for cornfields and is a broad-spectrum post-emergence herbicide with good control effects against weeds resistant to glyphosate, triazine, acetolactate synthase (ALS) inhibitors, and acetyl-CoA carboxylase (ACCase) inhibitors.

[0005] Related technologies have reported the synthesis of intermediate 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole from 3-nitro-o-xylene as a starting material via oximeization, chlorination, 1,3-dipolar addition, reduction, diazotization, and oxidation. However, this synthetic route has poor selectivity and low product yield. Summary of the Invention

[0006] In view of this, the present invention provides a method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole. The preparation method provided by the present invention has good unit reaction selectivity, high product yield, simple operation, and readily available raw materials.

[0007] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0008] A method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole includes the following steps:

[0009] A mixture of 3-amino-o-xylene, dimethyl disulfide, a copper-containing catalyst, and n-butyl nitrite was subjected to a diazotization reaction to obtain a compound with the structure shown in Formula B; the copper-containing catalyst was a magnesium oxide-supported titanium polyalkyl copper-supported catalyst.

[0010]

[0011] The compound with the structure shown in Formula B, bromine, and solvent are mixed and subjected to a bromination reaction to obtain the compound with the structure shown in Formula C.

[0012]

[0013] The compound with the structure shown in Formula C, acetic acid, sodium tungstate and an oxidant are mixed and subjected to an oxidation reaction to obtain the compound with the structure shown in Formula D.

[0014]

[0015] The compound with the structure shown in Formula D, a basic catalyst, n-butyl nitrite, and a solvent are mixed and subjected to an oxime reaction to obtain a reaction solution containing the compound with the structure shown in Formula E. The pH of the reaction solution containing the compound with the structure shown in Formula E is adjusted to 2-3, and then a chlorinating reagent is added to carry out a chlorination reaction to obtain a reaction solution containing a chlorinated intermediate. The reaction solution containing the chlorinated intermediate, an acid-binding agent, and ethylene are mixed and subjected to a 1,3-dipolar addition reaction to obtain 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole; the structural formula of the chlorinated intermediate is shown in Formula F.

[0016]

[0017] Preferably, the preparation method of the magnesium oxide-supported titanium polyalkylene copper-supported catalyst includes the following steps:

[0018] Magnesium oxide, titanium tetrachloride, benzene solvent and ammonia were mixed and carried out in the first reaction to obtain magnesium oxide supported polytitanium alkane;

[0019] The magnesium oxide-supported polytitane, copper salt, and alcohol are mixed and subjected to a second reaction to obtain the magnesium oxide-supported titanium polyalkane copper-supported catalyst.

[0020] Preferably, the molar ratio of magnesium oxide to titanium tetrachloride is 1 to 5:1; the mass ratio of magnesium oxide to benzene solvent is 1:1.5 to 3; the mass ratio of magnesium oxide-supported polytitane to copper salt is 1:0.01 to 0.07; and the mass ratio of magnesium oxide to alcohol is 1:4 to 6.

[0021] The temperature of the first reaction is 0–30°C, the pressure is 1–2.5 MPa, and the reaction time is 5–12 h;

[0022] The temperature of the second reaction is 70–85°C, and the reaction time is 5–12 hours.

[0023] Preferably, the molar ratio of 3-amino-o-xylene to butyl nitrite used in the diazotization reaction is 1:1 to 1.2; the mass ratio of 3-amino-o-xylene to the copper-containing catalyst is 1:0.01 to 0.05; and the molar ratio of 3-amino-o-xylene to dimethyl disulfide is 1:1 to 4.5.

[0024] In the diazotization reaction, n-butyl nitrite is added dropwise over a period of 1–3 hours.

[0025] The diazotization reaction is carried out at a temperature of 10–50 °C for 1–3 h.

[0026] Preferably, after the diazotization reaction is completed, the resulting reaction solution is filtered, and the resulting solid is a recycled catalyst, which is reused.

[0027] Preferably, the molar ratio of the compound with the structure shown in Formula B to bromine is 1:1 to 1.3; the bromine is added dropwise over a period of 1 to 3 hours; the bromination reaction is carried out at a temperature of 25 to 30°C for a period of 1 to 3 hours.

[0028] Preferably, the oxidant is hydrogen peroxide; the molar ratio of the compound with the structure shown in Formula C to the oxidant is 1:2.5 to 3; the mass ratio of the compound with the structure shown in Formula C, acetic acid, and sodium tungstate is 1:21 to 3:0.01 to 1.

[0029] The oxidation reaction is carried out at a temperature of 35–45°C for 2–3 hours.

[0030] Preferably, the alkaline catalyst comprises one or more of sodium alkoxide, potassium alkoxide, and alkali metal carbonate; the solvent for the oxime reaction comprises one or more of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, ethanol, and 1,8-diazabicyclo[5.4.0]undec-7-ene;

[0031] The mass ratio of the compound with the structure shown in Formula D to the solvent used in the oxime reaction is 1:4 to 8; the molar ratio of the compound with the structure shown in Formula D to the basic catalyst is 1:1.5 to 3; the molar ratio of the compound with the structure shown in Formula D to n-butyl nitrite used in the oxime reaction is 1:1.2 to 2.5.

[0032] The oxime reaction is carried out at a temperature of -30 to 30°C for a time of 1 to 6 hours.

[0033] Preferably, the molar ratio of the compound with the structure shown in Formula D to the chlorinating reagent is 1:1 to 2.2; the chlorinating reagent is N-chlorosuccinimide.

[0034] The chlorination reaction is carried out at a temperature of -30 to 30°C for 1 to 5 hours.

[0035] Preferably, the acid-binding agent comprises one or more of amine compounds and alkali metal carbonates; the molar ratio of the compound with the structure shown in Formula D to the acid-binding agent is 1:1 to 3;

[0036] The 1,3-dipolar addition reaction is carried out at a temperature of 10–80 °C, a pressure of 0.1–2 MPa, and a time of 1–3 h.

[0037] This invention provides a method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole. The method uses 3-amino-o-xylene as a starting material and proceeds through diazotization, bromination, oxidation, oxime formation, chlorination, and a 1,3-dipolar addition reaction to obtain the 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole. This invention employs a magnesium oxide-supported titanium polyalkylene copper-supported catalyst to catalyze the diazotization reaction, which significantly improves the selectivity and yield of the reaction. Example results show that the selectivity of the diazotization reaction reaches over 98%, and the product yield reaches over 96%. Furthermore, the magnesium oxide-supported titanium polyalkylene copper-supported catalyst can be recycled, reducing the generation of solid waste. Furthermore, this invention combines the three-step reactions of oximation, chlorination, and 1,3-dipolar addition into a single continuous reaction, eliminating the intermediate processing steps of the oximation and chlorination reactions, simplifying the synthesis steps, reducing the difficulty of synthesizing key intermediates, and greatly improving the selectivity and yield of the product. The results of the examples show that, using the method of this invention for the oximation, chlorination, and 1,3-dipolar addition reactions, the selectivity of the oximation intermediate, chlorination intermediate, and target product reaches over 98%, and the final content of 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole can reach over 99.0%, with a yield of over 95%. Detailed Implementation

[0038] This invention provides a method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole, comprising the following steps:

[0039] A mixture of 3-amino-o-xylene, dimethyl disulfide, a copper-containing catalyst, and n-butyl nitrite was subjected to a diazotization reaction to obtain a compound with the structure shown in Formula B; the copper-containing catalyst was a magnesium oxide-supported titanium polyalkyl copper-supported catalyst.

[0040]

[0041] The compound with the structure shown in Formula B, bromine, and solvent are mixed and subjected to a bromination reaction to obtain the compound with the structure shown in Formula C.

[0042]

[0043] The compound with the structure shown in Formula C, acetic acid, sodium tungstate and an oxidant are mixed and subjected to an oxidation reaction to obtain the compound with the structure shown in Formula D.

[0044]

[0045] The compound with the structure shown in Formula D, a basic catalyst, n-butyl nitrite, and a solvent are mixed and subjected to an oxime reaction to obtain a reaction solution containing the compound with the structure shown in Formula E. The pH of the reaction solution containing the compound with the structure shown in Formula E is adjusted to 2-3, and then a chlorinating reagent is added to carry out a chlorination reaction to obtain a reaction solution containing a chlorinated intermediate. The reaction solution containing the chlorinated intermediate, an acid-binding agent, and ethylene are mixed and subjected to a 1,3-dipolar addition reaction to obtain 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole; the structural formula of the chlorinated intermediate is shown in Formula F.

[0046]

[0047] In this invention, the synthetic route for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole is as follows:

[0048]

[0049] The following is a detailed explanation of the synthetic route.

[0050] This invention involves a diazotization reaction of 3-amino-o-xylene (structural formula A as shown in the synthetic route), dimethyl disulfide, a copper-containing catalyst, and n-butyl nitrite to obtain a compound with the structure shown in formula B. The copper-containing catalyst is a magnesium oxide-supported titanium polyalkyl copper supported catalyst. In this invention, the magnesium oxide-supported titanium polyalkyl copper supported catalyst preferably comprises a magnesium oxide support and titanium polyalkyl copper supported on the magnesium oxide support.

[0051] In this invention, the preparation method of the magnesium oxide-supported titanium polyalkylene copper-supported catalyst preferably includes the following steps: mixing magnesium oxide, titanium tetrachloride, benzene solvent and ammonia to carry out a first reaction to obtain magnesium oxide-supported polytitane; mixing the magnesium oxide-supported polytitane, copper salt and alcohol to carry out a second reaction to obtain the magnesium oxide-supported titanium polyalkylene copper-supported catalyst; the molar ratio of magnesium oxide to titanium tetrachloride is preferably 1-5:1, more preferably 4-4.5:1; the mass ratio of magnesium oxide to benzene solvent is preferably 1:1.5-3, more preferably 1:1.7-2.3; the benzene solvent is preferably benzene; the mass ratio of magnesium oxide-supported polytitane to copper salt is preferably 1:0.01-0.07, more preferably 1:0.05-0.06; the copper salt is preferably copper chloride, specifically copper chloride dihydrate; the mass ratio of magnesium oxide to alcohol is preferably 1:4-6, and the alcohol is preferably ethanol.

[0052] In this invention, the temperature of the first reaction is preferably 0–30°C, more preferably 20–30°C; the pressure of the first reaction is preferably 1–2.5 MPa, more preferably 1.5–2 MPa; and the time of the first reaction is preferably 5–12 h, more preferably 8–10 h. In a specific embodiment of this invention, magnesium oxide and titanium tetrachloride are preferably stirred evenly in a benzene solvent, and then ammonia gas is introduced at 2–3 MPa, controlling the reaction pressure at 1–2.5 MPa, and the reaction is carried out under heat and pressure conditions. After the first reaction is completed, the resulting reaction solution is preferably filtered after standing to obtain a wet product of magnesium oxide-supported polytitane (MgO-Ti-N). The wet product is dried and ground to obtain the magnesium oxide-supported polytitane (MgO-Ti-N). The drying temperature is preferably 400–600°C, more preferably 450–500°C, and the drying time is preferably 2–10 h. The drying is preferably carried out in a muffle furnace. This invention removes moisture and residual organic solvents from the product through drying.

[0053] In this invention, the reaction principle of the first reaction is shown in the following formula:

[0054]

[0055] In this invention, the preferred temperature for the second reaction is 70–85°C, and the preferred reaction time is 5–12 h. In a specific embodiment of this invention, the second reaction is preferably carried out under reflux conditions. Preferably, the magnesium oxide-supported polytitane and copper salt are added to alcohol for a reflux reaction. When the reaction solution becomes colorless and transparent, and the solid becomes light green, the resulting reaction solution is cooled, allowed to stand, filtered, and dried to obtain the magnesium oxide-supported titanium polyane copper-supported catalyst (MgO-Ti-N-Cu). The equation for the second reaction is as follows:

[0056]

[0057] In this invention, the molar ratio of 3-amino-o-xylene to n-butyl nitrite is preferably 1:1 to 1.2, more preferably 1:1.2; the mass ratio of 3-amino-o-xylene to the copper-containing catalyst is preferably 1:0.01 to 0.05, more preferably 1:0.02 to 0.04; the molar ratio of 3-amino-o-xylene to dimethyl disulfide is preferably 1:1 to 4.5, more preferably 1:3 to 4; in this invention, the n-butyl nitrite is preferably added dropwise for 1 to 3 hours; the temperature of the diazotization reaction is preferably 10 to 50°C; the reaction time is preferably 1 to 3 hours, and the diazotization reaction time is started from the time when the n-butyl nitrite is completely added.

[0058] In a specific embodiment of the present invention, copper-containing catalyst, dimethyl disulfide, and 3-amino-o-xylene are preferably added to the reaction apparatus first, stirred evenly, and then n-butyl nitrite is added dropwise. After the addition is complete, the mixture is kept at a constant temperature to carry out the diazotization reaction. After GC sampling analysis shows that 3-amino-o-xylene is ≤1wt%, the reaction is stopped.

[0059] In this invention, after the diazotization reaction is completed, the resulting reaction solution is preferably filtered, and the resulting solid is a recovered catalyst, which is reused. After desolventizing the filtrate, a compound with the structure shown in Formula B is obtained. The desolventizing method is preferably vacuum distillation.

[0060] After obtaining the compound with the structure shown in Formula B, the present invention mixes the compound with the structure shown in Formula B, bromine, and a solvent to carry out a bromination reaction to obtain the compound with the structure shown in Formula C. In the present invention, the molar ratio of the compound with the structure shown in Formula B to bromine is preferably 1:1 to 1.3, more preferably 1:1.05; the bromine is added dropwise, and the dropwise addition time is preferably 1 to 3 hours; the temperature of the bromination reaction is preferably 25 to 30°C, and the reaction time is preferably 1 to 3 hours; the solvent used in the bromination reaction is preferably a chloroalkane, more preferably dichloromethane.

[0061] In a specific embodiment of the present invention, it is preferable to first add the compound with the structure shown in Formula B and the solvent to the reaction flask, and then slowly add bromine dropwise. After the addition is complete, the reaction is carried out at 25-30°C. HPLC sampling and analysis are used to track the reaction. The reaction endpoint is defined as ≤1.0 wt% of the compound with the structure shown in Formula B and ≥95.0% of the product content. After post-processing, the compound with the structure shown in Formula C is obtained.

[0062] After obtaining the compound with the structure shown in Formula C, the present invention mixes the compound with the structure shown in Formula C, acetic acid, sodium tungstate, and an oxidant to carry out an oxidation reaction to obtain the compound with the structure shown in Formula D. In the present invention, the oxidant is preferably hydrogen peroxide, which is preferably used in the form of hydrogen peroxide solution; the molar ratio of the compound with the structure shown in Formula C to the oxidant is preferably 1:2.5 to 3; the mass ratio of the compound with the structure shown in Formula C, acetic acid, and sodium tungstate is preferably 1:1 to 3:0.01 to 0.1, more preferably 1:2:0.05; the temperature of the oxidation reaction is preferably 35 to 45°C, and the reaction time is preferably 2 to 3 hours.

[0063] In a specific embodiment of the present invention, it is preferable to first add the compound with the structure shown in Formula C, acetic acid, and sodium tungstate to the reaction apparatus, stir evenly, and then slowly add hydrogen peroxide dropwise. After the addition is complete, the reaction is kept at 35-45°C. HPLC sampling and analysis are used to track the reaction, and the reaction endpoint is defined as ≤1.0 wt% of the compound with the structure shown in Formula C. After the oxidation reaction is completed, it is preferable to cool the obtained reaction solution to room temperature, and after post-processing, obtain a wet product, which is then dried by forced air to obtain the compound with the structure shown in Formula D.

[0064] After obtaining the compound with the structure shown in Formula D, the present invention mixes the compound with the structure shown in Formula D, a basic catalyst, n-butyl nitrite, and a solvent to carry out an oxime reaction to obtain a reaction solution containing the compound with the structure shown in Formula E. In the present invention, the basic catalyst preferably includes one or more of sodium alkoxide, potassium alkoxide, and alkali metal carbonate; the sodium alkoxide preferably includes one or more of sodium methoxide, sodium ethoxide, and sodium tert-butoxide; the potassium alkoxide preferably includes one or more of potassium methoxide, potassium ethoxide, and potassium tert-butoxide; and the alkali metal carbonate is preferably potassium carbonate. In a specific embodiment of the present invention, the basic catalyst is preferably sodium alkoxide or potassium alkoxide, more preferably sodium ethoxide or potassium ethoxide.

[0065] In this invention, the solvent for the oxime reaction preferably includes one or more of tetrahydrofuran (THF), dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), dimethylacetamide (DMAC), ethanol, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), more preferably one of DMAC and DBU.

[0066] In this invention, the mass ratio of the compound with the structure shown in Formula D to the solvent used in the oxime reaction is preferably 1:4 to 8, more preferably 1:4 to 6; the molar ratio of the compound with the structure shown in Formula D to the basic catalyst is preferably 1:1.5 to 3, more preferably 1:2 to 2.5; the molar ratio of the compound with the structure shown in Formula D to n-butyl nitrite is preferably 1:1.2 to 2.5, more preferably 1:1.8 to 2.3; the temperature of the oxime reaction is preferably -30 to 30°C, the reaction time is preferably 1 to 6 hours, and the oxime reaction is preferably carried out under nitrogen protection.

[0067] In a specific embodiment of the present invention, preferably, the compound with the structure shown in Formula D, the solvent, and the basic catalyst are first added to the reaction apparatus and stirred until homogeneous. The temperature is then controlled at -30 to 30°C, and butyl nitrite is added dropwise under nitrogen protection. After the addition is complete, the mixture is kept at this temperature for further reaction. HPLC sampling and analysis are performed, with the reaction endpoint defined as ≤1 wt% of the compound with the structure shown in Formula D. No post-processing is required after the reaction is complete.

[0068] After obtaining a reaction solution containing the compound shown in Formula E, the pH of the reaction solution containing the compound shown in Formula E is adjusted to 2-3, and then a chlorination reagent is added to carry out a chlorination reaction to obtain a reaction solution containing a chlorinated intermediate. In this invention, the reagent used to adjust the pH is preferably hydrochloric acid; the molar ratio of the compound shown in Formula D to the chlorination reagent is preferably 1:1-2.2, more preferably 1:1.1-1.2; the chlorination reagent is preferably N-chlorosuccinimide (NCS); the temperature of the chlorination reaction is preferably -30 to 30°C, and the reaction time is preferably 1-5 h; in a specific embodiment of this invention, it is preferred to monitor the reaction by HPLC central control analysis, with the endpoint of the chlorination reaction being ≤1 wt% of the compound shown in Formula E; no post-processing is required after the chlorination reaction is completed.

[0069] After obtaining the reaction solution containing the chlorinated intermediate, the present invention mixes the reaction solution containing the chlorinated intermediate with an acid-binding agent and ethylene to carry out a 1,3-dipolar addition reaction to obtain the 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole. In the present invention, the acid-binding agent preferably includes one or more of amine compounds and alkali metal carbonates; the amine compounds preferably include one or more of triethylamine, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N,N-diisopropylethylamine (DIPEA), and diisopropylamine (DIPA); the alkali metal carbonate is preferably potassium carbonate; the molar ratio of the compound with the structure shown in Formula D to the acid-binding agent is preferably 1:1 to 3, more preferably 1:1 to 1.3;

[0070] In this invention, the preferred temperature for the 1,3-dipolar addition reaction is 10–80°C, more preferably 20–30°C; the preferred reaction pressure is 0.1–2 MPa, more preferably 0.3–0.5 MPa; and the preferred reaction time is 1–3 h. In a specific embodiment of this invention, the reaction solution containing the chlorinated intermediate is preferably transferred to a high-pressure reactor, followed by sequential nitrogen and ethylene gas purging, then triethylamine is added, and ethylene is introduced until the pressure reaches 0.1–2 MPa. The 1,3-dipolar addition reaction is carried out under heat and pressure conditions. HPLC analysis is used during the reaction, and the reaction endpoint is defined as ≤1 wt% of the compound with the structure shown in Formula E.

[0071] After the 1,3-dipolar addition reaction is completed, the solvent of the obtained reaction solution is preferably recovered under reduced pressure. The residue is mixed with dichloromethane and water, stirred until the solid is completely dissolved, and then allowed to stand for separation. The obtained organic layer is washed and desolventized to obtain a crude product. The crude product is then slurried with ethanol, filtered, and dried to obtain 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole (structural formula as shown in formula G in the synthetic route). The washing of the organic layer is preferably performed sequentially with sodium hydroxide solution and water. The volume fraction of ethanol used for slurrying is preferably 70%.

[0072] The technical solutions of this invention will be clearly and completely described below with reference to the embodiments thereof. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0073] Example 1: Preparation of magnesium oxide-supported titanium polyalkylene copper (MgO-Ti-N-Cu) supported catalyst

[0074] 20g of magnesium oxide, 23.29g of titanium tetrachloride, and 40g of benzene were added to a high-pressure reactor and stirred until homogeneous. The mixture was cooled to 30℃, and 2.0MPa of ammonia gas was introduced. The pressure was controlled at 1.5MPa, and the reaction was maintained at pressure for 8 hours. After the reaction was completed, water was added to the reaction solution, stirred until homogeneous, and allowed to stand. The mixture was then filtered to obtain a filter cake, which was washed three times with water (20mL each time) to obtain a wet product. The wet product was then dried in a muffle furnace at 480℃ to obtain 16.1g of MgO-Ti-N.

[0075] The 16.1g MgO-Ti-N obtained in the previous step was added to the reaction flask, followed by the addition of 0.97g copper chloride dihydrate and 96.6g ethanol. The mixture was stirred until homogeneous, heated to 80℃, and refluxed for 8 hours. After reflux, the mixture was cooled to 30℃ and allowed to stand for 1 hour. The mixture was then filtered to obtain a wet product of magnesium oxide-supported titanium polyalkyl copper MgO-Ti-N-Cu. After drying, 28.11g of the final product was obtained.

[0076] Example 2 Synthesis of the compound (2,3-methylbenzyl sulfide) with the structure shown in Formula B

[0077]

[0078] 10 g of 3-amino-o-xylene, 31.3 g of dimethyl disulfide, and 0.2 g of catalyst MgO-Ti-N-Cu (prepared in Example 1) were added to a reaction flask and stirred until homogeneous. 10.7 g of n-butyl nitrite was slowly added dropwise over 2 hours at 30°C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. HPLC sampling and analysis were performed until the 3-amino-o-xylene content was ≤1.0 wt% and the product yield was 98.6%. The mixture was filtered, and the catalyst cake was reused for the next batch. The filtrate was desolventized and then distilled at a pressure of 100–150 Pa and a temperature of 85–130°C to obtain 12.04 g of the compound with the structure shown in Formula B, with a purity of 99.3% and a yield of 95.6%.

[0079] Comparative Example 1: Copper powder was used as a catalyst.

[0080] 10 g of 3-amino-o-xylene, 60 g of dimethyl disulfide, and 2.1 g of copper powder were added to a 250 mL reaction flask and stirred until homogeneous. 10.7 g of n-butyl nitrite was slowly added dropwise over 2 hours at 40 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. HPLC analysis was performed using controlled sampling. The reaction proceeded until 3-amino-o-xylene was ≤1.0 wt%, and the product yield was 82.3%. The mixture was filtered, and the filtrate was desolventized and distilled at 100–150 Pa and 85–130 °C to obtain 10.7 g of the compound with the structure shown in Formula B, with a purity of 91.3% and a yield of 78.1%.

[0081] Comparative Example 2 uses cuprous chloride as a catalyst

[0082] 10 g of 3-amino-o-xylene, 60 g of dimethyl disulfide, and 2.1 g of cuprous chloride were added to a 250 mL reaction flask and stirred until homogeneous. 10.7 g of n-butyl nitrite was slowly added dropwise over 2 hours at 40 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. HPLC analysis was performed using controlled sampling. The reaction proceeded until 3-amino-o-xylene was ≤1.0 wt%, and the product yield was 82.3%. The mixture was filtered, and the filtrate was desolventized and distilled at a pressure of 100–150 Pa and a temperature of 85–130 °C to obtain 8.7 g of the compound with the structure shown in Formula B, with a purity of 68.3% and a yield of 47.78%.

[0083] Comparative Example 3 uses copper chloride as a catalyst

[0084] 10 g of 3-amino-o-xylene, 60 g of dimethyl disulfide, and 2.1 g of copper chloride were added to a 250 mL reaction flask and stirred until homogeneous. 10.7 g of n-butyl nitrite was slowly added dropwise over 2 hours at 40 °C. After the addition was complete, the reaction was maintained at this temperature for 2 hours. HPLC analysis was performed using controlled sampling. The reaction proceeded until 3-amino-o-xylene was ≤1.0 wt%, and the product yield was 82.3%. The mixture was filtered, and the filtrate was desolventized and distilled at 100–150 Pa and 85–130 °C to obtain 7.1 g of the compound with the structure shown in Formula B, with a purity of 76.1% and a yield of 43.4%.

[0085] The experimental results of Example 2 and Comparative Examples 1-3 are listed in Table 1.

[0086] Table 1 Comparative experimental data of catalysts

[0087] Example 2 Comparative Example 1 Comparative Example 2 Comparative Example 3 catalyst MgO-Ti-N-Cu (2%) Copper powder Cuprous chloride Copper chloride reaction temperature 30℃ 30℃ 30℃ 30℃ reaction time 2h 2h 2h 2h Compound B content % 99.3 91.3 68.3 76.1 3-Amino-o-xylene content / % 0.24 8.5 19.6 12.7 Yield of compound B (%) 95.6 78.1 47.78 43.4

[0088] As can be seen from Table 1, when using the MgO-Ti-N-Cu catalyst, the purity and yield of the product are much higher than those of copper powder, cuprous chloride and copper chloride.

[0089] Examples 3-6

[0090] The filter cake catalyst from Example 2 was reused in Example 3, and the filter cake catalyst from Example 3 was reused again, for a total of 4 batches. The reaction conditions for Examples 3 to 6 were the same as those for Example 2. The experimental data are shown in Table 2.

[0091] Table 2. Experimental data for the catalyst MgO-Ti-N-Cu.

[0092]

[0093]

[0094] As can be seen from Table 2, after the catalyst MgO-Ti-N-Cu is used four times, the product still has high selectivity and the product purity can still reach 99%.

[0095] Examples 7-9

[0096] The other conditions were the same as in Example 2, except that the amount of catalyst was changed. The purity and yield of the products obtained under different catalyst amounts are shown in Table 3.

[0097] Table 3 Purity and yield of products obtained under different catalyst dosages

[0098]

[0099] As can be seen from the data in Table 3, high purity and product yield can be obtained when the catalyst mass is 1% to 5% of 2,3-methylaniline.

[0100] Example 10

[0101] Synthesis steps three and four

[0102] The reaction equation is as follows:

[0103]

[0104] 20g of compound B was added to a reaction flask and mixed with 40ml of dichloromethane. 1.37mol of Br2 was slowly added dropwise at 30℃ over 2 hours. After the addition was complete, the mixture was kept at this temperature for 1 hour. HPLC analysis showed that compound B was ≤1.0 wt%. 40ml of water was added and stirred until homogeneous. The mixture was allowed to stand to separate the oil layer, which was then washed twice with water (40ml each time). The oil layers were combined and dried over anhydrous sodium sulfate. The oil layer was then concentrated to obtain 29.65g of compound C with a purity of 98.68% and a yield of 97.46%. This 29.65g of compound C was added to a reaction flask, followed by 1.48g of sodium tungstate and 59.3g of acetic acid. The mixture was stirred until homogeneous. 39.25g of hydrogen peroxide (0.318mol) was added dropwise at 35℃ over 2 hours. After the addition was complete, the mixture was kept at this temperature for 1 hour. HPLC analysis showed that compound C was ≤1.0%. The intermediate sulfoxide ≤1.0% was cooled to room temperature, stirred for 1 hour, filtered, and the filter cake was washed twice with water (60 ml / time). The wet product of compound D was obtained by filtration and dried at 70°C for 3 hours to obtain 32.84 g of the compound product with a purity of 99.1% and a yield of 95.2%.

[0105] Example 11

[0106] Synthesis steps four, five, and six

[0107]

[0108] Add 20g of the compound with the structure shown in formula D, 120g of DBU, and 13.1g of sodium ethoxide to a reaction flask. Cool to between -10 and 10°C, under nitrogen protection, and stir until homogeneous. Add 18.7g of n-butyl nitrite dropwise. After completion, maintain the reaction temperature and analyze under HPLC control until the compound with the structure shown in formula D is ≤1wt%. Add 19.88g (0.199mol) of hydrochloric acid dropwise to adjust the pH of the reaction solution to 3. After the addition is complete, stir for 0.5h. Add 11.12g of NCS in portions. After the addition is complete, stir for 1h. Analyze under HPLC control until the compound with the structure shown in formula E is ≤1wt%. The reaction solution was transferred to a high-pressure reactor, purged with nitrogen and then with ethylene gas. 9.11 g of triethylamine was added, and ethylene was introduced at a pressure of 0.5 MPa. The reaction was carried out for 1 h, and the reaction was controlled by HPLC. The reaction was stopped when the compound with the structure shown in formula E was ≤1 wt%. The mixed solution of DBU and n-butanol was recovered under reduced pressure. After recovery, 60 mL of dichloromethane and 40 mL of water were added and stirred until completely dissolved. The mixture was allowed to stand and separate into layers. The oil layer was washed three times with 5% NaOH (20 g / time) and three times with water (20 g / time) to remove solvent, yielding a brownish-yellow solid. 60 g of the solid was slurried once with 70% ethanol and filtered to obtain the solid. The solid was dried at 70 °C to obtain 22.98 g of 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole product with a purity of 99.0% and a yield of 95.4%.

[0109] Examples 12-16

[0110] Other conditions are the same as in Example 11, except that the type or amount of solvent is changed. Specific conditions are shown in Table 4. The purity and yield of the target product 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole are shown in Table 4.

[0111] Table 4. Product yield and purity under different solvent types or amounts.

[0112]

[0113] As shown in Table 4, the purity and yield of the product are highest when DBU is used as the solvent.

[0114] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole, characterized in that, Includes the following steps: A mixture of 3-amino-o-xylene, dimethyl disulfide, a copper-containing catalyst, and n-butyl nitrite was subjected to a diazotization reaction to obtain a compound with the structure shown in Formula B; the copper-containing catalyst was a magnesium oxide-supported titanium polyalkyl copper-supported catalyst. The compound with the structure shown in Formula B, bromine, and solvent are mixed and subjected to a bromination reaction to obtain the compound with the structure shown in Formula C. The compound with the structure shown in Formula C, acetic acid, sodium tungstate and an oxidant are mixed and subjected to an oxidation reaction to obtain the compound with the structure shown in Formula D. The compound with the structure shown in Formula D, an alkaline catalyst, n-butyl nitrite, and a solvent are mixed and subjected to an oxime reaction to obtain a reaction solution containing the compound with the structure shown in Formula E; the pH value of the reaction solution containing the compound with the structure shown in Formula E is adjusted to 2-3, and then a chlorination reagent is added to carry out a chlorination reaction to obtain a reaction solution containing a chlorinated intermediate. The reaction solution containing the chlorinated intermediate, an acid-binding agent, and ethylene were mixed and subjected to a 1,3-dipolar addition reaction to obtain the 3-[3-bromo-2-methyl-6-methylsulfonylphenyl]-4,5-dihydroisoxazole; the structural formula of the chlorinated intermediate is shown in Formula F.

2. The preparation method according to claim 1, characterized in that, The preparation method of the magnesium oxide-supported titanium polyalkylene copper-supported catalyst includes the following steps: Magnesium oxide, titanium tetrachloride, benzene solvent and ammonia were mixed and carried out in the first reaction to obtain magnesium oxide supported polytitanium alkane; The magnesium oxide-supported polytitane, copper salt, and alcohol are mixed and subjected to a second reaction to obtain the magnesium oxide-supported titanium polyalkane copper-supported catalyst.

3. The preparation method according to claim 2, characterized in that, The molar ratio of magnesium oxide to titanium tetrachloride is 1–5:1; the mass ratio of magnesium oxide to benzene solvent is 1:1.5–3; the mass ratio of magnesium oxide-supported polytitane to copper salt is 1:0.01–0.07; and the mass ratio of magnesium oxide to alcohol is 1:4–6. The temperature of the first reaction is 0–30°C, the pressure is 1–2.5 MPa, and the reaction time is 5–12 h; The temperature of the second reaction is 70–85°C, and the reaction time is 5–12 hours.

4. The preparation method according to claim 1, characterized in that, The molar ratio of 3-amino-o-xylene to butyl nitrite used in the diazotization reaction is 1:1 to 1.2; the mass ratio of 3-amino-o-xylene to the copper-containing catalyst is 1:0.01 to 0.05; and the molar ratio of 3-amino-o-xylene to dimethyl disulfide is 1:1 to 4.

5. In the diazotization reaction, n-butyl nitrite is added dropwise over a period of 1–3 hours. The diazotization reaction is carried out at a temperature of 10–50 °C for 1–3 h.

5. The preparation method according to claim 1 or 4, characterized in that, After the diazotization reaction is completed, the resulting reaction solution is filtered, and the resulting solid is the recovered catalyst, which can be reused.

6. The preparation method according to claim 1, characterized in that, The molar ratio of the compound with the structure shown in Formula B to bromine is 1:1 to 1.3; the bromine is added dropwise over a period of 1 to 3 hours; the bromination reaction is carried out at a temperature of 25 to 30°C for a period of 1 to 3 hours.

7. The preparation method according to claim 1, characterized in that, The oxidant is hydrogen peroxide; the molar ratio of the compound with the structure shown in Formula C to the oxidant is 1:2.5-3; the mass ratio of the compound with the structure shown in Formula C, acetic acid, and sodium tungstate is 1:1-3:0.01-1; The oxidation reaction is carried out at a temperature of 35–45°C for 2–3 hours.

8. The preparation method according to claim 1, characterized in that, The alkaline catalyst includes one or more of sodium alkoxide, potassium alkoxide, and alkali metal carbonate; the solvent for the oxime reaction includes one or more of tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, dimethylacetamide, ethanol, and 1,8-diazabicyclo[5.4.0]undec-7-ene. The mass ratio of the compound with the structure shown in Formula D to the solvent used in the oxime reaction is 1:4 to 8; the molar ratio of the compound with the structure shown in Formula D to the basic catalyst is 1:1.5 to 3; the molar ratio of the compound with the structure shown in Formula D to n-butyl nitrite used in the oxime reaction is 1:1.2 to 2.

5. The oxime reaction is carried out at a temperature of -30 to 30°C for a time of 1 to 6 hours.

9. The preparation method according to claim 1, characterized in that, The molar ratio of the compound with the structure shown in Formula D to the chlorinating reagent is 1:1 to 2.2; the chlorinating reagent is N-chlorosuccinimide. The chlorination reaction is carried out at a temperature of -30 to 30°C for 1 to 5 hours.

10. The preparation method according to claim 1, characterized in that, The acid-binding agent includes one or more of amine compounds and alkali metal carbonates; the molar ratio of the compound with the structure shown in Formula D to the acid-binding agent is 1:1 to 3; The 1,3-dipolar addition reaction is carried out at a temperature of 10–80 °C, a pressure of 0.1–2 MPa, and a time of 1–3 h.

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