Preparation method of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole

Abstract

The invention discloses a preparation method of 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole, which comprises the following steps: taking a hydroxylamine oxygen sulfonic acid aqueous solution and isopentenal as raw materials, carrying out oximation reaction in an organic solvent under an alkaline condition, then directly adding an acid or an organic base catalyst into the reaction system, and reacting for 2-4 hours to obtain 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole, thereby obtaining the 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole. Under the catalytic action of the catalyst, a cyclization reaction is carried out, after the reaction is finished, an intermediate solution containing 5, 5-dimethyl-4, 5-dihydroisoxazole is obtained, and the next step is directly carried out; and carrying out a chlorination reaction by taking the intermediate solution as a raw material and sodium hypochloride or chlorine as a chlorination reagent, and after the reaction is finished, carrying out post-treatment to obtain the 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole. The hydroxylamine oxygen sulfonic acid is used for enabling the isopentenal to be subjected to oximation reaction under the alkaline condition, then cyclization is carried out under the catalytic action of acid or alkali, the 5, 5-dimethyl-4, 5-dihydroisoxazole is generated, and the process has the advantages that the yield is high, the production steps are simplified, and the production cost is reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole. BACKGROUND

[0002] Pyroxasulfone is a pre-planting herbicide developed by Nippon Shokubai Co., Ltd. and Meiji Co., Ltd. It is widely used in crops such as wheat, corn, rice and sunflower. Compared with the traditional herbicide acetochlor, pyroxasulfone has a small dosage, a long persistence period and a good market development prospect. 5,5-dimethyl-4,5-dihydroisoxazole is an important intermediate for synthesizing pyroxasulfone.

[0003] Patent CN2023112579851 discloses a method for synthesizing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole. The patent uses isobutyraldehyde as a starting material, reacts with nitromethane to form 2-hydroxy-3-methyl-1-nitrobutane, and then generates 5,5-dimethyl-4,5-dihydroisoxazole under the catalytic conditions of an organic acid or an organic base. Finally, 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is obtained by chlorination with chlorine. This method needs to use nitrobutane, which is a flammable liquid. Its vapor can form an explosive mixture with air, and the process has high risk. The synthesis route is as follows: .

[0004] Patent CN119192093 B (Quzhou Kaiwo Chemical Co., Ltd.) discloses a route using acetic acid oxime as a starting material to prepare the target product in two steps: in the first step (S1), acetic acid oxime reacts with N-chlorosuccinimide in a solvent to obtain a reaction solution containing dichloromethyl oxime; in the second step (S2), dichloromethyl oxime reacts with isobutene in water in the presence of a catalyst (such as copper chloride, cuprous chloride, etc.) and a base (such as potassium bicarbonate, sodium carbonate, etc.), and after treatment, 5,5-dimethyl-3-chloro-4,5-dihydroisoxazole is obtained. Although this method optimizes the reaction conditions and the yield is improved to 43%-65% (GC purity >98%), it still has problems such as a wide range of solvent usage (200-2000 mL / mol of acetic acid oxime) and a low yield under some conditions (such as a yield of 43% when the solvent is toluene), and it needs to use isobutene gas as a raw material, which has high requirements for the sealing property of the reaction equipment.

[0005] .

[0006] Patent CN111393427 B (Anhui Jiuyi Agricultural Co., Ltd.) discloses a route, which takes 3,3-dimethyl ethyl acrylate (compound I) as a starting material, generates intermediate II (5,5-dimethyl-4,5-dihydroisoxazole-3-carboxylic acid) through cyclization reaction, and then takes phosphorus pentachloride or phosphorus oxychloride as a chlorinating reagent to perform chlorination reaction at 20-30 DEG C to obtain a target product (intermediate III). This method has two key deficiencies: first, the activity difference of the chlorinating reagent is large, and when phosphorus oxychloride is used, the yield is only 45%, which is much lower than 90% of phosphorus pentachloride; second, intermediate II (cyclization reaction yield 80%) needs to be synthesized through multiple steps first, and then chlorination is performed, the overall step is long, intermediate loss is increased, and the use of phosphorus pentachloride needs to be strictly controlled in terms of moisture (it reacts violently with water), which is harsh to the operating environment.

[0007] . SUMMARY

[0008] In view of the problems of many by-products in the synthesis of the intermediate 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole of metrafenone and complicated preparation process, the present application provides a synthesis method of the intermediate 5,5-dimethyl-4,5-dihydroisoxazole of metrafenone, aiming to reduce production cost and simplify synthesis steps.

[0009] The technical scheme adopted by the present application is as follows: A preparation method of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, comprising the following steps: .

[0010] Step 1: oximation reaction occurs between hydroxylamine sulfonic acid aqueous solution and isopentenyl aldehyde in an organic solvent under alkaline conditions, then an acid or an organic base catalyst is directly added into the reaction system, cyclization reaction occurs under the catalysis of the catalyst, and after the reaction is completed, an intermediate solution containing 5,5-dimethyl-4,5-dihydroisoxazole is obtained, which directly enters the next step; Step 2: chlorination reaction is performed between the intermediate solution and sodium hypochlorite or chlorine as a chlorinating reagent, after the reaction is completed, 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is obtained through post-treatment.

[0011] Further, in step 1, the molar ratio of hydroxylamine sulfonic acid to isopentenyl aldehyde is 1:0.8-1.2, preferably 1:1.

[0012] Further, in step 1, the pH condition of the oximation reaction is 7-8, the reaction temperature is 10-20 DEG C, preferably 15±2 DEG C, and the reaction time is 20-60 min, preferably 30-40 min.

[0013] Further, in step 1, the catalyst is one of nitric acid, trifluoroacetic acid, maleic acid, p-toluenesulfonic acid, N-methyl aniline, morpholine, pyrrolidine, and the molar ratio of the catalyst to isopentenal is 0.05-0.2:1, preferably 0.1-0.15:1.

[0014] Further, in step 1, the temperature of the cyclization reaction is 40-60℃, preferably 45-50℃, and the reaction time is 4-8h, preferably 5-6h.

[0015] Further, in step 2, when chlorine is used as the chlorination reagent, the reaction temperature is adjusted to 0-10℃, and chlorine is passed until the reaction is complete; in step 2, when sodium hypochlorite is used as the chlorination reagent, the reaction temperature is adjusted to 0-10℃, and an excess of sodium hypochlorite solution is added to the intermediate solution, the pH is adjusted to 2-3, and the reaction is allowed to proceed to completion.

[0016] Further, in step 1, the organic solvent is one or a combination of halogenated alkanes, benzene solvents, chlorobenzene solvents, and ether solvents.

[0017] Further, in step 1, the organic solvent is insoluble in water and is selected from one or more of dichloromethane, dichloroethane, toluene, and chlorobenzene, and the corresponding post-processing step in step 2 is: after the reaction is completed, the layers are separated by standing, the aqueous phase is extracted with the same extractant as the organic solvent, the organic phases are combined, and the liquid obtained by desolventizing is washed with water, and the aqueous phase is separated, and the organic phase is the target product.

[0018] Further, in step 1, the organic solvent is soluble in water and is selected from one or both of tetrahydrofuran and ethylene glycol dimethyl ether, and the corresponding post-processing step in step 2 is: after the reaction is completed, desolventize, and the liquid obtained by desolventizing is washed with water, and the aqueous phase is separated, and the organic phase is the target product.

[0019] Compared with the prior art, the present application has the following advantages: (1) Hydroxylamine sulfonic acid is used to oxime the isopentenal under alkaline conditions, and then cyclization under the catalysis of acid or base to generate 5,5-dimethyl-4,5-dihydroisoxazole, which has the advantages of high yield, simplified production steps, and reduced production cost. In the presence of an acid catalyst (selected from nitric acid, trifluoroacetic acid, maleic acid, and p-toluenesulfonic acid) or an acid-base catalyst (the acid is selected from nitric acid, trifluoroacetic acid, maleic acid, and p-toluenesulfonic acid; the base is selected from N-methyl aniline, morpholine, and pyrrolidine), an α,β-unsaturated carbonyl compound reacts with hydroxylamine to prepare an isoxazoline compound.

[0020] (2) The reaction conditions of the present application are mild, the operation difficulty and cost are low, and the yield and concentration of the product are both high.

[0021] (3) The 5,5-dimethyl-4,5-dihydroisoxazole solution prepared from isopentenal does not need to be separated and purified by desolventization, The 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is prepared by one-step reaction of adding sodium hypochlorite or chlorine in the original solvent system, with high yield and good purity. DETAILED DESCRIPTION

[0022] The application will be further described in conjunction with specific examples, but the scope of protection of the application is not limited thereto.

[0023] The route for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is shown as follows: .

[0024] Example 1: Preparation of an intermediate

[0025] Take 500 mL four-necked flask, add hydroxylamine sulfonic acid 67 g (592.9 mmol) and 24.5 g water, heat to dissolve, then cool to 15 ℃, add 70 g dichloromethane as a reaction solvent, then add 50 g isopentenal (595.2 mmol) dropwise, after the dropwise addition is completed, add liquid alkali to the reaction system, control the pH between 7-8, then incubate at 15 ℃±2 ℃ for 30 minutes, after the incubation is completed, add catalyst maleic acid 10 g (86.20 mmol) to the reaction system, warm to 48 ℃ and continue to incubate for 6 hours, after the time index is reached, take a sample for detection, after the reaction is qualified, transfer the material in the four-necked flask to a separatory funnel, and stand for 30 minutes. Collect the organic phase, extract the aqueous phase with 50 g dichloromethane once, and combine the organic phases to obtain a dichloromethane solution of the intermediate. The obtained dichloromethane solution of the intermediate is subjected to negative pressure desolventization to obtain 5,5-dimethyl-4,5-dihydroisoxazole, with a content of 95.6% and a yield of 94.4%.

[0026] Example 2: Preparation of an intermediate

[0027] The experimental process of Example 2 is repeated as in Example 1, except that "the catalyst maleic acid is replaced by the same molar amount of trifluoroacetic acid, nitric acid, p-toluenesulfonic acid, N-methyl aniline or morpholine", and the rest of the conditions remain unchanged.

[0028] The experimental data when different catalysts are selected in Example 2 are shown in Table 1.

[0029] Table 1 .

[0030] Example 3: Preparation of an intermediate

[0031] The experimental procedure of Example 3 was repeated in Example 1, except that the reaction solvent dichloromethane was replaced with an equal mass of dichloroethane or chlorobenzene. All other conditions remained the same, and maleic acid was still used as the catalyst in Example 3.

[0032] Example 4: Preparation of intermediates

[0033] Take a 500mL four-necked flask, add 67g of hydroxylamine sulfonic acid and 24.5g of water, heat to dissolve, then cool to 15℃, add 70g of ethylene glycol dimethyl ether reaction solvent, then add 50g of isopentenal dropwise. After the addition is complete, add liquid alkali to the reaction system to control the pH between 7 and 8, then keep it at 15℃±2℃ for 30 minutes. After the incubation is complete, add 10g of maleic acid to the reaction system, raise the temperature to 48℃ and continue to keep it at 6 hours. After the time index is reached, take a sample for testing to obtain the intermediate ethylene glycol dimethyl ether-water solution, and perform negative pressure desolventizing to obtain 5,5-dimethyl-4,5-dihydroisoxazole.

[0034] The experimental data for Examples 3-4 using different reaction solvents are shown in Table 2.

[0035] Table 2 .

[0036] Example 5: Preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole

[0037] Step 1: Take a 500mL four-necked flask, add 67g of hydroxylamine sulfonic acid and 24.5g of water, heat to dissolve, then cool to 15℃, add 70g of dichloromethane reaction solvent, then add 50g of isopentenal dropwise. After the addition is complete, add liquid alkali to the reaction system to control the pH between 7 and 8, then keep it at 15℃±2℃ for 30 minutes. After the incubation is complete, add 10g of maleic acid to the reaction system, raise the temperature to 48℃ and continue to keep it at 6 hours. After the time indicator is reached, take a sample for testing. If the reaction is qualified, the dichloromethane solution of the intermediate is obtained.

[0038] Step 2: The obtained intermediate solution in dichloromethane was subjected to dropwise addition of 530 g of 10% sodium hypochlorite at 7°C. Concentrated hydrochloric acid was added to adjust the pH to between 2 and 3. After the addition was complete, the solution was kept at this temperature for half an hour. Gas chromatography was used to detect the complete reaction of 5,5-dimethyl-4,5-dihydroisoxazole. The mixture was allowed to stand and separate into layers. The organic phase was collected, and the aqueous phase was extracted once with 50 g of dichloromethane. The organic phases were combined to obtain a dichloromethane solution of the product. The solvent was removed under reduced pressure to obtain 79.2 g of product, of which the content of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole was 95.6%, with a total yield of 92.3%.

[0039] Example 6: Preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole

[0040] Step 1: Take a 500mL four-necked flask, add 67g of hydroxylamine sulfonic acid and 24.5g of water, heat to dissolve, then cool to 15℃, add 70g of dichloromethane reaction solvent, then add 50g of isopentenal dropwise. After the addition is complete, add liquid alkali to the reaction system to control the pH between 7 and 8, then keep warm for 30 minutes. After the warming is complete, add 10g of maleic acid to the reaction system, raise the temperature to 48℃ and continue to keep warm for 6 hours. After the time indicator is reached, take a sample for testing. If the reaction is qualified, the dichloromethane solution of the intermediate is obtained.

[0041] Step 2: Cool the reaction system obtained in Step 1 to 7°C, and introduce 59g of chlorine gas for approximately 2 hours. After the chlorine gas is completely introduced, maintain the temperature for half an hour. Gas chromatography is used to determine if the 5,5-dimethyl-4,5-dihydroisoxazole reaction is complete. Allow the mixture to stand and separate into layers. Collect the organic phase. Extract the aqueous phase once with 50g of dichloromethane. Combine the organic phases to obtain a dichloromethane solution of the product. Remove the solvent under reduced pressure to obtain 78.5g of product, of which the 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole content is 95.2%, and the overall yield is 91.2%. Example 7: Preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole

[0042] Step 1: Take a 500mL four-necked flask, add 67g of hydroxylamine sulfonic acid and 24.5g of water, heat to dissolve, then cool to 15℃, add 70g of ethylene glycol dimethyl ether reaction solvent, then add 50g of isopentenal dropwise. After the addition is complete, add liquid alkali to the reaction system to control the pH between 7 and 8, then keep it at 15℃±10℃ for 30 minutes. After the incubation is complete, add 10g of maleic acid to the reaction system, raise the temperature to 48℃ and continue to keep it at 6 hours. After the time indicator is reached, take a sample for testing. If the reaction is qualified, the intermediate ethylene glycol dimethyl ether solution is obtained.

[0043] Step 2: The obtained intermediate ethylene glycol dimethyl ether solution was heated at 7°C, and 530 g of 10% sodium hypochlorite was added dropwise. Concentrated hydrochloric acid was added to adjust the pH to between 2 and 3. After the addition was complete, the mixture was kept at this temperature for half an hour. Gas chromatography was used to detect the complete reaction of 5,5-dimethyl-4,5-dihydroisoxazole. The mixture was then rotary evaporated until no fraction remained. 100 g of water was added to the rotary evaporator flask, and the product was washed to remove salts, yielding 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole with a purity of 93.4% and an overall yield of 89.4%. The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A process for the preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole, characterized in that, The method comprises the following steps: ； Step 1: oximation reaction is carried out in an organic solvent under alkaline conditions with hydroxylamine sulfonic acid aqueous solution and prenal as raw materials, then an acid or an organic base catalyst is directly added into the reaction system, and a cyclization reaction is carried out under the catalysis of the catalyst, and an intermediate solution containing 5, 5-dimethyl-4, 5-dihydroisoxazole is obtained after the reaction, which is directly used in the next step; Step 2: a chlorination reaction is carried out with sodium hypochlorite or chlorine gas as a chlorination reagent with the intermediate solution as raw material, and 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole can be obtained after post-treatment.

2. A process for the preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized in that, In step 1, the molar ratio of hydroxylamine sulfonic acid to prenal is 1:0.8-1.2, preferably 1:

1.

3. A process for the preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole as claimed in claim 1, wherein, In step 1, the pH condition of the oximation reaction is 7-8, the reaction temperature is 10-20 DEG C, preferably 15±2 DEG C, and the reaction time is 20-60 min, preferably 30-40 min.

4. The process for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, characterized by, In step 1, the catalyst is one of nitric acid, trifluoroacetic acid, maleic acid, p-toluenesulfonic acid, N-methylaniline, morpholine and pyrrolidine, and the molar ratio of the catalyst to prenal is 0.05-0.2:1, preferably 0.1-0.15:

1.

5. The process for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, wherein, ###00001### 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is prepared by the reaction of 3-chloro-5,5-dimethylisoxazole with a reducing agent in the presence of a solvent. In step 1, the temperature of the cyclization reaction is 40-60 DEG C, preferably 45-50 DEG C, and the reaction time is 4-8 h, preferably 5-6 h.

6. The process for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, wherein In step 2, when chlorine gas is used as the chlorination reagent, the reaction temperature is adjusted to 0-10 DEG C, and chlorine gas is passed until the reaction is complete; in step 2, when sodium hypochlorite is used as the chlorination reagent, the reaction temperature is adjusted to 0-10 DEG C, excess sodium hypochlorite solution is added into the intermediate solution, the pH is adjusted to 2-3, and the reaction is completed.

7. The process for preparing 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 1, wherein, ###00002### 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole is prepared by the reaction of 3-chloro-5,5-dimethylisoxazole with a reducing agent in the presence of a solvent. In step 1, the organic solvent is one or a combination of halogenated alkane solvents, benzene solvents, chlorobenzene solvents and ether solvents.

8. A process for the preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 7, characterized in that, The organic solvent in step 1 is insoluble in water and is selected from one or more of dichloromethane, dichloroethane, toluene and chlorobenzene, and the corresponding post-treatment step in step 2 is: after the reaction, the liquid is separated into layers, the water phase is extracted with the same extractant as the organic solvent, the organic phases are combined, the obtained liquid is washed with water, and the water phase is separated, and the organic phase is the target product.

9. A process for the preparation of 3-chloro-5,5-dimethyl-4,5-dihydroisoxazole according to claim 7, characterized in that, The organic solvent in step 1 is soluble in water and is selected from one or both of tetrahydrofuran and ethylene glycol dimethyl ether, and the corresponding post-treatment step in step 2 is: after the reaction, the liquid is desolventized, the obtained liquid is washed with water, the water phase is separated, and the organic phase is the target product.

Images