A process for the preparation of 5,5-disubstituted-4,5-dihydroisoxazoles
By reacting amine compounds with enaldehyde compounds under acid catalysis to generate compound III, and then cyclizing it with hydroxylamine or hydroxylamine salt, the problems of low yield and environmental unfriendliness in the prior art are solved, and the preparation of 5,5-disubstituted-4,5-dihydroisoxazole is achieved in a high-efficiency and economical manner, which is suitable for industrial applications.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU LIANHE CHEM TECH
- Filing Date
- 2024-12-31
- Publication Date
- 2026-06-30
AI Technical Summary
Existing methods for preparing 5,5-disubstituted-4,5-dihydroisoxazole suffer from problems such as low yield, expensive catalysts, and environmental unfriendliness.
A compound of formula III was prepared by reacting an amine compound with an enaldehyde compound under acid catalysis, followed by a cyclization reaction with hydroxylamine or hydroxylamine salt to prepare 5,5-disubstituted-4,5-dihydroisoxazole. This method uses an inexpensive acid catalyst and simplifies the processing steps after the cyclization reaction.
It improves reaction yield, reduces the generation of waste, lowers production costs, is suitable for industrial production, and is environmentally friendly.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing 5,5-disubstituted-4,5-dihydroisoxazole. Background Technology
[0002] 5,5-Disubstituted-4,5-dihydroisoxazole is an important intermediate in pharmaceuticals and pesticides, and its synthesis process and downstream products have a wide range of applications. Among them, pyroxasulfone is well-known as a herbicide with excellent herbicidal activity.
[0003] CN102666503A discloses a method for preparing 5,5-disubstituted 2-isooxazoline from an enal compound and acetone oxime under acid or acid-base catalysis, followed by vacuum distillation to obtain the 5,5-disubstituted 2-isooxazoline. The yield of this method is 66-84%. The specific synthetic route is shown below:
[0004]
[0005] The drawback of this method is that it generates a large amount of acetone byproducts, which are environmentally harmful wastes. Therefore, this synthesis method is environmentally unfriendly.
[0006] CN 111491926 A discloses a method for preparing 5,5-disubstituted-4,5-dihydroisoxazole by cyclization of an enal compound as a starting material, reacting it with hydroxylamine or hydroxylamine salt under alkaline conditions to generate an enal oxime, and then catalyzing it with acids such as nitric acid, trifluoroacetic acid, trichloroacetic acid, maleic acid, maleic anhydride, benzenesulfonic acid, and p-toluenesulfonic acid. The yield of this method is 70%-82%. The specific synthetic route is shown below:
[0007]
[0008] The disadvantages of this method are that the post-processing of the oxime products is complex, the yield is low, and the atom conversion rate is low.
[0009] CN 113891882 A discloses a method for preparing hydroxypropenal or methoxypropenal compounds from hydroxypropenol or methoxypropenol compounds using 2,2,6,6-tetramethylpiperidine 1-oxy radical, tetrabutylammonium bromide, etc., with sodium hypochlorite as a catalyst in the presence of phosphoric acid, copper, TBAB, etc., followed by reaction with acetone oxime to prepare dihydroisoxane. The yield of this method is 77-90%. The specific synthetic route is shown below:
[0010]
[0011] The catalyst used in this method is expensive, and it also introduces wastewater containing phosphorus / copper, which is not conducive to industrial production and poses a burden on the environment.
[0012] CN 115073390 A discloses a method for preparing 4,5-dihydroisoxazole derivatives from acrolein compounds and acetylhydroxylamine under acid catalysis, with yields ranging from 72.5% to 76.4%. The specific synthetic route is shown below:
[0013]
[0014] The drawback of this method is its low atomic conversion rate.
[0015] CN 116178294 A discloses a method for preparing acrolein oximes by reacting acrolein compounds with hydroxylamine, followed by cyclization under acid catalysis to obtain 5,5-dimethyl-4,5-dihydroisoxazole. The yield of this method is 79.36%-81.7%. The specific synthetic route is shown below:
[0016]
[0017] The catalyst used in this method is phosphotungstic acid, and phosphorus / tungsten-containing wastewater is introduced during the reaction, which poses a problem of environmental burden.
[0018] Therefore, there is an urgent need in this field for a new method for preparing 5,5-dimethyl-4,5-dihydroisoxazole that is environmentally friendly, increases yield, and meets the requirements for industrial production. Summary of the Invention
[0019] The technical problem to be solved by this invention is to overcome the shortcomings of existing methods for preparing 5,5-disubstituted-4,5-dihydroisoxazole, such as low yield, expensive catalysts, and environmental burden. This invention provides a cheap, economical, and environmentally friendly method for preparing 5,5-disubstituted-4,5-dihydroisoxazole, suitable for industrial-scale use.
[0020] The present invention mainly solves the above-mentioned technical problems through the following technical solutions:
[0021] This invention provides a method for preparing 5,5-disubstituted-4,5-dihydroisoxazole, which includes the following steps: under acid catalysis, a compound of formula III undergoes a cyclization reaction with "hydroxylamine and / or hydroxylamine salt" to obtain a compound of formula V;
[0022]
[0023] Wherein, R1 and R2 are each independently C1-C6 alkyl; R3 is hydrogen, C1-C6 alkyl, or C6-C 10Aryl or C6-C 10 Aryl-C1-C6 alkyl.
[0024] In one embodiment of the present invention, R3 is a C1-C6 alkyl group or a C6-C6 alkyl group. 10 Aryl group, preferably C1-C6 alkyl group.
[0025] In one embodiment of the present invention, R1 and R2 are each independently methyl.
[0026] In one embodiment of the present invention, R3 is methyl or phenyl.
[0027] In one embodiment of the present invention, the compound of formula III is N-(3-methyl-2-buten-1-yl)methylamine or N-(3-methyl-2-buten-1-yl)aniline; the corresponding compound of formula V is 5,5-dimethyl-4,5-dihydroisoxazole.
[0028] The hydroxylamine salt may be hydroxylamine hydrochloride or hydroxylamine sulfate.
[0029] The molar ratio of the compound of formula III and "hydroxylamine and / or hydroxylamine salt" can be 1:(0.5-5), for example 1:(1-3), or for example 1:1, 1:1.1, 1:1.5 or 1:3.
[0030] The acid catalyst may be selected from one or more of acetic acid, trifluoroacetic acid, trichloroacetic acid and dichloroacetic acid; preferably one to three types; more preferably one or two types; and even more preferably one type; the acid catalyst is preferably acetic acid or trifluoroacetic acid.
[0031] The molar ratio of the compound of formula III to the acid catalyst can be 1:(0.5-5), for example 1:(1-3), or even 1:1.
[0032] The cyclization reaction can be carried out in a solvent.
[0033] The solvent may be water or an organic solvent, wherein the organic solvent is one or more of benzene solvents, halogenated hydrocarbon solvents, ester solvents, nitrile solvents, and ketone solvents; preferably, the benzene solvent is chlorobenzene and / or toluene, the halogenated hydrocarbon solvent is dichloromethane and / or dichloroethane; the ester solvent is ethyl acetate; the nitrile solvent is acetonitrile; and the ketone solvent is acetone; more preferably, the solvent is water and acetone.
[0034] The mass ratio of the compound of formula III to the solvent can be 1:(1-5), for example 1:1.3.
[0035] The reaction temperature of the cyclization reaction can be 0-100℃, for example 0℃, 40℃, 50℃, 80℃ or 100℃, preferably 40-80℃.
[0036] The cyclization reaction can be monitored using conventional detection methods in the art (e.g., TLC, HPLC, or GC). The reaction endpoint is generally defined as the disappearance of the starting material. Preferably, the cyclization reaction takes 20-30 hours, for example, 25 hours.
[0037] The cyclization reaction may further include the following post-processing steps: removing the solvent, performing aqueous layer extraction, and performing vacuum distillation.
[0038] The preparation method of the 5,5-disubstituted-4,5-dihydroisoxazole further includes the following steps: reacting the compound of formula I with the compound of formula II in a Schiff base reaction to obtain the compound of formula III.
[0039]
[0040] R1, R2 and R3 are defined as described in any one of the present invention.
[0041] In one embodiment of the present invention, the compound of formula I is isopentenal.
[0042] In one embodiment of the present invention, the compound of formula II is methylamine or aniline, preferably methylamine. When the compound of formula II is methylamine, it can be added to the system in the form of an aqueous solution of methylamine or methylamine gas, wherein the aqueous solution of methylamine can be 30-40% (e.g., 35%).
[0043] The amounts of the compound of formula I and the compound of formula II can be the conventional amounts used in such reactions in the art. Preferably, the molar ratio of the compound of formula I to the compound of formula II is 1:(1-3), for example, 1:1, 1:1.1, 1:1.33 or 1:1.5, preferably 1:1.5, and more preferably 1:1.1.
[0044] The Schiff base reaction can be carried out in a solvent or without a solvent. When the reaction is carried out in the presence of a solvent, the solvent can be a solvent commonly used in this type of reaction in the art, for example, one or more of chlorobenzene, toluene, dichloromethane, dichloroethane, ethyl acetate, and acetonitrile. Preferably, the solvent is one or more of toluene, acetonitrile, dichloromethane, and ethyl acetate, and more preferably acetonitrile. Preferably, the Schiff base reaction is carried out in acetonitrile or without a solvent.
[0045] When the reaction is carried out in the presence of a solvent, the mass ratio of compound I to the solvent can be 1:(2-4), for example 1:3.7.
[0046] The Schiff base reaction can be carried out at a temperature that is conventional for this type of Schiff base reaction in the art. The Schiff base reaction temperature is -20-100℃, for example, -20℃, 0℃, 10℃, 20-25℃, 30℃, 50℃ or 100℃, preferably 0-50℃, and more preferably 10-30℃.
[0047] The progress of the Schiff base reaction can be monitored using conventional detection methods in the art (e.g., TLC, HPLC, or GC). The reaction endpoint is generally defined as the disappearance of the starting material. Preferably, the Schiff base reaction time is 0.3-5 hours, for example, 1 hour.
[0048] Preferably, no post-treatment is required after the Schiff base reaction, and the next reaction can proceed directly.
[0049] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.
[0050] The reagents and raw materials used in this invention are all commercially available.
[0051] The positive and progressive effects of this invention are as follows:
[0052] This invention synthesizes a compound of formula III using amine and enal compounds, and then reacts it with hydroxylamine and / or hydroxylamine salts under acid catalysis to generate 5,5-disubstituted-4,5-dihydroisoxazole. The introduction of amine compounds improves reaction selectivity and yield. Both the amine compounds and the solvent can be recycled, reducing waste generation. This method is industrially advantageous, economical, and environmentally friendly. Furthermore, this invention does not use expensive catalysts and can effectively produce the target compound through simple operation. Therefore, the method of this invention is industrially preferred and economical, environmentally friendly, and has high industrial value. Detailed Implementation
[0053] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.
[0054] Example 1
[0055] Preparation of imine compounds (formula III compounds)
[0056]
[0057] Add 56 g of acetonitrile and 15 g of isopentenal (purity 99%, 176.5 mmol) to a 250 ml four-necked flask. Maintain the temperature at 20–25 °C. Add 13.56 g (194.2 mmol) of 35% methylamine aqueous solution dropwise over 0.5 h. After the addition is complete, maintain the reaction temperature for 1 h. Take a sample and perform gas chromatography analysis. The resulting reaction mixture contains GC-A (formula I), 0.6%, and imine GC-A, 96.1% (excluding solvent). No further processing is required after the reaction; proceed directly to the next reaction step.
[0058] Examples 2 to 6
[0059] Except for the solvent being changed to that shown in the table below, the reaction and analysis were performed in the same manner as in Example 1.
[0060] The results of Examples 2 to 6 are shown in the table below.
[0061] Table 1
[0062]
[0063] Examples 7 to 9
[0064] Except for the change of ammonia source as shown in the table below, the reaction and analysis were carried out in the same manner as in Example 1.
[0065] The results of Examples 7 to 9 are shown in the table below.
[0066] Table 2
[0067]
[0068] Examples 10 to 18
[0069] Except for changing the reaction temperature and the equivalent of the 35% methylamine aqueous solution as shown in the table below, the reaction and analysis were performed in the same manner as in Example 1. The results of Examples 10 to 18 are shown in the table below.
[0070] Table 3
[0071]
[0072] Example 19
[0073] Manufacturing of 5,5-dimethyl-4,5-dihydroisoxazole
[0074] In a 250 ml four-necked flask, 13.6 g (194.2 mmol) of hydroxylamine hydrochloride, 19.8 g (1091 mmol) of water, and 10.6 g (174.8 mmol) of acetic acid were added. The temperature was maintained at 50 °C. The N-(3-methyl-2-buten-1-yl)methylamine (CAS: 744175-28-8) reaction solution from Example 2 was added dropwise to the four-necked flask. The temperature was maintained at 50 °C. 20.1 g of acetone was added to the reaction vessel, and the mixture was kept at this temperature for 25 h. The solvent was removed from the reaction mixture, and the aqueous layer was extracted twice with 50 ml of dichloromethane (2 times). The dichloromethane was removed under reduced pressure to obtain 5,5-dimethyl-4,5-dihydroisoxazole (14.9 g of colorless oil, purity: 96% (GC area percentage)): yield 81.8% (based on the two-step reaction yield of isopentenal).
[0075] Examples 20 to 22
[0076] Except for changing the reactant hydroxylamine hydrochloride and the catalyst used when the reactant is hydroxylamine hydrochloride as shown in the table below, the reaction and analysis were performed in the same manner as in Example 19. The results of Examples 20 to 22 are shown in the table below.
[0077] Table 4
[0078]
[0079] Examples 23 to 29
[0080] Except for changing the reaction temperature and the equivalent of hydroxylamine hydrochloride as the reactant as shown in the table below, the reaction and analysis were performed in the same manner as in Example 19. The results of Examples 23 to 29 are shown in the table below.
[0081] Table 5
[0082]
[0083] Examples 30 to 31
[0084] Except for changing the compound of formula III to that shown in the table below, the reaction and analysis were performed in the same manner as in Example 19. The results of Examples 30 to 31 are shown in the table below.
[0085]
[0086] Table 6
[0087]
Claims
1. A method for preparing 5,5-disubstituted-4,5-dihydroisoxazole, characterized in that, It includes the following steps: under acid catalysis, compound III undergoes a cyclization reaction with "hydroxylamine and / or hydroxylamine salt" to obtain compound V; wherein R1and R2are each independently C1-C6alkyl; R3is hydrogen, C1-C6alkyl, C6-C 10 aryl or C6-C 10 aryl-C1-C6alkyl.
2. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 1, characterized in that, It meets one or more of the following conditions: (1) R3is C1-C6alkyl or C6-C10aryl; 10 aryl; (2) The hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate; (3) The molar ratio of the compound of formula III and "hydroxylamine and / or hydroxylamine salt" is 1:(0.5-5); (4) The acid catalyst is selected from one or more of acetic acid, trifluoroacetic acid, trichloroacetic acid and dichloroacetic acid; (5) The molar ratio of the compound of formula III to the acid catalyst is 1:(0.5-5); (6) The cyclization reaction described herein is carried out in a solvent; (7) The reaction temperature of the cyclization reaction is 0-100℃; (8) The cyclization reaction takes 20-30 hours; and (9) The cyclization reaction further includes the following post-processing steps: removing the solvent, performing aqueous layer extraction, and performing vacuum distillation.
3. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 2, characterized in that, It meets one or more of the following conditions: (1) R3 is a C1-C6 alkyl group; (2) The molar ratio of the compound of formula III and "hydroxylamine and / or hydroxylamine salt" is 1:(1-3); (3) The acid catalyst is selected from 1-3 of acetic acid, trifluoroacetic acid, trichloroacetic acid and dichloroacetic acid; (4) The molar ratio of the compound of formula III to the acid catalyst is 1:(1-3); (5) The solvent is water and an organic solvent, wherein the organic solvent is one or more of benzene solvents, halogenated hydrocarbon solvents, ester solvents, nitrile solvents, and ketone solvents; and (6) The mass ratio of the compound of formula III to the solvent is 1:(1-5).
4. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 3, characterized in that, It meets one or more of the following conditions: (1) R1 and R2 are each independently methyl; (2) R3 is methyl or phenyl; (3) The molar ratio of the compound of formula III and "hydroxylamine and / or hydroxylamine salt" is 1:1, 1:1.1, 1:1.5 or 1:3; (4) The acid catalyst is acetic acid or trifluoroacetic acid; (5) The molar ratio of the compound of formula III to the acid catalyst is 1:1; (6) The benzene solvent is chlorobenzene and / or toluene; (7) The halohydrocarbon solvent is dichloromethane and / or dichloroethane; (8) The ester solvent mentioned is ethyl acetate; (9) The nitrile solvent is acetonitrile; (10) The ketone solvent mentioned is acetone; (11) The mass ratio of the compound of formula III to the solvent is 1:1.3; (12) The cyclization reaction temperature is 0°C, 40°C, 50°C, 80°C, or 100°C; and (13) The reaction time for the cyclization reaction is 25 hours.
5. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 2, characterized in that, It meets one or more of the following conditions: (1) The compound of formula III is N-(3-methyl-2-buten-1-ylidene)methylamine and N-(3-methyl-2-buten-1-ylidene)aniline; the corresponding compound of formula V is 5,5-dimethyl-4,5-dihydroisoxazole; (2) The solvents are water and acetone; (3) The cyclization reaction is carried out at a temperature of 40-80℃; and (4) The acid catalyst is selected from one or two of acetic acid, trifluoroacetic acid, trichloroacetic acid and dichloroacetic acid; more preferably one.
6. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole according to any one of claims 1-5, characterized in that, The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole further includes the following steps: reacting compound I with compound II via a Schiff base reaction to obtain compound III. The definitions of R1, R2 and R3 are as described in any one of claims 1-5.
7. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 6, characterized in that, It meets one or more of the following conditions: (1) The compound of formula I is isopentenal; (2) The compound of formula II is methylamine or aniline; (3) The molar ratio of the compound of formula I to the compound of formula II is 1:(1-3); (4) The Schiff base reaction is carried out in a solvent or without a solvent; (5) The Schiff base reaction temperature is -20 to 100℃; (6) The Schiff base reaction time is 0.3-5 h; and (7) No post-treatment is required after the Schiff base reaction; the next reaction can proceed directly.
8. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 7, characterized in that, It meets one or more of the following conditions: (1) The compound of formula II is methylamine; (2) When the compound of formula II is methylamine, it is added to the system in the form of an aqueous solution of methylamine or methylamine gas; (3) The molar ratio of the compound of formula I to the compound of formula II is 1:1, 1:1.1, 1:1.33 or 1:1.5; (4) When the reaction is carried out in the presence of a solvent, the solvent is one or more selected from chlorobenzene, toluene, dichloromethane, dichloroethane, ethyl acetate, and acetonitrile; and (5) When the reaction is carried out in the presence of a solvent, the mass ratio of compound I to the solvent is 1:(2-4).
9. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 8, characterized in that, It meets one or more of the following conditions: (1) The methylamine aqueous solution is a 30-40% (e.g., 35%) methylamine aqueous solution; (2) When the reaction is carried out in the presence of a solvent, the solvent is one or more of toluene, acetonitrile, dichloromethane and ethyl acetate; (3) When the reaction is carried out in the presence of a solvent, the mass ratio of compound I to the solvent is 1:3.7; (4) The Schiff base reaction temperature is -20℃, 0℃, 10℃, 20-25℃, 30℃, 50℃, or 100℃; and (5) The Schiff base reaction time is 1 hour.
10. The method for preparing 5,5-disubstituted-4,5-dihydroisoxazole as described in claim 6, characterized in that, It meets one or more of the following conditions: (1) The Schiff base reaction is carried out in acetonitrile or in solvent-free form; (2) The Schiff base reaction temperature is 0-50℃, preferably 10-30℃.