阅读说明：本技术 一种3-(2-甲基-6-硝基苯基)-4,5-二氢异噁唑的制备方法 (Preparation method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole ) 是由 虞孝云 刘双瑾 席树文 许向飞 罗先福 谢小国 吴迪 谭胜辉 李建华 游丹 尹红 于 2021-09-16 设计创作，主要内容包括：本发明公开了一种3-(2-甲基-6-硝基苯基)-4,5-二氢异噁唑的制备方法,包括将2-甲基-6-硝基苯甲醛肟和乙烯在氧化剂的作用下发生一锅法反应；所述氧化剂为锰基氧化物。本发明的制备方法,由于调整了制备原料,能够实现一锅法反应,避免了传统制备方法中生成中间产物2-甲基-6-硝基苯甲酰氯肟带来的安全隐患。(The invention discloses a preparation method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole, which comprises the steps of carrying out one-pot reaction on 2-methyl-6-nitrobenzaldehyde oxime and ethylene under the action of an oxidant; the oxidant is a manganese-based oxide. According to the preparation method, the preparation raw materials are adjusted, so that the one-pot reaction can be realized, and the potential safety hazard caused by the generation of the intermediate product 2-methyl-6-nitrobenzoyl chloride oxime in the traditional preparation method is avoided.)

1. A preparation method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is characterized by comprising the step of carrying out one-pot reaction on 2-methyl-6-nitrobenzaldehyde oxime and ethylene under the action of an oxidant;

the oxidant is a manganese-based oxide.

2. The method of claim 1, wherein the temperature of the one-pot reaction is 20 ℃ to 80 ℃.

3. The preparation method according to claim 1, wherein the one-pot reaction time is 2 to 10 hours.

4. The method of claim 1, wherein the manganese-based oxide comprises at least one of manganese dioxide and metal-doped manganese dioxide.

5. The method according to claim 4, wherein the doping metal in the metal-doped manganese dioxide is at least one of iron, cobalt, nickel, copper and silver.

6. The method according to claim 4, wherein the metal-doped manganese dioxide contains a doping metal in an amount of 0.1 to 5% by mass of the metal-doped manganese dioxide.

7. The method according to claim 1, wherein the molar ratio of the 2-methyl-6-nitrobenzaldehyde oxime to the oxidizing agent is 1: 2 to 6.

8. The production method according to claim 1, wherein the one-pot reaction is carried out in an organic solvent; preferably, the organic solvent is at least one of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene, and o-dichlorobenzene.

9. The preparation method according to claim 8, wherein the mass ratio of the organic solvent to the 2-methyl-6-nitrobenzaldehyde oxime is 2-8: 1.

10. The preparation method according to any one of claims 1 to 9, further comprising purifying the obtained 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole after the one-pot reaction; preferably, the purification comprises successive desolvation and recrystallization.

Technical Field

The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole.

Background

The molecular structural formula of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is as follows:

is an important intermediate for synthesizing topramezone. Topramezone is the first active ingredient in pyrazolone compounds, is often used as a post-emergence herbicide for preventing and killing grassy weeds and broadleaf weeds in corn fields, and has the trade names of Convey, Impact, Clio, bractene and the like. The corn field herbicide is characterized in that the corn field herbicide is a corn field herbicide, wherein the corn field herbicide is a corn field herbicide, and the corn field herbicide is used for corn fields with various types of crops, including conventional corn, sweet corn, seed production corn, popcorn and the like. And the research on the preparation method of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is an important ring for further expanding the application range of the topramezone.

The existing synthesis method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is mostly prepared by using 2-methyl-6-nitrobenzaldehyde oxime as a raw material, adding an acid-binding agent after chlorination, and introducing ethylene for reaction:

with respect to the above synthesis methods, research focus has been mainly on the development and selection of chlorination reagents, chlorination reaction solvents, acid-binding agents, cyclization solvents, and cyclization reaction pressures. However, the chlorination reaction in the method is a dangerous reaction, the generated intermediate 2-methyl-6-nitrobenzoyl chloride oxime is unstable in property and easy to explode when heated, and potential safety hazards exist during solvent removal.

With the continuous improvement of the requirements on safety and environmental protection and the continuous increase of the demand of topramezone in the market, a new production process of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is needed to be developed, so that the safety of operation of enterprises, the economical efficiency of production and the social benefit of production are improved.

Disclosure of Invention

The present invention is directed to solving at least one of the problems of the prior art described above. Therefore, the invention provides a preparation method of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole, which can realize one-pot reaction due to adjustment of preparation raw materials and avoid potential safety hazards caused by generation of an intermediate product, namely 2-methyl-6-nitrobenzoyl chloride oxime in the traditional preparation method.

According to one aspect of the invention, the preparation method of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole comprises the steps of carrying out one-pot reaction on 2-methyl-6-nitrobenzaldehyde oxime and ethylene under the action of an oxidant;

the oxidant is a manganese-based oxide.

According to a preferred embodiment of the present invention, at least the following advantages are provided:

(1) the manganese-based oxide can be used as a mild oxidant in organic synthesis and is mainly used for preparing aldehyde ketone compounds by oxidizing alcohol compounds and toluene compounds; while the oxidizing agents used for preparing 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole in production often have very high activity, such as hydrogen peroxide and the like;

the manganese-based oxide is used as an oxidant for synthesizing the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by using the 2-methyl-6-nitrobenzaldehyde oxime through a one-pot method, the manganese-based oxide can effectively oxidize an aldoxime structure in a 2-methyl-6-nitrobenzaldehyde oxime molecule into a nitrile-oxygen structure in the process, the generated intermediate nitrile-oxygen compound immediately performs 1, 3-dipolar cycloaddition reaction with ethylene to obtain the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole, and the product has good stability in the presence of the manganese-based oxide.

(2) The preparation method provided by the invention is based on the design of a reaction path, the reaction process of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is fundamentally improved, the use of a chlorination reagent which pollutes the environment is avoided, a dangerous chlorination reaction process is avoided, the generation of a chlorinated intermediate 2-methyl-6-nitrobenzoyl chloride oxime which is easy to explode under heat is avoided, and an oxide with poor stability is also avoided, so that the safe production is realized essentially.

(3) According to the preparation method provided by the invention, the yield of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is up to 88.5-92.3% (liquid chromatography, external standard); the content is up to 98.0-99.2% (liquid chromatogram, external standard).

(4) The raw materials and the solvent used in the preparation method provided by the invention are cheap and easy to obtain, and the process is simple and is beneficial to industrial production.

In some embodiments of the invention, the 2-methyl-6-nitrobenzaldehyde oxime is prepared by the method of example 1 in the patent US20030216580, which is made by the laboratory.

In some embodiments of the invention, the reaction formula of the one-pot reaction is as follows:

in some embodiments of the invention, the temperature of the one-pot reaction is from 20 ℃ to 80 ℃.

In some embodiments of the invention, the one-pot reaction time is 2h to 10 h.

In some embodiments of the invention, the pressure of the one-pot reaction is about 3.0 MPa.

Besides being used as a reactant, the ethylene also has the functions of ensuring the reaction pressure of the one-pot method and serving as a protective gas.

In some embodiments of the invention, the manganese-based oxide comprises at least one of manganese dioxide and metal doped manganese dioxide.

When the oxidant is the metal-doped manganese dioxide, the yield of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole synthesized by the 2-methyl-6-nitrobenzaldehyde oxime one-pot reaction under the appropriate reaction condition is more than or equal to the yield of the manganese dioxide as the oxidant.

In some embodiments of the invention, the doping metal in the metal-doped manganese dioxide is at least one of iron, cobalt, nickel, copper and silver.

In some embodiments of the invention, the amount of doped metal species in the metal doped manganese dioxide is between 0.1% and 5% of the amount of species of the metal doped manganese dioxide.

In some embodiments of the invention, the molar ratio of the 2-methyl-6-nitrobenzaldehyde oxime to the oxidizing agent is 1: 2 to 6.

In some embodiments of the invention, the one-pot reaction is carried out in an organic solvent.

In some embodiments of the invention, the organic solvent is at least one of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, chlorobenzene, and o-dichlorobenzene.

In some embodiments of the invention, the mass ratio of the organic solvent to the 2-methyl-6-nitrobenzaldehyde oxime is 2-8: 1.

In some embodiments of the invention, the preparation process further comprises purifying the resulting 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole after the one-pot reaction.

In some embodiments of the invention, the purification comprises successive desolventization and recrystallization.

In some embodiments of the invention, the desolventizing comprises filtering off solid impurities and then distilling the filtrate.

In some embodiments of the invention, the distillation is at least one of atmospheric distillation or vacuum distillation.

In some embodiments of the invention, the recrystallization is by adding methanol to the system obtained by the desolventizing.

Detailed Description

The concept and technical effects of the present invention will be clearly and completely described below in conjunction with the embodiments to fully understand the objects, features and effects of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments, and those skilled in the art can obtain other embodiments without inventive effort based on the embodiments of the present invention, and all embodiments are within the protection scope of the present invention.

Example 1

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 52.2g of manganese dioxide and 218.4g of dichloromethane into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 50 ℃, keeping the temperature for reaction for 6 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure of 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 56.5g of brown granular solid.

Example 2

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 65g of 3% iron ion doped manganese dioxide and 273g of trichloromethane into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 20 ℃, keeping the temperature for reaction for 10 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 55.7g of brown granular solid.

Example 3

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 80.8g of 2% cobalt ion doped manganese dioxide and 109.2g of carbon tetrachloride into a 1000mL high-pressure autoclave in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 45 ℃, keeping the temperature for reaction for 6 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 57g of brown granular solid.

Example 4

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 90.5g of 1% nickel ion doped manganese dioxide and 436.8g of 1, 2-dichloroethane into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 40 ℃, keeping the temperature for reaction for 7 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 56.5g of brown granular solid.

Example 5

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 105g of 0.1% copper ion doped manganese dioxide and 109.2g of chlorobenzene into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, controlling the temperature to be 30 ℃, keeping the temperature and reacting for 8 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure to be 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 56.7g of brown granular solid.

Example 6

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 135g of 5% silver ion doped manganese dioxide and 163.8g of o-dichlorobenzene in sequence into a 1000mL high-pressure kettle, introducing ethylene to the pressure of 3.0MPa, heating to 80 ℃, keeping the temperature for reaction for 2 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 55.9g of brown granular solid.

Example 7

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 156.5g of 2% cobalt ion doped manganese dioxide and 327.6g of 1, 2-dichloroethane into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 60 ℃, keeping the temperature for reaction for 4 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 57.9g of brown granular solid.

Example 8

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 52.2g of 2% cobalt ion doped manganese dioxide and 218.4g of dichloromethane into a 1000mL high-pressure autoclave in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 50 ℃, keeping the temperature for reaction for 6 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 56.7g of brown granular solid.

Example 9

This example prepares a 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by the following specific steps:

s1, adding 54.6g (99%, 0.3mol) of 2-methyl-6-nitrobenzaldehyde oxime, 92.6g of 2% cobalt ion doped manganese dioxide and 218.4g of dichloromethane into a 1000mL high-pressure kettle in sequence, introducing ethylene to the pressure of 3.0MPa, heating to 50 ℃, keeping the temperature for reaction for 6 hours, continuously supplementing ethylene in the reaction process, and keeping the pressure at 3.0 MPa;

s2, after the reaction is finished, filtering a reaction product, removing the solvent from the filtrate under reduced pressure, and adding methanol for recrystallization to obtain 57.6g of brown granular solid.

Test examples

The experimental examples tested the basic properties of the solids obtained in each example, as follows:

melting point (m.p.): 102.6-103.3 ℃;

liquid chromatography-mass spectrometry (LC-MS): 207.0[ M +1], 208.0[ M +2 ];

nuclear magnetism: 1H-NMR (CDCl)₃，300M)δ：2.40(s，3H，CH₃)，3.32(t，2H，CH₂)，4.60(t，2H，CH₂O)，7.55(t，1H，Ar-H)，7.58(d，1H，Ar-H)，8.00(d，1H，Ar-H)；

From the calculation, the molar mass of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole was 206g/mol, and the results of 207.0[ M +1], 208.0[ M +2] and nuclear magnetic resonance results show that 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole was indeed synthesized in examples 1 to 9 of the present invention.

The mass percentage of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole in the solid obtained in the example was also obtained by a liquid chromatography external standard method, and the test results and the yield results calculated according to the content are shown in table 1.

The method for calculating the yield comprises the following steps: the product of the mass of the obtained solid and the mass content of the 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole therein is divided by the theoretical yield; for example, in example 1, the ethylene continues to be in excess, theoretically 0.3mol 2-methyl-6-nitrobenzaldehyde oxime reacting completely to give 0.3mol 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole (molar mass 206g/mol), and therefore the theoretical yield is 61.8 g; the yield of 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole is 56.5X 98.9%/61.8 ≈ 90.4%.

TABLE 1 information on the solids obtained in the examples

The results in table 1 show that the preparation method provided by the invention can prepare 3- (2-methyl-6-nitrophenyl) -4, 5-dihydroisoxazole by a mild method, the product purity is as high as 99.2%, and the yield is as high as 92.3%.

The embodiments of the present invention have been described in detail, but the present invention is not limited to the embodiments, and various changes can be made without departing from the gist of the present invention within the knowledge of those skilled in the art. Furthermore, the embodiments of the present invention and the features of the embodiments may be combined with each other without conflict.