阅读说明：本技术 一种含氟烷基取代异噁唑衍生物及其制备方法和应用 (Fluoroalkyl-substituted isoxazole derivative and preparation method and application thereof ) 是由 张勇 赖国伟 葛进 严素琼 范小林 于 2019-10-31 设计创作，主要内容包括：本发明属于有机氟化合物合成技术领域,尤其涉及一种含氟烷基取代异噁唑衍生物及其制备方法和应用。本发明提供的含氟烷基取代异噁唑衍生物同时含有双氟亚甲基和异噁唑环,是一类重要的二氟烷基合成砌块,可用于制备3-二氟异噁唑取代-3-羟基氧化吲哚等一系列结构新颖的含异噁唑取代的有机氟化合物,选择性好,收率高,对于有机合成和药物研发具有重要价值。(The invention belongs to the technical field of synthesis of organic fluorine compounds, and particularly relates to a fluoroalkyl-substituted isoxazole derivative, and a preparation method and application thereof. The fluoroalkyl-substituted isoxazole derivative provided by the invention contains a difluromethylene and an isoxazole ring at the same time, is an important difluoroalkyl synthesis building block, can be used for preparing a series of isoxazole-substituted organic fluorine compounds with novel structures, such as 3-difluoroisoxazole-substituted-3-hydroxyoxindole and the like, has good selectivity and high yield, and has important value for organic synthesis and drug research and development.)

1. A fluoroalkyl-substituted isoxazole derivative, characterized by having the structure shown in formula I:

wherein R is¹Is hydrogen, 3-bromo, 4-chloro, 4-bromo, 4-fluoro, 4-nitro, 2, 6-dichloro or 3, 4-dichloro; r²Is methyl or phenyl.

2. The fluoroalkyl-substituted isoxazole derivative according to claim 1, wherein the fluoroalkyl-substituted isoxazole derivative comprises:

3. a process for producing a fluoroalkyl-substituted isoxazole derivative according to claim 1 or 2, which comprises the steps of:

mixing 3-substituted-4-nitro-5-methylisoxazole, aromatic aldehyde, a catalyst A and a first solvent, and carrying out nucleophilic addition reaction to obtain a first intermediate;

mixing the first intermediate, an oxidant and a second solvent, and carrying out an oxidation reaction to obtain a second intermediate;

mixing the second intermediate, the selective fluorine reagent, the catalyst B and a third solvent, and carrying out a fluorination reaction to obtain a fluoroalkyl-substituted isoxazole derivative;

wherein the 3-substituted-4-nitro-5-methylisoxazole has a structure shown in formula II:

the aromatic aldehyde has the structure shown in formula III:

4. the method according to claim 3, wherein the catalyst A is triethylamine, imidazole, diisopropylamine, diisopropylethylamine, 1, 4-diazabicyclo [2,2,2] octane, N-dimethylpyridine or 1, 8-diazabicycloundec-7-ene; the temperature of the nucleophilic addition reaction is room temperature, and the time is 1-3 d.

5. The method according to claim 3, wherein the oxidizing agent is 2-iodoxybenzoic acid, pyridinium chlorochromate, or pyridinium dichromate.

6. The production method according to claim 3 or 5, wherein the oxidation reaction is carried out under an oil bath at a temperature of 40 to 100 ℃ for 12 to 48 hours.

7. The method of claim 3, wherein the selective fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2,2,2] octane bis (tetrafluoroborate) salt; the catalyst B is potassium phosphate; the fluorination reaction is carried out at room temperature for 1-3 d.

8. The method according to claim 3,5 or 7, wherein the molar ratio of the 3-substituted-4-nitro-5-methylisoxazole to the aromatic aldehyde to the catalyst A to the oxidizing agent to the selective fluorine reagent to the catalyst B is 1.00:1.1:0.2 (0.38-0.94) to (0.51-1.1) to (0.24-0.52).

9. Use of a fluoroalkyl-containing substituted isoxazole derivative according to claim 1 or 2 for the preparation of an isoxazole-containing substituted organofluoro compound, characterized in that: the fluorine-containing alkyl substituted isoxazole derivative is used as a reaction substrate and reacts with indoline-2, 3-diketone compounds under the action of alkali catalysis to obtain the isoxazole substituted organic fluoride.

10. The use according to claim 9, wherein the indoline-2, 3-dione compound has the structure of formula IV:

wherein R is³Including 4-chloro, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 5-methoxy, 5-nitro, 6-bromo or 4, 7-dichloro; r⁴Including phenyl or benzyl.

Technical Field

The invention relates to the technical field of synthesis of organic fluorine compounds, in particular to a fluoroalkyl-substituted isoxazole derivative and a preparation method and application thereof.

Background

Fluorine atoms have unique properties, and a number of facts indicate: the introduction of difluoromethylene into molecules can effectively improve the biological activity of organic compounds, for example, HMG-CoA reductase inhibitor can inhibit HMG-CoA reductase and hinder cholesterol synthesis, thereby playing a role in regulating blood fat; lubiprostone can be used for treating intestinal dysfunction caused by opioid. Thus, difluoromethylene becomes a very valuable building block in the fields of organic synthesis and drug development.

On the other hand, isoxazole has a unique five-membered heterocyclic structure and is widely applied to the fields of medicines, pesticides and the like. For example, Valdecoxib (Valdecoxib) is a novel non-steroidal anti-inflammatory drug; hymexazol (Hymexazol) is a systemic fungicide, soil disinfectant and plant growth regulator. Therefore, it is important to develop a simple and efficient method for preparing fluoroalkyl-substituted isoxazole derivatives.

At present, although many difluromethenation techniques have been reported, there is no report of introducing a difluromethylene and an isoxazole ring at the same time. Therefore, the development of a new technology for simultaneously introducing the difluromethylene and the isoxazole ring has great innovation and practicability.

Disclosure of Invention

The invention aims to provide a fluoroalkyl-substituted isoxazole derivative, and a preparation method and application thereof.

In order to achieve the above object, the present invention provides the following technical solutions:

the invention provides a fluorine-containing alkyl substituted isoxazole derivative which has a structure shown in a formula I:

wherein R is¹Is hydrogen, 3-bromo, 4-chloro, 4-bromo, 4-fluoro, 4-nitro, 2, 6-dichloro or 3, 4-dichloro; r²Is methyl or phenyl.

Preferably, the fluoroalkyl-containing substituted isoxazole derivative includes:

the invention provides a preparation method of the fluoroalkyl-containing substituted isoxazole derivative, which comprises the following steps:

mixing 3-substituted-4-nitro-5-methylisoxazole, aromatic aldehyde, a catalyst A and a first solvent, and carrying out nucleophilic addition reaction to obtain a first intermediate;

mixing the first intermediate, an oxidant and a second solvent, and carrying out an oxidation reaction to obtain a second intermediate;

mixing the second intermediate, the selective fluorine reagent, the catalyst B and a third solvent, and carrying out a fluorination reaction to obtain a fluoroalkyl-substituted isoxazole derivative;

wherein the 3-substituted-4-nitro-5-methylisoxazole has a structure shown in formula II:

the aromatic aldehyde has the structure shown in formula III:

preferably, the catalyst A is triethylamine, imidazole, diisopropylamine, diisopropylethylamine, 1, 4-diazabicyclo [2,2,2] octane, N-dimethylpyridine or 1, 8-diazabicycloundec-7-ene; the temperature of the nucleophilic addition reaction is room temperature, and the time is 1-3 d.

Preferably, the oxidizing agent is 2-iodoxybenzoic acid, pyridinium chlorochromate, or pyridinium dichromate.

Preferably, the oxidation reaction is carried out under the condition of an oil bath, the temperature of the oil bath is 40-100 ℃, and the time of the oxidation reaction is 12-48 h.

Preferably, the selective fluorine reagent is 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2,2,2] octane bis (tetrafluoroborate) salt; the catalyst B is potassium phosphate; the fluorination reaction is carried out at room temperature for 1-3 d.

Preferably, the molar ratio of the 3-substituted-4-nitro-5-methylisoxazole to the aromatic aldehyde to the catalyst A to the oxidant to the selective fluorine reagent to the catalyst B is 1.00:1.1:0.2 (0.38-0.94) to (0.51-1.1) to (0.24-0.52).

The invention provides an application of the fluoroalkyl-containing substituted isoxazole derivative in the technical scheme in preparation of isoxazole-containing substituted organic fluoride, which is characterized in that: the fluorine-containing alkyl substituted isoxazole derivative is used as a reaction substrate and reacts with indoline-2, 3-diketone compounds under the action of alkali catalysis to obtain the isoxazole substituted organic fluoride.

Preferably, the indoline-2, 3-dione compound has a structure shown in formula IV:

wherein R is³Including 4-chloro, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 5-methoxy, 5-nitro, 6-bromo or 4, 7-dichloro; r⁴Including phenyl or benzyl.

The invention provides a fluoroalkyl-substituted isoxazole derivative, which simultaneously contains a difluromethylene and an isoxazole ring, is an important difluoroalkyl synthesis building block, can be used for preparing a series of isoxazole-substituted organic fluorine compounds with novel structures, such as 3-difluoroisoxazole-substituted-3-hydroxyoxindole, and the like, has good selectivity and high yield, and has important value for organic synthesis and drug research and development.

Drawings

FIG. 1 is a nuclear magnetic hydrogen spectrum of the product prepared in example 1;

FIG. 2 is a nuclear magnetic carbon spectrum of the product prepared in example 1;

FIG. 3 is a fluorine spectrum of the product prepared in example 1;

FIG. 4 is a nuclear magnetic hydrogen spectrum of the product prepared in example 2;

FIG. 5 is a nuclear magnetic carbon spectrum of the product prepared in example 2;

FIG. 6 is a nuclear magnetic hydrogen spectrum of the product prepared in example 3;

FIG. 7 is a nuclear magnetic carbon spectrum of the product prepared in example 3;

FIG. 8 is a nuclear magnetic hydrogen spectrum of the product produced in example 4;

FIG. 9 is a nuclear magnetic carbon spectrum of the product prepared in example 4;

FIG. 10 is a nuclear magnetic hydrogen spectrum of the product produced in example 5;

FIG. 11 is a nuclear magnetic carbon spectrum of the product prepared in example 5;

FIG. 12 is a nuclear magnetic hydrogen spectrum of the product produced in example 6;

FIG. 13 is a nuclear magnetic carbon spectrum of the product prepared in example 6;

FIG. 14 is a nuclear magnetic hydrogen spectrum of the product produced in example 7;

FIG. 15 is a nuclear magnetic carbon spectrum of the product prepared in example 7;

FIG. 16 is a nuclear magnetic hydrogen spectrum of the product produced in example 8;

FIG. 17 is a nuclear magnetic carbon spectrum of the product prepared in example 8;

FIG. 18 is a nuclear magnetic hydrogen spectrum of the product produced in example 9;

FIG. 19 is a nuclear magnetic carbon spectrum of the product prepared in example 9;

FIG. 20 is a fluorine spectrum of the product prepared in example 9.

Detailed Description

The invention provides a fluorine-containing alkyl substituted isoxazole derivative which has a structure shown in a formula I:

wherein R is¹Is hydrogen, 3-bromo, 4-chloro, 4-bromo, 4-fluoro, 4-nitro, 2, 6-dichloro or 3, 4-dichloro; r²Is methyl or phenyl.

In the present invention, the structure of the fluoroalkyl group-containing substituted isoxazole derivative preferably includes:

the invention provides a preparation method of the fluoroalkyl-containing substituted isoxazole derivative, which comprises the following steps:

mixing 3-substituted-4-nitro-5-methylisoxazole, aromatic aldehyde, a catalyst A and a first solvent, and carrying out nucleophilic addition reaction to obtain a first intermediate;

mixing the first intermediate, an oxidant and a second solvent, and carrying out an oxidation reaction to obtain a second intermediate;

mixing the second intermediate, the selective fluorine reagent, the catalyst B and a third solvent, and carrying out a fluorination reaction to obtain a fluoroalkyl-substituted isoxazole derivative;

wherein the 3-substituted-4-nitro-5-methylisoxazole has a structure shown in formula II:

the aromatic aldehyde has the structure shown in formula III:

in the present invention, unless otherwise specified, all the starting materials required for the preparation are commercially available products well known to those skilled in the art.

According to the invention, 3-substituted-4-nitro-5-methylisoxazole, aromatic aldehyde, a catalyst A and a first solvent are mixed for nucleophilic addition reaction to obtain a first intermediate. In the present invention, the catalyst A is preferably triethylamine, imidazole, diisopropylamine, diisopropylethylamine, 1, 4-diazabicyclo [2,2,2] octane (DABCO), N-Dimethylpyridine (DMAP) or 1, 8-diazabicycloundec-7-ene (DBU); the first solvent is preferably water, acetonitrile, methanol or N, N-dimethylformamide. In the invention, the dosage ratio of the 3-substituted-4-nitro-5-methyl isoxazole to the first solvent is preferably 1.00mmol (1.0-3.0) mL.

In the invention, the temperature of the nucleophilic addition reaction is preferably room temperature, and the time is preferably 1-3 d, and more preferably 1.5-2.5 d. The present invention preferably detects the completion of the reaction by TLC.

In the present invention, the nucleophilic addition reaction proceeds as follows:

after the nucleophilic addition reaction is completed, the invention preferably adds ethyl acetate and water (the volume ratio of the ethyl acetate to the water is preferably 10:1) into the system obtained by the reaction, separates the solution, extracts the water phase with ethyl acetate, combines the organic phases, dries with anhydrous sodium sulfate, and performs column chromatography (eluent: petroleum ether/ethyl acetate 10:1, ethyl acetate) to obtain the first intermediate. The specific operation processes of the extraction, drying and column chromatography are not particularly limited in the invention, and the operation known by the skilled person can be selected.

After the first intermediate is obtained, the first intermediate, an oxidant and a second solvent are mixed for oxidation reaction to obtain a second intermediate. The present invention preferably uses all of the first intermediate obtained from the nucleophilic addition reaction in the subsequent oxidation reaction. In the present invention, the oxidizing agent is preferably 2-iodoxybenzoic acid (IBX), pyridinium chlorochromate (PCC), or Pyridinium Dichromate (PDC); the second solvent is preferably ethyl acetate, dichloromethane or 1, 2-dichloroethane. In the invention, the dosage ratio of the oxidant to the second solvent is preferably 1.0mmol (10.0-30.0) mL.

In the invention, the oxidation reaction is preferably carried out under the condition of an oil bath, the temperature of the oil bath is preferably 40-100 ℃, more preferably 60-80 ℃, and the time of the oxidation reaction is preferably 12-48 h, more preferably 20-35 h, and most preferably 25-30 h. The invention detects the completion of the reaction by TLC.

In the present invention, the process of the oxidation reaction is as follows:

after the oxidation reaction is finished, the obtained system is preferably subjected to suction filtration, ethyl acetate washing and concentration in sequence, and then ethanol is added for recrystallization to obtain a second intermediate. The process of the present invention is not particularly limited, and may be any process known to those skilled in the art.

After the second intermediate is obtained, the second intermediate, the selective fluorine reagent, the catalyst B and a third solvent are mixed for fluorination reaction to obtain the fluoroalkyl-substituted isoxazole derivative. All of the second intermediate obtained from the oxidation reaction is preferably used in the subsequent fluorination reaction. In the present invention, the selective fluorine reagent is preferably 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2,2]Octane bis (tetrafluoroborate) salt (F-TEDA-BF)₄) (ii) a The catalyst B is preferably potassium phosphate and the third solvent is preferably acetonitrile or water. In the invention, the dosage ratio of the catalyst B to the third solvent is preferably 1.0mmol (2.0-10.0) mL. In the invention, the molar ratio of the 3-substituted-4-nitro-5-methylisoxazole, the aromatic aldehyde, the catalyst A, the oxidant, the selective fluorine reagent and the catalyst B is preferably 1.00:1.1:0.2 (0.38-0.94): 0.51-1.1): 0.24-0.52, more preferably 1.00:1.1:0.2 (0.42-0.84): 0.6-0.9): 0.3-0.5.

In the invention, the temperature of the fluorination reaction is preferably room temperature, and the time is preferably 1-3 d, and more preferably 1.5-2.5 d. The present invention preferably detects the completion of the reaction by TLC. In the present invention, the process of the fluorination reaction is as follows:

after the fluorination reaction is finished, the obtained system is preferably subjected to suction filtration, dichloromethane washing and column chromatography in sequence to obtain the fluoroalkyl-substituted isoxazole derivative. The process of the present invention is not particularly limited, and may be any process known to those skilled in the art.

In the invention, the synthetic process of the fluoroalkyl-containing substituted isoxazole derivative is as follows:

the invention provides an application of the fluoroalkyl-containing substituted isoxazole derivative in the technical scheme in preparation of isoxazole-containing substituted organic fluoride, which comprises the following steps: the fluorine-containing alkyl substituted isoxazole derivative is used as a reaction substrate and reacts with indoline-2, 3-diketone compounds under the action of alkali catalysis to obtain the isoxazole substituted organic fluoride. In the present invention, the indoline-2, 3-dione compound preferably has a structure represented by formula IV:

wherein R is³Including 4-chloro, 5-fluoro, 5-chloro, 5-bromo, 5-methyl, 5-methoxy, 5-nitro, 6-bromo or 4, 7-dichloro; r⁴Including phenyl or benzyl.

In the invention, the preparation process of the organic fluoride containing isoxazole substitution is as follows:

the preparation method is not specially limited in conditions of the preparation process of the organic fluoride containing isoxazole substitution, and in the embodiment of the invention, specifically, indoline-2, 3-diketone compound and fluoroalkyl-containing substituted isoxazole derivative are dissolved in methanol, triethylamine is added at room temperature, the reaction is carried out under the catalysis of alkali, the TLC detection reaction is complete, and then the reaction is concentrated and separated to obtain the organic fluoride containing isoxazole substitution.

The technical solution of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.