阅读说明：本技术 一种4-氨甲基异恶唑的合成方法 (Synthesis method of 4-aminomethyl isoxazole ) 是由 王昭松 于 2018-07-12 设计创作，主要内容包括：本发明公开了一种4-氨甲基异恶唑的合成方法,通过N,N-二甲基甲酰胺、溴乙酸、三氯氧磷反应得到氟硼酸盐,再加入氟硼酸、盐酸羟胺得到异恶唑4-甲醛肟,最后通过铝汞齐的催化作用的到4-氨甲基异恶唑。本发明的优点在于：原材料合成难度低,提纯过程简单,合成方法还具有操作简单、高效,原料成本低的优点,这种合成路线有工艺简单方便、适合工厂放大生产的优点。(The invention discloses a synthesis method of 4-aminomethyl isoxazole, which comprises the steps of reacting N, N-dimethylformamide, bromoacetic acid and phosphorus oxychloride to obtain fluoborate, adding fluoboric acid and hydroxylamine hydrochloride to obtain isoxazole 4-formaldehyde oxime, and finally obtaining the 4-aminomethyl isoxazole under the catalytic action of aluminum amalgam. The invention has the advantages that: the raw material synthesis difficulty is low, the purification process is simple, the synthesis method also has the advantages of simple and efficient operation and low raw material cost, and the synthesis route has the advantages of simple and convenient process and suitability for industrial mass production.)

1. A synthetic method of 4-aminomethyl isoxazole is characterized by comprising the following steps:

(1) adding bromoacetic acid into N, N-dimethylformamide, uniformly stirring, heating to 60 ℃, and then dropwise adding phosphorus oxychloride;

(2) after the phosphorus oxychloride is added, the temperature is raised to 110 ℃, the temperature is kept for 3 hours, and then the temperature is gradually reduced to 0 ℃;

(3) dripping a methanol solution of 50 percent of fluoboric acid, and then dripping isopropanol;

(4) stirring at room temperature overnight, performing suction filtration, and washing a filter cake with isopropanol to obtain fluoborate;

(5) dissolving fluoroborate in ethanol, uniformly stirring, and then adding a hydroxylamine hydrochloride solution;

(6) heating and refluxing the mixed solution until the reaction solution is clear;

(7) concentrating dry ethanol under reduced pressure, adding distilled water into residue, extracting with ethyl acetate, mixing extractive phases, drying with sodium sulfate, and spin drying;

(8) dissolving the residue in the last step in a 1:1 mixed solution of ethyl acetate and petroleum ether, passing through a short silica gel column, concentrating, and pulping by using a mixed solution of ethyl acetate/petroleum ether (1/3) to obtain isoxazole 4-formaldehyde oxime;

(9) adding aluminum amalgam into ethanol and isoxazole 4-formaldoxime solution, heating to 60 ℃ and keeping for 2-4 hours;

(10) and cooling the reacted solution, adding water, filtering, extracting the filtrate for 3-5 times by using dichloromethane, and drying the extract liquor to obtain the product 4-aminomethyl isoxazole.

2. The synthesis method of 4-aminomethyl isoxazole according to claim 1, characterized in that: the dosage ratio of the bromoacetic acid, the N, N-dimethylformamide, the phosphorus oxychloride, the 50% fluoroboric acid, the methanol and the isopropanol is 100 g: 333.5 ml: 200 ml: 500 g: 200 ml: 1000 ml.

3. The synthesis method of 4-aminomethyl isoxazole according to claim 2, characterized in that: the dosage ratio of the borate to the ethanol to the hydroxylamine hydrochloride is 1 g: (5.317-5.714) ml: (0.385-0.392) g.

4. The synthesis method of 4-aminomethyl isoxazole according to claim 3, characterized in that: the temperature of the phosphorus oxychloride is not higher than 90 ℃.

5. The synthesis method of 4-aminomethyl isoxazole according to claim 1, characterized in that: the preparation method of the aluminum amalgam comprises the following steps of (1) adding an aluminum sheet and mercuric chloride into methanol, and then adding distilled water; (2) heating by a hair drier under stirring until a large amount of bubbles are generated; (3) the preparation is completed when the surface of the bright aluminum sheet becomes a rough surface; (4) the product was taken out and washed twice with ethanol.

6. The synthesis method of 4-aminomethyl isoxazole according to claim 5, characterized in that: the weight ratio of the aluminum sheet to the mercuric chloride is 1: 10.

7. The synthesis method of 4-aminomethyl isoxazole according to claim 6, characterized in that: the volume ratio of the aluminum sheet to the methanol to the distilled water is 1:20: 20.

8. The synthesis method of 4-aminomethyl isoxazole according to claim 7, characterized in that: the mercuric chloride may be replaced by mercurous chloride.

Technical Field

The invention designs a synthetic method of an isoxazole compound, and particularly relates to a synthetic method of 4-aminomethyl isoxazole.

Background

4-aminomethyl isoxazole is taken as an important heterocyclic compound, and isoxazole compounds have unique chemical structures and important pharmacological activities, so that the 4-aminomethyl isoxazole has attracted the attention of researchers in chemistry and pharmaceutical chemistry in recent years. 4-aminomethyl isoxazole is used as a small molecular compound, is a new medical intermediate, is used for research, development and screening of new drugs, has the characteristics of difficult synthesis and difficult purification, and has no good synthetic method.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a synthesis method of 4-aminomethyl isoxazole, which has low synthesis difficulty and simple purification process.

The invention solves the technical problems through the following technical means: a synthetic method of 4-aminomethyl isoxazole is characterized by comprising the following steps:

(1) adding bromoacetic acid into N, N-dimethylformamide, uniformly stirring, heating to 60 ℃, and then dropwise adding phosphorus oxychloride;

(2) after the phosphorus oxychloride is added, the temperature is raised to 110 ℃, the temperature is kept for 3 hours, and then the temperature is gradually reduced to 0 ℃;

(3) dripping a methanol solution of 50 percent of fluoboric acid, and then dripping isopropanol;

(4) stirring at room temperature overnight, performing suction filtration, and washing a filter cake with isopropanol to obtain fluoborate;

(5) dissolving fluoroborate in ethanol, uniformly stirring, and then adding a hydroxylamine hydrochloride solution;

(6) heating and refluxing the mixed solution until the reaction solution is clear;

(7) concentrating dry ethanol under reduced pressure, adding distilled water into residue, extracting with ethyl acetate, mixing extractive phases, drying with sodium sulfate, and spin drying;

(8) dissolving the residue in the last step in a 1:1 mixed solution of ethyl acetate and petroleum ether, passing through a short silica gel column, concentrating, and pulping by using a mixed solution of ethyl acetate/petroleum ether (1/3) to obtain isoxazole 4-formaldehyde oxime;

(9) adding aluminum amalgam into ethanol and isoxazole 4-formaldoxime solution, heating to 60 ℃ and keeping for 2-4 hours;

(10) and cooling the reacted solution, adding water, filtering, extracting the filtrate for 3-5 times by using dichloromethane, and drying the extract liquor to obtain the product 4-aminomethyl isoxazole.

The dosage ratio of the bromoacetic acid, the N, N-dimethylformamide, the phosphorus oxychloride, the 50% fluoroboric acid, the methanol and the isopropanol is 100 g: 333.5 ml: 200 ml: 500 g: 200 ml: 1000 ml.

The dosage ratio of the borate to the ethanol to the hydroxylamine hydrochloride is 1 g: (5.317-5.714) ml: (0.385-0.392) g.

The temperature of the phosphorus oxychloride is not higher than 90 ℃.

The preparation method of the aluminum amalgam comprises the following steps of (1) adding an aluminum sheet and mercuric chloride into methanol, and then adding distilled water; (2) heating by a hair drier under stirring until a large amount of bubbles are generated; (3) the preparation is completed when the surface of the bright aluminum sheet becomes a rough surface; (4) the product was taken out and washed twice with ethanol.

The weight ratio of the aluminum sheet to the mercuric chloride is 1: 10.

The volume ratio of the aluminum sheet to the methanol to the distilled water is 1:20: 20.

The mercuric chloride may be replaced by mercurous chloride.

The invention has the advantages that: the raw material synthesis difficulty is low, the purification process is simple, the synthesis method also has the advantages of simple and efficient operation and low raw material cost, and the synthesis route has the advantages of simple and convenient process and suitability for industrial mass production.

Drawings

FIG. 1 is a diagram of the synthetic pathway of the present invention;

FIG. 2 is a nuclear magnetic diagram of isoxazole 4-carbaldehyde oxime according to the present invention;

FIG. 3 is a nuclear magnetic diagram of 4-aminomethyl isoxazole according to the invention;

Detailed Description

In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are some, but not all, embodiments of the present 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.