阅读说明：本技术 一种一步法合成4-氯-1h-咪唑-2-羧酸乙酯的方法 (Method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by one-step method ) 是由 许义波 王超 于 2020-06-24 设计创作，主要内容包括：本发明属于医药中间体,具体涉及一种一步法合成4-氯-1H-咪唑-2-羧酸乙酯的方法。本发明首次提供了一种4-氯-1H-咪唑-2-羧酸乙酯的合成方法,为4-氯-1H-咪唑-2-羧酸乙酯的合成方法提供了合成路线,合成方法路线简短,设计合理,且操作简单,易于控制；本发明是以化合物A(1H-咪唑-2-羧酸乙酯)作为原料,在低温及有机酸的环境下,通过有机酸为N-氯代丁二酰亚胺分子提供了较好的极化环境,并同时提高了底物的亲电活性,促进了反应进行,降低了副产物的产生,提高了产品的产率及纯度。(The invention belongs to a medical intermediate, and particularly relates to a method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method. The invention provides a synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester for the first time, provides a synthetic route for the synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester, and has the advantages of short synthetic route, reasonable design, simple operation and easy control; the compound A (1H-imidazole-2-carboxylic acid ethyl ester) is used as a raw material, a better polarization environment is provided for N-chlorosuccinimide molecules by organic acid under the environment of low temperature and organic acid, the electrophilic activity of a substrate is improved, the reaction is promoted, the generation of byproducts is reduced, and the yield and the purity of the product are improved.)

1. A one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester is characterized in that the chemical reaction formula of the synthesis is as follows:

compound a compound B;

the synthesis comprises the following steps:

and (2) uniformly mixing the compound A and a solvent, adding organic acid, cooling, dropwise adding an N-chlorosuccinimide solution, and stirring for reaction to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.

2. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solvent is any one of dimethylformamide and N-methylpyrrolidone.

3. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound A to the solvent is 1: 30-35.

4. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.

5. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the solid-to-liquid ratio g/mL of the compound A to the organic acid is 5-9: 1.

6. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the mass ratio of the compound A to N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing N-chlorosuccinimide and a solvent according to a solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.

7. The one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester according to claim 1, wherein the end point of the temperature reduction is-5 to 0 ℃.

Technical Field

The invention belongs to a medical intermediate, and particularly relates to a method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method.

Background

The synthesis method of the compound 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester and related derivatives have wide application in pharmaceutical chemistry and organic synthesis. At present, the synthesis method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester is only reported in documents. Therefore, it is necessary to develop a synthesis method which has easily available raw materials, convenient operation, easy control of reaction, proper overall yield and suitability for industrial production.

Disclosure of Invention

The technical problems to be solved by the invention are as follows: aiming at the existing problems, the method for synthesizing the 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by the one-step method is provided.

In order to solve the technical problems, the invention adopts the following technical scheme:

a one-step method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester has the following chemical reaction formula:

compound a compound B;

the synthesis comprises the following steps:

and (2) uniformly mixing the compound A and a solvent, adding organic acid, cooling, dropwise adding an N-chlorosuccinimide solution, and stirring for reaction to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.

Preferably, the solvent is any one of dimethylformamide and N-methylpyrrolidone.

Preferably, the solid-liquid ratio g/mL of the compound A to the solvent is 1: 30-35.

Preferably, the organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.

Preferably, the solid-to-liquid ratio g/mL of the compound A and the organic acid is 5-9: 1.

Preferably, the mass ratio of the compound A to the N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing the N-chlorosuccinimide and a solvent according to the solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.

Preferably, the end point of the temperature reduction is-5-0 ℃.

Compared with other methods, the method has the beneficial technical effects that:

(1) the invention provides a synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester for the first time, and provides a synthetic route for the synthetic method of 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester;

(2) the synthetic method of the 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester provided by the invention is short in route, reasonable in design, simple to operate and easy to control;

(3) the compound A (1H-imidazole-2-carboxylic acid ethyl ester) is used as a raw material, a better polarization environment is provided for N-chlorosuccinimide molecules by organic acid under the environment of low temperature and organic acid, the electrophilic activity of a substrate is improved, the reaction is promoted, the generation of byproducts is reduced, and the yield and the purity of the product are improved.

Detailed Description

The invention is further illustrated by the following examples, without restricting its scope to these examples. Numerous other changes and modifications can be made by those skilled in the art without departing from the spirit and scope of the invention. In particular, certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve the same or similar results, and reactions may be carried out under conditions outside the preferred ranges, albeit less than optimally. Accordingly, such obvious substitutions and modifications are intended to be included within the scope of the appended claims.

The solvent is any one of dimethylformamide and N-methylpyrrolidone.

The organic acid is any one of acetic acid, trifluoroacetic acid and methanesulfonic acid.

The mass ratio of the compound A to the N-chlorosuccinimide is 1: 0.5-1, and the N-chlorosuccinimide solution is prepared by mixing the N-chlorosuccinimide and a solvent according to the solid-to-liquid ratio g/mL of 1: 10; the solvent is any one of dimethylformamide and N-methylpyrrolidone.

A method for synthesizing 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester by a one-step method, which comprises the following steps: uniformly mixing the compound A and the solvent according to the solid-liquid ratio g/mL of the compound A and the solvent of 1: 30-35, adding the organic acid according to the solid-liquid ratio g/mL of the compound A and the organic acid of 5-9: 1, cooling to-5-0 ℃, dropwise adding an N-chlorosuccinimide solution, stirring and reacting for 15-20 hours to obtain a compound B, namely 4-chloro-1H-imidazole-2-carboxylic acid ethyl ester.