阅读说明：本技术 一种2-氨基-5-氯-n，3-二甲基苯甲酰胺的制备方法 (Preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide ) 是由 沈冰良 黄忠林 韦伟 徐剑锋 曾淼 程晓文 于 2019-11-08 设计创作，主要内容包括：本发明公开一种2-氨基-5-氯-N,3-二甲基苯甲酰胺合成方法,以式I为原料,和氯化试剂在氨基邻对位进行氯代反应,生成式II所示化合物,式II所示化合物在碱性催化条件下,利用氨基邻对位氯热力学稳定性差异,和氰基发生选择性取代反应,以氨基邻位氯取代为主,生成式III所示化合物,然后式III所示化合物水解成式IV所示化合物；式IV所示化合物酯化生成式V所示化合物,式V所示化合物和一甲胺甲醇溶液反应,生成2-氨基-5-氯-N,3-二甲基苯甲酰胺。本发明提供的制备方法收率高、反应简单、毒副作用小。<Image he="161" wi="700" file="DDA0002265198320000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses a method for synthesizing 2-amino-5-chloro-N, 3-dimethyl benzamide, which takes a formula I as a raw material and a chlorinating agentPerforming chlorination reaction on amino ortho-para position to generate a compound shown in a formula II, performing selective substitution reaction on the compound shown in the formula II and cyano by utilizing thermodynamic stability difference of amino ortho-para position chlorine under the condition of alkaline catalysis, mainly substituting amino ortho-position chlorine to generate a compound shown in a formula III, and hydrolyzing the compound shown in the formula III into a compound shown in a formula IV; esterifying the compound shown in the formula IV to generate a compound shown in the formula V, and reacting the compound shown in the formula V with a monomethylamine methanol solution to generate 2-amino-5-chloro-N, 3-dimethylbenzamide. The preparation method provided by the invention has the advantages of high yield, simple reaction and small toxic and side effects.)

1. A method for preparing 2-amino-5-chloro-N, 3-dimethylbenzamide, which is characterized by comprising the following steps:

mixing the compound shown in the formula I with hydrochloric acid and hydrogen peroxide for reaction, separating by-products, and precipitating solids to obtain a compound shown in the formula II;

mixing a compound shown as a formula II, cuprous cyanide and copper halide in a solvent for reaction, mixing and stirring a reaction product and ammonia water after the reaction is finished, and refining to obtain a compound shown as a formula III;

mixing the compound shown in the formula III with an alkaline compound for reaction to obtain a compound shown in a formula IV;

reacting the compound shown in the formula IV with methanol and concentrated sulfuric acid to obtain a compound shown in a formula V;

mixing a compound shown as a formula V with monomethylamine methanol for amidation reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide;

2. the preparation method of claim 1, wherein the concentration of the hydrogen peroxide is 15-50%.

3. The preparation method according to claim 1, wherein the molar ratio of the hydrochloric acid to the hydrogen peroxide to the compound represented by the formula I is 1: 5-15: 2.2 to 7.

4. The method according to claim 1, wherein the refining process specifically comprises:

and mixing the ammonia water mixture with an organic solvent for extraction, performing alkali washing, water washing, drying, suction filtration, drying by distillation, and recrystallizing methanol to obtain the compound shown in the formula III.

5. The preparation method according to claim 4, wherein the extraction is specifically: the extraction is carried out in several steps using methylene chloride, dichloroethane, ethyl acetate, toluene, chloroform, etc.

6. The preparation method according to claim 4, wherein the alkaline washing is specifically: the organic phase obtained after extraction is washed with an alkaline solution.

7. The method according to claim 1, wherein the compound of formula II is used in a ratio of 1: 0.85-1.05: 0.05 to 0.2.

8. The method according to claim 1, wherein the ratio of the compound represented by the formula III to the basic compound is 1:1.05 to 1.8.

9. The method according to claim 1, wherein the ratio of the compound represented by IV to methanol and concentrated sulfuric acid is 1:2 to 20:0.05 to 0.5.

10. The preparation method according to claim 1, wherein the ratio of the compound represented by the formula V to monomethylamine methanol is 1: 1.3-7.

Technical Field

The invention relates to the field of chemical synthesis, in particular to a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide.

Background

2-amino-5-chloro-N, 3-dimethylbenzamide is an important intermediate of chlorantraniliprole. The chlorantraniliprole pesticide is safe and environment-friendly to mammals, has good activity to lepidoptera insects, and has no cross resistance with other existing pesticides.

2-amino-5-chloro-N, 3-dimethyl benzamide has more reported processes, wherein the process taking 2-nitro-3-methylbenzoic acid as a raw material is the most common:

(1) 2-nitro-3-methylbenzoic acid is used as a raw material, the 2-nitro-3-methylbenzoic acid is esterified with methanol to generate 2-nitro-3-methyl benzoate, the ester and a monomethylamine methanol solution are subjected to a methylaminoization reaction to generate 2-nitro-N, 3-dimethylbenzamide, the 2-nitro-N, 3-dimethylbenzamide is generated by reduction (iron powder, palladium carbon and the like), and then the 2-amino-5-chloro-N, 3-dimethylbenzamide is obtained by chlorination;

(2) 2-nitro-3-methylbenzoic acid is used as a raw material, and is firstly reduced into 2-nitro-3-methylbenzoic acid, then the 2-nitro-3-methylbenzoic acid and phosgene (solid light and diphosgene) are used for generating a cyclic compound, then the cyclic compound reacts with sulfonyl chloride, chlorination is carried out, and finally methyl amination is carried out to obtain the 2-amino-5-chloro-N, 3-dimethyl benzamide.

Disclosure of Invention

In view of the above, the invention provides a preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide, which has high yield, simple reaction and small toxic and side effects

In order to solve the above technical problems, the technical solution of the present invention is a method for preparing 2-amino-5-chloro-N, 3-dimethylbenzamide, preferably, the method comprises:

mixing the compound shown in the formula I with hydrochloric acid and hydrogen peroxide for reaction, separating by-products, and precipitating solids to obtain a compound shown in the formula II;

mixing a compound shown as a formula II, cuprous cyanide and copper halide in a solvent for reaction, mixing and stirring a reaction product and ammonia water after the reaction is finished, and refining to obtain a compound shown as a formula III;

mixing the compound shown in the formula III with an alkaline compound for reaction to obtain a compound shown in a formula IV;

reacting the compound shown in the formula IV with methanol and concentrated sulfuric acid to obtain a compound shown in a formula V;

mixing a compound shown as a formula V with monomethylamine methanol for amidation reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide;

preferably, the concentration of the hydrogen peroxide is 15-50%, and more preferably 20-45%.

Preferably, the molar ratio of the hydrochloric acid to the hydrogen peroxide to the compound shown in the formula I is 5-15: 2.2-7: 1. preferably, the refining process specifically includes:

and mixing the ammonia water mixture with an organic solvent for extraction, performing alkali washing, water washing, drying, suction filtration, drying by distillation, and recrystallizing methanol to obtain the compound shown in the formula III.

Preferably, the extraction is specifically: the extraction is carried out in several steps using methylene chloride, dichloroethane, ethyl acetate, toluene, chloroform, etc.

Preferably, the alkali washing is specifically as follows: the organic phase obtained after extraction is washed with an alkaline solution.

Preferably, the ratio of the compound shown in the formula II to cuprous cyanide and copper halide is 1: 0.85-1.05: 0.05 to 0.2.

Preferably, the ratio of the compound shown in the formula III to the basic compound is 1: 1.05-1.8.

Preferably, the ratio of the compound shown in IV to methanol and concentrated sulfuric acid is 1: 2-20: 0.05-0.5.

Preferably, the ratio of the compound shown in the formula V to monomethylamine methanol is 1: 1.3-7.

The invention provides a method for synthesizing 2-amino-5-chloro-N, 3-dimethyl benzamide, which comprises the steps of carrying out chlorination reaction on a compound shown in a formula II by taking a formula I as a raw material and a chlorinating agent at an amino ortho-para position to generate a compound shown in the formula II, carrying out selective substitution reaction on the compound shown in the formula II and a cyano group by utilizing thermodynamic stability difference of the amino ortho-para position chlorine under an alkaline catalysis condition, and mainly substituting the amino ortho-position chlorine to generate a compound shown in a formula III, and then hydrolyzing the compound shown in the formula III into a compound shown in a formula IV; esterifying the compound shown in the formula IV to generate a compound shown in the formula V, and reacting the compound shown in the formula V with a monomethylamine methanol solution to generate 2-amino-5-chloro-N, 3-dimethylbenzamide. Wherein the yield of the second chlorination in the first step is as follows: 85-90%, and the cyano group substitution yield in the second step: 75-80%, and the total yield of the three steps of hydrolysis, methyl esterification and methylamine: 90-95%. Because the starting material compound shown as the formula I in the patent is a common compound, the preparation process taking 2-nitro-3-methylbenzoic acid as a key raw material is avoided, the 2-nitro-3-methylbenzoic acid is prepared by nitration of 3-methylbenzoic acid, a large amount of acid is required in the nitration reaction, the environment is not friendly, and the nitration yield is not high; the novel point of the patent is that the compound shown in the formula I is used as the initial two steps of selective substitution of dichloro and cyano, and the key intermediate compound shown in the formula III is prepared through the two steps; hydrolyzing the cyano group into carboxylic acid, esterifying, and aminomethylating to obtain 2-amino-5-chloro-N, 3-dimethyl benzamide; meanwhile, in the reaction process, reagents used in the steps of dichloro, cyano substitution, hydrolysis, esterification, methyl amination and the like are common reagents, the yield of each step is high, the total yield is 58-68%, and the method is economical, so that the method has a certain industrial production value.

Drawings

FIG. 1 is a hydrogen spectrum of 2-amino-5-chloro-N, 3-dimethylbenzamide.

Detailed Description

In order that those skilled in the art will better understand the technical solutions of the present invention, the present invention will be further described in detail with reference to the following embodiments.

The technical scheme of the invention is as follows: a preparation method of 2-amino-5-chloro-N, 3-dimethyl benzamide comprises the following steps:

mixing the compound shown in the formula I with hydrochloric acid and hydrogen peroxide for reaction, separating by-products, and precipitating solids to obtain a compound shown in the formula II;

mixing a compound shown as a formula II, cuprous cyanide and copper halide in a solvent for reaction, mixing and stirring a reaction product and ammonia water after the reaction is finished, and refining to obtain a compound shown as a formula III;

mixing the compound shown in the formula III with an alkaline compound for reaction to obtain a compound shown in a formula IV;

reacting the compound shown in the formula IV with methanol and concentrated sulfuric acid to obtain a compound shown in a formula V;

mixing a compound shown as a formula V with monomethylamine methanol for amidation reaction to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide;

according to the invention, specifically, a compound shown as a formula I is added into a reactor, the temperature is controlled to be 10-75 ℃, hydrochloric acid is dropwise added, the mixture is stirred uniformly, the temperature is kept for half an hour, hydrogen peroxide is dropwise added at 10-75 ℃ for 1-8 hr, then the temperature is kept at 30-75 ℃ for reaction for 2-8 hr, the reaction is finished, the temperature is cooled to 10-25 ℃, the pH value is adjusted to 6-8, solids are separated out, and the 2, 4-dichloro-6-methylaniline is subjected to suction filtration and drying. The concentration of the hydrogen peroxide is preferably 15-50%, and more preferably 20-45%. The molar ratio of the hydrochloric acid to the hydrogen peroxide to the compound shown in the formula I is 5-15: 2.2-7: 1.

adding a compound shown as a formula II, a solvent, cuprous cyanide and copper halide into a reactor, heating to 50-150 ℃, reacting for 4-24 hours, cooling after the reaction is finished, and refining. Preferably, the refining process specifically includes:

and mixing the ammonia water mixture with an organic solvent for extraction, performing alkali washing, water washing, drying, suction filtration, drying by distillation, and recrystallizing methanol to obtain the compound shown in the formula III. The extraction is specifically as follows: the extraction is carried out in several steps using methylene chloride, dichloroethane, ethyl acetate, toluene, chloroform, etc. The solvent is preferably dichloromethane, and the alkali washing is specifically as follows: the organic phase obtained after extraction is washed with an alkaline solution. Preferably, the ratio of the compound shown in the formula II to cuprous cyanide and copper halide is 1: 0.85-1.05: 0.05 to 0.2.

Mixing the compound shown in the formula III with dilute alkali, heating to 50-100 ℃, reacting for 5-24 hr, completely reacting, cooling, adjusting to be neutral by using acid, precipitating solid, and performing suction filtration to obtain the compound shown in the formula VI. Preferably, the ratio of the compound shown in the formula III to the basic compound is 1: 1.05-1.8.

And mixing the compound shown in the formula VI with methanol, stirring, dropwise adding concentrated sulfuric acid, carrying out reflux reaction for 8-24 hr, cooling, carrying out suction filtration, and washing the solid with water to obtain the compound shown in the formula V. Preferably, the ratio of the compound shown in IV to methanol and concentrated sulfuric acid is 1: 2-20: 0.05-0.5.

Mixing the compound shown in the formula V with a monomethylamine methanol solution, heating to 30-68 ℃, reacting for 5-16 hr, completely reacting, evaporating most of methylamine methanol, adding water, and performing suction filtration to obtain the 2-amino-5-chloro-N, 3-dimethylbenzamide. Preferably, the ratio of the compound shown in the formula V to monomethylamine methanol is 1: 1.3-7.

The following is the synthesis reaction equation of the present invention.

The following are specific embodiments of the present invention: