阅读说明：本技术 邻氨基苯乙酮的制备方法 (Preparation method of o-aminoacetophenone ) 是由 成家钢 于 2020-06-11 设计创作，主要内容包括：本发明涉及有机中间体合成技术领域,具体涉及一种邻氨基苯乙酮的制备方法。本发明所提供的邻氨基苯乙酮的制备方法,由邻硝基乙苯在稀硫酸的酸性环境中分批加入高锰酸钾发生氧化反应生成邻硝基苯乙酮；邻硝基苯乙酮再用铁粉还原成邻氨基苯乙酮,之后水蒸汽蒸馏出邻氨基苯乙酮,反应条件温和、生产成本低,适宜进行工业化大生产,邻硝基苯乙酮的收率能达到70％以上,邻氨基苯乙酮的收率能达到90％以上,其中,当采用弱酸冰醋酸作为催化剂、各原料保持最佳的配比,并在最优的反应条件下进行反应时,邻硝基苯乙酮和邻氨基苯乙酮的收率均能达到95％以上。(The invention relates to the technical field of synthesis of organic intermediates, and particularly relates to a preparation method of o-aminoacetophenone. The preparation method of o-aminoacetophenone provided by the invention comprises the steps of adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to carry out oxidation reaction to generate o-nitroacetophenone; the method has the advantages that the o-nitroacetophenone is reduced into the o-aminoacetophenone by using the iron powder, then the o-aminoacetophenone is distilled by using water vapor, the reaction condition is mild, the production cost is low, the industrial large-scale production is suitable, the yield of the o-nitroacetophenone can reach more than 70%, the yield of the o-aminoacetophenone can reach more than 90%, when weak acid glacial acetic acid is used as a catalyst, the optimal proportion of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of the o-nitroacetophenone and the yield of the o-aminoacetophenone can both reach more.)

1. The preparation method of o-aminoacetophenone is characterized by comprising the following steps:

(1) reacting an oxidant potassium permanganate, an acid catalyst and o-nitroethylbenzene in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;

(2) and (2) adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into the reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain the o-aminoacetophenone.

2. The process for producing o-aminoacetophenone according to claim 1, characterized in that the acid catalyst used in the step (1) is weak acid glacial acetic acid.

3. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the molar ratio of o-nitroethylbenzene to potassium permanganate in step (1) is 1 (1.3-1.8).

4. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the weak acid catalyst used in step (1) is 2-4% by weight of o-nitroethylbenzene.

5. The process for producing o-aminoacetophenone according to claim 1, characterized in that the reaction temperature in the step (1) is 30 to 40 ℃.

6. The process for producing o-aminoacetophenone according to any one of claims 1 to 5, characterized in that the extraction in step (1) comprises two steps: the first step is industrial salt extraction; the second step is the co-extraction of industrial salt and benzene.

7. The process for producing o-aminoacetophenone according to any one of claims 1 to 5, characterized in that the washing in the step (1) comprises two steps: the first step is washing with alkali liquor and the second step is washing with water.

8. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the molar ratio of o-nitroacetophenone to the reducing metal in step (2) is 1: (2-6).

9. The method for preparing o-aminoacetophenone according to claim 1, characterized in that the ammonium chloride solution in step (2) is added in portions according to the reaction progress, the molar ratio of ammonium chloride to iron powder is 1: (10-12).

10. The process for producing o-aminoacetophenone according to claim 1, characterized in that the temperature of the reflux reaction in the step (2) is 75 to 90 ℃.

Technical Field

The invention relates to the technical field of synthesis of organic intermediates, and particularly relates to a preparation method of o-aminoacetophenone.

Background

O-aminoacetophenone is an important intermediate of the hypoglycemic drug linagliptin, and is one of important hot fields of the current drug research.

Patent CN107162923B discloses a preparation method of o-aminoacetophenone, which comprises: in an anhydrous or nearly anhydrous solvent, reacting methyllithium with isatoic anhydride at a reaction temperature below-50 ℃, and performing post-treatment to obtain the target product o-amino acetophenone. In the preparation method, two related main raw materials, namely methyl lithium and isatoic anhydride, are high in price, and in addition, the reaction is carried out at the temperature of minus 50 ℃, the reaction conditions are harsh, and the production cost is high;

the invention patent with application number 201911252092.1 discloses a preparation method of o-aminoacetophenone, which comprises the following steps: (1) mixing o-nitroethylbenzene, an oxidant, a cocatalyst and an organic solvent, heating the mixed solution to a certain temperature for reaction, and cooling, quenching and extracting the reacted solution to obtain o-nitroacetophenone; (2) adding a polar solvent and a metal catalyst into the obtained o-nitroacetophenone, carrying out hydrogenation reduction reaction to obtain an o-aminoacetophenone crude product, and filtering and rectifying the o-aminoacetophenone crude product to obtain an o-aminoacetophenone refined product. In the preparation method, the yield of the o-nitroacetophenone in the step (1) is only 40-70%, so that the yield of the final product is low.

Therefore, the development of a preparation method of o-aminoacetophenone with low production cost, mild reaction condition and high yield is of great significance.

Disclosure of Invention

Therefore, the development of the preparation method of the o-aminoacetophenone with low production cost, mild reaction condition and high yield is of great significance.

The technical scheme for solving the technical problems is as follows:

the invention provides a preparation method of o-aminoacetophenone, which comprises the following steps:

(1) reacting an oxidant potassium permanganate, an acid catalyst and o-nitroethylbenzene in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;

(2) and (2) adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into the reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain the o-aminoacetophenone.

Wherein the acid catalyst used in the step (1) is weak acid glacial acetic acid.

Wherein the molar ratio of o-nitroethylbenzene to potassium permanganate in the step (1) is 1 (1.3-1.8).

Wherein, the dosage of the weak acid catalyst in the step (1) is 2-4% of the weight of the o-nitroethylbenzene.

Wherein the reaction temperature in the step (1) is 30-40 ℃.

Wherein, the extraction in the step (1) comprises two steps: the first step is industrial salt extraction; the second step is the co-extraction of industrial salt and benzene.

Wherein the washing in step (1) comprises two steps: the first step is washing with alkali liquor and the second step is washing with water.

Wherein the mol ratio of the o-nitroacetophenone to the reducing metal in the step (2) is 1: (2-6).

Wherein, the ammonium chloride solution in the step (2) is added in batches according to the reaction process, and the molar ratio of the ammonium chloride to the iron powder is 1: (10-12).

Wherein the temperature of the reflux reaction in the step (2) is 75-90 ℃.

The preparation method of o-aminoacetophenone provided by the invention comprises the steps of adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to carry out oxidation reaction to generate o-nitroacetophenone; the o-nitroacetophenone is reduced into o-aminoacetophenone by using iron powder, and then the o-aminoacetophenone is distilled by using water vapor, so that the reaction condition is mild, the production cost is low, the industrial large-scale production is suitable, the yield of the o-nitroacetophenone can reach more than 70%, and the yield of the o-aminoacetophenone can reach more than 90%; wherein, when weak acid glacial acetic acid is used as a catalyst, the optimal mixture ratio of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of o-nitroacetophenone and o-aminoacetophenone can reach more than 95%.

Detailed Description

The principles and features of this invention are described below in conjunction with specific embodiments, the examples given are intended to illustrate the invention and are not intended to limit the scope of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

A preparation method of o-aminoacetophenone comprises the following steps:

(1) reacting an oxidant potassium permanganate, an acid catalyst and o-nitroethylbenzene in a dilute sulfuric acid environment, and after the reaction is finished, extracting, washing and drying to obtain o-nitroacetophenone;

(2) and (2) adding the o-nitroacetophenone obtained in the step (1) and a reducing metal into an ammonium chloride aqueous solution for continuous reflux reaction, introducing steam into the reaction kettle for distillation after the reaction is finished, and separating the distilled solution to obtain the o-aminoacetophenone.

It should be noted that: the reaction in step (1) can only be carried out under acidic conditions, and when the reaction is carried out under alkaline environmental conditions, the obtained product can be affected, for example, when the reaction is carried out under alkaline conditions of sodium hydroxide, the obtained product is o-nitrobenzoic acid. The oxidant in the step (1) can only use potassium permanganate, and the applicant adopts dichromate, perchloric acid and other oxidants to carry out experiments, so that the yield of the obtained o-nitroacetophenone is below 55%.

Wherein, the acid catalyst used in step (1) is preferably weak acid glacial acetic acid, and it should be noted that, when other strong acids such as hydrochloric acid and other weak acids such as boric acid are used, the yield of the obtained product o-nitroacetophenone is reduced, for example, when boric acid is used, the yield of the obtained product o-nitroacetophenone is only 40%, when hydrochloric acid is used, the yield of the product o-nitroacetophenone is reduced compared with the yield when glacial acetic acid is used, and hydrochloric acid is not generally used because hydrochloric acid has high corrosivity to equipment.

Wherein the molar ratio of o-nitroethylbenzene to potassium permanganate in the step (1) is 1: (1.3-1.8), among them, 1: (1.4-1.6), most preferably 1: 1.5. when the molar ratio of the o-nitroethylbenzene to the potassium permanganate is 1: (1.3-1.8), the yield of the o-nitroacetophenone can reach more than 72%, and when the molar ratio of the o-nitroethylbenzene to the potassium permanganate is 1: (1.4-1.6), the yield of the o-nitroacetophenone can reach more than 81%, and when the molar ratio of the o-nitroethylbenzene to the potassium permanganate is 1: 1.5, the yield of the o-nitroacetophenone can reach more than 90%, wherein when the raw materials, the reaction conditions and the like adopt the optimized optimal scheme, the yield of the o-nitroacetophenone can reach more than 95%.

Wherein, the weak acid catalyst is used in the step (1) in an amount of 2-4% by weight, preferably 2.5-3.5% by weight, and more preferably 3% by weight, based on the o-nitroethylbenzene.

Wherein, the reaction temperature in the step (1) is 30-40 ℃, when the temperature is too low, the reaction time is longer, when the temperature is too high, and when the temperature exceeds 50 ℃, the decarboxylation and ring opening of the o-nitroethylbenzene are carried out, the yield of the obtained product o-nitroacetophenone can be obviously reduced, for example, when the reaction is carried out at 55-65 ℃, the yield of the o-nitroacetophenone is only 80%.

Wherein, the extraction in the step (1) comprises two steps: the first step is extracting by using industrial salt; in the second step, industrial salt and benzene are used for co-extraction. The specific operation steps are as follows: after the reaction is finished, adding industrial salt, stirring, cooling, standing, and sucking out the oil layer under negative pressure after the manganese dioxide mud is obviously separated from the oil layer; adding industrial benzene and industrial salt into the oil-containing manganese mud left in the kettle, stirring, after the manganese mud is obviously separated from the oil layer containing the benzene, sucking out the oil layer under negative pressure, discarding the manganese mud, combining the oil layers obtained twice, washing, drying and evaporating the benzene to obtain the manganese-containing manganese oil. The industrial salt used in the step can be sodium chloride or ammonium chloride, and the purpose is to increase the specific gravity of water and facilitate layering.

Wherein, the washing in the step (1) also comprises two steps: the first step is washing with an alkaline solution capable of neutralizing the acid, and the second step is washing with water. The specific operation steps are as follows: and combining the obtained oil layers after extraction, washing twice with alkaline liquor, then washing twice with water, drying the oil layers, and evaporating benzene to obtain the o-nitroacetophenone. The alkali liquor used in the step can be sodium hydroxide alkali liquor or other alkali liquor capable of neutralizing acid, such as potassium hydroxide alkali liquor; the oil layer may be dried with anhydrous calcium chloride or dried with other means such as molecular sieve.

Wherein the mol ratio of the o-nitroacetophenone to the iron powder in the step (2) is 1: (2-6), preferably 1: (3-5), more preferably 1: 4.

wherein, the ammonium chloride solution in the step (2) is added in batches according to the reaction process, and the molar ratio of the ammonium chloride to the iron powder is 1: (10-12). The method comprises the following specific operation steps: ammonium chloride is prepared into a 20% aqueous solution, and then added in batches according to the reaction progress. It should be noted that the ammonium chloride used in this step also has the effect of activating the iron powder, and the use of ammonium chloride has little corrosion to equipment and better activation effect to iron powder, and when other chlorides, such as hydrochloric acid, are used, the product yield is low and the corrosion to equipment is severe.

Wherein, the temperature of the reflux reaction in the step (2) is 75-90 ℃, wherein the effect is best when the temperature is 84-84 ℃, when the temperature is higher than 90 ℃, a large amount of water vapor can be generated in the reaction process, the product yield is low, and when the temperature is too low, the reaction is slow.

The reaction process of the reaction is as follows: adding o-nitroethylbenzene into potassium permanganate in batches in an acidic environment of dilute sulfuric acid to perform oxidation reaction to generate o-nitroacetophenone; the o-nitroacetophenone is reduced into o-aminoacetophenone by iron powder, and then the o-aminoacetophenone is distilled by water vapor, so that the content of the obtained product can reach more than 99.5 percent, the yield of the o-nitroacetophenone can reach 70 percent, and the yield of the o-aminoacetophenone can reach 90 percent. Wherein, when weak acid glacial acetic acid is used as a catalyst, the optimal mixture ratio of the raw materials is kept, and the reaction is carried out under the optimal reaction condition, the yield of o-nitroacetophenone and o-aminoacetophenone can reach more than 95%. The reaction principle of the above reaction is as follows: