KR20020049673A - Method for preparing 2-amino-3,5-dibromobenzaldehyde having high purity and yield - Google Patents

Abstract

PURPOSE: Provided is a process for producing 2-amino-3,5-dibromobenzaldehyde in high purity and yield from 2-amino-3,5-dibromobenzoic hydrazide, which can reduce byproducts and improve quality. CONSTITUTION: The 2-amino-3,5-dibromobenzaldehyde(formula 1) is produced by mixing and reacting the 2-amino-3,5-dibromobenzoic hydrazide(formula 2) as a starting material, 0.1-2wt.(based on the starting material) of a ketone compound, 0.05-0.5wt.pts. of an oxidizing agent, and 0.5-2.0wt.pts. of water in 2-11wt.pts. of a mixed solvent at a temperature of 0-80deg.C for 1-10 hours, followed by filtering, washing, and recovering the solvent. The mixed solvent comprises a polar solvent, organic and inorganic alkalis, an antioxidant, and water in the weight ratio of 1.0-4.0:0.5-1.5:0.001-0.05:1.0-5.0.

Description

Method for preparing 2-amino-3,5-dibromobenzaldehyde with high purity and high yield {Method for preparing 2-amino-3,5-dibromobenzaldehyde having high purity and yield}

The present invention relates to a method of preparing 2-amino-3,5-dibromobenzaldehyde of high purity and high yield, wherein 2-amino-3,5-dibromobenzoic hydrazide of Formula 2 is used as a starting material. The present invention relates to a method for preparing 2-amino-3,5-dibromobenzaldehyde of Chemical Formula 1 with high yield and high purity by improving the manufacturing process, reducing the amount of by-products, and improving the quality and manufacturing cost.

2-amino-3,5-dibromobenzaldehyde represented by the formula (1) is an important compound used as an intermediate of Ambroxol, a bronchodilator.

Therefore, various manufacturing methods have been researched and developed conventionally. For example, in British Patent Publication No. 2,239,241, a high temperature reaction was performed at 120 to 125 ° C. for 1 hour using a benzoylhydrazide compound represented by the following Chemical Formula 3, a mixed solvent of ethylene glycol and water, to Chemical Formula 1 Instantly preparing the indicated 2-amino-3,5-dibromobenzaldehyde, without separating it It is described a method of reacting with a compound of to convert into a compound of formula (4). However, since the starting material should be added at 115 ° C. or more, which is the flash point of ethylene glycol as the main solvent, there is a risk of explosion due to static electricity and it is difficult to industrially apply the input method. In addition, since the 2-amino-3,5-dibromobenzaldehyde which is chemically unstable by high temperature reaction proceeds to the subsequent reaction without separating, the preparation of 2-amino-3,5-dibromobenzaldehyde of Chemical Formula 1 The results are not disclosed.

In addition, U.S. Patent No. 4,363,766 discloses a benzanilide compound represented by Formula 5 below at room temperature with lithium aluminum hydride (LiAlH ₄ ) in THF solvent, followed by hydrolysis with dilute sulfuric acid to form 2-amino represented by Formula 1 A process for preparing -3,5-dibromobenzaldehyde in 60% yield is described. However, since the method uses a highly combustible lithium aluminum hydride organometallic reducing agent of LiAlH ₄ , there is a problem in that it is difficult to apply industrially due to low safety and additional recovery process. In addition, according to the above method, since the alcohol compound represented by the following Chemical Formula 6, which is overreduced as a by-product besides the target compound of Chemical Formula 1, is produced, purity and yield are reduced, and a process of separating and removing the same is required.

On the other hand, Korean Patent No. 218150 discloses the benzhydrazide compound represented by Chemical Formula 3 by mixing carbonates and hydroxides and adding a phenolic antioxidant and a bleaching agent to react at 50 to 100 ° C. for 1 to 15 hours. A method for preparing 2-amino-3,5-dibromobenzaldehyde represented by 1 is described. However, the benzhydrazide compound of Chemical Formula 3, which is the starting material of Korean Patent No. 218150, is 2-amino-3,5-dibromobenzoic hydra represented by Chemical Formula 2 from the compound represented by Chemical Formula 7 below. After being prepared with zides, it is manufactured from benzoylhydrazide of Formula 3 using paratoluenesulfonyl chloride raw material, and the manufacturing process is complicated, resulting in excessive wastewater and lack of economic efficiency due to excessive expenditure such as raw material cost and facility investment cost. There is.

Accordingly, an object of the present invention is to solve the problems of the prior art, improve the manufacturing process to reduce the amount of by-products, improve quality and yield, and at the same time save the manufacturing cost, 2-amino-3,5 To provide a process for producing dibromobenzaldehyde in high purity, high yield.

In order to achieve the above object, a method for preparing 2-amino-3,5-dibromobenzaldehyde having high purity and high yield according to the present invention is a mixture of a polar solvent, an organic-inorganic alkali, an antioxidant, and water. 2-amino-3,5-dibromobenzoic hydrazide as a starting material, and 0.1 to 2 parts by weight of ketone compound, 0.05 to 0.5 parts by weight of oxidizing agent and 0.5 to 2.0 parts by weight of water After mixing and reacting at 0 to 80 ° C. for 1 to 10 hours, the process includes filtration, washing and solvent recovery.

Formula 1

Formula 2

Hereinafter, the present invention will be described in more detail.

2-amino-3,5-dibromobenzaldehyde represented by Chemical Formula 1 has unstable aldehyde and amino groups at the same time, so it is easily deteriorated or oxidized according to reaction conditions and ambient conditions and converted to other materials. It is a very difficult compound to prepare.

However, in the reactant composition and the reaction conditions according to the present invention, the formation of side reactants is suppressed to a minimum, and a purity of 99% (HPLC) or more and a yield of 80% or more, preferably 85% or more can be obtained. In addition, high quality products can be manufactured with good economics and simple processes.

As described above, in Korean Patent No. 218150, after the step of preparing the compound represented by Chemical Formula 2 as the compound of Chemical Formula 3, a compound of Chemical Formula 1, which is a target compound, was obtained, and the reaction mechanism is represented by the following Scheme 1 Same as Namely, the compound represented by the formula (1) is obtained by pyrolysis of the tosylhydrazide of the formula (3) under alkali addition.

However, in the present invention, through the reaction mechanism of Scheme 2, the compound of Formula 1 could be directly obtained by directly oxidizing the hydrazine moiety of Formula 2 without tosylation of the compound of Formula 2 that could not be solved in the conventional Scheme 1. Thus, the compound of Formula 1 can be obtained without solving the possibility of generating amine or hurting amino group or oxidizing aldehyde, without going through Formula 3.

In the preparation method according to the present invention, the starting material is 2-amino-3,5-dibromobenzoic hydrazide of Formula 2 as starting material. In addition, the mixed solvent usable in the present invention comprises a polar solvent, an organic-inorganic alkali, an antioxidant, and water, and the component ratio thereof is 1.0 to 4.0: 0.5 to 1.5: 0.001 to 0.05: 1.0 to 5.0 by weight, and the mixed solvent thus constructed Is preferably used in 2 to 11 by weight based on the starting material. If the content of each component of the mixed solvent is out of the above range it will have a decisive result in the reaction rate, purity and yield decrease. In addition, even when the content of the mixed solvent is out of the above range, the purity, yield is reduced and a bright color product cannot be obtained.

The polar solvent usable in the present invention is selected from the group consisting of alcohols and dioxane, and the organic-inorganic alkali is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and ammonium hydroxide.

In addition, the starting material, the ketone compound, the oxidizing agent and water are mixed under the mixed solvent and reacted at 0 to 80 ° C. for 1 to 10 hours, followed by filtration, washing, and solvent recovery. At this time, the reaction temperature is 0 ° C. If it is lower, the reaction rate is slowed, and if it exceeds 80 ° C, side reactions occur, and the effect on purity, yield and color is lowered. In addition, when the reaction time is less than 1 hour, unreacted substances are present, and when more than 10 hours, impurities are present due to overreaction.

Antioxidant used in the present invention is selected from the group consisting of Irganox family of Ciba-geigy and Ultranox, the amount of the amount is preferably 0.001 to 0.05 based on the starting material, 0.001 for the starting material If it is less than the weight ratio, there is a problem that a high purity product is not obtained, and if it exceeds 0.05 weight ratio, it is present as an impurity.

In addition, the oxidizing agent used in the present invention is selected from the group consisting of organic and inorganic peroxides including hydrogen peroxide, sodium hypochloride and organic peroxide, the amount is preferably a weight ratio of 0.05 to 0.5 based on the starting material, If the ratio is less than 0.05 weight ratio, the reaction rate is slow and there is a problem that an unreacted substance is present. If it exceeds 0.5 weight ratio, impurities are present due to overreaction.

The ketone compound used in the present invention is selected from the group consisting of methyl ethyl ketone, ketone and acetone, the amount is preferably a weight ratio of 0.1 to 2 based on the starting material, the reaction proceeds if less than 0.1 weight ratio with respect to the starting material There is a problem that does not occur and the yield exceeds 2 weight ratio results.

Due to the shortening of the manufacturing process of the present invention, 2-amino-3,5-dibromobenzaldehyde of the formula (1) prepared by a simple and economic method affects the properties of the bronchial dilator Ambroxol and the color of the product. Since the drug substance and the drug substance intermediate, such as color is very important, conventionally dark yellow to blueish yellow, but the compound prepared according to the present invention is light yellow.

Hereinafter, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the scope of the present invention is not limited thereto.

Example 1

A 250 ml four-necked round flask was equipped with a mechanical stirrer, a cooler, and a thermometer, and then mixed with 80 g of dioxane, 15 g of water, and 60 g of ammonium hydroxide to prepare a mixed solvent. 23 g of the compound was prepared and stirred for 30 minutes. 18 g of ketone and 7.7 g of sodium hypochlorite were further added to the flask, and the mixture was reacted for 2 hours while maintaining 20 ° C. After completion of the reaction, the reaction mixture was filtered at room temperature and washed with 30 g of water to obtain 15.89 g of 2-amino-3,5-dibromobenzaldehyde of Formula 1 having a light yellow color, and a yield of 85% was obtained. Purity was calculated through an analyzer, yielding 99.5% purity.

Example 2

The reaction was carried out in the same manner as in Example 1, except that the reaction time was 5 hours, to obtain 15.79 g of yellow 2-amino-3,5-dibromobenzaldehyde. This was 84.5% yield and 99.4% purity (HPLC).

Example 3

Except that the ketone was used in 41.4g, it was carried out in the same manner as in Example 1, to obtain 14.69g of 2-amino-3,5-dibromobenzaldehyde in a yellow phase. This was found to be 80% yield and 99.3% purity (HPLC).

Example 4

Except for using 115g ammonium hydroxide was carried out in the same manner as in Example 1, to obtain 15.70g of 2-amino-3,5-dibromobenzaldehyde in the yellow phase. This yielded 84% yield, 99.0% purity (HPLC).

Example 5

The same procedure as in Example 1 was repeated except that 0.2 g of the antioxidant Irganox was used to obtain 15.89 g of 2-amino-3,5-dibromobenzaldehyde in a yellow color. This was 85% yield and 99.2% purity (HPLC).

Comparative Example 1

Put 200ml of ethylene glycol and 500ml of water in the reactor and add 34.5g of potassium carbonate 20.17 g of the compound was added and then heated to 125 ° C. At this temperature, 48.4 g of the compound represented by Chemical Formula 3 in powder form was added within 5 minutes. After reacting at 130 ° C. for one hour, the mixture was cooled to room temperature. The reaction was filtered and washed with water to give 39.5 g of a dark yellow compound represented by the following formula (4). As a result of measurement by liquid chromatography (HPLC), the purity was 70%, the yield was 75%, the melting point was 125 ℃.

Comparative Example 2

54 ml of tetrahydrofuran and 9.22 g of an anilide compound represented by the following Chemical Formula 5 are added to the reactor. 16 ml of lithium aluminum hydride-containing tetrahydrofuran solution (1.0 M) was added and reacted. The reaction solution was then treated with dilute sulfuric acid solution and the solvent was removed. It was then precipitated in water and filtered to give 4.0 g of 2-amino-3,5-dibromobenzaldehyde in blue yellow color. Yield was 60%.

Comparative Example 3

90 g of ethylene glycol, 8 g of methanol, and 10 g of water were added to the reactor, 0.5 g of antioxidant (Irganox) was added, and 0.08 g of sodium hypochloride was added to the reaction. Then 13 g of potassium carbonate and 20 g of the compound of Formula 3 were added and reacted at a reaction temperature of 95 ° C. for 8 hours to obtain 8.5 g of 2-amino-3,5-dibromobenzaldehyde as a yellow phase. This resulted in 75% yield, 95% purity (HPLC).

Comparative Example 4

Except that the reaction temperature was 90 ℃ was carried out in the same manner as in Example 1, to give a yellow 2-amino-3,5-dibromobenzaldehyde. This was 75% yield, 94% purity (HPLC).

As can be seen from the above examples and comparative examples, 2-amino-3,5-dibromobenzaldehyde prepared by the method according to the present invention is economical due to cost reduction due to a shorter manufacturing process than the prior art. In addition, it minimizes the formation of relative side reactions, obtains high purity and yield, and is excellent in color.

Claims (7)

Under a mixed solvent consisting of a polar solvent, an organic-inorganic alkali, an antioxidant, and water, 2-amino-3,5-dibromobenzoic hydrazide of the following formula (2) is used as a starting material, and 0.1 to 2 weight ratio based on the starting material. Ketone compound, 0.05 to 0.5 weight ratio of oxidizing agent and 0.5 to 2.0 weight ratio of water were mixed and reacted at 0 to 80 ° C. for 1 to 10 hours, followed by filtration, washing and solvent recovery to obtain high yield and high purity. A method for producing 2-amino-3,5-dibromobenzaldehyde of 1. Formula 1 Formula 2 The method of claim 1, wherein the mixed solvent is used in 2 to 11 weight ratio based on the starting material. The method according to claim 1, wherein the component ratio of the polar solvent, the organic-inorganic alkali, the antioxidant, and the water constituting the mixed solvent is 1.0 to 4.0: 0.5 to 1.5: 0.001 to 0.05: 1.0 to 5.0 by weight. The polar solvent according to any one of claims 1 to 3, wherein the polar solvent is selected from the group consisting of alcohols and dioxane, and the organic-inorganic alkali is potassium carbonate, sodium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide and And ammonium hydroxide. The method according to claim 1, wherein the antioxidant is selected from the group consisting of Irgaox and Ultranox from Ciba-Geigy Company. The method of claim 1 wherein the oxidizing agent is selected from the group consisting of organic and inorganic peroxides including hydrogen peroxide, sodium hypochloride and organic peroxides. The method of claim 1, wherein the ketone compound is selected from the group consisting of methyl ethyl ketone, ketone and acetone.