CN116854603A - A kind of preparation method of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid - Google Patents

Abstract

A method for preparing a pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid, which relates to a method for preparing a pharmaceutical intermediate compound. The invention uses polyamine ligands to greatly increase the dissolution of the cuprous halide catalyst. properties and improved catalyst activity, which can reduce the amount of ammonia and hydrochloric acid used for subsequent neutralization by at least 50% each, and reduce the amount of ammonium chloride generated by at least 50%, without adding EDTA complex copper salt. Compared with the traditional method of using a large amount of ammonia, cuprous oxide, and adding ethyl acetate, there is no significant difference in the yield and content of 2-amino-4-bromo-5-chlorobenzoic acid. The 2-amino-4- obtained by the present invention The content and yield of the bromo-5-chlorobenzoic acid product exceed 95%, the amount of waste salt generated is small, the operation time is shorter, and the heat released by neutralization is less, making it suitable for industrial production.

Description

A kind of preparation method of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid

Technical field

The invention belongs to a method for preparing pharmaceutical intermediate compounds, and in particular relates to a method for preparing 2-amino-4-bromo-5-chlorobenzene through amination reaction of 2,4-dibromo-5-chlorobenzoic acid using polyamine as a ligand. Formic acid method.

Background technique

2-Amino-4-bromo-5-chlorobenzoic acid is an anthranilic acid compound substituted by halogen. It is one of the important intermediates used in the preparation of the broad-spectrum anti-coccidial drug oftenanone. This compound is usually made by adding 2,4-dibromo-5-chlorobenzoic acid to a mixture of ammonia and ethyl acetate, adding catalyst cuprous oxide, so that the bromine ortho-position of the carboxyl group is replaced by an amino group, and adding hydrochloric acid to adjust the pH. is 3-4, and the organic phase is concentrated to obtain 2-amino-4-bromo-5-chlorobenzoic acid. Due to the large amount of ammonia water, a large amount of hydrochloric acid is needed for neutralization. This process releases a lot of heat, which puts higher requirements on the heat exchange capacity of the production equipment. It also takes a long time to complete the neutralization process; in addition, the water after neutralization A large amount of ammonium chloride will be formed in the phase, and the treatment of such waste salt requires additional environmental protection costs, which is not conducive to controlling manufacturing costs. This route was first announced by Schmand in 1993 (DE4200512). Mao Zhongxing and Lu Yu published similar methods (CN1651428, CN102351790) in 2005 and 2012 respectively. The amount of ammonia used in the above three schemes is close to 3 times the weight of the raw material, and Post-processing must use EDTA to complex the copper salt to prevent copper salt from remaining in the organic phase and entering the product.

Reducing the amount of ammonia can shorten the manufacturing cycle, reduce waste salt emissions, and reduce equipment heat exchange pressure. Therefore, developing a method to synthesize 2-amino-4-bromo-5-chlorobenzoic acid at a lower ammonia dosage is a problem that needs to be solved.

Contents of the invention

The object of the present invention is to provide a preparation method for the pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid. The method uses 2,4-dibromo-5-chlorobenzoic acid as raw material and ammonia water as the amination agent. Reagent, but there is no need to add ethyl acetate during the reaction. The catalyst uses cuprous halide, and polyamine ligands are added to increase the solubility of the copper salt. Ethyl acetate is added for post-processing extraction, and hydrochloric acid is used to adjust the pH to acidity. Compared with existing methods, this method can reduce the amount of ammonia used by at least 50%, and the amount of hydrochloric acid used for neutralization is also reduced by 50%. There is no need to add EDTA, which reduces manufacturing costs, causes less environmental pollution, and is more suitable for industrial production.

A preparation method of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid. The preparation method is as follows: use 2,4-dibromo-5-chlorobenzoic acid as raw material, add tap water and 25% ammonia water and cool down to below 20°C, add copper halide and polyamine ligands, stir at 15-25°C until the solid is completely dissolved, add ethyl acetate and 31% hydrochloric acid to pH=2-3, collect the organic phase, add tap water and distill under normal pressure. , a large amount of solid is precipitated, filtered and dried to obtain the product 2-amino-4-bromo-5-chlorobenzoic acid.

Preferably, the mass ratio of 2,4-dibromo-5-chlorobenzoic acid to 25% ammonia water and water is 1.0:1.0:2.0.

Preferably, the cuprous halide is cuprous chloride.

Preferably, the polyamine ligand is N,N,N′,N″,N″-pentamethyldiethylenetriamine.

Preferably, the amount of copper halide is 2% of 2,4-dibromo-5-chlorobenzoic acid, and the amount of polyamine ligand is 4% of 2,4-dibromo-5-chlorobenzoic acid.

The beneficial effects of the present invention are:

The present invention uses polyamine ligands to greatly increase the solubility of the cuprous halide catalyst and improve the catalyst activity. It can reduce the amount of ammonia water and the use of hydrochloric acid for subsequent neutralization by at least 50% each, and reduce the amount of ammonium chloride generated by at least 50%. No need to add EDTA complex copper salt. Compared with the traditional method of using a large amount of ammonia, cuprous oxide, and adding ethyl acetate, there is no significant difference in the yield and content of 2-amino-4-bromo-5-chlorobenzoic acid, which is suitable for industrial production.

Description of the drawings

Figure 1 is the proton nuclear magnetic spectrum ( ¹ H NMR) of 2-amino-4-bromo-5-chlorobenzoic acid;

Figure 2 shows the carbon nuclear magnetic spectrum ( ¹³ C NMR) of 2-amino-4-bromo-5-chlorobenzoic acid.

Detailed ways

The present invention will be further described below in conjunction with the examples. The examples will help to better understand the present invention, but the present invention is not limited to the following examples.

The reaction equation of the present invention is as follows:

Example 1

Conventional synthesis method of 2-amino-4-bromo-5-chlorobenzoic acid:

To a 2000mL three-necked round-bottomed flask equipped with mechanical stirring, nitrogen bubbling, and a condenser tube, add 120.0g of dry 2,4-dibromo-5-chlorobenzoic acid, and add 400.0g of 25% mass fraction ammonia water and 400.0g of ammonia water at one time. Ethyl acetate 200.0g. After starting the mechanical stirring, add nitrogen for at least 15 minutes and cool down to 15°C. Add a total of 3.0g of cuprous oxide in 4 batches. The time interval between each addition should not be shorter than 30 minutes, and the control temperature should not be higher than 35 ℃. After 2 hours, 280.0g of ethyl acetate and 9.0g of EDTA disodium salt were added in one go, and then 450.0g of industrial hydrochloric acid with a mass fraction of 31% was slowly added through a dropping funnel. After neutralization is completed, discard the lower aqueous phase by static liquid separation, wash the organic phase with saturated brine, retain the organic phase and add 500.0g of tap water, distill under normal pressure until the fraction is free of ethyl acetate, cool to room temperature, filter, beat with tap water, and dry. Afterwards, a light yellow solid was obtained, which was 2-amino-4-bromo-5-chlorobenzoic acid, with a dry weight of 90.3g, a yield of 94.5%, and a content of 96.3% (HPLC area method). ¹ HNMR (400MHz, DMSO-d ₆ ) δ7.78–7.73 (s, 1H), 7.21–7.16 (s, 1H). ¹³ C NMR (101MHz, DMSO-d ₆ ) δ 168.37, 151.20, 132.17, 127.37, 121.07 ,117.82,110.87. The spectra are shown in Figure 1 and Figure 2.

Example 2

The preferred synthesis method of 2-amino-4-bromo-5-chlorobenzoic acid in the present invention:

To a 2000mL three-necked round-bottomed flask equipped with mechanical stirring, nitrogen bubbling, and a condenser tube, add 120.0g of dry 2,4-dibromo-5-chlorobenzoic acid, N,N,N′,N″,N″ - 2.65g of pentamethyldiethylenetriamine, 120.0g of 25% mass fraction of ammonia water and 240.0g of tap water were added at one time. After starting the mechanical stirring, introduce nitrogen for at least 15 minutes and control the temperature to 15°C. Add 0.76g of copper chloride at one time and control the temperature not to be higher than 35°C. After 2 hours, 500.0g of ethyl acetate was added in one go, and then 140.0g of industrial hydrochloric acid with a mass fraction of 31% was slowly added through a dropping funnel. After neutralization is completed, discard the lower aqueous phase by static liquid separation, wash the organic phase with saturated brine, retain the organic phase and add 500.0g of tap water, distill under normal pressure until the fraction is free of ethyl acetate, cool to room temperature, filter, beat with tap water, and dry. Afterwards, a light yellow solid was obtained, which was 2-amino-4-bromo-5-chlorobenzoic acid, with a dry weight of 91.2g, a yield of 95.4%, and a content of 95.7% (HPLC area method).

Comparing with Example 1, it can be found that there is no significant difference in the yield and content. The dosage of ammonia water dropped by about 70%, and the dosage of hydrochloric acid dropped by about 69%. The corresponding amount of ammonium chloride generated should be reduced by at least 70%. During the neutralization process, dripping The time required for hydrochloric acid is shortened by about 50%.

Example 3

Compared with Example 2, the ratio of 25% mass fraction of ammonia water and tap water was adjusted.

Using the same reaction device, operation and feeding ratio, only the amount of 25% mass fraction ammonia water was adjusted to 240.0g, the amount of tap water was adjusted to 120.0g, and the amount of hydrochloric acid was adjusted to 270.0g. The dry weight of 2-amino-4-bromo-5-chlorobenzoic acid obtained was 90.7g, the yield was 94.9%, and the content was 96.1% (HPLC area method).

Example 4

Compared with Example 2, an equal amount of copper bromide was used as the catalyst.

The same reaction device, operation and feed ratio were used, except that the catalyst was replaced with 1.1g of cuprous bromide. The dry weight of 2-amino-4-bromo-5-chlorobenzoic acid obtained was 90.9g, the yield was 95.1%, and the content was 96.3% (HPLC area method).

Claims (5)

1. A preparation method of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid, which is characterized in that: the method uses 2,4-dibromo-5-chlorobenzoic acid as raw material, adds tap water and 25% ammonia water and cool it to below 20°C, add copper halide and polyamine ligand, stir at 15-25°C until the solid is completely dissolved, add ethyl acetate and 31% hydrochloric acid to pH=2-3, collect the organic phase, and add After tap water is distilled under normal pressure, the solid is precipitated, filtered and dried to obtain the product 2-amino-4-bromo-5-chlorobenzoic acid. 2. The preparation method of a kind of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: 2,4-dibromo-5-chlorobenzoic acid and 25% The mass ratio of ammonia and water is 1.0:(1.0-2.0):(1.0-2.0). 3. The preparation method of a kind of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: the cuprous halide is cuprous chloride, cuprous bromide , one or more types of copper iodide. 4. The preparation method of a kind of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: the polyamine ligand is N, N, N′, N One or more of ",N"-pentamethyldiethylenetriamine and 1,1,4,7,10,10-hexamethyltriethylenetetramine. 5. The preparation method of a kind of pharmaceutical intermediate compound 2-amino-4-bromo-5-chlorobenzoic acid according to claim 1, characterized in that: the copper halide dosage is 2,4-dibromo-5-chloro The dosage of benzoic acid is 2%-5%, and the polyamine ligand dosage is 4%-10% of 2,4-dibromo-5-chlorobenzoic acid.