阅读说明：本技术 制备常山酮中间体2-氨基-4-溴-5-氯苯甲酸方法 (Method for preparing halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid ) 是由 王金娟 蒋健 陆小丽 于 2019-10-16 设计创作，主要内容包括：一种抗球虫药常山酮中间体的制备方法,涉及一种具体的化合物2-氨基-4-溴-5-氯苯甲酸的制备方法。该方法依次包括如下步骤：采用对溴苯甲酸作为原料,通过氯化、硝化和选择性还原反应得到产品。本发明提出了一条新的合成路线和反应条件,所用原料市场供应充足且来源广泛,并且各步反应条件温和、工艺简洁,符合绿色生产的要求,有效的降低了生产成本。(A preparation method of an anticoccidial drug halofuginone intermediate, which relates to a preparation method of a specific compound 2-amino-4-bromo-5-chlorobenzoic acid. The method sequentially comprises the following steps: the p-bromobenzoic acid is adopted as a raw material, and a product is obtained through chlorination, nitration and selective reduction reactions. The invention provides a new synthesis route and reaction conditions, the used raw materials are sufficient in market supply and wide in source, the reaction conditions in each step are mild, the process is simple, the requirements of green production are met, and the production cost is effectively reduced.)

1. A method for preparing a halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid is characterized by comprising the following steps: the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid represented by formula (I) is obtained as follows:

(Ⅱ) (Ⅲ) (Ⅰ)

preparation of 3-chloro-4-bromobenzoic acid (II)

Adding 1 time of p-bromobenzoic acid, 0.73-0.74 time of anhydrous aluminum trichloride (weight ratio) and 5-10 times of 1,1, 2-trichloroethane (weight ratio) into a reactor with a stirring and heating device;

cooling to 0 ℃ after uniform stirring, introducing 0.35-0.43 time (weight ratio) of chlorine, heating to 80 ℃, continuing to stir for 8-12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, carrying out reduced pressure distillation to remove most of solvent, adding obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting precipitated solid which is a crude product of 3-chloro-4-bromobenzoic acid (II), detecting the content by HPLC (high performance liquid chromatography) to be more than 95%, and directly using the crude product in the next reaction without further purification;

b.preparation of 2-nitro-4-bromo-5-chlorobenzoic acid (III)

Adding 1 time of 3-chloro-4-bromobenzoic acid (II) and 5-6 times of concentrated sulfuric acid (weight ratio) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding concentrated sulfuric acid solution of HNO3 with the mass fraction of 10% in an amount which is 3.23-3.52 times (weight ratio), keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring and reacting for 6-10 hours, after the reaction is finished, slowly pouring the mixture into a large amount of ice water, controlling the temperature within 30 ℃, stirring for 30 minutes, filtering and collecting separated solid which is a crude product of the 2-nitro-4-bromo-5-chlorobenzoic acid (III), detecting the content by HPLC to be more than 95%, and directly using the crude product in the next reaction without further purification;

preparation of C.2-amino-4-bromo-5-chlorobenzoic acid (I)

Adding 1 time of 2-nitro-4-bromo-5-chlorobenzoic acid (III), 0.02-0.05 time of ferric chloride, 0.35-0.55 time of hydrazine hydrate solution with the mass fraction of 50% and 3-6 times of deionized water into a reactor, stirring and reacting for 6-12 hours at room temperature, adjusting the pH to 12 by using 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of filtrate to 7 by using 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting precipitated solid, wherein the precipitated solid is a crude product of 2-amino-4-bromo-5-chlorobenzoic acid (I), the content of the crude product is more than 95% by HPLC (high performance liquid chromatography), and the precipitated solid can be directly used for the subsequent reaction step of preparing halofuginone without further purification;

the crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).

Technical Field

The invention relates to a preparation method of an anticoccidial drug halofuginone intermediate, and particularly relates to a method for preparing a compound 2-amino-4-bromo-5-chlorobenzoic acid.

Background

Dichrone is a derivative of dichroine extracted from Chinese traditional medicine dichroa febrifuga. The hydrobromide salt of halofuginone was developed by Roussel-uefiaf, france under the trade name sudan, and was a halofuginone hydrobromide 0.6% premix. The composition is mainly used for preventing and treating coccidiosis and malaria of domesticated animals such as livestock and poultry (turkey, sheep, goat, cattle and rabbit).

The asymmetric synthesis of halofuginone compounds has begun since the 90 s of the last century and various methods have been used to date to produce this type of compound. Most of these methods, however, require more severe reaction conditions such as: the commercialization of halofuginone is greatly limited by the preparation at a low temperature of-78 ℃ and rare earth metal catalysts, or parts of the method have expensive raw materials, long steps and low overall yield, wherein 2-amino-4-bromo-5-chlorobenzoic acid is used as a key intermediate of the whole route, and the process and the cost directly restrict the whole route of halofuginone.

The patent summarizes a brand-new synthesis route through a series of experiments, and the product is obtained by chlorination, nitration and selective reduction reaction by taking p-bromobenzoic acid as a raw material. The method greatly improves the selectivity of the reaction, obviously improves the yield and the product quality, and effectively controls the cost of the product.

Disclosure of Invention

The invention aims to provide a preparation method of halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid, which has the advantages of simple process, convenient operation and no environmental pollution.

In order to achieve the purpose, a series of experiments are carried out, and a brand new synthetic route is provided.

The technical scheme for realizing the invention is as follows:

a new method for preparing the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid is characterized in that: the halofuginone intermediate 2-amino-4-bromo-5-chlorobenzoic acid represented by formula (I) is obtained as follows:

(Ⅱ) (Ⅲ) (Ⅰ)

preparation of 3-chloro-4-bromobenzoic acid (II)

Adding 1 time of p-bromobenzoic acid, 0.73-0.74 time of anhydrous aluminum trichloride (weight ratio) and 5-10 times of 1,1, 2-trichloroethane (weight ratio) into a reactor with a stirring and heating device. Cooling to 0 ℃ after uniform stirring, introducing 0.35-0.43 time (weight ratio) of chlorine, heating to 80 ℃, continuing to stir for 8-12 hours, cooling to room temperature after the reaction is finished, filtering to remove insoluble substances, carrying out reduced pressure distillation to remove most of solvent, adding the obtained residue into petroleum ether, stirring for 30 minutes, filtering and collecting precipitated solid which is a crude product of 3-chloro-4-bromobenzoic acid (II), detecting the content by HPLC (high performance liquid chromatography) to be more than 95%, and directly using the crude product in the next reaction without further purification.

B.preparation of 2-nitro-4-bromo-5-chlorobenzoic acid (III)

Adding 1 time of 3-chloro-4-bromobenzoic acid (II) and 5-6 times of concentrated sulfuric acid (weight ratio) into a reactor, uniformly stirring, cooling to 0-5 ℃, then dropwise adding concentrated sulfuric acid solution of HNO3 with the mass fraction of 10% in an amount which is 3.23-3.52 times (weight ratio), keeping the temperature of the mixture at 0-5 ℃ in the dropwise adding process, continuously stirring for 30 minutes after the dropwise adding is finished, removing the ice bath, naturally heating to room temperature, then heating to 50 ℃, continuously stirring and reacting for 6-10 hours, after the reaction is finished, slowly pouring the mixture into a large amount of ice water, controlling the temperature within 30 ℃, stirring for 30 minutes, filtering and collecting separated solid which is a crude product of the 2-nitro-4-bromo-5-chlorobenzoic acid (III), detecting the content by HPLC to be more than 95%, and directly using the crude product in the next reaction without further purification.

Preparation of C.2-amino-4-bromo-5-chlorobenzoic acid (I)

Adding 1 time of 2-nitro-4-bromo-5-chlorobenzoic acid (III), 0.02-0.05 time of ferric chloride, 0.35-0.55 time of hydrazine hydrate solution with the mass fraction of 50% and 3-6 times of deionized water into a reactor, stirring and reacting for 6-12 hours at room temperature, adjusting the pH to 12 by using 5% sodium hydroxide solution after the reaction is finished, filtering to remove insoluble substances, adjusting the pH of filtrate to 7 by using 10% glacial acetic acid, stirring for 30 minutes, filtering and collecting precipitated solid which is 2-amino-4-bromo-5-chlorobenzoic acid (I) crude product, detecting the content to be more than 95% by HPLC, and directly using the crude product in the subsequent reaction step for preparing halofuginone without further purification. The crude product is recrystallized by a methanol-water mixed solution to obtain a refined product of the 2-amino-4-bromo-5-chlorobenzoic acid (I).

The invention has the advantages that:

1. the invention adopts a brand new synthesis route, improves the selectivity of each step of reaction, and effectively improves the utilization rate and the total yield of raw materials.

2. The raw materials adopted by the method are all sold in the market, the reactions in each step are all conventional operations, the reaction conditions are mild, the control is easy, the cost is reduced, and the product competitiveness is improved.

Detailed Description

How this invention can be carried out is further illustrated by the following specific examples: