阅读说明：本技术 一种工业化生产醋氯芬酸的方法 (Industrial production method of aceclofenac ) 是由 张鲁峰 向文强 于 2020-07-17 设计创作，主要内容包括：本发明涉及一种工业化生产醋氯芬酸的方法。该方法包括：将有机酸、除水剂和路易斯酸混合,充分搅拌后,加入醋氯芬酸叔丁酯酸解反应。本发明反应条件温和,反应速率快,没有出现高温高能耗,操作简便,环保经济,无重大污染物参与或生成,大部分溶剂能进行回收利用,减少废弃溶剂的排放,从而降低成本,保护环境。(The invention relates to a method for industrially producing aceclofenac. The method comprises the following steps: mixing organic acid, water remover and Lewis acid, stirring fully, and adding aceclofenac tert-butyl ester for acidolysis reaction. The method has the advantages of mild reaction conditions, high reaction rate, no high temperature and high energy consumption, simple and convenient operation, environmental protection and economy, no major pollutants are involved or generated, most of the solvent can be recycled, and the emission of the waste solvent is reduced, so that the cost is reduced and the environment is protected.)

1. A method for industrially producing aceclofenac, comprising:

mixing organic acid, a water removing agent and Lewis acid, fully stirring, adding aceclofenac tert-butyl ester for acidolysis reaction to obtain aceclofenac, wherein the molar ratio of the aceclofenac tert-butyl ester to the Lewis acid to the organic acid to the water removing agent is 1:0.15-0.35:10-11: 0.05-0.5.

2. The method according to claim 1, wherein said preparation of tert-butyl aceclofenac comprises: diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and a solvent in a molar ratio of 1:1-1.5:0.05-0.08:9-10 are subjected to heat preservation reaction at 60-70 ℃ for 4-5h, and the tert-butyl aceclofenac is obtained through cooling crystallization and filtration.

3. The method of claim 2, wherein the solvent is ethanol; the iodide is potassium iodide.

4. The method of claim 1, wherein the water scavenger is acetic anhydride; the organic acid is acetic acid; the Lewis acid is aluminum trichloride.

5. The method of claim 1, wherein the stirring time is from 5 minutes to 120 minutes.

6. The method as claimed in claim 1, wherein the acidolysis reaction is carried out at a temperature of 60-65 ℃ for 2.5-3 hours.

7. The method as claimed in claim 1, wherein the acidolysis is completed, water is added to quench the reaction, the reaction is cooled and crystallized, the crude aceclofenac is obtained by filtration, then the crude aceclofenac is dissolved in ethyl acetate and heated for reflux, the temperature is reduced for recrystallization, and the refined aceclofenac product is obtained by filtration, wherein the molar ratio of the crude aceclofenac to the ethyl acetate is 1: 5-6.

8. The method according to claim 7, wherein the weak acid solvent used for crystallization is acetic acid, and the molar ratio of the weak acid solvent to diclofenac tert-butyl ester is 9-11: 1; the molar ratio of water for quenching reaction to diclofenac tert-butyl ester is 13-20: 1.

Technical Field

The invention belongs to the field of aceclofenac preparation, and particularly relates to a method for industrially producing aceclofenac.

Background

Many documents on the synthesis of aceclofenac are reported, and patent CN101531607A discloses that the product is obtained by acidolysis of aceclofenac tert-butyl ester under the combined action of phenol and acid, but the method has the disadvantages of large phenol dosage, strong toxicity and large environmental protection pressure. Patent CN103086907A discloses acidolysis of tert-butyl aceclofenac by using a mixed solution of hydrogen halide and low-molecular organic acid, but the method has strong corrosion to equipment, complicated operation, slow reaction rate and low conversion rate.

Disclosure of Invention

The technical problem to be solved by the invention is to provide a method for industrially producing aceclofenac, so as to overcome the defects of large raw material consumption, strong toxicity, harsh reaction conditions, environmental pollution, complex operation, poor product quality and the like of the industrial preparation of aceclofenac in the prior art.

The invention relates to a method for industrially producing aceclofenac, which comprises the following steps:

mixing organic acid, a water removing agent and Lewis acid, fully stirring, adding aceclofenac tert-butyl ester for acidolysis reaction to obtain aceclofenac, wherein the molar ratio of the aceclofenac tert-butyl ester to the Lewis acid to the organic acid to the water removing agent is 1:0.15-0.35:10-11: 0.05-0.5.

The preparation method of the aceclofenac tert-butyl ester comprises the following steps: diclofenac sodium, tert-butyl bromoacetate, catalyst iodide and a solvent in a molar ratio of 1:1-1.5:0.05-0.08:9-10 are subjected to heat preservation reaction at 60-70 ℃ for 4-5h, and the tert-butyl aceclofenac is obtained through cooling crystallization and filtration.

The solvent is ethanol; the iodide is potassium iodide.

The water remover is acetic anhydride; the organic acid is acetic acid; the Lewis acid is aluminum trichloride.

The stirring time is 5 minutes to 120 minutes.

The temperature of the acidolysis reaction is 60-65 ℃, and the time of the acidolysis reaction is 2.5-3 h.

Adding water to the mixture after complete acidolysis for quenching reaction, cooling for crystallization, filtering to obtain crude aceclofenac, dissolving the crude aceclofenac in ethyl acetate, heating for reflux, cooling for recrystallization, and filtering to obtain a refined aceclofenac product, wherein the molar ratio of the crude aceclofenac to the ethyl acetate is 1: 5-6.

The weak acid solvent adopted for crystallization is acetic acid or propionic acid, and the molar ratio of the weak acid solvent to diclofenac tert-butyl ester is 9-11: 1; the molar ratio of water for quenching reaction to diclofenac tert-butyl ester is 13-20: 1.

The formula for preparing aceclofenac according to the present invention is as follows:

the method uses ethanol, acetic acid and ethyl acetate as solvents, is more environment-friendly and economical, is easy to recover, saves cost, is simple and convenient to operate, and is more suitable for technological production. The method uses an environment-friendly solvent to carry out industrial production of aceclofenac, and the iodide is added to activate halogen bromine in the bromoacetic acid tert-butyl ester, so that the reaction can be carried out under a mild condition, and the reaction time is greatly shortened; removing tert-butyl from aceclofenac tert-butyl ester by acidification, controlling reaction time and temperature, tracking reaction progress, adding water after reaction to quench and remove salt. The total reaction condition is mild, high temperature and high energy consumption are avoided, the method is environment-friendly and economical, and the method has good industrial prospect.

Compared with the literature (journal of Chinese medicine industry, 2008,39 (6): 408-409), the invention adds acetic anhydride, which has the function of reacting with water in a reaction system, reduces the generation of hydrolysis impurities and has better product quality. The process of the invention comprises the steps of adding acetic acid, acetic anhydride and aluminum chloride, fully stirring, adding aceclofenac tert-butyl ester for reaction, adding the aceclofenac tert-butyl ester, glacial acetic acid and anhydrous aluminum trichloride into a reaction bottle for stirring reaction in the literature (J.J. China pharmaceutical industry, 2008,39 (6): 408:. 409.), and carrying out the reaction. The addition of the water removing agent and the addition sequence of the raw materials can influence the hydrolysis impurities in the aceclofenac product. Repeating the literature process to obtain a product containing about 2.6% of hydrolyzed impurities, i.e., diclofenac acid (the acid-formed product of diclofenac sodium as raw material); the product obtained by the process has hydrolysis impurities less than 0.1 percent, and the product quality far exceeds that of the literature process.

The invention defines the charging sequence of acidolysis, firstly mixing organic acid, water removing agent and Lewis acid, stirring for 5-120 minutes, then adding aceclofenac tert-butyl ester for acidolysis reaction, and the hydrolysis impurity of the obtained product is less than 0.1%. If organic acid, water removing agent and aceclofenac tert-butyl ester are mixed firstly and Lewis acid is added for acidolysis, the hydrolysis impurity of the obtained product can be up to 0.5 percent.

Advantageous effects

The method adopts dehalogenation esterification and acetic acid and Lewis acid tert-butyl removal reaction, has mild reaction conditions, high reaction rate, good product quality, high yield, low energy consumption, environmental protection, economy and simple and convenient operation, can recycle most of the solvents, and reduces the discharge of waste solvents, thereby reducing the cost and protecting the environment.

Detailed Description

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Further, it should be understood that various changes or modifications of the present invention may be made by those skilled in the art after reading the teaching of the present invention, and such equivalents may fall within the scope of the present invention as defined in the appended claims.