CN-121990935-A - Preparation method of 2-amino-4-fluorobenzoic acid

Abstract

The invention discloses a preparation method of 2-amino-4-fluorobenzoic acid. The micro-reactor is adopted as a reactor, 3-fluoroaniline is adopted as a raw material, and the 2-amino-4-fluorobenzoic acid is obtained through condensation reaction, cyclization reaction and oxidation ring-opening reaction. The 2-amino-4-fluorobenzoic acid obtained by the process is a white gray solid product, the purity is more than 98%, and the total yield of three steps is 73.6%. The preparation method of the 2-amino-4-fluorobenzoic acid is specifically limited, and on the premise of obtaining high yield, the whole steps are safe and simple to operate, the reaction time is short, and the preparation is easy.

Inventors

• BAO XIAOJUN
• CHEN AO
• CHEN XINGQUAN
• WEN BIN
• LI SHIYUN
• HUANG JUN

Assignees

• 福州大学

Dates

Publication Date

20260508

Application Date

20260331

Claims (5)

1. 1. A preparation method of 2-amino-4-fluorobenzoic acid is characterized in that a microreactor is adopted as a reactor, 3-fluoroaniline is used as a raw material, and the 2-amino-4-fluorobenzoic acid is obtained through condensation reaction, cyclization reaction and oxidation ring-opening reaction.
2. 2. The method for producing 2-amino-4-fluorobenzoic acid according to claim 1, wherein the microreactor is formed by connecting reaction modules having microfluidic circuits in series, the number of the reaction modules in a single microreactor is 10, and the total liquid holding capacity of a single microreactor is 110 mL.
3. 3. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, wherein the process for preparing N- (3-fluorophenyl) -2- (hydroxyimino) acetamides by condensation reaction comprises the steps of dissolving chloral hydrate, hydroxylamine hydrochloride and anhydrous sodium sulfate in water at a molar ratio of 1.00-1.25:3.35-3.75:5.20-5.60 to prepare a chloral hydrate-hydroxylamine hydrochloride mixed solution and anhydrous sodium sulfate solution, mixing the two solutions by utilizing a microreactor, controlling the temperature of the first microreactor at 30-35 ℃ and the flow ratio of the two solutions at 1:1, introducing the mixed solution into a second microreactor after the reaction is finished, and simultaneously introducing the mixed solution of 3-fluoroaniline and hydrochloric acid into the microreactor, wherein the molar ratio of 3-fluoroaniline and HCl is in the range of 1.00:1.00-1.25, the temperature setting range of the second microreactor is 65-85 ℃, and the mixed solution of chloral hydrate, hydroxylamine and anhydrous sodium sulfate and hydrochloric acid at the flow ratio of 3-fluoroaniline and hydrochloric acid is in the range of 1.00:1.25.
4. 4. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, wherein the process for preparing 6-fluoroisatin by cyclization reaction comprises the steps of mixing N- (3-fluorophenyl) -2- (hydroxyimino) p-acetamide obtained by preparation with concentrated sulfuric acid according to a mass ratio of 1:5, and heating to 90 ℃ for reaction of 0.5 h.
5. 5. The preparation method of 2-amino-4-fluorobenzoic acid according to claim 1, wherein the oxidative ring-opening reaction process comprises the steps of adding the prepared 6-fluoroindigo red into 10 wt% sodium hydroxide solution in batches, introducing the mixed solution into a microreactor under a stirring state, introducing 30 wt% hydrogen peroxide into the microreactor to be mixed with the 6-fluoroindigo red mixed solution when the temperature is reduced to 2 ℃, wherein the molar ratio of the 6-fluoroindigo red to the H 2 O 2 to the sodium hydroxide is 1.0:5.2-5.8:4.0-5.0, and controlling the temperature to be 0 ℃ in the reaction process, wherein the flow ratio of the 6-fluoroindigo red mixed solution to 30 wt% hydrogen peroxide is 4.3:1.0.

Description

Preparation method of 2-amino-4-fluorobenzoic acid Technical Field The invention belongs to the field of chemical synthesis, and particularly relates to a preparation method of 2-amino-4-fluorobenzoic acid. Background 2-Amino-4-fluorobenzoic acid is an important organic compound, and the demand for synthesizing afatinib has been continuously increasing in recent years. This is mainly due to the remarkable therapeutic effect of afatinib in the treatment of malignant tumors such as non-small cell lung cancer. With the emphasis on targeted therapy and personalized medicine, afatinib has received increasing attention as an effective EGFR inhibitor. 2-Amino-4-fluorobenzoic acid has unique properties, so that the 2-amino-4-fluorobenzoic acid has important application value in a plurality of fields. The combination of amino and fluorine atoms in the molecule obviously enhances the biological activity and improves the antibacterial and antitumor effects of the medicine. In addition, the compound shows good reactivity in chemical reactions, can serve as an intermediate of various chemical reactions, and promotes the synthesis of new compounds. The introduction of fluorine atoms also improves the solubility and stability of the fluorine atoms, so that the fluorine atoms keep good performance under different environmental conditions, and are suitable for development of medicines and pesticides. In agricultural chemistry, 2-amino-4-fluorobenzoic acid can be used as an intermediate for pesticide synthesis, so that the disease resistance of crops can be enhanced, and the yield and quality of the crops can be improved. Therefore, the unique property of the 2-amino-4-fluorobenzoic acid not only promotes the development of medicines and agricultural chemicals, but also provides an important basis for the development of new medicines and pesticides. At present, the polish patent PL 187784B 1 discloses a preparation method of 2-amino-4-fluorobenzoic acid, which takes 6-fluoroindigo red as a starting material for synthesizing 2-amino-4-fluorobenzoic acid, dissolves 6-fluoroindigo red in sodium hydroxide solution, drops hydrogen peroxide, reacts at a proper temperature, acidizes the mixture with hydrochloric acid, and finally obtains pure 2-amino-4-fluorobenzoic acid through precipitation and recrystallization. However, during the synthesis of 2-amino-4-fluorobenzoic acid, H 2O2 was added dropwise with a large amount of heat release. The traditional kettle type reaction has the problem of inaccurate reaction control relative to a micro-reactor, and is difficult to realize accurate adjustment of temperature, pressure and reaction time, so that incomplete reaction or side reaction and even explosion can be caused. Disclosure of Invention The invention aims to provide a process method for preparing 2-amino-4-fluorobenzoic acid, which adopts a microreactor as a reactor, and compared with the traditional kettle type process, the microreactor has excellent heat and mass transfer performance, can control the reaction temperature and residence time more accurately, and reduces the risk of thermal runaway and side reaction, thereby remarkably reducing the risk coefficient, improving the reaction selectivity and the product purity, facilitating the scale-up and realizing the safe and controllable industrial production. In order to achieve the above purpose, the invention adopts the following technical scheme: A preparation method of 2-amino-4-fluorobenzoic acid adopts a microreactor as a reactor, and takes 3-fluoroaniline as a raw material to obtain the 2-amino-4-fluorobenzoic acid through condensation reaction, cyclization reaction and oxidation ring-opening reaction. The specific synthetic route is as follows: Further, the microreactor is formed by connecting reaction modules with a microfluidic circuit in series, the number of the reaction modules in the single microreactor is 10, and the total liquid holdup of the single microreactor is 110 mL. Further, the process for preparing the N- (3-fluorophenyl) -2- (hydroxyimino) acetamides by the condensation reaction comprises the steps of firstly, dissolving chloral hydrate and hydroxylamine hydrochloride in water to prepare a chloral hydrate-hydroxylamine hydrochloride mixed solution, and dissolving anhydrous sodium sulfate in water to prepare an anhydrous sodium sulfate solution, wherein the molar ratio of chloral hydrate to hydroxylamine hydrochloride to anhydrous sodium sulfate is 1.00-1.25:3.35-3.75:5.20-5.60. Then, the two solutions are mixed by utilizing a micro-reactor, the temperature of the first micro-reactor is controlled to be 30-35 ℃, and the flow ratio of the two solutions is 1:1. After the reaction is finished, the mixed solution is led into a second micro-reactor, and meanwhile, the mixed solution of 3-fluoroaniline and hydrochloric acid is also led into the reactor, wherein the mol ratio of 3-fluoroaniline to HCl is 1.00:1.00-1.25. The temperature of the second microreact