Preparation method of 2-amino-4-fluorobenzoic acid

Abstract

The invention discloses a preparation method of 2-amino-4-fluorobenzoic acid. A microreactor is used as a reactor, 3-fluoroaniline is used as a raw material, and 2-amino-4-fluorobenzoic acid is obtained through a condensation reaction, a cyclization reaction and an oxidation ring-opening reaction. The 2-amino-4-fluorobenzoic acid obtained in the process is a white gray solid product, the purity is greater 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 step operation is safe and simple, the reaction time is short, and the preparation is easy.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis, specifically relating to a method for preparing 2-amino-4-fluorobenzoic acid. Background Technology

[0002] 2-Amino-4-fluorobenzoic acid is an important organic compound, and its demand in the synthesis of afatinib has been steadily increasing in recent years. This is mainly attributed to afatinib's significant efficacy in treating malignant tumors such as non-small cell lung cancer. With the growing emphasis on targeted therapy and personalized medicine, afatinib, as an effective EGFR inhibitor, has received increasing attention.

[0003] 2-Amino-4-fluorobenzoic acid possesses unique properties that make it valuable in multiple fields. The combination of amino and fluorine atoms in its molecule significantly enhances its biological activity, improving the antibacterial and antitumor effects of drugs. Furthermore, this compound exhibits good reactivity in chemical reactions, serving as an intermediate in various processes and promoting the synthesis of new compounds. The introduction of the fluorine atom also improves its solubility and stability, allowing it to maintain good performance under different environmental conditions, making it suitable for drug and pesticide development. In agricultural chemistry, as an intermediate in pesticide synthesis, 2-amino-4-fluorobenzoic acid can enhance crop disease resistance and improve crop yield and quality. Therefore, the unique properties of 2-amino-4-fluorobenzoic acid not only drive the development of pharmaceutical and agricultural chemistry but also provide an important foundation for the research and development of new drugs and pesticides.

[0004] Currently, Polish patent PL187784 B1 discloses a method for preparing 2-amino-4-fluorobenzoic acid. This method uses 6-fluoroindigo as the starting material for synthesizing 2-amino-4-fluorobenzoic acid. 6-fluoroindigo is dissolved in sodium hydroxide solution, hydrogen peroxide is added dropwise, and the reaction is carried out at a suitable temperature. The mixture is then acidified with hydrochloric acid, and finally, pure 2-amino-4-fluorobenzoic acid is obtained through precipitation and recrystallization. However, the addition of H2O2 during the synthesis of 2-amino-4-fluorobenzoic acid is highly exothermic. Traditional batch reactors, compared to microreactors, suffer from imprecise reaction control, making it difficult to precisely regulate temperature, pressure, and reaction time. This can lead to incomplete reactions, side reactions, or even explosions. Summary of the Invention

[0005] The purpose of this invention is to provide a process for preparing 2-amino-4-fluorobenzoic acid. The method uses a microreactor as the reactor. Compared with the traditional batch process, the microreactor has excellent heat and mass transfer performance, can more accurately control the reaction temperature and residence time, reduce the risk of thermal runaway and side reactions, thereby significantly reducing the risk factor, improving reaction selectivity and product purity, facilitating large-scale production and achieving safe and controllable industrial production.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing 2-amino-4-fluorobenzoic acid involves using a microreactor as the reactor and 3-fluoroaniline as the raw material, followed by condensation reaction, cyclization reaction, and oxidative ring-opening reaction to obtain 2-amino-4-fluorobenzoic acid.

[0007] The specific synthesis route is as follows:

[0008] Furthermore, the microreactor is composed of reaction modules with microfluidic circuits connected in series, with 10 reaction modules in a single microreactor and a total liquid holding capacity of 110 mL in a single microreactor.

[0009] Furthermore, the process for preparing N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide by the condensation reaction includes: first, 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, hydroxylamine hydrochloride, and anhydrous sodium sulfate is 1.00-1.25:3.35-3.75:5.20-5.60. Then, the two solutions are mixed using a microreactor. The temperature of the first microreactor is controlled at 30-35 °C, and the flow rate ratio of the two solutions is 1:1. After the reaction is complete, the mixture is introduced into a second microreactor, and simultaneously, a mixture of 3-fluoroaniline and hydrochloric acid is also introduced into this reactor, wherein the molar ratio of 3-fluoroaniline to HCl is in the range of 1.00:1.00-1.25. The temperature of the second microreactor was set at 65-85 ℃, and the flow ratio of the mixture of chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate to the mixture of 3-fluoroaniline and hydrochloric acid was 5.8:1.0, with a residence time of 5.5-7.5 min. After the reaction was completed, the mixture was filtered to obtain a flocculent solid, namely N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide.

[0010] Furthermore, the process of preparing 6-fluoroindigo by the cyclization reaction includes: adding 98wt% concentrated sulfuric acid to a reactor, adding N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide in batches while stirring, controlling the temperature between 80-90 °C, and the mass ratio of sulfuric acid to N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide is 5:1; maintaining the temperature for 30 min, stopping the reaction, cooling to room temperature, pouring into ice water, and precipitating solid as 6-fluoroindigo.

[0011] Furthermore, the process for preparing 2-amino-4-fluorobenzoic acid via the oxidative ring-opening reaction includes: adding 10 wt% sodium hydroxide solution to a reactor, and adding 6-fluoroindigo in batches while stirring to ensure complete dissolution. The mixture is then introduced into a microreactor, and the temperature is lowered to 2 °C using a temperature control system. Subsequently, 30 wt% hydrogen peroxide solution is introduced and mixed with the 6-fluoroindigo mixture, maintaining the temperature at 0 °C. The molar ratio of 6-fluoroindigo, H₂O₂, and sodium hydroxide is 1.0:5.2-5.8:4.0-5.0; the flow rate ratio of the 6-fluoroindigo mixture to 30 wt% hydrogen peroxide is 4.3:1.0, and the residence time is 10-18 min. After the reaction is complete, the entire reaction solution is discharged. Acetic acid is added to adjust the pH to 4-5, and the mixture is filtered and washed with water to obtain solid 2-amino-4-fluorobenzoic acid.

[0012] As can be seen from the above description of the present invention, compared with the prior art, the beneficial effects of the present invention are: the present invention specifically defines a method for preparing 2-amino-4-fluorobenzoic acid, which, while achieving a high yield, has simple overall operation, is safe and controllable, has a short reaction time, and is easy to produce. The 2-amino-4-fluorobenzoic acid obtained by the present invention is a white-gray solid product with a purity greater than 98%, and the total yield of the three steps reaches 73.6%. Attached Figure Description

[0013] Figure 1 This is a synthetic route diagram of the present invention. Detailed Implementation

[0014] The present invention will be further described below through specific embodiments.

[0015] A method for preparing 2-amino-4-fluorobenzoic acid, the synthetic route of which is described in [reference needed]. Figure 1 A microreactor was used as the reactor, and 2-amino-4-fluorobenzoic acid was obtained from 3-fluoroaniline through condensation, cyclization, and oxidative ring-opening reactions. The specific steps are as follows: Condensation reaction: A chloral hydrate-hydroxylamine hydrochloride mixed solution was prepared by dissolving chloral hydrate and hydroxylamine hydrochloride in water, and an anhydrous sodium sulfate solution was prepared by dissolving anhydrous sodium sulfate in water. The molar ratio of chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate was 1.00-1.25:3.35-3.75:5.20-5.60. Then, the two solutions were mixed using a microreactor. The temperature of the first microreactor was controlled at 35 °C, and the flow rate ratio of the two solutions was 1:1. The mixture flowing out of the first microreactor was directly introduced into the second microreactor, and a mixture of 3-fluoroaniline and hydrochloric acid was also introduced into the second microreactor, with a molar ratio of 3-fluoroaniline to HCl of 1.00:1.15. The temperature of the second microreactor was set at 75 °C, and the flow ratio of the mixture of chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate to the mixture of 3-fluoroaniline and hydrochloric acid was 5.8:1.0, with a residence time of 6.5 min. The reaction liquid flowing out of the second microreactor was cooled to 5 °C and kept at that temperature for more than 0.5 h, filtered to obtain a filter cake, and dried to obtain a pale yellow solid N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide.

[0016] Cyclization reaction: 98wt% concentrated sulfuric acid was added to the reactor, and the mixture was stirred and heated to about 80 °C. The product from the previous step was added in small batches, with the temperature controlled not to exceed 90 °C. After the addition was complete, the reaction was maintained at about 85 °C for 0.5 h, then cooled to about 30 °C. The cooled reaction solution was slowly poured into crushed ice water, and a solid precipitated. The solid was kept in the ice water for 0.5 h, filtered, and dried to obtain a yellow solid, 6-fluoroindigo.

[0017] Oxidative ring-opening reaction: A 10 wt% sodium hydroxide solution was added to the reactor, and 6-fluoroindigo was added in batches while stirring to ensure complete dissolution. The mixture was then introduced into a microreactor, and the temperature was lowered to 2°C using a temperature control system. Subsequently, a 30 wt% hydrogen peroxide solution was introduced, and the temperature was maintained at 0°C until the reaction was complete, at which point the entire reaction solution was discharged. Acetic acid was added to adjust the pH to 4-5, and the mixture was filtered and washed with water to obtain a white-gray solid, 2-amino-4-fluorobenzoic acid. Example 1

[0018] A preparation method for 2-amino-4-fluorobenzoic acid, the specific steps of which are as follows: Step 1, condensation reaction 7.80 g of chloral hydrate and 8.92 g of hydroxylamine hydrochloride were dissolved in 60 mL of water, as were 28.0 g of anhydrous sodium sulfate. The two solutions were mixed using a microreactor. The temperature of the first microreactor was controlled at 35 °C, with flow rates of 11 mL / min and 11 mL / min for each solution, and a residence time of 5 min. The mixture exiting the first microreactor was directly introduced into the second microreactor. Simultaneously, 4 g of 3-fluoroaniline was mixed with 22.4 mL of 2 mol / L hydrochloric acid and also introduced into the second microreactor. The temperature of the second microreactor was set at 75 °C, with flow rates of 14.5 mL / min for the mixture of chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate, and 2.5 mL / min for the mixture of 3-fluoroaniline and hydrochloric acid, and a residence time of 6.5 min. The reaction liquid flowing out of the second microreactor was cooled to 5 °C and kept at that temperature for more than 0.5 h. The filter cake was obtained by filtration and dried to obtain 6.45 g of pale yellow solid N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide with a purity of 94.3% and a yield of 92.8%.

[0019] Step 2, cyclization reaction 50 g of 98 wt% concentrated sulfuric acid was added to the reactor, and the mixture was stirred and heated to approximately 80 °C. 10 g of the product from the previous step was added in small batches, controlling the temperature to not exceed 90 °C. After the addition was complete, the reaction mixture was kept at approximately 85 °C for 30 min, then cooled to approximately 30 °C. The cooled reaction system was slowly poured into crushed ice water, causing a solid to precipitate. The precipitate was kept in the ice water for 30 min, filtered, and dried to obtain the solid. 7.87 g of a yellow solid, 6-fluoroindigo, with a purity of 96.9% and a yield of 89.3%, was obtained.

[0020] Step 3, Oxidation ring-opening reaction 100 mL of 10 wt% sodium hydroxide solution was added to the reactor, and 10 g of 6-fluoroindigo from the previous step was added in batches while stirring to ensure complete dissolution. The mixture was then introduced into a microreactor, and the temperature was lowered to 2 °C using a temperature control system. Subsequently, 36.5 mL of 30 wt% hydrogen peroxide solution was introduced, and the temperature was maintained at 0 °C. The flow rates of the 6-fluoroindigo mixture and the 30 wt% hydrogen peroxide were 6 mL / min and 1.4 mL / min, respectively, with a residence time of 15 min. After the reaction was completed, the entire reaction solution was discharged. Acetic acid was added to adjust the pH to 4, and the mixture was filtered, washed with water to remove impurities, yielding 8.25 g of a white-gray solid, 2-amino-4-fluorobenzoic acid, with a purity of 98.1% and a yield of 88.9%. Example 2

[0021] A preparation method for 2-amino-4-fluorobenzoic acid, the specific steps of which are as follows: Step 1, condensation reaction 7.80 g of chloral hydrate and 8.92 g of hydroxylamine hydrochloride were dissolved in 60 mL of water, as were 28.0 g of anhydrous sodium sulfate. The two solutions were mixed using a microreactor. The temperature of the first microreactor was controlled at 35 °C, with flow rates of 11 mL / min and 11 mL / min for each solution, and a residence time of 5 min. The mixture exiting the first microreactor was directly introduced into the second microreactor, along with a mixture of 4 g of 3-fluoroaniline and 22.4 mL of 2 mol / L hydrochloric acid. The temperature of the second microreactor was set at 75 °C, with flow rates of 17.1 mL / min for the mixture of chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate, and 2.9 mL / min for the mixture of 3-fluoroaniline and hydrochloric acid, and a residence time of 7.5 min. The reaction liquid flowing out of the second microreactor was cooled to 5 °C and kept at that temperature for more than 0.5 h. The filter cake was obtained by filtration and dried to obtain 6.34 g of pale yellow solid N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide with a purity of 78.7% and a yield of 76.1%.

[0022] Step 2, cyclization reaction 50 g of 98 wt% concentrated sulfuric acid was added to the reactor, and the mixture was stirred and heated to approximately 80 °C. 10 g of the product from the previous step was added in small batches, controlling the temperature to not exceed 90 °C. After the addition was complete, the reaction mixture was kept at approximately 85 °C for 30 min, then cooled to approximately 30 °C. The cooled reaction system was slowly poured into crushed ice water, causing a solid to precipitate. The precipitate was kept in the ice water for 30 min, filtered, and dried to obtain the solid. 7.87 g of a yellow solid, 6-fluoroindigo, with a purity of 96.9% and a yield of 89.3%, was obtained.

[0023] Step 3, Oxidation ring-opening reaction 100 mL of 10 wt% sodium hydroxide solution was added to the reactor, and 10 g of 6-fluoroindigo from the previous step was added in batches while stirring to ensure complete dissolution. The mixture was then introduced into a microreactor, and the temperature was lowered to 2 °C using a temperature control system. Subsequently, 36.5 mL of 30 wt% hydrogen peroxide solution was introduced, and the temperature was maintained at 0 °C. The flow rates of the 6-fluoroindigo mixture and the 30 wt% hydrogen peroxide were 9.0 mL / min and 2.1 mL / min, respectively, with a residence time of 10 min. After the reaction was complete, the entire reaction solution was discharged. Acetic acid was added to adjust the pH to 4, and the mixture was filtered and washed with water to remove impurities, yielding 5.95 g of a white-gray solid, 2-amino-4-fluorobenzoic acid, with a purity of 91.4% and a yield of 59.8%. Example 3

[0024] A preparation method for 2-amino-4-fluorobenzoic acid, the specific steps of which are as follows: Step 1: Condensation Reaction. 7.80 g of chloral hydrate and 8.92 g of hydroxylamine hydrochloride were dissolved in 60 mL of water, as were 28.0 g of anhydrous sodium sulfate. The two solutions were mixed using a microreactor. The temperature of the first microreactor was controlled at 35 °C, with flow rates of 11 mL / min and 11 mL / min for each solution, and a residence time of 5 min. The mixture exiting the first microreactor was directly introduced into the second microreactor, along with a mixture of 4 g of 3-fluoroaniline and 22.4 mL of 2 mol / L hydrochloric acid. The temperature of the second microreactor was set at 75 °C, with flow rates of 12.6 mL / min for the chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate mixture, and 2.16 mL / min for the 3-fluoroaniline and hydrochloric acid mixture, and a residence time of 7.5 min. The reaction liquid flowing out of the second microreactor was cooled to 5 °C and kept at that temperature for more than 0.5 h. The filter cake was obtained by filtration and dried to obtain 6.19 g of pale yellow solid N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide with a purity of 83.6% and a yield of 79.1%.

[0025] Step 2, cyclization reaction 50 g of 98 wt% concentrated sulfuric acid was added to the reactor, and the mixture was stirred and heated to approximately 80 °C. 10 g of the product from the previous step was added in small batches, controlling the temperature to not exceed 90 °C. After the addition was complete, the reaction mixture was kept at approximately 85 °C for 30 min, then cooled to approximately 30 °C. The cooled reaction system was slowly poured into crushed ice water, causing a solid to precipitate. The precipitate was kept in the ice water for 30 min, filtered, and dried to obtain the solid. 7.87 g of a yellow solid, 6-fluoroindigo, with a purity of 96.9% and a yield of 89.3%, was obtained.

[0026] Step 3, Oxidation ring-opening reaction 100 mL of 10 wt% sodium hydroxide solution was added to the reactor, and 10 g of 6-fluoroindigo from the previous step was added in batches while stirring to ensure complete dissolution. The mixture was then introduced into a microreactor, and the temperature was lowered to 2 °C using a temperature control system. Subsequently, 36.5 mL of 30 wt% hydrogen peroxide solution was introduced, and the temperature was maintained at 0 °C. The flow rates of the 6-fluoroindigo mixture and the 30 wt% hydrogen peroxide were 4.95 mL / min and 1.16 mL / min, respectively, with a residence time of 18 min. After the reaction was complete, the entire reaction solution was discharged. Acetic acid was added to adjust the pH to 4, and the mixture was filtered, washed with water to remove impurities, yielding 7.52 g of a white-gray solid, 2-amino-4-fluorobenzoic acid, with a purity of 95.5% and a yield of 78.9%.

[0027] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A method for preparing 2-amino-4-fluorobenzoic acid, characterized in that: A microreactor was used as the reactor to obtain 2-amino-4-fluorobenzoic acid from 3-fluoroaniline via condensation, cyclization and oxidative ring-opening reactions.

2. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, characterized in that, The microreactor is composed of reaction modules with microfluidic circuits connected in series. The number of reaction modules in a single microreactor is 10, and the total liquid holding capacity of a single microreactor is 110 mL.

3. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, characterized in that, The process for preparing N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide by condensation reaction includes: First, chloral hydrate, hydroxylamine hydrochloride, and anhydrous sodium sulfate are dissolved in water at a molar ratio of 1.00-1.25:3.35-3.75:5.20-5.60 to prepare a mixed solution of chloral hydrate-hydroxylamine hydrochloride and anhydrous sodium sulfate solution. The two solutions are then mixed using a microreactor. The temperature of the first microreactor is controlled at 30-35 °C, and the flow ratio of the two solutions is 1:

1. After the reaction, the mixture is introduced into a second microreactor, and a mixture of 3-fluoroaniline and hydrochloric acid is also introduced into this reactor, with the molar ratio of 3-fluoroaniline to HCl ranging from 1.00:1.00-1.

25. The temperature of the second microreactor is set within the range of 65-85 °C. At ℃, the flow rate ratio of the mixture of chloral hydrate, hydroxylamine hydrochloride and anhydrous sodium sulfate to the mixture of 3-fluoroaniline and hydrochloric acid was 5.8:1.

0.

4. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, characterized in that, The process of preparing 6-fluoroindigo by cyclization reaction includes: mixing the prepared N-(3-fluorophenyl)-2-(hydroxyimino)-p-acetamide with concentrated sulfuric acid at a mass ratio of 1:5, and heating to 90 °C for 0.5 h.

5. The method for preparing 2-amino-4-fluorobenzoic acid according to claim 1, characterized in that, The oxidative ring-opening reaction process includes: adding the prepared 6-fluoroindigo in batches to a 10 wt% sodium hydroxide solution, and introducing the mixture into a microreactor under stirring. When the temperature drops to 2 ℃, introducing 30 wt% hydrogen peroxide into the microreactor to mix with the 6-fluoroindigo mixture. The molar ratio of 6-fluoroindigo, H2O2, and sodium hydroxide is in the range of 1.0:5.2-5.8:4.0-5.

0. During the reaction, the temperature is controlled at 0 ℃, and the flow rate ratio of the 6-fluoroindigo mixture to 30 wt% hydrogen peroxide is 4.3:1.0.

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