Synthesis method of 2-fluoro-3-nitrobenzoic acid

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of 2-fluoro-3-nitrobenzoic acid, which comprises the following steps of: synthesizing 2-fluoro-3-nitrobenzoic acid by taking 2-amino-3-nitrobenzoic acid as a starting raw material through two steps; compared with the prior art, the synthesis method of 2-fluoro-3-nitrobenzoic acid has the advantages that carboxyl exists in the raw material, subsequent construction is not needed, the most difficult methyl oxidation step is avoided, and the raw material with carboxyl is directly used; the high reaction activity of diazonium salt is utilized, fluorine ions are used as nucleophilic reagents to directly attack benzene rings, and aromatic nucleophilic substitution is achieved; the diazo group is an extremely good leaving group, so that the reaction does not need harsh conditions, and the reaction conditions are mild; the synthesis method of 2-fluoro-3-nitrobenzoic acid provided by the invention is shorter in whole process route, milder, more economical and more environment-friendly.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a method for synthesizing 2-fluoro-3-nitrobenzoic acid. Background Technology

[0002] 2-Fluoro-3-nitrobenzoic acid plays an indispensable role in the field of organic chemical engineering, and its market demand continues to increase with the development of the pharmaceutical and pesticide industries. Currently, there are several methods for synthesizing 2-fluoro-3-nitrobenzoic acid. Some methods use relatively expensive raw materials, such as specific fluorinated reagents, resulting in high production costs and hindering large-scale industrial production. Other methods require harsh reaction conditions, such as high reaction temperatures or pressures, and impose strict requirements on reaction equipment, increasing safety risks and equipment investment costs during production.

[0003] CN119775143A discloses a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: S1, 2-methyl-6-nitroaniline is subjected to a diazotization reaction to obtain an aromatic diazonium salt; S2, under catalyst a, the aromatic diazonium salt is reacted with fluoroboric acid in a Schiemann reaction to give 2-fluoro-3-nitrotoluene; the catalyst a is one or more of the elements or oxides of iron, copper, and manganese. In step S3, under catalyst b and oxidant conditions, 2-fluoro-3-nitrotoluene undergoes an oxidation reaction to yield 2-fluoro-3-nitrobenzoic acid. Step S3 involves the oxidation of the methyl group to a carboxyl group. This step typically requires strong oxidants such as potassium permanganate, dichromate, or high-concentration nitric acid, which not only increases the number of reaction steps but also increases raw material consumption and waste treatment costs. The benzene ring already has a strongly electron-withdrawing nitro group and a fluorine atom. Under strong oxidizing conditions, there is a potential risk of over-oxidation or benzene ring breakage. Although catalyst b can improve selectivity, its process control (temperature, pH, oxidant dosage) is difficult. Dry diazonium fluoroborate has a potential explosion risk when heated, and the use of a strong oxidant in the S3 oxidation step itself carries safety risks (intense exothermic reaction, generation of waste acid), therefore, there is a potential explosion risk in step S3.

[0004] CN118271177A discloses a production process for 2-fluoro-3-nitrobenzoic acid, including the following steps: a: 2-Chloro-3-nitrotoluene is oxidized to produce 2-chloro-3-nitrobenzaldehyde in the presence of a catalyst; b: 2-chloro-3-nitrobenzaldehyde is obtained by chlorine-fluorine exchange reaction in the presence of a fluorinating agent; c: 2-Fluoro-3-nitrobenzaldehyde is oxidized in the presence of a catalyst to obtain 2-fluoro-3-nitrobenzic acid.

[0005] CN118271177A relates to the conversion of chlorobenzene to fluorobenzene. The technical problems are: the chlorine atom on the aromatic ring is very inert (due to the double bond characteristics of the carbon-chlorine bond), usually requiring activation by a strong electron-withdrawing group (such as an ortho / para nitro group), and necessitating a polar aprotic solvent, the use of a highly reactive fluorinating agent, and high temperature. High temperatures easily lead to side reactions (such as solvent decomposition and hydrolysis to generate phenols), and require high-quality (corrosion-resistant) equipment. Step a requires the selective oxidation of the methyl group to an aldehyde group. Oxidating the methyl group to an aldehyde group is more difficult to control than oxidizing it to a carboxyl group because the aldehyde group is usually unstable under oxidizing conditions and easily over-oxidizes to a carboxylic acid. Steps a and c require the use of oxidants (such as potassium permanganate, dichromate, or high-valence metal catalysts), which will produce metal-containing solid waste. Step b (chlorine-fluorine exchange) will generate a large amount of fluoride-containing wastewater, which is difficult to treat.

[0006] Furthermore, existing synthetic methods suffer from poor reaction conversion rates and a variety of byproducts, increasing the difficulty and cost of subsequent separation and purification. Therefore, developing a synthetic method for 2-fluoro-3-nitrobenzoic acid that uses readily available raw materials, has relatively low costs, mild reaction conditions, good selectivity, is environmentally friendly, and suitable for industrial production is of significant practical importance. Summary of the Invention

[0007] This invention addresses the technical problems in the synthesis of 2-fluoro-3-nitrobenzoic acid in the prior art, such as harsh reaction conditions, high operational risks, multiple steps, and relatively low yield, by providing a method for synthesizing 2-fluoro-3-nitrobenzoic acid.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows: a method for synthesizing 2-fluoro-3-nitrobenzoic acid, comprising the following steps: Step 1: Under gas protection, 2-amino-3-nitrobenzoic acid is added to hydrochloric acid solution and stirred until dissolved. The hydrochloric acid solution system is then kept at -5~5℃, and sodium nitrite aqueous solution is added dropwise. After the addition is complete, the reaction is stirred for 0.5-1h. Thin-layer chromatography is used to monitor the completion of the reaction of the raw materials to obtain the diazonium salt system for later use. Step 2: Add potassium fluoride and solvent to another reaction flask equipped with a stirrer, thermometer, and reflux condenser, and stir until homogeneous. Under gas protection, slowly add the diazonium salt system obtained in Step 1 to the reaction flask system. When transferring the diazonium salt system, maintain the temperature of the reaction flask system at 20-30°C. After the addition is complete, raise the temperature of the reaction flask system to 60-80°C and stir for 4-6 hours. Monitor the reaction progress using high-performance liquid chromatography (HPLC). After the reaction is complete, cool the reaction solution in the reaction flask system to room temperature, then slowly pour it into purified water, stir for 0.5-1 hour, filter, and wash to obtain crude 2-fluoro-3-nitrobenzoic acid.

[0009] Preferably, the process also includes step three: after the reaction in step two is completed, water is added to the crude 2-fluoro-3-nitrobenzoic acid system, and a large amount of solid precipitates out. After stirring for 0.5 to 1 hour, the mixture is filtered to obtain filter cake one. Filter cake one is washed with purified water and collected. Filter cake one is added to anhydrous ethanol and heated to reflux. After filter cake one is completely dissolved, the temperature is slowly lowered to 0 to 10°C, and stirring is continued for 2 to 4 hours. After filtration, filter cake two is obtained. Filter cake two is washed with ice-cold ethanol and collected. Filter cake two is dried under reduced pressure with a temperature T≤60°C and a pressure P≤-0.06MPa to obtain the 2-fluoro-3-nitrobenzoic acid product.

[0010] Preferably, nitrogen or argon is used for gas protection in steps one and two.

[0011] Preferably, in step one, the molar ratio of 2-amino-3-nitrobenzoic acid to sodium nitrite is 1:1.05; and the molar concentration of the hydrochloric acid solution is 6 mol / L.

[0012] Preferably, the solvent used in the thin-layer chromatography in step one is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 10:1.

[0013] Preferably, the molar ratio of potassium fluoride to 2-amino-3-nitrobenzoic acid in the synthesis method is 1.2~1.5:1.0.

[0014] Preferably, the solvent in step two is dimethyl sulfoxide or dimethylformamide; the volume of the added solvent is five times the volume of potassium fluoride.

[0015] Preferably, in step two, when monitoring the reaction process, the reaction is stopped when the mass percentage of 2-amino-3-nitrobenzoic acid is ≤2%.

[0016] Compared with the prior art, the advantages and positive effects of the method for synthesizing 2-fluoro-3-nitrobenzoic acid of the present invention are as follows: (1) In the synthesis method of 2-fluoro-3-nitrobenzoic acid of the present invention, the carboxyl group already exists in the raw material and no further construction is required; the most difficult methyl oxidation step is avoided and the raw material with carboxyl group is used directly; this makes the whole process route shorter, milder, more economical and more environmentally friendly, which is very suitable for small-scale preparation in the laboratory or for scenarios where cost control is strict in industrial production. (2) The method for synthesizing 2-fluoro-3-nitrobenzoic acid in this invention utilizes the high reactivity of diazonium salts. Fluoride ions act as nucleophiles to directly attack the benzene ring, which is an aromatic nucleophilic substitution. Since the diazonium group is an extremely good leaving group, the reaction does not require harsh conditions and the reaction conditions are mild. (3) Raw materials are readily available: The main raw materials used in this invention, 2-amino-3-nitrobenzoic acid and potassium fluoride, are common chemical raw materials on the market. They are relatively inexpensive and easy to obtain, which reduces production costs. (4) Mild conditions: The diazotization reaction is carried out at 0~5℃ and the fluorination reaction is carried out at 20~80℃. It does not require extremely high temperature or pressure, has low requirements for reaction equipment, is easy to operate, and reduces safety risks and equipment investment costs in the production process. (5) High yield: There are fewer reaction steps (each additional reaction step means one more loss) and by optimizing the reaction process parameters, such as the raw material molar ratio, reaction temperature, reaction time, etc., and adding a suitable catalyst, the selectivity of the reaction is improved and the generation of by-products is reduced. The yield of the target product 2-fluoro-3-nitrobenzoic acid is over 85% and the purity is ≥98%, which meets the requirements of industrial production. (6) Environmentally friendly: The main byproducts of this invention are nitrogen (which is directly discharged into the atmosphere without pollution) and inorganic salts, which are very environmentally friendly; the solvents and reagents used in this invention have less pollution to the environment, and the wastewater generated in the post-processing can be treated by conventional sewage treatment methods, which is in line with the development trend of modern green chemical production. Attached Figure Description

[0017] To more clearly illustrate the technical solutions of the embodiments of the present invention, the accompanying drawings used in the description of the embodiments will be briefly introduced below: Figure 1 This is a schematic diagram of the synthesis method of 2-fluoro-3-nitrobenzoic acid; Figure 2 This is the chemical reaction formula for step one of the synthesis method of 2-fluoro-3-nitrobenzoic acid in this invention; Figure 3 This is the chemical reaction formula for step two in the synthesis method of 2-fluoro-3-nitrobenzoic acid of the present invention. Detailed Implementation

[0018] To better understand the above-mentioned objectives, features and advantages of the present invention, the present invention will be further described below in conjunction with the accompanying drawings and embodiments.

[0019] Numerous specific details are set forth in the following description in order to provide a full understanding of the invention. However, the invention may also be practiced in other ways than those described herein, and therefore the invention is not limited to the specific embodiments disclosed in the following specification.

[0020] Example 1 The following is combined Figure 1 The method for synthesizing 2-fluoro-3-nitrobenzoic acid in Example 1 is further described, including the following steps: It is obtained from 2-amino-3-nitrobenzoic acid and potassium fluoride through diazotization and substitution reactions. The specific steps include: Step 1: Diazotization reaction: At -5~5℃, 2-amino-3-nitrobenzoic acid is dissolved in 6 mol / L hydrochloric acid solution, sodium nitrite solution is added dropwise, and the reaction is carried out for 0.5~1 h to obtain a diazonium salt solution; Step 2: Fluorination reaction: Add the diazonium salt solution dropwise to the reaction system containing potassium fluoride and solvent, react at 20-30℃ first, then heat to 60-80℃ and reflux for 4-6 hours; Step 3 Post-processing: After cooling the reaction solution, pour it into purified water, filter it, and rinse the filter cake with purified water and collect the filter cake; Purification: Recrystallize the rinsed filter cake with anhydrous ethanol, and dry it to obtain 2-fluoro-3-nitrobenzoic acid product.

[0021] Step 1: Under nitrogen protection, add 30 mL of concentrated hydrochloric acid and 30 mL of water to a 250 mL reaction flask. Cool to -5 to 5 °C, and stir while adding 18.2 g (0.1 mol) of 2-amino-3-nitrobenzoic acid until dissolved. Slowly add sodium nitrite solution (7.245 g dissolved in 15 mL of purified water) dropwise through a dropping funnel, maintaining the temperature at 0-5 °C during the addition. After the addition is complete, continue stirring for 45 minutes to obtain a diazonium salt solution. The chemical reaction formula for Step 1 is as follows: Figure 2 As shown, the chemical reaction in step one is described in words as follows: 2-Amino-3-nitrobenzoic acid + sodium nitrite + hydrochloric acid → 3-nitro-2-diazobenzoic acid chloride salt + sodium chloride + water.

[0022] Step Two: At room temperature, add 90 mL of a mixed solution of potassium fluoride and dimethyl sulfoxide (6.96 g of potassium fluoride) to a 1000 mL reaction flask (another reaction flask equipped with a stirrer, thermometer, and reflux condenser). After stirring thoroughly, adjust the temperature to 20-30°C. Slowly add the above diazonium salt solution dropwise to the reaction flask, maintaining the temperature of the reaction flask system at 20-30°C during the addition. After the addition is complete, raise the temperature of the reaction system to 70°C and reflux for 5 hours. The reaction formula for Step Two is as follows: Figure 3 As shown, the chemical reaction in step two is described in words as follows: 3-Nitro-2-diazobenzoic acid chloride salt + potassium fluoride → 2-fluoro-3-nitrobenzoic acid + nitrogen gas↑ + potassium chloride.

[0023] After the reaction was complete, the system was cooled to 15-30℃, 360 mL of water was added, and the mixture was stirred for 0.5-1 h. A large amount of solid precipitated out. The solid was filtered to obtain filter cake one. Filter cake one was washed three times with purified water, 18 mL each time. Filter cake one was added to anhydrous ethanol (90 mL), and the mixture was heated to reflux until it was completely dissolved. The mixture was then slowly cooled to 0-10℃, stirred for 2-4 h, and filtered to obtain filter cake two. Filter cake two was washed with ice-cold ethanol (0-10℃, 9 mL), and the mixture was collected. The mixture was dried under reduced pressure at a controlled temperature of T≤60℃ and P≤-0.06 MPa to obtain 15.7 g of 2-fluoro-3-nitrobenzoic acid with a purity of 98%, a yield of 85%, and a melting point of 138-140℃.

[0024] Example 2 The difference between this embodiment and Embodiment 1 is that in step 2, the amount of potassium fluoride in the 90 mL mixed solution of potassium fluoride and dimethyl sulfoxide is 8.70 g. After stirring evenly, the temperature is adjusted to 20-30°C, and the above diazonium salt solution is slowly added dropwise to the reaction flask. During the addition process, the temperature of the reaction flask system is controlled at 20-30°C. After the addition is completed, the reaction system is heated to 70°C and refluxed for 5 hours.

[0025] After the reaction was complete, the system was cooled to 15-30℃, 360 mL of water was added, and the mixture was stirred for 0.5-1 h. A large amount of solid precipitated out. The solid was filtered to obtain filter cake one. Filter cake one was washed three times with purified water, 18 mL each time. Filter cake one was added to anhydrous ethanol (90 mL), and the mixture was heated to reflux until it was completely dissolved. The mixture was then slowly cooled to 0-10℃, stirred for 2-4 h, and filtered to obtain filter cake two. Filter cake two was washed with ice-cold ethanol (0-10℃, 9 mL), and the mixture was collected. The mixture was dried under reduced pressure at a controlled temperature of T≤60℃ and P≤-0.06 MPa to obtain 15.8 g of 2-fluoro-3-nitrobenzoic acid with a purity of 98%, a yield of 86%, and a melting point of 138-140℃.

[0026] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any other way. Any person skilled in the art may make changes or modifications to the above-disclosed technical content to create equivalent embodiments that can be applied to other fields. However, any simple modifications or equivalent changes made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the protection scope of the present invention.

Claims

1. A method for synthesizing 2-fluoro-3-nitrobenzoic acid, characterized in that, Includes the following steps: Step 1: Under gas protection, 2-amino-3-nitrobenzoic acid is added to hydrochloric acid solution and stirred until dissolved. The hydrochloric acid solution system is then kept at -5~5℃, and sodium nitrite aqueous solution is added dropwise. After the addition is complete, the reaction is stirred for 0.5-1h. Thin-layer chromatography is used to monitor the completion of the reaction of the raw materials to obtain the diazonium salt system for later use. Step 2: Add potassium fluoride and solvent to another reaction flask equipped with a stirrer, thermometer, and reflux condenser, and stir until homogeneous. Under gas protection, slowly add the diazonium salt system obtained in Step 1 to the reaction flask system. When transferring the diazonium salt system, maintain the temperature of the reaction flask system at 20-30°C. After the addition is complete, raise the temperature of the reaction flask system to 60-80°C and stir for 4-6 hours. Monitor the reaction progress using high-performance liquid chromatography (HPLC). After the reaction is complete, cool the reaction solution in the reaction flask system to room temperature, then slowly pour it into purified water, stir for 0.5-1 hour, filter, and wash to obtain crude 2-fluoro-3-nitrobenzoic acid.

2. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The process also includes step three: after the reaction in step two is completed, water is added to the crude 2-fluoro-3-nitrobenzoic acid system, and a large amount of solid precipitates out. After stirring for 0.5 to 1 hour, the mixture is filtered to obtain filter cake one. Filter cake one is washed with purified water and collected. Filter cake one is added to anhydrous ethanol and heated to reflux. After filter cake one is completely dissolved, the temperature is slowly lowered to 0 to 10°C, and stirring is continued for 2 to 4 hours. After filtration, filter cake two is obtained. Filter cake two is washed with ice-cold ethanol and collected. Filter cake two is dried under reduced pressure with a temperature T≤60°C and a pressure P≤-0.06MPa to obtain the 2-fluoro-3-nitrobenzoic acid product.

3. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The gas used for gas protection in steps one and two is nitrogen or argon.

4. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step one, the molar ratio of 2-amino-3-nitrobenzoic acid to sodium nitrite is 1:1.05; the molar concentration of the hydrochloric acid solution is 6 mol / L.

5. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, The solvents used in the thin-layer chromatography in step one are dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 10:

1.

6. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In the synthesis method, the molar ratio of potassium fluoride to 2-amino-3-nitrobenzoic acid is 1.2~1.5:1.

0.

7. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step two, the solvent is dimethyl sulfoxide or dimethylformamide; the volume of the added solvent is five times the volume of potassium fluoride.

8. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step two, when monitoring the reaction process, the reaction is stopped when the mass percentage of 2-amino-3-nitrobenzoic acid is ≤2%.

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