CN-122010739-A - Synthesis method of 2-fluoro-3-nitrobenzoic acid

Abstract

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

Inventors

• LIU FANLEI
• FAN LUMING
• LI ZHEN

Assignees

• 山东佰隆医药有限公司

Dates

Publication Date

20260512

Application Date

20260325

Claims (8)

1. 1. The synthesis method of the 2-fluoro-3-nitrobenzoic acid is characterized by comprising the following steps of: adding 2-amino-3-nitrobenzoic acid into hydrochloric acid solution under the protection of gas, stirring until the solution is clear, controlling the temperature of the hydrochloric acid solution system to-5 ℃, dropwise adding sodium nitrite aqueous solution, stirring for reaction for 0.5-1h after the dropwise adding, and monitoring the reaction of the raw materials by using a thin layer chromatography to obtain a diazonium salt system for later use; Adding potassium fluoride and a solvent into another reaction bottle provided with a stirrer, a thermometer and a reflux condenser, stirring uniformly, slowly dripping the diazonium salt system obtained in the step one into the reaction bottle system under the protection of gas, controlling the temperature of the reaction bottle system to be 20-30 ℃ when transferring the diazonium salt system, heating the reaction bottle system to 60-80 ℃ after dripping, stirring for 4-6h, monitoring the reaction progress by using High Performance Liquid Chromatography (HPLC), cooling the reaction liquid in the reaction bottle system to room temperature after the reaction is finished, slowly pouring the reaction liquid into purified water, stirring for 0.5-1 h, and leaching to obtain a crude product of 2-fluoro-3-nitrobenzoic acid.
2. 2. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, further comprising the steps of adding water into a crude 2-fluoro-3-nitrobenzoic acid system after the reaction of the step two is finished, precipitating a large amount of solids, stirring for 0.5-1 h, performing suction filtration to obtain a filter cake I, leaching the filter cake I by purified water, collecting the filter cake I, adding the filter cake I into absolute ethyl alcohol, heating to reflux, slowly cooling to 0-10 ℃ after the filter cake I is completely dissolved, continuing stirring for 2-4 h, performing suction filtration to obtain a filter cake II, leaching the filter cake II by using ice ethyl alcohol, collecting the filter cake II, controlling the temperature T to be less than or equal to 60 ℃, controlling the pressure P to be less than or equal to-0.06 MPa, and performing vacuum drying to obtain a 2-fluoro-3-nitrobenzoic acid product.
3. 3. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the gas used for the gas protection in the first and second steps is nitrogen or argon.
4. 4. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the molar ratio of 2-amino-3-nitrobenzoic acid to sodium nitrite in the first step is 1:1.05, and the molar concentration of the hydrochloric acid solution is 6 mol/L.
5. 5. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the solvent used in the thin layer chromatography in the first step is dichloromethane and methanol, and the volume ratio of dichloromethane to methanol is 10:1.
6. 6. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the molar ratio of potassium fluoride to 2-amino-3-nitrobenzoic acid in the method is 1.2-1.5:1.0.
7. 7. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the solvent in the second step is dimethyl sulfoxide or dimethylformamide, and the volume of the solvent added is five times the volume of potassium fluoride.
8. 8. The method for synthesizing 2-fluoro-3-nitrobenzoic acid according to claim 1, wherein the reaction is stopped when the mass ratio of 2-amino-3-nitrobenzoic acid is 2% or less while monitoring the progress of the reaction in the second step.

Description

Synthesis method of 2-fluoro-3-nitrobenzoic acid Technical Field The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 2-fluoro-3-nitrobenzoic acid. Background 2-Fluoro-3-nitrobenzoic acid has an indispensable position in the field of organic chemical industry, and the market demand of the 2-fluoro-3-nitrobenzoic acid is continuously increased along with the development of the pharmaceutical and pesticide industries. At present, a plurality of methods for synthesizing 2-fluoro-3-nitrobenzoic acid mainly exist, wherein part of the methods adopt expensive raw materials, such as specific fluoro reagents, so that the production cost is high, the large-scale industrial production is not favored, and the reaction conditions of the methods are severe, such as high reaction temperature or pressure, strict requirements on reaction equipment are met, and the safety risk and equipment investment cost in the production process are increased. CN119775143a discloses a method for synthesizing 2-fluoro-3 nitrobenzoic acid, which comprises the following steps: S1, diazotizing 2-methyl-6-nitroaniline to obtain aromatic diazonium salt; S2, carrying out a Hieman reaction on the aromatic diazonium salt and fluoboric acid under the condition of a catalyst a to obtain 2-fluoro-3-nitrotoluene, wherein the catalyst a is one or more of simple substances or oxides corresponding to iron, copper and manganese; S3, under the conditions of a catalyst b and an oxidant, carrying out an oxidation reaction on the 2-fluoro-3-nitrotoluene to obtain the 2-fluoro-3-nitrobenzoic acid. And (3) oxidizing the methyl group into a carboxyl group in the step S3. This step usually requires the use of strong oxidants such as potassium permanganate, dichromate or high concentration nitric acid, which not only increases the reaction steps, but also increases the raw material consumption and the cost of three-waste treatment. The benzene ring already has a strong electron withdrawing nitro group and a fluorine atom. Under strong oxidizing conditions, there is a risk of potential excessive oxidation or cracking of the benzene ring. Although catalyst b can improve selectivity, its process control (temperature, pH, oxidant usage) is difficult. The dried diazonium salt fluoroborate salt presents a potential explosion risk when heated, whereas the use of a strong oxidizer itself presents a safety risk (intense exotherm, waste acid generation) in the S3 oxidation step, so there is a potential explosion risk in step S3. CN118271177a discloses a process for producing 2-fluoro-3-nitrobenzoic acid, which comprises the following steps: a, oxidizing 2-chloro-3-nitrotoluene under the action of a catalyst to generate 2-chloro-3-nitrobenzaldehyde; b, under the action of a fluorination reagent, performing a chlorine-fluorine exchange reaction on the 2-chlorine-3-nitrobenzaldehyde to obtain 2-fluorine-3-nitrobenzaldehyde; And c, oxidizing the 2-fluoro-3-nitrobenzaldehyde under the action of a catalyst to obtain the 2-fluoro-3-nitrobenzoic acid. CN118271177a relates to the conversion of chlorobenzene to fluorobenzene, and has the technical problems that the chlorine atom on the aromatic ring is very inactive (because of the nature of carbon-chlorine bond with a double bond), usually requires activation of a strong electron withdrawing group (e.g. ortho/para nitro group), and requires the use of a highly active fluorination reagent in a polar aprotic solvent and at high temperature. Side reactions (such as solvolysis and phenol generation by hydrolysis) are easy to occur at high temperature, and the requirements on equipment materials are high (corrosion resistance). Step a requires selective oxidation of methyl groups to aldehyde groups, which are more difficult to control than oxidation to carboxyl groups, as aldehyde groups are generally unstable under oxidation conditions and are extremely susceptible to excessive oxidation to carboxylic acids. Steps a and c require the use of an oxidizing agent (e.g., potassium permanganate, dichromate or a high-valence metal catalyst) which produces a metal-containing solid waste residue. Step b (chloro-fluoro exchange) produces a large amount of fluorine-containing wastewater, which is difficult to treat. In addition, the existing synthesis method has the problems of poor reaction conversion rate and more byproduct types, and the difficulty and cost of subsequent separation and purification are increased. Therefore, the development of the synthesis method of the 2-fluoro-3-nitrobenzoic acid, which has the advantages of easily available raw materials, relatively low cost, mild reaction conditions, good selectivity, environmental friendliness and suitability for industrial production, has important practical significance. Disclosure of Invention Aiming at the technical problems of harsh reaction conditions, high operation risk, relatively low step yield and the like in th