A process for the preparation of 2-fluoro-3-nitrobenzoic acid
The preparation of 2-fluoro-3-nitrobenzoic acid is achieved by reacting 2-fluoro-3-nitrotoluene with DMF-DMA to generate an enamine intermediate, followed by low-temperature ozone oxidation and acidic crystallization. This method solves the problems of wastewater treatment and high cost in existing technologies, and realizes an efficient and environmentally friendly preparation of 2-fluoro-3-nitrobenzoic acid.
Patent Information
- Application Number
- CN202610104139.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2026-01-26
- Publication Date
- 2026-05-15
- Estimated Expiration
- 2046-01-26
AI Technical Summary
Existing synthetic routes for 2-fluoro-3-nitrobenzoic acid face challenges such as wastewater treatment difficulties, high costs, and difficulty in industrialization, especially due to the environmental and economic pressures caused by the use of potassium permanganate, dichromate oxidation, and lithium reagents.
An enamine intermediate was generated by reflux reaction of 2-fluoro-3-nitrotoluene with DMF-DMA, then selectively oxidized with ozone at low temperature, and finally crystallized in an acidic system to obtain 2-fluoro-3-nitrobenzoic acid, thus avoiding the use of strong oxidants such as potassium permanganate.
It achieves high yield and high purity of 2-fluoro-3-nitrobenzoic acid production, simplifies post-processing, is suitable for industrial continuous or batch production, and reduces environmental and economic costs.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical intermediates technology, specifically to a method for preparing 2-fluoro-3-nitrobenzoic acid. Background Technology
[0002] 2-Fluoro-3-nitrobenzoic acid is widely used in constructing biologically active molecular frameworks, particularly in the following areas: targeted drug molecule construction, kinase inhibitors, antibacterial agents, and antiviral agents. The fluorine atom and benzoic acid structure are key pharmacophores in many kinase inhibitors (such as some anticancer drugs). The carboxyl group can be readily condensed with amine compounds to form amides or modified into other groups to optimize the drug's water solubility, target binding affinity, and pharmacokinetic properties. Fluorinated benzoic acid derivatives are often used to synthesize analogs or new structural entities of antibacterial drugs such as quinolones. The amino group obtained after nitro reduction can be further used to synthesize heterocycles (such as benzimidazole and oxadiazole), which are commonly found in antibacterial and antiviral drugs.
[0003] In complex drug synthesis routes, 2-fluoro-3-nitrobenzoic acid often serves as a "starting module" or "structural unit." For example, it can be used to construct drug side chains by linking its carboxyl group to amino acids, peptides, or amines. Reducing its nitro group to an amino group yields 2-fluoro-3-aminobenzoic acid, an important precursor for the synthesis of more complex heterocyclic systems (such as quinazolinones and benzothiazoles).
[0004] Currently, the main synthetic routes for 2-fluoro-3-nitrobenzoic acid are as follows:
[0005] (1) The traditional process route is as follows:
[0006]
[0007] The methyl oxidation process involves direct oxidation using chromium trioxide or potassium permanganate, which results in wastewater that is difficult to treat.
[0008] (2) Chinese patent CN118146099A discloses the following process route:
[0009]
[0010] The target product was synthesized by using 2-fluoro-benzoic acid as the starting material and removing the sulfonic acid group through sulfonation and nitration. However, experimental verification showed that the process of removing the sulfonic acid group was difficult and not easy to industrialize.
[0011] (3) Chinese patent CN113861034A discloses the following process route:
[0012]
[0013] This route utilizes lithium diisopropylamino or tert-butyllithium at -80°C, followed by fluorination at the ortho-position and dry ice carbonylation of 2-fluoronitrobenzene, and then acidic hydrolysis to obtain the target product, 2-fluoro-3-nitrobenic acid. This method uses expensive and highly corrosive lithium reagents, requires ultra-low temperatures, is costly, and incurs high costs for organic wastewater treatment, making it difficult to industrialize.
[0014] (4) The product was synthesized from 2-chloro-3-nitrobenzoic acid and its derivatives via a KF / CsF substitution reaction. The process route is as follows:
[0015]
[0016] The process generates a large amount of high-salt, high-acid wastewater, which is detrimental to environmental protection and requires complex subsequent treatment.
[0017] Therefore, it is of great significance to develop a process route that is highly efficient, easy to industrialize, and has a high yield. Summary of the Invention
[0018] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for preparing 2-fluoro-3-nitrobenzoic acid.
[0019] To achieve the above objectives, the present invention provides the following technical solution:
[0020] A method for preparing 2-fluoro-3-nitrobenzoic acid includes the following steps:
[0021] S1: 2-Fluoro-3-nitrotoluene reacted with DMF-DMA under reflux to give intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine;
[0022] S2: The intermediate is dissolved in an aprotic solvent, oxidized with ozone at low temperature, and the solvent is removed by vacuum distillation. 2-Fluoro-3-nitrobenzoic acid is obtained by crystallization in an acidic system.
[0023] Its synthetic route is as follows:
[0024] .
[0025] In step S1, the mass ratio of 2-fluoro-3-nitrotoluene to DMF-DMA is 1:(0.86-1).
[0026] In step S1, the reflux reaction time is 8-12 hours.
[0027] In step S2, the aprotic solvent is one of THF, 2-methyltetrahydrofuran, diethyl ether, dichloromethane, dichloroethane, DMF, and acetonitrile.
[0028] In step S2, the mass ratio of the intermediate to the aprotic solvent is (3.8-4.1):2.5.
[0029] In step S2, the temperature of the low-temperature ozone oxidation is 0-10℃, and the time of the low-temperature ozone oxidation is 3-5h.
[0030] In step S2, the ozone volume concentration is 1.5-3%.
[0031] In step S2, the solution used for crystallization of the acidic system is a mixture of concentrated hydrochloric acid, deionized water, and dichloroethane, with a mixing weight ratio of 1:2:3.
[0032] In step S2, the steps for the acidic system crystallization operation are as follows: the crude product obtained by vacuum distillation is added to a mixture of concentrated hydrochloric acid, deionized water, and dichloroethane, heated to 60-70℃ and stirred until dissolved, cooled to 0-10℃ to crystallize, and then filtered.
[0033] Due to the adoption of the above technical solutions, the beneficial effects of the present invention include:
[0034] This route uses 2-fluoro-3-nitrotoluene as a starting material. First, it undergoes a Knoevenagel-type condensation reaction with DMF-DMA under reflux conditions. Under the synergistic effect of the strongly electron-withdrawing nitro group and fluorine, the methyl hydrogen is activated, reacting with DMF-DMA to generate the enamine intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine. This enamine structure contains a carbon-carbon double bond that is easily oxidized by ozone. Subsequently, ozone is introduced into a low-temperature THF solution, selectively oxidizing and cleaving the enamine double bond, accompanied by the formation of N,N-dimethylformamide and hydroxylamine byproducts. Finally, hydrolysis yields 2-fluoro-3-nitrobenzoic acid. This method cleverly utilizes the enamine as a "hidden aldehyde" equivalent to achieve the efficient conversion of the aromatic ring side-chain methyl group into a carboxylic acid.
[0035] This route achieves efficient conversion of methyl groups to carboxyl groups through an "activation-directed oxidation" strategy, avoiding the safety and environmental problems associated with strong oxidizing systems such as potassium permanganate and dichromate. Ozone oxidation offers high selectivity and a mild reaction, effectively suppressing side reactions involving aromatic ring nitro groups and fluorinated substituents, resulting in high product purity. The overall process conditions are controllable, with high yield and liquid-phase purity, good scale-up stability, and simple post-processing, making it suitable for continuous or batch industrial production. Attached Figure Description
[0036] Figure 1 The liquid chromatogram of 2-fluoro-3-nitrobenzoic acid prepared in Example 1;
[0037] Figure 2The proton NMR spectrum of the intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine prepared in Example 1;
[0038] Figure 3 The 1H NMR spectrum of 2-fluoro-3-nitrobenzoic acid prepared in Example 1. Detailed Implementation
[0039] The following description, in conjunction with specific embodiments, provides further details, but the present invention is not limited to these embodiments.
[0040] Example 1
[0041] S1: 3.1 kg of 2-fluoro-3-nitrotoluene and 2.67 kg of DMF-DMA (N,N-dimethylformamide dimethyl acetal) were added to a 10 L reactor. The mixture was heated to reflux and stirred for 8 h. The mixture was then concentrated under reduced pressure (-0.9 MPa) at 80 °C for 2 h to remove excess DMF-DMA, yielding 4.12 kg of a yellow oily liquid, namely the intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine, with a yield of 98.08% and a liquid phase purity of 97.50%. The 1H NMR spectrum is shown below. Figure 2 As shown, the analysis data is as follows: 1 H NMR(400MHz, DMSO-d): δppm 7.97 (dd, J1 = 4Hz, J2 = 4Hz,1H), 7.68(m, 1H), 7.36 (m,2H), 6.33 (m, 1H), 2.90 (s, 6H).
[0042] S2: 3.8 kg of intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine and 2.5 kg of THF were added to a 10 L reactor, stirred, and cooled to 0 °C. Ozone with a volume concentration of 1.5% was introduced at a gas rate of 22 L / h for 3 h of ozone oxidation, resulting in a colorless and clear system. Nitrogen gas was introduced for 0.5 h, and the solvent was removed by vacuum distillation. 1.0 kg of concentrated hydrochloric acid, 2.0 kg of deionized water, and 3.0 kg of DCE (dichloroethane) were added, and the mixture was heated to 60 °C to dissolve completely. The mixture was then cooled to 0 °C to crystallize, filtered, and dried under vacuum at 50 °C for 10 h to obtain 3.16 kg of white crystalline 2-fluoro-3-nitrobenzoic acid, with a yield of 96.85% and a liquid phase purity of 99.35% (see [link to relevant documentation]). Figure 1 The proton NMR spectrum is shown below. Figure 3 As shown, the analysis data is as follows: 1H NMR (400 MHz, DMSO-d) δppm 13.85 (s, 1H), 8.33 (t, J = 6.8 Hz, 1H), 8.21 (t, J = 6.8 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H).
[0043] Example 2
[0044] S1: 3.1 kg of 2-fluoro-3-nitrotoluene and 2.8 kg of DMF-DMA (N,N-dimethylformamide methyl acetal) were added to a 10 L reactor, heated to reflux, stirred for 10 h, concentrated under reduced pressure (-0.9 MPa) at 90 °C for 2 h, and excess DMF-DMA was removed to obtain 4.11 kg of yellow oily liquid, namely the intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine, with a yield of 97.84% and a liquid phase purity of 97.88%.
[0045] S2: 4.0 kg of crude intermediate and 2.5 kg of THF were added to a 10 L reactor, stirred, cooled to 5 °C, and ozone with a volume concentration of 2% was introduced at a gas rate of 20 L / h. Ozone oxidation was carried out for 4 h to obtain a colorless and clear system. Nitrogen gas was introduced for 0.5 h, and the solvent was removed by vacuum distillation. 1.0 kg of concentrated hydrochloric acid, 2.0 kg of deionized water, and 3.0 kg of DCE were added, and the mixture was heated to 65 °C to dissolve the solids. The mixture was then cooled to 5 °C to crystallize. The crystals were filtered and dried under vacuum at 55 °C for 8 h to obtain 3.36 kg of white crystalline 2-fluoro-3-nitrobenzoic acid, with a yield of 97.46% and a liquid phase purity of 99.38%.
[0046] Example 3
[0047] S1: 3.1 kg of 2-fluoro-3-nitrotoluene and 3.1 kg of DMF-DMA (N,N-dimethylformamide methyl acetal) were added to a 10 L reactor, heated to reflux, stirred for 12 h, concentrated under reduced pressure (-0.9 MPa) at 85 °C for 2 h, and excess DMF-DMA was removed to obtain 4.14 kg of yellow oily liquid, namely the intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine, with a yield of 98.56% and a liquid phase purity of 97.61%.
[0048] S2: 4.1 kg of crude intermediate and 2.5 kg of THF were added to a 10 L reactor, stirred, and cooled to 10 °C. Ozone with a volume concentration of 3% was introduced at a rate of 18 L / h. Ozone oxidation was carried out for 5 h to obtain a colorless and clear system. Nitrogen was introduced for 0.5 h, and the solvent was removed by vacuum distillation. 1.0 kg of concentrated hydrochloric acid, 2.0 kg of deionized water, and 3.0 kg of DCE were added. The mixture was heated to 70 °C to dissolve the solids, cooled to 10 °C to crystallize, filtered, and dried under vacuum at 60 °C for 5 h to obtain 3.43 kg of white crystalline 2-fluoro-3-nitrobenzoic acid, with a yield of 97.33% and a liquid phase purity of 99.41%.
[0049] Examples 4-10 and Comparative Examples 1-2 are experiments on the preparation of 2-fluoro-3-nitrobenzoic acid under different process control parameters than Example 2. The different process parameters and yields are shown in Table 1.
[0050] Table 1
[0051]
[0052] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. However, any modifications, alterations, and variations made by those skilled in the art without departing from the scope of the present invention based on the disclosed technical content are equivalent embodiments of the present invention. Furthermore, any modifications, alterations, and variations made to the above embodiments based on the essential technology of the present invention are still within the protection scope of the present invention.
Claims
1. A method for preparing 2-fluoro-3-nitrobenzoic acid, characterized in that, Includes the following steps: S1: 2-Fluoro-3-nitrotoluene reacted with DMF-DMA under reflux to give intermediate (E)-2-(2-fluoro-3-nitrophenyl)-N,N-dimethylethylene-1-amine; S2: Dissolve the intermediate in an aprotic solvent, oxidize with ozone at low temperature, remove the solvent by vacuum distillation, and crystallize in an acidic system to obtain 2-fluoro-3-nitrobenzoic acid; Its synthetic route is as follows: ； In step S1, the reflux reaction time is 8-12 hours; In step S2, the aprotic solvent is THF; In step S2, the temperature of the low-temperature ozone oxidation is 0-10℃, and the time of the low-temperature ozone oxidation is 3-5h. In step S2, the solution used for crystallization of the acidic system is a mixture of concentrated hydrochloric acid, deionized water, and dichloroethane, with a mixing weight ratio of 1:2:
3. In step S2, the steps for the acidic system crystallization operation are as follows: the crude product obtained by vacuum distillation is added to a mixture of concentrated hydrochloric acid, deionized water, and dichloroethane, heated to 60-70℃ and stirred until dissolved, cooled to 0-10℃ to crystallize, and then filtered.
2. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step S1, the mass ratio of 2-fluoro-3-nitrotoluene to DMF-DMA is 1:(0.86-1).
3. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step S2, the mass ratio of the intermediate to the aprotic solvent is (3.8-4.1):2.
5.
4. The method for preparing 2-fluoro-3-nitrobenzoic acid according to claim 1, characterized in that, In step S2, the ozone volume concentration is 1.5-3%.