A process for the preparation of 1,2-difluoro-4-methoxy-5-nitrobenzene
By controlling the reaction conditions and selecting the catalyst, 3,4-difluorophenol was reacted with ferric nitrate nonahydrate to generate 4,5-difluoro-2-nitrophenol, followed by phenol methylation. This solved the problems of poor selectivity and low yield in the synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene in the prior art, and achieved the preparation of the target product with high purity and high yield, which is suitable for industrial application.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- COOL PHARM LTD
- Filing Date
- 2026-03-16
- Publication Date
- 2026-06-12
AI Technical Summary
The existing synthesis methods for 1,2-difluoro-4-methoxy-5-nitrobenzene suffer from poor selectivity, numerous byproducts, and low yields. In particular, the selective control of the nitration reaction is difficult to achieve when there is a methoxy group and two fluorine atoms on the benzene ring.
Using 3,4-difluorophenol as a raw material, it reacts with ferric nitrate nonahydrate under the action of a catalyst to generate 4,5-difluoro-2-nitrophenol. Then, phenolic methylation is performed with dimethyl sulfate. By controlling the reaction conditions and selecting the catalyst, 1,2-difluoro-4-methoxy-5-nitrobenzene is preferentially generated.
It improves the position selectivity of the nitration reaction, significantly reduces the occurrence of side reactions, significantly improves product yield and purity, simplifies the post-processing, reduces production costs, and is suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention relates to a method for preparing fluorinated nitro aromatic ethers, specifically a method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene, belonging to the field of fluorinated fine chemical intermediate preparation technology. Background Technology
[0002] 1,2-Difluoro-4-methoxy-5-nitrobenzene (CAS No: 66684-64-8) is an important intermediate in the synthesis of fluorinated organic compounds. The nitro group in its molecular structure is readily reduced to an amino group, allowing for the introduction of various functional groups through diazotization, coupling, and other reactions. It is widely used in the synthesis of pharmaceuticals, pesticides, and liquid crystal materials. In particular, it holds significant market value as a core fragment in the synthesis of key active molecules such as quinolone antibacterial drugs and fluorinated herbicides.
[0003] For the synthesis of 1,2-difluoro-4-methoxy-5-nitrobenzene, most of the methods reported in the literature are based on the direct nitration of 1,2-difluoro-4-methoxybenzene. However, since the benzene ring already contains a methoxy group and two fluorine atoms, the electronic and steric effects make the selective control of the nitration reaction difficult. Conventional nitration systems using mixed nitrate and sulfuric acid are often too acidic and oxidizing, which can easily lead to side reactions such as polynitration, dealkylation, and ring-opening oxidation of the benzene ring. This results in low selectivity and yield of the 6-position nitration of the target product, and the product contains many isomer impurities, which makes subsequent purification difficult [WO2023 / 11299A1;Journal of Fluorine Chemistry, 2015, 180, 77; Organic Process Research & Development, 2019, 23, 456].
[0004] Therefore, developing a mild, highly selective, well-yielding, and easily industrialized method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene is of great significance for promoting the development of downstream fluorinated fine chemicals. Summary of the Invention
[0005] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: 3,4-difluorophenol is used as a raw material and reacted with ferric nitrate nonahydrate under the action of a catalyst to generate 4,5-difluoro-2-nitrophenol; subsequently, phenolic methylation is performed with dimethyl sulfate to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene. This process overcomes the defects of poor selectivity, numerous by-products, and low yield in existing nitration methods for 1,2-difluoro-4-methoxy-5-nitrobenzene, and provides an improved preparation method for 1,2-difluoro-4-methoxy-5-nitrobenzene.
[0006] This invention provides a method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene, comprising the following steps: A. 3,4-Difluorophenol was mixed in hexafluoroisopropanol, a catalyst was added, and ferric nitrate nonahydrate was added in batches under heating conditions. After the reaction was completed, 4,5-difluoro-2-nitrophenol was obtained. B. 4,5-Difluoro-2-nitrophenol and potassium carbonate were mixed in dimethyl sulfate and reacted at room temperature to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene.
[0007] The synthetic route of this invention is represented by the following reaction equation: Further, under preferred conditions, in step A, the Lewis acid catalyst is selected from triphenylboron, tri(pentafluorophenyl)boron, or boron trifluoride diethyl ether complex; under most preferred conditions, it is tri(pentafluorophenyl)boron.
[0008] Furthermore, under preferred conditions, in step A, the heating condition is 30-40°C.
[0009] Further, under preferred conditions, in step A, the molar ratio of 3,4-difluorophenol, Lewis acid catalyst, and ferric nitrate nonahydrate is 1:0.03-0.1:0.35-0.5.
[0010] Further, under preferred conditions, in step B, the molar ratio of 4,5-difluoro-2-nitrophenol to potassium carbonate is 1:1-1.2.
[0011] Further, under preferred conditions, in step B, after the reaction is completed, isopropanol and heptane (v / v=8 / 2) are added for recrystallization and purification.
[0012] Compared to existing technologies, the technological advancements achieved are as follows: 1. The present invention employs a tri(pentafluorophenyl)boron and ferric nitrate nonahydrate nitration system, in which tri(pentafluorophenyl)boron acts as a catalyst, which can greatly improve the position selectivity of the nitration reaction (preferentially attacking the 6- position) and significantly suppress nitration side reactions.
[0013] 2. This invention is simple and safe to operate by precisely controlling the nitrifying agent ratio, reaction temperature and feeding method. The reaction conditions are mild and do not require a low temperature or highly corrosive environment, making it easy to scale up for industrial production.
[0014] 3. The product obtained by the method of the present invention has high yield and high purity, and the post-processing is simple, which effectively reduces production costs and the generation of waste, and has significant industrial application value. Specific Implementation
[0015] The present invention will be further illustrated below with specific examples. These embodiments should be understood as illustrative only and not as limiting the scope of protection of the present invention. After reading the description of the present invention, those skilled in the art can make various alterations or modifications to the present invention, and these equivalent changes and modifications also fall within the scope defined by the claims of the present invention. Example 1
[0016]
[0017] Under nitrogen protection, 0.1 mol (13 g) of 3,4-difluorophenol was mixed in 100 mL of hexafluoroisopropanol, and 0.006 mol (1.45 g) of triphenylboron was added. The mixture was heated to 40 °C, and 0.045 mol (18.2 g) of ferric nitrate nonahydrate was added in portions. The reaction was continued for 3 hours. After the reaction was completed, a sample was taken for HPLC analysis, and the product / isomer ratio was found to be 82 / 18. The mixture was cooled to room temperature, concentrated, dissolved in 80 mL of dichloroethane, washed twice with 80 mL of water, and the organic layer was concentrated. Then, 55 mL of sulfolane was added, followed by vacuum distillation to obtain 12.4 g of 4,5-difluoro-2-nitrophenol, with a yield of 71% and an HPLC purity of 99.2%. 1 H-NMR (400MHz, CDCl3): 11.4(s, 1H), 8.01-7.97(m, 1H), 7.02-6.97(m, 1H) ppm. Example 2
[0018]
[0019] Under nitrogen protection, 0.1 mol (13 g) of 3,4-difluorophenol was mixed in 100 mL of hexafluoroisopropanol, and 0.004 mol (2.05 g) of tris(pentafluorophenyl)boron was added. The mixture was heated to 35 °C, and 0.045 mol (18.2 g) of ferric nitrate nonahydrate was added in portions. The reaction was continued for 2 hours. After the reaction was completed, a sample was taken for HPLC analysis, and the product / isomer ratio was found to be 91 / 9. The mixture was cooled to room temperature, concentrated, dissolved in 80 mL of dichloroethane, washed twice with 80 mL of water, and the organic layer was concentrated. Then, 55 mL of sulfolane was added, followed by vacuum distillation to obtain 14.7 g of 4,5-difluoro-2-nitrophenol, with a yield of 84% and an HPLC purity of 99.4%. Example 3
[0020]
[0021] Under nitrogen protection, 0.1 mol (13 g) of 3,4-difluorophenol was mixed in 100 mL of hexafluoroisopropanol, and 0.006 mol (0.85 g) of boron trifluoride diethyl ether complex was added. The mixture was heated to 40 °C, and 0.045 mol (18.2 g) of ferric nitrate nonahydrate was added in portions. The reaction was continued for 5 hours. After the reaction was completed, a sample was taken for HPLC analysis, and the product / isomer ratio was found to be 66 / 34. The mixture was cooled to room temperature, concentrated, dissolved in 80 mL of dichloroethane, washed twice with 80 mL of water, and the organic layer was concentrated. Then, 55 mL of sulfolane was added, followed by vacuum distillation to obtain 7.5 g of 4,5-difluoro-2-nitrophenol, with a yield of 43% and an HPLC purity of 96.8%. Example 4
[0022]
[0023] Under nitrogen protection, 0.1 mol (17.5 g, 99.2%) of 4,5-difluoro-2-nitrophenol, 150 mL of acetone, 0.11 mol (15.2 g) of potassium carbonate, and 0.13 mol (16.4 g) of dimethyl sulfate were added to a reaction flask and reacted at room temperature for 3 hours. The residue obtained after concentration was further purified by vacuum distillation after adding 110 mL of sulfolane to yield 17.96 g of 1,2-difluoro-4-methoxy-5-nitrobenzene (95% yield, HPLC purity 99.6%). 1 H-NMR (400M Hz, CDCl3): 7.86 (d, 1H), 6.92 (d,1H), 3.95 (s, 3H) ppm. Example 5
[0024]
[0025] Under nitrogen protection, 0.1 mol (13 g) of 3,4-difluorophenol was mixed in 100 mL of hexafluoroisopropanol, and 0.004 mol (2.05 g) of tris(pentafluorophenyl)boron was added. The mixture was heated to 35 °C, and 0.045 mol (18.2 g) of ferric nitrate nonahydrate was added in portions. The reaction was continued for 2 hours. The mixture was cooled to room temperature, concentrated, dissolved in 80 mL of dichloroethane, washed twice with 80 mL of water, dried of the organic layer, and concentrated to obtain 17.4 g of crude product of a mixture of 4,5-difluoro-2-nitrophenol and 3,4-difluoro-2-nitrophenol (HPLC analysis showed 4,5-difluoro-2-nitrophenol / 3,4-difluoro-2-nitrophenol 90.6% / 9.4%), which was directly used for the next reaction.
[0026] Under nitrogen protection, a mixture of 0.1 mol (17.4 g) of 4,5-difluoro-2-nitrophenol and 3,4-difluoro-2-nitrophenol obtained in the previous step, 150 mL of acetone, and potassium carbonate (0.11 mol (15.2 g) and dimethyl sulfate (0.13 mol (16.4 g) were mixed and reacted at room temperature for 3 hours. The mixture was filtered and concentrated. The crude product was recrystallized from the crude product in 85 mL of isopropanol and heptane (v / v = 8 / 2) to give 15.7 g of 1,2-difluoro-4-methoxy-5-nitrobenzene, with a yield of 83% and an HPLC purity of 98.9%.
[0027] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any equivalent substitutions or modifications made by those skilled in the art within the scope of the technology disclosed in the present invention, based on the technical solution and inventive concept of the present invention, should be covered within the scope of protection of the present invention.
Claims
1. A method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene, characterized in that, Includes the following steps: A. 3,4-Difluorophenol was mixed in hexafluoroisopropanol, a Lewis acid catalyst was added, and ferric nitrate nonahydrate was added in batches under heating conditions. After the reaction was completed, 4,5-difluoro-2-nitrophenol was obtained. B. 4,5-Difluoro-2-nitrophenol and potassium carbonate were mixed in dimethyl sulfate and reacted at room temperature to obtain 1,2-difluoro-4-methoxy-5-nitrobenzene.
2. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 1, characterized in that: In step A, the Lewis acid catalyst is selected from triphenylboron, tri(pentafluorophenyl)boron, or boron trifluoride diethyl ether complex.
3. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 2, characterized in that: In step A, the Lewis acid catalyst is selected from tris(pentafluorophenyl)boron.
4. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 1, characterized in that: In step A, the heating condition is 30-40℃.
5. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 1, characterized in that: In step A, the molar ratio of 3,4-difluorophenol, Lewis acid catalyst, and ferric nitrate nonahydrate is 1:0.03-0.1:0.35-0.
5.
6. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 1, characterized in that: In step B, the molar ratio of 4,5-difluoro-2-nitrophenol to potassium carbonate is 1:1-1.
2.
7. The method for preparing 1,2-difluoro-4-methoxy-5-nitrobenzene according to claim 1, characterized in that: In step B, after the reaction is complete, the mixture is purified by recrystallization using isopropanol and heptane (v / v=8 / 2).