Synthetic method for preparing 4, 4 '-difluorobenzophenone through one-pot domino reaction
By using a one-pot domino reaction with 4-fluorobenzoic acid and fluorobenzene as raw materials, and reacting in a solvent-free environment under an acidic catalyst, the problems of expensive raw materials, complex processes, and environmental pollution in DFBP synthesis have been solved, achieving efficient and low-cost DFBP preparation.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JIANGSU SANJILI CHEM
- Filing Date
- 2026-01-09
- Publication Date
- 2026-05-12
AI Technical Summary
Existing methods for synthesizing DFBP suffer from problems such as expensive raw materials, excessively long reaction routes, high energy consumption, low product selectivity, low yield and product purity, complex post-processing, and environmental pollution.
A one-pot domino reaction was used, with 4-fluorobenzoic acid and fluorobenzene as raw materials, and a solvent-free reaction was carried out under the action of an acidic catalyst. The post-processing included extraction, washing, drying and concentration to obtain 4,4'-difluorobenzophenone.
It achieves green and environmentally friendly processes, significantly reduces costs, ensures efficient and precise reactions, produces excellent product quality, and is safe and easy to operate, making it suitable for industrial production.
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Figure CN122010702A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of fluorine-containing intermediate preparation technology, specifically a method for synthesizing 4,4'-difluorobenzophenone via a one-pot domino reaction. Background Technology
[0002] 4,4'-Difluorobenzophenone (DFBP) has a symmetrical molecular structure and high reactivity, making it an important intermediate in fluorinated organic fine chemicals and pharmaceuticals. DFBP's applications are relatively concentrated, primarily as a monomer for synthesizing high-performance specialty engineering plastics, such as polyaryletherketone (PAEK), polyetherketone (PEK), and polyetheretherketone (PEEK). These high-performance specialty plastics possess excellent mechanical properties, chemical resistance, high-temperature resistance, and flame retardancy, and are widely used in high-end fields such as aerospace, medical devices, automotive manufacturing, and electronics. Furthermore, in the pharmaceutical intermediate field, it is used to synthesize flunarizine (a cerebral vasodilator), degliptin (for treating diabetes), and amitriazine (for treating Alzheimer's disease). DFBP can also be used to synthesize pesticides, dyes, electronic chemicals, and other fine chemicals. With increasing demand, the synthesis process of DFBP has also attracted the attention of researchers, and the innovation and optimization of its preparation process is an important research topic in the field of organic synthesis.
[0003] The synthesis of DFBP mainly includes the following categories:
[0004] The mainstream method in China uses fluorobenzene and 4-fluorobenzoyl chloride as raw materials, and then performs FC acylation under the catalysis of Lewis acids (including anhydrous aluminum trichloride, ferric chloride, boron trifluoride, trifluoromethanesulfonic acid, etc.), followed by hydrolysis and distillation to obtain the product. This method has good selectivity (purity ≥99.5%) and high yield (85% ~ 90%), but the 4-fluorobenzoyl chloride used is expensive, air-sensitive, the byproducts cannot be directly utilized, and a large amount of aluminum-containing wastewater is generated, which is difficult to treat, puts great pressure on the environment, and has high overall costs.
[0005]
[0006] DFBP was prepared by alkylation of fluorobenzene and carbon tetrachloride via FC to generate an intermediate, followed by hydrolysis, distillation, and recrystallization. This method is low-cost and has mild reaction conditions, but the product contains a large number of ortho-substituted isomers, resulting in an overall yield of approximately 63.9%. Furthermore, carbon tetrachloride is highly toxic and hazardous, the raw materials are difficult to obtain, and the equipment suffers severe corrosion. This method has been largely phased out.
[0007] Using 4,4'-dichlorobenzophenone as a raw material, it reacts with KF or KOH under high temperature and strong alkaline conditions to replace chlorine atoms and generate fluoroketone. This method is atom-economical in terms of molecular structure, but the reaction conditions are harsh, requiring high temperature (>200℃) and strong alkaline conditions. Furthermore, the halogen exchange reaction is reversible, which makes it difficult to control the conversion rate and selectivity, and requires multiple recrystallizations.
[0008] Using 4,4'-diaminodiphenylmethane as a raw material, a diazonium salt is generated through diazotization, followed by fluorination and oxidation reactions to obtain the target product. This method is currently one of the mainstream industrial routes both domestically and internationally. It can directly introduce fluorine atoms, is simple to operate, has few impurities (purity ≥90%), and a high yield (70% ~ 80%). However, the diazotization reaction carries an explosion risk, making it too dangerous, and HF is highly corrosive, causing severe equipment corrosion.
[0009]
[0010] Fluoroketones are produced from fluorobenzene, phosgene, and boron trifluoride under high temperature and pressure. This method is simple and produces the target product in one step. However, phosgene is a highly toxic gas, making operation dangerous, and it also produces 25% of the 2,4'-isomer as a byproduct, which is difficult to separate.
[0011]
[0012] In recent years, some methods have been developed to produce DFBP using fluoroboric acid and carbon monoxide as raw materials under the catalysis of metals such as palladium, nickel, and iron. These methods have high yields and fast reaction rates, but due to the high cost of raw materials and the harsh reaction conditions, they are not suitable for large-scale production.
[0013] In summary, existing methods for synthesizing DFBP suffer from problems such as complex processes, long processing times, high energy consumption, high risk, difficulty in catalyst recovery, and expensive raw materials. To address these issues, a one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone is proposed. Summary of the Invention
[0014] The purpose of this invention is to solve the problems of high raw material prices, excessively long reaction routes, high energy consumption, low product selectivity, low yield and product purity, complex post-processing and environmental pollution in existing processes, and to provide a one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone.
[0015] To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing 4,4'-difluorobenzophenone via a one-pot domino reaction, using 4-fluorobenzoic acid and fluorobenzene as raw materials, and carrying out a one-pot reaction under solvent-free conditions in the presence of an acidic catalyst. After the reaction, 4,4'-difluorobenzophenone is obtained through post-treatment. The specific steps are as follows: Step 1, Reaction Stage: At low temperature, add acidic catalyst and fluorobenzene to the reaction flask, stir for 1 to 10 min, add 4-fluorobenzoic acid, stir for 5 to 20 min, and then react at 50 to 90 °C for 4 to 15 h. The acid catalyst is any one or more of trifluoromethanesulfonic anhydride, phosphorus pentoxide, trifluoroacetic anhydride, and paraformaldehyde; The molar ratio of 4-fluorobenzoic acid, fluorobenzene, and acidic catalyst is 1: (6 ~ 18): (0.1 ~ 10.0); Step 2, Post-processing stage: After the reaction is complete, unreacted fluorobenzene is recovered first; then the reaction residue is poured into 6-18 times its volume of the first solvent and stirred for 10-30 minutes; then 0.1-0.5 times its volume of the second solvent is added for extraction, and the product-containing organic phase is obtained by separation; the organic phase is washed with 0.1-0.5 times its volume of the third solvent, and separated; after drying with inorganic salts, filtration, and concentration, 4,4'-difluorobenzophenone is obtained. The pH of the washed alkaline aqueous phase was adjusted to 1-6 using a fourth solvent, and unreacted 4-fluorobenzoic acid could be recovered after extraction. The first solvent may be one or more of 1,2-dichloroethane, ethylene glycol dimethyl ether, tributyl phosphate, water, n-hexane, n-heptane or petroleum ether; The second solvent is one or more of ethyl acetate, dichloromethane, and butyl acetate; The third solvent is one or more of saturated sodium carbonate, saturated potassium carbonate, saturated sodium bicarbonate, and 10% sodium hydroxide; The fourth solvent is an acidic solution.
[0016] As a preferred embodiment of the present invention, the low temperature of step 1 is 0 ~ 10℃; the stirring time for adding acidic catalyst and fluorobenzene in the reaction flask in step 1 is 5 ~ 8 min; the stirring time for adding 4-fluorobenzoic acid is 10 ~ 15 min; the reaction temperature of step 1 is 60 ~ 85℃; and the reaction time is 6 ~ 10 h.
[0017] As a preferred embodiment of the present invention, the molar ratio of 4-fluorobenzoic acid, fluorobenzene and acidic catalyst in step 1 is 1: (8 ~ 12): (0.5 ~ 4.0).
[0018] As a preferred technical solution of the present invention, the method for recovering fluorobenzene in step 2 is vacuum distillation or atmospheric distillation; the first solvent in step 2 is water, and the first solvent is 8 to 15 times the volume of the reaction residue; the stirring time in step 2 is 15 to 20 minutes.
[0019] As a preferred embodiment of the present invention, the second solvent in step 2 is 0.15 to 0.3 times the volume of the reaction residue.
[0020] As a preferred embodiment of the present invention, the third solvent in step 2 is 0.15 to 0.3 times the volume of the organic phase.
[0021] As a preferred embodiment of the present invention, the inorganic salt in step 2 is a commonly used dehydrated inorganic salt, including but not limited to anhydrous sodium sulfate, anhydrous potassium sulfate, and anhydrous calcium chloride.
[0022] As a preferred embodiment of the present invention, the acidic solution is glacial acetic acid, 10% dilute hydrochloric acid, or 10% dilute sulfuric acid.
[0023] In a preferred embodiment of the present invention, the pH in step 2 is 2 to 3.
[0024] Compared with the prior art, the beneficial effects of the present invention are: 1. Green and environmentally friendly process with significantly reduced costs: This invention employs a solvent-free one-pot reaction method, avoiding the large-scale use of organic solvents and subsequent treatment problems inherent in traditional processes. It uses inexpensive and readily available 4-fluorobenzoic acid instead of expensive and air-sensitive 4-fluorobenzoyl chloride as a raw material. Furthermore, excess fluorobenzene and unreacted 4-fluorobenzoic acid can be efficiently recovered and directly reused, reducing raw material consumption and waste generation at the source, significantly lowering production costs and reducing environmental pressure.
[0025] 2. Highly efficient and precise reaction, resulting in superior product quality: By selecting specific acidic catalysts (such as trifluoromethanesulfonic anhydride and phosphorus pentoxide) and optimizing process conditions, a highly selective domino reaction under mild conditions was achieved. This method effectively suppresses the formation of byproducts such as isomers, resulting in a conversion rate of 4-fluorobenzoic acid exceeding 99%, and a stable yield of the target product, 4,4'-difluorobenzophenone, above 95% with a purity exceeding 99%. The product quality is significantly superior to that of traditional methods.
[0026] 3. Safe and simple operation, suitable for industrial production: The entire process is simple, avoiding the use of high-risk raw materials such as phosgene and diazonium salts, or high-temperature, high-pressure, and highly corrosive conditions, ensuring high production safety. Post-processing steps are simple, requiring no complex purification, and the equipment requirements are conventional, making it easy to achieve large-scale, continuous production, and possessing excellent prospects for industrial application. Attached Figure Description
[0027] Figure 1 This is the liquid chromatogram of Example 1 of the present invention; Figure 2 This is the hydrogen NMR spectrum of Example 1 of the present invention; Figure 3This is the NMR fluorine spectrum of Example 1 of the present invention; Figure 4 This is a high-resolution mass spectrum of Example 1 of the present invention; Figure 5 This is the liquid chromatogram of Example 2 of the present invention; Figure 6 This is the liquid chromatogram of Example 3 of the present invention; Figure 7 This is the liquid chromatogram of Example 4 of the present invention; Figure 8 This is the liquid chromatogram of Example 5 of the present invention; Figure 9 The 1H NMR spectrum of 4-fluorobenzoic anhydride, an intermediate of this invention; Figure 10 The NMR fluorine spectrum of 4-fluorobenzoic anhydride, an intermediate of this invention; Figure 11 This is the liquid chromatogram of Example 8 of the present invention; Figure 12 This is the liquid chromatogram of Comparative Example 1 of the present invention; Figure 13 This is the liquid chromatogram of Comparative Example 2 of the present invention. Detailed Implementation
[0028] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby providing a clearer and more explicit definition of the scope of protection of the present invention.
[0029] Example 1: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 0℃, 56.4 g of trifluoromethanesulfonic anhydride and 55 g of fluorobenzene were added to a reaction flask and stirred for 5 min. Then, 10 g of 4-fluorobenzoic acid was added, and the mixture was stirred for 10 min. The reaction was carried out at 70℃ for 8 h. After the reaction was completed, 46.46 g of fluorobenzene was recovered by atmospheric distillation, with a recovery rate of 96.51%. The reaction system was poured into 150 mL of ice water and stirred for 15 min. The mixture was separated, and the aqueous phase was extracted twice with 80 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 80 mL of saturated sodium bicarbonate. The organic phase was washed with 80 mL of water and saturated sodium chloride, dried with 10 g of anhydrous sodium sulfate, and evaporated to dryness to obtain 14.88 g of white solid powder, with a yield of 96.31%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute hydrochloric acid. Then, 50 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 0.08 g of the raw material was recovered. Figure 1 It can be seen that the purity of the target product, as determined by liquid chromatography, is 99.874%. Figure 2 The hydrogen spectrum is as follows: 1H NMR (400 MHz, CDCl3): δ 7.82–7.79 (m, 4 H), 7.18–7.14 ppm (m, 4 H); Figure 3 The fluorine spectrum is a hydrogen spectrum, and the fluorine spectrum is consistent with the standard spectrum. Figure 4 For mass spectrometry, mass spectrometry [M+H] calcd for C13H9F2O 219.0621; found: 232.0618.
[0030] Example 2: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 5℃, 22.7 g of phosphorus pentoxide and 53 g of fluorobenzene were added to a reaction flask and stirred for 5 min. Then, 7 g of 4-fluorobenzoic acid was added, and the mixture was stirred for 10 min. The reaction was carried out at 60℃ for 10 h. After the reaction was complete, 47.54 g of fluorobenzene was recovered by vacuum distillation, with a recovery rate of 98.64%. The reaction system was poured into 120 mL of ice water and stirred for 15 min. The mixture was separated, and the aqueous phase was extracted twice with 60 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 60 mL of saturated sodium bicarbonate. The organic phase was washed with 60 mL of water and saturated sodium chloride. After drying with 5 g of anhydrous potassium sulfate, the mixture was evaporated to dryness, yielding 10.49 g of a white solid powder, with a yield of 97.12%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute sulfuric acid. Then, 40 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 0.06 g of the raw material was recovered. Figure 5 It can be seen that the purity of the target product, as measured by liquid chromatography, is 99.883%.
[0031] Example 3: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 2℃, 70 g of phosphorus pentoxide and 196 g of fluorobenzene were added to a reaction flask and stirred for 8 min. Then, 22 g of 4-fluorobenzoic acid was added, and the mixture was stirred for 15 min. The reaction was carried out at 65℃ for 8 h. After the reaction was completed, 178.9 g of fluorobenzene was recovered by vacuum distillation, with a recovery rate of 98.89%. The reaction system was poured into 300 mL of ice water and stirred for 17 min. The mixture was separated, and the aqueous phase was extracted twice with 150 mL of dichloromethane. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 70 mL of saturated sodium carbonate. The organic phase was washed with 80 mL of water and saturated sodium chloride. After drying with 8 g of anhydrous sodium sulfate, the mixture was evaporated to dryness, yielding 32.86 g of a white solid powder, with a yield of 96.82%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute hydrochloric acid. Then, 50 mL of dichloromethane was added, and the mixture was separated. After evaporation to dryness, 0.21 g of the raw material was recovered. Figure 6 The purity of the target product, as determined by liquid chromatography, is 99.831%.
[0032] Example 4: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 5℃, 63.8 g of phosphorus pentoxide and 161 g of fluorobenzene were added to a reaction flask and stirred for 10 min. Then, 18 g of 4-fluorobenzoic acid was added, and the mixture was stirred for 15 min. The reaction was carried out at 80℃ for 7 h. After the reaction was completed, 147 g of fluorobenzene was recovered by vacuum distillation, with a recovery rate of 98.91%. The reaction system was poured into 300 mL of ice water and stirred for 20 min. The mixture was separated, and the aqueous phase was extracted twice with 200 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 50 mL of 10% sodium hydroxide. The organic phase was washed with 200 mL of water and saturated sodium chloride, dried with 10 g of anhydrous sodium sulfate, and then evaporated to dryness, yielding 27.39 g of a white solid powder, with a yield of 98.31%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute hydrochloric acid. Then, 50 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 0.11 g of the raw material was recovered. Figure 7 It can be seen that the purity of the target product, as measured by liquid chromatography, is 99.894%.
[0033] Example 5: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 0℃, 94.21 g of phosphorus pentoxide and 226 g of fluorobenzene were added to a reaction flask and stirred for 10 min. Then, 30 g of 4-fluorobenzoic acid was added, and the mixture was stirred for 15 min. The reaction was carried out at 70℃ for 8 h. After the reaction was completed, 203.6 g of fluorobenzene was recovered by vacuum distillation, with a recovery rate of 99.11%. The reaction system was poured into 350 mL of ice water and stirred for 20 min. The mixture was separated, and the aqueous phase was extracted twice with 220 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 220 mL of saturated sodium bicarbonate. The organic phase was washed with 200 mL of water and saturated sodium chloride, dried with 10 g of anhydrous sodium sulfate, and then evaporated to dryness to obtain 44.46 g of white solid powder, with a yield of 95.93%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute sulfuric acid. Then, 50 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 0.27 g of the raw material was recovered. Figure 8 It can be seen that the purity of the target product, as measured by liquid chromatography, is 99.924%.
[0034] Example 6: A one-pot domino reaction method for the synthesis of 4,4'-difluorobenzophenone, the specific steps of which are as follows: At 0℃, 5.32 g of phosphorus pentoxide and 34 g of fluorobenzene were added to a reaction flask and stirred for 5 min. Then, 5 g of 4-fluorobenzoic acid was added and stirred for 10 min. The reaction was carried out at 70℃ for 6 h. After the reaction was completed, 30.31 g of fluorobenzene was recovered by vacuum distillation, with a recovery rate of 98.61%. The reaction system was poured into 100 mL of ice water and stirred for 16 min. The mixture was separated, and the aqueous phase was extracted twice with 80 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 80 mL of saturated sodium bicarbonate. The organic phase was washed with 80 mL of water and saturated sodium chloride. After drying with 10 g of anhydrous sodium sulfate, the mixture was evaporated to dryness, yielding 8.71 g of white solid powder, with a yield of 97.79%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute hydrochloric acid. Then, 50 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 0.24 g of the raw material was recovered. Figure 9 The data is for the proton spectrum: 1 H NMR (400 MHz, CDCl3): δ 8.19–8.14 (m, 4 H), 7.23–7.17 ppm (m, 4 H). Figure 10 The fluorine spectrum is a hydrogen spectrum, and the fluorine spectrum is consistent with the standard spectrum.
[0035] Example 7: Preparation of 4,4'-difluorobenzophenone using Eaton's reagent as a catalyst, the specific steps are as follows: At 0℃, 125 g Eaton's reagent and 7 g fluorobenzene were added to a reaction flask and stirred for 10 min. Then, 5 g 4-fluorobenzoic acid was added, and the mixture was stirred for 15 min. The reaction was carried out at 80℃ for 8 h. After the reaction was complete, the reaction mixture was poured into 350 mL of ice water and stirred for 20 min. The mixture was separated, and the aqueous phase was extracted twice with 220 mL of ethyl acetate. The organic phases were combined, and the pH of the organic phase was adjusted to 7-8 with 220 mL of saturated sodium bicarbonate. The organic phase was washed with 200 mL of water and saturated sodium chloride, dried with 5 g of anhydrous sodium sulfate, and then evaporated to dryness to obtain 4.41 g of white solid powder, with a yield of 75.93%. The saturated sodium bicarbonate aqueous solution was collected, and the pH was adjusted to approximately 2 with 10% dilute sulfuric acid. 50 mL of ethyl acetate was added, and the mixture was separated. After evaporation to dryness, 1.27 g of the starting material was recovered. Figure 11 It can be seen that the purity of the target product, as measured by liquid chromatography, is 99.816%.
[0036] Comparative Example 1: Add 45g of fluorobenzene and 100g of 1,2-dichloroethane to a reaction flask, cool in an ice-water bath, add 42g of aluminum trichloride, stir in an ice-water bath for 30 min after the addition, then add 50g of 4-fluorobenzoyl chloride dropwise, and react at 30℃ for 10 h after the addition is complete. After the reaction is complete, pour the reaction mixture into 200 mL of ice water, stir for 30 min, separate the layers, extract the aqueous phase twice with 200 mL of ethyl acetate, combine the organic phases, adjust the pH of the organic phase to 7-8 with 100 mL of saturated sodium bicarbonate, wash with 100 mL of water, wash once with saturated sodium chloride, dry with 10g of anhydrous sodium sulfate, and evaporate to dryness to obtain 60.77g of white solid powder. Figure 12 The purity of the liquid phase was 98.716%, and the yield was 88.32%.
[0037] Comparative Example 2: Add 45g of fluorobenzene and 50g of 4-fluorobenzoyl chloride to a reaction flask. Add 44g of aluminum trichloride in portions under ice-water bath conditions. React at 35℃ for 8 h. After the reaction is complete, pour the reaction mixture into 800 mL of ice water, stir for 30 min, separate the layers, extract the aqueous phase twice with 300 mL of ethyl acetate, combine the organic phases, adjust the pH of the organic phase to 7-8 with 100 mL of saturated sodium bicarbonate, wash with 100 mL of water and once with saturated sodium chloride, dry with 10 g of anhydrous sodium sulfate, and evaporate to dryness to obtain 62.37g of white solid powder. Figure 13 It can be seen that the purity of the liquid phase is 99.335% and the yield is 90.65%.
[0038] In summary, compared with Examples 1-7 and Comparative Examples 1-2, this invention provides a one-pot domino reaction for the preparation of 4,4'-difluorobenzophenone. This invention is solvent-free, uses readily available raw materials, has a simple process, mild reaction conditions, and convenient post-processing. Both 4-fluorobenzoic acid and fluorobenzene can be directly reused after recovery. It has a high raw material conversion rate (>99%), high yield (>95%), and high purity (>99.5%), and has broad application prospects, making it more suitable for widespread application.
[0039] The synthesis method provided by this invention effectively solves a series of problems existing in the background technology, such as high cost, heavy pollution, complex process and poor safety, through synergistic innovation of raw materials, catalysts and process mode. It is a new technology for the preparation of 4,4'-difluorobenzophenone with high economy, high selectivity and high environmental protection, and has broad prospects for industrial application.
[0040] The above embodiments merely illustrate implementation methods of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that for those skilled in the art, any modifications and improvements to the raw material ratios or reaction methods made without departing from the concept of the present invention are all within the protection scope of the present invention.
Claims
1. A method for synthesizing 4,4'-difluorobenzophenone via a one-pot domino reaction, characterized in that: Using 4-fluorobenzoic acid and fluorobenzene as raw materials, a one-pot reaction was carried out under solvent-free conditions in the presence of an acidic catalyst. After the reaction, post-treatment yielded 4,4'-difluorobenzophenone. The specific steps are as follows: Step 1, Reaction Stage: At low temperature, add acidic catalyst and fluorobenzene to the reaction flask, stir for 1 to 10 min, add 4-fluorobenzoic acid, stir for 5 to 20 min, and then react at 50 to 90 °C for 4 to 15 h. The acid catalyst is any one or more of trifluoromethanesulfonic anhydride, phosphorus pentoxide, trifluoroacetic anhydride, and paraformaldehyde; The molar ratio of 4-fluorobenzoic acid, fluorobenzene, and acidic catalyst is 1: (6 ~ 18): (0.1 ~ 10.0); Step 2, Post-processing stage: After the reaction is complete, unreacted fluorobenzene is recovered first; then the reaction residue is poured into 6-18 times its volume of the first solvent and stirred for 10-30 minutes; then 0.1-0.5 times its volume of the second solvent is added for extraction, and the product-containing organic phase is obtained by separation; the organic phase is washed with 0.1-0.5 times its volume of the third solvent, and separated; after drying with inorganic salts, filtration, and concentration, 4,4'-difluorobenzophenone is obtained. The pH of the washed alkaline aqueous phase was adjusted to 1-6 using a fourth solvent, and unreacted 4-fluorobenzoic acid could be recovered after extraction. The first solvent may be one or more of 1,2-dichloroethane, ethylene glycol dimethyl ether, tributyl phosphate, water, n-hexane, n-heptane or petroleum ether; The second solvent is one or more of ethyl acetate, dichloromethane, and butyl acetate; The third solvent is one or more of saturated sodium carbonate, saturated potassium carbonate, saturated sodium bicarbonate, and 10% sodium hydroxide; The fourth solvent is an acidic solution.
2. The synthesis method according to claim 1, characterized in that: The low temperature of step 1 is 0 ~ 10℃; the stirring time for adding acidic catalyst and fluorobenzene in the reaction flask in step 1 is 5 ~ 8 min; the stirring time for adding 4-fluorobenzoic acid is 10 ~ 15 min; the reaction temperature of step 1 is 60 ~ 85℃; and the reaction time is 6 ~ 10 h.
3. The synthesis method according to claim 1, characterized in that: In step 1, the molar ratio of 4-fluorobenzoic acid, fluorobenzene, and acidic catalyst is 1: (8 ~ 12): (0.5 ~ 4.0).
4. The synthesis method according to claim 1, characterized in that: In step 2, fluorobenzene is recovered by vacuum distillation or atmospheric distillation; the first solvent in step 2 is water, which is 8 to 15 times the volume of the reaction residue; and the stirring time in step 2 is 15 to 20 minutes.
5. The synthesis method according to claim 1, characterized in that: The second solvent in step 2 is 0.15 to 0.3 times the volume of the reaction residue.
6. The synthesis method according to claim 1, characterized in that: The third solvent in step 2 is 0.15 to 0.3 times the volume of the organic phase.
7. The synthesis method according to claim 1, characterized in that: The inorganic salts used in step 2 are commonly used dehydrated inorganic salts, including but not limited to anhydrous sodium sulfate, anhydrous potassium sulfate, and anhydrous calcium chloride.
8. The synthesis method according to claim 1, characterized in that: The acidic solution is glacial acetic acid, 10% dilute hydrochloric acid, and 10% dilute sulfuric acid.
9. The synthesis method according to claim 1, characterized in that: The pH in step 2 is 2 to 3.