The method comprises the following steps: synthesizing 4, 4 apos from p-nitrobenzoyl chloride; process for preparing-difluorobenzophenone
By reacting p-nitrobenzoyl chloride with aromatic fluorides, and combining nitro reduction and diazotization cleavage, the problems of poor selectivity and impurity generation in the synthesis of 4,4'-difluorobenzophenone were solved, achieving the preparation of high-purity and high-yield products and ensuring the quality of downstream polyether ether ketone materials.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- JILIN ZHONGYAN HIGH PERFORMANCE PLASTIC CO LTD
- Filing Date
- 2026-01-05
- Publication Date
- 2026-04-21
AI Technical Summary
The existing synthesis methods for 4,4'-difluorobenzophenone have poor selectivity, generate many isomers, are difficult to separate, and have low product purity and yield. In addition, the conventional diazotization method makes it difficult to remove 4-fluorobenzophenone impurities, which affects the quality of downstream polyether ether ketone materials.
4-Nitro-4'-fluorobenzophenone is generated by reacting p-nitrobenzoyl chloride with aromatic fluorides. The formation of isomers is avoided through nitro reduction and diazotization cleavage reactions, thereby reducing 4-fluorobenzophenone impurities and improving product purity.
It improves reaction selectivity, reduces the formation of 4-fluorobenzophenone impurities, enhances product purity, and ensures the quality of downstream polyether ether ketone products.
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Figure CN121895136A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing 4,4'-difluorobenzophenone from p-nitrobenzoyl chloride. Background Technology
[0002] Currently reported methods for synthesizing 4,4'-difluorobenzophenone include acylation reactions using fluorobenzene, p-fluorobenzoyl chloride, or p-fluorobenzoic acid as raw materials and anhydrous aluminum trichloride as a catalyst. The method using fluorobenzene and p-fluorobenzoyl chloride with anhydrous aluminum trichloride as a catalyst to prepare 4,4'-difluorobenzophenone suffers from poor selectivity, generating numerous isomers, making product separation difficult, resulting in complex post-processing and low product yield. Conventional diazotization methods generate a monofluorinated intermediate during pyrolysis, leading to a high 4-fluorobenzophenone content and low purity in the final product. Furthermore, this impurity is difficult to remove, requiring multiple purification steps to achieve the required purity, resulting in low yield and high cost. Summary of the Invention
[0003] The purpose of this invention is to provide a method for synthesizing 4,4'-difluorobenzophenone from p-nitrobenzoyl chloride. Compared with traditional production methods, the preparation method of this invention avoids the formation of isomers, improves reaction selectivity, reduces the formation of 4-fluorobenzophenone impurities, improves product purity, and ensures the quality of downstream polyether ether ketone products.
[0004] The method for synthesizing 4,4'-difluorobenzophenone from p-nitrobenzoyl chloride provided by the present invention includes the following steps: (1) p-Nitrobenzoyl chloride reacts with aromatic fluorides in the presence of a catalyst to give 4-nitro-4'-fluorobenzophenone; (2) The 4-nitro-4'-fluorobenzophenone obtained in step (1) undergoes a nitro reduction reaction to give 4-amino-4'-fluorobenzophenone; (3) The 4-amino-4'-fluorobenzophenone obtained in step (2) undergoes a diazotization reaction with anhydrous hydrogen fluoride and sodium nitrite. After the reaction is completed, the temperature is raised to carry out a cracking reaction to obtain the product 4,4'-difluorobenzophenone.
[0005] This invention first prepares 4-nitro-4'-fluorobenzophenone, then successfully substitutes the fluoride ion at the other end through a diazotization pyrolysis reaction. This avoids the significant reduction in electron density of the benzene ring due to the strong electron-withdrawing effect of the fluoride atom (-I effect), which would hinder the second acylation reaction. The introduction of the first fluoride substituent leads to a decrease in the electron density of the benzene ring, drastically reducing the rate of further acylation reactions, even causing them to stall at the mono-substitution stage, thus generating the impurity 4-fluorobenzophenone. Directly using the corresponding amino compound for diazotization pyrolysis can result in the shedding of fluoride ions during the Heemann reaction due to factors such as reaction temperature and time, generating the 4-fluorobenzophenone impurity. This impurity is one of the key impurities affecting the quality of downstream products of 4,4'-difluorobenzophenone. Since 4,4'-difluorobenzophenone is one of the main raw materials for synthesizing polyetheretherketone (PEEK) materials, the content of the 4-fluorobenzophenone impurity directly affects the molecular weight distribution and viscosity of PEEK materials, thus affecting their mechanical and thermal properties.
[0006] In step (1) of the above method, the aromatic fluoride is fluorobenzene; The molar ratio of p-nitrobenzoyl chloride to the aromatic fluoride can be 1:10-1:20; The catalyst is a Lewis acid, selected from at least one of aluminum chloride, ferric chloride, antimony chloride, and tin chloride; The molar ratio of p-nitrobenzoyl chloride to the catalyst can be 1:1.1 to 1:2.0; The reaction can be carried out in the presence of a solvent or in the absence of a solvent; When a solvent is present, the solvent may be selected from: alkane solvents, haloalkane solvents, haloolefin solvents, haloaromatic solvents, and more specifically from: at least one of dichloromethane, trichloromethane, n-hexane, cyclohexane, chlorobenzene, and fluorobenzene; The reaction temperature can be 20-80℃, and the time can be 6-10 hours.
[0007] In step (2) of the above method, the nitro reduction reaction is achieved by reacting 4-nitro-4'-fluorobenzophenone under heating conditions in the presence of water, ammonium chloride and reduced iron powder; The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to reduced iron powder can be 1:1.1-1:3, specifically 1:1.5; The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to ammonium chloride can be 1:1.1-1:3, specifically 1:1.5; The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to water can be 1:20-1:40, specifically 1:36.1; The temperature of the nitro reduction reaction can be 90-100℃, and the reaction time can be 4-8 hours.
[0008] After the reaction is completed, the reaction solution is purified by the following operations, such as extraction, layering, washing, distillation, crystallization, etc., to remove the reaction byproducts and obtain 4-amino-4'-fluorobenzophenone with higher purity before proceeding to step (3).
[0009] In step (3) of the above method, the molar ratio of 4-amino-4'-fluorobenzophenone to anhydrous hydrogen fluoride can be 1:5-1:40, specifically 1:25; The molar ratio of 4-amino-4'-fluorobenzophenone to sodium nitrite can be 1:1.0 to 1:1.1; The temperature of the diazotization reaction can be -5℃ to 20℃ (specifically (-2)℃ to 20℃), and the time can be 6 to 10 hours; The diazotization reaction is performed as follows: 4-amino-4'-fluorobenzophenone and anhydrous hydrogen fluoride are first stirred and reacted at 10-20°C for 3-5 hours, and then sodium nitrite is added and reacted at -5°C to -2°C for 3-5 hours.
[0010] The diazotization and pyrolysis reactions are carried out in a one-pot process, that is, the pyrolysis reaction is carried out directly after the diazotization reaction is completed without any post-processing. The reaction temperature of the pyrolysis reaction can be 10-60℃, and the reaction time can be 12-24 hours, specifically 14-24 hours; In step (3), no reaction solvent is added; instead, anhydrous hydrogen fluoride is used as the reaction solvent. Step (3) of the above method further includes the following operations: after the pyrolysis reaction is completed, the reaction system is cooled down, a solvent is added for extraction and separation, the upper layer is collected, the upper layer is washed and neutralized with water, the solvent is removed, distilled, and crystallized to purify the product. The solvent used for extraction can be selected from at least one of acetone, petroleum ether, xylene, and toluene.
[0011] This invention avoids the formation of isomers during the synthesis process, improves reaction selectivity, reduces the formation of 4-fluorobenzophenone impurities, improves product purity, and provides a guarantee for the quality of downstream polyether ether ketone products. Attached Figure Description
[0012] Figure 1 This is a reaction flow diagram of the present invention. Detailed Implementation
[0013] The present invention will now be described in further detail with reference to specific embodiments. The given embodiments are merely illustrative of the invention and not intended to limit its scope. The embodiments provided below can serve as a guide for further improvements by those skilled in the art and do not constitute a limitation on the invention in any way.
[0014] Unless otherwise specified, the experimental methods used in the following examples are conventional methods, performed according to the techniques or conditions described in the literature in this field or according to the product instructions. Unless otherwise specified, the materials and reagents used in the following examples are commercially available.
[0015] Example 1 Step S1: In a 3L three-necked reactor equipped with a stirrer, thermometer, and reflux condenser, 1540g (16.02mol) of fluorobenzene and 278.4g (1.50mol) of p-nitrobenzyl chloride were added sequentially. After stirring at room temperature until the solids were completely dissolved, 240.0g (1.80mol) of anhydrous aluminum chloride was slowly added, and the reaction began. The generated hydrogen chloride gas entered the gas absorption system. The temperature was initially raised to 70℃ and maintained for 8 hours. After cooling to room temperature, the reaction solution was distilled under reduced pressure until the system was completely evaporated. The resulting fraction was washed with acid and alkali, recrystallized, and dried to obtain 4-nitro-4'-fluorobenzophenone.
[0016] Examples 2-9 The operation was the same as in Example 1, with the feed ratio and reaction conditions shown in Table 1.
[0017] Comparative Example 1 The operation and feed amount of this comparative example are the same as those of Example 1, except for the reaction temperature and reaction time. In Comparative Example 1, the temperature was raised to 15°C and kept at that temperature for 10 hours.
[0018] Comparative Example 2 Compared with other examples, the feed ratio of p-nitrobenzoyl chloride to anhydrous aluminum chloride in this comparative example is 1:1, and the temperature is raised to 50°C and kept at that temperature for 10 hours.
[0019] Table 1 Comparison of data from examples with different feed ratios and reaction temperatures in step S1
[0020] Table 1 shows that the feed ratio of each material and the reaction temperature in reaction step S1 have a significant impact on the product yield of this step. When the amount of fluorobenzene, which is both a reactant and a solvent, is too small or too large, the yield will decrease due to either vigorous reaction, increased side reactions, or a slower reaction rate. When the amount of anhydrous chlorine trichloride catalyst is too small (compared to Example 1 in Example 5), the amount of catalyst is insufficient due to the formation of complexes, resulting in a decrease in yield. When the amount is too large (compared to Example 1 in Example 6), the difficulty of post-processing increases. When the reaction temperature is too low (compared to Example 1 in Examples 7, 8, and Comparative Example 1), the reaction is slow and incomplete, and the accumulation of intermediates leads to a sharp drop in yield. When the temperature is too high (compared to Example 1 in Example 9), the reaction is vigorous, the amount of by-products increases, the difficulty of post-processing increases, and the yield decreases. Based on the above experimental results, Example 1 is the optimal process condition for S1, and the obtained 4-amino-4'-fluorobenzophenone (II) is used in step S2.
[0021] Example 10 Step S2: In a 3L three-necked reactor equipped with a stirrer, thermometer, and reflux condenser, 650g of water, 80.3g of ammonium chloride, and 84g of reduced iron powder were added sequentially. The temperature was raised to 95°C with stirring, and 245.2g of 4-nitro-4'-fluorobenzophenone was slowly added. The reaction was maintained at this temperature for 5 hours. After the reaction was completed, the temperature was lowered to room temperature. After extraction and separation with chloroform, the solvent was distilled off, and the resulting product was washed, recrystallized, and dried to obtain 4-amino-4'-fluorobenzophenone.
[0022] Examples 11-18 The operation was the same as in Example 10, with the feed ratio and reaction conditions shown in Table 2.
[0023] Comparative Example 3 This comparative example has a reduced amount of reduced iron powder compared to Example 10, while the operation and other parameters remain unchanged.
[0024] Comparative Example 4 The reaction temperature in this comparative example is lower than that in Example 10, while the operation and other parameters remain the same.
[0025] Comparative Example 5 Compared to Example 10, this comparative example involves a reduced amount of water, while the operation and other parameters remain unchanged.
[0026] Table 2 Comparison of data from examples with different feed ratios and reaction temperatures in step S2
[0027] As shown in Table 2, the ratio of each material added in step S2 is crucial to the reaction. The reaction temperature also determines the reaction time and product yield. When the amount of ammonium chloride is too small, the reaction rate is slow and incomplete (compared to Example 11 in Example 10), while too much (compared to Example 12 in Example 10) results in a violent reaction, wasting solvent and increasing costs. The amount of iron powder directly affects the product yield. Too little iron powder leads to incomplete reaction (compared to Example 13 and Comparative Example 3 in Example 10), resulting in intermediate accumulation, increased byproducts, and decreased yield. Excessive iron powder (compared to Example 14 in Example 10) increases the difficulty of post-processing and increases costs. Too much water in the reaction system (compared to Example 16 in Example 10) or too little water (compared to Example 15 and Comparative Example 5 in Example 10) also affects the reaction yield. When the reaction temperature is too low (compared to Example 17 and Comparative Example 4 in Example 10), the reaction will be slow or even stop, resulting in a large amount of raw material remaining and a low yield, according to the reaction kinetics. When the temperature is too high (compared to Example 18 in Example 10), the byproducts will increase dramatically, and the yield and recovery rate will drop sharply. Based on the above experimental results, it is concluded that Example 10 is the optimal process condition for S2, and the obtained 4-amino-4'-fluorobenzophenone (II) is used in step S3.
[0028] Example 19 Step 3: Add 1160g of anhydrous hydrogen fluoride and 500g of 4-amino-4'-fluorobenzophenone to a 3L carbon steel reactor equipped with a stirrer, thermometer, and reflux condenser. Stir and react at 20℃ for 3 hours. Lower the temperature of the reactor to -2℃ and slowly add 164.5g of sodium nitrite. After diazotization for 3 hours, slowly raise the temperature to 50℃ for cracking reaction. After 14 hours, the reaction is complete. Cool to 30℃ and add solvent (petroleum ether) for extraction. After separation, wash the upper layer solution with water to neutralize, remove solvent by atmospheric distillation, distill the product under reduced pressure, and recrystallize to obtain 422.2g of white crystalline 4,4'-difluorobenzophenone, with a yield of 83.4% and a GC purity of 99.98%.
[0029] Examples 20-30 The operation was the same as in Example 19, with the feed ratio and reaction conditions shown in Table 3.
[0030] Comparative Example 6 The difference between this comparative example and Example 29 is that the pyrolysis temperature is increased to 65°C.
[0031] Comparative Example 7 The difference between this comparative example and Example 25 is that the diazotization reaction temperature is different; in Comparative Example 7, the diazotization reaction temperature is reduced to -8°C.
[0032] Table 3 Comparison of data from examples with different feed ratios and reaction temperatures in step S3
[0033] Note: Diazotization reaction refers to the reaction from the initial addition of anhydrous hydrogen fluoride to the completion of the reaction after the addition of sodium nitrite. As shown in Table 3, the amounts of anhydrous hydrogen fluoride and sodium nitrite in step S3 directly affect the yield and purity of the final product, 4,4'-difluorobenzophenone. When the amount of anhydrous hydrogen fluoride is too low (compared to Examples 25 and 27), the pyrolysis reaction is more intense, resulting in more byproducts and a lower yield. Conversely, when the amount of solvent (anhydrous hydrogen fluoride) is too high (compared to Examples 25 and 28), the reaction rate decreases, and the pyrolysis temperature is not reached, leading to a decrease in both the yield and purity of the product. When the amount of sodium nitrite is too low, the pyrolysis reaction time is shortened (Example 26), resulting in unreacted aromatic amines that react with diazonium salts to form byproducts. When the amount of sodium nitrite is excessive (compared to Examples 25 and 30), it promotes the decomposition and oxidation of diazonium salts, generating byproducts such as tar or nitro compounds. When the diazotization reaction temperature is too low (compared to Comparative Example 7 in Example 25), the reaction is slow and incomplete, ultimately affecting the product yield. When the pyrolysis temperature is too low (in Examples 22 and 31), the pyrolysis reaction is slow or even stops, causing a sharp drop in product yield. Conversely, when the pyrolysis temperature is too high (in Examples 29 and Comparative Example 6), side reactions increase, leading to a decrease in both yield and purity, while also increasing the tar content and making post-processing more difficult. With appropriate process conditions, a high-quality product with a purity exceeding 99.90% can be obtained.
[0034] The present invention has been described in detail above. Those skilled in the art will recognize that the invention can be practiced in a wide range of ways with equivalent parameters, concentrations, and conditions without departing from its spirit and scope, and without requiring unnecessary experiments. While specific embodiments have been provided, it should be understood that further modifications can be made to the invention. In summary, according to the principles of the invention, this application is intended to include any changes, uses, or improvements to the invention, including changes made using conventional techniques known in the art that depart from the scope disclosed herein.
Claims
1. A method for synthesizing 4,4'-difluorobenzophenone, comprising the following steps: (1) p-Nitrobenzoyl chloride reacts with aromatic fluorides in the presence of a catalyst to give 4-nitro-4'-fluorobenzophenone (I); (2) The 4-nitro-4'-fluorobenzophenone (I) obtained in step (1) undergoes a nitro reduction reaction to give 4-amino-4'-fluorobenzophenone (II). (3) The 4-amino-4'-fluorobenzophenone (II) obtained in step (2) undergoes a diazotization reaction with anhydrous hydrogen fluoride and sodium nitrite. After the reaction is completed, the temperature is raised to carry out a cracking reaction to obtain the product 4,4'-difluorobenzophenone (III).
2. The method according to claim 1, characterized in that, In step (1), the aromatic fluoride is fluorobenzene; The molar ratio of p-nitrobenzoyl chloride to the aromatic fluoride is 1:10-1:20; The catalyst is a Lewis acid, selected from at least one of aluminum chloride, ferric chloride, antimony chloride, and tin chloride; The molar ratio of p-nitrobenzoyl chloride to the catalyst is 1:1.1-1:2.
0.
3. The method according to claim 1, characterized in that, In step (1), the reaction temperature is 20-80℃ and the time is 6-10 hours.
4. The method according to claim 1, characterized in that, In step (2), the nitro reduction reaction is achieved by reacting 4-nitro-4'-fluorobenzophenone in the presence of water, ammonium chloride and reduced iron powder under heating conditions.
5. The method according to claim 4, characterized in that, The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to reduced iron powder is 1:1.1-1:3; The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to ammonium chloride is 1:1.1-1:3; The molar ratio of 4-nitro-4'-fluorobenzophenone (I) to water is 1:20-1:
40.
6. The method according to claim 4, characterized in that, The nitro reduction reaction is carried out at a temperature of 90-100℃ for 4-8 hours.
7. The method according to claim 1, characterized in that, In step (3), the molar ratio of 4-amino-4'-fluorobenzophenone to anhydrous hydrogen fluoride is 1:5-1:40; The molar ratio of 4-amino-4'-fluorobenzophenone to sodium nitrite is 1:1.0-1:1.
1.
8. The method according to claim 1, characterized in that, In step (3), the temperature of the diazotization reaction is -5℃ to 20℃, and the time is 6 to 10 hours.
9. The method according to claim 8, characterized in that, The diazotization reaction is performed as follows: 4-amino-4'-fluorobenzophenone and anhydrous hydrogen fluoride are first stirred and reacted at 10-20°C for 3-5 hours, and then sodium nitrite is added and reacted at -5°C to -2°C for 3-5 hours.
10. The method according to claim 1, characterized in that, In step (3), the reaction temperature of the pyrolysis reaction is 10-60℃ and the reaction time is 12-24 hours.