A method for preparing 4,4'-difluorobenzophenone with high selectivity based on a synergistic catalytic system

Abstract

The application discloses a high-selectivity 4,4'-difluorobenzophenone preparation method based on a synergistic catalytic system. In the method, halogenated benzene is used as raw material, a Lewis acid catalyst and an acidic cocatalyst are added, halogenated benzoyl chloride is added dropwise at a certain temperature, and 4,4'-dihalogenated benzophenone is obtained through post-treatment. In addition, in order to further improve the reaction efficiency, a non-ionic surfactant is further added to the reaction system. Through the "high-temperature synergistic catalysis" strategy, the application overturns the cognition that the traditional process must adopt low temperature (such as 0-5 DEG C) control selectivity, not only significantly improves the reaction rate, but also realizes the ultra-high selectivity (greater than or equal to 99.5%) of the target product, and effectively inhibits the side reactions such as polysubstitution and isomerization. At the same time, the introduction of the surfactant improves the mass transfer efficiency of the heterogeneous reaction system. The method has the advantages of mild conditions, extremely high selectivity, high production efficiency and easy industrial expansion.

Description

Technical Field

[0001] This invention relates to a highly selective method for preparing 4,4'-difluorobenzophenone based on a synergistic catalytic system, belonging to the field of fine organic synthesis chemistry. Background Technology

[0002] 4,4'-Difluorobenzophenone (DFBP) is an important pharmaceutical and pesticide intermediate, and a key monomer for high-performance engineering plastics such as polyetheretherketone (PEEK). Its mainstream synthetic route involves the Friedel-Crafts acylation reaction of fluorobenzene with p-fluorobenzoyl chloride under Lewis acid catalysis (primarily anhydrous aluminum trichloride, AlCl3).

[0003] However, traditional processes have significant drawbacks. The reaction temperature is critical. To prevent side reactions such as polyacylation and intramolecular cyclization (forming fluorooxanthraphenones) of the highly reactive p-fluorobenzoyl chloride, traditional literature and patents (such as CN102964203 A) generally require the reaction to be carried out at low temperatures (such as 0-5°C or even lower) to control reaction activity and selectivity. Low-temperature operation places high demands on equipment, consumes a lot of energy, and has a long reaction cycle. Meanwhile, even under low-temperature conditions, the selectivity of the target product often hovers around 97%-98.5%, struggling to break through the 99% threshold, leading to difficulties in product purification and limited yield. Furthermore, the reaction system is heterogeneous (AlCl3 is partially insoluble), limiting mass transfer and further affecting the reaction rate and catalyst utilization.

[0004] To improve the process, existing technologies often focus on catalyst substitution (such as using solid superacids or ionic liquids) or reactor design, but this often brings new problems such as high cost, short catalyst life, or complex equipment. CN113620819 A discloses a composite solid acid catalyst, but the reaction temperature still needs to be controlled within 0-30℃, and no significant breakthrough in selectivity has been observed.

[0005] Therefore, developing a new method for synthesizing 4,4'-difluorobenzophenone under milder and easier-to-operate medium- and high-temperature conditions with ultra-high selectivity and high efficiency is of great significance for reducing production costs and improving product quality. Summary of the Invention

[0006] Purpose of the Invention: The purpose of this invention is to provide a highly selective method for preparing 4,4'-difluorobenzophenone based on a synergistic catalytic system. This invention overcomes the shortcomings of 4,4'-difluorobenzophenone synthesis, which requires deep low temperatures and has limited selectivity. It provides a synthesis method that achieves ultra-high selectivity (≥99.5%) and high reaction rate at moderate temperatures (40-70℃) using a synergistic catalytic system. This solves the problems of harsh reaction temperatures, difficulty in achieving breakthroughs in selectivity, low mass transfer efficiency, and difficulty in product purification in existing technologies.

[0007] Technical solution: The highly selective 4,4'-difluorobenzophenone preparation method based on a synergistic catalytic system of the present invention includes the following steps: under an inert atmosphere, using halobenzene as raw material, a Lewis acid catalyst and an acidic co-catalyst are added, and halobenzoyl chloride is added dropwise at a certain temperature to react, followed by post-treatment to obtain 4,4'-difluorobenzophenone.

[0008] Furthermore, the acidic co-catalyst is selected from one or more of methanesulfonic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

[0009] Preferably, the acidic co-catalyst is either methanesulfonic acid or p-toluenesulfonic acid; wherein the p-toluenesulfonic acid includes anhydrous p-toluenesulfonic acid and its hydrate.

[0010] Furthermore, the Lewis acid catalyst is selected from one or more of aluminum trichloride, ferric trichloride, zinc chloride, titanium tetrachloride, tin tetrachloride, and boron trifluoride.

[0011] Preferably, the Lewis acid catalyst is aluminum trichloride.

[0012] Furthermore, the halobenzene is selected from any one of fluorobenzene, chlorobenzene, or bromobenzene; the halobenzoyl chloride is selected from any one of p-fluorobenzoyl chloride, p-chlorobenzoyl chloride, or p-bromobenzoyl chloride.

[0013] Preferably, the halobenzene is fluorobenzene, and the halobenzoyl chloride is p-fluorobenzoyl chloride.

[0014] Further, the molar ratio of the Lewis acid catalyst to the halobenzoyl chloride is (1.0-1.2):1; the molar ratio of the acidic co-catalyst to the halobenzoyl chloride is (0.05-0.20):1; and the molar ratio of the halobenzene to the halobenzoyl chloride is (3.0-6.0):1.

[0015] Furthermore, the reaction is carried out in the presence of a nonionic surfactant; the amount of the nonionic surfactant added is 0.1%-1.0% of the total mass of the reaction raw materials.

[0016] Furthermore, the reaction temperature is 40-70℃; the dropping time is 1-3 hours, and the dropping reaction time is 0.5-2 hours.

[0017] Preferably, the reaction temperature is 50-60°C.

[0018] Furthermore, the inert atmosphere is nitrogen.

[0019] Furthermore, the nonionic surfactant is selected from one or more of alkylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, and sorbitan fatty acid ester.

[0020] Preferably, the nonionic surfactant is selected from either OP-10 or Tween-80.

[0021] Further, the post-processing includes: quenching the reaction solution, separating the phases, washing the organic phase with water, washing with alkali, washing with water again until neutral, recovering excess fluorobenzene by vacuum distillation to obtain a crude product, and recrystallizing the crude product to obtain high-purity 4,4'-difluorobenzophenone.

[0022] Preferably, the highly selective 4,4'-difluorobenzophenone preparation method based on a synergistic catalytic system of the present invention includes the following steps: Under a nitrogen atmosphere, fluorobenzene (which also serves as a solvent), anhydrous aluminum trichloride catalyst, and a sulfonic acid co-catalyst are added to a reaction vessel and mixed thoroughly. The system is heated to 40-70°C. At this temperature, p-fluorobenzoyl chloride is slowly added dropwise. After the addition is complete, the reaction is maintained at this temperature for a period of time. After the reaction is completed, high-purity 4,4'-difluorobenzophenone is obtained through post-treatment steps such as quenching, separation, washing, distillation to recover fluorobenzene, and recrystallization.

[0023] The present invention describes a highly selective method for preparing 4,4'-difluorobenzophenone based on a synergistic catalytic system, which yields 4,4'-dihalobenzophenone.

[0024] The application of the 4,4'-dihalobenzophenone described in this invention in the preparation of polyether ether ketone or as a pharmaceutical or pesticide intermediate.

[0025] The key technical features of this invention are as follows: A synergistic catalytic system: A combination of AlCl3 and a sulfonic acid co-catalyst (preferably methanesulfonic acid (MSA) or p-toluenesulfonic acid (p-TsOH)). It was found that the addition of a small amount of sulfonic acid not only forms a stronger catalytically active center with AlCl3, but also effectively "passivates" overactivated sites in the reaction intermediates, thus guiding the reaction to produce 4,4'-difluorobenzophenone with extreme specificity even at higher temperatures, almost completely suppressing polysubstituted and isomerization side reactions. Furthermore, a breakthrough in reaction temperature is achieved, significantly increasing the reaction temperature from the traditional ≤5℃ to 40-70℃. This not only reduces energy consumption but also represents a leap in reaction kinetics, significantly accelerating the reaction rate and shortening the production cycle. Finally, surfactant enhancement: The addition of nonionic surfactants (such as OP-10 and Tween-80) greatly improves the emulsification state of the heterogeneous reaction system, increasing the contact area between the AlCl3 catalyst and the organic raw materials, thereby simultaneously improving the reaction rate and final conversion rate, allowing the AlCl3 dosage to approach the theoretical lower limit.

[0026] The reaction mechanism of this invention is as follows: Anhydrous AlCl3 is used as the Friedel-Crafts main catalyst, which coordinates with p-fluorobenzoyl chloride to generate an acyl cationic active intermediate [RCO]. +AlCl4 - The fluorobenzene aromatic ring is attacked, and electrophilic substitution occurs to generate a 4,4'-difluorobenzophenone-AlCl3 complex. Traditional processes rely solely on AlCl3 catalysis, and low temperatures (0~5°C) are used to suppress side reactions (fluorobenzene self-polymerization, multiple substitution, and isomerization). However, the reaction rate is slow, and AlCl3 agglomeration leads to localized overheating.

[0027] This invention introduces sulfonic acid co-catalysts (such as methanesulfonic acid MSA or p-toluenesulfonic acid p-TsOH) to form an AlCl3 / ArSO3H synergistic catalytic system. The synergistic mechanism is as follows: (1) Promoting the dissociation of complexes: The Brønsted acidic sites of sulfonic acids can promote the dissociation of AlCl4. - The dissociation / displacement of the product complex releases more free AlCl3 to participate in the next catalytic cycle, reducing the actual demand for AlCl3 (10%~20% less than the traditional process) and accelerating the reaction process. (2) Inhibition of hydrolysis deactivation: Sulfonate can combine with trace amounts of water in the system to inhibit the hydrolysis deactivation of AlCl3, maintain the stability of catalytic activity, and allow the reaction to proceed smoothly at higher temperatures. (3) Mass transfer enhancement: The introduction of nonionic surfactants (such as OP-10) can reduce the interfacial tension of the fluorobenzene / p-fluorobenzoyl chloride / AlCl3 three-phase system, improve the mass transfer efficiency of the heterogeneous system, make the acyl chloride drop rate uniform, and remove the heat of reaction in time, avoiding side reactions caused by local overheating. The above synergistic effect allows the reaction to proceed smoothly at medium and high temperature conditions of 40~70°C (preferably 50~60°C) without side reactions, overturning the long-standing technical prejudice in this field that "selectivity must be controlled at low temperature".

[0028] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0029] (1) Ultra-high selectivity: At 50-60℃, the product selectivity can stably reach more than 99.5%, and even 99.8%, which is far higher than the traditional low temperature process (about 98%). This greatly simplifies the subsequent purification process and improves the product yield and purity. The preparation method is simple, the product has high purity and high yield, and there is no need for complicated low temperature equipment and lengthy purification process.

[0030] (2) Mild and efficient reaction conditions: It eliminates the need for deep freezing and can react efficiently at moderate temperatures. It has low equipment requirements, significantly reduces energy consumption, shortens reaction time by 30%-50%, and significantly improves production efficiency.

[0031] (3) Significant synergistic effect: The synergistic effect of AlCl3 and sulfonic acid achieves the effect of "1+1>2", and a qualitative leap in selectivity and temperature increase can be achieved with a small amount of sulfonic acid cost.

[0032] (4) Strong process adaptability: It is compatible with traditional equipment, and existing equipment can be upgraded and transformed by simply adding additives, making it easy to promote industrialization.

[0033] (6) Excellent product quality: The obtained product is a white needle-like crystal with a melting point of 107~108°C and a GC purity of ≥99.7%, which meets the strict requirements of PEEK grade raw materials.

[0034] (7) The products prepared by the method of the present invention have broad application prospects in the fields of high-performance engineering plastics such as polyether ether ketone, medicine and pesticides. Attached Figure Description

[0035] Figure 1 The graph shows the selectivity comparison between the method of the present invention and the conventional method of Comparative Example 1 at different reaction temperatures.

[0036] Figure 2 The ¹H-NMR spectrum of 4,4'-difluorobenzophenone obtained in Example 1 of this invention;

[0037] Figure 3 This is the GC chromatogram of 4,4'-difluorobenzophenone obtained in Example 1 of the present invention. Detailed Implementation

[0038] The technical solution of the present invention will be further described below with reference to the accompanying drawings. Unless otherwise specified, the experimental methods in the following embodiments are conventional methods, and the experimental materials used in the following embodiments are all obtainable through conventional commercial channels.

[0039] GC analysis conditions: An Agilent 7890B gas chromatograph equipped with a flame ionization detector (FID) and an HP-5 capillary column (30 m × 0.32 mm × 0.25 μm) was used. High-purity nitrogen was used as the carrier gas at a flow rate of 1.0 mL / min. The column temperature was 170℃ (isothermal) or programmed: initial temperature 50℃, held for 2 min, then increased to 250℃ at a rate of 10℃ / min and held for 5 min. The vaporization chamber temperature was 250℃, and the detector temperature was 260℃. The injection volume was 0.2 μL, with a split ratio of 20:1. The hydrogen flow rate was 30 mL / min, and the air flow rate was 300 mL / min.

[0040] Example 1

[0041] (1) In a 500 mL four-necked flask equipped with a stirrer, thermometer, dropping funnel, and condenser, under nitrogen protection, 219 g (2.28 mol) of fluorobenzene, 133.2 g (1.0 mol) of anhydrous aluminum trichloride, and 9.6 g (0.1 mol) of methanesulfonic acid (MSA) were added. The stirrer was turned on at 300 rpm, and the mixture was heated to 55 °C in an oil bath to ensure homogeneity. At this temperature, 158.5 g (1.0 mol) of p-fluorobenzoyl chloride was slowly added dropwise over 2 hours using a constant-pressure dropping funnel. During the addition, the internal temperature was controlled at 55 ± 2 °C. After the addition was completed, the mixture was stirred and kept at 55 °C for 1 hour. GC monitoring showed that the conversion rate of p-fluorobenzoyl chloride from the starting material was >99.8%.

[0042] (2) Cool the reaction solution from step (1) to room temperature, and while stirring, carefully pour it into a mixture of 500g crushed ice and 200mL 5% hydrochloric acid to quench the reaction. Allow it to stand and separate the layers, separating the organic phase. Wash the organic phase sequentially with 100mL water, 100mL 5% sodium bicarbonate solution, and 100mL water until neutral. After drying the organic phase with anhydrous sodium sulfate, first recover excess fluorobenzene by atmospheric distillation, and then distill under reduced pressure to obtain a pale yellow crude solid. Recrystallize the crude product from ethanol to obtain 232.5g of white needle-like crystals of 4,4'-difluorobenzophenone. See also Figure 3 GC analysis showed a purity of 99.80%. The separation yield, based on p-fluorobenzoyl chloride, was 96.0%; it consisted of white needle-like crystals with a melting point of 107.2℃.

[0043] See Figure 2 The analysis shows the ¹H-NMR spectrum of 4,4'-difluorobenzophenone obtained in Example 1 of this invention.

[0044] Example 2

[0045] Example 2 was prepared using the same method as Example 1 for the preparation of 4,4'-difluorobenzophenone, except that the methanesulfonic acid in step (1) was replaced with p-toluenesulfonic acid monohydrate (19.0 g, 0.1 mol). After the addition was complete, the reaction was maintained at this temperature for 1.5 hours. 229.8 g of 4,4'-difluorobenzophenone was obtained, with a GC purity of 99.76% and a yield of 94.9%; it was a white needle-like crystal with a melting point of 107.3 °C.

[0046] Example 3

[0047] The preparation method of 4,4'-difluorobenzophenone in Example 3 is the same as that in Example 1, except that in step (1), 1.5 g of dodecylphenol polyoxyethylene ether (OP-10, accounting for about 0.4% of the total mass of the feed) is added simultaneously with the addition of methanesulfonic acid. After the addition is completed, the reaction is kept at a constant temperature for 0.5 hours to obtain 233.8 g of 4,4'-difluorobenzophenone with a purity of 99.83% and a yield of 96.5%. The reaction time is shorter than that in Example 1. The 4,4'-difluorobenzophenone is a white needle-like crystal with a melting point of 107.5 °C.

[0048] Example 4

[0049] The preparation method of 4,4'-difluorobenzophenone in Example 4 is the same as that in Example 1, except that in step (1), the oil bath is heated to 60°C, and after the drop addition is completed, the reaction is kept at the temperature for 0.5 hours; 230.1g of 4,4'-difluorobenzophenone is obtained with a purity of 99.78% and a yield of 95.0%; it is a white needle-like crystal with a melting point of 107.4°C.

[0050] Comparative Example 1

[0051] The operating conditions were based on traditional literature (An In-depth Technical Guide to 4,4'-Difluorobenzophenone: Chemical Properties and Structure or Synthesis Study of Branched Polyether-Ether-Ketone Terpolymers, Dalian University of Technology,

[2013] ): p-fluorobenzoyl chloride (1.0 mol) was added dropwise to a mixture of 219 g of fluorobenzene and 146.6 g of anhydrous AlCl3 (1.1 mol) over 3 hours in an ice-salt bath at 0-5°C, followed by stirring at 0-5°C for 2 hours. Post-treatment was the same as in Example 1. 218.5 g of product was obtained, with a GC purity of 98.50% (main impurities were isomers and a small amount of multi-substituted products), yielding 90.2%; white needle-like crystals with a melting point of 107.6°C.

[0052] Comparative Example 2

[0053] The preparation method is the same as that used in Example 1 for preparing 4,4'-difluorobenzophenone, except that methanesulfonic acid is not added in step (1).

[0054] During the dropwise addition, the system color was observed to darken rapidly. After the reaction was complete, GC showed that the product was complex, the purity of the target product was only 95.2%, the yield was significantly reduced, and the melting point was 107.4℃.

[0055] Table 1 shows the comparison results of the synthesis processes of methyl 4-methoxyphenylacetic acid under different reaction conditions in Examples 1-4 and Comparative Examples 1-2.

[0056] Table 1. Comparison of methyl 4-methoxyphenylacetic acid synthesis processes under different reaction conditions

[0057]

[0058] As analyzed in Table 1, the introduction of sulfonic acid co-catalysts is the core of the breakthrough optimization of reaction conditions in this invention. In the four examples, at a mild temperature of 55–60°C, GC purity of 99.76–99.83% and separation yield of 94.9–96.5% were obtained in just 2.5–3.5 hours. This indicates that in the presence of sulfonic acid co-catalysts, the product selectivity of this invention can stably reach over 99.5%, and even 99.8%, at 50–60°C, fully verifying the effect of this invention in liberating the highly selective reaction from the "low-temperature forbidden zone" to the "medium-high temperature range." In Example 3, a combination of methanesulfonic acid and OP-10 was used as a catalyst, achieving a maximum purity of 99.83% and a maximum yield of 96.5% in 2.5 hours at 55°C. This further demonstrates that the addition of nonionic surfactants can further optimize reaction efficiency, indicating a significant synergistic effect between OP-10 and methanesulfonic acid, which can further accelerate the reaction and suppress side reactions, achieving a "1+1>2" effect.

[0059] In contrast, Comparative Example 1, using a traditional low-temperature (0–5℃) process, had a reaction time of up to 5 hours without a catalyst, with a purity of only 98.50% and a yield of 90.2%, demonstrating the inefficiency and lack of selectivity of the traditional method. Comparative Example 2, using no sulfonic acid catalyst at 55℃, saw its purity plummet to 95.2% and its yield extremely low, indicating that simply increasing the temperature without a catalyst would exacerbate side reactions. This further confirms the irreplaceable role of sulfonic acid co-catalyst in this reaction system and highlights the necessity of the synergistic effect between AlCl3 and sulfonic acid.

[0060] Furthermore, comparing Example 1 (methanesulfonic acid, 55°C, 3h) and Example 2 (p-toluenesulfonic acid, 55°C, 3.5h), it can be seen that methanesulfonic acid, due to its smaller molecule and stronger acidity, has a slightly better catalytic efficiency than p-toluenesulfonic acid, shortening the reaction time by 0.5h and increasing the yield from 95.4% to 96.5%. In Example 4, the temperature was increased from 55°C to 60°C. Although the reaction time was shortened by 0.5 hours, the yield decreased from 96.5% to 95.5%, indicating that the reaction is close to the optimal thermodynamic window around 55°C. Further heating has limited effect on the rate increase and is not conducive to maintaining the yield. Therefore, 55°C is the better reaction temperature.

[0061] In summary, the conditions in Example 3 represent the optimal process, with the reaction time shortened by 50% compared to Comparative Example 1, and the GC purity increased from 98.50% to 99.83%, achieving a GC purity ≥99.7%. Furthermore, the products obtained in Examples 1-4 are white needle-like crystals with a melting point of 107-108°C and a GC purity ≥99.7%, meeting the stringent requirements for polyaryletherketone (PEEK) raw materials. This provides a high-quality raw material guarantee for applications in high-performance engineering plastics, pharmaceuticals, and pesticides such as PEEK.

[0062] This invention successfully liberates highly selective reactions from the "low-temperature forbidden zone" to the "medium- and high-temperature range" by introducing a synergistic catalytic system constructed using sulfonic acid co-catalysts, achieving a breakthrough improvement in selectivity. The addition of nonionic surfactants further optimizes reaction efficiency. This invention features advanced technology, significant effects, and broad prospects for industrial application.

Claims

1. A highly selective method for preparing 4,4'-difluorobenzophenone based on a synergistic catalytic system, characterized in that, Includes the following steps: Under an inert atmosphere, 4,4'-difluorobenzophenone was obtained by adding halobenzene as a raw material, along with Lewis acid catalyst and acidic co-catalyst, and reacting it with halobenzoyl chloride dropwise at a certain temperature, followed by post-treatment.

2. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The acidic co-catalyst is selected from one or more of methanesulfonic acid, p-toluenesulfonic acid, or trifluoromethanesulfonic acid.

3. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The Lewis acid catalyst is selected from one or more of aluminum trichloride, ferric trichloride, zinc chloride, titanium tetrachloride, tin tetrachloride, and boron trifluoride.

4. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The halobenzene is selected from any one of fluorobenzene, chlorobenzene, or bromobenzene; the halobenzoyl chloride is selected from any one of p-fluorobenzoyl chloride, p-chlorobenzoyl chloride, or p-bromobenzoyl chloride.

5. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The molar ratio of the Lewis acid catalyst to the benzoyl halide is (1.0-1.2):1; the molar ratio of the acidic co-catalyst to the benzoyl halide is (0.05-0.20):1; and the molar ratio of the benzoyl halide to the benzoyl halide is (3.0-6.0):

1.

6. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The reaction temperature is 40-70℃; the dropping time is 1-3 hours, and the dropping reaction time is 0.5-2 hours.

7. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The reaction is also carried out in the presence of a nonionic surfactant.

8. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 7, wherein the nonionic surfactant is selected from one or more of alkylphenol polyoxyethylene ether, fatty alcohol polyoxyethylene ether, and sorbitan fatty acid ester.

9. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 7, characterized in that, The amount of nonionic surfactant added is 0.1%-1.0% of the total mass of the reaction raw materials.

10. The method for preparing highly selective 4,4'-difluorobenzophenone based on a synergistic catalytic system according to claim 1, characterized in that, The post-processing includes: quenching the reaction solution, separating the phases, washing the organic phase with water, washing with alkali, washing with water again until neutral, recovering excess fluorobenzene by vacuum distillation to obtain a crude product, and recrystallizing the crude product to obtain 4,4'-difluorobenzophenone.

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