Preparation method of 4, 4 '-difluorobenzophenone

Abstract

The invention provides a preparation method of 4, 4 '-difluorobenzophenone, which comprises the following steps: uniformly mixing carbon tetrachloride and lewis acid, adding fluorobenzene in an inert gas atmosphere at-30-25 DEG C, stirring and reacting for 8-24 hours, and post-treating the obtained reaction liquid to obtain the 4, 4'-difluorobenzophenone, the method is simple in reaction process, mild in condition and convenient to operate, a high-risk strong oxidant is not needed in the whole reaction process, strong acid with strong irritation and corrosivity is prevented from being used, generation of pollution gas is reduced, the synthesis efficiency is high, and the total yield reaches up to 93%.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical and chemical intermediate synthesis technology, specifically to a novel method for synthesizing 4,4′-difluorobenzophenone using fluorobenzene and carbon tetrachloride as starting materials. Background Technology

[0002] PEEK (polyetheretherketone), as an outstanding representative of specialty engineering plastics, achieves an excellent balance between rigidity and toughness. Compared to metal materials, it not only possesses superior specific strength but also, due to its lightweight characteristics, precisely aligns with the lightweight development trend of "replacing steel with plastics" and energy conservation and emission reduction in industries such as automotive. The superior comprehensive performance of PEEK materials is the fundamental reason for its widespread application. It combines heat resistance, wear resistance, fatigue resistance, creep resistance, and dimensional stability, while also exhibiting excellent performance in chemical resistance, radiation resistance, peel resistance, and flame retardancy, and is non-toxic and environmentally friendly. With these properties, PEEK has become an indispensable key material in high-demand fields such as electronics, aerospace, automotive manufacturing, energy industry, and medical health. As the core raw material of high-performance engineering plastic polyetheretherketone (PEEK), 4,4'-difluorobenzophenone (DFBP) is a crucial fluorinated fine chemical. The widespread application of PEEK materials in cutting-edge fields such as aerospace, electronics, and biomedicine has established DFBP's important market position. Currently, the industrial synthesis of DFBP mainly relies on Friedel-Crafts acylation and diazotization oxidation methods; however, these methods urgently need optimization in terms of efficiency, environmental friendliness, and cost. Therefore, studying the synthesis of its key intermediate, 4,4'-difluorobenzophenone (DFBP), not only has theoretical research value but also certain economic benefits.

[0003] The structural formula of 4,4′-difluorobenzophenone (DFBP) is shown in formula (I):

[0004] Prior to this invention, the main synthetic methods for 4,4′-difluorobenzophenone (I) were as follows: 1) In 2016, patent CN106045828B reported a synthetic route using fluorobenzene and p-fluorotrichlorobenzene as raw materials, undergoing a Friedel-Crafts acylation reaction catalyzed by aluminum chloride to obtain an intermediate, followed by hydrolysis to yield 4,4′-difluorobenzophenone. The synthetic route is as follows:

[0005] This route consists of two steps. The synthesis of the intermediate in the first step is difficult, and the hydrolysis temperature in the second step is too high, resulting in high energy consumption. Patent CN115925525A reports a method using fluorobenzoic acid, p-fluorotrichlorobenzyl, and fluorobenzene as raw materials, with fluorobenzene as a solvent, and raising the temperature under the catalysis of alumina to obtain 4,4′-difluorobenzophenone. This route is difficult to control and has a low yield.

[0006] 2) Patent CN 106008182A discloses a method for preparing white, flake-like 4,4′-difluorobenzophenone (DFBP) from 4,4′-diaminodiphenylmethane via a three-step reaction involving diazotization, thermal decomposition, and oxidation. The core advantage of this route is its ability to achieve benzene ring fluorination in one step, resulting in fewer steps, higher purity, and higher yield. However, this process also has significant drawbacks: the diazotization reaction is violently exothermic, and the intermediate heavy nitrogen salt is explosive, requiring extremely high process control; simultaneously, the use of large amounts of concentrated acid causes severe equipment corrosion and a harsh operating environment. Therefore, the process still needs significant improvement in terms of safety and operability. The synthetic route is as follows:

[0007] 3) Patent JP61221146 uses fluorobenzene as a raw material and performs a carbonylation reaction with carbon monoxide in an air atmosphere under the action of a PdCl2 and FeCl3 composite catalyst to prepare 4,4′-difluorobenzophenone. Although this route provides a direct synthetic path, its industrialization potential is affected by several limiting factors: firstly, it relies on expensive Pd catalysts, resulting in high production costs; secondly, the reaction conditions (temperature, pressure) are relatively harsh, requiring high standards for equipment and control systems; and thirdly, the chloride components in the catalytic system are prone to causing equipment corrosion problems. Therefore, from an economic and engineering perspective, the practicality of this process route needs further evaluation and optimization. The synthetic route is as follows:

[0008] 4) Patent CN104610035A describes a process for synthesizing 4,4′-difluorobenzophenone from p-fluorotoluene via a multi-step reaction. This route first utilizes HBr catalysis... p-Fluorotoluene is oxidized to p-fluorobenzoic acid; subsequently, this intermediate reacts with phosgene to generate p-fluorobenzoyl chloride; finally, it is further processed using Lewis acid catalyst AlC. Under the influence of phosgene, a Friedel-Crafts acylation condensation reaction occurs with fluorobenzene to yield the target product. While this synthetic strategy can construct the target molecule, its industrial application faces significant challenges: the reaction steps are lengthy, involving multiple reaction conditions, leading to complex process control and potential for fluctuations in final product quality due to accumulated deviations. Furthermore, a key drawback of this process is the use of highly toxic and hazardous phosgene as the acyl chloride reagent, imposing extremely high requirements on the safety protection of production facilities, waste treatment, and environmental compatibility, posing significant safety and environmental hazards. The synthetic route is as follows: Summary of the Invention

[0009] In view of the above-mentioned problems in the existing technology, the present invention aims to provide a new method for synthesizing 4,4′-difluorobenzophenone that is highly operable, has fewer steps, and is suitable for industrial production.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a method for preparing 4,4′-difluorobenzophenone as shown in formula (I).

[0011] The preparation method is characterized by the following steps: Carbon tetrachloride and Lewis acid are mixed evenly, and fluorobenzene is added under an inert gas atmosphere at -30 to 25 °C (preferably -10 to 0 °C) and the mixture is stirred for 8 to 24 hours. The resulting reaction solution is then post-treated to obtain the 4,4′-difluorobenzophenone. The molar ratio of fluorobenzene, carbon tetrachloride and Lewis acid is 1:1 to 2.0:0.5 to 2.

[0012] Further, the post-processing is as follows: ice water is added to the reaction solution and heated to 100°C and refluxed for 1 hour. After cooling, dichloromethane is added for extraction. The extract is concentrated under reduced pressure to obtain a crude product. The crude product is cooled, filtered, and recrystallized to obtain the 4,4′-difluorobenzophenone.

[0013] Furthermore, the Lewis acid is aluminum trichloride, [Et3NH][AlCl3], [Et3NH][Al2Cl7], [Et3NH][FeCl3] or [Et3NH][ZnCl3]; (preferably [Et3NH][Al2Cl7]).

[0014] Furthermore, the volume ratio of the ice-water mixture to the reaction solution is 1 to 1.5:1.

[0015] Furthermore, the molar ratio of the fluorobenzene, carbon tetrachloride and Lewis acid is 1:1 to 2:1 to 2 (more preferably 1:2:1).

[0016] Furthermore, the reaction temperature is -10~0 ℃, and the reaction time is 8-12 hours.

[0017] Furthermore, the inert gas is nitrogen.

[0018] Furthermore, the preparation method includes the following steps: Carbon tetrachloride and [Et3NH][Al2Cl7] were mixed evenly, and fluorobenzene was added under a nitrogen atmosphere at -10-0 °C and the mixture was stirred for 12 hours. The resulting reaction solution was then heated to 100 °C and refluxed for 1 hour after adding ice water. After cooling, dichloromethane was added for extraction. The extract was concentrated under reduced pressure to obtain a crude product. The crude product was cooled, filtered, and recrystallized to obtain the 4,4′-difluorobenzophenone. The molar ratio of fluorobenzene, carbon tetrachloride, and Lewis acid was 1:2:1.

[0019] The beneficial effects of this invention are as follows: 1. Using inexpensive and readily available fluorobenzene and carbon tetrachloride as starting materials, 4,4′-difluorobenzophenone can be prepared in a one-pot process without the need for separation and purification of intermediates. This route is innovative.

[0020] 2. The reaction process is simple, the conditions are mild, and the operation is convenient. Moreover, the entire reaction process does not require highly dangerous strong oxidants, avoids the use of strong acids with strong irritation and corrosiveness, and reduces the generation of polluting gases. Its synthesis efficiency is high, with a total yield of up to 93%.

[0021] 3. This process uses green and environmentally friendly ionic liquids as catalysts, which has good economic and environmental benefits. Detailed Implementation

[0022] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto.

[0023] Example 1: Preparation of [Et3NH][Al2Cl7]

[0024] Reference for the preparation of Lewis acids Catalysis Communications , 2008, 9(6): 1173-1177, Taking [Et3NH][Al2Cl7] as an example, the specific preparation steps are as follows: Under nitrogen atmosphere, take a 100 mL single-necked flask, add triethylamine hydrochloride (13.3 g, 0.1 mol) and anhydrous aluminum trichloride (26.7 g, 0.2 mol), and heat and mix in a magnetically stirred oil bath at 60~75 °C for 4~6 h. The resulting brown transparent liquid is the [Et3NH][Al2Cl7] ionic liquid (31.2 g, yield 88%).

[0025] Example 2: Preparation of 4,4′-difluorobenzophenone

[0026] In a 250 mL single-necked flask, carbon tetrachloride (120 mmol, 18.5 g) and [Et3NH][Al2Cl7] ionic liquid (60 mmol, 24.3 g) were added. The catalyst ([Et3NH][Al2Cl7]) was uniformly dispersed in the carbon tetrachloride by stirring. Nitrogen gas was purged, and the reaction solution was cooled to -10 to 0 °C in a low-temperature reaction bath. Fluorobenzene (60 mmol, 5.8 g) was added to the system, and the reaction was stirred for 12 h. After the reaction was complete, 30 mL of ice water was poured into 25 mL of the mixture and the mixture was heated to 100 °C and refluxed for 1 h. After cooling, the mixture was extracted with dichloromethane, and the dichloromethane was recovered by concentration under reduced pressure to obtain a crude product. The crude product was cooled, filtered, and recrystallized (using ethanol:water = 9:1 solvent) to obtain 4,4′-difluorobenzophenone (20.3 g, yield 93%, melting point 106 °C).

[0027] Spectral characterization of compound (Ⅰ): 1 H -NMR (400 MHz, CDCl3) δ 7.81 (dd, J = 8.7, 5.5 Hz, 4H), 7.16 (t, J= 8.6 Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 193.73, 165.40 (d, J C-F = 254.3 Hz), 133.74 (d, J C-F = 3.1 Hz), 132.47 (d, J C-F = 9.2 Hz), 115.54 (d, J C-F = 21.9Hz). 19 F NMR (376 MHz, CDCl3) δ -103.61.

[0028] Examples 3 to 26: The preparation of 4,4′-difluorobenzophenone was carried out by repeating the preparation method of Example 2 in each embodiment, except that certain reaction conditions were changed (such as the type of Lewis acid, fluorobenzene, the molar ratio of carbon tetrachloride to Lewis acid, and the reaction temperature). The specific changes in reaction conditions and the corresponding reaction effects in each embodiment are shown in Table 1 below.

[0029] Table 1

[0030] Referring to Table 1, in Examples 3, 4, 5, 6, and 7, the changed reaction conditions were all the same: the type of catalyst. In Examples 8 to 13, the changed reaction conditions were the molar ratio of fluorobenzene, carbon tetrachloride, and catalyst. In Examples 12, 13, 14, 15, and 16, the changed reaction conditions were the reaction temperature and time. The data in the table shows that different Lewis acids have a certain impact on the reaction effect. For example, in Examples 3 and 7, [Et3NH][Al2Cl7] showed the best effect. A suitable temperature is beneficial to improving the reaction yield; too low a reaction temperature will affect the reaction yield. In Examples 17 to 20, the changed reaction condition was the amount of ice water added. The optimal reaction conditions were: a reaction temperature of -10 to 0℃, [Et3NH][Al2Cl7] as the catalyst, a feed ratio of n(fluorobenzene):n(carbon tetrachloride):n(Lewis acid) = 1:2:1, a volume ratio of ice water mixture to reaction liquid of 1 to 1.5:1, and a reaction time of 12 h.

[0031] The contents described in this specification are merely an enumeration of the implementation forms of the inventive concept, and the scope of protection of this invention should not be regarded as limited to the specific forms described in the embodiments.

Claims

1. A method for preparing 4,4′-difluorobenzophenone as shown in formula (Ⅰ), Its features are, The preparation method steps are as follows: Carbon tetrachloride and Lewis acid are mixed evenly, and fluorobenzene is added under an inert gas atmosphere at -30 to 25 °C and the mixture is stirred for 8 to 24 hours. The resulting reaction solution is then post-treated to obtain the 4,4′-difluorobenzophenone. The molar ratio of fluorobenzene, carbon tetrachloride and Lewis acid is 1:1 to 2.0:0.5 to 2.

2. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The post-processing is as follows: ice water is added to the reaction solution and heated to 100°C and refluxed for 1 hour. After cooling, dichloromethane is added for extraction. The extract is concentrated under reduced pressure to obtain a crude product. The crude product is cooled, filtered, and recrystallized to obtain the 4,4′-difluorobenzophenone.

3. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The Lewis acid is aluminum trichloride, [Et3NH][AlCl3], [Et3NH][Al2Cl7], [Et3NH][FeCl3] or [Et3NH][ZnCl3].

4. The method for preparing 4,4′-difluorobenzophenone as described in claim 2, characterized in that, The volume ratio of the ice-water mixture to the reaction solution is 1~1.5:

1.

5. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The molar ratio of the fluorobenzene, carbon tetrachloride, and Lewis acid is 1:1~2:1~2.

6. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The reaction temperature is -10~0 ℃, and the reaction time is 8-12 hours.

7. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The inert gas mentioned is nitrogen.

8. The method for preparing 4,4′-difluorobenzophenone as described in claim 1, characterized in that, The preparation method steps are as follows: Carbon tetrachloride and [Et3NH][Al2Cl7] were mixed evenly, and fluorobenzene was added under a nitrogen atmosphere at -10-0 °C and the mixture was stirred for 12 hours. Ice water was added to the resulting reaction solution and the mixture was heated to 100 °C and refluxed for 1 hour. After cooling, dichloromethane was added for extraction. The extract was concentrated under reduced pressure to obtain a crude product. The crude product was cooled, filtered, and recrystallized to obtain the 4,4′-difluorobenzophenone. The molar ratio of fluorobenzene, carbon tetrachloride, and Lewis acid was 1:2:1.

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