Green synthesis method of 4, 4 '-difluorobenzophenone

Abstract

The invention relates to the technical field of compound synthesis, in particular to a green synthesis method of 4, 4 '-difluorobenzophenone, which comprises the following steps of: under the action of a supported catalyst, uniformly mixing fluorobenzene and p-fluorobenzoyl chloride, then carrying out Friedel-Crafts acylation reaction, and purifying to obtain the 4, 4'-difluorobenzophenone, a carrier of the supported catalyst is gamma-aluminum oxide and / or silicon dioxide, and an active component supported on the carrier is a chlorine-containing metal compound; according to the process, fluorobenzene and p-fluorobenzoyl chloride are used as raw materials, a supported catalyst is adopted, and Friedel-Crafts acylation reaction is performed to synthesize the 4, 4 '-difluorobenzene. The supported catalyst provided by the invention has the advantages of stable catalytic efficiency, reusability, no generation of aluminum salt wastewater after the reaction, greenness, environmental protection, high product yield and high purity, and meets the requirements of modern chemical industry.

Description

Technical Field

[0001] The invention relates to the technical field of compound synthesis, and in particular to a green synthesis method of 4,4'-difluorobenzophenone. Background Art

[0002] As an important fine chemical intermediate, 4,4'-difluorobenzophenone is mainly used in the synthesis of medicines and as a synthetic monomer for new special engineering plastics. The pharmaceutical industry uses 4,4'-difluorobenzophenone as a pharmaceutical intermediate, mainly for the production of the potent cerebral vasodilator flunarizine and the new drug for the treatment of Alzheimer's disease, amitrizine rhobaxin tablets. In the special engineering plastics industry, 4,4'-difluorobenzophenone is the main monomer for the synthesis of the new aromatic thermoplastic engineering plastic polyetheretherketone. Therefore, the market demand for 4,4'-difluorobenzophenone will continue to expand.

[0003] There are many methods for synthesizing 4,4'-difluorobenzophenone, the most common ones are halogen exchange, catalytic carbonylation, catalytic acylation, dichloroethylene oxidation, Friedel-Crafts alkylation, diazotization, etc. Currently, only diazotization and Friedel-Crafts acylation are used for industrial production. Patent CN106045828B uses 4-fluorobenzotrichloride to react with fluorobenzene in the presence of aluminum chloride for acylation, followed by hydrolysis to obtain 4,4'-difluorobenzophenone; Patent CN111440058A uses thionyl chloride and hydrogen peroxide as catalysts to oxidize 4-fluorobenzaldehyde to 4-fluorobenzoyl chloride, and simultaneously generates thionyl chloride which is oxidized to sulfurous acid by hydrogen peroxide as a catalyst for the next step, and then uses fluorobenzene and 4-fluorobenzoyl chloride to react with acylation in the presence of sulfurous acid to obtain 4,4'-difluorobenzophenone; Patent CN106008182A uses 4,4'-diaminodiphenylmethane as a raw material, and undergoes diazotization with sodium nitrite and fluoroboric acid, and then undergoes thermal decomposition, nitric acid oxidation, etc., and then obtains 4,4'-difluorobenzophenone after filtration, drying and recrystallization. The above patents involve the preparation of 4,4'-difluorobenzophenone by diazotization and Friedel-Crafts acylation. The diazotization method uses highly toxic products such as nitric acid and hydrofluoric acid, which cause huge pollution to the environment. In addition, the diazotization and thermal decomposition reactions are violent, which can easily cause safety problems. The Friedel-Crafts acylation method requires the use of aluminum chloride to produce hydrochloric acid, which is highly corrosive to the equipment and prone to accidents such as explosions. After the reaction is completed, a large amount of aluminum salt wastewater is produced, which puts huge pressure on the environmental protection. Summary of the invention

[0004] In view of the above problems, the environmental impact of toxic and harmful byproducts such as aluminum salt wastewater is avoided, and the safety of 4,4'-difluorobenzophenone in the production process is improved. The present invention provides a green synthesis method of 4,4'-difluorobenzophenone. The synthesis method of the present invention is green, environmentally friendly, simple and easy to operate, and has high product yield and high product purity.

[0005] In order to achieve the above objectives, the present invention is implemented by the following technical solutions:

[0006] The green synthesis method of 4,4'-difluorobenzophenone comprises the following steps:

[0007] Under the action of a supported catalyst, fluorobenzene and p-fluorobenzoyl chloride are uniformly mixed and then subjected to Friedel-Crafts acylation reaction to purify 4,4'-difluorobenzophenone;

[0008] The carrier of the supported catalyst is γ-alumina and / or silicon dioxide, and the active component supported on the carrier is a chlorine-containing metal compound. The active component is measured by chlorine content. The chlorine content in the supported catalyst is in the range of 3-30wt%, preferably in the range of 15-30wt%.

[0009] Furthermore, the chlorine-containing metal compound is selected from one or more of aluminum chloride, ferric chloride and lithium chloride.

[0010] Furthermore, the molar ratio of the fluorobenzene to the p-fluorobenzoyl chloride is 1:2-10.

[0011] Furthermore, the mass ratio of the supported catalyst to the p-fluorobenzoyl chloride is 1:0.5-5.

[0012] Furthermore, the temperature of uniformly mixing the fluorobenzene and the p-fluorobenzoyl chloride is lower than 35° C.; the uniformly mixing process is to drop one raw material into the other raw material while stirring, or to directly stir and mix the two raw materials.

[0013] Furthermore, during the uniform mixing, the system temperature is controlled at 10-20°C.

[0014] Furthermore, the temperature of the Friedel-Crafts acylation reaction is 60-85° C. and the reaction time is 2-6 h.

[0015] Furthermore, the purification process is: after the reaction is completed, the supported catalyst is recovered by filtration, and then the filtered liquid is filtered under reduced pressure, concentrated, and the concentrated liquid is recrystallized using an alcohol solvent to obtain 4,4'-difluorobenzophenone.

[0016] Furthermore, the method for obtaining the supported catalyst is:

[0017] preparing an alkali solution; preparing a homogeneous solution of a benzene solvent containing the active component;

[0018] Under a protective atmosphere, the carrier is added into an alkaline solution and immersed for 4-10 hours, and then dried and calcined;

[0019] Under a protective atmosphere, the calcined carrier is added to the prepared homogeneous solution, and the solution is heated and refluxed for 10-24 hours under stirring; after the reflux, the solvent is filtered out and dried to obtain a supported catalyst.

[0020] Further, the alkali in the alkali solution is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and the concentration is 0.5-3 mol / L;

[0021] The calcination temperature is 400-600° C. and the calcination time is 2-4 hours; the reflux temperature is higher than the boiling point of the benzene solvent, and the benzene solvent is an alkylbenzene, such as toluene, xylene, ethylbenzene, diethylbenzene, trimethylbenzene, etc., preferably toluene.

[0022] Beneficial technical effects:

[0023] In the traditional Friedel-Crafts acylation reaction to synthesize 4,4'-difluorobenzophenone, the catalyst used is anhydrous aluminum chloride, which is very easy to hydrolyze. The hydrolysis produces HCl gas that pollutes the air and corrodes the equipment. The hydrolysis causes the catalyst to be deactivated and affects the reaction activity. In addition, a large amount of aluminum salt wastewater is produced after the reaction is completed, causing environmental pollution, and subsequent treatment requires a large amount of cost. The process of the present invention uses fluorobenzene and p-fluorobenzoyl chloride as raw materials, uses a supported catalyst, and performs Friedel-Crafts acylation reaction to synthesize 4,4'-difluorobenzophenone, replacing the traditional aluminum chloride catalyst. The catalytic efficiency of the present invention is stable, and the catalyst can be reused. No aluminum salt wastewater is produced after the reaction is completed. It is green and environmentally friendly, has a high yield and high purity, and meets the requirements of modern chemical industry. DETAILED DESCRIPTION

[0024] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments. The following description of at least one exemplary embodiment is actually only illustrative and is by no means intended to limit the present invention and its application or use. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0025] Unless otherwise specifically stated, the numerical value set forth in these embodiments does not limit the scope of the present invention. The technology and method known to those of ordinary skill in the relevant art may not be discussed in detail, but in appropriate cases, the technology and method should be considered as a part of the specification. In all examples shown and discussed here, any specific value should be interpreted as being merely exemplary, rather than as a limitation. Therefore, other examples of exemplary embodiments may have different values.

[0026] The experimental methods in the following examples without specifying specific conditions are usually measured in accordance with national standards; if there is no corresponding national standard, the method is carried out in accordance with the general standard requirements or general methods.

[0027] Example 1

[0028] (I) Preparation of supported catalyst:

[0029] Prepare a 3 mol / L sodium carbonate solution; prepare a homogeneous solution of toluene containing aluminum chloride, wherein the aluminum chloride content is 0.2 mol / L;

[0030] Under N2 protection, 30 g of purchased γ-alumina (particle size 1-2 mm) was added to 3 mol / L sodium carbonate solution and immersed for 10 h, vacuum dried and calcined at 600 °C for 2 h.

[0031] Under the protection of N2, add the calcined γ-alumina to the prepared 300 mL homogeneous solution, and reflux for 24 h under stirring at a reflux temperature of 110°C.

[0032] After the reflux was completed, the toluene solvent was removed by filtration, and the product was washed with toluene and dried in vacuo to obtain 39.49 g of a supported catalyst (the chlorine content in the supported catalyst was 19.17 wt %).

[0033] (II) Green synthesis method of 4,4'-difluorobenzophenone:

[0034] 150g of fluorobenzene was used as a solvent (also a raw material), 40g of the above-mentioned supported catalyst was added, and then 44g of p-fluorobenzoyl chloride was added dropwise, the dropping speed was controlled, and the dropping was completed in 3h, and the temperature of the reaction system was controlled at 10-20°C; after the dropwise addition was completed, the temperature was slowly raised to 75°C and the reaction was continued for 4h; after the reaction was completed, the supported catalyst was filtered and recovered, and then the filtered feed liquid was vacuum filtered, concentrated, and recrystallized from a methanol solution to obtain 56.55g of 4,4'-difluorobenzophenone, with a yield of 93.4wt% and a purity of 99.8wt%.

[0035] The recovered supported catalyst set was used to prepare 4,4'-difluorobenzophenone. The supported catalyst activity did not decrease significantly after being recycled 10 times, and the yield and purity of the 4,4'-difluorobenzophenone product did not decrease significantly.

[0036] Example 2

[0037] (I) Preparation of supported catalyst:

[0038] Prepare a 1 mol / L sodium carbonate solution; prepare a homogeneous solution of toluene containing aluminum chloride, wherein the aluminum chloride content is 0.2 mol / L;

[0039] Under N2 protection, 30 g of purchased γ-alumina (particle size 1-2 mm) was added to 1 mol / L sodium carbonate solution and immersed for 10 h, vacuum dried and calcined at 600 °C for 2 h.

[0040] Under the protection of N2, add the calcined γ-alumina to the prepared 300 mL homogeneous solution, and reflux for 24 h under stirring at a reflux temperature of 110°C.

[0041] After the reflux was completed, the toluene solvent was removed by filtration, and the product was washed with toluene and dried in vacuo to obtain 42.26 g of a supported catalyst (the chlorine content in the supported catalyst was 23.14 wt %).

[0042] (II) Green synthesis method of 4,4'-difluorobenzophenone:

[0043] 150g of fluorobenzene was used as a solvent (also a raw material), 40g of the above-mentioned supported catalyst was added, and then 44g of p-fluorobenzoyl chloride was added dropwise, the dropping speed was controlled, and the dropping was completed in 3h, and the temperature of the reaction system was controlled at 10-20°C; after the dropwise addition was completed, the temperature was slowly raised to 75°C and the reaction was continued for 4h; after the reaction was completed, the supported catalyst was filtered and recovered, and then the filtered feed liquid was vacuum filtered, concentrated, and recrystallized from a methanol solution to obtain 57.52g of 4,4'-difluorobenzophenone, with a yield of 95.2wt% and a purity of 99.9wt%.

[0044] Example 3

[0045] (I) Preparation of supported catalyst:

[0046] Prepare a 1 mol / L sodium bicarbonate solution; prepare a homogeneous solution of toluene containing aluminum chloride, wherein the aluminum chloride content is 0.3 mol / L;

[0047] Under N2 protection, 30 g of purchased γ-alumina (particle size 1-2 mm) was added to 1 mol / L sodium carbonate solution and immersed for 10 h, vacuum dried and calcined at 500 °C for 2 h.

[0048] Under the protection of N2, add the calcined γ-alumina to the prepared 300 mL homogeneous solution, and reflux for 24 h under stirring at a reflux temperature of 110°C.

[0049] After the reflux was completed, the toluene solvent was removed by filtration, and the product was washed with toluene and dried in vacuo to obtain 44.33 g of a supported catalyst (the chlorine content in the supported catalyst was 25.78 wt %).

[0050] (II) Green synthesis method of 4,4'-difluorobenzophenone:

[0051] 150g of fluorobenzene was used as a solvent (also a raw material), 40g of the above-mentioned supported catalyst was added, and then 44g of p-fluorobenzoyl chloride was added dropwise, the dropping speed was controlled, and the dropping was completed in 3h, and the temperature of the reaction system was controlled at 10-20°C; after the dropwise addition was completed, the temperature was slowly raised to 75°C and the reaction was continued for 4h; after the reaction was completed, the supported catalyst was filtered and recovered, and then the filtered feed liquid was vacuum filtered, concentrated, and recrystallized from a methanol solution to obtain 58.43g of 4,4'-difluorobenzophenone, with a yield of 96.5wt% and a purity of 99.9wt%.

[0052] Example 4

[0053] The supported catalyst was prepared by the method of Example 1, wherein the carrier was silicon dioxide and the active substance was aluminum chloride. 4,4'-difluorobenzophenone was obtained by the method of Example 1 with a yield of 86.3 wt% and a purity of 99.9 wt%.

[0054] Example 5

[0055] The supported catalyst was prepared by the method of Example 1, wherein the carrier was γ-alumina and the active substance was ferric chloride. 4,4'-difluorobenzophenone was obtained by the method of Example 1 with a yield of 75.5 wt% and a purity of 99.9 wt%.

[0056] Example 6

[0057] The supported catalyst was prepared by the method of Example 1, wherein the carrier was γ-alumina and the active substance was lithium chloride. 4,4'-difluorobenzophenone was obtained by the method of Example 1 with a yield of 80.3 wt% and a purity of 99.9 wt%.

[0058] Example 7

[0059] The supported catalyst was prepared by the method of Example 1, the carrier was γ-alumina and silicon dioxide (in equal mass ratio), and the active substance was aluminum chloride and lithium chloride (in equal molar ratio). 4,4'-difluorobenzophenone was obtained by the method of Example 1 with a yield of 92.5wt% and a purity of 99.9wt%.

[0060] Comparative Example 1

[0061] 150g of fluorobenzene was used as solvent, 40g of aluminum chloride was added, and then 44g of p-fluorobenzoyl chloride was added dropwise, and the dropping speed was controlled so that the temperature of the reaction system was controlled at 10-20°C. After the addition was completed, the temperature was slowly raised to 75°C and the reaction was continued for 4h. After the reaction was completed, the catalyst was filtered out, and then the filtrate was concentrated under reduced pressure, and the methanol solution was recrystallized to obtain 40.63g of 4,4'-difluorobenzophenone, with a yield of 67.1wt% and a purity of 99.9wt%.

[0062] Comparative Example 2

[0063] The supported catalyst was prepared by the method of Example 1, wherein the carrier was γ-alumina and the active substance was zinc chloride. 4,4'-difluorobenzophenone was obtained by the method of Example 1 with a yield of 66.2 wt% and a purity of 99.9 wt%.

[0064] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A green synthesis method of 4,4'-difluorobenzophenone, characterized in that: The steps include: Under the action of a supported catalyst, fluorobenzene and p-fluorobenzoyl chloride are uniformly mixed to undergo Friedel-Crafts acylation reaction, and 4,4'-difluorobenzophenone is purified; The carrier of the supported catalyst is γ-alumina and / or silicon dioxide, the active component supported on the carrier is a chlorine-containing metal compound, and the active component is calculated by chlorine content. The chlorine content in the supported catalyst is in the range of 3-30wt%.

2. The green synthesis method of 4,4'-difluorobenzophenone according to claim 1, characterized in that: The chlorine-containing metal compound is selected from one or more of aluminum chloride, ferric chloride and lithium chloride; the chlorine content in the supported catalyst is in the range of 15-30wt%.

3. The green synthesis method of 4,4'-difluorobenzophenone according to claim 1, characterized in that: The molar ratio of the fluorobenzene to the p-fluorobenzoyl chloride is 1:2-10.

4. The green synthesis method of 4,4'-difluorobenzophenone according to claim 1, characterized in that: The mass ratio of the supported catalyst to the p-fluorobenzoyl chloride is 1:0.5-5.

5. The green synthesis method of 4,4'-difluorobenzophenone according to claim 1, characterized in that: The temperature of the uniform mixing of the fluorobenzene and the p-fluorobenzoyl chloride is lower than 35° C.; The uniform mixing process is to drop one raw material into another raw material while stirring, or to directly stir and mix the two raw materials.

6. The green synthesis method of 4,4'-difluorobenzophenone according to claim 5, characterized in that: During the uniform mixing, the system temperature is controlled at 10-20°C.

7. The green synthesis method of 4,4'-difluorobenzophenone according to claim 5, characterized in that: The temperature of the Friedel-Crafts acylation reaction is 60-85° C. and the reaction time is 2-6 h.

8. The green synthesis method of 4,4'-difluorobenzophenone according to any one of claims 1 to 7, characterized in that: The purification process is as follows: after the reaction is completed, the supported catalyst is recovered by filtration, and then the filtered liquid is filtered under reduced pressure, concentrated, and the concentrated liquid is recrystallized with ethanol to obtain 4,4'-difluorobenzophenone.

9. The green synthesis method of 4,4'-difluorobenzophenone according to any one of claims 1 to 7, characterized in that: The method for obtaining the supported catalyst is: preparing an alkaline solution; preparing a homogeneous solution of a benzene solvent containing the active component; Under a protective atmosphere, the carrier is added into an alkaline solution and immersed for 4-10 hours, and then dried and calcined; Under a protective atmosphere, the calcined carrier is added to the prepared homogeneous solution, and the solution is heated and refluxed for 10-24 hours under stirring; after the reflux, the solvent is filtered out and dried to obtain a supported catalyst.

10. The green synthesis method of 4,4'-difluorobenzophenone according to claim 9, characterized in that: The alkali in the alkali solution is selected from sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, and the concentration is 0.5-3 mol / L; The calcination temperature is 400-600°C and the calcination time is 2-4h; The reflux temperature is higher than the boiling point of the benzene solvent, and the benzene solvent is alkylbenzene.