CN116715569A - A kind of preparation method of 4,4'-difluorobenzophenone - Google Patents

Abstract

The invention provides a preparation method of 4,4'-difluorobenzophenone. The preparation method uses p-fluorobenzoic acid as a starting material, reacts with oxalyl chloride to generate p-fluorobenzoyl chloride, and then reacts with Friedel-Crafts reaction generates 4,4'-difluorobenzophenone; the reaction of the invention has high selectivity, high purity of the obtained product, little environmental pollution, high yield, simple process and broad industrial production prospects.

Description

A kind of preparation method of 4,4'-difluorobenzophenone

Technical field

The invention belongs to the technical field of fine chemicals, and specifically relates to a preparation method of 4,4'-difluorobenzophenone.

Background technique

4,4'-Difluoro-benzophenone, English name 4,4'-difluoro-benzophenon, referred to as DFBP, white crystal, melting point 102-105 °C, is a very important synthetic aromatic thermoplastic special engineering plastic ( Such as polyether ketone, polyether ether ketone, polyether ether ketone ketone, polyaryl ether ketone, polyaryl ether ketone phenol, etc.). DFBP is also an important pharmaceutical raw material, for example, it can be used to synthesize the new powerful cerebral vasodilator drug flunarizine, the anti-type 2 diabetes drug digagliptin, and the drug Dukexi for the treatment of Alzheimer's disease.

At present, with the wide application of polyetheretherketone resin in automobiles, electronics, machinery and other fields, and the increasing market demand for related drugs year by year, DFBP has an extremely wide application market.

In recent years, extensive research has been conducted on the synthesis technology of DFBP at home and abroad, and numerous synthesis processes for DFBP have been developed. According to the synthesis principles of various processes, they can be roughly divided into Friedel-Crafts reaction method, oxidative carbonylation method, 4,4'-disubstituted benzophenone fluorination method and other methods.

Through studying the existing synthesis methods of DFBP, there are certain shortcomings and defects.

At present, the first step of the industrial reaction is the synthesis of the intermediate p-fluorobenzoyl chloride. The industrial methods all use p-fluorobenzoic acid and thionyl chloride as raw materials. The reaction process is as follows:

,

Put p-fluorobenzoic acid into excess thionyl chloride. After the reaction is completed, the excess thionyl chloride is recovered by distillation under reduced pressure, and then distilled to obtain p-fluorobenzoyl chloride. The process produces a large amount of mixed acidic hydrogen chloride and sulfur dioxide. After the gas is absorbed by the alkali liquid, it becomes a mixed solution of sodium chloride and sodium sulfite. The purification process of the mixed salt is complicated and consumes high energy. Currently, it is mostly treated as solid waste or hazardous waste, causing great environmental pollution.

The second step of the reaction is the Friedel-Crafts reaction. The process requires a large amount of aluminum trichloride as a catalyst. The reaction and post-treatment process produce a large amount of aluminum trichloride wastewater, which seriously corrodes the production equipment. The reaction equation is as follows:

,

In view of the problems existing in the existing technology, to avoid the pollution of the environment by toxic and harmful chemicals, and to improve the safety and operational convenience of the 4.4' difluorobenzophenone production process, it is urgently needed to propose a method that can improve the production process of 4.4' difluorobenzophenone. The preparation method of ketone production process is safe and easy to operate.

Contents of the invention

In order to solve the above problems, the present invention discloses a preparation method of 4,4’-difluorobenzophenone.

In order to achieve the above objects, the technical solutions of the present invention are as follows:

A preparation method of 4,4'-difluorobenzophenone, the preparation method includes the following steps:

Step (1): Use fluorobenzene as solvent, add p-fluorobenzoic acid and catalyst N,N-dimethylformamide, stir and raise the temperature to 35°C, start adding oxalyl chloride dropwise, control the reaction temperature at 35-40°C, and drop The addition time is 4-5h. After the dropwise addition is completed, continue the insulation reaction for 2-3h. The first step of the reaction is completed. The reaction equation is as shown in formula (1):

;

Step (2): Add the catalyst directly to the reaction solution in step (1), continue to raise the temperature to 50-70°C, and keep the reaction for 3-7 hours. The second step reaction is completed. The reaction equation is as shown in formula (2):

;

Step (3): Filter the reaction solution of step (2) to recover the solid catalyst for secondary use. Wash the filtrate with an equal volume of clean water, add 32% alkali solution with 2-3% of clean water, and mix the water with Adjust the phase to a pH value of 7-8 to remove residual acidic substances such as oxalyl chloride, let it stand for 0.5 hours, separate the water phase, and obtain the organic phase;

Step (4): The organic phase is distilled under reduced pressure. The conditions of the reduced pressure distillation are 70°C water bath temperature and vacuum degree ≤ -0.095Mpa. Fluorobenzene is recovered. The remaining recombinants are divided into crude products. Add 3 times the mass of the crude product. Solvent and 0.5% of the solvent mass activated carbon, heat to 70-90°C, reflux for 2 hours, remove the activated carbon by hot filtration, cool the filtrate to 20-25°C, keep it for 2 hours, filter with suction, and dry the solid under reduced pressure for 6 hours. The conditions for drying under reduced pressure are a temperature of 80°C and a vacuum degree of ≤-0.095Mpa to obtain 4,4'-difluorobenzophenone.

As an improvement of the present invention, the amount of fluorobenzene added in step (1) is 2.5-4 times the mass of p-fluorobenzoic acid, and the reaction temperature is 35-45°C.

As an improvement of the present invention, the amount of oxalyl chloride added in step (1) is 1.05-1.1 times the molar amount of p-fluorobenzoic acid.

As an improvement of the present invention, the catalyst in step (2) is a solid recyclable catalyst, and the solid recyclable catalyst includes any one or more of acid clay, solid super acid and strong acid resin.

As an improvement of the present invention, the amount of catalyst added in step (2) is 5-10% of the mass of p-fluorobenzoic acid.

As an improvement of the present invention, the reaction temperature in step (2) is 50-70°C, and the reaction time is 5-7h.

As an improvement of the present invention, the solvent in step (4) includes any one or more of ethanol, dimethyl carbonate and ethyl methyl carbonate.

As an improvement of the present invention, the amount of solvent added in step (4) is 2-3 times the mass ratio of the crude product of 4,4’-difluorobenzophenone.

As an improvement of the present invention, the activated carbon in step (4) is coconut shell activated carbon, the iodine value is ≥900 mg/g, and the mesh number is any one or more of 200 mesh, 300 mesh, and 500 mesh.

As an improvement of the present invention, the amount of activated carbon added in step (4) is 0.3-1% of the solvent mass.

The beneficial effects of the present invention are:

1. In the first step of the chlorination reaction, efficient oxalyl chloride is used instead of traditional thionyl chloride to avoid the generation of solid waste or hazardous waste (a mixture of sodium chloride and sodium sulfite);

2. The Friedel-Crafts reaction of the present invention uses a recyclable solid catalyst. After the reaction is completed, the catalyst and the reaction liquid can be separated after simple filtration. The catalyst can be recycled and reused, avoiding the generation of aluminum trichloride wastewater in the traditional process, and extremely Dadi improves the environmental friendliness of the process;

3. The present invention combines the traditional two-step two-pot synthesis process into a one-pot method, which simplifies the operation process and improves the safety and environmental protection of the process.

Description of the drawings

Figure 1 shows the ultra-high liquid chromatography (HPLC) chart of 4,4’-difluorobenzophenone standard;

Figure 2 shows the ultra-high liquid chromatography (HPLC) chart of experimentally synthesized 4,4’-difluorobenzophenone.

Detailed ways

The present invention will be further clarified below with reference to the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention.

Example 1

Accurately weigh 350g of fluorobenzene into a 1L four-necked flask, add 140g (1mol) of p-fluorobenzoic acid and 0.5g of N,N-dimethylformamide, turn on magnetic stirring, then slowly raise the temperature to 35°C, and slowly add grass dropwise. Acid chloride 133.5g (1.05mol), the dropping time is 4 hours. During the dropping period, the temperature of the reaction solution is controlled to 35-40°C. The tail gas generated by the reaction is absorbed with 10% alkali solution. As the dropwise addition proceeds, the reaction solution gradually becomes clear. , after the dropwise addition, keep the temperature for 2 hours and the reaction solution is basically clear and transparent, indicating that the p-fluorobenzoic acid reaction is complete and the first step of the reaction is completed;

Pour 14g of dried acidic clay into the above reaction solution. The activity of the dried acidic clay is ≥250mmol/kg. Continue to raise the temperature to 50°C and keep the reaction for 7 hours. The tail gas generated by the reaction is absorbed with 10% alkali solution. The second The step reaction is completed;

The reaction solution is then suction filtered, and the solid is recovered as a catalyst. It is directly used in the next batch of reactions without drying. The filtrate is transferred to a 2L four-necked flask, 500g of water is added, and the pH value of the solution is adjusted with 32% alkali solution. 7-8, separate the water phase; use a rotary evaporator to distill the organic phase under reduced pressure (70°C water bath temperature, vacuum degree ≤ -0.095Mpa) to recover excess fluorobenzene. The remaining heavy component will be light red, add 450g of free Water ethanol and 2.25g of 200 mesh activated carbon were heated to 79°C, maintained for 2 hours, and then hot filtered. The filtrate was transferred to a jacketed glass reactor, cooled to 25°C with ice water, maintained for 1 hour, filtered, and the solid was vacuum After drying in a drying oven (temperature 80°C, vacuum degree ≤-0.095Mpa) for 6 hours, the finished product of 4,4'-difluorobenzophenone was obtained, with a yield of 209.2g and a yield of 96%. The product was tested by high-performance liquid chromatography. Content ≥99.5%, the product was detected by H1-NMR, δ7.28 (4H, t, hydrogen in the ortho position of the fluorine on the benzene ring); δ7.81 (4H, m, hydrogen in the ortho position of the carbonyl group on the benzene ring), consistent with 4 ,4'-difluorobenzophenone structure.

Example 2

Accurately weigh 560g of fluorobenzene into a 1L four-necked flask, add 140g (1mol) of p-fluorobenzoic acid and 0.5g of N,N-dimethylformamide, turn on the magnetic stirring, then slowly raise the temperature to 35°C, and start adding grass dropwise 140g of acid chloride (1.1mol), the dropping time is 4 hours. During the dropping period, the temperature of the reaction solution is controlled to 35-40°C. The tail gas generated by the reaction is absorbed with 10% alkali solution. As the dropwise addition proceeds, the reaction solution gradually becomes clear. After the dropwise addition is completed, the reaction solution is kept warm for 2 hours. The reaction solution is basically clear and transparent, indicating that the p-fluorobenzoic acid reaction is complete and the first step of the reaction is completed;

Add 8.5g of the catalyst recovered in Example 1 into the above reaction solution (the total mass of the wet catalyst is about 17g), continue to raise the temperature to 70°C, and keep the reaction for 5 hours. The tail gas generated by the reaction is absorbed with 10% alkali solution, and the second step of the reaction is completed;

The reaction solution is then suction filtered, and the solid is recovered as a catalyst. It is directly used for the next batch of reactions without drying. The filtrate is transferred to a 2L four-necked flask, 600g of water is added, and the pH value of the solution is adjusted with 32% alkali solution. 7-8, separate the water phase. The organic phase was distilled under reduced pressure using a rotary evaporator to recover excess fluorobenzene. The remaining heavy components are light red, add 675g absolute ethanol and 6.75g 500 mesh activated carbon, heat to 79°C, reflux for 2 hours, then hot filter, transfer the filtrate to a jacketed glass reactor, and cool to 20°C with ice water , after being incubated for 1 hour, filtered, and the solid was dried in a vacuum drying oven (temperature 80°C, vacuum degree ≤ -0.095Mpa) for 6 hours, and the finished product 4,4'-difluorobenzophenone was obtained, with an output of 205.4g and a yield of 94.2 %, the product was detected by high performance liquid chromatography, and its content was ≥99.5%. The product was detected by H1-NMR, δ7.28 (4H, t, hydrogen in the ortho position of fluorine on the benzene ring); δ7.81 (4H, m, benzene hydrogen ortho to the carbonyl group on the ring), consistent with the structure of 4,4'-difluorobenzophenone.

It should be noted that the above content only illustrates the technical idea of the present invention and cannot limit the protection scope of the present invention. For those of ordinary skill in the technical field, without departing from the principle of the present invention, they can also make Several improvements and modifications are made, and these improvements and modifications fall within the protection scope of the claims of the present invention.

Claims (10)

1. A preparation method of 4,4' -difluorobenzophenone is characterized in that: the preparation method comprises the following steps:

step (1): adding p-fluorobenzoic acid and a catalyst N, N-dimethylformamide into fluorobenzene serving as a solvent, stirring and heating to 35 ℃, dropwise adding oxalyl chloride, controlling the reaction temperature to be 35-40 ℃, dropwise adding for 4-5h, and after dropwise adding, preserving heat and reacting for 2-3h, wherein the reaction equation is shown in a formula (1):

；

step (2): directly adding a catalyst into the reaction liquid in the step (1), continuously heating to 50-70 ℃, and carrying out heat preservation reaction for 3-7h, wherein the reaction equation is shown in the formula (2):

；

step (3): filtering the reaction solution in the step (2), recovering the solid catalyst for secondary application, washing the filtrate with equal volume of clear water, adding 32% alkali liquor with 2-3% of clear water, adjusting the pH value of the water phase to 7-8, standing for 0.5h, and separating the water phase to obtain an organic phase;

step (4): the organic phase is distilled under reduced pressure by a rotary evaporator, the condition of the reduced pressure distillation is 70 ℃ water bath temperature, the vacuum degree is less than or equal to-0.095 Mpa, fluorobenzene is recovered, the residual heavy component is crude product, 3 times of solvent and active carbon which is 0.5% of the solvent mass are added, the temperature is raised to 70-90 ℃, the reflux reaction is carried out for 2h, the active carbon is removed by hot filtration, the filtrate is cooled to 20-25 ℃, the temperature is kept for 2h, the filtration is carried out, the solid is dried under reduced pressure for 6h, the condition of the reduced pressure drying is 80 ℃, the vacuum degree is less than or equal to-0.095 Mpa, and 4,4' -difluorobenzophenone is obtained.

2. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the adding amount of the fluorobenzene in the step (1) is 2.5-4 times of the mass of the p-fluorobenzoic acid.

3. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the addition amount of the oxalyl chloride in the step (1) is 1.05-1.1 times of the molar amount of the p-fluorobenzoic acid.

4. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the catalyst in the step (2) is a solid recoverable catalyst, and the solid recoverable catalyst comprises any one or more of acid clay, solid super acid and strong acid resin.

5. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the addition amount of the catalyst in the step (2) is 5-10% of the mass of the p-fluorobenzoic acid.

6. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the reaction temperature in the step (2) is 50-70 ℃ and the reaction time is 5-7h.

7. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the solvent in the step (4) comprises any one or more of ethanol, dimethyl carbonate and ethyl methyl carbonate.

8. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the addition amount of the solvent in the step (4) is 2-3 times of the mass ratio of the crude 4,4' -difluorobenzophenone.

9. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the activated carbon in the step (4) is coconut shell activated carbon, the iodine value is more than or equal to 900mg/g, and the mesh number is any one or more of 200 meshes, 300 meshes and 500 meshes.

10. The method for preparing 4,4' -difluorobenzophenone according to claim 1, wherein: the addition amount of the activated carbon in the step (4) is 0.3-1% of the mass of the solvent.