A kind of preparation method of perampanel

Abstract

The invention relates to a preparation method of perampanel. A certain amount of water is added during a reaction process, so that a Suzuki coupling reaction is promoted, the reaction time is shortened, no bromide residue is left, a copper ion catalyst does not need to be added, and the introduction of copper ions during the reaction process to make the post-treatment process complicated is avoided. The obtained reaction solution utilizes the property that perampanel is insoluble in water, water is added to cool and crystallize, and a perampanel crude product is directly filtered to obtain the crude product, which is then dissolved in a mixed solution of acetone and water, and recrystallized to obtain high-purity perampanel. The entire post-treatment operation is simple, the yield and purity of the target product are high, the purity is greater than 99%, the single impurity is less than 0.1%, the production efficiency is high, and the method is suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of raw material drug preparation, and specifically relates to a preparation method of perampanel. Background Art

[0002] The chemical name of perampanel is: 3-(2-cyanophenyl)-1-phenyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one (3 / 4) hydrate, and its structural formula is as follows:

[0003]

[0004] Epilepsy is a chronic disease caused by sudden abnormal discharges of brain neurons, which leads to transient brain dysfunction. According to the latest epidemiological data in China, the overall prevalence of epilepsy in China is 7.0‰, the annual incidence is 28.8 / 100,000, and the prevalence of active epilepsy with seizures within 1 year is 4.6‰. Based on this, it is estimated that there are about 9 million epilepsy patients in China, of which 5 to 6 million are active epilepsy patients. At the same time, there are about 400,000 new epilepsy patients each year. In China, epilepsy has become the second most common disease in neurology after headache.

[0005] The clinical phenomena of epileptic seizures are complex and diverse. Currently, many types of anti-epileptic drugs have been developed on the market for different symptoms. According to the development history of anti-epileptic drugs, they can basically be divided into three generations. Currently, the third-generation anti-epileptic drug Perampanel has entered the Chinese market in the form of tablets for the treatment of localized epilepsy and the treatment of epilepsy in children over 12 years old and adults.

[0006] Perampanel is an ion channel-type, non-competitive antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor glutamate on postsynaptic neurons. Glutamate is the main excitatory neurotransmitter in the central nervous system and is associated with many neurological diseases caused by excessive neuronal excitation. This product exerts anti-epileptic effects by inhibiting the activity of glutamate at postsynaptic AMPA receptors and reducing excessive neuronal excitation. Perampanel is the first non-competitive AMPA approved by the FDA. It was first launched in Germany in July 2012, in the United States in October 2012, and in Japan in 2016 under the trade name Fycompa. In 2018, the indication was expanded and it was approved for monotherapy in patients aged 4 years and above with partial epileptic seizures (POS), with or without secondary generalized epileptic seizures. Perampanel has not been reported to aggravate the onset of other types of epilepsy and has broad commercial prospects.

[0007] The synthesis route of perampanel reported in J Med. Chem. 2012.55:10584, SYNTHESIS. 2012.44:57 and patent CN CN1984890 is as follows:

[0008]

[0009] In the last step of this route, Suzuki coupling reaction, ethylene glycol dimethyl ether is used as a solvent, and raw materials such as potassium carbonate, palladium acetate, cuprous iodide, triphenylphosphine, etc. are added to carry out reflux reaction for 4 to 6 hours to obtain the target product, perampanel. In the reaction process, ethylene glycol dimethyl ether is used as a solvent. Since potassium carbonate and cuprous iodide are difficult to dissolve in ethylene glycol dimethyl ether, the reaction time is long, the bromide is difficult to react completely, and too much raw material remains. In the last step of the reaction, metal copper ions other than palladium are introduced, which makes post-treatment difficult, and the yield and purity are relatively low, and the properties of the obtained perampanel are poor. Summary of the invention

[0010] The invention aims to provide a preparation method of perampanel in view of the problems that a long reaction time, excessive bromine residues, low yield and purity of products and complicated post-treatment are common in the process of preparing perampanel in the prior art. A certain amount of water is added during the reaction process, so that the Suzuki coupling reaction is promoted, the reaction time is shortened, no bromine residues are left, the post-treatment operation is simple, no copper ion catalyst needs to be added, and the introduction of copper ions during the reaction process to make the post-treatment process complicated is avoided. The yield and purity of the product are high and the method is suitable for industrial production.

[0011] The technical solution of the present invention is as follows:

[0012] A preparation method of perampanel comprises the following steps: uniformly mixing compound 1 (brominated compound), compound 2, solvent, triphenylphosphine, palladium catalyst, base and water, and carrying out chemical reaction at 50-80° C. After the reaction is completed, filtering the obtained reaction solution, mixing the obtained filtrate with water, cooling and crystallizing, filtering again, and drying to obtain a crude perampanel product. The specific synthesis route is as follows:

[0013]

[0014] For the present invention, in the process of preparing perampanel, a certain amount of water is added, which promotes the Suzuki coupling reaction to proceed, shortens the reaction time, and the bromo compound is free of residue, does not need to add a copper ion catalyst, avoids the introduction of copper ions in the reaction process and makes the post-processing process complicated and other problems. In the process of preparing perampanel, under the condition of not adding water, the bromo compound reaction is incompletely residual, resulting in a low yield and purity of the product. Even if water is added during the reaction, it is also necessary to strictly control the addition of water, for example, in the case of too much water, because the bromo compound is easily hydrolyzed under alkaline conditions, the debromination impurities generated are larger, resulting in a significant decrease in the yield and purity of the product, which is unfavorable for subsequent purification.

[0015] In the present invention, the mass volume ratio of compound 1 to water is 2.0 to 15.0:1 g / mL, and may be but is not limited to 2.0:1 g / mL, 2.2:1 g / mL, 2.5:1 g / mL, 3.0:1 g / mL, 3.1:1 g / mL, 3.2:1 g / mL, 3.23:1 g / mL, 3.25:1 g / mL, 3.27:1 g / mL, 3.3:1 g / mL, 3.5:1 g / mL, 4.0:1 g / mL, 5.0:1 g / mL, 6.0:1 g / mL. / mL, 7.0:1g / mL, 8.0:1g / mL, 9.0:1g / mL, 10.0:1g / mL, 10.5:1g / mL, 10.8:1g / mL, 11:1g / mL, 12:1g / mL, 13:1g / mL, 10.4:1g / mL or 15:1g / mL. In order to obtain better effects, the mass volume ratio of compound 1 to water is 3.0-3.5:1g / mL, and further, the mass volume ratio of compound 1 to water is 3.25:1g / mL.

[0016] In the present invention, the molar ratio of compound 2 to compound 1 is 1.2 to 3.0:1, and can be but not limited to 1.2:1, 1.4:1, 1.5:1, 1.52:1, 1.54:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.5:1 or 3.0:1. In order to obtain better effects, the molar ratio of compound 2 to compound 1 is 1.5 to 2.0:1.

[0017] In the present invention, the mass ratio of compound 1 to triphenyl phosphine is 12.0-17.0:1, and can be but not limited to 12.0:1, 13.0:1, 14.0:1, 15.0:1, 15.1:1, 15.2:1, 15.3:1, 15.4:1, 15.5:1, 15.6:1, 15.7:1, 15.8:1, 16.0:1 or 17.0:1. In order to obtain better effect, the mass ratio of compound 1 to triphenyl phosphine is 15.0-16.0:1.

[0018] In the present invention, the palladium catalyst is palladium acetate, tetrakis(triphenylphosphine)palladium or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, preferably palladium acetate.

[0019] Wherein, the mass ratio of compound 1 to palladium catalyst is 70.0-75.0:1, and can be but not limited to 70.0:1, 71.0:1, 72.0:1, 72.1:1, 72.2:1, 72.3:1, 72.4:1, 72.5:1, 72.6:1, 72.7:1, 72.8:1, 72.9:1, 73.0:1, 74.0:1 or 75.0:1. In order to obtain better effect, the mass ratio of compound 1 to palladium catalyst is 72.0-73.0:1.

[0020] In the present invention, the base is potassium carbonate, sodium carbonate, potassium tert-butoxide or sodium tert-butoxide, preferably potassium carbonate.

[0021] Among them, the mass ratio of compound 1 to base is 1.0-2.0:1, and can be but not limited to 1.0:1, 1.1:1, 1.2:1, 1.4:1, 1.5:1, 1.52:1, 1.54:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2.0:1, 2.5:1 or 3.0:1. In order to obtain better effect, the mass ratio of compound 1 to base is 1.1-1.5:1.

[0022] In the present invention, the reaction temperature is 50-80°C, and can be but not limited to 50°C, 55°C, 60°C, 65°C, 70°C, 75°C or 80°C. In order to obtain better effects, the reaction temperature is 55-75°C. More preferably, the reaction temperature is 60-70°C.

[0023] Furthermore, the reaction time is 1 to 6 hours, preferably 2 to 4 hours.

[0024] In the present invention, the solvent is tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide or N-pyrrolidone, preferably tetrahydrofuran.

[0025] Among them, the volume ratio of solvent to water is 30-70:1, and can be but not limited to 30:1, 35:1, 40:1, 43:1, 45:1, 46:1, 47:1, 48:1, 49:1, 50:1, 51:1, 52:1, 53:1, 54:1, 55:1, 56:1, 60:1, 65:1 or 70:1. In order to obtain better effect, the volume ratio of solvent to water is 45-55:1.

[0026] The present invention also provides a refining process of the crude perampanel, which is specifically as follows: dissolving the crude perampanel in a mixed solution of acetone and water, cooling to 15-25° C., stirring and crystallizing for 3-6 hours, filtering, and drying to obtain a refined perampanel product.

[0027] Wherein, the mass volume ratio of the crude perampanel to the total volume of acetone and water is 1:20.0-50.0 g / mL, and can be but not limited to 1:20.0 g / mL, 1:22.0 g / mL, 1:25.0 g / mL, 1:25.5 g / mL, 1:25.7 g / mL, 1:26.0 g / mL, 1:30.0 g / mL, 1:35.0 g / mL, 1:38.0 g / mL, 1:38.5 g / mL, 1:39.0 g / mL, 1:40.0 g / mL, 1:45.0 g / mL or 1:50.0 g / mL. In order to obtain better effect, the mass volume ratio of the crude perampanel to the total volume of acetone and water is 1:25.0-40.0 g / mL.

[0028] In the mixed solution of acetone and water, the volume ratio of acetone to water is 1.5 to 3.5:1, and can be but not limited to 1.5:1, 1.7:1, 1.8:1, 2.0:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 3.0:1 or 3.5:1. In order to obtain better effect, the volume ratio of acetone to water is 2.0 to 2.5:1.

[0029] In the refining process of the crude perampanel, the crude perampanel is dissolved in a mixed solution consisting of acetone and part of water, and the remaining water is added after cooling to stir and crystallize.

[0030] Adopt the technical scheme of the present invention, the advantages are as follows:

[0031] The preparation method of perampanel provided by the invention comprises the following steps: adding a certain amount of water during the reaction process, promoting the Suzuki coupling reaction, shortening the reaction time, leaving no bromine residue, not needing to add a copper ion catalyst, avoiding the introduction of copper ions during the reaction process and making the post-treatment process complicated; the obtained reaction solution utilizes the property that perampanel is insoluble in water, adding water to cool and crystallize, directly filtering to obtain a crude perampanel product, dissolving it in a mixed solution of acetone and water, and recrystallizing to obtain a high-purity perampanel; the whole post-treatment operation is simple, the yield and purity of the target product are high, the purity is greater than 99%, the single impurity is less than 0.1%, the production efficiency is high, and the method is suitable for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 is the HNMR diagram of the refined perampanel in Example 1 of the present invention;

[0033] Figure 2It is the MS chart of the refined product of Perampanel in Example 1 of the present invention. DETAILED DESCRIPTION

[0034] The preparation method of perampanel of the present invention is further described by the following examples, but these examples do not constitute any limitation to the present invention.

[0035] Example 1

[0036]

[0037] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 74.8g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 20mL of water in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C for reflux reaction for 2-4 hours, and use TLC (PE:EA=1:1) to monitor the complete reaction of the bromo compound. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 65.2g of crude perampanel with a yield of 93.3%.

[0038] Purification: In a 2L three-necked flask, add 65g of the obtained crude perampanel, 1170mL of acetone and 130mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 370mL of water dropwise, keep warm and stir for 4h, filter, and dry to obtain 57.9g of white solid perampanel fine product, with a yield of 89.1%, a purity of 99.33%, and a maximum single impurity of 0.056%. Related spectra are shown in Figure 1 and Figure 2 .

[0039] 1 H NMR (500MHz, DMSO-d6): d=7.29–7.31(m,1H),7.53–7.54(1H,m),7.58–7.61(5H,m),7.76(1H,d,J=7.5Hz),7.79(1H,d,J=15Hz),7.84( 1H,d,J=6.7Hz), 7.95(1H,d,J=7.5Hz), 8.01(1H,d,J=8Hz), 8.50(1H,d,J=2.5Hz), 8.54(1H,d,J=1.5Hz), 8.62(1H,d,J=3.5Hz); MS: m / z C 23 H 15 N3O(MH + ):350.13266; (MNa + ):372.1489;(MK + ):388.0872.

[0040] Example 2

[0041] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 56.1g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 20mL of water in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C for reflux reaction for 2-4 hours, and use TLC (PE:EA=1:1) to monitor the complete reaction of the bromo compound. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 66g of crude perampanel with a yield of 95.2%.

[0042] Purification: In a 2L three-necked flask, add 55g of the obtained crude perampanel, 1485mL of acetone and 165mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 470mL of water dropwise, keep warm and stir for 4h, filter and dry to obtain 48.1g of white solid perampanel fine product, with a yield of 87.5%, a purity of 99.51%, and a maximum single impurity of 0.046%.

[0043] Example 3

[0044] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 56.1g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 30mL of water in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C for reflux reaction for 2-4 hours, and use TLC (PE:EA=1:1) to monitor the complete reaction of the bromo compound. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 60.3g of crude perampanel with a yield of 86.9%.

[0045] Purification: In a 2L three-necked flask, add 60g of the obtained crude perampanel, 1620mL of acetone and 180mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 510mL of water dropwise, keep warm and stir for 6h, filter, and dry to obtain 50.7g of white solid perampanel fine product, with a yield of 84.5%, a purity of 99.27%, and a maximum single impurity of 0.061%.

[0046] Example 4

[0047] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 56.1g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 6mL of water in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C for reflux reaction for 2-4 hours, and use TLC (PE:EA=1:1) to monitor the complete reaction of the bromo compound. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 59.4g of crude perampanel with a yield of 85.7%.

[0048] Purification: In a 2L three-necked flask, add 55g of the obtained crude perampanel, 1485mL of acetone and 165mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 470mL of water dropwise, keep warm and stir for 5h, filter, and dry to obtain 47.2g of white solid perampanel fine product, with a yield of 85.8%, a purity of 99.44%, and a maximum single impurity of 0.057%.

[0049] Comparative test 1:

[0050] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 74.8g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate and 56g of potassium carbonate in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C for reflux reaction for 2-4 hours, use TLC (PE:EA=1:1) to monitor the bromide, and the bromide reaction is incomplete. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 50.3g of crude perampanel, with a yield of 72.5%.

[0051] Purification: In a 2L three-necked flask, add 50g of the obtained crude perampanel, 1350mL of acetone and 150mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 430mL of water dropwise, keep warm and stir for 4h, filter, and dry to obtain 38.3g of white solid perampanel fine product, with a yield of 76.6%, a purity of 98.6%, and a maximum single impurity of 0.23%.

[0052] Comparative test 2:

[0053] In a 2L three-necked flask, add 65g of compound 1 (bromo compound), 74.8g of compound 2 and 1000mL of tetrahydrofuran, start stirring, and add 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 200ml of water in sequence. Pass N2 protection, heat the resulting mixed solution to 60-70°C and reflux for 2-4 hours, use TLC (PE:EA=1:1) to monitor the bromide, and the bromide reacts completely. The resulting reaction solution is cooled to 40-50°C and filtered. The resulting filtrate is poured into a 5L beaker, 2L of water is added under stirring, cooled to 15-25°C, filtered, washed with water, and dried to obtain 52.3g of crude perampanel, with a yield of 75.5%.

[0054] Purification: In a 2L three-necked flask, add 50g of the obtained crude perampanel, 1350mL of acetone and 150mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 430mL of water dropwise, keep warm and stir for 6h, filter, and dry to obtain 36.1g of white solid perampanel fine product, with a yield of 72.2%, a purity of 97.7%, and a maximum single impurity of 0.46%.

[0055] Combining Examples 1 to 4 and Comparative Experiments 1 to 2, it can be seen that when no water is added, the brominated product reacts incompletely and a large amount of residue remains; while when there is too much water, the brominated product is easily hydrolyzed under alkaline conditions, and the debrominated impurities generated are large, which affects the yield and purification effect.

[0056] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit it. Although the present invention has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that it is still possible to modify the technical solutions described in the aforementioned embodiments, or to perform equivalent replacements on some of the technical features therein. However, these modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing perampanel, characterized in that: It includes the following steps: (1) In a 2L three-necked flask, 65g of compound 1, 74.8g of compound 2 and 1000mL of tetrahydrofuran were added, stirring was started, and 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 20mL of water were added in sequence; N2 protection was passed through, and the resulting mixed solution was heated to 60-70°C for reflux reaction for 2-4 hours, and the reaction of the bromide was monitored by TLC. When monitored by TLC, the ratio of PE to EA was 1:1; the resulting reaction solution was cooled to 40-50°C and filtered; the resulting filtrate was poured into a 5L beaker, 2L of water was added under stirring, the temperature was cooled to 15-25°C, filtered, washed with water, and dried to obtain 65.2g of crude perampanel, with a yield of 93.3%; (2) Purification: In a 2L three-necked flask, add 65g of the obtained crude perampanel, 1170mL of acetone and 130mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 370mL of water dropwise, keep warm and stir for 4h, filter, and dry to obtain 57.9g of white solid perampanel fine product, with a yield of 89.1%, a purity of 99.33%, and a maximum single impurity of 0.056%. The specific synthetic route is as follows:

2. A method for preparing perampanel, characterized in that: It includes the following steps: (1) In a 2L three-necked flask, 65g of compound 1, 56.1g of compound 2 and 1000mL of tetrahydrofuran were added, stirring was started, and 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 20mL of water were added in sequence; N2 protection was passed through, and the resulting mixed solution was heated to 60-70°C for reflux reaction for 2-4 hours, and TLC was used to monitor the complete reaction of the bromide. Under TLC monitoring, the ratio of PE to EA was 1:1; the resulting reaction solution was cooled to 40-50°C and filtered; the resulting filtrate was poured into a 5L beaker, 2L of water was added under stirring, the temperature was cooled to 15-25°C, filtered, washed with water, and dried to obtain 66g of crude perampanel, with a yield of 95.2%; (2) Purification: In a 2L three-necked flask, add 55g of the obtained crude perampanel, 1485mL of acetone and 165mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 470mL of water dropwise, keep warm and stir for 4h, filter, and dry to obtain 48.1g of white solid perampanel fine product, with a yield of 87.5%, a purity of 99.51%, and a maximum single impurity of 0.046%. The specific synthetic route is as follows:

3. A method for preparing perampanel, characterized in that: It includes the following steps: (1) In a 2L three-necked flask, 65g of compound 1, 56.1g of compound 2 and 1000mL of tetrahydrofuran were added, stirring was started, and 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 30mL of water were added in sequence; N2 protection was passed through, and the resulting mixed solution was heated to 60-70°C for reflux reaction for 2-4 hours, and the reaction of the bromide was monitored by TLC. When monitored by TLC, the ratio of PE to EA was 1:1; the resulting reaction solution was cooled to 40-50°C and filtered; the resulting filtrate was poured into a 5L beaker, 2L of water was added under stirring, the temperature was cooled to 15-25°C, filtered, washed with water, and dried to obtain 60.3g of crude perampanel, with a yield of 86.9%; (2) Purification: In a 2L three-necked flask, add 60g of the obtained crude perampanel, 1620mL of acetone and 180mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 510mL of water dropwise, keep warm and stir for 6h, filter, and dry to obtain 50.7g of white solid perampanel fine product, with a yield of 84.5%, a purity of 99.27%, and a maximum single impurity of 0.061%. The specific synthetic route is as follows:

4. A method for preparing perampanel, characterized in that: It includes the following steps: (1) In a 2L three-necked flask, 65g of compound 1, 56.1g of compound 2 and 1000mL of tetrahydrofuran were added, stirring was started, and 4.3g of triphenylphosphine, 0.9g of palladium acetate, 56g of potassium carbonate and 6mL of water were added in sequence; N2 protection was passed through, and the resulting mixed solution was heated to 60-70°C for reflux reaction for 2-4 hours, and the reaction of the bromide was monitored by TLC. When monitored by TLC, the ratio of PE to EA was 1:1; the resulting reaction solution was cooled to 40-50°C and filtered; the resulting filtrate was poured into a 5L beaker, 2L of water was added under stirring, the temperature was cooled to 15-25°C, filtered, washed with water, and dried to obtain 59.4g of crude perampanel, with a yield of 85.7%; (2) Purification: In a 2L three-necked flask, add 55g of the obtained crude perampanel, 1485mL of acetone and 165mL of water, heat and reflux until completely dissolved, cool to 15-25°C, add 470mL of water dropwise, keep warm and stir for 5h, filter, and dry to obtain 47.2g of white solid perampanel fine product, with a yield of 85.8%, a purity of 99.44%, and a maximum single impurity of 0.057%. The specific synthetic route is as follows:

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