Method for removing metal impurities in pirfenidone

Abstract

The present application provides a method for removing metal impurities in pirfenidone. The method comprises the following steps: (1) mixing crude pirfenidone, solvent A, water and 1,2-propylenediamine, stirring and dissolving under heating, and stirring for 2 hours under insulation; (2) cooling, crystallization under insulation, collecting filter cake by filtration, washing, and drying under reduced pressure to obtain pirfenidone finished product. The method uses 1,2-propylenediamine as a decontamination reagent, which effectively forms a stable metal complex with metal impurities in the drug. In the provided appropriate solvent system, the complex is dissolved in the solvent system, thereby effectively separating from the pirfenidone solid, and achieving the purpose of removing metal impurities. The method is simple to operate, does not require large-scale equipment modification, completely achieves the requirement of metal impurity control limit of less than 10 ppm, and is suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a method for removing metal impurities in perampanel. BACKGROUND

[0002] Perampanel is a highly selective, non-competitive AMPA receptor antagonist, which can reduce the excessive excitation of neurons related to seizures by targeting the inhibition of glutamate activity of postsynaptic membrane AMPA receptors. Perampanel was first approved by FDA in 2012 for the adjuvant treatment of partial seizures in patients over 12 years old, regardless of whether the patients are accompanied by secondary generalized seizures, which is the first anti-epileptic drug with this mechanism of action approved by FDA.

[0003] Perampanel, the chemical name of which is 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, has the following chemical structural formula:

[0004]

[0005] In the prior art, the industrial synthesis of perampanel is usually carried out by the following method: 5-(2-pyridyl)-1,2-dihydropyridin-2-one (SMA) is used as a starting material, and is subjected to a copper acetate catalytic reaction with phenylboronic acid to prepare 1-phenyl-5-(pyridin-2-yl)-2(1H)-pyridinone (intermediate 1), the intermediate 1 is subjected to a bromination reaction to obtain 3-bromo-1-phenyl-5-(pyridin-2-yl)-1,2-dihydropyridin-2-one (intermediate 2), and then the intermediate 2 is subjected to a catalytic coupling reaction with 2-cyanophenylboronic acid under the action of a palladium acetate-triphenylphosphine system and cuprous iodide to prepare perampanel. The specific synthesis route is shown in the following formula: Figure 1

[0006] Elemental impurities mainly refer to substances generated, added or unintentionally introduced in the process of drug production or storage. Since elemental impurities in drugs cannot provide any therapeutic benefits (except for individual drugs), and may also cause adverse reactions, or may have adverse effects on the stability and shelf life of the drug, both ICH_Q3D and EMA and the US FDA have stated the importance of controlling elemental impurities in production, and the monitoring of elemental impurities is becoming more and more stringent. How to establish a scientific control strategy to effectively control the risk of elemental impurities in actual production and ensure product quality is particularly crucial.

[0007] ​According to the synthesis route of pirfenidone, the metal impurities in the finished product are obviously residual due to the use of metal catalysts such as palladium acetate, copper acetate and cuprous iodide in the production process, and it is extremely difficult to remove. According to the ICH-Q3D requirements, the control limit of metal impurities in pirfenidone is below 10 ppm.

[0008] In the prior art, there are few reports on the removal of metal impurities in pirfenidone. Only CN105294547A reports the use of reagents such as mercapto silica gel, cysteine, pyridine-2,6-dithiol, 2,4,6-mercapto-S-triazine or 1,4-dithiothreitol to remove metal impurities palladium in pirfenidone. The present inventors tried to apply the above reagents to the existing process to remove metal impurities, but failed to achieve the desired effect, and it is difficult to achieve a control limit of below 10 ppm. In addition, some of the above impurity removal reagents are expensive, and require complex process operations such as hot filtration, which increases production costs and increases the safety risk of the production process, which is not conducive to the industrial production of pirfenidone bulk drug.

[0009] Therefore, it is a new topic to be solved to develop an economical and efficient method for removing metal impurities in pirfenidone. SUMMARY

[0010] The purpose of the present application is to provide a method for removing metal impurities in pirfenidone. Compared with the prior art, the method has the advantages of simple operation, small environmental pollution, etc., and is suitable for industrial production. Most importantly, the method can effectively remove metal impurities in pirfenidone using cheaper impurity removal reagents, which is lower in process cost and higher in product quality.

[0011] The method for removing metal impurities in pirfenidone provided by the present application comprises the following steps:

[0012] (1) Mix pirfenidone crude product, solvent A, water and 1,2-propanediamine, heat and stir until clear, and keep stirring for 2-3 hours (specifically 2 hours);

[0013] (2) Cool, keep crystallizing, collect the filter cake, wash, and dry under reduced pressure to obtain pirfenidone finished product.

[0014] In step (1) of the above method, the solvent A is any one of acetone, acetonitrile, tetrahydrofuran, anhydrous ethanol and methanol, and specifically acetone or acetonitrile;

[0015] In step (1), the volume to mass ratio of solvent A to pirfenidone crude product can be 15-25 ml:1 g, and specifically 20 ml:1 g, 15 ml:1 g or 25 ml:1 g;

[0016] In step (1), the mass ratio of water to pirfenidone crude product can be 1.5-2.5:1, specifically 2.0:1, 1.5:1, 2.5:1.

[0017] In step (1), the mass ratio of 1,2-propanediamine to pirfenidone crude product can be 0.1-0.3:1, specifically 0.2:1, 0.1:1.

[0018] In step (1), the temperature of the stirring and keeping warm can be 40-80℃, specifically 55-65℃.

[0019] In step (2) of the above method, the temperature of the crystallization can be 10-25℃, specifically 15-20℃.

[0020] The time of the crystallization can be 2-4 hours, specifically 3 hours.

[0021] In step (2) of the above method, the washing is performed by using a mixed solution of solvent A and water, wherein the volume ratio of solvent A to water can be 1:1, and the volume mass ratio of the washing solution to pirfenidone crude product can be 2ml:1-1.5g, specifically 2ml:1g.

[0022] The technical point of the present application is to provide a method for removing metal impurities in pirfenidone. The principle is that in the process of preparing pirfenidone crude product, in the post-treatment stage, the metal ions such as palladium and copper in the system will be attached or inlaid in the solid with the crystallization of pirfenidone, although there is a washing agent for washing and purifying during the filtration, but still a considerable part of metal impurities remains in the pirfenidone product. Using 1,2-propanediamine as a decontamination reagent, it can effectively form a stable metal complex with the metal impurities in the drug, in the provided appropriate solvent system (mixed system of solvent A and water), the complex is dissolved in the solvent system, thereby realizing effective separation from the pirfenidone solid, and achieving the purpose of removing metal impurities. This method is simple to operate, without the need for large-scale equipment modification, completely realizing the requirement of controlling the limit of metal impurities to be below 10ppm, and being suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0023] Figure 1 The present application is related to the synthesis route of pirfenidone in the prior art. DETAILED DESCRIPTION

[0024] The present application will be further described in detail below in conjunction with specific embodiments, and the examples given are only for illustrating the present application, but not for limiting the scope of the present application. The examples provided below can serve as a guide for further improvement by those skilled in the art, and do not in any way constitute a limitation on the present application.

[0025] The experimental methods in the following examples are all conventional methods, unless otherwise specified, and are performed according to the techniques or conditions described in the literature in the art or according to the instructions of the products. The materials, reagents, etc. used in the following examples, unless otherwise specified, can be obtained commercially.

[0026] The pirfenidone crude in the following examples and comparative examples is prepared according to the process synthesis route of Figure 1 , and the specific steps are as follows:

[0027] Step (1)

[0028] Into a 2L glass reaction flask, N,N-dimethylformamide (500ml), SMA (100.2g), phenylboronic acid (77.1g), copper acetate (10.5g), pyridine (46.0g) were added in sequence, the suspension system was controlled at an internal temperature of 20-30°C for 10h of reaction, after the reaction was completed, the temperature was lowered to below 10°C, and an ammonia water solution (40.2g of ammonia water + 500ml of purified water) was added dropwise, and the solid was stirred at 10-15°C for 1h of crystallization, then filtered, the filter cake was washed with 100ml of purified water, and the solid was dried at 50°C under reduced pressure and vacuum to obtain about 118.7g of intermediate 1, with a yield of 82%.

[0029] Step (2)

[0030] Under nitrogen protection, into a 3L glass reaction flask, N,N-dimethylformamide (600ml), intermediate 1 (118.7g) were added, the internal temperature was controlled at 10-20°C, and NBS (85.2g) was added in batches, 20-30°C for 2h of reaction, after the reaction was completed, the temperature was lowered to below 15°C, and a sodium bisulfite solution (55.4g of sodium bisulfite + 1.2L of purified water) was added dropwise, and the solid was stirred at 10-20°C for 1h of crystallization, then filtered, the filter cake was washed with 300ml of purified water, and the solid was dried at 50°C under reduced pressure and vacuum to obtain about 146.2g of intermediate 2, with a yield of 94%.

[0031] Step (3)

[0032] Under nitrogen protection, into a 5L glass reaction flask, N,N-dimethylformamide (1.2L), intermediate 2 (146.2g), 2-cyanophenylboronic acid-1,3-propanediol cyclic ester (92.5g), potassium carbonate (124.0), palladium acetate (4.1g), triphenylphosphine (14.3g), cuprous iodide (3.5g) were added, the temperature was raised to 75-85°C for 4h of reaction, the temperature was lowered to below 20°C, and an ammonia water solution (300.6g of ammonia water + 2L of purified water) was added dropwise, and the solid was precipitated, and the temperature was kept at 0-10°C for 2h of stirring and crystallization, then filtered, the filter cake was washed with 400ml of purified water, and the solid was dried at 50°C under reduced pressure and vacuum to obtain about 117.3g of pirfenidone crude, with a yield of 75% (the content of palladium in the pirfenidone crude was 170ppm, and the content of copper was 89ppm).

[0033] Example 1

[0034] Into a 500ml reaction flask, add 200ml acetone, crude pirfenidone (10.02g), 20ml purified water, 1,2-propylenediamine (2.03g), stir to warm to 55-65°C, the system is clear and keep stirring for 2h, cooling crystallization, control the internal temperature 15-20°C, keep stirring for 3h, filter, filter cake with acetone aqueous solution (V:V=1:1) 20ml rinse, solid 50°C vacuum drying, pirfenidone product about 9.22g, yield: 92% (test results: palladium content 1.19ppm, copper content 0.82ppm).

[0035] Example 2

[0036] Into a 500ml reaction flask, add 150ml acetonitrile, crude pirfenidone (10.05g), 15ml purified water, 1,2-propylenediamine (2.03g), stir to warm to 55-65°C, the system is clear and keep stirring for 2h, cooling crystallization, control the internal temperature 15-20°C, keep stirring for 3h, filter, filter cake with acetonitrile aqueous solution (V:V=1:1) 20ml rinse, solid 50°C vacuum drying, pirfenidone product about 9.30g, yield: 93% (test results: palladium content 1.97ppm, copper content 0.93ppm).

[0037] Example 3

[0038] Into a 500ml reaction flask, add 250ml acetone, crude pirfenidone (10.00g), 25ml purified water, 1,2-propylenediamine (2.05g), stir to warm to 55-65°C, the system is clear and keep stirring for 2h, cooling crystallization, control the internal temperature 15-20°C, keep stirring for 3h, filter, filter cake with acetone aqueous solution (V:V=1:1) 20ml rinse, solid 50°C vacuum drying, pirfenidone product about 9.01g, yield: 90% (test results: palladium content 1.94ppm, copper content 1.38ppm).

[0039] Example 4

[0040] Into a 500ml reaction flask, add 200ml tetrahydrofuran, crude pirfenidone (10.03g), 20ml purified water, 1,2-propylenediamine (2.01g), stir to warm to 55-65°C, the system is clear and keep stirring for 2h, cooling crystallization, control the internal temperature 15-20°C, keep stirring for 3h, filter, filter cake with tetrahydrofuran aqueous solution (V:V=1:1) 20ml rinse, solid 50°C vacuum drying, pirfenidone product about 8.50g, yield: 85% (test results: palladium content 6.03ppm, copper content 3.24ppm).

[0041] Comparative Example 1

[0042] Into a 500ml reaction flask, 200ml acetone, crude pirfenidone (10.01g), 20ml purified water, mercapto-silica gel (2.00g) were added, and stirred to warm to 55-65°C, and stirred for 2h while maintaining the temperature, then filtered while hot, the filtrate was allowed to crystallize while cooling, and the internal temperature was controlled at 15-20°C, and stirred for 3h while maintaining the temperature, then filtered, the filter cake was rinsed with 20ml of an acetone aqueous solution (V:V=1:1), and the solid was dried under reduced pressure at 50°C in a vacuum, to obtain about 9.13g of pirfenidone finished product, with a yield of 91% (detection results: palladium content 10.97ppm, copper content 3.28ppm).

[0043] Comparative Example 2

[0044] Into a 500ml reaction flask, 200ml acetonitrile, crude pirfenidone (10.05g), 20ml purified water, cysteine (2.02g) were added, and stirred to warm to 55-65°C, and the system was stirred for 2h while maintaining the temperature after dissolving, then allowed to crystallize while cooling, and the internal temperature was controlled at 15-20°C, and stirred for 3h while maintaining the temperature, then filtered, the filter cake was rinsed with 20ml of an acetonitrile aqueous solution (V:V=1:1), and the solid was dried under reduced pressure at 50°C in a vacuum, to obtain about 8.92g of pirfenidone finished product, with a yield of 89% (detection results: palladium content 12.08ppm, copper content 2.17ppm).

[0045] Comparative Example 3

[0046] Into a 500ml reaction flask, 200ml acetone, crude pirfenidone (10.03g), 20ml purified water, pyridine-2,6-dithiol (2.03g) were added, and stirred to warm to 55-65°C, and the system was stirred for 2h while maintaining the temperature after dissolving, then allowed to crystallize while cooling, and the internal temperature was controlled at 15-20°C, and stirred for 3h while maintaining the temperature, then filtered, the filter cake was rinsed with 20ml of an acetone aqueous solution (V:V=1:1), and the solid was dried under reduced pressure at 50°C in a vacuum, to obtain about 9.18g of pirfenidone finished product, with a yield of 92% (detection results: palladium content 13.85ppm, copper content 4.26ppm).

[0047] The results of Comparative Examples 1-3 show that the impurity removal reagents in the prior art cannot achieve the effect of using 1,2-propanediamine in the present application, and cannot reduce the metal impurities below the limit requirement.

[0048] The application has been described in detail. For those skilled in the art, the application can be implemented in a wider range under the same parameters, concentrations and conditions without departing from the spirit and scope of the application and without unnecessary experiments. Although the application gives a special example, it should be understood that the application can be further improved. In summary, according to the principle of the application, the application intends to include any change, use or improvement of the application, including the change made by the conventional technology known in the art, which is out of the range disclosed in the application.

Claims

1. A method for removing metal impurities in perampanel, comprising the following steps: (1) Mix the crude perampanel, solvent A, water, and 1,2-propylenediamine, heat and stir until dissolved, and keep stirring for 2-3 hours; In step (1), the solvent A is any one of acetone, acetonitrile and tetrahydrofuran; (2) cooling, keeping the temperature to crystallize, collecting the filter cake by filtration, washing, and drying under reduced pressure to obtain the finished product of Perampanel; The metal impurities are palladium and copper.

2. The method according to claim 1, characterized in that In step (1), the volume-to-mass ratio of solvent A to crude perampanel is 15-25 ml:1 g.

3. The method according to claim 1 or 2, characterized in that In step (1), the mass ratio of water to crude perampanel is 1.5-2.5:

1.

4. The method according to claim 1 or 2, characterized in that In step (1), the mass ratio of 1,2-propylenediamine to the crude perampanel is 0.1-0.3:

1.

5. The method according to claim 1 or 2, characterized in that In step (1), the temperature for heat preservation and stirring is 40-80°C.

6. The method according to claim 1 or 2, characterized in that In step (2), the crystallization temperature is 10-25° C., and the crystallization time is 2-4 hours.

7. The method according to claim 1 or 2, characterized in that In step (2), the washing is performed by eluting with a mixed solution of solvent A and water, wherein the volume ratio of solvent A to water is 1:1, and the volume mass ratio of the eluting solution to the crude perampanel is 2 ml:1-1.5 g.

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