A kind of preparation method of pirfenidone
By synthesizing pirfenidone under mild conditions using 2-bromo(iodo)-5-methylpyridine, the high-risk problem of diazotization hydrolysis reaction in the prior art was solved, and high yield and high purity pirfenidone preparation was achieved.
Patent Information
- Application Number
- CN202410259527.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2024-03-07
- Publication Date
- 2025-04-25
- Estimated Expiration
- 2044-03-07
AI Technical Summary
In the existing pirfenidone synthesis methods, the diazotization hydrolysis reaction has a high risk of explosion, and the reaction conditions are harsh and the yield is not high.
2-bromo(iodo)-5-methylpyridine was used as the starting material, and the reaction was carried out at 50-80°C. The acid-base extraction and concentration crystallization were used to obtain 5-methyl-2(1H)-pyridone, and then nucleophilic substitution reaction was carried out with iodine or bromobenzene under a copper catalyst to produce pirfenidone.
Low temperature and mild reaction conditions are achieved, with a yield of more than 95%, avoiding safety hazards of azide reaction, high purity of the product, safe and reliable.
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Figure CN118344287B_ABST
Abstract
Description
Technical Field
[0001] The present invention relates to the technical field of pirfenidone raw material preparation, and in particular to a method for preparing pirfenidone. Background Art
[0002] Pirfenidone (PFD), chemical name is 5-methyl-1-phenyl-2-(1H)pyridone, CAS number is 53179-13-8, and its chemical structure is as follows:
[0003]
[0004] In the related art, the synthesis method of pirfenidone (as shown in chemical formula I) uses 2-amino-5-methylpyridone as the starting material, and uses the amino group to perform diazotization hydrolysis to obtain 5-methyl-2(1H)-pyridone; then it is coupled with iodobenzene under the catalysis of a copper catalyst to generate pirfenidone.
[0005]
[0006] The synthesis method of pirfenidone in the prior art has the following technical defects:
[0007] The first step requires a diazotization hydrolysis reaction, during which a diazonium salt intermediate is generated, which is an explosive hazardous chemical. It is easy to explode if not handled properly, especially in large-scale industrial production processes. It is a high-risk reaction and has great safety hazards. Summary of the invention
[0008] The present invention aims to solve at least one of the technical problems existing in the prior art or related art.
[0009] To this end, an object of the present invention is to provide a method for preparing pirfenidone, which has high safety, mild reaction conditions and high yield.
[0010] In order to achieve the above object, the technical solution of the present invention provides a method for preparing pirfenidone, comprising the following steps:
[0011] S1, 2-bromo(iodo)-5-methylpyridine, an organic solvent and an alkaline solution are stirred and mixed and heated to 50-80° C. for reaction;
[0012] S2, after monitoring the completion of the reaction, extracting the reaction product into an extraction solvent by acid-base extraction;
[0013] S3, concentrating and crystallizing the extract phase containing the reaction product to obtain 5-methyl-2(1H)-pyridone;
[0014] S4, the dried 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, a copper catalyst, and an organic solvent are stirred and mixed and heated to 110-120° C. to react, and after monitoring the completion of the reaction, the mixture is extracted into an extraction solvent, concentrated and recrystallized to obtain pirfenidone.
[0015] In this technical solution, as shown in chemical formula II, 2-bromo(iodo)-5-methylpyridine is used as a raw material and reacted at 50-80° C. to generate the pirfenidone intermediate 5-methyl-2(1H)-pyridone. The reaction temperature is low, the reaction conditions are mild, and the yield is above 95%. This method can replace the preparation method using 2-amino-5-methylpyridine as a starting material in the prior art, avoids the azidation reaction, and is safer and more reliable.
[0016]
[0017] Preferably, in step S1, the alkaline solution is a potassium hydroxide solution or a sodium hydroxide solution, wherein the molar amount of potassium hydroxide or sodium hydroxide is 1.5-2.5 times that of 2-bromo(iodo)-5-methylpyridine.
[0018] In this technical solution, 2-bromo(iodine)-5-methylpyridine is used as a raw material, and a potassium hydroxide solution or a sodium hydroxide solution is used as a reaction acid-binding agent. The reaction acid-binding agent only needs 1.5-2.5 times the equivalent, and generally 2 times the equivalent is used, so that a reaction yield of more than 95% can be achieved, the yield is high, and the generation of wastewater is greatly reduced.
[0019] Preferably, in step S1, the organic solvent is one or two of tetrahydrofuran, n-butanol and tert-butanol, and the amount of the organic solvent is 7-10 mL of the organic solvent per gram of 2-bromo(iodine)-5-methylpyridine.
[0020] Preferably, in step S1, the reaction temperature is 60-65°C.
[0021] In this technical solution, the reaction temperature is further limited, thereby further ensuring the reaction yield. In addition, the reaction temperature is low, the reaction conditions are milder, and the reaction is safer.
[0022] Preferably, the extraction solvent in steps S1 and S4 is ethyl acetate or dichloromethane.
[0023] Preferably, in step S2, after monitoring the completion of the reaction, the reaction product is extracted into an extraction solvent by acid-base extraction, which specifically includes the following steps:
[0024] S21, after monitoring the completion of the reaction, cooling to room temperature, adding an extraction solvent and water, and standing to separate the liquids, wherein the amount of the extraction solvent is 5-10 mL of the extraction solvent and 5-10 mL of water per gram of 2-bromo(iodo)-5-methylpyridine;
[0025] S22, adding an extraction solvent to the aqueous phase after separation, extracting and merging the aqueous phase into the extraction phase after separation in S21, wherein the amount of the extraction solvent used is 1 / 3 of the amount of the extraction solvent used in S21.
[0026] In this technical solution, the extraction and liquid separation effect is further guaranteed, and basically all the reaction products can be extracted, further ensuring the reaction yield.
[0027] Preferably, in step S3, the extract phase containing the reaction product is concentrated and crystallized to obtain 5-methyl-2(1H)-pyridone, which specifically includes the following steps:
[0028] The extract phase containing the reaction product is washed with water and concentrated, and then a crystallization solvent is added for crystallization to obtain 5-methyl-2(1H)-pyridone.
[0029] Preferably, the crystallization solvent used for concentration and crystallization in step S3 is ethanol, methanol, isopropanol or acetone;
[0030] The crystallization solvent used for the concentration and recrystallization in step S4 is ethanol, methanol, isopropanol or acetone.
[0031] Preferably, in step S4, the copper catalyst is cuprous bromide; in step S4, the organic solvent is one or more of dimethylformamide, 1,4-dioxane, and dimethyl sebacate.
[0032] Preferably, in step S4, the molar ratio of 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, and copper catalyst is 1:(1.5-2.5):(1.5-2.1):(0.09-0.11).
[0033] In this technical solution, the molar ratio of 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, and copper catalyst is limited, so that 5-methyl-2(1H)-pyridone can better undergo nucleophilic substitution reaction with iodobenzene or bromobenzene to generate pirfenidone, and the quality and yield of pirfenidone are relatively high.
[0034] The method for preparing pirfenidone proposed by the present invention has the following beneficial technical effects:
[0035] (1) The method for preparing pirfenidone proposed in the present invention uses 2-bromo(iodo)-5-methylpyridine as a starting material, which can replace the preparation method in the prior art using 2-amino-5-methylpyridine as a starting material, avoids the azidation reaction, and is safer and more reliable.
[0036] (2) The present invention proposes a method for preparing pirfenidone, which uses 2-bromo(iodo)-5-methylpyridine as a starting material and reacts at 50-80°C to generate the pirfenidone intermediate 5-methyl-2(1H)-pyridone. The reaction temperature is low, the reaction conditions are mild, the yield is above 95%, and the purity is relatively high, reaching above 99%.
[0037] (3) The method for preparing pirfenidone proposed in the present invention uses 2-bromo(iodo)-5-methylpyridine as a raw material and potassium hydroxide solution or sodium hydroxide solution as a reaction acid-binding agent. The reaction acid-binding agent only needs 1.5-2.5 equivalents, and generally 2 equivalents are used to achieve a reaction yield of more than 95%, which is high in yield and greatly reduces the generation of wastewater.
[0038] Additional aspects and advantages of the present invention will be given in part in the following description and, in part, will be obvious from the following description or learned through practice of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS
[0039] The above and / or additional aspects and advantages of the present invention will become apparent and easily understood from the description of the embodiments in conjunction with the following drawings, in which:
[0040] Figure 1 The HPLC spectrum of the product 5-methyl-2(1H)-pyridone prepared according to Example 1 of the present invention is shown;
[0041] Figure 2 The HPLC spectrum of the product 5-methyl-2(1H)-pyridone prepared according to Example 2 of the present invention is shown;
[0042] Figure 3 The HPLC spectrum of the product 5-methyl-2(1H)-pyridone prepared according to Example 3 of the present invention is shown;
[0043] Figure 4 The HPLC spectrum of the product 5-methyl-2(1H)-pyridone prepared according to Example 4 of the present invention is shown;
[0044] Figure 5 The HPLC spectrum of the product 5-methyl-2(1H)-pyridone prepared according to Example 5 of the present invention is shown. DETAILED DESCRIPTION
[0045] The present invention discloses a method for preparing pirfenidone, and those skilled in the art can refer to the content of this article and appropriately improve the process parameters to achieve it. It should be particularly noted that all similar replacements and modifications are obvious to those skilled in the art, and they are all considered to be included in the present invention. The method and application of the present invention have been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to realize and apply the technology of the present invention.
[0046] The present invention will be further described below in conjunction with embodiments:
[0047] Example 1
[0048] 20 g of 2-bromo-5-methylpyridine, 160 mL of tetrahydrofuran and 38.8 mL of 6M potassium hydroxide solution were added to a 500 mL four-necked bottle, mixed, and stirred and heated at 60-65°C to dissolve. The reaction raw materials were monitored by TLC. The temperature was cooled to room temperature, 150 mL of dichloromethane and 150 ml of water were added, and the liquids were separated; the aqueous phase was extracted with 50 mL of dichloromethane, and the dichloromethane phase was combined, and then washed with 200 mL of water. The dichloromethane phase was concentrated and crystallized with ethanol, and dried to obtain 12.43 g of a slightly yellowish white solid with a yield of 97.9%. The HPLC spectrum is shown as follows Figure 1 As shown. Figure 1 As shown in (a) and Table 1(a), wavelength 225nm, 99.99%, Figure 1 As shown in (b) and Table 1 (b), the wavelength is 260nm 99.87%. It can be seen that the purity of 5-methyl-2(1H)-pyridone is relatively high, reaching more than 99.90%.
[0049] Table 1 (a) HPLC spectrum analysis at 225 nm wavelength
[0050]
[0051] Table 1 (b) HPLC spectrum analysis at 260 nm wavelength
[0052]
[0053] 10 g of dried 5-methyl-2(1H)-pyridone, 27.8 g of iodobenzene, 25.1 g of potassium carbonate, 1.3 g of cuprous bromide, and 150 mL of dimethylformamide (DMF) were stirred and mixed, and heated to 110° C. The reaction was completed after TLC monitoring; the temperature was lowered, and 200 mL of dichloromethane and 200 mL of water were added thereto, and the mixture was stirred for 10 minutes to separate the liquids; 100 mL of dichloromethane was added to the aqueous phase for extraction, and the dichloromethane phases were combined; then the mixture was washed with 200 mL of water, and the dichloromethane phase was concentrated and then 100 mL of ethanol was added for recrystallization, and after drying, 13.65 g of off-white solid pirfenidone was obtained with a yield of 80.9%.
[0054] Example 2
[0055] 30 g of 2-iodo-5-methylpyridine, 250 mL of tetrahydrofuran and 43.65 mL of 6M sodium hydroxide solution were added to a 500 mL four-necked bottle, mixed, and heated at 50-55°C with stirring to dissolve. The reaction raw materials were monitored by TLC. The temperature was lowered to room temperature, and 150 mL of dichloromethane and 150 ml of water were added to separate the liquids. The aqueous phase was extracted with 50 mL of dichloromethane, and the dichloromethane phase was combined, then washed with 200 mL of water. The dichloromethane phase was concentrated and crystallized with isopropanol, and dried to obtain 14.7 g of a slightly yellowish white solid with a yield of 98.4%. The HPLC spectrum is shown as follows Figure 2 As shown. Figure 2 As shown in (a) and Table 2(a), wavelength 225nm, 99.99%, Figure 2 The wavelength of 260nm shown in (b) and Table 2 (b) is 99.98%. It can be seen that the purity of 5-methyl-2(1H)-pyridone is relatively high, reaching more than 99.90%.
[0056] Table 2 (a) HPLC spectrum analysis at 225 nm wavelength
[0057]
[0058] Table 2 (b) HPLC spectrum analysis at 260 nm wavelength
[0059]
[0060]
[0061] 10 g of dried 5-methyl-2(1H)-pyridone, 27.8 g of iodobenzene, 25.1 g of potassium carbonate, 1.3 g of cuprous bromide, and 150 mL of DMF were stirred and mixed, and heated to 110° C. The reaction was monitored by TLC until completion; the temperature was lowered, 200 mL of ethyl acetate and 200 mL of water were added thereto, and the mixture was stirred for 10 minutes to separate the liquids; 100 mL of ethyl acetate was added to the aqueous phase for extraction, and the ethyl acetate phases were combined; then the mixture was washed with 200 mL of water, and the ethyl acetate phase was concentrated and then 100 mL of isopropanol was added to recrystallize, and 13.34 g of off-white solid pirfenidone was obtained after drying, with a yield of 78.6%.
[0062] Example 3
[0063] 20 g of 2-bromo-5-methylpyridine, 160 mL of tert-butyl alcohol and 48.4 mL of 6M potassium hydroxide solution were added to a 500 mL four-necked bottle, mixed, and heated at 70-80°C with stirring to dissolve. After the reaction raw materials were completed under TLC monitoring, the temperature was lowered to room temperature, 150 mL of ethyl acetate and 150 ml of water were added, and the liquids were separated; the aqueous phase was extracted with 50 mL of ethyl acetate, the ethyl acetate phase was combined, and then washed with 200 mL of water, the ethyl acetate phase was concentrated, crystallized with acetone, and dried to obtain 12.06 g of a slightly yellowish white solid with a yield of 95.1%. The HPLC spectrum is shown as follows Figure 3 As shown. Figure 3 As shown in (a) and Table 3 (a), wavelength 225nm, 100%, as Figure 3 The wavelength of 260nm shown in (b) and Table 3 (b) is 99.97%. It can be seen that the purity of 5-methyl-2(1H)-pyridone is relatively high, reaching more than 99.90%.
[0064] Table 3 (a) HPLC spectrum analysis at 225 nm wavelength
[0065]
[0066] Table 3 (b) HPLC spectrum analysis at 260 nm wavelength
[0067]
[0068]
[0069] 10 g of dried 5-methyl-2(1H)-pyridone, 25.7 g of bromobenzene, 25.1 g of potassium carbonate, 1.3 g of cuprous bromide, and 150 mL of DMF were stirred and mixed, heated to 120° C., and the reaction was completed after TLC monitoring; the temperature was lowered, 200 mL of dichloromethane and 200 mL of water were added thereto, and the mixture was stirred for 10 minutes for separation; 100 mL of dichloromethane was added to the aqueous phase for extraction, and the dichloromethane phases were combined; then washed with 200 mL of water, the dichloromethane phase was concentrated, and 100 mL of ethanol was added for recrystallization, and after drying, 13.32 g of off-white solid pirfenidone was obtained with a yield of 78.5%.
[0070] Example 4
[0071] 20 g of 2-bromo-5-methylpyridine, 160 mL of n-butanol, and 48.4 mL of 6M potassium hydroxide solution were added to a 500 mL four-necked bottle, mixed, and stirred and heated at 60-70°C to dissolve. The reaction raw materials were monitored by TLC. The temperature was cooled to room temperature, 150 mL of ethyl acetate and 150 ml of water were added, and the liquids were separated; the aqueous phase was extracted with 50 mL of ethyl acetate, the ethyl acetate phase was combined, and then washed with 200 mL of water. The ethyl acetate phase was concentrated and crystallized with methanol, and dried to obtain 12.26 g of a slightly yellowish white solid with a yield of 96.7%. The HPLC spectrum is shown as follows Figure 4 As shown. Figure 4 As shown in (a) and Table 4 (a), wavelength 225nm, 100%, as Figure 4 As shown in (b) and Table 4 (b), the wavelength is 260nm 99.95%. It can be seen that the purity of 5-methyl-2(1H)-pyridone is relatively high, reaching more than 99.90%.
[0072] Table 4 (a) HPLC spectrum analysis at 225 nm wavelength
[0073]
[0074]
[0075] Table 4 (b) HPLC spectrum analysis at 260 nm wavelength
[0076]
[0077] 10 g of dried 5-methyl-2(1H)-pyridone, 45 g of iodobenzene, 46.1 g of cesium carbonate, 1.3 g of cuprous bromide, and 150 mL of 1,4-dioxane were stirred and mixed, heated to reflux, and the reaction was monitored by TLC. The temperature was lowered, 200 mL of dichloromethane and 200 mL of water were added thereto, and the mixture was stirred for 10 minutes to separate the liquids. 100 mL of dichloromethane was added to the aqueous phase for extraction, and the dichloromethane phases were combined. Then, the mixture was washed with 200 mL of water, and the dichloromethane phase was concentrated and then 100 mL of ethanol was added for recrystallization. After drying, 14.14 g of off-white solid pirfenidone was obtained with a yield of 83.3%.
[0078] Example 5
[0079] 30 g of 2-iodo-5-methylpyridine, 250 mL of tetrahydrofuran and 43.65 mL of 6M sodium hydroxide solution were added to a 500 mL four-necked bottle, mixed, and heated at 55-65°C with stirring to dissolve. After the reaction raw materials were completed under TLC monitoring, the temperature was lowered to room temperature, 150 mL of ethyl acetate and 150 ml of water were added, and the liquids were separated; the aqueous phase was extracted with 50 mL of ethyl acetate, the ethyl acetate phase was combined, and then washed with 200 mL of water, the ethyl acetate phase was concentrated, crystallized with isopropanol, and dried to obtain 14.37 g of a slightly yellowish white solid with a yield of 96.2%. The HPLC spectrum is shown as follows Figure 5 As shown. Figure 5 As shown in (a) and Table 5 (a), wavelength 225nm, 99.99%, Figure 5 As shown in (b) and Table 5 (b), the wavelength is 260 nm and the purity is 99.96%. It can be seen that the purity of 5-methyl-2(1H)-pyridone is relatively high, reaching more than 99.90%.
[0080] Table 5 (a) HPLC spectrum analysis at 225 nm wavelength
[0081]
[0082] Table 5 (b) HPLC spectrum analysis at 260 nm wavelength
[0083]
[0084] The dried 5-methyl-2(1H)-pyridone 10 g, iodobenzene 50 g, cesium carbonate 48 g, cuprous bromide 1.6 g, and DMS 150 mL were stirred and mixed, heated to 110° C., and the reaction was completed after TLC monitoring; the temperature was lowered, 200 mL of dichloromethane and 200 mL of water were added thereto, and the mixture was stirred for 10 minutes to separate the liquids; 100 mL of dichloromethane was added to the aqueous phase for extraction, and the dichloromethane phases were combined; then the mixture was washed with 200 mL of water, and the dichloromethane phase was concentrated and then 100 mL of methanol was added for recrystallization, and after drying, 13.55 g of off-white solid pirfenidone was obtained with a yield of 79.8%.
[0085] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.
Claims
1. A method for preparing pirfenidone, characterized in that: The following steps are involved: S1, 2-bromo-5-methylpyridine or 2-iodo-5-methylpyridine, an organic solvent, and an alkaline solution are stirred and mixed and heated to 50-80° C. for reaction, The alkaline solution is a potassium hydroxide solution, and the molar amount of potassium hydroxide is 1.5-2.5 times that of 2-bromo-5-methylpyridine or 2-iodo-5-methylpyridine. Alternatively, the alkaline solution is a sodium hydroxide solution, and the molar amount of sodium hydroxide is 1.5-2.5 times that of 2-bromo-5-methylpyridine or 2-iodo-5-methylpyridine; The organic solvent is one or two of tetrahydrofuran, n-butanol, and tert-butanol, and the amount of the organic solvent is 7-10 mL of the organic solvent per gram of 2-bromo-5-methylpyridine or 2-iodo-5-methylpyridine; S2, after monitoring the completion of the reaction, extracting the reaction product into an extraction solvent by acid-base extraction; S3, concentrating and crystallizing the extract phase containing the reaction product to obtain 5-methyl-2(1H)-pyridone; S4, the dried 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, a copper catalyst, and an organic solvent are stirred and mixed and heated to 110-120° C. to react, and after monitoring the completion of the reaction, the mixture is extracted into an extraction solvent, concentrated and recrystallized to obtain pirfenidone.
2. The method for preparing pirfenidone according to claim 1, wherein In step S1, the reaction temperature is 60-65°C.
3. The method for preparing pirfenidone according to claim 1 or 2, characterized in that: In steps S2 and S4, the extraction solvent is ethyl acetate or dichloromethane.
4. The method for preparing pirfenidone according to claim 3, characterized in that: In step S2, after monitoring the completion of the reaction, the reaction product is extracted into an extraction solvent by acid-base extraction, which specifically includes the following steps: S21, after monitoring the completion of the reaction, cooling to room temperature, adding an extraction solvent and water, and standing to separate the liquids, wherein the amount of the extraction solvent is 5-10 mL of the extraction solvent and 5-10 mL of water per gram of 2-bromo-5-methylpyridine or 2-iodo-5-methylpyridine; S22, adding an extraction solvent to the aqueous phase after separation, extracting and merging the aqueous phase into the extraction phase after separation in S21, wherein the amount of the extraction solvent used is 1 / 3 of the amount of the extraction solvent used in S21.
5. The method for preparing pirfenidone according to claim 4, characterized in that: In step S3, the extract phase containing the reaction product is concentrated and crystallized to obtain 5-methyl-2(1H)-pyridone, which specifically includes the following steps: The extract phase containing the reaction product is washed with water and concentrated, and then a crystallization solvent is added for crystallization to obtain 5-methyl-2(1H)-pyridone.
6. The method for preparing pirfenidone according to claim 5, characterized in that: The crystallization solvent used in the concentration and crystallization in step S3 is ethanol, methanol, isopropanol or acetone; The crystallization solvent used for the concentration and recrystallization in step S4 is ethanol, methanol, isopropanol or acetone.
7. The method for preparing pirfenidone according to claim 6, characterized in that: In step S4, the copper catalyst is cuprous bromide; in step S4, the organic solvent is one or more of dimethylformamide, 1,4-dioxane, and dimethyl sebacate.
8. The method for preparing pirfenidone according to claim 7, characterized in that: In step S4, the molar ratio of 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, and copper catalyst is 1:(1.5-2.5):(1.5-2.1):(0.09-0.11).