Preparation method of anti-fibrosis drug pirfenidone

Abstract

The invention belongs to the technical field of organic chemical synthesis, and discloses a preparation method of an anti-fibrosis drug pirfenidone. According to the synthesis method, 5-methyl-2 (1H)-pyridone and halogenated benzene are taken as raw materials, in the presence of Lewis alkali, copper salt and a small molecule organic ligand form a catalytic system, and Ullmann type C-N coupling reaction is carried out in a specific solvent at a certain temperature to generate pirfenidone. The synthesis route is mild in condition, short in reaction time, high in yield and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis and relates to a new method for preparing pirfenidone, an anti-fibrosis drug. Background Art

[0002] Pirfenidone (PFD) is the first anti-idiopathic pulmonary fibrosis (IPF) drug approved for marketing. It was approved in the EU in 2011 for the treatment of mild to moderate IPF in adults, and in the United States in 2014 for the treatment of IPF. It was marketed in China in the same year. Studies have found that PFD can downregulate pro-fibrotic growth factors (such as transforming growth factor (TGF-β), platelet-derived growth factor (PDGF), etc.), inhibit the production and release of inflammatory cytokines such as interleukins and tumor necrosis factor (TNF-α), reduce lipid peroxidation and oxidative stress in the body, and reduce the deposition of extracellular matrix (ECM), etc., to achieve the treatment of fibrotic diseases.

[0003] The synthesis of pirfenidone mainly uses 2-amino-5-methylpyridine as the starting material, which is hydrolyzed by diazotization to obtain 5-methyl-2(1H)-pyridone (or 2-hydroxy-5-methylpyridine), and then reacts with halogenated benzene under high temperature conditions under the catalysis of anhydrous potassium carbonate and copper to undergo N-arylation reaction, and finally pirfenidone is obtained through purification steps such as recrystallization, acid dissolution and alkali precipitation.

[0004]

[0005] In 1974, US03839346 first disclosed a method for preparing pirfenidone. In the presence of anhydrous potassium carbonate, copper powder precipitated with zinc was used as a catalyst, and 5-methyl-2 (1H)-pyridone and iodobenzene were refluxed for 18 hours to obtain the product. US20080319026 used active copper powder as a catalyst, and 2-hydroxy-5-methylpyridine and iodobenzene were refluxed for 7 hours to obtain the product. Both patents use copper powder as a catalyst, and iodobenzene is both a reactant and a reaction solvent. The reaction reflux temperature is high (180-190°C), the reaction time is long (7-18 hours), and the post-processing is relatively complicated, which is not suitable for industrial production. WO2003014087 uses bromobenzene instead of iodobenzene, and uses cuprous oxide as a catalyst. 5-methyl-2 (1H)-pyridone is reacted at the reflux temperature of bromobenzene (156°C) for 3.5 hours to obtain pirfenidone, with a yield of 64.8%. CN100396669C uses cuprous chloride as a catalyst, and 5-methyl-2(1H)-pyridone is refluxed in iodobenzene for 3 hours to obtain a product with a yield of 68.8%. CN10891676 uses cuprous bromide as a catalyst, reacts at the reflux temperature of bromobenzene for 12 hours, and recrystallizes with water as a solvent, with a yield of 60.3%. WO2010141600 uses bromobenzene (containing 0.15% dibromobenzene) instead of iodobenzene, and reacts with 5-methyl-2(1H)-pyridone at 125°C for 18 to 20 hours under the catalysis of cuprous oxide and DMF as a solvent to produce pirfenidone. Guo Cheng et al. (Anhui Medicine, 2014, 18(11): 2051-2053) used cuprous chloride as a catalyst and DMSO as a solvent to react 5-methyl-2(1H)-pyridone and iodobenzene at 180°C for 5 hours, with a pirfenidone yield of 65.2%, while reducing the amount of iodobenzene, which is more toxic.

[0006] Li Fa et al. (Anhui Chemical Industry, 2012, 38(4): 27, 31.) used DMF as solvent, cuprous bromide as catalyst, and added 5% 1,10-phenanthroline as ligand, 5-methyl-2(1H)-pyridone and bromobenzene were reacted at 90°C for 2 hours to obtain pirfenidone with a total yield of about 65%. US20180319747 reported a catalytic system consisting of monovalent copper (I) salt and ethylenediamine organic ligands, which can make chlorobenzene and 5-methyl-2(1H)-pyridone react in a pressure reactor at 160-180°C for 16-19 hours to obtain pirfenidone with a yield of 72%-84%.

[0007]

[0008] Patent CN111848503B uses 5-methyl-3,4-dihydro-2-pyridone instead of 5-methyl-2(1H)-pyridone, couples it with halogenated benzene (chlorobenzene, bromobenzene or iodobenzene) under a catalytic system consisting of copper salt and a new type of triazole ligand, and finally obtains pirfenidone through oxidative dehydrogenation with a yield of 70% to 78%.

[0009]

[0010] The organic ligands such as phenanthroline, ethylenediamine, and triazole reported in the above literature that participate in the catalytic action of the CN coupling reaction are all nitrogen-containing bidentate ligands, which may also undergo CN coupling with halogenated benzene in the Ullmann reaction to form by-products, increasing the difficulty of separation and purification of the reaction system. In addition, the ethylenediamine catalytic system needs to be carried out in a pressure autoclave, which increases the risk of the reaction. In addition, the CN coupling reaction system reported in the literature has a high reaction temperature and a long reaction time, which limits its industrial application and large-scale production. Summary of the invention

[0011] In view of the problems of high reaction temperature and long reaction time in the above-mentioned existing synthetic routes, the present invention is based on the catalytic effect of small molecule organic ligands. By selecting suitable small molecule organic ligands and copper salts to form a catalytic system, the purpose is to improve the catalytic activity of Cu salts in CN coupling reactions, reduce the reaction temperature, shorten the reaction time, and provide convenient conditions for large-scale production.

[0012] To achieve the above object, the present invention adopts the following technical solutions:

[0013] The novel method for synthesizing pirfenidone uses 5-methyl-2(1H)-pyridone and halogenated benzene as raw materials, adds copper salt and small molecule organic ligand to form a catalytic system in the presence of Lewis base, and generates pirfenidone by an Ullmann-type CN coupling reaction in a solvent under heating conditions.

[0014]

[0015] Wherein, X represents chlorine, bromine, or iodine;

[0016] The Lewis base includes sodium carbonate, potassium carbonate, rubidium carbonate, cesium carbonate, lithium hydroxide, potassium hydroxide, sodium hydroxide, rubidium hydroxide, cesium hydroxide, sodium phosphate, potassium phosphate, sodium methoxide, potassium methoxide, potassium tert-butoxide, sodium tert-butoxide, tetraethyl quaternary ammonium carbonate, tetrabutylammonium hydroxide, etc., preferably sodium carbonate, potassium carbonate, etc.

[0017] The copper salts include monovalent copper salts or divalent copper salts, wherein the monovalent copper salts include cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cuprous sulfate, cuprous nitrate, cuprous nitride, cuprous thiocyanate, cuprous thiophene-2-carboxylate, and cuprous trifluoromethanesulfonate; the divalent copper salts include cupric chloride, cupric bromide, iodide, cupric acetate, cupric nitrate, cupric sulfate, cupric oxalate, cupric oxide, cupric hydroxide, copper ferrate, cupric isooctanoate, and cupric trifluoromethanesulfonate, etc. Preferred are cuprous chloride (I), cuprous bromide (I), and cuprous iodide (I).

[0018] The small molecule organic ligand includes amino acids and structural analogs thereof, such as proline, hydroxyproline, histidine, serine, threonine, phenylalanine, tyrosine, pipecolic acid (including 2-pipecolic acid, 3-pipecolic acid, 4-pipecolic acid), hydroxypipecolic acid (including 1-hydroxypipecolic acid, 3-hydroxypipecolic acid, 4-hydroxypipecolic acid, 5-hydroxypipecolic acid), 1-(2-hydroxyethyl)-3-piperidinol carboxylic acid, piperidine methanol (2-piperidinol methanol, 3-piperidinol methanol, 4-piperidinol methanol), etc. or one of their structural analogs. Among them, amino acids and their structural analogs can be single chiral isomers such as L-configuration, D-configuration, or S-configuration, R-configuration, or racemates thereof. Preferably, L-proline, L-hydroxyproline, L-phenylalanine, pipecolic acid, hydroxypiperidinic acid or one of their structural analogs. More preferably, L-hydroxyproline.

[0019] The catalytic system composed of copper salt and small molecule organic ligand, the molar ratio of organic ligand to copper salt can be 20:1 to 1:1; wherein the amount of copper salt used is 1 mol% to 40 mol% of the amount of 5-methyl-2(1H)-pyridone.

[0020] The catalytic system composed of the copper salt and the small molecule organic ligand can be added to the reaction system in the form of monomers, or prepared in the form of metal copper complexes and added to the reaction system, such as metal copper complexes of proline copper, hydroxyproline copper, pipecolic acid copper, hydroxypiperidinol copper, serine copper, threonine copper, phenylalanine copper, etc. or their analogs.

[0021] The feeding molar ratio of the 5-methyl-2(1H)-pyridone and the halogenated benzene is 1:1-1:3.

[0022] The reaction temperature is in the range of 80°C to 180°C, preferably 100°C to 120°C.

[0023] The reaction solvent can be a halogenated benzene, or a mixed solvent consisting of one or two solvents of N, N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, chloroform, dichloromethane, acetonitrile, methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, cyclohexanol, toluene, o-xylene, ethylbenzene, 1,4-dioxane, N-methyl pyrrolidone, ethylene glycol, ethylene glycol ethyl ether, ethylene glycol methyl ether, ethylene glycol dimethyl ether, and water. A mixed solvent consisting of one or two solvents of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, cyclohexanol, toluene, o-xylene, ethylbenzene, etc. is preferred.

[0024] The novel method for synthesizing pirfenidone provided by the present invention has the advantages of low cost and easy availability of raw material 5-methyl-2(1H)-pyridone, short process flow and simple operation compared with the disclosed synthesis route; a catalytic system composed of copper salt and small molecule organic ligand is selected, the reaction temperature is reduced to 100-120° C. compared with 180° C. in the literature, and the reaction time is reduced to 0.5-2 hours compared with 4-18 hours in the literature, so that the energy consumption is greatly reduced, the reaction conditions are mild, the by-products are few, the separation and purification of the reaction system is facilitated, the method is suitable for standardized production and industrial application, and the yield reaches more than 73%. DETAILED DESCRIPTION

[0025] In order to better illustrate the present invention, the specific technical scheme of the present invention is further described in detail below in conjunction with some embodiments, but is not limited to the implementation conditions described in the following embodiments. Unless otherwise specified, the percentages described below are all mass percentages.

[0026] Among them, the raw material 5-methyl-2(1H)-pyridone can be prepared according to the method described in the literature (Synthetic Chemistry, 2004, 12(01): 89-90, 93), or can be purchased commercially; hydroxyproline copper complex can be prepared according to the literature (Feed Research, 2022, 45(20): 117-119); other reagents can be purchased commercially.

[0027] Example 1

[0028] Add 0.55g 5-methyl-2(1H)-pyridone, 2.0g iodobenzene, 0.8g anhydrous potassium carbonate, 0.1g CuI, 2.5mL toluene, and 0.7g L-hydroxyproline to a three-necked flask, heat the reaction at 120°C for 1h, cool to room temperature, and filter. Add excess ethyl acetate to the filtrate, add activated carbon for decolorization, filter, and concentrate the filtrate to dryness. Finally, purify by column chromatography (dichloromethane / methanol=30:1) to obtain 0.67g light yellow pirfenidone crystals with a yield of 73%. mp: 113.3℃-114.9℃, 1H NMR (400 MHz, CDCl3) δ 7.52-7.34 (m, 4H), 7.30-7.23 (m, 2H), 7.11 (s, 1H), 6.61 (d, J=9.3 Hz, 1H), 2.10 (s, 3H). Purity 99.6% (HPLC normalization method).

[0029] Comparative Example 1

[0030] 1.1g 5-methyl-2(1H)-pyridone, 2.3g bromobenzene, 0.7g potassium hydroxide, 0.2g CuBr and 5.0mLDMF, 0.6g L-proline were added to a three-necked flask, heated at 120°C for 1h, cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization and filtration. The filtrate was concentrated to dry brown oil. Then a small amount of petroleum ether was stirred and solidified, and dried to obtain a brown crude product. Finally, the crude product was dissolved with 5% acetic acid, and then 20% sodium hydroxide solution was slowly added dropwise, pH was adjusted to 13, and cooled for crystallization to obtain 1.1g light yellow pirfenidone crystals with a yield of 61%.

[0031] Comparative Example 2

[0032] 0.55g 5-methyl-2(1H)-pyridone, 1.5g iodobenzene, 0.8g anhydrous sodium carbonate, 0.1g CuCl and 2.5mL N-methylpyrrolidone, 0.3g pipecolic acid were added to a three-necked flask, heated at 110°C for 2h, cooled to room temperature, and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization, filtered, and the filtrate was concentrated to dryness. Finally, 0.54g light yellow pirfenidone crystals were obtained by column chromatography purification with a yield of 58%.

[0033] Comparative Example 3

[0034] 1.1g 5-methyl-2 (1H) -pyridone, 2.4g iodobenzene, 1.5g strontium carbonate, 0.4g CuI and 5.0mL ethylene glycol, 0.7g 5-hydroxypiperidine-2-carboxylic acid were added to a three-necked flask, heated at 120 ° C for 0.5h, cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization, filtered, and the filtrate was concentrated to dry brown oil, then solidified with petroleum ether, and dried to obtain a brown crude product. Finally, the crude product was dissolved with 10% acetic acid, and then 20% sodium hydroxide solution was slowly added dropwise, pH was adjusted to 13, and cooled for crystallization to obtain 1.2g light yellow pirfenidone crystals with a yield of 64%.

[0035] Comparative Example 4

[0036] 1.1 g 5-methyl-2(1H)-pyridone, 3.0 g iodobenzene, 1.8 g strontium carbonate, 0.1 g CuI, 5.0 mL 1,4-dioxane, and 0.8 g L-phenylalanine were added to a three-necked flask, heated at 100°C for 1 h, cooled to room temperature, and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization, filtered, and the filtrate was concentrated to dryness and recrystallized with 95% ethanol to obtain 1.3 g light yellow pirfenidone crystals with a yield of 68%.

[0037] Comparative Example 5

[0038] 1.1 g 5-methyl-2(1H)-pyridone, 3.0 g iodobenzene, 1.8 g strontium carbonate, 1.0 g L-hydroxyproline copper (II) complex and 5.0 mL water were added to a three-necked flask, heated at 100°C for 2 h, cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization, filtered, and the filtrate was concentrated to dryness and recrystallized with 95% ethanol to obtain 1.1 g light yellow pirfenidone crystals with a yield of 60%.

Claims

1. A method for synthesizing pirfenidone, characterized in that: In a solvent, 5-methyl-2(1H)-pyridone and halogenated benzene are used as raw materials, copper salt and small molecular organic ligand are added to form a catalytic system in the presence of a Lewis base, and the reaction is carried out under heating conditions to obtain pirfenidone; wherein X represents chlorine, bromine or iodine; The small molecule organic ligand is selected from L-hydroxyproline; the copper salt is selected from cuprous chloride, cuprous bromide or cuprous iodide.

2. The method for synthesizing pirfenidone according to claim 1, wherein The Lewis base is selected from sodium carbonate or potassium carbonate.

3. The method for synthesizing pirfenidone according to claim 1, wherein In the catalytic system composed of the copper salt and the small molecule organic ligand, the molar ratio of the organic ligand to the copper salt is 20:1 to 1:1; the amount of the copper salt used is 1 mol% to 40 mol% of the amount of 5-methyl-2(1H)-pyridone.

4. The method for synthesizing pirfenidone according to any one of claims 1 to 3, characterized in that: The solvent is selected from one of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, cyclohexanol, toluene, o-xylene, ethylbenzene, or a mixed solvent consisting of two of the solvents.

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