A preparation method of anti-fibrosis drug pirfenidone

Abstract

The present invention belongs to the technical field of organic chemical synthesis and discloses a preparation method of an anti-fibrosis drug pirfenidone. The synthesis method is based on 5-methyl-2 (1 H Using pyridone and halogenated benzene as raw materials, a copper salt and a small organic ligand as catalyst in the presence of a Lewis base, an Ullmann-type C-N coupling reaction occurs in a specific solvent at a specific temperature to produce pirfenidone. This synthetic route features mild conditions, short reaction time, and high yield, making it 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 approved drug for the treatment of idiopathic pulmonary fibrosis (IPF). It was approved in the EU in 2011 for the treatment of mild to moderate IPF in adults and in the US in 2014, launching in China the same year. Studies have shown that PFD can downregulate pro-fibrotic growth factors (such as transforming growth factor (TGF-β) and platelet-derived growth factor (PDGF)), inhibit the production and release of inflammatory cytokines such as interleukins and tumor necrosis factor (TNF-α), reduce lipid peroxidation and oxidative stress, and reduce extracellular matrix (ECM) deposition, thereby treating 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). Then, under the catalysis of anhydrous potassium carbonate and copper, it undergoes N-arylation reaction with halogenated benzene under high temperature conditions. 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, zinc-precipitated copper powder was used as a catalyst, and 5-methyl-2(1H)-pyridone and iodobenzene were refluxed for 18 hours to produce the product. US20080319026 used activated copper powder as a catalyst, and 2-hydroxy-5-methylpyridine and iodobenzene were refluxed for 7 hours to produce the product. Both patents used copper powder as a catalyst, and iodobenzene served as both a reactant and a reaction solvent. The reaction reflux temperature was high (180-190°C), the reaction time was long (7-18 hours), and the post-processing was relatively complicated, making it unsuitable for industrial production. WO2003014087 used bromobenzene instead of iodobenzene, and cuprous oxide was used as a catalyst. 5-methyl-2(1H)-pyridone was reacted at the reflux temperature of bromobenzene (156°C) for 3.5 hours to produce pirfenidone with a yield of 64.8%. CN100396669C uses cuprous chloride as a catalyst to produce 5-methyl-2(1H)-pyridone by refluxing iodobenzene for 3 hours, with a yield of 68.8%. CN10891676 uses cuprous bromide as a catalyst, reacting bromobenzene at the reflux temperature for 12 hours, followed by recrystallization from water, with a yield of 60.3%. WO2010141600 replaces iodobenzene with bromobenzene (containing 0.15% dibromobenzene), reacting 5-methyl-2(1H)-pyridone with cuprous oxide in DMF at 125°C for 18-20 hours 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 use of the more toxic iodobenzene.

[0006] Li Fa et al. (Anhui Chemical Industry, 2012, 38(4): 27, 31.) used DMF as solvent, cuprous bromide as catalyst, and 5% 1,10-phenanthroline as ligand to react 5-methyl-2(1H)-pyridone with bromobenzene at 90°C for 2 hours to obtain pirfenidone with a total yield of about 65%. US20180319747 reported a catalytic system consisting of a monovalent copper (I) salt and an organic ligand of ethylenediamine, which can react chlorobenzene and 5-methyl-2(1H)-pyridone 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, and couples it with halogenated benzene (chlorobenzene, bromobenzene or iodobenzene) under a catalytic system composed 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 reported in the literature for catalyzing CN coupling reactions, such as phenanthroline, ethylenediamine, and triazole, are all nitrogen-containing bidentate ligands. These ligands can also undergo CN coupling with halogenated benzenes in the Ullmann reaction to form byproducts, increasing the difficulty of separation and purification of the reaction system. Furthermore, the ethylenediamine-based catalytic system requires autoclave operation, increasing the risk of the reaction. Furthermore, the high reaction temperatures and long reaction times of the CN coupling reaction systems reported in the literature limit their industrial application and large-scale production. Summary of the Invention

[0011] To address the problems of high reaction temperature and long reaction time in the above-mentioned existing synthesis 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, its purpose is to improve the catalytic activity of Cu salts in the CN coupling reaction, 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 ferrite, cupric isooctanoate, and cupric trifluoromethanesulfonate. Preferred are cuprous (I) chloride, cuprous (I) bromide, and cuprous (I) iodide.

[0018] The small molecule organic ligand includes amino acids and their structural analogs, such as proline, hydroxyproline, histidine, serine, threonine, phenylalanine, tyrosine, pipecolic acid (including 2-piperidinic acid, 3-piperidinic acid, 4-piperidinic acid), hydroxypiperidinic acid (including 1-hydroxypiperidinic acid, 3-hydroxypiperidinic acid, 4-hydroxypiperidinic acid, 5-hydroxypiperidinic acid), 1-(2-hydroxyethyl)-3-piperidinic acid, piperidinemethanol (2-piperidinol, 3-piperidinol, 4-piperidinol), etc. or one of their structural analogs. Among them, the amino acid and its structural analog can be a single chiral isomer such as L-configuration, D-configuration, or S-configuration, R-configuration, or a racemic form thereof. Preferably, one of L-proline, L-hydroxyproline, L-phenylalanine, pipecolic acid, hydroxypiperidinic acid or their structural analogs. More preferably, L-hydroxyproline.

[0019] The catalytic system composed of copper salt and small molecule organic ligand can have a molar ratio of organic ligand to copper salt of 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 used.

[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 copper proline, copper hydroxyproline, copper pipecolate, copper hydroxypiperidinate, copper piperidinol, copper serine, copper threonine, copper phenylalanine, etc. or their analogs.

[0021] The molar ratio of the 5-methyl-2(1H)-pyridone to the halogenated benzene is 1:1 to 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 such as N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, chloroform, dichloromethane, acetonitrile, methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, tert-butyl alcohol, 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. Preferably, a mixed solvent consisting of one or two solvents such as methanol, ethanol, propanol, isopropyl alcohol, butanol, isobutyl alcohol, tert-butyl alcohol, cyclohexanol, toluene, o-xylene, and ethylbenzene is used.

[0024] The novel method for synthesizing pirfenidone provided by the present invention has the advantages of low cost and easy availability of the raw material 5-methyl-2(1H)-pyridone, a short process flow and simple operation compared to the previously disclosed synthetic routes; a catalytic system consisting of a copper salt and a small molecule organic ligand is selected, the reaction temperature is reduced to 100-120° C. compared to 180° C. in the literature, and the reaction time is reduced to 0.5-2 hours compared to 4-18 hours in the literature, thereby greatly reducing energy consumption, achieving mild reaction conditions, and producing few by-products, which is conducive to separation and purification of the reaction system, making the method suitable for standardized production and industrial application, and achieving a yield of over 73%. DETAILED DESCRIPTION

[0025] In order to better illustrate the present invention, the specific technical solutions of the present invention are further described in detail below in conjunction with some examples, but are not limited to the implementation conditions described in the following examples. Unless otherwise specified, the percentages mentioned below are all weight 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; the 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] 0.55 g of 5-methyl-2(1H)-pyridone, 2.0 g of iodobenzene, 0.8 g of anhydrous potassium carbonate, 0.1 g of CuI, 2.5 mL of toluene, and 0.7 g of L-hydroxyproline were added to a three-necked flask and heated at 120°C for 1 hour. The mixture was cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization. The filtrate was filtered and concentrated to dryness. Finally, it was purified by column chromatography (dichloromethane / methanol = 30:1) to obtain 0.67 g of light yellow pirfenidone crystals with a yield of 73%. mp: 113.3°C-114.9°C, 1H NMR (400 MHz, CDCl 3 ) 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 5.0mL DMF, 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, filtered, and the filtrate was concentrated to dryness to obtain a brown oil. It was then stirred and solidified with a small amount of petroleum ether 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, the 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, 2.5mL N-methylpyrrolidone, and 0.3g pipecolic acid were added to a three-necked flask and heated at 110°C for 2h. The mixture was cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, and activated carbon was added for decolorization. The filtrate was filtered and concentrated to dryness. Finally, it was purified by column chromatography to obtain 0.54g light yellow pirfenidone crystals 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 dryness to obtain a brown oil, which was 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, the 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 of 5-methyl-2(1H)-pyridone, 3.0 g of iodobenzene, 1.8 g of strontium carbonate, 0.1 g of CuI, 5.0 mL of 1,4-dioxane, and 0.8 g of L-phenylalanine were added to a three-necked flask and heated at 100°C for 1 hour. The mixture was then cooled to room temperature and filtered. Excess ethyl acetate was added to the filtrate, which was then decolorized with activated carbon. The mixture was filtered and concentrated to dryness. The resulting mixture was recrystallized from 95% ethanol to yield 1.3 g of light yellow pirfenidone crystals in a 68% yield.

[0037] Comparative Example 5

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

Claims

1. A method for synthesizing pirfenidone, characterized in that: In a solvent, 5-methyl-2(1 H )-pyridone and halogenated benzene are used as raw materials, copper salt and small molecule organic ligand are added to form a catalytic system in the presence of 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; The Lewis base is selected from sodium carbonate or potassium carbonate.

2. 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 used.

3. The method for synthesizing pirfenidone according to any one of claims 1 to 2, wherein: The solvent is selected from one or a mixed solvent consisting of two of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, cyclohexanol, toluene, o-xylene, and ethylbenzene.

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