A method for preparing pirfenidone using oxalyl dihydrazide polymer copper catalyst

Abstract

The present invention provides a method for preparing pirfenidone by catalytic oxalyl dihydrazide polymer copper catalyst, belongs to the field of pharmaceutical synthesis technology, comprising the following steps: adding 5 methyl 2 (1H) pyridone, alkali, solvent, bromobenzene and catalyst in a reaction vessel, heating for coupling reaction to obtain pirfenidone;Wherein, the preparation step of the catalyst is:adding oxalyl dihydrazide, 1,4 dibromonaphthalene, potassium phosphate and copper compound in a hydrothermal kettle, adding solvent, heating reaction, filtering the mixture, washing and drying to obtain a catalyst. In this preparation method, it is first proposed to use oxalyl dihydrazide polymer copper catalyst, recovery process is simple, and reuse rate is high.

Description

Technical Field

[0001] The invention relates to a method for preparing an oxalyl dihydrazide polymer copper catalyst and preparing pirfenidone by catalysis thereof, and belongs to the technical field of drug synthesis. Background Art

[0002] Pirfenidone (PFD) is a novel, broad-spectrum antifibrotic drug with the chemical name 5-methyl-1-phenyl-2-(1H)pyridone and the molecular formula C12H11NO. Pirfenidone can modulate multiple cytokines, alter collagen expression, synthesis, and accumulation, and inhibit extracellular matrix proliferation and expression, exhibiting anti-inflammatory, antioxidant, and anti-fibrotic effects. Clinical trials have demonstrated that PFD has broad-spectrum anti-fibrotic effects on the lungs, heart, liver, and kidneys. It can reduce lung function decline in patients with idiopathic pulmonary fibrosis and, to a certain extent, slow disease progression.

[0003] In 2017, Xiaomei Ding, Manna Huang, et al. prepared an aryl-substituted pyrrole hydrazide ligand via a CN coupling reaction of pyrrole hydrazide. This resulted in the establishment of a versatile and efficient CuI / N,N-diaryl-1h-pyrrole-2-carbohydrazide catalyst system. This protocol, requiring only 5 mol% of CuI and ligand, enabled the amination of various aryl brominations and iodinations with a wide range of aliphatic and arylamines (1.3 equivalents) (J. Org. Chem. 2017, 82, 5416-5423).

[0004] In 2020, Chen Yanjiao, Zhang Heng, Wang Zhengxiong, and others used 2-amino-5-methylpyridine as the starting material, subjected it to diazotization and hydrolysis to obtain the intermediate 5-methyl-2(1H)-pyridone. This intermediate then reacted with iodobenzene in the presence of anhydrous potassium carbonate and copper iodide to form the target product, pirfenidone, in a nucleophilic substitution reaction. After process optimization, the overall yield was 66.6%. This method has a low overall yield and uses iodobenzene as a raw material, resulting in poor atom economy and unfavorable for industrial production.

[0005] In 2016, Zheng Ruixi, Song Danbi, et al. developed a new mild synthetic method for the N-arylation of 2-pyridones with diaryl salts. Most reactions proceeded readily at room temperature in the presence of 10 mol% copper chloride. Consequently, a wide range of N-arylpyridin-2-ones were synthesized with yields ranging from 23% to 99% (J. Org. Chem. 2016, 81, 17, 7717–7724). This method used copper chloride as a catalyst, which is not easily recyclable.

[0006] Chinese patent document CN118344287A provides a method for the preparation of pirfenidone. 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; S2: after monitoring the completion of the reaction, the reaction product is extracted into the extraction solvent by acid-base extraction; S3: the extract phase containing the reaction product is concentrated and crystallized to obtain 5-methyl-2(1H)-pyridone; S4: 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 for reaction. After monitoring the completion of the reaction, the mixture is extracted into the extraction solvent, concentrated and recrystallized to obtain pirfenidone. The overall yield is about 80%. This method uses copper bromide as a catalyst, which is not conducive to recycling. Summary of the Invention

[0007] In order to solve the above-mentioned defects and deficiencies in the prior art, the present invention provides a method for preparing a copper oxalyl dihydrazide polymer catalyst and preparing pirfenidone by catalysis thereof.

[0008] To solve the above technical problems, the present invention provides a method for preparing an oxalyl dihydrazide polymer copper catalyst and catalytically preparing pirfenidone, the specific steps of which are as follows:

[0009] 5-methyl-2(1H)-pyridone, a base, a solvent, bromobenzene and a catalyst are added to a reaction vessel, and heating is performed to perform a coupling reaction to obtain pirfenidone;

[0010] The catalyst is prepared by adding oxalyl dihydrazide, 1,4-dibromonaphthalene, potassium phosphate and a copper compound into a hydrothermal kettle, adding a solvent, heating for reaction, filtering, washing and drying the mixture to obtain the catalyst.

[0011] Furthermore, in the step of preparing the catalyst, the copper compound is copper acetate or cuprous iodide, the solvent is DMF or DMSO, the reaction temperature is 130-150° C., and the reaction time is 10-15 hours.

[0012] Furthermore, the base is potassium phosphate or cesium carbonate, and the added molar amount of the base is 1-2 times that of the substrate; and the solvent is DMSO or DMF.

[0013] Furthermore, the reaction temperature of the coupling reaction is 110-150° C., and the reaction time is 5-10 h.

[0014] Furthermore, the added mass of the catalyst is 20-35% of 5-methyl-2(1H)-pyridone.

[0015] Furthermore, the preparation steps of the 5-methyl-2(1H)-pyridone are: adding 2-chloro-5-methylpyridine, a base, and a solvent into a reaction container, heating and performing a hydroxylation reaction to obtain 5-methyl-2(1H)-pyridone.

[0016] Furthermore, the base in the hydroxylation reaction is KOH or NaOH, and the added molar amount of the base is 1.5-3 times that of 2-chloro-5-methylpyridine; the solvent is DMSO, and the added mass is 2-4 times that of 2-chloro-5-methylpyridine.

[0017] Furthermore, the reaction temperature of the hydroxylation reaction is 140-160° C., and the reaction time is 5-10 h.

[0018] The reaction formula for preparing pirfenidone in the present invention is shown in Formula 1 below:

[0019]

[0020] The present invention achieves the following beneficial technical effects: The present invention provides a method for preparing a copper oxalyl dihydrazide polymer catalyst. Using 2-chloro-5-methylpyridine as a raw material, 5-methyl-2(1H)-pyridone is prepared via a hydroxylation reaction. This catalyst is then used to couple the catalyst with bromobenzene to produce pirfenidone. This reaction process is simple, the catalyst is easily recyclable and has a high reusability, and the product is easily separated, demonstrating promising industrial application prospects. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 This is the infrared spectrum of the catalyst prepared in Example 1 of the present invention;

[0022] Figure 2 This is the N2 adsorption-desorption isotherm of the catalyst prepared in Example 1 of the present invention;

[0023] Figure 3 This is the pore size distribution diagram of the catalyst prepared in Example 1 of the present invention. DETAILED DESCRIPTION

[0024] The present invention will be further described below in conjunction with specific examples. The following examples are only used to more clearly illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention.

[0025] The present invention is further described below with reference to the examples.

[0026]

[0027]

[0028] Example 1

[0029] Preparation of oxalyl dihydrazide polymer copper catalyst: 6 g of oxalyl dihydrazide (0.05 mol), 28.6 g of 1,4-dibromonaphthalene (0.1 mol), 42 g of potassium phosphate (0.2 mol), 100 ml of DMF, and 9.5 g of cuprous iodide (0.05 mol) were added to a hydrothermal autoclave, heated at 150° C. for 10 h, and the resulting mixture was filtered, washed with water, and dried to obtain the oxalyl dihydrazide polymer copper catalyst.

[0030]

[0031] Formula 2. One-step preparation of oxalyl dihydrazide polymer copper catalyst

[0032] Example 2

[0033] Preparation of oxalyl dihydrazide polymer copper catalyst: 6 g of oxalyl dihydrazide (0.05 mol), 28.6 g of 1,4-dibromonaphthalene (0.1 mmol), 42 g of potassium phosphate (0.2 mmol), 100 ml of DMSO, and 10 g of copper acetate (0.05 mmol) were added to a hydrothermal autoclave, heated at 130° C. for 15 h, and the resulting mixture was filtered, washed with water, and dried to obtain the oxalyl dihydrazide polymer copper catalyst.

[0034] Example 3

[0035] Preparation of oxalyl dihydrazide polymer copper catalyst: The difference from Example 1 is that the reaction is heated at 140° C. for 12 h to obtain the oxalyl dihydrazide polymer copper catalyst.

[0036] Fourier transform infrared spectroscopy, N2 adsorption-desorption isotherms, and pore size distribution tests were performed on Examples 1-3, respectively, indicating the formation of oxalyl dihydrazide polymers with a mesoporous structure. The characterization results of Example 1 are used for specific illustration: Figure 1 The infrared spectrum of the catalyst prepared in Example 1 is shown in Figure 1. According to the Fourier transform infrared spectroscopy analysis, 3461 cm -1 The NH bond stretching vibration in the hydrazide group is 1851 cm -1 The presence of hydrazide groups in the catalyst is caused by the vibration of the carbonyl group (C=O) in the hydrazide group; 3067 cm -1 The stretching vibration of the C-H bond in the aromatic group can be attributed to 1580 cm -1 and 1411cm -1 The above characteristic peaks prove the formation of oxalyl dihydrazide polymer. -1 and 408cm -1 The appearance of Cu-N bond at π indicates the successful coordination of copper. Figure 2The N2 adsorption-desorption isotherm of the catalyst prepared in Example 1 was tested for nitrogen adsorption and desorption at 77K liquid nitrogen. The N2 adsorption-desorption isotherm showed a type IV isotherm (i.e., Langmuir adsorption-desorption isotherm), indicating that the catalyst had a mesoporous structure with a specific surface area of ​​3.9688 m 2 / g. Figure 3 The pore size distribution of the catalyst prepared in Example 1 shows a peak centered at 18.14 nm, and its average pore size is calculated to be 13.41 nm, indicating that the catalyst is mainly mesoporous and has a wide pore size distribution, which is beneficial to reducing mass transfer resistance.

[0037] Example 4

[0038] Preparation of 5-methyl-2(1H)-pyridone: 127.6 g (1 mol) of 2-chloro-5-methylpyridine, 80 g of sodium hydroxide (2 mol), and 500 ml of DMSO were added to a reaction vessel and heated at 150°C for 5 h. After the reaction, the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and washed three times with saturated sodium chloride solution. The organic phase was evaporated under reduced pressure to remove the solvent to obtain 108 g of 5-methyl-2(1H)-pyridone, with a yield of 99%.

[0039] Example 5

[0040] Preparation of 5-methyl-2(1H)-pyridone: Replace 80g of sodium hydroxide with 178g of potassium hydroxide (3 mol). The remaining operations were as described in Example 4 to obtain 107.6g of 5-methyl-2(1H)-pyridone with a yield of 99%.

[0041] Example 6

[0042] Preparation of 5-methyl-2(1H)-pyridone: The amount of sodium hydroxide was changed to 60 g, the reaction temperature was changed to 160° C., and the remaining operations were carried out as described in Implementation 4 to obtain 102 g of 5-methyl-2(1H)-pyridone with a yield of 93%.

[0043] Example 7

[0044] Preparation of 5-methyl-2(1H)-pyridone: The reaction temperature was changed to 140°C, the reaction time was changed to 10 h, and the remaining operations were carried out as described in Example 4 to obtain 104 g of 5-methyl-2(1H)-pyridone with a yield of 95%.

[0045] Example 8

[0046] Preparation of pirfenidone: 109 g of 5-methyl-2(1H)-pyridone (1 mol) prepared in Example 4, 212 g of potassium phosphate (1 mol), 235.5 g of bromobenzene (1.5 mol), 500 ml of DMSO and 30 g of the catalyst prepared in Example 1 were added to a reaction vessel and heated at 120 ° C. for 5 h. After the reaction, the catalyst was separated by filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed three times with saturated brine. The solvent was evaporated under reduced pressure to obtain 178 g of pirfenidone with a yield of 96%.

[0047] Example 9

[0048] Preparation of pirfenidone: The reaction temperature was changed to 110° C., the reaction time was changed to 10 h, and the remaining operations were carried out as described in Example 8 to obtain 161 g of pirfenidone with a yield of 87%.

[0049] Example 10

[0050] Preparation of pirfenidone: The reaction temperature was changed to 150° C., the reaction time was changed to 3 h, and the remaining operations were carried out as described in Example 8 to obtain 183 g of pirfenidone with a yield of 99%.

[0051] Example 11

[0052] Preparation of pirfenidone: The added base was replaced with 650 g (2 mol) of cesium carbonate, and the remaining operations were carried out as described in Example 8 to obtain 176 g of pirfenidone with a yield of 95%.

[0053] Example 12

[0054] Preparation of pirfenidone: The solvent was changed to DMF, and the remaining operations were carried out as described in Example 8 to obtain 173 g of pirfenidone with a yield of 94%.

[0055] Example 13

[0056] Preparation of pirfenidone: The added mass of the catalyst was changed to 22 g, and the remaining operations were carried out as described in Example 8 to obtain 168 g of pirfenidone with a yield of 91%.

[0057] Example 14

[0058] Preparation of pirfenidone: The added mass of the catalyst was changed to 38.5 g, and the remaining operations were carried out as described in Example 8 to obtain 176 g of pirfenidone with a yield of 95%.

[0059] Example 15

[0060] Preparation of pirfenidone: The catalyst prepared in Example 1 was replaced with the catalyst prepared in Example 2, and the remaining operations were carried out as described in Example 8 to obtain 173 g of pirfenidone with a yield of 94%.

[0061] Example 16: The catalyst obtained by filtration and separation in Example 8 was added with water and centrifuged to separate the solid. This was repeated three times. The obtained solid was dried in an oven at 100°C for 10 hours to obtain the recovered catalyst, which was then reacted according to the conditions of Example 8. The results are shown in Table 1.

[0062] Table 1: Catalyst recovery times and reaction yield

[0063] Recycling times Pirfenidone 1 96％ 2 95％ 3 96％ 4 93％ 5 93％

[0064] It can be seen from the experimental results in Table 1 that the catalyst of the present application can be reused for catalytic reactions with only simple washing and drying steps, and the catalytic performance can still be maintained at a high level after being reused 5 times.

[0065] Comparative Example 1: Preparation of Pirfenidone

[0066] 207 g of anhydrous potassium carbonate was added instead of 212 g of potassium phosphate, and the remaining operations were carried out as described in Example 8 to obtain 150 g of pirfenidone with a yield of 81%.

[0067] Comparative Example 2: Preparation of Pirfenidone

[0068] 138 g of anhydrous potassium carbonate was added instead of 212 g of potassium phosphate, and the remaining operations were carried out as described in Example 8 to obtain 144 g of pirfenidone with a yield of 78%.

[0069] Comparative Example 3: Preparation of Pirfenidone

[0070] 95 g of cuprous iodide was added instead of 30 g of the catalyst prepared in Example 1, and the remaining operations were carried out as described in Example 8 to obtain 139 g of pirfenidone with a yield of 75%.

[0071] Comparative Example 4: Preparation of Pirfenidone

[0072] 30 g of cuprous iodide was added instead of the 30 g of catalyst prepared in Example 1, and the remaining operations were carried out as described in Example 8 to obtain 126 g of pirfenidone with a yield of 68%.

[0073] The present invention has been disclosed above with preferred embodiments, which are not intended to limit the present invention. Any technical solutions obtained by adopting equivalent replacement or equivalent transformation solutions fall within the protection scope of the present invention.

Claims

1. A method for preparing pirfenidone by catalyzing an oxalyl dihydrazide polymer copper catalyst, characterized in that The following steps are involved: 5-methyl-2(1H)-pyridone, a base, a solvent, bromobenzene and a catalyst are added to a reaction vessel, and heating is performed to perform a coupling reaction to obtain pirfenidone; The catalyst is prepared by adding oxalyl dihydrazide, 1,4-dibromonaphthalene, potassium phosphate and a copper compound into a hydrothermal kettle, adding a solvent, heating for reaction, filtering, washing and drying the mixture to obtain the catalyst.

2. The method for preparing pirfenidone using a catalytic oxalyl dihydrazide polymer copper catalyst according to claim 1, wherein: In the catalyst preparation step, the copper compound is copper acetate or cuprous iodide, the solvent is DMF or DMSO, the reaction temperature is 130-150° C., and the reaction time is 10-15 hours.

3. The method for preparing pirfenidone by catalyzing the oxalyl dihydrazide polymer copper catalyst according to claim 1, characterized in that: The base is potassium phosphate or cesium carbonate, and the added molar amount of the base is 1-2 times that of the substrate; the solvent is DMSO or DMF.

4. The method for preparing pirfenidone by catalyzing the oxalyl dihydrazide polymer copper catalyst according to claim 1, characterized in that: The reaction temperature of the coupling reaction is 110-150° C., and the reaction time is 5-10 h.

5. The method for preparing pirfenidone using the oxalyl dihydrazide polymer copper catalyst according to claim 1, characterized in that: The added mass of the catalyst is 20-35% of 5-methyl-2(1H)-pyridone.

6. The method for preparing pirfenidone using the oxalyl dihydrazide polymer copper catalyst according to claim 1, characterized in that: The preparation steps of the 5-methyl-2(1H)-pyridone are: adding 2-chloro-5-methylpyridine, a base, and a solvent into a reaction container, heating and performing a hydroxylation reaction to obtain 5-methyl-2(1H)-pyridone.

7. The method for preparing pirfenidone using the oxalyl dihydrazide polymer copper catalyst according to claim 6, characterized in that: The base in the hydroxylation reaction is KOH or NaOH, and the added molar amount of the base is 1.5-3 times that of 2-chloro-5-methylpyridine; the solvent is DMSO, and the added mass is 2-4 times that of 2-chloro-5-methylpyridine.

8. The method for preparing pirfenidone using the oxalyl dihydrazide polymer copper catalyst according to claim 6, characterized in that: The reaction temperature of the hydroxylation reaction is 140-160° C., and the reaction time is 5-10 h.

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