Method for preparing pirfenidone under catalysis of oxalyl dihydrazine polymer copper catalyst

Abstract

The invention provides a method for preparing pirfenidone through catalysis of an oxalyl dihydrazine polymer copper catalyst, and belongs to the technical field of drug synthesis, and the method comprises the following steps: adding 5-methyl-2 (1H)-pyridone, alkali, a solvent, bromobenzene and a catalyst into a reaction container, and heating for a coupling reaction to obtain pirfenidone; the preparation method of the catalyst comprises the following steps: adding oxalyl dihydrazine, 1, 4-dibromonaphthalene, potassium phosphate and a copper compound into a hydrothermal kettle, adding a solvent, carrying out a heating reaction, and filtering, washing and drying the mixture to obtain the catalyst. In the preparation method, the oxalyl dihydrazine polymer copper catalyst is used for the first time, the recovery process is simple, and the repeated utilization 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 new broad-spectrum anti-fibrotic drug with the chemical name of 5-methyl-1-phenyl-2-(1H)pyridone and the molecular formula of C12H11NO. Pirfenidone can regulate a variety of cytokines, change the expression, synthesis and accumulation of collagen, and inhibit the proliferation and expression of extracellular matrix. It has anti-inflammatory, antioxidant and anti-fibrotic effects. Clinical trials have shown that PFD has a broad-spectrum anti-fibrotic effect on the lungs, heart, liver and kidneys. PFD can reduce the decline in lung function in patients with idiopathic pulmonary fibrosis and delay the progression of the disease to a certain extent.

[0003] In 2017, Xiaomei Ding, Manna Huang et al. prepared an aryl-substituted pyrrole hydrazide ligand through the CN coupling reaction of pyrrole hydrazide. Thus, a universal and effective CuI / N, N-diaryl-1h-pyrrole-2-carbohydrazide catalyst system was established. In this scheme, only 5 mol% of CuI and ligand are required to affect various aryl brominations and aryl iodinations with a wide range of aliphatic amines and aryl amines (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, and obtained the intermediate 5-methyl-2(1H)-pyridone after diazotization and hydrolysis, and then reacted with iodobenzene in the presence of anhydrous potassium carbonate and copper iodide to undergo nucleophilic substitution reaction to generate the target product pirfenidone. After process optimization, the total yield of the reaction was 66.6%. This method has a low overall yield, and uses iodobenzene as a raw material, which has poor atom economy and is not conducive to industrial production.

[0005] In 2016, Zheng Ruixi, Song Danbi, etc. developed a new mild synthetic method for the N-arylation reaction of 2-pyridone with diaryl salts. Most reactions were easily carried out in the presence of 10 mol% copper chloride at room temperature. As a result, a wide range of N-aryl pyridin-2-ones were synthesized with yields ranging from 23% to 99% (J.Org.Chem.2016,81,17,7717–7724). This method uses copper chloride as a catalyst, which is not conducive to recycling.

[0006] Chinese patent document CN118344287A provides a method for preparing pirfenidone, S1, 2-bromo(iodo)-5-methylpyridine, an organic solvent, and an alkaline solution, stirring and mixing and heating to 50-80°C for reaction; 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 extraction phase containing the reaction product to obtain 5-methyl-2(1H)-pyridone; S4, stirring and mixing dried 5-methyl-2(1H)-pyridone, iodobenzene or bromobenzene, anhydrous potassium carbonate or cesium carbonate, a copper catalyst, and an organic solvent, heating to 110-120°C for reaction, monitoring the completion of the reaction, extracting into an extraction solvent, concentrating and recrystallizing 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 defects and shortcomings in the prior art, the present invention provides a method for preparing a copper oxalyl dihydrazide polymer catalyst and catalytically preparing pirfenidone.

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

[0009] Add 5-methyl-2(1H)-pyridone, a base, a solvent, bromobenzene and a catalyst into a reaction container, and heat to perform a coupling reaction to obtain pirfenidone;

[0010] The preparation steps of the catalyst are: 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 cupric 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 molar amount of the base added 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 step of the 5-methyl-2(1H)-pyridone is: adding 2-chloro-5-methylpyridine, a base, and a solvent into a reaction container, heating to carry out a hydroxylation reaction, and obtaining 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 beneficial technical effect achieved by the present invention is as follows: the present invention provides a method for preparing a copper oxalyl dihydrazide polymer catalyst, using 2-chloro-5-methylpyridine as a raw material, preparing 5-methyl-2(1H)-pyridone through a hydroxylation reaction, and preparing pirfenidone through a coupling reaction with bromobenzene under the catalysis of the catalyst. The reaction process is simple, the catalyst is easy to recover, the reuse rate is high, the product is easy to separate, and it has a good industrial application prospect. 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 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 in conjunction with examples.

[0026]

[0027]

[0028] Example 1

[0029] Preparation of oxalyl dihydrazide polymer copper catalyst: 6 g oxalyl dihydrazide (0.05 mol), 28.6 g 1,4-dibromonaphthalene (0.1 mol), 42 g potassium phosphate (0.2 mol), 100 ml DMF, and 9.5 g cuprous iodide (0.05 mol) were added to a hydrothermal autoclave, heated at 150° C. for 10 h, and the obtained 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: Add 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) into a hydrothermal autoclave, heat at 130° C. for 15 h, filter the resulting mixture, wash with water, and dry 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 that the oxalyl dihydrazide polymer was formed and had a mesoporous structure. The characterization results of Example 1 are used for specific description: Figure 1 This is the infrared spectrum of the catalyst prepared in Example 1. According to the Fourier transform infrared spectroscopy results, 3461 cm -1 The NH bond stretching vibration of the hydrazide group is 1851 cm -1 The vibration of carbonyl (C=O) in hydrazide group indicates the presence of hydrazide group in the catalyst; 3067cm -1 The 1580 cm-1 can be attributed to the stretching vibration of the CH bond in the aromatic group. -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 indicates the successful coordination of copper. Figure 2 The N2 adsorption-desorption isotherm of the catalyst prepared in Example 1 was tested under 77K liquid nitrogen conditions.2 The 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 the mixture was heated at 150° C. for 5 h. After the reaction, the solvent was evaporated under reduced pressure, the residue was dissolved with 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: 80 g of sodium hydroxide was replaced with 178 g of potassium hydroxide (3 mol), and the remaining operations were carried out as described in Example 4 to obtain 107.6 g 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 Example 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 the mixture was heated at 120 ° C for 5 h. After the reaction was completed, the catalyst was separated by filtration, the solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and washed three times with saturated brine, and 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] Embodiment 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 according to 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 according to Example 8 to obtain 168 g of pirfenidone with a yield of 91%.

[0057] Embodiment 14

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

[0059] Embodiment 15

[0060] Preparation of pirfenidone: The catalyst prepared in Example 1 was replaced by the catalyst prepared in Example 2, and the remaining operations were carried out according to 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, which was repeated three times. The obtained solid was placed in an oven and dried at 100° C. for 10 h to obtain a recovered catalyst and reacted according to the conditions of Example 8. The results are shown in Table 1.

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

[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] Instead of adding 30 g of the catalyst prepared in Example 1, 30 g of cuprous iodide was added, 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, but they 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: Add 5-methyl-2(1H)-pyridone, a base, a solvent, bromobenzene and a catalyst into a reaction container, and heat to perform a coupling reaction to obtain pirfenidone; The preparation steps of the catalyst are as follows: 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 by catalytic use of oxalyl dihydrazide polymer copper catalyst according to claim 1, characterized in that: In the step of preparing the catalyst, the copper compound is cupric 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 catalysis of 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 catalysis of 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 by catalysis of 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 by 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 as follows: 2-chloro-5-methylpyridine, a base and a solvent are added into a reaction container, and heated to perform a hydroxylation reaction to obtain 5-methyl-2(1H)-pyridone.

7. The method for preparing pirfenidone by catalyzing 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 catalyzed by 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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