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Method for preparing pirfenidone

A technology of pirfenidone and reverse method, which is applied in the field of preparation of anti-fibrosis drugs, can solve the problems of low yield and troublesome operation, and achieve the effects of high yield, easy operation and reduced production cost

Inactive Publication Date: 2012-07-11
CISEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method is cumbersome to operate and has a low yield

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Mix 21.6g of 2-amino-5-picoline, 20.7g of diazotization reagent sodium nitrite and 40g of cold water at 5°C in a blender to make a paste, then add ice to cool the paste to 0°C, Then slowly pour the paste into a constantly stirring hydrochloric acid solution with a concentration of 12% by mass, and stir at 0° C. for 1 hour to make the reaction complete. Then heated to 95°C for 30 minutes and then cooled to 20°C, then adjusted to pH 7 with 50% sodium hydroxide solution by mass percent, then heated to 60°C, extracted with 150ml×5 ethyl acetate, and combined the organic layers , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 18.4 g of a light yellow solid crude product; then 55 ml of absolute ethanol was added, heated to reflux for 1 h, cooled to 2°C, crystallized for 6 h, suction filtered, and washed with absolute ethanol , and dried at 50°C for 8 hours to obtain 15.3 g of light yellow crystal 2-hydroxy-5-m...

Embodiment 2

[0023] Mix 32.4g of 2-amino-5-picoline, 32.0g of diazotization reagent sodium nitrite and 60g of cold water at 0°C in a blender to make a paste, then add ice to cool the paste to -5 ℃, and then slowly pour the paste into a constantly stirring hydrochloric acid solution with a concentration of 10% by mass, and stir and react at 0 ℃ for 1 h to make the reaction complete. Then heated to 95°C for 30 minutes and then cooled to 20°C, then adjusted to pH 7 with 50% sodium hydroxide solution by mass percent, then heated to 60°C, extracted with 200ml×4 dichloromethane, and combined the organic layers , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 25.3 g of a light yellow solid crude product; then 100 ml of ethyl acetate was added, heated to reflux for 1 h, cooled to 0°C, crystallized for 6 h, suction filtered, and washed with ethyl acetate , and dried at 50°C for 8 hours to obtain 22.1 g of light yellow crystal 2-hydr...

Embodiment 3

[0026] Mix 43.2g of 2-amino-5-picoline, 41.4g of diazotization reagent sodium nitrite and 85g of 10°C cold water in a blender to make a paste, then add ice to cool the paste to 5°C , and then slowly pour the paste into a constantly stirring hydrochloric acid solution with a concentration of 15% by mass, stir and react at 0° C. for 1 h to make the reaction complete. Then heated to 95°C for 30 minutes and then cooled to 20°C, then adjusted to pH 7 with 50% sodium hydroxide solution by mass percent, then heated to 60°C, extracted with 250ml×5 ethyl acetate, and combined the organic layers , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 36.6g of a light yellow solid crude product; then 100ml of acetone was added, heated to reflux for 1h, cooled to 5°C, crystallized for 6h, suction filtered, washed with acetone, and dried at 50°C After 8 hours, 28.4 g of light yellow crystal 2-hydroxy-5-methylpyridine was obtained,...

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Abstract

The invention discloses a method for preparing pirfenidone, comprising the following steps: subjecting 2-amino-5-methylpyridine which is a starting material to inverse diazotization and hydrolysis, extracting with extraction solvent, and recrystallizing with recrystallization solvent to obtain 2-hydroxy-5-methylpyridine; heating the 2-hydroxy-5-methylpyridine together with iodobenzene in the presence of anhydrous potassium carbonate and active copper to subject the 2-hydroxy-5-methylpyridine and the iodobenzene to nucleophilic substitution reaction to generate a target compound which is the crude pirfenidone; and recrystallizing the crude pirfenidone for one time for purification with recrystallization solvents which are ethyl acetate and anhydrous ethyl alcohol to obtain the pure pirfenidone. Compared with the prior art, the method for preparing the pirfenidone has the characteristics that: the 2-amino-5-methylpyridine which is the starting material is a commercial chemical product, is cheap and is easy to get, the inverse diazotization replaces the conventional diazotization reaction so that the operation is simple, and the purification methods of the 2-hydroxy-5-methylpyridine and the end product which is the pirfenidone are easy to operate and have high yield. The method for producing the pirfenidone consumes less energy, and the production cost is lowered due to the adoption of the method.

Description

technical field [0001] The invention relates to the field of preparation of anti-fibrosis drugs, in particular to a preparation method of pirfenidone. Background technique [0002] Fibrotic diseases such as renal fibrosis, liver cirrhosis, and myocardial fibrosis are important diseases that seriously endanger human life and health. With global industrialization and changes in people's lifestyles and diets, the incidence of fibrotic diseases is gradually increasing. Correspondingly, many scholars at home and abroad have conducted a large number of researches on anti-fibrosis drugs from different fields such as chemical drugs, natural drugs, biological agents, and gene therapy for the pathogenesis of fibrosis. So far, it has been found that pyridone compounds are a class of effective anti-fibrosis compounds, among which, pyrfenidone is a representative compound. Various studies have been carried out abroad, and it is currently on the market in Japan. [0003] Pirfenidone (PFD...

Claims

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Application Information

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IPC IPC(8): C07D213/64
Inventor 杜振新卢秀莲李明丽李清涛宋倩李大涛张萌
Owner CISEN PHARMA