A kind of preparation method of pirfenidone

Abstract

The invention discloses a preparation method of pirfenidone, which uses diethyl malonate (or methyl ester) as a starting material, and 1,1,3,3-tetraethoxy-2-methylpropane Reflux reaction in catalyzer zinc chloride and solvent acetic anhydride obtains 2-(3-ethoxy-2-methyl allyl) malonate diethyl ester (or methyl ester), then obtains 5 with aniline ring closure -Methyl-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate ethyl (or) methyl ester followed by alkaline hydrolysis to give 5-methyl-2-oxo-1- Phenyl‑1,2‑dihydropyridine‑3‑carboxylic acid, and finally decarboxylated by heating to obtain pirfenidone. The starting materials are cheap and easy to obtain, and the structure is stable; although there are four steps in the synthesis process, the synthesis process is simple to operate, the reaction process and the quality control of the final product can be effectively guaranteed, the product yield is high, and it is suitable for large-scale industrial production of raw materials Require.

Description

technical field [0001] The invention belongs to the technical field of anti-fibrotic drug synthesis, in particular to a preparation method of pirfenidone. Background technique [0002] Idiopathic pulmonary interstitial fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease with lesions confined to the lungs. More than 60 years old, more men than women. Idiopathic pulmonary interstitial fibrosis (IPF) has an insidious onset, rapid exacerbation, and rapid exacerbation. Its mortality rate is higher than that of most tumors, and it is called a "tumor-like disease". Pirfenidone is an effective anti-idiopathic pulmonary interstitial fibrosis drug, the chemical name is 5-methyl-1-phenylpyridin-2(1H)-one, the English name is pirfenidone; the chemical structure is as follows: [0003] [0004] Pirfenidone was jointly developed by Intermune of the United States and Shionogi of Japan. It was approved for marketing in Japan on October 16, 2008, and then appro...

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Problems solved by technology

[0008] The first step reaction uses sodium nitrite for diazotization reaction, which requires a large amount of strong acid, which increases the difficulty of pollution treatment. In addition, it is easy to generate genotoxic impurities such as nitrite or nitrosamine, which are easily brought into the raw material medicine , which increases the difficulty of impurity control of raw materials and poses a greater risk to related preparations

The second-step reactant chlorobenzene, bromobenzene and iodobenzene are more toxic, and the copper catalyst is used in the last step reaction of raw material drug production. Higher reaction temperature is easy to produce more by-products, which all increase the production of raw materials. Difficulty in drug quality control

[0016] This route can obtain pirfenidone in a "one-pot method", but in the condensation and hydrolysis reactions of 2-methyl-1-alkoxy-4-cyano-1,3-butadiene (compound 12) and aniline In terms of control, it is more difficult and more impurities are easy to be obtained. The one-pot production does not meet the requirements for the production process control of the API declaration; the same starting material 2-pentenenitrile (compound 10) has poor stability and high price , more difficult to buy

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