Preparation method of favipiravir

Abstract

The invention relates to a preparation method of favipiravir, which comprises the following steps of: reacting 3,6-difluoro-2-cyanopyrazine under an alkaline condition at the temperature of between 40 and 70 DEG C to obtain 6-fluoro-3-hydroxy-2-cyanopyrazine, and then conducting a next-step reaction basically without treatment, and conducting reaction with inorganic alkali and hydrogen peroxide at 45-65 DEG C to obtain favipiravir. The preparation method avoids use of precursor control reagents or dangerous preparations, reduces dangerous factors in production, and has the advantages of simplicity and convenience in operation, high yield, high purity of the prepared product, safety, environmental protection, low cost, suitability for industrial production and the like.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and in particular relates to a preparation method of Favipiravir. Background technique [0002] Favipiravir (trade name AVIGAN) is an RNA-dependent RNA polymerase (RdRp) inhibitor broad-spectrum antiviral drug developed by Japan Fukuyama Chemical Co., Ltd. Bioterrorism attacks have important practical significance. [0003] [0004] CN1418220A discloses the preparation method of Favipiravir, comprising the following steps: [0005] [0006] This method has the following problems in the process of preparing 6-fluoro-3-hydroxyl-2-cyanopyrazine (compound II): one, heterogeneous reaction, stirring difficulty, increase processing difficulty; pH, extraction, washing, and drying and decompression to remove the solvent are cumbersome and costly. Third, column chromatography is used for purification, which is not suitable for industrial production. Fourth, the yield of this step is only 45.6%, and th...

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Problems solved by technology

[0006] This method has the following problems in the process of preparing 6-fluoro-3-hydroxyl-2-cyanopyrazine (compound II): one, heterogeneous reaction, stirring difficulty, increase processing difficulty; pH, extraction, washing, and drying and decompression to remove the solvent are cumbersome and costly; 3. Column chromatography is used for purification, which is not suitable for industrial production; 4. The yield of this step is only 45.6%, and the production cost has increased significantly

[0009] In this method, the intermediate 6-fluoro-3-hydroxyl-2-cyanopyrazine is made into an organic amine salt, and this step has the following problems: 1. After the reaction solution is filtered, it is necessary to adjust the pH and form a salt with ammonia water. It is cumbersome and complicated to handle; 2. In the salt-forming step, organic solvents acetone and toluene are introduced. The solvent itself is highly toxic, which increases the potential risk of solvent residue; 3. The introduced organic amine is difficult to remove from the product

In the step of preparing Favipiravir, there are the following problems: 1. Toluene is used as the reaction solvent, which is a carcinogenic solvent. It is used in large quantities in production, which affects the safety of operators, causes a large amount of waste liquid to affect environmental protection, and increases waste liquid treatment and environmental protection costs. , in addition, increase the solvent residue and increase the cost of quality control; 2. In the post-processing step, it is necessary to add seed crystals to precipitate solids.

[0012] This method has the following problems in the process of preparing 6-fluoro-3-hydroxyl-2-cyanopyrazine (compound II): one, the reaction solvent contains toluene, a carcinogenic solvent, two, concentrated hydrochloric acid is needed to adjust pH, extract, Washing requires drying and decompression to remove the solvent. The operation is cumbersome, costly, and inconvenient in production.

[0015] This method has the following problems in the process of preparing 6-fluoro-3-hydroxyl-2-cyanopyrazine: after the reaction, hydrochloric acid is required to adjust the pH, extract, wash, and also need to be dried and decompressed to remove the solvent, which is cumbersome and costly

In the step of preparing Favipiravir, one, using concentrated sulfuric acid as a solvent, which is very dangerous in itself, coupled with high temperature reaction, the risk factor increases, in addition, the equipment is severely corroded, and is not suitable for industrial production; two, concentrated sulfuric acid is dropped into water , a large amount of heat release, especially concentrated sulfuric acid solution at 50°C, the heat release is more serious, the risk factor increases, and it is very unsuitable for industrial production; 3. Water is used as a solvent, and there is a problem of difficulty in stirring; 4. Post-processing requires extraction and other operations, and it is also Need chromatographic column purification and separation, not suitable for suitability for suitability for industrialized production; Five, 3 embodiment two-step reaction average yields 64%

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