Favipiravir synthesis process

Abstract

The invention relates to a favipiravir synthesis process, which comprises: 1) dissolving a pyrazine compound in an organic reagent I, adding an oxidizing agent M, and carrying out a nitrogen oxidation reaction to obtain a white solid; 2) adding the obtained white solid to an organic reagent II, and carrying out a chlorination reaction to obtain a pale yellow solid; 3) uniformly mixing the obtained pale yellow solid, a dried aprotic polar solvent, a dried fluorine ion donor reagent and tetrabutylammonium bromide, and carrying out a stirring reaction to obtain a pale yellow solid; 4) adding the obtained pale yellow solid to water, and carrying out a reaction with 1,4-dioxane and sodium acetate to obtain a yellow oily matter; and 5) uniformly mixing the obtained yellow oily matter and concentrated sulfuric acid to obtain the target product favipiravir. According to the present invention, the method has advantages of simple and easily available raw materials, simple synthesis process and mild conditions, nitrogen oxidation, chlorination, fluorization and hydrolysis are performed to finally prepare the 6-fluoro-3-hydroxypyrazine-2-formamide, and the good industrial value is provided.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a synthesis process of Favipiravir. Background technique [0002] Favipiravir (Favipiravir, T-705), chemically named 6-fluoro-3-hydroxypyrazine-2-carboxamide, is a novel RNA-dependent RNA polymerase (RdRp) inhibitor class broad-spectrum antiviral drug, It itself has no antiviral activity, and can be rapidly converted into the form of favipiravir nucleoside triphosphate through metabolism in the body, and competitively inhibits RNA polymerase dependent on viral RNA by simulating guanosine triphosphate (GTP), inhibiting viral genome replication and Transcription to play an antiviral effect, the form of favipiravir nucleoside triphosphate can also penetrate into the viral gene, and play an antiviral effect by inducing fatal mutations. Favipiravir has a good therapeutic effect on type A influenza (including avian influenza and influenza A H1N1 infection) vir...

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Problems solved by technology

[0007] (2) Patent document CN 102775358A discloses a target compound prepared from 3-amino-2-pyrazinecarboxylic acid as a starting material through six steps of hydroxylation, esterification, amination, nitration, reduction, and fluorination. In the route, 6-nitro-3-hydroxyl-2-pyrazinamide has limited solubility in general organic solvents, and it is difficult to reduce it to amino compounds. The use of pyridine hydrofluoric acid in the last step is highly corrosive and the yield is low

[0009] (3) Wang Huan et al. (Chinese Journal of Pharmaceutical Industry, 2014, 45(11): 1009-1012.) Using diethyl aminomalonate hydrochloride as the starting material, after ammonolysis, cyclization and bromination Obtain 6-bromo-3-oxo-3,4-dihydropyrazine-2-carboxamide, and then use potassium acetate to select the 3-position fluorine after phosphorus oxychloride chlorination and potassium fluoride fluorination Hydrolysis and dicyclohexylamine salify, and then use hydrogen peroxide / sodium hydroxide to convert into amide to obtain the product favipiravir. The dicyclohexylamine used in this route belongs to flammable and highly toxic substances, and industrial processing is relatively troublesome. Suitable for industrial scale-up production, this method is cumbersome to operate, the reagents used are expensive, the production cost is high, and the total yield is less than 10%, so this method is not suitable for industrial production

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