- METHODS FOR PREPARING FAVIPIRAVIR
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The present invention provides methods for preparing Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide).
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Paragraph 0015; 0332
(2021/11/20)
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- Preparation method of favipiravir
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The invention relates to a preparation method of favipiravir. The preparation method comprises the following steps: dissolving 6-bromine-3-hydroxypyrazine-2-formamide in a first solvent, adding a first fluorinating agent, and carrying out a stirring reaction so as to prepare 6-bromine-3-fluoropyrazine-2-formamide; dissolving the 6-bromo-3-fluoropyrazine-2-formamide, a second fluorinating agent anda catalyst in a second solvent, and carrying out a heating reaction to prepare 6-fluoro-3-fluoropyrazine-2-formamide; and carrying out hydroxyl substitution on the 6-fluoro-3-fluoropyrazine-2-formamide to prepare the favipiravir. The invention further discloses a preparation method of the favipiravir. The preparation method of favipiravir has the advantages of simple and safe reaction operation,less three wastes, green and environment-friendly synthetic route and environmental friendliness; the favipiravir has the advantages of higher yield, stability and low production cost, and is suitablefor industrial production.
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Page/Page column 7-13
(2020/09/09)
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- Fapiravir and preparation method of intermediate thereof
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The invention relates to a fapiravir and a preparation method of an intermediate thereof, and belongs to the field of pharmaceutical chemicals. The invention provides a preparation method of a fapiravir intermediate 3-hydroxy sodium pyrazine-2-formamide, wherein the fapiravir intermediate 3-hydroxy sodium pyrazine-2-formamide is prepared by reacting aminopropanedioide with lithium chloride in thepresence of a NaOH solution and glyoxal. The invention also provides a preparation method of 6-bromo-3-hydroxy pyrazine-2-formamide, wherein the 6-bromo-3-hydroxy pyrazine-2-formamide is prepared froman acetonitrile solution of 3-hydroxy sodium pyrazine-2-formamide and an acetonitrile solution of liquid bromine in a microchannel reactor. The invention also provides a preparation method of 3, 6-difluoropyrazine-2-formamide, wherein the 3, 6-difluoropyrazine-2-formamide is prepared by reacting 6-bromo-3-hydroxy pyrazine-2-formamide with potassium bifluoride in the presence of PEG-400 and DMF. Finally, the invention also provides a total synthesis method for preparing fapiravir from the intermediate. The reactions avoid the use of highly dangerous diazotization reactions, and the methods have the advantages of high safety, low raw material price, short steps, low cost and simple post-treatment, and are suitable for industrial enlarged production.
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Paragraph 0060-0065; 0074-0079
(2020/12/08)
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- The complete synthesis of favipiravir from 2-aminopyrazine
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Favipiravir was first synthesized from an inexpensive and commercially available starting material, 2-aminopyrazine. The preferred route embedded within Scheme?4 consisted of seven steps, and was highlighted by the novel and efficient synthesis of 3,6-dichloropyrazine-2-carbonitrile 8. This intermediate was prepared in four successive steps which were regioselective chlorination of the pyrazine ring, bromination, Pd-catalyzed cyanation, and Sandmeyer diazotization/chlorination. This protocol eliminated the hazardous POCl3 of previous synthetic methods and offered a better yield (48%) which was 1.3-fold higher than a recently published procedure. From intermediate 8, the subsequent nucleophilic fluorination, nitrile hydration and hydroxyl substitution efficiently afforded the target product. Another synthetic approach with the same starting material was also investigated to bypass the allergy-causing dichloro intermediate 8. However, the key step of monofluorination at the pyrazine C6 position of intermediate 19 or 22 was not achieved.
- Guo, Qi,Xu, Mingshuo,Guo, Shuang,Zhu, Fuqiang,Xie, Yuanchao,Shen, Jingshan
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p. 1043 - 1051
(2019/04/25)
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- Favipiravir intermediate and synthetic method for favipiravir
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The invention relates to a favipiravir intermediate and a synthetic method for favipiravir, and specifically discloses a method for synthesizing 3,6-difluoro-2-cyanopyrazine with a formula 4 as shownin the specification. The method comprises the following steps: a) allowing a compound with a formula 1 as shown in the specification to react with a chlorinated reagent or a brominated reagent so asto obtain a compound with a formula 2 as shown in the specification; b) allowing the compound with the formula 2 as shown in the specification to react with phosphorus oxychloride in the presence of organic base so as to obtain a compound with a formula 3 as shown in the specification; and c) allowing the compound with the formula 3 as shown in the specification to react with a fluorinated reagentso as to obtain the compound with the formula 4 as shown in the specification. The invention also relates to a method for synthesizing the favipiravir by using the above-mentioned method.
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Paragraph 0065; 0069
(2018/04/02)
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- Method for synthesis of favipiravir
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The invention discloses a method for synthesis of favipiravir. The method comprises an esterification reaction of 3-aminopyrazine-2-carboxylic acid and an alcohol, a bromination reaction, a diazotization reaction, an ammonolysis reaction, a chlorination-dehydration reaction, a one-pot series connection aromatic ring fluorination reaction, a cyan-hydrolysis reaction, an aromatic ring hydroxyl substitution reaction, and purification treatment so that favipiravir is obtained. The method utilizes 3-amino-2-carboxypyrazine as a raw material to synthesize favipiravir through 8-step reactions and has a total yield of 26%. The key intermediates 3 and 6 in the method are purified by recrystallization so that column chromatography separation in the literature is avoided. The final three reactions are finished by a one-pot method so that the operation is simplified. The synthesis method improves a yield, realizes a low cost and green economy and is conducive to industrial production.
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- A practical and step-economic route to Favipiravir
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A practical and step-economic route to Favipiravir, an antiviral drug, was developed. Favipiravir was synthesized in only six steps from 3-aminopyrazine-2-carboxylic acid with an overall yield of about 22.3%. Key intermediates 3 and 6 were obtained in excellent purity via recrystallization from optimized solvents, which was beneficial to large-scale production. In the key synthetic reaction, 3,6-dichloropyrazine-2-carbonitrile (6) was reacted sequentially, in one pot, with KF and 30% H2O2 to give (after crystallization from 95% EtOH) favipiravir as colorless crystals, with a 60% yield for this final step of the synthesis.
- Liu, Feng-Liang,Li, Cui-Qin,Xiang, Hao-Yue,Feng, Si
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p. 2153 - 2158
(2017/09/30)
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- Favipiravir synthesis method
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The invention discloses a favipiravir synthesis method, which comprises the following steps that (1) a pyrazine compound is dissolved in an organic reagent I; nitrogen oxidation reaction is performed to obtain white solid matters; (2) the white solid matters of pyrazine dinitrogen oxides are added into an organic reagent II to perform chlorination reaction; light yellow solids are obtained; (3) the obtained light yellow solids, a dry aprotic polar solvent, a dry fluorion donor reagent and tetrabutylammonium bromide are uniformly mixed; stirring reaction is performed to obtain light yellow solids; (4) the prepared 3,6-dichloropyrazine-2-formonitrile and a fluorizating agent perform aromatic ring fluoronation; (5) hexafluoro reaction products are directly catalyzed through hydrogen peroxide; cyan-hydrolysis reaction is performed; (6) cyan-hydrolysis reaction products are directly catalyzed through an aqueous alkaline solution; aromatic ring hydroxyl substitution reaction is performed; then, through purification treatment, favipiravir is prepared. The method disclosed by the invention has the advantages that the raw materials are simple and are easily to obtain; the synthesis process is simple; good industrial value is realized; green and environment-friendly effects are achieved.
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- Novel pyrazine derivatives or salts thereof, pharmaceutical composition containing the same, and production intermediates thereof
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Pyrazine derivatives represented by general formula [1]: 1wherein the variables are as defined in the specification, or salts thereof have an excellent antiviral activity and are useful as a therapeutic agent for treating viral infections. Further, fluoropyrazine-carboxamide derivatives represented by general formula [2]: 2wherein the variables are as defined in the specification, or salts thereof are useful as an intermediate for production of the compounds of general formula [1], and as an intermediate for production of the fluoropyrazine-carboxamide derivatives of which one typical example is 6-fluoro-3-hyroxy-2-pyrazine-carboxamide having an antiviral activity.
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