356783-28-3Relevant academic research and scientific papers
PROCESS FOR THE PREPARATION OF 3,6-DICHLOROCYANO PYRAZINE, 3,6-DIOXOPIPERAZINE DERIVATIVES AND PRODUCTION OF FAVIPIRAVIR THEREOF
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, (2021/12/31)
The present invention relates to a method of preparing derivatives of 3,6-dichlorocyano pyrazine, 3,6-dioxopiperizin and the production of favipiravir by cyclization and chlorination mediated by ammonia or amine using POCl3 in the presence of pyridine or PCl5. [Formula] In derivatives of 3,6-dioxopiperazine (III), X represents CN, CONH2 or COOR2', R1, R 2 and R2' are individually selected from H, alkyl C1-C12, COOR3 and SO2R3, R 3 being a linear or branched lower alkyl substituted or unsubstituted.
METHODS FOR PREPARING FAVIPIRAVIR
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Paragraph 0017; 0333; 0334, (2021/11/20)
The present invention provides methods for preparing Favipiravir (6-fluoro-3-hydroxypyrazine-2-carboxamide).
Scalable synthesis of favipiravir: Via conventional and continuous flow chemistry
Charoensetakul, Netnapa,Khamkhenshorngphanuch, Thitiphong,Srikun, Onsiri,Srimongkolpithak, Nitipol,Thongpanchang, Chawanee,Tiyasakulchai, Thanat,Yuthavong, Yongyuth
, p. 38691 - 38693 (2021/12/20)
Decagram scale synthesis of favipiravir was performed in 9 steps using diethyl malonate as cheap starting material. Hydrogenation and bromination steps were achieved by employing a continuous flow reactor. The synthetic process provided a total of 16% yield and it is suitable for larger-scale synthesis and production. This journal is
Preparation method of 6 -fluoro -3 -hydroxypyrazine -2 - formamide
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Paragraph 0023-0025, (2021/12/07)
The invention provides a preparation method of a pyrazine compound represented by the formula (I). To the invention, 6 -fluoro -3 -hydroxypyrazine -2 - methyl cyanide is used as a starting material, dimethyl sulfoxide is added under the conditions of hydrogen peroxide and sodium hydroxide, so that generation of oxygen in the system is avoided, and the production safety is greatly improved. The method provided by the invention is safe and suitable for industrial amplification, and has great help for industrial mass production of laprevir API.
Favipiravir intermediate and synthesis method of favipiravir
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, (2020/08/12)
The invention discloses a favipiravir intermediate and a synthesis method of favipiravir. The synthesis method comprises the following steps: taking 2,5-dihalopyrazine as an initial raw material, reacting 2,5-dihalopyrazine with formamide under the action of an oxide and a catalyst to generate 6-halo-3-chloro-2-amide pyrazine; carrying out a reaction on 6-halo-3-chloro-2-amide pyrazine under the action of a dehydration chlorinating agent and an acid-binding agent to generate a favipiravir intermediate 3,6-dichloro-3-cyanopyrazine; carrying out an aromatic ring fluorination reaction on the obtained favipiravir intermediate and potassium fluoride in dimethyl sulfoxide to generate 3,6-difluoro-3-cyanopyrazine; adding the 3,6-difluoro-3-cyanopyrazine into a water solution containing sodium acetate, and carrying out hydrolysis to obtain 6-fluoro-3-hydroxyl-2-cyanopyrazine; and finally, carrying out a cyano hydrolysis reaction to obtain favipiravir. A mixture of 2,5-dichloropyrazine and 2-chloro-5-bromopyrazine are used as raw materials to synthesize the favipiravir intermediate, the raw material cost is remarkably reduced, and the provided synthesis method has the technical advantages of high yield and low cost.
The complete synthesis of favipiravir from 2-aminopyrazine
Guo, Qi,Xu, Mingshuo,Guo, Shuang,Zhu, Fuqiang,Xie, Yuanchao,Shen, Jingshan
, p. 1043 - 1051 (2019/04/25)
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.
Favipiravir intermediate and synthetic method for favipiravir
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, (2018/04/02)
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.
Favipiravir synthesis process
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, (2017/08/28)
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.
Method for synthesis of favipiravir
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, (2017/07/19)
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.
A practical and step-economic route to Favipiravir
Liu, Feng-Liang,Li, Cui-Qin,Xiang, Hao-Yue,Feng, Si
, p. 2153 - 2158 (2017/09/30)
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.
