- PROCESS FOR PREPARATION OF FAVIPIRAVIR
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The present invention relates to a process for the preparation of favipiravir and salts thereof. The present invention also relates to salts of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile with inorganic base, process for their preparation and conversion thereof to favipiravir. The present invention also relates to salts of 6-bromo-3-hydroxypyrazine-2-carboxamide with organic and inorganic base and their use in the preparation of favipiravir.
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Paragraph 0266
(2021/12/08)
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- 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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- Preparation method of fluoropyrazine compound
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The invention discloses a preparation method of a fluoropyrazine compound. The preparation method is characterized in that in a catalytic system, a compound A is directly subjected to a fluorination reaction to prepare the fluoropyrazine compound B. The preparation method is high in compatibility and suitable for various reaction substrates, different catalytic systems can be selected according to the activity of the reaction substrates, and the preparation method is flexible and easy and convenient to operate; and a reagent is simple and easily available, a catalytic condition is mild, and catalytic efficiency is high.
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Paragraph 0041-0045; 0052-0069
(2021/07/08)
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- Scalable synthesis of favipiravir: Via conventional and continuous flow chemistry
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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
- Charoensetakul, Netnapa,Khamkhenshorngphanuch, Thitiphong,Srikun, Onsiri,Srimongkolpithak, Nitipol,Thongpanchang, Chawanee,Tiyasakulchai, Thanat,Yuthavong, Yongyuth
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p. 38691 - 38693
(2021/12/20)
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- Preparation method of 6 -fluoro -3 -hydroxypyrazine -2 - formamide
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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.
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- Preparation method of favipiravir
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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.
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Paragraph 0045-0057
(2021/08/14)
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- Refining method of favipiravir
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The invention provides a refining method of favipiravir. The method specifically comprises the following steps: 6-fluoro-3-hydroxy-2-cyanopyrazine reacts with hydrogen peroxide under an alkaline condition to obtain 6-fluoro-3-hydroxy-2-pyrazinamide; the 6-fluoro-3-hydroxy-2-pyrazinamide is prepared into an organic alkali salt in an anhydrous organic solvent, and then the pH value in water is adjusted to prepare high-purity 6-fluoro-3-hydroxy-2-pyrazinamide; and 6-fluoro-3-hydroxy-2-pyrazinamide and organic alkali are salified in an organic solvent, the salt has excellent crystallinity, high-purity favipiravir can be prepared with high yield through simple operation, the yield can reach 90% or above, and the HPLC purity reaches 99.9% or above.
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Paragraph 0029-0036
(2021/04/14)
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- Favipiravir intermediate and synthesis method of favipiravir
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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.
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- Synthesis process of favipiravir and intermediate thereof
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The invention relates to the technical field of medicine synthesis, and in particular, relates to a synthesis process of favipiravir and an intermediate thereof. The synthesis method of favipiravir comprises the following steps: 1) 2-aminopropanediamide and glyoxal serve as raw materials, and generating a compound III through a cyclization reaction; 2) performing benzyl protection on the compoundIII under the catalysis of potassium carbonate to generate a compound IV; 3) performing fluorine substitution on the compound IV under the action of fluorine gas, a solvent and a catalyst to generatea compound V; and 4) performing debenzylation protection on the compound V to generate favipiravir. Compared with other synthetic routes of favipiravir, the synthetic route provided by the invention has the advantages that the whole process route is shortened by virtue of high-selectivity fluorination reaction, the production cost is greatly reduced, and the synthesis process is suitable for industrial production.
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Paragraph 0063-0067
(2020/07/15)
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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 0066-0067
(2020/12/08)
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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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- Preparation method of favipiravir and derivatives thereof
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The invention provides a novel preparation method of a favipiravir derivative. Specifically, a fluorinating reagent is directly used for an electrophilic fluorination reaction, fluorine atoms are selectively introduced to the 6-position, and favipiravir or the derivatives thereof are efficiently synthesized through one-step reaction. Compared with the existing synthesis method, the synthesis method adopting one-step reaction has the advantages of strong creativity, novelty, simplicity in operation, safety, low cost, less three wastes, environmental friendliness and high total yield, so that the synthesis method has extremely strong industrial advantages and significance.
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Paragraph 0021-0038
(2020/10/05)
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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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- Favipiravir synthesis process
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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.
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- A french pulls Wei synthetic method
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The invention belongs to the field of medicinal chemistry and particularly relates to a new synthesis method of Favipiravir. The method comprises the following steps: carrying out carboxyl protection on raw material shown in the formula (II) to generate a compound (III); carrying out diazotization hydrolysis reaction in the presence of concentrated sulfuric acid and sodium nitriteto generate a compound (IV); carrying out benzyl protection reaction to generate a compound (V), and then generating a compound (VI) in the presence of potassium fluoride and tetrabutylammonium bromide; removing a benzyl protection group to generate a compound (VII); and then adding an aminating agent to carry out amination to generate Favipiravir shown in the formula I. The method disclosed by the invention has the advantages that the reaction cycle is short, the operation is simple, the production cost is low, and the product is high in quality; therefore, the method is suitable for industrial production.
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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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- PYRAZINO[2,3-D]ISOXAZOLE DERIVATIVE
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The object of the present invention is to provide a compound which is useful as a production intermediate of pyrazine carboxamide derivative such as 6-fluoro-3-hydroxy-2-pyrazine carboxamide. The present invention provides a pyrazino[2,3-d]isoxazole derivative represented by the formula (I): wherein X represents a halogen atom, a hydroxyl group or a sulfamoyloxy group, and Y represents —C(═O)R or —CN; wherein R represents a hydrogen atom, an alkoxy group an aryloxy group, an alkyl group, an aryl group or an amino group.
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- METHOD FOR PRODUCING DICHLOROPYRAZINE DERIVATIVE
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A method for producing a hydroxypyrazine derivative represented by formula (I) (wherein R1 represents a halogen atom), the method including reacting a pyrazine derivative represented by formula (III) (wherein R2 represents a nitrile group, an N-unsubstituted or N-substituted carbamoyl group, an ester group or a carboxyl group, M represents a cation capable of forming a salt, and n represents a number corresponding with the valence of M) with a halogenating agent. Also, a method for producing a dichloropyrazine derivative represented by formula (II) (wherein R21 represents a nitrile group, an N-unsubstituted or N-substituted carbamoyl group, an ester group, a carboxyl group, or a group formed as a result of a change in the functional group of R2 during chlorination), the method including reacting the hydroxypyrazine derivative (I) with a chlorinating agent. According to the present invention, a dichloropyrazine derivative can be produced efficiently at low cost, and a hydroxypyrazine derivative that functions as a production intermediate for the dichloropyrazine derivative can be produced efficiently at low cost.
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- ORGANIC AMINE SALT OF 6-FLUORO-3-HYDROXY-2-PYRAZINECARBONITRILE AND METHOD FOR PRODUCING THE SAME
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Disclosed is an organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile, which is excellent in crystallinity and useful as a production intermediate for 6-fluoro-3-hydroxy-2-pyrazinecarboxamide.
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Page/Page column 6
(2010/06/17)
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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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- Nitrogen-containing heterocyclic carboxamide derivatives or salts thereof and antiviral agents comprising the same
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Nitrogen-containing heterocyclic carboxamide derivatives represented by the following general formula: 1wherein ring A is a substituted or unsubstituted pyrazine, pyrimidine, pyridazine or triazine ring; R1 is O or OH; R2 is a hydrogen atom, an acyl group or a substituted or unsubstituted carbamoylalkyl or carboxyalkyl group; and the broken line represents a single bond or a double bond; or salts thereof are useful for preventing and treating virus infections and especially influenza virus infections.
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