CN111704582A - Preparation method of Favipiravir and derivatives thereof - Google Patents
Preparation method of Favipiravir and derivatives thereof Download PDFInfo
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- CN111704582A CN111704582A CN202010583503.1A CN202010583503A CN111704582A CN 111704582 A CN111704582 A CN 111704582A CN 202010583503 A CN202010583503 A CN 202010583503A CN 111704582 A CN111704582 A CN 111704582A
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Abstract
The invention provides a novel preparation method of a Favipiravir derivative. In particular to a method for synthesizing the Pilarvir or the derivatives thereof by directly using a fluorinating reagent to carry out electrophilic fluorination, selectively introducing fluorine atoms at 6-position and carrying out one-step reaction and high efficiency. Compared with the existing synthesis method, the method has the advantages of strong creativity, novelty, simple operation, safety, low cost, less three wastes, environmental friendliness and high total yield, so the synthesis method has strong industrial advantages and significance.
Description
Technical Field
The invention relates to a novel preparation method of Favipiravir and derivatives thereof.
Background
Favipiravir (favipiravir, T-705, trade name Avigan, 1), chemically known as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, is a novel broad-spectrum antiviral drug developed by fukushan chemical pharmaceuticals corporation to target RNA-dependent RNA polymerase (RdRp), approved for marketing in japan 3 months 2014 for the treatment of new and recurrent influenza. Researches find that the Larvavir has good inhibitory activity to various RNA viruses in vitro or in vivo, is expected to be developed and applied to treatment of various virus infections, and has good market prospect.
The representative synthesis method of Favipiravir at present comprises the following steps:
1) taking patent CN102307865 as a representative, the generation route of the current mainstream is: preparing corresponding chloride, and performing fluorine-chlorine exchange with potassium fluoride to obtain a key intermediate, wherein the fluorine-halogen exchange has strict requirements on moisture and is difficult to industrialize; the steps are complicated, and a large amount of industrial wastewater and organic waste liquid are generated in the first step, the second step and the final cyano-group hydrolysis process, so the method is not environment-friendly; and the yield of each step is not high, and the total yield is lower than 30 percent. The route is difficult to industrialize, has more unstable factors and has higher risk of large-scale production.
2) CN102775358 is taken as a representative, amino is obtained by reduction after nitration, and fluorine atoms are introduced through BalzSchiemann reaction to obtain the Favipiravir. Both nitrification and diazotization in the process have certain safety risks, and the large-scale industrial production is difficult; and a large amount of nitrogen-containing wastewater is generated, so that the environment is not friendly; the reduction hydrogenation needs a pressure reaction and is generally avoided as much as possible; the diazotization process generates hydrogen fluoride which is extremely corrosive and highly toxic and cannot be avoided. This route is difficult to industrialize and is generally only at the laboratory stage.
The other existing synthesis processes of the Pilatavir have the industrial defects of multiple reaction steps, complex operation, unfriendly environment, poor safety or stability and low yield. And if the 3-hydroxypyrazine-2-formamide is used for realizing direct fluorination, the synthesis of the Favipiravir can be realized through one-step reaction, and no related literature report that the Favipiravir can be directly synthesized through fluorination is found at present.
Disclosure of Invention
The invention provides a new preparation method of Favipiravir and derivatives thereof. The method specifically comprises the following steps: the compound A is used as a raw material, through electrophilic fluorination, fluorine atoms are selectively introduced into 6-positions, and the synthesis method of the plalazvir or the derivatives thereof, namely the compound B, is a one-step reaction high-efficiency synthesis method. The reaction formula is as follows:
wherein R is1is-CONH2，-CONH2，-CONR3,-COOR3One of cyano groups.
Wherein R is2，R3Is H, C1-C6Alkyl of (C)1-C6Cycloalkyl, aryl substituted alkyl.
The one-step reaction is as follows: and (3) placing the compound A and a fluorinating reagent in a reaction solvent, and carrying out electrophilic fluorination reaction at a certain temperature. The reaction temperature is 30 to 150 ℃, preferably 70 to 100 ℃.
According to the above-mentioned production method, the reaction solvent may be a strongly polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile or the like, a halogenated hydrocarbon solvent such as methylene chloride, dichloroethane or the like, an alcohol solvent such as methanol, ethanol or the like, a mixed solvent of water and the above-mentioned solvent, water or the like. Tetrahydrofuran, acetonitrile, DMSO are preferred.
According to the above-mentioned production method, the amount of the reaction solvent for the electrophilic fluorination is 3 to 10 times, preferably 4 to 6 times the mass of the compound A.
The preparation method according to the above, wherein the electrophilic fluorination reaction uses a fluorinating reagent including but not limited to N-F reagent, specifically, comprising: the electrophilic fluorination reaction employs a fluorinating reagent selected from: n-fluorobenzenesulfonylimide (NFSI), fluorobis (benzenesulfonyl) methane, N-fluoro-N- [4- (trifluoromethyl) phenyl ] - (NFSA), 1-fluoro-4-hydroxy-1, 4-diazabicyclo [2.2.2] octane bistetrafluoroborate (Accnfluoror), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), N-fluoropyridinium (tetrafluoroborate or triflate), 1-fluoro-2, 4, 6-trimethylpyridine trifluoromethanesulfonate, 1-fluoro-2, 6-dichloropyridine trifluoromethanesulfonate, N-fluorobis (trifluoromethylsulfonyl) phthalimide, cobalt trifluoride and the like. NFSI, Selectfluor, N-fluoropyridinium are preferred.
According to the above-mentioned preparation method, the amount of the fluorinating agent is 1 to 3 times the molar equivalent, preferably 1.5 to 2 times the molar equivalent of the compound A.
The invention has the beneficial effects that: the invention creatively provides a method for preparing the peravir through direct fluorination in an industrialized way through research, only needs one step, is simple to operate, is safe, has low cost, few three wastes and high total yield, and is environment-friendly.
Drawings
FIG. 1 is a liquid phase diagram of example 1;
FIG. 2 is a nuclear magnetic spectrum of the product obtained in example 1.
Detailed Description
Example 1
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of DMF, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 12h, and cooling to 0-5 ℃. Unreacted raw materials are filtered, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 11 g of light yellow solid (99.2% by HPLC, yield 70%), the nuclear magnetic spectrum of the light yellow solid is shown in figure 2, and the light yellow solid is determined to be Favipiravir as shown in a reaction formula (1) B:
example 2
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of DMF, then adding 63 g of NSFI, heating to 70-80 ℃, reacting for 12h, and cooling to 0-5 ℃. Unreacted raw materials are filtered, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, the solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 10.2 g of light yellow solid (HPLC 99.3%, yield 65%) which has the same nuclear magnetic spectrum as that of example 1 and is determined to be Favipiravir as shown in reaction formula (2) B:
example 3
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 24 hours, cooling to 0-5 ℃, and adding 100 ml of ethyl acetate. Unreacted raw materials are filtered off, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, the solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 10.67 g of light yellow solid (HPLC 99.4%, yield 68%), the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and the light yellow solid is determined to be Favipiravir as shown in reaction formula (3) B:
example 4
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of dichloroethane and 10 ml of DMF, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 11.2 g of light yellow solid (HPLC 99.3%, yield 71.3%), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and determining the light yellow solid to be Favipiravir as shown in a reaction formula (4) B:
example 5
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 41.7 ml of water, then adding 35.4 g of Selectfluor, heating to 30-40 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 8.2 g of light yellow solid (HPLC 99.2%, yield 55.6%), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and determining that the light yellow solid is Favipiravir.
As shown in equation (4) B:
example 6
Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 417 ml of water, then adding 94.2 g of fluorobis (benzenesulfonyl) methane, heating to 140-150 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 9.2 g of light yellow solid (HPLC 99.6 percent, yield 58.6 percent), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and the light yellow solid is determined to be Favipiravir.
Example 7
Adding 13.9 g of 3-hydroxypyrazine-2-methyl formate into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 15h, cooling to 0-5 ℃, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 h, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 11.2 g of light yellow solid (HPLC 99.3%, yield 71.3%), wherein the structural formula is confirmed to be shown as a reaction formula (5) B through nuclear magnetic test:
example 8
Adding 13.9 g of 3-hydroxypyrazine-2-methyl cyanide into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 10h, cooling to 0-5 ℃, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 50 ml of methanol, refluxing for 1 h, cooling to 0-5 ℃, adding 100 ml of toluene, stirring for half an hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 7.8 g of light yellow solid (HPLC 99.7%, yield 55.3%) which has a structural formula shown in a reaction formula (6) B:
the foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.
Claims (6)
1. A preparation method of Favipiravir and derivatives thereof is characterized by comprising the following steps: taking a compound A as a raw material, selectively introducing fluorine atoms at the 6-position of the compound A through electrophilic fluorination reaction, and obtaining a compound B through one-step reaction, wherein the reaction general formula is as follows:
wherein R is1is-CONH2，-CONH2，-CONR3One of cyano groups.
Wherein R is2，R3Is C1-C6H, alkyl, C1-C6Cycloalkyl or aryl substituted alkyl.
2. The method according to claim 1, wherein the electrophilic fluorination reaction uses a fluorinating agent selected from the group consisting of: n-fluorobenzenesulfonylimide (NFSI), fluorobis (benzenesulfonyl) methane, N-fluoro-N- [4- (trifluoromethyl) phenyl ] - (NFSA), 1-fluoro-4-hydroxy-1, 4-diazabicyclo [2.2.2] octane bistetrafluoroborate (Accnfluoror), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), N-fluoropyridinium (tetrafluoroborate or triflate), 1-fluoro-2, 4, 6-trimethylpyridine trifluoromethanesulfonate, 1-fluoro-2, 6-dichloropyridine trifluoromethanesulfonate, N-fluorobis (trifluoromethylsulfonyl) phthalimide, cobalt trifluoride and the like.
3. The preparation method according to claim 1, wherein the reaction solvent for electrophilic fluorination is one or more of a strongly polar solvent, a halogenated hydrocarbon solvent, an alcohol solvent and water, wherein the strongly polar solvent comprises N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, tetrahydrofuran and acetonitrile, the halogenated hydrocarbon solvent comprises dichloromethane and dichloroethane, and the alcohol solvent comprises methanol and ethanol.
4. The method according to claim 1, wherein the reaction temperature of the electrophilic fluorination reaction is 30 to 150 ℃.
5. The method according to claim 1, wherein the amount of the fluorinating agent is 1 to 3 times the molar equivalent of the compound A.
6. The method according to claim 1, wherein the mass of the reaction solvent for the electrophilic fluorination is 3 to 10 times the mass of the compound A.
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| CN202010583503.1A CN111704582B (en) | 2020-06-23 | 2020-06-23 | Preparation method of Favipiravir and derivatives thereof |
| PCT/CN2020/106121 WO2021258500A1 (en) | 2020-06-23 | 2020-07-31 | Preparation method for favipiravir and derivative thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113072507A (en) * | 2021-03-18 | 2021-07-06 | 中国科学院上海有机化学研究所 | Preparation method of fluoropyrazine compound |
| CN113149995A (en) * | 2021-03-31 | 2021-07-23 | 安徽驱石医药科技有限公司 | Synthesis method and application of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile |
| CN113929633A (en) * | 2021-10-27 | 2022-01-14 | 山东大学 | Synthesis method and application of Favipiravir |
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| CN117417399A (en) * | 2022-11-30 | 2024-01-19 | 山东诚汇双达药业有限公司 | Preparation method of Mo Pila-leaf pyrrosia herb |
| CN116969899A (en) * | 2023-07-31 | 2023-10-31 | 江苏阿尔法药业股份有限公司 | Efficient synthesis process of Fabry-Perot |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003000666A1 (en) * | 2001-06-21 | 2003-01-03 | Pfizer Products Inc. | 5-ht receptor ligands and uses thereof |
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| CN1539828A (en) * | 1998-08-20 | 2004-10-27 | ��ɽ��ѧ��ҵ��ʽ���� | Nitrogen-contg. heterocyclic carboxamide derivatives or salt thereof |
| CN102775358A (en) * | 2012-08-22 | 2012-11-14 | 山东齐都药业有限公司 | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide |
| CN107641106A (en) * | 2016-07-22 | 2018-01-30 | 大连鸿凯化工科技发展有限公司 | The synthetic method of Favipiravir intermediate and Favipiravir |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866553B (en) * | 2017-03-28 | 2020-02-04 | 中南大学 | Synthesis method of Favipiravir |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1539828A (en) * | 1998-08-20 | 2004-10-27 | ��ɽ��ѧ��ҵ��ʽ���� | Nitrogen-contg. heterocyclic carboxamide derivatives or salt thereof |
| CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
| WO2003000666A1 (en) * | 2001-06-21 | 2003-01-03 | Pfizer Products Inc. | 5-ht receptor ligands and uses thereof |
| CN102775358A (en) * | 2012-08-22 | 2012-11-14 | 山东齐都药业有限公司 | Preparation method of 6-fluoro-3-hydroxy-2-pyrazinamide |
| CN107641106A (en) * | 2016-07-22 | 2018-01-30 | 大连鸿凯化工科技发展有限公司 | The synthetic method of Favipiravir intermediate and Favipiravir |
Non-Patent Citations (4)
| Title |
|---|
| JOHANNA HUCHTING ET AL.: "Prodrugs of the Phosphoribosylated Forms of Hydroxypyrazinecarboxamide Pseudobase T-705 and Its De-Fluoro Analogue T-1105 as Potent Influenza Virus Inhibitors", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| PATRICK S. FIER ET AL.: "Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction", 《SCIENCE》 * |
| YAWEI TIAN ET AL.: "Ag-Catalyzed selective fluorination of 6-substituted 2-amionpyrazines", 《JOURNAL OF FLUORINE CHEMISTRY》 * |
| 赵一玫等: "法匹拉韦的合成", 《中国药物化学杂志》 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113072507A (en) * | 2021-03-18 | 2021-07-06 | 中国科学院上海有机化学研究所 | Preparation method of fluoropyrazine compound |
| CN113072507B (en) * | 2021-03-18 | 2022-09-13 | 中国科学院上海有机化学研究所 | Preparation method of fluoropyrazine compound |
| CN113149995A (en) * | 2021-03-31 | 2021-07-23 | 安徽驱石医药科技有限公司 | Synthesis method and application of 7-fluoropyrazolo [1,2-b ] pyrazine-4-carbonitrile |
| CN113929633A (en) * | 2021-10-27 | 2022-01-14 | 山东大学 | Synthesis method and application of Favipiravir |
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