CN112300083B - Preparation method of Favipiravir - Google Patents
Preparation method of Favipiravir Download PDFInfo
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- CN112300083B CN112300083B CN202010313438.0A CN202010313438A CN112300083B CN 112300083 B CN112300083 B CN 112300083B CN 202010313438 A CN202010313438 A CN 202010313438A CN 112300083 B CN112300083 B CN 112300083B
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Abstract
The invention relates to the technical field of biological medicines, in particular to a preparation method of Favipiravir, which is characterized in that 3-hydroxypyrazine-2-formamide and a fluoro reagent are stirred in a solvent and react in one step to prepare the Favipiravir. The preparation method of the Favipiravir provided by the invention is short and novel in route, mild in reaction conditions, economic and effective, and higher in yield than the existing preparation method, and is suitable for large-scale industrial production.
Description
Technical Field
The invention relates to the technical field of biological medicines, and particularly relates to a preparation method of Favipiravir.
Background
Faviravir, chemically known as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, CAS accession No. 259793-96-9, is a novel broad-spectrum antiviral drug developed by fukushan chemical pharmaceuticals, japan 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.
Patent WO200010569A discloses a preparation method of Favipiravir, and the synthetic route is as follows:
the compound shown in the formula I is prepared by taking 6-bromo-3-methoxy-2-pyrazine methyl formate as a raw material through palladium catalytic coupling reaction, ammonolysis reaction, Balz-Schiemann reaction and hydrolysis reaction. The route has longer steps and lower yield; expensive palladium catalyst is used, which greatly increases the cost; undergoing a diazotization reaction, the decomposition of the diazonium salt can cause explosion risks.
Patent WO200160834A also discloses a preparation method of favipiravir, which is synthesized as follows:
the route takes 6-nitro-3-hydroxy-2 pyrazine-formamide as a raw material and prepares the compound shown in the formula I through chlorination reaction, fluorination reaction, hydroxylation reaction and hydrolysis reaction. The route has longer steps and lower yield; wherein, the phosphorus oxychloride with strong irritation is used, which is harmful to human health and is not beneficial to industrialized production.
In conclusion, the prior art generally faces the problems of long reaction route, low yield, expensive reagents, environmental friendliness and the like, and is not suitable for industrial production. In view of the good medicinal prospect of favipiravir, an economical and safe preparation method needs to be developed.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: provides a preparation method of Favipiravir with simple reaction route and higher yield.
The technical scheme for solving the technical problems is as follows:
a preparation method of Favipiravir comprises the following steps:
stirring the compound of the formula I and a fluoro reagent in a solvent to react to prepare a compound of a formula II;
wherein the X group is selected from chlorine, bromine, iodine, sulfonate group or nitro.
Preferably, the fluorinating agent is tetraalkylammonium fluoride or alkali metal fluoride.
Preferably, the molar ratio of the compound of the formula I to the fluorinating agent is 1: 1-5; further, the molar ratio of the compound shown in the formula I to the fluorinating agent is 1: 1-3.
Preferably, the reaction solvent is a polar aprotic solvent; further, the solvent is selected from one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran and N-methylpyrrolidone.
Preferably, the reaction temperature is 0-120 ℃; further, the reaction temperature is 25-80 ℃.
The inventors have surprisingly found that the yield of the reaction can be significantly increased by adding a carboxylic acid and a condensing agent to the reaction system. The applicant speculates that the possible reason is that the difficulty of F substitution at the 6-position is reduced after the carboxylic acid is condensed with the hydroxyl group at the 3-position of the pyrazine ring.
Preferably, carboxylic acid and a condensing agent are also added in the reaction, and after the reaction is finished, acid/alkali is added for hydrolysis to obtain the compound of the formula II.
Preferably, the molar ratio of the compound of formula I, the fluorinating agent, the carboxylic acid and the condensing agent in the reaction is 1: 1-5: 1-2: 1-2; further, the molar ratio of the compound of the formula I, the fluorinating agent, the carboxylic acid and the condensing agent in the reaction is 1: 1-3: 1-1.5: 1 to 1.5.
Preferably, the carboxylic acid is selected from monocarboxylic acids; further selected from C1～10A monobasic fatty acid or a monobasic aromatic acid; specifically, the acid may be selected from acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, benzoic acid, and the like.
The condensing agent is DCC dicyclohexylcarbodiimide.
The Chinese naming of the compound of the invention conflicts with the structural formula, and the structural formula is taken as the standard; except for obvious errors in the formula.
The preparation method of the Favipiravir provided by the invention has the advantages that the reaction steps are greatly shortened, the labor and raw material costs are effectively reduced, and the preparation method is suitable for industrial production; the fluoro reagent is cheap and easy to obtain, the reaction condition is mild, and the functional group tolerance is good; expensive metal catalysts are not needed, so that the cost is greatly reduced; the diazotization reaction is not needed, so that the risk of explosion caused by the decomposition of the diazonium salt is avoided; the method has the advantages of short and novel route, mild reaction conditions, economy and effectiveness, higher yield than the existing preparation method, and suitability for large-scale industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a compound of formula I (X is Br);
FIG. 2 shows a compound of formula I (X is NO)2) The nuclear magnetic resonance hydrogen spectrum of (a);
FIG. 3 is a NMR spectrum of a compound of formula II.
Detailed Description
The invention is illustrated but not limited by the following examples. The technical solutions protected by the present invention are all the simple replacements or modifications made by the skilled person in the art.
Example 1
Preparation of the Compound of formula I (X is Br)
Adding 14.7g of 3-hydroxypyrazine-2-formamide (with the molecular weight of 139.1 and 106mmol) into a three-necked bottle, adding 35ml of DMF and 14.2g of pyridine, heating the oil bath to 80 ℃, dropwise adding 21.1g of bromine (with the molecular weight of 159.8 and 132mmol), controlling the temperature to be 80-100 ℃, and finishing dropping within 60 min. After dropping, the reaction is kept for 3 hours. After the reaction is finished, 8mL of toluene is added, 60mL of water is dropwise added, the reaction solution is dripped for 15min, the temperature is reduced to room temperature after dripping is finished, the filtration is carried out, a filter cake is washed by 10mL of methanol, the filter cake is dried by air blowing at 50 ℃ for 6h, 15.0g of brown solid is obtained, the purity is determined by HPLC and is 95.1%, and the yield is as follows: 62.1 percent.
1HNMR(DMSO-d6)：13.60(1H,s),8.72(1H,s),8.56(1H,s),8.48(1H,s)
Example 2
Preparation of the Compound of formula I (X is NO)2)
Adding 2.0g 3-hydroxypyrazine-2-formamide (molecular weight 139.1, 14.4mmol) into 20ml concentrated sulfuric acid, cooling to 0-5 deg.C, and adding KNO in batches32.91g (molecular weight 101.1, 28.8mol), after the addition, the temperature is raised to 40 ℃ for reaction for 4 hours. Adding the reaction solution into 100ml of ice water, precipitating and filtering, washing a filter cake for 2 times by using 20ml of purified water, and drying the filter cake for 6 hours by blowing at 50 ℃ to obtain 1.93g of off-white solid, wherein the purity of the solid is 96.5 percent by HPCL determination, and the yield is as follows: 72.9 percent.
1HNMR(DMSO-d6)：8.98(1H,s),8.34(1H,s),8.07(1H,s)
Example 3
Preparation of the Compound of formula II (X is Br and the fluorinating agent is tetramethylammonium fluoride)
Dissolving 0.61g of acetic acid (molecular weight 60.1, 10.2mmol) in a 100mL three-neck flask, cooling to 0-5 ℃ under the protection of nitrogen, adding 2.28g of DCC (molecular weight 206.3, 11.1mmol), heating to room temperature, stirring for 1h, adding 2.10g of the compound of formula I (molecular weight 218, 9.17mmol) prepared in example 1, stirring for 12h, adding 1.72g of anhydrous tetramethylammonium fluoride (molecular weight 93.1, 18.5mmol), stirring at room temperature for 24h, adding 20mL of 2N sodium hydroxide solution, stirring until TLC detection reaction is complete, extracting impurities with 10mL of ethyl acetate, demixing, adjusting the pH of the aqueous layer to 3-4 with 2N HCl, extracting with 20mL of 3 ethyl acetate, combining the organic layers, filtering with suction, washing with saturated sodium bicarbonate solution, washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and carrying out suction filtration. Spin-drying to obtain the compound of formula II, and recrystallizing with methanol to obtain refined Lavir 1.23g with purity of 99.5% and yield of 84.9% by HPCL assay.
1HNMR(DMSO-d6)：13.42(1H,s),8.76(1H,s),8.53(1H,s),8.51(1H,s)
Example 4
Preparation of the Compound of formula II (X is Br and the fluorinating agent is tetramethylammonium fluoride)
2.10g of the compound of the formula I (molecular weight: 218, 9.17mmol) prepared in example 1 and 1.72g of anhydrous tetramethylammonium fluoride (molecular weight: 93.1, 18.5mmol) were put into a 100mL three-necked flask, and stirred at 80 ℃ for 24 hours under nitrogen protection, after completion of the reaction was detected by TLC, column chromatography gave 0.70g of the compound of the formula II, which was determined to have a purity of 95.6% by HPCL and a yield of 46%.
1HNMR(DMSO-d6)：13.42(1H,s),8.76(1H,s),8.53(1H,s),8.51(1H,s)
Example 5
Preparation of the Compound of formula II (X is NO)2The fluorinating agent is tetramethyl ammonium fluoride)
Dissolving 0.72g of acetic acid (molecular weight 60.1, 12.0mmol) in 20mL of DMF in a 100mL three-neck flask, cooling to 0-5 ℃ under the protection of nitrogen, adding 2.7g of DCC (molecular weight 206.3, 12.1mmol), heating to room temperature, stirring for 1h, adding 2.07g of the compound of formula I (molecular weight 184, 10.9mmol) prepared in example 2, stirring for 12h, adding 2g of anhydrous tetramethylammonium fluoride (molecular weight 93.1, 21.5mmol), stirring at room temperature for 24h, adding 20mL of 2N sodium hydroxide solution, stirring until TLC detection reaction is complete, extracting impurities with 10mL of ethyl acetate, separating layers, adjusting the pH of the aqueous layer to 3-4 with 2N HCl, extracting with 20mL of 3 ethyl acetate, combining organic layers, washing with saturated sodium bicarbonate solution, washing with water, washing with saturated sodium chloride, drying with anhydrous sodium sulfate, and suction filtering. Spin-drying to obtain compound of formula II, and recrystallizing with methanol to obtain refined Lavir 1.52g with purity of 99.6% and yield of 89.0%.
Example 6
Preparation of the Compound of formula II (X is NO)2The fluorinating agent is tetramethyl ammonium fluoride)
2.07g of the compound of the formula I (molecular weight: 184, 10.9mmol) prepared in example 2 and 2g of anhydrous tetramethylammonium fluoride (molecular weight: 93.1, 21.5mmol) were put in a 100mL three-necked flask, and then stirred at 80 ℃ for 24 hours under nitrogen protection, after completion of the TLC detection reaction, column chromatography was carried out to obtain 0.865g of the compound of the formula II, which was 94.8% pure by HPCL assay, and 47.9% yield was obtained.
1HNMR(DMSO-d6)：13.42(1H,s),8.76(1H,s),8.53(1H,s),8.51(1H,s)
Example 7
Preparation of the Compound of formula II (X is Br and the fluorinating agent is cesium fluoride)
2g of the compound of the formula I (molecular weight 218, 9.17mmol), 2.81g of anhydrous cesium fluoride (molecular weight 151.9, 18.5mmol) are added into a 100mL three-necked flask, nitrogen is protected, 50mLDMF is added, stirring is carried out at 120 ℃ for 24h, TLC detection is carried out to complete the reaction, column chromatography is carried out to obtain 0.195g of the compound of the formula II, the purity of HPCL determination is 92.2%, and the yield is 12%.
1HNMR(DMSO-d6)：13.42(1H,s),8.76(1H,s),8.53(1H,s),8.51(1H,s)
Example 8
Preparation of the Compound of formula II (X is NO)2The fluorinating agent is cesium fluoride
2.07g of the compound of the formula I (molecular weight: 184, 10.9mmol) prepared in example 2, 3.32g of anhydrous cesium fluoride (molecular weight: 151.9, 21.9mmol) were put in a 100mL three-necked flask, protected with nitrogen, 50mL of DMF was added, the mixture was stirred at 120 ℃ for 24 hours, the reaction was detected by TLC to be complete, and column chromatography gave 0.339g of the compound of the formula II, which was 94.3% pure by HPCL with a yield of 19%.
1HNMR(DMSO-d6)：13.42(1H,s),8.76(1H,s),8.53(1H,s),8.51(1H,s)。
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various changes and modifications can be made without departing from the inventive concept of the present invention, and these changes and modifications are all within the scope of the present invention.
Claims (7)
1. A preparation method of Favipiravir is characterized by comprising the following steps:
stirring the compound of the formula I and a fluoro reagent in a solvent to react to prepare a compound of a formula II;
the fluorinating reagent is tetraalkylammonium fluoride or alkali metal fluoride;
adding carboxylic acid and a condensing agent in the reaction, and adding acid or alkali for hydrolysis after the reaction is finished to obtain a compound shown in a formula II;
the molar ratio of the compound of the formula I in the reaction, the fluorinating reagent, the carboxylic acid and the condensing agent is 1: 1-5: 1-2: 1-2;
wherein the X group is selected from chlorine, bromine, iodine or nitro.
2. The process for preparing fapirovir according to claim 1 wherein the solvent is selected from polar aprotic solvents.
3. The process for preparing fapirovir according to claim 1 wherein the solvent is selected from one or more of dimethyl sulfoxide, dimethylformamide, dimethylacetamide, tetrahydrofuran, and N-methylpyrrolidinone.
4. The preparation method of fapirovir according to claim 1, wherein the reaction temperature is 0-120 ℃.
5. The preparation method of fapirovir according to claim 1, wherein the molar ratio of the compound of formula I in the reaction, the fluorinating agent, the carboxylic acid and the condensing agent is 1: 1-3: 1-1.5: 1 to 1.5.
6. The process for preparing fapirovir according to claim 1 wherein the carboxylic acid is selected from monocarboxylic acids.
7. The process for preparing fapirovir according to claim 1 wherein the condensing agent is DCC.
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| 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 |
| CN113234030A (en) * | 2021-04-29 | 2021-08-10 | 河北唯达生物医药产业技术研究有限公司 | Preparation method of 6-bromo-3-hydroxy-2-pyrazinecarboxamide |
Citations (7)
| 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 |
| CN1781911A (en) * | 2000-02-16 | 2006-06-07 | 富山化学工业株式会社 | Intermediate for producing novel pyrazine derivatives |
| CN102603658A (en) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | Preparation method of 6-fluorine-3-hydroxyl-2-pyrazinamide |
| 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 |
| CN104496917A (en) * | 2014-12-15 | 2015-04-08 | 南京华威医药科技开发有限公司 | Synthesis method of Favipiravir |
| CN105732523A (en) * | 2014-12-10 | 2016-07-06 | 青岛市黄岛区中医医院 | Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide |
| CN106866553A (en) * | 2017-03-28 | 2017-06-20 | 中南大学 | A kind of synthetic method of Favipiravir |
-
2020
- 2020-04-20 CN CN202010313438.0A patent/CN112300083B/en active Active
Patent Citations (7)
| 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 |
| CN1781911A (en) * | 2000-02-16 | 2006-06-07 | 富山化学工业株式会社 | Intermediate for producing novel pyrazine derivatives |
| CN102603658A (en) * | 2011-10-18 | 2012-07-25 | 山东齐都药业有限公司 | Preparation method of 6-fluorine-3-hydroxyl-2-pyrazinamide |
| 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 |
| CN105732523A (en) * | 2014-12-10 | 2016-07-06 | 青岛市黄岛区中医医院 | Preparation method for 6-fluoro-3-hydroxyl-2-pyrazinamide |
| CN104496917A (en) * | 2014-12-15 | 2015-04-08 | 南京华威医药科技开发有限公司 | Synthesis method of Favipiravir |
| CN106866553A (en) * | 2017-03-28 | 2017-06-20 | 中南大学 | A kind of synthetic method of Favipiravir |
Non-Patent Citations (4)
| Title |
|---|
| Synthesis and crystal structure of 6-fluoro-3-hydroxypyrazine-2-carboxamide;Fangyuan Shi等;《Drug Discoveries & Therapeutics》;20140630;第8卷(第3期);117-120 * |
| 法匹拉韦及赛红霉素中间体的合成研究;王皖;《延边大学硕士学位论文》;20160415;1-36 * |
| 法匹拉韦合成路线图解;刘涛等;《中国药物化学杂志》;20180220;第28卷(第01期);77-79 * |
| 法匹拉韦的合成工艺研究;杨柳;《济南大学硕士学位论文》;20170315;1-54 * |
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