CN111675663A - Preparation method of Favipiravir - Google Patents
Preparation method of Favipiravir Download PDFInfo
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- CN111675663A CN111675663A CN202010533414.6A CN202010533414A CN111675663A CN 111675663 A CN111675663 A CN 111675663A CN 202010533414 A CN202010533414 A CN 202010533414A CN 111675663 A CN111675663 A CN 111675663A
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- favipiravir
- organic solvent
- hydroxy
- fluoro
- cyanopyrazine
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- ZCGNOVWYSGBHAU-UHFFFAOYSA-N favipiravir Chemical compound NC(=O)C1=NC(F)=CNC1=O ZCGNOVWYSGBHAU-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 229950008454 favipiravir Drugs 0.000 title claims abstract description 22
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 20
- LJZHACRGZWYTAX-UHFFFAOYSA-N 5-fluoro-2-oxo-1h-pyrazine-3-carbonitrile Chemical compound OC1=NC=C(F)N=C1C#N LJZHACRGZWYTAX-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 11
- 239000002994 raw material Substances 0.000 claims abstract description 10
- -1 amine salt Chemical class 0.000 claims abstract description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 24
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 abstract description 16
- 230000008569 process Effects 0.000 abstract description 12
- 230000007062 hydrolysis Effects 0.000 abstract description 11
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 11
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 abstract description 7
- 230000002378 acidificating effect Effects 0.000 abstract description 4
- 239000002351 wastewater Substances 0.000 abstract description 4
- 238000004880 explosion Methods 0.000 abstract description 3
- 238000006864 oxidative decomposition reaction Methods 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012071 phase Substances 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 241001115402 Ebolavirus Species 0.000 description 2
- 108060004795 Methyltransferase Proteins 0.000 description 2
- 241000025505 Pyrrosia Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- CUEAMQKUSNCUDI-UHFFFAOYSA-N n-cyclohexylcyclohexanamine;5-fluoro-2-oxo-1h-pyrazine-3-carbonitrile Chemical compound FC1=CNC(=O)C(C#N)=N1.C1CCCCC1NC1CCCCC1 CUEAMQKUSNCUDI-UHFFFAOYSA-N 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 241000700605 Viruses Species 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 208000037797 influenza A Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 125000002264 triphosphate group Chemical group [H]OP(=O)(O[H])OP(=O)(O[H])OP(=O)(O[H])O* 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Communicable Diseases (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Virology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of Favipiravir, which comprises the following specific steps: one or two of 6-fluoro-3-hydroxy-2-cyanopyrazine and 6-fluoro-3-hydroxy-2-cyanopyrazine organic amine salt are used as raw materials to prepare the Lavipiravir with high yield under the alkaline condition in an anhydrous organic solvent. Compared with the existing hydrolysis process of concentrated sulfuric acid and the existing hydrolysis process of hydrogen peroxide, the preparation method avoids a large amount of acidic wastewater generated in the hydrolysis process of concentrated sulfuric acid, avoids the explosion danger possibly caused by using hydrogen peroxide, and avoids the hydrolysis and oxidative decomposition phenomena of products in the hydrolysis process of concentrated sulfuric acid and the hydrolysis process of hydrogen peroxide.
Description
Technical Field
The invention relates to a novel preparation method of Favipiravir.
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. Phase III clinical studies on influenza A have been completed in the United states at present, Favipiravir has a good therapeutic effect on patients infected with Ebola virus, and phase II clinical studies on Ebola virus resistance in the United states are ongoing. The action mechanism of the Favipiravir is mainly that after entering the body, the Favipiravir generates a nucleoside analogue triphosphate form under the action of a series of cellular phosphokinases, so that the replication and transcription of the virus are interfered. 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.
In patent CN102307865A, 6-fluoro-3-hydroxy-2-cyanopyrazine is prepared by reacting hydrogen peroxide in aqueous solution of NaOH to obtain pyrrosia faba, the reaction is carried out in aqueous solution of alkali to easily hydrolyze amido bond group of pyrrosia faba into acid, meanwhile, hydrogen peroxide has strong oxidation effect on the product to deteriorate the product, thereby greatly reducing yield of the reaction, and in addition, the use of double oxide has certain problem of safety operation, and peroxide is easy to cause explosion. The route is as follows:
in patent CN106478528A, 6-fluoro-3-hydroxy-2-cyanopyrazine is in concentrated H2SO4The process for preparing the Favipiravir by adding hot water for hydrolysis, a large amount of acidic waste water generated in the concentrated sulfuric acid hydrolysis process, and the reaction easily enables the amido bond group of the product Favipiravir to be continuously hydrolyzed into acid in an acidic aqueous solution, and concentrated H is concentrated2SO4Has stronger oxidation effect on a product liquid, and the product is deteriorated, so that the yield of the reaction is greatly reduced, and the route is as follows:
in conclusion, the existing synthesis method has a plurality of technical problems, such as low yield, unsafe operation, large amount of waste water and environmental friendliness.
Disclosure of Invention
The method can prepare the Favipiravir with high yield by enabling 6-fluoro-3-hydroxy-2-cyanopyrazine to be in an anhydrous organic solvent under an alkaline condition, and in the anhydrous alkaline organic solvent, the alkali provides hydroxy to promote the 6-fluoro-3-hydroxy-2-cyanopyrazine to react to obtain the Favipiravir with high yield.
The data of the embodiment shows that when the 6-fluoro-3-hydroxy-2-cyanopyrazine or the organic amine salt thereof is used for preparing the Favipiravir, the problem of product hydrolysis can be well avoided due to an anhydrous system, and the problem of oxidation and impurity change does not exist due to the absence of an oxidation reagent, so that the yield can reach more than 95%, the HPLC purity can reach more than 99.9%, and the synthetic route is as follows:
in certain embodiments, 6-fluoro-3-hydroxy-2-cyanopyrazine is prepared by the following process:
according to the preparation method, the organic solvent can be one or more of tert-butyl alcohol, methanol, ethanol and isopropanol, tetrahydrofuran, and preferably tert-butyl alcohol, ethanol and isopropanol.
According to the above-mentioned production method, the potassium hydroxide may be an inorganic base such as sodium hydroxide or lithium hydroxide, and potassium hydroxide is preferred.
According to the above-mentioned production method, the molar amount of the base is 1 to 6 times, preferably 3 to 4 times the molar amount of the raw material.
According to the above-mentioned production method, the mass of the organic solvent is 4 to 12 times, preferably 5 to 8 times that of the raw material.
According to the above-mentioned preparation method, the reaction temperature is 30 to 80 ℃, preferably 50 to 70 ℃.
The invention has the beneficial effects that: compared with the existing concentrated sulfuric acid hydrolysis process and hydrogen peroxide hydrolysis process, the preparation method avoids a large amount of acidic wastewater generated in the concentrated sulfuric acid hydrolysis process, avoids the explosion danger possibly caused by using hydrogen peroxide, and avoids the hydrolysis and oxidative decomposition phenomena of products in the concentrated sulfuric acid hydrolysis process and the hydrogen peroxide hydrolysis process.
Drawings
FIG. 1 is a liquid phase diagram of the product obtained in example 1.
FIG. 2 is a nuclear magnetic diagram of the product obtained in example 1 (the nuclear magnetic diagrams of the products obtained in examples 2 to 4 are the same as in example 1).
Detailed Description
Example 1
30 g of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt was added to 100 g of anhydrous t-butanol, followed by 22.4 g of potassium hydroxide. Heating to 60 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butanol, adding 150 ml of water and 100 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing once by 100 ml of saturated saline, drying by anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 14.13 g of a product, wherein a nuclear magnetic diagram is shown in figure 2, and the product can be determined to be Favipiravir. The molar yield is 96 percent, and the purity is 99.9 percent.
Example 2
27.8 g of 6-fluoro-3-hydroxy-2-cyanopyrazine were added to 150 g of anhydrous isopropanol, followed by 32 g of sodium hydroxide. Heating to 60 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butyl alcohol, adding 150 ml of water and 150 ml of ethyl acetate, adjusting the pH of a water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing 150 ml of saturated salt solution once, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 29.85 g of a product, wherein the nuclear magnetic result is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 95 percent, and the purity is 99.9 percent.
Example 3
30 g of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt was added to 360 g of anhydrous tert-butanol, followed by 180 g of potassium hydroxide. The temperature is increased to 30 ℃, the reaction is carried out for 8h, and the TLC detects that the raw materials are completely reacted. Distilling off tert-butanol, adding 150 ml of water and 100 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing once by using 100 ml of saturated saline, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain a product, wherein the nuclear magnetic result of the product is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 98 percent, and the purity is 99.9 percent.
Example 4
27.8 g of 6-fluoro-3-hydroxy-2-cyanopyrazine were added to 11.12 g of anhydrous isopropanol, followed by 2.78 g of sodium hydroxide. Heating to 80 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butanol, adding 150 ml of water and 150 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing 150 ml of saturated salt solution once, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain a product, wherein the nuclear magnetic result of the product is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 96 percent, and the purity is 99.9 percent.
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 (7)
1. A preparation method of Favipiravir is characterized by comprising the following steps: the method comprises the following steps: one or two of 6-fluoro-3-hydroxy-2-cyanopyrazine and 6-fluoro-3-hydroxy-2-cyanopyrazine organic amine salt are used as raw materials, and the Favipiravir is prepared in an alkaline anhydrous organic solvent at the temperature of 30-80 ℃.
2. The method of claim 1, wherein: the organic solvent is one or more of tert-butyl alcohol, methanol, ethanol and isopropanol, and tetrahydrofuran.
3. The method of claim 2, wherein: the organic solvent is tert-butanol, ethanol and isopropanol.
4. The method of claim 1, wherein: wherein the alkaline anhydrous organic solvent is obtained by adding inorganic base into organic solvent, and the inorganic base comprises potassium hydroxide, sodium hydroxide and lithium hydroxide.
5. The method of claim 1, wherein: the molar amount of the base is 1 to 6 times the molar amount of the raw material.
6. The method of claim 1, wherein: the mass of the organic solvent is 4-12 times of the mass of the raw materials.
7. The method of claim 1, wherein: the reaction temperature is preferably 50 to 70 ℃.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114478404A (en) * | 2022-03-17 | 2022-05-13 | 浙江海正药业股份有限公司 | Purification method of faviravir intermediate hydroxyl |
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CN102307865A (en) * | 2009-01-28 | 2012-01-04 | 日本曹达株式会社 | Method for producing dichloropyrazine derivative |
CN106478528A (en) * | 2016-08-26 | 2017-03-08 | 武汉工程大学 | The synthesis technique of Favipiravir |
CN106866553A (en) * | 2017-03-28 | 2017-06-20 | 中南大学 | A kind of synthetic method of Favipiravir |
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 |
CN110773144A (en) * | 2019-10-28 | 2020-02-11 | 湖南科技学院 | A kind of catalytic system for preparing amide by hydrolysis of cyano group and its application |
-
2020
- 2020-06-11 CN CN202010533414.6A patent/CN111675663A/en active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
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CN102307865A (en) * | 2009-01-28 | 2012-01-04 | 日本曹达株式会社 | Method for producing dichloropyrazine derivative |
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 |
CN106478528A (en) * | 2016-08-26 | 2017-03-08 | 武汉工程大学 | The synthesis technique of Favipiravir |
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Non-Patent Citations (2)
Title |
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GANESH CHANDRA MIDYA ET AL.: "Transition-Metal-Free Hydration of Nitriles Using Potassium tert-Butoxide under Anhydrous Conditions", 《J. ORG. CHEM.》 * |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN114478404A (en) * | 2022-03-17 | 2022-05-13 | 浙江海正药业股份有限公司 | Purification method of faviravir intermediate hydroxyl |
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