CN106478528A - The synthesis technique of Favipiravir - Google Patents
The synthesis technique of Favipiravir Download PDFInfo
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Abstract
The present invention relates to the synthesis technique of Favipiravir, include following steps：1) pyrazine compound is dissolved in organic reagent I, adds oxidant M, carry out nitrogen oxidation reaction, obtain white solid matter；2) gained white solid matter is added in organic reagent II and carries out chlorination reaction, obtain faint yellow solid；3) by gained faint yellow solid and the aprotic polar solvent being dried, the fluorion donating agent of drying, tetrabutyl ammonium bromide mix homogeneously, stirring reaction, obtain faint yellow solid；4) gained faint yellow solid is added to the water, Isosorbide-5-Nitrae dioxane and sodium acetate, react to obtain yellow oil；5) gained yellow oil is mixed with concentrated sulphuric acid, target product Favipiravir can be obtained.The raw material that the method for the present invention is related to is simple and easy to get, and synthesis technique is simple, mild condition, finally 6 fluorine 3 HYDROXYPYRAZINE 2 Methanamide is obtained through nitrogen oxidation, chlorination, fluoro, hydrolysis, has good industrial value.
Description
Technical field
The invention belongs to field of medicine and chemical technology is and in particular to the synthesis technique of Favipiravir.
Background technology
Favipiravir (favipiravir, T-705), chemical entitled 6- fluoro- 3- HYDROXYPYRAZINE -2- Methanamide, is new
RNA polymerase (RdRp) the inhibitor class broad-spectrum antiviral drug that RNA relies on, itself does not have antiviral activity, is existed by metabolism
Favipiravir ribonucleoside triphosphote form can be rapidly converted in vivo, by simulating guanosine triphosphate (GTP) (GTP) competitive inhibition virus
The RNA polymerase that RNA relies on, suppression viral genome replicates and transcribes and play antivirus action, Favipiravir nucleoside three phosphorus
Sour form also can penetrate into viral gene, plays antivirus action by inducing fatefulue mutation.Favipiravir is to A type influenza
(including bird flu and influenza A H1N1 infection), virus had preferable therapeutical effect moreover it is possible to suppress the transcription of other viruses, such as
Arenaviruss, yellow fever virus, west Nile viruss, Bunyavirus and hand-foot-mouth disease virus etc., nearest document report it can be effective
Duplication (the IC of suppression Zaire type Ebola virus RNA90For 110 μm of ol/L).Its structural formula is as follows：
In prior art, the synthesis technique of Favipiravir mainly has following three kinds：
(1) patent documentation (WO00/10569) is urged through diazotising alcoholysis, palladium with 6- bromo- 3- Aminopyrazine -2- methyl formate
Change lower amino to replace and the prepared 6- amino -3- methoxypyrazine -2- Methanamide of amidation process, then replace through diazotising fluorine, so
Under trim,ethylchlorosilane and sodium iodide effect, demethylation is obtained Favipiravir, total recovery only 0.44% afterwards.Amino in method
Replace used catalyst three (dibenzalacetone) two palladium [Pd2(dba)3] and (S)-(-) double (the diphenyl phosphine) -1,1'- of -2,2'-
Dinaphthalene costly, and final step reaction be difficult to control to, yield only has 4.3%, is unfavorable for industrialized production.Reaction equation is such as
Under.
(2) patent documentation CN 102775358A discloses one kind and is passed through as initiation material by 3- amino -2- pyrazine carboxylic acid
Hydroxylating, esterification, amination, nitrification, reduction, fluorination six-step process are obtained target compound, and 6- nitro -3- hydroxyl in this route -
2- pyrazinamide dissolubility in general organic dissolution is limited, and it is more difficult to be reduced into amino-compound, makes in final step
Strong with pyridine Fluohydric acid. corrosivity, and yield is relatively low.Reaction equation is as follows.
(3) Wang Huan et al. (Chinese Journal of Pharmaceuticals, 2014,45 (11):1009-1012.) by amidomalonic acid diethyl
Ester hydrochloride is initiation material, obtains 6- bromo- 3- oxo -3 through ammonolysis, cyclization, bromo, 4- dihydro pyrazine -2- Methanamide, then through three
With potassium acetate, 3- position fluorine selective hydrolysis are become salt with hexanamine again after chlorethoxyfos chloro, potassium fluoride fluoro, then with hydrogen peroxide/
Sodium hydroxide is converted into amide and obtains product Favipiravir, and in this route, hexanamine used belongs to inflammable, high poison material, work
Industry processes and more bothers, and is not suitable for this method complex operation of industry's enlarging production, and agents useful for same is expensive, and production cost is high, total recovery
Less than 10%, therefore this method is unsuitable for industrialized production.Reaction equation is as follows.
Content of the invention
Problem to be solved by this invention is to provide a kind of synthesis technique of Favipiravir for above-mentioned prior art, pin
Route methods to original preparation are it is proposed that a new synthetic route.
The present invention solves above-mentioned technical problem and be employed technical scheme comprise that：The synthesis technique of Favipiravir, by following works
Skill route is carried out：
Wherein, the R in pyrazine compound is-CN or-CONH2.
By such scheme, described organic reagent I is organic acid or ethyl acetate, and described organic acid is glacial acetic acid, dense sulfur
One of acid, formic acid and trifluoroacetic acid or their mixing；Oxidant M is hydrogen peroxide, metachloroperbenzoic acid or peroxy acid.
By such scheme, described pyrazine compound, organic reagent I, the mol ratio of oxidant are 1:(5～10):(2～8).
By such scheme, described organic reagent II is 1,2- dichloroethanes, chlorobenzene and phosphorus oxychloride a kind of or they
Mixing；Described acid binding agent is triethylamine, dimethyl propylamine, diisopropylethylamine or pyridine.
By such scheme, described aprotic polar solvent is dimethyl sulfoxide, DMF, acetone or 1,3- bis-
Methyl -2- imidazolone.
By such scheme, described fluorion donating agent is Argentous fluoride, potassium fluoride, cesium fluoride, in tetrabutyl ammonium fluoride
A kind of or their mixing.
By such scheme, comprise the following steps that：
1) pyrazine compound is dissolved in organic reagent I, controls -5～5 DEG C of temperature, add oxidant M, finish system room
Temperature or be warming up to 0～95 DEG C reaction 16-24h, carry out nitrogen oxidation reaction, gained product is through solvent recrystallization, vacuum drying
Obtain white solid matter；
2) gained white solid matter pyrazine dinitrogen oxide is added in organic reagent II and carries out chlorination reaction, reaction
After finishing, it is punched in frozen water, ethyl acetate extracts, merge organic faciess, washing, be dried, filter, filtrate decompression is spin-dried for, post color
Through being vacuum dried to obtain faint yellow solid after spectrum purifies and separates；
3) by gained faint yellow solid and the aprotic polar solvent being dried, the fluorion donating agent of drying, the tetrabutyl
Ammonium bromide mix homogeneously, heated sealed, controlling reaction temperature 55-80 DEG C, stirring reaction 3h, it is punched into cold water after the completion of reaction
In, extraction, merge organic faciess, be dried, filter, filtrate decompression is spin-dried for, and obtains faint yellow solid；
4) gained faint yellow solid is added to the water, Isosorbide-5-Nitrae-dioxane and sodium acetate, control 55 DEG C of temperature, reaction
7h, after having reacted, is punched in water, adjusts pH 2.5, extraction with concentrated hydrochloric acid, merges organic faciess, be dried, filter, filtrate decompression is revolved
Dry, obtain yellow oil；
5) gained yellow oil is mixed with concentrated sulphuric acid, controls temperature 50 C, react 4h, be slowly dropped in frozen water,
Stirring, extracts, and merges organic faciess, is dried, and filters, and filtrate decompression is spin-dried for, and residue separates through chromatography and can obtain target product
Thing Favipiravir.
By such scheme, step 1) described in recrystallization solvent be mass percent 90% methanol or water.
By such scheme, step 2) described chlorination reaction is first to add by several times white solid matter pyrazine dinitrogen oxide
To in organic reagent II, it is warming up to 50 DEG C, stirs 50min, then be warming up to 70 DEG C of stirring 1h, be cooled to room temperature and add and tie up acid
Agent, is finally warming up to 90～110 DEG C of reaction 3-8h.
By such scheme, step 2) described in pyrazine dinitrogen oxide, organic solvent II, acid binding agent mol ratio be 1:
(3.6～5):(1.2～2.4).
The raw material that the method for the present invention is related to is simple and easy to get, and synthesis technique is simple, and mild condition, through nitrogen oxidation, chlorination, fluorine
Generation, hydrolysis are finally obtained 6- fluoro- 3- HYDROXYPYRAZINE -2- Methanamide, have good industrial value.
Specific embodiment
The present invention will be further described with reference to embodiments.
Embodiment 1
1) preparation of 1.4- dioxy pyrazinamide (2)：Control -5～5 DEG C of temperature, by 2 cyano pyrazine (1) 5.25g and ice
Acetic acid 29.95g, 30% hydrogen peroxide 45.30g mix homogeneously, are warming up to 95 DEG C, back flow reaction 22h, and TLC shows no after raw material,
40 DEG C of vacuum rotary steams remove solvent, add 15ml water, vacuum rotary steam, add 15ml water, add after being repeated several times removing glacial acetic acid
The chloroform extraction (15ml*3) of heat, water layer decompression is spin-dried for, and 90% recrystallizing methanol filters, and filter cake is vacuum dried to obtain white powder
Shape Isosorbide-5-Nitrae-dioxy pyrazinamide (2) 4.45g, fusing point is more than 300 DEG C, yield 57.43%.
2) preparation of the chloro- 2 cyano pyrazine of 3,6- bis- (3)：1.4- dioxy pyrazinamide (2) 6.20g is added to after steaming again
Phosphorus oxychloride 24.53g in mix homogeneously, 50 DEG C stirring 50min in, be warming up to 70 DEG C reaction 1h, be cooled to room temperature, add
Triethylamine 4.86g, finishes and is warming up to 96 DEG C, back flow reaction 6h, and after the completion of TLC display has been reacted, decompression is spin-dried for, and pours 10mL ice
Water, ethyl acetate (15mL*3) extracts, and merges organic faciess, saturated common salt water washing 2 times, organic faciess are after anhydrous sodium sulfate drying
Filter, filtrate decompression is spin-dried for, through being vacuum dried to obtain faint yellow solid 3, the chloro- 2 cyano pyrazine of 6- bis- after column chromatography purifies and separates
(3) 3.14g, yield 45.15%, 90-91 DEG C of fusing point.
3) preparation of the fluoro- 2 cyano pyrazine of 3,6- bis- (4)：By chloro- for 3,6- bis- 2 cyano pyrazine (3) 3.48g and drying
Dimethyl sulfoxide 10mL, the potassium fluoride 5.23g being dried and tetrabutyl ammonium bromide 2.15g mix homogeneously, heated sealed, control reaction temperature
55 DEG C of degree, stirring reaction 3h, it is punched into after the completion of reaction in 10mL cold water, is extracted three times with ethyl acetate (20mL*3), merge
Organic faciess, through saturated common salt water washing 2 times, filter after organic faciess anhydrous sodium sulfate drying, obtain faint yellow solid 3, the fluoro- 2- of 6- bis-
Cyanopyrazine (4) 1.49g, yield 52.80%, 56-57 DEG C of fusing point.
4) preparation of 6- fluoro- 3- hydroxyl -2 cyano pyrazine (5):By fluoro- for 3,6- bis- 2 cyano pyrazine (4) 2.82g and 1,4-
Dioxane 25mL and sodium acetate 6.64g is added in 25mL water, controls 55 DEG C of temperature, reacts 7h, after having reacted, is punched into
In 100mL water, adjust pH 2.5 with the concentrated hydrochloric acid of 3N, ethyl acetate (80mL*3) extracts three times, merge organic faciess, anhydrous sodium sulfate
Filter after drying, filtrate decompression is spin-dried for, and obtains yellow oil (5) 2.49g.
5) preparation of 6- fluoro- 3- hydroxyl -2- Methanamide (6)：By previous step gained yellow oil (5) 2.49g and dense sulfur
Sour 5mL mixes, and controls temperature 50 C, reacts 4h, is slowly dropped in 20mL frozen water, uses ethyl acetate (20mL*3) after stirring 1h
Extraction 3 times, merges organic faciess, filters after anhydrous sodium sulfate drying, and filtrate decompression is spin-dried for, and residue separates through chromatography can
Obtain faint yellow solid 6- fluoro- 3- hydroxyl -2- Methanamide (6) 1.94g, two step yields 61.78%.
Embodiment 2
1) preparation of 1.4- dioxy pyrazinamide (2)：Control 0～5 DEG C of temperature, pyrazinamide (1) 4.92g is in 5ml acetic acid
Disperse in ethyl ester, metachloroperbenzoic acid (85%) 17.92g be dissolved in 35ml ethyl acetate, saturated common salt water washing 1 time,
Organic layer anhydrous sodium sulfate drying, filters, by filtrate added drop-wise to pyrazinamide ethyl acetate solution, room temperature after completion of dropping
After reaction 24h, TLC display has been reacted, filter, filter cake is washed with ethyl acetate (10ml*3), filter cake 90% recrystallizing methanol,
White powder Isosorbide-5-Nitrae-dioxy pyrazinamide (2) 5.23g, yield 84.37% is obtained, fusing point is more than 300 DEG C after vacuum drying.
2) preparation of the chloro- 2 cyano pyrazine of 3,6- bis- (3)：By 1.4- dioxy pyrazinamide (2) 6.20g and chlorobenzene 10mL,
Phosphorus oxychloride 22.08g mix homogeneously, is warming up to 50 DEG C of stirring 50min, is warming up to 70 DEG C of reaction 1h, is cooled to room temperature, adds
Triethylamine 4.86g, finishes and is warming up to 110 DEG C, back flow reaction 8h, and after the completion of TLC display has been reacted, decompression is spin-dried for, and pours frozen water
10mL, ethyl acetate (15mL*3) extracts, and merges organic faciess, saturated common salt water washing 2 times, organic faciess are through anhydrous sodium sulfate drying
After filter, filtrate decompression is spin-dried for, after column chromatography purifies and separates through vacuum drying after faint yellow solid 3, the chloro- 2- cyano group pyrrole of 6- bis-
Piperazine (3) 3.36g, yield 48.32%, 91-93 DEG C of fusing point.
3) preparation of the fluoro- 2 cyano pyrazine of 3,6- bis- (4)：By chloro- for 2,5- bis- 3- cyanopyrazine (3) 3.48g and drying
10mL DMF, the potassium fluoride 5.23g being dried and tetrabutyl ammonium bromide 2.15g mix homogeneously, heated sealed,
60 DEG C of controlling reaction temperature, stirring reaction 3h, it is punched into after the completion of reaction in 10mL cold water, with ethyl acetate (20mL*3) extraction
Three times, merge organic faciess, through saturated common salt water washing 2 times, filter after organic faciess anhydrous sodium sulfate drying, filtrate decompression is spin-dried for,
Obtain faint yellow solid 3,6- bis- fluoro- 2 cyano pyrazine (4) 1.50g, yield 53.16%, 56-57 DEG C of fusing point.
4) preparation of 6- fluoro- 3- hydroxyl -2 cyano pyrazine (5):By fluoro- for 3,6- bis- 2 cyano pyrazine (4) 2.82g and 1,4-
Dioxane 25mL and sodium acetate 6.64g is added in 25mL water, controls 55 DEG C of temperature, reacts 7h, after having reacted, is punched into
In 100mL water, adjust pH 2.5 with the concentrated hydrochloric acid of 3N, ethyl acetate (80mL*3) extracts three times, merge organic faciess, anhydrous sodium sulfate
Filter after drying, filtrate decompression is spin-dried for, and obtains yellow oil (5) 2.62g.
5) preparation of 6- fluoro- 3- hydroxyl -2- Methanamide (6)：By previous step gained yellow oil (5) 2.62g and dense sulfur
Sour 5mL mixes, and controls temperature 50 C, reacts 4h, is slowly dropped in 20mL frozen water, uses ethyl acetate (20mL* afterwards after stirring 1h
3) extract 3 times, merge organic faciess, filter after anhydrous sodium sulfate drying, filtrate decompression is spin-dried for, residue separates through chromatography
Faint yellow solid 6- fluoro- 3- hydroxyl -2- Methanamide (6) 2.79g, yield 62.42% can be obtained.
Embodiment 3
1) preparation of 1.4- dioxy pyrazinamide (2)：Control 0～5 DEG C of temperature, pyrazinamide (1) 2.46g and 98% three
Fluoroethanoic acid 12g, 30% hydrogen peroxide 18g mix homogeneously, are warming up to 95 DEG C, back flow reaction 22h, and TLC shows no after raw material, 40 DEG C
Vacuum rotary steam removes solvent, adds 5ml water, adds the chloroform extraction (10ml*3) of heat after vacuum rotary steam, and water layer decompression is spin-dried for,
90% recrystallizing methanol, filters, and filter cake is vacuum dried to obtain white powder Isosorbide-5-Nitrae-dioxy pyrazinamide (2) 2.12g, and fusing point is more than
300 DEG C, yield 68.40%.
2) preparation of the chloro- 2 cyano pyrazine of 3,6- bis- (3)：By 1.4- dioxy pyrazinamide (2) 2.46g and chlorobenzene 5mL, three
Chlorethoxyfos 12.1g mix homogeneously, is warming up to 50 DEG C of stirring 50min, is warming up to 70 DEG C of reaction 1h, is cooled to room temperature, adds pyrrole
Pyridine 1.52g, finishes and is warming up to 110 DEG C, back flow reaction 8h, and after the completion of TLC display has been reacted, decompression is spin-dried for, and pours frozen water 5mL,
Ethyl acetate (10mL*3) extracts, and merges organic faciess, saturated common salt water washing 2 times, organic faciess mistake after anhydrous sodium sulfate drying
Filter, filtrate decompression is spin-dried for, and obtains faint yellow solid 3, the chloro- 2 cyano pyrazine of 6- bis- after column chromatography purifies and separates after vacuum drying
(3) 1.45g, yield 52.55%, 91-93 DEG C of fusing point.
3) preparation of the fluoro- 2 cyano pyrazine of 3,6- bis- (4)：By chloro- for 2,5- bis- 3- cyanopyrazine (3) 2.61g and drying
10mL1,3- dimethyl-2-imidazolinone, the tetrabutyl ammonium fluoride 17.24g being dried, tetrabutyl ammonium bromide 1.63g mix homogeneously,
Heated sealed, 60 DEG C of controlling reaction temperature, stirring reaction 3h, it is punched into after the completion of reaction in 10mL cold water, use ethyl acetate
(15mL*3) extract three times, merge organic faciess, through saturated common salt water washing 2 times, filter after organic faciess anhydrous sodium sulfate drying, filter
Liquid decompression is spin-dried for, and obtains faint yellow solid 3,6- bis- fluoro- 2 cyano pyrazine (4) 1.32g, yield 62.37%, 56-57 DEG C of fusing point.
4) preparation of 6- fluoro- 3- hydroxyl -2 cyano pyrazine (5):By fluoro- for 3,6- bis- 2 cyano pyrazine (4) 3.53g and 1,4-
Dioxane 30mL and sodium acetate 8.32g is added in 30mL water, controls 55 DEG C of temperature, reacts 7h, after having reacted, is punched into
In 100mL water, adjust pH 2.5 with the concentrated hydrochloric acid of 3N, ethyl acetate (80mL*3) extracts three times, merge organic faciess, anhydrous sodium sulfate
Filter after drying, filtrate decompression is spin-dried for, and obtains yellow oil (5) 3.26g.
5) preparation of 6- fluoro- 3- hydroxyl -2- Methanamide (6)：By previous step gained yellow oil (5) 3.26g and dense sulfur
Sour 5mL mixes, and controls temperature 50 C, reacts 4h, is slowly dropped in 20mL frozen water, uses ethyl acetate (20mL* afterwards after stirring 1h
3) extract 3 times, merge organic faciess, filter after anhydrous sodium sulfate drying, filtrate decompression is spin-dried for, residue separates through chromatography
Faint yellow solid 6- fluoro- 3- hydroxyl -2- Methanamide (6) 2.69g, yield 68.43% can be obtained.
Claims (10)
1. the synthesis technique of Favipiravir, is carried out by following process routes：
Wherein, the R in pyrazine compound is-CN or-CONH2.
2. synthesis technique according to claim 1 it is characterised in that described organic reagent I be organic acid or ethyl acetate,
Described organic acid is one of glacial acetic acid, concentrated sulphuric acid, formic acid and trifluoroacetic acid or their mixing；Oxidant M is dioxygen
Water, metachloroperbenzoic acid or peroxy acid.
3. synthesis technique according to claim 1 is it is characterised in that described pyrazine compound, organic reagent I, oxidant
Mol ratio is 1:(5～10):(2～8).
4. synthesis technique according to claim 1 is it is characterised in that described organic reagent II is 1,2- dichloroethanes, chlorobenzene
With a kind of of phosphorus oxychloride or their mixing；Described acid binding agent is triethylamine, dimethyl propylamine, diisopropylethylamine or pyrrole
Pyridine.
5. synthesis technique according to claim 1 it is characterised in that described aprotic polar solvent be dimethyl sulfoxide, N, N-
Dimethylformamide, acetone or 1,3- dimethyl-2-imidazolinone.
6. synthesis technique according to claim 1 is it is characterised in that described fluorion donating agent is Argentous fluoride, fluorination
One of potassium, cesium fluoride, tetrabutyl ammonium fluoride or their mixing.
7. synthesis technique according to claim 1 is it is characterised in that comprise the following steps that：
1) pyrazine compound is dissolved in organic reagent I, control -5～5 DEG C of temperature, add oxidant M, finish system room temperature or
Be warming up to 0～95 DEG C reaction 16-24h, carry out nitrogen oxidation reaction, gained product through solvent recrystallization, be vacuum dried in vain
Color solid matter；
2) gained white solid matter pyrazine dinitrogen oxide is added in organic reagent II and carries out chlorination reaction, reaction finishes
Afterwards, it is punched in frozen water, ethyl acetate extracts, merge organic faciess, washing, be dried, filter, filtrate decompression is spin-dried for, and column chromatography is pure
Change after separating through being vacuum dried to obtain faint yellow solid；
3) by gained faint yellow solid and the aprotic polar solvent being dried, the fluorion donating agent of drying, tetrabutyl phosphonium bromide
Ammonium mix homogeneously, heated sealed, controlling reaction temperature 55-80 DEG C, stirring reaction 3h, it is punched into after the completion of reaction in cold water, extraction
Take, merge organic faciess, be dried, filter, filtrate decompression is spin-dried for, and obtains faint yellow solid；
4) gained faint yellow solid is added to the water, Isosorbide-5-Nitrae-dioxane and sodium acetate, control 55 DEG C of temperature, react 7h, instead
After having answered, it is punched in water, adjust pH 2.5, extraction with concentrated hydrochloric acid, merge organic faciess, be dried, filter, filtrate decompression is spin-dried for, and obtains
Yellow oil；
5) gained yellow oil is mixed with concentrated sulphuric acid, control temperature 50 C, react 4h, be slowly dropped in frozen water, stirring,
Extraction, merges organic faciess, is dried, and filters, and filtrate decompression is spin-dried for, and residue separates through chromatography and can obtain target product method
Laevolac.
8. synthesis technique according to claim 7 is it is characterised in that step 1) described in the solvent of recrystallization be quality hundred
Divide ratio 90% methanol or water.
9. synthesis technique according to claim 7 is it is characterised in that step 2) described chlorination reaction is first by white solid
Material pyrazine dinitrogen oxide gradation is added in organic reagent II, is warming up to 50 DEG C, stirs 50min, then is warming up to 70 DEG C and stirs
Mix 1h, be cooled to room temperature and add acid binding agent, be finally warming up to 90～110 DEG C of reaction 3-8h.
10. synthesis technique according to claim 9 is it is characterised in that step 2) described in pyrazine dinitrogen oxide, organic
Solvent II, the mol ratio of acid binding agent are 1:(3.6～5):(1.2～2.4).
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107226794A (en) * | 2017-07-17 | 2017-10-03 | 郑州大学 | A kind of synthetic method of Favipiravir |
| CN111471025A (en) * | 2020-03-26 | 2020-07-31 | 兰州康寓信生物科技有限公司 | Favipiravir intermediate and synthesis method of favipiravir |
| CN111675663A (en) * | 2020-06-11 | 2020-09-18 | 杭州煌森生物科技有限公司 | Preparation method of Favipiravir |
| CN111793037A (en) * | 2020-07-24 | 2020-10-20 | 山东省药学科学院 | Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile |
| CN113135862A (en) * | 2021-04-30 | 2021-07-20 | 宁夏常晟药业有限公司 | Synthetic method of 6-fluoro-3-hydroxypyrazine-2-carboxylic acid |
| CN113200928A (en) * | 2020-02-01 | 2021-08-03 | 北京四环制药有限公司 | Refining method of Favipiravir and/or derivatives thereof |
| CN113248450A (en) * | 2020-02-07 | 2021-08-13 | 北京四环制药有限公司 | Preparation method of Favipiravir |
| WO2021250705A1 (en) * | 2020-06-12 | 2021-12-16 | Council Of Scientific And Industrial Research (An Indian Registered Body Incorporated Under The Regn. Of Soc. Act (Act Xxi Of 1860)) | A process for preparation of 3,6-dichlorocyano pyrazine, 3,6-dioxopiperazine derivatives and production of favipiravir thereof |
| CN115636796A (en) * | 2021-07-20 | 2023-01-24 | 新发药业有限公司 | Preparation method of Favipiravir |
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