CN107226794A - A kind of synthetic method of Favipiravir - Google Patents
A kind of synthetic method of Favipiravir Download PDFInfo
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- CN107226794A CN107226794A CN201710579926.4A CN201710579926A CN107226794A CN 107226794 A CN107226794 A CN 107226794A CN 201710579926 A CN201710579926 A CN 201710579926A CN 107226794 A CN107226794 A CN 107226794A
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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
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Abstract
The invention discloses a kind of synthetic method of Favipiravir, include following steps：1) pyrazine compound is dissolved in organic reagent I, carries out nitrogen oxidation reaction, obtain white solid matter；2) gained white solid matter pyrazine dinitrogen oxide 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 dried, the fluorine ion donating agent of drying, TBAB is well mixed, and stirring reaction obtains faint yellow solid；4) the obtained formonitrile HCN of 3,6 dichloropyrazine 2 is subjected to aromatic ring fluoro-reaction with fluorization agent；5) 6 fluoro-reaction products are directly catalyzed through hydrogen peroxide, carry out cyan-hydrolysis reaction；6) cyan-hydrolysis reaction product is directly catalyzed through aqueous alkali, carries out aromatic ring hydroxyl substitution reaction, and Favipiravir is made in then purified processing again.Raw material of the present invention is simple and easy to get, and synthesis technique is simple, with good industrial value, environmental protection.
Description
Technical field
The present invention relates to a kind of synthetic method of Favipiravir.
Background technology
Favipiravir (favipiravir), the chemical entitled fluoro- 3- HYDROXYPYRAZINEs -2- formamides of 6-, molecular formula is：
C5H4N3O2F, molecular weight is：157.1, with following structural formula：
Favipiravir is researched and developed by Japan folic hill Chemical Co., Ltd., 2011, and the clinic examination of III phases is completed in Japan
Test, approval listing in 2014 is clinically mainly used in treatment of influenza, it is the wide of the RNA polymerase inhibitor class that RNA is relied on
Compose antiviral drugs.Research shows, Favipiravir forms Favipiravir-ribofuranosyl -5- three in the presence of enzyme in the cell
Phosphoric acid (T-705RTP), competitively suppresses the RNA polymerase that viral RNA is relied on, and replicates and turns so as to suppress viral genome
Record；Viral gene can also be immersed in simultaneously, and Mutation induction plays antivirus action.
At present, the primary synthetic methods of domestic and international Favipiravir approximately as：
Route one：Patent WO00/01569 is reported, first is used after diazotising with the bromo- 3- Aminopyrazines -2- methyl formates of 6-
6- amino -3- IBMP -2- formamides are made in amino substitution and ammonolysis under alcohol alcoholysis, palladium chtalyst, are taken through diazotising and fluorine
In generation, then obtain target compound (synthetic line square formula 1) under trimethyl silane and sodium iodide effect.This method is by amino
The palladium of catalyst (dibenzalacetone) two used in substitution reaction and (S)-(-) -2,2 '-bis- (diphenyl phosphine) -1,1 ' -
Dinaphthalene price costly, and is difficult to control in final step reaction with trim,ethylchlorosilane and sodium iodide demethylation,
Yield is low, is not suitable for industrial production.In addition, the last of the synthetic line needs to be prepared into dicyclohexyl amine salt, into salt after again
Nitrile hydrolysis reactor is carried out, the yield of two steps is 26.4%, and influence of the moisture to dicyclohexyl amine salt-forming reaction is very big, excess moisture
Salt is then difficult into, causes yield to reduce, higher is required to experimental implementation.
Route two：Patent CN102775358A is reported, with 3- amino -2- pyrazine carboxylic acids as initiation material through perhydroxyl radical
Target compound (synthetic line square formula 2) is made although reacts in change, esterification, amination, nitrification, reduction, fluorination six-step process
Route is shorter, but because 6- nitro -3- hydroxyl -2- pyrazinamides solubility in common organic solvents is limited, is reduced into
Amino-compound is more difficult, and the step has used expensive palladium reagent, and total recovery is relatively low.
Route three：Li Hangzhou etc. using diethyl aminomalonate hydrochloride as raw material, neutralized, ammonolysis, cyclization, bromination,
Chloro and dehydration, fluorination, selective hydrolysis, into salt purifying, hydrolysis obtain Favipiravir.The route is longer, and yield is relatively low, only
9% (synthetic line square formula 3).Xiao Xinrong etc. is same using diethyl aminomalonate hydrochloride as initiation material, ammoniacal liquor ammonia
Pass through after solution with the directly obtained 3- hydroxyl -2- pyrazinamides of glyoxal cyclization, after nitrification, chloro, fluoro, hydrolysis salifying, again
Hydroxide is aoxidized, Favipiravir is made.The method yield is relatively low, and only 5.6%. patents US8835636 has similar report, only
It is, using amino malonamide as raw material, to be obtained through cyclization, bromination, chloro and dehydration, fluorination, 3-selective hydrolysis, nitrile hydrolysis
Favipiravir.
Route four：FangyuanShi etc. using 3- HYDROXYPYRAZINE -2- carboxylic acids as raw material, through over-churning, ammonolysis, nitrification, also
There is nitration reaction in former, fluorination 6 steps synthesis Favipiravir (synthetic line square formula 4), this route, it is higher to equipment requirement,
Yield is relatively low.
Route five：CN104496917 is using the bromo- 3- Aminopyrazines -2- carboxylic acids of 6- as raw material, through over-churning, in diazotising water 5
Solution reaction, hydroxyl protection, fluoro, deprotection, ammonification obtain Favipiravir (synthetic line square formula 5).This route uses Pd
Catalyst is deprotected, and cost is higher.
From the foregoing, it will be observed that also there is many technical problems in existing synthetic method, it is difficult to suitable for industrialized production.
The content of the invention
It is an object of the invention to provide a kind of synthetic method of Favipiravir, to solve what is proposed in above-mentioned background technology
Problem.
To achieve the above object, the present invention provides following technical scheme：
A kind of synthetic method of Favipiravir, is carried out by following process routes：
Wherein, the R in pyrazine compound is-CN or-CONH2。
By such scheme, the organic reagent I is organic acid or ethyl acetate, and described organic acid is glacial acetic acid, dense sulphur
Acid, formic acid and one kind in trifluoroacetic acid or their mixing；Oxidant M is hydrogen peroxide, metachloroperbenzoic acid or peroxy acid.
By such scheme, the pyrazine compound, organic reagent I, the mol ratio of oxidant are 1:(5~10):(2~8).
By such scheme, the organic reagent II be 1,2- dichloroethanes, one kind of chlorobenzene and POCl3 or they
Mixing；The acid binding agent is triethylamine, dimethyl propylamine, diisopropylethylamine or pyridine.
By such scheme, comprise the following steps that：
1) pyrazine compound is dissolved in organic reagent I, controls temperature -5~5 DEG C, added oxidant M, finish system room
Temperature is warming up to 0~95 DEG C of reaction 16-24h, carries out nitrogen oxidation reaction, gained reaction 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, reacted
After finishing, it is punched into frozen water, ethyl acetate extraction merges organic phase, washed, dry, filtering, filtrate decompression is spin-dried for, post color
Compose after purifies and separates through being dried in vacuo to obtain faint yellow solid；
3) by gained faint yellow solid and the aprotic polar solvent dried, the fluorine ion donating agent of drying, the tetrabutyl
Ammonium bromide is well mixed, and heated sealed, 55-80 DEG C of controlling reaction temperature, stirring reaction 3h is punched into cold water after the completion of reaction
In, extraction merges organic phase, dries, and filtering, filtrate decompression is spin-dried for, and obtains faint yellow solid；
4) obtained 3,6- dichloropyrazine -2- formonitrile HCNs are subjected to aromatic ring fluoro-reaction with fluorization agent；
5) 6 fluoro-reaction products are directly catalyzed through hydrogen peroxide, carry out cyan-hydrolysis reaction；
6) cyan-hydrolysis reaction product is directly catalyzed through aqueous alkali, aromatic ring hydroxyl substitution reaction is carried out, then again through pure
Change is handled, and Favipiravir is made.
By such scheme, step 1) described in the solvent that recrystallizes be the methanol of mass percent 90% or water.
By such scheme, step 2) chlorination reaction be first by white solid matter pyrazine dinitrogen oxide by several times add
Into organic reagent II, 50 DEG C are warming up to, stir 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, the mol ratio of acid binding agent be 1:
(3.6~5):(1.2~2.4).
By such scheme, step 4) prepared using series connection One-step Synthesis mode；Described series connection One-step Synthesis is to enter successively
The described reaction of row, and the reaction system reacted each step is without purifying, separating treatment.
By such scheme, step 4) in, by step 3) made from 3,6- dichloropyrazine -2- formonitrile HCNs and fluorization agent carry out aromatic ring
Fluoro-reaction；Without being purified to fluoro-reaction product (reaction solution), directly it is catalyzed through hydrogen peroxide, carries out cyan-hydrolysis anti-
Should；Cyan-hydrolysis reaction product (reaction solution) is directly catalyzed without being purified through aqueous alkali, carries out the substitution of aromatic ring hydroxyl anti-
Should, Favipiravir is made in subsequent purified processing.
By such scheme, step 4) in, reaction dissolvent is dimethyl sulfoxide (DMSO), Isosorbide-5-Nitrae-dioxane, N, N- dimethyl formyls
At least one of amine, pyridine, more preferably dimethyl sulfoxide (DMSO).
By such scheme, step 4) in, fluorization agent and phase transfer catalyst are added into the solution system of intermediate, is carried out
Described aromatic ring fluoro-reaction, fluorization agent is F- salt.
By such scheme, step 4) in, before the aromatic ring fluoro-reaction described in progress, to reaction system, such as solvent enters
Row removes water process, and reaction unit enters line replacement using dry protective atmosphere.
Compared with prior art, the beneficial effects of the invention are as follows：The raw material that the method for the present invention is related to is simple and easy to get, synthesis
Technique is simple, mild condition, can also obvious control targe product impurity content and yield, with good industrial value,
And by method for crystallising of the present invention, the impurity content in control key intermediate that can be well, and then beneficial to lifting
The quality of final purpose product, environmental protection.
Embodiment
The technical scheme in the embodiment of the present invention is clearly and completely described below, it is clear that described embodiment
Only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, the common skill in this area
The every other embodiment that art personnel are obtained under the premise of creative work is not made, belongs to the model that the present invention is protected
Enclose.
In the embodiment of the present invention, a kind of synthetic method of Favipiravir：
1) preparation of 1.4- dioxies pyrazinamide (2)：Temperature -5~5 DEG C are controlled, by 2 cyano pyrazine (1) 5.25g and ice
Acetic acid 29.95g, 30% hydrogen peroxide 45.30g are well mixed, and are warming up to 95 DEG C, back flow reaction 22h, and TLC is shown after no raw material,
40 DEG C of vacuum rotary steams remove solvent, add 15ml water, and vacuum rotary steam adds 15ml water after being repeated several times removing glacial acetic acid, added
The chloroform extraction (15ml*3) of heat, water layer decompression is spin-dried for, and 90% recrystallizing methanol, filtering, filter cake is dried in vacuo 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 pyrazines (3) of 3,6- bis-：1.4- dioxies pyrazinamide (2) 6.20g is added to steam again after
POCl3 24.53g in be well mixed, 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, after the completion of back flow reaction 6h, TLC display has been reacted, decompression is spin-dried for, and pours 10mL ice
Water, ethyl acetate (15mL*3) extraction, merging organic phase, saturated common salt water washing 2 times, organic phase is after anhydrous sodium sulfate drying
Filtering, filtrate decompression is spin-dried for, through being dried in vacuo to obtain faint yellow solid 3, the chloro- 2 cyano pyrazines 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 pyrazines (4) of 3,6- bis-：By chloro- 2 cyano pyrazine (3) 3.48g of 3,6- bis- and drying
Dimethyl sulfoxide 10mL, the potassium fluoride 5.23g of drying and TBAB 2.15g are well mixed, heated sealed, control reaction temperature
55 DEG C of degree, stirring reaction 3h is punched into after the completion of reaction in 10mL cold water, is extracted three times with ethyl acetate (20mL*3), is merged
Organic phase, through saturated common salt water washing 2 times, filters after organic phase anhydrous sodium sulfate drying, obtains faint yellow solid 3,6- bis- is fluoro-
2 cyano pyrazine (4) 1.49g, yield 52.80%, 56-57 DEG C of fusing point.
4) KF (1g, 6eq) and TBAB (372.3mg, 0.4eq) are dissolved in the mixed of toluene (10ml) and dimethyl sulfoxide (DMSO) (5ml)
In bonding solvent, after azeotropic removal of water, add under the conditions of compound 6 (500mg, 1eq), 55 DEG C, stir 3h.
5) TLC is shown after raw material reaction completely, is down to after room temperature, 30%H2O2 (0.35ml) is added under ice bath, at 27 DEG C
Lower reaction 2h.
6) add under water (1ml) and NaHCO3 (0.132g, 1.57mmol), 50 DEG C of reaction 8.5h, ice bath and use 6NHCl, adjust
PH=1.0 is saved, ethyl acetate (4 × 5ml) extraction, organic layer is washed twice with saturated common salt, and anhydrous sodium sulfate drying has been evaporated off
Machine solvent, with 20 times of ethyl alcohol recrystallizations (the weight ratio of crude product and ethanol is 1: 5~30), obtaining off-white powder, (method is drawn
Wei), yield is 65% (calculated and obtained by the amount of reactant 6).mp：175-177℃.
The raw material that is related to of method of the present invention is simple and easy to get, and synthesis technique is simple, mild condition, can also obvious control targe
The impurity content and yield of product, can be good with good industrial value, and by method for crystallising of the present invention
Control key intermediate in impurity content, and then beneficial to lifting final purpose product quality, environmental protection.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
The above is only the preferred embodiment of the present invention, it is noted that for those skilled in the art, not
On the premise of departing from present inventive concept, several modifications and improvements can also be made, these should also be considered as the protection model of the present invention
Enclose, these effects and practical applicability for implementing all without the influence present invention.
Claims (6)
1. a kind of synthetic method of Favipiravir, is carried out by following process routes：
Wherein, the R in pyrazine compound is-CN or-CONH2。
2. the synthetic method of Favipiravir according to claim 1, it is characterised in that the organic reagent I is organic acid
Or ethyl acetate, described organic acid is one kind in glacial acetic acid, the concentrated sulfuric acid, formic acid and trifluoroacetic acid or their mixing；Oxygen
Agent M is hydrogen peroxide, metachloroperbenzoic acid or peroxy acid.
3. the synthetic method of Favipiravir according to claim 1, it is characterised in that the organic reagent II is 1,2- bis-
Chloroethanes, one kind of chlorobenzene and POCl3 or their mixing；The acid binding agent is triethylamine, dimethyl propylamine, diisopropyl
Base ethamine or pyridine.
4. the synthetic method of Favipiravir according to claim 1, it is characterised in that comprise the following steps that：1) by pyrazine
Compound is dissolved in organic reagent I, controls temperature -5~5 DEG C, adds oxidant M, is finished system room temperature or is warming up to 0~95 DEG C
React 16-24h, carry out nitrogen oxidation reaction, gained reaction product through solvent recrystallization, be dried in vacuo to obtain white solid matter；2)
Gained white solid matter pyrazine dinitrogen oxide is added in organic reagent II and carries out chlorination reaction, after completion of the reaction, punching
Enter into frozen water, ethyl acetate extraction merges organic phase, washed, dry, filtering, filtrate decompression is spin-dried for, column chromatography purifies and separates
By being dried in vacuo to obtain faint yellow solid；3) by gained faint yellow solid with dry aprotic polar solvent, drying fluorine from
Sub- donating agent, TBAB is well mixed, heated sealed, 55-80 DEG C of controlling reaction temperature, stirring reaction 3h, reaction
After the completion of be punched into cold water, extract, merge organic phase, dry, filtering, filtrate decompression is spin-dried for, and obtains faint yellow solid；4) will system
3, the 6- dichloropyrazine -2- formonitrile HCNs obtained carry out aromatic ring fluoro-reaction with fluorization agent；5) by 6 fluoro-reaction products directly through hydrogen peroxide
Catalysis, carries out cyan-hydrolysis reaction；6) cyan-hydrolysis reaction product is directly catalyzed through aqueous alkali, carries out the substitution of aromatic ring hydroxyl anti-
Should, Favipiravir is made in then purified processing again.
5. the synthetic method of Favipiravir according to claim 4, it is characterised in that step 2) chlorination reaction is first
White solid matter pyrazine dinitrogen oxide is added in organic reagent II by several times, 50 DEG C are warming up to, 50min is stirred, then rise
Temperature is cooled to room temperature and adds acid binding agent to 70 DEG C of stirring 1h, is finally warming up to 90~110 DEG C of reaction 3-8h, the pyrazine two
Nitrogen oxides, organic solvent II, the mol ratio of acid binding agent are 1:(3.6~5):(1.2~2.4).
6. the synthetic method of Favipiravir according to claim 4, it is characterised in that step 4) in, reaction dissolvent is two
At least one of methyl sulfoxide, Isosorbide-5-Nitrae-dioxane, DMF, pyridine.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN113248450A (en) * | 2020-02-07 | 2021-08-13 | 北京四环制药有限公司 | Preparation method of Favipiravir |
| CN113735784A (en) * | 2020-05-28 | 2021-12-03 | 南京桦冠生物技术有限公司 | Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide |
| WO2022009036A1 (en) * | 2020-07-06 | 2022-01-13 | Optimus Drugs (P) Ltd | Synthesis of favipiravir |
| CN115636796A (en) * | 2021-07-20 | 2023-01-24 | 新发药业有限公司 | Preparation method of Favipiravir |
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| 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 |
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| US20020013316A1 (en) * | 1998-08-20 | 2002-01-31 | Yousuke Furuta | Nitrogen-containing heterocyclic carboxamide derivatives or salts thereof and antiviral agents comprising the same |
| 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 |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113248450A (en) * | 2020-02-07 | 2021-08-13 | 北京四环制药有限公司 | Preparation method of Favipiravir |
| CN113248450B (en) * | 2020-02-07 | 2024-04-12 | 北京四环制药有限公司 | Fapila preparation method of pyrrosia lingua |
| CN113735784A (en) * | 2020-05-28 | 2021-12-03 | 南京桦冠生物技术有限公司 | Preparation method of 6-fluoro-3-hydroxypyrazine-2-formamide |
| WO2022009036A1 (en) * | 2020-07-06 | 2022-01-13 | Optimus Drugs (P) Ltd | Synthesis 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 |
| CN111793037B (en) * | 2020-07-24 | 2023-07-25 | 山东省药学科学院 | Crystallization and purification method of fapirrevir 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 |
| CN115636796A (en) * | 2021-07-20 | 2023-01-24 | 新发药业有限公司 | Preparation method of Favipiravir |
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