CN107641106A - The synthetic method of Favipiravir intermediate and Favipiravir - Google Patents
The synthetic method of Favipiravir intermediate and Favipiravir Download PDFInfo
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- CN107641106A CN107641106A CN201610585418.2A CN201610585418A CN107641106A CN 107641106 A CN107641106 A CN 107641106A CN 201610585418 A CN201610585418 A CN 201610585418A CN 107641106 A CN107641106 A CN 107641106A
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Abstract
The present invention relates to Favipiravir intermediate and the synthetic method of Favipiravir.The method for specifically disclosing the cyanopyrazine of 3,6 difluoro 2 that a kind of synthesis type 4 represents, including：A) compound that formula 1 represents is made to be reacted with chlorinating agent or brominated reagent, to obtain the compound that formula 2 represents；B) in the presence of organic base, the compound that formula 2 represents and tribromo oxygen phosphorus reaction are made, to obtain the compound that formula 3 represents；C) compound that formula 3 represents is made to be reacted with fluoro reagent, to obtain the compound that formula 4 represents.The invention further relates to the method using above method synthesis Favipiravir.
Description
Technical field
The present invention relates to organic chemical synthesis field, more particularly to Favipiravir intermediate 3, bis- fluoro- 2 cyano pyrazines of 6-
Synthetic method and via this method synthesize Favipiravir method.
Background technology
Favipiravir (favipiravir) is the novel RNA polymerase inhibitor of Japan Toyama chemical pharmaceutical company exploitation
Class broad-spectrum antiviral drug, infected by influenza have preferable therapeutic action, to bunyavirus, flavivirus, west nile virus
Also there is good therapeutic effect with arenavirus etc..Its structural formula is as follows：
So far, the method for a variety of synthesis Favipiravirs is had reported, wherein, with EP1256588, WO2013180149
The method reported with WO2010087117 relatively has industrial value.In the above documents, synthesized by following route
Favipiravir.
From above route, 3,6- bis- fluoro- 2 cyano pyrazines are synthesized among the key of Favipiravir for industrialization at present
Body.Thus, the building-up process of research 3,6-, bis- fluoro- 2 cyano pyrazines will have great importance to the synthesis of Favipiravir.
Specifically, 3,6-, bis- fluoro- 2 cyano pyrazines mainly are synthesized by two lines：
Synthetic route I is come using 3- hydroxyl -2- pyrazinamides as initiation material by bromo, chloro and fluoro-reaction
To bis- fluoro- 2 cyano pyrazines of 3,6-.
Synthetic route II is come using 3- hydroxyl -2- pyrazinamides as initiation material by nitrification, chloro and fluoro-reaction
To bis- fluoro- 2 cyano pyrazines of 3,6-.
However, in said synthesis route, there is severe reaction conditions, post processing are cumbersome, it is unsuitable for industrialized production
And yield it is relatively low the problems such as.
Therefore, it is still necessary to the synthetic method of 3,6-, bis- fluoro- 2 cyano pyrazines is improved, to overcome above mentioned problem,
So as to large-scale industrial production 3, bis- fluoro- 2 cyano pyrazines of 6-, and then produce Favipiravir.
The content of the invention
It is an object of the invention to develop a kind of new bis- fluoro- 2 cyano pyrazines of 3,6- more suitable for industrialized production
Preparation method.Under relatively mild reaction condition, 3,6- bis- is produced with higher yields from cheap initiation material for this method
Fluoro- 2 cyano pyrazine and post-processing approach is simple, so as to be adapted to commercialization amplification production.
According to an aspect of the invention, there is provided a kind of method of synthesis 3,6-, bis- fluoro- 2 cyano pyrazines, wherein, institute
Method is stated to carry out according to process route as follows, including：
A) compound that formula 1 represents is made to be reacted with chlorinating agent or brominated reagent, to obtain the compound that formula 2 represents；
B) in the presence of organic base, the compound that formula 2 represents and tribromo oxygen phosphorus reaction are made, to obtain the change that formula 3 represents
Compound；
C) compound that formula 3 represents is made to be reacted with fluoro reagent, to obtain the compound 3 that formula 4 represents, the fluoro- 2- cyanogen of 6- bis-
Base pyrazine；
Wherein, X=Cl or Br.
According to an embodiment, in the step b), the mol ratio of the compound of tribromo oxygen phosphorus and the expression of formula 2 is 1 to 2
Between, preferably between 1.0 to 1.2.
According to an embodiment, remove the solvent used in the step a), so in step a) after completion of the reaction
Adding water afterwards makes reaction product be filtered after precipitating, and resulting product is directly used in step b).
According to an embodiment, remove the solvent used in the step b), so in step b) after completion of the reaction
Adding water afterwards makes reaction product be filtered after precipitating, and resulting product is directly used in step c).
According to an embodiment, in the step a), using pyridine and selected from DMF, diformazan
One or more in base sulfoxide, 1-METHYLPYRROLIDONE and acetonitrile are molten as solvent, the preferably mixing using pyridine and acetonitrile
Agent.According to an embodiment, when in the step a) using chlorinating agent, the chlorinating agent is chlorosuccinimide
NCS；When in the step a) using brominated reagent, the brominated reagent is bromine, bromo-succinimide NBS or dibromo sea
Cause, preferably bromine.Further, in the step a), the chlorinating agent or brominated reagent and the compound of the expression of formula 1
Mol ratio between 1 to 5, preferably between 2.0 to 2.5.
According to an embodiment, in the step b), the mol ratio for the compound that the organic base represents with formula 2 exists
Between 1 to 10, preferably between 3 to 4.
According to an embodiment, the fluoro reagent used in the step c) is in potassium fluoride and tetrabutyl ammonium fluoride
One or two kinds of combinations, preferably potassium fluoride.
According to another aspect of the present invention, the invention provides a kind of method for synthesizing Favipiravir, wherein, the side
Method comprises the following steps：
3,6-, the bis- fluoro- 2 cyano pyrazines that the formula 4 obtained by the above method represents are made to be reacted with anhydrous sodium acetate, to obtain
The fluoro- 3- hydroxyls of 6- -2 cyano pyrazine dicyclohexyl amine salt；
The fluoro- 3- hydroxyls -2 cyano pyrazine dicyclohexyl amine salt of 6- is set to be reacted with sodium hydroxide, to obtain Favipiravir.
With 3- hydroxyls in the method for the bis- fluoro- 2 cyano pyrazines of synthesis Favipiravir intermediate -3,6- according to the present invention
Base -2- pyrazinamides are initiation material, undergo bromo or chloro, then bromo, and the step of fluoro to synthesize the intermediate.
In the method for the invention, initiation material 3- hydroxyls -2- pyrazinamides commercially can be conveniently commercially available, or
Person is hydrolyzed using 3- amino -2- pyrazine carboxylic acids by nitrosation, esterification ammonolysis two-step reaction is easily made, this two-step reaction
Total recovery is up to 82%.Other raw materials, such as：Bromine, tribromo oxygen phosphorus, potassium fluoride, it is cheap, it is easy to purchase.Also,
In the method for the present invention, step a) especially of the present invention and step b) post processing are very easy, it is only necessary to after completion of the reaction, return
Solvent is received, it shows product then to add suitable quantity of water, finally filters out product, it is not necessary to which further purifying can is direct
For in next step.
Compared with the prior art, main improvement of the invention is the combination of halogenating reaction+bromo-reaction, and current work
Combination using nitration reaction+chlorination or the combination using bromo-reaction+chlorination in skill route.By using halo
The combination of reaction+bromo-reaction, the present invention creatively replace chlorine atom using bromine atoms, make step b) bromo-reaction more
Easily carry out, and the compound activity for representing formula 3 is higher, and then subsequent step c) fluoro-reaction is easier to make for,
So as to reduce byproduct of reaction, simplify last handling process and improve yield.
In addition, in step b), avoid making solvent using a large amount of POCl3s, and be only used only relative to the compound of formula 2
Mol ratio is between 1 to 2, or even the tribromo oxygen phosphorus can of about chemical equivalent meter realizes the bromo of high yield.Therefore, this hair
Bright method is more economical.Moreover, the product postprocessing so obtained is more succinct.
It can see according to specific embodiment hereafter, the experiment of method of the invention through upper hectogram scale, stable yield,
Product purity is high.This technique is easy to amplify, and is adapted to commercialization amplification production.
Brief description of the drawings
Fig. 1 shows the HPLC spectrograms of Favipiravir prepared by example 3 produced according to the present invention；
Fig. 2 shows the H NMR spectras of Favipiravir prepared by example 3 produced according to the present invention.
Embodiment
The present invention will be further described below, but it should be understood by those skilled in the art that the scope of the present invention and unlimited
In specific examples below.
Wherein, hereinafter, unless otherwise stated, ratio mentioned below is mol ratio.
Generally speaking, the invention provides a gentle reaction scheme to obtain 3,6-, bis- fluoro- 2 cyano pyrazines, and this is anti-
Answer route that there is higher total recovery, and the post processing of each step is easy so as to be applied to commercial Application.
According to an embodiment of the invention, there is provided 3,6-, the bis- fluoro- 2 cyano pyrazines that a kind of synthesis type 4 represents
Method.
As above shown in reaction scheme, the method according to the invention, first in step a), the 3- hydroxyls -2- shown in formula 1 is made
Pyrazinamide carries out halogenating reaction, and in particular chloro or bromo-reaction carrys out the compound shown in formula 2, wherein X be chlorine or
Bromine.
Specifically, the reaction is carried out in a solvent.According to an embodiment, pyridine is included in solvent.Pyridine represents with formula 1
Compound mol ratio be 1~10, preferably 1.5~2.0.In the present embodiment, pyridine serves not only as solvent, is also used as and ties up
Sour agent.Preferably, the reaction is carried out in the in the mixed solvent for also including other solvents.Other described solvents are conventionally used for such
The solvent of reaction, at least one be selected from DMF, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE and acetonitrile
Kind, but not limited to this.According to the preferred embodiment of the present invention, the solvent is for pyridine and selected from N, N- dimethyl formyls
One or more mixed solvents in amine, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE and acetonitrile, preferably using pyridine and acetonitrile
Mixed solvent.
Conventional chloro and brominated reagent can be used in chloro and bromo-reaction in the step.According to preferable embodiment party
Formula, chlorinating agent are chlorosuccinimide NCS；Brominated reagent is bromine, bromo-succinimide NBS or C5H6Br2N2O2, excellent
Elect bromine as.
1h~5h is reacted in the reaction at 60 DEG C~100 DEG C, preferably 80 DEG C~85 DEG C.Subsequent concentration and recovery solvent, adds
After water stirring the compound of the expression of formula 2 is obtained after reaction product precipitation, filtering, dried screening.The yield of the reaction is 80%
More than.
In the prior art, such as the embodiment according to EP1256588, it corresponds to the inventive method step a) reaction
For nitration reaction.Although the yield about 86% of nitrification is reported in the publication.However, implementation of the present inventor according to the document
Example, through the yield for also not obtaining the document and being reported is repeated several times.It is assumed that may be because the hydroxyl on aromatic rings be easily by oxygen
Change, cause the yield of the denitrification step relatively low, be only about 20%.In addition, the nitration reaction has explosion hazard, therefore not
It is adapted to industrially prepare bis- fluoro- 2 cyano pyrazines of 3,6- by this method.
Continue step b) after the compound of formula 2 is prepared, in the presence of an organic base, carry out bromo-reaction, obtain
The compound of formula 3.
According to an embodiment, the bromo-reaction is carried out in a solvent.Had no particular limits for solvent, suitable for this
The solvent of reaction can be used.DMF, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE, second are selected from for example, using
At least one of nitrile, chlorobenzene, toluene are used as solvent, but not limited to this.It is preferred that chlorobenzene is used as solvent.
The not specific limitation of the organic base used in the reaction, can be used those conventional use of organic bases, such as
Can be trialkylamine, alkyl can be the same or different, such as can be C1~C5 alkyl.Preferably triethylamine or diisopropyl
Base ethamine, more preferably diisopropylethylamine.
Step b) bromination is using tribromo oxygen phosphorus as bromating agent.The ratio of bromating agent and the compound of formula 2 is 1 equivalent~2
Equivalent, preferably 1~1.2 equivalent.
In a specific embodiment, tribromo oxygen phosphorus is disposably added in the solution for the compound that formula 2 represents.Its
In, the adition process hardly heat release, charging can be very simple compared with using the chlorination of POCl3 in the prior art
Singly carry out.Then, above-mentioned reaction system is made to react 1h~24h (preferably 2 at 80 DEG C~130 DEG C, preferably 125 DEG C~130 DEG C
~6h, more preferably 4h).After completion of the reaction, it is concentrated under reduced pressure and removes solvent, is subsequently cooled to room temperature.Water is then added, is stirred
Reaction product is precipitated, then filters, the compound of the expression of formula 3 is obtained after drying, the yield of the step is more than 75%.Due to
The dosage of tribromo oxygen phosphorus is close to reaction equivalent, therefore tribromo oxygen phosphorus remaining in system during reaction completion is less.So as to rear
It is filtered by adding appropriate water with regard to that can hydrolyze remnants tribromo oxygen phosphorus and precipitate product in processing procedure
Easily remove impurity and obtain reaction product.Above-mentioned last handling process avoids producing substantial amounts of acid filtrate, substantially reduces
Treatment cost of waste liquor, while reduce the pollution to environment.
A kind of method more similar with method of the invention is disclosed in WO2013180149.Wherein by 3- hydroxyls -2-
Pyrazinamide bromo obtains the bromo- 3- hydroxyls -2- pyrazinamides of 6-, and chlorination is then carried out using POCl3 as chloro agent,
Fluoro-reaction is carried out again obtains bis- fluoro- 2 cyano pyrazines of 3,6-.It is in chlorination, it is necessary to 6- is bromo- it can be seen from embodiment
3- hydroxyl -2- pyrazinamides are suspended in POCl3, and under ice bath, triethylamine is added dropwise.Then it is brought rapidly up and carries out
Stirring.Then, toluene is added, then instills ice-cold toluene and water again.Filtered after through two steps to obtain the chloro- 2- cyanogen of 3,6- bis-
Base pyrazine.That is, in WO2013180149 embodiment, it is also molten as reaction that POCl3 serves not only as reactant
Agent, causes the POCl3 for having used excess in the reaction, and this causes in extensive reaction, if by simply adding water
To be post-processed, substantial amounts of acid waste water will be produced, it is very difficult to handle.Thus need concentration and recovery POCl3 first.
And the concentration process then needs to carry out under condition of high vacuum degree.Then, after to be concentrated, water is added so that remnants POCl3
It is hydrolyzed into hydrochloric acid and phosphoric acid.Thus it is apparent that the process, which will be production equipment and post processing, proposes greatly challenge.It is thus unfavorable
In the production of industrially scalable.
Again for example it can be seen from EP1256588 embodiment, corresponding step is similarly chlorination.Due in the chloro
The accessory substance for being difficult with conventional method purifying is generated in reaction, so needing just obtain 3,6- through silica gel column chromatography purifying
Two chloro- 2 cyano pyrazines, so as to bring difficulty for large-scale industrial application.
It can be seen that compared to chloro, chlorine atom is replaced using bromine atoms in bromo, reduces the generation of byproduct of reaction,
The step is after completion of the reaction, it is only necessary to which recycling design, it shows product then to add suitable quantity of water, finally filters out product, no
Need further to purify can and be directly used in react in next step.Therefore, post processing has the advantages of simple and convenient.
Continue step c) after the compound of formula 3 is prepared.In a detailed embodiment, at 80 DEG C~100 DEG C
Under, the compound that formula 3 represents is reacted 10h~30h in organic solvent with anhydrous potassium fluoride.After reaction terminates, 20 are cooled to
℃.Then filtered, washed, the compound of the expression of formula 4 is obtained after drying, yield is more than 85%.
Wherein, the organic solvent used in step c) is not particularly limited, for example, selected from dimethyl sulfoxide (DMSO), N, N- diformazans
One or more in base formamide and 1-METHYLPYRROLIDONE are as solvent, but not limited to this, preferably using N, N- dimethyl
Formamide is as solvent.The mol ratio for the compound that potassium fluoride represents with formula 3 is 2~10, preferably 3~4.
Compared with using chloro thing to carry out fluoro-reaction in the prior art, in method of the invention, the step fluoro-reaction
Reactant is the bromo- 2- pyrazinamides of the chloro- 3- of 6- or is the bromo- 2- pyrazinamides of the bromo- 3- of 6-, and its reactivity is higher than prior art
In the chloro- 2- pyrazinamides of the chloro- 3- of 6-, thus yield is higher.The reaction of the wherein particularly preferred bromo- 2- pyrazinamides of the bromo- 3- of 6-
Route, higher yield can be obtained.
Hereinafter, the present invention will be described in a manner of specific embodiment.Those skilled in the art should know, this hair
It is bright to be not limited to specific examples below.Wherein, the reaction product in each embodiment passes through1H NMR(Bruke DRX-400)
Characterized with HPLC (Agilent 1200).
Preparation example 1：The synthesis of bis- fluoro- 2 cyano pyrazines of 3,6-
Step a)：Under nitrogen protection, by 35 grams of 3- hydroxyl -2- pyrazinamides, 33.6 grams of pyridine and 0.3 liter of second
Nitrile is mixed and heated to 80 DEG C~85 DEG C.40 grams of NCS is added dropwise in batches, while the temperature of reaction system is maintained at 80 DEG C~85
At DEG C.After being added dropwise, reaction is set to maintain at this temperature 4 hours.Then, concentration and recovery solvent.Then 0.6 liter of water is added,
Suspension 2 hours obtained by stirring, are filtrated to get 6- chloro-3-hydroxyl -2- pyrazinamide wet products at 20 DEG C~25 DEG C.In 50 DEG C~
The wet product is dried in vacuo at 55 DEG C, obtains 38.8 grams of off-white powder 6- chloro-3-hydroxyl -2- pyrazinamides.Yield is
88.7%, it is 99.1% through HPLC measure purity.
Step b)：36.7 grams of 6- chloro-3-hydroxyl -2- pyrazinamides and 0.3 liter of chlorobenzene are mixed, are cooled to 0 DEG C~5
℃.The disposable tribromo oxygen phosphorus for adding 78 grams.Then 53 grams of diisopropylethylamine is added dropwise at this temperature.After being added dropwise,
It is heated to reflux 4 hours.After question response, it is concentrated under reduced pressure and removes chlorobenzene, be then cooled to 20 DEG C~25 DEG C, adds 0.4 liter of water,
Stirred 2 hours at 20 DEG C~25 DEG C, be filtrated to get the bromo- 2 cyano pyrazine wet products of the chloro- 3- of 6-.In 50 DEG C~55 DEG C to the wet product
It is dried in vacuo, obtains 39 grams of bromo- 2 cyano pyrazines of the chloro- 3- of brown solid 6-.Yield 78%, it is through HPLC measure purity
98.1%.
1H NMR(DMSO)δ8.84(s,1H)
Step c)：The bromo- 2 cyano pyrazines of 38.3 grams of chloro- 3- of 6- and 38.3 grams of anhydrous potassium fluorides are added to 150 milliliters of N,
In dinethylformamide, 80 DEG C~85 DEG C are heated to, reaction is maintained at this temperature 20 hours.Question response terminates
Afterwards, 20 DEG C are cooled to, adds 0.5 liter of ethyl acetate.Then filtering, remove insoluble matter.By filtrate with 0.3 liter of water washing once,
Then again with 0.2 liter of water washing twice, 0.2 liter of saturated aqueous common salt washed once.Organic phase is dried with anhydrous sodium sulfate,
23.4 grams of bis- fluoro- 2- pyrazinamides of dark oil thing 3,6- are then concentrated under reduced pressure to give at 35 DEG C.Yield 91.2%, through HPLC
It is 98.4% to determine purity.
1H NMR(DMSO)δ8.71(s,1H)
Preparation example 2：The synthesis of bis- fluoro- 2 cyano pyrazines of 3,6-
Step a)：Under nitrogen protection, 175 grams of 3- hydroxyl -2- pyrazinamides, 168 grams of pyridines and 1.7 liters of N, N- diformazans are taken
Then to 80 DEG C~85 DEG C 290 grams of bromines are added dropwise, while the temperature of reaction system is maintained at 80 DEG C in base formamide Hybrid Heating
At~85 DEG C.After being added dropwise, reaction is set to maintain at this temperature 2 hours.Then, concentration and recovery solvent.Then 1.5 liters are added
Water, in suspension 2 hours obtained by 20 DEG C~25 DEG C stirrings, it is filtrated to get the bromo- 3- hydroxyls -2- pyrazinamide wet products of 6-.In 50 DEG C
The wet product is dried in vacuo at~55 DEG C, obtains the bromo- 3- hydroxyls -2- pyrazinamides of 220 grams of off-white powder 6-.Yield
80.1%, it is 100% through HPLC measure purity.
Step b)：The bromo- 3- hydroxyls -2- pyrazinamides of 220 grams of 6- and 1.8 liters of acetonitriles are mixed, are cooled to 0 DEG C~5 DEG C.One
Secondary property adds 233 grams of tribromo oxygen phosphorus.Then 315 grams of diisopropylethylamine are added dropwise at this temperature.After being added dropwise, it is heated to reflux
4 hours.After question response, 20 DEG C~25 DEG C are cooled to, adds 2 liters of water, stirs 2 hours, is filtrated to get at 20 DEG C~25 DEG C
The bromo- 2 cyano pyrazine wet products of 3,6- bis-.The wet product is dried in vacuo in 50 DEG C~55 DEG C, obtains 230 grams of brown solids 3,
Bis- bromo- 2 cyano pyrazines of 6-.Yield 87.1%, it is 98.6% through HPLC measure purity.
1H NMR(DMSO)δ8.88(s,1H)
Step c)：The bromo- 2- pyrazinamides of 230 grams of 3,6- bis- and 230 grams of anhydrous potassium fluorides are added to 900 milliliters of dimethyl
In sulfoxide, 80 DEG C~85 DEG C are heated to, reaction is maintained at this temperature 20 hours.After question response terminates, 20 are cooled to
DEG C, add 3 liters of ethyl acetate.Then filtering, remove insoluble matter.By filtrate with 2 liters of water washings once, then again with 1 liter washing
Wash twice, 1 liter of saturated aqueous common salt washed once.Organic phase is dried with anhydrous sodium sulfate, then depressurized at 35 DEG C dense
Contracting obtains 106 grams of bis- fluoro- 2- pyrazinamides of dark oil thing 3,6-.Yield 86.0%, it is 99.0% through HPLC measure purity.
1H NMR(DMSO)δ8.71(s,1H)
Preparation example 3：The synthesis of Favipiravir
By 39.9 grams of bis- fluoro- 2 cyano pyrazines of 3,6- and 72 grams of anhydrous sodium acetates in 0.35 liter of water and 0.35 liter of tetrahydrofuran
Middle mixing, it is heated to reflux 20 hours.After question response is complete, concentration of reaction solution, then system pH is adjusted with 20% dilute sulfuric acid
For 2.0 to 2.5.Then extracted with 0.2 liter of ethyl acetate.Gained organic phase is concentrated under reduced pressure to give grease.Add 0.2 liter of acetone
With 50 grams of dicyclohexyl amines, gained suspension stirs 2 hours at 0 DEG C~5 DEG C, is filtrated to get the fluoro- 3- hydroxyls -2 cyano pyrazines two of 6-
Cyclohexylamine salt wet product.Then 62.4 grams of light tan solids are obtained within 3 hours in 50 degree of vacuum drying, yield 70.3%, is surveyed through HPLC
Purity is determined for 99.2%.
1H NMR(DMSO)δ1.06(m,2H),1.23(m,8H),1.61(m,2H),1.73(m,4H),1.98(m,4H),
3.08(m,2H),8.02(s,2H)
By the fluoro- 3- hydroxyls -2 cyano pyrazine dicyclohexyl amine salt of 44.5 grams of 6- and 0.17 liter 6.5% of sodium hydrate aqueous solution
Mixing, is then washed with 0.1 liter of toluene.Aqueous phase is collected after liquid separation, and aqueous phase is cooled to 0 DEG C~5 DEG C, is then added dropwise 28 grams
30% hydrogen peroxide, stirred 4 hours at 10 DEG C~20 DEG C.After question response, system pH is adjusted with 20% dilute sulfuric acid
For 2.0~2.5.A large amount of solids separate out.QD-Z0212 wet product is filtrated to get, 4 are dried in vacuo at 50 DEG C
Hour, obtain 19.3 grams of off-white powders.Yield 89.6%, it is 99.9% through HPLC measure purity.
1H NMR(DMSO)δ8.50(d,2H),8.73(s,1H),13.50(s,1H)
Comparative example 1：With reference to the method synthesis 3- hydroxyl -6- nitro -2- pyrazinamides in EP1256588
13.9 grams of 3- hydroxyl -2- pyrazinamides are mixed with 70 milliliters of concentrated sulfuric acids, 0 DEG C~5 DEG C is cooled to, is added portionwise
19.6 grams of potassium nitrate solids, after adding, system is allowed to be warming up to 40 DEG C and insulation reaction 4 hours.After completion of the reaction, by reactant
System is slowly added in 600 milliliters of frozen water, and gained suspension stirs 1 hour at 20 DEG C~25 DEG C, filtering, is dried to obtain 3.6
Gram dark brown solid.Yield 20%.
1H NMR (DMSO) δ 8.06 (s, 1H), 8.32 (s, 1H), 8.97 (s, 1H), 12.00~15.00 (br, 1H)
Comparative example 2：The synthesis of bis- chloro- 2 cyano pyrazines of 3,6-
The bromo- 3- hydroxyls -2- pyrazinamides of 30.5 grams of 6- are added into 156 milliliters of POCl3s, stirred 0.5 hour at 55 DEG C,
Then 200 milliliters of diisopropylethylamine is added, 80 DEG C is warming up to and reacts 1 hour, then is warming up to 110 DEG C and reacts 4 hours.React
Bi Hou, reaction solution is added in 2 liters of frozen water, then extracted 3 times using 500 milliliters of ethyl acetate, merge organic phase, concentration is fallen
Solvent.Then use column chromatography to obtain 10.6 grams of faint yellow solids, yield 43.7%.
Claims (10)
1. a kind of method for 3,6-, the bis- fluoro- 2 cyano pyrazines that synthesis type 4 represents, wherein, methods described includes：
A) compound that formula 1 represents is made to be reacted with chlorinating agent or brominated reagent, to obtain the compound that formula 2 represents；
B) in the presence of organic base, the compound that formula 2 represents and tribromo oxygen phosphorus reaction are made, to obtain the compound that formula 3 represents；
C) compound that formula 3 represents is made to be reacted with fluoro reagent, to obtain the compound 3 that formula 4 represents, the fluoro- 2- cyano group pyrroles of 6- bis-
Piperazine；
Wherein, X=Cl or Br.
2. the method according to claim 11, wherein, in rubbing for the compound that the step b), tribromo oxygen phosphorus represent with formula 2
That ratio is between 1 to 2, preferably between 1.0 to 1.2.
3. according to the method for claim 1, wherein, remove makes in the step a) in step a) after completion of the reaction
Solvent, then adding water makes reaction product be filtered after precipitating, and resulting product is directly used in step b).
4. method according to claim 1 or 2, wherein, remove in the step b) in step b) after completion of the reaction
The solvent used, then adding water makes reaction product be filtered after precipitating, and resulting product is directly used in step c).
5. the method according to claim 11, wherein, in the step a), using pyridine and selected from N, N- dimethyl
One or more in formamide, dimethyl sulfoxide (DMSO), 1-METHYLPYRROLIDONE and acetonitrile are as solvent, preferably using pyridine and second
The mixed solvent of nitrile.
6. the method according to claim 11, wherein, when in the step a) using chlorinating agent, the chlorinating agent
For chlorosuccinimide NCS；When in the step a) using brominated reagent, the brominated reagent is bromine, bromo fourth two
Acid imide NBS or C5H6Br2N2O2, preferably bromine.
7. the method according to claim 11, wherein, in the step a), the chlorinating agent or brominated reagent and formula 1
The mol ratio of the compound of expression is between 1 to 5, preferably between 2.0 to 2.5.
8. method according to claim 1 or 2, wherein, in the step b), the organic base and the change of the expression of formula 2
The mol ratio of compound is between 1 to 10, preferably between 3 to 4.
9. according to the method for claim 1, wherein, the fluoro reagent used in the step c) is potassium fluoride and four fourths
The combination of one or both of base ammonium fluoride, preferably potassium fluoride.
10. a kind of method for synthesizing Favipiravir, wherein, it the described method comprises the following steps：
Make the bis- fluoro- 2 cyano pyrazines of 3,6- that the formula 4 obtained according to method according to any one of claims 1 to 9 represents with
Anhydrous sodium acetate reacts, to obtain the fluoro- 3- hydroxyls of 6- -2 cyano pyrazine dicyclohexyl amine salt；
The fluoro- 3- hydroxyls -2 cyano pyrazine dicyclohexyl amine salt of 6- is set to be reacted with sodium hydroxide, to obtain Favipiravir.
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| CN111349049A (en) * | 2020-02-28 | 2020-06-30 | 江苏阿尔法药业有限公司 | Favipiravir and synthesis process of intermediate thereof |
| CN111675663A (en) * | 2020-06-11 | 2020-09-18 | 杭州煌森生物科技有限公司 | Preparation method of Favipiravir |
| CN111704582A (en) * | 2020-06-23 | 2020-09-25 | 杭州煌森生物科技有限公司 | Preparation method of Favipiravir and derivatives thereof |
| CN112645889A (en) * | 2020-12-24 | 2021-04-13 | 杭州煌森生物科技有限公司 | Refining method of Favipiravir |
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| 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 |
| CN113248450A (en) * | 2020-02-07 | 2021-08-13 | 北京四环制药有限公司 | Preparation method of Favipiravir |
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