CN114656412A - Synthesis method of Favipiravir - Google Patents
Synthesis method of Favipiravir Download PDFInfo
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- CN114656412A CN114656412A CN202011527612.8A CN202011527612A CN114656412A CN 114656412 A CN114656412 A CN 114656412A CN 202011527612 A CN202011527612 A CN 202011527612A CN 114656412 A CN114656412 A CN 114656412A
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- 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
Abstract
The present disclosure provides a method for synthesizing Favipiravir, which comprises: firstly, bifluorination of a compound 1, then formamide reaction is utilized to prepare a compound 3, and finally hydrolysis and synthesis are carried out to obtain Favipiravir; or: firstly, preparing a compound 4 by virtue of a methyl amidation reaction, then carrying out double fluorination to prepare a compound 3, and finally, carrying out hydrolysis to synthesize the Favipiravir. According to the preparation method disclosed by the invention, the reaction steps can be reduced, the total yield can be improved, the reaction waste can be reduced, and the preparation method is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry and chemical synthesis, and particularly relates to a novel method for synthesizing Favipiravir.
Background
Favipiravir (favipiravir) is a novel broad-spectrum anti-RNA virus drug developed by Fushan chemical pharmaceutical companies in Japan, is approved to be marketed in 3 months 2014, and is used for antiviral treatment of influenza A and B. Research shows that the medicine has excellent antiviral activity on various RNA viruses except influenza virus, such as Ebola virus, arenavirus, bunyavirus, rabies virus, etc. The latest research shows that the Favipiravir has a certain inhibiting effect on the COVID-19. The structural formula of compound 5 is as follows:
at present, the routes of the synthesis method of the Pilaravir at home and abroad mainly comprise the following steps:
patent WO 2000/010569 reports a route (shown in the following reaction formula 1) in which 3-aminopyrazine-2-carboxylic acid is used as a raw material, and subjected to esterification and bromination to obtain an intermediate, diazotization, alcoholysis, amino substitution and ammonolysis under palladium catalysis to obtain an amide intermediate, and then subjected to diazotization, fluorination and demethylation to obtain the final product, namely piravir. This strategy requires longer steps, low overall yields, and requires expensive transition metal catalysts. In addition, highly corrosive fluorination reagents are used. Due to these factors, this strategy is not suitable for large scale preparation of compound 5.
Reaction scheme 1
In patent WO 2001/060834, a route (shown in the following reaction formula 2) is reported, which uses 3-hydroxypyrazine-2-carboxamide as a raw material, and compounds 5 are obtained by several steps such as nitration, chlorination, fluorination, and hydrolysis. The nitration reaction used in the route has high requirements on a reaction vessel and needs a large amount of phosphorus oxychloride. The synthesis of the intermediate 3, 6-dichloropyrazine-2-carbonitrile and hence compound 5 is reported in both patents WO 2010/087117 and chem.pap.2017,71,2153, which require large amounts of phosphorus oxychloride, and are a challenge for large-scale production and waste disposal.
Reaction formula 2
Professor xuwenfang, university of Shandong, designed and synthesized (Drug Discov. ther.2014,8,117.) A route (shown in the following reaction formula 3) is provided, which takes 3-hydroxypyrazine-2-carboxylic acid as raw material, and compounds 5 are synthesized through the steps of esterification, ammonolysis, nitration, reduction, fluorination and the like. Among them, this strategy uses nitration, which has high reactor requirements, and also uses highly corrosive fluorination reagents.
Reaction formula 3
In conclusion, the existing synthesis method has the technical problems of low total yield, more generated wastes and difficulty in being suitable for industrial production.
Disclosure of Invention
Object of the Invention
The invention aims to provide a synthesis method of Favipiravir to solve the problems.
Technical scheme
According to one aspect of the present disclosure, there is provided a method of synthesis of favipiravir, the method being carried out by a route comprising the steps of:
route one:
step (1): preparing 2, 5-difluoropyrazine (compound 2) from 2, 5-dichloropyrazine (compound 1) under the action of a fluorinating reagent;
step (2): carrying out a formamide reaction on the 2, 5-difluoropyrazine (compound 2) prepared in the step (1) and formamide under the action of persulfate to prepare 3, 6-difluoropyrazine-2-formamide (compound 3);
and (5): reacting the 3, 6-difluoropyrazine-2-carboxamide (compound 3) prepared in the step (2) with alkali for hydrolysis to prepare a compound 5, or
And a second route:
and (3): carrying out formamide reaction on 2, 5-dichloropyrazine (compound 1) and formamide under the action of persulfate to prepare 3, 6-dichloropyrazine-2-formamide (compound 4);
and (4): reacting the 3, 6-dichloropyrazine-2-formamide (compound 4) prepared in the step (3) with a fluorinating reagent to prepare 3, 6-difluoropyrazine-2-formamide (compound 3);
step (5'): and (3) reacting the 3, 6-difluoropyrazine-2-formamide (compound 3) prepared in the step (4) with alkali for hydrolysis to prepare a compound 5.
Advantageous effects
According to the preparation method disclosed by the invention, the synthesis process can be simplified, the total yield of the target product is improved, the generation of reaction waste is reduced, and the preparation method is suitable for industrial large-scale production so as to solve the problems in the route.
Detailed Description
To make the features and effects of the present invention comprehensible to those having ordinary knowledge in the art, general description and definitions are made with respect to terms and phrases mentioned in the specification and claims. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
In this document, the terms "comprising," "including," "having," "containing," or any other similar term, are intended to be open-ended franslational phrase (open-ended franslational phrase) and are intended to cover non-exclusive inclusions. For example, a composition or article comprising a plurality of elements is not limited to only those elements recited herein, but may include other elements not expressly listed or inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" is intended to mean an inclusive "or" rather than an exclusive "or". For example, the condition "a or B" is satisfied in any of the following cases: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), both a and B are true (or present). Furthermore, in this document, the terms "comprising," including, "" having, "" containing, "and" containing "are to be construed as specifically disclosed and to cover both closed and semi-closed conjunctions, such as" consisting of … "and" consisting essentially of ….
All features or conditions defined herein as numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of numerical ranges or percentage ranges should be considered to have covered and specifically disclosed all possible subranges and individual numerical values within the ranges, particularly integer numerical values. For example, a description of a range of "1 to 8" should be considered to have specifically disclosed all subranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, and so on, particularly subranges bounded by all integer values, and should be considered to have specifically disclosed individual values such as 1,2, 3, 4, 5, 6, 7, 8, and so on, within the range. Unless otherwise indicated, the foregoing explanatory methods apply to all matters contained in the entire disclosure, whether broad or not.
If an amount or other value or parameter is expressed as a range, preferred range, or a list of upper and lower limits, it is to be understood that all ranges subsumed therein for any pair of that range's upper or preferred value and that range's lower or preferred value, whether or not such ranges are separately disclosed, are specifically disclosed herein. Further, when a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the precision of the number of significant digits of the value, provided that the object of the invention is achieved. For example, the number 40.0 should be understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or Option language is used to describe features or examples of the invention, those skilled in the art will recognize that a sub-group of all elements or any individual element within a Markush group or list of options may also be used to describe the invention. For example, in the case ofIf X is described as "selected from" X1、X2And X3The group "also indicates that X has been fully described as X1Is claimed with X1And/or X2Claim (5). Furthermore, where Markush group or option terms are used to describe features or examples of the invention, those skilled in the art will recognize that any combination of sub-groups of all elements or individual elements within the Markush group or option list can also be used to describe the invention. Accordingly, for example, if X is described as being "selected from" X1、X2And X3Group consisting of "and Y is described as" selected from the group consisting of1、Y2And Y3The group "formed indicates that X has been fully described as X1Or X2Or X3And Y is Y1Or Y2Or Y3Claim (5).
The following detailed description is merely exemplary in nature and is not intended to limit the invention or the application thereof. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or the summary of the invention or the following detailed description or examples.
According to one embodiment of the present disclosure, there is provided a method of synthesis of favipiravir, the method being carried out by a route comprising the steps of:
route one:
step (1): preparing 2, 5-difluoropyrazine (compound 2) from 2, 5-dichloropyrazine (compound 1) under the action of a fluorinating reagent;
step (2): carrying out a formamide reaction on the 2, 5-difluoropyrazine (compound 2) prepared in the step (1) and formamide under the action of persulfate to prepare 3, 6-difluoropyrazine-2-formamide (compound 3);
and (5): reacting the 3, 6-difluoropyrazine-2-carboxamide (compound 3) prepared in the step (2) with alkali for hydrolysis to prepare a compound 5, or
And a second route:
and (3): carrying out formamide reaction on 2, 5-dichloropyrazine (compound 1) and formamide under the action of persulfate to prepare 3, 6-dichloropyrazine-2-formamide (compound 4);
and (4): reacting the 3, 6-dichloropyrazine-2-formamide (compound 4) prepared in the step (3) with a fluorination reagent to prepare 3, 6-difluoropyrazine-2-formamide (compound 3);
step (5'): and (5) reacting the 3, 6-difluoropyrazine-2-formamide (compound 3) prepared in the step (4) with alkali for hydrolysis to prepare a compound 5.
According to an embodiment of the present disclosure, the reaction of step (1) is performed in a solvent, and the fluorinating agent used in step (1) is one or a mixture of two or more of potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-tert-butyl alcohol complex, potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride-tert-butyl alcohol complex, cesium fluoride/tetrabutylammonium fluoride, and potassium fluoride/trimethylamine; the molar ratio of the fluorination reagent to the compound 1 is 2.0-10.0; the solvent used in step (1) is one or more selected from dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane.
According to an embodiment of the present disclosure, wherein the persulfate used in step (2) is selected from one or more of sodium persulfate, potassium persulfate, and ammonium persulfate; the molar ratio of the persulfate to the compound 2 is 1.5-5.0.
According to an embodiment of the present disclosure, wherein the persulfate used in step (3) is one or more selected from sodium persulfate, potassium persulfate, and ammonium persulfate; the molar ratio of the sulfate to the compound 1 is 1.0-5.0.
According to an embodiment of the present disclosure, the reaction of step (4) is performed in a solvent, and the fluorinating agent used in step (4) is one or a mixture of two or more of potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-tert-butyl alcohol complex, potassium fluoride/tetrabutylammonium fluoride-tert-butyl alcohol complex, and cesium fluoride/tetrabutylammonium fluoride; the molar ratio of the fluorination reagent to the compound 4 is 2.0-10.0; the solvent used in step (4) is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane.
According to an embodiment of the present disclosure, wherein the base used in step (5) or (5') is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate; the molar ratio of the alkali to the compound 3 is 0.5-5.0.
More specifically, the method according to the present disclosure is carried out by a route comprising the steps of:
route one:
firstly, compound 1 is bifluorinated, then compound 3 is prepared by utilizing formamide reaction, and finally compound 5 is synthesized by hydrolysis. The reaction route is as follows:
step (1): dissolving the compound 1 in an organic solvent, adding a fluorination reagent, heating the system to 70-140 ℃ after the addition is finished, reacting under the action of the fluorination reagent, adding water for quenching after the reaction is finished, extracting, combining organic phases, drying, filtering, performing reduced pressure spin drying on the filtrate, and performing column chromatography separation to obtain a compound 2;
step (2): dissolving the compound 2 prepared in the step (1) in a solvent, adding formamide and persulfate, heating the system to 50-100 ℃, filtering after the reaction is finished, adding diluted hydrochloric acid for quenching, extracting, combining organic phases, drying, filtering, performing reduced pressure spin drying on the filtrate, and performing column chromatography separation to obtain a compound 3;
and (5): and (3) dissolving the compound prepared in the step (2) in an organic solvent, adding an aqueous alkali solution, heating the system to 30-70 ℃, carrying out aromatic ring hydroxyl substitution reaction, and then carrying out purification treatment to obtain a compound 5.
Wherein the fluorinating agent in the step (1) is one or a mixture of two or more selected from potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-tert-butyl alcohol complex, potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride-tert-butyl alcohol complex, cesium fluoride/tetrabutylammonium fluoride, potassium fluoride/trimethylamine, and the like.
The molar ratio of the fluorinating agent to the compound 1 is 1.0-10.0, preferably 2.0-10.0;
the reaction temperature of the step (1) is 70-140 ℃;
the solvent in the step (1) is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane;
the reaction time of the step (1) is 0.5 to 24 hours.
Wherein, the persulfate in the step (2) is selected from one or more of sodium persulfate, potassium persulfate and ammonium persulfate;
the mole ratio of the formamide to the compound 2 is 1.0-50.0;
the molar ratio of the persulfate to the compound 2 is 1.0-5.0;
the reaction temperature of the step (2) is 50-100 ℃;
the solvent in the step (2) is selected from one or more of water, dichloromethane, dichloroethane, formamide, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, N-hexane, N-heptane and cyclohexane;
the reaction time of the step (2) is 1 to 24 hours.
Wherein the alkali in the step (5) is one or more selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate and the like;
the molar ratio of the compound 3 to the alkali is 0.5-2.0;
the reaction temperature of the step (5) is 30-70 ℃;
in the step (5), the solvent is selected from one or more of water, dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, toluene, xylene, chlorobenzene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, N-hexane and cyclohexane;
the reaction time of the step (5) is 1-24 hours; or
And a second route: firstly, preparing a compound 4 by utilizing a methyl amidation reaction, then carrying out difluorination to prepare a compound 3, and finally synthesizing the piravir by hydrolysis. The reaction route is as follows:
equation 4
The route comprises the following steps:
and (3): adding formamide and persulfate into the compound 1, heating the system to 50-100 ℃, filtering after the reaction is finished, adding diluted hydrochloric acid for quenching, extracting, combining organic phases, drying, filtering, performing reduced pressure spin drying on the filtrate, and performing column chromatography separation to obtain a compound 4;
and (4): dissolving the compound 2 prepared in the step (3) in a solvent, adding a fluorination reagent, heating the system to 70-140 ℃ after the addition is finished, reacting under the action of the fluorination reagent, adding water for quenching after the reaction is finished, extracting, combining organic phases, drying, filtering, performing reduced pressure spin drying on the filtrate, and performing column chromatography separation to obtain a compound 3;
step (5'): and (5) dissolving the compound prepared in the step (4) in an organic solvent, adding an aqueous alkali solution, heating the system to 30-70 ℃, carrying out aromatic ring hydroxyl substitution reaction, and then carrying out purification treatment to obtain the compound 5.
Wherein, the persulfate in the step (3) is one or more selected from sodium persulfate, potassium persulfate and ammonium persulfate;
the molar ratio of the formamide to the compound 1 is 1.0-20.0;
the molar ratio of the persulfate to the compound 1 is 1.0-5.0;
the reaction temperature of the step (3) is 50-100 ℃;
the solvent in the step (3) is selected from one or more of water, dichloromethane, dichloroethane, formamide, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, N-hexane, N-heptane and cyclohexane;
the reaction time of the step (3) is 1 to 24 hours.
Wherein, the fluorinating agent in the step (4) is one or a mixture of more than two of potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-tert-butyl alcohol complex, potassium fluoride/tetrabutylammonium fluoride-tert-butyl alcohol complex and cesium fluoride/tetrabutylammonium fluoride.
The molar ratio of the fluorination reagent to the compound 4 is 2.0-10.0;
the reaction temperature in the step (4) is 70-140 ℃;
the solvent in the step (4) is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane;
the reaction time of the step (4) is 0.5 to 24 hours.
Wherein, the alkali per step (5') is one or more selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate, etc.;
the molar ratio of the alkali to the compound 3 is 0.5-5.0;
the temperature of the reaction of step (5') is 30 ℃ to 70 ℃;
in the step (5'), the solvent is selected from one or more of water, dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, chlorobenzene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, N-hexane and cyclohexane;
the reaction time is 1-24 hours.
According to one embodiment of the present disclosure, wherein the reaction is performed using a one-pot process.
The following examples illustrate the specific steps of the present invention without limiting the scope of the invention;
example 1: preparation of 2, 5-difluoropyrazines using cesium fluoride
2, 5-dichloropyrazine (1.0mL, 1.0equiv.), cesium fluoride (9.0g, 6.0equiv.) was added to N, N-dimethylformamide (10.0mL), and the mixture was stirred with heating at 90 ℃. The reaction was monitored by TLC plate, after completion of the reaction, quenched by water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents to column to give compound 2(760mg, 66%) as a liquid product.
1H NMR(400MHz,CDCl3)δ8.52(dd,J=8.2,1.7Hz,1H);19F NMR(377MHz,CDCl3)δ-71.02.
Example 2: preparation of 2, 5-difluoropyrazine using potassium fluoride and tetrabutylammonium fluoride tert-butanol complex
2, 5-dichloropyrazine (1.0mL, 1.0equiv.), potassium fluoride (3.5g, 6.0equiv.), tetrabutylammonium fluoride tert-butanol complex (558mg, 0.1equiv.) were added to N, N-dimethylformamide (5.0mL), and the mixture was stirred with heating at 90 ℃. The reaction was monitored by TLC plate, after completion, quenched by addition of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents, and passed through column to give compound 2(813mg, 70%) as a liquid product.
Example 3: preparation of 2, 5-difluoropyrazine using potassium fluoride and tetramethylammonium fluoride
2, 5-dichloropyrazine (1.0mL, 1.0equiv.), potassium fluoride (3.5mg, 6.0equiv.) and tetramethylammonium fluoride (93.0mg, 0.1equiv.) were added to DMF (5.0mL) and stirred at 90 ℃. The reaction was monitored by TLC plate, after completion of the reaction, quenched by addition of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents, and passed through the column to give compound 2(790mg, 68%) as a liquid product.
Example 4: preparation method of 3, 6-dichloropyrazine-2-formamide
2, 5-dichloropyrazine (1.48g, 1.0equiv.) and formamide (5mL,12.6equiv.) were added to a reaction flask, potassium persulfate (5.4g,2.0equiv.) was added, stirring was carried out at 80 ℃ for 12 hours, a saturated solution of sodium bicarbonate was added for quenching, ethyl acetate extraction was carried out, drying was carried out over anhydrous sodium sulfate, filtration was carried out, the aqueous phase was concentrated under reduced pressure to remove all the solvent, and the mixture was subjected to column chromatography to obtain compound 4(1.44g, 75%) as a solid product.
Example 5: preparation of 3, 6-difluoropyrazine-2-carboxamides from 2, 5-difluoropyrazine
2, 5-difluoropyrazine (232mg, 1.0equiv.) and formamide (5mL) were placed in a reaction flask, potassium persulfate (1.8g,2.0equiv.) was added, stirring was carried out at 80 ℃ for 12 hours, a saturated solution of sodium bicarbonate was added and the mixture was quenched, extracted with ethyl acetate, the aqueous phase was concentrated under reduced pressure to remove all the solvent, and the mixture was subjected to column chromatography to obtain compound 3(185mg, 80%) as a solid product.
1H NMR(400MHz,CDCl3)δ8.55(dd,J=8.0,1.6Hz,1H),7.34(s,1H),6.14(s,1H).19F NMR(377MHz,CDCl3)δ-74.86,-83.34.
Example 6: preparation of 3, 6-difluoropyrazine-2-carboxamides from cesium fluoride
3, 6-dichloropyrazine-2-carboxamide (192mg, 1.0equiv.) and cesium fluoride (900mg, 6equiv.) were added to t-butanol (3.0mL), and heated with stirring at 90 ℃. The reaction was monitored by TLC plate, after completion, quenched by addition of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents, and passed through the column to afford compound 3(105mg, 66%) as a solid product.
Example 7: preparation of 3, 6-difluoropyrazine-2-carboxamide using potassium fluoride and tetrabutylammonium fluoride tert-butyl alcohol complex
3, 6-dichloropyrazine-2-carboxamide (192mg, 1.0equiv.), potassium fluoride (348mg, 6equiv.) and tetrabutylammonium fluoride tert-butanol complex (55.8mg, 0.1equiv.) were added to N, N-dimethylformamide (3.0mL), and the mixture was stirred and heated at 90 ℃. The reaction was monitored by TLC plate, after completion of the reaction, quenched by water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents, which was passed through the column to afford compound 3(95.4mg, 60%) as a solid product.
Example 8: preparation of 3, 6-difluoropyrazine-2-carboxamide using potassium fluoride and tetramethylammonium fluoride
3, 6-dichloropyrazine-2-carboxamide (192mg, 1.0equiv.), potassium fluoride (348mg, 6equiv.) and tetramethylammonium fluoride (9.3mg, 0.1equiv.) were added to N, N-dimethylformamide (3.0mL), and the mixture was stirred with heating at 90 ℃. The reaction was monitored by TLC plate, after completion, quenched by addition of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove all solvents, and passed through the column to give compound 3(100mg, 63%) as a solid product.
Example 9: preparation method of Favipiravir
3, 6-difluoropyrazine-2-carboxamide (159mg, 1.0equiv.), sodium bicarbonate (420mg, 5.0equiv.) was placed in a reaction flask, dioxane (2.0mL) and water (4.0mL) were added, and the mixture was heated to 60 ℃. And monitoring the reaction by a TLC (thin layer chromatography) spot plate, after the reaction is completed, dropwise adding 2M HCl to adjust the pH to 3-4, extracting by ethyl acetate, drying by anhydrous sodium sulfate, filtering, concentrating the aqueous phase under reduced pressure to remove all solvents, and recrystallizing to obtain the product namely the Favipiravir (118mg, 75%).
1H NMR(400MHz,CDCl3)δ12.35(br,1H),8.31(d,1H,J=8.0Hz),7.43(br,1H),5.89(br,1H).19F NMR(376MHz,CDCl3):δ-92.79.
Example 10: one-pot preparation method of Peruvir
3, 6-dichloropyrazine-2-carboxamide (1.92g, 1.0equiv.) and cesium fluoride (9.0g, 6equiv.) were placed in a 50mL Teflon reaction flask, and t-butanol (15mL) was added and the mixture was heated and stirred at 90 ℃. The reaction was monitored by TLC plate and after completion of the reaction, sodium bicarbonate (4.2g, 5.0equiv.) and water (15.0mL) were added to the reaction flask and heated to 60 ℃. And monitoring the reaction by a TLC (thin layer chromatography) spot plate, after the reaction is completed, dropwise adding 2M HCl to adjust the pH to 3-4, extracting by ethyl acetate, drying by anhydrous sodium sulfate, filtering, concentrating the water phase under reduced pressure to remove all solvents, and recrystallizing to obtain the product namely the Favipiravir (1.04g, 66%).
Example 11: preparation of piravir from 2, 5-dichloropyrazine
Taking 2, 5-dichloropyrazine (1.48g, 1.0equiv.) and formamide (5mL,12.6equiv.) into a reaction bottle, adding potassium persulfate (5.4g,2.0equiv.), stirring at 80 ℃ for 12 hours, adding a saturated sodium bicarbonate solution for quenching, extracting with ethyl acetate, drying with anhydrous sodium sulfate, filtering, and concentrating the aqueous phase under reduced pressure to remove all solvents to obtain a crude product of the 3, 6-dichloropyrazine-2-formamide. The crude product was transferred to a 50mL Teflon reaction flask, cesium fluoride (6.0g, 4equiv.) was added, followed by t-butanol (15mL), and the mixture was heated and stirred at 90 ℃. The reaction was monitored by TLC plate and after completion of the reaction, sodium bicarbonate (4.2g, 5.0equiv.) and water (10mL) were added to the reaction flask and heated to 60 ℃. And monitoring the reaction by a TLC (thin layer chromatography) point plate, after the reaction is completed, dropwise adding 2M HCl to adjust the pH to 3-4, extracting by ethyl acetate, drying by anhydrous sodium sulfate, filtering, concentrating the aqueous phase under reduced pressure to remove all solvents, and recrystallizing to obtain the product namely the Favipiravir (0.81g, 49%).
The above examples are for illustrative purposes only and the scope of the present invention is not limited thereto. Modifications will be apparent to those skilled in the art and the invention is limited only by the scope of the appended claims.
Claims (7)
1. A process for the synthesis of favipiravir, compound 5, by a route comprising the steps of:
route one:
step (1): 2, 5-dichloropyrazine, namely a compound 1, is prepared into 2, 5-difluoropyrazine, namely a compound 2, under the action of a fluorinating reagent;
step (2): carrying out a formamide reaction on the 2, 5-difluoropyrazine prepared in the step (1) and formamide under the action of persulfate to prepare 3, 6-difluoropyrazine-2-formamide, namely a compound 3;
and (5): reacting the 3, 6-difluoropyrazine-2-formamide prepared in the step (2) with alkali for hydrolysis to prepare a compound 5,
or
And a second route:
and (3): 2, 5-dichloropyrazine, namely a compound 1, and formamide are subjected to a formamide reaction under the action of persulfate to prepare 3, 6-dichloropyrazine-2-formamide, namely a compound 4;
and (4): reacting the 3, 6-dichloropyrazine-2-formamide prepared in the step (3) with a fluorination reagent to prepare 3, 6-difluoropyrazine-2-formamide, namely a compound 3;
step (5'): and (3) reacting the 3, 6-difluoropyrazine-2-formamide prepared in the step (4) with alkali for hydrolysis to prepare a compound 5.
2. The method according to claim 1, wherein the reaction of step (1) is carried out in a solvent, and the fluorinating agent used in step (1) is one or a mixture of two or more of potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-t-butanol complex, potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride-t-butanol complex, cesium fluoride/tetrabutylammonium fluoride, and potassium fluoride/trimethylamine; the molar ratio of the fluorination reagent to the compound 1 is 2.0-10.0; the solvent used in step (1) is one or more selected from dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane.
3. The method according to claim 1, wherein the persulfate used in the step (2) is one or more selected from the group consisting of sodium persulfate, potassium persulfate and ammonium persulfate; the molar ratio of the persulfate to the compound 2 is 1.5-5.0.
4. The method according to claim 1, wherein the persulfate used in the step (3) is one or more selected from the group consisting of sodium persulfate, potassium persulfate and ammonium persulfate; the molar ratio of the persulfate to the compound 1 is 1.0-5.0.
5. The method according to claim 1, wherein the reaction of step (4) is carried out in a solvent, and the fluorinating agent used in step (4) is one or a mixture of two or more of potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride-t-butanol complex, potassium fluoride/tetrabutylammonium fluoride-t-butanol complex, cesium fluoride/tetrabutylammonium fluoride; the molar ratio of the fluorination reagent to the compound 4 is 2.0-10.0; the solvent used in step (4) is selected from one or more of dichloromethane, dichloroethane, N-dimethylformamide, N-dimethylacetamide, dimethylsulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, N-hexane, N-heptane and cyclohexane.
6. The process according to claim 1, wherein the base used in step (5) or (5') is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium phosphate; the molar ratio of the alkali to the compound 3 is 0.5-5.0.
7. The process according to any one of claims 1 to 6, characterized in that the reaction is carried out using a one-pot process.
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CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
CN106083745A (en) * | 2016-08-15 | 2016-11-09 | 山东百诺医药股份有限公司 | The synthetic method of 6 fluorine 3 hydroxyl 2 pyrazinamide |
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 |
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CN1418220A (en) * | 2000-02-16 | 2003-05-14 | 富山化学工业株式会社 | Novel pyrazine derivatives or salts thereof, containing the derives or the salts and intermediates for the preparation of both |
CN106083745A (en) * | 2016-08-15 | 2016-11-09 | 山东百诺医药股份有限公司 | The synthetic method of 6 fluorine 3 hydroxyl 2 pyrazinamide |
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