CN114656412A - Synthesis method of Favipiravir - Google Patents

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

A kind of synthetic method of favipiravir

technical field

The invention belongs to the field of medicinal chemistry and chemical synthesis, in particular to a new favipiravir synthesis method.

Background technique

Favipiravir is a new broad-spectrum anti-RNA virus drug developed by Japan's Toyama Chemical Pharmaceutical Company. It was approved for marketing in March 2014 for the antiviral treatment of influenza A and B. Studies have shown that in addition to influenza virus, the drug also exhibits good antiviral activity against a variety of RNA viruses, such as Ebola virus, arena virus, bunya virus, rabies virus, etc. The latest research shows that favipiravir has a certain inhibitory effect on COVID-19. The structural formula of compound 5 is as follows:

At present, the routes for synthesizing favipiravir at home and abroad mainly include the following:

Patent WO 2000/010569 reports a route (shown in the following reaction formula 1), which uses 3-aminopyrazine-2-carboxylic acid as a raw material, undergoes esterification and bromination to obtain an intermediate, and then undergoes diazotization. , alcoholysis, amino substitution and aminolysis under palladium catalysis to obtain amide intermediates, and then diazotization, fluorination and demethylation to obtain the final product favipiravir. This strategy requires long steps, low overall yields, and requires expensive transition metal catalysts. In addition, highly corrosive fluorinated reagents are used. Due to these factors, this strategy is not suitable for the large-scale preparation of compound 5.

Reaction 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 is obtained through several steps such as nitration, chlorination, fluorination, and hydrolysis. Compound 5. The nitration reaction used in this route has high requirements on the reaction vessel and requires a large amount of phosphorus oxychloride. The synthesis of intermediate 3,6-dichloropyrazine-2-carbonitrile was reported in both patent WO 2010/087117 and Chem.Pap.2017, 71, 2153, and compound 5 was synthesized therefrom. These routes all require a large amount of three Phosphorus oxychloride is a challenge for large-scale production and waste disposal.

Reaction 2

Professor Xu Wenfang of Shandong University designed and synthesized (Drug Discov. Ther. 2014, 8, 117.) a route (shown in the following reaction formula 3), which uses 3-hydroxypyrazine-2-carboxylic acid as a raw material, through esterification, ammonia Compound 5 was synthesized through the steps of solution, nitration, reduction, and fluorination. Among them, this strategy uses a nitration reaction, which has high requirements on the reactor, and also uses a highly corrosive fluorination reagent.

Reaction 3

To sum up, there are still many technical problems in the existing synthesis methods, the total yield is not high, and the wastes are too much, so it is difficult to be suitable for industrial production.

SUMMARY OF THE INVENTION

Purpose of invention

The purpose of the present invention is to provide a kind of synthetic method of favipiravir to solve the above-mentioned problems.

Technical solutions

According to one aspect of the present disclosure, there is provided a method for synthesizing Favipiravir, which is implemented by a route comprising the following steps:

Route one:

Step (1): 2,5-dichloropyrazine (compound 1) is prepared under the action of a fluorinated reagent to obtain 2,5-difluoropyrazine (compound 2);

Step (2): The 2,5-difluoropyrazine (compound 2) obtained in step (1) is subjected to formamidation reaction with formamide under the action of persulfate to obtain 3,6-difluoropyrazine oxazine-2-carboxamide (compound 3);

Step (5): react the 3,6-difluoropyrazine-2-carboxamide (compound 3) obtained in step (2) with a base to hydrolyze to obtain compound 5, or

Route two:

Step (3): 2,5-dichloropyrazine (compound 1) and formamide are subjected to formamidation reaction under the action of persulfate to obtain 3,6-dichloropyrazine-2-carboxamide (compound 4);

Step (4): react the 3,6-dichloropyrazine-2-carboxamide (compound 4) obtained in step (3) with a fluorinating reagent to obtain 3,6-difluoropyrazine-2-methyl amide (compound 3);

Step (5'): The 3,6-difluoropyrazine-2-carboxamide (compound 3) prepared in step (4) is reacted with a base for hydrolysis to obtain compound 5.

beneficial effect

According to the preparation method of the present disclosure, the synthesis process can be simplified, the total yield of the target product can be improved, the generation of reaction waste can be reduced, and it is suitable for industrial large-scale production, so as to solve the problems existing in the above route.

Detailed ways

In order for those with ordinary knowledge in the art to understand the features and effects of the present invention, general descriptions and definitions of terms and terms mentioned in the specification and the scope of the patent application are provided below. Unless otherwise specified, all technical and scientific terms used herein have the ordinary meanings understood by those skilled in the art to the present invention, and in case of conflict, the definitions in this specification shall prevail.

As used herein, the terms "comprising", "including", "having", "containing" or any other similar terms are open-ended transitional phrases intended to cover non-exclusive inclusions. For example, a composition or article of manufacture containing a plurality of elements is not limited to only those elements listed herein, but can also include other elements not expressly listed, but which are generally inherent to the composition or article of manufacture. Otherwise, unless expressly stated to the contrary, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, the condition "A or B" is satisfied by any of the following: A is true (or present) and B is false (or absent), A is false (or absent) and B is true (or present), Both A and B are true (or exist). In addition, in this document, the terms "comprising", "including", "having", "containing" should be interpreted as having specifically disclosed and encompassing both "consisting of" and "substantially consisting of" and other closures Formal or semi-closed connectives.

In this document, all features or conditions defined 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 encompass and specifically disclose all possible sub-ranges and individual numerical values within the range, particularly integer numerical values. For example, a range description of "1 to 8" should be deemed 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, etc., particularly are sub-ranges bounded by all integer values, and should be deemed to have specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise indicated, the foregoing method of interpretation applies to all content throughout this disclosure, whether broad or not.

If a quantity or other value or parameter is expressed as a range, a preferred range, or a series of upper and lower limits, it should be understood that any upper or preferred value of the range and the lower limit of the range have been specifically disclosed herein or all ranges of preferred values, whether or not those ranges are disclosed separately. Furthermore, when a range of values is referred to herein, unless otherwise indicated, the range shall include its endpoints and all integers and fractions within the range.

As used herein, numerical values should be understood to have an accuracy of significant digits of the numerical value, provided that the purpose of the invention can be achieved. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

Where Markush group or alternative terminology is used herein to describe features or examples of the invention, those skilled in the art will understand the Markush group or subgroups of all elements within a list of options Groups or any individual element may also be used to describe the invention. For example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ ", it also means that the claim that X is X ₁ and that X is X ₁ and/or X ₂ have been fully described claim. Furthermore, where Markush group or option terminology is used to describe features or instances of the invention, those skilled in the art will recognize subgroups or individual elements of all elements within the Markush group or option list Any combination of , can also be used to describe the invention. Accordingly, for example, if X is described as "selected from the group consisting of X ₁ , X ₂ and X ₃ " and Y is described as "selected from the group consisting of Y ₁ , Y ₂ and Y ₃ group of "," means that the claim that X is X ₁ or X ₂ or X ₃ and Y is Y ₁ or Y ₂ or Y ₃ has been fully described.

The following detailed description is merely exemplary in nature and is not intended to limit the invention and its uses. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or this summary or in the following detailed description or examples.

According to one embodiment of the present disclosure, there is provided a method for synthesizing Favipiravir, which is implemented by a route comprising the following steps:

Route one:

Step (1): 2,5-dichloropyrazine (compound 1) is prepared under the action of a fluorinated reagent to obtain 2,5-difluoropyrazine (compound 2);

Step (2): The 2,5-difluoropyrazine (compound 2) obtained in step (1) is subjected to formamidation reaction with formamide under the action of persulfate to obtain 3,6-difluoropyrazine oxazine-2-carboxamide (compound 3);

Step (5): react the 3,6-difluoropyrazine-2-carboxamide (compound 3) obtained in step (2) with a base to hydrolyze to obtain compound 5, or

Route two:

Step (3): 2,5-dichloropyrazine (compound 1) and formamide are subjected to formamidation reaction under the action of persulfate to obtain 3,6-dichloropyrazine-2-carboxamide (compound 4);

Step (4): react the 3,6-dichloropyrazine-2-carboxamide (compound 4) obtained in step (3) with a fluorinating reagent to obtain 3,6-difluoropyrazine-2-methyl amide (compound 3);

Step (5'): The 3,6-difluoropyrazine-2-carboxamide (compound 3) prepared in step (4) is reacted with a base for hydrolysis to obtain compound 5.

According to an embodiment of the present disclosure, the reaction in step (1) is carried out in a solvent, and the fluorination reagent used in step (1) is potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutyl fluoride Ammonium fluoride, tetrabutylammonium fluoride tert-butanol complex, potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride tertiary One or more mixtures of butanol complex, cesium fluoride/tetrabutylammonium fluoride, potassium fluoride/trimethylamine; the molar ratio of the fluorination reagent to compound 1 is 2.0 to 10.0; The solvent used in step (1) is selected from dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl Pyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, One or more of 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 is 1.5 to 5.0.

According to an embodiment of the present disclosure, wherein, the persulfate used in step (3) is selected from one or more of sodium persulfate, potassium persulfate and ammonium persulfate; the molar ratio of the sulfate to compound 1 1.0 to 5.0.

According to an embodiment of the present disclosure, the reaction of step (4) is carried out in a solvent, and the fluorination reagent used in step (4) is potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutyl fluoride Ammonium fluoride, tetrabutylammonium fluoride tert-butanol complex, potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride tert-butanol complex, cesium fluoride/tetrabutylammonium fluoride One or more mixtures of butylammonium fluoride; the molar ratio of the fluorination reagent and compound 4 is 2.0 to 10.0; the solvent used in step (4) is selected from dichloromethane, dichloroethane , N,N-dimethylformamide, N,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, cyclohexane one or more of alkanes.

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 bicarbonate, and potassium phosphate; the The molar ratio of the base to compound 3 is 0.5 to 5.0.

More specifically, according to the method of the present disclosure, it is implemented by a route comprising the following steps:

Route one:

First, compound 1 is double-fluorinated, and then compound 3 is prepared by formamidation reaction, and finally compound 5 is synthesized by hydrolysis. The reaction route is as follows:

Step (1): Dissolve compound 1 in an organic solvent, add a fluorinating reagent, and after the addition, the system is heated to 70 ° C ~ 140 ° C, react under the action of a fluorinating reagent, after the reaction is completed, add water to quench, extract, and combine organic phase, dried, filtered, the filtrate was spin-dried under reduced pressure, and separated by column chromatography to obtain compound 2;

Step (2): Dissolve compound 2 prepared in step (1) in a solvent, add formamide and persulfate, heat the system to 50°C to 100°C, filter after completion of the reaction, add dilute hydrochloric acid to quench, and extract , the organic phases were combined, dried, filtered, the filtrate was spin-dried under reduced pressure, and separated by column chromatography to obtain compound 3;

Step (5): dissolving the compound prepared in step (2) in an organic solvent, adding an aqueous alkali solution, heating the system to 30° C. to 70° C., performing aromatic ring hydroxyl substitution reaction, and then purifying to obtain the compound 5.

Wherein, the fluorination reagent described in step (1) is selected from potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride, tetrabutylammonium fluoride tert-butanol complex, fluorine Potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride tert-butanol complex, cesium fluoride/tetrabutylammonium fluoride, fluorine One or a mixture of two or more of potassium chloride/trimethylamine, etc.

The molar ratio of the fluorination reagent to compound 1 is 1.0-10.0, preferably 2.0-10.0;

The temperature of the reaction in step (1) is 70°C to 140°C;

The solvent described in step (1) is selected from dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl Pyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, One or more of acetonitrile, benzonitrile, tert-butanol, n-hexane, n-heptane, cyclohexane;

The reaction time of step (1) is 0.5 hour to 24 hours.

Wherein, the persulfate described in step (2) is selected from one or more in sodium persulfate, potassium persulfate and ammonium persulfate;

The molar ratio of the formamide to compound 2 is 1.0 to 50.0;

The molar ratio of the persulfate to compound 2 is 1.0 to 5.0;

The temperature of the reaction in step (2) is 50°C～100°C;

The solvent described in step (2) is selected from water, dichloromethane, dichloroethane, formamide, N,N-dimethylformamide, N,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, diethyl ether One or more of methoxymethane, acetonitrile, benzonitrile, n-hexane, n-heptane and cyclohexane;

The reaction time of step (2) is 1 hour to 24 hours.

Wherein, the alkali described in step (5) is selected from one or more in sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium phosphate etc.;

The molar ratio of the compound 3 to the base is 0.5-2.0;

The temperature of the reaction in step (5) is 30°C to 70°C;

The solvent described in step (5) is selected from water, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, xylene , one or more of chlorobenzene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, n-hexane and cyclohexane;

The time of the described reaction in step (5) is 1 hour to 24 hours; or

Route 2: First, compound 4 is prepared by formamidation reaction, then compound 3 is prepared by double fluorination, and finally favipiravir is synthesized by hydrolysis. The reaction route is as follows:

Equation 4

The route includes the following steps:

Step (3): Compound 1 was added to formamide and persulfate, the temperature of the system was raised to 50°C to 100°C, the reaction was completed, filtered, quenched by adding dilute hydrochloric acid, extracted, combined with the organic phases, dried, filtered, and the filtrate was spun under reduced pressure. Dry, column chromatography to obtain compound 4;

Step (4): Dissolve the compound 2 prepared in step (3) in a solvent, add a fluorinating reagent, after the addition, the system is heated to 70 ° C ~ 140 ° C, react under the action of the fluorinating reagent, and add water after the reaction is completed. Quenched, extracted, combined the organic phases, dried, filtered, the filtrate was spin-dried under reduced pressure, and separated by column chromatography to obtain compound 3;

Step (5'): dissolving the compound obtained in step (4) in an organic solvent, adding an aqueous alkali solution, heating the system to 30°C to 70°C, performing aromatic ring hydroxyl substitution reaction, and then purifying to obtain Compound 5.

Wherein, the described persulfate of step (3) is selected from one or more in sodium persulfate, potassium persulfate and ammonium persulfate;

The molar ratio of the formamide to compound 1 is 1.0 to 20.0;

The molar ratio of the persulfate to compound 1 is 1.0-5.0;

The temperature of the reaction in step (3) is 50°C to 100°C;

The solvent described in step (3) is selected from water, dichloromethane, dichloroethane, formamide, N,N-dimethylformamide, N,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, diethyl ether One or more of methoxymethane, acetonitrile, benzonitrile, n-hexane, n-heptane and cyclohexane;

The reaction time of step (3) is 1 hour to 24 hours.

Wherein, the fluorination reagent described in step (4) is selected from potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetrabutylammonium fluoride, tetrabutylammonium fluoride tert-butanol complex one or more of potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride tert-butanol complex, cesium fluoride/tetrabutylammonium fluoride mixture.

The molar ratio of the fluorination reagent to compound 4 is 2.0-10.0;

The temperature of the reaction in step (4) is 70°C to 140°C;

The solvent described in step (4) is selected from dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methyl Pyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, One or more of acetonitrile, benzonitrile, tert-butanol, n-hexane, n-heptane, cyclohexane;

The reaction time of step (4) is 0.5 hour to 24 hours.

Wherein, the perbasic described in step (5') is selected from one or more in sodium carbonate, salt of wormwood, sodium bicarbonate, potassium bicarbonate, potassium phosphate etc.;

The molar ratio of the base to compound 3 is 0.5 to 5.0;

The temperature of the described reaction of step (5') is 30 ℃～70 ℃;

The solvent described in step (5') is selected from water, dichloromethane, dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, One or more of toluene, chlorobenzene, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, acetonitrile, n-hexane, cyclohexane;

The reaction time is 1 hour to 24 hours.

According to an embodiment of the present disclosure, wherein the reaction is performed using a one-pot method.

The specific implementation steps of the present invention are described in detail below through some embodiments, which do not constitute any limitation to the scope of the present invention;

Example 1: Preparation of 2,5-difluoropyrazine using cesium fluoride

Take 2,5-dichloropyrazine (1.0 mL, 1.0 equiv.) and cesium fluoride (9.0 g, 6.0 equiv.) into N,N-dimethylformamide (10.0 mL), at 90 °C Heat and stir. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain the liquid product compound 2 (760 mg, 66%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (dd, J=8.2, 1.7 Hz, 1H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ-71.02.

Example 2: Preparation of 2,5-difluoropyrazine using potassium fluoride and tetrabutylammonium fluoride tert-butanol complex

Take 2,5-dichloropyrazine (1.0mL, 1.0equiv.), potassium fluoride (3.5g, 6.0equiv.), tetrabutylammonium fluoride tert-butanol complex (558mg, 0.1equiv.) were added into N,N-dimethylformamide (5.0 mL), and heated with stirring at 90°C. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain liquid product compound 2 (813 mg, 70%).

Example 3: Preparation of 2,5-difluoropyrazine using potassium fluoride and tetramethylammonium fluoride

2,5-Dichloropyrazine (1.0 mL, 1.0 equiv.), potassium fluoride (3.5 mg, 6.0 equiv.) and tetramethylammonium fluoride (93.0 mg, 0.1 equiv.) were added to DMF (5.0 mL). ), heated and stirred at 90°C. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain liquid product compound 2 (790 mg, 68%).

Embodiment 4: the preparation method of 3,6-dichloropyrazine-2-carboxamide

Take 2,5-dichloropyrazine (1.48g, 1.0equiv.), formamide (5mL, 12.6equiv.) in a reaction flask, then add potassium persulfate (5.4g, 2.0equiv.), stir at 80°C After 12 hours, it was quenched by adding saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain compound 4 (1.44 g, 75%) as a solid product.

Example 5: Preparation of 3,6-difluoropyrazine-2-carboxamide from 2,5-difluoropyrazine

Take 2,5-difluoropyrazine (232mg, 1.0equiv.) and formamide (5mL) in a reaction flask, then add potassium persulfate (1.8g, 2.0equiv.), stir at 80°C for 12 hours, add carbonic acid Quenched with saturated sodium hydrogen solution, extracted with ethyl acetate, concentrated the aqueous phase under reduced pressure to remove all solvent, and passed through column to obtain solid product compound 3 (185 mg, 80%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (dd, J=8.0, 1.6 Hz, 1H), 7.34 (s, 1H), 6.14 (s, 1H). ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ- 74.86,-83.34.

Example 6: Preparation of 3,6-difluoropyrazine-2-carboxamide using cesium fluoride

3,6-Dichloropyrazine-2-carboxamide (192 mg, 1.0 equiv.) and cesium fluoride (900 mg, 6 equiv.) were added to tert-butanol (3.0 mL), and the mixture was heated and stirred at 90°C. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain solid product compound 3 (105 mg, 66%).

Example 7: Preparation of 3,6-difluoropyrazine-2-carboxamide using potassium fluoride and tetrabutylammonium fluoride tert-butanol complex

Take 3,6-dichloropyrazine-2-carboxamide (192 mg, 1.0 equiv.), potassium fluoride (348 mg, 6 equiv.) and tetrabutylammonium fluoride tert-butanol complex (55.8 mg, 0.1 equiv. .) was added to N,N-dimethylformamide (3.0 mL), and the mixture was heated and stirred at 90°C. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain solid product compound 3 (95.4 mg, 60%).

Example 8: Preparation of 3,6-difluoropyrazine-2-carboxamide using potassium fluoride and tetramethylammonium fluoride

Take 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 (3.0 mL) was heated and stirred at 90°C. The reaction was monitored by TLC dot plate. After the reaction was completed, water was added to quench, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all solvent, and passed through column to obtain solid product compound 3 (100 mg, 63%).

Embodiment 9: the preparation method of favipiravir

Take 3,6-difluoropyrazine-2-carboxamide (159mg, 1.0equiv.), sodium bicarbonate (420mg, 5.0equiv.) in a reaction flask, add dioxane (2.0mL) and water (4.0 mL), heated to 60°C. The reaction was monitored by TLC dot plate. After the reaction was completed, 2M HCl was added dropwise to adjust the pH to 3-4, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent, and recrystallized to obtain the product. Pilavir (118 mg, 75%).

¹ H NMR(400MHz, CDCl ₃ )δ12.35(br,1H),8.31(d,1H,J=8.0Hz),7.43(br,1H),5.89(br,1H) ^.19F NMR(376MHz, CDCl ₃ ): δ-92.79.

Example 10: One-pot preparation of favipiravir

Take 3,6-dichloropyrazine-2-carboxamide (1.92g, 1.0equiv.), cesium fluoride (9.0g, 6equiv.) and put them in a 50mL polytetrafluoroethylene reaction flask, add tert-butanol ( 15 mL), heated and stirred at 90 °C. The reaction was monitored by TLC spot plate. After the reaction was completed, sodium bicarbonate (4.2 g, 5.0 equiv.) and water (15.0 mL) were added to the reaction flask, and heated to 60°C. The reaction was monitored by TLC dot plate. After the reaction was completed, 2M HCl was added dropwise to adjust the pH to 3-4, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent, and recrystallized to obtain the product. Pilavir (1.04 g, 66%).

Example 11: Preparation of favipiravir from 2,5-dichloropyrazine

Take 2,5-dichloropyrazine (1.48g, 1.0equiv.), formamide (5mL, 12.6equiv.) in a reaction flask, then add potassium persulfate (5.4g, 2.0equiv.), stir at 80°C For 12 hours, add saturated sodium bicarbonate solution to quench, extract with ethyl acetate, dry over anhydrous sodium sulfate, filter, concentrate the aqueous phase under reduced pressure to remove all solvent, and obtain a crude product of 3,6-dichloropyrazine-2-carboxamide . The crude product was then transferred to a 50 mL polytetrafluoroethylene reaction flask, cesium fluoride (6.0 g, 4 equiv.) was added, tert-butanol (15 mL) was added, and the mixture was heated and stirred at 90°C. The reaction was monitored by TLC spot plate. After the reaction was completed, sodium bicarbonate (4.2 g, 5.0 equiv.) and water (10 mL) were added to the reaction flask, and heated to 60°C. The reaction was monitored by TLC dot plate. After the reaction was completed, 2M HCl was added dropwise to adjust the pH to 3-4, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove all the solvent, and recrystallized to obtain the product. Pilavir (0.81 g, 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 favipiravir, i.e. the synthetic method of compound 5, the method is implemented by the route comprising the following steps: Route one:

Step (1): 2,5-dichloropyrazine, namely compound 1, is prepared under the action of a fluorination reagent to obtain 2,5-difluoropyrazine, namely compound 2; Step (2): The 2,5-difluoropyrazine obtained in step (1) is subjected to formamidation reaction with formamide under the action of persulfate to obtain 3,6-difluoropyrazine-2- Formamide, which is compound 3; Step (5): reacting the 3,6-difluoropyrazine-2-carboxamide obtained in step (2) with a base for hydrolysis to obtain compound 5, or Route two:

Step (3): 2,5-dichloropyrazine, namely compound 1, is subjected to formamidation reaction with formamide under the action of persulfate to obtain 3,6-dichloropyrazine-2-carboxamide, Namely compound 4; Step (4): react the 3,6-dichloropyrazine-2-carboxamide obtained in step (3) with a fluorinating reagent to obtain 3,6-difluoropyrazine-2-carboxamide, which is the compound 3; Step (5'): The 3,6-difluoropyrazine-2-carboxamide prepared in step (4) is reacted with a base for hydrolysis to obtain compound 5. 2. method according to claim 1 is characterized in that, the reaction of step (1) is carried out in solvent, and the fluorination reagent used in step (1) is potassium fluoride, cesium fluoride, tetramethyl fluoride Ammonium, tetrabutylammonium fluoride, tetrabutylammonium fluoride tert-butanol complex, potassium fluoride/tetramethylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutyl One or more mixtures of tert-butanol complex of ammonium fluoride, cesium fluoride/tetrabutylammonium fluoride, potassium fluoride/trimethylamine; the molar ratio of the fluorination reagent to compound 1 is 2.0-10.0; the solvent used in step (1) is selected from dichloromethane, dichloroethane, N,N-dimethylformamide, N,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, diethyl ether One or more of methoxymethane, acetonitrile, benzonitrile, tert-butanol, n-hexane, n-heptane, and cyclohexane. 3. method according to claim 1, is characterized in that, the persulfate used in step (2) is selected from one or more in sodium persulfate, potassium persulfate and ammonium persulfate; Described persulfate The molar ratio of the salt to compound 2 is 1.5 to 5.0. 4. method according to claim 1, is characterized in that, the persulfate used in step (3) selects one or more in sodium persulfate, potassium persulfate and ammonium persulfate; Described persulfate The molar ratio to compound 1 is 1.0 to 5.0. 5. method according to claim 1 is characterized in that, the reaction of step (4) is carried out in solvent, and the fluorination reagent used in step (4) is potassium fluoride, cesium fluoride, tetramethyl fluoride Ammonium, tetrabutylammonium fluoride, tetrabutylammonium fluoride tert-butanol complex, potassium fluoride/tetrabutylammonium fluoride, potassium fluoride/tetrabutylammonium fluoride tert-butanol complex, One or more mixtures of cesium fluoride/tetrabutylammonium fluoride; the molar ratio of the fluorination reagent to compound 4 is 2.0 to 10.0; the solvent used in step (4) is selected from dichloromethane , dichloroethane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, sulfolane, N-methylpyrrolidone, toluene, xylene, chlorobenzene, tetrahydrofuran, methyl benzene tetrahydrofuran, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, methyl tert-butyl ether, diethoxymethane, dimethoxymethane, acetonitrile, benzonitrile, tert-butanol, n-hexane, n- One or more of heptane and cyclohexane. 6. method according to claim 1 is characterized in that, in step (5) or (5 '), alkali used is selected from the one in sodium carbonate, salt of wormwood, sodium bicarbonate, potassium bicarbonate, potassium phosphate or A variety of; the molar ratio of the base to compound 3 is 0.5 to 5.0. 7. The method of any one of claims 1 to 6, wherein the reaction is performed using a one-pot method.