CN113929633A - Synthesis method and application of Favipiravir - Google Patents
Synthesis method and application of Favipiravir Download PDFInfo
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- CN113929633A CN113929633A CN202111255256.3A CN202111255256A CN113929633A CN 113929633 A CN113929633 A CN 113929633A CN 202111255256 A CN202111255256 A CN 202111255256A CN 113929633 A CN113929633 A CN 113929633A
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- 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
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Abstract
The invention provides a synthesis method and application of Favipiravir, and belongs to the technical field of drug synthesis. The synthesis method comprises the following steps: adding a compound 1 into a first organic solvent, and reacting with ammonia water to generate a compound 2; the compound 2 and glyoxal are cyclized under the alkaline condition to generate a compound 3; adding the compound 3 into a second solvent, and reacting with a fluorinating reagent to generate a compound 4, namely the Favipiravir. The compound 1 is used as an initial raw material, the piravir is synthesized only by three steps of ammonolysis, cyclization and fluorination, the operation difficulty is low, the product yield is high, the price of a reactant is low, the production cost is reduced, the reaction condition is mild, three wastes are less, the synthetic route is environment-friendly, and the method is suitable for the amplification production of the piravir, so that the method has good value of industrial production and application.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and particularly relates to a synthesis method and application of Favipiravir.
Background
The information in this background section is only for enhancement of understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art that is already known to a person of ordinary skill in the art.
Favipiravir, chemical name: the 6-fluoro-3-hydroxypyrazine-2-formamide is a broad-spectrum antiviral drug of RNA polymerase inhibitors, is mainly used for treating novel or reoccurrence influenza of adults, has a better treatment effect on influenza virus, and recently researches show that the 6-fluoro-3-hydroxypyrazine-2-formamide also has a better inhibition effect on novel coronavirus.
The structural formula of Favipiravir is:
at present, the synthesis route of Favipiravir is mainly as follows:
route one
Optimization of the synthesis process of Favipiravir [ J ] food and medicine, 2020,22(02): 139) 142, by Dengyu et al, 2-aminomalonic acid diethyl ester hydrochloride is used as a starting material, and the Favipiravir is prepared through ammonolysis, cyclization, bromination, dehydration, chlorination, fluorination, substitution and hydrolysis. The reaction conditions of the route are mild, but the reaction route is long and the total yield is low.
Route two
CN 111675663 is improved in the last step on the basis of the first route, in an anhydrous alkaline organic solvent, alkali provides hydroxyl to promote the reaction of 6-fluoro-3-hydroxy-2-cyanopyrazine to obtain Favipiravir, the yield is improved, the use of hydrogen peroxide is avoided, but the reaction steps are long.
Route three
CN 102775358 reports that 3-aminopyrazine-2-carboxylic acid is used as raw material to undergo hydroxylation substitution, esterification, ester ammonolysis, nitration, reduction and diazotization fluorine atom substitution. The process has the advantages of short route, simple production operation and mild reaction. However, the reduction reaction using the noble metal palladium (palladium carbon) not only increases the cost, but also the reaction step is closer to the target product, and the heavy metal residue is not easy to control; dangerous diazotization reaction and nitration reaction are involved, and in addition, the use of hydrogen also causes greater potential safety hazard in industrial production.
Route four
In the synthetic route of CN107226794, the group R as the starting material is generally cyano or amide, pyrazine diazepoxide is firstly generated by the reaction of organic acid and oxidant, then the important intermediate 3, 6-dichloro-2-cyano pyrazine is generated, and then the target product is generated by the 3 steps of fluorination, acylation and hydroxylation. The raw materials are simple and easy to obtain, the reaction conditions are mild, but the yield is not high, and the cost is higher.
Route five
CN111471025 reports that Favipiravir is obtained by taking 2, 5-dichloropyrazine as a starting material and sequentially carrying out 5 steps of free radical reaction, dehydration reaction, fluorination reaction, hydrolysis reaction and cyano hydrolysis reaction. The raw material cost is reduced, the yield is high, but the safety of the synthetic scheme is not high due to the use of potassium persulfate with strong oxidizing property and phosphorus oxychloride which can generate anaphylactic reaction.
Route six
A new synthetic route to Favipiravir was reported by Guo, Q.et al, The complete synthesis of favipiravir from 2-aminopyrazine, published in Chemical Papers. The route takes 2-aminopyrazine as an initial raw material, and the process route comprises 7 steps: chlorination, bromination, palladium-catalyzed cyanation, sandmeyer reaction, nucleophilic reaction, nitrile hydration, and hydroxyl substitution. The method avoids the use of harmful phosphorus oxychloride, has high yield per step, but uses expensive palladium catalyst, thereby increasing the cost.
In conclusion, the currently known synthesis method of favipiravir has the problems of complicated synthesis scheme, long route, expensive reagent price and the like, so that a new synthesis method is required to be perfected.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a novel method for synthesizing Lavipiravir and application thereof, and the method has the advantages of short reaction route, mild reaction conditions, low raw material cost and relatively high overall yield, thereby having good practical application value.
Specifically, the invention relates to the following technical scheme:
in a first aspect of the present invention, there is provided a synthesis method of favipiravir, the synthesis method comprising:
adding a compound 1 into a first organic solvent, and reacting with ammonia water to generate a compound 2; the compound 2 and glyoxal are cyclized under the alkaline condition to generate a compound 3; adding the compound 3 into a second solvent, and reacting with a fluorinating reagent to generate a compound 4, namely the Favipiravir.
Wherein the structural formula of the compound 1 is as follows:
the structural formula of compound 2 is:
the structural formula of compound 3 is:
in a second aspect of the invention, the application of the synthesis method in industrial production of the fravirin is provided.
The beneficial technical effects of one or more technical schemes are as follows:
the technical scheme takes the compound 1 as an initial raw material, only three steps of ammonolysis, cyclization and fluorination are carried out to synthesize the piravir, the operation difficulty is low, the product yield is high, the price of reactants is low, the production cost is reduced, the reaction condition is mild, three wastes are less, the synthetic route is environment-friendly, and the method is suitable for the amplification production of the piravir, so that the method has good value of industrial production and application.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification, illustrate exemplary embodiments of the invention and together with the description serve to explain the invention and not to limit the invention.
FIG. 1 is a mass spectrum of the product of example 1 of the present invention;
FIG. 2 is a mass spectrum of the product of example 2 of the present invention;
FIG. 3 is a mass spectrum of the product of example 3 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of the product of example 2 of the present invention;
FIG. 5 is a nuclear magnetic spectrum of the product of example 3 of the present invention.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the disclosure. 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 application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments according to the present application. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, and it should be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof, unless the context clearly indicates otherwise.
The present invention is further illustrated by reference to specific examples, which are intended to be illustrative only and not limiting. If the experimental conditions not specified in the examples are specified, they are generally according to the conventional conditions, or according to the conditions recommended by the sales companies; materials, reagents and the like used in examples were commercially available unless otherwise specified.
As mentioned above, the existing synthesis method of the Lavipiravir has the problems of complicated synthesis scheme, long route, expensive reagent price and the like.
In view of the above, the invention provides a novel synthesis method of Pilarvir, which is a method for synthesizing Pilarvir by three steps of ammonolysis, cyclization and fluorination, and has the advantages of low operation difficulty, high product yield, low price of reactants, reduced production cost, mild reaction conditions, less three wastes, green and environment-friendly synthesis route and suitability for large-scale production.
In a typical embodiment of the present invention, the method for synthesizing favipiravir comprises:
adding a compound 1 into a first organic solvent, and reacting with ammonia water to generate a compound 2; the compound 2 and glyoxal are cyclized under the alkaline condition to generate a compound 3; adding the compound 3 into a second solvent, and reacting with a fluorinating reagent to generate a compound 4, namely the Favipiravir.
Wherein the structural formula of the compound 1 is as follows:
the structural formula of compound 2 is:
the structural formula of compound 3 is:
in another embodiment of the present invention, the first organic solvent and the second organic solvent may be the same or different; in some embodiments of the invention, the first organic solvent is selected from any one or more of methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene, and acetone.
In still another embodiment of the present invention, the second organic solvent is selected from any one or more of methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and N, N-dimethylformamide.
In another embodiment of the present invention, the molar ratio of the compound 1 to the aqueous ammonia is controlled to 1:4 to 6.
In another embodiment of the present invention, the reaction temperature of the reaction of the compound 1 with ammonia water is controlled to be 20 to 50 ℃.
In yet another embodiment of the present invention, during the cyclization of compound 2 with glyoxal under alkaline conditions to form compound 3, the alkaline environment is achieved by applying, for example, sodium hydroxide, potassium hydroxide, and the like.
In another embodiment of the present invention, the molar ratio of the compound 2 to glyoxal is 1:1 to 3, preferably 1:1.1 to 1.5.
In another embodiment of the present invention, the reaction temperature of the reaction of the compound 2 with glyoxal is controlled to 20-50 ℃.
In another embodiment of the invention, the compound 3 is added into the second solvent, and the reaction temperature is 40-100 ℃ in the process of generating the Favipiravir through the reaction with the fluorinating reagent;
in yet another embodiment of the present invention, the fluorinating agent can be any one or more of NFSI, Selectfluor, N-fluoropyridinium.
In another embodiment of the present invention, the molar ratio of the compound 3 to the fluorinating agent is 1:1 to 3.
In another embodiment of the present invention, the method for synthesizing favipiravir comprises:
in another embodiment of the present invention, the application of the above synthesis method in industrial production of fravirin is provided.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Example 1
Sealing at room temperature, adding 5g diethyl aminomalonate hydrochloride into 5ml methanol, stirring, adding 10ml ammonia water, and stirring at room temperature for 24 h; 20ml of ethanol is added to precipitate, and the product is washed by ethanol and is bright yellow solid. (yield 66.48%)
MS(ESI):m/z[C3H7N3O2 +H]+(M+H)+118.0614.
Example 2
1g of 2-aminomalonamide was added to 1.82ml of 20% NaOH aqueous solution at-10 ℃ and 1.16ml of 40% glyoxal was dropwise added; reacting for 1h at the temperature of minus 5 ℃; reacting for 3 hours at 22 ℃; cooling to 0 ℃, and adjusting the pH value of the solution to 2 by using 6mol/L HCl to separate out a precipitate; washing the precipitate with ethanol, and vacuum drying to obtain light yellow solid. (yield 77.45%)
1H NMR(600MHz,DMSO-d6):δ7.92(s,1H,-HPh),δ8.71(s,1H,-HPh),δ8.11(s,2H,-NH2),δ13.32(s,1H,-OH).MS(ESI):m/z[C5H5N3O2-H]-(M-H)-138.02943.
Example 3
0.1391g of 3-hydroxypyrazine-2-amide and 0.6g of fluorine reagent are added into 10ml of DMF, and the mixture is condensed, refluxed and stirred for 60 hours at 50 ℃; concentrating under reduced pressure, adding 10ml of water, extracting with equal amount of ethyl acetate, and combining organic phases; concentrating at 35 deg.C, and vacuum drying to obtain light yellow solid. (yield 62.89%)
1H NMR(600MHz,DMSO-d6):δ8.50-8.51(s,2H,-NH2),δ8.73(s,1H,-HPh),δ13.40(s,1H,-OH).MS(ESI):m/z[C5H4FN3O2-H]-(M-H)-156.0203.
Finally, it should be noted that: although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that changes may be made in the embodiments and/or equivalents thereof without departing from the spirit and scope of the invention. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of Favipiravir is characterized by comprising the following steps:
adding a compound 1 into a first organic solvent, and reacting with ammonia water to generate a compound 2; the compound 2 and glyoxal are cyclized under the alkaline condition to generate a compound 3; adding a compound 3 into a second solvent, and reacting with a fluorination reagent to generate a compound 4, namely Favipiravir;
wherein the structural formula of the compound 1 is as follows:
the structural formula of compound 2 is:
the structural formula of compound 3 is:
2. the method of synthesis according to claim 1, wherein the first organic solvent and the second organic solvent are the same or different;
preferably, the first organic solvent is selected from any one or more of methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, toluene, xylene, chlorobenzene and acetone;
preferably, the second organic solvent is selected from any one or more of methanol, ethanol, dichloromethane, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran and N, N-dimethylformamide.
3. The synthesis method according to claim 1, wherein the molar ratio of the compound 1 to the ammonia water is controlled to be 1: 4-6; or the reaction temperature of the compound 1 and ammonia water is controlled to be 20-50 ℃.
4. The method of synthesis according to claim 1, wherein during the cyclization of compound 2 with glyoxal under alkaline conditions to form compound 3, the alkaline environment is achieved by the application of sodium hydroxide or potassium hydroxide.
5. The synthesis method according to claim 1, wherein the molar ratio of the compound 2 to glyoxal is 1:1 to 3, preferably 1:1.1 to 1.5.
6. The synthesis method according to claim 1, wherein the reaction temperature of the reaction of the compound 2 with glyoxal is controlled to 20-50 ℃.
7. The synthesis method of claim 1, wherein the compound 3 is added into the second solvent, and the reaction temperature is controlled to be 40-100 ℃ in the process of reacting with the fluorinating reagent to generate the Favipiravir.
8. The synthesis method of claim 1, wherein the fluorinating agent is selected from one or more of NFSI, Selectfluor, and N-fluoropyridinium; or the like, or, alternatively,
the molar ratio of the compound 3 to the fluorinating agent is 1: 1-3.
9. The method of synthesis according to any one of claims 1 to 8, comprising:
10. use of the synthesis method according to any one of claims 1 to 9 for the industrial production of fravirin.
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| CN101835780A (en) * | 2007-08-21 | 2010-09-15 | 生物焦点解析有限公司 | Imidazo [1,2-alpha] pyrazine compounds for treatment of viral infections such as hepatitis |
| JP2010241806A (en) * | 2009-03-18 | 2010-10-28 | Toyama Chem Co Ltd | Method for producing 3-hydroxy-2-pyrazinecarboxamide |
| JP2010241805A (en) * | 2009-03-18 | 2010-10-28 | Toyama Chem Co Ltd | Method for producing aminomalonamide comprising reusing ammonia-containing filtrate |
| 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 |
| 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 |
| WO2021041970A1 (en) * | 2019-08-29 | 2021-03-04 | Hibercell, Inc. | Perk inhibiting imidazolopyrazine compounds |
| WO2021041976A1 (en) * | 2019-08-29 | 2021-03-04 | Hibercell, Inc. | Perk inhibiting indolinyl compounds |
-
2021
- 2021-10-27 CN CN202111255256.3A patent/CN113929633A/en active Pending
Patent Citations (7)
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| CN101835780A (en) * | 2007-08-21 | 2010-09-15 | 生物焦点解析有限公司 | Imidazo [1,2-alpha] pyrazine compounds for treatment of viral infections such as hepatitis |
| JP2010241806A (en) * | 2009-03-18 | 2010-10-28 | Toyama Chem Co Ltd | Method for producing 3-hydroxy-2-pyrazinecarboxamide |
| JP2010241805A (en) * | 2009-03-18 | 2010-10-28 | Toyama Chem Co Ltd | Method for producing aminomalonamide comprising reusing ammonia-containing filtrate |
| WO2021041970A1 (en) * | 2019-08-29 | 2021-03-04 | Hibercell, Inc. | Perk inhibiting imidazolopyrazine compounds |
| WO2021041976A1 (en) * | 2019-08-29 | 2021-03-04 | Hibercell, Inc. | Perk inhibiting indolinyl compounds |
| 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 |
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