CN111704582B

CN111704582B - Preparation method of Favipiravir and derivatives thereof

Info

Publication number: CN111704582B
Application number: CN202010583503.1A
Authority: CN
Inventors: 姚红; 罗瑾; 张广勤; 葛皓月; 王佳; 王楠楠; 陈璐岚
Original assignee: Zhejiang Hengkang Pharmaceutical Co ltd; Hangzhou Huangsen Biological Technology Co ltd
Current assignee: Zhejiang Hengkang Pharmaceutical Co ltd; Hangzhou Huangsen Biological Technology Co ltd
Priority date: 2020-06-23
Filing date: 2020-06-23
Publication date: 2021-06-11
Anticipated expiration: 2040-06-23
Also published as: CN111704582A; WO2021258500A1

Abstract

The invention provides a novel preparation method of a Favipiravir derivative. In particular to a method for synthesizing the Pilarvir or the derivatives thereof by directly using a fluorinating reagent to carry out electrophilic fluorination, selectively introducing fluorine atoms at 6-position and carrying out one-step reaction and high efficiency. Compared with the existing synthesis method, the method has the advantages of strong creativity, novelty, simple operation, safety, low cost, less three wastes, environmental friendliness and high total yield, so the synthesis method has strong industrial advantages and significance.

Description

Preparation method of Favipiravir and derivatives thereof

Technical Field

The invention relates to a novel preparation method of Favipiravir and derivatives thereof.

Background

Favipiravir (favipiravir, T-705, trade name Avigan, 1), chemically known as 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, is a novel broad-spectrum antiviral drug developed by fukushan chemical pharmaceuticals corporation to target RNA-dependent RNA polymerase (RdRp), approved for marketing in japan 3 months 2014 for the treatment of new and recurrent influenza. Researches find that the Larvavir has good inhibitory activity to various RNA viruses in vitro or in vivo, is expected to be developed and applied to treatment of various virus infections, and has good market prospect.

The representative synthesis method of Favipiravir at present comprises the following steps:

1) taking patent CN102307865 as a representative, the generation route of the current mainstream is: preparing corresponding chloride, and performing fluorine-chlorine exchange with potassium fluoride to obtain a key intermediate, wherein the fluorine-halogen exchange has strict requirements on moisture and is difficult to industrialize; the steps are complicated, and a large amount of industrial wastewater and organic waste liquid are generated in the first step, the second step and the final cyano-group hydrolysis process, so the method is not environment-friendly; and the yield of each step is not high, and the total yield is lower than 30 percent. The route is difficult to industrialize, has more unstable factors and has higher risk of large-scale production.

2) CN102775358 is taken as a representative, amino is obtained by reduction after nitration, and fluorine atoms are introduced through BalzSchiemann reaction to obtain the Favipiravir. Both nitrification and diazotization in the process have certain safety risks, and the large-scale industrial production is difficult; and a large amount of nitrogen-containing wastewater is generated, so that the environment is not friendly; the reduction hydrogenation needs a pressure reaction and is generally avoided as much as possible; the diazotization process generates hydrogen fluoride which is extremely corrosive and highly toxic and cannot be avoided. This route is difficult to industrialize and is generally only at the laboratory stage.

The other existing synthesis processes of the Pilatavir have the industrial defects of multiple reaction steps, complex operation, unfriendly environment, poor safety or stability and low yield. And if the 3-hydroxypyrazine-2-formamide is used for realizing direct fluorination, the synthesis of the Favipiravir can be realized through one-step reaction, and no related literature report that the Favipiravir can be directly synthesized through fluorination is found at present.

Disclosure of Invention

The invention provides a new preparation method of Favipiravir and derivatives thereof. The method specifically comprises the following steps: the compound A is used as a raw material, through electrophilic fluorination, fluorine atoms are selectively introduced into 6-positions, and the synthesis method of the plalazvir or the derivatives thereof, namely the compound B, is a one-step reaction high-efficiency synthesis method. The reaction formula is as follows:

wherein R is₁is-CONH₂，-CONH₂，-CONR₃,-COOR₃One of cyano groups.

Wherein R is_2，R₃Is H, C₁-C₆Alkyl of (C)₁-C₆Cycloalkyl, aryl substituted alkyl.

The one-step reaction is as follows: and (3) placing the compound A and a fluorinating reagent in a reaction solvent, and carrying out electrophilic fluorination reaction at a certain temperature. The reaction temperature is 30 to 150 ℃, preferably 70 to 100 ℃.

According to the above-mentioned production method, the reaction solvent may be a strongly polar solvent such as N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile or the like, a halogenated hydrocarbon solvent such as methylene chloride, dichloroethane or the like, an alcohol solvent such as methanol, ethanol or the like, a mixed solvent of water and the above-mentioned solvent, water or the like. Tetrahydrofuran, acetonitrile, DMSO are preferred.

According to the above-mentioned production method, the amount of the reaction solvent for the electrophilic fluorination is 3 to 10 times, preferably 4 to 6 times the mass of the compound A.

The preparation method according to the above, wherein the electrophilic fluorination reaction uses a fluorinating reagent including but not limited to N-F reagent, specifically, comprising: the electrophilic fluorination reaction employs a fluorinating reagent selected from: n-fluorobenzenesulfonylimide (NFSI), fluorobis (benzenesulfonyl) methane, N-fluoro-N- [4- (trifluoromethyl) phenyl ] - (NFSA), 1-fluoro-4-hydroxy-1, 4-diazabicyclo [2.2.2] octane bistetrafluoroborate (Accnfluoror), 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2] octane bis (tetrafluoroborate) salt (Selectfluor), N-fluoropyridinium (tetrafluoroborate or triflate), 1-fluoro-2, 4, 6-trimethylpyridine trifluoromethanesulfonate, 1-fluoro-2, 6-dichloropyridine trifluoromethanesulfonate, N-fluorobis (trifluoromethylsulfonyl) phthalimide, cobalt trifluoride and the like. NFSI, Selectfluor, N-fluoropyridinium are preferred.

According to the above-mentioned preparation method, the amount of the fluorinating agent is 1 to 3 times the molar equivalent, preferably 1.5 to 2 times the molar equivalent of the compound A.

The invention has the beneficial effects that: the invention creatively provides a method for preparing the peravir through direct fluorination in an industrialized way through research, only needs one step, is simple to operate, is safe, has low cost, few three wastes and high total yield, and is environment-friendly.

Drawings

FIG. 1 is a liquid phase diagram of example 1;

FIG. 2 is a nuclear magnetic spectrum of the product obtained in example 1.

Detailed Description

Example 1

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of DMF, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 12h, and cooling to 0-5 ℃. Unreacted raw materials are filtered, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 11 g of light yellow solid (99.2% by HPLC, yield 70%), the nuclear magnetic spectrum of the light yellow solid is shown in figure 2, and the light yellow solid is determined to be Favipiravir as shown in a reaction formula (1) B:

example 2

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of DMF, then adding 63 g of NSFI, heating to 70-80 ℃, reacting for 12h, and cooling to 0-5 ℃. Unreacted raw materials are filtered, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, the solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 10.2 g of light yellow solid (HPLC 99.3%, yield 65%) which has the same nuclear magnetic spectrum as that of example 1 and is determined to be Favipiravir as shown in reaction formula (2) B:

example 3

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 24 hours, cooling to 0-5 ℃, and adding 100 ml of ethyl acetate. Unreacted raw materials are filtered off, most of the solvent is distilled off under reduced pressure, 100 ml of water and 50 ml of methanol are added, the mixture is stirred for 1 hour, filtered, the solid is collected, and dried under reduced pressure at 50-60 ℃ to obtain 10.67 g of light yellow solid (HPLC 99.4%, yield 68%), the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and the light yellow solid is determined to be Favipiravir as shown in reaction formula (3) B:

example 4

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 100 ml of dichloroethane and 10 ml of DMF, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 11.2 g of light yellow solid (HPLC 99.3%, yield 71.3%), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and determining the light yellow solid to be Favipiravir as shown in a reaction formula (4) B:

example 5

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 41.7 ml of water, then adding 35.4 g of Selectfluor, heating to 30-40 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 8.2 g of light yellow solid (HPLC 99.2%, yield 55.6%), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1, and determining that the light yellow solid is Favipiravir.

As shown in equation (4) B:

example 6

Adding 13.9 g of 3-hydroxypyrazine-2-formamide into 417 ml of water, then adding 94.2 g of fluorobis (benzenesulfonyl) methane, heating to 140 ℃ and 150 ℃, reacting for 20h, cooling to 0-5 ℃, adding 50 ml of ethyl acetate, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 9.2 g of light yellow solid (HPLC 99.6 percent, yield 58.6 percent), wherein the nuclear magnetic spectrum of the light yellow solid is the same as that of example 1 and is determined to be Favipiravir.

Example 7

Adding 13.9 g of 3-hydroxypyrazine-2-methyl formate into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 15h, cooling to 0-5 ℃, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 100 ml of water and 50 ml of methanol, stirring for 1 h, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 11.2 g of light yellow solid (HPLC 99.3%, yield 71.3%), wherein the structural formula is confirmed to be shown as a reaction formula (5) B through nuclear magnetic test:

example 8

Adding 13.9 g of 3-hydroxypyrazine-2-methyl cyanide into 100 ml of dichloroethane, then adding 60 g of Selectfluor, heating to 70-80 ℃, reacting for 10h, cooling to 0-5 ℃, filtering out unreacted raw materials, distilling off most of solvent under reduced pressure, adding 50 ml of methanol, refluxing for 1 h, cooling to 0-5 ℃, adding 100 ml of toluene, stirring for half an hour, filtering, collecting solid, and drying under reduced pressure at 50-60 ℃ to obtain 7.8 g of light yellow solid (HPLC 99.7%, yield 55.3%) which has a structural formula shown in a reaction formula (6) B:

the foregoing is merely a preferred embodiment of the invention and is not intended to limit the invention in any manner. It should be noted that, for those skilled in the art, without departing from the principle of the present invention, several improvements and modifications can be made, and these improvements and modifications should also be construed as the protection scope of the present invention.

Claims

1. A preparation method of Favipiravir and derivatives thereof is characterized by comprising the following steps: taking a compound A as a raw material, selectively introducing fluorine atoms at the 6-position of the compound A through electrophilic fluorination reaction, and obtaining a compound B through one-step reaction, wherein the reaction general formula is as follows:

wherein R is₁is-CONH₂One of cyano groups;

wherein R is₂Is H; the electrophilic fluorination reaction adopts the following fluorinating reagents: n-fluorobenzenesulfonylimide (NFSI), fluorobis (benzenesulfonyl) methane, 1-chloromethyl-4-fluoro-1, 4-diazabicyclo [2.2.2]Octane bis (tetrafluoroborate) salt (Selectfluor);

wherein, the reaction solvent of the electrophilic fluorination reaction is one or more of N, N-dimethylformamide, dichloroethane or water;

the reaction temperature of the electrophilic fluorination reaction is 30-150 ℃;

the amount of the fluorinating agent is 1-3 times of the molar equivalent of the compound A;

the mass of the reaction solvent for the electrophilic fluorination reaction is 3 to 10 times of that of the compound A.