CN111675663A

CN111675663A - Preparation method of Favipiravir

Info

Publication number: CN111675663A
Application number: CN202010533414.6A
Authority: CN
Inventors: 姚红; 罗瑾; 张广勤; 郑杰; 葛皓月
Original assignee: Hangzhou Huangsen Biological Technology Co ltd
Current assignee: Hangzhou Huangsen Biological Technology Co ltd
Priority date: 2020-06-11
Filing date: 2020-06-11
Publication date: 2020-09-18

Abstract

The invention provides a preparation method of Favipiravir, which comprises the following specific steps: one or two of 6-fluoro-3-hydroxy-2-cyanopyrazine and 6-fluoro-3-hydroxy-2-cyanopyrazine organic amine salt are used as raw materials to prepare the Lavipiravir with high yield under the alkaline condition in an anhydrous organic solvent. Compared with the existing hydrolysis process of concentrated sulfuric acid and the existing hydrolysis process of hydrogen peroxide, the preparation method avoids a large amount of acidic wastewater generated in the hydrolysis process of concentrated sulfuric acid, avoids the explosion danger possibly caused by using hydrogen peroxide, and avoids the hydrolysis and oxidative decomposition phenomena of products in the hydrolysis process of concentrated sulfuric acid and the hydrolysis process of hydrogen peroxide.

Description

Preparation method of Favipiravir

Technical Field

The invention relates to a novel preparation method of Favipiravir.

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. Phase III clinical studies on influenza A have been completed in the United states at present, Favipiravir has a good therapeutic effect on patients infected with Ebola virus, and phase II clinical studies on Ebola virus resistance in the United states are ongoing. The action mechanism of the Favipiravir is mainly that after entering the body, the Favipiravir generates a nucleoside analogue triphosphate form under the action of a series of cellular phosphokinases, so that the replication and transcription of the virus are interfered. 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.

In patent CN102307865A, 6-fluoro-3-hydroxy-2-cyanopyrazine is prepared by reacting hydrogen peroxide in aqueous solution of NaOH to obtain pyrrosia faba, the reaction is carried out in aqueous solution of alkali to easily hydrolyze amido bond group of pyrrosia faba into acid, meanwhile, hydrogen peroxide has strong oxidation effect on the product to deteriorate the product, thereby greatly reducing yield of the reaction, and in addition, the use of double oxide has certain problem of safety operation, and peroxide is easy to cause explosion. The route is as follows:

in patent CN106478528A, 6-fluoro-3-hydroxy-2-cyanopyrazine is in concentrated H₂SO₄The process for preparing the Favipiravir by adding hot water for hydrolysis, a large amount of acidic waste water generated in the concentrated sulfuric acid hydrolysis process, and the reaction easily enables the amido bond group of the product Favipiravir to be continuously hydrolyzed into acid in an acidic aqueous solution, and concentrated H is concentrated₂SO₄Has stronger oxidation effect on a product liquid, and the product is deteriorated, so that the yield of the reaction is greatly reduced, and the route is as follows:

in conclusion, the existing synthesis method has a plurality of technical problems, such as low yield, unsafe operation, large amount of waste water and environmental friendliness.

Disclosure of Invention

The method can prepare the Favipiravir with high yield by enabling 6-fluoro-3-hydroxy-2-cyanopyrazine to be in an anhydrous organic solvent under an alkaline condition, and in the anhydrous alkaline organic solvent, the alkali provides hydroxy to promote the 6-fluoro-3-hydroxy-2-cyanopyrazine to react to obtain the Favipiravir with high yield.

The data of the embodiment shows that when the 6-fluoro-3-hydroxy-2-cyanopyrazine or the organic amine salt thereof is used for preparing the Favipiravir, the problem of product hydrolysis can be well avoided due to an anhydrous system, and the problem of oxidation and impurity change does not exist due to the absence of an oxidation reagent, so that the yield can reach more than 95%, the HPLC purity can reach more than 99.9%, and the synthetic route is as follows:

in certain embodiments, 6-fluoro-3-hydroxy-2-cyanopyrazine is prepared by the following process:

according to the preparation method, the organic solvent can be one or more of tert-butyl alcohol, methanol, ethanol and isopropanol, tetrahydrofuran, and preferably tert-butyl alcohol, ethanol and isopropanol.

According to the above-mentioned production method, the potassium hydroxide may be an inorganic base such as sodium hydroxide or lithium hydroxide, and potassium hydroxide is preferred.

According to the above-mentioned production method, the molar amount of the base is 1 to 6 times, preferably 3 to 4 times the molar amount of the raw material.

According to the above-mentioned production method, the mass of the organic solvent is 4 to 12 times, preferably 5 to 8 times that of the raw material.

According to the above-mentioned preparation method, the reaction temperature is 30 to 80 ℃, preferably 50 to 70 ℃.

The invention has the beneficial effects that: compared with the existing concentrated sulfuric acid hydrolysis process and hydrogen peroxide hydrolysis process, the preparation method avoids a large amount of acidic wastewater generated in the concentrated sulfuric acid hydrolysis process, avoids the explosion danger possibly caused by using hydrogen peroxide, and avoids the hydrolysis and oxidative decomposition phenomena of products in the concentrated sulfuric acid hydrolysis process and the hydrogen peroxide hydrolysis process.

Drawings

FIG. 1 is a liquid phase diagram of the product obtained in example 1.

FIG. 2 is a nuclear magnetic diagram of the product obtained in example 1 (the nuclear magnetic diagrams of the products obtained in examples 2 to 4 are the same as in example 1).

Detailed Description

Example 1

30 g of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt was added to 100 g of anhydrous t-butanol, followed by 22.4 g of potassium hydroxide. Heating to 60 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butanol, adding 150 ml of water and 100 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing once by 100 ml of saturated saline, drying by anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 14.13 g of a product, wherein a nuclear magnetic diagram is shown in figure 2, and the product can be determined to be Favipiravir. The molar yield is 96 percent, and the purity is 99.9 percent.

Example 2

27.8 g of 6-fluoro-3-hydroxy-2-cyanopyrazine were added to 150 g of anhydrous isopropanol, followed by 32 g of sodium hydroxide. Heating to 60 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butyl alcohol, adding 150 ml of water and 150 ml of ethyl acetate, adjusting the pH of a water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing 150 ml of saturated salt solution once, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain 29.85 g of a product, wherein the nuclear magnetic result is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 95 percent, and the purity is 99.9 percent.

Example 3

30 g of 6-fluoro-3-hydroxy-2-cyanopyrazine dicyclohexylamine salt was added to 360 g of anhydrous tert-butanol, followed by 180 g of potassium hydroxide. The temperature is increased to 30 ℃, the reaction is carried out for 8h, and the TLC detects that the raw materials are completely reacted. Distilling off tert-butanol, adding 150 ml of water and 100 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing once by using 100 ml of saturated saline, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain a product, wherein the nuclear magnetic result of the product is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 98 percent, and the purity is 99.9 percent.

Example 4

27.8 g of 6-fluoro-3-hydroxy-2-cyanopyrazine were added to 11.12 g of anhydrous isopropanol, followed by 2.78 g of sodium hydroxide. Heating to 80 ℃, reacting for 8h, and detecting the complete reaction of the raw materials by TLC. Distilling off tert-butanol, adding 150 ml of water and 150 ml of ethyl acetate, adjusting the pH of the water phase to 5-6 by using hydrochloric acid, stirring, standing for layering, separating an ethyl acetate layer, washing 150 ml of saturated salt solution once, drying by using anhydrous magnesium sulfate, and concentrating under reduced pressure to obtain a product, wherein the nuclear magnetic result of the product is the same as that of example 1, and the product can be determined to be Favipiravir; the molar yield is 96 percent, and the purity is 99.9 percent.

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 is characterized by comprising the following steps: the method comprises the following steps: one or two of 6-fluoro-3-hydroxy-2-cyanopyrazine and 6-fluoro-3-hydroxy-2-cyanopyrazine organic amine salt are used as raw materials, and the Favipiravir is prepared in an alkaline anhydrous organic solvent at the temperature of 30-80 ℃.

2. The method of claim 1, wherein: the organic solvent is one or more of tert-butyl alcohol, methanol, ethanol and isopropanol, and tetrahydrofuran.

3. The method of claim 2, wherein: the organic solvent is tert-butanol, ethanol and isopropanol.

4. The method of claim 1, wherein: wherein the alkaline anhydrous organic solvent is obtained by adding inorganic base into organic solvent, and the inorganic base comprises potassium hydroxide, sodium hydroxide and lithium hydroxide.

5. The method of claim 1, wherein: the molar amount of the base is 1 to 6 times the molar amount of the raw material.

6. The method of claim 1, wherein: the mass of the organic solvent is 4-12 times of the mass of the raw materials.

7. The method of claim 1, wherein: the reaction temperature is preferably 50 to 70 ℃.