Preparation method of favipiravir and derivatives thereof

A technology of derivatives and compounds, which is applied in the field of new preparation of Favipiravir and its derivatives, can solve the problems of cumbersome operation, unfriendly environment, and many reaction steps, and achieve simple operation, environmental friendliness, and high total yield Effect

Active Publication Date: 2020-09-25
HANGZHOU HUANGSEN BIOLOGICAL TECH CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] At present, other favipiravir synthesis processes all have many reaction steps, cumbersome operation, unfriendly environment, poor safety or stability, and low industrialization shortcomings
However, if the direct fluorination of 3-hydroxypyrazine-2-carboxamide is realized, the synthesis of favipiravir can be realized in one step reaction. At present, there is no relevant literature report on the direct fluorination of favipiravir.

Method used

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  • Preparation method of favipiravir and derivatives thereof
  • Preparation method of favipiravir and derivatives thereof
  • Preparation method of favipiravir and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] Add 13.9 g of 3-hydroxypyrazine-2-carboxamide to 100 ml of DMF, then add 60 g of Selectfluor, raise the temperature to 70-80°C, react for 12 hours, and cool down to 0-5°C. Filter out the unreacted raw material, distill off most of the solvent under reduced pressure, add 100 ml of water, 50 ml of methanol, stir for 1 hour, filter, collect the solid, obtain after drying under reduced pressure at 50-60 ° C, 11 g of light yellow solid (HPLC 99.2%, yield 70%), the nuclear magnetic spectrum of this light yellow solid is as figure 2 Shown, determine that it is Favipiravir, as shown in reaction formula (1) B:

[0023]

Embodiment 2

[0025] Add 13.9 g of 3-hydroxypyrazine-2-carboxamide to 100 ml of DMF, then add 63 g of NSFI, raise the temperature to 70-80°C, react for 12 hours, and cool down to 0-5°C. The unreacted raw material was filtered off, most of the solvent was distilled off under reduced pressure, 100 ml of water and 50 ml of methanol were added, stirred for 1 hour, filtered, and the solid was collected, dried under reduced pressure at 50-60°C to obtain 10.2 g of light yellow solid (HPLC99. 3%, yield 65%), the nuclear magnetic spectrum of this light yellow solid is the same as embodiment 1, confirms that it is Favipiravir, as shown in reaction formula (2) B:

[0026]

Embodiment 3

[0028] Add 13.9 g of 3-hydroxypyrazine-2-carboxamide to 100 ml of dichloroethane, then add 60 g of Selectfluor, heat up to 70-80°C, react for 24 hours, cool down to 0-5°C, add 100 ml of ethyl acetate ester. The unreacted raw materials were filtered off, most of the solvent was distilled off under reduced pressure, 100 ml of water and 50 ml of methanol were added, stirred for 1 hour, filtered, and the solid was collected, dried under reduced pressure at 50-60°C to obtain 10.67 g of light yellow solid (HPLC 99.4 %, yield 68%), the nuclear magnetic spectrum of this light yellow solid is the same as embodiment 1, confirms that it is Favipiravir, as shown in reaction formula (3) B:

[0029]

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PUM

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Abstract

The invention provides a novel preparation method of a favipiravir derivative. Specifically, a fluorinating reagent is directly used for an electrophilic fluorination reaction, fluorine atoms are selectively introduced to the 6-position, and favipiravir or the derivatives thereof are efficiently synthesized through one-step reaction. Compared with the existing synthesis method, the synthesis method adopting one-step reaction has the advantages of strong creativity, novelty, simplicity in operation, safety, low cost, less three wastes, environmental friendliness and high total yield, so that the synthesis method has extremely strong industrial advantages and significance.

Description

technical field [0001] The invention relates to a new preparation method of Favipiravir and its derivatives. Background technique [0002] Favipiravir (favipiravir, T-705, trade name Avigan, 1), the chemical name is 6-fluoro-3-hydroxy-2-pyrazine carboxamide, is a target RNA-dependent drug developed by Japan Toyama Chemical Pharmaceutical Co., Ltd. A new broad-spectrum antiviral drug based on RNA polymerase (RdRp), which was approved for marketing in Japan in March 2014, for the treatment of new and recurrent influenza. Studies have found that favipiravir has good inhibitory activity against various RNA viruses in vitro or in vivo, and it is expected to be developed and applied to the treatment of various viral infections, and has a good market prospect. [0003] At present, the representative synthetic methods of favipiravir are: [0004] 1) Represented by the patent CN102307865, the current mainstream production route is: first prepare the corresponding chlorinated compou...

Claims

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Application Information

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IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 姚红罗瑾张广勤葛皓月王佳王楠楠陈璐岚
Owner HANGZHOU HUANGSEN BIOLOGICAL TECH CO LTD
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