Preparation method of favipiravir

A compound and solvent technology, applied in the field of preparation of favipiravir, can solve problems such as being unfavorable to industrialized production, unsuitable for industrialized production, expensive environment for reagents, etc., and achieves a reduction in labor and raw material costs, a short and novel route, and an economical and effective method. Effect

Active Publication Date: 2021-02-02
CHANGZHOU PHARMA FACTORY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route step is longer, and yield is lower; Among them, strong irritating phosphorus oxychloride is used, which is harmful to human health and unfavorable for industrialized production
[0009] In summary, the existing technologies generally face problems such as long reaction routes, low yields, expensive reagents and unfriendly environment, and are not suitable for industrial production.

Method used

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  • Preparation method of favipiravir
  • Preparation method of favipiravir
  • Preparation method of favipiravir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0032] The preparation of formula I compound (X is Br)

[0033]

[0034] Add 14.7g of 3-hydroxypyrazine-2-carboxamide (molecular weight 139.1, 106mmol) into a three-necked flask, add 35mL of DMF and 14.2g of pyridine, heat the oil bath to 80°C, and dropwise add 21.1g of bromine (molecular weight: 159.8, 132mmol) , control the temperature at 80-100°C, and drop it in 60 minutes. After dropping, keep warm for 3h. After the reaction is complete, add 8 mL of toluene, add dropwise 60 mL of water, drop it for 15 minutes, drop it down to room temperature, filter it with suction, wash the filter cake with 10 mL methanol, and dry the filter cake at 50 ° C for 6 hours to obtain 15.0 g of a brown solid, which was determined by HPLC Purity: 95.1%, yield: 62.1%.

[0035] 1 HNMR (DMSO-d6): 13.60 (1H, s), 8.72 (1H, s), 8.56 (1H, s), 8.48 (1H, s)

Embodiment 2

[0037] The preparation of formula I compound (X is NO 2 )

[0038]

[0039] Add 2.0g of 3-hydroxypyrazine-2-carboxamide (molecular weight 139.1, 14.4mmol) into 20ml of concentrated sulfuric acid, cool to 0-5°C, and add KNO in batches 3 2.91g (molecular weight: 101.1, 28.8mol), after the addition, the temperature was raised to 40°C for 4h. The reaction solution was added to 100ml of ice water, precipitated, filtered, the filter cake was washed twice with 20ml of purified water, and the filter cake was air-dried at 50°C for 6h to obtain 1.93g of an off-white solid, the purity of which was determined by HPCL to be 96.5%. : 72.9%.

[0040] 1 HNMR (DMSO-d6): 8.98 (1H, s), 8.34 (1H, s), 8.07 (1H, s)

Embodiment 3

[0042] Preparation of formula II compound (X is Br, and fluorinating reagent is tetramethylammonium fluoride)

[0043]

[0044] In a 100mL three-neck flask, dissolve 0.61g of acetic acid (molecular weight 60.1, 10.2mmol) in 20mL of DMF, protect with nitrogen, cool down to 0-5°C, add 2.28g of DCC (molecular weight 206.3, 11.1mmol), raise to room temperature, stir for 1h, add 2.10 g the compound of formula I prepared in Example 1 (molecular weight 218, 9.17 mmol), stirred for 12 h, then added 1.72 g of anhydrous tetramethylammonium fluoride (molecular weight 93.1, 18.5 mmol), stirred at room temperature for 24 h, added 20 mL of 2N hydroxide Sodium solution, stir until the reaction is complete by TLC, extract impurities with 10mL ethyl acetate, separate layers, adjust the water layer to pH=3-4 with 2N HCl, extract with 20mL*3 ethyl acetate, combine the organic layers, and wash with saturated aqueous sodium bicarbonate solution , washed with water, washed with saturated sodium ...

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Abstract

The invention relates to the technical field of biological medicines, in particular to a preparation method of favipiravir, which comprises the following steps of: stirring 3-hydroxy pyrazine-2-formamide and a fluorinating reagent in a solvent, and carrying out one-step reaction to obtain favipiravir. The preparation method of favipiravir provided by the invention is short and novel in route, mildin reaction condition, economical and effective, higher in yield than the existing preparation method, and suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a preparation method of Favipiravir. Background technique [0002] Favipiravir, the chemical name is 6-fluoro-3-hydroxy-2-pyrazinecarboxamide, and the CAS registration number is 259793-96-9. It is a RNA-dependent RNA polymerase developed by Toyama Chemical Pharmaceutical Company in Japan (RdRp), a new broad-spectrum antiviral drug, 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] Patent WO200010569A discloses a preparation method of Favipiravir, and its synthetic route is as follows: [0004] [0005] The route uses methyl 6-bromo-3-methoxy-2-pyrazinecarboxylate as a raw materi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 马贯军张云然周付潮夏超刘超孙光祥唐井元
Owner CHANGZHOU PHARMA FACTORY
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