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Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile

A difluoropyrazine and purification method technology, applied in the direction of organic chemistry, etc., can solve the problems of difficult recovery, large amount of organic solvent, cumbersome operation process, etc.

Active Publication Date: 2020-10-20
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Journal Document 1 published the purification of 3,6-difluoropyrazine-2-carbonitrile by silica gel chromatography using PE / EA (50:1–10:1) as the eluent; Journal Document 2 published the use of PE / EA EA (10:1) is used as the eluent, and 3,6-difluoropyrazine-2-carbonitrile is purified by silica gel chromatography. The above purification method uses a mixed solvent as the eluent, and the amount of organic solvent is large and difficult to recover. The process is cumbersome and not suitable for industrial production

Method used

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  • Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile
  • Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile
  • Crystallization and purification method of favipiravir key intermediate 3, 6-difluoropyrazine-2-carbonitrile

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Take 20.0g of crude 3,6-difluoropyrazine-2-carbonitrile and add it to 60.0g of ethyl tert-butyl ether, stir, add 10.0g of column chromatography silica gel, heat to 50°C, stir for 0.5h to decolorize, pump After filtration, the obtained clear filtrate was cooled to -20~-15°C within 0.5~1h, stirred at -20~-15°C for 0.5h and then filtered, and the obtained solid was washed twice with ethyl tert-butyl ether, each time 5.0g. The obtained solid was vacuum-dried to dryness at 20° C. to obtain 17.9 g of 3,6-difluoropyrazine-2-carbonitrile. 99.52% purity.

Embodiment 2

[0032] Add 20.0g of crude 3,6-difluoropyrazine-2-carbonitrile to 300.0g of ethyl tert-butyl ether, stir, add 100.0g of silica gel for column chromatography, heat to 65°C, stir for 3h to decolorize, and filter with suction , the obtained clear filtrate was cooled to 15-20°C within 4-5h, stirred at 15-20°C for 6h and then filtered, and the obtained solid was washed twice with ethyl tert-butyl ether, 50g each time. The obtained solid was vacuum-dried to dryness at 30° C. to obtain 13.5 g of 3,6-difluoropyrazine-2-carbonitrile. 99.56% pure.

Embodiment 3

[0034] Take 20.0g of crude 3,6-difluoropyrazine-2-carbonitrile and add it to 80.0g of ethyl tert-butyl ether, stir, add 20.0g of silica gel for column chromatography, heat to 55°C, stir for 0.5h to decolorize, pump Filter, cool the obtained clear filtrate to -10~-5°C within 1~2h, stir at -10~-5°C for 1h and then filter, the obtained solid is washed twice with ethyl tert-butyl ether, each time 10.0 g. The obtained solid was vacuum-dried to dryness at 25°C to obtain 17.3 g of 3,6-difluoropyrazine-2-carbonitrile. 99.55% pure.

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Abstract

The invention relates to a crystallization purification method, and relates to a crystallization purification method of a favipiravir key intermediate 3,6-difluoropyrazine-2-carbonitrile, and belongsto the field of medicinal chemistry. The method comprises the following steps: mixing a crude product of 3, 6-difluoropyrazine-2-carbonitrile with ethyl tert-butyl ether, stirring the materials, adding column chromatography silica gel; heating to 50-65 DEG C, performing stirring decolorization for a period of time, performing solid-liquid separation, cooling the resulting clarified solution, stirring and crystallizing for a period of time; then, performing solid-liquid separation, and obtaining the product 3, 6-difluoropyrazine-2-carbonitrile; wherein the mass ratio of the 3, 6-difluoropyrazine-2-carbonitrile crude product to the ethyl tert-butyl ether is 1: 3-1: 15, wherein the mass ratio of the 3, 6-difluoropyrazine-2-carbonitrile crude product to the column chromatography silica gel is1: 1. 0.5 to 1: 5, column chromatography silica gel is used as a decolorizing agent; ethyl tert-butyl ether is used as a crystallization solvent, crystallization conditions are controlled, tar in the3, 6-difluoropyrazine-2-carbonitrile can be effectively removed, the content of impurities 6-chloro-3-fluoropyrazine-2-carbonitrile is reduced, the crystallinity of the 3, 6-difluoropyrazine-2-carbonitrile is enhanced, the purity of the obtained product is high, operation is simple, and industrial production is facilitated.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for crystallization and purification of the key intermediate of favipiravir, 3,6-difluoropyrazine-2-carbonitrile. Background technique [0002] Favipiravir (T-705) is a broad-spectrum antiviral drug developed by Toyama Chemical in Japan. It was approved for marketing by the Japanese government in March 2014. It is indicated for Type A influenza (including avian influenza and H1N1 influenza infection) , mainly for new or re-emerging influenza virus infections. The chemical name of Favipiravir is 6-fluoro-3-hydroxypyrazine-2-carboxamide. The structural formula is as shown in formula (1): [0003] [0004] The synthetic process route of favipiravir published in the patent document WO2010087117 has industrial prospects. This route uses 2-aminomalonamide as the starting material, and undergoes cyclization, bromination, dichloro substitution and dehydration, difluoro sub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24Y02A50/30
Inventor 邓玉晓孙晋瑞刘文涛段崇刚张宁赵思太张宗磊马新成任业明冯光玲樊志萍
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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