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Preparation method of high purity favipiravir impurity

The technology of a compound, hydroxypyrazine, is applied in the field of preparation of impurity 6-chloro-3-hydroxypyrazine-2-carboxamide, which achieves the effect of simple operation, short steps and reduced risk

Active Publication Date: 2017-04-26
SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0003] At present, there are few research reports on the quality impurities of favipiravir at home and abroad. Through the study of the synthetic literature CN200880109041, CN102307865, CN1418220, and CN1313768 of favipiravir, no matter which route is used, the final product favipiravir may be The process impurity compound of formula (1) containing the 6-position chlorine atom not replaced by fluorine atom, so the research on the impurity of the compound of formula (1) is very necessary

Method used

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  • Preparation method of high purity favipiravir impurity
  • Preparation method of high purity favipiravir impurity
  • Preparation method of high purity favipiravir impurity

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 36.8 g of the compound 6-nitro-3-hydroxypyrazine-2-carboxamide of formula (2) into a 250 ml reaction bottle, add 75 ml of phosphorus oxychloride, add 50 ml of pyridine dropwise, and react at room temperature for 1 hour; 80°C, react for 2h; heat up to reflux, react for 5h, TLC monitors the completion of the raw material reaction, concentrate under reduced pressure until no more liquid flows out, add 150g of ice water and 200ml of toluene to the residual solution, stir at room temperature for 0.5h, and separate the toluene layer , the toluene layer was washed with 150ml of water, 150ml of saturated brine, and evaporated to dryness to obtain 31.5g of yellow powder formula (3) compound 3.6-dichloropyrazine 2-carbonitrile, with a yield of 90% and a purity of 98.5% by HPLC;

Embodiment 2

[0026] Add 31.5g of the compound of formula (3) into a 500ml reaction flask, add 125ml of dichloromethane, stir and dissolve at room temperature, add 5.8g of tetrabutylammonium bromide, add 60ml of 28% sodium hydroxide, stir at room temperature for 3h, and monitor the raw materials by TLC After the reaction was complete, the organic layer was separated and washed with 100 ml of water and 100 ml of saturated brine, and evaporated to dryness to obtain 23.8 g of yellow oil compound 6-chloro-3-hydroxypyrazine-2-carbonitrile of formula (4). Yield 85%, HPLC purity 98.9%;

Embodiment 3

[0028] Take 23.8g of the compound of formula (4) and add it to a 100ml reaction flask, add 40ml of concentrated sulfuric acid, heat up to 50°C, react for 2h, cool down to 5°C, stir for 0.5h, a yellow solid precipitates, filter with suction, and wash the filter cake with 20ml of water , dried to obtain 19.1g of formula (1) 6-chloro 3-hydroxypyrazine-2-carboxamide crude product, yield 70%, HPLC purity 98.5%;

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Abstract

The invention relates to a preparation method of a favipiravir impurity 6-chloro-3-hydroxy-2-pyrazinecarboxamide shown as formula (1). By preparing the favipiravir impurity, and providing a referencesubstance for qualitative and quantitative analysis of favipiravir impurity, the invention improves the quality standard of favipiravir, and provides important guidance for safe medication of favipiravir.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a preparation method of impurity 6-chloro-3-hydroxypyrazine-2-carboxamide in the preparation process of favipiravir. Background technique [0002] Favipiravir (T-705) is a new RNA-dependent RNA polymerase (RdRp) inhibitor broad-spectrum antiviral drug developed by Toyama Chemical in Japan. Its trade name is "Avigan". It was approved by the Japanese government in March 2014. Approved for listing. Its indication is the treatment of type A influenza (including avian influenza and H1N1 influenza infection), mainly for new or re-emerging influenza virus infection. On February 24, 2015, the French National Institute of Health and Medical Research announced that the preliminary results of a clinical trial in Guinea showed that Favipiravir had a positive effect on reducing the mortality rate of early Ebola virus infection. [0003] At present, there are few research r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 邓玉晓刘葵葵孙晋瑞封静李丹
Owner SHANDONG ACADEMY OF PHARMACEUTICAL SCIENCES
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