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Preparation method of favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide

A technology of hydroxypyrazine and favipiravir, which is applied in the direction of organic chemistry, can solve the problems of high risk and severe reaction conditions, and achieve the effects of reducing risk, improving product purity and yield, and shortening reaction time

Active Publication Date: 2021-05-28
SHANDONG ZOUPING DAZHAN NEW MATERIALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006] Aiming at the technical problems of severe reaction conditions and high risk in the preparation of intermediate 6-bromo-3-hydroxypyrazine-2-carboxamide in the prior art, the present invention provides a favipiravir intermediate 6-bromo-3- The preparation method of hydroxypyrazine-2-carboxamide, to solve the above problems

Method used

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  • Preparation method of favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide
  • Preparation method of favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide
  • Preparation method of favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide

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Experimental program
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Effect test

Embodiment 1

[0030] Preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide

[0031] (1) Add 560mL of acetonitrile into a 1000mL three-necked flask, add 80g of sodium (3-oxo-3,4-dihydropyrazine-2-carbonyl)amide under stirring, and protect the reaction solution under nitrogen; control the reaction solution at 10-20°C, add 13g of acetic acid, the reaction solution pH=6 at this time;

[0032] (2) 86g of liquid bromine was added dropwise, and the temperature of the reaction solution was controlled to be 5 to 25°C during the dropwise addition;

[0033] (3) After the dropwise addition is completed, heat-preserve and react. After 1 hour, HPLC detects that the remaining intermediate II is less than 2%, stop the reaction, filter the reaction solution, beat the filter cake with water until the filtrate pH=6~7, and obtain a wet product;

[0034] (4) The wet product was dried in an oven at 65°C to obtain 87.3 g of 6-bromo-3-hydroxypyrazine-2-carboxamide, yield: 80.6%.

[0035] The 6-bromo-3-hydroxypy...

Embodiment 2

[0039] Preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide

[0040] (1) Add 560mL of acetonitrile into a 1000mL three-necked flask, add 80g of sodium (3-oxo-3,4-dihydropyrazine-2-carbonyl)amide under stirring, and protect the reaction solution under nitrogen; control the reaction solution at 10-20°C, add Phosphoric acid 9g, at this time the pH of the reaction solution=6;

[0041] (2) 86g of liquid bromine was added dropwise, and the temperature of the reaction solution was controlled to be 5 to 25°C during the dropwise addition;

[0042] (3) After the dropwise addition is completed, heat-preserve and react. After 1 hour, HPLC detects that the remaining intermediate II is less than 2%, stop the reaction, filter the reaction solution, beat the filter cake with water until the filtrate pH=6~7, and obtain a wet product;

[0043] (4) The wet product was dried in an oven at 65°C to obtain 86.0 g of 6-bromo-3-hydroxypyrazine-2-carboxamide, yield: 79.4%.

[0044] The 6-bromo-3-hy...

Embodiment 3

[0049] Preparation of 6-bromo-3-hydroxypyrazine-2-carboxamide

[0050] (1) Add 56L of acetonitrile into a 100L reaction kettle, add 8000g of sodium (3-oxo-3,4-dihydropyrazine-2-carbonyl)amide under stirring, and protect it under nitrogen; control the reaction liquid at 10-20°C, Then slowly add 1.3kg of acetic acid, and the reaction solution pH=5~6 at this time;

[0051] (2) Slowly add 8600 g of liquid bromine, and control the temperature of the reaction solution during the dropping process to be 5 to 25° C.;

[0052] (3) After the dropwise addition is completed, heat preservation reaction, HPLC detection after 2h, intermediate II remains less than 2%, stop the reaction, filter the reaction solution, and beat the filter cake with water until the filtrate pH=6~7 to obtain a wet product;

[0053] (4) The wet product was dried in an oven at 65°C to obtain 8911 g of 6-bromo-3-hydroxypyrazine-2-carboxamide, yield: 82.3%.

[0054] The 6-bromo-3-hydroxypyrazine-2-carboxamide prepare...

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Abstract

The invention relates to a preparation method of a favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide, and belongs to the technical field of organic synthesis. The 6-bromo-3-hydroxypyrazine-2-formamide is prepared by taking 3-hydroxypyrazine-2-amide as a raw material, controlling the pH value of a reaction solution and taking liquid bromine as a brominating agent. By adjusting the pH value of the reaction system to weak acidity, the bromination reaction can be ensured to be carried out under mild conditions, the high-temperature bromination method adopted in the existing synthesis method is avoided, the side reaction is reduced, and the purity and yield of the prepared product are obviously improved.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, in particular to a method for preparing a favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-carboxamide. Background technique [0002] Favipiravir, English name Favipiravir, chemical name: 6-fluoro-3-hydroxypyrazine-2-carboxamide, is mainly used to treat new or re-popular influenza in adults. [0003] In the prior art, the following route is used to synthesize Favipiravir: [0004] [0005] In the existing literature reports on the synthesis of intermediate Ⅰ (6-bromo-3-hydroxypyrazine-2-carboxamide) from intermediate II (3-hydroxypyrazine-2-carboxamide), liquid bromine is mostly used as raw material for bromine Made by substitution reaction. Chinese patent CN107635976A discloses a method for synthesizing intermediate I, which uses intermediate II and liquid bromine to react in DMF at 80-100°C to prepare intermediate I, and the yield of the obtained product is only 64.9%. Becau...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D241/24
CPCC07D241/24
Inventor 巩长胜杨波林泉生
Owner SHANDONG ZOUPING DAZHAN NEW MATERIALS
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