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

Abstract

The invention relates to a method for synthesizing a favipiravir intermediate 6-bromo-3-hydroxypyrazine-2-formamide (II), which comprises the following steps of: oxidizing bromide ions into high-activity bromine by taking 3-hydroxypyrazine-2-formamide (I) as a raw material, hydrobromic acid as a bromine source and hydrogen peroxide as an oxidizing agent, and carrying out bromination reaction. In the reaction, the utilization rate of bromine atoms is higher, and when the generated high-activity elemental bromine participates in the reaction, and then the generated by-product hydrogen bromide can be quickly oxidized to generate elemental bromine to participate in the bromination reaction. Therefore, the method avoids the use of bromine, and is environment-friendly, low in production cost, relatively high in purity and yield of the obtained product, and easy for industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing a drug intermediate, in particular to a method for synthesizing 6-bromo-3-hydroxypyrazine-2-carboxamide (II). Background technique [0002] Favipiravir is used for the treatment of novel and recurrent influenza, Wang Huan et al. (Chinese Journal of Pharmaceutical Industry, 2014, 45 (11): 1009-1012.) discloses the preparation method of Favipiravir (III), This method is also a conventional method for those skilled in the art to prepare Favipiravir (III), that is, 6-bromo-3-hydroxypyrazine-2-carboxamide (II) is chlorinated, fluorinated, selectively hydrolyzed, and salt-formed Purify and hydrolyze to obtain Favipiravir (III), the reaction formula is as follows: [0003] [0004] 6-bromo-3-hydroxypyrazine-2-carboxamide (II) is a key intermediate in the synthesis of favipiravir (III), and has broad application prospects. The inventor finds after a large numb...

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Problems solved by technology

[0006] Because 6-fluoro-3,5-dihydroxypyrazine-2-carboxamide (V) is close to the properties of Favipiravir (III), it is difficult to separate by methods such as recrystallization, column chromatography, and distillation, so the impurity ( Ⅴ) It is difficult to remove the finished product of Favipiravir in the finished product of Favipiravir, which causes the finished product of Favipiravir to fail to meet the enterprise standard (purity ≥ 98%). In order to make the finished product of Favipiravir finally meet the standard of the enterprise, it is necessary to ensure 6-bromo-3-hydroxypyrazine-2-carboxamide (II) external standard content ≥ 98%

[0007] Chinese patent CN107635976A discloses that 3-hydroxypyrazine-2-carboxamide (I) reacts with bromine to prepare 6-bromo-3-hydroxypyrazine-2-carboxamide (II), and the resulting product yield is only 64.9%. And the reaction temperature is required to be high (50-100°C). In the process of dropping bromine, if the dropping rate is slightly improperly controlled, there will be a sudden temperature rise, which is easy to flush the material, and the operation requirements are high. The dropping and reaction process temperature High potential safety hazard

In addition, the bromine used in the above reaction is a volatile highly corrosive and highly toxic liquid, and its storage requires special requirements, which increases storage costs, and the utilization rate of bromine atoms in the reaction is only half, which will produce equivalent or more hydrogen bromide, bromine-containing wastewater pollutes the environment and has high treatment costs

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