The Study On The Synthesis Process Improvement Of Favipiravir

Objective To investigate and design an effective synthetic route of the favipiravir with lower material cost,more secure,more stable and higher yield.Method The commercial available 3-hydroxy-2-carboxamide were selected as the starting material.We got 6-bromo-3-hydroxypyrazine-2-carboxamide reacting with liquid bromine in the presence of acetic acid and pyridine.Then 3,6-dichloropyrazine-2-carbonitrile was synthesized through the chlorination reaction and the amide dehydration reaction.And then,it worked with potassium fluoride for 3,6-difluoropyrazine-2-carbonitrile under the phase-transfer catalysis by halogen-exchange reaction.The reaction solution worked with DCHA for organic salt.This compound was further hydrolyzed and oxidized to give the target product.In this paper,the bromination reaction and fluoridation reaction of the synthetic route were optimized.Effects of reaction time,reaction temperature,molar ration,catalyst dosage and solvent selection were investigated.We analyzed the structures of the intermediates,the target compound and impurity by means of 1H-NMR,13C-NMR,MS.The impurity which produced from the reaction was synthesized.Results The target compound was prepared by the above synthetic route successfully,and the overall yield was 27.3%,while the overall yields of the original synthetic route was 0.44%and 22%?In this paper,the synthetic route had only five steps,the workers only needed one week to complete this task.The yield of the 6-bromo-3-hydroxypyrazine-2-carboxamide was 67.4%,and the purity detected by HPLC was 99.6%.So,the bromide could be applied directly to the next reaction.In the original synthetic route,3,6-difluoropyrazine-2-carbonitrile needed to be separated by silica gel column chromatography,and the yield was 63.5%.In this paper,the yield of the organic salt was 68.1%,and the purity detected by HPLC was 99.5%,and it could be applied directly to the next reaction.Conclusion The reaction condition are mild except the fluoridation reaction,in which all reagent should be dried completely.The synthetic procedure is simple,high-yield and suitable for scale preparation.