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对羟基苯甲硫酰胺与2-氯乙酰乙酸乙酯经Hantzsch环合和Duff反应制得2-[(3-甲酰基-4-羟基)苯基]-4-甲基-5-噻唑甲酸乙酯(4),4与盐酸羟胺肟化及氯化亚砜脱水生成2-[(3-氰基-4-羟基)苯基]-4-甲基-5-噻唑甲酸乙酯(5),5经酚羟基醚化及碱水解制得非布司他,总收率为50%。本研究还合成了制备4的主要工艺杂质,经结构确证为2-[(3,5-二甲酰基-4-羟基)苯基]-4-甲基-5-噻唑甲酸乙酯。
P-Hydroxybenzylsulfamide and ethyl 2-chloroacetoacetate were subjected to Hantzsch cyclization and Duff reaction to obtain 2 - [(3-formyl-4-hydroxy) phenyl] -4-methyl-5-thiazolecarboxylic acid B Oxidation of the ester (4), 4 with hydroxylamine hydrochloride and thionyl chloride gave ethyl 2 - [(3-cyano-4-hydroxy) phenyl] 5 phenolic hydroxyl etherification and alkaline hydrolysis to febuxostat, the total yield was 50%. In this study, we also synthesized the major technical impurities of Preparation 4 and confirmed the structure as ethyl 2 - [(3,5-diformyl-4-hydroxy) phenyl] -4-methyl-5-thiazolecarboxylate.