琥珀酸普芦卡必利关键中间体4-氨基-5-氯-2,3-二氢苯并呋喃-7-羧酸的合成工艺改进

Improved Synthetic Process of 4-Amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic Acid,a Key Intermediate of Prucalopride Succinate

本研究对琥珀酸普芦卡必利关键中间体4-氨基-5-氯-2,3-二氢苯并呋喃-7-羧酸(1)的合成工艺进行了优化。以4-乙酰胺基-5-氯-2-羟基苯甲酸甲酯(2)为起始原料,在碳酸钾存在下与碳酸亚乙酯经O-烷基化反应制得4-乙酰氨基-5-氯-2-(2-羟基乙氧基)苯甲酸甲酯(3),3在三氟化硼乙醚催化下发生分子内环化制得4-乙酰氨基-5-氯-2,3-二氢苯并呋喃-7-羧酸甲酯(4),最后4水解得目标产品1,纯度99.8%,收率76.0%(以2计)。改进后的工艺稳定、操作简便,适合工业化生产。

An improved synthetic process of 4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylic acid(1),a key intermediate for the preparation of prucalopride succinate,was developed.Methyl 4-acetamido-5-chloro-2-(2-hydroxyethoxy)benzoate(3)was prepared by O-alkylation of the starting material methyl 4-acetamido-5-chloro-2-hydroxybenzoate(2)with ethylene carbonate in the presence of potassium carbonate.Then,compound 3 was transformed into methyl 4-acetamido-5-chloro-2,3-dihydrobenzofuran-7-carboxylate(4)by the intramolecular cyclization on exposure to boron trifluoride etherate.Finally,the target compound 1 was obtained from 4 via hydrolysis reaction with an overall yield of 76.0%(based on 2)and a purity of 99.8%.The optimized process was robust with simple operation,which was suitable for industrial production.