依匹哌唑中间体7-羟基喹啉-(1H)-2-酮的合成

摘要

7-Hydroxyquinolin-(1H)-2-one,a key Intermediate for Brexpiprazole was synthesized via three reaction steps including chloration,ammonolysis,intramolecular Friedel-Craft cyclization using cinnamic acid and m-aminophenol as the raw material.The optimized conditions of the Friedel-Craft cyclization determined by orthogonal experiment and range analysis are reaction temperature 130 ℃,reaction time 6 h,n(aluminum chloride) ∶ n(compound 4) =3 ∶ 1 and dosage of solvent 750 mL.The yield of product was up to 87％ and the purity was 99％ by the analysis of HPLC.The reported method has the advantages of commercialized and cheap raw material,convenient procedures,mild reaction condition and no purification by silica gel column chromatography.It is suitable for scale-up production in industry.%以肉桂酸、间氨基苯酚为原料,经过氯化、氨解、分子内傅克环合三步反应得到依匹哌唑中间体7-羟基喹啉-(1H)-2-酮.并通过正交实验研究了关键的傅克环合工艺,确定了最佳合成条件为:反应温度130℃、反应时间6h、n(三氯化铝)∶n(化合物4)为3∶1、溶剂氯苯用量750 mL,收率87％,LC纯度达99％.该法原料价廉易得,工艺操作简便,反应温和可控,且无需柱层析,有利于工业化生产.