抗发作性睡病新药Pitolisant及其盐的合成进展

Recent Advances in the Synthesis of Pitolisant and its Salt as a New Anti-narcolepsy Drug

Pitolisant为由Bioprojet公司开发、被欧洲药品评审局批准用于治疗发作性睡病一种组胺H_3受体选择性拮抗剂/反向激动药。本文对迄今报道的pitolisant的5种合成路线及其2种盐的合成路线进行了综述和评价。揭示了pitolisant的合成均为汇聚式,包括两组重要中间体的合成:①3-(4-氯苯基)丙基甲磺酸酯与1-哌啶丙醇;②N-(3-溴丙基)哌啶与对3-(4-氯苯基)丙醇。

Pitolisant,discovered by Bioprojet,was approved by EMA for treating narcolepsy as the first selective histamine H 3 receptor antagonist and inverse agonist drug.In this paper,five synthesis routes of pitolisant and two routes of its salt,which have been reported so far,are reviewed.It is found that convergent strategies are often applied in the synthesis of pitolisant,which includes the synthesis of two groups of key intermediates:①3-(4-chlorophenyl) propyl methanesulfonate and 1-piperidinepropanol;②N-(3-bromopropyl)piperidine and 3-(4-chlorophenyl) propanol.