苏沃雷生关键手性高哌嗪中间体的合成及工艺优化

Synthesis and process optimization of key intermediate of suvorexant-chiral homopiperazine

目的优化苏沃雷生关键手性高哌嗪中间体的合成工艺。方法以(S)-3-羟基丁酸甲酯为起始原料,与4-甲氧基苄胺发生取代反应后经红铝还原,再与邻硝基苯磺酰氮丙啶发生开环加成反应,之后发生分子内Mitsunobu环合,最终用氯甲酸氯乙酯脱去对甲氧基苄基保护基,生成关键中间体(R)-7-甲基-1-[(2-硝基苯基)磺酰基]-1,4-二氮杂环庚烷盐酸盐。结果与结论目标产物结构经ESI-MS和1H-NMR谱确证,改进后的工艺路线原料价格低廉,纯化方法简便,产品质量稳定可控,适合工业化生产,并已用于中试放大生产。

Suvorexant is a dual orexin receptor antagonist for treating insomnia.The synthetic process of the key intermediate of suvorexant,chiral homopiperazine,was improved in this work.Using methyl(S)-3-hydroxybutyrate(1)as the starting material,the key intermediate(R)-7-methyl-1-[(4-nitrophenyl)sulfonyl]-1,4-diazepane hydrochloride(6)was obtained through substitution,reduction,ring cleavage,Mitsunobu cyclization and deprotection.The structure of target compound was confirmed by ESI-MS and'H-NMR.This improved process has advantages of inexpensive raw materials,simple purifying operation and stable and controllable product quality.