摘要
以N-苄基甘氨酸为起始原料,经酯化、缩合、氨解、还原、氨基保护、脱苄基、缩合、脱Boc保护基、亲核取代制得有关物质5-氯-2-[(7R)-7-甲基-4-[5-甲基-2-(2H-1,2,3-三唑-2-基)苯甲酰基]-1,4-二氮杂环庚烷-1-基]-1,3-苯并噁唑(1a)和5-氯-2-[(7S)-7-甲基-4-[5-甲基-2-(2H-1,2,3-三唑-2-基)苯甲酰基]-1,4-二氮杂环庚烷-1-基]-1,3-苯并噁唑(1b);(S)-1-苄基-5-甲基-1,4-二氮杂环庚烷经缩合、还原、亲核取代制得有关物质5-氯-2-[(5S)-5-甲基-4-[5-甲基-2-(2H-1,2,3-三唑-2-基)苯甲酰基]-1,4-二氮杂环庚烷-1-基]-1,3-苯并噁唑(1c)。有关异构体1a、1b和1c的结构均经MS和~1HNMR确证。其中化合物1b是未见文献报道的新化合物。
To perform the quality control of suvorexant, three related isomers were prepared. The isomerization impuritis 5-chloro-2-[（7R）-7-methyl-4-[5-methyl-2-（2H-1,2,3-triazol-2-yl）benzoyl]-1,4-diazacycloheptane-1-yl]-1,3-benzoxazole （1a） and 5-chloro-2-[（7S）-7-methyl-4-[5-methyl-2-（2H-1,2,3-triazol-2-yl）benzoyl]-1,4-
diazacycloheptane-1-yl] -1,3-benzoxazole （1b） were prepared via esterification, condensation, ammonolysis, reduction, amino protection, debenzylation, condensation, deprotection of Boc-group and nucleophilic substitution with N-benzylglycine as the starting material; The enantiomer of suvorexant, 5-chloro-2-[（5S）-5-methyl-4-[5-methyl-2-（2H-1,2,3-triazol-2-yl）benzoyl]-1,4-diazacycloheptane-1-yl]-1,3-benzoxazole （1c） was synthesized from （S）-1-benzyl-5-methyl-1,4-diazacycloheptane via condensation, reduction and nucleophilic substitution. The structures of these three isomers of suvorexant were confirmed by MS and 1H NMR. And compound 1b is a new compound which has not yet been reported in literature.
作者
季渊博
李春正
彭程
金勋奇
李伯男
JI Yuanbo LI Chunzheng PENG Cheng JIN Xunqi LI Bonan(Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai 201203 School of Engineering, China pharmaceutical University, Nanjing 211198 School of Chemistry and Molecular Science, Wuhan University, Wuhan 430072)
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
2017年第6期825-832,共8页
Chinese Journal of Pharmaceuticals
基金
上海市浦江人才计划(16PJ1432800)
关键词
苏沃雷生
抗失眠药
有关物质
食欲肽受体拮抗药
异构体
合成工艺
suvorexant
anti-insomnia drug
related substance
isomers
synthetic process
orexin receptor antagonist
