中枢镇痛药琥珀酸去氢他喷他多酯的合成  

Synthesis of Central Analgesic Succinate Dehydro-tapentadol Ester

作　　者：陶俊钰 徐奎 

机构地区：[1]合肥市食品药品检验中心,安徽合肥230001 [2]安徽省逸欣铭医药科技有限公司,安徽合肥230051

出　　处：《中国医药工业杂志》2016年第7期838-840,847,共4页Chinese Journal of Pharmaceuticals

摘　　要：1-二甲胺基-2-甲基-3-戊酮和间甲氧基苯基溴化镁经格氏反应制得1-二甲胺基-3-(3-甲氧基苯基)-2-甲基-3-戊醇盐酸盐(2),2用氯化亚砜氯代,经三溴化硼脱甲基得3-[3-氯-1-(二甲胺基)-2-甲基戊基-3-基]苯酚盐酸盐(4),4在4-叔丁基环己醇中用4-叔丁基环己醇钠顺式脱氯得去氢他喷他多(5),5与琥珀酸酐酯化得(Z)-3-[1-(二甲胺基)-2-甲基-2-戊烯-3-基)苯基丁二酸单酯(6),再经甲酯化、硼氢化钾还原、成盐得(Z)-3-[1-(二甲胺基)-2-甲基-2-戊烯-3-基]-苯基-4-羟丁酸酯琥珀酸盐(1),总收率31.8%。目标化合物为正在Ⅱ期临床试验的候选中枢性镇痛新药,命名为琥珀酸去氢他喷他多酯。1-Dimethylamino-2-methyl-3-pentanone reacted with m-methoxyphenyl magnesium bromide by Grignard reaction to give 1-dimethylamino-3-（3-methoxyphenyl）-2-methyl-3-pentanol hydrochloride （2）, 2 was chlorinated with thionyl chloride, and then demethylated by boron tribromide to give 3-[3-chloro-1-（dimethylamino）- 2-methylpentan-3-yl]phenol hydrochloride （4）, 4 reacted with 4-tert-butyl-cyclohexanol sodium in 4-tert-butyl-cyclohexanol to give dehydro-tapentadol （5） by cis-antichloration, 5 was esterificated with succinic anhydride to give （Z） - 3-[ 1-（dimethylamino）-2-methyl-2-penten-3-yl] phenyl succinic acid monoester （6）, followed by esterification, reduction and salinization to give （Z） -3- [ 1- （dimethylamino） -2-methyl-2-penten-3-yl] phenyl-4-hydroxybutyrate succinate （1） with an overall yield of 31.8 %. Compound 1, named as succinate dehydro-tapentadol ester, is a new candidate central analgesic drug in phase II clinical trial.

关 键 词：琥珀酸去氢他喷他多酯 中枢性镇痛药 合成 

分 类 号：R971.1[医药卫生—药品]