化学-酶法合成(-)-加兰他敏的研究

Study on chem-enzymatic synthesis of(-)-galanthamine

目的利用化学合成与酶法还原相结合的方法制备(-)-加兰他敏。方法以6-溴异香草醛和酪胺为起始原料,通过“一锅法”还原胺化、铁氰化钾为氧化剂的氧化偶合、钯催化的甲酸钠脱溴制得加兰他敏前体酮那维定,再采用异源表达的来源于罂粟(Papaver bracteatum)的短链羰基还原酶SAR,高效立体选择性地还原制备(-)-加兰他敏。结果与结论目标产物结构经质谱、核磁共振谱、比旋光度等确证,与标准品一致,总收率为16.1%(以6-溴异香草醛计),纯度为99.9%(HPLC)。该化学-酶法工艺操作简单,反应条件温和,避免使用昂贵的L-selectride试剂以及繁琐的拆分工艺,具有潜在的工业化生产价值。

(-)-Galanthamine is a tetracyclic amaryllidaceae alkaloid that has been used in the treatment of early stages of Alzheimer′s disease.Using 2-bromoisovanillin and tyramine as the starting materials,(-)-galanthamine was prepared by successive steps of reductive amination in“one-pot”operation,oxidative coupling with potassium ferricyanide,debromination with sodium formate,steroselective reduction by carbonyl reductase from Papaver bracteatum.The(-)-galanthamine prepared was identified to be consistent with the standard by MS,NMR and specific rotation.The total yield of(-)-galanthamine was up to 16.1%(calculated by 2-bromoisovanillin)with the purity of 99.9%(HPLC).This synthesis method avoids the use of harsh and expensive L-selectride reagents and is friendly to the environment,which has potential industrial application value.