沙丁胺醇-D2的合成

以水杨醛和溴乙酰氯为原料,经Friedel-Crafts酰基化制备得到5-溴乙酰基-2-羟基苯甲醛(Ⅱ),再与叔丁胺胺化和盐酸水解,过柱纯化后得到中间体5-{(1,1-二甲基乙基)氨基]乙酰基}-2-羟基苯甲醛盐酸盐(Ⅲ),化合物Ⅲ再用硼氘化钠还原制得目标产物沙丁胺醇-D2(Ⅳb)。合成路线优势在于最后一步反应引入氘代同位素,保证氘代物丰度的不稀释,且操作简单,工艺流程短,副产物少,收率可达70%以上。产品经MS和1HNMR表征和确认,氘标记同位素丰度>97.1%。

Synthesis of Albuterol-D2

Friedel-Crafts acylation of salicylaldehyde with bromoacetyl chloride affords 5-(bromoacetyl)-2-hydroxybenzaldehyde(2), which was amination with tert-butylamine and acid hydrolysis, after purification column the intermediate 5-(1,1-Dimethylethyl) amino]acetyl]-2- hydroxybenzaldehyde Hydrochloride(3) obtained. The target compound albuterol-D2(4b) was obtained by reduction with boron sodium deuteride. Synthetic routes advantage lies in the last step reaction to introduce deuterium isotope, deuterium labeled isotope abundance was not diluted, and had the advantages of simple operation, short process flow, less side product, The yield was more than 70%. The product was characterized by MS and 1H NMR, the deuterium enrichment was more than 97.1% .