微波辅助合成氘标记班布特罗-D_9盐酸盐

Microwave Assisted Synthesis of Deuterium Labelled Bambuterol-D_9 Hydrochloride

以3',5'-二(二甲氨基甲酰氧基)-α-溴苯乙酮(Ⅰ)为初始原料,经还原反应得1-[双-(3',5'-N,N-二甲氨基甲酰氧基)苯基]-2-溴乙醇(Ⅱ),Ⅱ再与叔丁胺-D_9在微波辅助下进行胺化反应,最后合成了氘标记1-[双-(3',5'-N,N-二甲氨基甲酰氧基)苯基]-2-N-叔丁基氨基乙醇-D_9盐酸盐(班布特罗-D_9盐酸盐)。对还原反应中硼氢化钠用量,胺化反应的物料配比、反应温度和反应时间进行了考察。结果表明:n(Na BH4)∶n(Ⅰ)=2.0∶1.0,乙醇为溶剂时,Ⅱ的收率最高,达87.1%;胺化产物可以起到缚酸剂的作用,与常规加热方法相比,微波辅助的胺化反应速率显著提高,反应时间由16~24 h缩短到30 min。在n(Ⅱ)∶n(叔丁胺-D_9)=1.0∶1.2,反应温度100℃,反应时间为30 min时,叔丁胺-D_9利用率可达74.4%(常规加热方法叔丁胺-D_9利用率不超过40%),班布特罗-D_9盐酸盐的收率为89.3%。产物经1HNMR、MS和UPLC进行了结构表征和性能测试,产物高效液相色谱纯度超过99.0%,氘丰度大于98.5 atom%D,班布特罗-D_9盐酸盐可用作食品安全检测的同位素内标试剂。

A reduction reaction of 5-（bromoacetyl）-1,3-phenylene bis（dimethylcarbamate）（Ⅰ） led to 1-[bis（3＇,5＇-N,N-dimethylcarbamoyloxy） phenyl]-2 bromoethanol（Ⅱ）.Intermediate was obtained by an amination reaction with tert-butylamine-D_9 under microwave irradiation（MWI） Subsequently,treatment of the intermediate with hydrochloric acid afforded deuterium labelled bambuterol-D_9 hydrochloride.At the same time,the factors affecting the reduction reaction,such as dosage of sodium borohydride,mole ratio of reactants,reaction temperature and time,were investigated.It was found that when mole ratio of sodium borohydride to compound I was 2.0∶1.0 and ethanol was used as solvent,the yield of compound Ⅱ reached 87.1%.The product from amination acts as acid-binding agent.Microwave irradiation obviously enhanced the speed of amination compared with conventional heating,and the reaction time decreased from 16 ~ 24 h to 30 min.Furthermore,when the molar ratio of compound Ⅱ to tert-butyamine D_9 was 1.0∶1.2 and the reaction was carried out at 100 ℃ for 30 min,the yield of the targeted product reached 89.3%,and the utilization rate of tert-butyamine D_9 （74.4%）was higher than that by conventional heating（less than 40%）.The product was confirmed by ~1HNMR,MS and UPLC,with a purity of more than 99.0% and deuterium enrichment over 98.5 atom% D,It could be used as internal standard in the field of food safety.