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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。
The reduction reaction of 1- [bis- (3 ’, 5’-N, N, N-dimethylthiocarbonyloxy) - dimethylcarbamyloxy) phenyl] -2-bromoethanol (Ⅱ), followed by amination with tert-butylamine-D_9 under microwave irradiation. Finally, deuterium labeled 1- [bis- 5’-N, N-dimethylcarbamyloxy) phenyl] -2-Nt-butylaminoethanol-D_9 hydrochloride (bambuterol-D_9 hydrochloride). The amount of sodium borohydride in the reduction reaction, the material ratio of the amination reaction, the reaction temperature and the reaction time were investigated. The results showed that the yield of Ⅱ was the highest (87.1%) when n (Na BH4): n (Ⅰ) = 2.0:1.0 and ethanol was the solvent. The aminated product could act as acid-binding agent. Compared with the conventional heating method The microwave-assisted amination reaction rate was significantly increased, the reaction time was shortened from 16 ~ 24 h to 30 min. Under the conditions of n (Ⅱ): n (tert-butylamine-D_9) = 1.0:1.2, reaction temperature 100 ℃ and reaction time 30 min, the utilization of tert-butylamine-D_9 can reach 74.4% (conventional heating method does not exceed 40% %), The yield of bambuterol-D_9 hydrochloride was 89.3%. The product was characterized by 1HNMR, MS and UPLC. The purity of the product was over 99.0% and the abundance of deuterium was over 98.5 atom% D. Bambuterol-D_9 hydrochloride was used as food safety test Isotope internal standard reagents.