妥洛特罗的合成工艺改进

Improved synthesis of tulobuterol

目的合成β2受体激动剂妥洛特罗。方法以邻氯苯乙酮为原料,经羰基α位的溴代、还原、胺化,得到目标产物妥洛特罗。结果与结论目标化合物的总收率为26.0%,其结构经质谱、核磁共振氢谱确证。改进后的合成工艺简化了操作、缩短了反应时间、降低了合成成本,适合工业化生产。

Tulobuterol, a β 2 adrenergic receptor agonist, developed by Abbot of Japan, was launched in 1981 for the treatment of bronchial asthma, and in 1998 for the treatment of COPD. Now, an improved synthetic route was designed on the basis of several references and the synthetic process was also investigated and op- timized. From the key intermediate 2-chloroacetophenone, tulobuterol was synthesized via a-bromination, re- duction and amination with an overall yield of 26. 0%. In the α-bromination process, water was used as a green solvent. In the reduction process, potassium borohydride was used instead of sodium borohydride and the molar ratio of reducing agent was also reduced. The improved process has several advantages comparing to the formers reported, such as low production cost, simple operations and short reaction time. The structure of tulobuterol was confn＇med by 1H-NMR and MS spectra, the intermediates and target compound were de- tected by ESI-MS.