阿拉莫林中间体的合成及表征

Synthesis and Characterization of Anamorelin Intermediate

以3-哌啶甲酸和乙醇为原料酯化生成3-哌啶甲酸乙酯,在碱性条件下与二碳酸二叔丁酯加成,经氢氧化锂水合物水解得到1-叔丁氧羰基-3-苄基-3-甲酸哌啶,通过R-(+)-α-甲基苄胺的手性拆分得目标产物,利用核磁共振氢谱和质谱对其结构进行了表征。并对催化剂及合成工艺进行了优化,结果表明,碳酸钠催化效率最高;1-叔丁氧羰基-3-苄基-3-甲酸乙酯哌啶、氢氧化锂水合物和乙醇的投料质量比为1∶4∶4时,目标产物收率最大。该合成工艺简单、高效,适合放大生产。

The present work introduced one synthetic method for the medicine intermediate of anamorelin.3-piperidine ethyl formate was firstly synthesized with 3-pipecolinic acid and ethanol as raw materials throughesterification reaction. Then the addition reaction the 3-piperidine ethyl formate with di-tert-butyl pyrocarbonatewas conducted under the alkaline condition. The 1-tert-butoxycarbonyl-3-benzyl-3-formic acid piperidine wasobtained through hydrolysis with lithium hydroxide hydrate. Finally,the target product was purified via aresolution by employing R-（＋）-α-methylbenzylamine as resolving agent. The compounds were characterized by1 H nuclear magnetic resonance spectroscopy and mass spectroscopy. The process optimization results found thatthe sodium carbonate demonstrated excellent catalytic performance for the reaction. The yield was highest with1∶4∶4 mole ration of 1-tert-butyloxycarbonyl-3-benzyl-3-ethyl formate peridine/lithium hydroxide hydrate/ethanol and with sodium carbonate as alkali. The present synthetic method is suitable in industry applicationwith its simple operation and high yield.