瑞博西尼的微波辅助合成新工艺

A novel microwave-assisted synthetic process of ribociclib

目的寻找抗肿瘤新药瑞博西尼的高效合成新工艺。方法首先采用一锅反应制备带有瑞博西尼C-6和N-7两个取代基团的2-环戊氨基-N,N-二甲基乙酰胺;然后,在微波辅助加热条件下,与起始物4-氯-2-甲硫基-嘧啶-5-醛经过第二个一锅反应构建吡咯并嘧啶骨架中间体;该中间体先后经过氧化、强碱条件下的芳香亲核取代反应和最后脱保护得到目标化合物瑞博西尼。结果该工艺虽然包括7步反应,实际只有5步需要简单后处理或纯化。微波加热提高了反应速率,反应时间明显缩短。合成总收率约15%,终产物HPLC纯度大于99.5%。结论此微波辅助新工艺试剂易得、操作简单、条件温和,可用于瑞博西尼的放量研究,亦适于2,6,7-取代吡咯并嘧啶类似物小分子库的快速建立。

Ribociclib is a selective CDK4/6 inhibitor for the treatment of breast cancer.To facilitate the rapid synthesis of ribociclib and 2,6,7-substituted pyrrolo[2,3-d]pyrimidine analogs,we developed a microwave-assisted 7-step synthetic process in this study.Moreover,two one-pot reactions significantly simplified actual procedures.The total yield was about 15%for this process and ribociclib was afforded with purity above 99%by this method.Simple procedure,usual reagents and gentle conditions made this process suitable for preparation of ribociclib in large-scale as well as rapid library establishment of pyrrolopyrimidine analogs.