化学
双环分子
部分
立体化学
腈
氰化
吲唑
吡啶
药物化学
四氟硼酸盐
有机化学
催化作用
离子液体
作者
Bachir Latli,Matt Hrapchak,Lalith P. Samankumara,Daniel R. Fandrick,Scott Pennino,Heewon Lee,Jinhua J. Song
摘要
( R )‐4‐(( R )‐1‐((6‐(1‐[ tert‐ butyl]‐1 H ‐pyrazol‐4‐yl)‐2‐methyl‐2 H ‐pyrazolo[3,4‐d]pyridin‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one ( BI 894416 , 1 ) and ( R )‐4‐(( R )‐1‐((6‐(1‐[ tert ‐butyl]‐1 H ‐pyrazol‐4‐yl)‐2,3‐dimethyl‐2 H ‐indazol‐4‐yl)oxy)ethyl)pyrrolidin‐2‐one ( BI 1342561 , 2 ) are two new potent and selective spleen tyrosine kinase inhibitors developed to treat severe asthma. Both compounds have similar structures and they differ only in the bicyclic moiety 2‐methyl‐2 H ‐pyrazolo[4,3‐c]pyridine in 1 versus 2,3‐dimethyl‐2 H ‐indazole in 2 . In the carbon 14 synthesis, 1‐(1‐[ tert ‐butyl]‐1 H ‐pyrazol‐4‐yl)ethan‐1‐one‐1‐ 14 C ( [ 14 C]‐8 ) was prepared from the cyanation of 4‐bromopyrazole using zinc [ 14 C]cyanide followed by methyl lithium addition on the nitrile group. The enolate of [ 14 C]‐8 was then used to access these two bicyclic moieties via pyrano‐pyrazoles [ 14 C]‐11 and [ 14 C]‐12 , which were further transformed in few more steps to [ 14 C]‐(1) and [ 14 C]‐2 . Both inhibitors contain a tert‐ butyl group. Introducing tert‐ butyl‐ d 9 will not only provide internal standards for bioanalytical studies, but it is also expected to slow down the metabolism of these two compounds. Most of the metabolites of compound 1 , for example, are the result of tert ‐butyl oxidation, like alcohol 3 , acid 4 , and the further N ‐demethylation of 4 to 5 . The detailed preparation of these deuterium‐labeled metabolites is also described.
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