An efficient and convergent synthesis of the potent and selective H3 antagonist ABT-239

Abstract: An efficient and convergent process for the preparation of a potent and selective H3 receptor antagonist, ABT-239, 1A was accomplished with an overall yield of 64%. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methylpyrrolidine ( 9 ) with 4′-hydroxy-3′-iodo-biphenyl-4-carbonitrile ( 3 ). Additionally, the key amine component 2-(R)-methylpyrrolidine ( 7 ) was effectively synthesized from the readily available Boc-l-prolinol with a simple catalytical hydrogenolysis as the key step. This column chromatography-free process is highlighted by several simple work-up and purification procedures and is amendable to the large-scale preparation of 1A . [Copyright &y& Elsevier]