Process development of an efficient and scalable synthesis of ABT-239, a potent and selective H3 antagonist

ORGN 163

Yi-Yin Ku, yiyin.ku@abbott.com1, Yu-Ming Pu1, Tim Grieme, timothy.grieme@abbott.com1, Padam Sharma1, Ashok V. Bhatia1, and Marlon Cowart2. (1) D-R450, Process Chemistry, Abbott Laboratories, 1401 Sheridan Rd, North Chicago, IL 60064, (2) Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, R4MN, AP9A, 100 Abbott Park Road, Abbott Park, IL 60064-6123
An efficient and scaleable process for the preparation of a potent and selective H3 receptor antagonist, ABT-239, was accomplished. The key step in the synthesis is a Sonogashira coupling/cyclization reaction of 1-but-3-ynyl-2-(R)-methyl-pyrrolidine with 4'-hydroxy-3'-iodo-biphenyl-4-carbonitrile. Additionally, the key amine component 2-(R)-methylpyrrolidine 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 ABT-239.