posted on 2020-03-16, 16:03authored byHelen Benson, Karen Bones, Gwydion Churchill, Gair Ford, Lianne Frodsham, Sophie Janbon, Fiona Millington, Lyn Powell, Steven A. Raw, Julie Reid, Andrew Stark, Alan Steven
Early chemical development studies
into the best way of assembling
AZD9742, an antibacterial drug candidate, have involved swapping the
order of two reductive aminations. The orthogonally functionalized
aminopiperidine partner for these couplings is now enantioselectively
synthesized using ruthenium-catalyzed asymmetric hydrogenation. The
challenge of controlling defluorination through an appropriate catalyst
choice has hitherto prevented this revised sequence from reaching
its full potential. However, it is still shown to allow access to
the active pharmaceutical ingredient in a stereochemically pure form
and has been demonstrated on a multikilogram scale. The reductive
aminations in both the original and revised sequences provided different
scale-up challenges, and the solutions implemented are described.