ABSTRACT
An efficient and practical synthetic process for an α-carboline-based Aurora B kinase inhibitor was achieved using an integrated Pd-catalyzed cross-coupling strategy. The process features a mild and efficient method for construction of the α-carboline core by employing a Pd-catalyzed sequence of Buchwald-Hartwig amination and intramolecular direct C-H arylation at the ortho position of an unsubstituted aniline moiety, which is a key functionality for further derivatization with a Suzuki coupling via Sandmeyer iodination. The process has eliminated expensive starting materials and column chromatography purifications and enabled considerable enhancement of the total yield from 11% to 48%.
Subject(s)
Aniline Compounds/chemistry , Aurora Kinase B/antagonists & inhibitors , Aurora Kinase B/chemistry , Carbolines/chemistry , Palladium/chemistry , Amination , Catalysis , Hydrogen Bonding , Molecular StructureABSTRACT
Efforts toward developing orally bioavailable factor VIIa inhibitors starting from parenteral lead compound 1 are described. SAR resulted in improved physicochemical properties, leading to enhanced oral absorption in rat.
