Synthesis of three isotopically labeled versions and a metabolite of Aurora A kinase inhibitor

Sodium ring‐¹⁴C]‐4‐9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido5,4‐d]2]benzazepin‐2‐yl]amino]‐benzoate (1A, MLN8054), an Aurora A kinase inhibitor, was synthesized from ¹⁴C]‐cyanamide in two steps in an overall radiochemical yield of 7%. The intermediate, ¹⁴C]‐4‐guanidinobenzoic acid, was prepared by coupling ¹⁴C]‐cyanamide with 4‐aminobenzoic acid. Sodium carboxyl‐¹⁴C]‐4‐9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido5,4‐d]2]benzazepin‐2‐yl]amino]‐benzoate (1B) was synthesized from carboxyl‐¹⁴C]‐4‐guanidinobenzoic acid in one step in a radiochemical yield of 35%. D₄,¹⁵N]‐4‐9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido5,4‐d]2]benzazepin‐2‐yl]amino]‐benzoic acid (1C) was synthesized from ¹⁵N₂]‐cyanamide and D₄]‐4‐aminobenzoic acid in two steps in an overall yield of 37%. The major metabolite, β‐acyl glucuronide of 4‐9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido5,4‐d]2]benzazepin‐2‐yl]amino]‐benzoic acid (14), was synthesized from D‐glucuronic acid in three steps in an overall yield of 1%. The key intermediate for synthesis of glucuronide was prepared by HATU catalyzed coupling of 4‐9‐chloro‐7‐(2,6‐difluorophenyl)‐5H‐pyrimido5,4‐d]2]benzazepin‐2‐yl]amino]‐benzoic acid with allyl glucuronate. Copyright © 2009 John Wiley & Sons, Ltd.