Synthesis of 5-substituted-1H-indol-2-yl-1H-quinolin-2-ones: a novel class of KDR kinase inhibitors.
[reaction: see text] A number of approaches for the synthesis of the 1H-indol-2-yl-1H-quinolin-2-one ring system found in the potent and selective KDR kinase inhibitor 1 are described. The preparation and reaction of trimethylsilylnitrobenzene 26 with 2-methoxy-3-quinolinecarboxaldehyde 28 afforded alcohol 30, which was the key intermediate for the preparation of the target compounds. Conversion of alcohol 30 to either nitroketone 36 or nitrostyrene 45 set the stage for reductive cyclization and the formation of indole 25. The quinolin-2-one functionality was unmasked in the last step to provide compound 1 in 56-60% overall yield from readily available starting materials.
Kuethe
Jeffrey T
JT
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA. jeffrey_kuethe@merck.com
Wong
Audrey
A
Qu
Chuanxing
C
Smitrovich
Jacqueline
J
Davies
Ian W
IW
Hughes
David L
DL
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015363:Quinolones / Q000138:chemical synthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D015363:Quinolones; D040301:Vascular Endothelial Growth Factor Receptor-2