Synthesis of novel KDR kinase inhibitors through catalytic reductive cyclization of o-nitrobenzylcarbonyl compounds.
An efficient synthesis of o-nitrobenzylcarbonyl compounds is demonstrated through the Swern-type oxidation of readily accessible phenethanol analogues. Reductive cyclization of o-nitrobenzylcarbonyl 3 using catalytic Raney nickel gives 1H-indol-2-yl-1H-quinoline 2 in 95% yield. Hydrolysis of 2 affords the KDR kinase inhibitor 1 in quantitative yield. The examination of the reductive cyclization reaction and optimization of conditions is described.
Wong
Audrey
A
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, USA. audrey_wong@merck.com
Kuethe
Jeffrey T
JT
Davies
Ian W
IW
Hughes
David L
DL
D002384:Catalysis; D003500:Cyclization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D009578:Nitrobenzenes / Q000737:chemistry*; D009596:Nitrophenols / Q000138:chemical synthesis* / Q000494:pharmacology; D010084:Oxidation-Reduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D009578:Nitrobenzenes; D009596:Nitrophenols; D040301:Vascular Endothelial Growth Factor Receptor-2