Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation.
[reaction: see text] An efficient five-step synthesis of 1,6-naphthyridone 3b, a p38 mitogen-activated protein (MAP) kinase inhibitor intermediate, in 32% overall yield starting from acetonedicarboxylate (ADC) is described. The synthesis began with a selective monoamidation of ADC dimethyl ester enolate 9. A novel concomitant enamine formation and an imide cyclization afforded the nitrogen differentially protected enamide imide 12. Treatment of 12 with KO(t)Bu and 3-ethoxyacrylate produced lactam 15 quantitatively, which was converted to tetrachloronaphthyridone 19 via a one-pot p-methoxybenzyl (PMB) deprotection and bischlorination. A highly regioselective Pd(OAc)2/IMes-catalyzed Suzuki coupling completed the synthesis.
Chung
John Y L
JY
Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07965, USA. john_chung@merck.com
Cai
Chaoxian
C
McWilliams
J Christopher
JC
Reamer
Robert A
RA
Dormer
Peter G
PG
Cvetovich
Raymond J
RJ
D000096:Acetone / Q000737:chemistry; D003998:Dicarboxylic Acids / Q000737:chemistry; D007659:Ketones / Q000138:chemical synthesis; D009287:Naphthyridines / Q000138:chemical synthesis*
D003998:Dicarboxylic Acids; D007659:Ketones; D009287:Naphthyridines; D000096:Acetone