Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation |
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Authors: | Chung John Y L Cai Chaoxian McWilliams J Christopher Reamer Robert A Dormer Peter G Cvetovich Raymond J |
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Affiliation: | Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07965, USA. john_chung@merck.com |
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Abstract: | [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. |
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