Efficient Synthesis of a Trisubstituted 1,6-Naphthyridone from Acetonedicarboxylate and Regioselective Suzuki Arylation

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 conco...

Full description

Saved in:
Bibliographic Details
Published in:Journal of organic chemistry 2005-12, Vol.70 (25), p.10342-10347
Main Authors: Chung, John Y. L, Cai, Chaoxian, McWilliams, J. Christopher, Reamer, Robert A, Dormer, Peter G, Cvetovich, Raymond J
Format: Article
Language:English
Subjects:
Acetone - chemistry
Chemistry
Dicarboxylic Acids - chemistry
Exact sciences and technology
Heterocyclic compounds
Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings
Ketones - chemical synthesis
Naphthyridines - chemical synthesis
Organic chemistry
Preparations and properties
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo0514927