Efficient synthesis of a trisubstituted 1,6-naphthyridone from acetonedicarboxylate and regioselective Suzuki arylation

被引：14

作者：

Chung, JYL ^{[1
]}

Cai, CX ^{[1
]}

McWilliams, JC ^{[1
]}

Reamer, RA ^{[1
]}

Dormer, PG ^{[1
]}

Cvetovich, RJ ^{[1
]}

机构：

[1] Merck Res Labs, Proc Res, Rahway, NJ 07965 USA

来源：

JOURNAL OF ORGANIC CHEMISTRY | 2005年 / 70卷 / 25期

关键词：

D O I：

10.1021/jo0514927

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

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 (KOBu)-Bu-t 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.

引用

页码：10342 / 10347

页数：6

共 33 条

[21]

PRATT JK, 2004, Patent No. 167123

[22] 5-(2-aminoethyl)dibenzo[c,h][1,6]naphthyridin-6-ones:: Variation of N-alkyl substituents modulates sensitivity to efflux transporters associated with multidrug resistance [J].