Parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo[1,5-a]pyridine-7-carboxylic acid amide derivatives

被引：12

作者：

Brodbeck, B ^{[1
]}

Püllmann, B ^{[1
]}

Schmitt, S ^{[1
]}

Nettekoven, M ^{[1
]}

机构：

[1] F Hoffmann La Roche & Co Ltd, Pharmaceut Res Basel, Discovery Chem, Lead Generat, CH-4070 Basel, Switzerland

来源：

TETRAHEDRON LETTERS | 2003年 / 44卷 / 08期

关键词：

triazolo[1,5-a]pyridine derivatives; combinatorial chemistry; iterative solution-phase chemistry; lead optimisation; N-amination;

D O I：

10.1016/S0040-4039(03)00062-5

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

The parallel iterative solution-phase synthesis of 5-amino-1-aryl-[1,2,4]triazolo [1,5-a]pyridine-7-carboxylic acid amide derivatives is described. The key intermediate 2,6-bis-aminopyridine-4-carboxylic acid methyl ester was synthesised in a two step procedure in 64% overall yield and elaborated to a variety of triazolopyridine-5-carboxylic acid methyl ester by selective pyridine-N-amination, condensation of the adduct with a wide selection of aldehydes and subsequent cyclisation and oxidation. The desired esters were obtained in yields up to 70%. The final transformation to the amide derivatives was accomplished by application of carefully optimised reaction conditions thus giving access to a library of total 500 triazolopyridine amide derivatives. Iterative synthetic cycles (12-48 library members each) allowing for maximal flexibility in chemistry and maximal efficiency in in vitro biological activity optimisation guided by molecular modelling efforts constitute a synergistic procedure for rapid lead optimisation. (C) 2003 Elsevier Science Ltd. All rights reserved.

引用

页码：1675 / 1678

页数：4

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