Palladium-Catalyzed Regioselective Arylation of Imidazo[1,2-b][1,2,4]triazine:  Synthesis of an α2/ 3-Selective GABA Agonist

A convergent, practical, and efficient synthesis of 2‘,6-difluoro-5‘-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABAA α2/ 3-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilo...

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Veröffentlicht in:Journal of organic chemistry 2005-07, Vol.70 (15), p.5938-5945
Hauptverfasser: Gauthier, Donald R, Limanto, John, Devine, Paul N, Desmond, Richard A, Szumigala, Ronald H, Foster, Bruce S, Volante, R. P
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Sprache:eng
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Zusammenfassung:A convergent, practical, and efficient synthesis of 2‘,6-difluoro-5‘-[3-(1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABAA α2/ 3-selective agonist, is described. The seven-step, chromatography-free synthesis was demonstrated on a multi-kilogram scale and utilized biaryl bromide 6 and imidazotriazine 22 as key intermediates. Biaryl bromide 6 was prepared via a highly selective aromatic bromination. The regioselective condensation of aminotriazine 15 with chloroacetaldehyde provided the desired imidazotriazine intermediate 22. A highly regioselective palladium-catalyzed arylation in the final step highlights the efficiency of the route.
ISSN:0022-3263
1520-6904
DOI:10.1021/jo0507035