Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine:: Synthesis of an α2/3-selective GABA agonist

被引:53
作者
Gauthier, DR [1 ]
Limanto, J [1 ]
Devine, PN [1 ]
Desmond, RA [1 ]
Szumigala, RH [1 ]
Foster, BS [1 ]
Volante, RP [1 ]
机构
[1] Merck & Co Inc, Merck Res Labs, Dept Proc Res, Rahway, NJ 07065 USA
关键词
D O I
10.1021/jo0507035
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
A convergent, practical, and efficient synthesis of 2',6-difluoro-5'-[3-(l-hydroxy-l-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2-carbonitrile (1), an orally active GABA(A) alpha(2/3)-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.
引用
收藏
页码:5938 / 5945
页数:8
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