Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-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 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.
Gauthier
Donald R
DR
Department of Process Research, Merck Research Laboratories, Merck & Co. Inc., P.O. Box 2000, Rahway, NJ 07065, USA. donald_gauthier@merck.com
Limanto
John
J
Devine
Paul N
PN
Desmond
Richard A
RA
Szumigala
Ronald H
RH
Foster
Bruce S
BS
Volante
R P
RP
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000737:chemistry; D001965:Bromides / Q000737:chemistry; D002384:Catalysis; D018755:GABA Agonists / Q000138:chemical synthesis*; D006841:Hydrocarbons, Aromatic / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D010165:Palladium / Q000737:chemistry*; D011963:Receptors, GABA-A; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis*; D014230:Triazoles / Q000737:chemistry
D001965:Bromides; D018755:GABA Agonists; D006841:Hydrocarbons, Aromatic; D007093:Imidazoles; D011963:Receptors, GABA-A; D014227:Triazines; D014230:Triazoles; D010165:Palladium; C004656:chloroacetaldehyde; D000079:Acetaldehyde