RESUMO
Nucleophilic displacement of readily available alpha,alpha-dibromoketones with excess morpholine gave the corresponding ketoaminals, which upon condensation with aminoguanidine in MeOH in the presence of AcOH afforded 5-substituted-3-amino-1,2,4-triazines in >95% regioselectivity and 45-76% isolated yield. [reaction: see text]
RESUMO
Asymmetric hydrogenation of allylic dimethylcarbinamide 2 with 1 mol % of cationic Rh(I)-Josiphos complex in THF under 500 psi of H2 generated the corresponding tertiary carbinamide 1 in 98.5% assay yield and a 94:6 enantiomeric ratio. Upon crystallization, the product was isolated in 91% isolated yield and 95:5 enantiomeric ratio.
Assuntos
Amidas/química , Hidrogênio/química , Rênio/química , Catálise , Cristalização , Espectroscopia de Ressonância Magnética , Espectrofotometria InfravermelhoRESUMO
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.
Assuntos
Agonistas GABAérgicos/síntese química , Hidrocarbonetos Aromáticos/química , Imidazóis/química , Paládio/química , Triazinas/síntese química , Acetaldeído/análogos & derivados , Acetaldeído/química , Brometos/química , Catálise , Receptores de GABA-A , Estereoisomerismo , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
[reaction: see text] An asymmetric synthesis of (S)-gamma-fluoroleucine ethyl ester 1 is described. The key transformation involves a lipase-catalyzed dynamic ring-opening of 2-(3-butenyl)azlactone 7b with EtOH to give amide ester (S)-6b in 84% enantiomeric excess. Removal of the N-pentenoyl group with N,N'-dibromodimethylhydantoin in the presence of trifluoroacetic acid afforded the titled compound, which was isolated as its hydrogen sulfate salt in 75% yield and >97% ee.