RESUMEN
A convenient method for the preparation of aryl trifluoromethylsulfones from the reactions of diaryliodonium salts with sodium trifluoromethanesulfinate in the presence of copper catalysts is described. Cuprous oxide in DMF was found to be the optimal catalyst for the reaction. The reaction conditions are tolerant of various functional groups as well as of various counteranions of the iodonium salt. The synthetic utility of the process is demonstrated by performing the reaction on a preparative scale (88 g).
Asunto(s)
Cobre/química , Hidrocarburos Fluorados/química , Hidrocarburos Yodados/química , Mesilatos/química , Catálisis , Estructura Molecular , Sales (Química)/química , Sulfonas/síntesis química , Sulfonas/químicaRESUMEN
A high-throughput screen against human DGAT-1 led to the identification of a core structure that was subsequently optimized to afford the potent, selective, and orally bioavailable compound 14. Oral administration at doses ≥0.03 mg/kg significantly reduced postprandial triglycerides in mice following an oral lipid challenge. Further assessment in both acute and chronic safety pharmacology and toxicology studies demonstrated a clean profile up to high plasma levels, thus culminating in the nomination of 14 as clinical candidate ABT-046.
Asunto(s)
Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Pirazoles/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Bases de Datos Factuales , Diacilglicerol O-Acetiltransferasa/química , Perros , Femenino , Hurones , Tránsito Gastrointestinal/efectos de los fármacos , Células HeLa , Hemodinámica/efectos de los fármacos , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Microsomas Hepáticos/metabolismo , Periodo Posprandial , Pirazoles/farmacocinética , Pirazoles/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Proteínas Recombinantes/antagonistas & inhibidores , Proteínas Recombinantes/química , Relación Estructura-Actividad , Triglicéridos/sangre , Vómitos/inducido químicamenteRESUMEN
A general method for Pd-catalyzed sulfonamidation of aryl nonafluorobutanesulfonates (aryl nonaflates) is described. A biaryl phosphine ligand, t-BuXPhos, formed the most active catalyst, and K(3)PO(4) in tert-amyl alcohol was found to be the optimal base-solvent combination for the reaction. The reaction conditions were tolerant of various functional groups such as cyano, nitro, ester, aldehyde, ketone, chloride, carbamate, and phenol. Heterocyclic aryl nonaflates were found to be suitable coupling partners. High yields of the coupled products were obtained from the reactions between inherently disfavored substrates such as electron-rich nonaflates and electron-poor sulfonamides. Kinetic data suggest reductive elimination to be the rate-limiting step for the reaction. The only limitation of this methodology that we have identified is the inability of 2,6-disubstituted aryl nonaflates to efficiently participate in the reaction.
Asunto(s)
Paladio/química , Sulfonamidas/química , Ácidos Sulfónicos/química , Catálisis , Hidrólisis , Cinética , Ligandos , Fosfinas/químicaRESUMEN
An intramolecular Stetter reaction of vinylphosphine oxides and vinylphosphonates has been developed. Treatment of an aldehyde with a nucleophilic N-heterocyclic carbene catalyst allows for addition of an acyl anion equivalent into a vinylphosphine oxide or vinylphosphonate Michael acceptor in yields up to 99% and ee values up to 96%.