RESUMO
Two new, reliable syntheses of a pyrido[2,3-d]-pyrimidine inhibitor of the CXCR3 receptor are described. A nine-step synthesis of the CXCR3 inhibitor (1) from 2-aminonicotinic acid was demonstrated on a multikilogram scale and incorporates a classic resolution to deliver the enantioenriched active pharmaceutical ingredient (API). A second synthesis of the CXCR3 inhibitor starts from (+)-(D)-Boc alanine and 2-chloronicotinic acid and utilizes a Goldberg coupling. This second synthesis, performed on a gram scale, intersects the former route at a common intermediate thereby completing a formal synthesis of the enantioenriched API in higher overall yield without the need for a resolution.
Assuntos
Acetamidas/síntese química , Acetamidas/farmacologia , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologia , Receptores CXCR3/antagonistas & inibidores , Acetamidas/química , Alanina/química , Aldeídos/química , Aminas/química , Estereoisomerismo , Tartaratos/químicaRESUMO
[reaction: see text] An enantioselective synthesis of the chiral bisnaphthopyrone natural product nigerone is reported. The key step was an eight-step isomerization process to form the final natural product. The isomerization precursor was constructed via asymmetric oxidative biaryl coupling of an advanced intermediate with a 1,5-diaza-cis-decalin copper catalyst.
Assuntos
Produtos Biológicos/síntese química , Naftalenos/síntese química , Compostos Bicíclicos com Pontes/química , Catálise , Cobre/química , Compostos Heterocíclicos com 2 Anéis/química , Isomerismo , Modelos Químicos , Naftalenos/química , Oxirredução , Piperidinas/química , Pironas/síntese química , Pironas/químicaRESUMO
By using oxygen as the terminal oxidant, copper complexes derived from chiral 1,5-diaza-cis-decalin catalyze the enantioselective oxidative biaryl coupling of highly functionalized naphthols to provide octa- and decasubstituted binaphthalenes with high selectivity (86-90% ee). Products containing very electron-rich naphthalenes were prone to epimerization under the reaction conditions. This epimerization could be suppressed by employing naphthol starting materials with phenol protecting groups that attenuated the electron-rich nature of the naphthalenes. Direct oxidation of the resultant chiral 1,1'-binaphthol framework completed the first asymmetric synthesis of a perylenequinone containing only an axial chirality element.