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Process Development and Large-Scale Synthesis of a PDE4 Inhibitor

2005; American Chemical Society; Volume: 10; Issue: 1 Linguagem: Inglês

10.1021/op050116l

1520-586X

David A. Conlon, Antoinette Drahus-Paone, Guo‐Jie Ho, Brenda Pipik, Roy Helmy, James M. McNamara, Yao‐Jun Shi, J. Michael Williams, Dwight Macdonald, Denis Deschênes, Michel Gallant, Anthony Mastracchio, Bruno Roy, John Scheigetz,

Chemical synthesis and alkaloids

An efficient, scalable synthesis of the PDE4 inhibitor, 6-[1-methyl-1-(methylsulfonyl)ethyl]-8-(3-{(E)-2-(3-methyl-1,2,4-oxadiazol-5-yl)-2-[4-(methylsulfonyl)phenyl]vinyl}phenyl)quinoline benzenesulfonate (10) is described. The synthesis is highly convergent, generating the penultimate 9 by coupling aldehyde 7 and oxadiazole 8 in a Knoevenagel reaction. The process consists of a total of nine chemical steps, five of which comprise the sequence to prepare aldehyde 7 via Skraup reaction, bromination, sulfone formation, methylation and Suzuki−Miyaura cross-coupling, and a two-step sequence for the synthesis of oxadiazole 8 that includes the methylamidoxime and oxadiazole steps. The final two steps are Knoevenagel coupling and salt formation. The process produced the drug candidate 10 in 46% overall yield from 2-bromo-4-methylaniline (1) on multikilogram scale.