Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction

T. Mase, I. N. Houpis, A. Akao, I. Dorziotis, K. Emerson, T. Hoang, T. Iida, T. Itoh, K. Kamei, S. Kato, Y. Kato, M. Kawasaki, F. Lang, J. Lee, J. Lynch, P. Maligres, A. Molina, T. Nemoto, S. Okada, R. ReamerJ. Z. Song, D. Tschaen, T. Wada, D. Zewge, R. P. Volante, P. J. Reider, K. Tomimoto

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Abstract

An efficient synthesis of a structurally unique, novel M3 antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl2-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF3·OEt2. The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu3MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Original languageEnglish (US)
Pages (from-to)6775-6786
Number of pages12
JournalJournal of Organic Chemistry
Volume66
Issue number20
DOIs
StatePublished - Oct 5 2001
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

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    Mase, T., Houpis, I. N., Akao, A., Dorziotis, I., Emerson, K., Hoang, T., Iida, T., Itoh, T., Kamei, K., Kato, S., Kato, Y., Kawasaki, M., Lang, F., Lee, J., Lynch, J., Maligres, P., Molina, A., Nemoto, T., Okada, S., ... Tomimoto, K. (2001). Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction. Journal of Organic Chemistry, 66(20), 6775-6786. https://doi.org/10.1021/jo0157425