| Abstract
| - An efficient synthesis of a structurally unique, novel M3 antagonist 1 is described. Compound 1 isconveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 andthe amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl2−MAEP complex19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) toestablish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorinationof ketone 17 using Deoxofluor in the presence of catalytic BF3·OEt2. The synthesis of the aminemoiety 3 is highlighted by the discovery of a novel n-Bu3MgLi magnesium−halogen exchangereaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalationprotocol 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 reductiveamination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highlyconvergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis hasbeen used to prepare multi-kilogram quantities of the bulk drug.
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