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

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