title: Synthesis of a muscarinic receptor antagonist via a diastereoselective Michael reaction, selective deoxyfluorination and aromatic metal-halogen exchange reaction.
abstract: An efficient synthesis of a structurally unique, novel M(3) 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 ZnCl(2)-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 BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi 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.
authors.affiliation: Process R & D, Laboratories for Technology Development, Banyu Pharmaceutical Co. Ltd., Kamimutsuna 3-Chome-9-1, Okazaki, Aichi 444-0858, Japan. masetk@banyu.co.jp
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authors.lastname: Mase
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authors.lastname: Houpis
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authors.lastname: Akao
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authors.lastname: Dorziotis
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authors.lastname: Emerson
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authors.lastname: Hoang
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authors.lastname: Iida
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authors.lastname: Itoh
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authors.lastname: Kamei
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authors.lastname: Kato
authors.forename: Y
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authors.lastname: Kato
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authors.lastname: Kawasaki
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authors.lastname: Lang
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authors.lastname: Lee
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authors.lastname: Lynch
authors.forename: P
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authors.lastname: Maligres
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authors.lastname: Molina
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authors.lastname: Nemoto
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authors.initials: S
authors.lastname: Okada
authors.forename: R
authors.initials: R
authors.lastname: Reamer
authors.forename: J Z
authors.initials: JZ
authors.lastname: Song
authors.forename: D
authors.initials: D
authors.lastname: Tschaen
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: D
authors.initials: D
authors.lastname: Zewge
authors.forename: R P
authors.initials: RP
authors.lastname: Volante
authors.forename: P J
authors.initials: PJ
authors.lastname: Reider
authors.forename: K
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authors.lastname: Tomimoto
mesh_terms: D000577:Amides / Q000138:chemical synthesis; D000818:Animals; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis; D018727:Muscarinic Antagonists / Q000138:chemical synthesis*; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic / Q000187:drug effects; D013237:Stereoisomerism
chemical_list: D000577:Amides; D006845:Hydrocarbons, Fluorinated; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic