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 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.
Mase
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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
Houpis
I N
IN
Akao
A
A
Dorziotis
I
I
Emerson
K
K
Hoang
T
T
Iida
T
T
Itoh
T
T
Kamei
K
K
Kato
S
S
Kato
Y
Y
Kawasaki
M
M
Lang
F
F
Lee
J
J
Lynch
J
J
Maligres
P
P
Molina
A
A
Nemoto
T
T
Okada
S
S
Reamer
R
R
Song
J Z
JZ
Tschaen
D
D
Wada
T
T
Zewge
D
D
Volante
R P
RP
Reider
P J
PJ
Tomimoto
K
K
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
D000577:Amides; D006845:Hydrocarbons, Fluorinated; D018727:Muscarinic Antagonists; D043587:Receptor, Muscarinic M3; D011976:Receptors, Muscarinic