Synthesis of an H3 Antagonist via Sequential One-Pot Additions of a Magnesium Ate Complex and an Amine to a 1,4-Ketoester followed by Carbonyl-Directed Fluoride Addition

• Joel M. Hawkins
• Pascal Dubé
• Mark T. Maloney
• Lulin Wei. Marcus Ewing
• Stephen M. Chesnut
• Joshua R. Denette
• Brett M. Lillie
• Rajappa Vaidyanathan

• Pharmaceutical Sciences, Pfizer Inc., Groton, USA

We describe the development of an efficient and scalable process for the preparation of fluorocyclobutane-containing H₃ antagonist, 1. The synthesis was accomplished by the chemoselective addition of a magnesium ate complex and an amine to a 1,4-ketoester in a one-pot sequence, followed by a diastereoselective carbonyl-directed fluorination. The chemoselective addition of the magnesium ate complex to the ketoester benefited from tight stoichiometric control, short addition times, and lower reaction temperatures, and thus was amenable to rapid mixing and excellent heat transfer in a flow reactor.

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