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  • A Continuous Flow Process f...
    Li, Hui; Sheeran, Jillian W; Kouvchinov, David; Clausen, Andrew M; Crouch, Ian T; Bio, Matthew M; Fang, Yuan-Qing; Frank, Scott A; Johnson, Martin D; Kerr, Mark S

    Journal of organic chemistry, 02/2022, Letnik: 87, Številka: 4
    Journal Article

    The ketone intermediate LSN647712 is a key synthetic intermediate for the drug substance lasmiditan manufacturing process. A three-step connected continuous flow process utilizing a Turbo Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, and lithiated 2,6-dibromopyridine sequentially added to double electrophile (OC­(++) synthon dimethylcarbamyl chloride (DMCC) was developed to deliver the ketone intermediate in a high chemical yield (>85%). This highly productive (>100 g/h lab system) and intensified process (τ ∼ 3 min) yields the product in high purity upon batch reactive crystallization to form a corresponding hydrobromide salt. In addition to the connected plug flow reactor system, the Grignard reagent, N-methylpiperidin-4-ylmagnesium chloride, was also prepared continuously in CSTR as a more soluble LiCl adduct in THF (Turbo Grignard).