A Continuous Flow Process for LSN647712 via Double Organometallic Additions to Dimethylcarbamyl Chloride

J Org Chem. 2022 Feb 18;87(4):2045-2054. doi: 10.1021/acs.joc.1c01354. Epub 2021 Aug 10.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbamates*
  • Crystallization
  • Halogens*
  • Indicators and Reagents

Substances

  • Carbamates
  • Halogens
  • Indicators and Reagents
  • dimethylcarbamyl chloride