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

Area of Science:

• Organic Chemistry
• Process Chemistry
• Pharmaceutical Manufacturing

Background:

• LSN647712 is a critical ketone intermediate in lasmiditan drug substance synthesis.
• Traditional synthesis routes may lack efficiency and scalability.

Purpose of the Study:

• To develop an intensified, continuous flow process for synthesizing the LSN647712 ketone intermediate.
• To improve yield, purity, and productivity compared to existing methods.

Main Methods:

• A three-step connected continuous flow process was designed.
• Utilized Turbo Grignard reagent (N-methylpiperidin-4-ylmagnesium chloride) and lithiated 2,6-dibromopyridine.
• Sequential addition to dimethylcarbamyl chloride (DMCC) followed by reactive crystallization.

Main Results:

• Achieved high chemical yield (>85%) of the ketone intermediate.
• Demonstrated high productivity (>100 g/h) and process intensification (residence time ~3 min).
• Obtained high product purity via batch reactive crystallization into a hydrobromide salt.

Conclusions:

• The developed continuous flow process is highly efficient for LSN647712 synthesis.
• This intensified method offers a scalable and productive route for pharmaceutical manufacturing.
• Continuous preparation of the Turbo Grignard reagent in CSTR enhances solubility and processability.