A Flow Process Built upon a Batch Foundation—Preparation of a Key Amino Alcohol Intermediate via Multistage Continuous Synthesis
- John Jin Lim,*,†
- Kenneth Arrington,*,†
- Anna L. Dunn,†
- David C. Leitch,‡,†
- Ian Andrews,†
- Neil R. Curtis,§
- Mark J. Hughes,§
- Daniel R. Tray,§
- Charles E. Wade,§
- Matthew P. Whiting,§
- Charles Goss,∥
- Yangmu Chloe Liu,§
- Brian M. Roesch§
- †Chemical Development, API Chemistry, GlaxoSmithKline, Upper Providence, Pennsylvania 19426, United States
- ‡Department of Chemistry, University of Victoria, Victoria, BC V8P 5C2, Canada
- §Chemical Development, API Chemistry, GlaxoSmithKline, Stevenage SG1 2NY, U.K.
- ∥Chemical Development, Product and Process Engineering, GlaxoSmithKline, Upper Providence, Pennsylvania 19426, United StatesRead the publication that featured this abstract
This paper describes recent efforts to apply flow technology in the preparation of the key amino alcohol intermediate 3b so as to address manufacturability issues present in the batch process of a PRMT5 inhibitor. The continuous process, one of the first reported pharmaceutical processes to use aqueous NH4OH in flow, eliminates an isolation and the use of dichloromethane in the workup and improves reaction time >140-fold compared with the batch process to deliver multigram quantities of 3b in 60–65% isolated yield with >99 HPLC area % and >99% ee. While the flow process greatly increases the efficiency compared with the batch process, small-scale batch experiments were crucial in gaining reaction understanding to increase the kinetics and minimize impurity formation. The holistic process design underscores our belief that large-scale flow processes are built upon the knowledge gained through well-chosen small-scale batch experiments.
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