Use of Lithium Diisopropylamide in Flow: Operability and Safety Challenges Encountered on a Multigram Scale

A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scaleup when transferring from batch to flow are highlighted. During the rapid process development, unexpected and expected issues concerned with the use of 1 M and 2 M lithium diisopropylamide in flow were encountered and overcome as they arose. Organolithium chemistry was operated in continuous flow mode; a reaction sequence of sp3 deprotonation and in-line acetone quench, followed by a semibatch workup was scaled up to multigram quantities in a rapid, fit-for-purpose manner for early-phase project delivery.

Automated summary

The study applied a workflow for organometallic processes in flow to synthesize a pharmaceutical intermediate, highlighting key factors and practical assessments required for scaleup. Unexpected and expected issues with the use of organolithium chemistry in flow were encountered and overcome during rapid process development. The reaction sequence was scaled up to multigram quantities in a rapid and fit-for-purpose manner for early-phase project delivery.