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

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journal contribution
posted on 31.03.2021, 08:29 by Marta Alonso, Maria Cruz Garcia, Christopher McKay, Lee R. Thorp, Michael Webb, Lee J. Edwards
A workflow for the development of organometallic processes in flow was applied to synthesize 1-(5-bromopyridin-2-yl)-2-methylpropan-2-ol, a pharmaceutical intermediate. Key factors and corresponding practical assessments required for the scale-up 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.