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

By Alonso, Marta; Garcia, Maria Cruz; McKay, Christopher; Thorp, Lee R.; Webb, Michael; Edwards, Lee J.

Published on

Abstract

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.

Journal

Organic Process Research & Development. Volume 25, 2021, 988-1000

DOI

10.1021/acs.oprd.1c00015

Type of publication

Peer-reviewed journal

Affiliations

  • GlaxoSmithKline

Article Classification

Research Article

Classification Areas

  • Intermediate

Tags