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

Abstract

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 sp 3 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.

Development of a Continuous Flow Synthesis of 2-Substituted Azetines and 3-Substituted Azetidines by Using a Common Synthetic Precursor

“…We reasoned that the use of an alkyllithium would have been problematic due to a competitive iodine/lithium exchange reaction. For this reason, we selected, lithium diisopropylammide (LDA, p K a ∼ 35) as a suitable non-nucleophilic base capable of promoting β-elimination of 1 and C2-lithiation of the resulting azetine 3 . Aimed at developing a sustainable process, the entire sequence was developed under continuous flow conditions and using CPME as the green solvent (Scheme ).…”

Continuous Flow Chemistry with Solids: A Review

“…Alonso and co-workers from GlaxoSmithKline (GSK) report on the use of lithium diisopropylamide in flow and describe clogging issues also related to reagent concentration, noting the irreversible precipitation of LDA when concentrations greater than 0.95 M in THF are used. 58 Dunn et al at GSK also refer to challenges with solid formation for continuous organometallic chemistry, and associated clogging and over pressurization events. The authors report issues relating to solid formation during longer runtimes of their lab-scale continuous lithiation/iodination process using PhLi.…”

Efficient Cleaning Method for Flow Reactors in Flow Lithiation Reactions Under Water-free Conditions

“…3 In addition, yield and quality are often degraded during scale-up, attributed to poor heat removal efficiency and longer operating time. 4 In response to these challenges, several attempts have been made in recent years to handle highly reactive organolithium intermediates in a stable manner by harnessing the features of flow reactors, such as high-speed mixing, high heat transfer, and precise control of residence time. 5−8 For example, Yoshida et al have used "flash chemistry," which allows the generation and use of aryllithium intermediates, short-lived active species, on the millisecond time scale, to perform reactions deemed challenging in conventional batch conditions.…”

“…Organolithium reagents, synthesized through halogen–lithium exchange and deprotonation reactions using alkyllithium reagents, are important compounds used in a wide variety of C–C bond formation reactions, such as nucleophilic substitution, additions to CO double bonds or CN multiple bonds, condensation, and coupling reactions. , Their exceptional nucleophilicity and basicity make them inherently unstable, necessitating cryogenic conditions typically in the range of −78 to −40 °C during the reaction . In addition, yield and quality are often degraded during scale-up, attributed to poor heat removal efficiency and longer operating time …”