Lithium aluminum hydride in flow: overcoming exotherms, solids, and gas evolution en route to chemoselective reductions

Development and optimization of a continuous flow ester reduction with LiAlH4 in the synthesis of a key intermediate for a PI3Kδ inhibitor (CPL302415)

“…In all cases, it was impossible to avoid overreduction to alcohol, and we decided to return to LAH, which is twice as cheaper as DIBAL-H. We found only one publication with the reduction of acids and esters to alcohols using LAH, where for this transformation Mohammadzadeh et al designed a special flow system to avoid gas evolution and production of gelatinous solids. 29 In our work, we used a commercially available Vapourtec easy-Medchem system with three peristaltic pumps and two types of 10 mL PFA tube reactors (id = 1 mm). For the reactions at lowered temperatures (0-20 °C) we used Vapourtec cooled tube reactor.…”

“…No gelatinous products were formed. 29 We also applied DoE to find the critical reaction parameters.…”

Doing More with Less, On Time and In Full: An Intelligent Multiattribute Process Optimization Platform

“…The manufacturers failed to adapt to the sudden change in the demand causing the supply chain to fail unexpectedly . The chemists, when tasked to find a fix without having the time to prepare for the sudden outburst in demand, looked outside the box and, in some cases, found solutions in the fundamentals of Continuous Manufacturing (CM), an emerging mode of manufacturing chemicals that has been touted to make matters on demand and just in time. − With the latest pandemic in the rear view now, chemists across the world are left with a dire warning for the manufacturing sector. In the next pandemic cycle, we must find solutions fast, ideally using less material and without having to physically congregate in a highly equipped confined space that we take for granted, the laboratory.…”