Development and Scale-up of a Flow Chemistry Lithiation–Borylation Route to a Key Boronic Acid Starting Material

Abstract

A flow chemistry process for the synthesis of a key boronic acid starting material was developed utilizing flow flash chemistry that allowed formation and subsequent productive reaction of an unstable organolithium intermediate. Rapid scale-up from Discovery Chemistry and process optimization to kilogram-scale production was achieved using a short residence time (0.25 s) and noncryogenic temperature (0 °C), without the need to increase the number of reactors. A comparison of the flow process with a Miyaura borylation process suggested some potential benefit in the overall process operating efficiency from avoiding the use of Pd and genotoxic boron reagents.

Laboratory of the future: a modular flow platform with multiple integrated PAT tools for multistep reactions

“…This appearance could be explained by "gumming", which is a known phenomenon in organometallic reactions in flow and can be tolerated indefinitely, provided there is no further disturbance. 33 Although this was observed to grow in size over time, it had no effect on the extent of deprotonation observed at the IR probe. Furthermore, the additional information obtained by sensors positioned throughout the reactor system illustrated a stable process, with no significant changes in temperature or pressure.…”

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

“…By switching to a flow process this reaction was also made safer and more efficient due to a short residence time in the flow reactor and the use of less toxic chemicals. [31] …”

“…She studied chemistry at the Graz University of Technology and University of Graz (Austria Thus,u nlike the Pd-catalyzed reaction, synthesizing the key boronic acid intermediate through al ithiation-borylation procedure had many potential advantages,i ncluding increased efficiencya nd safety;h owever manually performing the corresponding lithiation chemistry on scale was associated with important challenges.A utomation of this process using batch conditions proved to be difficult because of clogging issues.H owever,t his reaction sequence was successfully automated under continuous flow conditions in conjunction with abatch workup and isolation of the desired intermediate on kilogram scale.Even though the raw material costs of the continuous flow method exceed the costs of the Pd-catalyzed batch version because of the necessary Boc-protection, the flow process has potential benefits arising from avoiding the use of Pd and potentially mutagenic boron reagents.B ys witching to af low process this reaction was also made safer and more efficient owing to as hort residence time in the flow reactor and the use of less toxic chemicals. [31]…”

Synthesis of Organometallic Compounds in Flow

“…The Miyaura borylation is an important reaction for the preparation of pharmaceutical intermediates. Usutani and Sedelmeier reported a flow process for the kilogram‐scale synthesis of a boronic acid starting material for the synthesis of TAK‐117, a selective PI3 K α inhibitor …”

“…[33] The Miyaura borylation is an important reaction for the preparation of pharmaceutical intermediates. Usutani and Sedelmeier reported a flow process for the [34] Trifluoroborates are very often a stable alternative to boronic acids in Suzuki-Miyaura reactions. The synthesis of bromomethyltrifluoroborates in flow conditions has been reported by Broom and coworkers.…”