Development and Scale-up of an Efficient Miyaura Borylation Process Using Tetrahydroxydiboron

Abstract

A revised Miyaura borylation process has been developed using tetrahydroxydiboron that avoids the use of bis(pinacolato) diboron and hence the need to hydrolyze the resulting boronic ester to its corresponding acid. The process was greatly simplified and successfully scaled-up in the pilot plant on a 65 kg scale, reducing plant cycle time and resulting in a 47% overall cost reduction. Furthermore, methodology for the study of the oxygen sensitivity of the process is reported that allowed for optimization of the amount of tetrahydroxydiboron and catalyst used. These studies also demonstrated an oxygen-induced decomposition of tetrahydroxydiboron.

The Molecular Industrial Revolution: Automated Synthesis of Small Molecules

“…In the original batch process, the boronic acid moiety was introduced via an expensive Pd-catalyzed borylation. [29] Additionally, the bis-boronic acid starting material was shown to be prone to oxygen-mediated degradation and a source of potentially genotoxic impurities. [30] Thus, alternative to the Pd-catalyzed reaction, synthesizing the key boronic acid intermediate via a lithiation-borylation procedure had many potential advantages, including increased efficiency and safety, but manually performing the corresponding lithiation chemistry on scale was associated with important challenges.…”

“…In the original batch process,t he boronic acid moiety was introduced through an expensive Pd-catalyzed borylation. [29] Additionally,t he bis-boronic acid starting material was shown to be prone to oxygen-mediated degradation and as ource of potentially genotoxic impurities. [30] Melanie Trobe was born in 1988 in Austria.…”

“…They were able to automatically produce on kilogram scale a key boronic acid intermediate ( 8 ) for the manufacturing of TAK‐117, a selective PI3Kα inhibitor currently in Phase 1 b clinical trials (Scheme ). In the original batch process, the boronic acid moiety was introduced through an expensive Pd‐catalyzed borylation . Additionally, the bis‐boronic acid starting material was shown to be prone to oxygen‐mediated degradation and a source of potentially genotoxic impurities .…”

Automation Technologies to Enable Data-Rich Experimentation: Beyond Design of Experiments for Process Modeling in Late-Stage Process Development

“…The incorporation of automated sampling technologies amenable to chromatographic analysis represents a paradigm shift for our laboratories. The ability to perform in situ sampling along with automated quench and dilution has greatly improved access to the time-course data needed for late-stage development efforts, whether coupled to automated or other benchtop reactor systems. − This technology has reduced the overall experimental burden and has proven to be widely deployable, thereby enabling every scientist to perform data-rich experiments.…”

Process Development of a Sonogashira Cross-Coupling Reaction as the Key Step of Tirasemtiv Synthesis Using Design of Experiments

“…The scale-up of palladium-catalyzed coupling reactions to production scale can sometimes be challenging. The main challenges are the sensitivity of the catalyst to the presence of oxygen, , the need to remove residual traces of the metal from the API in order to comply with ICH guidelines, the catalyst cost, and the reaction robustness.…”