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.

A modeling-based strategy is disclosed for identifying reaction conditions for the safe and effective scale-up of highly energetic hydrogenation reactions. The model was developed within Scale-up Systems’s DynoChem 2011 and takes under consideration the kinetics of the reaction, the reactor heat transfer capabilities, and the degree of mass transfer. Fourier transform infrared spectroscopy (FT-IR), heat flow, and H2 uptake data were used to determine the reaction kinetics that were found to be most accurately described by a Langmuir–Hinshelwood type model. The scale-up model was validated within our kilo-laboratory using a 5 L reactor.