Application of a Rotor–Stator High-Shear System for Cr/Mn-Mediated Reactions in Eribulin Mesylate Synthesis

Potential issues associated with the scale up of a catalytic Nozaki-Hiyama-Kishi reaction and a Cr/Mn-mediated desulfonylation used in eribulin mesylate synthesis were evaluated, and countermeasures were investigated. When stir bar agitation, which is typically used for laboratory-scale reactions, was changed to impeller-type agitation upon scale up of these reactions, the conversion rate and yield decreased considerably. Traditional methods for overcoming such decreases, such as preactivation of the Mn or the use of fine particles of Mn, did not improve the conversion rate sufficiently, whereas a physical shearing approach was effective. Specifically, we found that the use of a rotor-stator high-shear system as a stirring device afforded the same conversion rate as that observed with a stir bar.