Lessons Learned during 50 kg Manufacturing of Suzuki–Miyaura Coupling Reaction

Abstract

This study presents the lessons learned from scaling up the Suzuki–Miyaura coupling reaction to a 50 kg scale. The reaction conditions were optimized at 89–90 °C, corresponding to the boiling point of the solvent system (2-BuOH/H₂O, 7/3). Manufacturing at this scale was conducted at a contract manufacturing organization (CMO) situated at high altitude, requiring the use of a pressure vessel to maintain the internal temperature within the desired range. Reaction, workup, and crystallization processes were performed under stringent anaerobic conditions to prevent adverse events typically associated with palladium-catalyzed reactions. However, the obtained crystals exhibited unexpected impurity levels and elevated residual palladium concentrations. Comprehensive investigations identified elevated external temperatures during the reaction and strict anaerobic conditions during workup and crystallization as the primary contributors to these deviations. The findings underscore critical considerations for scaling up palladium-catalyzed reactions and highlight potential blind spots in temperature and oxygen control.