(120c) From Batch to Semi-Continuous: Development and Optimization of Reformatsky Reaction for ?-Hydroxyester Synthesis Using Dibal-Activated Zinc.

The Reformatsky reaction is a powerful method for synthesizing β-hydroxyesters, but scale-up is challenging due to its exothermic nature and sequential steps. This work presents a continuous Reformatsky process using in situ DIBAL-H activated zinc, avoiding pyrophoric reagents like diethylzinc.

The process includes three stages: zinc enolate formation in a jacketed CSTR, aldehyde addition in a PFR, and citric acid quenching in a cooled PFR. Batch studies using TLC, GC/MS, and temperature profiling identified key parameters: zinc activation (>2 h at >30 °C) and optimized aldehyde addition (~95% relative to benzyl bromoacetate). Impurities were reduced by optimizing reaction time, adopting semi-continuous operation, recrystallization, and antisolvent precipitation.

Experimental runs examined solvent effects (THF vs. MTBE), residence time, and dosing strategies. Thermal mapping informed scale-up to a 50 L pilot plant. Highest yields were achieved by delaying bromoacetate addition until zinc was fully activated and removing zinc before aldehyde addition.

The continuous system improved yields (up to 90% post-recrystallization), consistency, and safety, while minimizing batch-related losses. Standard procedures were developed for startup, operation, and shutdown. This scalable, safer method advances Reformatsky chemistry for fine chemical and pharmaceutical applications.