Overcoming Scale-Dependent Impurity Escalation in Epalrestat Synthesis: Identification, Mechanistic Elucidation, and Robust Process Control

Epalrestat is a clinically vital aldose reductase inhibitor for diabetic neuropathy. An unknown impurity exhibited an unacceptable increase from laboratory batches to approximately 2% in 100 kg pilot-scale batches, accompanied by a 20% yield reduction. This study investigates the impurity’s origin, structure, and control strategies. Through high-resolution mass spectrometry (HRMS) and NMR analyses, the impurity was identified as 4-methyl-5-phenyl-2-thiophenecarboxylic acid, a previously unreported impurity in Epalrestat synthesis. Mechanistic studies revealed that the impurity forms through base-mediated hydrolysis of rhodanine-N-acetic acid, followed by a Michael addition with α-methylcinnamaldehyde, and subsequent cyclization with concurrent hydrolysis and oxidation, ultimately leading to the impurity. Corresponding control strategies were established. Critical process parameters (CPPs), including NH₃·H₂O equivalents, reaction temperature, and EtOH volume, were optimized to suppress the impurity generation. Implementing these control strategies in scale-up lab batches suppressed this unknown impurity to undetectable levels while achieving >95% yield and >97% purity, and enabled transfer to pilot-scale facility. This systematic investigation of impurity profiling, combined with mechanism-driven process optimization, presents an effective strategy for pilot-scale process development of Epalrestat.