Voclosporin from Cyclosporine A: Process Optimization and Impurities Characterization

An industrial process for the conversion of the fungal cyclopeptide cyclosporine A (2) into voclosporin (1a,b) was optimized and scaled up to the kilogram scale. The combined optimization of reaction conditions and final purification made it possible to obtain voclosporin in excellent purity (HPLC % area >99.5%) and reasonable overall yield (40−45%), with an E/Z diastereomeric ratio complying with the pharmaceutical requirements (90−95% E-isomer dominance). A study of the stability of voclosporin (2) under basic conditions revised the nature of the process involved in its degradation, identifying two major reactions responsible for the formation of impurities in the final products, namely, dehydration at C-22/C-23 (residue 1) and L-to Disomerization of the N-methyl leucines residues 4 and 9. These impurities were isolated, structurally characterized, and quantified in the final product.