Chinese Journal of Pharmaceuticals, Volume. 56, Issue 7, 871(2025)
Synthesis and Purification of Related Substances of Voclosporin
MAI Zidan1, JIANG Bibo2, LIU Jiajia2, XU Shengjun3, ZHANG Fuli2, and ZHAO Chuanmeng2、*
Author Affiliations
1College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 2012032Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry Co., Ltd., Shanghai 2012033Boxiao (Hangzhou) Biopharmaceutical Co., Ltd., Hangzhou 311404show less
Herein two related substances (A and B) of voclosporin (1) were prepared and purified. Compound B was Z-isomer of 1, named cyclo-[[(6Z)-(2S, 3R, 4R)-3-hydroxy-4-methyl-2-(methylamino)-6, 8-nonadienoyl]-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]. E configuration of acetylated voclosporin (5) was transferred into related substance B via configuration conversion and acetyl group removal under triethylamine/lithium bromide with high-purity, which was reported at the first time. In addition, in the process optimization of 1, the over-oxidized impurity, related substance A was found and prepared for the first time. Its structure was confirmed as acetylated cyclosporine A acid by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. The above two compounds can be served as the references for the quality control of 1.
