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Impurity identification and scale-up of a novel glycopeptide antibiotic
Jiao, S., Guan, D., Xu, L., Liu, B., Shi, W., Li, J., Tang, F., & Huang, W. (2021). Impurity identification and scale-up of a novel glycopeptide antibiotic. Organic Process Research and Development, 25(11), 2390-2402. https://doi.org/10.1021/acs.oprd.1c00064
A variety of novel glycopeptide antibiotics have been developed to combat the drug-resistant bacterial strains. Previously, we reported a series of vancomycin derivatives that are modified with lipid tails and extra sugars. SM-V-61, as one of the vancomycin analogues with a trifluoromethyl-biphenyl fragment and galactose, showed enhanced antibacterial activity, improved PK/PD, better water solubility, and safety. However, the deficient synthetic procedure, lower yield, and complicated impurities hindered the further development of the drug candidate SM-V-61. Herein, we reported a further study on SM-V-61 impurity analysis and process optimization. We first synthesized and identified a variety of impurities and established the analytical method for quality analysis and control of SM-V-61. Based on the defined analytical method, we optimized the synthetic procedure for SM-V-61 and operated the synthesis on 30-40 and 500-600 g scales in the laboratory and manufacturing workshop, respectively.