Discovering new antibiotic drugs is a critical approach to addressing the issue of bacterial and fungal resistance. Developing novel antibiotic based on existing ones has proven to be an effective strategy. Currently, due to issues such as resistance and toxicity, many antibiotics have been developed into semi-synthetic drugs that are either on the market or in clinical trials. The complexity and stability of natural antibiotic products make the pharmaceutical chemistry development of semi-synthetic antibiotics particularly challenging, with subsequent synthetic processes presenting even greater difficulties. These process chemistries must address challenges in chemical, regio-, and stereo-selective transformations, as well as overcome technical obstacles in separation and purification. Over the century-long history of antibiotic development, chemists have developed many classic antibiotic chemical synthesis processes, such as tetracycline chemistry and macrolide chemistry. These classic semi-synthetic antibiotic processes are reviewed, detailing the chemical synthesis challenges, original and improved processes, and potential process optimizations.

Key words: antibiotic, semi-synthesis, process chemistry, fermentation, antibacterial drug, antifungal drug