A Short Synthesis of Cyclo(‐RGDfK) Using a Microflow Reactor

Cyclic RGD‐containing peptides are highly potent and useful as selective inhibitors of the α v β 3 integrin. Their derivatives have been utilized as the integrin‐targeted radiotracers for molecular imaging and therapeutic applications. However, typical synthetic methods generally require long reaction times and expensive and wasteful coupling agents. These become particularly problematic when scaled‐up synthesis is required. In this study, we demonstrate a rapid and short synthesis of cyclo(‐RGDfK) by integrating a one‐flow three‐component coupling (3CC) with rapid flow macrolactamization via mixed carbonic anhydrides. This approach significantly reduces waste generation associated with deprotection steps and minimizes the use of costly coupling agents. Furthermore, investigations using Karl Fischer titration and in‐line Fourier Transform Infrared Spectroscopy (FT‐IR) analysis revealed that precise control of water content and base amount is essential for suppressing undesired reactions and improving reproducibility in the 3CC process.