Upscaled Synthesis of α‐ and β‐Peptides in a Continuous‐Flow Reactor Using Propylene Carbonate as an Eco‐Friendly Solvent

A rapid, eco‐friendly, and scalable continuous‐flow solid‐phase peptide synthesis (CF‐SPPS) technology has been developed using propylene carbonate (PC) as a solvent. PC, a greener alternative to DMF, is selected based on the GSK solvent selection guide. To evaluate its compatibility with CF‐SPPS, four α‐peptides were synthesized, achieving high yields and purity. The method is further validated with challenging sequences, including four β‐peptide foldamers and an α/β‐peptide chimera. To scale up this innovative approach, larger column geometries are optimized to ensure the appropriate resin load and flow rate for desired residence times. The technology demonstrated its capability to synthesize peptides on a >4 g scale with satisfactory efficiency. A key feature is the use of PC in minimal amounts, significantly enhancing the process's green credentials. The low solvent consumption and high efficiency align with green chemistry principles, reducing waste and improving sustainability. The low process mass intensity of the method highlights its environmental benefits, making it a sustainable alternative for large‐scale peptide synthesis. This breakthrough showcases the potential of CF‐SPPS with PC as a solvent to meet the demands of greener and more efficient peptide production.