Continuous-Flow Synthesis of the Key Nicergoline Intermediate 10α-Methoxy-9,10-dihydrolyserol via Photomethoxylation

Abstract

Abstract At present, the key nicergoline intermediate 10α-methoxy-9,10-dihydrolyserol (3) is predominantly synthesized by photomethoxylation in batch photoreactors, a conventional method plagued by issues such as poor light penetration, low energy efficiency, severe scale-up barriers, and potential safety risks. In this work, a novel continuous-flow photochemical process for manufacturing this intermediate has been developed using a plate-type mesoscale photoreactor. This approach offers substantial advantages over the traditional batch synthesis, including higher yields, shorter reaction time, excellent stereoselectivity, milder conditions, and enhanced scalability. Optimal conditions were found that led to considerably higher productivity, achieving a throughput of up to 0.73 mol/h of 2 with a residence time of only 20 s. The photochemical sequence was demonstrated at the kilogram scale, highlighting its viability, efficiency, and robustness.