A Scalable and Sustainable Synthesis of Indirubin Frameworks Enabled by Deep Eutectic Solvents

Indirubin, the active component of the traditional Chinese remedy Dang Gui Long Hui Wan, exhibits broad therapeutic potential. However, its scalable and sustainable synthesis remains challenging when using conventional methods. We report a green and efficient synthetic protocol using deep eutectic solvents (DESs) as environmentally benign media. Indirubin was synthesized from isatin using NaBH₄ in a choline chloride/urea DES at 70°C under air, achieving a 70% overall yield in 24 h without chromatographic purification. This approach, combined with an optimized work-up, significantly reduces organic solvent use, improving both process safety and environmental sustainability. The protocol is robust and scalable, as demonstrated by a pilot-scale preparation (386 g of isatin in 1.94 kg of DES), and grants access to a variety of indirubin derivatives, such as 5,5'-difluoro, 5,5'-dibromo, 5,5'-dimethoxy, 5,5'-dimethyl, 5-bromoindirubin, 3'-oxime, and N-alkylated analogs, the latter being of particular interest as photoswitchable molecular platforms. A comprehensive CHEM21 metrics assessment reveals a 3.7-fold reduction in E-factor and improved effective mass yield (EM) and process mass intensity (PMI) values compared to conventional methanol-based methods, underscoring the reduced environmental footprint of this approach. Overall, this strategy provides a greener, safer, and industrially viable route to pharmaceutically relevant indirubin scaffolds, fully aligned with sustainable chemistry principles.