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

## TL;DR

A new green method uses deep eutectic solvents to efficiently and sustainably produce indirubin and its derivatives, reducing environmental impact.

## Contribution

A scalable, solvent-free synthesis of indirubin using deep eutectic solvents with high yield and low environmental impact.

## Key findings

- Indirubin was synthesized in 70% yield using a choline chloride/urea deep eutectic solvent without chromatography.
- The method enabled the production of various indirubin derivatives, including N-alkylated analogs with photoswitchable properties.
- CHEM21 metrics showed a 3.7-fold reduction in E-factor and improved sustainability compared to traditional methods.

## Abstract

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.

A sustainable protocol for the synthesis of indirubin in a choline chloride/urea deep eutectic solvent at 70°C under air affords the product in 70% yield without chromatography. The method is robust, scalable to pilot scale, and enables late‐stage functionalization, granting access to a wide range of indirubin derivatives. CHEM21 green metrics validate its markedly lower environmental impact compared to conventional routes.© 2026 WILEY‐VCH GmbH