Sustainable and Scalable Amidations in Water Using Continuous Slurry-Flow Technology

The widespread use of peptide-based drugs and the prevalence of amide-containing pharmaceuticals underscore the critical need for efficient, sustainable, and environmentally friendly amidation methods in the pharmaceutical industry. However, traditional approaches rely on harmful solvents, highlighting the urgent need for a paradigm shift toward greener alternatives. We leveraged continuous slurry flow technology to facilitate solid handling and develop scalable and sustainable protocols for amide bond formation in water as the reaction medium. To ensure optimal mass transfer through efficient active mixing, we utilized a spinning disc reactor and an agitated continuous stirred-tank reactor series, both of which are commercially available, including industrial-scale versions. As model reactions, we selected the synthesis of a key efaproxiral intermediate and a technically challenging amidation involving a protected tryptophan derivative. The best results were achieved using hydroxypropyl methylcellulose, a cost-effective, nontoxic, cellulose-derived surface-active agent in water. The optimized lab-scale protocols enabled rapid amidations with productivities of up to 2 kg per day. Notably, neither the synthesis nor the isolation processes required any organic solvents, resulting in minimal waste generation.