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, harmful solvents have traditionally been relied upon, highlighting the urgent need for a paradigm shift toward greener alternatives. Continuous slurry flow technology was leveraged to facilitate solid handling and to develop scalable and sustainable protocols for amide bond formation with water as the reaction medium. To ensure optimal mass transfer through efficient active mixing, a spinning disc reactor and an agitated continuous stirred-tank reactor series—both commercially available, including industrial-scale versions—were utilized. The synthesis of a key efaproxiral intermediate and a technically challenging amidation involving a protected tryptophan derivative were selected as model reactions. The best results were achieved using hydroxypropyl methylcellulose, a cost-effective, non-toxic, cellulose-derived surface-active agent in water. Rapid amidations with productivities of up to 2 kilograms per day were enabled by the optimized lab-scale protocols. Notably, neither the synthesis nor the isolation processes required any organic solvents, and minimal waste was generated.

• Rajendran, S
• Kogler, S
• Kögl, P
• Braje, W
• Ötvös, S
• Kappe, C

• Research Center Pharmaceutical Engineering (Austria)

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