Development and Scale-Up of a Fully Continuous Flow Synthesis of 2-Hydroxypyridine-N-oxide

A fully continuous flow synthesis of 2-hydroxypyridine-N-oxide (HOPO), an important peptide coupling reagent used in a variety of pharmaceutical ingredient preparations, was designed, developed, and scaled up. The process involved the catalytic oxidation of 2-hydroxypyridine using hydrogen peroxide, followed by quenching and hydrolysis to obtain HOPO in an aqueous solution. A mixed fixed bed reactor was designed featuring a 3D-printed static mixer to achieve the complete conversion of the raw materials, and a continuous post-treatment process involving acid crystallization was developed to obtain a high-quality solid HOPO product. The continuous reaction process and post-treatment process resulted in >90% isolated yield with no need for additional separation and purification steps, thus avoiding an interruption of the continuous reaction. The scale-up process successfully achieved a production rate of 8 kg/day, making this synthesis method highly suitable for industrial applications.