Development and Scale-Up of a Fully Continuous Flow Synthesis of 2-Hydroxypyridine-N-oxide,Organic Process Research & Development

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Development and Scale-Up of a Fully Continuous Flow Synthesis of 2-Hydroxypyridine-N-oxide
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-12-16 , DOI: 10.1021/acs.oprd.3c00285
Jian Tao _{1,

2} , Hongjian Li ₂ , Jian Zuo ₂ , Ying Li ₂ , Furong Chen ₂ , Yong Kang ₁

Affiliation

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.

中文翻译：

2-羟基吡啶-N-氧化物的完全连续流动合成的开发和放大

2-羟基吡啶-N-氧化物 (HOPO) 是一种重要的肽偶联试剂，用于多种药物成分制剂，我们设计、开发并扩大了其完全连续流程合成。该过程涉及使用过氧化氢催化氧化 2-羟基吡啶，然后淬灭和水解以在水溶液中获得 HOPO。设计了具有3D打印静态混合器的混合固定床反应器，以实现原料的完全转化，并开发了涉及酸结晶的连续后处理工艺，以获得高质量的固体HOPO产品。连续反应过程和后处理过程导致分离收率>90%，无需额外的分离和纯化步骤，从而避免了连续反应的中断。放大过程成功实现了8公斤/天的生产率，使得该合成方法非常适合工业应用。

更新日期：2023-12-16

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