Six-step continuous flow synthesis of diclofenac sodium via cascade etherification/smiles rearrangement strategy: tackling the issues of batch processing
Six-step continuous flow synthesis of diclofenac sodium via cascade etherification/smiles rearrangement strategy: tackling the issues of batch processing
复制标题
通过级联醚化/smile重排策略六步连续流程合成双氯芬酸钠：解决批量处理问题
DOI：
10.1002/chem.202201420
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Fener Chen
中科院分区：
文献类型：
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作者：
Lulu Wang;Minjie Liu;Meifen Jiang;Li Wan;Weijian Li;Dang Cheng;Fener Chen
双氯芬酸钠是一种广泛使用的非甾体抗炎药（NSAID），作为治疗炎症性疾病的非处方（OTC）药物。本文介绍了一种由市售苯胺和氯乙酸强化的六步连续流合成双氯芬酸钠的方法。2 -氯- N -苯乙酰胺和2,6 -二氯苯酚的醚化/Smiles重排级联反应是该多步合成化学的关键步骤，具有挑战性和前所未有的，并且在连续流中精确控制反应条件。解决了Smiles重排中不希望的酰胺水解问题，避免了当前工业批处理模式下n -氯乙酰基的额外安装。双氯芬酸钠的分离收率为63%，每步平均收率在90%以上，总停留时间为205 min。
Diclofenac sodium is a widely used nonsteroidal anti‐inflammatory drug (NSAID) as over‐the‐counter (OTC) medication for the treatment of inflammatory diseases. Herein, the development of an intensified six‐step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid is described. A challenging and unprecedented etherification/Smiles rearrangement cascade of 2‐chloro‐N‐phenylacetamide and 2,6‐dichlorophenol into hydroxyacetyldiphenylamine operated with the precise control of reaction conditions in continuous flow was realized as the key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation ofN‐chloroacetyl group in current industrial batch mode was avoided. Diclofenac sodium was obtained in 63 % isolated yield with an average yield of above 90 % for each step in a total residence time of 205 min.