Lulu Wang, Min-jie Liu, Meifen Jiang
May 31, 2022
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Influential Citations
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Journal
Chemistry
Abstract
Diclofenac sodium is a widely used nonsteroidal anti-inflammatory drug (NSAID) as over-the-counter (OTC) medication for the treatment of inflammatory diseases. Herein, we described the development of an intensified six-step continuous flow synthesis of diclofenac sodium from commercially available aniline and chloroacetic acid. 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 key step in this multistep synthetic chemistry. The undesired amide hydrolysis in Smiles rearrangement was addressed and the extra installation of N-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.