An Efficient Method for the Synthesis of Laquinimod |
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Authors: | Yanyan Huang Ying Feng Wensheng Gao Chao Zhang Ligong Chen |
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Institution: | 1. School of Chemical Engineering and Technology, Tianjin University, Tianjin, People's Republic of China;2. Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin, People's Republic of China |
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Abstract: | Laquinimod, 5‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐ phenyl‐3‐quinoline carboxamide, is an oral drug in clinical trials for the treatment of multiple sclerosis. An efficient synthetic method for laquinimod from 2‐amino‐6‐chlorobenzoic acid via four steps was established. The overall yield of laquinimod is up to 82% as compared with 70% reported in literature. It has also been demonstrated that green reagent dimethyl carbonate is not suitable for the N‐methylation of 5‐chloroisatoic anhydride owing to the ring‐cleavage reaction induced by the generated methanol. The ring‐cleavage by‐products were isolated and characterized by 1H‐NMR and 13C‐NMR. In addition, in the study of laquinimod derivatives, we found that 5‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐phenyl‐3‐quinoline carboxamide (laquinimod) was obtained in much higher yield than 7‐chloro‐1,2‐dihydro‐N‐ethyl‐4‐hydroxy‐1‐methyl‐2‐oxo‐N‐phenyl‐3‐quinoline carboxamide under the same reaction conditions, and it is possibly attributed to a neighboring group effect. |
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