- An Efficient Method for the Synthesis of Laquinimod
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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.
- Huang, Yanyan,Feng, Ying,Gao, Wensheng,Zhang, Chao,Chen, Ligong
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- INTERMEDIATE COMPOUNDS AND PROCESSES FOR THE PREPARATION OF QUINOLINE DERIVATIVES SUCH AS LAQUINIMOD SODIUM
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The present invention relates to processes for the preparation of quinoline-3 -carboxamide derivatives, such as sodium 5-chloro-3-(ethylphenylcarbamoyl)-l-methyl-2- oxo-l,2-dihydroquinolin-4-olate (Laquinimod sodium). The present invention further relates to intermediates formed in such processes.
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Page/Page column 21-23
(2012/06/15)
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