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An Efficient Method for the Synthesis of Laquinimod
Author(s) -
Huang Yanyan,
Feng Ying,
Gao Wensheng,
Zhang Chao,
Chen Ligong
Publication year - 2016
Publication title -
journal of heterocyclic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.321
H-Index - 59
eISSN - 1943-5193
pISSN - 0022-152X
DOI - 10.1002/jhet.2324
Subject(s) - chemistry , quinoline , reagent , ring (chemistry) , yield (engineering) , carboxamide , cleavage (geology) , methanol , organic chemistry , medicinal chemistry , stereochemistry , materials science , geotechnical engineering , fracture (geology) , engineering , metallurgy
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 1 H‐NMR and 13 C‐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.