Study On The Synthesis Of Laquinimod

Laquinimod, 5-chloro-1, 2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carboxamide, is a novel immunoregulative agent developed by Active Biotech and Teva. It displays precisely clinic effect, excellent tolerability and favorable side effect profile over the other drugs, will have a bright future for treating multiple sclerosis. Therefore, the synthesis of laquinimod was systematically investigated in this paper, and an efficient synthetic route of laquinimod from 2-amino-6-chlorobenzoic acid via four steps of cyclization(yield 97%), N-methylation(yield 87%), nucleophilic substitution(yield 99%) and N-acylation(yield 97%) was successfully established. The reaction parameters for each related reaction were optimized, under the optimized reaction conditions, laquinimod was obtained in the overall yield of 82% as compared with 71% 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 ringcleavage reaction induced by the generated methanol. The ring-cleavage byproducts were isolated and characterized by 1H NMR and 13 C NMR. In addition, in the synthesis of laquinimod derivatives, we accidentally found that 5-chloro-1,2-dihydro-N-ethyl-4-hydroxy-1-methyl-2-oxo-N-phenyl-3-quinoline carbo xamide 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 stereo-hindrance effect or intramolecular hydrogen bond.Moreover, the nonhygroscopic sodium salt of laquinimod was chosen as the final drug form due to its excellent stability during storage and the fact that some minor impurities in laquinimod were removed in the salt-forming step. Sodium salt of laquinimod was obtain in 95% yield and 99.5% purity.