Process for Preparing Quinoline-3-Carboxamide Derivatives
AssigneeActavis Group Ptc Ehf
InventorsGirish Dixit, Krishnadatt Sharma, Kundan Singh Shekhawat, Nitin Sharadchandra Pradhan, Jon Valgeirsson
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Abstract
Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of quinoline-3-carboxamide derivatives such as laquinimod, or a pharmaceutically acceptable salt thereof, in high yield and purity.
Claims29
A process for the preparation of substituted quinoline-3-carboxamide compound of formula I:
- wherein
- R is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec.-butyl and allyl;
- R1 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, methylthio, ethylthio, n-propylthio, methylsulphinyl, ethylsulphinyl, fluoro, chloro, bromo, trifluoromethyl, difluoromethoxy and trifluoromethoxy;
- R2 is hydrogen;
- or
- R1 and R2 together can be methylenedioxy, ethylenedioxy and isopropylidenedioxy;
- R3 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethoxy and trifluoromethoxy;
- and
- R4 is selected from hydrogen, fluoro and chloro, with the proviso that R4 is selected from fluoro and chloro only when R3 is selected from fluoro and chloro;
- comprising:
- reacting a quinoline-3-carboxylic acid derivative of formula II:
- wherein R1 and R2 are as defined in formula I;
- with an aniline derivative of formula III:
- wherein R, R3 and R4 are as defined in formula I;
- in the presence of a coupling agent in a solvent to provide a substantially pure compound of formula I and optionally converting the compound of formula I obtained into a pharmaceutically acceptable salt thereof;
- wherein the coupling agent is selected from the group consisting of dichlorotriphenyl phosphorane, phosphorous oxychloride, O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU), and combinations comprising one or more of the foregoing coupling agents.
A process for the preparation of laquinimod of formula I(i) or a pharmaceutically acceptable salt thereof, comprising reacting 1,2-dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid with N-ethyl aniline in the presence of thionyl chloride and a base selected from the group consisting of diisopropylethylamine and pyridine;
- and isolating pure laquinimod from a suitable solvent and optionally converting the laquinimod obtained into a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.