Malate salt of n-(4-{ 6,7-bis(methyloxy)quinolin-4-yloxy} phenyl)-n-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer

摘要

Disclosed is a process for preparing cabozantinib (N-(4-{ [6,7-bis(methyloxy)quinolin-4-yl]oxy} phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide / N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide / BMS-907351 / XL-184), comprising the steps of: (a) preparing 4-chloro-6,7-dimethoxy-quinoline by reacting 6,7-dimethoxy-1H-quinolin-4-one / 6,7-dimethoxy-quinoline-4ol with phosphoryl chloride (POCl3) in acetonitrile; (b) preparing 6,7dimethoxy-4-(4-nitro-phenoxy)-quinoline by reacting 4-chloro-6,7-dimethoxy-quinoline with 4-nitrophenol in the presence of 2,6-lutidine; (c) preparing 6,7dimethoxy-4-(4-amino-phenoxy)-quinoline / 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine by reducing 6,7dimethoxy-4-(4-nitro-phenoxy)-quinoline in the presence of formic acid, potassium formate, and Palladium on carbon in tetrahydrofuran; and (d) preparing cabozantinib by reacting 4-(6,7-dimethoxy-quinolin-4-yloxy)-phenylamine with 1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride in the presence of potassium carbonate, water, and tetrahydrofuran. Also disclosed are processes for the preparation of crystalline and amorphous forms of cabozantinib malate.