Process for the preparation of marimastat, marimastat prepared by this process, a pharmaceutical composition comprising the same, and uses thereof

A process for the preparation of marimastat, characterized in that the process includes the following steps:

• a) (2S,3R)-2-hydroxy-3-isobutylsuccinic acid is reacted in the environment of 2,2-dimethoxypropane with the addition of p-toluenesulfonic acid, pyridinium p-toluenesulfonate or 10-camphorsulfonic acid at a temperature of 35-55° C. for 15-30 h, then after the reaction is completed, a tertiary amine selected from the group comprising diisopropylethylamine, triethylamine and N-methylmorpholine is added to obtain (R)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanoic acid;
• b) (R)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanoic acid is reacted with (S)-2-amino-N,3,3-trimethylbutanamide or its hydrochloride in the environment of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate and a tertiary amine selected from the group comprising diisopropylethylamine, triethylamine and N-methylmorpholine in acetonitrile or methylene chloride, then the reaction mixture is subjected to an extraction process to obtain crude (R)-N-((S)-3,3-dimethyl-1-methylamino-1-oxobutan-2-yl)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanamide, which is then used in step c) or macerated at boiling in methyl tert-butyl ether or isopropyl ether for 1-3 h, and then at room temperature for 15-30 h to obtain (R)-N-((S)-3,3-dimethyl-1-methylamino-1-oxobutan-2-yl)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanamide;
• and
• c) (R)-N-((S)-3,3-dimethyl-1-methylamino-1-oxobutan-2-yl)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanamide or crude (R)-N-((S)-3,3-dimethyl-1-methylamino-1-oxobutan-2-yl)-2-((S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)-4-methylpentanamide is reacted with a 50% aqueous solution of hydroxylamine in a solvent selected from a lower carboxylic acid ester, a non-polar solvent or a polar solvent, then acetone is added and stirred at boiling for 0.5-1 h, then the reaction mixture is subjected to azeotropic distillation process in order to remove water, and then stirred at room temperature for 15-30 h to obtain marimastat.