Preparation method of high-purity imatinib

Abstract

The invention relates to a preparation method of high-purity imatinib, which comprises the following steps: taking 4-[(4-methyl-1-piperazine) methyl] benzoyl chloride dihydrochloride and N-(5-amino-2-methyl phenyl)-4-(3-pyridine)-2-pyrilamine as raw materials, taking acetonitrile or pyridine as a solvent, and adding triethylamine as an acid-binding agent when the acetonitrile is taken as the solvent to react at the reaction temperature of -5-50 DEG C; removing the solvent in the reaction liquid to recycle the solvent; adding water into the residues; extracting impurities by ethyl acetate; separating the organic phase from the water phase; then neutralizing the water phase by ammonia water until the PH is 9-10; and adding saturated fatty alcohol to precipitate imatinib crystals. Because the purity of the product obtained by the preparation method of the invention is higher than 99.5%, the single impurity is less than 0.10%, and the solvent has low dosage and can be recycled, the production cost can be greatly reduced, and the pollution on the environment can be reduced. Moreover, the method has simple operation processes and mild reaction conditions, thus the method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine, in particular to a preparation method of high-purity imatinib. Background technique [0002] Imatinib is the precursor for the preparation of imatinib mesylate, which is clinically used to treat various tumors, especially for the treatment of chronic myeloid leukemia (CML). It was originally successfully developed by Swiss Novartis , and was approved by the FDA in 2001. In 2002, the FDA approved the drug as a drug for the treatment of gastrointestinal stromal tumors. The chemical name of this drug is 4-[(4-methyl-1-piperazine)methyl]-N-[4-methyl-3-[[4-(3-pyridine)-2-pyrimidine]amino] Phenyl]benzamide. [0003] In the prior art, many documents have reported the preparation method of imatinib, among which EP0564409, US20060149061, US20060223817, WO2004 / 074502, US2008 / 0103305 and WO2008 / 051597 and other patent documents all adopt the method shown in the following formula or A similar method is ...

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Problems solved by technology

[0005] But, the common shortcoming that above-mentioned this preparation method exists is that purity is mostly between 97%-98%, impurity content also does not see detailed report, and used pyridine solvent amount is large (volume / mass=40 / 1) and does not reclaim, Therefore, the pollution caused is large, and the cost is high, and the residual amount of solvent in the product is relatively large, resulting in insufficient purity

According to the Q3A regulations of ICH (International Council for Harmonization of Technical Requirements for Registration of Drugs for Human Use), the requirement for the bulk drug is that the purity is greater than 99.0%, and the content of a single impurity is less than 0.10%, so the above-mentioned preparation method cannot meet this requirement.

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