Preparation method of dasatinib

Abstract

The invention discloses a preparation method of dasatinib. The preparation method comprises the following steps: (1) preparing N-(2-chloro-6-methyl-phenyl)-2-[(6-chloro-2-methyl-4-pyrimidyl)amino]-5-thiazole carboxamides; (2) preparing a dasatinib crude product; (3) refining the dasatinib: adding the dasatinib crude product and absolute methanol into a reaction kettle, stirring, performing nitrogen displacement, heating to refluxing while stirring, cooling, adding a seed crystal, stirring materials uniformly, cooling to 5 to 10 DEG in a uniform-speed cooling way, stirring at a constant temperature, filtering the materials, leaching an obtained filter cake with a proper amount of methanol, and drying the filter cake in a gradient heating way to a constant weight to obtain a dasatinib product. The preparation method has the advantages of simple process, high product yield and high product purity; the prepared Dasatinib product of a Form I crystal form has high stability, and the bioavailability of the product is equivalent to an existing T1H1-7 crystal form product.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a preparation method of dasatinib. Background technique [0002] Dasatinib, also known as Sprycel, is an off-white to yellow solid chemical. Chemical name N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl ]amino]-5-thiazolecarboxamide, the molecular formula is C 22 h 26 ClN 7 o 2 S, the molecular weight is 488.01, and the structural formula is: [0003] [0004] Dasatinib is an antineoplastic drug, clinically mainly used for the treatment of chronic phase, accelerated phase and blast phase of Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) resistant to or intolerant of imatinib mesylate (acute myeloid change and acute lymphoblastic change) adult patients. [0005] The patent CN1980909 researched and disclosed by Bristol-Myers Squibb Company uses 2-amino-3-chloro-toluene and 2-methyl-3-chloro-5-...

AI Technical Summary

Problems solved by technology

The product yield of this method is low, and raw material cost is too high, and part raw material does not have industrialized product at the same time, so large-scale industrial production is restricted very much; Patent CN1980909, 4,6- Dichloro-2-methylpyrimidine was first reacted with N-hydroxyethylpiperazine, and then reacted with 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazole amide to synthesize dasatinib , the last step of the method is to use palladium acetate as a catalyst, BINAP as a chelating agent, and adopt column chromatography to separate, the production cost is high, and industrial production is limited

At present, there are still some deficiencies in the preparation method of dasatinib, and research and improvement are still needed, and the product developed by Bristol-Myers Squibb is the monohydrate T1H1-7, and the preparation of other crystal forms of dasatinib products Research and development and application of existing technologies are rarely disclosed

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