- Preparation method of intermediate (2-aminophenyl)dimethyl phosphine oxide of Brigatinib
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The invention provides a preparation method of an intermediate (2-aminophenyl)dimethyl phosphine oxide of Brigatinib, and belongs to the technical field of organic synthesis. The method comprises thefollowing steps: (1) reacting an intermediate I-1 with an intermediate I-2 in the presence of a catalyst at a certain temperature to obtain an intermediate I-3; (2) reacting the intermediate I-3 witha methyl Grignard reagent in a first solvent at a low temperature to obtain an intermediate I crude product; (3) reacting the intermediate I crude product with an acid in a second solvent to form a salt of the intermediate I, and performing recrystallization to obtain a pure product of the salt of the intermediate I; and (4) carrying out alkaline hydrolysis on the pure product of the salt of the intermediate I, and performing extraction with a third solvent to obtain the intermediate I pure product. In the first step, the coupling reaction conditions are mild, the formed intermediate is directly subjected to the next step of reaction without separation and purification, the obtained crude product is salified with a proper amount of acid to form a good solid, the solid is recrystallized toobtain the intermediate with very high purity, and the intermediate I pure product is obtained through free extraction under the alkaline condition. The cost is reduced by 50% or above compared with the prior art.
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Paragraph 0100-0105
(2020/02/14)
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