Method for controlling impurities difficult to remove in synthesis of antitumor drug sunitinib

Abstract

The invention discloses a method for controlling impurities difficult to remove in synthesis of an antitumor drug, namely sunitinib. The method comprises the following steps: (1) preparing a mixed solution of DCM and DMF, conducting cooling, then dropwise adding oxalyl chloride, carrying out heating, and performing reacting to obtain a solution A; (2) after cooling, dropwise adding a DCM solutionof an intermediate III into the solution A, and continuing stirring for a react until a solution B is completely obtained; (3) adding water into the solution B, separating out a water phase, adjustinga pH value to be slightly larger than 7 by using alkali, and conducting filtering to obtain a precipitate; (4) dissolving the precipitate with ethyl acetate, and successively carrying out washing, drying and filtering to obtain a crude product; (5) washing the crude product with ethyl acetate, and collecting a filtrate; (6) concentrating the filtrate under reduced pressure, and drying the filtrate to obtain an intermediate IV; and (7) mixing toluene, 5-fluoroindolone, the intermediate IV and a potassium hydroxide solution, conducting stirring at room temperature until a reaction is finished,carrying out filtering, pulping a solid with water, and conducting drying to obtain a product. The above operations are carried out under a dark condition. According to the method, the content of impurities difficult to remove can be controlled to be lower than 0.1%, and overall yield is not affected.

Description

technical field [0001] The invention relates to the field of synthesis of anti-tumor pharmaceutical compounds, in particular to a control method for difficult-to-remove impurities in the process of preparing the anti-tumor drug sunitinib. Background technique [0002] Sunitinib is an anti-tumor drug developed by Pfizer of the United States, which was first launched in the United States in 2006. It is a highly selective multi-target tyrosine kinase inhibitor, which can cut off the blood and nutrients needed for tumor growth, kill cancer cells, and is clinically used for the treatment of gastrointestinal stromal tumors and advanced renal cancer. [0003] Sunitinib will be degraded during the preparation process to produce a difficult-to-remove impurity, which is the deethylation product A (see the following formula). Since it differs from sunitinib in structure by only one ethyl group, and its properties are very similar, it is difficult and expensive to remove. [0004] ...

AI Technical Summary

Problems solved by technology

Since it differs from sunitinib in structure by only one ethyl group, and its properties are very similar, it is difficult and expensive to remove

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