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Crystallization purification method

A technology of crystallization and crystallization, applied in the direction of organic chemistry, etc., can solve the problems of difficulty in reducing, low product yield, unfavorable solvent recovery, etc., and achieves the effect of easy operation and high product purity.

Active Publication Date: 2015-03-11
SUNSHINE LAKE PHARM CO LTD
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  • Abstract
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  • Claims
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Problems solved by technology

[0004] There are double bonds in the structure of afatinib, and it is easy to produce cis-isomer impurities during the preparation process, which is difficult to remove
Documents such as PCT application WO2012121764 and WO2013052157 disclose the use of butyl acetate and methylcyclohexane mixed solution crystallization to obtain afatinib free base; the product cis-isomer impurity obtained according to the method is difficult to be reduced to below 0.1%, and the product The yield is low, and the use of mixed solvents is not conducive to solvent recovery in production

Method used

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specific Embodiment approach

[0016] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0017] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

[0018] In the present invention, g means gram, mL means milliliter, min means minute, and mmol means millimole.

Embodiment 1

[0020] Take 10.0g of afatinib crude product and add it to 50mL of isobutyl acetate, stir, and heat to 70°C. After stirring at ℃ for 5 hours, it was filtered, and the obtained solid was washed 3 times with isobutyl acetate, 20 mL each time. The obtained solid was vacuum-dried to dryness at 50° C. to obtain 9.4 g of afatinib with a purity of 99.81%, and a cis-isomer purity of 0.03%.

Embodiment 2

[0022] Take 40.0g of crude afatinib and add it to 400mL of isobutyl acetate, stir, heat to 80°C, dissolve the solution and filter it while it is hot, and cool the obtained filtrate to 25°C-35°C within 3 hours to 4 hours. After stirring at 25°C-35°C for 5 hours, it was filtered, and the obtained solid was washed with isobutyl acetate three times, 80 mL each time. The obtained solid was vacuum-dried to dryness at 60°C to obtain 36.79 g of afatinib with a purity of 99.84% and a cis-isomer of 0.03%.

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Abstract

Belonging to the field of pharmaceutical chemistry, the invention relates to a crystallization purification method for Afatinib. The method includes: mixing an Afatinib crude product with isobutyl acetate, conducting stirring and heating to obtain a clarified solution, then cooling the obtained clarified solution, carrying out stirring crystallization for certain period of time, and then performing solid-liquid separation to obtain the product Afatinib. Specifically, the Afatinib crude product and isobutyl acetate are in a mass ratio of 1:3-1:20. By using isobutyl acetate as the crystallization solvent and controlling the crystallization conditions, the cis-isomer impurities of Afatinib can be effectively reduced, the obtained product has high purity, and the operation is simple, thus being favorable of industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a method for crystallization and purification of afatinib, a drug that inhibits tyrosine kinase. Background technique [0002] Afatinib, the chemical name is (2E)-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -Oxo-2-buten-1-yl]amino}-7-((3S)-tetrahydrofuran-3-yloxy)-quinazoline; is epidermal growth factor receptor (EGFR) and human epidermal growth factor An irreversible inhibitor of receptor 2 (HER2) tyrosine kinase, its dimaleate has been approved for the treatment of diseases such as advanced non-small cell lung cancer (NSCLC), and the structure of afatinib is shown in formula (1) : [0003] [0004] There are double bonds in the structure of afatinib, which is easy to produce cis-isomer impurities during the preparation process, which is difficult to remove. Documents such as PCT application WO2012121764 and WO2013052157 disclose the use of butyl aceta...

Claims

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Application Information

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IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 杨凤智刘浩泉罗勇峰李林
Owner SUNSHINE LAKE PHARM CO LTD
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