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A kind of refining method of afatinib

A refining method and afatinib technology, which are applied in the refining field of afatinib, can solve the problems that afatinib dimaleate cannot meet the requirements for medicinal use, etc., and achieve good impurity removal effect and ease of use. Operation, effect of low impurity content

Active Publication Date: 2018-06-29
刘云涛 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] For the refining of the crude product of afatinib, in general, the prior art mainly carries out recrystallization with a single solvent such as ethanol, acetonitrile, or ethyl acetate / methylcyclohexane, ethyl acetate / n-heptane, dichloromethane / Mixed solvents such as n-heptane carry out recrystallization to remove the impurity generated in the synthesis reaction process, and its refining yield is in the range of 80-90%; and it is difficult to reduce the content of degraded impurity H to below 0.1% by using existing refining methods, Make subsequent preparation of afatinib dimaleate can not meet the requirements of medicine
Chinese patent application "A method for crystallization and impurity removal" (CN104402872A, published on March 11, 2015) discloses a method for crystallization and purification of afatinib, which discloses the use of a single solvent for cis-isomer impurities Isobutyl acetate is recrystallized, and the obtained product has high purity, but the removal of the hydroxylated impurity H (as shown in formula (B)) generated by the degradation and removal of dimethylamine that is most likely to occur in the preparation process has not been carried out. Inspection and explanation

Method used

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  • A kind of refining method of afatinib
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Examples

Experimental program
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Effect test

preparation example Construction

[0024] This reference example is used to illustrate the preparation method of afatinib crude product. Specific steps are as follows:

[0025] a. Add 6.49kg of carbonyldiimidazole to 15.0L of tetrahydrofuran, stir, raise the temperature to 40±2°C, add 7.85kg of diethylphosphonoacetic acid and 7.5L of tetrahydrofuran solution dropwise, and keep stirring at 35-40°C for 0.5- 1h, obtain solution A, standby;

[0026] b. 7.5kg of N-4-(3-chloro-4-fluorophenyl)-7-[[(3S)-tetrahydro-3-furyl]oxy]-4,6-quinazolinediamine Add to 30.0L tetrahydrofuran, heat up to 0±2°C, add the pre-prepared solution A; keep stirring at 30±2°C for 2 hours, after the reaction is complete, add 75.0L methyl tert-butyl ether, stir and crystallize at room temperature overnight, centrifuge, Use 20L of tetrahydrofuran / methyl tert-butyl ether mixed solution (1:1) and 20.0L of purified water to wash the solid successively, and dry to obtain (S)-diethyl(2-((4-((3-chloro-4 -Fluorophenyl)amino)-7-((tetrahydro-3-furyl)o...

Embodiment 1

[0030] Take 300g of the crude product of afatinib prepared in the reference example, add it to a mixed solution of 300mL of anhydrous methanol and 300mL of acetone, heat up to 50°C, stir to dissolve, slowly add 3.0L of methyl tert-butyl ether, at 50°C Insulated and stirred for 30 minutes, cooled to 25°C for 2 hours, crystallized at 25°C for 3 hours, centrifuged, washed the solid with 500 mL of methyl tert-butyl ether, and dried to obtain 239 g of afatinib as a white solid.

[0031] The purity of the obtained solid was 99.737%, the impurity H content was 0.048%, the largest unknown monomer impurity content was 0.076%, and the total impurity content was 0.263%.

Embodiment 2

[0033] Take 1.00 kg of the crude product of afatinib prepared in the reference example, add it to a mixed solution of 1.0 L of anhydrous methanol and 1.0 L of acetone, raise the temperature to 50 ° C, stir and dissolve, and slowly add 10.0 L of methyl tert-butyl ether, Stir at 50°C for 30min, cool down to 20-30°C for 1h, crystallize at 20-30°C for 2h, centrifuge, rinse the solid with 1.0L of methyl tert-butyl ether, and dry to obtain 826g of afatinib as a white solid.

[0034] The obtained solid had a purity of 99.878%, an impurity H content of 0.023%, a maximum unknown monomer impurity content of 0.050%, and a total impurity content of 0.122%.

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Abstract

The invention relates to a refinement method of afatinib. The method comprises the following steps: 1) adding an afatinib crude product into an alcohol-acetone mixed solvent, heating and stirring until the afatinib crude product is completely dissolved; 2) adding methyl tert-butyl ether into the mixture in the step 1) while keeping the temperature, and uniformly stirring; 3) cooling the mixture in the step 2) until crystals precipitate, and meanwhile, stirring; 4) carrying out vacuum filtration on the crystals obtained in the step 3), and drying to obtain the refined afatinib. The method provided by the invention is easy to operate, and has the advantages of simple technique, favorable impurity removal effect and low cost. The purity of the refined afatinib product is up to 99.0 wt% or above, the maximum monomer impurity content is less than 0.1 wt%, and the total impurity content is less than 1.0 wt%, so the impurity content is very low.

Description

technical field [0001] The invention belongs to the technical field of medicine refining, and in particular relates to a method for refining afatinib. Background technique [0002] Afatinib, the chemical name is N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[[(3S)-tetrahydro-3-furyl]oxy] -6-quinazolinyl]-4-(dimethylamino)-2-butenamide. The structural formula of Afatinib is shown in the following formula (A): [0003] [0004] Afatinib dimaleate was approved in the United States in 2013 for the treatment of metastatic non-small cell lung cancer with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation (NSCLC) treatment under the trade name This species is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER-2) dual tyrosine kinase (TK) developed by Boehringer Ingelheim Pharmaceutical Company of Germany . 2003094921 [0005] Patent literature "Utilization of inhib...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/12
CPCC07D405/12
Inventor 邱军刘云涛
Owner 刘云涛
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