Methanesulfonic acid imatinib polymorphic substance and medical combination thereof

A technology of imatinib mesylate and polymorphs, which is applied in drug combinations, antineoplastic drugs, pharmaceutical formulations, etc., can solve the problems of inability to effectively remove mechanical impurities, unstable reproducibility, and poor product purity, etc. problem, to achieve the effect suitable for industrial scale preparation, good stability and high purity

Active Publication Date: 2014-09-03
NANJING CAVENDISH BIO ENG TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These existing methods have a series of shortcomings such as cumbersome process, unstable reproducibility, technical solutions that cannot ensure the effective removal of mechanical impurities, technical solutions that will lead to the risk of genotoxic impurities remaining in the product, unsuitable for industrial production, and poor product purity.

Method used

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  • Methanesulfonic acid imatinib polymorphic substance and medical combination thereof
  • Methanesulfonic acid imatinib polymorphic substance and medical combination thereof
  • Methanesulfonic acid imatinib polymorphic substance and medical combination thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] The preparation of embodiment 1 imatinib mesylate crude product

[0102] Add imatinib (2Kg), methanesulfonic acid (390g) and acetone (20L) into the reaction flask, heat up to reflux for 2.5 hours under stirring. Cool down to room temperature, stir and crystallize for 3 hours. After suction filtration, the obtained filter cake was collected and dried under reduced pressure at 70°C to constant weight to obtain 2.2Kg of crude imatinib mesylate. Yield, 92.1%.

[0103] Purity: 98.7%.

Embodiment 2

[0104] The preparation of embodiment 2 polymorph III

[0105] Preparation of imatinib free base

[0106] The crude imatinib mesylate obtained in Example 1 (1.5 Kg) was added into water (15 L), heated to 60° C., and stirred to dissolve. Suction to remove impurities. The filtrate was cooled to room temperature, and acetone (4.5 L) was added with stirring. Sodium bicarbonate (214 g) was added and crystallized at room temperature for 3 hours. After suction filtration, the filter cake was washed with water and dried to constant weight to obtain 1.17Kg of imatinib. Yield: 92.9%.

[0107] Preparation of imatinib mesylate

[0108] The imatinib (80g) obtained above, methanesulfonic acid (15.6g) and methyl tert-butyl ether (800ml) were added into the reaction flask, and the temperature was raised to reflux for 2 hours under stirring. Cool down to room temperature, stir and crystallize for 1 hour. After suction filtration, the obtained filter cake was collected and dried under red...

Embodiment 3

[0111] The preparation of embodiment 3 polymorph III

[0112] According to the existing method, we used different crystal forms of imatinib mesylate prepared by different processes as raw materials, and used the scheme of Example 2 to prepare the data list of polymorph III as follows:

[0113]

[0114] It can be seen from the above test data that the crude product of imatinib mesylate in any crystal form can be converted into the crystal form of the present invention. At the same time, impurities can be effectively removed to obtain high-purity imatinib mesylate up to 99.9%.

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Abstract

The invention discloses methanesulfonic acid imatinib polymorphic substance III. In addition, the invention further discloses a preparation and medical combination of the methanesulfonic acid imatinib polymorphic substance III.

Description

technical field [0001] The present invention relates to the polymorphic form of pharmaceutical compound, more specifically, relate to a kind of novel polymorphic form of imatinib mesylate, in addition, the present invention also relates to the preparation method of this polymorphic form and its pharmaceutical composition. Background technique [0002] Imatinib mesylate, a tyrosinase inhibitor, is used in the treatment of gastrointestinal stromal tumors (GISTs). Its chemical name is 4-(4-methylpiperazine-1-methyl)-N-[4-methyl-3-(4-pyridin-3-yl)pyrimidine-2-amino]phenyl]-benzene Formamide methanesulfonate, the chemical structure is as follows: [0003] [0004] Chinese patent application-Application No. 98807303.X (hereinafter referred to as Patent Application No. 303) discloses two polymorphs α and β of imatinib mesylate; wherein, the α crystal form is characterized by hygroscopicity, flow Needle crystal with poor properties, its typical XRPD pattern shows that the α-fo...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04A61K31/506A61P35/00
Inventor 严荣杨浩许永翔
Owner NANJING CAVENDISH BIO ENG TECH
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