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Ultrasonic preparation method for imatinib mesylate crystal

A technology of imatinib mesylate and imatinib base, which is applied in the field of ultrasonic preparation of imatinib mesylate crystals, and can solve the problem of poor product stability, deterioration of imatinib, and methanesulfonic acid. Excessive and other problems, to achieve the effect of low solvent residue, firm binding state and good stability

Active Publication Date: 2012-07-18
SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] But the imatinib mesylate prepared by this method, no matter in the reaction process or in the storage process, is easy to deteriorate, and the color turns yellow, which makes the product invalid
[0007] Possible reason is that imatinib base is an inhomogeneous particle, and the solution of methanesulfonic acid cannot fully contact with imatinib base, thereby making mesylate excess, and free methanesulfonic acid makes imatinib in the reaction process. Matini metamorphism
During the storage process, imatinib mesylate contains an equivalent amount of methanesulfonic acid in the molecule. If the combination of methanesulfonic acid in the obtained crystal structure is not strong enough, it will be stored for a long time within a certain period of time, and methanesulfonic acid will be released continuously. , causing the product to decompose and deteriorating the stability of the product

Method used

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  • Ultrasonic preparation method for imatinib mesylate crystal
  • Ultrasonic preparation method for imatinib mesylate crystal
  • Ultrasonic preparation method for imatinib mesylate crystal

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In a 2000mL reaction flask, add 50.0g of imatinib base and 1200ml of acetone, turn on the ultrasonic equipment, the ultrasonic condition is 24KHz, the temperature of the water bath is raised to 50°C, add 4.96g of methanesulfonic acid in 50ml of acetone solution dropwise in 2 hours, drop After the addition, slowly cool down to 0-5°C, filter, wash the filter cake with acetone, and dry under vacuum (-0.095MPa) at 50°C to obtain 57.1g of imatinib mesylate white crystals with a purity of 99.9% and a yield of 95.6 %. The XRD patterns and DSC patterns of the prepared crystals are shown in figure 1 and figure 2 , conforming to the α-crystal form.

Embodiment 2

[0025] In a 1000mL reaction bottle, add 50.0g imatinib base and 200ml butanone, turn on the ultrasonic equipment, the ultrasonic condition is 23KHz, heat the water bath to 60°C, add 4.96g methanesulfonic acid solution in 50ml butanone dropwise for 2 hours , after the dropwise addition was completed, the temperature was slowly lowered to 0-5° C., filtered, the filter cake was washed with butanone, and dried under vacuum (-0.095 MPa) at 50° C. to obtain 56.6 g of imatinib mesylate white crystals with a purity of 99.9%. The yield is 94.8%, conforming to the α-crystal form.

Embodiment 3

[0027] In a 2000mL reaction bottle, add 50.0g imatinib base and 1200ml methyl isoamyl ketone, turn on the ultrasonic equipment, the ultrasonic condition is 21KHz, raise the temperature of the water bath to 70°C, add 50ml of 4.96g methanesulfonic acid dropwise for 1 hour Methyl isoamyl ketone solution, after the dropwise addition, slowly cool down to 0-5°C, filter, wash the filter cake with methyl isoamyl ketone, and dry under vacuum (-0.095MPa) at 50°C to obtain 57.9g of ima mesylate Tini is a white crystal with a purity of 99.9% and a yield of 97.0%, conforming to the α-crystal form.

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Abstract

The invention discloses a preparation method for an imatinib mesylate crystal, which belongs to the technical field of anti-tumor medicaments. The ultrasonic preparation method of the imatinib mesylate crystal comprises the following steps of: under an ultrasonic condition, dropwise adding a ketone solution of methanesulfonic acid into a ketone suspension containing imatinib alkali; and cooling, filtering, washing, and drying in vacuum to obtain the imatinib mesylate crystal, wherein the ratio of the total volume of ketone to the weight of imatinib mesylate is (5-50):1; the volume of the ketone is counted by ml; and the weight of the imatinib mesylate is counted by g. In the invention, a solvent ultrasonic synergetic nucleation method is adopted, so that the imatinib mesylate crystal of which the granularity is uniform and the impurity adsorption is small can be obtained, and the crystal has the advantages of high stability, firm combining state, low solvent residue content, low process cost, easiness in operating and long-time storage under an economic condition.

Description

technical field [0001] The invention relates to an ultrasonic preparation method of imatinib mesylate crystal, which belongs to the technical field of antitumor drugs. Background technique [0002] Imatinib mesylate, trade name: Gleevec, Chinese name: 4-[(4-methyl-1-piperazine)methyl]N-[4-methyl-3-[[4-( 3-pyridine)-2-pyrimidine]amino]phenyl]-aniline methanesulfonate, chemical structural formula: [0003] [0004] Imatinib Mesylate is a new anticancer drug invented and developed by Novartis, Switzerland. It is a selective tyrosine kinase inhibitor and belongs to aniline quinazoline compounds. Imatinib mesylate is a specific inhibitor of tyrosine kinase Bcr-Abl designed according to the structure-activity relationship. It can effectively treat gastrointestinal stromal tumors and blood cancers by inhibiting tyrosine kinases, that is, chronic myelogenous leukemia. [0005] Patent WO2005077933A1 and patent WO2006054314A1 disclose a preparation method of imatinib mesylate, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/04
Inventor 李湛江刘刚高殿博孟宾
Owner SHANDONG JINCHENG PHARMACEUTICAL GROUP CO LTD
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