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Preparation method of imatinib mesylate alpha crystal form

A technology of imatinib mesylate and imatinib base, which is applied in the field of preparation of polymorphic drugs, can solve the problems of unqualified solvent residues, and achieve the effects of solving solvent residues, single crystal form, and stable process

Inactive Publication Date: 2013-12-25
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

When the crystallization solvent is isopropanol, although the applicant has obtained a single α crystal, there is a problem about unqualified solvent residues commonly found in the prior art. After many experiments, the applicant unexpectedly found a The method of achieving the object of the invention

Method used

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  • Preparation method of imatinib mesylate alpha crystal form
  • Preparation method of imatinib mesylate alpha crystal form
  • Preparation method of imatinib mesylate alpha crystal form

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Embodiment 1: the preparation of imatinib mesylate α crystal form

[0032] Take imatinib base 5.0g, add 12.0mL dimethyl sulfoxide, stir and heat to 85°C to completely dissolve, cool down to 40°C, add 0.9725g (1eq.) methanesulfonic acid, stir for 1h, heat up to 60°C, add 75mg of imatinib mesylate in the α crystal form was used as the initiation seed crystal, and 180ml of isopropanol was slowly added dropwise, cooled to 25°C, stirred and crystallized for 10h, filtered and dried to obtain 5.4g of off-white powder, with a purity of 99.70%, and a yield of 90% %. Embodiment 2: the preparation of imatinib mesylate α crystal form

Embodiment 2

[0032] Take imatinib base 5.0g, add 12.0mL dimethyl sulfoxide, stir and heat to 85°C to completely dissolve, cool down to 40°C, add 0.9725g (1eq.) methanesulfonic acid, stir for 1h, heat up to 60°C, add 75mg of imatinib mesylate in the α crystal form was used as the initiation seed crystal, and 180ml of isopropanol was slowly added dropwise, cooled to 25°C, stirred and crystallized for 10h, filtered and dried to obtain 5.4g of off-white powder, with a purity of 99.70%, and a yield of 90% %. Embodiment 2: the preparation of imatinib mesylate α crystal form

[0033] At room temperature, take 10.0g of imatinib base, add 90mL of ethanol, slowly dropwise add 1.94g of ethanol solution of methanesulfonic acid, after the addition is complete, continue to stir for 3-5h, filter and dry to obtain imatinib methanesulfonic acid Salt coarse product.

[0034] Take 5.0g of the crude product of imatinib mesylate, add 10.0mL of dimethyl sulfoxide, stir and heat to 85°C to dissolve completely,...

Embodiment 4

[0038] Embodiment 4: measure the residual solvent of product in embodiment 1-3

[0039] Determination of isopropanol dissolution residue:

[0040] Take about 0.1g of the test sample, accurately weigh it into a 20mL headspace bottle, add 1.0mL of dimethylformamide accurately, dissolve it by ultrasonic, and use it as the test solution. According to the residual solvent determination method (Chinese Pharmacopoeia 2010 edition two appendix VIIIP second method) test. Adopt DB-624 (30m×0.53mm×3.0μm) chromatographic column, temperature program, the initial temperature is 40°C, keep for 5 minutes, and rise to 220°C at a rate of 20°C per minute; the detector is FID, and the temperature is 250°C ; The temperature of the injection port is 160°C; the carrier gas is nitrogen; headspace injection, the headspace equilibrium temperature is 80°C, and the equilibrium time is 30min.

[0041] Determination of dimethylformamide and dimethyl sulfoxide dissolution residues:

[0042] Take about 0....

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Abstract

The invention provides a preparation method of imatinib mesylate alpha crystal form. The preparation method comprises the following steps: adding imatinib base to dimethyl sulphoxide, heating for full dissolving, adding methanesulfonic acid for a reaction, adding imatinib mesylate of alpha crystal form as an initiation seed, and adding an alcohol solvent to obtain crystalline imatinib mesylate of the alpha crystal form. The imatinib mesylate of the alpha crystal form obtained through the preparation method has the characteristics of single crystal form, simple operation, stable technology, solving of a solvent residual problem, and high quality, and can completely satisfy demands of medicinal preparations.

Description

technical field [0001] The invention relates to the technical field of preparation of polymorphic drugs, more specifically, to a method for preparing α-crystal form of imatinib mesylate. Background technique [0002] Imatinib mesylate, Chinese chemical name: 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[4-(3-pyridyl) )-2-pyrimidinyl] amino]-phenyl] benzamide methanesulfonate, its chemical structural formula is as follows: [0003] [0004] Imatinib mesylate is an orally active protein tyrosine kinase inhibitor developed by Novartis, Switzerland, which is effective in the treatment of a variety of cancers. At present, it is widely used in the treatment of chronic myelogenous leukemia (CML) in blast phase, accelerated phase, or chronic phase patients after failure of α-interferon therapy, as well as adults with unresectable or metastatic malignant gastrointestinal stromal tumor (GIST). patient. [0005] Drug polymorphism is a common phenomenon in drug research and de...

Claims

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Application Information

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IPC IPC(8): C07D401/04C07C309/04C07C303/32
Inventor 郑赛利王天明马凤莹寇景平
Owner SUNSHINE LAKE PHARM CO LTD
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