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Novel polymorphs of dasatinib, and preparation method thereof

A polymorph, dasatinib technology, applied in the field of new polymorph and its preparation, can solve the problem of poor solubility, difficult to effectively improve product purity, affecting the stability and bioavailability of raw materials and preparations And other issues

Inactive Publication Date: 2013-01-30
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the polymorphs obtained by the above method have the following defects: one, because the solubility of dasatinib is poor, it is slightly soluble or almost insoluble in water, alcohols and other organic solvents, even under heating conditions, it needs a large amount of Solvent, and the yield is low, so it is difficult to realize in industrial production; the second is that the above methods are difficult to effectively improve the product purity in the production process, and it is difficult for a single impurity to reach below 0.1%; the third is that the above polymorphs basically have no Mention issues such as quality and stability, and for polymorphic forms of drugs, different polymorphic forms may have different stability, physical properties, solubility, etc., and these properties can directly affect the stability of raw materials and preparations and bioavailability

Method used

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  • Novel polymorphs of dasatinib, and preparation method thereof
  • Novel polymorphs of dasatinib, and preparation method thereof
  • Novel polymorphs of dasatinib, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0163] Example 1: Preparation of Dasatinib Polymorph I

[0164] Take 10g of Dasatinib crude product and place it in a reaction flask, add a mixed solvent of 60ml DMF and 120ml isopropanol, heat up to 70-80°C under stirring to dissolve, slowly cool to 50-60°C and stir for 1 hour, Crystallize at 30°C for 1 hour, and finally lower the temperature to 5-10°C to fully separate out the solid and grow the crystal for 2 hours, filter with suction, wash the filter cake with isopropanol and drain it. The solid was dried at 50°C under reduced pressure (-0.09 MPa) to obtain 8.1 g of white solid, yield 81%. The purity of related substances is 99.95%.

Embodiment 2

[0165] Example 2: Preparation of Dasatinib Polymorph I

[0166] Take 10g of Dasatinib crude product and place it in a reaction flask, add a mixed solvent of 50ml DMSO and 150ml isopropanol, heat up to 70-80°C under stirring to dissolve, slowly cool to 50-60°C and stir for 1 hour, then in 20-60°C Crystallize at 30°C for 1 hour, and finally lower the temperature to 5-10°C to fully separate out the solid and grow the crystal for 3 hours, filter with suction, wash the filter cake with isopropanol and drain it. The solid was dried at 50°C under reduced pressure (-0.09MPa) to obtain 8.3g of white solid, yield 83%. The purity of the related substance is 99.94%.

Embodiment 3

[0167] Example 3: Preparation of Dasatinib Polymorph I

[0168] Take 1g of Dasatinib crude product and place it in a reaction bottle, add a mixed solvent of 5ml DMF and 5ml isopropanol, heat up to 70-80°C under stirring to dissolve, slowly cool to 50-60°C and stir for 1 hour, then in 20-60°C Crystallize at 30°C for 1 hour, and finally lower the temperature to 5-10°C to fully separate out the solid and grow the crystal for 2 hours, filter with suction, wash the filter cake with isopropanol and drain it. The solid was dried at 50°C under reduced pressure (-0.09MPa) to obtain 0.84g of a white solid, with a yield of 84%. The purity of the related substance is 99.93%.

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Abstract

The invention belongs to the field of pharmaceutical chemistry, and specifically belongs to novel polymorphs of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide (dasatinib), and a preparation method thereof. Four polymorphs I, II, III, IV of dasatinib disclosed by the invention have good stability, excellent solubility, easily industrialized preparation process, good quality reappearance and easily controllable product purity.

Description

technical field [0001] The present invention belongs to the field of medicinal chemistry, specifically N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]- 2-Methyl-4-pyrimidinyl]amino]-5-thiazole carboxamide is a new polymorph of dasatinib and a preparation method thereof. Background technique [0002] N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4-pyrimidinyl]amino ]-5-thiazolecarboxamide, whose generic name is dasatinib, is an oral multiple tyrosine kinase inhibitor developed by Bristol-Myers Squibb, which can inhibit chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic Excessive proliferation of white blood cells in the bone marrow of patients with leukemia. It was approved by the US FDA in June 2006 for the treatment of leukemia caused by BCR-ABL kinase mutation. Its chemical structural formula is as follows: [0003] [0004] Since dasatinib can have many different crystalline states,...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12A61K31/506A61P35/02
Inventor 赵俊宗在伟胡文波
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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