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Preparation method of high-purity dasatinib and by-product of dasatinib

A dasatinib, high-purity technology, applied in the field of preparation of dasatinib, can solve problems such as difficulty in separation and impact on the quality of the final product of dasatinib, and achieve the effect of small side effects, high safety and definite curative effect

Inactive Publication Date: 2012-12-26
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The inventor finds in experimental research, in intermediate 2 During the reaction with 4,6-dichloro-2-methylpyrimidine, a bipyrimidine ring compound by-product will be generated, and the nature of the by-product is the same as that of the intermediate 4 Similar, difficult to separate, and very easy to bring into the next step reaction, in the next step reaction with N-hydroxyethylpiperazine and other compounds to generate more by-products, which has a great impact on the quality of the final product of dasatinib

Method used

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  • Preparation method of high-purity dasatinib and by-product of dasatinib
  • Preparation method of high-purity dasatinib and by-product of dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Example 1 Preparation of compound 6

[0066] Add 300ml of tetrahydrofuran and 7g of potassium hydride into a 500ml three-necked flask, cool in an ice-water bath, add 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide (20g, 74.7mmol), React for 1 hour. Add 4,6-dichloro-2-methylpyrimidine (25 g, 153.3 mmol), heat to reflux, monitor by HPLC, and react for 4 hours. Cool in an ice-water bath, quench with 2N hydrochloric acid, filter, and spin dry. The obtained solid was purified by column, and the eluent was ethyl acetate:petroleum ether=1:3. Obtain compound 6 product 22 grams, its NMR H spectrum sees attached figure 1 .

[0067]

Embodiment 2

[0068] Example 2 Preparation of Compound 6

[0069] Add 300ml of dioxane and 8.9 grams of sodium hydride into a 500ml three-necked flask, cool in an ice-water bath, add 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazolecarboxamide (20g, 74.7 mmol), reacted for 2 hours. Add 4,6-dichloro-2-methylpyrimidine (36 g, 220.9 mmol), heat to reflux, monitor by HPLC, and react for 6 hours. Cool in an ice-water bath, quench with 2N hydrochloric acid, filter, and spin dry. The obtained solid was purified by column, and the eluent was ethyl acetate:petroleum ether=1:3. 19.3 g of compound 6 was obtained.

[0070]

Embodiment 3

[0071] Example 3 Preparation of Compound 6

[0072] Add 500ml of ethylene glycol dimethyl ether, 5g of sodium ethoxide and 2g of sodium hydride into a 500ml three-necked bottle, cool in an ice-water bath, add 2-amino-N-(2-chloro-6-methylphenyl)-5-thiazole Amide (20g, 74.7mmol), reacted for 2 hours. Add 4,6-dichloro-2-methylpyrimidine (60.8g, 373.5mmol), heat to reflux, monitor by HPLC, and react for 5 hours. Cool in an ice-water bath, quench with 2N hydrochloric acid, filter, and spin dry. The obtained solid was purified by column, and the eluent was ethyl acetate:petroleum ether=1:3. 20.1 g of Compound 6 was obtained.

[0073]

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Abstract

The invention relates to a preparation method of high-purity dasatinib and a by-product of the dasatinib and belongs to the technical field of medicines. An optimized preparation method of the dasatinib is disclosed, and the prepared dasatinib is high in product purity and low in compound 6 content. The invention further discloses the by-product of the dasatinib and a synthetic method. The by-product which is difficult to separate is generated in a synthetic process of the dasatinib, and the by-product is determined to be a compound 6 through systemization and identification. The compound has important significant on quality control of the dasatinib. A structural formula of the compound 6 is shown in the specification.

Description

Technical field [0001] The preparation method of a high -purity Dashantinib and one of its by -products belong to the field of pharmaceutical technology. The specific method of preparation of a optimized Disusidib is also provided with a giant -produced by -products of Disusinibinib.And its synthesis method. Background technique [0002] Dasatinib (dasatinib), chemical name n- (2-chlorine-6-methamphetamine) -2-[6- [4- (2-hydroxye ethyl) -1-thozide group]-2-methyl-4-pyrimidinel] Amino-based] -5-chimrazolamide is an oral multi-tyrosine kinase inhibitor developed by the American Belief Schimibao Company.Outdoor proliferation of white blood cells in bone marrow patients in cell leukemia.It was approved by the US FDA in June 2006 and was used to treat leukemia caused by BCR-ABL kinase mutation. [0003] Dansinib has the following structure: [0004] Essence [0005] Regarding the synthesis of Dashantinib, there are many domestic and foreign literature reports. Among them, patented W...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12C07D417/14
Inventor 陈庆财杜有国胡文波
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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