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Preparation and refining methods of dasatinib

A dasatinib and refining method technology, which is applied in the new preparation and refining field, can solve the problems of cumbersome refining steps in the refining method, harsh requirements on the reaction vessel, and deterioration of dasatinib, and achieve simple operation, good stability, short-term effect

Active Publication Date: 2012-12-26
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thereby solving the problem of using n-butanol as solvent in the traditional synthesis method, high cost, long reaction time, high reaction temperature, and strict requirements on the reaction vessel
[0016] Another object of the present invention is to provide a method for refining the crude product of dasatinib, thereby solving the problem of cumbersome refining steps and partial deterioration of dasatinib caused by high-temperature dehydration

Method used

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  • Preparation and refining methods of dasatinib
  • Preparation and refining methods of dasatinib
  • Preparation and refining methods of dasatinib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation and purification of dasatinib

[0051] Preparation of Dasatinib

[0052]Dissolve 100g of N-(2-chloro-6-methylphenyl)-2[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide in 300ml of dimethylsulfoxide Add 98.9g of 1-(2-hydroxyethyl)piperazine and 65.5g of diisopropylethylamine respectively, heat at 80°C, stir for 2-3h, monitor by HPLC, stop the reaction until the raw materials disappear completely. Naturally cooled to room temperature, 900ml of isopropanol was added to the reaction solution, solids were precipitated, cooled and stirred for 2h. After the precipitation was complete, it was filtered, and the filter cake was washed successively with a small amount of isopropanol and water to obtain 101.2 g of crude dasatinib. The calculated yield was 78.8%.

[0053] Refining of Dasatinib

[0054] Mix and dissolve the crude dasatinib obtained in the above experiment with 95% ethanol-water (2L: 0.4L), heat to 70°C, filter while hot after dissolution...

Embodiment 2

[0066] Investigation on drying conditions of dasatinib

[0067] Weigh 120g of crude dasatinib, heat it to 75°C with 95% ethanol-water (2L: 0.4L), and filter it while it is hot after the dissolution is complete. Cool the filtrate to room temperature, freeze and crystallize. Filter, wash with a small amount of cold 50% ethanol-water (1:1 / v:v), and dry at 50°C under normal pressure for 3 hours to obtain 90.4g of white solid with a yield of 75.3%, crushed and sieved, and weighed accurately Take 10.0g of each 8 parts in total, and dry them under vacuum at 105°C. See Table 1 for the drying time.

[0068] Table 1 Investigation of drying conditions of dasatinib

[0069] serial number temperature (°C) pressure time (h) Moisture content (%) color 1 0 3.66 White 2 105 vacuum 2 0.70 White 3 105 vacuum 4 0.38 White 4 105 vacuum 6 0.36 White 5 105 vacuum 8 0.33 White 6 105 vacuum 10 0.31 White 7 ...

Embodiment 3

[0072] Preparation and purification of dasatinib

[0073] Preparation of Dasatinib

[0074] Dissolve 100g of N-(2-chloro-6-methylphenyl)-2[(6-chloro-2-methyl-4-pyrimidinyl)amino]-5-thiazolecarboxamide in 500ml hexamethylphosphoramide (HMPA), add 165.1g of 1-(2-hydroxyethyl)piperazine and 65.5g of diisopropylethylamine respectively, heat to 75°C, stir for 2-3h, monitor by HPLC until the raw materials disappear completely, stop the reaction, After cooling to room temperature, 1500 ml of isopropanol was added to the reaction liquid, and solids were precipitated, cooled and stirred for 2 h. After the precipitation was complete, it was filtered, and the filter cake was washed with a small amount of isopropanol and water in sequence to obtain 98.2 g of crude product. Yield: 76.5%.

[0075] Refining of Dasatinib

[0076] Mix and dissolve the crude product with 95% ethanol-water (2L: 0.4L), heat to 80°C, filter while hot after dissolution, cool the filtrate to room temperature...

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Abstract

The invention relates to the field of pharmaceutical chemistry, in particular to the synthesis field of dasatinib and novel preparation and refining methods of the dasatinib. The preparation method of the dasatinib comprises the step of allowing an intermediate N-(2-chlorine-6-methoxyphenyl)-2[(6-chlorine-2-methyl-4-pyrimidyl) amino]-5-thiazole formamide to perform homogeneous nucleophilic substitution reaction with 1-(2-ethoxyl) piperazine in a high-polar solvent. The preparation method solves the problems that n-butyl alcohol is adopted as a solvent in the traditional synthesis method, the cost is high, the reaction time is long, the reaction temperature is high, and the requirements on a reaction vessel are high. The invention provides a simple and feasible refining method, which improves the purity of the dasatinib effectively.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to the field of synthesis of dasatinib, in particular to a new preparation and purification method of dasatinib. [0002] Background technique [0003] Dasatinib, a tyrosine kinase inhibitor developed by Bristol-Myers Squibb, is used for all stages of adult chronic myelogenous leukemia (CML) patients who have failed or are intolerant to previous treatment. For the treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ph+ALL) who are resistant or intolerant to other therapies. Its chemical name is N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl]-2-methyl-4- Pyrimidinyl]amino]-5-thiazolecarboxamide, the molecular formula is C 22 h 28 ClN 7 o 2 S, the molecular weight is 488.01, and the structural formula is: [0004] [0005] Currently, the most common synthetic methods of Dasatinib are: [0006] One, t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/12
Inventor 王勇张仓符伟沙向阳张文萍沈振涛
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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