Crystallizing and drying method for preparing high-purity azacitidine

A technology for azacitidine and crude azacitidine, which is applied in the field of crystallization and drying for the preparation of high-purity azacitidine, which can solve the problems of hydrolysis impurities, azacitidine being hydrolyzed in large quantities, and yield reduction, etc. Reduce the production of hydrolyzed impurities, great commercial application value, and stable quality

Active Publication Date: 2013-01-02
杭州容立医药科技有限公司
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Problems solved by technology

[0011] The biggest defect of the above-mentioned method (1) is: using pure water to crystallize, it is easy to cause a large amount of hydrolysis of azacitidine, the yield is reduced, and hydrolysis impurities are produced; there will be crystallization water and crystallization ethanol in azacitidine, and the removal of tougher
[0012] The defect of the above-mentioned method (2) is: o...

Method used

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  • Crystallizing and drying method for preparing high-purity azacitidine
  • Crystallizing and drying method for preparing high-purity azacitidine
  • Crystallizing and drying method for preparing high-purity azacitidine

Examples

Experimental program
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Effect test

Embodiment 1

[0020] Preparation of Crude Azacitidine

[0021]

[0022] In a 10-liter three-neck flask, add 6 liters of anhydrous methanol, add 800 grams of triacetylazacitidine, control the internal temperature at 20-30 ° C, add 20 grams of sodium methoxide under stirring, and stir for 16 hours. Cloudy, filtered, the filter cake was washed with 1 liter of methanol, vacuum filtered and dried, and the solid was dried under vacuum with phosphorus pentoxide to constant weight to obtain 250 grams of azacitidine crude product (HPLC normalization method 89%)

[0023] Triacetylazacitidine: {4-amino-1-(2',3',5'-tri-O-acetyl-β-D-ribofuranosyl)-1,3,5-triazine-2 (1H)-ketone}

Embodiment 2

[0025] Crystallization and drying method for preparing high-purity azacitidine

[0026] 83 grams of the crude product obtained in Example 1 was dissolved in 1.45 liters of water preheated to 90°C, 1 gram of activated carbon was added, stirred for 2 minutes, filtered while hot, 10.1 liters of methanol preheated to 45°C was added to the filtrate, and the temperature was lowered. to 40°C, add a small amount of seed crystals, slowly cool down to below 10°C, and keep warm at 0-10°C for 13 hours. After vacuum filtration, the filter cake was vacuum-dried to constant weight at room temperature to obtain about 25 g of dry product (HPLC normalization method 99%).

[0027] The obtained 25 grams of crude product was refluxed with 20 liters of methanol to dissolve, naturally cooled to room temperature, left to stand for crystallization for 3 days, filtered, and the filter cake was vacuum-dried at room temperature to obtain 22 grams of white needle-shaped crystalline powder. (HPLC normaliz...

Embodiment 3

[0033] Crystallization and drying method for preparing high-purity azacitidine

[0034] 83 grams of the crude product obtained in Example 1 was dissolved in 692 milliliters of water preheated to 60 ° C, 1 gram of activated carbon was added, stirred for 2 minutes, filtered while hot, 3458 milliliters of methanol preheated to 65 ° C was added to the filtrate, and the temperature was lowered to 40°C, add a small amount of seed crystals, slowly cool down to below 10°C, and keep warm at 0-10°C for 13 hours. After vacuum filtration, the filter cake was vacuum-dried to constant weight at room temperature to obtain about 50 g of dry product (HPLC normalization method 93%).

[0035] 50 g of the obtained crude product was dissolved in 692 ml of water preheated to 75 °C, 1 g of activated carbon was added, stirred for 2 minutes, filtered while hot, 3458 ml of methanol preheated to 60 °C was added to the filtrate, and the temperature was lowered to 40 °C , add a small amount of seed cryst...

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Abstract

The invention provides a crystallizing and drying method for preparing high-purity azacitidine as myelodysplastic syndrome medicine. The method can reduce the generation of hydrolysis impurity, the obtained product has high purity, and the method is simple, effective, and suitable for large-scale industrial production, and has larger commercial application value.

Description

technical field [0001] The invention relates to a crystallization and drying method of azacitidine, a medicine for treating myelodysplastic syndrome. technical background [0002] Azacitidine (azacitidine, formula I), as a hypomethylated DNA methyltransferase inhibitor (DMTI) drug, was developed by Pharmion Pharmaceutical Company of the United States. In May 2004, Pharmion Pharmaceuticals' azacitidine was approved by the US Food and Drug Administration (FDA) for the treatment of all subtypes of myelodysplastic syndrome, thus becoming the first marketed drug in this field of therapeutic drugs. Its synthetic method has been widely reported in the literature, and its crystallization method is also reported in the literature, summarized as follows: [0003] (1) The document "Direct Glycosylation of 1,3,5-Triazinones. A New Approach to the Synthesis of the Nucleoside Antibiotic 5-Azacytidine" (The Journal of Organic Chemistry, 1970, vol.35, 491-495) reported the previous Use h...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/06
Inventor 任建强胡雅芳钟万德邵秀芬
Owner 杭州容立医药科技有限公司
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