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Refining method of azacitidine with high purity and low residual solvent content

A technology of azacitidine and refining methods, which is applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., and can solve problems such as low refining yield, non-conformity of product quality, and non-conformity of refined products to quality standards , to achieve the effect of high refining yield, low solvent residue and stable crystal form

Active Publication Date: 2021-02-02
北京益佰医药研究有限公司 +1
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The inventor, on the basis of summarizing the literature, refers to the literature method, selects the third class of solvent DMSO as a good solvent, selects methanol, ethanol, isopropanol or mixed alcohols as a poor solvent, and carries out a refining test. The product obtained mainly has the following problems: 1. Choose DMSO as a good solvent, heat to 80-90°C to dissolve, add a poor solvent to slowly drop to -20°C to crystallize, and the refining yield is between 50% and 60%, and the refining yield is low; 2. The obtained refined The product does not meet the quality standards, especially the monoacetyl impurity (formula II) exceeds the limit defined by the Chinese Pharmacopoeia or ICH; 3. The obtained refined product generally exceeds 10000ppm in solvent residual DMSO, far exceeding the DMSO limit specified in the Pharmacopoeia of 5000ppm
In summary, the crude product of azacitidine is refined by the method reported in the literature, but there are defects such as low refining yield and product quality not meeting drug standards

Method used

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  • Refining method of azacitidine with high purity and low residual solvent content
  • Refining method of azacitidine with high purity and low residual solvent content
  • Refining method of azacitidine with high purity and low residual solvent content

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preparation example Construction

[0054] According to the preparation process of the present invention, the obtained samples are vacuum-dried, the drying temperature is generally 50°C-90°C, preferably 60°C-80°C; the drying time is 12-24 hours.

[0055] The azacitidine crystal form obtained according to the preparation process of the present invention is crystal form I, which can be used for the treatment of myelodysplastic syndrome, leukemia and other diseases.

[0056] The present invention and its beneficial technical effects will be described in detail below in conjunction with the accompanying drawings and various specific embodiments.

Embodiment 1

[0064] Add 300ml DMSO to a 2L reaction flask, continue to add 50g of crude azacitidine, under nitrogen protection, heat the solution to 40°C, stir to dissolve; slowly add 900ml ethyl acetate, slowly cool down to 20°C, stir for 2h; filter , to obtain a primary refined product with a wet weight of 52.2g. The weight loss on drying was measured, and the dry weight was 47.7g, and the yield was 95.4%.

[0065] Add 280ml of DMSO into a 2L reaction flask, continue to add a refined product (wet weight 55.2g), under nitrogen protection, heat to 35°C, stir to dissolve; slowly add 860ml of methanol, slowly cool down to 15°C, stir for 3 hours, filter The obtained filter cake was beaten three times with 280ml methanol respectively, filtered, dried under reduced pressure at 80°C (controlling vacuum degree ≤-0.08MPa), and dried for 12h to obtain 46.7g, with a refined total yield of 90.4%. Measured product purity 99.77%, monoacetyl impurity (formula II) 0.04%, DMSO solvent residual 1120ppm, X...

Embodiment 2

[0067] Add 200ml DMSO into a 2L reaction flask, continue to add 50g of crude azacitidine, under nitrogen protection, heat the solution to 45°C, stir to dissolve; slowly add 800ml of isopropyl acetate, slowly cool down to 15-20°C, stir 2h; filter to obtain a primary refined product with a wet weight of 53.0g. The weight loss on drying was measured, and the dry weight was 45.1g, and the yield was 90.2%.

[0068] Add 170ml DMSO to a 2L reaction flask, continue to add a refined product (wet weight 53.0g), under nitrogen protection, heat to 45°C, stir to dissolve; slowly add 680ml of isopropanol, slowly cool down to 15-20°C, stir After 3 hours, filter; the obtained filter cake was beaten three times with 170ml of isopropanol, filtered, dried under reduced pressure at 75°C (controlling vacuum degree ≤-0.08MPa), and dried for 18h to obtain 43.6g, with a refined total yield of 87.1%. Measure product purity 99.61%, monoacetyl impurity (formula II) 0.08%, DMSO solvent residual 2700ppm,...

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Abstract

The invention relates to the field of medicines and chemistry, and provides an azacitidine refining method. The method comprises the steps of 1, adding an azacitidine crude product to a good solvent for dissolving; 2, adding a poor solvent into a solution obtained in the step 1, and performing filtration to obtain an azacitidine primary refined product; and 3, adding the azacitidine primary refined product obtained in the step 2 into the good solvent for dissolving, adding the poor solvent, and performing filtration, pulping and drying to obtain an azacitidine refined product. The method is mild in refining process condition, simple to operate, suitable for industrial amplification and high in product purity; and the content of the residual solvent, especially the residual solvent DMSO with high boiling point, in the product is low.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a refining method with high purity, low residual solvent content and stable crystal form. Background technique [0002] Azacitidine is a cytidine nucleoside analog, also known as 5-azacytidine, its chemical name is 4-amino-1-β-D-ribofuranosyl-1,3,5-triazine- 2(1H)-one. Azacitidine for injection was first launched in the United States in May 2004, and then in the European Union, Japan and other countries. In April 2017, it was approved to be imported from China. The product name is Vidaza, which is mainly used for adult myelodysplastic syndromes. syndrome (MDS), chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML) and other diseases. Its mechanism of action is to produce anti-tumor effects by causing DNA demethylation and direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Azacitidine, its molecular formula is C8H12N4O5, molecul...

Claims

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Application Information

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IPC IPC(8): C07H1/06C07H19/12
CPCC07H1/06C07H19/12
Inventor 窦雅琪魏可贵宿彦伟卞爱华姚定丽李金泽赵秋颖易崇勤
Owner 北京益佰医药研究有限公司
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