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Preparation method of azacitidine

A technology for azacitidine and a compound is applied in the field of preparation of azacitidine, which can solve the problems of increased impurities, unfavorable purification, difficult operation, etc., and achieves reduction of hydrolysis side reactions and generation of impurities, reduction of solvent usage, and improved performance. The effect of reaction efficiency

Active Publication Date: 2012-10-03
HUZHOU ZHANWANG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The preparation of compound II in the above method is carried out in a solvent. After the reaction is completed, the compound II is extracted in the water phase. Since a large amount of insoluble by-products are generated in the reaction, it is difficult to separate layers during the extraction process, and the operation is difficult. At the same time, due to the introduction of water, Compound II is easily hydrolyzed in water to produce side reactions as described in J. Chromatography, 353(1986) 309-318, resulting in the increase of impurities, which is unfavorable for later purification

Method used

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  • Preparation method of azacitidine
  • Preparation method of azacitidine
  • Preparation method of azacitidine

Examples

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Embodiment 1

[0035] Preparation of Compound I: Hexamethyldisilane (5600 mL), 5-azacytosine (800 g, 7.14 mol) and ammonium sulfate (34 g) were put into a dry 20 L reaction pot. Turn on the stirring, stir well, heat to 140-142°C and reflux for about 1 hour, the system gradually changes from cloudy to clear. Continue to keep the temperature at 140-142° C. for reflux reaction for 15 hours. Naturally cool to 75-80°C and turn on the vacuum pump, transfer the material to the distillation bottle of the rotary evaporator, and carry out vacuum distillation. In addition to hexamethyldisilazane. The obtained viscous liquid was compound Ⅰ (1687g, 7mol).

[0036] Preparation of compound Ⅱ: Add tetraacetyl ribose (2720g, 8.55mol), mix well, vacuumize, control the vacuum degree -0.09MPa, and slowly heat up the oil bath to 160-170°C until the reaction material melts, and continue the reaction under this condition After 1.5-2.5 hours, it was cooled to 20-25°C at room temperature to obtain 2518 g (6.8 mol...

Embodiment 2

[0041] The same as Example 1, the difference is the preparation of compound II: add tetraacetyl ribose (3342g, 10.5mol), mix well, vacuumize and feed nitrogen, control the vacuum degree -0.1MPa, and slowly raise the temperature of the oil bath to 170-180 ℃ until the reaction material melted, reacted under this condition for 2.5-3.5 hours, then cooled in vacuum for 0.1-0.5h to 30-40 ℃ to obtain 2599g (7.02mol) of compound II as a foamy solid.

[0042]

Embodiment 3

[0044] The same as Example 1, the difference is the preparation of compound II: add tetraacetyl ribose (1781g, 5.6mol), mix well, vacuumize, control the vacuum degree -0.01MPa, and slowly heat up the oil bath to 145-150°C until the reaction material Melted, reacted under this condition for 3.5 to 4.5 hours, then cooled to obtain 2407 g (6.5 mol) of compound II as a foamy solid.

[0045]

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Abstract

The invention relates to the fields of chemical industry and chemical pharmaceutical industry and particularly relates to a preparation method of azacitidine. The preparation method disclosed by the invention comprises the steps of: preparing compound I, then uniformly mixing the compound I and 1,2,3,5-Tetra-O-Acetyl-D-Ribose, vacuumizing, controlling the vacuum degree at -0.001-0.95MPa, fusing the uniformly mixed compound I and the 1,2,3,5-Tetra-O-Acetyl-D-Ribose at 145-190 DEG C, cooling the mixture to obtain compound II after reacting for 1.5-4.5 hours, and carrying out alcoholysis on the compound II to prepare the azacitidine. According to the method, the usage amount of the solvent can be reduced, the side reaction and generation of impurities are reduced, and the reaction efficiency is improved.

Description

technical field [0001] The invention relates to the fields of chemical industry and chemical medicine, in particular to a preparation method of azacitidine. Background technique [0002] Azacitidine (5-Azacytidine), also known as 5-azacytidine, has the following structural formula: [0003] Azacitidine is a hypomethylated DNA methyltransferase inhibitor (DMTI) drug developed by Pharmion Pharmaceuticals of the United States. In May 2004, Pharmion Pharmaceuticals' azacitidine was approved by the U.S. 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. [0004] The current common preparation method of azacitidine is the reaction of 5-azacytosine and hexamethyldisilazane (HMDS) under the catalysis of ammonium sulfate to obtain compound Ⅰ , compound Ⅰ is condensed with tetraacetyl ribose in dichloromethane or acetonitrile under the catalysis of tin tetrac...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00
Inventor 刘光海金晓民
Owner HUZHOU ZHANWANG PHARMA
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