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Method for synthesizing azacitidine

A synthesis method and azacitidine technology are applied in the field of azacitidine synthesis, which can solve the problems of affecting the purity of azacitidine finished products, destruction of azacitidine, and general low efficiency, and shorten the silanization reaction time. , low price, and the effect of improving reaction efficiency

Active Publication Date: 2012-08-08
CHONGQING SINTAHO PHARM CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0006] The above-mentioned synthesis method generally has low efficiency and takes a long time when carrying out the silanization reaction
At the same time, a large amount of HMDS is used in the synthesis, resulting in a large amount of HMDS waste liquid
In addition, in the purification stage, the above-mentioned methods all use methanol or ethanol solvents for purification, and methanol or ethanol is a hydrophilic solvent, and azacitidine is easily destroyed in water, which affects the purity of the finished product of azacitidine

Method used

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  • Method for synthesizing azacitidine
  • Method for synthesizing azacitidine
  • Method for synthesizing azacitidine

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preparation example Construction

[0030] According to the present invention, the synthetic method of described azacitidine comprises the following steps:

[0031] Step 1. Under the condition of cutting off moisture, bistrimethyldisilamine and 5-azacytosine use toluene as a solvent to carry out a silanization reaction under the catalysis of a quaternary ammonium salt phase transfer catalyst to generate a compound with the structure of formula II , the molar ratio of the 5-azacytosine to the quaternary ammonium salt phase transfer catalyst is 1:0.005-0.5;

[0032] Step 2, the compound of formula II undergoes a condensation reaction with tetraacetyl ribose to generate a compound with the structure of formula IV, and the compound of formula IV undergoes alcoholysis in an alkaline environment to generate azacitidine;

[0033]

[0034] Wherein, as preferably, the quaternary ammonium salt phase transfer catalyst is tetrabutylammonium bisulfate, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylamm...

Embodiment 1

[0043] Embodiment 1: the synthetic method of azacitidine described in the present invention

[0044] Under nitrogen protection, put 25.8g (0.23mol) of 5-azacytosine and 1.0g (0.003mol) of tetrabutylammonium bisulfate into a 1L three-necked flask, add 125ml of HMDS and 500ml of toluene and stir to raise the temperature to 125°C. The solution was clarified in about 6 hours, and then the solvent was distilled off under reduced pressure to constant weight to obtain N-trimethylsilyl-4-trimethylsilyloxy-2-amine-1,3,5-triazine, namely formula II Compound 65.0 g (0.25 mol).

[0045] Under the protection of nitrogen, after dissolving 65.0g (0.25mol) of the compound of formula II in 500ml of tetrahydrofuran, put it into a 1L three-necked flask and stir, then add 120.0g (0.38mol) of tetraacetyl ribose, then rinse the addition funnel with 100ml of tetrahydrofuran, and Slowly add 64.5ml (0.36mol) of trifluoromethyltrimethylsilicone, and stir the reaction. After 4 hours of reaction, the re...

Embodiment 2

[0047] Embodiment 2: the synthetic method of azacitidine described in the present invention

[0048] Under nitrogen protection, put 25.8g (0.23mol) of 5-azacytosine and 0.4g (0.001mol) of tetrabutylammonium bromide into a 1L three-necked flask, add 120ml (0.575mol) of HMDS and 258ml of toluene and stir to raise the temperature After reaching 125°C, the solution was clarified for about 5 hours, and then the solvent was distilled off under reduced pressure to constant weight to obtain N-trimethylsilyl-4-trimethylsilyloxy-2-amine-1,3,5-triazine , namely 62.0 g (0.24 mol) of the compound of formula II.

[0049] Under the protection of nitrogen, after dissolving 62.0g (0.24mol) of the compound of formula II in 500ml of tetrahydrofuran, put it into a 1L three-necked flask and stir, then add 115.0g (0.36mol) of tetraacetylribose, then rinse the addition funnel with 100ml of tetrahydrofuran, and Slowly add 64.5ml (0.36mol) of trifluoromethyltrimethylsilicone, and stir the reaction. A...

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Abstract

The invention relates to the field of pharmaceutical synthesis process and discloses a method for synthesizing azacitidine. The method comprises the following steps: performing silanization reaction on bis(trimethyl disilylamine) and 5-azacytosine by taking toluene as solvent under the catalysis of phase transfer catalyst of quaternary ammonium compounds under a moisture-isolated condition to generate a compound with structure of formula II; performing condensation reaction between the compound and ribose tetracetate to generate a compound with a structure of formula IV; and performing alcoholysis on the compound in an alkaline environment to generate the azacitidine. The synthesis method of the invention shortens the time of silanization reaction, reduces the waste amount of the bis(trimethyl disilylamine) and avoids influence of the moisture in methanol and ethanol in the purification stage on the purity of the finished product of azacitidine; moreover, the synthesis method has the advantages of cheap reagents, few reaction steps and mild reaction conditions and is favorable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine synthesis technology, in particular to a synthesis method of azacitidine. Background technique [0002] Azacitidine, molecular formula C 8 h 12 N 4 o 5 , the English name is Azacitidine, the chemical name is 1-(β-D-ribofuranosyl)-4-amino-1,3,5-triazin-2(1H)-one, also known as 5-azacytidine, Azacitidine has the structure shown in formula V: [0003] [0004] Azacitidine is a white needle-like crystal, which belongs to cytosine nucleoside drugs, and is a DNA methyltransferase inhibitor developed by Pharmion Company of the United States. It is mainly used clinically to treat myelodysplastic syndrome. Azacitidine is the first anti-tumor drug developed based on the abnormality of tumor expression genes. It can be directly incorporated into DNA, inhibit DNA and RNA synthesis, and can kill cells in S phase. It is effective for breast cancer, colon cancer, melanoma, etc. It has a certain curative effect. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H19/12C07H1/00B01J31/02
Inventor 姚全兴李靖杨俊波
Owner CHONGQING SINTAHO PHARM CO LTD
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