Synthesis of decitabine

A sitabine and reaction technology, which is applied in the field of drug synthesis, can solve the problem that the ratio of chlororibose azacytosine α configuration isomer is large, the content of sitabine α configuration impurities is high, and the β configuration chlororibose nitrogen The problem of low purity of heterocytosine

Inactive Publication Date: 2014-12-17
NANJING UNIV OF TECH
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Problems solved by technology

[0005] The α-configuration isomer of chlororibose-azacytosine prepared by the above synthesis method has a large proportion, and the purity of β-structure chloro-ribose-azacytosine is not high, only 60%-70%, resulting in diazepam after hydrolysis The impurity content of the α-form of histabine is high, and the purity of decitabine has been increased, which affects the purity of the finished product of decitabine

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  • Synthesis of decitabine

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Embodiment Construction

[0019] The preparation method of decitabine is made up of following five steps:

[0020] Step A: Synthesis of 1-methoxy-3,5-di-O-p-methylbenzoyl-2-deoxy-D-ribofuranose (2)

[0021] Add 15g (112mmol) 2-deoxy-D ribose, 15ml 1% HCl-CH 3 OH solution, 90ml of methanol, reacted at 30°C for 30min, added 0.375ml of pyridine and stirred for 5min, and evaporated the reaction solution to dryness under reduced pressure to obtain a viscous oil.

[0022] Step B: Dissolve 75ml of pyridine and transfer it to a four-necked reaction flask, add 33ml (247mmol) p-toluoyl chloride dropwise at -10°C, react at 25°C for 12h after dropping, add 60ml of dichloromethane, and slowly add it under stirring 90ml of 10% sodium carbonate solution, let stand to separate layers, extract the water phase with 30ml of dichloromethane, combine the dichloromethane phase, wash with 75ml of concentrated hydrochloric acid + 150g of crushed ice, 45ml of saturated brine, dry over anhydrous sodium sulfate, and filter with...

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Abstract

The invention discloses a synthesis method of decitabine. The synthesis method comprises the following steps: subjecting 2-deoxy-D-ribose to methoxylation in the presence of HCl, subjecting the reaction product to acylation reactions with p-methyl benzoyl chloride, coupling the reaction product with 5-azacytosine in the presence of lithium trifluoromethanesulfonate so as to obtain 1-(3,5-bi-O-p-methylbenzoyl-2-deoxy-D-ribose)-5-azacytosine, and finally subjecting the 1-(3,5-bi-O-p-methylbenzoyl-2-deoxy-D-ribose)-5-azacytosine to sodium methoxide deprotection and methanol recrystallization so as to obtain the antitumor drug decitabine, and the total yield of the synthesis method is 30.2%.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing decitabine. technical background [0002] Decitabine, whose English name is Decitabine, is a cytidine drug developed by SuperGen and marketed by MGIPHARM. It was approved in the United States in May 2006 for the treatment of myelodysplastic syndrome (MDS). As a specific DNA methyltransferase inhibitor, decitabine can reverse the methylation process of DNA, induce tumor cells to differentiate and die like normal cells, and exert its cytotoxic effect: low concentrations of decitabine can replace tumor Cytosine in the cell is covalently combined with DNA methyltransferase to activate the silenced and inactivated tumor suppressor gene without cytotoxicity. MGI Pharmaceuticals has reached an agreement with SuperGen, and is planning to apply the drug to more hematologic malignancies, including all French, American, and British (FAB types) treated and untreated, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/00
Inventor 郭成梅杰王建强孙俊刘光林张娟张京超
Owner NANJING UNIV OF TECH
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