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Synthetic method of decitabine

A synthetic method, the technology of decitabine, applied in the field of drug synthesis, can solve the problem of large α-configuration isomer of chlororibose-azacytosine, insufficient purity of β-type chloro-ribose-azacytosine, Solve the problems of high impurity content in the α-alpha configuration, and achieve the effects of reducing the difficulty of purification, low price, and beneficial to industrial production

Active Publication Date: 2011-10-12
CHONGQING SINTAHO PHARM CO LTD
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0008] The ratio of the α-configuration isomer of chlororibose-azacytosine prepared by the above synthesis method is relatively large, and the purity of β-type chloro-ribose-azacytosine is not high enough, only 60-70%, resulting in decetaxel after hydrolysis The high content of impurities in α-configuration increases the difficulty of purification of decitabine and affects the purity of decitabine finished product

Method used

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Examples

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Embodiment 1

[0037] Example 1: Detection of the purity of β-chlororibose azacytosine

[0038] Chromatographic conditions: Octadecylsilane-bonded silica gel is used as filler, methanol-water=78:22 is used as mobile phase, flow rate is 1.0 mL / min, and detection wavelength is 240 nm.

[0039] Preparation of the reference substance solution: Weigh an appropriate amount of the reference substance β-chlororibose azacytosine (purchased from Jiangsu Handerson Pharmaceutical Technology Co., Ltd.), dissolve it with methanol and dilute to the mark to make a solution containing 1.0 mg per 1 mL. solution.

[0040] Preparation of the test solution: Weigh an appropriate amount of the test sample, dissolve it with methanol and dilute to the mark to make a solution containing 1.0 mg per 1 mL.

[0041] Determination method: Take 10 μL of the reference substance solution and the test solution respectively and inject them into the liquid chromatograph, record the chromatograms for 30 minutes, and calculate t...

Embodiment 2

[0042] Embodiment 2: Detection of the purity of β-type decitabine

[0043]Chromatographic conditions: Octadecylsilane bonded silica gel as filler, water (A)-methanol (B) as mobile phase, linear gradient elution, elution sequence as shown in Table 1, 1.0mL / min, detection The wavelength is 240nm, and the column temperature is 30°C.

[0044] Table 1 water (A)-methanol (B) elution sequence table

[0045] time (min)

Mobile phase A(%)

Mobile phase B(%)

0

100

0

4

100

0

15

97

3

35

40

60

55

40

60

55.1

100

0

60

100

0

[0046] Preparation of reference solution: Accurately weigh about 20.0 mg of β-type decitabine (purchased from Nanjing Zhongyuan Science and Technology Co., Ltd.), place it in a 10 mL measuring bottle, dissolve it with dimethyl sulfoxide, and dilute to the mark to prepare Each 1mL contains 1.0mg of the solution.

[0047]...

Embodiment 3

[0050] Under nitrogen protection, after dissolving 60.0g (0.23mol) 2,4-bis-(trimethylsilyl)-5-azacytosine with 500mL dichloromethane, put it into a 1L three-necked flask and stir, add 85g (0.20 mol) 1-chloro-3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose and 10.5g (0.075mol) p-nitrophenol, then rinse the addition funnel with 100mL dichloromethane, 30°C Stir the reaction for 12 hours, concentrate the reaction solution to dryness at 30°C under reduced pressure, dissolve the oily substance with 1000mL dichloromethane, then pour it into 1200mL pre-cooled saturated sodium carbonate solution under stirring, separate the layers, and wash the water layer with 500mL dichloromethane Methane was extracted twice, the organic layers were combined, the organic layer was washed with water, dried overnight with anhydrous sodium sulfate, filtered with diatomaceous earth, and concentrated to dryness under reduced pressure to obtain 97 g of chlororiboazacytosine shown in formula III, with a yield of ...

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Abstract

The invention relates to the field of medicament synthesis and discloses a synthetic method of decitabine. The method comprises the following specific steps of: undergoing a condensation reaction on 2,4-di-(trimethyl silicane)-5-aza-cytimidine and chloro-ribose under the catalytic action of nitrophenol; and hydrolyzing in an alkaline environment for removing acetyl to generate decitabine. In the synthetic method of decitabine, disclosed by the invention, nitrophenol is taken as a catalyst, the ratio of a beta configurational isomer in the obtained chloro-ribose aza-cytimidine is large, the content of beta configurational decitabine generated after hydrolysis is high, the purifying difficulty of decitabine is lowered, and the purity of a decitabine finished product is increased. During purification, ethyl acetate is used instead of methanol or ethanol, so that the influence of methanol or ethanol on the purity of the decitabine finished product at the purifying stage is avoided; and moreover, the synthetic method has the advantages of cheap reagents, less reaction steps, mild reaction condition and contribution to industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for synthesizing decitabine. Background technique [0002] Decitabine, known as Decitabine in English, is a cytosine nucleoside drug developed by SuperGen and marketed by MGIPHARMA. 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 DNA methylation process, induce tumor cells to differentiate like normal cells or induce tumor cell apoptosis. In tumor cells, high-concentration decitabine is phosphorylated by deoxycytidine kinase, blends with DNA in the form of phosphate, directly acts on DNA, inhibits DNA methyltransferase, thereby hypomethylating DNA and inducing Cell differentiation and death exerts its cytotoxic effect; low concentration of decitabine can replace cytosine in tumor cells and covalently bind with DNA methyltransferase to activate sil...

Claims

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Application Information

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