Azacitidine disaccharide impurity and preparation method and application thereof

A reaction, ribose technology, applied in the field of azacitidine disaccharide impurities and its preparation and application

Active Publication Date: 2019-04-19
WUHU SIMCERE ZHONGREN PHARM +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Regarding the preparation and separation method of this impurity, there is no literature report at home and abroad, so the disacc

Method used

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  • Azacitidine disaccharide impurity and preparation method and application thereof
  • Azacitidine disaccharide impurity and preparation method and application thereof
  • Azacitidine disaccharide impurity and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Embodiment 1: the preparation of formula III compound

[0029] Mix 20 g (62.9 mmol) of tetraacetyl ribose with 57 g (222.7 mmol) of the compound of formula IV, add dichloromethane, raise the temperature to 30°C, add 21 g (157.9 mmol) of aluminum trichloride, and react for 23 hours. Cool down to room temperature 25°C, pour the reaction solution into ice water of sodium bicarbonate, add dichloromethane at the same time, filter to remove insoluble matter, separate the layers, and concentrate the organic phase to dryness. Purified by silica gel column chromatography (eluent: dichloromethane / methanol=30:1) to obtain 24.1 g (38.3 mmol, yield 61%) of off-white solid.

Embodiment 2

[0030] Embodiment 2: the preparation of formula III compound

[0031] Mix 17g (53.4mmol) of tetraacetylribose with 55g (214.5mmol) of the compound of formula IV, add 1,2-dichloromethane, raise the temperature to 50°C, add 18g (133.5mmol) of aluminum trichloride, and react for 19 hours . Cool down to room temperature 25°C, pour the reaction solution into ice water of sodium bicarbonate, add dichloromethane at the same time, filter to remove insoluble matter, separate the layers, and concentrate the organic phase to dryness. Purified by silica gel column chromatography (eluent: dichloromethane / methanol=30:1) to obtain 19.1 g (30.4 mmol, yield 57%) of off-white solid.

Embodiment 3

[0032] Embodiment 3: the preparation of formula III compound

[0033] Mix 15g (47.1mmol) of tetraacetyl ribose with 60g (235.6mmol) of the compound of formula IV, add 1,2-dichloromethane, heat up to 30°C, add 42g (188.4 mmol.), reacted for 19 hours. Cool down to room temperature 25°C, pour the reaction solution into ice water of sodium bicarbonate, add dichloromethane at the same time, filter to remove insoluble matter, separate the layers, and concentrate the organic phase to dryness. Purified by silica gel column chromatography (eluent: dichloromethane / methanol=30:1) to obtain 13.0 g (20.7 mmol, yield 44%) of off-white solid.

[0034] The structure verification data of the compound represented by formula III are shown in Table 1 and Table 2.

[0035]

[0036] Table 1 Hydrogen Spectrum Determination Results

[0037] chemical shift

proton number

peak shape

Correlative proton chemical shift

attribution

Remark

9.18

1

d

5.70

H...

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PUM

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Abstract

The invention relates to azacitidine disaccharide impurity and a preparation method and an application thereof. According to the invention, a compound shown as a formula IV is used as a starting material, the compound as a formula III is prepared by catalysis of Lewis acid with tetraacetylribofuranose, and the compound as the formula III is hydrolyzed to prepare the compound as a formula II. The prepared compound as the formula II can be used as a reference for the detection of related substances of azacitidine, and can be used for quality control application of azacitidine and its related preparations.

Description

technical field [0001] The invention relates to azacitidine disaccharide impurities, a preparation method and application thereof. Background technique [0002] Azacitidine was first synthesized by Czechoslovakian scientists Piskala and Sorm, and was later isolated from the fermentation broth of Streptoverticillium ladakanus. [0003] Azacitidine, a 5-aza analogue of cytidine, belongs to a class of epigenetic antineoplastic agents known as hypomethylating agents. Abnormal DNA methylation inactivates key genes regulating normal cell growth, differentiation and apoptosis, which is related to the occurrence and development of tumors. The effectiveness of azacitidine in the treatment of MDS is mainly due to its DNA hypomethylation activity and direct cytotoxicity to abnormal hematopoietic cells in the bone marrow. Azacitidine is a DNA methyltransferase inhibitor that does not significantly inhibit DNA synthesis at concentrations that maximally inhibit DNA methylation. [0004...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00
CPCC07H1/00C07H19/12C07D251/06Y02P20/55
Inventor 邓海存郭起蒋兵任晋生张连第
Owner WUHU SIMCERE ZHONGREN PHARM
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