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5-azacytidine compound and preparation method thereof

A technology of azacytidine nucleoside and compound, applied in the field of 5-azacytidine nucleoside compound related substances and its preparation

Pending Publication Date: 2020-02-04
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There is no report on the structure of the compound of formula I and the preparation method

Method used

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  • 5-azacytidine compound and preparation method thereof
  • 5-azacytidine compound and preparation method thereof
  • 5-azacytidine compound and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0050] Preparation of silyl 5-azacytosine:

[0051]

[0052] 5-azacytosine (10.0 g), hexamethyldisilazane (200 mL) and ammonium sulfate (0.2 g) were mixed, heated to reflux, and the reaction was stirred for 18 hours. After the reaction was complete, it was concentrated under reduced pressure, heated with n-heptane (200 mL) to make a slurry, and filtered. The filter cake was dried at 50° C. for 12 hours to obtain 19.5 g of white silyl 5-azacytosine with a mass yield of 195% (calculated as 5-azacytosine).

Embodiment 2

[0054] Preparation of triacetyl azacitidine:

[0055]

[0056] Tetraacetylribose (38.3g) and silyl 5-azacytosine (19.5g) were added to dichloromethane (200mL), and at 20-30°C, trimethylsilyl trifluoromethanesulfonate (25.5 g) was added dropwise to the reaction solution. After the dropwise addition was completed, the reaction was stirred for 5 hours. After the reaction was completed, it was washed with sodium bicarbonate solution (100 mL), purified water (100 mL) and sodium chloride solution (100 mL), respectively. Add anhydrous magnesium sulfate to dry for 5 hours, filter, wash the filter cake with dichloromethane, and concentrate under reduced pressure to obtain 24.2 g of oily triacetylazacitidine, with a mass yield of 124% (based on silyl 5-azacitidine pyrimidine meter).

Embodiment 3

[0058] Preparation of diacetyl azacitidine:

[0059]

[0060] Triacetylazacitidine (24.2 g) was added to anhydrous methanol (250 mL), and a 30% methanol solution of sodium methoxide (6 mL) was added dropwise to the reaction solution at 0-10°C. After the dropwise addition was completed, the internal temperature of the reaction was controlled at 0-10° C. and the reaction was stirred for 12 hours. Acetic acid was added dropwise to adjust the pH to 6-7, concentrated, and purified by column chromatography to obtain 14.5 g of diacetyl azacitidine with a mass yield of 60% (calculated as triacetyl azacitidine).

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Abstract

The invention relates to a 5-azacytidine compound and a preparation method thereof. The structural formula of the 5-azacytidine compound is shown in a formula I (shown in the specification). The compound is obtained from 5-azacytosine as a starting material by upper protection, condensation, deprotection, recondensation and a deprotection rection. Through studies of related substances, recognitionand control of an impurity profile in the 5-azacytidine compound are strengthened, the quality of a finished product is advantageously controlled, and a guarantee is provided for the safety of clinical medication. The synthesis process is simple in operation, good in yield and purity, and is environment friendly.

Description

technical field [0001] The invention relates to a 5-azacytidine nucleoside compound-related substance and a preparation method thereof. Background technique [0002] 5-Azacytidine Nucleoside Compounds Many compounds have been developed into medicines, such as 5-azacytidine (azacitidine), 2′-deoxy-5-azacytidine (decita Decitabine) is suitable for the treatment of diseases, especially myelodysplastic syndrome (MDS). [0003] At present, there are many examples of synthetic methods of 5-azacytidine nucleoside compounds, taking azacitidine as an example: [0004] Collect.Czech.Chem.Commum., 29, 2060 (1964) reported the preparation method of azacitidine for the first time, the method uses chlorinated triacetyl ribose as the starting raw material, and obtains three by reacting with silver isocyanate Acetyl ribosyl isocyanate is coupled with methylisourea, and azacitidine is obtained by high-temperature ring closure in triethyl orthoformate and deprotected ammoniation with ammoni...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/00
CPCC07H1/00C07H19/12Y02P20/55
Inventor 王俊亮王永恒余雷余俊张小兵
Owner JIANGSU HANSOH PHARMA CO LTD
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