Preparation method of azacitidine impurity

A technology of ammeline pentose and compound, which is applied in the field of medicinal chemistry and can solve the problems of long synthesis steps, low yield and complicated operation

Inactive Publication Date: 2015-06-03
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] This process route has long synthesis steps, low yield, relatively complicated operation, and involves some highly toxic solvents (such as 1,2-dichloroethane, toluene, etc.), and isocyanic acid derivatives also have certain potential genes. toxicity
In the prior art, there is no method for preparing impurity ammeline pentose with high yield, high purity and easy operation

Method used

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  • Preparation method of azacitidine impurity
  • Preparation method of azacitidine impurity
  • Preparation method of azacitidine impurity

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 N 2 ,N 4 - Preparation of bis(trimethylsilyl)-6-trimethylsiloxy-1,3,5-triazine-2,4-diamine

[0037]

[0038] Weigh 2.54g of 6-amino-5-azacytosine into a 100mL three-neck flask, add 50.2ml of hexamethyldisilazane (HMDS) and 50mg of ammonium sulfate, stir and heat to reflux, react for 10h, and stop after the solution is clarified After heating, the reaction solution was evaporated to dryness under reduced pressure to obtain the title compound.

[0039] ESI-MS m / z:[M+H] + =344.2.

Embodiment 2

[0040] Example 2 (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(4,6-diamino-2-oxo-1,3,5-triazine-1(2H )-yl)tetrahydrofuran-3,4-diyl diacetate

[0041]

[0042] Weigh 6.86g (0.02mol) of the compound prepared in Example 1 into a 250ml four-neck flask, add 80ml of dichloromethane and 5.72g (0.018mol) of tetraacetyl ribose, stir, cool down to about 0°C, and add AlCl 3 A total of 3.2g (0.024mol), after 5 hours of reaction at 0~20°C, pour the reaction solution into 100ml of cold saturated sodium bicarbonate solution, separate the liquids, take the organic phase, and wash it twice with cold water (50ml / time×2times) ), the organic phase was taken, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 2.31 g of the title compound, yield: 33.3%.

[0043] 1 H NMR (500MHz, DMSO-d 6)δ: 7.48 (2H), 6.87 (1H), 6.72 (1H), 5.81 (1H), 5.60 (1H), 5.46 (1H), 4.32 (1H), 4.13 (2H), 2.02-2.05 (9H).

[0044] ESI-MS m / z:[M+H] + =386.1.

Embodiment 3

[0045] Example 3 (2R,3R,4R,5R)-2-(benzoyloxymethyl)-5-(4,6-diamino-2-oxo-1,3,5-triazine-1 (2H)-yl)tetrahydrofuran-3,4-diyldibenzoate

[0046]

[0047] Weigh 6.86g (0.02mol) of the compound prepared in Example 1 into a 250ml four-neck flask, add 80ml of dichloromethane and 11.32g (0.02mol) of tetrabenzoyl ribose, stir, cool down to below 5°C, and add AlCl 3 A total of 4g (0.03mol), after 6.5h reaction at 0~15°C, pour the reaction solution into 100ml cold saturated sodium bicarbonate solution, separate the liquids, take the organic phase, wash twice with cold water (50ml / time×2times) ), the organic phase was taken, dried over anhydrous sodium sulfate, filtered, and purified by column chromatography to obtain 4.27 g of the title compound, yield: 37.4%.

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Abstract

The invention belongs to the field of medical chemistry, and particularly relates to a preparation method of impurity component cyanurodiamide pentose of azacitidine. The method is characterized in that N2, N4-bi(trimethylsilyl)-6-trimethylsilyl-1,3,5,- triazine-2,4-diamine which is adopted as a raw material has condensation reaction with tetra-o-acetyl-d-ribose under the protection of trimethylsilyl and under the catalysis of aluminium trichloride, boron trifluoride, zinc chloride or titanium tetrachloride at the temperature of -10 to 20 DEG C, and then a protecting group on the sugar is removed to prepare the cyanurodiamide pentose.

Description

field of invention [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of ammeline pentose, an impurity component of azacitidine. Background technique [0002] Myelodysplastic syndrome (MDS) is a group of diseases characterized by clonal abnormalities of hematopoietic stem cells. High risk of acute myeloid leukemia (AML). The disease is divided into five types namely refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with increased blasts (RAEB), refractory anemia with increased blasts -Transformation (RAEB-T), chronic myelomonocytic leukemia (CMML). [0003] Azacitidine, the structure is shown in formula A, also known as 5-azacytidine, 5-azacytidine nucleoside, azacytidine, azacytidine, trade name Vidaza (Vidaza) , can be used for the treatment of all subtypes of myelodysplastic syndrome. As a DNA methyltransferase inhibitor of cytidine nucleosides, azacitidine is c...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/00
CPCY02P20/55C07H19/12C07H1/00
Inventor 王勇储刚王利娟谢同张圣淼沙向阳张仓张迪
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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