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Method for preparing beta-enriched Decitabine precursor

A decitabine and precursor technology, which is applied in the field of preparation of decitabine precursors, can solve the problems of high recovery cost, unrefined, large solvent usage, etc., and achieves stable and controllable operation and simple process. , the effect of high yield

Active Publication Date: 2013-08-07
连云港杰瑞药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Patent CN101948493A proposes to use the crude decitabine precursor to form a suspension in C5-C7 hydrocarbons, stir, filter, and dry to obtain the β-enriched decitabine precursor, but the inventor found that when repeating the patent example , the crude decitabine precursor is almost insoluble in C5-C7 hydrocarbons, and the purpose of refining cannot be achieved, and the method recorded in this patent cannot be replicated
[0008] Patent CN102212097A mentions that β-enriched decitabine precursor can be obtained by crystallization with glacial acetic acid, but no crystallization method is proposed
[0009] Patent CN102391338A mentions the purification method of dissolving the decitabine precursor in dichloromethane, slowly adding toluene dropwise to precipitate a solid, then cooling and standing, crystallizing, and filtering and drying. The ratio of the purified β isomer is not provided. And this method uses a large amount of solvent, and the recovery cost is high

Method used

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  • Method for preparing beta-enriched Decitabine precursor
  • Method for preparing beta-enriched Decitabine precursor
  • Method for preparing beta-enriched Decitabine precursor

Examples

Experimental program
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Embodiment 1

[0032] Embodiment 1: Preparation of crude product of decitabine precursor

[0033] Add 600g of 5-azacytosine, 6.0g of ammonium sulfate, and 6L of hexamethyldisilazane into a 10L glass reactor in sequence, react at 120°C~125°C under stirring to obtain a clear solution, and concentrate the unreacted Hexamethyldisilazane, the obtained residue was dissolved in 6L of dichloromethane, transferred to a 50L glass reactor, 1L of trimethylsilyl trifluoromethanesulfonate was added at 1~5°C, and then 2kg of 1-chloro -20L dichloromethane solution of -3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose, keep warm for 20 hours, add an appropriate amount of saturated sodium bicarbonate solution to terminate the reaction, add 20L dichloromethane to dilute the reaction solution , washed twice with purified water, the organic layer was concentrated under reduced pressure until a large amount of solids were precipitated, filtered, and dried to obtain 2.1 kg of crude decitabine precursor (α / β=1 / 1.2, such a...

Embodiment 2

[0034] Embodiment 2: Preparation of crude product of decitabine precursor

[0035] Add 600g of 5-azacytosine, 6.0g of ammonium sulfate, and 6L of hexamethyldisilazane into a 10L glass reactor in sequence, and react at 125~130°C under stirring to a clear solution, and concentrate the unreacted hexamethyldisilazane under reduced pressure. Methyldisilazane, the obtained residue was dissolved in 6L of dichloromethane, transferred to a 50L glass reactor, 1L of trimethylsilyl trifluoromethanesulfonate was added at 5~10°C, and then 2kg of 1-chloro- 20L dichloromethane solution of 3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose, keep warm for 20h, add an appropriate amount of saturated sodium bicarbonate solution to terminate the reaction, add 20L dichloromethane to dilute the reaction solution, Washed twice with purified water, the organic layer was concentrated under reduced pressure until a large amount of solids precipitated, filtered and dried to obtain 2.1 kg of crude decitabine pre...

Embodiment 3

[0036] Example 3: Preparation of β-enriched decitabine precursor

[0037] Add 500g of the crude decitabine precursor prepared in Example 1 into a 20L glass reactor, add 10L of a mixed solvent of water / ethanol (V / V)=1 / 10, heat to reflux, and then let stand at about 25°C Cool and crystallize for 12 hours (precipitate α-enriched body), filter, concentrate the filtrate to near dryness under reduced pressure, filter, and vacuum-dry the filter cake to obtain 254 g of β-enriched decitabine (α / β=1 / 11, such as figure 2 ).

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Abstract

The invention discloses a method for preparing beta-enriched decitabine precursor, which comprises the following steps: heating reflux of decitabine precursor crude product at the ratio of isomer alpha to beta being 1 to 0.8-2 in a mixed solvent containing water, organic solvent C1-C3 alcohol, acetone or tetrahydrofuran, cooling and filtering, filtrate condensation, crystallization, filtering, vacuum drying of filter cake, obtaining of the beta-enriched decitabine precursor at the ratio of the isomer alpha to beta being 1 to 7-18. After a protective group of the obtained beta-enriched decitabine precursor is removed, a high-yield and high purity decitabine is obtained.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and relates to a preparation method of a decitabine precursor, in particular to a preparation method of a β-enriched decitabine precursor. Background technique [0002] Decitabine is a natural nucleoside 2-deoxycytidine analog, a DNA methyltransferase inhibitor, developed by Supergen and launched by MGI Pharma in Europe and the United States in April and May 2006, respectively. , launched in China in September 2008 with the trade name "Dacogen", the dosage form is freeze-dried powder injection, the specification is 50 mg, and it is used for the treatment of primary and secondary myelodysplastic syndrome (MDS). Decitabine is a hypomethylating drug with a unique therapeutic mechanism as a methyltransferase inhibitor. As an adenosine analogue of 2`-deoxycytidine acid, decitabine can be converted into a 5`-monophosphate deoxycytidine analogue in the body, which penetrates into DNA under ...

Claims

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Application Information

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IPC IPC(8): C07H19/12C07H1/06
CPCY02P20/55
Inventor 毛联岗温树启峁辉王媛季锡平张兰平王寅陈龙严静尹红珍
Owner 连云港杰瑞药业有限公司
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