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A method for preparing β-enriched decitabine precursor

A technology of decitabine and its precursor, which is applied in the field of preparation of decitabine precursor, can solve the problems of high recovery cost, lack of purification, and large amount of solvent used, and achieve stable and controllable operation and simple process , the effect of high yield

Active Publication Date: 2015-12-09
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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  • A method for preparing β-enriched decitabine precursor
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  • A method for preparing β-enriched decitabine precursor

Examples

Experimental program
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Embodiment 1

[0032] Example 1: Preparation of crude decitabine precursor

[0033] 600g of 5-azacytosine, 6.0g of ammonium sulfate, and 6L of hexamethyldisilazane were added to the 10L glass reactor successively, and the reaction was carried out at 120°C to 125°C under stirring to obtain a clear solution, and the unreacted hexamethylene was concentrated under reduced pressure. Methyldisilazane, the obtained residue was dissolved in 6L of methylene chloride, transferred to a 50L glass reactor, added 1L of trimethylsilyl trifluoromethanesulfonate at 1~5°C, and then added 2kg of 1-chloro-3 , 20L dichloromethane solution of 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose, incubated for 20h, adding an appropriate amount of saturated sodium bicarbonate solution to stop the reaction, adding 20L dichloromethane to dilute the reaction solution, purifying Washed with water twice, the organic layer was concentrated under reduced pressure to a large amount of solid precipitation, filtered and dried to obtain ...

Embodiment 2

[0034] Example 2: Preparation of crude decitabine precursor

[0035] 600g of 5-azacytosine, 6.0g of ammonium sulfate, and 6L of hexamethyldisilazane were successively added to the 10L glass reaction kettle, reacted to a clear solution at 125~130°C under stirring, and the unreacted hexamethyl was concentrated under reduced pressure. base disilazane, 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-3, A solution of 5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in 20L dichloromethane was incubated for 20h, an appropriate amount of saturated sodium bicarbonate solution was added to terminate the reaction, 20L dichloromethane was added to dilute the reaction solution, and water was purified After washing twice, the organic layer was concentrated under reduced pressure to precipitate a large amount of solid, which was filtered and dried to obtain 2....

Embodiment 3

[0036] Example 3: Preparation of beta-enriched decitabine precursors

[0037] In a 20L glass reactor, add 500g of the crude decitabine precursor prepared in Example 1, add 10L of a mixed solvent of water / ethanol (V / V)=1 / 10, heat to reflux, and then stand at a temperature of about 25°C. Cool and crystallize for 12h (precipitation of α-rich body), filter, concentrate the filtrate under reduced pressure to near dryness, filter, and vacuum dry the filter cake to obtain 254g 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 in Europe and the United States by MGIPharma in April and May 2006, respectively. In September 2008, it was listed in China under the trade name "Dacogen". The dosage form is freeze-dried powder injection, with a specification of 50 mg. It is used for the treatment of primary and secondary myelodysplastic syndromes (MDS). Decitabine is a demethylating drug with a unique therapeutic mechanism of methyltransferase inhibitors. As an adenosine analog of 2`-deoxycytidine, decitabine can be converted into a 5`-monophosphate deoxycytidine analog in vivo, which penetrates into DNA under the action o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
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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