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A kind of preparation method of azacitidine

A technology for azacitidine and azacytosine, which is applied in the field of preparation of azacitidine, can solve the problems of increased risk, complicated process, long time consumption, etc., and achieves improved purity and yield, mild reaction conditions, and high reaction efficiency. short time effect

Active Publication Date: 2022-06-07
LUNAN BETTER PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although there are many reports on the synthesis of azacitidine, the process is complicated and the purity of azacitidine is low
The silylation reaction generally has low efficiency and takes a long time, and the reaction mostly uses toxic benzene or toluene as a solvent; trimethylsilyl trifluoromethanesulfonate reacts violently with water, which increases the risk of the reaction; Using anhydrous tin tetrachloride and aluminum trichloride as catalysts has the problems of excessive heavy metals and cumbersome post-treatment, which greatly increases the risk of solvent residue and heavy metals in the finished product of azacitidine, which is not conducive to industrial production

Method used

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  • A kind of preparation method of azacitidine
  • A kind of preparation method of azacitidine
  • A kind of preparation method of azacitidine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Put 33.6g of 5-azacytosine into a three-necked flask, add 134.4ml of trimethylchlorosilane and 0.85g of ammonium sulfate, heat up to 70°C, the solution is clarified for about 2h, and then the solvent is evaporated under reduced pressure to constant weight. Zacytidine Intermediate I.

[0026] Dissolve 76.8g (0.3mol) of azacitidine intermediate I with 614.4ml of dichloromethane, put it into a three-necked flask and stir, and then add 0.27mol of 1-chloro-2,3,5-tri-O-p-chlorobenzyl Acyl-β-D-ribose, slowly add 0.33mol boron trifluoride dropwise, control the temperature to -5 °C and stir the reaction, after the reaction for 2 hours, add saturated brine, and separate the liquid to obtain the organic phase, and then add saturated hydrogen carbonate to the organic phase. Sodium solution, separated to obtain the organic phase, dried over anhydrous sodium sulfate for 2 hours, suction filtered to obtain the organic phase, and distilled under reduced pressure to constant weight to o...

Embodiment 2

[0029] Put 33.6g of 5-azacytosine into a three-necked flask, add 336ml of trimethylchlorosilane and 0.85g of ammonium sulfate, heat up to 80°C, the solution is clarified for about 2h, and then the solvent is evaporated under reduced pressure to a constant weight to obtain a Zacytidine Intermediate I.

[0030] Dissolve 76.8g (0.3mol) of azacitidine intermediate I with 1536ml of dichloromethane, put it into a three-necked flask and stir, and then add 0.39mol of 1-chloro-2,3,5-tri-O-p-chlorobenzoyl -β-D-ribose, slowly add 0.45mol boron trifluoride dropwise, control the temperature to 15 °C and stir the reaction, after the reaction for 2 hours, add saturated brine, and separate the liquid to obtain the organic phase, and then add saturated sodium bicarbonate solution to the organic phase. , the organic phase was obtained by liquid separation, dried over anhydrous sodium sulfate for 2 hours, and the organic phase was obtained by suction filtration, which was distilled under reduced...

Embodiment 3

[0033] Put 33.6g of 5-azacytosine into a three-necked flask, add 168ml of trimethylchlorosilane and 0.85g of ammonium sulfate, heat up to 80°C, the solution is clarified for about 2 hours, and then the solvent is evaporated under reduced pressure to constant weight to obtain aza Cytidine Intermediate I.

[0034] Dissolve 76.8g (0.3mol) of azacitidine intermediate I with 691.2ml of dichloromethane, put it into a three-necked flask and stir, and then add 0.285mol of 1-chloro-2,3,5-tri-O-p-chlorobenzyl Acyl-β-D-ribose, slowly add 0.36mol boron trifluoride dropwise, control the temperature to 5 °C and stir the reaction, after 2 hours of reaction, add saturated brine, and separate the liquid to obtain an organic phase, and then add saturated sodium bicarbonate to the organic phase. The solution was separated and the organic phase was obtained. After drying with anhydrous sodium sulfate for 2 hours, the organic phase was obtained by suction filtration, and the azacitidine intermedia...

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a preparation method of azacitidine, comprising the following steps: reacting 5-azacytosine and trimethylchlorosilane at 70-80°C for 2 hours to obtain azacitidine Glycoside intermediate Ⅰ; Azacitidine intermediate Ⅰ is dissolved in dichloromethane, under the catalysis of boron trifluoride, and 1-chloro-2,3,5-tri-O-p-chlorobenzoyl-β- D-ribose undergoes a condensation reaction. After the reaction is completed, wash, dry, and suction filter, and the filtrate is distilled under reduced pressure to obtain the azacitidine intermediate II of the formula IV; the azacitidine intermediate II is alcoholylated with ammonia to obtain azacitidine The crude product was purified to obtain high-purity azacitidine. The invention has mild reaction conditions, short reaction time and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical synthesis technology, in particular to a preparation method of azacitidine. Background technique [0002] Azacitidine, chemical name 1-(β-D-ribofuranosyl)-4-amino-1,3,5-triazine-2(1H)-one, is a DNA developed by Pharmion Company in the United States The methyltransferase inhibitor was first listed in the United States in July 2004 under the trade name Vidaza. Its mechanism of action is that azacitidine binds to DNA molecules after phosphorylation, and DNA methyltransferase undergoes methylation reaction with azacitidine to form a covalently bound product, and the activity of DNA methyltransferase is inhibited. Degradation occurs, causing the DNA methylation level in tumor tissue to decrease, and the hypermethylation tumor suppressor gene demethylation, which restores gene expression and inhibits tumor cells. It is mainly used in the treatment of myelodysplastic syndrome (MDS) acute non-lymphocytic l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07H1/00C07H19/12
CPCC07H1/00C07H19/12
Inventor 张贵民占金宝陈成富
Owner LUNAN BETTER PHARMA
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