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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 improved reaction efficiency. short time effect

Active Publication Date: 2019-08-16
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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  • Preparation method of azacitidine
  • Preparation method of azacitidine
  • Preparation method of azacitidine

Examples

Experimental program
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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, raise the temperature to 70°C, the solution is clear for about 2 hours, and then distill off the solvent under reduced pressure to constant weight to obtain A Zacitidine intermediate Ⅰ.

[0026] Dissolve 76.8g (0.3mol) of azacitidine intermediate I in 614.4ml of dichloromethane, put it into a three-neck flask and stir, then add 0.27mol of 1-chloro-2,3,5-tri-O-p-chlorobenzyl For acyl-β-D-ribose, slowly add 0.33mol boron trifluoride dropwise, control the temperature at -5°C and stir the reaction. After reacting for 2 hours, add saturated saline, separate the liquids to obtain an organic phase, and then add saturated bicarbonate to the organic phase Sodium solution was separated to obtain an organic phase, which was dried with anhydrous sodium sulfate for 2 hours, filtered to obtain an organic phase, and distilled under reduced pressure to constant weig...

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, and the solution is clear for about 2 hours, then distill off the solvent under reduced pressure to constant weight to obtain A Zacitidine intermediate Ⅰ.

[0030] Dissolve 76.8g (0.3mol) of azacitidine intermediate I in 1536ml of dichloromethane, put it into a three-neck flask and stir, 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 at 15°C and stir the reaction, after reacting for 2 hours, add saturated saline, separate the liquids to obtain an organic phase, then add saturated sodium bicarbonate solution to the organic phase , separated to obtain an organic phase, dried over anhydrous sodium sulfate for 2 hours, filtered to obtain an organic phase, and distilled under reduced pressure to constant weight to obtain azacitidine intermediate II...

Embodiment 3

[0033] Put 33.6g of 5-azacytosine into a three-necked flask, add 168ml of trimethylchlorosilane and 0.85g of ammonium sulfate, raise the temperature to 80°C, the solution is clear for about 2 hours, and then evaporate the solvent under reduced pressure to constant weight to obtain Aza Cytidine intermediate I.

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

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Abstract

The invention belongs to the field of pharmaceutical synthesis, and specifically relates to a preparation method of azacitidine, wherein the preparation method comprises the following steps: carryingout a reaction of 5-azacytosine with trimethylchlorosilane at the temperature of 70-80 DEG C for 2 h to obtain an azacitidine intermediate I; dissolving the azacitidine intermediate I with dichloromethane, under catalysis of boron trifluoride, carrying out condensation reaction with 1-chloro-2,3,5-tri-O-p-chlorobenzoyl-beta-D-ribose, after completion of the reaction, washing, drying, carrying outsuction filtration and carrying out reduced pressure distillation of the filtrate, to obtain an azacitidine intermediate II represented by the formula IV; and carrying out alcoholysis of the azacitidine intermediate II with ammonia gas, to obtain crude azacitidine, and purifying to obtain high-purity azacitidine. The preparation method has the advantages of mild reaction conditions, short reactiontime and high yield, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of medicine synthesis technology, in particular to a preparation method of azacitidine. Background technique [0002] Azacitidine (Azacitidine), the chemical name is 1-(β-D-ribofuranosyl)-4-amino-1,3,5-triazin-2(1H)-one, is a DNA developed by Pharmion Company of the United States. Methyltransferase inhibitors, first listed in the United States in July 2004, trade name Vidaza (Vidaza). Its mechanism of action is that azacitidine binds to DNA molecules after phosphorylation, DNA methyltransferase undergoes a methylation reaction with azacitidine to form a covalently bonded product, the activity of DNA methyltransferase is inhibited and Degradation occurs, resulting in a decrease in the level of DNA methylation in tumor tissue, demethylation of hypermethylated tumor suppressor genes, restoration of gene expression and inhibition of tumor cells. It is mainly used clinically for the treatment of myelodysplastic syndrome ...

Claims

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Application Information

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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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