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Method for purifying decitabine intermediate crude product

A purification method and decitabine technology are applied in the field of purification of crude decitabine intermediates, which can solve the problems of large proportion of impurities, dark color and large number of impurities, and achieve the effect of improving the purity

Inactive Publication Date: 2012-03-28
CHONGQING TAIHAO PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The compound 1-chloro-3,5-di-p-chlorobenzoyloxy-2-deoxy-D-riboazacytosine with the structure shown in formula I obtained by the above synthetic method has a large number of impurities, and the impurities contained The proportion is relatively large, and the decitabine solid cannot be stably prepared with this intermediate, and even if the decitabine solid is obtained, the color is dark and the subsequent refining is difficult to effectively remove the color, and there are many related substances, which require Multiple refinements are needed to prepare decitabine suitable for pharmaceutical use

Method used

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  • Method for purifying decitabine intermediate crude product
  • Method for purifying decitabine intermediate crude product
  • Method for purifying decitabine intermediate crude product

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Embodiment 1

[0047] The purification of embodiment 1 decitabine intermediate

[0048] Add 1.62g of 5-azacytosine, 0.162g of ammonium sulfate, and 40mL of hexamethyldisilamine into a 4-necked reaction flask in turn, under nitrogen protection, heat up to 117°C under stirring, keep at this temperature for 2 hours, and obtain clarification The solution was then concentrated under reduced pressure to remove unreacted hexamethyldisilamine. The obtained residue was dissolved in 25 mL of anhydrous chloroform. Add this solution dropwise to a solution of 5.0 g of 1-chloro-3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in anhydrous chloroform at 1 °C under nitrogen protection. After the drop is complete, add 1.0 10 mL of anhydrous chloroform solution of trimethylsilyl trifluoromethanesulfonate was added dropwise to the reaction solution, and after the drop was completed, the reaction was incubated for 21 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 6, 100 mL of chlorof...

Embodiment 2

[0050] The purification of embodiment 2 decitabine intermediate

[0051] Add 1.62g of 5-azacytosine, 0.324g of ammonium sulfate, and 80mL of hexamethyldisilamine into a 4-necked reaction flask in turn, under nitrogen protection, heat up to 115°C under stirring, keep at this temperature for 2 hours, and obtain clarification The solution was then concentrated under reduced pressure to remove unreacted hexamethyldisilamine. The obtained residue was dissolved in 25 mL of anhydrous chloroform. Add this solution dropwise to a solution of 10.0 g of 1-chloro-3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in anhydrous chloroform at 1 °C under nitrogen protection. After the drop is complete, add 2.0 10 mL of anhydrous chloroform solution of trimethylsilyl trifluoromethanesulfonate was added dropwise to the reaction solution, and after the drop was completed, the reaction was incubated for 21 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 6, 100 mL of chloro...

Embodiment 3

[0053] The purification of embodiment 3 decitabine intermediate

[0054] Add 1.62g of 5-azacytosine, 0.486g of ammonium sulfate, and 120mL of hexamethyldisilazide into a 4-necked reaction flask in turn, under nitrogen protection, heat up to 120°C under stirring, keep at this temperature for 2 hours, and obtain clarification The solution was then concentrated under reduced pressure to remove unreacted hexamethyldisilamine. The obtained residue was dissolved in 25 mL of anhydrous chloroform. Add this solution dropwise to a solution of 15.0 g of 1-chloro-3,5-di-p-chlorobenzoyloxy-2-deoxy-D-ribose in anhydrous chloroform at 1 °C under nitrogen protection. After the drop is complete, add 1.0 10 mL of anhydrous chloroform solution of trimethylsilyl trifluoromethanesulfonate was added dropwise to the reaction solution, and after the drop was completed, the reaction was incubated for 21 hours, then saturated sodium bicarbonate solution was added to adjust the pH to 6, 100 mL of chlor...

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Abstract

The invention relates to the field of chemical synthesis, in particular to a method for purifying a decitabine intermediate crude product. According to the purifying method, the decitabine intermediate crude product is dissolved into a first organic solvent such as dichloromethane and the like, and a second organic solvent such as methylbenzene and the like is added, so that the impurities of the decitabine intermediate with the structure shown as a formula I can be effectively removed, and the purity of the decitabine intermediate is improved.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a method for purifying a crude intermediate of decitabine. Background technique [0002] Decitabine, the English name is Decitabine, the chemical name is 1-(β-D-2-deoxyribose)-4-amino-1,3,5-triazin-2(1H)-one, and the molecular formula is C 8 h 12 N 4 o 4 , also known as 5-aza-2'-deoxycytidine, is a cytidine nucleoside drug, developed by SuperGen and marketed by MGIPHARMA, and was approved in the United States for the treatment of myelodysplastic syndrome in May 2006 (MDS). As a specific DNA methyltransferase inhibitor, decitabine can reverse the DNA methylation process, induce tumor cells to differentiate like normal cells or induce tumor cell apoptosis. In tumor cells, high-concentration decitabine is phosphorylated by deoxycytidine kinase, blends with DNA in the form of phosphate, directly acts on DNA, inhibits DNA methyltransferase, thereby hypomethylating DNA and induci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/06C07H1/00
Inventor 王信见姚全兴李靖
Owner CHONGQING TAIHAO PHARM CO LTD