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Separation method of decitabine and alpha-type isomer

A decitabine and separation method technology, which is applied in the field of separation and recovery of decitabine and α-isomer, can solve the problem of low recovery efficiency of decitabine, low total yield of decitabine, etc. problem, to achieve the effect of simple and reliable process method, realizing recycling and reducing yield loss

Pending Publication Date: 2022-06-21
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The prior art utilizes the difference in solubility between decitabine and α isomers in alcoholic solvents to carry out recrystallization separation, and high-purity decitabine (≥99.9%) can be obtained through multiple resolutions, but when α in the mother liquor When the content of isomer (≥70%) was too high, it was difficult to obtain decitabine by recrystallization, and therefore the recovery efficiency of decitabine was lower, resulting in a lower total yield for the preparation of decitabine. low phenomenon

Method used

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  • Separation method of decitabine and alpha-type isomer
  • Separation method of decitabine and alpha-type isomer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Take 100g of mother liquor containing decitabine and alpha isomer (content of alpha isomer is 80%), add it to the reaction kettle, add 16L of anhydrous methanol, heat to reflux, continue to add 64L of methyl tert-butyl ether , continue to stir and reflux for 1h, stop heating, add a small amount of seed crystals, naturally stand to cool down to 25°C, crystallize for 4h, filter, and dry to obtain α isomer 65.2g, HPLC: 99.1%.

[0030] The filtrate was concentrated under reduced pressure to 44L, then cooled to 5°C, left to stand for crystallization for 5h, filtered and dried to obtain 16.6g of decitabine, HPLC: 99.3%.

Embodiment 2

[0032] Take 100g of mother liquor containing decitabine and α isomer (α-isomer content 80%), add it to the reaction kettle, add 22 L of anhydrous methanol, heat to reflux, and continue to add 66 L of methyl tert-butyl ether , continue to stir and reflux for 1h, stop heating, add a small amount of seed crystals, naturally stand to cool down to 20°C, crystallize for 3h, filter, and dry to obtain α isomer 64.5g, HPLC: 98.9%.

[0033] The filtrate was concentrated under reduced pressure to 44 L, then cooled to 0° C., left for crystallization for 3 h, filtered, and dried to obtain 17.5 g of decitabine, HPLC: 99.0%.

Embodiment 3

[0035] Take 100g of mother liquor containing decitabine and α isomer (α-isomer content 80%), add it to the reaction kettle, add 20 L of anhydrous methanol, heat to reflux, and continue to add 60 L of methyl tert-butyl ether , continue to stir and reflux for 1h, stop heating, add a small amount of seed crystals, naturally stand to cool down to 25°C, crystallize for 6h, filter, and dry to obtain α isomer 62.6g, HPLC: 99.2%.

[0036] The filtrate was concentrated to 40 L under reduced pressure, then cooled to 5° C., left to stand for crystallization for 6 h, filtered, and dried to obtain 16.7 g of decitabine, HPLC: 99.3%.

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Abstract

The invention belongs to the technical field of medicinal chemistry, and particularly provides a method for separating decitabine and an alpha isomer, in particular to a method for separating and purifying a decitabine recovery mother solution with high content of the alpha isomer, and the high-purity alpha isomer and decitabine can be obtained only by sequential splitting through control of a crystallization process. According to the method, the decitabine mother liquor is recycled, the yield loss of decitabine is reduced, and the method is simple, reliable and suitable for industrial treatment of the decitabine mother liquor.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and specifically relates to the separation and recovery of decitabine and α-isomer in decitabine mother liquor. Background technique [0002] Decitabine is chemically named 4-amino-1-(2-deoxy-β-D-erythro-ribofuranosyl)-1,3,5-triazin-2-(1H)-one, also known as 5- Aza-2'-deoxycytidine, the structure is shown in formula (I). [0003] [0004] Decitabine is a cytosine nucleoside analog developed and marketed by SuperGen Company. It is a non-selective DNA methylation inhibitor. As a DNA methyltransferase inhibitor, it can prevent cytosine residues in DNA. As an anticancer drug, decitabine has a very significant effect on acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and myelodysplastic syndrome (MDS). [0005] So far, many synthetic methods of decitabine have been reported in the literature, but usually a mixture containing α and β configurations is obtained, and then th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/12C07H1/06
CPCC07H19/12C07H1/06
Inventor 郑艺白文钦
Owner LUNAN PHARMA GROUP CORPORATION
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