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Method of producing high purity clofarabine

A high-purity technology for clofarabine, which is applied in the field of preparation of clofarabine, can solve the problems that clofarabine cannot be prepared economically and effectively, the refined yield is only 31.6%, and it is difficult to effectively separate, so as to achieve low cost and reduce impurities content, the effect of economic production

Inactive Publication Date: 2008-04-02
BEIJING D VENTUREPHARM TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In the document J.Med.Chem., 1992, Vol.35, No.2, it is reported to react with a molecular sieve catalyst, and finally adopt the method of twice column chromatography to remove isomers, but the method is complicated and cumbersome to operate, and the purification The yield is only 31.6%
Low production efficiency and high production cost
[0011] The polarity and solubility of clofarabine and its "α-isomer" are very similar, and it is difficult to separate effectively
Using the methods described in WO03011877 and other disclosed methods for preparing clofarabine cannot economically and effectively prepare and refine high-purity clofarabine

Method used

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  • Method of producing high purity clofarabine
  • Method of producing high purity clofarabine
  • Method of producing high purity clofarabine

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Under the protection of nitrogen, 12.9g of 2-chloroadenine, 100ml of isopropanol and 75ml of acetonitrile were added into a 500ml three-neck flask, and stirred evenly. At room temperature, 3.2 g of sodium methoxide and 3.4 g of calcium hydride were added. A mixture of 100ml of chloroform and 30.5g of the compound of formula I was slowly added dropwise. The reaction was carried out at room temperature overnight, and TLC detected that the reaction was complete. Filter and wash the filter cake with chloroform. The organic phases were combined and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated under reduced pressure. Cooling and crystallization, suction filtration, and vacuum drying at room temperature yielded 27.6 g of a solid (compound of formula III). Yield 75%.

Embodiment 2

[0028] Add 18.8g of the compound of formula III obtained in Example 1, 3.4g of lithium hydroxide, 200ml of acetonitrile and 350ml of water into a 1L reaction flask. Stir to mix well, and stir at room temperature for 3 hours. Adjust the pH to 7-8 with acetic acid, concentrate under reduced pressure to remove acetonitrile, and cool the residue to crystallize. Suction filtration, the filter cake is beaten with acetonitrile. Suction filtration, and the filter cake was vacuum-dried at 50°C until constant weight. 7.2 g of off-white solid was obtained, the yield was 65%. HPLC analysis did not detect the "α-isomer" of clofarabine.

Embodiment 3

[0030] Under the protection of nitrogen, 12.9g of 2-chloroadenine, 100ml of isopropanol and 50ml of acetonitrile were added into a 500ml three-necked flask, and stirred evenly. At room temperature, 3.2 g of sodium methoxide and 3.4 g of calcium hydride were added. A mixture of 130ml of chloroform and 30.5g of the compound of formula I was slowly added dropwise. The reaction was carried out at room temperature overnight, and TLC detected that the reaction was complete. Filter and wash the filter cake with chloroform. The organic phases were combined and dried over anhydrous sodium sulfate. Suction filtration, and the filtrate was concentrated under reduced pressure. Cooling and crystallization, suction filtration, and vacuum drying at room temperature yielded 27.6 g of a solid (compound of formula III). Yield 70%. According to the method hydrolysis in embodiment 2 again, the product obtained is analyzed by HPLC, and the content of the "α-type isomer of clofarabine is 2.0%....

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Abstract

The present invention relates to a preparation method of clofarabine, comprising mixture of 2-adenine chlorine and the compound of formula I. the reaction is done under mild conditions and an appropriate temperature; the basically pure compound of the formula III can be prepared after separation. The high-purity clofarabine can be got through hydrolysis under alkaline conditions.

Description

technical field [0001] The invention relates to a preparation method of clofarabine, in particular to a preparation method of high-purity clofarabine. Background technique [0002] Clofarabine is a nucleoside purine antimetabolite drug used to treat relapsed or refractory acute lymphoblastic leukemia in children. It is the first new drug approved for the treatment of childhood leukemia in the past ten years. Its structural formula is as follows As shown in the figure: [0003] [0004] Leukemia, especially acute lymphoblastic leukemia, is the most common malignancy in children and adolescents. Although the cure rate of leukemia in children is relatively high, there are no anti-leukemia drugs specially used for children. Adults using drugs for children will bring great side effects and seriously affect children's physical and mental health and quality of life. Clofarabine is a drug specially used for childhood leukemia. The drug has a high cure rate, is well tolerated by...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/173
Inventor 杨利民
Owner BEIJING D VENTUREPHARM TECH DEV
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