Preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate

A technology of triethyl phosphate and fludarabine phosphate, which is applied to the preparation of sugar derivatives, chemical instruments and methods, sugar derivatives, etc., can solve the problems of complicated post-processing operations, harsh reaction temperatures, and cumbersome refining steps. Achieve the effects of simple and easy operation, short reaction time and high purity after reaction

Active Publication Date: 2015-05-06
SHANDONG NEWTIME PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] Aiming at the harsh reaction temperature of the prior art, long reaction time, and complicated post-treatment operations, an object of the present invention is to provide a method for synthesizing fludarabine phosphate
[0015] Another object of the present invention is to provide a method for refining the crude product of fludarabine phosphate, so as to solve the problem of passing through resin columns and chromatographic columns in the refining method, complicated refining steps, and high temperature water dissolution causing part of fludarabine phosphate to deteriorate and degrade to generate new Impurities, insufficient purity, etc.

Method used

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  • Preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate
  • Preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate

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Embodiment 1

[0033] Under stirring conditions, put fludarabine (10g), triethyl phosphate (115mL), and phosphorus oxychloride (7.5mL) in a low-temperature circulation pump at -5 to -10°C, while maintaining the internal temperature at -5 ~-1°C; Stir the reaction at -5~-1°C for 15 hours; when the amount of fludarabine is less than 2% in the HPLC detection area, the reaction is considered complete, and then pure water (105mL) is added under stirring The obtained mixture was washed with dichloromethane, the obtained aqueous phase was adjusted to pH = 3 with 50% NaOH solution, concentrated under reduced pressure at 35-40°C, refrigerated for crystallization, filtered, and the filter cake was washed with a small amount of ethanol and water to obtain a white solid , the white solid was vacuum-dried at 45-50°C for 10-12 hours to obtain the crude product of fludarabine phosphate with a purity of 99.1% and a yield of 74.2%.

[0034] Add the fludarabine phosphate crude product obtained by the above pre...

Embodiment 2

[0036] Under stirring conditions, put fludarabine (10g), triethyl phosphate (90mL), and phosphorus oxychloride (6mL) in a low-temperature circulation pump at -5 to -10°C, while keeping the internal temperature at -5 to -1°C; Stir the reaction at -5~-1°C for 15 hours; when the amount of fludarabine is less than 2% in the HPLC detection area, the reaction is considered complete, and then pure water (50mL) is added under stirring The mixture was washed with dichloromethane, the obtained aqueous phase was adjusted to pH = 3 with 50% NaOH solution, concentrated under reduced pressure at 35-40°C, refrigerated for crystallization, filtered, and the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was vacuum-dried at 45-50°C for 10-12 hours to obtain the crude product of fludarabine phosphate with a purity of 99.2% and a yield of 73.3%.

[0037] Add the fludarabine phosphate crude product obtained by the above preparation method ...

Embodiment 3

[0039] Under stirring conditions, put fludarabine (10g), triethyl phosphate (150mL), and phosphorus oxychloride (12mL) in a low-temperature circulation pump at -5 to -10°C, while maintaining an internal temperature of -5 to -1°C; Stir the reaction at -5~-1°C for 15 hours; when the amount of fludarabine is less than 2% in the HPLC detection area, the reaction is considered complete, and then pure water (200mL) is added under stirring The mixture was washed with dichloromethane, the obtained aqueous phase was adjusted to pH = 3 with 50% NaOH solution, concentrated under reduced pressure at 35-40°C, refrigerated for crystallization, filtered, and the filter cake was washed with a small amount of ethanol and water to obtain a white solid. The white solid was vacuum-dried at 45°C-50°C for 10-12 hours to obtain the crude product of fludarabine phosphate with a purity of 99.1% and a yield of 71%.

[0040]Add the fludarabine phosphate crude product obtained by the above preparation me...

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Abstract

The invention discloses a preparation method for 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate. The method employs 9-beta-D-arabinofuranosyl-2-fluoroadenine as an initial raw material, enables the raw material to be reacted with a mixture of triethyl phosphate and phosphorus oxychloride and employs water for post-processing, thereby solving the problems in other synthetic methods that reaction temperature is sever, reaction time is long and post-processing operation is complex. Also, the invention discloses a simple practicable refining method, and helps to effectively improve the purity of 9-beta-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of 9-β-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate. Background technique [0002] Fludarabine phosphate (9-β-D-arabinofuranosyl-2-fluoroadenine-5'-phosphate), English name; fludarabine phosphate, molecular formula: C 10 h 13 FN 5 o 7 P, molecular weight: 365.2117, its structural formula is: [0003] [0004] Developed by Berlex Labs in Germany, it was first launched in the United States in 1991 for the treatment of B-cell chronic lymphocytic leukemia (CLL). After ingestion, this product undergoes dephosphorylation to generate the metabolite 9-β-fluoroarabinoadenosine (F-Ara-A), which becomes F-Ara-ATP with anti-tumor activity after phosphorylation in cells. The anti-tumor mechanism of this product involves participating in the DNA or RNA chain of tumor cells, so that the chain stops extending, so as to achieve the purpose of inhibiting DNA or RN...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/20C07H1/02C07H1/06
Inventor 赵志全高鹏潘高峰吴素珍王亚辉
Owner SHANDONG NEWTIME PHARMA
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