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Synthesis method of fludarabine

A technology of fludarabine and its synthetic method, which is applied in the field of drug preparation, can solve the problems of being unsuitable for industrial production and harsh reaction conditions, and achieve the effects of cheap raw materials, short reaction time and high yield

Inactive Publication Date: 2013-02-06
HUAIHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] Although this method has a high yield, it needs to use expensive enzymes, and the reaction conditions are relatively harsh, so it is not suitable for industrial production

Method used

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  • Synthesis method of fludarabine
  • Synthesis method of fludarabine
  • Synthesis method of fludarabine

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Experimental program
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Embodiment 1

[0026] The synthesis of embodiment 1 fludarabine

[0027] Add 400mL of 2.5N NaOH solution and 300mL of concentrated ammonia water into the reaction flask, put the reaction flask into an ice-water bath and cool to 0~5°C; add 4L of 2-methyltetrahydrofuran and 400mL of water into the above reaction flask, stir and cool to 0~5℃; under stirring, add 225g of 2-fluoro-9-β-D-(2′,3′,5′-tri-O-acetylarabinofuranosyl)adenine in portions; after the addition, the mixture Stir and react at 0-5°C for 2 h; after TLC (developing agent: chloroform:methanol=9:1) shows that the reaction is complete, add 35 mL of glacial acetic acid to the reaction mixture, and stir for 5-10 min. The reaction mixture was concentrated to dryness under reduced pressure, 1.5 L of water was added to the residue, stirred at room temperature for 5-10 min, and filtered to obtain crude fludarabine. The crude product was recrystallized with water and decolorized with activated carbon, and the precipitated solid was filtere...

Embodiment 2

[0028] The synthesis of embodiment 2 fludarabine

[0029] Add 400mL of 2.5N NaOH solution and 280mL of concentrated ammonia water into the reaction flask, put the reaction flask into an ice-water bath and cool to 0~5°C; add 5L of 2-methyltetrahydrofuran and 400mL of water into the above reaction flask, stir and cool to 0~5℃; 283g 2-fluoro-9-β-D-(3′,5′-di-O-acetyl-2′-O-(4-nitrobenzoyl)arabinofuranose Base) adenine was added in portions; after the addition, the mixture was stirred and reacted at 0-5°C for 2-2.5h; after TLC (developing agent: chloroform:methanol=9:1) showed that the reaction was complete, add 30mL glacial acetic acid, stirred for 5-10min. The reaction mixture was concentrated to dryness under reduced pressure, 1.2 L of water was added to the residue, stirred at room temperature for 5-10 min, and filtered to obtain crude fludarabine. The crude product was recrystallized with water, and decolorized with activated carbon, and the precipitated solid was filtered, w...

Embodiment 3

[0030] The synthesis of embodiment 3 fludarabine

[0031] Add 400mL 2.5N NaOH solution and 250mL concentrated ammonia water into the reaction flask, put the reaction flask into an ice-water bath and cool to 0~5°C; add 4000mL 2-methyltetrahydrofuran and 450mL water into the above reaction flask, stir and cool to 0~5℃; under stirring, add 225g of 2-fluoro-9-β-D-(2′,3′,5′-tri-O-acetylarabinofuranosyl)adenine in portions; after the addition, the mixture Stir and react at 0-5°C for 1.5 h; after TLC (developing agent: chloroform:methanol=9:1) shows that the reaction is complete, add 30 mL of glacial acetic acid to the reaction mixture, and stir for 5-10 min. The reaction mixture was concentrated to dryness under reduced pressure, 1.2 L of water was added to the residue, stirred at room temperature for 5-10 min, and filtered to obtain crude fludarabine. The crude product was recrystallized with water and decolorized with activated carbon, and the precipitated solid was filtered, was...

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Abstract

The invention discloses a novel method for synthesizing fludarabine, which comprises the following steps: by using 2-fluoro-9-beta-D-(2',3',5'-tri-alkoxyarabinofuranosyl)adenine as a raw material, a sodium hydroxide and ammonia water mixed solution as a reaction reagent and a water and 2-methyltetrahydrofuran mixed solution as a solvent, carrying out reaction at 0-5 DEG C for 1-3 hours, neutralizing with glacial acetic acid, carrying out vacuum filtration, recrystallizing the obtained crude solid with water, and decolorizing with activated carbon to obtain the pure fludarabine. The preparation method disclosed by the invention uses the mixed solution of water and green solvent 2-methyltetrahydrofuran as the solvent, and thus, is environment-friendly. Besides, compared with the existing method, the synthesis method has the advantages of short reaction time, cheap raw material and the like, and is safe and simple to operate; and the product is easy to purify. The invention is suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, and in particular relates to a synthesis method of fludarabine. Background technique [0002] Fludarabine, chemical name 9-β-D-arabinofuranosyl-2-fluoroadenine, is an antimetabolite fluorinated purine nucleoside analogue, which is highly selective for lymphocytes , its mechanism of action is to incorporate into the DNA chain or RNA chain of tumor cells, prevent the extension of the chain, inhibit the biosynthesis of DNA and RNA in tumor cells; Synthesis of cellular DNA, and has the effect of promoting the apoptosis of these tumor cells, inhibiting the activities of DNA and RNA polymerase, DNA primerase, DNA helicase and ribonucleic acid reductase, showing good curative effect. The drug is currently widely used in the treatment of various blood system diseases, especially the treatment of chronic lymphocytic leukemia (CLL), and has become the drug of choice for the treatment of chron...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/19C07H1/00C07H1/06
Inventor 程青芳王启发帅美王明逍谈婷
Owner HUAIHAI INST OF TECH
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