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Method for preparing fludarabine

A technology of fludarabine and fatty alcohol, which is applied in the field of preparation of fludarabine, can solve the problems of long reaction time, complicated operation process, high enzyme price, etc., and achieve the effects of short reaction time, high product purity and simple operation

Active Publication Date: 2010-06-16
TIANJIN WEIJIE TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The disadvantage of this preparation method is that the reaction time is long; due to the use of chlorinated solvents, it will cause environmental pollution; in addition, concentration treatment is required, so the operation process is complicated
Another preparation method of fludarabine is disclosed in U.S. Patent No. 5,712,099, which uses enzymes and 2-fluoro-9-β-D-(2′,3′,5′-tri-O-acetyl arabinofuranosyl) adenine as raw material, prepared into fludarabine through reaction, the shortcoming of this method is that the enzyme price is high (130U / mg), so it is not suitable for industrialized production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0013] Add 10ml of ethanol and 10ml of ammonia water into a 50ml reaction bottle and mix well, then cool the above mixture to 5°C, then add 1g (2.43mmol) 2-fluoro-9-β-D-(2', 3', 5′-tri-O-acetylarabinofuranosyl) adenine was reacted at a temperature of 5° C. for 24 hours. After the TLC or HPLC test results showed that the reaction was complete, the above reaction solution was suction filtered to obtain 0.66 g of crude product , the crude product yield is 99%, and the mother liquor does not need to be reclaimed, then the filter cake is recrystallized as a solvent with 15ml ethanol and 5ml water to obtain 0.58g white solid fludarabine, the yield of this product is 84%, the HPLC content ≥99.8%, main impurity HPLC content: 0.02%, 0.1%, 0.01% and 0.01%.

Embodiment 2

[0015] Add 100ml of ethanol and 200ml of ammonia water into a 500ml reaction flask and mix well, then cool the mixture to 15°C, then add 10g (24.3mmol) 2-fluoro-9-β-D-(2',3',5 '-tri-O-acetylarabinofuranosyl) adenine was reacted at a temperature of 15° C. for 36 hours, and after the TLC or HPLC detection results showed that the reaction was complete, the above reaction solution was suction filtered to obtain 6.1 g of crude product , the yield of the crude product is 90%, the mother liquor does not need to be reclaimed, then the filter cake is recrystallized with 120ml ethanol and 40ml water as a solvent to obtain 5.1g white solid fludarabine, the yield of this product is 75%, the HPLC content 99.2%, main impurity HPLC content: 0.1%, 0.2%, 0.2% and 0.1%.

Embodiment 3

[0017] Add 100ml of ethanol and 50ml of ammonia water into a 250ml reaction flask and mix well, then cool the mixture to 10°C, then add 10g (24.3mmol) 2-fluoro-9-β-D-(2',3',5 '-Tri-O-acetylarabinofuranosyl) adenine was reacted at a temperature of 10°C for 36 hours. After the TLC or HPLC detection results showed that the reaction was complete, the above reaction solution was suction filtered to obtain 5.8 g of crude product , the crude product yield is 86%, mother liquor need not reclaim, then filter cake is recrystallized as solvent with 100ml ethanol and 33.3ml water and obtains 4.8g white solid fludarabine, and the yield of this product is 72%, HPLC Content 99.5%, main impurity HPLC content: 0.1%, 0.2%, 0.1% and 0.08%.

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Abstract

The invention relates to a method for preparing fludarabine, which takes 2-fluoro-9-beta-D-(2',3',5'-tri-O-acetyl arabinofuranose) adenine as a raw material, saturated aliphatic alcohols as a solvent, and ammonia water as a reagent, and comprises the following steps: reacting for 24 to 48 hours at the temperature of between -5 and 15 DEG C; filtering the mixture to obtain a crude product; and finally, recrystallizing the crude product to obtain the fludarabine. The method for preparing the fludarabine takes the saturated aliphatic alcohols as the solvent and does not use a chloric solvent so as not to pollute environment. In addition, compared with the prior art, the preparation method has the advantages of short reaction time, low cost of the raw material, high product purity, simple operation and the like so as to be suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of medicine preparation, in particular to a preparation method of fludarabine. Background technique [0002] The chemical name of fludarabine is 9-β-D-arabinofuranosyl-2-fluoroadenosine, which is an antineoplastic drug. A variety of preparation methods of the drug have been reported in the existing literature, among which the U.S. Patent No. 5602246 discloses a preparation method of fludarabine, which is based on 2-fluoro-9-β-D-(2 ', 3', 5'-tri-O-acetylarabinofuranosyl) adenine and absolute ethanol (80ml / g) as raw materials, reacted at a temperature of 0 to 5°C for more than 96 hours, then concentrated, and then It was extracted with chloroform, and finally the pure product was obtained after recrystallization. The disadvantage of this preparation method is that the reaction time is long; since the chlorinated solvent is used, it will cause environmental pollution; in addition, concentration treatment is r...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/19C07H1/00
Inventor 宋洪海林大勇彭啸杨民文马春磊
Owner TIANJIN WEIJIE TECH
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