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Synthetic method of 2-fluoroadenosine

A synthetic method, fluoroadenosine technology, applied in chemical instruments and methods, preparation of sugar derivatives, sugar derivatives, etc., can solve the problems of unfavorable industrial scale production, high cost, low synthesis efficiency, etc., to achieve industrial production, Easy operation and high synthesis efficiency

Inactive Publication Date: 2013-10-02
HUAIHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The purpose of the present invention is to overcome the defects of high cost, low synthesis efficiency and unfavorable industrial scale production in the prior art, and provide a convenient method for synthesizing 2-fluoroadenosine

Method used

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Examples

Experimental program
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Effect test

Embodiment 1

[0024] Embodiment 1 Formula (III) compound N, the preparation of N-dibenzoyl-2', 3', 5'-three-O-benzoyl adenosine

[0025] Add 40.2g (150mmol) of the compound of formula (II) adenosine, 250mL of pyridine and 147g (1046mmol) of benzoyl chloride into the reaction flask, stir and mix well. Raise the temperature of the system to 60-65°C, and stir for 4 hours to stop the reaction. After cooling, add 250 mL of ethanol, stir at room temperature for 10 minutes, evaporate the solvent under reduced pressure, add 800 mL of dichloromethane and 800 mL of water to the residue, separate Dichloromethane, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined, washed with 200 mL of saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the solid was dried in vacuo to obtain 58 g, with a yield of 96%.

Embodiment 2

[0026] Example 2 Preparation of Formula (IV) Compound 2-nitro-N, N-dibenzoyl-2', 3', 5'-tri-O-benzoyl adenosine

[0027] NaZSM-5 molecular sieve powder was prepared by hydrothermal crystallization with inorganic ammonium as a template, and HZSM-5 was obtained by ammonium nitrate exchange.

[0028] Take the newly made N 2 o 5 16.2g (150mmol) was dissolved in 150mL of dichloromethane to make a concentration of 1mol / L N 2 o 5 dichloromethane solution. 94.6g (120mmol) of the compound of formula (III) was dissolved in 100mL of dichloromethane, and added to the above prepared N 2 o 5 4.5 g of HZSM-5 molecular sieves were added to the dichloromethane solution, and the reaction mixture was stirred at 45° C. for 2 h. After cooling, filter the catalyst, recover the catalyst, evaporate the solvent under reduced pressure, add 400 mL of ethyl acetate to the residue, wash the ethyl acetate layer with 400 mL of distilled water and 200 mL of saturated brine, dry over anhydrous magnesium...

Embodiment 3

[0029] The preparation of embodiment 3 formula (I) compound 2-fluoroadenosine

[0030] Add 41.7g (50mmol) of the compound of formula (IV), 5.8g (100mmol) of KF, 250mL of DMF and 0.28g (2.5mmol) of tetramethylammonium chloride into the reaction flask, and heat the reaction mixture to reflux for 5h. After cooling, filter the insoluble matter, distill off the solvent under reduced pressure, add 60mL of 2.5N NaOH solution, 350mL of 2-methyltetrahydrofuran and 45mL of water to the residue, put the reaction bottle in an ice-water bath to cool to 0-5°C, and The reaction was stirred at high temperature for 2.0 h; 6 mL of glacial acetic acid was added to the reaction mixture, and the reaction was stirred for 5-10 min. The reaction mixture was concentrated to dryness under reduced pressure, 1000 mL of ethyl acetate and 100 mL of ethanol were added to the residue, and it was placed in the refrigerator overnight, the precipitated solid was filtered and dried under reduced pressure to obta...

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Abstract

The invention discloses a synthetic method of 2-fluoroadenosine which is an important intermediate of fludarabine. The synthetic method comprises following steps: (1) a compound represented by formula (II) is reacted with benzoyl chloride in pyridine, and a compound represented by formula (III) is obtained; (2) the compound represented by formula (III) and N2O5 which is a cheap nitrating agent are subjected to nitration reaction in the presence of home-made HZSM-5 molecular sieve catalyst, and a compound represented by formula (IV) is obtained; (3) the compound represented by formula (IV) is reacted with a cheap fluorinating agent in an organic solvent in the presence of a catalyst, 2-fluoroadenosine with a protective group is obtained, and then the protective group is removed in a mixed solvent under alkaline conditions, and a compound represented by formula (I) is obtained. The raw materials of the synthetic method of 2-fluoroadenosine of the invention are cheap and easily available; reaction conditions are mild; operational procedures are simple; synthetic efficiency is high; the method is environment-friendly, and is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the technical field of preparation of key intermediates of medicines, and in particular relates to a method for synthesizing 2-fluoroadenosine, an intermediate of fludarabine, a medicine for chronic lymphocytic leukemia and low-grade malignant lymphoma. Background technique [0002] Fludarabine, whose chemical name is 9-β-D-arabinofuranosyl-2-fluoroadenine, was developed by German Schering Pharmaceutical Co., Ltd., and was first listed in the United States in 1991. Its phosphate trade name is Fludara, and it is widely used It is widely used in the treatment of various blood system diseases, especially the treatment of chronic lymphocytic leukemia (CLL), and is currently used in more than 30 countries in the world. Fludarabine has a relatively significant curative effect in the treatment of CLL, and has become the drug of choice for the treatment of chronic lymphocytic leukemia and low-grade lymphoma, and its safety has also bee...

Claims

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Application Information

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IPC IPC(8): C07H19/167C07H1/00
CPCY02P20/55
Inventor 程青芳王启发张勇超
Owner HUAIHAI INST OF TECH
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