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A technology for gemcitabine and intermediates, which is applied in the field of preparation of gemcitabine intermediates, can solve the problems of expensive catalysts, etc., and achieve the effects of simple operation, friendly process environment and cost reduction
Inactive Publication Date: 2011-06-15
SHANGHAI ECUST BIOMEDICINE CO LTD
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[0006] U.S. Patent No. 5,426,183 reports that 2-deoxy-2,2-difluoro-D-ribosefuran-3,5-di-O-benzoyl-methanesulfonate is used as raw material, and trifluoromethanesulfonic acid, sulfuric acid , perchloric acid, nitric acid and trifluoroacetic acid potassium, barium, cesium, and trialkyl quaternary ammonium salts are used as catalys
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Embodiment 1
[0022] The preparation of embodiment 1 compound III
[0023] Under the protection of nitrogen, 10 g of cytosine was added to 50 ml of hexamethyldisilazane, and 0.01 g of ammonium bisulfate was added, the temperature was raised to reflux for 4 hours, cooled and concentrated to obtain white solid compound III.
Embodiment 2
[0024] The preparation of embodiment 2 compound I
[0025] N 2 For protection, add 100ml 1,2-dichloroethane to compound III to dissolve it completely, add NaBr2.6g, drop 5.7g 2-deoxy-2,2-difluoro-D-ribofuran-3,5 -Di-O-benzoyl-methanesulfonate (α:β=2.4:1) in 1,2-dichloroethane (20ml) solution, after dropping, raise the temperature and reflux to react until the raw materials disappear, and TLC detects the end of the reaction. Cool down to room temperature, add 500 ml of ice water dropwise, continue stirring for 30 minutes after the dropwise addition, filter with suction, and wash the filter cake with 1,2-dichloroethane. The organic phase was concentrated and evaporated to dryness to obtain 5.6 g of the target compound with a yield of 92.4% and an HPLC purity of 97.3% (α:β=1:1.9).
Embodiment 3
[0026] The preparation of embodiment 3 compound I
[0027] N 2 For protection, add 100ml of dichloromethane to the compound III obtained in Example 1 to dissolve it completely, add 4.5g of KBr, and dropwise add 5.7g of 2-deoxy-2,2-difluoro-D-ribofuran-3, 5-Di-O-benzoyl-methanesulfonate compound (compound II) (α:β=3:1) in dichloromethane (20ml) solution, the temperature was raised to reflux until the raw material disappeared, and the end of the reaction was detected by TLC. Cool down to room temperature, add 500 ml of ice water dropwise, continue stirring for 30 minutes after the dropwise addition, filter with suction, and wash the filter cake with dichloromethane. The organic phase was concentrated and dried to obtain 5.7 g of the target compound with a yield of 93.2% and an HPLC purity of 96.6% (α:β=1:2.3).
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Abstract
The invention discloses a method for preparing an anti-tumor medicament, namely a gemcitabine intermediate 4-amino-1-(2'-deoxygenation-2',2'-difluoro-3,5-bi-O-benzoyl-D-ribofuranose-2-group)-1H-pyrimidine-2-ketone. In the method, 2-deoxygenation-2,2-difluoro-D-ribofuranose-3,5-bi-O-benzoyl-mesylate and trimethyl silicon-protected cytosine which serve as raw materials are reacted with each other in ether, halogenated hydrocarbon and nitrile organic solvents under the action of alkali metal halides to obtain a product, namely the 4-amino-1-(2'-deoxygenation-2',2'-difluoro-3,5-bi-O-benzoyl-D-ribofuranose-2-group)-1H-pyrimidine-2-ketone.
Description
technical field [0001] The invention relates to a preparation method of an intermediate of anticancer drug gemcitabine. Background technique [0002] Gemcitabine hydrochloride is a difluoronucleoside antimetabolite and antineoplastic drug, which has a good inhibitory effect on human leukocytes, some solid tumors in mice and human tumor xenografts. As a difluoronucleoside antimetabolite anticancer drug that disrupts cell replication, gemcitabine is a water-soluble analogue of deoxycytidine, an inhibitory substrate substitute for ribonucleotide reductase , this enzyme is critical for the generation of deoxynucleotides required during DNA synthesis and repair. Clinically, gemcitabine is especially suitable for the treatment of inoperable advanced or metastatic pancreatic cancer and the treatment of locally advanced or metastatic non-small cell lung cancer [1] . [0003] Gemcitabine hydrochloride, chemical name: 4-amino-1-(2'-deoxy-2',2'-difluoro-3,5-di-O-benzoyl-D-ribofurano...
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