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A clofarabine and synthesis method technology, applied in the field of drug synthesis, can solve the problems of difficult control, cumbersome reaction operation, low yield and the like, and achieve the effects of easy control, simple reaction operation and high yield
Inactive Publication Date: 2014-03-26
南通康鑫药业有限公司
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[0003] Chinese Journal of Pharmaceutical Industry 2006, 37 (8): 508-510, discloses a synthetic method of clofarabine; thereafter, Chemical Times 2010, 24 (8): 36-38, also discloses a synthesis method of clofarabine Synthetic method, the reaction operation of these two methods is cumbersome, difficult to control, and has greater toxicity, the total yield is between 5%-10%, and the yield is low
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[0021] 1. Preparation of 2-chloro-9-(2-deoxy-2-fluoro-3,5-di-oxo-benzoyl-α, β-D-arabinosyl)adenine (3)
[0022] Add 25g 2-deoxy-2-?-fluoro-1,3,5-tri-oxo-benzoyl-1-α-D-ribofuranose and 150ml dichloromethane into a 500ml three-neck flask, stir to dissolve, add 36ml Hydrogen bromide acetic acid solution, stirred at 30°C for 6h, after the reaction was completed, washed with 20% sodium carbonate solution 50ml×3, separated the organic phase, dried overnight with anhydrous magnesium sulfate, filtered, and the filtrate was used for later use.
[0023] Add 8.2g of 2-chloroadenine and 48ml of acetonitrile into a 500ml three-neck flask, stir to dissolve, add 5.9g of potassium tert-butoxide and 2.4g of calcium hydride, heat the mixture to 45°C, and add the filtrate of the previous step to the reaction solution dropwise After the dropwise addition, continue to react for 9 hours. After the reaction is completed, filter and wash with dichloromethane. The filtrate is concentrated under reduce...
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Abstract
The invention discloses a synthesis method of clofarabine, which comprises the following steps of: 1) dissolving a chemical compound shown as Formula (I) in dichloromethane, adding a hydrogen bromide acetic acid solution for reaction, washing, separating an organic phase, drying, filtering, leaving a filtrate for future use, dissolving 2-chlorine adenine in acetonitrile, adding potassium tert-butoxide, calcium hydride and the above filtrate for reaction, filtering, washing with dichloromethane, reducing pressure, condensing, evaporating to dryness, adding butyl acetate, stirring, dropwise adding methyl tertiary butyl ether, stirring for crystallization, filtering, washing a filter cake with methyl tertiary butyl ether, drying to obtain a yellow solid, and 2) adding the yellow solid into a mixed solution of methanol and sodium methoxide, regulating pH (potential of hydrogen) to 6-6.5, filtering, washing a filter cake with methanol, obtaining a clofarabine crude product, adding absolute ethyl alcohol, stirring, heating to backflow, dissolving, filtering, washing a filter cake with alcohol, performing vacuum drying, and obtaining a target product. The method is simple in reaction operation, easy to control, high in yield and suitable for industrial production.
Description
technical field [0001] The invention relates to a synthesis method of clofarabine, which belongs to the field of drug synthesis. Background technique [0002] Clofarabine (Clofarabine), chemical name 2-chloro-9-(2-deoxy-2-fluoro-β-D-ribofuranosyl) adenine, belongs to a kind of nucleotide analogue, which is passed through deoxycytidine kinase After being phosphorylated into triphosphate, it can effectively inhibit nucleotide reductase and terminate DNA synthesis; it can also inhibit DNA polymerase α, so that the DNA chain is no longer extended, and the elimination in human leukemia cells is slower. Therefore, it has better cytotoxicity. The US FDA approved clofarabine in 2004 for the treatment of refractory or relapsed acute lymphoblastic leukemia in children. As the only chemotherapy drug that can be specifically used for childhood leukemia, it has a high overall response rate in the treatment of leukemia and is well tolerated without unpredictable adverse reactions. It h...
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