Synthesis method of clofarabine

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...

AI Technical Summary

Problems solved by technology

[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