Method for synthesizing cladribine through nitration-chlorination method

Abstract

The invention discloses a novel method for synthesizing cladribine through a nitration-chlorination method. According to the method, cheap 6-chloropurine and 1-chloro-2,3,5-tris-O-p-chlorobenzoyl-D-ribose are taken as raw materials, sodium hydride is taken as alkali, acetonitrile is taken as reaction solvent, and a beta isomer is obtained through a high-selectivity reaction; the obtained beta isomer does not need to remove protecting groups, the beta isomer reacts with trifluoromethanesulfonic anhydride after being separated, and nitryl is introduced at the second position; the nitryl is transformed into chlorine atoms in an ethanol solution of NH4Cl; two steps of reactions of protecting group removal and chlorine atom ammonolysis are completed in a methanol solution saturated by ammonia gas, and then the cladribine is obtained through four steps at the total yield of 78%. The method has the advantages that the raw materials are low in cost and easy to obtain, the technology is simple and convenient, the total yield is higher, the cost is low, amplification is easy, expensive reagents and poisonous and harmful heavy metal catalysts are prevented from being used, and when the reaction scale is expanded to the 100-g scale, the yield is not decreased obviously. A novel synthesizing path is supplied to synthesizing of the cladribine, and the potential application prospect is achieved.

Description

technical field [0001] The invention relates to a synthetic method of cladribine, in particular to a new method for synthesizing cladribine by a nitration-chlorination method. Background technique [0002] Cladribine (cladribine, 1), chemical name 2-chloro-2'-deoxyadenosine, trade name Leustatin, jointly developed by OnhoBiotech and Johnson & Johnson. First launched in the United States in 1993, it is used to treat hairy cell leukemia (HCL) and Walden-Strom's macroglobulinemia. As a representative drug of 2′-deoxynucleosides, it is the first-line drug among nucleoside anti-leukemia drugs. The synthesis methods of cladribine reported in the literature mainly include the "post-modification method" using existing nucleosides as raw materials, and the "condensation reaction method" using purine bases and deoxyribose derivatives as raw materials. It is easy to get more attention. But the biggest problem encountered by the condensation reaction method is that nearly half of the α...

AI Technical Summary

Problems solved by technology

[0004] In order to solve the problems of low synthesis yield, high cost and small reaction scale in the prior art, the invention provides a method for synthesizing cladribine by nitration-chlorination

Images