Abstract:

Cladribine, an anti-leukemia drug, was synthesized in 43.5% total yield by 4 steps. Readily available 6-chloropurine was glycosylated with 1-chloro-3,5-di-O-p-benzoyl-D-ribose with good selectivity for β anomer in the presence of NaH. The C2-H of β-glycosylated product was converted into C2-NO₂ using 2,2,2-trifluoroacetic anhydride and tetrabutylammonium nitrate, followed by the transformation of C2-NO₂ into C2-Cl in NH₄Cl/EtOH solution. The deprotection step and ammonolysis of C6-Cl were accomplished in NH₃/CH₃OH. The separation of α-anomer, expensive starting materials and chromatography are not required. Moreover, cladribine could be produced on a 100 gram scale with maintained yield, indicating good potential in industrial applications.

Key words: chloropurine, cladribine, nitration reaction, scalable synthesis