Synthetic Studies on Formamidopyrimidines Related to Clofarabine

Abstract

Degradation of clofarabine (3) in 0.9% saline solution at 100°C afforded three degradation products which were determined to be formamidopyrimidines 4–6.Compounds 4 and 5 were assigned as C_1′ anomers on the basis of one-dimensional and two-dimensional NMR experiments, whereas 6 was found to be the formamidopyrimidine lacking the sugar moiety. An improved procedure for the synthesis of formamidopyrimidines was developed, wherein benzoylated clofarabine (11) was treated with allyl chloroformate, followed by deprotection of the alloc group with catalytic Pd(PPh₃)₄ and dimedone. A synthesis of compound 6 from 4 is also described.

Keywords:

• Purine degradation
• NMR characterization

Notes

^aNA = not applicable.

^bThe apparent multiplet containing the H_3′ and H_4′ resonances was further analyzed using DFQ-COSY and TOCSY to give the chemical shifts and couplings shown for each of these hydrogen atoms. The ddd designation for H_3′ is based primarily on DFQ-COSY.

^aNA = not applicable.