Synthesis of Novel 2-Cyano-7-deaza-8-azapurine- and 2-Cyano-8-azapurine-Derived Nucleosides

Abstract

A novel systematic approach to the synthesis of 2-cyano-7-deaza-8-azapurine derived nucleosides is described. It is shown how this chemistry was developed with the labile 2-substituted nitrile position in mind, and also how the same approach is applicable to 2-cyano-8-azapurine derived nucleosides.Nucleosides and their analogues continue to be investigated to treat a range of diseases including cancer and viral infections. 1 In addition, nucleosides and nucleotides form the primary building blocks for the construction of natural and modified genetic material. For example, oligomeric nucleoside constructs form the basis of antisense/RNA interference applications. 2 Finally, nucleosides are intimately involved in key processes such as metabolic regulation and energy storage. 3 A large body of synthetic methodology to access modified bases and riboses has accumulated over the last several decades, 4 spurred along by several highly successful drugs in this class. 5 Research in this area is complicated by a requirement that the nucleoside must be converted into its triphosphate in cellular assays followed by effective inhibition of the target in the designated pathway. Lack of biological activity due to poor or no recognition by the cellular kinases required to activate the parent nucleoside is often a high hurdle to overcome. The effect of structural modifications on the conformational preference of nucleoside analogues has been proposed as a significant driver of subsequent recognition by biological systems. 6 Two strong drivers in nucleoside design include a desire to stay close in structure to the natural bases and riboses, while designing novelty into target compounds.With these considerations in mind, we became interested in 2-cyano-8-aza-7-deazapurines ( Figure 1) as a potential adenine mimic by virtue of a replacement of the C2-hydrogen of adenine with CN and an isomeric movement of N7 to C8. 7 Figure 1

2-Amino-6-hydroxypyrimidine-4(3H)-one

“…17 These compounds were utilized to prepare nucleoside derivatives. The guanine framework was prepared similarly from an intermediate 6, which was prepared by nitration of 3 (eq 8).…”

One-Pot Acid-Promoted Synthesis of 6-Aminopyrazolopyrimidines from 1H-Pyrazol-5-yl-N,N-dimethylformamidines or 5-Amino-1H-pyrazole-4-carbaldehydes with Cyanamide

“…Wainwright et al have simultaneously developed a more satisfactory procedure that uses 2-amino-4,6-dihydroxypyrimidine as starting material, whereby the formylation and chlorination with a Vilsmeier reagent (POCl 3 /DMF) and cyclization with hydrazine provides a 78% yield in two steps ((2) of Scheme ). On the basis of this observation, we aimed to develop a convenient and efficient acid-promoted method for synthesis of 6-aminopyrazolo­[3,4- d ]­pyrimidines, by treating 1 H -pyrazol-5-yl- N , N -dimethylformamidines with cyanamide (NH 2 CN) in the presence of an acid-mediated solvent (Scheme ). In comparison with the method described by Wainwright et al, our isolated yields and material costs are similar.…”