Acyclic nucleoside bisphosphonates: synthesis and properties of chiral 2-amino-4,6-bis[(phosphonomethoxy)alkoxy]pyrimidines

Abstract

2-Amino-4,6-bis[(phosphonomethoxy)alkoxy]pyrimidines bearing two equal or different achiral or chiral phosphonoalkoxy chains have been prepared either by aromatic nucleophilic substitution of 2-amino-4,6-dichloropyrimidine or by alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine with appropriate phosphonate-bearing building block. Alkylation of 4,6-dihydroxy-2-(methylsulfanyl)pyrimidine proved to be the method of choice for efficient preparation of variety of bisphosphonates. The enantiomeric purity of selected compounds was determined by capillary electrophoresis. Antiviral activity of bisphosphonates is discussed.

Figure 1

Acyclic nucleoside phosphonates.

Figure 2

Acyclic nucleoside bisphosphonates.

Figure 3

A: CE separation of enantiomers 27a (S), 0.1mM and 27b (R), 0.2 mM in chiral BGE (background electrolyte) composed of 50 mM borax, adjusted by NaOH to pH 10.0, with chiral selector β-cyclodextrin (20 mg/ml). B: CE analysis of enantiomer 27a in the above chiral BGE. C: CE analysis of enantiomer 27b in the above chiral BGE. eof = electroosmotic flow marker.

Scheme 1

Synthesis of bis-HPMPO derivatives.

Scheme 2

Alkylation of 4,6-(dihydroxy)pyrimidines.

Scheme 3

Synthesis of bisphosphonates by alkylation of 4,6-(dihydroxy)-2-(methylsulfanyl)pyrimidine.

Scheme 4

Alkylation of 2-amino-4,6-(disulfanyl)pyrimidine.

Scheme 5

Synthesis of alkoxyalkyl esters of bisphosphonates.