Collect. Czech. Chem. Commun. 2010, 75, 371-381
Published online 2010-03-29 10:43:39

Alternative synthesis of 9-{3-[(diisopropoxyphosphoryl)methoxy]-2-hydroxypropyl}adenine and its free phosphonates substituted at the C-8 position of purine base

Zlatko Janeba*, Milena Masojídková and Antonín Holý

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., Flemingovo nám. 2, 166 10 Prague 6, Czech Republic


For its high therapeutic effect, (S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine (HPMPA) is an important member of a class of acyclic nucleoside phosphonates (ANPs). Although its constitutional isomer, 9-[2-hydroxy-3-(phosphonomethoxy)propyl]adenine (iso-HPMPA), exhibits no antiviral activity, our general interest in C-8 substituted adenine ANPs led us to prepare certain iso-HPMPA derivatives modified at the C-8 position of adenine. Novel alkylating agent, diisopropyl {[2-(tetrahydro-2-pyranyl)oxy-3-tosyloxypropoxy]methyl}phosphonate (9), was prepared by procedure starting from allyl alcohol (4). 9-{3-[(Diisopropoxyphosphoryl)methoxy]-2-hydroxypropyl}adenine (12) was prepared by alkylation of adenine with the alkylating agent 9 followed by acid hydrolysis, although elimination by-product 9-{3-[(diisopropoxyphosphoryl)methoxy]prop-1-enyl}adenine (11) predominated in the reaction mixture. Bromination of the compound 12 gave 8-bromoadenine derivative 13 quantitatively. Nucleophilic substitutions of the bromine atom of compound 13 with N- and O-nucleophiles, followed by phosphonate deprotection, afforded the free phoshonic acids 1518.

Keywords: Acyclic nucleoside phosphonates; Acyclic nucleotide analogues; HPMPA; Alkylation; Nucleophilic substitution; Intramolecular cyclization.

References: 46 live references.