ALTERNATIVE SYNTHESIS OF 9-{3-[(DIISOPROPOXYPHOSPHORYL)METHOXY]-2-HYDROXYPROPYL}ADENINE AND ITS FREE PHOSPHONATES SUBSTITUTED AT THE C-8 POSITION OF PURINE BASE

作者：Janeba Zlatko^*; Masojidkova Milena; Holy Antonin

来源：Collection of Czechoslovak Chemical Communications, 2010, 75(3): 371-381.

DOI：10.1135/cccc2009569

• Acyclic nucleoside phosphonates
• Acyclic nucleotide analogues
• HPMPA
• Alkylation
• Nucleophilic substitution
• Intramolecular cyclization

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 15-18.

• 出版日期2010