SYNTHESIS OF SOME 2'-C-ALKYL DERIVATIVES OF 9-(2-PHOSPHONOMETHOXYETHYL)ADENINE AND RELATED COMPOUNDS
To study the effect of β-substitution in 2'-alkyl derivatives of 9-(2-phosphonomethoxyethyl)adenine ( Ia ) on the antiviral activity or group specificity, these derivatives were synthesized. 9-(2-Hydroxyalkyl)adenines VIII were prepared by alkylation of adenine with suitably substituted oxiranes XIII or 2-hydroxyalkyl p -toluenesulfonates IV and VI . After protection of the adenine amino group by benzoylation (compounds IX ) or amidine formation (compounds X ), the intermediates were alkylated with diisopropyl p -toluenesulfonyloxymethanephosphonate ( XI ) in the presence of sodium hydride. After deprotection, the obtained phosphonate diesters XII were converted into phosphonic acids I by transsilylation and hydrolysis. This synthetic scheme was used for the preparation of ethyl ( Ie ), propyl ( If ), 2-propyl ( Ig ), 2-methylpropyl ( Ih ), cyclopropyl ( Ii ), cyclohexyl ( Ij ), benzyl ( Ik ) and phenyl ( Il ) derivatives. The 2'-trifluoromethyl derivative XXIIa was prepared analogously from 9-(2-hydroxy-3,3,3-trifluoropropyl)adenine ( XXa ), obtained by alkylation of adenine sodium salt with 2-hydroxy-3,3,3-trifluoropropyl bromide. 2'-Trimethylsilyl derivative XIXa was obtained by alkylation of adenine with 2-diisopropylphosphonomethoxy-3-(4-toluenesulfonyloxy)propyltrimethylsilane ( XVII ) followed by transsilylation and hydrolysis of diester XVIIIa . 2,6-Diaminopurine derivatives XVIIId and XXIIb were obtained analogously. 9-(3-Phosphonomethoxybutyl)adenine ( XXVIII ) and 9-(2-methyl-2-phosphonomethoxypropyl)adenine ( XXXV ) were prepared from the corresponding hydroxy derivatives XXVIb and XXXII , respectively, by the same reaction pathway as derivatives I .