SYNTHESIS OF N-(3-FLUORO-2-PHOSPHONOMETHOXYPROPYL) (FPMP) DERIVATIVES OF HETEROCYCLIC BASES

Article abstract of DOI:10.1135/cccc19931645

A new groupnof compounds has been prepared: N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) derivatives of purine and pyrimidine bases which exhibit a significant selective activity against a broad spectrum of retroviruses.Racemic N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of adenine (V), guanine (IX), cytosine (XIII), 2,6-diaminopurine (XXI), 3-deazaadenine (XVII), xanthine (X) and hypoxanthine (VI) were prepared from the corresponding n-(3-fluoro-2-hydroxypropyl) derivatives after protection of amino group at the heterocyclic ring by selective benzoylation, reaction with diisopropyl p-toluenesulfonyloxymethylphosphonate (II), and subsequent removal of the protecting groups.Chiral FPMP derivatives were prepared by reaction of heterocyclic base with corresponding chiral synthon (XXX; XXXVII) followed by deprotection.The required chiral synthons were obtained from enantiomeric 3-fluoro-1,2-propanediols by two methods.In the first, the primary hydroxyl group was tritylated, the obtained derivative was reacted with compound II, the trityl group was removed and the product was mesylated to give synthon XXXVII.The second pathway considered tosylation of the primary hydroxyl group and conversion of the secondary hydroxyl into the acetoxymethyl ether via the methoxymethyl ether; treatment of the acetoxy compound with bromotrimethylsilane and triisopropyl phosphite afforded the desired synthon XXX.