合成路线1

Treatment of adenosine (I) with ethylene carbonate (II) in the presence of NaOH in refluxing DMF gives 9-(2-hydroxyethyl)adenosine (III). Diethyl phosphite (IV) is then condensed with formaldehyde, followed by reaction with p-toluenesulfonyl chloride and Et3N to afford diethyl (tosyloxymethyl)phosphonate (V). Subsequent condensation of tosylate (V) with (III) in the presence of t-BuONa gives the phosphonyloxymethoxyethyl adenosine (PMEA) diethyl ester (VI), which is hydrolyzed to the corresponding phosphonic acid adefovir (VII) by means of in situ-generated iodotrimethylsilane. The condensation of phosphonic acid (VII) with 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) utilizing DCC/pyridine leads to the cyclic phosphonate (IX) as a roughly equimolecular mixture of diastereoisomers, which can be chromatographically separated to furnish the title cis-isomer pradefovir. In an improved procedure, activation of adefovir (VII) with oxalyl chloride and N,N-diethylformamide generates the formamidine-protected phosphonyl dichloridate (X), which upon condensation with diol (VIII) at low temperature gives the cyclic phosphonate (XI) as a mixture in which the desired cis-diastereoisomer predominates. After hydrolysis of the formamidine (XI) with ethanolic AcOH, recrystallization as the corresponding mesylate salt provides the title adefovir prodrug in high diastereomeric excess (1-5). Scheme 1.