合成路线1

2) The reaction of 2(R),3-O-isopropylideneglycerol (IV) with benzyl bromide by means of benzyltriethylammonium bromide (BTA) in refluxing aqueous NaOH gives (S)-3-O-benzylglycerol (V), which is monotritylated with 4-methoxytriphenylmethyl chloride (VI) and dimethylaminopyridine (DMAP) yielding the secondary alcohol (VII). The condensation of (VII) with diethyl tosyloxymethylphosphonate (VIII) by means of NaH in THF affords the fully protected phosphorylmethoxy derivative (IX), which is detritylated by treatment with aqueous acetic acid at 100 C to give 3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)-1-propanol (X). The reaction of (X) with methanesulfonyl chloride and triethylamine in dichloromethane yields the corresponding mesylate (XI), which is condensed with cytosine (XII) by means of cesium carbonate in hot DMF affording 1-[3-benzyloxy-2(S)-(diethoxyphosphorylmethoxy)propyl]cytosine (XIII). The debenzylation of (XIII) by treatment with Pd(OH)2 on carbon in refluxing ethanol/cyclohexene gives the corresponding alcohol (XIV), which is finally treated with bromotrimethylsilane in acetonitrile to eliminate the ethyl groups of the phosphonate.

合成路线2

3) The reaction of 2(S),3-O-isopropylideneglycerol (XV) with methanesulfonyl chloride and triethylamine in dichloromethane gives the corresponding mesylate (XVI), which is condensed with cytosine (XII) by means of cesium carbonate as before yielding 1-[2(S),3-(isopropylidenedioxy)propyl]cytosine (XVII). The deprotection of (XVII) with aqueous acetic acid at 100 C affords the corresponding diol (XVIII), which is treated with trityl chloride, DMAP and triethylamine in DMF to give the monotrityl compound (XIX). The condensation of (XIX) with diethyl tosyloxymethylphosphonate (VIII) [obtained by reaction of diethylphosphite (XX) with paraformaldehyde, followed by tosylation with tosyl chloride] by a previous treatment of (XX) with DMF dimethylacetal, then condensation by means of NaH in DMF, and a final hydrolysis with hot aqueous acetic acid yields the 1-[2(S)-(diethoxyphosphorylmethoxy)-3-hydroxypropyl]cytosine (XIV) (already obtained), which is finally treated with bromotrimethylsilane as before. 4) The reaction of the acetonide (XVI) with N4-benzoylcytosine (XXI) by means of potassium tert-butoxide or cesium carbonate gives the condensation product (XXII), which is deprotected with HCl in acetic acid yielding the diol (XXIII). The reaction of (XXIII) with trityl chloride and DMAP in refluxing pyridine affords the monotritylated compound (XXIV), which is condensed with the phosphonate (VIII) by means of NaH in DMF to give the fully protected HPMPC compound (XXV). The successive deprotections of (XXV), first with HCl in dichloromethane to eliminate the trityl group yielding (XXVI), then with bromotrimethylsilane to obtain the free phosphono group giving (XXVII), and finally with concentrated aqueous NH4OH to eliminate the benzoyl group affords cidofovir. 5) The benzoylation of acetonide derivative (XVII) with benzoyl anhydride in refluxing pyridine gives the benzoyl citosine derivative (XXII) already obtained.

合成路线3

An optimized process for large-scale production of adefovir dipivoxil has been reported: The reaction of adenine (I) with 1,3-dioxolan-2-one (II) by means of NaOH in hot DMF gives 9-(2-hydroxyethyl)adenine (III), which is condensed with diethyl p-toluenesulfonyloxymethylphosphonate (IV) by means of sodium tert-butoxide, (instead of NaH, originally used) in DMF yielding 9-[2-(diethylphosphonomethoxy)ethyl]adenine (V). The hydrolysis of intermediate (V) by means of TMS-Br in hot acetonitrile affords the phosphonic acid (VI), which is finally condensed with chloromethyl pivalate (VII) by means of triethylamine in hot N-methylpyrrolidine.

合成路线4

3) The catalytic hydrogenation of (S)-glycidol (XVI) over Pd/C gives the (R)-1,2-propanediol (XVII), which is esterified with diethyl carbonate (XVIII)/NaOEt, yielding the cyclic carbonate (XIX). The reaction of (XIX) with adenine (V) by means of NaOH in DMF affords 9-[2(R)-hydroxypropyl]adenine (VII), which is condensed with tosyloxymethylphosphonic acid diethyl ester (XX) by means of lithium tert-butoxide in THF, giving 9-[2(R)-(diethoxyphosphorylmethoxy)propyl]adenine (XXI). Finally, this compound is hydrolyzed with bromotrimethylsilane as before. Compound (XX) is obtained by reaction of diethyl phosphite (XXII) with paraformaldehyde, yielding hydroxy- methylphosphonic acid diethyl ester (XXIII), which is finally tosylated as usual.

合成路线5

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.

合成路线6