合成路线1

A new synthesis of neplanocin A has been reported: The triphenylmethyl (Tr) ether of 2,3-O-(isopropylidene)-D-ribose (I) is reduced with LiAlH4 to the corresponding diol, which without isolation is partially protected with tert-butyldimethylsilyl chloride (TBDMS-Cl) to yield the secondary alcohol (II). The oxidation of (II) with oxalyl chloride affords the ketone (III), which is alkylated with the lithium derivative of trimethylsilyl (TMS) diazomethane in THF to give the carbene intermediate (IV), which cyclizes to the cyclopentene (V). The partial deprotection of (V) followed by oxidation with pyridinium dichromate (PDC) yields the cyclopentenone (VI), which is reduced with LiAlH4 in THF to the cyclopentanol (VII) as a single stereoisomer. The condensation of (VII) with adenine (VIII) under Mitsunobu's conditions (triphenylphosphine and diethylazodicarboxylate [DEAD]) in THF affords protected neplanocin A (VIII), which is finally deprotected with HCl in methanol.

合成路线2

The monoprotection of acetonide dol (I) by means of Pmb-Cl and KOH in refluxing benzene gives the alcohol (II), which is submitted to a Swern oxidation, yielding the aldehyde (III). The Horner Wadswort Emmons condensation of (III) with phosphonate (IV) by means of NaH in THF affords the unsaturated ester (V), which is deprotected by means of HCl in hot ethanol to provide the diol (VI), which is reprotected by means of Tbdms-OTf and TEA in dichloromethane to gives the bis silyl ether (VII).The selective deprotection of (VII) by means of DDQ in aqueous acetonitrile yields the primary alcohol (VIII), which is submitted to a Swern oxidation to afford the corresponding aldehyde (IX). The cyclization of (IX) by means of PhCH2-S-Li in THF provides the chiral cyclopentanol (X), which is desilylated by means of HF in aqueous acetonitrile to give the trihydroxy compound (XI). The vicinal cis diols of (XI) are selectively protected with acetone and Ts-OH to yield the acetonide (XII), which is desulfurized by oxidation with NaIO4 and heating at 180 C in decalin to afford the cyclopentenol (XIII). The oxidation of (XIII) by means of PDC in dichloromethane provides the cyclopentenone (XIV), which is reduced at the ester and ketone groups by means of DIBAL in toluene to give the diol (XV). The selective silylation of the primary OH group of (XV) by means of Tbdms-Cl, TEA and DMAP in dichloromethane yields the primary silyl ether (XVI), which is condensed with adenine (XVII) by means of DIAD and PPH3 in THF to afford the protected adduct (XVIII). Finally this compound is deprotected by means of HCl in methanol to provide the target Neplanocin A.

合成路线3

PMEA was prepared by a straightforward route from readily available 2-acetoxyethoxymethyl chloride (I). The key intermediate, diethyl 2-bromoethylmethoxyphosphonate (IV), was coupled with adenine (V) in the presence of sodium hydride, followed by hydrolysis to afford PMEA.

合成路线4

A new synthesis of 2',3'-dideoxyadenosine has been described: The reaction of uridine (I) with methyl orthoformate and p-toluenesulfonic acid gives the cyclic orthoester (II), which is acetylated with acetic anhydride at 100 C to the acetate (III). The reaction of (III) with acetic anhydride at temperatures over 120 C yields 5'-O-acetyl-2',3'-dideoxy-2',3'-didehydrouridine (IV), which is hydrogenated to 5'-O-acetyl-2',3'-dideoxyuridine (V).

合成路线5

The hydrolysis of (V) affords 2',3'-dideoxyuridine (VI), which is finally submitted to transdeoxyribosilation with adenine (VII) by means of Escherichia coli AJ-2595 microorganisms.

合成路线6

The treatment of 2,3-O-dimesyl-5-O-(4-methoxybenzyl)-1-O-methyl-alpha-D-xylofuranose (XXX) with NaBH4 gives 3-deoxy-5-O-(4-methoxybenzyl)-1-O-methyl-alpha-D-xylofuranose (XXXI), which is fluorinated with diethylamido sulfur trifluoride as before, yielding 2,3-dideoxy-2-fluoro-5-O-(4-methoxybenzyl)-alpha-D-arabinofuranose (XXXII). The condensation of (XXXII) with adenine (XXXIII) by means of acetyl bromide affords 9-[2,3-dideoxy-2-fluoro-5-O-(4-methoxybenzyl)-beta-D-arabinofuraosyl]adenine (XXXIV), which is finally deprotected by hydrogenation over Pd/C in ethanol.

合成路线7

The condensation of adenine (I) with ethyl acrylate (II) by means of NaOEt in refluxing ethanol gives 3-(6-amino-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (III), which is treated with NaNO2 and HOAc to yield 3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (IV). Finally, this compound is treated with 1-(3-aminopropyl)-2-pyrrolidinone (V) in refluxing acetonitrile to afford the target propionamide.

合成路线8

Adefovir dipivoxil can be obtained by two similar ways: 1) The reaction of adenine (I) with 2-(diisopropoxyphosphorylmethoxy)ethyl methanesulfonate (II) by means of cesium carbonate in DMF gives the expected condensation product (III), which is converted into the phosphonic acid (IV) by treatment with trimethylsilyl bromide in acetonitrile (1). Finally, this compound is condensed with chloromethyl pivalate (V) by means of N,N'-dicyclohexylmorpholine-4-carboxamidine in DMF. 2) The final condensation of the phosphonic acid (IV) can also be performed with iodomethyl pivalate (VI) in pyridine.

合成路线9

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10

The 9-[2-(phosphonomethoxy)ethyl]adenine (VIII), intermediate in the synthesis of adefovir has been obtained as follows: 1) The partial hydrolysis of 2-acetoxyethoxymethylphosphonic acid diethyl ester (I) with Dowex 50XB in ethanol gives the corresponding 2-hydroxyethoxymethylphosphonate (II), which is treated with CCl4/PPh3, with CBr4/PPh3 or with TsCl yielding 2-choroethoxy (III), 2-bromoethoxy (IV) or 2-tosyloxyethoxy (V) derivatives, respectively (1). The condensation of (III), (IV) or (V) with adenine (VI) by means of NaH in hot DMF affords 9-[2-(diethoxyphosphorylmethoxy)ethyl]adenine (VII), which is finally treated with TMS-Br in acetonitrile to give the desired intermediate 9-[2-(phosphonomethoxy)ethyl]adenine (VIII). 2) The condensation of N6-benzoyl-9-(2-hydroxyethyl)adenine (IX) with tosyloxymethylphosphonic acid dimethyl ester (X) by means of NaH in warm DMF gives 9-[2-(dimethoxyphosphorylmethoxy)ethyl]adenine (X), which is treated first with NaOH in DMF/water and finally with TMS-I in DMF to afford the desired intermediate 9-[2-(phosphonomethoxy)ethyl]adenine (VIII).

合成路线11

The reaction of cyclopentadiene (I) with Br2 gives 1,4-dibromo-2-cyclopentene (II), which is treated with potassium acetate in tert-butanol yielding 1,4-diacetoxy-2-cyclopentene (III). The hydrolysis of (III) with KHCO3 in methanol affords 2-cyclopentene-1,4-diol (IV) as a mixture of the cis and trans isomers. The treatment of (cis/trans) (IV) or (cis) (IV) with pancreatin, vinyl acetate (V) and triethylamine gives (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is hydrogenated with H2 over RaNi in ethanol to yield the corresponding saturated (1S,3R)-3-acetoxycyclopentanol (VII). The reaction of (VII) with methanesulfonyl chloride and TEA in dichloromethane affords the corresponding mesylate (VIII), which is condensed with adenine (IX) by means of NaH in hot DMF providing the final intermediate (X). Finally, this compound is deacetylated with HCl in refluxing ethanol.

合成路线12

The rearrangement of furfuryl alcohol (XI) in acidic medium (KH2PO4, H3PO4) gives 4-hydoxy-2-penten-1-one (XII), which is silylated with TBDMS-Cl, Et3N and DMAP in THF yielding the silyl ether (XIII). The reduction of (XIII) with LiAlH4 in toluene affords the (rac)(cis)-4-(tert-butyldimethylsilyloxy)-2-penten-1-ol (XIV), which is submitted to optical resolution by digestion with pancreatin (8xUSP) and vinyl acetate in tert-butyl methyl ether yielding a mixture of (1S,4R)-4-(tert-butyldimethylsilyloxy)-2-cyclopentenyl acetate (XV) and (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI), which were separated by column chromatography. Both compounds (XV) and (XVI) were used by independent routes to obtain the target compound: a) The desilylation of (XV) with TBAF in THF gives the previously described (1R,4S)-4-acetoxy-2-cyclopenten-1-ol (VI), which is converted into the target compound by the previously described route (VI) - (VII) - (VIII) - (X) - target adenine derivative. b) The hydrogenation of (1R,4S)- 4-(tert-butyldimethylsilyloxy)-2-cyclopenten-1-ol (XVI) with H2 over Ni2B in ethanol gives the corresponding saturated alcohol (XVII), which is treated with methanesulfonyl chloride and triethylamine in tert-butyl methyl ether yielding the mesylate (XVIII). The condensation of (XVIII) with adenine (IX) by means of NaH in hot DMA affords the silylated target compound (XIX), which is finally deprotected with HCl in ethanol.

合成路线13

The condensation of adenine (I) with ethyl acrylate (II) by means of sodium ethoxide in methanol gives 3-(9-adenyl)propionic acid ethyl ester (III), which is treated with NaNO2/acetic acid yielding 3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionic acid ethyl ester (IV). The hydrolysis of (IV) with KOH in water affords the corresponding free acid (V), which is esterified with 4-chlorophenyl trifluoroacetate (VI) in pyridine giving the expected 4-chlorophenyl ester (VII). The condensation of ester (VII) with ethyl 4-aminobenzoate (VIII) by heating (35-40 C) in DMSO yields 4-[3-(6-oxo-1,6-dihydro-9H-purin-9-yl)propionamido]benzoic acid ethyl ester (IX), which is finally hydrolyzed with KOH in water.

合成路线14

The reaction of silylated (S)-glycidol (I) with the vinyl copper compound (II) in ethyl ether gives the monosilylated unsaturated diol (III), which is desilylated with Bu4NF in THF yielding the diol (IV). The cyclization of (IV) by means of I2 and NaHCO3 in acetonitrile affords a mixture of the cis and trans diastereomers from which the trans isomer (V) was isolated. The acylation of (V) with potassium 4-nitrobenzoate (VI) in DMSO/18-crown-6 yields the 4-nitrobenzoyl ester (VII), which is condensed with adenine (VIII) by means of DEAD and triphenylphosphine in DMF providing the 4-nitrobenzoyl percursor (IX). Finally, (IX) is debenzoylated with NaOMe in methanol.

合成路线15

1) The protection of isobutyl D-(+)-lactate (I) with dihydropyran (DHP)/HCl in DMF gives the tetrahydropyranyloxy derivative (II), which is reduced with bis(2-methoxyethoxy)aluminum hydride in refluxing ether/ toluene yielding 2(R)-(tetrahydropyranyloxy)-1-propanol (III). The tosylation of (III) with tosyl chloride as usual affords the expected tosylate (VI), which is condensed with adenine (V) by means of Cs2CO3 in hot DMF, affording 9-[2(R)-(tetrahydropyranyloxy)propyl]adenine (VI). The deprotection of (VI) with sulfuric acid affords 9-[2(R)-hydroxypropyl]adenine (VII), which is N-benzoylated with benzoyl chloride/chlorotrimethylsilane in pyridine to give the benzamide (VIII), which is condensed with tosyl-oxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in DMF to yield 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X). Finally, this compound is hydrolyzed by means of bromotrimethylsilane in acetonotrile.

合成路线16

2) The reaction of the previously described (R)-2-(2-tetrahydropyranyloxy)-1-propanol (III) with benzyl bromide (XI) by means of NaH in DMF, followed by a treatment with Dowex 50X, gives 1-benzyloxy-2(R)-propanol (XII), which is condensed with tosyloxymethylphosphonic acid diisopropyl ester (IX) by means of NaH in THF, yielding 2-benzyloxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIII). The hydrogenolysis of (XIII) over Pd/C in methanol affords 2-hydroxy-1(R)-methylethoxymethylphosphonic acid diisopropyl ester (XIV), which is tosylated with tosyl chloride/dimethyl-aminopyridine in pyridine to give the expected tosylate (XV). The condensation of (XV) with adenine (VI) by means of Cs2CO3 in hot DMF yields 9-[2(R)-(diisopropoxyphosphorylmethoxy)propyl]adenine (X), which is finally hydrolyzed as before.

合成路线17

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18

The addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) catalyzed by dirhodium tetraacetate in CH2Cl2 yielded a mixture of E- (III) and Z- (IV) cyclopropanes. Alkylation of adenine (V) with the mixture of bromoesters (III) and (IV) in the presence of either NaH in DMF at r.t. or K2CO3 at 80 C provided the diastereomeric (cyclopropylmethyl)adenines (VI). Elimination of HBr was carried out with potassium tert-butoxide in cold DMF or with NaH in THF to yield an unseparable mixture of Z- (VII) and E- (VIII) methylene cyclopropanes. Alternatively, simultaneous alkylation of adenine (V) and elimination of HBr to give (VII) + (VIII) was effected using K2CO3 in DMF at 100 C. Reduction of the ester groups of (VII) and (VIII) with DIBALH afforded a mixture of the racemic (Z) title compound (IX) and its its E-isomer (X). The unseparable mixture of (IX) and (X) was treated with dimethylformamide dimethylacetal in DMF to give the corresponding (dimethylamino)methylene derivatives that allowed a chromatographic separation. The desired racemic (Z)-isomer (XI) was further deprotected in methanolic ammonia to furnish racemic (IX) (1). Optical resolution was then achieved on treatment with adenosine deaminase, to produce the (Z)(S)-(+)-hypoxanthine derivative (XII) that was separated chromatographically from the unchanged (Z)(R)-(-)-isomer, the target compound.

合成路线19

Adenine (I) was oxidized with hydrogen peroxide in aqueous acetic acid to give adenine 1-N-oxide (II). Diazotization of (II) with sodium nitrite and acetic acid, followed by hydrolysis of the diazonium salt provided hypoxanthine 1-N-oxide (III). 2,6-Dichloropurine (IV) was then obtained by treatment of (III) with phosphoryl chloride in the presence of triethylamine. Displacement of the 6-chlorine atom of (IV) by benzylamine (V) in boiling n-butanol yielded 6-benzylamino-2-chloropurine (VI), which was subsequently alkylated at the 9-N with isopropyl iodide and NaH to give (VII). Finally, the remaining 2-chloro atom of (VII) was displaced by thiomorpholine (VIII) to furnish the title compound.

合成路线20

Demethylation of compound (XI) by means of BBr3 in refluxing dichloromethane gives 5-hydroxytetralinyl derivative (XII), which is then condensed with bromoacetic acid ethyl ester (XIII) by means of K2CO3 in DMF or acetonitrile to furnish (ethoxycarbonylmethoxy)tetraline derivative (XIV). Finally, the target product is obtained by saponification of the ethyl ester group of (XIV) by means of NaOH in 1,2-dimethoxyethane.

合成路线21

Addition of ethyl diazoacetate (II) to 2,3-dibromopropene (I) in the presence of dirhodium tetraacetate furnished ethyl 2-bromo-2-(bromomethyl)cyclopropane-1-carboxylate (III) as a mixture of cis- and trans-isomers. Subsequent condensation of the dibromo ester (III) with the sodium salt of adenine (IV) produced adduct (V) as a diastereomeric mixture. Then, elimination of HBr using potassium tert-butoxide gave olefin (VIa-b). Alternatively, a direct synthesis of (VIa-b) was carried out by reaction of adenine (IV) with dibromo ester (III) in the presence of K2CO3 in hot DMF. Reduction of ester (VIa-b) with diisobutylaluminum hydride afforded alcohol (VIIa-b) as a mixture of syn- and anti-isomers. Isolation of the desired syn-isomer (VIII) was achieved by conversion to the corresponding formamidines, followed by chromatographic separation. The formamidine function of (VIII) was then hydrolyzed with methanolic ammonia to yield the racemic synadenol (IX). Incubation of (IX) with adenosine deaminase converted the (S)-enantiomer to the hypoxanthine derivative (XI), which was separated from the unreacted (R)-synadenol (X) by column chromatography. Acetylation of alcohol (XI) with Ac2O in pyridine provided ester (XII). Chloropurine derivative (XIV) was then obtained by treatment of (XII) with N,N-dimethylamino(chloromethylene)ammonium chloride (XIII) in CHCl3. Finally, chloride displacement in (XIV) and simultaneous ester cleavage with methanolic ammonia in a pressure vessel gave rise to the title compound.

合成路线22

Alkylation of adenine (I) by means of (R)-propylene carbonate (II) in the presence of NaOH in hot DMF provided (R)-9-(2-hydroxypropyl)adenine (III). This was condensed with tosylate (IV) using magnesium tert-butoxide to furnish the alkoxymethylphosphonate (V). Phosphonic acid (VI) was then obtained by hydrolysis of the phosphate ester groups with bromotrimethylsilane. Monophenyl phosphonate (IX) was prepared by either coupling of acid (VI) with phenol (VII) in the presence of DCC or by previous activation of (VI) with SOCl2, and then coupling with phenoxytrimethylsilane (VIII). Further activation of (IX) with SOCl2 to give (X), followed by its condensation with L-alanine isopropyl ester (XI), yielded phosphonamide (XII) as a mixture of diastereomers. The title isomer was then isolated by several alternative procedures, including column chromatography over various supports and fractional crystallization.

合成路线23

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24

合成路线25