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【结 构 式】

【药物名称】Carbovir, GR-90352, NSC-614846

【化学名称】(±)-2-Amino-9-[4beta-(hydroxymethyl)-2-cyclopenten-1beta-yl]-9H-purin-6(1H)-one
　　　　　　(±)-9-[4beta-(Hydroxymethyl)-2-cyclopenten-1beta-yl]guanine
　　　　　　(±)-Carbocyclic 2',3'-didehydro-2',3'-dideoxyguanosine

【CA登记号】118353-05-2

【 分 子 式 】C11H13N5O2

【 分 子 量 】247.25856

【开发单位】GlaxoSmithKline (Originator)

【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Antiviral Drugs

合成路线1合成路线2合成路线3合成路线4合成路线5合成路线6合成路线7合成路线8合成路线9合成路线10合成路线11合成路线12合成路线13合成路线14合成路线15合成路线16合成路线17合成路线18合成路线19合成路线20

合成路线1

The enantiocontrolled condensation of the protected guanine (I) with cis-1,3-bis(benzoyloxy)-4-cyclopentene (II) catalyzed by a chiral Pd catalyst gives the alkylated guanine (III), which is condensed with the nitrosulfone (IV) by means of PPh3 and TEA to yield the intermediate (V). The oxidation of (V) with oxone, tetramethylguanidine, and Na2CO3 in methanol/dichloromethane affords the cyclopentenecarboxylate (VI), which is finally reduced with calcium borohydride and deprotected with ammonia to provide the target compound.

参考文献 中间体
【1】 Madsen, R.; Brown, B.; Guile, S.D.; Trost, B.M.; Palladium-catalyzed enantioselective synthesis of carbanucleosides. J Am Chem Soc 2000, 122, 25, 5947.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37775 2-(acetamido)-9H-purin-6-yl diphenylcarbamate C20H16N6O3 详情 详情
(II) 37776 (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate C19H16O4 详情 详情
(III) 37777 (1S,4R)-4-(2-(acetamido)-6-[[(diphenylamino)carbonyl]oxy]-9H-purin-9-yl)-2-cyclopenten-1-yl benzoate C32H26N6O5 详情 详情
(IV) 37778 (nitromethyl)(dioxo)phenyl-lambda(6)-sulfane; nitromethyl phenyl sulfone 21272-85-5 C7H7NO4S 详情 详情
(V) 37779 2-(acetamido)-9-[(1R,4S)-4-[(S)-nitro(phenylsulfonyl)methyl]-2-cyclopenten-1-yl]-9H-purin-6-yl diphenylcarbamate C32H27N7O7S 详情 详情
(VI) 37780 methyl (1S,4R)-4-(2-(acetamido)-6-[[(diphenylamino)carbonyl]oxy]-9H-purin-9-yl)-2-cyclopentene-1-carboxylate C27H24N6O5 详情 详情

合成路线2

The hydrolysis of the diacetyl derivative (I) with Ba(OH)2 in refluxing water gives the amino alcohol (II), which is condensed with 4,6-dichloro-2-aminopyrimidine (III) by means of TEA in refluxing tert-butanol to yield the adduct (IV). The condensation of (IV) with the diazonium salt (V) affords the azo compound (VI), which is reduced with Zn/HOAc to provide the diamine (VII). The cyclization of (VII) with triethyl orthoformate gives the 6-chloropurine derivative (VIII), which is finally treated with NaOH in refluxing water to afford the target guanine derivative as a racemic compound.

参考文献 中间体
【1】 Vince, R.; Hua, M.; Synthesis and anti-HIV activity of carbocyclic 2',3'-didehydro-2',3'-dideoxy 2,6-disubstituted purine nucleosides. J Med Chem 1990, 33, 1, 17-21.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 45366 [(1S,4R)-4-(acetamido)-2-cyclopenten-1-yl]methyl acetate C10H15NO3 详情 详情
(II) 17647 [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol C6H11NO 详情 详情
(III) 14404 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine 56-05-3 C4H3Cl2N3 详情 详情
(IV) 17657 [(1S,4R)-4-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H13ClN4O 详情 详情
(V) 10197 4-Chlorobenzenediazonium chloride C6H4Cl2N2 详情 详情
(VI) 17659 [(1S,4R)-4-([2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]amino)-2-cyclopenten-1-yl]methanol C16H16Cl2N6O 详情 详情
(VII) 17660 [(1S,4R)-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H14ClN5O 详情 详情
(VIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线3

The condensation of 6-chloropurine-2-amine (I) with epoxide (II) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (III), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (IV). The condensation of (IV) with ethyl 2-nitroacetate (V) by means of Pd in THF affords the adduct (VI), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VII). The reaction of (VII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (VIII), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VII) can also be obtained by condensation of carbonate (IV) with 2-(trimethylsilyl)ethyl 2-nitroacetate (IX) by means of Pd in THF to give the adduct (X), which is decarboxylated by means of CsF in hot acetonitrile, affording (VII).

参考文献 中间体
【1】 Peel, M.R.; et al.; A short, enantioselective synthesis of the carbocyclic nucleoside carbovir. J Org Chem 1991, 56, 16, 4990.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(II) 45367 6-oxabicyclo[3.1.0]hex-2-ene C5H6O 详情 详情
(III) 45368 (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol C10H10ClN5O 详情 详情
(IV) 45369 (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl methyl carbonate C12H12ClN5O3 详情 详情
(V) 15050 ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester 626-35-7 C4H7NO4 详情 详情
(VI) 45370 ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate C14H15ClN6O4 详情 详情
(VII) 45371 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylamine; 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-amine C11H11ClN6O2 详情 详情
(VIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(IX) 45372 2-(trimethylsilyl)ethyl 2-nitroacetate C7H15NO4Si 详情 详情
(X) 45373 2-(trimethylsilyl)ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate C17H23ClN6O4Si 详情 详情

合成路线4

The condensation of 6-chloropurine-2-amine (III) with the chiral monoacetate (II) (obtained by enzymatic desymmetrization of diacetate (I)) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (IV), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (V). The condensation of (V) with ethyl 2-nitroacetate (VI) by means of Pd in THF affords the adduct (VII), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VIII). The reaction of (VIII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (IX), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VIII) can also be obtained by condensation of carbonate (V) with 2-(trimethylsilyl)ethyl 2-nitroacetate (X) by means of Pd in THF to give the adduct (XI), which is decarboxylated by means of CsF in hot acetonitrile, affording (VIII).

参考文献 中间体
【1】 Peel, M.R.; et al.; A short, enantioselective synthesis of the carbocyclic nucleoside carbovir. J Org Chem 1991, 56, 16, 4990.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 45374 (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(II) 33169 (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate C7H10O3 详情 详情
(III) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(IV) 45368 (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol C10H10ClN5O 详情 详情
(V) 45369 (1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl methyl carbonate C12H12ClN5O3 详情 详情
(VI) 15050 ethyl 2-nitroacetate; Acetic acid, nitro-, ethyl ester 626-35-7 C4H7NO4 详情 详情
(VII) 45370 ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate C14H15ClN6O4 详情 详情
(VIII) 45371 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylamine; 6-chloro-9-[(1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl]-9H-purin-2-amine C11H11ClN6O2 详情 详情
(IX) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(X) 45372 2-(trimethylsilyl)ethyl 2-nitroacetate C7H15NO4Si 详情 详情
(XI) 45373 2-(trimethylsilyl)ethyl (2S)-2-[(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]-2-nitroethanoate C17H23ClN6O4Si 详情 详情

合成路线5

The protection of the chiral epoxy-alcohol (I) with Pmb-Cl, NaH and tetrabutylammonium iodide (TBAI) gives the protected compound (II), which is condensed with 2-amino-6-(2-methoxyethoxy)purine (III) in hot DMF to yield the adduct (IV). Elimination of the OH group of (IV) by means of a treatment with phenyl chlorothioformate, followed by a thermal elimination reaction with Bu3SnH and AIBN, affords the carbocyclic purine (V). The selective deprotection of (V) with DDQ in dichloromethane provides the cyclopentanol derivative (VI), which is treated with MsCl and DMAP to give the mesylate (VII).The reaction of (VII) with sodium 2-methoxyethanolate (A) in DMF yields the cyclopentene derivative (VIII), which is treated with AlI3 in hot acetonitrile to afford the carbocyclic guanine derivative (IX). The deprotection of (X) with BF3/Et2O and Ac2O provides the diacetyl derivative (X), which is finally deacetylated to the target chiral compound by means of NH3 in methanol.

参考文献 中间体
【1】 Jones, M.F.; et al.; Total synthesis of (-)-carbovir. J Chem Soc - Perkins Trans I 1991, 10, 2479.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(A) 45380 sodium 2-methoxy-1-ethanolate 3139-99-9 C3H7NaO2 详情 详情
(I) 29889 (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol C13H16O3 详情 详情
(II) 45375 benzyl [(1S,2R,3S,5R)-3-[(4-methoxybenzyl)oxy]-6-oxabicyclo[3.1.0]hex-2-yl]methyl ether; (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-3-[(4-methoxybenzyl)oxy]-6-oxabicyclo[3.1.0]hexane C21H24O4 详情 详情
(III) 14440 2,5-pyridinedicarboxylic acid 100-26-5 C7H5NO4 详情 详情
(IV) 45376 (1S,2S,3S,5S)-5-[2-amino-6-(2-methoxyethoxy)-9H-purin-9-yl]-2-[(benzyloxy)methyl]-3-[(4-methoxybenzyl)oxy]cyclopentanol C29H35N5O6 详情 详情
(V) 45377 9-[(1R,3R,4S)-3-[(benzyloxy)methyl]-4-[(4-methoxybenzyl)oxy]cyclopentyl]-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-[(1R,3R,4S)-3-[(benzyloxy)methyl]-4-[(4-methoxybenzyl)oxy]cyclopentyl]-6-(2-methoxyethoxy)-9H-purin-2-amine C29H35N5O5 详情 详情
(VI) 45378 (1S,2R,4R)-4-[2-amino-6-(2-methoxyethoxy)-9H-purin-9-yl]-2-[(benzyloxy)methyl]cyclopentanol C21H27N5O4 详情 详情
(VII) 45379 9-((1R,3R,4S)-3-[(benzyloxy)methyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-((1R,3R,4S)-3-[(benzyloxy)methyl]-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]cyclopentyl)-6-(2-methoxyethoxy)-9H-purin-2-amine C24H33N5O4S 详情 详情
(VIII) 45381 9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-6-(2-methoxyethoxy)-9H-purin-2-ylamine; 9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-6-(2-methoxyethoxy)-9H-purin-2-amine C21H25N5O3 详情 详情
(IX) 45382 2-amino-9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-1,9-dihydro-6H-purin-6-one C18H19N5O2 详情 详情
(X) 45383 [(1S,4R)-4-[2-(acetamido)-6-oxo-1,6-dihydro-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C15H17N5O4 详情 详情

合成路线6

The reaction of the chiral epoxy-alcohol (I) with MsCl, TEA and DMAP gives the mesylate (II), which is treated with TBAF in THF to yield the unsaturated epoxide (III).The condensation of (III) with diaminopurine (IV) by means of NaH in DMF affords the carbocyclic purine (V), which is dehydroxylated by reaction with phenyl chlorothioformate, followed by a thermal elimination reaction with Bu3SnH and AIBN to provide the carbocyclic purine (VI). The debenzylation of (VI) by means of BF3/Et2O and Ac2O gives the diacetyl derivative (VII), which is selectively O-deacetylated with NH3 in methanol, yielding 2-acetamido-6-aminopurine (VIII). The reaction of (VIII) with NaNO2 and acetic acid affords the N-acetylated guanine derivative (IX), which is finally treated with NH3 in methanol to provide the target compound.

参考文献 中间体
【1】 Jones, M.F.; et al.; Total synthesis of (-)-carbovir. J Chem Soc - Perkins Trans I 1991, 10, 2479.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 29889 (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol C13H16O3 详情 详情
(II) 45390 benzyl ((1S,2S,3S,5R)-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxabicyclo[3.1.0]hex-2-yl)methyl ether; (1S,2S,3S,5R)-2-[(benzyloxy)methyl]-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxabicyclo[3.1.0]hexane C16H22O3S 详情 详情
(III) 45384 benzyl (1S,2S,5R)-6-oxabicyclo[3.1.0]hex-3-en-2-ylmethyl ether; (1R,4S,5S)-4-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hex-2-ene C13H14O2 详情 详情
(IV) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(V) 45385 (1S,2S,5S)-2-[(benzyloxy)methyl]-5-(2,6-diamino-9H-purin-9-yl)-3-cyclopenten-1-ol C18H20N6O2 详情 详情
(VI) 45386 2-amino-9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-9H-purin-6-ylamine; 9-[(1R,4S)-4-[(benzyloxy)methyl]-2-cyclopenten-1-yl]-9H-purine-2,6-diamine C18H20N6O 详情 详情
(VII) 45387 [(1S,4R)-4-[2-(acetamido)-6-amino-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate C15H18N6O3 详情 详情
(VIII) 45388 N-[6-amino-9-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purin-2-yl]acetamide C13H16N6O2 详情 详情
(IX) 45389 N-[9-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-6-oxo-6,9-dihydro-1H-purin-2-yl]acetamide C13H15N5O3 详情 详情

合成路线7

The hydrolysis of the chiral unsaturated bicyclic lactam (I) with aqueous refluxing HCl gives the amino acid (II), which is esterified with 2,2-dimethoxypropane, methanol and HCl to yield the methyl ester (III). The acylation of (III) with Ac2O and pyridine in dichloromethane affords the acetamide (IV), which is reduced with calcium borohydride in THF, providing the carbinol (V). The hydrolysis of the amido group of (V) with HCl in refluxing ethanol/water gives the chiral amino alcohol (VI), which is condensed with 2-amino-4,6-dichloropyrimidine (VII) by means of DIEA in refluxing butanol, yielding the adduct (VIII). The reaction of (VIII) with 4-chlorophenyldiazonium chloride (IX) by means of HOAc and NaOAc in water affords the azo compound (X), which is reduced with Zn and HOAc to provide the triaminopyrimidine (XI). The cyclization of (XI) with triethyl orthoformate gives the carbocyclic chloropurine (XII), which is finally treated with NaOH in refluxing water to yield the target carbocyclic guanine.

参考文献 中间体
【1】 Evans, C.T.; et al.; Potential use of carbocyclic nucleosides for the treatment of AIDS - Chemo-enzymatic syntheses of the enantiomers of carbovir. J Chem Soc - Perkins Trans I 1992, 5, 589.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 33410 cis-2-azabicyclo[2.2.1]hept-5-en-3-one C6H7NO 详情 详情
(II) 33411 cis-4-amino-2-cyclopentene-1-carboxylic acid 168471-40-7 C6H9NO2 详情 详情
(III) 33412 methyl cis-4-amino-2-cyclopentene-1-carboxylate C7H11NO2 详情 详情
(IV) 45391 methyl (1S,4R)-4-(acetamido)-2-cyclopentene-1-carboxylate C9H13NO3 详情 详情
(V) 45392 N-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]acetamide 130931-86-1 C8H13NO2 详情 详情
(VI) 17647 [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol C6H11NO 详情 详情
(VII) 14404 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine 56-05-3 C4H3Cl2N3 详情 详情
(VIII) 17657 [(1S,4R)-4-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H13ClN4O 详情 详情
(IX) 10197 4-Chlorobenzenediazonium chloride C6H4Cl2N2 详情 详情
(X) 17659 [(1S,4R)-4-([2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]amino)-2-cyclopenten-1-yl]methanol C16H16Cl2N6O 详情 详情
(XI) 17660 [(1S,4R)-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H14ClN5O 详情 详情
(XII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线8

The condensation of the cis-dibenzoyloxycyclopentene (I) with the lithium salt of 2-nitrovinyl(phenyl)sulfone (II) by means of a chiral palladium catalyst and PPh3 in THF gives the chiral isoxazoline-N oxide (III), which is deoxygenated by means of SnCl2 in acetonitrile, yielding the isoxazoline (IV). The solvolysis of (IV) with K2CO3 in methanol affords the methoxy compound (V), which is treated with Mo(CO)6 and boric acid in methanol to provide the chiral 2-hydroxy-3-cyclopentene-1-carboxylic acid methyl ester (VI). The reduction of (VI) with LiAlH4 in ether yields the hydroxymethyl derivative (VII), which is esterified with methyl chloroformate and BuLi in THF to afford the bis-carbonate (VIII). The condensation of (VIII) with 2-amino-6-chloropurine (IX) by means of a Pd catalyst in THF provides the carbocyclic purine (X), which is finally treated with NaOH in refluxing water to yield the target carbocyclic guanine.

参考文献 中间体
【1】 Trost, B.M.; et al.; A novel Pd-catalyzed cycloalkylation to isoxazoline 2-oxides. Application for the asymmetric synthesis of carbanucleosides. J Am Chem Soc 1992, 114, 22, 8745.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 37776 (1R,4S)-4-(benzoyloxy)-2-cyclopenten-1-yl benzoate C19H16O4 详情 详情
(II) 45393 lithium oxo[(phenylsulfonyl)methylene]-lambda(5)-azanolate C7H6LiNO4S 详情 详情
(III) 45394 (3aS,6aR)-3-(phenylsulfonyl)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-2-ium-2-olate C12H11NO4S 详情 详情
(IV) 45395 (3aS,6aR)-3-(phenylsulfonyl)-4,6a-dihydro-3aH-cyclopenta[d]isoxazole; (3aS,6aR)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-3-yl phenyl sulfone C12H11NO3S 详情 详情
(V) 45396 (3aS,6aR)-3-methoxy-4,6a-dihydro-3aH-cyclopenta[d]isoxazole; (3aS,6aR)-4,6a-dihydro-3aH-cyclopenta[d]isoxazol-3-yl methyl ether C7H9NO2 详情 详情
(VI) 45397 methyl (1S,2R)-2-hydroxy-3-cyclopentene-1-carboxylate C7H10O3 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(IX) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(X) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线9

The photooxidation of cyclopentadiene (I) gives cis-4-cyclopentene-1,3-diol (II), which is acylated with Ac2O to yield the diacetate (II). Enzymatic selective hydrolysis of (II) using porcine pancreas lipase (PPL) affords the chiral monoacetate (IV), which is protected with dihydropyran (DHP) and Ts-OH to provide the tetrahydropyranyl ether (V). The hydrolysis of the acetate group of (V) with KOH in methanol gives the alcohol (VI), which is silylated with TbdmsCl and imidazole to yield the silyl ether (VII). Elimination of the THP-protecting group of (VII) with Me2AlCl in dichloromethane affords the cyclopentenol (VIII), which is oxidized with PCC to the cyclopentenone (IX). The condensation of (IX) with chloroiodomethane and BuLi in THF gives the chiral chloromethyl derivative (X), which is treated with potassium methoxide in THF to obtain the chiral epoxide (XI). Stereocontrolled opening of the epoxide ring of (XI) by means of DIBAL in hexane provides the cyclopentenyl-methanol derivative (XII), which is desilylated with TBAF in THF to give the chiral diol (XIII). The esterification of the diol (XIII) with methyl chloroformate and pyridine yields the bis-carbonate (XIV), which is condensed with 2-amino-6-chloropurine (XV) by means of Pd(PPh3)4 in DMF to afford the carbocyclic purine derivative (XVI). Finally, this compound is hydrolyzed with NaOH in refluxing water to provide the target carbocyclic guanine.

参考文献 中间体
【1】 Nokami, J.; et al.; Palladium-catalyzed chemoselective reaction of allylic carbonate with nucleoside bases and its application for the synthesis of carbocyclic nucleosides. (-)-and (+)-carbovirs. Chem Lett 1994, 1071.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33168 (1R,3S)-4-cyclopentene-1,3-diol C5H8O2 详情 详情
(III) 45374 (1R,4S)-4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(IV) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(V) 45339 　 C8H11N 详情 详情
(VI) 45400 (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-ol C11H18O3 详情 详情
(VII) 45401 tert-butyl(dimethyl)([(1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl]oxy)silane; tert-butyl(dimethyl)silyl (1R,4S)-4-[(tetrahydro-2H-pyran-2-yloxy)methyl]-2-cyclopenten-1-yl ether C17H32O3Si 详情 详情
(VIII) 33174 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol C11H22O2Si 详情 详情
(IX) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(X) 45402 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-1-(chloromethyl)-2-cyclopenten-1-ol C12H23ClO2Si 详情 详情
(XI) 45403 tert-butyl(dimethyl)silyl (3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yl ether; tert-butyl(dimethyl)[(3S,5R)-1-oxaspiro[2.4]hept-6-en-5-yloxy]silane C12H22O2Si 详情 详情
(XII) 45404 ((1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl)methanol C12H24O2Si 详情 详情
(XIII) 45405 (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XIV) 45406 [(1S,4R)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XV) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XVI) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线10

The reaction of cyclopentadiene (I) with tosyl cyanide in acidic water gives the racemic bicyclic lactam (II), which is opened by means of TsCl and NaH to yield cis-3-(tosylamino)-4-cyclopentene-1-carboxylic acid (III). The reduction of (III) with NaBH4 affords the corresponding carbinol (IV), which is acylated with Ac2O and pyridine to provide the acetate (V). The reaction of (V) with Ts-Cl and NaH yields the ditosylamino derivative (VI), which is condensed with 2-amino-6-chloropurine (VII) by means of a Pd catalyst, affording the carbocyclic purine (VIII). Finally, this compound is hydrolyzed with hot aqueous NaOH to give the target carbocyclic guanine.

参考文献 中间体
【1】 Jung, M.E.; Rhee, H.; pi-Allylpalladium formation from allylic amines via N,N-ditosylimides and N-tosylamides: Efficient synthesis of the antiviral agent carbovir. J Org Chem 1994, 59, 17, 4719.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33410 cis-2-azabicyclo[2.2.1]hept-5-en-3-one C6H7NO 详情 详情
(III) 45408 (1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopentene-1-carboxylic acid C13H15NO4S 详情 详情
(IV) 45409 N-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-4-methylbenzenesulfonamide C13H17NO3S 详情 详情
(V) 45410 ((1S,4R)-4-[[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate C15H19NO4S 详情 详情
(VI) 45411 ((1S,4R)-4-[bis[(4-methylphenyl)sulfonyl]amino]-2-cyclopenten-1-yl)methyl acetate C22H25NO6S2 详情 详情
(VII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(VIII) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线11

The epoxidation of 3-cyclopentene-1-carboxylic acid methyl ester (I) with MCPBA in cyclohexane gives the trans-epoxide (II) along with some cis-isomer that is separated by chromatography. The reduction of the ester group of (II) with LiAlH4 in ether yields the corresponding trans-carbinol (III), which is silylated with Tbdms-Cl and imidazole to afford the silyl ether (IV). The reaction of the epoxide (IV) with the chiral lithium pyrrolidide (V) in benzene provides the (1S,3S)(trans) 3-(tertbutyldimethylsilyloxy)-4-cyclopenten-1-ol (VI). The condensation of (VI) with 2-amino-6-chloropurine by means of diethyl azodicarboxylate (DEAD) and PPh3 in dioxane gives the carbocyclic purine derivative (VIII), which is desilylated by means of TBAF in THF to the chloropurine (IX). Finally, this compound is hydrolyzed with refluxing aqueous NaOH to yield the target carbocyclic guanine.

参考文献 中间体
【1】 Asami, M.; Inoue, S.; Takahashi, J.; An asymmetric synthesis of (-)-carbovir. Tetrahedron Asymmetry 1994, 5, 9, 1649.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 45412 methyl 3-cyclopentene-1-carboxylate C7H10O2 详情 详情
(II) 45413 methyl (1R,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylate C7H10O3 详情 详情
(III) 45414 (1R,5S)-6-oxabicyclo[3.1.0]hex-3-ylmethanol C6H10O2 详情 详情
(IV) 45415 tert-butyl(dimethyl)[(1R,5S)-6-oxabicyclo[3.1.0]hex-3-ylmethoxy]silane; tert-butyl(dimethyl)silyl (1R,5S)-6-oxabicyclo[3.1.0]hex-3-ylmethyl ether C12H24O2Si 详情 详情
(V) 45416 　 C9H17LiN2 详情 详情
(VI) 45417 (1S,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-ol 886-65-7 C12H24O2Si 详情 详情
(VII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(VIII) 45418 9-[(1R,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-yl]-6-chloro-9H-purin-2-ylamine; 9-[(1R,4S)-4-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-yl]-6-chloro-9H-purin-2-amine C17H26ClN5OSi 详情 详情
(IX) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线12

The addition of HCl to cyclopentadiene (I) gives 3-chlorocyclopentene (II), which is converted to racemic 2-cyclopentene-1-carboxylic acid (III). Optical resolution of (II) by crystallization of its (-)-1-phenylethylamine yields the desired enantiomer (IV), which is reduced with LiAlH4 in ethyl ether affording the chiral carbinol (V) (ee 98%). The reaction of (V) successively with BuLi, CO2 and I2 provides the iodinated cyclic carbonate (VI), which is treated with DBU in hot toluene to give the unsaturated cyclic carbonate (VII). The condensation of (VII) with 2-amino-6-chloropurine (VIII) by means of a Pd catalyst yields the carbocyclic purine (IX), which is finally hydrolyzed with aqueous NaOH to afford the target carbocyclic guanine. Alternatively, carbinol (V) can also be obtained by the vitamin B12/Zn/NH4Cl-catalyzed isomerization of 1,2-epoxycyclopentane (X) to the chiral cyclopentenol (XI), which by a [2,3]-sigmatropic Wittig rearrangement with KH, ICH2-SnBu4 and BuLi yields the target carbinol (V). However, the enantiomeric excess obtained is only ee 54%.

参考文献 中间体
【1】 Hildbrand, S.; et al.; A short synthesis of (-)-carbovir. Helv Chim Acta 1994, 77, 5, 1236.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 19541 3-chloro-1-cyclopentene C5H7Cl 详情 详情
(III) 45419 2-cyclopentene-1-carboxylic acid C6H8O2 详情 详情
(IV) 45420 (1S)-2-cyclopentene-1-carboxylic acid C6H8O2 详情 详情
(V) 45421 (1S)-2-cyclopenten-1-ylmethanol C6H10O 详情 详情
(VI) 45422 (4aR,7S,7aS)-7-iodohexahydrocyclopenta[d][1,3]dioxin-2-one C7H9IO3 详情 详情
(VII) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(VIII) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(IX) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情
(X) 38011 6-oxabicyclo[3.1.0]hexane 285-67-6 C5H8O 详情 详情
(XI) 45423 (1R)-2-cyclopenten-1-ol C5H8O 详情 详情

合成路线13

The condensation of the chiral oxazolidinone (I) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinone (III), which is condensed with acrolein (IV) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (V). The ring-closing metathesis of (V) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (VI), which is reduced to the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) by means of LiBH4 in THF. The reaction of diol (VII) with Ac2O; with methyl chloroformate, TEA and DMAP; or with ethyl chloroformate and pyridine gives the diacetate (VIII), the cyclic carbonate (IX) or the dicarbonate (X), respectively. The condensation of (VIII), (IX) or (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Finally, these compounds are hydrolyzed with aqueous NaOH to the target carbocyclic guanine.

参考文献 中间体
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 14694 (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone 90719-32-7 C10H11NO2 详情 详情
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(III) 17667 (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one C15H17NO3 详情 详情
(IV) 17668 acrylaldehyde; Acrolein 107-02-8 C3H4O 详情 详情
(V) 17669 (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one C18H21NO4 详情 详情
(VI) 17670 (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one C16H17NO4 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VIII) 17674 [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate C10H14O4 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 17672 [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate C10H14O6 详情 详情
(XI) 11664 4-Chloro-3-nitroquinoline C9H5ClN2O2 详情 详情
(XII) 45424 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate C13H14ClN5O2 详情 详情
(XIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XIV) 45398 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate C13H14ClN5O3 详情 详情

合成路线14

Alternatively, the (R,R)-5-(hydroxymethyl)-2-cyclopenten-1-ol (VII) can also be obtained as follows: The condensation of the chiral oxazolidinethione (XV) with the pentenoic anhydride (II) by means of n-BuLi in THF gives the N-pentenoyloxazolidinethione (XVI), which is condensed with crotonaldehyde (XVII) catalyzed by TiCl4 and (-)-spartein in dichloromethane, yielding the chiral adduct (XVIII). The ring-closing metathesis of (XVIII) by means of a Ru catalyst in dichloromethane affords the chiral cyclopentenol derivative (XIX), which is reduced to the target diol (VII) by means of LiBH4 in THF.

参考文献 中间体
【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(II) 17666 1,1-dimethylpropionic 4-pentenoic anhydride C10H16O3 详情 详情
(VII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(XV) 45425 (4S)-4-benzyl-1,3-oxazolidine-2-thione C10H11NOS 详情 详情
(XVI) 41704 1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-4-penten-1-one C15H17NO2S 详情 详情
(XVII) 22517 (E)-2-butenal 4170-30-3 C4H6O 详情 详情
(XVIII) 45426 (2S,3R,4E)-2-allyl-1-[(4S)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-3-hydroxy-4-hexen-1-one C19H23NO3S 详情 详情
(XIX) 45427 [(4S)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl][(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]methanone C16H17NO3S 详情 详情

合成路线15

The condensation of 6-chloropurine-2-amine (III) with the chiral monoacetate (II) (obtained by enzymatic desymmetrization of diacetate (I)) by means of Pd(PPh3)4 in DMSO gives the cyclopentenol derivative (IV), which is treated with dimethyl dicarbonate and DMAP in dichloromethane to yield the carbonate (V). The condensation of (V) with ethyl 2-nitroacetate (VI) by means of Pd in THF affords the adduct (VII), which is decarboxylated by means of NaCl in DMSO/water at 150 C to provide the nitromethylcyclopentene derivative (VIII). The reaction of (VIII) with tBuOK, O3 and NaBH4 in methanol gives the corresponding hydroxymethyl derivative (IX), which is finally hydrolyzed with NaOH in refluxing water to afford the target guanine as a racemic compound. Alternatively, the nitromethyl-cyclopentene derivative (VIII) can also be obtained by condensation of carbonate (V) with 2-(trimethylsilyl)ethyl 2-nitroacetate (X) by means of Pd in THF to give the adduct (XI), which is decarboxylated by means of CsF in hot acetonitrile, affording (VIII).

参考文献 中间体
【1】 Brown, B.; Hegedus, L.S.; A novel, one pot ring expansion of cyclobutanones. Synthesis of carbovir and aristeromycin. J Org Chem 2000, 65, 6, 1865.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 54216 　 n/a C15H17CrO7 详情 详情
(II) 54225 (4S,5R)-4,5-diphenyl-3-vinyl-1,3-oxazolidin-2-one n/a C17H15NO2 详情 详情
(III) 54217 (4S,5R)-3-[(1S,2R)-2-(benzyloxy)-2-ethoxy-3-oxocyclobutyl]-4,5-diphenyl-1,3-oxazolidin-2-one n/a C28H27NO5 详情 详情
(IV) 54218 (4S,5R)-3-[(1S)-2-(benzyloxy)-4-oxo-2-cyclopenten-1-yl]-4,5-diphenyl-1,3-oxazolidin-2-one n/a C27H23NO4 详情 详情
(V) 54219 (4S,5R)-3-[(1S,2R)-2-(benzyloxy)-4-oxocyclopentyl]-4,5-diphenyl-1,3-oxazolidin-2-one n/a C27H25NO4 详情 详情
(VI) 54220 (4R)-4-(benzyloxy)-2-cyclopenten-1-one n/a C12H12O2 详情 详情
(VII) 54221 (1S,4R)-4-(benzyloxy)-2-cyclopenten-1-ol n/a C12H14O2 详情 详情
(VIII) 54222 (1S,4R)-4-(benzyloxy)-2-cyclopenten-1-yl ethyl carbonate n/a C15H18O4 详情 详情
(IX) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(X) 54223 9-[(1S,4R)-4-(benzyloxy)-2-cyclopenten-1-yl]-6-chloro-9H-purin-2-amine; 9-[(1S,4R)-4-(benzyloxy)-2-cyclopenten-1-yl]-6-chloro-9H-purin-2-ylamine n/a C17H16ClN5O 详情 详情
(XI) 54224 (1R,4S)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-ol n/a C10H10ClN5O 详情 详情

合成路线16

The reaction of 14C-labeled cyanhydric acid (I) with HCl and ethanol gives the iminoester (II), which by reaction with more ethanol in chloroform yields the labeled orthoester (III). The cyclization of the triaminopyrimidinone (IV) with orthoester (III) by means of Ms-OH in chloroform affords the chloropurine derivative (V), which is finally hydrolyzed with NaOH to afford the target compound, the 14C-labeled carbovir.

参考文献 中间体
【1】 Gopinathan, M.B.; Kepler, J.A.; Synthesis of carbon-14 labelled cis-2-amino-1,9-dihydro-9-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-H6-purine-6-one; [8-14C]carbovir: A promising anti-AIDS drug. J Label Compd Radiopharm 1991, 29, 6, 645.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55517 nitrilomethane CHN 详情 详情
(I) 55518 nitrilomethane CHN 详情 详情
(II) 13213 ethyl iminoformate C3H7NO 详情 详情
(II) 55519 ethyl iminoformate C3H7NO 详情 详情
(III) 27311 trimethoxymethane;Trimethyl orthoformate;Methyl orthoformate 149-73-5 C4H10O3 详情 详情
(III) 55520 trimethoxymethane; dimethoxymethyl methyl ether C4H10O3 详情 详情
(IV) 17660 [(1S,4R)-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol C10H14ClN5O 详情 详情
(V) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(V) 55521 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线17

The reaction of 2-azabicyclo[2,2,1]-5-hepten-3-one (I) with 2-nitrophenylsulfonyl chloride (II) by means of BuLi in THF gives the sulfonamide (III), which is condensed with the chloropurine (IV) by means of Pd[P(OPr)3]4 in THF or NMP to yield the adduct (V). The N-protection of the formamide group of (V) with Boc2O and NaH in THF affords compound (VI), which is reduced and deprotected with NaBH4 in methanol to provide the N-Boc protected chloropurine (VII). Finally, this compound is treated with hot HOAc to furnish the target chloropurine (VIII) (see schemes 14673102a intermediate (VIII), 14673103a intermediate (VIII), 14673104a intermediate (IX), 14673107a intermediate (XII), 14673111a intermediate (IX) and 14673113a intermediate (XIII)).

参考文献 中间体
【1】 katagiri, N.; et al.; Efficient synthesis of carbovir and its congener via pi-allylpalladium complex formation by ring strain-assisted C-N bond cleavage. J Org Chem 1997, 62, 6, 1580.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55527 2-azabicyclo[2.2.1]hept-5-en-3-one C6H7NO 详情 详情
(II) 32624 2-Nitrobenzenesulfonyl chloride 1694-92-4 C6H4ClNO4S 详情 详情
(III) 55522 2-[(2-nitrophenyl)sulfonyl]-2-azabicyclo[2.2.1]hept-5-en-3-one C12H10N2O5S 详情 详情
(IV) 55523 6-chloro-9H-purin-2-ylformamide C6H4ClN5O 详情 详情
(V) 55524 N-({(1S,4R)-4-[6-chloro-2-(formylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl}carbonyl)-2-nitrobenzenesulfonamide C18H14ClN7O6S 详情 详情
(VI) 55525 tert-butyl 6-chloro-9-[(1R,4S)-4-({[(2-nitrophenyl)sulfonyl]amino}carbonyl)-2-cyclopenten-1-yl]-9H-purin-2-yl(formyl)carbamate C23H22ClN7O8S 详情 详情
(VII) 55526 tert-butyl 6-chloro-9-[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]-9H-purin-2-ylcarbamate C16H20ClN5O3 详情 详情
(VIII) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情

合成路线18

The reaction of the commercially available (1S-cis)-2-cyclopentan-1,4-diol 4-acetate (I) with methyl pyrocarbonate and DMAP in THF gives the carbonate ester (II), which by reaction with nitromethane (III), triisopropyl phosphite and a Pd catalyst, yields (1R-cis)-1-acetoxy-4-(nitromethyl)-2-cyclopentene (IV). The hydrolysis of (IV) by means of Ts-OH in methanol affords the corresponding alcohol (V), which by treatment with O3, NaOMe and NaBH4 in methanol provides (1R-cis)-4-(hydroxymethyl)-2-cyclopenten-1-ol (VI). The selective monotritylation of the primary OH group of (VI) with trityl chloride (VII) in pyridine gives the trityl ether (VIII), which is condensed with 2-amino-6-chloropurine (IX) by means of Pd(PPh3)4 in THF to yield the adduct (X). The destritylation of (X) with HOAc/water affords the hydroxymethyl compound (XI), which is finally dechlorinated by hydrolysis with hot HCl or NaOH to provide the target (-)-carbovir. Alternatively, the dechlorination of (XI) can be performed by reaction of (XI) with liquid ammonia at 75-80 C in a Parr bomb to give the diaminopurine (XII), which is finally submitted to an enzymatic deamination with adenosine deaminase (from calf intestinal mucosa).

参考文献 中间体
【1】 Vince, R.; Peterson, M.L.; Lackey, J.W.; Mook, R.A. Jr.; Partridge, J.J. (GlaxoSmithKline plc); Synthesis of purine substd. cyclopentene derivs.. US 5126452 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 45407 (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate; (1S,4R)-4-acetoxy-2-cyclopentenol 60410-16-4 C7H10O3 详情 详情
(II) 55528 (1R,4S)-4-[(methoxycarbonyl)oxy]-2-cyclopenten-1-yl acetate C9H12O5 详情 详情
(III) 39563 nitromethane 75-52-5 CH3NO2 详情 详情
(IV) 55529 (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-yl acetate C8H11NO4 详情 详情
(V) 55530 (1R,4S)-4-(nitromethyl)-2-cyclopenten-1-ol C6H9NO3 详情 详情
(VI) 45405 (1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(VII) 28630 Triphenylchloromethane; 1-[Chloro(diphenyl)methyl]benzene; Trityl chloride 76-83-5 C19H15Cl 详情 详情
(VIII) 55531 (1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-ol C25H24O2 详情 详情
(IX) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(X) 55532 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-amine; 6-chloro-9-{(1R,4S)-4-[(trityloxy)methyl]-2-cyclopenten-1-yl}-9H-purin-2-ylamine C30H26ClN5O 详情 详情
(XI) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
(XII) 55533 [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H14N6O 详情 详情

合成路线19

The selective silylation of (-)-aristeromycin (I) with Hdms-Cl and imidazole gives the monosilyl ether (II), which is treated with thiocarbonyl dimidazole (TCDI) in hot ethyl acetate to yield the cyclic thiocarbonate (III). The reaction of (III) with 1,3-dimethyl-1,3,2-diazaphospholidine (DMPDP) in refluxing THF affords the desired cyclopentene derivative (IV). In an alternative method, the reaction of (II) with methyl orthoformate provides the cyclic orthoester (V), which undergoes thermal elimination with acetic acid at high temperature giving the desired cyclopentene derivative (IV). The oxidation of (IV) with MCPBA in chloroform yields the N-oxide (VI), which by reaction with Br-CN in methanol affords the oxadiazole derivative (VII). The cleavage of the oxadiazole ring of (VII) and simultaneous methylation with TEA and Me-I provided the cyanoimino derivative (VIII), which is submitted to a Dimroth rearrangement by means of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) in refluxing aqueous ethanol to give the methoxylated diaminopurine (IX). The reductive cleavage of the methoxyamino group of (IX) with Al/Hg in aqueous THF yields the silylated diaminopurine (X), which is deprotected with HCl in ethanol to afford the free diaminopurine precursor (XI). Finally, this compound is enzymatically deaminated by means of adenosine deaminase to furnish the target (-)-carbovir.

参考文献 中间体
【1】 Exall, A.M.; et al.; Synthesis from (-)-aristeromycin and x-ray structure of (-)-carbovir. J Chem Soc - Perkins Trans I 1991, 10, 2467.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 55534 (1R,2S,3R,5R)-3-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)-1,2-cyclopentanediol C11H15N5O3 详情 详情
(II) 55535 (1R,2S,3R,5R)-3-(6-amino-9H-purin-9-yl)-5-({[hexyl(dimethyl)silyl]oxy}methyl)-1,2-cyclopentanediol C19H33N5O3Si 详情 详情
(III) 55536 (4R,6R)-4-(6-amino-9H-purin-9-yl)-6-({[hexyl(dimethyl)silyl]oxy}methyl)tetrahydro-3aH-cyclopenta[d][1,3]dioxole-2-thione C20H31N5O3SSi 详情 详情
(IV) 55537 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-amine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-ylamine C19H31N5OSi 详情 详情
(V) 55538 9-[(4R,6R)-6-({[hexyl(dimethyl)silyl]oxy}methyl)-2-methoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(4R,6R)-6-({[hexyl(dimethyl)silyl]oxy}methyl)-2-methoxytetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine C21H35N5O4Si 详情 详情
(VI) 55539 6-amino-9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-1-ium-1-olate C19H31N5O2Si 详情 详情
(VII) 55540 7-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl][1,2,4]oxadiazolo[3,2-i]purin-2(7H)-imine C20H30N6O2Si 详情 详情
(VIII) 55541 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-1-methoxy-1,9-dihydro-6H-purin-6-ylidenecyanamide C21H32N6O2Si 详情 详情
(IX) 55542 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-6-(methoxyamino)-9H-purin-2-ylamine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-6-(methoxyamino)-9H-purin-2-amine C20H34N6O2Si 详情 详情
(X) 55543 2-amino-9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purin-6-ylamine; 9-[(1R,4S)-4-({[hexyl(dimethyl)silyl]oxy}methyl)-2-cyclopenten-1-yl]-9H-purine-2,6-diamine C19H32N6OSi 详情 详情
(XI) 55533 [(1S,4R)-4-(2,6-diamino-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H14N6O 详情 详情

合成路线20

The cyclization of glyoxylic acid (I) with cyclopentadiene (II) gives the racemic hydroxylactone (III), which is acylated with Ac2O to yield acetoxy compound (rac)-(IV). The enzymatic optical resolution of (rac)-(IV) by means of Pseudomonas fluorescens affords the chiral hydroxylactone (-)-(V), which is reduced with LiAlH4 in refluxing THF to provide the lactol (VI). The oxidation of (VI) with NaIO4 in ethyl ether/water gives the chiral carbaldehyde (VII), which is reduced with NaBH4 in ethanol to afford the diol (VIII). The reaction of (VIII) with triphosgene by means of TEA in dichloromethane affords the cyclic carbonate (IX), which is condensed with chloropurine (X) by means of Pd(PPh3)4 in DMSO/THF to provide the adduct (XI). Finally, this compound is hydrolyzed with NaOH to afford the target (-)-carbovir.

参考文献 中间体
【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(I) 15618 2-Oxoacetic acid; Glyoxylic Acid 298-12-4 C2H2O3 详情 详情
(II) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(III) 55545 (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(IV) 17679 (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate C9H10O4 详情 详情
(V) 17678 (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one C7H8O3 详情 详情
(VI) 55544 (3S,3aR,6aR)-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2,3-diol C7H10O3 详情 详情
(VII) 17682 (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde C6H8O2 详情 详情
(VIII) 17671 (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol C6H10O2 详情 详情
(IX) 17673 (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one C7H8O3 详情 详情
(X) 11644 6-Chloro-9H-purin-2-amine; 6-Chloro-9H-purin-2-ylamine; 2-Amino-6-chloropurine 10310-21-1 C5H4ClN5 详情 详情
(XI) 17650 [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol C11H12ClN5O 详情 详情
Extended Information