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【结 构 式】

【分子编号】33168

【品名】(1R,3S)-4-cyclopentene-1,3-diol

【CA登记号】

【 分 子 式 】C5H8O2

【 分 子 量 】100.11732

【元素组成】C 59.98% H 8.05% O 31.96%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(II)

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.

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2

该中间体在本合成路线中的序号:(cis)(IV)

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.

1 Borcherding, D.R.; et al.; Carbocyclic nucleosides as inhibitors of human Tumor Necrosis Factor-alpha production: Effects of the stereoisomers of (3-hydroxycyclopentyl)adenines. J Med Chem 1996, 39, 13, 2615.
2 Watson, T.J.N.; et al.; Development of the carbocyclic nucleoside MDL 201449A. A tumor necrosis factor-alpha inhibitor. Org Process Res Dev 1998, 2, 6, 357.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(cis/trans)(IV) 21533 4-cyclopentene-1,3-diol C5H8O2 详情 详情
(cis)(IV) 33168 (1R,3S)-4-cyclopentene-1,3-diol C5H8O2 详情 详情
(I) 11183 1,3-Cyclopentadiene C5H6 详情 详情
(II) 33167 3,5-dibromo-1-cyclopentene C5H6Br2 详情 详情
(III) 21534 4-(acetoxy)-2-cyclopenten-1-yl acetate C9H12O4 详情 详情
(V) 24543 vinyl acetate 108-05-4 C4H6O2 详情 详情
(VI) 33169 (1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate C7H10O3 详情 详情
(VII) 33170 (1R,3S)-3-hydroxycyclopentyl acetate C7H12O3 详情 详情
(VIII) 33171 (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate C8H14O5S 详情 详情
(IX) 10343 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine 73-24-5 C5H5N5 详情 详情
(X) 33172 (1R,3R)-3-(6-amino-9H-purin-9-yl)cyclopentyl acetate C12H15N5O2 详情 详情
Extended Information