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【结 构 式】

【分子编号】33169

【品名】(1S,4R)-4-hydroxy-2-cyclopenten-1-yl acetate

【CA登记号】

【 分 子 式 】C7H10O3

【 分 子 量 】142.1546

【元素组成】C 59.14% H 7.09% O 33.76%

与该中间体有关的原料药合成路线共 3 条

合成路线1

该中间体在本合成路线中的序号:(II)

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).

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2

该中间体在本合成路线中的序号:(VI)

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

合成路线3

该中间体在本合成路线中的序号:(VI)

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.

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
(rac)(XIV) 33174 (1S,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol C11H22O2Si 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
(XI) 13848 2-Furylmethanol; Furfuryl Alcohol 98-00-0 C5H6O2 详情 详情
(XII) 33173 4-hydroxy-2-cyclopenten-1-one C5H6O2 详情 详情
(XIII) 13805 (4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one C11H20O2Si 详情 详情
(XV) 33175 (1S)-2-cyclopenten-1-yl acetate C7H10O2 详情 详情
(XVI) 64705 (1R,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopenten-1-ol C11H22O2Si 详情 详情
(XVII) 33176 (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentanol C11H24O2Si 详情 详情
(XVIII) 33177 (1R,4S)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl methanesulfonate C12H24O4SSi 详情 详情
(XIX) 33178 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-amine; 9-((1R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]cyclopentyl)-9H-purin-6-ylamine C16H27N5OSi 详情 详情
Extended Information