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【结 构 式】 
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【分子编号】29889 【品名】(1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol 【CA登记号】 |
【 分 子 式 】C13H16O3 【 分 子 量 】220.26824 【元素组成】C 70.89% H 7.32% O 21.79% |
合成路线1
该中间体在本合成路线中的序号：(I)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.
| 【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2
该中间体在本合成路线中的序号：(I)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.
| 【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3
该中间体在本合成路线中的序号：(V)The regioselective reaction of cyclopentadiene (I) and sodium or commercial sodium cyclopentadienide (II) with benzyl chloromethyl ether (III) by means of the chiral catalyst (-)-diisopinocampheylborane in THF, followed by hydroxylation with H2O2/NaOH, gives (1S-trans)-2-(benzyloxymethyl)-3-cyclopenten-1-ol (IV), which is regioselectively epoxidized with tert-butyl hydroperoxide and vanadyl acetylacetonate in 2,2,4-trimethylpentane, yielding [1S-(1alpha,2alpha,3beta,5alpha)-2-(benzyloxymethyl)-6-oxabicyclo[3.1.0]hexan-3-ol (V). The protection of (V) with benzyl bromide and NaH affords the corresponding ether (VI), which is condensed with 6-O-benzylguanine (VII) by means of LiH in DMF to give the guanine derivative (VIII). The protection of the amino group of (VIII) with 4-methoxyphenyl(diphenyl)chloromethane (IX), TEA and DMAP in dichloromethane gives intermediate (X), which is oxidized at the free hydroxyl group with methylphosphonic acid, DCC and oxalic acid in DMSO or Dess Martin periodinane in dichloromethane, yielding the cyclopentanone derivative (XI). The reaction of (XI) with (i) Zn/TiCl4/CH2Br2 complex in THF/CH2Cl2, (ii) activated Zn/PbCl2/CH2I2/TiCl4 in THF/CH2Cl2 (2), (iii) Nysted reagent/TiCl4 in THF/CH2Cl2 or (iv) Tebbe reagent in toluene affords the corresponding methylene derivative (XII), which is partially deprotected with 3N HCl in hot THF, providing the dibenzylated compound (XI). Finally, this compound is treated with BCl3 in dichloromethane. (Scheme 18263401a)
| 【1】 Bisacchi, G.S.; Chao, S.T.; Bachard, C.; et al.; BMS-200475. A novel carbocyclic 2'-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro. Bioorg Med Chem Lett 1997, 7, 2, 127. |
| 【2】 Castaner, J.; Graul, A.; BMS-200475. Drugs Fut 1999, 24, 111, 1173. |
| 【3】 Zahler, R.; Slusarchyk, W.A. (Bristol-Myers Squibb Co.); Hydroxymethyl(methylenecyclopentyl)purines and pyrimidines. EP 0481754; JP 1992282373; US 5206244 . |
| 【4】 Bisacchi, G.S.; Sundeen, J.E. (Bristol-Myers Squibb Co.); Improved process for preparing the antiviral agent [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one. WO 9809964 . |
| 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) | 29887 | Sodium cyclopentadienide | 4984-82-1 | C5H5Na | 详情 | 详情 |
| (III) | 14560 | Benzyl chloromethyl ether; 1-[(chloromethoxy)methyl]benzene | 3587-60-8 | C8H9ClO | 详情 | 详情 |
| (IV) | 29888 | (1S,2R)-2-[(benzyloxy)methyl]-3-cyclopenten-1-ol | C13H16O2 | 详情 | 详情 | |
| (V) | 29889 | (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexan-3-ol | C13H16O3 | 详情 | 详情 | |
| (VI) | 29890 | (1S,2R,3S,5R)-3-(benzyloxy)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hexane; benzyl (1S,2R,3S,5R)-2-[(benzyloxy)methyl]-6-oxabicyclo[3.1.0]hex-3-yl ether | C20H22O3 | 详情 | 详情 | |
| (VII) | 14383 | 6-(benzyloxy)-9H-purin-2-ylamine; 6-(benzyloxy)-9H-purin-2-amine | 19916-73-5 | C12H11N5O | 详情 | 详情 |
| (VIII) | 29891 | (1S,2S,3S,5S)-5-[2-amino-6-(benzyloxy)-9H-purin-9-yl]-3-(benzyloxy)-2-[(benzyloxy)methyl]cyclopentanol | C32H33N5O4 | 详情 | 详情 | |
| (IX) | 12700 | 4-[Chloro(diphenyl)methyl]phenyl methyl ether; 1-[Chloro(diphenyl)methyl]-4-methoxybenzene; p-Anisylchlorodiphenylmethane | 14470-28-1 | C20H17ClO | 详情 | 详情 |
| (X) | 29892 | (1S,2S,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanol | C52H49N5O5 | 详情 | 详情 | |
| (XI) | 29893 | (2R,3S,5S)-3-(benzyloxy)-5-(6-(benzyloxy)-2-[[(4-methoxyphenyl)(diphenyl)methyl]amino]-9H-purin-9-yl)-2-[(benzyloxy)methyl]cyclopentanone | C52H47N5O5 | 详情 | 详情 | |
| (XII) | 29894 | 6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-N-[(4-methoxyphenyl)(diphenyl)methyl]-9H-purin-2-amine; N-(6-(benzyloxy)-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-9H-purin-2-yl)-N-[(4-methoxyphenyl)(diphenyl)methyl]amine | 142217-80-9 | C53H49N5O4 | 详情 | 详情 |
| (XIII) | 29895 | 2-amino-9-[(1S,3R,4S)-4-(benzyloxy)-3-[(benzyloxy)methyl]-2-methylenecyclopentyl]-1,9-dihydro-6H-purin-6-one | 142217-81-0 | C26H27N5O3 | 详情 | 详情 |