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【结 构 式】 
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【分子编号】45405 【品名】(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-ol 【CA登记号】 |
【 分 子 式 】C6H10O2 【 分 子 量 】114.1442 【元素组成】C 63.14% H 8.83% O 28.03% |
合成路线1
该中间体在本合成路线中的序号：(XIII)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：(VI)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).
| 【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 |