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【结 构 式】 
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【分子编号】17657 【品名】[(1S,4R)-4-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol 【CA登记号】 |
【 分 子 式 】C10H13ClN4O 【 分 子 量 】240.69228 【元素组成】C 49.9% H 5.44% Cl 14.73% N 23.28% O 6.65% |
合成路线1
该中间体在本合成路线中的序号：(IV)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.
| 【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2
该中间体在本合成路线中的序号：(VIII)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.
| 【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3
该中间体在本合成路线中的序号：(XVI)3) The condensation of (±)-cis-4-acetamido-2-cyclopentenylmethyl acetate (XIV) with 2-amino-4,6-dichloropyrimidine (XV) by means of Ba(OH)2 and triethylamine in refluxing butanol gives the expected condensation product (XVI), which is treated with 4-chlorophenyldiazonium chloride (XVII) in water/acetic acid to yield the corresponding azo-compound (XVIII). The reduction of (XVIII) with Zn/acetic acid in ethanol affords the diamine (XIX), which is cyclized with refluxing diethoxymethyl acetate (XX) to afford the corresponding purine (XXI). The reaction of (XXI) with cyclopropylamine (X) in refluxing ethanol affords racemic abacavir (XXII), which is phosphorylated with POCl3 giving the racemic 4'-O-phosphate (XXIII). Finally, this compound is submitted to stereoselective enzymatic dephosphorylation using snake venom 5'-nucleotidase (EC 3.1.3.5) from Crotalus atrox yielding the (-)-enantiomer, abacavir.
| 【1】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
| 【2】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. EP 0434450; JP 1996092252; JP 1999158160; JP 1999343292 . |
| 【3】 Daluge, S.M. (Glaxo Wellcome plc); Therapeutic nucleosides. AU 8937025; EP 0349242; JP 1990045486; JP 1999139976; US 5034394; US 5089500 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XIV) | 17655 | (1S,4R)-4-(acetamido)-2-cyclopenten-1-yl acetate | C9H13NO3 | 详情 | 详情 | |
| (XV) | 14404 | 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine | 56-05-3 | C4H3Cl2N3 | 详情 | 详情 |
| (XVI) | 17657 | [(1S,4R)-4-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol | C10H13ClN4O | 详情 | 详情 | |
| (XVII) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (XVIII) | 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 | |
| (XIX) | 17660 | [(1S,4R)-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]-2-cyclopenten-1-yl]methanol | C10H14ClN5O | 详情 | 详情 | |
| (XX) | 17661 | Diethoxymethyl acetate | 14036-06-7 | C7H14O4 | 详情 | 详情 |
| (XXI) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XXII) | 17663 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methanol | C14H18N6O | 详情 | 详情 | |
| (XXIII) | 17664 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl dihydrogen phosphate | C14H19N6O4P | 详情 | 详情 |