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【结 构 式】 
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【药物名称】Abacavir sulfate, 1592U89 sulfate, Ziagen 【化学名称】(1R,4S)-cis-2-Amino-6-(cyclopropylamino)-9-[4-(hydroxymethyl)-2-cyclopentenyl]-9H-purine sulfate (2:1) 【CA登记号】188062-50-2, 136777-49-6 (diHCl), 136470-78-5 (free base), 136777-48-5 (monoHCl), 168146-84-7 (succinate) 【 分 子 式 】C28H38N12O6S 【 分 子 量 】670.75586 |
【开发单位】GlaxoSmithKline (Orphan Drug), GlaxoSmithKline (Originator) 【药理作用】AIDS Medicines, Anti-HIV Agents, ANTIINFECTIVE THERAPY, Reverse Transcriptase Inhibitors |
合成路线1
1) The reaction of 4,6-dihydroxypyrimidine-2,5-diamine (I) with (chloromethylene)dimethylammonium chloride (II) in refluxing chloroform gives 4,6-dichloro-2,5-bis(dimethylaminomethyleneamino)pyrimidine (III), which by reaction with aqueous HCl in hot ethanol yields monoamine (IV). The reaction of (IV) with a refluxing phosphate buffer (pH 3.2) affords N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (V). The condensation of (V) with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) (which was obtained by optical resolution of the cis-racemate (VII) with D-dibenzoyltartaric acid, and elimination of the acid with ion exchange resin Amberlite IA-400, by means of triethylamine and NaOH in refluxing ethanol) gives N-[2-amino-4-chloro-6-[4(S)-(hydroxymethyl)-2-cyclopenten-1(R)-ylamino]pyrimidin-5-yl]formamide (VIII). The cyclization of (VIII) with refluxing diethoxymethyl acetate or triethyl orthoformate yields the corresponding purine derivative (IX), which is finally treated with cyclopropylamine (X) in refluxing n-butanol. 2) The formylation of N-(5-amino-4,6-dichloropyrimidin-2-yl)acetamide (XI) with 95% formic acid in acetic anhydride gives the expected formamide (XII), which is condensed with (1S,4R)-4-amino-2-cyclopentene-1-methanol (VI) by means of triethylamine in hot ethanol to yield the substituted pyrimidine (XIII). Finally, the cyclization of (XIII) with diethoxymethyl acetate as before affords the purine intermediate (IX).
| 【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 . |
| 【4】 Daluge, S.M.; Martin, M.T.; Fugett, M.J.F.; Chloropyrimide intermediates. WO 9521161 . |
| 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) | 17642 | 2,5-diamino-4,6-pyrimidinediol | C4H6N4O2 | 详情 | 详情 | |
| (II) | 17643 | (Chloromethylene)dimethylammonium chloride; N-(chloromethylene)-N-methylmethanaminium chloride | 3724-43-4 | C3H7Cl2N | 详情 | 详情 |
| (III) | 17644 | N'-(4,6-dichloro-2-[[(E)-(dimethylamino)methylidene]amino]-5-pyrimidinyl)-N,N-dimethyliminoformamide | C10H14Cl2N6 | 详情 | 详情 | |
| (IV) | 17645 | N'-(2-amino-4,6-dichloro-5-pyrimidinyl)-N,N-dimethyliminoformamide | C7H9Cl2N5 | 详情 | 详情 | |
| (V) | 17646 | 2-amino-4,6-dichloro-5-pyrimidinylformamide | C5H4Cl2N4O | 详情 | 详情 | |
| (VI) | 17647 | [(1S,4R)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (VII) | 63843 | (rac)-[(1R*,4S*)-4-amino-2-cyclopenten-1-yl]methanol | C6H11NO | 详情 | 详情 | |
| (VIII) | 17649 | 2-amino-4-chloro-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-5-pyrimidinylformamide | C11H14ClN5O2 | 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) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XI) | 17652 | N-(5-amino-4,6-dichloro-2-pyrimidinyl)acetamide | C6H6Cl2N4O | 详情 | 详情 | |
| (XII) | 17653 | N-[4,6-dichloro-5-(formylamino)-2-pyrimidinyl]acetamide | C7H6Cl2N4O2 | 详情 | 详情 | |
| (XIII) | 17654 | N-(4-chloro-5-(formylamino)-6-[[(1R,4S)-4-(hydroxymethyl)-2-cyclopenten-1-yl]amino]-2-pyrimidinyl)acetamide | C13H16ClN5O3 | 详情 | 详情 |
合成路线2
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 |
合成路线3
4) The acylation of 4(S)-benzyloxazolidin-2-one (XXIV) with 4-pentenoyl pivaloyl anhydride (XXV) by means of NaH in THF gives 4(S)-benzyl-3-(4-pentenoyl)oxazolidin-2-one (XXVI), which is submitted to a diastereoselective syn aldol condensation with acrolein (XXVII), using dibutylboron triflate as catalyst, affording the aldol (XXVIII). The cyclization of (XXVIII) by means of the Grubbs catalyst in dichloromethane yields the cyclopentenol (XXIX), which is reduced with LiBH4 in THF/methanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). The reaction of (XXX) with methyl chloroformate/pyridine/DMAP or methyl chloroformate/triethylamine/DMAP or acetic anhydride gives the diols (XXXI), (XXXII) and (XXXIII), respectively, each of which coupled with 2-amino-6-chloropurine (XXXIV) in the presence of NaH and palladium tetrakis(triphenylphosphine) in THF/DMSO, affords the purine intermediate (IX) already reported.
| 【1】 King, B.W.; Crimmins, M.T.; An efficient asymmetric approach to carbocyclic nucleosides: Asymmetric synthesis of 1592U89, a potent inhibitor of HIV reverse transcriptase. J Org Chem 1996, 61, 13, 4192-3. |
| 【2】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IX) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XXIV) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (XXV) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (XXVI) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (XXVII) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (XXVIII) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (XXIX) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (XXX) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XXXI) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XXXII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 详情 | 详情 | |
| (XXXIV) | 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 |
合成路线4
5) The water promoted condensation of glyoxylic acid (XXXV) with cyclopentadiene (XXXVI) gives the racemic cis-hydroxylactone (XXXVII), which is acetylated with acetic anhydride to the acetate (XXXVIII). The selective enzymatic hydrolysis of (XXXVIII) with Pseudomonas fluorescens lipase yields the pre (-)-enantiomer (XXXIX), which is reduced with LiAlH4 in refluxing THF, affording triol (XL). The oxidation of the vicinal glycol of (XL) with NaIO4 in ethyl ether/water yields the hydroxyaldehyde (XLI), which is reduced with NaBH4 in ethanol to give the key intermediate 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (XXX). This compound, by reaction with triphosgene and triethylamine in dichloromethane, results in the cyclic carbonate intermediate (XXXII), already reported.
| 【1】 Yu, J.; Olivo, H.F.; Practical enantiodivergent syntheses of both enantiomers of carbovir, 1592U89 and six-membered ring analogues. J Chem Soc - Perkins Trans I 1998, 3, 3, 391-2. |
| 【2】 Graul, A.; Castaner, J.; Leeson, P.A.; Abacavir Sulfate. Drugs Fut 1998, 23, 11, 1155-1167. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXX) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XXXII) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXV) | 15618 | 2-Oxoacetic acid; Glyoxylic Acid | 298-12-4 | C2H2O3 | 详情 | 详情 |
| (XXXVI) | 11183 | 1,3-Cyclopentadiene | C5H6 | 详情 | 详情 | |
| (XXXVII) | 63844 | (rac)-(3R*,3aS*,6aS*)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (XXXVIII) | 17679 | (3S,3aR,6aR)-2-oxo-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-3-yl acetate | C9H10O4 | 详情 | 详情 | |
| (XXXIX) | 17678 | (3S,3aR,6aR)-3-hydroxy-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2-one | C7H8O3 | 详情 | 详情 | |
| (XL) | 17681 | (1S)-1-[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]-1,2-ethanediol | C7H12O3 | 详情 | 详情 | |
| (XLI) | 17682 | (1S,2R)-2-hydroxy-3-cyclopentene-1-carbaldehyde | C6H8O2 | 详情 | 详情 |
合成路线5
A new solid phase synthesis of abacavir has been reported: Condensation of the chiral 4(R)-benzyl-3-(4-pentenoyl)oxazolidin-2-thione (I) with acrolein (II) by means of TiCl4 and DIEA gives the adduct (III), which was transformed into the chiral cyclopentene (IV) by catalytic ring-closing metathesis. The reductive removal of the chiral auxiliary with LiBH4 affords the chiral diol (V), which is selectively silylated with TBDMSCl providing the primary silyl ether (VI). Acylation of the secondary alcohol of (VI) with benzoic anhydride gives the benzoate (VII), which is desilylated with HF in acetonitrile yielding the allylic benzoate (VIII). Benzoate (VIII) is condensed with a p-nitrophenyl Wang carbonate resin (IX) by means of DIEA and DMAP affording the solid phase resin (X) which is condensed with 2-amino-6-chloropurine (XI) by means of a Pd catalyst furnishing the adduct (XII). Thermal condensation of (XII) with cyclopropylamine (XIII) yields the diaminopurine resin (XIV) which, after cleavage from the resin by a treatment with TFA in dichloromethane, gives directly abacavir.
| 【1】 Zuercher, W.J.; Crimmins, M.T.; Solid-phase synthesis of carbocyclic nucleosides. Org Lett 2000, 2, 8, 1065. |
| 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) | 41704 | 1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-4-penten-1-one | C15H17NO2S | 详情 | 详情 | |
| (II) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (III) | 41705 | (2S,3R)-2-allyl-1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-3-hydroxy-4-penten-1-one | C18H21NO3S | 详情 | 详情 | |
| (IV) | 41706 | [(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl][(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]methanone | C16H17NO3S | 详情 | 详情 | |
| (V) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VI) | 41707 | (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-ol | C12H24O2Si | 详情 | 详情 | |
| (VII) | 41708 | (1R,5R)-5-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-cyclopenten-1-yl benzoate | C19H28O3Si | 详情 | 详情 | |
| (VIII) | 41709 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-yl benzoate | C13H14O3 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIII) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
合成路线6
An efficient asymmetric synthesis of abacavir has been reported: Acylation of the chiral oxazolidinone (I) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyloxazolidinone (III), which by condensation with acrolein (IV) catalyzed by TiCl4 and ()-spartein in dichloromethane yields the chiral adduct (V). The ring-closing metathesis of adduct (V) by means of the ruthenium catalyst (Cy3P)Cl2Ru=CHPh in dichloromethane affords the chiral cyclopentenol (VI), which is reduced to 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) by means of LiBH4 in THF. Reaction of diol (VII) with a) Ac2O, TEA and DMAP, b) methyl chloroformate, TEA and DMAP or c) methyl chloroformate, pyridine and DMAP gives a) the diacetate (VIII), b) the cyclic carbonate (IX) or c) the dicarbonate (X), respectively. The condensation of diacetate (VIII), cyclic carbonate (IX) or dicarbonate (X) with 2-amino-6-chloropurine (XI) by means of Pd(PPh3)4 yields the carbocyclic purines (XII), (XIII) or (XIV), respectively. Treatment of these chloro-purines (XII), (XIII) and (XIV) with cyclopropylamine (XV) in hot DMSO provides the corresponding cyclopropylaminopurine carbonate (XVI), abacavir or cyclopropylaminopurine acetate (XVII), respectively. Finally, the protecting groups of purines (XVI) and (XVII) are hydrolyzed with aqueous NaOH.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 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) | 14694 | (S)-4-Benzyl-2-oxazolidinone; (4S)-4-Benzyl-1,3-oxazolan-2-one; (S)-(-)-4-Benzyl-2-oxazolidinone | 90719-32-7 | C10H11NO2 | 详情 | 详情 |
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (III) | 17667 | (4S)-4-benzyl-3-(4-pentenoyl)-1,3-oxazolidin-2-one | C15H17NO3 | 详情 | 详情 | |
| (IV) | 17668 | acrylaldehyde; Acrolein | 107-02-8 | C3H4O | 详情 | 详情 |
| (V) | 17669 | (4S)-3-[(2S,3R)-2-allyl-3-hydroxy-4-pentenoyl]-4-benzyl-1,3-oxazolidin-2-one | C18H21NO4 | 详情 | 详情 | |
| (VI) | 17670 | (4S)-4-benzyl-3-[[(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]carbonyl]-1,3-oxazolidin-2-one | C16H17NO4 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 详情 | 详情 | |
| (IX) | 17673 | (4aR,7aR)-4,4a,5,7a-tetrahydrocyclopenta[d][1,3]dioxin-2-one | C7H8O3 | 详情 | 详情 | |
| (X) | 17672 | [(1R,2R)-2-[(methoxycarbonyl)oxy]-3-cyclopenten-1-yl]methyl methyl carbonate | C10H14O6 | 详情 | 详情 | |
| (XI) | 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 |
| (XII) | 45424 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl acetate | C13H14ClN5O2 | 详情 | 详情 | |
| (XIII) | 17650 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methanol | C11H12ClN5O | 详情 | 详情 | |
| (XIV) | 45398 | [(1S,4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-cyclopenten-1-yl]methyl methyl carbonate | C13H14ClN5O3 | 详情 | 详情 | |
| (XV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XVI) | 49433 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate | C16H20N6O2 | 详情 | 详情 | |
| (XVII) | 49434 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl methyl carbonate | C16H20N6O3 | 详情 | 详情 |
合成路线7
Alternatively, 5(R)-(hydroxymethyl)-2-cyclopenten-1(R)-ol (VII) can also be obtained as follows: Acylation of the chiral oxazolidinethione (XIX) with the mixed anhydride (II) by means of BuLi in THF gives the N-pentenoyl-oxazolidinethione (XX), which by condensation with crotonaldehyde (XXI) catalyzed by TiCl4 and ()-spartein in dichloromethane yields the chiral adduct (XXII). The ring-closing metathesis of (XXII) by means of the ruthenium catalyst in dichloromethane affords the chiral cyclopentenol derivative (XXIII), which is reduced to the target diol (VII) by means of LiBH4 in THF.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 17666 | 1,1-dimethylpropionic 4-pentenoic anhydride | C10H16O3 | 详情 | 详情 | |
| (VII) | 17671 | (1R,5R)-5-(hydroxymethyl)-2-cyclopenten-1-ol | C6H10O2 | 详情 | 详情 | |
| (XIX) | 45425 | (4S)-4-benzyl-1,3-oxazolidine-2-thione | C10H11NOS | 详情 | 详情 | |
| (XX) | 41704 | 1-[(4R)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-4-penten-1-one | C15H17NO2S | 详情 | 详情 | |
| (XXI) | 22517 | (E)-2-butenal | 4170-30-3 | C4H6O | 详情 | 详情 |
| (XXII) | 45426 | (2S,3R,4E)-2-allyl-1-[(4S)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl]-3-hydroxy-4-hexen-1-one | C19H23NO3S | 详情 | 详情 | |
| (XXIII) | 45427 | [(4S)-4-benzyl-2-thioxo-1,3-oxazolidin-3-yl][(1S,2R)-2-hydroxy-3-cyclopenten-1-yl]methanone | C16H17NO3S | 详情 | 详情 |
合成路线8
Alternatively, 2-amino-6-chloropurine (XI) is treated with cyclopropylamine (XV) in hot DMSO to give 2-amino-6-(cyclopropylamino)purine (XVIII), which is condensed with the chiral diacetate (VIII) by means of Pd(PPh3)4 to yield the carbocyclic purine acetate (XVI). Finally, purine (XVI) is deprotected by hydrolysis with aqueous NaOH.
| 【1】 Crimmins, M.T.; et al.; An efficient, general asymmetric synthesis of carbocyclic nucleosides: Application of an asymmetric aldol/ring-closing metathesis strategy. J Org Chem 2000, 65, 25, 8499. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIII) | 17674 | [(1R,2R)-2-(acetoxy)-3-cyclopenten-1-yl]methyl acetate | C10H14O4 | 详情 | 详情 | |
| (XI) | 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 |
| (XV) | 12263 | Cyclopropylamine; Cyclopropanamine | 765-30-0 | C3H7N | 详情 | 详情 |
| (XVI) | 49433 | [(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopenten-1-yl]methyl acetate | C16H20N6O2 | 详情 | 详情 | |
| (XVIII) | 41890 | N-(2-amino-9H-purin-6-yl)-N-cyclopropylamine; N(6)-cyclopropyl-9H-purine-2,6-diamine | C8H10N6 | 详情 | 详情 |