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【结 构 式】 
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【分子编号】14404 【品名】4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine 【CA登记号】56-05-3 |
【 分 子 式 】C4H3Cl2N3 【 分 子 量 】163.99344 【元素组成】C 29.3% H 1.84% Cl 43.24% N 25.62% |
合成路线1
该中间体在本合成路线中的序号：(III)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：(VII)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：(XXXIII)4) The reaction of the previously described chiral cyclobutanone (IX) with hydroxylamine gives the corresponding oxime (XXXI), which is reduced with H2 over PtO2 yielding [1R-(1alpha,2beta,3alpha)]-2,3-di(cyclohexylcarbonyloxymethyl) cyclobutane-1-amine (XXXII). The condensation of (XXXII) with 4,6-dichloropyrimidine-2-amine (XXXIII) affords (XXXIV), which is further condensed with 4-chlorophenyldiazonium chloride (XXXV) to give the 5-azo-pyrimidine derivative (XXXVI). The hydrogenation of the azo group of (XXXVI) with Zn/HCl yields the 2,5-diaminopyrimidine derivative (XXXVII), which is cyclized with triethyl orthoformate to afford [1R-(1alpha,2beta,3alpha)]-2-amino-9-[2,3-bis (cyclohexylcarbonyloxymethyl)cyclobutyl]-6-chloropurine (XXXVIII). Finally, this compound is converted into the final product in the usual way.
| 【1】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 【2】 Honjo, M.; Maruyama, T.; Sato, Y. (Nippon Kayaku Co., Ltd.); Production of carboxetanocin G or A and intermediates therefor. WO 9110665 . |
| 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) | 14380 | [(1S,2S)-2-[(benzoyloxy)methyl]-4-oxocyclobutyl]methyl benzoate | C20H18O5 | 详情 | 详情 | |
| (XXXI) | 14402 | [(1S,2R)-2-[(benzoyloxy)methyl]-3-(hydroxyimino)cyclobutyl]methyl benzoate | C20H19NO5 | 详情 | 详情 | |
| (XXXII) | 14403 | ((1S,2R,3R)-3-amino-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C20H33NO4 | 详情 | 详情 | |
| (XXXIII) | 14404 | 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine | 56-05-3 | C4H3Cl2N3 | 详情 | 详情 |
| (XXXIV) | 14405 | ((1S,2R,3R)-3-[(2-amino-6-chloro-4-pyrimidinyl)amino]-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C24H35ClN4O4 | 详情 | 详情 | |
| (XXXV) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (XXXVI) | 14407 | ((1S,2R,3R)-3-([2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]amino)-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C30H38Cl2N6O4 | 详情 | 详情 | |
| (XXXVII) | 14408 | [(1R,2S,4S)-2-[[(cyclohexylcarbonyl)oxy]methyl]-4-[(2,5-diamino-6-chloro-4-pyrimidinyl)amino]cyclobutyl]methyl cyclohexanecarboxylate | C24H36ClN5O4 | 详情 | 详情 | |
| (XXXVIII) | 14409 | ((1S,2R,3R)-3-(2-amino-6-chloro-9H-purin-9-yl)-2-[[(cyclohexylcarbonyl)oxy]methyl]cyclobutyl)methyl cyclohexanecarboxylate | C25H34ClN5O4 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XXXIII)7) [14C]-labeled lobucavir has been synthesized as follows: The reaction of [1R-(1alpha,2beta,3alpha)]-2,3-di(benzyloxymethyl)cyclobutan-1-amine (LVI) with 4,6-dichloropyrimidine-2-amine (XXXIII) by means of triethylamine in acetonitrile gives [1R-(1alpha,2beta,3alpha]-4-[2,3-di(benzyloxymethyl)cyclobutylamino]-6-chloropyrimidine-2-amine (LVII), which is condensed with 4-chlorophenyldiazonium chloride (XXXV) to afford the azo derivative (LVIII). The reduction of (LVIII) with Zn/acetic acid yields the corresponding 2,5-diaminopyrimidine derivative (LIX), which is cyclized with [14C]-labeled triethyl orthoformate to give [8-14C]-[1R-(1alpha,2beta,3alpha)]-9-[2,3-di(benzyloxymethyl) cyclobutyl]-6-chloropurine-2-amine (LX). The reaction of (LX) with sodium methoxide in methanol yields the corresponding 6-O-methylguanine derivative (LXI), which is debenzylated by hydrogenolysis with H2 over Pd(OH)2 in ethanol/cyclohexane affording [8-14C]-[1R-(1alpha,2beta,3alpha)]-9-[2,3-di(hydroxymethyl)cyclobutyl]-6-O-methylguanine (LXII). Finally, this compound is demethylated with aqueous HCl.
| 【1】 Egli, P.; Rinehart, J.K.; Synthesis of [14C]BMS-180194, an antiviral compound. In: Synthesis and Applications of Isotopically Labelled Compounds 1995, 689-91. |
| 【2】 Ireland, C.; Leeson, P.A.; Castaner, J.; Lobucavir. Drugs Fut 1997, 22, 4, 359. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XXXIII) | 14404 | 4,6-dichloro-2-pyrimidinamine; 2-Amino-4,6-dichloropyrimidine; 4,6-dichloro-2-pyrimidinylamine | 56-05-3 | C4H3Cl2N3 | 详情 | 详情 |
| (XXXV) | 10197 | 4-Chlorobenzenediazonium chloride | C6H4Cl2N2 | 详情 | 详情 | |
| (LVI) | 14426 | (1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutylamine; (1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutanamine | C20H25NO2 | 详情 | 详情 | |
| (LVII) | 14427 | N(4)-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-2,4-pyrimidinediamine; N-(2-amino-6-chloro-4-pyrimidinyl)-N-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]amine | C24H27ClN4O2 | 详情 | 详情 | |
| (LVIII) | 14428 | N-[2-amino-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-4-pyrimidinyl]-N-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]amine; N(4)-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-5-[(E)-2-(4-chlorophenyl)diazenyl]-2,4-pyrimidinediamine | C30H30Cl2N6O2 | 详情 | 详情 | |
| (LIX) | 14429 | N-[(E)-2-amino-1-chloroethylidene]-N''-[([(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]amino)methyl]guanidine | C24H32ClN5O2 | 详情 | 详情 | |
| (LX) | 14430 | 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-9H-purin-2-ylamine; 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-9H-purin-2-amine | C25H26ClN5O2 | 详情 | 详情 | |
| (LX) | 45221 | 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-9H-purin-2-amine; 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-chloro-9H-purin-2-ylamine | C25H26ClN5O2 | 详情 | 详情 | |
| (LXI) | 14431 | 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-methoxy-9H-purin-2-amine; 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-methoxy-9H-purin-2-ylamine | C26H29N5O3 | 详情 | 详情 | |
| (LXI) | 45222 | 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-methoxy-9H-purin-2-amine; 9-[(1R,2R,3S)-2,3-bis[(benzyloxy)methyl]cyclobutyl]-6-methoxy-9H-purin-2-ylamine | C26H29N5O3 | 详情 | 详情 | |
| (LXII) | 14432 | [(1R,2R,4S)-2-(2-amino-6-methoxy-9H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methanol | C12H17N5O3 | 详情 | 详情 | |
| (LXII) | 45223 | [(1R,2R,4S)-2-(2-amino-6-methoxy-9H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methanol | C12H17N5O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(XV)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 |