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【结 构 式】 
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【分子编号】18716 【品名】6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol 【CA登记号】2004-06-0 |
【 分 子 式 】C10H11ClN4O4 【 分 子 量 】286.6746 【元素组成】C 41.9% H 3.87% Cl 12.37% N 19.54% O 22.32% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The esterification of 1H-imidazole-4,5-dicarboxylic acid (I) with EtOH and sulfuric acid gives the diethyl ester (II), which is brominated with NBS in acetonitrile, yielding the 2-bromo derivative (III). The hydrolysis of (III) by means of hot aqueous Na2CO3 affords the 2-bromo-1H-imidazole-4,5-dicarboxylic acid (IV), which is diazocoupled with the labeled diazonium ion (V) to provide the monolabeled azo acid (VI). The reaction of acid (VI) with 15NH4Cl and DEC in acetonitrile gives the doubly labeled azoamide (VII), which is reduced with H2 over Pd/C in methanol to yield the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII). The cyclization of (VIII) with sodium 13C-ethylxanthate (IX) in DMF affords the mercaptoxanthine (X), which is reduced to the hypoxanthine (XI) with Raney Ni and formic acid. The reaction of (XI) with POCl3 in hot N,N-dimethylaniline provides the triply labeled chloropurine (XII), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (PNP) and thymidine phosphorylase (TP) to give the glycosylated chloropurine (XIII). Finally, this compound is treated with 15NH4Cl and KHCO3 in hot anhydrous DMSO to afford the target tetralabeled adenine nucleoside.
| 【1】 Abad, J.-L.; Gaffney B.L.; Jones R.A.; 15N-multilabeled adenine and guanine nucleosides syntheses of [1,3,NH2-15N3]- and [2-13C-1,3NH2-15N3]-labeled adenosine, guanosine , 2'-deoxyadenosine, and 2'-deoxyguanosine. J Org Chem 1999, 64, 18, 6575. |
| 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) | 31951 | 1H-imidazole-4,5-dicarboxylic acid | 570-22-9 | C5H4N2O4 | 详情 | 详情 |
| (II) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (III) | 51896 | diethyl 2-bromo-1H-imidazole-4,5-dicarboxylate | C9H11BrN2O4 | 详情 | 详情 | |
| (IV) | 51897 | 2-bromo-1H-imidazole-4,5-dicarboxylic acid | C5H3BrN2O4 | 详情 | 详情 | |
| (V) | 51898 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (V) | 51907 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (VI) | 51899 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VI) | 51908 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VII) | 51900 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VII) | 51909 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VIII) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (VIII) | 51901 | 5-amino-1H-imidazole-4-carboxamide | C4H6N4O | 详情 | 详情 | |
| (IX) | 51902 | C3H5NaOS2 | 详情 | 详情 | ||
| (IX) | 51910 | C3H5NaOS2 | 详情 | 详情 | ||
| (X) | 51903 | C5H3N4NaOS | 详情 | 详情 | ||
| (X) | 51911 | C5H3N4NaOS | 详情 | 详情 | ||
| (XI) | 51904 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XI) | 51912 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XII) | 51905 | 6-chloro-9H-purine | C5H3ClN4 | 详情 | 详情 | |
| (XIII) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (XIII) | 51906 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11ClN4O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIII)The esterification of 1H-imidazole-4,5-dicarboxylic acid (I) with EtOH and sulfuric acid gives the diethyl ester (II), which is brominated with NBS in acetonitrile, yielding the 2-bromo derivative (III). The hydrolysis of (III) by means of hot aqueous Na2CO3 affords the 2-bromo-1H-imidazole-4,5-dicarboxylic acid (IV), which is diazocoupled with the labeled diazonium ion (V) to provide the monolabeled azo acid (VI). The reaction of acid (VI) with 15NH4Cl and DEC in acetonitrile gives the doubly labeled azoamide (VII), which is reduced with H2 over Pd/C in methanol to yield the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII). The cyclization of (VIII) with sodium ethylxanthate (IX) in DMF affords the mercaptoxanthine (X), which is reduced to the hypoxanthine (XI) with Raney Ni and formic acid. The reaction of (XI) with POCl3 in hot N,N-dimethylaniline provides the doubly labeled chloropurine (XII), which is submitted to enzymatic trans-glycosylation with 7-methylguanosine or thymidine and purine nucleoside phosphorylase (PNP) and thymidine phosphorylase (TP) to give the glycosylated chloropurine (XIII). Finally, this compound is treated with 15NH4Cl and KHCO3 in hot anhydrous DMSO to afford the target triply labeled adenine nucleoside. Alternatively, the intermediate hypoxanthine (XI) can also be obtained directly by cyclization of the doubly labeled 5-amino-1H-imidazole-4-carboxamide (VIII) with formic acid and diethoxymethyl acetate (DEMA) in DMF.
| 【1】 Abad, J.-L.; Gaffney B.L.; Jones R.A.; 15N-multilabeled adenine and guanine nucleosides syntheses of [1,3,NH2-15N3]- and [2-13C-1,3NH2-15N3]-labeled adenosine, guanosine , 2'-deoxyadenosine, and 2'-deoxyguanosine. J Org Chem 1999, 64, 18, 6575. |
| 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) | 31951 | 1H-imidazole-4,5-dicarboxylic acid | 570-22-9 | C5H4N2O4 | 详情 | 详情 |
| (II) | 27424 | 3-(1-trityl-1H-imidazol-4-yl)-1-propanol | C25H24N2O | 详情 | 详情 | |
| (III) | 51896 | diethyl 2-bromo-1H-imidazole-4,5-dicarboxylate | C9H11BrN2O4 | 详情 | 详情 | |
| (IV) | 51897 | 2-bromo-1H-imidazole-4,5-dicarboxylic acid | C5H3BrN2O4 | 详情 | 详情 | |
| (V) | 51898 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (V) | 51907 | 4-bromobenzenediazonium | C6H4BrN2 | 详情 | 详情 | |
| (VI) | 51899 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VI) | 51908 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxylic acid | C10H7BrN4O2 | 详情 | 详情 | |
| (VII) | 51900 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VII) | 51909 | 2-bromo-5-[(E)-2-phenyldiazenyl]-1H-imidazole-4-carboxamide | C10H8BrN5O | 详情 | 详情 | |
| (VIII) | 11015 | 5-Amino-1H-imidazole-4-carboxamide | 360-97-4 | C4H6N4O | 详情 | 详情 |
| (VIII) | 51901 | 5-amino-1H-imidazole-4-carboxamide | C4H6N4O | 详情 | 详情 | |
| (IX) | 51910 | C3H5NaOS2 | 详情 | 详情 | ||
| (X) | 51911 | C5H3N4NaOS | 详情 | 详情 | ||
| (X) | 51913 | C5H3N4NaOS | 详情 | 详情 | ||
| (XI) | 51912 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XI) | 51914 | 1,9-dihydro-6H-purin-6-one | C5H4N4O | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XII) | 51915 | 6-chloro-9H-purine | C5H3ClN4 | 详情 | 详情 | |
| (XIII) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (XIII) | 51916 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H11ClN4O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)A new synthesis of lodenosine has been described: The selective benzoylation of the 6-chloropurine riboside (I) with benzoyl chloride and triethylamine through the formation of a complex with dibutyl tin oxide, gives the 3'-O-benzoyl derivative (II), which is purified by crystallization (minor impurities, about 3%, of the 2'-O derivative are present). The protection of the primary OH group of (II) by reaction with trityl chloride, DMAP and Et3N in DMF yields the 5'-O-trityl derivative (III), which is treated with DAST and pyridine to afford the fluorinated arabinofuranoside (IV). The reaction of (IV) with ammonia in methanol displaces the 6-Cl atom and hydrolyzes the 3'-O-benzoyl group giving the fluorinated arabinofuranosyladenine (V). The reaction of (V) with phenyl chlorothionoformate and DMAP in acetonitrile yields the thiocarbonate (VI), which is treated with tris(trimethylsilyl)silane and AIBN in hot toluene to afford the 3'-deoxy compound (VII). Finally, this compound is deprotected by reaction with HCl in methanol/water.
| 【1】 Izawa, K.; Satoh, Y.; Takamatsu, S.; Kozai, S.; Maruyama, T.; Synthesis of 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine bearing selectively removable protecting group. Chem Pharm Bull 1999, 47, 7, 966. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 | |
| (I) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 29871 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-(hydroxymethyl)tetrahydro-3-furanyl benzoate | C17H15ClN4O5 | 详情 | 详情 | |
| (III) | 29872 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H29ClN4O5 | 详情 | 详情 | |
| (IV) | 29873 | (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H28ClFN4O4 | 详情 | 详情 | |
| (V) | 29874 | (2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanol | C29H26FN5O3 | 详情 | 详情 | |
| (VI) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (VII) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)An improved synthesis of lodenosine has been reported: The reaction of the chloropurine derivative (I) with trityl chloride and diisopropylamine in DMF gives the 5'-O-trityl-purine (II), which is treated with benzoyl chloride and pyridine in toluene to afford the 3'-O-benzoyl-5'-O-trityl-purine (III) -- some of the 2'-O-benzyl regioisomer is also isolated and is recycled after acyl migration by reaction with TEA. The reaction of purine (III) with trifluoromethanesulfonyl chloride and DMAP in toluene yields the 3'-O-benzoyl-2'-O-sulfonyl-5'-O-trityl-purine (IV), which is treated with HF and TEA to provide the 2'-beta-fluoro-purine (V). The reaction of compound (V) with ammonia in methanol gives the adenosine derivative (VI), which is treated with O-phenyl chlorothioformate and DMAP in pyridine to yield the thiocarbonate (VIII). The deoxygenation of (VIII) is performed with diphenylsilane and AIBN affording 5'-O-trityl-lodenosine (IX), which is finally deprotected with 80% HOAc.
| 【1】 Katayama, S.; Hirose, N.; Izawa, K.; Takamatsu, S.; Maruyama, T.; Improved synthesis of 9-(2,3-dideoxy-2-fluoro-beta-D-threo-pentofuranosyl)adenine (FddA) using triethylamine trihydrofluoride. Tetrahedron Lett 2001, 42, 12, 2321. |
| 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) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 48718 | (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-[(trityloxy)methyl]tetrahydro-3,4-furandiol | C29H25ClN4O4 | 详情 | 详情 | |
| (III) | 29872 | (2R,3S,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-hydroxy-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H29ClN4O5 | 详情 | 详情 | |
| (IV) | 48719 | (2R,3R,4R,5R)-5-(6-chloro-9H-purin-9-yl)-4-[[(trifluoromethyl)sulfonyl]oxy]-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C37H28ClF3N4O7S | 详情 | 详情 | |
| (V) | 29873 | (2R,3R,4S,5R)-5-(6-chloro-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl benzoate | C36H28ClFN4O4 | 详情 | 详情 | |
| (VI) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (VII) | 25805 | 1-[(chlorocarbothioyl)oxy]benzene; Phenylchlorothioformate | 1005-56-7 | C7H5ClOS | 详情 | 详情 |
| (VIII) | 29875 | O-[(2R,3R,4S,5R)-5-(6-amino-9H-purin-9-yl)-4-fluoro-2-[(trityloxy)methyl]tetrahydro-3-furanyl] O-phenyl carbonothioate | C36H30FN5O4S | 详情 | 详情 | |
| (IX) | 29876 | 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-ylamine; 9-[(2R,3S,5S)-3-fluoro-5-[(trityloxy)methyl]tetrahydro-2-furanyl]-9H-purin-6-amine | C29H26FN5O2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)This compound has been obtained by two similar ways: 1) By condensation of the chloropurine (I) with (1S-trans)-2-aminocyclopentanol (1S-trans)-(II) by means of DEA in refluxing isopropanol. 2) The condensation of chloropurine (I) with (rac-trans)-2-aminocyclopentanol (rac-trans)-(II) (obtained by reaction of cyclopentene oxide (III) with ammonia) give a diastereomeric mixture, from which the target compound can be isolated by flash chromatography.
| 【1】 Evans, B. (Glaxo Wellcome plc); Adenosine derivs.. AU 8827401; BE 1002167; CH 677495; DE 3843609; EP 0322242; FR 2663936; US 5032583 . |
| 【2】 Knutsen, L.J.S.; Lau, J. (Novo Nordisk A/S); Purine derivs.. US 5672588 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (1S-trans)-(II) | 38010 | (1S,2S)-2-aminocyclopentanol | C5H11NO | 详情 | 详情 | |
| (rac)-(II) | 63649 | 2-aminocyclopentanol | C5H11NO | 详情 | 详情 | |
| (I) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (III) | 38011 | 6-oxabicyclo[3.1.0]hexane | 285-67-6 | C5H8O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The condensation of the ribosyl chloropurine (I) with (rac-trans)-2-amino-3-cyclopentenol (II) by means of NaHCO3 in isopropanol gives a diastereomeric mixture of adenosine derivatives (III) + (IV) that is separated by HPLC. The desired isomer (III) is acetylated with Ac2O and pyridine yielding the tetraacetate (V), which is hydrogenated with tritium over Pt in THF to afford the tetraacetate (VI) of the target compound. Finally, (VI) is deacetylated by means of t-BuNH2 in methanol.
| 【1】 Wadsworth, A.H.; et al.; Synthesis of isotopically labelled versions of adenosine agonist GR79236. J Label Compd Radiopharm 2000, 43, 1, 11. |
| 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) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 38017 | (1S,2S)-2-amino-3-cyclopenten-1-ol | C5H9NO | 详情 | 详情 | |
| (III) | 38019 | (2R,3R,4S,5R)-2-(6-[[(1S,5S)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C15H19N5O5 | 详情 | 详情 | |
| (IV) | 38020 | (2R,3R,4S,5R)-2-(6-[[(1R,5R)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C15H19N5O5 | 详情 | 详情 | |
| (V) | 38021 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,5S)-5-hydroxy-2-cyclopenten-1-yl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C21H25N5O8 | 详情 | 详情 | |
| (VI) | 38018 | (2R,3R,4R,5R)-4-(acetoxy)-2-[(acetoxy)methyl]-5-(6-[[(1S,2S)-2-hydroxycyclopentyl]amino]-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C21H27N5O8 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(IX)The reaction of 3-tetrahydrofuroic acid (I) with diphenyl phosphoryl azide (DPPA) in refluxing dioxane gave the intermediate isocyanate (II), which was treated with benzyl alcohol (III) to yield carbamate (IV). Subsequent hydrogenolysis in the presence of Pd/C afforded racemic amine (V), which was resolved by treatment with S-(+)-10-camphorsulfonyl chloride (VI) in pyridine, followed by column chromatography and recrystallization from acetone of the resulting sulfonamide (VII). Then, hydrolysis in HCl-AcOH provided the S-amine (VIII). Condensation of amine (VIII) with 6-chloropurine riboside (IX) in the presence of triethylamine in refluxing MeOH furnished the title compound.
| 【1】 Sorbera, L.A.; Bayes, M.; Castañer, J.; Martín, L.; Tecadenoson. Drugs Fut 2002, 27, 9, 846. |
| 【2】 Lum, R.T.; Pfister, J.R.; Schow, S.R.; Wick, M.M.; Nelson, M.G.; Schreiner, G.F. (CV Therapeutics, Inc.); N6 Heterocyclic substd. adenosine derivs.. EP 0920438; EP 0992510; JP 2000501426; US 5789416; WO 9808855 . |
| 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) | 18708 | tetrahydro-3-furancarboxylic acid | 89364-31-8 | C5H8O3 | 详情 | 详情 |
| (II) | 18709 | tetrahydro-3-furanyl isocyanate; 3-isocyanatotetrahydrofuran | C5H7NO2 | 详情 | 详情 | |
| (III) | 18710 | Benzyl alcohol; Phenylmethanol | 100-51-6 | C7H8O | 详情 | 详情 |
| (IV) | 18711 | benzyl tetrahydro-3-furanylcarbamate | C12H15NO3 | 详情 | 详情 | |
| (V) | 18712 | tetrahydro-3-furanylamine; tetrahydro-3-furanamine | C4H9NO | 详情 | 详情 | |
| (VI) | 18713 | (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonyl chloride | C10H15ClO3S | 详情 | 详情 | |
| (VII) | 18714 | (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)-N-[(3S)tetrahydro-3-furanyl]methanesulfonamide | C14H23NO4S | 详情 | 详情 | |
| (VIII) | 18715 | (3S)tetrahydro-3-furanamine; (3S)tetrahydro-3-furanylamine | C4H9NO | 详情 | 详情 | |
| (IX) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The reaction of the chloropurine (I) with tetrahydrofuran-2(R)-amine (II) gives N6-(furan-2(R)-yl)adenosine (III), which is treated with 2,2-dimethoxypropane and Ts-OH in hot DMF to yield N6-(furan-2-(R)-yl)-2'O,3'O-isopropylideneadenosine (IV). The reaction of (IV) with CDI and methylamine in THF affords N6-(furan-2-(R)-yl)-2'O,3'O-isopropylidene-5'O-(N-methylcarbamoyl)adenosine (V), which is finally deprotected with HOAc in hot water to provide the target adenosine derivative.
| 【1】 Palle, V.P.; et al.; A1 adenosine receptor agonist- SAR of 5'-carbamates and 5'-thionocarbamates of N6-substituted adenosine derivatives. 223rd ACS Natl Meet (April 7 2002, Orlando) 2002, Abst MEDI 23. |
| 【2】 Belardinelli, L.; Zablocki, J.A.; Palle, V.P.; Ibrahim, P.N.; Varkhedkar, V. (CV Therapeutics, Inc.); N6 Heterocylic 5' modified adenosine derivs.. US 6258793; WO 0140244; WO 0140245 . |
| 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) | 18716 | 6-chloropurine riboside; (2R,3R,4S,5R)-2-(6-chloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | 2004-06-0 | C10H11ClN4O4 | 详情 | 详情 |
| (II) | 53578 | (3R)-tetrahydro-3-furanamine; (3R)-tetrahydro-3-furanylamine | n/a | C4H9NO | 详情 | 详情 |
| (III) | 53575 | (2R,3S,4R,5R)-2-(hydroxymethyl)-5-{6-[(3R)tetrahydro-3-furanylamino]-9H-purin-9-yl}tetrahydro-3,4-furandiol | n/a | C14H19N5O5 | 详情 | 详情 |
| (IV) | 53576 | ((3aR,4R,6R,6aS)-2,2-dimethyl-6-{6-[(3R)tetrahydro-3-furanylamino]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methanol | n/a | C17H23N5O5 | 详情 | 详情 |
| (V) | 53577 | ((3aR,4R,6R,6aS)-2,2-dimethyl-6-{6-[(3R)tetrahydro-3-furanylamino]-9H-purin-9-yl}tetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methyl methylcarbamate | n/a | C19H26N6O6 | 详情 | 详情 |