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【结 构 式】 
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【分子编号】32565 【品名】(2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate 【CA登记号】 |
【 分 子 式 】C31H22Cl2N4O7 【 分 子 量 】633.44384 【元素组成】C 58.78% H 3.5% Cl 11.19% N 8.84% O 17.68% |
合成路线1
该中间体在本合成路线中的序号：(VII)4-Hydroxypiperidine (I) was protected as the tert-butyl carbamate (II) upon treatment with (Boc)2O. Subsequent Mitsunobu coupling of (II) with diphenyl disulfide using tributylphosphine and diethyl azodicarboxylate afforded thioether (III). Acid deprotection of the Boc group of (III), followed by nitrosation of the resulting amine (IV) gave N-nitrosopiperidine (V). Further reduction of (V) with LiAlH4 yielded hydrazine (VI). Condensation of (VI) with dichloropurine derivative (VII) produced piperidinyladenosine (VIII). Debenzoylation of the tribenzoate ester (VIII) with methanolic ammonia gave (IX). Then, chlorination at position 5' with concomitant formation of the 2',3' cyclic sulfite (X) by reaction with thionyl chloride and pyridine was followed by sulfite hydrolysis with methanolic ammonia to yield the title compound.
| 【1】 Lau, J.; Judge, M.E.; Sheardown, M.J.; Petersen, H.; Shalmi, M.; Knutsen, L.J.S.; Hansen, A.J.; Thomsen, C.; Weis, J.U.; N-substituted adenosines as novel neuroprotective A1 agonists with diminished hypotensive effects. J Med Chem 1999, 42, 18, 3463. |
| 【2】 Lau, J.; Knutsen, L.J.S. (Novo Nordisk A/S); Chemical cpds., their preparation and use. EP 0719275; JP 1999511436; US 5589467; WO 9507921 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17473 | diphenyl disulfide; 1-(phenyldisulfanyl)benzene; diphenyldisulfide | 882-33-7 | C12H10S2 | 详情 | 详情 | |
| (I) | 12076 | 4-Piperidinol; 4-Hydroxypiperidine | 5382-16-1 | C5H11NO | 详情 | 详情 |
| (II) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (III) | 32561 | tert-butyl 4-(phenylsulfanyl)-1-piperidinecarboxylate | C16H23NO2S | 详情 | 详情 | |
| (IV) | 32562 | 4-(phenylsulfanyl)piperidine; phenyl 4-piperidinyl sulfide | C11H15NS | 详情 | 详情 | |
| (V) | 32563 | 1-nitroso-4-piperidinyl phenyl sulfide; 1-nitroso-4-(phenylsulfanyl)piperidine | C11H14N2OS | 详情 | 详情 | |
| (VI) | 32564 | 4-(phenylsulfanyl)-1-piperidinamine; 4-(phenylsulfanyl)-1-piperidinylamine | C11H16N2S | 详情 | 详情 | |
| (VII) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (VIII) | 32568 | [(2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2-furanyl]methyl benzoate | C42H37ClN6O7S | 详情 | 详情 | |
| (IX) | 32566 | (2R,3R,4S,5R)-2-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C21H25ClN6O4S | 详情 | 详情 | |
| (X) | 32567 | (3aR,4S,6R,6aR)-4-(chloromethyl)-6-(2-chloro-6-[[4-(phenylsulfanyl)-1-piperidinyl]amino]-9H-purin-9-yl)tetrahydro-2lambda(4)-furo[3,4-d][1,3,2]dioxathiol-2-one | C21H22Cl2N6O4S2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)Alternatively, condensation of 2,6-dichloropurine (VIII) with protected ribose (IX) at 140 C gave the ribofuranosyl purine (X). Subsequent displacement of the 6-chloro of (V) by amine (V), followed by hydrolysis of the benzoate esters afforded the intermediate (VII).
| 【1】 Gregson, M.; Ayres, B.E.; Ewan, G.B.; Ellis, F.; Knight, J. (Glaxo Wellcome plc); 2,6-Diaminopurine derivs.. EP 0680488; JP 1996505864; US 5925624; WO 9417090 . |
| 【2】 Keeling, S.E.; et al.; The discovery and synthesis of highly potent, A2A receptor agonists. Bioorg Med Chem Lett 2000, 10, 4, 403. |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (IX) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (X) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (XI) | 38962 | 2,2-diphenylethylamine; 2,2-diphenyl-1-ethanamine | 3963-62-0 | C14H15N | 详情 | 详情 |
| (XII) | 38963 | ((2R,3R,4R,5R)-3,4-bis(benzoyloxy)-5-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]tetrahydro-2-furanyl)methyl benzoate | C45H36ClN5O7 | 详情 | 详情 | |
| (XIII) | 38961 | (2R,3R,4S,5R)-2-[2-chloro-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl]-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C24H24ClN5O4 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)
| 【1】 Schaeffer HJ, Thomas HJ. 1958. Synthesis of potential anticancer agents XIV. Ribosides of 2,6-disubstituted purines. J Am Chem Soc, 80: 3738～3741. |
| 【2】 Zablocki J, Elzein E. 2007. Process for preparaing an A2A-adenosine receptor agonist and its polymorphs. WO 2007/092372A1 (CV Therapeutics Inc). |
| 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) | 25254 | 2,6-dichloro-9H-purine | 5451-40-1 | C5H2Cl2N4 | 详情 | 详情 |
| (III) | 67380 | (2R,3R,4R,5R)-2-acetoxy-5-((benzoyloxy)methyl)tetrahydrofuran-3,4-diyl dibenzoate | 14215-97-5 | C28H24O9 | 详情 | 详情 |
| (IV) | 67381 | (2R,3R,4R,5R)-2-((benzoyloxy)methyl)-5-chlorotetrahydrofuran-3,4-diyl dibenzoate | C26H21ClO7 | 详情 | 详情 | |
| (V) | 32565 | (2R,3R,4R,5R)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]-5-(2,6-dichloro-9H-purin-9-yl)tetrahydro-3-furanyl benzoate | C31H22Cl2N4O7 | 详情 | 详情 | |
| (VI) | 67382 | (3R,4R,5R)-2-(2,6-dichloro-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3,4-diol | 13276-52-3 | C10H10Cl2N4O4 | 详情 | 详情 |
| (VII) | 54960 | (2R,3R,4S,5R)-2-(6-amino-2-hydrazino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H15N7O4 | 详情 | 详情 | |
| (VIII) | 67383 | ethyl 1-(9-((3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-6-(((E)-3-ethoxy-2-formyl-3-oxoprop-1-en-1-yl)amino)-9H-purin-2-yl)-1H-pyrazole-4-carboxylate | C22H25N7O9 | 详情 | 详情 |