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【结 构 式】 
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【药物名称】NNC-21-0147 【化学名称】5'-Deoxy-2,5'-dichloro-N-[4-(phenylsulfanyl)-1-piperidinyl]adenosine 【CA登记号】169190-51-6 【 分 子 式 】C21H24Cl2N6O3S 【 分 子 量 】511.43383 |
【开发单位】Novo Nordisk (Originator) 【药理作用】Cerebrovascular Diseases, Treatment of, Ischemic Stroke, Treatment of, NEUROLOGIC DRUGS, Stroke, Treatment of, Adenosine A1 Agonists |
合成路线1
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 |