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【结 构 式】 
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【药物名称】CV-1808 【化学名称】2-Anilinoadenosine 【CA登记号】53296-10-9, 53296-11-0 (HCl) 【 分 子 式 】C16H18N6O4 【 分 子 量 】358.35966 |
【开发单位】Takeda (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Vasodilators |
合成路线1
The reaction of guanosine-2',3',5'-triacetate (I) with amyl nitrite and bromoform at 90 C gives 2-bromoinosine-2',3',5'-triacetate (II), which is condensed with aniline (III) in refluxing methanol to afford N-phenylguanosine-2',3',5'-triacetate (IV). The reaction of (IV) with POCl3 and N,N-dimethylaniline in refluxing acetonitrile gives 6-chloro-N-phenyl-9-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-9H-purine-2-amine (V), which is finally treated with ammonia in methanol to give CV-1808.
| 【1】 Trivedi, B.K.; Studies toward synthesis of C2-substituted adenosines: An efficient synthesis of 2-(phenylamino)adenosine [CV-1808]. Nucleosides Nucleotides 1988, 7, 3, 393. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20827 | 1-nitrosopentane | C5H11NO | 详情 | 详情 | |
| (I) | 20822 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H19N5O8 | 详情 | 详情 | |
| (II) | 20823 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-bromo-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C16H17BrN4O8 | 详情 | 详情 | |
| (III) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (IV) | 20825 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-anilino-6-oxo-1,6-dihydro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C22H23N5O8 | 详情 | 详情 | |
| (V) | 20826 | 4-(acetoxy)-2-[(acetoxy)methyl]-5-(2-anilino-6-chloro-9H-purin-9-yl)tetrahydro-3-furanyl acetate | C22H22ClN5O7 | 详情 | 详情 |
合成路线2
This compound can be obtained in two different ways: 1) The acylation of 5-amino-1-beta-D-ribofuranosylimidazole-4-carboxamide (I) with propionic anhydride (A) in pyridine gives the corresponding tri-O-propionyl derivative (II), which by treatment with POCl3 and triethylamine in CHCl3 is converted into 5-amino-4-cyano-1-(2,3,5-tri-O-propionyl-beta-D-ribofuranosyl)imidazole (III). The hydrolysis of (III) with methanolic ammonia yields 5-amino-4-cyano-1-beta-D-ribofuranosylimidazole (IV), which is finally cyclized with phenylcyanamide (V) in methanolic ammonia at 180 C in a pressure vessel. This cyclization can also be performed with (III) and (V) directly, using the same procedure. 2) By reaction of 2-bromoadenosine (VI) with aniline (VII) in 2-methoxyethanol at 120 C.
| 【1】 Marumoto, R.; et al.; Synthesis and coronary vasodilating activity of 2-substituted adenosines. Chem Pharm Bull 1975, 23, 4, 759-774. |
| 【2】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); 2,6-Diaminonebularine derivs.. US 3936439 . |
| 【3】 Marumoto, R.; et al. (Takeda Chemical Industries, Ltd.); Production of 2,6-diaminonebularines. DE 2845435 . |
| 【4】 Castaner, J.; Serradell, M.N.; Blancafort, P.; Thorpe, P.J.; CV-1808. Drugs Fut 1981, 6, 4, 222. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 20095 | propionic anhydride | 123-62-6 | C6H10O3 | 详情 | 详情 |
| (I) | 37427 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carboxamide | C9H14N4O5 | 详情 | 详情 | |
| (II) | 37428 | [(2R,3R,4R,5R)-5-[5-amino-4-(aminocarbonyl)-1H-imidazol-1-yl]-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H26N4O8 | 详情 | 详情 | |
| (III) | 37429 | [(2R,3R,4R,5R)-5-(5-amino-4-cyano-1H-imidazol-1-yl)-3,4-bis(propionyloxy)tetrahydro-2-furanyl]methyl propionate | C18H24N4O7 | 详情 | 详情 | |
| (IV) | 37430 | 5-amino-1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-1H-imidazole-4-carbonitrile | C9H12N4O4 | 详情 | 详情 | |
| (V) | 37431 | phenylcyanamide | C7H6N2 | 详情 | 详情 | |
| (VI) | 37432 | (2R,3R,4S,5R)-2-(6-amino-2-bromo-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydro-3,4-furandiol | C10H12BrN5O4 | 详情 | 详情 | |
| (VII) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |