|
【结 构 式】 
|
【药物名称】Atipamezole, MPV-1248, Antisedan 【化学名称】4-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)imidazole 【CA登记号】104054-27-5 【 分 子 式 】C14H16N2 【 分 子 量 】212.29702 |
【开发单位】Orion Pharma (Originator), US Department of Health & Human Services (Originator) 【药理作用】RENAL-UROLOGIC DRUGS, Treatment of Male Sexual Dysfunction, alpha2-Adrenoceptor Antagonists |
合成路线1
This compound can be obtained in two different ways: 1) The bromination of 1-(2-ethylindan-2-yl)-1-ethanone (I) with Br2 in ether gives 2-bromo-1-(2-ethylindan-2-yl)-1-ethanone (II), which is then cyclized with formamide by heating at 170-80 C. 2) The cyclization of alpha,alpha'-dibromo-o-xylene (III) with 4-penten-2-one (IV) by means of tetrabutylammonium hydroxide in toluene at 100 C gives 1-(2-vinylindan-2-yl)-1-ethanone (V), which is brominated with Br2 in dichloromethane to yield 2-bromo-1-(2-vinylindan-2-yl)-1-ethanone (VI). The cyclization of (VI) with formamide at 160 C as before affords 4-(2-vinylindan-2-yl)-1H-imidazole (VII), which is finally hydrogenated with H2 over Pd/C in ethanol.
| 【1】 Graziano, M.P.; Maxham, C.P.; Malbon, C.C.; Purified rat hepatic beta2-adrenergic receptor: Structural similarities in the rat fat cell beta1-adrenergic receptor. J Biol Chem 1985, 260, 7665-74. |
| 【2】 Karjalainen, A.L.; Karjalainen, A.J. (Orion Pharma); 4(5)-Substd. imidazole derivs., and intermediates and processes for their preparation. EP 0247764; US 4933359 . |
| 【3】 Karjalainen, A.J.; Virtanen, R.E.; Kurkela, K.O.A.; Karjalainen, A. (Orion Pharma); Substd. imidazole derivs. and their preparation and use. AU 8550083; EP 0183492; EP 0310745; ES 8704462; ES 8801248; GB 2167408; JP 1986143366 . |
| 【4】 Prous, J.; Castaner, J.; Atipamezole. Drugs Fut 1990, 15, 5, 448. |
| 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) | 11612 | 1-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H16O | 详情 | 详情 | |
| (II) | 11613 | 2-Bromo-1-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H15BrO | 详情 | 详情 | |
| (III) | 11614 | 1,2-Bis(bromomethyl)benzene; alpha,alpha'-Dibromo-o-xylene | 91-13-4 | C8H8Br2 | 详情 | 详情 |
| (IV) | 11615 | 4-Penten-2-one | C5H8O | 详情 | 详情 | |
| (V) | 11616 | 1-(2-Vinyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H14O | 详情 | 详情 | |
| (VI) | 11617 | 2-Bromo-1-(2-vinyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H13BrO | 详情 | 详情 | |
| (VII) | 11618 | 4-(2-Vinyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole | C14H14N2 | 详情 | 详情 |
合成路线2
A new synthesis of atipamezole has been described: The cyclization of alpha,alpha'-dibromo-o-xylene (I) with acetylacetone (II) by means of NaOH and tetrabutylammonium bromide in toluene/water at 80 C under phase-transfer conditions gives the unstable diacetyl derivative (III), which presumably undergoes cleavage to afford 2-acetylindane (IV). The alkylation of (IV) with ethyl iodide and potassium tert-butoxide yields 2-acetyl-2-ethylindane (V), which is brominated with Br2 to give 2-(bromoacetyl)-2-ethylindane (VI). Finally, this compound is cyclized with formamide at 160 C [some 2-ethyl-2-(4-oxazolyl)indane is also formed but is easily eliminated]; the cyclization can also be carried out with formamidine in liquid ammonia.
| 【1】 Wong, W.C.; Gluchowski, C.; A concise synthesis of atipamezole. Synthesis 1995, 2, 2, 139. |
| 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) | 11619 | 2,2-Bis(bromomethyl)indane | C11H12Br2 | 详情 | 详情 | |
| (II) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (III) | 11621 | 1-(2-Acetyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H14O2 | 详情 | 详情 | |
| (IV) | 11622 | 1-(2,3-Dihydro-1H-inden-2-yl)-1-ethanone | C11H12O | 详情 | 详情 | |
| (V) | 11612 | 1-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H16O | 详情 | 详情 | |
| (VI) | 11613 | 2-Bromo-1-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H15BrO | 详情 | 详情 |
合成路线3
The alkylation of indane-2-carboxylic acid methyl ester (I) with ethyl iodide by means of lithium isopropylcyclohexylamide (LiICA) in THF/DMSO gives the 2-ethyl substituted compound (II), which is hydrolyzed with tBu-OK in DMSO, yielding 2-ethylindane-2-carboxylic acid (III). The reaction of (III) with methanesulfonyl chloride and diazomethane affords the alpha-diazoketone (IV), which is treated with dimethyldioxirane (DMDO) in acetone to provide the ketoaldehyde (V). Finally, this compound is cyclized with 11C-formaldehyde and NH4OH by means of ZnO in THF/water to yield the target labeled imidazole derivative. The intermediate ketoaldehyde (V) has also been obtained in two other ways: a) The alkylation of 2-(diethoxyacetyl)indane (VI) with ethyl iodide by means of tBu-OK in THF gives the corresponding 2-ethyl-substituted compound (VII), which is finally hydrolyzed to the desired ketoaldehyde (V) with HCl in THF/water. b) The oxidation of 2-acetyl-2-ethylindane (VIII) with SeO2 in hot acetic acid/water gives also the desired ketoaldehyde (V).
| 【1】 Roeda, D.; et al.; Synthesis of [11C]atipamezole, a potential PET ligand for the alpha2-adrenergic receptor in the brain. J Label Compd Radiopharm 2002, 45, 1, 37. |
| 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) | 54919 | methyl 2-indanecarboxylate | C11H12O2 | 详情 | 详情 | |
| (II) | 54920 | methyl 2-ethyl-2-indanecarboxylate | C13H16O2 | 详情 | 详情 | |
| (III) | 54921 | 2-ethyl-2-indanecarboxylic acid | C12H14O2 | 详情 | 详情 | |
| (IV) | 54922 | C13H14N2O | 详情 | 详情 | ||
| (V) | 54923 | 2-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-2-oxoacetaldehyde | C13H14O2 | 详情 | 详情 | |
| (VI) | 54924 | 1-(2,3-dihydro-1H-inden-2-yl)-2,2-diethoxy-1-ethanone | C15H20O3 | 详情 | 详情 | |
| (VII) | 54925 | 1-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-2,2-dimethoxy-1-ethanone | C15H20O3 | 详情 | 详情 | |
| (VIII) | 11612 | 1-(2-Ethyl-2,3-dihydro-1H-inden-2-yl)-1-ethanone | C13H16O | 详情 | 详情 |