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【结 构 式】 
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【药物名称】Tecastemizole, Norastemizole, Soltara 【化学名称】1-(4-Fluorobenzyl)-2-(piperidin-4-ylamino)-1H-benzimidazole 【CA登记号】75970-99-9, 75970-64-8 (diHBr salt) 【 分 子 式 】C19H21FN4 【 分 子 量 】324.40442 |
【开发单位】Sepracor (Originator) 【药理作用】Drugs for Allergic Rhinitis, RESPIRATORY DRUGS, Treatment of Upper Respiratory Tract Disorders, Histamine H1 Antagonists |
合成路线1
Norastemizole can be obtained in the following way as shown in scheme: The synthesis is carried out by mild and selective palladium coupling of readily available 1-(4-fluorobenzyl)- 2-chlorobenzimidazole (I) with 4-aminopiperidine dihydrochloride (II) to obtain norastemizole in 84% isolated yield. The synthesis is highly selective and involves a one-step process.
| 【1】 Xiang, T.; Hong, Y.; Wald, S.A.; Tanoury, T.; Senanayake, C.H.; Vandenbossche, C.P.; Bakale, R.P.; Remarkably Selective Palladium-Catalyzed Amination Process: Rapid Assembly of Multiamino Based Structures. Tetrahedron Lett 1998, 39, 3121-4. |
| 【2】 Wald, S.A.; Hong, Y.; Wilkinson, H.S.; Senanayake, C.H.; Tanoury, G.J.; Bakale, R.P.; Palladium catalyzed amination of 2-chloro-1,3-azole derivatives: Mild entry to potent H1-antihistaminic norastemizole. Tetrahedron Lett 1997, 38, 5607-10. |
| 【3】 Senanayake, C.; Hong, Y.; Bakale, R.; Handley, D.A.; Norastemizole. Drugs Fut 1998, 23, 9, 966. |
合成路线2
The condensation of 2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole (I) with methoxymethyl bromide (II) in toluene gives the benzimidazolium bromide (III), which is condensed with 4-aminopiperidine-1-carboxylic acid ethyl ester (IV) in hot toluene to yield the adduct (V). Finally, this compound is treated first with BBr3 in dichloromethane and then with HBr or HCl at 110 C to provide the target Norastemizole.
| 【1】 Hong, Y.; Senanayake, C.H.; Bakale, R.P. (Sepracor Inc.); Methods for synthesizing 2-substd. imidazoles. EP 0977740; JP 2001520658; US 5817823; WO 9846571 . |
| 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) | 12043 | 1-(4-Fluorobenzyl-2-chlorobenzimidazol; 2-Chloro-1-(4-fluorobenzyl)-1H-benzimidazole; 1-(4-Fluorobenzyl)-2-chlorobenzimidazole | 84946-20-3 | C14H10ClFN2 | 详情 | 详情 |
| (II) | 19619 | bromo(methoxy)methane; bromomethyl methyl ether | 13057-17-5 | C2H5BrO | 详情 | 详情 |
| (III) | 61777 | 2-chloro-3-(4-fluorobenzyl)-1-(methoxymethyl)-3H-benzimidazol-1-ium | C16H15ClFN2O | 详情 | 详情 | |
| (IV) | 61778 | propyl 4-amino-1-piperidinecarboxylate | C9H18N2O2 | 详情 | 详情 | |
| (V) | 61779 | 3-(4-fluorobenzyl)-1-(methoxymethyl)-2-{[1-(propoxycarbonyl)-4-piperidinyl]amino}-3H-benzimidazol-1-ium bromide | C25H32BrFN4O3 | 详情 | 详情 |
合成路线3
The condensation of 2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole (I) with 2-methoxyethoxymethyl bromide (II) in toluene gives the benzimidazolium bromide (III), which is condensed with 1-acetyl-4-aminopiperidine (IV) in hot toluene to yield the adduct (V). Finally, this compound is treated first with BBr3 in dichloromethane and then with HBr or HCl at 110 C to provide the target Norastemizole.
| 【1】 Hong, Y.; Senanayake, C.H.; Bakale, R.P. (Sepracor Inc.); Methods for synthesizing 2-substd. imidazoles. EP 0977740; JP 2001520658; US 5817823; WO 9846571 . |
| 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) | 12043 | 1-(4-Fluorobenzyl-2-chlorobenzimidazol; 2-Chloro-1-(4-fluorobenzyl)-1H-benzimidazole; 1-(4-Fluorobenzyl)-2-chlorobenzimidazole | 84946-20-3 | C14H10ClFN2 | 详情 | 详情 |
| (II) | 61780 | 1-(bromomethoxy)-2-methoxyethane; 2-(bromomethoxy)ethyl methyl ether | C4H9BrO2 | 详情 | 详情 | |
| (III) | 61781 | 2-chloro-3-(4-fluorobenzyl)-1-[(2-methoxyethoxy)methyl]-3H-benzimidazol-1-ium bromide | C18H19BrClFN2O2 | 详情 | 详情 | |
| (IV) | 61782 | 1-(4-amino-1-piperidinyl)-1-ethanone | C7H14N2O | 详情 | 详情 | |
| (V) | 61783 | 2-[(1-acetyl-4-piperidinyl)amino]-3-(4-fluorobenzyl)-1-[(2-methoxyethoxy)methyl]-3H-benzimidazol-1-ium bromide | C25H32BrFN4O3 | 详情 | 详情 |