|
【结 构 式】 
|
【分子编号】12043 【品名】1-(4-Fluorobenzyl-2-chlorobenzimidazol; 2-Chloro-1-(4-fluorobenzyl)-1H-benzimidazole; 1-(4-Fluorobenzyl)-2-chlorobenzimidazole 【CA登记号】84946-20-3 |
【 分 子 式 】C14H10ClFN2 【 分 子 量 】260.6979832 【元素组成】C 64.5% H 3.87% Cl 13.6% F 7.29% N 10.75% |
合成路线1
该中间体在本合成路线中的序号：(I)Mizolastine can be obtained by two related ways: 1) The condensation of 2-chloro-1-(4-fluorobenzyl)benzimidazole (I) with N-(4-piperidyl)carbamic acid ethyl ester (II) by means of NaOCH3 at 14 C gives N-[1-[1-(4-fluorobenzyl)benzimidazol-2-yl]piperidin-4-yl]carbamic acid ethyl ester (III), which is methylated with methyl iodide and NaH in DMF to yield the corresponding N-methyl derivative (IV). The decarboxylative hydrolysis of (IV) with 48% HBr in acetic acid affords N-[1-[1-(4-fluorobenzyl)benzimidazol-2-yl]piperidin-4-yl]-N-methylamine (V), which is finally condensed with 2-(methylsulfanyl)pyrimidin-4(3H)-one (VI) by heating at 170 C. 2) Compound (V) can also be obtained by direct condensation of 2-chloro-1-(4-fluorobenzyl)benzimidazole (I) with 4-(methylamino)piperidine (VII) by means of K2CO3 in refluxing isoamyl alcohol.
| 【1】 Mealy, N.; Ngo, J.; Castaner, J.; Mizolastine. Drugs Fut 1996, 21, 8, 799. |
| 【2】 Manoury, P.; Binet, J.; Defosse, G. (Sanofi-Synthelabo ); EP 217700, FR 2587029, JP 87061979, US 4820710. EP 0217700; FR 2587029; JP 1987061979; US 4820710 . |
| 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) | 12044 | ethyl N-(4-piperidinyl)carbamate | C8H16N2O2 | 详情 | 详情 | |
| (III) | 12045 | ethyl N-[1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]carbamate | C22H25FN4O2 | 详情 | 详情 | |
| (IV) | 12046 | ethyl N-[1-[1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methylcarbamate | C23H27FN4O2 | 详情 | 详情 | |
| (V) | 12047 | 1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-N-methyl-4-piperidinamine; N-[1-[1-(4-Fluorobenzyl)-1H-benzimidazol-2-yl]-4-piperidinyl]-N-methylamine | C20H23FN4 | 详情 | 详情 | |
| (VI) | 12048 | 2-(Methylsulfanyl)-4(3H)-pyrimidinone | C5H6N2OS | 详情 | 详情 | |
| (VII) | 12049 | N-Methyl-N-(4-piperidinyl)amine; N-Methyl-4-piperidinamine | C6H14N2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)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3
该中间体在本合成路线中的序号：(I)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4
该中间体在本合成路线中的序号：(I)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 |