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【结 构 式】 
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【药物名称】Ketoconazole, R-41400, Sebazole, Extina, Panfungol, Ketoderm, Nizoral 【化学名称】cis-1-Acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxy]phenyl]piperazine 【CA登记号】65277-42-1 【 分 子 式 】C26H28Cl2N4O4 【 分 子 量 】531.44346 |
【开发单位】Janssen (Originator), Barrier Therapeutics (Not Determined), Esteve (Licensee), Connetics (Formulation) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, DERMATOLOGIC DRUGS, Antiestrogens, Aromatase Inhibitors |
合成路线1
The cyclization of 2,4-dichlorophenacyl bromide (I) with glycerol (II) gives cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-hydroxymethyl-1,3-dioxolane (III), which is then benzoylated with benzoyl chloride (A) yielding cis-2-(2,4-dichlorophenyl)-2-bromomethyl-4-benzoyloxymethyl-1,3-dioxolane (IV). The condensation of (IV) with 1H-imidazole (V) affords cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-benzoyloxymethyl-1,3-dioxolane (VI), which is then debenzoylated in basic medium giving cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-4-hydroxymethyl-1,3-dioxolane (VII). The reaction of (VII) with methanesulfonyl chloride (B) yields cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethyl methanesulfonate (VIII). Finally, this compound is condensed with 1-acetyl-4-(4-hydroxyphenyl)piperazine (IX) by means of NaH in benzene - DMSO. Compound (IX) is obtained by reaction of 4-(1-piperazinyl)phenol dihydrobromide (X) with acetic anhydride by means of K2CO3 in refluxing acetic acid.
| 【1】 Heeres, J.; et al.; DE 2804096 . |
| 【2】 Blancafort, P.; Sweetman, A.J.; Castaner, J.; Serradell, M.N.; Ketoconazole. Drugs Fut 1979, 4, 7, 496. |
| 【3】 Backx, L.J.J.; Mostmans, J.H.; Heeres, J. (Janssen Pharmaceutica NV); 1-(1,3-Dioxolan-2-ylmethyl)-1H-imidazoles. US 4335125 . |
| 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) | 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 |
| (B) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (I) | 36408 | 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone | C8H5BrCl2O | 详情 | 详情 | |
| (II) | 13289 | Glycerine; Glycerin; Glycerol | 56-81-5 | C3H8O3 | 详情 | 详情 |
| (III) | 39602 | [(2S,4R)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methanol | C11H11BrCl2O3 | 详情 | 详情 | |
| (IV) | 30485 | [(2S,4S)-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate; cis-2-(bromomethyl)-2-(2,4-dichlorophenyl)-1,3-dioxolan-4-yl]methyl benzoate | C18H15BrCl2O4 | 详情 | 详情 | |
| (V) | 10255 | Imidazole; 1H-Imidazole | 288-32-4 | C3H4N2 | 详情 | 详情 |
| (VI) | 39603 | [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl benzoate | C21H18Cl2N2O4 | 详情 | 详情 | |
| (VII) | 39604 | [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol | 170210-50-1 | C14H14Cl2N2O3 | 详情 | 详情 |
| (VIII) | 39605 | [(2S,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate; cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methyl methanesulfonate | C15H16Cl2N2O5S | 详情 | 详情 | |
| (IX) | 29119 | 1-Acetyl-4-(4-hydoxyphenyl)piperazine; 1-[4-(4-hydroxyphenyl)-1-piperazinyl]-1-ethanone; N-Acetyl-4-(4-hydoxyphenyl)piperazine | 67914-60-7 | C12H16N2O2 | 详情 | 详情 |
| (X) | 39606 | 4-(1-piperazinyl)phenol; 1-(4-Hydroxyphenyl)piperazine | 56621-48-8 | C10H14N2O | 详情 | 详情 |