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【结 构 式】 
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【分子编号】30485 【品名】[(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 【CA登记号】 |
【 分 子 式 】C18H15BrCl2O4 【 分 子 量 】446.1241 【元素组成】C 48.46% H 3.39% Br 17.91% Cl 15.89% O 14.35% |
合成路线1
该中间体在本合成路线中的序号：(I)The condensation of 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-(benzoyloxymethyl)-1,3-dioxolane (I) with triazole (II) by means of NaH in DMSO, followed by hydrolysis with NaOH in dioxane water gives 2-(2,4-dichlorophenyl)-2-(1H)-1,2,4-triazol-1-ylmethyl)-1,3-dioxolane-4-methanol (III), which is acylated with methanesulfonyl chloride in pyridine affording the corresponding 4-mesyloxymethyldioxolane (IV). Finally, this compound is condensed with 4-(4-isopropylpiperazin-1-yl)phenol (V) by means of NaH in hot DMSO. Compound (V) is obtained as follows: 4-(4-methoxyphenyl)piperazine (VI) is reductocondensed with acetone (A) by means of H2 over Pd/C giving 1-isopropyl-4-(4-methoxyphenyl)piperazine (VII), which is then demethylated with refluxing aqueous 48% HBr yielding (V)
| 【1】 Van Cutsem, J.; Heeres, J.; Hendrickx, R.; Antimycotic azoles. 6. Synthesis and antifungal properties of terconazole, a novel triazole ketal. J Med Chem 1983, 26, 4, 611-613. |
| 【2】 Heeres, J.; Backx, L.J.J.; Mostmans, J.H. (Janssen Pharmaceutica NV); Novel 1-(1,3-dioxolan-2-ylmethyl)-1H-imidazoles. BE 0863382; FR 2378778; GB 1594859; JP 7895973; US 4144346; US 4223036 . |
| 【3】 Serradell, M.N.; Castaner, J.; Fromtling, R.A.; Terconazole. Drugs Fut 1984, 9, 7, 529. |
| 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) | 30488 | 4-(4-isopropyl-1-piperazinyl)phenol; 1-Isopropyl-4-(4-hydroxyphenyl)piperazine | C13H20N2O | 详情 | 详情 | |
| (I) | 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 | |
| (II) | 13135 | 1H-1,2,4-Triazole; 1,2,4-Triazole | 288-88-0 | C2H3N3 | 详情 | 详情 |
| (III) | 30486 | [(2S,4R)-2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methanol | C13H13Cl2N3O3 | 详情 | 详情 | |
| (IV) | 30487 | 1-[[(2S,4S)-2-(2,4-dichlorophenyl)-4-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)-1,3-dioxolan-2-yl]methyl]-1H-1,2,4-triazole | C16H19Cl2N3O3S | 详情 | 详情 | |
| (V) | 16312 | 1-(4-Methoxyphenyl)piperazine; Methyl 4-piperazinophenyl ether | 38212-30-5 | C11H16N2O | 详情 | 详情 |
| (VI) | 23199 | 2-Propanone; Acetone; beta-ketopropane; chevron acetone;propan-2-one； Dimethyl formaldehyde; Dimethyl ketone; dimethylketal; Ketone propane; Methyl ketone; Propanone; Pyroacetic acid; Pyroacetic ether | 67-64-1 | C3H6O | 详情 | 详情 |
| (VII) | 30489 | 1-isopropyl-4-(4-methoxyphenyl)piperazine; 4-(4-isopropyl-1-piperazinyl)phenyl methyl ether | C14H22N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)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 |