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【结 构 式】 
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【分子编号】33804 【品名】methyl 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate 【CA登记号】 |
【 分 子 式 】C21H20FN3O4 【 分 子 量 】397.4060232 【元素组成】C 63.47% H 5.07% F 4.78% N 10.57% O 16.1% |
合成路线1
该中间体在本合成路线中的序号：(VII)The known diarylimidazole (I) was protected as the N-[2-(trimethylsilyl)ethoxy]methyl derivative (II) by treatment with 2-(trimethylsilyl)ethoxymethyl chloride and NaH. Lithiation of (II) with BuLi at -78 C, followed by quenching with N-formylmorpholine (III) provided aldehyde (IV). This was converted to the dimethyl acetal (V) upon treatment with trimethyl orthoformate and p-toluenesulfonic acid. Further condensation of (V) with methyl 2,2-bis(hydroxymethyl)propionate (VI) produced the dioxane derivative (VII) as a mixture of cis and trans isomers. Basic hydrolysis of the methyl ester group of (VII) afforded the corresponding carboxylic acid. The desired trans isomer (VIII) was then isolated by selective precipitation of the acidified methanolic solution. Finally, coupling of (VIII) with morpholine (IX) using EDC and HOBt furnished the title amide.
| 【1】 McLay, I.M.; Halley, F.; Souness, J.E.; et al.; The discovery of RPR 200765A, a p38 MAP kinase inhibitor displaying a good oral anti-anthritic efficacy. Bioorg Med Chem 2001, 9, 2, 537. |
| 【2】 Halley, F.; Porter, B.; Bamborough, P.L.; Lewis, R.A.; Ratcliffe, A.J.; Wallace, P.A.; McLay, I.M.; McKenna, J.M.; Lythgoe, D.J.; Collis, A.J. (Rhone-Poulenc Rorer Ltd.); Imidazolyl-cyclic acetals. EP 0988301; WO 9856788 . |
| 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) | 33798 | 4-[4-(4-fluorophenyl)-1H-imidazol-5-yl]pyridine | C14H10FN3 | 详情 | 详情 | |
| (II) | 33799 | [4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine | C20H24FN3OSi | 详情 | 详情 | |
| (III) | 33800 | 4-morpholinecarbaldehyde | 4394-85-8 | C5H9NO2 | 详情 | 详情 |
| (IV) | 33801 | 4-(4-fluorophenyl)-5-(4-pyridinyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-carbaldehyde | C21H24FN3O2Si | 详情 | 详情 | |
| (V) | 33802 | [2-(dimethoxymethyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-1-yl]methyl 2-(trimethylsilyl)ethyl ether; 4-(2-(dimethoxymethyl)-4-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazol-5-yl)pyridine | C23H30FN3O3Si | 详情 | 详情 | |
| (VI) | 33803 | methyl 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate | C6H12O4 | 详情 | 详情 | |
| (VII) | 33804 | methyl 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylate | C21H20FN3O4 | 详情 | 详情 | |
| (VIII) | 33805 | 2-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-5-methyl-1,3-dioxane-5-carboxylic acid | C20H18FN3O4 | 详情 | 详情 | |
| (IX) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |