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【结 构 式】 
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【药物名称】Ambrisentan, BSF-208075, LU-208075 【化学名称】(+)-2(S)-(4,6-Dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid 【CA登记号】177036-94-1 【 分 子 式 】C22H22N2O4 【 分 子 量 】378.43164 |
【开发单位】Abbott (Originator), Myogen (Licensee) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Pulmonary Hypertension, Treatment of, Renal Failure, Agents for, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Endothelin ETA Receptor Antagonists |
合成路线1
The condensation of benzophenone (I) with methyl 2-chloroacetate (II) by means of NaOMe in THF gives 3,3-diphenyloxirane-2-carboxylic acid methyl ester (III), which by treatment with BF3/Et2O and methanol, followed by optical resolution, yielded the pure enantiomer 2(S)-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethyl-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethylpyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is finally hydrolyzed with KOH in hot dioxane to afford the target propionic acid as a racemic mixture.
| 【1】 Riechers, H.; Albrecht, H.-P.; Amberg, W.; et al.; Discovery and optimization of a novel class of orally active nonpeptidic endothelin-A receptor antagonists. J Med Chem 1996, 39, 11, 2123. |
| 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) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 21148 | methyl 3,3-diphenyl-2-oxiranecarboxylate | C16H14O3 | 详情 | 详情 | |
| (IV) | 38710 | methyl (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropanoate | C17H18O4 | 详情 | 详情 | |
| (V) | 38714 | 4,6-dimethyl-2-(methylsulfonyl)pyrimidine; 4,6-dimethyl-2-pyrimidinyl methyl sulfone | C7H10N2O2S | 详情 | 详情 | |
| (VI) | 56710 | methyl (2S)-2-[(4,6-dimethyl-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate | C23H24N2O4 | 详情 | 详情 |
合成路线2
| 【1】 Jansen R, Knopp M, Amberg W, et al. 2001. Structural similarity and its surprises: endothelin receptor antagonists-process research and development report. Org Proc Res Dev, 5(1):16～22. |
| 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) | 18732 | benzophenone | 119-61-9 | C13H10O | 详情 | 详情 |
| (II) | 10257 | methyl 2-chloroacetate; methyl chloroacetate | 96-34-4 | C3H5ClO2 | 详情 | 详情 |
| (III) | 21148 | methyl 3,3-diphenyl-2-oxiranecarboxylate | C16H14O3 | 详情 | 详情 | |
| (IV) | 21149 | methyl 2-hydroxy-3-methoxy-3,3-diphenylpropanoate | C17H18O4 | 详情 | 详情 | |
| (V) | 21153 | 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid | C16H16O4 | 详情 | 详情 | |
| (VI) | 67028 | (S)-1-(p-tolyl)ethanamine | 27298-98-2 | C9H13N | 详情 | 详情 |
| (VII) | 67029 | C16H16O4.C9H13N | 详情 | 详情 | ||
| (VIII) | 21150 | 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone | C7H10N2O4S | 详情 | 详情 |