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【结 构 式】 
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【药物名称】Darusentan, HMR-4005, LU-135252 【化学名称】(+)-2(S)-(4,6-Dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid 【CA登记号】171714-84-4 【 分 子 式 】C22H22N2O6 【 分 子 量 】410.43044 |
【开发单位】Abbott (Originator), Aventis Pharma (Licensee) 【药理作用】Acute Myocardial Infarction, Treatment of, CARDIOVASCULAR DRUGS, Heart Failure Therapy, Hypertension, Treatment of, Restenosis Treatment of, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, Endothelin ETA Receptor Antagonists |
合成路线1
The condensation of benzophenone (I) with chloroacetic acid methyl ester (II) by means of sodium methoxide in THF gives the epoxide (III), which is treated with methanol/BF3.Et2O, yielding 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid methyl ester (IV). The condensation of (IV) with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) by means of K2CO3 in DMF affords 2-(4,6-dimethoxypyrimidin-2-yloxy)-3-methoxy-3,3-diphenylpropionic acid methyl ester (VI), which is hydrolyzed with NaOH in hot dioxane/water to give the corresponding free acid (VII). Finally, this compound is submitted to optical resolution, affording LU-135252. Optical resolution of (VIII), the free acid derivative of (IV), with (R)-phenylethylamine, L-proline methyl ester, (S)-1-(4-nitrophenyl)ethylamine or (S)-1-(4--chlorophenyl)ethylamine leads to the enantiomerically pure (S)-enatiomer (IX), which by reaction with 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine (V) directly affords LU-135252.
| 【1】 Jansen, R.; et al.; Structural similarity and its suprises: Endothelin receptor antagonists - Process research and development report. Org Process Res Dev 2001, 5, 1, 16. |
| 【2】 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. |
| 【3】 Silvestre, J.S.; Sorbera, L.A.; Castañer, J.; LU-135252. Drugs Fut 1999, 24, 2, 141. |
| 【4】 Riechers, H.; Klinge, D.; Amberg, W.; Kling, A.; Müller, S.; Baumann, E.; Rheinheimer, J.; Vogelbacher, U.J.; Wernet, W.; Unger, L.; Raschack, M. (BASF AG); New carboxylic acid derivs., their preparation and their use. EP 0785926; JP 1998507190; WO 9611914 . |
| 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 |
| (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) | 21150 | 4,6-dimethoxy-2-(methylsulfonyl)pyrimidine; 4,6-dimethoxy-2-pyrimidinyl methyl sulfone | C7H10N2O4S | 详情 | 详情 | |
| (VI) | 21151 | methyl 2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate | C23H24N2O6 | 详情 | 详情 | |
| (VII) | 21152 | 2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropionic acid | C22H22N2O6 | 详情 | 详情 | |
| (VIII) | 21153 | 2-hydroxy-3-methoxy-3,3-diphenylpropionic acid | C16H16O4 | 详情 | 详情 | |
| (IX) | 21154 | (2S)-2-hydroxy-3-methoxy-3,3-diphenylpropionic acid | C16H16O4 | 详情 | 详情 |