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【结 构 式】 
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【分子编号】21151 【品名】methyl 2-[(4,6-dimethoxy-2-pyrimidinyl)oxy]-3-methoxy-3,3-diphenylpropanoate 【CA登记号】 |
【 分 子 式 】C23H24N2O6 【 分 子 量 】424.45344 【元素组成】C 65.08% H 5.7% N 6.6% O 22.62% |
合成路线1
该中间体在本合成路线中的序号：(VI)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 |