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【结 构 式】 
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【药物名称】EMD-122946 【化学名称】2-(2,1,3-Benzothiadiazol-5-yl)-4-(3-fluoro-4-methoxyphenyl)-4-oxo-3-(3,4,5-trimethoxybenzyl)-2(Z)-butenoic acid sodium salt 【CA登记号】 【 分 子 式 】C27H22FN2NaO7S 【 分 子 量 】560.53779 |
【开发单位】Merck KGaA (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Endothelin ETA Receptor Antagonists |
合成路线1
The acetylation of 2-(4-aminophenyl)acetic acid (I) with acetic anhydride, followed by nitration with nitric acid in acetic acid and treatment with HCl in ethanol gives 2-(4-amino-3-nitrophenyl)acetic acid ethyl ester (II), which is reduced at the nitro group, and cyclized with SOCl2 yielding the benzothiadiazole (III). The condensation of (III) with 3-fluoro-4-methoxyphenacyl bromide (IV) by means of potassium tert-butoxide affords the 4-oxobutyrate (V), which is condensed with 3,4,5-trimethoxybenzaldehyde (VI) by means of sodium methopxide in methanol to provide the the dihydrofuranone (VII). Finally, this compound is treated with NaOH in methanol to promote the opening of the lactone ring yielding the target compound.
| 【1】 Mederski, W.W.K.R.; Osswald, M.; Dorsch, D.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Wilm, C.; Endothelin antagonists: Evaluation of 2,1, 3-benzothiadiazole as a methylendioxyphenyl bioisoster. Bioorg Med Chem Lett 1998, 8, 1, 17. |
| 【2】 Mederski, W.W.K.R.; Dorsch, D.; Osswald, M.; Anzali, S.; Christadler, M.; Schmitges, C.J.; Schelling, P.; Wilm, C.; Fluck, M.; 3. Endothelin antagonists: Discovery of EMD 122946, a highly potent and orally active ETA selective antagonist. Bioorg Med Chem Lett 1998, 8, 13, 1771. |
| 【3】 Dorsch, D.; Osswald, M.; Mederski, W.; Wilm, C.; Schmitges, C.; Christadler, M.; Anzali, S. (Merck Patent GmbH); 2,1,3-Benzothia(oxa)diazole derivs. having an endothelin receptor antagonistic effect. DE 19607096; EP 0882030; WO 9730982 . |
| 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) | 21229 | 2-(4-Aminophenyl)acetic acid | 5345-54-0 | C8H9NO2 | 详情 | 详情 |
| (II) | 26095 | ethyl 2-(4-amino-3-nitrophenyl)acetate | C10H12N2O4 | 详情 | 详情 | |
| (III) | 26096 | ethyl 2-(2,1,3-benzothiadiazol-5-yl)acetate | C10H10N2O2S | 详情 | 详情 | |
| (IV) | 26097 | 2-bromo-1-(3-fluoro-4-methoxyphenyl)-1-ethanone | C9H8BrFO2 | 详情 | 详情 | |
| (V) | 26098 | ethyl 2-(2,1,3-benzothiadiazol-5-yl)-4-(3-fluoro-4-methoxyphenyl)-4-oxobutanoate | C19H17FN2O4S | 详情 | 详情 | |
| (VI) | 11136 | 3,4,5-Trimethoxybenzaldehyde | 86-81-7 | C10H12O4 | 详情 | 详情 |
| (VII) | 26099 | 3-(2,1,3-benzothiadiazol-5-yl)-5-(3-fluoro-4-methoxyphenyl)-5-hydroxy-4-(3,4,5-trimethoxybenzyl)-2(5H)-furanone | C27H23FN2O7S | 详情 | 详情 |