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【结 构 式】 
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【药物名称】Bervastatin, LS-2904 【化学名称】(±)-erythro-7-[4-(4-Fluorophenyl)spiro[2H-1-benzopyran-2,1'-cyclopentan]-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid ethyl ester 【CA登记号】132017-01-7 【 分 子 式 】C28H31FO5 【 分 子 量 】466.55467 |
【开发单位】Lipha (Originator) 【药理作用】Antifungal Agents, ANTIINFECTIVE THERAPY, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, HMG-CoA Reductase Inhibitors, Prostanoid TP (Thromboxane A2) Antagonists |
合成路线1
The synthesis of bervastatin is outlined: Heating of 2-hydroxyacetophenone (A) with cyclopentanone (B) and pyrrolidine in toluene gave 3,4-dihydrospiro[1-benzopyran-2(2H),1'-cyclopentan]-4-one (I). 1,2-Addition of 4-fluorophenylmagnesium bromide (D) on (I) followed by dehydration of the intermediate alcohol (II) upon treatment with p-toluenesulfonic acid yielded 4-(4-fluorophenyl)spiro[1-benzopyran-2(2H),1'-cyclopentane] (III). Vilsmeier reaction on (III) using 3-morpholinoacrolein (E) gave the corresponding prop-2-enal (IV). Addition of the dianion of ethyl acetoacetate to aldehyde (IV) and stereospecific reduction of the resulting delta-hydroxy-beta-ketoester (V) with diethylmethoxyborane and sodium borohydride yielded bervastatin.
| 【1】 Festal, D.; Bervastatin. Drugs Fut 1995, 20, 12, 1217. |
| 【2】 Festal, D.; Nioche, J.-Y.; Descours, D.; Bellemin, R.; Decerprit, J. (Lipha Santé); Derivs. of benzocycloalkenyldihydroxyalkanoic acids, inhibitors of HMG-CoA reductase, antagonists of thromboxane A2 receptors and antifungals. AU 9048797; EP 0380392; FR 2642065; JP 1990258738; US 5082859; US 5183924 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (D) | 13643 | 4-fluorophenyl magnesium bromide;Bromo(4-fluorophenyl)magnesium;bromo(p-fluorophenyl)Magnesium;p-Fluorophenylmagnesium bromide | 352-13-6 | C6H4BrFMg | 详情 | 详情 |
| (B) | 15113 | cyclopentanone | 120-92-3 | C5H8O | 详情 | 详情 |
| (A) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (E) | 44198 | (E)-3-(4-morpholinyl)-2-propenal | C7H11NO2 | 详情 | 详情 | |
| (I) | 14114 | 3,4-Dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-one | C13H14O2 | 详情 | 详情 | |
| (II) | 14115 | 4-(4-Fluorophenyl)-3,4-dihydro-2H-spiro[1-benzopyran-2,1'-cyclopentan]-4-ol | C19H19FO2 | 详情 | 详情 | |
| (III) | 14116 | 4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentane] | C19H17FO | 详情 | 详情 | |
| (IV) | 14117 | 3-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-2(E)-propenal | C22H19FO2 | 详情 | 详情 | |
| (V) | 14118 | 5-Hydroxy-7-[4-(4-Fluorophenyl)-2H-spiro[1-benzopyran-2,1'-cyclopentan]-3-yl]-3-oxo-6(E)-heptenoic acid ethyl ester | C28H29FO5 | 详情 | 详情 | |
| (C) | 29012 | 1-bromo-4-fluorobenzene | 460-00-4 | C6H4BrF | 详情 | 详情 |