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【结 构 式】 
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【药物名称】Ropinirole hydrochloride, SK&F-101468A, ReQuip 【化学名称】4-[2-(Dipropylamino)ethyl]-2,3-dihydro-1H-indol-2-one hydrochloride 【CA登记号】91374-20-8, 91374-21-9 (free base) 【 分 子 式 】C16H25ClN2O 【 分 子 量 】296.84345 |
【开发单位】GlaxoSmithKline (Originator), SkyePharma (Formulation) 【药理作用】Antiparkinsonian Drugs, Extrapyramidal Disorders, Treatment of, Myoclonus, Treatment of, NEUROLOGIC DRUGS, Restless Legs Syndrome, Treatment of, Dopamine D2 Agonists |
合成路线1
The condensation of 2-(2-methyl-3-nitrophenyl)acetic acid (I) with dipropylamine (II) by means of refluxing SOCl2 gives the corresponding amide (III), which is reduced with borane/THF yielding the tertiary amine (IV). The condensation of (IV) with diethyl oxalate by means of sodium ethoxide in refluxing ethanol affords the pyruvate ester (V), which is treated with NaOH and H2O2 yielding the acetic acid derivative (VI). Finally, this compound is cyclyzed by hydrogenation with H2 over Pd/C in ethanol.
| 【1】 Gallagher, G. Jr. (SmithKline Beecham Corp.); 4-Aminoalkyl-2(3H)-indolones. EP 0113964; ES 8600239; ES 8604143; US 4452808 . |
| 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) | 34861 | 2-(2-methyl-3-nitrophenyl)acetic acid | C9H9NO4 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (III) | 34862 | 2-(2-methyl-3-nitrophenyl)-N,N-dipropylacetamide | C15H22N2O3 | 详情 | 详情 | |
| (IV) | 34863 | N-(2-methyl-3-nitrophenethyl)-N,N-dipropylamine; N-(2-methyl-3-nitrophenethyl)-N-propyl-1-propanamine | C15H24N2O2 | 详情 | 详情 | |
| (V) | 17571 | Diethyl oxalate; Ethyl 2-ethoxy-2-oxoacetate | 95-92-1 | C6H10O4 | 详情 | 详情 |
| (VI) | 34864 | ethyl 3-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]-2-oxopropanoate | C19H28N2O5 | 详情 | 详情 | |
| (VII) | 34865 | 2-[2-[2-(dipropylamino)ethyl]-6-nitrophenyl]acetic acid | C16H24N2O4 | 详情 | 详情 |
合成路线2
The bromination of 3,4-dihydro-1H-2-benzopyran (VII) with Br2 gives the 1-bromo derivative (VIII), which, without isolation, is treated with hot HBr yielding 2-(2-bromoethyl)benzaldehyde (IX). The condensation of (IX) with nitromethane in acidic medium affords the nitrostyrene (X), which is cyclized with treatment with FeCl3 and acetyl chloride giving 4-(2-bromoethyl)-3-chloroindolin-2-one (XI). The dechlorination of (XI) with NaH2PO2 over Pd/C yields 4-(2-bromoethyl)indolin-2-one (XII), which is finally condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (VIII) | 34867 | 1-bromo-3,4-dihydro-1H-isochromene | C9H9BrO | 详情 | 详情 | |
| (IX) | 34868 | 2-(2-bromoethyl)benzaldehyde | C9H9BrO | 详情 | 详情 | |
| (X) | 34869 | 1-(2-bromoethyl)-2-[(E)-2-nitroethenyl]benzene | C10H10BrNO2 | 详情 | 详情 | |
| (XI) | 34870 | 4-(2-bromoethyl)-3-chloro-1,3-dihydro-2H-indol-2-one | C10H9BrClNO | 详情 | 详情 | |
| (XII) | 34871 | 4-(2-bromoethyl)-1,3-dihydro-2H-indol-2-one | C10H10BrNO | 详情 | 详情 |
合成路线3
The reaction of 3,4-dihydro-1H-2-benzopyran (VII) with benzoyl chloride and ZnCl2 gives benzoic acid 2-[2-(chloromethyl)phenyl]ethyl ester (XIII), which is condensed with hexamethylenetetramine (XIV) yielding the amminium salt (XV). The hydrolysis of (XV) affords 2-(2-benzoyloxyethyl) benzaldehyde (XVI), which is condensed with nitromethane as before to give the nitrostyrene (XVII). The cyclization of (XVII) with FeCl3 and acetyl chloride as before yields 4-(2-benzoyloxyethyl)-3-chloroindolin-2-one (XVIII), which is dechlorinated with hydrazine and Pd/C to the indolinone (XIX). The hydrolysis of (XIX) with NaOH affords 4-(2-hydroxyethyl)indolin-2-one (XX), which is acylated with TsCl giving the tosylate (XXI). Finally, this compound is condensed with dipropylamine (II).
| 【1】 Hayler, J.D.; et al.; Development of large-scale syntheses or ropinirole in the pursuit of a manufacturing process. Org Process Res Dev 1998, 2, 1, 3. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 10463 | Benzoyl chloride | 98-88-4 | C7H5ClO | 详情 | 详情 | |
| 19273 | acetyl chloride | 75-36-5 | C2H3ClO | 详情 | 详情 | |
| 39563 | nitromethane | 75-52-5 | CH3NO2 | 详情 | 详情 | |
| (II) | 21856 | N,N-dipropylamine; N-propyl-1-propanamine | 142-84-7 | C6H15N | 详情 | 详情 |
| (VII) | 34866 | 3,4-dihydro-1H-isochromene | 493-05-0 | C9H10O | 详情 | 详情 |
| (XIII) | 34872 | 2-(chloromethyl)phenethyl benzoate | C16H15ClO2 | 详情 | 详情 | |
| (XIV) | 34873 | 1,3,5,7-tetraazatricyclo[3.3.1.1(3,7)]decane | 100-97-0 | C6H12N4 | 详情 | 详情 |
| (XV) | 34874 | 1-[2-[2-(benzoyloxy)ethyl]benzyl]-3,5,7-triaza-1-azoniatricyclo[3.3.1.1(3,7)]decane chloride | C22H27ClN4O2 | 详情 | 详情 | |
| (XVI) | 34875 | 2-formylphenethyl benzoate | C16H14O3 | 详情 | 详情 | |
| (XVII) | 34876 | 2-[(E)-2-nitroethenyl]phenethyl benzoate | C17H15NO4 | 详情 | 详情 | |
| (XVIII) | 34877 | 2-(3-chloro-2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H14ClNO3 | 详情 | 详情 | |
| (XIX) | 34878 | 2-(2-oxo-2,3-dihydro-1H-indol-4-yl)ethyl benzoate | C17H15NO3 | 详情 | 详情 | |
| (XX) | 34879 | 4-(2-Hydroxyethyl)indolin-2-one | 139122-19-3 | C10H11NO2 | 详情 | 详情 |
| (XXI) | 34880 | 4-heptanol | 589-55-9 | C7H16O | 详情 | 详情 |