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【结 构 式】 
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【分子编号】18699 【品名】1,3-dihydro-2H-indol-2-one 【CA登记号】59-48-3 |
【 分 子 式 】C8H7NO 【 分 子 量 】133.14972 【元素组成】C 72.17% H 5.3% N 10.52% O 12.02% |
合成路线1
该中间体在本合成路线中的序号：(IV)Vilsmeier reaction between 2,4-dimethylpyrrole (I) and dimethylformamide (II) by means of phosphorous oxychloride in dichloroethane provides carbaldehyde (III), which is then condensed with 2-indolinone (IV) in ethanol in the presence of piperidine.
| 【1】 Tang, P.C.; Sun, L.; McMahon, G.; Hirth, K.P.; Shawver, L.K. (Sugen, Inc.); Indolinone combinatorial libraries and related products and methods for the treatment of disease. EP 0929520; JP 2001503736; WO 9807695 . |
| 【2】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |
合成路线2
该中间体在本合成路线中的序号：(I)Title compound was prepared by condensation of oxindole (I) and formylpyrrole (II) in the presence of a catalytic amount of piperidine in refluxing EtOH.
| 【1】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |
合成路线3
该中间体在本合成路线中的序号：(III)The reaction of 1-phenylpiperazine (I) with DMF and POCl3 in dichloroethane gives 4-(4-formylpiperazin-1-yl)benzaldehyde (II), which is condensed with indolin-2-one (III) by means of piperidine in refluxing ethanol.
| 【1】 Sun, L.; et al.; Synthesis and biological evaluations of 3-substituted indolin-2-ones: A novel class of tyrosine kinase inhibitors that exhibit selectivity toward particular receptor tyrosine kinases. J Med Chem 1998, 41, 14, 2588. |
| 【2】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Indolinone cpds. for the treatment of disease. EP 0769947; JP 2000026412; US 5780496; US 5792783; US 5880141; US 5883113; US 5883116; WO 9640116 . |
合成路线4
该中间体在本合成路线中的序号：(V)Basic hydrolysis of the known 2,4-dimethyl-5-ethoxycarbonyl-3-(2-ethoxycarbonyl ethyl)pyrrole (I) and subsequent decarboxylation of the resulting diacid (II) in the presence of HCl furnished 2,4-dimethyl-3-pyrrolepropionic acid (III). Vilsmeier formylation of (III) employing dimethylformamide and POCl3 produced aldehyde (IV). The title compound was then obtained by condensation of aldehyde (IV) with oxindole (V) in the presence of pyrrolidine, followed by acid treatment of the intermediate (VI). Alternatively, direct condensation of aldehyde (IV) with oxindole (V) in the presence of NaOH gave rise to the title compound.
| 【1】 Tang, P.C.; Sun, L.; McMahon, G. (Sugen, Inc.); Pyrrole substd. 2-indolinone protein kinase inhibitors. WO 9961422 . |
| 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) | 39751 | ethyl 4-(3-ethoxy-3-oxopropyl)-3,5-dimethyl-1H-pyrrole-2-carboxylate | C14H21NO4 | 详情 | 详情 | |
| (II) | 39752 | 4-(2-carboxyethyl)-3,5-dimethyl-1H-pyrrole-2-carboxylic acid | C10H13NO4 | 详情 | 详情 | |
| (III) | 39753 | 3-(2,4-dimethyl-1H-pyrrol-3-yl)propionic acid | C9H13NO2 | 详情 | 详情 | |
| (IV) | 39754 | 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)propionic acid | C10H13NO3 | 详情 | 详情 | |
| (V) | 18699 | 1,3-dihydro-2H-indol-2-one | 59-48-3 | C8H7NO | 详情 | 详情 |
| (VI) | 39755 | 3-[2,4-dimethyl-5-[(2-oxo-2,3-dihydro-1H-indol-3-yl)(1-pyrrolidinyl)methyl]-1H-pyrrol-3-yl]propionic acid | C22H27N3O3 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(VIII)Condensation of ethyl succinyl chloride (II) with 4-(1-cyclohexenyl)morpholine (I) in the presence of Et3N produced enamino ketoester (III). Cyclization of (III) with diethyl aminomalonate (IV) gave the tetrahydroindole (V). Hydrolysis of the ester functions of (V) with NaOH, followed by acidic decarboxylation, afforded the tetrahydroindolylpropionic acid (VI). Vilsmeier formylation of (VI) with DMF and POCl3 furnished aldehyde (VII). This was then condensed with 5-bromo-2-oxindole (IX) (obtained by treatment of (VIII) with N-bromosuccinimide), using either pyrrolidine or piperidine in refluxing EtOH to yield the title compound.
| 【2】 Miller, T.A.; Tang, P.C.; Sun, L.; Tran, N.M.; Liang, C.; Nguyen, A.T.; Nematalla, A. (Sugen, Inc.); 3-Methylidenyl-2-indolinone modulators of protein kinase. WO 0008202 . |
| 【1】 Liang, C.; Sun, L.; Tran, N.; et al.; Identification of substituted 3-[(4,5,6,7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2-ones as growth factor receptor inhibitors for VEGF-R2 (F1k-1/KDR), FGF-R1, and PDGF-Rbeta tyrosine kinases. J Med Chem 2000, 43, 14, 2655. |
| 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) | 44735 | 4-(1-cyclohexen-1-yl)morpholine | 670-80-4 | C10H17NO | 详情 | 详情 |
| (II) | 40684 | ethyl 4-chloro-4-oxobutanoate; Ethyl succinyl chloride | 14794-31-1 | C6H9ClO3 | 详情 | 详情 |
| (III) | 44737 | ethyl 4-[2-(4-morpholinyl)-1-cyclohexen-1-yl]-4-oxobutanoate | C16H25NO4 | 详情 | 详情 | |
| (IV) | 44738 | Diethyl aminomalonate; diethyl 2-aminomalonate | C7H13NO4 | 详情 | 详情 | |
| (V) | 44739 | ethyl 3-(3-ethoxy-3-oxopropyl)-4,5,6,7-tetrahydro-1H-indole-2-carboxylate | C16H23NO4 | 详情 | 详情 | |
| (VI) | 44740 | 3-(4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid | C11H15NO2 | 详情 | 详情 | |
| (VII) | 44741 | 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)propionic acid | C12H15NO3 | 详情 | 详情 | |
| (VIII) | 18699 | 1,3-dihydro-2H-indol-2-one | 59-48-3 | C8H7NO | 详情 | 详情 |
| (IX) | 44743 | 5-bromo-1,3-dihydro-2H-indol-2-one | C8H6BrNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(III)The Vilsmeier formylation of 5-methoxy-6-methyloxindole (I) with DMF/POCl3 gives rise to the chloro aldehyde (II). This is then condensed with oxindole (III) in methanol in the presence of piperidine to furnish the target bis-indole derivative.
| 【1】 Andreani, A.; et al.; Synthesis and antitumor activity of 1,5,6-substituted E-3-(2-chloro-3-indolylmethylene)-1,3-dihydroindol-2-ones. J Med Chem 2002, 45, 12, 2666. |