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【结 构 式】 
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【分子编号】44738 【品名】Diethyl aminomalonate; diethyl 2-aminomalonate 【CA登记号】 |
【 分 子 式 】C7H13NO4 【 分 子 量 】175.18456 【元素组成】C 47.99% H 7.48% N 8% O 36.53% |
合成路线1
该中间体在本合成路线中的序号：(IV)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2
该中间体在本合成路线中的序号：(II)The known N-(2-hydroxypropyl)-methacrylamide copolymer (I) which has a p-nitrophenyl peptide side chain is coupled to ethyl aminomalonate (II) in the presence of Et3N in DMF to give the corresponding amide (III). Alkaline hydrolysis of the diethyl malonate ester groups of (III) affords the sodium carboxylate salt (IV). This is then complexed with the platinum species, generated in situ from cisplatin (V) and silver nitrate, to produce the title polymer-linked platinum complex.
| 【1】 Duncan, R.; Evagorou, E.G.; Buckley, R.G.; Gianasi, E. (Access Pharmaceuticals, Inc.); Polymer-platinum cpds.. WO 9847537 . |