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【结 构 式】 
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【分子编号】56650 【品名】diethyl (2S)-2-(5-amino-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate 【CA登记号】 |
【 分 子 式 】C17H20N2O6 【 分 子 量 】348.35568 【元素组成】C 58.61% H 5.79% N 8.04% O 27.56% |
合成路线1
该中间体在本合成路线中的序号：(IV)The condensation of L-glutamic acid diethyl ester (I) with 4-nitrophthalic anhydride (II) by means of DIEA in refluxing toluene gives the 4-nitrophthalimide (III), which is reduced with H2 over Pd/C to yield the 4-aminophthalimide (IV). The reduction of (IV) with Zn/HCl in ethanol affords a 3:1 mixture of the 5-aminoisoindolinone (V) and 6-aminoisoindolinone (VI) that is separated by chromatography. The desired isomer (V) is condensed with 9-(bromomethyl)-3-methylbenzo[f]quinazolin-1(2H)-one (VII) (obtained by bromination of 3,9-dimethylbenzo[f]quinazolin-1(2H)-one (VIII) with NBS) in DMF at 110?C to provide the precursor (IX). Finally, the ester groups of (IX) are hydrolyzed with NaOH in methanol.
| 【1】 Pendergast, W.; Dickerson, S.H.; Johnson, J.V.; Ferone, R. (GlaxoSmithKline plc); Pharmaceutically active benzoquinazoline cpds.. EP 0535034; EP 1199307; JP 1993507704; US 5405851; US 5663337; US 6306865; WO 9119700 . |
| 【2】 Pendergast, W.; et al.; Benzo[f]quinazoline inhibitors of thymidylate synthase: Methyleneamino-linked aroylglutamate derivatives. J Med Chem 1994, 37, 6, 838. |
| 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) | 11013 | diethyl (2S)-2-aminopentanedioate | C9H17NO4 | 详情 | 详情 | |
| (II) | 31028 | 5-nitro-2-benzofuran-1,3-dione | 5466-84-2 | C8H3NO5 | 详情 | 详情 |
| (III) | 56649 | diethyl (2S)-2-(5-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H18N2O8 | 详情 | 详情 | |
| (IV) | 56650 | diethyl (2S)-2-(5-amino-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H20N2O6 | 详情 | 详情 | |
| (V) | 56651 | diethyl (2S)-2-(5-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H22N2O5 | 详情 | 详情 | |
| (VI) | 56652 | diethyl (2S)-2-(6-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C17H22N2O5 | 详情 | 详情 | |
| (VII) | 56653 | 9-(bromomethyl)-3-methylbenzo[f]quinazolin-1(2H)-one | C14H11BrN2O | 详情 | 详情 | |
| (VIII) | 56654 | 3,9-dimethylbenzo[f]quinazolin-1(2H)-one | C14H12N2O | 详情 | 详情 | |
| (IX) | 56655 | diethyl (2S)-2-(5-{[(3-methyl-1-oxo-1,2-dihydrobenzo[f]quinazolin-9-yl)methyl]amino}-1-oxo-1,3-dihydro-2H-isoindol-2-yl)pentanedioate | C31H32N4O6 | 详情 | 详情 |