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【结 构 式】 
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【分子编号】34427 【品名】tert-butyl (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate 【CA登记号】 |
【 分 子 式 】C17H19N3O7 【 分 子 量 】377.35388 【元素组成】C 54.11% H 5.08% N 11.14% O 29.68% |
合成路线1
该中间体在本合成路线中的序号：(XVIIIb)The oxidative ring opening of 2-oxa-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXIII) with NaOH in methanol, followed by a treatment with CrO2Cl2 in CCl4 gives 2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)-1-cyclopentanone (XXIV), which by reaction with methyl trimethylsilylacetate (XXV) by means of butyllithium and diisopropylamine in THF is converted into 1-(methoxycarbonylmethylidene)-2-methoxycarbonylmethyl-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVI). The hydrogenation of (XXVI) with H2 over Pd/C in ethanol affords 1,2-bis(methoxycarbonylmethyl)-3-benzyloxymethyl-4-(tetrahydropyranyloxy)cyclopentane (XXVII), which is cyclized by means of potassium tert-butoxide in refluxing benzene to 2 (or 4)-methoxycarbonyl-6-benzyloxymethyl-7-(tetrahydropyranyloxy)-cis-bicyclo[3.3.0]octan-3-one (XXVIII). Finally, this compound is hydrolyzed and decarboxylated in HMPT - water at 160 C giving the ketone (VIII), already obtained.
| 【1】 Hayashi, M.; Konishi, Y.; Arai, Y.; 6,9-Methano-PGI2 analogues. CH 639360; DE 2912409; FR 2422635; GB 2017699; IT 1113341; US 4479966 . |
| 【2】 Kottegoda, S.R.; Serradell, M.N.; Adaikan, P.G.; Castaner, J.; ONO-41483. Drugs Fut 1984, 9, 11, 833. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XVIIIa) | 34426 | tert-butyl (2S)-2,5-diamino-5-oxopentanoate | C9H18N2O3 | 详情 | 详情 | |
| (XVIIIb) | 34427 | tert-butyl (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate | C17H19N3O7 | 详情 | 详情 | |
| (XXIII) | 34421 | 5,6,7-trimethoxy-2-benzofuran-1(3H)-one | C11H12O5 | 详情 | 详情 | |
| (XXIV) | 34422 | 3-bromo-5,6,7-trimethoxy-2-benzofuran-1(3H)-one | C11H11BrO5 | 详情 | 详情 | |
| (XXV) | 34423 | 1-naphthylmethylphosphonic acid | 4730-77-2 | C11H11O3P | 详情 | 详情 |
| (XXVI) | 34424 | 4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide | 603-62-3 | C8H4N2O4 | 详情 | 详情 |
| (XXVII) | 34425 | ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate | C11H8N2O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IV)Treatment of 3-nitrophthalimide (I) with ethyl chloroformate and triethylamine produced 3-nitro-N-(ethoxycarbonyl)phthalimide (II), which was condensed with L-glutamine tert-butyl ester hydrochloride (III) to afford the phthaloyl glutamine derivative (IV). Acidic cleavage of the tert-butyl ester of (IV) provided the corresponding carboxylic acid (V). This was cyclized to the required glutarimide (VI) upon treatment with thionyl chloride and then with triethylamine. The nitro group of (VI) was finally reduced to amine by hydrogenation over Pd/C.
| 【1】 Muller, G.W.; Huang, S.-Y.; Chen, R.; et al.; Amino-substituted thalidomide analogs: Potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999, 9, 11, 1625. |
| 【2】 Stirling, D.I.; Chen, R.S.-C.; Muller, G.W. (Celgene Corp.); Substd. 2-(2,6-dioxopiperidin-3-yl)-phthalimides and 1-oxoisoindolines and method of reducing TNFalpha levels. EP 0925294; EP 0984955; US 5635517; WO 9803502; WO 9854170 . |
| 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) | 34424 | 4-nitro-1H-isoindole-1,3(2H)-dione；3-nitrophthalimide | 603-62-3 | C8H4N2O4 | 详情 | 详情 |
| (II) | 34425 | ethyl 4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate | C11H8N2O6 | 详情 | 详情 | |
| (III) | 34426 | tert-butyl (2S)-2,5-diamino-5-oxopentanoate | C9H18N2O3 | 详情 | 详情 | |
| (IV) | 34427 | tert-butyl (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoate | C17H19N3O7 | 详情 | 详情 | |
| (V) | 34428 | (2S)-5-amino-2-(4-nitro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-oxopentanoic acid | C13H11N3O7 | 详情 | 详情 | |
| (VI) | 34429 | 2-[(3S)-2,6-dioxopiperidinyl]-4-nitro-1H-isoindole-1,3(2H)-dione | C13H9N3O6 | 详情 | 详情 |