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【结 构 式】 
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【分子编号】19188 【品名】1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE 【CA登记号】3027-05-2 |
【 分 子 式 】C8H10N2O4 【 分 子 量 】198.17848 【元素组成】C 48.49% H 5.09% N 14.14% O 32.29% |
合成路线1
该中间体在本合成路线中的序号：(I)Condensation of 1,4-diacetyl-2,5-piperazinedione (I) with the equimolecular amount of benzaldehyde in the presence of triethylamine affords the benzylidene compound (II), which is N-methylated on treatment with iodomethane and sodium hydride to give III. Alkylation of the tetrahydroisoquinoline (V) with 4-(2-bromoethyl)nitrobenzene (IV) provides the tertiary amine (VI). The nitro group of (VI) is reduced by treatment with iron powder and concentrated HCl in refluxing MeOH to give aniline VII, which is condensed with 3-formylbenzoic acid (VIII) in the presence of 2-chloro-1-methylpyridinium iodide to afford the corresponding amide (IX). Finally, condensation between the previously obtained piperazinedione (III) and aldehyde (IX) in the presence of Cs2CO3 leads to the title compound.
| 【1】 Ashworth, P.A.; Hunjan, S.; Pretswell, I.A.; Ryder, H.; Brocchini, S.J. (Xenova Group plc); Piperazine-2,5-dione derivs. as modulators of multidrug resistance. EP 0799210; GB 2311780; JP 1998511385; US 5935955; WO 9620180 . |
| 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) | 19188 | 1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE | 3027-05-2 | C8H10N2O4 | 详情 | 详情 |
| (II) | 19189 | 1-acetyl-3-[(Z)-benzylidene]-2,5-piperazinedione | C13H12N2O3 | 详情 | 详情 | |
| (III) | 19190 | 1-acetyl-4-methyl-3-[(Z)-benzylidene]-2,5-piperazinedione | C14H14N2O3 | 详情 | 详情 | |
| (IV) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
| (V) | 19192 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride | 2328-12-3 | C11H16ClNO2 | 详情 | 详情 |
| (VI) | 19193 | 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C19H22N2O4 | 详情 | 详情 | |
| (VII) | 19194 | 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]aniline; 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]phenylamine | C19H24N2O2 | 详情 | 详情 | |
| (VIII) | 19195 | 3-formylbenzoic acid | 619-21-6 | C8H6O3 | 详情 | 详情 |
| (IX) | 19196 | N-(4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]phenyl)-3-formylbenzamide | C27H28N2O4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XI)Dioxopiperazine (X) was diacetylated in refluxing acetic anhydride to yield (XI). Aldol condensation of (XI) with the precursor aldehyde (VI) using potassium tert-butoxide in THF gave the mono-arylidene piperazine (XII). Further condensation of (XII) with the intermediate aldehyde (IX) in the presence of Cs2CO3 in DMF furnished the deacetylated bis-arylidene piperazine (XIII). The methyl ester group of (XIII) was finally hydrolyzed to the title carboxylic acid using NaOH in H2O/MeOH/THF.
| 【1】 Folkes, A.; et al.; Synthesis and in vitro evaluation of a series of diketopiperazine inhibitors of plasminogen activator inhibitor-1. Bioorg Med Chem Lett 2001, 11, 19, 2589. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 53129 | N-(4-formylphenyl)-2-thiophenecarboxamide | n/a | C12H9NO2S | 详情 | 详情 |
| (IX) | 53131 | methyl 8-(4-formylphenoxy)octanoate | n/a | C16H22O4 | 详情 | 详情 |
| (X) | 29800 | 2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl) | 106-57-0 | C4H6N2O2 | 详情 | 详情 |
| (XI) | 19188 | 1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE | 3027-05-2 | C8H10N2O4 | 详情 | 详情 |
| (XII) | 53132 | N-{4-[(4-acetyl-3,6-dioxo-2-piperazinylidene)methyl]phenyl}-2-thiophenecarboxamide | n/a | C18H15N3O4S | 详情 | 详情 |
| (XIII) | 53133 | methyl 8-(4-{[3,6-dioxo-5-((Z)-{4-[(2-thienylcarbonyl)amino]phenyl}methylidene)-2-piperazinylidene]methyl}phenoxy)octanoate | n/a | C32H33N3O6S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(II)2,5-Piperazinedione (I) is acylated with acetic anhydride at 110 oC in the presence of catalytic NaOAc to afford the diacetyl derivative (II). Claisen condensation of N,N’-diacetyl-2,5-piperazinedione (II) with 5-tert-butylimidazole-4-carbaldehyde (III) by means of Cs2CO3 in DMF at room temperature leads to the monoacetylated (imidazolylmethylene) piperazinedione (IV), which is finally condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at 80 °C. In a related alternative method, diketopiperazine (II) is first condensed with benzaldehyde (V) in the presence of Cs2CO3 in DMF at room temperature, yielding the benzylidene piperazinedione (VI), which is subsequently condensed with the imidazole-aldehyde (III) by means of Cs2CO3 in hot DMF .
| 【1】 Hayashi, Y., Grodberg, J., Palladino, M. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins dehydrophenylahistins and analogs thereof. EP 1529044, JP 2006511534, WO 2004054498. |
| 【2】 Palladino, M.A., Lloyd, G.K., Hayashi, Y., Nicholson, B. (Nereus Pharmaceuticals, Inc). Dehydrophenylahistins and analogs thereof and the synthesis of dehydrophenylahistins and analogs thereof. EP 1711487, JP 2007520565, WO 2005077940. |
| 【3】 Palladino, M., Lloyd, G.K., Hayashi, Y. (Nereus Pharmaceuticals, Inc). Analogs of dehydrophenylahistins and their therapeutic use. EP 1926724, US 2007078138, WO 2007035841. |
| 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) | 29800 | 2,5-piperazinedione；2,5-diketopiperazine;cycloglycylglycine；2,5-dioxopiperazine;cyclodiglycine;cyclo(glycylglycyl) | 106-57-0 | C4H6N2O2 | 详情 | 详情 |
| (II) | 19188 | 1,4-diacetyl-2,5-piperazinedione;N,N'-DIACETYLGLYCINE ANHYDRIDE;1,4-DIACETYL-PIPERAZINE-2,5-DIONE;1,4-DIACETYLTETRAHYDRO-2,5-PYRAZINEDIONE;1,4-DIACETYL-2,5-DIKETOPIPERAZINE;1,4-DIACETYL-2,5-DIOXOPIPERAZINE | 3027-05-2 | C8H10N2O4 | 详情 | 详情 |
| (III) | 69002 | 5-tert-butylimidazole-4-carbaldehyde;5-(1,1-dimethylethyl)-1H-Imidazole-4-carboxaldehyde;4-(1,1-dimethylethyl)-1H-Imidazole-5-carboxaldehyde | 714273-83-3 | C8H12N2O | 详情 | 详情 |
| (IV) | 69003 | (Z)-1-acetyl-3-((5-(tert-butyl)-1H-imidazol-4-yl)methylene)piperazine-2,5-dione | C14H18N4O3 | 详情 | 详情 | |
| (V) | 10498 | Benzaldehyde;Benzoic aldehyde;Phenylmethanal | 100-52-7 | C7H6O | 详情 | 详情 |
| (VI) | 19189 | 1-acetyl-3-[(Z)-benzylidene]-2,5-piperazinedione | C13H12N2O3 | 详情 | 详情 |