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【结 构 式】 
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【分子编号】19193 【品名】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 【CA登记号】 |
【 分 子 式 】C19H22N2O4 【 分 子 量 】342.39476 【元素组成】C 66.65% H 6.48% N 8.18% O 18.69% |
合成路线1
该中间体在本合成路线中的序号：(III)The condensation of 2-(4-nitrophenyl)ethyl bromide (I) with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (II) by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (III), which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine (IV). Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) by means of DCC and HOBt in DMF to afford the target carboxamide. The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) has been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid (VI) with 2-bromobenzoic acid (VII) by means of K2CO3 and copper dust give the diphenylamine (VIII), which is cyclized to the target acridine (V) by means of POCl3 in refluxing acetonitrile.
| 【1】 Dodic, N.; et al.; Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides. J Med Chem 1995, 38, 13, 2418. |
| 【2】 Dumaitre, B.A.; Dodic, N. (GlaxoSmithKline plc); Acridine derivs.. EP 0494623; EP 0569380; JP 1994506440; US 5604237; WO 9212132 . |
| 【3】 Sharp, M.J.; Mader, C.J.; Strachan, C. (GlaxoSmithKline plc); Synthesis of acridine deriv. multidrug-resistant inhibitors. WO 9852923 . |
| 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) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
| (II) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 | |
| (III) | 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 | |
| (IV) | 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 | |
| (V) | 53881 | 5-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | n/a | C15H11NO4 | 详情 | 详情 |
| (VI) | 53879 | 2-Amino-3-methoxybenzoic acid; 2-Amino-m-anisic acid; 3-Methoxyanthranilic acid | 3177-80-8 | C8H9NO3 | 详情 | 详情 |
| (VII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (VIII) | 53880 | 2-(2-carboxyanilino)-3-methoxybenzoic acid | n/a | C15H13NO5 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)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 |