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【结 构 式】 
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【分子编号】33007 【品名】1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one 【CA登记号】 |
【 分 子 式 】C18H17ClN2O2 【 分 子 量 】328.79796 【元素组成】C 65.75% H 5.21% Cl 10.78% N 8.52% O 9.73% |
合成路线1
该中间体在本合成路线中的序号：(XII)5-Chloro-2-nitrobenzoic acid (I) was converted into methyl ester (II) using dimethyl sulfate and K2CO3 in acetone. The nitro group of (II) was then reduced with SnCl2 to afford aniline (III), which was protected as the p-toluenesulfonamide (IV) with tosyl chloride in pyridine. Alkylation of (IV) with ethyl 4-bromobutyrate (V) yielded diester (VI). Subsequent Dieckmann cyclization of (VI) in the presence of potassium tert-butoxide provided benzazepinone (VIIa-b) as a mixture of ethyl and methyl esters, which was decarboxylated to (VIII) by heating with HCl in AcOH. Deprotection of the tosyl group of (VIII) was carried out in hot polyphosphoric acid. The resulting benzazepinone (IX) was condensed with 2-methyl-4-nitrobenzoyl chloride (X) to give amide (XI). After reduction of the nitro group of (XI) to the corresponding aniline (XII), condensation with 2-methylbenzoyl chloride (XIII) provided diamide (XIV). Finally, ketone reduction in (XIV) by means of NaBH4 led to the target compound.
| 【1】 Sorbera, L.A.; Silvestre, J.S.; Castañer, J.; Bayes, M.; Tolvaptan. Drugs Fut 2002, 27, 4, 350. |
| 【2】 Kondo, K.; Yamashita, H.; Ogawa, H.; et al.; 7-Chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem 1999, 7, 8, 1743. |
| 【3】 Yabuuchi, Y.; Kora, S.; Tanaka, M.; Miyamoto, H.; Komatsu, H.; Kondo, K.; Yamashita, H.; Tominaga, M.; Ogawa, H.; Nakaya, K. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. US 5985869 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 33001 | methyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate | C19H18ClNO5S | 详情 | 详情 | |
| (VIIb) | 33002 | ethyl 7-chloro-1-[(4-methylphenyl)sulfonyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-4-carboxylate | C20H20ClNO5S | 详情 | 详情 | |
| (I) | 32996 | 5-chloro-2-nitrobenzoic acid | 2516-95-2 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 32997 | methyl 5-chloro-2-nitrobenzoate | 51282-49-6 | C8H6ClNO4 | 详情 | 详情 |
| (III) | 32998 | methyl 2-amino-5-chlorobenzoate | 5202-89-1 | C8H8ClNO2 | 详情 | 详情 |
| (IV) | 32999 | methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate | C15H14ClNO4S | 详情 | 详情 | |
| (V) | 11263 | ethyl 4-bromobutanoate; Ethyl 4-bromobutyrate | 2969-81-5 | C6H11BrO2 | 详情 | 详情 |
| (VI) | 33000 | methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate | C21H24ClNO6S | 详情 | 详情 | |
| (VIII) | 33003 | 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16ClNO3S | 详情 | 详情 | |
| (IX) | 33004 | 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C10H10ClNO | 详情 | 详情 | |
| (X) | 33005 | 2-methyl-4-nitrobenzoyl chloride | C8H6ClNO3 | 详情 | 详情 | |
| (XI) | 33006 | 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H15ClN2O4 | 详情 | 详情 | |
| (XII) | 33007 | 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H17ClN2O2 | 详情 | 详情 | |
| (XIII) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |
| (XIV) | 33008 | N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide | C26H23ClN2O3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)
| 【1】 Kondo K, Ogawa H, Yamashita H, et al.1999.7-chloro-5-hydroxy-1-[2-methyl-4-(2-methylbenzoyl-amino) benzoyl]-2,3,4,5-tetrahydro-1H-1-benzazepine (OPC-41061): A potent, orally active nonpeptide arginine vasopressin V2 receptor antagonist. Bioorg Med Chem, 7: 1743～1754. |
| 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) | 32996 | 5-chloro-2-nitrobenzoic acid | 2516-95-2 | C7H4ClNO4 | 详情 | 详情 |
| (II) | 32999 | methyl 5-chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoate | C15H14ClNO4S | 详情 | 详情 | |
| (III) | 33000 | methyl 5-chloro-2-[(4-ethoxy-4-oxobutyl)[(4-methylphenyl)sulfonyl]amino]benzoate | C21H24ClNO6S | 详情 | 详情 | |
| (IV) | 33003 | 7-chloro-1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H16ClNO3S | 详情 | 详情 | |
| (V) | 33004 | 7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C10H10ClNO | 详情 | 详情 | |
| (VI) | 33006 | 7-chloro-1-(2-methyl-4-nitrobenzoyl)-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H15ClN2O4 | 详情 | 详情 | |
| (VII) | 33007 | 1-(4-amino-2-methylbenzoyl)-7-chloro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C18H17ClN2O2 | 详情 | 详情 | |
| (VIII) | 33008 | N-[4-[(7-chloro-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl)carbonyl]-3-methylphenyl]-2-methylbenzamide | C26H23ClN2O3 | 详情 | 详情 |