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【结 构 式】 
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【药物名称】Mozavaptan, OPC-31260, Physuline 【化学名称】5-(Dimethylamino)-1-[4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine 【CA登记号】137975-06-5 【 分 子 式 】C27H29N3O2 【 分 子 量 】427.55108 |
【开发单位】Otsuka (Orphan Drug), Otsuka (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Heart Failure Therapy, RENAL-UROLOGIC DRUGS, Treatment of Renal Diseases, Vasopressin V2 Antagonists |
合成路线1
By acylation of 5-(dimethylamino)-2,3,4,5-tetrahydro-1H-benzazepine (I) with 4-(2-methylbenzamido)benzoyl chloride (II) in the presence of potassium carbonate in acetone - H2O.
| 【1】 Ogawa, H.; Miyamoto, H.; Kondo, K.; Yamashita, H.; Nakaya, K.; Komatsu, H.; Tanaka, M.; Kora, S.; Tominaga, M.; Yabuuchi, Y. (Otsuka Pharmaceutical Co., Ltd.); Benzoheterocyclic cpds. EP 0450097; JP 1992154765; WO 9105549 . |
| 【2】 Castaner, J.; Prous, J.; Mealy, N.; OPC-31260. Drugs Fut 1993, 18, 9, 802. |
合成路线2
A new synthesis of OPC-31260 has been published: The reductocondensation of 1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-one (I) with methylamine and NaBH4 gives N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N-methylamine (II), which is methylated with formaldehyde and sodium cyanoborohydride to yield N-(1-tosyl-2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (III). The hydrolysis of (III) with polyphosphoric acid affords N-(2,3,4,5-tetrahydro-1-benzazepin-5-yl)-N,N-dimethylamine (IV), which is acylated with 4-nitrobenzoyl chloride to the expected benzoyl derivative (VI). The reduction of the nitro group of (VI) with H2 over Pd/C affords the corresponding 4-aminobenzoyl derivative (VII), which is finally acylated with 2-methylbenzoyl chloride by means of triethylamine in dichloromethane.
| 【1】 Ogawa, H.; Yamashita, H.; Kondo, K.; et al.; Orally active, nonpeptide vasopressin V2 receptor antagonists: A novel series of 1-[4-(benzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepines and related compounds. J Med Chem 1996, 39, 18, 3574. |
| 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) | 14763 | 1-[(4-methylphenyl)sulfonyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-one | C17H17NO3S | 详情 | 详情 | |
| (II) | 14764 | N-methyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N-methyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C18H22N2O2S | 详情 | 详情 | |
| (III) | 14765 | N,N-dimethyl-1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-[1-[(4-methylphenyl)sulfonyl]-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]amine | C19H24N2O2S | 详情 | 详情 | |
| (IV) | 14762 | N,N-dimethyl-2,3,4,5-tetrahydro-1H-1-benzazepin-5-amine; N,N-dimethyl-N-(2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl)amine | C12H18N2 | 详情 | 详情 | |
| (V) | 18941 | p-nitrobenzoyl chloride; 4-nitrobenzoyl chloride | 122-04-3 | C7H4ClNO3 | 详情 | 详情 |
| (VI) | 14768 | [5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl](4-nitrophenyl)methanone | C19H21N3O3 | 详情 | 详情 | |
| (VII) | 14769 | (4-aminophenyl)[5-(dimethylamino)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]methanone | C19H23N3O | 详情 | 详情 | |
| (VIII) | 14770 | 2-methylbenzoyl chloride; o-Toluoyl chloride | 933-88-0 | C8H7ClO | 详情 | 详情 |