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【结 构 式】 
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【药物名称】 【化学名称】(3R)-N-(9-Methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin-3-yl)-1H-indole-2-carboxamide 【CA登记号】 【 分 子 式 】C27H22N4O3 【 分 子 量 】450.50139 |
【开发单位】Jouveinal (Originator) 【药理作用】Antiallergy/Antiasthmatic Drugs, Asthma Therapy, Bronchodilators, RESPIRATORY DRUGS, Phosphodiesterase IV Inhibitors |
合成路线1
The hydrogenation of 5-methoxy-1H-indole (I) by means of NaCNBH3 in acetic acid gives 5-methoxyindoline (II), which is benzoylated with benzonitrile (III) by means of BCl3/AlCl3 in dichloroethane yielding 7-benzoyl-5-methoxyindoline (IV). The cyclization of (IV) with glycine ethyl ester (V) in pyridine affords the pyrrolo[1,4]benzodiazepine (VI), which is treated with amyl nitrite in toluene/THF to provide the oxime (VII). The reduction of (VII) with H2 over Ru/C in methanol gives the racemic amine (VIII), which is submitted to optical resolution with di-p-toluoyl-D-tartaric acid yielding the corresponding (R)-isomer (IX). Finally, this compound is condensed with 1H-indole-2-carboxylic acid (X) by means of TOTU and DIEA in dichloromethane.
| 【1】 Feru, F.; et al.; Synthesis and structure-activity relationships of 9-methoxy-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indolines: Novel PDE 4 inhibitors. 216th ACS Natl Meet (Aug. 23-27, Boston) 1998, Abst MEDI 049. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40665 | cyclopentyl nitrite | C5H9NO2 | 详情 | 详情 | ||
| (I) | 25902 | 1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole | 1006-94-6 | C9H9NO | 详情 | 详情 |
| (II) | 25903 | 5-methoxyindoline; 2,3-dihydro-1H-indol-5-yl methyl ether | C9H11NO | 详情 | 详情 | |
| (III) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (IV) | 25905 | (5-methoxy-2,3-dihydro-1H-indol-7-yl)(phenyl)methanone | C16H15NO2 | 详情 | 详情 | |
| (V) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (VI) | 25906 | 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H16N2O2 | 详情 | 详情 | |
| (VII) | 25907 | 9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C18H15N3O3 | 详情 | 详情 | |
| (VIII) | 25908 | 3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O2 | 详情 | 详情 | |
| (IX) | 25909 | (3R)-3-amino-9-methoxy-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C18H17N3O2 | 详情 | 详情 | |
| (X) | 25226 | 1H-Indole-2-carboxylic acid; Indole-2-carboxylic acid | 1477-50-5 | C9H7NO2 | 详情 | 详情 |