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【结 构 式】 
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【分子编号】47459 【品名】(3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one 【CA登记号】 |
【 分 子 式 】C17H15N3O 【 分 子 量 】277.32572 【元素组成】C 73.63% H 5.45% N 15.15% O 5.77% |
合成路线1
该中间体在本合成路线中的序号：(I)3(R)-Amino-1-phenyl-6,7-dihydro-3H-[1,4]diazepin[6,7,1-hi]indol-4-one (I) was nitrated using KNO3 in concentrated H2SO4 to furnish the 9-nitro derivative (II). Coupling of (II) with 2-amino-6-(methoxycarbonyl)pyridine-3-carboxylic acid (III) in the presence of DCC and HOBt gave amide (IV). Imidate (V) was prepared by heating (IV) with trimethyl orthoacetate under vacuum distillation of the generated MeOH. Cyclization of (V) to produce the target pyridopyrimidine system (VI) was achieved using scandium triflate as the catalyst. The nitro group was finally hydrogenated over Ru/C to yield the title amino derivative.
| 【1】 Bernardelli, P. (Pfizer Inc.); Method for preparing substd. [1,4]diazepino[6,7,1-hi]indol-4-ones. FR 2795731; WO 0102403 . |
| 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) | 47459 | (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (II) | 47460 | (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N4O3 | 详情 | 详情 | |
| (III) | 48352 | 2-amino-6-(methoxycarbonyl)nicotinic acid | C8H8N2O4 | 详情 | 详情 | |
| (IV) | 48353 | methyl 6-amino-5-([[(3R)-9-nitro-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]amino]carbonyl)-2-pyridinecarboxylate | C25H20N6O6 | 详情 | 详情 | |
| (V) | 48354 | methyl 6-[[(Z)-1-methoxyethylidene]amino]-5-([[(3R)-9-nitro-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]amino]carbonyl)-2-pyridinecarboxylate | C28H24N6O7 | 详情 | 详情 | |
| (VI) | 48355 | methyl 2-methyl-3-[(3S)-9-nitro-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl]-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-7-carboxylate | C27H20N6O6 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VIII)Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III), which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine. The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide, followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1). The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII). Nitration of (VIII) with KNO3 in H2SO4 gave (IX), which was reduced to the diamino derivative (X) using stannous chloride. Finally, regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
| 【2】 Pascal, Y.; Jacobelli, H.; Calvet, A.; Payne, A.; Dahl, S.G. (Institut de Recherche Jouveinal); Diazepino-indoles as phosphodiesterase IV inhibitors. EP 0828742; US 5972927; WO 9736905 . |
| 【1】 Burnouf, C.; Auclair, E.; Avenel, N.; et al.; Synthesis, structure-activity relationships, and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent, selective phosphodiesterase type 4 inhibitors. J Med Chem 2000, 43, 25, 4850. |
| 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) | 19652 | indoline | 496-15-1 | C8H9N | 详情 | 详情 |
| (II) | 25904 | benzonitrile | 100-47-0 | C7H5N | 详情 | 详情 |
| (III) | 47455 | 2,3-dihydro-1H-indol-7-yl(phenyl)methanone | C15H13NO | 详情 | 详情 | |
| (IV) | 10309 | ethyl 2-aminoacetate; Glycine ethyl ester | 459-73-4 | C4H9NO2 | 详情 | 详情 |
| (V) | 47456 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N2O | 详情 | 详情 | |
| (VI) | 47457 | 1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indole-3,4-dione 3-oxime | C17H13N3O2 | 详情 | 详情 | |
| (VII) | 47458 | 3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (VIII) | 47459 | (3R)-3-amino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H15N3O | 详情 | 详情 | |
| (IX) | 47460 | (3R)-3-amino-9-nitro-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H14N4O3 | 详情 | 详情 | |
| (X) | 47461 | (3R)-3,9-diamino-1-phenyl-6,7-dihydro[1,4]diazepino[6,7,1-hi]indol-4(3H)-one | C17H16N4O | 详情 | 详情 | |
| (XI) | 10752 | Nicotinic acid; Niacin | 59-67-6 | C6H5NO2 | 详情 | 详情 |