|
【结 构 式】 
|
【分子编号】22811 【品名】5-bromoisoquinoline 【CA登记号】 |
【 分 子 式 】C9H6BrN 【 分 子 量 】208.05738 【元素组成】C 51.96% H 2.91% Br 38.4% N 6.73% |
合成路线1
该中间体在本合成路线中的序号：(I)Nitration of 5-bromoisoquinoline (I) using KNO3 in H2SO4 gave 5-bromo-8-nitroisoquinoline (II), which upon methylation with dimethyl sulfate was converted to the isoquinolinium salt (III). Subsequent reduction of (III) with NaBH4 in AcOH provided tetrahydroisoquinoline (IV). This was coupled with phenylboronic acid (V) in the presence of Pd(PPh3)4 and NaHCO3 to yield the 5-phenylisoquinoline (VI). Further reduction of the nitro group of (VI) by catalytic hydrogenation over Pd/C afforded amine (VII). The pyrroloisoquinoline (VIII) was then formed by condensation of (VII) with chloral and hydroxylamine in boiling water, followed by cyclization of the intermediate (oxymino)acetamide in methanesulfonic acid at 120 C. After chlorosulfonation of (VIII), the sulfonyl chloride (IX) was condensed with dimethylamine in THF to afford sulfonamide (X). Hydroxylamine derivative (XIV) was prepared by O-alkylation of N-hydroxyphthalimide (XI) with alpha-bromo-gamma-butyrolactone (XII), followed by hydrolysis of the phthalimide (XIII) in boiling 1 M HCl. Hydroxylamine derivative (XIV) was then condensed with sulfonamide (X) to furnish oxime (XV). Finally, hydrolysis of the butyrolactone group of (XV) with aqueous NaOH gave the title compound.
| 【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); Novel indole-2,3-dione-3-oxime derivs.. EP 0869958; JP 2000501432; US 6124285; WO 9814447 . |
| 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) | 22811 | 5-bromoisoquinoline | C9H6BrN | 详情 | 详情 | |
| (II) | 22812 | 5-bromo-8-nitroisoquinoline | C9H5BrN2O2 | 详情 | 详情 | |
| (III) | 22813 | 5-bromo-2-methyl-8-nitro-2lambda(5)-isoquinoline | C10H8BrN2O2 | 详情 | 详情 | |
| (IV) | 22814 | 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C10H11BrN2O2 | 详情 | 详情 | |
| (V) | 16593 | Phenylboronic acid；Benzeneboronic acid;Phenylboron dihydroxide | 98-80-6 | C6H7BO2 | 详情 | 详情 |
| (VI) | 22816 | 2-methyl-8-nitro-5-phenyl-1,2,3,4-tetrahydroisoquinoline | C16H16N2O2 | 详情 | 详情 | |
| (VII) | 22817 | 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinylamine; 2-methyl-5-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine | C16H18N2 | 详情 | 详情 | |
| (VIII) | 22818 | 8-methyl-5-phenyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione | C18H16N2O2 | 详情 | 详情 | |
| (IX) | 22819 | 4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonyl chloride | C18H15ClN2O4S | 详情 | 详情 | |
| (X) | 22820 | N,N-dimethyl-4-(8-methyl-2,3-dioxo-2,3,6,7,8,9-hexahydro-1H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C20H21N3O4S | 详情 | 详情 | |
| (XI) | 13505 | N-Hydroxyphthalimide; 2-Hydroxy-1H-isoindole-1,3(2H)-dione | 524-38-9 | C8H5NO3 | 详情 | 详情 |
| (XII) | 22822 | 3-bromodihydro-2(3H)-furanone | 5061-21-2 | C4H5BrO2 | 详情 | 详情 |
| (XIII) | 22823 | 2-[(2-oxotetrahydro-3-furanyl)oxy]-1H-isoindole-1,3(2H)-dione | C12H9NO5 | 详情 | 详情 | |
| (XIV) | 22824 | 3-(aminooxy)dihydro-2(3H)-furanone | C4H7NO3 | 详情 | 详情 | |
| (XV) | 22825 | N,N-dimethyl-4-(8-methyl-2-oxo-3-[[(2-oxotetrahydro-3-furanyl)oxy]imino]-1,2,6,7,8,9-hexahydro-3H-pyrrolo[3,2-h]isoquinolin-5-yl)benzenesulfonamide | C24H26N4O6S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Nitration of 5-bromoisoquinoline (I) employing KNO3 in H2SO4 provides 5-bromo-8-nitroisoquinoline (II). Quaternization of isoquinoline (II) with dimethyl sulfate, followed by reduction of the resultant N-methyl isoquinolinium salt (III) with NaBH4 in cold HOAc furnishes the tetrahydroisoquinoline (IV). Subsequent Suzuki coupling between the bromotetrahydroisoquinoline (IV) and 4-chlorophenylboronic acid (V) yields the 5-aryl isoquinoline derivative (VI). The nitro group of (VI) is further reduced to amine (VII) by catalytic hydrogenation over Raney nickel. The key isatin compound (IX) is then obtained by condensation of amine (VII) with chloral (VIII) in the presence of hydroxylamine hydrochloride and sodium sulfate. Finally, isatin (IX) is converted to the desired oxime by treatment with hydroxylamine hydrochloride in EtOH.
| 【1】 Watjen, F.; Drejer, J. (NeuroSearch A/S); AMPA antagonists and a method of treatment therewith. EP 0698025; JP 1996510221; US 5780493; US 5843945; WO 9426747 . |
| 【2】 Moeller, A.; Peters, D.; Groenborg, M. (NeuroSearch A/S); Isatine derivs. with neurotrophic activity. EP 1255734; US 2003040518; WO 0155110 . |
| 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) | 22811 | 5-bromoisoquinoline | C9H6BrN | 详情 | 详情 | |
| (II) | 22812 | 5-bromo-8-nitroisoquinoline | C9H5BrN2O2 | 详情 | 详情 | |
| (III) | 58406 | 5-bromo-2-methyl-8-nitroisoquinolinium methanesulfonate | C11H11BrN2O5S | 详情 | 详情 | |
| (IV) | 22814 | 5-bromo-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C10H11BrN2O2 | 详情 | 详情 | |
| (V) | 17575 | 4-chlorophenylboronic acid | 1679-18-1 | C6H6BClO2 | 详情 | 详情 |
| (VI) | 58407 | 5-(4-chlorophenyl)-2-methyl-8-nitro-1,2,3,4-tetrahydroisoquinoline | C16H15ClN2O2 | 详情 | 详情 | |
| (VII) | 58408 | 5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinamine; 5-(4-chlorophenyl)-2-methyl-1,2,3,4-tetrahydro-8-isoquinolinylamine | C16H17ClN2 | 详情 | 详情 | |
| (VIII) | 58409 | 2,2,2-trichloroacetaldehyde | 75-87-6 | C2HCl3O | 详情 | 详情 |
| (IX) | 58410 | 5-(4-chlorophenyl)-8-methyl-6,7,8,9-tetrahydro-1H-pyrrolo[3,2-h]isoquinoline-2,3-dione | C18H15ClN2O2 | 详情 | 详情 |