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【结 构 式】 
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【分子编号】21621 【品名】2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione 【CA登记号】 |
【 分 子 式 】C22H24N2O3 【 分 子 量 】364.44424 【元素组成】C 72.51% H 6.64% N 7.69% O 13.17% |
合成路线1
该中间体在本合成路线中的序号：(III)Reductive condensation of tetrahydroisoquinoline (I) with 4-phthalimidobutyraldehyde (II) in the presence of sodium triacetoxy borohydride yielded the phthalimidobutyl isoquinoline (III). O-Demethylation of (III) was then accomplished by conversion to the hydrochloride salt, followed by treatment with BBr3 in CH2Cl2 yielding (IV). Reaction of the resulting 7-hydroxy derivative (IV) with trifluoromethanesulfonic anhydride in pyridine afforded triflate (V). Subsequent treatment of (V) with hydrazine hydrate in EtOH removed the phthalimido group, and the resulting amine (VI) was finally coupled with 3-(3-indolyl)propenoic acid (VII) in the presence of EDC and HOBt to give the target amide.
| 【1】 Austin, N.E.; et al.; Novel 1,2,3,4-tetrahydroisoquinolines with high affinity and selectivity for the dopamine D3 receptor. Bioorg Med Chem Lett 1999, 9, 2, 179. |
| 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) | 21619 | 7-methoxy-1,2,3,4-tetrahydroisoquinoline; methyl 1,2,3,4-tetrahydro-7-isoquinolinyl ether | C10H13NO | 详情 | 详情 | |
| (II) | 21620 | 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanal | C12H11NO3 | 详情 | 详情 | |
| (III) | 21621 | 2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (IV) | 21622 | 2-[4-[7-hydroxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C21H22N2O3 | 详情 | 详情 | |
| (V) | 21623 | 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C22H21F3N2O5S | 详情 | 详情 | |
| (VI) | 21624 | 2-(4-aminobutyl)-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C14H19F3N2O3S | 详情 | 详情 | |
| (VII) | 21625 | trans-3-(3-Indolyl)-2-propenoic acid; trans-Indole-3-acrylic acid; trans-beta-Indoleacrylic acid; Indole-3-acrylic acid; 3-(3-Indolyl)acrylic acid; (E)-3-(1H-indol-3-yl)-2-propenoic acid | 29953-71-7 | C11H9NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VI)4-Aminobutyraldehyde diethyl acetal (I) was treated with N-(ethoxycarbonyl)phthalimide (II) in THF to produce the phthalimido acetal (III), which was hydrolyzed to aldehyde (IV) with HCl in aqueous THF. Subsequent reductive alkylation of 7-methoxy-1,2,3,4-tetrahydroisoquinoline (V) with (IV) in the presence of sodium triacetoxyborohydride provided (VI). After conversion to the hydrochloride salt, the methyl ether of (VI) was cleaved using BBr3 in CH2Cl2 to give the phenol (VII), which was treated with trifluoromethanesulfonic anhydride in pyridine to afford triflate (VIII). The phthalimido group of (VIII) was then removed with ethanolic hydrazine and the resulting primary amine (IX) was finally coupled with 3-(3-indolyl)acrylic acid (X) in the presence of EDC and HOBt to yield the target amide.
| 【1】 Nash, D.J.; Stemp, G. (SmithKline Beecham plc); Tetrahydroisoquinoline derivs. and their pharmaceutical use. EP 0922035; WO 9806699 . |
| 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) | 23323 | 4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine | 6346-09-4 | C8H19NO2 | 详情 | 详情 |
| (II) | 10293 | methyl (2R)-2-amino-3-(2-chloro-4-quinolinyl)propanoate | C13H13ClN2O2 | 详情 | 详情 | |
| (III) | 23325 | 2-(4,4-diethoxybutyl)-1H-isoindole-1,3(2H)-dione | C16H21NO4 | 详情 | 详情 | |
| (IV) | 21620 | 4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butanal | C12H11NO3 | 详情 | 详情 | |
| (V) | 21619 | 7-methoxy-1,2,3,4-tetrahydroisoquinoline; methyl 1,2,3,4-tetrahydro-7-isoquinolinyl ether | C10H13NO | 详情 | 详情 | |
| (VI) | 21621 | 2-[4-[7-methoxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C22H24N2O3 | 详情 | 详情 | |
| (VII) | 21622 | 2-[4-[7-hydroxy-3,4-dihydro-2(1H)-isoquinolinyl]butyl]-1H-isoindole-1,3(2H)-dione | C21H22N2O3 | 详情 | 详情 | |
| (VIII) | 21623 | 2-[4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)butyl]-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C22H21F3N2O5S | 详情 | 详情 | |
| (IX) | 21624 | 2-(4-aminobutyl)-1,2,3,4-tetrahydro-7-isoquinolinyl trifluoromethanesulfonate | C14H19F3N2O3S | 详情 | 详情 | |
| (X) | 21625 | trans-3-(3-Indolyl)-2-propenoic acid; trans-Indole-3-acrylic acid; trans-beta-Indoleacrylic acid; Indole-3-acrylic acid; 3-(3-Indolyl)acrylic acid; (E)-3-(1H-indol-3-yl)-2-propenoic acid | 29953-71-7 | C11H9NO2 | 详情 | 详情 |