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【结 构 式】 
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【分子编号】41145 【品名】tert-butyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate 【CA登记号】 |
【 分 子 式 】C14H20N2O2 【 分 子 量 】248.32508 【元素组成】C 67.72% H 8.12% N 11.28% O 12.89% |
合成路线1
该中间体在本合成路线中的序号：(VII)4-Bromophenethyl amine (I) was refluxed with ethyl formate to afford formamide (II). Cyclization of (II) employing polyphosphoric acid and phosphorus pentoxide at 200 C furnished 7-bromo-3,4-dihydroisoquinoline, which was isolated as the corresponding hydrochloride salt (III). Reduction of (III) with NaBH4 gave the tetrahydroisoquinoline (IV), that was nitrated with KNO3 and H2SO4 to provide (V). After protection of (V) as the N-Boc derivative (VI), reduction of the nitro group with concomitant hydrogenolysis of the bromine by hydrogenation over Pd/CaCO3 yielded aminoisoquinoline (VII). This was coupled with 4’-(trifluoromethyl)biphenyl-2-carboxylic acid (VIII) by means of EDC to produce amide (IX). Cleavage of the Boc group of (IX) with trifluoroacetic acid gave amine (X). Finally, reductive alkylation of (X) with imidazole-2-carbaldehyde (XI) and sodium cyanoborohydride furnished the title compound.
| 【1】 Quallich, G.J.; Dorff, P.H.; Chang, G. (Pfizer Inc.); Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivs., their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. JP 1999514964; US 5919795; WO 9640640 . |
| 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) | 41139 | 4-bromophenethylamine; 2-(4-bromophenyl)-1-ethanamine | 73918-56-6 | C8H10BrN | 详情 | 详情 |
| (II) | 41140 | 4-bromophenethylformamide | C9H10BrNO | 详情 | 详情 | |
| (III) | 41141 | 7-bromo-3,4-dihydroisoquinoline | C9H8BrN | 详情 | 详情 | |
| (IV) | 41142 | 7-bromo-1,2,3,4-tetrahydroisoquinoline | C9H10BrN | 详情 | 详情 | |
| (V) | 41143 | 7-bromo-6-nitro-1,2,3,4-tetrahydroisoquinoline | C9H9BrN2O2 | 详情 | 详情 | |
| (VI) | 41144 | tert-butyl 7-bromo-6-nitro-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H17BrN2O4 | 详情 | 详情 | |
| (VII) | 41145 | tert-butyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VIII) | 41132 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid | C14H9F3O2 | 详情 | 详情 | |
| (IX) | 41146 | tert-butyl 6-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C28H27F3N2O3 | 详情 | 详情 | |
| (X) | 41147 | N-(1,2,3,4-tetrahydro-6-isoquinolinyl)-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide | C23H19F3N2O | 详情 | 详情 | |
| (XI) | 41148 | 1H-imidazole-2-carbaldehyde | 10111-08-7 | C4H4N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(VII)Condensation of 2-chloro-4-nitrobenzoic acid (XII) with dimethyl malonate produced the arylmalonate (XIII). Hydrolysis and subsequent decarboxylation of (XIII) afforded diacid (XIV). This was converted into cyclic anhydride (XV) upon refluxing with Ac2O and then reduced to diol (XVI) with borane in THF. Optionally, diol (XVI) was obtained by direct reduction of diacid (XIV) with borane. After conversion of (XVI) to dimesylate (XVII), cyclization with ammonia produced tetrahydroisoquinoline (XVIII). This was protected as the N-Boc derivative (XIX) and the nitro group was reduced to the target amine (VII) by hydrogenation over Pt/C .
| 【1】 Quallich, G.J.; Dorff, P.H.; Chang, G. (Pfizer Inc.); Biphenyl-2-carboxylic acid-tetrahydro-isoquinolin-6-yl amide derivs., their preparation and their use as inhibitors of microsomal triglyceride transfer protein and/or apolipoprotein B (Apo B) secretion. JP 1999514964; US 5919795; WO 9640640 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 41145 | tert-butyl 6-amino-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (XII) | 41126 | 2-chloro-4-nitrobenzoic acid | 99-60-5 | C7H4ClNO4 | 详情 | 详情 |
| (XIII) | 41127 | 2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid | C12H11NO8 | 详情 | 详情 | |
| (XIV) | 41128 | 2-(carboxymethyl)-4-nitrobenzoic acid | C9H7NO6 | 详情 | 详情 | |
| (XV) | 41129 | 6-nitro-1H-isochromene-1,3(4H)-dione | C9H5NO5 | 详情 | 详情 | |
| (XVI) | 41130 | 2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol | C9H11NO4 | 详情 | 详情 | |
| (XVII) | 41149 | 2-[[(methylsulfonyl)oxy]methyl]-5-nitrophenethyl methanesulfonate | C11H15NO8S2 | 详情 | 详情 | |
| (XVIII) | 41150 | 6-nitro-1,2,3,4-tetrahydroisoquinoline | C9H10N2O2 | 详情 | 详情 | |
| (XIX) | 41151 | tert-butyl 6-nitro-3,4-dihydro-2(1H)-isoquinolinecarboxylate | C14H18N2O4 | 详情 | 详情 |