【结 构 式】 |
【分子编号】41129 【品名】6-nitro-1H-isochromene-1,3(4H)-dione 【CA登记号】 |
【 分 子 式 】C9H5NO5 【 分 子 量 】207.14244 【元素组成】C 52.19% H 2.43% N 6.76% O 38.62% |
合成路线1
该中间体在本合成路线中的序号:(IV)Condensation of 2-chloro-4-nitrobenzoic acid (I) with dimethyl malonate produced the arylmalonate (II). This was subjected to hydrolysis and subsequent decarboxylation to afford diacid (III). Conversion of (III) to the cyclic anhydride (IV) upon refluxing with Ac2O, and then reduction with borane in THF gave rise to diol (V). Optionally, diol (V) was obtained by direct reduction of diacid (III) with borane. Nitro diol (V) was reduced to amine (VI) by hydrogenation over Pt/C. This was condensed with acid chloride (VIII) (prepared from carboxylic acid (VII) and SOCl2) to afford amide (IX). After conversion to dimesylate (X), cyclization with N-acetyl ethylenediamine (XI) furnished the tetrahydroisoquinoline (XII). Acidic hydrolysis of the acetamido group of (XIV) gave primary amine (XIII) which was finally treated with methyl chloroformate to furnish the title carbamate.
【1】 Chang, G.; Quallich, G.J. (Pfizer Inc.); Apo B-secretion/MTP inhibitory amides. EP 0944602; JP 2000505810; WO 9823593 . |
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) | 41126 | 2-chloro-4-nitrobenzoic acid | 99-60-5 | C7H4ClNO4 | 详情 | 详情 |
(II) | 41127 | 2-[2-methoxy-1-(methoxycarbonyl)-2-oxoethyl]-4-nitrobenzoic acid | C12H11NO8 | 详情 | 详情 | |
(III) | 41128 | 2-(carboxymethyl)-4-nitrobenzoic acid | C9H7NO6 | 详情 | 详情 | |
(IV) | 41129 | 6-nitro-1H-isochromene-1,3(4H)-dione | C9H5NO5 | 详情 | 详情 | |
(V) | 41130 | 2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol | C9H11NO4 | 详情 | 详情 | |
(VI) | 41131 | 2-[5-amino-2-(hydroxymethyl)phenyl]-1-ethanol | C9H13NO2 | 详情 | 详情 | |
(VII) | 41132 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid | C14H9F3O2 | 详情 | 详情 | |
(VIII) | 41133 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride | C14H8ClF3O | 详情 | 详情 | |
(IX) | 41134 | N-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide | C23H20F3NO3 | 详情 | 详情 | |
(X) | 41135 | 2-[[(methylsulfonyl)oxy]methyl]-5-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate | C25H24F3NO7S2 | 详情 | 详情 | |
(XI) | 41136 | N-(2-aminoethyl)acetamide | 1001-53-2 | C4H10N2O | 详情 | 详情 |
(XII) | 41137 | N-[2-[2-(acetamido)ethyl]-1,2,3,4-tetrahydro-6-isoquinolinyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide | C27H26F3N3O2 | 详情 | 详情 | |
(XIII) | 41138 | N-[2-(2-aminoethyl)-1,2,3,4-tetrahydro-6-isoquinolinyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide | C25H24F3N3O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XV)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 |