|
【结 构 式】 
|
【分子编号】41132 【品名】4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid 【CA登记号】 |
【 分 子 式 】C14H9F3O2 【 分 子 量 】266.2194696 【元素组成】C 63.16% H 3.41% F 21.41% O 12.02% |
合成路线1
该中间体在本合成路线中的序号：(VII)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：(VIII)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3
该中间体在本合成路线中的序号：(VIII)In a further procedure, nitro diol (XVI) was hydrogenated over Pt/C, and the resulting amine (XX) was condensed with acid chloride (XXI) (prepared from carboxylic acid (VIII) and SOCl2) to afford amide (XXII). After conversion of (XXII) to dimesylate (XXIII), cyclization with ammonia furnished intermediate (X).
| 【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 |
|---|---|---|---|---|---|---|
| (VIII) | 41132 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid | C14H9F3O2 | 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 | |
| (XVI) | 41130 | 2-[2-(hydroxymethyl)-5-nitrophenyl]-1-ethanol | C9H11NO4 | 详情 | 详情 | |
| (XX) | 41131 | 2-[5-amino-2-(hydroxymethyl)phenyl]-1-ethanol | C9H13NO2 | 详情 | 详情 | |
| (XXI) | 41133 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carbonyl chloride | C14H8ClF3O | 详情 | 详情 | |
| (XXII) | 41134 | N-[3-(2-hydroxyethyl)-4-(hydroxymethyl)phenyl]-4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide | C23H20F3NO3 | 详情 | 详情 | |
| (XXIII) | 41135 | 2-[[(methylsulfonyl)oxy]methyl]-5-([[4'-(trifluoromethyl)[1,1'-biphenyl]-2-yl]carbonyl]amino)phenethyl methanesulfonate | C25H24F3NO7S2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XIII)The requisite nitrodiamine (VIII) was prepared via conversion of 4-methyl-1,2-phenylenediamine (V) to the selenocycle (VI) upon treatment with SeO2 and HCl, followed by nitration to afford regioselectively the nitro derivative (VII). Conversion to the diamine (VIII) was effected by treatment of (VII) with HI. Subsequent reaction of (VIII) with 2,4-pentanedione (IX) in the presence of HCl gave rise to the benzimidazole (X). Alkylation of (X) with bromide (IV) using K2CO3 in DMF provided adduct (XI) as the major regioisomer. Catalytic hydrogenation of the nitro group of (XI) then gave amine (XII). Finally, coupling of amine (XII) with 4'-(trifluoromethyl)biphenyl-2-carboxylic acid (XIII) was achieved via EDC activation or by previous conversion of (XIII) to the corresponding acid chloride with oxalyl chloride.
| 【1】 Sun, C.-Q.; Robl, J.A.; Sulsky, R.; et al.; A novel series of highly potent benzimidazole-based microsomal triglyceride transfer protein inhibitors. J Med Chem 2001, 44, 6, 851. |
| 【3】 Sulsky, R.B.; Poss, M.A.; Slusarchyk, W.A.; Dickson, J.K.; Biller, S.A.; Tino, J.A.; Magnin, D.R.; Lawrence, R.M.; Robl, J.A.; Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. US 5760246 . |
| 【2】 Biller, S.A.; Dickson, J.K.; Lawrence, R.M.; Magnin, D.R.; Poss, M.A.; Robl, J.A.; Slusarchyk, W.A.; Sulsky, R.B.; Tino, J.A. (Bristol-Myers Squibb Co.); Conformationally restricted aromatic inhibitors of microsomal triglyceride transfer protein and method. EP 0904262; JP 2000502355; WO 9726240 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47746 | 9-(4-bromobutyl)-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C20H19BrF3NO | 详情 | 详情 | |
| (V) | 47747 | 4-methyl-1,2-benzenediamine; 2-amino-4-methylphenylamine; 3,4-Diaminotoluene; 3,4-Toluenediamine; 4-methyl-1,2-phenylenediamine; 4-Methyl-O-Phenylenediamine; asym-o-Tolylenediamine; o-Toluylenediamine; ortho-toluenediamine; Tolylene-3,4-diamine | 496-72-0 | C7H10N2 | 详情 | 详情 |
| (VI) | 47748 | 5-methyl-2,1,3-benzoselenadiazole | C7H6N2Se | 详情 | 详情 | |
| (VII) | 47749 | 5-methyl-4-nitro-2,1,3-benzoselenadiazole | C7H5N3O2Se | 详情 | 详情 | |
| (VIII) | 47750 | 2-amino-4-methyl-3-nitrophenylamine; 4-methyl-3-nitro-1,2-benzenediamine | C7H9N3O2 | 详情 | 详情 | |
| (IX) | 11620 | 2,4-Pentanedione;acetylacetone | 123-54-6 | C5H8O2 | 详情 | 详情 |
| (X) | 47751 | 2,5-dimethyl-4-nitro-1H-benzimidazole | C9H9N3O2 | 详情 | 详情 | |
| (XI) | 47752 | 9-[4-(2,5-dimethyl-4-nitro-1H-benzimidazol-1-yl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C29H27F3N4O3 | 详情 | 详情 | |
| (XII) | 47753 | 9-[4-(4-amino-2,5-dimethyl-1H-benzimidazol-1-yl)butyl]-N-(2,2,2-trifluoroethyl)-9H-fluorene-9-carboxamide | C29H29F3N4O | 详情 | 详情 | |
| (XIII) | 41132 | 4'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid | C14H9F3O2 | 详情 | 详情 |