|
【结 构 式】 
|
【分子编号】15546 【品名】2-bromobenzoic acid; o-bromobenzoic acid 【CA登记号】88-65-3 |
【 分 子 式 】C7H5BrO2 【 分 子 量 】201.0195 【元素组成】C 41.83% H 2.51% Br 39.75% O 15.92% |
合成路线1
该中间体在本合成路线中的序号：(I)By condensation of o-bromobenzoic acid (I) with 2,6-dichloro-3-methylaniline (II) by means of CuBr2 in diethylene glycol dimethyl ether containing N-ethylmorpholine and heated at 145-55 C.
| 【1】 Scherrer, R.A.; Short, F.W.; Anthranilic acids and derivatives. US 3313848 . |
| 【2】 Arrigoni-Martelli, E.; Castaner, J.; Meclofenamic acid. Drugs Fut 1978, 3, 4, 307. |
合成路线2
该中间体在本合成路线中的序号：(XII)3) The condensation of 2-bromobenzoic acid (XII) with 4-nitroaniline (XIII) by means of SOCl2 in DMF gives the corresponding amide (XIV), which is cyclized with sodium azide and SOCl2 in acetonitrile - DMF, yielding 5-(2-bromophenyl)-1-(4-nitrophenyl)tetrazole (XV). The condensation of (XV) with the boronic acid (VI, Scheme 1) by means of Na2CO3 and tetrakis(triphenylphosphine)palladium in methanol - water - toluene affords 5-(4'-methylbiphenyl-2-yl)-1-(4-nitrophenyl)tetrazole (XVI), which is brominated with NBS and AIBN to the corresponding bromomethyl derivative (XVII). The condensation of (XVII) with quinolone (III, Scheme 1) by means of K2CO3 in hot N-methylpyrrolidone gives 2-ethyl-4-[2'-[1-(4-nitrophenyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XVIII), which is finally deprotected with NaH and propanethiol in N-methylpyrrolidone. 4) The dehydration of the boronic acid (VI), followed by bromination with bromine and AIBN, gives 4-(bromomethyl)boronic anhydride (XIX), which is condensed with quinolone (III) by means of K2CO3 in N-methylpyrrolidone, yielding 4-(2-ethylquinolin-4-yloxymethyl)phenylboronic acid (XX). The condensation of (XX) with the bromophenyl-tetrazole (XV) by means of K2CO3 and tetrakis(triphenylphosphine)palladium in water - methanol - toluene yields compound (XVIII), already obtained (5). Scheme 2. 5) The reaction of the boronic acid (VI) with 2,2-dimethylpropane-1,3-diol (XXI) in refluxing cyclohexane gives the cyclic boronic ester (XXII), which is brominated with BBS as before to the bromomethyl derivative (XXIII). The condensation of (XXIII) with quinolone (III) affords 2-[4-(2-ethylquinolin-4-yloxymethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane (XXIV), which is condensed with (XV) as before to give (XVIII), already obtained.
| 【1】 Roberts, D.A.; Russell, S.T.; Pearce, R.J. (AstraZeneca plc); Quinoline derivs., process for their preparation and their use as medicaments. AU 9160955; EP 0412848; GB 2234748; JP 1991169863; US 5444071 . |
| 【2】 Prous, J.; Castaner, J.; Graul, A.; ICI-D8731. Drugs Fut 1993, 18, 5, 428. |
| 【3】 Bradbury, R.H.; Allott, C.P.; Dennis, M.; et al.; New nonpeptide angiotensin II receptor antagonists. 2. Synthesis, biological properties, and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives. J Med Chem 1992, 35, 22, 4027. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (XII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (XIII) | 15547 | 4-nitrophenylamine; p-Nitroaniline; 4-nitroaniline | 100-01-6 | C6H6N2O2 | 详情 | 详情 |
| (XIV) | 15548 | 2-bromo-N-(4-nitrophenyl)benzamide | C13H9BrN2O3 | 详情 | 详情 | |
| (XV) | 11451 | 5-(2-Bromophenyl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C13H8BrN5O2 | 详情 | 详情 | |
| (XVI) | 15550 | 5-(4'-methyl[1,1'-biphenyl]-2-yl)-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H15N5O2 | 详情 | 详情 | |
| (XVII) | 15551 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-1-(4-nitrophenyl)-1H-1,2,3,4-tetraazole | C20H14BrN5O2 | 详情 | 详情 | |
| (XVIII) | 15552 | 2-ethyl-4-quinolinyl [2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-([2'-[1-(4-nitrophenyl)-1H-1,2,3,4-tetraazol-5-yl][1,1'-biphenyl]-4-yl]methoxy)quinoline | C20H14BrN5O2 | 详情 | 详情 | |
| (XIX) | 15553 | 1,3-bis[4-(bromomethyl)phenyl]-3-hydroxy-1-diboroxanol | C14H14B2Br2O3 | 详情 | 详情 | |
| (XX) | 15554 | 4-[[(2-ethyl-4-quinolinyl)oxy]methyl]phenylboronic acid | C18H18BNO3 | 详情 | 详情 | |
| (XXI) | 12641 | Neopentyl glycol; 2,2-Dimethyl-1,3-propanediol | 126-30-7 | C5H12O2 | 详情 | 详情 |
| (XXII) | 15556 | 5,5-dimethyl-2-(4-methylphenyl)-1,3,2-dioxaborinane | C12H17BO2 | 详情 | 详情 | |
| (XXIII) | 15557 | 2-[4-(bromomethyl)phenyl]-5,5-dimethyl-1,3,2-dioxaborinane | C12H16BBrO2 | 详情 | 详情 | |
| (XXIV) | 15558 | 4-[[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl]oxy]-2-ethylquinoline; 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzyl 2-ethyl-4-quinolinyl ether | C23H26BNO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(VII)The condensation of 2-(4-nitrophenyl)ethyl bromide (I) with 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (II) by means of K2CO3 and KI in DMF at 100 C gives 6,7-dimethoxy-2-[2-(4-nitrophenyl)ethyl]-1,2,3,4-tetrahydroisoquinoline (III), which is reduced with H2 over Pd/C in ethanol to yield the corresponding amine (IV). Finally, this compound is condensed with 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) by means of DCC and HOBt in DMF to afford the target carboxamide. The intermediate 5-methoxy-9-oxo-9,10-dihydroacridine-4-carboxylic acid (V) has been obtained as follows: The condensation of 2-amino-3-methoxybenzoic acid (VI) with 2-bromobenzoic acid (VII) by means of K2CO3 and copper dust give the diphenylamine (VIII), which is cyclized to the target acridine (V) by means of POCl3 in refluxing acetonitrile.
| 【1】 Dodic, N.; et al.; Synthesis and activity against multidrug resistance in Chinese hamster ovary cells of new acridone-4-carboxamides. J Med Chem 1995, 38, 13, 2418. |
| 【2】 Dumaitre, B.A.; Dodic, N. (GlaxoSmithKline plc); Acridine derivs.. EP 0494623; EP 0569380; JP 1994506440; US 5604237; WO 9212132 . |
| 【3】 Sharp, M.J.; Mader, C.J.; Strachan, C. (GlaxoSmithKline plc); Synthesis of acridine deriv. multidrug-resistant inhibitors. WO 9852923 . |
| 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) | 19191 | 1-(2-bromoethyl)-4-nitrobenzene | 5339-26-4 | C8H8BrNO2 | 详情 | 详情 |
| (II) | 25859 | 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C11H15NO2 | 详情 | 详情 | |
| (III) | 19193 | 6,7-dimethoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydroisoquinoline; 6-methoxy-2-(4-nitrophenethyl)-1,2,3,4-tetrahydro-7-isoquinolinyl methyl ether | C19H22N2O4 | 详情 | 详情 | |
| (IV) | 19194 | 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]aniline; 4-[2-[6,7-dimethoxy-3,4-dihydro-2(1H)-isoquinolinyl]ethyl]phenylamine | C19H24N2O2 | 详情 | 详情 | |
| (V) | 53881 | 5-methoxy-9-oxo-9,10-dihydro-4-acridinecarboxylic acid | n/a | C15H11NO4 | 详情 | 详情 |
| (VI) | 53879 | 2-Amino-3-methoxybenzoic acid; 2-Amino-m-anisic acid; 3-Methoxyanthranilic acid | 3177-80-8 | C8H9NO3 | 详情 | 详情 |
| (VII) | 15546 | 2-bromobenzoic acid; o-bromobenzoic acid | 88-65-3 | C7H5BrO2 | 详情 | 详情 |
| (VIII) | 53880 | 2-(2-carboxyanilino)-3-methoxybenzoic acid | n/a | C15H13NO5 | 详情 | 详情 |