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【结 构 式】 
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【药物名称】ZD-8731, ICI-D8731 【化学名称】2-Ethyl-4-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethoxy]quinoline hydrochloride 【CA登记号】135015-84-8 (monoHCl) 【 分 子 式 】C25H22ClN5O 【 分 子 量 】443.93999 |
【开发单位】AstraZeneca (Originator) 【药理作用】CARDIOVASCULAR DRUGS, Hypertension, Treatment of, Angiotensin AT1 Antagonists |
合成路线1
1) The cyclization of aniline (I) with propionylacetic acid methyl ester (II) by means of p-toluenesulfonic acid in refluxing cyclohexane gives 2-ethylquinolin-4(1H)-one (III), which is condensed with 5-[4'-(bromomethyl)biphenyl-2-yl]-2-(triphenylmethyl)tetrazole (IV) by means of NaH in DMF, yielding 2-ethyl-4-[2'-[1-(triphenylmethyl)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (V). Finally, this compound is deprotected with HCl in ethanol - methanol. 2) The condensation of 4-methylphenylboronic acid (VI) with 2-bromobenzonitrile (VII) by means of Na2CO3 and PdCl2 in toluene - methanol gives 2-(4-methylphenyl)benzonitrile (VIII), which is brominated with N-bromosuccinimide (NBS) and azobis(isobutyronitrile) (AIBN) in hot chlorobenzene, yielding the bromomethyl derivative (IX). The condensation of (IX) with quinolone (III) by means of K2CO3 in N-methylpyrrolidone affords 4-(2'-cyanobiphenyl-4-ylmethoxy)-2-ethylquinoline (X), which is treated with tributyltin hydrazide in refluxing toluene to afford 2-ethyl-4-[2'-[2-(tributyltin)tetrazol-5-yl]biphenyl-4-ylmethoxy] quinoline (XI). Finally, this compound is deprotected with NaNO2 and HCl in cool water.
| 【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 |
|---|---|---|---|---|---|---|
| (I) | 12294 | Aniline; Phenylamine | 62-53-3 | C6H7N | 详情 | 详情 |
| (II) | 15536 | methyl 3-oxopentanoate | 30414-53-0 | C6H10O3 | 详情 | 详情 |
| (III) | 15537 | 2-ethyl-4(1H)-quinolinone | C11H11NO | 详情 | 详情 | |
| (IV) | 15538 | 5-[4'-(bromomethyl)[1,1'-biphenyl]-2-yl]-2-trityl-2H-1,2,3,4-tetraazole | 124750-51-2 | C33H25BrN4 | 详情 | 详情 |
| (V) | 15539 | 2-ethyl-4-quinolinyl [2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methyl ether; 2-ethyl-4-[[2'-(2-trityl-2H-1,2,3,4-tetraazol-5-yl)[1,1'-biphenyl]-4-yl]methoxy]quinoline | C44H35N5O | 详情 | 详情 | |
| (VI) | 15540 | 4-methylphenylboronic acid; p-Tolylboronic acid | 5720-05-8 | C7H9BO2 | 详情 | 详情 |
| (VII) | 15541 | o-bromobenzonitrile; 2-bromobenzonitrile | 2042-37-7 | C7H4BrN | 详情 | 详情 |
| (VIII) | 13929 | 2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile | 114772-53-1 | C14H11N | 详情 | 详情 |
| (IX) | 15332 | 4'-(bromomethyl)[1,1'-biphenyl]-2-carbonitrile; 4'-bromomethyl-2-cyanobiphenyl | 114772-54-2 | C14H10BrN | 详情 | 详情 |
| (X) | 15544 | 4'-[[(2-ethyl-4-quinolinyl)oxy]methyl][1,1'-biphenyl]-2-carbonitrile | C25H20N2O | 详情 | 详情 | |
| (XI) | 15545 | 5-[4'-(2-Ethylquinolin-4-yloxymethyl)biphenyl-2-yl]-2-(tributylstannyl)-2H-tetrazole | C37H47N5OSn | 详情 | 详情 |
合成路线2
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 |