合成路线: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.
合成路线: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.
参考文献标题:New nonpeptide angiotensin II receptor antagonists.2.Synthesis,biological properties,and structure-activity relationships of 2-alkyl-4-(biphenylylmethoxy)quinoline derivatives
文献作者:Bradbury,R.H.; Allott,C.P.; Dennis,M.; Fisher,E.; Major,J.S.; Masek,B.B.; Oldham,A.A.; Pearce,R.J.; Rankine,N.; Revill,J.M.; et al.
参考来源:J Med Chem 1992,35(22),4027
合成路线: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.
合成路线: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.
参考文献标题:ICI-D8731
文献作者:Prous,J.; Castar,J.; Graul,A.
参考来源:Drugs Fut 1993,18(5),428
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