合成路线:The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a:4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II).Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III),which is then regiospecifically brominated with N-bromosuccinimide to give (IV).A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V),which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).
合成路线:The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII).Two routes may be used to construct the diaryl ether phenol (X).The first route,utilizing an Ullmann ether synthesis,begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX).Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X).In the alternative route,compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI).The addition of 2-fluorobenzonitrile to (XI),mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile,provides nitrile (XII).Boron tribromide-assisted demethylation of (XII),followed by hydrolysis and esterification,completes the alternate synthesis of intermediate (X).
合成路线:The final coupling of fragments (VI) and (X) to give (XIII) is shown in Scheme 19757001c,and is accomplished in the presence of potassium carbonate in N,N-dimethylformamide.The final deprotection sequence is effected by hydrogenolysis of the benzyl ether followed by hydrolysis of the resulting ester to provide LY293111 as the sodium salt.
参考文献标题:Biphenylyl-substituted xanthones: Highly potent leukotriene B4 receptor antagonists
文献作者:Sawyer,J.S.; Baldwin,R.F.; Sofia,M.J.; Floreancig,P.; Marder,P.; Saussy,D.L.Jr.; Froelich,L.L.; Silbaugh,S.A.; Stengel,P.W.; Cockerham,S.L.; et al.
参考来源:J Med Chem 1993,36(24),3982-4
合成路线:The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a:4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II).Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III),which is then regiospecifically brominated with N-bromosuccinimide to give (IV).A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V),which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).
合成路线:The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII).Two routes may be used to construct the diaryl ether phenol (X).The first route,utilizing an Ullmann ether synthesis,begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX).Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X).In the alternative route,compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI).The addition of 2-fluorobenzonitrile to (XI),mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile,provides nitrile (XII).Boron tribromide-assisted demethylation of (XII),followed by hydrolysis and esterification,completes the alternate synthesis of intermediate (X).
合成路线:The final coupling of fragments (VI) and (X) to give (XIII) is shown in Scheme 19757001c,and is accomplished in the presence of potassium carbonate in N,N-dimethylformamide.The final deprotection sequence is effected by hydrogenolysis of the benzyl ether followed by hydrolysis of the resulting ester to provide LY293111 as the sodium salt.
参考文献标题:Synthetic and structure/activity studies on acid-substituted 2-arylphenols: The discovery of 2-[2-propyl-3-[3-[2-ethyl-4-(4-fluorophenyl)-5-hydroxyphenoxy]propoxy]phenoxy]benzoic acid,a high-affinity leukotriene B4 receptor antagonist
文献作者:Sawyer,J.S.; Bach,N.J.; Baker,S.R.; Baldwin,R.F.; Borromeo,P.S.; Cockerham,S.L.; Fleisch,J.H.; Floreancig,P.; Froelich,L.L.; Jackson,W.T.; et al.
参考来源:J Med Chem 1995,38(22),4411-32
合成路线:The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a:4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II).Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III),which is then regiospecifically brominated with N-bromosuccinimide to give (IV).A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V),which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).
合成路线:The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII).Two routes may be used to construct the diaryl ether phenol (X).The first route,utilizing an Ullmann ether synthesis,begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX).Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X).In the alternative route,compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI).The addition of 2-fluorobenzonitrile to (XI),mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile,provides nitrile (XII).Boron tribromide-assisted demethylation of (XII),followed by hydrolysis and esterification,completes the alternate synthesis of intermediate (X).
合成路线:The final coupling of fragments (VI) and (X) to give (XIII) is shown in Scheme 19757001c,and is accomplished in the presence of potassium carbonate in N,N-dimethylformamide.The final deprotection sequence is effected by hydrogenolysis of the benzyl ether followed by hydrolysis of the resulting ester to provide LY293111 as the sodium salt.
参考文献标题:LY-293111 Sodium
文献作者:Sawyer,J.S.
参考来源:Drugs Fut 1996,21(6),610
合成路线:The biphenyl side chain of LY293111 can be constructed as illustrated in Scheme 19757001a:4-Benzyloxy-2-hydroxyacetophenone (I) is alkylated with 1-bromo-3-chloropropane to provide compound (II).Reduction of the keto group with triethylsilane in trifluoroacetic acid provides (III),which is then regiospecifically brominated with N-bromosuccinimide to give (IV).A Suzuki biaryl coupling of (IV) with 4-fluorophenylboronic acid is used to prepare chloride (V),which is treated with sodium iodide in refluxing 2-butanone to give intermediate iodide (VI).
合成路线:The key diaryl ethyl fragment of LY293111 begins with the deprotonation and alkylation of 1,3-dimethoxybenzene (VII) to provide compound (VIII).Two routes may be used to construct the diaryl ether phenol (X).The first route,utilizing an Ullmann ether synthesis,begins with the demethylation of (VIII) with molten pyridinium hydrochloride to give diol (IX).Subsequent coupling of (IX) with methyl 2-iodobenzoate in the presence of copper and potassium carbonate in refluxing pyridine provides the target phenol (X).In the alternative route,compound (VIII) is mono-demethylated with sodium ethanethiolate in hot N,N-dimethylformamide to provide phenol (XI).The addition of 2-fluorobenzonitrile to (XI),mediated by potassium fluoride-alumina and 18-crown-6 in refluxing acetonitrile,provides nitrile (XII).Boron tribromide-assisted demethylation of (XII),followed by hydrolysis and esterification,completes the alternate synthesis of intermediate (X).
合成路线:The final coupling of fragments (VI) and (X) to give (XIII) is shown in Scheme 19757001c,and is accomplished in the presence of potassium carbonate in N,N-dimethylformamide.The final deprotection sequence is effected by hydrogenolysis of the benzyl ether followed by hydrolysis of the resulting ester to provide LY293111 as the sodium salt.
参考文献标题:Synthesis of diaryl ethers,diaryl thioethers,and diaryl amines mediated by potassium fluoride-alumina and 18-crown-6
文献作者:Schmittling,E.A.; Sawyer,J.S.
参考来源:J Org Chem 1993,583229-30
产品链接: CAS No. 161172-51-6››