合成路线:The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III),which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1).The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI),which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII).The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII),which is finally hydrolyzed with concentrated HCl in refluxing EtOH
合成路线:The reaction of 4-fluoro-2-nitrobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X),which is then condensed with alpha-acetyl-gamma-butyrolactone (XI) by means of Mg(OEt)2 in toluene yielding alpha-acetyl-alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XII).The hydrolysis of (XII) with HCl affords alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XIII),which by treatment with HBr (d,1.48) at 85 C is converted into gamma-bromo-4-fluoro-2-nitrobutyrophenone (XIV).The ketalization of (XIV) with ethyleneglycol and ethylenesulfite by means of p-toluenesulfonic acid in refluxing toluene yields the corresponding ketal (XV),which is condensed with the piperidine (V) by means of K2CO3 in hot methyl isobutylketone giving 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane (XVI).The hydrolysis of (XVI) HCl in refluxing isopropanol affords gamma-[hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone (XVII),which is finally reduced with H2 over Pd/C in MeOH The direct condensation of butyrophenone (XIV) with piperidine (V) by means of K2CO3 as before gives the already obtained butyrophenone (XVII).
参考文献标题:ID - 4708
文献作者:Blancafort,P.; Serradell,M.N.; Castar,J.; Owen,R.T.
参考来源:Drugs Fut 1979,4(7),492
合成路线:The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III),which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1).The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI),which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII).The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII),which is finally hydrolyzed with concentrated HCl in refluxing EtOH
参考文献标题:The XIAP antisense compound AEG35156/GEM640 demonstrates significant antitumor activity in multiple human cancer xenograft models
文献作者:Honma,T.; et al.
参考来源:Arzneim-Forsch Drug Res 1974,24(9),1248
合成路线:The reaction of 4-fluoro-2-nitrobenzoic acid (IX) with refluxing SOCl2 gives the corresponding acyl chloride (X),which is then condensed with alpha-acetyl-gamma-butyrolactone (XI) by means of Mg(OEt)2 in toluene yielding alpha-acetyl-alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XII).The hydrolysis of (XII) with HCl affords alpha-(4-fluoro-2-nitrobenzoyl)-gamma-butyrolactone (XIII),which by treatment with HBr (d,1.48) at 85 C is converted into gamma-bromo-4-fluoro-2-nitrobutyrophenone (XIV).The ketalization of (XIV) with ethyleneglycol and ethylenesulfite by means of p-toluenesulfonic acid in refluxing toluene yields the corresponding ketal (XV),which is condensed with the piperidine (V) by means of K2CO3 in hot methyl isobutylketone giving 4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-1-(4-fluoro-2-nitrophenyl)-1,1-ethylenedioxy-n-butane (XVI).The hydrolysis of (XVI) HCl in refluxing isopropanol affords gamma-[hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone (XVII),which is finally reduced with H2 over Pd/C in MeOH The direct condensation of butyrophenone (XIV) with piperidine (V) by means of K2CO3 as before gives the already obtained butyrophenone (XVII).
参考文献标题:
文献作者:Sasajima,K.; et al.(Sumitomo Chemical Co.,Ltd.)
参考来源:DE 2632414
合成路线:The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III),which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1).The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI),which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII).The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII),which is finally hydrolyzed with concentrated HCl in refluxing EtOH
参考文献标题:
文献作者:Yamamoto,H.; et al.(Sumitomo Chemical Co.,Ltd.)
参考来源:DE 2065311; JP 754670; JP 754671
合成路线:The condensation of 6-fluoro-2-methylindole (I) with beta-chloropropionitrile (II) by means of ethylmagnesium iodide (that forms the magnesium salt of (I)) in refluxing ether gives 3-(6-fluoro-2-methyl-3-indolyl)propionitrite (III),which is hydrolyzed with KOH in refluxing water yielding 3-(6-fluoro-2-methyl-3-indolyl)propionic acid (IV) (1).The condensation of (IV) with 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (V) by means of ethyl chloroformate and triethylamine in refluxing THF affords 1-[3-(6-fluoro-2-methyl-3-indolyl)propionyl]-4-hydroxy-4-(3-trifluromethylphenyl)piperidine (VI),which is reduced with LiAlH4 in refluxing THF giving 1-[3-(6-fluoro-2-methyl-3-indolyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VII).The ozonolysis of (VII) in HOAc affords 1-[3-(2-acetamido-4-fluorobenzoyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine (VIII),which is finally hydrolyzed with concentrated HCl in refluxing EtOH
参考文献标题:
文献作者:(Sumitomo Chemical Co.,Ltd.)
参考来源:FR 2196153
产品链接: CAS No. 42048-72-6››