合成路线:The synthesis of SK&F 96067 can be achieved in five stages:Reaction of ethyl butyrylacetate with triethyl orthoformate and acetic anhydride gives ethyl 2-butyryl-3-ethoxyacrylate (II) as a mixture of (E)- and (Z)-isomers.Treatment of (II) with o-anisidine provides the acyclic quinolone precursor (III),which on thermal cyclization in diphenyl ether gives the quinolone (IV).Conversion to the 4-chloroquinoline (V) is achieved by treatment with phosphorus oxychloride.Reaction of the chloroquinoline (V) with o-toluidine gives SK&F 96067 (VI).
参考文献标题:SK&F-96067
文献作者:Ife,R.J.
参考来源:Drugs Fut 1992,17(9),796
合成路线:The synthesis of SK&F 96067 can be achieved in five stages:Reaction of ethyl butyrylacetate with triethyl orthoformate and acetic anhydride gives ethyl 2-butyryl-3-ethoxyacrylate (II) as a mixture of (E)- and (Z)-isomers.Treatment of (II) with o-anisidine provides the acyclic quinolone precursor (III),which on thermal cyclization in diphenyl ether gives the quinolone (IV).Conversion to the 4-chloroquinoline (V) is achieved by treatment with phosphorus oxychloride.Reaction of the chloroquinoline (V) with o-toluidine gives SK&F 96067 (VI).
参考文献标题:Reversible inhibitors of the gastric (H+/K+)-ATPase.3.3-Substituted-4-phenylaminoquinolines
文献作者:Ife,R.J.; Brown,T.H.; Keeling,D.J.; Leach,C.A.; Meeson,M.L.; Parsons,M.E.; Reavill,D.R.; Theobald,C.J.; Wiggall,K.J.
参考来源:J Med Chem 1992,35(18),3413
合成路线:The reaction of 3-methoxy-2-nitrobenzoic acid methyl ester (I) with 2-pentanone (II) by means of LDA gives 1-(3-methoxy-2-nitrophenyl)hexane-1,3-dione (III),which is condensed with dimethylformamide dimethyl acetal (DMFA) yielding the enamine (IV).The cyclization of (IV) by hydrogenation with H2 over Pd/C affords quinolone (V),which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI).Finally,this compound is condensed with o-toluidine in refluxing dioxane.The intermediate,the quinolone (V) has also been obtained as follows: The reaction of 1-chloro-1-hexen-3-one (VIII) with NaOH in methanol gives 3-oxohexanal (IX) (enol form),which is condensed with 2-amino-3-methoxybenzoic acid methyl ester (X) yielding the enamine (XI).Finally,this compound is cyclized by means of sodium methoxide to afford the desired quinolone (V).
合成路线:The condensation of 8-methoxyquinolin-4(1H)-one (XII) with o-toluidine (VII) gives the secondary amine (XIII),which is brominated with NBS to the 3-bromo derivative (XIV).Finally,this compound is condensed with N-methoxy-N-methylbutyramide (XV) by means of BuLi to afford the target compound.
合成路线:The condensation of ethoxymethylenemalonic acid diethyl ester (XVI) with 2-methoxyaniline (XVII) in hot toluene gives the aminomethylene derivative (XVIII),which is cyclized with POCl3 and polyphosphoric acid (PPA) at 100 C yielding 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XIX),which is hydrolyzed with NaOH in methanol to the corresponding free acid (XX),and treated with refluxing SOCl2 to afford 4-chloro-8-methoxyquinoline-3-carbonyl chloride (XXI).The reaction of (XXI) with dimethylamine gives the corresponding amide (XXII),which is condensed with o-toluidine (VII) in refluxing dioxane yielding the expected secondary amine (XXIII).Finally,this compound is treated with propylmagnesium chloride (XXIV) to afford the target compound.
合成路线:The reaction of acyl chloride (XXI) with propylmagnesium chloride (XXIV) gives 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (XXV),which is finally condensed with o-toluidine (VII) in refluxing dioxane to afford the target compound.
合成路线:The cyclization of (XVIII) in refluxing POCl3 gives 4-chloro-8-methoxyquinoline-3-carboxylic acid ethyl ester (XXVI),which is condensed with o-toluidine (VII) in refluxing dioxane yielding the secondary amine (XXVII).Finally,this compound is condensed with propylmagnesium chloride (XXIV) to afford the target compound.
合成路线:This compound has been obtained by several related ways:1) The reaction of ethyl butyrylacetate (I) with triethyl orthoformate and Ac2O gives acrylate (II),which by reaction with o-toluidine (III) yields the aminoacrylate (IV).The cyclization of (IV) by heating at 255 C in diphenyl ether affords the quinolone (V),which is treated with refluxing POCl3 to give 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (VI).The demethylation of (VI) with AlCl3 or BBr3 yields the 8-hydroxyquinoline (VII),which is condensed with o-toluidine (VIII) in refluxing dioxane affording 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).Finally,this compound is condensed with 2-bromomethanol (X) by means of potassium tert-butoxide or with ethylene carbonate (XI) by means of K2CO3.2) The condensation of chloroquinoline (VI) with o-toluidine (VIII) in refluxing dioxane gives 1-[8-methoxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (XII),which is demethylated with AlCl3 or BBr3 as before yielding the previously reported 1-[8-hydroxy-4-(2-methylphenylamino)quinolin-3-yl-1-butanone (IX).
合成路线:The intermediate quinolone (V) has also been obtained by two other ways:a) The reaction of 3-methoxy-2-nitrobenzoic acid methyl ester (XIII) with 2-pentanone (XIV) by means of LDA gives 1-(3-methoxy-2-nitrophenyl)hexane-1,3-dione (XV),which is condensed with dimethylformamide dimethyl acetal (DMFA) yielding the enamine (XVI).Finally,this compound is cyclized by hydrogenation with H2 over Pd/C to afford the desired quinolone (V).b) The reaction of 1-chloro-1-hexen-3-one (XVII) with NaOH in methanol gives 3-oxohexanal (XVIII) (enol form),which is condensed with 2-amino-3-methoxybenzoic acid methyl ester (XIX) yielding the enamine (XX).Finally,this compound is cyclized by means of sodium methoxide to afford the desired quinolone (V).
合成路线:The condensation of 8-methoxyquinolin-4(1H)-one (XXI) with o-toluidine (VIII) gives the secondary amine (XXII),which is brominated with NBS to the 3-bromo derivative (XXIII).Finally,this compound is condensed with N-methoxy-N-methylbutyramide (XXIV) by means of BuLi to afford intermediate (XII).
合成路线:The condensation of ethoxymethylenemalonic acid diethyl ester (XXV) with 2-methoxyaniline (XXVI) in hot toluene gives the aminomethylene derivative (XXVII),which is cyclized with POCl3 and polyphosphoric acid (PPA) at 100 C yielding 8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XXVIII),which is hydrolyzed with NaOH in methanol to the corresponding free acid (XXIX),and treated with refluxing SOCl2 to afford 4-chloro-8-methoxyquinoline-3-carbonyl chloride (XXX).The reaction of (XXX) with dimethylamine gives the corresponding amide (XXXI),which is condensed with o-toluidine (VIII) in refluxing dioxane yielding the expected secondary amine (XXXII).Finally,this compound is treated with propylmagnesium chloride (XXXIII) to afford the intermediate (XII).
合成路线:The reaction of acyl chloride (XXX) with propylmagnesium chloride (XXXIII) gives 1-(4-chloro-8-methoxyquinolin-3-yl)-1-butanone (XXXIV),which is finally condensed with o-toluidine (VIII) in refluxing dioxane to afford the intermediate (XII).
合成路线:The cyclization of (XXVII) in refluxing POCl3 gives 4-chloro-8-methoxyquinoline-3-carboxylic acid ethyl ester (XXXV),which is condensed with o-toluidine (VIII) in refluxing dioxane yielding the secondary amine (XXXVI).Finally,this compound is condensed with propylmagnesium chloride (XXXIII) to afford the intermediate (XII).
参考文献标题:Synthetic routes to quinoline derivatives: Novel syntheses of 3-butyryl-8-methoxy-4-[(2-methylphenyl)amini]quinoline and 3-butyryl-8-(2-hydroxyethoxy)-4-[(2-methylphenyl)amino]quin
文献作者:Atkins,R.J.; et al.
参考来源:Org Process Res Dev 1997,1(3),185
产品链接: CAS No. 115607-61-9››