新产品编号:28985

3-丁酰-4-(2-甲基苯基氨基)-8-(2-羟基乙氧基)喹啉Chemical Name: 3-Butyryl-8-(2-hydroxyethoxy)-4-(2-methylphenylamino)quinoline
CAS No. 125500-29-0
项目整合开发状态: Biological Testing
项目研究机构: GlaxoSmithKline (Originator)
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).