合成路线:Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II),which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV).The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V),which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI).The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII),which is hydrolyzed with K2CO3 to yield the target oxazole (IX).Alternatively,the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI),which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
合成路线:The reaction of D-asparagine (XXIV) with methyl trifluoroacetate (XXII) in methanol gives N-(trifluoroacetyl)-D-asparagine (XXV),which is esterified with MeOH and Ac-Cl,yielding the methyl ester (XXVI).The reaction of (XXVI) with TsCl and pyridine in dichloromethane affords the 3-cyanopropionic ester (XXVII),which is cyclized by hydrogenation over a Rh/Al2O3 catalyst in ethanol to provide the pyrrolidinone (XXVIII).Finally,this compound is condensed with benzyl chloroformate and BuLi in THF to furnish the target pyrrolidinone intermediate (XXIII).Assembly of the target compound: The reductive methylation of intermediate pyrrolidinone (XXIII) by means of LiBH4 in THF,followed by treatment with EtOH and conc.H2SO4,gives 2-ethoxy-3(R)-(trifluoroacetamido)pyrrolidine-1-carboxylic acid benzyl ester (XXIX),which is condensed with the intermediate silyl enol ether (XIII) by means of BF3/Et2O in dichloromethane to yield the adduct (XXX).The deprotection of the amino group of (XXX) with K2CO3 in ethanol/water yields the aminopyrrolidine (XXXI),which is cyclized by means of t-butylmagnesium bromide and TMEDA in THF to afford the bicyclic compound (XXXII).The reaction of the free NH group of (XXXII) with methanesulfonyl chloride and LiHMDS in THF provides the cyclic methanesulfonamide (XXXIII),which is decarboxylated by hydrogenation with H2 over Pd/C in dioxane/ethyl acetate to give the bipyrrolidine derivative (XXXIV).Finally,this compound is condensed with the oxazole intermediate (IX) by means of HOBT and DEC in acetonitrile.
参考文献标题:Process for preparing oxazole derivs.
文献作者:Hermitage,S.A.; Cardwell,K.S.(Glaxo Group Ltd.)
参考来源:WO 0053589
合成路线:Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II),which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV).The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V),which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI).The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII),which is hydrolyzed with K2CO3 to yield the target oxazole (IX).Alternatively,the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI),which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
合成路线:The reaction of D-asparagine (XXIV) with methyl trifluoroacetate (XXII) in methanol gives N-(trifluoroacetyl)-D-asparagine (XXV),which is esterified with MeOH and Ac-Cl,yielding the methyl ester (XXVI).The reaction of (XXVI) with TsCl and pyridine in dichloromethane affords the 3-cyanopropionic ester (XXVII),which is cyclized by hydrogenation over a Rh/Al2O3 catalyst in ethanol to provide the pyrrolidinone (XXVIII).Finally,this compound is condensed with benzyl chloroformate and BuLi in THF to furnish the target pyrrolidinone intermediate (XXIII).Assembly of the target compound: The reductive methylation of intermediate pyrrolidinone (XXIII) by means of LiBH4 in THF,followed by treatment with EtOH and conc.H2SO4,gives 2-ethoxy-3(R)-(trifluoroacetamido)pyrrolidine-1-carboxylic acid benzyl ester (XXIX),which is condensed with the intermediate silyl enol ether (XIII) by means of BF3/Et2O in dichloromethane to yield the adduct (XXX).The deprotection of the amino group of (XXX) with K2CO3 in ethanol/water yields the aminopyrrolidine (XXXI),which is cyclized by means of t-butylmagnesium bromide and TMEDA in THF to afford the bicyclic compound (XXXII).The reaction of the free NH group of (XXXII) with methanesulfonyl chloride and LiHMDS in THF provides the cyclic methanesulfonamide (XXXIII),which is decarboxylated by hydrogenation with H2 over Pd/C in dioxane/ethyl acetate to give the bipyrrolidine derivative (XXXIV).Finally,this compound is condensed with the oxazole intermediate (IX) by means of HOBT and DEC in acetonitrile.
参考文献标题:Pyrrolopyrrolone derivs.as inhibitors of neutrophil elastase
文献作者:Johnson,M.R.; Shah,P.; MacDonald,S.J.F.; Harrison,L.A.; Finch,H.; Smith,R.A.; Inglis,G.G.A.; Clarke,G.D.E.; Dowle,M.D.(Glaxo Group Ltd.)
参考来源:WO 9912933
合成路线:Synthesis of oxazole intermediate (IX): The reaction of 2,2-dichloroacetonitrile (I) with sodium methoxide in methanol gives methyl 2,2-dichloroethanimidoate (II),which is cyclized with DL-serine methyl ester (III) in methanol to yield oxazoline (IV).The reaction of (IV) with sodium methoxide in methanol affords 2-(chloromethyl)-4-methoxy-4,5-dihydrooxazole-4-carboxylic acid methyl ester (V),which is treated with Ts-OH in refluxing toluene to provide the chloromethyloxazole (VI).The reaction of (VI) with pyrrolidine (VII) in toluene gives the 2-(1-pyrrolidinylmethyl)oxazole-4-carboxylic acid methyl ester (VIII),which is hydrolyzed with K2CO3 to yield the target oxazole (IX).Alternatively,the reaction of 2-(bromomethyl)oxazole-4-carboxylic acid ethyl ester (X) with pyrrolidine (VII) gives the precursor (XI),which is hydrolyzed with K2CO3 as before to afford the target oxazole intermediate (IX).
参考文献标题:An efficient,practical approach to the synthesis of 2,4-disubstituted thiazoles and oxazoles: Application to the synthesis of GW475151
文献作者:Hermitage,S.A.; et al.
参考来源:Org Process Res Dev 2001,5(1),37
产品链接: CAS No.221323-43-9››