合成路线:The enantioselective reduction of phenacyl bromide (I) with BH3.S(CH3)2 in THF catalyzed by the chiral borolidine (II) (obtained by reaction of (1R,2S)-1-amino-2-indanol (III) with BH3.S(CH3)2 in THF) gives the (R)-2-bromo-1-(4-benzyloxy-3-nitrophenyl)ethanol (IV),which is reduced with H2 over PtO2 in THF/toluene yielding the corresponding amino derivative (V).The reaction of (V) with formic acid and Ac2O affords the formamide (VI),which is condensed with the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) in THF/methanol providing the protected target compound (VIII).Finally,this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol.The intermediate the chiral (R)-N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (VII) has been obtained by reductocondensation of 1-(4-methoxyphenyl)-2-propanone (IX) and benzylamine by hydrogenation with H2 over Pd/C in methanol yielding racemic N-benzyl-N-[2-(4-methoxyphenyl)-1-methylethyl]amine (X),which is submitted to optical resolution with (S)-mandelic acid to obtain the desired (R)-enantiomer (VII).
参考文献标题:Large-scale synthesis of enantio- and diastereomerically pure (R,R)-formoterol
文献作者:Hett,R.; et al.
参考来源:Org Process Res Dev 1998,2(2),96
合成路线:The intermediate N-benzyl-N-[1(R)-methyl-2-(4-methoxyphenyl)ethyl]amine (IV) has been obtained as follows: The reductocondensation of 1-(4-methoxyphenyl)-2-propanone (I) with benzylamine (II) by H2 over Pd/C gives the N-benzyl-N-[1-methyl-2-(4-methoxyphenyl)ethyl]amine (III) as a racemic mixture,which is submitted to optical resolution with L-mandelic acid in methanol to obtain the desired (R)-enantiomer (IV).The reaction of cis-(1R,2S)-1-aminoindan-2-ol (V) with trimethylboroxine in toluene gives the (1R,2S)-oxazaborolidine (VI),which is used as chiral catalyst in the enantioselective reduction of 4-benzyloxy-3-nitrophenacyl bromide (VII) by means of BH3/THF,yielding the chiral bromoethanol derivative (VIII).The reaction of (VIII) with NaOH in aqueous methanol affords the epoxide (IX),which is condensed with the intermediate amine (IV) by heating the mixture at 90 C to provide the adduct (X).The reduction of the nitro group of (X) with H2 over PtO2 gives the corresponding amino derivative (XI),which is acylated with formic acid to afford the formamide compound (XII).Finally,this compound is debenzylated by hydrogenation with H2 over Pd/C in ethanol,providing the target compound.
参考文献标题:Modulation of catalyst reactivity for the chemoselective hydrogenation of functionalized nitroarene: Preparation of a key intermediate in the synthesis of (R,R)-formoterol tartrate
文献作者:Wilkinson,H.S.; et al.
参考来源:Org Process Res Dev 2000,4(6),567
合成路线:The synthesis of the chiral borolidine catalyst (II) starting from indoline (I),as well as the enantioselective reduction of 4'-(benzyloxy)-3'-nitrophenacyl bromide (III),catalyzed by borolidine (II),and using various borane complexes (borane/dimethylsulfide,borane/THF and borane/diethylaniline),has been studied in order to solve the problems presented in large-scale synthesis.The conclusions of the study are that the complex borane/diethylaniline (DEANB) is the most suitable reagent for large-scale reduction of phenacyl bromide (III) since the chemical hazards and inconsistent reagent quality of the borane/THF and borane/dimethylsulfide complexes disqualified their use in large-scale processes.The best reaction conditions of the reduction with this complex are presented.
参考文献标题:Diethylanilineborane: A practical,safe,and consistent-quality borane source for the large-scale enantioselective reduction of a ketone intermediate in the synthesis of (R,R)-formoterol
文献作者:Wilkinson,H.S.; et al.
参考来源:Org Process Res Dev 2002,6(2),146
产品链接: CAS No. 67346-49-0›› 产品链接: CAS No.200815-49-2››