合成路线:The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (II),which is regioselectively demethylated with conc.H2SO4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (III).The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 in ethanol affords the secondary amine (V),which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (VI).The oxidative cyclization of (VI) by means of potassium ferricyanide and K2CO3 in toluene/water gives the (+/-)-bromoformylnarwedine (VII),which is protected with propyleneglycol (VIII) and TsOH in hot toluene yielding the ketal (IX).The reduction of the formyl group of (IX) with LiAlH4 in THF affords racemic narwedine (X),which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing TEA,an 80% of (-)-narwedine (XI) is obtained.Finally,this compound is stereoselectively reduced to the target compound by means of L-selectride in THF.
合成路线:The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in acetic acid gives 2-bromo-4,5-dimethoxybenzaldehyde (II),which is selectively demethylated with H2SO4 yielding 2-bromo-5-hydroxy-4-methoxybenzaldehyde (III).The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 affords the secondary amine (V),which is formylated with ethyl formate in dioxane/DMF giving the formamide (VI).The cyclization of (VI) by means of potassium hexacyanoferrate (III) and K2CO3 in hot toluene yields racemic N-formylbromonarwedine (+/-)(VII),which is reduced with lithium tri-tert-butoxyaluminum hydride furnishing a mixture of N-demethylbromogalanhamine (+/-)(VIII) and N-demethylepibromogalanthamine (+/-)(IX).After chromatographic separation of the two racemic epimers,resolution of racemic (+/-)(VIII) is carried out employing di-p-toluoyl tartaric acid to afford the required levo isomer.Alkylation of (-)(VIII) with 1-(3-chloropropyl)piperidine (X) gives (XI),which is finally converted to the title compound by reductive debromination in the presence of Zn and CaCl2.
参考文献标题:Development of a pilot scale process for the anti-Alzheimer drug (-)-galanthamine using large-scale phenolic oxidative coupling and crystallisation-induced chiral conversion
文献作者:K黣nburg,B.; et al.
参考来源:Org Process Res Dev 1999,3(6),425
合成路线:The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (II),which is regioselectively demethylated with conc.H2SO4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (III).The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 in ethanol affords the secondary amine (V),which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (VI).The oxidative cyclization of (VI) by means of potassium ferricyanide and K2CO3 in toluene/water gives the (+/-)-bromoformylnarwedine (VII),which is protected with propyleneglycol (VIII) and TsOH in hot toluene yielding the ketal (IX).The reduction of the formyl group of (IX) with LiAlH4 in THF affords racemic narwedine (X),which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing TEA,an 80% of (-)-narwedine (XI) is obtained.Finally,this compound is stereoselectively reduced to the target compound by means of L-selectride in THF.
参考文献标题:New kilogram-synthesis of the anti-Alzheimer drug (-)-galanthamine
文献作者:Czollner,L.; et al.
参考来源:Tetrahedron Lett 1998,39(15),2087
合成路线:The bromination of 3,4-dimethoxybenzaldehyde (I) with Br2 in methanol gives the 6-bromo-3,4-dimethoxybenzaldehyde (II),which is regioselectively demethylated with conc.H2SO4 yielding 6-bromo-3-hydroxy-4-methoxybenzaldehyde (III).The reductocondensation of (III) with 2-(4-hydroxyphenyl)ethylamine (IV) by means of NaBH4 in ethanol affords the secondary amine (V),which is formylated with ethyl formate and formic acid in dioxane furnishing the formamide (VI).The oxidative cyclization of (VI) by means of potassium ferricyanide and K2CO3 in toluene/water gives the (+/-)-bromoformylnarwedine (VII),which is protected with propyleneglycol (VIII) and TsOH in hot toluene yielding the ketal (IX).The reduction of the formyl group of (IX) with LiAlH4 in THF affords racemic narwedine (X),which is submitted to a crystallization-induced chiral transformation using a catalytic amount of seed crystals of (-)-narwedine in refluxing ethanol containing TEA,an 80% of (-)-narwedine (XI) is obtained.Finally,this compound is stereoselectively reduced to the target compound by means of L-selectride in THF.
参考文献标题:A concise,scaleable synthesis of narwedine
文献作者:Chaplin,D.A.; et al.
参考来源:Tetrahedron Lett 1997,38(45),7931
合成路线:The enantioselective condensation of 2-bromovanillin (I) with cyclohexenecarboxylate (II) by means of the chiral phosphine ligand (III) gives the chiral aryl ether (IV),which is reduced with DIBAL to yield the diol (V).The protection of (V) with Tbdms-OTf affords the bis silyl ether (VI),which is cyclized by means of Pd(OAc)2 to furnish the tetrahydrodibenzofuran (VII).The deprotection of (VII) with TBAF gives the diol (VIII),which is chemoselectively oxidized with MnO2 to yield the hydroxyaldehyde (IX).The reductocondensation of (IX) with methylamine and NaBH3CN affords the secondary amine (X),which is protected with Boc2O,providing the carbamate (XI).The oxidation of (XI) with DMP gives the aldehyde (XII),which is condensed with the phosphonium bromide (XIII) and NaHMDS,yielding the vinyl ether (XIV).The deprotection and cyclization of (XIV) by means of TFA affords the seven-member ring hemiaminal (XV),which is reduced with NaBH3CN to provide deoxygalanthamine (XVI).The epoxidation of (XVI) with dimethyldioxirane (DMDO) and TsOH furnishes the epoxide (XVII),which is regioselectively opened with diphenyl diselenide and NaBH4 to give the alpha-hydroxy selenide (XVIII).Elimination of the selenide group of (XVIII) by oxidation with NaIO4 at 80 C yielded isogalanthamine (XIX),which is finally isomerized to the target compound by treatment with Osborn's rhenium catalyst (Ph3SiO-ReO3).
参考文献标题:Enantioselective total synthesis of (-)-galanthamine
文献作者:Trost,B.M.; Toste,F.D.
参考来源:J Am Chem Soc 2000,122(45),11262
合成路线:The oxidative cyclization of the formamide derivative (I) with iodosobenzene bis(trifluoroacetate) (PIFA) gives the tricyclic semiquinone (II),which is debenzylated by means of TFA and Me2S and cyclized with Ms-OH to yield the tetracyclic ketone (III).Elimination of the extra OH group of (III) by means of Tf2O,Pd(OAc)2 and TEA affords the intermediate (IV),which is reduced by means of L-Selectride and LiAlH4 to provide racemic galanthamine (V).Finally,this compound is submitted to optical resolution to furnish the target (-)-galanthamine.Alternatively,the protection of the ketonic group of (IV) with ethyleneglycol and PPTS gives the spiroketal (VI),which is selectively reduced with LiAlH4 and hydrolyzed with HCl to yield racemic narwedine (VII).Finally,the reduction of (VII) with L-Selectride affords the already described racemic galanthamine.
参考文献标题:An efficient synthesis of (?-narwedine and (?-galanthamine by an improved phenolic oxidative coupling
文献作者:Node,M.; et al.
参考来源:Angew Chem.Int Ed Engl 2001,40(16),3060
合成路线:The reaction of (-)-galanthamine hydrobromide (I) with H2O2 in formic acid at 100 C gives 8-bromo-(-)galanthamine (II),which is then treated with LiAlD4 and D2O to yield the target deuterated compound.
合成路线:The reduction of (-)-narwedine (I) with BuLi,D2,tris(sec-butyl)borane and N,N,N',N'-tetramethylethylenediamine in hexane gives the target deuterated compound.
合成路线:The reduction of (-)-narwedine (I) with BuLi,3H2,tris(sec-butyl)borane and N,N,N',N'-tetramethylethylenediamine in hexane gives the target tritiated compound.
参考文献标题:Synthesis of 3H-(-)-galanthamine
文献作者:Fels,G.; Linnemann,E.
参考来源:J Label Compd Radiopharm 2001,44(9),661
产品链接: CAS No. 1953-04-4›› 产品链接: CAS No.357-70-0››