SPH-1286

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