New Methods On Synthesis Of A Key Intermediate Of Huperzine A

Huperzine A has shown to be a highly effective inhibitor of acetylcholinesterase. Methyl6-hydroxy-2-methoxy-7,8-dihydroquinoline-5-carboxylate is a key intermediate forsynthesis of Huperzine A. Different synthetic methods are overviewed in this thesis, andtwo novel synthetic methods for key intermediate of Huperzine A are described.Method a: After treatment of1,4-cyclohexanedione monoethylene acetal withN,N-dimethyl formamide dimethyl acetal, and subsequently followed by cyclization withmethyl cyanoacetate, a crucial intermediate methyl2’-oxo-2’,5’,7’,8’-tetrahydro-1’H-spiro[[1,3]dioxolane-2,6’-quinoline]-3’-carboxylate was obtained, which was finally led topreparation of compound1by the known methods.Method b: Selective bromination of2-methoxy-6-methylpyridine with1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione, followed by reaction withN-bromosuccinimide and treatment with diethyl phosphite afforded3-bromo-2-(bromomethyl)-6-methoxypyridine. Treatment of methyl acetoacetate withbase generated double-anion intermediate, which reacted with3-bromo-2-(bromomethyl)-6-methoxypyridine to give the key intermediate ethyl5-(3-bromo-6-methoxypyridin-2-yl)-3-oxopentanoate. Compound1was finally obtainedby intramolecular cyclization of ethyl5-(3-bromo-6-methoxypyridin-2-yl)-3-oxopentanoate using Pd or CuI/amino acid as thecatalyst.In summary, both of above-mentioned methods avoided using allergenic reagentpropiolic amide that was often used in traditional methods. The method b also avoided using expensive reagents such as silver carbonate. Furthermore, this route is moreeconomic and provides compound1in46%yield.