石杉碱甲类似物的研究II.N-甲基吡啶酮石杉碱甲类似物的合成

石杉碱甲(1)是从中草药石杉属植物千层塔(Lycopodium serratum Thunb.)中分得的一种高效可逆的乙酰胆碱酯酶抑制剂,临床试验证实它对早老性痴呆症有显著疗效。本文报道N-甲基吡啶酮石杉碱甲类似物2和3的合成。2-甲氧基-5-甲氧羰基-11-亚甲基-5,9-甲撑环辛-7-烯并吡啶(9)在乙腈中用三甲基氯硅烷和碘化钠选择性脱保护以定量的产率得吡啶酮10,再用甲醇钠和碘甲烷甲基化得N-甲基吡啶酮11,11经碱性水解,Curtius重排和氨基的脱保护得N-甲基吡啶酮石杉碱甲类似物2。通过类似的途径从中间体2-甲氧基-5-甲氧羰基-7-甲基-11-酮-5,9-甲撑环辛-7-烯并吡啶(14)合成了类似物3。类似物2和3的乙酰胆碱酯酶抑制活性均低于天然石杉碱甲。

STUDIES ON ANALOGUES OF HUPERZINE A Ⅲ. SYNTHESIS OF N-METHYL PYRIDONE ANALOGUES OF HUPERZINE A

Huperzinc A(1),an alkaloid isolated from the Chinese folk medicine Huperzia serrata, is a potent and reversible inhibitor of acetylcholinesterase.Clinical trials have confirmed thathuoerzine A is effective in the treatment of senile dementia including Alzheimer's disease.In thispaper the synthesis of N-methyl pyridone analogues 2 and 3 of huperzine A is reported.The selective deprotection of intermediate 9 with chlorotrimethylsilane and sodium iodide inacetonitrile gave a quantitative yield of pyridone 10, which was regioselectively converted to N-methyl pyridone 11 in 94% yield with sodium methoxide and iodomethane.Hydrolysis of ester 11,followed by medified Curtius rearrangement and TMSI- promoted decarbomethoxylation affordedanalogue 2.Similarly,analogue 3 was prepared by using methacrolein instead of acrolein in Michael-Aldol condensations. The acetylcholinesterase inhibitory activities of analogues 2 and 3 were found to be much weakerthan that of huperzine A.