伊曲茶碱的合成研究

Synthesis of istradefylline

目的优化抗帕金森病药伊曲茶碱1的合成工艺以适用于工业化生产。方法将碳酸二甲酯和乙胺经缩合、环合、亚硝化、还原得1,3-二乙基-5,6-二氨基尿嘧啶(6),化合物6与(E)-3,4-二甲氧基苯丙烯酸(8)进行缩合、闭环、甲基化反应制得伊曲茶碱1。化合物8可由3,4-二甲氧基苯甲醛(7)和丙二酸经Knoevenagel缩合反应制得。中间体及目标化合物经过MS和~1H-NMR确证。结果与结论对各关键工艺质量控制点的工艺进行优化,使合成总收率达26.2%,产品纯度为99.76%。改进后的工艺条件温和,操作简便,无需柱层析,适合工业化生产。

Objective To optimize the synthesis process of istradefylline 1 for industrial production.Methods Istradefylline was synthesized from dimethyl carbonate and ethylamine through a series reactions including condensation,cyclization,nitrosation,and reduction to produce 1,3-diethyl-5,6-diaminouraeil（6）,which was subjected to amidation with（E）-3,4-dimethoxycinnamic acid（8）.followed by cyclization and methylation reaction.Compound 8 was prepared from veratraldehyde and propanedioic acid by Knoevenagel condensation.The structures of intermediate and target compounds were confirmed by MS and 1 H-NMR.Results and Conclusion The quality control points of each key process were optimized so that the total yield was 26.2%and the purity of the product was 99.76%.This improved synthesis method has some advantages,such as mild reaction conditions,simple operation,and applicability to industrial production.