新型抗帕金森伊曲茶碱药物的合成工艺
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摘要
以1,3-二乙基-5,6-二氨基脲嘧啶为起始原料与3,4-二甲氧基肉桂酰氯进行N-酰基化反应,再在碱作用下发生环合反应,然后和碳酸二甲酯发生甲基化反应制备得到伊曲茶碱。N-酰基化和环合反应通过"一锅煮"法省去了中间产物的分离,提高了产率;且甲基化反应选用了环境友好试剂碳酸二甲酯替代碘甲烷或硫酸二甲酯,提高了制备工艺的经济性与环保性。本路线反应条件温和,后处理简单易行,适合工业化生产。
N-acylation with 3,4-dimethoxycinnamoyl chloride starting from 1,3-diethyl-5,6-diaminouracil, followed by cyclization under the action of a base, and then istradefylline is prepared by methylation reaction with dimethyl carbonate. The N-acylation and cyclization reactions eliminate the separation of intermediates by the "one-pot" process and increase the yield. The methylation reaction uses dimethyl carbonate as an environmentally friendly reagent instead of methyl iodide or dimethyl sulfate, which improves the economic and environmental protection of the preparation process. The reaction conditions of this route are mild and the post-treatment is not complicated, which is more suitable for industrial production.
N-acylation with 3,4-dimethoxycinnamoyl chloride starting from 1,3-diethyl-5,6-diaminouracil, followed by cyclization under the action of a base, and then istradefylline is prepared by methylation reaction with dimethyl carbonate. The N-acylation and cyclization reactions eliminate the separation of intermediates by the "one-pot" process and increase the yield. The methylation reaction uses dimethyl carbonate as an environmentally friendly reagent instead of methyl iodide or dimethyl sulfate, which improves the economic and environmental protection of the preparation process. The reaction conditions of this route are mild and the post-treatment is not complicated, which is more suitable for industrial production.
引文
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[2]张雪,张雯,杜立达,等.抗帕金森病药物及其作用靶点研究进展[J].国际药学研究杂志, 2016,43(1):87-96.
[3]李娟,韩雨霏,李颖修,等.腺苷A2a受体抑制剂伊曲茶碱的合成工艺改进[J].中国药物化学杂志, 2018,28(3):200-224.
[4]李兴泰,李程鹏.伊曲茶碱合成工艺改进[J].药学研究,2015,34(9):553-555.
[5]罗芳,何祖莺,朱钢国,等.一种8-硫杂黄嘌呤化合物的制备方法[P]. CN:103254194A,2013-08-21.
[6] Huang Y, Song F, Wang Z, et al. Cheminform abstract:dehydrogenative heck coupling of biologically relevant N heteroarenes with alkenes:discovery of fluorescent core frameworks[J]. Cheminform, 2012, 48(23):2864-2866.
[7] Labeaume P,Dong M,Sitkovsky M,et al.An efficient route to xanthine based A(2A)adenosine receptor antagonists and functional derivatives[J]. Org Biomol Chem,2010,8(18):4155-4157.
[8]龚登凰,王洁,胡瑞,等.伊曲茶碱的合成工艺改进[J].精细化工中间体,2015,45(2):26-29.
[9]刘路宽,刘仕伟,李露,等.对甲氧基肉桂酸的合成研究[J].化工科技,2013,21(2):5-7.