Preparation of methyl 2-methoxycarbonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylate
Preparation of methyl 2-methoxycarbonylmethyl-6-oxo-1,6-dihydropyridine-3-carboxylate
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DOI：
10.1080/00304940409355383
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发表时间：
2004-04-01
影响因子：
1.5
通讯作者：
Bai, D
中科院分区：
文献类型：
--
作者：
Feng, S;He, XC;Bai, D
石杉碱甲 (Huperzine A) 是一种从中药石杉 (Huperia serrata (Thunb.) Trev.) 中分离出来的石松生物碱，是一种有效的、可逆的乙酰胆碱酯抑制剂。在中国，它已被批准作为治疗阿尔茨海默病的药物。多个研究小组已经实现了石杉碱的全合成，其中受保护的四氢喹诺酮酮酯7是常见的关键中间体。已经开发了多种从不同起始材料制备 7 的方法。 Ji等人首次全合成石杉碱甲，合成了化合物7。由2-甲基-6-羟基烟酸乙酯通过一系列有点费力的反应制成。 Kozikowski’sgrou~~-~ 开发了一种一锅三组分缩合方法，只需在 Parr 反应器中将 1, 4-环己二酮、丙炔酸甲酯的单乙烯缩酮与氨饱和的甲醇混合，'O，然后进行 α-甲甲氧基化即可得到 7。最近，Langlois 等人。 679报告称，通过5步从2-甲氧基-6-甲基吡啶得到7，总产率为43%。然而，通过这些方法获得的7的总产率并不令人满意，需要使用有机金属和昂贵的试剂并且在关键的反应条件下。本文描述了一种通过 7 个步骤从丙酮-1, 3-二甲酸二甲酯制备 7 的新方法（方案）。将市售的丙酮-1, 3-二甲酸二甲酯用丙酰酰胺在 5% Na 中处理。 $O，溶液，得到2-吡啶酮，产率61%。吡啶酮 1 在 CH2Cl2 中用 CH、I/Ag2CO3 进行 0-甲基化后，化合物 2 在 THF 中用 LiAlH 顺利还原，得到二醇 3，收率 85%。然后按照Qian等人报道的反应顺序将Diol3转化为7 Diol3用SOCl在CHCl中处理2.5小时，得到二氯化物4
Huperzine A,’a Lycopodium alkaloid isolated from Chinese folk medicine, Huperia serrata (Thunb.) Trev., is a potent, reversible inhibitor of acetylcholinesteme. In China, it has been approved as a drug for the treatment of Alzheimer’s disease. Several groups have achieved the total synthesis of huperzine in which the protected tetrahydroquinolone Eketo ester 7 is a common key intermediate. A number of methods have been developed for the preparation of 7 from different starting materials. In the first total synthesis of huperzine A, compound 7 was prepared by Ji et al. from ethyl 2-methyl-6-hydroxynicotinate via a somewhat laborious sequence of reactions. Kozikowski’sgrou~~-~ developed a one-pot, three-component condensation by simply admixing the mono-ethylene ketal of 1, 4-cyclohexanedione, methyl propiolate in ammonia-saturated methanol in a Parr reactor,’O followed by a-carbomethoxylation to obtain 7., Recently, Langlois et al. 679 reported that 7 was obtained from 2-methoxy-6-methylpyridine in five steps with a 43% overall yield. However, the overall yields of 7 obtained by these methods were not satisfactory, requiring the use of organometallic and expensive reagents and under critical reaction conditions. This paper describes a new approach to 7 from dimethyl acetone-l, 3dicarboxylate in 7 steps (Scheme).Commercially available dimethyl acetone-1, 3-dicarboxylate was treated with propiolyl amide in 5% Na. $ O, solution, affording 2-pyridone in 61% yield. After 0-methylation of pyridone 1 with CH, I/Ag2C0, in CHCl,, compound 2 was smoothly reduced with LiAlH, in THF furnishing diol3 in 85% yield. Diol3 was then transformed into 7 via the sequence of reactions reported by Qian et aL8 Diol3 was treated with SOCl, in CHC1, for 2.5 h, leading to dichloride 4