Solid-phase synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-one- 5-carboxylic acid amide derivatives: a Biginelli three-component condensation protocol based on immobilized beta-ketoamides.
Solid-phase synthesis of 4,6-diaryl-3,4-dihydropyrimidine-2(1H)-one- 5-carboxylic acid amide derivatives: a Biginelli three-component condensation protocol based on immobilized beta-ketoamides.
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DOI：
10.1021/cc050074c
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发表时间：
2006-03
影响因子：
--
通讯作者：
G. Groß;H. Wurziger;A. Schober
中科院分区：
文献类型：
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作者：
G. Groß;H. Wurziger;A. Schober
1893年，Pietro Biginelli发现了一种多组分反应，该反应导致部分还原的嘧啶酮衍生物(4)。1从那时起，“Biginelli反应”一直被认为是制备3，4-二氢嘧啶-2(1H)-酮(DHPM)衍生物的有效的一锅反应方案(4)。2 DHPM衍生物被认为是药物研究的重要杂环支架。Biginelli反应的基本形式如方案1所示。在过去的十年中，人们发现了具有不同药理性质的DHPM衍生物。DHPM的核心结构被发现具有Cachannel调节、肾上腺素能激动剂、有丝分裂激动素抑制、抗菌、抗真菌等药理活性。3此外，在几种海洋天然产物中还发现了二氢嘧啶-5-羧酸根。4 DHPM衍生物被认为是药物研究中的特权结构。5、6为了使新的DHPM衍生物可用于药物发现，需要适当的合成方案。在这里，我们描述了一种在固相Biginelli条件下制备4，6-二芳基DHPM衍生物的简单而有效的方法。在之前的一篇文章中，我们描述了两种制备β-酮酰胺前体的方法。7根据三组分反应的组成单元，选择固定化策略。在最近的文献中描述了至少三种不同的在固体载体上制备DHPM衍生物(4)的策略。第一种是利用固定化尿素或硫脲基团(3)。第二种使用固定化β-酮酯(1)，第三种使用S连接的异硫氰酸酯-
In 1893, Pietro Biginelli discovered a multicomponent reaction which leads to partly reduced pyrimidinone derivatives (4). 1 Since that time, the “Biginelli reaction” has been known as an efficient one-pot reaction protocol to prepare 3, 4-dihydropyrimidine-2 (1H)-one (DHPM) derivatives (4). 2 DHPM derivatives are known as interesting heterocyclic scaffolds for drug research. The basic form of the Biginelli reaction is illustrated in Scheme 1. In the past decade, DHPM derivatives with different pharmacological properties were found. The DHPM core structure was found to possess Cachannel modulating, adrenergic agonistic, mitotic kinesin inhibiting, antibacterial, fungicidal, and other pharmacological properties. 3 In addition, the dihydropyrimidine-5-carboxylate core has been found in several marine natural products. 4 DHPM derivatives are regarded as privileged structures in drug research. 5, 6 To make new DHPM derivatives available to drug discovery, appropriate synthetic protocols are needed. Here, we describe a simple and efficient procedure for the preparation of 4, 6-diaryl DHPM derivatives under solidphase Biginelli conditions. In a previous publication, we described two methods for the preparation of the β-ketoamide precursors. 7Depending on the building blocks for the three-component reaction, the immobilization strategies were chosen. At least three different strategies for the preparation of DHPM derivatives (4) on solid support were described in recent literature. The first one makes use of immobilized urea or thiourea moieties (3). The second uses an immobilized β-ketoester (1), and the third one uses an S-linked isothiou-