微波辅助制备1-Aryl-1 H-pyrazole-5胺
Summary
1-Aryl-1H-pyrazole-5-胺由丙烯氢化物制备,与使用微波反应器的1M HCl溶液中的3氨基克罗诺辛或β-氰酮结合制备。大多数反应在10-15分钟内完成,纯产品可以通过真空过滤获得,典型的隔离产量为70-90%。
Abstract
开发了一种用于制备各种1-aryl-1H-pyrazole-5胺的合成工艺。该方法的微波介导特性使其在时间和资源上都有效,并利用水作为溶剂。3-氨基克罗酮酸盐或适当的β-氰酮与丙烯氢化物结合,溶解在1 M HCl中。然后,在微波反应器中,在150°C下加热混合物,通常加热10-15分钟。该产品可以通过10%NaOH对溶液进行bas-beh化,并通过简单的真空过滤隔离所需的化合物,从而轻松获得。在这种反应中使用水作为溶剂,使其在生产中易于和实用,并且该方法很容易用于各种功能组。典型的分离产量范围从70-90%,反应可以在毫克到克尺度上执行,而观察到的产量变化很小或没有变化。这些分子及其衍生物的一些应用包括杀虫剂、抗疟疾和化疗药物等。
Introduction
由于这些小分子的无数应用,能够推动1-aryl-1 H-pyrazole-5胺的流线化合成。它们出现在激酶抑制剂1,抗生素2,杀虫剂3,和许多其他生物活性化合物4,5。这些化合物的合成方案非常丰富,但大多数都涉及复杂的隔离和纯化技术。一种常见的方法包括在酒精或水溶液中反流丙烯和3-氨基克罗诺辛,然后通过色谱和/或再结晶进行随后的纯化 6、7、 8,9,10.少数孤立的报告详细说明了这些化合物使用微波辐射的合成,但所有方法都需要大量的加热时间,与以前报告的其他方法11、12相比,几乎没有任何优势。.
尽管它们用途广泛,但从商业供应商那里可以获得的1-aryl-1 H-pyrazole-5胺数量有限。我们最近成功地利用微波反应器13制备了氮异变周期,并决定研究一种用于pyrazole-5-胺模拟物的相关方法。在本文中,我们详细介绍了在微波辐射下,在微波辐射下,在1M HCl中与3氨基甲苯或β-氰酮反应的丙烯氢化物,制备1-aryl-1 H-pyrazole-5-胺的程序。这个程序的优点包括反应时间短,并能够纳入各种功能组,包括卤化物,硝基,酚类,磺胺和硝基组14。
Protocol
Representative Results
Discussion
通过将β-氰酮或3-氨基克罗尼酮与1M HCl中的丙烯氢化物结合,并在微波反应器中加热至150°C,制备了多种1-aryl-1 H-pyrazole-5胺。几乎所有的化合物在10-15分钟内合成,最慢的基板需要35分钟的加热14。使用水作为溶剂可快速加热溶液,并最大限度地减少危险有机溶剂的使用。
微波反应器中当然可以达到更高的温度和压力,但反应混合物只加热到150°C,以便安全地将…
Disclosures
The authors have nothing to disclose.
Acknowledgements
这项研究得到了比尔和琳达·弗罗斯特基金的支持。
Materials
| 2-5mL Microwave vial set | Chemglass | CG-4920-01 | Set includes appropriate stir bars and 20mm aluminum seals |
| Biotage Initiator+ microwave | Biotage | 356007 | Includes crimper and decapper tool. |
| Sonicator | Kendal | Ultrasonic Cleaner GB-928 | |
| Glassware oven | Quincy Lab | 20GC | |
| 4-Fluorophenylhydrazine hydrochloride | Fisher | AC119590100 | |
| 3-Aminocrotonitrile | Fisher | AC152451000 | |
| CDCl3 | Cambridge Labs | DLM-7-100 | 99.8% D |
| Hydrochloric acid, concentrated | Fisher | A144SI-212 | Used to prepare 1 M HCl solution |
| Sodium hydroxide pellets | Fisher | S318-100 | Used to prepare 10% NaOH solution |
References
- Gradler, U., et al. Fragment-based discovery of focal adhesion kinase inhibitors. Bioorganic & Medicinal Chemistry Letters. 23 (19), 5401-5409 (2013).
- Chandak, N., Kumar, S., Kumar, P., Sharma, C., Aneja, K. R., Sharma, P. K. Exploration of antimicrobial potential of pyrazolo[3,4-b]pyridine scaffold bearing benzenesulfonamide and trifluoromethyl moieties. Medicinal Chemistry Research. 22 (11), 5490-5503 (2013).
- Huo, J., et al. Synthesis and biological activity of novel N-(3-furan-2-yl-1-phenyl-1H-pyrazol-5-yl) amides derivatives. Chinese Chemical Letters. 27 (9), 1547-1550 (2016).
- Anand, D., et al. Antileishmanial activity of pyrazolopyridine derivatives and their potential as an adjunct therapy with miltefosine. Journal of Medicinal Chemistry. 60 (3), 1041-1059 (2017).
- Eldehna, W. M., El-Naggar, D. H., Hamed, A. R., Ibrahim, H. S., Ghabbour, H. A., Abdel-Aziz, H. A. One-pot three-component synthesis of novel spirooxindoles with potential cytotoxic activity against triple-negative breast cancer MDA-MB-231 cells. Journal of Enzyme Inhibition and Medicinal Chemistry. 33 (1), 309-318 (2017).
- Briebenow, N., et al. Identification and optimization of substituted 5-aminopyrazoles as potent and selective adenosine A1 receptor antagonists. Bioorganic & Medicinal Chemistry Letters. 20 (19), 5891-5894 (2010).
- Marinozzi, M., et al. Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists. Bioorganic & Medicinal Chemistry. 20 (11), 3429-3445 (2012).
- Ochiai, H., et al. Discovery of new orally available active phosphodiesterase inhibitors. Chemical and Pharmaceutical Bulletin. 52 (9), 1098-1104 (2004).
- Ganesan, A., Heathcock, C. H. Synthesis of unsymmetrical pyrazines by reaction of an oxadiazinone with enamines. Journal of Organic Chemistry. 58 (22), 6155-6157 (1993).
- Sumesh, R. V., et al. Multicomponent dipolar cycloaddition strategy: combinatorial synthesis of novel spiro-tethered pyrazolo[3,4-b]quinoline hybrid heterocycles. ACS Combinatorial Science. 18 (5), 262-270 (2016).
- Bagley, M. C., Davis, T., Dix, M. C., Widdowson, C. S., Kipling, D. Microwave-assisted synthesis of N-pyrazole ureas and the p38α inhibitor BIRB 796 for study into accelerated cell ageing. Organic & Biomolecular Chemistry. 4 (22), 4158-4164 (2006).
- Su, W., Lin, T., Cheng, K., Sung, K., Lin, S., Wong, F. An efficient on-pot synthesis of N-(1,3-diphenyl-1H-pyrazol-5-yl)amides. Journal of Heterocyclic Chemistry. 47 (4), 831-837 (2010).
- Eagon, S., Anderson, M. O. Microwave-assisted synthesis of tetrahydro-β-carbolines and β-carbolines. European Journal of Organic Chemistry. (8), 1653-1665 (2014).
- Everson, N., et al. Microwave synthesis of 1-aryl-1H-pyrazole-5-amines. Tetrahedron Letters. 60 (1), 72-74 (2019).
