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71.
72.
V. Narayana Murthy Satish P. Nikumbh Krishnaji Tadiparthi M.
V. Madhubabu Subba Rao Jammula L. Vaikunta Rao Akula Raghunadh 《RSC advances》2018,8(40):22331
A new one pot multicomponent annulation strategy for the synthesis of various dihydroquinazolinone compounds has been developed using Amberlite-15 as a catalyst, giving good to moderate yields. In this reaction the substrate scope for amines and aldehydes was also investigated. The reaction has been checked on a large scale and the possible reaction mechanism has also been proposed.A new one pot multicomponent annulation strategy for the synthesis of various dihydroquinazolinone compounds has been developed using Amberlite-15 as a catalyst, giving good to moderate yields.Functionalized dihydroquinazolinone frameworks are present in many biologically active molecules like quinethazone (A), fenquizone (D), benzouracil (B), evodiamine (C), NC1 substance1D19143 (E) and proquazone (F) (Fig. 1). Among the various dihydroquinazolinone compounds, some of them show various potential therapeutic effects, such as antidiabetic,1 anticancer,2 antihypertension,3 anticonvulsant,4 antibacterial,5 anti-inflammatory,6 and antianxietic activities.7 Moreover these compounds have also been used as antihistamine, antidepressant and vasodilating agents. Owing to their application in the medicinal and agro industries,8,9 many researchers around the world have put substantial efforts into the preparation of these compounds by various synthetic approaches.Open in a separate windowFig. 1Few examples of natural and biologically active molecules with dihydroquinazolinone unit.Indeed from the last few years various synthetic methods have been reported for the construction of various dihydroquinazolinones derivatives (Scheme 1).10,11 Bunce et al. reported the synthesis of substituted quinazolinones using a dissolving metal reduction–condensative cyclization strategy,12 Pal et al. synthesized 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives by employing a three component reaction of isatoic anhydride, an amine and 2-formyl benzoic acid, using montmorillonite K10 as the catalyst,13 and the Sashidhara team also reported the synthesis of dihydroisoindolo[2,1-a]quinazoline-5,11-dione by using acetic acid.14 However among all the methods, the investigation of a practical and efficient multicomponent reaction for the synthesis of isoquinoline units with different nucleophiles has attracted many researchers because of their broad functional groups and simple construction of molecular architectures. Our group previously reported numerous protocols for the synthesis of quinazolinone based biologically active natural products and their derivatives. In continuation of our earlier efforts15 for the development of novel synthetic methods, herein we would like to report a new elegant one pot strategy for the construction of novel functionalized dihydroquinazolinones by the condensation of isatoic anhydride, amine and aldehyde.Open in a separate windowScheme 1Various pathways for the construction of different dihydroquinazolinones moieties from isatoic anhydride.We commenced our investigation with the model substrate by taking isatoic anhydride (3), butyl amine and aldehyde (4) as depicted in Table 1. In the first step of optimization, the reaction was screened with various catalysts like Wang resin, glacial acetic acid, BF3·OEt2, TiCl4, FeCl3 and Amberlite-15 in the presence of 1,4-dioxane as a solvent. Gratifyingly by using Amberlite-15 as a catalyst, we found a new functionalized dihydroquinazolinones compound. But using the other acid catalysts, the product with one double bond compound 13 was obtained as depicted in Fig. 2 along with the product 1. To optimize the molar ratio of the Amberlite-15 catalyst, initially we screened the reaction with 0.05 (w/w%) of Amberlite-15 and reaction was completed within 7–8 h and whereas with 0.10 (w/w%) of the catalyst, the reaction was completed within 3–4 h. In the next stage, the reaction was investigated in different solvents like DMSO, DMF, 1,4-dioxane, ethanol, methanol, THF, toluene and acetonitrile. Among all the solvents, the reaction was not progressed well with polar protic solvents like ethanol and methanol, whereas in polar aprotic solvents DMSO and DMF nearly 30% of the product formation was observed. Finally, we found that the reaction providing promising yields in 1,4-dioxane as solvent (Table 1). Indeed, the reaction rate is slow at room temperature and is fast under reflux conditions. Further the reaction was also checked in 10 and 20 vol but there is no difference in terms of yield and purity. The aza Michael addition step was attempted with 1 eq. of TBAF but only 15% of the product was observed whereas with 2 equivalent of TBAF, 60% of the product was observed whereas with3 equivalent of TBAF the reaction was completed.Screening of solvents using Amberlite-15 as catalyst
Open in a separate windowOpen in a separate windowFig. 2The product with other acid catalysts.After optimizing the reaction conditions, we extended our studies for substrate scope of amines, aldehydes with isatoic anhydride and bromoisatoic anhydride. The substrate scope with various aliphatic, cyclic and aryl amines were studied and to our delight there is no abnormality in terms of yield and purity. This clearly states that all the substrates are well tolerated under these conditions to get the reasonable good yields (Table 2). Furthermore in order to elaborate the synthetic utility of this methodology we have extended our studies by performing a reaction on gram scale (Scheme 2) and gratefully we could replicate the yield and purity which clearly indicating that the reaction can be carried out on large scale.Synthesis of various dihydroquinazolinones derivativesa
Open in a separate windowaReaction conditions: isatoic anhydride (1 mmol), amine (1 mmol), aldehyde (1 mmol), Amberlite-15 (0.1 w/w%), 1,4-dioxane (5 mL).Open in a separate windowScheme 2Gram scale experiment.In order to gain insight into the mechanism, few control experiments have also been carried out. In the first experiment, the reaction with isatoic anhydride and amine without the aldehyde was carried out which provided the ring opening of the anhydride to get the anthranilide. In the second experiment, aldehyde with amine was carried out and the corresponding imine was obtained. In the third experiment, isatoic anhydride with aldehyde was carried out in the presence of the catalyst but the starting materials were intact (Scheme 3).Open in a separate windowScheme 3Control experiments.From the above experimental data and literature reports, we have postulated a new possible reaction mechanism (Scheme 4). In addition to the spectroscopic evidence, the chemical structure of dihydroquinazolinone 1 was further confirmed from the single crystal X-ray diffraction analysis (Fig. 3).Open in a separate windowScheme 4Plausible mechanism for the formation of dihydroquinazolinonesOpen in a separate windowFig. 3X-ray crystal structure of 1a (ORTEP diagram).The Scheme 4 describes a plausible mechanism for the three component reaction leading to the compound 1. The nucleophilic attack of primary amine on carbonyl group of isatoic anhydride followed by ring opening and subsequent decarboxylation will yield to compound 7. Nucleophilic attack of amine to the aldehyde will yield imine intermediate 8; which on subsequent cyclization lead to the formation of 9. Nucleophilic attack of amine on the double bond via aza Michael reaction will yield the tetracyclic intermediate 10 or 11 which on further rearrangement leads to the formation of dihydroquinazolinones 1. 相似文献
| S. no. | Solvent | Isolated yield (%) |
|---|---|---|
| 1 | DMSO | 28 |
| 2 | DMF | 30 |
| 3 | 1,4-Dioxane | 64 |
| 4 | Methanol | Trace |
| 5 | Ethanol | Trace |
| 6 | THF | 48 |
| 7 | Toluene | 40 |
| 8 | Acetonitrile | 53 |
73.
74.
75.
Lau EMC; Cooper C; Fung H; Lam D; Tsang KK 《Journal of public health (Oxford, England)》1999,21(3):249-250
76.
77.
目的:建立大鼠小脑外形三维重构的可视化数据集,为小脑中央核团的三维重建摸索一个可行的方案。方法:实验于2003-03/2005-05在首都医科大学解剖教研室实验室完成。取SD大鼠5只,麻醉后处死取小脑,固定后进行冰冻连续切片、贴片,后经尼氏染色,用扫描仪对各切片进行投射扫描,图像大小为(1868×1491),获取原始图像数据库,并通过首都医科大学生物工程学院开发的配准软件及图像处理软件photoshop7.0对数据库中的数据进行半自动配准及人工分割,应用哈佛大学开发的图像处理专业软件3DSlicer对分割后的数据库进行三维重建。并应用牙科Cad-cam仪器对小脑外形进行扫描,获取完整的小脑外形图像。结果:①小脑尼氏染色获得的原始图像共159张,图像边缘清晰,可见深染的皮质和浅染的白质部分,白质间的小脑中央核深染,边界清晰。②共获得159个小脑外形的三维表面模型数据库(.vtk文件)。在3DSlicer应用程序上可选择小脑外形的三维表面模型数据进行三维显示,并构建了它们的动画显示文件(.gif),使用WindowsMediaPlayer应用软件即可以播放;与应用牙科Cad-cam仪器对小脑表面扫描获取的小脑表面的图像比较,信息更饱满,图像更真实,层次感强。结论:通过切片、配准、分割等方法获得了大鼠小脑外形微细结构信息的数据库,此法更适用于组织微细结构的三维重建。 相似文献
78.
脐血间充质干细胞分离培养的理论研究与应用 总被引：1，自引：0，他引：1
目的:间充质干细胞具有多向分化潜能,在一定的实验条件控制下可分化为骨、软骨、肌肉、神经、肝和内皮等多种细胞,本文在于进一步综合分析脐血间充质干细胞的优化分离培养条件。资料来源:应用计算机检索Medline、PubMed数据库1980-01/2006-12期间有关脐血间充质干细胞分离培养的文献,检索词“mesenchymal stem cells,human umbilical cord blood(HUCB),isolation,culture”,并限定文章语言种类为English。同时计算机检索CNKI,万方数据库1990-01/2006-12期间相关文献,限定文章语言种类为中文,检索词“间充质干细胞,脐血,分离,培养”。并手工查阅相关书籍。资料选择:检索有关脐血间充质干细胞分离培养的综述和实验论据,参考综合各文献中脐血间充质干细胞培养的方法条件,选择比较典型和比较新颖的文献进行综合。资料提炼:共检索到79篇有关脐血间充质干细胞分离纯化、培养扩增的文献,纳入30篇。资料综合:国内外有大量的实验证实,间充质干细胞具有肯定的支持造血功能,而且在一定实验条件控制下可分化为骨、软骨、脂肪、肌腱、肌肉、神经、基质、肝、内皮等多种细胞。脐血来源间充质干细胞具有低免疫原性等很多优点已成为干细胞研究领域的热点,目前分离培养间充质干细胞的方法多样,日趋成熟,但仍存在许多不足,需进一步探索间充质干细胞的分离纯化技术。结论:目前已经建立了多种脐血间充质干细胞分离纯化培养扩增的方法,为其在细胞工程和组织工程的应用提供了基础。 相似文献
79.
Adenosine is one of the inhibitory neuromodulators in the brain and is considered to be responsible for seizure arrest and postictal refractoriness. Adenosine, adenosine receptor agonists, and adenosine uptake blockers are known to reduce the severity and duration of amygdala-kindled seizures. The present study was carried out to elucidate the anticonvulsant and neuromodulatory effect of systemic adenosine on the pentylenetetrazol (PTZ)-induced chemical kindling in mice. Kindling was induced by chronic administration of a subconvulsive dose of PTZ (40 mg/kg, i.p.) on every other day for a total period of 9 days. Adenosine was administered daily, 30 min before PTZ or vehicle. The kindling score was recorded immediately following PTZ administration according to a prevalidated scoring scale. Various behavioral and biochemical estimations were performed on day 10 (i.e. 24 h after the last dose of PTZ). Chronic PTZ treatment progressively increased the seizure score with the maximum score reached on day 9. Behavioral analysis found hyperlocomotor activity, anxiogenic response, hyperalgesia and amnesia in kindled mice. Biochemical analysis revealed that chronic treatment with PTZ significantly increased lipid peroxidation (malondialdehyde levels), nitrite (NO(2-) levels), adenosine deaminase (ADA) and total RNA levels and decreased catalase, reduced glutathione (GSH) levels in brain homogenates, and a depletion of adrenal ascorbic acid. Daily treatment with adenosine (25 and 50 mg/kg, i.p.) for 9 days led to a significant decrease in PTZ-induced kindling score and also reversed various behavioral and biochemical alterations produced by PTZ. The results of the present study suggested that systemic adenosine administration reversed the behavioral and biochemical alterations induced by chronic PTZ. 相似文献
80.
自美国国家骨髓库(NMDP)开展第一例无关供者移植以来,至今已有20年.NMDP目前的库容量已逾700万,已为6大洲提供了30 000多份无关供者造血干细胞.这一辉煌成就是美国国家骨髓库600多名工作人员共同努力的结果,同时也得益于广泛的国际合作,包括171个移植中心,73个供者中心,24个脐血库,97个骨髓采集中心,91个血液净化中心,26个HLA分型实验室和26个合作供者登记处.本文回顾了美国国家骨髓库的历史,阐述了20年来移植病人、移植物来源和预处理方案几方面的主要变化趋势. 相似文献