- Suzuki?Miyaura coupling and O?arylation reactions catalysed by palladium(II) complexes of bulky ligands bearing naphthalene core, Schiff base functionality and biarylphosphine moiety
-
Schiff bases L1 [i.e., 2-(diphenylphosphino)-N-(naphthalen-1-ylmethylene)ethanamine], L2 [i.e., 2- (diphenylphosphino)-N-(naphthalen-2-ylmethylene)ethanamine], L3 [i.e., 2-(1-(2-(diphenylphosphino)ethylim- ino)ethyl)naphthalen-1-ol] and L4 [i.e., 2-((2-(diphenylphosphino)ethylimino)methyl)naphthalen-1-ol] have been synthesized using a straightforward methodology which involves a condensation reaction between H2N?CH2?CH2?PPh2 and appropriate carbonyl compound. Due to the presence of diphenylphosphine (?PPh2) moiety and >C = N? functionality, these compounds behave as ligands and undergo complexation reaction with palladium on treatment with Na2PdCl4 to yield the palladium(II) complexes (1–4). Ligands as well as complexes have been characterized using standard NMR spectroscopic techniques. ESI?MS and single crystal X?ray diffraction studies corroborate the structures of complexes. Crystal structures of complexes 1?3 reveal clearly that the geometry around Pd centre is distorted square planar. Ligands L1 and L2 are coordinated to Pd centre in bidentate (P, N type) mode, however, L3 and L4 act as a tridentate (P,N,O type) ligand and bind with metal in anionic mode. The Pd P and Pd N bond distances in complexes 1?3 are in the ranges 2.204?2.212 ? and 2.023?2.072 ?, respectively. Complex 3 [i.e., PdCl(L3?H)] also has a Pd-O bond, the length of which is found to be 2.009(3) ?. All the complexes have potential for catalysing O-arylation (C-O coupling) of phenol and Suzuki-Miyaura coupling (SMC) reactions. Both bromoarenes and chloroarenes can be used as substrates in Suzuki coupling and converted into biaryl derivatives. For O-arylation reactions of phenol, bromoarenes are used as arylating agents. For catalysis of such reactions (i.e., C-O coupling), high (0.1 mol%) catalyst loading is required. However, Suzuki reactions require low (0.001 mol%) loading of catalysts to occur with bromoarenes and give the products. The high potential of the complexes is also evident from the fact that they also convert different aryl chlorides into the coupled products in Suzuki coupling. 31P{1H} NMR data reveal that the electronic environments of nuclei of phosphorous donors are closely similar in all the four ligands. Similar magnitude of deshielding of the 31P{1H} signals in all the complexes indicate that, while forming the dative bond, the P donor of all the ligands transfer the electron density to the palladium to a similar extent. Hence, the electronic effects created by the ligands through the phosphorous donor are similar in all the complexes. Therefore, it is inferred that variation in their catalytic performance is because of difference in the binding mode of the ligand and/or minor alteration in the architecture of organic ligand. Amongst them, complex 2 shows the highest catalytic activity, and the least active catalyst is complex 3 for C-C coupling reactions. For C-O coupling reactions, the efficiencies of complexes 1 and 2 are slightly higher than those of complexes 3 and 4.
- Arora, Aayushi,Kaushal, Jolly,Kumar, Arun,Nautiyal, Divyanshu,Oswal, Preeti,Singh, Siddhant
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-
- Photoinduced FeCl3-Catalyzed Alkyl Aromatics Oxidation toward Degradation of Polystyrene at Room Temperature?
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While polystyrene is widely used in daily life as a synthetic plastic, the subsequently selective degradation is still very challenging and highly required. Herein, we disclose a highly practical and selective reaction for the catalytically efficient oxidation of alkyl aromatics (including 1°, 2°, and 3° alkyl aromatics) to carboxylic acids. While dioxygen was used as the sole terminal oxidant, this protocol was catalyzed by the inexpensive and readily available ferric compound (FeCl3) with irradiation of visible light (blue LEDs) under only 1 atmosphere of O2 at room temperature. This system could further facilitate the selective degradation of polystyrene to benzoic acid, providing an important and practical tool to generate high-value chemical from abundant polystyrene wastes.
- Zhang, Guoxiang,Zhang, Zongnan,Zeng, Rong
-
supporting information
p. 3225 - 3230
(2021/09/28)
-
- Oxidative α-C-C Bond Cleavage of 2° and 3° Alcohols to Aromatic Acids with O2at Room Temperature via Iron Photocatalysis
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The selective α-C-C bond cleavage of unfunctionalized secondary (2°) and tertiary alcohols (3°) is essential for valorization of macromolecules and biopolymers. We developed a blue-light-driven iron catalysis for aerobic oxidation of 2° and 3° alcohols to acids via α-C-C bond cleavages at room temperature. The first example of oxygenation of the simple tertiary alcohols was reported. The iron catalyst and blue light play critical roles to enable the formation of highly reactive O radicals from alcohols and the consequent two α-C-C bond cleavages.
- Zhang, Zongnan,Zhang, Guoxiang,Xiong, Ni,Xue, Ting,Zhang, Junjie,Bai, Lu,Guo, Qinyue,Zeng, Rong
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p. 2915 - 2920
(2021/05/05)
-
- Hit-to-lead optimization on aryloxybenzamide derivative virtual screening hit against SIRT
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Sirtuins (SIRTs) are a class of nicotinamide adenine dinucleotide (NAD+)-dependent protein histone deacetylases (HDACs) that are evolutionarily conserved from bacteria to mammals. This group of enzymes catalyses the reversible deacetylation of lysine residues in the histones or non-histone substrates using NAD+ as a cosubstrate. Numerous studies have demonstrated that the aberrant enzymatic activity of SIRTs has been linked to various diseases like diabetes, cancer, and neurodegenerative disorders. Previously, we performed a pharmacophore-based virtual screening campaign and an aryloxybenzamide derivative (1) displaying SIRT1/2 inhibitory effect was identified as a hit compound. In the current study, the hit-to-lead optimization on the hit compound was explored in order to improve the SIRT binding and inhibition. Fourteen compounds, ten of which were new, have been synthesized and subjected to in vitro biological evaluation for their inhibitory activity against SIRT1-3. By the structural modifications performed, a significant improvement was observed in selective SIRT1 inhibition for ST01, ST02, and ST11 compared to that of the hit compound. The highest SIRT2 inhibitory activity was observed for ST14, which was designed according to compatibility with pharmacophore model developed for SIRT2 inhibitors and thus, providing the interactions required with key residues in SIRT2 active site. Furthermore, ST01, ST02, ST11, and ST14 were subjected to in vitro cytotoxicity assay against MCF-7 human breast cancer cell line to determine the influence of the improvement in SIRT1/2 inhibition along with the structural modifications on the cytotoxic properties of the compounds. The cytotoxicity of the compounds was found to be correlated with their SIRT inhibitory profiles indicating the effects of SIRT1/2 inhibition on cancer cell viability. Overall, this study provides structural insights for further inhibitor improvement.
- Yagci, Semih,Gozelle, Mahmut,Kaya, Selen Gozde,Ozkan, Yesim,Aksel, Ahmet Bugra,Bakar-Ates, Filiz,Dundar, Yasemin,Eren, Gokcen
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-
- Novel fatty acid-thiadiazole derivatives as potential antimycobacterial agents
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The discovery of antibiotics around the middle twentieth century led to a decrease in the interest in antimycobacterial fatty acids. In order to re-establish the importance of naturally abundant fatty acid, a series of fatty acid-thiadiazole derivatives were designed and synthesized based on molecular hybridization approach. In vitro antimycobacterial potential was established by a screening of synthesized compounds against Mycobacterium tuberculosis H37Rv strain. Among them, compounds 5a, 5d, 5h, and 5j were the most active, with compound 5j exhibiting minimum inhibitory concentration of 2.34?μg/ml against M.tb H37Rv. Additionally, the compounds were docked to determine the probable binding interactions and understand the mechanism of action of most active molecules on enoyl-acyl carrier protein reductases (InhA), which is involved in the mycobacterium fatty acid biosynthetic pathway.
- Mali, Jaishree K.,Sutar, Yogesh B.,Pahelkar, Akshata R.,Verma, Preeti M.,Telvekar, Vikas N.
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p. 174 - 181
(2019/11/03)
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- 4-phenoxybenzoic acid synthesis method
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The invention relates to the technical field of chemical industry synthesis, and particularly discloses a 4-phenoxybenzoic acid synthesis method, which comprises: carrying out a mixing heating reaction on phenol as a raw material, sodium hydroxide and water to obtain a sodium phenolate solution; slowly adding the sodium phenolate solution into a mixture of tetrahydronaphthalene and p-chlorobenzoicacid in a dropwise manner while heating, and carrying out a thermal insulation reaction; after completing the reaction, cooling the reaction liquid, filtering, washing the obtained solid, filtering,mixing by adding clear water, adjusting the pH value, and filtering to obtain crude and wet 4-phenoxybenzoic acid; and dissolving the crude and wet 4-phenoxybenzoic acid in ethanol, adsorbing with active carbon, filtering, cooling, and filtering to obtain the product. According to the present invention, the process route is simple and easy to operate, the reaction can be completed in one step, thestarting raw material is simple and cheap, and is easy to obtain, the generated waste water is less, and the method is suitable for industrial production, and is a completely-new synthesis route.
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Paragraph 0015-0020
(2019/11/21)
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- Synthesis and structure–activity relationship of N-(piperidin-4-yl)benzamide derivatives as activators of hypoxia-inducible factor 1 pathways
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Guided by bioisosterism and pharmacokinetic parameters, we designed and synthesized a series of novel benzamide derivatives. Preliminary in vitro studies indicated that compounds 10b and 10j show significant inhibitory bioactivity in HepG2 cells (IC50 values of 0.12 and 0.13?μM, respectively). Compounds 10b and 10j induced the expression of HIF-1α protein and downstream target gene p21, and upregulated the expression of cleaved caspase-3 to promote tumor cells apoptosis.
- Huang, Zhi-Ning,Liang, Han,Qiao, Hong,Wang, Bao-Rui,Qu, Ning,Li, Hua,Zhou, Run-Run,Wang, Li-Juan,Li, Shan-Hua,Li, Fu-Nan
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p. 1149 - 1161
(2018/07/21)
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- Visible-Light-Mediated Hydroxycarbonylation of Diazonium Salts
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A visible light-promoted catalytic photoredox hydroxycarbonylation was achieved on aryl diazonium salts whether preformed or generated in situ from the corresponding anilines. This strategy allows a straightforward access to a variety of carboxylic acids under mild conditions. (Figure presented.).
- Gosset, Cyrille,Pellegrini, Sylvain,Jooris, Romain,Bousquet, Till,Pelinski, Lydie
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p. 3401 - 3405
(2018/08/06)
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- Method for preparing ibrutinib
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The invention discloses a method for preparing ibrutinib. The method includes the following steps of 1, preparation of IB-A, 2, preparation of IB-B, 3, preparation of IB-C, 4, preparation of IB-D, 5,preparation of IB-E, 6, preparation of IB-F, 7, preparation of IB-G, 8, preparation of IB-H, and 9, preparation of IB-J. The method has the advantages that the process is mature and stable, the quality of the product is stable, the production process is safe and reliable, and the ibrutinib is suitable for industrial production.
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- Design, synthesis, and structure-activity relationship studies of novel diaryl ether amides as potential antitumor agents
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Sorafenib is a drug that has been verified to be effective on hepatoma cells. Three series of diaryl ethers have been designed and synthesized based on the structure of sorafenib. The 5m compound shows better inhibitory potency against HepG2 cells (IC50 = 1.96 μM) than sorafenib (IC50 = 9.61μM). These results have been verified with MTT assay and colony-forming assay. Moreover, compound 5m exhibits good antitumor activities against PLC/PRF5, HeLa, A549, and HT-29 cell lines. The excellent bioactivity of compound 5m confirms that a single optical conformation is superior to the racemate. A western blotting analysis indicates that compound 5m induces the apoptosis of HepG2 cells by enhancing the protein levels of p21 and Cl-caspase3.
- Zheng, Man-Yi,Huang, Zhi-Ning,Yang, Shao-Mei,Han-Liang,Lu-Xu,Wang, Bao-Rui,Wang, Li-Juan,Wang, Hai-Li,Li, Shan-Hua,Li, Fu-Nan
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p. 727 - 736
(2019/05/22)
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- IMIDAZOLE UV-ABSORBENT COMPOUNDS FOR FUNCTIONAL COSMETICS
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The present invention relates to an imidazole-based UV absorbent composition for functional cosmetic products. More specifically, the present invention relates to an imidazole-based UV absorbent composition for functional cosmetic products, by having a specific structure that includes two sulfonic acid groups in addition to an imidazole moiety, which exhibits excellent absorption characteristics in both a UV-B region and a UV-A region, has desirable light stability, formulation stability and safety to skin, shows high hydrophilicity compared to conventional imidazole materials, and thus may be extremely useful as a raw material for UV blocking cosmetic products including sunscreens; to a method of preparing the same; and to a functional cosmetic composition comprising the same.COPYRIGHT KIPO 2018
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Paragraph 0063-0069; 0071
(2018/04/20)
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- Carboxylation of Aromatic and Aliphatic Bromides and Triflates with CO2 by Dual Visible-Light–Nickel Catalysis
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We report the efficient carboxylation of bromides and triflates with K2CO3 as the source of CO2 in the presence of an organic photocatalyst in combination with a nickel complex under visible light irradiation at room temperature. The reaction is compatible with a variety of functional groups and has been successfully applied to the synthesis and derivatization of biologically active molecules. In particular, the carboxylation of unactivated cyclic alkyl bromides proceeded well with our protocol, thus extending the scope of this transformation. Spectroscopic and spectroelectrochemical investigations indicated the generation of a Ni0 species as a catalytic reactive intermediate.
- Meng, Qing-Yuan,Wang, Shun,K?nig, Burkhard
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supporting information
p. 13426 - 13430
(2017/10/07)
-
- Carbazole oxime ester compound and synthetic method and application thereof
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The invention discloses a carbazole oxime ester compound shown as in general formula I that is shown in the description; the carbazole oxime ester compound with the structure of general formula I has the advantages of good solubility, thermal stability, high photosensitive activity and low toxicity; a photoinitiator has excellent applicability and very high photosensitivity, exhibits very high photosensitive activity when exposed to LEDs, LDI (Liniarc direct/indirect) and other light sources, the production efficiency of photosensitive compositions such as in the preparation of color filters and other application fields is significantly improved, and the efficiency is significantly better than that of existing products.
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-
Paragraph 0147; 0148; 0149
(2017/09/13)
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- INHIBITOR OF BRUTON'S TYROSINE KINASE
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Provided are a compound represented by formula (III) or pharmaceutically acceptable salts, solvates, active metabolites, polymorphs, esters, tautomers or prodrugs thereof, pharmaceutical compositions containing the compound represented by formula (III), and the application of the pharmaceutical compositions as selective inreversible inhibitor of Bruton's tyrosine kinase for the prevention and treatment of inflammation, autoimmune diseases (such as rheumatoid arthritis) associated with aberrant B cell proliferation and cancers.
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- Probing the Azaaurone Scaffold against the Hepatic and Erythrocytic Stages of Malaria Parasites
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The potential of azaaurones as dual-stage antimalarial agents was investigated by assessing the effect of a small library of azaaurones on the inhibition of liver and intraerythrocytic lifecycle stages of the malaria parasite. The whole series was screened against the blood stage of a chloroquine-resistant Plasmodium falciparum strain and the liver stage of P. berghei, yielding compounds with dual-stage activity and sub-micromolar potency against erythrocytic parasites. Studies with genetically modified parasites, using a phenotypic assay based on the P. falciparum Dd2-ScDHODH line, which expresses yeast dihydroorotate dehydrogenase (DHODH), showed that one of the azaaurone derivatives has the potential to inhibit the parasite mitochondrial electron-transport chain. The global urgency in finding new therapies for malaria, especially against the underexplored liver stage, associated with chemical tractability of azaaurones, warrants further development of this chemotype. Overall, these results emphasize the azaaurone chemotype as a promising scaffold for dual-stage antimalarials.
- Carrasco, Marta P.,Machado, Marta,Gon?alves, Lídia,Sharma, Moni,Gut, Jiri,Lukens, Amanda K.,Wirth, Dyann F.,André, Vania,Duarte, Maria Teresa,Guedes, Rita C.,dos Santos, Daniel J. V. A.,Rosenthal, Philip J.,Mazitschek, Ralph,Prudêncio, Miguel,Moreira, Rui
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supporting information
p. 2194 - 2204
(2016/10/19)
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- Method for synthesizing 4-phenoxybenzoyl chloride, important intermediate of ibrutinib
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The invention discloses a method for synthesizing 4-phenoxybenzoyl chloride, an important intermediate of ibrutinib. The method comprises the following steps: firstly, diphenyl ether is taken as a raw material and 4-phenoxyacetophenone is synthesized through one acylation reaction; then, 4-phenoxybenzoic acid is synthesized through an oxidation reaction; finally, the target product 4-phenoxybenzoyl chloride is generated through another acylation reaction. The method provided by the invention is used for synthesizing 4-phenoxybenzoic acid and 4-phenoxybenzoyl chloride, which serve as a starting material and the important intermediate of ibrutinib respectively; the raw material is easy to obtain, the operation is simple, the purification is convenient, and the synthesis yield is relatively high; and the method has a great function of reducing the synthesis cost and is beneficial to the industrialized production of ibrutinib.
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Paragraph 0036; 0038
(2016/10/08)
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- Synthesizing process of 4-phenoxyl benzoic acid
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The invention discloses synthesizing process of 4-phenoxyl benzoic acid and belongs to the technical field of chemical synthesis. The synthesizing process includes the steps of firstly, performing an acylation reaction, to be more specific, adding dichloromethane, phenylate and aluminum trichloride into a reaction kettle, stirring at low temperature, dripping acetylchloride, then performing a temperature-controlled reaction, slowly adding reaction liquid into ice water after the reaction, stirring, standing for layering, collecting the organic phase, concentrating, adding n-hexane into the concentrated organic phase, stirring after cooling, centrifuging, and drying to obtain intermediate; secondly, performing a haloform reaction, to be more specific, adding the intermediate and methane into a reaction kettle, heating, dripping sodium hypochlorite solution, allowing the reaction to continue, cooling the reaction liquid after the reaction, adjusting the pH of the reaction liquid, centrifuging, and drying to obtain a crude product; thirdly, refining, to be more specific, adding ethanol into the crude product, heating after mixing, cooling, crystalizing, centrifuging, and drying to obtain the 4-phenoxyl benzoic acid. The synthesizing process is easy in raw material obtaining, low in product cost, simple to operate, reasonable in step design, convenient in scale-up experiment and high in safety.
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-
Paragraph 0006; 0018; 0021; 0022
(2017/01/02)
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- PROCESS FOR THE PREPARATION OF 1-[(3R)-3-[4-AMINO-3-(4-PHENOXYPHENVL)-1H- PVRAZOLO[3,4-D]PYRINIIDIN-1-Y1]-1-PIPERIDINVL]-2-PROPEN-1-ONE AND ITS POLYMORPHS THEREOF
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The present invention relates to an improved process for the preparation of 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)- 1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]- 1 -piperidin yl]-2-propen-1-one compound of formula- 1 and its polymorphs thereof, which is represented by the following structural formula:
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Page/Page column 38; 39
(2016/11/14)
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- P-phenylbutoxy benzoic acid and preparation method thereof
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The invention discloses a preparation method of p-phenylbutoxy benzoic acid. The preparation method comprises the following steps: by using 1,4-dibromobutane as a raw material, carrying out reaction on the 1,4-dibromobutane and benzene to obtain 4-phenylbromobutane; carrying out reaction on the 4-phenylbromobutane and methyl p-hydroxybenzoate to obtain methyl p-phenylbutoxy benzoate; and oxidizing the methyl p-phenylbutoxy benzoate, and meanwhile, carrying out hydrolysis to obtain the pranlukast intermediate p-phenylbutoxy benzoic acid. The p-phenylbutoxy benzoic acid prepared by the method has the advantages of high purity and high yield; and the method has the advantages of cheap and accessible raw materials, mild preparation conditions, high controllability and low production cost.
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Paragraph 0024
(2017/07/12)
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- Evaluation of Novel N-(piperidine-4-yl)benzamide Derivatives as Potential Cell Cycle Inhibitors in HepG2 Cells
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In this study, a series of novel N-(piperidine-4-yl)benzamide derivatives was designed, synthesized, and evaluated for antitumor activity. Some compounds were found to have potent antitumor activity. In particular, compound 47 showed the most potent biological activity against HepG2 cells, with an IC50 value of 0.25 μm. Western blot analysis demonstrated that compound 47 inhibited the expression of cyclin B1 and p-Rb and enhanced the expression of p21, p53, Rb, and phospho-adenosine monophosphate-activated protein kinase (p-AMPK). Further, cell cycle arrest was observed by flow cytometry (FCM). In summary, compound 47 was screened to have potential activity for the treatment of hepatocarcinoma via the induction of cell cycle arrest by a p53/p21-dependent pathway.
- Hou, Jin,Zhao, Wei,Huang, Zhi-Ning,Yang, Shao-Mei,Wang, Li-Juan,Jiang, Yu,Zhou, Zhong-Shi,Zheng, Man-Yi,Jiang, Ji-Li,Li, Shan-Hua,Li, Fu-Nan
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p. 223 - 231
(2015/11/24)
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- A Metal-Free Approach to Carboxylic Acids by Oxidation of Alkyl, Aryl, or Heteroaryl Alkyl Ketones or Arylalkynes
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The metal-free oxidation of dialkyl, alkyl aryl, or alkyl heteroaryl ketones or arylalkynes to the corresponding carboxylic acids is achieved using an oxidative mixture of Oxone and trifluoroacetic acid. This green method is a simple and mild protocol to obtain carboxylic derivatives in excellent yields.
- Aravinda Kumar,Venkateswarlu, Vunnam,Vishwakarma, Ram A.,Sawant, Sanghapal D.
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p. 3161 - 3168
(2015/10/19)
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- DMSO/I2 mediated C-C bond cleavage of α-ketoaldehydes followed by C-O bond formation: A metal-free approach for one-pot esterification
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A novel and efficient I2/DMSO mediated metal-free strategy is presented for the direct C-C bond cleavage of aryl-/heteroaryl- or aliphatic α-ketoaldehydes by C2-decarbonylation and C1-carbonyl oxidation to give the corresponding carboxylic acids followed by esterification in one pot, offering excellent yields in both the steps. Here, DMSO acts as the oxygen source/oxidant and this reaction works very well under both conventional heating and microwave irradiation. This is a very simple and convenient protocol.
- Venkateswarlu, Vunnam,Aravinda Kumar,Gupta, Sorav,Singh, Deepika,Vishwakarma, Ram A.,Sawant, Sanghapal D.
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p. 7973 - 7978
(2015/07/27)
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- Aryl amide small-molecule inhibitors of microRNA miR-21 function
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MicroRNAs (miRNAs) are single stranded RNA molecules of ~22 nucleotides that negatively regulate gene expression. MiRNAs are involved in fundamental cellular processes, such as development, differentiation, proliferation, and survival. MiRNA misregulation has been linked to various human diseases, most notably cancer. MicroRNA-21 (miR-21), a well-established oncomiR, is significantly overexpressed in many types of human cancers, thus rendering miR-21 a potential therapeutic target. Using a luciferase-based reporter assay under the control of miR-21 expression, a high-throughput screen of >300,000 compounds led to the discovery of a new aryl amide class of small-molecule miR-21 inhibitors. Structure-activity relationship (SAR) studies resulted in the development of four aryl amide derivatives as potent and selective miR-21 inhibitors. The intracellular levels of various miRNAs in HeLa cells were analyzed by qRT-PCR revealing specificity for miR-21 inhibition over other miRNAs. Additionally, preliminary mechanism of action studies propose a different mode of action compared to previously reported miR-21 inhibitors, thus affording a new chemical probe for future studies.
- Naro, Yuta,Thomas, Meryl,Stephens, Matthew D.,Connelly, Colleen M.,Deiters, Alexander
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p. 4793 - 4796
(2015/10/28)
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- Structure-based design, structure-activity relationship analysis, and antitumor activity of diaryl ether derivatives
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To identify novel therapeutic agents to treat cancer, we synthesized a series of diaryl ether derivatives. Structure-activity relationship studies revealed that the presence of a chlorine or hydroxyl at the para-position on the phenyl ring (5h or 5k) significantly enhanced antitumor activity. Compound 5h had stronger growth inhibitory activity in HepG2, A549, and HT-29 cells than compound 5k, with IC50 values of 2.57, 5.48, and 30.04 μM, respectively. Compound 5h also inhibited the growth of other cells lines, including Hep3B, PLC/PRF5, SMMC-7721, HeLa, and A375, with IC50 values of 2.76, 4.26, 29.66, 18.86, and 10.21 μM, respectively. The antitumor activity of compound 5h was confirmed by a colony forming assay. Further, our results indicated that the antitumor activity of compound 5h may be mediated by enhancing expression of p21 and cl-caspase3, and leading to apoptosis of cancer cells.
- Yang, Shao-Mei,Huang, Zhi-Ning,Zhou, Zhong-Shi,Hou, Jin,Zheng, Man-Yi,Wang, Li-Juan,Jiang, Yu,Zhou, Xin-Yi,Chen, Qiu-Yue,Li, Shan-Hua,Li, Fu-Nan
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p. 1761 - 1773
(2015/03/14)
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- INHIBITORS OF BRUTON'S TYROSINE KINASE
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The invention provides novel poly-substituted 5-membered heterocyclic compounds represented by Formula (IV), or a pharmaceutically acceptable salt, solvate, metabolites, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as selective irreversible bruton's tyrosine kinase (Btk) inhibitors and is further useful to treat inflammatory, auto immune diseases associated with aberrant B-cell proliferation such as RA (rheumatoid arthritis) and cancers. This invention also provided the preparation of a medicament using of Formula (IV), and methods of preventing or treating diseases associated with excessive Btk activity in mammals, especially humans. Formula (IV)
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- NEW COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
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-
- Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist
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S1P3-sparing S1P1 agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC50 value of 4.0 nM for human S1P1 and over 5000-fold selectivity against S1P3. The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID 50 value was determined at 0.407 mg/kg. The docking studies of CS-2100 with the homology model of S1P1 and S1P3 showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P3, not in the case of Leu276 in S1P1. This observation gives an explanation for the excellent S1P3-sparing characteristic of CS-2100.
- Nakamura, Tsuyoshi,Asano, Masayoshi,Sekiguchi, Yukiko,Mizuno, Yumiko,Tamaki, Kazuhiko,Kimura, Takako,Nara, Futoshi,Kawase, Yumi,Shimozato, Takaichi,Doi, Hiromi,Kagari, Takashi,Tomisato, Wataru,Inoue, Ryotaku,Nagasaki, Miyuki,Yuita, Hiroshi,Oguchi-Oshima, Keiko,Kaneko, Reina,Watanabe, Nobuaki,Abe, Yasuyuki,Nishi, Takahide
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scheme or table
p. 1788 - 1792
(2012/04/04)
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- Silver(i)-catalyzed carboxylation of arylboronic esters with CO2
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A variety of arylboronic esters were efficiently carboxylated with CO 2 using a simple AgOAc/PPh3 catalyst, affording the corresponding carboxylic acids in good yield. This simple and efficient silver(i) catalytic system showed wide functional group compatibility. The Royal Society of Chemistry 2012.
- Zhang, Xiao,Zhang, Wen-Zhen,Shi, Ling-Long,Guo, Chun-Xiao,Zhang, Ling-Ling,Lu, Xiao-Bing
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supporting information; experimental part
p. 6292 - 6294
(2012/07/16)
-
- NEW COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention provides novel compounds and the novel compounds for use as a medicine, more in particular for the prevention or treatment of neurodegenerative disorders, more specifically certain neurological disorders, such as disorders collectively known as tauopathies, and disorders characterised by cytotoxic α-synuclein amyloidogenesis. The present invention also relates to the use of said novel compounds for the manufacture of medicaments useful for treating such neurodegenerative disorders. The present invention further relates to pharmaceutical compositions including said novel compounds and to methods for the preparation of said novel compounds. The compounds have the formula (A1) wherein R1, R2, R4, R6, E, n, Y1, Y2, Y3, Y4, Y5, L, B, R8, and m are as defined in the claims.
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- Design, synthesis and evaluation of novel molecules with a diphenyl ether nucleus as potential antitubercular agents
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A series of compounds with a diphenyl ether nucleus were synthesized by incorporating various amines into the diphenyl ether scaffold with an amide bond. Their antitubercular activities were evaluated against Mycobacterium tuberculosis H37Rv by a microdilution method, with MIC values ranging from 4 to 64 μg/mL. Through structure-activity relationship studies, the two chlorine atoms at 3 and 4 positions in the phenyl ring of R2 group were found to play a significant role in the antitubercular activity. The most potent compound 6c showed an MIC value of 4 μg/mL and a good safety profile in HepG2 cell line by the MTT assay. Compound 6c was further found to be effective in a murine model of BCG infection, providing a good lead for subsequent optimization.
- Yang, Yinghong,Wang, Zhenling,Yang, Jianzhong,Yang, Tao,Pi, Weiyi,Ang, Wei,Lin, Yanni,Liu, Yuanyuan,Li, Zicheng,Luo, Youfu,Wei, Yuquan
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supporting information; experimental part
p. 954 - 957
(2012/03/11)
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- Synthesis, insecticidal evaluation of novel 1,3,4-thiadiazole chrysanthemamide derivatives formed by an EDCI/HOBt condensation
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A series of novel pesticides with two components derived from a 1,3,4-thiadiazole and chrysanthemic acid were synthesised via an EDCI/HOBt condensation. These 1,3,4-thiadiazole chrysanthemamides were identified by IR, 1H NMR and elemental analyses. Their insecticidal activity was also evaluated.
- Yu, Peng,Hu, Jun,Zhou, Tao-Yu,Wang, Peng,Xu, Yan-Hua
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experimental part
p. 703 - 706
(2012/03/10)
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- Fe3O4@mesoporouspolyaniline: A highly efficient and magnetically separable catalyst for cross-coupling of aryl chlorides and phenols
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A high surface, magnetic Fe3O4@mesoporouspolyaniline core-shell nanocomposite was synthesized from magnetic iron oxide (Fe 3O4) nanoparticles and mesoporouspolyaniline (mPANI). The novel porous magnetic Fe3O4 was obtained by solvothermal method under sealed pressure reactor at high temperature to achieve high surface area. The mesoporouspolyaniline shell was synthesized by in situ surface polymerization onto porous magnetic Fe3O4 in the presence of polyvinylpyrrolidone (PVP) and sodium dodecylbenzenesulfonate (SDBS), as a linker and structure-directing agent, through 'blackberry nanostructures' assembly. The material composition, stoichiometric ratio and reaction conditions play vital roles in the synthesis of these nanostructures as confirmed by variety of characterization techniques. The role of the mesoporouspolyaniline shell is to stabilize the porous magnetic Fe3O4 nanoparticles, and provide direct access to the core Fe3O4 nanoparticles. The catalytic activity of magnetic Fe3O 4@mesoporousPANI nanocomposite was evaluated in the cross-coupling of aryl chlorides and phenols. Copyright
- Arundhathi,Damodara,Likhar, Pravin R.,Kantam, M. Lakshmi,Saravanan,Magdaleno, Travis,Kwon, Sun Hee
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supporting information; experimental part
p. 1591 - 1600
(2011/08/03)
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- COMPOSITIONS AND METHODS FOR INHIBITING SPHINGOSINE KINASE
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Amidine analogs that can inhibit the activity of sphingosine kinase 1 and sphingosine kinase 2 (SphK1 and SphK2) are provided. The compounds can prevent angiogenesis in tumor cells.
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Page/Page column 43
(2009/12/27)
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- Synthesis, antitubercular activity and docking study of novel cyclic azole substituted diphenyl ether derivatives
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The re-emergence of tuberculosis (TB) as a global health problem over the past few decades, accompanied by the rise of drug-resistant strains of Mycobacterium tuberculosis, emphasizes the need for discovery of new therapeutic drugs against this disease. The emerging serious problem both in terms of TB control and clinical management prompted us to synthesize a novel series of heterocyclic o/m/p substituted diphenyl ether derivatives and determine their activity against H37Rv strain of Mycobacterium. All 10 compounds inhibited the growth of the H37Rv strain of mycobacterium at concentrations as low as 1 μg/mL. This level of activity was found comparable to the reference drugs rifampicin and isoniazid at the same concentration. Molecular modeling of the binding of the diphenyl ether derivatives on enoyl-ACP reductase, the molecular target site of triclosan, indicated that these compounds fit within the binding domain occupied by triclosan. Hence the diphenyl ether derivatives tested in this study were docked to ENR and the binding of the diphenyl ether derivatives was also estimated using a variety of scoring functions that have been compiled into the single consensus score. As the scores ranged from 47.27% to 65.81%, these bioactive compounds appear to have a novel mechanism of action against M. tuberculosis, and their structural features should be studied further for their potential use as new antitubercular drugs.
- Kini, Suvarna G.,Bhat, Anilchandra R.,Bryant, Byron,Williamson, John S.,Dayan, Franck E.
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experimental part
p. 492 - 500
(2009/08/07)
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- Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases
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The invention relates to BCAT inhibitors and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, neuropathic pain, Parkinson's disease, diabetic retinopathy, glaucoma, CMV retinitis, urinary incontinence, opioid tolerance or withdrawal, and inducing anesthesia, as well as for enhancing cognition.
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- CARBOXYLIC ACID DERIVATIVES AND DRUGS CONTAINING THE SAME
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The present invention provides a novel carboxylic acid compound, a salt thereof or a hydrate of them useful as an insulin-resistant improver, and a medicament comprising the compound as an active ingredient. That is, the present invention provides a carboxylic acid compound represented by the following formula (I), a salt thereof, an ester thereof or a hydrate of them. In the formula, R1 represents hydrogen atom, hydroxyl group or a C1-6 alkyl group etc. which may have one or more substituents; L represents a single or double bond or a C1-6 alkylene group etc. which may have one or more substituents; M represents a single bond or a C1-6 alkylene group etc. which may have one or more substituents; T represents a single bond or a C1-3 alkylene group which may have one or more substituents; W represents carboxyl group or a group represented by the formula -CON(Rw1)Rw2 (wherein Rw1 and Rw2 are the same as or different from each other and each represents hydrogen atom, formyl group etc.) etc.; represents a single or double bond; X represents oxygen atom or a C2-6 alkenylene group etc. which may have one or more substituents; Y represents a C5-12 aromatic hydrocarbon group etc. which may have one or more substituents and which may have one or more heteroatoms; and ring Z represents a C5-6 aromatic hydrocarbon group which may have 0 to 4 substituents and which may have one or more heteroatoms.
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- An in-depth study of the biotransformation of nitriles into amides and/or acids using Rhodococcus rhodochrous AJ270
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A variety of aliphatic, aromatic and heterocyclic nitriles have been readily hydrolysed into the corresponding amides and/or acids under very mild conditions using Rhodococcus sp. AJ270. The nitrile hydratase involved in this novel nitrile-hydrolysing microorganism efficiently hydrates most nitriles tested, irrespective of the electronic and steric effects of the substituents, to form the amides. Conversion of amides into acids catalysed by the associated amidase is rapid and efficient in most cases. Substrates bearing an adjacent substituent (which may be an ortho substituent on an aromatic nitrile, an adjacent heteroatom in a heterocyclic ring or a geminal substituent in an α,β-unsaturated nitrile) undergo slow hydrolysis of the amides allowing efficient amide isolation. The scope, limitations and reaction mechanism of this enzymatic process have been systematically studied. A molecular size of >7 A diameter and the presence of functions capable of metal complexation near to the nitrile inhibit hydrolysis.
- Meth-Cohn, Otto,Wang, Mei-Xiang
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p. 1099 - 1104
(2007/10/03)
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- Rat hepatic microsomal aldehyde dehydrogenase. Identification of 3- and 4-substituted aromatic aldehydes as substrates of the enzyme
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The rat hepatic microsomal aldehyde dehydrogenase (mALDH) metabolizes aliphatic and aromatic aldehydes to the corresponding acids with NAD as the optimal cofactor. However, dehydrogenation of the aliphatic compounds is substantially more efficient. In the present study, a series of aromatic aldehydes was evaluated as substrates of the purified mALDH so that the physicochemical factors that contribute to substrate affinity could be evaluated. Substitution of the aromatic system in the 3- and 4-positions produced relatively good substrates, but 2-substituted congeners did not undergo dehydrogenation. However, aldehydes with hydrophilic substituents in the 3- or 4-positions and those with extremely bulky substituents at both positions (e.g., 3,4-dibenzyloxy) were also poor substrates for the enzyme and dehydrogenation was undetectable. A quantitative structure-activity relationship was determined that related the logarithm of the Michaelis constants for 27 substituted aromatic aldehydes with the zero-order connectivity function of the molecule (0χ), the shapes of the 3-and 4-substituents (κ), and the electronic nature of the 4-substituent (σ). In this equation, 81% of the data variance was explained. From a consideration of the dimensions of 3-phenoxybenzaldehyde, which was a relatively good substrate, the mALDH possesses a narrow cleft within the active site that is at least 7.5 A wide and extends at least 12 A from the the catalytic residue (probably cysteine). Previously established relationships between connectivity functions and molecular polarizability suggest that dipolar interactions within the active site, as well as dispersion forces, may play a role in substrate specificity. Although optimal shapes for carbocyclic substituents were not provided by the analysis, the unfavorable effect on dehydrogenation from hydrophilic and large substituents suggests that the active site of the mALDH is relatively rigid and that the orientation of the substrate in relation to the catalytic cysteine and the cofactor binding site is critical.
- Martini, Robert,Murray, Michael
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p. 268 - 276
(2007/10/03)
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- Process for the preparation of aromatic acid
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A process for the preparation of an aromatic acid comprising the step of combining an aromatic halide having at least one iodine or bromine substituent with: a. a water-immiscible organic solvent, b. a palladium-based catalyst, c. a palladium-complexing agent, d. a tertiary nitrogen-containing organic base, e. water and f. carbon monoxide. The process is performed in a two-phase liquid medium and in the substantial absence of a phase transfer agent.
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- The palladium(II) / carbon monoxide-mediated biaryl formation from aryltellurium trihalides
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Treatment of aryltellurium trihalides (ArTeX3: Ar=Ph, 4-BrC6H4, 4-MeC6H4, 4-MeOC6H4, 4-BuOC6H4, 4-PhOC6H4, 2-naphthyl; X=Cl,Br) with a palladium(II) salt in acetonitrile at 25 deg C affords, in good yields (29-78 percent), the corresponding biaryls (ArAr) either in the atmosphere or under 1 atm CO.The presence of CO accelerates this aromatic coupling significantly to produce some active palladium carbonyl species, the formation of which was confirmed by IR spectroscopy of Li2PdCl4 in acetonitrile solution under CO; a strong sharp absorption and a weaker sharp one appeared at 2140 and 1908 cm-1, respectively, attributable to the ν(CO) of the (Pd-CO) species.Treatment with alkali after reaction was essential to producing the biaryls.
- Takahashi, Hidetaka,Ohe, Kouichi,Uemura, Sakae,Sugita, Nobuyuki
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p. 227 - 234
(2007/10/02)
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- Process for the preparation of aromatic monocarboxylic acids from toluene and substituted toluenes
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In a process for preparing aromatic monocarboxylic acids by oxidation of toluene or of toluenes substituted in the nucleus, the starting substances are reacted in the liquid phase with oxygen or with a gas containing oxygen, at a temperature of 80°-180° C. and a pressure of 5 to 50 bar in the presence of acetic acid as diluent and a soluble cobalt and/or manganese salt in combination with a bromide, and the aromatic monocarboxylic acids are then obtained by solid-liquid separation of the cooled reaction mixture. To reduce the dimensions of the oxidation reactor, for which particularly corrosion-resistant materials are necessary, and to isolate the target products in high yield and purity, as well as to reduce the technical complexity and cost of the treatment of the amounts of solvents that are yielded, relatively small amounts of acetic acid are used as solvents or diluents, namely at a ratio by weight of the alkyl aromatic being oxidized and acetic acid of 0.5:1 to 6:1. Not until the reaction has ended is the dilution, which is necessary for the isolation of the target product by solid-liquid separation of the cooled reaction mixture, performed by the addition of dilute aqueous acetic acid or of the washing filtrate from a preceding oxidation run. A typical example is the preparation of p-tert-butylbenzoic acid from p-tert-butyltoluene by the method described.
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- Analogues of clofibrate and clobuzarit containing fluorine in the side chains
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A series of analogues of clofibrate and 2-[4-(4-chlorophenyl)phenylmethoxy]-2-methylpropionic acid (clobuzarit) has been prepared by replacing the methyl groups by trifluoromethyl groups and changing the aromatic moiety. The activity of these compounds has been assayed on the plasma levels of cholesterol, Total Esterified Fatty Acids (T.E.F.A.) and fibrinogen in rats. It appears that derivatives of the first series which contain only one trifluoromethyl group are hypocholesterolaemic and that many mono- of bis- trifluoromethyl derivatives of the second series lower the levels of both cholesterol and T.E.F.A. in contrast to clobuzarit.
- Haydock,Mulholland,Telford,et al.
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p. 205 - 214
(2007/10/02)
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- ELECTROSYNTHESE CATALYTIQUE D'ACIDES BENZOIQUES para-SUBSTITUES A PARTIR DU DERIVE HALOGENE CORRESPONDANT ET DE L'ANHYDRIDE CARBONIQUE
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Electrochemical reduction of the complex formed by insertion of an electrogenerated nickel(0) atom into the carbon-halogen bond of a p-halogeno-substituted aromatic compound in the presence of CO2 leads to formation of the corresponding aromatic carboxylate.At room temperature the electrochemical synthesis needs catalytic quantities of nickel chloride coordinated to triphenylphosphine or 1,2-bis(diphenylphosphino)ethane.
- Fauvarque, J.F.,Chevrot, C.,Jutand, A.,Francois, M.,Perichon, J.
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p. 273 - 282
(2007/10/02)
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- Effect of Chain Length on Mesomorphism of Steroid Esters of 4-(4-Alkylphenyl-X)benzoic Acids with X = CO, O, S, and CH2
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To examine the effect of bent shapes on mesomorphic properties a homologous series of steroid esters have been prepared: H(CH2)n-4-C6H4-X-4-C6H4COOR, X = CO, O, S, CH2, R = cholesteryl, β-sitosteryl, cholestanyl, stigmasteryl, ergosteryl; n = 0-15.The chain elongation results in an increase in not only the molecular length but also the breadth due to the angular linkage, X.The steroid portions are of primary importance for the mesomorphic properties of the present series, and the thermal stability of the mesophases is strongly dependent on the mesogenic power of the aryl portions, where the effective order is CO > O > S > CH2.The transition enthalpies and entropies for the smectic A-cholesteric and cholesteric-isotropic (Ch-I) transitions are almost independent of the chain length of the alkyl group, indicating that a long alkyl chain has no role from a thermodynamical piont of view.Within the mesophases, the aryl and steroid cores are assumed to be piled up, interacting with each other, and the alkyl groups are apart from each other to avoid short-range interaction.
- Koden, Mitsuhiro,Yagyu, Tadao,Takenaka, Shunsuke,Kusabayashi, Shigekazu
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p. 4730 - 4737
(2007/10/02)
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- INFLUENCE OF THE ANGULAR LINKAGE ON THE MESOMORPHIC PROPERTIES OF CHOLESTERYL ARYLBENZOATES.
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Some cholesteryl esters of arylbenzoic acids incorporating angular linkage such as -Co-, -O-, -S-, and -CH//2-, were prepared, and the transition temperatures and heats determined. The cholesteric-isotropic transition temperatures are likely to correlate with the angular correlation parameters of these carboxylic acid moieties. The mesomorphic phenomena are discussed in terms of the molecular structure and electronic effect of these linkages.
- Koden,Takenaka,Kusabayashi
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p. 137 - 150
(2007/10/02)
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