- Synthesis of methyl acetoacetate from acetone and dimethyl carbonate with alkali-promoted MgO catalysts
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The synthesis of methyl acetoacetate (MAA) by methoxycarbonylation of acetone with dimethyl carbonate (DMC) was carried out in the presence of MgO and alkali-promoted MgO catalysts. From among Li, Na, K, and Cs, potassium was found to be the most effective promoter to improve the activity of MgO. The effect of K/MgO with variable content of K was also investigated, and the individual catalysts were characterised by the XRD, BET, SEM, CO2-TPD, and in situ CO2 IR techniques. The results showed that the addition of a small amount of K (1.97 mass %) could promote MAA formation, but a higher K loading caused a decrease in the yield of MAA, which might result from particle agglomeration and the presence of stable potassium carbonates. In situ FTIR experiments of co-adsorbed reactants indicated that the reaction probably proceeded via abstraction of Hα from acetone by base sites.
- Wu, Dudu,Chen, Zhi
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- Catalytic Dimerization of Ketene. A Simple and Convenient Method for the Preparation of Diketene and Esters of Acetoacetic Acid
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A new method for the preparation of diketene is described.The main feature of the procedure is the dimerization of ketene in the presence of tetramethylethylenediamine (TMEDA) and the direct use of crude diketene in the syntheses of acetoacetic esters.Keywords: Dimerization of ketene; Tetramethylethylenediamine, catalytic action of
- Jarowicki, Krzysztof,Kwitakowski, Stefan
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- Asymmetric Aerobic Epoxidation of Unfunctionalized Olefins Catalyzed by Optically Active α-Alkoxycarbonyl-β-ketoiminato Manganese(III) Complexes
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Optically active N,N'-ethylenebis(α-alkoxycarbonyl-β-ketoimine) was found to be a new class of effective ligand of manganese(III) complex catalyst for the asymmetric aerobic epoxidation of simple olefins, such as 1,2-dihydronaphthalene derivatives, to afford the corresponding optically active epoxides with good to high enantioselectivities.
- Mukaiyama, Teruaki,Yamada, Tohru,Nagata, Takushi,Imagawa, Kiyomi
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- Synthesis of β-keto esters by carbonylation of halomethylketones
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A number of β-keto esters were synthesized by Pd-catalyzed carbonylation of halomethylketones in the presence of tributylamine in 68-86percent yields. The reaction is completed in 2 hours at 110°C and 10 bar CO pressure. Chloromethylketones are carbonylated selectively while 2-bromoacetophenone is partly reduced to acetophenone as a byproduct. The reaction can be carried out at atmospheric pressure though the rate stays low. The reaction mechanism is discussed.
- Lapidus,Eliseev,Bondarenko,Sizan,Ostapenko,Beletskaya
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- New method of zinc activation by electrochemistry: synthetic applications to the Blaise reaction
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A new electrochemical zinc metal activation method based on the cathodic reduction of a catalytic amount of zinc bromide in the presence of a zinc anode is described.This procedure is applied to the coupling of α-bromoesters with nitriles, and affords β-ketoesters in good yield.
- Zylber, N.,Zylber, J.,Rollin, Y.,Dunach, E.,Perichon, J.
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- Inversion of cpADH5 Enantiopreference and Altered Chain Length Specificity for Methyl 3-Hydroxyalkanoates
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Expanding the substrate scope of enzymes opens up new routes for synthesis of valuable chemicals. Ketone-functionalized fatty acid derivatives and corresponding chiral alcohols are valuable building blocks for the synthesis of a variety of chemicals including pharmaceuticals. The alcohol dehydrogenase from Candida parapsilosis (cpADH5) catalyzes the reversible oxidations of chiral alcohols and has a broad substrate range; a challenge for cpADH5 is to convert alcohols with small substituents (methyl or ethyl) next to the oxidized alcohol moiety. Molecular docking studies revealed that W286 is located in the small binding pocket and limits the access to substrates that contain aliphatic chains longer than ethyl substituent. In the current manuscript, we report that positions L119 and W286 are key residues to boost oxidation of medium chain methyl 3-hydroxy fatty acids; interestingly the enantiopreference toward methyl 3-hydroxybutyrate was inverted. Kinetic characterization of W286A showed a 5.5 fold increase of Vmax and a 9.6 fold decrease of Km values toward methyl 3-hydroxyhexanoate (Vmax: 2.48 U mg? and Km: 4.76 mm). Simultaneous saturation at positions 119 and 286 library yielded a double mutant (L119M/W286S) with more than 30-fold improved activity toward methyl 3-hydroxyoctanoate (WT: no conversion; L119M/W286S: 30 %) and inverted enantiopreference (S-enantiomer ≥99 % activity decrease and R-enantiomer >20-fold activity improvement) toward methyl 3-hydroxybutyrate.
- Ensari, Yunus,Dhoke, Gaurao V.,Davari, Mehdi D.,Bocola, Marco,Ruff, Anna Jo?lle,Schwaneberg, Ulrich
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- Carbonylation of chloroacetone to methyl acetoacetate
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Methyl acetoacetate was prepared by the selective carbonylation of chloroacetone in the presence of a homogeneous palladium catalyst at 100 °C and under a CO pressure of 1.5 MPa.
- Lapidus,Eliseev,Bondarenko,Sizan,Ostapeako
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- A NEW PREPARATIVE METHOD FOR 1,3-DICARBONYL COMPOUNDS BY THE REGIOSELECTIVE OXIDATION OF α,β-UNSATURATED CARBONYL COMPOUNDS, CATALYZED BY PdCl2 USING HYDROGENPEROXIDES AS THE REOXIDANT OF Pd0
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α,β-Unsaturated esters and ketones are oxidized regioselectively to give β-keto esters and 1,3-diketones in good yields in aqueous acetic acid using Na2PdCl4 as the catalyst and t-butyl hydroperoxide or hydrogen peroxide as the reoxidant of Pd0.
- Tsuji, Jiro,Nagashima, Hideo,Hori, Kimihiko
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- Versatile PdTe/C catalyst for liquid-phase oxidations of 1,3-butadiene
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A commercial Pd catalyst based on Sibunit carbon support was treated with H6TeO6 in a reducing media to obtain a Te coating on the surface of Pd particles. The PdTe/C catalyst prepared in this way showed the ability to control the radical chain oxidation of 1,3-butadiene by promoting the selective formation of 2-butene-1,4-diol, 4-hydroxybut-2-enal and furan in DMA (total selectivity of 61% and yield of 7%). At the same time, the catalyst induced oxidation of 1,3-butadiene by a non-radical heterolytic mechanism involving the formation of two groups of primary products: (1) crotonaldehyde and methyl vinyl ketone and (2) the products of oxygenation at the 1,4-positions. The compounds of the second group including 1,4-dimethoxy-2-butene and maleic acid dimethyl ester were formed on PdTe centers in MeOH. Increasing the Te concentration in the PdTe/C catalyst forced the conversion of 1,3-butadiene toward 1,4-oxygenation and simultaneously decreased the intensity of secondary oxidation, resulting in the selective formation of derivatives of the 1,4-oxygenation - 1,4-dimethoxy-2-butene and allenic alcohol methyl ether (total selectivity of 84% and yield of 48%).
- Kuznetsova,Zudin,Kuznetsova,Zaikovskii,Kajitani,Utsunomiya,Takahashi
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- Revisiting ageless antiques; synthesis, biological evaluation, docking simulation and mechanistic insights of 1,4-Dihydropyridines as anticancer agents
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The historic DHP nucleus was serendipitously discovered by Arthur Hantzsch about 130 years ago and is still considered a hidden treasure for various pharmacological activities. Twenty-one DHP analogues were synthesized using the expedient one pot Hantzsch synthesis for screening as anticancer agents. Initially, the in vitro anti-proliferative single dose against a panel of 18 cancer cell lines showed that compounds 11b and 8f were the superlative candidates regarding their antitumor effect (GI% mean = 66.40% and 50.42%, correspondingly) compared to cisplatin (GI% mean = 65.58%) and doxorubicin (GI% mean = 74.56%). Remarkably, compound 11b showed a remarkable MDA-MB-468 anticancer activity (GI%=80.81%), higher than cisplatin (64.44%) and doxorubicin (76.72%), as well as strong antitumor activity against lung cancer A549 (GI%= 83.02%), more powerful than both cisplatin and doxorubicin. Compound 11b exhibited an exceptional anticancer activity against lung cancer cell line (A549) as its GI50 in nanomolar was (540 nM) with a 9-fold increase greater than cisplatin (GI50 = 4.93 μM) and with a selectivity index = 131 to cancer cells over normal cells. Further mechanistic investigations proved that DHPs anticipate simultaneously TOPI and RTKs (VEGFR-2, HER-2 and BTK) which can stimulate BAX/BAK and the executioner caspases via rtPCR studies.
- Sidhom, Peter A.,El-Bastawissy, Eman,Salama, Abeer A.,El-Moselhy, Tarek F.
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supporting information
(2021/06/21)
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- Electrochemical synthesis of versatile ammonium oxides under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions
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An electrochemical oxidative cross-coupling reaction between 2.5-substituted-pyrazolin-5-ones and ammonium thiocyanate has been developed, which resulted in a series of unprecedented cross-coupling products under metal catalyst-, exogenous-oxidant-, and exogenous-electrolyte-free conditions. It is worth noting that since the resulting cross-coupling products are nearly insoluble in MeCN, the pure product could be afforded without silica gel column purification. In addition, the prepared ammonium oxides are versatile building blocks for synthesizing functionalized pyrazole derivatives.
- Yuan, Yong,Li, Liang-Sen,Zhang, Lin,Wang, Feng,Jiang, Lin,Zuo, Lin,Wang, Qi,Hu, Jian-Guo,Lei, Aiwen
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supporting information
p. 2768 - 2771
(2021/03/23)
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- MnO2as a terminal oxidant in Wacker oxidation of homoallyl alcohols and terminal olefins
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Efficient and mild reaction conditions for Wacker-type oxidation of terminal olefins of less explored homoallyl alcohols to β-hydroxy-methyl ketones have been developed by using a Pd(ii) catalyst and MnO2 as a co-oxidant. The method involves mild reaction conditions and shows good functional group compatibility along with high regio- and chemoselectivity. While our earlier system of PdCl2/CrO3/HCl produced α,β-unsaturated ketones from homoallyl alcohols, the present method provided orthogonally the β-hydroxy-methyl ketones. No overoxidation or elimination of benzylic and/or β-hydroxy groups was observed. The method could be extended to the oxidation of simple terminal olefins as well, to methyl ketones, displaying its versatility. An application to the regioselective synthesis of gingerol is demonstrated.
- Fernandes, Rodney A.,Ramakrishna, Gujjula V.,Bethi, Venkati
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p. 6115 - 6125
(2020/10/27)
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- Method for synthesizing methyl acetoacetate
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The invention relates to a novel method for synthesizing methyl acetoacetate, which comprises the following steps: using methyl crotonate as a raw material, oxygen or air as an oxidant and nickel chloride and organic amine as catalysts, carrying out oxidation reaction to directly prepare methyl acetoacetate from methyl crotonate. Compared with the existing process for preparing methyl acetoacetate, the method has the advantages that the use of a strong acid catalyst in a diketene route is avoided, and the methyl acetoacetate synthesis method which is low in cost and environment-friendly and does not need noble metal palladium is provided.
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Paragraph 0014-0031
(2020/08/09)
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- Quinolones modulate ghrelin receptor signaling: Potential for a novel small molecule scaffold in the treatment of cachexia
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Cachexia is a metabolic wasting disorder characterized by progressive weight loss, muscle atrophy, fatigue, weakness, and appetite loss. Cachexia is associated with almost all major chronic illnesses including cancer, heart failure, obstructive pulmonary disease, and kidney disease and significantly impedes treatment outcome and therapy tolerance, reducing physical function and increasing mortality. Current cachexia treatments are limited and new pharmacological strategies are needed. Agonists for the growth hormone secretagogue (GHS-R1a), or ghrelin receptor, prospectively regulate the central regulation of appetite and growth hormone secretion, and therefore have tremendous potential as cachexia therapeutics. Non-peptide GHS-R1a agonists are of particular interest, especially given the high gastrointestinal degradation of peptide-based structures, including that of the endogenous ligand, ghrelin, which has a half-life of only 30 min. However, few compounds have been reported in the literature as non-peptide GHS-R1a agonists. In this paper, we investigate the in vitro potential of quinolone compounds to modulate the GHS-R1a in both transfected human cells and mouse hypothalamic cells. These chemically synthesized compounds demonstrate a promising potential as GHS-R1a agonists, shown by an increased intracellular calcium influx. Further studies are now warranted to substantiate and exploit the potential of these novel quinolone-based compounds as orexigenic therapeutics in conditions of cachexia and other metabolic and eating disorders.
- Torres-Fuentes, Cristina,Pastor-Cavada, Elena,Cano, Rafael,Kandil, Dalia,Shanahan, Rachel,Juan, Rocio,Shaban, Hamdy,McGlacken, Gerard P.,Schellekens, Harri?t
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- High-stability ion liquid for catalyzing esterification of alcohol and acid to generate ester and preparation method
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The invention discloses high-stability ion liquid for catalyzing esterification of alcohol and acid to generate ester and a preparation method, and belongs to the technical field of esterification ofalcohol and acid. A main component of the ion liquid is N-ethylpyrrolidone p-toluenesulfonate and is obtained by synthesizing N-ethyl-2-pyrrolidinone and p-toluenesulfonic acid at the temperature of 80 to 120 DEG C in a one-step method. The high-stability ion liquid has unexpected stability in the reaction for catalyzing the synthesis of alcohol and acid into ester, has the advantages of high activity, high selectivity and low preparation cost, and can realize the esters environment-friendly industrialized production.
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Paragraph 0061; 0062; 0063
(2018/11/03)
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- Production method for carrying out low boiler recycling on methyl acetoacetate
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The invention discloses a production method for carrying out low boiler recycling on methyl acetoacetate. The production method comprises the following steps: adding methanol and a catalyst triethylene diamine in a reaction kettle; carrying out heating reflux; dropwise adding diketene; keeping warm; cooling a reaction solution after a reaction is completed; adding concentrated sulfuric acid; keeping warm; filtering; carrying out continuous rectification on filtrate; rectifying a low boiler; adding acid in the low boiler for esterifying; rectifying the low boiler at normal pressure after carrying out the heating reflux for 1 to 2 hours; stopping rectifying after rising the kettle temperature to be 115 to 125 DEG C; cooling to 40 to 50 DEG C; neutralizing by using solid base; enabling a neutralized material to enter a conventional negative pressure rectifying system, and rectifying a methyl acetoacetate finished product, wherein the content of the methyl acetoacetate finished product is greater than 99.0 percent, the acidity is smaller than 0.05 percent, and the product recovery rate is 95 percent or above. According to the production method disclosed by the invention, loss of the methyl acetoacetate is reduced, the total yield of the methyl acetoacetate is increased, a resource can be recycled and reutilized, and the cost is reduced.
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Paragraph 0021; 0022; 0023; 0024
(2017/08/29)
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- Reactivity, Selectivity, and Stability in Sulfenic Acid Detection: A Comparative Study of Nucleophilic and Electrophilic Probes
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The comparative reaction efficiencies of currently used nucleophilic and electrophilic probes toward cysteine sulfenic acid have been thoroughly evaluated in two different settings-(i) a small molecule dipeptide based model and (ii) a recombinant protein model. We further evaluated the stability of corresponding thioether and sulfoxide adducts under reducing conditions which are commonly encountered during proteomic protocols and in cell analysis. Powered by the development of new cyclic and linear C-nucleophiles, the unsurpassed efficiency in the capture of sulfenic acid under competitive conditions is achieved and thus holds great promise as highly potent tools for activity-based sulfenome profiling.
- Gupta, Vinayak,Paritala, Hanumantharao,Carroll, Kate S.
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p. 1411 - 1418
(2016/06/09)
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- Photodegradation of 4-methylphenol on palladium phthalocyaninesulfonate functionalized mesopolymer under visible light irradiation
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A versatile photocatalyst has been prepared by grafting palladium phthalocyaninesulfonate (PdPcS) onto the FDU-14 mesopolymer with 3-D cubic mesostructure (FDU-14-PdPcS) via multi-step chemical modification processes. The FDU-14-PdPcS was characterized by the X-ray diffraction (XRD), diffuse reflectance UV-vis spectroscopy and inductively coupled plasma (ICP) techniques. In the photodegradation studies of 4-methylphenol, the FDU-14-PdPcS catalyst exhibited excellent visible light photocatalytic activity and reusability in the present of H2O2. The photodegradation intermediate of 4-methylphenol was investigated by gas chromatoghraphy-mass spectrometry (GC-MS) technique. Quenching experiments with isopropanol, sodium azide and benzoquinone suggested that 1O2 and O2 were the prominent active species during the photodegradation process. A possible mechanism involved in the photodegradation of -methylphenol has also been discussed.
- Xing, Rong,Wu, Lin,Fei, Zhenghao
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p. 406 - 413
(2014/07/08)
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- Rhodium-catalyzed enantioseletive hydrogenation of tetrasubstituted α-acetoxy β-enamido esters: A new approach to chiral α-hydroxyl-β-amino acid derivatives
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Asymmetric hydrogenation of tetrasubtitued α-acetoxy β-enamido esters with rhodium catalysts based on chiral diphosphine ligands provides an efficient and concise route to the synthesis of chiral α-hydroxyl-β-amino acid derivatives in excellent enantioselectivities. The products are valuable chiral building blocks in many biologically active compounds and have important applications in organic synthesis.
- Wang, Qingli,Huang, Wenhua,Yuan, Haoquan,Cai, Qin,Chen, Liming,Lv, Hui,Zhang, Xumu
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supporting information
p. 16120 - 16123
(2015/02/18)
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- Asymmetric formal total synthesis of the stemofoline alkaloids: The evolution, development, and application of a catalytic dipolar cycloaddition cascade
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A formal synthesis of didehydrostemofoline and isodidehydrostemofoline has been accomplished by preparing an intermediate in the Overman synthesis of these alkaloids from commercially available 2-deoxy-d-ribose. The work presented in this account chronicles the evolution of our explorations to identify the optimal steric and electronic control elements necessary to generate the tricyclic core structure of these alkaloids in a single operation from an acyclic precursor. The key step in the synthesis is a novel dipolar cycloaddition cascade sequence that is initiated by cyclization of a rhodium-derived carbene onto the nitrogen atom of a proximal imine group to generate an azomethine ylide that then undergoes spontaneous cyclization via dipolar cycloaddition. The synthesis features several other interesting reactions, including a Boord elimination to prepare a chiral allylic alcohol, a highly diastereoselective Hirama-It? cyclization, and a useful modification of the Barton decarboxylation protocol.
- Shanahan, Charles S.,Fang, Chao,Paull, Daniel H.,Martin, Stephen F.
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p. 7592 - 7607
(2013/08/23)
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- Organic-inorganic hybrid supermicroporous iron(III) phosphonate nanoparticles as an efficient catalyst for the synthesis of biofuels
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Here we report a novel family of crystalline, supermicroporous iron(III) phosphonate nanomaterials (HFeP-1-3, HFeP-1-2, and HFeP-1-4) with different FeIII-to-organophosphonate ligand mole ratios. The materials were synthesized by using a hydrothermal reaction between benzene-1,3,5-triphosphonic acid and iron(III) chloride under acidic conditions (pH≈4.0). Powder X-ray diffraction, N2 sorption, transmission and scanning electron microscopy (TEM and SEM) image analysis, thermogravimetric and differential thermal analysis (TGA-DTA), and FTIR spectroscopic tools were used to characterize the materials. The triclinic crystal phase [P1(2) space group] of the hybrid iron phosphonate was established by a Rietveld refinement of the PXRD analysis of HFeP-1-3 by using the MAUD program. The unit cell parameters are a=8.749(1), b=8.578(1), c=17.725(3) ?; α=104.47(3), β=97.64(1), γ=113.56(3)°; and V=1013.41 ?3. With these crystal parameters, we proposed an 24-membered-ring open framework structure for HFeP-1. Compound HFeP-1-3, with an starting Fe/ligand molar ratio of 3.0, shows the highest Brunauer-Emmett-Telller (BET) surface area of 556 m2g -1 and uniform supermicropores of approximately 1.1 nm. The acidic surface of the porous iron(III) phosphonate nanoparticles was used in a highly efficient and recyclable catalytic transesterification reaction for the synthesis of biofuels under mild reaction conditions. Iron brews biofuels: Highly crystalline, supermicroporous iron(III) phosphonate nanoparticles have been synthesized through a hydrothermal reaction between benzene-1,3,5- triphosphonic acid and FeCl3. The resulting material was used as an efficient and recyclable catalyst for the synthesis of biofuels under mild reaction conditions (see scheme). Copyright
- Pramanik, Malay,Bhaumik, Asim
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p. 8507 - 8514
(2013/07/26)
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- Critical profiles of chiral diether-mediated asymmetric conjugate aminolithiation of enoate with lithium amide as a key to the total synthesis of (-)-kopsinine
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Chiral diether-mediated asymmetric aminolithiation of indolylpropenoate with lithium amide in toluene at -78 °C for 15 min gave, after aqueous ammonium chloride quench, the corresponding conjugate addition product with 97% ee in 89% yield. If hydrogen chloride in methanol was selected as a quencher, however, aminolithiation at -78 °C for 3 h gave the corresponding adduct with 97% ee in 54% yield, along with recovery of the starting enoate in 39% yield. Based on this finding of an incomplete and slow reaction at -78 °C, the aminolithiation conditions were optimized to be at -60 °C for 15 h and subsequent enolate trap with alkyl halide upon an addition of DMPU afforded the desired aminoalkylation product with 98% ee in 89% yield. Further approach toward total synthesis of (-)-kopsinine was carried out by examining asymmetric aminolithiation with N-hydroxyethylamine equivalent, one-pot piperidine formation, and Claisen condensation.
- Harada, Shingo,Sakai, Takeo,Takasu, Kiyosei,Yamada, Ken-Ichi,Yamamoto, Yasutomo,Tomioka, Kiyoshi
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p. 3264 - 3273
(2013/05/08)
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- Highly atom-efficient oxidation of electron-deficient internal olefins to ketones using a palladium catalyst
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A 100 % atom-efficient synthesis of ketones from electron-deficient internal olefins was achieved using O2 as a "green" oxidant (see scheme, DMA=N,N-dimethylacetamide, EWG=electron-withdrawing group). Various electron-deficient olefins were oxidized to the corresponding ketones with over 99 % selectivity and without the formation of olefin isomers or their oxidized products. Copyright
- Mitsudome, Takato,Yoshida, Syuhei,Mizugaki, Tomoo,Jitsukawa, Koichiro,Kaneda, Kiyotomi
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p. 5961 - 5964
(2013/06/27)
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- Direct β-acyloxylation of enamines via PhIO-mediated intermolecular oxidative C-O bond formation and its application to the synthesis of oxazoles
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A direct β-acyloxylation of enamine compounds has been achieved by using iodosobenzene (PhIO) as an oxidant to realize the intermolecular oxidative C(sp2)-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. The transformation tolerates a wide range of functional groups and furnishes a variety of β-acyloxy enamines that can be conveniently converted to oxazole compounds via cyclodehydration.
- Liu, Xin,Cheng, Ran,Zhao, Feifei,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
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supporting information
p. 5480 - 5483,4
(2012/12/12)
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- Direct β-acyloxylation of enamines via PhIO-mediated intermolecular oxidative C-O bond formation and its application to the synthesis of oxazoles
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A direct β-acyloxylation of enamine compounds has been achieved by using iodosobenzene (PhIO) as an oxidant to realize the intermolecular oxidative C(sp2)-O bond formation between enamines and various carboxylic acids, including N-protected amino acids. The transformation tolerates a wide range of functional groups and furnishes a variety of β-acyloxy enamines that can be conveniently converted to oxazole compounds via cyclodehydration.
- Liu, Xin,Cheng, Ran,Zhao, Feifei,Zhang-Negrerie, Daisy,Du, Yunfei,Zhao, Kang
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supporting information
p. 5480 - 5483
(2013/01/15)
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- Design and synthesis of new 1,4-dihydropyridines containing 4(5)-chloro-5(4)-imidazolyl substituent as a novel calcium channel blocker
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New analogues of nifedipine, in which the ortho-nitro phenyl group at position 4 has been replaced by 4(5)-chloro-5(4)-imidazolyl substituent and which are able to interact with the receptor by hydrogen binding were designed, synthesized, and evaluated as calcium channel antagonists. The designed dihydropyridines were synthesized using the Hantzsch condensation and evaluated as calcium channel antagonists using the high K+ contraction of guineapig ileal longitudinal smooth muscle. A docking study was performed using the AutoDock4 program, and QSAR equations were obtained using multilinear regression. Our computational studies indicated that the oxygen of the ester (O10) and the N3′ of the imidazole ring form a hydrogen bonding interaction with the NH of HIS 363 and NH of LYS354, respectively, and that the sum of the BEHp5 and RDF075p are the most significant descriptors. The results of calcium channel antagonist evaluation demonstrated that increasing the chain length in C3 and C5 ester substituents increased activity. The most potent compound was the bis-phenylpropyl ester (5l) derivative, in that it was more active than the reference drug nifedipine and that the bis-phenylethyl ester (5k) derivative had comparable activity with nifedipine. The present research revealed that the 4(5)-chloro-5(4)-imidazolyl moiety is a bioisoster of o-nitrophenyl in nifedipine and provided novel dihydropyridines with more activity as calcium channel antagonists.
- Iman, Maryam,Davood, Asghar,Nematollahi, Ali Reza,Dehpoor, Ahmad Rerza,Shafiee, Abbas
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scheme or table
p. 1417 - 1426
(2012/05/04)
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- Discovery of a potent nicotinic acid receptor agonist for the treatment of dyslipidemia
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Nicotinic acid has been used clinically for decades to control serum lipoproteins. Nicotinic acid lowers very low-density lipoprotein (VLDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, and lipoprotein-a (LPa), and it is also effective in raising high-density lipoprotein (HDL)-cholesterol. However, nicotinic acid has several side effects in clinical use. The most notable is intense cutaneous vasodilation "flushing"+ on the upper body and face. We discovered a pyranopyrimidinedione series to be nicotinic acid receptor agonists. A potent nicotinic acid receptor agonist from this series {5-(3-cyclopropylpropyl)-2-(difluoromethyl)-3H-pyrano[2,3-d] pyrimidine-4,7-dione}with reduced flushing side effect in dogs was identified.
- Qin, Jun,Rao, Ashwin,Chen, Xiao,Zhu, Xiaohong,Liu, Zhidan,Huang, Xianhai,Degrado, Sylvia,Huang, Ying,Xiao, Dong,Aslanian, Robert,Cheewatrakoolpong, Boonlert,Zhang, Hongtao,Greenfeder, Scott,Farley, Constance,Cook, John,Kurowski, Stan,Li, Qiu,Van Heek, Margaret,Chintala, Madhu,Wang, Ganfeng,Hsieh, Yunsheng,Li, Fangbiao,Palani, Anandan
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scheme or table
p. 171 - 176
(2011/03/23)
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- Highly enantioselective synthesis of β-amino acid derivatives by the lewis base catalyzed hydrosilylation of β-enamino esters
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A study was conducted to demonstrate highly enantioselective synthesis of β-amino acid derivatives by the Lewis base catalyzed hydrosilylation of βenamino esters. It was found that these catalyst and its analogue displayed excellent activities and enantioselectivities in promoting hydrosilylation of N-aryl β-enamino esters. N-picolinoylpyrrolidine derivatives and N-picolioylephedrine were also evaluated in hydrosilylation of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate. The generality of the Lewis base organocatalyzed hydrosilylation of various β-enamino esters were examined under the optimized conditions. It was observed that the catalytic system exhibited a high sensitivity to the N-substituents, while all the N-aryl β-enamino esters underwent the hydrosilylation smoothly to give corresponding β-amino esters.
- Zheng, Hong-Jie,Chen, Wen-Bing,Wu, Zhi-Jun,Deng, Jin-Gen,Lin, Wen-Qing,Yuan, Wei-Cheng,Zhang, Xiao-Mei
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supporting information; experimental part
p. 9864 - 9867
(2009/10/02)
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- HYDANTOIN DERIVATIVES USEFUL AS ANTIBACTERIAL AGENTS
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This invention relates to compounds of the Formula (I): or a pharmaceutically acceptable salt, solvate, ester or isomer thereof, which is useful for the treatment of diseases or conditions mediated by LpxC.
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Page/Page column 67
(2008/06/13)
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- Process for the preparation of pleuromutilins
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A process for the preparation of 14-O-[(N-(3-methyl-2-amino-butyryl-piperidinyl)sulfanyl) acetyl]mutilins of formula feasible for large-scale production of high purity products, and wherein the carbon atom at the piperidine ring attached to the sulphur atom is either in the (S)-configuration or in the (R)-configuration, and a new crystalline form of 14-O-[(N-3-methyl-2-(R)-amino-butyryl-piperidine-3(S)-yl)sulfanyl)acetyl]mutilin - hydrochloride.
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Page/Page column 8
(2008/06/13)
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- Structure-activity relationship study of [1,2,3]thiadiazole necroptosis inhibitors
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Necroptosis is a regulated caspase-independent cell death mechanism that results in morphological features resembling non-regulated necrosis. This form of cell death can be induced in an array of cell types in apoptotic deficient conditions with death receptor family ligands. A series of [1,2,3]thiadiazole benzylamides was found to be potent necroptosis inhibitors (called necrostatins). A structure-activity relationship study revealed that small cyclic alkyl groups (i.e. cyclopropyl) and 2,6-dihalobenzylamides at the 4- and 5-positions of the [1,2,3]thiadiazole, respectively, were optimal. In addition, when a small alkyl group (i.e. methyl) was present on the benzylic position all the necroptosis inhibitory activity resided with the (S)-enantiomer. Finally, replacement of the [1,2,3]thiadiazole with a variety of thiophene derivatives was tolerated, although some erosion of potency was observed.
- Teng, Xin,Keys, Heather,Jeevanandam, Arumugasamy,Porco Jr., John A.,Degterev, Alexei,Yuan, Junying,Cuny, Gregory D.
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p. 6836 - 6840
(2008/03/14)
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- Microwave assisted rapid and efficient synthesis of aryl methyl ketones and β-keto esters using Meldrum's acid
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Microwave mediated rapid and efficient synthesis of aryl methyl ketones and β-keto esters from acyl Meldrum's acid by hydrolysis and alcoholysis, respectively, has been reported.
- More,Mahulikar
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p. 823 - 825
(2007/10/03)
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- PROCESS FOR THE PREPARATION OF DIALKYL 3-OXOGLUTARATES
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This invention relates to a process for the preparation of 3-oxoglutarates of general formula (I), wherein R stands for methyl or ethyl. Said process comprises reacting citric acid of the formula (II) or the monohydrate thereof with chlorosulphonic acid in a lower chlorinated aliphatic hydrocarbon and reacting the intermediate thus obtained with methanol or ethanol by applying a ratio of lower chlorinated aliphatic hydrocarbon to chlorosulphonic acid in the range of 0,1:1 to 1:1 by volume and carrying out the addition of citric acid to the mixture of chlorosulphonic acid and lower aliphatic hydrocarbon at a rate of 1 - 2 kg/minute. The dialkyl 3-oxoglutarates are valuable pharmaceutical intermediates.
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- Ozonolysis of 1,4-cyclohexadienes in the presence of methanol and acid. Mechanism and intermediates in the conversion of 1,4-cyclohexadiene derivatives to β-keto esters
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Conditions for the preparation of β-keto esters directly from 1,4-cyclohexadiene derivatives are described. This procedure is a further step in the application of the synthetic methodology, which consists of the combination of Birch reduction of available benzene derivatives followed by ozonolysis. In this work, the syntheses of derivatives of dimethyl γ-keto-α-aminoadipate and dimethyl β-keto glutamate from the corresponding 1,4-cyclohexadiene derivatives are described. The latter compounds are prepared from phenylalanine and phenylglycine, respectively. The study of the ozonolysis of simple alkyl derivatives of 1,4-cyclohexadiene in the presence of methanol, both in the presence and absence of acid, helped to establish the mechanism of this reaction. The proximity of the two double bonds, which are cleaved, leads to the intermediate formation of 1,2-dioxolane derivatives that could be identified by NMR spectroscopy. It is shown that regardless of the regioselectivity of the cleavage of the primary ozonide, which is formed, all 1,2-dioxolane derivatives can lead to β-keto esters. This is due to the equilibrium between these dioxolanes in the presence of methanol and acid.
- Gbara-Haj-Yahia, Isra,Zvilichovsky, Gury,Seri, Noa
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p. 4135 - 4139
(2007/10/03)
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- Lipophilic 4-imidazoly-1,4-dihydropyridines: Synthesis, calcium channel antagonist activity and protection against pentylenetetrazole-induced seizure
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A group of alkyl, cycloalkyl and aryl ester analogs of nifedipine, in which the o-nitrophenyl group at position 4 is replaced by a 2-phenyl-4(5)-imidazolyl substituent, were synthesized and evaluated as calcium channel antagonist using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle, and the activity of 5a-d, 8b and 8f against pentylenetetrazole (PTZ)-induced seizure was assessed. The results for symmetrical esters showed that lengthening of the methylene chain in C3 and C5 ester substituents increased activity. When increasing of the length is accompanied by increasing the hindrance, the activity decreased. In contrast to symmetrical derivatives, comparison of the activities of asymmetrical esters showed that increasing the length of the methylene chain was accompanied by a decrease in their activity. The results demonstrate that 8a was more active, and 5c and 8f were similar in effect to that of the reference drug nifedipine. The time-course of anticonvulsant effect on PTZ-induced seizure threshold of said compounds was assessed and showed that increasing the lipophilicity decreases the time needed for maximum effect. Mice treated with intraperitoneal injection of 25 mg/kg of these derivatives all exhibited increase seizure threshold as compared with control.
- Navidpour, Latifeh,Shafaroodi, Hamed,Miri, Ramin,Dehpour, Ahmad Reza,Shafiee, Abbas
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p. 261 - 269
(2007/10/03)
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- ACETOACETYLATION OF ALCOHOLS, THIOLS AND AMINES IN A MICROREACTOR
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The invention relates to a method for the production of β-ketocarboxylic acid derivatives of formula (I) or the salts thereof, where X = NR', O or S, R, R', R1-R4 independently = H, alkyl, alkenyl, aryl or heteroaryl, by reaction of a diketene of formula (II) with a compound comprising an active hydrogen of formula ROH, NHRR' or RSH, characterised in that the reaction is continuously carried out in a microreactor.
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- Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one
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The present invention relates to a novel process for producing a δ-lactone of the formula: using an acyl halide of the formula: wherein R1, R2R3and X are described herein, as well as novel intermediates. In particular, the present invention relates to a process for enantioselectively producing the (R)-δ-lactone.
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- Synthesis of 3,6-dialkyl-5,6-dihydro-4-hydroxy-pyran-2-one
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The present invention relates to a novel process for producing a δ-lactone of the formula: using an acyl halide of the formula: wherein R1, R2R3and X are described herein. In particular, the present invention relates to a process for enantioselectively producing the δ-lactone and novel intermediates disclosed herein.
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- Method for preparing chiral diphosphines
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The invention concerns a method for preparing a compound of formula (1) wherein: A represents naphthyl or phenyl optionally substituted; and Ar1, Ar2independently represent a saturated or aromatic carbocyclic group, optionally substituted.
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- Process for preparing malonate derivatives or beta -keto esters from epoxide derivatives
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A process for preparing a malonic acid monoester or β-ketoester from an epoxide includes the steps of reacting an epoxide with carbon monoxide and an alcohol in the presence of a catalytic amount of a cobalt compound and at least one promoter to produce a β-hydroxyester, separating the β-hydroxyester from the cobalt compound and the promoter, and oxidizing the β-hydroxyester to produce a malonic acid monoester or β-ketoester.
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- Preparation of higher alpha, beta-unsaturated alcohols
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Higher α,β-unsaturated alcohols are prepared by monoethynylation of a ketone by the NH3/KOH method, if desired hydrogenation of the acetylene alcohol in the presence of hydrogen over a Pd-containing thin layer catalyst, purifying distillation of the hydrogenation product, preferably in a dividing wall column with recirculation of the unreacted ketone to the ethynylation step, and, if desired, preparation of higher alcohols having in each case 5 more carbon atoms in the chain by reacting the alcohols prepared by monoethynylation and, if desired, partial hydrogenation with alkyl acetoacetatesor diketene in a Carroll reaction to form ketones and using these as starting materials for the steps ethynylation, optional hydrogenation and fractional distillation.
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- A mild and effective method for the transesterification of carboxylic acid esters
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An extraordinarily versatile transesterification of simple or highly functionalized esters of aliphatic and aromatic carboxylic acids in high yields is catalyzed by dibutyltin oxide [Eq. (1)]. The reaction is compatible with several functional groups, for example, acetals, ketals, aliphatic bromides, enol ethers, urethanes, as well as free hydroxy, phenolic, and amino groups, and even with water.
- Baumhof, Patrick,Mazitschek, Ralph,Giannis, Athanassios
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p. 3672 - 3674
(2007/10/03)
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- Liquid oligomers containing acrylate unsaturation
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The liquid oligomeric compositions of this invention are made by the Michael addition reaction of acetoacetate functional donor compounds with multifunctional acrylate receptor compounds where the equivalent ratios of multifunctional acrylate to acetoacetate vary from >/=1:1 to >/=13.2:1 depending on the functionality of both multifunctional acrylate and acetoacetate. Unuseable gelled or solid oligomer products occur below the claimed ranges. The liquid oligomers of this invention are further crosslinked to make coatings, laminates and adhesives.
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- Asymmetric hydrogenation method of a ketonic compound and derivative
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The present invention relates to a process for the asymmetric hydrogenation of a ketonic compound and derivative. The invention relates to the use of optically active metal complexes as catalysts for the asymmetric hydrogenation of a ketonic compound and derivative. The process for the asymmetric hydrogenation of a ketonic compound and derivative is characterized in that the asymmetric hydrogenation of said compound is carried out in the presence of an effective amount of a metal complex comprising as ligand an optically active diphosphine corresponding to one of the following formulae: STR1
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- Nitrolysis of carboxylic t-butyl and 1-adamantyl esters
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A cheap, less problematic, efficient and selective reagent for the removal of the t-butyl and 1-adamantyl protecting groups from carboxylic esters was found to be commercial 100% HNO3 in CH2Cl2. Incidentally, 1,1- dimethylethyl nitrate and tricyclo[3.3.1.13,7]dec-1-yl (1-adamantyl) nitrate are coproducts in a clean reaction. The procedure is in many ways superior to the method employing CF3COOH.
- Strazzolini, Paolo,Dali'Arche, Maria Grazia,Giumanini, Angelo G.
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p. 9255 - 9258
(2007/10/03)
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- Synthesis and calcium-channel antagonist activity of 4-imidazolyl-1,4-dihydropyridines
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The o-nitrophenyl group at position 4 of dihydropyridine of nifedipine analogues was replaced by 1-methylimidazole. These compounds were evaluated as calcium-channel antagonists using the high K+ contraction of guinea-pig ileal longitudinal smooth muscle. The results for the symmetrical esters showed that increasing the length of methylene chain of ester more than 3 units decreases activity. For cyclic esters, cyclopropylmethyl ester was more active than cyclohexylmethyl ester. Our results revealed two compounds with activities similar to the reference drug nifedipine; the symmetrical cyclopropylmethyl ester, and the asymmetrical phenethyl ethyl derivatives were the most potent antagonists tested.
- Pourmorad,Hadizadeh,Shafiee
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p. 165 - 168
(2007/10/03)
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- Reactions of fused and unfused α-pyrones with magnesium alkoxide, sodium alkoxide and water as the nucleophile: effects of chelation
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The reactions between a series of α-pyrones (two mono- and three fused) and the non-chelating base sodium alkoxide, the chelating base magnesium alkoxide and water as the nucleophile, have been studied.Aromatic and other products formed reflect the points of attack on the pyrone systems and when sodium methoxide is used the ensuing cyclisation is preferentially by aldol mechanisms.The employment of excess magnesium methoxide or ethoxide gives magnesium-chelated precursors and the nature of products now depends on these intermediates, and the protection afforded by such magnesium chelation to the reaction products.In the case of structures containing chelated β-keto ester features the chelates are screened from attack as aldol acceptors, but are effective Claisen acceptors.In such chelates an adjacent methylene is activated by further magnesium alkoxide to act as an aldol or Claisen donor.These contrasting aldol/Claisen reactivities, as between a non-chelating and a chelating base, are illustrated in the ensuing chemistry of the pyrones.Treatment with water releases the main carbon chain with decarboxylation, from which new products may form.
- Crombie, Leslie,Games, David E.,James, Alun W. G.
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p. 2715 - 2724
(2007/10/03)
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- Synthesis of bicyclic guanidines from pyrrolidin-2-one
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The syntheses of three bicyclic guanidines as model compounds for the guanidine alkaloid ptilomycalin A are described. The guanidines are prepared from pyrrolidin-2-one via an N-acyliminium ion coupling reaction with silyl enol ethers and a direct guanylation with bis-Boc-thiourea and HgCl2 as the key steps.
- Louwrier, Saskia,Tuynman, Antonin,Hiemstra, Henk
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p. 2629 - 2646
(2007/10/03)
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- The Reformatsky Reaction of 1-Acyl-3,5-dimethylpyrazoles. A Convenient Preparation of 4-Amino-3-oxoalkanoic Acid Derivatives
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The conversion of N-acylpyrazoles into β-keto esters was accomplished efficiently by the treatment with α-bromo esters and zinc dust.Using this Reformatsky reaction of N-acylpyrazoles, 4-(protected amino)-3-oxoalkanoic acid derivatives were conveniently prepared as the key intermediates in the synthesis of statines.
- Kashima, Choji,Kita, Isanobu,Takahashi, Katsumi,Hosomi, Akira
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p. 723 - 726
(2007/10/02)
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- Cyclicondensation of alkylacetoacetates with 1,3,5-trinitrobenzene and base
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The condensation reaction between alkylacetoacetates and 1,3,5-trinitrobenzene has been carried out in the presence of triethylamine and diethylamine as the catalysing bases.The reaction kinetics with different alkylacetoacetates is studied and linear steric energy correlation is established.The resultant condensation product has been characterized by elemental analysis, IR, UV/visible and 1H NMR spectral studies.
- Radha, N.,Kamala, V.
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p. 399 - 403
(2007/10/03)
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- Reactive dyes which contain a triazinyl group linked to a substituted alkyl group and an amino group which contains a vinylsulfone-type reactive radical
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Water-soluble dyes, such as, for example, azo dyes, heavy metal complex azo dyes, anthraquinone, phthalocyanine and formazan dyes containing the group of the formula STR1 are described, in which Rx is hydrogen or substituted or unsubstituted lower alkyl, U is hydrogen, cyano, lower alkanoyl, lower alkoxycarbonyl, nitro, lower alkylsulfonyl or substituted or unsubstituted arylsulfonyl, V is cyano, lower alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl, carboxy, lower alkylaminocarbonyl, substituted or unsubstituted arylaminocarbonyl, lower alkylcarbonyl, substituted or unsubstituted arylcarbonyl or arylsulfonyl, aminocarbonyl, dialkylaminocarbonyl, trifluoromethyl, nitro or lower alkylsulfonyl and Q is an amino group which is mono- or disubstituted by the radical --W--(SO2 --Y)z, in which W is an arylene or alkylene radical or a combination of such radicals, the alkylene radicals being those having 1 to 8 carbon atoms, and it being possible for them to be substituted, and the arylene radicals being substituted or unsubstituted phenylene or napthylene radicals, it being possible for the alkylene radicals to be interrupted by one or more hetero groups and for the alkylene and arylene moieties in the combined alkylene/arylene radicals to be separated from one another by a hetero group, the radical --SO2 --Y is a fiber-reactive group from the vinylsulfone series and z is a number 1 or 2, or Q is an nitrogen-containing radical which is bound to the triazine radical via the nitrogen atom and contains a fiber-reactive group from the vinylsulfone series bound via a lower alkylene radical. The dyes are suitable for dyeing hydroxy and/or carboxamido-containing material, in particular fiber material.
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- Acidity and tautomerism of β-keto esters and amides in aqueous solution
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The pH-rate profiles for the keto-enol tautomerization of 17 β-keto esters and amides (RCOCH2COX: R = methyl; phenyl; 2-, 3-, and 4-pyridyl; 3(and 4)-(N-methylpyridinio); X = OCH3, OC2H5, NH2, or N(CH3)2) have been measured by stopped-flow spectrophotometry in aqueous solution (ionic strength 0.1, 25 °C) over the range pH = 2-12. Analysis of these profiles gives the microscopic rate constants for ketonization and enolization of each of these species in these aqueous solutions. Analysis of the pH dependence of the buffer catalysis for the general-acid-catalyzed protonation of these enolate conjugate bases allowed the evaluation of paE for the deprotonation of each enol species. In combination with pKaeq, these data in turn allow the calculation of the acidities of the keto tautomers (pKaK) and the equilibrium constants for enolization (KE = [enol]/[keto] ). In all cases, both the keto and enol tautomers of the amides are more acidic than the corresponding ester derivatives. The equilibrium enol/keto ratios (KE) were found to decrease in the order: 2-pyridyl > 4-pyridyl > 3-pyridyl > 4-(N-methylpyridinio) > 3-(N-methylpyridinio) > methyl ≈ phenyl for both β-keto esters and amides. A simple linear correlation between pKaE and pKaKwas observed for these series of β-keto esters and amides. Bronsted plots of second-order rate constants for deprotonation of the keto tautomer as a function of keto tautomer acidity were found to be linear, with a values in the range 0.37-0.54 for hydroxide ion, acetate ion, and several amine bases. However, the "water-catalyzed" reaction is unusual with Br?nsted α = -0.17. This α value is only readily explicable in terms of a combined general acid + general base catalysis involving two water molecules for the equilibration of the keto tautomer and the neutral enol species.
- Bunting, John W.,Kanter, James P.
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p. 11705 - 11715
(2007/10/02)
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