- Method for synthesizing 1-amino-4-methylpiperazine through catalytic hydrogenation
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The invention relates to a method for synthesizing 1-amino-4-methylpiperazine through catalytic hydrogenation. The invention discloses the green synthesis method for synthesizing 1-amino-4-methylpiperazine by hydrogenating 1-methyl-4-nitrosopiperazine in a water and organic mixed solvent system under the catalysis of an iron oxide and ferrous oxide supported palladium catalyst, wherein the methodcomprises the steps: adding 1-methyl-4-nitrosopiperazine into a paramagnetic Pd/Fe3O4-FeO catalyst, carrying out a hydrogenation reaction in a three-phase system of water, an organic solvent and the catalyst at a certain temperature, and finally, carrying out reduced pressure distillation separation to obtain the target product 1-amino-4-methylpiperazine. The 1-amino-4-methylpiperazine is preparedby innovatively using a catalytic hydrogenation method in a three-phase system, and compared with a traditional synthesis method, the method is more environmentally friendly and safer, and the cost is saved.
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Paragraph 0035-0043
(2020/07/28)
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- Electrochemical Nonacidic N-Nitrosation/N-Nitration of Secondary Amines through a Biradical Coupling Reaction
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An acid-free N-nitrosation/nitration of the N?H bonds in secondary amines with Fe(NO3)3 ? 9H2O as the nitroso/nitro source through an electrocatalyzed radical coupling reaction was developed. Cyclic aliphatic amines and N-heteroaromatic compounds were N-nitrosated and N-nitrated, respectively, under mild conditions. Control and competition experiments, as well as kinetic studies, demonstrate that N-nitrosation and N-nitration involve two different radical reaction pathways involving N+ and N. radicals. Moreover, the electrocatalysis method enables the preferential activation of the N?H bond over the electrode and thus provides high selectivity for specific N atoms. Finally, this strategy exhibits a broad scope and provides a green and straightforward approach to generate useful N-nitroso/nitro compounds in good yields. (Figure presented.).
- Zhao, Ji-Ping,Ding, Lu-jia,Wang, Peng-Cheng,Liu, Ying,Huang, Min-Jun,Zhou, Xin-Li,Lu, Ming
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supporting information
p. 5036 - 5043
(2020/07/13)
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- Optimization of biaryloxazolidinone as promising antibacterial agents against antibiotic-susceptible and antibiotic-resistant gram-positive bacteria
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We previously discovered a series of novel biaryloxazolidinone analogues bearing a hydrazone moiety with potent antibacterial activity. However, the most potent compound OB-104 exhibited undesirable chemical and metabolic instability. Herein, novel biaryloxazolidinone analogues were designed and synthesized to improve the chemical and metabolic stability. Compounds 6a-1, 6a-3, 14a-1, 14a-3 and 14a-7 showed significant antibacterial activity against the tested Gram-positive bacteria as compared to radezolid and linezolid. Further studies indicated that most of them exhibited improved water solubility and chemical stability. Compound 14a-7 had MIC values of 0.125–0.25 μg/mL against all tested Gram-positive bacteria, and showed excellent antibacterial activity against clinical isolates of antibiotic-susceptible and antibiotic-resistant bacteria. Moreover, it was stable in human liver microsome. From a safety viewpoint, it showed non-cytotoxic activity against hepatic cell and exhibited lower inhibitory activity against human MAO-A compared to linezolid. The potent antibacterial activity and all these improved drug-likeness properties and safety profile suggested that compound 14a-7 might be a promising drug candidate for further investigation.
- Wu, Yachuang,Ding, Xiudong,Yang, Yifeng,Li, Yingxiu,Qi, Yinliang,Hu, Feng,Qin, Mingze,Liu, Yajing,Sun, Lu,Zhao, Yanfang
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- Oxazolidinone compound containing combined aromatic hydrazine and its preparation method
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The invention relates to oxazolidinone compound containing combined aromatic hydrazine shown in general formula I, its optical isomer, pharmaceutical acceptable salt and/or solvent compound, and it preparation method, and the drug composition containing the compound, wherein the substituent groups R1, R2, R3, X and A rings have the meaning given in the specification. The invention further relatesto the compound, the substituent group, solvent compound or application of its prodrug using as antibacterial drug in treatment, and application of treating gram positive bacterial infection and mycobacterium tuberculosis infection especially.
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Paragraph 0119; 0120
(2018/04/03)
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- Synthesis and antibacterial activity evaluation of novel biaryloxazolidinone analogues containing a hydrazone moiety as promising antibacterial agents
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A series of linezolid analogues containing a hydrazone moiety were designed, synthesized and evaluated for their antibacterial activity. Most compounds exhibited more potent antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens as compared with linezolid and radezolid. Compounds 9a, 9c, 9f, 9g, 10m and 10t were more potent against tested clinical isolates of MRSA, MSSA, VRE and LREF as compared to linezolid. Compound 9a exhibited comparable activity with linezolid against human MAO-A for safety evaluation and showed moderate metabolism in human liver microsome. The most promising compound 9a showed remarkable antibacterial activity against S.aureus, MRSA, MSSA, LREF and VRE pathogens with MIC value of 0.0675 mg/mL, respectively, which was 15- to 30-fold more potent than linezolid.
- Wu, Yachuang,Ding, Xiudong,Ding, Liang,Zhang, Yongsheng,Cui, Lei,Sun, Lu,Li, Wei,Wang, Di,Zhao, Yanfang
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p. 247 - 258
(2018/09/18)
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- DEUTERIUM-MODIFIED BRIGATINIB DERIVATIVES, PHARMACEUTICAL COMPOSITIONS COMPRISING SAME, AND USE THEREOF
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The present invention relates to the field of pharmaceutical chemistry, and relates to a deuterium-modified Brigatinib derivative, preparation method thereof, pharmaceutical composition containing the same and the uses of the deuterium-modified Brigatinib derivative and the pharmaceutical composition thereof in preparing a medicament for treating the disease mediated by anaplastic lymphoma kinase. The deuterium-modified Brigatinib derivative of the present invention has an excellent inhibitory activity on anaplastic lymphoma kinase and has better pharmacodynamic or pharmacokinetic properties relative to Brigatinib.
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Paragraph 0174; 0175
(2018/10/15)
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- N-nitrosation of secondary amines using p-TSA-NaNO2 as a novel nitrosating agent under mild conditions
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A combination of p-toluenesulfonic acid (p-TSA) and sodium nitrite was used as a novel effective nitrosating agent for the N-nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
- Borikar, Sanjay P.,Paul, Vincent
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experimental part
p. 654 - 660
(2011/02/27)
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- Molybdate sulfuric acid/NaNO2: A novel heterogeneous system for the N-nitrosation of secondary amines under mild conditions
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Wet molybdate sulfuric acid (=dioxo[bis(sulfato-κO)]molybdenum; MSA), a new solid acid, can be used in combination with sodium nitrite (NaNO 2) to transform a variety of secondary amines to the corresponding N-nitroso compounds under mild, heterogeneous conditions (Table). The process has several advantages: the reagents are inexpensive and non-hazardous, the reaction is clean, fast, and high-yielding, and MSA can be readily removed by filtration and re-used (after treatment with HCl) without loss of activity. Further, only N-nitrosation was observed, but no C- or O-nitrosation.
- Montazerozohori, Morteza,Karami, Bahador
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p. 2922 - 2926
(2007/10/03)
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- Dinitrogen tetroxide-impregnated charcoal (N2O 4/charcoal): Selective nitrosation of amines, amides, ureas, and thiols
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Efficient N-nitrosation of amines, amides, and ureas, and also S-nitrosation of thiols were performed with dinitrogen tetroxide impregnated on activated charcoal (N2O4/charcoal) in CH 2Cl2 at room temperature. High selectivity was observed for N-nitrosation of dialkyl amines, N-alkylamides and N-alkylureas. Dealkylation and N-nitrosation of trialkylamines were also performed by this reagent. Copyright Taylor & Francis, Inc.
- Iranpoor, Nasser,Firouzabadi, Habib,Pourali, Ali Reza
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p. 1517 - 1526
(2007/10/03)
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- Selective N-nitrosation of amines, N-alkylamides and N-alkylureas by N2O4 supported on cross-linked polyvinylpyrrolidone (PVP-N2O4)
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N2O4 was supported on the cross-linked polyvinylpyrrolidone (PVP) to afford a solid, stable and recyclable nitrosating agent. This reagent shows excellent selectivity for N-nitrosation of dialkyl amines in the presence of diaryl-, arylalkyl-, trialkylamines and also for secondary amides in dichloromethane at room temperature under mild and heterogeneous conditions. Also N-nitroso-N-alkyl amides can be selectively prepared in the presence of primary amides and N-phenylamides under similar reaction conditions. Selective N-nitrosation or dealkylation and N-nitrosation of tertiary amines can also be performed by this reagent.
- Iranpoor, Nasser,Firouzabadi, Habib,Pourali, Ali-Reza
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p. 1591 - 1597
(2007/10/03)
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- Nitrosation of Amines in Nonaqueous Solvents, 1. Evidence of a Stepwise Mechanism
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We studied the nitrosation of piperidine, morpholine, pyrrolidine, N-methylpiperazine, N,N′-dimethylethylenediamine and diethylamine by 2-bromoethyl nitrite, 2,2-dichloroethyl nitrite, 2,2,2-trichloroethyl nitrite, or N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in cyclohexane, isooctane, dichloromethane, 1,4-dioxane, or tetrahydrofuran. The dependence of the first-order pseudoconstant k0 on the amine concentration (always in excess) was sigmoid for nitrosation by alkyl nitrites and linear or quadratic for nitrosation by MNTS. The effects on k0 of isotopic substitution, temperature, and base catalysis by a less reactive amine were also determined. The experimental data are in keeping with a reaction mechanism involving a zwitterionic tetrahedral intermediate T± analogous to intermediates postulated for the aminolysis of carboxylic esters in similar solvents: according to this mechanism, T± is formed either directly from the amine and nitrosating agent (in the case of MNTS) or indirectly via a hydrogen-bonded complex between the amine and nitrosating agent (in the case of alkyl nitrites) and decomposes either spontaneously or with the catalytic assistance of a second amine molecule. For alkyl nitrites, the rate-controlling step is the formation of T± at high amine concentrations and its decomposition at low amine concentrations; for MNTS, the rate-controlling step is the formation of T± in more polar solvents and its decomposition in less polar solvents. An alternative mechanism, involving the formation of T± from both monomers and dimers of the amine, is ruled out.
- Garcia Rio,Leis,Iglesias
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p. 4701 - 4711
(2007/10/03)
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- Nitrosation of Amines in Nonaqueous Solvents. 2. Solvent-Induced Mechanistic Changes
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We studied the nitrosation of amines (pyrrolidine, piperidine, diethylamine, N-methylpiperazine, N,N′-dimethylethylenediamine, and morpholine) by alkyl nitrites (2-bromoethyl nitrite or 2,2- dichloroethyl nitrite) or by N-methyl-N-nitroso-p-toluenesulfonamide (MNTS) in the solvents chloroform, acetonitrile, and dimethyl sulfoxide (DMSO). The mechanism of nitrosation by alkyl nitrites depends on the solvent: in chloroform, all the results were in keeping with formation of a hydrogen-bonded complex between the amine and alkyl nitrite being followed by rate-controlling formation of a tetrahedral intermediate T± that rapidly decomposes to afford the final products; in acetonitrile, a situation intermediate between those obtaining in chloroform and cyclohexane results in the [amine] dependence of the first-order pseudoconstant k0 being qualitatively influenced by temperature and by the identities of both the amine and the alkyl nitrite; in DMSO, the results suggest a mechanism close to the mechanism acting in water. For nitrosation by MNTS, k0 depended linearly on [amine] in all three solvents. The Grunwald-Winstein coefficients correlating the rate constants k for nitrosation by MNTS in the chloroform, acetonitrile, DMSO, dioxane, dichloromethane, and water were l = 0.12 and m = 0.29. Correlation with the Kamlet-Abboud-Taft equation confirmed that k depends largely on the dipolarity of the solvent and, to a lesser extent, its capacity for hydrogen bonding.
- Garcia-Rio,Leis,Iglesias
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p. 4712 - 4720
(2007/10/03)
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- Formation of Nitrosamines in Alkaline Conditions: a Kinetic Study of the Nitrosation of Linear and Cyclic Secondary Amines by Nitroalkanes
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A study has been made of the nitrosation of sixteen secondary amines, six alkylamines (dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamine, diisobutylamine) and ten cyclic secondary amines (2-methylaziridine, azetidine, pyrrolidine, piperidine, 2-methylpiperidine, homopiperidine, heptamethyleneimine, piperazine, 1-methylpiperazine and morpholine) by nitropropane and nitrobutane in a strongly basic medium (-> = 0.1 mol dm-3).The nitrites were not formed in situ (i.e. in the actual bulk of the reaction medium) but rather were isolated,purified and used in pure form.The rate equation (i) was found v = k2obs (i).The fitting of the experimental results to the Taft correlation points to a nucleophilic attack on nitrite esters by the amines.Analysis of the log k2/pKa and log k2/Ei(v) correlations indicates orbital control of the reactions studied.These results, together with the fact that the reactivity of the different amines diminishes ostensibly when the values of the 13C-H nuclear spin coupling constant in the series of corresponding cycloalkanes increase, show that the overall hybridization of the nitrogen atom in the cycle changes from sp2 in the triangular nucleophile methylaziridine to sp3 in larger cycles.The results obtained at different temperatures and with water-tetrahydrofuran media, together with a study of isotope effects suggest that these reactions occur through a highly ordered transition state and that the role of solvation should not be overlooked.
- Calle, Emilio,Casado, Julio,Cinos, Jose L.,Mateos, Francisco J. Garcia,Tostado, Manuel
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p. 987 - 991
(2007/10/02)
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- Structure-reactivity correlations in nitrosation reactions of secondary amines by alkyl nitrites in basic media
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A study was conducted on the influence of the basic character of different secondary amines on the rate of their nitrosation reactions by propyl and 2-hydroxyethyl nitrites in basic medium (pH = 9-12).For the series of the five structurally similar amines studied (morpholine, piperazine, N-methylpiperazine, piperidine, and pyrrolidine) an excellent linear correlation was observed between the values of the logarithm of the second order rate constant - corresponding to the attack of the alkyl nitrites on the unprotonated amines - and the pKa of these amines.These results, together with the scattering of linearity when including non structurally similar substrates, confirm that the reactions studied are mainly orbital-controlled and have permitted us a rough estimation of the vertical Ionization Potentials, vIP, of piperazine, N-methylpiperazine and morpholine.The kinetic study of nitrosation reaction of N-methylaniline has led to results from which, when compared with those obtained referring to the five above-mentioned substrates, it is possible to infer again that the reactivity of the nitrosatable substrates studied does not depend exclusively on their pKa.
- Casado, Julio,Castro, Albino,Lopez-Quintela, M. Arturo,Lorenzo-Barral, M. Francisco
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p. 401 - 404
(2007/10/02)
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- The Chemystry of Nitroso-compounds. Part 17. Formation of N-Nitrosoamine in Solution from Dissolved Nitric Oxide in the Presence of Hydriodic Acid or Metal Iodides
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The rapid formation of N-nitrosamines from the reaction of N-methylpiperazine, morpholine, and piperidine with nitric oxide (NO) in the presence of HI (KI plus HCl) neutral metal iodides, and acid halides plus KI is reported for ethanolic and aqueous ethanolic solutions at 25 deg C.Spectroscopic studies show that a feature common to all these reactions is the oxidation of iodide ion to molecular iodine by NO under acidic conditions with concurrent formation of nitrous oxide (N2O). since interaction of NO with iodine produces nitrosyl iodide (NOI), this reagent is considered to form the N-nitrosamine by reaction with unprotonated amine.Kinetic studies with N-methylpiperazine in the presence of KI and HCl suggest that the formation of nitrosyl iodide and its interaction with the N-methylpiperazinium ion are rate-limiting under neutral and mildly acidic conditions, respectively.This gives a complicated kinetic-acidity dependence with a maximum rate pH ca. 2.1.When NO is not bubbled into the reaction solution continuously, there is strong evidence that diffusion of NO from the gaseous phase becomes rate-limiting for the fastest reactions.Because of their higher basicity, significant reaction by morpholine and piperidine is only observed with equimolar KI and HCl where passage of NO effectively neutralises the solution by converting HI into I2, H2O, and N2O.In the presence of ZnI2, N-methylpiperazine, morpholine, and piperidine in ETOH all react readily with NO at 25 deg C to give limiting yields of N-nitrosamine in ca. 25 min.Reaction also proceeds in aqueous EtOH but not significantly in MeCN, which suggests that initial solvolysis of ZnI2 to HI is important.This conclusion is supported by observation that N-nitrosamine formation is rapid in the presence of soluble (e.g.FeI2, SnI4, BiI3) compared to insoluble metal iodides (e.g.PdI2 , MnI2, CdI2, Cu2I2).The formation of N-nitrosopiperidine is promoted less readily by ZnBr2 than ZnI2, and to an even lesser extent by ZnCl2, Zn(OAc)2, and ZnSO4.Independent measurements confirm that HI is oxidised to I2 by NO in solution.This effectively neutralises the solution by converting HI into H2O.
- Challis, Brian C.,Outram, Jerry R.
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p. 693 - 700
(2007/10/02)
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- Biologically active compounds
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Biologically active geldanamycin derivatives of Formula III, SPC1 wherein R5, R6, R7 and R8 are the same or different and selected from hydrogen, hydroxy, halo, alkyl, alkoxy, carboxyl, carboalkoxyl, amino, amido, or N-alkylsubstituted amido; pharmaceutical compositions and therapeutic methods involving the same.
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