- Structure-guided optimization of 1H-imidazole-2-carboxylic acid derivatives affording potent VIM-Type metallo-β-lactamase inhibitors
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Production of metallo-β-lactamases (MBLs) in bacterial pathogens is an important cause of resistance to the ‘last-resort’ carbapenem antibiotics. Development of effective MBL inhibitors to reverse carbapenem resistance in Gram-negative bacteria is still needed. We herein report X-ray structure-guided optimization of 1H-imidazole-2-carboxylic acid (ICA) derivatives by considering how to engage with the active-site flexible loops and improve penetration into Gram-negative bacteria. Structure-activity relationship studies revealed the importance of appropriate substituents at ICA 1-position to achieve potent inhibition to class B1 MBLs, particularly the Verona Integron-encoded MBLs (VIMs), mainly by involving ingenious interactions with the flexible active site loops as observed by crystallographic analyses. Of the tested ICA inhibitors, 55 displayed potent synergistic antibacterial activity with meropenem against engineered Escherichia coli strains and even intractable clinically isolated Pseudomonas aeruginosa producing VIM-2 MBL. The morphologic and internal structural changes of bacterial cells after treatment further demonstrated that 55 crossed the outer membrane and reversed the activity of meropenem. Moreover, 55 showed good pharmacokinetic and safety profile in vivo, which could be a potential candidate for combating VIM-mediated Gram-negative carbapenem resistance.
- Yan, Yu-Hang,Li, Wenfang,Chen, Wei,Li, Chao,Zhu, Kai-Rong,Deng, Ji,Dai, Qing-Qing,Yang, Ling-Ling,Wang, Zhenling,Li, Guo-Bo
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- Triazole derivative as well as preparation method and application thereof
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The invention relates to a triazole derivative as well as a preparation method and application thereof, which belong to the technical field of organic synthetic drugs. The structure of the triazole derivative is shown as a formula I. In the formula I, R1 and R2 are H, Cl, Br,-CF3,-CH(CH3)2 or -OCH3, and R1 and R2 are not H at the same time. R3 is -CH2 or -COCH2; X and Y are N or C, X and Y are not C at the same time, and X and Y are not N at the same time. The triazole derivative disclosed by the invention has a certain inhibition effect on germs of various crop diseases. Small toxic andside effects on plants are achieved. The preparation method of the triazole derivative is simple.
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- N -Hydroxyphthalimide/benzoquinone-catalyzed chlorination of hydrocarbon C-H bond using N -chlorosuccinimide
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The direct chlorination of C-H bonds has received considerable attention in recent years. In this work, a metal-free protocol for hydrocarbon C-H bond chlorination with commercially available N-chlorosuccinimide (NCS) catalyzed by N-hydroxyphthalimide (NHPI) with 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) functioning as an external radical initiator is presented. Aliphatic and benzylic substituents and also heteroaromatic ones were found to be well tolerated. Both the experiments and theoretical analysis indicate that the reaction goes through a process wherein NHPI functions as a catalyst rather than as an initiator. On the other hand, the hydrogen abstraction of the C-H bond conducted by a PINO species rather than the highly reactive N-centered radicals rationalizes the high chemoselectivity of the monochlorination obtained by this protocol as the latter is reactive towards the C(sp3)-H bonds of the monochlorides. The present results could hold promise for further development of a nitroxy-radical system for the highly selective functionalization of the aliphatic and benzylic hydrocarbon C-H.
- Li, Zi-Hao,Fiser, Béla,Jiang, Biao-Lin,Li, Jian-Wei,Xu, Bao-Hua,Zhang, Suo-Jiang
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supporting information
p. 3403 - 3408
(2019/04/01)
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- Organocatalytic Chlorination of Alcohols by P(III)/P(V) Redox Cycling
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A catalytic system for the chlorination of alcohols under Appel conditions was developed. Benzotrichloride is used as a cheap and readily available chlorinating agent in combination with trioctylphosphane as the catalyst and phenylsilane as the terminal reductant. The reaction has several advantages over other variants of the Appel reaction, e.g., no additional solvent is required and the phosphane reagent is used only in catalytic amounts. In total, 27 different primary, secondary, and tertiary alkyl chlorides were synthesized in yields up to 95%. Under optimized conditions, it was also possible to convert epoxides and an oxetane to the dichlorinated products.
- Longwitz, Lars,Jopp, Stefan,Werner, Thomas
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p. 7863 - 7870
(2019/06/27)
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- Halogenation through Deoxygenation of Alcohols and Aldehydes
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An efficient reagent system, Ph3P/XCH2CH2X (X = Cl, Br, or I), was very effective for the deoxygenative halogenation (including fluorination) of alcohols (including tertiary alcohols) and aldehydes. The easily available 1,2-dihaloethanes were used as key reagents and halogen sources. The use of (EtO)3P instead of Ph3P could also realize deoxy-halogenation, allowing for a convenient purification process, as the byproduct (EtO)3Pa?O could be removed by aqueous washing. The mild reaction conditions, wide substrate scope, and wide availability of 1,2-dihaloethanes make this protocol attractive for the synthesis of halogenated compounds.
- Chen, Jia,Lin, Jin-Hong,Xiao, Ji-Chang
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supporting information
p. 3061 - 3064
(2018/05/28)
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- Preparation method for 4-trifluoromethylbenzyl chloride
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The invention relates to a preparation method for 4-trifluoromethylbenzyl chloride, wherein the preparation method comprises the specific steps: A, adding a proper amount of tetrahydrofuran, magnesium, iodine, bromoethane and p-chlorobenzotrifluoride into a reaction kettle, introducing nitrogen, stirring to rise the temperature to reflux, refluxing for 20 min-40 min, then controlling the temperature at 40 DEG C-60 DEG C, dropping p-trifluoromethyl chlorobenzene, after the dropping is finished, carrying out a heat preservation reaction for 1.5 h-3 h, then cooling to 5 DEG C-15 DEG C, adding a proper amount of paraformaldehyde, then controlling the temperature at 0 DEG C-60 DEG C, carrying out a reaction for 5 h-7 h, then recycling tetrahydrofuran, and carrying out reduced pressure distillation to obtain 4-trifluoromethylbenzyl alcohol; and B, adding a proper amount of hydrochloric acid and 4-trifluoromethylbenzyl alcohol into another reaction kettle, stirring to rise the temperature toreflux, carrying out a heat preservation reaction for 20 h-30 h, cooling to room temperature, stratifying, dehydrating, and carrying out reduced pressure distillation to obtain 4-trifluoromethylbenzylchloride. The preparation method for 4-trifluoromethylbenzyl chloride is simple in route and high in yield.
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Paragraph 0013; 0016
(2018/03/25)
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- Preparation method for 3-trifluoromethylbenzyl chloride
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The invention relates to a preparation method for 3-trifluoromethylbenzyl chloride. The preparation method comprises the following concrete steps: A, adding a proper amount of dimethyltetrahydrofuran,magnesium, iodine, bromoethane and bromobenzotrifluoride into a reaction vessel, introducing nitrogen, carrying out stirring and heating for refluxing for 20 to 40 min, then controlling a temperatureto be 40 to 60 DEG C, adding bromobenzotrifluoride drop by drop, carrying out a reaction under a heat preserved condition for 1.5 to 3 h, then carrying out cooling to 5 to 15 DEG C, adding a proper amount of paraformaldehyde, then carrying out a reaction with a temperature controlled to be 0 to 60 DEG C for 5 to 7 h, recovering dimethyltetrahydrofuran, and carrying out vacuum rectification so asto obtain trifluoromethylbenzyl methanol; and B, adding a proper amount of hydrochloric acid and trifluoromethylbenzyl methanol into another reaction vessel, carrying out stirring and heating for refluxing, carrying out a heat-preserved reaction for 20 to 30 h, and then successively carrying out cooling to room temperature, layering, dehydration and pressure-reduced distillation so as to obtain 3-trifluoromethylbenzyl chloride. The preparation method for 3-trifluoromethylbenzyl chloride is concise in route and high in yield.
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Paragraph 0011; 0012; 0014
(2018/03/25)
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- Ferric(III) Chloride Catalyzed Halogenation Reaction of Alcohols and Carboxylic Acids Using α,α-Dichlorodiphenylmethane
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A new method for chlorination of alcohols and carboxylic acids, using α,α-dichlorodiphenylmethane as the chlorinating agent and FeCl3 as the catalyst, was developed. The method enables conversions of various alcohols and carboxylic acids to their corresponding alkyl and acyl chlorides in high yields under mild conditions. Particulary interesting is the observation that the respective alkyl bromides and iodides can be generated from alcohols when either LiBr or LiI are present in the reaction mixtures.
- Lee, Chang-Hee,Lee, Soo-Min,Min, Byul-Hana,Kim, Dong-Su,Jun, Chul-Ho
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supporting information
p. 2468 - 2471
(2018/04/25)
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- METHOD OF CONVERTING ALCOHOL TO HALIDE
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The present invention relates to a method of converting an alcohol into a corresponding halide. This method comprises reacting the alcohol with an optionally substituted aromatic carboxylic acid halide in presence of an N-substituted formamide to replace a hydroxyl group of the alcohol by a halogen atom. The present invention also relates to a method of converting an alcohol into a corresponding substitution product. The second method comprises: (a) performing the method of the invention of converting an alcohol into the corresponding halide; and (b) reacting the corresponding halide with a nucleophile to convert the halide into the nucleophilic substitution product.
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Page/Page column 51; 98
(2017/01/02)
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- Gallium-catalyzed reductive chlorination of carboxylic acids with copper(II) chloride
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Described herein is the direct chlorination of carboxylic acids using copper(II) chloride via a gallium(III)-catalyzed reduction in the presence of a hydrosiloxane. During this reductive chlorination, the counteranions of CuCl2 functioned as a chloride source.
- Sakai, Norio,Nakajima, Takumi,Yoneda, Shinichiro,Konakahara, Takeo,Ogiwara, Yohei
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p. 10619 - 10623
(2015/02/19)
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- Sulfite formation versus chlorination of benzyl alcohols with thionyl chloride
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Recently, we have reported the photolytic decay of a library of para-substituted dibenzylic sulfites in a Srinivasan-Griffin-Rayonet photochemical reactor. In an attempt to synthesize the complete library for that study we discovered that bis(p-methoxybenzyl) sulfite and bis(p-phenoxybenzyl) sulfite could not be formed and only their corresponding benzyl chlorides were synthesized. Thus, sulfite formation versus chlorination of a range of para-substituted benzyl alcohols with thionyl chloride was investigated. Sulfite formation was observed to be parabolically related to Swain and Lupton's Field ?-values while chloride formation was found to be linearly related to Swain and Lupton's Field ?-values.
- Rodriguez, Deana A.,Priefer, Ronny
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p. 3045 - 3048
(2014/05/20)
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- Cu-Catalyzed Suzuki-Miyaura reactions of primary and secondary benzyl halides with arylboronates
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A copper-catalyzed Suzuki-Miyaura coupling of benzyl halides with arylboronates is described. Varieties of primary benzyl halides as well as more challenging secondary benzyl halides with β hydrogens or steric hindrance could be successfully converted into the corresponding products. Thus it provides access to diarylmethanes, diarylethanes and triarylmethanes. This journal is the Partner Organisations 2014.
- Sun, Yan-Yan,Yi, Jun,Lu, Xi,Zhang, Zhen-Qi,Xiao, Bin,Fu, Yao
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supporting information
p. 11060 - 11062
(2014/09/30)
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- FUNGAL CELL WALL SYNTHESIS GENE
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A reporter system reflecting the transport process that transports GPI-anchored proteins to the cell wall was constructed and compounds inhibiting this process were discovered. Further, genes conferring resistance to the above compounds were identified and methods of screening for compounds that inhibit the activity of the proteins encoded by these genes were developed.Therefore, through the novel compounds, the present invention showed that antifungal agents having a novel mechanism, i.e. inhibiting the process that transports GPI-anchored proteins to the cell wall, could be achieved.
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- A duality of mechanisms for the fragmentation of substituted benzyloxychlorocarbenes
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Substituted benzyloxychlorocarbenes (X-PhCH2OCCl) were generated photochemically at 25 °C in dichloroethane from appropriate diazirine precursors. Fragmentations of the carbenes produced were determined by laser flash photolysis. The data (X, kfrag in s-1) were: p-Me, 2.6 × 105; p-Ph, 8.3 × 104; H, 6.0 × 104; p-Cl, 5.2 × 104; m-Cl, 1.3 × 105; p-F3C, 2.1 × 106; p-O2N, 6.3 × 106. A Hammett correlation of log kfrag versus σ+ was parabolic. The curvature was taken to imply the gradual change of the fragmentation mechanism from predominantly heterolytic for X-PhCH2CCl with electron-donating X (with developing positive charge on the benzylic carbon in the transition state) to predominantly homolytic for carbenes with electron-withdrawing X. This idea was supported by computational studies. Copyright
- Moss, Robert A.,Ma, Yan,Sauers, Ronald R.
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p. 13968 - 13969
(2007/10/03)
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- Gas-phase substituent effects in highly electron-deficient systems. II. stabilities of 1-aryl-2,2,2-trifluoroethyl cations based on chloride-transfer equilibria
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The relative stabilities of 1-aryl-2,2,2-trifluoroethyl cations were determined based on the chloride ion-transfer equilibria in the gas phase. An application of the Yukawa-Tsuno equation to this substituent effect on the equilibrium constants gave a remarkably larger r+ of 1.53 and a ρ of-10.6, supporting our previous conclusion that the highly electron-deficient benzylic carbocation systems are characterized by extremely high resonance demands. This r+ value, furthermore, conformed a linear relationship between the r+ value and the relative stability of the unsubstituted member of the respective benzylic carbocations, clearly demonstrating a continuous spectrum of varying resonance demands characteristic of the stabilities of carbocations. The π-delocalization of the positive charge into the aryl π-system increases with the destabilization of a carbocation by the α-substituent(s) linked to the central carbon. In addition, the r + value of 1.53 for 1-aryl-2,2,2-trifluoroethyl cations was found to be in complete agreement with that for the solvolysis of 1-aryl-2,2,2- trifluoroethyl tosylates in 80% aq acetone. This reveals that the r+ value observed for this solvolysis must be the intrinsic resonance demand of a highly electron-deficient cationic transition state in the SN 1 ionizing process. The identity of the r+ value was consistent with our previous observation for other benzylic carbocation systems, indicating that the degree of the π-delocalization of the positive charge is identical between the cationic transition state and an intermediate cation for all benzylic systems, which cover a wide range of reactivity and stability of the carbocation. This leads us to the conclusion that the geometry of the transition state in the ionizing process of the SN1 solvolysis, which is a highly endothermic reaction, closely resembles the high-energy product, an intermediate cation.
- Mishima, Masaaki,Inoue, Hiroki,Fujio, Mizue,Tsuno, Yuho
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p. 1163 - 1169
(2007/10/03)
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- 4-Trifluoromethylbenzyl Chloride: Preparation, Kinetics and Mechanism of its Change into Bis (4-Trifluoromethylbenzyl) Ether in Alkaline Dioxane-Water Media
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The expected α-proton abstraction step from the title compound by alkali in dioxane-water media, due to the electron-withdrawing 4-trifluoromethyl group, does not take place instead an SN2 reaction followed by an etherification step occurs.This consecutive reaction was studied kinetically in different dioxane-water media at various temperatures.
- Riad, Y.,Gundermann, K. D.,Bardan, A. A. El
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p. 123 - 130
(2007/10/03)
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- 4-Hydroxy-1,3-benzenedimethanol derivatives
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Compounds of the general formula (I): STR1 in which one or more substituents R1 may be present and in which: R1 represents a halogen atom, preferably fluorine or chlorine, or a trifluoromethyl group or a group --NR5 R6 in which R5 and R6 which may be the same or different represent a hydrogen atom, or an alkyl group containing from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms or an acyl group, preferably the residue of a C1 -C6 alkanoic acid; X represents a straight or branched chain alkyl group containing 2 to 6 carbon atoms; and R2 and R3 which may be the same or different each represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms, preferably a methyl group; and R4 represents a hydrogen atom or an alkyl group containing 1 to 4 carbon atoms, are provided together with processes for the production thereof. They have a β2 -stimulant activity.
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