- Zur Synthese sulfonierter Derivate von 4-Fluoranilin
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Syntheses of Sulfonated Derivatives of 4-Fluoroaniline; Synthesis of 2-amino-5-fluorobenzenesulfonic acid (2) was achieved by baking the hydrogen sulfate of 4-fluoroaniline (1).Sulfonation of p-fluoroacetanilide (4) with oleum followed by hydrolysis gave 5-amino-2-fluorobenzenesulfonic acid (3).The same reaction with 1 yielded 3 in an impure state.The structures of 2 and 3 were confirmed by converting the diazonium chlorides derived from 5-fluoro-2-nitroaniline (5) and from 2-fluoro-5-nitroaniline (8) to 5-fluoro-2-nitrobenzenesulfonyl chloride (6) and 2-fluoro-5-nitrobenzenesulfonyl chloride (9), respectively, followed by hydrolysis of 6 to 5-fluoro-2-nitrobenzenesulfonic acid (7), and of 9 to 2-fluoro-5-nitrobenzenesulfonic acid (10), and by final reduction.Compound 10 was also obtained by sulfonation of 1-fluoro-4-nitrobenzene (11) with oleum.
- Courtin, Alfred
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Read Online
- A Metal-Free Direct Arene C?H Amination
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The synthesis of aryl amines via the formation of a C?N bond is an essential tool for the preparation of functional materials, active pharmaceutical ingredients and bioactive products. Usually, this chemical connection is only possible by transition metal-catalyzed reactions, photochemistry or electrochemistry. Here, we report a metal-free arene C?H amination using hydroxylamine derivatives under benign conditions. A charge transfer interaction between the aminating reagents TsONHR and the arene substrates enables the chemoselective amination of the arene, even in the presence of various functional groups. Oxygen was crucial for an effective conversion and its accelerating role for the electron transfer step was proven experimentally. In addition, this was rationalized by a theoretical study which indicated the involvement of a dioxygen-bridged complex with a “Sandwich-like” arrangement of the aromatic starting materials and the aminating agents at the dioxygen molecule. (Figure presented.).
- Wang, Tao,Hoffmann, Marvin,Dreuw, Andreas,Hasagi?, Edina,Hu, Chao,Stein, Philipp M.,Witzel, Sina,Shi, Hongwei,Yang, Yangyang,Rudolph, Matthias,Stuck, Fabian,Rominger, Frank,Kerscher, Marion,Comba, Peter,Hashmi, A. Stephen K.
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supporting information
p. 2783 - 2795
(2021/04/05)
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- From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently validated therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C). Through phenotypic screening, we previously discovered a class of small-molecules with a 2,3′-diindolymethane (DIM) skeleton that can decrease the expression of PCSK9. But these compounds have low potency and low metabolically stability. After performing structure-activity relationship (SAR) optimization by nitrogen scan, deuterium substitution and fluorine scan, we identified a series of much more potent and metabolically stable PCSK9 modulators. A preliminary in vivo pharmacokinetic study was performed for representative analogues difluorodiindolyketone (DFDIK) 12 and difluorobenzoimidazolylindolylketone (DFBIIK-1) 13. The in vitro metabolic stability correlate well with the in vivo data. The most potent compound 21 has the EC50 of 0.15 nM. Our SAR studies also indicated that the NH on the indole ring of 21 can tolerate more function groups, which may facilitate the mechanism of action studies and also allow further improvement of the pharmacological properties.
- Xie, Haibo,Yang, Ka,Winston-McPherson, Gabrielle N.,Stapleton, Donnie S.,Keller, Mark P.,Attie, Alan D.,Smith, Kerry A.,Tang, Weiping
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- 5-fluoro-2-nitrophenol preparation method
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The invention belongs to the field of organic synthesis, and particularly relates to a 5-fluoro-2-nitrophenol preparation method. In the prior art, the existing synthesis method has disadvantages of low conversion rate and long reaction time so as not to easily achieve industrial operation. A purpose of the present invention is to solve the technical problem in the prior art. The technical schemeis to provide a 5-fluoro-2-nitrophenol preparation method, which comprises: a) carrying out a reaction on 2,4-difluoronitrobenzene and NH 3 to obtain 5-fluoro-2-nitroaniline; and b) carrying out a reaction on the 5-fluoro-2-nitroaniline under the actions of sulfuric acid and sodium nitrite to obtain the 5-fluoro-2-nitrophenol. According to the present invention, the 5-fluoro-2-nitrophenol preparation method has advantages of good selectivity, almost no side reaction, high yield, short reaction time, simple operation and easy industrialization.
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Paragraph 0023; 0039-0041
(2018/06/15)
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- Fluorinated 2-Amino-4-(Benzylamino)Phenylcarbamate Derivatives
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The invention relates to fluorinated compounds and their use as anti-epileptic, muscle-relaxing, fever-reducing and peripherally analgesically acting medications and as imaging agents. Novel fluorinated 2-amino-4-(benzylamino)phenyl carbamate derivatives of ezogabine and pharmaceutically acceptable salts or solvates thereof and their use are described.
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Paragraph 0155; 0156
(2013/11/06)
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- The kinetics and mechanisms of aromatic nucleophilic substitution reactions in liquid ammonia
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The rates of aromatic nucleophilic substitution reactions in liquid ammonia are much faster than those in protic solvents indicating that liquid ammonia behaves like a typical dipolar aprotic solvent in its solvent effects on organic reactions. Nitrofluorobenzenes (NFBs) readily undergo solvolysis in liquid ammonia and 2-nitrofluorobenzene is about 30 times more reactive than the 4-substituted isomer. Oxygen nucleophiles, such as alkoxide and phenoxide ions, readily displace fluorine of 4-NFB in liquid ammonia to give the corresponding substitution product with little or no competing solvolysis product. Using the pKa of the substituted phenols in liquid ammonia, the Bronsted βnuc for the reaction of 4-NFB with para-substituted phenoxides is 0.91, indicative of the removal of most of the negative charge on the oxygen anion and complete bond formation in the transition state and therefore suggests that the decomposition of the Meisenheimer σ-intermediate is rate limiting. The aminolysis of 4-NFB occurs without general base catalysis by the amine and the second-order rate constants generate a Bronsted βnuc of 0.36 using either the pKa of aminium ion in acetonitrile or in water, which is also interpreted in terms of rate limiting breakdown of the Meisenheimer σ-intermediate. Nitrobenzene and diazene are formed as unusual products from the reaction between sodium azide and 4-NFB, which may be due to the initially formed 4-nitroazidobenzene decomposing to give a nitrene intermediate, which may then give diazene or be trapped by ammonia to give the unstable hydrazine which then yields nitrobenzene.
- Ji, Pengju,Atherton, John H.,Page, Michael I.
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scheme or table
p. 3286 - 3295
(2011/07/07)
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- The [Cu]-catalyzed SNAR reactions: Direct amination of electron deficient aryl halides with sodium azide and the synthesis of arylthioethers under Cu(II) - Ascorbate redox system
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A one pot [Cu]-promoted SNAr reaction of electron-deficient halobenzenes with sodium azide and the reduction of the intermediate aryl azides under the same Cu(II)-ascorbate redox conditions leading to anilines has been documented. Control experiments revealed that both ascorbate and proline play important role in the reaction path way. Further, the use of this catalytic Cu(II)-ascorbate redox system has been explored for the synthesis of arylthioethers.
- Goriya, Yogesh,Ramana
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experimental part
p. 7642 - 7650
(2010/12/19)
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- Combination therapy with CHK1 inhibitors
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Compounds of Structure I, and salts, tautomers, stereoisomers, and mixtures thereof may be used in methods of inhibiting checkpoint kinase 1 in subjects, in methods for inducing cell cycle progression, and in methods for increasing apoptosis in cells. Such compounds may be used to prepare pharmaceutical compositions and may be used in conjunction with DNA damaging agents.
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- Inhibition of FGFR3 and treatment of multiple myeloma
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Methods of inhibiting fibroblast growth factor receptor 3 and treating various conditions mediated by fibroblast growth factor receptor 3 are provided that include administering to a subject a compound of Structure I, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I have the following structure where and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting fibroblast growth factor receptor 3 and for use in treating conditions mediated by fibroblast growth factor receptor 3 such as multiple myeloma.
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- Hyperbranched polyphenylquinoxalines from self-polymerizable AB 2 and A2B monomers
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A self-polymerizable AB2 monomer, 2,3-bis(4-hydroxyphenyl)-6-fluoroquinoxaline, and an A2B monomer, 2,3-bis(4-fluorophenyl)-6-(4-hydrcixyphenoxy)quinoxaline) were prepared and polymerized to afford phenol-terminated and aryl fluoride terminated, hyperbranched polyphenylquinoxalines (HPPQs), respectively. MALDI-TOF analysis showed that intramolecular cyclization was a dominant process for the low molecular weight portion during the polymerizations. After isolation and complete dryness, the phenol-terminated HPPQ 1 was only soluble in strong organic acids, while the aryl fluoride terminated HPPQ 2 was soluble in most common organic solvents. HPPQ 1 was treated with allyl bromide to afford an allyl ether terminated HPPQ 3, which was also soluble in most organic solvents. Intrinsic viscosity measurements and SEC analysis indicated that HPPQ 2 had a much higher Mw and a much broader molecular weight distribution (PDI ~ 60) than HPPQ 1 and HPPQ 3 (PDI ~ 4). The results also suggested that HPPQ 1 formed aggregates in solution and that HPPQ 2 had a much more extended and open conformation. All the HPPQs, which were highly fluorescent, had UV absorption maxima near 375 nm in THF. However, the wavelength of their emission maxima, which ranged from 424 to 466 nm, depended on their end groups.
- Back, Jong-Beom,Harris, Frank W.
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p. 297 - 306
(2007/10/03)
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- BENZIMIDAZOLE QUINOLINONES AND USES THEREOF
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Methods of inhibiting various enzymes and treating various conditions are provided that include administering to a subject a compound of Structure I or IB, a pharmaceutically acceptable salt thereof, a tautomer thereof, or a pharmaceutically acceptable salt of the tautomer. Compounds having the Structure I and IB have the following structures and have the variables described herein. Such compounds may be used to prepare medicaments for use in inhibiting various enzymes and for use in treating conditions mediated by such enzymes.
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- INDOLYL PYRAZINONE DERIVATIVES USEFUL FOR TREATING HYPER-PROLIFERATIVE DISORDERS AND DISEASES ASSOCIATED WITH ANGIOGENESIS
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This invention relates to a compound of Formula I (I)and its use in treating hyper-proliferative disorders and diseases associated with angiogenesis.
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- Quinolinone derivatives
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Organic compounds having the formulas I and II are provided where the variables have the values described herein. Pharmaceutical formulations include the organic compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier and may be prepared by mixing the organic compounds or pharmaceutically acceptable salts of the organic compounds with a carrier and water. A method of treating a patient includes administering a pharmaceutical formulation according to the invention to a patient in need thereof.
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- Synthesis and biological evaluation of menthol-based derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
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Compound 1 was identified by high throughput screening as a novel PAI-1 inhibitor. Optimization of the B and C-segments of 1 resulted in a series of structurally simplified compounds with improved potency. The synthesis and SAR data of these compounds are presented here.
- Ye, Bin,Bauer, Shawn,Buckman, Brad O.,Ghannam, Ameen,Griedel, Brian D.,Khim, Seock-Kyu,Lee, Wheeseong,Sacchi, Karna L.,Shaw, Kenneth J.,Liang, Amy,Wu, Qingyu,Zhao, Zuchun
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p. 3361 - 3365
(2007/10/03)
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- Heterocyclic compounds
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Organic compounds having the structural formulas I, II, and III are provided where the variables have the values described herein and R1 and R2 in structure I join together to form a 5 to 7 membered substituted or unsubstituted ring including at least one O, N, or S atom, and Z is an O, S, NH or NR group in structures I and II. Pharmaceutical formulations include the organic compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. A method of treating a patient includes administering a pharmaceutical formulation according to the invention to a patient in need thereof.
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- Quinolinone derivatives
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Organic compounds having the formulas I and II are provided where the variables have the values described herein. Pharmaceutical formulations include the organic compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier and may be prepared by mixing the organic compounds or pharmaceutically acceptable salts of the organic compounds with a carrier and water. A method of treating a patient includes administering a pharmaceutical formulation according to the invention to a patient in need thereof.
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- The influence of nucleophile substituents on the orientation in the reaction between 2,4-difluoronitrobenzene and lithium phenoxides in liquid ammonia
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The dependence of the orientation of aryloxydefluorination of 2,4-difluoronitrobenzene (1) (o/p ratio) by the action of X-substituted lithium phenoxides 2 (X = p-OMe, p-Me, p-Et, p-iPr, p-tBu, m-Me, H, p-F) in liquid ammonia in the temperature range from -55 to -35 °C has been investigated. The enthalpic preference for ortho-fluorine substitution decreases with weakening substituent electron-donating capability in the order: p-OMe > p-Me ≈ p-Et > m-Me > H ≥ p-F. The predominant fluorine substitution at the ortho position for X = p-Me, p-Et turns into a preference for substitution at the para position when X = p-iPr, and this increases further on going to X = p-tBu, PM3, AM1 and MNDO MO calculations showed greater stability of the intermediate anionic σ-complexes formed on nucleophile addition at the para position, thus suggesting that the predominant ortho substitution manifested for X = p-OMe, m-Me, H, p-F and p-Alk = Me, Et is due to control over orientation by the charge distribution in the substrate. The substrate electronic structure, as a controlling factor, is probably changed by the relative stability of intermediate anionic σ-complexes on going to p-Alk = iPr, tBu, as a consequence of an enhancement of the substituent's electron-withdrawing nature with the increase in alkyl group polarizability in the order: p-Me ≈ p-Et p-iPr p-tBu.
- Politanskaya, Larisa,Malykhin, Evgenij,Shteingarts, Vitalij
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p. 405 - 411
(2007/10/03)
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- A convenient copper-catalyzed direct animation of nitroarenes with 9-alkylhydroxylamines
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O-Alkylhydroxylamines, particularly O-methylhydroxylamine, aminate nitroarenes in the presence of a strong base and a copper catalyst to give aminonitroarenes in good yields, ortho- or para-Animation with respect to the nitro group takes place, and in some cases the ortho-aminated product is preferentially obtained. With 3-substituted nitrobenzenes where the substituent has a lone pair of electrons, preferential amination occurs at the 2-position to give the sterically most congested 3c-f, 14 and 22g.
- Seko, Shinzo,Miyake, Kunihito,Kavvamura, Norio
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p. 1437 - 1444
(2007/10/03)
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- Nitroarylamines via the Vicarious Nucleophilic Substitution of Hydrogen: Amination, Alkylamination, and Arylamination of Nitroarenes with Sulfenamides
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A new reaction of sulfenamides with electrophilic arenes under basic conditions is described. The σ adducts formed from nitroarenes and the anions of sulfenamides undergo elimination of thiol to produce the corresponding o- and/or p-nitroanilines. This reaction is analogous to the known alkylation and hydroxylation of nitroarenes via the vicarious nucleophilic substitution of hydrogen (VNS). The reaction gives access to a wide range of substituted nitroanilines, nitronaphthylamines, and aminoheterocycles. By means of the reaction with N-alkyl- and N-arylsulfenamides, it is possible to obtain N-alkylnitroanilines and nitrodiarylamines. By varying the structure of sulfenamide and the reaction conditions, particularly the nature and concentration of the base, it is possible to control the orientation of animation.
- Makosza, Mieczyslaw,Bialecki, Maciej
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p. 4878 - 4888
(2007/10/03)
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- Reactions of Aromatic Compounds with Nucleophilic Reagents in Liquid Ammonia. XVI. Thermodynamic Aspects of Orientation in Reactions of 2,4-Difluoronitrobenzene with Substituted Lithium Phenoxides
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The relation between the reaction temperature and orientation of fluorine substitution in 2,4-difluoronitrobenzene by lithium phenoxides XC6H4OLi (X = p-OMe, p-Me, m-Me, N, p-F) in liquid ammonia suggests the enthalpy control of the competing reactions at the ortho and para positions with respect to the nitro group in the temperature range from -55 to -33°C. Increase in the electron-donor power of the substituent in the nucleophile in the series p-F ≈ H m-Me p-Me p-OMe favors preferential substitution of the ortho-fluorine atom for enthalpy considerations. PM3, AM1, and MNDO semiempirical calculations of the relative heats of formation of anionic intermediates in the phenoxydefluorination of 2,4-difluoronitrobenzene indicate higher stability of a complexes corresponding to nucleophile addition at the para position of the aromatic substrate.
- Politanskaya,Malykhin,Shteingarts
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p. 644 - 651
(2007/10/03)
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- Reaction of Aromatic Compounds with Nucleophilic Reagents in Liquid Ammonia. XIV. Effect of Liquid Ammonia as Solvent on the Orientation of Phenoxydefluorination of 2,4-Difluoronitrobenzene by Substituents in the Nucleophile
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A relation is revealed between the orientation of fluorine substitution in 2,4-dinitrofluorobenzene (ortho/para ratio) by phenoxy group under the action of X-substituted lithium phenoxides (X = H, p-Me, m-Me, p-OMe, p-F, p-Cl, m-Cl, m-F) in liquid ammonia at -35 to -33°C and the nature of substituent X. Comparison of log (ortho/para) with values of -δΔG0 = ΔG0H - ΔG1X, which characterize the effect of substituent X on the Gibbs energies of protonation of substituted phenoxides in the gas phase and aqueous and DMSO solutions, together with the data on the relative contributions of various components of substituent effect in the title reaction, shows that liquid ammonia behaves like aprotic dipolar solvent.
- Politanskaya,Malykhin,Shteingarts
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p. 1131 - 1142
(2007/10/03)
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- Cardiotonic Agents. Synthesis and Cardiovascular Properties of Novel 2-Arylbenzimidazoles and Azabenzimidazoles
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Novel 2-arylbenzimidazoles and azabenzimidazoles were synthesized, and their inotropic action was evaluated.Changes in left ventricular pressure, dP/dt max, were measured as an index of cardiac contractility.The structural features that impart optimal inotropic activity are presented.The most potent compounds were evaluated orally in conscious dogs with implanted Konigsberg pressure transducers.To investigate the mechanism of action, the most potent compounds were tested for their calcium-sensitizing properties and their potential for the inhibition of phosphodiesterase.Two compounds, 1 and 41, showed interesting in vitro and oral activity without side effects.They have a more potent calcium-sensitizing effect than MCI-154 and are under further investigation.
- Guengoer, Timur,Fouquet, Andre,Teulon, Jean-Marie,Provost, Daniel,Cazes, Michele,et al.
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p. 4455 - 4463
(2007/10/02)
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- Benzimidazolinone derivatives
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Benzimidazolinone derivatives of the general formula (I): STR1 wherein R1, R2 and R3, which may be the same or different, each is a hydrogen or halogen atom or a lower alkyl, halo-lower alkyl, hydroxy-lower alkyl, hydroxyl, lower alkoxy, aryloxy, acyl, cyano, carboxyl, a lower alkoxycarbonyl, carbamoyl, nitro or nitrogen-containing 5- or 6-membered heterocyclic group; A is an ethylene group which may optionally have at least one branch; R4 and R5, which may be the same or different, each is a lower alkyl group or R4 and R5, together with the adjacent nitrogen atom, represent a pyrrolidinyl, piperidino or a morpholino group provided that when STR2 is a piperidino or diethylamino group, at least one of R1, R2 and R3 is other than a hydrogen atom, or pharmaceutically acceptable salts thereof, methods of producing the same and pharmaceutical compositions containing the same are disclosed. Pharmacologically, the above compounds (I) have pulmonary surfactant secretion promoting activity.
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- o-Nitroaniline Derivatives. Part 9. Benzimidazole N-Oxides Unsubstituted at N-1 and C-2
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Since previous routes to the title compounds (1) have proved unsatisfactory as general methods, a simple new synthesis has been devised.N-Cyanomethyl-o-nitroanilines (5) are cyclised in basic media, giving 2-cyanobenzimidazole N-oxides (12) in good yield.Hydrolysis of these products with hydrochloric acid gives, directly, the title compounds as their hydrochloride salts (13), which may be isolated and purified, and which give the free N-oxides (1) by treatment with aqueous ammonia followed by evaporation. o-Nitrophenylglycine esters (4) may satisfactorily replace the nitriles (5) in certain cases.A modification of this kind in the related nitropyridylglycine series leads to 3H-imidazolpyridine 1-oxide (20).
- Harvey, Ian W.,McFarlane, Michael D.,Moody, David J.,Smith, David M.
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p. 681 - 690
(2007/10/02)
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- REACTION OF AROMATIC COMPOUNDS WITH NUCLEOPHILIC REAGENTS IN LIQUID AMMONIA. X. AMINATION OF POLYFLUORINATED AROMATIC COMPOUNDS CONTAINING ELECTRON-WITHDRAWING SUBSTITUENTS
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It was shown for the case of 2,4-difluoro-, 2,4,6-trifluoro-, and pentafluoronitrobenzenes that both liquid ammonia and sodium amide in liquid ammonia are effective reagents for aminodefluorination with respect to the fluorine derivatives of nitrobenzene.The observed tendency for the ortho-orientation with respect to the nitro group to change to para-orientation with increase in the number of fluorine atoms is more clearly defined for sodium amide than for liquid ammonia as nucleophile on account, clearly, of the stabilization of the transition state of ortho-substitution in the latter case by an intramolcular hydrogen bond.
- Selivanova, G. A.,Chuikova, T. V.,Shtark, A. A.,Shteingarts, V. D.
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p. 2267 - 2272
(2007/10/02)
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- 6-(1-Piperazinyl)quinoxaline
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6-(1-Piperazinyl)quinoxaline and pharmaceutically acceptable salts thereof have serotoninmimetic activity. It is prepared by reducing the nitro group of 1-(3-amino-4-nitrophenyl)piperazine followed by treatment with glyoxal.
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