- Direct para-Selective C-H Amination of Iodobenzenes: Highly Efficient Approach for the Synthesis of Diarylamines
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Iodine(III)-mediated synthesis of 4-iodo-N-phenylaniline from iodobenzene has been achieved, and the reaction can proceed under mild conditions. A variety of functional groups were well tolerated, providing the corresponding products in moderate to good yields. The remaining iodine group provides an effective platform for converting the products into several valuable asymmetric diphenylamines. Most importantly, this reaction can be easily scaled up to the ten-gram scale, highlighting its synthetic utility. The mechanistic study revealed that the in situ generated aryl hypervalent iodine intermediate is the key factor to realize this para-selective C-H amination reaction.
- Chen, Yujie,Huang, Zhibin,Jiang, Yaqiqi,Shu, Sai,Yang, Shan,Shi, Da-Qing,Zhao, Yingsheng
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p. 8226 - 8235
(2021/06/28)
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- Direct Superacid-Promoted Difluoroethylation of Aromatics
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Under superacid conditions, aromatic amines are directly and regioselectively 1,1-difluoroethylated. Low temperature in situ NMR studies confirmed the presence of benzylic α-fluoronium and α-chloronium ions as key intermediates in the reaction. This method has a wide substrate scope and can be applied to the late-stage functionalization of natural alkaloids and active pharmaceutical ingredients.
- Artault, Maxime,Martin-Mingot, Agnès,Thibaudeau, Sébastien,Vitse, Kassandra
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supporting information
(2021/12/22)
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- Complementary Site-Selective Sulfonylation of Aromatic Amines by Superacid Activation
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Under superacidic conditions, aniline and indole derivatives are sulfonylated at low temperature with easy-to-access arenesulfonic acids or arenesulfonyl hydrazides. By modification of the functional-group directing effect through protonation, this method allows nonclassical site functionalization by overcoming the innate regioselectivity of electrophilic aromatic substitution. This superacid-mediated sulfonylation of arenes is complementary to existing methods and can be applied, through protection by protonation, to the late-stage site-selective functionalization of natural alkaloids and active pharmaceutical ingredients.
- Bourbon, Paul,Appert, Emeline,Martin-Mingot, Agnès,Michelet, Bastien,Thibaudeau, Sébastien
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p. 4115 - 4120
(2021/06/21)
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- Complementary Site-Selective Halogenation of Nitrogen-Containing (Hetero)Aromatics with Superacids
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Site-selective functionalization of arenes that is complementary to classical aromatic substitution reactions remains a long-standing quest in organic synthesis. Exploiting the generation of halenium ion through oxidative process and the protonation of the nitrogen containing function in HF/SbF5, the chlorination and iodination of classically inert Csp2?H bonds of aromatic amines occurs. Furthermore, the superacid-promoted (poly)protonation of the molecules acts as a protection, favoring the late-stage selective halogenation of natural alkaloids and active pharmaceutical ingredients.
- Mamontov, Alexander,Martin-Mingot, Agnès,Métayer, Benoit,Karam, Omar,Zunino, Fabien,Bouazza, Fodil,Thibaudeau, Sébastien
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supporting information
p. 10411 - 10416
(2020/07/30)
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- Proliferation inhibition of novel diphenylamine derivatives
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Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used drugs in the world but some NSAIDs such as diclofenac and tolfenamic acid display levels of cytotoxicity, an effect which has been attributed to the presence of diphenylamine contained in their structures. A novel series of diphenylamine derivatives were synthetised and evaluated for their cytotoxic activities and proliferation inhibition. The most active compounds in the cytotoxicity tests were derivative 6g with an IC50 value of 2.5 ± 1.1 × 10?6 M and derivative 6f with an IC50 value of 6.0 ± 3.0 × 10?6 M (L1210 cell line) after 48 h incubation. The results demonstrate that leukemic L1210 cells were much more sensitive to compounds 6f and 6g than the HEK293T cells (IC50 = 35 × 10?6 M for 6f and IC50 > 50 × 10?6 M for 6g) and NIH-3T3 (IC50 > 50 × 10?6 M for both derivatives). The IC50 values show that these substances may selectively kill leukemic cells over non-cancer cells. Cell cycle analysis revealed that a primary trend of the diphenylamine derivatives was to arrest the cells in the G1-phase of the cell cycle within the first 24 h. UV–visible, fluorescence spectroscopy and circular dichroism were used in order to study the binding mode of the novel compounds with DNA. The binding constants determined by UV–visible spectroscopy were found to be in the range of 2.1–8.7 × 104 M?1. We suggest that the observed trend for binding constant K is likely to be a result of different binding thermodynamics accompanying the formation of the complexes.
- Janovec, Ladislav,Jano?ková, Jana,Matejová, Mária,Konko?ová, Eva,Paulíková, Helena,Lichancová, Daniela,Júno?ová, Lenka,Hamu?aková, Slávka,Imrich, Ján,Ko?urková, Mária
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supporting information
p. 487 - 499
(2018/11/24)
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- Method for preparing prucalopride
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The invention provides a method for preparing prucalopride. The method comprises the following steps: taking 3-chloro-4-methylaniline as an initial raw material, performing amino protection, nucleophilic substitution, hydroxy protection, aromatic hydrocarbon chlorination, free radical bromination, hydrolysis, molecular Friedel-Crafts alkylation reaction ring closure, amino deprotection and oxidative amidation, thereby obtaining the prucalopride. According to the scheme, a dangerous process is not adopted, any highly toxic reagent is not used, the method is safe, green and environmental-friendly, the amount of by-products produced in the reaction is small, and the yield is improved.
- -
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Paragraph 0046; 0047; 0056; 0057; 0066; 0067
(2019/02/03)
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- Synthesis of acetamides from aryl amines and acetonitrile by diazotization under metal-free conditions
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An efficient and metal-free coupling reaction has been developed that affords acetamides from the corresponding aryl amines and acetonitrile. This method tolerates a wide range of functional groups and is selective toward aryl amines. Preliminary mechanistic studies were conducted.
- Duan, Pan,Guo, Yu,Kang, Huan,Li, Yi-Na,Wen, Xianghao,Xiao, Fang,Zeng, Yao-Fu,Zhang, Na-Na
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supporting information
p. 2169 - 2172
(2019/11/25)
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- Efficient Heterogeneous Gold(I)-Catalyzed Direct C(sp2)–C(sp) Bond Functionalization of Arylalkynes through a Nitrogenation Process to Amides
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The first heterogeneous gold(I)-catalyzed direct C(sp2)–C(sp) bond functionalization of arylalkynes through a nitrogenation process to amides has been achieved by using an ordered mesoporous silica (MCM-41)-immobilized phosphine gold(I) complex [MCM-41-PPh3-AuCl] as catalyst and silver carbonate (Ag2CO3) as cocatalyst with trimethylsilyl azide (TMSN3) as a nitrogen source, yielding a variety of amides in moderate to excellent yields under mild conditions. This heterogeneous phosphine gold(I) complex shows the same turnover numbers as the homogeneous chloro(triphenylphosphine)gold(I) (Ph3PAuCl) and can easily be recovered by simple filtration of the reaction solution and recycled at least eight times without significant loss of activity, providing a novel, efficient, practical and economic method for the synthesis of amides from alkynes. (Figure presented.).
- Nie, Quan,Yi, Feiyan,Huang, Bin,Cai, Mingzhong
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p. 3968 - 3976
(2017/11/20)
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- BENZAMIDE DERIVATIVE
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The present invention relates to benzamide derivatives represented by formula (I) or pharmaceutically acceptable salts thereof.
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Paragraph 1123
(2015/03/16)
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- QUINAZOLINEDIONE DERIVATIVE
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The present invention relates to quinazolinedione derivatives represented by formula (I) or pharmaceutically acceptable salts thereof.
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Paragraph 1406; 1407
(2015/03/16)
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- Design, synthesis, and biological evaluation of novel 2-methylpiperazine derivatives as potent CCR5 antagonists
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Three series of novel 2-methylpiperazine derivatives were designed and synthesized using a fragment-assembly strategy. Among them, six compounds (13, 16, 18, 22, 33, and 36) showed potent activity against CCR5 comparable to that of the positive control, maraviroc, in calcium mobilization assay. Moreover, some compounds were selected and further tested for their antiviral activity in HIV-1 single cycle assay. As a result, four compounds (13, 16, 33, and 36) showed antiviral activity at the nanomolar level. Additionally, the potent four compounds showed no cytotoxicity at a concentration of 10 μM.
- Hu, Suwen,Wang, Zhilong,Hou, Tingjun,Ma, Xiaodong,Li, Jing,Liu, Tao,Xie, Xin,Hu, Yongzhou
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p. 1157 - 1168
(2015/03/04)
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- Novel trisubstituted acridines as human telomeric quadruplex binding ligands
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A novel series of trisubstituted acridines were synthesized with the aim of mimicking the effects of BRACO19. These compounds were synthesized by modifying the molecular structure of BRACO19 at positions 3 and 6 with heteroacyclic moieties. All of the derivatives presented in the study exhibited stabilizing effects on the human telomeric DNA quadruplex. UV-vis spectroscopy, circular dichroism, linear dichroism and viscosimetry were used in order to study the nature of the DNA binding in more detail. The results show that all of the novel derivatives were able to fold the single-stranded DNA sequences into antiparallel G-quadruplex structures, with derivative 15 exhibiting the highest stabilizing capability. Cell cycle analysis revealed that a primary trend of the "braco"-like derivatives was to arrest the cells in the S- and G 2M-phases of the cell cycle within the first 72 h, with derivative 13 and BRACO19 proving particularly effective in suppressing cell proliferation. All studies derivatives were less toxic to human fibroblast cell line in comparison with HT 29 cancer cell line.
- Ungvarsky, Jan,Plsikova, Jana,Janovec, Ladislav,Koval, Jan,Mikes, Jaromir,Mikesová, Lucia,Harvanova, Denisa,Fedorocko, Peter,Kristian, Pavol,Kasparkova, Jana,Brabec, Viktor,Vojtickova, Maria,Sabolova, Danica,Stramova, Zuzana,Rosocha, Jan,Imrich, Jan,Kozurkova, Maria
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- FLAVIN DERIVATIVES
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The present invention relates novel flavin derivatives and other flavin derivatives, their use and compositions for use as riboswitch ligands and/or anti-infectives. The invention also provides method of making novel flavin derivatives.
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Page/Page column 166-167
(2010/04/03)
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- Analogues of 4-[(7-Bromo-2-methyl-4-oxo-3 H -quinazolin-6-yl)methylprop-2- ynylamino]- N -(3-pyridylmethyl)benzamide (CB-30865) as potent inhibitors of nicotinamide phosphoribosyltransferase (Nampt)
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We have shown previously that the target of the potent cytotoxic agent 4-[(7-bromo-2-methyl-4-oxo-3H-quinazolin-6-yl)methyl-prop-2-ynylamino] -N-(3-pyridylmethyl)benzamide (CB38065, 1) is nicotinamide phosphoribosyltransferase (Nampt). With its cellular target known we sought to optimize the biochemical and cellular Nampt activity of 1 as well as its cytotoxicity. It was found that a 3-pyridylmethylamide substituent in the A region was critical to cellular Nampt activity and cytotoxicity, although other aromatic substitution did yield compounds with submicromolar enzymatic inhibition. Small unsaturated groups worked best in the D-region of the molecule, with 3,3-dimethylallyl providing optimal potency. The E region required a quinazolin-4-one or 1,2,3-benzotriazin-4-one group for activity, and many substituents were tolerated at C2 of the quinazolin-4-one. The best compounds showed subnanomolar inhibition of Nampt and low nanomolar cytotoxicity in cellular assays.
- Lockman, Jeffrey W.,Murphy, Brett R.,Zigar, Daniel F.,Judd, Weston R.,Slattum, Paul M.,Gao, Zhong-Hua,Ostanin, Kirill,Green, Jeremy,McKinnon, Rena,Terry-Lorenzo, Ryan T.,Fleischer, Tracey C.,Boniface, J. Jay,Shenderovich, Mark,Willardsen, J. Adam
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experimental part
p. 8734 - 8746
(2011/02/23)
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- One-step reductive amidation of nitro arenes: Application in the synthesis of Acetaminophen
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A novel thioacetate mediated one-step reductive acetamidation of aryl nitro compounds was developed and applied to an efficient synthesis of acetaminophen. The reaction also proceeds well without a solvent in the presence of a catalytic amount of surfactant.
- Bhattacharya, Apurba,Purohit, Vikram C.,Suarez, Victor,Tichkule, Ritesh,Parmer, Gaurang,Rinaldi, Frank
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p. 1861 - 1864
(2007/10/03)
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- ONE-POT REDUCTIVE ACETAMIDATION OF ARYL NITRO COMPOUNDS
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The present invention provides a method for the reductive acetamidation of an aryl nitro compound by reacting a substituted acid with an aryl nitro compound and adding a catalytic amount of a base with the substituted acid and the aryl nitro compound to form an acetamidation aryl nitro compound. The acetamidation aryl nitro compound is then purified.
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Page/Page column 12; 13
(2008/06/13)
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- Pd-catalyzed ortho-selective oxidative coupling of halogenated acetanilides with acrylates
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Coupling of different halogenated acetanilides with acrylates using Pd-catalyzed ortho-selective C-H bond activation is reported. The yields of coupled products are low to high depending on the substrate. In general, arenes with electron-rich substituents like methoxy and methyl groups gave higher yields of the coupled products. The presence of the halogen substituent did not interfere with the activation process under these conditions.
- Lee, George T.,Jiang, Xinglong,Prasad, Kapa,Repic, Oljan,Blacklock, Thomas J.
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p. 1921 - 1924
(2007/10/03)
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- Heteroaryl alkyl piperazine derivatives
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Novel compounds of the general formula: and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of diabetes, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
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-
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- Anti-quinazoline compounds
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Dihydroquinazoline derivatives of the formula where R3is —(CH2)p—A where p is from 1 to 4 and A is a 5- or 6-membered N-containing heterocyclic ring attached via the N atom or A is —NA′A″ wherein A′ and A″ are the same or different and are each a C1-C4alkyl group or their pharmaceutically acceptable salts possessing anti-cancer activity.
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Page column 14
(2010/02/05)
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- Heteroaryl alkyl piperazine derivatives
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Novel compounds of the general formula: and pharmaceutically acceptable acid addition salts thereof, wherein the compounds are useful in therapy to protect skeletal muscles against damage resulting from trauma or to protect skeletal muscles subsequent to muscle or systemic diseases such as intermittent claudication, to treat shock conditions, to preserve donor tissue and organs used in transplants, in the treatment of diabetes, in the treatment of cardiovascular diseases including atrial and ventricular arrhythmias, Prinzmetal's (variant) angina, stable angina, and exercise induced angina, congestive heart disease, and myocardial infarction.
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- The design and synthesis of water-soluble analogues of CB30865, a quinazolin-4-one-based antitumor agent
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4-[N-[7-Bromo-2-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl] -N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide (CB30865) is a quinazolin-4-one antitumor agent whose high growthinhibitory activity (W1L2 IC50 = 2.8 ± 0.50 nM) is believed to have a folate-independent locus of action. In addition, CB30865 represents a class of compounds with unique biochemical characteristics such as a delayed, non-phase specific, cell-cycle arrest. The low aqueous solubility of CB30865 prompted a search for more water-soluble analogues for in vivo evaluation of this class of compounds. It was thought that aqueous solubility could be increased by the introduction of amino functionalities at the 2-position of the quinazolin-4-one ring. A variety of compounds (5a-j, 31a-c, 32, and 33) were synthesized in a linear fashion starting from 3-chloro-4-methylaniline. Most of these compounds (e.g., 5a, 5b, 5g) were significantly more water-soluble than CB30865 (636 μM for 5a at pH 6 and 992 μM for 5g at pH 6). In addition, some of them were up to 6-fold more cytotoxic than CB30865 (e.g., for 5a, W1L2 IC50 = 0.49 ± 0.24 nM) and retained its novel biochemical characteristics.
- Bavetsias,Skelton,Yafai,Mitchell,Wilson,Allan,Jackman
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p. 3692 - 3702
(2007/10/03)
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- Bioconcentration and metabolism of [14C]3-chloro-p-toluidine hydrochloride by bluegill sunfish
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Bluegill sunfish (Lepomis macrochirus) were continuously exposed to 0.1 μg/ml of uniformly radiolabeled [14C]3-chloro-p-toluidine hydrochloride (CPTH) for 28 d, after which the fish were transferred to flowing untreated water for a 28-d depuration period. At periodic intervals during the treatment and depuration periods, samples of water and fish were analyzed for [14C] residues to determine the degree of CPTH absorption. Samples of bluegill that were exposed to the radiolabeled chemical for 28 d were analyzed to determine the distribution of the radiolabel and to isolate and identify possible metabolites. The steady-state concentrations in the bluegill tissues were reached by day 7 of exposure to the radiolabeled compound, with mean concentrations in the edible, nonedible, and whole body tissues determined to be 2.9, 12.0, and 7.5 μg/g of tissue, respectively. Bioconcentration factors of 33x, 150x, and 88x were calculated for the three types of tissues. About 64% of the accumulated radiolabeled CPTH and metabolites were eliminated from the fish on day 28 of depuration. The distribution of radioactivity was found to be similar in all tissue groups. One metabolite was confirmed as N-acetyl-3-chloro-p-toluidine, with two metabolites suggested to be 4-acetamido-2-chlorobenzoic acid and 4-amino-2- chlorobenzoic acid. The N-acetylated breakdown product has been previously reported to occur in both mammals and birds; thus, the metabolism of CPTH in fish may parallel that observed in these other species. Although the effects of biomagnification cannot be fully assessed at this time, we can conclude that when bluegill sunfish are continuously exposed to sublethal levels of CPTH, bioconcentration will not occur to an appreciable extent, and that residues will be rapidly excreted upon removal of the fish from the CPTH source. Furthermore, published information pertaining to various aquatic organisms indicates that bioaccumulation will not be a problem it the bioconcentration factor is below 100.
- Spanggord, Ronald J.,Gordon, G. Ross,Schocken, Mark J.,Starr, Robert I.
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p. 1655 - 1663
(2007/10/03)
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