- Enhanced catalytic activity of natural hematite-supported ppm levels of Pd in nitroarenes reduction
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In this work, Pd NPs supported on amine-modified natural hematite have been prepared and characterized. Using this simple catalyst, nitroaromatic compounds as a major cause of industrial pollution were reduced to corresponding amines with ppm levels of Pd in the presence of designer surfactant TPGS-750-M and NaBH4 at room temperature in aqueous media. Synergistic effect between hematite and Pd is responsible for the observed enhanced catalytic activity. This catalyst was recycled for at least four times with a small decrease in the activity.
- Gholinejad, Mohammad,Shojafar, Mohammad,Sansano, José M.
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- Influence of medium and temperature on the hydrolysis kinetics of propacetamol hydrochloride: Determination using derivative spectrophotometry
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Propacetamol hydrochloride (PRO) is a water-soluble prodrug of paracetamol (PA) which can be parenterally administered as analgesic for the treatment of postoperative pain, acute trauma, and gastric and/or intestinal disorders where oral administration is not possible. In these circumstances, PRO can be administered in physiologic or glucose solutions since it is rapidly and quantitatively hydrolyzed into PA by plasma estearases. We have studied the degradation kinetics of PRO in 5% glucose and 0.9% saline solutions at 4 °C and 25 °C (storage and room temperatures, respectively). The analytic technique used to determine PRO and PA quantitatively was first-derivative spectrophotometry. The degradation process of PRO can be best fitted to a second-order kinetics with independence of the medium used (saline or glucose solution). The hydrolysis kinetics of PRO conversion into PA depends on the temperature but not on the assay medium (saline or glucose solution). The degradation rate constants obtained for PRO were approximately 4.5 times higher at 25 °C than at 4 °C. The values of t90% for PRO were 3.17 h and 3.61 h at 25 °C, and 13.42 h and 12.36 h at 4 °C when the tests were performed in 5% glucose and 0.9% saline solutions, respectively.
- Barcia, Emilia,Martin, Alicia,Azuara, Ma. Luz,Negro, Sofia
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- Subphthalocyanines: Addressing water-solubility, nano-encapsulation and activation for optical imaging of B16 melanoma cells
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Water-soluble disulfonato-subphthalocyanines (SubPcs) or hydrophobic nano-encapsulated SubPcs are efficient probes for the fluorescence imaging of cells. 20 nm large liposomes (TEM and DLS) incorporated about 13% SubPc. Moreover, some of these fluorophores were found to be pH activatable.
- Bernhard, Yann,Winckler, Pascale,Chassagnon, Remi,Richard, Philippe,Gigot, lodie,Perrier-Cornet, Jean-Marie,Decrau, Richard A.
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- Regioselective preparation of 5-hydroxypropranolol and 4′-hydroxydiclofenac with a fungal peroxygenase
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An extracellular peroxygenase of Agrocybe aegerita catalyzed the H2O2-dependent hydroxylation of the multi-function beta-adrenergic blocker propranolol (1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-ol) and the non-steroidal anti-inflammatory drug diclofenac (2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetic acid) to give the human drug metabolites 5-hydroxypropranolol (5-OHP) and 4′-hydroxydiclofenac (4′-OHD). The reactions proceeded regioselectively with high isomeric purity and gave the desired 5-OHP and 4′-OHD in yields up to 20% and 65%, respectively. 18O-labeling experiments showed that the phenolic hydroxyl groups in 5-OHP and 4′-OHD originated from H2O2, which establishes that the reaction is mechanistically a peroxygenation. Our results raise the possibility that fungal peroxygenases may be useful for versatile, cost-effective, and scalable syntheses of drug metabolites.
- Kinne, Matthias,Poraj-Kobielska, Marzena,Aranda, Elisabet,Ullrich, Rene,Hammel, Kenneth E.,Scheibner, Katrin,Hofrichter, Martin
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- Preparation of β-cyclodextrin functionalized reduced graphene oxide: Application for electrochemical determination of paracetamol
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β-Cyclodextrin functionalized reduced graphene oxide (β-CD/RGO) was successfully prepared using a simple wet chemical method. The β-CD/RGO nanohybrid was characterized by UV-vis spectroscopy, FTIR, Raman spectroscopy, TEM and SEM. The results confirmed that β-CD had effectively covered the RGO surface. The β-CD/RGO nanohybrid modified glassy carbon electrode was employed for the sensitive electrochemical determination of paracetamol. Cyclic voltammetry measurements indicated that β-CD/RGO could significantly enhance the electrochemical response of paracetamol due to the outstanding electronic properties of RGO sheets and the high supramolecular recognition and enrichment capability of β-CD. The experimental factors were investigated and optimized. Under optimized conditions, the amperometric oxidation currents of paracetamol were linearly proportional to the concentration in the range of 0.01 to 0.8 mM with a detection limit of 2.3 μM (S/N = 3). Furthermore, the proposed sensor exhibited an excellent anti-interference property and acceptable reproducibility.
- Fu, Li,Lai, Guosong,Yu, Aimin
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- Spectrophotometric Determination of Aspirin by Transacetylation of 4-Aminophenol
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Aspirin transacetylates 4-aminophenol, yielding acetaminophen (N-acetyl-4-aminophenol), which can be determined by its oxidation to an orange-yellow product either by iodylbenzene in acetone when the absorbance is measured at 430 nm or by photometric titration with 2-iodylbenzoate in acetone-water medium at 444 nm.Salicylic acid, salicylamide, oxyphenbutazone, caffeine, and sodium hydrogen carbonate do not interfere.Drug mixtures of acetaminophen and aspirin have been analyzed by determining acetaminophen alone directly with iodyl reagents and then determining acetaminophen plus aspirin after 4-aminophenol reaction; aspirin is found b y difference
- Verma, Krishna K.,Jain, Archana
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- Assessment of cytochrome P450 (1A2, 2B6, 2C9 and 3A4) induction in cryopreserved human hepatocytes cultured in 48-well plates using the cocktail strategy
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1. A fast, straightforward and cost-effective assay was validated for the assessment of CYP induction in cryopreserved human hepatocytes cultured in 48-well plates. The cocktail strategy (in situ incubation) was used to assess the induction of CYP1A2, CYP2B6, CYP2C9 and CYP3A4 by using the recommended probe substrate, i.e. phenacetin, bupropion, diclofenac and midazolam, respectively. 2. Cryopreserved human hepatocytes were treated for 72 h with prototypical reference inducers, β-naphthoflavone (25 μM), phenobarbital (500 μM) and rifampicin (10 μM) as positive controls for CYP induction. The use of a cocktail strategy has been validated and compared to the classical approach (single incubation). The need of using phase II inhibitor (salicylamide) in CYP induction assay was also investigated. 3. By using three different batches of cryopreserved human hepatocytes and our conditions of incubations, we showed that there was no relevant drug-drug interaction using the cocktail strategy. The same conclusions were observed when a broad range of enzyme activity has to be assessed (wide range of reference inducers, i.e. EC50-Emax experiment). In addition, the interassay reproducibility assessment showed that the day-to-day variability was minimal. 4. In summary, the study showed that the conditions used (probe substrates, concentration of probe substrate and time of incubation) for the cocktail approach were appropriate for investigations of CYP induction potential of new chemical entities. In addition, it was also clear that the use of salicylamide in the incubation media was not mandatory and could generate drug-drug interactions. For this reason, we recommend to not use salicylamide in CYP induction assay.
- Gerin, Brigitte,Dell'aiera, Sylvie,Richert, Lysiane,Smith, Steven,Chanteux, Hugues
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- Oxidation of human cytochrome P450 1A2 substrates by Bacillus megaterium cytochrome P450 BM3
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Cytochrome P450 enzymes (P450s or CYPs) are good candidates for biocatalysis in the production of fine chemicals, including pharmaceuticals. Despite the potential use of mammalian P450s in various fields of biotechnology, these enzymes are not suitable as biocatalysts due to their low stability, low catalytic activity, and limited availability. Recently, wild-type and mutant forms of bacterial P450 BM3 (CYP102A1) from Bacillus megaterium have been found to metabolize various. It has therefore been suggested that CYP102A1 may be used to generate the metabolites of drugs and drug candidates. In this report, we show that the oxidation reactions of typical human CYP1A2 substrates (phenacetin, ethoxyresorufin, and methoxyresorufin) are catalyzed by both wild-type and mutant forms of CYP102A1. In the case of phenacetin, CYP102A1 enzymes show only O-deethylation product, even though two major products are produced as a result of O-deethylation and 3-hydroxylation reactions by human CYP1A2. Formation of the metabolites was confirmed by HPLC analysis and LC-MS to compare the metabolites with the actual biological metabolites produced by human CYP1A2. The results demonstrate that CYP102A1 mutants can be used for cost-effective and scalable production of human CYP1A2 drug metabolites. Our computational findings suggest that a conformational change in the cavity size of the active sites of the mutants is dependent on activity change. The modeling results further suggest that the activity change results from the movement of several specific residues in the active sites of the mutants.
- Kim, Dong-Hyun,Kim, Keon-Hee,Kim, Dooil,Jung, Heung-Chae,Pan, Jae-Gu,Chi, Youn-Tai,Ahn, Taeho,Yun, Chul-Ho
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- Identification of human cytochrome P450s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data
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Objective: Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P450 (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data. Methods: In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P450 (rCYP), were used to determine the intrinsic clearance (CLint) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs. Results and discussion: CLint determined in RLM and HLM showed low (r2=0.50) but significant (Pint values were scaled to predict in vivo hepatic clearance (CLH) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro-in vivo correlation analysis. Using the CLH predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (> 70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (int drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug-drug interactions in vivo.
- Li, Xue-Qing,Bjoerkman, Anders,Andersson, Tommy B.,Gustafsson, Lars L.,Masimirembwa, Collen
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- SELECTIVE ACYLATIONS OF AMINOPHENOLS AND HYDROXYALKYLPHENOLS WITH 1-ACETYL-v-TRIAZOLOPYRIDINE.
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The title triazolide serves as a convenient reagent for highly chemoselective acetylations of aminophenols and hydroxyalkylphenols.
- Paradisi, Mario Paglialunga,Zecchini, Giampiero Pagani,Torrini, Ines
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- Ytterbium triflate mediated selective deprotection of acetates
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Ytterbium triflate mediated selective deprotection of acetates in isopropyl alcohol at reflux temperature is reported. Unlike hafnium triflate, under the present reaction conditions aryl acetates also undergo deacetylation instead of Fries migration.
- Sharma,Ilangovan
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- Reagents with a Crystalline Coat
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Tetrakis(dimethoxyphenyl)adamantane (TDA) readily forms crystalline inclusion complexes with reactive, toxic, or malodorous reagents, such as benzoyl chloride, acetyl chloride, cyclohexyl isocyanide, phosphorus trichloride, and trimethylsilyl chloride. The crystals are stable and largely free of the problematic properties of the free reagents. When exposed to solvents such as DMSO or MeOH, the reagents react, and a large portion of the TDA precipitates. The TDA-coated reagents may lead to a safer way of storing, handling, and delivering reagents, and ultimately to synthetic protocols that do not require fume hoods.
- Schwenger, Alexander,Frey, Wolfgang,Richert, Clemens
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- Mechanism of Decomposition of N-Hydroxyacetaminophen, a Postulated Toxic Metabolite of Acetaminophen
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The decomposition of N-hydroxyacetaminophen (N-acetyl-N-hydroxy-p-aminophenol, 2) a postulated toxic metabolite of acetaminophen (N-acetyl-p-aminophenol, 1) in aqueous solution is quantitatively accounted for by the appearance of equimolar amounts of p-nitrosophenol and acetaminophen.The rate of decomposition depends on initial concentration and varies with pH.Antioxidants decrease the rate of decomposition and change the products.In the presence of cysteine, N-acetyl-3-(S-cysteine)-p-aminophenol, an in vivo metabolite of acetaminophen, is a product of decomposition.
- Gemborys, Mark W.,Mudge, Gilbert H.
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- The anticarcinogen 3,3'-diindolylmethane is an inhibitor of cytochrome P-450.
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Dietary indole-3-carbinol inhibits carcinogenesis in rodents and trout. Several mechanisms of inhibition may exist. We reported previously that 3,3'-diindolylmethane, an in vivo derivative of indole-3-carbinol, is a potent noncompetitive inhibitor of trout cytochrome P450 (CYP) 1A-dependent ethoxyresorufin O-deethylase with Ki values in the low micromolar range. We now report a similar potent inhibition by 3,3'-diindolylmethane of rat and human CYP1A1, human CYP1A2, and rat CYP2B1 using various CYP-specific or preferential activity assays. 3,3'-Diindolylmethane also inhibited in vitro CYP-mediated metabolism of the ubiquitous food contaminant and potent hepatocarcinogen, aflatoxin B1. There was no inhibition of cytochrome c reductase. In addition, we found 3,3'-diindolylmethane to be a substrate for rat hepatic microsomal monooxygenase(s) and tentatively identified a monohydroxylated metabolite. These observations indicate that 3,3'-diindolylmethane can inhibit the catalytic activities of a range of CYP isoforms from lower and higher vertebrates in vitro. This broadly based inhibition of CYP-mediated activation of procarcinogens may be an indole-3-carbinol anticarcinogenic mechanism applicable to all species, including humans.
- Stresser,Bjeldanes,Bailey,Williams
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- Retrorsine, but not monocrotaline, is a mechanism-based inactivator of P450 3A4
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Retrorsine (RTS) and monocrotaline (MCT) cause severe toxicities via P450-mediated metabolic activation. The screening of mechanism-based inhibitors showed RTS inactivated 3A4 in the presence of NADPH. Unlike RTS, MCT failed to inhibit P450 3A4 and other enzymes tested. Further studies showed the loss of P450 3A4 activity occurred in a time- and concentration-dependent way, which was not recovered after dialysis. Dextromethorphan, a P450 3A4 substrate, protected the enzyme from the inactivation. Exogenous nucleophile glutathione (GSH) and reactive oxygen species scavengers catalase and superoxide dismutase did not protect P450 3A4 from the inactivation. GSH trapping experiments showed both P450 3A4 and 2C19 converted RTS and MCT to the corresponding electrophilic metabolites which could be trapped by GSH to form 7-GSH-DHP conjugate. We conclude that RTS and MCT are metabolically activated by P450 3A4 and 2C19, and that RTS, but not MCT, is a mechanism-based inactivator of P450 3A4.
- Dai, Jieyu,Zhang, Fan,Zheng, Jiang
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- Silicon-grafted Ag/AgX/rGO nanomaterials (X = Cl or Br) as dip-photocatalysts for highly efficient p-nitrophenol reduction and paracetamol production
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In this work, plasmonic Ag/AgX/rGO (X?=?Cl or Br) nano-photocatalysts were grafted with silicon by adding trimethylsilyl chloride as silicon precursor. The synthesized Ag/AgX/rGO-Si hybrids showed a large improvement of photocatalytic activity towards the synthesis of p-aminophenol (PAP) as well as paracetamol (acetaminophen; APAP) through the photoreduction of p-nitrophenol (PNP). The prepared catalysts Ag/AgX/rGO were characterized using SEM, XRD, FTIR and the reduction reaction of p-nitrophenol was monitored by UV–Vis measurements, GC/MS and 1HNMR data. From the results, it was demonstrated that the rate order of reduction process of the PNP to PAP and to APAP under visible light irradiation of the samples was as follows; Ag/AgBr/rGO-Si?>?Ag/AgCl/rGO-Si?>?Ag/AgBr/rGO?>?Ag/AgCl/rGO. The reaction mechanism had been postulated that was supported with the spectroscopic data. In addition, the catalysts were recovered from the reaction medium and re-used in three cycles that indicated the reusability and stability of the catalysts. This study was featured by the following; i) fast reaction, ii) the reduction of p-nitrophenol to paracetamol was performed in a facile one-pot reaction compared to previous approaches that tends to reduce the production cost, and iii) investigations on the catalytic properties of Ag/AgX/rGO in organic transformations open the door to find a benefice of these catalysts in other organic reactions and in the development in the synthesis of pharmaceutical products.
- Attia, Yasser A.,Mohamed, Yasser M.A.
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- Amidation of phenol derivatives: A direct synthesis of paracetamol (acetaminophen) from hydroquinone
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A direct synthesis of paracetamol (acetaminophen) from hydroquinone has been developed using ammonium acetate as an amidating agent. The reaction proceeds in acetic acid at elevated temperatures without any metallic catalyst. Under these conditions, paracetamol was obtained with high yield and selectivity (>95%). The reaction has also been carried out on the multi-gram scale (44 g of hydroquinone) and a potential process has been proposed based on the recycling of the solvent and by-products. This amidation protocol has also been extended to other phenol derivatives. This journal is the Partner Organisations 2014.
- Joncour, Roxan,Duguet, Nicolas,Metay, Estelle,Ferreira, Amadeo,Lemaire, Marc
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- Introduction of a hydroxy group at the para position and N-iodophenylation of N-arylamides using phenyliodine(III) bis(trifluoroacetate)
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The reaction of anilides with phenyliodine(III) bis(trifluoroacetate) (PIFA) in trifluoroacetic acid (TFA), TFA-CHCl3, or hexafluoroisopropyl alcohol (HFIP) is described. When the acyl group of the anilide is highly electronegative, such as trifluoroacetyl, or the phenyl group is substituted with an electron-withdrawing group, the 4-iodophenyl group is transferred from PIFA to the amide nitrogen to afford acetyldiarylamines. On the other hand, when the acyl group contains an electron-donating function, such as 4-methoxyphenyl, or the phenyl group is substituted with an electron-donating group, a trifluoroacetoxy group is transferred to the para position of the anilide aromatic ring. This group is hydrolyzed during workup to produce the corresponding phenol.
- Itoh, Naoki,Sakamoto, Takeshi,Miyazawa, Etsuko,Kikugawa, Yasuo
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- A Realistic Model for Heme-containing Catalases and Peroxidases: the X-Ray Structural Characterisation of a Non-porphyrin Iron(III) Macrocyclic Complex, and the Mechanism of Its Peroxidation of Aromatic Substrates
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In acidic buffered aqueous solution the complex dichloroheptadeca-1(17),13,15-triene>iron(III) tetrafluoroborate, BF4, exhibits both catalase- and peroxidase-like activity.The predominant cation in aqueous buffered solution at pH 4.65 is the mixed species 2+.The catalase- and peroxidase-like activity is proposed to occur via a high oxidation state intermediate rather than through involvement of free hydroxyl radicals.Quantitative compliance with the algebraic forms of theoretical rate laws fails to distinguish between these possibilities.However, the kinetics of dioxygen evolution in the presence of hydroxyl radical traps leads to the elimination of the hydroxyl radical model.In addition, the peroxidase-like reactivity of substituted benzenes toward the 2+-H2O2 model system parallels that expected for an electrophilic oxidant, and not that of free OH radicals.Parallel experiments with Fenton's reagent support this view.An X-ray structural determination on the dichloro complex indicates that the macrocycle adopts a folded conformation allowing the two chloride ligands to occupy cis positions in the co-ordination sphere.This stereochemistry is proposed to be retained in aqueous solution, and may allow bidentate co-ordination of hydrogen peroxide,a structural feature that may be critical to the catalase- and peroxidase-like activity.The iron(III) complex crystallises in the orthorhombic system, a=10.046(2), b=13.322(2), c=15.262(3) Angstroem, space group Pnma, with four molecules per unit cell.Final residuals had values of 0.042 and 0.043, for R and R', respectively, upon convergence for 1525 observed reflections.Both the cationic, macrocyclic complex and the BF4 anion display crystallographically imposed mirror symmetry.The iron(III) ion displays an approximately octahedral geometry, with co-ordination angles ranging from 77 to 95 deg.An analysis of associated torsion angles suggests that the folded conformation of the macrocycle is almost strain free.
- Cairns, Colin J.,Heckman, Roger A.,Melnyk, Alexandra C.,Davis, William M.,Busch, Daryle H.
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- Cerium(IV) sulfate tetrahydrate: A catalytic and highly chemoselective deprotection of THP, MOM, and BOM ethers
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Tetrahydropyranyl (THP), methoxymethyl (MOM), and benzyloxymethyl (BOM) phenyl/alkyl ethers were efficiently cleaved to the corresponding parent hydroxyl compounds in good yields using catalytic amounts of Ce(SO 4)2·4H2O by microwave-assisted or conventional heating in methanol solution. Intramolecular and competitive experiments demonstrated the chemoselective deprotection of THP ethers in the presence of triisopropylsilyl (TIPS) and tert-butyldiphenylsilyl (TBDPS) phenyl ethers.
- González-Calderón, Davir,González-González, Carlos A.,Fuentes-Benítez, Aydeé,Cuevas-Yá?ez, Erick,Corona-Becerril, David,González-Romero, Carlos
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- Aluminium chloride hexahydrate (AlCl3.6H2o): An efficient, facile, mild, and highly chemoselective catalytic deprotection of tert-butyldimethylsilyl (tbs) ethers
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tert-Butyldimethylsilyl (TBS) phenyl / alkyl ethers were cleaved to the corresponding efficiently parent hydroxyl compounds in good yields using catalytic amounts of AlCl3.6H2O by conventional or microwave-assisted heating in methanol or isopropanol solution. Intramolecular and competitive experiments demonstrated the chemoselective deprotection of TBS ethers in the presence of triisopropylsilyl and tert-butyldiphenylsilyl ethers.
- Gonzalez-Calderon, Davir,Benitez-Puebla, Luis J.,Gonzalez-Gonzalez, Carlos A.,Garcia-Eleno, Marco A.,Fuentes-Benitez, Aydee,Cuevas-Yanez, Erick,Corona-Becerril, David,Gonzalez-Romero, Carlos
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- Intensification of paracetamol (acetaminophen) synthesis from hydroquinone using ultrasound
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Paracetamol (acetaminophen) is one of the most frequently used analgesic and antipyretic drugs. This work deals with ultrasound assisted synthesis (UAS) of paracetamol from hydroquinone using ammonium acetate as an amidating agent. The optimization of various reaction and ultrasound parameters was performed to minimize the energy and time requirement. UAS of paracetamol was achieved at a lower temperature (60 °C) and the time (150 min) without formation of salt as a byproduct, making reaction green and inherently safer. On the other hand, the conventional process requires high reaction temperature (220 °C) and time (15 h). The quantification of the product was done by using high performance liquid chromatography (HPLC). Optimization of parameters revealed that the percent yield of 57.72% can be obtained in 150 min by performing the reaction in the ultrasound bath at 22 kHz frequency, 60 °C temperature, hydroquinone to ammonium acetate and acetic acid in a molar ratio of 1:6:5, 125 W power, 50% duty cycle and agitation speed of 300 RPM. Hence, ultrasound assisted synthesis can be considered as a process intensification tool for the synthesis of paracetamol and possibly other pharmaceutical compounds.
- Mane, Swapnil N.,Gadalkar, Sagar M.,Rathod, Virendra K.
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- A population approach to enzyme characterization and identification: Application to phenacetin O-deethylation
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Purpose. To determine the enzyme kinetics (EK) and identify the human cytochrome(s) P450 (CYP) involved in the deethylation of phenacetin to acetaminophen using a population-based method. Methods. A sparse data set was generated from incubations containing human liver microsomes (n = 19) with phenacetin. Estimates of the EK parameters were obtained by fitting the concentration-velocity data to Michaelis-Menten models by using nonlinear mixed effects modeling. Relationships between the EK parameters and the CYP activities determined for these liver microsomes were examined. Results. A two-enzyme kinetic model with a saturated, low KM enzyme and an unsaturated, high KM enzyme capable of forming acetaminophen best fit the data. The population estimates of the EK parameters were Vmax1, 911 pmol/min/mg protein; KM1, 11.3 μM; and Clint2 0.4 μl/min/mg. The coefficients of variation for interliver variability in Vmax1 and residual error of the model were 39% and 15%, respectively. When the selective catalytic activities were examined as potential covariates, 7-ethoxyresorufin O-deethylation (CYP1A2) activity was found to be associated with the low KM enzyme, however, the high KM enzyme(s) could not be identified. Conclusions. The population approach characterized the EK parameters and identified the low KM enzyme responsible for phenacetin O-deethylation as CYP1A2. Population modeling of EK provides valuable information on inter- and intraliver variability in CYP dependent activities.
- Belle,Ring,Allerheiligen,Heathman,O'Brien,Sinha,Roskos,Wrighton
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- Evaluation of the impact of 16-dehydropregnenolone on the activity and expression of rat hepatic cytochrome P450 enzymes
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16-dehydropregnenolone (DHP) is a promising novel antihyperlipidemic agent developed and patented by Central Drug Research Institute (CDRI), India. The purpose of the present study was to investigate whether DHP influences the activities and mRNA expression of hepatic drug-metabolizing cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C11, CYP2D2, CYP2E1 and CYP3A1) in Sprague-Dawley (SD) rats. A cocktail suspension of CYP probe substrates which contained caffeine (CYP1A2), tolbutamide (CYP2C11), dextromethorphan (CYP2D2), chlorzoxazone (CYP2E1) and dapsone (CYP3A1) was administered orally on eighth- or fifteenth-day to rats pre-treated with DHP intragastrically at a dose of 36 and 72?mg/kg for one week and two weeks. The concentrations of probe drugs in plasma were estimated by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Alongside, the effect of DHP on CYPs activity and mRNA expression levels were assayed in isolated rat liver microsomes and by real-time reverse transcription-polymerase chain reaction (RT-PCR), respectively. DHP had significant inducing effects on CYP1A2, 2C11, 2D2 and 2E1 with no effect on CYP3A1 in dose- and time-dependent manner, as revealed from the pharmacokinetic profiles of the probe drugs in rats. In-vitro microsomal activities and mRNA expression results were in good agreement with the in-vivo pharmacokinetic results. Collectively, the results unveiled that DHP is an inducer of rat hepatic CYP enzymes. Hence, intense attention should be paid when DHP is co-administered with drugs metabolized by CYP1A2, 2C11, 2D2 and 2E1, which might result in drug-drug interactions and therapeutic failure.
- Ramakrishna, Rachumallu,Bhateria, Manisha,Singh, Rajbir,Bhatta, Rabi Sankar
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- Large scale Biginelli reaction via water-based biphasic media: A green chemistry strategy
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An important stage in process development is kilo scale preparation of the target compound. For this reason, a procedure involving water-based biphasic reaction media has been developed for conducting some exothermic reactions on a large scale. This protocol is illustrated by the energy-efficient and rapid preparation of dihydropyrimidinones by a solvent-free, green chemistry procedure applied to the Biginelli reaction using p-toluenesulfonic acid as catalyst. 2005 Elsevier Ltd.
- Bose, Ajay K.,Manhas, Maghar S.,Pednekar, Suhas,Ganguly, Subhendu N.,Dang, Hoang,He, William,Mandadi, Arun
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- IMMUNOCHEMICAL MODELING OF LIGAND-RECEPTOR REACTIONS. COMMUNICATION V. PROPERTIES OF ANTIBODIES RAISED AGAINST THE TRIETHYLAMMONIUM DETERMINANT
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The properties of antibodies to immunogens determined by triethylammonium were studied.The immunochemical method is suggested for determining the ligands of a cholinergic receptor with a predominantly antidepolarizing type of action.
- Burkin, A. A.,Zoryan, V. G.
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- Preparation of an organic–inorganic hybrid based on synergy of Br?nsted and Lewis acid centres as heterogeneous magnetic nanocatalyst for ultrafast synthesis of acetaminophen
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A heterogeneous nanocatalyst based on a Cu(II) complex containing phosphotungstic acid and N/O-donor ligands supported on cobalt ferrite nanoparticles was successfully prepared. The synthesized nanocatalyst was characterized using various techniques. The magnetic nanocatalyst was examined as an efficient and synergistic catalyst for ultrafast synthesis of acetaminophen at room temperature and under solventless conditions. The examined synergistic nanocatalyst, which has both Lewis and Br?nsted acidic sites, could be easily separated from the reaction system and reused several times without significant loss of its activity. The synthesized acetaminophen was also fully characterized.
- Kooti,Nasiri
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- Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: Potential implications for combination therapies
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1. Cytochrome P450 enzyme system is the most important contributor to oxidative metabolism of drugs. Modification, and more specifically inhibition, of this system is an important determinant of several drug-drug interactions (DDIs). 2. Effects of the antimalarial agent artemisinin and its structural analogues, artemether, artesunate and dihydroartemisinin, on seven of the major human liver CYP isoforms (CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6 and 3A4) were evaluated using recombinant enzymes (fluorometric assay) and human liver microsomes (LC-MS/MS analysis). Inhibitory potency (IC50) and mechanisms of inhibition were evaluated using nonlinear regression analysis. In vitro-in vivo extrapolation using the [I]/Ki ratio was applied to predict the risk of DDI in vivo. 3. All compounds tested inhibited the enzymatic activity of CYPs, mostly through a mixed type of inhibition, with CYP1A2, 2B6, 2C19 and 3A4 being affected. A high risk of interaction in vivo was predicted if artemisinin is coadministrated with CYP1A2 or 2C19 substrates. 4. With respect to CYP1A2 inhibition in vivo by artemisinin compounds, our findings are in line with previously published data. However, reported risks of interaction may be overpredicted and should be interpreted with caution.
- Ericsson, Therese,Sundell, Jesper,Torkelsson, Angelica,Hoffmann, Kurt-Jürgen,Ashton, Michael
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- Human cytochromes p450 mediating phenacetin 0-deethylation in vitro: Validation of the high affinity component as an index of CYP1A2 activity
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Phenacetin 0-deethylation, widely used as an index reaction for cytochrome P450 1A2 (CYP1A2) activity, displays biphasic kinetics in human liver microsomes. CYP1A2 has been identified as contributing to the high affinity component, but is not verified as the sole contributor to the high affinity phase. In addition, the human CYP isoforms accounting for the low affinity phase have not been identified. We have used heterologously expressed human CYP isoforms to identify, kinetically characterize, and predict the relative contribution of the major human liver CYP isoforms mediating phenacetin 0-deethylation. CYP1A2 (Km 31 /J.M) is the only high affinity phenacetin 0-deethylase in human liver microsomes, while CYPs 2A6 (Km 4098 pM), 2C9 (Km 566 μM), 2C19 (Km 656 μM), 2D6 (Km 1021 μM), and 2E1 (Km 1257 μM) all contribute to the low affinity phase of the reaction. Considering the relative abundance of the various CYPs in human liver, CYP1A2 accounts for 86% of net reaction velocity at a substrate concentration of 100 fM, while CYP2C9 becomes the primary phenacetin 0-deethylase at substrate concentrations of 865 /M and higher and accounts for 31% of the net Vmsst of the reaction. Predictions from kinetic studies on heterologously expressed CYPs are consistent with chemical inhibition studies on human liver microsomes with sulfaphenazole and a-naphthoflavone that suggest a greater role for CYP2C9, and a smaller role for CYP1A2, at higher substrate concentrations. Thus CYP1A2 is the only high affinity human liver phenacetin 0-deethylase, thereby validating the use of the high affinity component as an index of CYP1A2 activity in human liver microsomes.
- Venkatakrishnan, Karthik
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- In vitro evaluations for pharmacokinetic drug-drug interactions of a novel serotonin-dopamine activity modulator, brexpiprazole
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Brexpiprazole, a serotonin-dopamine activity modulator, is indicated for the treatment of schizophrenia and also adjunctive therapy to antidepressants for the treatment of Major Depressive Disorder. To determine the drug–drug interaction risk for cytochrome P450, and SLC and ABC transporters, brexpiprazole and its metabolite, DM-3411 were assessed in this in?vitro investigation. Brexpiprazole exhibited weak inhibitory effects (IC50 >13 μmol/L) on CYP2C9, CYP2C19, CYP2D6 and CYP3A4 activities, but had moderate inhibitor activity on CYP2B6 (IC50 8.19 μmol/L). The ratio of systemic unbound concentration (3.8 nmol/L) to the Ki value was sufficiently low. DM-3411 had comparable inhibitory potentials with brexpiprazole only for CYP2D6 and CYP3A4. The mRNA expressions of CYP1A2, CYP2B6 and CYP3A4 were not changed by the exposure of brexpiprazole to human hepatocytes. Brexpiprazole and DM-3411 exhibited weak or no inhibitory effects for hepatic and renal transporters (OATPs, OATs, OCTs, MATE1, and BSEP), except for MATE-2K (0.156 μmol/L of DM-3411), even for which the ratio to systemic unbound concentration (5.3 nmol/L) was sufficiently low. Brexpiprazole effected the functions of P-gp and BCRP with IC50 values of 6.31 and 1.16 μmol/L, respectively, however, the pharmacokinetic alteration was not observed in the clinical concomitant study on P-gp and BCRP substrates. These in?vitro data suggest that brexpiprazole is unlikely to cause clinically relevant drug interactions resulting from the effects on CYPs or transporters mediating the absorption, metabolism, and/or disposition of co-administered drugs.
- Sasabe, Hiroyuki,Koga, Toshihisa,Furukawa, Masayuki,Matsunaga, Masayuki,Sasahara, Katsunori,Hashizume, Kenta,Oozone, Yoshihiro,Amunom, Immaculate,Torii, Mikako,Umehara, Ken,Kashiyama, Eiji,Takeuchi, Kenji
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- Functionalized nanomagnetic graphene by ion liquid containing phosphomolybdic acid for facile and fast synthesis of paracetamol and aspirin
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A nanocomposite has been synthesized by supporting of polyaniline-modified polyoxometalate-paired poly(ionic liquid) on the surface of magnetic graphene and characterized by various techniques. The fabricated nanocomposite was found to be a versatile catalyst for the synthesis of paracetamol and aspirin drugs showing high activity and selectivity. The observed high catalytic activity of the newly synthesized catalyst, in the preparation of these two important drugs, can be attributed to the presence of graphene, which provides high surface area for the supporting of polyaniline–polyoxometalate pair and also to the strong acidity of the solid acid. This catalytic system has several advantages, such as simple experimental process, easy separation of the product, solvent-free condition, efficient isolation, and recovery of the magnetic catalyst as well as high reusability.
- Nasiri, Elahe,Kooshki, Feridoon,Kooti, Mohammad,Rezaeinasab, Rezvan
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- KHF2: A mild and selective desilylating agent for phenol tert-butyldimethylsilyl (TBDMS) ethers
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TBDMS (t-BuMe2Si, tert-butyldimethylsilyl) ethers of a variety of phenols have been deprotected with KHF2 in MeOH, at room temperature. Carboxylic ester and labile phenolic acetate were unaffected under these conditions. In competition reactions between TBDMS ethers of a phenol and two primary benzylic alcohols, the phenolic ether underwent cleavage whereas the alcohol ethers remained intact. From a substrate containing both a phenolic hydroxyl group and a secondary, doubly benzylic hydroxyl group protected as TBDMS ethers, the phenol was rapidly and selectively released. Cleavage of TBDMS, TBDPS, and TIPS ethers of a phenol was also compared. TBDMS and TBDPS ethers underwent cleavage at room temperature within 30 minutes, whereas removal of the TIPS ether required 2.5 hours. Ease of cleavage appears to be TBDMS ≈ TBDPS > TIPS. At 60°C, TBDMS ethers of primary benzylic, allylic, and unactivated alcohols can be efficiently desilylated over a prolonged period (13-17 h). Thus, KHF2 proves to be a mild and effective reagent for the selective desilylation of phenol TBDMS ethers at room temperature.
- Lakshman, Mahesh K.,Tine, Fatou A.,Khandaker, Tashrique A.,Basava, Vikram,Agyemang, Nana B.,Benavidez, Michael S.A.,Ga?i, Marikone,Guerrera, Lisa,Zajc, Barbara
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- Microwave initiated reactions: Pechmann coumarin synthesis, Biginelli reaction, and acylation
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An energy-efficient protocol has been developed for solvent-free reactions that are mildly exothermic but not spontaneous. The exothermic reaction mixture-on several g-scale-is exposed for about 30 s to low power (about 200 W) microwaves and then the microwave oven is switched off. After this short burst of energy, the exothermic reaction gets initiated and proceeds on its own to completion. A number of coumarins were synthesized by the Pechmann reaction using this strategy.
- Manhas, Maghar S.,Ganguly, Subhendu N.,Mukherjee, Somdatta,Jain, Amit K.,Bose, Ajay K.
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- Process modeling of reduction and acetylation reactions by spectrophotometric and chemometrics methods
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Achieving high levels of chemoselectivity is a pivotal feature of chemical synthesis. Although significant progress has been made in this regards, lots of challenges lie ahead. Herein, multivariate curve resolution-alternating least square (MCR-ALS) was employed to overcome the spectral overlapping of the reactants and products in the model reactions of methyl-(4-formyl) benzoate by NaBH4 and acetylation of p-aminophenol by acetyl chloride. The first-order ultraviolet/visible absorbance spectra were recorded during the addition of different quantities of reagent to the substrate. The absorbing species, coexisting in the system, were detected through employing factor analysis. The soft-modeling analysis of the evolutionary absorbance data by MCR-ALS revealed that both model reactions proceed through a two-step consecutive manner. Using the obtained concentration profiles, one can obtain an idea about the suitable molar ratio of reagent/substrate for selective production of one of the reaction products. Moreover, the pure spectrum of the intermediate species could be estimated.
- Hemmateenejad, Bahram,Shadabipour, Parisa,Mohamadizadeh, Moahamad Reza
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- Kinetics and inhibition by fluvoxamine of phenacetin O-deethylation in V79 cells expressing human CYP1A2
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The kinetics of phenacetin O-deethylation and its inhibition by fluvoxamine was investigated in a V79 cell line (V79MZh1A2) transfected with human CYP1A2. In four sets of experiments the apparent Km values for phenacetin O-deethylation ranged from 35 to 95 μM and the Ki for fluvoxamine-mediated inhibition of the reaction ranged from 2.7 to 14.5 nM, i.e. comparable to values obtained in human liver microsomes. The kinetic performance of the V79MZh1A2 cell line demonstrates its usefulness as an analytical tool in a variety of toxicological and drug metabolism studies involving CYP1A2.
- Gjervig Jensen,Enghusen Poulsen,Doehmer,Loft
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- Large-scale crystallization of a pure metastable polymorph by reaction coupling
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A maximum of more than 40 g of acetaminophen Form II crystals with a yield of 65 mol % is made reproducibly in a 500 mL reactor by coupling the acetylation of p-aminophenol with the neutralization of acetic acid before the crystallization of acetaminophen Form II crystals. This novel working principle involves a sudden drop of the solubility of acetaminophen from the acetic acid-water environment to the acetate-water system in addition to temperature cooling but without agitation. This particular processing pathway is capable of maintaining a large supersaturation for quite some time for the system to enter the metastable zone of Form II with respect to the acetate-water system. The large amount of Form II crystals so produced are then isolated by filtration and oven drying to prevent Form II crystals in the mother liquor from transforming to the thermodynamically stable Form I crystals by the Ostwalds rule of stages.
- Lee, Hung Lin,Lin, Hong Yu,Lee, Tu
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- Acetylshikonin is a novel non-selective cytochrome P450 inhibitor
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Acetylshikonin is a biologically active compound with anti-cancer and anti-inflammatory activity, which is isolated from the roots of Lithospermum erythrorhizoma. An inhibitory effect of acetylshikonin against CYP2J2 activity was discovered recently. Based on this result, this study was expanded to evaluate the inhibitory effects of acetylshikonin against nine different cytochrome P450 (P450) isoforms in human liver microsomes (HLMs) using substrate cocktails incubation assay. Acetylshikonin showed a strong inhibitory effect against all P450s tested with IC50 values of 1.4–4.0 μ m. Pre-incubation of acetylshikonin with HLMs and NADPH did not alter the inhibition potency, indicating that acetylshikonin is not a mechanism-based inhibitor. SKF-525A, a widely used non-specific P450 inhibitor, had no inhibitory activity against CYP1A2, 2A6, 2E1 and 2J2, while it showed an inhibitory effect against CYP2B6, CYP2C19 and 2D6 with IC50 values of 2.5, 3.6 and 0.5 μ m, respectively. Our findings indicate that acetylshikonin may be a novel general P450 inhibitor, which could replace SKF-525A.
- Shon, Jong Cheol,Phuc, Nguyen Minh,Kim, Won Cheol,Heo, Jae Kyung,Wu, Zhexue,Lee, Hyunyoung,Liu, Kwang-Hyeon
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- Direct Synthesis of Paracetamol via Site-Selective Electrochemical Ritter-type C-H Amination of Phenol
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The synthesis of paracetamol still relies on multistep protocols involving the utilization of a stoichiometric amount of oxidizing/reducing or other corrosive agents. Herein we report a regioselective electrochemical Ritter-type reaction at the C(sp2)-H of unprotected phenol toward the environmentally benign and direct synthesis of paracetamol. The reaction proceeds under exogenous oxidant- and catalyst-free conditions. The protocol is scalable, can be deployed to a variety of phenols, and offers a sustainable alternative for the synthesis of paracetamol.
- Banerjee, Prabal,Saha, Debarshi,Taily, Irshad Maajid
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supporting information
(2022/04/07)
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- Pyridazine N-Oxides as Photoactivatable Surrogates for Reactive Oxygen Species
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A method for the photoinduced evolution of atomic oxygen from pyridazine N-oxides was developed. This underexplored oxygen allotrope mediates arene C-H oxidation within complex, polyfunctional molecules. A water-soluble pyridazine N-oxide was also developed and shown to promote photoinduced DNA cleavage in aqueous solution. Taken together, these studies highlight the utility of pyridazine N-oxides as photoactivatable O(3P) precursors for applications in organic synthesis and chemical biology.
- Basistyi, Vitalii S.,Frederich, James H.
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supporting information
p. 1907 - 1912
(2022/03/27)
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- Efficient nitriding reagent and application thereof
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The invention discloses an efficient nitriding reagent and application thereof, wherein the nitriding reagent comprises nitrogen oxide, an active agent, a reducing agent and an organic solvent. By applying the nitriding reagent, nitrogen-containing compounds such as amide, nitrile and the like can be produced, and the method is simple in condition, low in waste discharge amount and simple in reaction equipment.
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Paragraph 0137-0139
(2021/03/31)
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- Cyclic (Alkyl)(amino)carbene Ligand-Promoted Nitro Deoxygenative Hydroboration with Chromium Catalysis: Scope, Mechanism, and Applications
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Transition metal catalysis that utilizes N-heterocyclic carbenes as noninnocent ligands in promoting transformations has not been well studied. We report here a cyclic (alkyl)(amino)carbene (CAAC) ligand-promoted nitro deoxygenative hydroboration with cost-effective chromium catalysis. Using 1 mol % of CAAC-Cr precatalyst, the addition of HBpin to nitro scaffolds leads to deoxygenation, allowing for the retention of various reducible functionalities and the compatibility of sensitive groups toward hydroboration, thereby providing a mild, chemoselective, and facile strategy to form anilines, as well as heteroaryl and aliphatic amine derivatives, with broad scope and particularly high turnover numbers (up to 1.8 × 106). Mechanistic studies, based on theoretical calculations, indicate that the CAAC ligand plays an important role in promoting polarity reversal of hydride of HBpin; it serves as an H-shuttle to facilitate deoxygenative hydroboration. The preparation of several commercially available pharmaceuticals by means of this strategy highlights its potential application in medicinal chemistry.
- Zhao, Lixing,Hu, Chenyang,Cong, Xuefeng,Deng, Gongda,Liu, Liu Leo,Luo, Meiming,Zeng, Xiaoming
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supporting information
p. 1618 - 1629
(2021/01/25)
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- Visible-light-induced direct construction of amide bond from carboxylic acids with amines in aqueous solution
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A novel visible-light-promoted N-acylation for the synthesis of amides from easily available carboxylic acids with amines in the presence of I2 within 2.5 h in aqueous solution has been developed. Using sunlight as the visible light source greatly reduces the cost of experiments and produces almost no toxic effects. Hence, this study provides an alternative catalytic system for the construction of a wide range of amides with readily available materials. Moreover, the strategy was successfully applied in the preparation of N-(3-(2,6-dimethoxyphenoxy)-7-nitroquinoxalin-2-yl)benzohydrazide, which displayed a signification anti-proliferation effect on A549, MCF-7 and HCT116 cell lines.
- Wang, Jin,Hou, Huiqing,Hu, Yongzhi,Lin, Jin,Wu, Min,Zheng, Zhiqiang,Xu, Xiuzhi
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supporting information
(2021/02/09)
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- Aluminum Metal-Organic Framework-Ligated Single-Site Nickel(II)-Hydride for Heterogeneous Chemoselective Catalysis
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The development of chemoselective and heterogeneous earth-abundant metal catalysts is essential for environmentally friendly chemical synthesis. We report a highly efficient, chemoselective, and reusable single-site nickel(II) hydride catalyst based on robust and porous aluminum metal-organic frameworks (MOFs) (DUT-5) for hydrogenation of nitro and nitrile compounds to the corresponding amines and hydrogenolysis of aryl ethers under mild conditions. The nickel-hydride catalyst was prepared by the metalation of aluminum hydroxide secondary building units (SBUs) of DUT-5 having the formula of Al(μ2-OH)(bpdc) (bpdc = 4,4′-biphenyldicarboxylate) with NiBr2 followed by a reaction with NaEt3BH. DUT-5-NiH has a broad substrate scope with excellent functional group tolerance in the hydrogenation of aromatic and aliphatic nitro and nitrile compounds under 1 bar H2 and could be recycled and reused at least 10 times. By changing the reaction conditions of the hydrogenation of nitriles, symmetric or unsymmetric secondary amines were also afforded selectively. The experimental and computational studies suggested reversible nitrile coordination to nickel followed by 1,2-insertion of coordinated nitrile into the nickel-hydride bond occurring in the turnover-limiting step. In addition, DUT-5-NiH is also an active catalyst for chemoselective hydrogenolysis of carbon-oxygen bonds in aryl ethers to afford hydrocarbons under atmospheric hydrogen in the absence of any base, which is important for the generation of fuels from biomass. This work highlights the potential of MOF-based single-site earth-abundant metal catalysts for practical and eco-friendly production of chemical feedstocks and biofuels.
- Antil, Neha,Kumar, Ajay,Akhtar, Naved,Newar, Rajashree,Begum, Wahida,Dwivedi, Ashutosh,Manna, Kuntal
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p. 3943 - 3957
(2021/04/12)
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- Amide bond formation in aqueous solution: Direct coupling of metal carboxylate salts with ammonium salts at room temperature
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Herein, we report a green, expeditious, and practically simple protocol for direct coupling of carboxylate salts and ammonium salts under ACN/H2O conditions at room temperature without the addition of tertiary amine bases. The water-soluble coupling reagent EDC·HCl is a key component in the reaction. The reaction runs smoothly with unsubstituted/substituted ammonium salts and provides a clean product without column chromatography. Our reaction tolerates both carboxylate (which are unstable in other forms) and amine salts (which are unstable/volatile when present in free form). We believe that the reported method could be used as an alternative and suitable method at the laboratory and industrial scales. This journal is
- Nielsen, John,Tung, Truong Thanh
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supporting information
p. 10073 - 10080
(2021/12/10)
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- An Environmentally Benign, Catalyst-Free N?C Bond Cleavage/Formation of Primary, Secondary, and Tertiary Unactivated Amides
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Herein, we report an operationally simple, cheap, and catalyst-free method for the transamidation of a diverse range of unactivated amides furnishing the desired products in excellent yields. This protocol is environmentally friendly and operates under extremely mild conditions without using any promoter or additives. Significantly, this strategy has been implied in the chemoselective synthesis of a pharmaceutical molecule, paracetamol, on a gram-scale with excellent yield. We anticipate that this universally applicable strategy will be of great interest in drug discovery, biochemistry, and organic synthesis.
- Kumar, Vishal,Dhawan, Sanjeev,Girase, Pankaj Sanjay,Singh, Parvesh,Karpoormath, Rajshekhar
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p. 5627 - 5639
(2021/11/11)
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- Redox-Neutral Selenium-Catalysed Isomerisation of para-Hydroxamic Acids into para-Aminophenols
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A selenium-catalysed para-hydroxylation of N-aryl-hydroxamic acids is reported. Mechanistically, the reaction comprises an N?O bond cleavage and consecutive selenium-induced [2,3]-rearrangement to deliver para-hydroxyaniline derivatives. The mechanism is studied through both 18O-crossover experiments as well as quantum chemical calculations. This redox-neutral transformation provides an unconventional synthetic approach to para-aminophenols.
- Chuang, Hsiang-Yu,Schupp, Manuel,Meyrelles, Ricardo,Maryasin, Boris,Maulide, Nuno
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supporting information
p. 13778 - 13782
(2021/03/31)
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- Ethyl 2-Cyano-2-(2-nitrobenzenesulfonyloxyimino) Acetate (ortho-NosylOXY)-Mediated Double Beckmann Rearrangement of Ketoximes under Microwave Irradiation: A Mechanistic Perception
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A method for Beckmann rearrangement using ethyl 2-cyano-2-(2-nitrobenzenesulfonyloxyimino) acetate (o-NosylOXY) under microwave irradiation is reported. Ketoximes (19 examples) are converted to the corresponding amides/lactams with 69–97% yields in ～10 minutes without any Lewis acid or co-catalyst. This is an example of halogen-free organocatalytic Beckmann rearrangement. Nuclear magnetic resonance (NMR)- and high-resolution mass spectrometry (HRMS)-based detailed mechanistic investigation suggest that o-NosylOXY acts as an initiator. Such initiators are reported before based on density functional theory (DFT) calculations. However, we report here the HRMS signatures of two transient intermediates, the nitrilium ion and the nitrilium ion's dimeric species. Rigorous NMR-based investigation of the reaction mechanism is performed. Our results indicate that the reported Beckmann rearrangement proceeds via two consecutive rearrangements. (Figure presented.).
- Dev, Dharm,Kalita, Tapasi,Mondal, Tanmay,Mandal, Bhubaneswar
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p. 1427 - 1435
(2021/01/04)
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- Beckmann rearrangement of ketoximes promoted by cyanuric chloride and dimethyl sulfoxide under a mild condition
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Synthesis of amides via Beckmann rearrangement of ketoximes promoted by cyanuric chloride (TCT)/DMSO under mild conditions has been reported. Conditions of the Beckmann rearrangement, e.g., solvents, the ratios of TCT/DMSO, and the temperature, were investigated using diphenylmethanone oxime as a substrate. The optimized conditions were adopted to afford fourteen amides with yields ranging from 20% to 99%. A plausible mechanism involving an active dimethyl alkoxysulfonium intermediate was proposed according to the mass spectrometry analysis. To our best knowledge, this is the first case of study on Beckmann rearrangement of ketoximes promoted by TCT/DMSO under a mild condition to afford amides efficiently.
- Ma, Ruonan,Chen, Xueyuan,Xiao, Zhiyin,Natarajan, Mookan,Lu, Chunxin,Jiang, Xiujuan,Zhong, Wei,Liu, Xiaoming
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supporting information
(2021/01/06)
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- Nickel-catalyzed deallylation of aryl allyl ethers with hydrosilanes
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An efficient and mild catalytic deallylation method of aryl allyl ethers is developed, with commercially available Ni(COD)2 as catalyst precursor, simple substituted bipyridine as ligand and air-stable hydrosilanes. The process is compatible with a variety of functional groups and the desired phenol products can be obtained with excellent yields and selectivity. Besides, by detection or isolation of key intermediates, mechanism studies confirm that the deallylation undergoes η3-allylnickel intermediate pathway.
- Ding, Guangni,Fan, Sijie,Wang, Jingyang,Wang, Yu,Wu, Xiaoyu,Xie, Xiaomin,Yang, Liqun,Zhang, Zhaoguo
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supporting information
(2021/09/28)
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- Dehydrative Beckmann rearrangement and the following cascade reactions
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The Beckmann rearrangement has been predominantly studied for the synthesis of amide and lactam. By strategically using the in situ generated Appel's salt or Mitsunobu's zwitterionic adduct as the dehydrating agent, a series of Beckmann rearrangement and following cascade reactions have been developed herein. The protocol allows the conversion of various ketoximes into amide, thioamide, tetrazole and imide products in modular procedures. The generality and tolerance of functionalities of this method have been demonstrated.
- Liu, Yinghui,Wei, Yongjiao,Xie, Lan-Gui
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supporting information
(2021/11/16)
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- Iron-catalyzed arene C-H hydroxylation
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The sustainable, undirected, and selective catalytic hydroxylation of arenes remains an ongoing research challenge because of the relative inertness of aryl carbon-hydrogen bonds, the higher reactivity of the phenolic products leading to over-oxidized by-products, and the frequently insufficient regioselectivity. We report that iron coordinated by a bioinspired L-cystine-derived ligand can catalyze undirected arene carbon-hydrogen hydroxylation with hydrogen peroxide as the terminal oxidant. The reaction is distinguished by its broad substrate scope, excellent selectivity, and good yields, and it showcases compatibility with oxidation-sensitive functional groups, such as alcohols, polyphenols, aldehydes, and even a boronic acid. This method is well suited for the synthesis of polyphenols through multiple carbon-hydrogen hydroxylations, as well as the late-stage functionalization of natural products and drug molecules.
- Cheng, Lu,Wang, Huihui,Cai, Hengrui,Zhang, Jie,Gong, Xu,Han, Wei
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- Method for promoting iron-catalyzed oxidation of aromatic compound carbon - hydrogen bond to synthesize phenol by ligand
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The method comprises the following steps: iron is used as - a catalyst metal; a sulfur-containing amino acid or cystine-derived dipeptide is a ligand; and under the common action of hydrogen peroxide as an oxidizing agent, an aromatic compound is synthesized to prepare a phenol. Under the action of an acid as an accelerant and hydrogen peroxide as an oxidizing agent, the aryl carbon - hydrogen bond is directly hydroxylated to form a phenolic compound, and the method for preparing the phenol by the catalytic oxidation reaction has a plurality of advantages. The reaction raw materials, the oxidant and the promoter are wide in source, low in price, environment-friendly and good in stability. The aromatic compound carbon - hydrogen bonds directly participate in the reaction to react in one step to form phenol. The reaction condition is mild, the functional group compatibility and the application range are wide. The reaction selectivity is good; under the optimized reaction conditions, the target product separation yield can reach 85%.
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Paragraph 0080-0081; 0128
(2021/09/21)
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- Magnetically recyclable silica-coated ferrite magnetite-K10montmorillonite nanocatalyst and its applications in O, N, and S-acylation reaction under solvent-free conditions
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Novel silica-coated ferrite nanoparticles supported with montmorillonite (K10) have been prepared successfully by using a simple impregnation method. Further, these nanoparticles were characterized by using different analytical methods like FT-IR, PXRD, EDS, and FE-SEM techniques. In addition, these nanoparticles have been explored for their catalytic activity for the O, N, and S-acylation reactions under solvent-free conditions which gave moderate to excellent yields in a much shorter reaction time. Moreover, these nanoparticles could easily be separated out from the reaction medium after the reaction completion by using an external magnetic field and have been re-used for 10 cycles without any significant loss of the catalytic activity.
- Kumar, Pushpendra,Patil, Shripad M.,Tandon, Nitin,Tandon, Runjhun
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p. 21291 - 21300
(2021/07/01)
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- Antimalarial Benzimidazole Derivatives Incorporating Phenolic Mannich Base Side Chains Inhibit Microtubule and Hemozoin Formation: Structure-Activity Relationship and in Vivo Oral Efficacy Studies
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A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure-activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.
- Dziwornu, Godwin Akpeko,Coertzen, Dina,Leshabane, Meta,Korkor, Constance M.,Cloete, Cleavon K.,Njoroge, Mathew,Gibhard, Liezl,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Wittlin, Sergio,Birkholtz, Lyn-Marie,Chibale, Kelly
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supporting information
p. 5198 - 5215
(2021/05/06)
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- Paracetamol and other acetanilide analogs as inter-molecular hydrogen bonding assisted diamagnetic CEST MRI contrast agents
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Paracetamol and a few other acetanilide derivatives are reported as a special class of diamagnetic Chemical Exchange Saturation Transfer (diaCEST) MRI contrast agents, that exhibit contrast only when the molecules form inter-molecular hydrogen bonding mediated molecular chains or sheets. Without the protection of the hydrogen bonding their contrast producing labile proton exchanges too quickly with the solvent to produce any appreciable contrast. Through a number of variable temperature experiments we demonstrate that under the conditions when the hydrogen bond network breaks and the high exchange returns back, the contrast drops quickly. The well-known analgesic drug paracetamol shows 12% contrast at a concentration of 15 mM at physiological conditions. With the proven safety track-record for human consumption and appreciable physiological contrast, paracetamol shows promise as a diaCEST agent forin vivostudies.
- Chakraborty, Subhayan,Peruncheralathan,Ghosh, Arindam
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p. 6526 - 6534
(2021/02/21)
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- Oxygen bridge bicyclo - [2.2.1] - heptene compounds containing different covalent bullet structures, and preparation and application thereof
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The invention discloses an oxygen bridge bicyclo - [2.2.1] - heptene compound containing different covalent popping structures as well as preparation and application thereof, and belongs to the technical field of targeted drugs. As shown in general formula (I) or general formula (II), furan derivatives and vinylsulfonamide derivatives or vinylsulfonate derivatives containing different covalent popping heads are prepared by reacting Diels-Alder to obtain a compound of the present invention. The compound can be used for preparing anti-breast cancer drugs. A medicament for the degradation of estrogen receptors, a medicament for a mutant estrogen receptor. Compared with the existing anti-breast cancer drug tamoxifen, MCF-7 cells have stronger inhibitory activity and have the ability to down-regulate the estrogen receptor level, and the activity shown for the mutant estrogen receptor is 4 - times of 5-10 hydroxytamoxifen.
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Paragraph 0140
(2021/11/03)
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- De novo biosynthesis and whole-cell catalytic production of paracetamol on a gram scale in Escherichia coli
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The synthetic drug paracetamol is one of the most commonly used analgesic, antipyretic agents around the world. Global massive demand promoted its synthesis in large quantities. Chemical synthesis is the main approach for paracetamol production. However, the reaction process contributes toward environmental pollution, and the reaction conditions are harsh. Herein, we reported the construction of the paracetamol de novo biosynthetic pathway in Escherichia coli. Five enzymes from different microbial sources were heterologously expressed into E. coli to construct the APAP (1) producing strain PA1. Through protein engineering of ABH (4-aminobenzoate hydroxylase) and PANAT (arylamine N-acetyltransferase), enhancement of the host cell resistance to the substrate or final product, and utilizing synthetic protein scaffolds to optimize the metabolic flux, the engineered strain could produce 942.5 mg L-1 (6.24 mM) paracetamol in a fed-batch 5 L fermenter directly from glucose or glycerol, which circumvents the fossil fuel resource use. Moreover, we established a whole-cell cascade biocatalytic synthesis way to paracetamol and analogues. Using p-aminobenzoate as the substrate, 4.2 g L-1 (27.7 mM) paracetamol can be formed after 9 h (95% conversion rate). After metabolic engineering, enzyme molecular modification, and other optimizations, we created the biotransformation strategy to manufacture paracetamol on a gram scale. This study provides a promising green and efficient alternative to the traditional chemical manufacturing method.
- Hou, Feifei,Huang, Wei,Xian, Mo
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p. 8280 - 8289
(2021/11/01)
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- Aryl phenol compound as well as synthesis method and application thereof
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The invention discloses a synthesis method of an aryl phenol compound shown as a formula (3). All systems are carried out in an air or nitrogen atmosphere, and visible light is utilized to excite a photosensitizer for catalyzation. In a reaction solvent, ArNR1R2 as shown in a formula (1) and water as shown in a formula (2) are used as reaction raw materials and react under the auxiliary action of acid to obtain the aryl phenol compound as shown in a formula (3). The ArNR1R2 in the formula (1) can be primary amine and tertiary amine, can also be steroid and amino acid derivatives, and can also be drugs or derivatives of propofol, paracetamol, ibuprofen, oxaprozin, indomethacin and the like. The synthesis method has the advantages of cheap and easily available raw materials, simple reaction operation, mild reaction conditions, high reaction yield and good compatibility of substrate functional groups. The fluid reaction not only can realize amplification of basic chemicals, but also can realize amplification of fine chemicals, such as synthesis of drugs propofol and paracetamol. The invention has wide application prospect and use value.
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Paragraph 0153-0157
(2021/05/12)
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- Electrochemical Cleavage of the Carbon-Boron Bond in p-Acetamidophenylboronic Acid at Neutral pH Conditions
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Herein, it is reported that p-acetamidophenylboronic acid can be electrolytic cleavage of the carbon-boron bond to p-acetamidophenol at an electric potential of 1.2V vs. Ag/AgCl in 100mM phosphate buffer of pH 7.4 (containing 10% acetonirile). The electro
- Fujimura, Tsutomu,Komatsu, Sachiko,Sato, Katsuhiko,Sugiyama, Kyoko,Watanabe, Kazuhiro
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p. 1206 - 1208
(2021/12/29)
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- Direct synthesis of secondary amides from ketones through Beckmann rearrangement using O-(mesitylsulfonyl)hydroxylamine
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The Beckmann rearrangement is a versatile method for the preparation of secondary amides from ketones via oxime intermediates and has been widely used in the synthesis of bioactive natural products and pharmaceuticals. Herein, we have developed a highly efficient direct method for the preparation of secondary amides and lactams from ketones using O-(mesitylsulfonyl)hydroxylamine (MSH). The reactions proceed rapidly at room temperature under mild condition without requiring any additive, and tolerate multiple functional groups. A simple aqueous work-up often furnished the products in excellent yield with high purity.
- Chandra, Dinesh,Verma, Saumya,Pandey, Chandra Bhan,Yadav, Ajay K.,Kumar, Puneet,Tiwari, Bhoopendra,Jat, Jawahar L.
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supporting information
(2020/03/23)
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- Zinc(II)-Catalyzed Synthesis of Secondary Amides from Ketones via Beckmann Rearrangement Using Hydroxylamine-O-sulfonic Acid in Aqueous Media
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A zinc(II)-catalyzed single-step protocol for the Beckmann rearrangement using hydroxylamine-O-sulfonic acid (HOSA) as the nitrogen source in water was developed. This direct method efficiently produces secondary amides under open atmosphere in a pure form after basic aqueous workup. It isenvironmentally benign and operationally simple.
- Verma, Saumya,Kumar, Puneet,Khatana, Anil K.,Chandra, Dinesh,Yadav, Ajay K.,Tiwari, Bhoopendra,Jat, Jawahar L.
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p. 3272 - 3276
(2020/11/02)
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- Beckmann rearrangement: Thiamine hydrochloride as a remarkable catalyst for one-pot synthesis of amides from ketones
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Thiamine hydrochloride catalyzed synthesis of amides from ketones including 3-acetyl coumarin via Beckmann rearrangement has been reported. The reaction is believed to involve oxime formation, cleavage of C[sbnd]C bond followed by C[sbnd]N bond formation in one-pot. Thiamine hydrochloride is stable, cheap, easy to handle and environmentally friendly.
- Mahajan, Sheena,Slathia, Nancy,Kapoor, Kamal K.
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supporting information
(2020/04/08)
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- Nitromethane as a nitrogen donor in Schmidt-type formation of amides and nitriles
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The Schmidt reaction has been an efficient and widely used synthetic approach to amides and nitriles since its discovery in 1923. However, its application often entails the use of volatile, potentially explosive, and highly toxic azide reagents. Here, we report a sequence whereby triflic anhydride and formic and acetic acids activate the bulk chemical nitromethane to serve as a nitrogen donor in place of azides in Schmidt-like reactions. This protocol further expands the substrate scope to alkynes and simple alkyl benzenes for the preparation of amides and nitriles.
- Jiao, Ning,Liu, Jianzhong,Qiu, Xu,Song, Song,Wei, Jialiang,Wen, Xiaojin,Zhang, Cheng,Zhang, Ziyao
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supporting information
p. 281 - 285
(2020/01/28)
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- Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics
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We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D2, 5-HT1A, and 5-HT2A receptors, but low affinity for the 5-HT2C and histamine H1 receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.
- Huang, Ling,Gao, Lanchang,Zhang, Xiaohua,Yin, Lei,Hu, Jintao,Song, Ting,Chen, Yin
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supporting information
(2020/09/01)
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- Chlorotropylium Promoted Conversions of Oximes to Amides and Nitriles
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Chlorotropylium chloride as a catalyst for the transformations of oximes, ketones, and aldehydes to their corresponding amides and nitriles in excellent yields (up to 99 %) and in short reaction times (mostly 10–15 min). Oximes were electrophilically attacked on the hydroxyl oxygen by chlorotropylium. The produced tropylium oxime ethers were the key intermediates, of which the ketoxime ether led to amide through Beckmann rearrangement, and the aldoxime ether led to nitrile by nitrogen base DBU assisted formal dehydration. This chlorotropylium activation protocol offered general, mild, and efficient avenues bifurcately from oximes to both amides and nitriles by one organocatalyst.
- Xu, Jiaxi,Gao, Yu,Li, Zhenjiang,Liu, Jingjing,Guo, Tianfo,Zhang, Lei,Wang, Haixin,Zhang, Zhihao,Guo, Kai
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p. 311 - 315
(2020/01/25)
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- Visible-light-induced Beckmann rearrangement by organic photoredox catalysis
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A facile and general strategy for efficient direct conversion of oximes to amides using an inexpensive organic photocatalyst and visible light is described. This radical Beckmann rearrangement can be performed under mild conditions. Various alkyl aryl ketoximes and diaryl ketoximes can be effectively converted into the corresponding amides in excellent yields.
- Tang, Li,Wang, Zhi-Lv,Wan, Hai-Lan,He, Yan-Hong,Guan, Zhi
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supporting information
p. 6182 - 6186
(2020/09/01)
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- Br?nsted Acid and H-Bond Activation in Boronic Acid Catalysis
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Boronic acid catalysis has emerged as a mild method for promoting a wide variety of reactions. It has been proposed that the mode of catalysis involves Lewis acid or covalent activation of hydroxyl groups by boron, but limited mechanistic evidence exists. In this work, representative boronic acid catalyzed reactions of alcohols and oximes have been reinvestigated. A series of control experiments with boronic and Br?nsted acids were interpreted along with correlations between their reactivity and their acidity measured by the Gutmann–Beckett method. Overall, it was concluded that the major modes of catalysis involve either dual H-bond catalysis or Br?nsted acid catalysis. Strong Br?nsted acids were shown to be generated in situ from covalent assembly of the boronic acids with hexafluoroisopropanol, explaining why the solvent had such a major impact on the reactivity. This new insight should guide the future development of boronic acid catalysis, where the diverse and solvent-specific nature of catalytic modes has been overlooked.
- Zhang, Shaofei,Leb?uf, David,Moran, Joseph
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supporting information
p. 9883 - 9888
(2020/06/10)
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- An Electrochemical Beckmann Rearrangement: Traditional Reaction via Modern Radical Mechanism
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Abstract: Electrosynthesis as a potential means of introducing heteroatoms into the carbon framework is rarely studied. Herein, the electrochemical Beckmann rearrangement, i. e. the direct electrolysis of ketoximes to amides, is presented for the first time. Using a constant current as the driving force, the reaction can be easily carried out under neutral conditions at room temperature. Based on a series of mechanistic studies, a novel radical Beckmann rearrangement mechanism is proposed. This electrochemical Beckmann rearrangement does not follow the trans-migration rule of the classical Beckmann rearrangement.
- Tang, Li,Wang, Zhi-Lv,He, Yan-Hong,Guan, Zhi
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p. 4929 - 4936
(2020/08/21)
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- Catalyst- And oxidant-free electrochemical: para -selective hydroxylation of N -arylamides in batch and continuous-flow
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Hydroxyl compounds serve as key building blocks in the preparation of biologically active natural products and drugs. Traditionally, hydroxylation of the aromatic ring is achieved using stoichiometric amounts of oxidants, which leads to low atom-economy, undesired by-products, potential explosion risk and environmental pollution. Recently, electrosynthesis has attracted increasing attention as it employs clean electrical energy to promote redox reactions avoiding the use of oxidants. However, due to the poor mass and heat transfers of batch cells, low productivity and selectivity limit its further application. Herein, we develop a catalyst-, oxidant-, acidic solvent- and quaternary ammonium salt-free electrochemical para-selective hydroxylation of N-arylamides at room temperature in batch and continuous-flow. This proposal features excellent position control and water, air and functional group tolerance. Also, it is easy to scale up with higher productivity and selectivity using a flow electrolysis cell.
- Chen, Meng-Yi,Fang, Zheng,Guo, Kai,Lin, Xin-Xin,Liu, Cheng-Kou
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supporting information
p. 6437 - 6443
(2020/11/09)
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- Synthesis of 2-Amino-1,3-dienes from Propargyl Carbonates via Palladium-Catalyzed Carbon-Nitrogen Bond Formation
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A catalytic method to synthesize 1,3,-dienes from propargylic precursors is reported. This palladium-catalyzed carbon-nitrogen bond-forming reaction furnishes 2-amino-1,3-dienes in excellent yields (up to 98%) and shows a broad tolerance to functional group diversity. The reaction has been demonstrated for over 30 amine substrates, including anilines and indoles, and proceeds under mild neutral conditions. The resulting 1,3-dienes are of great synthetic interest because of their further reaction potential.
- O'Broin, Calvin Q.,Guiry, Patrick J.
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supporting information
p. 879 - 883
(2020/02/04)
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- Environmentally benign decarboxylative: N-, O-, and S-Acetylations and acylations
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An operationally simple and general method for acetylation and acylation of a wide variety of substrates (amines, alcohols, phenols, thiols, and hydrazones) has been reported. Meldrum's acid and its derivatives have been used as an air-stable, non-volatile, cost-effective, and easy to handle acetylating/acylating agent. Easily separable byproducts (CO2 and acetone) allowed the isolation of analytically pure acetylated products without the requirement of work-up and any chromatography. This journal is
- Ghosh, Santanu,Purkait, Anisha,Jana, Chandan K.
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supporting information
p. 8721 - 8727
(2020/12/30)
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- Mechanochemical Synthesis of N-Aryl Amides from O-Protected Hydroxamic Acids
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Two robust and efficient mechanochemical protocols for the synthesis of an array of N-arylamides have been developed. This was achieved by a C?N cross-coupling between O-pivaloyl hydroxamic acids and aryl iodides or aryl boronic acids, in the presence of a stoichiometric amount of a copper mediator. The effectiveness of this method is highlighted by the high-yielding (up to 94 %), scalable (up to 8 mmol), and rapid (20 minutes) synthesis of N-aryl amides (15 examples), using a variety of deactivated and sterically encumbered substrates, whilst employing mild conditions and in the absence of solvents. In addition, it was determined that whilst the O-pivaloyl hydroxamic acid precursors can be synthesised mechanochemically, iron contamination originating from the steel jars was found to occur which can hinder the efficacy of this process. Furthermore, 3D printing was used to produce custom milling jars that could successfully accommodate a scaled-up version of the two protocols.
- Broumidis, Emmanouil,Jones, Mary C.,Lloyd, Gareth O.,Vilela, Filipe
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p. 1754 - 1761
(2020/09/02)
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- Synthesis of acetamides via oxidative C–C bond cleavage of ketones catalyzed by Cu-immobilized magnetic nanoparticles
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Copper supported on magnetite nanoparticles modified with environmentally friendly ligand tricine was devised for synthesis of acetamides via C–C oxidative cleavage of ketones with amines. The catalyst was characterized using different techniques, including Fourier transform infrared, X-ray diffraction, scannin electron microscopy, vibrating sample magnetometry, thermogravimetric analysis, and energy dispersive x-ray spectroscopy. The protocol showed relatively high yields of acetamide products. Furthermore, the magnetic recovery of the catalyst rendered the overall process fast and efficient. It was used in the reaction for six consecutive cycles with negligible loss of catalytic activity. This research is the first report of application of magnetic nanocatalysts for synthesis of acetamides from ketones of low activity through a C–C bond cleavage strategy.
- Yazdani, Elahe,Pazoki, Farzane,Salamatmanesh, Arefe,Nejad, Masoume Jadidi,Miraki, Maryam Kazemi,Heydari, Akbar
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- N-acetylation of amines in continuous-flow with acetonitrile—no need for hazardous and toxic carboxylic acid derivatives
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A continuous-flow acetylation reaction was developed, applying cheap and safe reagent, acetonitrile as acetylation agent and alumina as catalyst. The method developed utilizes milder reagent than those used conventionally. The reaction was tested on various aromatic and aliphatic amines with good conversion. The catalyst showed excellent reusability and a scale-up was also carried out. Furthermore, a drug substance (paracetamol) was also synthesized with good conversion and yield.
- Fül?p, Ferenc,Mándity, István M.,Orsy, Gy?rgy
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- Synthetic method of p-acetamidobenzoic acid
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The invention belongs to the technical field of chemical materials, and particularly relates to a synthetic method of p-acetamidobenzoic acid. The method comprises the following synthesis steps: dissolving p-aminobenzoic acid in glacial acetic acid, adding acetic anhydride while stirring, carrying out heating to 80 +/-2 DEG C, conducting a reaction for 1 +/-0.1 hour to obtain a reaction solution,and cooling and filtering the reaction solution to obtain the finished product of acetaminobenzoic acid. According to the invention, recrystallization is omitted; a filtrate is repeatedly and indiscriminately used, so problems in solvent use and solvent recovery are greatly reduced; only glacial acetic acid is used as a reaction solvent, so post-treatment only needs cooling separation, and the solvent can be directly recycled; and the finished p-acetamidobenzoic acid has yield of 96% or above and purity of 99.85%, and can be directly used as a reaction raw material for other substances.
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Paragraph 0009-0018
(2020/03/09)
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- Graphene oxide: A convenient metal-free carbocatalyst for facilitating amidation of esters with amines
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Herein, we report a graphene oxide (GO) catalyzed condensation of non-activated esters and amines, that can enable diverse amides to be synthesized from abundant ethyl esters forming only volatile alcohol as a by-product. GO accelerates ester to amide conversion in the absence of any additives, unlike other catalysts. A wide range of ester and amine substrates are screened to yield the respective amides in good to excellent yields. The improved catalytic activity can be ascribed to the oxygenated functionalities present on the graphene oxide surface which forms H-bonding with the reactants accelerating the reaction. Improved yields and a wide range of functional group tolerance are some of the important features of the developed protocol.
- Patel, Khushbu P.,Gayakwad, Eknath M.,Shankarling, Ganapati S.
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p. 2661 - 2668
(2020/02/20)
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- A scalable and green one-minute synthesis of substituted phenols
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A mild, green and highly efficient protocol was developed for the synthesis of substituted phenols via ipso-hydroxylation of arylboronic acids in ethanol. The method utilizes the combination of aqueous hydrogen peroxide as the oxidant and H2O2/HBr as the reagent under unprecedentedly simple and convenient conditions. A wide range of arylboronic acids were smoothly transformed into substituted phenols in very good to excellent yields without chromatographic purification. The reaction is scalable up to at least 5 grams at room temperature with one-minute reaction time and can be combined in a one-pot sequence with bromination and Pd-catalyzed cross-coupling to generate more diverse, highly substituted phenols.
- Elumalai, Vijayaragavan,Hansen, J?rn H.
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p. 40582 - 40587
(2020/11/18)
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- Visible Light-Induced Amide Bond Formation
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A metal-, base-, and additive-free amide bond formation reaction was developed under an organic photoredox catalyst. This green approach showed excellent functional selectivity without affecting other functional groups such as alcohols, phenols, ethers, esters, halogens, or heterocycles. This method featured a broad substrate scope, good compatibility with water and air, and high yields (≤95%). The potential utilities were demonstrated by the synthesis of important drug molecules such as paracetamol, melatonin, moclobemide, and acetazolamide.
- Song, Wangze,Dong, Kun,Li, Ming
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supporting information
p. 371 - 375
(2019/11/29)
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- Method for preparing amide by visible light-induced metal-free participation (by machine translation)
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The method for preparing the amide in the, preparation method of the novel amide disclosed by the invention has the advantages that, the reaction: conditions are mild, the 9 - reaction conditions are mild, and the yield 71%. of the reaction conditions is not lower than the reaction conditions . (by machine translation)
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Paragraph 0043-0046
(2020/02/14)
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- Cu(OTf) 2 -Catalyzed Beckmann Rearrangement of Ketones Using Hydroxylamine- O -sulfonic Acid (HOSA)
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The Beckmann rearrangement (BKR) of ketones to secondary amides often requires harsh reaction conditions that limit its practicality and scope. Herein, the Cu(OTf) 2 -catalyzed BKR of ketones under mild reaction conditions using hydroxylamine- O -sulfonic acid (HOSA), a commercial water soluble aminating agent, is described. This method is compatible with most functional groups and directly provides the desired amides in good to excellent yields.
- Anugu, Raghunath Reddy,Chandra, Dinesh,Falck, John R.,Jat, Jawahar L.,Munnuri, Sailu,Verma, Saumya
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p. 3709 - 3714
(2019/09/30)
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- An unsymmetrical covalent organic polymer for catalytic amide synthesis
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Herein, we present the first report on the Covalent Organic Polymer (COP) directed non-classical synthesis of an amide bond. An economical route has been chosen for the synthesis of APC-COP using p-aminophenol and cyanuric chloride. APC-COP acts as a smart, valuable and sustainable catalyst for efficient access to the amide bond under mild conditions at room temperature in 30 min. APC-COP exhibits selectivity towards carboxylic acids over esters. The key features of this protocol involve the variety of parameters, viz. wider substrate scope, no use of additive and recyclability, which makes this approach highly desirable in gramscale synthesis. Moreover, we have shown the practical utility of the present method in the catalytic synthesis of paracetamol.
- Yadav, Deepika,Awasthi, Satish Kumar
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p. 179 - 186
(2019/12/28)
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- Catalyst-Free Transamidation of Aromatic Amines with Formamide Derivatives and Tertiary Amides with Aliphatic Amines
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A simple catalyst- and promoter-free protocol has been developed for the transamidation of weakly nucleophilic aromatic amines with formamide derivatives and low-reactivity tertiary amides with aliphatic amines. This strategy is advantageous because no catalyst or promoters are needed, no additives are required, separation and purification is easy, and the reaction is scalable. Significantly, this strategy was further applied to synthesize several pharmaceutical molecules on a gram scale, and excellent yields were achieved.
- Yin, Jiawen,Zhang, Jingyu,Cai, Changqun,Deng, Guo-Jun,Gong, Hang
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supporting information
p. 387 - 392
(2019/01/11)
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- A non-catalyst non-promoter under the conditions of amide derivatives of aromatic amine with transfers the amine reaction
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The present invention discloses a non-catalyst under the condition of non-accelerator [...] amide derivatives of aromatic amine with transfers the amine reaction, yield of synthetic N - aryl amide derivatives. The method has a wide range of the substrate, its raw materials and cheap and easy to obtain acylation reagent, the reaction yield is high, one-step reaction, low cost, high reaction selectivity, simple operation and the like. Adopting this method can be gram scale can realize the high yield of the synthesis of drug molecules. Therefore, the method in the N - aryl amide derivatives of synthesis application field has very good application prospect. The method overcomes the existing technologies such as the reaction reagent toxicity is large, the need to use different type catalyst, synthesis method and the cost is high, more reaction steps, more byproducts and the like.
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Paragraph 0114; 0115
(2019/03/28)
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