80-11-5Relevant academic research and scientific papers
Scalable Synthesis of β-Lactamase Inhibitor QPX7728 by Sequential Nickel-Catalyzed Boron Insertion into a Benzofuran Substrate and Enantioselective Cyclopropanation of the Resulting Vinylboronate
Boyer, Serge H.,De Vries, André H. M.,Dielemans, J. A. Hubertus,Gnahn, Matthias,Gonzalez-De-Castro, Angela,Hecker, Scott J.,Lefort, Laurent,Sch?rghuber, Julia,Steinhofer, Stefan,Zhu, Zuolin
supporting information, (2021/10/01)
We report the scalable, high-yielding, and highly selective synthesis of the β-lactamase inhibitor QPX7728 featuring two key synthetic steps: nickel-catalyzed boron insertion of benzofuran 1 followed by enantioselective cyclopropanation of the resulting cyclic vinylboronate 2. The identification of the key reagents (catalyst and chiral auxiliary) for both steps relied on the use of high-throughput experimentation. Further optimization allowed for the cost-effective and scalable production of QPX7728.
BORONIC ACID DERIVATIVES AND SYNTHESIS, POLYMORPHIC FORMS, AND THERAPEUTIC USES THEREOF
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Paragraph 0306-0308, (2021/11/13)
Disclosed herein are antimicrobial compounds, polymorphic forms, compositions, pharmaceutical compositions, the method of use and preparation thereof. Some embodiments relate to boronic acid derivatives and their use as therapeutic agents, for example, β-lactamase inhibitors (BLIs).
Efficient, scalable and economical preparation of tris(deuterium)- and 13C-labelled N-methyl-N-nitroso-p-toluenesulfonamide (Diazald) and their conversion to labelled diazomethane
Shields, Samuel W.J.,Manthorpe, Jeffrey M.
, p. 674 - 679 (2015/01/16)
A method for the preparation of multi-gramme quantities of N-methyl-d3-N-nitroso-p-toluenesulfonamide (Diazald-d3) and N-methyl-13C-N-nitroso-p-toluenesulfonamide (Diazald-13C) and their conversion to diazomethane-d2 and diazomethane-13C, respectively, is presented. This approach uses robust and reliable chemistry, and critically, employs readily commercially available and inexpensivemethanol as the label source. Several reactions of labelled diazomethane are also reported, including alkene cyclopropanation, phenolmethylation and α-diazoketone formation, as well as deuteriumscrambling in the preparation of diazomethane-d2 and subsequent methyl esterification of benzoic acid.
Continuous in situ generation, separation, and reaction of diazomethane in a dual-channel microreactor
Maurya, Ram Awatar,Park, Chan Pil,Lee, Jang Han,Kim, Dong-Pyo
supporting information; experimental part, p. 5952 - 5955 (2011/08/02)
A fierce dog: A method for the continuous in-situ on-demand generation, separation, and reaction of diazomethane in a dual-channel microreactor has been developed (see picture; Diazald=N-methyl-N-nitroso-p-toluenesulfonamide). The microchemical system allows a variety of diazomethane reactions to be performed without the most common problems of preparation, handling, transfer, and decomposition.
Photochemical activities of n-nitroso carboxamides and sulfoximides and their application to DNA cleavage
Hwu, Jih Ru,Huang, Joseph Jen Tse,Tsai, Fu-Yuan,Tsay, Shwu-Chen,Hsu, Ming-Hua,Hwang, Kuo Chu,Horng, Jia-Cherng,Ho, Ja An Annie,Lin, Chun-Cheng
scheme or table, p. 8742 - 8750 (2010/03/31)
N-Nitroso compounds containing benzene, fluorene or fluorenone rings were synthesized. Photolysis of these compounds with 312-nm UV light provided the NO species, the presence of which was corroborated by use of an EPR method and of 2phenyl-4,4,5,5-tetramethylimidazolin-loxyl 3-oxide (PTIO) as a trapping agent. During irradiation of N-methylN-nitroso-9-fluorenone carboxamide (14c) in the absence of PTIO, it underwent decomposition followed by re-combination to give the heterocyclic nitric oxide radical 15. Incorporation of intercalating moieties endowed the Nnitroso compounds with DNA-cleaving ability through single-strand scission upon UV irradiation in a phosphate buffer (pH 5.0-8.0) under aerobic conditions.
Continuous production of the diazomethane precursor JV-Methyl-N-nitroso-p- toluenesulfonamide: Batch optimization and transfer into a microreactor setup
Struempel, Michael,Ondruschka, Bernd,Stark, Annegret
experimental part, p. 1014 - 1021 (2010/04/22)
The goal of this study was to develop a continuous multistep synthesis for the preparation of N-methyl-N-nitroso-p-toluene- sulfonamide (3, MNTS, Diazald) starting from p-toluenesulfonyl chloride (1), making use of microreaction technology (MRT). MNTS is an important precursor for diazomethane, a highly reactive and selective reagent for the production of pharmaceuticals and fine chemicals. Due to the properties of the successive reaction steps (exothermic reactions, use of toxic and highly reactive reagents), it was envisaged that MRT could provide advantages when compared to its batch-wise preparation. The research strategy included preliminary batch investigations, in which the effects of the solvent system, feed concentration, relative molar ratio, temperature, and residence time were established. Starting from these results, the reactions were translated into the MRT setup. As a result, the amidation of 1 to N-methyl-p- toluenesulfonamide (2) as the first reaction step is performed continuously in >90% yield and maximum space-time yields of up to 75 kg L-1 h-1. By making use of salting-out effects, the product separates nearly quantitatively in high concentrations in organic solution from the saline-waste stream. It is continuously converted to 3 by addition of NaNO2 with quantitative conversions: yields of >90% and maximum space-time yields of up to 9 kg L-1 h-1. The method presented allows for the connection of the diazomethane precursor preparation to its continuous liberation by addition of a base, and conversion with a substrate, as previously demonstrated using MRT (Struempel, M.; On- druschka, B.; Daute, R.; Stark, A. Green Chem. 2008,10, 41).
Determination of N-NO bond dissociation energies of N-Methyl-N- nitrosobenzenesulfonamides in acetonitrile and application in the mechanism analyses on NO transfer
Zhu, Xiao-Qing,Hao, Wei-Fang,Tang, Hui,Wang, Chun-Hua,Cheng, Jin-Pei
, p. 2696 - 2708 (2007/10/03)
The heterolytic and homolytic N-NO bond dissociation energies of seven substituted N-methyl-N-nitrosobenzenesulfonamides (abbreviated as G-MNBS, G = p-OCH3, p-CH3, p-H, p-Cl, p-Br, 2,5-2Cl, m-NO2) in acetonitrile solution were evaluated for the first time by using titration calorimetry and relative thermodynamic cycles according to Hess' law. The results show that the energetic scales of the heterolytic and homolytic N-NO bond dissociation energies of G-MNBS in acetonitrile solution cover the ranges from 44.3 to 49.5 and from 33.0 to 34.9 kcal/mol for the neutral G-MNBS, respectively, which indicates that N-methyl-N-nitrosobenzenesulfonamides are much easier to release a NO radical (NO.) than to release a NO cation (NO+). The estimation of the heterolytic and homolytic (N-NO) -. bond dissociation energies of the seven G-MNBS radical anions in acetonitrile solution gives the energetic ranges of -15.8 to -12.9 and -3.1 to 1.8 kcal/mol for the (N-NO)-. bond homolysis and heterolysis, respectively, which means that G-MNBS radical anions are very unstable at room temperature and able to spontaneously or easily release a NO radical or NO anion (NO-), but releasing a NO radical is easier than releasing NO anion. These determined N-NO bond dissociation energies of G-MNBS and their radical anions have been successfully used in the mechanism analyses of NO transfer from G-MNBS to 3,6-dibromocarbazole and the reactions of NO with the substituted N-methyl-benzenesulfonamide nitranions (G-MBSN-) in acetonitrile solution.
Nitrosation and denitrosation of substituted N-methylbenzenesulfonamides. Evidence of an imbalanced concerted mechanism
Garcia-Rio, Luis,Leis, J. Ramon,Moreira, Jose A.,Norberto, Fatima
, p. 1613 - 1620 (2007/10/03)
The kinetics of the nitrosation reaction of several substituted sulfonamides and of the denitrosation of the resulting products have been studied. The denitrosation rate is first-order with respect to both the nitroso compound and acid concentration and no effect of added nucleophiles was observed. The denitrosation reaction is general-acid catalysed, with a Bronsted parameter αd, of 0.7, which is independent of the substituents on the aromatic ring. Kinetic solvent isotope effects range from kH3O+d/ kD3O+d = 1.20 ± 0.05 to 2.04 ± 0.06 for denitrosation by L3O+ and from kAHd/kADd = 1.5 ± 0.2 to 2.3 ± 0.3 for denitrosation by dichloroacetic acid, which suggest that a rate-determining proton transfer is involved in this reaction. For nitrosation reaction, the absence of catalysis by nucleophilic anions, the observed general-base catalysis (βNO = 0.3) and the substituent effects suggest a concerted nitrosation-denitrosation process. The Leffler parameters obtained for N ... H bond formation (αnuc = 0.7) as well as for N ... N=O bond breaking (αlg = 0.17) are in favour of an imbalance in the transition state (αimbalance = 0.53) with the development of a positive charge on the nitrogen adjacent to the nitroso group.
Stability and nitrosation efficiency of substituted N-methyl-N-nitrosobenzenesulfonamides
Garcia-Rio,Leis,Moreira,Norberto
, p. 756 - 760 (2007/10/03)
A series of substituted N-methyl-N-nitrosobenzenesulfonamides [2,4,6-(CH3)3, 4-CH3O, 4-CH3 4-Cl and 4-NO2] were synthesized. All of them transfer their nitroso group to N-methylaniline in a quantitative manner, the more reactive being those substituted with electron-withdrawing groups, thus resembling some of the known alkyl nitrites. Studies of their acid denitrosation and base-catalysed hydrolysis demonstrated that the nitrosobenzenesulfonamides are fairly stable in aqueous media between pH 2 and 11. Their relative stability in aqueous media together with their ability to transfer the nitroso group to nucleophiles suggest their use as excellent alternatives to alkyl nitrites in both neutral and basic media.
