Nitroaromatic Derivatives Research Articles

Simple and robust method for the synthesis of Metopimazine by utilising smile’s rearrangement. Elimination of genotoxic impurities via derivatization

A simple, efficient and scalable methodology has been developed for the synthesis of Metopimazine, a dopamine D2–receptor antagonist. Starting from nitrophenylthio substituted methylsulfonyl benzenamine subjected to simple N–formylation using formic acid followed by base–catalysed cyclization resulted the formation of 2–(methylsulfonyl)–10H–phenothiazine. This method does not involve the conventional peracid oxidation that exemplifies the formation of several oxidized species that are tedious to separate. The later derivative is proven effective in the synthesis of title active pharmaceutical ingredient via N–chloroproylation followed by treating piperidine–4–carboxamide resulted in the formation of Metopimazine in high yield. The potential genotoxic impurities such as nitroaromatic derivatives were effectively removed by reduction using simple zinc dust formic acid treatment, which effectually converts nitro derivatives into amine hydrochlorides that are water soluble. Similarly, the N–alkylation of phenothiazine derivative forms potential impurities such as the formation of N–allyl and propyl bridged dimer derivatives that are removed by effective recrystallization. This method has been scaled up and evidenced no compromise with the yield and hence can be considered as industry ready.

Design, synthesis and characterization of triphenylamine-based conjugated porous polymers as fluorescent receptors for nitroaromatic derivatives

Two series of hyperbranched conjugated polymers were synthesized via straightforward oxidative coupling polymerization, starting from star-shaped triphenylamine compounds with different internal π-spacers, each varying through the electron-withdrawing properties and rigidity. Excellent total reaction yields were achieved, exceeding 80 % under emulsion reaction conditions, particularly when employing compounds with high electron-withdrawing character (-CN). The polymers containing p-phenylene-vinylene and mixed p-phenylene (vinylene)-ethynylene structures were obtained predominantly as insoluble powders, mainly due to their fully aromatic backbone structure or highly cross-linked formed networks, and their chemical structures were validated by FT-IR analysis. Optical studies revealed that polymers synthesized under classical reaction conditions exhibited enhanced π-conjugation compared to those obtained via emulsion oxidative conditions, which was clearly reflected in a red-shift of the absorption and emission maxima. Conversely, the use of surfactants along with planar and rigid triple bonds facilitated the formation of more porous polymer networks, with the highest specific surface areas of 492 m2g-1, compared to analogous networks based on vinylene hyperbranched polymers (99 m2g-1) and (cyano)vinylene hyperbranched polymers (44 m2g-1). The fluorescence emission of these polymers as solid dispersions in chloroform, although of low intensity for the CN-containing polymers, enables them to detect the nitro-aromatic derivatives via fluorescence quenching. The dependence of both detection limit and emission quenching efficiency on the polymers backbone structure and employed synthesis method was obvious. Notably, the Stern-Volmer quenching constant (KSV) was highest for TNP, reaching 17.9 × 103 M-1 in the case of p-phenylene-vinylene polymer synthesized under emulsion reaction conditions, indicating promising avenues for the development of solid-state fluorescence sensors.

Electrocatalytic, Sm‐Promoted Synthesis of Aminoarenes from Nitroaromatic Derivatives in MeOH

A new mild and chemoselective method for the preparation of various aminoarenes is described, based on the electrochemical catalytic reduction of nitroaryl derivatives promoted by samarium salts in methanol. The reactions are carried out in air, in an undivided electrochemical cell, at room temperature and tolerate a wide range of functional groups, including some reducible ones, without leading to by‐products. This procedure is also effective for the complete reduction of challenging substrates, namely those capable of coordinating metals, traditionally leading to the need for drastic conditions in terms of pressure, reaction time or temperature. 47 examples are described, including one nitroalkane, and all lead to the targeted reduced product in yields that are almost always over 90%.

Surface Deposition of Magnesium Ferrite-Based Supports with Bimetallic Gold/Silver Nanoparticles for the Catalytic Reduction of Nitroaromatics.

Surface deposition of magnesium ferrite nanoparticles (MgFe2O4 NPs) with bimetallic gold/silver (Au/Ag) nanoparticles was conducted using the seed-mediated growth method to obtain magnetic-metallic composite catalysts for use in the catalytic reduction of nitroaromatics. Two types of amine-functionalized MgFe2O4 and MgFe2O4@SiO2 NPs were used as magnetic supports for the surface deposition process. The combination of several characterization analyses (i.e., XRD, XPS, TEM, SEM, EDS, and VSM) confirmed the successful syntheses of the MgFe2O4/Au/Ag and MgFe2O4@SiO2/Au/Ag NPs. The catalytic reduction of 4-nitrophenol using sodium borohydride as a reducing agent revealed that the reaction was completed within 2 min by using MgFe2O4/Au/Ag and MgFe2O4@SiO2/Au/Ag NPs as catalysts. The appearance rate constant of the MgFe2O4/Au/Ag NPs was slightly higher than that of the MgFe2O4@SiO2/Au/Ag NPs. In terms of reusability, high conversion (>80%) of the reduction of 4-nitrophenol was still obtained after 7 and 10 consecutive cycles for the MgFe2O4/Au/Ag and MgFe2O4@SiO2/Au/Ag catalysts, respectively. Interestingly, these two catalysts exhibited the highly catalytic conversion of the chosen nitroaromatic derivatives (i.e., 4-nitrobenzaldehyde and 4-nitroaniline). On the whole, the MgFe2O4/Au/Ag and MgFe2O4@SiO2/Au/Ag NPs could be utilized as suitable and sustainable catalysts for the catalytic reduction of nitroaromatics due to several desirable features (i.e., high activity, facile and rapid separation by a magnet, and good reusability).

Access to carbonyl compounds via the electroreduction of N-benzyloxyphthalimides: Mechanism confirmation and preparative applications

A method to access carbonyl compounds using reductive conditions was evaluated via electrochemical reduction of their corresponding N-benzyloxyphthalimide derivatives (NBOPIs). The mechanism of this originally reported electrochemical reaction was proposed based on DFT calculation and is experimentally confirmed herein, contrasting simulated and experimental cyclic voltammetry data. The reaction scope studied in a preparative scale and using redox sensitive functional groups showed good selectivity and tolerance toward oxidation under the reaction conditions with a moderate to good yield (50–71%). Nevertheless, some restrictions with reducible functional groups, like benzyl-brominated and nitro-aromatic derivatives, were observed. The present approach can be considered a self-sustainable electrochemical catalysis for the synthesis of aromatic carbonylic compounds passing through anion radical intermediates produced by a cathodic reaction.

Tandem catalytic hydrogen gas generation and reduction of nitro aromatic derivatives via hydrolysis of ammonia borane over Ag NPs@ZIF-8 nanocomposites in aqueous media

In this research, three composites composed of ZIF-8 metal–organic framework and silver nanoparticles (Ag NPs) with different mole ratios were successfully synthesized. The fabricated Ag NPs@ZIF-8 composites were characterized by Fourier-transform infrared spectroscopy (FT-IR), powder X-ray diffraction (PXRD), energy-dispersive X-ray (EDX) mapping, field emission scanning electron microscopy (FE-SEM), and transmission electron microscopy (TEM) techniques. The composite Ag NPs@ZIF-8 (1:1 mol ratio) was also characterized by Brunauer–Emmett–Teller (BET) and X-ray photoelectron spectroscopy (XPS) analyses. Catalytic activity of the Ag NPs@ZIF-8 composites in tandem hydrogen generation from ammonia borane (H3N-BH3) and reduction of nitro-aromatic derivatives was investigated in one-pot reactions. The rate of evaluated H2 gas from the hydrolysis of H3N-BH3 by the Ag NPs@ZIF-8 (1:1) composite was measured to be about 198.9 (mL/g−1.min−1) in these catalytic reactions. Various derivatives of nitro compounds, including electron-withdrawing and electron-donating groups were converted to the corresponding amines with excellent yields by this catalytic system in less than one hour.

Tuning Electrochemical Properties of Nitroaromatic Cathodes by Function‐Oriented Design for Rechargeable Lithium‐Ion Batteries

AbstractRechargeable lithium‐ion batteries (LIBs) based on organic cathodes are an attractive alternative energy storage technology owing to the low cost and sustainability. Recently, nitro functionality in dinitrobenzenes is successfully demonstrated as an electrochemically reversible high‐capacity redox group. In this study, a function‐oriented design is employed to further disclose the effects of substituting functional groups and molecular conjugate structures on electrochemical properties of a range of nitroaromatic derivatives as organic cathodes for rechargeable LIBs. In specific, it is revealed that the redox potential of nitroaromatic cathodes can be effectively adjusted by introducing distinct electronically inducible functional groups, while the cyclic life can be significantly prolonged with the introduction of the hydrophilic groups. When constructed with extended π‐conjugated structures, the electronic conductivity and electrochemical kinetics of nitroaromatics are increased significantly owing to their various long‐range π–π stacking. Moreover, density‐functional theory calculations further provide theoretical insights into the distinct electrochemical behaviors of the various nitroaromatics in the molecular level. This is the first study that reveals the influences of substituting groups and conjugated structures on the electrochemical performance of nitroaromatic cathode materials, which enables a function‐oriented molecular design of such organic materials and sheds light on their future development.

Gold Nanoparticles Immobilized in Porous Aromatic Frameworks with Abundant Metal Anchoring Sites as Heterogeneous Nanocatalysts.

Porous aromatic frameworks (PAFs) with rich metal coordination sites are highly effective support materials for gold nanoparticles (AuNPs), which would not only prevent AuNPs agglomeration but also facilitate mass transfer during the catalytic process. In this work, PAF-160, -161, and -162 bearing diphosphine units are synthesized via the Friedel-Crafts alkylation reaction to act as efficient platforms for AuNPs immobilization. These PAFs possess high surface areas (up to 655 m2 g-1) together with excellent stabilities, and the different linkage lengths between P centers allow more scattered and accessible sites for gold coordination. In the resultant Au-PAFs, AuNPs with uniform sizes are stabilized dispersedly. The catalytic performances of these Au-PAFs are monitored by the reduction of 4-nitrophenol (4-NP), and all materials exhibit excellent catalytic activities on the reduction of 4-NP, especially Au-PAF-162 with the apparent rate constant (kapp) up to 0.019 s-1. Additionally, the reductions of various nitroarenes with different functional groups are explored and all Au-PAFs can convert most nitroaromatic derivatives to the corresponding arylamines with high conversions of 99%, in which the reaction mechanism is also proposed. Furthermore, a continuous catalytic device with Au-PAF-160 catalyst is explored, and Au-PAF-160 can convert 1-chloro-4-nitrobenzene, 2,6-dichoronitrobenzene and 1-chloro-2,4-dinitrobenzene into the corresponding amines in sequence in the continuous flow catalytic experiments. This work has enriched the variety of porous materials for noble metal immobilization and promotes their applications in heterogeneous catalysis.

Effect of kinetics on the photocatalytic degradation of acetaminophen and the distribution of major intermediate with anatase-Ag synthesized by sol gel under visible irradiation

The degradation of acetaminophen (ACET) was studied with TiO2-Ag catalysts, whose predominant crystalline phase was anatase, synthesized by the sol–gel method and doped by photo-deposition under UV radiation with silver particles. The catalyst was characterized by energy dispersive X-ray fluorescence (EDXRF) and X-ray diffraction (DRX). The acetaminophen degradation was determined by high-performance liquid chromatography (HPLC) and total organic carbon (TOC). The reaction behavior was studied under the Langmuir–Hinshelwood (LH-HW) equation and in a TOC-based model. With the experimental data, mass balances were performed to introduce the constants (reaction and adsorption kinetics) to the LH-HW equation. With the analysis of the generation and consumption behavior of the organic intermediate compounds (OI), coupled differential equations were generated, which express the degradation and formation-consumption behavior. The kinetic constants were obtained by nonlinear regression using the Levenberg–Marquardt equation. The results show high removal percentages, and the behavior of the experimental data is assumed to fit the LH-HW equation. The analysis of the organic intermediates by solid phase micro-extraction (SPE), HPLC and gas chromatography (CG-MS), shows that the transformation is feasible under the formation of nitro-aromatic derivatives and hydroxylated species.

Dual-Purpose CuFe2O4-rGO-Based Nanocomposite for Asymmetric Flexible Supercapacitors and Catalytic Reduction of Nitroaromatic Derivatives.

Energy storage and environmental pollution are two major global concerns in today’s scenario. As a result of the momentous exhaustion of fossil fuels, the generation of energy from renewable sources is gaining immense importance. However, the irregular availability of energy from these renewable sources is the major encounter to achieve sustainable energy harvesting technology, yielding efficient but continuous and reliable energy supplies. Apart from the requirement of state-of-the-art heavy-duty technologies such as transportation, defense, etc., in the modern lifestyle to fulfill the demand for flexible electronic devices, the development of high-performance mechanically flexible all-solid-state supercapacitors is increasing massively. On the other hand, to cater to the need for accessibility of clean water for healthy lives, several technologies are evolving to treat wastewater and groundwater. Hence, the development of efficient catalysts for destroying water pollutants is an attractive approach. Considering these two crucial facets, in this paper, we have demonstrated the multifunctional features of a CuFe2O4-rGO nanocomposite, which was exploited to fabricate a high-performance mechanically flexible all-solid-state asymmetric supercapacitor and simultaneously used as an efficient but easily recoverable catalyst for the transformation of different nitroaromatic compounds. We have also demonstrated the conversion of trifluralin (a herbicide), which is present in the water body as a pollutant, to its corresponding amine derivatives, which can be utilized in the preparation of important pharmaceutical products.

Electrochemical Reduction of 4‐Nitrobenzyl Phenyl Thioether for Activation and Capture of CO2

AbstractIn this work, a new simple molecule, 4‐nitrobenzyl phenyl thioether (1), is prepared and used for controlling and tuning CO2 reactivity in function of the electrode potential. The first part of the study is devoted to determining the electrochemical reduction mechanism of 1 in N,N‐dimethylformamide under nitrogen. The compound shows a first reversible one‐electron transfer process, whereas the reaction cleavage of the C−S bond takes place after a second electron transfer process through a stepwise mechanism (thermodynamic and kinetic parameters are conveniently determined). In the second part of the study, the inert atmosphere was replaced by a CO2 atmosphere. At low potential values, compound 1 acts as a redox mediator that allows the reduction of CO2 at ca. −1.2 V vs. SCE. The electrochemical generation of 12− at more negative potential values leads to a C−S bond cleavage reaction that yields the corresponding nitrobenzyl and thiosulfate anions, which react with CO2. The nitro aromatic anion derivative makes it possible to obtain electrocarboxylated derivatives, whereas the thiophenolate anion captures CO2 reversibly. Hence, this research opens a new way of tuning and controlling the reaction processes associated with CO2 from homogenous catalysis at low negative potentials, to electrocarboxylation processes passing to CO2 reversible electrochemically triggered adsorption processes.

Protonation- and electrostatic-interaction-based fluorescence probes for the selective detection of picric acid (2,4,6-trinitrophenol) – an explosive material

Picric acid, due to its low pKa value, possesses distinct physicochemical features from all other nitroaromatic derivatives, enabling the design of fluorescent probes for its sensitive and selective detection.

Synthesis of Melamine‐Formaldehyde Microcapsules Containing Polyfluorene for Fluorescent Detection of Picric Acid in Aqueous Medium

To detect nitroaromatic picric acid (PA) in water, polyfluorene (PF) encapsulated melamine‐formaldehyde microcapsules (PF@MFMs) were fabricated via in situ polymerizations. Because of the microcapsule structure, PF@MFMs were uniformly dispersed in water maintaining the blue fluorescence of PF in the capsules. The fluorescence intensity of PF@MFMs linearly decreased with increase in the PA concentrations with high limit of detection of 3.0 × 10−6 M. The addition of other nitroaromatic derivatives, which had structure similar to PA, or various ions did not affect the fluorescence of PF@MFMs, showing high specificity of the microcapsules toward PA.

8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

An antikinetoplastid pharmacomodulation study was done at position 8 of a previously identified pharmacophore in 3-nitroimidazo[1,2-a]pyridine series. Twenty original derivatives bearing an alkynyl moiety were synthesized via a Sonogashira cross-coupling reaction and tested in vitro, highlighting 3 potent (40 nM ≤ EC50 blood stream form≤ 70 nM) and selective (500 ≤ SI ≤ 1800) anti-T. brucei brucei molecules (19, 21 and 22), in comparison with four reference drugs. Among these hit molecules, compound 19 also showed the same level of activity against T. cruzi (EC50 amastigotes = 1.2 μM) as benznidazole and fexinidazole. An in vitro comet assay showed that nitroaromatic derivative 19 was not genotoxic. It displayed a low redox potential value (−0.68 V/NHE) and was shown to be bioactivated by type 1 nitroreductases both in Leishmania and Trypanosoma. The SAR study indicated that an alcohol function improved aqueous solubility while maintaining good activity and low cytotoxicity when the hydroxyl group was at position beta of the alkyne triple bond. Hit-compound 19 was also evaluated regarding in vitro pharmacokinetic data: 19 is BBB permeable (PAMPA assay), has a 16 min microsomal half-life and a high albumin binding (98.5%). Moreover, compound 19 was orally absorbed and was well tolerated in mouse after both single and repeated administrations at 100 mg/kg. Its mouse plasma half-life (10 h) is also quite encouraging, paving the way toward further efficacy evaluations in parasitized mouse models, looking for a novel antitrypanosomal lead compound.

Electrochemical Tuning of CO2 Reactivity in Ionic Liquids Using Different Cathodes: From Oxalate to Carboxylation Products

There is currently quite a lot of scientific interest in carbon dioxide (CO2) capture and valorization with ionic liquids (ILs). In this manuscript, we analyze the influence of the potential applied, the nature of the cathode and the electrolyte using different organic mediators, such as nitro or cyano aromatic derivatives, to promote the electrochemical activation of CO2. An electrocatalytic process using a homogeneous catalysis is seen when nitroderivatives are used, yielding to oxalate in organic electrolytes and ILs. Turnover frequency (TOF) values and Farafay efficiencies were slightly higher in N,N’-dimethylformamide (DMF) than in ILs probably due to the viscosity of the electrolyte. The use of cyano derivatives allows to tune the electrochemical reactivity in function of the reduction potential value applied from electrocarboxylated products (via a nucleophile-electrophile reaction) to oxalate. These electrochemical reactions were also performed using three different cathodes, organic electrolytes and ionic liquids. The use of copper, as a cathode, and ionic liquids, as electrolytes, would be a cheaper and greener alternative for activating carbon dioxide.

A spirobifluorene-based supramolecular polymer: Solvent-induced SCSC transformation and fluorescent sensing

Three crystalline supramolecular polymers (SPs), [(TCPSBF)·(C4H8O2)3]n (intermediate), [(TCPSBF)·(C4H8O2)2]n (UPC-S3) and [(TCPSBF)0.5]n (UPC-S4), were constructed by solvent diffusion method based on 2,2′,7,7′-tetrakis(4- cyanophenyl)-9,9′-spirobi-[9H-fluorene] (TCPSBF). Interestingly, single crystal diffraction and PXRD analyses display the solvent-induced single-crystal-to-single-crystal (SCSC) transformation among three SPs. The unstable intermediate crystal gradually changes to UPC-S3 with the loss of a lattice dioxane molecule at room temperature, and UPC-S3 may be further transformed into UPC-S4 with the loss of the other two lattice dioxane molecules by solvent soaking. Meanwhile, the intermediate crystal can also be directly transformed into UPC-S4 by solvent soaking. As a result, UPC-S4 exhibits highly thermal and chemical stability. The fluorescent spectrum tests show that UPC-S4 possesses potential applications not only in the detecting of small molecules including n-hexane and nitroaromatic derivatives, but also in selective sensing of Fe3+.

Structure-Activity Relationships of Cinnamate Ester Analogues as Potent Antiprotozoal Agents.

Protozoal infections are still a global health problem, threatening the lives of millions of people around the world, mainly in impoverished tropical and sub‐tropical regions. Thus, in view of the lack of efficient therapies and increasing resistances against existing drugs, this study describes the antiprotozoal potential of synthetic cinnamate ester analogues and their structure‐activity relationships. In general, Leishmania donovani and Trypanosoma brucei were quite susceptible to the compounds in a structure‐dependent manner. Detailed analysis revealed a key role of the substitution pattern on the aromatic ring and a marked effect of the side chain on the activity against these two parasites. The high antileishmanial potency and remarkable selectivity of the nitro‐aromatic derivatives suggested them as promising candidates for further studies. On the other hand, the high in vitro potency of catechol‐type compounds against T. brucei could not be extrapolated to an in vivo mouse model.

Fluorescence quenching study of a block copolymer with uracil end units by means of nitroaromatic derivatives and metal cations

The fluorescent uracil-poly(methyl methacrylate)-block-poly(vinyl acetate) block copolymer (Ur-PMMA-b-PVAc) was synthesized by atom transfer radical polymerization (ATRP) to be tested as sensor. This block copolymer was characterized through specific techniques (FT-IR, 1H and 13C NMR, GPC, TGA, DTG) and its fluorescence behaviour at the addition of nitroderivatives and metal ions was followed in solution, the best results being obtained especially for picric acid (Clim ≈ 8 × 10−7 M) and Fe3+ (Clim ≈ 4 × 10−6 M). Also, the quenching mechanism was investigated by Stern-Volmer equation, observing that the resulted plots showed a positive deviation from linearity, demonstrating that the quenching is due to a combination of static and dynamic processes.

Electrocatalytic oxidation of NADH in a new nanostructured interface with an entrapped butylpyrene nitroaromatic derivative

In a previous study, we revealed a new way to modify multi-walled carbon nanotubes (MWCNTs) with 3,5-dinitrobenzoic acid (35DNB). Furthermore, we proved that a 35DNB-MWCNTGC electrode efficiently catalysed the oxidation of NADH. In this paper, with the aim of obtaining a stronger bond of the electrocatalytic mediator 35DNB with the MWCNTs, we have synthesized a modified compound of 35DNB. The modification consisted of adding a 4-(piren-1-yl)butyl terminal to 35DNB to form 4-(pyren-1-yl)butyl 3,5-dinitrobenzoate (35DNBpy). The synthesis of 35DNBpy was obtained with a yield of 78.3% (mp=202–204°C). With this change, we improved the electrocatalytic activity by several oxidation cycles, conferring electrocatalytic stability.The preparation and modification of electrodes with carbon nanotubes and 35DNBpy is fast and simple. The electrochemical study was performed by cyclic voltammetry in 3mM NADH solutions. Oxidation of NADH occurs at 0.1 (V vs Ag/AgCl) in aqueous media at pH7 and the same electrode can be used for up to 50min.In this work, the electrocatalytic activity of new modified electrodes with MWCNTs and 35DNBpy is reported. The electrocatalytic activity was evaluated by cyclic voltammetry. The electrocatalytic capacity of the electrode and the heterogeneous electron transfer rate constant were calculated.Sensitivity of the modified electrode 35DNBpy/MWCNT/GCE is measured by voltammetric method which showed linear variation with NADH concentration with limit of detection (LOD) and sensitivity of 0.885μM (3S/N) and 0.33μA/μM, respectively.

Novel 8-nitroquinolin-2(1H)-ones as NTR-bioactivated antikinetoplastid molecules: Synthesis, electrochemical and SAR study

To study the antiparasitic 8-nitroquinolin-2(1H)-one pharmacophore, a series of 31 derivatives was synthesized in 1–5 steps and evaluated in vitro against both Leishmania infantum and Trypanosoma brucei brucei. In parallel, the reduction potential of all molecules was measured by cyclic voltammetry. Structure-activity relationships first indicated that antileishmanial activity depends on an intramolecular hydrogen bond (described by X-ray diffraction) between the lactam function and the nitro group, which is responsible for an important shift of the redox potential (+0.3 V in comparison with 8-nitroquinoline). With the assistance of computational chemistry, a set of derivatives presenting a large range of redox potentials (from −1.1 to −0.45 V) was designed and provided a list of suitable molecules to be synthesized and tested. This approach highlighted that, in this series, only substrates with a redox potential above −0.6 V display activity toward L. infantum. Nevertheless, such relation between redox potentials and in vitro antiparasitic activities was not observed in T. b. brucei. Compound 22 is a new hit compound in the series, displaying both antileishmanial and antitrypanosomal activity along with a low cytotoxicity on the human HepG2 cell line. Compound 22 is selectively bioactivated by the type 1 nitroreductases (NTR1) of L. donovani and T. brucei brucei. Moreover, despite being mutagenic in the Ames test, as most of nitroaromatic derivatives, compound 22 was not genotoxic in the comet assay. Preliminary in vitro pharmacokinetic parameters were finally determined and pointed out a good in vitro microsomal stability (half-life > 40 min) and a 92% binding to human albumin.