Multi-Step Continuous-Flow Organic Synthesis: Opportunities and Challenges

Continuous-flow multi-step synthesis takes the advantages of microchannel flow chemistry and may transform the conventional multi-step organic synthesis by using integrated synthetic systems. To realize the goal, however, innovative chemical methods and techniques are urgently required to meet the significant remaining challenges. In the past few years, by using green reactions, telescoped chemical design, and/or novel in-line separation techniques, major and rapid advancement has been made in this direction. This minireview summarizes the most recent reports (2017–2020) on continuous-flow synthesis of functional molecules. Notably, several complex active pharmaceutical ingredients (APIs) have been prepared by the continuous-flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous-flow chemistry for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.     

含中介值ξ-η-ζ等式的证明方法

介绍含三个中介值ξ-η-ζ等式的几种证明方法,并结合实例加以说明.     

Strong Convergence Theorems for the Generalized Viscosity Implicit Rules of Asymptotically Nonexpansive Mappings in the Intermediate Sense in Hilbert Spaces

Abstract

The aim of this paper is to introduce the generalized viscosity implicit rules of one asymptotically nonexpansive mapping in the intermediate sense in Hilbert spaces. We obtain some strong convergence theorems under certain assumptions imposed on the parameters. We also give a numerical example to support our main results. The results obtained in this paper improve and extend many recent ones in this culture.     

Practical guide for selection of 1H qNMR acquisition and processing parameters confirmed by automated spectra evaluation

In our recent paper, a new technique for automated spectra integration and quality control of the acquired results in qNMR was developed and validated (Monakhova & Diehl, Magn. Res. Chem. 2017, doi: 10.1002/mrc.4591 ). The present study is focused on the influence of acquisition and postacquisition parameters on the developed automated routine in particular, and on the quantitative NMR (qNMR) results in general, which has not been undertaken previously in a systematic and automated manner. Results are presented for a number of model mixtures and authentic pharmaceutical products measured on 500‐ and 600‐MHz NMR spectrometers. The influence of the most important acquisition (spectral width, transmitter [frequency] offset, number of scans, and time domain) and processing (size of real spectrum, deconvolution, Gaussian window multiplication, and line broadening) parameters for qNMR was automatically investigated. Moderate modification of the majority of the investigated parameters from default instrument settings within evaluated ranges does not significantly affect the trueness and precision of the qNMR. Lite Gaussian window multiplication resulted in accuracy improvement of the qNMR output and is recommended for routine measurements. In general, given that the acquisition and processing parameters were selected based on the presented guidelines, automated qNMR analysis can be employed for reproducible high‐precision concentration measurements in practice.     

Simultaneous Determination of Acetaminophen and Phenobarbital in Suppositories by Partial Least-Squares Spectrophotometric Calibration

Abstract

The use of partial least-squares spectrophotometric calibration for the simultaneous determination of suppositories in a multicomponent formulation is presented. This method is applied to the deternination of acetaminophen and phenobarbital in suppository preparations. The results show that these components in a molar ratio of about 61:1 in suppositories have been determined simultaneously with high precision.     

Complexation Based Voltammetric Determination of Pantoprazole Sodium in Pharmaceutical Formulations and Rabbit Plasma

Square wave adsorptive stripping voltammetric (SQWASV) method has been utilized to confirm and elucidate the possible complexation reaction between pantoprazole sodium and cobalt as a transition metal in Britton‐Robinson buffer (pH=7.0). The current signal due to the oxidation process was a function of the amount of pantoprazole sodium, pH of the medium, cobalt concentration and accumulation time at the electrode surface. The oxidation peak current has varied linearly with the concentration over the range of 0.1–9.0 nM. The limit of detection was found to be 0.04 nM. The validity of the method was successfully applied for the determination of pantoprazole sodium in pharmaceutical formulations with a pharmacokinetic study in rabbit plasma. The simplicity, rapidity, sensitivity and selectivity of this method make it a very attractive alternative to the other existing methods in the quality control laboratories.     

Selective oxidation of benzyl alcohol to benzaldehyde, 1‐phenylethanol to acetophenone and fluorene to fluorenol catalysed by iron (II) complexes supported by pincer‐type ligands: Studies on rapid degradation of organic dyes

Hexacoordinated non‐heme iron complexes [Fe^II(L¹)₂](ClO₄)₂ ( 1 ) and [Fe^II(L²)₂](PF₆)₂ ( 2 ) have been synthesized using ligands L¹ = (E)‐2‐chloro‐6‐(2‐(pyridin‐2ylmethylene) hydrazinyl)pyridine and L² = (E)‐2‐chloro‐6‐(2‐(1‐(pyridin‐2‐yl)ethylidene)hydrazinyl) pyridine]. These complexes are highly active non‐heme iron catalysts to catalyze the C (sp³)?H bonds of alkanes. These iron complexes have been characterized using ESI?MS analysis and molecular structures were determined by X‐ray crystallography. ESI ? MS analysis also helped to understand the generation of intermediate species like Fe^III?OOH and Fe^IV=O. DFT and TD?DFT calculations revealed that the oxidation reactions were performed through high‐valent iron center and a probable reaction mechanism was proposed. These complexes were also utilized for the degradation of orange II and methylene blue dyes.     

Recyclable MoO3 nanobelts for photocatalytic degradation of Rhodamine B by near infrared irradiation

Molybdenum trioxide (MoO₃) represented an excellent photocatalytic performance with many applications, including degradation of organic contaminants and splitting of water. This paper presented a new route to synthesize MoO₃ nanobelts with high aspect ratios and crystallinity by a hydrothermal technique. This work showed that the as-synthesized nanobelts exhibited strong photocatalytic activity to degrade an organic dye of Rhodamine B (RhB) in aqueous solution under the exposure of the light source in the near infrared wavelength range, significantly improving the photocatalytic activity of the nanobelts. The results also showed that for a small concentration of RhB at 7.5 mg/L a complete photodegradation (for a given MoO₃ nanobelts quantity of 0.1 g) can be reached after exposing for 60 min. For all concentrations of the RhB solution, the photodegradation exhibited an exponential dependence on the exposure time followed by a sudden shutdown, but no complete photodegradation can be reached. Also, the residual quantity of RhB in solution after the photocatalytic reaction was determined by the initial RhB concentration. The photocatalytic degradation can be interpreted by the pseudo–first-order equation for the absorption of liquid/solid based on solid capacity; thus, photocatalytic degradation can be attributed to the interaction between the photoexcited electrons in the substrate and the antibonding orbital of the RhB in solution. The sudden shutdown was due to the inability of the photoexcited electrons in the substrate hopping to the antibonding orbital of RhB in the presence of the RhB intermediate products from the degraded RhB. In addition, this work showed that the photocatalytic reaction can be recovered after a thermal treatment of postreacted MoO₃ nanobelts, enhancing the utilization efficiency of the catalysis.     

Development and validation of a RP-HPLC method for Roflumilast and its degradation products

Roflumilast is a phosphodiesterase type 4 inhibitor that is administered orally as a long-term, in the clinical treatment of chronic obstructive pulmonary disease and asthma. Launched in 2010 for the European market, it currently does not have an official monograph. Here, a reproducible gradient RP-HPLC method was developed and validated for the separation and determination of Roflumilast in the presence of its six major degradation products. Separation was performed on a C₁₈ analytical column (250?×?4.6?mm, 5?µm) with a mobile phase-A of ACN and a phase-B of ammonium acetate buffer (5?mM, pH 4.2) containing triethylamine (0.5% v/v). The most effective RP-HPLC gradient program was determined to be 0/80, 35/10, 36/80, 40/80 (time in minutes/% mobile phase-B). The flow rate was 1.0?ml/min and the column temperature was 25°C. The success of separation of the degradation products with different chemical characteristics was obtained by extending the time of the gradient, changing the proportion of the mobile phases and increasing the velocity of the flow. Two detectors were evaluated for the identification of degradation products and Roflumilast: a diode-arrary detector and a charged aerosol detector. The inability of the charged aerosol detector to dectect one of the six degradation products indicated that the method developed with RP-HPLC and the diode-array detector was more suitable for Roflumilast analysis. The method was validated according to specificity, linearity, LOD, LOQ, accuracy, precision and robustness.