37350-58-6Relevant articles and documents
The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation
Rossi, Patrizia,Paoli, Paola,Chelazzi, Laura,Conti, Luca,Bencini, Andrea
, p. 87 - 96 (2019)
Metoprolol {systematic name: (RS)-1-isopropylamino-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol}, C15H25NO3, is a cardioselective β1-adrenergic blocking agent that shares part of its molecular skeleton with a large number of other β-blockers. Results from its solid-state characterization by single-crystal and variable-temperature powder X-ray diffraction and differential scanning calorimetry are presented. Its molecular and crystal arrangements have been further investigated by molecular modelling, by a Cambridge Structural Database (CSD) survey and by Hirshfeld surface analysis. In the crystal, the side arm bearing the isopropyl group, which is common to other β-blockers, adopts an all-trans conformation, which is the most stable arrangement from modelling data. The crystal packing of metoprolol is dominated by an O—H…N/N…H—O pair of hydrogen bonds (as also confirmed by a Hirshfeld surface analysis), which gives rise to chains containing alternating R and S metoprolol molecules extending along the b axis, supplemented by a weaker O…H—N/N—H…O pair of interactions. In addition, within the same stack of molecules, a C—H…O contact, partially oriented along the b and c axes, links homochiral molecules. Amongst the solid-state structures of molecules structurally related to metoprolol deposited in the CSD, the β-blocker drug betaxolol shows the closest analogy in terms of three-dimensional arrangement and interactions. Notwithstanding their close similarity, the crystal lattices of the two drugs respond differently on increasing temperature: metoprolol expands anisotropically, while for betaxolol, an isotropic thermal expansion is observed.
The synthesis of metoprolol monitored using Raman spectroscopy and chemometrics
Svensson, Olof,Josefson, Mats,Langkilde, Frans W.
, p. 141 - 155 (2000)
The synthesis of Metoprolol base was studied using Raman spectroscopy with a 785-nm laser, optical fibres, a holographic transmission grating, confocal optics and a charge-coupled device (CCD) detector. The reaction mixture was heated according to a temperature gradient and spectra of the reaction mixture were obtained by focusing the laser beam through ordinary reaction flasks. Because of overlapping bands, multivariate techniques such as principal components analysis (PCA) and partial least-squares projections to latent structures (PLS) were used in the evaluation of the obtained spectra. The use of PCA or PLS against time does not require any calibration samples and a quantitative calibration is not necessary in order to monitor the reaction. A method for reaction endpoint determination, based on euclidean distances in the score space, is presented. The use of multivariate batch control charts have been demonstrated and a number of problems and solutions regarding the sample presentation have been discussed. The effect of spectral pretreatment on the multivariate results is shown and discussed. The monitoring results show that the time to produce Metoprolol base could be reduced. Copyright (C) 2000 Elsevier Science B.V.
Method for continuously synthesizing metoprolol and salts thereof
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, (2021/04/14)
The invention discloses a method for continuously synthesizing metoram, which comprises the following steps: (1) carrying out vacuum rectification on a 1-(2, 3-epoxypropoxy)-4-(2-methoxyethyl)benzene raw material to obtain a pure product with the purity of more than 99%, and preparing the pure product into an ethanol solution; (2) uniformly mixing the ethanol solution obtained in the step (1) with isopropylamine, feeding the mixture into a pipeline reactor, and reacting to obtain a metoprolol reaction solution; and (3) depressurizing the reaction liquid, and recovering isopropylamine in a rectifying tower, wherein the tower bottom liquid contains high-purity metoprolol. The purity of the raw materials reaches 99% or above through the rectification step, and colored impurities are also removed; when metoprolol is synthesized, a rapid reaction method of large excess of isopropylamine in the pipeline reactor is adopted, so that secondary condensation side reactions are obviously reduced, and the purity of metoprolol reaches 98% or above; and after metoprolol is salified with succinic acid, a crude drug finished product with the purity larger than 99.5% can be obtained through crystallization. The method is high in yield, low in cost and easy to operate, and is an environment-friendly process route capable of realizing industrial production.
Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC
Shuang, Yazhou,Liao, Yuqin,Wang, Hui,Wang, Yuanxing,Li, Laisheng
, p. 168 - 184 (2019/11/25)
A triazole-bridged bis(β-cyclodextrin) was synthesized via a high-yield Click Chemistry reaction between 6-azido-β-cyclodextrin and 6-propynylamino-β-cyclodextrin, and then it was bonded onto ordered silica gel SBA-15 to obtain a novel triazole-bridged bis (β-cyclodextrin)–bonded chiral stationary phase (TBCDP). The structures of the bridged cyclodextrin and TBCDP were characterized by the infrared spectroscopy, mass spectrometry, elemental analysis, and thermogravimetric analysis. The chiral performance of TBCDP was evaluated by using chiral pesticides and drugs as probes including triazoles, flavanones, dansyl amino acids and β-blockers. Some effects of the composition in mobile phase and pH value on the enantioseparations were investigated in different modes. The nine triazoles, eight flavanones, and eight dansyl amino acids were successfully resolved on TBCDP under the reversed phase with the resolutions of hexaconazole, 2′-hydroxyflavanone, and dansyl-DL-tyrosine, which were 2.49, 5.40, and 3.25 within 30 minutes, respectively. The ten β-blockers were also separated under the polar organic mode with the resolution of arotinolol reached 1.71. Some related separation mechanisms were discussed preliminary. Compared with the native cyclodextrin stationary phase (CDSP), TBCDP has higher enantioselectivity to separate more analytes, which benefited from the synergistic inclusion ability of the two adjacent cavities and bridging linker of TBCDP, thereby enabling it a promising prospect in chiral drugs and food analysis.
Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
, p. 236 - 247 (2019/02/01)
The drug chirality is attracting increasing attention because of different biological activities, metabolic pathways, and toxicities of chiral enantiomers. The chiral separation has been a great challenge. Optimized high-performance liquid chromatography (HPLC) methods based on vancomycin chiral stationary phase (CSP) were developed for the enantioseparation of propranolol, atenolol, metoprolol, venlafaxine, fluoxetine, and amlodipine. The retention and enantioseparation properties of these analytes were investigated in the variety of mobile phase additives, flow rate, and column temperature. As a result, the optimal chromatographic condition was achieved using methanol as a main mobile phase with triethylamine (TEA) and glacial acetic acid (HOAc) added as modifiers in a volume ratio of 0.01% at a flow rate of 0.3?mL/minute and at a column temperature of 5°C. The thermodynamic parameters (eg, ΔH, ΔΔH, and ΔΔS) from linear van 't Hoff plots revealed that the retention of investigated pharmaceuticals on vancomycin CSP was an exothermic process. The nonlinear behavior of lnk′ against 1/T for propranolol, atenolol, and metoprolol suggested the presence of multiple binding mechanisms for these analytes on CSP with variation of temperature. The simulated interaction processes between vancomycin and pharmaceutical enantiomers using molecular docking technique and binding energy calculations indicated that the calculated magnitudes of steady combination energy (ΔG) coincided with experimental elution order for most of these enantiomers.
Light-assisted preparation of a cyclodextrin-based chiral stationary phase and its separation performance in liquid chromatography
Tang, Qi,Yu, Bing,Gao, Lilong,Cong, Hailin,Zhang, Shuai
supporting information, p. 1115 - 1120 (2018/02/06)
A cyclodextrin-based chiral stationary phase (CD-CSP) is one of the most widely applied CSPs due to its powerful enantioseparation ability. In this study, a facile method was developed to prepare a CD-CSP via carboxyl methyl β-cyclodextrin (CD-COOH) and diazo-resin (DR). Monodisperse silica particles were synthesized using a modified St?ber method. Then DR and CD-COOH were coated on the silica particles via ionic bonding successively and UV light was finally used to couple silica, DR and CD-COOH and the ionic bonds turned into covalent bonds. The resultant CD-DR silica particles were characterized using Fourier transform infrared spectroscopy (FT-IR), thermo-gravimetric analysis (TGA) and scanning electron microscopy (SEM). The enantioselectivity of the CD@SiO2 particles was explored in reversed phase high-performance liquid chromatography (RP-HPLC). Baseline separation of chiral drugs was achieved and the effects of separation parameters (elution mode, buffer and analyte mass) were investigated in detail. By using water soluble non-toxic DR to replace a highly toxic and moisture sensitive silane agent to modify silica microspheres, this light-assisted strategy can provide a green and effective technique to manufacture packing materials for enantioseparation applications.
A protein-based mixed selector chiral monolithic stationary phase in capillary electrochromatography
Xu, Shujuan,Wang, Yuying,Tang, Yixia,Ji, Yibing
supporting information, p. 13520 - 13528 (2018/08/21)
A new mixed selector chiral stationary phase (CSP) was prepared with co-immobilized human serum albumin and cellulase on a poly(glycidylmethacrylate-co-ethylene glycol dimethacrylate) (poly(GMA-co-EDMA)) monolith and the evaluation of its usefulness in chiral separation research was presented. For comparison, two single selector chiral stationary phases (CSPs) were also fabricated with the corresponding proteins. The enantioseparation ability of these CSPs was investigated by capillary electrochromatography (CEC) with various racemates. The mixed selector CSP exhibited a broader range of enantioselectivities than the single selectors and it could separate 10 chiral analytes while the two single selector CSPs resolved 3 and 8 respectively. Moreover, for (±)-warfarin, the enantioresolution was improved on the mixed selector CSP. Meanwhile, compared with the single selector CSPs, no additional preparation stage or reagent consumption was required in the simultaneous immobilization of different proteins, which is more favorable from economical and practical points of view. Consequently, by mixing HSA and cellulase together, the composite column combines the enantioselectivities of both individual proteins, thus expanding their application range practically.
Method using tartrate-polybasic acid complex to extract and separate metoprolol enantiomer
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Paragraph 0011; 0012; 0013; 0014; 0015, (2017/06/02)
The invention relates to a new method for extracting and separating metoprolol enantiomer in a chirality manner. The method has the advantages that the high selectivity of tartrate-polybasic acid complex to R type and S type metoprolol enantiomer is utilized, separation factors reaches above 2.2, the centrifuge acting force of a centrifugal extractor is utilized to strengthen mass transfer efficiency, mass transfer and reaction of the metoprolol enantiomer in water phase and organic phase are accelerated, and extraction phase and raffinate phase outlet purity and productivity are increased greatly; the problem that the common extraction technology is low in mass transfer efficiency, single-stage extraction purity and yield is solved; fast and high-selectivity separation of metoprolol can be achieved by multistage counter-flow extraction, and the method is simple in equipment and simple to operate.
Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
supporting information, p. 239 - 246 (2017/05/29)
The enantioselective potential of two polysaccharide-based chiral stationary phases for analysis of chiral structurally diverse biologically active compounds was evaluated in supercritical fluid chromatography using a set of 52 analytes. The chiral selectors immobilized on 2.5?μm silica particles were tris-(3,5-dimethylphenylcarmabate) derivatives of cellulose or amylose. The influence of the polysaccharide backbone, different organic modifiers, and different mobile phase additives on retention and enantioseparation was monitored. Conditions for fast baseline enantioseparation were found for the majority of the compounds. The success rate of baseline and partial enantioseparation with cellulose-based chiral stationary phase was 51.9% and 15.4%, respectively. Using amylose-based chiral stationary phase we obtained 76.9% of baseline enantioseparations and 9.6% of partial enantioseparations of the tested compounds. The best results on cellulose-based chiral stationary phase were achieved particularly with propane-2-ol and a mixture of isopropylamine and trifluoroacetic acid as organic modifier and additive to CO2, respectively. Methanol and basic additive isopropylamine were preferred on amylose-based chiral stationary phase. The complementary enantioselectivity of the cellulose- and amylose-based chiral stationary phases allows separation of the majority of the tested structurally different compounds. Separation systems were found to be directly applicable for analyses of biologically active compounds of interest.
Comparison of three S-β-CDs with different degrees of substitution for the chiral separation of 12 drugs in capillary electrophoresis
Wang, Zhaokun,Zhang, Qiongwen,Luo, Linda,Sun, Tiemin,Guo, Xingjie
, p. 558 - 565 (2017/08/26)
Three kinds of sulfated β-cyclodextrin (S-β-CD), including a single isomer, heptakis-6-sulfato-β-cyclodextrin (HS-β-CD), degree of substitution (DS) of 7, which was synthesized in our laboratory and another two commercialized randomly substituted mixtures, a sulfated β-cyclodextrin with DS of 7 to 11, as well as a highly sulfated-β-cyclodextrin with DS of 12 to 15, were used for the enantioresolution of 12 drugs (the β-blockers, phenethylamines, and anticholinergic agents) in capillary electrophoresis. The enantioseparation under varying concentrations of S-β-CD and background electrolyte pH were systematically investigated and compared. Based on the experimental results, the effect of the nature of S-β-CD and analyte structure on the enantioseparation is discussed.
