- The solid-state structure of the β-blocker metoprolol: a combined experimental and in silico investigation
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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.
- Rossi, Patrizia,Paoli, Paola,Chelazzi, Laura,Conti, Luca,Bencini, Andrea
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Read Online
- The synthesis of metoprolol monitored using Raman spectroscopy and chemometrics
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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.
- Svensson, Olof,Josefson, Mats,Langkilde, Frans W.
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Read Online
- Method for continuously synthesizing metoprolol and salts thereof
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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.
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Paragraph 0032-0034; 0036-0038; 0040-0042; 0044-0046
(2021/04/14)
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- Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC
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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.
- Shuang, Yazhou,Liao, Yuqin,Wang, Hui,Wang, Yuanxing,Li, Laisheng
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p. 168 - 184
(2019/11/25)
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- Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
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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.
- Li, Jiaxi,Liu, Ruixia,Wang, Liyang,Liu, Xiaoling,Gao, Hongjie
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p. 236 - 247
(2019/02/01)
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- Light-assisted preparation of a cyclodextrin-based chiral stationary phase and its separation performance in liquid chromatography
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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.
- Tang, Qi,Yu, Bing,Gao, Lilong,Cong, Hailin,Zhang, Shuai
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supporting information
p. 1115 - 1120
(2018/02/06)
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- A protein-based mixed selector chiral monolithic stationary phase in capillary electrochromatography
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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.
- Xu, Shujuan,Wang, Yuying,Tang, Yixia,Ji, Yibing
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supporting information
p. 13520 - 13528
(2018/08/21)
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- Method using tartrate-polybasic acid complex to extract and separate metoprolol enantiomer
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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.
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Paragraph 0011; 0012; 0013; 0014; 0015
(2017/06/02)
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- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
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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.
- Kucerova, Gabriela,Kalikova, Kveta,Tesarova, Eva
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supporting information
p. 239 - 246
(2017/05/29)
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- Comparison of three S-β-CDs with different degrees of substitution for the chiral separation of 12 drugs in capillary electrophoresis
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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.
- Wang, Zhaokun,Zhang, Qiongwen,Luo, Linda,Sun, Tiemin,Guo, Xingjie
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p. 558 - 565
(2017/08/26)
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- Solvent-Directed Epoxide Opening with Primary Amines for the Synthesis of β-Amino Alcohols
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An efficient synthesis of β-amino alcohols from a variety of epoxides and primary unbranched amines in the absence of any catalyst in high yields and regioselectivities is reported. A variety of polar mixed solvent systems allow for the selective formation of secondary amino alcohols over tertiary amino alcohols. The reaction scope extends to a wide variety of aromatic and aliphatic substituted epoxides and primary amines bearing complex functionality.
- Lizza, Joseph R.,Moura-Letts, Gustavo
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supporting information
p. 1231 - 1242
(2017/03/11)
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- Preparation method of metoprolol
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The invention discloses a preparation method of metoprolol. The method comprises the following steps: firstly, preparing p-hydroxyphenylethyl methyl ether and sodium hydroxide solution into an alkalescence solution, heating the alkalescence solution, mixing with heated epoxy chloropropane, and introducing into an extracting tower type reactor for reaction; meanwhile, introducing methylbenzene into the extracting tower type reactor for extraction, pumping reaction liquid into a rectifying tower after the reaction liquid enters a receiving groove, enabling the methylbenzene steamed out of the upper part of the rectifying tower and a small quantity of the epoxy chloropropane to enter the extracting tower type reactor from the bottom for continuous reaction, thus obtaining an intermediate (II) at the bottom of the rectifying tower, and then carrying out ammonolysis reaction on the intermediate (II) and isopropylamine, thus obtaining the metoprolol. The method provided by the invention is simple and environment-friendly in operation, the dosage of alkali is accurately controlled by adjusting a pH value, and thus the open-loop side reaction on the epoxy chloropropane and the intermediate is reduced. In addition, by adopting the tower-type continuous reaction, the time is shortened by a large margin, and the dosage of the epoxy chloropropane is reduced, so that the open-loop side reaction is correspondingly reduced, and the quality and yield of a product are improved.
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Paragraph 0031; 0033; 0034; 0037; 0040
(2017/07/23)
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- Effect of basic and acidic additives on the separation of some basic drug enantiomers on polysaccharide-based chiral columns with acetonitrile as mobile phase
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The separation of enantiomers of 16 basic drugs was studied using polysaccharide-based chiral selectors and acetonitrile as mobile phase with emphasis on the role of basic and acidic additives on the separation and elution order of enantiomers. Out of the studied chiral selectors, amylose phenylcarbamate-based ones more often showed a chiral recognition ability compared to cellulose phenylcarbamate derivatives. An interesting effect was observed with formic acid as additive on enantiomer resolution and enantiomer elution order for some basic drugs. Thus, for instance, the enantioseparation of several β-blockers (atenolol, sotalol, toliprolol) improved not only by the addition of a more conventional basic additive to the mobile phase, but also by the addition of an acidic additive. Moreover, an opposite elution order of enantiomers was observed depending on the nature of the additive (basic or acidic) in the mobile phase.
- Gogaladze, Khatuna,Chankvetadze, Lali,Tsintsadze, Maia,Farkas, Tivadar,Chankvetadze, Bezhan
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p. 228 - 234
(2015/03/18)
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- Continuous and convergent access to vicinyl amino alcohols
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Five active pharmaceutical ingredients (APIs) containing the vicinyl amino alcohol moiety were synthesized using a convergent chemical assembly system. The continuous system is composed of four flow reaction modules: biphasic oxidation, Corey-Chaykovsky epoxidation, phenol alkylation, and epoxide aminolysis. Judicious choice of reagents and module order allowed for two classes of β-amino alcohols, aryl and aryloxy, to be synthesized in good (27-69%) overall yields.
- Nobuta, Tomoya,Xiao, Guozhi,Ghislieri, Diego,Gilmore, Kerry,Seeberger, Peter H.
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supporting information
p. 15133 - 15136
(2015/10/12)
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- Asymmetric hydrolytic kinetic resolution with recyclable polymeric Co(iii)-salen complexes: A practical strategy in the preparation of (S)-metoprolol, (S)-toliprolol and (S)-alprenolol: Computational rationale for enantioselectivity
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A series of chiral polymeric Co(iii)-salen complexes based on a number of achiral and chiral linkers were synthesized and their catalytic performances were assessed in the asymmetric hydrolytic kinetic resolution of terminal epoxides. The effects of the linker were judiciously studied and it was found that in the case of the chiral BINOL-based polymeric salen complex 1, there was an enrichment in catalyst reactivity and enantioselectivity of the unreacted epoxide, particularly in the case of short as well as long chain aliphatic epoxides. Good isolated yields of the unreacted epoxide (up to 46% compared to 50% theoretical yield) along with high enantioselectivity (up to 99%) were obtained in most cases using catalyst 1. Further studies showed that catalyst 1 could retain its catalytic activity for six cycles under the present reaction conditions without any significant loss in activity or enantioselectivity. To show the practical applicability of the above synthesized catalyst we have synthesised some potent chiral β-blockers in moderate yield and high enantioselectivity using complex 1. The DFT (M06-L/6-31+G??//ONIOM(B3LYP/6-31G?:STO-3G)) calculations revealed that the chiral BINOL linker influences the enantioselectivity achieved with Co(iii)-salen complexes. Further, the transition state calculations show that the R-BINOL linker with the (S,S)-Co(iii)-salen complex is energetically preferred over the corresponding S-BINOL linker with the (S,S)-Co(iii)-salen complex for the HKR of 1,2-epoxyhexane. The role of non-covalent C-H?π interactions and steric effects has been discussed to control the HKR reaction of 1,2-epoxyhexane.
- Roy, Tamal,Barik, Sunirmal,Kumar, Manish,Kureshy, Rukhsana I.,Ganguly, Bishwajit,Khan, Noor-Ul H.,Abdi, Sayed H. R.,Bajaj, Hari C.
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p. 3899 - 3908
(2015/02/19)
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- Predictability of enantiomeric chromatographic behavior on various chiral stationary phases using typical reversed phase modeling software
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Pharmaceutical companies worldwide tend to apply chiral chromatographic separation techniques in their mass production strategy rather than asymmetric synthesis. The present work aims to investigate the predictability of chromatographic behavior of enantiomers using DryLab HPLC method development software, which is typically used to predict the effect of changing various chromatographic parameters on resolution in the reversed phase mode. Three different types of chiral stationary phases were tested for predictability: macrocyclic antibiotics-based columns (Chirobiotic V and T), polysaccharide-based chiral column (Chiralpak AD-RH), and protein-based chiral column (Ultron ES-OVM). Preliminary basic runs were implemented, then exported to DryLab after peak tracking was accomplished. Prediction of the effect of % organic mobile phase on separation was possible for separations on Chirobiotic V for several probes: racemic propranolol with 97.80% accuracy; mixture of racemates of propranolol and terbutaline sulphate, as well as, racemates of propranolol and salbutamol sulphate with average 90.46% accuracy for the effect of percent organic mobile phase and average 98.39% for the effect of pH; and racemic warfarin with 93.45% accuracy for the effect of percent organic mobile phase and average 99.64% for the effect of pH. It can be concluded that Chirobiotic V reversed phase retention mechanism follows the solvophobic theory. 2013 Wiley Periodicals, Inc.
- Wagdy, Hebatallah A.,Hanafi, Rasha S.,El-Nashar, Rasha M.,Aboul-Enein, Hassan Y.
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p. 506 - 513
(2013/09/12)
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- Asymmetric synthesis of (S)-metoprolol via sharpless asymmetric dihydroxylation induced by a recoverable polymer ligand QN-AQNOPEG-OMe
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The catalytic asymmetric dihydroxylation (AD) discovered by Sharpless, a Nobel Prize winner in 2001, has rapidly become an invaluable synthetic tool in the possibility of converting prochiral olefins to chiral vicinal diols. After our long-running investi
- Cheng, Sikun,Liu, Xueying,Wang, Pingan,Li, Xiaoye,He, Wei,Zhang, Shengyong
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p. 516 - 519
(2012/10/30)
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- Zinc tetrafluoroborate hydrate as a mild catalyst for epoxide ring opening with amines: Scope and limitations of metal tetrafluoroborates and applications in the synthesis of antihypertensive drugs (RS)/(R)/(S)-metoprolols
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The scope and limitations of metal tetrafluoroborates have been studied for epoxide ring-opening reaction with amines, and Zn(BF4) 2?xH2O has been found to be a mild and efficient catalyst affording high yields under solvent-free conditions at rt with excellent chemo-, regio-, and stereoselectivities. The catalytic efficiency followed the order Zn(BF4)2?xH2O ? Cu(BF4)2?xH2O > Co(BF4) 2?6H2O ? Fe(BF4)2? 6H2O > LiBF4 for reactions with cyclohexene oxide and Zn(BF4)2?xH2O ? Co(BF4) 2?6H2O ? Fe(BF4)2? 6H2O > Cu(BF4)2?xH2O for stilbene oxide, but AgBF4 was ineffective. For reaction of styrene oxide with aniline, the metal tetrafluoroborates exhibited comparable regioselectivity (1:99-7:93) with preferential reaction at the benzylic carbon of the epoxide ring. A reversal of regioselectivity (91:1-69:31) in favor of the reaction at the terminal carbon of the epoxide ring was observed for reaction with morpholine. The regioselectivity was dependent on the electronic and steric factors of the epoxide and the pKa of the amine and independent of amine nucleophilicity. The role of the metal tetrafluoroborates is envisaged as "electrophile nucleophile dual activation" through cooperativity of coordination, charge-charge interaction, and hydrogen-bond formation that rationalizes the catalytic efficiency, substrate reactivity, and regioselectivity. The methodology was used for synthesis of cardiovascular drug metoprolol as racemic and enriched enantiomeric forms.
- Pujala, Brahmam,Rana, Shivani,Chakraborti, Asit K.
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experimental part
p. 8768 - 8780
(2011/12/04)
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- Regioselective synthesis of amphiphilic metoprolol-saccharide conjugates by enzymatic strategy in organic media
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An efficient protocol to prepare metoprolol-saccharide conjugates by a selective enzymatic synthesis method was developed. Firstly, the transesterification of metoprolol with three divinyl dicarboxylates (divinyl succinate, divinyl adipate and divinyl sebacate) was performed. The influences of organic solvents, sources of enzymes and acylating reagents on the synthesis of N-(vinyloxycarbonyl)metoprolol were investigated. A series of lipophilic metoprolol derivatives with vinyl group were obtained by using a lipase from porcine pancreas (PPL) in anhydrous tetrachloromethane at 50 °C. Subsequently, alkaline protease from Bacillus subtilis catalyzed highly regioselective acylation of three monosaccharides (glucose, mannose and galactose) and two disaccharides (maltose and sucrose) with N-(5- vinyloxycarbonylpentanoyl)metoprolol in anhydrous pyridine at 50 °C to give metoprolol-saccharide conjugates in good yields. The partition coefficients of the products were investigated. The results indicated that the aqueous solubility of metoprolol-monosaccharide and metoprolol-disaccharide conjugates was improved markedly compared with the parent drug of metoprolol, and the aqueous solubility of metoprolol-disaccharide conjugates was much better than that of metoprolol-monosaccharide conjugates.
- Zheng, Cheng-Zhen,Wang, Jun-Liang,Li, Xia,Liu, Bo-Kai,Wu, Qi,Lin, Xian-Fu
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experimental part
p. 123 - 127
(2011/08/06)
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- CONTINUOUS FLOW SYNTHESIS OF AMINO ALCOHOLS USING MICROREACTORS
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The present invention provides various methods for the synthesis of chemical species in a microreactor environment. In some cases, reaction products of the present invention may be valuable as intermediates and/or products in pharmaceutical and polymer research. For example, the method may involve the synthesis of amino alcohols within a microchannel. Embodiment described herein may allow for reactions with significantly shorter reaction times and increased efficiency.
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Page/Page column 10-11
(2011/06/10)
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- Chiral separations of some β-adrenergic agonists and antagonists on AmyCoat column by HPLC
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Sixteen β-adrenergic antagonists namely acebutalol, alprenolol, atenolol, bisoprolol, bopindolol, bufurolol, carazolol, celiprolol, indenolol, metaprolol, nebivolol, oxprenolol, practolol, propranolol, tertalol, and timolol, and two β-adrenergic agonists namely cimeterol and clenbuterol were resolved on AmyCoat (150 x 46 mm, 3 μm size of silica particle) by using (85:15:0.1, v/v/v), (90:10:0.1, v/v/v), and (95:05:0.1, v/v/v) combinations of η-heptane, ethanol, and diethylamine solvents, respectively. The flow rates used were 0.5, 1.0, 2.0, and 3.0 ml/min with detection at 225 nm. The values of capacity, separation, and resolution factors ranged from 0.38 to 19.70, 1.08-2.33, and 1.0 and 4.50, respectively. The maximum and minimum resolutions were achieved for celiprolol and bufurolol, respectively. The chiral recognition mechanisms were also discussed. The values of validation parameters were calculated.
- Ali, Imran,Saleem, Kishwar,Gaitonde, Vinay D.,Aboul-Enein, Hassan Y.,Hussain, Iqbal
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experimental part
p. 24 - 28
(2010/09/14)
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- Aminolysis of epoxides in a microreactor system: A continuous flow approach to β-Amino alcohols
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The use of a continuous flow microreactor for β-amino alcohol formation by epoxide aminolysis is evaluated. Comparison to microwave batch reactions reveals that conditions obtainable in the microreactor can match or improve yields in many cases. By increasing the pressure of the system, maximum temperatures can also exceed those accessible using a microwave unit. The use of a microreactor for epoxide aminolysis reactions in the synthesis of two pharmaceutical relevant compounds is described.
- Jensen, Klavs F.,Bedore, Matthew W.,Zaborenko, Nikolay,Jamison, Timothy F.
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experimental part
p. 432 - 440
(2011/04/22)
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- SYNTHESIS AND PREPARATIONS OF METOPROLOL AND ITS SALTS
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The invention relates to an improved process for preparing metoprolol and its salts.
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Page/Page column 3-4
(2009/10/06)
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- THERAPY FOR COMPLICATIONS OF DIABETES
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A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
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- ANTIHYPERTENSIVE THERAPY
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A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
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- FLUORESCENCE BASED DETECTION OF SUBSTANCES
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A method for the fluorescent detection of a substance, the method comprising providing particles comprising a metal or a metal oxide core, wherein one or more optionally fluorescently tagged antibodies or human specific peptide nucleic acid (PNA) oligomers for binding to a substance is/are bound, directly or indirectly, to the surface of the metal or metal oxide; contacting a substrate, which may or may not have the substance on its surface, with the particles for a time sufficient to allow the antibody/PNA oligomer to bind with the substance; removing those particles which have not bound to the substrate; if the antibodies or PNA oligomers are not fluorescently tagged, contacting the substrate with one or more fluorophores that selectively bind with the antibody and/or substance, then optionally washing the substrate to remove unbound fluorophores; and illuminating the substrate with appropriate radiation to show the fluorophores on the substrate.
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- Method for preparing free base compositions and formulations thereof
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Disclosed is a process for preparing a free base composition of a pharmaceutical compound comprising combining an acid addition salt of a pharmaceutical compound, at least one solvent and a sufficient amount of at least one base to convert the acid addition salt of the pharmaceutical to a free base of the pharmaceutical, to form a free base composition of the pharmaceutical compound.
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Page/Page column 6-7
(2008/06/13)
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- Concise synthesis of β-blockers (S)-metoprolol and (S)-betaxolol using hydrolytic kinetic resolution
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Enantiopure (S)-metoprolol and (S)-betaxolol were prepared in an extremely simple and practical way using Jacobsen's hydrolytic kinetic resolution of terminal epoxides in isopropanol.
- Muthukrishnan,Garud, Dinesh R.,Joshi,Joshi
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p. 1872 - 1876
(2007/10/03)
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- Method for treating resistant hypertension
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A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
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- PROCESS FOR MANUFACTURE OF METOPROLOL AND SALTS THEREOF
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Metoprolol manufacturing process with optimized reaction temperatures and reactant molar ratios, to avoid the manufacture of excessive epoxide intermediates, thus avoiding the need for purification of epoxide intermediates, thus achieving higher yields and higher-purity product than that seen in the prior art teachings.
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Page/Page column 6-8
(2008/06/13)
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- Metoprolol manufacturing process
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Metoprolol manufacturing process with optimized reaction temperatures and reactant molar ratios, to avoid the manufacture of excessive epoxide intermediates, thus avoiding the need for purification of epoxide intermediates, thus achieving higher yields and higher-purity product than that seen in the prior art teachings.
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Page/Page column 2
(2010/02/11)
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- Application of cyclam-capped β-cyclodextrin-bonded silica particles as a chiral stationary phase in capillary electrochromatography for enantiomeric separations
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Two novel types of substituted cyclam-capped β-cyclodextrin (β-CD)-bonded silica particles have been prepared and used as chiral stationary phases in capillary electrochromatography (CEC). The two stationary phases have a chiral selector with three recognition sites: β-CD, cyclam, and the latter's sidearm. They exhibit excellent enantioselectivities in CEC for a wide range of compounds as a result of the cooperative functioning of the anchored β-CD and cyclam. After inclusion of the metal ion (Ni2+) from the running buffer into the substituted cyclams and their sidearm ligands, the bonded stationary phases become positively charged and can provide extra electrostatic interactions with ionizable solutes and enhance the dipolar interactions with some polar neutral solutes. This enhances the host-guest interaction with some solutes and improves chiral recognition and enantioselectivity. These new types of stationary phases exhibit great potential for fast chiral separations in CEC.
- Gong, Yinhan,Lee, Hian Kee
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p. 1348 - 1354
(2007/10/03)
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- Manufacturing process of metoprolol
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A method for the manufacture of metoprolol wherein the process is performed in water as solvent.
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- Dynamic kinetic asymmetric synthesis of β-aminoalcohols from racemic epoxides in cyclodextrin complexes under solid state conditions
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It has been shown for the first time that enantiopure β-aminoalcohols can be prepared from racemic epoxides by dynamic kinetic resolution involving enantio-differentiating racemisation in cyclodextrin complexes under solid state conditions.
- Reddy,Bhanumathi,Rao
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p. 2321 - 2322
(2007/10/03)
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- Enantioselective ring opening of epoxides with trimethylsilyl azide (TMSN3) in the presence of β-cyclodextrin: An efficient route to 1,2-azido alcohols
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The ring opening of epoxides with nucleophiles such as TMSN3 and isopropylamine takes place enantioselectively in the presence of β- cyclodextrin under extremely mild conditions and the azido alcohols and amino alcohols are formed as (S)-isomers. (C) 1999 Published by Elsevier Science Ltd.
- Kamal, Ahmed,Arifuddin,Rao, Maddamsetty V.
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p. 4261 - 4264
(2007/10/03)
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- Kinetic resolution of aryl glycidyl ethers : A practical synthesis of optically pure β-blocker - S-metoprolol
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Kinetic resolution of (±)-aryl glycidyl ethers using (R,R)-salen Co(III)OAc and water provided enantiomerically pure arylglycidyl ether and 1-arylglycerol derivatives with high enantiomeric excess. Application of this approach to (S)-metoprolol has been d
- Gurjar, Mukund K.,Sadalapure, Kashinath,Adhikari, Susanta,Sarma, Bugga V. N. B. S.,Talukdar, Arindam,Chorghade, Mukund S.
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p. 1471 - 1476
(2007/10/03)
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- Efficient asymmetric hydrogenation of α-amino ketone derivatives. A highly enantioselective synthesis of phenylephrine, levamisole, carnitine and propranolol
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The complexes of pyrrolidine bisphosphine ligands (CPMs) with rhodium (I) were found to be efficient catalysts for asymmetric hydrogenation of α-amino ketone hydrochloride derivatives. Utilizing this methodology, we have developed efficient asymmetric syntheses of the optically active β-amino alcohols, phenylephrine, levamisole, carnitine and propranolol.
- Sukuraba,Takahashi,Takeda,Achiwa
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p. 738 - 747
(2007/10/02)
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- Composition and method containing optically pure (S) metoprolol
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Optically pure (S) metoprolol, which is substantially free of the (R) enantiomer, is a potent beta-blocker for treating myocardial infarction and for relieving the symptoms of angina pectoris, cardiac arrhythmia and hypertension in individuals. A method is disclosed utilizing the optically pure (S) configurational enantiomer of metoprolol for treating cardiovascular disorders while reducing undesirable side effects associated with the administration of beta-blockers.
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- New optically active metoprolol tartrate salts, and method of preparing them, and method of preparing optically active metoprolol from the tartrate salts
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This invention relates to new optically active metoprolol tartrate salts, (2S)-1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol-(2S?, 3S?)-O,O-di-p-toluoyltartrate salts (formula 1), and (2R)-1-isopropylamino-3-[p-(2-methoxyethyl)phenoxy]-2-propanol-(2R?, 3R?)-O,O-di-p-toluoyltartrate salts (formula 2), and preparation thereof and of optically active metoprolol from the tartrate salts which is caracterized in that optically active substances of metoprolol, which function as cures for essential hypertension, angina pectoris, and tachycardiac arhythmia can be provided readily and industrially.
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- Process for S-metoprolol via oxazolidin-2-one
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A process for preparing S-metoprolol of the formula STR1 or a salt thereof, with high enantiomeric purity, is described, whereby a (S)-5-hydroxymethyl-3-isopropyloxazolidin-2-one sulfonic acid ester of the formula STR2 is prepared, and further reacted wit
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- Method for the synthesis of pharmacologically active compounds and intermediates for such synthesis
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A process for the preparation of an aryloxypropanolamine of the formula wherein Ar is a carbocyclic or heterocyclic aromatic group and R is an alkyl or substituted alkyl group having 1 to 6 carbon atoms, characterized in subjecting a compound of the formula STR1 to oxidative cleavage to a dialdehyde of the formula STR2 which is then made subject to reduction, amination, acetal hydrolysis, and, where required, removal of a nitrogen protective group, to the formation of a compound of formula I, or an acid addition salt thereof, a compound of formula II and the preparation thereof from mannitol.
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- A New Route from D-Mannitol to Enantiomerically Pure (S)-1-Alkylamino-3-aryloxy-2-propanols
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A new route to (S)-1-alkylamino-3-aryloxy-2-propanols starting from D-mannitol is described.The overall strategy involves preparation of 2,5-O-methylene-D-mannitol, tosylation of the 1,6-hydroxy groups, protection of the 3,4-hydroxy groups as a cyclic ort
- Lamm, Bo,Ankner, Kjell,Frantsi, Marianne
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p. 202 - 207
(2007/10/02)
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- Process for the preparation of arylglycidyl ethers and 3-substituted 1-alkylamino-2-propanols
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A process for the preparation of a pharmaceutically active compound in a stereospecific form of the formula, R1-O-CH2-CHOH-CH2-NH-R2 (I), or a pharmaceutically acceptable salt thereof, like an acid addition salt, and/or a compound in a stereospecific form of the formula wherein R1 is an optionally substituted aryl group including a phenyl or naphthyl group optionally included in a heterocyclic ring system, which is optionally substituted, or is a heteroaromatic 5 or 6 membered ring containing in addition to carbon atoms, one or more atoms selected from nitrogen, sulphur and oxygen, this ring being optionally substituted, and wherein R2 is an alkyl group of 2 to 6 carbon atoms, this alkyl group being optionally substituted, which comprises subjecting a compound of the formula, R1-O-CH2-CH=CH2 (III), to the action of a micro-organism having the ability for stereoselective epoxidation of compound (III) into compound (II), having at least 80% by weight the Sconfiguration, at least partly separating compound (II) and/or reacting compound (II) with a C2-C6 alkylamine group optionally substituted and at least partly separating compound (I) and/or converting compound (I) into the pharmaceutically acceptable salt thereof.
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- Enteric coated mixture of 4-(2-hydroxy-3-isopropylamino-propoxy) indole and sodium lauryl sulphate
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The present invention provides a pharmaceutical composition for controlled release of 4-(2-hydroxy-3-isopropylamino-propoxy) indole in the intestinal tract, admixed with sodium lauryl sulphate, and enteric coated.
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