- An in-vitro and in-vivo correlative approach to the evaluation of ester prodrugs to improve oral-delivery of propranolol
-
A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight: alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the β-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration. The in-vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate >> plasma > buffers. The pH-rate profile the prodrugs showed maximum stability around pH 4.0; the hydrolysis rates were drastically increased over pH 6.8. QSAR analysis revealed hydrophobic (π) and electronic (σ) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O-acetyl-, O-butyryl-, O-isovaleryl- and O-cyclopropanoyl-propranolol) were selected for oral administration based on their hydrolysis in-vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranol were about 2-4 fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0-0.5 h. Intact prodrug levels were also observe which varied depending on their respective stabilities in in-vitro media. A linear relationship between F propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation. The overall in-vitro and in-vivo results showed that lipophilic prodrugs having higher chemical and enzymatic stability buffers and plasma, but susceptible to hydrolysis in the liver homogenate, to be the most promising prodrugs for improving oral bioavailability of propranolol.
- Shameem,Imai,Otagiri
-
-
Read Online
- Solution and mixing thermodynamics of propranolol and atenolol in aqueous media
-
Based on the van't Hoff and Gibbs equations, the thermodynamic functions Gibbs energy, enthalpy, and entropy of dissolution, and of mixing of propranolol (PPN) and atenolol (ATN) in water at pH=11.5, were evaluated from solubility values determined at sev
- Triana, Maria T.,Reyes, Andrea C.,Jimenez-Kairuz, Alvaro F.,Manzo, Ruben H.,Martinez, Fleming
-
-
Read Online
- Synthetic method of propranolol hydrochloride
-
The invention belongs to the field of medicines, and particularly relates to a synthetic method of propranolol hydrochloride. The preparation method comprises the following steps: by taking epoxy chloropropane and methyl naphthol as raw materials and acetonitrile as a solvent, firstly reacting in tetramethylammonium hydroxide to obtain an intermediate product, then reacting the intermediate product with isopropylamine in the presence of a metal salt Ni/alpha-Al2O3 catalyst to obtain propranolol, and finally salinizing to obtain the propranolol hydrochloride. The method can significantly improve the yield and purity of the propranolol hydrochloride.
- -
-
Paragraph 0015; 0019; 0021; 0023-0025; 0027-0034; 0036; ...
(2021/09/04)
-
- Synthesis and application of Cu(II) immobilized MCM-41 based solid Lewis acid catalyst for aminolysis reaction under solvent-free condition
-
In this paper, a Cu(II) immobilized periodic mesoporous organosilica (PMOs) was synthesized and used as a reusable solid Lewis acid catalyst for the aminolysis of epoxides under solvent-free conditions. An amide-based ligand, L-propylsilyl (1) having a specific binding pocket was prepared and fabricated on mesoporous MCM-41 to produce mesoporous organosilica L-propylsilyl@MCM-41 (2). Further, it has been utilized for anchoring Cu(II) ions under controlled reaction conditions to yield solid Lewis acid catalyst Cu(II)-L-propylsilyl@MCM-41 (3). The synthesized catalyst 3 exhibits significantly higher catalytic activity for aminolysis compared to hitherto known solid Lewis acid catalysts. An extensive range of β-amino alcohols with high regio and stereoselectivity were prepared by using catalyst 3. The catalyst was recovered easily and reused eight times without any loss in its catalytic activity. Furthermore, the synthesis of clinically significant propranolol (β-blocker) from α- naphthyl glycidyl ether was attained successfully using catalyst 3 in a very decent yield.
- Chaudhary, Garima,Gupta, Neha,Singh, Amit Pratap
-
-
- Preparation of a novel hydroxypropyl-γ-cyclodextrin functionalized monolith for separation of chiral drugs in capillary electrochromatography
-
In this study, a novel hydroxypropyl-γ-cyclodextrin (HP-γ-CD) functionalized monolithic capillary column was prepared by one-pot sequential strategy and used for chiral separation in capillary electrochromatography for the first time. In one pot, GMA-HP-γ-CD as functional monomer was allowed to be formed via the ring opening reaction between HP-γ-CD and glycidyl methacrylate (GMA) catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and then copolymerized directly with ethylene dimethacrylate (EDMA) and 2-acrylamido-2-methyl propane sulfonic acid (AMPS) in the presence of porogenic solvents via thermally initiated free radical polymerization. The preparation conditions of monoliths were optimized. Enantiomer separations of six chiral drugs including pindolol, clorprenaline, tulobuterol, clenbuterol, propranolol, and tropicamide were achieved on the monolith. Among them, pindolol, clorprenaline, and tropicamide were baseline separated with resolution values of 1.62, 1.73, and 1.55, respectively. The mechanism of enantiomer separation was discussed by comparison of the HP-γ-CD and HP-β-CD functionalized monoliths.
- Deng, Miaoduo,Xue, Mengyao,Liu, Yanru,Zhao, Min
-
p. 188 - 195
(2021/02/26)
-
- Preparation method of propranolol
-
The invention discloses a preparation method of propranolol. The method comprises the following preparation steps: taking naphthol, epichlorohydrin and isopropylamine as initial raw materials, adding a phase transfer catalyst and a reaction solvent, and reacting under the action of alkali to generate propranolol. The process route and post-treatment steps of the route are greatly simplified, the reaction conditions are not harsh and are easy to control, and industrial production can be realized; and the raw materials adopted by the route are easy to obtain on the market, and the price is relatively low, so that the cost is saved.
- -
-
Paragraph 0018-0020
(2021/06/23)
-
- Synthesis method of beta-amino alcohol compounds
-
The invention discloses a synthesis method of beta-amino alcohol compounds. A carboxylic acid is adopted as a catalyst to promote amination of an epoxide to generate the beta-amino alcohol compounds.Compared with reported methods, this method has advantages of no use of metal catalysts, mild reaction conditions, the safe, non-toxic, cheap and readily available catalyst, a high product yield and high regioselectivity. In addition, a low-boiling-point carboxylic acid can be selected as the catalyst. When the low-boiling-point catalyst is used, excess raw materials and the catalyst can be recycled and reused, almost no waste is discharged to the environment, a post-treatment process does not require extraction, drying, filtration or the like, and a mixture after the reaction is finished is simply distilled or distilled under reduced pressure to obtain a crude product with higher purity. The synthesis process is simple, efficient, and environmentally friendly.
- -
-
Paragraph 0142-0160
(2020/03/29)
-
- Synthetic method of propranolol hydrochloride (by machine translation)
-
To the method, methylnaphthol and epichlorohydrin are subjected to etherification reaction under the action of an alkali condition and a phase transfer catalyst to obtain the key intermediate 3 - (1 - naphthyloxy) -1, 2 - epoxypropane, and then refined to obtain the propranolol hydrochloride crude product which has the advantages of short synthetic route, simple operation and suitableness for industrial production 99.8%. (by machine translation)
- -
-
Paragraph 0030-0033
(2020/06/30)
-
- Facile Synthesis of Propranolol and Novel Derivatives
-
Propranolol is one of the first medications of the beta-blocker used for antihypertensive drugs. This study reports the facile route for the synthesis of propranolol and its novel derivatives. Herein, propranolol synthesis proceeded from 1-naphthol and isopropylamine under mild and less toxic conditions. Novel propranolol derivatives were designed by reactions of propranolol with benzoyl chloride, pyridinium chlorochromate, and n-butyl bromide through esterification, oxidation reduction, and alkylation, respectively. The isolation and purity of compounds were conducted using column chromatography and thin-layer chromatography. Mass spectrometry and 1H-NMR spectroscopy were applied to identify new compounds structure. Propranolol derivatives from 2-chlorobenzoyl chloride (compound 3), 2-fluorobenzoyl chloride (compound 5), and especially acetic anhydride (compound 6) manifested high yields and significantly increased water solubility. Six semisynthetic propranolol derivatives promise to improve antioxidative and biological activities.
- Bach, Long Giang,Le, Van Thuan,Nguyen, Tan Tai,Nguyen, Thi Anh Nga,Nguyen, Thi Thuong,Nguyen, Trinh Duy,Tran, Nguyen Hai Tai,Tran, Vy Anh,Vo, The Ky,Vo, Thu-Thao Thi
-
-
- Preparation and evaluation of a triazole-bridged bis(β-cyclodextrin)–bonded chiral stationary phase for HPLC
-
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
-
p. 168 - 184
(2019/11/25)
-
- Enantioseparation of mandelic acid on vancomycin column: Experimental and docking study
-
So far, no detailed view has been expressed regarding the interactions between vancomycin and racemic compounds including mandelic acid. In the current study, a chiral stationary phase was prepared by using 3-aminopropyltriethoxysilane and succinic anhydride to graft carboxylated silica microspheres and subsequently by activating the carboxylic acid group for vancomycin immobilization. Characterization by elemental analysis, Fourier transform infrared spectroscopy, solid-state nuclear magnetic resonance, and thermogravimetric analysis demonstrated effective functionalization of the silica surface. R and S enantiomers of mandelic acid were separated by the synthetic vancomycin column. Finally, the interaction between vancomycin and R/S mandelic acid enantiomers was simulated by Auto-dock Vina. The binding energies of interactions between R and S enantiomers and vancomycin chiral stationary phase were different. In the most probable interaction, the difference in mandelic acid binding energy was approximately 0.2 kcal/mol. In addition, circular dichroism spectra of vancomycin interacting with R and S enantiomers showed different patterns. Therefore, R and S mandelic acid enantiomers may occupy various binding pockets and interact with different vancomycin functions. These observations emphasized the different retention of R and S mandelic acid enantiomers in vancomycin chiral column.
- Shahnani, Mostafa,Sefidbakht, Yahya,Maghari, Shokoofeh,Mehdi, Ahmad,Rezadoost, Hassan,Ghassempour, Alireza
-
supporting information
p. 1289 - 1298
(2020/08/19)
-
- Continuous flow upgrading of glycerol toward oxiranes and active pharmaceutical ingredients thereof
-
A robust continuous flow procedure for the transformation of bio-based glycerol into high value-added oxiranes (epichlorohydrin and glycidol) is presented. The flow procedure features a central hydrochlorination/dechlorination sequence and provides economically and environmentally favorable conditions involving an organocatalyst and aqueous solutions of hydrochloric acid and sodium hydroxide. Pimelic acid (10 mol%) shows an exceptional catalytic activity (>99% conversion of glycerol, a high selectivity toward 1,3-dichloro-2-propanol and 81% cumulated yield toward intermediate chlorohydrins) for the hydrochlorination of glycerol (140 °C) with 36 wt% aqueous HCl. These conditions are validated on a sample of crude bio-based glycerol. The dechlorination step is effective (quantitative conversion based on glycerol) with concentrated aqueous sodium hydroxide (20 °C) and can be directly concatenated to the hydrochlorination step, hence providing a ca. 2:3 separable mixture of glycidol and epichlorohydrin (74% cumulated yield). An in-line membrane separation unit is included downstream, providing usable streams of epichlorohydrin (in MTBE, with an optional concentrator) and glycidol (in water). The scalability of the dechlorination step is then assessed in a commercial pilot-scale continuous flow reactor. Next, bio-based epichlorohydrin is further utilized for the continuous flow preparation of β-amino alcohol active pharmaceutical ingredients including propranolol (hypertension, WHO essential), naftopidil (prostatic hyperplasia) and alprenolol (angina pectoris) within a concatenable two-step procedure using a FDA class 3 solvent (DMSO). This work provides the first example of direct upgrading of bio-based glycerol into high value-added pharmaceuticals under continuous flow conditions.
- Morodo, Romain,Gérardy, Romaric,Petit, Guillaume,Monbaliu, Jean-Christophe M.
-
p. 4422 - 4433
(2019/08/21)
-
- Effect of vitamin C template on morphology and structure of alumina: emerging application in enantiomer separation
-
Mesoporous nano-aluminas were prepared using aluminium isopropoxide, vitamin C (VC as a chiral template and a co-structural directing agent with molar ratios of 50:50 and 90:10) and water. These compositions when dried at 120?°C and calcined at 250, 350 and 500?°C for 8?h under air atmosphere transformed to boehmite and γ-alumina depending on the concentration of VC. The influence of vitamin C and its degradation products on the morphology and texture of alumina was investigated by the means of XRD, FT-IR, SEM, EDX, TEM, TGA, DSC, BET and N2 adsorption–desorption isotherm. Mesoporous aluminas possess excellent characteristics such as large surface area (ca. 394?m2/g), 0.4?cm3/g pore volume and narrow pore size distributions that can be synthesized through a facile and green procedure. In addition, the enantiomers of propranolol hydrochloride were successfully resolved from its racemate using Al50VC50T350 (AlMolar ratio of the Aluminium isopropoxide, VCMolar ratio of the Vitamin C,TTemperature) (Rs = 2.5) as chiral stationary phase. The synthesis of chiral stationary phase was accomplished in a green, facile and inexpensive procedure that is of paramount importance in food and pharmaceutical industries.
- Dabbagh, Hossein A.,Mozaffari Majd, Mahdieh,Bahrami, Fahimeh,Gholami, Ali
-
p. 1931 - 1943
(2019/09/03)
-
- Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances
-
Three novel β-cyclodextrin compounds derived with piperidine which is flexible, L-proline containing a chiral center, ionic liquid with 3,5-diamino-1,2,4-triazole as the cation were designed and synthesized as chiral selectors for enantiomer separation, whose name were (mono-6-deoxy-6-(piperidine)-β-cyclodextrin, mono-6-deoxy-6-(L-proline)-β-cyclodextrin, mono-6-deoxy-6-(3,5-diamino-1,2,4-triazole)-β-cyclodextrin, multi-substituted 3,5-diamino-1,2,4- triazole-(p-toluenesulfonic)-β-cyclodextrin), respectively. In addition, to enhance the polarity of chiral stationary phases, hydrosilylation and silylation reactions were implemented to derive ordinary silica, the common used selector carrier, to hydride silica, whose surface is covered with proton. 31 pyrrolidine compounds and some chiral drugs were tested in both polar organic mobile phase mode and normal mobile phase mode. 6-Deoxy-6-L-proline-β-cyclodextrin-CSP showed satisfactory separations in polar organic mobile phase mode and exihibited a strong separation capability in different pH values; multi-substituted 3,5-diamino-1,2,4-triazole-(p-toluenesulfonic)-β-cyclodextrin-CSP can separate pyrrolidine compounds in both mobile phase modes with high resolutions and separation efficiency compared to commercially available CSPs, making it to be the most valuable object to study. The composition of mobile phase, type of stationary phase as well as the peak problem of chromatograms was discussed deeply.
- Zhao, Baojing,Li, Lan,Wang, Yuting,Zhou, Zhiming
-
p. 643 - 649
(2018/11/27)
-
- Enantioseparation of chiral pharmaceuticals by vancomycin-bonded stationary phase and analysis of chiral recognition mechanism
-
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
-
p. 236 - 247
(2019/02/01)
-
- HPLC with cellulose Tris (3,5-DimethylPhenylcarbamate) chiral stationary phase: Influence of coating times and coating amount on chiral discrimination
-
Coating cellulose tris (3,5-dimethylphenylcarbamate) (CDMPC) on silica gels with large pores have been demonstrated as an efficient way for the preparation of chiral stationary phase (CSP) for high-performance liquid chromatography (HPLC). During the process, a number of parameters, including the type of coating solvent, amount of coating, and the method for subsequent solvent removing, have been proved to affect the performance of the resultant CSPs. Coating times and the concentration of coating solution, however, also makes a difference to CSPs' performance by changing the arrangement of cellulose derivatives while remaining the coating amount constant, have much less been studied before, and thereby, were systematically investigated in this work. Results showed that CSPs with more coating times exhibited higher chiral recognition and column efficiency, suggesting that resolution was determined by column efficiency herein. Afterwards, we also investigated the effect of coating amount on the performance of CSPs, and it was shown that the ability of enantio-recognition did not increase all the time as the coating amount; and four of seven racemates achieved best resolution when the coating amount reached to 18.37%. At the end, the reproducibility of CDMPC-coated CSPs were further confirmed by two methods, ie, reprepared the CSP-0.15-3 and reevaluated the effect of coating times.
- Wei, Qiuhong,Su, Hongjiu,Gao, Diannan,Wang, Shudong
-
p. 164 - 173
(2019/01/18)
-
- Hexafluoroisopropanol as the Acid Component in the Passerini Reaction: One-Pot Access to β-Amino Alcohols
-
A new Passerini-type reaction in which hexafluoroisopropanol functions as the acid component is reported. The reaction tolerates a broad range of isocyanides and aldehydes, and the formed imidates can be reduced toward β-amino alcohols under mild and metal-free conditions. In addition, the imidate products were shown to undergo an unprecedented retro-Passerini-type reaction under microwave conditions, providing valuable mechanistic information about the Passerini reaction and its variations.
- Saya, Jordy M.,Berabez, Rayan,Broersen, Pim,Schuringa, Imme,Kruithof, Art,Orru, Romano V. A.,Ruijter, Eelco
-
supporting information
p. 3988 - 3991
(2018/07/15)
-
- Enantiomeric separation of β-blockers and tryptophan using heparin as stationary and pseudostationary phases in capillary electrophoresis
-
The separation methods of the enantiomers of two β-blockers and tryptophan were studied using capillary electrochromatography with heparin covalently as well as non-covalently, bonded onto the capillary inner wall as stationary phase and electrokinetic chromatography with heparin as pseudostationary phase. In the case of heparin, used as a stationary phase, the method was unable to resolve enantiomers in both cases β-blockers and tryptophan. On the other hand, when heparin was used as a pseudostationary phase, the resolution of the enantiomers was obtained only with 3-aminopropyltriethoxysilane which were immobilised onto the inner phase of the capillary. The results of this study let us infer that the electrostatic, hydrophobic, and steric interactions were involved in the separation mechanisms. The separation was achieved in less than 10?minutes under the optimized conditions: 30?mM phosphate buffer (pH?2.5) with the adding of 15?mg/mL of heparin at 15°C and 10?kV. The usefulness of heparin as a chiral selector both in electrokinetic chromatography using 3-aminopropyltriethoxysilane attached to the capillary was demonstrated for the first time. The developed method was powerful, sensitive, and fast, and it could be considered an important alternative to conventional methods used for chiral separation.
- Liu, Yi,Sombra, Lorena L.,Stege, Patricia W.
-
p. 988 - 995
(2018/07/29)
-
- Cellulose type chiral stationary phase based on reduced graphene oxide@silica gel for the enantiomer separation of chiral compounds
-
The graphene oxide (GO) was covalently coupled to the surfaces of silica gel (SiO2) microspheres by amide bond to get the graphene oxide@silica gel (GO@SiO2). Then, the GO@SiO2 was reduced with hydrazine to the reduced graphene oxide@silica gel (rGO@SiO2), and the cellulose derivatives were physically coated on the surfaces of rGO@SiO2 to prepare a chiral stationary phase (CSP) for high performance liquid chromatography. Under the optimum experimental conditions, eight benzene-enriched enantiomers were separated completely, and the resolution of trans-stilbene oxide perfectly reached 4.83. Compared with the blank column of non-bonded rGO, the separation performance is better on the new CSP, which is due to the existence of rGO to produce special retention interaction with analytes, such as π-π stacking, hydrophobic effect, π-π electron-donor–acceptor interaction, and hydrogen bonding. Therefore, the obtained CSP shows special selectivity for benzene-enriched enantiomers, improves separation selectivity and efficiency, and rGO plays a synergistic effect with cellulose derivatives on enantioseparation.
- Li, Yuanyuan,Li, Qiang,Zhu, Nan,Gao, Zhuxian,Ma, Yulong
-
p. 996 - 1004
(2018/07/29)
-
- Evaluation of the Edman degradation product of vancomycin bonded to core-shell particles as a new HPLC chiral stationary phase
-
A modified macrocyclic glycopeptide-based chiral stationary phase (CSP), prepared via Edman degradation of vancomycin, was evaluated as a chiral selector for the first time. Its applicability was compared with other macrocyclic glycopeptide-based CSPs: TeicoShell and VancoShell. In addition, another modified macrocyclic glycopeptide-based CSP, NicoShell, was further examined. Initial evaluation was focused on the complementary behavior with these glycopeptides. A screening procedure was used based on previous work for the enantiomeric separation of 50 chiral compounds including amino acids, pesticides, stimulants, and a variety of pharmaceuticals. Fast and efficient chiral separations resulted by using superficially porous (core-shell) particle supports. Overall, the vancomycin Edman degradation product (EDP) resembled TeicoShell with high enantioselectivity for acidic compounds in the polar ionic mode. The simultaneous enantiomeric separation of 5 racemic profens using liquid chromatography-mass spectrometry with EDP was performed in approximately 3?minutes. Other highlights include simultaneous liquid chromatography separations of rac-amphetamine and rac-methamphetamine with VancoShell, rac-pseudoephedrine and rac-ephedrine with NicoShell, and rac-dichlorprop and rac-haloxyfop with TeicoShell.
- Hellinghausen, Garrett,Lopez, Diego A.,Lee, Jauh T.,Wang, Yadi,Weatherly, Choyce A.,Portillo, Abiud E.,Berthod, Alain,Armstrong, Daniel W.
-
p. 1067 - 1078
(2018/08/01)
-
- Preparation method of propranolole hydrochloride
-
The invention belongs to the field of medical chemistry, and especially relates to a preparation method of propranolole hydrochloride. The preparation method comprises following steps: 1, 1-naphthol is reacted with 1,3-dibromo(iodo)propanone in a sodium hydroxide solution so as to obtain 1-bromo(iodo)-3-(1-naphthyloxy)-2-propanone; 2, 1-bromo(iodo)-3-(1-naphthyloxy)-2-propanone is subjected to reduction with sodium borohydride in an organic solvent so as to obtain 1-bromo(iodo)-3-(1-naphthyloxy)-2-propanol; 3, 1-bromo(iodo)-3-(1-naphthyloxy)-2-propanol is reacted with isopropylamine in an organic solvent so as to obtain 1-isopropylamino-3-(1-naphthyloxy)-2-propanol; and 4, 1-isopropylamino-3-(1-naphthyloxy)-2-propanol is reacted with hydrochloric acid so as to obtain 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol hydrochloride (propranolole hydrochloride). The preparation method is capable of avoiding using of chloropropylene oxide, is more safe and friendly to the environment, no intermediate containing ethylene oxide structure is adopted in reaction process, so that the drug safety is higher.
- -
-
Paragraph 0063; 0064; 0065; 0066; 0075; 0077
(2018/10/11)
-
- Preparation method for propranolol
-
The invention discloses a preparation method for propranolol. The preparation method is characterized by comprising the following preparation steps: naphthol (I), epichlorohydrin and isopropylamine are used as initial raw materials, a reaction is performed under effects of a reaction solvent, an alkali and a phase transfer catalyst, and therefore the propranolol (TM) is obtained. According to thepreparation process, the reaction is finished in one step, thus the process steps are greatly simplified and easy to control, industrialized production can be realized, and process costs are reduced.
- -
-
Paragraph 0006; 0009; 0010; 0012-0014
(2018/04/01)
-
- FORMULATIONS OF PROPRANOLOL AND ANALOGS AS AN AMORPHOUS MELT OR IONIC LIQUID FOR TRANSDERMAL DRUG DELIVERY
-
Melts or ionic liquids containing amorphous propranolol, topical formulations and patches for transdermal drug delivery, and methods of making and using thereof are described herein. The melts or ionic liquids may be in a topical drug delivery formulation or patch to be applied to the skin. The drug delivery formulation or patch contains a sufficient amount of the amorphous propranolol to deliver a therapeutically effective amount of the amorphous propranolol to the patient in need of treatment, such as for the treatment or amelioration of infantile hemangioma. The formulations have a low viscosity and reduced skin irritation compared to the crystalline propranolol free base (PFB). The melts or ionic liquids can be formed by a salt metathesis reaction.
- -
-
Paragraph 0099
(2018/07/04)
-
- Ultrafast chiral separations for high throughput enantiopurity analysis
-
Recent developments in fast chromatographic enantioseparations now make high throughput analysis of enantiopurity on the order of a few seconds achievable. Nevertheless, routine chromatographic determinations of enantiopurity to support stereochemical investigations in pharmaceutical research and development, synthetic chemistry and bioanalysis are still typically performed on the 5-20 min timescale, with many practitioners believing that sub-minute enantioseparations are not representative of the molecules encountered in day to day research. In this study we develop ultrafast chromatographic enantioseparations for a variety of pharmaceutically-related drugs and intermediates, showing that sub-minute resolutions are now possible in the vast majority of cases by both supercritical fluid chromatography (SFC) and reversed phase liquid chromatography (RP-LC). Examples are provided illustrating how such methods can be routinely developed and used for ultrafast high throughput analysis to support enantioselective synthesis investigations.
- Barhate, Chandan L.,Joyce, Leo A.,Makarov, Alexey A.,Zawatzky, Kerstin,Bernardoni, Frank,Schafer, Wes A.,Armstrong, Daniel W.,Welch, Christopher J.,Regalado, Erik L.
-
supporting information
p. 509 - 512
(2017/01/13)
-
- Enantioselective potential of polysaccharide-based chiral stationary phases in supercritical fluid chromatography
-
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
-
supporting information
p. 239 - 246
(2017/05/29)
-
- Comparison of three S-β-CDs with different degrees of substitution for the chiral separation of 12 drugs in capillary electrophoresis
-
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
-
p. 558 - 565
(2017/08/26)
-
- Optimization of throughput in semipreparative chiral liquid chromatography using stacked injection
-
An interesting mode of chromatography for preparation of pure enantiomers from pure samples is the method of stacked injection as a pseudocontinuous procedure. Maximum throughput and minimal production costs can be achieved by the use of total chiral column length in this mode of chromatography. To maximize sample loading, often touching bands of the two enantiomers is automatically achieved. Conventional equations show direct correlation between touching-band loadability and the selectivity factor of two enantiomers. The important question for one who wants to obtain the highest throughput is “How to optimize different factors including selectivity, resolution, run time, and loading of the sample in order to save time without missing the touching-band resolution?” To answer this question, tramadol and propranolol were separated on cellulose 3,5-dimethyl phenyl carbamate, as two pure racemic mixtures with low and high solubilities in mobile phase, respectively. The mobile phase composition consisted of n-hexane solvent with alcohol modifier and diethylamine as the additive. A response surface methodology based on central composite design was used to optimize separation factors against the main responses. According to the stacked injection properties, two processes were investigated for maximizing throughput: one with a poorly soluble and another with a highly soluble racemic mixture. For each case, different optimization possibilities were inspected. It was revealed that resolution is a crucial response for separations of this kind. Peak area and run time are two critical parameters in optimization of stacked injection for binary mixtures which have low solubility in the mobile phase.
- Taheri, Mohammadreza,Fotovati, Mohsen,Hosseini, Seyed-Kiumars,Ghassempour, Alireza
-
p. 579 - 588
(2017/09/29)
-
- Catalytic Reductions and Tandem Reactions of Nitro Compounds Using in Situ Prepared Nickel Boride Catalyst in Nanocellulose Solution
-
A mild and efficient method for the in situ reduction of a wide range of nitroarenes and aliphatic nitrocompounds to amines in excellent yields using nickel chloride/sodium borohydride in a solution of TEMPO-oxidized nanocellulose in water (0.01 wt %) is described. The nanocellulose has a stabilizing effect on the catalyst, which increases the turnover number and enables low loading of nickel catalyst (0.1-0.25 mol % NiCl2). In addition, two tandem protocols were developed in which the in situ formed amines were either Boc-protected to carbamates or further reacted with an epoxide to yield β-amino alcohols in excellent yields.
- Prathap, Kaniraj Jeya,Wu, Qiong,Olsson, Richard T.,Dinér, Peter
-
supporting information
p. 4746 - 4749
(2017/09/23)
-
- Enantiomer separation of propranolol and tryptophan using bovine serum albumin functionalized silica nanoparticles as adsorbents
-
The immobilization of popular chiral selectors on the surface of nanomaterials to prepare new chiral adsorbents for preparative chiral separation is a research hotspot in separation science nowadays. In this study, bovine serum albumin (BSA) modified silica nanoparticles were prepared by using polydopamine (PDA) as a versatile multifunctional secondary reaction platform. The preparation method was facile, cost-effective and environmentally friendly. The new chiral adsorbents were then investigated for the separation of representative chiral drug enantiomers. For propranolol and tryptophan, the multi-step adsorption enhanced the chiral performance to a great degree. On increasing the starting percent enantiomeric excess (%, e.e.) of the enantiomeric mixtures, the %, e.e. value of the resulting solution increased to almost 100% under the same operating conditions. For simplicity and rapidness, the results of adsorption were measured by capillary electrophoresis (CE) using carboxymethyl-β-cyclodextrin (CM-β-CD) or α-cyclodextrin (α-CD) as additives into the background electrolyte solution. The experimental results also showed that the thus-prepared nanomaterials could be readily recycled at least three times, demonstrating their great stability and possibility in practical use.
- Li, Wei,Ding, Guo-Sheng,Tang, An-Na
-
p. 93850 - 93857
(2015/11/17)
-
- Chemoenzymatic synthesis of (R)- and (S)-propranolol using an engineered epoxide hydrolase with a high turnover number
-
Simultaneous synthesis of the R- and S-enantiomers of biologically active propranolol, a typical β-blocker, was achieved in high optical purity via an epoxide hydrolase-catalyzed resolution of racemic α-naphthyl glycidyl ether (rac-1). A preparative resolution of 100 g/L rac-1 was accomplished with high enantioselectivity (E = 92) using a variant of Bacillus megaterium epoxide hydrolase (BmEHF128T). A biphasic system (isopropyl ether/isooctane/aqueous) was used, in which the product 3-(1′-naphthyloxy)-propane-1,2-diol (2) precipitated instantly, facilitating its separation and increasing the enantiopurity of (R)-2 (>99.5% ee). This enzymatic resolution had a total turnover number of 70,000, affording enantiopure epoxide (S)-1 (>99% ee) and 1,2-diol (R)-2 (>99% ee) in 45.3% and 42.4% yields, respectively. (R)-2 and (S)-1 were subsequently converted to (R)- and (S)-propranolol (3) (>99% ee) in overall yields of 31.4% and 44.8%. To the best of our knowledge, this is the best case for enzymatic resolution of rac-1 using an epoxide hydrolase, giving high space-time yields [136 g L-1 days-1 for (S)-1 and 139 g L-1 days-1 for (R)-2] under mild reaction conditions. It provides a new and eco-friendly route that complements other methods using organometallic catalysts.
- Kong, Xu-Dong,Yu, Hui-Lei,Yang, Sheng,Zhou, Jiahai,Zeng, Bu-Bing,Xu, Jian-He
-
p. 275 - 281
(2015/11/02)
-
- Synthesis of (S)-(-)-propranolol by using Cs2.5H0.5PW12O40 nanocatalyst as green, eco-friendly, reusable, and recyclable catalyst
-
The Cs2.5H0.5PW12O40 nanoparticle catalyst appear to be a new and efficient solid acid catalyst for an economical, environmentally benign synthesis of (S)-(-)-propranolol. Cs2.5H0.5PW12O40 nanocatalyst are used as a new, recyclable and reusable. Synthesis of (S)-(-)-propranolol is carried out in two steps with usual reagents: heteropolyacid, (+)-tartaric acid catalyzed enantioselective synthesis of (S)-(-)-propranolol via kinetic resolution of key intermediate α-naphthyl glycidyl ether with high optical and chemical yield. With this synthesis, we have two products in the first reaction and it is not necessary to purify the crude oil. This by-product is removed in the second step by extraction and yield is satisfactory. The nanocatalyst of Cs2.5H0.5PW12O40 catalyzed the synthesis of propranolol in high yields and good selectivity.
- Gharib, Ali,Jahangir, Manouchehr,Roshani, Mina,Pesyan, Nader Noroozi,Scheeren,Mohadesazadeh, Sara,Lagzian, Shirin
-
p. 350 - 355
(2015/02/02)
-
- Continuous and convergent access to vicinyl amino alcohols
-
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.
-
supporting information
p. 15133 - 15136
(2015/10/12)
-
- Magnetic nano Fe3O4 catalyzed solvent-free stereo- and regioselective a-aminolysis of epoxides by amines; A green method for the synthesis of β-amino alcohols
-
We report the use of magnetic nano Fe3O4 as a mild heterogeneous catalyst for the aminolysis of epoxides with amines. The approach constitutes a green method for the formation of a variety of β-amino alcohols with very high stereo- and regioselectivity under solvent-free and ambient reaction conditions. The aminolysis of chiral epoxides with amines gave the corresponding chiral β-amino alcohols with complete inversion of stereochemistry. The magnetic nano Fe3O4 catalyst can be easily recovered and recycled. Georg Thieme Verlag Stuttgart New York.
- Kumar, Amit,Parella, Ramarao,Babu, Srinivasarao Arulananda
-
p. 835 - 842
(2014/04/17)
-
- HPLC-fluorescence method for the enantioselective analysis of propranolol in rat serum using immobilized polysaccharide-based chiral stationary phase
-
A stereoselective high-performance liquid chromatographic (HPLC) method was developed and validated to determine S-(-)- and R-(+)-propranolol in rat serum. Enantiomeric resolution was achieved on cellulose tris(3,5- dimethylphenylcarbamate) immobilized onto spherical porous silica chiral stationary phase (CSP) known as Chiralpak IB. A simple analytical method was validated using a mobile phase consisted of n-hexane-ethanol-triethylamine (95:5:0.4%, v/v/v) at a flow rate of 0.6 mL min-1 and fluorescence detection set at excitation/emission wavelengths 290/375 nm. The calibration curves were linear over the range of 10-400 ng mL-1 (R = 0.999) for each enantiomer with a detection limit of 3 ng mL-1. The proposed method was validated in compliance with ICH guidelines in terms of linearity, accuracy, precision, limits of detection and quantitation, and other aspects of analytical validation. Actual quantification could be made for propranolol isomers in serum obtained from rats that had been intraperitoneally (i.p.) administered a single dose of the drug. The proposed method established in this study is simple and sensitive enough to be adopted in the fields of clinical and forensic toxicology. Molecular modeling studies including energy minimization and docking studies were first performed to illustrate the mechanism by which the active enantiomer binds to the β-adrenergic receptor and second to find a suitable interpretation of how both enantiomers are interacting with cellulose tris(3,5-dimethylphenylcarbamate) CSP during the process of resolution. The latter interaction was demonstrated by calculating the binding affinities and interaction distances between propranolol enantiomers and chiral selector. Chirality 26:194-199, 2014. 2014 Wiley Periodicals, Inc. Copyright
- Alanazi, Amer M.,Hefnawy, Mohamed M.,Al-Majed, Abdulrahman A.,Al- Suwailem, Aymen K.,Kassem, Mohamed G.,Mostafa, Gamal A.,Attia, Sabry M.,Khedr, Mohammed M.
-
p. 194 - 199
(2014/04/17)
-
- Electrically assisted liquid-phase microextraction combined with capillary electrophoresis for quantification of propranolol enantiomers in human body fluids
-
In this study, electromembrane extraction (EME) combined with cyclodextrin (CD)-modified capillary electrophoresis (CE) was applied for the extraction, separation, and quantification of propranolol (PRO) enantiomers from biological samples. The PRO enantiomers were extracted from aqueous donor solutions, through a supported liquid membrane (SLM) consisting of 2-nitrophenyl octyl ether (NPOE) impregnated on the wall of the hollow fiber, and into a 20-μL acidic aqueous acceptor solution into the lumen of hollow fiber. Important parameters affecting EME efficiency such as extraction voltage, extraction time, pH of the donor and acceptor solutions were optimized using a Box-Behnken design (BBD). Then, under these optimized conditions, the acceptor solution was analyzed using an optimized CD-modified CE. Several types of CD were evaluated and best results were obtained using a fused-silica capillary with ammonium acetate (80 mM, pH 2.5) containing 8 mM hydroxypropyl-β-CD as a chiral selector, applied voltage of 18 kV, and temperature of 20C. The relative recoveries were obtained in the range of 78-95%. Finally, the performance of the present method was evaluated for the extraction and determination of PRO enantiomers in real biological samples. Chirality 26:260-267, 2014. 2014 Wiley Periodicals, Inc.
- Tabani, Hadi,Fakhari, Ali Reza,Shahsavani, Abolfath,Gharari Alibabaou, Hossein
-
p. 260 - 267
(2014/05/06)
-
- Predictability of enantiomeric chromatographic behavior on various chiral stationary phases using typical reversed phase modeling software
-
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.
-
p. 506 - 513
(2013/09/12)
-
- Asymmetric synthesis of propranolol, naftopidil and (R)-monobutyrin using a glycerol desymmetrization strategy
-
Herein, an approach for desymmetrization of glycerol by using a readily available camphorsulfonamide as a starting material is described. The strategy for asymmetric synthesis of (R)/(S)-propranolol, (R)/(S)-naftopidil and (R)-monobutyrin with spiroketal formation by desymmetrization was employed and Mitsunobu reaction was used for epoxide and ether formation. Steglich esterification and CAN (cerium ammonium nitrate) mediated ketal deprotection, were key steps in the synthesis. Regioselective ring opening of epoxide gave desired molecule with good overall yield and optical purity.
- Lokhande, Mahendra N.,Chopade, Manojkumar U.,Bhangare, Dattatrya N.,Nikalje, Milind D.
-
p. 406 - 409
(2013/08/25)
-
- An efficient protocol for regioselective ring opening of epoxides using sulfated tungstate: Application in synthesis of active pharmaceutical ingredients atenolol, propranolol and ranolazine
-
Sulfated tungstate was found to be a new and highly efficient catalyst for opening of epoxide rings by amines to give β-amino alcohols with high regioselectivity. Various advantages associated with this novel and environmental friendly protocol include solvent-free conditions, short reaction times, high product yields, simple workup procedure and easy recovery and reusability of the catalyst. This protocol has been applied for the synthesis of active pharmaceutical ingredients atenolol, propranolol and ranolazine.
- Pathare, Sagar P.,Akamanchi, Krishnacharya G.
-
p. 6455 - 6459
(2013/11/19)
-
- Acetylation of (R,S)-propranolol catalyzed by Candida antarctica lipase B: An experimental and computational study
-
The chemo- and enantioselectivity of the Candida antarctica lipase B (CalB)-catalyzed acetylation reaction of (R,S)-propranolol using vinyl acetate as acyl donor and toluene as organic solvent was studied. Because of the poor solubility of propranolol in toluene small quantities of methanol were added as cosolvent. The effects of the propranolol/vinyl acetate ratio, the enzyme purification procedure and the methanol concentration on the reaction were investigated. The reactions occurring in the system were quantitatively investigated using 1H and 13C NMR spectroscopy. The major reactions were the hydrolysis and alcoholysis of vinyl acetate, as a consequence of the presence of residual water and methanol in the reaction medium. Furthermore, the NMR analysis confirmed that O-acetyl-propranolol was formed exclusively. The reaction was also found to be enantioselective favoring the faster transformation of the R-propranolol. In addition to the experiments, molecular modeling was used to study the formation of the reactive Michaelis complexes between propranolol and acetylated CalB, using a combined molecular docking and molecular dynamics (MD) procedure. Only for the O-acetylation we found binding modes of the substrate leading to formation of the product, which explains the experimentally observed chemoselectivity of CalB.
- Escorcia, Andres M.,Molina, Daniel,Daza, Martha C.,Doerr, Markus
-
-
- Chiral separation of basic compounds on sulfated β-cyclodextrin-coated zirconia monolith by capillary electrochromatography
-
Sulfated β-cyclodextrin (SCD)-coated zirconia monolith was used as the chiral stationary phase in capillary electrochromatography for enantiomeric separation of basic chiral compounds. SCD adsorbed on the zirconia surface provided a stable chiral stationary phase in reversed-phase eluents. Retention, chiral selectivity and resolution of a set of six basic chiral compounds were measured in eluents of varying pH, composition of methanol and buffer. Optimum mobile phase condition for the separation of the compounds was found to be methanol content of 30%, buffer concentration of 30 mM and pH of 4.0.
- Hong, Jong-Seong,Park, Jung Hag
-
p. 1809 - 1813
(2013/07/26)
-
- Synthesis, biological evaluation and mechanistic studies of totarol amino alcohol derivatives as potential antimalarial agents
-
Herein we report on the semisynthesis and biological evaluation of β-amino alcohol derivatives of the natural product totarol and other simple aromatic systems. All β-amino alcohol derivatives of totarol exhibited higher antiplasmodial activity than totarol [IC50: 11.69 μM (K1, chloroquine and multi-drug resistant strain), and 11.78 μM (D10, chloroquine sensitive strain)] - 12e was the most active [IC50: 0.63 μM (K1), and 0.61 μM (D10)]. The phenyl and naphthyl β-amino alcohol derivatives were much less active than their corresponding totarol equivalents. The majority of the β-amino alcohol derivatives of totarol were more active against K1 than the D10 strains of Plasmodium falciparum, a trend similar to the inverse relationship observed with the established aryl-amino alcohol antimalarial mefloquine. Selected compounds were shown to affect erythrocyte morphology, inhibit erythrocyte invasion and trigger CQ accumulation.
- Tacon, Claire,Guantai, Eric M.,Smith, Peter J.,Chibale, Kelly
-
experimental part
p. 893 - 902
(2012/03/22)
-
- Glycerine and CeClH: An efficient and recyclable reaction medium for ring opening of epoxides with thioamides and amines
-
Oxiranes undergo rapid ring-opening reaction with a range of thioamides and amines to afford the corresponding -amino alcohol derivatives. The reactions were carried out using glycerine and cerium(III) chloride as a recyclable reaction medium. All the reactions were carried out at room temperature and the products were obtained in excellent yields. Georg Thieme Verlag Stuttgart New York.
- Narsaiah, A. Venkat,Wadavrao, Sachin B.,Reddy, A. Ramesh,Yadav
-
experimental part
p. 485 - 489
(2011/04/16)
-
- The reactions of 4-chloro-2-butanol and 3-chloro-1-butanol with aqueous sodium hydroxide, and 1-chloro-2-propanol and 2-chloro-1-propanol with isopropyl amine
-
The total reaction of 4-chloro-2-butanol 1 with NaOH(aq) is dominated (74%) by intramolecular substitution (SNi), besides which bimolecular substitution (SN2, 12%) and 1,4-elimination (i.e. fragmentation, contrary to earlier arguments) exhibit a significant contribution (11%). The total reaction of 3-chloro-1-butanol 2 instead is dominated by 1,4-(72%) and 1,2-elimination (25%), the substitution reactions being just observable (SNi 2% and SN2 1%). In 1 both the +I-effect and the conformational factors in the intermediate γ-chloroalkoxy anion favour the SNi-reaction, whereas in 2 the situation is opposite and the location of Cl on a secondary carbon also makes the SNi-reaction less favourable. The relative proportions of 1,4-and 1,2-eliminations for 2 can be explained by thermodynamic basis since the consequent products are more stable than the corresponding products from 1. 1-chloro-2-propanol 3 and 2-chloro-1-propanol 4 both react with isopropyl amine giving the same product, namely 1-isopropylamino-2-propanol, which indicates that the reaction proceeds through the propylene oxide intermediate. Compound 1 also reacted with isopropyl amine predominantly via SNi-reaction, giving first 2-methyloxetane which then further gave 4-isopropylamino-2-butanol, whereas 2 gave 3-isopropylamino-1-butanol through a direct S N2-reaction. ARKAT-USA, Inc.
- Pihlaja, Kalevi,Aaljoki, Kari,Lyytinen, Maija-Riitta,Huusko, Marja-Liisa,Hotokka, Marjut
-
body text
p. 188 - 199
(2011/07/07)
-
- Disinfection facility
-
PROBLEM TO BE SOLVED: To provide a seed disinfecting unit capable of efficiently conducting disinfecting treatment of a large amount of seeds, such as seed rice, in a short time, when the unit is used for sterilizing and disinfecting various saprophytic bacteria attached to the seeds, by immersing the seeds in warm water. SOLUTION: This seed disinfecting unit has work lines L on which containers 21 for receiving the seeds are transported, wherein each of the work line L is equipped with a warm bath 2 for storing warm water, a cold bath 3 for storing cold water, and a self-propelled carriage 11 capable of reciprocating along the work line L. In one of the work lines, a carrying-in conveyor 4, the warm bath 2, the cold bath 3, and a carrying-out conveyor 5 are arranged at equal intervals of a pitch P1 in a direction in which the work line L extends. The self-propelled carriage 11 is equipped with 3 arm means 14a to 14c for attachably and detachably holding the container 21 are arranged so as to ascend and descend and to be aligned along the work line L at the same intervals of the pitch P1 to the above intervals of the pitch P1. COPYRIGHT: (C)2007,JPOandINPIT
- -
-
-
- Synthesis of dendrimer-type chiral stationary phases based on the selector of (1S,2R)-(+)-2-amino-1,2-diphenylethanol derivate and their enantioseparation evaluation by HPLC
-
In our recent work, a series of dendritic chiral stationary phases (CSPs) were synthesized, in which the chiral selector was L-2-(p-toluenesulfonamido)-3- phenylpropionyl chloride (selector I), and the CSP derived from three-generation dendrimer showed the best separation ability. To further investigate the influence of the structures of dendrimer and chiral selector on enantioseparation ability, in this work, another series CSPs (CSPs 1-4) were prepared by immobilizing (1S,2R)-1,2-diphenyl-2-(3-phenylureido)ethyl 4-isocyanatophenylcarbamate (selector II) on one- to four-generation dendrimers that were prepared in previous work. CSPs 1 and 4 demonstrated the equivalent enantioseparation ability. CSPs 2 and 3 showed the best and poorest enantioseparation ability respectively. Basically, these two series of CSPs exhibited the equivalent enantioseparation ability although the chiral selectors were different. Considering the enantioseparation ability of the CSP derived from aminated silica gel and selector II is much better than that of the one derived from aminated silica gel and selector I, it is believed that the dendrimer conformation essentially impacts enantioseparation.
- He, Bao-Jiang,Yin, Chuan-Qi,Li, Shi-Rong,Bai, Zheng-Wu
-
experimental part
p. 69 - 76
(2010/09/09)
-
- Chiral separations of some β-adrenergic agonists and antagonists on AmyCoat column by HPLC
-
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
-
experimental part
p. 24 - 28
(2010/09/14)
-
- THERAPY FOR COMPLICATIONS OF DIABETES
-
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.
- -
-
-
- ANTIHYPERTENSIVE THERAPY
-
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.
- -
-
-
- FLUORESCENCE BASED DETECTION OF SUBSTANCES
-
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.
- -
-
-
- Zinc(II) perchlorate hexahydrate catalyzed opening of epoxide ring by amines: Applications to synthesis of (RS)/(R)-propranolols and (RS)/(R)/(S)-naftopidils
-
(Figure Presented) Commercially available zinc(II) Perchlorate hexahydrate [Zn(ClO4)2·6H2O] was found to be a new and highly efficient catalyst for opening of epoxide rings by amines affording 2-amino alcohols in high yields under solvent-free conditions and with excellent chemo-, regio-, and stereoselectivities. For unsymmetrical epoxides, the regioselectivity was influenced by the electronic and steric factors associated with the epoxides and the amines. A complementarity in the regioselectivity was observed during the reaction of styrene oxide with aromatic and aliphatic amines: aromatic amines provided amino alcohols from nucleophilic attack at the benzylic carbon as major products whereas aliphatic amines resulted in formation of the amino alcohols through reaction at the terminal carbon atom of the epoxide ring as the major/sole products. Reaction of aniline with various glycidic ethers gave the amino alcohols by regioselective nucleophilic attack at the terminal carbon atom of the epoxide ring as the only/major product. Zinc(II) Perchlorate hexahydrate was found to be the best catalyst compared to other metal Perchlorates. The counteranion modulated the catalytic property of the various Zn(II) compounds that followed the order Zn(ClO4) 2·6H2O Zn(BF4)2 ～ Zn(OTf)2 ZnI2 > ZnBr2 > ZnCl2 > Zn(OAc)2 > Zn(CO3)2 in parallelism with the acidic strength of the corresponding protic acids (except for TfOH). The applicability of the methodology was demonstrated by the synthesis of cardiovascular drugs propranolol and naftopidil as racemates and optically active enantiomers.
- Shivani,Pujala, Brahmam,Chakraborti, Asit K.
-
p. 3713 - 3722
(2008/02/05)
-
