- Asymmetric metal-free synthesis of fluoroquinolones by organocatalytic hydrogenation
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A highly enantioselective organocatalytic transfer hydrogenation enabling the synthesis of both 6-fluoro-2-methyltetrahydroquinoline and 7,8-difluoro-3-methyl-benzoxazine has been developed. These key building blocks can for the first time be synthesized using the same methodology allowing fast and efficient, metal-free access to the antibiotic fluoroquinolones flumequine and levofloxacine.
- Rueping, Magnus,Stoeckel, Mirjam,Sugiono, Erli,Theissmann, Thomas
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- In-situ and one-step preparation of protein film in capillary column for open tubular capillary electrochromatography enantioseparation
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In this work, the phase-transitioned BSA (PTB) film using the mild and fast fabrication process adhered to the capillary inner wall uniformly, and the fabricated PTB film-coated capillary column was applied to realize open tubular capillary electrochromatography (OT-CEC) enantioseparation. The enantioseparation ability of PTB film-coated capillary was evaluated with eight pairs of chiral analytes including drugs and neurotransmitters, all achieving good resolution and symmetrical peak shape. For three consecutive runs, the relative standard deviations (RSD) of migration time for intra-day, inter-day, and column-to-column repeatability were in the range of 0.3%–3.5%, 0.2%–4.9% and 2.1%–7.7%, respectively. Moreover, the PTB film-coated capillary column ran continuously over 300 times with high separation efficiency. Therefore, the coating method based on BSA self-assembly supramolecular film can be extended to the preparation of other proteinaceous capillary columns.
- Li, Ling,Xue, Xuqi,Zhang, Huige,Lv, Wenjuan,Qi, Shengda,Du, Hongying,Manyande, Anne,Chen, Hongli
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supporting information
p. 2139 - 2142
(2021/04/07)
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- Experimental and computational study on the enantioseparation of four chiral fluoroquinolones by capillary electrophoresis with sulfated-β-cyclodextrin as chiral selector
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In this work, enantioseparation of four chiral fluoroquinolones (FQs), namely, ofloxacin, gemifloxacin, lomefloxacin, and gatifloxacin, was achieved by capillary electrophoresis with sulfated-β-cyclodextrin (S-β-CD) as chiral selector. Factors affecting the enantiomeric resolution, such as the concentrations of S-β-CD, BGE pH conditions, and the buffer types and concentrations, were optimized and discussed. A BGE consisting of 30 g/L S-β-CD and 30-mM phosphate at pH?4.0 was found fit for enantiomeric resolution of ofloxacin and gemifloxacin, while the same BGE at pH?3.0 was suitable for enantioseparation of lomefloxacin and gatifloxacin. The pH-dependent experiments showed that separation resolutions of four FQs enantiomers were significantly affected by BGE pH, which was thought to be related with the varying electrostatic attraction between the enantiomers and chiral selector. To verify this speculation, molecular docking studies were used for further investigation of the enantiomeric recognition mechanism of S-β-CD. Molecular model indicated that hydrophobic effect and hydrogen bond were involved in host-guest inclusion, but the electrostatic attraction enhanced the chiral discrimination by increasing the difference in binding energy between individual enantiomers and S-β-CD. This work provided a further insight into the chiral recognition mechanisms of CD derivatives.
- Ma, Qianyun,Cong, Wei,Liu, Ye,Geng, Zikai,Lin, Ying,Wang, Zhaokun
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p. 549 - 557
(2021/07/20)
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- Preparation of polar group derivative β-cyclodextrin bonded hydride silica chiral stationary phases and their chromatography separation performances
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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
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p. 643 - 649
(2018/11/27)
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- Structure-retention relationship for enantioseparation of selected fluoroquinolones
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Fluoroquinolones are popular class of antibiotics with distinct chemical functionality. Most of them are ampholytes with one chiral center. Stereogeneic center is located either in the side ring of Gatifloxacin (GFLX) or in the quinolone core of Ofloxacin (OFLX). These two amphoteric fluoroquinolones have terminal amino groups in common. The unusual Nadifloxacin (NFLX) is an acidic fluoroquinolone with a core chiral center. Owing to chirality and functionality differences among GFLX, OFLX, and NFLX, we mapped these enantiomers onto structure-retention relationship. Amount of acetic acid modifier was studied in screened mobile phase and cellulose tris(3-chloro-4-methyl phenyl carbamate) (Lux cellulose-2) stationary phase. Experimental design of acetic acid% along with column temperature have been applied. Resolution and enantioselectivity have been related to structural features of the studied enantiomers. High amount of acid (0.4%) was optimum for the separation of either side chirality with a proximate amino group (GFLX) or core chirality without basic functionality (NFLX), while low amount (0.2%) is optimum for core chiral center with distal amino group (OFLX). Temperature has no significant effect on resolution and retention of enantiomers except for OFLX. Enantio-retention explains possible chiral selective and nonselective interactions. The proposed methods have been validated for pharmaceutical analyses.
- Hassan, Rasha M.,Yehia, Ali M.,Saleh, Ola A.,El-Azzouny, Aida A.,Aboul-Enein, Hassan Y.
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p. 828 - 836
(2018/04/10)
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- Chiral separation and modeling of quinolones on teicoplanin macrocyclic glycopeptide antibiotics CSP
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New chiral high-performance liquid chromatography (HPLC) method for the enantiomeric resolution of quinolones is developed and described. The column used was Chirobiotic T (150?×?4.6?mm, 5.0?μm). Three mobile phases used were MeOH:ACN:Water:TEA (70:10:20:0.1%), (60:30:10:0.1%), and (50:30:20:0.1%). The flow rate of the mobile phases was 1.0?mL/min with UV detection at different wavelengths. The values of retention, resolution, and separation factors ranged from 1.5 to 6.0, 1.80 to 2.25, and 2.86 to 6.0, respectively. The limit of detection and quantification ranged from 4.0 to 12?ng and 40 to 52?ng, respectively. The modeling studies indicated strong interactions of R-enantiomers with teicoplanin chiral selector than S-enantiomers. The supra molecular mechanism of the chiral recognition was established by modeling and chromatographic studies. It was observed that hydrogen bondings and π-π interactions are the major forces for chiral separation. The present chiral HPLC method may be used for enantiomeric resolution of quinolones in any matrices.
- Ali, Imran,Suhail, Mohd,Asnin, Leonid
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p. 1304 - 1311
(2018/10/24)
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- Ofloxacin turns on lathe the thingsha Xingxiao split reagent and method
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The invention discloses a split reagent and a split method for an ofloxacin racemic mixture. The method is as below: dissolving an ofloxacin racemic mixture and an alkyl imidazole L-tartaric acid salt ionic liquid in deionized water to form an aqueous phase, and at the same time dissolving D-dibenzoyl tartaric acid in n-decyl alcohol to form an organic phase; mixing the organic phase and the aqueous phase; oscillating the mixture in an oscillator and standing; detecting concentration of L-ofloxacin and D-ofloxacin in a clear aqueous phase; acquiring the concentration of L-ofloxacin and D-ofloxacin in organic phase respectively by the law of conservation of mass; respectively calculating the distribution coefficient of the L-ofloxacin and D-ofloxacin; and further calculating a separation factor. The reagent and the method have good separation effect, and is successfully in splitting. The invention uses alkyl imidazole L-tartaric acid salt ionic liquid and D-dibenzoyl tartaric acid for splitting of the ofloxacin racemic mixture, improves the splitting efficiency and reduces the reagents required by splitting; and the method has simple operation and high selectivity, and is suitable for industrial production.
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Paragraph 0020; 0021
(2017/02/09)
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- Intrinsic enantioselectivity of natural polynucleotides modulated by copper ions
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Natural polynucleotides including Micrococcus lysodeikticus and calf thymus DNA exhibit enantioselective recognition to S-ofloxacin regulated by Cu2+. This is the first report that ofloxacin and Cu2+ have cooperative effects on the local distortions of polynucleotides. At the [Cu2+]/[base] ratio of 0.1, S-ofloxacin is more liable to induce the locally distorted structures of polynucleotides, of which the association constant of S-ofloxacin toward DNA-Cu(II) is three times higher than that of the R-enantiomer. The apparent increase of adsorption capability and cooperativity, as well as the change of adsorption mechanism were detected in the adsorption of ofloxacin enantiomers on polynucleotides upon Cu(II)-coordination. This study not only discloses the effect of the chiral drug on the structural transition of long double-stranded DNA, but provides fundamental data to develop a novel enantioseparation method based on natural polynucleotides.
- Fu, Yan,Chen, Xiongfei,Zhang, Jinli,Li, Wei
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p. 306 - 313
(2015/03/30)
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- Enantioselective separation of chiral ofloxacin using functional Cu(ii)-coordinated G-rich oligonucleotides
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The DNA-based selector for discriminating chiral ofloxacin with high enantioselectivity and affinity is constructed through Cu(ii)-coordination with G-rich duplex containing successive guanines. Using this chiral selector, R- and S-ofloxacin can be direct
- Fu, Yan,Duan, Xiaoli,Chen, Xiongfei,Zhang, Jinli,Li, Wei
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p. 1329 - 1333
(2014/01/06)
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- Combined use of ionic liquid and hydroxypropyl-β-cyclodextrin for the enantioseparation of ten drugs by capillary electrophoresis
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In the present study, hydroxypropyl-β-cyclodextrin and an ionic liquid (1-ethyl-3-methylimidazolium-l-lactate) were used as additives in capillary electrophoresis for the enantioseparation of 10 analytes, including ofloxacin, propranolol hydrochloride, dioxopromethazine hydrochloride, isoprenaline hydrochloride, chlorpheniramine maleate, liarozole, tropicamide, amlodipine benzenesulfonate, brompheniramine maleate, and homatropine methylbromide. The effects of ionic liquid concentrations, salt effect, cations, and anions of ionic liquids on enantioseparation were investigated and the results proved that there was a synergistic effect between hydroxypropyl-β-cyclodextrin and the ionic liquid, and the cationic part of the ionic liquid played an important role in the increased resolution. With the developed dual system, all the enantiomers of 10 analytes were well separated in resolutions of 5.35, 1.76, 1.85, 2.48, 2.88, 1.43, 5.45, 4.35, 2.76, and 2.98, respectively. In addition, the proposed method was applied to the determination of the enantiomeric purity of S-ofloxacin after validation of the method in terms of selectivity, repeatability, linearity range, accuracy, precision, limit of detection (LOD), and limit of quality (LOQ). Chirality 25:409-414, 2013.
- Cui, Yan,Ma, Xiaowei,Zhao, Min,Jiang, Zhen,Xu, Shuying,Guo, Xingjie
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p. 409 - 414
(2013/07/26)
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- Equilibrium and structural characterization of ofloxacin-cyclodextrin complexation
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The enantiomer-specific characterization of ofloxacin-cyclodextrin complexes was carried out by a set of complementary analytical techniques. The apparent stability constants of the ofloxacin enantiomers with 20 different cyclodextrins at two different pH values were determined to achieve good resolution capillary electrophoresis enantioseparation either to establish enantioselective drug analysis assay, or to interpret and design improved host-guest interactions at the molecular level. The cyclodextrins studied differed in the nature of substituents, degree of substitution (DS), charge and purity, allowing a systematic test of these properties on the complexation. The seven-membered beta-cyclodextrin and its derivatives were found to be the most suitable hosts. Highest stability and best enantioseparation were observed for the carboxymethylated-beta-cyclodextrin (DS 3.5). The effect of substitution pattern (SP) was investigated by molecular modeling, verifying that SP greatly affects the complex stability. Induced circular dichroism was observed and found especially significant on carboxymethylated-beta- cyclodextrin. The complex stoichiometry and the geometry of the inclusion complexes were determined by 1H NMR spectroscopy, including 2D ROESY techniques. Irrespective of the kind of cyclodextrin, the complexation ratio was found to be 1:1. The alfa-cyclodextrin cavity can accommodate the oxazine ring only, whereas the whole tricyclic moiety can enter the beta- and gamma-cyclodextrin cavities. These equilibrium and structural information offer molecular basis for improved drug formulation. Springer Science+Business Media B.V. 2012.
- Toth, Gergo,Mohacsi, Reka,Racz, Akos,Rusu, Aura,Horvath, Peter,Szente, Lajos,Beni, Szabolcs,Noszal, Bela
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p. 291 - 300
(2014/01/06)
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- Enantioseparation of racemic mixtures based on solvent sublation
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A method of solvent sublation was developed for the enantioseparation of racemic ofloxacin (rac Oflx) and racemic tryptophan (rac Trp). In this method, dibenzoyl-L-tartaric acid (L-DBTA) and di-(2-ethylhexyl) phosphoric acid (D2EHPA) and sodium lauryl sulfate (SDS) were used as chiral coextractants and foamer, respectively. Several important parameters influencing the separation performances, such as pH in aqueous phase, concentrations of rac mixtures, L-DBTA, D2EHPA, and SDS, were investigated. Under the optimal operation conditions, the enantiomeric excess and enantioselectivity were 60.08% and 5.58 for Oflx and 65.09% and 6.31 for Trp, respectively. The yields of D-enantiomer and L-enantiomer were 34.23% and 8.54% for Oflx and 18.59% and 3.93% for Trp, respectively. The results suggest that the enantioselectivities have been enhanced compared with the traditional chiral extraction. This technique is an efficient chiral separation method, with many advantages such as low expenditures of organic solvent, low consumption of chiral extractant, and easy realization of multistage operation. Chirality 24:661-667, 2012. 2012 Wiley Periodicals, Inc. Copyright
- Jiao, Feipeng,Yang, Weijie,Wang, Fen,Tian, Lingxing,Li, Lin,Chen, Xiaoqing,Mu, Kelang
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experimental part
p. 661 - 667
(2012/10/18)
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- Enantioselective extraction of racemic ofloxacin by di(2-ethylhexyl) phosphoric acid and tartaric acid derivatives as mixed complex chiral selectors
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The distribution behavior of ofloaxcin (OFLX) enantiomers in a two-phase system was examined using a new mixed complex chiral selector consisting of di(2-ethylhexyl) phosphoric acid (D2EHPA) and two tartaric acid derivatives with n-octanol as diluents. The influence of composition of mixed complex chiral selector, initial concentration of OFLX, pH of aqueous phase and temperature was investigated. A maximum enantioselectivity of 2.43 was obtained when the molar concentration ratio of L-(-)-DBTA to L-(-)-DTTA is 2:3 L-(-)-DTTA concentration 0.18 mol/L, L-(-)-DBTA concentration 0.12mol/L) and the pH of aqueous phase is 6.86 at 25°C, with DD and DL up to a relative high value of 10.2 and 4.20, respectively. The results indicated a useful way of searching new efficient chiral selectors and it was proved also helpful to optimize the extraction systems and realize the large-scale production of the pure isomer of racemic mixtures with extraction methods.
- Tian, Lingxing,Yang, Weijie,Chen, Xiaoqing,Xie, Yixi
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experimental part
p. 642 - 645
(2012/02/14)
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- Determination of levofloxacin in human urine with capillary electrophoresis and fluorescence detector
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In this study, we developed an analytical method for the enantioseparation of ofloxacin, using capillary electrophoresis with fluorescence detection. The optimum background electrolyte was obtained to be 60 mM hydroxylpropyl-β- cyclodextrin (HP-β-CD) in 50 mM phosphate buffer at pH 2.30. Under these conditions, the (+) and (-) ofloxacin were completely separated, with the detection limit of 10 nM when the sample was prepared in deionized water. The linear ranges of levofloxacin in deionized water and untreated urine were 10-7 to 5 × 10-3 M with R2 = 0.9989 and 5 × 10-6 to 5 × 10-3 M with R2 = 0.9943, respectively. We also applied this method to investigate the purity of a commercial drug. The results revealed that the ratio between (+)-ofloxacin and (-)-ofloxacin (levofloxacin) was 99.9:0.1, and there is about 93 mg levofloxacin per tablet (200 mg). The concentration of levofloxacin in patient's urine was founded to be 7.9 × 10-4 M, and the ratio between the two optical isomers was 99.3:0.7.
- Tsai, Yu-Hsien,Bair, Ming-Jong,Hu, Cho-Chun
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p. 991 - 995
(2008/02/13)
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- An efficient synthesis of ofloxacin and levofloxacin from 3,4- difluoroaniline
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The functionalization at either C-2 or C-3 of N-(tert-butoxycarbonyl)- 3,4-difluoroaniline based on its ortho-deprotonation under different experimental conditions is described. This kind of products can be readily applied to the synthesis of ofloxacin, levofloxacin and related compounds.
- Adrio, Javier,Carretero, Juan C.,Garcia Ruano, Jose L.,Pallares, Antonio,Vicioso, Mercedes
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p. 1563 - 1572
(2007/10/03)
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- Optically active benzoxazines and bezothiazines and a process for their stereospecific preparation
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Optically active 7,8-difluoro-3,4-dihydro-3--methyl-2H-[1,4]benzoxazines and 7,8-difluoro-3,4-dihydro-2--methyl-2H-[1,4]benzoxazines and the corresponding benzothiazines of formula III, where, one of the substituents R1, R2, R3 and R4 is CH2OH or -CH2Z, the remaining being hydrogen, X denotes fluoro, chloro, methyl or hydrogen, Y is oxygen or sulfur and Z is hydrogen, fluoro or protected hydroxyl are obtained as the stereochemically pure products of a stereospecific synthesis using a 3,4-difluoronitrobenzene substituted with a stereochemically pure 2-(1-hydroxyisopropoxy), 2-(2--hydroxypropoxy), 2-(1-hydroxyisopropylthio) or 2-(2--hydroxypropylthio) substituent. The obtained compounds are suited for the production of optically active pyridobenzoxazines and pyridobenzothiazines, among which are useful antibacterial optically active quinolones, particularly (S)-(-)-ofloxacin.
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- Chiral DNA gyrase inhibitors. 2. Asymmetric synthesis and biological activity of the enantiomers of 9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7H-py ido[1,2,3,-de]-1,4-benzoxazine-6-carboxylic acid (ofloxacin)
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A short and efficient synthesis, starting with (R)- and (S)-alaninol, of the two optical antipodes of the quinolone antimicrobial agent ofloxacin has been devised. Testing in vitro of the products against a range of bacteria and in an assay system incorporating purified DNA gyrase from different bacterial species demonstrates that the S-(-) enantiomer is substantially the more active.
- Mitscher,Sharma,Chu,Shen,Pernet
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p. 2283 - 2286
(2007/10/02)
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