- 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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- 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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- 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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- GSH Induced Controlled Release of Levofloxacin from a Purpose-Built Prodrug: Luminescence Response for Probing the Drug Release in Escherichia coli and Staphylococcus aureus
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Fluoroquinolones are third-generation broad spectrum bactericidal antibiotics and work against both Gram-positive and Gram-negative bacteria. Levofloxacin (L), a fluoroquinolone, is widely used in anti-infective chemotherapy and treatment of urinary tract infection and pneumonia. The main pathogen for urinary tract infections is Escherichia coli, and Streptococcus pneumoniae is responsible for pneumonia, predominantly a lower respiratory tract infection. Poor permeability of L leads to the use of higher dose of this drug and excess drug in the outer cellular fluid leads to central nervous system (CNS) abnormality. One way to counter this is to improve the lipophilicity of the drug molecule, and accordingly, we have synthesized two new Levofloxacin derivatives, which participated in the spatiotemporal release of drug via disulfide bond cleavage induced by glutathione (GSH). Recent studies with Streptococcus mutants suggest that it is localized in epithelial lining fluid (ELF) of the normal lower respiratory tract and the effective [GSH] in ELF is ～430 μM. E. coli typically cause urinary tract infections and the concentration of GSH in porcine bladder epithelium is reported as 0.6 mM for a healthy human. Thus, for the present study we have chosen two important bacteria (Gram + ve and Gram - ve), which are operational in regions having high extracellular GSH concentration. Interestingly, this supports our design of new lipophilic Levofloxacin based prodrugs, which released effective drug on reaction with GSH. Higher lipophilicity favored improved uptake of the prodrugs. Site specific release of the drug (L) could be achieved following a glutathione mediated biochemical transformation process through cleavage of a disulfide bond of these purpose-built prodrugs. Further, appropriate design helped us to demonstrate that it is possible also to control the kinetics of the drug release from respective prodrugs. Associated luminescence enhancement helps in probing the release of the drug from the prodrug in bacteria and helps in elucidating the mechanistic pathway of the transformation. Such an example is scarce in the contemporary literature.
- Pal, Suman,Ramu, Vadde,Taye, Nandaraj,Mogare, Devraj G.,Yeware, Amar M.,Sarkar, Dhiman,Reddy, D. Srinivasa,Chattopadhyay, Samit,Das, Amitava
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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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- 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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- Conventional and microwave-assisted synthesis of quinolone carboxylic acid derivatives
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Various antibacterial fluoroquinolone compounds are synthesized by the direct amination of 7-halo-6-fluoroquinolone-3-carboxylic acids with a variety of piperazine derivatives and (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b]pyridine using microwave under different reaction conditions. Solvent free high yield microwave synthesis of antibacterial fluoroquinolone compounds is convenient, rapid and environmentally friendly method.
- Mirzaie,Lari,Vahedi,Hakimi
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- Nano-Fe3 O4@ZrO2-SO3 H as highly efficient recyclable catalyst for the green synthesis of fluoroquinolones
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Nano-Fe3 O4 @ZrO2-SO3 H (n-FZSA), was utilized as a magnetic catalyst for the synthesis of various fluoroquinolone compounds. These compounds were prepared by the direct amination of 7-halo-6-fluoroquinolone-3-carboxylic acids with piperazine derivatives and (4aR,7aR)-octahydro-1H-pyrrolo[3,4-b] pyridine in water. The results showed that n-FZSA exhibited high catalytic activity towards the synthesis of fluoroquinolone derivatives, giving the desired products in high yields. Furthermore, the catalyst was recyclable and could be used at least seven times without any discernible loss in its catalytic activity. Overall, this new catalytic method for the synthesis of fluoroquinolone derivatives provides rapid access to the desired compounds in refluxing water following a simple work-up procedure, and avoids the use of organic solvents.
- Nakhaei, Ahmad,Ramezani, Shirin,Shams-Najafi, Sayyed Jalal,Farsinejad, Sadaf
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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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- 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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- 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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- 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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- 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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- 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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- Novel marking method of levofloxacin
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The invention provides a synthetic method of levofloxacin, which uses formaldehyde and formic acid to methylate N-demethylated levofloxacin to obtain levofloxacin, and the method has the characteristics of high yield and high purity, and is suitable for labeling levofloxacin and isotopes thereof.
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Paragraph 0019-0030
(2021/01/30)
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- Preparation method of levofloxacin and intermediates thereof
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The invention relates to a preparation method of levofloxacin and intermediates thereof, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: carrying out amino substitution and ring closing reaction on a fluorine-substituted substrate to integrate a plurality of intermediates into a one-pot reaction, and hydrolyzing under acidic conditions to obtain levofloxacin. According to the method, the reaction operation is simplified, the production period is greatly shortened, multiple times of after-treatment are not needed, emission of three wastes is reduced, the method is more environmentally friendly, the reaction yield is increased by about 20% compared with the prior art, and the method is suitable for industrial amplification.
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- Preparation method of levofloxacin and intermediates thereof
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The invention relates to a preparation method of levofloxacin and intermediates thereof, and belongs to the field of medicinal chemistry. The preparation method comprises the following steps of: carrying out amino substitution and ring closing reaction on an intermediate substrate to integrate a plurality of intermediates into a one-pot reaction, and hydrolyzing under an acidic condition to obtainlevofloxacin. According to the method provided by the invention, the intermediates do not need to be separated, the reaction operation is simplified, the production period is greatly shortened, multiple times of after-treatment are not needed, emission of three wastes is reduced, the method is more environmentally friendly, the reaction yield is increased compared with the prior art, and the method is suitable for industrial amplification.
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Paragraph 0053-0056
(2021/03/30)
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- Synthesizing method of ofloxacin and levofloxacin
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The invention relates to a novel method for preparing ofloxacin and levofloxacin. The method includes: using ofloxacin carboxylic acid (ester) or levofloxacin carboxylic acid (ester) as the raw material, allowing the ofloxacin carboxylic acid (ester) or levofloxacin carboxylic acid (ester) to have reaction with borate to generate intermediate 1A or intermediate 1, allowing the intermediate 1A or intermediate 1 to have reaction with N- methyl piperazine to generated intermediate 2A or intermediate 2, hydrolyzing the intermediate 2A or intermediate 2 under an acid condition to obtain levofloxacin/ofloxacin salt, and freeing and extracting the levofloxacin/ofloxacin salt under a corresponding alkaline condition to obtain levofloxacin/ofloxacin or hydrate thereof. The method has the advantagesthat the initial materials and reagents used by the method are easy to obtain, the method is simple to operate, mild in reaction conditions, high in yield, low in cost and suitable for industrial production, and the purity of the levofloxacin/ofloxacin or hydrate thereof prepared by the method reaches up to 99.9%.
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Paragraph 0017; 0023
(2019/01/06)
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- Environment-friendly method for preparing levofloxacin hydrochloride
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The invention provides an environment-friendly method for preparing levofloxacin hydrochloride. The method comprises the following steps: preparing 3-(2-hydroxy-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparing levo-oxy main naphthenic acid, and preparing the levofloxacin hydrochloride. The method provided by the invention is concise, low in production cost, high in product yield, good in quality, economic and environment-friendly, fewer three wastes are discharged, and most byproducts are effectively separated and recycled, so that the method is convenient for industrial production and has great popularization significance.
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Paragraph 0020; 0024; 0028
(2017/10/05)
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- Method for preparing high-quality levofloxacin hydrochloride
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The invention provides a method for preparing high-quality levofloxacin hydrochloride. The method comprises the following steps: preparation of 3-(2-hydroxy-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparation of levo naphthenic acid and preparation of levofloxacin hydrochloride; the method is concise, the production cost is low, the product yield is high, quality is good, the method has the advantages of economic performance and environmental protection, three waste discharge capacity is little, effective separating and recycling on most by-product can be simultaneously realized, the method is convenient for industrial production, and has large popularization meaning.
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Paragraph 0020; 0024; 0028
(2017/10/07)
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- Method for preparing levofloxacin hydrochloride
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The invention provides a method for preparing levofloxacin hydrochloride. The method comprises preparation of 3-(2-hydroxyl-1-methyl-ethylamino)-2-(2,3,4,5-tetrafluorobenzoyl)-ethyl acrylate, preparation of levo-oxygen main naphthenic acid, and preparation of the levofloxacin hydrochloride. The method is simple, low in production cost, high in product yield, good in product quality, economical, environmentally friendly, and low in three-waste emission load, and realizes effective separation and recycling of most byproducts, is convenient for industrial production and has great significance of promotion.
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Paragraph 0020; 0024; 0028
(2017/10/26)
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- Levofloxacin and ofloxacin preparation method
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The invention discloses a preparing method for levofloxacin and ofloxacin. According to the preparing method, (S)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridino-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester (or9,10- difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyridino-[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid ethyl ester) is taken as a raw material and subjected to a shrinkage piperazine reaction with N-methyl-piperazine or water or an organic solvent to obtain levofloxacin ethyl ester or a mixture of levofloxacin and levofloxacin ethyl ester (or levofloxacin ethyl ester or levofloxacin and levofloxacin ethyl ester); levofloxacin ethyl ester or the mixture of levofloxacin and levofloxacin ethyl ester is then hydrolyzed in an organic solvent 2 or water or a mixed solvent of the organic solvent 2 and water under the acid or alkaline condition to obtain levofloxacin (or ofloxacin). According to the preparing method, operation is easy and fast, the reaction cost is lowered, the production cycle is short, and pollution is greatly reduced. Furthermore, the yield and purity of obtained levofloxacin or ofloxacin are high.
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Paragraph 0035-0038
(2017/09/01)
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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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- LEVO-ofloxacin and oxfloxacin synthetic method
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The invention provides a levofloxacin and ofloxacin synthesis method. S-9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-delta]-[1,4]-benzoxazinyl-6-carboxylate or 9,10-difluoro-2,3-dihydro-3- methyl-7-oxo-7H-pyrido[1,2,3-delta]-[1,4]-benzoxazinyl-6?-carboxylate is adopted as a raw material, two steps of hydrolysis and N-methylpiperazine replacement are improved, and one-pot process is carried out to synthesize. The method is a simple, economical and efficient one-step synthesis method Specific impurities generated in relevant operations are separated, identified and prepared. The method has the advantages of high raw material utilization rate, high yield and purity, original step simplification, reaction period shortening and convenience for the industrial production. The invention also provides a detection method of the relevant purities to discriminate products obtained through the synthesis method from products obtained through other synthesis methods.
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Paragraph 0052-0053
(2017/02/24)
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- Ofloxacin preparation method (by machine translation)
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The invention provides a preparation method of ofloxacin. The preparation method comprises the following steps of: reacting (N,N)-dimethylamino ethyl acrylate with aminopropanols in methylbenzene; directly adding lewis base serving as a catalyst and trimethylchlorosilane to protect hydroxyl and amido; after reaction is completely finished, dropwise adding (2,3,4,5)-tetrafluorobenzoyl chloride; preserving heat; performing acid washing; removing protecting groups; concentrating an organic layer to obtain an oil layer; adding a proper amount of dimethyl formamide (DMF); diluting and dropwise adding backflow DMF having anhydrous potassium fluoride; recovering DMF and adding water to centrifuge; adding acid water into a solid to hydrolyze to obtain difluorocarboxylic acid; and completely reacting difluorocarboxylic acid and N-methyl piperazine in dimethylsulfoxide (DMSO) by using triethylamine as an acid-binding agent at 90-100 DEG C to obtain ofloxacin. According to the process, hydroxyl and amido are protected by using trimethylchlorosilane, so that the utilization degree of (2,3,4,5)-tetrafluorobenzoyl chloride is effectively increased, and the generation of impurities is reduced to ensure that the reaction yield of intermediate difluorocarboxylic acid is increased by 10 percent.
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Paragraph 0019; 0033; 0034
(2016/10/09)
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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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- ANTI-OFLOXACIN MONOCLONAL ANTIBODY AND IMMUNOASSAY OF OFLOXACIN USING THE SAME
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A method that accurately and conveniently detects a compound shown by the formula (I) in a human sample is disclosed. An antibody that reacts with the compound shown by the formula (I), but does not cross-react with the N-oxide metabolite and the desmethyl levofloxacin metabolite of the compound shown by the formula (I) is prepared using an antigen produced by binding bovine serum albumin to the compound shown by the formula (I) through the 6-position carboxyl group. Immunoassay that measures the compound shown by the formula (I) that has not been metabolized is implemented using the above antibody.
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- METHOD FOR PRODUCING QUINOLONE CARBOXYLIC ACID DERIVATIVE
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The present invention relates to a method for producing a quinolone compound having high antibacterial activity and high safety, at high yield and in a simple manner. A quinolonecarboxylic acid derivative (1) of interest is produced through a one-pot manner by reacting a compound (2) with a salt of a cyclic amine (3) and with a boron derivative in a solvent in the presence of a base.
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Page/Page column 12
(2009/12/24)
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- Process for the preparation of an antibacterial quinolone compound
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It comprises a process for the preparation of levofloxacin based on a cyclisation reaction of a compound of formula (IV), which has the alcohol group protected, followed by a deprotection reaction and the conversion of the compound obtained to levofloxacin by a process comprising a hydrolysis reaction and a second cyclisation reaction. It also comprises new intermediates compounds.
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Page/Page column 11-12
(2008/12/06)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN HEMIHYDRATE
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The present invention relates to an improved process for the preparation of Levofloxacin hemihydrate by adjusting the moisture content of the solvent to about 12% to about 20% during crystallization.
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Page/Page column 5
(2008/06/13)
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- PROCESS FOR PREPARING LEVOFLOXACIN OR ITS HYDRATE
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The present invention provides a process of preparing levofloxacin hemihydrate or monohydrate without impurities, i.e. Impurities B, C, D, E, and F. The process comprises (a) adding crude levofloxacin to a novel mixed solvent, (b) refluxing the mixture obtained in (a) to form a solution, and (c) recovering levofloxacin hemihydrate or monohydrate from the solution obtained in (b).
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Page/Page column 3-4
(2008/06/13)
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- Novel anhydrous crystalline form of Levofloxacin and process for preparation there of
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The present invention is directed to novel anhydrous crystalline form of Levofloxacin is depicted as Formula (I), further more its process for preparation thereof. The process for the preparation of novel anhydrous crystalline form of Levofloxacin comprises the condensation of N-Methyl piperazine with S(?)-9,10-difluoro-7-oxo 2,3-dihydro 7H-pyrido[1,2,3-DE] [1,4] Benzoxazine-6-carboxylic acid in Acetonitrile followed by distillation of solvent to afford the residue, the resultant residue is refluxed with toluene and the solid is filtered at room temperature to afford the Levofloxacin. Thus resulted Levofloxacin is further refluxed in Acetonitrile and filtered the Novel anhydrous crystalline form of Levofloxacin as undissolved material. The anhydrous crystalline form of Levofloxacin is characterized by X-ray diffractogram, Differential Scanning Calorimetry thermogram and Infrared Spectra.
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Page/Page column 2-3
(2008/06/13)
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- PROCESS FOR PREPARATION OF OPTICALLY ACTIVE PROPOXYANILINE DERIVATIVES
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Treatment of a lactic acid ester derivative with an enzyme or the like, which has asymmetric ester-hydrolyzing ability, can specifically hydrolyze the ester moiety of an isomer existing as the pair to the racemic derivative. Use of the compound obtained by this hydrolysis makes it possible to produce an optically active propoxyaniline derivative by a shorter process than the conventional art.
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- Preparation of levofloxacin and forms thereof
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Levofloxacin was prepared by reacting (S)-(?)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid with N-methyl piperazine in a polar solvent or in a neat mixture to form levofloxacin. Further processing of the levofloxacin produced novel levofloxacin forms, including a hemihydrate and Forms A, B, C, F, G and H.
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- Methods for the purification of levofloxacin
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Levofloxacin has been purified by dissolving levofloxacin in a polar solvent at an elevated temperature and crystallizing purified levofloxacin. Preferably, an antioxidant is added to increase the purity.
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- PROCESS FOR THE PREPARATION OF BENZOXAZINE DERIVATIVES AND INTERMEDIATES THEREFOR
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A processes which is industrially advantageous in producing antibacterial agents. An industrially advantageous process for producing an intermediate useful in producing antibactrial agents is provided by producing compound (VI-a) in accordance with the following reaction schema. A process for producing the compound represented by the above formulae and production intermediates thereof.
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- Process for selectively producing an (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3-dihydro-7h-pyrido (1,2,3, -de) (1,4) benzoxazine-6-carboxylic acid hemihydrate or monohydrate
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A process for selectively producing an (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2,3 -dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid hemihydrate or monohydrate as depicted below, which comprises controlling the water content of an aqueous solvent in which an (S)-9-fluoro-3-methyl-10-(4-methyl-1-piperazin -yl)-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid is dissolved during a crystallization. STR1
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- Optically active pyridobenzoxazine derivatives and intermediates thereof
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An optically action pyridobenzoxazine derivative, a process for preparing the same and a novel intermediate useful for preparing the optically active pyridobenzoxazine derivative are disclosed. The optically active pyridobenzoxazine derivative possesses increased antimicrobial activity and reduced toxicity. The intermediate is useful for preparing such optically active pyridobenzoxazine derivatives such as Ofloxacin and anolog compounds.
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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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