- Novel ofloxacin derivatives: Synthesis, antimycobacterial and toxicological evaluation
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Thirty novel 9-fluoro-2,3-dihydro-8,10-(mono/di-sub)-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acids were synthesized from 2,3,4,5-tetrafluoro benzoic acid and evaluated for in vitro and in vivo antimycobacterial activities against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant Mycobacterium tuberculosis (MDR-TB), and Mycobacterium smegmatis (MC2) and also tested for the ability to inhibit the supercoiling activity of DNA gyrase from mycobacteria. Among the synthesized compounds, 10-[2-carboxy-5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active compound in vitro with MIC99 of 0.19 μM and 0.09 μM against MTB and MTR-TB, respectively. In the in vivo animal model also the same compound decreased the bacterial load in lung and spleen tissues with 1.91 and 2.91 - log 10 protections, respectively, at the dose of 50 mg/kg body weight. Compound 10-[(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)]-9-fluoro-2,3-dihydro-3-methyl-8-nitro-7-oxo-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid was found to be the most active in the inhibition of the supercoiling activity of DNA gyrase with an IC50 of 10.0 μg/mL. The results demonstrate the potential and importance of developing new oxazino quinolone derivatives against mycobacterial infections.
- Dinakaran, Murugesan,Senthilkumar, Palaniappan,Yogeeswari, Perumal,China, Arnab,Nagaraja, Valakunja,Sriram, Dharmarajan
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- Preparation method of levofloxacin intermediate
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The invention relates to a preparation method of a levofloxacin intermediate, which comprises the following steps: adding a compound shown as a formula I into water, adding alkali under the conditionof introducing gas to carry out alkaline hydrolysis, and further reacting with acid to obtain a compound shown as a formula II. The method has the advantages of simple post-treatment, low impurity content in the product, and no need of adding an organic solvent.
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Paragraph 0017; 0042-0056
(2020/09/16)
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- Synthesis method of levofloxacin carboxylic acid (by machine translation)
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The method comprises the following steps, mixing: dimethylaminopropyl methacrylate with an acid-binding agent in an organic solvent A, and then carrying out an amine exchange reaction A, to obtain N,N -tetrafluorobenzoyl - 3 3 3 3 3-dimethylaminopropyl A acrylate as shown in formula III B, in the reaction mixture A to obtain a mixture liquid, and a mixed solution 2 - (2, 3, 4, 5) - condensation reaction A; to obtain the compound. A. The reaction liquid L - is dissolved in an organic solvent, The reaction solution 2 - (2, 3, 4, 5) - is obtained by a condensation reaction with a mixture solution.) - The method comprises the following steps, (II). The method comprises the following steps of: adding B aminopropanol, to the reaction solution; and HCl, HOAc, H carrying out an amine exchange reaction with a mixed solution of N- propyl methyl acrylate. 2 The reaction of the acid system of O to give the levofloxacin carboxylic acid. of formula V prevents the preparation N,N - dimethylaminoethyl acrylate from being unstable and difficult, unsafe and expensive sodium ethoxide, to corrosion of the device. (by machine translation)
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Paragraph 0037-0045
(2020/02/27)
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- ANTIBIOTIC RESISTANCE BREAKERS
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The invention relates to antibiotic compounds of formula (A1) and pharmaceutically acceptable salts, solvates, tautomers and combinations thereof, wherein X and L are optional linkers and one of RA or R1 comprises Ar1, wherein Ar1 is an antibiotic resistance breaker moiety which comprises an optionally substituted C6-10 aryl, C7-13 aralkyl, C5-10 heteroaryl, C6-13 heteroaralkyl, C5-10 heterocyclyl, C6-13 heterocyclalkyl, C3-10 carbocyclyl, C4-13 carbocyclalkyl, -C(=NR')-NR'R'' or –CH2- CH=CH2 group; wherein after administration of the compound to a bacterial infection this moiety reduces or prevents efflux. The invention also discloses pharmaceutical compositions comprising compounds of formula (A1) and the use of such compounds as medicaments, in particular, to treat bacterial infections, such as drug-resistant bacterial infections.
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Page/Page column 77; 78
(2019/01/05)
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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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- 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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- 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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- 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; 0030; 0031
(2016/10/09)
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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 preparation of Levofloxacin hemihydrate having single individual impurity not more than 0.1% and free from particulate matter and from the other enantiomer (R-form) which comprises dissolving levofloxacin technical grade in aqueous alkaline solution, treating the resulting solution with activated carbon at room temperature, removing the undissolved particulate matter filtration, bringing the pH of the aqueous alkaline levofloxacin solution to neutral using dilute mineral acid, removing the precipitated particulate matter by filtration, acidifying the resulting solution, treating the acidified solution with activated carbon at room temperature, filtering the undissolved particulate matter by filtration, neutralizing the acidic solution, filtering again to remove any particulate matter present and, extracting the resulting product with chlorinated solvent and concentrating under vacuum using aqueous tetrahydrofuran or in admixture with other organic solvents to get highly pure levofloxacin hemihydrate having single individual impurity is less than 0.1% and fee from particulate matter and from the other enantiomer (R-form).
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Page/Page column 18
(2008/06/13)
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- Novel oxazolidinone-quinolone hybrid antimicrobials
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Antimicrobial compounds incorporating oxazolidinone and quinolone pharmacophore substructures have been synthesized and evaluated. Representative analogues 2, 5, and 6 display an improved potency versus linezolid against gram-positive and fastidious gram-negative pathogens. The compounds are also active against linezolid- and ciprofloxacin-resistant Staphylococcus aureus and Enterococcus faecium strains. The MOA for these new antimicrobials is consistent with a combination of protein synthesis and gyrase A/topoisomerase IV inhibition, with a structure-dependent degree of the contribution from each inhibitory mechanism.
- Gordeev, Mikhail F.,Hackbarth, Corinne,Barbachyn, Michael R.,Banitt, Lee S.,Gage, James R.,Luehr, Gary W.,Gomez, Marcela,Trias, Joaquim,Morin, Sara E.,Zurenko, Gary E.,Parker, Christian N.,Evans, Jonathan M.,White, Richard J.,Patel, Dinesh V.
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p. 4213 - 4216
(2007/10/03)
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- An improved synthesis of levofloxacin
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The benzoxazinecarboxylic acid (8), a precursor of levofloxacin (1), was prepared from (S)-2-amino-l-propanol (2) in 4 steps in good overall yield. The synthesis is characterized by one pot construction of 8 from the useful benzoylacrylates (7) which are effectively prepared in three steps. The key intermediates (7) were obtained from 2-nitrobenzoyl derivative (6a) and 2-fluorobenzoyl derivative (6b) through acylation of the acrylates (5), respectively.
- Kang, Soon Bang,Park, Seonhee,Kim, Yong Hae,Kim, Youseung
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p. 137 - 145
(2007/10/03)
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- Method for the preparation of (-)piperazine benzoxazine derivatives
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There is disclosed a method for the preparation of the antibacterial (-) piperazine benzoxazine derivative having formula I comprising the steps of reacting (+)2-aminomethylene-3-oxo-3-phenylpropionate derivative of formula II with a base in an organic polar solvent, to give a (-) benzoxazine derivative of formula III: and reacting the (-) benzoxazine derivative of formula III with a piperazine derivative of formula IV in an organic polar solvent. 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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