- Linezolid preparation method and linezolid refining method
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The invention provides a linezolid preparation method, which comprises: hydrogenation reduction, amino protection and reduction reaction. The invention further provides a linezolid refining method, which comprises: purifying, refining, crystal transformation, impurity removal and other processes. According to the present invention, the reaction of the linezolid synthesis process is simple, the reagent used in the reaction is safe and non-toxic, the reaction yield is high, and the purification process of the refining method is simple, and does not require complicated chromatographic purification; and the linezolid preparation method and the refining method are suitable for large-scale industrial production.
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Paragraph 0034; 0039-0041; 0045; 0058; 0063-0065; 0069; 0073
(2019/09/10)
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- cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
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While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD-5) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD-6), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.
- Belousoff, Matthew J.,Venugopal, Hari,Wright, Alexander,Seoner, Samuel,Stuart, Isabella,Stubenrauch, Chris,Bamert, Rebecca S.,Lupton, David W.,Lithgow, Trevor
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p. 527 - 531
(2019/02/19)
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- A process for the preparation of linezolid
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The invention relates to a linezolid (1) preparation method. The method comprises the following steps: reacting a raw material 3,4-difluoronitrobenzene with morpholine, reducing, reacting with benzyl chloroformate to obtain N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline, carrying out a ring closure reaction of N-benzyloxycarbonyl-3-fluoro-4-morpholinylaniline and (S)-N-(2,3-epoxypropyl)phthalimide, ammonolyzing, and acetylating to obtain linezolid (1).
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- A kind of linezolid intermediate, preparation method thereof, and method for preparing and enduring zolamide
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The invention discloses a novel Linezolid intermediate, its preparation method and a novel preparation method of Linezolid, a structure of the Linezolid key intermediate is shown as a formula (I), in the formula (I), X is fluorine, chlorine, bromine or iodine. According to the invention, the Linezolid intermediate solves the problems of poor solubility of the Linezolid intermediate, and low yield and purity of the synthesized Linezolid in the prior art. The preparation methods of the invention have the advantages of easy preparation process, easy raw material acquisition, low cost, easy purification of intermediate product and final product, high yield and purity, and are suitable for large-scale industrial production.
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- PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF LINEZOLID AND ITS COMPOSITIONS
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The present invention relates to a process for the preparation of crystalline form I of linezolid, comprising providing a solution of linezolid in a solvent, crystallizing and recovering the solid of Linezolid in crystalline form I at elevated temperature. The present invention also relates to the use of crystalline form I of linezolid prepared by the method of the present invention for preparing pharmaceutical compositions.
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- Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives
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Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5′-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity.
- Phillips, Oludotun A.,D'Silva, Roselyn,Bahta, Teklu O.,Sharaf, Leyla H.,Udo, Edet E.,Benov, Ludmil,Eric Walters
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p. 120 - 131
(2015/11/24)
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- Convenient synthesis of the antibiotic linezolid via an oxazolidine-2,4-dione intermediate derived from the chiral building block isoserine
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We describe a new synthesis of the 5-(aminomethyl)oxazolidin-3-one core of linezolid in enantiomerically pure form. The expedient cyclization of the α-hydroxy amide derived from isoserine and 3-fluoro-4-morpholinoaniline to give the corresponding (aminomethyl)oxazolidine-2,4-dione, followed by its mild selective reduction at the C(4)-position, gave linezolid in almost quantitative overall yield. The 1,3-oxazolidin-2-one core of linezolid was obtained from isoserine in just three steps and with almost quantitative overall yield; the key features of the protocol are the expedient formation of the intermediate oxazolidine-2,4-dione, and its regioselective reduction at the 4-position.
- Greco, Arianna,De Marco, Rossella,Tani, Sara,Giacomini, Daria,Galletti, Paola,Tolomelli, Alessandra,Juaristi, Eusebio,Gentilucci, Luca
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p. 7614 - 7620
(2015/04/22)
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- PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID
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The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.
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- Novel promising linezolid analogues: Rational design, synthesis and biological evaluation
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A new series of 5-substituted oxazolidinones derived from linezolid, having urea and thiourea moieties at the C-5 side chain of the oxazolidinone ring, were prepared and their in vitro antibacterial activity was evaluated. The compound 10f demonstrated high antimicrobial activity, comparable to that of linezolid against Staphylococcus aureus.
- De Rosa, Margherita,Zanfardino, Anna,Notomista, Eugenio,Wichelhaus, Thomas A.,Saturnino, Carmela,Varcamonti, Mario,Soriente, Annunziata
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p. 779 - 785
(2013/10/22)
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- Microwave-assisted expeditious synthesis of 5-fluoroalkyl-3-(aryl/alkyl)- oxazolidin-2-ones
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An efficient and convenient protocol for synthesis of 5-fluoroalkyl-3- (aryl/alkyl)-oxazolidin-2-ones is described. The reaction of allyl (aryl/alkyl) carbamates with fluoroalkyl iodide initiated by sodium dithionite in aqueous acetonitrile resulted in adducts that undergoes a cyclization assisted by microwave irradiation to form 5-fluoroalkyl-3-(aryl/alkyl)-oxazolidin-2-ones with high yields. It was also found that the products can be more efficiently formed via an AIBN-initiated one-pot addition-cyclization sequence from benzyl allyl(aryl/alkyl) carbamates and fluoroalkyl iodide.
- Yang, Bo,Shi, Luyan,Wu, Jingjing,Fang, Xiang,Yang, Xueyan,Wu, Fanhong
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supporting information
p. 3331 - 3337
(2013/04/24)
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- PROCESS FOR THE PREPARATION OF LINEZOLID
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The present invention provides an improved process for the preparation of Linezolid of formula (D. The present invention relates to preparation of intermediate (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl |-2-oxo-5-oxazolidinyl] methanol of formula (II), Linezolid amine of formula (Ia) and their use in the preparation of Linezolid. The present invention further provides process for the preparation of Form I of Linezolid of formula (I).
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- PROCESSES FOR THE PREPARATION OF LINEZOLID
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Disclosed herein a process for preparing linezolid, wherein the resultant linezolide is devoid of impurities and involve easy and economical process. The present invention further relates to preparation of linezolid by employing an azide intermediate and process for said intermediate.
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- PROCESSES FOR PREPARING LINEZOLID
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Processes and intermediates for preparing linezolid, and pharmaceutically acceptable salts thereof, are described herein.
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- METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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A method for preparing the linezolid (compound 1), which comprises the steps of: (1) carrying out the debenzyl reaction of compound 4 in solvent, to obtain the compound 5 or its acetate; (2) carrying out the acetylation reaction in the amino of the compound 5 or its acetate obtained in step (1) in solvent to obtain the compound 1. The intermediates to prepare the compound 1 and the acetate of compound 5. The present preparation method is easy to obtain the chiral materials and the chiral materials are cheap, the process and the post treatment are simple, the intermediate products and the end product are easy to be purified, the total yield is high, their purities are also high, this preparation method is easy to be used in the industry manufacture.
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- METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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A method for preparing the linezolid (compound 1), which comprises the steps of: (1) carrying out the debenzyl reaction of compound 4 in solvent, to obtain the compound 5 or its acetate; (2) carrying out the acetylation reaction in the amino of the compound 5 or its acetate obtained in step (1) in solvent to obtain the compound 1. The intermediates to prepare the compound 1 and the acetate of compound 5. The present preparation method is easy to obtain the chiral materials and the chiral materials are cheap, the process and the post treatment are simple, the intermediate products and the end product are easy to be purified, the total yield is high, their purities are also high, this preparation method is easy to be used in the industry manufacture.
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Page/Page column 7
(2011/11/13)
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- Design and synthesis of novel 5-acetylthiomethyl oxazolidinone analogs
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The oxazolidinone class of antimicrobial agents represents a promising advance in the fight against resistant Gram-positive bacterial infections. To improve antibacterial activity and expand the spectrum of activity including Gram-negative bacteria, a series of novel 5-acetylthiomethyl oxazolidinone analogs were designed and synthesized based on the structure-activity relationship studies. The structures of the target compounds and main intermediates were confirmed by 1H NMR, 13C NMR, infrared (IR), mass spectra (MS), and elemental analysis.
- Chen, Lei,Wang, Jian-Wei,Hai, Li,Wang, Guang-Ming,Wu, Yong
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experimental part
p. 789 - 798
(2010/05/18)
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- Syntheses and antibacterial activity studies of new oxazolidinones from nitroso Diels-Alder chemistry
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A series of novel oxazolidinone antibiotics having [2.2.1] and [2.2.2] bicyclic oxazine moieties at the C-5 side chain of the A-ring was synthesized by nitroso Diels-Alder reactions, from three linezolid analogs containing morpholine, piperazine and thiomorpholine, respectively, as the C-ring components. Subsequent N-O bond cleavage generated oxazolidinones with 4-amino cyclo-2-en-1-ol substituents. The in vitro antibacterial activities of these oxazolidinone analogs were evaluated.
- Yan, Shanshan,Miller, Marvin J.,Wencewicz, Timothy A.,Moellmann, Ute
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supporting information; experimental part
p. 1302 - 1305
(2010/06/15)
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- PROCESS FOR PREPARATION OF (S) (N-[[3-[3-FLUORO-4-(4-MORPHOLINYL) HEN L -2-OXO-5-OXAZOLIDIN L METHYL]ACETAMIDE
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The present invention provides novel process for preparation of (S)-N-[[3-[3-Fluoro-4-(4- morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] -acetamide which comprises combining (R)-N-[3-[3-fluoro-4-morpholinyl phenyl]-2-oxo-5-oxazolidinyl]methylazide in suitable solvent, acetylating agent and acid in presence of a catalyst.
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Page/Page column 13
(2009/06/27)
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- An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: SN1(Ar*) vs. S R+N1(Ar*) mechanism
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The morpholinofluorophenyloxazolidinone 1 (the antibacterial drug linezolid) is found to undergo reductive defluorination upon irradiation in water (Φ 0.33), in some of the products accompanied by the simultaneous oxidative degradation of the morpholine side chain. In the presence of chloride, iodide and pyrrole, the fluorine is substituted by these groups (with pyrrole, in position 2). The defluorination is less efficient in methanol and mainly leads to reduction (Φ 0.053). These data can be accommodated through two different mechanisms, viz. either C-F bond heterolysis to give a phenyl cation [SN1(Ar*)], or ionization to give a radical cation [S R+N1(Ar*)]. Steady-state and time resolved data have been gathered for clarifying this issue. It is found that, indeed, ionization of 1 is efficient and proceeds from the singlet, but leads to no irreversible change. On the contrary, triplet 31 (lifetime 0.5 μs in MeOH, 0.1 μs in water) fragments and gives the corresponding triplet phenyl cation. The last intermediate explains well the observed hydrogen abstraction both inter- (from the solvent, when this is reducing) and intramolecularly (from the morpholine group), as well as addition to a charged anion or to a neutral π nucleophile such as pyrrole. The rationalization is supported by the study of some related molecules. Thus, the only photochemical reaction from the non fluorinated analogue of linezolid (that ionizes just as 1) is an inefficient degradation of the morpholine chain (Φ 0.001), while a simple model such as N-(2-fluorophenyl)morpholine undergoes photosolvolysis in water and is not trapped by pyrrole.
- Fasani, Elisa,Tilocca, Fedele,Protti, Stefano,Merli, Daniele,Albini, Angelo
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experimental part
p. 4634 - 4642
(2009/03/12)
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- Synthesis and antibacterial activity of linezolid analogues
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Several new compounds of oxazolidinone class were designed and synthesized referring to the structure-activity relationship studies and the synthesis of Linezolid, and their antibacterial activity was studied.
- Yu, Du,Huiyuan, Guo
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p. 857 - 859
(2007/10/03)
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- Substituted oxazine and thiazine oxazolidinone antimicrobials
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A compound of structural Formula I: STR1 or pharmaceutically acceptable salts thereof wherein: X is O, S, SO, SO2, SNR10 or S(O)NR10 ; R is (a) hydrogen, (b) C1 -C8 alkyl optionally substituted with one or more of the following: F, Cl, hydroxy, C1 -C8 alkoxy, C1 -C8 acyloxy or --O--CH2 --Ph, (c) C3 -C6 cycloalkyl, (d) amino, (e) C1 -C8 alkylamino, (f) C1 -C8 dialkylamino or (g) C1 -C8 alkoxy; R1 is H, except when X is O then R1 can be H, CH3, CN, CO2 H, CO2 R or (CH2)m R11 (m is 1 or 2); R2 is independently H, F or Cl; R3 is H except when X is O and R1 is CH3 then R3 can be H or CH3 ; R10 is independently H, C1 -C4 alkyl (optionally substituted with chloro, fluoro, hydroxy, C1 -C8 alkoxy, amino, C1 -C8 alkylamino, or C1 -C8 dialkylamino) or p-toluenesulfonyl; R11 is hydrogen, OH, OR, OCOR, NH2, NHCOR or N(R10)2 ; and n is 0, 1 or 2. The oxazine and thiazine oxazolidinone derivatives are useful antimicrobial agents, effective against a number of human and veterinary pathogens, including gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms such as Bacteroides spp. and Clostridia spp. species, and acid-fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium and Mycobacterium spp.
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- Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections.
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Bacterial resistance development has become a very serious clinical problem for many classes of antibiotics. The 3-aryl-2-oxazolidinones are a relatively new class of synthetic antibacterial agents, having a new mechanism of action which involves very early inhibition of bacterial protein synthesis. We have prepared two potent, synthetic oxazolidinones, U-100592 and U-100766, which are currently in clinical development for the treatment of serious multidrug-resistant Gram-positive bacterial infections caused by strains of staphylococci, streptococci, and enterococci. The in vitro and in vivo (po and iv) activities of U-100592 and U-100766 against representative strains are similar to those of vancomycin. U-100592 and U-100766 demonstrate potent in vitro activity against Mycobacterium tuberculosis. A novel and practical asymmetric synthesis of (5S)-(acetamidomethyl)-2-oxazolidinones has been developed and is employed for the synthesis of U-100592 and U-100766. This involves the reaction of N-lithioarylcarbamates with (R)-glycidyl butyrate, resulting in excellent yields and high enantiomeric purity of the intermediate (R)-5-(hydroxymethyl)-2-oxazolidinones.
- Brickner, Steven J.,Hutchinson, Douglas K.,Barbachyn, Michael R.,Manninen, Peter R.,Ulanowicz, Debra A.,et al.
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p. 673 - 679
(2007/10/03)
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