168828-90-8Relevant articles and documents
New linezolid synthesis method
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, (2019/05/16)
The invention belongs to the field of organic synthesis, and particularly relates to a new linezolid synthesis method, which comprises: synthesizing 3-fluoro-4-morpholinophenyl isocyanate by using 3,4-difluoronitrobenzene as a starting raw material, carrying out cyclization on the 3-fluoro-4-morpholinophenyl isocyanate and (R)-epichlorohydrin under the catalysis of MgI2 or MgBr2 in the absence ofa solvent to obtain (R)-3-fluoro-4-morpholinophenyl oxazolidone, and carrying out azide group substitution, reduction and acetylation to obtain linezolid. According to the present invention, by usingthe new linezolid synthesis method, the reaction rate can be significantly accelerated, the yield can be increased, the cost can be reduced, the environment can be protected, the operation is simple,the post-treatment is convenient, and the method is suitable for industrial production.
cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
Belousoff, Matthew J.,Venugopal, Hari,Wright, Alexander,Seoner, Samuel,Stuart, Isabella,Stubenrauch, Chris,Bamert, Rebecca S.,Lupton, David W.,Lithgow, Trevor
, p. 527 - 531 (2019/02/19)
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.
Linezolid preparation method
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Paragraph 0020, (2019/02/03)
The invention relates to a linezolid preparation method. 3-fluoro-4-morpholinyl aniline is taken as a starting material and subjected to a reaction with (S)-(+)-N-(2,3-ethoxypropyl) phthalimide, an intermediate 1 is generated and subjected to a cyclization reaction with a carbonylation agent, an intermediate 2 is generated, an ammonolysis reaction and an acetylation reaction are performed, and a target compound is obtained. The problems of poor safety, strict conditions, many impurities and low yield, which are not suitable for industrial production, of a linezolid preparation method in the prior art are solved, the starting material of the route is cheap and available, the operation is simple, hazardous reagents are avoided, the solvent is easily recycled and reused, reaction yield is higher, purity of a final product is up to 99.9% or higher, and the linezolid preparation method is suitable for industrial production.
Method for preparing linezolid intermediate
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Paragraph 0023-0034, (2019/10/01)
The invention provides a method for preparing a linezolid intermediate (S)-5-(aminomethyl)-3-(3-fluoro-4-morpholinophenyl)oxazolidin-2-one. The method comprises the following steps of adding ammoniumhydroxide, basic nickel carbonate and a platinum carbon or palladium carbon catalyst into a reaction bottle respectively, and stirring to obtain a catalyst, wherein the weight ratio of the basic nickel carbonate to the ammonium hydroxide to the palladium carbon or platinum carbon is 1 to (1 to 10) to (1 to 5); adding a compound 9 into a high pressure kettle, adding the catalyst prepared in the step (1), introducing hydrogen while stirring, removing the pressure after the reaction is completed, filtering a reaction material to remove the catalyst, and concentrating and drying the filter liquorto obtain a white solid. According to the method provided by the invention, on the basis of catalytic hydrogenation reaction of the palladium carbon or platinum carbon, the compound basic nickel carbonate is added, so that the defluorination reaction is effectively inhibited, enabling the product to have high purity without the need of refining, reach the high standard of crude drugs, thereby effectively saving the cost.
Method of preparing linezolid
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, (2018/04/02)
The invention relates to a method of preparing an oxazolidine antibacterial agent-linezolid. The method includes: enabling (S, E)-N-benzal-1-(ethylene oxide-2-group)-methylamine and morpholino fluoro-phenyl carbamate to react in a non-nucleophilic agent under action of alkali and catalyst to obtain a high-purity imine intermediate; subjecting the intermediate to hydrolysis and acylation to generate linezolid. The method is high in yield, simple to operate, mild in reaction condition and suitable for industrial production.
Preparation method of linezolid
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Paragraph 0035; 0063; 0064, (2017/07/12)
The invention discloses a preparation method of linezolid. (S)-4-chloro-1,3-butanediol (compound 1) is taken as a raw material, and linezolid is obtained after potassium phthalimide substitution, Curtius rearrangement ring closure, Ullmann coupling, hydrazinolysis and amidation; a synthesis process causes small pollution and is easy to treat, the yield and purity in each step are high, and the method is environment-friendly, low in production cost and suitable for industrial production.
A novel method for preparation of linezolid, (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide
Seku, Kondaiah,Badathala, Vijayakumar,RaoVelivelad, Venkata Srinivasa,Desireddy, Srinivasa Reddy
, p. 56 - 60 (2017/03/08)
Background: Linezolid (I) [(S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide] is a synthetic antibiotic used for the treatment of serious infections caused by grampositive bacteria that are resistant to other antibiotics. Linezolid empirical formula is C16H20FN3O4and its molecular weight is 337.35. It is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). The main uses are infections of the skin and pneumonia, although it may be used for a variety of other infections. Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. Lohray et al., in 1999, have reported a synthetic method for Linezolid starting from D-mannitol, the chemical synthesis of Linezolid by alternate route has attracted several research groups in the past 15years. Methods: An improved and economically viable process is described to prepare Linezolid wherein methyl 3-fluoro-4-morphinolino phenyl carbamate (V) is reacted with R-epichlorohydrin in the presence of n-butyllithium in hexane to obtain (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (IV) which reacts with potassium phthalimide in presence of polar solvent to give (S)-2-[3-(3-3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidine-5-yl methyl]-isoindole-1,3-dione (III), which is subsequently converted to Linezolid. Results: Linezolid was obtained via only four steps with yield 90% and high purity. This process avoids formation and use of sensitive intermediates. It is an improved process for the preparation of an intermediate (R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (formula IV). Conclusion: Linezolid was successfully synthesized from (3-fluoro-4-morpholin-4-yl-phenyl)-carbamic ester via R-epichlorohydrin and potassium phthalimide and developed new intermediate (5R)-5-chloromethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl) oxazolidin-2-one (IV). The present method relates to a novel, cost effective and industrially viable process. Thus, the process described is less cumbersome by way of reduced reaction stages, high purity and quantity of the yield. In comparison with previously reported synthetic strategies, this novel approach is believed to be the shortest and the most efficient synthetic route to date.
Process for the preparation of linezolid
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Page/Page column 19, (2017/05/31)
The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing (S)—N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (S)-glycidyl phthalimide intermediates, which are used in the preparation of Linezolid.
AN IMPROVED PROCESS FOR THE PREPARATION OF LINEZOLID
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Page/Page column 20, (2017/11/14)
The present invention relates to an improved process for the preparation of Linezolid. More specifically, the present invention relates to an improved process for preparing(S)-N-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl] phthalimide and (S)-glycidyl phthalimide intermediates, which are used in the preparation of Linezolid.
Compound design guidelines for evading the efflux and permeation barriers of Escherichia coli with the oxazolidinone class of antibacterials: Test case for a general approach to improving whole cell Gram-negative activity
Spaulding, Andrew,Takrouri, Khuloud,Mahalingam, Pornachandran,Cleary, Dillon C.,Cooper, Harold D.,Zucchi, Paola,Tear, Westley,Koleva, Bilyana,Beuning, Penny J.,Hirsch, Elizabeth B.,Aggen, James B.
supporting information, p. 5310 - 5321 (2017/11/13)
Previously we reported the results from an effort to improve Gram-negative antibacterial activity in the oxazolidinone class of antibiotics via a systematic medicinal chemistry campaign focused entirely on C-ring modifications. In that series we set about testing if the efflux and permeation barriers intrinsic to the outer membrane of Escherichia coli could be rationally overcome by designing analogs to reside in specific property limits associated with Gram-negative activity: i) low MW (7.4 1), and iii) zwitterionic character at pH 7.4. Indeed, we observed that only analogs residing within these limits were able to overcome these barriers. Herein we report the results from a parallel effort where we explored structural changes throughout all three rings in the scaffold for the same purpose. Compounds were tested against a diagnostic MIC panel of Escherichia coli and Staphylococcus aureus strains to determine the impact of combining structural modifications in overcoming the OM barriers and in bridging the potency gap between the species. The results demonstrated that distributing the charge-carrying moieties across two rings was also beneficial for avoidance of the outer membrane barriers. Importantly, analysis of the structure-permeation relationship (SPR) obtained from this and the prior study indicated that in addition to MW, polarity, and zwitterionic character, having ≤4 rotatable bonds is also associated with evasion of the OM barriers. These combined results provide the medicinal chemist with a framework and strategy for overcoming the OM barriers in GNB in antibacterial drug discovery efforts.
