- Linezolid preparation method
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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.
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Paragraph 0019
(2019/02/03)
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- ONE POT SYNTHESIS FOR THE PREPARATION OF SUBSTITUTED PHTHALIMIDO OXAZOLIDINONE ANTIBACTERIALS AND OXAZOLIDINONE ANTIHAROMBOTICS COMPOUNDS BY USING RECYCLABLE HETEROGENEOUS CATALYST
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A novel one pot and high yield process for the preparation of substituted phthalimidooxazolidinone compounds by using recyclable heterogeneous catalyst and preparation of oxazolidinoneantibacterials and oxazolidinoneantithrombotics thereof.
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Page/Page column 10-11
(2018/04/20)
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- A novel method for preparation of linezolid, (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide
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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.
- Seku, Kondaiah,Badathala, Vijayakumar,RaoVelivelad, Venkata Srinivasa,Desireddy, Srinivasa Reddy
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- Preparation method of linezolid
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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.
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- Process for the preparation of linezolid
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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.
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Page/Page column 17
(2017/05/31)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF LINEZOLID
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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.
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Page/Page column 17
(2017/11/14)
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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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Paragraph 0032; 0060-0061
(2017/01/05)
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- PROCESS FOR THE PREPARATION OF OXAZOLIDINONE DERIVATIVES
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The present invention relates to an improved process for the preparation of Oxazolidinone derivatives. 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, an intermediate used in the preparation of Oxazolidinone derivatives.
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Paragraph 0043
(2016/04/26)
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- METHOD FOR PREPARING LINEZOLID INTERMEDIATE
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Disclosed is a new method for preparing a methyl substitute of a linezolid intermediate, (S)-2-(3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) (I), wherein the intermediate (I) is obtained by the cyclization of 3-fluoro-4-morpholinophenyl isocyanate (II) and epoxy compound (III). This process has a short process route, low cost, easy operation, and high yield, so is suitable for a large-scale industrial production.
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Paragraph 0030-0033
(2015/02/18)
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- PROCESS FOR PREPARATION OF LINEZOLID
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The present invention discloses an in-situ process for preparation of Linezolid polymorphic Form II free of impurities.
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Page/Page column 10; 11; 13; 14
(2015/11/16)
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- METHOD FOR PREPARING LINEZOLID INTERMEDIATE
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Disclosed is a new method for preparing a methyl substitute of a linezolid intermediate, (S)-2-(3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazoline) (I), wherein the intermediate (I) is obtained by the cyclization of 3-fluoro-4-morpholinophenyl isocyanate (II) and epoxy compound (III). This process has a short process route, low cost, easy operation, and high yield, so is suitable for a large-scale industrial production.
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Paragraph 0031
(2015/01/18)
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- A novel synthesis of oxazolidinone derivatives (A key intermediate of linezolid)
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Oxazolidinone derivatives a very key intermediate of Linezolid 7(a-e) have been synthesized from 3-fluoro-4-morpholinyl aniline 2 in good yield.The structures of all the compounds were confirmed by IR, 1H NMR, 13C NMR and Mass Spectral data.
- Reddy, Pingili Krishna,Mukkanti,Rao, Dodda Mohan
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p. 1015 - 1019
(2014/03/21)
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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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- A facile synthesis of the oxazolidinone antibacterial agent linezolid
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A facile synthetic route of linezolid 1 has been developed. Using commercially available (R)-epichlorohydrin as the starting material, 1 was obtained through a sequence of cyclization, substitution, a Goldberg coupling, aminolysis and acetylation reactions. The synthetic route is easy to perform and can be scaled up.
- Li, Yan-Wu,Liu, Yan,Jia, Yun-Can,Yuan, Jian-Yong
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p. 230 - 232
(2013/06/26)
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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4-morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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- NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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A novel process for preparing oxazolidinone antibacterial agent Linezolid including key intermediates of oxazolidinones comprising: reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; carbonylation to form oxazolidinone derivative; acetylation of (5R)-5-(chloromethyl)-3-(3-fluoro-4- morpholinophenyl-oxazolidin-2-one with sodium acetate to get novel intermediate; hydrolysis of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl acetate; mesylation of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methanol; reaction of (R)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl methane sulphonate with potassium phthalimide; hydrolysis of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl phthalimide with hydrazine hydrate; acetylation of (S)-3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl methyl amine with acetic anhydride yields Linezolid in high yield.
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- Synthesis of antibiotic linezolid analogues
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Several new compounds of oxazolidinone class were designed, synthesized and their analogs were evaluated for antibacterial activity against Staphylococcus aureus, Staphylococcus citreus, Proteus vulgaris, Salmonella typhimurium and Klabsiella phenumoniae. The structures of all the compounds were confirmed by IR, 1H NMR, 13C NMR and mass spectral data.
- Reddy, Pingili Krishna,Mukkanti,Rao, Dodda Mohan
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p. 3479 - 3482
(2012/07/28)
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- An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: A short and efficient synthesis of Linezolid
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A short, concise and efficient synthesis of Linezolid was accomplished through a convergent scheme utilizing either (S)-1-azido-3-chloropropan-2-yl chloroformate or (S)-1- phthalimido-3- chloropropan-2-yl chloroformate as a key starting material. The synthesis demonstrates utility of (S)-1-azido-3- chloropropan-2-yl chloroformate and/or (S)-1-phthalimido-3-chloropropan-2-yl chloroformate to facilitate the expeditious construction of 3-aryl-5- (substituted methyl)-2- oxazolidinones and offers the possibility of accessing related 2-oxazolidinone members easily as well as making additional analogues of Linezolid. ARKAT-USA, Inc.
- Tammana, Rajesh,Vemula, Kiran Kumar,Guruvindapalli, Ramadasu,Yanamandr, Ramesh,Gutta, Madhusudhan
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- Novel process for the preparation of linezolid and related compounds
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The present invention provides a novel process for preparation of 5-aminomethyl substituted oxazolidinones, key intermediates for oxazolidinone antibacterials including linezolid. Thus linezolid is prepared by a) reacting 3-fluoro-4-morpholinyl aniline with R-epichlorohydrin; b) subjecting N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline produced above to carbonylation; c) reacting (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone produced above with potassium phthalinide; d) reacting (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide produced above with hydrazine hydrate; and e) reacting S-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazo-lidinyl]methyl]amine produced above with acetic anhydride to produce linezolid.
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Page/Page column 5
(2008/06/13)
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- NOVEL INTERMEDIATES FOR LINEZOLID AND RELATED COMPOUNDS
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The present invention provides a novel process for preparation of 5-aminomethyl substituted oxazolidinones, key intermediates for oxazolidinone antibacterials including linezolid. Thus, the key intermediate of linezolid is prepared by a) reacting N-[3-Chloro-2-(R)-hydroxypropyl]-3-fluoro-4-morpholinyI aniline with potassium phthalimide; b) subjecting N-[3-pthalimido-2-(R)-hydroxypropyl]-3-fluoro-4-(morpholinyl) aniline produced in the above step to carbonylation; and c) reacting (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidiriyl] methyl]phthalimide produced in the above step with hydrazine hydrate to produce (S)-N-[[3-[3-Fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl]amine.
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Page/Page column 11
(2008/06/13)
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