cas 168828-90-8, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine

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Method for preparing linezolid intermediate
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.
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Paragraph 0023-0034

(2019/10/01)

cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
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
p. 527 - 531
(2019/02/19)

Linezolid preparation method
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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(2019/02/03)

New linezolid synthesis method
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.
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(2019/05/16)

Method of preparing linezolid
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.
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Paragraph 0017; 0065; 0066

(2018/04/02)

A novel method for preparation of linezolid, (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxo-5-oxazolidinyl) methyl) acetamide
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
p. 56 - 60
(2017/03/08)

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
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.
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)

Preparation method of linezolid
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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Paragraph 0035; 0063; 0064

(2017/07/12)

Process for the preparation of linezolid
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 19

(2017/05/31)

AN IMPROVED PROCESS FOR THE PREPARATION OF LINEZOLID
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 20

(2017/11/14)

A kind of linezolid intermediate, preparation method thereof, and method for preparing and enduring zolamide
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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(2017/04/04)

Linezolid for the preparation of the intermediate and its preparation method
The invention relates to a novel intermediate which is used for preparing linezolid and is represented by formula I, and a preparation method thereof. Raw materials of the preparation method are cheap and easily available; process route is short; operation is simple; cost is low; reaction process conditions are mild and safe; reaction time is short; no special equipment is required, and the preparation method is suitable for industrialized production. In formula I, R1 is used for representing alkoxy.
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Paragraph 0066-0069

(2017/03/08)

PROCESS FOR PREPARATION OF CRYSTALLINE FORM I OF LINEZOLID AND ITS COMPOSITIONS
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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Page/Page column 7; 12; 13

(2015/05/26)

A convenient synthesis of the antibacterial agent linezolid
Starting with 3,4-difluorobenzoic acid (8) and (S)-epichlorohydrin (13) a convergent synthesis of linezolid (1) was developed that is attractive for large scale preparation of the drug. The synthetic strategy involves a 1+3 cycloaddition reaction between the chiral epoxide 11 (prepared from 13) and isocyanate 3 (obtained from 8) that was generated in situ by a Curtius rearrangement. The resulting Schiff base precursor of linezolid (12) crystallized from the reaction mixture and was readily converted to linezolid by an acid-catalyzed hydrolysis followed by an acetylation.
McCarthy, James R.
p. 6846 - 6847
(2015/11/27)

ALPHA,BETA-UNSATURATED MONOMERS CAPABLE OF MULTIMERIZATION IN AN AQUEOUS SOLUTION, AND METHODS OF USING SAME
Described herein are monomers capable of forming a biologically useful multimer when in contact with one, two, three or more other monomers in an aqueous media. In one aspect, such monomers may be capable of binding to another monomer in an aqueous media (e.g. in vivo) to form a multimer, (e.g. a dimer). Contemplated monomers may include a ligand moiety, a linker element, and a connector element that joins the ligand moiety and the linker element. In an aqueous media, such contemplated monomers may join together via each linker element and may thus be capable of modulating one or more biomolecules substantially simultaneously, e.g., modulate two or more binding domains on a protein or on different proteins.
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Paragraph 0306; 0307; 0308

(2015/03/28)

PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES
A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.
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Page/Page column 32; 33

(2014/11/11)

Convenient synthesis of the antibiotic linezolid via an oxazolidine-2,4-dione intermediate derived from the chiral building block isoserine
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
p. 7614 - 7620
(2015/04/22)

IMPROVED PROCESSES FOR THE PREPARATION OF LINEZOLID USING NOVEL INTERMEDIATES
Provided herein are improved, commercially viable and industrially advantageous processes for the preparation of Linezolid, in high yield and purity, using novel intermediates. In one aspect, provided herein are efficient, industrially advantageous and environmentally friendly processes for the preparation of linezolid, in high yield and with high purity, using novel intermediates. The processes disclosed herein avoid the tedious and cumbersome procedures of the prior processes, thereby resolving the problems associated with the processes described in the prior art, which is more convenient to operate at lab scale and in commercial scale operations.
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Page/Page column 58

(2014/11/13)

PROCESS FOR MAKING LINEZOLID
The present invention relates to a benzoate salt of the compound 3-(3-fluoro-4- (morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine of formula (II-D), which is useful in the purification of the compound of formula (II) and in a process for making linezolid of formula (I).
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Page/Page column 17

(2014/05/24)

Synthesis, biological evaluation of new oxazolidino-sulfonamides as potential antimicrobial agents
A number of linezolid-like oxazolidino-sulfonamides (7a-y and 8a-b) were designed and synthesized with a view to develop antimicrobial agents with improved properties. Most of the synthesized compounds showed good to moderate activity against a panel of standard Gram-positive and Gram-negative bacteria and fungal strains. The compounds 7i and 7v exhibited significant activity, with a MIC value of 2.0-6.0 μg/mL against a panel of Gram-positive and Gram-negative bacteria. These compounds also showed activity against Candida albicans, with a MIC value of 4.0 μg/mL. A correlation of the antimicrobial activity with calculated lipophilicity values (C log P) is also presented.
Kamal, Ahmed,Swapna,Shetti, Rajesh V.C.R.N.C.,Shaik, Anver Basha,Narasimha Rao,Gupta, Soma
p. 661 - 669
(2013/05/09)

Novel promising linezolid analogues: Rational design, synthesis and biological evaluation
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
p. 779 - 785
(2013/10/22)

PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID
The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.
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(2013/06/05)

NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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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(2014/01/07)

A novel synthesis of oxazolidinone derivatives (A key intermediate of linezolid)
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
p. 1015 - 1019
(2014/03/21)

A facile synthesis of the oxazolidinone antibacterial agent linezolid
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
p. 230 - 232
(2013/06/26)

A facile solvent-free synthesis of chiral oxazolidinone derivatives catalyzed by MgI2 etherate: An approach to enantiopure synthesis of linezolid
A highly efficient and stereoselective cycloaddition of aryl isocyanates with chiral oxiranes catalyzed by MgI2 etherate under solvent-free conditions was developed to prepare the chiral oxazolidinone derivatives. This methodology has been applied into the practical synthesis of antibacterial drug linezolid.
Zhang, Xingxian,Zhao, Chengfeng,Gu, Yue
p. 1143 - 1146,4
(2020/09/16)

NOVEL PROCESS FOR PREPARATION OF LINEZOLID AND ITS NOVEL INTERMEDIATES
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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(2012/09/11)

Synthesis of antibiotic linezolid analogues
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
p. 3479 - 3482
(2012/07/28)

A new method for the oxazolidinone key intermediate of linezolid and its formal synthesis
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Park, HoonGyu,Kim, Bojung,Bae, Daeil,Lim, Byungjo,Ko, Misun,Oh, Sehan,Kim, Hakwon
p. 1389 - 1392
(2012/07/13)

PROCESS FOR MAKING LINEZOLID
The present invention relates to a process for making the compound 3-(3-fluoro-4- (morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine of formula (II) and/or an acid addition salt thereof comprising b) reacting the compound of formula (VII) wherein L is a leaving group, with a metal salt of diformylamide of formula (VIII) wherein Me+ is a sodium or potassium cation, b) subjecting the reaction product of the step (a) comprising, alone or in admixture, compounds of formula (IXa) and/or (IXb), to a reaction with an acid, and to the making of linezolid by acetylation of the compound of formula (II), and to the compounds (IXa) and (IXb) in making linezolid.
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Page/Page column 10

(2012/03/09)

PROCESS FOR MAKING LINEZOLID
The present invention relates to a process for making the compound 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine of formula (II) and/or an acid addition salt thereof comprising b) reacting the compound of formula (VII) wherein L is a leaving group, with a metal salt of diformylamide of formula (VIII) wherein Me+ is a sodium or potassium cation, b) subjecting the reaction product of the step (a) comprising, alone or in admixture, compounds of formula (IXa) and/or (IXb), to a reaction with an acid, and to the making of linezolid by acetylation of the compound of formula (II).
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Page/Page column 10-11

(2012/03/09)

An expeditious construction of 3-aryl-5-(substituted methyl)-2- oxazolidinones: A short and efficient synthesis of Linezolid
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
scheme or table
p. 45 - 56
(2012/03/11)

The effect of systematic structural modifications on the antibacterial activity of novel oxazolidinones
A novel series of tetraethylene glycol (TEG) triazolyl and squaramide containing oxazolidinones were synthesized and tested for their antibacterial activity against a selected panel of Gram-positive and Gram-negative bacteria. The 4-TEG-triazolyl derivatives were prepared by 'click reaction'. The introduction of the TEG and squaramide groups did not favor antibacterial activity. The three nucleoside-containing oxazolidinones were also prepared by 'click' methodology resulted in weak antibacterial activity.
Pinter, Gabor,Bereczki, Ilona,Roth, Elizabeth,Sipos, Attila,Varghese, Reny,Udo, Edet Ekpenyong,Ostorhazi, Eszter,Rozgonyi, Ferenc,Phillips, Oludotun Adebayo,Herczegh, Pal
experimental part
p. 45 - 55
(2012/01/11)

PROCESS FOR THE PREPARATION OF LINEZOLID
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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Page/Page column 19

(2011/07/09)

PROCESSES FOR THE PREPARATION OF LINEZOLID
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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Page/Page column 24

(2011/10/10)

PROCESSES FOR PREPARING LINEZOLID
Processes and intermediates for preparing linezolid, and pharmaceutically acceptable salts thereof, are described herein.
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(2011/11/13)

METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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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(2011/12/03)

METHOD FOR PREPARING LINEZOLID AND INTERMEDIATES THEREOF
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 9

(2011/11/13)

A PROCESS FOR THE PREPARATION OF (5S)-(N)-[[3-[3-FLUORO-4-(4-MORPHOLINYL) PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL] ACETAMIDE
The present invention is directed to a novel, industrially viable, cost effective process for manufacturing (5S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide going through a novel intermediate of Formula XXI and XXII.
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Page/Page column 17

(2010/08/08)

Process for the preparation of an oxazolidinone antibacterial agent and intermediates thereof
Comprising a preparation process of linezolid from a compound of formula (IV) where R1 is selected from a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom, and a straight or branched (C3-C10)-alkenyl radical attached to the N atom such that the C=C double bond is separated from the N atom by a methylene group. Compound (IV) is submitted either first to an acetylation reaction and then to a dealkylation reaction or, alternatively, first to a dealkylation reaction and then to an acetylation reaction to yield linezolid. It also comprises new intermediate compounds useful in such a preparation process, which are obtained with high yields and high chemical and optical purity, and which are processed easily to linezolid.
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Page/Page column 11

(2010/04/24)

Synthesis and antibacterial activity of novel 5-(4-methyl-1H-1,2,3-triazole) methyl oxazolidinones
A series of 5-(4-methyl-1,2,3-triazole)methyl oxazolidinones were synthesized and tested for their antibacterial activity against a panel of Gram-positive and Gram-negative clinical isolates in comparison with linezolid and vancomycin. Most of the compounds demonstrated strong to moderate in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria. Antibacterial activity varied with substitutions at the phenyl C4 position with bulky alkylcarbonyl and alkoxycarbonyl substitutions on the piperazine N4 being detrimental to antibacterial activity. Whereas the presence of the 4-methyl-1,2,3-triazole moiety in the acyl-piperazine containing analogs resulted in increased protein binding, and decreased antibacterial activity particularly against Streptococcus pneumoniae strains.
Phillips, Oludotun A.,Udo, Edet E.,Abdel-Hamid, Mohammed E.,Varghese, Reny
experimental part
p. 3217 - 3227
(2009/12/04)

An efficient and practical synthesis of antibacterial linezolid
A convergent and efficient synthesis of linezolid was developed using the cycloaddition of commercially available (R)-epichlorohydrin with morpholine substituted phenylisocyanate catalysed by MgI2 or MgBr2 etherate as the key step in the 50% overall yield.
Zhang, Xingxian,Chen, Wei,Li, Cheng,Wu, Xiang
experimental part
p. 739 - 740
(2010/03/24)

An exploratory and mechanistic study of the defluorination of an (aminofluorophenyl)oxazolidinone: SN1(Ar*) vs. S R+N1(Ar*) mechanism
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
experimental part
p. 4634 - 4642
(2009/03/12)

Regioselective and stereospecific synthesis of enantiopure 1,3-oxazolidin-2-ones by intramolecular ring opening of 2-(Boc-aminomethyl) aziridines. Preparation of the antibiotic linezolid
The amide moiety of several enantiopure unactivated 1-aryl- or 1-alkylaziridine-2-carboxamides were reduced and then W-Boc-protected to afford enantiopure 2-(Boc-aminomethyl)aziridines, which were further converted into enantiopure 5-(aminomethyl)-1,3-oxazolidin-2-ones by means of a stereospecific and fully regioselective BF3-Et2O-promoted intramolecular nucleophilic ring opening. One of these oxazolidinones was transformed into the antibiotic linezolid through a Cul-catalyzed N-arylation reaction at its carbamate moiety.
Moran-Ramallal, Roberto,Liz, Ramon,Gotor, Vicente
supporting information; experimental part
p. 1935 - 1938
(2009/04/18)

Novel process for the preparation of linezolid and related compounds
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)

Short and practical enantioselective synthesis of linezolid and eperezolid via proline-catalyzed asymmetric α-aminooxylation
An efficient enantioselective synthesis of the antibacterials, linezolid (U-100766), and eperezolid (U-100592) using d-proline-catalyzed asymmetric α-aminooxylation of aldehydes as the key step is described here. This is the first report on the enantioselective synthesis of linezolid and eperezolid using asymmetric catalysis.
Narina, Srinivasarao V.,Sudalai, Arumugam
p. 6799 - 6802
(2007/10/03)

NOVEL INTERMEDIATES FOR LINEZOLID AND RELATED COMPOUNDS
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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(2008/06/13)

OXAZOLIDINONE DERIVATIVES, PROCESS FOR THEIR PREPERATION AND THEIR USE AS ANTIMYCOBACTERIAL AGENTS
Novel compounds belonging to the class of oxazolidinones possessing potent antimycobacterial properties especially useful in the treatment of acid fast organisms such as Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai. The compound and its pharmaceutically acceptable salts thereof act as antibacterial agents. Also disclosed is a method for inhibiting growth of mycobacterial cells a well as a method of treating mycobacterial conditions such as Mycobacterium tuberculoses, drug resistant Mycobacterium tuberculosis, Mycobacterium avium-intracellular complex, M. fortuitum and M. kansai, comprising administering an antimycobacterially effective amount of the said compound and/or pharmaceutically acceptable salts thereof. There is also disclosed a process for the manufacture of the said compound or its pharmaceutically acceptable salts.
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Page 31

(2008/06/13)

Synthesis and antibacterial activity of linezolid analogues
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
p. 857 - 859
(2007/10/03)

Structure-activity relationship (SAR) studies on oxazolidinone antibacterial agents. 2.1) Relationship between lipophilicity and antibacterial activity in 5-thiocarbonyl oxazolidinones
5-Thiourea and 5-dithiocarbamate oxazolidinones were synthesized as a continuation of research on 5-thiocarbonyl oxazolidinone antibacterial agents considering the hydrophobic parameters of the molecule. The structure-activity relationship (SAR) study revealed that the antibacterial activity on 5-thiocarbonyl oxazolidinones was significantly affected by the lipophilicity, especially the calculated log P value and the balance between 5-hydrophilic (or hydrophobic) substituent and hydrophobic (or hydrophilic) substituents on the benzene ring. Some of 5-thiocarbonyl oxazolidinones were found to have good in vitro antibacterial activity against gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).
Tokuyama,Takahashi,Tomita,Tsubouchi,Yoshida,Iwasaki,Kado,Okezaki,Nagata
p. 353 - 360
(2007/10/03)