- An efficient and practical synthesis of antibacterial linezolid
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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
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Read Online
- Stereoselective synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones from (S)-epichlorohydrin: a key precursor for the oxazolidinone class of antibacterial agents
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A facile synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones starting from (S)-epichlorohydrin is described. The (R)-azide was utilized for the preparation of Linezolid.
- Madhusudhan,Om Reddy,Rajesh,Ramanatham,Dubey
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Read Online
- 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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Read Online
- The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban
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The human drugs - the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) - belong among modern pharmaceutics, which contain an oxazolidine-2-one moiety bearing a stereogenic center. The chirality of these drugs is a fundamental attribute for their biological activity. Herein, one of the efficient asymmetric syntheses of these drugs was studied in detail. Highly enantioselective catalysts were tested in the key step of the synthetic procedure, i.e., the asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates in the syntheses of these drugs were obtained in high yields and enantiomeric excesses of up to 91% ee.
- Drabina, Pavel,Macek, Karel,Pochobradsky, Jaroslav,Sedlák, Milo?,Svoboda, Jan,Vrbicky, Martin
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supporting information
p. 438 - 445
(2022/05/18)
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- Industrial production method of linezolid
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The invention belongs to the field of medicinal chemistry, and relates to an industrial production method of linezolid. A compound I and a compound II are used as initial raw materials, and linezolid is generated through cyclization and acylation reactions. The preparation method of linezolid has the advantages of simple steps, mild reaction conditions, short reaction time, cheap and easily available raw materials, safe and economic reagents, low equipment requirements and high purity of the final product, and is suitable for industrial production. A reaction formula is defined in the specification.
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Paragraph 0026-0029
(2021/07/01)
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- Synthesis, microbiological evaluation and structure activity relationship analysis of linezolid analogues with different C5-acylamino substituents
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Antimicrobial resistance and lack of new antibiotics to treat multidrug-resistant (MDR) bacteria is a significant public health problem. There is a discovery void and the pipeline of new classes of antibiotics in clinical development is almost empty. Therefore, it is important to understand the structure activity relationships (SAR) of current chemical classes as that can help the drug discovery community in their efforts to develop new antibiotics by modifying existing antibiotic classes. We studied the SAR of the C5-acylaminomethyl moiety of the linezolid, an oxazolidinone antibiotic, by synthesizing 25 compounds containing various aromatic, heteroaromatic and aliphatic substitutions. Our findings suggest that this position is highly important for the function of this antibiotic class, since only smaller non-polar fragments are tolerated at this position while larger and polar ones lead to a decrease in activity compared to linezolid. Our findings have led us to construct a structure activity relationship, around the C5-acylaminomethyl moiety of linezolid, that provides valuable insight into the function of the oxazolidinone class of antibiotics.
- Matsingos, Christos,Al-Adhami, Taha,Jamshidi, Shirin,Hind, Charlotte,Clifford, Melanie,Mark Sutton,Rahman, Khondaker Miraz
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- New linezolid synthesis method
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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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- Seven-Step Continuous Flow Synthesis of Linezolid Without Intermediate Purification
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Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h?1.
- Russell, M. Grace,Jamison, Timothy F.
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p. 7678 - 7681
(2019/05/16)
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- 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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- 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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supporting information
p. 527 - 531
(2019/02/19)
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- C-N Cross-Couplings for Site-Selective Late-Stage Diversification via Aryl Sulfonium Salts
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We report diverse C-N cross-coupling reactions of aryl thianthrenium salts that are formed site-selectively by direct C-H functionalization. The scope of N-nucleophiles ranges from primary and secondary alkyl and aryl amines to various N-containing hetero
- Berger, Florian,Berger, Georg,Engl, Pascal S.,H?ring, Andreas P.,Pérez-Bitrián, Alberto,Ritter, Tobias
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- 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; 0042-0045; 0058; 0066-0069; 0073; 0081-0084
(2019/09/10)
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- Method of preparing linezolid
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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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- Bacterial protein synthesis inhibitor for the preparation of crystalline form III
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The invention discloses a bacterial protein synthesis inhibitor for the preparation of crystalline form III, through the bacteria protein synthesis inhibitor linezolid preparing bacterial protein synthesis inhibitor crystalline form III; the process of the invention has simple process, raw materials are easy, synthetic condition is simple, economic and environmental protection, product yield and purity of the product is high, help to realize industrialization, and reduces the production cost, and is suitable for mass production, the search for new bacterial protein synthesis inhibitor linezolid preparation method for linezolid very meaningful economic and technical; the invention preparation of bacterial protein synthesis inhibitor crystalline form III high optical purity, can improve its bioavailability, conducive to its pharmaceutical processing and in the use of the drug combination in, can be used for the treatment of methoxy Xilin drug-resistant Staphylococcus aureus infection, to further study the solid curative effect of the medicament has important significance.
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Paragraph 0021-0030
(2018/07/30)
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- Stereocontrolled, Divergent, Al(lll)-Catalyzed Coupling of Chiral N-Aryl Epoxy Amines and CO2
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A divergent coupling reaction was achieved between N-aryl epoxy amines and CO2. By using two different cocatalysts, tetrabutylammonium iodide (TBAI) or 4-dimethylaminopyridine (DMAP) together with an Al(III) Lewis acid, cyclic carbonates or oxazolidinones were selectively produced through two distinct reaction pathways, respectively. The proposed reaction mechanism was supported by the stereochemical determination of the products. A gram-scale production of Linezolid was successfully achieved.
- Lee, Yuseop,Choi, Jonghoon,Kim, Hyunwoo
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supporting information
p. 5036 - 5039
(2018/08/24)
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- Preparation methods of medicine linezolid for treating bacteremia and crystal form VI of medicine linezolid
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The invention discloses preparation methods of a medicine linezolid for treating bacteremia and a crystal form VI of the medicine linezolid. The crystal form VI of the medicine linezolid for treatingthe bacteremia is prepared from the medicine linezolid for treating the bacteremia. The preparation method comprises the following steps of putting the medicine linezolid for treating the bacteremia into a ball milling jar according to that every 100mg of the medicine linezolid for treating the bacteremia is added into 10mu L to 20mu L of tetrahydrofuran, and milling for 40min to 90min with the milling frequency of 6HZ to 12HZ, so as to obtain the crystal form VI of the medicine linezolid for treating the bacteremia. The preparation method adopts a preparation technique in which raw materialsare easily obtained, which is economical and environmentally friendly and the quality is further superior; the reaction yield is improved; further, the optical purity of the crystal form VI of the medicine linezolid for treating the bacteremia, which is prepared and obtained by the method, through the cooperation of the milling frequency and a milling time is 99.5 percent or above, and the qualityof a product is greatly improved.
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Paragraph 0026; 0027; 0028
(2019/04/11)
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- Method for preparing linezolid
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The invention relates to a method for preparing linezolid. The method comprises the following steps: mixing N-benzyloxycarbonyl-3-fluoro-4-morpholinoaniline, lithium tert-butoxide, tetrahydrofuran andmethanol; then mixing a mixture obtained in the previous step with (S)-N-(2-acetoxy-3-chloropropyl)acetamide; heating a mixture obtained in the previous step to 20-30 DEG C and carrying out a reaction for about 12 to 15 hours; and subjecting the prepared linezolid to recrystallization with tetrahydrofuran. The method does not involve harsh reaction conditions and special production equipment; rawmaterials and reagents used in the method are cheap and easily available, and are low in toxicity; the prepared linezolid has high purity, few impurities and high yield; and the method is simple to operate, greatly shortened in reaction time, and suitable for industrial production.
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Paragraph 0033-0053
(2018/04/01)
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- Environment-friendly synthesis method of linezolid and intermediate thereof
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The invention relates to a more environment-friendly synthesis method of linezolid and a key intermediate thereof. The more environment-friendly synthesis method is characterized in that the key intermediate of linezolid is prepared through the steps of hydroxyl protection, carboxyl reduction, hydroxyl halogenation, ring closing, halogenation after hydroxyl deprotection, ring opening and the likeby taking a natural chiral product L-serine as an initial raw material. According to the more environment-friendly synthesis method provided by the invention, a chiral center is introduced by adoptingthe natural chiral product, the reaction yield is high, the technological operation is simple, the product purity is high, and the synthesis method is more environment-friendly and is suitable for industrial production.
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Paragraph 0046; 0047; 0048
(2018/11/22)
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- Oxazolone derivative and application thereof in antibacterial medicine
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The invention provides an oxazolone derivative. The chemical structural formula of the oxazolone derivative is represented by formula (I) shown in the description. The oxazolone derivative is a bacterial protein synthesis inhibitor, has a good antibacterial effect on methicillin-sensitive or resistant staphylococcus, vancomycin-sensitive or resistant enterococcus, penicillin-sensitive or resistantstreptococcus pneumoniae and the like, and also has antibacterial activity against anaerobic bacteria. Different from other medicines, the oxazolone derivative does not affect peptidyl transferase activity. The oxazolone derivative has unique sites and modes of action. Therefore, in positive bacteria having essential or acquired drug resistance characteristics, the oxazolone derivative does not easily undergo cross resistance of an antibacterial medicine synthesized by other inhibit proteins, and the oxazolone derivative also does not easily induce bacterial resistance in vitro.
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Paragraph 0022-0025
(2021/05/26)
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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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- 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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- Process For Preparation Of Linezolid
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The present invention relates to an improved process for the preparation of Linezolid of Formula-I comprising reacting compound of Formula-II with compound of Formula-III in presence of metal base wherein, said metal base is prepared in situ in a single lot. The invention also relates to an isolated acetamide impurity of Formula-IV produced in the process for preparation of Linezolid, its purification and its use as a reference marker.
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Paragraph 0098-0106; 0107-0115
(2017/08/26)
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- A preparation method of linezolid
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The invention discloses a linezolid preparation method. Dichloromethane is taken as a solvent, a potassium bromide solution is added, cooling is carried out, (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-hydroxymethyl-2-oxazolidinone is added, a catalyst of a tetramethyl piperidinyloxyl nitride oxide is added while stirring is carried out, a sodium hypochlorite solution is added dropwise, after adding is carried out dropwise, reaction is carried out for 1-3 hours at the temperature of 0-10 DEG C, dichloromethane is added for extraction, an organic phase is dried and filtered through anhydrous sodium sulfate, and (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-formaldehyde-2-oxazolidinone is obtained after the solvent is condensed. Methyl alcohol is taken as a solvent, the (5R)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-5-formaldehyde-2-oxazolidinone is added and heated to 20-50 DEG C, acetamide is slowly added, liquid-phase chromatogram track reaction is conducted, a reduction agent is directly added after the reaction is completed, precipitation and filtering are carried out, and linezolid is obtained. The method is moderate in reaction condition and environmentally friendly, and can be used for industrial large-scale production.
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Paragraph 0014; 0016; 0017; 0018
(2017/08/25)
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- A process for preparing [...] method
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The invention discloses a method for preparing linezolid. The method comprises: dissolving (N)-{2(R)-2-[(3-fluoro-4-morpholin-4-ylphenyl)amino]-2-hydroxyethyl}acetamide and a carbonylation reagent inan orgnic solvent, adding an aluminium-oxide-supported
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Paragraph 0019; 0020; 0021; 0022; 0023; 0024
(2017/08/24)
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- A oxazolidinone compounds of preparation method
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The invention discloses a method for preparing an oxazolidinone compound. The method comprises the following steps of carrying out ammonolysis reaction on a racemic or optically active 3-chloro-2-hydroxypropyl aniline compound (2) as a starting material and ammonia in a proper solvent and under alkaline condition to obtain a 3-amino-2-hydroxypropyl aniline compound (3); carrying out acylation reaction on the compound (3) to obtain 3-acylamino-2-hydroxypropyl aniline compound (4); and carrying out cyclization reaction on the compound (4) and a corresponding acylating reagent to obtain the racemic or optically active oxazolidinone compound (II) as shown in the description, wherein R1 represents morpholinyl or 3-oxo-4-morpholinyl; R2 represents H or F; and R3 represents C1-12 alkyl, 5-chloro-thiophen-2-yl, thiophen-2-yl or 4,5-dichloro-2-yl; and the compound is a racemate and (S)- or (R)- optical isomers.
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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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- 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 20
(2017/11/14)
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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 19
(2017/05/31)
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- Preparation method of linezolid injection degradation impurity
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The invention discloses a preparation method of a linezolid injection degradation impurity. The method consists of: carrying out condensation reaction on N-carboxybenzyl-3-fluoro-4-morpholinoaniline and R-epichlorohydrin, then conducting acetylation, and finally carrying out hydrolysis aminolysis so as to obtain the linezolid injection degradation impurity N-[(2S)-3-amino-2-hydroxpropyl]-N-[3-fluoro-4-(4-morpholinyl)phenyl]-acetamide, the chemical structure of which is shown as the specification.
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Paragraph 0015; 0016
(2017/02/17)
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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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- A method for synthesis of linezolid (by machine translation)
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The invention relates to a synthetic method of linezolid. The synthetic method of the linezolid comprises the following steps: with (S)-N-((3-(3-fluoro-4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl) orthophthalic dicarboximide as a raw material, carrying out a reaction on (S)-N-((3-(3-fluoro-4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl) methyl) orthophthalic dicarboximide and hydrazine hydrate, carrying out suction filtration for removing solids, concentrating filtrate, completely extracting by adopting water and dichloromethane, concentrating, adding massive methylbenzene into a concentrated solution, concentrating until water and dichloromethane are discharged at the temperature of 30-110 DEG C, and carrying out a reaction on the concentrated solution and acetic anhydride, thus the linezolid is prepared. Compared with the prior art, the synthetic method of the linezolid has the advantages that the linezolid with higher purity and higher yield can be prepared, cost for producing the linezolid in a large-scale industrial production manner can be greatly reduced and the synthetic method of the linezolid is environment-friendly.
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Paragraph 0048
(2017/01/05)
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- A Process for preparing linezolid and its intermediate
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The present invention relates to a manufacturing method of linezolid which is an oxazolidinone-based antibiotic. More specifically, the present invention relates to a novel manufacturing method of linezolid; and to an intermediate compound of linezolid, and the manufacturing method of linezolid uses a novel halomethyl ethanone compound as an intermediate for the manufacture of linezolid, thereby simplifying a manufacturing process and reducing manufacturing costs in comparison with a conventional manufacturing method. The intermediate compound is a novel compound, and is an (S)-1-(5-(halomethyl)-2, 2-dimethyl oxazolidine-3-yl)ethanone compound represented by chemical formula 1. In chemical formula 1, R is one element selected from F, Cl, Br, and I. The manufacturing method of linezolid comprises: a step (A) of performing a reaction process of a compound represented by chemical formula 1 and a compound represented by chemical formula 2 to manufacture a compound represented by chemical formula 3; a step (B) of hydrolyzing the compound represented by chemical formula 3 to obtain a compound represented by chemical formula 4; and a step (C) of performing carbonylation of the compound represented by chemical formula 4.COPYRIGHT KIPO 2016
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- Preparation method for Linezolid
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The invention relates to the oxazolidinone antibiotic medicine preparation field, and concretely relates to a preparation method for Linezolid. A compound I and a compound II are employed as raw materials, halogenated lithium, alkyl alcohol sodium or alkyl alcohol potassium and trimethylchlorosilane are added to promote construction of an oxazolone ring, and furthermore a Linezolid bulk drug is prepared. The reaction chemical equation is shown in the specification. The preparation method has advantages of atom economy, easily available reagents, mild reaction conditions, environmental protection, high yield and purity and the like compared with the prior art.
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Paragraph 0018
(2016/10/07)
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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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- N-epoxy propyl-N-acyl aniline compounds, process for their preparation and use
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The present invention discloses a class of N-epoxypropyl-N-acylaniline compounds represented by a formula (I), and further discloses a preparation method of the N-epoxypropyl-N-acylaniline compounds, and applications of the N-epoxypropyl-N-acylaniline compounds in preparation of oxazolidinone treating drugs including but being not limited to linezolid and rivaroxaban racemate or optical isomers, wherein R1 represents morpholinyl or 3-O-4-morpholinyl, R2 represents H or F, R3 represents C1-12 alkyl, thien-2-yl or 5-chlorothiophen-2-yl, and the compounds are racemates, (S)-optical isomers, or (R)-optical isomers.
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- Linezolid for the preparation of the intermediate and its preparation method
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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)
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- Preparing method for linezolid and intermediate thereof
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The invention relates to a preparing method for linezolid and an intermediate thereof. The preparing method includes the step that 4-chloracetyl acetate compound (I) serves as a starting raw material and is subjected to asymmetric chiral reduction, acetylation, condensation, ammonolysis, Hoffman degradation, acetylation and cyclization to obtain (S)-N-[[3-[3-fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide (linezolid). Compared with other linezolid synthesis methods, the preparing method is high in total yield and product purity, raw materials are cheap and easy to obtain, flammable, combustible and poisonous reagents are avoided, and the production technology is safe and environmentally friendly.
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- Linezolid crystal form B and preparation method and application thereof
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The invention provides a linezolid crystal form B. In a powder X-ray diffraction pattern of the crystal form, characteristic absorption peaks exist in the 9.43-degree position, the 11.29-degree position, the 13.27-degree position, the 14.13-degree position, the 15.55-degree position, the 16.69-degree position, the 19.04-degree position, the 21.92-degree position and the 22.35-degree position of the diffraction angle 2theta (+/-0.2 degree). The crystal form has the advantages of being small in grain diameter, good in dissolution rate and the like. The invention further provides a preparation method of the crystal form, a medicine composition containing the crystal form in the treatment effective dose, and an application of the medicine composition in treating skin infection caused by various germs.
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Paragraph 0045; 0046
(2016/10/24)
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- S-epihydric a phthalic acid imide preparation method
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The invention relates to a preparation method of S-glycidylphthalimide. The preparation method is characterized in that in a reaction of potassium phthalimide or phthalimide and (S) epichlorohydrin, a phase transfer catalyst and potassium iodide are used so that S-glycidylphthalimide synthesis is realized. Compared with the prior art, the preparation method greatly improves an S-glycidylphthalimide yield, has simple and safe processes, produces high-purity products, has a low cost and is suitable for industrial production of S-glycidylphthalimide.
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Paragraph 0074; 0075
(2017/03/08)
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- A method for preparing [...]
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The invention relates to a method for preparing linezolid. The method comprises the following steps: (1) under nitrogen protection, firstly, adding acetamide to methylbenzene, and then adding sodamide, lithium amide or metallic potassium, so as to prepare an acetamide monosodium salt, an acetamide monolithium salt or an acetamide mono potassium salt; and (2) respectively adding R)-N-[3-(3-fluoro-(4-morpholinyl) phenyl)-2-oxo-5-oxazolidinyl] methanol methanesulfonate and the acetamide monosodium salt, the acetamide monolithium salt or the acetamide mono potassium salt prepared in the step (1) to a solvent to stir and react, after reaction is ended, pouring a reaction solution into purified water and separating out a lot of almost white solid, so as to obtain a target product linezolid. The method has the advantages of few reaction steps, low production cost and high yield.
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Paragraph 0019
(2017/04/03)
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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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- 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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- A convenient synthesis of the antibacterial agent linezolid
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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.
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p. 6846 - 6847
(2015/11/27)
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- PROCESS FOR THE PREPARATION OF STABLE CRYSTALLINE FORM-I OF LINEZOLID, SUBSTANTIALLY FREE OF RESIDUAL SOLVENT
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The invention relates to a substantially pure linezolid hydroxide having R-isomer content more than about 99.9% relative to its S-isomer. Further aspect of invention provides the ambient moisture condition, which is critical for enantiomeric pure linezolid hydroxide. The obtained substantially enantiomerically pure linezolid hydroxide compound of formula-II can be subsequently converted into the linezolid compound of formula-I, having S-isomer content more than 99.9% relative to R-isomer. Further the invention provides an improved process for preparation of enantiomeric pure linezolid Form-I, wherein linezolid Form-I having the purity more than 99.9% relative to any other known polymorphic form of linezolid. The obtained enantiomeric pure linezolid Form-I can be subsequently converted into the other known polymorphic forms linezolid. The invention also provides stable and substantially solvent-free crystal of Form-I of linezolid.
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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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- IMPROVED PROCESSES FOR THE PREPARATION OF LINEZOLID USING NOVEL INTERMEDIATES
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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 57; 56; 57
(2014/11/13)
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- PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES
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A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.
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- PROCESS FOR MAKING LINEZOLID
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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 20
(2014/05/24)
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- ANHYDROUS LINEZOLID CRYSTALLINE FORM-II
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The present invention relates to oxazolidinone antibacterial agent anhydrous Linezolid crystalline Form-II. The anhydrous Linezolid crystalline Form-II of the invention comprises less than 0.5% of water content. The anhydrous Linezolid crystalline Form-II of the invention is characterized by the XRPD spectrum and IR spectrum described in the specification.
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Page/Page column
(2014/05/07)
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- LINEZOLID INTERMEDIATE AND METHOD FOR SYNTHESIZING LINEZOLID
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Provided are a linezolid intermediate and the preparation method thereof and a method for synthesizing linezolid. The structure of the intermediate is shown as formula F2, wherein the compound is prepared by a condensation reaction of (S)—N—(3-chloro-2-hydroxy-1-propyl) acetamide and the compound shown in formula F4. In the preparation methods of the compound shown in formula F2 and linezolid, the reaction system is mild, side reactions are few and the product yield is high.
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Paragraph 0066
(2014/02/16)
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- 1,3-OXAZOLIDINE-2-ONE-LIKE COMPOUND, PREPARATION METHOD AND USES THEREOF
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This invention provides 1,3-oxazolidin-2-one compounds of formula I and their salts, their preparation methods, and use in the preparation of linezolid racemate and its optical isomer, which are used as oxazolidinone antibacterial agents. In the formula, R is H, hydroxyl, halogen, C1-C12 alkyl, C1-C12 alkoxy, nitro and carboxyl; and R can be placed at any position on the benzene rings; and the compound is a racemate or an optical isomer.
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Paragraph 0059; 0060
(2014/06/25)
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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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