168828-81-7

Basic information

• Product Name: N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE
• Synonyms: N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE;N-CARBOBENZOXY-3-FLUORO-4-MORPHOLINYL-ANILINE;(3-Fluoro-4-morpholin-4-ylphenyl)carbamic acid benzyl ester;Benzyl (3-fluoro-4-Morpholinophenyl)carbaMate;CarbaMic acid, N-[3-fluoro-4-(4-Morpholinyl)phenyl]-, phenylMethyl ester;Linezolid Benzyl IMpurity;Benzyl 3-Fluoro-4-(4-Morpholinyl)phenyl)carbaMate;[3-Fluoro-4-(4-Morpholinyl)phenyl]carbaMic Acid PhenylMethyl Ester
• CAS NO: 168828-81-7
• Molecular Formula: C₁₈H₁₉FN₂O₃
• Molecular Weight: 330.35
• EINECS: 1806241-263-5
• Mol File: 168828-81-7.mol

Chemical Properties

• Melting Point: 123.0 to 127.0 °C
• Boiling Point: 451.8 °C at 760 mmHg
• Flash Point: 227 °C
• Appearance: /
• Density: 1.284 g/cm³
• Vapor Pressure: 2.36E-08mmHg at 25°C
• Refractive Index: 1.605
• Storage Temp.: Inert atmosphere,Room Temperature
• Solubility: Chloroform (Slightly), Methanol (Slightly, Heated)
• PKA: 12.74±0.70(Predicted)
• CAS DataBase Reference: N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE(CAS DataBase Reference)
• NIST Chemistry Reference: N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE(168828-81-7)
• EPA Substance Registry System: N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE(168828-81-7)

Safety Data

• Hazardous Substances Data: 168828-81-7(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE is used as an intermediate in the synthesis of Linezolid Dimer (L466520), which is an impurity of the antibacterial agent Linezolid (L466500). Its role in the synthesis process is crucial for the development of effective antibacterial drugs, as it contributes to the formation of the final product with desired pharmacological properties.
As an intermediate, N-BENZYLOXYCARBONYL-3-FLUORO-4-MORPHOLINOANILINE is used for [application reason] in the pharmaceutical industry to facilitate the production of Linezolid and its related compounds. This application is significant because it aids in the development of new and improved antibacterial agents to combat drug-resistant bacterial infections.

InChI:InChI=1/C18H19FN2O3/c19-16-12-15(6-7-17(16)21-8-10-23-11-9-21)20-18(22)24-13-14-4-2-1-3-5-14/h1-7,12H,8-11,13H2,(H,20,22)

Upstream product

• 501-53-1 benzyl chloroformate 
• 93246-53-8 3-fluoro-4-(morpholinyl)aniline 
• 369-34-6 3,4-difluoronitrobenzene 
• 2689-39-6 3-fluoro-4-(4-morpholinyl)nitrobenzene 
• 350-31-2 1-chloro-2-fluoro-4-nitrobenzene 
• 100-00-5 4-chlorobenzonitrile 
• 110-91-8 morpholine 

Downstream Products

• 165800-03-3 linezolid 
• 565176-85-4 (S)-5-((dibenzylamino)methyl)-3-(3-fluoro-4-morpholino phenyl)-isooxazol-2-one 
• 224323-50-6 linezolid 
• 620-05-3 iodomethylbenzene 
• 168828-89-5 2-({(5S)-2-oxo-3-[(4-morpholino-3-fluorophenyl)]-4,5-dihydro-1,3-oxazole-5-yl}methyl)-isoindole-1,3-dione 

Relevant articles and documents

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.

Linezolid preparation method and linezolid refining method

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.

A process for the preparation of linezolid

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).

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.

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.

Synthesis and biological evaluation of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives

Research activities on the oxazolidinone antibacterial class of compounds continue to focus on developing newer derivatives with improved potency, broad-spectrum activity and safety profiles superior to linezolid. Among the safety concerns with the oxazolidinone antibacterial agents is inhibition of monoamine oxidases (MAO) resulting from their structural similarity with toloxatone, a known MAO inhibitor. Diverse substitution patterns at the C-5 position of the oxazolidinone ring have been shown to significantly affect both antibacterial activity and MAO inhibition to varying degrees. Also, the antibacterial activity of compounds containing iron-chelating functionalities, such as the hydroxamic acids, 8-hydroxyquinolines and catechols have been correlated to their ability to alter iron intake and/or metabolism. Hence a series of novel 5-(hydroxamic acid)methyl oxazolidinone derivatives were synthesized and evaluated for their antibacterial and MAO-A and -B inhibitory activities. The compounds were devoid of significant antibacterial activity but most demonstrated moderate MAO-A and -B inhibitory activities. Computer modeling studies revealed that the lack of potent antibacterial activity was due to significant steric interaction between the hydroxamic acid N-OH oxygen atom and one of the G2540 5′-phosphate oxygen atoms at the bacterial ribosomal binding site. Therefore, the replacement of the 5-acetamidomethyl group of linezolid with the 5-(N-hydroxyacetamido)methyl group present in the hydroxamic acid oxazolidinone derivatives was concluded to be detrimental to antibacterial activity. Furthermore, the 5-(hydroxamic acid)methyl oxazolidinone derivatives were also less active as MAO-A and -B inhibitors compared with linezolid and the selective inhibitors clorgyline and pargyline. In general, the 5-(hydroxamic acid)methyl oxazolidinone derivatives demonstrated moderate but selective MAO-B inhibitory activity.

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.

PROCESS FOR THE PREPARATION OF CRYSTALLINE LINEZOLID

The present invention discloses a stable crystalline Form-I of linesolid process for preparation thereof.

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.

Microwave-assisted expeditious synthesis of 5-fluoroalkyl-3-(aryl/alkyl)- oxazolidin-2-ones

An efficient and convenient protocol for synthesis of 5-fluoroalkyl-3- (aryl/alkyl)-oxazolidin-2-ones is described. The reaction of allyl (aryl/alkyl) carbamates with fluoroalkyl iodide initiated by sodium dithionite in aqueous acetonitrile resulted in adducts that undergoes a cyclization assisted by microwave irradiation to form 5-fluoroalkyl-3-(aryl/alkyl)-oxazolidin-2-ones with high yields. It was also found that the products can be more efficiently formed via an AIBN-initiated one-pot addition-cyclization sequence from benzyl allyl(aryl/alkyl) carbamates and fluoroalkyl iodide.