A Novel Method for Preparation of Linezolid, (S)-N-((3-(3-Fluoro-4- Morpholinophenyl)-2-Oxo-5-Oxazolidinyl) Methyl) Acetamide

Author(s): Kondaiah Seku , Vijayakumar Badathala , Venkata Srinivasa Rao Velivela , Srinivasa Reddy Desireddy .

Journal Name: Letters in Organic Chemistry

Volume 14 , Issue 1 , 2017

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Abstract:

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 C16H20FN3O4 and 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.

Keywords: Characterization, linezolid, potassium phthalimide, R-epichlorohydrin, synthesis.

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Article Details

VOLUME: 14
ISSUE: 1
Year: 2017
Page: [56 - 60]
Pages: 5
DOI: 10.2174/1570178614666161230163455
Price: $58

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