Process for the preparation of linezolid and related compounds

Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system

Reexamination Certificate

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Reexamination Certificate

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10524746

ABSTRACT:
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.

REFERENCES:
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patent: 95/07271 (1995-03-01), None
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K.V.S.R. Krishna Reddy, S. Mahender Rao, G. Om Reddy, T. Suresh, J. Moses Babu, P.K.Dubey, K. Vyas, Isolation And Characterization of Process-Related Impurities in Linezolid, Journal of Pharmaceutical and Biomedical Analysis, 30 (2002) 635-642.
Braj B. Lohray, Sundarababu Baskaran, B. Srinivasa Rao, B. Yadi Reddy and I. Nageswarn Rao, A Short Synthesis of Oxazolidinone Derivatives Linezolid and Eperezolid: A New Class of Antibacterials, Tetrahedron Letters 40 (1999) 4855-4856.
Steven J. Brickner, Douglas K. Hutchinson, Michael R. Barbachyn, Peter R. Manninen, Debra A. Ulanowicz, Stuart A. Garmon, Kevin C. Grega, Susan K. Hendes, Dana S. Toops, Charles W. Ford, and Gary E. Zurenko, Synthesis and antibacterial Activity of U-100592 and U-100766, Two Oxazolidinone Antibacterial Agents for the Potential Treatment of Multidrug Resistant Gram-Positive Bacterial Infections, J. Med. Chem. 1996, 39, 673-679.

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