The Synthesis of N-Aryl-5(S)-aminomethyl-2-oxazolidinone Antibacterials and Derivatives in One Step from Aryl Carbamates

William R. Perrault,*^§ Bruce A. Pearlman, Delara B. Godrej, Azhwarsamy Jeganathan,^§ Koji Yamagata,^§ Jiong J. Chen,^§ Cuong V. Lu,^§ Paul M. Herrinton,^§ Robert C. Gadwood,^† Lai Chan,^‡ Mark A. Lyster,^§ Mark T. Maloney,^§ Jeffery A. Moeslein,^§ Meredith L. Greene,^† and Michael R. Barbachyn^†

Org. Proc. Res. Dev., 2003, 7 (4), pp 533–546

DOI: 10.1021/op034028h

Publication Date (Web): June 7, 2003

Copyright © 2003 American Chemical Society

, , , ,

Since 1993, a significant process research and development effort directed towards the large-scale synthesis of oxazolidinone antibacterial agents has been ongoing in both Early Chemical Process Research and Development, and Chemical Process Research and Development at Pharmacia. This work has led to the successful development of the current commercial process to produce Zyvox (linezolid), recently approved by the FDA as an antibacterial. While this synthesis is appropriate for the preparation of linezolid in particular, a more convergent and versatile synthesis was developed for the rapid preparation of numerous other oxazolidinone analogues. Toward this end, economical methods for the large-scale preparation of N-[(2S)-2-(acetyloxy)-3-chloropropyl]acetamide 3 and tert-butyl [(2S)-3-chloro-2-hydroxypropyl]carbamate 27 from commercially available (S)-epichlorohydrin via the common intermediate (2S)-1-amino-3-chloro-2-propanol hydrochloride 2a were developed. Also, general methods for coupling these reagents with N-aryl carbamates to give N-aryl-5(S)-aminomethyl-2-oxazolidinone derivatives in one step were developed. These reagents and procedures have proven widely applicable in the preparation of a diverse array of oxazolidinone analogues such as 23 and 28 in both process and medicinal chemistry research.