Wednesday, June 25, 2008 - 2:00 PM
New York (Capital Hilton)

Convergent Green Synthesis of Linezolid (Zyvox)

William R. Perrault, James B. Keeler, William C. Snyder, Christian L. Clark, Michael R. Reeder, Richard J. Imbordino, Rebecca M. Anderson, Nabil Ghazal, Stephen L. Seacrest, and Bruce A. Pearlman. Pfizer, Kalamazoo, MI

Pfizer has developed a novel, convergent, green, second generation synthesis of Linezolid (the active ingredient in ZyvoxTM). The second generation process will replace the launch process after approval by appropriate regulatory agencies and has numerous green chemistry benefits: overall yield is increased by 8%; total waste is reduced by 56%; non-recycled w is eliminated. At current volumes, total waste will be reduced 1.9 million kilograms per year and 1.7 million kg per year non-recyclable waste will be eliminated. The improved process utilizes a highly efficient low dilution convergent synthesis to replace the more dilute linear synthesis utilized in the launch process. The key chlorohydrin imine reagent 1 contains both the chiral center and the key 5-S-aminomethyl moiety of linezolid. In the launch process, S-1-chloro-2,3-propanediol was utilized to install the oxazolidinone functionality. However, this yielded a 5-S-hydroxymethyl group which required activation as the 3-nitrobenzenesulfonate and displacement with excess ammonia to generate the corresponding aminomethyl group of linezolid. The second generation process affords the oxazolidinone imine 3 in the convergent step. The penultimate 5-S-aminomethyl oxazolidinone 4 is then easily formed via hydrolysis with stoichiometric hydrochloric acid. Acylation of this amine with acetic anhydride, utilizing an improved Schotten Baumann reaction, affords high purity linezolid.