The Development of a Convergent Green Synthesis of Linezolid, an Oxazolidinone Antibacterial Agent

Abstract

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. Secreast, and Bruce A. Pearlman Global API Process Technology, Pfizer Global Manufacturing, Pfizer, Inc., PORT-91-201, 7000 Portage Rd. Kalamazoo, MI 49001, USA wrperrault@kalexsyn.comPfizer has developed a novel, convergent, green synthesis oflinezolid (the active ingredient in Zyvox TM). The second-generationprocess has replaced the launch process and has numerousgreen chemistry benefits. 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, thisyielded a 5-S-hydroxymethyl group requiring activation as 3nitrobenzenesulfonate and displacement with excess ammonia togenerate the corresponding aminomethyl group of linezolid. Thesecond-generation process affords oxazolidinone imine 3 in a convergent step. The penultimate 5-S-aminomethyl oxazolidinone 4is then easily formed via hydrolysis with stoichiometric hydrochloricacid. Acylation of this amine with acetic anhydride, utilizing animproved Schotten-Baumann reaction, affords high-purity linezolid.Linezolid, approved by the Food and Drug Administration (FDA) in2000, is the onlymember of the oxazolidinone class of antibacterialson the market, the first new class of antibiotics in over 30 years.Linezolid is approved for the treatment of antibiotic-resistantgram-positive bacterial infections, including vancomycin-resistantEnterococcus faecium (VREF), methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant Streptococcus pneumonia (MDRSP). These antibiotic-resistant bacterial infections have be-come an ever-increasing threat to public health. Rapid growth inglobal demand for this valuable life-saving drug has led us to developa greener and more efficient convergent synthetic process in orderto meet future needs, while at the same time reducing the cost andenvironmental impact of production.