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.com
Pfizer has developed a novel, convergent, green synthesis of
linezolid (the active ingredient in Zyvox TM
). The second-generation
process has replaced the launch process and has numerous
green 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, this
yielded a 5-S-hydroxymethyl group requiring activation as 3nitrobenzenesulfonate and displacement with excess ammonia to
generate the corresponding aminomethyl group of linezolid. The
second-generation process affords oxazolidinone imine 3 in a 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.
Linezolid, approved by the Food and Drug Administration (FDA) in
2000, is the onlymember of the oxazolidinone class of antibacterials
on the market, the first new class of antibiotics in over 30 years.
Linezolid is approved for the treatment of antibiotic-resistant
gram-positive bacterial infections, including vancomycin-resistant
Enterococcus 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 in
global demand for this valuable life-saving drug has led us to develop
a greener and more efficient convergent synthetic process in order
to meet future needs, while at the same time reducing the cost and
environmental impact of production.
