Development of a Pilot-Scale Preparation of <i>N</i>-[[(5S)-3-[4-(1,1-Dioxido-4- thiomorpholinyl)-3,5-difluorophenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, PNU-288034, an Oxazolidinone Antibacterial Agent

Abstract

As part of Pfizer's continuing efforts in the oxazolidinone area, we have developed an efficient synthesis of PNU-288034 and successfully implemented it on pilot scale. The key step was a novel, acid-catalyzed, double Michael addition of 2,6-difluoroaniline with divinyl sulfone to install the desired dioxidothiomorpholinyl ring. Regioselective nitration provided the desired para-nitrogen, which was converted to the penultimate carbamate using standard chemistry. The resulting carbamate proved to be an excellent substrate for the recently reported oxazolidinone synthesis. As is normally the case, removing impurities to achieve our quality targets for API was a challenge, but unexpectedly, some impurities also caused significant processing difficulties as well. In the end, a safe and robust process was developed which provided clinical-quality material in five linear steps with an overall yield of 41% and was proven reproducible in multiple pilot-plant campaigns.