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.

FeCl3 catalyzed an isomerization-free Friedel-Crafts sulfonylation between 1-naphthalenesulfonyl chloride and halobenzenes. The coupled halide was then displaced using 35% hydrazine in DMSO to provide the Fischer indole precursor. Pure 5-chloro-2-pentanone was the key for a successful Grandberg modification of Fischer indole synthesis that effectively constructed both the indole core and side chain of the target molecule. The development of these methods enabled a rapid preparation of kilogram quantities of PHA-565272A.

Sulfone 2 was initially prepared using a zinc-mediated one-pot coupling procedure. A traditional sodium sulfite-mediated two-pot procedure was found to eliminate a major impurity, yet modest yields prevailed. Design of experiment methods with the aid of a basic parallel synthesizer rapidly led to a high-yielding one-pot process.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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.

Substituted anilines and vinyl sulfone undergo a facile double Michael addition to form substituted phenylthiomorpholine dioxide, catalyzed with AlCl3 or H3PO4. Scope and conditions were explored.