In Situ FTIR Study and Scale-Up of An Enolization−Azidation Sequence

A key step in the synthesis of an optically active aminoalcohol-containing active pharmaceutical ingredient (API) involved the diastereoselective introduction of an azido functional group on a functionalized chiral oxazolidinone. This was accomplished via a low-temperature enolization, followed by a quench with triisopropylbenzenesulfonyl azide. To enable scale-up of this process, the enolization temperature had to be increased from the original <−65 °C to approximately −40 °C. In situ FTIR was used to study the enolization and quench stages of the reaction. The half-life of the enolate at −45 °C was estimated to be 12 h on the basis of in situ FTIR profiling. Examination of the in situ FTIR data also provided evidence that the reaction between the enolate and triisopropylbenzenesulfonyl azide was instantaneous and demonstrated that accumulation of triisopropylbenzenesulfonyl azide did not occur. A combination of in situ FTIR experiments and traditional parameter ranging experiments resulted in a process that was successfully run at −40 °C without an appreciable erosion of facial selectivity or yield.