Modified Chelation-Controlled Reduction of an N-Acryloyloxazolidin-2-one

A key step in the synthesis of an optically active aminoalcohol-containing active pharmaceutical ingredient (API) involved the diasteroselective reduction of a chiral 3-acryloyl-4-benzyloxazolidin-2-one. Preliminary work identified that excellent facial selectivity could be achieved by performing the hydrogenation in tetrahydrofuran in the presence of magnesium bromide. During an intermediate scale-up to support a 500-g batch of API, a side reaction between the product and magnesium bromide was observed that led to a significant deterioration in the isolated yield of product. An examination of alternative chelators and processing solvents identified that magnesium chloride in 2-methyltetrahydrofuran offered comparable facial selectivity with significantly diminished liabilities for scale-up. This revised process was incorporated into campaigns to produce larger lots of API and afforded the product in 85% yield, averaged over 18 batches.