Development of scalable processes to prepare a key chiral, nonracemic intermediate en route to LpxC inhibitors for Gram-negative infections

Abstract

Deaths resulting from drug-resistant Gram-negative bacterial infections are a growing public health concern. Pyridone methylsulfone hydroxamic acid LpxC inhibitors, such as 1, are being developed for the treatment of serious Gram-negative infections. Carboxylic acid 2 is a key intermediate in the synthesis of analogs of type 1. The current synthesis of 2 is unsuitable as a manufacturing process due to safety concerns and high cost. Two scalable and potentially lower cost processes have been developed, one based on chromatographic resolution of a novel intermediate and a second based on a classical resolution of the key intermediate 3. The advantages of these new chemical approaches are illustrated in the process details described in this letter.