Development of a Scalable Stereoselective Synthesis of Selected Potent ROMK Inhibitors

An efficient and scalable synthesis of two small-molecule renal outer medullary potassium (ROMK) inhibitors 1 and 2 was developed from readily available raw material. The alternative approach includes a newly developed asymmetric reduction of the keto intermediate to access compound 1 and a chiral resolution of an amine intermediate for the synthesis of compound 2, respectively, which circumvented the large-scale supercritical fluid chromatography (SFC) separation of the homochiral intermediates. A safe, robust, and scalable synthesis of 1 and 2 was successfully demonstrated.