Bio- and Chemocatalysis for the Synthesis of Late Stage SAR-Enabling Intermediates for ROMK Inhibitors and MK-7145 for the Treatment of Hypertension and Heart Failure

A synthetic strategy to provide two late-stage intermediates for the synthesis of diverse analogues of ROMK inhibitors for the treatment of hypertension and heart failure is described. Key transformations include carbonylation of a bromoarene, regioselective vinyl ether Heck coupling and bromination, and asymmetric enzyme-mediated ketone reduction and epoxide ring closure. On selection of MK-7145 (1) as clinical candidate, conditions were developed to convert 2 equiv of the epoxide intermediates to the C2-symmetric active pharmaceutical ingredient.