Process Development of a Potent Bradykinin 1 Antagonist

As part of Merck's continued research effort on inflammation and pain, a safe synthesis of an orally bioavailable and CNS penetrant bradykinin I antagonist was developed and demonstrated on kilogram scale. The key step included a novel regioselective metal-halogen exchange reaction on 1,2-dibromo-5-chloro-3-fluorobenzene using isopropyl magnesium chloride to install the 1,2,4-oxadiazole ring structure. Suzuki cross-coupling reaction between a highly functionalized and sterically hindered electrophile and boronic ester generated the biaryl ring system, which was converted to the target molecule (1) using standard chemistry. The safe installation of a 1,2,4-oxadiazole ring proved to be challenging since the original synthetic route relied on the preparation of a highly functionalized benzonitrile using potassium cyanide and resulted in low yields and large amounts of potentially hazardous waste. Overall, a safe and robust synthesis was developed, which occurred in eight linear steps with an overall yield of 28%.