Development an Efficient Route to the 5-Lipoxygenase Inhibitor PF-04191834

A convergent six-step process for the synthesis of PF-04191834 (1), a potent and selective 5-lipoxygenase inhibitor, has been developed and used to deliver over 20 kg of API. The process uses the same bond-forming steps as the initial medicinal chemistry route, including the use of two consecutive Pd-catalyzed Ar–S couplings to form the key diaryl thioether linkage. The reaction conditions and downstream processing have been optimized to eliminate column chromatography and aqueous work-ups and to minimize disproportionation of 1, to ensure successful scale-up.