Development of\na Robust Pd-Catalyzed C–S Coupling\nfor the Synthesis of Janus Kinase Inhibitor GDC-9918

The development of an in situ formed (Xantphos)Pd oxidative\naddition\ncomplex made possible a robust, scalable C–S coupling of a\nfunctionalized aryl bromide with 2-mercaptoethanol that ultimately\nenabled the synthesis of Janus Kinase inhibitor <b>GDC-9918</b> on a kilogram scale. An insoluble, catalytically inactive, [12]metallacrown-6\npalladium(II) complex, [Pd<sub>6</sub>(μ<sub>2</sub>-SCH<sub>2</sub>CH<sub>2</sub>OH)<sub>12</sub>], was found to form quickly\nunder most reaction conditions in the presence of 2-mercaptoethanol\nand a Pd catalyst and required up to 12 mol % Pd for full conversion\nin our generation route. A second-generation process was developed\nto minimize the formation of the [12]metallacrown-6 palladium(II)\ncomplex and enabled the decrease in catalyst loading to 2 mol % Pd.\nA soluble Pd scavenger, PIX, effectively removed Pd to <5 ppm.\nCatalytic sodium tungstate oxidation of the resulting thioether smoothly\nprovided crude <b>GDC-9918</b> that was recrystallized to the\ndesired polymorph and micronized to a particle size distribution suitable\nfor development as an inhalable treatment for asthma.