Scalable Synthesisof a Masked Thiophenol as an Air-Stable,Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680)

Abstract The use of thiophenols on process scales is fraught with challenges relating to their toxicity, malodor, and air sensitivity. We previously demonstrated that the Ni-catalyzed C–S coupling of aryl iodides and thiourea provides a discovery-scale route to S-aryl isothiouronium salts, which serve as bench stable, odorless, and highly crystalline surrogates of thiophenols. Here, we report the process optimization of this methodology for the synthesis of a key intermediate to kinase inhibitor tozasertib (VX-680). The corollary is a reduction in catalyst loading to 0.5 mol %, elimination of NMP solvent, and introduction of a direct crystallization, giving 95% yield on a 100 g scale.