Full Oxidation of an α-Arylated Isochromane: Development of a Two-Step Sequence as an Alternative to the Carcinogenic Jones Reagent and Application to the Manufacturing Process of Servier Phase II Clinical Candidate S44819

An original two-step sequence allowing the full oxidation of an α-arylated isochromane is described. This method has been safely implemented to manufacture diketone 2 at the kg scale, a key intermediate in the manufacturing route of a phase II post stroke Servier clinical candidate S44819. This second-generation synthesis showcased better safety, replicability, and sustainability compared to the first-generation synthesis using an excess amount of Jones reagent. Further functionalization of 2 by cyclodehydration and condensation with hydrazine is also demonstrated, allowing the manufacture of clinical candidate S44819 at the kg scale.