Development of a 2nd Generation Process for 3-Ethyl-4-Hydroxy-5-Methylbenzonitrile – A Key Building Block of S1P1 Receptor Modulator Cenerimod – through a Non-Classical Nitrile Formation Using Hydroxylamine-O-sulfonic Acid (HOSA)

A new, improved 2nd generation route for the synthesis of 3-ethyl-4-hydroxy-5-methylbenzonitrile has been developed. The original route started from 2-ethyl-6-methylaniline, which was converted by a classical sequence of para-bromination, cyanation and Sandmeyer hydroxylation into the desired phenol. This route was used on multi-kg scale and delivered the product with the desired purity. However, the route was not ideal, as it featured safety critical steps (cyanation), employed undesirable solvents (DMF), included laborious workup and isolation procedures, and suffered from a low overall yield (40–45 %) and suboptimal green metrics (PMI: 210). We envisioned a new, non-classical approach to the product by introducing the nitrile through a para-selective formylation, followed by transformation of the intermediate aldehyde into the nitrile with hydroxylamine-O-sulfonic acid (HOSA). The new sequence of Sandmeyer hydroxylation, Duff formylation and HOSA-promoted nitrile formation was thoroughly optimized and finally scaled up to 400 g. This novel 3-step sequence delivered 3-ethyl-4-hydroxy-5-methylbenzonitrile in 69 % overall yield with excellent purity (99.3 % a/a) and a vastly improved PMI of 81.