Practical Synthesis of a S1P Receptor 1 Agonist via a Guareschi–Thorpe Reaction

A practical synthesis of S1P receptor 1 agonist ACT-334441 (1) through late-stage convergent coupling of two key intermediates is described. The first intermediate is 2-cyclopentyl-6-methoxyisonicotinic acid whose skeleton was built from 1-cyclopentylethanone, ethyl oxalate, and cyanoacetate in a Guareschi–Thorpe reaction in 42% yield over five steps. The second, chiral intermediate, is a phenol ether derived from enantiomerically pure (R)-isopropylidene glycerol ((R)-solketal) and 3-ethyl-4-hydroxy-5-methylbenzonitrile in 71% yield in a one-pot reaction. The overall sequence entails 18 chemical steps with 10 isolated intermediates. All raw materials are cheap and readily available in bulk quantities, the reaction conditions match with standard pilot plant equipment, and the route reproducibly afforded 3–20 kg of 1 in excellent purity and yield for clinical studies.