Development of a Fully Telescoped Synthesis of the S1P1 Agonist GSK1842799

The development of a fully telescoped synthesis of the potent and selective S1P1 agonist GSK1842799 is described. Key features in the synthesis, which has been implemented on a multikilogram scale, include a nucleophilic aromatic substitution to install a lipophilic 1-octyloxy chain, introduction of a chiral quaternary centre, and the use of Lawesson's reagent to form a thiadiazole ring. Due to the lack of crystalline intermediates, workup protocols that took advantage of the lipophilic nature of the compounds were developed. This allowed full combination of the five chemistry stages and a salt formation, with the only isolation being that of the final hemifumarate salt of the drug substance. The synthesis of the O-phosphorylated active metabolite is also described.