TNO155, a clinical-stage SHP2 inhibitor, was synthesized using a divergent approach employing building blocks 11 and 12 with the longest linear sequence of 9 steps. The chiral methyl group in the spiro-ring of 11 was obtained from a chiral pool starting material, L-Lactide 3, while the chiral amine was generated through diastereoselective hydrogenation of oxime 5, facilitated by the chiral methyl group acting as a directing group.
Three different conditions were assessed for the formation of the thioether in constructing block 12. These conditions included a Cu-catalyzed Ullmann coupling, a Pd-catalyzed coupling and a citric acid-mediated SNAr reaction. Among these, the metal-free reaction demonstrated optimal performance and was chosen for production purposes.
It is noteworthy that several SHP2 inhibitors with known structures at various clinical stages incorporate building block 11. Furthermore, more than eight clinical-stage SHP2 inhibitors may possess the same scaffold. Consequently, building block 11 or its salt form 11-01, is anticipated to be in high demand, given its significant market value amounting to millions of dollars (the cost for 10 g of material is estimated to range from $1200 to 2000).
