Synthesis of the Original Hit

It was deemed useful to resynthesise the molecule and have tested again to remove any possible false positive from the original GSK screen. Compound OSM-S-106 was made in a convergent 6 step synthesis. The resynthesised compound also had good antimalarial activity. Technical details are in a composite document of synthetic chemistry data for original hit assembled by Tha Bhebhe.

The amino thienopyrimidine half of OSM-S-106 was synthesised. Firstly, the commercially available methyl-3-aminothiophene-2-carboxylate underwent a cyclisation reaction to give OSM-S-171 with 85% yield. This was followed by the chlorination of the carbonyl with phosphoryl chloride to yield OSM-S-70 with a yield of 61%. OSM-S-121 was synthesised by the bromination of OSM-S-70 with the aid of bromine and n-BuLi with a yield of 30%. The chlorine on the new compound was substituted for an amine to afford OSM-S-139 (65% yield). This compound (A) was then ready to be coupled with the sulfonamide. The sulfonamide was prepared by substituting the bromine on the commercially available 3-bromobenzenesulfonamide for a boronic ester to give B (OSM-S-154) with a yield of 46%. Molecules A and B were Suzuki coupled together to give the target molecule OSM-S-106 (27% yield).