A scaleable synthetic route to the potent PPAR
/
dualagonistic agent, lobeglitazone (
1), used for the treatment oftype-2 diabetes was developed. The synthetic pathway comprisesan effective five-step synthesis. This process involves a consecutive synthesis of the intermediate, pyrimidinyl aminoalcohol (
6),from the commercially available 4,6-dichloropyrimidine (
3)without the isolation of pyrimidinyl phenoxy ether (
4). Significant improvements were also made in the regioselective 1,4-reduction of the intermediate, benzylidene-2,4-thiazolidinedione(
10), using
Hantzsch dihydropyridine ester (HEH) with silicagel as an acid catalyst. The sulfate salt form of lobeglitazonewas selected as a candidate compound for further preclinicaland clinical study. More t
han 2 kg of lobeglitazone sulfate(
CKD-501,
2) was prepared in 98.5% purity after the GMPbatch. Overall yield of
2 was improved to 52% from 17% ofthe original medicinal chemistry route.