Radotinib Dihydrochloride

Clinical Use

In January 2012, radotinib hydrochloride (marketed as Supect ®) obtained its approval from the KFDA (Korea Food and Drug Administration) for the treatment of patients with Philadelphia chromosomepositive chronic myeloid leukemia (CML) who have become resistant to existing drugs such as Gleevec, Tasigna and Sprycel. Originally developed by IL-YANG pharmaceuticals of South Korea as an orally second-generation tyrosine kinase inhibitor, the drug inhibits both Bcr-Abl fusion protein and the platelet-derived growth factor receptor (PDGFR).

Synthesis

Because of the structural similarity of radotinib to that of nilotinib (Tasigna ®), the process-scale synthetic route (which is depicted in the scheme) is capable of furnishing both drugs.Claisen condensation of commerical 2-acetylpyrazine (142) with N,N-dimethylformamide dimethylacetal gave rise to the enamino ketone 143 in 81% yield. Under basic conditions, vinylogous amide 143 was coupled with commercial guanidine nitrate 144187 to produce aminopyridine 145. Subsequent condensation with commercial aniline (146) by means of potassium t-butoxide in THF constructed radotinib 147 in 85% yield as the free base, and this material could be converted to the radotinib dihydrochloride (XXII) upon exposure to concentrated hydrochloric acid in chilled acetone.