Effect of Temperature and Solvent of Solvent-Mediated Polymorph Transformation on ASP3026 Polymorphs and Scale-up

ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date. Process development was conducted for large-scale pilot plant manufacturing, and obtaining the desired polymorph A04 was key after a synthetic route of ASP3026 was selected for scale-up. The effects of temperature and solvent species on induction time of polymorph transformation were investigated using in situ Raman spectroscopy, and selective transformation conditions of A02 to A03 and A04 were examined in detail. A04 was obtained at high temperatures using highly polar non-hydrogen-bond-donating solvents, while A03 was obtained at low temperatures using low-polarity or hydrogen-bond-donating solvents. Further, the desired polymorph A04 was successfully obtained in high purity in first...